KR20230140396A - Novel compound for inhibition or selective degradation of nuclear receptor - Google Patents

Abstract

The present invention relates to novel compounds, stereoisomers thereof, or pharmaceutically acceptable salts thereof that bind to and inhibit nuclear receptors or selectively decompose nuclear receptors. The compounds of the present invention can be used for the prevention or treatment of nuclear receptor-related diseases or lipid metabolism diseases.

Description

Novel compounds that induce inhibition or degradation of nuclear receptors {NOVEL COMPOUND FOR INHIBITION OR SELECTIVE DEGRADATION OF NUCLEAR RECEPTOR}

The present invention relates to novel compounds, stereoisomers thereof, or pharmaceutically acceptable salts thereof that bind to and inhibit nuclear receptors or selectively decompose nuclear receptors. The compounds of the present invention can be used for the prevention or treatment of nuclear receptor-related diseases or lipid metabolism diseases.

PROTAC stands for proteolysis targeting chimera and induces intracellular protein hydrolysis to selectively remove unwanted proteins. Protac is a heterodimeric molecule in which the ligand of the target protein and the ligand that binds to E3 ligase are connected through a linker. ProTac binds to both proteins simultaneously, bringing the target protein very close to the E3 ligase. Through this, the E3 ligase recognizes the target protein as a substrate, leading to polyubiquitination and subsequent proteasomal degradation.

Meanwhile, conventional nuclear receptor inhibitors have the problem of eventually developing resistance as amplification or mutation of nuclear receptor genes is observed as the disease progresses.

Under this background, there is a continuous need for the development of drugs that can improve the shortcomings of existing inhibitors while providing excellent therapeutic effects in the treatment of diseases targeting nuclear receptors.

Korean Patent Publication No. 10-2019-0055260

The purpose of the present invention is to provide novel compounds that have the ability to bind to nuclear receptors.

Another object of the present invention is to provide a novel chimeric compound capable of selectively degrading nuclear receptors.

Another object of the present invention is to provide a pharmaceutical composition for preventing or treating nuclear receptor-related diseases or lipid metabolism diseases containing the chimeric compound.

Another object of the present invention is to provide a method for preventing or treating nuclear receptor-related diseases or lipid metabolism diseases, including the step of administering the pharmaceutical composition to an individual.

One aspect of the present invention for achieving the above object relates to a compound represented by the following formula (1), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[Formula 1]

Wherein R ₁ is -H, -CH ₂ CH ₂ OH or ego,

Above R ₂ is -H, , , , , , , and It is selected from the group consisting of.

In the present invention, the pharmaceutically acceptable salt is not particularly limited as long as it is commonly used in the art, and specific examples include non-toxic inorganic acids such as hydrochloric acid, hydrobromic acid, sulfonic acid, amidosulfuric acid, phosphoric acid, and nitric acid. Salts can be formed using non-toxic organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, tartaric acid, citric acid, p-toluenesulfonic acid, and methanesulfonic acid. In addition, sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, iodide, fluoride, acetate, Propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, Maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methyl benzoate, dinitro benzoate, hydroxybenzoate, methoxybenzoate, phthalate, terelate. Phthalate, benzenesulfonate, toluenesulfonate, chlorobenzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, malate, tartrate, It may include methanesulfonate, propane sulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate, etc.

Specifically, the compound represented by Formula 1 may be one or more selected from the group consisting of Formulas 2 to 10 below, but is not limited thereto.

[Formula 2]

[Formula 3]

[Formula 4]

[Formula 5]

[Formula 6]

[Formula 7]

[Formula 8]

[Formula 9]

[Formula 10]

Also specifically, the compound represented by Formula 1 is:

(4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(5-hydroxynaphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6, 6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide,

(4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(6-hydroxynaphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6, 6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide,

(4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(7-hydroxynaphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6, 6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide,

(4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(5-methoxynaphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6, 6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide,

(4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(6-methoxynaphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6, 6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide,

2-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b ,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamido)-2-methylpropanoic acid,

(4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl-N-(2-methyl-1-(methylamino)-1-oxopropan-2-yl)-2-oxo- 2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide ,

(4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-ethyl-N-(2-hydroxyethyl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6, 6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide; and

(4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(1-hydroxy-2-methylpropan-2-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b, 5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide selected from the group consisting of There may be more than one, but it is not limited thereto.

Additionally, specifically, the compound represented by Formula 1 may bind to a nuclear receptor.

In the present invention, the nuclear receptor (NR) is a protein that serves to accept steroid hormones or thyroid hormones within cells. It regulates gene expression by directly binding to DNA, and is a type of transcription factor that is activated by a ligand through a ligand-receptor reaction.

The nuclear receptor (NR) superfamily includes the mineralocorticoid receptor (MR) (or aldosterone receptor), estrogen receptor (ER), androgen receptor (AR), progesterone receptor (PR), and glucocorticoid receptor (GR). , which includes the steroid nuclear receptor superfamily. Specifically, the nuclear receptor of the present invention may be an androgen receptor, but is not limited thereto.

These nuclear receptors perform important functions in the body, some of which are involved in transcriptional homeostasis, including electrolyte and water balance, growth, development and wound healing, fertility, stress response, immunological and cognitive functions. .

Another aspect of the present invention relates to a compound represented by the following formula (A), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. This is a chimeric compound in which a linker and a ULM (E3 ubiquitin ligase binding moiety) are connected to the compound represented by Chemical Formula 1 above.

[Formula A]

The R ₁ is -H or -CH ₂ CH ₃ ,

The R ₃ is , , , , , and It is selected from the group consisting of,

The ULM is a VHL E3 ubiquitin ligase binding moiety,

The Linker is It is a group that chemically connects ULM and is bonded to the -OH portion of R ₃ .

Specifically, the VHL E3 ubiquitin ligase binding moiety may be represented by the following formula B, but is not limited thereto.

[Formula B]

In Formula B,

is a 5-membered heteroaryl ring, and Y ₁ is hydrogen or C _1-3 alkyl.

Also specifically, the Linker may be represented by the formula L below.

[Formula L]

In the formula L , and is a combination,

L _{Formula A} is connected to this Combined with formula A through,

L _ULM is connected to this Combined with the ULM moiety through,

L _ULM and L _PTM are each independently a single bond, -CH ₂ -, -NH-, -O-, -CO-, -OCO-, -CONH- or -NHCO-,

L _INT is -CH ₂ -, -CH ₂ CH ₂ -, -CHCH-, -CC-, -CH ₂ CH ₂ O-, -OCH ₂ CH ₂ -, -CH ₂ CH ₂ S-, -SCH ₂ CH ₂ -, -COO-, -CONH-, -NHCO- and is selected from the group consisting of (here, is a ring selected from the group consisting of 3- to 10-membered cycloalkyl, 4- to 10-membered heterocycloalkyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl), and p is an integer of 1 to 10.

Additionally, specifically, the compound represented by Formula A may be one or more selected from the group consisting of the following Formulas A-1 to A-31, but is not limited thereto.

[Formula A-1]

[Formula A-2]

[Formula A-3]

[Formula A-4]

[Formula A-5]

[Formula A-6]

[Formula A-7]

[Formula A-8]

[Formula A-9]

[Formula A-10]

[Formula A-11]

[Formula A-12]

[Formula A-13]

[Formula A-14]

[Formula A-15]

[Formula A-16]

[Formula A-17]

[Formula A-18]

[Formula A-19]

[Formula A-20]

[Formula A-21]

[Formula A-22]

[Formula A-23]

[Formula A-24]

[Formula A-25]

[Formula A-26]

[Formula A-27]

[Formula A-28]

[Formula A-29]

[Formula A-30]

[Formula A-31]

Also specifically, the compound represented by Formula A is,

(4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(1-(2-(((S)-1-((2S,4R)-4-hydroxy-2-((4- (4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-2-oxoethoxy)- 2-methylpropan-2-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradeca Hydro-1H-indeno[5,4-f]quinoline-7-carboxamide,

(4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(1-(3-(((S)-1-((2S,4R)-4-hydroxy-2-((4- (4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-3-oxopropoxy)- 2-methylpropan-2-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradeca Hydro-1H-indeno[5,4-f]quinoline-7-carboxamide,

(4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(5-(2-(((S)-1-((2S,4R)-4-hydroxy-2-((4- (4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-2-oxoethoxy)naphthalene -1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H- Indeno[5,4-f]quinoline-7-carboxamide,

(4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(5-(3-(((S)-1-((2S,4R)-4-hydroxy-2-((4- (4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-3-oxopropoxy)naphthalene -1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H- Indeno[5,4-f]quinoline-7-carboxamide,

(4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(5-(4-(((S)-1-((2S,4R)-4-hydroxy-2-((4- (4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-4-oxobutoxy)naphthalene -1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H- Indeno[5,4-f]quinoline-7-carboxamide,

(4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(5-(2-(2-(((S)-1-((2S,4R)-4-hydroxy-2-( (4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-2-oxo Toxy)ethoxy)naphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a- Tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide,

(4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(5-(3-(2-(((S)-1-((2S,4R)-4-hydroxy-2-( (4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-2-oxo Toxy)propoxy)naphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a- Tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide,

(4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(5-(2-(2-(2-(((S)-1-((2S,4R)-4-hydroxy- 2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-2 -oxoethoxy)ethoxy)ethoxy)naphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b, 10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide,

2-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b ,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamido)-2-methylpropyl 7-(((S)-1-((2S,4R )-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutane-2 -yl)amino)-7-oxoheptanoate,

2-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b ,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamido)-2-methylpropyl 12-(((S)-1-((2S,4R )-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutane-2 -yl)amino)-12-oxododecanoate,

8-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidine-1- yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-8-oxooctyl 2-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl- 2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7 -carboxamido)-2-methylpropanoate,

12-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidine-1- Il)-3,3-dimethyl-1-oxobutan-2-yl)amino)-12-oxododecyl 2-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl -2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline- 7-carboxamido)-2-methylpropanoate,

10-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidine-1- yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-10-oxodecyl 2-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl- 2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7 -carboxamido)-2-methylpropanoate,

2-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-ethyl-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9 ,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamido)ethyl 7-(((S)-1-((2S,4R )-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutane-2 -yl)amino)-7-oxoheptanoate,

2-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-ethyl-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9 ,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamido)ethyl 12-(((S)-1-((2S,4R )-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutane-2 -yl)amino)-12-oxododecanoate,

(4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-((S)-14-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazole- 5-yl)benzyl)carbamoyl)pyrrolidine-1-carbonyl)-2,15,15-trimethyl-3,12-dioxo-7,10-dioxa-4,13-diazahexadecane- 2-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H- No[5,4-f]quinoline-7-carboxamide,

(4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(1-((2-(2-(((S)-1-((2S,4R)-4-hydroxy-2- ((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-2-oxo Ethoxy)ethyl)amino)-2-methyl-1-oxopropan-2-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9, 9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide,

(4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-((S)-14-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazole- 5-yl)benzyl)carbamoyl)pyrrolidine-1-carbonyl)-2,15,15-trimethyl-3,12-dioxo-7,10-dioxa-4,13-diazahexadecane- 2-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H- No[5,4-f]quinoline-7-carboxamide,

(4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(5-((8-(((S)-1-((2S,4R)-4-hydroxy-2-((4 -(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-8-oxooctyl)oxy )naphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro- 1H-indeno[5,4-f]quinoline-7-carboxamide,

(4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(5-((7-(((S)-1-((2S,4R)-4-hydroxy-2-((4 -(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-7-oxoheptyl)oxy )naphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro- 1H-indeno[5,4-f]quinoline-7-carboxamide,

(4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(5-((12-(((S)-1-((2S,4R)-4-hydroxy-2-((4 -(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-12-oxododecyl) Oxy)naphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro -1H-indeno[5,4-f]quinoline-7-carboxamide,

(4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(5-((10-(((S)-1-((2S,4R)-4-hydroxy-2-((4 -(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-10-oxodecyl)oxy )naphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro- 1H-indeno[5,4-f]quinoline-7-carboxamide,

(4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(5-((11-(((S)-1-((2S,4R)-4-hydroxy-2-((4 -(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-11-oxoundecyl) Oxy)naphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro -1H-indeno[5,4-f]quinoline-7-carboxamide,

(4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(5-((9-(((S)-1-((2S,4R)-4-hydroxy-2-((4 -(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-9-oxononyl) Oxy)naphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro -1H-indeno[5,4-f]quinoline-7-carboxamide,

(4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(7-(2-(2-(2-(((S)-1-((2S,4R)-4-hydroxy- 2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-2 -oxoethoxy)ethoxy)ethoxy)naphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b, 10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide,

(4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(6-(2-(2-(2-(((S)-1-((2S,4R)-4-hydroxy- 2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-2 -oxoethoxy)ethoxy)ethoxy)naphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b, 10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide,

(4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(4-(2-(2-(2-(((S)-1-((2S,4R)-4-hydroxy- 2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-2 -oxoethoxy)ethoxy)ethoxy)phenyl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11, 11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide,

(4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(5-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1 ,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethoxy)naphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6, 6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide,

(4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(5-(2-(2-(3-(((S)-1-((2S,4R)-4-hydroxy- 2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-3 -Oxopropoxy)ethoxy)ethoxy)naphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b, 10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide,

(4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(5-(((S)-13-((2S,4R)-4-hydroxy-2-((4-(4- Methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidine-1-carbonyl)-14,14-dimethyl-11-oxo-3,6,9-trioxa-12-azapentadecyl)oxy) Naphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H -Indeno[5,4-f]quinoline-7-carboxamide; and

(4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(5-(((S)-14-((2S,4R)-4-hydroxy-2-((4-(4- Methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidine-1-carbonyl)-15,15-dimethyl-12-oxo-3,6,9-trioxa-13-azahexadecyl)oxy) Naphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H -It may be one or more selected from the group consisting of indeno[5,4-f]quinoline-7-carboxamide, but is not limited thereto.

Specifically, the compound represented by Formula A may decompose nuclear receptors. More specifically, the nuclear receptor may be an androgen receptor, but is not limited thereto.

Another aspect of the present invention relates to a pharmaceutical composition for preventing or treating nuclear receptor-related diseases or lipid metabolism diseases, comprising the compound represented by Formula A, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. . The compound of the present invention represented by Formula A, its stereoisomer or its pharmaceutically acceptable salt is as described above.

In the present invention, 'nuclear receptor-related disease' refers to a disorder in the maintenance of homeostasis in the body due to abnormalities in the role of nuclear receptors in receiving or activating steroid hormones or thyroid hormones and regulating gene expression.

These nuclear receptor-related diseases may be caused by sex hormone abnormalities or disorders, but are not limited thereto. More specifically, the sex hormone may be an androgen.

More specifically, the nuclear receptor-related disease may be cancer, hair loss, hirsutism, or acne. The cancer may be caused by abnormalities in the generation, delivery, or binding of sex hormones to nuclear receptors, and may be prostate cancer, but is not limited thereto.

In one example, it was confirmed that the chimeric compound of the present invention exhibits binding ability to the androgen receptor (Table 1) and can decompose it, which is caused by abnormalities in the generation, delivery, or binding to nuclear receptors of sex hormones, especially androgens. It can be applied to prevent, improve, or treat existing diseases.

Additionally, specifically, the lipid metabolism disease may be one or more selected from the group consisting of hypertriglyceridemia, hypercholesterolemia, or dyslipidemia including hyperlipidemia, fatty liver, and obesity, but is not limited thereto.

The dyslipidemia is a state in which blood lipids are increased or decreased compared to normal, more specifically, a state in which total cholesterol, LDL cholesterol, and triglycerides in the blood are increased or HDL cholesterol is decreased, hypertriglyceridemia, It may include, but is not limited to, hypercholesterolemia or hyperlipidemia. Hypertriglyceridemia refers to a condition in which triglycerides are increased in the blood, and hypercholesterolemia is a condition in which cholesterol is increased in the blood, resulting in high total cholesterol and LDL cholesterol. In addition, hyperlipidemia is a condition in which lipids, including cholesterol and neutral fat, are increased in the blood, which can increase the risk of coronary artery diseases such as arteriosclerosis and myocardial infarction.

The fatty liver disease is a reversible disease that occurs when excessive fat, mainly neutral fat, accumulates in the liver and the fat content increases. It may also appear along with diseases such as hyperlipidemia.

Additionally, obesity may include abdominal obesity related to the accumulation of visceral fat. The visceral fat is a tissue made up of fat cells in the human body and is also called white adipose tissue. White adipose tissue is distributed subcutaneously and in the retroperitoneal cavity, and is a tissue that stores energy in the form of neutral fat, which accounts for more than 80% of fat cells.

In one embodiment, it was confirmed that the chimeric compound of the present invention reduces lipid synthesis (FIGS. 3 and 4), so it can be used to improve lipid metabolism.

In the present invention, “prevention” refers to any action by which the composition of the present invention delays the occurrence of a disease.

In the present invention, “treatment” means any action that allows the composition of the present invention to improve or benefit the symptoms of a disease.

In addition, the pharmaceutical composition of the present invention can be applied in a pharmaceutically effective amount, and “pharmaceutically effective amount” means an amount sufficient to treat a disease with a reasonable benefit/risk ratio applicable to medical treatment. The dosage level is determined by factors including the patient's gender, age, type and severity of the disease, activity of the drug, sensitivity to the drug, time of administration, route of administration and excretion rate, duration of treatment, concurrently used drugs, and other factors well known in the field of medicine. It can be determined depending on factors.

Another aspect of the present invention relates to a method for preventing or treating nuclear receptor-related diseases or lipid metabolism diseases, comprising administering the pharmaceutical composition to an individual. Nuclear receptor-related diseases and lipid metabolism diseases are as described above.

The novel compound of the present invention can bind to nuclear receptors and induce their decomposition. Accordingly, the compound of the present invention, its stereoisomer or its pharmaceutically acceptable salt can be applied to prevent, improve or treat nuclear receptor-related diseases or lipid metabolism diseases.

The effects of the present invention are not limited to the effects described above, and should be understood to include all effects that can be inferred from the configuration of the invention described in the detailed description or claims of the present invention.

Figure 1 shows the results of confirming the androgen receptor degrading ability of the chimeric compound of the present invention through Western blot.
Figure 2 shows the results of confirming the selective resolution of the chimeric compound of the present invention for the progesterone receptor.
Figure 3 shows the results confirming through Nile-red staining that lipid synthesis is reduced upon treatment with the chimeric compound of the present invention.
Figure 4 shows the results confirming through FACs that lipid synthesis is reduced upon treatment with the chimeric compound of the present invention.
Figure 5 shows the results of confirming the androgen receptor decomposition ability of the chimeric compound of the present invention.

Hereinafter, the present invention will be described in detail by examples. However, the following examples only illustrate the present invention, and the present invention is not limited by the following examples.

Preparation Example 1. Preparation of a novel androgen receptor inhibitory compound

1-1. (4aR,4bS,6aS,7S,9aS,9bS,11aR)-S-pyridin-2-yl 4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9 ,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carbothioate ((4aR,4bS,6aS,7S,9aS,9bS,11aR)- S-pyridin-2-yl 4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno Preparation of [5,4-f]quinoline-7-carbothioate)

3-Oxo-4-aza-5α-androst-1-ene-17βcarboxylic acid (3-Oxo-4-aza-5α-androst-1-ene-17βAcid) (5.0 g, 15.75 mol) was dissolved in toluene ( 30 mL). Afterwards, 2,2'-Dipyridyl disulfide (7.0 g, 31.50 mmol) and triphenylphosphine (8.26 g, 31.50 mol) were added and stirred at room temperature for 15 hours. . When the reaction is completed, the solid is filtered and dried to obtain (4aR,4bS,6aS,7S,9aS,9bS,11aR)-S-pyridin-2-yl 4a,6a-dimethyl-2-oxo-2,4a,4b,5 ,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carbothioate (3.0 g, 45%) was obtained, and it was designated as I-1.

1-2. (4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(5-hydroxynaphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6, 6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide ((4aR,4bS,6aS,7S, 9aS,9bS,11aR)-N-(5-hydroxynaphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b Preparation of ,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide)

Step 1: Preparation of 5-((tert-butyldimethylsilyl)oxy)naphthalen-1-amine (5-((tert-butyldimethylsilyl)oxy)naphthalen-1-amine)

5-aminonaphthalen-1-ol (1.0 g, 6.286 mol) was dissolved in tetrahydrofuran (20 mL). After adding tert-Butyldimethylsilyl chloride (1.14 g, 7.544 mol), imidazole (0.641 mg, 9.430 mol) was slowly added and stirred at room temperature for 15 hours. When the reaction was completed, the solvent was removed by reduced pressure distillation, and ethyl acetate (50 ml) and distilled water (50 ml) were added to the resulting residue, which was separated into water and organic layers. The separated organic layer was dried with anhydrous magnesium sulfate, filtered, and distilled under reduced pressure. The residue was separated by column chromatography (ethyl acetate:n-hexane = 1:1 (volume ratio)) to obtain 5-((tert-butyldimethylsilyl)oxy)naphthalen-1-amine (1.1 g, 64%). .

Step 2: (4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(5-((tert-butyldimethylsilyl)oxy)naphthalen-1-yl)-4a,6a-dimethyl-2-oxo -2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxylic Mid((4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(5-((tert-butyldimethylsilyl)oxy)naphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2, Preparation of 4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide)

The compound prepared in step 1 (3.8 g, 13.896 mol) and compound I-1 (3.8 g, 9.26 mol) were dissolved in tetrahydrofuran (20 mL). Afterwards, silver trifluoromethanesulfonate (2.4 g, 9.26 mol) was added and stirred at room temperature for 18 hours. After the reaction was completed, the solid was removed by filtration. The filtrate was concentrated and the solvent was removed by distillation under reduced pressure. Ethyl acetate (50 ml) and distilled water (50 ml) were added to the resulting residue, and the mixture was separated into water and organic layers. The separated organic layer was dried with anhydrous magnesium sulfate, filtered, and distilled under reduced pressure. The residue was separated by column chromatography (ethyl acetate: n-hexane = 1: 1 (volume ratio)) and (4aR, 4bS, 6aS, 7S, 9aS, 9bS, 11aR)-N-(5-((tert-butyldimethyl Silyl)oxy)naphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a, 4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetra Decahydro-1H-indeno[5,4-f]quinoline-7-carboxamide (3.3 g, 62%) was obtained.

Step 3: (4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(5-hydroxynaphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5 ,6,6a, 7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide ((4aR,4bS,6aS ,7S,9aS,9bS,11aR)-N-(5-hydroxynaphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9, Preparation of 9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide)

The compound (3.3 g, 5.761 mol) obtained in step 2 above was dissolved in methanol (20 mL). Afterwards, 4N HCl (7.2 mL, 28.803 mol) solution diluted in 1,4-dioxane was added and stirred at room temperature for 12 hours. When the reaction was completed, the solvent was removed by distillation under reduced pressure, and then dichloromethane (50 ml) was added to the resulting residue to precipitate a solid. The precipitated solid was filtered and dried to produce (4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(5-hydroxynaphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2, 4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide (2.0 g, 76%) was obtained, which was designated as I-2.

1-3. (4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(6-hydroxynaphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6, 6a, 7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide ((4aR,4bS,6aS,7S, 9aS,9bS,11aR)-N-(6-hydroxynaphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b Preparation of ,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide)

Step 1: Preparation of 6-((tert-butyldimethylsilyl)oxy)naphthalen-1-amine (6-((tert-butyldimethylsilyl)oxy)naphthalen-1-amine)

5-amino-2-naphtol (1.0 g, 6.286 mol) was dissolved in tetrahydrofuran (20 mL). After adding tert-Butyldimethylsilyl chloride (1.14 g, 7.544 mol), imidazole (0.64 mg, 9.430 mol) was slowly added and stirred at room temperature for 15 hours. When the reaction was completed, the solvent was removed by reduced pressure distillation, and ethyl acetate (50 ml) and distilled water (50 ml) were added to the resulting residue, which was separated into water and organic layers. The separated organic layer was dried with anhydrous magnesium sulfate, filtered, and distilled under reduced pressure. The residue was separated by column chromatography (ethyl acetate:n-hexane = 1:1 (volume ratio)) to obtain 6-((tert-butyldimethylsilyl)oxy)naphthalen-1-amine (1.2 g, 69%). .

Step 2: (4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(6-((tert-butyldimethylsilyl)oxy)naphthalen-1-yl)-4a,6a-dimethyl-2-oxo -2,4a, 4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxylic Mid((4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(6-((tert-butyldimethylsilyl)oxy)naphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2, Preparation of 4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide)

The compound prepared in step 1 (1.0 g, 1.20 mol) and compound I-1 (1.0 g, 1.80 mol) were dissolved in tetrahydrofuran (20.0 mL). Silver trifluoromethanesulfonate (0.6 g, 1.20 mol) was added and stirred at room temperature for 18 hours. When the reaction was completed, the solid was removed by filtration. The filtrate was concentrated and the solvent was removed by distillation under reduced pressure. Ethyl acetate (50 ml) and distilled water (50 ml) were added to the resulting residue, and the mixture was separated into water and organic layers. The separated organic layer was dried with anhydrous magnesium sulfate, filtered, and distilled under reduced pressure. The residue was separated by column chromatography (ethyl acetate: n-hexane = 1: 1 (volume ratio)) and (4aR, 4bS, 6aS, 7S, 9aS, 9bS, 11aR)-N-(6-((tert-butyldimethyl Silyl)oxy)naphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetra Decahydro-1H-indeno[5,4-f]quinoline-7-carboxamide (0.47 g, 70%) was obtained.

Step 3: (4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(6-hydroxynaphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5 ,6,6a, 7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide ((4aR,4bS,6aS ,7S,9aS,9bS,11aR)-N-(6-hydroxynaphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9, Preparation of 9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide)

The compound (0.47 g, 0.84 mol) obtained in step 2 above was dissolved in methanol (20 mL). Afterwards, 4N HCl (1.0 mL, 4.22 mol) diluted in 1,4-dioxane was added and stirred at room temperature for 12 hours. When the reaction was completed, the solvent was removed by distillation under reduced pressure, and then dichloromethane (50 ml) was added to the resulting residue to precipitate a solid. The precipitated solid was filtered and dried to produce (4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(6-hydroxynaphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2, 4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide (0.37 g, 87%) was obtained, which was designated as I-3.

1-4. (4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(7-hydroxynaphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6, 6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide ((4aR,4bS,6aS,7S, 9aS,9bS,11aR)-N-(7-hydroxynaphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b Preparation of ,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide)

Step 1: Preparation of 7-((tert-butyldimethylsilyl)oxy)naphthalen-1-amine (7-((tert-butyldimethylsilyl)oxy)naphthalen-1-amine)

8-amino-2-naphtol (1.0 g, 6.286 mol) was dissolved in tetrahydrofuran (20 mL). After adding tert-Butyldimethylsilyl chloride (1.14 g, 7.544 mol), imidazole (0.64 mg, 9.430 mol) was slowly added and stirred at room temperature for 15 hours. When the reaction was completed, the solvent was removed by reduced pressure distillation, and ethyl acetate (50 ml) and distilled water (50 ml) were added to the resulting residue, which was separated into water and organic layers. The separated organic layer was dried with anhydrous magnesium sulfate, filtered, and distilled under reduced pressure. The residue was separated by column chromatography (ethyl acetate:n-hexane = 1:1 (volume ratio)) to obtain 7-((tert-butyldimethylsilyl)oxy)naphthalen-1-amine (1.0 g, 62%). .

Step 2: (4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(7-((tert-butyldimethylsilyl)oxy)naphthalen-1-yl)-4a,6a-dimethyl-2-oxo -2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxylic Mid((4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(7-((tert-butyldimethylsilyl)oxy)naphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2, Preparation of 4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide)

The compound prepared in step 1 (1.0 g, 1.20 mol) and I-1 (1.0 g, 1.80 mol) were dissolved in tetrahydrofuran (20.0 mL). Silver trifluoromethanesulfonate (0.6 g, 1.20 mol) was added and stirred at room temperature for 18 hours. When the reaction is completed, the solid is removed by filtration. The filtrate was concentrated and the solvent was removed by distillation under reduced pressure. Ethyl acetate (50 ml) and distilled water (50 ml) were added to the resulting residue, and the mixture was separated into water and organic layers. The separated organic layer was dried with anhydrous magnesium sulfate, filtered, and distilled under reduced pressure. The residue was separated by column chromatography (ethyl acetate: n-hexane = 1: 1 (volume ratio)) and (4aR, 4bS, 6aS, 7S, 9aS, 9bS, 11aR)-N-(7-((tert-butyldimethyl Silyl)oxy)naphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetra Decahydro-1H-indeno[5,4-f]quinoline-7-carboxamide (0.47 g, 70%) was obtained.

Step 3: (4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(7-hydroxynaphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5 ,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide ((4aR,4bS,6aS ,7S,9aS,9bS,11aR)-N-(7-hydroxynaphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9, Preparation of 9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide)

The compound (0.47 g, 0.84 mol) obtained in step 2 above was dissolved in methanol (20 mL). 4N HCl (1.0 mL, 4.22 mol) diluted in 1,4-dioxane was added and stirred at room temperature for 12 hours. When the reaction was completed, the solvent was removed by distillation under reduced pressure, and then dichloromethane (50 ml) was added to the resulting residue to precipitate a solid. The precipitated solid was filtered and dried to produce (4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(7-hydroxynaphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2, 4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide (0.40 g, 91%) was obtained, which was designated as I-4.

1-5. (4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(7-hydroxynaphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6, 6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide ((4aR,4bS,6aS,7S, 9aS,9bS,11aR)-N-(7-hydroxynaphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b Preparation of ,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide)

Step 1: Preparation of 4-((tert-butyldimethylsilyl)oxy)aniline (4-((tert-butyldimethylsilyl)oxy)aniline)

4-aminopheol (0.50 g, 9.17 mol) was dissolved in tetrahydrofuran (20 mL). After adding tert-butyldimethylsilyl chloride (0.85 g, 11.00 mol), imidazole (0.47 mg, 13.75 mol) was slowly added and stirred at room temperature for 6 hours. When the reaction was completed, the solvent was removed by reduced pressure distillation, and ethyl acetate (50 ml) and distilled water (50 ml) were added to the resulting residue, which was separated into water and organic layers. The separated organic layer was dried with anhydrous magnesium sulfate, filtered, and distilled under reduced pressure. The residue was separated by column chromatography (ethyl acetate: n-hexane = 1:1 (volume ratio)) to obtain 4-((tert-butyldimethylsilyl)oxy)aniline (0.90 g, 44%).

Step 2: (4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(4-((tert-butyldimethylsilyl)oxy)phenyl)-4a,6a-dimethyl-2-oxo-2,4a ,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide ((4aR ,4bS,6aS,7S,9aS,9bS,11aR)-N-(4-((tert-butyldimethylsilyl)oxy)phenyl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6, Preparation of 6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide)

The compound prepared in step 1 (0.30 g, 1.34 mol) and I-1 (0.37 g, 0.90 mol) were dissolved in tetrahydrofuran (10.0 mL). Silver trifluoromethanesulfonate (0.23 g, 0.90 mol) was added and stirred at room temperature for 18 hours. When the reaction was completed, the solid was removed by filtration. The filtrate was concentrated and the solvent was removed by distillation under reduced pressure. Ethyl acetate (50 ml) and distilled water (50 ml) were added to the resulting residue, and the mixture was separated into water and organic layers. The separated organic layer was dried with anhydrous magnesium sulfate, filtered, and distilled under reduced pressure. The residue was separated by column chromatography (ethyl acetate: n-hexane = 1: 1 (volume ratio)) and (4aR, 4bS, 6aS, 7S, 9aS, 9bS, 11aR)-N-(4-((tert-butyldimethyl Silyl)oxy)phenyl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H -Indeno[5,4-f]quinoline-7-carboxamide (0.40 g, 62%) was obtained.

Step 3: (4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(7-hydroxynaphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5 ,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide ((4aR,4bS,6aS ,7S,9aS,9bS,11aR)-N-(7-hydroxynaphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9, Preparation of 9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide)

The compound (0.40 g, 0.75 mol) obtained in step 2 above was dissolved in methanol (20 mL). A solution of 4N HCl (0.1 mL, 3.80 mol) diluted in 1,4-dioxane was added and stirred at room temperature for 12 hours. When the reaction was completed, the solvent was removed by distillation under reduced pressure, and then dichloromethane (50 ml) was added to the resulting residue to precipitate a solid. The precipitated solid was filtered and dried to produce (4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(7-hydroxynaphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2, 4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide (0.19 g, 66%) was obtained, which was designated as I-5.

1-6. (4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(5-methoxynaphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6, 6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide ((4aR,4bS,6aS,7S, 9aS,9bS,11aR)-N-(5-methoxynaphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b Preparation of ,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide)

I-2 (100 mg, 0.22 mmol) was dissolved in N,N'-dimethylformamide (2.0 mL). Iodomethane (47 mg, 0.33 mmol) and potassium carbonate (45.0 mg, 0.33 mmol) were added and stirred at room temperature for 15 hours. When the reaction was completed, ethyl acetate (50 ml) and distilled water (50 ml) were added to separate the water and organic layers. The separated organic layer was dried with anhydrous magnesium sulfate, filtered, and distilled under reduced pressure. The residue was separated by column chromatography (ethyl acetate: n-hexane = 1: 1 (volume ratio)) and (4aR, 4bS, 6aS, 7S, 9aS, 9bS, 11aR)-N-(5-methoxynaphthalene-1- I)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[ 5,4-f]quinoline-7-carboxamide (50 mg, 43%) was obtained, designated as I-6.

1-7. (4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(6-methoxynaphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6, 6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide ((4aR,4bS,6aS,7S, 9aS,9bS,11aR)-N-(6-methoxynaphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b Preparation of ,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide)

I-3 (100 mg, 0.22 mmol) was dissolved in N,N'-dimethylformamide (2.0 mL). Iodomethane (47 mg, 0.33 mmol) and potassium carbonate (45.0 mg, 0.33 mmol) were added and stirred at room temperature for 15 hours. When the reaction was completed, ethyl acetate (50 ml) and distilled water (50 ml) were added to separate the water and organic layers. The separated organic layer was dried with anhydrous magnesium sulfate, filtered, and distilled under reduced pressure. The residue was separated by column chromatography (ethyl acetate: n-hexane = 1: 1 (volume ratio)) and (4aR, 4bS, 6aS, 7S, 9aS, 9bS, 11aR)-N-(6-methoxynaphthalene-1- I)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[ 5,4-f]quinoline-7-carboxamide (50 mg, 43%) was obtained, which was designated as I-7.

1-8. 2-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b ,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamido)-2-methylpropanoic acid (2-((4aR,4bS,6aS,7S,9aS ,9bS,11aR)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[ Preparation of 5,4-f]quinoline-7-carboxamido)-2-methylpropanoic acid)

Step 1: Preparation of ethyl 2-amino-2-methylpropanoate

2-Aminoisobutyric acid (5.04 g, 48.9 mmol) was dissolved in ethanol (20.0 mL), and the reaction mixture was cooled to 0oC. Thionyl chloride (5.40 mL, 73.3 mmol) was slowly added dropwise and stirred at room temperature for 15 hours. When the reaction was completed, the mixture was concentrated under reduced pressure, and ethyl acetate (50 mL) and water (50 mL) were added to separate the layers. The organic layer was recovered, anhydrous sodium sulfate was added, filtered, and the filtrate was concentrated, concentrated under reduced pressure, and dried to obtain ethyl 2-amino-2-methylpropanoate (6.2 g).

Step 2: Ethyl 2-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9 ,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamido)-2-methylpropanoate (ethyl 2-((4aR,4bS ,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a- Preparation of tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamido)-2-methylpropanoate)

The compound (1.0 g, 7.6 mmol) prepared in Step 1 was dissolved in N,N'-dimethylformamide. 3-oxo-4-aza-5α-androst-1-ene-17βacid) (2.0 g, 6.3 mmol), 1- [Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-hexafluorophosphate oxide (1-[Bis(dimethylamino)methylene]-1H-1,2 ,3-triazolo[4,5-b]pyridinium 3-Oxide Hexafluorophosphate) (3.6 g, 9.5 mmol) and diisopropylethylamide (3.4 mL, 18.9 mmol) were added dropwise and stirred at room temperature for 3 hours. When the reaction was completed, ethyl acetate (30 mL) and saturated aqueous sodium chloride solution (30 mL) were added to separate the layers, and the organic layer was recovered, anhydrous sodium sulfate was added, and filtered. The filtrate was concentrated and purified by column chromatography to produce ethyl 2-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6, 6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamido)-2-methylpropanoate (1.3 g, 48%) was obtained.

Step 3: 2-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9, 9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamido)-2-methylpropanoic acid (2-((4aR,4bS,6aS, 7S,9aS,9bS,11aR)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H Preparation of -indeno[5,4-f]quinoline-7-carboxamido)-2-methylpropanoic acid)

The compound prepared in step 2 (1.3 g, 3.0 mmol) was dissolved in tetrahydrofuran/ethanol/water (30 mL, 1:1:1 (volume ratio)). Lithium hydroxide monohydrate (0.6 g, 15.1 mmol) was added and stirred at room temperature for 5 hours. When the reaction was completed, it was titrated with 1N HCl aqueous solution and ethyl acetate (50 mL) was added to separate the layers. The organic layer was recovered, anhydrous sodium sulfate was added, and filtered. The filtrate was concentrated, concentrated under reduced pressure, and dried to obtain 2-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a, 7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamido)-2-methylpropanoic acid (1.2 g, 99 %) was obtained, which was designated as I-8.

1-9. (4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl-N-(2-methyl-1-(methylamino)-1-oxopropan-2-yl)-2-oxo- 2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide ((4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl-N-(2-methyl-1-(methylamino)-1-oxopropan-2-yl)-2-oxo-2 Manufacture of ,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide)

I-8 (300 mg, 0.75 mmol) was dissolved in N,N'-dimethylformamide (10.0 mL). Methylamine (35.0 mg, 0.11 mmol), 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-hexafluorophosphate oxide (1-[ Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-Oxide Hexafluorophosphate) (172 mg, 0.11 mmol), diisopropylethylamide (193 mg, 0.15 mmol) It was added dropwise and stirred at room temperature for 3 hours. When the reaction was completed, ethyl acetate (10 mL) and saturated aqueous sodium chloride solution (10 mL) were added to separate the layers, and the organic layer was recovered, anhydrous sodium sulfate was added, and filtered. The filtrate was concentrated and purified by column chromatography to produce (4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl-N-(2-methyl-1-(methylamino)-1-oxopropane. -2-yl)-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4 -f]quinoline-7-carboxamide (210 mg, 67%) was obtained, which was designated as I-9.

1-10. (4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-ethyl-N-(2-hydroxyethyl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6, 6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide ((4aR,4bS,6aS,7S, 9aS,9bS,11aR)-N-ethyl-N-(2-hydroxyethyl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b Preparation of ,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide)

3-oxo-4-aza-5α-androst-1-ene-17βcarboxylic acid (3-oxo-4-aza-5α-androst-1-ene-17βacid) (500 mg, 1.6 mmol) was added to N, It was dissolved in N'-dimethylformamide (10.0 mL). 2-(ethylamino)ethanol (2-(ethylamino)ethanol) (0.2 ml, 1.6 mmol), 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b ]Pyridinium 3-Oxide Hexafluorophosphate (1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-Oxide Hexafluorophosphate) (910 mg, 2.4 mmol), Diisopropylethylamide (610 mg, 4.7 mmol) was added dropwise and stirred at room temperature for 3 hours. When the reaction was completed, ethyl acetate (30 mL) and saturated aqueous sodium chloride solution (30 mL) were added to separate the layers, and the organic layer was recovered, anhydrous sodium sulfate was added, and filtered. The filtrate was concentrated and purified by column chromatography (4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-ethyl-N-(2-hydroxyethyl)-4a,6a-dimethyl-2-oxo- 2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide (280 mg, 45%) was obtained, which was designated as I-10.

1-11. (4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(1-hydroxy-2-methylpropan-2-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b, 5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide ((4aR,4bS, 6aS,7S,9aS,9bS,11aR)-N-(1-hydroxy-2-methylpropan-2-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7 ,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide) production

3-oxo-4-aza-5α-androst-1-ene-17βcarboxylic acid (3-oxo-4-aza-5α-androst-1-ene-17βacid) (500 mg, 1.6 mmol) was added to N, It was dissolved in N'-dimethylformamide (10.0 mL). 2-amino-2-methyl-1-propanol (140 mg, 1.6 mmol), 1-[Bis(dimethylamino)methylene]-1H-1,2,3 -Triazolo[4,5-b]pyridinium 3-Oxide Hexafluorophosphate ) (910 mg, 2.4 mmol) and diisopropylethylamide (610 mg, 4.7 mmol) were added dropwise and stirred at room temperature for 3 hours. When the reaction was completed, ethyl acetate (30 mL) and saturated aqueous sodium chloride solution (30 mL) were added to separate the layers, and the organic layer was recovered, anhydrous sodium sulfate was added, and filtered. The filtrate was concentrated and purified by column chromatography to (4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(1-hydroxy-2-methylpropan-2-yl)-4a,6a-dimethyl- 2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7 -Carboxamide (320 mg, 56%) was obtained, designated I-11.

1-12. 7-(((S)-1-((2S,4R)-4-((4-methoxybenzyl)oxy)-2-((4-(4-methylthiazol-5-yl)benzyl)carba moyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-7-oxoheptanoic acid (7-(((S)-1-((2S,4R )-4-((4-methoxybenzyl)oxy)-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2 Preparation of -yl)amino)-7-oxoheptanoic acid)

Step 1: Ethyl 7-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrroli din-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-7-oxoheptanoate (ethyl 7-(((S)-1-((2S,4R)- 4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-7-oxoheptanoate )Manufacture of

(S,R,S)-AHPC HYDROCHLORIDE (2.0 g, 4.28 mmol) was dissolved in N,N'-dimethylformamide (20 mL). Ethyl hydrogen pimelate (0.8 g, 4.28 mmol), 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3- Hexafluorophosphate (1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-Oxide Hexafluorophosphate) (1.5 g, 5.06 mmol), diisopropylethylamide (0.9 mL, 5.35 mmol) was added and stirred at room temperature for 4 hours. When the reaction was completed, ethyl acetate and distilled water were added to separate the layers, and the organic layer was recovered, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography to obtain ethyl 7-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl) Carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-7-oxoheptanoate (0.7 g, 30%) was obtained.

Step 2: Ethyl 7-(((S)-1-((2S,4R)-4-((4-methoxybenzyl)oxy)-2-((4-(4-methylthiazol-5-yl )benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-7-oxoheptanoate (ethyl 7-(((S)-1 -((2S,4R)-4-((4-methoxybenzyl)oxy)-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl Preparation of -1-oxobutan-2-yl)amino)-7-oxoheptanoate)

The compound prepared in step 1 (1.4 g, 2.33 mmol) was dissolved in N,N'-dimethylformamide (20 mL). Sodium hydride (0.1 g, 4.66 mmol) was slowly added dropwise and stirred at room temperature for 5 minutes. 4-methoxybenzyl chloride (0.4 g, 2.80 mmol) was added and stirred at room temperature for 15 hours. When the reaction was completed, ethyl acetate and distilled water were added to separate the layers, and the organic layer was recovered, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography to obtain ethyl 7-(((S)-1-((2S,4R)-4-((4-methoxybenzyl)oxy)-2-((4-(4-methylthia) Zol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-7-oxoheptanoate (0.7 g, 38% ) was obtained.

Step 3: 7-(((S)-1-((2S,4R)-4-((4-methoxybenzyl)oxy)-2-((4-(4-methylthiazol-5-yl) Benzyl) carbamoyl) pyrrolidin-1-yl) -3,3-dimethyl-1-oxobutan-2-yl) amino) -7-oxoheptanoic acid (7-(((S)-1-(( 2S,4R)-4-((4-methoxybenzyl)oxy)-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1- Preparation of oxobutan-2-yl)amino)-7-oxoheptanoic acid)

The compound (650 mg, 0.90 mmol) prepared in step 2 was dissolved in tetrahydrofuran/methanol/water (8 mL/4 mL/4 mL). Lithium hydroxide monohydrate (113 mg, 2.71 mmol) was added and stirred at room temperature for 15 hours. When the reaction was completed, it was titrated with 1N HCl aqueous solution and ethyl acetate was added to separate the layers. The organic layer was recovered, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 7-(((S)-1-((2S,4R)-4-((4-methoxybenzyl)oxy)-2-((4-( 4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-7-oxoheptanoic acid (625 mg , 100%) was obtained.

1-13. 7-(((S)-1-((2S,4R)-4-((4-methoxybenzyl)oxy)-2-((4-(4-methylthiazol-5-yl)benzyl)carba moyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-7-oxoheptanoic acid (7-(((S)-1-((2S,4R )-4-((4-methoxybenzyl)oxy)-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2 Preparation of -yl)amino)-7-oxoheptanoic acid)

Step 1: Ethyl 12-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrroli din-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-12-oxododecanoate (ethyl 12-(((S)-1-((2S,4R)- 4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-12-oxododecanoate )Manufacture of

(S,R,S)-AHPC HYDROCHLORIDE (2.0 g, 4.28 mmol) was dissolved in N,N'-dimethylformamide (20 mL). Dodecanedioic acid monoethyl ester (0.9 g, 4.28 mmol), 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-Hexafluorophosphate (1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-Oxide Hexafluorophosphate) (1.5 g, 5.06 mmol), diisopropyl After adding ethylamide (0.9 mL, 5.35 mmol), it was stirred at room temperature for 4 hours. When the reaction was completed, ethyl acetate and distilled water were added to separate the layers, and the organic layer was recovered, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography to obtain ethyl 12-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl) Carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-12-oxododecanoate (0.7 g, 30%) was obtained.

Step 2: Ethyl 7-(((S)-1-((2S,4R)-4-((4-methoxybenzyl)oxy)-2-((4-(4-methylthiazol-5-yl )benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-7-oxoheptanoate (ethyl 7-(((S)-1 -((2S,4R)-4-((4-methoxybenzyl)oxy)-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl Preparation of -1-oxobutan-2-yl)amino)-7-oxoheptanoate)

The compound prepared in Step 1 (1.0 g, 1.49 mmol) was dissolved in N,N'-dimethylformamide (10 mL). Sodium hydride (0.05 g, 2.98 mmol) was slowly added dropwise and stirred at room temperature for 5 minutes. 4-methoxybenzyl chloride (0.3 g, 1.93 mmol) was added and stirred at room temperature for 15 hours. When the reaction was completed, ethyl acetate and distilled water were added to separate the layers, and the organic layer was recovered, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography to obtain ethyl 7-(((S)-1-((2S,4R)-4-((4-methoxybenzyl)oxy)-2-((4-(4-methylthia) Zol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-7-oxoheptanoate (0.1 g, 8% ) was obtained.

Step 3: 7-(((S)-1-((2S,4R)-4-((4-methoxybenzyl)oxy)-2-((4-(4-methylthiazol-5-yl) Benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-7-oxoheptanoic acid (7-(((S)-1-(( 2S,4R)-4-((4-methoxybenzyl)oxy)-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1- Preparation of oxobutan-2-yl)amino)-7-oxoheptanoic acid)

The compound (100 mg, 0.13 mmol) prepared in step 2 was dissolved in tetrahydrofuran/methanol/water (8 mL/4 mL/4 mL). Lithium hydroxide monohydrate (16 mg, 0.38 mmol) was added and stirred at room temperature for 15 hours. When the reaction was completed, it was titrated with 1N HCl aqueous solution and ethyl acetate was added to separate the layers. The organic layer was recovered, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 7-(((S)-1-((2S,4R)-4-((4-methoxybenzyl)oxy)-2-((4-( 4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-7-oxoheptanoic acid (96 mg , 100%) was obtained.

Preparation Example 2. Preparation of a chimeric compound (Proteolysis-Targeting Chimera, PROTAC) containing the compound of Preparation Example 1

A chimeric compound (Proteolysis-Targeting Chimera, PROTAC) capable of degrading the target protein was prepared by connecting the E3 ubiquitin ligase binding moiety to the compound prepared through Preparation Example 1 through a linker.

2-1. (4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(1-(2-(((S)-1-((2S,4R)-4-hydroxy-2-((4- (4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-2-oxoethoxy)- 2-methylpropan-2-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradeca Hydro-1H-indeno[5,4-f]quinoline-7-carboxamide((4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(1-(2-(((S) -1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan- 2-yl)amino)-2-oxoethoxy)-2-methylpropan-2-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a Preparation of ,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide)

Step 1: Ethyl 2-(2-((tert-butoxycarbonyl)amino)-2-methylpropoxy)acetate (ethyl 2-(2-((tert-butoxycarbonyl)amino)-2-methylpropoxy)acetate) manufacture of

tert-butyl(1-hydroxy-2-methylpropan-2-yl)carbamate (1.00 g, 5.30 mmol) was dissolved in tetrahydrofuran. (20 mL). It was cooled to 0°C, and sodium hydride (0.42 g, 10.6 mmol, 60% in oil) was slowly added dropwise. The mixture was stirred at 0°C for 1 hour, ethyl bromoacetate (1.06 g, 6.36 mmol) was added, and stirred at room temperature for 16 hours. When the reaction was completed, it was concentrated under reduced pressure and the residue was purified by column chromatography to obtain ethyl 2-(2-((tert-butoxycarbonyl)amino)-2-methylpropoxy)acetate (0.60 g, 41%). .

Step 2: Preparation of ethyl 2-(2-amino-2-methylpropoxy)acetate

The compound (0.60 g, 2.20 mmol) prepared in Step 1 was dissolved in 1,4-dioxane (5 mL). 4N HCl solution (5 mL) diluted in 1,4-dioxane was added and stirred at room temperature for 3 hours. When the reaction was completed, it was concentrated under reduced pressure and dried to obtain ethyl 2-(2-amino-2-methylpropoxy)acetate (0.30 g, 78%).

Step 3: Ethyl 2-(2-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7, 8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamido)-2-methylpropoxy)acetate (ethyl 2-( 2-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b Preparation of ,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamido)-2-methylpropoxy)acetate)

The compound (0.30 g, 1.33 mmol) prepared in step 2 was dissolved in N,N'-dimethylformamide (5 mL). Diisopropylethylamine (0.69 g, 5.32 mmol), 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-hexafluorophosphate oxide ( 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-Oxide Hexafluorophosphate)(0.60 g, 1.60 mmol), 3-oxo-4-aza-5α- Androst-1-ene-17βcarboxylic acid (3-oxo-4-aza-5α-androst-1-ene-17βacid) (0.42 g, 1.33 mmol) was added and stirred at room temperature for 15 hours. When the reaction was completed, ethyl acetate and distilled water were added to separate the layers, and the organic layer was recovered, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography to obtain ethyl 2-(2-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6 ,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamido)-2-methylpropoxy)acetate (0.20 g, 32%) was obtained.

Step 4: 2-(2-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8 ,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamido)-2-methylpropoxy)acetic acid (2-(2- ((4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10 Preparation of ,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamido)-2-methylpropoxy)acetic acid)

The compound (200 mg, 0.42 mmol) prepared in step 3 was dissolved in methanol. A solution of sodium hydroxide (67 mg, 1.68 mmol) dissolved in distilled water (1 mL) was added and stirred at room temperature for 3 hours. When the reaction was completed, it was concentrated under reduced pressure, titrated with 1N HCl solution, and then ethyl acetate was added to separate the layers. The organic layer was recovered, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 2-(2-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl-2-oxo-2,4a,4b ,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamido)-2-methyl Propoxy)acetic acid (200 mg) was obtained.

Step 5: (4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(1-(2-(((S)-1-((2S,4R)-4-hydroxy-2-( (4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-2-oxo Toxy)-2-methylpropane-2-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a -tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide((4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(1-(2-(( (S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1 -oxobutan-2-yl)amino)-2-oxoethoxy)-2-methylpropan-2-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8, Preparation of 9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide)

The compound prepared in step 4 (200 mg, 0.42 mmol) was dissolved in N,N'-dimethylformamide (5 mL). Diisopropylethylamine (217 mg, 1.68 mmol), 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-hexafluorophosphate oxide ( 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-Oxide Hexafluorophosphate)(191 mg, 0.50 mmol), (4R)-3-methyl-L- Valyl-4-hydroxy-N-[[4-(4-methyl-5-thiazolyl)phenyl]methyl]-L-prolinamide, monohydrochloride ((4R)-3-methyl-L-valyl-4 -hydroxy-N-[[4-(4-methyl-5-thiazolyl)phenyl]methyl]-L-prolinamide, monohydrochloride) (180 mg, 0.42 mmol) was added and stirred at room temperature for 15 hours. When the reaction was completed, ethyl acetate and distilled water were added to separate the layers, and the organic layer was recovered, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(1-(2-(((S)-1-((2S,4R)-4-hyde Roxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino) -2-oxoethoxy)-2-methylpropane-2-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b, 10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide (25 mg, 7%) was obtained, which was designated as DT02P023.

^1H NMR (CDCl3, 600MHz) 8.68 (s, 1H), 7.37-7.34 (m, 5H), 7.14 (d, 1H), 6.77-6.75 (d, 1H), 5.80-5.78 (m, 1H), 5.61 (s, 1H), 5.33(s, 1H), 4.75-4.70(m, 1H), 4.53-4.46(m, 3H), 4.37(d, 1H), 4.07-4.05(d, 1H), 3.98(s , 2H), 3.68-3.66(d, 2H), 3.64-3.62(d, 1H), 3.57-3.55(d, 1H), 3.48-3.46(m, 1H), 2.51(s, 4H), 2.14-2.09 (m, 3H), 1.99-1.95(m, 7H), 1.75-1.72(m, 6H), 1.59-1.57(m, 2H), 1.44-1.42(m, 6H), 1.38-1.35(m, 2H) , 1.26-1.25(m, 1H), 1.08 -0.99(m, 15H).

2-2. (4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(1-(3-(((S)-1-((2S,4R)-4-hydroxy-2-((4- (4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-3-oxopropoxy)- 2-methylpropan-2-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradeca Hydro-1H-indeno[5,4-f]quinoline-7-carboxamide((4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(1-(3-(((S) -1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan- 2-yl)amino)-3-oxopropoxy)-2-methylpropan-2-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a Preparation of ,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide)

Step 1: Ethyl 3-(2-((tert-butoxycarbonyl)amino)-2-methylpropoxy)propanoate (ethyl 3-(2-((tert-butoxycarbonyl)amino)-2-methylpropoxy) Manufacture of propanoate)

tert-butyl(1-hydroxy-2-methylpropan-2-yl)carbamate (1.00 g, 5.30 mmol) was added to N,N '-Dissolved in dimethylformamide (20 mL). _Cs2CO3 (3.50 g, 10.6 mmol) and ethyl acrylate (1.06 g, 10.6 mmol) were added and stirred at 60°C for 6 hours. When the reaction was completed, ethyl acetate and distilled water were added to separate the layers, and the organic layer was recovered, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography to obtain ethyl 3-(2-((tert-butoxycarbonyl)amino)-2-methylpropoxy)propanoate (0.60 g, 39%).

Step 2: Preparation of ethyl 3-(2-amino-2-methylpropoxy)propanoate

The compound (0.60 g, 2.08 mmol) prepared in Step 1 was dissolved in 1,4-dioxane (5 mL). 4N HCl solution (5 mL) diluted in 1,4-dioxane was added and stirred at room temperature for 3 hours. When the reaction was completed, the mixture was concentrated under reduced pressure and dried to obtain ethyl 3-(2-amino-2-methylpropoxy)propanoate (0.40 g, 100%).

Step 3: Ethyl 3-(2-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7, 8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamido)-2-methylpropoxy)propanoate (ethyl 3) -(2-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a Preparation of ,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamido)-2-methylpropoxy)propanoate)

The compound (0.30 g, 1.33 mmol) prepared in step 2 was dissolved in N,N'-dimethylformamide (10 mL). Diisopropylethylamine (1.09 g, 8.48 mmol), 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-hexafluorophosphate oxide ( 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-Oxide Hexafluorophosphate)(0.96 g, 2.54 mmol), 3-oxo-4-aza-5α- Androst-1-ene-17βcarboxylic acid (3-oxo-4-aza-5α-androst-1-ene-17βacid) (0.67 g, 2.12 mmol) was added and stirred at room temperature for 15 hours. When the reaction was completed, ethyl acetate and distilled water were added to separate the layers, and the organic layer was recovered, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography to produce ethyl 3-(2-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6 ,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamido)-2-methylpropoxy)prop Panoate (0.30 g, 29%) was obtained.

Step 4: 3-(2-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8 ,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamido)-2-methylpropoxy)propionic acid (3-(2- ((4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10 Preparation of ,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamido)-2-methylpropoxy)propanoic acid)

The compound (300 mg, 0.61 mmol) prepared in step 3 was dissolved in methanol (5 mL). A solution of sodium hydroxide (98 mg, 2.45 mmol) dissolved in distilled water (1 mL) was added and stirred at room temperature for 3 hours. When the reaction was completed, it was concentrated under reduced pressure, titrated with 1N HCl solution, and then ethyl acetate was added to separate the layers. The organic layer was recovered, dried over anhydrous sodium sulfate, filtered and concentrated to produce 3-(2-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl-2-oxo-2,4a,4b ,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamido)-2-methyl Propoxy)propionic acid (200 mg) was obtained.

Step 5: :(4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(1-(3-(((S)-1-((2S,4R)-4-hydroxy-2- ((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-3-oxo propoxy)-2-methylpropan-2-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11, 11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide((4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(1-(3-( ((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl- 1-oxobutan-2-yl)amino)-3-oxopropoxy)-2-methylpropan-2-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8 ,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide) production

The compound prepared in step 4 (200 mg, 0.43 mmol) was dissolved in N,N'-dimethylformamide (5 mL). Diisopropylethylamine (330 mg, 2.56 mmol), 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-hexafluorophosphate oxide ( 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-Oxide Hexafluorophosphate)(245 mg, 0.64 mmol), (4R)-3-methyl-L- Valyl-4-hydroxy-N-[[4-(4-methyl-5-thiazolyl)phenyl]methyl]-L-prolinamide, monohydrochloride ((4R)-3-methyl-L-valyl-4 -hydroxy-N-[[4-(4-methyl-5-thiazolyl)phenyl]methyl]-L-prolinamide, monohydrochloride) (185 mg, 0.43 mmol) was added and stirred at room temperature for 15 hours. When the reaction was completed, ethyl acetate and distilled water were added to separate the layers, and the organic layer was recovered, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(1-(3-(((S)-1-((2S,4R)-4-hyde Roxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino) -3-oxopropoxy)-2-methylpropan-2-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b, 10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide (28 mg, 8%) was obtained, designated as DT02P024.

¹ H NMR (CDCl3, 600 MHz) 8.68 (s, 1H), 7.38-7.33 (m, 4H), 6.79-6.75 (t, 2H), 6.80 (m, 1H), 5.46 (s, 2H), 4.70-4.66 (t, 1H), 4.57-4.53(m, 3H), 4.35-4.30(m, 1H), 4.06-4.04(d, 1H), 3.72-3.70(m, 2H), 3.65-3.55(m, 1H) , 3.52-3.48(m, 3H), 3.42(s, 1H), 3.33-3.32(m, 1H), 2.52(s, 4H), 2.46(s, 2H), 2.14-2.11(m, 3H), 2.02 -1.98(m, 1H), 1.75-1.73(m, 2H), 1.68-1.60(m, 2H), 1.59-1.57(m, 2H), 1.44-1.43(m, 2H), 1.32-1.30(m, 6H), 1.25-1.23(m, 2H), 1.20-1.15(m, 1H), 1.10-1.01(m, 2H), 0.99 -0.95(m, 13H), 0.60(s, 3H).

2-3. (4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(5-(2-(((S)-1-((2S,4R)-4-hydroxy-2-((4- (4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-2-oxoethoxy)naphthalene -1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H- Indeno[5,4-f]quinoline-7-carboxamide((4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(5-(2-(((S)-1-( (2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl) amino)-2-oxoethoxy)naphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11, Preparation of 11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide)

Step 1: Preparation of tert-butyl(5-hydroxynaphthalen-1-yl)carbamate

5-aminonaphthalen-1-ol (5-aminonaphthalen-1-ol) (10 g, 62.9 mmol) and (Boc)2O (20 g, 91.7 mmol) were dissolved in methanol (10 mL) and incubated at 60°C for 8 hours. It was stirred. When the reaction was completed, the mixture was concentrated under reduced pressure and the residue was purified by column chromatography to obtain tert-butyl(5-hydroxynaphthalen-1-yl)carbamate (13 g, 80%).

Step 2: Ethyl 2-((5-((tert-butoxycarbonyl)amino)naphthalen-1-yl)oxy)acetate (ethyl 2-((5-((tert-butoxycarbonyl)amino)naphthalen-1- Preparation of yl)oxy)acetate)

The compound prepared in Step 1 (1 g, 3.86 mmol) and ethyl 2-bromoacetate (768.6 mg, 4.63 mmol) were dissolved in N,N'-dimethylformamide (10 mL). Cesium carbonate (2.52 g, 7.72 mmol) was added dropwise and stirred at 60°C for 4 hours. When the reaction was completed, ethyl acetate and distilled water were added to separate the layers, and the organic layer was recovered, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography to obtain ethyl 2-((5-((tert-butoxycarbonyl)amino)naphthalen-1-yl)oxy)acetate (580 mg, 44%).

Step 3: Preparation of ethyl 2-((5-aminonaphthalen-1-yl)oxy)acetate hydrochloride

The compound (580 mg, 1.68 mmol) prepared in step 2 was dissolved in ethyl acetate (6 mL). 6N HCl solution (6 mL) dissolved in ethyl acetate was added and stirred at room temperature for 15 hours. When the reaction was completed, it was concentrated under reduced pressure and dried to obtain ethyl 2-((5-aminonaphthalen-1-yl)oxy)acetate hydrochloride (473 mg, 100%).

Step 4: Ethyl 2-((5-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7 ,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamido)naphthalen-1-yl)oxy)acetate (ethyl 2 -((5-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9, Preparation of 9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamido)naphthalen-1-yl)oxy)acetate)

The compound (587.2 mg, 1.85 mmol) prepared in step 3 was dissolved in dichloromethane (6 mL). Oxalyl chloride (1.15 g, 9.09 mmol) and a small amount of N,N'-dimethylformamide were added and stirred at room temperature for 1 hour. When the reaction was completed, it was concentrated under reduced pressure and dissolved in 1,4-dioxane (10 mL). 3-oxo-4-aza-5α-androst-1-ene-17βacid) (473 mg, 1.68 mmol) and triethyl Amine (562 mg, 5.55 mmol) was added and stirred at 80°C for 2 hours. When the reaction was completed, ethyl acetate and distilled water were added to separate the layers, and the organic layer was recovered, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography to produce ethyl 2-((5-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl-2-oxo-2,4a,4b,5, 6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamido)naphthalen-1-yl)oxy ) Acetate (50 mg, 5%) was obtained.

Step 5: 2-((5-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7, 8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamido)naphthalen-1-yl)oxy)acetic acid (2-( (5-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a, Preparation of 9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamido)naphthalen-1-yl)oxy)acetic acid)

The compound (50 mg, 0.092 mmol) prepared in step 4 was dissolved in tetrahydrofuran/methanol/water (2 mL/1 mL/1 mL). Lithium hydroxide monohydrate (15.5 mg, 0.37 mmol) was added dropwise and stirred at 50°C for 3 hours. When the reaction is completed, titrate with 0.5N HCl solution, concentrate under reduced pressure, and dry to obtain 2-((5-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl-2-oxo-2 ,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamido) Naphthalen-1-yl)oxy)acetic acid (47 mg, 100%) was obtained.

Step 6: (4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(5-(2-(((S)-1-((2S,4R)-4-hydroxy-2-( (4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-2-oxo Toxy)naphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro -1H-indeno[5,4-f]quinoline-7-carboxamide (4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(5-(2-(((S)-1 -((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2- yl)amino)-2-oxoethoxy)naphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10, Preparation of 11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide

The compound (47.4 mg, 0.09 mmol) prepared in step 5 above was dissolved in N,N'-dimethylformamide (3 mL). (4R)-3-methyl-L-valyl-4-hydroxy-N-[[4-(4-methyl-5-thiazolyl)phenyl]methyl]-L-prolinamide, monohydrochloride ((4R) -3-methyl-L-valyl-4-hydroxy-N-[[4-(4-methyl-5-thiazolyl)phenyl]methyl]-L-prolinamide, monohydrochloride)(47.5 mg, 0.11mmol), 1-[ Add Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-Oxide Hexafluorophosphate (42 mg, 0.11 mmol) and diisopropylethylamine (35.6 mg, 0.28 mmol). It was stirred at room temperature for 15 hours. When the reaction was completed, ethyl acetate and distilled water were added to separate the layers, and the organic layer was recovered, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(5-(2-(((S)-1-((2S,4R)-4-hyde Roxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino) -2-oxoethoxy)naphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11, 11a-Tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide (15 mg, 18%) was obtained, which was designated as DT02P025.

^1H NMR(CDCl3) 8.72(s, 1H), 8.07-8.01(m, 2H), 7.53-7.40(m, 9H), 7.01(s, 1H), 6.83-6.81(m, 2H), 5.85-5.81 (m, 1H), 5.38-5.36(m, 2H), 4.78-4.76(m, 5H), 4.67-4.57(m, 5H), 4.39-4.34(m, 1H), 4.13-4.07(m, 2H) , 3.77-3.65(m, 4H), 3.55-3.51(m, 2H), 3.38(s, 4H), 2.91-2.87(m, 1H), 266-2.59(m, 2H), 2.40-2.33(m, 4H), 2.26-2.22(m, 4H), 2.22-2.18(m, 4H), 2.05-2.01(m, 8H)

2-4. (4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(5-(3-(((S)-1-((2S,4R)-4-hydroxy-2-((4- (4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-3-oxopropoxy)naphthalene -1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H- Indeno[5,4-f]quinoline-7-carboxamide((4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(5-(3-(((S)-1-( (2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl) amino)-3-oxopropoxy)naphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11, Preparation of 11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide)

Step 1: Preparation of tert-butyl(5-hydroxynaphthalen-1-yl)carbamate

5-aminonaphthalen-1-ol (5-aminonaphthalen-1-ol) (10 g, 62.9 mmol) and (Boc)2O (20 g, 91.7 mmol) were dissolved in methanol (20 mL) and incubated at 60°C for 8 hours. It was stirred. When the reaction was completed, the mixture was concentrated under reduced pressure and the residue was purified by column chromatography to obtain tert-butyl(5-hydroxynaphthalen-1-yl)carbamate (13 g, 80%).

Step 2: Ethyl 3-((5-((tert-butoxycarbonyl)amino)naphthalen-1-yl)oxy)propanoate (ethyl 3-((5-((tert-butoxycarbonyl)amino)naphthalen- Preparation of 1-yl)oxy)propanoate)

The compound prepared in Step 1 (1 g, 3.86 mmol) and ethyl acrylate (768.6 mg, 4.63 mmol) were dissolved in N,N'-dimethylformamide (10 mL). Cesium carbonate (2.52 g, 7.72 mmol) was added dropwise and stirred at 60°C for 4 hours. When the reaction was completed, ethyl acetate and distilled water were added to separate the layers, and the organic layer was recovered, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography to obtain ethyl 3-((5-((tert-butoxycarbonyl)amino)naphthalen-1-yl)oxy)propanoate (829 mg, 60%).

Step 3: Preparation of ethyl 3-((5-aminonaphthalen-1-yl)oxy)propanoate hydrochloride

The compound (829 mg, 2.31 mmol) prepared in step 2 was dissolved in ethyl acetate (9 mL). 6N HCl solution (9 mL) dissolved in ethyl acetate was added and stirred at room temperature for 15 hours. When the reaction was completed, it was concentrated under reduced pressure and dried to obtain ethyl 3-((5-aminonaphthalen-1-yl)oxy)propanoate hydrochloride (612 mg, 100%).

Step 4: Ethyl 3-((5-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7 ,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamido)naphthalen-1-yl)oxy)propanoate ( ethyl 3-((5-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8, Preparation of 9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamido)naphthalen-1-yl)oxy)propanoate)

The compound (723.6 mg, 2.28 mmol) prepared in step 3 was dissolved in dichloromethane (7 mL). Oxalyl chloride (1.42 g, 11.20 mmol) and a small amount of N,N'-dimethylformamide were added and stirred at room temperature for 1 hour. When the reaction was completed, it was concentrated under reduced pressure and dissolved in 1,4-dioxane (10 mL). 3-oxo-4-aza-5α-androst-1-ene-17βcarboxylic (3-oxo-4-aza-5α-androst-1-ene-17β) (612 mg, 2.07 mmol) and triethyl Amine (693 mg, 6.84 mmol) was added and stirred at 80°C for 2 hours. When the reaction was completed, ethyl acetate and distilled water were added to separate the layers, and the organic layer was recovered, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography to produce ethyl 3-((5-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl-2-oxo-2,4a,4b,5, 6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamido)naphthalen-1-yl)oxy ) Propanoate (153 mg, 13%) was obtained.

Step 5: 3-((5-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7, 8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamido)naphthalen-1-yl)oxy)propanoic acid (3- ((5-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a Preparation of ,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamido)naphthalen-1-yl)oxy)propanoic acid)

The compound (153 mg, 0.27 mmol) prepared in step 4 was dissolved in tetrahydrofuran/methanol/water (2 mL/1 mL/1 mL). Lithium hydroxide monohydrate (46 mg, 1.10 mmol) was added dropwise and stirred at 50°C for 3 hours. When the reaction is completed, titrate with 0.5N HCl solution, concentrate under reduced pressure, and dry to obtain 3-((5-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl-2-oxo-2 ,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamido) Naphthalen-1-yl)oxy)propanoic acid (95 mg, 66%) was obtained.

Step 6: (4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(5-(3-(((S)-1-((2S,4R)-4-hydroxy-2-( (4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-3-oxoprop Poxy)naphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro -1H-indeno[5,4-f]quinoline-7-carboxamide((4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(5-(3-(((S)- 1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2 -yl)amino)-3-oxopropoxy)naphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10 Preparation of ,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide)

The compound prepared in step 5 (95 mg, 0.18 mmol) was dissolved in N,N'-dimethylformamide (3 mL). (4R)-3-methyl-L-valyl-4-hydroxy-N-[[4-(4-methyl-5-thiazolyl)phenyl]methyl]-L-prolinamide, monohydrochloride ((4R) -3-methyl-L-valyl-4-hydroxy-N-[[4-(4-methyl-5-thiazolyl)phenyl]methyl]-L-prolinamide, monohydrochloride) (100 mg, 0.22 mmol), 1-[ Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-hexafluorophosphate oxide (1-[Bis(dimethylamino)methylene]-1H-1,2, 3-triazolo[4,5-b]pyridinium 3-Oxide Hexafluorophosphate) (114 mg, 0.30 mmol) and diisopropylethylamine (124 mg, 0.96 mmol) were added and stirred at room temperature for 15 hours. When the reaction was completed, ethyl acetate and distilled water were added to separate the layers, and the organic layer was recovered, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(5-(3-(((S)-1-((2S,4R)-4-hyde Roxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino) -3-oxopropoxy)naphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11, 11a-Tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide (11 mg, 6%) was obtained, designated as DT02P026.

2-5. (4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(5-(4-(((S)-1-((2S,4R)-4-hydroxy-2-((4- (4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-4-oxobutoxy)naphthalene -1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H- Indeno[5,4-f]quinoline-7-carboxamide((4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(5-(4-(((S)-1-( (2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl) amino)-4-oxobutoxy)naphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11, Preparation of 11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide)

Step 1: Preparation of tert-butyl(5-hydroxynaphthalen-1-yl)carbamate

5-aminonaphthalen-1-ol (10 g, 62.9 mmol) and (Boc)2O (20 g, 91.7 mmol) were dissolved in methanol (30 mL) and incubated at 60°C for 8 hours. It was stirred. When the reaction was completed, the mixture was concentrated under reduced pressure and the residue was purified by column chromatography to obtain tert-butyl(5-hydroxynaphthalen-1-yl)carbamate (13 g, 80%).

Step 2: Ethyl 4-((5-((tert-butoxycarbonyl)amino)naphthalen-1-yl)oxy)butanoate (ethyl 4-((5-((tert-butoxycarbonyl)amino)naphthalen- Preparation of 1-yl)oxy)butanoate)

The compound prepared in step 1 (390 mg, 1.5 mmol) and ethyl 4-bromobutanoate (350 mg, 1.8 mmol) were added to N,N'-dimethylformamide (10 mL). melted Cesium carbonate (981 mg, 3.0 mmol) was added dropwise and stirred at 60°C for 4 hours. When the reaction was completed, ethyl acetate and distilled water were added to separate the layers, and the organic layer was recovered, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography to obtain ethyl 4-((5-((tert-butoxycarbonyl)amino)naphthalen-1-yl)oxy)butanoate (246 mg, 44%).

Step 3: Preparation of ethyl 4-((5-aminonaphthalen-1-yl)oxy)butanoate hydrochloride

The compound (246 mg, 0.66 mmol) prepared in step 2 was dissolved in ethyl acetate (4 mL). 6N HCl solution (4 mL) dissolved in ethyl acetate was added and stirred at room temperature for 15 hours. When the reaction was completed, it was concentrated under reduced pressure and dried to obtain ethyl 4-((5-aminonaphthalen-1-yl)oxy)butanoate hydrochloride (200 mg, 98%).

Step 4: Ethyl 4-((5-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7 ,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamido)naphthalen-1-yl)oxy)butanoate ( ethyl 4-((5-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8, Preparation of 9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamido)naphthalen-1-yl)oxy)butanoate)

The compound (250 mg, 0.79 mmol) prepared in step 3 was dissolved in dichloromethane (6 mL). Oxalyl chloride (500 mg, 3.93 mmol) and a small amount of N,N'-dimethylformamide were added and stirred at room temperature for 1 hour. When the reaction was completed, it was concentrated under reduced pressure and dissolved in 1,4-dioxane (5 mL). 3-oxo-4-aza-5α-androst-1-ene-17βcarboxylic (3-oxo-4-aza-5α-androst-1-ene-17β) (200 mg, 0.73 mmol) and triethyl Amine (240 mg, 2.37 mmol) was added and stirred at 80°C for 2 hours. When the reaction was completed, ethyl acetate and distilled water were added to separate the layers, and the organic layer was recovered, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography to produce ethyl 4-((5-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl-2-oxo-2,4a,4b,5, 6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamido)naphthalen-1-yl)oxy ) Butanoate (60 mg, 16%) was obtained.

Step 5: 4-((5-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7, 8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamido)naphthalen-1-yl)oxy)butanoic acid (4- ((5-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a Preparation of ,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamido)naphthalen-1-yl)oxy)butanoic acid)

The compound (60 mg, 0.10 mmol) prepared in step 4 was dissolved in tetrahydrofuran/methanol/water (2 mL/1 mL/1 mL). Lithium hydroxide monohydrate (18 mg, 0.42 mmol) was added dropwise and stirred at 50°C for 3 hours. When the reaction is completed, titrate with 0.5N HCl solution, concentrate under reduced pressure, and dry to obtain 4-((5-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl-2-oxo-2 ,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamido) Naphthalen-1-yl)oxy)butanoic acid (57 mg, 100%) was obtained.

Step 6: (4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(5-(4-(((S)-1-((2S,4R)-4-hydroxy-2-( (4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-4-oxobutan Toxy)naphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro -1H-indeno[5,4-f]quinoline-7-carboxamide (4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(5-(4-(((S)-1 -((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2- yl)amino)-4-oxobutoxy)naphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10, Preparation of 11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide

The compound (57 mg, 0.11 mmol) prepared in step 5 above was dissolved in N,N'-dimethylformamide (3 mL). (4R)-3-methyl-L-valyl-4-hydroxy-N-[[4-(4-methyl-5-thiazolyl)phenyl]methyl]-L-prolinamide, monohydrochloride ((4R) -3-methyl-L-valyl-4-hydroxy-N-[[4-(4-methyl-5-thiazolyl)phenyl]methyl]-L-prolinamide, monohydrochloride)(54 mg, 0.13 mmol), 1-[ Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-hexafluorophosphate oxide (1-[Bis(dimethylamino)methylene]-1H-1,2, 3-triazolo[4,5-b]pyridinium 3-Oxide Hexafluorophosphate) (48 mg, 0.13 mmol) and diisopropylethylamine (41 mg, 0.31 mmol) were added and stirred at room temperature for 15 hours. When the reaction was completed, ethyl acetate and distilled water were added to separate the layers, and the organic layer was recovered, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(5-(4-(((S)-1-((2S,4R)-4-hyde Roxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino) -4-oxobutoxy)naphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11, 11a-Tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide (20 mg, 20%) was obtained, designated as DT02P027.

^1H NMR(CDCl3) 8.70(s, 1H), 8.14(d, 1H), 8.01-7.97(t, 1H), 7.50-7.34(m, 9H), 6.84-6.82(d, 1H), 6.78- 6.76(d, 1H), 6.35-6.31(t, 1H), 5.83-5.81(d, 1H), 5.70(s, 1H), 5.62-5.60(d, 1H),4.65-4.52(m, 4H), 4.36-4.31(m, 1H), 4.19-4.14(m, 2H), 4.06-4.04(d, 1H), 3.77-3.72(m, 1H), 3.62-3.60(m,1H), 3.38-3.31(m) , 3H), 2.56-2.50(m, 6H), 2.44-2.38(m, 2H), 2.31-2.24(m, 3H), 2.14-2.11(m, 2H), 1.48-1.42(m, 4H), 1.30 -1.26(m, 7H), 0.91(s, 10H), 0.84(s, 3H), 0.81(s,3H).

2-6. (4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(5-(2-(2-(((S)-1-((2S,4R)-4-hydroxy-2-( (4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-2-oxo Toxy)ethoxy)naphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a- Tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide((4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(5-(2-(2- (((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl -1-oxobutan-2-yl)amino)-2-oxoethoxy)ethoxy)naphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8 ,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide) production

Step 1: Preparation of tert-butyl(5-hydroxynaphthalen-1-yl)carbamate

5-aminonaphthalen-1-ol (10 g, 62.9 mmol) and (Boc)2O (20 g, 91.7 mmol) were dissolved in methanol (20 mL) and incubated at 60°C for 8 hours. It was stirred. When the reaction was completed, the mixture was concentrated under reduced pressure and the residue was purified by column chromatography to obtain tert-butyl(5-hydroxynaphthalen-1-yl)carbamate (13 g, 80%).

Step 2: Ethyl 2-(2-((5-((tert-butoxycarbonyl)amino)naphthalen-1-yl)oxy)ethoxy)acetate (ethyl 2-(2-((5-((tert Preparation of -butoxycarbonyl)amino)naphthalen-1-yl)oxy)ethoxy)acetate)

The compound prepared in step 1 (261 mg, 1.5 mmol) and ethyl 2-(2-(tosyloxy)ethoxy)acetate (365 mg, 1.2 mmol) ) was dissolved in N,N'-dimethylformamide (3 mL). Cesium carbonate (657 mg, 2.0 mmol) was added dropwise and stirred at 60°C for 4 hours. When the reaction was completed, ethyl acetate and distilled water were added to separate the layers, and the organic layer was recovered, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography to obtain ethyl 2-(2-((5-((tert-butoxycarbonyl)amino)naphthalen-1-yl)oxy)ethoxy)acetate (247 mg, 63%) did.

Step 3: Ethyl 2-(2-((5-aminonaphthalen-1-yl)oxy)ethoxy)acetate hydrochloride (ethyl 2-(2-((5-aminonaphthalen-1-yl)oxy)ethoxy)acetate manufacture of hydrochloride)

The compound (247 mg, 0.63 mmol) prepared in step 2 was dissolved in ethyl acetate (4 mL). 6N HCl solution (4 mL) dissolved in ethyl acetate was added and stirred at room temperature for 15 hours. When the reaction was completed, it was concentrated under reduced pressure and dried to obtain ethyl 2-(2-((5-aminonaphthalen-1-yl)oxy)ethoxy)acetate hydrochloride (173 mg, 100%).

Step 4: Ethyl 2-(2-((5-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6, 6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamido)naphthalen-1-yl)oxy) Toxy)acetate (ethyl 2-(2-((5-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6 ,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamido)naphthalen-1-yl)oxy)ethoxy)acetate) manufacturing

The compound (186 mg, 0.54 mmol) prepared in step 3 was dissolved in dichloromethane (4 mL). Oxalyl chloride (365 mg, 2.87 mmol) and a small amount of N,N'-dimethylformamide were added and stirred at room temperature for 1 hour. When the reaction was completed, it was concentrated under reduced pressure and dissolved in 1,4-dioxane (3 mL). 3-oxo-4-aza-5α-androst-1-ene-17βcarboxylic (3-oxo-4-aza-5α-androst-1-ene-17β) (173 mg, 0.53 mmol) and triethyl Amine (178 mg, 1.76 mmol) was added and stirred at 80°C for 2 hours. When the reaction was completed, ethyl acetate and distilled water were added to separate the layers, and the organic layer was recovered, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography to obtain ethyl 2-(2-((5-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl-2-oxo-2,4a,4b ,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamido)naphthalene-1- I)oxy)ethoxy)acetate (30 mg, 10%) was obtained.

Step 5: 2-(2-((5-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a ,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamido)naphthalen-1-yl)oxy)ethoxy ) Acetic acid (2-(2-((5-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a ,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamido)naphthalen-1-yl)oxy)ethoxy)acetic acid)

The compound (30 mg, 0.05 mmol) prepared in step 4 was dissolved in tetrahydrofuran/methanol/water (2 mL/1 mL/1 mL). Lithium hydroxide monohydrate (9 mg, 0.20 mmol) was added dropwise and stirred at 50°C for 3 hours. When the reaction is completed, titrate with 0.5N HCl solution, concentrate under reduced pressure, and dry to obtain 2-(2-((5-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl-2- Oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-car Copamido)naphthalen-1-yl)oxy)ethoxy)acetic acid (29 mg, 100%) was obtained.

Step 6: (4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(5-(2-(2-(((S)-1-((2S,4R)-4-hydroxy- 2-((4-(4-methyltriazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-2 -oxoethoxy)ethoxy)naphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11 ,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide (4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(5-(2-( 2-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3 -dimethyl-1-oxobutan-2-yl)amino)-2-oxoethoxy)ethoxy)naphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7 Preparation of ,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide

The compound (29 mg, 0.05 mmol) prepared in step 5 above was dissolved in N,N'-dimethylformamide (3 mL). (4R)-3-methyl-L-valyl-4-hydroxy-N-[[4-(4-methyl-5-thiazolyl)phenyl]methyl]-L-prolinamide, monohydrochloride ((4R) -3-methyl-L-valyl-4-hydroxy-N-[[4-(4-methyl-5-thiazolyl)phenyl]methyl]-L-prolinamide, monohydrochloride)(28 mg, 0.06 mmol), 1-[ Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-hexafluorophosphate oxide (1-[Bis(dimethylamino)methylene]-1H-1,2, 3-triazolo[4,5-b]pyridinium 3-Oxide Hexafluorophosphate) (24 mg, 0.06 mmol) and diisopropylethylamine (21 mg, 0.16 mmol) were added and stirred at room temperature for 15 hours. When the reaction was completed, ethyl acetate and distilled water were added to separate the layers, and the organic layer was recovered, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(5-(2-(2-(((S)-1-((2S,4R)- 4-hydroxy-2-((4-(4-methyltriazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl )amino)-2-oxoethoxy)ethoxy)naphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a, 9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide (12 mg, 24%) was obtained, designated as DT02P028.

2-7. (4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(5-(3-(2-(((S)-1-((2S,4R)-4-hydroxy-2-( (4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-2-oxo Toxy)propoxy)naphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a- Tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide((4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(5-(3-(2- (((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl -1-oxobutan-2-yl)amino)-2-oxoethoxy)propoxy)naphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8 ,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide) production

Step 1: Preparation of tert-butyl(5-hydroxynaphthalen-1-yl)carbamate

5-aminonaphthalen-1-ol (10 g, 62.9 mmol) and (Boc)2O (20 g, 91.7 mmol) were dissolved in methanol and stirred at 60°C for 8 hours. When the reaction was completed, the mixture was concentrated under reduced pressure and the residue was purified by column chromatography to obtain tert-butyl(5-hydroxynaphthalen-1-yl)carbamate (13 g, 80%).

Step 2: Ethyl 2-(3-((5-((tert-butoxycarbonyl)amino)naphthalen-1-yl)oxy)propoxy)acetate (ethyl 2-(3-((5-((tert Preparation of -butoxycarbonyl)amino)naphthalen-1-yl)oxy)propoxy)acetate)

The compound prepared in step 1 (420 mg, 1.62 mmol) and ethyl 2-(3-(tosyloxy)propoxy)acetate (616 mg, 1.95 mmol) ) was dissolved in N,N'-dimethylformamide (5 mL). Cesium carbonate (1.1 g, 3.24 mmol) was added dropwise and stirred at 60°C for 4 hours. When the reaction was completed, ethyl acetate and distilled water were added to separate the layers, and the organic layer was recovered, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography to obtain ethyl 2-(3-((5-((tert-butoxycarbonyl)amino)naphthalen-1-yl)oxy)propoxy)acetate (300 mg, 46%) did.

Step 3: Ethyl 2-(3-((5-aminonaphthalen-1-yl)oxy)propoxy)acetate hydrochloride (ethyl 2-(3-((5-aminonaphthalen-1-yl)oxy)propoxy)acetate manufacture of hydrochloride)

The compound (300 mg, 0.74 mmol) prepared in step 2 was dissolved in ethyl acetate (6 mL). 6N HCl solution (6 mL) dissolved in ethyl acetate was added and stirred at room temperature for 15 hours. When the reaction was completed, it was concentrated under reduced pressure and dried to obtain ethyl 2-(3-((5-aminonaphthalen-1-yl)oxy)propoxy)acetate hydrochloride (232 mg, 92%).

Step 4: Ethyl 2-(3-((5-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6, 6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamido)naphthalen-1-yl)oxy)prop Oxy)acetate (ethyl 2-(3-((5-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6 ,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamido)naphthalen-1-yl)oxy)propoxy)acetate) manufacturing

The compound (239 mg, 0.75 mmol) prepared in step 3 was dissolved in dichloromethane (4 mL). Oxalyl chloride (469 mg, 3.69 mmol) and a small amount of N,N'-dimethylformamide were added and stirred at room temperature for 1 hour. When the reaction was completed, it was concentrated under reduced pressure and dissolved in 1,4-dioxane (6 mL). 3-oxo-4-aza-5α-androst-1-ene-17βacid) (232 mg, 0.68 mmol) and triethyl Amine (228 mg, 2.26 mmol) was added and stirred at 80°C for 2 hours. When the reaction was completed, ethyl acetate and distilled water were added to separate the layers, and the organic layer was recovered, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography to obtain ethyl 2-(3-((5-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl-2-oxo-2,4a,4b ,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamido)naphthalene-1- I)oxy)propoxy)acetate (62 mg, 15%) was obtained.

Step 5: 2-(3-((5-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a ,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamido)naphthalen-1-yl)oxy)propoxy ) Acetic acid (2-(3-((5-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a Preparation of ,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamido)naphthalen-1-yl)oxy)propoxy)acetic acid)

The compound (62 mg, 0.10 mmol) prepared in step 4 was dissolved in tetrahydrofuran/methanol/water (2 mL/1 mL/1 mL). Lithium hydroxide monohydrate (17 mg, 0.41 mmol) was added dropwise and stirred at 50°C for 3 hours. When the reaction is completed, titrate with 0.5N HCl solution, concentrate under reduced pressure, and dry to obtain 2-(3-((5-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl-2- Oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-car Copamido)naphthalen-1-yl)oxy)propoxy)acetic acid (59 mg, 100%) was obtained.

Step 6: (4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(5-(3-(2-(((S)-1-((2S,4R)-4-hydroxy- 2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-2 -oxoethoxy)propoxy)naphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11 ,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide (4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(5-(3-( 2-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3 -dimethyl-1-oxobutan-2-yl)amino)-2-oxoethoxy)propoxy)naphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7 Preparation of ,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide

The compound (59 mg, 0.10 mmol) prepared in step 5 above was dissolved in N,N'-dimethylformamide (3 mL). (4R)-3-methyl-L-valyl-4-hydroxy-N-[[4-(4-methyl-5-thiazolyl)phenyl]methyl]-L-prolinamide, monohydrochloride ((4R) -3-methyl-L-valyl-4-hydroxy-N-[[4-(4-methyl-5-thiazolyl)phenyl]methyl]-L-prolinamide, monohydrochloride)(53 mg, 0.12 mmol), 1-[ Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-hexafluorophosphate oxide (1-[Bis(dimethylamino)methylene]-1H-1,2, 3-triazolo[4,5-b]pyridinium 3-Oxide Hexafluorophosphate) (47 mg, 0.12 mmol) and diisopropylethylamine (40 mg, 0.31 mmol) were added and stirred at room temperature for 15 hours. When the reaction was completed, ethyl acetate and distilled water were added to separate the layers, and the organic layer was recovered, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(5-(3-(2-(((S)-1-((2S,4R)- 4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl )amino)-2-oxoethoxy)propoxy)naphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a, 9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide (15 mg, 15%) was obtained, designated as DT02P029.

^1H NMR(CDCl3) 8.70(s, 1H), 8.12-8.10(d, 1H), 8.06-8.01(t, 1H), 7.48-7.34(m, 9H), 7.20-7.18(d, 1H), 6.87 -6.85(d,1H), 6.84-6.81(m, 1H), 5.85-5.83(d, 1H), 5.47(s, 1H), 4.70-4.66(s, 1H), 4.61-4.50(m, 3H) , 4.30-4.27(m, 2H), 4.02-4.00(m, 2H), 3.87-3.82(m, 3H), 3.75-3.73(m, 2H), 3.63-3.59(m, 2H), 3.38(s, 3H), 2.52-2.51(m, 3H), 2.29-2.24(m, 4H), 2.07(s, 6H), 2.03(s, 1H), 1.10-1.08(d, 2H), 1.01(s, 2H) , 0.85-0.91(m, 17H).

2-8. (4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(5-(2-(2-(2-(((S)-1-((2S,4R)-4-hydroxy- 2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-2 -oxoethoxy)ethoxy)ethoxy)naphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b, 10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide ((4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(5- (2-(2-(2-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1 -yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-2-oxoethoxy)ethoxy)ethoxy)naphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a, Preparation of 4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide)

Step 1: tert-Butyl 2-(2-(2-((5-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl-2-oxo-2,4a,4b ,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamido)naphthalene-1- 1)oxy)ethoxy)ethoxy)acetate (tert-butyl 2-(2-(2-((5-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl- 2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamido) Preparation of naphthalen-1-yl)oxy)ethoxy)ethoxy)acetate)

I-2 (1.0 g, 2.18 mmol) and tert-butyl 2-(2-(2-bromoethoxy)ethoxy)acetate (741 mg, 2.62 mmol, 1.2 eq) and cesium carbonate (1.4 g, 4.36 mmol) were dissolved in N,N'-dimethylformamide (10.0 ml) and stirred at 60°C for 18 hours. When the reaction was completed, ethyl acetate (50 mL) and distilled water (50 mL) were added to separate the layers, and the organic layer was recovered, anhydrous sodium sulfate was added, and filtered. The filtrate was concentrated and purified by column chromatography to produce tert-butyl 2-(2-(2-((5-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl- 2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7 -Carboxamido)naphthalen-1-yl)oxy)ethoxy)ethoxy)acetate (1.0 g, 76%) was obtained.

Step 2: 2-(2-(2-((5-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl-2-oxo-2,4a,4b,5, 6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamido)naphthalen-1-yl)oxy )Ethoxy)ethoxy)acetic acid (2-(2-(2-((5-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl-2-oxo-2, 4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamido)naphthalen-1-yl) Production of oxy)ethoxy)ethoxy)acetic acid)

The compound prepared in step 1 (1.0 g, 1.65 mmol) was dissolved in trifluoroacetic acid (1.0 mL) and stirred at room temperature for 2 hours. When the reaction was completed, it was concentrated and the next reaction proceeded without filtration.

Step 3: (4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(5-(2-(2-(2-(((S)-1-((2S,4R)-4- Hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino )-2-oxoethoxy)ethoxy)ethoxy)naphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a ,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide (4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-( 5-(2-(2-(2-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin -1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-2-oxoethoxy)ethoxy)ethoxy)naphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2, Preparation of 4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide

The compound prepared in step 2 was dissolved in N,N'-dimethylformamide (10.0 ml), diisopropylethylamide (2.9 mL, 16.5 mmol) was added, and the mixture was stirred at room temperature for 5 minutes. (S,R,S)-AHPC hydrochloride (927 mg, 1.98 mmol), 1-[Bis(dimethylamino)methylene]-1H-1,2,3- 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-Oxide Hexafluorophosphate) (943 mg, 2.48 mmol) was added dropwise and stirred at room temperature for 5 hours. When the reaction was completed, ethyl acetate (50 mL) and distilled water (50 mL) were added to separate the layers, and the organic layer was recovered, anhydrous sodium sulfate was added, and filtered. The filtrate was concentrated and purified by column chromatography (4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(5-(2-(2-(2-(((S)-1-(( 2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxo butan-2-yl) amino)-2-oxoethoxy)ethoxy)ethoxy)naphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a, 7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide (1.0 g, 59%) was obtained, Marked as DT02P030.

^1H NMR (400 MHz, DMSO) δ9.52(s, 2H), 8.95(s, 2H), 8.63-8.55(m, 2H), 8.02(d, J = 8.3 Hz, 2H), 7.66(d, J = 7.3 Hz, 2H), 7.59 (d, J = 8.6 Hz, 2H), 7.49-7.36 (m, 17H), 6.97 (d, J = 7.7 Hz, 2H), 6.85 (d, J = 9.9 Hz, 2H), 5.62(d, J = 9.9 Hz, 2H), 4.57(d, J = 9.5 Hz, 2H), 4.45(t, J = 8.1 Hz, 2H), 4.42-4.20(m, 11H), 4.04- 3.88 (m, 9H), 3.80-3.56 (m, 14H), 3.24-3.15 (m, 3H), 2.64 (t, J = 9.2 Hz, 2H), 2.42 (s, 6H), 2.20-1.95 (m, 10H), 1.95-1.72(m, 7H), 1.63(m, J = 31.1, 14.3 Hz, 9H), 1.41(m, J = 26.1, 12.7 Hz, 7H), 1.34-1.12(m, 11H), 1.08 -0.97(m, 5H), 0.93(s, 19H), 0.87(s, 8H), 0.72(s, 7H).

2-9. 2-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b ,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamido)-2-methylpropyl 7-(((S)-1-((2S,4R )-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutane-2 -yl)amino)-7-oxoheptanoate (2-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl-2-oxo-2,4a,4b,5, 6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamido)-2-methylpropyl 7-(((S)- 1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2 Preparation of -yl)amino)-7-oxoheptanoate)

Step 1: 2-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9, 9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamido)-2-methylpropyl 7-(((S)-1-(( 2S,4R)-4-((4-methoxybenzyl)oxy)-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3 ,3-dimethyl-1-oxobutan-2-yl)amino)-7-oxoheptanoate (2-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl-2 -oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamido)- 2-methylpropyl 7-(((S)-1-((2S,4R)-4-((4-methoxybenzyl)oxy)-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl) Preparation of pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-7-oxoheptanoate)

II-1 (200 mg, 0.29 mmol) was dissolved in N,N'-dimethylformamide (4.0 ml). 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride (67 mg, 0.43 mmol), 4-(dimethylamino)pyridine (4-(Dimethylamino)pyridine) (39 mg, 0.32 mmol) and I-11 (113 mg, 0.29 mmol) were added and stirred at room temperature for 15 hours. When the reaction was completed, ethyl acetate (50 mL) and distilled water (50 mL) were added to separate the layers, and the organic layer was recovered, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography to obtain 2-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7 ,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamido)-2-methylpropyl 7-(((S) -1-((2S,4R)-4-((4-methoxybenzyl)oxy)-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidine-1 -yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-7-oxoheptanoate (90 mg, 29%) was obtained.

Step 2: 2-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9, 9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamido)-2-methylpropyl 7-(((S)-1-(( 2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxo Butan-2-yl) amino)-7-oxoheptanoate (2-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl-2-oxo-2,4a,4b ,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamido)-2-methylpropyl 7-((( S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1- Preparation of oxobutan-2-yl)amino)-7-oxoheptanoate)

The compound (20 mg, 0.02 mmol) prepared in step 1 was dissolved in dichloromethane (1 mL). 4N HCl solution (1.0 mL) diluted in 1,4-dioxane was added and stirred at room temperature for 5 hours. When the reaction is completed, concentrate and dry under reduced pressure to obtain 2-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a, 7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamido)-2-methylpropyl 7-(((S )-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3 -Dimethyl-1-oxobutan-2-yl)amino)-7-oxoheptanoate (28 mg, 100%) was obtained, designated as DTO2P031.

^1H NMR (CDCl3, 400MHz) 8.69 (s, 1H), 7.38-7.35 (m, 5H), 7.15 (d, 1H), 6.78-6.76 (d, 1H), 5.84-5.81 (m, 1H), 5.61 (s, 1H), 5.33(s, 1H), 4.75-4.70(m, 1H), 4.53-4.46(m, 3H), 4.39-4.37(d, 1H), 4.10-4.08(d, 1H), 3.98 (s, 2H), 3.70-3.68(d, 2H), 3.64(d, 1H), 3.57-3.55(d, 1H), 3.48-3.45(m, 3H), 2.51(s, 4H), 2.16-2.14 (m, 3H), 1.98-1.95(m, 10H), 1.75-1.72(m, 6H), 1.60-1.58(m, 2H), 1.44-1.42(m, 6H), 1.38-1.35(m, 2H) , 1.26-1.24(m, 1H), 1.08 -0.99(m, 14H).

2-10. 2-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b ,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamido)-2-methylpropyl 12-(((S)-1-((2S,4R )-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutane-2 -yl)amino)-12-oxododecanoate (2-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl-2-oxo-2,4a,4b,5, 6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamido)-2-methylpropyl 12-(((S)- 1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2 Preparation of -yl)amino)-12-oxododecanoate)

Step 1: 2-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9, 9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamido)-2-methylpropyl 12-(((S)-1-(( 2S,4R)-4-((4-methoxybenzyl)oxy)-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3 ,3-dimethyl-1-oxobutan-2-yl)amino)-12-oxododecanoate (2-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl-2 -oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamido)- 2-methylpropyl 12-(((S)-1-((2S,4R)-4-((4-methoxybenzyl)oxy)-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl) Preparation of pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-12-oxododecanoate)

II-2 (96 mg, 0.13 mmol) was dissolved in N,N'-dimethylformamide (4.0 ml). 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride (29 mg, 0.19 mmol), 4-(dimethylamino)pyridine (4-(Dimethylamino)pyridine) (17 mg, 0.14 mmol) and I-11 (49 mg, 0.13 mmol) were added and stirred at room temperature for 15 hours. When the reaction was completed, ethyl acetate (50 mL) and distilled water (50 mL) were added to separate the layers, and the organic layer was recovered, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography to obtain 2-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7 ,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamido)-2-methylpropyl 12-(((S) -1-((2S,4R)-4-((4-methoxybenzyl)oxy)-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidine-1 -yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-12-oxododecanoate (45 mg, 31%) was obtained.

Step 2: 2-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9, 9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamido)-2-methylpropyl 12-(((S)-1-(( 2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxo Butan-2-yl)amino)-12-oxododecanoate (2-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl-2-oxo-2,4a,4b ,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamido)-2-methylpropyl 12-((( S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1- Preparation of oxobutan-2-yl)amino)-12-oxododecanoate)

The compound (45 mg, 0.04 mmol) prepared in step 1 was dissolved in dichloromethane (1 mL). 4N HCl solution (0.1 mL) diluted in 1,4-dioxane was added and stirred at room temperature for 5 hours. When the reaction was completed, the layers were separated with dichloromethane and distilled water, and the organic layer was recovered, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography to obtain 2-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7 ,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamido)-2-methylpropyl 12-(((S) -1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3- Dimethyl-1-oxobutan-2-yl)amino)-12-oxododecanoate (10 mg, 25%) was obtained, designated as DTO2P032.

^1H NMR (CDCl3, 400MHz) 8.70 (s, 1H), 7.39-7.36 (m, 5H), 7.15-7.13 (d, 1H), 6.78-6.76 (d, 1H), 5.81-5.79 (m, 1H) , 5.60(s, 1H), 5.32(s, 1H), 4.75-4.70(m, 1H), 4.53-4.46(m, 3H), 4.37-4.35(d, 1H), 4.10(d, 1H), 3.98 (s, 2H), 3.68-3.66(d, 2H), 3.64-3.62(d, 1H), 3.57-3.55(d, 1H), 3.46-3.43(m, 3H), 2.50-2.48(m, 4H) , 2.15-2.13(m, 3H), 1.98-1.95(m, 10H), 1.75-1.72(m, 6H), 1.60-1.58(m, 2H), 1.44-1.42(m, 6H), 1.38-1.35( m, 2H), 1.26-1.24(m, 1H), 1.10-0.98(m, 16H).

2-11. 8-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidine-1- yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-8-oxooctyl 2-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl- 2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7 -Carboxamido)-2-methylpropanoate (8-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl )carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-8-oxooctyl 2-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a ,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline Preparation of -7-carboxamido)-2-methylpropanoate)

Step 1: (2S,4R)-1-((S)-2-(8-bromooctanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4- Methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide ((2S,4R)-1-((S)-2-(8-bromooctanamido)-3,3-dimethylbutanoyl)-4- Preparation of hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide)

(S,R,S)-AHPC hydrochloride ((S,R,S)-AHPC HYDROCHLORIDE) (1.0 g, 2.1 mmol) was dissolved in N,N'-dimethylformamide (10 mL). 8-bromooctanoic acid (0.4 g, 2.1 mmol), 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3 -Hexafluorophosphate (1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-Oxide Hexafluorophosphate) (0.7 g, 2.4 mmol), diisopropylethyl Amide (0.56 mL, 3.2 mmol) was added and stirred at room temperature for 15 hours. When the reaction was completed, ethyl acetate (50 mL) and distilled water (50 mL) were added to separate the layers, and the organic layer was recovered, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (2S,4R)-1-((S)-2-(8-bromooctanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-( 4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (0.4 g, 31%) was obtained.

Step 2: 8-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidine -1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-8-oxooctyl 2-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a -Dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f] Quinoline-7-carboxamido)-2-methylpropanoate (8-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5- yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-8-oxooctyl 2-((4aR,4bS,6aS,7S,9aS,9bS,11aR )-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4- Preparation of f]quinoline-7-carboxamido)-2-methylpropanoate)

The compound prepared in step 1 (100 mg, 0.16 mmol) was dissolved in N,N'-dimethylformamide (2 mL). 3-oxo-4-aza-5α-androst-1-ene-17βoxylic acid (95 mg, 0.24 mmol), carbonic acid Potassium carbonate (33 mg, 0.24 mmol) was added and stirred at room temperature for 15 hours. When the reaction was completed, ethyl acetate (50 mL) and distilled water (50 mL) were added to separate the layers, and the organic layer was recovered, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography to obtain 8-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carba Moyl) pyrrolidin-1-yl) -3,3-dimethyl-1-oxobutan-2-yl) amino) -8-oxooctyl 2-((4aR, 4bS, 6aS, 7S, 9aS, 9bS, 11aR )-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5 ,4-f]quinoline-7-carboxamido)-2-methylpropanoate (10 mg, 6%) was obtained, which was designated as DT02P033.

2-12. 12-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidine-1- Il)-3,3-dimethyl-1-oxobutan-2-yl)amino)-12-oxododecyl 2-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl -2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline- 7-Carboxamido)-2-methylpropanoate (12-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl) benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-12-oxododecyl 2-((4aR,4bS,6aS,7S,9aS,9bS,11aR)- 4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f] Preparation of quinoline-7-carboxamido)-2-methylpropanoate)

Step 1: (2S,4R)-1-((S)-2-(12-bromododecanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4- Methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide ((2S,4R)-1-((S)-2-(12-bromododecanamido)-3,3-dimethylbutanoyl)-4- Preparation of hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide)

(S,R,S)-AHPC hydrochloride ((S,R,S)-AHPC HYDROCHLORIDE) (1.0 g, 2.1 mmol) was dissolved in N,N'-dimethylformamide (10 mL). 12-bromododecanoic acid (0.6 g, 2.1 mmol), 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-Hexafluorophosphate (1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-Oxide Hexafluorophosphate) (0.7 g, 2.4 mmol), diisopropyl Ethylamide (0.56 mL, 3.2 mmol) was added and stirred at room temperature for 15 hours. When the reaction was completed, ethyl acetate (50 mL) and distilled water (50 mL) were added to separate the layers, and the organic layer was recovered, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (2S,4R)-1-((S)-2-(12-bromododecanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-( 4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (0.3 g, 23%) was obtained.

Step 2: 12-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidine -1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-12-oxododecyl 2-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a, 6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f ]quinoline-7-carboxamido)-2-methylpropanoate (12-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5 -yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-12-oxododecyl 2-((4aR,4bS,6aS,7S,9aS,9bS, 11aR)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4 -f]quinoline-7-carboxamido)-2-methylpropanoate) Preparation

The compound (100 mg, 0.14 mmol) prepared in Step 1 was dissolved in N,N'-dimethylformamide (2 mL). 3-oxo-4-aza-5α-androst-1-ene-17βacid) (87 mg, 0.22 mmol), potassium carbonate (potassium carbonate) (30 mg, 0.22 mmol) was added and stirred at room temperature for 15 hours. When the reaction was completed, ethyl acetate (50 mL) and distilled water (50 mL) were added to separate the layers, and the organic layer was recovered, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography to obtain 12-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carba moyl) pyrrolidin-1-yl) -3,3-dimethyl-1-oxobutan-2-yl) amino) -12-oxododecyl 2-((4aR, 4bS, 6aS, 7S, 9aS, 9bS, 11aR)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[ 5,4-f]quinoline-7-carboxamido)-2-methylpropanoate (20 mg, 14%) was obtained, designated as DT02P034.

^1H NMR (CDCl3, 400MHz) 8.68 (s, 1H), 7.40-7.37 (m, 5H), 7.14 (d, 1H), 6.77-6.75 (d, 1H), 5.80-5.78 (m, 1H), 5.58 (s, 1H), 5.32(s, 1H), 4.75-4.70(m, 2H), 4.53-4.46(m, 3H), 4.35-4.33(d, 1H), 4.15-4.13(d, 1H), 3.98 (s, 2H), 3.69-3.67(d, 2H), 3.65-3.63(d, 1H), 3.57-3.55(d, 1H), 3.46-3.43(m, 3H), 2.50-2.48(m, 4H) , 2.15-2.13(m, 3H), 2.10(s, 6H), 1.99-1.96(m, 10H), 1.75-1.72(m, 6H), 1.60-1.58(m, 2H), 1.44-1.39(m, 6H), 1.38-1.32(m, 4H), 1.28-1.24(m, 3H), 1.12-1.00(m, 12H).

2-13. 10-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidine-1- yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-10-oxodecyl 2-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl- 2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7 -Carboxamido)-2-methylpropanoate (10-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl )carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-10-oxodecyl 2-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a ,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline Preparation of -7-carboxamido)-2-methylpropanoate)

Step 1: (2S,4R)-1-((S)-2-(10-bromodecaneamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4- Methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide ((2S,4R)-1-((S)-2-(10-bromodecanamido)-3,3-dimethylbutanoyl)-4- Preparation of hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide)

(S,R,S)-AHPC hydrochloride ((S,R,S)-AHPC HYDROCHLORIDE) (1.0 g, 2.1 mmol) was dissolved in N,N'-dimethylformamide (10 mL). 10-bromodecanoic acid (0.5 g, 2.1 mmol), 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-Hexafluorophosphate (1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-Oxide Hexafluorophosphate) (0.7 g, 2.4 mmol), diisopropyl Ethylamide (0.56 mL, 3.2 mmol) was added and stirred at room temperature for 15 hours. When the reaction was completed, ethyl acetate (50 mL) and distilled water (50 mL) were added to separate the layers, and the organic layer was recovered, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (2S,4R)-1-((S)-2-(10-bromodecanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-( 4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (0.3 g, 27%) was obtained.

Step 2: 10-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidine -1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-10-oxodecyl 2-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a -Dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f] Quinoline-7-carboxamido)-2-methylpropanoate (10-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5- yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-10-oxodecyl 2-((4aR,4bS,6aS,7S,9aS,9bS,11aR )-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4- Preparation of f]quinoline-7-carboxamido)-2-methylpropanoate)

The compound (100 mg, 0.15 mmol) prepared in step 1 was dissolved in N,N'-dimethylformamide (2 mL). 3-oxo-4-aza-5α-androst-1-ene-17βcarboxylic acid (3-oxo-4-aza-5α-androst-1-ene-17βacid) (61 mg, 0.15 mmol), potassium carbonate (potassium carbonate) (31 mg, 0.23 mmol) was added and stirred at room temperature for 15 hours. When the reaction was completed, ethyl acetate (50 mL) and distilled water (50 mL) were added to separate the layers, and the organic layer was recovered, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography to obtain 10-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carba Moyl) pyrrolidin-1-yl) -3,3-dimethyl-1-oxobutan-2-yl) amino) -10-oxodecyl 2-((4aR, 4bS, 6aS, 7S, 9aS, 9bS, 11aR )-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5 ,4-f]quinoline-7-carboxamido)-2-methylpropanoate (15 mg, 10%) was obtained, which was designated as DT02P035.

^1H NMR (CDCl3, 400MHz) 8.68 (s, 1H), 7.40-7.37 (m, 5H), 7.15-7.13 (d, 1H), 6.77-6.75 (d, 1H), 5.78-5.76 (m, 1H) , 5.58(s, 1H), 5.32(s, 1H), 4.75-4.70(m, 2H), 4.53-4.46(m, 3H), 4.35-4.33(d, 1H), 4.13-4.11(d, 1H) , 3.98(s, 2H), 3.66-3.64(m, 3H), 3.58-3.55(d, 1H), 3.45-3.42(m, 3H), 2.51-2.49(m, 4H), 2.16-2.13(m, 3H), 2.10(s, 6H), 2.00-1.98(m, 10H), 1.74-1.70(m, 6H), 1.60-1.58(m, 2H), 1.45-1.40(m, 6H), 1.39-1.35( m, 2H), 1.28-1.24(m, 2H), 1.09-1.02(m, 10H).

2-14. 2-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-ethyl-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9 ,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamido)ethyl 7-(((S)-1-((2S,4R )-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutane-2 -yl)amino)-7-oxoheptanoate (2-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-ethyl-4a,6a-dimethyl-2-oxo-2,4a, 4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamido)ethyl 7-(((S) -1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan- Preparation of 2-yl)amino)-7-oxoheptanoate)

Step 1: 2-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-ethyl-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7, 8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamido)ethyl 7-(((S)-1-(( 2S,4R)-4-((4-methoxybenzyl)oxy)-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3 ,3-dimethyl-1-oxobutan-2-yl)amino)-7-oxoheptanoate (2-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-ethyl-4a,6a -dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7 -carboxamido)ethyl 7-(((S)-1-((2S,4R)-4-((4-methoxybenzyl)oxy)-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl ) Preparation of pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-7-oxoheptanoate)

II-1 (100 mg, 0.14 mmol) was dissolved in N,N'-dimethylformamide (4.0 ml). 1-Ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride (34 mg, 0.21 mmol), 4-(Dimethylamino)pyridine ( 20 mg, 0.16 mmol) and I-10 (113 mg, 0.29 mmol) were added and stirred at room temperature for 15 hours. When the reaction was completed, ethyl acetate (50 mL) and distilled water (50 mL) were added to separate the layers, and the organic layer was recovered, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography to obtain 2-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-ethyl-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6 ,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamido)ethyl 7-(((S) -1-((2S,4R)-4-((4-methoxybenzyl)oxy)-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidine-1 -yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-7-oxoheptanoate (67 mg, 44%) was obtained.

Step 2: 2-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-ethyl-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7, 8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamido)ethyl 7-(((S)-1-(( 2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxo Butan-2-yl) amino)-7-oxoheptanoate (2-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-ethyl-4a,6a-dimethyl-2-oxo-2 ,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamido)ethyl 7-(( (S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1 Preparation of -oxobutan-2-yl)amino)-7-oxoheptanoate)

The compound (31 mg, 0.03 mmol) prepared in step 1 was dissolved in dichloromethane (1 mL). 4N HCl solution (1.0 mL) diluted in 1,4-dioxane was added and stirred at room temperature for 5 hours. When the reaction was completed, ethyl acetate (50 mL) and distilled water (50 mL) were added to separate the layers, and the organic layer was recovered, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography to obtain 2-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-ethyl-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6 ,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamido)ethyl 7-(((S) -1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3- Dimethyl-1-oxobutan-2-yl)amino)-7-oxoheptanoate (13 mg, 48%) was obtained, designated as DT02P036.

^1H NMR (CDCl3, 400MHz) 8.70 (s, 1H), 7.39-7.35 (m, 5H), 7.14 (d, 1H), 6.78-6.76 (d, 1H), 5.82-5.80 (m, 1H), 5.58 (s, 1H), 5.33(s, 1H), 4.75-4.73(m, 2H), 4.53-4.46(m, 3H), 4.30-4.27(m, 3H), 3.98(s, 2H), 3.68(d) , 2H), 3.66-3.64(d, 1H), 3.58-3.55(d, 1H), 3.45-3.42(m, 3H), 2.51-2.49(m, 4H), 2.16-2.13(m, 3H), 1.99 -1.95(m, 2H), 1.74-1.70(m, 4H), 1.45-1.40(m, 6H), 1.39-1.35(m, 2H), 1.28-1.23(m, 5H), 1.09-1.02(m, 7H).

2-15. 2-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-ethyl-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9 ,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamido)ethyl 12-(((S)-1-((2S,4R )-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutane-2 -yl)amino)-12-oxododecanoate (2-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-ethyl-4a,6a-dimethyl-2-oxo-2,4a, 4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamido)ethyl 12-(((S) -1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan- Preparation of 2-yl)amino)-12-oxododecanoate)

Step 1: 2-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-ethyl-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7, 8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamido)ethyl 12-(((S)-1-(( 2S,4R)-4-((4-methoxybenzyl)oxy)-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3 ,3-dimethyl-1-oxobutan-2-yl)amino)-12-oxododecanoate (2-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-ethyl-4a,6a -dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7 -carboxamido)ethyl 12-(((S)-1-((2S,4R)-4-((4-methoxybenzyl)oxy)-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl ) Preparation of pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-12-oxododecanoate)

II-2 (100 mg, 0.15 mmol) was dissolved in N,N'-dimethylformamide (4.0 ml). 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride (29 mg, 0.19 mmol), 4-(dimethylamino)pyridine (4-(Dimethylamino)pyridine) (17 mg, 0.14 mmol) and I-10 (49 mg, 0.13 mmol) were added and stirred at room temperature for 15 hours. When the reaction was completed, ethyl acetate (50 mL) and distilled water (50 mL) were added to separate the layers, and the organic layer was recovered, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography to obtain 2-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-ethyl-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6 ,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamido)ethyl 12-(((S) -1-((2S,4R)-4-((4-methoxybenzyl)oxy)-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidine-1 -yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-12-oxododecanoate (43 mg, 37%) was obtained.

Step 2: 2-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-ethyl-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7, 8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamido)ethyl 12-(((S)-1-(( 2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxo Butan-2-yl) amino)-12-oxododecanoate (2-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-ethyl-4a,6a-dimethyl-2-oxo-2 ,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamido)ethyl 12-(( (S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1 Preparation of -oxobutan-2-yl)amino)-12-oxododecanoate)

The compound (41 mg, 0.05 mmol) prepared in step 1 was dissolved in dichloromethane (1 mL). 4N HCl solution (0.1 mL) diluted in 1,4-dioxane was added and stirred at room temperature for 5 hours. When the reaction was completed, the layers were separated with dichloromethane and distilled water, and the organic layer was recovered, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography to obtain 2-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-ethyl-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6 ,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamido)ethyl 12-(((S) -1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3- Dimethyl-1-oxobutan-2-yl)amino)-12-oxododecanoate (17 mg, 28%) was obtained, designated as DT02P037.

^1H NMR (CDCl3, 400MHz) 8.70 (s, 1H), 7.40-7.36 (m, 5H), 7.14 (d, 1H), 6.78-6.76 (d, 1H), 5.80-5.78 (m, 1H), 5.58 (s, 1H), 5.32(s, 1H), 4.64-4.50(m, 5H), 4.35-4.33(d, 1H), 4.12-4.10(d, 1H), 3.98(s, 2H), 3.66-3.64 (m, 3H), 3.58-3.55(d, 1H), 3.44-3.41(m, 3H), 2.51-2.49(m, 4H), 2.16-2.13(m, 3H), 1.99-1.95(m, 2H) , 1.74-1.70(m, 4H), 1.45-1.40(m, 4H), 1.39-1.35(m, 2H), 1.30-1.22(m, 6H), 1.06-0.99(m, 8H).

2-16. (4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-((S)-14-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazole- 5-yl)benzyl)carbamoyl)pyrrolidine-1-carbonyl)-2,15,15-trimethyl-3,12-dioxo-7,10-dioxa-4,13-diazahexadecane- 2-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H- No[5,4-f]quinoline-7-carboxamide((4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-((S)-14-((2S,4R)-4- hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidine-1-carbonyl)-2,15,15-trimethyl-3,12-dioxo-7,10-dioxa-4, 13-diazahexadecan-2-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H Preparation of -indeno[5,4-f]quinoline-7-carboxamide)

Step 1: tert-Butyl(2-(2-(2-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazole-5- yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-2-oxoethoxy)ethoxy)ethyl)carbamate (tert- butyl(2-(2-(2-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin- Preparation of 1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-2-oxoethoxy)ethoxy)ethyl)carbamate)

(S,R,S)-AHPC hydrochloride ((S,R,S)-AHPC HYDROCHLORIDE) (1.0 g, 2.1 mmol) was dissolved in N,N'-dimethylformamide (10 mL). Boc-8-amino-3,6-dioxaoctanoic acid (0.5 g, 2.1 mmol), 1-[Bis(dimethylamino)methylene]-1H-1, 2,3-triazolo[4,5-b]pyridinium 3-hexafluorophosphate oxide (1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3 -Oxide Hexafluorophosphate (0.7 g, 2.4 mmol) and diisopropylethylamide (0.56 mL, 3.2 mmol) were added and stirred at room temperature for 15 hours. When the reaction was completed, ethyl acetate (50 mL) and distilled water (50 mL) were added to separate the layers, and the organic layer was recovered, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography to obtain tert-butyl (2-(2-(2-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methyl Thiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-2-oxoethoxy)ethoxy)ethyl) Carbamate (0.3 g, 25%) was obtained.

Step 2: (2S,4R)-1-((S)-2-(2-(2-(2-aminoethoxy)ethoxy)acetamido)-3,3-dimethylbutanoyl)-4- Hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide((2S,4R)-1-((S)-2-(2-( Preparation of 2-(2-aminoethoxy)ethoxy)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide)

The compound (300 mg, 0.4 mmol) prepared in step 1 was dissolved in dichloromethane (5 mL). 4N HCl solution (0.5 mL) diluted in 1,4-dioxane was added and stirred at room temperature for 15 hours. When the reaction was completed, saturated aqueous sodium bicarbonate solution and distilled water were added to separate the layers, and the organic layer was recovered, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was dried to (2S,4R)-1-((S)-2-(2-(2-(2-aminoethoxy)ethoxy)acetamido)-3,3-dimethylbutanoyl)-4 -Hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (200 mg, 87%) was obtained.

Step 3: (4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-((S)-14-((2S,4R)-4-hydroxy-2-((4-(4-methyl Thiazol-5-yl)benzyl)carbamoyl)pyrrolidine-1-carbonyl)-2,15,15-trimethyl-3,12-dioxo-7,10-dioxa-4,13-diaza hexadecane-2-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro- 1H-indeno[5,4-f]quinoline-7-carboxamide((4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-((S)-14-((2S,4R) -4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidine-1-carbonyl)-2,15,15-trimethyl-3,12-dioxo-7,10-dioxa -4,13-diazahexadecan-2-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a- Preparation of tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide)

The compound prepared in step 2 (100 mg, 0.16 mmol) was dissolved in N,N'-dimethylformamide (2 mL). 1-hydroxybenzotriazole hydrate (22.0 mg, 0.25 mmol), 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride (1-ethyl-3-(3) '-dimethylaminopropyl)carbodiimide hydrochloride (47 mg, 0.25 mmol) and triethylamine (0.1 mL, 0.65 mmol) were added and stirred at room temperature for 4 hours. When the reaction was completed, ethyl acetate and distilled water were added to separate the layers, and the organic layer was recovered, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-((S)-14-((2S,4R)-4-hydroxy-2-((4 -(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidine-1-carbonyl)-2,15,15-trimethyl-3,12-dioxo-7,10-dioxa-4 ,13-diazahexadecane-2-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a -Tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide (40 mg, 26%) was obtained, designated as DT02P038.

^1H NMR (CDCl3, 400MHz) 8.68 (s, 1H), 7.40-7.37 (m, 5H), 7.14-7.12 (d, 1H), 6.77-6.75 (d, 1H), 5.78-5.76 (m, 1H) , 5.58(s, 1H), 5.32(s, 1H), 4.74-4.72(m, 2H), 4.53-4.46(m, 3H), 4.35-4.33(d, 1H), 4.12-4.07(m, 4H) , 3.98-.394(m, 4H), 3.68(d, 2H), 3.66-3.64(d, 1H), 3.58-3.55(m, 1H), 3.45-3.42(m, 4H), 2.51-2.49(m) , 4H), 2.16-2.13(m, 4H), 2.10(s, 6H), 2.00-1.98(m, 4H), 1.60-1.58(m, 2H), 1.45-1.40(m, 2H), 1.28-1.24 (m, 4H), 1.10-1.08(m, 2H)

2-17. (4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(1-((2-(2-(((S)-1-((2S,4R)-4-hydroxy-2- ((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-2-oxo Ethoxy)ethyl)amino)-2-methyl-1-oxopropan-2-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9, 9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide ((4aR,4bS,6aS,7S,9aS,9bS,11aR)-N -(1-((2-(2-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin -1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-2-oxoethoxy)ethyl)amino)-2-methyl-1-oxopropan-2-yl)-4a,6a-dimethyl -2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide )Manufacture of

Step 1: tert-Butyl(2-(2-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl ) carbamoyl) pyrrolidin-1-yl) -3,3-dimethyl-1-oxobutan-2-yl) amino) -2-oxoethoxy) ethyl) carbamate (tert-butyl (2-(2) -(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3- Preparation of dimethyl-1-oxobutan-2-yl)amino)-2-oxoethoxy)ethyl)carbamate)

(S,R,S)-AHPC hydrocyclolide ((S,R,S)-AHPC HYDROCHLORIDE) (1.0 g, 2.1 mmol) was dissolved in N,N'-dimethylformamide (10 mL). Boc-5-Amino-3-oxapentanoic acid (0.4 g, 2.1 mmol), 1-[Bis(dimethylamino)methylene]-1H-1,2,3- 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-Oxide Hexafluorophosphate) (0.7 g, 2.4 mmol) and diisopropylethylamide (0.56 mL, 3.2 mmol) were added and stirred at room temperature for 15 hours. When the reaction was completed, ethyl acetate (50 mL) and distilled water (50 mL) were added to separate the layers, and the organic layer was recovered, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography to obtain tert-butyl (2-(2-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazole- 5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-2-oxoethoxy)ethyl)carbamate (0.3 g, 28%) was obtained.

Step 2: (2S,4R)-1-((S)-2-(2-(2-aminoethoxy)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-( 4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide ((2S,4R)-1-((S)-2-(2-(2-aminoethoxy)acetamido) Preparation of -3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide)

The compound (300 mg, 0.5 mmol) prepared in step 1 was dissolved in dichloromethane (5 mL). 4N HCl solution (0.5 mL) diluted in 1,4-dioxane was added and stirred at room temperature for 15 hours. When the reaction was completed, saturated aqueous sodium bicarbonate solution and distilled water were added to separate the layers, and the organic layer was recovered, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was dried to (2S,4R)-1-((S)-2-(2-(2-aminoethoxy)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N- (4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (210 mg, 90%) was obtained.

Step 3: (4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(1-((2-(2-(((S)-1-((2S,4R)-4-hydroxy -2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)- 2-oxoethoxy)ethyl)amino)-2-methyl-1-oxopropan-2-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8 ,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide ((4aR,4bS,6aS,7S,9aS,9bS,11aR )-N-(1-((2-(2-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl) carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-2-oxoethoxy)ethyl)amino)-2-methyl-1-oxopropan-2-yl)-4a, 6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline- Preparation of 7-carboxamide)

The compound (100 mg, 0.2 mmol) prepared in step 2 was dissolved in N,N'-dimethylformamide (2 mL). I-8 (72.0 mg, 0.2 mmol), 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-hexafluorophosphate oxide (1- [Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-Oxide Hexafluorophosphate) (94.0 mg, 0.4 mmol), diisopropylethylamine (0.1 mL, 0.6 mmol) was added and stirred at room temperature for 18 hours. When the reaction was completed, ethyl acetate and distilled water were added to separate the layers, and the organic layer was recovered, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography to obtain (4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(1-((2-(2-(((S)-1-((2S,4R) -4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutane-2- I) amino)-2-oxoethoxy)ethyl)amino)-2-methyl-1-oxopropan-2-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6, 6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide (28 mg, 15%) was obtained. , it was marked as DT02P039.

^1H NMR (CDCl3, 400MHz) 8.69 (s, 1H), 7.40-7.37 (m, 5H), 7.12-7.10 (d, 1H), 6.76-6.74 (d, 1H), 5.78-5.76 (m, 1H) , 5.58(s, 1H), 5.32(s, 1H), 4.74-4.71(m, 2H), 4.49-4.40(m, 4H), 4.12-4.07(m, 4H), 3.68(d, 2H), 3.58 -3.55(m, 2H), 3.44-3.42(m, 2H), 2.51-2.49(m, 2H), 2.16-2.13(m, 2H), 2.11(s, 6H), 2.00-1.98(m, 4H) , 1.60-1.58(m, 2H), 1.45-1.40(m, 2H), 1.28-1.24(m, 4H), 1.10-1.08(m, 2H)

2-18. (4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-((S)-14-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazole- 5-yl)benzyl)carbamoyl)pyrrolidine-1-carbonyl)-2,15,15-trimethyl-3,12-dioxo-7,10-dioxa-4,13-diazahexadecane- 2-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H- No[5,4-f]quinoline-7-carboxamide((4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-((S)-14-((2S,4R)-4- hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidine-1-carbonyl)-2,15,15-trimethyl-3,12-dioxo-7,10-dioxa-4, 13-diazahexadecan-2-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H Preparation of -indeno[5,4-f]quinoline-7-carboxamide)

Step 1: tert-Butyl(2-(2-(2-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazole-5- yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-2-oxoethoxy)ethoxy)ethyl)carbamate (tert- butyl(2-(2-(2-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin- Preparation of 1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-2-oxoethoxy)ethoxy)ethyl)carbamate)

(S,R,S)-AHPC hydrochloride ((S,R,S)-AHPC HYDROCHLORIDE) (1.0 g, 2.1 mmol) was dissolved in N,N'-dimethylformamide (10 mL). Boc-8-amino-3,6-dioxaoctanoic acid (0.5 g, 2.1 mmol), 1-[Bis(dimethylamino)methylene]-1H-1, 2,3-triazolo[4,5-b]pyridinium 3-hexafluorophosphate oxide (1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3 -Oxide Hexafluorophosphate (0.7 g, 2.4 mmol) and diisopropylethylamide (0.56 mL, 3.2 mmol) were added and stirred at room temperature for 15 hours. When the reaction was completed, ethyl acetate (50 mL) and distilled water (50 mL) were added to separate the layers, and the organic layer was recovered, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography to obtain tert-butyl (2-(2-(2-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methyl Thiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-2-oxoethoxy)ethoxy)ethyl) Carbamate (0.3 g, 25%) was obtained.

Step 2: (2S,4R)-1-((S)-2-(2-(2-(2-aminoethoxy)ethoxy)acetamido)-3,3-dimethylbutanoyl)-4- Hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide((2S,4R)-1-((S)-2-(2-( Preparation of 2-(2-aminoethoxy)ethoxy)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide)

The compound (300 mg, 0.4 mmol) prepared in step 1 was dissolved in dichloromethane (5 mL). 4N HCl solution (0.5 mL) diluted in 1,4-dioxane was added and stirred at room temperature for 15 hours. When the reaction was completed, saturated aqueous sodium bicarbonate and dichloromethane were added to separate the layers, and the organic layer was recovered, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was dried to (2S,4R)-1-((S)-2-(2-(2-(2-aminoethoxy)ethoxy)acetamido)-3,3-dimethylbutanoyl)-4 -Hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (200 mg, 87%) was obtained.

Step 3: tert-Butyl((S)-16-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbonoyl)pinolidine -1-carbonyl)-17,17-dimethyl-5,14-dioxo-3,9,12-trioxa-6,15-diazaoctadecyl)carbamate (tert-butyl((S)-16 -((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidine-1-carbonyl)-17,17-dimethyl-5,14-dioxo- 3,9,12-trioxa-6,15-diazaoctadecyl)carbamate)

The compound prepared in step 2 (200 mg, 0.34 mmol) was dissolved in N,N'-dimethylformamide (2.0 mL). Boc-5-Amino-3-oxapentanoic acid (76.0 mg, 0.34 mmol), 1-[Bis(dimethylamino)methylene]-1H-1,2,3- 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-Oxide Hexafluorophosphate) (198 mg, 0.52 mmol) and diisopropylethylamide (0.1 mL, 0.70 mmol) were added and stirred at room temperature for 15 hours. When the reaction was completed, saturated distilled water and dichloromethane were added to separate the layers, and the organic layer was recovered, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography to obtain tert-butyl((S)-16-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbohydrate. Noyl) pinolidine-1-carbonyl)-17,17-dimethyl-5,14-dioxo-3,9,12-trioxa-6,15-diazaoctadecyl)carbamate (200 mg, 76 %) was obtained.

Step 4: (2S,4R)-1-((S)-17-amino-2-(tert-butyl)-4,13-dioxo-6,9,15-trioxa-3,12-diaza Heptadecane-1-oil)-4-hydroxy-N-(4-(4-methyltriazol-5-yl)benzyl)pyrrolidine-2-carboxamide((2S,4R)-1-( (S)-17-amino-2-(tert-butyl)-4,13-dioxo-6,9,15-trioxa-3,12-diazaheptadecan-1-oyl)-4-hydroxy-N-(4- Preparation of (4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide)

The compound (200 mg, 0.3 mmol) prepared in step 3 was dissolved in dichloromethane (10 mL). 4N HCl solution (0.5 mL) diluted in 1,4-dioxane was added and stirred at room temperature for 15 hours. When the reaction was completed, saturated aqueous sodium bicarbonate and dichloromethane were added to separate the layers, and the organic layer was recovered, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was dried to (2S,4R)-1-((S)-17-amino-2-(tert-butyl)-4,13-dioxo-6,9,15-trioxa-3,12-dia. Zaheptadecane-1-oil)-4-hydroxy-N-(4-(4-methyltriazol-5-yl)benzyl)pyrrolidine-2-carboxamide (150 mg, 100%) was obtained. did.

Step 5: (4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-((S)-14-((2S,4R)-4-hydroxy-2-((4-(4-methyl Thiazol-5-yl)benzyl)carbamoyl)pyrrolidine-1-carbonyl)-2,15,15-trimethyl-3,12-dioxo-7,10-dioxa-4,13-diaza hexadecane-2-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro- 1H-indeno[5,4-f]quinoline-7-carboxamide((4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-((S)-14-((2S,4R) -4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidine-1-carbonyl)-2,15,15-trimethyl-3,12-dioxo-7,10-dioxa -4,13-diazahexadecan-2-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a- Preparation of tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide)

The compound (150 mg, 0.2 mmol) prepared in step 4 was dissolved in N,N'-dimethylformamide (2 mL). I-8 (89.0 mg, 0.2 mmol), 1-hydroxybenzotriazole hydrate (45.0 mg, 0.3 mmol), 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide Hydrochloride (1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride) (64.0 mg, 0.3 mmol) and diisopropylethylamine (0.1 mL, 0.6 mmol) were added and stirred at room temperature for 18 hours. When the reaction was completed, ethyl acetate and distilled water were added to separate the layers, and the organic layer was recovered, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-((S)-14-((2S,4R)-4-hydroxy-2-((4 -(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidine-1-carbonyl)-2,15,15-trimethyl-3,12-dioxo-7,10-dioxa-4 ,13-diazahexadecane-2-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a -Tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide (32 mg, 17%) was obtained, designated as DT02P040.

^1H NMR (CDCl3, 400MHz) 8.67 (s, 1H), 7.40-7.37 (m, 5H), 7.13 (d, 1H), 6.78-6.76 (d, 1H), 5.80-5.78 (m, 1H), 5.58 (s, 1H), 5.33(s, 1H), 4.77-4.74(m, 2H), 4.52-4.44(m, 6H), 4.35-4.33(d, 4H), 4.12-4.07(m, 6H), 3.68 (d, 2H), 3.58-3.54(m, 6H), 3.45-3.42(m, 2H), 2.51-2.49(m, 2H), 2.16-2.13(m, 2H), 2.11(s, 6H), 2.00 -1.98(m, 4H), 1.61-1.59(m, 2H), 1.45-1.40(m, 2H), 1.30-1.26(m, 4H), 108-1.05(m, 2H)

2-19. (4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(5-((8-(((S)-1-((2S,4R)-4-hydroxy-2-((4 -(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-8-oxooctyl)oxy )naphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro- 1H-indeno[5,4-f]quinoline-7-carboxamide((4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(5-((8-(((S)- 1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2 -yl)amino)-8-oxooctyl)oxy)naphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b Preparation of ,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide)

Step 1: Methyl 8-((5-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7 ,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamido)naphthalen-1-yl)oxy)octanoate ( methyl 8-((5-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8, Preparation of 9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamido)naphthalen-1-yl)oxy)octanoate)

I-2 (100 mg, 0.22 mmol), methyl-8-bromooctanoate (52 mg, 0.22 mmol), and cesium carbonate (143 mg, 0.44 mmol) were added to N , N'-dimethylformamide (5.0 ml) was dissolved and stirred at 60°C for 18 hours. When the reaction was completed, ethyl acetate (50 mL) and distilled water (50 mL) were added to separate the layers, and the organic layer was recovered. Anhydrous sodium sulfate was added and filtered. The filtrate was concentrated and purified by column chromatography to produce methyl 8-((5-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl-2-oxo-2,4a,4b, 5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamido)naphthalen-1-yl )Oxy)octanoate (84 mg, 62%) was obtained.

Step 2: 8-((5-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7, 8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamido)naphthalen-1-yl)oxy)octanoic acid (8- ((5-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a ,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamido)naphthalen-1-yl)oxy)octanoic acid) Preparation

The compound prepared in step 1 (84 mg, 0.14 mmol) was dissolved in tetrahydrofuran/methanol/water (2.5 mL, 2:2:1). Lithium hydroxide (17 mg, 0.41 mmol) was added and stirred at room temperature for 5 hours. When the reaction was completed, it was titrated with 1N HCl aqueous solution and ethyl acetate was added to separate the layers. The organic layer was recovered, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 8-((5-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl-2-oxo-2,4a, 4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamido)naphthalene-1 -I)oxy)octanoic acid (64 mg, 77%) was obtained.

Step 3: (4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(5-((8-(((S)-1-((2S,4R)-4-hydroxy-2- ((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-8-oxo octyl)oxy)naphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetra Decahydro-1H-indeno[5,4-f]quinoline-7-carboxamide((4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(5-((8-((( S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1- oxobutan-2-yl)amino)-8-oxooctyl)oxy)naphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9, Preparation of 9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide)

The compound prepared in step 2 (64 mg, 0.11 mmol) was dissolved in N,N'-dimethylformamide (2.0 ml), diisopropylethylamide (56 uL, 0.32 mmol) was added, and stirred at room temperature for 5 minutes. . (S,R,S)-AHPC hydrochloride (50 mg, 0.11 mmol), 1-[Bis(dimethylamino)methylene]-1H-1,2,3- 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-Oxide Hexafluorophosphate) (61 mg, 0.50 mmol) was added dropwise and stirred at room temperature for 6 hours. When the reaction was completed, ethyl acetate (50 mL) and distilled water (50 mL) were added to separate the layers, and the organic layer was recovered, anhydrous sodium sulfate was added, and filtered. The filtrate was concentrated and purified by column chromatography (4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(5-((8-(((S)-1-((2S,4R)- 4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl )amino)-8-oxooctyl)oxy)naphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b, 10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide (5 mg, 5%) was obtained, which was designated as DT02P041.

^1H NMR (400 MHz, CDCl3) δ8.64(s, 1H), 8.06(d, J = 8.1 Hz, 1H), 7.98(d, J = 7.0 Hz, 1H), 7.33(md, J = 22.2, 14.1, 6.7 Hz, 9H), 6.88(s, 1H), 6.74(t, J = 9.2 Hz, 2H), 6.03(d, J = 8.2 Hz, 1H), 5.75(d, J = 9.9 Hz, 1H) , 5.37(s, 1H), 4.65(t, J = 7.8 Hz, 1H), 4.55-4.36(m, 4H), 4.24(m, J = 14.8, 4.8 Hz, 1H), 4.06(d, J = 7.0) Hz, 4H), 3.58(s, 1H), 3.51(d, J = 8.6 Hz, 1H), 3.41(m, J = 7.1 Hz, 3H), 3.28(s, 1H), 2.45(s, 4H), 2.39(t, J = 9.2 Hz, 1H), 2.28(d, J = 7.7 Hz, 2H), 2.20-2.07(m, 2H), 2.07-1.99(m, 2H), 1.90-1.80(m, 4H) , 1.72(s, 3H), 1.19(s, 9H), 0.85(s, 3H).

2-20. (4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(5-((7-(((S)-1-((2S,4R)-4-hydroxy-2-((4 -(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-7-oxoheptyl)oxy )naphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro- 1H-indeno[5,4-f]quinoline-7-carboxamide((4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(5-((7-(((S)- 1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2 -yl)amino)-7-oxoheptyl)oxy)naphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b Preparation of ,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide)

Step 1: Methyl 7-((5-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7 ,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamido)naphthalen-1-yl)oxy)heptanoate ( methyl 7-((5-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8, Preparation of 9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamido)naphthalen-1-yl)oxy)heptanoate)

I-2 (50 mg, 0.11 mmol), methyl 7-bromoheptanoate (25 mg, 0.11 mmol), and cesium carbonate (71 mg, 0.22 mmol) were added to N,N' -Dissolve in dimethylformamide (2.0 ml) and stir at 60°C for 18 hours. When the reaction is completed, ethyl acetate (10 mL) and distilled water (10 mL) are added to separate the layers, and the organic layer is recovered and anhydrous sodium sulfate is added. added and filtered. The filtrate was concentrated and purified by column chromatography to produce methyl 7-((5-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl-2-oxo-2,4a,4b, 5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamido)naphthalen-1-yl )Oxy)heptanoate (40 mg, 62%) was obtained.

Step 2: 7-((5-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7, 8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamido)naphthalen-1-yl)oxy)heptanoic acid (7- ((5-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a Preparation of ,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamido)naphthalen-1-yl)oxy)heptanoic acid)

The compound prepared in step 1 (10 mg, 0.02 mmol) was dissolved in tetrahydrofuran/methanol/water (2.5 mL, 2:2:1). Lithium hydroxide (3.0 mg, 0.05 mmol) was added and stirred at room temperature for 5 hours. When the reaction was completed, it was titrated with 1N HCl aqueous solution and ethyl acetate was added to separate the layers. The organic layer was recovered, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 7-((5-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl-2-oxo-2,4a, 4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamido)naphthalene-1 -I)oxy)heptanoic acid (8 mg, 80%) was obtained.

Step 3: (4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(5-((7-(((S)-1-((2S,4R)-4-hydroxy-2- ((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-7-oxo Heptyl)oxy)naphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetra Decahydro-1H-indeno[5,4-f]quinoline-7-carboxamide (4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(5-((7-(((S )-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan -2-yl)amino)-7-oxoheptyl)oxy)naphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a Preparation of ,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide

The compound prepared in step 2 (8 mg, 0.01 mmol) was dissolved in N,N'-dimethylformamide (2.0 ml), diisopropylethylamide (7 uL, 0.02 mmol) was added, and the mixture was stirred at room temperature for 5 minutes. . (S,R,S)-AHPC hydrochloride ((S,R,S)-AHPC hydrochloride) (8 mg, 0.01 mmol), 1-[Bis(dimethylamino)methylene]-1H-1,2,3- 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-Oxide Hexafluorophosphate) (7 mg, 0.01 mmol) was added dropwise and stirred at room temperature for 6 hours. When the reaction was completed, ethyl acetate (10 mL) and distilled water (10 mL) were added to separate the layers, and the organic layer was recovered, anhydrous sodium sulfate was added, and filtered. The filtrate was concentrated and purified by column chromatography (4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(5-((7-(((S)-1-((2S,4R)- 4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl )amino)-7-oxoheptyl)oxy)naphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b, 10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide (7 mg, 70%) was obtained, which was designated as DT02P042.

¹ H NMR (400 MHz, CDCl3) δ8.61 (s, 1H), 8.11-7.90 (m, 4H), 7.41-7.23 (m, 9H), 6.74 (m, J = 13.2, 9.0 Hz, 2H), 6.07(d, J = 8.4 Hz, 1H), 5.75(d, J = 9.8 Hz, 1H), 5.36(s, 1H), 4.63(t, J = 7.9 Hz, 1H), 4.56-4.37(m, 3H) ), 4.24(m, J = 14.9, 4.9 Hz, 1H), 4.04(d, J = 6.5 Hz, 3H), 3.55(m, J = 32.8, 5.9 Hz, 6H), 3.42(s, 1H), 3.28 (s, 2H), 2.89(s, 5H), 2.81(s, 6H), 2.54-2.40(m, 5H), 2.32(dt, J = 21.4, 8.7 Hz, 3H), 2.22-2.09(m, 4H) ), 2.07-1.91(m, 2H), 1.84(d, J = 6.6 Hz, 4H), 1.71(s, 3H), 1.38(d, J = 15.6 Hz, 4H), 1.02(d, J = 10.4 Hz) , 3H), 0.90(s, 3H), 0.85(s, 9H), 0.75(s, 3H).

2-21. (4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(5-((12-(((S)-1-((2S,4R)-4-hydroxy-2-((4 -(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-12-oxododecyl) Oxy)naphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro -1H-indeno[5,4-f]quinoline-7-carboxamide((4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(5-((12-(((S) -1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan- 2-yl)amino)-12-oxododecyl)oxy)naphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a, Preparation of 9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide)

Step 1: (2S,4R)-1-((S)-2-(12-bromododecanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4- Methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide ((2S,4R)-1-((S)-2-(12-bromododecanamido)-3,3-dimethylbutanoyl)-4- Preparation of hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide)

(S,R,S)-AHPC hydrochloride ((S,R,S)-AHPC HYDROCHLORIDE) (0.84 g, 1.79 mmol) was dissolved in N,N'-dimethylformamide (4 mL). 12-bromododecanoic acid (0.50 g, 1.79 mmol), 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-Hexafluorophosphate (1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-Oxide Hexafluorophosphate) (1.00 g, 2.69 mmol), triethylamine (0.50 mL, 5.37 mmol) was added and stirred at room temperature for 4 hours. When the reaction was completed, ethyl acetate (50 mL) and distilled water (50 mL) were added to separate the layers, and the organic layer was recovered, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (2S,4R)-1-((S)-2-(12-bromododecanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-( 4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (0.35 g, 28%) was obtained.

Step 2: (4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(5-((12-(((S)-1-((2S,4R)-4-hydroxy-2- ((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-12-oxo dodecyl)oxy)naphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a- Tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide((4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(5-((12-(( (S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1 -oxobutan-2-yl)amino)-12-oxododecyl)oxy)naphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9 Preparation of ,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide)

The compound (75 mg, 0.11 mmol) prepared in step 2 was dissolved in N,N'-dimethylformamide (2 mL). I-2 (50 mg, 0.11 mmol) and cesium carbonate (71 mg, 0.22 mmol) were added and stirred at 60oC for 12 hours. When the reaction was completed, ethyl acetate and distilled water were added to separate the layers, and the organic layer was recovered, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(5-((12-(((S)-1-((2S,4R)-4- Hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino )-12-oxododecyl)oxy)naphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10 , 11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide (13 mg, 11%) was obtained, which was designated as DT02P043.

^1H NMR (400 MHz, CDCl3) δ8.73(s, 1H), 8.12(m, J = 34.4, 8.0 Hz, 2H), 7.53-7.31(m, 9H), 6.84(t, J = 8.7 Hz, 2H), 6.12(d, J = 8.3 Hz, 1H), 5.85(d, J = 9.8 Hz, 1H), 5.35(d, J = 19.0 Hz, 4H), 4.75(t, J = 7.9 Hz, 1H) , 4.67-4.46(m, 3H), 4.36(m, J = 14.9, 5.1 Hz, 1H), 4.22-4.05(m, 3H), 3.61(d, J = 11.0 Hz, 1H), 3.43-3.31(m) , 1H), 2.64-2.46(m, 5H), 2.38(d, J = 10.5 Hz, 1H), 2.20(qd, J = 21.8, 10.2 Hz, 5H), 1.99-1.90(m, 3H), 1.83( d, J = 12.9 Hz, 3H), 1.68-1.50(m, 9H), 1.40(d, J = 6.7 Hz, 3H), 1.01(s, 3H), 0.95(s, 9H), 0.87(s, 3H) ).

2-22. (4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(5-((10-(((S)-1-((2S,4R)-4-hydroxy-2-((4 -(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-10-oxodecyl)oxy )naphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro- 1H-indeno[5,4-f]quinoline-7-carboxamide((4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(5-((10-(((S)- 1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2 -yl)amino)-10-oxodecyl)oxy)naphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b Preparation of ,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide)

Step 1: (2S,4R)-1-((S)-2-(10-bromodecaneamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4- Methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide ((2S,4R)-1-((S)-2-(10-bromodecanamido)-3,3-dimethylbutanoyl)-4- Preparation of hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide)

(S,R,S)-AHPC hydrochloride ((S,R,S)-AHPC HYDROCHLORIDE) (1.9 g, 3.98 mmol) was dissolved in N,N'-dimethylformamide (10 mL). 10-bromodecanoic acid (1.5 g, 3.98 mmol), 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-Hexafluorophosphate (1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-Oxide Hexafluorophosphate) (2.3 g, 5.97 mmol), triethylamine (1.7 mL, 11.9 mmol) was added and stirred at room temperature for 4 hours. When the reaction was completed, ethyl acetate (50 mL) and distilled water (50 mL) were added to separate the layers, and the organic layer was recovered, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (2S,4R)-1-((S)-2-(10-bromodecanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-( 4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (1.0 g, 38%) was obtained.

Step 2: (4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(5-((10-(((S)-1-((2S,4R)-4-hydroxy-2- ((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-10-oxo Decyl)oxy)naphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetra Decahydro-1H-indeno[5,4-f]quinoline-7-carboxamide (4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(5-((10-(((S )-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan -2-yl)amino)-10-oxodecyl)oxy)naphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a Preparation of ,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide

The compound prepared in step 2 (108 mg, 0.16 mmol) was dissolved in N,N'-dimethylformamide (3 mL). I-2 (50 mg, 0.11 mmol) and cesium carbonate (71 mg, 0.22 mmol) were added and stirred at 60oC for 12 hours. When the reaction was completed, ethyl acetate and distilled water were added to separate the layers, and the organic layer was recovered, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(5-((10-(((S)-1-((2S,4R)-4- Hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino )-10-oxodecyl)oxy)naphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10, 11,11a-Tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide (2 mg, 3%) was obtained, designated as DT02P044.

¹ H NMR (400 MHz, CDCl3) δ8.68 (d, J = 9.5 Hz, 1H), 8.02 (m, J = 27.2, 7.5 Hz, 1H), 7.48-7.24 (m, 8H), 6.75 (d, J = 5.9 Hz, 2H), 5.99(s, 1H), 5.76(d, J = 9.8 Hz, 1H), 5.23(d, J = 35.4 Hz, 5H), 4.67(s, 1H), 4.56-4.37( m, 3H), 4.31-4.23(m, 1H), 4.13-4.00(m, 3H), 3.51(d, J = 9.7 Hz, 1H), 3.30(s, 1H), 2.44(m, J = 9.2 Hz) , 5H), 2.27(d, J = 7.3 Hz, 2H), 2.21-2.02(m, 8H), 1.94(d, J = 5.6 Hz, 4H), 1.85(d, J = 7.9 Hz, 2H), 1.73 (s, 4H), 0.93(s, 3H), 0.86(s, 9H), 0.82(s, 3H).

2-23. (4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(5-((11-(((S)-1-((2S,4R)-4-hydroxy-2-((4 -(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-11-oxoundecyl) Oxy)naphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro -1H-indeno[5,4-f]quinoline-7-carboxamide((4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(5-((11-(((S) -1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan- 2-yl)amino)-11-oxoundecyl)oxy)naphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a, Preparation of 9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide)

Step 1: (2S,4R)-1-((S)-2-(11-bromundecanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4- Methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide ((2S,4R)-1-((S)-2-(11-bromoundecanamido)-3,3-dimethylbutanoyl)-4- Preparation of hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide)

(S,R,S)-AHPC HYDROCHLORIDE (880 mg, 1.89 mmol) was dissolved in N,N'-dimethylformamide (2 mL). 11-Bromoundecane Acid (11-bromoundecanoic acid) (500 mg, 1.89 mmol), 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-hexafluorophosphate Oxide (1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-Oxide Hexafluorophosphate) (860 mg, 2.26 mmol), triethylamine (788 mg, 5.66 mmol) and stirred at room temperature for 5 hours. When the reaction was completed, ethyl acetate (10 mL) and distilled water (10 mL) were added to separate the layers, and the organic layer was recovered, anhydrous sodium sulfate was added, dried, filtered, and concentrated. The residue was purified by column chromatography to obtain (2S,4R)-1-((S)-2-(11-bromoundecanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N- (4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (998 mg, 78%) was obtained.

Step 2: (4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(5-((11-(((S)-1-((2S,4R)-4-hydroxy-2- ((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-11-oxo undecyl)oxy)naphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a- Tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide((4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(5-((11-(( (S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1 -oxobutan-2-yl)amino)-11-oxoundecyl)oxy)naphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9 Preparation of ,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide)

The compound (85 mg, 0.13 mmol) prepared in step 2 was dissolved in N,N'-dimethylformamide (3 mL). I-2 (50 mg, 0.11 mmol) and cesium carbonate (71 mg, 0.22 mmol) were added and stirred at 60oC for 12 hours. When the reaction was completed, ethyl acetate and distilled water were added to separate the layers, and the organic layer was recovered, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(5-((11-(((S)-1-((2S,4R)-4- Hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino )-11-oxoundecyl)oxy)naphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10 , 11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide (15 mg, 9%) was obtained, which was designated as DT02P045.

¹ H NMR (400 MHz, chloroform-d) δ8.71 (d, J = 14.2 Hz, 1H), 8.16 (d, J = 8.6 Hz, 1H), 8.08 (d, J = 7.4 Hz, 1H), 7.51 -7.32(m, 9H), 6.84(t, J = 8.9 Hz, 2H), 6.12(d, J = 8.4 Hz, 1H), 5.85(d, J = 9.7 Hz, 1H), 5.34(d, J = 17.0 Hz, 2H), 4.75 (t, J = 7.8 Hz, 1H), 4.65-4.47 (m, 3H), 4.35 (m, J = 14.8, 5.0 Hz, 1H), 4.22-4.09 (m, 3H), 3.60 (d, J = 8.2 Hz, 1H), 3.38 (t, J = 7.7 Hz, 1H), 2.65-2.45 (m, 5H), 2.45-2.32 (m, 1H), 2.32-2.08 (m, 6H) , 2.01-1.89(m, 4H), 1.83(d, J = 11.1 Hz, 5H), 1.70-1.48(m, 10H), 1.45-1.23(m, 16H), 1.11(s, 2H), 1.01(s) , 3H), 0.95(s, 9H), 0.87(s, 3H).

2-24. (4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(5-((9-(((S)-1-((2S,4R)-4-hydroxy-2-((4 -(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-9-oxononyl) Oxy)naphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro -1H-indeno[5,4-f]quinoline-7-carboxamide((4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(5-((9-(((S) -1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan- 2-yl)amino)-9-oxononyl)oxy)naphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a, Preparation of 9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide)

Step 1: (2S,4R)-1-((S)-2-(9-bromononanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4- Methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide ((2S,4R)-1-((S)-2-(9-bromononanamido)-3,3-dimethylbutanoyl)-4- Preparation of hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide)

(S,R,S)-AHPC HYDROCHLORIDE (985 mg, 2.11 mmol) was dissolved in N,N'-dimethylformamide (3 mL). 9-bromononanoic acid (500 mg, 2.11 mmol), 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3 -Hexafluorophosphate (1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-Oxide Hexafluorophosphate) (962 mg, 2.53 mmol), triethylamine ( 588 mg, 4.28 mmol) was added and stirred at room temperature for 4 hours. When the reaction was completed, ethyl acetate (10 mL) and distilled water (10 mL) were added to separate the layers, and the organic layer was recovered, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (2S,4R)-1-((S)-2-(9-bromononanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-( 4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (500 mg, 36%) was obtained.

Step 2: (4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(5-((9-(((S)-1-((2S,4R)-4-hydroxy-2- ((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-9-ox Sononyl)oxy)naphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a- Tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide((4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(5-((9-(( (S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1 -oxobutan-2-yl)amino)-9-oxononyl)oxy)naphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9 Preparation of ,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide)

The compound (111 mg, 0.16 mmol) prepared in step 2 was dissolved in N,N'-dimethylformamide (3 mL). I-2 (50 mg, 0.11 mmol) and cesium carbonate (71 mg, 0.22 mmol) were added and stirred at 60oC for 12 hours. When the reaction was completed, ethyl acetate and distilled water were added to separate the layers, and the organic layer was recovered, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(5-((9-(((S)-1-((2S,4R)-4- Hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino )-9-oxononyl)oxy)naphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10 , 11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide (50 mg, 30%) was obtained, which was designated as DT02P046.

¹ H NMR (400 MHz, CDCl3) δ8.71 (s, 1H), 8.16 (d, J = 8.7 Hz, 1H), 8.09 (d, J = 7.1 Hz, 1H), 7.52-7.32 (m, 9H) , 6.84(t, J = 8.3 Hz, 2H), 6.07(d, J = 9.2 Hz, 1H), 5.85(d, J = 10.0 Hz, 1H), 5.26(s, 1H), 4.75(t, J = 7.8 Hz, 1H), 4.65-4.52(m, 2H), 4.49(d, J = 8.7 Hz, 1H), 4.34(m, J = 14.2, 4.7 Hz, 1H), 4.16(d, J = 7.0 Hz, 3H), 3.60(d, J = 9.0 Hz, 1H), 3.52(s, 2H), 3.39(s, 1H), 2.66-2.45(m, 6H), 2.37(s, 1H), 2.23(m, J = 15.6, 7.9 Hz, 4H), 2.15(d, J = 8.1 Hz, 1H), 2.06-1.88(m, 4H), 1.84(s, 3H), 1.12(s, 3H), 1.02(s, 9H) , 0.87(s, 3H).

2-25. (4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(7-(2-(2-(2-(((S)-1-((2S,4R)-4-hydroxy- 2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-2 -oxoethoxy)ethoxy)ethoxy)naphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b, 10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide ((4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(7- (2-(2-(2-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1 -yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-2-oxoethoxy)ethoxy)ethoxy)naphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a, Preparation of 4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide)

Step 1: tert-Butyl 2-(2-(2-((8-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl-2-oxo-2,4a,4b ,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamido)naphthalene-2- 1)oxy)ethoxy)ethoxy)acetate (tert-butyl 2-(2-(2-((8-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl- 2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamido) Preparation of naphthalen-2-yl)oxy)ethoxy)ethoxy)acetate)

I-4 (1.0 g, 2.18 mmol) and tert-butyl 2-(2-(2-bromoethoxy)ethoxy)acetate (0.7 g, 2.62 mmol, 1.2 eq) and cesium carbonate (1.4 g, 4.36 mmol) were dissolved in N,N'-dimethylformamide (10.0 ml) and stirred at 60°C for 18 hours. When the reaction was completed, Ethyl acetate (50 mL) and distilled water (50 mL) were added to separate the layers, and the organic layer was recovered, anhydrous sodium sulfate was added, and filtered. The filtrate was concentrated and purified by column chromatography to produce tert-butyl 2-(2-(2-((8-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl-2- Oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-car Copamido)naphthalen-2-yl)oxy)ethoxy)ethoxy)acetate (0.1 g, 8%) was obtained.

Step 2: 2-(2-(2-((8-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl-2-oxo-2,4a,4b,5, 6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamido)naphthalen-2-yl) Oxy)ethoxy)ethoxy)acetic acid (2-(2-(2-((8-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl-2-oxo-2 ,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamido)naphthalen-2-yl )oxy)ethoxy)ethoxy)acetic acid) production

The compound prepared in step 1 (120 mg, 0.18 mmol) was dissolved in trifluoroacetic acid (4.0 mL) and stirred at room temperature for 2 hours. When the reaction was completed, it was concentrated and the next reaction proceeded without filtration.

Step 3: (4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(7-(2-(2-(2-(((S)-1-((2S,4R)-4- Hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino )-2-oxoethoxy)ethoxy)ethoxy)naphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a ,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide ((4aR,4bS,6aS,7S,9aS,9bS,11aR)-N- (7-(2-(2-(2-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl) pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-2-oxoethoxy)ethoxy)ethoxy)naphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2 Manufacture of ,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide)

The compound prepared in step 2 was dissolved in N,N'-dimethylformamide (2.0 ml), diisopropylethylamide (235 mg, 1.8 mmol) was added, and the mixture was stirred at room temperature for 5 minutes. (S,R,S)-AHPC hydrochloride ((S,R,S)-AHPC hydrochloride) (85 mg, 0.18 mmol), 1-[Bis(dimethylamino)methylene]-1H-1,2,3- 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-Oxide Hexafluorophosphate) (102 mg, 0.27 mmol) was added dropwise and stirred at room temperature for 5 hours. When the reaction was completed, ethyl acetate (10 mL) and distilled water (10 mL) were added to separate the layers, and the organic layer was recovered, anhydrous sodium sulfate was added, and filtered. The filtrate was concentrated and purified by column chromatography (4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(7-(2-(2-(2-(((S)-1-(( 2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxo butan-2-yl) amino)-2-oxoethoxy)ethoxy)ethoxy)naphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a, 7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide (100 mg, 54%) was obtained, It was marked as DT02P048.

^1H NMR (400 MHz, CDCl3) δ8.67(s, 1H), 7.41(t, 1H), 7.35-7.33(m, 4H), 7.12(s, 1H), 6.85(d, 2H), 6.80( d, 1H), 5.81(m, 1H), 5.49(s, 1H), 5.33(s, 1H), 4.75-4.72(t, 1H), 4.62-4.47(m, 3H), 4.33(m, 1H) , 4.16-4.06(m, 3H), 4.04-4.02(d, 2H), 3.86-3.84(t, 2H), 3.73(m, 4H), 3.64(m, 1H), 3.39-3.30(m, 1H) , 2.58-2.47(m, 4H), 2.36-2.21(m, 2H), 2.20-2.05(m, 3H), 1.89-1.70(m, 4H), 1.62(m, 2H), 1.55-1.15(m, 6H), 1.15-1.03(m, 2H), 0.98-0.96(d, 12H), 0.78(s, 3H).

2-26. (4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(6-(2-(2-(2-(((S)-1-((2S,4R)-4-hydroxy- 2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-2 -oxoethoxy)ethoxy)ethoxy)naphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b, 10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide ((4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(6- (2-(2-(2-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1 -yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-2-oxoethoxy)ethoxy)ethoxy)naphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a, Preparation of 4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide)

Step 1: tert-Butyl 2-(2-(2-((5-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl-2-oxo-2,4a,4b ,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamido)naphthalene-2- 1)oxy)ethoxy)ethoxy)acetate (tert-butyl 2-(2-(2-((5-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl- 2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamido) Preparation of naphthalen-2-yl)oxy)ethoxy)ethoxy)acetate)

I-3 (0.50 g, 1.1 mmol) and tert-butyl 2-(2-(2-bromoethoxy)ethoxy)acetate (0.37 mg, 1.3 mmol) and cesium carbonate (0.70 g, 2.2 mmol) were dissolved in N,N'-dimethylformamide (10.0 ml) and stirred at 60°C for 18 hours. When the reaction was completed, ethyl acetate ( 30 mL) and distilled water (30 mL) were added to separate the layers, and the organic layer was recovered, anhydrous sodium sulfate was added, and filtered. The filtrate was concentrated and purified by column chromatography to produce tert-butyl 2-(2-(2-((5-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl-2- Oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-car Copamido)naphthalen-2-yl)oxy)ethoxy)ethoxy)acetate (0.12 g, 16%) was obtained.

Step 2: 2-(2-(2-((5-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl-2-oxo-2,4a,4b,5, 6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamido)naphthalen-2-yl)oxy )Ethoxy)ethoxy)acetic acid (2-(2-(2-((5-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl-2-oxo-2, 4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamido)naphthalen-2-yl) Production of oxy)ethoxy)ethoxy)acetic acid)

The compound prepared in step 1 (120 mg, 0.18 mmol) was dissolved in trifluoroacetic acid (4.0 mL) and stirred at room temperature for 2 hours. When the reaction was completed, it was concentrated and the next reaction proceeded without filtration.

Step 3: (4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(6-(2-(2-(2-(((S)-1-((2S,4R)-4- Hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino )-2-oxoethoxy)ethoxy)ethoxy)naphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a ,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide ((4aR,4bS,6aS,7S,9aS,9bS,11aR)-N- (6-(2-(2-(2-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl) pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-2-oxoethoxy)ethoxy)ethoxy)naphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2 Manufacture of ,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide)

The compound prepared in step 2 was dissolved in N,N'-dimethylformamide (2.0 ml), diisopropylethylamide (235 mg, 1.8 mmol) was added, and the mixture was stirred at room temperature for 5 minutes. (S,R,S)-AHPC hydrochloride ((S,R,S)-AHPC hydrochloride) (85 mg, 0.18 mmol), 1-[Bis(dimethylamino)methylene]-1H-1,2,3- 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-Oxide Hexafluorophosphate) (102 mg, 0.27 mmol) was added dropwise and stirred at room temperature for 5 hours. When the reaction was completed, ethyl acetate (10 mL) and distilled water (10 mL) were added to separate the layers, and the organic layer was recovered, anhydrous sodium sulfate was added, and filtered. The filtrate was concentrated and purified by column chromatography (4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(6-(2-(2-(2-(((S)-1-(( 2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxo butan-2-yl) amino)-2-oxoethoxy)ethoxy)ethoxy)naphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a, 7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide (110 mg, 61%) was obtained. It was marked as DT02P049.

^1H NMR (400 MHz, CDCl3) δ8.69(s, 1H), 7.41(t, 1H), 7.37-7.32(m, 4H), 7.14(s, 1H), 6.86(d, 2H), 6.80( d, 1H), 5.83(m, 1H), 5.50(s, 1H), 5.32(s, 1H), 4.75-4.72(t, 1H), 4.62-4.47(m, 3H), 4.33(m, 1H) , 4.16-4.06(m, 3H), 4.04-4.02(d, 2H), 3.86(t, 2H), 3.73(m, 4H), 3.63(m, 1H), 3.39-3.30(m, 1H), 2.58 -2.47(m, 4H), 2.36-2.21(m, 2H), 2.20-2.05(m, 3H), 1.89-1.70(m, 4H), 1.62(m, 2H), 1.55-1.15(m, 6H) , 1.15-1.03(m, 2H), 0.98-0.96(d, 12H), 0.78(s, 3H).

2-27. (4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(4-(2-(2-(2-(((S)-1-((2S,4R)-4-hydroxy- 2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-2 -oxoethoxy)ethoxy)ethoxy)phenyl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11, 11a-Tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide((4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(4-(2-( 2-(2-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)- 3,3-dimethyl-1-oxobutan-2-yl)amino)-2-oxoethoxy)ethoxy)ethoxy)phenyl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a, Preparation of 7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide)

Step 1: tert-Butyl 2-(2-(2-(4-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl-2-oxo-2,4a,4b, 5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamido)phenoxy)ethoxy )Ethoxy)acetate (tert-butyl 2-(2-(2-(4-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl-2-oxo-2,4a ,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamido)phenoxy)ethoxy)ethoxy)acetate )Manufacture of

I-5 (150 mg, 0.37 mmol) and tert-butyl 2-(2-(2-bromoethoxy)ethoxy)acetate (125 mg, 0.44 mmol) and cesium carbonate (239 mg, 0.73 mmol) were dissolved in N,N'-dimethylformamide (3.0 ml) and stirred at 50°C for 15 hours. When the reaction was completed, ethyl acetate ( 30 mL) and distilled water (30 mL) were added to separate the layers, and the organic layer was recovered, anhydrous sodium sulfate was added, and filtered. The filtrate was concentrated and purified by column chromatography to produce tert-butyl 2-(2-(2-(4-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl-2-oxo -2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxylic Mido) phenoxy) ethoxy) ethoxy) acetate (187 mg, 83%) was obtained.

Step 2: 2-(2-(2-(4-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6 ,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamido)phenoxy)ethoxy)ethoxy ) Acetic acid (2-(2-(2-(4-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6 Preparation of ,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamido)phenoxy)ethoxy)ethoxy)acetic acid)

The compound prepared in Step 1 (187 mg, 0.31 mmol) was dissolved in trifluoroacetic acid (2.0 mL) and stirred at room temperature for 2 hours. When the reaction is completed, concentrate to obtain 2-(2-(2-(4-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl-2-oxo-2,4a,4b, 5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamido)phenoxy)ethoxy )Ethoxy)acetic acid (170 mg) was obtained.

Step 3: (4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(4-(2-(2-(2-(((S)-1-((2S,4R)-4- Hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino )-2-oxoethoxy)ethoxy)ethoxy)phenyl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10 ,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide ((4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(4-( 2-(2-(2-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1- yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-2-oxoethoxy)ethoxy)ethoxy)phenyl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6 Preparation of ,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide)

The compound prepared in step 2 (170 mg, 0.31 mmol) was dissolved in N,N'-dimethylformamide (2.0 ml), diisopropylethylamide (0.5 mL, 3.06 mmol) was added, and the mixture was stirred at room temperature for 5 minutes. . (S,R,S)-AHPC hydrochloride (172 mg, 0.37 mmol), 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3 -Hexafluorophosphate (1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-Oxide Hexafluorophosphate) (174 mg, 0.46 mmol) was added dropwise and incubated at room temperature. It was stirred for 5 hours. When the reaction was completed, ethyl acetate (10 mL) and distilled water (10 mL) were added to separate the layers, and the organic layer was recovered, anhydrous sodium sulfate was added, and filtered. The filtrate was concentrated and purified by column chromatography (4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(4-(2-(2-(2-(((S)-1-(( 2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxo butan-2-yl) amino) -2-oxoethoxy) ethoxy) ethoxy) phenyl) -4a, 6a-dimethyl-2-oxo-2,4a, 4b, 5,6,6a, 7,8, 9,9a,9b,10,11,11a-tetradecahyro-1H-indeno[5,4-f]quinoline-7-carboxamide (100 mg, 32%) was obtained, designated as DT02P050. did.

^1H NMR (400 MHz, CDCl3) δ8.71(s, 1H), 7.43(t, J = 5.9 Hz, 1H), 7.40-7.30(m, 7H), 7.14(s, 1H), 6.86(d, J = 9.0 Hz, 2H), 6.80(d, J = 10.0 Hz, 1H), 5.83(m, J = 9.9, 2.2 Hz, 1H), 5.50(s, 1H), 5.32(s, 1H), 4.73( t, J = 7.9 Hz, 1H), 4.62-4.47(m, 3H), 4.33(m, J = 15.0, 5.3 Hz, 1H), 4.16-4.06(m, 3H), 4.02(d, J = 6.4 Hz) , 2H), 3.86(t, J = 4.9 Hz, 2H), 3.73(md, J = 12.5, 3.8, 1.7 Hz, 4H), 3.63(m, J = 11.3, 3.7 Hz, 1H), 3.39-3.30( m, 1H), 2.58-2.47(m, 4H), 2.36-2.21(m, 2H), 2.20-2.05(m, 3H), 1.89-1.70(m, 4H), 1.62(m, J = 11.3, 8.3 Hz, 2H), 1.55-1.15(m, 6H), 1.15-1.03(m, 2H), 0.97(d, J = 9.5 Hz, 12H), 0.78(s, 3H).

2-28. (4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(5-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1 ,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethoxy)naphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6, 6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide ((4aR,4bS,6aS,7S, 9aS,9bS,11aR)-N-(5-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy )ethoxy)ethoxy)naphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a- Preparation of tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide)

Step 1: 2-(2,6-dioxopiperidin-3-yl)-4-((2-(2-(2-hydroxyethoxy)ethoxy)ethyl)amino)isoindoline-1, Preparation of 3-dione (2-(2,6-dioxopiperidin-3-yl)-4-((2-(2-(2-hydroxyethoxy)ethoxy)ethyl)amino)isoindoline-1,3-dione)

4-fluoro-thalidomide (1.0 g, 3.62 mmol) was dissolved in N,N'-dimethylformamide (20 mL). Diisopropylethylamide (0.63 mL, 3.62 mmol) and 2-(2-(2-aminoethoxy)ethoxy)ethanol (0.36 mL, 3.62 mmol) ) was added and stirred at 90oC for 15 hours. When the reaction was completed, ethyl acetate and distilled water were added to separate the layers, and the organic layer was recovered, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography and 2-(2,6-dioxopiperidin-3-yl)-4-((2-(2-(2-hydroxyethoxy)ethoxy)ethyl)amino)iso Indoline-1,3-dione (0.37 g, 28%) was obtained.

Step 2: 2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy ) Ethyl 4-methylbenzenesulfonate (2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethyl Preparation of 4-methylbenzenesulfonate)

The compound prepared in step 1 (200 mg, 0.49 mmol) was dissolved in dichloromethane (5 mL). 4-Toluenesulfonyl chloride (188 mg, 0.99 mmol) and triethylamine (0.1 mL, 0.99 mmol) were added and stirred at room temperature for 12 hours. When the reaction was completed, ethyl acetate and distilled water were added to separate the layers, and the organic layer was recovered, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography to obtain 2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino) Ethoxy)ethoxy)ethyl 4-methylbenzenesulfonate (150 mg, 44%) was obtained.

Step 3: (4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(5-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl )-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethoxy)naphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5 ,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide ((4aR,4bS,6aS ,7S,9aS,9bS,11aR)-N-(5-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl) amino)ethoxy)ethoxy)ethoxy)naphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11 Preparation of ,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide)

The compound (74 mg, 0.13 mmol) prepared in step 2 was dissolved in N,N'-dimethylformamide (2 mL). I-2 (50 mg, 0.11 mmol) and cesium carbonate (71 mg, 0.22 mmol) were added and stirred at 60oC for 15 hours. When the reaction was completed, ethyl acetate and distilled water were added to separate the layers, and the organic layer was recovered, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(5-(2-(2-(2-((2-(2,6-dioxopiperi din-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethoxy)naphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2, 4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide (20 mg, 17%) was obtained, which was designated as DT02P051.

^1H NMR (400 MHz, CDCl3) δ8.09-8.07(d, 1H), 7.96-7.94(d, 1H), 7.84(s, 1H), 7.38-7.26(m, 5H), 6.99-6.97(d) , 1H), 6.78-6.74(m, 3H), 6.40(s, 1H), 5.77-5.75(d, 1H), 5.29-5.27(m, 1H), 5.17(s, 1H), 4.70-4.67(m) , 1H), 4.26-4.24(t, 1H), 4.15-4.07(m, 1H), 3.98-3.95(t, 2H), 3.77-3.75(t, 2H), 3.69-3.65(m, 4H), 3.36 -3.28(m, 3H), 3.19-3.16(m, 1H), 2.72-2.61(m, 2H), 2.50-2.39(m, 2H), 2.30-2.26(m, 2H), 2.17-2.08(m, 2H), 1.95-1.92(m, 2H), 1.77-1.73(m, 2H).

2-29. (4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(5-(2-(2-(3-(((S)-1-((2S,4R)-4-hydroxy- 2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-3 -Oxopropoxy)ethoxy)ethoxy)naphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b, 10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide ((4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(5- (2-(2-(3-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1 -yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-3-oxopropoxy)ethoxy)ethoxy)naphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a, Preparation of 4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide)

Step 1: tert-Butyl 3-(2-(2-((5-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl-2-oxo-2,4a,4b ,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamido)naphthalene-1- I)oxy)ethoxy)ethoxy)propanoate (tert-butyl 3-(2-(2-((5-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a- dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7- Preparation of carboxamido)naphthalen-1-yl)oxy)ethoxy)ethoxy)propanoate)

I-2 (50 mg, 0.11 mmol) and tert-butyl 3-(2-(2-bromoethoxy)ethoxy)propanoate ) (40 mg, 0.13 mmol) and cesium carbonate (71 mg, 0.22 mmol) were dissolved in N,N'-dimethylformamide (2.0 ml) and stirred at 50°C for 12 hours. When the reaction was completed, ethyl acetate (10 mL) and distilled water (10 mL) were added to separate the layers, and the organic layer was recovered, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography to produce tert-butyl 3-(2-(2-((5-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl-2-oxo- 2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamido )Naphthalen-1-yl)oxy)ethoxy)ethoxy)propanoate (46 mg, 65%) was obtained.

Step 2: 3-(2-(2-((5-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl-2-oxo-2,4a,4b,5, 6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamido)naphthalen-1-yl)oxy )Ethoxy)ethoxy)propanoic acid (3-(2-(2-((5-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl-2-oxo-2 ,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamido)naphthalen-1-yl )oxy)ethoxy)ethoxy)propanoic acid) production

The compound prepared in step 1 (46 mg, 0.07 mmol) was dissolved in trifluoroacetic acid (1.0 mL) and stirred at room temperature for 2 hours. When the reaction is completed, concentrate to obtain 3-(2-(2-((5-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl-2-oxo-2,4a,4b ,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamido)naphthalene-1- I)oxy)ethoxy)ethoxy)propanoic acid (37 mg) was obtained.

Step 3: (4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(5-(2-(2-(3-(((S)-1-((2S,4R)-4- Hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino )-3-oxopropoxy)ethoxy)ethoxy)naphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a ,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide ((4aR,4bS,6aS,7S,9aS,9bS,11aR)-N- (5-(2-(2-(3-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl) pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-3-oxopropoxy)ethoxy)ethoxy)naphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2 Manufacture of ,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide)

The compound prepared in step 2 (37 mg, 0.06 mmol) was dissolved in N,N'-dimethylformamide (1.0 ml), diisopropylethylamide (0.1 mL, 0.60 mmol) was added, and the mixture was stirred at room temperature for 5 minutes. . (S,R,S)-AHPC hydrochloride ((S,R,S)-AHPC hydrochloride) (34 mg, 0.07 mmol), 1-[Bis(dimethylamino)methylene]-1H-1,2,3- 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-Oxide Hexafluorophosphate) (33 mg, 0.09 mmol) was added dropwise and stirred at room temperature for 5 hours. When the reaction was completed, ethyl acetate (10 mL) and distilled water (10 mL) were added to separate the layers, and the organic layer was recovered, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(5-(2-(2-(3-(((S)-1-((2S, 4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutane- 2-yl) amino) -3-oxopropoxy) ethoxy) ethoxy) naphthalen-1-yl) -4a, 6a-dimethyl-2-oxo-2,4a, 4b, 5,6, 6a, 7, 8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide (20 mg, 29%) was obtained, which was obtained as DT02P055. indicated.

^1H NMR (400 MHz, CDCl3) δ8.59(s, 1H), 8.06-8.04(d, 1H), 7.97-7.95(d, 1H), 7.45-7.26(m, 9H), 6.97-6.93(m) , 1H), 6.77-6.73(m, 2H), 5.77-5.75(d, 1H), 5.23(s, 1H), 5.17(s, 1H), 4.63-4.59(t, 1H), 4.51-4.46(m) , 1H), 4.41(s, 3H), 4.35-4.33(d, 1H), 4.23-4.18(m, 3H), 4.05-4.02(d, 1H), 3.92-3.90(t, 2H), 3.74-3.72 (m, 2H), 3.68-3.62(m, 4H), 3.46-3.44(m, 1H), 3.31-3.27(m, 1H), 2.49-2.41(m, 7H), 2.30-2.28(m, 1H) , 2.19-2.17(m, 1H), 2.02-1.96(m, 1H), 1.93-1.89(m, 1H), 1.76-1.73(m, 4H), 1.31-1.26(m, 2H), 1.21-1.18( m, 6H), 1.05-1.01(m, 2H), 0.92(s, 3H), 0.85(s, 3H), 0.78(s, 3H).

2-30. (4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(5-(((S)-13-((2S,4R)-4-hydroxy-2-((4-(4- Methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidine-1-carbonyl)-14,14-dimethyl-11-oxo-3,6,9-trioxa-12-azapentadecyl)oxy) Naphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H -Indeno[5,4-f]quinoline-7-carboxamide((4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(5-(((S)-13-((2S ,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidine-1-carbonyl)-14,14-dimethyl-11-oxo-3,6,9- trioxa-12-azapentadecyl)oxy)naphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11 Preparation of ,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide)

Step 1: tert-Butyl 2-(2-(2-(2-((5-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl-2-oxo-2, 4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamido)naphthalene -1-yl)oxy)ethoxy)ethoxy)ethoxy)acetate (tert-butyl 2-(2-(2-(2-((5-((4aR,4bS,6aS,7S,9aS,9bS, 11aR)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4 Preparation of -f]quinoline-7-carboxamido)naphthalen-1-yl)oxy)ethoxy)ethoxy)ethoxy)acetate)

I-2 (50 mg, 0.11 mmol) and tert-butyl 2-(2-(2-(2-bromoethoxy)ethoxy)ethoxy)acetate (tert-butyl 2-(2-(2-(2) -bromoethoxy)ethoxy)ethoxy)acetate) (43 mg, 0.13 mmol) and cesium carbonate (71 mg, 0.22 mmol) were dissolved in N,N'-dimethylformamide (2.0 ml) and stirred at 50°C for 12 hours. When the reaction was completed, ethyl acetate (10 mL) and distilled water (10 mL) were added to separate the layers, and the organic layer was recovered, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography to obtain tert-butyl 2-(2-(2-(2-((5-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl-2 -Oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7- Carboxamido)naphthalen-1-yl)oxy)ethoxy)ethoxy)ethoxy)acetate (50 mg, 65%) was obtained.

Step 2: 2-(2-(2-(2-((5-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl-2-oxo-2,4a,4b ,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamido)naphthalene-1- 1)oxy)ethoxy)ethoxy)ethoxy)acetic acid (2-(2-(2-(2-((5-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a -dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7 Preparation of -carboxamido)naphthalen-1-yl)oxy)ethoxy)ethoxy)ethoxy)acetic acid)

The compound prepared in step 1 (50 mg, 0.07 mmol) was dissolved in trifluoroacetic acid (1.0 mL) and stirred at room temperature for 2 hours. When the reaction is completed, concentrate to obtain 2-(2-(2-(2-((5-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl-2-oxo-2, 4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamido)naphthalene -1-yl)oxy)ethoxy)ethoxy)ethoxy)acetic acid (46 mg) was obtained.

Step 3: (4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(5-(((S)-13-((2S,4R)-4-hydroxy-2-((4- (4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidine-1-carbonyl)-14,14-dimethyl-11-oxo-3,6,9-trioxa-12-azapentadecyl )oxy)naphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradeca Hydro-1H-indeno[5,4-f]quinoline-7-carboxamide((4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(5-(((S)-13- ((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidine-1-carbonyl)-14,14-dimethyl-11-oxo-3,6 ,9-trioxa-12-azapentadecyl)oxy)naphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b, Preparation of 10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide)

The compound prepared in step 2 (46 mg, 0.07 mmol) was dissolved in N,N'-dimethylformamide (1.0 ml), diisopropylethylamide (0.1 mL, 0.70 mmol) was added, and the mixture was stirred at room temperature for 5 minutes. . (S,R,S)-AHPC hydrochloride (40 mg, 0.08 mmol), 1-[Bis(dimethylamino)methylene]-1H-1,2,3- 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-Oxide Hexafluorophosphate) (41 mg, 0.11 mmol) was added dropwise and stirred at room temperature for 5 hours. When the reaction was completed, ethyl acetate (10 mL) and distilled water (10 mL) were added to separate the layers, and the organic layer was recovered, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(5-(((S)-13-((2S,4R)-4-hydroxy-2 -((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidine-1-carbonyl)-14,14-dimethyl-11-oxo-3,6,9-trioxa- 12-azapentadecyl)oxy)naphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11 , 11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide (20 mg, 27%) was obtained, which was designated as DT02P056.

^1H NMR (400 MHz, CDCl3) δ8.69(s, 1H), 8.16-8.14(d, 1H), 8.05-8.03(d, 1H), 7.50-7.30(m, 10H), 6.88-6.82(m) , 2H), 5.86-5.83(d, 1H), 5.32-5.30(m, 2H), 4.71-4.67(t, 1H), 4.59-4.47(m, 3H), 4.35- 4.30(m, 3H), 4.10 -4.07(d, 1H), 4.02-3.99(m, 4H), 3.82-3.80(m, 2H), 3.73-3.69(m, 6H), 3.60, 3.59-3.56(m, 1H), 3.40-3.36( t, 1H), 2.58-2.49(m, 6H), 2.42-2.36(m, 1H), 2.28-2.27(m, 1H), 2.11-2.06(m, 1H), 2.02-1.98(m, 1H), 1.85-1.64(m, 14H), 1.56-1.54(m, 3H), 1.47-1.36(m, 2H), 1.33-1.29(m, 8H), 1.15-1.10(m, 2H), 1.01(s, 3H) ), 0.96(s, 9H), 0.92-0.87(m, 8H).

2-31. (4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(5-(((S)-14-((2S,4R)-4-hydroxy-2-((4-(4- Methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidine-1-carbonyl)-15,15-dimethyl-12-oxo-3,6,9-trioxa-13-azahexadecyl)oxy) Naphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H -Indeno[5,4-f]quinoline-7-carboxamide((4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(5-(((S)-14-((2S ,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidine-1-carbonyl)-15,15-dimethyl-12-oxo-3,6,9- trioxa-13-azahexadecyl)oxy)naphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11 Preparation of ,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide)

Step 1: tert-Butyl 3-(2-(2-(2-((5-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl-2-oxo-2, 4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamido)naphthalene -1-yl)oxy)ethoxy)ethoxy)ethoxy)propanoate (tert-butyl 3-(2-(2-(2-((5-((4aR,4bS,6aS,7S,9aS, 9bS,11aR)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5 ,4-f]quinoline-7-carboxamido)naphthalen-1-yl)oxy)ethoxy)ethoxy)ethoxy)propanoate) Preparation

I-2 (50 mg, 0.11 mmol) and tert-butyl 3-(2-(2-(2-bromoethoxy)ethoxy)ethoxy)propanoate (tert-butyl 3-(2-(2- (2-bromoethoxy)ethoxy)ethoxy)propanoate) (45 mg, 0.13 mmol) and cesium carbonate (71 mg, 0.22 mmol) were dissolved in N,N'-dimethylformamide (2.0 ml) and incubated at 50°C. It was stirred for 12 hours. When the reaction was completed, ethyl acetate (10 mL) and distilled water (10 mL) were added to separate the layers, and the organic layer was recovered, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography to produce tert-butyl 3-(2-(2-(2-((5-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl-2 -Oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7- Carboxamido)naphthalen-1-yl)oxy)ethoxy)ethoxy)ethoxy)propanoate (74 mg, 94%) was obtained.

Step 2: 3-(2-(2-(2-((5-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl-2-oxo-2,4a,4b ,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamido)naphthalene-1- I)oxy)ethoxy)ethoxy)ethoxy)propanoic acid (3-(2-(2-(2-((5-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a, 6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline- Preparation of 7-carboxamido)naphthalen-1-yl)oxy)ethoxy)ethoxy)ethoxy)propanoic acid)

The compound prepared in Step 1 (74 mg, 0.10 mmol) was dissolved in trifluoroacetic acid (1.0 mL) and stirred at room temperature for 2 hours. When the reaction is completed, concentrate to obtain 3-(2-(2-(2-((5-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl-2-oxo-2, 4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamido)naphthalene -1-yl)oxy)ethoxy)ethoxy)ethoxy)propanoic acid (68 mg) was obtained.

Step 3: (4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(5-(((S)-14-((2S,4R)-4-hydroxy-2-((4- (4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidine-1-carbonyl)-15,15-dimethyl-12-oxo-3,6,9-trioxa-13-azahexadecyl )oxy)naphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradeca Hydro-1H-indeno[5,4-f]quinoline-7-carboxamide((4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(5-(((S)-14- ((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidine-1-carbonyl)-15,15-dimethyl-12-oxo-3,6 ,9-trioxa-13-azahexadecyl)oxy)naphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b, Preparation of 10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide)

The compound prepared in step 2 (68 mg, 0.10 mmol) was dissolved in N,N'-dimethylformamide (1.0 ml), diisopropylethylamide (0.2 mL, 1.03 mmol) was added, and stirred at room temperature for 5 minutes. . (S,R,S)-AHPC hydrochloride ((S,R,S)-AHPC hydrochloride) (62 mg, 0.13 mmol), 1-[Bis(dimethylamino)methylene]-1H-1,2,3- 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-Oxide Hexafluorophosphate) (58 mg, 0.15 mmol) was added dropwise and stirred at room temperature for 5 hours. When the reaction was completed, ethyl acetate (10 mL) and distilled water (10 mL) were added to separate the layers, and the organic layer was recovered, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(5-(((S)-14-((2S,4R)-4-hydroxy-2 -((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidine-1-carbonyl)-15,15-dimethyl-12-oxo-3,6,9-trioxa- 13-azahexadecyl)oxy)naphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11 , 11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide (30 mg, 27%) was obtained, which was designated as DT02P057.

1H NMR (400 MHz, CDCl3) δ8.69(s, 1H), 8.16-8.14(d, 1H), 8.06-8.04(d, 1H), 7.54-7.53(m, 1H), 7.48-7.34(m, 8H), 7.04-7.02(d, 1H), 6.87-6.82(d, 2H), 5.86-5.83(d, 1H), 5.32-5.29(m, 2H), 4.75-4.71(t, 1H), 4.60- 4.55(m, 1H), 4.49(s, 1H), 4.43-4.41(d, 1H), 4.35-4.30(m, 3H), 4.14-4.11(d, 1H), 4.02-3.99(t, 2H), 3.81-3.79(m, 2H), 3.71-3.64(m, 8H), 3.55-3.53(m, 1H), 3.41-3.36(m, 1H), 2.57-2.50(m, 5H), 2.48-2.46(m) , 2H), 2.40-2.37(m, 1H), 2.28-2.27(m, 1H), 2.12-2.07(m, 1H), 2.02-1.96(m, 2H), 1.85-1.82(m, 4H), 1.60 -1.55(m, 3H), 1.32-1.28(m, 3H), 1.18-1.13(m, 2H), 1.02(s, 3H), 0.95-0.94(m, 9H), 0.87(s, 3H).

Experimental Example 1. Analysis of the binding ability of the compounds of the present invention to the androgen receptor (AR binding assay)

The binding force of the compound synthesized in Preparation Example 1 was measured by evaluating the binding affinity for the androgen receptor (AR).

The androgen receptor binding capacity of 9 compounds was measured. The test was conducted at Eurofin Cerep, and the test method was as follows. LNCaP cell cytosol (10 ⁶ cells/point) was reacted with 1 nM [3H] methyltrienolone at 22°C for 4 hours in the presence or absence of the test substance. The buffer conditions for the reaction were 25mM Hepes-Tris (pH 7.4), 1mM EDTA, 10mM Na ₂ MoO ₄ , 2mM DTT, 5 μM triamcinolone acetonide, and 10% glycerol. Non-specific binding was tested under 1 μM testosterone conditions. After reaction, the sample was quickly filtered under reduced pressure using a glass fiber filter pre-absorbed with 0.3% PEI, and washed several times with ice-cold 50 mM Tris-HCl using a 96-sample cell harvester. Washed. After drying the filter, the radioactivity in the scintillation counter was measured using a scintillator, and the results are shown in Table 1 below. Testosterone was used as the standard substance.

Experimental Example 2. Confirmation of androgen receptor decomposition ability of the chimeric compound of the present invention

The degrading ability of the chimeric compound prepared through Preparation Example 2 on the androgen receptor was confirmed using a prostate cancer cell line (22Rv1). ARCC-4 was used as a control material.

22Rv1 cells were seeded at 2x10 ⁶ cells/well in a 6 well plate and cultured overnight. The next day, each prepared chimeric compound was added at concentrations of 0.01, 0.03, 0.1, 0.3, and 1 μM and reacted for 24 hours. After removing the medium, the cells were washed with PBS, cells were harvested using a cell scraper, and lysis was performed using RIPA buffer. After BCA was quantified, 30 μg was loaded onto an 8% SDS-PAGE gel and Western blot was performed using AR antibody. The Western blot results are shown in Figure 1.

The basis for calculating the resolution was to measure the intensity of the Western blot band using ImageQuant software (ver 10.2, cytiva) after Western blotting, and calculate the relative value compared to the control group (100%). Based on this, DC ₅₀ was calculated, and the resolution grade of each compound is shown in Table 2 below (DC ₅₀ : A (≤100 nM), B (100~500 nM), C (≥500 nM).

Experimental Example 2. Confirmation of selectivity of DT02P028, DT02P029, and DT02P030 for other receptors in MCF7 cells

Synthesized in Preparation Example 2 using MCF7, a triple-positive breast cancer cell line. When treating the DT02P028, DT02P029, and DT02P030 chimeric compounds, it was confirmed whether they had selectivity for other hormone receptors: Estrogen receptor (ER), Progesterone receptor (PR), and Glucocorticoid receptor (GR).

Specifically, MCF7 cells were distributed at 1.5x10 ⁶ cells/well in a 6-well plate and cultured overnight. The next day, DT02P028, DT02P029, and DT02P030 were added at concentrations of 0.01, 0.03, 0.1, 0.3, and 1 μM, respectively, and reacted for 24 hours. After removing the medium, the cells were washed with PBS, harvested using a cell scraper, and then lysed using RIPA buffer. After BCA was quantified, 30 μg was loaded onto an 8% SDS-PAGE gel and Western blot was performed using an androgen receptor antibody. The Western blot results are as shown in Figure 2.

As a result, treatment with DT02P028, DT02P029, and DT02P030 did not affect the decomposition of ER and GR, and only PR was confirmed to be decomposed depending on concentration. That is, it was confirmed that the compound of the present invention has selectivity for the progesterone receptor.

Experimental Example 3. Confirmation of the inhibitory effect of DHT-induced lipid synthesis by DT02P030 in SZ-95 cells

This study was conducted using a human sebaceous gland cell line (SZ95) to determine whether lipids produced under dihydrotestosterone (DHT) treatment conditions are reduced when treated with the test substance dihydrotestosterone (DHT).

SZ95 cells were distributed in a 6-well plate at 6x10 ⁴ cells/well and cultured overnight. The next day, the medium was changed to a new medium, and DT02P030 was added at concentrations of 10, 50, 100, and 500 nM under the conditions of DHT 15, 25, and 50 μM, and reacted for 72 hours. To confirm lipid synthesis, cells were subjected to Nile-red staining and the results were confirmed through fluorescence microscopy and FACs, respectively.

As a result, as shown in Figures 3 and 4, lipid synthesis increased under DHT treatment conditions, and DT02P030 treatment reduced lipid synthesis to an equivalent level or higher than the control substance Clascoterone. confirmed.

Experimental Example 4. Confirmation of androgen receptor (AR) resolution by DT02P030 in HFDPC cells

Using human dermal papilla cell line (HFDPC), it was confirmed whether androgen receptors were decomposed upon treatment with the test substance DT02P030.

HFDPC was dispensed into 6 wells/plate at 4x10 ⁵ cells/well and cultured overnight. The next day, DT02P030 was added at concentrations of 0.01, 0.1, and 1 μM and reacted for 24 hours. After removing the medium, the cells were washed with PBS, harvested using a cell scraper, and then lysed using RIPA buffer. After BCA was quantified, 30 μg was loaded onto an 8% SDS-PAGE gel and Western blot was performed using AR antibody. The Western blot results are as shown in Figure 5.

It was confirmed that AR decomposition decreased rapidly starting from 0.1 μM depending on the treatment at each concentration of DT02P030. As an evaluation to confirm the resolution of androgen receptors in dermal papilla cells, this substance can be applied as a treatment for hair loss indications.

The description of the present invention described above is for illustrative purposes, and those skilled in the art will understand that the present invention can be easily modified into other specific forms without changing the technical idea or essential features of the present invention. will be. Therefore, the embodiments described above should be understood in all respects as illustrative and not restrictive. For example, each component described as unitary may be implemented in a distributed manner, and similarly, components described as distributed may also be implemented in a combined form.

The scope of the present invention is indicated by the claims described below, and all changes or modified forms derived from the meaning and scope of the claims and their equivalent concepts should be construed as being included in the scope of the present invention.

Claims (16)

A compound represented by the following formula (1), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
[Formula 1]

Wherein R ₁ is -H, -CH ₂ CH ₂ OH or ego,
Above R ₂ is -H, , , , , , , and It is selected from the group consisting of. According to paragraph 1,
The compound represented by Formula 1 is any one or more selected from the group consisting of Formulas 2 to 10 below, a compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
[Formula 2]

[Formula 3]

[Formula 4]

[Formula 5]

[Formula 6]

[Formula 7]

[Formula 8]

[Formula 9]

[Formula 10]
According to paragraph 1,
The compound represented by Formula 1 is,
(4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(5-hydroxynaphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6, 6a, 7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide,
(4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(6-hydroxynaphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6, 6a, 7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide,
(4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(7-hydroxynaphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6, 6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide,
(4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(5-methoxynaphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6, 6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide,
(4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(6-methoxynaphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6, 6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide,
2-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b ,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamido)-2-methylpropanoic acid,
(4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl-N-(2-methyl-1-(methylamino)-1-oxopropan-2-yl)-2-oxo- 2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide ,
(4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-ethyl-N-(2-hydroxyethyl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6, 6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide; and
(4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(1-hydroxy-2-methylpropan-2-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b, 5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide selected from the group consisting of One or more compounds, stereoisomers thereof, or pharmaceutically acceptable salts thereof. According to paragraph 1,
The compound represented by Formula 1 is a compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof that binds to a nuclear receptor. According to paragraph 4,
A compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the nuclear receptor is an androgen receptor. A compound represented by the following formula (A), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
[Formula A]

The R ₁ is -H or -CH ₂ CH ₃ ,
The R ₃ is , , , , , and It is selected from the group consisting of,
The ULM is a VHL E3 ubiquitin ligase binding moiety,
The Linker is It is a group that chemically connects ULM and is bonded to the -OH portion of R ₃ . According to clause 6,
The VHL E3 ubiquitin ligase binding moiety is a compound represented by the following formula (B), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
[Formula B]

In Formula B,
is a 5-membered heteroaryl ring, and Y ₁ is hydrogen or C _1-3 alkyl. According to clause 6,
The Linker is a compound represented by the following formula L, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
[Formula L]

In the formula L , and is a combination,
L _{Formula A} is connected to this Combined with formula A through,
L _ULM is connected to this Combined with the ULM moiety through,
L _ULM and L _PTM are each independently a single bond, -CH ₂ -, -NH-, -O-, -CO-, -OCO-, -CONH- or -NHCO-,
L _INT is -CH ₂ -, -CH ₂ CH ₂ -, -CHCH-, -CC-, -CH ₂ CH ₂ O-, -OCH ₂ CH ₂ -, -CH ₂ CH ₂ S-, -SCH ₂ CH ₂ -, -COO-, -CONH-, -NHCO- and is selected from the group consisting of (here, is a ring selected from the group consisting of 3- to 10-membered cycloalkyl, 4- to 10-membered heterocycloalkyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl),
p is an integer from 1 to 10. According to clause 6,
The compound represented by the formula A is any one or more selected from the group consisting of the following formulas A-1 to A-31, a compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
[Formula A-1]

[Formula A-2]

[Formula A-3]

[Formula A-4]

[Formula A-5]

[Formula A-6]

[Formula A-7]

[Formula A-8]

[Formula A-9]

[Formula A-10]

[Formula A-11]

[Formula A-12]

[Formula A-13]

[Formula A-14]

[Formula A-15]

[Formula A-16]

[Formula A-17]

[Formula A-18]

[Formula A-19]

[Formula A-20]

[Formula A-21]

[Formula A-22]

[Formula A-23]

[Formula A-24]

[Formula A-25]

[Formula A-26]

[Formula A-27]

[Formula A-28]

[Formula A-29]

[Formula A-30]

[Formula A-31]
According to clause 6,
The compound represented by formula A is,
(4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(1-(2-(((S)-1-((2S,4R)-4-hydroxy-2-((4- (4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-2-oxoethoxy)- 2-methylpropan-2-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradeca Hydro-1H-indeno[5,4-f]quinoline-7-carboxamide,
(4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(1-(3-(((S)-1-((2S,4R)-4-hydroxy-2-((4- (4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-3-oxopropoxy)- 2-methylpropan-2-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradeca Hydro-1H-indeno[5,4-f]quinoline-7-carboxamide,
(4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(5-(2-(((S)-1-((2S,4R)-4-hydroxy-2-((4- (4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-2-oxoethoxy)naphthalene -1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H- Indeno[5,4-f]quinoline-7-carboxamide,
(4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(5-(3-(((S)-1-((2S,4R)-4-hydroxy-2-((4- (4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-3-oxopropoxy)naphthalene -1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H- Indeno[5,4-f]quinoline-7-carboxamide,
(4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(5-(4-(((S)-1-((2S,4R)-4-hydroxy-2-((4- (4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-4-oxobutoxy)naphthalene -1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H- Indeno[5,4-f]quinoline-7-carboxamide,
(4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(5-(2-(2-(((S)-1-((2S,4R)-4-hydroxy-2-( (4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-2-oxo Toxy)ethoxy)naphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a- Tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide,
(4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(5-(3-(2-(((S)-1-((2S,4R)-4-hydroxy-2-( (4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-2-oxo Toxy)propoxy)naphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a- Tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide,
(4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(5-(2-(2-(2-(((S)-1-((2S,4R)-4-hydroxy- 2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-2 -oxoethoxy)ethoxy)ethoxy)naphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b, 10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide,
2-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b ,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamido)-2-methylpropyl 7-(((S)-1-((2S,4R )-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutane-2 -yl)amino)-7-oxoheptanoate,
2-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b ,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamido)-2-methylpropyl 12-(((S)-1-((2S,4R )-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutane-2 -yl)amino)-12-oxododecanoate,
8-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidine-1- yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-8-oxooctyl 2-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl- 2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7 -carboxamido)-2-methylpropanoate,
12-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidine-1- Il)-3,3-dimethyl-1-oxobutan-2-yl)amino)-12-oxododecyl 2-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl -2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline- 7-Carboxamido)-2-methylpropanoate,
10-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidine-1- yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-10-oxodecyl 2-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl- 2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7 -carboxamido)-2-methylpropanoate,
2-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-ethyl-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9 ,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamido)ethyl 7-(((S)-1-((2S,4R )-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutane-2 -yl)amino)-7-oxoheptanoate,
2-((4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-ethyl-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9 ,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamido)ethyl 12-(((S)-1-((2S,4R )-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutane-2 -yl)amino)-12-oxododecanoate,
(4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-((S)-14-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazole- 5-yl)benzyl)carbamoyl)pyrrolidine-1-carbonyl)-2,15,15-trimethyl-3,12-dioxo-7,10-dioxa-4,13-diazahexadecane- 2-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H- No[5,4-f]quinoline-7-carboxamide,
(4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(1-((2-(2-(((S)-1-((2S,4R)-4-hydroxy-2- ((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-2-oxo Ethoxy)ethyl)amino)-2-methyl-1-oxopropan-2-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9, 9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide,
(4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-((S)-14-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazole- 5-yl)benzyl)carbamoyl)pyrrolidine-1-carbonyl)-2,15,15-trimethyl-3,12-dioxo-7,10-dioxa-4,13-diazahexadecane- 2-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H- No[5,4-f]quinoline-7-carboxamide,
(4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(5-((8-(((S)-1-((2S,4R)-4-hydroxy-2-((4 -(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-8-oxooctyl)oxy )naphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro- 1H-indeno[5,4-f]quinoline-7-carboxamide,
(4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(5-((7-(((S)-1-((2S,4R)-4-hydroxy-2-((4 -(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-7-oxoheptyl)oxy )naphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro- 1H-indeno[5,4-f]quinoline-7-carboxamide,
(4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(5-((12-(((S)-1-((2S,4R)-4-hydroxy-2-((4 -(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-12-oxododecyl) Oxy)naphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro -1H-indeno[5,4-f]quinoline-7-carboxamide,
(4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(5-((10-(((S)-1-((2S,4R)-4-hydroxy-2-((4 -(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-10-oxodecyl)oxy )naphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro- 1H-indeno[5,4-f]quinoline-7-carboxamide,
(4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(5-((11-(((S)-1-((2S,4R)-4-hydroxy-2-((4 -(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-11-oxoundecyl) Oxy)naphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro -1H-indeno[5,4-f]quinoline-7-carboxamide,
(4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(5-((9-(((S)-1-((2S,4R)-4-hydroxy-2-((4 -(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-9-oxononyl) Oxy)naphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro -1H-indeno[5,4-f]quinoline-7-carboxamide,
(4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(7-(2-(2-(2-(((S)-1-((2S,4R)-4-hydroxy- 2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-2 -oxoethoxy)ethoxy)ethoxy)naphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b, 10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide,
(4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(6-(2-(2-(2-(((S)-1-((2S,4R)-4-hydroxy- 2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-2 -oxoethoxy)ethoxy)ethoxy)naphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b, 10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide,
(4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(4-(2-(2-(2-(((S)-1-((2S,4R)-4-hydroxy- 2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-2 -oxoethoxy)ethoxy)ethoxy)phenyl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11, 11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide,
(4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(5-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1 ,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethoxy)naphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6, 6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide,
(4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(5-(2-(2-(3-(((S)-1-((2S,4R)-4-hydroxy- 2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-3 -Oxopropoxy)ethoxy)ethoxy)naphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b, 10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide,
(4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(5-(((S)-13-((2S,4R)-4-hydroxy-2-((4-(4- Methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidine-1-carbonyl)-14,14-dimethyl-11-oxo-3,6,9-trioxa-12-azapentadecyl)oxy) Naphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H -Indeno[5,4-f]quinoline-7-carboxamide; and
(4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-(5-(((S)-14-((2S,4R)-4-hydroxy-2-((4-(4- Methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidine-1-carbonyl)-15,15-dimethyl-12-oxo-3,6,9-trioxa-13-azahexadecyl)oxy) Naphthalen-1-yl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H -Indeno[5,4-f]quinoline-7-carboxamide, a compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, which is at least one selected from the group consisting of. According to clause 6,
The compound represented by Formula A is a compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof that decomposes nuclear receptors. According to clause 11,
A compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the nuclear receptor is an androgen receptor. A pharmaceutical composition for the prevention or treatment of nuclear receptor-related diseases or lipid metabolism diseases, comprising the compound of claim 6, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. According to clause 13,
A pharmaceutical composition, wherein the nuclear receptor-related disease is caused by sex hormone abnormality or disorder. According to clause 13,
A pharmaceutical composition, wherein the nuclear receptor-related disease is cancer, hair loss, hirsutism, or acne. According to clause 13,
A pharmaceutical composition, wherein the lipid metabolism disease is at least one selected from the group consisting of hypertriglyceridemia, dyslipidemia including hypercholesterolemia or hyperlipidemia, fatty liver, and obesity.