WO2025249897A1 - Novel sulfamide camptothecin derivatives with antitumor activity - Google Patents

Abstract

Provided are: a compound defined by chemical formula 1; a stereoisomer thereof; a tautomer thereof; and pharmaceutically acceptable salts of the compound, the stereoisomer, and the tautomer. The compound of the invention can inhibit the activity of topoisomerase I. [Chemical formula 1]

Description

Novel sulfamide camptothecin derivatives with antitumor activity

The present invention relates to novel camptothecin derivative compounds as topoisomerase I inhibitors and their uses. More specifically, the present invention relates to novel camptothecin derivatives having antitumor activity and useful as anticancer agents, and pharmaceutical compositions thereof.

Camptothecin induces apoptosis by inhibiting topoisomerase I. Due to its cytotoxic mechanism and broad antitumor activity, significant efforts have been made to develop clinical analogues of camptothecin. However, clinical development of camptothecin analogues as anticancer therapeutics has been limited due to factors such as low solubility under physiological conditions, high or irregular toxicity, and poor storage stability.

Therefore, the demand for novel camptothecin derivatives with improved activity and properties and for anticancer treatments using such derivatives is not yet sufficiently met.

The technical task of the present invention is to provide a novel compound capable of inhibiting the activity of topoisomerase I. Furthermore, the technical task of the present invention is to provide a novel drug that inhibits topoisomerase I. More specifically, the technical task of the present invention is to provide a novel antitumor drug that inhibits topoisomerase I.

In one aspect of the present invention, a compound defined by chemical formula 1 or a tautomer thereof, a stereoisomer thereof, and a pharmaceutically acceptable salt thereof are provided.

[Chemical Formula 1]

In the chemical formula 1 above

(1) A ¹ is CH ₂ , CHX ¹ , CX ¹ X ² , O, S or NH, A ² is CH ₂ , O, S, S=O, S(=O) ₂ or NH, A ³ is a chemical bond or CH ₂ , and in A ¹ , A ² and A ³ The symbols indicate that A ¹ and A ³ , A ² and A ³ are directly connected by a single bond, Z ¹ is NHS(=O) ₂ , Z ² is H or halogen, Z ³ is NH ₂ or NHQ ¹ NH ₂ , and the bond between Z ¹ and Z ³ The symbol indicates that the sulfur of Z ¹ and Z ³ are directly connected by a single bond, and that between Z ² and Z ³ The symbol indicates that Z ² and Z ³ are not directly connected by a bond, X ¹ and X ² are each independently selected halogen, and Q ¹ is C _1~4 alkylene; or

(2) A ¹ is Q ¹ , A ² is H, A ³ is H, CF ₃ or OH, and in A ¹ , A ² and A ³ The symbol indicates that A ¹ and A ³ are directly connected by a single bond and that A ² and A ³ are not directly connected by a bond, Z ¹ is NHS(=O) ₂ , Z ² is H or halogen, Z ³ is NH ₂ or NHQ ² NH ₂ , and the bond between Z ¹ and Z ³ The symbol indicates that the sulfur of Z ¹ and Z ³ are directly connected by a single bond, and that between Z ² and Z ³ The symbol indicates that Z ² and Z ³ are not directly connected by a bond, and Q ¹ and Q ² are independently selected C _1~4 alkylene; or

(3) A ¹ and A ² are H, A ³ is absent, and in A ¹ , A ² and A ³ The notation indicates that there is no direct bond between A ¹ and A ³ , and also between A ² and A ³ , Z ¹ is NHS(=O) ₂ , Z ² is H or halogen, and Z ³ is NH ₂ , NHQ ¹ NH ₂ , NHQ ¹ NHR ² , NR ¹ Q ¹ NH ₂ or NR ¹ Q ¹ NHR ² , and between Z ¹ and Z ³ The symbol indicates that the sulfur of Z ¹ and Z ³ are directly connected by a single bond, and that between Z ² and Z ³ The symbol indicates that Z ² and Z ³ are not directly connected by a bond, Q ¹ is C _1~4 alkylene, R ¹ and R ² are each independently C _1~4 alkyl; or

(4) A ¹ is Q ¹ , A ² is H, A ³ is NHS(=O) ₂ NH ₂ , NQ ³ S(=O) ₂ NH ₂ or NHS(=O) ₂ NHQ ² NH ₂ , and in A ¹ , A ² and A ³ The symbol indicates that A ¹ and A ³ are directly connected by a single bond and that A ² and A ³ are not directly connected by a bond, Z ¹ is H, Z ² is H or halogen, Z ³ is absent, and between Z ¹ and Z ³ The symbol indicates that Z ¹ and Z ³ are not directly connected by a bond, and that there is a bond between Z ² and Z ^3. The symbol indicates that Z ² and Z ³ are not directly connected by a bond, Q ¹ and Q ² are each independently selected C _1~4 alkylene, and Q ³ is C _1~4 alkyl; or

(5) A ¹ is Q ¹ , A ² is H, A ³ is NHS(=O) ₂ NH ₂ , NQ ³ S(=O) ₂ NH ₂ or NHS(=O) ₂ NHQ ² NH ₂ , and in A ¹ , A ² and A ³ The symbol indicates that A ¹ and A ³ are directly connected by a single bond and that A ² and A ³ are not directly connected by a single bond, Z ¹ is O, S or NH, Z ² is O, S or NH, Z ³ is CH ₂ , and between Z ¹ and Z ³ The symbol indicates that Z ¹ and Z ³ are directly connected by a single bond, and that between Z ² and Z ³ The symbol indicates that Z ² and Z ³ are directly connected by a single bond, Q ¹ and Q ² are independently selected C _1~4 alkylene, and Q ³ is C _1~4 alkyl; or

(6) A ¹ is Q ¹ , A ² is H, A ³ is NHS(=O) ₂ NH ₂ , NQ ³ S(=O) ₂ NH ₂ or NHS(=O) ₂ NHQ ² NH ₂ , and in A ¹ , A ² and A ³ The symbol indicates that A ¹ and A ³ are directly connected by a single bond and that A ² and A ³ are not directly connected by a bond, Z ³ is CH, Q ¹ and Q ² are each independently selected C _1~4 alkylene, and Q ³ is C _1~4 alkyl,

a. When Z ¹ is N and Z ² is O, S or NH, between Z ¹ and Z ³ The symbol indicates that Z ¹ and Z ³ are directly connected by a double bond, and that between Z ² and Z ³ The symbol indicates that Z ² and Z ³ are directly connected by a single bond,

B. When Z ² is N and Z ¹ is O, S or NH, between Z ¹ and Z ³ The symbol indicates that Z ¹ and Z ³ are directly connected by a single bond, and that between Z ² and Z ³ The symbol indicates that Z ² and Z ³ are directly connected by a double bond.

In another aspect of the present invention, a pharmaceutical composition for the treatment of cancer is provided, comprising a therapeutically effective amount of the compound described above, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

In another aspect of the present invention, a method for treating cancer is provided. The method comprises administering to a subject a therapeutically effective amount of a compound of the present invention, such as a compound defined by Formula 1, or a pharmaceutical composition comprising such a compound of the present invention.

The compound of the present invention can inhibit topoisomerase I activity. The compound of the present invention exhibits antitumor activity. The compound of the present invention has superior solubility in water and buffered aqueous solutions compared to camptothecin and deruxtecan, a camptothecin derivative. The compound of the present invention exhibits improved partitioning properties toward hydrophilic media compared to deruxtecan between lipophilic and hydrophilic media, making it advantageous for formulation.

Hereinafter, embodiments of the present invention will be described in detail. Prior to this, it should be noted that the terms and words used in this specification and claims should not be construed as limited to their conventional or dictionary meanings. Based on the principle that the inventor can appropriately define the concept of a term to best explain his or her invention, they should be interpreted in a way that aligns with the technical spirit of the present invention.

Therefore, the embodiments described in this specification are merely examples presented for the purpose of helping to understand the present invention and do not represent all of the technical ideas of the present invention. Therefore, it should be understood that there may be various equivalents and modified examples that can replace them at the time of filing this application.

Unless otherwise defined, all technical terms used herein have the same meaning as commonly understood by those skilled in the art. While preferred methods and samples are described herein, similar or equivalent methods are also included within the scope of the present invention. Numerical values described herein are considered to include the meaning of "about" even if not explicitly stated. The numerical range indicated using the term "to" herein includes the ranges that include the values described before and after the term "to" as the lower and upper limits, respectively.

Definition of Terms

In this specification, the prefix "C _x~y " or "C _x ~C _y " (wherein x and y are natural numbers) is used in front of a functional group to indicate the number of carbon atoms that the functional group has in its backbone. For example, a C _1~4 alkyl group indicates an alkyl group having 1 to 4 carbon atoms, and a C _1~3 alkyl group indicates an alkyl group having 1 to 3 carbon atoms, respectively. For example, C ₁ ~C ₄ alkoxy groups include methoxy, ethoxy, n -propoxy, i -propoxy, n -butoxy, sec -butoxy, and tert -butoxy. For example, a C ₃ ~C ₆ cycloalkyl group includes cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl groups. For example _{, C 1-4 alkylenes} include methylene, ethylene, n- propylene, i -propylene, n -butylene, i -butylene, and tert -butylene.

In addition, in the present specification, when the number of elements forming the ring is indicated in front of a ring functional group or compound (including both carbon rings and heterocycles), the ring is a ring formed of the corresponding number of elements, i.e., carbon and/or heteroatoms. For example, a six-membered ring heteroaryl refers to a heteroaryl group that contains one or more heteroatoms and is formed together with carbon, and the number of elements forming the ring is 6.

Unless otherwise specified herein, when a functional group is linked to another part of a compound by a bond, the linkage may be via any atom of that functional group, provided that it is a suitable atom. For example, when referring to a propyl group, both prop-1-yl and prop-2-yl are included.

As used herein, the term "halogen", when referred to in connection with a substituent in a chemical structure, refers to an atom selected from fluorine, chlorine, bromine and iodine.

The term "C _1~6 alkyl" as used herein refers to a monovalent saturated hydrocarbon atom group having the chemical formula C _n H _2n+1 , where n is a natural number from 1 to 6. The C _1~6 alkyl group encompasses all linear or branched saturated hydrocarbons having from 1 to 6 carbon atoms, for example , n -propyl, i -propyl, 2-methyl-ethyl, sec -butyl, tert -butyl, etc.

The term "C _m~n alkylene" in this specification refers to a divalent saturated hydrocarbon group having a chemical formula ranging from C _m H _2m to C _n H _2n , where the number of carbon atoms is a natural number from m to n.

The term "cycloalkyl" as used herein refers to a monovalent group of atoms that is a saturated hydrocarbon ring having the chemical formula C _n H _2n- 1. Examples of C _3-6 cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

As used herein, the term "bicyclic" refers to a carbon ring compound or heterocyclic compound composed of two rings, which is formed by sharing one or more ring atoms between the two constituent rings. In a bicyclic compound, the atom shared between the two rings is called a bridgehead atom. Bicyclic compounds are divided into three types depending on the number of bridgehead atoms and whether or not there is a direct connection between the bridgehead atoms. A fused bicyclic compound has two bridgehead atoms, which are directly connected to each other by a bond. Examples of fused bicyclic compounds include decalin, naphthalene, anthracene, phenanthrene, indole, benzofuran, purine, and quinoline. A ring compound with only one bridgehead atom is a spirocyclic compound. A bridged ring compound has two bridgehead carbon atoms, which are not directly adjacent, but have one or more ring atoms between them. Examples of bridged ring compounds include norbornane, 7-oxabicyclo[2.2.1]heptane, and adamantane.

In this specification, fused bicyclic compounds can be expressed by specifying the number of ring atoms in each of the two rings that make up the compound. For example, thienopyridine, benzofuran, indole, etc. can be referred to as five- or six-membered fused bicyclic compounds. Similarly, naphthalene, chromane, tetrahydroquinoline, quinoline, quinoxaline, pteridine, etc. can be referred to as six- or six-membered fused bicyclic compounds.

The term "aryl" as used herein refers to a monovalent hydrocarbon group having aromatic _C6 - _C14 atoms and optionally containing one to three aromatic rings. For example, aryl includes _C6 , _C10 , _C13 , and _C14 aromatic hydrocarbon ring groups, such as phenyl, naphthyl, anthracenyl, and fluorenyl.

The term "heteroaryl" as used herein refers to a monovalent aromatic ring composed of an unsaturated ring and one or more heteroatoms selected from nitrogen, oxygen, and sulfur. The ring system of a heteroaryl can be a single ring, a double ring, or a triple ring in the form of a fused ring. The term heteroaryl excludes rings that contain a direct linkage between oxygen and sulfur atoms, such as -O-O-, -O-S-, or -S-S-. Some examples of heteroaryl include pyrrolyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidyl, triazolyl, quinazolinyl, 2-furyl, 3-furyl, benzofuryl, 2-thienyl, oxazolyl, isothiazolyl, and thiadiazolyl. Heteroaryl can also be defined by specifying the heteroatom. For example, heteroaryl in which the heteroatom is nitrogen includes pyrrolyl, imidazolyl, pyrazolyl, 2-pyridyl, etc., but excludes furyl, thienyl, etc.

Fused bicyclic heteroaryl groups include six- and five-membered fused bicyclic heteroaryl groups such as benzimidazolyl, benzofuranyl, benzothiophenyl, isoindolyl, indazolyl, imidazopyridinyl, imidazopyrimidinyl, imidazopyridazinyl, indazolyl, pyrazolopyridinyl, pyrrolopyrimidinyl, pyrrolopyridinyl, pyrrolopyrazinyl, triazolopyridinyl, triazolopyrimidinyl, purinyl, benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl, benzoxazolyl, benzothiadiazolyl, etc., and six- and six-membered fused bicyclic heteroaryl compounds such as benzopyridinyl, benzopyrimidinyl, quinolinyl, isoquinolinyl, phthalazinyl, Examples include quinazolinyl, quinoxalinyl, naphthyridinyl, quinolinzinyl, and cinnolinyl.

The term "heterocycloalkyl" as used herein refers to a monovalent atomic group in which at least one carbon atom forming a ring in a cycloalkyl group is independently replaced in each instance by a heteroatom selected from nitrogen, oxygen, and sulfur. Examples of heterocycloalkyl groups include pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolyl, piperazinyl, morpholinyl, and thiazolidinyl.

The term "substituted" or "substituted" in front of a functional group in this specification, unless otherwise stated in the specification, refers to a structure in which at least one of the hydrogens of the functional group is replaced with a functional group other than the designated hydrogen, assuming that the substituted functional group maintains its normal valence and yields a chemically stable functional group. In typical cases, the substituent is selected from halogen, CN, OH, C _1-6 alkyl, C _3-6 cycloalkyl, C _3-14 heteroaryl, C _1-6 alkoxy and CF ₃ .

In this specification, a specific atom of a substituent forming part of a compound is " " indicates that the substituent is directly chemically bonded to the rest of the compound through that atom.

In this specification, "--" or " between adjacent ring atoms of a carbon ring or heterocycle represented by a chemical structural formula "When there is a dotted line like this, it indicates that it is an optional element that may or may not have a covalent bond between the two adjacent ring atoms. For example, A notation like "--" implies that this structural formula encompasses benzene and 1,3-cyclohexadiene. However, "--" or " "The maximum possible number of covalent bonds between two adjacent ring atoms implied or implied by a single dotted line mark such as "is not necessarily one, but is determined by the number specified therein, e.g., the number designated as no bond, single bond or double bond, if otherwise specified for the chemical structure in this specification.

As used herein, the term "pharmaceutically acceptable salt" for a compound refers to a salt that does not impair the desired biological activity of the compound and does not cause inappropriate toxicity, irritation, or allergic reactions when used in contact with human or animal tissues. Pharmaceutically acceptable salts are well known in the art. For example, reference may be made to prior literature such as the paper by Berge et al., J. Pharmaceutical Sciences (1977), Vol. 66, pp. 1-19. Some examples of pharmaceutically acceptable salts include acid addition salts such as hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, acetate, oxalate, maleate, tartrate, citrate, succinate, malonate, adipate, alginate, ascorbate, aspartate, benzoate, benzenesulfonate, and hydrosulfide, and base addition salts such as alkali metal salts, alkaline earth metal salts, ammonium salts, and quaternary ammonium (N ⁺ (C _1-4 alkyl) ₄ ), examples of alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium.

Those skilled in the art will appreciate that some of the compounds of the present invention may exist in more than one tautomeric form. Since a single chemical structural formula can only represent one tautomeric form, it is well understood that when a compound is referred to by a single structural formula for convenience, the structural formula also encompasses the tautomeric variations of that compound. Depending on the compound, one tautomer may exist primarily in one form, a mixture of multiple tautomers may exist at room temperature, or only one tautomer may be isolated. Examples of tautomers include those between the pyridone and hydroxypyridine forms, and those between the keto and enol forms.

compound

In one aspect of the present invention, a compound defined by chemical formula 1, a tautomer thereof, a stereoisomer thereof, and a pharmaceutically acceptable salt thereof are provided.

In the chemical formula 1 above

(1) A ¹ is CH ₂ , CHX ¹ , CX ¹ X ² , O, S or NH, A ² is CH ₂ , O, S, S=O, S(=O) ₂ or NH, A ³ is a chemical bond or CH ₂ , and in A ¹ , A ² and A ³ The symbols indicate that A ¹ and A ³ , A ² and A ³ are directly connected by a single bond, Z ¹ is NHS(=O) ₂ , Z ² is H or halogen, Z ³ is NH ₂ or NHQ ¹ NH ₂ , and the bond between Z ¹ and Z ³ The symbol indicates that the sulfur of Z ¹ and Z ³ are directly connected by a single bond, and that between Z ² and Z ³ The symbol indicates that Z ² and Z ³ are not directly connected by a bond, X ¹ and X ² are each independently selected halogen, and Q ¹ is C _1~4 alkylene; or

(2) A ¹ is Q ¹ , A ² is H, A ³ is H, CF ₃ or OH, and in A ¹ , A ² and A ³ The symbol indicates that A ¹ and A ³ are directly connected by a single bond and that A ² and A ³ are not directly connected by a bond, Z ¹ is NHS(=O) ₂ , Z ² is H or halogen, Z ³ is NH ₂ or NHQ ² NH ₂ , and the bond between Z ¹ and Z ³ The symbol indicates that the sulfur of Z ¹ and Z ³ are directly connected by a single bond, and that between Z ² and Z ³ The symbol indicates that Z ² and Z ³ are not directly connected by a bond, and Q ¹ and Q ² are independently selected C _1~4 alkylene; or

(3) A ¹ and A ² are H, A ³ is absent, and in A ¹ , A ² and A ³ The notation indicates that there is no direct bond between A ¹ and A ³ , and also between A ² and A ³ , Z ¹ is NHS(=O) ₂ , Z ² is H or halogen, and Z ³ is NH ₂ , NHQ ¹ NH ₂ , NHQ ¹ NHR ² , NR ¹ Q ¹ NH ₂ or NR ¹ Q ¹ NHR ² , and between Z ¹ and Z ³ The symbol indicates that the sulfur of Z ¹ and Z ³ are directly connected by a single bond, and that between Z ² and Z ³ The symbol indicates that Z ² and Z ³ are not directly connected by a bond, Q ¹ is C _1~4 alkylene, R ¹ and R ² are each independently C _1~4 alkyl; or

(4) A ¹ is Q ¹ , A ² is H, A ³ is NHS(=O) ₂ NH ₂ , NQ ³ S(=O) ₂ NH ₂ or NHS(=O) ₂ NHQ ² NH ₂ , and in A ¹ , A ² and A ³ The symbol indicates that A ¹ and A ³ are directly connected by a single bond and that A ² and A ³ are not directly connected by a bond, Z ¹ is H, Z ² is H or halogen, Z ³ is absent, and between Z ¹ and Z ³ The symbol indicates that Z ¹ and Z ³ are not directly connected by a bond, and that there is a bond between Z ² and Z ^3. The symbol indicates that Z ² and Z ³ are not directly connected by a bond, Q ¹ and Q ² are each independently selected C _1~4 alkylene, and Q ³ is C _1~4 alkyl; or

(5) A ¹ is Q ¹ , A ² is H, A ³ is NHS(=O) ₂ NH ₂ , NQ ³ S(=O) ₂ NH ₂ or NHS(=O) ₂ NHQ ² NH ₂ , and in A ¹ , A ² and A ³ The symbol indicates that A ¹ and A ³ are directly connected by a single bond and that A ² and A ³ are not directly connected by a single bond, Z ¹ is O, S or NH, Z ² is O, S or NH, Z ³ is CH ₂ , and between Z ¹ and Z ³ The symbol indicates that Z ¹ and Z ³ are directly connected by a single bond, and that between Z ² and Z ³ The symbol indicates that Z ² and Z ³ are directly connected by a single bond, Q ¹ and Q ² are independently selected C _1~4 alkylene, and Q ³ is C _1~4 alkyl; or

(6) A ¹ is Q ¹ , A ² is H, A ³ is NHS(=O) ₂ NH ₂ , NQ ³ S(=O) ₂ NH ₂ or NHS(=O) ₂ NHQ ² NH ₂ , and in A ¹ , A ² and A ³ The symbol indicates that A ¹ and A ³ are directly connected by a single bond and that A ² and A ³ are not directly connected by a bond, Z ³ is CH, Q ¹ and Q ² are each independently selected C _1~4 alkylene, and Q ³ is C _1~4 alkyl,

a. When Z ¹ is N and Z ² is O, S or NH, between Z ¹ and Z ³ The symbol indicates that Z ¹ and Z ³ are directly connected by a double bond, and that between Z ² and Z ³ The symbol indicates that Z ² and Z ³ are directly connected by a single bond,

B. When Z ² is N and Z ¹ is O, S or NH, between Z ¹ and Z ³ The symbol indicates that Z ¹ and Z ³ are directly connected by a single bond, and that between Z ² and Z ³ The symbol indicates that Z ² and Z ³ are directly connected by a double bond.

The compound according to the present invention can inhibit the activity of topoisomerase I.

In one embodiment, the compound of the present invention is a compound of formula 1 wherein A ¹ and A ³ are CH ₂ and Z ³ is NH ₂ or NHCH ₂ CH ₂ NH ₂ .

In another embodiment, the compound of the present invention has formula 1, wherein A ¹ is NHS(=O) ₂ NH ₂ .

In one specific embodiment, the compound of formula 1 of the present invention has a structure of formula 2.

In the above chemical formula 2, X ³ is CH ₂ , O, S, S=O, S(=O) ₂ or NH, Z ⁴ is H or Q ¹ NH ₂ , where Q ¹ is C _1~4 alkylene.

In a more specific embodiment, the compound of formula 2 is wherein X ³ is CH ₂ , O, NH or S.

In another specific embodiment, the compound of formula 2 is wherein Z ⁴ is H or CH ₂ CH ₂ NH ₂ .

In another specific embodiment of the compound of the present invention, the compound of the present invention having the chemical formula 1 has a structure of the chemical formula 3.

In the above chemical formula 3, Q ⁴ is C _1~3 alkyl, C _1~3 alkylene-CF ₃ or C _1~3 alkylene-OH, Z ⁴ is H or Q ¹ NH ₂ , and in this case, Q ¹ is C _1~4 alkylene.

In another specific embodiment of the compound of the present invention, the compound of formula 1 has a structure of formula 4.

In the above chemical formula 4, Q ⁵ is a chemical bond or C _1~2 alkylene, R ⁴ is H, and R ¹ and R ³ are each independently O, S, NH or N.

a. When R ¹ is O, S, or NH, and R ³ is also O, S, or NH independently of R ¹ , then R ² is CH, and between R ¹ and R ² The symbol indicates that R ¹ and R ² are directly connected by a single bond, and that between R ² and R ³ The symbol indicates that R ² and R ³ are directly connected by a single bond,

B. When R ¹ is N, R ² is C, R ³ is O, S or NH and between R ¹ and R ² The symbol indicates that R ¹ and R ² are directly connected by a double bond, and that between R ² and R ³ The symbol indicates that R ² and R ³ are directly connected by a single bond,

When R ¹ is O, S or NH and R ³ is N, R ² is C and between R ¹ and R ² The symbol indicates that R ¹ and R ² are directly connected by a single bond, and that between R ² and R ³ The symbol indicates that R ² and R ³ are directly connected by a double bond.

In another specific embodiment of the compound of the present invention, the compound of formula 1 has a structure of formula 5.

In the above chemical formula 5, Q ¹ is C _1~4 alkylene, R ⁶ is H or C _1~4 alkyl, R ⁷ is H or C _1~4 alkylene NH ₂ , and Z ⁵ is hydrogen or halogen.

In another specific embodiment of the compound of the present invention, the compound of formula 1 has a structure of formula 6.

In the above chemical formula 6, Z ⁶ is halogen, R ⁵ is H, Q ¹ NH ₂ or Q ¹ NHR ¹ , where Q ¹ is C _1~4 alkylene and R ¹ is C _1~4 alkyl.

In one specific embodiment of chemical formula 6, R ⁵ is H.

In another specific embodiment of formula 6, R ⁵ is CH ₂ CH ₂ NH ₂ .

In another specific embodiment of formula 6, R ⁵ is CH ₂ CH ₂ NHCH ₃ .

In a most specific embodiment, the compound of the present invention is the following compound, a stereoisomer, a tautomer, a solvate or a pharmaceutically acceptable salt thereof:

( S )-4-((sulfamide)amino)-9-ethyl-9-hydroxy-1,2,3,9,12,15-hexahydro-10 H ,13 H -benzo[ de ]pyrano[3',4':6,7]indolizino[1,2- b ]quinoline-10,13-dione,

( S )-4-((sulfamide)amino)-9-ethyl-9-hydroxy-1,9,12,15-tetrahydro-13 H -pyrano[4,3,2- de ]pyrano[3',4':6,7]indolizino[1,2- b ]quinoline-10,13-dione,

( S )-4-((sulfamide)amino)-9-ethyl-9-hydroxy-1,9,12,15-tetrahydro-13 H -pyrano[3',4':6,7]indolizino[1,2- b ]thiopyrano[4,3,2- de ]quinoline-10,13(2 H )-dione,

( S )-4-((((2-aminoethyl)amino)sulfamide)amino)-9-ethyl-9-hydroxy-1,2,3,9,12,15-hexahydro-10 H ,13 H -benzo[ de ]pyrano[3',4':6,7]indolizino[1,2- b ]quinoline-10,13-dione,

( S )-14-(((sulfamide)amino)methyl)-7-ethyl-7-hydroxy-10,13-dihydro-11 H -[1,3]dioxolo[4,5- g ]pyrano[3',4':6,7]indolizino[1,2 -b ]quinoline-8,11(7 H )-dione,

( S )-9-((sulfamide)amino)-4,11-diethyl-4-hydroxy-1,12-dihydro-14 H -pyrano[3',4':6,7]indolizino[1,2- b ]quinoline-3,14(4 H )-dione,

( S )-9-(((sulfamide)amino)-4-ethyl-8-fluoro-4-hydroxy-1,12-dihydro-14 H -pyrano[3',4':6,7]indolizino[1,2- b ]quinoline-3,14(4 H )-dione,

( S )-14-(( N -((2-aminoethyl)sulfamide)amino)methyl)-7-ethyl-7-hydroxy-10,13-dihydro-11 H -[1,3]dioxolo[4,5- g ]pyrano[3',4':6,7]indolizino[1,2- b ]quinoline-8,11(7 H )-dione,

( S )-4-( N -((2-aminoethyl)sulfamide)amino)-9-ethyl-5-fluoro-9-hydroxy-1,9,12,15-tetrahydro-13 H -pyrano[3',4':6,7]indolizino[1,2- b ]thiopyrano[4,3,2- de ]quinoline-10,13(2 H )-dione,

( S )-9- N -((2-aminoethyl)sulfamide)amino)-4-ethyl-8-fluoro-4-hydroxy-1,12-dihydro-14 H -pyrano[3',4':6,7]indolizino[1,2- b ]quinoline-3,14(4 H )-dione,

( S )-9- N -((2-(methylamino)ethyl)sulfamide)amino)-4-ethyl-8-fluoro-4-hydroxy-1,12-dihydro-14 H -pyrano[3',4':6,7]indolizino[1,2- b ]quinoline-3,14(4 H )-dione or

( S )-4-Ethyl-hydroxy-11-((2-isopropylsulfamide)amino)ethyl)-1,12-dihydro-14- H -pyrano[3',4':6,7]indolizino[1,2- b ]quinoline-3,14(4 H )-dione.

The compound of the present invention can inhibit the activity of topoisomerase I.

Synthesis of the compound of the present invention

The compounds of formula (I) of the present invention can be synthesized by synthetic routes including methods well known in the chemical art. Starting materials are generally available from commercial sources, such as Aldrich Chemicals (Milwaukee, Wis.), or can be prepared using methods well known to those skilled in the art (e.g., methods generally described in Louis F. Fieser and Mary Fieser, Reagents for Organic Synthesis, v. 1-19, Wiley, N.Y. (eds. 1967-1999) or Beilsteins Handbuch der organischen Chemie, 4, Aufl. ed. Springer-Verlag, Berlin, including appendix (also available through the Beilstein online database)).

For illustrative purposes, general methods for preparing compounds of the present invention are shown in Reaction Schemes 1 and 2 through 4. For a more detailed description of the individual reaction steps, see the Examples that follow. Those skilled in the art will recognize that other synthetic routes can also be used to synthesize compounds of the present invention. While specific starting materials and reagents are depicted in the reaction schemes and discussed below, other starting materials and reagents can be readily substituted to provide a variety of derivatives and/or reaction conditions. Furthermore, most compounds prepared by the methods described below can be further modified in light of the present disclosure using conventional chemistry well known to those skilled in the art.

[Reaction Summary 1] Preparation method of chemical formula 1

In reaction scheme 1, PGHN represents an amino group protected by a protecting group (PG) and R represents hydrogen or aminoalkylene.

An "amino protecting group" or "amine protecting group" is a substituent attached to an amino group that blocks or protects the amino functionality of a compound. Such substituents are well known in the art (see, e.g., Chapter 7 of P. Wuts and T. Greene, Protective Groups in Organic Synthesis, J. Wiley & Sons, USA), and include carbamates such as methyl and ethyl carbamates, fluorenylmethyleneoxycarbonyl (Fmoc), substituted ethyl carbamates, carbamates cleaved by 1,6-β elimination (also called "immolative"), ureas, amides, peptides, alkyl and aryl derivatives. Suitable amine protecting groups include acetyl, trifluoroacetyl, tert-butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ), and 9-fluorenylmethyleneoxycarbonyl (Fmoc). For a general description of protectors and their uses, see the preceding literature.

[Reaction Summary 2] Manufacturing Method of Chemical Formula 1

In reaction outline 2, PGHN represents an amino group protected by a protecting group (PG), R represents hydrogen or aminoalkylene, and X represents O, S, NH, etc.

The term "leaving group" refers to a charged or uncharged functional group that is removed from a reactant molecule in a substitution reaction. Such leaving groups are well known in the art and include, but are not limited to, halogens, esters, alkoxyl groups, hydroxyl groups, tosylates, triflate groups, mesylates, nitriles, azides, carbamates, disulfides, thioesters, thioethers, and diazonium compounds.

[Reaction Summary 3] Manufacturing Method of Chemical Formula 1

In reaction scheme 3, PGHN represents an amino group protected by a protecting group (PG), R represents hydrogen or aminoalkylene, Y represents hydrogen, alkylene or hydroxyalkylene, and X represents hydrogen or halogen.

[Reaction Summary 4] Preparation method of chemical formula 1

In reaction scheme 4, NHPG represents an amino group protected by a protecting group (PG), R represents hydrogen or aminoalkylene, and X represents halogen.

pharmaceutical composition

In another aspect of the present invention, a pharmaceutical composition is disclosed, comprising a therapeutically effective amount of a compound of the present invention and further comprising a pharmaceutically acceptable excipient. A pharmaceutical composition for the treatment of cancer comprising a compound of the present invention and a pharmaceutically acceptable excipient can be used to inhibit the activity of topoisomerase I in the body, for example, for the treatment of cancer.

In the pharmaceutical composition of the present invention, the aforementioned compounds may be present as pharmaceutically acceptable salts. Pharmaceutically acceptable salts include, for example, base addition salts and acid addition salts. Pharmaceutically acceptable base addition salts may be formed with addition salts of metals or amines, such as alkali metal bases, alkaline earth metal bases, or organic amines. Pharmaceutically acceptable salts of the compounds may also be prepared using pharmaceutically acceptable cations. Pharmaceutically acceptable acid addition salts include salts of inorganic or organic acids.

In the present invention, a pharmaceutically acceptable excipient refers to an inactive ingredient approved by a relevant administrative agency (e.g., the Ministry of Food and Drug Safety of the Republic of Korea, the Federal Food and Drug Administration (FDA) of the United States) as being suitable for use together with an active pharmaceutical ingredient for the purpose of manufacturing a medicine for treating a disease in humans or livestock. Such pharmaceutically acceptable excipients include, but are not limited to, carriers, lubricants, fluidizing agents, disintegrating agents, sweeteners, diluents, preservatives, coloring agents, flavoring agents, surfactants, wetting agents, dispersing agents, suspending agents, stabilizers, isotonic agents, solvent emulsifiers, and adjuvants.

The pharmaceutical composition of the present invention may be in a form suitable for oral administration, such as a tablet, capsule, pill, powder, sustained-release preparation, solution, or suspension; in a form suitable for parenteral injection, such as a sterile solution, suspension, or emulsion; in a form suitable for topical administration, such as an ointment or cream; or in a form suitable for rectal administration, such as a suppository.

The pharmaceutical composition according to the present invention can be prepared in a conventional manner, for example, by conventional mixing, dissolving, granulating, sugar-coated tablet preparation, powdering, emulsifying, encapsulating, encapsulating, or lyophilizing processes. The appropriate formulation will vary depending on the chosen route of administration.

Pharmaceutical compositions suitable for oral administration can be readily formulated by combining the compounds disclosed herein with pharmaceutically acceptable excipients, such as carriers well known in the art. Using such excipients and carriers, the compounds disclosed herein can be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, and the like for oral ingestion by a subject to be treated. Oral pharmaceutical preparations can be obtained by adding the compounds of the present invention together with solid excipients, grinding the resulting mixture if necessary, adding suitable auxiliaries if necessary, and then processing the granulated mixture to form tablets or dragee cores. Suitable excipients include, for example, fillers and cellulose preparations. If desired, a disintegrant may be added.

For pharmaceutical compositions for oral administration of a therapeutically effective amount of a compound of the present disclosure, the compositions are generally in the form of solid (e.g., tablets, capsules, pills, powders, or troches) or liquid formulations (e.g., aqueous suspensions, solutions, elixirs, or syrups).

When administered in tablet form, the composition may additionally contain functional solids and/or solid carriers such as gelatin or adjuvants. Compositions in the form of tablets, capsules, and powders may contain from about 1 to about 95 wt% of the compound of the present invention, preferably from about 15 to about 90 wt% of the compound of the present invention, based on the total weight of the composition. An example of a tablet composition may contain, for example, up to about 80 wt% of the active pharmaceutical ingredient, from about 10 wt% to about 90 wt% of a binder, from about 0 wt% to about 85 wt% of a diluent, from about 2 wt% to about 10 wt% of a disintegrant, and from about 0.25 wt% to about 10 wt% of a lubricant.

When administered in liquid or suspension form, a functional liquid and/or liquid carrier such as water, petroleum, or animal or vegetable oil may be added. Liquid compositions may further contain saline, sugar alcohol solutions, dextrose or other sugar solutions, or glycols. When administered in liquid or suspension form, the composition may contain from about 0.5% to about 90% by weight of the compound of the present invention, preferably from about 1% to about 50% by weight of the compound of the present invention. In one contemplated embodiment, the liquid carrier is non-aqueous or substantially non-aqueous. For administration in liquid form, the composition may be supplied as a rapidly dissolving solid formulation for dissolution or suspension immediately prior to administration.

When the pharmaceutical composition of the present invention is administered intravenously, transdermally, or subcutaneously, it is in the form of a parenteral aqueous solution that does not contain a pyrogen. Preparation of such parenteral solutions, taking into account pH, isotonicity, stability, etc., is within the skill of the art. Preferred compositions for intravenous, transdermal, or subcutaneous injection generally contain an isotonic vehicle. Such compositions may be prepared for administration as a solution of the free base or a pharmacologically acceptable salt in water suitably mixed with a surfactant such as hydroxypropyl cellulose. Dispersions in glycerol, liquid polyethylene glycol, and mixtures thereof, as well as dispersions in oils, may also be prepared. Under normal storage and use conditions, such preparations may optionally contain a preservative to prevent the growth of microorganisms.

Injectable compositions may include sterile aqueous solutions, suspensions, or dispersions, and sterile powders for the extemporaneous preparation of sterile injectable solutions, suspensions, or dispersions. Sterile injectable solutions are prepared by incorporating the active compound in the required amount in an appropriate solvent with various other ingredients, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterile active ingredients into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above. In embodiments of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and freeze-drying techniques, which produce a powder of the active ingredient and any additional required ingredients from a previously sterile-filtered solution thereof.

To achieve controlled release of the active compound upon contact with body fluids in the gastrointestinal tract and to provide substantially constant and effective levels of the active compound in the plasma, sustained-release or sustained-release formulations may be prepared. For example, release may be controlled by one or more of dissolution, diffusion, and ion exchange. Furthermore, sustained-release approaches may enhance absorption through saturation or restriction pathways within the gastrointestinal tract. For example, for this purpose, the compound may be embedded in a polymer matrix comprising a biodegradable polymer, a water-soluble polymer, or a mixture thereof, and optionally a suitable surfactant. Embedding in this context may mean incorporating microparticles into the polymer matrix. Controlled-release formulations may also be obtained by encapsulating dispersed microparticles or emulsified microdroplets using known dispersion or emulsion coating techniques.

The pharmaceutical composition of the present invention may be formulated for parenteral administration by injection (e.g., bolus injection or continuous infusion). The injectable formulation may be presented in unit dosage form (e.g., ampoules or multi-dose containers) with an added preservative. The composition may take the form of a suspension, solution, or emulsion in an oily or aqueous vehicle, and may contain formulatory agents such as suspending, stabilizing, and/or dispersing agents.

The pharmaceutical composition may be presented in unit dosage form suitable for single administration of precise dosages.

A pharmaceutical composition containing the compound of the present invention can be used according to the method described below.

Treatment methods

In another aspect, the present invention provides a method for treating cancer. The method comprises administering to a subject in need of treatment a therapeutically effective amount of a compound of the present invention, such as a compound of the present invention defined by Formula 1. Alternatively, the present invention comprises administering to a subject a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention and a pharmaceutically acceptable excipient.

In a method for treating cancer, the compound of the present invention may be administered alone or in combination with at least one other drug. These other drugs and the compound of the present invention may be administered simultaneously or sequentially.

As used herein, unless specifically stated otherwise, a “therapeutically effective amount” of a compound refers to an amount of the compound sufficient to delay or minimize one or more symptoms associated with a disease, disorder, or condition, or to provide a therapeutic effect for a disease, disorder, or condition. The term “therapeutically effective amount” encompasses an amount that improves overall healing, an amount that alleviates or avoids a symptom or cause of a disease or condition, and an amount that enhances the therapeutic effectiveness of another therapeutic agent.

The amount of compound administered may vary depending on the subject being treated, the subject's age, health, sex, and body weight, the type (if any) of concurrent treatment, the severity of the pain, the nature of the desired effect, the treatment regimen and frequency, and the prescribing physician's judgment. The frequency of administration may also vary depending on the pharmacodynamic effects on arterial oxygen pressure. However, the most desirable dosage can be tailored to the individual subject, as understood and determined by those skilled in the art without undue experimentation. This typically involves adjusting the standard dose (e.g., reducing the dose if the subject's body weight is low).

While individual needs may vary, determining the optimal therapeutically effective dose of a compound is common knowledge in this art. When administered to humans for the therapeutic or preventive treatment of conditions and disorders using the compounds of the present invention, the dosage of the compounds of the present invention may range from about 0.01 mg/kg/day to about 50 mg/kg/day, for example, from 0.5 mg/day to about 500 mg/day. These doses may be administered as a single dose or divided into multiple doses.

In another aspect of the present invention, a use of a compound according to formula 1 is provided as a medicament. The medicament may be a medicament for the treatment of cancer. In one embodiment, a use of a compound according to formula 1 is provided for the treatment or prevention of cancer.

In another aspect of the present invention, a composition comprising a compound according to Formula 1 and a pharmaceutically acceptable excipient is provided for use as a medicament. The medicament may be a medicament for the treatment of cancer. In one embodiment, the composition is used for the treatment or prevention of cancer.

In another aspect of the present invention, there is provided a use of a compound according to formula 1 or a composition thereof, for the manufacture of a medicament, such as a composition comprising a therapeutically effective amount of a compound according to formula 1 and a pharmaceutically acceptable salt. The medicament may be a medicament for the treatment of cancer. In one embodiment, there is provided a use of a compound according to formula 1 or a composition thereof for the manufacture of a medicament for the treatment or prevention of cancer.

In another aspect of the present invention, a method for inhibiting intracellular topoisomerase I activity is provided. The method comprises the step of contacting a cell in which topoisomerase I activity is to be inhibited with an effective amount of a compound of the present invention, e.g., a compound defined by Formula 1.

Hereinafter, the present invention will be described in more detail through the following examples and experimental examples. However, these examples and experimental examples are intended only to aid understanding of the present invention and are not intended to limit the scope of the present invention in any way. Various changes and modifications may be made to the present examples, and such changes and modifications also fall within the scope of the appended claims.

[Example 1]

( S )-4-((sulfamide)amino)-9-ethyl-9-hydroxy-1,2,3,9,12,15-hexahydro-10 H ,13 H -Benzo[ de ]Pyrano[3',4':6,7]Indolizino[1,2- b ] Preparation of quinoline-10,13-dione

[Step-1] 5-Bromo-8-nitro-3,4-dihydronaphthalene-1(2 H )-On's manufacturing

5-Bromo-3,4-dihydronaphthalen-1(2 H )-one (11.0 g, 48.87 mmol) was dissolved in 100 mL of sulfuric acid at 0°C, and sodium nitrate (4.7 g, 55.30 mmol) was slowly added dropwise at 0°C. The mixture was stirred at 0°C for 1 hour, ice water was added dropwise, and the resulting solid was filtered through a filter. The filtered solid was dried and recrystallized from acetone and n-hexane, and the solid impurities were filtered through the filter. The filtered solution was concentrated under reduced pressure, and the next reaction was carried out without further purification.

¹ H-NMR (300 MHz, CDCl ₃ ): δ 7.86 (d, 1H), 7.27 (d, 1H), 3.09 (t 2H), 2.75 (t, 2H), 2.25 (qn, 2H).

[Step 2] tert Preparation of butyl (4-nitro-5-oxo-5,6,7,8-tetrahydronaphthalen-1-yl)carbamate

5-Bromo-8-nitro-3,4-dihydronaphthalen-1(2 H )-one (7.8 g, 28.88 mmol), tert -butyl carbamate (4.4 g, 37.56 mmol), cesium carbonate (19.0 g, 58.31 mmol), Expos (2.8 g, 5.87 mmol), and palladium acetate (650 mg, 2.90 mmol) obtained in the above [Step-1] were dissolved in 150 mL of 1,4-dioxane and degassed with nitrogen. The mixture was stirred at 80°C for 14 hours. After completion of the reaction, it was cooled to room temperature and water was added dropwise. The mixture was extracted twice with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (hexane: ethyl acetate = 10:1 (v/v) to 1:1 (v/v)) to obtain 6.0 g of the title compound in 68% yield.

¹ H-NMR (300 MHz, CDCl ₃ ): δ 8.22 (d, 1H), 7.41 (d, 1H), 6.52 (brs, 1H), 2.83 (t, 2H), 2.74 (t, 2H), 2.24 (qn, 2H), 1.51 (s, 9H).

[Step 3] tert Preparation of butyl (4-amino-5-oxo-5,6,7,8-tetrahydronaphthalen-1-yl) carbamate

Tert -Butyl (4-nitro-5-oxo-5,6,7,8-tetrahydronaphthalen-1-yl)carbamate (6.0 g, 19.60 mmol) obtained in the above [Step-2] was dissolved in 150 mL of methanol, and 5% palladium/carbon (1.2 g, 20 wt%) was added dropwise. The mixture was stirred at room temperature under hydrogen conditions for 14 hours. After completion of the reaction, the mixture was filtered through a filter filled with Celite and washed with methanol. The filtered organic layer was concentrated under reduced pressure and used for the next reaction without further purification.

¹ H-NMR (300 MHz, DMSO- d ₆ ): δ 8.28 (brs, 1H), 7.35 (brs, 2H), 7.05 (d, 1H), 6.56 (d, 1H), 2.69 (t, 2H), 2.50 (m, 2H), 1.88 (m, 2H), 1.43 (s, 9H).

[Step-4] 5,8-Diamino-3,4-dihydronaphthalene-1(2 H )-Manufacture of hydrochloride

Tert-butyl(4-amino-5-oxo-5,6,7,8-tetrahydronaphthalen-1-yl)carbamate (3.0 g, 10.86 mmol) obtained in the above [Step-3] was dissolved in 30 mL of methanol, and 5 mL of concentrated hydrochloric acid was added dropwise at 0°C. After stirring at room temperature for 14 hours, the solution was concentrated under reduced pressure. The residue was recrystallized from methanol and diethyl ether to obtain 1.8 g of the title compound in a 67% yield.

¹ H-NMR (300 MHz, DMSO- d ₆ ): δ 10.17 (brs, 2H), 7.41 (d, 1H), 6.69 (d, 1H), 2.88 (t, 2H), 2.55 (t, 2H), 1.94 (qn, 2H).

[Step-5]( S )-4-Amino-9-ethyl-9-hydroxy-1,2,3,9,12,15-hexahydro-10 H ,13 H -Benzo[ de ]Pyrano[3',4':6,7]Indolizino[1,2- b ] Preparation of quinoline-10,13-dione

In the above [Step-4], 5,8-diamino-3,4-dihydronaphthalen-1(2 H )-one hydrochloride (100 mg, 0.40 mmol) was dissolved in 2 mL of ethanol and 4 mL of acetic acid, and ( S )-4-ethyl-4-hydroxy-7,8-dihydro-1 H -pyrano[3,4- f ]indolizine-3,6,10(4 H )-trione (110 mg, 0.42 mmol) and para-toluenesulfonic acid monohydrate (20 mg, 0.11 mmol) were added dropwise. The mixture was stirred at 100°C for 14 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, and the obtained residue was neutralized with a saturated aqueous sodium bicarbonate solution at low temperature. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane: methanol = 10:1 (v/v)) to obtain 100 mg of the title compound in 62% yield.

¹ H-NMR (300 MHz, DMSO- d ₆ ): δ 7.73 (d, 1H), 7.30 (d, 1H), 7.18 (s, 1H), 6.44 (s, 1H), 5.64 (brs, 2H), 5.41 (s, 2H), 5.16 (s, 2H), 3.04 (t, 2H), 2.75 (t, 2H), 2.01 (t, 2H), 1.87 (m, 2H), 0.88 (t, 3H).

[Step-6]( S )-4-((sulfamide)amino)-9-ethyl-9-hydroxy-1,2,3,9,12,15-hexahydro-10 H ,13 H -Benzo[ de ]Pyrano[3',4':6,7]Indolizino[1,2- b ]Quinoline-10,13-dione production

( S )-4-amino-9-ethyl-9-hydroxy-1,2,3,9,12,15-hexahydro- 10H , 13H -benzo[ de ]pyrano[3',4':6,7]indolizino[1,2- b ]quinoline-10,13-dione (400 mg, 0.99 mmol) obtained in the above [Step-5] was dissolved in 20 mL of dichloromethane and 5 mL of dimethylacetamide, and then triethylamine (726 mg, 7.17 mmol) and sulfamoyl chloride (300 mg, 2.60 mmol) were added dropwise at 0°C. The mixture was stirred at room temperature for 14 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, and the obtained residue was purified by column chromatography (dichloromethane: methanol = 10:1 (v/v)) to obtain 100 mg of the title compound in a yield of 21%.

¹ H-NMR (300 MHz, DMSO- d ₆ ): δ 9.00 (brs, 1H), 7.98 (d, 1H), 7.89 (d, 1H), 7.31 (s, 1H), 7.05 (brs, 2H), 6.50 (s, 1H), 5.44 (s, 2H), 5.27 (s, 2H), 3.16 (m, 4H), 2.03 (t, 2H), 1.88 (m, 2H), 0.89 (t, 3H).

MS (ESI+, m/z): 483.1 [M+H] ⁺

[Example 2]

( S )-4-((sulfamide)amino)-9-ethyl-9-hydroxy-1,9,12,15-tetrahydro-13 H -Pirano[4,3,2- de ]Pyrano[3',4':6,7]Indolizino[1,2- b ] Preparation of quinoline-10,13-dione

[Step 1] N Preparation of -(2-hydroxy-4-nitrophenyl)acetamide

2-Amino-5-nitrophenol (50.0 g, 324.42 mmol) was dissolved in 200 mL of acetic acid, cooled to 0°C, acetic anhydride (49.68 g, 486.62 mmol) was slowly added dropwise, and stirred at room temperature for 2 hours. After the reaction was completed, the obtained solid was filtered under reduced pressure to obtain 65.0 g of the title compound in a 99% yield.

¹ H-NMR (300 MHz, DMSO- d ₆ ): δ 11.02 (brs, 1H), 9.52 (s, 1H), 8.29 (d, 1H), 7.73-7.66 (m, 2H), 2.17 (s, 3H).

[Step 2] N Preparation of -(2-(3-hydroxypropoxy)-4-nitrophenyl)acetamide

N- (2-hydroxy-4-nitrophenyl)acetamide (65.0 g, 331.36 mmol) and 18-crown-6 (875.19 mg, 3.313 mmol) obtained in the above [Step-1] were dissolved in 650 mL of N,N -dimethylformamide, cooled to 0°C, 60% sodium hydride (13.92 g, 347.93 mmol) was slowly added dropwise, and stirred for 30 minutes. 3-Chloropropan-1-ol (46.99 g, 497.04 mmol) was slowly added dropwise at 0°C, and stirred at 80°C for 2 hours. After the reaction was completed, it was cooled to room temperature, and 1.3 L of water was added dropwise. The resulting solid was filtered under reduced pressure and washed with water to obtain 72.0 g of the title compound in 85% yield.

¹ H-NMR (300 MHz, DMSO- d ₆ ): δ 9.42 (s, 1H), 8.36 (d, 1H), 7.87 (d, 1H), 7.82 (s, 1H), 4.70 (t, 1H), 4.26 (t, 2H), 3.62 (m, 2H), 2.18 (s, 3H), 1.97 (m, 2H).

[Step-3] Preparation of 3-(2-acetamido-5-nitrophenoxy)propanoic acid

N- (2-(3-hydroxyproxy)-4-nitrophenyl)acetamide (31 g, 121.93 mmol) obtained in the above [Step-2] was dissolved in 300 mL of acetone, and chromium trioxide (22.92 g, 229.23 mmol) dissolved in a mixture of 30 mL of sulfuric acid and 60 mL of water was slowly added dropwise at 0°C, followed by stirring for 15 minutes. After the reaction was completed, 600 mL of water was added dropwise. The resulting solid was filtered under reduced pressure and washed with water to obtain 20 g of the title compound in a 61% yield.

¹ H-NMR (300 MHz, DMSO- d ₆ ): δ 9.32 (s, 1H), 8.40 (d, 1H), 7.93-7.87 (m, 2H), 4.36 (t, 2H), 2.85 (t, 2H), 2.19 (s, 3H).

[Step 4] Preparation of 3-(2-acetamido-5-aminophenoxy)propanoic acid

3-(2-acetamide-5-nitrophenoxy)propanoic acid (20 g, 74.56 mmol) obtained in the above [Step-3] was dissolved in 200 mL of methanol, and 10% palladium/carbon (4 g, 20 wt%) was added dropwise. The mixture was stirred for 4 hours at room temperature under hydrogen conditions. After completion of the reaction, the mixture was filtered through a filter filled with Celite and washed with methanol. The filtered organic layer was filtered under reduced pressure and concentrated to obtain 12 g of the title compound in a 67% yield.

¹ H-NMR (300 MHz, DMSO- d ₆ ): δ 8.62 (s, 1H), 7.38 (d, 1H), 6.29 (s, 1H), 6.11 (d, 1H), 4.06 (t, 2H), 2.70 (t, 2H), 1.95 (s, 3H).

[Step 5] N Preparation of -(8-acetamide-4-oxochroman-5-yl)-2,2,2-trifluoroacetamide

3-(2-acetamido-5-aminophenoxy)propanoic acid (12 g, 50.37 mmol) obtained in the above [Step-4] was dissolved in 120 mL of trifluoroacetic acid, and then trifluoroacetic anhydride (181 g, 863 mmol) was added dropwise. The mixture was stirred at room temperature for 14 hours. After completion of the reaction, the mixture was concentrated under reduced pressure and neutralized with a saturated aqueous sodium bicarbonate solution. The mixture was extracted with ethyl acetate, and the extracted solution was dried over anhydrous sodium sulfate. The dried solution was filtered and concentrated under reduced pressure to obtain 6 g of the title compound in a yield of 38%.

¹ H-NMR (300 MHz, DMSO- d ₆ ): δ 9.46 (s, 1H), 8.21 (d, 1H), 7.94 (d, 1H), 4.64 (t, 2H), 2.95 (t, 2H), 2.10 (s, 3H).

[Step 6] N Preparation of -(5-amino-4-oxochroman-8-yl)acetamide

N- (8-acetamido-4-oxochroman-5-yl)-2,2,2-trifluoroacetamide (6 g, 18.97 mmol) obtained in the above [Step-5] was dissolved in 120 mL of methanol, and an aqueous solution of potassium carbonate (12.17 g, 88.034 mmol) dissolved in 40 mL of water was added dropwise, followed by stirring at room temperature for 2 hours. After completion of the reaction, the mixture was concentrated under reduced pressure and extracted with ethyl acetate. The extracted solution was dried over anhydrous sodium sulfate, and the dried solution was filtered and concentrated under reduced pressure to obtain 6 g of the title compound in a yield of 38%.

¹ H-NMR (300 MHz, DMSO- d ₆ ): δ 8.94 (s, 1H), 7.43 (d, 1H), 7.24 (br, 2H), 6.23 (d, 1H), 4.42 (t, 2H), 2.71 (t, 2H), 1.98 (s, 3H).

[Step-7]( S )- N -(9-Ethyl-9-hydroxy-10,13-dioxo-1,2,9,10,13,15-hexahydro-12 H -Pirano[4,3,2- de ]Pyrano[3',4':6,7]Indolizino[1,2- b Preparation of quinolin-4-yl)acetamide

N- (5-amino-4-oxochroman-8-yl)acetamide (120 mg, 0.549 mmol) and (4 S )-4-ethyl-4-hydroxy-7,8-dihydro-1 H -pyrano[3,4- f ]indolizine-3,6,10-trione (155 mg, 0.589 mmol) obtained in the above [Step-6] were dissolved in 2 mL of toluene, and the mixture was stirred under reflux at 120°C for 14 hours. After completion of the reaction, the mixture was concentrated under reduced pressure, and the obtained residue was purified by column chromatography (dichloromethane: methanol = 10:1 (v/v)) to obtain 40 mg of the title compound in a 16% yield.

¹ H-NMR (300 MHz, DMSO- d ₆ ): δ 9.63 (s, 1H), 8.37 (d, 1H), 7.72 (d, 1H), 7.31 (s, 1H), 5.45 (s, 2H), 5.27 (s, 2H), 4.54 (t, 2H), 4.13 (t, 1H), 3.40 (t, 2H), 2.15 (s, 3H), 1.99 (q, 2H), 0.78 (t, 3H).

[Step-8] ( S )-4-amino-9-ethyl-9-hydroxy-1,9,12,15-tetrahydro-13 H -Pirano[4,3,2- de ]Pyrano[3',4':6,7]Indolizino[1,2- b ]quinoline-10,13(2 H )-Manufacture of dione

( S ) -N- (9-ethyl-9-hydroxy-10,13-dioxo-1,2,9,10,13,15-hexahydro- 12H -pyrano[4,3,2- de ]pyrano[3',4':6,7]indolizino[1,2- b ]quinolin-4-yl)acetamide (320 mg, 0.715 mmol) obtained in the above [Step-7] was dissolved in 3 mL of concentrated hydrochloric acid and stirred at 80°C for 3 hours. After completion of the reaction, the mixture was concentrated under reduced pressure, and the obtained residue was purified by column chromatography (dichloromethane:methanol = 10:1 (v/v)) to obtain 289 mg of the title compound in a yield of 99%.

¹ H-NMR (300 MHz, DMSO- d ₆ ): δ 7.87 (d, 1H), 7.36 (d, 1H), 7.21 (s, 1H), 5.41 (s, 2H), 5.40 (s, 2H), 5.20 (s, 2H), 4.42 (t, 2H), 3.32 (t, 2H), 1.86 (q, 2H), 0.88 (t, 3H).

[Step-9]( S )-4-((sulfamide)amino)-9-ethyl-9-hydroxy-1,9,12,15-tetrahydro-13 H -Pirano[4,3,2- de ]Pyrano[3',4':6,7]Indolizino[1,2- b ] Preparation of quinoline-10,13-dione

( S )-4-amino-9-ethyl-9-hydroxy-1,9,12,15-tetrahydro-13 H -pyrano[4,3,2 -de ]pyrano[3',4':6,7]indolizino[1,2- b ]quinoline-10,13(2 H )-dione (100 mg, 0.248 mmol) obtained in the above [Step-8] was dissolved in 2 mL of dichloromethane, and sulfamoyl chloride (86 mg, 0.744 mmol) and triethylamine (75 mg, 0.744 mmol) were added dropwise, and the mixture was stirred at room temperature for 14 hours. After completion of the reaction, the mixture was extracted with a solvent of chloroform/isopropyl alcohol (3/1 (v/v)) ratio and dried over anhydrous magnesium sulfate. The dried solution was filtered and concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane: methanol = 10:1 (v/v)) to obtain 2 mg of the title compound in a 1% yield.

MS (ESI+, m/z): 485.1 [M+H] ⁺

[Example 3]

( S )-4-((sulfamide)amino)-9-ethyl-9-hydroxy-1,9,12,15-tetrahydro-13 H -Pyrano[3',4':6,7]Indolizino[1,2- b ]Thiopyrano[4,3,2- de ]quinoline-10,13(2 H )-Manufacture of dione

[Step-1] Preparation of 2-amino-5-nitrobenzenethiol

6-Nitrobenzothiazole (10.0 g, 55.5 mmol) was dissolved in 100 mL of ethanol, and hydrazine monohydrate (11.1 g, 222 mmol) was added dropwise. The mixture was stirred at room temperature for 15 hours. After the reaction was completed, ice water was added dropwise, and the mixture was acidified with 3 N hydrochloric acid until the pH reached 3. The resulting solid was stirred at room temperature for 1 hour and filtered under reduced pressure. The filtered solid was washed with water to obtain 8.2 g of the title compound in an 86% yield.

¹ H-NMR (300 MHz, CDCl ₃ ): δ 8.34 (d, 1H), 8.02 (dd, 1H), 6.70 (d, 1H), 4.93 (brs, 2H), 3.00 (s, 1H).

[Step 2] Preparation of ethyl 3-((2-amino-5-nitrophenyl)thio)propanoate

2-Amino-5-nitrobenzenethiol (7.2 g, 42.31 mmol) obtained in the above [Step-1] was dissolved in 72 mL of tetrahydrofuran, and cooled to 5°C. After cooling, ethyl acrylate (8.47 g, 84.621 mmol) and tetrabutylammonium fluoride (22.12 g, 84.61 mmol) were added to the reaction solution, the temperature was raised to room temperature, and the mixture was stirred for 15 hours. After the reaction was completed, water was added dropwise, and the mixture was extracted with ethyl acetate. The extracted solution was washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The dried solution was filtered and concentrated under reduced pressure. The residue was purified by column chromatography (hexane: ethyl acetate = 2:1 (v/v)) to obtain 5.8 g of the title compound in a 51% yield.

¹ H-NMR (300 MHz, CDCl ₃ ): δ 8.31 (d, 1H), 8.01 (dd, 1H), 6.70 (d, 1H), 5.28 (brs, 2H), 4.13 (q, 2H), 3.01 (t, 2H), 2.56 (t, 2H), 1.25 (t, 3H).

[Step-3] Preparation of ethyl 3-((2-acetamide-5-nitrophenyl)thio)propanoate

Ethyl 3-((2-amino-5-nitrophenyl)thio)propanoate (5.8 g, 21.46 mmol) obtained in the above [Step-2] was dissolved in 58 mL of acetic acid, and acetic anhydride (3.29 g, 32.19 mmol) was added dropwise. The mixture was stirred at room temperature for 15 hours. After completion of the reaction, the mixture was neutralized with a saturated aqueous sodium bicarbonate solution, and extracted with ethyl acetate. The extracted solution was washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The dried solution was filtered and concentrated under reduced pressure. The obtained residue (6.7 g) was used for the next reaction without further purification.

¹ H-NMR (300 MHz, CDCl ₃ ): δ 9.03 (brs, 1H), 8.71 (d, 1H), 8.44 (d, 1H), 8.22 (dd, 1H), 4.19 (q, 2H), 3.07 (t, 2H), 2.58 (t, 2H), 2.34 (s, 3H), 1.28 (t, 3H).

[Step 4] Preparation of ethyl 3-((2-acetamido-5-aminophenyl)thio)propanoate

Ethyl 3-((2-acetamide-5-nitrophenyl)thio)propanoate (6.7 g, 21.45 mmol) obtained in the above [Step-3] was dissolved in 67 mL of ethanol, and 10% palladium/carbon (1.34 g, 20 wt%) was added. The mixture was stirred at room temperature under hydrogen conditions for 15 hours. After completion of the reaction, the mixture was filtered through a filter filled with cellite and washed with ethanol. The filtered organic layer was concentrated under reduced pressure, and the obtained residue (6.0 g) was used for the next reaction without further purification.

¹ H-NMR (300 MHz, DMSO- d ₆ ): δ 8.93 (s, 1H), 6.97 (d, 1H), 6.60 (d, 1H), 6.40 (dd, 1H), 5.10 (brs, 2H), 4.07 (q, 3H), 2.97 (t, 2H), 2.58 (t, 2H), 1.95 (s, 3H), 1.20 (t, 3H).

[Step 5] Preparation of ethyl 3-((2,5-diacetamide phenyl)thio)propanoate

Ethyl 3-((2-acetamido-5-aminophenyl)thio)propanoate (6.0 g, 21.25 mmol) obtained in the above [Step-4] was dissolved in 60 mL of acetic acid, and acetic anhydride (3.25 g, 31.87 mmol) was added dropwise. The mixture was stirred at room temperature for 15 hours. After the reaction was completed, the mixture was neutralized with a saturated aqueous sodium bicarbonate solution, and extracted with ethyl acetate. The extracted solution was washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The dried solution was filtered and concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane: methanol = 20:1 (v/v)), and then crystallized (hexane: acetone = 10:2 (v/v)) to obtain 2.5 g of the title compound in a 36% yield.

¹ H-NMR (300 MHz, CDCl ₃ ): δ 8.49 (s, 1H), 8.30 (d, 1H), 7.90 (d, 1H), 7.27 (dd, 2H), 4.16 (q, 2H), 3.02 (t, 2H), 2.54 (t, 2H), 2.24 (s, 3H), 2.16(s, 3H), 1.27 (t, 3H).

[Step 6] Preparation of 3-((2,5-diacetamide phenyl)thio)propanoic acid

Ethyl 3-((2,5-diacetamidophenyl)thio)propanoate (1.0 g, 3.08 mmol) obtained in the above [Step-5] was dissolved in 20 mL of a solution of tetrahydrofuran/water (3/1 (v/v)) and cooled to an internal temperature of 5°C. Lithium hydroxide monohydrate (0.52 g, 12.33 mmol) was added and stirred at 5°C for 1 hour and then at room temperature for 3 hours. After completion of the reaction, the mixture was concentrated under reduced pressure, and 900 mg of the obtained residue was used for the next reaction without further purification.

¹ H-NMR (300 MHz, DMSO- d ₆ ): δ 10.31 (s, 1H), 9.47 (s, 1H), 7.73 (d, 1H), 7.43 (q, 2H), 2.96 (t, 2H), 2.39 (t, 2H), 2.04 (s. 6H).

[Step 7] N,N' Preparation of -(4-oxothiochroman-5,8-diyl)diacetamide

3-((2,5-diacetamidophenyl)thio)propanoic acid (900 mg, 3.04 mmol) obtained in the above [Step-6] was dissolved in 18.0 mL of trifluoroacetic acid, and trifluoroacetic anhydride (27.2 g, 129 mmol) was added dropwise. The mixture was stirred at 50°C for 15 hours. After completion of the reaction, the mixture was concentrated under reduced pressure. The obtained residue was dissolved in ethyl acetate, and neutralized by dropwise addition of saturated aqueous sodium bicarbonate solution. The mixture was extracted twice with ethyl acetate and dried over anhydrous sodium sulfate. The dried solution was filtered and concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane: methanol = 20:1 (v/v)) to obtain 225 mg of the title compound in a 26% yield.

¹ H-NMR (300 MHz, CDCl ₃ ): δ 11.99 (s, 1H), 8.54 (d, 1H), 7.81 (d, 1H), 6.98 (s,1H), 3.18 (q, 2H), 3.06 (q, 2H), 2.23 (s, 3H), 2.21 (s, 3H).

[Step 8] Preparation of 5,8-diaminothiochroman-4-one

N,N' -(4-oxothiochroman-5,8-diyl) diacetamide (225 mg, 1.69 mmol) obtained in the above [Step-7] was dissolved in 2.25 mL of 12N hydrochloric acid, and the mixture was refluxed at 105°C for 15 hours. After completion of the reaction, the reaction solution was cooled to room temperature and neutralized by dropwise addition of 4 M aqueous sodium hydroxide solution. The mixture was extracted twice with ethyl acetate and dried over anhydrous sodium sulfate. The dried solution was filtered and concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane: methanol = 20:1 (v/v)) to obtain 160 mg of the title compound in a 98% yield.

¹ H-NMR (300 MHz, DMSO- d ₆ ): δ 6.74 (d, 1H), 6.35 (d, 1H), 6.21 (brs, 2H), 3.42 (bs, 2H), 3.16 (q, 2H), 2.99 (q, 2H).

[Step-9] ( S )-4-amino-9-ethyl-9-hydroxy-1,9,12,15-tetrahydro-13 H -Pyrano[3',4':6,7]Indolizino[1,2- b ]Thiopyrano[4,3,2- de ]quinoline-10,13(2 H )-Manufacture of dione

5,8-Diaminothiochroman-4-one (160 mg, 0.82 mmol), ( S )-4-ethyl-4-hydroxy-7,8-dihydroxy-1 H -pyrano[3,4- f ]indolizine-3,6,10(4 H )trione (217 mg, 0.82 mmol) obtained in the above [Step-8] were dissolved in 4.8 mL of a solution of toluene/ N,N -dimethylformamide (5/1 (v/v)) and stirred under reflux at 120°C for 16 hours. After the reaction was completed, it was cooled to room temperature and a saturated aqueous sodium bicarbonate solution was added dropwise. This was extracted three times with a solution of chloroform/isopropyl alcohol (3/1 (v/v)) and dried over anhydrous sodium sulfate. The dried solution was filtered and concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane:methanol = 10:1 (v/v)) to obtain 26 mg of the title compound in a 7% yield.

¹ H-NMR (300 MHz, DMSO- d ₆ ): δ 7.71 (d, 1H), 7.33 (d, 1H), 7.19 (s, 1H), 6.46 (s, 1H), 5.68 (s, 2H), 5.41 (s, 2H), 5.20 (s, 2H), 3.42 (t, 2H), 3.19 (t, 2H), 1.86 (dd, 2H), 0.87 (t, 3H).

MS (ESI+, m/z): 422.1 [M+H] ⁺

[Step-10]( S )-4-((sulfamide)amino)-9-ethyl-9-hydroxy-1,9,12,15-tetrahydro-13 H -Pyrano[3',4':6,7]Indolizino[1,2- b ]Thiopyrano[4,3,2- de ]quinoline-10,13(2 H )-Manufacture of dione

( S )-4-amino-9-ethyl-9-hydroxy-1,9,12,15-tetrahydro-13 H -pyrano[3',4':6,7]indolizino[1,2- b ]thiopyrano[4,3,2- de ]quinoline-10,13(2 H )-dione (20 mg, 0.05 mmol), sulfamoyl chloride (16 mg, 0.14 mmol), and triethylamine (33.6 mg, 0.33 mmol) obtained in the above [Step-9] were dissolved in 1.0 mL of a solution of dichloromethane/ N,N -dimethylacetamide (4/1 (v/v)) and stirred at room temperature for 15 hours. After the reaction was completed, it was cooled to room temperature and water was added dropwise. This was extracted three times with a solution of chloroform/isopropyl alcohol (3/1 (v/v)) and dried over anhydrous sodium sulfate. The dried solution was filtered and concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane: methanol = 10:1 (v/v)) to obtain 3 mg of the title compound in a 13% yield.

¹ H-NMR (300 MHz, DMSO- d ₆ ): δ 7.94 (d, 1H), 7.75 (d, 1H), 7.24 (s, 1H), 6.46 (s, 1H), 5.41 (s, 2H), 5.22 (s, 2H), 5.20 (s, 2H), 3.45 (t, 2H), 3.12 (t, 2H), 1.87 (dd, 2H), 0.88 (t, 3H).

MS (ESI+, m/z): 501.1 [M+H] ⁺

[Example 4]

( S )-4-((((2-aminoethyl)amino)sulfamide)amino)-9-ethyl-9-hydroxy-1,2,3,9,12,15-hexahydro-10 H ,13 H -Benzo[ de ]Pyrano[3',4':6,7]Indolizino[1,2- b ] Preparation of quinoline-10,13-dione

[Step 1] tert Preparation of -butyl(2-((2-oxooxazolidine)-3-sulfamido)ethyl) carbamate

2-Bromoethanol (5.0 mL, 70.42 mmol) was dissolved in 100 mL of dichloromethane, and a solution of chlorosulfonyl isocyanate (7.0 mL, 78.69 mmol) in 50 mL of dichloromethane was slowly added dropwise at 0°C. The mixture was stirred at 0°C for 1 hour and concentrated under reduced pressure. The residue was dissolved again in 100 mL of dichloromethane, and triethylamine (24.0 mL, 172.19 mmol) and tert -butyl(2-aminoethyl)carbamate (14.0 mL, 88.25 mmol) were slowly added dropwise at 0°C. The mixture was stirred at room temperature for 14 hours and cooled to 0°C. After adding ice water, the mixture was extracted with ethyl acetate, and the organic layer was washed with 1 M aqueous hydrochloric acid solution and saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized with ethyl acetate and n -hexane to obtain 17.3 g of the title compound in a 79% yield.

¹ H-NMR (300 MHz, CDCl ₃ ): δ 5.03 (brs, 1H), 4.46 (q, 2H), 4.09 (q, 2H), 3.32 (brs, 4H), 1.47 (s, 9H).

[Step 2] tert -Butyl( S )-(2-(( N -(9-Ethyl-9-hydroxy-10,13-dioxo-2,3,9,10,13,15-hexahydro-1 H ,12 H -Benzo[ de ]Pyrano[3',4':6,7]Indolizino[1,2- b Preparation of ]quinolin-4-yl)sulfamoyl)amino)ethyl)carbamate

Tert -butyl (2-((2-oxooxazolidine)-3-sulfamido)ethyl)carbamate (1.2 g, 5.22 mmol) obtained in the above [Step-1] and ( S )-4-amino-9-ethyl-9-hydroxy-1,2,3,9,12,15-hexahydro-10 H ,13 H -benzo[ de ]pyrano[3',4':6,7]indolizino[1,2- b ]quinoline-10,13-dione (0.3 g, 0.74 mmol) obtained in [Step-5] of Example 1 were dissolved in 10 mL of 1,4-dioxane, and then potassium carbonate (0.3 g, 2.17 mmol) was added dropwise. The mixture was stirred under reflux at 100°C for 2 hours and cooled to 0°C. After adding ice water dropwise, the mixture was extracted with ethyl acetate, and the organic layer was washed with 1 M aqueous hydrochloric acid solution and saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane: methanol = 20:1 (v/v)) to obtain 150 mg of the title compound in a 32% yield.

¹ H-NMR (300 MHz, DMSO-d6): δ 9.25 (s, 1H), 7.98 (d, 1H), 7.85 (d, 1H), 7.39 (brs, 1H), 7.31 (s, 1H), 6.79 (brs, 1H), 6.50 (s, 1H), 5.44 (s, 2H), 5.26 (s, 2H), 3.15 (brs, 4H), 3.15 (brs, 4H), 2.03 (m, 2H), 1.88 (m, 2H), 1.35 (s, 9H), 0.89 (t, 3H).

[Step-3]( S )-4-((((2-aminoethyl)amino)sulfamide)amino)-9-ethyl-9-hydroxy-1,2,3,9,12,15-hexahydro-10 H ,13 H -Benzo[ de ]Pyrano[3',4':6,7]Indolizino[1,2- b ] Preparation of quinoline-10,13-dione

tert -Butyl ( S )-(2-(( N -(9-ethyl-9-hydroxy-10,13-dioxo-2,3,9,10,13,15-hexahydro-1 H ,12 H -benzo[ de ]pyrano[3',4':6,7]indolizino[1,2- b ]quinolin-4-yl)sulfamoyl)amino)ethyl)carbamate (150 mg, 0.24 mmol) obtained in the above [Step-2] was dissolved in 5 mL of methanol, and then 0.5 mL of concentrated hydrochloric acid was slowly added dropwise at 0°C. The mixture was stirred at room temperature for 8 hours and concentrated under reduced pressure. The residue was dissolved in methanol and then crystallized from dichloromethane to obtain 70 mg of the title compound in a 49% yield.

¹ H-NMR (300 MHz, DMSO-d6): δ 9.44 (brs, 1H), 8.46 (brs, 1H), 8.17 (brs, 4H), 8.00 (d, 1H), 7.87 (d, 1H), 7.69 (brs, 1H), 7.37 (s, 1H), 5.44 (s, 2H), 5.26 (s, 2H), 3.26 (m, 4H), 2.91 (m, 2H), 2.05 (m, 2H), 1.88 (m, 2H), 0.89 (t, 3H).

[Example 5]

( S )-14-(((sulfamide)amino)methyl)-7-ethyl-7-hydroxy-10,13-dihydro-11 H -[1,3]dioxolo[4,5- g ]Pyrano[3',4':6,7]Indolizino[1,2- b ]quinoline-8,11(7 H )-Manufacture of dione

[Step 1] N -(Benzo[ d Preparation of [1,3]dioxol-5-yl)acetamide

Benzo[ d ][1,3]dioxol-5-amine (1.0 g, 7.29 mmol) was dissolved in 30 mL of dichloromethane, and triethylamine (1.5 mL, 10.76 mmol) and acetic anhydride (0.9 mL, 9.52 mmol) were slowly added dropwise at 0°C. The mixture was stirred at room temperature for 2 hours, and ice water was added dropwise. After extraction with dichloromethane, the organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate: n-hexane = 1:1 (v/v)) to obtain 1.0 g of the title compound in a yield of 76%.

¹ H-NMR (300 MHz, DMSO-d ₆ ): δ 9.82 (brs, 1H), 7.29 (d, 1H), 6.93 (dd, 1H), 6.83 (d, 1H), 5.97 (s, 2H), 2.00 (s, 3H).

[Step-2] Preparation of N- (6-(2-chloroacetyl)benzo[ d ][1,3]dioxol-5-yl)acetamide

Chloroacetyl chloride (1.5 mL, 18.86 mmol) was dissolved in 30 mL of nitrobenzene, and zinc chloride (2.5 g, 18.34 mmol) was slowly added at 0°C, and the mixture was stirred at room temperature for 30 minutes. N -(Benzo[ d ][1,3]dioxol-5-yl)acetamide (1.0 g, 5.58 mmol) obtained in [Step-1] above was dissolved in 30 mL of nitrobenzene, and the mixture was slowly added dropwise to the reaction solution. The mixture was stirred under reflux at 100°C for 2 hours and cooled to 0°C. Ice water was added dropwise, and the mixture was extracted twice with dichloromethane, and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate: n-hexane = 1:2 (v/v)) to obtain 150 mg of the title compound in a 10% yield.

¹ H-NMR (300 MHz, CDCl ₃ ): δ 11.81 (brs, 1H), 8.44 (s, 1H), 7.20 (s, 1H), 6.08 (s, 2H), 4.66 (s, 2H), 2.25 (s, 3H).

[Step-3] Preparation of 1-(6-aminobenzo[ d ][1,3]dioxol-5-yl)-2-chloroethan-1-one

N- (6-(2-chloroacetyl)benzo[ d ][1,3]dioxol-5-yl)acetamide (350 mg, 1.37 mmol) obtained in the above [Step-2] was dissolved in 10 mL of ethanol, and 1 mL of concentrated hydrochloric acid was slowly added dropwise at 0°C. The mixture was stirred under reflux at 100°C for 1 hour and cooled to 0°C. Ice water was added dropwise, and the mixture was neutralized with 2 M aqueous sodium hydroxide solution, followed by extraction twice with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 200 mg of the title compound in a yield of 68%.

¹ H-NMR (300 MHz, CDCl ₃ ): δ 7.00 (s, 1H), 6.55 (brs, 2H), 6.17 (s, 1H), 5.94 (s, 2H), 4.53 (s, 2H).

[Step-4] Preparation of ( S )-14-(chloromethyl)-7-ethyl-7-hydroxy-10,13-dihydro-11 H -[1,3]dioxolo[4,5- g ]pyrano[3',4':6,7]indolizino[1,2- b ]quinoline-8,11(7 H )-dione

1-(6-Aminobenzo[ d ][1,3]dioxol-5-yl)-2-chloroethane-1-one (200 mg, 0.94 mmol) and ( 4S )-4-ethyl-4-hydroxy-7,8-dihydro- 1H -pyrano[3,4- f ]indolizine-3,6,10-trione (300 mg, 1.14 mmol) obtained in the above [Step-3] were dissolved in 10 mL of toluene, stirred under reflux at 120°C for 10 minutes, and cooled to room temperature. To this solution, para-toluenesulfonic acid monohydrate (0.1 g, 0.56 mmol) and 10 mL of toluene were added dropwise. The mixture was stirred under reflux at 140°C for 14 hours, and cooled to 0°C. The resulting solid was filtered and washed with toluene and ethanol, and the filtrate was distilled under reduced pressure, and the residue was purified by column chromatography (100% ethyl acetate) to obtain 400 mg of the title compound in a 97% yield.

¹ H-NMR (300 MHz, DMSO-d ₆ ): δ 7.76 (s, 1H), 7.56 (s, 1H), 7.24 (s, 1H), 6.32 (s, 2H), 5.43 (s, 2H), 5.35 (s, 2H), 5.29 (s, 2H), 1.85 (m, 2H), 0.88 (t, 3H).

[Step-5] Preparation of ( S )-14-(aminomethyl)-7-ethyl-7-hydroxy-10,13-dihydro-11 H -[1,3]dioxolo[4,5- g ]pyrano[3',4':6,7]indolizino[1,2- b ]quinoline-8,11(7 H )-dione

( S )-14-(chloromethyl)-7-ethyl-7-hydroxy-10,13-dihydro-11 H -[1,3]dioxolo[4,5- g ]pyrano[3',4':6,7]indolizino[1,2- b ]quinoline-8,11(7 H )-dione (350 mg, 0.79 mmol) obtained in the above [Step-4] was dissolved in 10 mL of ethanol, and hexamethylenetetramine (500 mg, 3.57 mmol) was added dropwise. The mixture was stirred under reflux at 140°C for 4 hours and cooled to 0°C. 5 mL of concentrated hydrochloric acid was added dropwise at 0°C, stirred at room temperature for 30 minutes, and concentrated under reduced pressure. The residue was dissolved in dichloromethane/methanol, neutralized with sodium bicarbonate, and filtered. The filtrate was distilled under reduced pressure, and the residue was purified by column chromatography (methanol:dichloromethane = 1:4 (v/v)) to obtain 80 mg of the title compound in a 13% yield.

¹ H-NMR (300 MHz, DMSO-d ₆ ): δ 7.69 (s, 1H), 7.51 (s, 1H), 7.25 (s, 1H), 6.50 (s, 1H), 6.29 (s, 2H), 5.42 (s, 2H), 5.41 (s, 2H), 4.24 (s, 2H), 1.86 (m, 2H), 0.88 (t, 3H).

[Step-6] Preparation of ( S )-14-(((sulfamide)amino)methyl)-7-ethyl-7-hydroxy-10,13-dihydro-11 H -[1,3]dioxolo[4,5- g ]pyrano[3',4':6,7]indolizino[1,2- b ]quinoline-8,11(7 H )-dione

( S )-14-(aminomethyl)-7-ethyl-7-hydroxy-10,13-dihydro-11 H -[1,3]dioxolo[4,5- g ]pyrano[3',4':6,7]indolizino[1,2- b ]quinoline-8,11(7 H )-dione (40 mg, 0.09 mmol) obtained in the above [Step-5] was dissolved in 10 mL of dichloromethane/dimethylacetamide (4/1), and then triethylamine (0.5 mL, 3.59 mmol) and sulfamoyl chloride (100 mg, 0.87 mmol) were slowly added dropwise at 0°C. The mixture was stirred at room temperature for 4 hours and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate: methanol = 10:1 (v/v)) to obtain 6 mg of the title compound in a 12% yield.

¹ H-NMR (300 MHz, DMSO- d ₆ ): δ 7.66 (s, 1H), 7.54 (s, 1H), 7.34 (m, 1H), 7.26 (s, 1H), 6.86 (s, 2H), 6.51 (s, 1H), 6.31 (s, 2H), 5.44 (s, 2H), 5.39 (s, 2H), 4.55 (d, 2H), 1.88 (m, 2H), 0.88 (t, 3H).

MS (ESI+, m/z): 501.1 [M+H] ⁺

[Example 6]

( S )-9-((sulfamide)amino)-4,11-diethyl-4-hydroxy-1,12-dihydro-14 H -Pyrano[3',4':6,7]Indolizino[1,2- b ]quinoline-3,14(4 H )-Manufacture of dione

[Step-1] Preparation of 1-(2-fluoro-5-nitrophenyl)propan-1-one

12 mL of sulfuric acid was cooled to -20°C, and 1-(2-fluorophenyl)propan-1-one (3 g, 19.7 mmol) and sodium nitrate (2.01 g, 23.7 mmol) were slowly added dropwise, and the mixture was stirred at -20°C for 4 hours. Ice water was added dropwise to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate: n-hexane = 1:4 (v/v)) to obtain 1.4 g of the title compound in a 36% yield.

¹ H-NMR (300 MHz, CDCl ₃ ): δ 8.79 (d, 1H), 8.41 (dd, 1H), 7.34 (t, 1H), 3.06 (q, 2H), 1.28 (t, 3H).

[Step 2] Preparation of 1-(2-amino-5-nitrophenyl)propan-1-one

1-(2-Fluoro-5-nitrophenyl)propan-1-one (1.4 g, 7.10 mmol) obtained in the above [Step-1] was dissolved in 5 mL of 1,4-dioxane, and 5 mL of ammonia water was added dropwise. The reaction solution was stirred at 60°C for 4 hours. The mixture was extracted with ethyl acetate, and the obtained organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate: n-hexane = 1:4 (v/v)) to obtain 1.3 g of the title compound in a yield of 94%.

¹ H-NMR (300 MHz, CDCl ₃ ): δ 8.78 (d, 1H), 8.15 (dd, 1H), 6.69 (d, 1H), 3.09 (q, 2H), 1.26 (t, 3H).

[Step-3] ( S )-4,11-diethyl-4-hydroxy-9-nitro-1,12-dihydro-14 H -Pyrano[3',4':6,7]Indolizino[1,2- b ]quinoline-3,14(4 H )-Manufacture of dione

1-(2-Amino-5-nitrophenyl)propan-1-one (500 mg, 2.57 mmol) and ( S )-4-ethyl-4-hydroxy-7,8-dihydroxy-1 H -pyrano[3,4- f ]indolizine-3,6,10(4 H )trione (881 mg, 3.35 mmol) obtained in the above [Step-2] were dissolved in 5 mL of toluene, and pyridinium paratoluenesulfonate (97.9 mg, 0.51 mmol) was stirred at 120°C for 14 hours. After completion of the reaction, it was cooled to room temperature and concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane:methanol = 10:1 (v/v)) to obtain 247 mg of the title compound in a yield of 23%.

¹ H-NMR (300 MHz, CDCl ₃ ): δ 9.10 (s,1H), 8.59 (d, 1H), 8.39 (d, 1H), 7.73 (s, 1H), 5.79 (d, 1H), 5.35 (d, 1H), 5.35 (s, 2H), 3.76 (s, 1H), 3.32 (q, 2H), 1.93 (m, 2H), 1.49 (t, 3H), 1.07 (t, 3H).

[Step-4]( S )-9-Amino-4,11-diethyl-4-hydroxy-1,12-dihydro-14 H -Pyrano[3',4':6,7]Indolizino[1,2- b ]quinoline-3,14(4 H )-Manufacture of dione

( S )-4,11-diethyl-4-hydroxy-9-nitro-1,12-dihydro- 14H -pyrano[3',4':6,7]indolizino[1,2- b ]quinoline-3,14( 4H ) dione (247 mg, 0.59 mmol) obtained in the above [Step-3] was dissolved in 1 mL of methanol, and 5% palladium/carbon (50 mg, 20 wt%) was added dropwise. The mixture was stirred for 15 hours under hydrogen conditions at room temperature. After the reaction was completed, the mixture was filtered through a filter filled with cellite and washed with methanol. The filtered organic layer was concentrated under reduced pressure, and the obtained residue was purified by column chromatography (dichloromethane: methanol = 10:1 (v/v)) to obtain 100 mg of the title compound in 44% yield.

¹ H-NMR (300 MHz, CDCl ₃ ): δ 8.06 (d, 1H), 7.58 (s, 1H), 7.24 (d, 1H), 7.15 (s, 1H), 5.77 (d, 1H), 5.32 (d, 1H), 5.22 (s, 2H), 4.19 (s, 2H), 3.10 (q, 2H), 1.90 (m, 2H), 1.41 (t, 3H), 1.05 (t, 3H).

[Step-5] ( S )-9-((sulfamide)amino)-4,11-diethyl-4-hydroxy-1,12-dihydro-14 H -Pyrano[3',4':6,7]Indolizino[1,2- b ]quinoline-3,14(4 H )-Manufacture of dione

( S )-9-amino-4,11-diethyl-4-hydroxy-1,12-dihydro-14 H -pyrano[3',4':6,7]indolizino[1,2- b ]quinoline-3,14(4 H )-dione (10 mg, 0.026 mmol) obtained in the above [Step-4] was dissolved in 1 mL of acetone, and triethylamine (5 mg, 0.05 mmol) and sulfamoyl chloride (9 mg, 0.076 mmol) were added dropwise at 0°C. The mixture was stirred at room temperature for 14 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, and the obtained residue was purified by column chromatography (dichloromethane: methanol = 10:1 (v/v)) to obtain 1 mg of the title compound in a yield of 7%.

¹ H-NMR (300 MHz, DMSO- d ₆ ): δ 10.10 (s, 1H), 8.10 (d, 1H), 7.88 (s, 1H), 7.68 (d, 1H), 7.41 (s, 2H), 7.27 (s, 1H), 6.51 (s, 1H), 5.43 (s, 2H), 5.3. (s, 2H), 3.16 (m, 2H), 1.86 (m, 2H), 1.32 (t, 3H), 0.88 (t, 3H).

MS (ESI+, m/z): 471.1 [M+H] ⁺

[Example 7]

( S )-9-(((sulfamide)amino)-4-ethyl-8-fluoro-4-hydroxy-1,12-dihydro-14 H -Pyrano[3',4':6,7]Indolizino[1,2- b ]quinoline-3,14(4 H )-Manufacture of dione

[Step 1] tert Preparation of butyl(2-fluoro-5-formyl-4-nitrophenyl)carbamate

5-Bromo-4-fluoro-2-nitrobenzaldehyde (5.0 g, 20.16 mmol), tert -butyl carbamate (2.8 g, 24.19 mmol), cesium carbonate (13.1 g, 40.32 mmol), Xphos (1.9 g, 4.03 mmol), and tris(dibenzylideneacetone)dipalladium(0) (226 mg, 1.01 mmol) were dissolved in 50 mL of toluene and degassed with nitrogen. The mixture was stirred at 90°C for 15 hours. After the reaction was completed, it was cooled to room temperature and water was added dropwise. The mixture was extracted twice with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate: n-hexane = 1:10 (v/v)) to obtain 3.8 g of the title compound in 66% yield.

¹ H-NMR (300 MHz, DMSO- d ₆ ): δ 10.24 (s, 1H), 9.96 (s, 1H), 8.41 (d, 1H), 8.16 (d, 1H), 1.50 (s, 9H).

[Step 2] tert - Preparation of butyl (4-amino-2-fluoro-5-formylphenyl) carbamate

tert -Butyl (2-fluoro-5-formyl-4-nitrophenyl) carbamate (3.8 g, 13.37 mmol) obtained in the above [Step-1] was dissolved in 76 mL of ethanol:water (1:1), and then ammonium chloride (1.6 g, 21.39 mmol) and iron (2.99 g, 53.48 mmol) were added dropwise. The mixture was stirred at 80°C for 3 hours. After the reaction was completed, it was cooled to room temperature. The reaction solution was filtered through a filter filled with Celite and washed with ethyl acetate. The filtered organic layer was concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate:n-hexane = 1:10 (v/v)) to obtain 2.0 g of the title compound in a 59% yield.

¹ H-NMR (300 MHz, DMSO- d ₆ ): δ 9.74 (s, 1H), 8.60 (s, 1H), 7.57 (d, 1H), 7.22 (s, 2H), 6.52 (d, 1H), 1.43 (s, 9H).

[Step 3] tert -Butyl ( S )-(4-Ethyl-8-fluoro-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1 H -Pyrano[3',4':6,7]Indolizino[1,2- b Preparation of quinolin-9-yl)carbamate

In the above [Step-2], tert -butyl(4-amino-2-fluoro-5-formylphenyl)carbamate (2.0 g, 7.87 mmol) was dissolved in 2 mL of toluene, and ( S )-4-ethyl-4-hydroxy-7,8-dihydro-1 H -pyrano[3,4- f ]indolizine-3,6,10(4 H )-trione (2.1 g, 7.87 mmol) and para-toluenesulfonic acid monohydrate (224 mg, 1.18 mmol) were added dropwise. The mixture was stirred at 110°C for 2 hours. After the reaction was completed, it was cooled to room temperature. The reaction mixture was concentrated under reduced pressure, and the obtained residue was neutralized with a saturated aqueous sodium bicarbonate solution at low temperature. This was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane: methanol = 10:1 (v/v)) to obtain 1.5 g of the title compound in a 40% yield.

¹ H-NMR (300 MHz, DMSO- d ₆ ): δ 9.50 (s, 1H), 8.67 (s, 1H), 8.44 (d, 1H), 7.99 (d, 1H), 7.32 (s, 1H), 6.55 (s, 1H), 5.43 (s, 2H), 5.27 (s, 2H), 1.87 (m, 2H), 1.50 (s, 2H), 0.87 (t, 3H).

[Step-4] ( S )-9-Amino-4-ethyl-8-fluoro-4-hydroxy-1,12-dihydroxy-14 H -Pyrano[3',4':6,7]Indolizino[1,2- b ]quinoline-3,14(4 H )-Manufacture of dione

tert -Butyl ( S )-(4-ethyl-8-fluoro-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1 H -pyrano[3',4':6,7]indolizino[1,2- b ]quinolin-9-yl)carbamate (300 mg, 0.62 mmol) obtained in the above [Step-3] was dissolved in 3 mL of dichloromethane, and 1 mL of trifluoroacetic acid was added dropwise. The reaction solution was stirred at room temperature for 3 hours. After completion of the reaction, the mixture was concentrated under reduced pressure, and the obtained residue was purified by column chromatography (dichloromethane: methanol = 10:1 (v/v)) to obtain 200 mg of the title compound in a yield of 84%.

¹ H-NMR (300 MHz, DMSO- d ₆ ): δ 8.33 (s, 1H), 7.75 (d, 1H), 7.22 (s, 1H), 5.40 (s, 1H), 5.38 (d, 1H), 5.20 (s, 2H), 1.84 (m, 2H), 0.88 (t, 3H).

[Step-5] ( S )-9-(((sulfamide)amino)-4-ethyl-8-fluoro-4-hydroxy-1,12-dihydro-14 H -Pyrano[3',4':6,7]Indolizino[1,2- b ]quinoline-3,14(4 H )-Manufacture of dione

( S )-9-amino-4-ethyl-8-fluoro-4-hydroxy-1,12-dihydroxy-14 H -pyrano[3',4':6,7]indolizino[1,2- b ]quinoline-3,14(4 H )-dione (200 mg, 0.52 mmol) obtained in the above [Step-4] was dissolved in 2 mL of dichloromethane and 1 mL of dimethylacetamide, and then triethylamine (0.15 mL, 1.05 mmol) and sulfamoyl chloride (121 mg, 1.05 mmol) were added dropwise at 0°C. The mixture was stirred at room temperature for 14 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, and the obtained residue was purified by column chromatography (dichloromethane: methanol = 10:1 (v/v)) to obtain 100 mg of the title compound in a yield of 21%.

¹ H-NMR (300 MHz, DMSO- d ₆ ): δ 8.35 (s, 1H), 7.76 (s, 1H), 7.24 (s, 1H), 6.47 (s, 1H), 5.41 (m, 2H), 5.22 (s, 2H), 1.91 (m, 2H), 0.89 (t, 3H).

MS (ESI+, m/z): 461.0 [M+H] ⁺

[Example 8]

( S )-14-(( N -((2-aminoethyl)sulfamide)amino)methyl)-7-ethyl-7-hydroxy-10,13-dihydro-11 H -[1,3]dioxolo[4,5- g ]Pyrano[3',4':6,7]Indolizino[1,2- b ]quinoline-8,11(7 H )-Manufacture of dione hydrochloride

[Step-1] Preparation of tert -butyl( S )-(2-(( N -((7-ethyl-7-hydroxy-8,11-dioxo-7,8,11,13-tetrahydro-10 H -[1,3]dioxolo[4,5- g ]pyrano[3',4':6,7]indolizino[1,2- b ]quinolin-14-yl)methyl)sulfamoyl)amino)ethyl)carbamate

tert -Butyl(2-((2-oxooxazolidine)-3-sulfonamido)ethyl)carbamate (0.5 g, 1.62 mmol) obtained in [Step-1] of Example 4 and ( S )-14-(aminomethyl)-7-ethyl-7-hydroxy-10,13-dihydro-11 H -[1,3]dioxolo[4,5- g ]pyrano[3',4':6,7]indolizino[1,2- b ]quinoline-8,11(7 H )-dione dihydrochloride (150 mg, 0.30 mmol) obtained in [Step-5] of Example 5 were dissolved in 10 mL of 1,2-dichloroethane, and then triethylamine (0.20 mL, 1.43 mmol) was added dropwise. This was stirred under reflux at 80˚C for 4 hours. After cooling to room temperature, the residue was concentrated under reduced pressure and purified by column chromatography (dichloromethane: acetone = 2:1 (v/v)) to obtain 40 mg of the title compound in a 20% yield.

¹ H-NMR (300 MHz, DMSO- d ₆ ): δ 7.75 (m, 1H), 7.65 (s, 1H), 7.53 (s, 1H), 7.26 (s, 1H), 7.16 (t, 1H), 6.82 (t, 1H), 6.49 (s, 1H), 6.31(s, 2H), 5.43(s, 2H), 5.35(s, 2H), 4.50(d, 2H), 2.96(m, 2H), 2.80(m, 2H), 1.87(m, 2H), 1.36(m, 9H), 0.88(t, 3H).

[Step-2] Preparation of ( S )-14-(( N -((2-aminoethyl)sulfamide)amino)methyl)-7-ethyl-7-hydroxy-10,13-dihydro-11 H -[1,3]dioxolo[4,5- g ]pyrano[3',4':6,7]indolizino[1,2- b ]quinoline-8,11(7 H )-dione hydrochloride

tert -Butyl ( S )-(2-(( N -((7-ethyl-7-hydroxy-8,11-dioxo-7,8,11,13-tetrahydro-10 H -[1,3]dioxolo[4,5- g ]pyrano[3',4':6,7]indolizino[1,2- b ]quinolin-14-yl)methyl)sulfamoyl)amino)ethyl)carbamate (10 mg, 0.016 mmol) obtained in the above [Step-2] was dissolved in 0.5 mL of methanol, and then 0.5 mL of 4-molecular hydrochloric acid dissolved in 1,4-dioxane was slowly added dropwise at 0˚C. The mixture was stirred at room temperature for 30 minutes, and 10 mL of dichloromethane was added dropwise. The resulting solid was filtered under reduced pressure and washed with dichloromethane to obtain 5.0 mg of the title compound in a 52% yield.

¹ H-NMR (300 MHz, DMSO- d ₆ ): δ 8.35 (brs, 1H), 8.03 (m, 5H), 7.70 (s, 1H), 7.55 (s, 1H), 7.44 (m, 1H), 7.26 (s, 1H), 6.31 (s, 2H), 5.41(d, 2H), 4.57(d, 2H), 3.07(brs, 2H), 2.90(brs, 4H), 1.89(m, 2H), 0.88(t, 3H).

MS(ESI+, m/z): 544.2 [M+H] ⁺

[Example 9]

( S )-4-( N -((2-aminoethyl)sulfamide)amino)-9-ethyl-5-fluoro-9-hydroxy-1,9,12,15-tetrahydro-13 H -Pyrano[3',4':6,7]Indolizino[1,2- b ]Thiopyrano[4,3,2- de ]quinoline-10,13(2 H )-Manufacture of dione hydrochloride

[Step-1] Preparation of tert -butyl ( S )-(2-(( N -(9-ethyl-9-hydroxy-10,13-dioxo-2,3,9,10,13,15-hexahydro-1 H ,12 H -benzo[ de ]pyrano[3',4':6,7]indolizino[1,2- b ]quinolin-4-yl)sulfamoyl)amino)ethyl)carbamate

Tert -butyl (2-((2-oxooxazolidine)-3-sulfamido)ethyl)carbamate (0.7 g, 2.28 mmol) obtained in [Step-1] of the above Example 4 and (( S )-4-amino-9-ethyl-9-hydroxy-1,9,12,15-tetrahydro-13 H -pyrano[3',4':6,7]indolizino[1,2- b ]thiopyrano[4,3,2- de ]quinoline-10,13(2 H )-dione (150 mg, 0.36 mmol) obtained in [Step-10] of Example 3 were dissolved in 5 mL of 1,2-dichloroethane, and then triethylamine (0.35 mL, 2.86 mmol) was added dropwise. The mixture was refluxed at 100°C for 2 hours. The mixture was stirred. After cooling to room temperature, the residue was concentrated under reduced pressure and purified by column chromatography (dichloromethane: acetone = 2:1 (v/v)) to obtain 200 mg of the title compound in 87% yield.

¹ H-NMR (300 MHz, DMSO- d ₆ ): δ 9.12 (brs, 1H), 7.66 (m, 2H), 7.32 (s, 2H), 6.52 (s, 1H) 5.75 (s, 2H), 5.44 (s, 2H), 5.27 (s, 2H), 3.22(m, 2H), 3.05(m, 4H), 1.88(m, 2H), 1.37(s, 9H), 0.89(t, 3H).

[Step-2] ( S )-4-( N -((2-aminoethyl)sulfamide)amino)-9-ethyl-5-fluoro-9-hydroxy-1,9,12,15-tetrahydro-13 H -Pyrano[3',4':6,7]Indolizino[1,2- b ]Thiopyrano[4,3,2- de ]quinoline-10,13(2 H )-Manufacture of dione hydrochloride

tert -Butyl( S )-(2-(( N -(9-ethyl-9-hydroxy-10,13-dioxo-1,2,9,10,13,15-hexahydro-12 H -pyrano[3',4':6,7]indolizino[1,2- b ]thiopyrano[4,3,2- de ]quinolin-4-yl)sulfamoyl)amino)ethyl)carbamate (10 mg, 0.015 mmol) obtained in the above [Step-1] was dissolved in 0.5 mL of methanol, and then 0.5 mL of 4 molar concentration hydrochloric acid dissolved in 1,4-dioxane was slowly added dropwise at 0˚C. The mixture was stirred at room temperature for 30 minutes, and 10 mL of dichloromethane was added dropwise. The resulting solid was filtered under reduced pressure and washed with dichloromethane to obtain 6.0 mg of the title compound in a 63% yield.

¹ H-NMR (300 MHz, DMSO- d ₆ ): δ 9.32 (s, 1H), 7.88 (m, 5H), 7.60 (t, 1H), 7.33 (s, 1H), 5.45 (s, 2H) 5.30 (s, 2H), 3.70 (s, 2H), 3.25(m, 2H), 2.95(m, 4H), 1.90(m, 2H), 0.89(t, 3H).

MS(ESI+, m/z): 544.1 [M+H] ⁺

[Example 10]

( S )-9- N -((2-aminoethyl)sulfamide)amino)-4-ethyl-8-fluoro-4-hydroxy-1,12-dihydro-14 H -Pyrano[3',4':6,7]Indolizino[1,2- b ]quinoline-3,14(4 H )-Manufacture of dione hydrochloride

[Step 1] tert -Butyl ( S )-(2-(( N -(4-Ethyl-8-fluoro-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1 H -Pyrano[3',4':6,7]Indolizino[1,2- b Preparation of ]quinolin-9-yl)sulfamoyl)amino)ethyl)carbamate

Tert -Butyl(2-((2-oxooxazolidine)-3-sulfamido)ethyl)carbamate (1.0 g, 3.23 mmol) obtained in [Step-1] of Example 4 and ( S )-9-amino-4-ethyl-8-fluoro-4-hydroxy-1,12-dihydroxy-14 H -pyrano[3',4':6,7]indolizino[1,2- b ]quinoline-3,14(4 H )-dione (200 mg, 0.52 mmol) obtained in [Step-5] of Example 7 were dissolved in 30 mL of 1,2-dichloroethane, and then triethylamine (2.0 mL, 14.35 mmol) was added dropwise. The mixture was stirred under reflux at 100˚C for 4 hours. After cooling to room temperature, the residue was concentrated under reduced pressure and purified by column chromatography (ethyl acetate 100%) to obtain 250 mg of the title compound in a 79% yield.

¹ H-NMR (300 MHz, DMSO- d ₆ ): δ 10.10(brs, 1H), 8.60(s, 1H), 8.06(d, 1H), 8.00(d, 1H), 7.82(brs, 1H),7.32(s, 1H), 6.77(brs, 1H), 6.52(s, 1H), 5.44(s, 2H), 5.28(s, 2H), 2.98(m, 4H), 1.88(m, 2H), 1.31(m, 9H), 0.89(t, 3H).

[Step-2] Preparation of ( S )-9- N -((2-aminoethyl)sulfamide)amino)-4-ethyl-8-fluoro-4-hydroxy-1,12-dihydro-14 H -pyrano[3',4':6,7]indolizino[1,2- b ]quinoline-3,14(4 H )-dione hydrochloride

tert -Butyl( S )-(2-(( N -(4-ethyl-8-fluoro-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1 H -pyrano[3',4':6,7]indolizino[1,2- b ]quinolin-9-yl)sulfamoyl)amino)ethyl)carbamate (250 mg, 0.41 mmol) obtained in the above [Step-1] was dissolved in 2.0 mL of methanol, and then 2.0 mL of 4 molar concentration hydrochloric acid dissolved in 1,4-dioxane was slowly added dropwise at 0˚C. The mixture was stirred at room temperature for one hour, and 50 mL of dichloromethane was added dropwise. The resulting solid was filtered under reduced pressure and washed with dichloromethane to obtain 70 mg of the title compound in a 30% yield.

¹ H-NMR (300 MHz, DMSO- d ₆ ): δ 10.20 (s, 1H), 8.66 (s, 1H), 8.17 (m, 3H), 8.02 (m, 4H), 7.33 (s, 1H), 5.44 (s, 2H) 5.29 (s, 2H), 3.20(m, 2H), 2.93(m, 2H), 1.90(m, 2H), 0.89(t, 3H).

MS(ESI+, m/z): 504.1 [M+H] ⁺

[Example 11]

( S )-9- N -((2-(methylamino)ethyl)sulfamide)amino)-4-ethyl-8-fluoro-4-hydroxy-1,12-dihydro-14 H -Pyrano[3',4':6,7]Indolizino[1,2- b ]quinoline-3,14(4 H )-Manufacture of dione hydrochloride

[Step 1] tert -Butyl ( S )-(2-(( N -(4-Ethyl-8-fluoro-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1 H -Pyrano[3',4':6,7]Indolizino[1,2- b Preparation of ]quinolin-9-yl)sulfamoyl)amino)ethyl)(methyl)carbamate

Tert -Butyl(2-((2-oxooxazolidine)-3-sulfamido)ethyl)carbamate (450 mg, 1.39 mmol) obtained in [Step-1] of Example 4 and ( S )-9-amino-4-ethyl-8-fluoro-4-hydroxy-1,12-dihydro-14 H -pyrano[3',4':6,7]indolizino[1,2- b ]quinoline-3,14(4 H )-dione (70 mg, 0.18 mmol) obtained in [Step-5] of Example 7 were dissolved in 10 mL of 1,2-dichloroethane, and then triethylamine (1.0 mL, 7.17 mmol) was added dropwise. The mixture was stirred under reflux at 100˚C for 1 hour. After cooling to room temperature, the residue was concentrated under reduced pressure and purified by column chromatography (ethyl acetate 100%) to obtain 50 mg of the title compound in a 44% yield.

[Step-2] Preparation of ( S )-9- N -((2-(methylamino)ethyl)sulfamide)amino)-4-ethyl-8-fluoro-4-hydroxy-1,12-dihydro-14 H -pyrano[3',4':6,7]indolizino[1,2- b ]quinoline-3,14(4 H )-dione hydrochloride

tert -Butyl( S )-(2-(( N -(4-ethyl-8-fluoro-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1 H -pyrano[3',4':6,7]indolizino[1,2- b ]quinolin-9-yl)sulfamoyl)amino)ethyl)(methyl)carbamate (50 mg, 0.081 mmol) obtained in the above [Step-1] was dissolved in 1.0 mL of 1,4-dioxane, and then 1.0 mL of 4 molar concentration hydrochloric acid dissolved in 1,4-dioxane was slowly added dropwise at 0˚C. The mixture was stirred at room temperature for one hour, and 10 mL of dichloromethane was added dropwise. The resulting solid was filtered under reduced pressure and washed with dichloromethane to obtain 3 mg of the title compound in a 5% yield.

¹ H-NMR (300 MHz, DMSO- d ₆ ): δ 10.20 (brs, 1H), 8.87 (brs, 1H), 8.66 (s, 1H), 8.34 (s, 1H), 8.17 (m, 1H), 8.02 (d, 1H), 7.77 (d, 1H), 7.25(d, 1H), 7.17(d, 1H), 5.44(d, 2H), 5.25(d, 2H), 3.33(s, 3H), 3.26(m, 2H), 3.03(m, 2H), 1.88(m, 2H), 0.88(t, 3H).

MS(ESI+, m/z): 518.2 [M+H] ⁺

[Example 12]

( S )-4-ethyl-hydroxy-11-((2-isopropylsulfamide)amino)ethyl)-1,12-dihydro-14- H -Pyrano[3',4':6,7]Indolizino[1,2- b ]quinoline-3,14(4 H )-Manufacture of dione

( S )-4-Ethyl-4-hydroxy-11-(2-isopropylamino)ethyl)-1,12-dihydro-14- H -pyrano[3',4':6,7]indolizino[1,2- b ]quinoline-3,14(4 H )-dione (100 mg, 0.21 mmol) was dissolved in 2 mL of dichloromethane and 1 mL of dimethylacetamide, and then triethylamine (3 mL) and sulfamoyl chloride (400 mg, 3.46 mmol) were added dropwise at 0˚C. The mixture was stirred at 25˚C for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, and the obtained residue was purified by column chromatography (ethyl acetate: acetone = 1:1 (v/v)) to obtain 35 mg of the title compound in a 30% yield.

¹ H-NMR (300 MHz, DMSO- d ₆ ): δ 8.37(d, 1H), 8.20(d, 1H), 7.89(t, 1H), 7.78(t, 1H), 7.36(s, 1H), 6.82(s, 2H), 6.53(1H, s), 5.45(s, 2H), 5.42(s, 2H), 3.91(t, 2H), 3.05-3.08(m, 3H), 1.86(m, 2H), 1.01(d,6H), 0.89(t, 3H).

MS(ESI+, m/z): 513.2 [M+H] ⁺

[Experimental Example 1] Cell growth inhibition test of compounds

To evaluate whether the aforementioned compounds inhibit cell growth, MDA-MB-468 cells, a HER2-negative breast cancer cell line, and NCI-N87 cells, a HER2-positive gastric cancer cell line, were treated and cell growth was observed. Sulforhodamine B (SRB) staining was used to evaluate cell growth. This staining method involves fixing cells, specifically staining living cells with SRB, and measuring the absorbance of the cells.

Specifically, NCI-N87 cells were cultured in a 96-well plate at a concentration of 5.0 × 10 ³ /100 μL or MDA-MB-468 cells at a concentration of 7.0 × 10 ³ /100 μL for 16 hours, and then the cells were treated with the corresponding example compound diluted to a set concentration (1,000 to 0.0128 nM, serially diluted by 1/5). At this time, some of the cultured cells were fixed with 10% trichloroacetic acid and used to measure the cell number before treatment with the example compound (Seeding Control). After drug treatment, NCI-N87 cells were cultured for 7 days, and MDA-MB-468 cells were cultured for 5 days. The culture medium was removed, the cells were fixed by treatment with 10% trichloroacetic acid, and the fixed cells were stained with 0.4% SRB dye. After washing with 1% acetic acid aqueous solution, the SRB dye was dissolved in 10 mM Tris base solution. The absorbance of the dissolved SRB was measured at a wavelength of 540 nm using a microplate reader.

The cell growth after drug treatment was evaluated by subtracting the absorbance value of the number of cells before test drug treatment from the measured absorbance. The relative cell growth rate (%) was evaluated by standardizing the absorbance of the untreated group, which is the control group for cell growth, and the cell growth inhibition concentration (IC ₅₀ ), which is the concentration that inhibits cell growth by 50% of each compound, was calculated using Microsoft Standard Excel 2013 software. The cell growth inhibition ability of the example compounds as a result is shown in Table 1 below. In Table 1 below, when the cell growth IC ₅₀ value is 50 nM or less, it is graded as A, when it is more than 50 nM and less than 100 nM, it is graded as B, and when it is more than 100 nM, it is graded as C. In Table 1, - indicates that it was not measured.

[Experimental Example 2] Solubility Test

A solubility comparison test was performed on the compounds prepared in Examples 1, 4, 7, 8, 9, and 10 and Deruxtecan (DXd), a representative material compound of topoisomerase I inhibitor. DXd and each of the compounds of these examples were prepared as samples in deionized water (DW) or phosphate buffered saline (PBS) buffer under the conditions below, and each solution was analyzed by high-performance liquid chromatography (HPLC) according to the compound content measurement conditions to measure the dissolved amount based on the compound, and the values were converted and the results are shown in Tables 2 and 3 below.

Specifically, 1 mg of each example compound or DXd was added to 1 mL of deionized water (DW) or PBS buffer and mixed at 25˚C using a Thermomixer comfort ^TM (Eppendorf, Germany) or a constant temperature shaking incubator (MBR-024, Taitec, Japan) at 25˚C or 37˚C, and the mixed solution was filtered using a GH Polypro membrane Acrodisc ^® filter (PALL, USA) with a pore size of 0.2 μm, and the resulting filtrate was diluted with a dilution solvent for high-performance liquid chromatography analysis.

As shown in Table 2 above, the compounds of Examples 1, 4, and 7 exhibited higher solubility overall compared to the solubility of DXd. In particular, the compound of Example 4 exhibited a high solubility of 3008.1 μM under deionized water conditions at 25˚C, and also exhibited excellent solubility of 1764.1 μM under buffer conditions at 37˚C.

As shown in Table 3 above, the compounds of Examples 8 and 9 showed higher solubility overall compared to the solubility of DXd. In particular, the compound of Example 9 showed a high solubility of 2377.5 μM under deionized water conditions at 25˚C, and also showed excellent solubility of 1256.9 μM under buffer conditions at 37˚C. In particular, the compounds of Examples 4, 7, and 9 showed significantly higher solubility than the solubility of DXd (9.8 μM and 41.8 μM) even under similar pH conditions, suggesting the possibility that the compounds may have improved physical and chemical properties.

[Experimental Example 3] Partition coefficient (Log D)

In order to confirm the lipid-soluble and water-soluble properties of the compounds prepared in Examples 4, 7, 9, and 10 and the comparative substance DXd, the partition coefficient (LogD _7.4 ) between n-octanol/buffer solution (pH 7.4) was measured using a shaking flask method. DXd and the compounds of the examples, respectively, were prepared in buffer solution (pH 7.4), standard solution, and test solution under the following conditions, and the results were confirmed by analyzing them using high-performance liquid chromatography (HPLC) according to the compound content measurement conditions.

Specifically, a buffer solution of pH 7.4 was prepared by diluting 4.0 mL of a 500 mM PBS stock solution with deionized water to a total volume of 100 mL, and the final concentration was 20 mM. The standard solution was prepared by taking a fixed amount of each compound, placing it in a 20 mL glass vial, adding a specified amount of dilution solvent, and then sonicating it to prepare a homogeneous solution. The test solution for measuring LogD _7.4 was prepared as follows. Approximately 1 mg of each compound was placed in a 20 mL vial, 2 mL of octanol was added, and the solution was shaken for 0.5 hour. The solution was then filtered through a 0.2 μm filter. The filtered solution was dispensed at a total volume of 0.9 mL by setting the mixing ratio of octanol:PBS (pH 7.4) to 1:2, 1:1, and 2:1. The mixed solution was shaken again for 0.5 h, then centrifuged at 4000 rpm for 5 minutes to collect the upper (n-octanol) and lower (PBS) layers, respectively. The octanol layer was diluted 1/20 with acetonitrile, and the PBS layer was subjected to HPLC analysis undiluted.

Compounds of Examples 4, 7, 9 and 10 showed a lower LogD value _{of 7.4 compared} to that of DXd, indicating that their water solubility was greatly improved, suggesting that these compounds may have improved physicochemical properties.

Although the present invention has been described through limited embodiments as described above, the technical idea and scope of the present invention are not limited to these embodiments, and the invention of the patent claims described below, as well as various modifications or variations of the invention described in the patent claims that are obvious to a person having ordinary skill in the art to which the present invention pertains, are also included in the scope of the present invention within the equivalent scope of the invention described in the patent claims.

Claims (5)

A compound of formula 1 or a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: [Chemical Formula 1] In chemical formula 1 (1) A ¹ is CH ₂ , CHX ¹ , CX ¹ X ² , O, S or NH, A ² is CH ₂ , O, S, S=O, S(=O) ₂ or NH, A ³ is a chemical bond or CH ₂ , and in A ¹ , A ² and A ³ The symbols indicate that A ¹ and A ³ , A ² and A ³ are directly connected by a single bond, Z ¹ is NHS(=O) ₂ , Z ² is H or halogen, Z ³ is NH ₂ or NHQ ¹ NH ₂ , and the bond between Z ¹ and Z ³ The symbol indicates that the sulfur of Z ¹ and Z ³ are directly connected by a single bond, and that between Z ² and Z ³ The symbol indicates that Z ² and Z ³ are not directly connected by a bond, X ¹ and X ² are each independently selected halogen, and Q ¹ is C _1~4 alkylene; or (2) A ¹ is Q ¹ , A ² is H, A ³ is H, CF ₃ or OH, and in A ¹ , A ² and A ³ The symbol indicates that A ¹ and A ³ are directly connected by a single bond and that A ² and A ³ are not directly connected by a bond, Z ¹ is NHS(=O) ₂ , Z ² is H or halogen, Z ³ is NH ₂ or NHQ ² NH ₂ , and the bond between Z ¹ and Z ³ The symbol indicates that the sulfur of Z ¹ and Z ³ are directly connected by a single bond, and that between Z ² and Z ³ The symbol indicates that Z ² and Z ³ are not directly connected by a bond, and Q ¹ and Q ² are independently selected C _1~4 alkylene; or (3) A ¹ and A ² are H, A ³ is absent, and in A ¹ , A ² and A ³ The notation indicates that there is no direct bond between A ¹ and A ³ , and also between A ² and A ³ , Z ¹ is NHS(=O) ₂ , Z ² is H or halogen, and Z ³ is NH ₂ , NHQ ¹ NH ₂ , NHQ ¹ NHR ² , NR ¹ Q ¹ NH ₂ or NR ¹ Q ¹ NHR ² , and between Z ¹ and Z ³ The symbol indicates that the sulfur of Z ¹ and Z ³ are directly connected by a single bond, and that between Z ² and Z ³ The symbol indicates that Z ² and Z ³ are not directly connected by a bond, Q ¹ is C _1~4 alkylene, R ¹ and R ² are each independently C _1~4 alkyl; or (4) A ¹ is Q ¹ , A ² is H, A ³ is NHS(=O) ₂ NH ₂ , NQ ³ S(=O) ₂ NH ₂ or NHS(=O) ₂ NHQ ² NH ₂ , and in A ¹ , A ² and A ³ The symbol indicates that A ¹ and A ³ are directly connected by a single bond and that A ² and A ³ are not directly connected by a bond, Z ¹ is H, Z ² is H or halogen, Z ³ is absent, and between Z ¹ and Z ³ The symbol indicates that Z ¹ and Z ³ are not directly connected by a bond, and that there is a bond between Z ² and Z ^3. The symbol indicates that Z ² and Z ³ are not directly connected by a bond, Q ¹ and Q ² are each independently selected C _1~4 alkylene, and Q ³ is C _1~4 alkyl; or (5) A ¹ is Q ¹ , A ² is H, A ³ is NHS(=O) ₂ NH ₂ , NQ ³ S(=O) ₂ NH ₂ or NHS(=O) ₂ NHQ ² NH ₂ , and in A ¹ , A ² and A ³ The symbol indicates that A ¹ and A ³ are directly connected by a single bond and that A ² and A ³ are not directly connected by a single bond, Z ¹ is O, S or NH, Z ² is O, S or NH, Z ³ is CH ₂ , and between Z ¹ and Z ³ The symbol indicates that Z ¹ and Z ³ are directly connected by a single bond, and that between Z ² and Z ³ The symbol indicates that Z ² and Z ³ are directly connected by a single bond, Q ¹ and Q ² are independently selected C _1~4 alkylene, and Q ³ is C _1~4 alkyl; or (6) A ¹ is Q ¹ , A ² is H, A ³ is NHS(=O) ₂ NH ₂ , NQ ³ S(=O) ₂ NH ₂ or NHS(=O) ₂ NHQ ² NH ₂ , and in A ¹ , A ² and A ³ The symbol indicates that A ¹ and A ³ are directly connected by a single bond and that A ² and A ³ are not directly connected by a bond, Z ³ is CH, Q ¹ and Q ² are each independently selected C _1~4 alkylene, and Q ³ is C _1~4 alkyl, a. When Z ¹ is N and Z ² is O, S or NH, between Z ¹ and Z ³ The symbol indicates that Z ¹ and Z ³ are directly connected by a double bond, and that between Z ² and Z ³ The symbol indicates that Z ² and Z ³ are directly connected by a single bond, B. When Z ² is N and Z ¹ is O, S or NH, between Z ¹ and Z ³ The symbol indicates that Z ¹ and Z ³ are directly connected by a single bond, and that between Z ² and Z ³ The symbol indicates that Z ² and Z ³ are directly connected by a double bond. A compound characterized in that in claim 1, A ¹ and A ³ are CH ₂ and Z ³ is NH ₂ or NHCH ₂ CH ₂ NH ₂ . A compound characterized in that in claim 1, A ¹ is CH ₂ , A ² is H, and A ³ is NHS(=O) ₂ NH ₂ . Any one compound selected from the group consisting of the following compounds, a stereoisomer, a tautomer, a solvate or a pharmaceutically acceptable salt thereof: ( S )-4-((sulfamide)amino)-9-ethyl-9-hydroxy-1,2,3,9,12,15-hexahydro-10 H ,13 H -benzo[ de ]pyrano[3',4':6,7]indolizino[1,2- b ]quinoline-10,13-dione, ( S )-4-((sulfamide)amino)-9-ethyl-9-hydroxy-1,9,12,15-tetrahydro-13 H -pyrano[4,3,2- de ]pyrano[3',4':6,7]indolizino[1,2- b ]quinoline-10,13-dione, ( S )-4-((sulfamide)amino)-9-ethyl-9-hydroxy-1,9,12,15-tetrahydro-13 H -pyrano[3',4':6,7]indolizino[1,2- b ]thiopyrano[4,3,2- de ]quinoline-10,13(2 H )-dione, ( S )-4-((((2-aminoethyl)amino)sulfamide)amino)-9-ethyl-9-hydroxy-1,2,3,9,12,15-hexahydro-10 H ,13 H -benzo[ de ]pyrano[3',4':6,7]indolizino[1,2- b ]quinoline-10,13-dione, ( S )-14-(((sulfamide)amino)methyl)-7-ethyl-7-hydroxy-10,13-dihydro-11 H -[1,3]dioxolo[4,5- g ]pyrano[3',4':6,7]indolizino[1,2 -b ]quinoline-8,11(7 H )-dione, ( S )-9-((sulfamide)amino)-4,11-diethyl-4-hydroxy-1,12-dihydro-14 H -pyrano[3',4':6,7]indolizino[1,2- b ]quinoline-3,14(4 H )-dione, ( S )-9-(((sulfamide)amino)-4-ethyl-8-fluoro-4-hydroxy-1,12-dihydro-14 H -pyrano[3',4':6,7]indolizino[1,2- b ]quinoline-3,14(4 H )-dione, ( S )-14-(( N -((2-aminoethyl)sulfamide)amino)methyl)-7-ethyl-7-hydroxy-10,13-dihydro-11 H -[1,3]dioxolo[4,5- g ]pyrano[3',4':6,7]indolizino[1,2- b ]quinoline-8,11(7 H )-dione, ( S )-4-( N -((2-aminoethyl)sulfamide)amino)-9-ethyl-5-fluoro-9-hydroxy-1,9,12,15-tetrahydro-13 H -pyrano[3',4':6,7]indolizino[1,2- b ]thiopyrano[4,3,2- de ]quinoline-10,13(2 H )-dione, ( S )-9- N -((2-aminoethyl)sulfamide)amino)-4-ethyl-8-fluoro-4-hydroxy-1,12-dihydro-14 H -pyrano[3',4':6,7]indolizino[1,2- b ]quinoline-3,14(4 H )-dione, ( S )-9- N -((2-(methylamino)ethyl)sulfamide)amino)-4-ethyl-8-fluoro-4-hydroxy-1,12-dihydro-14 H -pyrano[3',4':6,7]indolizino[1,2- b ]quinoline-3,14(4 H )-dione and ( S )-4-Ethyl-hydroxy-11-((2-isopropylsulfamide)amino)ethyl)-1,12-dihydro-14- H -pyrano[3',4':6,7]indolizino[1,2- b ]quinoline-3,14(4 H )-dione. A pharmaceutical composition for the treatment of cancer comprising a therapeutically effective amount of a compound according to claim 1 and a pharmaceutically acceptable excipient.