Aminonaphthoquinone compounds for treatment and / or prevention of fibrosis diseases

Abstract

The present disclosure relates to the use of a compound of Formula (I) as described herein and its effective dose in the prevention and / or treatment of fibrosis diseases. The compound can effectively prevent and / or treat a fibrosis disease without cytotoxicity or genotoxicity.

Description

<DP=1>²AIVIINONAPHTHOQUINONE COMPOUNDS FOR TREATMENT AND / OR ²PREVENTION OF FIBROSIS DISEASES²Field of the Invention ²

[0001] The invention relates to a method or use for treating and / or preventing ²fibrosis disease.²Particularly, the method uses aminonaphthoquinone compounds to treat and / or ²prevent fibrosis²diseases.²Back2round of the Invention ²[ 0002 ] Normal tissue repair processes are critical for maintaining proper ²tissue function. Fibrosis²is an excessive growth of fibrous connective tissue in an organ, any part, or ²tissue thereof, for²example in a liver, any part or tissue thereof, especially in response to an ²injury. Fibrosis affects ²many organ systems, including the lung, kidney, liver and heart; and many ²disease processes, ²including cardiomyopathies, hypertension, chronic hepatitis C infection, adult ²respiratory distress ²syndrome, and sarcoidosis are accompanied by fibrosis. For example, hepatic ²fibrosis is overly²exuberant wound healing in which excessive connective tissue builds up in the ²liver. Chronic liver²diseases can lead to liver fibrosis with the principle causes chronic viral ²hepatitis B and alcoholic ²liver disease. Pulmonary fibrosis (literally "scarring of the lungs") is a ²respiratory disease in which ²scars are formed in the lung tissues, leading to serious breathing problems. ²Scar formation, the ²accumulation of excess fibrous connective tissue (the process called ²fibrosis), leads to thickening of²the walls, and causes reduced oxygen supply in the blood. As a consequence ²patients suffer from²perpetual shortness of breath. Renal fibrosis is the inevitable consequence of ²an excessive ²accumulation of extracellular matrix that occurs in virtually every type of ²chronic kidney disease. ²Intestinal fibrosis is a common complication of inflammatory bowel disease ²(IBD) and can occur in ²both ulcerative colitis (UC) and Crohn's disease (CD), but is much more ²prevalent in CD. Fibrosis²can also occur in the heart, e.g., cardiac fibrosis can occur as a thickening ²of a heart valve. Current²therapies to treat fibrotic conditions, including dermal fibrosis and liver ²fibrosis, have a limited ²efficacy.²

[0003] Proteasomes play a major role in the degradation of many proteins that ²are involved in ²cell cycling, proliferation, and apoptosis. They have at least three distinct ²endopeptidase activities²which include hydrolysis of peptide bonds on the carboxyl side of hydrophobic, ²basic, and acidic²amino acid residues. Proteasomes, through their protein degradation activity, ²have been implicated ²in several important cell functions, including DNA repair, cell cycle ²progression, signal transduction, ²transcription, and antigen presentation. Proteasome inhibition represents an ²important new strategy²- 1 -²Date Recue / Date Received 2021-11-10²<DP=2>²in cancer treatment. US 7,442,830, US 8,003,819 and US 8,058,262 relate to ²boronic acid and ²boronic ester compounds useful as proteasome inhibitors. US 8,389,564 provides ²salinosporamide ²used to treating and / or ameliorating a disease or condition, such as cancer, a ²microbial disease and / or ²inflammation. WO 2010 / 005534 provides compounds having activity as inhibitors ²of proteasomes.²[ 0004 ] However, there are no reports showing that proteasome inhibitors are ²related to fibrosis²diseases.²Summary of the Invention ²[ 0005 ] The invention provides a method for prevention and / or treatment of a ²fibrosis disease²in a subject, comprising administering an effective amount of a compound of ²Formula (I)²described herein or a pharmaceutically acceptable salt, solvate or prodrug as ²an active ingredient²to the subject. Preferably, the effective amount is in a range of about 1.5 ²mg / kg / day to about 20 ²mg / kg / day to the subject. In some embodiments, the effective amount of the ²active ingredient ²ranges from about 1.5 mg / kg / day to about 15 mg / kg / day, about 1.5 mg / kg / day to ²about 13 ²mg / kg / day, about 1.5 mg / kg / day to about 12 mg / kg / day, about 1.5 mg / kg / day to ²about 10²mg / kg / day, about 2.0 mg / kg / day to about 20 mg / kg / day, about 2.0 mg / kg / day to ²about 15 ²mg / kg / day, about 2.0 mg / kg / day to about 13 mg / kg / day or about 2.0 mg / kg / day to ²about 12 ²mg / kg / day, about 5 mg / kg / day to about 20 mg / kg / day, about 5 mg / kg / day to about ²15 mg / kg / day ²or about 5 mg / kg / day to about 10 mg / kg / day. In some embodiments, the active ²ingredient of the ²method of the invention is further co-administered with a second anti-fibrosis ²agent. Preferably,²the second anti-fibrosis agent is ESBRIET (pirfenidone), OFEV (nintedanib), ²LOXL2 antibody²(such as simtuzumab), IL-13 antibody (lebrikizumab), ctV06 antibody (such as ²STX-100), CTGF ²antibody (such as FG-3019), tipelukast (such as MN-001) or aerosol pirfenidone ²(such as GP-²101). In some embodiments, the fibrosis disease is skin fibrosis, lung ²fibrosis, renal fibrosis, ²liver fibrosis, intestinal fibrosis, cystic fibrosis, cardiac fibrosis, ²uterine leiomyoma or²adenomyosis. In a further embodiment, the lung fibrosis is idiopathic ²pulmonary fibrosis.²[ 0006] The invention also provides a pharmaceutical composition comprising a ²compound of ²Formula (I) or a pharmaceutically acceptable salt, solvate or prodrug as an ²active ingredient in ²one or more unit dosage forms. Preferably, the dosage form is in one or more ²capsule forms or ²tablet forms.² Brief Description of the Drawing²[ 0007 ] Figure 1 (A) and (B) show the effect of L056 on TGF-P-induced CTGF ²expression in²W1-38 cells. W1-38 lung fibroblasts were incubated with different ²concentrations of L056 (0.3, 1, 3²- 2 -²Date Recue / Date Received 2021-11-10²<DP=3>²or 10 M) for 30 min before and during incubation for 2 h with TGF-P (10 ²ng / mL). L056 ²significantly inhibited TGF-P-induced CTGF production from WI-38 lung ²fibroblasts in a ²concentration-dependent manner. (A), Western blot plot; (B), Quantitative ²assay of Western blot. ²

[0008] Figure 2 (A) and (B) show the effect of L056 on ET-1-induced CTGF ²expression in WI-²38 cells. WI-38 lung fibroblasts were incubated with different concentrations ²of L056 (0.3, 1, 3 or 10²M) for 30 min before and during incubation for 2 h with ET-1 (10 nM). L056 ²significantly ²inhibited ET-1-induced CTGF production from WI-38 lung fibroblasts in a ²concentration-dependent ²manner. (A), Western blot plot; (B), Quantitative assay of Western blot.²

[0009] Figure 3 (A) and (B) show the effect of L056 on thrombin-induced CTGF ²expression in²WI-38 cells. WI-38 lung fibroblasts were incubated with different ²concentrations of L056 (0.3, 1, 3²or 10 M) for 30 min before and during incubation for 2 h with thrombin (1 ²U / ml). L056 ²significantly inhibited thrombin-induced CTGF production from WI-38 lung ²fibroblasts in a ²concentration-dependent manner. (A), Western blot plot; (B), Quantitative ²assay of Western blot.²[ 0010 ] Figure 4 (A), (B) and (C) show the effect of L056 on TGF-P-induced ²collagen expression²in WI-38 cells. WI-38 lung fibroblasts were incubated with different ²concentrations of L056 (0.3, 1,²3 or 10 M) for 30 min before and during incubation for 2 h with TGF-p (10 ²ng / mL). L056 ²significantly inhibited TGF-P-induced collagen production from WI-38 lung ²fibroblasts in a ²concentration-dependent manner. (A), Western blot plot; (B), Quantitative ²assay of Western blot; ²(C), Immunofluorescence plot.²

[0011] Figure 5 (A) and (B) show the effect of L056 on TGF-P-induced a-SMA ²expression in²WI-38 cells. WI-38 lung fibroblasts were incubated with different ²concentrations of L056 (0.3, 1, 3 ²or 10 M) for 30 min before and during incubation for 2 h with TGF-p (10 ²ng / mL). L056 ²significantly inhibited TGF-P-induced a-SMA production from WI-38 lung ²fibroblasts in a ²concentration-dependent manner. (A), Western blot plot; (B), Quantitative ²assay of Western blot²

[0012] Figure 6 (A), (B) and (C) show the effect of L056 on TGF-P-induced ²fibronectin²expression in WI-38 cells. WI-38 lung fibroblasts were incubated with ²different concentrations of ²L056 (0.3, 1, 3 or 10 M) for 30 min before and during incubation for 2 h with ²TGF-P (10 ng / mL). ²L056 significantly inhibited TGF-P-induced fibronectin production from WI-38 ²lung fibroblasts in a ²concentration-dependent manner. (A), Western blot plot; (B), Quantitative ²assay of Western blot;² (C), Immunofluorescence plot.²[00131 Figure 7 shows the effect of L056 on cell viability in WI38 cells.²- 3 -²Date Recue / Date Received 2021-11-10²<DP=4>²

[0014] Figure 8 (A) and (B) show the effect of L056 effect on fibrosis score ²of BLM-induced ²lung fibrosis in mice. C57BL / 6 mice (8 weeks) were treated with bleomycin ²(BLM, 0.05 U / 50 IA)²or PBS (50 IA) by endotracheal administration. L056 (25, 50, 100 mg / kg / day, ²q.d.), nintedanib ²(OFEV) (200 mg / kg / day, q.d.) or esbriet (ie., pirfenidone) (200 mg / kg / day, ²q.d.) were²administered orally to bleomycin-treated mice from 10 to 38 days after BLM ²treatment. On day²39, the mice were sacrificed and, the histologic analysis of lung tissue was ²performed by ²hematoxylin-eosin (H&E) staining (original magnification, x100). ²Semiquantitative analysis of ²the histology showed that bleomycin administration led to elevated histology ²fibrosis score in the ²lungs. (A), Histology fibrosis score plot; (B), H&E staining plot.²

[0015] Figure 9 (A) to (D) show the inhibitory effects on pro-fibrogenic ²mediators, collagen,²CTGF, fibronectin and a-SMA, respectively. (A), H&E staining plot for ²collagen; (B), H&E ²staining plot for CTGF; (C), H&E staining plot for fibronectin; (D), H&E ²staining plot for a-SMA. ²

[0016] Figure 10 (A) and (B) shows the effect of L056 on CCI4-induced liver ²fibrosis in mice ²(therapeutic model). (A) sirius red stain; (B), the inhibition of MPTOL056 on ²CC14-induced liver² fibrosis.²

[0017] Figure 11 shows the effect of L056 on CC14-induced a-SMA expression in ²mice²(therapeutic model).²Detailed Description of the Invention ²

[0018] The invention is, at least in part, based on the discovery of using ²aminonaphthoquinone².. compounds and their effective dose in the prevention and / or treatment of ²fibrosis diseases.²Particularly, the compounds can effectively prevent and / or treat a fibrosis ²disease without ²cytotoxicity or genotoxicity.²

[0019] As used herein, except where the context requires otherwise, the term ²"comprise" and ²variations of the term, such as "comprising," "comprises" and "comprised" are ²not intended to² exclude other additives, components, integers or steps.²

[0020] As used herein, except where the context requires otherwise, the method ²steps disclosed²are not intended to be limiting nor are they intended to indicate that each ²step is essential to the²method or that each step must occur in the order disclosed.²

[0021] As used herein, the use of "or" means "and / or" unless stated otherwise. ²In the context of a²multiple dependent claim, the use of "or" refers back to more than one ²preceding independent or²dependent claim in the alternative only.²

[0022] As used herein, all numbers are approximate, and may be varied to ²account for ²measurement error and the rounding of significant digits. The use of "about" ²before certain measured²- 4 -²Date Recue / Date Received 2021-11-10²<DP=5>²quantities includes variations due to sample impurities, measurement error, ²human error, and ²statistical variation, as well as the rounding of significant digits.²[ 0023 ] As used herein, the term "pharmaceutically acceptable salt" refers to ²those salts which ²are, within the scope of sound medical judgment, suitable for use in contact ²with the tissues of².. humans and lower animals without undue toxicity, irritation, allergic ²response and the like, and are²commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable ²salts are well known ²in the art. For example, Berge et al., describe pharmaceutically acceptable ²salts in detail in J. ²Pharmaceutical Sciences, 1977, 66, 1-19. Pharmaceutically acceptable salts of ²the compounds of this ²invention include those derived from suitable inorganic and organic acids and ²bases. Examples of²pharmaceutically acceptable, nontoxic acid addition salts are salts of an ²amino group formed with²inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, ²sulfuric acid, and ²perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic ²acid, tartaric acid, citric ²acid, succinic acid, or malonic acid or by using other methods known in the ²art such as ion exchange. ²Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, ²aspartate,²benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, ²camphorsulfonate, citrate,²cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, ²fumarate, ²glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, ²hexanoate, hydroiodide, 2-²hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, ²malate, maleate, malonate, ²methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, ²oxalate, palmitate, pamoate,²pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, ²propionate, stearate, succinate,²sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate ²salts, and the like. Salts ²derived from appropriate bases include alkali metal, alkaline earth metal and ²ammonium salts. ²Representative alkali or alkaline earth metal salts include sodium, lithium, ²potassium, calcium, ²magnesium, and the like. Further pharmaceutically acceptable salts include, ²when appropriate,²nontoxic ammonium, quaternary ammonium, and amine cations formed using ²counterions such as²halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl ²sulfonate, and aryl sulfonate.²[ 0024 ] The term "solvate" refers to forms of the compound that are ²associated with a solvent, ²usually by a solvolysis reaction. This physical association may include ²hydrogen bonding. ²Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, ²THF, diethyl ether, and²the like. The compounds described herein may be prepared, e.g., in crystalline ²form, and may be²solvated. Suitable solvates include pharmaceutically acceptable solvates and ²further include both ²stoichiometric solvates and non-stoichiometric solvates. In certain instances, ²the solvate will be ²capable of isolation, for example, when one or more solvent molecules are ²incorporated in the crystal²- 5 -²Date Recue / Date Received 2021-11-10²<DP=6>²lattice of a crystalline solid. "Solvate" encompasses both solution-phase and ²isolable solvates. ²Representative solvates include hydrates, ethanolates, and methanolates.²

[0025] The term "prodrug" refers to compounds, including derivatives of the ²compounds ²described herein, which have cleavable groups and become by solvolysis or ²under physiological²conditions the compounds described herein, which are pharmaceutically active ²in vivo. Such²examples include, but are not limited to, choline ester derivatives and the ²like, N-alkylmorpholine ²esters and the like. Other derivatives of the compounds of this invention have ²activity in both their ²acid and acid derivative forms, but in the acid sensitive form often offer ²advantages of solubility, ²tissue compatibility, or delayed release in the mammalian organism (see, ²Bundgard, H., Design of²Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs include acid ²derivatives well known²to practitioners of the art, such as, for example, esters prepared by reaction ²of the parent acid with a ²suitable alcohol, or amides prepared by reaction of the parent acid compound ²with a substituted or ²unsubstituted amine, or acid anhydrides, or mixed anhydrides.²

[0026] The terms "administer," "administering," or "administration," as used ²herein, refers to²implanting, absorbing, ingesting, injecting, inhaling, or otherwise ²introducing an inventive²compound, or a pharmaceutical composition thereof, in or on a subject.²[ 0027 ] As used herein, the terms "condition," "disease," and "disorder" are ²used interchangeably. ²

[0028] An "effective amount" of a compound described herein refers to an ²amount sufficient to ²elicit the desired biological response, i.e., treating the condition. As will ²be appreciated by those of²ordinary skill in this art, the effective amount of a compound described ²herein may vary depending²on such factors as the desired biological endpoint, the pharmacokinetics of ²the compound, the ²condition being treated, the mode of administration, and the age and health of ²the subject. An ²effective amount encompasses therapeutic and prophylactic treatment.²

[0029] A "therapeutically effective amount" of a compound described herein is ²an amount²sufficient to provide a therapeutic benefit in the treatment of a condition or ²to delay or minimize one²or more symptoms associated with the condition. A therapeutically effective ²amount of a compound ²means an amount of therapeutic agent, alone or in combination with other ²therapies, which provides ²a therapeutic benefit in the treatment of the condition. The term ²"therapeutically effective amount" ²can encompass an amount that improves overall therapy, reduces or avoids ²symptoms or causes of²the condition, and / or enhances the therapeutic efficacy of another therapeutic ²agent.²

[0030] A "prophylactically effective amount" of a compound described herein is ²an amount ²sufficient to prevent a condition, or one or more symptoms associated with the ²condition or prevent ²its recurrence. A prophylactically effective amount of a compound means an ²amount of a therapeutic²- 6 -²Date Recue / Date Received 2021-11-10²<DP=7>²agent, alone or in combination with other agents, which provides a ²prophylactic benefit in the ²prevention of the condition. The term "prophylactically effective amount" can ²encompass an amount ²that improves overall prophylaxis or enhances the prophylactic efficacy of ²another prophylactic ²agent.²

[0031] As used herein, the term "pharmaceutically acceptable carrier" refers ²to a solid,²semisolid, or liquid filler, diluent, encapsulating material, formulation ²auxiliary, or carrier ²conventional in the art for use with a therapeutic agent for administration to ²a subject. A ²pharmaceutically acceptable carrier is non-toxic to recipients at the dosages ²and concentrations ²employed and is compatible with other ingredients of the formulation. ²Pharmaceutically acceptable².. carriers are determined in part by the particular composition being ²administered, as well as by the²particular method used to administer the composition.²[00321 As used herein, the term "subject" is defined herein to include animals ²such as mammals, ²including, but not limited to, primates (e.g., humans), cows, sheep, goats, ²horses, dogs, cats, rabbits, ²rats, mice and the like. In specific embodiments, the subject is a human. The ²terms "subject" and²"patient" are used interchangeably herein in reference, for example, to a ²mammalian subject, such as²a human.²

[0033] As used herein, the terms "treat," "treating" and "treatment" refer to ²the eradication or ²amelioration of a disease or disorder, or of one or more symptoms associated ²with the disease or ²disorder. In certain embodiments, the terms refer to minimizing the spread or ²worsening of the²disease or disorder resulting from the administration of one or more ²prophylactic or therapeutic²agents to a subject with such a disease or disorder. In some embodiments, the ²terms refer to the ²administration of a compound or dosage form provided herein, with or without ²one or more ²additional active agents, after the diagnosis or onset of symptoms of the ²particular disease.²

[0034] As used herein, the terms "prevent," "preventing" and "prevention" ²refer to the prevention².. of the onset, recurrence or spread of a disease or disorder, or of one or ²more symptoms thereof. In²certain embodiments, the terms refer to the treatment with or administration ²of a compound or an ²antibody or dosage form provided herein, with or without one or more other ²additional active agents, ²prior to the onset of symptoms, particularly to patients at risk of disease or ²disorders provided herein. ²The terms encompass the inhibition or reduction of a symptom of the particular ²disease. In this²regard, the term "prevention" may be interchangeably used with the term ²"prophylactic treatment."²

[0035] As used herein, the terms "co-administration" and "in combination with" ²include the ²administration of two or more therapeutic agents simultaneously, concurrently, ²separately or ²sequentially within no specific time limits unless otherwise indicated. In one ²embodiment, the²- 7 -²Date Recue / Date Received 2021-11-10²<DP=8>²therapeutic agents are in the same composition or unit dosage form. In other ²embodiments, the ²therapeutic agents are in separate compositions or unit dosage forms.²[ 0036] In one aspect, the invention provides a method for prevention and / or ²treatment of a²fibrosis disease in a subject, comprising administering an effective amount of ²a compound with the²following general Formula (I) or an isomer, a stereoisomer, a pharmaceutically ²acceptable salt,²solvate or prodrug thereof as an active ingredient to a subject,²0²mifiti)²(CHOn.²R4²It3²5²(I)²wherein²Ri is halogen, Ci-ioalkyl, C2-ioalkenyl, C2-ioalkynyl, NH2, NO2, OH or CN;²each R2 is the same or different, representing H, Cmoalkyl, C2-malkenyl, C2-²ioalkynyl, NH2, NO2, Ci-²ioalkyloxy, Ci-ioalkylthio, Ci-ioalkylamino, Ci-ioalkyloxyCi-ioalkyl, OH or ²CN, C6-ioaryl or C5-²7heterocyclic having 1 to 3 heteroatoms selected from the group consisting of ²N, 0 and S;²R3 is H, Cmoalkyl, C24oalkenyl, C2-ioalkynyl, NH2, NO2, OH or CN;²R4 is H, Ci-ioalkyl, C2-1oalkenyl, C2-ioalkynyl, ² NO2, OH or CN, or R4 together with nitrogen²atom attached therefrom and R5 form a fused bicyclic ring having 0 to 3 ²heteroatoms selected from 0;²N and S;²R5 is absent, OH, C3-iocycloalkyl, C6-ioaryl, C5-7heterocyclic ring having 0 ²to 3 heteroatoms selected ²from 0; N and S or C10-12 fused heterocyclic ring having 0 to 3 heteroatoms ²selected from 0; N and S, ²each of cycloalkyl, aryl, heterocyclic ring and fused heterocyclic ring is ²unsubstituted or substituted²with one to three of OH; halogen; NH2; NO2, CN, Ci-ioalkyl; C2-ioalkenyl; C2-²ioalkynyl; Ci-ioalkyloxy;²C5-10heteroaryl having 1 to 3 heteroatoms selected from the group consisting ²of N, 0 and S, ²unsubstituted or substituted with Ci-ioalkyl, C2-ioalkenyl, C2-ioalkynyl, OH, ²halogen, CN, NH2 or NO2; ²-S(0)2-phenyl wherein the phenyl is unsubstituted or substituted with halogen, ²OH, CN, NH2, NO2, ²Ci-ioalkyl, C2-ioalkenyl, C2-ioalkynyl or Ci-ioalkyloxy; -C(0)NHOH; -C(0)NH2; -²C(0)-phenyl²wherein phenyl is unsubstituted or substituted with 1-5 same or different ²substituents selected from²the group consisting of OH, halogen, CN, NH2, NO2, Ci-ioalkyl, C2-ioalkenyl, ²C2-ioalkynyl or Ci-²ioalkyloxy; -C(0)NR.Rb; NHS(0)2pheny1 wherein phenyl is optionally substituted ²with OH, halogen,²- 8 -²Date Recue / Date Received 2021-11-10²<DP=9>²CN, NH2, NO2, Ci-ioalkyl, C2-ioalkenyl, C2-ioalkyny1 or Ci-ioalkyloxy; Ci-²ioalkylene-heteroaryl; - ²S(0)2-heteroaryl; -S(0)2-heterocylic ring; -S(0)2N(H)-heteroary1; -alkylene-²N(H)-heteroaryl; ²heterocylic ring unsubstituted or substituted with Ci-ioalkyl; or²R5 is alkylene-R6 wherein R6 is OH, NO2, CN, alkyl, alkenyl, alkynyl, NR.Rb, ²cycloalkyl, aryl,²heterocyclic ring having 0 to 3 heteroatoms selected from 0; N and S or fused ²heterocyclic ring²having 0 to 3 hetero atoms selected from 0, N and S, each of cycloalkyl, aryl, ²heterocyclic ring and ²fused heterocyclic ring is unsubstituted or substituted with one to three of ²OH; halogen; NH2; NO2, ²CN, alkyl; alkenyl; alkynyl; alkyloxy; heteroaryl having 1 to 3 heteroatoms ²selected from the group ²consisting of N, 0 and S, unsubstituted or substituted with alkyl, alkenyl, ²alkynyl, OH, halogen, CN,² NH2 or NO2; and²R. and Rb are the same or different, independently representing H; OH; alkyl; ²alkenyl; alkynyl; ²alkyloxy; cycloalkyl; heterocylyl; alkyleneamino; alkylene-N-(alky1)2; aryl ²unsubstituted or ²substituted with OH, halogen, CN, N1-12, NO2, alkyl, alkenyl, alkynyl, ²alkyloxy or heteroaryl;²heteroaryl unsubstituted or substituted with OH, halogen, CN, ² NO2, alkyl, alkenyl, alkynyl or²alkyloxy; alkylene-heteroaryl; or alkylene-heterocylyl unsubstituted or ²substituted with alkyl;²X is -C(0), -S(0)2 or -NH-C(0)-;²Y is ¨C- or ¨N-;²m is an integer of 0-3; and²n is an integer of 0-7.²

[0037] In another aspect, the invention provides a compound with the general ²Formula (I)²described herein or an isomer, a stereoisomer, a pharmaceutically acceptable ²salt, solvate or prodrug ²thereof for prevention and / or treatment of a fibrosis disease in a subject. ²Alternatively, the invention ²provides a use of a compound with the general Formula (I) described herein or ²an isomer, a ²stereoisomer, a pharmaceutically acceptable salt, solvate or prodrug thereof ²for the manufacture of a²medicament for prevention and / or treatment of a fibrosis disease in a subject.²

[0038] In some embodiments of formula (I), m is 0; Ri is halogen; n is any ²integer of 1-4; R3 is H; ²X is -C(0)-; R4 is H; and R5 is OH; C3-8cyc10a1ky1; phenyl unsubstituted or ²substituted with one to ²three same or different substituents selected from OH, CN, halogen, NH2 or Ci-²4alkylpiperazinyl; Ci-²6alkylpiperazinyl; Ci_6a1ky1pyridiny1; Ci_6a1ky1pyrr01idiny1; pyridinyl; ²pyrimidinyl; pyrazinyl;²piperazinyl; pyrrolidinyl; thiazolyl; benzimidazolyl; pyrazolyl; indazolyl; ²pyrazolyl; quinolinyl;²indolyl; Ci-4indoly1; indazolyl; azaindolyl; azaindazolyl; deazapurinyl; ²indanyl; morpholinoyl or Ci-²4a1ky1m0rph01in0y1, each of which is unsubstituted or substituted with one, ²two or three groups ²selected from OH, CN, halogen or NH2.²- 9 -²Date Recue / Date Received 2021-11-10²<DP=10>²[ 0039] In some embodiments of formula (I), m is 0; Ri is halogen; n is any ²integer of 1-2; R3 is H; ²X is -C(0); R4 is H; and Rs is OH; C3-8cyc10a1ky1; pyridinyl; phenyl ²substituted by one to three of ²NH2, halogen, OH, CN or Ci-alkylpiperazinyl; pyrinidinyl unsubstituted or ²substituted NO2, NH2 or ²Ci-alkyl; pyrazinyl unsubstituted or substituted NO2, NH2 or Ci-alkyl; ²thiazolyl unsubstituted or²substituted NO2, NH2 or CI-alkyl; benzimidazolyl unsubstituted or substituted ²NO2, NH2 or CI-alkyl;²pyrazolyl unsubstituted or substituted NO2, NH2 or Ci-alkyl; indazolyl ²unsubstituted or substituted ²NO2, NI-12 or CI-alkyl; thiazolyl unsubstituted or substituted NO2, NI-12 or ²CI-alkyl; quinolinyl ²unsubstituted or substituted NO2, NI-12 or CI-alkyl; indolyl unsubstituted or ²substituted NO2, NH2 or ²Ci-alkyl; indazolyl unsubstituted or substituted NO2, NI-12 or Ci-alkyl; ²azaindazolyl unsubstituted or²substituted NO2, NH2 or CI-alkyl; deazapurinyl unsubstituted or substituted ²NO2, NH2 or CI-alkyl;²indanyl unsubstituted or substituted NO2, NH2 or Ci_alkyl; or morpholinoyl ²unsubstituted or ²substituted NO2, NI-12 or CI-alkyl.²

[0040] In some embodiments of formula (I), m is 0; n is 0; Xis -C(0); Y is ¨N-²; Ri is halogen or ²CI-alkyl; R3 is H; R4 is H or C1-4a1ky1; and Rs is pyridinyl, pyrazinyl, or ²pyrimidinyl.²

[0041] In some embodiments of formula (I), m is 0; n is 0; Xis -C(0); Y is ¨N-²; Ri is halogen; R3²is H; R4 is H; and Rs is pyridinyl, pyrazinyl, or pyrimidinyl.²[ 0042 ] In some embodiments of formula (I), m is 0; n is 0; X is S(0)2; Y is ²¨N-; Ri is halogen or ²CI-alkyl; R3 is H; and R4 together with nitrogen atom attached therefrom and ²Rs form a fused ²bicyclic ring. Preferably, the fused bicyclic ring is indolyl or azaindolyl.²

[0043] In some embodiments of formula (I), m is 0; Ri is halogen; n is any ²integer of 1-4; R3 is H;²X is C(0); R4 is H; Rs is alkylene-R6 wherein R6 is NR.Rb, CsAeterocyclic ring ²having 0 to 3 hetero ²atoms selected from 0, N and S; or Cio-12 fused heterocyclic ring haying 0 to ²3 hetero atoms selected ²from 0, N and S; and R. and Rb are alkyl.²

[0044] In some embodiments of formula (I), m is 0; Ri is halogen; n is any ²integer of 1-2; R3 is H;²X is C(0); R4 is H; Rs is (CH2)1-4R6 wherein R6 is unsubstituted or ²substituted pyrrolidinyl, oxolanyl,²thiolanyl, pyrrolyl, furanyl, thiophenyl, piperidinyl, oxanyl, thianyl, ²morpholinoyl, pyridinyl, ²piperidinyl, piperazinyl, thiopyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, ²thiazolyl; ²benzimidazolyl; pyrazolyl; indazolyl; pyrazolyl; quinolinyl; indolyl; ²indazolyl; azaindolyl; ²azaindazolyl; deazapurinyl; or indanyl.²

[0045] In some embodiments of formula (I), m is 0; Ri is halogen; n is any ²integer of 1-2; R3 is H;²X is C(0); R4 is H; Rs is (CH2)1-4R6 wherein R6 is unsubstituted or ²substituted pyrrolidinyl, ²morpholinoyl, pyridinyl, piperidinyl, piperazinyl, or indolyl.²- 10 -²Date Recue / Date Received 2021-11-10²<DP=11>²[00461 In some embodiments of formula (I), the compounds include but are not ²limited to the ²following:²0²m(R2)²RI²(CH2)ii²N 410²0²R3² -IKR5²iS 0; R3 is H; X is C(0); and R is²Example ² Structure of²Code Number R1 (CH2).²(Compound #)²Exa 1 - ²)81,1²Example 2(2) ²N²MPTOL018 19-1312 Cl CH2²Exam le 3 (3)²Ad .1 õ119 9-1313² / Ng²Example 4(4)²MPTOL055 31-324 Cl CH2 ,N²7²Exam!le 5 (5)²mPTOL056 31-326 CI CHi,²Example 39 (6)²MPTOL080 19-1637 Br CI-12²Exam!le 42 (7) -²mPTOL101 31-482 Ci H2² ............ 0 / 11 / M / 1 / 1 / 1 / 1 / 1 / 1 / 1 / 1 / 1 / 1 / 1 / 11 / 1 / 11,1 ²Example 43 (8)²N N²MPTOL076 31-396 CI CH2²Example 6(9) - 11 ² F²mPTOL081 i9-1652 C1 CH2²Example 7(10)²MPTOL082 19-1653 Cl CH2²F²- 1 1 -²Date Recue / Date Received 2021-11-10²<DP=12>²- I - ...........õ - ....,' ... õõ, ..., .. ² I -V1171111111111111111111111111= -110²Exam ' le 8(11) MPTOLO8 ", ,,!-.,'²Example 9(12) H²MPTOL084 19-1655 Cl CH2 leo so²Exam', õõimilm²ip1,,,²(13),s²v' ²Example 11 H²(14) MPTOL086 19-1659 Cl 0-12 \NHN--²)1-9,²..... , ,²Example 12²I've 1 .1 : =. . '. ,², / , / d t / * * * / 1. / / 7 / / ²(14'²fifill1111111 II fill fififil#11111 Ififilli ,²Example 13 ii²MPTOL088 19-1673 Cl CH-, k ²ao²(16)². 1²Example 14 , , 19-²MPTOL092 Cll CH2²(17) 1678A²Example 15 H², = N²MPTOL093 9-1703 Cl CH2²(18) N²H²Example 16²MPTOL094 9-1704 Cl CH2².,,,²(19) , mV: '²Example 17 H²MPTOL095 9-1705 Cl CH-, N² ' 7²(20)²Example 18 , r ,² H ...,²....²MPTOL096 9-1706 Cl 'CH2 i²if²(21) , ,,. , , , ² v' , ²Example 19 ........................................................... H²MPTOL097 19-1708 Cl CH2 \ N ² \²N²1111111. N.²(22) H²Example 20 ,²MPTOL098 19-1709 ClI CI-ft...... ,,,,,,,e'''²(23)² OffilliMmememozammemeimPRIEN / 11 / 7 / ' .²Example 21 19- , H²MPTOL099 Cl CH2 \ N ²...I.;:r²(24) 1712A-2²... , 1²Exall'iple 22 19- .²MPTOL100 Cl Clii, / i²0 i5) 171 ,:,,,,,,,' '². v², ²Example 23 19- ²H NO2²MPTOL103 Cl CH2 \Nb²1²(26) 1716B -²N²H²Example 24 ²MPTOL108 19-1830- CI CH2 1²...-- N-²-²- 12 -²Date Recue / Date Received 2021-11-10²<DP=13>²(28) 2²,²ExaTple 25 mipill111111.1111Prcj² i ,,²õ. i . ²,²I²rr ' ²Example 26 H², N²MPTOL110 19-1834 Cl CH2²(30) ²N²,²Exam'iple 27²A²Example 28 19-1854- ) 40²MPTOL112 Cl CH2 I²(32) 2 - ²N²EXamliPle 29 ,õ 1²MPTOL113 Cl CI-12- ----ege""'' r r ' ²1²(3) 2 i²dfigag / il ²Example 30 19- H²MPT01.114 CI CH2 iN ²riiii \²(34) 1859B ²111111111111 N²H²Example 31 ' il²MPTOL115 19-1867 Cl, 'CH2-- / i, ²\ g 011'² ,, / , A P²Example 32 ²...,,NH 00--- NH²MPTOL116 19-1875 Cl CH2²(36)²r TO 117 19-1879 C,²(,7)²Example 34 H²MPTOL118 9-1887 C1 CH2 ².,,, N l N²(38) -.7-----( / ²i²Exan'ip1e 35 _²,²MPTOL119 9-1890 Cv ²I²(39)²Example 36 H², MPTOL120 9-1891 CI CH N2²(40)²H²Exan'ip1e 37²MPTOL121 CI CH \ ²(41) , 898A ²i²Example 38 11 =²MPTOL124 19-1903 CI CH \ 40²(42)²Example²Code Number R1 (CH2). ² Structure of R²(Compound #)²- 13 -²Date Recue / Date Received 2021-11-10²<DP=14>²Example 44 ² N²MPTOL102 19-1717 Cl CH2²(27)²Example 45²MPTOL122 19-1935 Cl CH2²46o,²(43)²Example 46² MPTOL123 19-1936 Cl CH2 N²(44) NH²Example 47²MPTOL132 Cl CH2²(45)²Example 48²MPTOL133 Cl CH2 ² ANN0²(46)²Example 49²(47) MPTOL134 ² Cl CH2 ANN / ²Example 50²(48) MPTOL136 Cl CH2²Example 51²(49) MPTOL137 Cl CH2²

[0047] The compounds of the present invention can be prepared using methods ²known to those ²skilled in the art in view of this disclosure. The compounds and their ²preparation methods described ²herein are disclosed in PCT / US2015 / 041767 and USSN 62 / 199,207. For example, ²the preferred²compounds of the invention can be prepared as shown in the following schemes: ²Scheme 1²- 14 -²Date Recue / Date Received 2021-11-10²<DP=15>²0 0² 0 ci ci ci²a b or c²CI 0 OH 0²0²0 ²0² 96 97 1-5, 9-26, 28-42²*Reagents and conditions²(a) 4-aminomethylbenzoic acid, TEA, Et0H, reflux.²(b) EDC, HCI, HOBt, NMM, DMF, NH2OTHP, r.t. then 10% TFA(aq.), Me0H, r.t., for ²1.²(c) substituted amine, HBTU, DIPEA, DMF, r.t. for 2-5, 9-26, 28-42.²Scheme 2²0 0² 0 ci ci ci²a b or c²CI 0 OH 0²0²0 ²0² 96 97 27, 43-49²*Reagents and conditions²(a) 4-aminomethylbenzoic acid, TEA, Et0H, reflux.²(b) substituted amine, HBTU, DIPEA, DMF, r.t. for 27, 43, 44²(c) substituted amine, EDC, HO!, HOBt, NMM, DMF, r.t. for 45-49.²

[0048] In one embodiment, the effective amount is in a range of about 1.5 ²mg / kg / day to about 20 ²mg / kg / day. In another embodiment, the effective amount for a human is in a ²range of about 2.0 ²mg / kg / day to about 15 mg / kg / day. On the other hand, the invention also ²provides a use of an ²effective amount of a compound of Formula (I) or a pharmaceutically acceptable ²salt, solvate or²prodrug as an active ingredient for the manufacture of a medicament for ²prevention and / or treatment²of a fibrosis disease.²[ 0049 ] In some further embodiments, the effective amount of the active ²ingredient or an isomer, ²a stereoisomer, a pharmaceutically acceptable salt, solvate or prodrug thereof ²used in the invention ²ranges from about 1.5 mg / kg / day to about 15 mg / kg / day, about 1.5 mg / kg / day to ²about 13 mg / kg / day,²about 1.5 mg / kg / day to about 12 mg / kg / day, about 1.5 mg / kg / day to about 10 ²mg / kg / day, about 2.0²- 15 -²Date Recue / Date Received 2021-11-10²<DP=16>²mg / kg / day to about 20 mg / kg / day, about 2.0 mg / kg / day to about 15 mg / kg / day, ²about 2.0 mg / kg / day ²to about 13 mg / kg / day or about 2.0 mg / kg / day to about 12 mg / kg / day, about 5 ²mg / kg / day to about 20 ²mg / kg / day, about 5 mg / kg / day to about 15 mg / kg / day or about 5 mg / kg / day to ²about 10 mg / kg / day. ²In a further embodiment, the effective amount used in the invention is about ²2.3 mg / kg / day to about² 11 mg / kg / day.²

[0050] In one embodiment, the active ingredient of the invention is further co-²administered with ²a second anti-fibrosis agent. Preferably, the second anti-fibrosis agent is ²ESBRIET (pirfenidone), ²OFEV (nintedanib), LOXL2 antibody (such as simtuzumab), IL-13 antibody ²(lebrikizumab), aV(36 ²antibody (such as STX-100), CTGF antibody (such as FG-3019), tipelukast (such ²as MN-001) or²aerosol pirfenidone (such as GP-101). In a further embodiment, the co-²administration is²simultaneous, separate or sequential administration.²[ 0051 ] In some embodiments, the fibrosis disease is skin fibrosis, lung ²fibrosis, renal fibrosis, ²liver fibrosis, intestinal fibrosis, cystic fibrosis, cardiac fibrosis, ²uterine leiomyoma or adenomyosis. ²In a further embodiment, the lung fibrosis is idiopathic pulmonary fibrosis. ²In another further²embodiment, the treatment of lung fibrosis further comprises a co-administered ²therapy with lung²transplantation, hyperbaric oxygen therapy (HBOT) or pulmonary rehabilitation.²[00521 In another aspect, the invention provides a pharmaceutical composition ²comprising a ²compound of Formula (I) or a pharmaceutically acceptable salt, solvate or ²prodrug as an active ²ingredient in one or more unit dosage forms. Preferably, the dosage form is in ²one or more²capsule forms or tablet forms. In one embodiment, the compound of Formula (I) ²is 4-(((3-chloro-²1,4-dioxo-1,4-dihydronaphthal en-2-yl)amino)methyl)-N-(pyridin-3-y1)benzami ²de.²[ 0053 ] In some embodiments, the pharmaceutical composition of the invention ²is in one or more ²capsule forms or tablet forms. In a further embodiment, the pharmaceutical ²composition of the ²invention comprises about 100 mg to about 300 mg, about 150 mg to about 300 ²mg, about 150 mg to²about 250 mg, about 200 mg to 250 mg, about 220 mg to about 280 mg, about 220 ²mg to about 250²mg or about 200 mg to about 220 mg of the active ingredient in a single ²tablet; preferably, about 200 ²mg or 220 mg in a single tablet. In another further embodiment, the ²pharmaceutical composition of ²the invention comprises about 100 mg to about 500 mg, about 150 mg to about ²500 mg, about 180 ²mg to about 500 mg, about 200 mg to about 500 mg, about 150 mg to about 350 ²mg, about 150 mg to²about 300 mg, about 200 mg to about 400 mg, about 200 mg to about 400 about ²350 mg, about 200²mg to about 300 mg, about 250 mg to about 500 mg, about 250 mg to about 400 ²mg, about 250 mg to ²about 350 mg or about 250 mg to about 300 mg of the active ingredient in a ²single capsule; ²preferably, about 250 mg of the active ingredient in a single capsule.²- 16 -²Date Recue / Date Received 2021-11-10²<DP=17>²[ 0054 ] In one embodiment, the pharmaceutical composition of the invention ²comprises a second ²anti-fibrosis agent. Preferably, the second anti-fibrosis agent is ESBRIET ²(pirfenidone), OFEV ²(nintedanib), LOXL2 antibody (such as simtuzumab), IL-13 antibody ²(lebrikizumab), aV136 antibody ²(such as STX-100), CTGF antibody (such as FG-3019), tipelukast (such as MN-²001) or aerosol² pirfenidone (such as GP-101).²[ 0055 ] While it may be possible for the compounds of the invention to be ²administered as the ²raw chemical, it is also possible to present them as a pharmaceutical ²formulation. Accordingly, the ²present invention provides a pharmaceutical formulation or composition ²comprising a compound or a ²pharmaceutically acceptable salt, prodrug or solvate thereof, together with ²one or more²pharmaceutically acceptable carriers thereof and optionally one or more other ²therapeutic²ingredients. The carrier(s) must be "acceptable" in the sense of being ²compatible with the other ²ingredients of the formulation and not deleterious to the recipient thereof. ²Proper formulation is ²dependent upon the route of administration chosen. Formulations may take the ²form of tablets, pills, ²capsules, semisolids, powders, sustained release formulations, solutions, ²suspensions, elixirs,²aerosols, or any other appropriate compositions; and comprise at least one ²compound of this²invention in combination with at least one pharmaceutically acceptable ²excipient. Suitable excipients ²are well known to persons of ordinary skill in the art, and they, and the ²methods of formulating the ²compositions, may be found in such standard references as Remington: The ²Science and Practice of ²Pharmacy, A. Gennaro, ed., 20th edition, Lippincott, Williams & Wilkins, ²Philadelphia, Pa. Suitable²liquid carriers, especially for injectable solutions, include water, aqueous ²saline solution, aqueous²dextrose solution, and glycols. The pharmaceutical compositions of the present ²invention may be ²manufactured in a manner that is itself known, e.g., by means of conventional ²mixing, dissolving, ²granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping ²or compression ²processes.²

[0056] The formulations include those suitable for oral, parenteral (including ²subcutaneous,²intradermal, intramuscular, intravenous, intraarticular, and intramedullary), ²intraperitoneal, ²transmucosal, transdermal, rectal and topical (including dermal, buccal, ²sublingual and intraocular) ²administration, although the most suitable route may depend, for example, upon ²the condition and ²disorder of the recipient. Oral administration is a preferred route. The ²formulations may².. conveniently be presented in unit dosage form and may be prepared by any of ²the methods well²known in the art of pharmacy. All methods include the step of bringing into ²association a compound ²of the present invention or a pharmaceutically acceptable salt, prodrug or ²solvate thereof ("active ²ingredient") with the carrier which constitutes one or more accessory ²ingredients. In general, the²- 17 -²Date Recue / Date Received 2021-11-10²<DP=18>²formulations are prepared by uniformly and intimately bringing into ²association the active ingredient ²with liquid carriers or finely divided solid carriers or both and then, if ²necessary, shaping the product ²into the desired formulation.²

[0057] For oral administration, suitable pharmaceutical compositions of the ²invention include²powders, granules, pills, tablets, lozenges, chews, gels, and capsules as well ²as liquids, syrups,²suspensions, elixirs, and emulsions. These compositions may also include anti-²oxidants, flavorants, ²preservatives, suspending, thickening and emulsifying agents, colorants, ²flavoring agents and other ²pharmaceutically acceptable additives. Formulations for oral administration ²may be formulated to be ²immediate release or modified release, where modified release includes ²delayed, sustained, pulsed,² controlled, targeted and programmed release.²

[0058] For parenteral administration, the compounds of the present invention ²are administered ²directly into the blood stream, into muscle, or into an internal organ via an ²intravenous, intraarterial, ²intraperitoneal, intramuscular, subcutaneous or other injection or infusion. ²Parenteral formulations ²may be prepared in aqueous injection solutions which may contain, in addition ²to the compound of²the invention, buffers, antioxidants, bacteriostats, salts, carbohydrates, and ²other additives commonly²employed in such solutions. Parenteral administrations may be immediate ²release or modified ²release (such as an injected or implanted depot).²

[0059] Compounds or compositions of the present invention may also be ²administered topically, ²(intra)dermally, or transdermally to the skin or mucosa. Typical formulations ²include gels,²hydrogels, lotions, solutions, creams, ointments, dressings, foams, skin ²patches, wafers, implants and²microemulsions. Compounds or compositions of the present invention may also be ²administered via ²inhalation or intranasal administration, such as with a dry powder, an aerosol ²spray or as drops. ²Additional routes of administration for compounds of the present invention ²include intravaginal and ²rectal (by means of a suppository, pessary or enema), and ocular and aural.²

[0060] Dosage regimens can be adjusted to provide the optimum therapeutic ²response. For²example, several divided dosages may be administered daily or the dosage may ²be proportionally ²reduced as indicated by the exigencies of the therapeutic situation.²

[0061] It is especially advantageous to formulate the compounds in dosage unit ²form for ease of ²administration and uniformity of dosage. Dosage unit form as used herein ²refers to physically²discrete units suited as unitary dosages for the subjects to be treated; each ²containing a²therapeutically effective quantity of the compound and at least one ²pharmaceutical excipient. A drug ²product will comprise a dosage unit form within a container that is labelled ²or accompanied by a ²label indicating the intended method of treatment.²- 18 -²Date Recue / Date Received 2021-11-10²<DP=19>²[00621 It is understood that the examples described herein are merely ²illustrative of the present ²invention. Certain modifications of the articles and / or methods employed may ²be made and still ²achieve the objectives of the invention. Such modifications are contemplated ²as within the scope of ²the claimed invention.² Example ²Preparation Examples ²Example 1 4-(((3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-²yl)amino)methyl)-N-²hydroxybenzamide (1)²0²CI²N²H I H²0 N²'OH²0²

[0063] A mixture of 97 (0.36 g, 1.05 mmol), EDC.HC1 (0.30 g, 1.58 mmol), HOBt ²(0.17 g, 1.26²mmol), NMM (0.28 ml, 2.52 mmol) and DMF (2.5 ml) was stirred for a while, to ²which was then ²added the o-(tetrahydro-2H-pyran-2-yl)hydroxylamine (0.15 g, 1.26 mmol) at ²room temperature, and ²the mixture was stirred overnight. The residue was purified by flash column ²over silica gel (ethyl ²acetate: n-hexane = 2:1, Rf = 0.45) to obtain the oily product. The oily ²product was then dissolved in²Me0H (3 ml) and 10% TFA (aq.) (3 ml) added at room temperature and the mixture ²was stirred ²overnight. H20 was added to the reaction to produce the precipitant. The ²residue was filtered ²without further purification to afford 1 (0.24 g, 98.93 %) as a red solid. 1-1-²1-NMR (500MHz, DMSO-²d6): 6 4.98 (s, 2H), 7.35 (d, J= 8.5 Hz, 2H), 7.68 (d, J= 8.5 Hz, 2H), 7.73 ²(m, 1H), 7.81 (m, 1H), 7.96 ²(m, 2H), 8.03 (s, 1H).²Example 2 4-(((3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-yl)amino)methyl)-²N-(pyridin-2-²yl)benzamide (2)²0²CI²N²H ii I H²0 N N²---- ...--..z_²0²

[0064] A mixture of 97 (0.25 g, 0.73 mmol), EDC.HC1 (0.21 g, 1.10 mmol), HOBt ²(0.12 g, 0.88 ²mmol), NMM (0.19 ml, 1.75 mmol) and DMF (2.0 ml) was stirred for a while, to ²which was then²added 2-aminopyridine (0.08 g, 0.88 mmol) at room temperature and the mixture ²was stirred²- 19 -²Date Recue / Date Received 2021-11-10²<DP=20>²overnight. The residue was purified by flash column over silica gel ²(dichloromethane: methanol = ²30:1, Rf = 0.50) to afford 2(0.04 g, 13.11 %) as a red solid. 1H-NMR (300MHz, ²CDC13): 6 5.15 (d, ²J= 6.6 Hz, 2H), 6.33 (s, 1H), 7.08-7.12 (m, 1H), 7.49 (d, j 8.4 Hz, 2H), 7.67 ²(m, 1H), 7.77 (m, 2H), ²7.97 (d, .1= 8.4 Hz, 2H), 8.08 (m, 1H), 8.18 (m, 1H), 8.33 (m, 1H), 8.40 (d, ²J= 8.4 Hz, 1H), 8.59 (br,² 1H).²Example 3 N-(2-aminopheny1)-4-(((3-chloro-1,4-dioxo-1,4-²dihydronaphthalen-2-²y1)amino)methyl)benzamide (3)²0²CI²NH2²0²

[0065] A mixture of 97 (0.25 g, 0.73 mmol), EDC.HC1 (0.21 g, 1.10 mmol), HOBt ²(0.12g. 0.88²mmol), NMM (0.19 ml, 1.75 mmol) and DMF (2.0 ml) was stirred for a while, to ²which was then²added o-Phenylenediamine (0.08 g, 0.88 mmol) at room temperature and the ²mixture was stirred ²overnight. The residue was purified by flash column over silica gel ²(dichloromethane: methanol = ²30:1, Rf = 0.50) to afford 3 (0.06 g, 19.03 %) as a red solid. 1H-NMR (300 ²MHz, DMSO-d6): 6 4.86 ²(s, 2H), 5.03 (s, 2H), 6.57 (t, J= 7.8 Hz, 1H), 6.75 (d, J= 6.6 Hz, 1H), 6.95 ²(t, J= 7.8 Hz, 1H), 7.14 (d,²J= 6.6 Hz, 1H), 7.42 (d, J= 7.8 Hz, 2H), 7.74 (t, J= 7.2 Hz, 1H), 7.82 (t, J= ²7.2 Hz, 1H), 7.95 (m,²4H), 8.10 (br, 1H), 9.59 (s, 1H).²Example 4 4-(((3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-Aamino)methyl)-²N-(pyridin-3-²y1)benzamide (4)²0²CI²N1 H²0 N²0²

[0066] A mixture of 97 (0.10 g, 0.29 mmol), HBTU (0.11 g, 0.29 mmol), DIPEA ²(0.06 ml, 0.35²mmol) and DMF (1.0 ml) was stirred for a while, to which was then added 3-²aminopyridine (0.03 g, ²0.35 mmol). The reaction was stirred for 16 h at room temperature. The residue ²was filtered without ²further purification to afford 4 (0.08 g, 66.02 %). 1H NMR (300 MHz, DMSO-d6): ²6 5.03 (d, J= 7.2 ²Hz, 2H), 7.37 (q, J= 4.8 Hz, 1H), 7.46 (d, J= 8.1 Hz, 2H), 7.74-7.82 (m, 2H), ²7.91 (d, J= 8.1 Hz, 2H),² 7.95-7.98 (m, 2H), 8.13-8.17 (m, 2H), 8.27-8.29 (m, 1H), 10.42 (s, 1H).²- 20 -²Date Recue / Date Received 2021-11-10²<DP=21>²Example 5 4-(((3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-²yl)amino)methyl)-N-(pyridin-3-²yl)benzamide (5)²0²CI²0 N²0²

[0067] A mixture of 97 (0.10 g, 0.29 mmol), HBTU (0.11 g, 0.29 mmol), DIPEA ²(0.06 ml, 0.35²mmol) and DMF (1.0 ml) was stirred for a while, to which was then added 4-²aminopyridine (0.03 g,²0.35 mmol). The reaction was stirred for 16 h at room temperature. The residue ²was filtered without ²further purification to afford 5 (0.08g, 66.02%). 1H NMR (300 MHz, DMSO-d6): 6 ²5.03 (d, J= 7.2 ²Hz, 2H), 7.37 (d, J= 8.4 Hz, 2H), 7.73-7.76 (m, 3H), 7.79-7.84 (m, 1H), 7.90 ²(d, J= 8.4 Hz, 2H), ²7.95-7.98 (m, 2H), 8.08-8.13 (m, 1H), 8.43-8.45 (m, 2H), 10.53 (s, 1H).²Example 6 4-(((3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-yl)amino)methyl)-²N-(3-²fluorophenyl)benzamide (9)²0²CI²0 N F²0²

[0068] A mixture of 97 (0.30 g, 0.88 mmol), HBTU (0.50 g, 1.32 mmol), DIPEA ²(0.23 ml, 1.32 ²mmol) and DMF (2.5 ml) was stirred for a while, to which was then added 3-²fluoroaniline (0.13 g,²1.32 mmol) at room temperature and the mixture was stirred overnight. The ²residue was purified by²flash column over silica gel (ethyl acetate: n-hexane = 1:2, Rf = 0.30) to ²afford 9 (0.04g, 10.45%) as ²a red solid. 1H-NMR (300MHz, DMSO-d6): 6 5.03 (s, 2H), 6.92 (m, 1H), 7.36 (m, ²1H), 7.45 (d, J= ²8.1 Hz, 2H), 7.52 (m, 1H), 7.72 (m, 2H), 7.80 (m, 1H), 7.88 (d, J= 8.4 Hz, ²2H), 7.97 (m, 2H), 8.11 ²(br, 1H), 10.37 (s, 1H).²Example 7 4-(((3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-yl)amino)methyl)-²N-(4-²fluorophenyl)benzamide (10)²- 21 -²Date Recue / Date Received 2021-11-10²<DP=22>²0²CI²N²H H²O N²0²F²

[0069] A mixture of 97 (0.30 g, 0.88 mmol), HBTU (0.50 g, 1.32 mmol), DIPEA ²(0.23 ml, 1.32 ²mmol) and DMF (2.5 ml) was stirred for a while, to which was then added 4-²fluoroaniline (0.13g, ²1.32mmo1) at room temperature and the mixture was stirred overnight. The ²residue was purified by²flash column over silica gel (ethyl acetate: n-hexane = 1:2, Rf = 0.35) to ²afford 10 (0.02 g, 5.23 %) as²a red solid. 1-H-NMR (300 MHz, DMSO-d6): 6 5.02 (s, 2H), 7.16 (t, J= 9.0 Hz, ²2H), 7.43 (d, J= 8.1 ²Hz, 2H), 7.75 (m, 3H), 7.82 (m, 1H), 7.88 (d, J= 8.4 Hz, 2H), 7.97 (m, 2H), ²8.08 (br, 1H), 10.24 (s, ²1H).²Example 8 4-(((3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-Aamino)methyl)-²N-² phenylbenzamide (11)²0²CI²N²H H²O N²0 1101²

[0070] A mixture of 97 (0.30 g, 0.88 mmol), HBTU (0.50 g, 1.32 mmol), DIPEA ²(0.23 ml, 1.32 ²mmol) and DMF (2.5 ml) was stirred for a while, to which was then added ²aniline (0.12 g, 1.32 ²mmol) at room temperature and the mixture was stirred overnight. The residue ²was filtered by²suction filtration to yield a red product. The residue was filtered without ²further purification to afford²11 (0.28 g, 76.33 %) as a red solid. 1-H-NMR (300MHz, DMSO-d6): 6 5.02 (s, ²2H), 7.07 (t, J= 7.5 ²Hz, 1H), 7.32 (d, J= 7.5 Hz, 2H), 7.44 (d, J= 8.4 Hz, 2H), 7.75 (m, 3H), 7.83 ²(m, 1H), 7.88 (d, J= 8.4 ²Hz, 2H), 7.97 (m, 2H), 8.10 (br, 1H), 10.18 (s, 1H).²Example 9 4-(((3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-Aamino)methyl)-²N-(2-² 2 0 fluorophenyl)benzamide (12)²0²CI²N F²H H²O N²0 el²- 22 -²Date Recue / Date Received 2021-11-10²<DP=23>²

[0071] A mixture of 97 (0.30 g, 0.88 mmol), HBTU (0.50 g, 1.32 mmol), DIPEA ²(0.23 ml, 1.32 ²mmol) and DMF (2.5 ml) was stirred for a while, to which was then added 2-²fluoroaniline (0.13 g, ²1.32 mmol) at room temperature and the mixture was stirred overnight. The ²residue was purified by ²flash column over silica gel (ethyl acetate: n-hexane = 1:2, Rf = 0.25) to ²afford 12 (0.02 g, 5.23 %) as²a red solid. 1-1-1-NMR (300 MHz, DMSO-d6): 6 5.03 (s, 2H), 7.23 (m, 3H), 7.44 ²(d, J= 8.1 Hz, 2H),²7.56 (t, J= 7.5 Hz, 1H), 7.74 (m, 1H), 7.80 (m, 1H), 7.91 (d, J= 8.1 Hz, 2H), ²7.97 (m, 2H), 8.10 (br, ²1H), 10.05(s, 1H).²Example 10 4-(((3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-yl)amino)methyl)-N-²(thiazol-2-²yl)benzamide (13)²0²CI²0 LyNS² 0 N---1²

[0072] A mixture of 97 (0.30 g, 0.88 mmol), HBTU (0.50 g, 1.32 mmol), DIPEA ²(0.23 ml, 1.32 ²mmol) and DMF (2.5 ml) was stirred for a while, to which was then added 2-²aminothiazole (0.13 g, ²1.32 mmol) at room temperature and the mixture was stirred overnight. The ²residue was filtered by ²suction filtration to yield a red product. The residue was filtered without ²further purification to²afford 13 (0.15 g, 40.21 %) as a red solid. 1-1-1-NMR (300 MHz, DMSO-d6): 6 ²5.03 (d, J= 7.2 Hz, 2H),²7.26 (d, J= 3.6 Hz, 1H), 7.45 (d, J= 8.4 Hz, 2H), 7.53 (d, J= 3.6 Hz, 1H), ²7.75 (m, 1H), 7.82 (m, 1H), ²7.97 (m, 2H), 8.04 (d, J= 8.4 Hz, 2H), 8.10 (t, J= 7.5 Hz, 1H), 12.55 (s, 1H).²Example 11 N-(1H-benzo[d]imidazol-2-yl)-4-(((3-chloro-1,4-dioxo-1,4-²dihydronaphthalen-2-²yl)amino)methyl)benzamide (14)²0²CI²H H²0²II / ²0 N²

[0073] A mixture of 97 (0.30 g, 0.88 mmol), HBTU (0.50 g, 1.32 mmol), DIPEA ²(0.23 ml, 1.32 ²mmol) and DMF (2.5 ml) was stirred for a while, to which was then added 2-²aminobenzimidazole ²(0.18 g, 1.32 mmol) at room temperature and the mixture was stirred overnight. ²The residue was ²filtered by suction filtration to yield a red product. The residue was ²filtered without further²purification to afford 14 (0.27 g, 67.16 %) as a red solid. 1-1-1-NMR (300 ²MHz, DMSO-d6): 6 5.03 (d,²- 23 -²Date Recue / Date Received 2021-11-10²<DP=24>²J= 6.9 Hz, 2H), 7.11 (m, 2H), 7.43 (d, J= 9.0 Hz, 4H), 7.74 (m, 1H), 7.82 (m, ²1H), 7.96 (d, J= 5.7²Hz, 2H), 8.07 (d, J= 8.4 Hz, 3H), 12.22 (s, 1H).²Example 12 4-(((3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-Aamino)methyl)-N-(4-²²hydroxyphenyl)benzamide (15)²0²CI²N²H H²0 N²0² OH²[00741 A mixture of 97 (0.15 g, 0.44 mmol), HBTU (0.25 g, 0.66 mmol), DIPEA ²(0.11 ml, 0.66 ²mmol) and DMF (2.5 ml) was stirred for a while, to which was then added 4-²aminophenol (0.07 g, ²0.66 mmol) at room temperature and the mixture was stirred overnight. The ²residue was purified by ²flash column over silica gel (ethyl acetate: n-hexane = 1:2, Rf = 0.30) to ²afford 15 (0.02 g, 10.50 %)²as a brown solid. 1-1-1-NMR (300 MHz, DMSO-d6): 6 5.01 (d, J= 6.3 Hz, 2H), ²6.70 (d, J= 9.0 Hz, 2H),²7.41 (d, J= 8.4 Hz, 2H), 7.48 (d, J= 8.7 Hz, 2H), 7.74 (m, 1H), 7.80 (m, 1H), ²7.85 (d, J= 8.4 Hz, 2H), ²7.98 (m, 2H), 8.09 (br, 1H), 9.25 (br, 1H), 9.95 (s, 1H).²Example 13 4-(((3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-Aamino)methyl)-N-(3-²²ethynylphenyl)benzamide (16)²0²CI²N²H H / ²0 N / ²0²

[0075] A mixture of 97 (0.30 g, 0.88 mmol), HBTU (0.50 g, 1.32 mmol), DIPEA ²(0.23 ml, 1.32 ²mmol) and DMF (2.5 ml) was stirred for a while, to which was then added 3-²ethynylaniline (0.15 g, ²1.32 mmol) at room temperature and the mixture was stirred overnight. The ²residue was purified by ²flash column over silica gel (ethyl acetate: n-hexane = 1:4, Rf = 0.25) to ²afford 16 (0.12 g, 30.93 %)²as a red solid. 1-1-1-NMR (300 MHz, DMSO-d6): 6 4.17 (s, 1H), 5.03 (s, 2H), ²7.18 (d, J= 7.5 Hz, 1H),²7.34 (t, J= 8.1 Hz, 1H), 7.45 (d, J= 8.4 Hz, 2H), 7.87 (m, 8H), 8.11 (br, 1H), ²10.27 (s, 1H).²Example 14 4-(((3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-Aamino)methyl)-N-(2-²fluoro-²4-iodophenyl)benzamide (17)²- 24 -²Date Recue / Date Received 2021-11-10²<DP=25>²0²CI²N F²H H²0 N²0 I²

[0076] A mixture of 97 (0.30 g, 0.88 mmol), HBTU (0.50 g, 1.32 mmol), DIPEA ²(0.23 ml, 1.32 ²mmol) and DMF (2.5 ml) was stirred for a while, to which was then added 2-²fluoro-4-iodoaniline ²(0.31 g, 1.32 mmol) at room temperature and the mixture was stirred overnight. ²The residue was²purified by flash column over silica gel (ethyl acetate: n-hexane = 1:2, Rf = ²0.45) to afford 17 (0.02²g, 4.05 %) as a red solid. 111-NMR (300 MHz, CDC13): 6 5.03 (d, J= 6.9 Hz, ²2H), 7.41 (m, 3H), 7.56 ²(m, 1H), 7.73 (m, 1H), 7.81 (m, 1H), 7.90 (d, J= 8.4 Hz, 2H), 7.96 (m, 2H), ²8.10 (m, 1H), 10.09 (s, ²1H).²Example 15 N-(1H-benzo Id] imidazol-5-y1)-4-((3-chloro-1,4-dioxo-1,4-dihy ²dronaphth alen-2-² ylamino)methyl)benzamide (18)²0²(LyCI²N²H H²0 N N²0²N²H²[00771 A mixture of 97 (0.30 g, 0.88 mmol), HBTU (0.50 g, 1.32 mmol), DIPEA ²(0.23 ml, 1.32 ²mmol) and DMF (2.5 ml) was stirred for a while, to which was then added 5-²aminobenzimidazole ²(0.18 g, 1.32 mmol) at room temperature and the mixture was stirred overnight. ²The residue was²filtered by suction filtration to yield a red product. The residue was ²filtered without further²purification to afford 18 (0.26 g, 64.67 %) as a red solid. 1-H-NMR (300MHz, ²DMSO-d6): 6 5.03 (d, ²J= 7.2 Hz, 2H), 7.43-7.48 (m, 3H), 7.54 (d, J= 8.7 Hz, 1H), 7.72-7.77 (m, 1H), ²7.80-7.85 (m, 1H), ²7.91 (d, J= 8.4 Hz, 2H), 7.96-7.99 (m, 2H), 8.09-8.15 (m, 2H), 8.20 (s, 1H), ²10.20 (s, 1H).²Example 16 2-(4-(3-amin o-1H-pyrazole-1-carb onyl)benzylamin o)-3-²chloronaphthalene-1,4-² 2 0 dione (19)²0²CI²NH2²H²0 N / ²0²- 25 -²Date Recue / Date Received 2021-11-10²<DP=26>²

[0078] A mixture of 97 (0.30 g, 0.88 mmol), HBTU (0.50 g, 1.32 mmol), DIPEA ²(0.23 ml, 1.32 ²mmol) and DMF (2.5 ml) was stirred for a while, to which was then added 3-²aminopyrazole (0.11 g, ²1.32 mmol) at room temperature and the mixture was stirred overnight. The ²residue was filtered by ²suction filtration to yield a red product. The residue was filtered without ²further purification to afford²19 (0.17 g, 47.49 %) as a red solid. 11-1-NMR (300 MHz, DMSO-d6): 6 5.03 (s, ²2H), 5.64 (s, 2H),²5.99 (d, J= 3.0 Hz, 1H), 7.42 (d, J= 8.4 Hz, 2H), 7.71-7.77 (m, 1H), 7.79-7.85 ²(m, 1H), 7.92-7.98 (m, ²4H), 8.11 (s, 1H), 8.15 (d, J= 3.0 Hz, 1H).²Example 17 4-((3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-ylamino)methyl)-N-²cyclopropylbenzamide (20)²0²CI²N²H H²0²V² 0²

[0079] A mixture of 97 (0.30 g, 0.88 mmol), HBTU (0.50 g, 1.32 mmol), DIPEA ²(0.23 ml, 1.32 ²mmol) and DMF (2.5 ml) was stirred for a while, to which was then added ²cyclopropylamine (0.09 ²ml, 1.32 mmol) at room temperature and the mixture was stirred overnight. The ²residue was filtered ²by suction filtration to yield a red product. The residue was filtered without ²further purification to²afford 20 (0.12 g, 35.81 %) as a red solid. 11-1-NMR (300 MHz, DMSO-d6): 6 ²0.52-0.55 (m, 2H),²0.63-0.69 (m, 2H), 2.77-2.83 (m, 1H), 4.98 (s, 2H), 7.34 (d, J= 8.4 Hz, 2H), ²7.72-7.75 (m, 3H), 7.82 ²(t, J= 7.5 Hz, 1H), 7.96 (d, J= 7.8 Hz, 2H), 8.05 (s, 1H), 8.36 (d, J= 4.2 Hz, ²1H).²Example 18 4-((3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-ylamino)methyl)-N-²cyclopentylbenzamide (21)²0²CI²N²H H²0 N² 0²

[0080] A mixture of 97 (0.30 g, 0.88 mmol), HBTU (0.50 g, 1.32 mmol), DIPEA ²(0.23 ml, 1.32 ²mmol) and DMF (2.5 ml) was stirred for a while, to which was then added ²cyclopentylamine (0.13 ²ml, 1.32 mmol) at room temperature and the mixture was stirred overnight. The ²residue was filtered ²by suction filtration to yield a red product. The residue was filtered without ²further purification to²afford 21(0.25 g, 69.48 %) as a red solid. 11-1-NMR (300 MHz, DMSO-d6): 6 1.50-²1.56 (m, 4H), 1.66²- 26 -²Date Recue / Date Received 2021-11-10²<DP=27>²(br, 2H), 1.80-1.89 (m, 2H), 4.15-4.22 (m, 1H), 4.98 (s, 2H), 7.35 (d, J= 8.4 ²Hz, 2H), 7.71-7.84 (m, ²4H), 7.96 (d, J= 7.8, 2H), 8.06 (s, 1H), 8.19 (d, J= 7.2 Hz, 1H).²Example 19 4-((3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-ylamino)methyl)-N-²(1H-²indazol-5-yl)benzamide (22)²0²CI²N²H H²0 N²\ N²0 NI'² H²[00811 A mixture of 97 (0.30 g, 0.88 mmol), HBTU (0.50 g, 1.32 mmol), DIPEA ²(0.23 ml, 1.32 ²mmol) and DMF (2.5 ml) was stirred for a while, to which was then added 5-²aminoindazole (0.18 g, ²1.32 mmol) at room temperature and the mixture was stirred overnight. The ²residue was filtered by ²suction filtration to yield a red product. The residue was filtered without ²further purification to²afford 22 (0.20 g, 49.74 %) as a red solid. 11-1-NMR (300 MHz, DMSO-d6): 6 ²5.04 (d, J=7.2 Hz, 2H),²7.43-7.51 (m, 3H), 7.59-7.62 (m, 1H), 7.72-7.77 (m, 1H), 7.80-7.85 (m, 1H), ²7.90-7.99 (m, 4H), 8.03 ²(s, 1H), 8.13 (t, J= 7.2 Hz, 1H), 8.21 (s, 1H), 10.20 (s, 1H), 12.99 (s, 1H).²Example 20 4-((3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-ylamino)methyl)-N-(5-²²methylthiazol-2-yl)benzamide (23)²0²CI²N²H H²0 N S²----² 0 N²[00821 A mixture of 97 (0.30 g, 0.88 mmol), HBTU (0.50 g, 1.32 mmol), DIPEA ²(0.23 ml, 1.32 ²mmol) and DMF (2.5 ml) was stirred for a while, to which was then added 2-²amino-5-methylthiazole ²(0.15 g, 1.32 mmol) at room temperature and the mixture was stirred overnight. ²The residue was ²filtered by suction filtration to yield a red product. The residue was ²filtered without further²purification to afford 23 (0.38 g, 98.61 %) as a red solid. 11-1-NMR (300 MHz, ²DMSO-d6): 6 2.36 (s,²3H), 5.03 (d, J= 7.2 Hz, 2H), 7.20 (s, 1H), 7.45 (d, J= 8.1 Hz, 2H), 7.72-7.78 ²(m, 1H), 7.80-7.85 (m, ²1H), 7.50-7.99 (m, 2H), 8.03 (d, J= 8.1 Hz, 2H), 8.10 (t, J= 8.1 Hz, 1H), ²12.21 (br, 1H).²Example 21 4-((3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-ylamino)methyl)-N-(5-²methyl-²3H-pyrazol-3-yl)benzamide (24)²- 27 -²Date Recue / Date Received 2021-11-10²<DP=28>²0²CI²N²H H²0 N N²T_N H²0 -²

[0083] A mixture of 97 (0.30 g, 0.88 mmol), HBTU (0.50 g, 1.32 mmol), DIPEA ²(0.23 ml, 1.32 ²mmol) and DMF (2.5 ml) was stirred for a while, to which was then added 3-²amino-5-²methylpyrazole (0.13 g, 1.32 mmol) at room temperature and the mixture was ²stirred overnight. The²residue was purified by flash column over silica gel (ethyl acetate: n-hexane ²= 1:9, Rf = 0.20) to²afford 24 (0.05 g, 13.50 %) as a red solid. 1H-NMR (300 MHz, CDC13): 6 5.14 ²(d, J= 6.3 Hz, 2H), ²5.34 (s, 1H), 5.60 (br, 2H), 6.29 (br, 1H), 7.44 (d, J= 8.4 Hz, 2H), 7.64-7.68 ²(m, 1H), 7.73-7.78 (m, ²1H), 8.07 (d, J= 7.8 Hz, 1H), 8.12 (d, J= 8.4 Hz, 2H), 8.17 (d, J= 6.3 Hz, ²1H).²Example 22 2-(4-(3-amino-5-methyl-1H-pyrazole-1-carbonyl)benzylamino)-3-² chloronaphthalene-1,4-dione (25)²0²CI²NH2²N²H²0²

[0084] A mixture of 97 (0.30g, 0.88 mmol), HBTU (0.50 g, 1.32 mmol), DIPEA ²(0.23 ml, 1.32 ²mmol) and DMF (2.5 ml) was stirred for a while, to which was then added 3-²amino-5-²methylpyrazole (0.13 g, 1.32 mmol) at room temperature and the mixture was ²stirred overnight. The²residue was purified by flash column over silica gel (ethyl acetate: n-hexane ²= 1:4, Rf = 0.25) to²afford 25 (0.04 g, 10.80 %) as a red solid. 1H-NMR (300 MHz, DMSO-d6): 6 2.49 ²(s, 3H), 5.03 (s, ²2H), 5.44 (s, 2H), 5.78 (s, 1H), 7.38 (d, J= 8.4 Hz, 2H), 7.73-7.86 (m, 4H), ²7.98 (d, J= 7.8 Hz, 2H), ²8.10(s, 1H).²Example 23 4-((3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-ylamino)methyl)-N-(3-²² 2 0 nitropyridin-4-yl)benzamide (26)²0²CI²N²H HiNO2²0 N²I²0 N²- 28 -²Date Recue / Date Received 2021-11-10²<DP=29>²

[0085] A mixture of 97 (0.30 g, 0.88 mmol), HBTU (0.50 g, 1.32 mmol), DIPEA ²(0.23 ml, 1.32 ²mmol) and DMF (2.5 ml) was stirred for a while, to which was then added 4-²amino-3-nitropyridine ²(0.18 g, 1.32 mmol) at room temperature and the mixture was stirred overnight. ²The residue was ²purified by flash column over silica gel (ethyl acetate: n-hexane = 1:2, Rf = ²0.25) to afford 26 (0.06²g, 14.73 %) as a red solid. 111-NMR (300 MHz, DMSO-d6): 6 5.05 (d, J= 6.9 Hz, ²2H), 7.52 (d, J= 8.4²Hz, 2H), 7.72-7.78 (m, 1H), 7.80-7.86 (m, 1H), 7.92 (d, J= 8.4 Hz, 2H), 7.96-²8.00 (m, 4H), 8.13 (t, ²J= 6.9 Hz, 1H), 8.76 (d, J= 5.7 Hz, 1H), 9.12 (s, 1H), 11.07 (s, 1H).²Example 24 4-((3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-ylamino)methyl)-N-²(quinolin-6-²yl)benzamide (28)²0²CI²0²0²

[0086] A mixture of 97 (0.30 g, 0.88 mmol), HBTU (0.50 g, 1.32 mmol), DIPEA ²(0.23 ml, 1.32 ²mmol) and DMF (2.5 ml) was stirred for a while, to which was then added 6-²aminoquinoline (0.19 g, ²1.32 mmol) at room temperature and the mixture was stirred overnight. The ²residue was purified by ²flash column over silica gel (ethyl acetate: n-hexane = 1:2, Rf = 0.20) to ²afford 28 (0.11 g, 26.72 %)²as a red solid. 1-1-1-NMR (300 MHz, DMSO-d6): 6 5.04 (s, 2H), 7.46-7.49 (m, ²3H), 7.72-7.77 (m, 1H),²7.80-7.85 (m, 1H), 7.94-8.00 (m, 6H), 8.12 (br, 1H), 8.30 (d, J= 8.7 Hz, 1H), ²8.51 (s, 1H), 8.78-8.80 ²(m, 1H), 10.52 (s, 1H).²Example 25 4-((3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-ylamino)methyl)-N-²(quinolin-8-²yl)benzamide (29)²0²CI²N²0² 0²

[0087] A mixture of 97 (0.30 g, 0.88 mmol), HBTU (0.50 g, 1.32 mmol), DIPEA ²(0.23 ml, 1.32 ²mmol) and DMF (2.5 ml) was stirred for a while, to which was then added 8-²aminoquinoline (0.19 g, ²1.32 mmol) at room temperature and the mixture was stirred overnight. The ²residue was filtered by ²suction filtration to yield a red product. The residue was filtered without ²further purification to².. afford 29 (0.15 g, 36.43 %) as a red solid. 111-NMR (300 MHz, DMSO-d6): 6 ²5.07 (d, J= 6.9 Hz, 2H),²- 29 -²Date Recue / Date Received 2021-11-10²<DP=30>²7.55 (d, J= 8.4 Hz, 2H), 7.62-7.69 (m, 2H), 7.72-7.78 (m, 2H), 7.81-7.84 (m, ²1H), 7.86-8.02 (m, 4H), ²8.14 (t, J= 6.6 Hz, 1H), 8.44-8.47 (m, 1H), 8.70-8.73 (m, 1H), 8.94-8.95 (m, ²1H), 10.62 (s, 1H). ²Example 26 4-((3-chloro-1,4-dioxo-1,4-dihydron aphth alen-2-ylamin o)methyl)-N-²(qu in olin-3-²yl)benzamide (30)²0²CI²N²H H²0 N ,²I²0² N²[00881 A mixture of 97 (0.30 g, 0.88 mmol), HBTU (0.50 g, 1.32 mmol), DIPEA ²(0.23 ml, 1.32 ²mmol) and DMF (2.5 ml) was stirred for a while, to which was then added 3-²aminoquinoline (0.19 g, ²1.32 mmol) at room temperature and the mixture was stirred overnight. The ²residue was purified by ²flash column over silica gel (ethyl acetate: n-hexane = 1:2, Rf = 0.43) to ²afford 30 (0.10 g, 24.29 %)²as a red solid. 11-I-NMR (300 MHz, DMSO-d6): 6 5.05 (s, 2H), 7.49 (d, J= 8.4 ²Hz, 2H), 7.55-7.60 (m,²1H), 7.63-7.68 (m, 1H), 7.72-7.85 (m, 2H), 7.93-7.99 (m, 6H), 8.11 (br, 1H), ²8.82 (s, 1H), 9.12 (s, ²1H), 10.66 (br, 1H).²Example 27 4-((3-chloro-1,4-dioxo-1,4-dihydron aphth alen-2-ylamin o)methyl)-N-²(qu in olin-5-²Abenzamide (31)²0²CI²N²H H I²0 N N²0²[ 008 9 1 A mixture of 97 (0.30 g, 0.88 mmol), HBTU (0.50 g, 1.32 mmol), DIPEA ²(0.23 ml, 1.32 ²mmol) and DMF (2.5 ml) was stirred for a while, to which was then added 5-²aminoquinoline (0.13 g, ²1.32 mmol) at room temperature and the mixture was stirred overnight. The ²residue was purified by ²flash column over silica gel (ethyl acetate: n-hexane = 1:2, Rf = 0.20) to ²afford 31 (0.10 g, 24.29 %)²as a red solid. 11-I-NMR (300 MHz, DMSO-d6): 6 5.06 (s, 2H), 7.47-7.53 (m, ²3H), 7.68 (d, J= 6.9 Hz,²1H), 7.73-7.83 (m, 3H), 7.92-8.05 (m, 5H), 8.14 (s, 1H), 8.37 (d, J= 8.7 Hz, ²1H), 8.91 (s, 1H), 10.48 ²(s, 1H).²Example 28 4-((3-chloro-1,4-dioxo-1,4-dihydron aphth alen-2-ylamin o)methyl)-N-²(2-²methylqu in olin-4-yl)b enzamide (32)²- 30 -²Date Recue / Date Received 2021-11-10²<DP=31>²0²CI²N²H H²0 N²1²0 N²

[0090] A mixture of 97 (0.30 g, 0.88 mmol), HBTU (0.50 g, 1.32 mmol), DIPEA ²(0.23 ml, 1.32 ²mmol) and DMF (2.5 ml) was stirred for a while, to which was then added 2-²methylquinolin-4-²amine (0.21 g, 1.32 mmol) at room temperature and the mixture was stirred ²overnight. The residue²was purified by flash column over silica gel (ethyl acetate: n-hexane = 1:1, ²Rf = 0.13) to afford 32²(0.22 g, 51.87 %) as a red solid. 11-1-NMR (300 MHz, DMSO-d6): 6 2.65 (s, 3H), ²5.07 (d, J= 6.9 Hz, ²2H), 7.49-7.52 (m, 3H), 7.70-7.76 (m, 2H), 7.78-7.86 (m, 2H), 7.91-7.80 (m, ²3H), 8.03 (d, J= 8.4 Hz, ²2H), 8.13-8.18 (m, 2H), 10.54 (s, 1H).²Example 29 4-((3-chloro-1,4-dioxo-1,4-dihydron aphth alen-2-ylamin o)methyl)-N-²(1H-in doI-5-² Abenzamide (33)²0²CI²N²H H²0 N²\²0 N²H²[ 0091 ] A mixture of 97 (0.26 g, 0.76 mmol), HBTU (0.43 g, 1.13 mmol), DIPEA ²(0.20 ml, 1.13 ²mmol) and DMF (2.5 ml) was stirred for a while, to which was then added 5-²aminoindole (0.15 g, ²1.13 mmol) at room temperature and the mixture was stirred overnight. The ²residue was purified by²flash column over silica gel (ethyl acetate: n-hexane = 2:3, Rf = 0.35) to ²afford 33 (0.03 g, 8.66 %) as²a red solid. 111-NMR (300MHz, DMSO-d6): 6 5.04 (d, J= 6.6 Hz, 2H), 639 (s, ²1H), 730-738 (m, ²3H), 7.44 (d, J= 8.1 Hz, 2H), 7.73-7.78 (m, 1H), 7.81-7.86 (m, 1H), 7.91 (d, ²J= 8.4 Hz, 2H), 7.96-²8.00 (m, 3H), 8.11 (s, 1H), 10.02 (s, 1H), 11.01 (s, 1H).²Example 30 4-((3-chloro-1,4-dioxo-1,4-dihydron aphth alen-2-ylamin o)methyl)-N-²(2-methyl-² 2 0 1H-indo1-5-Abenzamide (34)²-31 -²Date Recue / Date Received 2021-11-10²<DP=32>²0²CI²N²H H²0 N²\²0 LLN²H²[00921 A mixture of 97 (0.26 g, 0.76 mmol), HBTU (0.43 g, 1.13 mmol), DIPEA ²(0.20 ml, 1.13 ²mmol) and DMF (2.5 ml) was stirred for a while, to which was then added 5-²amino2-methylindole ²(0.17 g, 1.13 mmol) at room temperature and the mixture was stirred overnight. ²The residue was²purified by flash column over silica gel (ethyl acetate: n-hexane = 1:1, Rf = ²0.13) to afford 34 (0.08²g, 22.40 %) as a red solid. 1-H-NMR (300 MHz, DMSO-d6): 6 2.36 (s, 3H), 5.03 ²(s, 2H), 6.08 (s, 1H), ²7.18-7.28 (m, 2H), 7.43 (d, J= 8.4 Hz, 2H), 7.73-7.86 (m, 3H), 7.90 (d, J= 8.1 ²Hz, 2H), 7.95-8.00 (m, ²2H), 8.11 (br, 1H), 9.96 (s, 1H), 10.82 (s, 1H).²Example 31 4-((3-chloro-1,4-dioxo-1,4-dihydron aphth alen-2-ylamin o)methyl)-N-²(1H-in doI-5-² Abenzamide (35)²0²CI²N HN²H H \²0 N²0²

[0093] A mixture of 97 (0.30 g, 0.88 mmol), HBTU (0.50 g, 1.32 mmol), DIPEA ²(0.23 ml, 1.32 ²mmol) and DMF (2.5 ml) was stirred for a while, to which was then added 7-²aminoindole (0.17 g, ²1.32 mmol) at room temperature and the mixture was stirred overnight. The ²residue was purified by²flash column over silica gel (ethyl acetate: n-hexane = 1:1, Rf = 0.13) to ²afford 35 (0.02 g, 4.99 %) as²a red solid. 1-H-NMR (300 MHz, DMSO-d6): 6 5.04 (s, 2H), 6.44 (s, 1H), 6.97 ²(t, J= 7.8 Hz, 1H), ²7.30-7.33 (m, 2H), 7.39 (d, J=7.8 Hz, 1H), 7.46 (d, J= 8.1 Hz, 2H), 7.72-7.78 ²(m, 1H), 7.80-7.86 (m, ²1H), 7.86-7.99 (m, 4H), 8.12 (br, 1H), 10.05 (s, 1H), 10.86 (s, 1H).²Example 32 4-((3-chloro-1,4-dioxo-1,4-dihydron aphth alen-2-ylamin o)methyl)-N-²(1H-in doI-4-² 2 0 yl)benzamide (36)²0²CI²N ¨²H H²0 N N H²0²- 32 -²Date Recue / Date Received 2021-11-10²<DP=33>²

[0094] A mixture of 97 (0.30 g, 0.88 mmol), HBTU (0.50 g, 1.32 mmol), DIPEA ²(0.23 ml, 1.32 ²mmol) and DMF (2.5m1) was stirred for a while, to which was then added 4-²aminoindole (0.17 g, ²1.32 mmol) at room temperature and the mixture was stirred overnight. The ²residue was purified by ²flash column over silica gel (ethyl acetate: n-hexane = 1:1, Rf = 0.45) to ²afford 36 (0.30 g, 74.78 %)²as a red solid. 111-NMR (300 MHz, DMSO-d6): 6 5.04 (s, 2H), 6.56 (s, 1H), 7.04 ²(t, J= 7.8 Hz, 1H),²7.20 (d, J 1.5 Hz, 1H), 7.27 (t, J= 3.0 Hz, 1H), 7.35 (d, J= 7.2 Hz, 1H), 7.44 ²(d, J= 8.4 Hz, 2H), ²7.72-7.77 (m, 1H), 7.80-7.85 (m, 1H), 7.93-7.99 (m, 4H), 8.11 (br, 1H), 9.99 ²(s, 1H), 11.10 (s, 1H). ²Example 33 4-((3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-ylamino)methyl)-N-(4-²(4-²ethylpiperazin-1-yl)phenyl)benzamide (37)²0²CI²0²0²

[0095] A mixture of 97 (0.30 g, 0.88 mmol), HBTU (0.50 g, 1.32 mmol), DIPEA ²(0.23 ml, 1.32 ²mmol) and DMF (2.5 ml) was stirred for a while, to which was then added 4-(4-²ethylpiperazin- 1-²yl)aniline (0.27 g, 1.32 mmol) at room temperature and the mixture was stirred ²overnight. The ²residue was filtered by suction filtration to yield a red product. The residue ²was filtered without²further purification to afford 37 (0.40 g, 85.92 %) as a red solid. 111-NMR ²(300 MHz, DMSO-d6): 6²1.01 (t, J= 7.2 Hz, 3H), 2.34 (q, J= 7.2 Hz, 2H), 3.07 (br, 4H), 5.01 (s, 2H), ²6.89 (d, J= 9.0 Hz, 2H), ²7.41 (d, J= 8.1 Hz, 2H), 7.56 (d, J= 9.0 Hz, 2H), 7.74 (t, J= 8.1 Hz, 1H), ²7.77-7.88 (m, 3H), 7.95-²7.98 (m, 2H), 8.09 (s, 1H), 9.98 (s, 1H).²Example 34 4-((3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-ylamino)methyl)-N-²(1H-² 2 0 .. indazol-6-yl)benzamide (38)²0²CI²0 N N,²0²

[0096] A mixture of 97 (0.30 g, 0.88mmo1), HBTU (0.50 g, 1.32mmo1), DIPEA ²(0.23 ml, 1.32 ²mmol) and DMF (2.5 ml) was stirred for a while, to which was then added 6-²aminoindazole (0.18 g, ²1.32 mmol) at room temperature and the mixture was stirred overnight. The ²residue was filtered by²- 33 -²Date Recue / Date Received 2021-11-10²<DP=34>²suction filtration to yield a red product. The residue was filtered without ²further purification to afford ²38 (0.13 g, 37.94 %) as a red solid. 1E-NMR (300 MHz, DMSO-d6): 6 5.05 (s, ²2H), 7.36 (d, J= 8.4 ²Hz, 1H), 7.46 (d, J= 8.1 Hz, 2H), 7.68 (d, J= 8.7 Hz, 1H), 7.75 (t, J= 6.9 Hz, ²1H), 7.83 (t, J= 6.9 Hz, ²1H), 7.92 (d, J= 8.1 Hz, 2H), 7.97-7.98 (m, 3H), 8.12 (br, 1H), 8.24 (s, 1H), ²10.32 (s, 1H), 12.94 (s,² 1H).²Example 35 4-((3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-ylamino)methyl)-N-²(1H-²pyrrolo [2,3-b] pyridin-5-yl)benzamide (39)²0²CI²0²[ 00 97 ] A mixture of 97 (0.30 g, 0.88 mmol), HBTU (0.50 g, 1.32 mmol), DIPEA ²(0.23 ml, 1.32²mmol) and DMF (2.5 ml) was stirred for a while, to which was then added 5-²amino-7-azaindole²(0.18 g, 1.32 mmol) at room temperature and the mixture was stirred overnight. ²The residue was ²filtered by suction filtration to yield a red product. The residue was ²filtered without further ²purification to afford 39 (0.31 g, 77.10 %) as a red solid. 11-I-NMR (300 MHz, ²DMSO-d6): 6 5.05 (d, ²J= 7.2 Hz, 2H), 6.44 (s, 1H), 7.45-7.47 (m, 3H), 7.76 (t, J= 8.1 Hz, 1H), 7.84 ²(t, J= 7.8 Hz, 1H),²7.93-8.00 (m, 4H), 8.12 (br, 1H), 8.31 (s, 1H), 8.44 (s, 1H), 10.23 (s, 1H), ²11.57 (s, 1H).²Example 36 4-((3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-ylamino)methyl)-N-²(1H-²pyrazolo[3,4-b] pyridin-5-yl)benzamide (40)²0²CI²0 LLyN²I²NN²[ 00 98 ] A mixture of 97 (0.28 g, 0.82 mmol), HBTU (0.47 g, 1.23 mmol), DIPEA ²(0.21 ml, 1.23²mmol) and DMF (2.5 ml) was stirred for a while, to which was then added 5-²amino-7-azaindazole²(0.12 g, 0.90 mmol) at room temperature and the mixture was stirred overnight. ²The residue was ²purified by flash column over silica gel (ethyl acetate: n-hexane = 2:1, Rf = ²0.18) to afford 40 (0.09 ²g, 23.97 %) as a red solid. 11-I-NMR (300 MHz, DMSO-d6): 6 5.05 (s, 2H), 7.48 ²(d, J= 8.4 Hz, 2H),²- 34 -²Date Recue / Date Received 2021-11-10²<DP=35>²7.73-7.78 (m, 1H), 7.81-7.86 (m, 1H), 7.94-8.00 (m, 4H), 8.14 (s, 2H), 8.60 ²(d, J= 2.4 Hz, 1H), 8.73²(d, J= 2.1 Hz, 1H), 10.44 (s, 1H), 13.59 (br, 1H).²Example 37 4-((3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-ylamino)methyl)-N-(7-²methyl-²7H-pyrrolo 12,3-(1] pyrimidin-4-yl)benzamide (41)²0²CI²N²H H²0 N C\--- N------²I² 0 N N²[00 9 9] A mixture of 97 (0.30 g, 0.88 mmol), HBTU (0.50 g, 1.32 mmol), DIPEA ²(0.23 ml, 1.32 ²mmol) and DMF (2.5 ml) was stirred for a while, to which was then added 6-²amino-9-methy1-7-²deazapurine (0.20 g, 1.32 mmol) at room temperature and the mixture was ²stirred overnight. The ²residue was purified by flash column over silica gel (ethyl acetate: n-hexane ²= 2:1, Rf = 0.45) to²afford 41 (0.07 g, 16.86 %) as a red solid. 1H-NMR (300 MHz, DMSO-d6): 6 3.81 ²(s, 3H), 5.05 (d,²J= 7.2 Hz, 2H), 6.61 (d, J= 3.6 Hz, 1H), 7.44-7.47 (m, 3H), 7.72-7.78 (m, 1H), ²7.81-7.86 (m, 1H), ²7.95-8.04 (m, 4H), 8.12 (t, J= 7.5 Hz, 1H), 8.57 (s, 1H), 11.00 (s, 1H).²Example 38 4-((3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-ylamino)methyl)-N-²(2,3-²dihydro-1H-inden-4-Abenzamide (42)²0²CI²N²H H²0 N²0²[001 0 0] A mixture of 97 (0.30 g, 0.88 mmol), HBTU (0.50 g, 1.32 mmol), DIPEA ²(0.13 ml, 1.32 ²mmol) and DMF (2.5 ml) was stirred for a while, to which was then added 4-²aminoindane (0.24 ml, ²1.32 mmol) at room temperature and the mixture was stirred overnight. The ²residue was filtered by ²suction filtration to yield a red product. The residue was filtered without ²further purification to²afford 42 (0.33 g, 82.07 %) as a red solid. 111-NMR (300 MHz, DMSO-d6): 6 1.89-²1.98 (m, 2H), 2.81²(t, J= 7.5 Hz, 2H), 2.88 (t, J= 7.5 Hz, 2H), 5.02 (d, J= 7.2 Hz, 2H), 7.05-²7.13 (m, 2H), 7.22 (d, J= 7.5 ²Hz, 1H), 7.42 (d, J= 8.1 Hz, 2H), 7.71-7.76 (m, 1H), 7.79-7.85 (m, 1H), 7.89 ²(d, J= 8.4 Hz, 2H), ²7.95-7.98 (m, 2H), 8.10 (t, J= 7.5 Hz, 1H), 9.82 (s, 1H).²Example 39 4-(((3-bromo-1,4-dioxo-1,4-dihydron aphth alen-2-yl)amino)methyl)-N-²(pyridin-² 2-yl)benzamide (6)²- 35 -²Date Recue / Date Received 2021-11-10²<DP=36>²0²Br²N²H H²0 N N²0 1²[001011 A mixture of 2,3-dibromo-1,4-naphthaquinone (0.31 g, 0.97 mmol), 4-²(aminomethyl)-N-²(pyridin-2-yl)benzamide (0.20 g, 0.88 mmol) and Et0H (10 ml) was stirred and ²refluxed overnight. ²The residue was purified by flash column over silica gel (ethyl acetate: n-²hexane = 1:2, Rf = 0.20) to²afford 6(0.13 g, 31.95 %) as a red solid. 1-1-1-NMR (300 MHz, DMSO-d6): 6 5.05 ²(d, J= 7.2 Hz, 2H),²7.14 (m, 1H), 7.41 (d, J= 8.1 Hz, 2H), 7.73 (t, J= 7.5 Hz, 1H), 7.81 (m, 2H), ²7.97 (m, 5H), 8.15 (d,²J= 8.1 Hz, 1H), 8.36 (d, J= 4.8 Hz, 1H), 10.69 (s, 1H).²Example 40 tert-butyl 4-(pyrimidin-4-ylcarbamoyl)benzylcarbamate (100)²Boc,N²H H I H²N²0 N N²

[00102] 4-(aminomethyl)benzoic acid (5.0 g, 32.95 mmol) was added slowly to ²the corresponding²sodium hydroxide (1.45 g, 36.25 mmole) and di-t-butyl-dicarbonate (7.95 g, ²36.25 mmol) in H20 ²(62.5 ml) and THF (25 ml) at 0 C. The reaction mixture was warmed to room ²temperature, and ²stirring was continued for another 18 h. The solution was evaporated to give a ²residue. To the ²residue, DMF (0.36 mL) , pyridine (18 mL), oxalyl chloride ( 6.24 ml) and ²toluene (144 ml) were²added and the mixture was stirred at rt for 6 hrs. The solution was filtered, ²washed with toluene, and²the filtrate evaporated to give a residue. To the residue, pyridine (112 mL), ²and 4-aminopyrimidine ²(3.74 g, 39.4 mmol) were added and the mixture was stirred at room temperature ²for 16 hrs. The ²solution was evaporated to give a residue, which was purified by flash column ²over silica gel (Et0Ac ²: n-hexane = 2 : 3) to afford 100 (3.03g, 28.00%).1-H NMR (300 MHz, CDC13): 6 ²1.48 (s, 3H), 4.41²(d, J= 6.0 Hz, 2H), 5.02 (brs, 1H), 7.45 (d, J= 8.4 Hz, 2H), 7.91 (d, J= 8.1 ²Hz, 2H), 8.33-8.36 (m,²1H), 8.69 (d, J= 5.7 Hz, 1H), 8.72 (brs, 1H), 8.88 (s, 1H).²Example 41 tert-butyl 4-(pyrazin-2-ylcarbamoyl)benzylcarbamate (101)²Boc,N²H H I H²N,²I 1²0 N,,,²

[00103] 4-(aminomethyl)benzoic acid (5.0 g, 32.95 mmol) was added slowly to ²the corresponding²sodium hydroxide (1.45 g, 36.25 mmol) and di-t-butyl-dicarbonate (7.95 g, ²36.25 mmol) in H20²- 36 -²Date Recue / Date Received 2021-11-10²<DP=37>²(62.5 ml) and THF (25 mL) at 0 C. The reaction mixture was warmed to room ²temperature, and ²stirring was continued for another 18 h. The solution was evaporated to give a ²residue. To the ²residue, DMF (0.36 ml), pyridine (18 ml), oxalyl chloride (6.24 ml) and ²toluene (144 ml) were added ²and the mixture was stirred at room temperature for 6 hrs. The solution was ²filtered, washed with²toluene, and the filtrate evaporated to give a residue. To the residue, ²pyridine (112 ml), and 2-²aminopyrazine (3.74g, 39.4mmo1) were added and the mixture was stirred at room ²temperature for 16 ²hrs. The residue was purified by flash column over silica gel (Et0Ac : n-²hexane = 2 : 3) to afford ²101 (3.90 g, 36.05 %). 1H NMR (300 MHz, DMSO-d6): 6 1.44 (s, 3H), 4.37 (d, J= ²5.4 Hz, 2H), 4.98 ²(brs, 1H), 7.41 (d, J= 8.4 Hz, 2H), 7.88 (d, J= 8.4 Hz, 2H), 8.23-8.25 (m, ²1H), 8.34-8.36 (m, 1H),² 8.54 (s, 111), 9.67 (s, 111).²Example 42 4-(((3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-yl)amino)methyl)-N-²(pyrimidin-4-yl)benzamide (7)²0²CI²N²H H²0 N²0 N N²[ 00104 ] A mixture of 2,3-dichloro-1,4-naphthoquinone (0.25 g, 1.10 mmol) and ²100 (0.28 g, 1.23²mmol) and ethanol (10 ml) was refluxed for 16 h. The reaction mixture was ²filtered washed. The²residue was filtered without further purification to afford 7 (0.08 g, 17.36 ²%) as a red solid. 1H NMR ²(300 MHz, DMSO-d6): 6 5.04 (d, J= 6.6 Hz, 2H), 7.45 (d, J= 8.1 Hz, 2H), 7.72-²7.85 (m, 2H), 7.97-²7.99 (m, 4H), 8.11 (m, 1H), 8.19 (d, J= 4.5 Hz, 1H), 8.70 (d, J= 5.4 Hz, 1H), ²8.93 (s, 1H), 11.18 (s, ²1H).²Example 43 4-(((3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-yl)amino)methyl)-N-²(pyrazin-²2-yl)benzamide (8)²0²CI²N²H H²0 N²N²0 N-²[001051 A mixture of 2,3-dichloro-1,4-naphthoquinone (1.19 g, 5.26 mmol) and ²101 (1.5 g, 6.57 ²mmol) and ethanol (20 ml) was refluxed for 16 h. The reaction mixture was ²filtered and washed. The²residue was filtered without further purification to afford 8 (0.48 g, 21.79 ²%) as a red solid. 1H NMR²- 37 -²Date Recue / Date Received 2021-11-10²<DP=38>²(300 MHz, DMSO-d6): 6 5.04 (d, J= 7.2 Hz, 2H), 7.45 (d, J= 8.4 Hz, 2H), 7.74-²7.85 (m, 2H), 7.95-²8.01 (m, 4H), 8.11 (t, J= 6.9 Hz, 1H), 8.40 (d, J= 2.4 Hz, 1H), 8.44-8.46 (m, ²1H), 9.39 (d, J= 1.5 Hz, ²1H), 11.04 (s, 1H).²Example 44 4-(((3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-Aamino)methyl)-N-²(pyridin-4-² ylmethyl)benzamide (27)²0²CI²N N²H²IRII1²0²0²[001 0 6] A mixture of 97 (0.30 g, 0.88 mmol), HBTU (0.50 g, 1.32 mmol), DIPEA ²(0.23 ml, 1.32 ²mmol) and DMF (2.5 ml) was stirred for a while, to which was then added 4-²aminomethylpyridine ²(0.13 ml, 1.32 mmol) at room temperature and stirred overnight. The residue ²was purified by flash²column over silica gel (dichloromethane: methanol = 9:1, Rf = 0.48) to afford ²27 (0.31 g, 81.57 %)²as a red solid. 1-1-1-NMR (300 MHz, DMSO-d6): 6 4.47 (d, J= 6.0 Hz, 2H), 5.01 ²(s, 1H), 7.28 (d, J= ²5.7 Hz, 2H), 7.41 (d, J= 8.1 Hz, 2H), 7.75 (t, J= 6.3 Hz, 1H), 7.80-7.87 (m, ²3H), 7.97 (d, J= 7.8 Hz, ²2H), 8.08 (s, 1H), 8.48 (d, J= 6.0 Hz, 2H), 9.08 (t, J= 6.0 Hz, 1H).²Example 45 4-(((3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-Aamino)methyl)-N-(2-²² morpholinoethyl)benzamide (43)²0²CI²N²H H²0 N.-----.N.----...,²0 0²[001 0 7] A mixture of 97 (0.30 g, 0.88 mmol), HBTU (0.50 g, 1.32 mmol), DIPEA ²(0.13 ml, 1.32 ²mmol) and DMF (2.5 ml) was stirred for a while, to which was then added 2-²morpholinoethanamine ²(0.17 ml, 1.32 mmol) at room temperature, and the mixture was stirred ²overnight. The residue was²filtered by suction filtration to yield a red product. The residue was without ²further purification to²afford 43 (0.23 g, 57.58 %) as a red solid. 1E-NMR (300 MHz, DMSO-d6): 6 2.38-²2.45 (m, 6H), 3.54 ²(s, 4H), 4.99 (s, 2H), 7.36 (d, J= 8.1 Hz, 2H), 7.71-7.84 (m, 4H), 7.96 (d, J= ²7.5 Hz, 2H), 8.05 (s, ²1H), 8.33 (t, J= 5.1 Hz, 1H).²Example 46 N-(2-(1H-indo1-3-yl)ethyl)-4-(((3-chloro-1,4-dioxo-1,4-²dihydronaphthalen-2-² yl)amino)methyl)benzamide (44)²- 38 -²Date Recue / Date Received 2021-11-10²<DP=39>²0²CI²N²H H²0 N²\²0 NH²[001 0 8] A mixture of 97 (0.30 g, 0.88 mmol), HBTU (0.50 g, 1.32 mmol), DIPEA ²(0.13 ml, ²1.32mmo1) and DMF (2.5 ml) was stirred for a while, to which was then added ²tryptamine (0.21 g, ²1.32 mmol) at room temperature and stirred overnight. The residue was purified ²by flash column²over silica gel (ethyl acetate: n-hexane = 2:1, Rf = 0.45) to afford 44 (0.13 ²g, 30.53 %) as a red solid.²III-NMR (300 MHz, DMSO-d6): 6 2.72-2.94 (m, 2H), 3.47-3.54 (m, 2H), 4.99 (s, ²2H), 6.92-6.98 (m, ²1H), 7.01-7.07 (m, 1H), 7.15 (d, J= 2.4 Hz, 1H), 7.31 (d, J= 8.1 Hz, 1H), 7.36 ²(d, J= 8.1 Hz, 2H), ²7.55 (d, J= 7.5 Hz, 1H), 7.73-7.82 (m, 4H), 7.96 (d, J= 8.1 Hz, 2H), 8.06 (s, ²1H), 8.54 (t, J= 5.7 Hz, ²1H), 10.78 (s, 1H).²Example 47 4-(((3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-Aamino)methyl)-N-(2-²²(dimethylamino)ethyl)benzamide (45)²0²CI²N²H I H²0 N N²0 I²[001 0 9] A mixture of 97 (0.30 g, 0.88 mmol), EDC.HC1 (0.25 g, 1.32 mmol), ²HOBt (0.14 g, 1.06²mmol), NMM (0.23 ml, 2.11 mmol) and DMF (2.5 ml) was stirred for a while, to ²which was then²added 2-dimethylaminoethylamine (0.12 ml, 1.06 mmol) at room temperature and ²stirred overnight.²The residue was purified by flash column over silica gel (dichloromethane: ²methanol = 9:1, Rf = ²0.33) to afford 45 (0.05 g, 13.79 %) as a red solid. III-NMR (300 MHz, CD30D): ²6 2.92 (s, 6H), 3.72 ²(t, J= 6.0 Hz, 2H), 5.10 (s, 2H), 7.44 (d, J= 8.4 Hz, 2H), 7.68-7.81 (m, 2H), ²7.85 (d, J= 8.4 Hz, 2H), ²8.02-8.06 (m, 2H).²Example 48 4-(((3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-Aamino)methyl)-N-(2-²²(pyrrolidin-1-y1)ethyl)benzamide (46)²- 39 -²Date Recue / Date Received 2021-11-10²<DP=40>²0²CI²N²H H²0²0²

[00110] A mixture of 97 (0.30 g, 0.88 mmol), EDC.HC1 (0.25 g, 1.32 mmol), HOBt ²(0.14g. 1.06 ²mmol), NMM (0.23 ml, 2.11 mmol) and DMF (2.5 ml) was stirred for a while, to ²which was then ²added 2-(pyrrolidin-1-ypethanamine (0.13 ml, 1.06 mmol) at room temperature ²and stirred overnight.²The residue was purified by flash column over silica gel (dichloromethane: ²methanol = 9:1, Rf =²0.33) to afford 46 (0.22 g, 57.09 %) as a red solid. 1-H-NMR (300 MHz, DMSO-²d6): 6 1.89 (s, 4H), ²3.22-3.25 (m, 5H), 3.54-3.60 (m, 3H), 5.00 (t, J= 7.2 Hz, 2H), 7.38 (d, J= 8.1 ²Hz, 2H), 7.72-7.82 (m, ²2H), 7.85 (d, J= 8.4 Hz, 2H), 7.94-7.98 (m, 2H), 8.08 (t, J= 7.2 Hz, 1H), 8.74 ²(t, J= 5.7 Hz, 1H). ²Example 49 4-(((3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-Aamino)methyl)-N-(2-²² (diethylamino)ethyl)benzamide (47)²0²CI²N²H H²0 N...-----õN.------,,,²0 )²

[00111] A mixture of 97 (0.30 g, 0.88 mmol), EDC.HC1 (0.25 g, 1.32 mmol), HOBt ²(0.14 g, 1.06 ²mmol), NMM (0.23 ml, 2.11 mmol) and DMF (2.5 ml) was stirred for a while, to ²which was then ²added 2-diethylaminoethylamine (0.15 ml, 1.06 mmol) at room temperature and ²stirred overnight.²The residue was purified by flash column over silica gel (dichloromethane: ²methanol = 9:1, Rf =²0.30) to afford 47 (0.06 g, 15.50 %) as a red solid. 1-H-NMR (300 MHz, CD30D): ²6 1.33 (t, J= 7.2 ²Hz, 6H), 3.32-3.38 (m, 3H), 3.73 (t, J= 6.0 Hz, 2H), 5.10 (s, 2H), 7.45 (d, J= ²8.1 Hz, 2H), 7.67-7.80 ²(m, 2H), 7.85 (d, J= 8.1 Hz, 2H), 8.02-8.06 (m, 2H).²Example 50 4-(((3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-Aamino)methyl)-N-(2-²² 2 0 (piperidin-l-yl)ethyl)benzamide (48)²0²CI²N²H H²0 N N²0²-40 -²Date Recue / Date Received 2021-11-10²<DP=41>²

[00112] A mixture of 97 (0.30 g, 0.88 mmol), EDC.HC1 (0.25 g, 1.32 mmol), HOBt ²(0.14 g, 1.06 ²mmol), NMM (0.23 ml, 2.11 mmol) and DMF (2.5 ml) was stirred for a while, to ²which was then ²added 2-(piperidin-1-yl)ethanamine (0.15 ml, 1.06 mmol) at room temperature ²and stirred overnight. ²The residue was purified by flash column over silica gel (dichloromethane: ²methanol = 9:1, Rf =²0.55) to afford 48(0.08 g, 20.11 %) as a red solid. 111-NMR (300 MHz, DMSO-²d6): 6 1.42-1.44 (m,²2H), 1.58-1.60 (m, 4H), 2.78 (br, 6H), 3.44-3.48 (m, 2H), 4.99 (d, J= 7.2 Hz, ²2H), 7.37 (d, J= 8.4 Hz, ²2H), 7.71-7.84 (m, 4H), 7.94-7.97 (m, 2H), 8.07 (t, J= 7.2 Hz, 1H), 8.53 (br, ²1H).²Example 51 4-(((3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-yl)amino)methyl)-N-²(2-(4-²methylpiperazin-1-yl)ethyl)benzamide (49)²0²CI²0² 0²

[00113] A mixture of 97 (0.30 g, 0.88 mmol), EDC.HC1 (0.25 g, 1.32 mmol), HOBt ²(0.14 g, 1.06 ²mmol), NMM (0.23 ml, 2.11 mmol) and DMF (2.5 ml) was stirred for a while, to ²which was then ²added 2-(4-methylpiperazin-1-ypethylamine (0.16 ml, 1.06 mmol) at room ²temperature and stirred ²overnight. The residue was purified by flash column over silica gel ²(dichloromethane: methanol =²9:1, Rf = 0.19) to afford 49(0.08 g, 19.47%) as a red solid. 111-NMR (300 MHz, ²DMSO-d6): 6 2.13²(s, 3H), 2.36-2.42 (br, 12H), 4.91 (d, J= 6.3 Hz, 2H), 7.29 (d, J= 7.8 Hz, ²2H), 7.67-7.77 (m, 4H), ²7.88 (d, J= 6.9 Hz, 2H), 7.98 (br, 1H), 8.25 (br, 1H).²Biolo2ical Assay ² Cell culture²

[00114] WI-38 cells, a normal human embryonic lung fibroblast cell line, were ²obtained from ²American Type Culture Collection (Manassas, VA). Cells were grown in MEM ²nutrient mixture, ²containing 10% FCS, 2 mM L-glutamine, 0.1 mM NEAA, 1 mM sodium pyruvate, 50 ²U / ml ²penicillin G, and 100 pg / m1 streptomycin, in a humidified 37 C incubator with ²5% CO2 Cells were²used between passages 18 and 30 for all experiments. After reaching ²confluence, cells were seeded²onto 6-cm dishes for immunoblotting.²Compound use in Assay²

[00115] The compound, 4-(((3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-²yl)amino)methyl)-N-²(pyridin-3-yl)benzamide (MPTOL056 or L056 used herein), was used in the assay ²described herein.²-41 -²Date Recue / Date Received 2021-11-10²<DP=42>²

[00116] ²Western blot analysis²

[00117] Western blot analyses were performed as described previously (Chen BC, ²Chang YS,²Kang JC, Hsu MJ, Sheu JR, Chen TL, et al. Peptidoglycan induces nuclear factor-²kappaB activation²and cyclooxygenase-2 expression via Ras, Raf-1, and ERK in RAW 264.7 ²macrophages. J Biol Chem²2004;279:20889-97). Briefly, WI-38 lung fibroblasts were cultured in 6-cm ²dishes. After reaching ²confluence, cells were pretreated with specific inhibitors (E028 and G009) as ²indicated for 30 min, ²and then treated with the vehicle (H20) or 10 ng / ml TGF-P for 2 h (CTGF assay) ²or 24 h (collagen I ²assay). Whole-cell lysates (30 lag) were subjected to 12% (CTGF) or 8% ²(collagen I) SDS-PAGE,²and transferred onto a polyvinylidene difluoride membrane which was then ²incubated in TBST buffer²(150 mM NaCl, 20 mM Tris-HC1, and 0.02% Tween 20; pH 7.4) containing 5% BSA. ²Proteins were ²visualized by specific primary antibodies and then incubated with HRP-²conjugated secondary ²antibodies. The immunoreactivity was detected using enhanced chemiluminescence ²(ECL) following ²the manufacturer's instructions. Quantitative data were obtained using a ²computing densitometer² with scientific imaging systems (Kodak, Rochester, NY).²Statistical Analyses²

[00118] Results are expressed as the mean + SEM for the indicated number of ²separate²experiments. Means were checked for statistical difference using t-test and P-²values < 0.05 were²considered significant.²Example 1 Inhibition of Pro-fibrogenic Mediators-induced Fibrotic Protein, ²CTGF and²Collagen I Production²

[00119] To determine whether the inhibitory effects of the compound MPTOL056 ²on pro-²fibrogenic mediators (TGF-P, thrombin, and ET-1) were related to the ²modulation of CTGF and ²Collagen I production, Western blot analysis was performed. First, WI-38 lung ²fibroblasts were²incubated with different concentrations of MPTOL056 (0.3, 1, 3 or 10 M) for ²30 min before and²during incubation for 2 h with TGF-P (10 ng / mL). L056 significantly inhibited ²TGF-P-induced ²CTGF production from WI-38 lung fibroblasts in a concentration-dependent ²manner (Figure 1). ²Furthermore, we examined the effects of MPTOL056 on other pro-fibrogenic ²mediators. MPTOL0560 ²also inhibited ET-1- and thrombin- induced CTGF expression form WI-38 lung ²fibroblasts, as shown²in Figure 2 and 3, respectively. In addition, as shown in Figure 4, MPTOL056 ²also inhibited TGF-P-²induced collagen expression in WI-38 cells. These results showed that MPTOL056 ²apparently ²inhibited pro-fibrogenic mediators-induced CTGF expression and collagen ²production.²-42 -²Date Recue / Date Received 2021-11-10²<DP=43>²

[00120] In addition, pro-fibrogenic mediators, pro-fibrogenic mediators and a-²SMA, fibronectin ²were also examined.²

[00121] WI-38 lung fibroblasts were incubated with different concentrations of ²MPT0L056 (0.3, ²1, 3 or 10 1.1M) for 30 min before and during incubation for 24 h with TGF-P ²(10 ng / mL). L056²significantly inhibited TGF-P-induced a-SMA (see Figure 5) and fibronectin ²expression (see Figure²6) from WI-38 lung fibroblasts in a concentration-dependent manner. These ²results suggested that ²MPT0L056 inhibited TGF-P-mediated fibrogenic protein expression in WI-38 ²cells.²Example 2 Cell Viability Test²[ 00122 ] WI-38 lung fibroblasts were incubated with different concentrations ²of MPT0L056 (0.3,²1, 3 or 10 1.1M) for 2 hours before MTT-assay. Figure 7 shows the effect of ²L056 on cell viability in²WI38 cells. These data suggested that L056 did not affect cell viability.²Example 3 In vivo Efficacy: Bleomycin (BLM)-Induced Lung Fibrosis Mice ²Model Assay ²

[00123] C57BL / 6JNarl mice (8 weeks) were treated with bleomycin (BLM, 0.05 ²U / 50 [11) or PBS ²(50 1.11) by endotracheal administration. L056 (25, 50, 100 mg / kg / day, q.d.) ²and pirfenidone (200²mg / kg / day, q.d.) were administered orally to bleomycin-treated mice from 10 to ²38 days after BLM²treatment. On day 39, the mice were sacrificed, and the histologic analysis of ²lung tissue was ²performed by hematoxylin-eosin (H&E) staining (original magnification, x100).²[ 00124] The results of MPTOL056 in reducing refibrosis score are shown in ²below table.²Group I Mean ! SEM Efficacy %²1²I PBS 1.42 0.13²1BLM 5.19 0.19²BLI\14-1_056 25 mg² 3.27 0.03 50.94²BLM-F-L056 50 mg %² 2.03 0.21 83.90 %²BLM+1_056 100 mg 2.65 0.17 67.38%² I BLM+Esbriet 200 mg 3.91 0.21 34.08 %²_______________________________ v²WO FOFEV 60 mg 3.62 0.30 41.66%²

[00125] Figure 8 shows the antifibrotic effects of MPTOL056 on bleomydcin-²induced pulmonary²fibrosis in mice. The results show that MPTOL056 inhibits BLM-induced lung ²fibrosis in a dose-²dependent manner (see Fig. 8(A)), and the efficacy of L056 in the inhibition ²is significantly higher ²than the PBS control (see Fig. 8(B)).²-43 -²Date Recue / Date Received 2021-11-10²<DP=44>²[ 00126] The pro-fibrogenic mediators, pro-fibrogenic mediators, collagen, ²CTGF, fibronectin and ²cc-SMA were also examined and the results are shown in Fig. 9 (A) to (D), ²respectively. These data ²suggested that pro-fibrogenic mediators expression were inhibited by L056 ²treatment in Neomycin-²induced mice lung fibrosis model.² Example 4 Effect of MPTOL056 on CC14-Induced Liver Fibrosis in Mice²[ 00127 ] C57BL / 6JNarl mice (8 weeks) were treated with CC14 (1 pl / pg / BW, ²q.w.) or PBS (1 ²pl / pg / BW, q.w.) by i.p. injection for 6 weeks. MPTOL056 (25, 50 and 100 ²mg / kg / day, q.d.) and ²silymarin (200 mg / kg / day, q.d.) were administered orally to CC14-injected mice ²from 2 weeks to ²6 weeks. On day 43, the mice were sacrificed, and the a-SMA analysis of liver ²tissue was²performed by IHC staining (original magnification, x100) (see Fig. 11). Figure ²10 shows the²antifibrotic effects of MPTOL056 and silymarin on CC14-induced liver fibrosis ²in mice. Figure 10 ²(A) shows the results of sirius red stain. As shown in Figure 10 (B), the ²inhibition of MPTOL056 ²on CC14-induced liver fibrosis is dose-dependent, and the efficacy of MPTOL056 ²in inhibition is ²higher than silymarin. The results of MPTOL056 in reducing refibrosis score ²are shown in below²table.²Group Moan SEM Efficacy g;'r.²Contro 0.75 01²3 . 75 0. 22²C.,C14+ f], 2 40 .if.7 a 5.3²I. fi.5c, 2..35 0.25 45..7 %²C C.14+ [...051:1' .1 al ri 1.70 (118 68.33 %²CC.L+Silyniarin 200 img 2 5'3. .t O. 27.50²-44 -²Date Recue / Date Received 2021-11-10²

Claims

<DP=1>²Claims ²What is claimed is:²1. A use, for prevention and / or treatment of a fibrosis disease in a subject, ²of an effective²amount of a compound of Formula (I) or a pharmaceutically acceptable salt, or ²solvate as the²active ingredient to the subject,²0²mi(R2)²si²(CH2)n²R41²TIT²R35²(I)²wherein²Ri is halogen;²each R2 is the same or different, representing H, Ci-ioalkyl, C2-loalkenyl, C2-²loalkynyl, NH2, NO2, Ci-²ioalkyloxy, Ci-ioalkylthio, Ci-ioalkylamino, Ci-loalkyloxyCi-loalkyl, OH or ²CN, C6-loaryl or C5-²7heterocyclic having 1 to 3 heteroatoms selected from the group consisting of ²N, 0 and S;²R3 is H;²R4 is H;²R5 is OH; C3-scycloalkyl; phenyl unsubstituted or substituted with one to ²three same or different ²substituents selected from the group consisting of OH, CN, halogen, NH2 and Ci-²alkylpiperazinyl; ²C1-6alkylpiperazinyl; C -6alkylpyri dinyl ; C1-6alkylpyrrolidinyl; pyridinyl; ²pyrimidinyl; pyrazinyl; ²piperazinyl; pyrrolidinyl; thiazolyl; benzimidazolyl; pyrazolyl; indazolyl; ²pyrazolyl; quinolinyl; ²indolyl; Ci_4indoly1; indazolyl; azaindolyl; azaindazolyl; deazapurinyl; ²indanyl; morpholinoyl and Ci-²aalkylmorpholinoyl, each of which is unsubstituted or substituted with one, ²two or three groups ²selected from the group consisting of OH, CN, halogen and NH2; or²R5 is alkylene-R6 wherein R6 is NRaltb, C5-7heterocyclic ring having 0 to 3 ²hetero atoms selected ²from the group consisting of 0, N and S; or C10-12 fused heterocyclic ring ²having 0 to 3 hetero atoms ²selected from the group consisting of 0, N and S; and Ra and Rb are alkyl; and²X is -C(0);²m is 0; and²n is any integer of 1-4.²- 45 -²Date Reçue / Date Received 2023-11-15²<DP=2>²2. The use of Claim 1, wherein m is 0; RI is halogen; n is any integer of 1-2; ²R3 is H; X is - ²C(0); R4 is H; and Rs is OH; C3-scycloalkyl; pyridinyl; phenyl substituted by ²one to three of NH2, ²halogen, OH, CN or Ci-aalkylpiperazinyl; pyrinidinyl unsubstituted or ²substituted NH2; pyrazinyl ²unsubstituted or substituted NH2; thiazolyl unsubstituted or substituted NH2; ²benzimidazolyl ²unsubstituted or substituted NH2; pyrazolyl unsubstituted or substitutedNH2; ²indazolyl unsubstituted ²or substituted NH2; thiazolyl unsubstituted or substituted NH2; quinolinyl ²unsubstituted or substituted ²NH2; indolyl unsubstituted or substituted NH2; indazolyl unsubstituted or ²substituted NH2; ²azaindazolyl unsubstituted or substituted NH2; deazapurinyl unsubstituted or ²substituted NH2; ²indanyl unsubstituted or substituted NH2; or morpholinoyl unsubstituted or ²substituted NH2.²3. The use of Claim 1, wherein m is 0; Ri is halogen; n is any integer of 1-2; ²R3 is H; X is ²C(0); 12.4 is H; Rs is (CH2)1-4R6 wherein R6 is unsubstituted or substituted ²pyrrolidinyl, oxolanyl, ²thiolanyl, pyrrolyl, furanyl, thiophenyl, piperidinyl, oxanyl, thianyl, ²morpholinoyl, pyridinyl,²piperidinyl, piperazinyl, thiopyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, ²thiazolyl;²benzimidazolyl; pyrazolyl; indazolyl; pyrazolyl; quinolinyl; indolyl; ²indazolyl; azaindolyl; ²azaindazolyl; deazapurinyl; or indanyl.²4. The use of Claim 1, wherein m is 0; Ri is halogen; n is any integer of 1-2; ²R3 is H; X is ²C(0); R4 is H; Rs is (CH2)1-4R6 wherein R6 is unsubstituted or substituted ²pyrrolidinyl, ²morpholinoyl, pyridinyl, piperidinyl, piperazinyl, or indolyl.²5. The use of Claim 1, wherein the compound is:²4- (((3 -chloro- 1,4-di oxo- 1,4-dihydronaphthal en-2-y pamino)methyl)-N-²hydroxybenzami de ;²4- (((3 -chloro- 1,4-d ioxo- 1,4-di hydronaphthal en-2-y pamino)methyl)-N-(py ²ridin-2-²yl)benzamide;²N-(2-aminopheny1)-4-(((3-chloro- 1,4-dioxo- 1,4-di hydronaphthalen-2-²yl)amino)methyl)benzamide;²4- (((3 -chloro- 1,4-dioxo- 1 ,4-dihydronaphthal en-2-y pamino)methyl)-N-²(pyridin- 3 - ²yl)benzamide;²- 46 -²Date Recue / Date Received 2023-11-15²<DP=3>²4- (((3-chloro- 1,4-dioxo-1,4-dihydronaphthal en-2-y Damino)m ethyl)-N-(3 -²fluorophenyl)benzamide;²4- (((3-chloro- 1,4-dioxo- 1,4-dihydronaphthal en-2-y pamino)methyl)-N-(4-²fluorophenyl)benzamide;²4- (((3-chloro- 1,4-d ioxo- 1,4-dihydronaphthalen-2-yl)amino)methyl)-N-pheny ²lbenzami de;²4- (((3-chloro- 1 ,4-dioxo- 1,4-dihydronaphthal en-2-yl)amino)methyl)-N-(2-²fluorophenyl)benzami de;²4- (((3 -chloro-1,4-dioxo- 1,4-di hydronaphthal en-2-y pamino)methyl)-N-(th ²iazol-2-²yl)benzami de ;²N-(1H-benzo [d]imidazol-2-y1)-4-(((3 -chloro- 1,4-dioxo-1,4-dihy dronaphthalen-²2-²yl)amino)methyl)benzami de;²4- (((3-chloro- 1,4-di oxo- 1,4-dihydronaphthal en-2-y pamino)methyl)-N-(4-²hydroxyphenyl)benzamide;²4- (((3-chloro- 1 ,4-dioxo- 1,4-dihydronaphthal en-2-yl)amino)methyl)-N-(3 -²ethynylphenyl)benzamide;²4- (((3 -chloro-1,4-dioxo- 1,4-di hydronaphthal en-2-y pamino)methyl)-N-(2 -²fluoro-4-²iodoph enyl)b enzamide;²N-(1H-benzo [d]imidazol-5-y1)-44(3-chloro- 1,4-di oxo- 1,4-dihy dronaphth alen-²2-²ylamino)methyl)benzami de;²2- (4-(3-amino- 1H-pyrazole- 1-carbonyl)benzylamino)-3-chloronaphthalene-1,4-²dione;²4- ((3- chloro- 1,4-d ioxo- 1 ,4-dihy dronaphthalen-2-ylamino)methyl)-N-cy ²clopropy lbenzami de;²4- ((3-chloro-1 ,4-dioxo-1 ,4-dihy dronaphthalen-2-y1 amino)methyl)-N-²cyclopentylbenzami de;²443-chloro-1,4-dioxo-1 ,4-dihydronaphthalen-2-ylamino)methyl)-N-(1H-indazol-5-²yl)benzamide;²4- ((3-chloro-1 ,4-dioxo- 1 ,4-dihy dronaphthalen-2-ylamino)methyl)-N-(5-²methylthiazol-2-²y1)benzamide;²4- ((3-chloro-1,4-dioxo- 1 ,4-dihy dronaphthalen-2-ylamino)methyl)-N-(5-methy1-²311-pyrazol-²3-yl)benzami de;²2-(4-(3-amino-5-methyl- 1H-py razo le- 1-c arbonyl)benzy lamino)-3-²chloronaphthalene- 1 ,4-²dione;²4- ((3-chloro-1 ,4-di oxo-1 ,4-dihy dronaphthalen-2-ylamino)methyl)-N-(3-n ²itropyri din-4-²yl)benzamide ;²- 47 -²Date Recue / Date Received 2023-11-15²<DP=4>²4- ((3-chloro- 1,4-dioxo- 1 ,4-dihy dronaphthalen-2-y1 amino)methy 1)-N-²(quinolin-6-²yl)benzamide ;²4- ((3-chloro- 1,4-dioxo- 1 ,4-dihy dronaphthalen-2-ylamino)methyl)-N-(quinol ²in- 8-²yl)benzami de ;²4- ((3- chloro- 1,4-dioxo- 1 ,4-dihy dronaphthalen-2-ylamino)methyl)-N-(qui²yl)benzami de ;²443-chloro- 1,4-dioxo- 1 ,4-dihy dronaphthal en-2-ylamino)methyl)-N-(qui nol ²in-5 -²yl)benzamide ;²4- ((3-chloro- 1,4-dioxo- 1 ,4-dihy dronaphthalen-2-ylamin o)methyl)-N-(2-²methy lquino²yl)benzamide ;²4- ((3-chloro- 1,4-dioxo- 1 ,4-dihy dronaphthalen-2-ylamino)methyl)-N4 1H-²indo1-5-²yl)benzami de ;²4- ((3- chloro- 1,4-dioxo- 1 ,4-dihy dronaphthalen-2-ylamino)methyl)-N-(2-²methyl- 1H-i ndo1-5-²yl)benzami de ;²443-chloro- 1,4-dioxo- 1 ,4-dihy dronaphthalen-2-ylamino)methyl)-N-(1H-indo1-5-²²y1)benzamide;²4- ((3-chloro- 1 ,4-dioxo- 1 ,4-dihy dronaphthalen-2-ylamino)methyl)-N-(1H-²indo1-4-²y1)benzamide;²4- ((3-chloro- 1,4-dioxo- 1 ,4-dihy dro naphthalen-2-ylamino)methyl)-N-(4-(4-²ethylpiperazin- 1 -²yl)phenyl)benzamide;²4- ((3- chloro- 1,4-dioxo- 1 ,4-dihy dronaphthalen-2-ylamino)methyl)-N-(1H-²indazol-6-²yl)benzami de ;²4- ((3-chloro- 1 ,4-di oxo- 1 ,4-dihy dronaphthal en-2-ylamino)methyl)-N-( 1H-²pyrrol o [2,3-²b]pyrid in-5-yl)benzamide ;²4- ((3-chloro- 1 ,4-dioxo- 1 ,4-dihy dronaphthalen-2-ylamino)methyl)-N-( 1H-²pyrazolo [3 ,4-²b]pyridin-5-yl)benzamide ;²4- ((3-chloro- 1,4-dioxo- 1 ,4-dihy dronaphthalen-2-ylamino)methyl)-N-(7-²methy1-7H-²pyrrolo [2,3-d]pyrimidin-4-yl)benzamide;²4-((3-chloro- 1,4-dioxo- 1 ,4-dihy dronaphthalen-2-ylamino)methyl)-N-(2,3-dihy ²dro- 1H-inden-²4-yl)benzami de;²4- (((3-bromo- 1,4-di oxo- 1 ,4-dihydronaphthalen-2-y pamino)methyl)-N-²(pyridin-2-²yl)benzamide ;²- 4 8 -²Date Recue / Date Received 2023-11-15²<DP=5>²4-(((3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-yDamino)methyl)-N-(pyrimidin-4-²²yl)benzamide;²4-(((3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-yl)amino)methyl)-N-(pyrazin-2-²yl)benzamide;²4-((3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-ylamino)methyl)-N-(pyridin-4-²ylmethyl)benzamide;²443-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-ylamino)methyl)-N-(2-²morpholinoethyl)benzamide;²N-(2-(1H-indo1-3-yl)ethyl)-4-((3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-²ylamino)methyl)benzamide;²4-(((3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-yl)amino)methyl)-N-(2-²(dimethylamino)ethyl)benzamide;²4- (((3-chloro-1,4-d ioxo-1,4-dihydronaphthal en-2-y pamino)methyl)-N-(2-²(pyrrolidin-1-²y1)ethyl)benzamide;²4-(((3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-yl)amino)methyl)-N-(2-²(diethylamino)ethyl)benzamide;²4-(((3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-yl)amino)methyl)-N-(2-²(piperidin-1-²y1)ethyl)benzamide; and²4-(((3-chloro-1,4-dioxo-1,4-dihydronaphthal en-2-yl)amino)methyl)-N-(2-(4-²methylpiperazin-1-yl)ethyl)benzamide.²6. The use of Claim 1, wherein the compound is 4-(((3-chloro-1,4-dioxo-1,4-²dihydronaphthalen-2-yDamino)methyl)-N-(pyri din-4-yl)benzamide, having the ²following ²formula:²0²CI²0 N²0 N²7. The use of Claim 1, wherein the effective amount ranges from about 1.5 ²mg / kg / day to ²about 20 mg / kg / day.²- 49 -²Date Recue / Date Received 2023-11-15²<DP=6>²8. The use of Claim 1, wherein the effective amount is about 5.0 mg / kg / day to ²about 15 ²mg / kg / day.²9. The use of Claim 1, wherein the effective amount is about 1.5 mg / kg / day to ²about 8 ²mg / kg / day.²10. The use of Claim 1, wherein the active ingredient is for use with a second ²anti-fibrosis ²agent.²11. The use of Claim 10, wherein the second anti-fibrosis agent is ²pirfenidone, nintedanib, ²LOXL2 antibody, simtuzumab, IL-13 antibody, lebrikizumab, ctV136 antibody, STX-²100, CTGF ²antibody, FG-3019, tipelukast, MN-001, or GP-101.²12. The use of Claim 10, use the second anti-fibrosis agent is for ²simultaneous, separate ²or sequential use.²13. The use of Claim 1, wherein the fibrosis disease is skin fibrosis, lung ²fibrosis, renal ²fibrosis, liver fibrosis, intestinal fibrosis, cystic fibrosis, cardiac ²fibrosis, uterine leiomyoma or ²adenomyosis.²14. The use of Claim 13, wherein the lung fibrosis is idiopathic pulmonary ²fibrosis.²15. The use of Claim 13, wherein the subject is or has undergone lung ²transplantation, ²hyperbaric oxygen therapy (HBOT) or pulmonary rehabilitation.²16. A pharmaceutical composition comprising a compound of Formula (I) as ²defined in ²Claim 1, a pharmaceutically acceptable salt thereof, or a solvate thereof ²together with a ²pharmaceutically acceptable excipient, diluent, or carrier.²- 50 -²Date Recue / Date Received 2023-11-15²<DP=7>²17. The pharmaceutical composition of Claim 16, comprising from about 100 mg ²to ²about 1,400 mg of the active ingredient.²18. The pharmaceutical composition of Claim 16, which is in capsule form or ²tablet form.²19. The pharmaceutical composition of Claim 16, comprising about 140 mg to ²about ²1,050 mg of the active ingredient.²20. The pharmaceutical composition of Claim 16, comprising about 100 mg to ²about 300 ²mg of the active ingredient in a single tablet.²21. The pharmaceutical composition of Claim 16, which is in capsule form, and ²wherein ²the active ingredient is in an amount of about 100 mg to about 500 mg.²22. The pharmaceutical composition of Claim 16, further comprising a second ²anti-²fibrosis agent.²23. The pharmaceutical composition of Claim 22, wherein the second anti-²fibrosis agent ²is pirfenidone, nintedanib, LOXL2 antibody, simtuzumab, IL-13 antibody, ²lebrikizumab, ctVf36 ²antibody, STX-100, CTGF antibody, FG-3019, tipelukast, MN-001, or GP-101.²- 51 -²Date Recue / Date Received 2023-11-15²