Hydroxypropylamine difunctional compound and medical application thereof

Abstract

The invention relates to a hydroxypropylamine compound as shown in a formula I and pharmaceutically acceptable salt of the hydroxypropylamine compound. The invention further relates to medical application of the hydroxypropyl cyclic amine compound and the pharmaceutically acceptable salt of the hydroxypropyl cyclic amine compound, and the compound shown in the formula I has an anti-tumor function by blocking a ubiquitination-like Neddylation pathway; the compound shown in the formula I has beta-adrenergic receptor retarding activity and anti-inflammatory and anti-oxidation activity, and plays a role in protecting the heart; the external embodies of the anti-tumor function and the heart protection function are respectively remarkable anti-tumor activity and heart protection activity.

Description

Technical Field

[0001] This invention relates to the fields of medicinal chemistry and pharmacotherapeutic science, and more particularly to hydroxypropylcycloamine bifunctional compounds and their pharmaceutically acceptable salts and medicinal uses. Background Technology

[0002] Cancer patients undergoing long-term anti-tumor drug treatment often develop severe cardiotoxicity-related complications, such as cardiac dysfunction, myocardial infarction, and heart failure—fatal cardiovascular diseases (CVD). This leads to cancer-associated cardiotoxicity and has become the second leading cause of long-term morbidity and death among cancer survivors. However, reports of targeted new drug development are currently scarce in addressing this critical clinical problem.

[0003] While the pathological manifestations of cardiotoxicity associated with tumors are complex and varied, their root causes can be mainly attributed to two mechanisms: First, cardiotoxicity resulting from inherent defects in the targets of antitumor drugs. For example, angiogenesis-related targets such as ErbB2 and VEGFR participate in cardiomyocyte growth by regulating intracellular phosphorylation signals. When antitumor drugs inhibit these targets in cardiac tissue, they can induce apoptosis and necrosis of normal cardiomyocytes. Second, cardiotoxicity induced by the pan-target activity of antitumor drugs. For example, chemotherapeutic drugs such as doxorubicin simultaneously affect multiple signaling pathways within cardiomyocytes during antitumor treatment, continuously activating intracellular oxidative stress responses and leading to free radical accumulation, resulting in myocardial damage and decreased cardiac function.

[0004] These two mechanisms determine that single-function therapeutic drugs (cardioprotective drugs or antitumor drugs) cannot comprehensively treat cancer combined with cardiotoxicity, while simple multidrug combination therapy will bring about the aforementioned problems. Therefore, developing highly effective and low-toxicity single-molecule bifunctional therapeutic drugs is a potential way to overcome this dilemma. The core lies in antitumor activity, and the key is to have dual-function efficacy that combines antitumor and cardiotoxicity treatment. Specifically, the single drug molecule should not only have highly effective and low-toxicity antitumor activity, but also take into account cardiotoxicity treatment function. It should be able to exert dual-function efficacy on its own, and also effectively alleviate cardiotoxicity induced by other antitumor drugs in synergistic therapy.

[0005] The key to developing such single-molecule bifunctional drugs lies in two aspects: first, discovering safer and more effective new anti-tumor targets / mechanisms to reduce the risk of cardiotoxicity caused by intrinsic target defects; and then, identifying excellent candidate drugs targeting these targets / mechanisms that not only do not induce cardiotoxicity during tumor treatment but also possess good cardioprotective efficacy. Unfortunately, there are currently no reports of bifunctional small molecule drugs possessing both anti-tumor and cardioprotective effects.

[0006] Neddylation is the process by which the ubiquitin-like protein Nedd8 (Neuronal precursor cell-expressed developmentally down-regulated protein 8), with the participation of ATP, is activated by the activating enzyme E1 (NAE) and translocated to the conjugating enzyme E2 (UBE2M or UBE2F). Subsequently, under the catalysis of the major ligase E3 (Rbx1 or Rbx2), it modifies the substrate protein and exerts its physiological function. The cullins protein family (major subunits including cullin1, 2, 3, 4a / b, 5, and 7) is not only a major substrate in the neddylation pathway but also an important skeletal protein of the CRL (Cullin-RING ligase) ubiquitin ligase complex. CRLs can specifically regulate the degradation of approximately 20% of intracellular ubiquitinated proteins, and their dysfunction is closely related to the occurrence and development of various tumors.

[0007] Meanwhile, neddylation modification is overactivated in tumor tissues (including various solid tumors), and only about a dozen related substrates exist (mainly cullins family proteins), endowing it with natural tumor targeting selectivity. Previous studies by our research group and other teams have confirmed that inhibiting neddylation can block cullins family modification, thereby promoting the accumulation of various tumor suppressor proteins, specifically inducing apoptosis, cell cycle arrest, and senescence in various types of tumor cells, achieving efficient tumor killing through multiple pathways. Therefore, this pathway is a highly promising target for tumor therapy, potentially avoiding the cardiotoxicity of traditional therapies, and is also the main mechanism by which the compounds in this invention exert their pharmacological effects.

[0008] The inventors previously discovered that the antihypertensive drug β-blocker carvedilol possesses potential antitumor activity, and found that it exerts its antitumor activity by inhibiting Neddylation (ZL202011291425.4; Acta Pharmaceutica Sinica B, 2024, 14(2):729-750.). Using carvedilol as a lead compound, structural modification and optimization were carried out to obtain an allylamine bifunctional pharmacological molecule with both antitumor activity and cardioprotective activity (ZL202011291425.4). Based on the above invention, this invention introduces a cyclic structure into the hydroxypropylamine side chain for the first time. The resulting novel hydroxypropylcyclic amine compound not only effectively breaks through the compound structure covered by the original patent, but also significantly improves the in vivo metabolic stability of the new compound, enabling it to possess oral therapeutic effects not previously reported, and enhancing its antitumor and chemotherapy-induced heart failure therapeutic effects. Therefore, this invention is practical, original, and novel. Summary of the Invention

[0009] The present invention aims to provide a hydroxypropylcycloamine compound of Formula I, and to provide the dual-function pharmaceutical use of the hydroxypropylcycloamine compound or a pharmaceutically acceptable salt thereof and pharmaceutical compositions thereof for the prevention, delay or treatment of tumors complicated with cardiotoxicity.

[0010] Hydroxypropylamine cyclic compounds shown in Formula I:

[0011] I In Formula I: R 1 It is 1,2-cyclopropanediamine, 1,3-cyclopentanediamine, 1,4-cyclohexanediamine, 1,3-cyclohexanediamine, 1,4-piperazinyl, 4-aminopiperidinyl, 3-aminopyranyl, 3-aminoazacyclobutyl, 3,9-diazaspiro[5,5]undecyl, 2,6-diazaspiro[3,3]pentyl, 2,8-diazaspiro[4,4]heptyl, 2,6-diazaspiro[3,4]hexyl, 3,7-diazabicyclo[3,3,0]octyl, 4-aminomethylpiperidinyl, 3-aminomethylpyranyl, 3-aminomethylazacyclobutyl, or 2,6-diaminospiro[4,4]heptyl; R 2 The substituted phenyl, naphthyl, carbazole, indolyl, dibenzofuranyl, 3,4-dihydro-2(1H)-quinolinone, benzophenone, biphenyl, diphenylamino, aromatic aminophenyl, benzocyclopentyl, or benzocyclohexyl R 3 For substituted phenyl; The preferred hydroxypropylcycloamine compounds of the present invention are: 1-((9H-carbazole-4-yl)oxy)-3-(((1r,4r)-4-((2-methoxyphenyl)amino)cyclohexyl)amino)prop-2-ol (I-01), 1-((9H-carbazole-4-yl)oxy)-3-(((1s,4s)-4-((2-methoxyphenyl)amino)cyclohexyl)amino)prop-2-ol (I-02), 1-((9H-carbazole-4-yl)oxy)-3-((4-((2-methoxyphenyl)amino)amino)prop-2-ol (I-02), 1-(9H-carbazole-4-yl)oxy)-3-((4-(2-methoxyphenyl ... 1-((9H-carbazole-4-yl)oxy)-3-(4-(2-methoxyphenyl)piperazin-1-yl)prop-2-ol (I-04), 1-((9H-carbazole-4-yl)oxy)-3-(6-(2-methoxyphenyl)-2,6-diazaspiro[3.3]hept-2-yl)prop-2-ol (I-05), 1-((9H-carbazole-4-yl)oxy)-3-(9-(2-methoxyphenyl)-3,9-diazaspiro[5. 5] Undecane-3-yl)prop-2-ol (I-06), 1-((9H-carbazol-4-yl)oxy)-3-(7-(2-methoxyphenyl)-2,7-diazaspiro[4.4]nonane-2-yl)prop-2-ol (I-07), 1-((9H-carbazol-4-yl)oxy)-3-(4-((2-methoxyphenyl)amino)piperidin-1-yl)prop-2-ol (I-08), 1-((9H-carbazol-4-yl)oxy)-3-(3-((2-methoxyphenyl)amino)pyrrole Alkyl-1-yl)prop-2-ol (I-09), 1-((9H-carbazol-4-yl)oxy)-3-(3-((2-methoxyphenyl)amino)azacyclobutane-1-yl)prop-2-ol (I-10), 1-((9H-carbazol-4-yl)oxy)-3-(6-(2-methoxyphenyl)-2,6-diazaspiro[3.4]octyl-2-yl)prop-2-ol (I-11), 1-((9H-carbazol-4-yl)oxy)-3-(5-(2-methoxyphenyl)hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-yl)prop-2-ol (I-12), 1-((9H-carbazole-4-yl)oxy)-3-(4-(((2-methoxyphenyl)amino)methyl)piperidin-1-yl)prop-2-ol (I-13), 1-((9H-carbazole-4-yl)oxy)-3-(3-(((2-methoxyphenyl)amino)methyl)pyrrolo-1-yl)prop-2-ol (I-14), 1-((9H-carbazole-4-yl)oxy)-3-(3-(((2-methoxyphenyl)amino)methyl)azacyclobutane-1-yl)prop-2-ol (I-15), 1-((9H-carbazole-4-yl)oxy)-3-((3-((2-methoxyphenyl)amino)cyclobutyl) Amino)2-propanol (I-16), 1-((9H-carbazole-4-yl)oxy)-3-((3-((2-methoxyphenyl)amino)cyclopentyl)amino)prop-2-ol (I-17), 1-((9H-carbazole-4-yl)oxy)-3-((6-((2-methoxyphenyl)amino)spiro[3.3]hept-2-yl)amino)prop-2-ol (I-18), 1-((9H-carbazole-4-yl)oxy)-3-((3-((2-methoxyphenyl)amino)cyclohexyl)amino)prop-2-ol (I-19), 1-(((1r,4r)-4-((2-methoxyphenyl)amino)cyclohexyl)amino)-3-(naphthyl-1-yloxy)prop-2-ol (I-20), 1- ((9H-carbazole-2-yl)oxy)-3-(((1r,4r)-4-((2-methoxyphenyl)amino)cyclohexyl)amino)prop-2-ol (I-21), 1-(((1r,4r)-4-((2-methoxyphenyl)amino)cyclohexyl)amino)-3-(naphthyl-2-yloxy)prop-2-ol (I-22), 1-(((1r,4r)-4-((2-methoxyphenyl)amino)cyclohexyl)amino)-3-(3-(phenylamino)phenoxy)prop-2-ol (I-23), 1-((9H-carbazole-3-yl)oxy)-3-(((1r,4r)-4-((2-methoxyphenyl)amino)cyclohexyl)amino)prop-2-ol (I-24), 1-( ((1r,4r)-4-((2-methoxyphenyl)amino)cyclohexyl)amino)-3-(naphth-1-yloxy)prop-2-ol (I-25), 1-((1H-indol-4-yl)oxy)-3-(((1r,4r)-4-((2-methoxyphenyl)amino)cyclohexyl)amino)prop-2-ol (I-26), 1-(4-cyclohexylphenoxy)-3-(((1r,4r)-4-((2-methoxyphenyl)amino)cyclohexyl)amino)prop-2-ol (I-27), 1-((1H-indol-5-yl)oxy)-3-(((1r,4r)-4-((2-methoxyphenyl)amino)cyclohexyl)amino)prop-2-ol (I-28), 1-(((1r,4r)-4-((2-methoxyphenyl)amino)cyclohexyl)amino)prop-2-ol (I-28), 1-(((1r,4r)-4-((2-methoxyphenyl)amino)cyclohexyl)amino)-3-(4-phenoxyphenoxy)prop-2-ol (I-29), 5-(2-hydroxy-3-(((1r,4r)-4-((2-methoxyphenyl)amino)cyclohexyl)amino)propoxy)-3,4-dihydroquinoline-2(1H)-one (I-30), 6-(2-hydroxy-3-(((1r,4r)-4-((2-methoxyphenyl)amino)cyclohexyl)amino)propoxy)-3,4-dihydroquinoline-2(1H)-one (31), 1-(((1r,4r)-4-((2-methoxyphenyl)amino)cyclohexyl)amino)-3-((2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1 -ij] Quinolin-8-yl)oxy)prop-2-ol (I-32), 1-(((1r,4r)-4-((2-methoxyphenyl)amino)cyclohexyl)amino)-3-phenoxyprop-2-ol (I-33), 1-(4-benzylphenoxy)-3-(((1r,4r)-4-((2-methoxyphenyl)amino)cyclohexyl)amino)prop-2-ol (I-34), 1-(((1r,4r)-4-((2-methoxyphenyl)amino)cyclohexyl)amino)-3-(4-(phenylamino) )phenoxy)prop-2-ol (I-35), 1-([1,1'-biphenyl]-4-yloxy)-3-(((1r,4r)-4-((2-methoxyphenyl)amino)cyclohexyl)amino)prop-2-ol (I-36), 1-([1,1'-biphenyl]-3-yloxy)-3-(((1r,4r)-4-((2-methoxyphenyl)amino)cyclohexyl)amino)prop-2-ol (I-37), N-(3-(2-hydroxy-3-(((1r,4r)-4-((2-methoxyphenyl)) Acetamide (I-38), 1-([1,1'-biphenyl]-2-yloxy)-3-(((1r,4r)-4-((2-methoxyphenyl)amino)cyclohexyl)amino)prop-2-ol (I-39), 1-(((1r,4r)-4-((2-methoxyphenyl)amino)cyclohexyl)amino)-3-(4-phenoxyphenoxy)prop-2-ol (I-40), 1-(4-(benzyloxy)phenoxy)-3-(((1r,4r)- 4-((2-methoxyphenyl)amino)cyclohexyl)amino)prop-2-ol (I-41), 1-(((1r,4r)-4-((2-methoxyphenyl)amino)cyclohexyl)amino)-3-((5,6,7,8-tetrahydronaphthyl-2-yl)oxy)prop-2-ol (I-42), 1-((2,3-dihydro-1H-indene-5-yl)oxy)-3-(((1r,4r)-4-((2-methoxyphenyl)amino)cyclohexyl)amino)prop-2-ol (I-43), 1-(((1r,4r)-4-((2-methoxyphenyl)amino)cyclohexyl)amino)-3-(m-tolyloxy)prop-2-ol (I-44), 1-(((1r,4r)-4-((2-methoxyphenyl)amino)cyclohexyl)amino)-3-(4-(naphthyl-2-ylamino)phenoxy)prop-2-ol (I-45), 1-(((1r,4r)-4-((2-methoxyphenyl)amino)cyclohexyl)amino)-3-(4-(quinolin-6-ylamino)phenoxy)prop-2-ol (I-46 ... r)-4-((2-methoxyphenyl)amino)cyclohexyl)amino)-3-(4-(pyridin-2-ylamino)phenoxy)prop-2-ol (I-47), 1-(((1r,4r)-4-((2-methoxyphenyl)amino)cyclohexyl)amino)-3-(4-(pyridin-2-ylamino)phenoxy)prop-2-ol (I-48), 1-(4-((2,3-dihydro-1H-indole-5-yl)amino)phenoxy)-3-(((1r,4r)-4-((2-methoxyphenyl)amino)cyclohexyl)amino)2-propanol (I-49), 1-(((1r,4r)-4-((2-methoxyphenyl)amino)cyclohexyl)amino)-3-(4-((1-methyl-1H-indole-5-yl)amino)phenoxy)prop- 2-Alcohol (I-50), 1-(((1r,4r)-4-((2-methoxyphenyl)amino)cyclohexyl)amino)-3-(4-(thiophen-3-ylamino)phenoxy)prop-2-ol (I-51), 1-(((1r,4r)-4-((2-methoxyphenyl)amino)cyclohexyl)amino)-3-(4-(thiophen-3-ylamino)phenoxy)prop-2-ol (I-52), 1-(((1r,4r)-4-((2-methoxyphenyl)amino)cyclohexyl)amino)-3-(4-((5,6,7,8-tetrahydronaphthyl-2-yl)amino)phenoxy) 2-Propanol (I-53), 1-(((1s,4s)-4-((2-methoxyphenyl)amino)cyclohexyl)amino)-3-(4-(phenylamino)phenoxy)prop-2-ol (I-54), 1-([1,1'-biphenyl]-4-yloxy)-3-(((1s,4s)-4-((2-methoxyphenyl)amino)cyclohexyl)amino)prop-2-ol (I-55), 1-(((1r,4r)-4-((3-methoxyphenyl) )amino)cyclohexyl)amino)-3-(4-(phenylamino)phenoxy)prop-2-ol (I-56), 1-(((1r,4r)-4-((4-methoxyphenyl)amino)cyclohexyl)amino)-3-(4-(phenylamino)phenoxy)prop-2-ol (I-57), 1-(4-(phenylamino)phenoxy)-3-(((1r,4r)-4-(o-tolylamino)cyclohexyl)amino)prop-2-ol (I-58), -(((1r,4r)-4-((2-ethylphenyl)amino)cyclohexyl)amino)-3-(4-(phenylamino)phenoxy)prop-2-ol (I-59), 1-(((1r,4r)-4-((2-isopropylphenyl)amino)cyclohexyl)amino)-3-(4-(phenylamino)phenoxy)prop-2-ol (I-60), 1-(4-(phenylamino)phenoxy)-3-(((1r,4r)-4-(p-tolylamino)cyclohexyl)amino)prop-2-ol (I-61), 1-(((1r,4r)-4-(phenylamino)cyclohexyl)amino)-3-(4-(phenylamino)phenoxy)prop-2-ol (I-62).

[0012] According to embodiments, the present invention further provides the use of hydroxypropylamine compounds, or pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof in the preparation of dual-function antitumor and cardioprotective drugs. The pharmaceutically acceptable salts of the hydroxypropylamine compounds are preferably hydrochlorides, phosphates, sulfates, acetates, trichloroacetic acids, lactates, or citrates. The pharmaceutical compositions of the hydroxypropylamine compounds are preferably anthracycline antitumor drugs, nucleoside antitumor drugs, kinase inhibitors, platinum-based antitumor drugs, or currently reported antitumor drugs that can induce cardiac damage.

[0013] In the pharmaceutical use of the aforementioned hydroxypropylcycloamine compounds, or pharmaceutically acceptable salts thereof, and their pharmaceutical compositions, the tumor is lung cancer, liver cancer, stomach cancer, breast cancer, colorectal cancer, or a highly activated tumor or disease modified by neddylation; the cardiac injury is cardiovascular disease or cardiac injury-related conditions caused by taking other antitumor drugs, and the cardiac injury-related treatment conditions are myocardial injury, heart failure, or myocardial infarction.

[0014] In the pharmaceutical use of the aforementioned hydroxypropylcycloamine compounds, or pharmaceutically acceptable salts thereof, and their pharmaceutical compositions, the compounds of Formula I exert antitumor function by blocking the ubiquitination-like Neddylation pathway; the compounds of Formula I exert cardioprotective function through β-adrenergic receptor blocking activity and anti-inflammatory and antioxidant activity; the external manifestations of the antitumor function and the cardioprotective function are significant antitumor activity and cardioprotective activity, respectively.

[0015] Compared to existing technologies, the compounds involved in this invention are novel hydroxypropylcycloamine small molecules. The design concept involves using carvedilol, a β-receptor blocker and antihypertensive drug, as a lead compound, and then modifying and optimizing its structure to obtain a bifunctional pharmacologically active molecule possessing both antitumor and cardioprotective activities. These small molecules have been evaluated in vitro using various tumor cell proliferation inhibition experiments; in vitro cardiomyocyte injury repair experiments; cellular neddylation inhibition activities; in vivo antitumor activity in mouse xenograft experiments; therapeutic activity in mice with doxorubicin-induced myocardial injury; and mouse pharmacokinetic (PK) evaluation, fully demonstrating the significant bifunctional activity and oral bioactivity of this class of molecules. Attached Figure Description

[0016] Figure 1 This study demonstrates the evaluation of the inhibitory effects of the preferred derivatives I-35 and I-59 on isoproterenol (ISO)-induced tachycardia in rabbit hearts during isolated heart perfusion experiments. Heart rate refers to the heart rate; a higher value indicates a faster heartbeat. QRS width represents the time required for ventricular depolarization, i.e., the time interval from the onset of ventricular excitation to complete excitation. QT interval represents the total electrical activity cycle of the ventricular myocardium from the start of depolarization to complete repolarization, i.e., the electrophysiological process of ventricular contraction and relaxation. QTc interval is the heart rate-corrected QT interval, used to eliminate the influence of heart rate on the QT interval, thus more accurately assessing ventricular repolarization time.

[0017] Figure 2 The experiment on subcutaneous tumors in nude mice (A549) evaluates the in vivo antitumor activity of I-35. Mice weight represents the trend of mouse body weight change before and after administration; Tumor volume represents the trend of tumor size change before and after administration, with smaller trend changes indicating stronger antitumor efficacy.

[0018] Figure 3 This study demonstrates the in vivo cardioprotective activity of I-35 in a DOX-induced mouse heart failure model. HW / BW represents the ratio of heart weight to mouse body weight; long-term chemotherapy leads to cardiac fibrosis and reduced myocardial contractility, and a lower HW / BW ratio indicates more severe cardiac damage in mice. CKMB and LDH are indicators of cardiac function; higher values ​​indicate poorer cardiac function. Detailed Implementation

[0019] The following specific embodiments illustrate the implementation of the present invention. Those skilled in the art can easily understand other advantages and effects of the present invention from the content disclosed in this specification. It should be noted that, unless otherwise specified, the following embodiments and features can be combined with each other. In addition to the specific methods, equipment, and materials used in the embodiments, based on the knowledge of the prior art and the description of the present invention by those skilled in the art, any prior art methods, equipment, and materials similar to or equivalent to the methods, equipment, and materials in the embodiments of the present invention can be used to implement the present invention.

[0020] It should be understood that the terminology used in the embodiments of this invention is for describing specific implementations and not for limiting the scope of protection of this invention. Unless otherwise defined, all technical and scientific terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art.

[0021] In the following description, numerous details are explored to provide a more thorough explanation of embodiments of the invention. However, it will be apparent to those skilled in the art that embodiments of the invention may be practiced without these specific details. In some embodiments, well-known structures and devices are shown in block diagram form rather than in detail to avoid obscuring embodiments of the invention.

[0022] Example 1

[0023] a Reagents and conditions : (a) 1 M NaOH, DMSO, 25℃, 12h, 70%; (b) t-BuONa, BrettPhos-Pd-G3, BrettPhos, 1, 4-Dioxane, 80℃, 12h; (c) CF3COOH, DCM, 25℃, 1h; (d) i-PrOH, reflux, 8 h, 30~40%. 4-(ethylene oxide-2-ylmethoxy)-9H-carbazole (intermediate I) A Preparation of ) 4-Hydroxycarbazole (732 mg, 4 mmol) was dissolved in 1.5 mL of DMSO, and then 4 mL of a prepared 1M NaOH aqueous solution was added dropwise. The mixture was stirred vigorously at room temperature for 1 h. Epichlorohydrin (680 mg, 5 mmol) was added to the solution, and the reaction was stirred overnight at room temperature. The next day, TLC monitoring was performed. After the reaction was complete, the reaction solution was quenched with saturated NH4Cl (5 mL), and then extracted with EA (5 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate for 12 h and then evaporated to dryness. The oily substance was purified by column chromatography (SiO2, PE / EA) to obtain I. A Intermediate (688 mg, 70% yield). 1 H NMR (400 MHz, CDCl3) δ 8.30 (dq, J = 7.8, 0.9 Hz, 1H), 7.98 (s, 1H), 7.39 – 7.29 (m, 2H), 7.22– 7.18 (m, 1H), 6.98 (dd, J = 8.1, 0.6 Hz, 1H), 6.60 (d, J = 7.9 Hz, 1H),4.40 (dd, J = 11.0, 3.3 Hz, 1H), 4.20 (dd, J = 11.0, 5.4 Hz, 1H), 3.57 – 3.39 (m,1H), 2.94 (dd, J = 4.9, 4.1 Hz, 1H), 2.83 (dd, J = 4.9, 2.6 Hz, 1H). General method A for the synthesis of intermediates 1a~19a and 1b~19b: HR available on the market 1-Boc reacts with o-methoxybromobenzene (1.3 eq.) under nitrogen protection with 6 mL of ultra-dry dioxane as solvent, using BrettPhos-Pd-G3 (0.05 eq.) as catalyst, BrettPhos (0.05 eq.) as ligand, and sodium tert-butoxide (3 eq.) as base. The mixture is stirred and refluxed overnight at 80 °C. After the reaction is completed as monitored by TLC, the palladium catalyst is removed by filtration, the organic phase is collected, and the solvent is evaporated to dryness under reduced pressure. The residue is purified by silica gel column chromatography (SiO2, PE / EA) to obtain the corresponding Boc-containing intermediates 1a-19a in yields of 30-59%. The purified intermediates 1a-19a were dissolved in 5 mL of DCM until a clear solution was obtained. 1 mL of trifluoroacetic acid was added dropwise, and the reaction was stirred at room temperature for 1 hour until the reaction was complete. The mixture was then neutralized with saturated sodium bicarbonate solution under ice bath until no bubbles were observed. The mixture was extracted 5 times with EA, dried over anhydrous sodium sulfate, and the organic phase was evaporated to obtain intermediates 1b-19b with a yield of 98%. The product did not require purification and was directly used in the next step.

[0024] General Method B for the Synthesis of End Products 1-19: Intermediate 1b~19b (1 eq.) and intermediate I A (1 eq.) was refluxed at 80°C overnight with isopropanol as solvent, and the isopropanol was directly evaporated to dryness the next day. The residue was subjected to silica gel column chromatography. SiO2 The final product 1-19 was obtained by purification with DCM / MeOH, with a yield of 42-49%.

[0025] Preparation of ((1r,4r)-4-((2-methoxyphenyl)amino)cyclohexyl)carbamate tert-butyl ester (intermediate 1a): Intermediate 1a was synthesized from trans-(4-aminocyclohexyl)carbamate tert-butyl ester using general synthetic method A, with a yield of 55%. 1 H NMR (400 MHz, Acetone- d 6) δ 6.78 (dd, J = 11.6, 7.8 Hz, 2H),6.66 – 6.46 (m, 2H), 5.93 (s, 1H), 4.38 (s, 1H), 3.81 (s, 3H), 3.59 (s, 1H),3.50 (s, 1H), 1.71 (m, 8H), 1.40 (s, 9H). Preparation of (1r,4r)-N-(2-methoxyphenyl)cyclohexane-1,4-diamine (intermediate 1b): Following general synthetic method A, intermediate 1a was used as a starting material. Trifluoroacetic acid was added to remove the Boc group, and the mixture was extracted and evaporated to dryness to obtain intermediate 1b. 1¹H NMR (400 MHz, DMSO-d⁶) δ 6.76 (ddd, J = 15.4, 7.8, 1.4 Hz, 2H), 6.64–6.40 (m, 2H), 4.28 (d, J = 8.5 Hz, 1H), 3.75 (s, 3H), 3.22–3.11 (m, 1H), 2.61 (td, J = 7.5, 6.8, 4.2 Hz, 1H), 2.08–1.70 (m, 4H), 1.23–1.13 (m, 4H), with a yield of 98%.

[0026] Preparation of 1-((9H-carbazol-4-yl)oxy)-3-(((1r,4r)-4-((2-methoxyphenyl)amino)cyclohexyl)amino)prop-2-ol (I-01):

[0027] I-01 According to general synthesis method B, intermediate I A Intermediate 1b was refluxed overnight in isopropanol, and purified by column chromatography to give final product I-01, a white solid. 1 H NMR (400 MHz, DMSO- d 6) δ 11.28 (s, 1H), 8.21 (d, J = 7.7Hz, 1H), 7.45 (d, J = 8.0 Hz, 1H), 7.40 – 7.25 (m, 2H), 7.21 – 7.11 (m, 1H),7.08 (d, J = 8.1 Hz, 1H), 6.76 (ddd, J = 15.3, 7.7, 1.4 Hz, 2H), 6.69 (d, J = 7.9Hz, 1H), 6.62 – 6.45 (m, 2H), 4.35 (d, J = 8.5 Hz, 1H), 4.18 (s, 3H), 3.75 (s,3H), 3.25 – 3.12 (m, 1H), 3.06 (d, J = 12.0 Hz, 1H), 2.92 (d, J = 9.5 Hz, 1H), 2.67 (s, 1H), 2.06 – 1.91 (m, 4H), 1.43 – 1.14 (m, 5H). 13C NMR (101 MHz, DMSO- d 6) δ 141.09, 138.90, 126.47, 124.50, 122.41, 121.73, 121.05, 118.46, 115.31,110.34, 109.86, 109.82, 109.71, 103.80, 100.45, 70.50, 68.63, 55.31, 53.15,49.90, 48.41, 39.97, 39.55, 39.13, 28.29, 28.23, 27.37, 27.34. HRMS (ESI) m / zcalcd 28 H 33 N3O3[M+H] + 460.2595, found 460.2599. Example 2 Preparation of 1-((9H-carbazole-4-yl)oxy)-3-(((1s,4s)-4-((2-methoxyphenyl)amino)cyclohexyl)amino)prop-2-ol (I-02):

[0028] I-02 According to general synthesis method B, intermediate I A Intermediate 2b was refluxed overnight in isopropanol, and purified by column chromatography to give the final product I-02, a white solid. 1 H NMR (400 MHz, DMSO- d 6) δ 11.27 (s, 1H), 8.21 (d, J = 7.7Hz, 1H), 7.45 (d, J = 8.0 Hz, 1H), 7.37 – 7.26 (m, 2H), 7.14 – 7.05 (m, 2H), 6.83 – 6.74 (m, 2H), 6.70 (d, J = 7.9 Hz, 1H), 6.59 – 6.49 (m, 2H), 4.37 (d, J =8.0 Hz, 1H), 4.20 (s, 3H), 3.78 (s, 3H), 3.45 (s, 1H), 3.05 (d, J = 11.7 Hz, 1H), 2.87 (d, J= 16.9 Hz, 2H), 1.81 – 1.66 (m, 4H), 1.60 (d, J = 9.2 Hz, 4H). 13 CNMR (101 MHz, DMSO- d 6) δ 155.46, 146.78,141.58,139.39,137.28,126.96,124.99,122.90,122.22,121.53, 118.96, 115.80,112.06, 110.84, 110.31, 110.20, 104.28,100.94, 70.99, 69.13, 55.79, 53.63, 50.40, 48.89,29.50, 28.79, 28.72,27.83.HRMS (ESI) m / z calcd C 28 H 33 N3O3[M+H] + 460.2595, found 460.2598 Example 3 Preparation of 1-((9H-carbazole-4-yl)oxy)-3-((4-((2-methoxyphenyl)amino)cyclohexyl)amino)prop-2-ol (I-03):

[0029] I-03 According to general synthesis method B, intermediate I A Intermediate 3b was refluxed overnight in isopropanol, and purified by column chromatography to give the final product I-03, a white solid. 1 H NMR (400 MHz, DMSO- d 6) δ 11.24 (s, 1H), 8.21 (d, J = 7.8Hz, 1H), 7.44 (d, J = 8.1 Hz, 1H), 7.30 (dt, J = 13.5, 7.7 Hz, 2H), 7.19 – 7.01(m, 2H), 6.82 – 6.72 (m, 2H), 6.69 (d, J = 7.9 Hz, 1H), 6.53 (dd, J = 17.7, 8.2Hz, 2H), 5.11 (s, 1H), 4.34 (d, J= 8.3 Hz, 1H), 4.23 – 4.12 (m, 2H), 4.08 (q, J = 5.7 Hz, 1H), 3.76 (s, 3H), 2.89 (dd, J = 11.8, 4.6 Hz, 1H), 2.73 (dd, J = 11.8,6.8 Hz, 1H), 2.66 (s, 1H), 1.62 (t, J = 7.1 Hz, 6H), 1.50 (d, J = 14.9 Hz, 2H). 13 CNMR (151 MHz, DMSO- d 6) δ 155.47, 146.78, 141.58, 139.39, 137.29, 126.97,125.00, 122.90, 122.22, 121.54, 118.97, 115.80, 112.05,112.91, 110.84,110.31, 110.20, 104.28, 100.94, 70.99, 69.13, 55.80, 53.62, 50.40, 48.89,40.54, 28.79,27.82.HRMS (ESI) m / z calcd C 28 H 33 N3O3[M+H] + 460.2522, found 460.2527 Example 4 Preparation of 1-((9H-carbazol-4-yl)oxy)-3-(4-(2-methoxyphenyl)piperazin-1-yl)prop-2-ol (I-04):

[0030] I-04 According to general synthesis method B, intermediate I A Intermediate 4b was refluxed overnight in isopropanol, and purified by column chromatography to give the final product I-04, a white solid. 1 H NMR (400 MHz, DMSO- d 6) δ 11.24 (s, 1H), 8.26 (d, J = 7.8Hz, 1H), 7.45 (d, J= 8.0 Hz, 1H), 7.38 – 7.26 (m, 2H), 7.20 – 7.13 (m, 1H), 7.10 – 7.02 (m, 1H), 6.97 – 6.84 (m, 4H), 6.70 (d, J = 7.9 Hz, 1H), 5.01 (d, J =4.2 Hz, 1H), 4.18 (dt, J = 20.1, 5.2 Hz, 3H), 3.76 (s, 3H), 2.97 (t, J = 4.7 Hz,4H), 2.77 – 2.54 (m, 6H). 13 C NMR (151 MHz, DMSO) δ 155.08, 152.03, 141.32,141.17, 138.97, 126.59, 124.61, 122.61, 122.41, 121.82, 120.90, 118.64,117.95, HRMS (ESI) m / z calcd C 27 H 31 N3O3[M+H] + 432.2282, found 432.2289 Example 5 Preparation of 1-((9H-carbazol-4-yl)oxy)-3-(6-(2-methoxyphenyl)-2,6-diazaspiro[3.3]hept-2-yl)prop-2-ol (I-05):

[0031] I-05 According to general synthesis method B, intermediate I A Intermediate 5b was refluxed overnight in isopropanol, and purified by column chromatography to give final product I-05, a white solid. 1 H NMR (400 MHz, DMSO- d 6) δ 11.24 (d, J= 3.3 Hz, 1H), 8.30 –8.17 (m, 1H), 7.48 – 7.42 (m, 1H), 7.39 – 7.25 (m, 2H), 7.20 – 7.12 (m, 1H),7.07 (dd, J = 7.9, 1.8 Hz, 1H), 6.84 – 6.73 (m, 2H), 6.72 – 6.64 (m, 2H), 6.34(dd, J = 7.8, 1.8 Hz, 1H), 5.11 (s, 1H), 4.20 – 4.06 (m, 2H), 3.98 (s, 1H), 3.86 (s, 3H), 3.69 (s, 3H), 3.46 (s, 3H), 2.82 (dd, J = 12.1, 5.2 Hz, 1H), 2.73– 2.63 (m, 1H). 13 C NMR (101 MHz, DMSO- d 6) δ 155.33, 141.58, 141.38, 139.39,126.97, 125.02, 123.03, 122.18,122.08, 121.29, 119.27, 119.05, 113.35,112.12, 112.03, 110.84, 104.39, 100.92, 70.70, 67.78, 64.98, 63.44, 61.70,55.93, 40.63,39.59,35.54. HRMS (ESI) m / z calcd C 27 H 29 N3O3[M+H] + 444.2282, found 444.2286 Example 6 Preparation of 1-((9H-carbazol-4-yl)oxy)-3-(9-(2-methoxyphenyl)-3,9-diazaspiro[5.5]undecane-3-yl)prop-2-ol (I-06):

[0032] I-06 According to general synthesis method B, intermediate I A Intermediate 6b was refluxed overnight in isopropanol, and purified by column chromatography to give the final product I-06, a white solid. 1 H NMR (400 MHz, DMSO- d6) δ 11.23 (s, 1H), 8.24 (d, J = 7.7Hz, 1H), 7.44 (d, J = 8.0 Hz, 1H), 7.36 – 7.31 (m, 1H), 7.29 (t, J = 8.0 Hz, 1H),7.16 – 7.10 (m, 1H), 7.06 (d, J = 8.0 Hz, 1H), 6.90 (ddt, J = 5.8, 3.3, 2.0 Hz,3H), 6.87 – 6.82 (m, 1H), 6.69 (d, J = 7.9 Hz, 1H), 4.92 (s, 1H), 4.22 – 4.08(m, 3H), 3.75 (s, 3H), 2.88 (t, J = 5.4 Hz, 4H), 2.64 (s, 1H), 1.54 (t, J = 5.6Hz, 4H), 1.49 (t, J = 5.2 Hz, 4H). 13 C NMR (101 MHz, DMSO- d 6) δ 155.52, 152.51,142.54,141.57, 139.38, 126.96, 124.99, 123.01, 122.58,122.23, 121.23, 118.99,118.58, 112.26, 112.07,110.81, 104.27, 100.93, 71.35, 67.26, 62.15, 55.74,50.01,49.48, 46.47, 40.22,36.36,36.05,36.00, 29.49,29.16. (ESI) m / z calcdC 31 H 37 N3O3[M+H] + 500.2908, found 500.2914 Example 7 Preparation of 1-((9H-carbazol-4-yl)oxy)-3-(7-(2-methoxyphenyl)-2,7-diazaspiro[4.4]nonane-2-yl)prop-2-ol (I-07):

[0033] I-07 According to general synthesis method B, intermediate I A Intermediate 7b was refluxed overnight in isopropanol, and purified by column chromatography to give final product I-07, a white solid. 1 H NMR (400 MHz, DMSO- d 6) δ 11.23 (s, 1H), 8.23 ​​(d, J = 7.8Hz, 1H), 7.44 (d, J = 8.0 Hz, 1H), 7.35 – 7.23 (m, 2H), 7.12 (t, J = 7.5 Hz, 1H), 7.06 (dd, J = 8.0, 2.3 Hz, 1H), 6.86 (d, J = 7.9 Hz, 1H), 6.78 (t, J = 7.3 Hz, 1H), 6.69 (t, J = 7.7 Hz, 2H), 6.59 (d, J = 7.9 Hz, 1H), 5.00 (s, 1H), 4.54 (s, 1H), 4.20 (d, J = 6.0 Hz, 1H), 4.13 (d, J = 7.5 Hz, 2H), 3.70 (d, J = 1.3 Hz, 3H), 3.26(d, J = 9.2 Hz, 3H), 2.67 (p, J = 1.9 Hz, 2H), 2.48 (s, 5H), 2.37 – 2.30 (m, 1H), 2.12 (s, 4H), 1.91 (s, 1H), 1.80 (s, 3H). HRMS (ESI) m / z calcd C 29 H 33 N3O3[M+H] + 472.2595, found 472.2599 Example 8 Preparation of 1-((9H-carbazol-4-yl)oxy)-3-(4-((2-methoxyphenyl)amino)piperidin-1-yl)prop-2-ol (I-08):

[0034] I-08 According to general synthesis method B, intermediate IA Intermediate 8b was refluxed overnight in isopropanol, and purified by column chromatography to give final product I-08, a white solid. 1 H NMR (400 MHz, DMSO- d 6) δ 11.24 (s, 1H), 8.24 (d, J = 7.7Hz, 1H), 7.44 (dt, J = 8.1, 0.9 Hz, 1H), 7.38 – 7.25 (m, 2H), 7.14 (ddd, J = 8.0,7.2, 1.1 Hz, 1H), 7.06 (d, J = 8.0 Hz, 1H), 6.81 – 6.72 (m, 2H), 6.69 (d, J = 7.9Hz, 1H), 6.59 – 6.48 (m, 2H), 4.96 (d, J = 4.1 Hz, 1H), 4.39 (d, J = 8.4 Hz, 1H), 4.23 – 4.07 (m, 3H), 3.75 (s, 3H), 3.23 (d, J = 10.0 Hz, 1H), 2.91 (dd, J = 19.6,12.0 Hz, 2H), 2.65 (dd, J = 12.6, 5.3 Hz, 1H), 2.29 – 2.15 (m, 2H), 2.12 (s,1H), 1.89 (dd, J = 10.8, 5.1 Hz, 2H), 1.44 (td, J = 14.4, 13.8, 7.4 Hz, 2H). 13 CNMR (101 MHz, DMSO- d 6) δ 155.51,146.81, 141.58, 139.39, 137.26, 126.97,124.99, 123.01, 122.23,121.54, 119.02, 115.93, 112.07,110.82, 110.39, 110.23,104.28, 100.91, 71.34, 67.39, 61.82, 55.75, 53.46, 49.31, 40.63,39.38,32.39.HRMS (ESI) m / z calcd C27 H 31 N3O3[M+H] + 446.2438, found 446.2445 Example 9 Preparation of 1-((9H-carbazol-4-yl)oxy)-3-(3-((2-methoxyphenyl)amino)pyrrolidine-1-yl)prop-2-ol (I-09):

[0035] I-09 According to general synthesis method B, intermediate I A Intermediate 9b was refluxed overnight in isopropanol, and purified by column chromatography to give final product I-09, a white solid. 1 H NMR (400 MHz, DMSO- d 6) δ 11.24 (s, 1H), 8.23 ​​(d, J = 7.8Hz, 1H), 7.44 (d, J = 8.1 Hz, 1H), 7.32 (t, J = 7.7 Hz, 1H), 7.27 (dt, J = 7.9, 3.9Hz, 1H), 7.12 (td, J = 7.5, 2.9 Hz, 1H), 7.08 – 7.03 (m, 1H), 6.81 – 6.72 (m,2H), 6.67 (dd, J = 8.0, 2.7 Hz, 1H), 6.58 – 6.50 (m, 2H), 5.07 (s, 1H), 4.66(s, 1H), 4.19 (q, J = 6.4 Hz, 1H), 4.12 (d, J = 6.7 Hz, 2H), 3.92 (s, 1H), 3.74(s, 3H), 2.93 – 2.72 (m, 3H), 2.59 (s, 2H), 2.22 (dd, J = 20.1, 5.8 Hz, 1H),1.60 (s, 1H). 13 C NMR (101 MHz, DMSO- d6) δ 155.48,147.04, 141.58,139.38,137.69, 126.95, 124.99, 123.00, 122.22,121.51, 119.02, 116.34, 112.08,110.81,110.21, 104.29, 100.90, 71.12, 68.27, 61.57, 61.46, 59.42, 55.70, 53.89,51.94, 32.31.HRMS (ESI) m / z calcd C 26 H 29 N3O3[M+H] + 432.2282, found 432.2286 Example 10 Preparation of 1-((9H-carbazol-4-yl)oxy)-3-(3-((2-methoxyphenyl)amino)azacyclobutan-1-yl)prop-2-ol (I-10):

[0036] I-10 According to general synthesis method B, intermediate I A Intermediate 10b was refluxed overnight in isopropanol, and purified by column chromatography to give final product I-10, a white solid. 1 H NMR (400 MHz, DMSO- d 6) δ 11.24 (s, 1H), 8.22 (d, J = 7.8Hz, 1H), 7.44 (dt, J = 8.1, 1.0 Hz, 1H), 7.37 – 7.30 (m, 1H), 7.28 (d, J = 8.0Hz, 1H), 7.13 (ddd, J = 8.0, 7.1, 1.1 Hz, 1H), 7.06 (d, J = 8.0 Hz, 1H), 6.80 (dd, J = 7.9, 1.4 Hz, 1H), 6.73 (td, J = 7.6, 1.4 Hz, 1H), 6.67 (d, J = 7.9 Hz, 1H), 6.57 (td, J = 7.7, 1.5 Hz, 1H), 6.39 (dd, J= 7.8, 1.6 Hz, 1H), 5.18 – 5.00(m, 2H), 4.16 (dd, J = 9.7, 4.6 Hz, 1H), 4.09 (dd, J = 9.7, 5.3 Hz, 1H), 3.99 (q, J = 7.5, 6.1 Hz, 2H), 3.76 (s, 3H), 3.03 (s, 2H), 2.84 (s, 1H), 2.71 (s, 1H). 13 C NMR (101 MHz, DMSO- d 6) δ 155.42, 147.00,141.57, 139.37, 137.13, 126.97,124.99, 123.00, 122.21,121.51, 119.04, 116.80, 112.04,110.82, 110.37, 110.05,104.31, 100.89, 70.80, 68.25, 63.04, 62.95, 62.55, 55.71, 44.46.HRMS (ESI) m / z calcd C 25 H 27 N3O3[M+H] + 418.2125, found 418.2130 Example 11 Preparation of 1-((9H-carbazol-4-yl)oxy)-3-(6-(2-methoxyphenyl)-2,6-diazaspiro[3.4]oct-2-yl)prop-2-ol (I-11):

[0037] I-11 According to general synthesis method B, intermediate I A The intermediate 11b was refluxed overnight in isopropanol, and purified by column chromatography to give the final product I-11, a white solid. 1 H NMR (400 MHz, DMSO- d 6) δ 11.24 (s, 1H), 8.22 (d, J = 7.7Hz, 1H), 7.46 – 7.41 (m, 1H), 7.35 – 7.29 (m, 1H), 7.27 (d, J = 8.0 Hz, 1H),7.16 – 7.10 (m, 1H), 7.06 (d,J = 8.0 Hz, 1H), 6.87 (dd, J = 7.8, 1.6 Hz, 1H), 6.78 (dd, J = 7.5, 1.7 Hz, 1H), 6.73 (dd, J = 7.6, 1.7 Hz, 1H), 6.68 (d, J = 8.0Hz, 1H), 6.62 (dd, J = 7.8, 1.8 Hz, 1H), 4.54 (s, 1H), 4.14 (td, J = 11.3, 10.5,4.9 Hz, 2H), 3.72 (s, 3H), 3.20 (t, J = 6.8 Hz, 2H), 2.67 (s, 1H), 2.47 (s, 3H), 2.11 (s, 3H), 2.04 (s, 1H). 13 C NMR (101 MHz, DMSO- d 6) δ 155.45, 146.77,141.56, 139.38, 137.27, 126.96, 125.00, 122.89, 122.21, 121.53, 118.96,115.80, 112.03,110.83, 110.30, 110.19, 104.28, 100.93, 70.97, 69.09, 55.79,53.63, 50.37, 48.86, 40.61,39.36,28.75, 27.82.HRMS (ESI) m / z calcd C 28 H 31 N3O3[M+H] + 458.2438, found 458.2443 Example 12 Preparation of 1-((9H-carbazol-4-yl)oxy)-3-(5-(2-methoxyphenyl)hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-yl)prop-2-ol (I-12):

[0038] I-12 According to general synthesis method B, intermediate I A Intermediate 12b was refluxed overnight in isopropanol, and purified by column chromatography to give the final product I-12, a white solid. 1H NMR (400 MHz, DMSO- d 6) δ 11.24 (s, 1H), 8.23 (d, J = 7.7Hz, 1H), 7.44 (d, J = 8.0 Hz, 1H), 7.33 (t, J = 7.6 Hz, 1H), 7.25 (t, J = 8.0 Hz,1H), 7.13 (t, J = 7.5 Hz, 1H), 7.05 (d, J = 8.0 Hz, 1H), 6.88 (td, J = 7.5, 2.3 Hz,1H), 6.83 (dt, J = 6.3, 2.5 Hz, 2H), 6.71 (dd, J = 7.0, 2.5 Hz, 1H), 6.66 (d, J =7.9 Hz, 1H), 5.07 (s, 1H), 4.24 – 4.17 (m, 1H), 4.13 (d, J = 7.6 Hz, 2H), 3.75(s, 3H), 3.17 (d, J = 7.8 Hz, 2H), 2.98 (s, 2H), 2.91 – 2.78 (m, 2H), 2.74 (s,2H), 2.42 (s, 1H), 2.28 – 2.18 (m, 1H). 13 C NMR (101 MHz, DMSO- d 6) δ 155.45,146.77, 141.56, 139.38, 137.27, 126.97, 125.00, 122.90, 122.21, 121.53,118.96, 115.80, 112.04,110.84, 110.30, 110.20, 104.28, 100.93, 70.98, 69.11,55.79, 53.64, 50.38, 48.87, 29.84,28.76, 28.70, 27.83.HRMS (ESI) m / z calcdC 28 H 31 N3O3[M+H] + 458.2438, found 458.2443 Example 13 Preparation of 1-((9H-carbazol-4-yl)oxy)-3-(4-(((2-methoxyphenyl)amino)methyl)piperidin-1-yl)prop-2-ol (13):

[0039] I-13 According to general synthesis method B, intermediate I A Intermediate 13b was refluxed overnight in isopropanol, and purified by column chromatography to give the final product I-13, a white solid. 1 H NMR (400 MHz, DMSO- d 6) δ 11.25 (s, 1H), 8.23 ​​(d, J = 7.7Hz, 1H), 7.44 (d, J = 8.1 Hz, 1H), 7.37 – 7.24 (m, 2H), 7.13 (t, J = 7.4 Hz, 1H), 7.06 (d, J = 8.1 Hz, 1H), 6.83 – 6.72 (m, 2H), 6.68 (d, J = 7.9 Hz, 1H), 6.58 –6.45 (m, 2H), 4.94 (s, 1H), 4.76 (t, J = 6.0 Hz, 1H), 4.23 – 4.04 (m, 3H), 3.76(s, 3H), 2.94 (t, J = 6.4 Hz, 3H), 2.61 (s, 1H), 2.01 (s, 2H), 1.68 (d, J = 12.5Hz, 2H), 1.57 (s, 1H), 1.21 (d, J = 12.4 Hz, 2H). 13 C NMR (101 MHz, DMSO- d6) δ155.52, 146.70,141.58, 139.39, 138.69, 126.96, 124.99, 123.01,122.24, 121.55,119.01, 115.66, 112.08,110.81, 110.17, 109.48, 104.27, 100.92, 71.34, 67.26,62.11, 55.75, 54.53, 54.46, 49.04, 40.63,35.30, 30.57.HRMS (ESI) m / z calcdC 28 H 33 N3O3[M+H] + 460.2595, found 460.2601 Example 14 Preparation of 1-((9H-carbazol-4-yl)oxy)-3-(3-(((2-methoxyphenyl)amino)methyl)pyrrolidine-1-yl)prop-2-ol (I-14):

[0040] I-14 According to general synthesis method B, intermediate I A Intermediate 14b was refluxed overnight in isopropanol, and purified by column chromatography to give the final product I-14, a white solid. 1 H NMR (400 MHz, DMSO- d 6) δ 11.25 (s, 1H), 8.24 (d, J = 7.8Hz, 1H), 7.44 (d, J = 8.0 Hz, 1H), 7.36 – 7.30 (m, 1H), 7.27 (td, J = 8.0, 2.9Hz, 1H), 7.12 (t, J = 7.5 Hz, 1H), 7.06 (d, J = 8.1 Hz, 1H), 6.80 – 6.71 (m, 2H), 6.68 (d, J = 7.9 Hz, 1H), 6.51 (td, J = 7.8, 7.0, 3.3 Hz, 2H), 5.09 (s, 1H), 4.94(d, J = 5.9 Hz, 1H), 4.27 – 4.08 (m, 3H), 3.74 (s, 3H), 3.02 (q,J = 5.7 Hz, 2H), 2.85 (s, 1H), 1.93 (s, 1H), 1.51 (d, J = 10.8 Hz, 1H). 13 C NMR (101 MHz, DMSO- d 6)δ 155.46, 146.69,141.59, 139.39, 138.67, 126.94, 124.99, 123.03, 122.22,121.55, 119.02, 115.83, 112.09,110.81, 110.12, 109.37, 104.31, 100.94, 71.14,59.45, 59.15, 55.71, 54.80, 54.71, 48.18, 36.68, 28.57. HRMS (ESI) m / z calcdC 27 H 31 N3O3[M+H] + 446.2438, found 446.2446 Example 15 Preparation of 1-((9H-carbazol-4-yl)oxy)-3-(3-(((2-methoxyphenyl)amino)methyl)azacyclobutane-1-yl)prop-2-ol (I-15):

[0041] I-15 According to general synthesis method B, intermediate I A Intermediate 15b was refluxed overnight in isopropanol, and purified by column chromatography to give the final product I-15, a white solid. 1 H NMR (400 MHz, DMSO- d 6) δ 11.27 (s, 1H), 8.22 (d, J = 7.8Hz, 1H), 7.45 (d, J = 8.1 Hz, 1H), 7.37 – 7.30 (m, 1H), 7.28 (d, J = 8.0 Hz, 1H), 7.14 (t, J = 7.5 Hz, 1H), 7.08 (d, J = 8.1 Hz, 1H), 6.85 – 6.73 (m, 2H), 6.69 (d, J = 7.9 Hz, 1H), 6.54 (t,J = 7.0 Hz, 2H), 5.48 (s, 1H), 5.08 (s, 1H), 4.14 (d, J = 5.0 Hz, 3H), 3.75 (s, 3H), 3.51 (s, 1H), 3.08 (d, J = 46.9 Hz, 2H), 2.88 (s, 1H). 13 C NMR (151 MHz, DMSO- d 6) δ 154.98, 146.54, 141.11, 138.92, 137.14,126.50, 124.53, 122.44, 121.74, 121.02, 118.54, 115.78, 111.56, 110.37,109.55, 103.84, 100.43, 70.35, 68.35, 55.19, 50.05, 49.87, 47.23, 44.72,41.27,36.00. HRMS (ESI) m / z calcd C 26 H 29 N3O3[M+H] + 432.2282, found 432.2288 Example 16 Preparation of 1-((9H-carbazole-4-yl)oxy)-3-((3-((2-methoxyphenyl)amino)cyclobutyl)amino)2-propanol (16):

[0042] I-16 According to general synthesis method B, intermediate I A Intermediate 16b was refluxed overnight in isopropanol, and purified by column chromatography to give the final product I-16, a white solid. 1 H NMR (400 MHz, DMSO- d 6) δ 11.23 (s, 1H), 8.21 (dd, J =7.9, 3.7 Hz, 1H), 7.44 (d, J = 8.1 Hz, 1H), 7.37 – 7.25 (m, 2H), 7.12 (t, J = 7.5Hz, 1H), 7.06 (d, J = 8.1 Hz, 1H), 6.78 (d, J= 8.0 Hz, 1H), 6.70 (dt, J = 13.4, 6.8 Hz, 2H), 6.54 (t, J = 7.7 Hz, 1H), 6.26 (d, J = 7.7 Hz, 1H), 5.10 (d, J = 5.1Hz, 1H), 4.84 (d, J = 5.9 Hz, 1H), 4.16 (h, J = 4.5 Hz, 2H), 4.06 (tq, J = 14.5,7.3, 6.1 Hz, 1H), 3.88 (q, J = 6.4 Hz, 1H), 3.75 (s, 3H), 3.39 (d, J = 12.5 Hz, 1H), 2.80 (td, J = 10.6, 9.1, 4.8 Hz, 1H), 2.68 (td, J = 14.7, 13.3, 7.1 Hz, 2H),2.07 (ddd, J = 23.9, 11.1, 5.0 Hz, 3H), 1.58 (q, J = 9.3, 8.7 Hz, 1H). 13 C NMR (151MHz, DMSO- d 6) δ 154.97,146.52, 141.09, 138.91, 137.14, 126.49, 124.51,122.43, 121.73, 121.00, 118.52, 115.75, 111.55, 110.36, 109.65, 109.53,103.81, 100.42, 70.36, 68.41, 55.21, 55.18, 50.10, 49.87, 44.74, 36.07.HRMS(ESI) m / z calcd C 26 H 29 N3O3[M+H] + 432.2282, found 432.2288 Example 17 Preparation of 1-((9H-carbazol-4-yl)oxy)-3-((3-((2-methoxyphenyl)amino)cyclopentyl)amino)prop-2-ol (I-17):

[0043] I-17 According to general synthesis method B, intermediate I A Intermediate 17b was refluxed overnight in isopropanol, and purified by column chromatography to give the final product I-17, a white solid. 1 H NMR (400 MHz, DMSO- d 6) δ 11.24 (d, J = 2.7 Hz, 1H), 8.22(dd, J = 7.8, 3.4 Hz, 1H), 7.44 (dd, J = 8.2, 2.8 Hz, 1H), 7.30 (dtd, J = 15.9,7.6, 3.5 Hz, 2H), 7.17 – 7.01 (m, 2H), 6.76 (tdd, J = 7.3, 6.0, 1.5 Hz, 2H),6.69 (dd, J = 7.8, 6.3 Hz, 1H), 6.56 – 6.46 (m, 2H), 5.19 – 4.90 (m, 1H), 4.49(d, J = 6.9 Hz, 1H), 4.18 (ddd, J = 11.1, 5.4, 2.6 Hz, 2H), 4.14 – 4.05 (m, 1H), 3.83 (dd, J = 13.7, 7.1 Hz, 1H), 3.77 – 3.66 (m, 3H), 3.21 (dt, J = 28.4, 6.0 Hz, 1H), 2.89 (dd, J = 11.7, 4.6 Hz, 1H), 2.75 (ddd, J = 11.7, 6.9, 2.5 Hz, 1H), 2.54(s, 1H), 2.26 – 2.04 (m, 1H), 1.86 (dtd, J = 25.4, 19.1, 10.1 Hz, 2H), 1.68(dq, J= 12.7, 6.3 Hz, 1H), 1.62 – 1.48 (m, 1H), 1.48 – 1.31 (m, 2H), 1.31 –1.16 (m, 1H). HRMS (ESI) m / z calcd C 27 H 31 N3O3[M+H] + 446.2438, found 446.2446 Example 18 Preparation of 1-((9H-carbazol-4-yl)oxy)-3-((6-(((2-methoxyphenyl)amino)spiro[3.3]hept-2-yl)amino)prop-2-ol (I-18):

[0044] I-18 According to general synthesis method B, intermediate I A Intermediate 18b was refluxed overnight in isopropanol, and purified by column chromatography to give the final product I-18, a white solid. 1 H NMR (400 MHz, DMSO- d 6) δ 11.25 (s, 1H), 8.21 (d, J = 7.8Hz, 1H), 7.45 (d, J = 8.1 Hz, 1H), 7.31 (dt, J = 20.9, 7.7 Hz, 2H), 7.14 (t, J =7.4 Hz, 1H), 7.07 (d, J = 8.1 Hz, 1H), 6.83 – 6.70 (m, 2H), 6.68 (d, J = 8.0 Hz, 1H), 6.53 (td, J = 7.7, 1.5 Hz, 1H), 6.39 (d, J = 7.8 Hz, 1H), 5.20 (s, 1H), 4.76(d, J = 6.8 Hz, 1H), 4.20 – 4.11 (m, 2H), 4.06 (dq, J = 14.7, 7.3, 6.5 Hz, 1H), 3.75 (s, 3H), 3.72 – 3.66 (m, 1H), 3.21 (q, J = 7.7 Hz, 1H), 2.82 (dd,J = 12.2, 4.6 Hz, 1H), 2.71 (dd, J = 12.0, 7.0 Hz, 1H), 2.45 (d, J = 8.3 Hz, 1H), 2.32 (td, J = 12.0, 6.4 Hz, 2H), 2.15 (dq, J = 8.5, 4.6 Hz, 1H), 1.82 (dtd, J = 25.7, 11.7,11.0, 7.9 Hz, 4H). 13 C NMR (151 MHz, DMSO- d 6) δ 154.91,146.38, 141.10, 138.92,136.98, 126.49, 124.55, 122.46, 121.72, 121.03, 118.53, 115.76, 111.55,110.38, HRMS (ESI) m / z calcd C 29 H 33 N3O3[M+H] + 472.2595, found 472.2601 Example 19 Preparation of 1-((9H-carbazol-4-yl)oxy)-3-((3-((2-methoxyphenyl)amino)cyclohexyl)amino)prop-2-ol (I-19):

[0045] I-19 According to general synthesis method B, intermediate I A Intermediate 19b was refluxed overnight in isopropanol, and purified by column chromatography to give the final product I-19, a white solid. 1 H NMR (400 MHz, DMSO- d 6) δ 11.23 (s, 1H), 8.21 (dt, J =7.8, 1.6 Hz, 1H), 7.44 (d, J= 8.0 Hz, 1H), 7.37 – 7.23 (m, 2H), 7.14 – 7.02(m, 2H), 6.78 (dt, J = 8.0, 1.4 Hz, 1H), 6.74 – 6.65 (m, 2H), 6.55 (d, J = 7.8Hz, 1H), 6.50 (tt, J = 7.7, 1.3 Hz, 1H), 5.13 (d, J = 15.1 Hz, 1H), 4.32 (d, J =8.4 Hz, 1H), 4.19 (ddd, J = 11.5, 8.7, 4.7 Hz, 2H), 4.12 (dd, J = 13.6, 4.5 Hz,1H), 3.75 (s, 3H), 3.73 – 3.64 (m, 1H), 2.91 (s, 2H), 2.75 (dd, J = 16.5, 8.6Hz, 1H), 1.76 (s, 2H), 1.70 – 1.52 (m, 3H), 1.45 (s, 2H), 1.39 – 1.28 (m,1H). 13 C NMR (101 MHz, DMSO- d 6) δ 155.43, 141.58, 139.39, 137.36, 126.95,124.99, 122.92, 121.55, 118.98, 115.77, 110.83, 110.31, 110.02, 109.98,104.32, 100.91, 71.00, 68.99, 68.81, 55.77, 52.83, 52.70, 50.41, 46.59,37.15, 31.87, 30.82, 19.81.HRMS (ESI) m / z calcd C 28 H 33 N3O3[M+H] + 460.2595, found460.2599 General synthetic route C for intermediates 20a-44a, 54a, and 55a

[0046] a Reagents and conditions: (a) t-BuONa, BrettPhos-Pd-G3, BrettPhos, 1,4-Dioxane, 80℃, 12h, 40%; (b) CF3COOH, DCM, 25℃, 1h, 95%; (c) t-BuONa, BINAP,Pd2(dba)3, tolunen, 120℃, overnight, 55%; (d) 1M NaOH, DMSO, 25℃, 12h, 30~70%; (e) i-PrOH, reflux, 8 h, 33~40%. Different hydroxyl groups (2 mmol) were dissolved in DMSO (2 mL) in a 25 mL round-bottom flask. A prepared NaOH aqueous solution (1 M, 45 mL) was added at 0 °C and stirred for 30 minutes. Then, epichlorohydrin (320 μL, 4 mmol) was added, and the mixture was allowed to react at room temperature for 8 hours. After the reaction was complete, saturated NH4Cl aqueous solution (10 mL) was added to neutralize the reaction, followed by extraction with ethyl acetate (15 mL). The organic phase was then washed with saturated NaCl aqueous solution (10 mL × 3). The organic phase was collected and dried over anhydrous Na2SO4. The solvent was removed by vacuum distillation, and the crude product was purified by silica gel column chromatography (SiO2, PE / EA) to obtain the corresponding intermediates 20a–44a, 54a, and 55a (yields 20%–80%).

[0047] General synthetic route D for final products I-20~44, I-54, and I-55 To a 25 mL round-bottom flask, intermediates 20a-44a (1 mmol) and 1b (1 mmol) were dissolved, and intermediates 54a, 55a (1 mmol) and 2b (1 mmol) were dissolved in 12 mL of anhydrous isopropanol. After the addition was complete, the mixture was refluxed at 85 °C for 10 h. After the reaction was complete, the mixture was cooled to room temperature, quenched with water, and extracted three times with 15 mL of ethyl acetate. The organic phase was collected, dried over anhydrous NaSO4, and the solvent was evaporated under reduced pressure. The crude product was purified by silica gel column chromatography (SiO2, DCM / MeOH) to obtain final products I-20~44, I-54, and I-55 (yields 20%~55%).

[0048] General synthetic route for intermediates 47a~55a E Using p-hydroxyaniline as a starting material, Pd2(dba)3 (0.05 eq.) as a catalyst, BINAP (0.1 eq.) as a ligand, and sodium tert-butoxide (3 equiv.) as a base, a substitution reaction was carried out with the brominated derivative to give 47a~55a. Under nitrogen protection, 6 mL of ultra-dry toluene was added as a solvent, and the mixture was stirred and refluxed overnight at 120 °C. After the reaction was completed by TLC monitoring, the palladium catalyst was removed by filtration, the organic phase was collected, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (SiO2, PE / EA) to obtain the corresponding intermediates in yields of 40-59%.

[0049] General synthetic route for intermediates 47b~55b F

[0050] a Reagents and conditions : (a) 1 M NaOH, DMSO, 25℃, 12h, 30~70%; (b)2b, i-PrOH, reflux, 8 h, 33~40%; (c)1b, i-PrOH, reflux, 8 h, 30~40%. The purified intermediate was dissolved in DMSO (2 mL), and a prepared NaOH aqueous solution (1 M, 45 mL) was added at 0 °C and stirred for 30 minutes. Then, epichlorohydrin (320 μL, 4 mmol) was added, and the mixture was allowed to react at room temperature for 8 hours. After the reaction was complete, saturated NH4Cl aqueous solution (10 mL) was added to neutralize the reaction, followed by extraction with ethyl acetate (15 mL). The organic phase was then washed with saturated saline solution (10 mL × 3). The organic phase was collected and dried over anhydrous sodium sulfate. The solvent was removed by vacuum distillation, and the crude product was purified by silica gel column chromatography (SiO2, PE / EA) to obtain the corresponding intermediates 45b~53b.

[0051] General synthetic route for final product I-45~53 G The corresponding intermediates 45b~53b (1 eq.) and intermediates 1b and 16b (1 eq.) were stirred and refluxed overnight at 80°C with isopropanol as solvent. The isopropanol was directly evaporated the next day, and the residue was purified by silica gel column chromatography (SiO2, DCM / MeOH) to obtain the final product 45~53, with a yield of 40-55%.

[0052] Preparation of 2-((naphthyl-1-yloxy)methyl)ethylene oxide (intermediate 20a): Following general route C, using 1-naphthol as a starting material, 20a was obtained as a white solid with a yield of 74%. 1 H NMR (400MHz, CDCl3) δ7.88 (d, J = 0.7 Hz, 1H), 7.76 (d, J = 0.8 Hz, 1H), 7.51 (d, J = 12.6Hz, 2H), 7.35 (d, J = 7.3 Hz, 2H), 6.98 (s, 1H), 4.24 (d, J = 12.5 Hz, 1H), 4.17(d, J = 12.5 Hz, 1H), 3.76 (s, 1H), 3.66 – 3.56 (m, 2H). Example 20 Preparation of 1-(((1r,4r)-4-((2-methoxyphenyl)amino)cyclohexyl)amino)-3-(naphth-1-yloxy)prop-2-ol (I-20):

[0053] I-20 Following general route D, the final product I-20 was obtained as a brown solid with a yield of 39%. 1 H NMR (400 MHz, DMSO- d 6) δ 8.29 – 8.18 (m, 1H), 7.92 – 7.82 (m, 1H), 7.59 – 7.34 (m, 4H), 6.96(dd, J = 7.5, 1.2 Hz, 1H), 6.76 (ddd, J = 15.9, 7.8, 1.4 Hz, 2H), 6.61 – 6.41 (m,2H), 5.21 (d, J = 27.7 Hz, 1H), 4.31 (d, J = 8.5 Hz, 1H), 4.22 – 3.97 (m, 3H), 3.75 (s, 3H), 3.18 (s, 1H), 2.88 (dd, J = 11.9, 4.4 Hz, 1H), 2.76 (dd, J = 11.8,6.7 Hz, 1H), 2.10 – 1.61 (m, 4H), 1.19 (t, J = 9.4 Hz, 4H). 13 C NMR (101 MHz, DMSO- d6) δ 154.62,146.69,137.42,134.50, 127.87,126.90, 126.72,125.63, 125.48,122.24, 121.53, 120.34,115.74, 110.32, 110.11, 105.64, 71.35, 68.68, 56.64,55.70, 51.06, 50.00, 40.20, 31.86, 31.78, 31.59.HRMS (ESI) m / z calcd C 26 H 32 N₂O₃[M+H] + 421.2486, found 421.2492 Example 21 Preparation of 1-((9H-carbazol-2-yl)oxy)-3-(((1r,4r)-4-((2-methoxyphenyl)amino)cyclohexyl)amino)prop-2-ol (I-21):

[0054] I-21 Following general route D, the final product I-21 was obtained, a white solid, with a yield of 44%. 1 H NMR (400 MHz, DMSO- d 6) δ 11.09 (s, 1H), 7.97 (dd, J = 9.7, 8.0 Hz, 2H), 7.42 (d, J = 8.0 Hz, 1H), 7.28(ddd, J = 8.2, 7.1, 1.2 Hz, 1H), 7.14 – 7.06 (m, 1H), 6.97 (d, J = 2.3 Hz, 1H), 6.83 – 6.69 (m, 3H), 6.61 – 6.45 (m, 2H), 5.13 (d, J = 10.3 Hz, 1H), 4.32 (d, J =8.5 Hz, 1H), 4.04 (p, J = 3.9 Hz, 1H), 3.96 (dq, J = 10.1, 5.4 Hz, 2H), 3.75 (s,3H), 3.26 – 3.10 (m, 1H), 2.83 (dd, J= 11.7, 4.0 Hz, 1H), 2.70 (dd, J = 11.9,6.8 Hz, 1H), 2.09 – 1.85 (m, 4H), 1.21 (t, J = 9.8 Hz, 4H). 13 C NMR (101 MHz, DMSO- d 6) δ 155.52, 146.69, 141.61,141.58, 139.38, 138.72,126.97, 125.00,123.01, 122.23, 121.55, 119.02, 115.67, 112.11,110.82, 110.16, 109.47,104.27, 100.92, 71.34, 67.30, 62.15, 55.74, 54.54, 54.49, 49.06, 35.33,30.61.HRMS (ESI) m / z calcd C 28 H 33 N3O3[M+H] + 460.2595, found 460.2596 Example 22 Preparation of 1-(((1r,4r)-4-((2-methoxyphenyl)amino)cyclohexyl)amino)-3-(naphth-2-yloxy)prop-2-ol (I-22):

[0055] I-22 Following general route D, the final product I-22 was obtained, a white solid, in 39% yield. 1 H NMR (400 MHz, DMSO- d 6) δ 7.90 – 7.75 (m, 3H), 7.46 (ddd, J = 8.2, 6.8, 1.3 Hz, 1H), 7.40 – 7.31(m, 2H), 7.19 (dd, J = 8.9, 2.5 Hz, 1H), 6.77 (ddd, J = 15.7, 7.8, 1.4 Hz, 2H),6.58 (dd, J = 8.0, 1.5 Hz, 1H), 6.53 (td, J = 7.6, 1.5 Hz, 1H), 4.38 (d, J= 8.5Hz, 1H), 4.15 (d, J = 16.0 Hz, 1H), 4.13 – 4.05 (m, 2H), 3.76 (s, 3H), 3.25 –3.14 (m, 1H), 3.08 (d, J = 11.8 Hz, 1H), 2.93 (dd, J = 12.3, 8.6 Hz, 1H), 2.86(s, 1H), 2.03 (d, J = 14.3 Hz, 4H), 1.42 (dq, J = 22.6, 11.2 Hz, 2H), 1.33 – 1.14(m, 4H). 13 C NMR (101 MHz, DMSO- d 6) δ 155.47, 147.04, 141.57, 139.37, 137.68,126.96, 125.00, 123.00, 122.21, 121.51, 119.02, 116.35, 110.82, 110.54,110.20, 104.30, 100.90, 71.13, 68.25, 61.54, 59.40, 55.69, 53.88, 53.84,51.92, 32.29. HRMS (ESI) m / z calcd C 26 H 32 N₂O₃[M+H] + 421.2486, found 421.2492 Example 23 Preparation of 1-(((1r,4r)-4-((2-methoxyphenyl)amino)cyclohexyl)amino)-3-(3-(phenylamino)phenoxy)prop-2-ol (I-23):

[0056] I-23 Following general route D, the final product I-23 was obtained, a white solid, in 38% yield. 1 H NMR (400 MHz, DMSO- d6) δ 8.20 (s, 1H), 7.28 – 7.20 (m, 2H), 7.17 – 7.04 (m, 3H), 6.88 – 6.72 (m,3H), 6.69 – 6.61 (m, 2H), 6.61 – 6.49 (m, 2H), 6.45 – 6.38 (m, 1H), 4.39 (d, J = 8.5 Hz, 1H), 4.13 (s, 1H), 3.92 (d, J = 5.3 Hz, 2H), 3.75 (s, 3H), 3.18 (t, J =6.3 Hz, 1H), 3.08 (dd, J = 12.7, 3.2 Hz, 1H), 2.92 (dd, J = 20.2, 7.8 Hz, 2H), 2.05 (t, J = 13.2 Hz, 4H), 1.47 (t, J = 13.3 Hz, 2H), 1.23 (td, J = 11.4, 10.9, 5.2Hz, 3H). HRMS (ESI) m / z calcd C 28 H 35 N3O3[M+H] + 462.2751, found 462.2758 Example 24 Preparation of 1-((9H-carbazol-3-yl)oxy)-3-(((1r,4r)-4-((2-methoxyphenyl)amino)cyclohexyl)amino)prop-2-ol (I-24):

[0057] I-24 Following general route D, the final product I-24 was obtained as a gray solid with a yield of 33%. 1 H NMR (400 MHz, DMSO- d 6) δ 11.06 (s, 1H), 8.08 (d, J = 7.8 Hz, 1H), 7.70 (d, J = 2.5 Hz, 1H), 7.47 –7.30 (m, 3H), 7.11 (ddd, J = 7.9, 7.0, 1.1 Hz, 1H), 7.05 (dd,J = 8.8, 2.5 Hz, 1H), 6.77 (ddd, J = 15.2, 7.8, 1.4 Hz, 2H), 6.61 – 6.48 (m, 2H), 4.36 (d, J = 8.6Hz, 1H), 4.15 – 3.97 (m, 3H), 3.75 (s, 3H), 3.19 (dd, J = 12.6, 4.2 Hz, 2H), 3.01 (dd, J = 12.2, 3.4 Hz, 1H), 2.85 (dd, J = 12.2, 7.7 Hz, 1H), 2.74 (s, 1H), 2.11 – 1.91 (m, 4H), 1.47 – 1.29 (m, 2H), 1.28 – 1.12 (m, 3H). 13 C NMR (101MHz, DMSO- d 6) δ 152.66, 146.71, 140.86, 137.38, 135.10, 125.85, 123.22, 122.89,121.54, 120.72, 118.45, 117.46,115.81, 115.76, 112.03,111.45,110.35,110.14,104.58,71.84,68.05,56.64,55.71,50.86,49.52,31.41,30.89,30.72. 28 H 33 N3O3[M+H] + 460.2595, found 460.2599 Example 25 Preparation of 1-(((1r,4r)-4-((2-methoxyphenyl)amino)cyclohexyl)amino)-3-(4-benzophenonephenyl-1-yloxy)prop-2-ol (25):

[0058] I-25 Following general route D, the final product I-25 was obtained as a white solid with a yield of 45%. 1 H NMR (400 MHz, DMSO- d 6) δ7.80 – 7.71 (m, 2H), 7.72 – 7.60 (m, 3H), 7.55 (dd, J = 8.1, 6.9 Hz, 2H),7.16 – 7.05 (m, 2H), 6.77 (ddd, J = 16.1, 7.8, 1.4 Hz, 2H), 6.61 – 6.48 (m,2H), 4.36 (d, J = 8.4 Hz, 1H), 4.08 (dq, J = 11.5, 6.8 Hz, 3H), 3.75 (s, 3H), 3.25 – 3.12 (m, 2H), 3.04 – 2.95 (m, 1H), 2.86 (t, J = 11.5 Hz, 1H), 2.75 (d, J =14.8 Hz, 1H), 2.08 – 1.96 (m, 3H), 1.49 – 1.29 (m, 2H), 1.28 – 1.12 (m, 3H). 13 C NMR (101 MHz, DMSO- d 6) δ 194.90, 168.67, 163.00, 162.92, 146.70,138.27,137.40,132.67, 132.57, 129.80, 129.71, 128.93, 126.39,121.53, 115.77, HRMS (ESI) m / z calcd C 29 H 34 N₂O₄[M+H] + 475.2591, found 475.2599 Example 26 Preparation of 1-((1H-indol-4-yl)oxy)-3-(((1r,4r)-4-((2-methoxyphenyl)amino)cyclohexyl)amino)prop-2-ol (26):

[0059] I-26 Following the general route D, the final product I-26 was obtained as a brown solid with a yield of 49%. 1 H NMR (400 MHz, DMSO- d 6) δ 11.11 (s, 1H), 7.22 (t, J = 2.8 Hz, 1H), 7.07 – 6.93 (m, 2H), 6.77 (ddd, J =15.6, 7.8, 1.3 Hz, 2H), 6.58 (dd, J = 8.0, 1.5 Hz, 1H), 6.55 – 6.43 (m, 2H), 4.39 (d, J = 8.7 Hz, 1H), 4.24 – 4.13 (m, 1H), 4.12 – 4.01 (m, 2H), 3.75 (s,3H), 3.25 – 3.06 (m, 2H), 2.94 (dd, J = 25.4, 14.0 Hz, 2H), 2.02 (d, J = 13.8 Hz,4H), 1.53 – 1.32 (m, 2H), 1.24 (q, J = 9.0, 7.9 Hz, 3H), 1.03 (d, J = 6.1 Hz, 1H). 13 C NMR (101 MHz, DMSO- d 6) δ 146.73, 137.83, 137.40, 123.99, 122.21, 115.82,110.36, 110.16,105.40, 100.43, 98.89, 70.79, 67.99, 56.58, 55.73, 50.88,49.55, 40.23, 40.18, 39.98, 39.77, 39.56, 31.42, 30.96.HRMS (ESI) m / z calcdC 24 H 31 N3O3[M+H] + 410.2438, found 410.2446 Example 27 Preparation of 1-(4-cyclohexylphenoxy)-3-(((1r,4r)-4-((2-methoxyphenyl)amino)cyclohexyl)amino)prop-2-ol (27):

[0060] I-27 Following general route D, the final product I-27 was obtained as a white solid with a yield of 38%. 1 H NMR (400 MHz, DMSO- d 6) δ 7.10 (d, J = 8.4 Hz, 2H), 6.97 – 6.67 (m, 4H), 6.65 – 6.40 (m, 2H), 4.30(d, J = 8.7 Hz, 1H), 4.02 – 3.80 (m, 3H), 3.75 (s, 3H), 3.17 (d, J = 10.2 Hz, 2H), 2.73 (dd, J = 11.9, 3.9 Hz, 1H), 2.60 (dd, J = 11.9, 6.0 Hz, 1H), 2.42 (d, J =9.6 Hz, 2H), 2.09 – 1.83 (m, 4H), 1.72 (dt, J = 25.5, 10.4 Hz, 5H), 1.35 (q, J =11.1, 9.8 Hz, 4H), 1.25 – 0.98 (m, 6H). HRMS (ESI) m / z calcd C 28 H 40 N₂O₃[M+H] + 453.3112, found 453.3112 Example 28 Preparation of 1-((1H-indol-5-yl)oxy)-3-(((1r,4r)-4-((2-methoxyphenyl)amino)cyclohexyl)amino)prop-2-ol (I-28):

[0061] I-28 Following general route D, the final product I-28 was obtained as a white solid with a yield of 41%. 1 H NMR (400 MHz, DMSO- d 6) δ 10.95 (s, 1H), 7.37 – 7.20 (m, 2H), 7.07 (d, J= 2.5 Hz, 1H), 6.86 – 6.69(m, 3H), 6.64 – 6.47 (m, 2H), 6.33 (t, J = 2.4 Hz, 1H), 4.40 (d, J = 8.5 Hz, 1H), 4.14 (d, J = 6.6 Hz, 1H), 3.96 (p, J = 4.5 Hz, 2H), 3.75 (s, 3H), 3.16 (dd, J =12.7, 3.2 Hz, 2H), 3.00 (dd, J = 8.6, 4.0 Hz, 2H), 2.16 – 1.92 (m, 4H), 1.58 –1.39 (m, 2H), 1.24 (q, J = 3.6 Hz, 4H). 13 C NMR (101 MHz, DMSO- d 6) δ 152.89,146.72,137.36, 131.60, 128.45, 126.29, 121.54, 115.82, 112.41, 112.08,111.18,110.35, 110.14, 103.37, 101.27, 71.56, 67.85, 62.47,56.59, 55.71,50.81, 49.37, 31.36,30.47.HRMS (ESI) m / z calcd C 24 H 31 N3O3[M+H] + 410.2438, found 410.2445 Example 29 Preparation of 1-(((1r,4r)-4-((2-methoxyphenyl)amino)cyclohexyl)amino)-3-(4-phenoxyphenoxy)prop-2-ol (I-29):

[0062] I-29 Following general route D, the final product I-29 was obtained, a white solid, in 40% yield. 1 H NMR (400 MHz, DMSO- d 6) δ 8.14 (d, J = 7.6 Hz, 1H), 7.74 (d, J= 2.6 Hz, 1H), 7.66 (d, J = 8.2 Hz, 1H), 7.60 (d, J = 8.9 Hz, 1H), 7.50 (td, J = 7.7, 7.1, 1.3 Hz, 1H), 7.38 (t, J = 7.5 Hz, 1H), 7.12 (dd, J = 8.9, 2.6 Hz, 1H), 6.82 – 6.72 (m, 2H), 6.59 – 6.47 (m, 2H), 4.33 (d, J = 8.5 Hz, 1H), 4.14 – 3.97 (m, 3H), 3.75 (s, 3H), 3.22 – 3.14 (m,1H), 2.90 (dd, J = 11.7, 3.7 Hz, 1H), 2.76 (dd, J = 11.9, 7.2 Hz, 1H), 2.59 (dt, J = 11.3, 6.7 Hz, 1H), 1.98 (td, J = 10.2, 9.6, 4.8 Hz, 4H), 1.40 – 1.05 (m, 5H). 13 C NMR (101 MHz, DMSO- d 6) δ 156.62, 155.47, 150.53, 146.72, 137.37, 128.00,124.62, 124.37, 123.27, 121.70, 121.53, 116.45, 115.81, 112.64, 112.15,110.35, 110.13, 105.68, 71.81, 67.96, 56.64, 55.71, 50.86, 49.38, 31.42,31.39,30.92,30.72. HRMS (ESI) m / z cald C 28 H 32 N₂O₄[M+H] + 461.2435, found 461.2438 Example 30 Preparation of 5-(2-hydroxy-3-(((1r,4r)-4-((2-methoxyphenyl)amino)cyclohexyl)amino)propoxy)-3,4-dihydroquinoline-2(1H)-one (I-30):

[0063] I-30 Following general route D, final product 30 was obtained, a white solid, with a yield of 47%. 1 H NMR (400 MHz, DMSO- d 6)δ 10.03 (s, 1H), 7.07 (t, J = 8.1 Hz, 1H), 6.76 (ddd, J = 15.4, 7.8, 1.4 Hz, 2H), 6.66 – 6.41 (m, 4H), 4.33 (d, J = 8.5 Hz, 1H), 3.95 (qd, J = 9.7, 9.0, 4.1 Hz,3H), 3.75 (s, 3H), 3.18 (d, J = 8.0 Hz, 2H), 2.95 – 2.79 (m, 3H), 2.79 – 2.70(m, 1H), 2.61 (s, 1H), 2.41 (t, J = 7.7 Hz, 2H), 1.98 (t, J = 11.1 Hz, 4H), 1.33– 1.12 (m, 4H). HRMS (ESI) m / z calcd C 25 H 33 N3O4[M+H] + 440.2544, found 440.2543 Example 31 Preparation of 6-(2-hydroxy-3-(((1r,4r)-4-((2-methoxyphenyl)amino)cyclohexyl)amino)propoxy)-3,4-dihydroquinoline-2(1H)-one (I-31):

[0064] I-31 Following general route D, the final product I-31 was obtained, a white solid, in 50% yield. 1 H NMR (400 MHz, DMSO- d 6) δ 9.90 (s, 1H), 6.83 – 6.64 (m, 5H), 6.61 – 6.45 (m, 2H), 5.09 (d, J = 32.3Hz, 1H), 4.32 (d,J = 8.5 Hz, 1H), 3.92 – 3.78 (m, 3H), 3.74 (s, 3H), 3.17 (s,1H), 2.82 (t, J = 7.5 Hz, 3H), 2.64 (s, 1H), 2.38 (dd, J = 8.5, 6.5 Hz, 2H), 2.04– 1.85 (m, 4H), 1.29 – 1.13 (m, 4H). HRMS (ESI) m / z calcd C 25 H 33 N3O4[M+H] + 440.2544, found 440.2543 Example 32 Preparation of 1-(((1r,4r)-4-((2-methoxyphenyl)amino)cyclohexyl)amino)-3-((2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinoline-8-yl)oxy)prop-2-ol (I-32):

[0065] I-32 Following general route D, the final product I-32 was obtained as a red solid with a yield of 30%. 1 H NMR (400 MHz, DMSO- d 6) δ 6.75 (dt, J = 11.0, 5.8 Hz, 2H), 6.62 (t, J = 5.8 Hz, 1H), 6.59 – 6.46 (m,2H), 6.10 (dd, J = 8.2, 3.6 Hz, 1H), 4.32 (d, J = 8.4 Hz, 1H), 3.91 – 3.77 (m,3H), 3.77 – 3.69 (m, 3H), 3.17 (s, 1H), 3.09 – 2.95 (m, 4H), 2.80 (d, J = 11.9Hz, 1H), 2.59 (dd, J = 15.8, 9.8 Hz, 5H), 2.08 – 1.88 (m, 4H), 1.83 (q, J = 6.0Hz, 4H), 1.20 (q, J= 12.2, 9.8 Hz, 5H). HRMS (ESI) m / z calcd C 28 H 39 N3O3[M+H] + 466.3064, found 466.3072 Example 33 Preparation of 1-(((1r,4r)-4-((2-methoxyphenyl)amino)cyclohexyl)amino)-3-phenoxyprop-2-ol (I-33):

[0066] I-33 Following general route D, the final product I-33 was obtained, a white solid, in 45% yield. 1 H NMR (400 MHz, DMSO- d 6) δ 7.37 – 7.23 (m, 2H), 7.05 – 6.87 (m, 3H), 6.77 (ddd, J = 15.7, 7.8, 1.4Hz, 2H), 6.64 – 6.45 (m, 2H), 4.36 (d, J = 8.5 Hz, 1H), 4.06 (tq, J = 7.0, 3.9,3.0 Hz, 1H), 4.01 – 3.87 (m, 2H), 3.75 (s, 3H), 3.19 (qd, J = 10.8, 9.0, 5.6Hz, 1H), 2.99 (dd, J = 12.3, 3.7 Hz, 1H), 2.92 – 2.72 (m, 2H), 2.13 – 1.88 (m,4H), 1.46 – 1.29 (m, 2H), 1.29 – 1.08 (m, 3H). HRMS (ESI) m / z calcd C 22 H 30 N₂O₃[M+H] + 371.2329, found 371.2336 Example 34 Preparation of 1-(4-benzylphenoxy)-3-(((1r,4r)-4-((2-methoxyphenyl)amino)cyclohexyl)amino)prop-2-ol (I-34):

[0067] I-34 Following general route D, the final product I-34 was obtained as a white solid with a yield of 41%. 1 H NMR (400 MHz, DMSO- d 6) δ 7.27 (t, J = 7.4 Hz, 2H), 7.22 – 7.07 (m, 5H), 6.90 – 6.81 (m, 2H), 6.76(ddd, J = 16.2, 7.8, 1.4 Hz, 2H), 6.63 – 6.42 (m, 2H), 4.30 (d, J = 8.6 Hz, 1H), 3.85 (d, J = 5.4 Hz, 5H), 3.75 (s, 3H), 3.17 (s, 1H), 2.75 (dd, J = 12.2, 4.0 Hz, 1H), 2.62 (dd, J = 11.6, 6.1 Hz, 1H), 2.04 – 1.79 (m, 4H), 1.19 (q, J = 11.6, 9.0Hz, 4H). HRMS (ESI) m / z calcd C 29 H 36 N₂O₃[M+H] + 461.2799, found 460.2806 Example 35 Preparation of 4-(ethylene oxide-2-ylmethoxy)-N-phenylaniline (intermediate 35a): Following general route C, using p-hydroxydiphenylamine as a starting material, 35a, a gray solid, was obtained in 78% yield. 1 H NMR (400 MHz, Chloroform- d ) δ 7.81 (s, 1H), 7.26 – 7.12 (m, 4H), 7.09 – 6.95 (m,2H), 6.92 – 6.83 (m, 3H), 4.18 (s, 2H), 4.02 (s, 1H), 3.69 (d, J = 5.0 Hz, 1H), 3.63 (d, J = 5.0 Hz, 1H). Preparation of 1-(((1r,4r)-4-((2-methoxyphenyl)amino)cyclohexyl)amino)-3-(4-(phenylamino)phenoxy)prop-2-ol (I-35):

[0068] I-35 Following general route D, the final product I-35 was obtained as a white solid with a yield of 49%. 1 H NMR (400 MHz, DMSO- d 6) δ 7.84 (s, 1H), 7.19 – 7.12 (m, 2H), 7.06 – 7.00 (m, 2H), 6.89 (ddd, J =14.6, 7.7, 1.8 Hz, 4H), 6.82 – 6.74 (m, 2H), 6.74 – 6.67 (m, 1H), 6.60 – 6.48(m, 2H), 4.34 (d, J = 8.5 Hz, 1H), 3.90 (td, J = 9.3, 4.1 Hz, 3H), 3.75 (s, 3H), 3.19 (d, J = 9.8 Hz, 1H), 2.88 (d, J = 11.9 Hz, 1H), 2.78 – 2.70 (m, 1H), 2.62(s, 1H), 1.99 (d, J = 12.7 Hz, 4H), 1.38 – 1.10 (m, 6H). 13 C NMR (151 MHz, DMSO- d 6) δ 153.03, 146.25, 145.06, 136.90, 136.29, 129.10, 121.07, 121.07, 120.22,118.30, 115.34, 115.29, 114.86, 114.86, 109.87, 109.67, 70.78, 56.13, 55.23,50.36, 40.06, 30.90.HRMS (ESI) m / z calcd C 28 H 35 N3O3[M+H] + 462.2751, found 462.2756 Example 36 Preparation of 2-(([1,1'-biphenyl]-4-yloxy)methyl)ethylene oxide (intermediate 36a): Following general route C, using p-hydroxybiphenyl as a starting material, 36a was obtained as a white solid with a yield of 88%. 1 H NMR (400 MHz, Chloroform- d ) δ 7.63 – 7.45 (m, 4H), 7.45 – 7.36 (m, 2H), 7.35 –7.26 (m, 1H), 7.09 – 6.86 (m, 2H), 4.46 (d, J = 12.5 Hz, 1H), 4.06 – 3.87 (m,2H), 3.77 – 3.57 (m, 2H). Preparation of 1-([1,1'-biphenyl]-4-yloxy)-3-(((1r,4r)-4-((2-methoxyphenyl)amino)cyclohexyl)amino)prop-2-ol (I-36):

[0069] I-36 Following general route D, the final product I-36 was obtained as a white solid with a yield of 48%. 1 H NMR (400 MHz, Acetone- d 6) δ 7.59 (td, J = 7.5, 7.1, 1.8 Hz, 4H), 7.42 (dd, J = 8.4, 7.0 Hz,2H), 7.34 – 7.25 (m, 1H), 7.09 – 7.00 (m, 2H), 6.82 – 6.72 (m, 2H), 6.60 (dd, J = 7.9, 1.6 Hz, 1H), 6.54 (td, J = 7.7, 1.5 Hz, 1H), 4.37 (s, 1H), 4.16 – 4.01(m, 3H), 3.81 (s, 3H), 3.49 (s, 1H), 2.96 (d, J = 3.6 Hz, 1H), 1.78 (d, J = 2.8Hz, 2H), 1.75 (d, J = 3.7 Hz, 2H), 1.71 (dd, J= 9.7, 4.4 Hz, 2H), 1.67 (s, 2H), 1.41 (d, J = 7.6 Hz, 1H), 1.36 – 1.22 (m, 6H), 0.86 (dt, J = 9.6, 6.4 Hz, 2H). 13 CNMR (101 MHz, DMSO- d 6) δ 158.82, 146.80,146.78,140.30, 137.27,137.24,132.99,129.34, 128.20, 127.17, 126.63, 121.54, 115.85, 115.46, 110.31, 110.20,71.29, 55.83, 53.98, 49.91, 40.66, 40.45, 40.24, 40.03, 39.82, 39.62, 39.41,27.84.HRMS (ESI) m / z calcd C 28 H 33 N₂O₃[M+H] + 447.2642, found 447.2654 Example 37 Preparation of 1-([1,1'-biphenyl]-3-yloxy)-3-(((1r,4r)-4-((2-methoxyphenyl)amino)cyclohexyl)amino)prop-2-ol (I-37):

[0070] I-37 Following general route D, the final product I-37 was obtained as a brown solid with a yield of 56%. 1 H NMR (400 MHz, DMSO- d 6) δ 7.71 – 7.63 (m, 2H), 7.51 – 7.43 (m, 2H), 7.42 – 7.34 (m, 2H), 7.26 –7.17 (m, 2H), 7.00 – 6.91 (m, 1H), 6.77 (ddd, J = 15.7, 7.8, 1.4 Hz, 2H), 6.54(dtd, J = 15.3, 7.8, 1.6 Hz, 2H), 4.35 (d, J = 8.7 Hz, 1H), 4.04 (dt, J= 11.6, 5.6Hz, 3H), 3.75 (s, 3H), 3.21 – 3.13 (m, 1H), 2.97 (d, J = 12.4 Hz, 1H), 2.82 (d, J = 12.4 Hz, 1H), 2.78 – 2.68 (m, 1H), 2.08 – 1.87 (m, 4H), 1.42 – 1.28 (m,2H), 1.21 (d, J = 13.3 Hz, 4H). HRMS (ESI) m / z calcd C 28 H 33 N₂O₃[M+H] + 447.2642, found 447.2647 Example 38 Preparation of N-(3-(2-hydroxy-3-(((1r,4r)-4-((2-methoxyphenyl)amino)cyclohexyl)amino)propoxy)phenyl)acetamide (I-38):

[0071] I-38 Following general route D, the final product I-38 was obtained as a white solid with a yield of 19%. 1 H NMR (400 MHz, DMSO- d 6) δ 9.89 (d, J = 21.3 Hz, 1H), 7.35 (t, J = 2.2 Hz, 1H), 7.18 (t, J = 8.1 Hz, 1H), 7.05 (dd, J = 7.9, 1.9 Hz, 1H), 6.76 (ddd, J = 16.0, 7.8, 1.4 Hz, 2H), 6.66– 6.45 (m, 3H), 4.34 (d, J = 8.5 Hz, 1H), 3.90 (td, J = 14.1, 11.6, 6.5 Hz, 3H), 3.75 (s, 3H), 3.18 (t, J = 6.5 Hz, 1H), 2.87 (s, 1H), 2.75 (s, 1H), 2.02 (d, J=5.1 Hz, 4H), 1.98 (s, 2H), 1.42 – 1.10 (m, 5H), 0.92 – 0.75 (m, 2H). HRMS(ESI) m / z calcd C 24 H 33 N3O4[M+H] + 428.2544, found 428.2546 Example 39 Preparation of 1-([1,1'-biphenyl]-2-yloxy)-3-(((1r,4r)-4-((2-methoxyphenyl)amino)cyclohexyl)amino)prop-2-ol (I-39):

[0072] I-39 Following general route D, the final product I-39 was obtained as a yellow solid with a yield of 31%. 1 H NMR (400 MHz, DMSO- d 6) δ 7.57 – 7.49 (m, 2H), 7.41 (dd, J = 8.3, 6.6 Hz, 2H), 7.38 – 7.30 (m, 3H),7.13 (d, J = 8.2 Hz, 1H), 7.06 (t, J = 7.4 Hz, 1H), 6.78 (ddd, J = 13.8, 7.8, 1.4Hz, 2H), 6.63 – 6.48 (m, 2H), 4.41 (d, J = 8.5 Hz, 1H), 4.13 – 4.02 (m, 2H), 3.98 (dd, J = 8.0, 2.9 Hz, 1H), 3.76 (s, 3H), 3.24 – 3.11 (m, 1H), 3.00 (dd, J =12.6, 2.8 Hz, 1H), 2.95 – 2.82 (m, 2H), 2.08 – 1.89 (m, 4H), 1.50 – 1.32 (m,2H), 1.31 – 1.17 (m, 3H). HRMS (ESI) m / z calcd C 28 H 33 N₂O₃[M+H] + 447.2642, found 447.2649 Example 40 Preparation of 1-(((1r,4r)-4-((2-methoxyphenyl)amino)cyclohexyl)amino)-3-(4-phenoxyphenoxy)prop-2-ol (I-40):

[0073] I-40 Following general route D, the final product I-40 was obtained, a gray solid, with a yield of 46%. 1 H NMR (400 MHz, DMSO- d 6) δ 7.39 – 7.27 (m, 2H), 7.11 – 7.03 (m, 1H), 6.98 (s, 4H), 6.94 – 6.89 (m,2H), 6.76 (ddd, J = 15.4, 7.8, 1.4 Hz, 2H), 6.61 – 6.47 (m, 2H), 4.33 (d, J = 8.5Hz, 1H), 4.02 – 3.85 (m, 3H), 3.18 (dq, J = 10.7, 5.4, 3.7 Hz, 1H), 2.84 (dd, J =11.8, 3.4 Hz, 1H), 2.71 (dd, J = 11.9, 6.4 Hz, 1H), 2.57 (s, 1H), 2.11 – 1.80(m, 4H), 1.23 (qd, J = 13.8, 12.4, 7.0 Hz, 4H). HRMS (ESI) m / z calcd C 28 H 34 N₂O₄[M+H] + 463.2591, found 463.2596 Example 41 Preparation of 1-(4-(benzyloxy)phenoxy)-3-(((1r,4r)-4-((2-methoxyphenyl)amino)cyclohexyl)amino)prop-2-ol (I-41):

[0074] I-41 Following general route D, the final product I-41 was obtained, a white solid, in 30% yield. 1 H NMR (400 MHz, DMSO- d6) δ 7.46 – 7.35 (m, 4H), 7.34 – 7.26 (m, 1H), 6.98 – 6.91 (m, 2H), 6.91 –6.85 (m, 2H), 6.77 (ddd, J = 15.4, 7.7, 1.4 Hz, 2H), 6.63 – 6.46 (m, 2H), 5.04(s, 2H), 4.37 (d, J = 8.5 Hz, 1H), 4.03 (h, J = 4.8 Hz, 1H), 3.89 (d, J = 5.3 Hz, 2H), 3.75 (s, 3H), 3.37 (d, J = 6.5 Hz, 1H), 3.25 – 3.10 (m, 1H), 3.00 (dd, J =12.3, 3.5 Hz, 1H), 2.93 – 2.73 (m, 2H), 2.01 (q, J = 5.9, 5.3 Hz, 4H), 1.49 –1.29 (m, 2H), 1.22 (q, J = 12.3 Hz, 2H). 13 C NMR (101 MHz, DMSO- d 6) δ 153.23,152.88,146.71,137.83,137.37, 128.86, 128.20, 128.13,128.08, 121.53, 116.17,115.86, 115.81,115.60,110.35, 110.13,90.86,73.45, 71.44, 70.10, 67.92,62.41,56.60, 55.71, 50.85, 49.35, 39.85, 31.39,30.77. HRMS (ESI) m / z calcd C 29 H 36 N₂O₄[M+H] + 477.2748, found 477.2752 Example 42 Preparation of 1-(((1r,4r)-4-((2-methoxyphenyl)amino)cyclohexyl)amino)-3-((5,6,7,8-tetrahydronaphth-2-yl)oxy)prop-2-ol (I-42):

[0075] I-42 Following general route D, the final product I-42 was obtained as a white solid with a yield of 29%. 1 H NMR (400 MHz, DMSO- d 6) δ 6.97 (dtd, J = 24.3, 8.4, 2.3 Hz, 2H), 6.86 (ddt, J = 10.4, 7.5, 3.9 Hz,1H), 6.81 – 6.71 (m, 1H), 6.69 – 6.57 (m, 2H), 6.56 – 6.45 (m, 2H), 4.71 (d, J = 4.5 Hz, 1H), 4.35 (d, J = 8.5 Hz, 1H), 4.12 (s, 1H), 4.03 (q, J = 7.1 Hz, 1H), 3.93 (ddt, J = 11.5, 7.5, 3.7 Hz, 1H), 3.86 (dt, J = 8.2, 5.6 Hz, 2H), 3.75 (s, 3H), 3.57 (s, 1H), 3.17 (s, 3H), 2.96 – 2.80 (m, 1H), 2.70 – 2.55 (m, 7H), 1.69 (dq, J = 8.9, 3.9, 3.4 Hz, 6H), 1.39 – 1.20 (m, 4H), 1.17 (t, J = 7.1 Hz,2H). HRMS (ESI) m / z calcd C 26 H 36 N₂O₃[M+H] + 425.2799, found 425.2805 Example 43 Preparation of 1-((2,3-dihydro-1H-inden-5-yl)oxy)-3-(((1r,4r)-4-((2-methoxyphenyl)amino)cyclohexyl)amino)prop-2-ol (I-43):

[0076] I-43 Following general route D, the final product I-43 was obtained as a brown solid with a yield of 28%. 1H NMR (400 MHz, DMSO- d 6) δ 7.10 (dd, J = 8.2, 3.2 Hz, 1H), 7.06 – 6.94 (m, 1H), 6.83 – 6.79 (m, 1H), 6.79 – 6.73 (m, 1H), 6.72 – 6.64 (m, 1H), 6.61 – 6.46 (m, 2H), 4.38 (d, J = 8.5Hz, 1H), 4.06 – 3.98 (m, 1H), 3.92 – 3.85 (m, 2H), 3.75 (d, J = 1.2 Hz, 3H), 3.58 (s, 1H), 3.17 (dt, J = 12.6, 4.0 Hz, 1H), 2.87 – 2.69 (m, 7H), 1.99 (dq, J =9.8, 7.3 Hz, 6H), 1.77 (dd, J = 26.3, 12.4 Hz, 1H), 1.43 – 1.32 (m, 2H), 1.28 –1.14 (m, 3H). HRMS (ESI) m / z calcd C 25 H 34 N₂O₃[M+H] + 411.2642, found 411.2642 Example 44 Preparation of 1-(((1r,4r)-4-((2-methoxyphenyl)amino)cyclohexyl)amino)-3-(m-tolyloxy)prop-2-ol (I-44):

[0077] I-44 Following general route D, the final product I-44 was obtained as a brown solid with a yield of 36%. 1 H NMR (400 MHz, DMSO- d 6) δ 7.16 (t, J = 7.8 Hz, 1H), 7.03 – 6.91 (m, 1H), 6.82 – 6.67 (m, 4H), 6.64– 6.40 (m, 2H), 4.36 (d, J= 8.5 Hz, 1H), 4.01 (s, 1H), 3.96 – 3.84 (m, 2H), 3.75 (s, 3H), 3.24 – 3.11 (m, 1H), 3.00 – 2.87 (m, 1H), 2.85 – 2.65 (m, 2H),2.27 (d, J = 3.0 Hz, 3H), 2.23 (s, 1H), 2.06 – 1.94 (m, 3H), 1.77 (dd, J = 22.8, 13.0 Hz, 1H), 1.33 (h, J = 7.8, 6.4 Hz, 2H), 1.28 – 1.10 (m, 3H). HRMS (ESI) m / z calcd C 23 H 32 N₂O₃[M+H] + 385.2486, found 385.2486 Example 45 Preparation of 1-(((1r,4r)-4-((2-methoxyphenyl)amino)cyclohexyl)amino)-3-(4-(naphth-2-ylamino)phenoxy)prop-2-ol (I-45):

[0078] I-45 Following the general route G, the final product I-45, a pale red solid, was obtained in 39% yield. 1 H NMR (400 MHz, DMSO- d 6) δ 8.13 (s, 1H), 7.70 (t, J = 8.3 Hz, 2H), 7.58 (d, J = 8.2 Hz, 1H), 7.38– 7.27 (m, 1H), 7.22 (d, J = 2.2 Hz, 1H), 7.17 (td, J = 9.0, 8.3, 6.2 Hz, 4H), 6.97 – 6.89 (m, 2H), 6.76 (ddd, J = 15.5, 7.8, 1.3 Hz, 2H), 6.60 – 6.47 (m,2H), 4.34 (d, J = 8.5 Hz, 1H), 3.91 (dt, J= 16.4, 5.1 Hz, 3H), 3.75 (s, 3H), 3.19 (d, J = 9.8 Hz, 1H), 2.89 – 2.79 (m, 1H), 2.71 (dt, J = 11.6, 4.9 Hz, 1H),2.57 (s, 1H), 1.97 (t, J = 12.9 Hz, 4H), 1.23 (q, J = 7.0 Hz, 6H). 13 C NMR (151MHz, DMSO- d 6) δ 157.92, 148.36, 141.91, 140.02, 138.01, 134.31, 134.29,128.70, 128.09, 127.22, 127.13, 126.79, 125.83, 125.44, HRMS (ESI) m / z calcd C 32 H 37 N3O3[M+H] + 512.2980, found 512.2917 Example 46 Preparation of 1-(((1r,4r)-4-((2-methoxyphenyl)amino)cyclohexyl)amino)-3-(4-(quinolin-6-ylamino)phenoxy)prop-2-ol (I-46):

[0079] I-46 Following the general route G, the final product I-46 was obtained as a white solid with a yield of 44%. 1 H NMR (400 MHz, DMSO- d 6) δ 8.56 (dd, J = 4.2, 1.6 Hz, 1H), 8.31 (s, 1H), 8.02 (d, J = 8.2 Hz, 1H), 7.82 (d, J = 9.1 Hz, 1H), 7.40 (dd, J= 9.1, 2.6 Hz, 1H), 7.32 (dd, J = 8.3, 4.2Hz, 1H), 7.23 – 7.15 (m, 3H), 6.96 (d, J = 8.5 Hz, 2H), 6.84 – 6.71 (m, 2H), 6.60 – 6.48 (m, 2H), 4.36 (d, J = 8.5 Hz, 1H), 4.02 (s, 1H), 3.94 (h, J = 5.5 Hz, 2H), 3.75 (s, 3H), 2.97 (d, J = 12.0 Hz, 1H), 2.83 (t, J = 10.3 Hz, 1H), 2.74 (d, J = 9.6 Hz, 1H), 2.07 – 1.93 (m, 4H), 1.34 (d, J = 6.5 Hz, 2H), 1.24 (d, J = 5.8Hz, 5H). HRMS (ESI) m / z calcd C 31 H 36 N4O3[M+H] + 513.2860, found 513.2867 Example 47 Preparation of 1-(((1r,4r)-4-((2-methoxyphenyl)amino)cyclohexyl)amino)-3-(4-(pyridin-2-ylamino)phenoxy)prop-2-ol (I-47):

[0080] I-47 Following the general route G, the final product I-47 was obtained as a white solid with a yield of 44%. 1 H NMR (400 MHz, DMSO- d 6) δ 8.80 (s, 1H), 8.07 (dd, J = 5.1, 1.9 Hz, 1H), 7.58 – 7.52 (m, 2H), 7.49(ddd, J = 8.8, 7.0, 2.0 Hz, 1H), 6.87 (dd, J = 9.3, 2.6 Hz, 2H), 6.81 – 6.70 (m,3H), 6.65 (dd,J = 7.1, 5.0 Hz, 1H), 6.57 (dd, J = 8.0, 1.5 Hz, 1H), 6.52 (td, J =7.7, 1.5 Hz, 1H), 4.36 (d, J = 8.6 Hz, 1H), 3.98 (d, J = 11.3 Hz, 1H), 3.89 (dd, J = 5.4, 2.5 Hz, 2H), 3.75 (s, 3H), 3.18 (d, J = 11.4 Hz, 1H), 2.88 (s, 1H), 2.72(s, 1H), 2.06 – 1.94 (m, 4H), 1.23 (q, J = 3.3, 2.9 Hz, 7H). HRMS (ESI) m / zcalcd C 27 H 34 N4O3[M+H] + 463.2704, found 463.2710 Example 48 Preparation of 1-(((1r,4r)-4-((2-methoxyphenyl)amino)cyclohexyl)amino)-3-(4-(benzofuran-2-ylamino)phenoxy)prop-2-ol (I-48):

[0081] I-48 Following the general route G, the final product I-48 was obtained as a white solid with a yield of 40%. 1 H NMR (400 MHz, DMSO- d 6) δ 7.82 (d, J = 2.2 Hz, 1H), 7.70 (s, 1H), 7.37 (d, J = 8.8 Hz, 1H), 7.13 (d, J = 2.3 Hz, 1H), 6.96 (d, J = 8.8 Hz, 2H), 6.88 (dd, J = 8.8, 2.3 Hz, 1H), 6.82 (d, J = 8.7 Hz, 2H), 6.78 – 6.68 (m, 3H), 6.53 (d, J= 7.8 Hz, 1H), 6.48 (t, J = 7.6Hz, 1H), 4.32 (d, J = 8.6 Hz, 1H), 3.93 (dd, J = 8.2, 4.4 Hz, 1H), 3.88 – 3.79(m, 2H), 3.71 (s, 3H), 2.88 (d, J = 11.6 Hz, 1H), 2.73 (t, J = 10.0 Hz, 1H), 1.96(d, J = 11.2 Hz, 4H), 1.23 – 1.11 (m, 6H). HRMS (ESI) m / z calcd C 30 H 35 N3O4[M+H] + 502.2700, found 502.2709 Example 49 Preparation of 1-(4-((2,3-dihydro-1H-inden-5-yl)amino)phenoxy)-3-(((1r,4r)-4-((2-methoxyphenyl)amino)cyclohexyl)amino)2-propanol (I-51):

[0082] I-49 Following the general route G, the final product I-49 was obtained, a white solid, in 44% yield. 1 H NMR (400 MHz, DMSO- d 6) δ 7.63 (s, 1H), 6.96 (dd, J = 13.8, 8.3 Hz, 3H), 6.84 – 6.77 (m, 3H), 6.71(dt, J = 23.4, 8.0 Hz, 3H), 6.57 – 6.40 (m, 2H), 4.32 (d, J = 8.5 Hz, 1H), 4.00 –3.89 (m, 1H), 3.85 (q, J = 7.9, 6.1 Hz, 2H), 3.71 (s, 3H), 3.15 (d, J = 10.0 Hz, 2H), 2.86 (d, J = 9.2 Hz, 1H), 2.71 (q, J= 5.7, 3.8 Hz, 5H), 2.65 – 2.55 (m,1H), 2.03 – 1.84 (m, 6H), 1.23 – 1.09 (m, 5H). HRMS (ESI) m / z calcd C 31 H 39 N3O3[M+H] + 502.3064, found 502.3069 Example 50 Preparation of 1-(((1r,4r)-4-((2-methoxyphenyl)amino)cyclohexyl)amino)-3-(4-((1-methyl-1H-indole-5-yl)amino)phenoxy)prop-2-ol (I-50):

[0083] I-50 Following the general route G, the final product I-50 was obtained, a white solid, in 44% yield. 1 H NMR (400 MHz, DMSO- d 6) δ 7.46 (s, 1H), 7.28 (t, J = 4.3 Hz, 2H), 7.20 (d, J = 3.1 Hz, 1H), 7.13 (d, J = 2.1 Hz, 1H), 6.93 – 6.83 (m, 3H), 6.83 – 6.68 (m, 4H), 6.59 – 6.46 (m, 2H), 6.24 (d, J = 3.0 Hz, 1H), 4.36 (d, J = 8.5 Hz, 1H), 3.97 (d, J = 12.4 Hz, 1H), 3.85(d, J = 5.3 Hz, 2H), 3.73 (d, J = 7.4 Hz, 6H), 3.22 – 3.11 (m, 2H), 2.97 (d, J =12.0 Hz, 1H), 2.82 (d, J = 14.6 Hz, 2H), 2.05 – 1.92 (m, 4H), 1.53 (s, 1H),1.22 (s, 5H). HRMS (ESI) m / z calcd C 31 H 38 N4O3[M+H]+ 515.3017, found 515.3021 Example 51 Preparation of 1-(((1r,4r)-4-((2-methoxyphenyl)amino)cyclohexyl)amino)-3-(4-(thiophen-3-ylamino)phenoxy)prop-2-ol (I-51):

[0084] I-51 Following the general route G, the final product I-51 was obtained, a white solid, with a yield of 44%. 1 H NMR (400 MHz, DMSO- d 6) δ 7.92 (s, 1H), 7.76 (d, J = 8.7 Hz, 1H), 7.64 (d, J = 5.4 Hz, 1H), 7.39 (d, J = 2.2 Hz, 1H), 7.29 – 7.23 (m, 1H), 7.12 – 7.04 (m, 2H), 7.01 (dd, J = 8.7, 2.2Hz, 1H), 6.94 – 6.86 (m, 2H), 6.77 (ddd, J = 15.9, 7.8, 1.4 Hz, 2H), 6.61 –6.47 (m, 2H), 4.36 (d, J = 8.6 Hz, 1H), 4.01 (d, J = 7.8 Hz, 1H), 3.91 (dd, J =5.3, 3.6 Hz, 2H), 3.19 (d, J = 8.3 Hz, 2H), 2.95 (dd, J = 12.5, 3.7 Hz, 1H), 2.80(dd, J = 12.1, 8.1 Hz, 1H), 2.76 – 2.63 (m, 1H), 2.08 – 1.90 (m, 4H), 1.53 (s, 1H), 1.23 (s, 5H). 13 C NMR (151 MHz, DMSO- d6) δ 157.92, 148.36, 141.91, 140.02,138.01, 136.42, 135.01, 128.70, 128.01, 127.49, 126.63, 123.42, 123.09,118.97, 116.39, 114.90, 114.61, 111.55, 70.90, 69.55, 56.49, 55.71, 51.43,49.77, 29.48, 28.24. HRMS (ESI) m / z calcd C 30 H 33 N3O3S[M+H] + 518.2472, found 518.2479 Example 52 Preparation of 1-(((1r,4r)-4-((2-methoxyphenyl)amino)cyclohexyl)amino)-3-(4-(thiophen-3-ylamino)phenoxy)prop-2-ol (I-52):

[0085] I-52 Following the general route G, the final product I-52 was obtained, a white solid, in 44% yield. 1 H NMR (400 MHz, DMSO- d 6) δ 8.06 (s, 1H), 7.40 (dd, J = 5.1, 3.0 Hz, 1H), 7.06 – 6.92 (m, 2H), 6.84(dt, J = 6.7, 2.1 Hz, 3H), 6.77 (q, J = 7.8 Hz, 2H), 6.62 – 6.55 (m, 2H), 6.52(td, J = 7.7, 1.8 Hz, 1H), 4.36 – 4.30 (m, 1H), 4.23 (dd, J = 9.7, 5.1 Hz, 1H), 3.96 (d, J = 15.0 Hz, 1H), 3.90 – 3.82 (m, 2H), 3.75 (s, 3H), 3.20 (d, J = 14.0Hz, 1H), 2.63 (dd, J = 10.0, 6.7 Hz, 1H), 2.00 (d, J= 12.5 Hz, 4H), 1.85 (d, J =11.3 Hz, 1H), 1.24 (q, J = 3.5 Hz, 6H). HRMS (ESI) m / z calcd C 26 H 33 N3O3S[M+H] + 468.2315, found 468.2323 Example 53 Preparation of 1-(((1r,4r)-4-((2-methoxyphenyl)amino)cyclohexyl)amino)-3-(4-((5,6,7,8-tetrahydronaphthyl-2-yl)amino)phenoxy)2-propanol (I-53):

[0086] I-53 Following the general route G, the final product I-53 was obtained, a white solid, in 49% yield. 1 H NMR (400 MHz, DMSO- d 6) δ 7.59 (d, J = 2.3 Hz, 1H), 7.00 – 6.92 (m, 2H), 6.84 (dd, J = 8.7, 3.7 Hz,3H), 6.80 – 6.72 (m, 2H), 6.68 (dd, J = 8.3, 2.4 Hz, 1H), 6.63 (d, J = 2.3 Hz, 1H), 6.56 (d, J = 7.7 Hz, 1H), 6.54 – 6.48 (m, 1H), 4.33 (d, J = 3.5 Hz, 1H), 4.23 (s, 1H), 3.94 – 3.86 (m, 2H), 3.75 (s, 3H), 3.18 (s, 1H), 2.83 (d, J =11.8 Hz, 1H), 2.74 – 2.64 (m, 1H), 2.60 (d, J = 5.2 Hz, 4H), 1.98 (d, J = 13.0Hz, 3H), 1.69 (p, J = 3.0 Hz, 4H), 1.54 (s, 1H), 1.22 (q, J= 9.8 Hz, 6H). 13 C NMR (101 MHz, DMSO-) d 6) δ 153.00, 152.82,147.17,146.71, 142.77, 137.61,137.43,130.52,129.89, 127.35,121.53, 119.76, 119.68, 115.99, 115.75, 114.23, 110.34,110.13, 71.36,70.35,68.08, 56.61, 55.70, 52.16,50.90, 49.54,44.86,40.63,31.44, 29.54, 28.56, 23.63, 23.40.HRMS (ESI) m / z calcd C 32 H 41 N3O3[M+H] + 516.3221.found516.3225 Example 54 Preparation of 1-(((1s,4s)-4-((2-methoxyphenyl)amino)cyclohexyl)amino)-3-(4-(phenylamino)phenoxy)prop-2-ol (I-54):

[0087] I-54 Following general route D, the final product I-54 was obtained as a white solid with a yield of 45%. 1 H NMR (400 MHz, DMSO- d 6) δ 7.84 (s, 1H), 7.19 – 7.11 (m, 2H), 7.06 – 6.98 (m, 2H), 6.89 (ddd, J =13.9, 7.7, 1.8 Hz, 4H), 6.80 (dd, J = 7.9, 1.4 Hz, 1H), 6.76 (td, J = 7.7, 1.4Hz, 1H), 6.73 – 6.67 (m, 1H), 6.54 (ddd, J = 15.3, 7.8, 1.5 Hz, 2H), 4.37 (d, J =8.1 Hz, 1H), 3.95 (d, J= 6.1 Hz, 1H), 3.92 – 3.84 (m, 2H), 3.78 (s, 3H), 3.45(s, 1H), 2.90 – 2.75 (m, 2H), 2.75 – 2.66 (m, 1H), 1.69 (d, J = 7.3 Hz, 4H),1.64 – 1.49 (m, 4H). Example 55 Preparation of 1-([1,1'-biphenyl]-4-yloxy)-3-(((1s,4s)-4-((2-methoxyphenyl)amino)cyclohexyl)amino)prop-2-ol (I-55):

[0088] I-55 Following general route D, the final product I-55 was obtained as a white solid with a yield of 47%. 1 H NMR (400 MHz, DMSO- d 6) δ 7.68 – 7.54 (m, 4H), 7.43 (t, J = 7.7 Hz, 2H), 7.35 – 7.25 (m, 1H), 7.10 – 6.99 (m, 2H), 6.85 – 6.71 (m, 2H), 6.54 (ddd, J = 15.5, 8.0, 1.5 Hz, 2H),4.37 (d, J = 8.1 Hz, 1H), 4.15 – 3.91 (m, 3H), 3.77 (s, 3H), 3.45 (s, 1H), 2.85(d, J = 11.4 Hz, 1H), 2.76 (d, J = 15.3 Hz, 2H), 1.79 – 1.64 (m, 4H), 1.58 (dt, J =18.2, 6.9 Hz, 4H). Example 56 General synthetic route for final products I-56~62 H

[0089] aReagents and conditions: (a) t-BuONa, BrettPhos-Pd-G3, BrettPhos, 1,4-Dioxane, 80℃, 12h, 40%; (b) CF3COOH, DCM, 25℃, 1h, 95%; (c) 1 M NaOH, DMSO, 25℃, 12h, 30~70%; (d) i-PrOH, Reflux, 8 h, 33~40%. Brominated compounds with different substitution positions and substituents (1.2 equiv.) were reacted with trans-N-Boc-cyclohexanediamine (1 equiv.) to obtain intermediates 56a-62a. The Boc was then removed with trifluoroacetic acid to obtain intermediates 56b-62b, which were then reacted with intermediate 36a to generate the final products 56-62.

[0090] Preparation of 1-(((1r,4r)-4-((3-methoxyphenyl)amino)cyclohexyl)amino)-3-(4-(phenylamino)phenoxy)prop-2-ol (I-56):

[0091] I-56 Following the general route H, the final product I-56 was obtained as a white solid with a yield of 59%. 1 H NMR (400 MHz, DMSO- d 6) δ 7.84 (s, 1H), 7.25 – 7.10 (m, 2H), 7.07 – 6.99 (m, 2H), 6.96 – 6.82 (m,5H), 6.70 (td, J = 7.2, 1.2 Hz, 1H), 6.14 (dd, J = 8.0, 2.0 Hz, 1H), 6.11 – 6.02(m, 2H), 5.36 (d, J = 8.1 Hz, 1H), 3.99 – 3.79 (m, 3H), 3.65 (s, 3H), 3.10 (tt, J = 9.8, 5.2 Hz, 2H), 2.80 (dd, J = 11.8, 3.6 Hz, 1H), 2.65 (ddd, J = 14.3, 10.7,6.4 Hz, 1H), 1.95 (t, J= 12.9 Hz, 4H), 1.42 – 1.29 (m, 1H), 1.28 – 1.05 (m, 5H). 13 C NMR (101 MHz, DMSO- d 6) δ 160.84,153.56, 149.84, 145.54,136.69,130.05,129.56, 120.71, 120.63, 118.75, 115.73, 115.36,115.30, 105.77, HRMS (ESI) m / z calcd C 28 H 35 N3O3[M+H] + 462.2751, found 462.2751 Example 57 Preparation of 1-(((1r,4r)-4-((4-methoxyphenyl)amino)cyclohexyl)amino)-3-(4-(phenylamino)phenoxy)prop-2-ol (I-57):

[0092] I-57 Following the general route H, the final product I-57 was obtained as a white solid with a yield of 57%. 1 H NMR (400 MHz, DMSO- d 6) δ 7.85 (d, J = 3.1 Hz, 1H), 7.16 (t, J = 7.8 Hz, 2H), 7.03 (dd, J = 8.9, 5.4Hz, 2H), 6.89 (ddd, J = 14.7, 9.0, 2.2 Hz, 4H), 6.76 – 6.64 (m, 3H), 6.51 (dd, J = 8.9, 2.3 Hz, 2H), 4.88 (s, 1H), 4.31 – 4.16 (m, 1H), 3.98 (d, J = 6.3 Hz, 1H), 3.90 (t, J= 4.4 Hz, 2H), 3.62 (s, 3H), 3.11 – 3.02 (m, 1H), 1.99 (d, J =12.9 Hz, 3H), 1.85 (d, J = 12.3 Hz, 1H), 1.32 – 1.19 (m, 5H), 1.10 (q, J = 11.9Hz, 2H). 13 C NMR (101 MHz, DMSO- d 6) δ 146.73, 141.57, 139.38, 137.35, 126.96,124.99, 122.92, 122.20, 121.55, 118.99, 115.77, 110.83, 110.01, 109.98,104.32, 100.91, 71.02, 70.98, 68.98, 68.80, 55.77, 52.83, 52.70, 50.39,46.58, 31.86, 30.82, 19.80.HRMS (ESI) m / z calcd C 28 H 35 N3O3[M+H] + 462.2751, found 462.2756 Example 58 Preparation of 1-(4-(phenylamino)phenoxy)-3-(((1r,4r)-4-(o-tolylamino)cyclohexyl)amino)prop-2-ol (I-58):

[0093] I-58 Following the general route H, the final product I-58 was obtained as a white solid with a yield of 50%. 1 H NMR (400 MHz, DMSO- d 6) δ 7.85 (s, 1H), 7.15 (dd, J = 8.5, 7.2 Hz, 2H), 7.06 – 7.01 (m, 2H), 6.98(td, J = 7.6, 1.7 Hz, 1H), 6.95 – 6.91 (m, 2H), 6.91 – 6.84 (m, 3H), 6.75 –6.65 (m, 1H), 6.55 (d, J = 8.0 Hz, 1H), 6.46 (td,J = 7.3, 1.1 Hz, 1H), 4.26 (d, J = 8.0 Hz, 1H), 3.90 (ddt, J = 14.5, 9.6, 4.2 Hz, 3H), 3.20 (s, 1H), 2.92 – 2.82(m, 2H), 2.76 – 2.66 (m, 2H), 2.57 (d, J = 12.0 Hz, 1H), 2.04 (s, 3H), 2.02 –1.94 (m, 3H), 1.26 – 1.20 (m, 5H). 13 C NMR (101 MHz, Chloroform- d ) δ 153.04,145.48,145.05,136.26,129.95,129.09, 126.71, 121.72,120.22, 118.29,115.46,115.28, 114.84, 109.77, 70.83,67.50,56.29, 50.74,49.02, 40.15, 39.94, 39.73,39.52, 39.31, 39.10, 38.89, 30.88, 29.00,17.71.HRMS (ESI) m / z calcd C 28 H 35 N3O2[M+H] + 446.2802, found 446.2809 Example 59 Preparation of 1-(((1r,4r)-4-((2-ethylphenyl)amino)cyclohexyl)amino)-3-(4-(phenylamino)phenoxy)prop-2-ol (I-59):

[0094] I-59 Following the general route H, the final product I-59 was obtained as a white solid with a yield of 45%. 1 H NMR (400 MHz, DMSO- d 6) δ 7.81 (s, 1H), 7.16 – 7.06 (m, 2H), 7.02 – 6.78 (m, 8H), 6.65 (t, J = 7.3Hz, 1H), 6.52 (d, J = 8.1 Hz, 1H), 6.46 (t,J = 7.3 Hz, 1H), 4.24 (d, J = 8.1 Hz, 1H), 3.85 (qq, J = 9.6, 5.9, 5.2 Hz, 3H), 3.17 (s, 2H), 2.88 – 2.76 (m, 1H), 2.73 – 2.63 (m, 1H), 2.61 – 2.49 (m, 1H), 2.38 (q, J = 7.5 Hz, 2H), 2.01 – 1.84(m, 4H), 1.26 – 1.14 (m, 5H), 1.06 (t, J = 7.4 Hz, 3H). 13 C NMR (101 MHz, DMSO- d 6) δ 153.55, 146.24, 145.54,136.71, 130.07,129.81, 129.56, 123.97, 120.71,118.76, 115.74, 115.31, 113.02, 71.35, 68.15, 61.29,56.74, 51.27, 49.60,45.25,40.20, 39.78, 31.49,31.08,30.86,30.31,29.47,20.54.HRMS(ESI)m / zcalcdC 28 H 35 N3O3[M+H] + 460.2959, found 460.2966 Example 60 Preparation of 1-(((1r,4r)-4-((2-isopropylphenyl)amino)cyclohexyl)amino)-3-(4-(phenylamino)phenoxy)prop-2-ol (I-60):

[0095] I-60 Following the general route H, the final product I-60 was obtained as a pale red solid in 36% yield. 1 H NMR (400 MHz, DMSO- d 6) δ 7.85 (s, 1H), 7.21 – 7.10 (m, 2H), 7.06 – 7.00 (m, 3H), 6.97 (td, J = 7.6, 1.6 Hz, 1H), 6.89 (ddd, J= 14.4, 7.7, 1.7 Hz, 4H), 6.75 – 6.65 (m, 1H), 6.62 – 6.51 (m, 2H), 4.34 (d, J = 8.0 Hz, 1H), 3.90 (ddt, J = 13.2, 9.5, 5.2 Hz,3H), 3.22 (s, 2H), 3.00 (p, J = 6.7 Hz, 1H), 2.93 – 2.83 (m, 1H), 2.80 – 2.69(m, 1H), 2.61 (s, 1H), 1.98 (t, J = 8.4 Hz, 4H), 1.30 – 1.19 (m, 5H), 1.12 (d, J = 6.8 Hz, 6H). 13 C NMR (151 MHz, DMSO- d 6) δ 157.73, 145.89, 145.54, 140.92,140.02, 129.15, 129.08, 127.16, 124.86, 120.14, 118.03, 117.99, 116.62,114.66, 70.90, 69.55, 56.43, 51.43, 50.07, 29.48, 27.98, 27.29, 22.96. HRMS(ESI) m / z calcd C 30 H 39 N3O2[M+H] + 474.3115, found 474.3120 Example 61 Preparation of 1-(4-(phenylamino)phenoxy)-3-(((1r,4r)-4-(p-tolylamino)cyclohexyl)amino)prop-2-ol (I-61):

[0096] I-61 Following the general route H, the final product I-61 was obtained, a colorless oily liquid, in 37% yield. 1 H NMR (400 MHz, DMSO- d 6) δ 7.82 (s, 1H), 7.19 – 7.07 (m, 2H), 7.05 – 6.97 (m, 2H), 6.94 –6.78 (m, 6H), 6.68 (t, J= 7.3 Hz, 1H), 6.50 – 6.39 (m, 2H), 5.05 (d, J = 8.2 Hz,1H), 3.98 – 3.77 (m, 3H), 3.07 (d, J = 8.7 Hz, 1H), 2.80 (dd, J = 12.2, 3.7 Hz, 1H), 2.66 (dd, J = 12.0, 6.6 Hz, 1H), 2.57 – 2.49 (m, 1H), 2.10 (s, 3H), 2.05 –1.84 (m, 4H), 1.27 – 1.02 (m, 5H). 13 C NMR (151 MHz, DMSO- d 6) δ 157.63, 148.04,145.87, 140.31, 131.22, 129.47, 129.06, 118.12, 116.11, 115.65, 114.97,114.66, 70.93, 69.26, 56.49, 51.90, 50.07, 29.45, 29.12, 21.14. HRMS (ESI) m / z calcd C 28 H 35 N3O2[M+H] + 446.2802, found 446.2809 Example 62 Preparation of 1-(((1r,4r)-4-(phenylamino)cyclohexyl)amino)-3-(4-(phenylamino)phenoxy)prop-2-ol (I-62):

[0097] I-62 Following the general route H, the final product I-62 was obtained as a white solid with a yield of 49%. 1 H NMR (400 MHz, DMSO- d 6) δ 7.78 (s, 1H), 7.14 – 7.06 (m, 2H), 6.97 (dt, J = 8.6, 3.4 Hz, 4H), 6.84(ddd, J= 16.7, 7.7, 1.7 Hz, 4H), 6.69 – 6.61 (m, 1H), 6.52 – 6.45 (m, 2H), 6.44 – 6.37 (m, 1H), 5.26 (d, J = 8.1 Hz, 1H), 3.90 – 3.74 (m, 3H), 3.07 (dtd, J = 10.8, 7.7, 4.6 Hz, 1H), 2.76 (dd, J = 11.8, 3.7 Hz, 1H), 2.69 – 2.57 (m, 1H), 2.49 (d, J = 5.7 Hz, 1H), 1.91 (ddd, J = 15.7, 10.0, 3.5 Hz, 4H), 1.24 – 0.99 (m,5H). 13 C NMR (101 MHz, DMSO- d 6) δ 153.57,148.51, 145.55, 136.70, 129.57,129.36, 120.72,120.63,118.76,115.74,115.62,115.37,115.31,112.77,74.97,71.38,68.25,68 .23,61.21,60.27,56.70,51.02,50.74,49.68,31.45,29.46,28.53.HRMS(ESI)m / zcalcdC 27 H 33 N3O2[M+H] + 432.4646, found 432.2652 Example 63 Preparation method of hydrochloride salt form: Dissolve 0.01 molar mass of compound I-01~I-62 in 10 mL of acetone, stir at room temperature to dissolve, and add a small amount of THF to aid dissolution until all compounds are dissolved; slowly pass hydrogen chloride gas, and yellow, pale yellow or white solids precipitate from the reaction solution, filter, and dry to obtain hydrochloride salt form of I-01~I-62.

[0098] Preparation method of sulfate, phosphate, acetate and trichloroacetic acid salt forms: Dissolve 0.01 mol of compounds I-01~I-62 in 10 mL of diethyl ether, stir at room temperature to dissolve, and add a small amount of THF to aid dissolution until all compounds are dissolved; dissolve equal amounts of sulfuric acid, phosphoric acid, acetic acid and trichloroacetic acid in methanol respectively, and slowly add them dropwise to the diethyl ether solution. Yellow, pale yellow or white solids precipitate from the reaction solution. Filter and dry to obtain the sulfate, phosphate, acetate and trichloroacetic acid salt forms of I-01~I-62.

[0099] Preparation method of lactate and citrate salts: Dissolve 0.01 mol of compounds I-01~I-62 in 10 mL of diethyl ether, stir at room temperature to dissolve, and add a small amount of THF to aid dissolution until all compounds are dissolved; dissolve equal amounts of lactic acid and citric acid in ethyl acetate, and slowly add them dropwise to the diethyl ether solution. Yellow, pale yellow or white solids precipitate from the reaction solution. Filter and dry to obtain lactate and citrate salts of I-01~I-62.

[0100] Example 64 Compounds I-01 to I-62 exhibited in vitro antitumor activity by inhibiting the neddylation pathway.

[0101] 1. In vitro tumor cell proliferation experiment The proliferative activity of candidate compounds I-01 to I-62 against human tumor cells was evaluated using CCK8 assay.

[0102] (1) Experimental materials: human lung cancer cells A549, human lung cancer cells H1299, 10% bovine serum culture medium, PBS solution, trypsin (Sigma), ×10 CCK8 (Sigma).

[0103] (2) Experimental method: (i) A549 cell resuscitation and passage: Remove the A549 cell cryopreservation solution from the -80°C freezer and centrifuge (1200 rpm, 3 min). Remove the supernatant, resuspend in 2 ml of 10% bovine serum medium, and transfer to a 10 cm culture dish. Incubate at 37°C for 24 hours. Select cells with good growth, aspirate the culture medium, wash with PBS and digest with trypsin, centrifuge (1200 rpm, 3 min), remove the supernatant, and resuspend in 2 ml of 10% bovine serum medium; (ii) Cell seeding: Count the above cells and evenly distribute 3000-5000 cells per well into each 96-well plate. Incubate overnight at 37°C; (iii) Add different concentrations of the test compound and incubate for a total of 24 hours; (iv) Aspirate the supernatant, add 100 μL of 10% CCK8 medium to each well, and incubate for 1 hour; (v) The microplate reader detects the change in absorbance of each well at 450 nm and calculates the IC50 value.

[0104] 2. Intracellular neddylation blocking assay based on Western blotting (1) Experimental materials: human lung cancer cells A549, 10% bovine serum medium, PBS solution, trypsin (Sigma), primary antibody (anti-cullin1 rabbit, anti-cullin2 rabbit, anti-cullin3 rabbit, anti-cullin4a rabbit, anti-cullin5 rabbit, anti-Nedd8 rabbit, anti-wee1 rabbit, anti-p27 rabbit, Abcam, 2000:1 dilution), secondary antibody (IgG rabbit), protein lysis buffer, ×4 SDS-loading.

[0105] (2) Experimental method: (i) Resuscitation and passage of A549 cells: The cell cryopreservation solution containing A549 cells was taken out of the -80°C freezer and centrifuged (1200 rpm, 3 minutes). The supernatant was removed, and the cells were resuspended in 2 ml of 10% bovine serum medium and transferred to a 10 cm culture dish. The cells were incubated in a 37°C incubator for 24 hours. Select cells with good growth, aspirate the culture medium, wash with PBS and digest with trypsin, centrifuge (1200 rpm, 3 minutes), remove the supernatant, and resuspend in 2 ml of 10% bovine serum medium; (ii) Seed cells: count the above cells, distribute 300,000 cells per dish into each culture dish, and incubate overnight at 37 degrees Celsius; (iii) Add the test compound and incubate for a total of 6 hours; (iv) After incubation, quantify the protein; (iv) Prepare a 10% SDS-PAGE gel and perform electrophoresis; (v) After transferring the membrane for 1 hour, block with 20% milk for 1 hour, add primary antibody and incubate overnight; (vi) Wash the membrane and add secondary antibody and incubate for 1 hour.

[0106] The activity data are shown in Table 1 below. A represents compounds with neddylation inhibitory activity greater than 50% @ 10 μM; B represents compounds with neddylation inhibitory activity greater than 50% @ 20 μM; C represents compounds with tumor cell proliferation inhibitory activity greater than 50% @ 10 μM; and D represents compounds with tumor cell proliferation inhibitory activity greater than 50% @ 40 μM. The results show that all the above compounds exhibited good neddylation pathway inhibitory activity and in vitro antitumor activity.

[0107] Table 1.

[0108] Example 65 Compounds I-01 to I-62 exhibit cardioprotective activity.

[0109] In the doxorubicin-induced cardiomyocyte injury protection experiment, cardiomyocytes remained viable after 7 passages. They were resuspended in normal saccharified medium and aliquoted into 96-well plates at 1×10⁴ cells / well, incubated overnight at 37°C. Doxorubicin (final concentration 2 μM) was added, and incubation continued for 6 hours. After incubation, the supernatant was aspirated and washed with PBS. The test compound (final concentration 10 μM) and the positive control drug dexazosin (final concentration 10 μM) were added, and incubation continued for 12 hours. Cardiomyocyte viability was tested using the Cell Counting Kit-8 (CCK8 method), and the protective effect of the compound on cardiomyocytes was calculated.

[0110] The hypoxia / reoxygenation-induced cardiomyocyte injury protection experiment was performed with the same pretreatment and overnight cell adhesion; the supernatant was removed, washed with PBS, and normal sugar-containing medium was added. The cells were placed in a hypoxic chamber, which was then filled with nitrogen to create a hypoxic environment; after 6 hours of incubation, reoxygenation was performed, and the test compound (final concentration 10 μM) and the positive control drug nicorol (final concentration 10 μM) were added. The cells were then incubated for another 6 hours, the supernatant was removed, and the cells were washed with PBS. The viability of cardiomyocytes was tested using the Cell Counting Kit-8 (CCK8 method), and the protective effect of the compound on cardiomyocytes was calculated.

[0111] The activity data are shown in Table 2 below. A represents a cardiomyocyte survival rate greater than 60%@10μM, and B represents a cardiomyocyte survival rate greater than 50%@10μM. The results show that all the above compounds exhibited good in vitro cardioprotective activity, and their activity was no worse than that of the two positive control drugs.

[0112] Table 2.

[0113] Example 66 The CCK8 assay evaluated the inhibitory activity of the preferred compounds I-35 and I-59 on the proliferation of various tumor cells.

[0114] The methods and steps for testing proliferation inhibition activity were the same as in Example 64, and highly activated tumor cell lines with neddylation, such as human liver cancer cells HepG2 and Huh7, gastric cancer cells MKN45 and MGC803, breast cancer cells T-47D, MCF-7 and MB231, and colon cancer cells SW480, were selected respectively. The activity data are shown in Table 3 below: I-35 and I-59 not only exhibit inhibitory activity against the proliferation of various tumor cells, but their effects are also comparable to those of the positive control drug MLN4924. The activity data are shown in Table 3 below. A represents the compound's half-maximal inhibitory concentration (IC50 value) against tumor cells being less than 1 μM, and B represents the compound's half-maximal inhibitory concentration (IC50 value) against tumor cells being less than 5 μM. The results show that all the above compounds exhibited good inhibitory activity against tumor cell proliferation, and their activity was comparable to that of the positive control drug MLN4924.

[0115] Table 3

[0116] Example 67 Rabbit cardiac perfusion experiments were conducted to evaluate the inhibitory activity of compounds I-35 and I-59 against ISO-induced tachycardia. Rabbits were randomly assigned to the treatment group and terminally anesthetized via intraperitoneal injection of sodium pentobarbital (approximately 140 mg / kg body weight). The heart was rapidly removed and cannulated while beating, and continuously perfused in isovolumic Langendorff mode with phosphate-free Krebs-Henseleit (KH) buffer (18.5 mM NaCl, 4.8 mM KCl, 2.5 mM CaCl2•2H2O, 25 mM NaHCO3, 1.2 mM MgSO4, 5.5 mM D-glucose, 0.5 mM EDTA, 1.2 mM KH2PO4, with a continuous flow of a mixture of 95% O2 and 5% CO2, pH = 7.2–7.4). The heart was perfused for 30 minutes to reach equilibrium, followed by reperfusion with 5 μM ISO for 15 minutes, and electrocardiograms were recorded. Subsequently, I-35 (0.5 μM and 1 μM) or I-59 (4 μM) was administered to the heart via the Langendorff device for 15 minutes, and an electrocardiogram was recorded. This procedure was repeated three times in the same heart for two independent experiments.

[0117] The results are as follows Figure 1 As shown, perfusion with both I-35 and I-59 improved sodium pentobarbital-induced tachycardia. In particular, compared with the control group and the I-59 treatment group, compound I-35 more effectively reduced heart rate (RT) and QRS width, and reversed ISO-induced QT and QTc interval values. Data statistics method: Student's t-test (two-tailed): * P <0.05,** P <0.01, *** P <0.001, ns indicates no difference. Example 68 A549 xenograft experiment evaluated the oral antitumor activity of the preferred compound I-35. 1.5×10 6 A549 cells were dissolved in 100 mL of PBS and subcutaneously injected into female nude mice. After tumors were induced and grew to 30–80 mm³, the mice were randomly divided into four groups: a control group (10% 2-hydroxypropyl-β-cyclodextrin aqueous solution), a MLN4924-treated group (30 mg / kg), and two I-35-treated groups (20 and 40 mg / kg), all administered orally. Treatment was once daily, with a five-day treatment followed by a two-day rest period constituting one treatment cycle. Body weight and tumor volume were measured every three days. All mice were sacrificed (tumor volume >1000 mm³). Tumor volume and mass were measured in each group.

[0118] The results are as follows Figure 2 As shown, oral administration of I-35 significantly inhibited the growth of A549 subcutaneous tumors in mice, even as a positive control. Data analysis method: Student's t-test (two-tailed): * P <0.05,** P <0.01, *** P <0.001, ns indicates no difference. Example 69 In vivo cardioprotective activity test of preferred compound I-35.

[0119] C57BL / 6 mice were randomly divided into groups of 5. The modeling group received intraperitoneal injection of doxorubicin 2.5 mg / kg twice a week, while the control group received intraperitoneal injection of physiological saline. After successful modeling, doxorubicin was continued, but two groups were simultaneously given 20 mg / kg of the test drug I-35 at the same frequency and duration as doxorubicin for another 6-8 weeks. A positive control group (10 mg / kg) was also included for comparison. During the administration period, the mice's behavior, food intake, activity level, and body weight were observed. After administration, the mice were anesthetized with 10% chloral hydrate, and blood was collected, centrifuged, and serum was obtained to detect biochemical indicators related to the myocardium, including lactate dehydrogenase (LDH) and creatine kinase isoenzyme MB (CK-MB). After cardiac perfusion, the heart was removed to test the heart-to-body ratio (HW / BW), fixed, embedded in paraffin, sectioned, and the morphology and fibrosis area of ​​cardiomyocytes were detected by HE staining and Masson staining.

[0120] The results are as follows Figure 3 As shown, compared to the control group, the doxorubicin model group exhibited a certain decrease in body weight, loss of appetite, dull coat color, and reluctance to move; the feeding frequency, coat color, and agility of the mice in the drug-treated group were significantly better than those in the doxorubicin model group. Section results showed a significant difference: the cells in the drug-treated group were plump and had a neat and dense structure, compared to the doxorubicin model group, where cells were irregularly shrunken and the overall structure was loose. Relevant indicators are as follows... Figure 3As shown, the heart-to-body ratio was significantly smaller in the DOX-treated group, and lactate dehydrogenase and creatine kinase isoenzyme MB were elevated. These abnormal values ​​significantly recovered after I-35 administration, suggesting that I-35 exhibits significant in vivo myocardial injury protective activity. Data analysis method: Student's t-test (two-tailed): * P <0.05,** P <0.01, *** P <0.001, ns indicates no difference. Example 70 In vivo pharmacokinetic testing of the preferred compound I-35.

[0121] SD rats (~260g) were randomly divided into groups of 3 and administered I-35 orally or via tail vein injection once. Blood samples were collected 24 hours later. LC MS / MS was used to detect the I-35 content in blood samples.

[0122] The results are shown in Table 4 below: the in vivo half-life of I-35 is 6.1 hours and the bioavailability is 45.7%, indicating that it has good oral efficacy.

[0123] Table 4

[0124] In summary, the compounds described in this invention exhibit excellent antitumor and cardioprotective activities both in vitro and in vivo, and also demonstrate oral activity. This provides a novel mode of administration for the development of drugs to treat cancer complicated with cardiotoxicity. Currently, no similar therapeutic compounds have been reported, demonstrating significant novelty, originality, and practicality.

Claims

1. Hydroxypropylcyclic amine compounds of Formula I and their pharmaceutically acceptable salts: I In Formula I: R 1 It is 1,2-cyclopropanediamine, 1,3-cyclopentanediamine, 1,4-cyclohexanediamine, 1,3-cyclohexanediamine, 1,4-piperazinyl, 4-aminopiperidinyl, 3-aminopyranyl, 3-aminoazacyclobutyl, 3,9-diazaspiro[5,5]undecyl, 2,6-diazaspiro[3,3]pentyl, 2,8-diazaspiro[4,4]heptyl, 2,6-diazaspiro[3,4]hexyl, 3,7-diazabicyclo[3,3,0]octyl, 4-aminomethylpiperidinyl, 3-aminomethylpyranyl, 3-aminomethylazacyclobutyl, or 2,6-diaminospiro[4,4]heptyl; R 2 The substituted phenyl, naphthyl, carbazolyl, indolyl, dibenzofuranyl, 3,4-dihydro-2(1H)-quinolinone, benzophenone, biphenyl, diphenylamino, aromatic aminophenyl, benzocyclopentyl, or benzocyclohexyl; R 3 It is a substituted phenyl group.

2. The hydroxypropylcycloamine compound and its pharmaceutically acceptable salt according to claim 1, characterized in that, The hydroxypropylamine compounds are: 1-((9H-carbazole-4-yl)oxy)-3-(((1r,4r)-4-((2-methoxyphenyl)amino)cyclohexyl)amino)prop-2-ol (I-01), 1-((9H-carbazole-4-yl)oxy)-3-(((1s,4s)-4-((2-methoxyphenyl)amino)cyclohexyl)amino)prop-2-ol (I-02), 1-((9H-carbazole-4-yl)oxy)-3-((4-((2-methoxyphenyl)amino)cyclohexyl)prop-2-ol (I-02), 1-(9H-carbazole-4-yl)oxy)-3-((4- ... 1-((9H-carbazole-4-yl)oxy)-3-(4-(2-methoxyphenyl)piperazin-1-yl)prop-2-ol (I-04), 1-((9H-carbazole-4-yl)oxy)-3-(6-(2-methoxyphenyl)-2,6-diazaspiro[3.3]hept-2-yl)prop-2-ol (I-05), 1-((9H-carbazole-4-yl)oxy)-3-(9-(2-methoxyphenyl)-3,9-diazaspiro[5.5]+ 1-((9H-carbazol-4-yl)oxy)-3-(7-(2-methoxyphenyl)-2,7-diazaspiro[4.4]nonane-2-yl)prop-2-ol (I-07), 1-((9H-carbazol-4-yl)oxy)-3-(4-((2-methoxyphenyl)amino)piperidin-1-yl)prop-2-ol (I-08), 1-((9H-carbazol-4-yl)oxy)-3-(3-((2-methoxyphenyl)amino)pyrrolidine -1-yl)prop-2-ol (I-09), 1-((9H-carbazole-4-yl)oxy)-3-(3-((2-methoxyphenyl)amino)azacyclobutane-1-yl)prop-2-ol (I-10), 1-((9H-carbazole-4-yl)oxy)-3-(6-(2-methoxyphenyl)-2,6-diazaspiro[3.4]oct-2-yl)prop-2-ol (I-11), 1-((9H-carbazole-4-yl)oxy)-3-(5-(2-methoxyphenyl)hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-yl)prop-2-ol (I-12), 1-((9H-carbazole-4-yl)oxy)-3-(4-(((2-methoxyphenyl)amino)methyl)piperidin-1-yl)prop-2-ol (I-13), 1-((9H-carbazole-4-yl)oxy)-3-(3-(((2-methoxyphenyl)amino)methyl)pyrrolo-1-yl)prop-2-ol (I-14), 1-((9H-carbazole-4-yl)oxy)-3-(3-(((2-methoxyphenyl)amino)methyl)azacyclobutane-1-yl)prop-2-ol (I-15), 1-((9H-carbazole-4-yl)oxy)-3-((3-((2-methoxyphenyl)amino)cyclobutyl) Amino)2-propanol (I-16), 1-((9H-carbazole-4-yl)oxy)-3-((3-((2-methoxyphenyl)amino)cyclopentyl)amino)prop-2-ol (I-17), 1-((9H-carbazole-4-yl)oxy)-3-((6-((2-methoxyphenyl)amino)spiro[3.3]hept-2-yl)amino)prop-2-ol (I-18), 1-((9H-carbazole-4-yl)oxy)-3-((3-((2-methoxyphenyl)amino)cyclohexyl)amino)prop-2-ol (I-19), 1-(((1r,4r)-4-((2-methoxyphenyl)amino)cyclohexyl)amino)-3-(naphthyl-1-yloxy)prop-2-ol (I-20), 1- ((9H-carbazole-2-yl)oxy)-3-(((1r,4r)-4-((2-methoxyphenyl)amino)cyclohexyl)amino)prop-2-ol (I-21), 1-(((1r,4r)-4-((2-methoxyphenyl)amino)cyclohexyl)amino)-3-(naphthyl-2-yloxy)prop-2-ol (I-22), 1-(((1r,4r)-4-((2-methoxyphenyl)amino)cyclohexyl)amino)-3-(3-(phenylamino)phenoxy)prop-2-ol (I-23), 1-((9H-carbazole-3-yl)oxy)-3-(((1r,4r)-4-((2-methoxyphenyl)amino)cyclohexyl)amino)prop-2-ol (I-24), 1-( ((1r,4r)-4-((2-methoxyphenyl)amino)cyclohexyl)amino)-3-(naphth-1-yloxy)prop-2-ol (I-25), 1-((1H-indol-4-yl)oxy)-3-(((1r,4r)-4-((2-methoxyphenyl)amino)cyclohexyl)amino)prop-2-ol (I-26), 1-(4-cyclohexylphenoxy)-3-(((1r,4r)-4-((2-methoxyphenyl)amino)cyclohexyl)amino)prop-2-ol (I-27), 1-((1H-indol-5-yl)oxy)-3-(((1r,4r)-4-((2-methoxyphenyl)amino)cyclohexyl)amino)prop-2-ol (I-28), 1-(((1r,4r)-4-((2-methoxyphenyl)amino)cyclohexyl)amino)prop-2-ol (I-28), 1-(((1r,4r)-4-((2-methoxyphenyl)amino)cyclohexyl)amino)-3-(4-phenoxyphenoxy)prop-2-ol (I-29), 5-(2-hydroxy-3-(((1r,4r)-4-((2-methoxyphenyl)amino)cyclohexyl)amino)propoxy)-3,4-dihydroquinoline-2(1H)-one (I-30), 6-(2-hydroxy-3-(((1r,4r)-4-((2-methoxyphenyl)amino)cyclohexyl)amino)propoxy)-3,4-dihydroquinoline-2(1H)-one (31), 1-(((1r,4r)-4-((2-methoxyphenyl)amino)cyclohexyl)amino)-3-((2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1 -ij] Quinolin-8-yl)oxy)prop-2-ol (I-32), 1-(((1r,4r)-4-((2-methoxyphenyl)amino)cyclohexyl)amino)-3-phenoxyprop-2-ol (I-33), 1-(4-benzylphenoxy)-3-(((1r,4r)-4-((2-methoxyphenyl)amino)cyclohexyl)amino)prop-2-ol (I-34), 1-(((1r,4r)-4-((2-methoxyphenyl)amino)cyclohexyl)amino)-3-(4-(phenylamino) )phenoxy)prop-2-ol (I-35), 1-([1,1'-biphenyl]-4-yloxy)-3-(((1r,4r)-4-((2-methoxyphenyl)amino)cyclohexyl)amino)prop-2-ol (I-36), 1-([1,1'-biphenyl]-3-yloxy)-3-(((1r,4r)-4-((2-methoxyphenyl)amino)cyclohexyl)amino)prop-2-ol (I-37), N-(3-(2-hydroxy-3-(((1r,4r)-4-((2-methoxyphenyl)) Acetamide (I-38), 1-([1,1'-biphenyl]-2-yloxy)-3-(((1r,4r)-4-((2-methoxyphenyl)amino)cyclohexyl)amino)prop-2-ol (I-39), 1-(((1r,4r)-4-((2-methoxyphenyl)amino)cyclohexyl)amino)-3-(4-phenoxyphenoxy)prop-2-ol (I-40), 1-(4-(benzyloxy)phenoxy)-3-(((1r,4r)- 4-((2-methoxyphenyl)amino)cyclohexyl)amino)prop-2-ol (I-41), 1-(((1r,4r)-4-((2-methoxyphenyl)amino)cyclohexyl)amino)-3-((5,6,7,8-tetrahydronaphthyl-2-yl)oxy)prop-2-ol (I-42), 1-((2,3-dihydro-1H-indene-5-yl)oxy)-3-(((1r,4r)-4-((2-methoxyphenyl)amino)cyclohexyl)amino)prop-2-ol (I-43), 1-(((1r,4r)-4-((2-methoxyphenyl)amino)cyclohexyl)amino)-3-(m-tolyloxy)prop-2-ol (I-44), 1-(((1r,4r)-4-((2-methoxyphenyl)amino)cyclohexyl)amino)-3-(4-(naphthyl-2-ylamino)phenoxy)prop-2-ol (I-45), 1-(((1r,4r)-4-((2-methoxyphenyl)amino)cyclohexyl)amino)-3-(4-(quinolin-6-ylamino)phenoxy)prop-2-ol (I-46 ... r)-4-((2-methoxyphenyl)amino)cyclohexyl)amino)-3-(4-(pyridin-2-ylamino)phenoxy)prop-2-ol (I-47), 1-(((1r,4r)-4-((2-methoxyphenyl)amino)cyclohexyl)amino)-3-(4-(pyridin-2-ylamino)phenoxy)prop-2-ol (I-48), 1-(4-((2,3-dihydro-1H-indole-5-yl)amino)phenoxy)-3-(((1r,4r)-4-((2-methoxyphenyl)amino)cyclohexyl)amino)2-propanol (I-49), 1-(((1r,4r)-4-((2-methoxyphenyl)amino)cyclohexyl)amino)-3-(4-((1-methyl-1H-indole-5-yl)amino)phenoxy)prop- 2-Alcohol (I-50), 1-(((1r,4r)-4-((2-methoxyphenyl)amino)cyclohexyl)amino)-3-(4-(thiophen-3-ylamino)phenoxy)prop-2-ol (I-51), 1-(((1r,4r)-4-((2-methoxyphenyl)amino)cyclohexyl)amino)-3-(4-(thiophen-3-ylamino)phenoxy)prop-2-ol (I-52), 1-(((1r,4r)-4-((2-methoxyphenyl)amino)cyclohexyl)amino)-3-(4-((5,6,7,8-tetrahydronaphthyl-2-yl)amino)phenoxy) 2-Propanol (I-53), 1-(((1s,4s)-4-((2-methoxyphenyl)amino)cyclohexyl)amino)-3-(4-(phenylamino)phenoxy)prop-2-ol (I-54), 1-([1,1'-biphenyl]-4-yloxy)-3-(((1s,4s)-4-((2-methoxyphenyl)amino)cyclohexyl)amino)prop-2-ol (I-55), 1-(((1r,4r)-4-((3-methoxyphenyl) )amino)cyclohexyl)amino)-3-(4-(phenylamino)phenoxy)prop-2-ol (I-56), 1-(((1r,4r)-4-((4-methoxyphenyl)amino)cyclohexyl)amino)-3-(4-(phenylamino)phenoxy)prop-2-ol (I-57), 1-(4-(phenylamino)phenoxy)-3-(((1r,4r)-4-(o-tolylamino)cyclohexyl)amino)prop-2-ol (I-58), -(((1r,4r)-4-((2-ethylphenyl)amino)cyclohexyl)amino)-3-(4-(phenylamino)phenoxy)prop-2-ol (I-59), 1-(((1r,4r)-4-((2-isopropylphenyl)amino)cyclohexyl)amino)-3-(4-(phenylamino)phenoxy)prop-2-ol (I-60), 1-(4-(phenylamino)phenoxy)-3-(((1r,4r)-4-(p-tolylamino)cyclohexyl)amino)prop-2-ol (I-61), or 1-(((1r,4r)-4-(phenylamino)cyclohexyl)amino)-3-(4-(phenylamino)phenoxy)prop-2-ol (I-62).

3. The hydroxypropylcyclic amine compound and its pharmaceutically acceptable salt according to claim 1 or 2, characterized in that, Pharmaceutically acceptable salts include hydrochloride, phosphate, sulfate, acetate, trichloroacetate, lactate, or citrate.

4. Use of the hydroxypropylcycloamine compound of claim 1, 2 or 3 and its pharmaceutically acceptable salt in the preparation of an antitumor drug or a medicament for a condition related to cardiac injury caused by an antitumor drug.

5. The use according to claim 4, characterized in that, Antitumor drugs include anthracycline antitumor drugs, nucleoside antitumor drugs, kinase inhibitors, or platinum-based antitumor drugs.

6. The use according to claim 4, characterized in that, The tumor is lung cancer, liver cancer, stomach cancer, breast cancer, colorectal cancer, or a highly activated tumor or disease modified by neddylation.

7. The use according to claim 4, characterized in that, Treatment for heart-related conditions includes myocardial injury, heart failure, or myocardial infarction.

8. The use according to any one of claims 4-7, characterized in that, The hydroxypropylcycloamine compounds exert their anti-tumor function by blocking the ubiquitination-like Neddylation pathway; the β-adrenergic receptor blocking activity and anti-inflammatory and antioxidant activity of the hydroxypropylcycloamine compounds exert their cardioprotective function.

9. The use according to claim 8, characterized in that, The external manifestations of its anti-tumor function and cardioprotective function are significant anti-tumor activity and cardioprotective activity, respectively.

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