Estrogen receptor modulating compounds

Abstract

Compounds of Formula I'as estrogen receptor modulators are described herein. Also described are pharmaceutical compositions and medicaments including compounds described herein, and methods of using such estrogen receptor modulators, alone and in combination with other compounds, for treatment of estrogen receptor mediated or dependent diseases or conditions;

Description

This application is a divisional application of Chinese patent application No. 2019800211037 (filed on January 22, 2019, invention title: estrogen receptor regulatory compound). CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application 62 / 620,441, filed January 22, 2018, pursuant to 35 U.S.SC §119(e). The disclosure of the earlier application is considered part of the disclosure of this application, and the entire contents of that application are incorporated herein by reference. Technical Field

[0002] This article describes compounds (including their pharmaceutically acceptable salts, solvates, metabolites, and prodrugs), methods for preparing such compounds, pharmaceutical compositions comprising such compounds, and methods for treating, preventing, or diagnosing estrogen-sensitive, estrogen receptor-dependent, or estrogen receptor-mediated diseases or conditions using such compounds. Background Technology

[0003] The estrogen receptor (“ER”) is a ligand-activated transcriptional regulatory protein that mediates the induction of a variety of biological effects through its interaction with endogenous estrogens. Endogenous estrogens include 17β-estradiol and estrone. Two isoforms of the estrogen receptor have been identified: ER-α (ESR1) and ER-β (ESR2). Estrogens and estrogen receptors are associated with many diseases or conditions, such as breast cancer, lung cancer, ovarian cancer, colon cancer, prostate cancer, endometrial cancer, uterine cancer, and others, such as infertility, osteoporosis, vaginal atrophy, dyspareunia, contraception, male hypogonadism, gynecomastia, and breast pain. Therefore, they have been found to be useful in treating these and other conditions and diseases that are at least partially attributable to estrogen receptor regulation.

[0004] Selective estrogen receptor modulators (SERMs) are a class of drugs that act on estrogen receptors. They tend to be competitive ligands for estrogen receptors. A distinguishing feature of these substances, compared to pure ER agonists and antagonists (i.e., full agonists and silent antagonists), is their varying effects across different tissues, thus offering the potential for selective inhibition or stimulation of estrogen-like effects in diverse tissues. For example, ER-α is typically found predominantly in the female reproductive tract and breast, while higher levels of ER-β are found in vascular endothelial cells, bone, and male prostate tissue. Different tissues have varying degrees of sensitivity and activity to endogenous estrogens; therefore, SERMs produce estrogenic or anti-estrogenic effects depending on the specific tissue discussed and the percentage of the SERM's intrinsic activity (IA). Furthermore, their levels in various tissues can change in response to physical development, aging, or disease states. ER antagonism occurs through competitive inhibition, where one ligand replaces a more agonistic ligand (e.g., 17β-estradiol) and signals with less or no signaling relative to the agonist ligand. There is a second mode of inhibiting ER agonist signaling, which involves ligand binding to ER and inducing one or more conformations that trigger ER degradation in the proteasome. Typically, degradation is triggered by ubiquitination and / or palmitoylation of ER following the binding event of the degrading compound. Compounds that bind to ER and accelerate its degradation are generally referred to as selective estrogen receptor degraders (“SERDs”). Referring to compounds as SERMs or SERDs is a general approach focusing on their pharmacological aspects. It has been shown that many compounds acting as SERMs imply that they possess at least some agonist activity in some (but not all) ER-expressing tissues and can also trigger at least some receptor degradation. Therefore, it should be understood that many (if not most) compounds falling into the embodiments of this invention represent a range of SERM / SERD activities. Regardless of SERM, SERD, or SERM / SERD, the compounds of this disclosure are capable of implementing the methods disclosed herein. Summary of the Invention

[0005] On the one hand, this document provides compounds of formulas I to VII, I' to X', or pharmaceutically acceptable salts, solvates, or prodrugs thereof, which alter the effects of endogenous estrogen acting via the ER and / or trigger ER degradation, and are therefore usable as agents for the treatment or prevention of diseases or conditions in which the action of estrogen and / or estrogen receptors is related to the etiology or pathology of the disease or condition, or causes at least one symptom of the disease or condition, and in which such action of estrogen and / or estrogen receptors is undesirable. In some embodiments, the compounds disclosed herein are selective estrogen receptor degrading compounds.

[0006] On the one hand, compounds of formulas I to VII, I' to X', or pharmaceutically acceptable salts, solvates, or prodrugs thereof may be used to treat ER-related diseases or conditions, including but not limited to cancer-related ER-α dysfunction, such as breast cancer, lung cancer, colorectal cancer, endometrial cancer, prostate cancer, ovarian cancer, and uterine cancer, including metastatic cancer.

[0007] On the one hand, this document describes compounds of formulas I to VII, I' to X', and their pharmaceutically acceptable salts, solvates, metabolites, and prodrugs. The compounds described herein are estrogen receptor modulators. In some embodiments, compounds of formulas I to VII or I' to X' are estrogen receptor antagonists. In some embodiments, compounds of formulas I to VII or I' to X' exhibit minimal estrogen receptor agonist activity. In some embodiments, in the treatment of cancer, compounds of formulas I to VII or I' to X' can provide improved therapeutic activity, characterized by complete or more durable tumor regression, a lower rate or incidence of treatment resistance, and / or reduced tumor invasiveness.

[0008] In some embodiments, the compounds disclosed herein exhibit high specificity for estrogen receptors and possess desired tissue-selective pharmacological activities. These desired tissue-selective pharmacological activities include, but are not limited to, ER antagonist activity in mammary cells and ER-free agonist activity in uterine cells. In some embodiments, the compounds disclosed herein are estrogen receptor degraders exhibiting full estrogen receptor antagonist activity and negligible or minimal estrogen receptor agonist activity.

[0009] In some embodiments, the compounds disclosed herein are estrogen receptor degraders. In some embodiments, the compounds disclosed herein are estrogen receptor antagonists. In some embodiments, the compounds disclosed herein have minimal or negligible estrogen receptor agonist activity.

[0010] In some embodiments, this document provides compounds consisting of active metabolites, tautomers, pharmaceutically acceptable solvates, pharmaceutically acceptable salts, and prodrugs of compounds selected from formulas I to VII or I' to X'.

[0011] In some embodiments, the present invention describes a compound of formula I, or a pharmaceutically acceptable salt thereof; in: B is either nitrogen or carbon; D stands for carbon; A is a fused ring system selected from the following groups: Each R e Independently select the group consisting of hydrogen, halogen, OH, O(CO)R, O(CO)NR1R2, OPO3, OSO3, and O(SO2)NR1R2, or any two adjacent R values. e Together they form: Each R is independently a C1-C6 alkyl or aryl group; Each of R1 and R2 is independently hydrogen or a C1-C6 alkyl group; Each R3 is hydrogen, C1-C 12 Acyl or C1-C 12 Acyloxy group; Each R4 is independently hydrogen, C1-C3 alkyl, fluorine, or chlorine; Each R h It can be hydrogen or CH3 independently; R g It can be hydrogen, C1-C3 alkyl, C1-C3 fluoroalkyl, CN, fluorine, chlorine or bromine; Each R a Independently, it is H, C1-C3 alkyl, C1-C3 fluoroalkyl, phenyl (optionally substituted by 1-3 groups selected from fluorine, chlorine, C1-C3 alkyl, CN, OC1-C3 alkyl, OH), OH, OC 1-3 Alkyl, CN, fluorine, chlorine, bromine, O(CO)R, O(CO)NR1R2, OPO3, OSO3, O(SO2)NR1R2, or two adjacent R a Together they form: When B is carbon, X is O, S, CH2, NH or a bond; or when B is nitrogen, X is CH2 or a bond. Y and Z are each independently selected from CR f Or N; U and V are each independently selected from CR a Or N; Each R f Independently, it is H, C1-C3 alkyl, OC1-C3 alkyl, fluorine, or chlorine; and W represents -CHR'-CHR'-NH-C1-C4 alkyl, -CHR'-CHR'-NH-C1-C4 fluoroalkyl, -CHR'-CHR'-NH-C3-C6 cycloalkyl, -CHR'-CHR'-NH-C1-C4 alkyl-C3-C6 cycloalkyl. Each R' is independently H or a C1-C3 alkyl group.

[0012] In some embodiments, W is -CH2-CH2-NH-CH2-CH2-CH3; in some embodiments, W is -CH2-CH2-NH-CH2-CH2-CH2F; in some embodiments, W is... In some implementations, W is

[0013] In some embodiments, this document provides pharmaceutical compositions comprising a compound selected from the group consisting of embodiments of formulas I-VII, I' to X' and all structures described herein, and at least one pharmaceutically acceptable excipient.

[0014] In some embodiments, this document provides a method for modulating estrogen receptors in cells, the method comprising administering a compound to the cells, wherein the compound is selected from embodiments of formulas I-VII, I' to X' and all structures described herein, or pharmaceutically acceptable salts thereof.

[0015] In some embodiments, this document provides a method for identifying compounds capable of modulating estrogen receptors, the method comprising contacting cells expressing estrogen receptors with a compound according to Formula I and monitoring the effect of the compound on the cells.

[0016] This document also describes prodrugs of compounds selected from the group consisting of formulas I-VII, I' to X', and all structures described herein. Pharmaceutically acceptable salts of the prodrugs of compounds selected from the group consisting of formulas I-VII, I' to X', and all structures described herein are also described. In some embodiments, a pharmaceutically acceptable salt of the prodrug of a compound of formulas I-VII, I' to X' is a hydrochloride salt.

[0017] In some embodiments, a pharmaceutical composition is described herein comprising a pharmaceutically acceptable salt or prodrug of a compound selected from the group consisting of embodiments of formulas I-VII, I' to X' and all structures described herein, or a compound selected from the group consisting of embodiments of formulas I-VII, I' to X' and all structures described herein. In some embodiments, the pharmaceutical composition is formulated for intravenous injection, subcutaneous injection, oral administration, or topical administration. In some embodiments, the pharmaceutical composition is a tablet, pill, capsule, liquid, suspension, gel, dispersion, solution, emulsion, ointment, or lotion.

[0018] The present invention also provides a method for treating diseases, syndromes, disorders, or symptoms associated with insufficient or excessive estrogen levels in mammals in need (e.g., preventing or improving associated symptoms, or reducing their incidence, mitigating their pathogenesis, promoting their recovery, or delaying their onset), wherein the method comprises administering to the mammal an effective amount of a compound selected from the group consisting of embodiments of formulas I-VII, I' to X', and all structures described herein, or a pharmaceutical composition comprising a compound of formulas I-VII, I' to X', or one of the structures described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In one particular embodiment, the mammal is a human.

[0019] In some aspects, the present invention describes a method for treating prostate cancer, breast cancer, endometrial cancer, lung cancer, hepatocellular carcinoma, lymphoma, multiple endocrine adenomas, vaginal cancer, kidney cancer, thyroid cancer, testicular cancer, leukemia, and ovarian cancer in mammals in need of it (e.g., preventing or improving associated symptoms, or reducing their incidence, mitigating their pathogenesis, promoting their recovery, or delaying their onset), said method comprising administering to said mammal a compound selected from embodiments of formulas I-VII, I' to X', and all structures described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound selected from embodiments of formulas I-VII, I' to X', and all structures described herein (including pharmaceutically acceptable salts thereof) and a pharmaceutically acceptable excipient. In one embodiment, the mammal is a human. In some embodiments, the cancer is positive for ESR1 expression. In some embodiments, the cancer is resistant to prior treatment routes (e.g., prior endocrine therapy). In some embodiments, cancer develops after exposure to one or more agents selected from the group consisting of tamoxifen, toremifene, letrozole, aromasin, anastrozole, and faslodex. In some embodiments, treatment is performed in an adjuvant setting, while in other embodiments, treatment is performed in a metastatic setting. In some embodiments, the SERD and / or SERM compounds disclosed herein are combined with other active compounds, including CDK4 / 6 inhibitors, PI3k inhibitors, mTOR inhibitors, taxanes, and Her2 inhibitors. Detailed Implementation

[0020] As used above and throughout the disclosure, unless otherwise stated, the following terms should be understood to have the following meanings.

[0021] Unless otherwise stated, the following terms used in this application (including the specification and claims) have the definitions given below. It must be noted that, as used in the specification and appended claims, the singular forms “a,” “an,” and “the” include plural indicators unless the context clearly indicates otherwise. Unless otherwise stated, conventional methods of mass spectrometry, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques, and pharmacology are employed. In this application, “or” and “and” are used to mean “and / or” unless otherwise stated. Furthermore, the use of the term “including” and other forms (e.g., “include,” “includes,” and “included”) is non-limiting. Section headings used herein are for organizational purposes only and should not be construed as limiting the subject matter.

[0022] The term "bond" or "single bond" refers to a chemical bond between two atoms, or, when atoms connected by a bond are considered part of a larger substructure, a chemical bond between two parts. On the one hand, when the group described herein is a bond, the mentioned group is absent, thus allowing bonds to form between the remaining identified groups.

[0023] The term "moiety" refers to a specific segment or functional group of a molecule. A chemical moiety is typically a recognized chemical entity that is embedded in or attached to a molecule.

[0024] In some cases, compounds can exist as tautomers. All tautomers are included within the scope of the compounds presented herein.

[0025] As used herein, the term “modulate” refers to interacting with a target, directly or indirectly, to alter the target’s activity, including, by way of example, enhancing, inhibiting, limiting, or prolonging the target’s activity.

[0026] As used herein, the term "modulator" refers to a molecule that interacts directly or indirectly with a target. This interaction includes, but is not limited to, interactions between agonists, partial agonists, inverse agonists, antagonists, degraders, or combinations thereof. In some embodiments, the modulator is an antagonist. In some embodiments, the modulator is a degrader.

[0027] As used herein, "selective estrogen receptor modulator" or "SERM" refers to a molecule that differentially modulates estrogen receptor activity in different tissues. For example, in some embodiments, a SERM exhibits ER antagonist activity in some tissues and ER agonist activity in others. In some embodiments, a SERM exhibits ER antagonist activity in some tissues and minimal or no ER agonist activity in others. In some embodiments, a SERM exhibits ER antagonist activity in breast tissue, ovarian tissue, endometrial tissue, and / or cervical tissue.

[0028] As used in this article, the term "antagonist" refers to a small molecule drug that binds to the nuclear hormone receptor and subsequently reduces agonist-induced transcriptional activity of the nuclear hormone receptor.

[0029] As used in this article, the term "agonist" refers to a small molecule agent that binds to the nuclear hormone receptor and subsequently increases the transcriptional activity of the nuclear hormone receptor in the absence of a known agonist.

[0030] As used in this article, the term "reverse agonist" refers to a small molecule agent that binds to the nuclear hormone receptor and subsequently reduces the basal level of nuclear hormone receptor transcriptional activity in the absence of a known agonist.

[0031] As used herein, the term "degrading agent" refers to a small molecule agent that binds to a nuclear hormone receptor and subsequently reduces the homeostatic protein level of said receptor. In some embodiments, the degrading agent as described herein reduces homeostatic estrogen receptor levels by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95%. In some embodiments, the degrading agent as described herein reduces homeostatic estrogen receptor levels by at least 65%. In some embodiments, the degrading agent as described herein reduces homeostatic estrogen receptor levels by at least 85%.

[0032] As used herein, “selective estrogen receptor degrader” or “SERD” refers to a small molecule agent that preferentially binds to estrogen receptors compared to other receptors and subsequently reduces homeostatic estrogen receptor levels. Additionally, SERD can refer to a compound that degrades more in one cell or tissue type than in another, thus potentially expressing SERM-type activity, while its degradation varies depending on the cellular or tissue environment.

[0033] As used in this article, the term "estrogen receptor dependent" refers to a disease or condition that would not occur or would not occur to the same degree in the absence of estrogen receptors.

[0034] As used in this article, the term "estrogen receptor-mediated" refers to a disease or condition that is at least partially dependent on estrogen signaling states.

[0035] As used herein, the term "estrogen receptor sensitive" refers to a disease or condition that would not occur or would not occur to the same degree in the absence of estrogen. Estrogen receptor sensitive also refers to cells or tissues that respond to the presence of estrogen receptor agonists, antagonists, SERMs, and / or SERDs.

[0036] As used in this article, the term "cancer" refers to the abnormal growth of cells that tend to proliferate in an uncontrolled manner and, in some cases, to metastasize (spread). Types of cancer include, but are not limited to, solid tumors (such as solid tumors of the bladder, intestines, brain, breast, endometrium, heart, kidneys, lungs, uterus, lymphoid tissue (lymphoma), ovary, pancreas or other endocrine organs (thyroid), prostate or skin (melanoma or basal cell carcinoma)) or hematologic malignancies with or without metastasis at any stage of the disease (such as leukemia and malignant lymphoma).

[0037] As used herein, the term "co-administration" refers to treatment regimens that include administering selected therapeutic agents to a single patient and are intended to include treatment regimens in which agents are administered via the same or different routes of administration or at the same or different times.

[0038] As used herein, the term "effective amount" or "therapeutic effective amount" refers to an adequate amount of a drug or compound administered that alleviates one or more symptoms of the disease or condition being treated to a certain degree. The result may be a reduction and / or relief of the signs, symptoms, or cause of the disease, or any other desired alteration of the biological system. For example, an "effective amount" for therapeutic use is the amount of a composition containing a compound disclosed herein that provides a clinically significant reduction in the symptoms of a disease. An appropriate "effective" amount in any individual case can be determined using techniques such as dose-escalation studies.

[0039] As used herein, the terms “enhance” or “enhancing” refer to increasing or prolonging the potency or duration of a desired effect. Therefore, in relation to enhancing the effect of a therapeutic agent, the term “enhancing” refers to the ability to increase or prolong the effect of another therapeutic agent on the system in terms of potency or duration. As used herein, “enhancing effective amount” refers to an amount sufficient to enhance the effect of another therapeutic agent in the desired system.

[0040] As used herein, the term "drug combination" refers to a product obtained by mixing or combining one or more active ingredients, including fixed and non-fixed combinations of active ingredients. The term "fixed combination" refers to an active ingredient (e.g., compounds of formulas I to VII, I' to X', or pharmaceutically acceptable salts thereof) and an adjuvant, both administered simultaneously to a patient as a single entity or dose. The term "non-fixed combination" refers to an active ingredient (e.g., compounds of formulas I to VII, I' to X', or pharmaceutically acceptable salts thereof) and an adjuvant, which may be administered simultaneously, concurrently, or sequentially as single entities to a patient without specific intervention time restrictions, wherein such administration provides effective levels of both compounds in the patient. The latter also applies to "cocktail therapy," such as the administration of three or more active ingredients.

[0041] The terms “kit” and “product” are used as synonyms.

[0042] The terms "subject" or "patient" include mammals. Examples of mammals include, but are not limited to, any member of the mammal class: humans, non-human primates (such as chimpanzees and other apes and monkeys); livestock (such as cattle, horses, sheep, goats, and pigs); domestic animals (such as rabbits, dogs, and cats); and laboratory animals (including rodents such as rats, mice, and guinea pigs). In some implementations, the mammal is a human.

[0043] As used herein, the terms “treat,” “treating,” and “treatment” include relieving, reducing, or improving at least one symptom of a disease or condition, preventing additional symptoms, inhibiting a disease or condition, such as preventing the development of a disease or condition, alleviating a disease or condition, causing the remission of a disease or condition, relieving symptoms caused by a disease or condition, or preventing and / or therapeutically stopping the symptoms of a disease or condition.

[0044] In the context of this disclosure, the phrases “formula I through VII”, “formula I to VII”, or “formula I-VII” in each case refer to compounds comprising formulas I, II, IIa, IIb, IIc, IId, IIe, IIf, IIg, IIh, IIj, III, IIIa, IIIb, IIIc, IIId, IIIe, IIIf, IV, IVa, IVb, IVc, IVd, IVe, IVf, IVg, IVh, IVj, V, Va, Vb, Vc, Vd, Ve, Vf, Vg, Vh, VI, VIa, VIb, VIc, VId, VIe, VIf, VIg, VIh, and VII.

[0045] As used herein, the term "alkyl" refers to straight-chain and branched hydrocarbon groups having a number of carbon atoms within a specified range. For example, C 1-4 Alkyl groups refer to linked hydrocarbon groups that may contain 1-4 carbon atoms, with the remaining valences filled by hydrogen atoms. This definition also includes each permutation individually, as if it were listed separately. Therefore, C 1-2 Alkyl groups include methyl and ethyl. Term C 1-3 Alkyl groups include methyl, ethyl, propyl, and 2-propyl. Term C 1-4 Alkyl groups include methyl, ethyl, n-propyl, 2-propyl, n-butyl, 2-butyl, isobutyl, and tert-butyl. Term C 1-5 Alkyl groups include methyl, ethyl, 2-propyl, n-butyl, 2-methylbutyl, tert-butyl, n-pentyl, pent-2-yl, pent-3-yl, tert-pentyl, and isopentyl.

[0046] As used in this article, the term "halogen" refers to a group consisting of fluorine, chlorine, bromine, or iodine.

[0047] The term "haloalkyl" refers to the same alkyl group as defined by the term "alkyl," except that the alkyl group additionally has 1-5 halogen atoms linked to the alkyl chain. For example, C1 haloalkyl groups include -CH2F, -CHF2, -CF3, etc. 1-2 Alkyl halides include --CH2F, CHF2, CF3, --CH2CH2F, --CH2CHF2, --CH2CF3, --CF2CHF2, --CF2CF3, etc. C 1-3 Alkyl halides are defined as including -CH2F, -CHF2, -CF3, -CH2CF3, -CHFCF3, -CF2CF3, -CHClCH3, -CH2CH2Cl, -CH2CH2CH2F, -CH2CH2CF3, etc. C 1-4Alkyl halides are defined as including -CH2F, -CHF2, -CF3, -CH2CF3, -CHFCF3, -CF2CF3, -CHClCH3, -CH2CH2Cl, -CH2CH2CF3, -CH2CH2CH2CF3, CHClCF2CH2CH3, CF2CH2CH2CHF2, CH2CH2CH2CH2F, CH2CH2CH2CH2Cl, etc. The term "fluoroalkyl" in "C1-C4 fluoroalkyl" includes straight or branched C1, C2, C3, and C4 alkyl chains having 1 to 4 fluorine atoms, such as --CH2CH2F, --CH2CHF2, --CH2CF3, --CF2CHF2, --CH2F, --CHF2, --CF3, --CH2CF3, --CHFCF3, --CF2CF3, --CH2CH2CF3, CH2CH2CH2F, --CH2CH2CH2CF3, CF2CH2CH2CHF2, CH2CH2CH2CH2F, CH(CH3)CH2F, CH2(CH)(CH3)CH2F, CH2(CH)(CH2F)(CH2F).

[0048] The term "aryl" refers to a monocyclic six- to fourteen-membered single-carbon ring or a bicyclic ring, wherein the monocyclic ring is aromatic and at least one ring in the bicyclic ring is aromatic. Unless otherwise stated, the valence of the group can be located on any atom of any ring within the group, provided that the valence rules permit. Representative examples include phenyl, naphthyl, and indanyl.

[0049] The term "acyl" refers to a group having the general formula -(CO)-alkyl, wherein the alkyl group is the same as defined by the term "alkyl", and wherein the alkyl portion of the acyl group has a number of carbon atoms falling within a specified range.

[0050] The term "acyloxy" refers to a group having the general formula -O(CO)-alkyl, wherein the alkyl group is the same as defined by the term "alkyl", and wherein the alkyl portion of the acyloxy group has a number of carbon atoms falling within a specified range.

[0051] The compounds of this invention may contain at least one stereocenter and thus exist in various stereoisomer forms. Stereoisomers are compounds that differ only in their spatial arrangement. Enantiomers are stereoisomer pairs whose mirror images are not superimposed, most commonly because they contain asymmetrically substituted carbon atoms that act as the chiral center. "Enantiomer" refers to one of a pair of molecules that are mirror images of each other and are not superimposed. Diastereomers are stereoisomers independent of mirror images, most commonly because they contain two or more asymmetrically substituted carbon atoms. "R" and "S" represent the configuration of the substituents surrounding one or more chiral carbon atoms. Thus, "R" and "S" represent the relative configuration of the substituents surrounding one or more chiral carbon atoms. When the stereochemistry of the disclosed compounds is named or described by structure, the named or described stereoisomer has a purity of at least 50 wt%, 60 wt%, 70 wt%, 80 wt%, 90 wt%, 95 wt%, 98 wt%, 99 wt%, or 99.9 wt% relative to other stereoisomers. When a single enantiomer is named or described by structure, the optical purity of the described or named enantiomer is at least 50 wt%, 60 wt%, 70 wt%, 80 wt%, 90 wt%, 95 wt%, 98 wt%, 99 wt%, or 99.9 wt%. The weight percentage of optical purity is the ratio of the weight of the enantiomer to the weight of the enantiomer plus the weight of its optical isomer.

[0052] The compounds of the present invention can be prepared as individual isomers by introducing or starting with specific isomers, isomer-specific synthesis, separation of diastereomers, or resolution from mixtures of isomers. Conventional resolution techniques include using optically active acids to form salts of the free bases of the isomers of isomer pairs (followed by fractional crystallization and regeneration of the free bases), using optically active amines to form salts of the acidic forms of the isomers of the isomer pairs (followed by fractional crystallization and regeneration of the free acids), using optically pure acids, amines, or alcohols to form esters or amides of the isomers of the isomer pairs (followed by chromatographic separation and removal of chiral auxiliaries), or using various known chromatographic methods to resolve mixtures of isomers of starting materials or final products.

[0053] Use of compounds of formulas I to VII or I' to X', or compositions comprising compounds of formulas I to VII or I' to X', wherein the compound contains at least one stereoisomer center, refers to the racemic mixture of the compounds of formulas I to VII or I' to X' in the composition or any optical purity, including but not limited to optically pure compounds.

[0054] In some embodiments, the enantiomer ratio of compounds of formulas I to VII or I' to X' having a stereoisomer center is greater than 90:10. In some embodiments, the enantiomer ratio of compounds of formulas I to VII or I' to X' is greater than 95:5. In some embodiments, the enantiomer ratio of compounds of formulas I to VII or I' to X' is greater than 99:1. In some embodiments, the compounds of formulas I to VII or I' to X' are optically pure.

[0055] When compounds of formulas I to VII or I' to X' include one or more basic sites (such as amines), acid addition salts can be prepared, and this invention includes such acid addition salts. Some representative (non-limiting) acid addition salts include hydrochlorides, hydrobroms, hydroiodates, acetates, benzenesulfonates, methanesulfonates, besylates, benzoates, toluenesulfonates, citrates, tartrates, sulfates, hydrogen sulfates, lactates, maleates, mandelates, valerates, laurates, caprylates, propionates, succinates, phosphates, salicylates, napsylates, nitrates, tannates, resorcinates, etc., including multiprotic salts and mixtures of acid addition salts. In the presence of amines, this invention also includes quaternary ammonium salts of those amines. Similarly, when compounds of this invention include one or more acidic sites (such as carboxylic acids, phenols, etc.), base addition salts can be prepared, and this invention includes such base addition salts. For example, some representative (non-limiting) acidic compounds of the present invention may exist in their lithium, sodium, potassium, ammonium, trialkylammonium, calcium, magnesium, barium, etc.

[0056] The compounds of this invention may also exist in the form of solvates, and such solvates are included within the scope of this invention even if not explicitly described. These solvates are preferably hydrates, but may be solvates composed of other solvents, preferably humans, when those solvents are considered non-toxic or at least acceptable for administration to mammals. Solvates may be stoichiometric or non-stoichiometric, single or combined. Some exemplary solvates include water, ethanol, acetic acid, etc.

[0057] When used as a therapeutic agent, the compounds of the present invention can be administered by any method known to those skilled in the art, such as oral, buccal, intravenous, subcutaneous, intramuscular, transdermal, intradermal, intravascular, intranasal, sublingual, intracranial, rectal, intratumoral, intravaginal, intraperitoneal, lung, eye, and intratumoral administration.

[0058] When administered, the compounds and compositions of the present invention may be given once or more daily, such as twice, three times or four times daily.

[0059] In one embodiment of the invention, the compound is administered orally when it can be formulated into a solid dosage form or a liquid dosage form. Solid dosage forms may be tablets, granules, capsules, pills, powders, etc. Liquid dosage forms include syrups, solutions, gels, suspensions, elixirs, emulsions, colloids, oils, etc.

[0060] As previously stated, the compounds of the present invention may be solids, and when present as solids, they may have defined particle sizes. When the compounds of the present invention are not particularly water-soluble, it is sometimes preferable to administer compounds having a certain particle size, which has a preferred range, wherein the average particle diameter is less than 100 micrometers, or 75 micrometers, or 50 micrometers, or 35 micrometers, or 10 micrometers, or 5 micrometers.

[0061] The solid dosage form will contain at least one compound of the present invention and one or more pharmaceutical excipients.

[0062] The solid dosage forms of the present invention also include capsules, wherein the drug is encapsulated in the form of powder together with optional excipients or in the form of granules, the granules typically comprising one or more excipients and the drug, and wherein the granules may, in turn, optionally be coated, for example, enteric or non-enteric coated.

[0063] The compounds of the present invention can be used alone or in combination with other therapeutic agents. As a non-limiting example, the compounds of the present invention can be used in combination with one or more of cdk4 / 6 inhibitors, PI3K inhibitors, mTOR inhibitors, and taxanes.

[0064] The compounds of the present invention can be administered according to different dosage regimens, and the dosage can be adjusted as deemed necessary by the subject or preferably through consultation between the subject and a qualified medical practitioner. The compounds of the present invention can be administered via multiple routes; therefore, the dosage and administration regimen depend not only on the specific subject's weight, sex, age, and the treatment under consideration, but also on the chosen route of administration.

[0065] As a non-limiting example, the compounds of the present invention can be considered as being administered orally with the goal of achieving optimal efficacy and / or safety.

[0066] It should be understood that the amount of the compound administered daily can be daily, every other day, every two days, every three days, every four days, every five days, etc. For example, in the case of administration every other day, a dose of 5 mg daily can be started on Monday, with the first refill of 5 mg daily on Wednesday, followed by a second refill of 5 mg daily on Friday, and so on. In one embodiment, the compound is administered once every seven days.

[0067] The present invention also provides a method for treating diseases, syndromes, disorders, or symptoms associated with insufficient or excessive estrogen levels in mammals in need of such treatment (e.g., preventing or improving associated symptoms, or reducing their incidence, mitigating their pathogenesis, promoting their recovery, or delaying their onset), wherein the method comprises administering to the mammal an effective amount of a compound selected from the group consisting of embodiments of formulas I-VII, I' to X', and all structures described herein, or a pharmaceutical composition comprising a compound of formulas I-VII, I' to X', or one of the structures described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In one particular embodiment, the mammal is a human.

[0068] In some aspects, the present invention describes a method for treating prostate cancer, breast cancer, endometrial cancer, lung cancer, hepatocellular carcinoma, lymphoma, multiple endocrine adenomas, vaginal cancer, kidney cancer, thyroid cancer, testicular cancer, leukemia, and ovarian cancer in mammals in need of it (e.g., preventing or improving associated symptoms, or reducing their incidence, mitigating their pathogenesis, promoting their recovery, or delaying their onset), said method comprising administering to said mammal a compound selected from embodiments of formulas I-VII, I' to X', and all structures described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound selected from embodiments of formulas I-VII, I' to X', and all structures described herein (including pharmaceutically acceptable salts thereof) and a pharmaceutically acceptable excipient. In one embodiment, the mammal is a human. In some embodiments, the cancer is positive for ESR1 expression. In some embodiments, the cancer is resistant to prior treatment routes (e.g., prior endocrine therapy). In some embodiments, cancer develops after exposure to one or more agents selected from the group consisting of tamoxifen, toremifene, letrozole, aromasin, anastrozole, and faslodex. In some embodiments, treatment is performed in an adjuvant setting, while in others, treatment is performed in a metastatic setting. In some embodiments, the SERD and / or SERM compounds disclosed herein are combined with other active compounds, including CDK4 / 6 inhibitors, PI3k inhibitors, mTOR inhibitors, taxanes, and Her2 inhibitors.

[0069] This document also provides a method for inhibiting tumor growth or inducing tumor regression in a subject with estrogen receptor α-positive cancer, the method comprising administering to the subject a therapeutically effective amount of a compound of formulas I to VII or I' to X', or a pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the estrogen receptor α-positive cancer is drug-resistant estrogen receptor α-positive cancer. In some embodiments, the cancer is selected from breast cancer, uterine cancer, ovarian cancer, and pituitary cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is metastatic. In some embodiments, the cancer is positive for a mutant estrogen receptor α, said mutant estrogen receptor α comprising one or more mutations selected from Y537X1 (where X1 is S, N, or C), L536X2 (where X2 is R or Q), P535H, V534E, S463P, V392I, E380Q, D538G, and combinations thereof. In some embodiments, the mutation is Y537S. In some embodiments, the subject has osteoporosis or is at high risk of developing osteoporosis. In some embodiments, the subject is a premenopausal woman. In some embodiments, the subject is a postmenopausal woman who has relapsed or progressed after prior treatment with SERM, CDK inhibitors, and / or AIs. In some embodiments, the tumor is resistant to a drug selected from the group consisting of anti-estrogens (e.g., tamoxifen or fulvestrant), aromatase inhibitors (e.g., arnoxin), CDK inhibitors (e.g., abemaciclib, ribociclib, or palbociclib), and combinations thereof. In some embodiments, a therapeutically effective amount of a compound of formulas I to VII or I' to X', or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is used in combination with one or more of anti-estrogens, aromatase inhibitors, CDK inhibitors, PI3K inhibitors, mTOR inhibitors, and taxanes.

[0070] This document also provides a method for inhibiting tumor growth or inducing tumor regression in a subject with a mutant estrogen receptor α-positive cancer, the method comprising administering to the subject a therapeutically effective amount of a compound of formulas I to VII or I' to X', or a pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the cancer is selected from breast cancer, uterine cancer, ovarian cancer, and pituitary cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is metastatic. In some embodiments, the cancer is positive for a mutant estrogen receptor α, said mutant estrogen receptor α comprising one or more mutations selected from Y537X1 (where X1 is S, N, or C), L536X2 (where X2 is R or Q), P535H, V534E, S463P, V392I, E380Q, D538G, and combinations thereof. In some embodiments, the mutation is Y537S. In some embodiments, the subject has osteoporosis or is at high risk of osteoporosis. In some embodiments, the subject is a premenopausal woman. In some embodiments, the subject is a postmenopausal woman who has relapsed or progressed after prior treatment with SERM, CDK inhibitors, and / or AIs. In some embodiments, the tumor is resistant to a drug selected from the group consisting of anti-estrogens (e.g., tamoxifen or fulvestrant), aromatase inhibitors (e.g., arnoxin), CDK inhibitors (e.g., abemaciclib, ribociclib, or palbociclib), and combinations thereof. In some embodiments, a therapeutically effective amount of a compound of formulas I to VII or I' to X', or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is used in combination with one or more of anti-estrogens, aromatase inhibitors, CDK inhibitors, PI3K inhibitors, mTOR inhibitors, and taxanes.

[0071] This article also provides a method for treating breast cancer in a subject with drug-resistant estrogen receptor α-positive cancer, the method comprising administering to the subject a therapeutically effective amount of a compound of formulas I to VII or I' to X', or a pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the drug-resistant breast cancer is resistant to one or more anti-estrogens (e.g., tamoxifen, toremifene, fulvestrant), CDK inhibitors (e.g., abecilib, nivolumab, or palbociclib), and / or aromatase inhibitors (e.g., anoxin, letrozole, anastrozole). In some embodiments, a therapeutically effective amount of a compound of formulas I to VII or I' to X', or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is used in combination with one or more of anti-estrogens, aromatase inhibitors, CDK inhibitors, PI3K inhibitors, mTOR inhibitors, and taxanes. In some embodiments, the subject expresses at least one mutant estrogen receptor α selected from D538G, Y537S, Y537N, Y537C, E380Q, S463P, L536R, L536Q, P535H, V392I, and V534E. In some embodiments, the mutant estrogen receptor α is selected from Y537S, Y537N, Y537C, D538G, L536R, S463P, and E380Q. In some embodiments, the mutant receptor α is Y537S. In some embodiments, the subject is a postmenopausal woman.In some implementations, treatment of a subject is first identified by measuring an increase in the expression of one or more genes selected from ABL1, AKT1, AKT2, ALK, APC, AR, ARID1A, ASXL1, ATM, AURKA, BAP, BAP1, BCL2L11, BCR, BRAF, BRCA1, BRCA2, CCND1, CCND2, CCND3, CCNE1, CDH1, CDK4, CDK6, CDK8, CDKN1A, CDKN1B, CDKN2A, CDKN2B, CEBPA, CTNNB1, DDR2, DNMT3A, E2F3, EGFR, EML4, EPHB2, ERBB2, ERBB3, ESR1, EWSR1, FBXW7, FGF4, FGFR1, FG FR2, FGFR3, FLT3, FRS2, HIF1A, HRAS, IDH1, IDH2, IGF1R, JAK2, KDM6A, KDR, KIF5B, KIT, KRAS, LRP1B, MAP2K1, MAP2K4, MCL1, MDM2, MDM4, MET, MGMT, MLL, MPL, MSH6, MTOR, MYC, NF1, N F2, NKX2-1, NOTCH1, NPM, NRAS, PDGFRA, PIK3CA, PIK3R1, PML, PTEN, PTPRD, RARA, RB1, RET, RICTOR, ROS1, RPTOR, RUNX1, SMAD4, SMARCA4, SOX2, STK11, TET2, TP53, TSC1, TSC2, and VHL. In some implementations, one or more genes are selected from AKT1, AKT2, BRAF, CDK4, CDK6, PIK3CA, PIK3R1, and MTOR.

[0072] The compounds of this invention can be prepared by a variety of synthetic routes and techniques known to those skilled in the art. The methods disclosed herein should not be considered as limiting the examples or scope of the invention in any way, but are provided merely as some representative ways in which the compounds of this invention can be prepared.

[0073] In some cases, protecting groups are employed in the synthesis of the compounds of the present invention, and it should be understood that there are various protecting groups and strategies that can be employed in organic synthesis (TWGreen and PGMWuts (2006) Greene's Protective Groups in Organic Synthesis, the entire contents of which are incorporated herein by reference), and any suitable protecting group should be considered when referring to protecting groups in general.

[0074] In some cases, leaving groups are employed in the synthesis of the compounds of this invention. When a particular leaving group is referred to, it should be understood that other leaving groups may also be used. Leaving groups typically include those groups that can stabilize anions. In the case of nucleophilic aromatic substitution, the leaving group can be an anionic or neutrally charged group. In some cases, leaving groups used for nucleophilic aromatic substitution can be groups that are typically not considered to stabilize anions (e.g., fluorides or hydrides). While not wishing to be bound by theory or examples, some typical nucleophilic leaving groups include halogens, sulfonates (O-methanesulfonates, O-toluenesulfonates, etc.), hydrides, quaternary ammonium amines, nitro groups, etc. Other discussions and examples can be found in major textbooks on organic chemistry, including, for example, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th Edition, the entire contents of which are incorporated herein by reference.

[0075] When any variable appears more than once in any component or formula, its definition in each occurrence is independent of its definition in every other occurrence. Combinations of substituents and / or variables are permitted, provided that such combinations produce stable compounds.

[0076] Therefore, in one embodiment, the present invention provides a novel pharmaceutically active compound of Formula I or a pharmaceutically acceptable salt thereof: in: B is either nitrogen or carbon; D stands for carbon; A is a fused ring system selected from the following groups: Each R e Independently, it can be hydrogen, halogen, OH, O(CO)R, O(CO)NR1R2, OPO3, OSO3, O(SO2)NR1R2, or any of the following, two adjacent Rs. e Together they form: R is a C1-C6 alkyl or aryl group; R1 and R2 are each independently hydrogen or C1-C6 alkyl; Each R3 is hydrogen, C1-C 12 Acyl group; C1-C 12 Acyloxy group; Each R4 is independently hydrogen, C1-C3 alkyl, fluorine, or chlorine; Each R hIt can be hydrogen or CH3 independently; R g It can be hydrogen, C1-C3 alkyl, C1-C3 fluoroalkyl, CN, fluorine, chlorine or bromine; Each R a Independently selected from: H, C1-C3 alkyl, C1-C3 fluoroalkyl, phenyl (optionally substituted by 1-3 groups of fluorine, chlorine, C1-C3 alkyl, CN, OC1-C3 alkyl, OH), OH, OC 1-3 Alkyl groups, CN, fluorine, chlorine, O(CO)R, O(CO)NR1R2, OPO3, OSO3, O(SO2)NR1R2, or two adjacent Ra groups together form: When B is carbon, X is O, S, CH2, NH or a bond; or when B is nitrogen, X is CH2 or a bond. Y and Z are each independently CR f Or N; U and V are each independently CR a Or N; Each R f Independently, it is H, C1-C3 alkyl, OC1-C3 alkyl, fluorine, or chlorine; and W represents -CHR'-CHR'-NH-C1-C4 alkyl, -CHR'-CHR'-NH-C1-C4 fluoroalkyl, -CHR'-CHR'-NH-C3-C6 cycloalkyl, -CHR'-CHR'-NH-C1-C4 alkyl-C3-C6 cycloalkyl. Each R' is independently H or a C1-C3 alkyl group; Or a pharmaceutically acceptable salt, solvate, or prodrug.

[0077] In some embodiments, the compound of formula I is the compound described above. In other embodiments, the compound is a pharmaceutically acceptable salt thereof.

[0078] In some embodiments, the Formula I compound is a pharmaceutically acceptable salt, solvate, or prodrug.

[0079] In some embodiments, the pharmaceutically acceptable salt of the compound is an acid addition salt.

[0080] In other embodiments, the compound of formula I is a prodrug. In other embodiments, the compound of formula I is a pharmaceutically acceptable salt of a prodrug. In some aspects, a pharmaceutically acceptable salt of the prodrug of the compound of formula I is a hydrochloride salt.

[0081] In some embodiments, pharmaceutical compositions comprising a compound of formula I or a pharmaceutically acceptable salt or prodrug of a compound of formula I are described. In other embodiments, the pharmaceutical composition is formulated for intravenous injection, subcutaneous injection, oral administration, or topical administration. In some embodiments, the pharmaceutical composition is a tablet, pill, capsule, liquid, suspension, gel, dispersion, solution, emulsion, ointment, or lotion.

[0082] In some embodiments of the compound of formula I, W is -CH2-CH2-NH-CH2-CH2-CH3; in other embodiments, W is -CH2-CH2-NH-CH2-CH2-CH2F.

[0083] In some embodiments of the compound of formula I, B is carbon. When B is carbon, X is O, S, CH2, NH, or a bond. In some embodiments, when B is carbon, X is O, CH2, or a bond. In other embodiments, B is nitrogen. When B is nitrogen, X is CH2 or a bond. In some embodiments, when B is nitrogen, X is CH2.

[0084] In some embodiments of the compound of formula I, A is selected from the group consisting of:

[0085] In other embodiments of the compound of formula I, A is:

[0086] In some embodiments of the compound of formula I, B and D are adjacent ring atoms on ring A.

[0087] In some other embodiments of the compound of formula I, each R e Independently, it can be hydrogen, halogen, OH, O(CO)R, O(CO)NR1R2, OPO3 and OSO3, O(SO2)NR1R2, or any two adjacent Rs. e Together they form:

[0088] In some embodiments of the compound of formula I, each R e The R is independently selected from the group consisting of hydrogen, halogen, OH, O(CO)R, O(CO)NR1R2, OPO3 and OSO3, O(SO2)NR1R2. In other embodiments of the compound of formula I, each R is selected from the group consisting of hydrogen, halogen, OH, O(CO)R, O(CO)NR1R2, OPO3 and OSO3, O(SO2)NR1R2. e It can be hydrogen or OH on its own.

[0089] In some other embodiments of the compound of formula I, two adjacent R a Together they form: In embodiments of the compound of formula I, wherein two adjacent Ra Together they form: Any other R a Each of these elements is independently hydrogen, halogen, OH, O(CO)R, O(CO)NR1R2, OPO3, OSO3, and O(SO2)NR1R2. In other embodiments of the compound of formula I, at least one R... a For H, or at least two R a For H.

[0090] In some embodiments of the compound of formula I, each R h Independently hydrogen or CH3. In some embodiments of compounds of formula I, at least one R h It is hydrogen; in other embodiments of the compound of formula I, both are hydrogen.

[0091] In other embodiments of the compound of formula I, R is a C1-C6 alkyl group; in other embodiments, R is an aryl group.

[0092] In some embodiments of the compound of formula I, R1 and R2 are each independently hydrogen or C1-C6 alkyl. In some embodiments of the compound of formula I, at least one of R1 and R2 is hydrogen.

[0093] In other embodiments of the compound of formula I, each R3 is hydrogen, C1-C 12 Acyl group; or C1-C 12 Acyloxy group.

[0094] In other embodiments of the Formula I compound, each R4 is independently hydrogen, C1-C3 alkyl, fluorine, or chlorine. When R4 is C1-C3 alkyl, it is methyl, ethyl, or C3 alkyl, or any combination or subcombination thereof. In some embodiments of the Formula I compound, R4 is hydrogen. In some embodiments of the Formula I compound, R4 is fluorine.

[0095] In other embodiments of the compound of formula I, R g It is hydrogen, C1-C3 alkyl, C1-C3 fluoroalkyl, CN, fluorine, chlorine, or bromine. In some embodiments of compounds of formula I, R... g It is hydrogen, C1-C3 alkyl, or fluorine. In other embodiments of the compound of formula I, R... g It is a C1-C3 alkyl group or fluorine. When R... g When it is a C1-C3 alkyl group, it is methyl, ethyl, or C3 alkyl, or any combination or subcombination thereof.

[0096] In some embodiments of the compound of formula I, each R aIndependently selected from H, C1-C3 alkyl, C1-C3 fluoroalkyl, phenyl (optionally substituted by 1-3 groups selected from fluorine, chlorine, C1-C3 alkyl, CN, OC1-C3 alkyl, OH), OH, OC 1-3 The group consisting of alkyl, CN, fluorine, chlorine, O(CO)R, O(CO)NR1R2, OPO3, OSO3 and O(SO2)NR1R2, or two adjacent Ra together: In some embodiments of the compound of formula I, each R a Independently selected from H, C1-C3 alkyl, C1-C3 fluoroalkyl, or phenyl (optionally substituted by 1-3 groups selected from fluorine, chlorine, C1-C3 alkyl, OC1-C3 alkyl, OH), OH, OC 1-3 Alkyl, fluorine, chlorine. In other embodiments of compounds of formula I, R a Located at the ortho or para position of the bond connected to D, in some embodiments of compounds of formula I, Ra is a -OCH3 bonded to the para position of the bond connected to D, and in some embodiments of compounds of formula I, R... a It is a methyl group attached to the ortho position of the bond linked to D. In some other embodiments of compounds of formula I, the two adjacent R groups are... a Together they form: In the implementation, two adjacent R a Together they form: Any other R a Each is independently selected from hydrogen, halogen, OH, O(CO)R, O(CO)NR1R2, OPO3, OSO3 and O(SO2)NR1R2.

[0097] In some other embodiments of the compound of Formula I, when B is carbon, X is O, S, CH2, NH, or a bond; or when B is nitrogen, X is CH2 or a bond. In other embodiments of the compound of Formula I, B is carbon and X is O, CH2, or a bond. In some embodiments, when B is carbon, X is O or CH2.

[0098] In some embodiments of the compound of formula I, Y and Z are each independently selected from CR. f Or N, and U and V are each independently selected from CR a Or N. In some embodiments of the compound of formula I, Y is CR. f In other embodiments of the compound of formula I, Y is N. In some embodiments of the compound of formula I, U is CR. a In some embodiments of the compound of formula I, Z is CR. f In some embodiments of the compound of formula I, V is CR. aIn some embodiments of the compound of formula I, Y and Z are each CR. f And U and V are each CR a .

[0099] In some embodiments of the compound of formula I, each R f Independently, it is H, C1-C3 alkyl, fluorine, or chlorine. In some embodiments of compounds of formula I, each R... f For H.

[0100] In other embodiments of the compound of formula I, W is -CHR'-CHR'-NH-C1-C4 alkyl, -CHR'-CHR'-NH-C1-C4 fluoroalkyl, -CHR'-CHR'-NH-C3-C6 cycloalkyl, -CHR'-CHR'-NH-C1-C4 alkyl-C3-C6 cycloalkyl, Each R' is independently H or a C1-C3 alkyl group or any combination or subcombination thereof; when W is -CHR'-CHR'-NH-C1-C4 alkyl, each R' is independently methyl, ethyl, C3 alkyl, or hydrogen, or any combination or subcombination thereof. In some embodiments of the compound of formula I, when W is -CHR'-CHR'-NH-C1-C4 fluoroalkyl, each R' is independently methyl, ethyl, C3 alkyl, or any combination or subcombination thereof, wherein 1-3 fluorine atoms are attached to an alkyl group. In other embodiments of the compound of formula I, when W is -CHR'-CHR'-NH-C3-C6 cycloalkyl, the C3-C6 cycloalkyl group is cyclopropyl or cyclobutyl. In other embodiments of the compound of formula I, when W is -CHR'-CHR'-NH-C1-C4alkyl-C3-C6cycloalkyl, each R' is independently methyl, ethyl, C3alkyl, or C4alkyl, or any combination or subcombination thereof, and the C3-C6 cycloalkyl is cyclopropyl or cyclobutyl. In some embodiments, the C1-C4 alkyl is C1 alkyl. In some other embodiments of the compound of formula I, when W is In this case, the C1-C6 alkyl group is methyl, ethyl, or C3 alkyl. In other embodiments of the compound of formula I, when W is... In this case, the C1-C6 alkyl group is methyl, ethyl, or C3 alkyl, wherein 1-3 fluorine atoms are attached to the alkyl group. In some embodiments, W is -CH2-CH2-NH-CH2-CH2-CH3; in some embodiments, W is -CH2-CH2-NH-CH2-CH2-CH2F; in some embodiments, W is... In some implementations, W is In some embodiments, W is -CH2-CH2-NH-CH2-CH3; in some embodiments, W is -CH2-CH2-NH-cyclopropyl; in some embodiments, W is -CH2-CH2-NH-CH2-cyclopropyl.

[0101] In some embodiments, the present invention describes compounds of formula I having a structure of formula II or pharmaceutical salts thereof: in Each R a Independently selected from H, C1-C3 alkyl, phenyl (optionally substituted by 1-3 groups selected from fluorine, chlorine, C1-C3 alkyl, CN, OC1-C3 alkyl, OH), OH, OC 1-3 Alkyl, CN, fluorine, chlorine, O(CO)R, O(CO)NR1R2, OPO3, OSO3, O(SO2)NR1R2, or two adjacent R a Together they form: R is a C1-C6 alkyl or aryl group; R1 and R2 are each independently hydrogen or C1-C6 alkyl; Each R3 is independently hydrogen; C1-C 12 Acyl or C1-C 12 Acyloxy group; Each R4 is independently hydrogen, C1-C3 alkyl, fluorine, or chlorine; Each R e Independently selected from hydrogen, halogen, OH, O(CO)R, O(CO)NR1R2, OPO3, OSO3, O(SO2)NR1R2, or two adjacent Rs. e Together they form: Each R f Independently, it is H, C1-C3 alkyl, OC1-C3 alkyl, fluorine, or chlorine; R g It can be hydrogen, C1-C3 alkyl, C1-C3 fluoroalkyl, CN, fluorine, chlorine or bromine; X is CH2 or a bond; Y and Z are each independently selected from CR f Or N; U and V are each independently selected from CR a Or N; and W represents -CHR'-CHR'-NH-C1-C4 alkyl, -CHR'-CHR'-NH-C1-C4 fluoroalkyl, -CHR'-CHR'-NH-C3-C6 cycloalkyl, -CHR'-CHR'-NH-C1-C4 alkyl-C3-C6 cycloalkyl. Each R' is independently H or a C1-C3 alkyl group.

[0102] In some embodiments of the compound of formula II, W is -CH2-CH2-NH-CH2-CH2-CH3; in some embodiments of the compound of formula II, W is -CH2-CH2-NH-CH2-CH2-CH2F; in some embodiments of the compound of formula II, W is In some embodiments of the compound of formula II, W is

[0103] In some embodiments of the compound of formula II, X is CH2.

[0104] In other embodiments of the compound of formula II, Y and Z are each CR f And U and V are each CR a .

[0105] In some embodiments of the compound of formula II, each R a Independently selected from H, C1-C3 alkyl, C1-C3 fluoroalkyl, phenyl (optionally substituted by 1-3 groups selected from fluorine, chlorine, C1-C3 alkyl, CN, OC1-C3 alkyl, OH), OH, OC 1-3 Alkyl, CN, fluorine, and chlorine.

[0106] In some other embodiments of the compound of formula II, two adjacent R e Together they form: In some embodiments of the compound of formula II, two adjacent R e Together they form: Wherein, R4 is H. In some other embodiments of the compound of formula II, two adjacent R... e Together they form: Wherein, R4 is fluorine. In some embodiments of the compound of formula II, two adjacent R... e Together they form: Where R4 is H.

[0107] In some other embodiments of the compound of formula II, two adjacent R e Together they form: R4 is fluorine.

[0108] In some embodiments of the compound of formula II, two adjacent Re are formed together: R3 is hydrogen.

[0109] In some embodiments of the compound of formula II, two adjacent Re are formed together: In this case, R3 is hydrogen and R4 is hydrogen.

[0110] In some embodiments of the compound of formula II, two adjacent R e Together they form: In this case, R3 is hydrogen and R4 is fluorine.

[0111] In some embodiments of the compound of formula II, each R e It is independently selected from H and OH.

[0112] In other embodiments of the compound of formula II, R f It is H or fluorine.

[0113] In other embodiments of the compound of formula II, R f For H.

[0114] In other embodiments of the compound of formula II, W is -CHR'-CHR'-NH-C1-C4 alkyl or -CHR'-CHR'-NH-C1-C4 fluoroalkyl, wherein each R' is independently H or C1-C3 alkyl. In some embodiments, one or more R's are H.

[0115] In some embodiments of the compound of formula II, W is -CHR'-CHR'-NH-C3-C6 cycloalkyl, or -CHR'-CHR'-NH-C1-C4 alkyl-C3-C6 cycloalkyl, wherein each R' is independently H or C1-C3 alkyl. In some embodiments of the compound of formula II, one or more R's are H. In other embodiments of the compound of formula II, W contains a C3-C6 cycloalkyl moiety, wherein the cycloalkyl group is C3-C4 cycloalkyl.

[0116] In other embodiments of the compound of formula II, W is In some embodiments, W is -CH2-CH2-NH-CH2-CH2-CH3; in some embodiments, W is -CH2-CH2-NH-CH2-CH2-CH2F; in some embodiments, W is... In some implementations, W is In some embodiments, W is -CH2-CH2-NH-CH2-CH3; in some embodiments, W is -CH2-CH2-NH-cyclopropyl; in some embodiments, W is -CH2-CH2-NH-CH2-cyclopropyl.

[0117] In other embodiments of the compound of formula II, R g It is hydrogen, C1-C3 alkyl, or fluorine. In other embodiments, R g R is methyl; in other embodiments, R g It is fluorine.

[0118] In some embodiments of the compound of formula II, each R f For H. In other embodiments of the compound of formula II, when R f When it is H, each R e It is independently selected from H and OH.

[0119] In some other embodiments of the compound of formula II, R a At least one of them is OCH3, fluorine, -OH, -CH3 or chlorine.

[0120] Some embodiments of compounds of formula II have formula IIa, IIb or IIc:

[0121] In some embodiments, the compound of formula II has formula IId, IIe, or IIf:

[0122] In other embodiments, the compound of formula II has formula IIg, IIh, or IIj:

[0123] In some embodiments, the compounds of formula II, IIa, IIb, IIc, IId, IIe, IIf, IIg, IIh, or IIj are pharmaceutically acceptable salts, solvates, or prodrugs.

[0124] In some embodiments, the pharmaceutically acceptable salt of the compound is an acid addition salt.

[0125] In other embodiments, the compounds of formula II, IIa, IIb, IIc, IId, IIe, IIf, IIg, IIh, or IIj are prodrugs. In other embodiments, the compound of formula II is a pharmaceutically acceptable salt of a prodrug. In some aspects, the pharmaceutically acceptable salt of the prodrug of the compounds of formula II, IIa, IIb, IIc, IId, IIe, IIf, IIg, IIh, or IIj is a hydrochloride salt.

[0126] In some embodiments, pharmaceutical compositions comprising compounds of formulas II, IIa, IIb, IIc, IId, IIe, IIf, IIg, IIh, or IIj, or pharmaceutically acceptable salts or prodrugs thereof, are described. In other embodiments, the pharmaceutical composition is formulated for intravenous injection, subcutaneous injection, oral administration, or topical administration. In some embodiments, the pharmaceutical composition is a tablet, pill, capsule, liquid, suspension, gel, dispersion, solution, emulsion, ointment, or lotion.

[0127] In some embodiments, the present invention describes compounds of formula I having a structure of formula III or pharmaceutical salts thereof: in Each R a Independently selected from H, C1-C3 alkyl, phenyl (optionally substituted by 1-3 groups selected from fluorine, chlorine, C1-C3 alkyl, CN, OC1-C3 alkyl, OH), OH, OC 1-3 Alkyl, CN, fluorine, chlorine, O(CO)R, O(CO)NR1R2, OPO3, OSO3, O(SO2)NR1R2, or two adjacent R a Together they form: R is a C1-C6 alkyl or aryl group; R1 and R2 are each independently hydrogen or C1-C6 alkyl; Each R3 is independently hydrogen or a C1-C3 alkyl group; Each R4 is independently hydrogen, C1-C3 alkyl, fluorine, or chlorine; Each R e Independently selected from hydrogen, halogen, OH, O(CO)R, O(CO)NR1R2, OPO3, OSO3, O(SO2)NR1R2, or two adjacent Rs. e Together they form: Each R f Independently, it is H, C1-C3 alkyl, fluorine, or chlorine; X is O, CH2, N, S, or a bond; Y and Z are each independently selected from CR f Or N; U and V are each independently selected from CR a Or N; and W represents -CHR'-CHR'-NH-C1-C4 alkyl, -CHR'-CHR'-NH-C1-C4 fluoroalkyl, -CHR'-CHR'-NH-C3-C6 cycloalkyl, -CHR'-CHR'-NH-C1-C4 alkyl-C3-C6 cycloalkyl. Each R' is independently H or a C1-C3 alkyl group.

[0128] In some embodiments, W is -CH2-CH2-NH-CH2-CH2-CH3; in some embodiments, W is -CH2-CH2-NH-CH2-CH2-CH2F; in some embodiments, W is... In some implementations, W is In some embodiments, W is -CH2-CH2-NH-CH2-CH3; in some embodiments, W is -CH2-CH2-NH-cyclopropyl; in some embodiments, W is -CH2-CH2-NH-CH2-cyclopropyl.

[0129] In some embodiments of the compound of formula III, X is O.

[0130] In other embodiments of the compound of formula III, Y and Z are each CR f And U and V are each CR a .

[0131] In some embodiments of the compound of formula III, each R a Independently selected from H, phenyl, OH, OC 1-3 Alkyl, fluorine, and chlorine. In other embodiments of the compounds of formula III, each R a Independently selected from H, phenyl, OH, OCH3, fluorine, and chlorine. In some embodiments of compounds of formula III, R a Independently selected from H, OCH3, fluorine, and chlorine. In some other embodiments of the compound of formula III, R a At least one of them is OCH3, fluorine, or chlorine. In some embodiments, R a It can be C 1-3 alkyl.

[0132] In some other embodiments of the compound of formula III, two adjacent R e Together they form: In some embodiments of the compound of formula III, two adjacent R e Together they form: Where R4 is H.

[0133] In some other embodiments of the compound of formula III, two adjacent R eTogether they form: R4 is fluorine.

[0134] In some embodiments of the compound of formula III, two adjacent R e Together they form: Where R4 is H.

[0135] In some other embodiments of the compound of formula III, two adjacent R e Together they form: R4 is fluorine.

[0136] In some embodiments of the compound of formula III, each R e The components are independently selected from H and OH. In other embodiments, R... f H is used. In some implementations, one or more R's are H.

[0137] In other embodiments of the compound of formula III, W is -CHR'-CHR'-NH-C1-C4 alkyl or -CHR'-CHR'-NH-C1-C4 fluoroalkyl, wherein one or more R's are H or C1-C3 alkyl. In some embodiments, one or more R's are H.

[0138] In some embodiments of the compound of formula III, W is -CHR'-CHR'-NH-C3-C6 cycloalkyl, or -CHR'-CHR'-NH-C1-C4 alkyl-C3-C6 cycloalkyl, wherein each R' is independently H or C1-C3 alkyl. In some embodiments, one or more R's are H. In other embodiments, W contains a C3-C6 cycloalkyl moiety, wherein the cycloalkyl group is C3-C4 cycloalkyl.

[0139] In other embodiments of the compound of formula III, W is In some embodiments, W is -CH2-CH2-NH-CH2-CH2-CH3; in some embodiments, W is -CH2-CH2-NH-CH2-CH2-CH2F; in some embodiments, W is... In some implementations, W is

[0140] In some other embodiments of the compound of formula III, R a At least one of them is OCH3, fluorine, or chlorine.

[0141] In some implementations, R a At least one of them is -CH3.

[0142] In some embodiments of the compound of formula III, each Rf For H. In other embodiments of the compound of formula III, when R f When it is H, each R e It is independently selected from H and OH.

[0143] Some embodiments of the compound of formula III have formula IIIa, IIIb or IIIc:

[0144] In some embodiments, the compound of formula III has formula IIId, IIIe, or IIIf:

[0145] In some other embodiments, the compound of formula III has formula IIIg, IIIh, or IIIj:

[0146] In some embodiments, compounds of formula III, IIIa, IIIb, IIIc, IIId, IIIe, or IIIf are pharmaceutically acceptable salts, solvates, or prodrugs.

[0147] In some embodiments, the pharmaceutically acceptable salt of the compound is an acid addition salt.

[0148] In other embodiments, the compound of formula III is a prodrug. In other embodiments, the compound of formula III, IIIa, IIIb, IIIc, IIId, IIIe, or IIIf is a pharmaceutically acceptable salt of the prodrug. In some aspects, the pharmaceutically acceptable salt of the prodrug of the compound of formula III, IIIa, IIIb, IIIc, IIId, IIIe, or IIIf is a hydrochloride salt.

[0149] In some embodiments, pharmaceutical compositions are described that comprise compounds of formula III, IIIa, IIIb, IIIc, IIId, IIIe, or IIIf, or pharmaceutically acceptable salts or prodrugs thereof. In other embodiments, the pharmaceutical composition is formulated for intravenous injection, subcutaneous injection, oral administration, or topical administration. In some embodiments, the pharmaceutical composition is a tablet, pill, capsule, liquid, suspension, gel, dispersion, solution, emulsion, ointment, or lotion.

[0150] In some embodiments, the present invention describes compounds of formula I having the structure of formula IV, or pharmaceutical salts thereof: in Each R aIndependently selected from H, C1-C3 alkyl, phenyl (optionally substituted by 1-3 groups selected from fluorine, chlorine, C1-C3 alkyl, CN, OC1-C3 alkyl, OH), OH, OC 1-3 Alkyl, CN, fluorine, chlorine, O(CO)R, O(CO)NR1R2, OPO3, OSO3, O(SO2)NR1R2, or two adjacent R a Together they form: R is a C1-C6 alkyl or aryl group; R1 and R2 are each independently hydrogen or C1-C6 alkyl; Each R3 is independently hydrogen or a C1-C3 alkyl group; Each R4 is independently hydrogen, C1-C3 alkyl, fluorine, or chlorine; Each R e Independently selected from hydrogen, halogen, OH, O(CO)R, O(CO)NR1R2, OPO3, OSO3, O(SO2)NR1R2, or two adjacent Rs. e Together they form: Each R f Independently, it is H, C1-C3 alkyl, fluorine, or chlorine; Y and Z are each independently selected from CR f Or N; U and V are each independently selected from CR a Or N; and W represents -CHR'-CHR'-NH-C1-C4 alkyl, -CHR'-CHR'-NH-C1-C4 fluoroalkyl, -CHR'-CHR'-NH-C3-C6 cycloalkyl, -CHR'-CHR'-NH-C1-C4 alkyl-C3-C6 cycloalkyl. Each R' is independently H or a C1-C3 alkyl group.

[0151] In some embodiments, W is -CH2-CH2-NH-CH2-CH2-CH3; in some embodiments, W is -CH2-CH2-NH-CH2-CH2-CH2F; in some embodiments, W is... In some implementations, W is In some embodiments, W is -CH2-CH2-NH-CH2-CH3; in some embodiments, W is -CH2-CH2-NH-cyclopropyl; in some embodiments, W is -CH2-CH2-NH-CH2-cyclopropyl.

[0152] In some embodiments of the compound of formula IV, X is CH2.

[0153] In other embodiments of the compound of formula IV, Y and Z are each CR f And U and V are each CR a .

[0154] In some embodiments of the compound of formula IV, each R a Independently selected from H, phenyl, OH, OC 1-3 Alkyl, fluorine, and chlorine. In other embodiments, each R... a The components are independently selected from H, phenyl, OH, OCH3, fluorine, and chlorine. In some embodiments, R... a Independently selected from H, OCH3, fluorine, and chlorine. In some other embodiments of the compound of formula IV, R a At least one of them is methyl, OCH3, fluorine or chlorine.

[0155] In some other embodiments of the compound of formula IV, two adjacent R e Together they form: In some embodiments of the compound of formula IV, two adjacent R e Together they form: Where R4 is H.

[0156] In some other embodiments of the compound of formula IV, two adjacent R e Together they form: R4 is fluorine.

[0157] In some embodiments of the compound of formula IV, two adjacent R e Together they form: Where R4 is H.

[0158] In some other embodiments of the compound of formula IV, two adjacent R e Together they form: R4 is fluorine.

[0159] In some embodiments of the compound of formula IV, each R e Independently selected from H and OH. In other embodiments of the compound of formula IV, R f In some embodiments of the compound of formula IV, one or more R' are H.

[0160] In other embodiments of the compound of formula IV, W is -CHR'-CHR'-NH-C1-C4 alkyl or -CHR'-CHR'-NH-C1-C4 fluoroalkyl, wherein each R' is independently H or C1-C3 alkyl. In some embodiments of the compound of formula IV, each R' is independently H.

[0161] In some embodiments of the compound of formula IV, W is -CHR'-CHR'-NH-C3-C6 cycloalkyl, or -CHR'-CHR'-NH-C1-C4 alkyl-C3-C6 cycloalkyl, wherein each R' is independently H or C1-C3 alkyl. In some embodiments of the compound of formula IV, one or more R's are H. In other embodiments of the compound of formula IV, W contains a C3-C6 cycloalkyl moiety, wherein the cycloalkyl group is C3-C4 cycloalkyl.

[0162] In other embodiments of the compound of formula IV, W is In some embodiments, W is -CH2-CH2-NH-CH2-CH2-CH3; in some embodiments, W is -CH2-CH2-NH-CH2-CH2-CH2F; in some embodiments, W is... In some implementations, W is In this embodiment, each R' is independently H or a C1-C3 alkyl group. In some embodiments of the compound of formula IV, one or more R's are H. In some embodiments of the compound of formula IV, each R... f For H. In other embodiments of the compound of formula IV, when R f When it is H, each R e It is independently selected from H and OH.

[0163] Some embodiments of compounds of formula IV have formula IVa or IVb:

[0164] In some embodiments of the compound of formula IV, the compound of formula IV has formula IVc, IVd, IVe, or IVf:

[0165] In other embodiments of the compound of formula IV, the compound of formula IV has formula IVg, IVh, or IVj:

[0166] In some embodiments, the compounds of formula IV, IVa, IVb, IVc, IVd, IVe, IVf, IVg, IVh, or IVj are pharmaceutically acceptable salts, solvates, or prodrugs.

[0167] In some embodiments, the pharmaceutically acceptable salt of the compound is an acid addition salt.

[0168] In other embodiments, the compound of formula IV, IVa, IVb, IVc, IVd, IVe, IVf, IVg, IVh, or IVj is a prodrug. In other embodiments, the compound of formula IV, IVa, IVb, IVc, IVd, IVe, IVf, IVg, IVh, or IVj is a pharmaceutically acceptable salt of the prodrug. In some aspects, the pharmaceutically acceptable salt of the prodrug of the compound of formula IV, IVa, IVb, IVc, IVd, IVe, IVf, IVg, IVh, or IVj is a hydrochloride salt.

[0169] In some embodiments, pharmaceutical compositions comprising compounds of formulas IV, IVa, IVb, IVc, IVd, IVe, IVf, IVg, IVh, or IVj, or pharmaceutically acceptable salts or prodrugs thereof, are described. In other embodiments, the pharmaceutical composition is formulated for intravenous injection, subcutaneous injection, oral administration, or topical administration. In some embodiments, the pharmaceutical composition is a tablet, pill, capsule, liquid, suspension, gel, dispersion, solution, emulsion, ointment, or lotion.

[0170] In some embodiments, the present invention describes compounds of formula I having the structure of formula V or pharmaceutical salts thereof: in Each R a Independently selected from H, C1-C3 alkyl, phenyl (optionally substituted by 1-3 groups selected from fluorine, chlorine, C1-C3 alkyl, CN, OC1-C3 alkyl, OH), OH, OC 1-3 Alkyl, CN, fluorine, chlorine, O(CO)R, O(CO)NR1R2, OPO3, OSO3, O(SO2)NR1R2, or two adjacent R a Together they form: R is a C1-C6 alkyl or aryl group; R1 and R2 are each independently hydrogen or C1-C6 alkyl; Each R3 is independently hydrogen or a C1-C3 alkyl group; Each R4 is independently hydrogen, C1-C3 alkyl, fluorine, or chlorine; Each R e Independently selected from hydrogen, halogen, OH, O(CO)R, O(CO)NR1R2, OPO3, OSO3, O(SO2)NR1R2, or two adjacent Rs. e Together they form: Each R f Independently, it is H, C1-C3 alkyl, fluorine, or chlorine; Each R h Independently selected from hydrogen or CH3; X is O, CH2, N, S, or a bond; Y and Z are each independently selected from CR f Or N; U and V are each independently selected from CR a Or N; and W is -CHR'-CHR'-NH-C1-C4 alkyl, -CHR'-CHR'-NH-C1-C4 fluoroalkyl, -CHR'-CHR'-NH-C3-C6 cycloalkyl, -CHR'-CHR'-NH-C1-C4 alkyl-C3-C6 cycloalkyl; wherein each R' is independently H or C1-C3 alkyl.

[0171] In some embodiments, W is -CH2-CH2-NH-CH2-CH2-CH3; in some embodiments, W is -CH2-CH2-NH-CH2-CH2-CH2F; in some embodiments, W is... In some implementations, W is In some embodiments, W is -CH2-CH2-NH-CH2-CH3; in some embodiments, W is -CH2-CH2-NH-cyclopropyl; in some embodiments, W is -CH2-CH2-NH-CH2-cyclopropyl. In some embodiments of the compound of formula V, X is a bond.

[0172] In other embodiments of the compound of formula V, Y and Z are each CR f And U and V are each CR a .

[0173] In some embodiments of the compound of formula V, each R a Independently selected from H, phenyl, OH, OC 1-3 Alkyl, fluorine, and chlorine. In other embodiments of compounds of formula V, each R... a Independently selected from H, phenyl, OH, OCH3, fluorine, and chlorine. In some embodiments of compounds of formula V, R a Independently selected from H, OCH3, fluorine, and chlorine. In some other embodiments of the compound of formula V, R a At least one of them is methyl, OCH3, fluorine or chlorine.

[0174] In some other embodiments of the compound of formula V, two adjacent R e Together they form: In some embodiments of the compound of formula V, two adjacent R e Together they form: Where R4 is H.

[0175] In some other embodiments of the compound of formula V, two adjacent R e Together they form: R4 is fluorine.

[0176] In some embodiments of the compound of formula V, two adjacent R e Together they form: Where R4 is H.

[0177] In some other embodiments of the compound of formula V, two adjacent R e Together they form: R4 is fluorine.

[0178] In some embodiments of the compound of formula V, each R e Independently selected from H and OH. In other embodiments of the compound of formula V, R f In some embodiments of the compound of formula V, one or more R' are H.

[0179] In other embodiments of the compound of formula V, W is -CHR'-CHR'-NH-C1-C4 alkyl or -CHR'-CHR'-NH-C1-C4 fluoroalkyl, wherein each R' is independently H or C1-C3 alkyl. In some embodiments of the compound of formula V, one or more R's are H.

[0180] In some embodiments of the compound of formula V, W is -CHR'-CHR'-NH-C3-C6 cycloalkyl, or -CHR'-CHR'-NH-C1-C4 alkyl-C3-C6 cycloalkyl, wherein each R' is independently H or C1-C3 alkyl. In some embodiments of the compound of formula V, one or more R's are H. In other embodiments of the compound of formula V, W contains a C3-C6 cycloalkyl moiety, wherein the cycloalkyl group is C3-C4 cycloalkyl.

[0181] In other embodiments of the compound of formula V, W is In some embodiments, W is -CH2-CH2-NH-CH2-CH2-CH3; in some embodiments, W is -CH2-CH2-NH-CH2-CH2-CH2F; in some embodiments, W is... In some implementations, W is Each R' is independently H or a C1-C3 alkyl group. In some embodiments of the compound of formula V, one or more R's are H.

[0182] In some embodiments of the compound of formula V, R fEach is H. In other embodiments of the compound of formula V, when R... f When it is H, each R e It is independently selected from H and OH.

[0183] Some embodiments of compounds of formula V have formula Va or Vb:

[0184] In some embodiments, the compound of formula V has the formulas Vc, Vd, Ve, or Vf:

[0185] In some embodiments, the compounds of formula V, Va, Vb, Vc, Vd, Ve, Vf, Vg, or Vh are pharmaceutically acceptable salts, solvates, or prodrugs. In some embodiments, for compounds of formula V, Va, Vb, Vc, Vd, Ve, Vf, Vg, or Vh, at least one R f It is fluorine, and in some embodiments, the fluorine is at the 2-position, if two R f If they are both fluorine, then they are at positions 2 and 6.

[0186] In some embodiments, the pharmaceutically acceptable salt of the compound is an acid addition salt.

[0187] In other embodiments, the compound of formula V, Va, Vb, Vc, Vd, Ve, Vf, Vg, or Vh is a prodrug. In other embodiments, the compound of formula V, Va, Vb, Vc, Vd, Ve, Vf, Vg, or Vh is a pharmaceutically acceptable salt of the prodrug. In some aspects, the pharmaceutically acceptable salt of the prodrug of the compound of formula V, Va, Vb, Vc, Vd, Ve, Vf, Vg, or Vh is a hydrochloride salt.

[0188] In some embodiments, pharmaceutical compositions comprising compounds of the formula V, Va, Vb, Vc, Vd, Ve, Vf, Vg, or Vh, or pharmaceutically acceptable salts or prodrugs thereof, are described. In other embodiments, the pharmaceutical composition is formulated for intravenous injection, subcutaneous injection, oral administration, or topical administration. In some embodiments, the pharmaceutical composition is a tablet, pill, capsule, liquid, suspension, gel, dispersion, solution, emulsion, ointment, or lotion.

[0189] In some embodiments, the present invention describes compounds of formula I having the structure of formula VI, or pharmaceutical salts thereof: in Each R aIndependently selected from H, C1-C3 alkyl, phenyl (optionally substituted by 1-3 groups selected from fluorine, chlorine, C1-C3 alkyl, CN, OC1-C3 alkyl, OH), OH, OC 1-3 Alkyl, CN, fluorine, chlorine, O(CO)R, O(CO)NR1R2, OPO3, OSO3, O(SO2)NR1R2, or two adjacent R a Together they form: R is a C1-C6 alkyl or aryl group; R1 and R2 are each independently hydrogen or C1-C6 alkyl; Each R3 is independently hydrogen or a C1-C3 alkyl group; Each R4 is independently hydrogen, C1-C3 alkyl, fluorine, or chlorine; Each R e Independently selected from hydrogen, halogen, OH, O(CO)R, O(CO)NR1R2, OPO3, OSO3, O(SO2)NR1R2, or two adjacent Rs. e Together they form: Each R f Independently, it is H, C1-C3 alkyl, fluorine, or chlorine; Each R h Independently selected from hydrogen or CH3; Y and Z are each independently selected from CR f Or N; U and V are each independently selected from CR a Or N; and W represents -CHR'-CHR'-NH-C1-C4 alkyl, -CHR'-CHR'-NH-C1-C4 fluoroalkyl, -CHR'-CHR'-NH-C3-C6 cycloalkyl, -CHR'-CHR'-NH-C1-C4 alkyl-C3-C6 cycloalkyl. Each R' is independently H or a C1-C3 alkyl group.

[0190] In some embodiments, W is -CH2-CH2-NH-CH2-CH2-CH3; in some embodiments, W is -CH2-CH2-NH-CH2-CH2-CH2F; in some embodiments, W is... In some implementations, W is In some embodiments of the compound of formula VI, X is a bond.

[0191] In other embodiments of the compound of formula VI, Y and Z are each CR fAnd U and V are each CR a .

[0192] In some embodiments of the compound of formula VI, each R a Independently selected from H, phenyl, OH, OC 1-3 Alkyl, fluorine, and chlorine. In other embodiments of compounds of formula VI, each R a Independently selected from H, phenyl, OH, OCH3, fluorine, and chlorine. In some embodiments of compounds of formula VI, R a Independently selected from H, OCH3, fluorine, and chlorine. In some other embodiments of the compound of formula VI, R a At least one of them is methyl, OCH3, fluorine or chlorine.

[0193] In some other embodiments of the compound of formula VI, two adjacent R e Together they form: In some embodiments of the compound of formula VI, two adjacent R e Together they form: Where R4 is H.

[0194] In some other embodiments of the compound of formula VI, two adjacent R e Together they form: R4 is fluorine.

[0195] In some embodiments of the compound of formula VI, two adjacent R e Together they form: Where R4 is H.

[0196] In some other embodiments of the compound of formula VI, two adjacent R e Together they form: R4 is fluorine.

[0197] In some embodiments of the compound of formula VI, each R e Independently selected from H and OH. In other embodiments of the compound of formula VI, R f In some embodiments of compounds of formula VI, one or more R' are H.

[0198] In other embodiments of the compound of formula VI, W is -CHR'-CHR'-NH-C1-C4 alkyl or -CHR'-CHR'-NH-C1-C4 fluoroalkyl, wherein each R' is independently H or C1-C3 alkyl. In some embodiments of the compound of formula VI, one or more R's are H.

[0199] In some embodiments of the compound of formula VI, W is -CHR'-CHR'-NH-C3-C6 cycloalkyl, or -CHR'-CHR'-NH-C1-C4 alkyl-C3-C6 cycloalkyl, wherein each R' is independently H or C1-C3 alkyl. In some embodiments of the compound of formula VI, one or more R's are H. In other embodiments of the compound of formula VI, W contains a C3-C6 cycloalkyl moiety, wherein the cycloalkyl group is C3-C4 cycloalkyl.

[0200] In other embodiments of the compound of formula VI, W is In some embodiments, W is -CH2-CH2-NH-CH2-CH2-CH3; in some embodiments, W is -CH2-CH2-NH-CH2-CH2-CH2F; in some embodiments, W is... In some implementations, W is Each R' is independently H or a C1-C3 alkyl group. In some embodiments of the compound of formula VI, one or more R's are H.

[0201] In some embodiments of the compound of formula VI, each R f For H. In other embodiments of the compound of formula VI, when R f When it is H, each R e It is independently selected from H and OH.

[0202] Some embodiments of compounds of formula VI have formula VIa or VIb:

[0203] In some embodiments, the compound of formula VI has the formulas VIc, VId, VIe, VIf, VIg, or VIh:

[0204] In some embodiments, the compounds of formula VI, VIa, VIb, VIc, VId, VIe, VIf, VIg, or VIh are pharmaceutically acceptable salts, solvates, or prodrugs.

[0205] In some embodiments, the pharmaceutically acceptable salt of the compound is an acid addition salt. In other embodiments, the compound of formula VI, VIa, VIb, VIc, VId, VIe, VIf, VIg, or VIh is a prodrug. In other embodiments, the compound of formula VI, VIa, VIb, VIc, VId, VIe, VIf, VIg, or VIh is a pharmaceutically acceptable salt of a prodrug. In some aspects, the pharmaceutically acceptable salt of the prodrug of the compound of formula VI, VIa, VIb, VIc, VId, VIe, VIf, VIg, or VIh is a hydrochloride salt.

[0206] In some embodiments, pharmaceutical compositions comprising compounds of formula VI, VIa, VIb, VIc, VId, VIe, VIIf, VIg, or VIh, or pharmaceutically acceptable salts or prodrugs thereof, are described. In other embodiments, the pharmaceutical composition is formulated for intravenous injection, subcutaneous injection, oral administration, or topical administration. In some embodiments, the pharmaceutical composition is a tablet, pill, capsule, liquid, suspension, gel, dispersion, solution, emulsion, ointment, or lotion.

[0207] In some embodiments, a compound comprising the structure of formula VII is disclosed. in Each R a Independently selected from H, C1-C3 alkyl, phenyl (optionally substituted by 1-3 groups selected from fluorine, chlorine, C1-C3 alkyl, CN, OC1-C3 alkyl, OH), OH, OC 1-3 Alkyl, CN, fluorine, chlorine, O(CO)R, O(CO)NR1R2, OPO3, OSO3, O(SO2)NR1R2, or two adjacent R a Together they form: R is a C1-C6 alkyl or aryl group; R1 and R2 are each independently hydrogen or C1-C6 alkyl; Each R3 is independently hydrogen or a C1-C3 alkyl group; Each R4 is independently hydrogen, C1-C3 alkyl, fluorine, or chlorine; Each R e Independently selected from hydrogen, halogen, OH, O(CO)R, O(CO)NR1R2, OPO3, OSO3, O(SO2)NR1R2, or two adjacent Rs. e Together they form: Each R fIndependently, it is H, C1-C3 alkyl, fluorine, or chlorine; R g It can be hydrogen, CH3, F, Cl, or CN; W represents -CHR'-CHR'-NH-C1-C4 alkyl, -CHR'-CHR'-NH-C1-C4 fluoroalkyl, -CHR'-CHR'-NH-C3-C6 cycloalkyl, -CHR'-CHR'-NH-C1-C4 alkyl-C3-C6 cycloalkyl. Each R' is independently H or a C1-C3 alkyl group.

[0208] In some embodiments, W is -CH2-CH2-NH-CH2-CH2-CH3; in some embodiments, W is -CH2-CH2-NH-CH2-CH2-CH2F; in some embodiments, W is... In some implementations, W is

[0209] In some embodiments of the compound of formula VII, each R a Independently selected from H, phenyl, OH, OC 1-3 Alkyl, fluorine, and chlorine. In other embodiments of compounds of formula VII, each R a Independently selected from H, phenyl, OH, OCH3, fluorine, and chlorine. In some embodiments of compounds of formula VII, R a Independently selected from H, OCH3, fluorine, and chlorine. In some other embodiments of the compound of formula VII, R a At least one of them is methyl, OCH3, fluorine or chlorine.

[0210] In some other embodiments of the compound of formula VII, two adjacent R e Together they form: In some embodiments of the compound of formula VII, two adjacent R e Together they form: Where R4 is H.

[0211] In some other embodiments of the compound of formula VII, two adjacent R e Together they form: R4 is fluorine.

[0212] In some embodiments of the compound of formula VII, two adjacent R e Together they form: Where R4 is H.

[0213] In some other embodiments of the compound of formula VII, two adjacent R e Together they form: R4 is fluorine.

[0214] In some embodiments of the compound of formula VII, each R e Independently selected from H and OH. In other embodiments of the compound of formula VII, R f H is used. In some embodiments of compounds of formula VII, one or more R' are H.

[0215] In other embodiments of the compound of formula VII, W is -CHR'-CHR'-NH-C1-C4 alkyl or -CHR'-CHR'-NH-C1-C4 fluoroalkyl, wherein each R' is independently H or C1-C3 alkyl. In some embodiments of the compound of formula VII, one or more R's are H.

[0216] In some embodiments of the compound of formula VII, W is -CHR'-CHR'-NH-C3-C6 cycloalkyl, or -CHR'-CHR'-NH-C1-C4 alkyl-C3-C6 cycloalkyl, wherein each R' is independently H or C1-C3 alkyl. In some embodiments of the compound of formula VI, one or more R's are H. In other embodiments of the compound of formula VII, W contains a C3-C6 cycloalkyl moiety, wherein the cycloalkyl group is C3-C4 cycloalkyl.

[0217] In other embodiments of the compound of formula VII, W is In some embodiments, W is -CH2-CH2-NH-CH2-CH2-CH3; in some embodiments, W is -CH2-CH2-NH-CH2-CH2-CH2F; in some embodiments, W is... In some implementations, W is Each R' is independently H or a C1-C3 alkyl group. In some embodiments of the compound of formula VII, one or more R's are H.

[0218] In some embodiments of the compound of formula VII, each R f For H. In other embodiments of the compound of formula VII, when R f When it is H, each R e It is independently selected from H and OH.

[0219] In some embodiments, a compound according to formula I' is described. in: B is either nitrogen or carbon; D stands for carbon; A is selected from the following fused ring systems: Each R e Independently selected from hydrogen, halogen, OH, O(CO)R, O(CO)NR1R2, OPO3, OSO3, O(SO2)NR1R2, or two adjacent Rs. e Together they form: R is a C1-C6 alkyl or aryl group; R1 and R2 are each independently hydrogen or C1-C6 alkyl; Each R3 is hydrogen, C1-C 12 Acyl group; C1-C 12 Acyloxy group; Each R4 is independently hydrogen, C1-C3 alkyl, fluorine, or chlorine; Each R h Independently selected from hydrogen or CH3; R g It can be hydrogen, C1-C3 alkyl, C1-C3 fluoroalkyl, CN, fluorine, chlorine or bromine; Each R a Independently selected from: H, C1-C3 alkyl, C1-C3 fluoroalkyl, phenyl (optionally substituted by 1-3 groups selected from fluorine, chlorine, C1-C3 alkyl, CN, OC1-C3 alkyl, OH), OH, OC 1-3 Alkyl groups, CN, fluorine, chlorine, O(CO)R, O(CO)NR1R2, OPO3, OSO3, O(SO2)NR1R2, or two adjacent Ra groups together form: When B is carbon, X is O, S, CH2, NH or a bond; or when B is nitrogen, X is CH2 or a bond. Y and Z are each independently selected from CR f Or N; U and V are each independently selected from CR a Or N; Each R f Independently, it is H, C1-C3 alkyl, OC1-C3 alkyl, fluorine, or chlorine; and W represents -CHR'-CHR'-NH-C1-C4 alkyl, -CHR'-CHR'-NH-C1-C4 fluoroalkyl, -CHR'-CHR'-NH-C3-C6 cycloalkyl, -CHR'-CHR'-NH-C1-C4 alkyl-C3-C6 cycloalkyl. Each R' is independently H or a C1-C3 alkyl group; or a pharmaceutically acceptable salt thereof.

[0220] In some embodiments of formula I', W is -CH2-CH2-NH-CH2-CH2-CH3; -CH2-CH2-NH-CH2-CH2-CH2F; or a pharmaceutically acceptable salt thereof.

[0221] In some embodiments, a compound according to formula II' is described: Each R a Independently selected from H, C1-C3 alkyl, phenyl (optionally substituted by 1-3 groups selected from fluorine, chlorine, C1-C3 alkyl, CN, OC1-C3 alkyl, OH), OH, OC 1-3 Alkyl, CN, fluorine, chlorine, O(CO)R, O(CO)NR1R2, OPO3, OSO3, O(SO2)NR1R2, or two adjacent R a Together they form: R is a C1-C6 alkyl or aryl group; R1 and R2 are each independently hydrogen or C1-C6 alkyl; Each R3 is independently hydrogen; C1-C 12 Acyl or C1-C 12 Acyloxy group; Each R4 is independently hydrogen, C1-C3 alkyl, fluorine, or chlorine; Each R e Independently selected from hydrogen, halogen, OH, O(CO)R, O(CO)NR1R2, OPO3, OSO3, O(SO2)NR1R2, or two adjacent Rs. e Together they form: Each R f Independently, it is H, C1-C3 alkyl, OC1-C3 alkyl, fluorine, or chlorine; R g It can be hydrogen, C1-C3 alkyl, C1-C3 fluoroalkyl, CN, fluorine, chlorine or bromine; X is CH2 or a bond; Y and Z are each independently selected from CR f Or N; U and V are each independently selected from CR a Or N; and W represents -CHR'-CHR'-NH-C1-C4 alkyl, -CHR'-CHR'-NH-C1-C4 fluoroalkyl, -CHR'-CHR'-NH-C3-C6 cycloalkyl, -CHR'-CHR'-NH-C1-C4 alkyl-C3-C6 cycloalkyl. Each R' is independently H or a C1-C3 alkyl group; or a pharmaceutically acceptable salt thereof.

[0222] In some embodiments of formula II', X is CH2; Y and Z are each CR. f U and V are each CR a ; R g It is F, Cl or CH3; each Ra is independently selected from H, OH, CH3 and Cl; each R f H is represented by H; W is represented by -CH2-CH2-NH-CH2-CH2-CH3, -CH2-CH2-NH-CH2-CH2-CH2F, or a pharmaceutically acceptable salt thereof.

[0223] In some embodiments of II', each R e Independently selected from hydrogen, OH, or two adjacent R atoms. e Together they form: Where R3 is H and R4 is H.

[0224] In some embodiments, a compound having the structure of formula III' is disclosed: Wherein: Q is H or F; Rg is F, Cl or CH3; Ra is CH3, Cl or OMe; Ra' is H, F or OH; or a pharmaceutically acceptable salt thereof. In some implementations of III', Rg is F. In some embodiments of III', Rg is F; Ra is CH3; Ra' is H. In some embodiments, a compound having structure IV' is disclosed: Wherein: Q is H or F; Rg is F, Cl or CH3; Ra is CH3, Cl or OMe; Ra' is H, F or OH; or a pharmaceutically acceptable salt thereof. In some implementations of IV', Rg is F. In some embodiments of IV', Rg is F; Ra is CH3; Ra' is H. In some embodiments, a compound of formula V' is described: Wherein: Q is H or F; Rg is F, Cl or CH3; Ra is CH3, Cl or OMe; Ra' is H, F or OH; or a pharmaceutically acceptable salt thereof. In some implementations of V', Rg is F. In some implementations of V', Rg is F; Ra is CH3; Ra' is H. In some embodiments, a structure of formula VI' is disclosed: Wherein: Q is H or F; Rg is F, Cl or CH3; Ra is CH3, Cl or OMe; Ra' is H, F or OH; or a pharmaceutically acceptable salt thereof.

[0225] In some embodiments, the Rg of compound VI' is F.

[0226] In some embodiments of VI', Rg is F and Ra is CH3.

[0227] In some implementations of VI', Rg is F; Ra is CH3; Ra' is H.

[0228] In some embodiments of the compound of formula VII', the following are disclosed: Wherein: Q is H or F; Ra is CH3, Cl or OMe; Ra' is H, F or OH; or a pharmaceutically acceptable salt thereof.

[0229] In some embodiments of structure VII', Ra is CH3 and Ra' is H.

[0230] In some embodiments, a structure of formula VIII' is disclosed: Wherein: Q is H or F; Ra is CH3, Cl or OMe; Ra' is H, F or OH; or a pharmaceutically acceptable salt thereof.

[0231] In some implementations, Ra is CH3 and Ra' is H in formula VIII'.

[0232] In some embodiments, a compound of formula IX' is described. Wherein: Q is H or F; Ra is CH3, Cl or OMe; Ra' is H, F or OH; or a pharmaceutically acceptable salt thereof.

[0233] In some implementations of IX', Ra is CH3 and Ra' is H.

[0234] In some embodiments, a compound of formula X' is described: Wherein: Q is H or F; Ra is CH3, Cl or OMe; Ra' is H, F or OH; or a pharmaceutically acceptable salt thereof.

[0235] In some implementations of X', Ra is CH3 and Ra' is H.

[0236] In some embodiments of the compounds of formulas I to VII and I' to X', the enantiomer ratio of the compound is greater than 95:5. In some embodiments, the enantiomer ratio of the compound is greater than 99:1.

[0237] An article is provided comprising: packaging material; a compound of formulas I to VII, I' to X', or a pharmaceutically acceptable salt, active metabolite, prodrug, or pharmaceutically acceptable solvate thereof, or a combination thereof, within the packaging material; and a label indicating that the compound, or a pharmaceutically acceptable salt, active metabolite, prodrug, or pharmaceutically acceptable solvate thereof, or a combination thereof, is used to reduce, attenuate, or eliminate the effect of estrogen receptors, or to treat, prevent, or improve one or more symptoms of a disease or condition that would benefit from a reduction or elimination of estrogen receptor activity.

[0238] Other objects, features, and advantages of the compounds, methods, and compositions described herein will become apparent from the following detailed description. However, it should be understood that the detailed description and specific examples are given only by way of illustration when indicating particular embodiments, as various changes and modifications within the spirit and scope of this disclosure will become apparent to those skilled in the art based on this detailed description.

[0239] The compounds described herein are synthesized using standard synthetic techniques or in combination with methods known in the art. Additionally, the solvents, temperatures, and other reaction conditions given herein may be varied.

[0240] The starting materials used to synthesize the compounds described herein are synthetic or commercially available, such as, but not limited to, Sigma-Aldrich, Fluka, Acros Organics, Alfa Aesar, etc. The compounds described herein and other related compounds with different substituents, including those discovered in March, Advanced Organic Chemistry 4, are synthesized using the techniques and materials described herein or otherwise. th Ed., (Wiley 1992); Carey and Sundberg, ADVANCED ORGANIC CHEMISTRY 4 thEd., Vols. A and B (Plenum 2000, 2001) and Green and Wuts, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS 3 rd The techniques described in Ed. (Wiley 1999). General methods for preparing compounds can be modified by introducing the various parts found in the formulas provided herein using appropriate reagents and conditions.

[0241] In some embodiments, the compounds described herein are prepared as outlined in the following schemes.

[0242] Treatment of 1-1 with bromine, followed by reaction with p-benzyloxyaniline, yields 1-4. Subsequently, N-alkylation with benzyl bromide under basic conditions gives intermediate 1-5. Reduction with LAH yields D-01 (Scheme I).

[0243] Reducing acid 3-1 yields alcohol 3-2, which is protected with TBDMS chloride to give 3-3. 3-3 is reacted with 1-4 under basic conditions (Scheme I) to give 3-5, which is then deprotected with TBAF and converted to the corresponding primary iodide 3-7 with iodine and triphenylphosphine (Scheme II). Iodide 3-7 reacts with various amines, and after debenzylation, yields compounds D-02, D-03, and D-08.

[0244] Indole 1-4 is reacted with benzyl bromide 3 under alkaline conditions, and the resulting 12-5 is catalytically deprotected to give 12-6, which is then reduced with LAH to give D-12 (Scheme III). Alternatively, 1-4 is fluorinated (15-5), N-benzylated and deprotected (15-6), tosylated (15-7), and reacted with cyclopropylamine (15-8) and debenzylated to give D-15. Tosylate 15-7 is also converted with ethylamine and deprotected to give D-16.

[0245] 13-1-hydroxybenzaldehyde was benzylated to give 13-2, which was then reacted with carbon tetrabromide and triphenylphosphine to give 13-3. 13-3 was treated with (4-methoxyphenyl)boronic acid in the presence of palladium acetate to give 13-4, which was then chlorinated with N-chlorosuccinimide and subsequently reacted with (4-(bromomethyl)phenethoxy)(tert-butyl)dimethylsilane under basic conditions to give 13-7. Toluenesulfonation gave 13-8, which was then reacted with ethylamine to give 13-9 and debenzylated to give D-13 (Scheme IV). 1,1-Dibromoene 13-3 was treated with (4-methylphenyl)boronic acid in the presence of palladium acetate to give 28-1, which was fluorinated with selectifluor and subsequently N-benzylated to give TBDMS-protected 28-3. After removing the TBDMS protecting group, 28-4 was toluenesulfonicated to 28-5, reacted with cyclopropylamine to 28-6 and then debenzylated to obtain D-28 (Scheme IV).

[0246] In the presence of palladium catalyst, 13-3 was treated with (2-methoxyphenyl)boronic acid to obtain 87-2, which was then fluorinated with selectifluor and subsequently N-benzylated to give TBDMS-protected 87-4. After removing the TBDMS protecting group, it was toluenesulfonated to 87-6, then reacted with propylamine to 87-7, and debenzylated to give D-87 (Scheme IVb).

[0247] In the presence of palladium catalyst, 13-3 was treated with (2,6-dimethylphenyl)boric acid to obtain 50-1, which was then fluorinated with selectifluor and subsequently N-benzylated to give TBDMS-protected 50-3. After removing the TBDMS protecting group, toluenesulfonation was performed to 50-5, which was then reacted with cyclobutamine to give 50-5 and debenzylated to give D-50 (Scheme IVc). Intermediate 50-5 was also reacted with ethylamine to generate 78-1, which was then debenzylated to give D-78.

[0248] In the presence of palladium catalyst, 13-3 was treated with (2-methyl-4-methoxyphenyl)boronic acid to give 52-1, which was then fluorinated with selectifluor and subsequently N-benzylated to give TBDMS-protected 52-3. After removing the TBDMS protecting group, it was toluenesulfonated to 52-5, which was then reacted with cyclopropylamine to generate 52-6, and debenzylated / demethylated with BBr3 to give D-52 (Scheme IVd). Intermediate 52-2 was N-benzylated to give TBDMS-protected 103-7. After removing the TBDMS protecting group, it was toluenesulfonated to 103-9, which was then reacted with potassium phthalimide and hydrazine to give 103-11. Primary amine 103-11 was reacted with fluoroiodopropane and debenzylated to give D-103. Primary amine 103-11 was similarly reacted with fluoroiodopropane and debenzylated to give D-104.

[0249] In the presence of palladium catalyst, 1,1-dibromoolefin 13-3 was treated with (4-fluoro-2-methylphenyl)boric acid to give 36-1, which was then fluorinated with selectifluor and subsequently N-benzylated to give TBDMS-protected 36-3. After removing the TBDMS protecting group, 36-4 was toluenesulfonated to 36-5, reacted with cyclopropylamine to give 36-6, and then debenzylated to give D-36.

[0250] Intermediate 96-5 was obtained in a similar sequence to that used to prepare 52-5 from 13-3 (see also scheme IVd). 96-5 was then reacted with propylamine to 96-6 and debenzylated to give D-96 (scheme IVf). Intermediate 13-3 was treated with (2-phenylphenyl)boronic acid in the presence of palladium catalyst to give 66-3, which was then fluorinated with selectifluor and subsequently N-benzylated to give TBDMS-protected 66-5. After removing the TBDMS protecting group, it was toluenesulfonated to 66-7, then reacted with propylamine to 66-8 and debenzylated to give D-66 (scheme IVf).

[0251] Toluenesulfonate 28-5 was treated with ethylamine (see Scheme IV) to give 29-1, which was then catalytically debenzylated to give D-29 (Scheme V). Similarly, 28-5 was treated with cyclopropylmethylamine, cyclobutylamine, propylamine, or butylamine, followed by catalytic debenzylation to give D-39, D-46, D-67, and D-68, respectively.

[0252] Toluenesulfonate 28-5 was reacted with potassium phthalimide (see Scheme IV), followed by reaction with hydrazine to give 69-7. Primary amine 69-7 was reacted with fluoroiodopropane and debenzylated to give D-69. Primary amine 69-7 was similarly reacted with fluoroiodoethane and debenzylated to give D-70. Intermediate 28-2 was N-alkylated with p-bromomethylphenylacetic acid 32-2, followed by reaction with N-methyl-N-methoxyamine to give 32-3. Compound 32-3 was treated with methylmagnesium bromide, and the resulting ketone 32-4 was reacted with cyclopropylamine and debenzylated to give D-32.

[0253] Compound 40-1 was N-benzylated to give TBDMS-protected 40-2. After removing the TBDMS protecting group, it was toluenesulfonated to 40-4, which was then reacted with cyclopropylmethylamine, cyclopropylamine or ethylamine, followed by catalytic removal of the benzyl protecting group to give D-40, D-33 and D-34 (Scheme VI), respectively.

[0254] In the presence of palladium catalyst, 1,1-dibromoolefin 13-3 was treated with (2-chlorophenyl)boric acid to give 37-1, which was then fluorinated with selectifluor and subsequently N-benzylated to give TBDMS-protected 37-3. After removing the TBDMS protecting group, 37-4 was toluenesulfonated to 37-5, reacted with cyclopropylamine to give 37-6, and then debenzylated to give D-37.

[0255] Compound 85-1 was N-sulfonated, followed by reduction with hydrazine to give indazole amine 85-3. After aromatic iodination with N-iodosuccinimide, compound 85-4 was acetylated with trifluoroacetic anhydride to give 85-5. Arylation / cyclization of 85-5 yielded 85-6, which was fluorinated with selectifluor and then N-benzylated to give TBDMS-protected 85-8. After removing the TBDMS protecting group, 85-9 was toluenesulfonated to 85-10, reacted with ethylamine to give 85-11, and then debenzylated to give D-85.

[0256] In a similar manner, 85-10 was reacted with cyclopropylmethylamine, cyclobutylamine, cyclopropylamine and propylamine, and sulfonated in the presence of alkaline methanol / water to generate D-88, D-89, D-90 and D-91, respectively.

[0257] 85-10 is also reacted with potassium phthalimide, followed by reaction with hydrazine to give 101-12. The primary amine 101-12 is then reacted with fluoroiodoethane or fluoroiodopropane, followed by desulfonation in the presence of basic methanol / water to give D-101 and D-102, respectively.

[0258] Compound L18-1 was arylated in the presence of palladium acetate, and the resulting ketone L18-2 was converted to the corresponding vinyl bromide using PBr3. Compound L18-3 was arylated with 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxapentylborane-2-yl)phenyl)ethyl-1-ol to give L18-4, which was then toluenesulfonated to give L18-5 and reacted with ethylamine to give L18-6. The reduction of the tetrasubstituted double bond in L18-6 gave the cis compound L18-7, which was then demethylated with BBr3 to give LA-18. (Scheme IX) L18-5 was also treated with cyclopropylmethylamine, followed by reduction and demethylation to give LA-19.

[0259] Compound L18-1 was arylated (2-methyl-bromobenzene) in the presence of palladium acetate, and the resulting ketone L21-2 was converted to the corresponding vinyl bromide with PBr3. Compound L21-3 was arylated with 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxapentylborane-2-yl)phenyl)ethyl-1-ol to give L21-4, which was then toluenesulfonated to give L21-5 and reacted with ethylamine to give L21-6. The tetrasubstituted double bond in L21-6 was reduced to give cis compound L21-7, which was then demethylated with BBr3 to give LA-21. (Scheme IXb) L21-5 was also treated with cyclopropylmethylamine, followed by reduction and demethylation to give LA-22.

[0260] Compound L18-1 was arylated (4-isopropyl-bromobenzene) in the presence of palladium acetate, and the resulting ketone L31-2 was converted to the corresponding vinyl bromide with PBr3. Compound L31-3 was arylated with 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxapentylborane-2-yl)phenyl)ethyl-1-ol to give L31-4, which was then toluenesulfonated to give L31-5 and reacted with ethylamine to give L31-6. The tetrasubstituted double bond in L31-6 was reduced to give cis compound L31-7, which was then demethylated with BBr3 to give LA-31. (Scheme IXc) L31-5 was also treated with cyclopropylmethylamine, followed by reduction and demethylation to give LA-33.

[0261] Compound T05-1 was alkylated with 2-bromo-1,1-diethoxyethane, followed by cyclization in the presence of a Lewis acid to the corresponding benzo{b}thiophene T05-3. After bromination with NBS, the heteroaryl bromide was coupled with o-methylphenylboronic acid in the presence of a palladium catalyst to give T05-6. Bromination was then performed, followed by oxidation of the sulfur atom to generate T05-8. The bromide was replaced with p-hydroxyethylphenol, followed by toluenesulfonation to the hydroxyethyl functional group to give T05-10. Intermediate T05-10 was treated with cyclopropylamine, followed by reduction of the sulfonyl group and demethylation to give BT-05 (Scheme X). Similarly, intermediate T05-10 was treated with cyclopropylmethylamine, followed by reduction of the sulfonyl group and demethylation to give BT-12.

[0262] The bromide was replaced by p-hydroxybenzaldehyde, followed by reduction of the aldehyde with LAH, and then conversion of the resulting benzyl alcohol with phosphorus tribromide to give benzyl bromide T17-4. T17-4 was Wittig olefinated with tert-butyl 3-oxazacyclobutane-1-carboxylate in the presence of triphenylphosphine to give T17-5. The Boc protecting group was removed with acid to give T17-6, which was then alkylated with propionaldehyde in the presence of sodium triacetoxyborohydride to form T17-7. The penultimate intermediate T17-7 was demethylated to give BT-17 (Scheme XI).

[0263] O-alkylation of m-methoxyphenol under basic conditions yields X6-2, which is then deesterified with LiOH and subsequently cyclized with Eatons' reagent to produce X6-4. Coupling of X6-4 with 2-bromotoluene in the presence of palladium acetate produces ketone X6-5, which is treated with a Grignard reagent formed from (4-(bromomethyl)phenethoxy)(tert-butyl)dimethylsilane. After dehydration and deprotection with acid, it yields the primary alcohol X6-7. Following toluenesulfonation of the alcohol, the toluenesulfonate ester is replaced with cyclopropylamine and demethoxylated to give BX-06 (Scheme XII). Similarly, toluenesulfonate X6-8 is reacted with ethylamine and demethoxylated with BBr3 to produce BX-07. Example

[0264] Materials: All chemicals were reagent grade and used without further purification. Chromatographic elution solvent systems are reported as volume:volume ratios. LC-MS data were obtained using Thermo Finnigan Surveor-MS Thermo Finnigan AQA in either positive or negative mode as described below: LCMS-Condition 01: Method: -LCMS_X-Select (Formic Acid)

[0265] Column: X-selected CSH C18 (4.6*50)mm 2.5u, mobile phase: A. 0.1% formic acid aqueous solution B. 0.1% formic acid in acetonitrile solution, injection volume: 5.0μL, flow rate: 1.0 mL / min, gradient program: change 2% B to 98% B in 2.8 min, hold for 4.8 min, B concentration is 2% at 5.0 min, continue for 7.0 min. LCMS-Condition 02: Method: -LCMS_X-Bridge (NH3)

[0266] Column: X-bridge C18 (3.0*50) mm 2.5 μm; Mobile phase: A. 0.05% NH3 aqueous solution; B. 0.05% NH3 in acetonitrile solution; Injection volume: 2 μL; Flow rate: 1.0 mL / min; Gradient program: Change 1% B to 90% B in 1.5 min, change to 100% B in 2.5 min, hold for 2.8 min, B concentration is 1% at 3.0 min, continue for 4.0 min. LCMS-Condition 03: Method: -LCMS_X-Select (Ammonium Bicarbonate)

[0267] Column: X-selected CSH C18 (3.0*50)mm 2.5u; Mobile phase: A: 5mM ammonium bicarbonate aqueous solution; B: acetonitrile; Injection volume: 2μL; Flow rate: 1.2mL / min; Column oven temperature: 50℃; Gradient program: Change 0% B to 98% B within 2.0 min, hold for 3.0 min, B concentration is 0% at 3.2 min, continue until 4.0 min. 1-(4-(2-(ethylamino)ethyl)benzyl)-2-(4-methoxyphenyl)-3-methyl-1H-indole-5-ol (D-01)

[0268] Bromine (1.72 mL, 33.49 mmol) was added dropwise to a solution of 1-(4-methoxyphenyl)prop-1-one 1-1 (5 g, 30.45 mmol) in 50 mL of diethyl ether at 0 °C, and the mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction mixture was quenched with saturated Na₂S₂O₃ solution and extracted with diethyl ether (3x). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography, eluting with 0-40% ethyl acetate in n-hexane to give 4.5 g (61% yield) of compound 1-2 as a grayish-white solid. LCMS - Condition 01: [M+H] + =242.90; Rt=3.08min 1H NMR (400MHz, DMSO-d6) δ: 8.03 (d, J = 8.80Hz, 2H), 7.07 (d, J = 8.80Hz, 2H), 5.78 (q, J = 6.36Hz, 1H), 3.86 (s, 3H), 1.76 (d, J = 6.36Hz, 3H).

[0269] 4-(benzyloxy)aniline (3.68 g, 18.51 mmol) was added to a DMF (30 mL) solution of 2-bromo-1-(4-methoxyphenyl)prop-1-one 1-2 (3 g, 12.34 mmol) at room temperature, and the mixture was degassed with argon for 15 min. The reaction mixture was then heated at 150 °C for 3 h. After the reaction was complete, the reaction mixture was cooled to room temperature, quenched with water, and extracted with ethyl acetate (3×). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography, eluting with a solution of 0-20% ethyl acetate in n-hexane to give 2.60 g (61% yield) of compounds 1-4 as a grayish-white solid. LCMS - Condition 01: [M+H] + =343.05; Rt=3.65min 1 H NMR (400MHz, DMSO-d6) δ: 10.88 (s, 1H), 7.57 (d, J = 8.31Hz, 2H), 7.49 (d, J = 7.34Hz, 2H), 7.37-7 .42(m,3H),7.22(d,J=8.80Hz,1H),7.04-7.09(m,4H),5.12(s,2H),3.81(s,3H),2.33(s,3H).

[0270] Sodium hydride (60% oil dispersion, 524 mg, 13.10 mmol) was added fractionally to a DMF (15 mL) solution of 5-(benzyloxy)-2-(4-methoxyphenyl)-3-methyl-1H-indole 1-4 (1.50 g, 4.367 mmol) at 0 °C, and the mixture was stirred for 30 min. 2-(4-(bromomethyl)phenyl)-N-ethylacetamide (1.23 g, 4.803 mmol) was added to the resulting solution at 0 °C. The reaction mixture was further stirred for 18 h at room temperature. After the reaction was complete, the reaction mixture was quenched with ice water and extracted with ethyl acetate (3×). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography, eluting with a solution of 0-40% ethyl acetate in n-hexane to give 1.3 g (57% yield) of compounds 1-5 as a grayish-white solid. LCMS - Condition 01: [M+H] +=519.30; Rt=3.28 / 3.66min 1 H NMR(400MHz, DMSO-d6)δ:8.17(d,J=8.80Hz,1H),7.85(t,J=5.14Hz,1H),7.46-7.53(m,2H),7.39-7.44(m,2H) ,7.37(d,J=5.38Hz,1H),7.31(d,J=8.31Hz,2H),7.25-7.27(m,1H),7.05-7.10(m,2H),6.88(dd,J=2.45,8.80 Hz,1H),6.80(dd,J=2.45,8.80Hz,1H),6.76(d,J=7.83Hz,1H),6.72(d,J=8.31Hz,1H),6.36(d,J=7.83Hz,1H) ,5.16-5.21(m,2H),5.12(s,2H),3.86(s,3H),3.79(s,2H),2.95-3.03(m,2H),2.49(s,3H),0.91-1.00(m,3H).

[0271] Lithium aluminum hydride (292 mg, 7.712 mmol) was added fractionally to a solution of 2-(4-((5-(benzyloxy)-2-(4-methoxyphenyl)-3-methyl-1H-indol-1-yl)methyl)phenyl)-N-ethylacetamide 1-5 (400 mg, 0.771 mmol) in 20 mL of THF at 0 °C. The reaction mixture was further heated to 70 °C for 24 hours. After the reaction was complete, the reaction mixture was cooled to room temperature, quenched with saturated Na₂SO₄ solution, and extracted with ethyl acetate (3x). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude compound was purified by preparative HPLC to give 16 mg (5% yield) of D-01 as a grayish-white solid. LCMS - Condition 01: [M+H] + =415.05; Rt=2.17min 1H NMR(400MHz,CD3OD)δ:8.44(br.s,1H),7.97(t,J=9.54Hz,1H),7.13(d,J=8.80Hz,2H ),6.99(d,J=7.83Hz,2H),6.87(d,J=8.80Hz,3H),6.81(d,J=1.96Hz,1H),6.73(d,J= 7.83Hz,2H),6.53(dd,J=2.45,8.80Hz,1H),5.07(s,2H),3.72(s,3H),2.94-3.00(m, 2H), 2.84 (q, J = 7.17Hz, 2H), 2.72-2.78 (m, 2H), 2.07 (s, 3H), 1.13 (t, J = 7.34Hz, 3H). 1-(4-(2-(cyclopropylamino)ethyl)benzyl)-2-(4-methoxyphenyl)-3-methyl-1H-indole-5-ol (D-02)

[0272] Triethylamine (0.05 mL, 0.357 mmol) was added to a DMF (5 mL) solution of 5-(benzyloxy)-1-(4-(2-iodoethyl)benzyl)-2-(4-methoxyphenyl)-3-methyl-1H-indole 3-7 (70 mg, 0.119 mmol) and cyclopropylamine (20 mg, 0.357 mmol) and stirred for 16 hours. After the reaction was complete, the reaction mixture was quenched with water and extracted with ethyl acetate (3×). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give 70 mg (crude) of compound 2-2 as a light brown solid, which could be used directly in the next step without further purification. LCMS - Condition 01: [M+H] + =517.25; Rt=1.85min

[0273] Trifluoroacetic acid (0.1 mL) was added to a solution of N-(4-((5-(benzyloxy)-2-(4-methoxyphenyl)-3-methyl-1H-indol-1-yl)methyl)phenethyl)cyclopropylamine 2-2 (70 mg, 0.135 mmol) in toluene (1 mL) at room temperature. The reaction mixture was then heated at 90 °C for 16 hours. After the reaction was complete, the reaction mixture was quenched with saturated NaHCO3 solution and extracted with DCM (3×). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude compound was purified by preparative HPLC column chromatography to give 6 mg (10% yield) of D-02 as a grayish-white solid. LCMS - Condition 01: [M+H] + =427.05; Rt=1.40min 1H NMR (400MHz, CDCl3) δ: 7.24 (d, J = 8.80Hz, 2H), 7.06 (d, J = 8.31Hz, 2H), 6.98 -7.01(m,2H),6.93(d,J=8.80Hz,2H),6.87(d,J=8.31Hz,2H),6.70(dd,J=2. 45,8.80Hz,1H),5.14(s,2H),3.84(s,3H),2.90-2.96(m,2H),2.73-2.80(m ,2H),2.22(s,3H),2.10-2.18(m,1H),0.43-0.47(m,2H),0.38-0.43(m,2H). 1-(4-(2-((cyclopropylmethyl)amino)ethyl)benzyl)-2-(4-methoxyphenyl)-3-methyl-1H-indole-5-ol (D-03)

[0274] Borane dimethyl sulfide (12.4 mL, 130.96 mmol) was added dropwise to a solution of 2-(4-(bromomethyl)phenyl)acetic acid (20 g, 87.30 mmol) in 200 mL of THF at 0 °C. The reaction mixture was stirred at room temperature for 3 hours. After the reaction was complete, the reaction mixture was cooled to 0 °C and quenched dropwise with methanol. The resulting reaction mixture was concentrated under reduced pressure, the resulting solid was filtered, and washed with n-hexane to give 14 g of compound 3-2 as a grayish-white solid, which could be used directly in the next step without further purification. 1 H NMR (400MHz, CDCl3) δ: 7.35 (d, J = 7.83Hz, 2H), 7.21 (d, J = 7.83Hz, 2H), 4.49 (s, 2H), 3.86 (t, J = 6.36Hz, 2H), 2.87 (t, J = 6.60Hz, 2H)

[0275] Imidazole (0.77 mL, 13.94 mmol) was added to a solution of 2-(4-(bromomethyl)phenyl)ethyl-1-ol 3-2 (1 g, 4.649 mmol) in 15 mL of DCM at 0 °C, and the mixture was stirred for 15 min. Tert-butyldimethylchlorosilane (840 mg, 5.579 mmol) was added to the resulting solution at the same temperature. The reaction mixture was then stirred at room temperature for 16 h. After the reaction was complete, the reaction mixture was quenched with water and extracted with DCM (3×). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography, eluting with a solution of 0–30% ethyl acetate in n-hexane to give 1.2 g (78% yield) of compound 3-3 as a colorless oil. 1H NMR(400MHz, CDCl3)δ:7.32(d,J=7.82Hz,2H),7.20(d,J=7.82Hz,2H),4.51(s, 2H), 3.81 (t, J = 7.09Hz, 2H), 2.83 (t, J = 7.09Hz, 2H), 0.88 (s, 9H), 0.02 (s, 6H).

[0276] Sodium hydride (60% oil dispersion, 109 mg, 2.737 mmol) was added in portions to a DMF (5 mL) solution of 5-(benzyloxy)-2-(4-methoxyphenyl)-3-methyl-1H-indole 3-4 (470 mg, 1.368 mmol) at 0 °C and stirred for 30 min. At the same temperature, (4-(bromomethyl)phenylethoxy)(tert-butyl)dimethylsilane 3 (584 mg, 1.779 mmol) was added to the resulting solution. The reaction mixture was further stirred for 3 h at room temperature. After the reaction was complete, the reaction mixture was quenched with ice water and extracted with ethyl acetate (3×). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography, eluting with a solution of 0-30% ethyl acetate in n-hexane to give 660 mg (81% yield) of 3-5 as a brown liquid. LCMS - Condition 01: [M+H] + =592.30; Rt=2.86min

[0277] At room temperature, a 1M tetrabutylammonium fluoride THF solution (1.3 mL, 1.317 mmol) was added dropwise to a THF solution of 5-(benzyloxy)-1-(4-(2-((tert-butyldimethylsilyl)oxy)ethyl)benzyl)-2-(4-methoxyphenyl)-3-methyl-1H-indole 3-5 (650 mg, 1.098 mmol) and stirred for 1 hour. After the reaction was complete, the reaction mixture was quenched with saturated NaHCO3 solution and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography, eluting with 0-40% ethyl acetate in n-hexane to give 425 mg (81% yield) of compound 3-6 as a grayish-white solid. LCMS - Condition 01: [M+H] + =478.15; Rt=2.32min 1H NMR (400MHz, CDCl3) δ: 7.49 (d, J = 7.34Hz, 2H), 7.39 (t, J = 7.58Hz, 2H), 7.32 (d, J =7.34Hz,1H),7.22-7.25(m,3H),7.15(d,J=1.96Hz,1H),7.08(d,J=7.83Hz,2H), 7.04(d,J=8.80Hz,1H),6.92-6.96(m,2H),6.90(d,J=8.31Hz,2H),5.16(s,2H),5 .13(s,2H),3.84(s,3H),3.79-3.83(m,2H),2.80(t,J=6.36Hz,2H),2.25(s,3H).

[0278] Imidazole (300 mg, 4.396 mmol) and iodine (1.11 g, 4.396 mmol) were added to a DCM (30 mL) solution of triphenylphosphine (1.15 g, 4.396 mmol) at 0 °C. The reaction mixture was allowed to reach room temperature and stirred for 1 hour. 2-(4-((5-(benzyloxy)-2-(4-methoxyphenyl)-3-methyl-1H-indol-1-yl)methyl)phenyl)ethyl-1-ol 3-6 (420 mg, 0.879 mmol) was added to the resulting solution and stirred for 16 hours at room temperature. After the reaction was complete, the reaction mixture was quenched with water and extracted with DCM (3×). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography, eluting with a solution of 0-20% ethyl acetate in n-hexane to give 425 mg (82% yield) of compound 3-7 as a grayish-white solid. LCMS - Condition 01: [M+H] + =588.05; Rt=2.55min 1 H NMR (400MHz, CDCl3) δ: 7.49 (d, J = 7.83Hz, 2H), 7.39 (t, J = 7.34Hz, 2H), 7.29-7.34 (m, 1H), 7.22 (d, J = 8.80Hz, 2H), 7.14 (d, J = 2.45Hz, 1H) ,7.02-7.06(m,3H),6.85-6.95(m,5H),5.14(br.s,2H),5.13(br.s,2H),3.84(s,3H),3.26-3.32(m,2H),3.06-3.14(m,2H),2.24(s,3H).

[0279] Triethylamine (0.14 mL, 1.021 mmol) was added to a DMF (5 mL) solution of 5-(benzyloxy)-1-(4-(2-iodoethyl)benzyl)-2-(4-methoxyphenyl)-3-methyl-1H-indole 3-7 (200 mg, 0.340 mmol) and cyclopropylmethylamine (72 mg, 1.021 mmol) and stirred for 16 hours. After the reaction was complete, the reaction mixture was quenched with water and extracted with ethyl acetate (3×). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography, eluting with 0-5% methanol in DCM solution to give 80 mg (44% yield) of compound 3-8 as a light brown solid. LCMS - Condition 01: [M+H] + =531.30; Rt=1.85min 1 H NMR (400MHz, CDCl3) δ: 7.48 (d, J = 7.34Hz, 2H), 7.38-7.41 (m, 1H), 7.36 (d, J = 4.40Hz, 1H), 7.30-7.34 (m,1H),7.22(d,J=8.80Hz,2H),7.14(d,J=2.45Hz,1H),7.07(d,J=7.83Hz,2H),7.02(d,J=8.31Hz,1 H),6.92(d,J=8.80Hz,2H),6.87(d,J=8.31Hz,3H),5.13(s,2H),5.12(s,2H),3.81(s,3H),3.18(br. s, 4H), 2.75 (d, J = 7.34Hz, 2H), 2.24 (s, 3H), 1.14-1.21 (m, 1H), 0.57-0.64 (m, 2H), 0.32-0.39 (m, 2H).

[0280] Trifluoroacetic acid (0.1 mL) was added to a solution of 2-(4-((5-(benzyloxy)-2-(4-methoxyphenyl)-3-methyl-1H-indol-1-yl)methyl)phenyl)-N-(cyclopropylmethyl)ethyl-1-amine 3-8 (100 mg, 0.188 mmol) in toluene (1 mL) at room temperature. The reaction mixture was heated at 90 °C for 16 hours. After the reaction was complete, the reaction mixture was quenched with saturated NaHCO3 solution and extracted with DCM (3×). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude compound was purified by preparative HPLC column chromatography to give 8 mg (9% yield) of D-03 as a grayish-white solid. LCMS - Condition 01: [M+H] +=441.25; Rt=1.48min 1 H NMR (400MHz, CDCl3) δ: 8.58 (s, 1H), 7.21 (d, J = 8.31Hz, 2H), 6.99 (d, J = 1.96Hz, 1H), 6 .89-6.95(m,4H),6.87(d,J=8.31Hz,1H),6.82(d,J=7.83Hz,2H),6.68(d,J=6.85Hz,1 H),5.07(s,2H),3.82(s,3H),2.99-3.06(m,2H),2.85-2.92(m,2H),2.70(d,J=7.34Hz ,2H),2.21(s,3H),0.79-0.90(m,1H),0.56(d,J=7.34Hz,2H),0.25(d,J=4.40Hz,2H). 1-(4-(2-(isopropylamino)ethyl)benzyl)-2-(4-methoxyphenyl)-3-methyl-1H-indole-5-ol (D-08)

[0281] Triethylamine (0.21 mL, 1.531 mmol) was added to a DMF (3 mL) solution of 5-(benzyloxy)-1-(4-(2-iodoethyl)benzyl)-2-(4-methoxyphenyl)-3-methyl-1H-indole 3-7 (300 mg, 0.510 mmol) and propan-2-amine (90 mg, 1.531 mmol) at room temperature. The reaction mixture was stirred for 16 hours at room temperature. After the reaction was complete, the reaction mixture was quenched with water and extracted with ethyl acetate (3×). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude compound was purified by silica gel column chromatography, eluting with 0–5% methanol in DCM solution to give 145 mg (55% yield) of compound 8-2 as a light brown solid. LCMS - Condition 01: [M+H] + =519.25; Rt=1.77min 1H NMR(400MHz, CDCl3)δ:7.48(d,J=7.34Hz,2H),7.38(t,J=7.34Hz,2H),7.28-7.34(m,1H ),7.23(d,J=8.80Hz,2H),7.14(d,J=2.45Hz,1H),7.07(d,J=7.82Hz,2H),7.03(d,J=8.8 0Hz,1H),6.93(d,J=8.80Hz,2H),6.87(d,J=7.82Hz,3H),5.13(br.s,2H),5.12(s,2H), 3.83(s,3H),3.00-3.05(m,1H),2.87-2.99(m,4H),2.24(s,3H),1.22(d,J=6.36Hz,6H).

[0282] Palladium hydroxide (5 mg) was added to a THF:EtOAc (1:1) solution of N-(4-((5-(benzyloxy)-2-(4-methoxyphenyl)-3-methyl-1H-indol-1-yl)methyl)phenethyl)propyl-2-amine 8-2 (30 mg, 0.057 mmol) at room temperature. The reaction mixture was stirred for 16 hours at room temperature under a hydrogen atmosphere. After the reaction was complete, the reaction mixture was passed through a Celite tube. TMTM The mixture was filtered through a pad, and the filtrate was concentrated under reduced pressure. The resulting crude compound was purified by preparative HPLC to give 6 mg (40% yield) of D-08 as a grayish-white solid. LCMS Condition 1: [M+H] + =429.30; Rt=1.45min 1 H NMR(400MHz, CDCl3)δ:8.64(br.s,1H),7.21(d,J=8.31Hz,2H),7.00(br.s,1H),6.90(d,J=8.31Hz,4H),6.85(d,J=8.80Hz,2H) ,6.80(d,J=7.34Hz,2H),6.69(d,J=7.82Hz,1H),5.05(s,2H),3.82(s,3H),2.83-3.23(m,6H),2.20(s,3H),1.09-1.18(m,6H). 1-(4-(2-(cyclohexylamino)ethyl)benzyl)-2-(4-methoxyphenyl)-3-methyl-1H-indole-5-ol (D-09)

[0283] Triethylamine (0.10 mL, 0.765 mmol) was added to a DMF (3 mL) solution of 5-(benzyloxy)-1-(4-(2-iodoethyl)benzyl)-2-(4-methoxyphenyl)-3-methyl-1H-indole 3-7 (150 mg, 0.255 mmol) and cyclohexylamine (76 mg, 0.765 mmol). The reaction mixture was stirred for 16 hours at room temperature. After the reaction was complete, the reaction mixture was quenched with water and extracted with ethyl acetate (3×). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude compound was purified by silica gel column chromatography, eluting with 0–5% methanol in DCM solution to give 105 mg (74% yield) of compound 9-2 as a light brown solid. LCMS - Condition 01: [M+H] + =559.35; Rt=1.86min

[0284] Palladium hydroxide (10 mg) was added to a solution of N-(4-((5-(benzyloxy)-2-(4-methoxyphenyl)-3-methyl-1H-indol-1-yl)methyl)phenethyl)cyclohexylamine 9-2 (100 mg, 0.178 mmol) in EtOAc (20 mL) at room temperature. The reaction mixture was stirred for 16 hours at room temperature under a hydrogen atmosphere. After the reaction was complete, the reaction mixture was passed through a Celite tube. TM The mixture was filtered through a filter pad, and the filtrate was concentrated. The resulting crude compound was purified by preparative HPLC column chromatography to give 50 mg (60% yield) of the title compound D-09 as a grayish-white solid. LCMS - Condition 01: [M+H] + =469.20; Rt=1.55min 1 H NMR(400MHz, DMSO-d6)δ:8.72(s,1H),7.29(d,J=7.82Hz,2H),7.00-7.08(m,4H),6.82(s,1H),6.76(d,J=7.82Hz,2H),6.58(d,J=7.82Hz,1H),5 .16(s,2H),3.79(s,3H),2.62-2.86(m,6H),2.12(s,3H),1.78-1.87(m, 2H), 1.65 (d, J = 11.74Hz, 2H), 1.54 (d, J = 9.29Hz, 2H), 1.02-1.20 (m, 4H). 2-(4-Methoxyphenyl)-3-methyl-1-(4-(2-(((2,2,2-trifluoroethyl)amino)ethyl)benzyl)-1H-indole-5-ol (D-12)

[0285] A solution of 5-(benzyloxy)-2-(4-methoxyphenyl)-3-methyl-1H-indole 3-4 (1.5 g, 4.373 mmol) in DMF (10 mL) was added in portions to an oil dispersion of 60% sodium hydride (420 mg, 17.49 mmol) at 0 °C, and the mixture was stirred for 30 min at the same temperature. A solution of 2-(4-(bromomethyl)phenyl)-N-(2,2,2-trifluoroethyl)acetamide (1.62 g, 52.47 mmol) in DMF was added to the resulting solution, and the mixture was stirred at room temperature for 16 h. After the reaction was complete, the reaction mixture was quenched with ice water and extracted with ethyl acetate (3×). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography, eluting with 0–10% methanol in DCM solution to give 510 mg (20% yield) of compound 12-5 as a brown oil. 1 H NMR(400MHz, DMSO-d6)δ:8.66(t,J=5.87Hz,1H),7.44-7.49(m,2H),7.38(t,J=7.58Hz,2H),7.27-7.34(m,3H),7.11-7.18(m,2H),7. 04(dd,J=8.07,14.92Hz,4H),6.73-6.81(m,3H),5.19(s,2H),5.11(s,2H),3.82-3.90(m,2H),3.78(s,3H),3.39(s,2H),2.16(s,3H).

[0286] At room temperature, 20% palladium hydroxide / carbon (100 mg, 50% water) was added to a solution of 2-(4-((5-(benzyloxy)-2-(4-methoxyphenyl)-3-methyl-1H-indol-1-yl)methyl)phenyl)-N-(2,2,2-trifluoroethyl)acetamide 12-5 (250 mg, 437.1 mmol) in ethyl acetate (40 mL). The reaction mixture was stirred for 16 hours under a hydrogen atmosphere. After the reaction was complete, the reaction mixture was passed through a Celite tube. TM The mixture was filtered through a pad and washed with ethyl acetate. The filtrate was concentrated under reduced pressure, and the crude compound was purified by preparative HPLC to give 210 mg (99% yield) of compound 12-6 as a grayish-white viscous solid. LCMS Condition 1: [M+H] + =483.10; Rt=2.01min 1H NMR(400MHz, DMSO-d6)δ:8.72(s,1H),7.29(d,J=8.31Hz,2H),7.01-7.09(m,5H),6.82(d,J=1.96Hz,1H),6.77(d,J= 8.31Hz, 2H), 6.58 (dd, J = 1.96, 8.80Hz, 1H), 5.16 (s, 2H), 3.82-3.89 (m, 2H), 3.79 (s, 3H), 3.40 (s, 2H), 2.12 (s, 3H).

[0287] Lithium aluminum hydride (46 mg, 1211.1 mmol) was added in portions to a solution of 2-(4-((5-hydroxy-2-(4-methoxyphenyl)-3-methyl-1H-indol-1-yl)methyl)phenyl)-N-(2,2,2-trifluoroethyl)acetamide 12-6 (195 mg, 403.7 mmol) in THF (30 mL) at 0 °C. The reaction mixture was then heated at 70 °C for 16 hours. After the reaction was complete, the reaction mixture was cooled and quenched with saturated Na2SO4 solution, and passed through a Celite tube. TM The mixture was filtered and washed with ethyl acetate. The separated organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude compound was purified by preparative HPLC to give 13 mg (7% yield) of D-12 as a pale yellow solid. LCMS Condition 1: [M+H] + =469.20; Rt=1.80min 1 H NMR (400MHz, DMSO-d6) δ: 8.70 (s, 1H), 7.27 (d, J = 8.80Hz, 2H), 6.99-7.07 (m, 5H), 6.79-6.82 (m, 1H), 6.70-6.76 (m, 2H), 6.5 7(dd,J=2.20,8.56Hz,1H),5.14(s,2H),3.78(s,3H),3.13-3.23(m,2H),2.70-2.74(m,2H),2.56-2.61(m,2H),2.11(s,3H). 1-(4-(2-(cyclopropylamino)ethyl)benzyl)-3-fluoro-2-(4-methoxyphenyl)-1H-indole-5-ol (D-15)

[0288] Selectfluor (1.53 g, 4.328 mmol) was added to an aqueous solution of 5-(benzyloxy)-2-(4-methoxyphenyl)-1H-indole 3-4 (1.78 g, 5.410 mmol) in acetonitrile:DMSO (3:2; 20 mL) at -10 °C under an argon atmosphere. The reaction mixture was stirred further at 0 °C for 2 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (100 mL), washed with water (40 mL), and then washed with brine (30 mL). The separated organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The obtained crude compound was purified by silica gel column chromatography, eluting with 0-20% ethyl acetate in n-hexane to give 402 mg (21% yield) of compound 15-5 as a grayish-white solid. LCMS - Condition 01: [M+18] + =366.10; Rt=2.24min 1 H NMR(400MHz, DMSO-d6)δ:11.07(s,1H),7.71-7.75(m,2H),7.47(d,J=6.85Hz,2H),7.39(t,J=7.34Hz,2H),7.30-7.33(m,1H),7.25 (dd,J=2.45,8.80Hz,1H),7.07(d,J=8.80Hz,2H),7.04(d,J=2.45Hz,1H),6.84(dd,J=2.45,8.80Hz,1H),5.12(s,2H),3.80(s,3H).

[0289] Sodium hydride (60% oil dispersion, 203 mg, 5.115 mmol) was added fractionally to a DMF (10 mL) solution of 5-(benzyloxy)-3-fluoro-2-(4-methoxyphenyl)-1H-indole 15-5 (590 mg, 1.705 mmol) at 0 °C. The reaction mixture was further stirred at 0 °C for 30 min. (4-(bromomethyl)phenylethoxy)(tert-butyl)dimethylsilane (671 mg, 2.046 mmol) was added to the resulting solution. The reaction mixture was stirred at room temperature for 18 h. After the reaction was complete, the reaction mixture was quenched with ice water and extracted with ethyl acetate (3×). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The resulting crude compound was purified by silica gel column chromatography, eluting with a solution of 0-80% ethyl acetate in n-hexane to give 405 mg (49% yield) of compound 15-6 as a brown solid. LCMS-condition 01: [M-18] + =464.25; Rt=2.34min 1H NMR(400MHz, DMSO-d6)δ:7.52-7.56(m,2H),7.44-7.51(m,4H),7.37-7.42(m,2H),7.19(d,J=2.45Hz,1H),7.14(t,J=8.07Hz,4H),6.95(dd,J=2.4 5,8.80Hz,1H),6.84(d,J=8.31Hz,2H),5.36(s,2H),5.21(s,2H),4.64(t ,J=5.38Hz,1H),3.87(s,3H),3.55-3.61(m,2H),2.69(t,J=6.85Hz,2H).

[0290] Triethylamine (0.35 mL, 2.526 mmol) was added to a solution of 2-(4-(5-(benzyloxy)-3-fluoro-2-(4-methoxyphenyl)-1H-indol-1-yl)methyl)phenyl)ethyl-1-ol 15-6 (405 mg, 0.842 mmol) in 10 mL of CH₂Cl₂ at 0 °C, followed by p-TsCl (241 mg, 1.263 mmol). The reaction mixture was stirred for 18 hours at room temperature. After the reaction was complete, the reaction mixture was diluted with 100 mL of CH₂Cl₂ and washed with 30 mL of water and 30 mL of brine. The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give 365 mg (68% yield) of compound 15-7 as a brown solid. LCMS - Condition 01: [M+H] + =636.35; Rt=2.54min 1 H NMR(400MHz,DMSO-d6)δ:7.63(d,J=7.83Hz,2H),7.51(d,J=7.34Hz,2H),7.40-7.47 (m,4H),7.31-7.39(m,4H),7.18(d,J=2.45Hz,1H),7.11(d,J=8.31Hz,2H),7.02(d,J =8.31Hz,2H),6.93(dd,J=2.20,9.05Hz,1H),6.79(d,J=7.83Hz,2H),5.33(s,2H),5. 18(s,2H),4.18(t,J=6.36Hz,2H),3.83(s,3H),2.82(t,J=6.36Hz,2H),2.39(s,3H).

[0291] In a sealed tube, DIPEA (0.81 mL, 1.072 mmol) and cyclopropylamine (mL, 2.670 mmol) were added to a solution of 4-((5-(benzyloxy)-3-fluoro-2-(4-methoxyphenyl)-1H-indol-1-yl)methyl)phenethyl 4-methylbenzenesulfonate 15-7 (170 mg, 0.267 mmol) in acetonitrile (5 mL). The reaction mixture was stirred at room temperature for 24 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure, washed with n-hexane (2 × 10 mL) and decanted, and then dried to give 135 mg (96% yield) of compound 15-8 as a white solid. LCMS - Condition 01: [M+H] + =521.31; Rt=1.74min 1 H NMR(400MHz, DMSO-d6)δ:7.47(d,J=6.85Hz,2H),7.36-7.44(m,5H),7.33(d,J=7.34 Hz,2H),7.10-7.14(m,1H),7.05(t,J=8.80Hz,4H),6.88(d,J=8.80Hz,1H),6.77(d, J=7.34Hz,2H),5.28(br.s,2H),5.14(s,2H),3.80(s,3H),2.67-2.73(m,2H),2.54- 2.62 (m, 2H), 2.03 (d, J = 2.93Hz, 1H), 0.31 (d, J = 5.87Hz, 2H), 0.15 (d, J = 1.96Hz, 2H).

[0292] Methanesulfonic acid (0.13 mL, 2.002 mmol) and triethylsilane (0.41 mL, 2.566 mmol) were added to a TFA solution of N-(4-((5-(benzyloxy)-3-fluoro-2-(4-methoxyphenyl)-1H-indol-1-yl)methyl)phenethyl)cyclopropylamine 15-8 (140 mg, 0.269 mmol) at 0 °C under an argon atmosphere. The reaction mixture was stirred for 2 hours at room temperature under an argon atmosphere. After the reaction was complete, the reaction mixture was concentrated under reduced pressure and diluted with ethyl acetate (50 mL). The organic layer was washed with saturated NaHCO3 (15 mL), then with brine (15 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude substance was purified by preparative HPLC to give 18 mg (16% yield) of D-15 as a white solid. LCMS - Condition 01: [M+H] + =431.20; Rt=1.46min 1H NMR (400MHz, DMSO-d6) δ: 9.04 (s, 1H), 7.40 (d, J = 8.31Hz, 2H), 7.18-7.23 (m, 1 H),7.03-7.08(m,4H),6.82(d,J=1.96Hz,1H),6.77(d,J=7.82Hz,2H),6.67(dd ,J=2.20,9.05Hz,1H),5.24(s,2H),3.80(s,3H),2.67-2.74(m,2H),2.56-2.6 3(m,2H),2.03(tt,J=3.36,6.66Hz,1H),0.28-0.34(m,2H),0.11-0.17(m,2H). 1-(4-(2-(ethylamino)ethyl)benzyl)-3-fluoro-2-(4-methoxyphenyl)-1H-indole-5-ol (D-16)

[0293] In a sealed tube, DIPEA (0.24 mL, 1.380 mmol) was added to a solution of 4-((5-(benzyloxy)-3-fluoro-2-(4-methoxyphenyl)-1H-indol-1-yl)methyl)phenethyl-4-methylbenzenesulfonate 15-7 (175 mg, 0.276 mmol) in acetonitrile (10 mL), followed by a solution of 2N ethylamine in THF (1.37 mL, 2.760 mmol). The reaction mixture was stirred at room temperature for 24 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure, washed with n-hexane (2 × 10 mL) and decanted, then dried to give 135 mg (95% yield) of compound 16-8 as a white solid. LCMS - Condition 01: [M-18] + =491.30; Rt=1.76min 1 H NMR(400MHz, DMSO-d6)δ:7.54-7.58(m,3H),7.46-7.53(m,4H),7.39-7.43(m,2H),7.17-7.23(m,4H),7.15(s,1H),6.97(dd,J=2.20,9.05Hz,1H),6 .91(d,J=8.31Hz,2H),5.40(s,2H),5.22(s,2H),3.89(s,3H),3.03-3.09( m, 2H), 2.93 (q, J = 7.34Hz, 2H), 2.81-2.87 (m, 2H), 1.20 (t, J = 7.34Hz, 3H).

[0294] Methanesulfonic acid (0.18 mL, 2.772 mmol) and triethylsilane (0.48 mL, 3.005 mmol) were added to a TFA (1 mL) solution of 2-(4-(5-(benzyloxy)-3-fluoro-2-(4-methoxyphenyl)-1H-indol-1-yl)methyl)phenyl)-N-ethyl-1-amine 16-8 (145 mg, 0.285 mmol) at 0 °C under an argon atmosphere. The reaction mixture was stirred for 2 hours at room temperature under an argon atmosphere. After the reaction was complete, the reaction mixture was concentrated under reduced pressure and diluted with ethyl acetate (50 mL). The organic layer was washed with saturated NaHCO3 solution (15 mL), then washed with brine (15 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude compound was purified by preparative HPLC to give 9 mg (7% yield) of D-16 as a white solid. LCMS - Condition 01: [M+H] + =419.20; Rt=1.39min 1 H NMR (400MHz, DMSO-d6) δ: 9.06 (br.s, 1H), 7.41 (d, J = 8.80Hz, 2H), 7.20 (d, J = 8.80Hz, 1H), 7.06 (dd, J = 2.69, 8.56Hz, 4H), 6.82 (d, J = 1.96Hz, 1H), 6 .78(d,J=7.82Hz,2H),6.67(dd,J=1.96,8.80Hz,1H),5.24(s,2H),3.80( s, 3H), 2.59-2.73 (m, 5H), 2.56 (d, J = 6.85Hz, 2H), 0.99 (t, J = 7.09Hz, 3H). 3-Chloro-1-(4-(2-(ethylamino)ethyl)benzyl)-2-(4-methoxyphenyl)-1H-indole-5-ol (D-13)

[0295] Potassium carbonate (18.6 g, 134.7 mmol) and benzyl bromide (12 mL, 98.80 mmol) were added to a DMF (100 mL) solution of 15 g (89.82 mmol) of 5-hydroxy-2-nitrobenzaldehyde 13-1 at 0 °C under an argon atmosphere. The reaction mixture was then heated at 80 °C for 3 hours. After the reaction was complete, the reaction mixture was quenched with ice water and extracted with ethyl acetate (3×). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude compound was purified by grinding in n-hexane to give 22 g (95% yield) of compound 13-2 as a grayish-white solid. LCMS - Condition 01: [M+H] + =257.95; Rt=1.94min

[0296] To a solution of 200 mL CH₂Cl₂ containing 20 g (77.82 mmol) of 5-(benzyloxy)-2-nitrobenzaldehyde 13-2, carbon tetrabromide (39 g, 116.7 mmol) and 50 mL CH₂Cl₂ containing 60 g (233.46 mmol) of triphenylphosphine, anhydrous sodium tetrabromide (60 g, 233.46 mmol) were added dropwise, the mixture was stirred at room temperature for 2 hours. After the reaction was complete, the mixture was filtered through a silica mat and washed with CH₂Cl₂. The filtrate was concentrated under reduced pressure, and the crude intermediate was dissolved in ethanol (200 mL), to which SnCl₂ (52 g, 233.46 mmol) was added at room temperature. The mixture was then heated to 80 °C and stirred for 2.5 hours. After the reaction was complete, the mixture was diluted with ethyl acetate, quenched with solid potassium carbonate (100 g), stirred, and filtered. The filtrate was washed with brine (600 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography and eluted with n-hexane solution of 0-30% ethyl acetate to give 14 g (48% yield) of compound 13-3 as a dark brown liquid. LCMS - Condition 01: [M+H] + =383.95; Rt=2.13min 1 H NMR(400MHz,DMSO-d6)δ:7.46-7.48(m,1H),7.26-7.41(m,5H),6.97(d,J=2.45Hz,1 H), 6.80 (dd, J = 2.69, 8.56Hz, 1H), 6.62 (d, J = 8.80Hz, 1H), 4.96 (s, 2H), 4.85 (s, 2H).

[0297] To a solution of 100 mL of toluene containing 14 g (36.55 mmol) of 4-(benzyloxy)-2-(2,2-dibromovinyl)aniline 13-3, and K3PO4, was added simultaneously to (8.33 g (54.83 mmol) and K3PO4, and the mixture was degassed for 10 min at room temperature under an argon atmosphere. A solution of 1.5 g (0.365 mmol) of Pd(OAc)2 and 2 g (0.731 mmol) of toluene, prepared in another flask, was degassed for 10 min under an argon atmosphere and then added to the above reaction mixture at room temperature under an argon atmosphere. The reaction mixture was heated and stirred at 90 °C for 4 hours. After the reaction was complete, the reaction mixture was diluted with water and extracted with ethyl acetate (3×). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography and eluted with a solution of 0-30% ethyl acetate in n-hexane to give 4.8 g (40% yield) of compound 13-4 as a grayish-white solid. LCMS - Condition 01: [M+H] + =330.00; Rt=2.19min 1 H NMR (400MHz, DMSO-d6) δ: 11.23 (s, 1H), 7.74 (d, J = 8.80Hz, 2H), 7.46 (d, J = 7.34Hz, 2H), 7.35-7.41 (m, 2H), 7.27-7.32 (m, 1H), 7.24 (d, J = 8. 80Hz, 1H), 7.06 (d, J = 2.45Hz, 1H), 7.00 (d, J = 8.80Hz, 2H), 6.77 (dd, J = 2.45, 8.80Hz, 1H), 6.65 (d, J = 1.5Hz, 1H), 5.08 (s, 2H), 3.78 (s, 3H).

[0298] N-chlorosuccinimide (568 mg, 4.255 mmol) was added to a CH₂Cl₂ (20 mL) solution of 5-(benzyloxy)-2-(4-methoxyphenyl)-1H-indole 13-4 (1.75 g, 5.319 mmol) at -10 °C. The reaction mixture was then stirred at -10 °C for 1 hour. After the reaction was complete, the reaction mixture was diluted with CH₂Cl₂ (50 mL), washed with an aqueous sodium sulfite solution (20 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The resulting crude compound was stirred in methanol (2 mL) for 10 minutes, filtered, and dried to give 825 mg (43% yield) of compound 13-5 as a grayish-white solid. LCMS - Condition 01: [M+H] +=363.95; Rt=2.30min.

[0299] Sodium hydride (60% oil dispersion, 320 mg, 6.756 mmol) was added in portions to a DMF (10 mL) solution of 5-(benzyloxy)-3-chloro-2-(4-methoxyphenyl)-1H-indole 13-5 (820 mg, 2.525 mmol) at 0 °C. The reaction mixture was further stirred at 0 °C for 30 min. (4-(bromomethyl)phenylethoxy)(tert-butyl)dimethylsilane (960 mg, 2.929 mmol) was added to the resulting solution. The reaction mixture was stirred at room temperature for 18 h. After the reaction was complete, the reaction mixture was quenched with ice water and extracted with ethyl acetate (3×). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The resulting crude compound was purified by silica gel column chromatography, eluting with a solution of 0-80% ethyl acetate in n-hexane to give 605 mg (54% yield) of compound 13-7 as a grayish-white viscous solid. LCMS - Condition 01: [M+H] + =498.10; Rt=2.32min 1 H NMR(400MHz, DMSO-d6)δ:7.46-7.50(m,2H),7.31-7.43(m,6H),7.04-7.10(m,5H),6.91(dd,J=2.45,8.80Hz ,1H),6.73-6.78(m,2H),5.29(s,2H),5.15(s,2H),3.81(s,3H),3.47-3.54(m,2H),2.61(t,J=7.09Hz,2H).

[0300] Triethylamine (0.46 mL, 3.319 mmol) was added to a solution of 2-(4-(5-(benzyloxy)-3-chloro-2-(4-methoxyphenyl)-1H-indol-1-yl)methyl)phenyl)ethyl-1-ol 13-7 (550 mg, 1.106 mmol) in 10 mL of CH2Cl2 at 0 °C, followed by the addition of p-TsCl (318 mg, 1.660 mmol). The reaction mixture was stirred for 18 hours at room temperature. After the reaction was complete, the reaction mixture was diluted with 100 mL of CH2Cl2 and washed with 30 mL of water and 30 mL of brine. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 590 mg (81% yield) of compound 13-8 as a grayish-white solid. LCMS - Condition 01: [M+H] + =652.25; Rt=2.57min 1 H NMR(400MHz,DMSO-d6)δ:7.67(d,J=7.82Hz,2H),7.57(d,J=7.34Hz,2H),7.45-7.5 1(m,4H),7.40-7.45(m,2H),7.37(d,J=8.31Hz,2H),7.15-7.19(m,3H),7.06(d,J=7 .82Hz,2H),7.01(dd,J=1.96,8.80Hz,1H),6.83(d,J=7.82Hz,2H),5.39(s,2H),5.2 5(s,2H),4.23(t,J=6.36Hz,2H),3.90(s,3H),2.87(t,J=6.36Hz,2H),2.44(s,3H).

[0301] In a sealed tube, a solution of 2N ethylamine in THF (4.4 mL, mmol) and DIPEA (0.5 mL, 2.673 mmol) was added to a solution of 4-((5-(benzyloxy)-3-chloro-2-(4-methoxyphenyl)-1H-indol-1-yl)methyl)phenethyl 4-methylbenzenesulfonate 13-8 (580 mg, 0.891 mmol) in acetonitrile (15 mL). The reaction mixture was then stirred at room temperature for 24 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure, washed with n-hexane (2 × 10 mL) and decanted, and then dried to give 252 mg (53% yield) of compound 13-9 as a white solid. LCMS - Condition 01: [M+H] + =525.15; Rt=1.82min 1 H NMR(400MHz, DMSO-d6)δ:7.54-7.58(m,3H),7.46-7.53(m,4H),7.40-7.45(m,2H),7.15-7.22(m,5H),7.00(dd,J=2.20,9.05Hz,1H),6.91(d, J=8.31Hz,2H),5.40(s,2H),5.24(s,2H),3.90(s,3H),3.07-3.12(m,2H),2.97(q,J=7.34Hz,2H),2.83-2.89(m,2H),1.21(t,J=7.09Hz,3H).

[0302] Methanesulfonic acid (0.25 mL, 3.850 mmol) and triethylsilane (0.75 mL, 4.695 mmol) were added to a TFA (1.5 mL) solution of 2-(4-((5-(benzyloxy)-3-chloro-2-(4-methoxyphenyl)-1H-indol-1-yl)methyl)phenyl)-N-ethyl-1-amine 13-9 (250 mg, 0.476 mmol) at 0 °C under an argon atmosphere. The reaction mixture was stirred for 2 hours at room temperature under an argon atmosphere. After the reaction was complete, the reaction mixture was concentrated under reduced pressure and diluted with ethyl acetate (100 mL). The separated organic layer was washed with saturated NaHCO3 (30 mL), then washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude compound was purified by preparative HPLC to give 45 mg (22% yield) of D-13 as a white solid. LCMS - Condition 01: [M+H] + =435.20; Rt=1.46min 1 H NMR (400MHz, DMSO-d6) δ: 8.32 (s, 1H), 7.39 (d, J = 8.80Hz, 2H), 7.21 (d, J = 8.80Hz, 1H), 7.06 (d, J = 8.80Hz, 4H), 6.81 (d, J = 2.45Hz, 1H) ,6.78(d,J=7.82Hz,2H),6.65-6.70(m,1H),5.24(s,2H),3.80(s,3H),2.75-2.82(m,2H),2.62-2.69(m,4H),1.02(t,J=7.34Hz,3H). 1-(4-(2-(cyclopropylamino)ethyl)benzyl)-3-fluoro-2-(o-tolyl)-1H-indole-5-ol (D-28)

[0303] 2-Methylphenylboronic acid (2.54 g, 18.66 mmol) and 2M Na₂CO₃ solution (4.56 g, 43.08 mmol) were added to a toluene:ethanol (9:1; 60 mL) solution of 4-(benzyloxy)-2-(2,2-dibromovinyl)aniline 13-3 (5.5 g, 14.360 mmol) at room temperature under an argon atmosphere, and the mixture was degassed with argon for 30 min. Pd(PPh₃)₄ (830 mg, 0.718 mmol) was added to the resulting solution, and degassed for another 10 min at room temperature. The reaction mixture was then heated and stirred at 90 °C for 18 h. After the reaction was complete, the reaction mixture was diluted with water and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography and eluted with a solution of 0-15% ethyl acetate in n-hexane to give 2.35 g (52% yield) of compound 28-1 as a viscous oil. LCMS - Condition 01: [M+H] + =314.10; Rt=2.38min 1 H NMR (400MHz, CDCl3) δ: 8.03 (br.s, 1H), 7.48 (d, J = 7.46Hz, 2H), 7.43-7.46 (m, 1H), 7.39 (t, J = 7.46Hz, 2H), 7.22- 7.34(m,5H),7.18(d,J=1.96Hz,1H),6.95(dd,J=1.90,8.74Hz,1H),6.51-6.54(m,1H),5.12(s,2H),2.49(s,3H).

[0304] Selectfluor (2.1 g, 6.134 mmol) was added to an aqueous solution of 5-(benzyloxy)-2-(o-tolyl)-1H-indole 28-1 (2.34 g, 7.667 mmol) in ACN:DMSO (3:2; 25 mL) at -10 °C under an argon atmosphere. The reaction mixture was then stirred at 0 °C for 2 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (100 mL), washed with water (40 mL), and then washed with brine (30 mL). The separated organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The resulting crude compound was purified by silica gel column chromatography, eluting with a solution of 0-15% ethyl acetate in n-hexane, followed by preparative TLC to give 820 mg (33% yield) of compound 28-2 as a grayish-white solid. LCMS - Condition 01: [M-18] + =314.11; Rt=2.38min 1 H NMR(400MHz, CDCl3)δ:8.04(s,1H),7.47-7.51(m,2H),7.38-7.45(m,3H),7.26-7.33(m,4H ),7.21-7.25(m,1H),7.16(d,J=2.45Hz,1H),6.95-7.00(m,1H),5.14(s,2H),2.43(3,3H).

[0305] Sodium hydride (60% oil dispersion, 163 mg, 4.092 mmol) was added in portions to a DMF (10 mL) solution of 5-(benzyloxy)-3-fluoro-2-(o-tolyl)-1H-indole 28-2 (450 mg, 1.364 mmol) at 0 °C. The reaction mixture was then stirred at 0 °C for 30 min. Tert-butyl(4-(bromomethyl)phenylethoxy)dimethylsilane (591 mg, 1.773 mmol) was added to the resulting solution. The reaction mixture was stirred at room temperature for 2 h. After the reaction was complete, the reaction mixture was quenched with ice water and extracted with ethyl acetate (3 × 25 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 902 mg (crude) of compound 28-3 as a colorless viscous liquid. LCMS - Condition 01: [M-18] + =562.30; Rt=3.09min 1 H NMR(400MHz,DMSO-d6)δ:7.44-7.48(m,2H),7.35-7.42(m,4H),7.28-7.34(m,3H) ,7.11-7.16(m,2H),7.00(d,J=7.83Hz,2H),6.88(dd,J=1.96,8.80Hz,1H),6.66(d ,J=7.83Hz,2H),5.13(s,1H),5.12(s,1H),5.09(br.s,1H),5.07(br.s,1H),3.65( t,J=6.60Hz,2H),2.61(t,J=6.85Hz,2H),2.09(s,3H),0.76(s,9H),-0.13(s,6H).

[0306] At room temperature, a 1M tetrabutylammonium fluoride THF solution (2.3 mL, 2.339 mmol) was added dropwise to a 10 mL THF solution of 5-(benzyloxy)-1-(4-(2-((tert-butyldimethylsilyl)oxy)ethyl)benzyl)-3-fluoro-2-(o-tolyl)-1H-indole 28-3 (900 mg, 1.559 mmol) at 0 °C, and the mixture was stirred for 2 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure and diluted with ethyl acetate. The separated organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 780 mg (crude) of compound 28-4 as a colorless viscous liquid, which could be used directly in the next step without further purification. LCMS - Condition 01: [M-18] + =448.10; Rt=2.39min 1 H NMR(400MHz, CDCl3)δ:7.45-7.51(m,2H),7.37-7.43(m,2H),7.29-7.35(m,3H),7.22-7.24( m,2H),7.17(d,J=2.45Hz,1H),7.13(dd,J=2.20,9.05Hz,1H),7.04(d,J=7.83Hz,2H),6.92(d d,J=2.45,8.80Hz,1H),6.78(d,J=7.83Hz,2H),5.13(s,1H),5.12(s,1H),5.07(s,1H),5.03 (s, 1H), 3.79 (t, J = 6.36Hz, 2H), 3.48 (q, J = 6.85Hz, 1H), 2.78 (t, J = 6.36Hz, 2H), 2.19 (s, 3H).

[0307] Triethylamine (0.67 mL, 4.839 mmol) was added to a solution of 2-(4-((5-(benzyloxy)-3-fluoro-2-(o-tolyl)-1H-indol-1-yl)methyl)phenyl)ethyl-1-ol 28-4 (750 mg, 1.613 mmol) in 10 mL of CH2Cl2 at 0 °C, followed by the addition of toluenesulfonyl chloride (371 mg, 1.936 mmol). The reaction mixture was stirred for 18 hours at room temperature. After the reaction was complete, the reaction mixture was diluted with DCM and washed with water and brine. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude compound was purified by silica gel column chromatography, eluting with a solution of 0-30% ethyl acetate in n-hexane to give 451 mg (45% yield) of compound 28-5 as a colorless viscous liquid. LCMS - Condition 01: [M-18] + =602.22; Rt=2.62min 1 H NMR (400MHz, CDCl3) δ: 7.63 (d, J = 8.31Hz, 2H), 7.46-7.50 (m, 2H), 7.39-7.42 (m, 1H) ,7.38(s,2H),7.30-7.36(m,3H),7.23(d,J=4.40Hz,3H),7.12-7.17(m,2H),6.92(d ,J=7.83Hz,3H),6.72(d,J=7.83Hz,2H),5.12(s,1H),5.11(s,1H),5.07(s,1H),5.0 1(s,1H),4.12(t,J=6.85Hz,2H),2.85(t,J=6.85Hz,2H),2.39(s,3H),2.16(s,3H).

[0308] In a sealed tube, DIPEA (0.6 mL, 3.635 mmol) and cyclopropylamine (208 mg, 3.635 mmol) were added to a solution of 4-((5-(benzyloxy)-3-fluoro-2-(o-tolyl)-1H-indol-1-yl)methyl)phenethyl 4-methylbenzenesulfonate 28-5 (225 mg, 0.363 mmol) in acetonitrile (5 mL). The reaction mixture was stirred at room temperature for 72 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure and diluted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain 210 mg (crude) of compound 28-6 as a grayish-white solid, which could be used directly in the next step without further purification. LCMS - Condition 01: [M+H] + =505.35; Rt=1.48min 1 H NMR(400MHz, CDCl3)δ:7.46-7.50(m,2H),7.36-7.42(m,2H),7.28-7.35(m,2H),7.20 -7.23(m,2H),7.13-7.18(m,3H),6.96(d,J=8.31Hz,2H),6.92(dd,J=2.45,8.80Hz,1 H),6.72(d,J=7.83Hz,2H),5.12(s,1H),5.11(s,1H),5.04(s,1H),4.99(s,1H),3.02 -3.07(m,2H),2.89-2.95(m,2H),2.35-2.40(m,1H),2.32(s,3H),1.40-1.50(m,4H).

[0309] 20% palladium hydroxide / carbon (55 mg, 20% w / w) was added to a solution of N-(4-((5-(benzyloxy)-3-fluoro-2-(o-tolyl)-1H-indol-1-yl)methyl)phenethyl)cyclopropylamine 28-6 (280 mg, 0.555 mmol) in ethyl acetate:methanol (4:1; 7 mL) at room temperature. The reaction mixture was stirred for 18 hours under a hydrogen atmosphere. After the reaction was complete, the reaction mixture was passed through a Celite tube. TM The mixture was filtered through a pad and washed with ethyl acetate. The filtrate was concentrated under reduced pressure, and the crude compound was purified by preparative HPLC to give 28 mg (12% yield) of D-28 as a white solid. LCMS - Condition 01: [M+H] + =415.22; Rt=1.52min 1 H NMR (400MHz, DMSO-d6) δ: 9.05 (s, 1H), 7.27-7.34 (m, 5H), 6.98 (d, J = 7.78Hz, 2H), 6.83 (d, J = 2.01Hz, 1H), 6.69 (dd, J = 2.13, 8.91Hz, 1H), 6.64 (d ,J=7.78Hz,2H),5.01-5.11(m,2H),2.67-2.69(m,2H),2.55-2.58(m,2H ),2.07(s,3H),1.99-2.03(m,1H),0.18-0.25(m,2H),0.02-0.08(m,2H). 3-Fluoro-2-(2-methoxyphenyl)-1-(4-(2-(propylamino)ethyl)benzyl)-1H-indole-5-ol (D-87)

[0310] At room temperature and under an argon atmosphere, 2-methoxyphenylboronic acid (7.73 g, 50.86 mmol) and an aqueous solution of Na₂CO₃ (12.45 g, 117.45 mmol) were simultaneously added to a solution of 4-(benzyloxy)-2-(2,2-dibromovinyl)aniline 13-3 (15 g, 39.16 mmol) in toluene:ethanol (3:1, 80 mL), and the mixture was degassed for 30 min. Pd(PPh₃)₄ (2.26 g, 1.956 mmol) was added to the resulting solution, and degassed for another 10 min. The reaction mixture was further heated to 90 °C and stirred for 18 h. After the reaction was complete, the reaction mixture was diluted with water and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography and eluted with n-hexane solution of 0-8% ethyl acetate to give 5 g (39% yield) of compound 87-2 as a viscous solid. LCMS Condition 1: [M+H] + =329.70; Rt=2.21min 1 H NMR(400MHz, DMSO-d6)δ:11.02(s,1H),7.77(dd,J=1.47,7.83Hz,1H),7.46-7.49(m,2H),7.39(t,J=7.34Hz ,2H),7.29-7.36(m,3H),7.10-7.15(m,2H),7.01-7.07(m,1H),6.79-6.84(m,2H),5.10(s,2H),3.93(s,3H).

[0311] Selectfluor (4.84 g, 13.67 mmol) was added to an aqueous solution of acetonitrile:DMSO (5:2, 35 mL) of 4.5 g (4.5 g, 13.67 mmol) of 5-(benzyloxy)-2-(2-methoxyphenyl)-1H-indole 87-2 under an argon atmosphere at -10 °C. The reaction mixture was stirred for 4 hours at room temperature. After the reaction was complete (monitored by TLC and LCMS), the reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (100 mL), washed with water (40 mL), and then washed with brine (30 mL). The separated organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography, eluted with a solution of 0–5% ethyl acetate in n-hexane, and then subjected to preparative TLC to give 2.2 g (46% yield) of compound 87-3 as a brown solid. LCMS Condition 1: [M+H] + =348.10; Rt=2.29min 1 H NMR (400MHz, DMSO-d6) δ: 10.64 (s, 1H), 7.54 (d, J = 7.53Hz, 1H), 7.36-7.40 (m, 2H), 7.26-7.33 (m, 3H), 7.21- 7.26(m,2H),7.06-7.10(m,1H),6.95-6.99(m,2H),6.77(dd,J=2.13,8.91Hz,1H),5.04(s,2H),3.79(s,3H).

[0312] Sodium hydride (60% oil dispersion, 863 mg, 21.58 mmol) was added fractionally to a DMF (10 mL) solution of 5-(benzyloxy)-3-fluoro-2-(2-methoxyphenyl)-1H-indole 87-3 (1.5 g, 4.319 mmol) at 0 °C and stirred at 0 °C for 30 min. (4-(bromomethyl)phenylethoxy)(tert-butyl)dimethylsilane (1.7 g, 5.182 mmol) was added to the resulting solution. The reaction mixture was then stirred at room temperature for 2 h. After the reaction was complete (monitored by TLC and LCMS), the reaction mixture was quenched with ice water and extracted with ethyl acetate (3 × 75 mL). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography, eluting with a solution of 0–4% ethyl acetate in n-hexane to give 2 g (77% yield) of compound 87-4 as a viscous yellow oil. LCMS Condition 1: [M+Na] + =618.35; Rt=2.76min 1 H NMR(400MHz, DMSO-d6)δ:7.44(d,J=7.82Hz,2H),7.37(t,J=7.58Hz,2H),7.29(d,J=5 .87Hz,2H),7.22-7.26(m,1H),7.11-7.18(m,2H),7.02-7.05(m,1H),7.00(d,J=7.34H z,3H),6.83(dd,J=2.45,9.29Hz,1H),6.74(d,J=7.83Hz,2H),5.74(s,2H),5.11(s,2H ), 3.71 (s, 3H), 3.60-3.68 (m, 2H), 2.60 (t, J = 6.60Hz, 2H), 0.76 (s, 9H), -0.13 (s, 6H).

[0313] At room temperature, a 1M tetrabutylammonium fluoride THF solution (5 mL, 5.042 mmol) was added dropwise to a 20 mL THF solution of 5-(benzyloxy)-1-(4-(2-((tert-butyldimethylsilyl)oxy)ethyl)benzyl)-3-fluoro-2-(2-methoxyphenyl)-1H-indole 87-4 (2 g, 3.361 mmol) at 0 °C, and the mixture was stirred for 2 hours. After the reaction was complete (monitored by TLC and LCMS), the reaction mixture was concentrated under reduced pressure, diluted with water, and then diluted with ethyl acetate (2 × 10 mL). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography, eluting with a 0–30% ethyl acetate solution in n-hexane to give 1.3 g (81% yield) of compound 87-5 as a colorless viscous paste. LCMS Condition 1: [M+Na] + =504.15; Rt=2.35min 1 H NMR(400MHz,DMSO-d6)δ:7.55(d,J=7.34Hz,2H),7.47(t,J=7.34Hz,2H),7.36-7.43 (m,3H),7.22-7.28(m,2H),7.19(d,J=2.45Hz,1H),7.14(t,J=7.34Hz,1H),7.09(d,J =7.83Hz,2H),6.95(dd,J=2.20,9.05Hz,1H),6.83(d,J=7.82Hz,2H),5.09-5.14(m, 4H), 4.63 (t, J = 5.14Hz, 1H), 3.81 (s, 3H), 3.54-3.61 (m, 2H), 2.68 (t, J = 6.85Hz, 2H).

[0314] Triethylamine (1.1 mL, 8.108 mmol) was added to a solution of 2-(4-((5-(benzyloxy)-3-fluoro-2-(2-methoxyphenyl)-1H-indol-1-yl)methyl)phenyl)ethyl-1-ol 87-5 (1.3 g, 2.702 mmol) in 15 mL of CH2Cl2 at 0 °C, followed by the addition of toluenesulfonyl chloride (621 mg, 3.243 mmol). The reaction mixture was stirred at room temperature for 3 hours. After the reaction was complete (monitored by TLC and LCMS), the reaction mixture was concentrated under reduced pressure, diluted with water, and extracted with ethyl acetate (2 × 50 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography, eluting with a solution of 0–10% ethyl acetate in n-hexane to give 1.3 g (76% yield) of compound 87-6 as a light brown solid. LCMS Condition 1: [M+Na] + =658.20; Rt=2.53min 1H NMR(400MHz, DMSO-d6)δ:7.54(d,J=8.31Hz,2H),7.45(d,J=8.31Hz,3H),7.34-7.40(m,2H),7.27-7 .33(m,3H),7.24(d,J=8.31Hz,2H),7.12-7.19(m,1H),7.10(d,J=1.96Hz,1H),7.04(t,J=7.34Hz,1 H),6.91(d,J=7.82Hz,2H),6.86(dd,J=2.20,9.05Hz,1H),6.71(d,J=7.82Hz,2H),5.12(s,2H),5.0 8(s,1H),5.00(br.s,1H),4.10(t,J=6.36Hz,2H),3.70(s,3H),2.74(t,J=6.36Hz,2H),2.32(s,3H).

[0315] In a sealed tube, DIPEA (0.5 mL, 2.834 mmol) and propylamine (83 mg, 1.417 mmol) were added to a solution of 4-((5-(benzyloxy)-3-fluoro-2-(2-methoxyphenyl)-1H-indol-1-yl)methyl)phenethyl 4-methylbenzenesulfonate 87-6 (300 mg, 0.472 mmol) in acetonitrile (4 mL). The reaction mixture was then stirred at room temperature for 48 hours. After the reaction was complete (monitored by TLC and LCMS), the reaction mixture was concentrated under reduced pressure, diluted with water, and extracted with ethyl acetate (2 × 20 mL). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography, eluting with 0–5% methanol in DCM solution to give 200 mg (65% yield) of compound 87-7 as a yellow viscous solid. LCMS Condition 1: [M+H] + =523.30; Rt=1.94min 1H NMR(400MHz, DMSO-d6)δ:7.46(d,J=7.88Hz,3H),7.39(t,J=7.63Hz,2H),7.27-7.34(m,3H),7.15- 7.20(m,1H),7.11(d,J=1.97Hz,1H),7.05-7.08(m,1H),7.03(d,J=8.37Hz,2H),6.86(dd,J=2.46,8 .86Hz,1H),6.78(d,J=8.37Hz,2H),5.14(s,2H),4.96-5.13(m,2H),3.73(s,3H),2.74-2.81(m,2H) ,2.62-2.69(m,2H),2.58(t,J=7.38Hz,2H),1.38-1.47(m,2H),1.23(br.s,1H),0.80-0.86(m,3H).

[0316] At room temperature, 20% palladium hydroxide / carbon (100 mg) was added to an ethyl acetate:methanol (1:1; 3 mL) solution of N-(4-((5-(benzyloxy)-3-fluoro-2-(2-methoxyphenyl)-1H-indol-1-yl)methyl)phenethyl)propyl-1-amine 87-7 (200 mg, 0.361 mmol). The reaction mixture was stirred for 18 hours under a hydrogen atmosphere. After the reaction was complete (monitored by TLC and LCMS), the reaction mixture was passed through a Celite filter. TM The mixture was filtered through a pad and washed with ethyl acetate. The filtrate was concentrated under reduced pressure, and the crude compound was purified by preparative HPLC to give 55 mg (16% yield) of D-87 as a grayish-white solid. LCMS Condition 1: [M+H] + =433.20; Rt=1.39min 1 H NMR(400MHz,DMSO-d6)δ:9.04(br.s,1H),7.43-7.49(m,1H),7.31(dd,J=1.71,7.58Hz ,1H),7.14-7.20(m,2H),6.98-7.07(m,3H),6.81(d,J=2.45Hz,1H),6.74(d,J=8.31Hz, 2H),6.65(dd,J=2.45,8.80Hz,1H),5.06-5.20(m,1H),4.87-5.02(m,1H),3.72(s,3H) ,2.53-2.64(m,4H),2.41(t,J=7.09Hz,2H),1.23-1.38(m,3H),0.80(t,J=7.58Hz,3H). 1-(4-(2-(cyclobutylamino)ethyl)benzyl)-2-(2,6-dimethylphenyl)-3-fluoro-1H-indole-5-ol (D-50)

[0317] At room temperature and under an argon atmosphere, 2,6-dimethylphenylboronic acid (2.5 g, 16.78 mmol) and an aqueous solution of Na₂CO₃ (4.1 g, 38.67 mmol) in toluene-ethanol (35:6 mL) were simultaneously added, followed by degassing for 30 min. Pd(PPh₃)₄ (753 mg, 0.652 mmol) was added to the resulting solution, and degassing continued for another 10 min at room temperature. The reaction mixture was then heated to 90 °C for 18 h. After the reaction was complete (monitored by TLC and LCMS), the reaction mixture was diluted with water and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography and eluted with a hexane solution of 0-15% ethyl acetate to give 1 g (24% yield) of compound 50-1 as a viscous brown paste. LCMS - Condition 01: [M+H] + =328.20; Rt=2.38min 1 H NMR (400MHz, DMSO-d6) δ: 10.95 (br.s, 1H), 7.45-7.50 (m, 2H), 7.40 (t, J = 7.34Hz, 2H), 7.33 (d, J = 7.34Hz, 1H), 7.2 2(t,J=7.83Hz,2H),7.14(d,J=7.82Hz,3H),6.80(dd,J=1.96,8.80Hz,1H),6.20(s,1H),5.11(s,2H),2.11(s,6H).

[0318] Selectfluor (1.08 g, 3.051 mmol) was added to an aqueous solution of 5-(benzyloxy)-2-(2,6-dimethylphenyl)-1H-indole 50-1 (1 g, 3.058 mmol) in acetonitrile:DMSO (3:1 mL) at -10 °C under an argon atmosphere. The reaction mixture was stirred further at 0 °C for 2 hours. After the reaction was complete (monitored by TLC and LCMS), the reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (100 mL), washed with water (40 mL), and then washed with brine (30 mL). The separated organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude compound was purified by silica gel column chromatography, eluted with a solution of 0-10% ethyl acetate in n-hexane, and then subjected to preparative TLC to give 500 mg (52% yield) of compound 50-2 as a brown solid. LCMS - Condition 01: [M+18] + =364.00; Rt=2.49min 1 H NMR (400MHz, DMSO-d6) δ: 10.83 (br.s, 1H), 7.48 (d, J = 7.34Hz, 3H), 7.36-7. 43(m,2H),7.28-7.36(m,2H),7.15-7.26(m,4H),5.14(s,2H),2.14(s,6H).

[0319] Sodium hydride (60% oil dispersion, 145 mg, 6.041 mmol) was added in portions to a DMF (5 mL) solution of 5-(benzyloxy)-2-(2,6-dimethylphenyl)-3-fluoro-1H-indole 50-2 (500 mg, 1.449 mmol) at 0 °C and stirred for 30 min. Tert-butyl(4-(chloromethyl)phenethoxy)dimethylsilane (572 mg, 1.738 mmol) was added to the resulting solution. The reaction mixture was then stirred at room temperature for 2 h. After the reaction was complete (monitored by TLC and LCMS), the reaction mixture was quenched with ice water and extracted with ethyl acetate (3 × 25 mL). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The resulting crude compound was purified by silica gel column chromatography, eluting with a solution of 0–10% ethyl acetate in n-hexane to give 500 mg (60% yield) of compound 50-3 as a viscous oil. LCMS - Condition 01: [M+H] + =594.20; Rt=3.17min 1H NMR(400MHz, DMSO-d6)δ:7.39-7.49(m,4H),7.28-7.35(m,2H),7.14-7.22(m,4H),6.98(d,J=6.85Hz,2H),6.88(d,J=9.29Hz,1H),6.6 6(d,J=6.85Hz,2H),5.15(s,2H),4.95(s,2H),3.73(t,J=6.85Hz,2H),2.70(t,J=6.36Hz,2H),1.90(s,6H),0.78(s,9H),-0.09(s,6H).

[0320] At room temperature, a solution of 1 M tetrabutylammonium fluoride in THF (1.25 mL, 4.809 mmol) was added dropwise to a solution of 5-(benzyloxy)-1-(4-(2-((tert-butyldimethylsilyl)oxy)ethyl)benzyl)-2-(2,6-dimethylphenyl)-3-fluoro-1H-indole 50-3 (500 mg, 0.842 mmol) in 10 mL of THF and stirred for 1 hour. After the reaction was complete (monitored by TLC and LCMS), the reaction mixture was quenched with saturated NaHCO3 solution and extracted with ethyl acetate (20 mL × 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography, eluting with 0-40% ethyl acetate in n-hexane to give 400 mg (82% yield) of compound 50-4 as a grayish-white solid. LCMS - Condition 01: [M-18] + =462.50; Rt=2.36min 1 H NMR(400MHz, DMSO-d6)δ:7.54(d,J=6.85Hz,3H),7.43-7.48(m,2H),7.36-7.41(m,3H),7.31(d,J=7.82Hz,1H),7.22(d,J=7.34Hz,2H),7.06 (d,J=7.83Hz,2H),6.72(d,J=7.82Hz,2H),5.21(s,2H),5.00(s,2H),4.59-4.64(m,1H),3.61-3.67(m,2H),2.75-2.81(m,2H),1.98(s,6H).

[0321] Triethylamine (0.46 mL, 3.366 mmol) was added to a solution of 2-(4-((5-(benzyloxy)-2-(2,6-dimethylphenyl)-3-fluoro-1H-indol-1-yl)methyl)phenyl)ethyl-1-ol 50-4 (400 mg, 0.834 mmol) in 10 mL of CH2Cl2 at 0 °C, followed by the addition of toluenesulfonyl chloride (236 mg, 1.248 mmol). The reaction mixture was then stirred at room temperature for 18 hours. After the reaction was complete (monitored by TLC and LCMS), the reaction mixture was diluted with CH2Cl2. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 400 mg (78% yield) of compound 50-5 as a colorless, viscous oil. LCMS - Condition 01: [M+H] + =634.25; Rt=2.62min 1 H NMR(400MHz, DMSO-d6)δ:7.64(d,J=7.83Hz,2H),7.54(d,J=4.89Hz,2H),7.43-7.49(m,3H),7.35(t,J=6.60Hz,4H),7.19-7.24(m,3H),6.9 9(d,J=7.83Hz,3H),6.69(d,J=7.82Hz,2H),5.16(s,2H),4.96(s,2H),4.15-4.21(m,2H),2.83(t,J=5.87Hz,2H),2.40(s,3H),1.97(s,6H).

[0322] In a sealed tube, 2 mL of acetonitrile (200 mg, 0.316 mmol) of 4-((5-(benzyloxy)-2-(2,6-dimethylphenyl)-3-fluoro-1H-indol-1-yl)methyl)phenethyl 4-methylbenzenesulfonate 50-5 was added to 112 mg, 1.577 mmol, and DIPEA (0.4 mL, 2.158 mmol). The reaction mixture was stirred further at room temperature for 48 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure and washed with ethyl acetate (2 × 10 mL). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography, eluting with 0–10% methanol in CH₂Cl₂ solution to give 100 mg (60% yield) of the title compound 50-6 as a viscous oil. LCMS - Condition 01: [M+H] + =533.65; Rt=1.81min 1H NMR(400MHz,DMSO-d6)δ:7.45-7.51(m,3H),7.40(t,J=7.58Hz,2H),7.31(dd ,J=7.58,15.89Hz,2H),7.11-7.19(m,3H),6.98-7.04(m,2H),6.93(dd,J=1.9 6,8.80Hz,1H),6.67(d,J=7.83Hz,2H),5.15(s,2H),4.95(s,2H),3.19-3.29( m,1H),2.55-2.67(m,4H),2.01-2.12(m,2H),1.91(s,6H),1.49-1.74(m,5H).

[0323] 20% palladium hydroxide / carbon (25 mg) was added to a solution of N-(4-((5-(benzyloxy)-2-(2,6-dimethylphenyl)-3-fluoro-1H-indol-1-yl)methyl)phenethyl)cyclobutylamine 50-6 (100 mg, 0.187 mmol) in ethyl acetate:methanol (1:1, 4 mL) at room temperature. The reaction mixture was then stirred for 18 hours under a hydrogen atmosphere. After the reaction was complete (monitored by TLC and LCMS), the reaction mixture was passed through a Celite filter. TM The mixture was filtered through a pad and washed with ethyl acetate. The filtrate was concentrated under reduced pressure, and the crude compound was purified by preparative HPLC to give 20 mg (24% yield) of D-50 as a grayish-white solid. LCMS - Condition 01: [M+H] + =443.15; Rt=1.61min 1 H NMR(400MHz,DMSO-d6)δ:9.06(br.s,1H),7.37(dd,J=2.45,8.80Hz,1H),7.27-7 .32(m,1H),7.15(d,J=7.34Hz,2H),6.98(d,J=7.83Hz,2H),6.84(d,J=1.96Hz,1 H),6.72(dd,J=2.20,9.05Hz,1H),6.65(d,J=8.31Hz,2H),4.90(s,2H),3.06-3. 12(m,1H),2.52-2.55(m,3H),2.00-2.08(m,2H),1.91(s,6H),1.49-1.63(m,5H). 2-(2,6-Dimethylphenyl)-1-(4-(2-(ethylamino)ethyl)benzyl)-3-fluoro-1H-indole-5-ol (D-78)

[0324] In a sealed tube, ethylamine (1.57 mL, 3.15 mmol) and DIPEA (326 mg, 2.52 mmol) were added to a solution of 50-5 (200 mg, 0.315 mmol) of 4-((5-(benzyloxy)-2-(2,6-dimethylphenyl)-3-fluoro-1H-indol-1-yl)methyl)phenethyl 4-methylbenzenesulfonate in acetonitrile (0.5 mL). The reaction mixture was then stirred at room temperature for 4 days. After the reaction was complete (monitored by TLC and LCMS), the reaction mixture was concentrated under reduced pressure, and the crude compound was purified by silica gel column chromatography, eluting with 0-20% ethyl acetate in n-hexane to give 100 mg (60% yield) of compound 78-1 as a semi-solid. LCMS - Condition 1: [M+H] + =507.30; Rt=1.87min 1 H NMR(400MHz, DMSO-d6)δ:7.45-7.49(m,3H),7.39-7.43(m,2H),7.29-7.35(m,2H),7.05-7.19(m,5H),6.91-6.94(m,1H),6.73(d,J=8.0Hz,2H ),5.16(s,2H),4.97(s,2H),2.99-3.01(m,2H),2.87(d,J=7.6Hz,2H),2.74-2.79(m,2H),2.28(br.S,1H),1.94(s,6H),1.12(t,J=7.6Hz,3H).

[0325] 20% palladium hydroxide / carbon (25 mg) was added to a solution of 2-(4-((5-(benzyloxy)-2-(2,6-dimethylphenyl)-3-fluoro-1H-indol-1-yl)methyl)phenyl)-N-ethylethane-1-amine 78-1 (100 mg, 0.196 mmol) in ethyl acetate:methanol (1:1; 4 mL) at room temperature. The reaction mixture was then stirred for 18 hours under a hydrogen atmosphere. After the reaction was complete (monitored by TLC and LCMS), the reaction mixture was passed through a Celite filter. TM The mixture was filtered through a pad and washed with ethyl acetate. The filtrate was concentrated under reduced pressure, and the crude compound was purified by preparative HPLC to give 18 mg (10% yield) of D-78 as a grayish-white solid. LCMS - Condition 1: [M+H] + =417.50; Rt=1.45min 1H NMR(400MHz, DMSO-d6)δ:9.02(s,1H),7.38(dd,J=1.96,8.80Hz,1H),7.26-7.32(m,1H),7.15(d,J=7.34Hz,2H),6.99(d,J=7.82Hz,2H),6.84( d,J=1.96Hz,1H),6.72(dd,J=2.45,8.80Hz,1H),6.66(d,J=8.31Hz,2H),4.90(s,2H),2.53-2.68(m,6H),1.91(s,6H),0.95(t,J=7.09Hz,3H). 1-(4-(2-(cyclopropylamino)ethyl)benzyl)-3-fluoro-2-(4-hydroxy-2-methylphenyl)-1H-indole-5-ol (D-52)

[0326] 2-Methyl-4-methoxy-phenylboronic acid (3.4 g, 20.36 mmol) and a saturated solution of Na₂CO₃ (5.06 g, 46.99 mmol) were simultaneously added to a toluene-ethanol (1:1, 50 mL) solution of 4-(benzyloxy)-2-(2,2-dibromovinyl)aniline 13-3 (6 g, 15.66 mmol) at room temperature and under an argon atmosphere, and the mixture was degassed for 30 min. Pd(PPh₃)₄ (906 mg, 0.784 mmol) was added to the resulting solution, and degassed for another 10 min at room temperature. The reaction mixture was then heated and stirred at 90 °C for 18 h. After the reaction was complete (monitored by TLC and LCMS), the reaction mixture was diluted with water and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography and eluted with a solution of 0-10% ethyl acetate in n-hexane to give 1.91 g (36% yield) of compound 52-1 as a viscous brown paste. LCMS - Condition 1: [M+H] + =344.10; Rt=2.35min 1H NMR (400MHz, DMSO-d6) δ: 11.08 (s, 1H), 7.52 (t, J = 7.09Hz, 3H), 7.45 (t, J = 7. 34Hz,2H),7.39(d,J=7.34Hz,1H),7.32(d,J=8.31Hz,1H),7.17(d,J=2.45Hz, 1H),6.97(d,J=2.45Hz,1H),6.93(dd,J=2.45,8.80Hz,1H),6.86(dd,J=2.45 ,8.80Hz,1H),6.45(d,J=1.96Hz,1H),5.16(s,2H),3.85(s,3H),2.49(s,3H).

[0327] Selectfluor (1.76 g, 4.98 mmol) was added to an aqueous solution of 5-(benzyloxy)-2-(4-methoxy-2-methylphenyl)-1H-indole 52-1 (1.9 g, 5.539 mmol) in acetonitrile:DMSO (4:1, 30 mL) at -10 °C under an argon atmosphere. The reaction mixture was then stirred at 0 °C for 2 hours. After the reaction was complete (monitored by TLC and LCMS), the reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (100 mL), washed with water (40 mL), and then washed with brine (30 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography, eluted with a solution of 0-10% ethyl acetate in n-hexane, and then subjected to preparative TLC to give 790 mg (40% yield) of compound 52-2 as a brown solid. LCMS - Condition 1: [M-18] + =344.05; Rt=2.39min 1 H NMR(400MHz, DMSO-d6)δ:10.84(s,1H),7.45-7.49(m,2H),7.36-7.41(m,2H),7.30-7.34(m,2H),7.24(dd,J=2.22,8.61Hz,1H) ,7.06(d,J=1.97Hz,1H),6.93(d,J=2.46Hz,1H),6.87(ddd,J=2.46,8.86,10.83Hz,2H),5.13(s,2H),3.79(s,3H),2.31(s,3H).

[0328] Sodium hydride (60% oil dispersion, 320 mg, 6.630 mmol) was added in portions to a DMF (10 mL) solution of 5-(benzyloxy)-3-fluoro-2-(4-methoxy-2-methylphenyl)-1H-indole 52-2 (800 mg, 2.216 mmol) at 0 °C and stirred at 0 °C for 30 min. Tert-butyl(4-(chloromethyl)phenethoxy)dimethylsilane (904 mg, 2.756 mmol) was added to the resulting solution. The reaction mixture was stirred at room temperature for 18 h. After the reaction was complete (monitored by TLC), the reaction mixture was quenched with ice water, extracted with ethyl acetate (3 × 25 mL), and washed with water (50 mL) and brine (20 mL). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography and eluted with a hexane solution of 0-10% ethyl acetate to give 960 mg (72% yield) of compound 52-3 as a brown viscous oil. LCMS - Condition 1: [M+H] + =609.86; Rt=2.27min 1 H NMR(400MHz, CDCl3)δ:7.46-7.50(m,2H),7.37-7.42(m,3H),7.15-7.17(m,1H),7.09 (dd,J=2.46,8.86Hz,1H),7.02(d,J=7.88Hz,3H),6.89(dd,J=2.46,8.86Hz,1H),6.83 (d,J=2.46Hz,1H),6.75-6.79(m,3H),5.13(s,2H),4.97-5.10(m,2H),3.84(s,3H),3 .72(t,J=7.14Hz,2H),2.73(t,J=6.89Hz,2H),2.17(s,3H),0.85(s,9H),0.01(s,3H).

[0329] At room temperature, a solution of 1 M tetrabutylammonium fluoride in THF (0.58 mL, 0.580 mmol) was added dropwise to a solution of 5-(benzyloxy)-1-(4-(2-((tert-butyldimethylsilyl)oxy)ethyl)benzyl)-3-fluoro-2-(4-methoxy-2-methylphenyl)-1H-indole 52-3 (900 mg, 1.477 mmol) in 10 mL of THF, and the mixture was stirred for 1 hour. After the reaction was complete (monitored by TLC), the reaction mixture was quenched with saturated NaHCO3 solution and extracted with ethyl acetate (3 × 25 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography, eluting with 0–40% ethyl acetate in n-hexane to give 600 mg (82% yield) of compound 52-4 as a colorless, viscous oil. LCMS - Condition 1: [M+H] + =496.10; Rt=2.39min 1 H NMR(400MHz,DMSO-d6)δ:7.49-7.53(m,2H),7.35-7.47(m,4H),7.28(d,J=8.37Hz,1H) ,7.16(d,J=1.97Hz,1H),7.06(d,J=7.88Hz,2H),6.98(d,J=2.46Hz,1H),6.92(ddd,J=2 .46,5.66,8.61Hz,2H),6.73(d,J=7.88Hz,2H),5.79-5.80(m,2H),5.18(s,2H),4.59( t,J=5.17Hz,1H),3.83(s,3H),3.50-3.58(m,2H),2.64(t,J=6.89Hz,2H),2.12(s,3H).

[0330] Triethylamine (0.5 mL, 3.597 mmol) was added to a solution of 2-(4-((5-(benzyloxy)-3-fluoro-2-(4-methoxy-2-methylphenyl)-1H-indol-1-yl)methyl)phenyl)ethyl-1-ol 52-4 (600 mg, 1.212 mmol) in 10 mL of CH2Cl2 at 0 °C, followed by the addition of toluenesulfonyl chloride (385 mg, 1.816 mmol). The reaction mixture was stirred at room temperature for 18 hours. After the reaction was complete (monitored by TLC and LCMS), the reaction mixture was diluted with CH2Cl2 (3 x 30 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 600 mg (76% yield) of compound 52-5 as a colorless, viscous oil. LCMS - Condition 1: [M+H] +=650.25; Rt=2.59min 1 H NMR(400MHz, DMSO-d6)δ:7.57(d,J=8.31Hz,2H),7.45-7.49(m,2H),7.37-7.43(m, 3H),7.33(d,J=6.85Hz,1H),7.26(dd,J=8.31,16.63Hz,3H),7.11-7.17(m,1H),6. 92-6.96(m,3H),6.85-6.91(m,2H),6.66(d,J=7.82Hz,2H),5.06-5.15(m,4H),4.1 3(t,J=6.60Hz,2H),3.78(s,3H),2.77(t,J=5.87Hz,2H),2.34(s,3H),2.06(s,3H).

[0331] In a sealed tube at room temperature, DIPEA (0.7 mL, 3.736 mmol) and cyclopropylamine (0.26 mL, 4.61 mmol) were added to a solution of 300 mg (0.461 mmol) of 4-((5-(benzyloxy)-3-fluoro-2-(4-methoxy-2-methylphenyl)-1H-indol-1-yl)methyl)phenethyl 4-methylbenzenesulfonate 52-5 in acetonitrile (3 mL). The reaction mixture was stirred at room temperature for 72 hours. After the reaction was complete (monitored by TLC and LCMS), the reaction mixture was concentrated under reduced pressure and washed with ethyl acetate (2 × 15 mL). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography, eluting with 0–10% methanol in CH₂Cl₂ solution to give 180 mg (73% yield) of compound 52-6 as a colorless oil. LCMS - Condition 1: [M+H] + =535.25; Rt=1.87min 1H NMR(400MHz,DMSO-d6)δ:7.44-7.49(m,2H),7.36-7.43(m,3H),7.31-7.35(m,1H),7.23(d ,J=7.83Hz,1H),7.11(br.s,1H),7.01(d,J=7.34Hz,2H),6.84-6.93(m,3H),6.68(d,J=7.8 3Hz,2H),5.14(s,2H),5.03-5.13(m,2H),3.79(s,3H),2.67-2.72(m,2H),2.54-2.61(m,2 H),2.04(s,3H),2.04-2.07(m,1H),1.23(br.s,1H),0.28-0.35(m,2H),0.12-0.19(m,2H).

[0332] BBr3 (130 mg, 0.520 mmol) was added dropwise to a solution of N-(4-((5-(benzyloxy)-3-fluoro-2-(4-methoxy-2-methylphenyl)-1H-indol-1-yl)methyl)phenethyl)cyclopropylamine 52-6 (140 mg, 0.261 mmol) in DCM (14 mL) at 0 °C. The reaction mixture was stirred for 30 min at the same temperature. After the reaction was complete (monitored by TLC and LCMS), the reaction mixture was quenched with saturated sodium bicarbonate solution and extracted with DCM (3 × 15 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude compound was purified by preparative HPLC to give 10 mg (10% yield) of D-52 as a grayish-white solid. LCMS - Condition 1: [M+H] + =431.25; Rt=1.41min 1 H NMR(400MHz, DMSO-d6)δ: δ9.63(s,1H),8.98(s,1H),7.24(d,J=9.29Hz,1H),7.09(d,J=7.82Hz,1H),7.01(d,J=7.34Hz,2H),6.81(s,1H),6.64 -6.74(m,5H),4.96-5.10(m,2H),2.66-2.74(m,2H),2.57-2.62(m,2H) ,2.00-2.07(m,1H),1.98(s,3H),1.07-1.98(m,1H),0.09-0.19(m,4H). 3-Fluoro-1-(4-(2-(((2-fluoroethyl)amino)ethyl)benzyl)-2-(4-methoxy-2-methylphenyl)-1H-indole-5-ol (D-103)

[0333] A 60% sodium hydride oil dispersion (1.1 g, 27.66 mmol) was added fractionally to a DMF (15 mL) solution of 5-(benzyloxy)-3-fluoro-2-(4-methoxy-2-methylphenyl)-1H-indole 52-2 (2 g, 5.540 mmol) at 0 °C. The reaction mixture was further stirred at 0 °C for 30 min. (4-(bromomethyl)phenylethoxy)(tert-butyl)dimethylsilane (2.18 g, 6.643 mmol) was added to the resulting solution. The reaction mixture was stirred at room temperature for 2 h. After the reaction was complete, the reaction mixture was quenched with ice water and extracted with ethyl acetate (3 × 25 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography, eluting with a solution of 0–30% ethyl acetate in n-hexane to give 2 g (60% yield) of compound 103-7 as a viscous yellow oil. LCMS Condition 1: [M+H] + =610.25; Rt=3.14min 1 H NMR(400MHz, DMSO-d6)δ:7.45-7.49(m,2H),7.39(t,J=7.34Hz,2H),7.31-7.36(m,2H),7.22(d ,J=8.31Hz,1H),7.11(d,J=2.45Hz,1H),7.03(d,J=7.83Hz,2H),6.93(d,J=2.45Hz,1H),6.86( ddd,J=2.45,5.75,8.44Hz,2H),6.69(d,J=7.83Hz,2H),5.14(s,2H),3.79(s,2H),3.67(t,J=6 .60Hz,2H),2.63(t,J=6.85Hz,2H),2.06-2.10(m,3H),1.99(s,3H),0.77(s,9H),-0.12(s,6H).

[0334] At room temperature, a solution of 1 M tetrabutylammonium fluoride in THF (6.1 mL, 6.149 mmol) was added dropwise to a THF solution of 5-(benzyloxy)-1-(4-(2-((tert-butyldimethylsilyl)oxy)ethyl)benzyl)-3-fluoro-2-(4-methoxy-2-methylphenyl)-1H-indole 103-7 (2.5 g, 4.099 mmol) at 0 °C and stirred for 2 hours. After the reaction was complete, the reaction mixture was diluted with water and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography, eluting with 0–30% ethyl acetate in n-hexane to give 2 g (98% yield) of compound 103-8 as a brown viscous solid. LCMS-condition-1: [M+H] + =496.20; Rt=2.49min 1 H NMR(400MHz, DMSO-d6)δ:7.45-7.49(m,2H),7.32-7.42(m,4H),7.24(d,J=8.31H z,1H),7.12(d,J=2.45Hz,1H),7.02(d,J=8.31Hz,2H),6.94(d,J=2.45Hz,1H),6 .85-6.91(m,2H),6.69(d,J=8.31Hz,2H),5.14(s,2H),4.56(t,J=5.38Hz,1H),3 .79(s,3H),3.46-3.52(m,2H),2.60(t,J=7.09Hz,2H),2.07(s,3H),1.99(s,2H).

[0335] Triethylamine (1.6 mL, 12.12 mmol) was added to a solution of 2-(4-(5-(benzyloxy)-3-fluoro-2-(4-methoxy-2-methylphenyl)-1H-indol-1-yl)methyl)phenyl)ethyl-1-ol 103-8 (2 g, 4.036 mmol) in 30 mL of CH2Cl2 at 0 °C, followed by the addition of toluenesulfonyl chloride (928 mg, 4.845 mmol). The reaction mixture was stirred at room temperature for 12 hours. After the reaction was complete, the reaction mixture was diluted with water and extracted with CH2Cl2 (3 x 30 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography, eluting with a solution of 0-10% ethyl acetate in n-hexane to give 2.4 g (90% yield) of compound 103-9 as a white viscous solid. LCMS Condition 1: [M+H] + =650.80; Rt=2.50min 1 H NMR(400MHz,DMSO-d6)δ:7.66(d,J=8.31Hz,2H),7.54-7.58(m,2H),7.46-7.51(m,3H),7.4 2(d,J=6.85Hz,1H),7.36(d,J=7.83Hz,2H),7.32(d,J=8.80Hz,1H),7.22(d,J=2.45Hz,1H) ,7.01-7.05(m,3H),6.94-7.01(m,2H),6.75(d,J=7.83Hz,2H),5.22-5.25(m,2H),4.22(t, J=6.36Hz,2H),3.87(s,3H),3.41(s,3H),2.86(t,J=6.36Hz,2H),2.43(s,3H),2.15(s,2H).

[0336] Potassium phthalimide (512 mg, 2.771 mmol) was added to a DMF (5 mL) solution of 1.5 g (2.309 mmol) of 4-((5-(benzyloxy)-3-fluoro-2-(4-methoxy-2-methylphenyl)-1H-indol-1-yl)methyl)phenethyl 4-methylbenzenesulfonate 103-9 at room temperature. The reaction mixture was further heated to 80 °C and stirred for 3 hours. After the reaction was complete, the reaction mixture was diluted with water and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography, eluting with 0–10% ethyl acetate in n-hexane to give 1.4 g (98% yield) of compound 103-10 as a light brown solid. LCMS-condition-1: [M+H] + =625.10; Rt=2.47min 1 H NMR(400MHz,DMSO-d6)δ:7.80-7.85(m,4H),7.45-7.50(m,2H),7.40(t,J=7.34Hz,2H) ,7.31-7.37(m,2H),7.16(d,J=8.31Hz,1H),7.11(d,J=2.45Hz,1H),7.02(d,J=8.31Hz, 2H),6.86-6.91(m,2H),6.82-6.85(m,1H),6.66(d,J=7.83Hz,2H),5.15(s,2H),5.03- 5.10(m,2H),3.79(s,3H),3.73(t,J=7.34Hz,2H),2.83(t,J=7.09Hz,2H),1.99(s,3H).

[0337] Hydrazine hydrate (112 mg, 2.241 mmol) was added to a solution of 1.4 g (2.241 mmol) of 2-(4-(benzyloxy)-3-fluoro-2-(4-methoxy-2-methylphenyl)-1H-indol-1-yl)methyl)phenethyl)isoindololin-1,3-dione 103-10 in ethanol (15 mL) at room temperature. The reaction mixture was further heated to 80 °C and stirred for 4 hours. After the reaction was complete, the reaction mixture was filtered, washed with DCM (50 mL), and the filtrate was concentrated under reduced pressure. The resulting crude compound was purified by silica gel column chromatography, eluting with 0-3% methanol in DCM to give 828 mg (73% yield) of compound 103-11 as a white solid. LCMS Condition 1: [M+H] + =495.25; Rt=1.70min 1 H NMR(400MHz, DMSO-d6)δ:8.07(dd,J=3.18,5.62Hz,1H),7.88(dd,J=3.42,5.87Hz,1H),7.45-7 .50(m,2H),7.30-7.43(m,4H),7.24(d,J=8.31Hz,1H),7.12(d,J=2.45Hz,1H),7.02(d,J=7.83 Hz,2H),6.94(d,J=2.45Hz,1H),6.88(dt,J=2.69,8.44Hz,2H),6.70(d,J=7.83Hz,2H),5.15(s ,2H),5.06-5.12(m,2H),3.79(s,3H),2.69-2.75(m,2H),2.56(t,J=7.34Hz,2H),2.06(s,3H).

[0338] In a sealed tube, potassium carbonate (83.7 mg, 0.606 mmol) and 1-fluoro-2-iodo-1-ethylhexane (105 mg, 0.606 mmol) were added to a solution of 2-(4-((5-(benzyloxy)-3-fluoro-2-(4-methoxy-2-methylphenyl)-1H-indol-1-yl)methyl)phenyl)ethyl-1-amine 103-11 (300 mg, 0.606 mmol) acetonitrile (4 mL). The reaction mixture was stirred further at room temperature for 24 hours. After the reaction was complete, the reaction mixture was diluted with water and extracted with ethyl acetate (2 x 10 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography, eluting with 0-3% methanol in DCM solution to give 250 mg (76% yield) of compound 103-12 as a colorless viscous solid. LCMS Condition 1: [M+H] + =541.35; Rt=1.73min

[0339] At room temperature, 20% palladium hydroxide / carbon (75 mg, 20% w / w) was added to a solution of N-(4-((5-(benzyloxy)-3-fluoro-2-(4-methoxy-2-methylphenyl)-1H-indol-1-yl)methyl)phenethyl)-2-fluoroethane-1-amine 103-12 (250 mg, 0.455 mmol) in ethyl acetate:methanol (1:1; 10 mL). The reaction mixture was further stirred for 1 hour under a hydrogen atmosphere. After the reaction was complete, the reaction mixture was passed through a Celite tube. TM The mixture was filtered through a filter pad and washed with ethyl acetate. The filtrate was concentrated under reduced pressure, and the crude compound was purified by preparative HPLC to give 20 mg (9.6% yield) of D-103 as a grayish-white solid. LCMS Condition 1: [M+H] + =451.25; Rt=1.54min 1 H NMR(400MHz, DMSO-d6)δ:9.01(s,1H),7.24-7.27(m,1H),7.22(d,J=8.31Hz,1H),7.02(d,J=8.3 1Hz,2H),6.92(d,J=2.45Hz,1H),6.86(dd,J=2.45,8.31Hz,1H),6.82(d,J=2.45Hz,1H),6.65-6 .70(m,3H),4.97-5.12(m,2H),4.47(t,J=5.14Hz,1H),4.35(t,J=5.14Hz,1H),3.78(s,3H),2.7 9(t,J=5.14Hz,1H),2.72(t,J=5.14Hz,1H),2.65-2.70(m,2H),2.55-2.61(m,2H),2.06(s,3H). 3-Fluoro-1-(4-(2-(((3-fluoropropyl)amino)ethyl)benzyl)-2-(4-methoxy-2-methylphenyl)-1H-indole-5-ol (D-104)

[0340] In a sealed tube, potassium carbonate (83.7 mg, 0.606 mmol) and 1-fluoro-3-iodopropane (114 mg, 0.606 mmol) were added to a solution of 2-(4-((5-(benzyloxy)-3-fluoro-2-(4-methoxy-2-methylphenyl)-1H-indol-1-yl)methyl)phenyl)ethyl-1-amine 103-11 (300 mg, 0.606 mmol) in acetonitrile (4 mL). The reaction mixture was stirred at room temperature for 24 hours. After the reaction was complete (monitored by TLC and LCMS), the reaction mixture was diluted with water and extracted with ethyl acetate (2 × 10 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography, eluting with 0–3% methanol in DCM solution to give 250 mg (74% yield) of compound 104-12 as a colorless viscous solid. LCMS Condition 1: [M+H] + =555.25; Rt=1.76min 1 H NMR(400MHz, DMSO-d6)δ:7.46-7.49(m,2H),7.32-7.42(m,4H),7.24(d,J=8.31Hz, 1H),7.12(d,J=2.45Hz,1H),7.03(d,J=7.83Hz,2H),6.94(d,J=2.45Hz,1H),6.85-6 .91(m,2H),6.70(d,J=8.31Hz,2H),5.02-5.14(m,4H),4.51(t,J=6.11Hz,1H),4.39 (t,J=5.87Hz,1H),3.79(s,3H),2.58-2.73(m,6H),2.06(s,3H),1.70-1.83(m,2H).

[0341] To a solution of N-(4-((5-(benzyloxy)-3-fluoro-2-(4-methoxy-2-methylphenyl)-1H-indol-1-yl)methyl)phenethyl)-3-fluoropropane-1-amine 104-12 (250 mg, 0.458 mmol) in ethyl acetate:methanol (1:1; 10 mL), 20% palladium hydroxide / carbon (75 mg, 20% w / w) was added at room temperature. The reaction mixture was stirred for 12 hours under a hydrogen atmosphere. After the reaction was complete (monitored by TLC and LCMS), the reaction mixture was passed through a Celite filter. TM The mixture was filtered through a pad and washed with methanol. The filtrate was concentrated under reduced pressure, and the crude compound was purified by preparative HPLC to give 50 mg (23% yield) of D-104 as a grayish-white solid. LCMS Condition 1: [M+H] +=465.25; Rt=1.88min 1 H NMR (400MHz, DMSO-d6) δ: 9.01 (s, 1H), 7.24-7.27 (m, 1H), 7.22 (d, J = 8.31Hz, 1H), 7.01 (d, J=8.31Hz,2H),6.92(d,J=2.45Hz,1H),6.86(dd,J=2.69,8.56Hz,1H),6.82(d,J=1.96Hz, 1H),6.69(d,J=1.47Hz,1H),6.65-6.68(m,2H),4.97-5.09(m,2H),4.50(t,J=6.11Hz,1H) ,4.38(t,J=5.87Hz,1H),3.78(s,3H),2.53-2.64(m,6H),2.06(s,3H),1.64-1.78(m,2H). 1-(4-(2-(cyclopropylamino)ethyl)benzyl)-3-fluoro-2-(4-fluoro-2-methylphenyl)-1H-indole-5-ol (D-36)

[0342] At room temperature, 2-methyl-4-fluoro-phenylboronic acid (7.2 g, 46.96 mmol) and Na₂CO₃ (12.4 g, 117.4 mmol) were added to a toluene (60 mL) solution of 4-(benzyloxy)-2-(2,2-dibromovinyl)aniline D-13-3 (15 g, 39.16 mmol), and the mixture was degassed with argon for 10 min. Pd(PPh₃)₄ (2.25 g, 1.950 mmol) was added to the resulting solution, and the mixture was degassed with argon for another 10 min. The reaction mixture was further heated to 90 °C and stirred for 18 h. After the reaction was complete, the reaction mixture was diluted with water and extracted three times with ethyl acetate. The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The resulting crude compound was purified by silica gel column chromatography, eluting with a solution of 0–8% ethyl acetate in n-hexane to give 5 g (38% yield) of compound 36-1 as a brown solid. LCMS: [M+H] + =333.35; Rt=2.29min 1H NMR(400MHz,DMSO-d6)δ:11.13(br.s,1H),7.50-7.56(m,1H),7.45-7.50(m,2H),7.39(t,J=7.34Hz,2H),7.26-7.3 4(m,2H),7.20(d,J=10.27Hz,1H),7.13(br.s,2H),6.83(d,J=8.80Hz,1H),6.46(s,1H),5.11(s,2H),2.45(s,3H).

[0343] Selectfluor (10.6 g, 30.16 mmol) was added to an aqueous solution of 5-(benzyloxy)-2-(4-fluoro-2-methylphenyl)-1H-indole 36-1 (10 g, 30.21 mmol) in acetonitrile:DMSO (3:2; 80 mL) at -10 °C under an argon atmosphere. The reaction mixture was allowed to reach room temperature and stirred for 4 hours. After the reaction was complete, the reaction mixture was quenched with water and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The resulting crude compound was purified by silica gel column chromatography, eluting with a solution of 0–5% ethyl acetate in n-hexane to give 1 g (9.5% yield) of compound 36-2 as a brown solid. LCMS: [M+H] + =350.30; Rt=2.30min 1 H NMR (400MHz, DMSO-d6) δ: 11.01 (br.s, 1H), 7.49-7.55 (m, 3H), 7.44 (t, J = 7.34Hz, 2H), 7.37 (d, J = 7.34Hz, 1H), 7.30(t,J=9.29Hz,2H),7.21(t,J=8.56Hz,1H),7.13(s,1H),6.94(d,J=8.80Hz,1H),5.18(s,2H),2.39(s,3H).

[0344] Sodium hydride (60% oil dispersion, 82 mg, 3.410 mmol) was added in portions to a DMF (10 mL) solution of 5-(benzyloxy)-3-fluoro-2-(4-fluoro-2-methylphenyl)-1H-indole 36-2 (400 mg, 1.136 mmol) at 0 °C and stirred for 30 min. (4-(bromomethyl)phenylethoxy)(tert-butyl)dimethylsilane (487 mg, 1.478 mmol) was added to the resulting solution. The reaction mixture was then stirred at room temperature for 18 h. After the reaction was complete (monitored by TLC and LCMS), the reaction mixture was quenched with ice water and extracted with ethyl acetate (3 × 15 mL). The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography, eluting with a solution of 0–4% ethyl acetate in n-hexane to give 550 mg (92% yield) of compound 36-3 as a pale yellow oil. LCMS - Condition 01: [M-18] + =580.30; Rt=2.87min 1 H NMR (400MHz, CDCl3) δ: 7.48 (d, J = 7.34Hz, 2H), 7.37-7.43 (m, 2H), 7.32-7.36 (m, 1H), 7.10-7.21 (m, 4H), 7.02 (d, J = 8.07Hz, 2H), 6.84-6.95 (m, 2H) ),6.74(d,J=8.07Hz,2H),5.13(m,2H),4.95-5.09(m,2H),3.72(t,J=6.9 1Hz, 2H), 2.73 (t, J = 6.85Hz, 2H), 2.15 (s, 3H), 0.87 (s, 9H), 0.00 (s, 6H).

[0345] TBAF (361 mg, 1.380 mmol) was added to a THF (10 mL) solution of 5-(benzyloxy)-1-(4-(2-((tert-butyldimethylsilyl)oxy)ethyl)benzyl)-3-fluoro-2-(4-fluoro-2-methylphenyl)-1H-indole 36-3 (550 mg, 0.920 mmol) at 0 °C. The reaction mixture was then stirred at room temperature for 1 hour. After the reaction was complete (monitored by TLC and LCMS), the reaction mixture was quenched with ice water and extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The compound was purified by silica gel column chromatography, eluting with a solution of 0-50% ethyl acetate in n-hexane to give 500 mg of crude compound 36-4 as a pale yellow oil. LCMS - Condition 01: [M-18] + =466.05; Rt=2.33min 1 H NMR(400MHz, CDCl3)δ:7.47-7.50(m,2H),7.28-7.43(m,3H),7.18-7.23(m,1H),7.17(d,J=2.45Hz,1H),7.12-7.15(m,1H),7.05(d,J=8.31 Hz,2H),6.89-7.02(m,3H),6.77(d,J=7.83Hz,2H),5.14(s,2H),4.97-5.13(m,2H),3.77-3.82(m,2H),2.79(t,J=6.60Hz,2H),2.14(s,3H).

[0346] Triethylamine (0.43 mL, 3.102 mmol) was added to a CH₂Cl₂ (10 mL) solution of 2-(4-(5-(benzyloxy)-3-fluoro-2-(4-fluoro-2-methylphenyl)-1H-indol-1-yl)methyl)phenyl)ethyl-1-ol 36-4 (500 mg, 1.033 mmol) at 0 °C, followed by the addition of p-TsCl (256 mg, 1.344 mmol). The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete (monitored by TLC and LCMS), the reaction mixture was diluted with water (30 mL) and extracted with DCM (3 x 20 mL). The combined organic layers were washed with saturated sodium bicarbonate solution (20 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give 500 mg (76% yield) of compound 36-5 as a yellow solid. LCMS - Condition 01: [M+H] + =638.20; Rt=2.51min 1 H NMR(400MHz, CDCl3)δ:7.63-7.72(m,2H),7.48(d,J=7.34Hz,2H),7.37-7.43(m,2H),7.23(d,J=7.83Hz,2H),7.08-7.20(m,4H),6.97-7.02(m,1H) ,6.91-6.96(m,4H),6.68-6.75(m,2H),5.13(s,2H),4.94-5.08(s,2H),4 .13(t,J=7.09Hz,2H),2.87(t,J=6.85Hz,2H),2.40(s,3H),2.13(s,3H).

[0347] Cyclopropylamine (224 mg, 3.920 mmol) and DIPEA (0.68 mL, 3.920 mmol) were added to a solution of 4-((5-(benzyloxy)-3-fluoro-2-(4-fluoro-2-methylphenyl)-1H-indol-1-yl)methyl)phenethyl 4-methylbenzenesulfonate 36-5 (250 mg, 0.392 mmol) in acetonitrile (1 mL) and a sealed tube. The reaction mixture was then stirred at room temperature for 72 hours. After the reaction was complete (monitored by TLC and LCMS), the reaction mixture was concentrated under reduced pressure and diluted with ethyl acetate. The separated organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography, eluting with a solution of 0-50% ethyl acetate in n-hexane to give 160 mg (78% yield) of compound 36-6 as a grayish-white solid. LCMS - Condition 01: [M+H] + =523.20; Rt=1.85min 1 H NMR (400MHz, CDCl3) δ: 7.49 (d, J = 7.34Hz, 2H), 7.38-7.43 (m, 2H), 7.30-7.36 ( m,1H),7.14-7.22(m,3H),7.03(d,J=7.83Hz,2H),6.87-7.01(m,3H),6.74(d, J=7.80Hz,2H),5.14(s,2H),4.97-5.09(m,2H),2.86-2.92(m,2H),2.70-2.76 (m,2H),2.14(s,3H),2.07-2.11(m,1H),0.40-0.48(m,2H),0.30-0.39(m,2H).

[0348] To a solution of N-(4-((5-(benzyloxy)-3-fluoro-2-(4-fluoro-2-methylphenyl)-1H-indol-1-yl)methyl)phenethyl)cyclopropylamine 36-6 (160 mg, 0.3061 mmol) in ethyl acetate (5 mL), 20% palladium hydroxide / carbon (40 mg) was added at room temperature. The reaction mixture was then stirred for 18 hours under a hydrogen atmosphere. After the reaction was complete (monitored by TLC and LCMS), the reaction mixture was passed through a Celite filter. TM The mixture was filtered through a pad and washed with ethyl acetate. The filtrate was concentrated under reduced pressure, and the crude compound was purified by preparative HPLC to give 28 mg (21% yield) of D-36 as a white solid. LCMS - Condition 01: [M+H] + =433.10; Rt=1.54min 1H NMR (400MHz, CDCl3) δ: 7.18 (dd, J = 6.11, 8.07Hz, 1H), 7.06-7.11 (m, 1H), 6.96-7.04 (m, 4H), 6.87-6.94 (m, 1H), 6.70-6.78 (m, 3H), 4 .93-5.07(m,2H),2.89-2.95(m,2H),2.70-2.76(m,2H),2.12(s,3H),0.81-0.92(m,1H),0.44(d,J=6.36Hz,2H),0.35-0.41(m,2H). 3-Fluoro-2-(4-methoxy-2-methylphenyl)-1-(4-(2-(propylamino)ethyl)benzyl)-1H-indole-5-ol (D-96)

[0349] At room temperature and under an argon atmosphere, 4-(benzyloxy)-2-(2,2-dibromovinyl)aniline 13-3 (10 g, 26.10 mmol) was simultaneously added to a toluene:ethanol (60:20 mL) solution and 4-methoxy-2-methylphenyl)boronic acid (5.6 g, 33.94 mmol) and Na₂CO₃ solution (8.3 g, 78.32 mmol), and the mixture was degassed for 30 min. The resulting solution was then treated with catalyst Pd(PPh₃)₄ (1.5 g, 1.305 mmol) and degassed with argon at room temperature for an additional 10 min. The reaction mixture was further heated to 90 °C and stirred for 18 h. After the reaction was complete, the reaction mixture was diluted with water and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography and eluted with n-hexane solution of 0-20% ethyl acetate to give 3 g (33% yield) of compound 96- as a yellow solid. LCMS Condition 1: [M+H] + =344.15; Rt=2.24min 1 H NMR (400MHz, DMSO-d6) δ: 11.01 (br.s, 1H), 7.44-7.49 (m, 2H), 7.42 (d, J = 6.36Hz, 1H), 7.36-7.40 (m, 2H), 7.32 (d, J = 7.34Hz, 1H), 7.26 (d, J=8.80Hz,1H),7.10(s,1H),6.90(s,1H),6.87(d,J=9.29Hz,1H),6.77-6.82(m,1H),6.38(s,1H),5.10(s,2H),3.79(s,3H),2.43(s,3H).

[0350] Selectfluor (2.58 g, 7.288 mmol) was added to an aqueous solution of 5-(benzyloxy)-2-(4-methoxy-2-methylphenyl)-1H-indole 96-1 (2.5 g, 7.288 mmol) in acetonitrile:DMSO (15:5 mL) at -10 °C under an argon atmosphere. The reaction mixture was stirred further for 4 hours at room temperature. After the reaction was complete, the reaction mixture was diluted with water and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The resulting crude compound was purified by silica gel column chromatography, eluting with a solution of 0–5% ethyl acetate in n-hexane to give 1.2 g (46% yield) of compound 96-2 as a brown solid. LCMS-Condition-1: [M-18] + =344.05; Rt=2.23min 1 H NMR (400MHz, DMSO-d6) δ: 10.85 (s, 1H), 7.48 (d, J = 7.34Hz, 2H), 7.40 (t, J = 7.58Hz, 2H), 7.34 (d, J = 8.31Hz, 2H), 7.25 (dd, J = 2.20, 9.05Hz,1H),7.07(d,J=1.96Hz,1H),6.94(s,1H),6.88(ddd,J=2.20,9.05,11.74Hz,2H),5.14(s,2H),3.80(s,3H),2.32(s,3H).

[0351] A 60% sodium hydroxide oil dispersion (110 mg, 2.770 mmol) was added fractionally to a DMF (mL) solution of 5-(benzyloxy)-3-fluoro-2-(4-methoxy-2-methylphenyl)-1H-indole 96-2 (400 mg, 1.108 mmol) at 0 °C. The reaction mixture was further stirred at 0 °C for 30 min. Tert-butyl(4-(bromomethyl)phenylethoxy)dimethylsilane (436 mg, 1.329 mmol) was added to the resulting solution. The reaction mixture was stirred at room temperature for 3 h. After the reaction was complete, the reaction mixture was quenched with ice water and extracted with ethyl acetate (3 × 25 mL). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography, eluting with a solution of 0-8% ethyl acetate in n-hexane to give the crude compound 96-3 as a viscous oil. LCMS Condition 1: [M+Na] + =633.25; Rt=3.05min 1H NMR(400MHz, DMSO-d6)δ:7.42-7.47(m,2H),7.37(t,J=7.34Hz,2H),7.30-7.34(m,2H),7.1 8-7.23(m,1H),7.10(d,J=2.45Hz,1H),7.01(d,J=7.82Hz,2H),6.92(d,J=2.45Hz,1H),6.81 -6.87(m,2H),6.68(d,J=7.82Hz,2H),5.10-5.13(m,2H),4.98-5.09(m,2H),3.77(s,3H),3. 65(t,J=6.85Hz,2H),2.61(t,J=6.60Hz,2H),2.06(s,3H),0.74-0.78(m,9H),-0.13(s,6H).

[0352] A 1M tetrabutylammonium fluoride THF solution (0.98 mL, 0.985 mmol) was added dropwise to a THF solution of 5-(benzyloxy)-1-(4-(2-((tert-butyldimethylsilyl)oxy)ethyl)benzyl)-3-fluoro-2-(4-methoxy-2-methylphenyl)-1H-indole 96-3 (400 mg, 0.656 mmol) at 0 °C. The reaction mixture was further stirred for 2 hours at room temperature. After the reaction was complete, the reaction mixture was quenched with water and extracted with ethyl acetate. The separated organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography, eluting with a solution of 30% ethyl acetate in n-hexane to give 280 mg (87% yield) of compound 96-4 as a pale yellow viscous oil. LCMS Condition 1: [M+H] + =496.25; Rt=2.40min 1 H NMR(400MHz, DMSO-d6)δ:7.54-7.59(m,2H),7.41-7.50(m,4H),7.33(d,J=8.31Hz, 1H),7.21(d,J=2.45Hz,1H),7.11(d,J=8.31Hz,2H),7.03(d,J=2.45Hz,1H),6.94- 6.99(m,2H),6.78(d,J=8.31Hz,2H),5.23(s,2H),5.12-5.21(m,2H),4.63-4.68(m ,1H),3.88(s,3H),3.58(dt,J=5.38,7.09Hz,2H),2.66-2.72(m,2H),2.17(s,3H).

[0353] Triethylamine (0.23 mL, 1.696 mmol) was added to a solution of 2-(4-((5-(benzyloxy)-3-fluoro-2-(4-methoxy-2-methylphenyl)-1H-indol-1-yl)methyl)phenyl)ethyl-1-ol 96-4 (280 mg, 0.565 mmol) in 3 mL of CH2Cl2 at 0 °C, followed by the addition of toluenesulfonyl chloride (129 mg, 0.678 mmol). The reaction mixture was stirred at room temperature for 18 hours. After the reaction was complete, the reaction mixture was diluted with CH2Cl2 (3 x 30 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography, eluting with a solution of 0-10% ethyl acetate in n-hexane to give 310 mg (84% yield) of compound 96-5 as a grayish-white solid. LCMS-Condition-1: [M-18] + =632.20; Rt=2.58min 1 H NMR(400MHz,DMSO-d6)δ:7.66(d,J=7.83Hz,2H),7.56(d,J=6.85Hz,2H),7.45-7.52(m,3H) ,7.42(d,J=6.85Hz,1H),7.36(d,J=7.83Hz,2H),7.31-7.35(m,1H),7.22(d,J=2.45Hz,1H) ,7.03(d,J=7.83Hz,3H),6.94-7.01(m,2H),6.75(d,J=7.83Hz,2H),5.23(s,2H),5.14-5.2 2(m,2H),4.21(t,J=6.11Hz,2H),3.87(s,3H),2.83-2.89(m,2H),2.43(s,3H),2.15(s,3H).

[0354] In a sealed tube, DIPEA (0.49 mL, 2.856 mmol) and propylamine (84.2 mg, 1.428 mmol) were added to a solution of 4-((5-(benzyloxy)-3-fluoro-2-(4-methoxy-2-methylphenyl)-1H-indol-1-yl)methyl)phenethyl 4-methylbenzenesulfonate 96-5 (309 mg, 0.476 mmol) in acetonitrile (3 mL). The reaction mixture was stirred further at room temperature for 72 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure, diluted with water, and extracted with ethyl acetate (2 × 10 mL). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography, eluting with 0–2% methanol in DCM solution to give 210 mg (82% yield) of compound 96-6 as a pale brown viscous oil. LCMS Condition 1: [M+H] + =537.30; Rt=1.94min 1 H NMR(400MHz, DMSO-d6)δ:7.39-7.44(m,2H),7.25-7.37(m,4H),7.17(d,J=8.31Hz,1H),7.06(d ,J=2.45Hz,1H),6.96(d,J=7.82Hz,2H),6.87(d,J=2.45Hz,1H),6.82(dt,J=2.45,8.31Hz,2H) ,6.64(d,J=8.31Hz,2H),5.08(s,2H),5.03(d,J=16.14Hz,2H),3.73(s,3H),2.62(d,J=6.85Hz ,2H),2.52-2.57(m,2H),2.00(s,3H),1.27-1.36(m,2H),1.17(s,3H),0.76(t,J=7.58Hz,3H).

[0355] 20% palladium hydroxide / carbon (100 mg) was added to an ethyl acetate:methanol (1:1; 3 mL) solution of N-(4-((5-(benzyloxy)-3-fluoro-2-(4-methoxy-2-methylphenyl)-1H-indol-1-yl)methyl)phenethyl)propyl-1-amine 96-6 (210 mg, 0.391 mmol) at room temperature. The reaction mixture was further stirred for 18 hours under a hydrogen atmosphere. After the reaction was complete, the reaction mixture was passed through a Celite tube. TM The mixture was filtered through a filter pad and washed with ethyl acetate. The filtrate was concentrated under reduced pressure, and the crude compound was purified by preparative HPLC to give 35 mg (11% yield) of D-96 as a grayish-white solid. LCMS Condition 1: [M+H] + =447.30; Rt=1.66min 1H NMR(400MHz,DMSO-d6)δ:9.01(br.s,1H),7.20-7.28(m,2H),7.01(d,J=7.83Hz,2 H),6.92(d,J=2.45Hz,1H),6.86(dd,J=2.45,8.31Hz,1H),6.82(d,J=1.96Hz,1H), 6.64-6.71(m,3H),4.96-5.11(m,2H),3.78(s,3H),2.55-2.66(m,4H),2.43(t,J= 7.09Hz, 2H), 2.06 (s, 3H), 1.31-1.40 (m, 2H), 1.23 (s, 1H), 0.81 (t, J = 7.34Hz, 3H). 2-([1,1'-biphenyl]-2-yl)-3-fluoro-1-(4-(2-(propylamino)ethyl)benzyl)-1H-indole-5-ol (D-66)

[0356] At room temperature and under an argon atmosphere, [1,1'-biphenyl]-2-ylboronic acid (672 mg, 3.393 mmol) and an aqueous solution of Na₂CO₃ (830 mg, 27.830 mmol) (2 mL) were simultaneously added to a toluene:ethanol (5:1, 12 mL) solution of 4-(benzyloxy)-2-(2,2-dibromovinyl)aniline 13-3 (1 g, 2.610 mmol), and the mixture was degassed with argon for 30 min. Pd(PPh₃)₄ (150 mg, 0.129 mmol) was added to the resulting solution, and degassed for another 10 min. The reaction mixture was then heated to 90 °C and stirred for 18 h. After the reaction was complete (monitored by TLC and LCMS), the reaction mixture was diluted with water and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography and eluted with a hexane solution of 0-8% ethyl acetate to give 400 mg (40% yield) of compound 66-3 as a viscous solid. LCMS - Condition -: [M+H] + =376.10; Rt=2.48min 1H NMR(400MHz, DMSO-d6)δ:10.99(br.s,1H),7.65(d,J=7.34Hz,1H),7.40-7.51(m,4H),7.34-7.40(m,4H),7.31(d,J=3.9 1Hz, 4H), 7.22-7.26 (m, 2H), 7.18 (d, J = 8.31Hz, 1H), 6.91 (d, J = 1.96Hz, 1H), 6.74 (dd, J = 1.96, 8.80Hz, 1H), 5.02 (s, 2H).

[0357] Selectfluor (380 mg, 1.072 mmol) was added to an aqueous solution of 2-([1,1'-biphenyl]-2-yl)-5-(benzyloxy)-1H-indole 66-3 (400 mg, 1.065 mmol) in acetonitrile:DMSO (3:2, 5 mL) at -10 °C under an argon atmosphere. The reaction mixture was then stirred at room temperature for 2 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (100 mL), washed with water (40 mL), and then washed with brine (30 mL). The separated organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography, eluting with a solution of 0–4% ethyl acetate in n-hexane to give 362 mg (86% yield) of compound 66-4 as a yellow viscous oil, which did not require further purification and could be used for the next reaction. LCMS-Condition-1: [M-18] + =376.15; Rt=2.48min

[0358] Sodium hydride (60% oil dispersion, 92 mg, 2.300 mmol) was added in portions to a DMF (5 mL) solution of 2-([1,1'-biphenyl]-2-yl)-5-(benzyloxy)-3-fluoro-1H-indole 66-4 (362 mg, 0.920 mmol) at 0 °C. The reaction mixture was then stirred at 0 °C for 30 min. (4-(bromomethyl)phenylethoxy)(tert-butyl)dimethylsilane (454 mg, 1.378 mmol) was added to the resulting solution, and the reaction mixture was stirred at room temperature for 4 h. After the reaction was complete (monitored by TLC and LCMS), the reaction mixture was quenched with ice water and extracted with ethyl acetate (3 × 25 mL). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography and eluted with a hexane solution of 0-4% ethyl acetate to give 360 ​​mg (61% yield) of compound 66-5 as a pale yellow viscous oil. LCMS-Condition-1: [M-18] +=624.35; Rt=2.90min 1 H NMR(400MHz, CDCl3)δ:7.45-7.52(m,5H),7.40(ddd,J=2.22,4.68,6.89Hz, 3H),7.18-7.22(m,5H),7.14-7.18(m,2H),6.96(d,J=7.88Hz,2H),6.85-6.9 1(m,1H),6.77-6.83(m,1H),6.61(d,J=8.37Hz,2H),5.09(s,2H),4.51(s,2H ), 3.80 (t, J = 7.14Hz, 2H), 2.83 (t, J = 6.89Hz, 2H), 0.88 (s, 9H), 0.85 (s, 6H).

[0359] At room temperature, a solution of 1 M tetrabutylammonium fluoride in THF (0.84 mL, 0.841 mmol) was added dropwise to a solution of 2-([1,1'-biphenyl]-2-yl)-5-(benzyloxy)-1-(4-(2-((tert-butyldimethylsilyl)oxy)ethyl)benzyl)-3-fluoro-1H-indole 66-5 (360 mg, 0.560 mmol) in THF (0.84 mL, 0.580 mmol) and stirred for 3 hours. After the reaction was complete, the reaction mixture was quenched with ice water and extracted with ethyl acetate (3 × 25 mL). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography, eluting with a solution of 20-30% ethyl acetate in n-hexane to give 168 mg (57% yield) of compound 66-6 as a light brown semi-solid. LCMS Condition 1: [M+H] + =528.15; Rt=2.35min 1 H NMR(400MHz, CDCl3)δ:7.49-7.51(m,1H),7.43-7.49(m,4H),7.36-7.42(m,3H ),7.30-7.35(m,1H),7.12-7.22(m,5H),7.10(d,J=2.42Hz,1H),6.97(d,J=8. 07Hz,2H),6.88-6.92(m,1H),6.76-6.83(m,1H),6.63(d,J=8.07Hz,2H),5.08 (s,2H),4.73(s,1H),4.70(s,1H),3.77(q,J=5.79Hz,2H),2.73-2.78(m,2H).

[0360] Triethylamine (0.17 mL, 1.255 mmol) was added to a solution of 2-(4-((2-([[1,1'-biphenyl]-2-yl)-5-(benzyloxy)-3-fluoro-1H-indol-1-yl)methyl)phenyl)ethyl-1-ol 66-6 (160 mg, 0.303 mmol) in 3 mL of CH2Cl2 at 0 °C, followed by the addition of toluenesulfonyl chloride (92 mg, 0.480 mmol). The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, the reaction mixture was diluted with water and extracted with CH2Cl2 (3 x 30 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 178 mg (83% yield) of the title compound 66-7 as a pale yellow viscous oil. LCMS Condition 1: [M+H] + =682.20; Rt=2.54min 1 H NMR (400MHz, CDCl3) δ: 7.64 (d, J = 8.28Hz, 2H), 7.37-7.53 (m, 8H), 7.28-7.35 (m, 2H), 7.14-7.23 (m, 7H), 6.78-6.88 (m, 4 H),6.54-6.58(m,2H),5.08(s,2H),4.65-4.70(m,2H),4.06-4.14(m,2H),2.81-2.86(m,2H),2.39(s,2H),2.38(s,3H).

[0361] To a solution of 4-((2-([[1,1'-biphenyl]-2-yl]-5-(benzyloxy)-3-fluoro-1H-indol-1-yl)methyl)phenethyl 4-methylbenzenesulfonate 66-7 (175 mg, 0.256 mmol) in acetonitrile (3 mL), DIPEA (0.27 mL, 1.539 mmol) and propylamine (0.06 mL, 0.761 mmol) were added. The reaction mixture was stirred in a sealed tube at room temperature for 4 days. After the reaction was complete, the reaction mixture was concentrated under reduced pressure and washed with ethyl acetate (2 × 10 mL). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography, eluting with 0–5% methanol in DCM solution to give 131 mg (91% yield) of compound 66-8 as a pale yellow solid. LCMS Condition 1: [M+H] + =569.30; Rt=1.92min 1H NMR (400MHz, CDCl3) δ: 7.72 (d, J = 8.31Hz, 1H), 7.31-7.50 (m, 10H), 7.12-7.20 (m, 6H), 6.90 (d, J = 8.31Hz, 2H), 6.57 (d, J = 8.31Hz, 2H), 5.07(s,2H),4.67(d,J=8.31Hz,2H),2.97(s,3H),2.76-2.82(m,2H),2.31(s,2H),1.72(qd,J=7.50,15.16Hz,2H),0.85-0.92(m,3H).

[0362] At room temperature, 20% palladium hydroxide / carbon (40 mg, 20% w / w) was added to an ethyl acetate:methanol (2:1; 3 mL) solution of N-(4-((2-([[1,1'-biphenyl]-2-yl)-5-(benzyloxy)-3-fluoro-1H-indol-1-yl)methyl)phenethyl)propyl-1-amine 66-8 (120 mg, 0.211 mmol). The reaction mixture was then stirred for 3 hours at room temperature under a hydrogen atmosphere. After the reaction was complete, the reaction mixture was passed through a Celite tube. TM The mixture was filtered through a pad and washed with ethyl acetate. The filtrate was concentrated under reduced pressure, and the crude compound was purified by preparative HPLC to give 36 mg (36% yield) of D-66 as a light brown solid. LCMS Condition 1: [M+H] + =479.30; Rt=1.53min 1 H NMR (400MHz, CDCl3) δ: 7.49 (d, J = 3.42Hz, 2H), 7.41-7.46 (m, 1H), 7.36-7.41 (m, 1H) ),7.17(d,J=5.87Hz,3H),7.14(br.s,2H),6.88-6.97(m,3H),6.80(d,J=7.34Hz,1 H),6.56-6.65(m,3H),4.68(q,J=16.47Hz,2H),2.83-2.90(m,2H),2.71-2.78(m,2 H), 2.64 (t, J = 7.34Hz, 2H), 1.52 (qd, J = 7.34, 14.67Hz, 2H), 0.87 (t, J = 7.34Hz, 3H). 1-(4-(2-(ethylamino)ethyl)benzyl)-3-fluoro-2-(o-tolyl)-1H-indole-5-ol (D-29)

[0363] In a sealed tube, 225 mg (0.363 mmol) of 4-((5-(benzyloxy)-3-fluoro-2-(o-tolyl)-1H-indol-1-yl)methyl)phenethyl 4-methylbenzenesulfonate 28-5 in acetonitrile (5 mL) was added to a solution of DIPEA (0.63 mL, 3.364 mmol) and 2M ethylamine in THF (1.8 mL, 164 mg, 3.634 mmol). The reaction mixture was further stirred for 72 hours at room temperature. After the reaction was complete, the reaction mixture was concentrated under reduced pressure and diluted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 175 mg (97% yield) of compound 29-1 as a grayish-white solid. LCMS - Condition 01: [M+H] + =493.29; Rt=1.49min 1 H NMR (400MHz, CDCl3) δ: 9.43 (s, 1H), 7.70-7.75 (m, 1H), 7.48 (d, J = 7.34Hz, 1H), 7.3 9(t,J=7.09Hz,2H),7.28-7.35(m,2H),7.13-7.25(m,3H),7.05-7.11(m,1H),6.99( d,J=7.83Hz,2H),6.91(dd,J=2.45,8.80Hz,1H),6.69-6.79(m,2H),5.09-5.14(m,2 H),4.92-5.06(m,2H),2.98-3.14(m,4H),2.15-2.21(m,5H),1.41(t,J=7.34Hz,3H.

[0364] To a solution of 2-(4-((5-(benzyloxy)-3-fluoro-2-(o-tolyl)-1H-indol-1-yl)methyl)phenyl)-N-ethylpent-1-amine 29-1 (175 mg, 0.366 mmol) in ethyl acetate:methanol (4:1; 4 mL), 20% palladium hydroxide / carbon (35 mg, 20% w / w) was added at room temperature. The reaction mixture was further stirred for 3 hours under a hydrogen atmosphere. After the reaction was complete, the reaction mixture was passed through a Celite tube. TM The mixture was filtered through a pad and washed with ethyl acetate. The filtrate was concentrated under reduced pressure, and the crude compound was purified by preparative HPLC to give 15 mg (11% yield) of D-29 as a white solid. LCMS - Condition 01: [M+H] + =403.24; Rt=1.49min 1H NMR (400MHz, DMSO-d6) δ: 9.04 (s, 1H), 7.27-7.41 (m, 5H), 7.00 (d, J = 7.83Hz, 2H), 6.84 (d, J = 1.96Hz, 1H), 6.70 (dd, J = 2.45, 8.80Hz, 1H), 6.66(d,J=7.83Hz,2H),5.00-5.13(m,2H),2.54-2.68(m,4H),2.46-2.49(m,2H),2.08(s,3H),1.22-1.26(m,1H),0.95(t,J=7.09Hz,3H). 1-(4-(2-(((cyclopropylmethyl)amino)ethyl)benzyl)-3-fluoro-2-(o-tolyl)-1H-indole-5-ol (D-39)

[0365] Cyclopropyl methylamine (229 mg, 3.230 mmol) and DIPEA (416 mg, mL, 3.230 mmol) were added to a solution of 4-((5-(benzyloxy)-3-fluoro-2-(o-tolyl)-1H-indol-1-yl)methyl)phenethyl 4-methylbenzenesulfonate 28-5 (200 mg, 0.323 mmol) in acetonitrile (4 mL) and a sealed tube. The reaction mixture was then stirred at room temperature for 72 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure and diluted with ethyl acetate. The organic layer was washed with water (20 mL) and brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 140 mg (84% yield) of compound 39-1 as a colorless, viscous oil. LCMS - Condition 01: [M+H] + =519.30; Rt=1.89min

[0366] 20% palladium hydroxide / carbon (45 mg) was added to a solution of 1-(4-(2-(((cyclopropylmethyl)amino)ethyl)benzyl)-3-fluoro-2-(o-tolyl)-1H-indole-5-ol 39-1 (140 mg, 0.270 mmol) in ethyl acetate:methanol (1:1; 3 mL) at room temperature under a nitrogen atmosphere. The reaction mixture was then stirred for 2 hours under a hydrogen atmosphere. After the reaction was complete, the reaction mixture was passed through a Celite tube. TM The mixture was filtered through a filter pad and washed with a mixture of methanol and ethyl acetate. The filtrate was concentrated under reduced pressure, and the crude compound was purified by preparative HPLC to give 22 mg (19% yield) of D-39 as a grayish-white solid. LCMS - Condition 01: [M+H] + =429.55; Rt=1.55min 1H NMR(400MHz,DMSO-d6)δ:8.99-9.01(m,1H),7.30-7.37(m,2H),7.24-7.29(m,3H),6.97( d,J=8.31Hz,2H),6.80(d,J=1.96Hz,1H),6.67(dd,J=1.96,8.80Hz,1H),6.63(d,J=8.31 Hz,2H),5.03(d,J=8.31Hz,2H),2.60-2.65(m,2H),2.51-2.57(m,2H),2.40-2.43(m,1H) ,2.31(d,J=6.36Hz,2H),2.04(s,3H),1.20(s,1H),0.73-0.82(m,2H),0.29-0.35(m,2H). 1-(4-(2-(cyclobutylamino)ethyl)benzyl)-3-fluoro-2-(o-tolyl)-1H-indole-5-ol (D-46)

[0367] In a sealed tube, cyclobutylamine (232 mg, 3.230 mmol) and DIPEA (0.56 mL, 3.230 mmol) were added to a solution of 200 mg (0.323 mmol) of 4-((5-(benzyloxy)-3-fluoro-2-(o-tolyl)-1H-indol-1-yl)methyl)phenethyl 4-methylbenzenesulfonate 28-5 in acetonitrile (4 mL). The reaction mixture was then stirred at room temperature for 72 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure and diluted with ethyl acetate. The organic layer was washed with water (20 mL) and brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 150 mg (89% yield) of compound 46-1 as a colorless oil, which could be used in the next reaction without further purification. LCMS - Condition 01: [M+H] + =519.35; Rt=1.95min 1H NMR(400MHz,DMSO-d6)δ:7.47(d,J=7.83Hz,4H),7.37-7.43(m,4H),7.29-7.35( m,3H),7.11(d,J=8.31Hz,2H),7.04(d,J=7.83Hz,2H),6.91(dd,J=1.96,8.80Hz ,1H),6.71(d,J=7.83Hz,1H),5.15(s,2H),5.11(s,2H),2.90(t,J=6.60Hz,2H), 2.67(dt,J=7.34,19.07Hz,5H),2.28(s,3H),2.09-2.13(m,2H),0.9-1.2(m,2H).

[0368] To a solution of 1-(4-(2-(cyclobutylamino)ethyl)benzyl)-3-fluoro-2-(o-tolyl)-1H-indole-5-ylbenzoate 46-1 (150 mg, 0.289 mmol) in ethyl acetate:methanol (1:1; 3 mL) at room temperature, 20% palladium hydroxide / carbon (49 mg, 30% w / w) was added. The reaction mixture was stirred for 2 hours under a hydrogen atmosphere. After the reaction was complete, the reaction mixture was passed through a Celite tube. TM The mixture was filtered through a pad and washed with ethyl acetate. The filtrate was concentrated under reduced pressure, and the crude compound was purified by preparative HPLC to give 50 mg (39% yield) of D-46 as a brown solid. LCMS - Condition 01: [M+H] + =429.25; Rt=1.54min 1 H NMR(400MHz, DMSO-d6)δ:9.04(s,1H),7.27-7.41(m,5H),7.00(d,J=7.83Hz,2H),6.84(d,J=1.96Hz,1H),6.71(d,J=1.96Hz,1H) ,6.65-6.70(m,2H),4.99-5.13(m,2H),3.14-3.20(m,1H),2.54-2.60(m,4H),2.09(s,3H),2.01-2.07(m,2H),1.51-1.69(m,4H). 3-Fluoro-1-(4-(2-(propylamino)ethyl)benzyl)-2-(o-tolyl)-1H-indole-5-ol (D-67)

[0369] In a sealed tube, DIPEA (0.7 mL, 4.040 mmol) and propylamine (238 mg, 4.040 mmol) were added to a solution of 4-((5-(benzyloxy)-3-fluoro-2-(o-tolyl)-1H-indol-1-yl)methyl)phenethyl 4-methylbenzenesulfonate 28-5 (250 mg, 0.4038 mmol) in acetonitrile (4 mL). The reaction mixture was then stirred at room temperature for 72 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure and diluted with ethyl acetate. The organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give 145 mg (70% yield) of compound 67-1 as a colorless, viscous oil. LCMS: [M+H] + =507.65; Rt=1.77min 1 H NMR(400MHz, DMSO-d6)δ:7.47(d,J=7.34Hz,3H),7.30-7.43(m,7H),7.15(d,J=1.96Hz ,1H),7.11(d,J=7.82Hz,1H),7.06(d,J=7.82Hz,2H),6.91(dd,J=2.45,9.29Hz,1H),6 .73(d,J=8.31Hz,1H),5.15(s,2H),5.09-5.13(m,2H),2.90-2.98(m,2H),2.75(t,J=7 .58Hz,4H),2.28(s,1H),2.11-2.13(m,3H),1.47-1.58(m,2H),0.87(t,J=7.34Hz,3H).

[0370] At room temperature, 20% palladium hydroxide / carbon (48.4 mg, 30% w / w) was added to a solution of N-(4-((5-(benzyloxy)-3-fluoro-2-(o-tolyl)-1H-indol-1-yl)methyl)phenethyl)propyl-1-amine 67-1 (140 mg, 0.276 mmol) in ethyl acetate:methanol (1:1; 4 mL). The reaction mixture was stirred for 2 hours under a hydrogen atmosphere. After the reaction was complete, the reaction mixture was passed through a Celite tube. TM The mixture was filtered through a filter pad and washed with ethyl acetate. The filtrate was concentrated under reduced pressure, and the crude compound was purified by preparative HPLC to give 35 mg (30% yield) of D-67 as a grayish-white solid. LCMS: [M+H] + =417.45; Rt=1.43min 1H NMR (400MHz, DMSO-d6) δ: 9.05 (br.s, 1H), 7.28-7.41 (m, 5H), 7.00 (d, J = 8.31Hz, 2H), 6.84 (d, J = 1.96Hz, 1H), 6.70 (dd, J = 2.45, 8.80Hz, 1H), 6.66 (d ,J=7.83Hz,2H),5.00-5.12(m,2H),2.53-2.64(m,4H),2.42(t,J=7.09Hz, 2H), 2.08 (s, 3H), 1.29-1.40 (m, 2H), 1.23 (s, 1H), 0.81 (t, J = 7.34Hz, 3H). 1-(4-(2-(butylamino)ethyl)benzyl)-3-fluoro-2-(o-tolyl)-1H-indole-5-ol (D-68)

[0371] In a sealed tube, butylamine (295 mg, 4.040 mmol) and DIPEA (0.7 mL, 4.040 mmol) were added to a solution of 4-((5-(benzyloxy)-3-fluoro-2-(o-tolyl)-1H-indol-1-yl)methyl)phenethyl 4-methylbenzenesulfonate 28-5 (250 mg, 0.4038 mmol) in acetonitrile (4 mL). The reaction mixture was stirred at room temperature for 72 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure and diluted with ethyl acetate. The organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give 240 mg (crude) of compound 68-1 as a grayish-white solid. LCMS: [M+H] + =521.75; Rt=1.80min 1 H NMR(400MHz,DMSO-d6)δ:7.47(d,J=7.82Hz,4H),7.37-7.43(m,3H),7.25-7.36(m,4H) ,7.11(d,J=7.83Hz,2H),7.05(d,J=7.82Hz,1H),6.91(dd,J=2.20,9.05Hz,1H),6.73( d,J=7.83Hz,1H),5.15(s,2H),2.90-2.98(m,2H),2.70-2.80(m,4H),2.28(s,3H),2.1 0-2.14(m,2H),1.45-1.49(m,2H),1.28(dq,J=6.60,14.43Hz,3H),0.83-0.90(m,3H).

[0372] At room temperature, 20% palladium hydroxide / carbon (77.5 mg, 30% w / w) was added to a solution of N-(4-((5-(benzyloxy)-3-fluoro-2-(o-tolyl)-1H-indol-1-yl)methyl)phenethyl)but-1-amine 68-1 (240 mg, 0.4615 mmol) in ethyl acetate:methanol (1:1; 4 mL). The reaction mixture was further stirred for 18 hours under a hydrogen atmosphere. After the reaction was complete, the reaction mixture was passed through a Celite tube. TM The mixture was filtered through a filter pad and washed with ethyl acetate. The filtrate was concentrated under reduced pressure, and the crude compound was purified by preparative HPLC to give 50 mg (25% yield) of D-68 as a light brown solid. LCMS: [M+H] + =431.20; Rt=1.59min 1 H NMR(400MHz, DMSO-d6)δ:9.02-9.15(m,1H),7.27-7.41(m,5H),6.99(d,J=8.31Hz,2H),6.84(d,J=2.45Hz,1H),6.70(dd,J=1.96,8.80Hz,1H),6.6 6(d,J=7.82Hz,2H),5.00-5.12(m,2H),2.58(qd,J=5.79,11.49Hz,4H),2 .44(t,J=6.85Hz,2H),2.08(s,3H),1.20-1.36(m,5H),0.80-0.86(m,3H). 3-Fluoro-1-(4-(2-(((3-fluoropropyl)amino)ethyl)benzyl)-2-(o-tolyl)-1H-indole-5-ol (D-69)

[0373] Potassium phthalimide (164 mg, 0.886 mmol) was added to a DMF (10 mL) solution of 4-((5-(benzyloxy)-3-fluoro-2-(o-tolyl)-1H-indol-1-yl)methyl)phenethyl 4-methylbenzenesulfonate 28-5 (500 mg, 0.807 mmol) at room temperature. The reaction mixture was then heated to 80 °C for 3 hours. After the reaction was complete, the reaction mixture was cooled to room temperature, diluted with ethyl acetate (100 mL), and washed with water (30 mL) and brine (30 mL). The organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give 510 mg (crude) of compound 69-6 as a pale yellow solid, which could be used for the next reaction without further purification. LCMS Condition 1: [M+H] + =595.30; Rt=2.66min

[0374] Hydrazine hydrate (55.6 mg, 1.018 mmol) was added to an ethanol (8 mL) solution of 2-(4-((5-(benzyloxy)-3-fluoro-2-(o-tolyl)-1H-indol-1-yl)methyl)phenethyl)isoindololin-1,3-dione 69-6 (550 mg, 0.925 mmol) at room temperature. The reaction mixture was then heated at 80 °C for 2 hours. After the reaction was complete (monitored by TLC), the reaction mixture was concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography, eluting with 0–3% methanol in DCM solution to give 265 mg (62% yield) of compound 69-7 as a white solid. LCMS Condition 1: [M+H] + =465.25; Rt=1.98min 1 H NMR(400MHz,DMSO-d6)δ:7.52-7.57(m,2H),7.43-7.51(m,3H),7.37-7.43(m,3H) ,7.32-7.36(m,1H),7.20-7.25(m,1H),7.07-7.12(m,2H),6.99(dd,J=2.45,8.80H z,1H),6.90(dd,J=2.45,8.80Hz,1H),6.80(d,J=7.83Hz,1H),6.76(d,J=8.31Hz, 1H),5.14(s,2H),5.10(s,2H),2.75-2.77(m,2H),2.49-2.61(m,2H),2.09(s,3H).

[0375] Potassium carbonate (77.3 mg, 0.560 mmol) and 1-iodo-3-fluoropropane (105 mg, 0.560 mmol) were added to a solution of 2-(4-((5-(benzyloxy)-3-fluoro-2-(o-tolyl)-1H-indol-1-yl)methyl)phenyl)ethyl-1-amine 69-7 (260 mg, 0.560 mmol) in acetonitrile (4 mL) at room temperature, and the mixture was stirred for 24 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography, eluting with 0-2% methanol in DCM solution to give 140 mg (48% yield) of compound 69-8 as a colorless viscous oil. LCMS Condition 1: [M+H] + =525.25; Rt=1.76min 1H NMR(400MHz,DMSO-d6)δ:7.46-7.50(m,2H),7.32-7.44(m,6H),7.12-7.18(m,1H),7.00-7.05(m,2 H),6.92(dd,J=2.20,9.05Hz,1H),6.83(dd,J=2.45,8.80Hz,1H),6.72(d,J=7.83Hz,1H),6.68(d, J=7.83Hz,1H),6.39(s,1H),5.15(s,1H),5.11(s,1H),4.52(t,J=5.87Hz,1H),4.40(t,J=6.11Hz, 1H), 2.62 (d, J = 6.85Hz, 6H), 2.07-2.12 (m, 3H), 1.75 (qd, J = 6.32, 19.69Hz, 2H), 1.22-1.26 (m, 3H).

[0376] At room temperature, 20% palladium hydroxide / carbon (71.5 mg, 30% w / w) was added to an ethyl acetate:methanol (2:1, 3 mL) solution of N-(4-((5-(benzyloxy)-3-fluoro-2-(o-tolyl)-1H-indol-1-yl)methyl)phenethyl)-3-fluoropropane-1-amine 69-8 (130 mg, 0.248 mmol). The reaction mixture was then stirred for 2 hours under a hydrogen atmosphere. After the reaction was complete (monitored by TLC and LCMS), the reaction mixture was passed through a Celite filter. TM The mixture was filtered through a pad and washed with methanol and ethyl acetate. The filtrate was concentrated under reduced pressure, and the crude compound was purified by preparative HPLC to give 20 mg (19% yield) of D-69 as a pale yellow solid. LCMS Condition 1: [M+H] + =435.20; Rt=1.43min 1 H NMR(400MHz, DMSO-d6)δ:9.04(s,1H),7.27-7.42(m,5H),7.00(d,J=7.83Hz,2H),6.84(d,J=1.47Hz,1H),6.69-6.72(m,1H),6.66(d,J=7 .83Hz,2H),4.99-5.12(m,2H),4.50(t,J=5.87Hz,1H),4.38(t,J=5.87Hz,1H),2.53-2.65(m,8H),2.06-2.11(m,3H),1.65-1.78(m,3H). 3-Fluoro-1-(4-(2-(((2-fluoroethyl)amino)ethyl)benzyl)-2-(o-tolyl)-1H-indole-5-ol (D-70)

[0377] In a sealed tube at room temperature, triethylamine (0.13 mL, 0.969 mmol) and 1-fluoro-2-iodoethane (56.2 mg, 0.323 mmol) were added to a THF (8 mL) solution of 2-(4-((5-(benzyloxy)-3-fluoro-2-(o-tolyl)-1H-indol-1-yl)methyl)phenyl)ethyl-1-amine 69-7 (150 mg, 0.323 mmol). The reaction mixture was then heated to 80 °C and stirred for 18 hours. After the reaction was complete (monitored by TLC), the reaction mixture was concentrated under reduced pressure, and the crude residue was purified by silica gel column chromatography, eluting with 0-2% methanol in DCM solution to give 91 mg (55% yield) of compound 70-8 as a colorless viscous oil. LCMS Condition 1: [M+H] + =511.63; Rt=1.71min

[0378] At room temperature, 20% palladium hydroxide / carbon (29.6 mg, 30% w / w) was added to a solution of N-(4-((5-(benzyloxy)-3-fluoro-2-(o-tolyl)-1H-indol-1-yl)methyl)phenethyl)-2-fluoroethane-1-amine 70-8 (90 mg, 0.176 mmol) in ethyl acetate:methanol (2:1, 3 mL). The reaction mixture was then stirred for 12 hours under a hydrogen atmosphere. After the reaction was complete (monitored by TLC and LCMS), the reaction mixture was passed through a Celite filter. TM The mixture was filtered through a pad and washed with methanol and ethyl acetate. The filtrate was concentrated under reduced pressure, and the crude compound was purified by preparative HPLC to give 15 mg (20% yield) of D-70 as a light brown solid. LCMS Condition 1: [M+H] + =421.30; Rt=1.38min 1H NMR (400MHz, DMSO-d6) δ: 9.04 (s, 1H), 7.27-7.41 (m, 5H), 7.01 (d, J = 7.83Hz, 2H), 6.84(d,J=1.96Hz,1H),6.70(dd,J=2.45,8.80Hz,1H),6.67(d,J=7.83Hz,2H),5. 00-5.14(m,2H),4.49(t,J=4.89Hz,1H),4.37(t,J=4.89Hz,1H),2.83(t,J=4.89H z, 1H), 2.76 (t, J = 4.89Hz, 1H), 2.66-2.73 (m, 2H), 2.55-2.63 (m, 2H), 2.08 (s, 3H). 1-(4-(2-(cyclopropylamino)propyl)benzyl)-3-fluoro-2-(o-tolyl)-1H-indole-5-ol (D-32)

[0379] Sodium hydride (60% oil dispersion, 27.2 mg, 1.132 mmol) was added in portions to a DMF (3 mL) solution of 5-(benzyloxy)-3-fluoro-2-(o-tolyl)-1H-indole 28-2 (600 mg, 1.812 mmol) at 0 °C, and the mixture was stirred for 30 min at the same temperature. A DMF (1 mL) solution of 2-(4-(bromomethyl)phenyl)acetic acid 1 (456 mg, 1.994 mmol) was added to the resulting solution, and the mixture was stirred for 18 h at room temperature. After the reaction was complete, the reaction mixture was quenched with ice water and acidified to pH 2 with dilute hydrochloric acid solution. The precipitated solid was filtered and washed to give 820 mg (94% yield) of compound 32-2 as a yellow solid. LCMS - Condition 01: [M-18] + =462.50; Rt=2.29min 1 H NMR(400MHz,DMSO-d6)δ:12.24(br.s,1H),7.45-7.49(m,2H),7.23-7.42(m,10H),7.14(d,J=1.96Hz,1H),7.0 5(d,J=7.82Hz,2H),6.91(dd,J=2.20,9.05Hz,1H),6.67-6.72(m,2H),5.14(s,2H),3.44(s,2H),2.10(s,3H).

[0380] At room temperature, HATU (475 mg, 1.250 mmol), DIPEA (0.9 mL, 5.209 mmol), and N-methyl-N-methoxyamine (191 mg, 31.27 mmol) were added to a DMF (2 mL) solution of 2-(4-((5-(benzyloxy)-3-fluoro-2-(o-tolyl)-1H-indol-1-yl)methyl)phenyl)acetic acid 32-2 (500 mg, 1.043 mmol), and the mixture was stirred for 18 hours. After the reaction was complete, the reaction mixture was quenched with ice water and extracted with ethyl acetate (2x). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography, eluting with a solution of 0-20% ethyl acetate in n-hexane to give 350 mg (64% yield) of compound 32-3 as a yellow oil. LCMS - Condition 01: [M+H] + =523.60; Rt=2.36min 1 H NMR(400MHz, DMSO-d6)δ:7.46-7.50(m,2H),7.24-7.43(m,8H),7.14(d,J=2.49Hz,1H),7.03(d,J=7.98Hz,2H),6.91(dd,J=2.49 ,8.98Hz,1H),6.70(d,J=8.48Hz,2H),5.15(s,2H),5.09-5.12(m,2H),3.60-3.62(m,2H),3.60(s,3H),3.05(s,3H),2.10(s,3H).

[0381] A solution of 3M magnesium methyl bromide in diethyl ether (0.38 mL, 1.140 mmol) was added to a THF (5 mL) solution of 2-(4-((5-(benzyloxy)-3-fluoro-2-(o-tolyl)-1H-indol-1-yl)methyl)phenyl)-N-methoxy-N-methylacetamide 32-3 (300 mg, 0.574 mmol) at 0 °C. The reaction mixture was further stirred for 5 hours at room temperature. After the reaction was complete, the reaction mixture was quenched with ice water and extracted with ethyl acetate (2×). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography, eluting with 0-5% methanol in DCM solution to give 250 mg (91% yield) of compound 32-4 as a colorless oil. LCMS - Condition 01: [M-18] + =460.55; Rt=2.39min 1H NMR(400MHz, DMSO-d6)δ:7.46-7.50(m,2H),7.27-7.45(m,8H),7.14(d,J=2.45Hz,1H),6.98(d,J=8.31Hz,2H),6 .92(dd,J=2.45,9.29Hz,1H),6.69(d,J=8.31Hz,2H),5.11-5.15(m,4H),3.64(s,2H),2.10(s,3H),2.05(s,3H).

[0382] In a 6 mL EDC solution of 1-(4-((5-(benzyloxy)-3-fluoro-2-(o-tolyl)-1H-indol-1-yl)methyl)phenyl)prop-2-one 32-4 (250 mg, 0.524 mmol), sodium triacetoxyborohydride (555 mg, 2.617 mmol) was added in portions at 0 °C, followed by cyclopropylamine (89 mg, 1.558 mmol). The reaction mixture was stirred at room temperature for 18 hours. After the reaction was complete, the reaction mixture was quenched with ice water and extracted with ethyl acetate (2×). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography, eluting with a solution of 0-20% ethyl acetate in n-hexane to give 158 mg (58% yield) of compound 32-5 as a colorless oil. LCMS Condition 1: [M+H] + =519.60; Rt=1.78min 1 H NMR(400MHz,DMSO-d6)δ:7.80-7.87(m,1H),7.42-7.47(m,3H),7.25-7.40(m,7H),7 .08-7.14(m,1H),6.93(d,J=7.83Hz,2H),6.87-6.91(m,1H),6.61(d,J=7.83Hz,2H), 5.12(s,2H),5.08(d,J=4.89Hz,2H),2.74-2.85(m,1H),2.61-2.70(m,2H),2.50-2.5 8(m,1H),2.23-2.31(m,2H),2.00(s,3H),0.82(d,J=6.36Hz,3H),0.50-0.57(m,2H).

[0383] At room temperature, 20% palladium hydroxide / carbon (50 mg, 50% water / carbon) was added to an ethyl acetate:methanol (1:1 mL) solution of N-(1-(4-((5-(benzyloxy)-3-fluoro-2-(o-tolyl)-1H-indol-1-yl)methyl)phenyl)prop-2-yl)cyclopropylamine 32-5 (150 mg, 0.289 mmol). The reaction mixture was then stirred for 18 hours under a hydrogen atmosphere. After the reaction was complete, the reaction mixture was passed through a Celite tube. TM The solution was filtered and washed with ethyl acetate. The filtrate was concentrated under reduced pressure, and the crude compound was purified by preparative HPLC to give 40 mg (32% yield) of D-32 as a colorless oil. LCMS - Conditions - 1: [M+H] + =429.50; Rt=1.42min 1 H NMR (400MHz, DMSO-d6) δ: 9.04 (s, 1H), 7.28-7.40 (m, 6H), 6.95 (d, J = 7.82Hz, 2H), 6.84(d,J=1.96Hz,1H),6.71(dd,J=2.45,8.80Hz,1H),6.64(d,J=8.31Hz,2H),5. 07(s,2H),2.75-2.83(m,1H),2.67(ddd,J=2.69,5.75,13.08Hz,2H),2.53-2.60( m,1H),2.25-2.34(m,2H),2.03(s,3H),0.85(d,J=6.36Hz,3H),0.50-0.57(m,2H). 1-(4-(2-((cyclopropylmethyl)amino)ethyl)benzyl)-3-fluoro-2-(2-(trifluoromethyl)phenyl)-1H-indole-5-ol (D-40)

[0384] A 60% sodium hydroxide oil dispersion (370 mg, 7.791 mmol) was added fractionally to a DMF (10 mL) solution of 5-(benzyloxy)-3-fluoro-2-(2-(trifluoromethyl)phenyl)-1H-indole 40-1 (1 g, 2.597 mmol) at 0 °C. The reaction mixture was further stirred at 0 °C for 30 min. (4-(bromomethyl)phenylethoxy)(tert-butyl)dimethylsilane (1.1 g, 3.376 mmol) was added to the resulting solution. The reaction mixture was stirred at room temperature for 18 h. After the reaction was complete, the reaction mixture was quenched with ice water and extracted three times with ethyl acetate. The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The resulting crude compound was purified by silica gel column chromatography, eluting with a solution of 0-10% ethyl acetate in n-hexane to give 747 mg (45% yield) of compound 40-2 as a brown, viscous oil. LCMS - Condition 01: [M+H] + =634.25; Rt=2.83min 1 H NMR(400MHz, CDCl3)δ:7.82(d,J=7.34Hz,1H),7.52-7.60(m,1H),7.49(d,J=7.34Hz,2H),7.41(t,J=7.34H z,1H),7.33(dd,J=7.34,11.74Hz,2H),7.19(d,J=1.96Hz,1H),7.09-7.12(m,3H),7.03-7.08(m,2H),6.92 (dd,J=2.45,9.29Hz,1H),6.81(d,J=7.82Hz,2H),5.14(br.s,1H),5.13(s,1H),5.10(br.s,1H),4.79(d,J =17.12Hz,1H),3.75-3.80(m,2H),2.77-2.81(m,2H),0.89(s,6H),0.88(s,3H),0.01(s,3H),0.00(s,3H).

[0385] A solution of 2 MTBAF of THF (495 mg, 1.896 mmol) was added to an 8 mL solution of 5-(benzyloxy)-1-(4-(2-((tert-butyldimethylsilyl)oxy)ethyl)benzyl)-3-fluoro-2-(2-(trifluoromethyl)phenyl)-1H-indole 40-2 (800 mg, 1.263 mmol) in THF at 0 °C. The reaction mixture was further stirred for 2 hours at room temperature. After the reaction was complete, the reaction mixture was quenched with ice water and extracted three times with ethyl acetate. The dried and combined organic layers were washed with water (20 mL) and brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude compound was purified by silica gel column chromatography, eluting with a solution of 0-50% ethyl acetate in n-hexane to give 550 mg (84% yield) of compound 40-3 as a viscous, colorless paste. LCMS - Condition 01: [M+H] + =520.18; Rt=2.36min 1 H NMR(400MHz, CDCl3)δ:7.81(d,J=7.34Hz,1H),7.51-7.59(m,2H),7.48(d,J=7.34Hz,2H ),7.40(t,J=7.34Hz,2H),7.33(dd,J=7.58,10.03Hz,2H),7.18(d,J=1.96Hz,1H),7.05- 7.09(m,3H),6.93(dd,J=2.45,8.80Hz,1H),6.83(d,J=8.31Hz,2H),5.12(s,2H),5.09(s ,1H),4.81(d,J=16.63Hz,1H),4.09-4.15(m,1H),3.83-3.88(m,2H),2.83-2.87(m,2H).

[0386] Triethylamine (0.46 mL, 1.564 mmol) was added to a solution of 2-(4-((5-(benzyloxy)-3-fluoro-2-(2-(trifluoromethyl)phenyl)-1H-indol-1-yl)methyl)phenyl)ethyl-1-ol 40-3 (560 mg, 1.117 mmol) in 10 mL of CH2Cl2 at 0 °C, followed by the addition of toluenesulfonyl chloride (299 mg, 1.564 mmol). The reaction mixture was stirred for 3 hours at room temperature. After the reaction was complete, the reaction mixture was diluted with 50 mL of CH2Cl2 and washed with 20 mL of water and 10 mL of brine. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude compound was purified by silica gel column chromatography, eluting with a solution of 0-25% ethyl acetate in n-hexane to give 630 mg (86% yield) of compound 40-4 as a viscous, colorless paste. LCMS - Condition 01: [M+H] + =674.05; Rt=2.46min 1 H NMR(400MHz, CDCl3)δ:7.81(d,J=7.34Hz,1H),7.69(dd,J=8.31,10.76Hz,2H),7.46-7.59(m,3H), 7.40(t,J=7.58Hz,1H),7.34(d,J=6.85Hz,1H),7.28(d,J=8.80Hz,2H),7.25(br.s,1H),7.21-7.24 (m,2H),7.18(d,J=2.45Hz,1H),7.01-7.09(m,3H),6.94-6.98(m,2H),6.77(d,J=7.83Hz,1H),5.12 (s,2H),4.12-4.22(m,2H),2.86-2.96(m,2H),2.85(s,1H),2.43(s,2H),2.40(s,1H),2.00(s,1H).

[0387] Cyclopropyl methylamine (0.200 g, 3.324 mmol) and DIPEA (0.57 mL, 3.380 mmol) were added to a 4 mL solution of 4-((5-(benzyloxy)-3-fluoro-2-(2-(trifluoromethyl)phenyl)-1H-indol-1-yl)methyl)phenethyl 4-methylbenzenesulfonate 40-4 (225 mg, 0.334 mmol) in acetonitrile (4 mL). The reaction mixture was stirred further at room temperature for 72 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure and washed with ethyl acetate (2 × 10 mL). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give 210 mg (crude) of compound 40-5 as a colorless residue. LCMS - Condition 01: [M+H] + =573.20; Rt=1.79min 1 H NMR(400MHz, DMSO-d6)δ:7.91-7.95(m,1H),7.73-7.77(m,1H),7.46-7.49(m,3H),7.40(t,J=7.34Hz,1H), 7.16-7.35(m,4H),7.07-7.15(m,4H),6.93(dd,J=2.45,8.80Hz,1H),6.82(d,J=7.83Hz,1H),5.23(d,J=16. 63Hz,1H),5.16(s,1H),4.87(d,J=17.12Hz,1H),3.02(dd,J=9.29,19.07Hz,2H),2.79-2.86(m,2H),2.72-2 .78(m,2H),2.29(s,2H),0.94-1.01(m,1H),0.54(dt,J=1.96,6.11Hz,2H),0.29(dd,J=4.89,11.25Hz,2H).

[0388] 20% palladium hydroxide / carbon (51 mg) was added to a solution of 2-(4-((5-(benzyloxy)-3-fluoro-2-(2-(trifluoromethyl)phenyl)-1H-indol-1-yl)methyl)phenyl)-N-(cyclopropylmethyl)ethane-1-amine 40-5 (210 mg, 0.367 mmol) in ethyl acetate:methanol (2:2 mL) at room temperature. The reaction mixture was further stirred for 2 hours under a hydrogen atmosphere. After the reaction was complete, the reaction mixture was passed through a Celite tube. TM The mixture was filtered through a pad and washed with ethyl acetate. The filtrate was concentrated under reduced pressure, and the crude compound was purified by preparative HPLC to give 22 mg (13% yield) of D-40 as a grayish-white solid. LCMS Condition 1: [M+H] + =483.15; Rt=1.46min 1H NMR(400MHz,DMSO-d6)δ:8.25(s,1H),7.83-7.87(m,1H),7.65-7.69(m,2H),7.41-7.46(m,1H),7. 13(d,J=8.80Hz,1H),7.00(d,J=8.31Hz,2H),6.79(d,J=1.96Hz,1H),6.72(d,J=7.83Hz,2H),6.66 (dd,J=1.96,8.80Hz,1H),5.11(d,J=16.63Hz,1H),4.74(d,J=16.63Hz,1H),2.79-2.86(m,2H),2. 64-2.71(m,2H),2.54(d,J=6.85Hz,2H),0.81-0.91(m,1H),0.37-0.43(m,2H),0.10-0.16(m,2H). 1-(4-(2-(cyclopropylamino)ethyl)benzyl)-3-fluoro-2-(2-(trifluoromethyl)phenyl)-1H-indole-5-ol (D-33)

[0389] Cyclopropylamine (0.200 g, 3.324 mmol) and DIPEA (0.57 mL, 3.380 mmol) were added to a 4 mL solution of 4-((5-(benzyloxy)-3-fluoro-2-(2-(trifluoromethyl)phenyl)-1H-indol-1-yl)methyl)phenethyl 4-methylbenzenesulfonate D-40-4 (0.225 g, 0.334 mmol) in acetonitrile (4 mL). The reaction mixture was stirred at room temperature for 72 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure and extracted with ethyl acetate (3X). The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 220 mg (crude) of compound 33-3 as a colorless oil. LCMS - Condition 01: [M+H] + =559.20; Rt=1.75min 1H NMR(400MHz, DMSO-d6)δ:7.91-7.95(m,1H),7.73-7.77(m,1H),7.50-7.54(m,1H),7.45-7. 50(m,4H),7.40(t,J=7.34Hz,2H),7.29-7.36(m,2H),7.10(dd,J=3.67,8.07Hz,3H),6.93(d d,J=2.20,9.05Hz,1H),6.81(d,J=7.82Hz,1H),5.21(d,J=16.8Hz,1H),5.15(s,2H),4.48(d ,J=16.8Hz,1H),3.05-3.11(m,2H),2.75-2.80(m,2H),2.28(s,2H),1.25(d,J=6.85Hz,4H).

[0390] 20% palladium hydroxide / carbon (70 mg) was added to an ethyl acetate:methanol (2:2 mL) solution of N-(4-((5-(benzyloxy)-3-fluoro-2-(2-(trifluoromethyl)phenyl)-1H-indol-1-yl)methyl)phenethyl)cyclopropylamine 33-3 (0.230 g, 0.413 g) at room temperature. The reaction mixture was then stirred for 2 hours under a hydrogen atmosphere. After the reaction was complete, the reaction mixture was passed through a Celite tube. TM The mixture was filtered through a pad and washed with ethyl acetate. The filtrate was concentrated under reduced pressure, and the crude compound was purified by preparative HPLC to give 18 mg (10% yield) of D-33 as a grayish-white solid. LCMS Condition 1: [M+H] + =469.10; Rt=1.45min 1 H NMR(400MHz,DMSO-d6)δ:9.08(s,1H),8.16(s,1H),7.88-7.93(m,1H),7.70-7.76(m,2H),7.47-7 .50(m,1H),7.21(dd,J=1.83,8.93Hz,1H),7.04(d,J=8.07Hz,2H),6.85(d,J=2.08Hz,1H),6.75( d,J=7.95Hz,2H),6.72(dd,J=2.32,8.93Hz,1H),5.16(d,J=16.75Hz,1H),4.80(d,J=16.75Hz,1H ),2.73-2.78(m,2H),2.59-2.65(m,2H),2.10-2.14(m,1H),0.33-0.38(m,2H),0.19-0.24(m,2H). 1-(4-(2-(ethylamino)ethyl)benzyl)-3-fluoro-2-(2-(trifluoromethyl)phenyl)-1H-indole-5-ol (D-34)

[0391] In a sealed tube, a solution of 2M ethylamine in THF (150 mg, 1.66 mL, 3.324 mmol) and DIPEA (0.57 mL, 3.380 mmol) was added to a solution of 4-((5-(benzyloxy)-3-fluoro-2-(2-(trifluoromethyl)phenyl)-1H-indol-1-yl)methyl)phenethyl 4-methylbenzenesulfonate 33-2 (0.225 g, 0.334 mmol) in acetonitrile (5 mL). The reaction mixture was then stirred at room temperature for 72 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure and extracted with ethyl acetate (3X). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 195 mg (crude) of compound 34-1 as a colorless, viscous oil. LCMS - Condition 01: [M+H] + =547.26; Rt=1.77min 1 H NMR(400MHz, DMSO-d6)δ:8.24-8.33(m,1H),7.90-7.96(m,1H),7.75(d,J=3.91Hz,1H),7.52( br.s,1H),7.47(d,J=6.85Hz,3H),7.37-7.43(m,2H),7.26-7.37(m,2H),7.10(d,J=7.83Hz,3H ),6.93(d,J=8.80Hz,1H),6.83(d,J=7.83Hz,2H),5.24(d,J=16.63Hz,1H),5.15(br.s,2H),4 .81-4.90(m,1H),3.02-3.10(m,2H),2.91-3.00(m,2H),2.75-2.83(m,2H),1.12-1.17(m,3H).

[0392] 20% palladium hydroxide / carbon (60 mg) was added to a solution of 2-(4-((5-(benzyloxy)-3-fluoro-2-(2-(trifluoromethyl)phenyl)-1H-indol-1-yl)methyl)phenyl)-N-ethyl-1-amine 34-1 (0.195 g, 0.357 mmol) in ethyl acetate:methanol (1:1, 4 mL) at room temperature. The reaction mixture was stirred for 18 hours under a hydrogen atmosphere. After the reaction was complete, the reaction mixture was passed through a Celite tube. TMThe mixture was filtered through a pad and washed with ethyl acetate. The filtrate was concentrated under reduced pressure, and the crude compound was purified by preparative HPLC to give 40 mg (21% yield) of D-34 as a grayish-white solid. LCMS Condition 1: [M+H] + =457.10; Rt=1.42min 1 H NMR(400MHz,DMSO-d6)δ:9.08(s,1H),7.88-7.93(m,1H),7.71-7.75(m,2H), 7.46-7.51(m,1H),7.21(dd,J=1.90,8.86Hz,1H),7.03(d,J=7.95Hz,2H),6. 85(d,J=2.08Hz,1H),6.73-6.77(m,2H),6.69-6.72(m,1H),5.15(d,J=16.63 Hz, 1H), 4.80 (d, J = 16.75Hz, 1H), 2.52-2.69 (m, 6H), 0.95 (t, J = 7.09Hz, 3H). 2-(2-Chlorophenyl)-1-(4-(2-(cyclopropylamino)ethyl)benzyl)-3-fluoro-1H-indole-5-ol (D-37)

[0393] At room temperature and under an argon atmosphere, 2-Cl-phenylboronic acid (1.32 g, 8.48 mmol) and an aqueous solution of Na₂CO₃ (2.07 g, 19.58 mmol) in toluene-ethanol (9:1, 50 mL) were simultaneously added, followed by degassing for 30 min. Pd(PPh₃)₄ (376 mg, 0.326 mmol) was added to the resulting solution, and degassing continued for another 10 min at room temperature. The reaction mixture was then heated at 90 °C for 18 h. After the reaction was complete (monitored by TLC and LCMS), the reaction mixture was diluted with water and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude compound was purified by silica liquid column chromatography and eluted with n-hexane solution of 0-15% ethyl acetate to give 650 g (30% yield) of compound 37-1 as a viscous yellow liquid. LCMS - Condition 01: [M+H] + =334.35; Rt=2.39min 1H NMR(400MHz, DMSO-d6)δ:8.70(br.s,1H),7.67(dd,J=1.6,7.6Hz,1H),7.48-7.51(m,3H),7.39-7.43(m, 2H),7.30-7.37(m,4H),7.20(d,J=2.00Hz,1H),6.98(dd,J=2.40,8.80Hz,1H),6.80(s,1H),5.14(s,2H).

[0394] Selectfluor (690 mg, 1.94 mmol) was added to an aqueous solution of 5-(benzyloxy)-2-(2-chlorophenyl)-1H-indole 37-1 (650 mg, 1.94 mmol) in acetonitrile-DMSO (1:1, 12 mL) at -10 °C under an argon atmosphere. The reaction mixture was stirred further at 0 °C for 2 hours. After the reaction was complete (monitored by TLC), the reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (100 mL), washed with water (40 mL), and then washed with brine (30 mL). The separated organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography, eluted with a solution of 0-10% ethyl acetate in n-hexane, and then subjected to preparative TLC to give 300 mg (44% yield) of compound 37-2 as a light brown solid. LCMS - Condition 01: [M+18] + =360.90; Rt=2.38min 1 H NMR(400MHz, CDCl3)δ:7.87(d,J=7.6Hz,1H),7.56(dd,J=1.6,7.6Hz,1H),7.49-7 .54(m,2H),7.36-7.44(m,6H),7.22(d,J=2.0Hz,1H),7.06(dd,J=2.0,8.4Hz,1H).

[0395] Sodium hydride (60% oil dispersion, 102 mg, 2.558 mmol) was added fractionally to a DMF (10 mL) solution of 5-(benzyloxy)-2-(2-chlorophenyl)-3-fluoro-1H-indole 37-2 (300 g, 0.852 mmol) at 0 °C and stirred at 0 °C for 30 min. (4-(bromomethyl)phenylethoxy)(tert-butyl)dimethylsilane (365 mg, 1.108 mmol) was added to the resulting solution. The reaction mixture was stirred at room temperature for 18 h. After the reaction was complete (monitored by TLC and LCMS), the reaction mixture was quenched with ice water and extracted with ethyl acetate (3 × 15 mL). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography, eluting with a solution of 0–10% ethyl acetate in n-hexane to give 280 mg (55% yield) of compound 37-3 as a pale yellow oil. LCMS - Condition 01: [M+H] + =600.35; Rt=2.83min 1 H NMR(400MHz, CDCl3)δ:7.46-7.53(m,2H),7.28-7.42(m,5H),7.17-7.21(m,3H),7 .10(dd,J=2.08,8.68Hz,1H),7.02(d,J=8.07Hz,2H),6.92(dd,J=2.45,8.93Hz,1H ),6.79(d,J=8.07Hz,2H),5.16(d,J=16.40Hz,1H),5.12(s,2H),4.98(d,J=16.87H z, 1H), 3.79 (t, J = 7.09Hz, 2H), 2.82 (d, J = 7.2Hz, 2H), 0.87 (s, 9H), -0.055 (s, 6H).

[0396] TBAF (183 mg, 0.699 mmol) was added in portions to a THF (6 mL) solution of 5-(benzyloxy)-1-(4-(2-((tert-butyldimethylsilyl)oxy)ethyl)benzyl)-2-(2-chlorophenyl)-3-fluoro-1H-indole 37-3 (280 mg, 0.466 mmol) at 0 °C. The reaction mixture was further stirred for 1 hour at room temperature. After the reaction was complete, the reaction mixture was quenched with ice water and extracted three times with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude compound was purified by silica liquid column chromatography, eluting with a solution of 0-50% ethyl acetate in n-hexane to give 200 mg (88% yield) of compound 37-4 as a light brown viscous liquid. LCMS - Condition 01: [M+H] +=486.04; Rt=2.39min 1 H NMR(400MHz, CDCl3)δ:7.50(dd,J=7.34,12.23Hz,2H),7.30-7.42(m,5H),7.22( d,J=8.31Hz,2H),7.18(d,J=2.45Hz,1H),7.13(dd,J=1.96,9.29Hz,1H),7.04(d ,J=7.83Hz,2H),6.94(dd,J=2.20,9.05Hz,1H),6.81(d,J=8.31Hz,2H),5.15-5. 20(m,1H),5.12(s,2H),4.99-5.04(m,1H),3.75-3.89(m,2H),2.76-2.87(m,2H).

[0397] Triethylamine (0.21 mL, 1.543 mmol) was added to a CH₂Cl₂ (mL) solution of 2-(4-((5-(benzyloxy)-2-(2-chlorophenyl)-3-fluoro-1H-indol-1-yl)methyl)phenyl)ethyl-1-ol 37-4 (250 mg, 0.514 mmol), followed by TsCl (127 mg, 0.668 mmol). The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete (monitored by TLC and LCMS), the reaction mixture was quenched with sodium bicarbonate solution and extracted with ethyl acetate (3 × 20 mL). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography, eluting with 0–20% ethyl acetate in n-hexane to give 300 mg (91% yield) of compound 37-5 as a grayish-white solid. LCMS - Condition 01: [M+H] + =640.20; Rt=2.47min 1 H NMR(400MHz, CDCl3)δ:7.45-7.54(m,3H),7.29-7.42(m,6H),7.17-7.24(m,4H),7.08-7.12(m,2H),6.90-6.95(m,3H),6.76(d,J=8.3 1Hz, 2H), 5.16 (d, J = 16.63Hz, 1H), 5.12 (s, 2H), 4.98 (d, J = 16.63Hz, 1H), 2.95 (t, J = 7.09Hz, 2H), 2.86 (t, J = 7.09Hz, 2H), 2.39 (s, 3H).

[0398] Cyclopropylamine (178 mg, 3.124 mmol) and DIPEA (0.54 mL, 3.124 mmol) were added to a solution of 4-((5-(benzyloxy)-2-(2-chlorophenyl)-3-fluoro-1H-indol-1-yl)methyl)phenethyl 4-methylbenzenesulfonate 37-5 (200 mg, 0.312 mmol) in acetonitrile (3 mL) in a sealed tube. The reaction mixture was then stirred at room temperature for 72 hours. After the reaction was complete (monitored by TLC and LCMS), the reaction mixture was diluted with water and extracted with ethyl acetate (3 × 100 mL). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography, eluting with a solution of 0–50% ethyl acetate in n-hexane to give 90 mg (55% yield) of compound 37-6 as a grayish-white viscous solid. LCMS - Condition 01: [M+H] + =525.15; Rt=1.83min 1 H NMR(400MHz, CDCl3)δ:7.47-7.53(m,2H),7.30-7.42(m,5H),7.29(d,J=2.45Hz,1H),7.17-7.2 2(m,2H),7.14(dd,J=1.96,8.80Hz,1H),7.02(d,J=7.83Hz,2H),6.94(dd,J=2.45,8.80Hz,1H), 6.79(d,J=7.83Hz,2H),5.14-5.20(m,1H),5.12(s,2H),4.98-5.04(m,1H),2.93-2.99(m,1H), 2.86-2.91(m,1H),2.78-2.84(m,1H),2.68-2.74(m,1H),2.10-2.14(m,1H),0.33-0.45(m,4H).

[0399] 20% palladium hydroxide / carbon (30 mg) was added to a solution of N-(4-((5-(benzyloxy)-2-(2-chlorophenyl)-3-fluoro-1H-indol-1-yl)methyl)phenethyl)cyclopropylamine 37-6 (90 mg, 0.171 mmol) in ethyl acetate:methanol (2:1, 3 mL) at room temperature. The reaction mixture was then stirred for 18 hours under a hydrogen atmosphere. After the reaction was complete (monitored by TLC and LCMS), the reaction mixture was passed through a Celite filter. TM The mixture was filtered through a pad and washed with ethyl acetate. The filtrate was concentrated under reduced pressure, and the crude compound was purified by preparative HPLC to give 14 mg (19% yield) of D-37 as a white solid. LCMS - Condition 01: [M+H]+ =435.10; Rt=1.51min 1 H NMR (400MHz, CDCl3) δ: 7.51 (dd, J = 1.00, 8.03Hz, 1H), 7.29-7.39 (m, 3H), 7.00-7.12 (m, 4H), 6.74-6.82 (m, 3H), 5.12-5.18 (m,1H),4.95-5.03(m,1H),2.86-2.92(m,2H),2.68-2.76(m,2H),2.08-2.13(m,1H),0.81-0.91(m,2H),0.40-0.47(m,2H). N-Ethyl-2-(4-(((8-fluoro-7-(o-tolyl)pyrrolo[3,2-e]indazole-6(3H)-yl)methyl)phenyl)ethyl-1-amine (D-85)

[0400] Sodium hydroxide (6.1 g, 153.2 mmol) was added to a THF (100 mL) solution of 5-nitro-1H-indazole 85-1 (10 g, 61.29 mmol), followed by tetrabutylammonium sulfate (312 mg, 0.917 mmol), and the mixture was stirred at room temperature for 1 hour. Benzenesulfonyl chloride (12 g, 67.79 mmol) was added dropwise to the resulting solution, and the mixture was stirred for another 1 hour. After the reaction was complete (monitored by TLC and LCMS), the reaction mixture was quenched with water and extracted with ethyl acetate (3 × 100 mL). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The resulting crude compound was purified by grinding in diethyl ether to give 17.3 g (93% yield) of compound 85-2 as a white solid. LCMS: [M+H] + =303.95; Rt=1.85min 1 H NMR (400MHz, CDCl3) δ: 8.66 (d, J = 1.96 Hz, 1H), 8.44-8.47 (m, 1H), 8.34-8.38 (m, 2H), 8.02-8.06 (m, 2H), 7.62-7.67 (m, 1H), 7.50-7.55 (m, 2H).

[0401] Hydrazine hydrate (10 g, 199.8 mmol) and 20% palladium / carbon (2 g) were added to a methanol (200 mL) solution of 5-nitro-1-(benzenesulfonyl)-1H-indazole 85-2 (17.3 g, 57.09 mmol) at room temperature. The reaction mixture was heated at 70 °C for 3 hours. After the reaction was complete (monitored by TLC and LCMS), the reaction mixture was passed through a Celite filter.TM The mixture was filtered through a pad, and the filtrate was concentrated under reduced pressure. The crude compound was purified by grinding in diethyl ether to give 14.5 g (93% yield) of compound 85-3 as a light brown solid. LCMS: [M+H] + =274.15; Rt=1.43min 1 H NMR(400MHz,DMSO-d6)δ:8.27(s,1H),7.76-7.84(m,3H),7.64-7.71(m,1H),7.52 -7.59(m,2H),6.96(dd,J=1.96,8.80Hz,1H),6.77(d,J=1.96Hz,1H),5.30(s,2H).

[0402] N-iodosuccinimide (14.3 g, 63.73 mmol) was added to a solution of 1-(benzenesulfonyl)-1H-indazole-5-amine 85-3 (14.5 g, 53.11 mmol) in acetonitrile (300 mL) at room temperature, and the mixture was stirred for 2 hours. After the reaction was complete (monitored by TLC and LCMS), the reaction mixture was diluted with water and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography, eluting with a 10–15% ethyl acetate solution in n-hexane to give 11 g (52% yield) of compound 85-4 as a grayish-white solid. LCMS: [M+H] + =399.90; Rt=1.97min 1 H NMR (400MHz, DMSO-d6) δ: 8.07-8.10 (m, 1H), 7.83-7.88 (m, 3H), 7.68-7.74 (m, 1H), 7.54-7.62 (m, 2H), 7.11 (d, J = 9.29Hz, 1H), 5.48 (s, 2H).

[0403] Triethylamine (8 mL, 57.56 mmol) and TFAA (4 mL, 28.57 mmol) were added to a solution of 6 g (15.03 mmol) of 4-iodo-1-(benzenesulfonyl)-1H-indazole-5-amine 85-4 in 50 mL of CH2Cl2 at 0 °C. The reaction mixture was then stirred at room temperature for 2 hours. After the reaction was complete (monitored by TLC and LCMS), the reaction mixture was diluted with water and extracted with CH2Cl2 (3 × 50 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography, eluting with a solution of 0–20% ethyl acetate in n-hexane to give 5.5 g (71% yield) of compound 85-5 as a grayish-white solid. LCMS: [M+H] + =495.90; Rt=2.06min 1 H NMR (400MHz, DMSO-d6) δ: 11.43 (s, 1H), 8.45 (s, 1H), 8.20 (d, J = 8.80Hz, 1H), 7.96-8.01 (m, 2H), 7.73-7.79 (m, 1H), 7.60-7.67 (m, 3H).

[0404] At room temperature, copper iodide (212 mg, 1.115 mmol) was added to a DMF (75 mL) solution of 2,2,2-trifluoro-N-(4-iodo-1-(benzenesulfonyl)-1H-indazole-5-yl)acetamide 85-5 (5.5 g, 11.11 mmol), followed by triethylamine (7.7 mL, 55.55 mmol), and the mixture was degassed with argon for 15 min. Dichlorobis(triphenylphosphine)palladium(II) (779 mg, 1.112 mmol) and 1-ethynyl-2-methylbenzene (1.54 g, 13.33 mmol) were added to the resulting solution, and degassed for another 10 min. The reaction mixture was then heated at 130 °C for 18 h. After the reaction was complete (monitored by TLC and LCMS), the reaction mixture was passed through a Celite tube. TM The mixture was filtered through a filter pad, the filtrate was diluted with water, and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude compound was purified by Combiflash column chromatography, eluting with a 10–20% ethyl acetate solution in n-hexane to give 3.5 g (81% yield) of compound 85-6 as a white solid. LCMS: [M+H] + =388.30; Rt=2.08min 1H NMR(400MHz, DMSO-d6)δ:11.87(s,1H),8.74(s,1H),7.87-7.93(m,3H),7.72(d,J=8.80 Hz, 1H), 7.56 (t, J = 7.83Hz, 3H), 7.29-7.38 (m, 4H), 6.94 (d, J = 1.47Hz, 1H), 2.47 (s, 3H).

[0405] Selectfluor (1.28 g, 3.617 mmol) was added to an aqueous solution of acetonitrile:DMSO (4:1, 50 mL) of 1 g (1 g, 2.583 mmol) of 3-(benzenesulfonyl)-7-(o-tolyl)-3,6-dihydropyrrolo[3,2-e]indazole 85-6 under an argon atmosphere at -10 °C. The reaction mixture was stirred further at -10 °C for 2 hours. After the reaction was complete (monitored by TLC and LCMS), the reaction mixture was quenched with water and extracted with ethyl acetate (3 × 20 mL). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude compound was purified by Combiflash column chromatography, eluting with a solution of 0–20% ethyl acetate in n-hexane to give 450 mg (43% yield) of compound 85-7 as a pale yellow solid. LCMS: [M+H] + =406.35; Rt=2.13min 1 H NMR (400MHz, DMSO-d6) δ: 11.80 (s, 1H), 8.68 (s, 1H), 7.98 (d, J = 9.29Hz, 1H), 7.89-7.92 (m, 2H) ,7.68-7.72(m,2H),7.55-7.61(m,2H),7.46(d,J=6.85Hz,1H),7.33-7.39(m,3H),2.36(s,3H).

[0406] Sodium hydride (60% oil dispersion, 53 mg, 2.222 mmol) was added in portions to a DMF (10 mL) solution of 8-fluoro-3-(benzenesulfonyl)-7-(o-tolyl)-3,6-dihydropyrrolo[3,2-e]indazole 85-7 (450 mg, 1.111 mmol) at 0 °C and stirred for 30 min. (4-(bromomethyl)phenethoxy)(tert-butyl)dimethylsilane (437 mg, 1.333 mmol) was added to the resulting solution. The reaction mixture was stirred for 1 h at room temperature. After the reaction was complete (monitored by TLC and LCMS), the reaction mixture was quenched with water and extracted with ethyl acetate (3 × 20 mL). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude compound was purified by Combiflash column chromatography and eluted with n-hexane solution of 0-20% ethyl acetate to give 850 mg (100% yield) of compound 85-8 as a pale yellow solid. LCMS: [M+H] + =655.60; Rt=2.73min 1 H NMR(400MHz, CDCl3)δ:8.47-8.49(m,1H),7.98-8.03(m,2H),7.52-7.57(m,1H),7.41- 7.47(m,3H),7.31(d,J=8.31Hz,2H),7.23(d,J=3.42Hz,2H),7.18(d,J=7.83Hz,1H),7 .03(d,J=8.31Hz,2H),6.74(d,J=7.82Hz,2H),5.20-5.25(m,1H),5.09-5.15(m,1H),3 .79(t,J=6.85Hz,2H),2.73(t,J=6.85Hz,2H),2.16(s,3H),0.83(s,9H),0.00(s,6H).

[0407] A solution of tetrabutylammonium fluoride (1 M THF solution, 2 mL, 1.952 mmol) was added to a THF solution of 6-(4-(2-((tert-butyldimethylsilyl)oxy)ethyl)benzyl)-8-fluoro-3-(benzenesulfonyl)-7-(o-tolyl)-3,6-dihydropyrrolo[3,2-e]indazole 85-8 (850 mg, 1.301 mmol) in 15 mL of THF. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete (monitored by TLC and LCMS), the reaction mixture was quenched with water and extracted with ethyl acetate (3 × 30 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude compound was purified by Combiflash column chromatography, eluting with a solution of 30-40% ethyl acetate in n-hexane to give 360 ​​mg (51% yield) of compound 85-9 as a grayish-white solid. LCMS: [M+H] + =540.65; Rt=2.17min 1 H NMR(400MHz, CDCl3)δ:8.48(s,1H),7.98-8.05(m,3H),7.52-7.57(m,1H),7.42-7.48(m,3H),7.29-7.35(m,2H),7.24(d,J=3.45H z, 2H), 7.06 (d, J = 7.88Hz, 2H), 6.77 (d, J = 7.88Hz, 2H), 5.13-5.27 (m, 2H), 3.77-3.84 (m, 2H), 2.79 (t, J = 6.40Hz, 2H), 2.15 (s, 3H).

[0408] Triethylamine (0.23 mL, 1.948 mmol) was added to a CH₂Cl₂ (20 mL) solution of 2-(4-((8-fluoro-3-(benzenesulfonyl)-7-(o-tolyl)pyrrolo[3,2-e]indazole-6(3H)-yl)methyl)phenyl)ethyl-1-ol 85-9 (350 mg, 0.649 mmol), followed by toluenesulfonyl chloride (148 mg, 0.779 mmol). The reaction mixture was stirred at room temperature for 18 hours. After the reaction was complete (monitored by TLC and LCMS), the reaction mixture was quenched with water and extracted with ethyl acetate (2 × 20 mL). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude compound was purified by Combiflash column chromatography, eluting with a solution of 0–20% ethyl acetate in n-hexane to give 370 mg (45% yield) of compound 85-10 as a pale yellow solid. LCMS: [M+H] +=694.30; Rt=2.39min 1 H NMR (400MHz, CDCl3) δ: 8.49 (s, 1H), 8.03 (d, J = 9.35Hz, 1H), 7.98-8.01 (m, 2H), 7.65 (d, J =8.37Hz,2H),7.51-7.57(m,1H),7.40-7.47(m,4H),7.30-7.37(m,2H),7.23(s,1H),7.19 (d,J=7.88Hz,2H),6.95(d,J=7.88Hz,2H),6.72(d,J=7.88Hz,2H),5.19-5.26(m,1H),5.0 7-5.15(m,1H),4.13(t,J=7.14Hz,2H),2.87(t,J=6.89Hz,2H),2.37(s,3H),2.15(s,3H).

[0409] At room temperature, 120 mg (0.173 mmol) of 4-((8-fluoro-3-(benzenesulfonyl)-7-(o-tolyl)pyrrolo[3,2-e]indazole-6(3H)-yl)methyl)phenethyl 4-methylbenzenesulfonate 85-10 in acetonitrile-water (1:1, 4 mL) was added to an ethylamine solution (1.06 mL, 2.120 mmol of 2 M THF) and stirred for 72 hours. After the reaction was complete (monitored by TLC and LCMS), the reaction mixture was concentrated and diluted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography, eluting with 4-6% methanol in CH2Cl2 to give 95 mg (97% yield) of compound 85-11 as a white solid. LCMS: [M+H] + =567.20; Rt=1.64min

[0410] At room temperature, 1 mL of an aqueous solution of potassium carbonate (90.6 mg, 0.657 mmol) was added to a methanol (4 mL) solution of N-ethyl-2-(4-((8-fluoro-3-(benzenesulfonyl)-7-(o-tolyl)pyrrolo[3,2-e]indazole-6(3H)-yl)methyl)phenyl)ethyl-1-amine 85-11 (93 mg, 0.1643 mmol). The reaction mixture was heated under reflux for 2 hours. After the reaction was complete (monitored by TLC and LCMS), the reaction mixture was concentrated under reduced pressure, and the crude compound was purified by preparative HPLC to give 23 mg (33% yield) of D-85 as a grayish-white solid. LCMS: [M+H] + =427.25; Rt=1.39min 1 H NMR (400MHz, CDCl3) δ: 8.34 (s, 1H), 7.21-7.38 (m, 6H), 7.01 (d, J = 8.31Hz, 2H), 6.75 (d, J = 7.83Hz, 2H), 5.09-5 .25(m,2H),2.83-2.88(m,2H),2.74-2.78(m,2H),2.70(q,J=7.17Hz,2H),2.19(s,3H),1.11(t,J=7.09Hz,3H). N-(cyclopropylmethyl)-2-(4-(((8-fluoro-7-(o-tolyl))pyrrolo[3,2-e]indazole-6(3H)-yl)methyl)phenyl)ethyl-1-amine (D-88)

[0411] Cyclopropylmethylamine (122 mg, 1.731 mmol) and DIPEA (0.3 mL, 1.731 mmol) were added to a solution of 4-((8-fluoro-3-(benzenesulfonyl)-7-(o-tolyl)pyrrolo[3,2-e]indazole-6(3H)-yl)methyl)phenethyl 4-methylbenzenesulfonate 85-10 (120 mg, 0.173 mmol) in acetonitrile (10 mL) and sealed tubes. The reaction mixture was stirred at room temperature for 72 hours. After the reaction was complete (monitored by TLC and LCMS), the reaction mixture was concentrated and diluted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude compound was purified by Combiflash column chromatography, eluting with 0-6% methanol in CH2Cl2 solution to give 90 mg (88% yield) of compound 88-1 as a white solid. LCMS: [M+H] + =593.20; Rt=1.88min

[0412] At room temperature, 1 mL of an aqueous solution of potassium carbonate (83.7 mg, 0.607 mmol) was added to a methanol (4 mL) solution of N-(cyclopropylmethyl)-2-(4-((8-fluoro-3-(benzenesulfonyl)-7-(o-tolyl)pyrrolo[3,2-e]indazole-6(3H)-yl)methyl)phenyl)ethyl-1-amine 88-1 (90 mg, 0.152 mmol). The reaction mixture was heated under reflux for 2 hours. After the reaction was complete (monitored by TLC and LCMS), the reaction mixture was concentrated under reduced pressure, and the crude compound was purified by preparative HPLC to give 25 mg (36% yield) of D-88 as a grayish-white solid. LCMS: [M+H] + =453.25; Rt=1.45min 1H NMR(400MHz, CDCl3)δ:8.34(s,1H),7.23-7.37(m,6H),7.02(d,J=7.6Hz,2H),6.76(d,J=8.31Hz,2H),5.12-5.26(m,2H),2.85- 2.91(m,2H),2.73-2.79(m,2H),2.51(d,J=6.85Hz,2H),2.20(s,3H),0.87-0.98(m,1H),0.42-0.51(m,2H),0.05-0.14(m,2H). N-(4-((8-fluoro-7-(o-tolyl)pyrrolo[3,2-e]indazole-6(3H)-yl)methyl)phenethyl)cyclobutylamine (D-89)

[0413] In a sealed tube, 120 mg (0.173 mmol) of 4-((8-fluoro-3-(benzenesulfonyl)-7-(o-tolyl)pyrrolo[3,2-e]indazole-6(3H)-yl)methyl)phenethyl-4-methylbenzenesulfonate 85-10 in acetonitrile (10 mL) was added with cyclobutylamine (124 mg, 1.7316 mmol) and DIPEA (0.3 mL, 1.7316 mmol). The reaction mixture was stirred at room temperature for 72 hours. After the reaction was complete (monitored by TLC and LCMS), the reaction mixture was concentrated and diluted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude compound was purified by Combiflash column chromatography, eluting with 0–10% methanol in CH2Cl2 solution to give 101 mg (99% yield) of compound 89-1 as a white solid. LCMS: [M-18] + =575.25; Rt=1.66min

[0414] At room temperature, an aqueous solution of potassium carbonate (83 mg, 0.600 mmol) (1 mL) was added to a methanol (4 mL) solution of N-(4-((8-fluoro-3-(benzenesulfonyl)-7-(o-tolyl)pyrrolo[3,2-e]indazole-6(3H)-yl)methyl)phenethyl)cyclobutylamine 89-1 (85 mg, 0.150 mmol). The reaction mixture was heated under reflux for 2 hours. After the reaction was complete (monitored by TLC and LCMS), the reaction mixture was concentrated under reduced pressure, and the crude compound was purified by preparative HPLC to give 30 mg (44% yield) of D-89 as a grayish-white solid. LCMS: [M+H] + =453.25; Rt=1.45min 1H NMR(400MHz, CDCl3)δ:8.34(s,1H),7.27-7.38(m,5H),7.21-7.25(m,1H),7.01(d,J=7.83Hz,2H),6.75(d,J=7.82H z,2H),5.09-5.25(m,2H),3.22-3.30(m,1H),2.67-2.78(m,4H),2.20(s,3H),2.15-2.18(m,2H),1.62-1.69(m,5H). N-(4-((8-fluoro-7-(o-tolyl)pyrrolo[3,2-e]indazole-6(3H)-yl)methyl)phenethyl)cyclopropylamine (D-90)

[0415] Cyclopropylamine (98.7 mg, 1.731 mmol) and DIPEA (0.3 mL, 1.731 mmol) were added to a solution of 4-((8-fluoro-3-(benzenesulfonyl)-7-(o-tolyl)pyrrolo[3,2-e]indazole-6(3H)-yl)methyl)phenethyl 4-methylbenzenesulfonate 85-10 (120 mg, 0.173 mmol) in acetonitrile (10 mL) and sealed tubes. The reaction mixture was stirred at room temperature for 72 hours. After the reaction was complete (monitored by TLC and LCMS), the reaction mixture was concentrated and diluted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude compound was purified by Combiflash column chromatography, eluting with 0-10% methanol in CH2Cl2 solution to give 100 mg (99% yield) of compound 90-1 as a white solid. LCMS: [M+H] + =579.20; Rt=1.65min

[0416] At room temperature, 1 mL of an aqueous solution of potassium carbonate (100 mg, 0.726 mmol) was added to a methanol (4 mL) solution of N-(4-((8-fluoro-3-(benzenesulfonyl)-7-(o-tolyl)pyrrolo[3,2-e]indazole-6(3H)-yl)methyl)phenethyl)cyclopropylamine 90-1 (105 mg, 0.181 mmol). The reaction mixture was heated under reflux for 2 hours. After the reaction was complete (monitored by TLC and LCMS), the reaction mixture was concentrated under reduced pressure, and the crude compound was purified by preparative HPLC to give 32 mg (40% yield) of D-90 as a grayish-white solid. LCMS: [M+H] + =439.20; Rt=1.42min 1H NMR (400MHz, CDCl3) δ: 8.35 (s, 1H), 7.27-7.37 (m, 6H), 7.22-7.25 (m, 1H), 7.02 (d, J = 8.31Hz, 2H), 6.76 (d, J = 8.31Hz, 2H), 5. 10-5.26(m,2H),2.86-2.92(m,2H),2.69-2.74(m,2H),2.20(s,3H),2.07-2.12(m,1H),0.39-0.45(m,2H),0.29-0.35(m,2H). N-(4-((8-fluoro-7-(o-tolyl)pyrrolo[3,2-e]indazole-6(3H)-yl)methyl)phenethyl)propyl-1-amine (D-91)

[0417] In a sealed tube, propan-1-amine (102 mg, 1.731 mmol) and DIPEA (0.3 mL, 1.731 mmol) were added to a solution of 4-((8-fluoro-3-(benzenesulfonyl)-7-(o-tolyl)pyrrolo[3,2-e]indazole-6(3H)-yl)methyl)phenethyl 4-methylbenzenesulfonate D-85-10 (120 mg, 0.173 mmol) in acetonitrile (10 mL). The reaction mixture was stirred further at room temperature for 72 hours. After the reaction was complete, the reaction mixture was diluted with water and extracted with ethyl acetate (2 x 10 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude compound was purified by Combiflash column chromatography, eluting with 0–10% methanol in CH2Cl2 solution to give 85 mg (85% yield) of compound 91-1 as a grayish-white solid. LCMS: [M+H] + =581.25; Rt=1.86min

[0418] At room temperature, 1 mL of an aqueous solution of potassium carbonate (81 mg, mmol) was added to a methanol (4 mL) solution of N-(4-((8-fluoro-3-(benzenesulfonyl)-7-(o-tolyl)pyrrolo[3,2-e]indazole-6(3H)-yl)methyl)phenethyl)propyl-1-amine 91-1 (85 mg, 0.146 mmol). The reaction mixture was further heated under reflux at 70 °C and stirred for 2 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure, and the crude compound was purified by preparative HPLC to give 20 mg (31% yield) of D-91 as a grayish-white solid. LCMS: [M+H] + =441.20; Rt=1.62min 1H NMR (400MHz, CDCl3) δ: 8.35 (s, 1H), 7.52 (s, 1H), 7.28-7.37 (m, 4H), 7.20-7.23 (m, 1H), 6.99-7.03 (m, 2H), 6.76 (d, J = 7.82Hz, 2H), 5.10-5.2 6(m,2H),3.49(s,1H),2.77-2.84(m,2H),2.70-2.76(m,2H),2.56(t,J =7.34Hz, 2H), 2.20 (s, 3H), 1.43-1.50 (m, 2H), 0.87 (t, J = 7.34Hz, 3H). 2-Fluoro-N-(4-(((8-Fluoro-7-(o-tolyl)pyrrolo[3,2-e]indazole-6(3H)-yl)methyl)phenethyl)ethyl-1-amine (D-101)

[0419] Potassium phthalimide (43.2 mg, 0.294 mmol) was added to a DMF (5 mL) solution of 4-((8-fluoro-3-(benzenesulfonyl)-7-(o-tolyl)pyrrolo[3,2-e]indazole-6(3H)-yl)methyl)phenethyl 4-methylbenzenesulfonate 85-10 (170 mg, 0.245 mmol). The reaction mixture was further heated to 90 °C and stirred for 3 hours. After the reaction was complete, the reaction mixture was cooled to room temperature, quenched with water, and extracted with ethyl acetate (3 × 20 mL). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give 155 mg (95% yield) of compound 101-11 as a brown solid. LCMS Condition 1: [M+H] + =669.20; Rt=2.40min

[0420] Hydrazine hydrate (143 mg, 4.486 mmol) was added to a 40 mL ethanol solution of 2-(4-((8-fluoro-3-(benzenesulfonyl)-7-(o-tolyl)pyrrolo[3,2-e]indazole-6(3H)-yl)methyl)phenethyl)isoindoline-1,3-dione 101-11 (2 g, 2.990 mmol). The reaction mixture was further heated to 80 °C and stirred for 1 hour. After the reaction was complete, the reaction mixture was concentrated under reduced pressure, DCM for 15 minutes, and filtered. The filtrate was concentrated under reduced pressure to give a crude compound, which was purified by silica gel column chromatography, eluting with 0-5% methanol in DCM to give 1.1 g (68% yield) of compound 101-12 as a yellow solid. LCMS-Condition-1: [M-18] + =521.10; Rt=1.61min

[0421] At room temperature, 550 mg (1.021 mmol) of 2-(4-((8-fluoro-3-(benzenesulfonyl)-7-(o-tolyl)pyrrolo[3,2-e]indazol-6(3H)-yl)methyl)phenyl)ethyl-1-amine 101-12 in acetonitrile (4 mL) was added to DIPEA (1.77 mL, 10.21 mmol) and 1-fluoro-2-iodoethane (1.8 g, 10.21 mmol), and the mixture was stirred for 48 hours. After the reaction was complete, the reaction mixture was diluted with water and extracted with DCM (3 × 25 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography, eluting with 0–2% methanol in DCM to give 380 mg (63% yield) of compound 101-13A as a pale yellow solid. LCMS Condition 1: [M+H] + =585.15; Rt=1.71min 1 H NMR(400MHz, CDCl3)δ:8.39-8.50(m,1H),7.96-8.05(m,3H),7.50-7.58(m,1H),7.44( t,J=8.07Hz,3H),7.28-7.38(m,2H),7.20-7.24(m,2H),7.04(d,J=7.82Hz,2H),6.72- 6.81(m,2H),5.10-5.26(m,2H),4.61(t,J=4.40Hz,1H),4.49(t,J=4.40Hz,1H),2.98( t,J=4.16Hz,1H),2.90(t,J=6.85Hz,3H),2.75-2.83(m,2H),2.14(s,2H),2.11(s,1H).

[0422] Potassium carbonate (189 mg, 1.369 mmol) was added to a methanol (4 mL) solution of 2-fluoro-N-(4-((8-fluoro-3-(benzenesulfonyl)-7-(o-tolyl)pyrrolo[3,2-e]indazole-6(3H)-yl)methyl)phenethyl)ethyl-1-amine 101-13A (200 mg, 0.342 mmol) at room temperature. The reaction mixture was further heated under reflux at 60 °C and stirred for 3 hours. After the reaction was complete, the reaction mixture was diluted with water and extracted with DCM (3 × 25 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude compound. The crude compound was purified by silica gel column chromatography, eluting with 0–6% methanol in DCM to give 10 mg (6.5% yield) of D-101 as a grayish-white solid. LCMS Condition 1: [M+H] + =445.20; Rt=1.39min 1 H NMR(400MHz, CDCl3)δ:8.32(s,1H),7.30-7.36(m,2H),7.26(2H merged insolvent peak),7.19-7.24(m,2H),7.01(d,J=7.83Hz,2H),6.75(d,J=7.83Hz,2H),5.07-5.25(m,2H),4.62(t,J=4 .40Hz,1H),4.48-4.54(m,1H),3.03-3.07(m,1H),2.95-3.01(m,3H),2.80(t,J=7.09Hz,2H),2.19(s,3H). 3-Fluoro-N-(4-((8-Fluoro-7-(o-tolyl)pyrrolo[3,2-e]indazole-6(3H)-yl)methyl)phenethyl)propyl-1-amine (D-102)

[0423] At room temperature, 200 mg (0.371 mmol) of 2-(4-((8-fluoro-3-(benzenesulfonyl)-7-(o-tolyl)pyrrolo[3,2-e]indazol-6(3H)-yl)methyl)phenyl)ethyl-1-amine 101-12 in acetonitrile (3 mL) was added to DIPEA (0.16 mL, 0.742 mmol) and 1-fluoro-3-iodopropane (70 mg, 0.371 mmol), and the mixture was stirred for 48 hours. After the reaction was complete (monitored by TLC and LCMS), the reaction mixture was diluted with water and extracted with DCM (3 × 25 mL). The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography, eluting with 0–2% methanol in DCM to give 90 mg (40% yield) of compound 102-13B as a pale yellow solid. LCMS Condition 1: [M+H] + =599.15; Rt=1.67min 1H NMR(400MHz, CDCl3)δ:8.48(s,1H),7.98-8.05(m,2H),7.52-7.59(m,1H),7 .45(t,J=8.07Hz,2H),7.23-7.39(m,6H),7.05(d,J=7.82Hz,2H),6.76(d,J =7.34Hz,2H),5.09-5.26(m,2H),4.57(t,J=5.38Hz,1H),4.46(t,J=5.38Hz ,1H),2.88-3.02(m,4H),2.15(s,3H),1.98-2.05(m,2H),0.87-0.91(m,2H).

[0424] Potassium carbonate (72 mg, 0.526 mmol) was added to a methanol (3 mL) solution of 90 mg (90 mg, 0.150 mmol) of 3-fluoro-N-(4-((8-fluoro-3-(benzenesulfonyl)-7-(o-tolyl)pyrrolo[3,2-e]indazole-6(3H)-yl)methyl)phenethyl)propyl-1-amine 102-13B at room temperature. The reaction mixture was heated under reflux for 20 min. After the reaction was complete (monitored by TLC and LCMS), the reaction mixture was quenched with water and extracted with ethyl acetate (3 × 25 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography, eluted with 0–3% methanol in DCM solution, and then ground in diethyl ether and n-pentane to give 30 mg (43% yield) of D-102 as a grayish-white solid. LCMS Condition 1: [M+H] + =459.60; Rt=1.41min 1 H NMR (400MHz, CDCl3) δ: 8.35 (s, 1H), 7.27-7.36 (m, 5H), 7.21-7.24 (m, 1H), 7.02 (d, J = 7.82Hz, 2H), 6.76 (d, J = 7.82Hz, 2H), 5.09-5 .26(m,2H),4.53(t,J=5.87Hz,1H),4.41(t,J=5.87Hz,1H),2.78-2.84(m,2H),2.69-2.75(m,4H),2.20(s,3H),1.76-1.90(m,4H). (5R,6S)-5-(4-(2-(ethylamino)ethyl)phenyl)-6-phenyl-5,6,7,8-tetrahydronaphthalene-2-ol (LA-18)

[0425] In a sealed tube at room temperature, a mixture of 6-methoxy-3,4-dihydronaphthyl-1(2H)-one L18-1 (20 g, 120.5 mmol), benzyl bromide (22.7 g, 144.5 mmol), and cesium carbonate (117 g, 359.1 mmol) in xylene (200 mL) was degassed with argon for 15 min. Pd(OAc)₂ (1.34 g, 5.982 mmol) and Xanthphos (3.5 g, 6.055 mmol) were added to the resulting solution, and degassed for another 15 min. The reaction mixture was appropriately sealed and heated to 130 °C for 24 h. After the reaction was complete (monitored by TLC and LCMS), the reaction mixture was diluted with water and extracted with ethyl acetate (3x). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography and eluted with n-hexane solution of 0-10% ethyl acetate to give 10 g (33% yield) of compound L18-2 as a grayish-white solid. LCMS - Condition 01: [M+H] + =253.05; Rt=1.95min 1 H NMR(400MHz, DMSO-d6)δ:7.87(d,J=9.29Hz,1H),7.29-7.34(m,2H),7.22-7.26(m,1H),7.17(d,J=7.34Hz,2H),6.89-6 .95(m,2H),3.88(d,J=4.89Hz,1H),3.85(s,3H),3.06-3.16(m,1H),2.95(td,J=4.04,16.87Hz,1H),2.21-2.39(m,2H).

[0426] PBr3 (12 g, 44.42 mmol) was added to a toluene (100 mL) solution of 10 g (36.76 mmol) of 6-methoxy-2-phenyl-3,4-dihydronaphthyl-1(2H)-one L18-2 at room temperature. The reaction mixture was heated under reflux for 16 hours. After the reaction was complete (monitored by TLC and LCMS), the reaction mixture was quenched with water and extracted with ethyl acetate (3×). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude compound was purified by silica gel column chromatography, eluting with a solution of 0–5% ethyl acetate in n-hexane to give 9 g (77% yield) of compound L18-3 as a white solid. LCMS - Condition 01: [M+H] + =315.00; Rt=2.46min 1H NMR(400MHz,DMSO-d6)δ:7.50-7.55(m,1H),7.35-7.43(m,4H),7.29-7.35(m ,1H),6.84-6.88(m,2H),3.79(s,3H),2.88-2.95(m,2H),2.63-2.69(m,2H).

[0427] In a sealed tube, 8 mL of an aqueous solution of cesium carbonate (6.2 g, 19.04 mmol) was added to a DMF solution of 4-bromo-7-methoxy-3-phenyl-1,2-dihydronaphthalene L18-3 (2 g, 6.349 mmol) and 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenyl)ethane-1-ol (1.57 g, 6.349 mmol) and degassed with argon for 20 min. Palladium acetate (71 mg, 0.316 mmol) and TPP (166 mg, 0.633 mmol) were added sequentially to the resulting solution, and degassed for another 15 min. The reaction mixture was heated at 100 °C for 16 h. After the reaction was complete (monitored by TLC and LCMS), the reaction mixture was cooled to room temperature, quenched with ice water, and extracted with ethyl acetate (3x). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude compound was purified by silica gel column chromatography, eluting with n-hexane solution of 0-15% ethyl acetate to give 1 g (44% yield) of compound L18-4 as a yellow solid. LCMS Condition 1: [M+H] + =357.10; Rt=2.31min 1 H NMR (400MHz, DMSO-d6) δ: 7.09 (d, J = 7.34Hz, 4H), 7.04 (d, J = 6.85Hz, 1H), 6.99-7.03 (m, 2H), 6.90 (d, J = 8.31Hz, 2H), 6.85 (d, J = 1.96Hz, 1H), 6.64 (d d,J=2.45,8.31Hz,1H),6.51(d,J=8.80Hz,1H),4.63(t,J=5.38Hz,1H),3 .74(s,3H),3.56-3.64(m,2H),2.87-2.94(m,2H),2.69(t,J=7.34Hz,4H).

[0428] At room temperature, triethylamine (0.9 mL, 6.734 mmol) and toluenesulfonyl chloride (481 mg, 2.525 mmol) were added to a DCM (10 mL) solution of 600 mg (1.683 mmol) of 2-(4-(6-methoxy-2-phenyl-3,4-dihydronaphth-1-yl)phenyl)ethyl-1-ol L18-4. The mixture was stirred for 18 hours until the reaction was complete (monitored by TLC and LCMS). The reaction mixture was then quenched with water and extracted with ethyl acetate 2 (3x). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography, eluting with a solution of 0-15% ethyl acetate in n-hexane to give 600 mg (70% yield) of compound L18-5 as a colorless viscous liquid. LCMS Condition 1: [M+H] + =511.20; Rt=2.60min 1 H NMR(400MHz, DMSO-d6)δ:7.76(d,J=8.31Hz,2H),7.48(d,J=8.31Hz,2H),7.02-7.17(m,7H),6.95(d,J=7.83Hz,2H),6.90(d,J=2.45Hz,1H),6 .69(dd,J=2.69,8.56Hz,1H),6.52(d,J=8.31Hz,1H),4.26(t,J=6.36Hz,2H),3.79(s,3H),2.89-2.98(m,4H),2.72-2.77(m,2H),2.45(s,3H).

[0429] In a sealed tube, ethylamine (240 mg, 5.876 mmol) and DIPEA (1.02 mL, 5.786 mmol) were added to a solution of 300 mg (0.587 mmol) of 4-(6-methoxy-2-phenyl-3,4-dihydronaphth-1-yl)phenethyl 4-methylbenzenesulfonate L18-5 in acetonitrile (2 mL). The reaction mixture was stirred for 3 days at room temperature. After the reaction was complete (monitored by TLC and LCMS), the reaction mixture was diluted with water and extracted with ethyl acetate (2×). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography, eluting with 0–10% methanol in CH2Cl2 solution to give 160 mg (71% yield) of compound L18-6 as a colorless semi-solid. LCMS Condition 1: [M+H] + =384.20; Rt=1.81min

[0430] 10% palladium / carbon (200 mg) was added to a 20 mL solution of N-ethyl-2-(4-(6-methoxy-2-phenyl-3,4-dihydronaphthyl-1-yl)phenyl)ethyl-1-amine L18-6 (160 mg, 0.417 mmol) in ethyl acetate at room temperature under a nitrogen atmosphere. The reaction mixture was stirred for 18 hours at room temperature under a hydrogen atmosphere. After the reaction was complete (monitored by TLC and LCMS), the reaction mixture was passed through a Celite filter. TM The solution was filtered through a pad and washed with methanol. The filtrate was concentrated under reduced pressure to give 150 mg (94% yield) L18-7 as a colorless, viscous solid. LCMS Condition 1: [M+H] + =386.20; Rt=1.39 / 1.83min

[0431] Boron tribromide (0.07 mL, 0.770 mmol) was added dropwise to a solution of N-ethyl-2-(4-(((1R,2S)-6-methoxy-2-phenyl-1,2,3,4-tetrahydronaphthyl-1-yl)phenyl)ethyl-1-amine L18-7 (150 mg, 0.389 mmol) in 15 mL of CH2Cl2 at 0 °C. The reaction mixture was stirred for 45 min at the same temperature. After the reaction was complete (monitored by TLC and LCMS), the reaction mixture was quenched with saturated NaHCO3 solution and extracted with CH2Cl2 (3X). The separated organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude compound was purified by preparative HPLC to give 62 mg (43% yield) of LA-18 (TFA salt) as a grayish-white solid. LCMS Condition 1: [M+H] + =372.20; Rt=1.62min 1 H NMR(400MHz,DMSO-d6)δ:9.15(br.s,1H),8.36(br.s,2H),7.10-7.17(m,3H),6.80-6 .88(m,3H),6.59-6.66(m,2H),6.49(dd,J=2.45,8.31Hz,1H),6.35(d,J=8.31Hz,2H), 4.21-4.26(m,1H),3.43-3.58(m,2H),3.35(dd,J=3.91,12.23Hz,1H),2.88-3.08(m, 5H),2.69-2.77(m,2H),2.01-2.17(m,1H),1.69-1.77(m,1H),1.15(t,J=7.34Hz,3H). (5R,6S)-5-(4-(2-(((cyclopropylmethyl)amino)ethyl)phenyl)-6-phenyl-5,6,7,8-tetrahydronaphthalene-2-ol (LA-19)

[0432] Cyclopropylmethylamine (417 mg, 5.876 mmol) and DIPEA (1.02 mL, 5.876 mmol) were added to a 2 mL solution of 4-(6-methoxy-2-phenyl-3,4-dihydronaphth-1-yl)phenethyl 4-methylbenzenesulfonate L18-5 (300 mg, 0.587 mmol) in acetonitrile (2 mL). The reaction mixture was stirred at room temperature for 3 days. After the reaction was complete (monitored by TLC and LCMS), the reaction mixture was diluted with water and extracted with ethyl acetate (2×). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography, eluting with 0–10% methanol in CH₂Cl₂ solution to give 160 mg (66% yield) of compound L19-6 as a colorless semi-solid. LCMS-condition-1: [M+H] + =410.20; Rt=1.86min

[0433] 10% palladium / carbon (200 mg) was added to a 20 mL solution of N-(cyclopropylmethyl)-2-(4-(6-methoxy-2-phenyl-3,4-dihydronaphthyl-1-yl)phenyl)ethyl-1-amine L19-6 (160 mg, 0.390 mmol) in ethyl acetate at room temperature and under a nitrogen atmosphere. The reaction mixture was further stirred for 18 hours at room temperature and under a hydrogen atmosphere. After the reaction was complete (monitored by TLC and LCMS), the reaction mixture was passed through a Celite filter. TM The mixture was filtered through a pad and washed with methanol. The filtrate was concentrated under reduced pressure to give 150 mg (94% yield) of compound L19-7 as a colorless viscous solid. LCMS Condition 1: [M+H] + =412.25; Rt=1.89min

[0434] Boron tribromide (0.07 mL, 0.729 mmol) was added dropwise to a solution of N-(cyclopropylmethyl)-2-(4-(((1R,2S)-6-methoxy-2-phenyl-1,2,3,4-tetrahydronaphthyl-1-yl)phenyl)ethyl-1-amine L19-7 (150 mg, 0.364 mmol) in 15 mL of CH2Cl2 at 0 °C. The reaction mixture was stirred for 45 min at the same temperature. After the reaction was complete (monitored by TLC and LCMS), the reaction mixture was quenched with saturated NaHCO3 solution and extracted with CH2Cl2 (3X). The separated organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude compound was purified by preparative HPLC to give 34 mg (24% yield) of LA-19 (TFA salt) as a grayish-white solid. LCMS Condition 1: [M+H] + =398.25; Rt=1.68min 1 H NMR(400MHz,DMSO-d6)δ:9.16(br.s,1H),8.49(br.s,2H),7.08-7.18(m,3H),6.84(dd,J=8.07,11 .49Hz,4H),6.60-6.65(m,2H),6.48(dd,J=1.96,8.31Hz,1H),6.35(d,J=7.82Hz,2H),4.24(d,J=4. 89Hz,1H),3.35(dd,J=2.93,13.20Hz,1H),2.92-3.08(m,4H),2.72-2.84(m,4H),2.02-2.15(m,1H ),1.70-1.78(m,1H),0.99(ddd,J=4.65,8.07,12.23Hz,1H),0.53-0.60(m,2H),0.28-0.35(m,2H). (5R,6S)-5-(4-(2-(ethylamino)ethyl)phenyl)-6-(o-tolyl)-5,6,7,8-tetrahydronaphthalene-2-ol (LA-21)

[0435] A mixture of 6-methoxy-3,4-dihydronaphthyl-1(2H)-one L18-1 (5 g, 28.41 mmol), 2-bromotoluene (5 mL, 42.10 mmol), and cesium carbonate (32.4 g, 99.41 mmol) in xylene (125 mL) was degassed with argon for 10 min. Pd(OAc)2 (636 mg, 2.839 mmol) and fulvic acid (2.5 g, 4.251 mmol) were added to the resulting solution, and degassed with argon for another 15 min at room temperature. The reaction mixture was heated at 130 °C for 24 h. After the reaction was complete (monitored by TLC and LCMS), the reaction mixture was cooled to room temperature and filtered; the filtrate was concentrated under reduced pressure. The resulting crude substance was purified by silica gel column chromatography, eluting with 0–8% ethyl acetate in n-hexane to give 3.3 g (44% yield) of compound L21-2 as a yellow solid. LCMS - Condition 01: [M+H] + =267.05; Rt=2.18min 1 H NMR(400MHz, CDCl3)δ:8.09(d,J=8.80Hz,1H),7.13-7.27(m,3H),7.02-7.08(m,1H),6.87(dd,J=2.45,8.80Hz,1H) ,6.75(d,J=2.45Hz,1H),3.90-3.99(m,1H),3.88(s,3H),2.97-3.15(m,2H),2.35-2.45(m,2H),2.32-2.35(m,3H).

[0436] PBr3 (2 mL, 21.42 mmol) was added dropwise to a toluene (150 mL) solution of 8.2 g (30.76 mmol) of 6-methoxy-2-(o-tolyl)-3,4-dihydronaphthyl-1(2H)-one L21-2 at 0 °C. The reaction mixture was then heated under reflux for 16 hours. After the reaction was complete (monitored by TLC and LCMS), the reaction mixture was washed with saturated NaHCO3 solution, and the separated organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography, eluting with 0–8% ethyl acetate in n-hexane to give 7 g (69% yield) of compound L21-3 as a grayish-white solid. LCMS - Condition 01: [M+H] + =329.30; Rt=2.53min 1H NMR (400MHz, CDCl3) δ: 7.62 (d, J = 8.80Hz, 1H), 7.17-7.26 (m, 3H), 7.08-7.12 (m, 1H), 6.79 (dd, J = 2.69 ,8.56Hz,1H),6.73(d,J=2.45Hz,1H),3.84(s,3H),2.87-3.04(m,2H),2.54-2.61(m,2H),2.30(s,3H).

[0437] In a sealed tube, 8 mL of an aqueous solution of cesium carbonate (5.9 g, 18.23 mmol) was added to a DMF solution of 4-bromo-7-methoxy-3-(o-tolyl)-1,2-dihydronaphthalene L21-3 (2 g, 6.349 mmol) and 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenyl)ethyl-1-ol (1.5 g, 6.079 mmol) in 40 mL, and the mixture was degassed with argon for 20 min. Palladium acetate (68 mg, 0.304 mmol) and TPP (166 mg, 0.633 mmol) were added to the resulting solution, and degassed for another 15 min. The reaction mixture was then heated at 100 °C for 16 h. After the reaction was complete (monitored by TLC and LCMS), the reaction mixture was cooled to room temperature, diluted with ice water, and extracted with ethyl acetate (3x). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude compound was purified by silica gel column chromatography, eluting with a hexane solution of 0-15% ethyl acetate to give 1 g (44% yield) of compound L21-4 as a yellow solid. LCMS Condition 1: [M+H] + =371.35; Rt=2.21min 1 H NMR(400MHz, DMSO-d6)δ:7.95(s,1H),6.88-7.02(m,6H),6.84(d,J=7.34Hz,2H),6.79(br.s,1H),6.57(d,J=8.31Hz,1H),6.45(d ,J=8.31Hz,1H),3.68(s,3H),3.52(t,J=7.09Hz,2H),2.77-2.84(m,2H),2.59(t,J=6.85Hz,2H),2.34-2.45(m,2H),2.09(s,3H).

[0438] Triethylamine (1.19 mL, 8.613 mmol) and toluenesulfonyl chloride (618 mg, 3.241 mmol) were added to a DCM (10 mL) solution of 2-(4-(6-methoxy-2-(o-tolyl)-3,4-dihydronaphthyl-1-yl)phenyl)ethyl-1-ol L21-4 (800 mg, 2.162 mmol) at room temperature, and the mixture was stirred for 18 hours. After the reaction was complete (monitored by TLC and LCMS), the reaction mixture was quenched with water and extracted with ethyl acetate (3x). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography, eluting with a solution of 0-15% ethyl acetate in n-hexane to give 700 mg (63% yield) of compound L21-5 as a colorless viscous solid. LCMS - Conditions - 1: [M + H2O] + =542.70; Rt=2.49min

[0439] 10% palladium / carbon (800 mg) was added to a 30 mL solution of 4-(6-methoxy-2-(o-tolyl)-3,4-dihydronaphthyl-1-yl)phenethyl 4-methylbenzenesulfonate L21-5 (700 mg, 1.334 mmol) in ethyl acetate at room temperature under a nitrogen atmosphere. The reaction mixture was stirred for 18 hours at room temperature under a hydrogen atmosphere. After the reaction was complete (monitored by TLC and LCMS), the reaction mixture was passed through a Celite filter. TM The mixture was filtered through a pad and washed with methanol. The filtrate was concentrated under reduced pressure to give 499 mg (70% yield) of compound L21-6 as a colorless viscous liquid. LCMS Condition 1: [M+Na] + =549.20; Rt=2.46min

[0440] In a sealed tube, ethylamine (171 mg, 3.802 mmol) and DIPEA (0.66 mL, 3.802 mmol) were added to a solution of 200 mg (0.380 mmol) of 4-(6-methoxy-2-(o-tolyl)-1,2,3,4-tetrahydronaphth-1-yl)phenethyl 4-methylbenzenesulfonate L21-6 in acetonitrile (2 mL). The reaction mixture was stirred for 3 days at room temperature. After the reaction was complete (monitored by TLC and LCMS), the reaction mixture was diluted with water and extracted with ethyl acetate (3×). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography, eluting with 0–10% methanol in CH2Cl2 solution to give 150 mg (99% yield) of compound L21-7 as a colorless semi-solid. LCMS Condition 1: [M+H] + =400.25; Rt=1.86min

[0441] Boron tribromide (0.05 mL, 0.595 mmol) was added dropwise to a solution of N-ethyl-2-(4-(((1R,2S)-6-methoxy-2-(o-tolyl)-1,2,3,4-tetrahydronaphth-1-yl)phenyl)ethyl-1-amine L21-7 (119 mg, 0.297 mmol) in 15 mL of CH2Cl2 at 0 °C. The reaction mixture was stirred for 45 min at the same temperature. After the reaction was complete (monitored by TLC and LCMS), the reaction mixture was quenched with saturated NaHCO3 solution and extracted with CH2Cl2. The separated organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude compound was purified by preparative HPLC to give 20 mg (16% yield) of LA-21 as a grayish-white solid. LCMS Condition 1: [M+H] + =386.20; Rt=1.44min 1 H NMR (400MHz, DMSO-d6) δ: 9.14 (br.s, 1H), 7.16 (d, J = 7.83Hz, 1H), 7.00 (t, J = 7.58Hz, 1H), 6.80 (d, J = 7.82Hz, 2H), 6. 74(t,J=7.34Hz,1H),6.66(d,J=8.31Hz,1H),6.62(d,J=1.96Hz,1H),6.49(dd,J=2.45,8.31Hz,1H),6.25(d,J=7.82 Hz,2H),6.09(d,J=7.82Hz,1H),4.24(d,J=4.89Hz,1H),3.46(dd,J=4.16,12.47Hz,1H),2.93-3.02(m,2H),2.63-2. 71(m,2H),2.56(q,J=6.85Hz,4H),2.44(s,3H),2.10-2.22(m,2H),1.61(d,J=11.25Hz,1H),0.99(t,J=7.09Hz,3H). (5R,6S)-5-(4-(2-(((cyclopropylmethyl)amino)ethyl)phenyl)-6-(o-tolyl)-5,6,7,8-tetrahydronaphthalene-2-ol (LA-22)

[0442] Cyclopropyl methylamine (269 mg, 3.802 mmol) and DIPEA (0.66 mL, 3.802 mmol) were added to a 2 mL solution of acetonitrile containing 200 mg (200 mg, 0.380 mmol) of 4-(6-methoxy-2-(o-tolyl)-1,2,3,4-tetrahydronaphth-1-yl)phenethyl-4-methylbenzenesulfonate 22-7 in a sealed tube. The reaction mixture was stirred at room temperature for 3 days. After the reaction was complete (monitored by TLC and LCMS), the reaction mixture was diluted with water and extracted with ethyl acetate (2×). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography, eluting with 0–5% methanol in CH₂Cl₂ solution to give 120 mg (74% yield) of compound 22-7 as a colorless semi-solid. LCMS Condition 1: [M+H] + =426.25; Rt=1.90min

[0443] Boron tribromide (0.08 mL, 0.563 mmol) was added dropwise to a solution of N-(cyclopropylmethyl)-2-(4-(((1R,2S)-6-methoxy-2-(o-tolyl)-1,2,3,4-tetrahydronaphth-1-yl)phenyl)ethyl-1-amine 22-7 (120 mg, 0.281 mmol) in 12 mL of CH2Cl2 at 0 °C. The reaction mixture was then stirred at the same temperature for 45 min. After the reaction was complete (monitored by TLC and LCMS), the reaction mixture was quenched with saturated NaHCO3 solution and extracted with CH2Cl2 (3X). The separated organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude compound was purified by preparative HPLC to give 30 mg (24% yield) of LA-22 (TFA salt) as a grayish-white solid. LCMS - Conditions - 1: [M+H] + =412.20; Rt=1.71min 1H NMR (400MHz, DMSO-d6) δ: 9.16 (br.s, 1H), 8.47 (br.s, 2H), 7.17 (d, J = 7.34Hz, 1H), 7.01 (t, J = 7.09Hz, 1H), 6. 85(d,J=7.82Hz,2H),6.76(t,J=7.34Hz,1H),6.57-6.68(m,2H),6.49(dd,J=2.69,8.07Hz,1H),6.31(d,J=7. 82Hz,2H),6.09(d,J=7.82Hz,1H),4.26(d,J=4.89Hz,1H),3.47(m,1H),2.93-3.09(m,4H),2.71-2.83(m,4H) ,2.45(s,3H),2.09-2.21(m,1H),1.59-1.67(m,1H),0.95-1.06(m,1H),0.54-0.61(m,2H),0.29-0.35(m,2H). 5-(4-(2-(ethylamino)ethyl)phenyl)-6-(4-isopropylphenyl)-5,6,7,8-tetrahydronaphthalene-2-ol (LA-31)

[0444] In a sealed tube, 1-bromo-4-isopropylbenzene (6.78 g, 34.07 mmol) was added to a xylene (125 mL) solution of 6-methoxy-3,4-dihydronaphthyl-1(2H)-one L31-1 (5 g, 28.41 mmol), followed by the addition of cesium carbonate (32.4 g, 99.41 mmol), and degassed with argon for 15 min. Pd(OAc)₂ (636 mg, 2.839 mmol) and fulvic acid (2.5 g, 4.251 mmol) were added to the resulting solution, and degassed for another 15 min. The reaction mixture was then properly sealed and heated to 130 °C for 24 h. After the reaction was complete (monitored by TLC and LCMS), the reaction mixture was passed through a Celite tube. TM The mixture was filtered through a filter pad, and the filtrate was concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography, eluting with a solution of 0-10% ethyl acetate in n-hexane to give 2.5 g (30% yield) of compound L31-2 as a brown oil. LCMS Condition 1: [M+H] + =295.05; Rt=2.22min 1H NMR(400MHz, DMSO-d6)δ:7.87(d,J=8.31Hz,1H),7.15-7.20(m,2H),7.08(d,J=8.31Hz,2H),6.89-6.94(m,2H),3.84(s ,3H),3.80(dd,J=4.89,11.25Hz,1H),3.02-3.13(m,1H),2.82-2.98(m,2H),2.20-2.36(m,2H),1.20(d,J=6.85Hz,6H).

[0445] PBr3 (1.2 mL, 12.74 mmol) was added dropwise to a toluene (50 mL) solution of 2-(4-isopropylphenyl)-6-methoxy-3,4-dihydronaphthyl-1(2H)-one L31-2 (2.5 g, 8.503 mmol) at 0 °C. The reaction mixture was then heated at 100 °C for 16 hours. After the reaction was complete (monitored by TLC and LCMS), the reaction mixture was quenched with saturated Na...

Claims

1. A compound according to formula I', or a pharmaceutically acceptable salt thereof, in: B is nitrogen or carbon; D is carbon; A is a fused ring system selected from the group consisting of: Each R e independently selected from hydrogen, halogen, OH, O(CO)R, O(CO)NR 1 R 2 、OPO 3 、OSO 3 、O(SO 2 )NR 1 R 2 , or where two adjacent R e Together they form: R is C 1 -C 6 Alkyl or aryl; R 1 and R 2 are independently hydrogen or C 1 -C 6 alkyl; Each R 3 For hydrogen, C 1 -C 12 Acyl; C 1 -C 12 acyloxy; Each R 4 are independently hydrogen, C 1 -C 3 Alkyl, fluorine or chlorine; Each R h are independently selected from hydrogen or CH 3 ; R g For hydrogen, C 1 -C 3 Alkyl, C 1 -C 3 Fluoroalkyl, CN, fluorine, chlorine or bromine; R a Each independently selected from: H, C 1 -C 3 Alkyl, C 1 -C 3 Fluoroalkyl, phenyl (optionally selected from fluorine, chlorine, C 1 -C 3 Alkyl, CN, OC 1 -C 3 alkyl, 1-3 OH groups substituted), OH, OC 1-3 Alkyl, CN, fluorine, chlorine, O(CO)R, O(CO)NR 1 R 2 , OPO 3 , OSO 3 , O(SO 2 )NR 1 R 2 , or two adjacent Ra together form: When B is carbon, X is O, S, CH 2 , NH or a bond, or when B is nitrogen, X is CH 2 or key; Y and Z are each independently selected from CR f or N; U and V are each independently selected from CR a or N; Each R f Independently H, C 1 -C 3 Alkyl, OC 1 -C 3 Alkyl, fluorine or chlorine; and W is –CHR'-CHR'-NH-C 1 -C 4 Alkyl, -CHR'-CHR'-NH-C 1 -C 4 Fluoroalkyl, -CHR'-CHR'-NH-C 3 -C 6 Cycloalkyl, -CHR'-CHR'-NH-C 1 -C 4 Alkyl-C 3 -C 6 Cycloalkyl, Wherein each R' is independently H or C 1 -C 3 alkyl.

2. The compound according to claim 1, in, W is –CH 2 -CH 2 -NH-CH 2 -CH 2 -CH 3 ; –CH 2 -CH 2 -NH-CH 2 -CH 2 -CH 2 F; or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 1, in, A is:

4. The compound according to claim 1, in, Y and Z are CR f , and U and V are CR a .

5. The compound according to claim 1, which has a structure according to formula II' in: Each R a Independently selected from H, C 1 -C 3 Alkyl, phenyl (optionally selected from fluorine, chlorine, C 1 -C 3 Alkyl, CN, OC 1 -C 3 alkyl, 1-3 OH groups substituted), OH, OC 1-3 Alkyl, CN, fluorine, chlorine, O(CO)R, O(CO)NR 1 R 2 , OPO 3 , OSO 3 , O(SO 2 )NR 1 R 2 , or two adjacent R a Together they form: R is C 1 -C 6 Alkyl or aryl; R 1 and R 2 are independently hydrogen or C 1 -C 6 alkyl; Each R 3 are independently hydrogen; C 1 -C 12 Acyl or C 1 -C 12 acyloxy; Each R 4 are independently hydrogen, C 1 -C 3 Alkyl, fluorine or chlorine; Each R e independently selected from hydrogen, halogen, OH, O(CO)R, O(CO)NR 1 R 2 、OPO 3 、OSO 3 、O(SO 2 )NR 1 R 2 , or where two adjacent R e Together they form: Each R f Independently H, C 1 -C 3 Alkyl, OC 1 -C 3 Alkyl, fluorine or chlorine; R g For hydrogen, C 1 -C 3 Alkyl, C 1 -C 3 Fluoroalkyl, CN, fluorine, chlorine or bromine; X is CH 2 or key; Y and Z are each independently selected from CR f or N; U and V are each independently selected from CR a or N; and W is –CHR'-CHR'-NH-C 1 -C 4 Alkyl, -CHR'-CHR'-NH-C 1 -C 4 Fluoroalkyl, -CHR'-CHR'-NH-C 3 -C 6 Cycloalkyl, -CHR'-CHR'-NH-C 1 -C 4 Alkyl-C 3 -C 6 Cycloalkyl, Wherein each R' is independently H or C 1 -C 3 alkyl; or a pharmaceutically acceptable salt thereof.

6. The compound according to claim 5, in: X is CH 2 ; Y and Z are CR respectively f ; U and V are CR respectively a ; R g is F, Cl or CH 3 ; Ra are each independently selected from H, OH, CH 3 and Cl; each R f is H; W is –CH 2 -CH 2 -NH-CH 2 -CH 2 -CH 3 , –CH 2 -CH 2 -NH-CH 2 -CH 2 -CH 2 F. or a pharmaceutically acceptable salt thereof.

7. The compound according to claim 6, in, Each R e are independently selected from hydrogen, OH, or wherein two adjacent R e Together they form: Among them, R 3 is H, and R 4 For H.

8. The compound according to claim 1, which has a structure according to Formula III': in: Q is H or F; Rg is F, Cl or CH 3 ; Ra is CH 3 , Cl or OMe; Ra' is H, F or OH; or a pharmaceutically acceptable salt thereof.

9. The compound according to claim 8, in, Rg is F.

10. The compound according to claim 9, in, Ra is CH 3 And Ra' is H.

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