Estrogen Receptor Modulating Compounds

Abstract

Described herein are compounds that are estrogen receptor modulators. Pharmaceutical compositions and medicaments containing the compounds described herein, as well as methods of using such estrogen receptor modulators, alone and in combination with other compounds, to treat diseases or conditions mediated by or dependent on the estrogen receptor, are also described.

Description

[Technical field]

[0001] REFERENCE TO RELATED APPLICATIONS This application claims priority under 35 USC §119(e) to U.S. Provisional Application No. 62 / 876,963, filed July 22, 2019, which is incorporated by reference in its entirety.

[0002] Technical Field Described herein are compounds, including pharma- ceutically acceptable salts, solvates, metabolites, prodrugs thereof, methods of making such compounds, pharmaceutical compositions containing such compounds, and methods of using such compounds to treat, prevent, or diagnose estrogen-sensitive, estrogen receptor-dependent, or estrogen receptor-mediated diseases or conditions. [Background technology]

[0003] background Estrogen receptor ("ER") is a ligand-activated transcriptional regulatory protein that mediates the induction of various biological effects through its interaction with endogenous estrogens. Endogenous estrogens include 17β-estradiol and estrone. Estrogen receptors have been found to have two isoforms, ER-α (ESR1) and ER-β (ESR2). Estrogen and estrogen receptors are associated with several diseases or conditions, such as breast cancer, lung cancer, ovarian cancer, colon cancer, prostate cancer, endometrial cancer, uterine cancer, and other diseases or conditions, such as infertility, osteoporosis, vaginal atrophy, dyspareunia, contraception, male hypogonadism, gynecomastia, breast pain, and therefore find use in the treatment of these and other conditions and diseases that may be at least partially attributable to the regulation of estrogen receptors.

[0004] Selective estrogen receptor modulators (SERMs) are a class of drugs that act on the estrogen receptor. They tend to be competitive ligands for the estrogen receptor. A feature that distinguishes these substances from pure ER agonists and antagonists (i.e., full agonists and silent antagonists) is that their actions differ in various tissues, thereby conferring the possibility of selectively inhibiting or stimulating estrogenic effects in various tissues. For example, ER-α is typically found as the predominant form in the female reproductive tract and mammary gland, while ER-β is found at higher levels in vascular endothelial cells, bone, and male prostate tissue. Because different tissues have different degrees of sensitivity to and activity of endogenous estrogens, SERMs produce estrogenic or antiestrogenic effects, and the proportion of intrinsic activity (IA) of the SERM, depending on the particular tissue in question. Furthermore, their levels in various tissues may change in response to physical development, aging, or disease states. Antagonism at the ER can occur through competitive inhibition, where one ligand displaces a more agonistic ligand (e.g., 17β-estradiol) and signals to a lesser or even lesser extent than the agonistic ligand. There is a second form of inhibition of ER-agonistic signaling, which involves the binding of a ligand to the ER and the induction of a conformation or conformations that induce degradation of the ER in the proteasome. Often, degradation is induced by ubiquination and / or palmoylation of the ER after a binding event of a degradation-inducing compound. Compounds that bind to the ER and promote its degradation are often referred to as selective estrogen receptor degraders ("SERDs"). Calling a compound a SERM or SERD is a common way of focusing on aspects of its pharmacology. After all, many compounds that function as SERMs, meaning that they have at least some agonistic activity in some (but not all) ER-expressing tissues, can also induce at least some receptor degradation.Thus, it should be understood that many or most compounds falling within the embodiments of the present invention will exhibit a range of SERM / SERD activity. Compounds of the present disclosure, whether SERM, SERD and SERM / SERD or not, will be capable of achieving the methods disclosed herein. Summary of the Invention

[0005] Summary of the Invention In one aspect, provided herein are compounds of formulas I-VI, D-105-D-110 or pharma- ceutically acceptable salts, solvates or prodrugs thereof that modify the effect of endogenous estrogen acting through ER and / or inducing ER degradation, and thus are useful as medicaments for the treatment or prevention of diseases or conditions in which the action of estrogen and / or estrogen receptor is related to the etiology or pathology of the disease or condition or contributes to at least one symptom of the disease or condition, where such action of estrogen and / or estrogen receptor is undesirable.In some embodiments, the compounds disclosed herein are selective estrogen receptor degrader compounds.

[0006] In one aspect, the compounds of Formulas I-VI, D-105-D-110, or pharma- ceutically acceptable salts, solvates or prodrugs thereof, are useful for treating ER-associated diseases or conditions, including, but not limited to, ER-α dysfunction associated with cancers such as breast cancer, including metastatic cancer, lung cancer, colorectal cancer, endometrial cancer, prostate cancer, ovarian cancer and uterine cancer.

[0007] In one aspect, compounds of formulas I-VI, D-105-D-110, and pharma- ceutically acceptable salts, solvates, metabolites, and prodrugs thereof are described herein. The compounds described herein are estrogen receptor modulators. In some embodiments, compounds of formulas I-VI, D-105-D-110 are estrogen receptor antagonists. In some embodiments, compounds of formulas I-VI, D-105-D-110 exhibit minimal estrogen receptor agonist activity. In some embodiments, in the context of cancer treatment, compounds of formulas I-VI, D-105-D-110 may provide improved therapeutic activity characterized by complete or longer lasting tumor regression, lower incidence or rate of development of resistance to treatment, and / or reduced tumor aggressiveness.

[0008] In some embodiments, the compounds disclosed herein have high specificity for estrogen receptor and have desirable tissue-selective pharmacological activity.Desirable tissue-selective pharmacological activity includes but is not limited to ER antagonist activity in breast cells and no ER agonist activity in uterine cells.In some embodiments, the compounds disclosed herein are estrogen receptor decomposers that show complete estrogen receptor antagonist activity with 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, presented herein are compounds selected from the group consisting of active metabolites, tautomers, pharma-ceutically acceptable solvates, pharma-ceutically acceptable salts, and prodrugs of the compounds of Formulas I-VI, D-105-D-110.

[0011] In one embodiment, the present invention provides a compound represented by formula I: [ka] (In the formula: X is hydrogen, C1-C3 alkyl, C1-C3 fluoroalkyl, CN, fluorine, chlorine or bromine; R is hydrogen, C1-C3 alkyl, C1-C3 fluoroalkyl, CN, fluorine, chlorine or bromine; Each R a is independently selected from: H, C1-C3 alkyl, C1-C3 fluoroalkyl, OH, O-C1-3 alkyl, CN, fluorine, chlorine, or phenyl optionally substituted with 1 to 3 groups selected from fluorine, chlorine, C1-C3 alkyl, CN, O-C1-C3 alkyl, and OH; Each R b is independently selected from: H, C1-C3 alkyl, C1-C3 fluoroalkyl, OH, O-C1-3 alkyl, CN, fluorine, chlorine, or phenyl optionally substituted with 1 to 3 groups selected from fluorine, chlorine, C1-C3 alkyl, CN, O-C1-C3 alkyl, and OH; Y and Z are each independently CR b or N; U and V are independent of each other. a or N; 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, [ka] and; where each R' is independently H or C1-C3 alkyl. or a pharma- ceutically acceptable salt thereof.

[0012] In some embodiments of formula I, W is -CH2-CH2-NH-CH2-CH2-CH3; -CH2-CH2-NH-CH2-CH2-CH2F; [ka] It is.

[0013] In some embodiments of formula I, Y and Z are each CR b where U and V are the CR a It is.

[0014] In some embodiments, Formula I is represented by Formula II: [ka] (In the formula: X is hydrogen, C1-C3 alkyl, C1-C3 fluoroalkyl, CN, fluorine, chlorine or bromine; R is hydrogen, C1-C3 alkyl, C1-C3 fluoroalkyl, CN, fluorine, chlorine or bromine; Each R a is independently selected from: H, C1-C3 alkyl, C1-C3 fluoroalkyl, OH, O-C1-3 alkyl, CN, fluorine, chlorine, or phenyl optionally substituted with 1 to 3 groups selected from fluorine, chlorine, C1-C3 alkyl, CN, O-C1-C3 alkyl, and OH; Each R b is independently selected from: H, C1-C3 alkyl, C1-C3 fluoroalkyl, OH, O-C1-3 alkyl, CN, fluorine, chlorine, or phenyl optionally substituted with 1 to 3 groups selected from fluorine, chlorine, C1-C3 alkyl, CN, O-C1-C3 alkyl, and OH; Y and Z are each independently CR b or N; U and V are independent of each other. a or N) or a pharma- ceutically acceptable salt thereof.

[0015] In some embodiments of formula II, X is hydrogen, methyl, fluorine, chlorine, or bromine; R is hydrogen, methyl, fluorine, chlorine, or bromine; Y and Z are each CR b and U and V are CR a and each R a is independently selected from H, fluorine or chlorine; each R b is independently selected from H, fluorine, or chlorine; or a pharma- ceutically acceptable salt thereof.

[0016] In some embodiments, Formula I and / or Formula II are represented by Formula III: [ka] (In the formula: X is hydrogen, C1-C3 alkyl, C1-C3 fluoroalkyl, CN, fluorine, chlorine or bromine; R is hydrogen, C1-C3 alkyl, C1-C3 fluoroalkyl, CN, fluorine, chlorine or bromine; Each R a is independently selected from: H, C1-C3 alkyl, C1-C3 fluoroalkyl, OH, O-C1-3 alkyl, CN, fluorine, chlorine, or phenyl optionally substituted with 1 to 3 groups selected from fluorine, chlorine, C1-C3 alkyl, CN, O-C1-C3 alkyl, and OH; Each R b is independently selected from: H, C1-C3 alkyl, C1-C3 fluoroalkyl, OH, O-C1-3 alkyl, CN, fluorine, chlorine, or phenyl optionally substituted with 1 to 3 groups selected from fluorine, chlorine, C1-C3 alkyl, CN, O-C1-C3 alkyl, and OH; U and V are independent of each other. a or N) or a pharma- ceutically acceptable salt thereof.

[0017] In some embodiments of formula III, X is hydrogen, methyl, fluorine, chlorine, or bromine; R is hydrogen, methyl, fluorine, chlorine, or bromine; U and V are each CR a and each R a is independently selected from H, fluorine or chlorine; each R b is independently selected from H, fluorine or chlorine.

[0018] In some embodiments of formula III, X is fluorine and R is fluorine or chlorine.

[0019] In some embodiments, Formula I, Formula II and / or Formula III are represented by Formula IV: [ka] (In the formula: X is hydrogen, C1-C3 alkyl, C1-C3 fluoroalkyl, CN, fluorine, chlorine or bromine; R is hydrogen, C1-C3 alkyl, C1-C3 fluoroalkyl, CN, fluorine, chlorine or bromine; Each R b are independently selected from: H, C1-C3 alkyl, C1-C3 fluoroalkyl, OH, O-C1-3 alkyl, CN, fluorine, chlorine, or phenyl optionally substituted with 1-3 groups selected from fluorine, chlorine, C1-C3 alkyl, CN, O-C1-C3 alkyl, and OH. or a pharma- ceutically acceptable salt thereof.

[0020] In some embodiments of Formula IV, X is hydrogen or fluorine, R is hydrogen, fluorine or chlorine, and each R b are independently hydrogen, fluorine or chlorine.

[0021] In some embodiments, Formula I, Formula II, Formula III and / or Formula IV is represented by Formula V: [ka] (In the formula: X is hydrogen, C1-C3 alkyl, C1-C3 fluoroalkyl, CN, fluorine, chlorine or bromine; R is hydrogen, C1-C3 alkyl, C1-C3 fluoroalkyl, CN, fluorine, chlorine or bromine; R b is selected from: H, C1-C3 alkyl, C1-C3 fluoroalkyl, OH, O-C1-3 alkyl, CN, fluorine, chlorine, or phenyl optionally substituted with 1 to 3 groups selected from fluorine, chlorine, C1-C3 alkyl, CN, O-C1-C3 alkyl, and OH. or a pharma- ceutically acceptable salt thereof.

[0022] In some embodiments of formula V, X is hydrogen or fluorine; R is hydrogen, fluorine or chlorine; R b is hydrogen, fluorine or chlorine.

[0023] In some embodiments, Formula I, Formula II and / or Formula III are represented by Formula VI: [ka] (In the formula: X is hydrogen, C1-C3 alkyl, C1-C3 fluoroalkyl, CN, fluorine, chlorine or bromine; R is hydrogen, C1-C3 alkyl, C1-C3 fluoroalkyl, CN, fluorine, chlorine or bromine; R a is selected from: H, C1-C3 alkyl, C1-C3 fluoroalkyl, OH, O-C1-3 alkyl, CN, fluorine, chlorine, or phenyl optionally substituted with 1 to 3 groups selected from fluorine, chlorine, C1-C3 alkyl, CN, O-C1-C3 alkyl, and OH; R b is selected from: H, C1-C3 alkyl, C1-C3 fluoroalkyl, OH, O-C1-3 alkyl, CN, fluorine, chlorine, or phenyl optionally substituted with 1 to 3 groups selected from fluorine, chlorine, C1-C3 alkyl, CN, O-C1-C3 alkyl, and OH. or a pharma- ceutically acceptable salt thereof.

[0024] In some embodiments of formula VI, X is hydrogen or fluorine; R is hydrogen, fluorine or chlorine; R a is C1-C3 alkyl, C1-C3 fluoroalkyl, chlorine or bromine; R b is hydrogen, fluorine or chlorine.

[0025] In some embodiments, Formula I is: [ka] or a pharma- ceutically acceptable salt thereof.

[0026] In certain embodiments, provided herein is a pharmaceutical composition comprising a compound selected from the group consisting of Formulas I-VI, D-105-D-110, and all structural embodiments described herein, and at least one pharma- ceutically acceptable excipient.

[0027] In certain embodiments, provided herein is a method of modulating an estrogen receptor in a cell comprising administering to the cell a compound, wherein the compound is selected from the group consisting of Formulas I-VI, D-105-D-110, and any structural embodiment described herein, or a pharma- ceutically acceptable salt thereof.

[0028] In one embodiment, provided herein is a method for identifying a compound capable of modulating an estrogen receptor, comprising contacting a cell expressing an estrogen receptor with a compound of formula I and monitoring the effect of the compound on the cell.

[0029] Also described herein are prodrugs of compounds selected from the group consisting of Formulae I-VI, D-105-D-110, and all structural embodiments described herein. Also described herein are pharma- ceutically acceptable salts of prodrugs of compounds selected from the group consisting of Formulae I-VI, D-105-D-110, and all structural embodiments described herein. In some embodiments, the pharma- ceutically acceptable salts of prodrugs of compounds of Formulae I-VI, D-105-D-110 are hydrochloride salts.

[0030] In some embodiments, described herein is a pharmaceutical composition comprising a compound selected from the group consisting of Formulae I-VI, D-105-D-110, and all structural embodiments described herein, or a pharma- ceutically acceptable salt or prodrug of a compound selected from the group consisting of Formulae I-VI, D-105-D-110, and all structural embodiments 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.

[0031] The present invention also provides a method of treating (e.g., preventing or ameliorating symptoms associated with, or reducing the incidence of, reducing the pathogenesis of, promoting recovery from, or delaying the onset of) a disease, syndrome, illness, or condition associated with insufficient or excessive estrogen levels in a mammal in need of such treatment, comprising administering to the mammal an effective amount of a compound selected from the group consisting of Formulae I-VI, D-105-D-110 and all structural embodiments described herein, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formulae I-VI, D-105-D-110, or one of the structural embodiments described herein, or a pharma-ceutically acceptable salt thereof, and a pharma-ceutically acceptable excipient. In certain embodiments, the mammal is a human.

[0032] In one aspect, the present invention provides a method for treating (e.g., preventing or ameliorating symptoms associated with, or reducing the incidence of, reducing the pathogenesis of, reversing, prostate cancer, breast cancer, endometrial cancer, lung cancer, hepatocellular carcinoma, lymphoma, multiple endocrine neoplasia, vaginal cancer, renal cancer, thyroid cancer, testicular cancer, leukemia, and ovarian cancer in a mammal in need of such treatment. The present invention describes a method of treating cancer (promoting or delaying the onset of cancer) in a mammal comprising administering to said mammal a compound selected from the group consisting of Formulae I-VI, D-105-D-110 and all structural embodiments described herein or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound selected from the group consisting of Formulae I-VI, D-105-D-110 and all structural embodiments described herein, such as a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient. In some embodiments, the mammal is a human. In some embodiments, the cancer is positive for expression of ESR1. In some embodiments, the cancer is resistant to a previous treatment of choice (e.g., a previous endocrinological treatment). In some embodiments, the cancer progresses after exposure to one or more agents selected from the group consisting of tamoxifen, toremifene, letrozole, aromasin, anastrazole, and faslodex. In some embodiments, the treatment is in an adjuvant setting, and in some embodiments, the treatment is in a metastatic setting. In certain embodiments, the SERD and / or SERMS compounds disclosed herein are combined with other active compounds, such as CDK4 / 6 inhibitors, PI3k inhibitors, mTOR inhibitors, taxanes, HER2 inhibitors, PARP inhibitors, BCL-2 inhibitors and MCL-1 inhibitors. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0033] Detailed Description of the Invention As used above and throughout this disclosure, the following terms, unless otherwise indicated, shall be understood to have the following meanings:

[0034] Unless otherwise indicated, the following terms used in this application, including the specification and claims, have the definitions set forth below. As used in the specification and the appended claims, it should be noted that the singular forms "a", "an" and "the" include plural referents unless the context clearly indicates otherwise. Conventional methods of mass spectrometry, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA technology and pharmacology are used unless otherwise indicated. In this application, the use of "or" or "and" means "and / or" unless otherwise indicated. Furthermore, the use of the term "including" as well as other forms such as "include", "includes" and "included" is not limiting. The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described. When used in a list of two or more items, the term "and / or" means that any one of the listed items may be used alone or any combination of two or more of the listed items may be used. For example, if a composition is described as comprising components A, B and / or C, the composition may comprise A alone; B alone; C alone; A and B in combination; A and C in combination; B and C in combination; or A, B and C in combination.

[0035] The term "bond" or "single bond" refers to a chemical bond between two atoms, or two moieties when the atoms connected by the bond are considered to be part of a larger substructure. In one aspect, when a group described herein is a bond, the referenced group is absent, thereby forming a bond between the remaining identified groups.

[0036] The term "moiety" refers to a specific section or functional group of a molecule. A chemical moiety is often recognized as a chemical entity that is implanted or attached to a molecule.

[0037] In some situations, compounds may exist as tautomers, and all tautomers are included within the scope of the compounds presented herein.

[0038] The term "modulate," as used herein, means to interact with a target either directly or indirectly to alter the activity of the target, such as, by way of example only, enhancing the activity of the target, inhibiting the activity of the target, limiting the activity of the target, or expanding the activity of the target.

[0039] The term "modulator" as used herein refers to a molecule that interacts with a target either directly or indirectly.The interaction includes, but is not limited to, the interaction of an agonist, a partial agonist, an inverse agonist, an antagonist, a degrader, or a combination thereof.In some embodiments, the modulator is an antagonist.In some embodiments, the modulator is a degrader.

[0040] "Selective estrogen receptor modulator" or "SERM" as used herein refers to a molecule that differentially regulates the activity of estrogen receptor in different tissues.For example, in some embodiments, SERMs show ER antagonist activity in some tissues and ER agonist activity in other tissues.In some embodiments, SERMs show ER antagonist activity in some tissues and minimal or no ER agonist activity in other tissues.In some embodiments, SERMs show ER antagonist activity in breast tissue, ovarian tissue, endometrial tissue and / or cervical tissue.

[0041] The term "antagonist," as used herein, refers to a small molecule agent that binds to a nuclear hormone receptor and subsequently reduces agonist-induced transcriptional activity of the nuclear hormone receptor.

[0042] The term "agonist," as used herein, refers to a small molecule agent that binds to a nuclear hormone receptor and subsequently increases nuclear hormone receptor transcriptional activity in the absence of a known agonist.

[0043] The term "inverse agonism," as used herein, refers to a small molecule agent that binds to a nuclear hormone receptor and subsequently reduces the basal level of nuclear hormone receptor transcriptional activity that exists in the absence of a known agonist.

[0044] The term "degrader" as used herein refers to a small molecule agent that binds to nuclear hormone receptor and then reduces the steady-state protein level of the receptor.In some embodiments, degrader as described herein reduces steady-state estrogen receptor level 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, degrader as described herein reduces steady-state estrogen receptor level by at least 65%.In some embodiments, degrader as described herein reduces steady-state estrogen receptor level by at least 85%.

[0045] The term "selective estrogen receptor degrader" or "SERD" as used herein refers to a small molecule agent that preferentially binds to estrogen receptors over other receptors, and subsequently reduces steady-state estrogen receptor levels. SERD can also refer to compounds that may degrade one cell or tissue type more than another, thereby exhibiting SERM-type activity while effecting degradation in a differential manner in response to the cell or tissue context.

[0046] The term "estrogen receptor-dependent" as used herein refers to a disease or condition that does not occur, or does not occur to the same extent, in the absence of the estrogen receptor.

[0047] The term "estrogen receptor mediated" as used herein refers to diseases or conditions that depend at least in part on estrogen signaling for their condition.

[0048] The term "estrogen receptor sensitivity" as used herein refers to a disease or condition that does not occur or does not occur to the same extent in the absence of estrogen. Estrogen receptor sensitivity also refers to cells or tissues that respond to the presence of estrogen receptor agonists, antagonists, SERMs and / or SERDs.

[0049] The term "cancer" as used herein refers to the abnormal growth of cells that tend to grow in an uncontrolled manner and in some cases metastasize (spread).Types of cancer include, but are not limited to, solid tumors (e.g., of the bladder, intestine, brain, breast, endometrium, heart, kidney, lung, uterus, lymphatic tissue (lymphoma), ovary, pancreas or other endocrine organs (thyroid), prostate, or skin (melanoma or basal cell carcinoma)) or blood tumors (e.g., leukemia and lymphoma) at any stage of disease with or without metastasis.

[0050] The term "co-administration" and the like, as used herein, is meant to encompass the administration of selected therapeutic agents to a single patient, and is intended to include treatment regimens in which the agents are administered by the same or different routes of administration or at the same or different times.

[0051] The term "effective amount" or "therapeutically effective amount" as used herein refers to a sufficient amount of an agent or compound being administered that relieves to some extent one or more symptoms of the disease or condition being treated. The result may be a reduction and / or alleviation of the signs, symptoms or causes of a disease, or any other desired change in a biological system. For example, an "effective amount" for therapeutic use is the amount of a composition containing a compound as disclosed herein that is required to bring about a clinically significant reduction in disease symptoms. The appropriate "effective" amount in any individual case may be determined using techniques such as a dose escalation study.

[0052] The terms "enhance" or "enhancing," as used herein, mean to increase or prolong either the potency or duration of a desired effect. Thus, in terms of enhancing the effect of therapeutic agents, the term "enhancing" refers to the ability to increase or prolong either the potency or duration of the effect of other therapeutic agents on a system. An "enhancing-effective amount," as used herein, refers to an amount adequate to enhance the effect of another therapeutic agent in a desired system.

[0053] The term "pharmaceutical combination" as used herein means a product resulting from the mixing or co-administration of more than one active ingredient, including both fixed and non-fixed combinations of said active ingredients. The term "fixed combination" means that both active ingredients, e.g., compounds of formulae I-VI and D-105-D-110, or pharmaceutically acceptable salts thereof, and co-agents, are administered to a patient at the same time in the form of a single entity or single dose. The term "non-fixed combination" means that the active ingredients, e.g., compounds of formulae I-VI, D-105-D-110, or pharmaceutically acceptable salts thereof, and co-agents, are administered to a patient as separate entities, either simultaneously, concurrently or sequentially, without any specific intervening time restriction, where such administration provides effective levels of the two compounds in the patient's body. The latter also applies to cocktail therapy, e.g., administration of three or more active ingredients.

[0054] The terms "kit" and "article of manufacture" are used synonymously.

[0055] The term "subject" or "patient" includes mammals. Examples of mammals include, but are not limited to, any member of the class Mammalia: humans, non-human primates, such as chimpanzees, and other ape and monkey species; farm animals, such as cows, horses, sheep, goats, pigs; domestic animals, such as rabbits, dogs, and cats; laboratory animals, including rodents, such as rats, mice, and guinea pigs. In some embodiments, the mammal is a human.

[0056] The terms "treat," "treating," or "treatment," as used herein, include alleviating, eliminating, or ameliorating at least one symptom of a disease or condition, either prophylactically and / or therapeutically, preventing further symptoms, inhibiting a disease or condition, e.g., arresting the onset of a disease or condition, relieving a disease or condition, causing regression of a disease or condition, alleviating conditions caused by a disease or condition, or halting the symptoms of a disease or condition.

[0057] In the context of this disclosure, the phrases "I through VI", "I to VI" or "I-VI" are meant to include, in each instance, compounds of formulae 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. The same should apply to the phrases "D-105 to D-110", "D-105 through D-110" or "D-105 - D-110" with respect to the compounds involved. Also, the phrases "I through VI", "I to VI" or "I-VI" as used herein may be interpreted as "Formula I, Formula II, Formula III, Formula IV and / or Formula V". The phrases "D-105 to D-110", "D-105 through D-110" or "D-105 - D-110" as used herein may be interpreted as "D-105, D-106, D-107, D-108, D-109 and / or D-110".

[0058] The term "alkyl," as used herein, refers to both straight- and branched-chain hydrocarbon radicals having a number of carbon atoms within the specified range. For example, C 1-4 Alkyl means a hydrocarbon radical is attached, which may contain any one to four carbon atoms, with the remaining valences being filled with hydrogen atoms. The definition also includes each permutation separately as if listed separately. Thus, C 1-2 Alkyl includes methyl and ethyl. 1-3 Alkyl includes methyl, ethyl, propyl and 2-propyl. 1-4 Alkyl includes methyl, ethyl, n-propyl, 2-propyl, n-butyl, 2-butyl, iso-butyl and tert-butyl. 1-5 Alkyl includes methyl, ethyl, 2-propyl, n-butyl, 2-methylbutyl, tert-butyl, n-pentyl, pentan-2-yl, pentan-3-yl and tert-pentyl, iso-pentyl.

[0059] The term "halogen" as used herein refers to a radical of fluorine, chlorine, bromine or iodine.

[0060] The term "haloalkyl" refers to an alkyl radical, where the alkyl radical is the same as defined for the term "alkyl", except that the alkyl radical further has 1 to 5 halogen atoms attached to the alkyl chain. The terms "fluoroalkyl" and "chloroalkyl" refer to haloalkyls, for example, with a single specific type of halogen, such as fluorine or chlorine, respectively. In some embodiments, haloalkyls can also include the specific referenced halogen used in combination with other halogens, such as fluorine in fluoroalkyl. For example, C1 haloalkyls include C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C22, C23, C24, C25, C26, C27, C28, C29, C31, C32, C33, C34, C35, C36, C37, C38, C39, C41, C42, C43, C44, C45, C46, ​​C47, C48, C49, C48, C49, C41, C42, C43, C44, C45, C46, ​​C47, C48, C49, C49, C51, C41, C42, C43, C44, C45, C45, C46, ​​C47, C48, C49, C49, C51, C48, C49, C52, C41, C42, C43, C44, C45, C45, C46, ​​C47, C48, C49, C49, C53, C49, C54, C49, C55, C56, C57, C58, C59, C59, C61, C62, C63 1-2 Haloalkyl includes, for example, --CH2F, CHF2, CF3, --CH2CH2F, --CH2CHF2, --CH2CF3, --CF2CHF2, --CF2CF3, and the like. 1-3Haloalkyl is defined to include, --CH2F, --CHF2, --CF3, --CH2CF3, --CHFCF3, --CF2CF3, --CHClCH3, --CH2CH2Cl, --CH2CH2CH2F, --CH2CH2CF3, and the like. 1-4 Haloalkyl is defined to include, --CH2F, --CHF2, --CF3, --CH2CF3, --CHFCF3, --CF2CF3, --CHClCH3, --CH2CH2Cl, --CH2CH2CF3, --CH2CH2CH2CF3, CHClCF2CH2CH3, CF2CH2CH2CHF2, CH2CH2CH2CH2F, CH2CH2CH2CH2Cl, and the like. The term "fluoroalkyl", as well as "C1-C4 fluoroalkyl", includes C1, C2, C3 and C4 alkyl chains having 1 to 4 fluorine atoms, either linear or branched, 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).

[0061] The term "aryl" refers to a monovalent 6-14 membered, monocyclic or bicyclic carbocyclic ring, where a monocyclic ring is aromatic and at least one ring of a bicyclic ring is aromatic. Unless otherwise indicated, the valency of the group may be located on any atom of any ring within the radical, valency rules permitting. Representative examples include phenyl, naphthyl, indanyl, and the like.

[0062] The term "acyl" refers to a group having the general formula -(CO)-alkyl, where the alkyl radical is the same as defined for the term "alkyl", and the alkyl portion of the acyl group has a number of carbon atoms falling within the specified range.

[0063] The term "acyloxy" refers to a group having the general formula -O(CO)-alkyl, where the alkyl radical is the same as defined for the term "alkyl", and the alkyl portion of the acyloxy group has a number of carbon atoms falling within the specified range.

[0064] The compounds of the present invention may contain at least one stereocenter and therefore exist in various stereoisomeric forms. Stereoisomers are compounds that differ only in their spatial arrangement. Enantiomers are pairs of stereoisomers whose mirror images are not superimposable, most commonly because they contain an asymmetrically substituted carbon atom that acts as a chiral center. "Enantiomer" means one of a pair of molecules that are mirror images of each other and are not superimposable. Diastereomers are stereoisomers that are not related as mirror images, most commonly because they contain two or more asymmetrically substituted carbon atoms. "R" and "S" indicate the configuration of the substituents around one or more chiral carbon atoms. Thus, "R" and "S" indicate the relative configuration of the substituents around one or more chiral carbon atoms. When the stereochemistry of a disclosed compound is named or shown by structure, the named or shown stereoisomer is at least 50%, 60%, 70%, 80%, 90%, 95%, 98%, 99% or 99.9% pure by weight relative to the other stereoisomer. When one enantiomer is named or shown by structure, the shown or named enantiomer is at least 50%, 60%, 70%, 80%, 90%, 95%, 98%, 99% or 99.9% optically pure by weight. Weight percent optical purity is the ratio of the weight of the enantiomer to the weight of the enantiomer plus the weight of its optical isomer.

[0065] The compounds of the present invention may be prepared as individual isomers by incorporating or starting with a specific isomer, isomer-specific synthesis, separation of diastereomers or resolution from an isomeric mixture. Conventional resolution techniques include forming a salt of the free base of each isomer of an isomeric pair using an optically active acid (followed by fractional crystallization and regeneration of the free base), forming a salt of the acid form of each isomer of an isomeric pair using an optically active amine (followed by fractional crystallization and regeneration of the free acid), forming an ester or amide of each isomer of an isomeric pair using an optically pure acid, amine or alcohol (followed by chromatographic separation and removal of the chiral auxiliary), or resolving an isomeric mixture of either the starting material or the final product using a variety of well-known chromatographic methods.

[0066] References to the use of a compound of Formula I-VI or D-105-D-110 or a composition comprising a compound of Formula I-VI or D-105-D-110, where the compound may contain at least one stereomeric center, refer to the racemate or any optical purity of the compound of Formula I-VI or D-105-D-110 in the composition, including but not limited to optically pure compounds.

[0067] In some embodiments, the enantiomeric ratio of the compounds of formulae I-VI or D-105-D-110 having a stereoisomeric center is greater than 90:10. In some embodiments, the enantiomeric ratio of the compounds of formulae I-VI or D-105-D-110 is greater than 95:5. In some embodiments, the enantiomeric ratio of the compounds of formulae I-VI or D-105-D-110 is greater than 99:1. In some embodiments, the compounds of formulae I-VI or D-105-D-110 are optically pure.

[0068] When the compounds of formulas I-VI and D-105-D-110 contain one or more basic sites, such as amines, acid addition salts can be made and the present invention includes such acid addition salts. Some representative (non-limiting) acid addition salts include hydrochloride, hydrobromide, hydroiodide, acetate, benzenesulfonate, mesylate, besylate, benzoate, tosylate, citrate, tartrate, sulfate, bisulfate, lactate, maleate, mandelate, valerate, laurate, caprylate, propionate, succinate, phosphate, salicylate, napsylate, nitrate, tannate, resorcinate, etc., such as polybasic salts as well as mixtures of acid addition salts. When amines are present, the present invention also includes quaternary ammonium salts of these amines. Similarly, when the compounds of the present invention contain one or more acid sites, such as carboxylic acids, phenols, etc., base addition salts can be made and the present invention includes such base addition salts. For example, some representative (non-limiting) acidic compounds of the present invention may be present as their lithium, sodium, potassium, ammonium, trialkyammonium, calcium, magnesium, barium, and the like.

[0069] The compounds of the present invention may also exist as solvates, and such solvates are included in the scope of the present invention even if not explicitly stated.Such solvates are preferably hydrates, but may be solvates composed of other solvents, preferably solvents that are non-toxic or at least considered acceptable for administration to mammals, preferably humans.Such solvates may be single or combinations, stoichiometric or non-stoichiometric.Some exemplary solvates include water, ethanol, acetic acid, etc.

[0070] The compounds of the invention, when used as therapeutic agents, may be administered by any method known to those of skill in the art, such as orally, bucally, intravenously, subcutaneously, intramuscularly, transdermally, intradermally, intravascularly, intranasally, sublingually, intracranially, rectally, intratumorally, intravaginally, intraperitoneally, pulmonary, intraocularly and intratumorally.

[0071] When administered, the compounds and compositions of the invention may be provided, administered and / or given in one or multiple daily doses, such as twice daily, three times daily and four times daily.

[0072] In some embodiments of the present invention, the compound is administered orally, where the compound can be formulated for solid or liquid dose administration. Solid dose administration can be in the form of tablets, granules, capsules, pills, pellets, powders, etc. Liquid dose formulations include syrups, solutions, gels, suspensions, elixirs, emulsions, colloids, oils, etc.

[0073] In some embodiments, the compounds of the present invention may comprise solids, where particle size may be used to define the solid compound.When the compounds of the present invention are not particularly water-soluble, it is sometimes preferable to administer the compounds with a particular particle size.In some embodiments, the solids comprising the compounds of formulas I-VI and D-105-D110 may have an average median particle size diameter of less than 100 microns, or less than 75 microns, or less than 50 microns, or less than 35 microns, or less than 10 microns, or less than 5 microns.

[0074] Solid dose formulations contain at least one compound of the invention together with one or more pharmaceutical excipients.

[0075] Solid dosage forms of the present invention also include capsules, where the drug is enclosed within the capsule either as a powder along with optional excipients, or as granules that typically include one or more excipients along with the drug, and the granules can then be optionally coated, e.g., enteric or non-enteric.

[0076] 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.In some embodiments of the present invention, the compounds of the present invention can be used in combination with m-TOR inhibitors selected from the group consisting of sirolimus, temsirolimus, everolimus and ridafarolimus; CDK4 / 6 inhibitors selected from the group consisting of abemaciclib, ribociclib and palbociclib; PI3k inhibitors; PARP inhibitors; BCL-2 inhibitors; MCL-1 inhibitors; and any combination thereof.

[0077] The compounds of the present invention may be administered according to different dosing schedules, and dosing may be adjusted as deemed necessary by the subject, or preferably by the subject under the supervision of a medically qualified practitioner. Administration of the compounds of the present invention may be by several routes, and consequently, the dosing schedule and dosage will depend on the particular subject's weight, sex, age, intended treatment, etc., as well as the route of the drug selected.

[0078] By way of non-limiting example, compounds of the invention may be considered for administration by the oral route for optimal efficacy and / or safety.

[0079] It is understood that the amount of compound administered daily can be administered every day, every other day, every second day, every third day, every fourth day, every fifth day, etc. For example, every other day administration can begin with a dose of 5 mg per day on Monday, a first subsequent dose of 5 mg per day can be administered on Wednesday, a second subsequent dose of 5 mg per day can be administered on Friday, etc. In some embodiments, the compound is administered once every seven days.

[0080] The present invention also provides a method of treating (e.g., preventing or ameliorating symptoms associated with, or reducing the incidence of, reducing the pathogenesis of, promoting recovery from, or delaying the onset of) a disease, syndrome, illness, or condition associated with insufficient or excessive estrogen levels in a mammal in need of such treatment, comprising administering to the mammal an effective amount of a compound selected from the group consisting of Formulae I-VI, D-105-D-110 and all structural embodiments described herein, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formulae I-VI, D-105-D-110, or one of the structural embodiments described herein, or a pharma-ceutically acceptable salt thereof, and a pharma-ceutically acceptable excipient. In certain embodiments, the mammal is a human.

[0081] In one aspect, the present invention provides a method for treating (e.g., preventing or ameliorating symptoms associated with, or reducing the incidence of, reducing the etiology of, curing, or preventing) prostate cancer, breast cancer, endometrial cancer, lung cancer, hepatocellular carcinoma, lymphoma, multiple endocrine neoplasia, vaginal cancer, renal cancer, thyroid cancer, testicular cancer, leukemia, and ovarian cancer in a mammal in need of such treatment. The present invention describes a method of treating a patient with rheumatoid arthritis (promoting recurrence or delaying their onset) comprising administering to said mammal a pharmaceutical composition comprising a compound selected from the group consisting of Formulae I-VI, D-105-D-110 and all structural embodiments described herein or a pharmaceutically acceptable salt thereof, or a compound selected from the group consisting of Formulae I-VI, D-105-D-110 and all structural embodiments described herein including a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In embodiments, the mammal is a human. In some embodiments, the cancer is positive for expression of ESR1. In some embodiments, the cancer is resistant to a previous line of treatment (e.g., previous endocrine therapy). In some embodiments, the cancer progresses after exposure to one or more agents selected from the group consisting of tamoxifen, toremifene, letrozole, aromasin, anastrazole, and faslodex. In some embodiments, the treatment is in an adjuvant setting, and in some embodiments, the treatment is in a metastatic setting. In certain embodiments, the SERD and / or SERM compounds disclosed herein are combined with other active compounds, such as CDK4 / 6 inhibitors, PI3k inhibitors, mTOR inhibitors, taxanes, HER2 inhibitors, PARP inhibitors, BCL-2 inhibitors and MCL-1 inhibitors.

[0082] Also provided herein is a method of inhibiting tumor growth or causing tumor regression in a subject with an estrogen receptor alpha positive cancer, comprising administering to the subject a therapeutically effective amount of a compound of Formulae I-VI or D-105-D-110 or a pharma-ceutically acceptable salt, solvate or prodrug thereof. In some embodiments, the estrogen receptor alpha positive cancer is a drug-resistant estrogen receptor alpha 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 mutant estrogen receptor alpha comprising one or more mutations selected from the group consisting of Y537X1 (wherein X1 is S, N or C), L536X2 (wherein 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 a 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 previous treatment with a SERM, a CDK inhibitor and / or an AI. In some embodiments, the tumor is resistant to a drug selected from the group consisting of antiestrogen (e.g., tamoxifen or fulvestrant), aromatase inhibitor (e.g., aromasin), a CDK inhibitor (e.g., abemaciclib, ribociclib or palbociclib) and combinations thereof. In some embodiments, a therapeutically effective amount of a compound of formula I-VI or D-105-D-110 or a pharmacologic acceptable salt, solvate or prodrug thereof is combined with one or more of antiestrogen, aromatase inhibitor, CDK inhibitor, PI3K inhibitor, mTOR inhibitor, taxane, PARP inhibitor, BCL-2 inhibitor and MCL-1 inhibitor.

[0083] Also provided herein is a method of inhibiting tumor growth or causing tumor regression in a subject with a mutant estrogen receptor alpha positive cancer, comprising administering to the subject a therapeutically effective amount of a compound of Formulae I-VI or D-105-D-110 or a pharma- ceutically 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 mutant estrogen receptor alpha containing one or more mutations selected from the group consisting of Y537X1 (wherein X1 is S, N or C), L536X2 (wherein 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 female. In some embodiments, the subject is a postmenopausal female who has had recurrence or progression after previous treatment with a SERM, a CDK inhibitor and / or an AI. In some embodiments, the tumor is resistant to a drug selected from the group consisting of antiestrogen (e.g., tamoxifen or fulvestrant), an aromatase inhibitor (e.g., aromasin), a CDK inhibitor (e.g., abemaciclib, ribociclib or palbociclib) and combinations thereof. In some embodiments, a therapeutically effective amount of a compound of formula I-VI or D-105-D-110 or a pharmacologic acceptable salt, solvate or prodrug thereof is combined with one or more of antiestrogen, an aromatase inhibitor, a CDK inhibitor, a PI3K inhibitor, an mTOR inhibitor, a taxane, a PARP inhibitor, a BCL-2 inhibitor and an MCL-1 inhibitor.

[0084] Also provided herein is a method of treating breast cancer in a subject having drug-resistant estrogen receptor alpha positive cancer, comprising administering to the subject a therapeutically effective amount of a compound of formula I-VI or D-105-D-110 or a pharmaceutically acceptable salt, solvate or prodrug thereof. In some embodiments, the drug-resistant breast cancer is resistant to one or more antiestrogen (e.g., tamoxifen, toremifene, fulvestrant), CDK inhibitor (e.g., abemaciclib, ribociclib or palbociclib) and / or aromatase inhibitor (e.g., aromasin, letrozole, anastrozole). In some embodiments, a therapeutically effective amount of a compound of formula I-VI or D-105-D-110 or a pharmaceutically acceptable salt, solvate or prodrug thereof is combined with one or more of antiestrogen, aromatase inhibitor, CDK inhibitor, PI3K inhibitor, mTOR inhibitor, taxane, PARP inhibitor, BCL-2 inhibitor and MCL-1 inhibitor. In some embodiments, the subject expresses at least one mutant estrogen receptor alpha selected from D538G, Y537S, Y537N, Y537C, E380Q, S463P, L536R, L536Q, P535H, V392I and V534E. In some embodiments, the mutant estrogen receptor alpha is selected from Y537S, Y537N, Y537C, D538G, L536R, S463P and E380Q. In some embodiments, the mutant receptor alpha is Y537S. In some embodiments, the subject is a postmenopausal woman.In some embodiments, the subject is 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, FGFR2, 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, NF2, 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 embodiments, the one or more genes are selected from AKT1, AKT2, BRAF, CDK4, CDK6, PIK3CA, PIK3R1 and MTOR.

[0085] The compounds of the present invention can be prepared by various synthetic routes and techniques known to those skilled in the art. The processes disclosed herein should not be construed in any manner as examples or limiting the scope of the present invention, but are provided as only some of the exemplary methods by which the compounds of the present invention can be or have been prepared.

[0086] In some cases, protecting groups are used in the synthesis of the compounds of the invention; there are a wide variety of protecting groups and strategies that may be used in organic synthesis (TW Green and PGM Wuts (2006) Greene's Protective Groups in Organic Synthesis, which is incorporated herein by reference in its entirety), and it should be understood that when a protecting group is referred to generally, any suitable protecting group is intended to be considered.

[0087] In some instances, leaving groups are used in the synthesis of the compounds of the present invention. When a specific leaving group is mentioned, it should be understood that other leaving groups can also be used. The leaving group typically comprises a group that can stabilize an anion. In the case of nucleophilic aromatic substitution, the leaving group can be an anion or a neutrally charged group. In some instances, the leaving group for nucleophilic aromatic substitution can be a group that is not typically considered a stabilized anion (e.g., fluoride or hydride). Without intending to be bound by theory or examples, some typical nucleophilic leaving groups include halogens, sulfonates, (O-mesylates, O-tosylates, etc.), hydrides, quaternary amines, nitro, etc. Further discussion and examples can be found in major textbooks of organic chemistry, including, for example, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th Edition, which is incorporated herein by reference in its entirety.

[0088] When any variable occurs more than one time in any constituent or in any formula, its definition at each occurrence is independent of its definition at every other occurrence. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0089] Thus, in some embodiments, the present invention provides a compound according to formula I: [ka] (In the formula: X is hydrogen, C1-C3 alkyl, C1-C3 fluoroalkyl, CN, fluorine, chlorine or bromine; R is hydrogen, C1-C3 alkyl, C1-C3 fluoroalkyl, CN, fluorine, chlorine or bromine; Each R a is independently selected from: H, C1-C3 alkyl, C1-C3 fluoroalkyl, OH, O-C1-3 alkyl, CN, fluorine, chlorine, or phenyl optionally substituted with 1 to 3 groups selected from fluorine, chlorine, C1-C3 alkyl, CN, O-C1-C3 alkyl, and OH; Each R b is independently selected from: H, C1-C3 alkyl, C1-C3 fluoroalkyl, OH, O-C1-3 alkyl, CN, fluorine, chlorine, or phenyl optionally substituted with 1 to 3 groups selected from fluorine, chlorine, C1-C3 alkyl, CN, O-C1-C3 alkyl, and OH; Y and Z are each independently CR b or N; U and V are independent of each other. a or N; 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, [ka] where each R' is independently H or C1-C3 alkyl. or a pharmaceutical salt thereof, or a pharma- ceutically acceptable salt thereof.

[0090] In some embodiments, the compound of formula I is a compound. In other embodiments, the compound is a pharma- ceutically acceptable salt thereof.

[0091] In certain embodiments, the compound of formula I is a pharma- ceutically acceptable salt, solvate or prodrug thereof.

[0092] In certain embodiments, the pharma- ceutically acceptable salt of the compound of formula I is an acid addition salt.

[0093] In some embodiments, the compound of formula I is a prodrug. In yet other embodiments, the compound of formula I is a pharma- ceutically acceptable salt of the prodrug. In some aspects, the pharma-ceutically acceptable salt of the prodrug of the compound of formula I is a hydrochloride salt.

[0094] In some embodiments, pharmaceutical compositions are described that include a compound of formula I or a pharma- ceutically acceptable salt or prodrug of a compound of formula I. 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.

[0095] In certain embodiments of formula I, W is -CH2-CH2-NH-CH2-CH2-CH3; -CH2-CH2-NH-CH2-CH2-CH2F; [ka] It is.

[0096] In some embodiments of formula I, Y and Z are each CR b It is.

[0097] In some embodiments of formula I, U and V are each CR a It is.

[0098] In some embodiments, the present invention provides a compound of formula II: [ka] (In the formula: X is hydrogen, C1-C3 alkyl, C1-C3 fluoroalkyl, CN, fluorine, chlorine or bromine; R is hydrogen, C1-C3 alkyl, C1-C3 fluoroalkyl, CN, fluorine, chlorine or bromine; Each R a is independently selected from: H, C1-C3 alkyl, C1-C3 fluoroalkyl, OH, O-C1-3 alkyl, CN, fluorine, chlorine, or phenyl optionally substituted with 1 to 3 groups selected from fluorine, chlorine, C1-C3 alkyl, CN, O-C1-C3 alkyl, and OH; Each R b is independently selected from: H, C1-C3 alkyl, C1-C3 fluoroalkyl, OH, O-C1-3 alkyl, CN, fluorine, chlorine, or phenyl optionally substituted with 1 to 3 groups selected from fluorine, chlorine, C1-C3 alkyl, CN, O-C1-C3 alkyl, and OH; Y and Z are each independently CR b or N; U and V are independent of each other. a or N) or a pharma- ceutically acceptable salt thereof.

[0099] In certain embodiments of formula II, X is hydrogen, methyl, fluorine, chlorine, or bromine.

[0100] In certain embodiments of formula II, R is hydrogen, methyl, fluorine, chlorine, or bromine.

[0101] In some embodiments of formula II, Y and Z are each CR b where each R b is independently selected from H, fluorine or chlorine.

[0102] In some embodiments of formula II, U and V are each CR a where each R a is independently selected from H, fluorine or chlorine.

[0103] In some embodiments, the present invention provides a compound of formula III: [ka] (In the formula: X is hydrogen, C1-C3 alkyl, C1-C3 fluoroalkyl, CN, fluorine, chlorine or bromine; R is hydrogen, C1-C3 alkyl, C1-C3 fluoroalkyl, CN, fluorine, chlorine or bromine; Each R a is independently selected from: H, C1-C3 alkyl, C1-C3 fluoroalkyl, OH, O-C1-3 alkyl, CN, fluorine, chlorine, or phenyl optionally substituted with 1 to 3 groups selected from fluorine, chlorine, C1-C3 alkyl, CN, O-C1-C3 alkyl, and OH; Each R b is independently selected from: H, C1-C3 alkyl, C1-C3 fluoroalkyl, OH, O-C1-3 alkyl, CN, fluorine, chlorine, or phenyl optionally substituted with 1 to 3 groups selected from fluorine, chlorine, C1-C3 alkyl, CN, O-C1-C3 alkyl, and OH; U and V are independent of each other. a or N) or a pharma- ceutically acceptable salt thereof.

[0104] In some embodiments of formula III, X is hydrogen, methyl, fluorine, chlorine, or bromine; R is hydrogen, methyl, fluorine, chlorine, or bromine; U and V are each CR a and each R a is independently selected from H, fluorine or chlorine; each R b is independently selected from H, fluorine or chlorine.

[0105] In some embodiments of Formula III, X is fluorine and / or R is fluorine or chlorine.

[0106] In some embodiments, the present invention provides a compound of formula IV: [ka] (In the formula: X is hydrogen, C1-C3 alkyl, C1-C3 fluoroalkyl, CN, fluorine, chlorine or bromine; R is hydrogen, C1-C3 alkyl, C1-C3 fluoroalkyl, CN, fluorine, chlorine or bromine; Each R b are independently selected from: H, C1-C3 alkyl, C1-C3 fluoroalkyl, OH, O-C1-3 alkyl, CN, fluorine, chlorine, or phenyl optionally substituted with 1-3 groups selected from fluorine, chlorine, C1-C3 alkyl, CN, O-C1-C3 alkyl, and OH. or a pharma- ceutically acceptable salt thereof.

[0107] In some embodiments of Formula IV, X is hydrogen or fluorine, R is hydrogen, fluorine or chlorine, and / or each R b is independently selected from hydrogen, fluorine or chlorine.

[0108] In some embodiments, the present invention provides a compound of formula V: [ka] (In the formula: X is hydrogen, C1-C3 alkyl, C1-C3 fluoroalkyl, CN, fluorine, chlorine or bromine; R is hydrogen, C1-C3 alkyl, C1-C3 fluoroalkyl, CN, fluorine, chlorine or bromine; R b is selected from: H, C1-C3 alkyl, C1-C3 fluoroalkyl, OH, O-C1-3 alkyl, CN, fluorine, chlorine, or phenyl optionally substituted with 1 to 3 groups selected from fluorine, chlorine, C1-C3 alkyl, CN, O-C1-C3 alkyl, and OH. or a pharma- ceutically acceptable salt thereof.

[0109] In some embodiments of formula V, X is hydrogen or fluorine; R is hydrogen, fluorine or chlorine; and / or R b is hydrogen, fluorine or chlorine.

[0110] In some embodiments, the present invention provides a compound of formula VI: [ka] (In the formula: X is hydrogen, C1-C3 alkyl, C1-C3 fluoroalkyl, CN, fluorine, chlorine or bromine; R is hydrogen, C1-C3 alkyl, C1-C3 fluoroalkyl, CN, fluorine, chlorine or bromine; R a is selected from: H, C1-C3 alkyl, C1-C3 fluoroalkyl, OH, O-C1-3 alkyl, CN, fluorine, chlorine, or phenyl optionally substituted with 1 to 3 groups selected from fluorine, chlorine, C1-C3 alkyl, CN, O-C1-C3 alkyl, and OH; R b is selected from: H, C1-C3 alkyl, C1-C3 fluoroalkyl, OH, O-C1-3 alkyl, CN, fluorine, chlorine, or phenyl optionally substituted with 1 to 3 groups selected from fluorine, chlorine, C1-C3 alkyl, CN, O-C1-C3 alkyl, and OH. or a pharma- ceutically acceptable salt thereof.

[0111] In some embodiments of Formula VI, R is chlorine and R b is fluorine.

[0112] In some embodiments of Formula VI, R and R b is fluorine.

[0113] In some embodiments of Formula VI, R a is methyl, CF3 or chlorine.

[0114] In some embodiments of formula VI, X is hydrogen or fluorine; R is hydrogen, fluorine or chlorine; R a = C1-C3 alkyl, C1-C3 fluoroalkyl, chlorine or bromine; and / or R b is hydrogen, fluorine or chlorine.

[0115] In some embodiments, the present invention provides a method for the preparation of a method for treating atopic dermatitis comprising: [ka] [ka] or a pharma- ceutically acceptable salt thereof.

[0116] In some embodiments, the present invention provides N-(4-((8-chloro-7-(o-tolyl)pyrrolo[3,2-e]indazol-6(3H)-yl)methyl)phenethyl)-3-fluoropropan-1-amine; 3-fluoro-N-(3-fluoro-4-((1-fluoro-7-(o-tolyl)pyrrolo[3,2-e]indazol-6(3H)-yl)methyl)phenethyl)propan-1-amine; N-(4-((1,8-difluoro-7-(o-tolyl)pyrrolo[3,2-e]indazol-6(3H)-yl)methyl)phenethyl)-3-fluoropropan-1-amine; N-(3,5-difluoro-4-(( 8-Fluoro-7-(o-tolyl)pyrrolo[3,2-e]indazol-6(3H)-yl)methyl)phenethyl)-3-fluoropropan-1-amine; 3-fluoro-N-(3-fluoro-4-((8-fluoro-7-(o-tolyl)pyrrolo[3,2-e]indazol-6(3H)-yl)methyl)phenethyl)propan-1-amine; and N-(4-((8-chloro-7-(o-tolyl)pyrrolo[3,2-e]indazol-6(3H)-yl)methyl)-3-fluorophenethyl)-3-fluoropropan-1-amine, or a pharmaceutical salt thereof.

[0117] In one embodiment, provided herein is a pharmaceutical composition comprising a compound selected from the group consisting of Formulas I-VI, D-105-D-110, and all structural embodiments described herein, and at least one pharma- ceutically acceptable excipient.

[0118] In some embodiments of the compounds of Formulae I-VI and D-105-D-110, the enantiomeric ratio of the compounds is greater than 95:5. In some embodiments, the enantiomeric ratio of the compounds is greater than 99:1.

[0119] An article of manufacture is provided that includes packaging material; a compound of Formulas I-VI, D-105-D-110, or a pharma- ceutically acceptable salt, active metabolite, prodrug, or pharma- ceutically acceptable solvate thereof, or composition thereof within the packaging material; and indicia indicating that the compound, or a pharma- ceutically acceptable salt, active metabolite, prodrug, or pharma- ceutically acceptable solvate thereof, or composition thereof, is used to reduce, decrease, or eliminate the effect of estrogen receptors, or for the treatment, prevention, or amelioration of one or more symptoms of a disease or condition that would benefit from the reduction or elimination of estrogen receptor activity.

[0120] Other objects, features and advantages of the compounds, methods and compositions described herein will become apparent from the following detailed description. It should be understood, however, that the detailed description and specific examples, while indicating particular embodiments, are given by way of illustration only, since various changes and modifications within the spirit and scope of the disclosure will become apparent to those skilled in the art from this detailed description.

[0121] The compounds described herein are synthesized using standard synthetic techniques or using methods known in the art in combination with the methods described herein, and solvents, temperatures and other reaction conditions depicted herein may vary.

[0122] The starting materials used in the synthesis of the compounds described herein are either synthesized or obtained from commercial sources, 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 are synthesized using techniques and materials described herein or otherwise known, such as those found in March, ADVANCED ORGANIC CHEMISTRY 4th Edition, (Wiley 1992); Carey and Sundberg, ADVANCED ORGANIC CHEMISTRY 4th Edition, Vols. A and B (Plenum 2000, 2001) and Green and Wuts, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS 3rd Edition, (Wiley 1999). The general methods for the preparation of compounds can be modified by using appropriate reagents and conditions for the introduction of various moieties found in the formulas as provided herein.

[0123] In some embodiments, the compounds described herein are prepared as outlined in the following schemes.

[0124] [ka] Referring to Scheme I, compound 85-7 was alkylated with side chain 105-5 (prepared as shown) to give a mixture of 105-6 and 105-7. The major product, compound 105-7, was treated with HCl to deprotect the secondary amine to give D-105.

[0125] [ka] Intermediate 85-7 was alkylated with 106-10 (prepared in Scheme II) to give 106-11, followed by deprotection of the secondary amine with TFA to give 106-12, which was treated with base in aqueous methanol to give D-106.

[0126] [ka] Side chain 107-3 was prepared as shown in Scheme III and reacted with difluorinated scaffold 107-10 (prepared as shown) in the presence of NaH to give the deprotected intermediate 107-11, which was subsequently deprotected with TFA to give 107-12, which was then subjected to base hydrolysis / methanolysis to give the desired product D-107.

[0127] [ka] Referring now to Scheme IV, scaffold 107-9 was alkylated with side chain 105-5 to give intermediate 108-1, which was subsequently deprotected to give indazole 108-2, which was first deprotected by base methanolysis and further deprotected with TFA to give the desired product D-108.

[0128] [ka] Referring now to Scheme V, scaffold 85-6 was chlorinated at the 3-position with NCS to give 3-Cl indole scaffold 109-1, which was subsequently alkylated at the side chain 107-3, which was subsequently deprotected with TFA to give intermediate 109-3, followed by base to give D-109.

[0129] [ka] Scaffold 109-1 can be alkylated with 105-5 to give 110-1 as shown in Scheme VI, which can be subsequently deprotected with TFA (to remove the N-Boc group) and aqueous basic methanol (to remove the phenylsulfonyl group) to give D-110.

[0130] [ka] Now referring to Scheme VII, scaffolds 109-1 and 85-7 can be alkylated with 115-5 to give 111-1 and 112-1 (respectively), which can be subsequently deprotected with TFA (to remove the N-Boc group(s)) and aqueous basic methanol (to remove the phenylsulfonyl group(s)) to give D-111 / D112. Side chains 115-5 can be prepared as shown in the lower part of the scheme. EXAMPLES

[0131] Working Example Materials: All chemicals were reagent grade and used without further purification. Chromatographic elution solvent systems are reported in volume:volume ratios. LC-MS data were obtained using a LC Thermo Finnigan Surveyor-MS Thermo Finnigan AQA in either positive or negative mode as described below:

[0132] LCMS-Condition 01: Method:- LCMS_X-Selection (Formic Acid) Column: X-Select CSH C18 (4.6*50)mm 2.5u, Mobile phase: A. 0.1% formic acid in water, B. 0.1% formic acid in acetonitrile, Inj volume: 5.0μL, Flow rate: 1.0.mL / min, Gradient program: 2% B to 98% B in 2.8min, hold till 4.8min, B conc at 5.0min is 2% till 7.0min.

[0133] LCMS-Condition 02: Method:- LCMS_X-Crosslinking (NH3) Column: X-bridged C18 (3.0*50)mm 2.5μ; Mobile phase: A. 0.05% NH3 in water; B. 0.05% NH3 in acetonitrile, Inj volume: .2μL, Flow rate: 1.0mL / min; Gradient program: 1% B~90% B in 1.5min, 100% B in 2.8min, hold till 2.5min, B conc at 3.0min is 1% till 4.0min.

[0134] LCMS-Condition 03: Method:- LCMS_X-Select (Ammonium Bicarbonate) Column: X-Select CSH C18 (3.0*50)mm 2.5u; Mobile phase: A: 5mM ammonium bicarbonate in water); B: acetonitrile; Inj volume: 2μL, flow rate: 1.2mL / min; Column oven temp. 50 C; Gradient program: 0% B to 98% B in 2.0 min, hold till 3.0 min, B conc at 3.2 min is 0% till 4.0 min.

[0135] Example 1: Synthesis of 3-fluoro-N-(3-fluoro-4-((8-fluoro-7-(o-tolyl)pyrrolo[3,2-e]indazol-6(3H)-yl)methyl)phenethyl)propan-1-amine (D-105) Process 1 To 2-(3-fluoro-4-methylphenyl)acetonitrile 105-1 (5.00 g, 33.55 mmol) in THF (60 mL) was added BH3.DMS (7.65 g, 100.67 mmol) at 0° C. under argon atmosphere. The reaction mixture was heated to 70° C. for another 5 h. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to 0° C., quenched dropwise with a mixture of 1N HCl (10 mL) and methanol (10 mL), and heated to 70° C. for 1 h. The reaction mixture was concentrated under reduced pressure to give the crude compound. The crude compound was purified by trituration with diethyl ether, filtered and dried to give 5.00 g (78.7% yield) of 105-2 (HCl) as a white solid. LCMS-Condition-1: [M+H] + = 154.50; Rt = 0.792 minutes 1H NMR (400 MHz, DMSO-d6) δ: 8.15 (br. s, 3H), 7.23 (t, J = 7.82 Hz, 1H), 7.07 (d, J = 10.27 Hz, 1H), 6.99 (d, J = 7.34 Hz, 1H), 6.53 (br. s, 1H), 3.00 (br. s, 2H), 2.84 - 2.90 (m, 2H), 2.20 (s, 3H).

[0136] Process 2 To 2-(3-fluoro-4-methylphenyl)ethan-1-amine hydrochloride 105-2 (5.00 g, 26.36 mmol) in THF (80 mL) was added triethylamine (15.3 mL, 110.62 mmol) and stirred for 10 min, then 1-fluoro-3-iodopropane 3 (7.48 g, 39.82 mmol) was added at room temperature under argon atmosphere. The reaction mixture was further heated to 70° C. and stirred for 6 h. After consumption of 105-2 and 1-iodo-3-fluoropropane (monitored by TLC), the formation of 3-fluoro-N-(3-fluoro-4-methylphenethyl)propan-1-amine 105-3 was indicated. To the resulting solution was added Boc anhydride (14.5 g, 66.37 mmol) at room temperature and stirred for 18 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (2x100 mL). The combined organic layers were washed with water (2x40 mL), brine (40 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude compound obtained was purified by silica gel column chromatography eluting with 0-30% ethyl acetate in n-hexane to give 2.14 g (31% yield) of 105-4 as a colorless oil. LCMS-Condition-1: [M-tBu] + = 258.30; Rt = 2.216 minutes 1H NMR (400 MHz, CDCl3) δ: 7.08 (t, J = 7.83 Hz, 1H), 6.79 - 6.88 (m, 2H), 4.35 - 4.54 (m, 2H), 3.35 - 3.41 (m, 2H), 3.19 - 3.31 (m, 2H), 2.73 - 2.84 (m, 2H), 2.23 (s, 3H), 1.79 - 1.99 (m, 2H), 1.44 (br. s, 9H).

[0137] Process 3 To tert-butyl (3-fluoro-4-methylphenethyl)(3-fluoropropyl)carbamate 105-4 (2.10 g, 6.709 mmol) in CCl4 (30 mL) was added NBS (1.55 g, 8.722 mmol) and benzoyl peroxide (0.081 g, 0.335 mmol) at room temperature under argon atmosphere. The reaction mixture was further heated at 70 °C for 1.5 h. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to 0 °C and diluted with water. The separated aqueous layer was extracted with CHCl (2x50 mL). The combined organic layers were washed with water (40 mL) and brine (30 mL), dried over anhydrous NaSO, filtered and concentrated under reduced pressure to give the crude compound as a brown solid. The crude compound was purified by silica gel column chromatography eluting with 0-15% ethyl acetate in n-hexane to give 0.675 g (26% yield) of 105-5 as a thick colorless oil. LCMS-Condition-1: [M-18] + = 375.00; Rt = 2.241 minutes 1 H NMR (400 MHz, CDCl3) δ: 8.11 (d, J = 7.34 Hz, 1H), 7.48 (t, J = 7.83 Hz, 1H), 7.27 - 7.34 (m, 1H), 4.50 (s, 2H), 3.36 - 3.44 (m, 2H), 3.26 (d, J = 14.18 Hz, 2H), 2.74 - 2.88 (m, 2H), 2.19 - 2.31 (m, 1H), 1.79 - 1.99 (m, 3H), 1.44 (br. s, 9H).

[0138] Process 4 To 8-fluoro-3-(phenylsulfonyl)-7-(o-tolyl)-3,6-dihydropyrrolo[3,2-e]indazole 85-7 (1.02 g, 2.518 mmol) in DMF (10 mL) was added sodium hydride (60% dispersion in oil, 0.252 g, 6.295 mmol) portionwise at 0° C. The reaction mixture was allowed to reach room temperature for 10 min. The resulting solution was cooled to 0° C. and tert-butyl (4-(bromomethyl)-3-fluorophenethyl)(3-fluoropropyl)carbamate (1.18 g, 3.010 mmol) was added thereto. The reaction mixture was allowed to reach room temperature and stirred for 2 h. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to 0° C. and diluted with water (100 mL). The aqueous layer was separated and extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with water (2x40mL) and brine (40mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude compound as a brown solid. The crude compound obtained was purified by silica gel column chromatography eluting with 0-2% methanol in DCM to give the title compounds 105-6, 0.121g (12% yield) and 105-7, 0.520g (37% yield) as light yellow solids. 105-6 LCMS-Condition-1: [M+Na] + = 739.75; Rt = 2.503 minutes 105-7 LCMS-Condition-1: [M-tBu] + = 521.60; Rt = 2.301 minutes 1H NMR (400 MHz, DMSO-d6) δ: 13.22 (br. s, 1H), 8.17 (s, 1H), 7.52 (br. s, 1H), 7.26 - 7.42 (m, 5H), 6.93 (d, J = 10.76 Hz, 1H), 6.78 (d, J = 7.34 Hz, 1H), 6.30 (t, J = 7.83 Hz, 1H), 5.22 - 5.41 (m, 2H), 4.43 (d, J = 5.38 Hz, 1H), 4.31 (t, J = 4.89 Hz, 1H), 3.23 - 3.29 (m, 2H), 3.13 (br. s, 2H), 2.63 - 2.69 (m, 2H), 2.11 (br. s, 3H), 1.69 - 1.81 (m, 2H), 1.32 (br. s, 4H), 1.24 (br. s, 5H).

[0139] Process 5 To tert-butyl (3-fluoro-4-((8-fluoro-7-(o-tolyl)pyrrolo[3,2-e]indazol-6(3H)-yl)methyl)phenethyl)(3-fluoropropyl)carbamate 105-7 (0.250 g, 0.434 mmol) in diethyl ether (5 mL) was added 4M dioxane in HCl solution (2 mL) at 0° C. The reaction mixture was allowed to reach room temperature and stirred for 18 h. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated under reduced pressure to give the crude compound as HCl salt, which was washed with n-hexane, filtered and dried. The crude compound was purified by preparative HPLC to give 0.080 g (39% yield) of D-108 as an off-white solid. LCMS-Condition-1: [M+H] + = 477.55; Rt = 1.456 minutes 1H NMR (400 MHz, DMSO-d6) δ: 13.22 (br. s, 1H), 8.17 (br. s, 1H), 7.56 (d, J = 9.29 Hz, 1H), 7.26 - 7.44 (m, 5H), 6.94 (d, J = 11.25 Hz, 1H), 6.79 (d, J = 7.83 Hz, 1H), 6.29 (t, J = 7.82 Hz, 1H), 5.20 - 5.41 (m, 2H), 4.50 (t, J = 5.62 Hz, 1H), 4.38 (t, J = 5.62 Hz, 1H), 2.53 - 2.66 (m, 7H), 2.09 (s, 3H), 1.66 - 1.75 (m, 2H).

[0140] Example 2: Synthesis of N-(3,5-difluoro-4-((8-fluoro-7-(o-tolyl)pyrrolo[3,2-e]indazol-6(3H)-yl)methyl)phenethyl)-3-fluoropropan-1-amine (D-106) Process 1 To 4-bromo-2,6-difluorobenzaldehyde (15.0 g, 67.84 mmol) in DMA (220 mL) was added methyl acrylate (9.20 mL, 8.74 g, 101.52 mmol), triphenylphosphine (1.77 g, 6.756 mmol) and triethylamine (18.8 mL, 135.14 mmol) at room temperature and degassed with nitrogen for 10 min. To the resulting solution was added Pd(OAc)2 (0.759 g, 3.388 mmol) and further degassed with nitrogen for 10 min at room temperature. The reaction mixture was further heated to 80° C. and stirred for 6 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (2×100 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The obtained crude compound was purified by silica gel column chromatography eluting with 0-4% ethyl acetate in n-hexane to give 15.0 g (98.0% yield) of 106-1 as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ: 10.19 (s, 1H), 7.73 (d, J=10.27 Hz, 2H), 7.67 (d, J=16.14 Hz, 1H), 6.95 (d, J=16.14 Hz, 1H), 3.75 (s, 3H).

[0141] Process 2 To methyl (E)-3-(3,5-difluoro-4-formylphenyl)acrylate 106-1 (6.00 g, 26.43 mmol) in methanol (120 mL) and ethyl acetate (2 mL) was added 10% PtO2 (0.600 g, 2.643 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was further stirred at room temperature under hydrogen atmosphere using a hydrogen bladder for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a pad of Celite and washed with methanol (200 mL). The filtrate was concentrated under reduced pressure to give the crude compound. The crude compound was purified by silica gel column chromatography eluting with 0-30% ethyl acetate in n-hexane to give 6.00 g (99.6% yield) of 106-2 as a colorless oil. LCMS-Condition-1: [M+ACN] + = 269.90; Rt = 1.995 minutes 1 H NMR (400 MHz, DMSO-d6) δ: 10.16 (s, 1H), 7.18 (d, J=10.27 Hz, 2H), 3.59 (s, 3H), 2.90-2.96 (m, 2H), 2.69-2.75 (m, 2H).

[0142] Process 3 To methyl 3-(3,5-difluoro-4-formylphenyl)propanoate 106-2 (6.00 g, 26.29 mmol) in methanol (70 mL) was added sodium borohydride (0.500 g, 13.20 mmol) at 0° C. The reaction mixture was allowed to reach room temperature and stirred for 1 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water (50 mL) and extracted with DCM (3×50 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give 2.80 g (46.3% yield) of 106-3 as a colorless oil. LCMS-Condition-1: [M-H2O] + = 212.70; Rt = 1.768 minutes 1 H NMR (400 MHz, DMSO-d6) δ: 6.83-6.87 (m, 2H), 5.06 (t, J=5.62 Hz, 1H), 4.33 (d, J=5.87 Hz, 2H), 3.47 (s, 3H), 2.69-2.77 (m, 2H), 2.50-2.59 (m, 2H).

[0143] Process 4 To a solution of methyl 3-(3,5-difluoro-4-(hydroxymethyl)phenyl)propanoate 106-3 (4.50 g, 19.54 mmol) in DMF (50 mL) was added sodium hydride (60% dispersion in oil, 1.17 g, 29.32 mmol) portionwise at 0° C. and stirred for 20 min. To the resulting solution was added benzyl bromide (3.48 mL, 29.32 mmol) at 0° C. The reaction mixture was allowed to reach room temperature and stirred for 4 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (2×50 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude compound as a brown solid. The obtained crude compound was purified by 100-200 mesh size silica gel column chromatography eluting with 0-3% ethyl acetate in n-hexane to give 6.00 g (95.8% yield) of 106-4 as a colorless oil. LCMS-Condition-1: [M+Na]+ = 343.90; Rt = 2.326 minutes 1 H NMR (400 MHz, DMSO-d6) δ: 7.27-7.38 (m, 5H), 7.03 (d, J=8.31 ​​Hz, 2H), 4.51 (s, 4H), 3.58 (s, 3H), 2.86 (d, J=7.83 Hz, 2H), 2.63-2.70 (m, 2H).

[0144] Process 5 To methyl 3-(4-((benzyloxy)methyl)-3,5-difluorophenyl)propanoate 106-4 (5.50 g, 17.16 mmol) in THF or methanol (40 mL) was added a solution of lithium hydroxide (7.48 g, 39.82 mmol) in water (20 mL) at room temperature and stirred for 1 h. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated under reduced pressure, diluted with water (50 mL) and extracted with ethyl acetate (3x50 mL). The aqueous layer was acidified to pH=2 using citric acid and extracted with ethyl acetate (3x50 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give 5.00 g (95.2% yield) of the title compound 106-5 as a colorless oil. 1 H NMR (400 MHz, DMSO-d6) δ: 12.13 (br. s, 1H), 7.25-7.38 (m, 5H), 7.02 (d, J=8.31 ​​Hz, 2H), 4.51 (s, 4H), 2.79-2.87 (m, 2H), 2.57 (t, J=7.58 Hz, 2H).

[0145] Process 6 To 3-(4-((benzyloxy)methyl)-3,5-difluorophenyl)propanoic acid 106-5 (5.00 g, 16.32 mmol) in DCM (50 mL) was added thionyl chloride (11.8 mL, 163.23 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was further heated to reflux at 75° C. for 4 h. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated under reduced pressure to dryness under nitrogen atmosphere. To the obtained corresponding acid chloride of 106-5 (5.00 g, 15.39 mmol), dry acetone (50 mL) was added followed by sodium azide (2.00 g, 30.76 mmol) at room temperature under nitrogen atmosphere and stirred for 3 h. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated under reduced pressure to dryness under nitrogen atmosphere. To the obtained azide intermediate of 106-5 (4.50 g, 14.83 mmol), tert-butanol (40 mL) was added at room temperature under nitrogen atmosphere. The reaction mixture was further heated to reflux at 85 °C for 18 h. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated under reduced pressure to dryness to give crude Boc-protected 106-6 compound. The crude compound was purified by silica gel column chromatography eluting with 0-10% ethyl acetate in n-hexane to give 3 g of Boc-protected 106-6 as a colorless oil. Boc-protected 106-6 was dissolved in DCM (25 mL) and trifluoroacetic acid (5 mL) was added dropwise at room temperature and stirred for 3 h. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated under reduced pressure to dryness to give 2.20 g (48.5% yield) of 106-6 as a colorless oil. LCMS-Condition-1: [M+H] + = 277.90; Rt = 1.467 minutes 1 H NMR (400 MHz, DMSO-d6) δ: 7.25-7.38 (m, 5H), 6.98 (d, J=8.37 Hz, 2H), 4.51 (s, 4H), 2.76-2.83 (m, 2H), 2.64-2.70 (m, 2H).

[0146] Process 7 To 2-(4-((benzyloxy)methyl)-3,5-difluorophenyl)ethan-1-amine 106-6 (2.20 g, 7.933 mmol) in THF (20 mL) was added triethylamine (3.29 mL, 23.72 mmol) followed by a solution of 1-fluoro-3-iodopropane (1.49 g, 7.933 mmol) in THF (10 mL) at room temperature under argon atmosphere. The reaction mixture was further heated to 80° C. in a sealed tube and stirred for 18 h. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated under reduced pressure to give the crude compound. The crude compound was purified by 100-200 mesh size silica gel column chromatography eluting with 0-5% methanol in DCM to give 1.60 g (59.9% yield) of 106-7 as a thick brown oil. LCMS-Condition-1: [M+H] + = 338.10; Rt = 1.612 minutes 1 H NMR (400 MHz, DMSO-d6) δ: 7.25-7.39 (m, 5H), 7.01 (d, J=7.88 Hz, 2H), 4.53-4.55 (m, 1H), 4.51 (s, 4H), 4.37-4.46 (m, 1H), 2.75 (dd, J=4.92, 10.83 Hz, 4H), 2.63 (t, J=6.64 Hz, 2H), 1.66-1.87 (m, 2H).

[0147] Process 8 To a stirred solution of N-(4-((benzyloxy)methyl)-3,5-difluorophenethyl)-3-fluoropropan-1-amine 106-7 (1.60 g, 4.742 mmol) in DCM (30 mL) was added triethylamine (1.96 mL, 14.13 mmol) at 0° C. and stirred for 10 min. To the resulting solution was added Boc anhydride (1.55 g, 7.110 mmol) at the same temperature. The reaction mixture was allowed to reach room temperature and stirred for 3 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water (100 mL) and extracted with DCM (2×100 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The obtained crude compound was purified by 100-200 mesh size silica gel column chromatography eluting with 0-20% ethyl acetate in n-hexane to give 1.80 g (86.9% yield) of 106-8 as a yellow oil. LCMS-Condition-1: [M-Boc] + = 337.90; Rt = 2.490 minutes 1 H NMR (400 MHz, DMSO-d6) δ: 7.24-7.38 (m, 5H), 6.98 (d, J=7.88 Hz, 2H), 4.46-4.56 (m, 4H), 4.36 (t, J=5.91 Hz, 1H), 3.38 (t, J=6.89 Hz, 2H), 3.22 (br. s, 2H), 2.79 (t, J=6.89 Hz, 2H), 1.75-1.90 (m, 2H), 1.35 (br. s, 4H), 1.30 (br. s, 5H), 1.17 (t, J=7.14 Hz, 1H).

[0148] Process 9 To tert-butyl (4-((benzyloxy)methyl)-3,5-difluorophenethyl)(3-fluoropropyl)carbamate 106-8 (1.80 g, 4.114 mmol) in methanol:ethyl acetate (1:1; 100 mL) was added 10% Pd / C (50% humidity; 0.800 g) at room temperature under nitrogen atmosphere. The reaction mixture was further stirred at room temperature under hydrogen atmosphere for 8 h. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a pad of Celite and washed with methanol (200 mL). The filtrate was concentrated under reduced pressure to give 1.40 g (98.6% yield) of 106-9 as a colorless sticky liquid. LCMS-Condition-1: [M-Boc] + = 248.00; Rt = 2.168 minutes 1 H NMR (400 MHz, DMSO-d6) δ: 6.92 (d, J=7.88 Hz, 2H), 5.17 (br. s, 1H), 4.43-4.51 (m, 3H), 4.36 (t, J=5.91 Hz, 1H), 3.36 (t, J=7.14 Hz, 2H), 3.22 (t, J=6.64 Hz, 2H), 2.77 (t, J=7.14 Hz, 2H), 1.74-1.90 (m, 2H), 1.33 (br. s, 9H).

[0149] Step 10 To tert-butyl (3,5-difluoro-4-(hydroxymethyl)phenethyl)(3-fluoropropyl)carbamate 106-9 (1.40 g, 4.030 mmol) in DCM (50 mL) was added triphenylphosphine (1.58 g, 6.055 mmol) and carbon tetrabromide (2.00 g, 6.048 mmol) portionwise at 0 °C. The reaction mixture was allowed to reach room temperature and stirred for 5 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (3x100 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The obtained crude compound was purified by silica gel column chromatography eluting with 0-40% ethyl acetate in n-hexane to give 1.20 g (72.7% yield) of 106-10 as an off-white solid. LCMS-Condition-1: [M+ACN+Na] + = 474.30; Rt = 1.640 minutes 1 H NMR (400 MHz, DMSO-d6) δ: 7.02 (d, J=8.37 Hz, 2H), 4.62 (s, 2H), 4.48 (t, J=5.91 Hz, 1H), 4.36 (t, J=5.66 Hz, 1H), 3.39 (t, J=6.64 Hz, 2H), 3.23 (br. s, 2H), 2.79 (t, J=6.89 Hz, 2H), 1.75-1.90 (m, 2H), 1.35 (br. s, 4H), 1.29 (br. s, 5H)

[0150] Step 11 To 8-fluoro-3-(phenylsulfonyl)-7-(o-tolyl)-3,6-dihydropyrrolo[3,2-e]indazole (0.700 g, 1.726 mmol) 85-7 in DMF (10 mL) was added sodium hydride (60% dispersion in oil, 0.138 g, 3.452 mmol) portionwise at 0° C. The reaction mixture was allowed to reach room temperature and stirred for 15 min. The resulting solution was cooled to 0° C. and tert-butyl (4-(bromomethyl)-3,5-difluorophenethyl)(3-fluoropropyl)carbamate 106-10 (0.921 g, 2.245 mmol) was added thereto. The reaction mixture was allowed to reach room temperature and stirred for 2 h. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to 0° C. and diluted with water (100 mL). The aqueous layer was separated and extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with water (40 mL), then brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude compound as a brown solid. The crude compound obtained was purified by 100-200 mesh size silica gel column chromatography eluting with 0-30% ethyl acetate in n-hexane to give 1.20 g (95% yield) of 106-11 as a thick brown oil. LCMS-Condition-1: [M-tBu] + = 679.20; Rt = 1.850 minutes

[0151] Step 12 To tert-butyl (3,5-difluoro-4-((8-fluoro-3-(phenylsulfonyl)-7-(o-tolyl)pyrrolo[3,2-e]indazol-6(3H)-yl)methyl)phenethyl)(3-fluoropropyl)carbamate 106-11 (1.20 g, 1.633 mmol) in DCM (15 mL) was added trifluoroacetic acid (5 mL) portionwise at 0° C. The reaction mixture was allowed to reach room temperature and stirred for 2 h. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated under reduced pressure to give a crude residue. The crude residue was diluted with DCM (50 mL) and washed with saturated NaHCO3 solution (2×25 mL). The organic layer was separated, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude compound. The resulting crude compound was purified by 100-200 mesh size silica gel column chromatography eluting with 0-8% methanol in DCM to give 0.700 g (67.9% yield) of 106-12 as a sticky brown oil. LCMS-Condition-1: [M-H2O] + = 617.20; Rt = 1.715 minutes 1 H NMR (400 MHz, DMSO-d6) δ: 8.56 (s, 1H), 7.92 (s, 1H), 7.85 (d, J=6.85 Hz, 2H), 7.78-7.83 (m, 1H), 7.58-7.63 (m, 1H), 7.49 (t, J=7.83 Hz, 2H), 7.25-7.31 (m, 1H), 7.11-7.21 (m, 3H), 6.64 (d, J=8.80 Hz, 2H), 5.65 (d, J=0.98 Hz, 1H), 5.21-5.41 (m, 2H), 4.40 (t, J=5.62 Hz, 1H), 4.28 (t, J=5.62 Hz, 1H), 2.42-2.57 (m, 6H), 1.77 (s, 2H), 1.54-1.68 (m, 3H).

[0152] Step 13 To N-(3,5-difluoro-4-((8-fluoro-3-(phenylsulfonyl)-7-(o-tolyl)pyrrolo[3,2-e]indazol-6(3H)-yl)methyl)phenethyl)-3-fluoropropan-1-amine 106-12 (0.700 g, 1.102 mmol) in methanol (25 mL) was added an aqueous solution of potassium carbonate (0.305 g, 2.208 mmol) at room temperature and stirred for 1 h. The reaction mixture was further heated at 45° C. for 1 h. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated under reduced pressure, diluted with water (20 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude compound. The crude compound was purified by Combi flash column chromatography eluting with 0-10% methanol in DCM to give 0.010 g (11.0% yield) of D-106 as an off-white solid. LCMS-Condition-1: [M+H] + = 495.15; Rt = 1.492 minutes 1 H NMR (400 MHz, DMSO-d6) δ: 13.18 (br. s, 1H), 8.12 (br. s, 1H), 7.63 (d, J=9.29 Hz, 1H), 7.26-7.41 (m, 5H), 6.75 (d, J=9.29 Hz, 2H), 5.30-5.42 (m, 2H), 4.50 (t, J=5.87 Hz, 1H), 4.38 (t, J=6.11 Hz, 1H), 2.53-2.66 (m, 6H), 1.97 (s, 3H), 1.63-1.78 (m, 3H).

[0153] Example 3: Synthesis of N-(4-((1,8-difluoro-7-(o-tolyl)pyrrolo[3,2-e]indazol-6(3H)-yl)methyl)phenethyl)-3-fluoropropan-1-amine (D-107) Process 1 To 2-(p-tolyl)ethan-1-amine (20.0 g, 147.91 mmol) in THF (300 mL) was added triethylamine (61.6 mL, 444.35 mmol) and 1-fluoro-3-iodopropane 2 (27.8 g, 147.91 mmol) at room temperature under argon atmosphere. The reaction mixture was further heated to 80 °C and stirred for 18 h. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated under reduced pressure to give the crude compound. The crude compound was purified by 100-200 mesh size silica gel column chromatography eluting with 0-2% methanol in DCM to give 12.0 g (45.4% yield) of 107-1 as a colorless thick oil. LCMS-Condition-1: [M+H] + = 195.90; Rt = 1.042 minutes 1 H NMR (400 MHz, DMSO-d6) δ: 7.04-7.13 (m, 4H), 4.54 (t, J=5.87 Hz, 1H), 4.42 (t, J=5.87 Hz, 1H), 3.07 (br. s, 1H), 2.70-2.75 (m, 2H), 2.61-2.68 (m, 4H), 2.25 (s, 3H), 1.70-1.84 (m, 2H).

[0154] Process 2 To 3-fluoro-N-(4-methylphenethyl)propan-1-amine 107-1 (12.0 g, 61.45 mmol) in DCM or THF (250 mL) at 0 °C was added triethylamine (25.6 mL, 184.35 mmol) followed by Boc anhydride (20.1 g, 92.20 mmol) and stirred at the same temperature for 10 min. The reaction mixture was allowed to reach room temperature and stirred for 6 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water (100 mL) and extracted with DCM (3x100 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The obtained crude compound was purified by silica gel column chromatography eluting with 0-10% ethyl acetate in n-hexane to give 12.0 g (66.2% yield) of 107-2 as a yellow oil. LCMS-Condition-1: [M+Na] + = 318.15; Rt = 2.294 minutes 1 H NMR (400 MHz, DMSO-d6) δ: 7.04-7.13 (m, 4H), 4.47 (t, J=5.87 Hz, 1H), 4.35 (t, J=5.87 Hz, 1H), 3.29 (d, J=7.83 Hz, 2H), 3.19 (t, J=6.36 Hz, 2H), 2.71 (t, J=7.58 Hz, 2H), 2.26 (s, 3H), 1.72-1.89 (m, 2H), 1.35 (br. s, 9H).

[0155] Process 3 To tert-butyl (3-fluoropropyl) (4-methylphenethyl) carbamate 107-2 (17.0 g, 57.54 mmol) in CCl4 (170 mL) was added NBS (15.4 g, 86.41 mmol) and benzoyl peroxide (1.39 g, 5.738 mmol) at room temperature under argon atmosphere. The reaction mixture was further heated at 70 °C for 2 h. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a pad of Celite and the obtained filtrate was concentrated under reduced pressure to give the crude compound. The crude compound was purified by 100-200 mesh size silica gel column chromatography eluting with 0-20% ethyl acetate in n-hexane to give 7.00 g (32.5% yield) of 107-3 as a yellow oil. LCMS-Condition-1: [M+Na] + = 398.05; Rt = 2.262 minutes 1 H NMR (400 MHz, DMSO-d6) δ: 7.37 (d, J=7.83 Hz, 2H), 7.19 (d, J=6.85 Hz, 2H), 4.68 (s, 2H), 4.47 (t, J=5.87 Hz, 1H), 4.35 (t, J=5.87 Hz, 1H), 3.17-3.24 (m, 3H), 2.76 (t, J=7.34 Hz, 2H), 1.74-1.88 (m, 3H), 1.33 (br. s, 9H).

[0156] Process 4 To 5-nitro-1H-indazole (10.0 g, 61.34 mmol) in acetonitrile:acetic acid (1:1; 100 mL) was added Selectfluor (43.4 g, 122.67 mmol) at room temperature. The reaction mixture was further heated at 130 °C for 24 h. After completion of the reaction, the reaction mixture was quenched with ice-cold water and the precipitated solid was filtered and dried to give the crude compound. The crude compound was purified by 100-200 mesh size silica gel column chromatography eluting with 0-10% ethyl acetate in n-hexane to give 5.00 g (45% yield) of 107-4 as a pale yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ: 13.30 (br. s, 1H), 8.76 (d, J=1.96 Hz, 1H), 8.25 (dd, J=1.96, 9.29 Hz, 1H), 7.70 (dd, J=1.96, 9.29 Hz, 1H)

[0157] Process 5 To 3-fluoro-5-nitro-1H-indazole 107-4 (10 g, 55.25 mmol) in THF (100 mL) was added sodium hydroxide (5.52 g, 138.12 mmol), n-tetrabutylammonium sulfate (0.281 g, 0.827 mmol) at room temperature and stirred for 1 h. To the resulting solution was added benzenesulfonyl chloride (10.7 g, 60.58 mmol) dropwise and stirred for another 1 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with water (100 mL) and the precipitated solid was filtered and dried to give 14.0 g (78.8% yield) of 107-5 as a white solid. LCMS-Condition-1: [M-18] + = 304.00; Rt = 1.992 minutes 1H NMR (400 MHz, CDCl3) δ: 8.59-8.63 (m, 1H), 8.51 (dd, J=1.97, 9.35 Hz, 1H), 8.35 (d, J=8.37 Hz, 1H), 8.02 (d, J=8.37 Hz, 2H), 7.62-7.70 (m, 1H), 7.54 (t, J=7.88 Hz, 2H).

[0158] Process 6 To 3-fluoro-5-nitro-1-(phenylsulfonyl)-1H-indazole 107-5 (14.0 g, 43.57 mmol) in methanol (140 mL) and water (60 mL) was added iron powder (0.407 g, 7.288 mmol) and ammonium chloride (23.27 g, 435.03 mmol) at room temperature. The reaction mixture was further heated at 80° C. for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a pad of celite and washed with methanol (25 mL) and THF (25 mL). The filtrate was concentrated to dryness under reduced pressure to give 12.0 g (crude) of 107-6 as a brown solid, which was used directly in the next step without further purification. LCMS-Condition-1: [M+Na] + = 314.90; Rt = 1.735 minutes

[0159] Process 7 To 3-fluoro-1-(phenylsulfonyl)-1H-indazol-5-amine 107-6 (12.0 g, 41.19 mmol) in acetonitrile (150 mL) was added NIS (12.06 g, 53.60 mmol) dropwise at room temperature and stirred for 2 h. After completion of the reaction, the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (3x50 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude compound obtained was purified by 100-200 mesh size silica gel column chromatography eluting with 10-15% ethyl acetate in n-hexane to give 6.00 g (34.8% yield) of 107-7 as a yellow solid. LCMS-Condition-1: [M+H] += 417.95; Rt = 2.090 minutes 1 H NMR (400 MHz, DMSO-d6) δ: 7.88 (d, J=8.80 Hz, 1H), 7.83 (d, J=8.31 ​​Hz, 2H), 7.69-7.75 (m, 1H), 7.56-7.63 (m, 2H), 7.17 (d, J=9.29 Hz, 1H), 5.66 (br. s, 2H).

[0160] Process 8 To 3-fluoro-4-iodo-1-(phenylsulfonyl)-1H-indazol-5-amine 107-7 (8.00 g, 19.17 mmol) in CHCl (100 mL) was added triethylamine (10.6 mL, 76.70 mmol) and TFAA (5.40 mL, 8.05 g, 38.35 mmol) at 0 °C. The reaction mixture was allowed to reach room temperature and stirred for 2 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water (50 mL) and extracted with CHCl (3x50 mL). The combined organic layers were dried over anhydrous NaSO, filtered and concentrated under reduced pressure. The crude compound obtained was purified by 100-200 mesh size silica gel column chromatography eluting with 10-20% ethyl acetate in n-hexane to give 9.50 g (96.5% yield) of 107-8 as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ: 8.08 (d, J=8.86 Hz, 1H), 7.92 (d, J=7.88 Hz, 2H), 7.72-7.79 (m, 2H), 7.58-7.65 (m, 2H).

[0161] Process 9 To a solution of 2,2,2-trifluoro-N-(3-fluoro-4-iodo-1-(phenylsulfonyl)-1H-indazol-5-yl)acetamide 107-8 (9.50 g, 18.51 mmol) in DMF (150 mL) was added copper iodide (0.353 g, 1.853 mmol), triethylamine (12.8 mL, 92.31 mmol) at room temperature and degassed with argon for 30 min. To the resulting solution was added catalyst dichlorobis(triphenylphosphine)palladium(II) (1.29 g, 1.837 mmol) and 1-ethynyl-2-methylbenzene (2.58 g, 22.20 mmol) and degassed for another 30 min. The reaction mixture was further heated to 130 °C and stirred for 18 h. After completion of the reaction, the reaction mixture was filtered through a pad of Celite, the filtrate was diluted with water (50 mL) and extracted with ethyl acetate (3x50 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude compound obtained was purified by 100-200 mesh size silica gel column chromatography eluting with 10-20% ethyl acetate in n-hexane to give 4.00 g (53.3% yield) of 107-9 as a yellow solid. LCMS-Condition-1: [M+H] + = 405.90; Rt = 2.151 and 2.275 min 1 H NMR (400 MHz, DMSO-d6) δ: 12.12 (br. s, 1H), 7.83-7.95 (m, 3H), 7.63-7.75 (m, 2H), 7.53-7.61 (m, 3H), 7.33 (d, J=3.91 Hz, 3H), 6.81 (s, 1H), 2.47 (br. s, 1H), 2.45 (s, 2H).

[0162] Step 10 To 1-fluoro-3-(phenylsulfonyl)-7-(o-tolyl)-3,6-dihydropyrrolo[3,2-e]indazole 107-9 (1 g, 2.466 mmol) in acetonitrile:DMSO (1:1; 20 mL) at -10 °C was added Selectfluor (3.14 g, 8.863 mmol) dropwise over 1 h under nitrogen atmosphere. The reaction mixture was allowed to reach room temperature and stirred for 6 h. After completion of the reaction, the reaction mixture was concentrated to dryness under reduced pressure and diluted with ethyl acetate (100 mL). The organic layer was separated, washed with water (30 mL) and brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting crude compound was purified by 100-200 mesh size silica gel column chromatography eluting with 0-10% ethyl acetate in n-hexane to give 0.450 g (43% yield) of 107-10 as a brown solid. LCMS-Condition-1: [M+Na] + = 445.95; Rt = 2.296 minutes 1 H NMR (400 MHz, CDCl3) δ: 12.04 (br. s, 1H), 7.94-7.99 (m, 1H), 7.90 (d, J=7.98 Hz, 2H), 7.78-7.83 (m, 1H), 7.69-7.75 (m, 1H), 7.56-7.63 (m, 2H), 7.45 (d, J=6.98 Hz, 1H), 7.38-7.42 (m, 2H), 7.31-7.37 (m, 1H), 2.34 (s, 3H).

[0163] Step 11 To 1,8-difluoro-3-(phenylsulfonyl)-7-(o-tolyl)-3,6-dihydropyrrolo[3,2-e]indazole 107-10 (0.300 g, 0.708 mmol) in DMF (10 mL) was added sodium hydride (60% dispersion in oil, 0.056 g, 1.416 mmol) portionwise at 0° C. The reaction mixture was allowed to reach room temperature and stirred for 15 min. The resulting solution was cooled to 0° C. and 107-3 (0.344 g, 0.919 mmol) was added thereto. The reaction mixture was allowed to reach room temperature and stirred for 2 h. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to 0° C. and diluted with water (100 mL). The aqueous layer was separated and extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with water (40 mL), then brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude compound as a brown solid. The crude compound obtained was purified by 100-200 mesh size silica gel column chromatography eluting with 0-30% ethyl acetate in n-hexane to give 0.300 g (59.1% yield) of 107-11 as a thick brown oil. LCMS-Condition-1: [M-Boc] + = 617.20; Rt = 2.579 minutes 1 H NMR (400 MHz, DMSO-d6) δ: 7.84-7.92 (m, 1H), 7.74-7.83 (m, 3H), 7.55-7.62 (m, 1H), 7.46 (t, J=7.63 Hz, 2H), 7.12-7.34 (m, 4H), 6.86 (d, J=7.38 Hz, 2H), 6.55 (d, J=5.91 Hz, 2H), 5.09-5.25 (m, 2H), 4.28 (t, J=5.17 Hz, 1H), 4.16 (t, J=5.17 Hz, 1H), 3.88 (q, J=7.38 Hz, 1H), 3.09 (t, J=7.14 Hz, 1H), 2.97 (br. s, 2H), 2.50 (t, J=7.14 Hz, 2H),1.91 (s, 3H), 1.49-1.68 (m, 2H), 1.18 (br. s, 4H), 1.07 (br. s, 5H).

[0164] Step 12 To tert-butyl (4-((1,8-difluoro-3-(phenylsulfonyl)-7-(o-tolyl)pyrrolo[3,2-e]indazol-6(3H)-yl)methyl)phenethyl)(3-fluoropropyl)carbamate 107-11 (0.250 g, 0.348 mmol) in DCM (5 mL) was added trifluoroacetic acid (3 mL) portionwise at 0° C. The reaction mixture was allowed to reach room temperature and stirred for 2 h. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated under reduced pressure to give the crude residue. The crude residue was diluted with DCM (50 mL) and washed with saturated NaHCO3 solution (2×25 mL). The organic layer was separated, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude compound. The resulting crude compound was purified by 100-200 mesh size silica gel column chromatography eluting with 0-8% methanol in DCM to give 0.150 g (69.7% yield) of 107-12 as a sticky brown oil. LCMS-Condition-1: [M+H] + = 617.00; Rt = 1.984 minutes 1 H NMR (400 MHz, DMSO-d6) δ: 8.03-8.08 (m, 1H), 7.88-7.99 (m, 3H), 7.69-7.77 (m, 1H), 7.61 (t, J=7.58 Hz, 2H), 7.39-7.47 (m, 2H), 7.29-7.38 (m, 3H), 7.02 (d, J=7.82 Hz, 2H), 6.68 (d, J=7.82 Hz, 2H), 5.25-5.38 (m, 2H), 4.51 (t, J=6.11 Hz, 1H), 4.39 (t, J=5.62 Hz, 1H), 2.66 (d, J=6.85 Hz, 2H), 2.61 (d, J=5.87 Hz, 4H), 2.03 (s, 3H), 1.67-1.82 (m, 2H).

[0165] Step 13 To N-(4-((1,8-difluoro-3-(phenylsulfonyl)-7-(o-tolyl)pyrrolo[3,2-e]indazol-6(3H)-yl)methyl)phenethyl)-3-fluoropropan-1-amine 107-12 (0.150 g, 0.243 mmol) in methanol (6 mL) was added an aqueous solution of potassium carbonate (0.050 g, 0.362 mmol) at room temperature and stirred for 1 h. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated under reduced pressure, concentrated with water (20 mL) and extracted with ethyl acetate (3x20 mL). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude compound. The crude compound was purified by Combi flash column chromatography eluting with 0-10% methanol in DCM to give 0.010 g (8.6% yield) of D-107 as an off-white solid. LCMS-Condition-1: [M+H] + = 477.15; Rt = 1.539 minutes 1 H NMR (400 MHz, DMSO-d6) δ: 12.63 (br. s, 1H), 7.63 (dd, J=1.47, 9.29 Hz, 1H), 7.29-7.44 (m, 4H), 7.25 (dd, J=1.96, 9.29 Hz, 1H), 7.02 (d, J=7.83 Hz, 2H), 6.68 (d, J=7.83 Hz, 2H), 5.18-5.34 (m, 2H), 4.50 (t, J=5.87 Hz, 1H), 4.39 (t, J=6.11 Hz, 1H), 2.57-2.71 (m, 6H), 2.10 (s, 3H), 1.66-1.82 (m, 3H).

[0166] Example 4: Synthesis of 3-fluoro-N-(3-fluoro-4-((1-fluoro-7-(o-tolyl)pyrrolo[3,2-e]indazol-6(3H)-yl)methyl)phenethyl)propan-1-amine (D-108) Process 1 To 1-fluoro-3-(phenylsulfonyl)-7-(o-tolyl)-3,6-dihydropyrrolo[3,2-e]indazole (1.00 g, 2.466 mmol) 107-9 in DMF (15 mL) was added sodium hydride (60% dispersion in oil, 0.197 g, 4.932 mmol) portionwise at 0° C. The reaction mixture was allowed to reach room temperature for 15 min. The resulting solution was cooled to 0° C. and tert-butyl (4-(bromomethyl)-3-fluorophenethyl)(3-fluoropropyl)carbamate 105-5 (1.25 g, 3.187 mmol) was added thereto. The reaction mixture was allowed to reach room temperature and stirred for 2 h. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to 0° C. and diluted with water (100 mL). The aqueous layer was separated and extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with water (40 mL) and brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude compound as a brown solid. The crude compound obtained was purified by 100-200 mesh size silica gel column chromatography eluting with 0-30% ethyl acetate in n-hexane to give 1.00 g (56.8% yield) of 108-1 as a thick brown oil. LCMS-Condition-1: [M+Na] + = 739.10; Rt = 2.520 minutes

[0167] Process 2 To tert-butyl (3-fluoro-4-((1-fluoro-3-(phenylsulfonyl)-7-(o-tolyl)pyrrolo[3,2-e]indazol-6(3H)-yl)methyl)phenethyl)(3-fluoropropyl)carbamate 108-1 (1.00 g, 1.395 mmol) in methanol (15 mL) was added potassium carbonate (0.385 g, 2.789 mmol) at room temperature. The reaction mixture was further heated at 50° C. for 2 h. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated under reduced pressure, diluted with water (100 mL) and extracted with ethyl acetate (2×100 mL). The combined organic layer was washed with water (2×40 mL) and brine (40 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude compound. The resulting crude compound was purified by 100-200 mesh size silica gel column chromatography eluting with 0-5% methanol in DCM to give 0.700 g (87.0% yield) of 108-2 as a brown semi-solid. LCMS-Condition-1: [M+Na] + = 599.10; Rt = 2.426 minutes

[0168] Process 3 To 3-fluoro-N-(3-fluoro-4-((1-fluoro-3-(phenylsulfonyl)-7-(o-tolyl)pyrrolo[3,2-e]indazol-6(3H)-yl)methyl)phenethyl)propan-1-amine 108-2 (0.700 g, 1.213 mmol) in DCM (15 mL) was added trifluoroacetic acid (5 mL) portionwise at 0° C. The reaction mixture was allowed to reach room temperature and stirred for 2 h. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated under reduced pressure to give a crude residue. The crude residue was diluted with DCM (mL) and extracted with saturated NaHCO3 solution. The organic layer was separated, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude compound as a brown solid. The resulting crude compound was purified by silica gel column chromatography eluting with 0-8% methanol in DCM and then purified again using preparative HPLC to give 0.105 g (18.1% yield) of D-108 as a pale yellow solid. LCMS-Condition-1: [M+H] + = 477.10; Rt = 1.581 minutes 1 H NMR (400 MHz, DMSO-d6) δ: 8.34 (br. s, 1H), 7.53 (d, J=8.98 Hz, 1H), 7.32 (br. s, 2H), 7.15-7.26 (m, 3H), 6.97 (d, J=10.97 Hz, 1H), 6.81 (d, J=7.98 Hz, 1H), 6.66 (s, 1H), 6.28 (t, J=7.73 Hz, 1H), 5.28 (br. s, 2H), 4.51 (t, J=5.24 Hz, 1H), 4.39 (t, J=5.24 Hz, 1H), 2.88-2.95 (m, 2H), 2.84 (t, J=6.98 Hz, 2H), 2.68-2.77 (m, 2H), 2.06 (s, 3H), 1.78-1.93 (m, 3H).

[0169] Example 5: Synthesis of N-(4-((8-chloro-7-(o-tolyl)pyrrolo[3,2-e]indazol-6(3H)-yl)methyl)phenethyl)-3-fluoropropan-1-amine (D-109) Process 1 To a solution of 3-(phenylsulfonyl)-7-(o-tolyl)-3,6-dihydropyrrolo[3,2-e]indazole 85-6 (1.00 g, 2.582 mmol) in DCM (15 mL) was added NCS (0.689 g, 5.159 mmol) portionwise at 0° C. The reaction mixture was allowed to reach room temperature and stirred for 16 h. After completion of the reaction (monitored by TLC), the precipitated solid was filtered, washed with DCM (10 mL) and dried to give 0.900 g (83.3% yield) of 109-1 as an off-white solid. LCMS-Condition-1: [M+H] + = 421.90; Rt = 2.634 minutes 1H NMR (400 MHz, DMSO-d6) δ: 12.25 (s, 1H), 8.80 (s, 1H), 8.01 (d, J=8.80 Hz, 1H), 7.90 (d, J=7.82 Hz, 2H), 7.66-7.75 (m, 2H), 7.58 (t, J=7.58 Hz, 2H), 7.31-7.45 (m, 4H), 2.26 (s, 3H).

[0170] Process 2 To a solution of 8-chloro-3-(phenylsulfonyl)-7-(o-tolyl)-3,6-dihydropyrrolo[3,2-e]indazole 109-1 (0.900 g, 2.133 mmol) in DMF (20 mL) was added sodium hydride (60% dispersion in oil, 0.170 g, 4.266 mmol) portionwise at 0 °C. The reaction mixture was allowed to reach room temperature and stirred for 15 min. The resulting solution was cooled to 0 °C and tert-butyl (4-(bromomethyl)phenethyl)(3-fluoropropyl)carbamate 107-3 (1.03 g, 2.775 mmol) was added thereto. The reaction mixture was allowed to reach room temperature and stirred for 2 h. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to 0 °C and diluted with water (100 mL). The aqueous layer was separated and extracted with ethyl acetate (2x50 mL). The combined organic layers were washed with water (40 mL) then brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude compound obtained was purified by 100-200 mesh size silica gel column chromatography eluting with 0-30% ethyl acetate in n-hexane to give 1.30 g (85.5% yield) of the title compound 109-2 as a thick brown oil. LCMS-Condition-1: [M-Boc] + = 615.20; Rt = 2.581 minutes

[0171] Process 3 To tert-butyl (4-((8-chloro-3-(phenylsulfonyl)-7-(o-tolyl)pyrrolo[3,2-e]indazol-6(3H)-yl)methyl)phenethyl)(3-fluoropropyl)carbamate 109-2 (1.30 g, 1.817 mmol) in DCM (20 mL) was added trifluoroacetic acid (5 mL) portionwise at 0° C. The reaction mixture was allowed to reach room temperature and stirred for 2 h. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated under reduced pressure to give the crude residue. The crude residue was diluted with DCM (50 mL) and washed with saturated NaHCO3 solution (2×25 mL). The organic layer was separated, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude compound. The resulting crude compound was purified by 100-200 mesh size silica gel column chromatography eluting with 0-8% methanol in DCM to give 0.700 g (63.0% yield) of the title compound 109-3 as a brown sticky oil. LCMS-Condition-1: [M+H] + = 615.10; Rt = 1.200 minutes 1 H NMR (400 MHz, DMSO-d6) δ: 8.82 (s, 1H), 7.99-8.04 (m, 1H), 7.90-7.94 (m, 2H), 7.68-7.74 (m, 1H), 7.59 (t, J=7.67 Hz, 2H), 7.28-7.47 (m, 5H), 7.04 (d, J=7.89 Hz, 2H), 6.71 (d, J=7.89 Hz, 2H), 5.21-5.37 (m, 3H), 4.52 (t, J=5.70 Hz, 1H), 4.40 (t, J=5.48 Hz, 1H), 2.74-2.79 (m, 1H), 2.65 (d, J=6.58 Hz, 4H), 1.96 (s, 3H), 1.68-1.86 (m, 3H).

[0172] Process 4 To N-(4-((8-chloro-3-(phenylsulfonyl)-7-(o-tolyl)pyrrolo[3,2-e]indazol-6(3H)-yl)methyl)phenethyl)-3-fluoropropan-1-amine 109-3 (0.700 g, 1.137 mmol) in methanol (25 mL) was added an aqueous solution of potassium carbonate (0.314 g, 2.275 mmol) at room temperature and stirred for 1 h. The reaction mixture was further heated at 45° C. for 1 h. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated under reduced pressure, diluted with water (20 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layer was washed with water (2×25 mL) then brine (25 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude compound. The crude compound was purified by preparative HPLC purification to give 0.015 g (3.3% yield) of D-109 as an off-white solid. LCMS-Condition-1: [M+H] + = 475.15; Rt = 1.587 minutes 1 H NMR (400 MHz, DMSO-d6) δ: 13.08 (br. s, 1H), 8.17 (s, 1H), 8.11 (s, 1H), 7.41 (d, J=8.98 Hz, 1H), 7.21-7.31 (m, 3H), 7.18 (d, J=3.49 Hz, 2H), 6.90 (d, J=6.98 Hz, 2H), 6.58 (d, J=7.98 Hz, 2H), 4.99-5.20 (m, 2H), 4.37 (t, J=5.73 Hz, 1H), 4.25 (t, J=5.73 Hz, 1H), 2.53-2.62 (m, 2H), 2.44-2.53 (m, 4H), 1.88 (s, 3H), 1.54-1.70 (m, 2H).

[0173] Activity and Biological Data To demonstrate the usefulness of the compounds of the present invention, estrogen receptor binding assays were performed, in which it was shown that many of the compounds of the present invention exhibit significant affinity to estrogen receptor.Selected example compounds were evaluated for their ability to inhibit estradiol (E2)-induced proliferation and signal transduction, and their ability to degrade estrogen receptor (ER) in breast cancer cells.In addition, the ability of selected compounds to inhibit E2-induced increase in uterine weight in immature rats was evaluated by oral administration.Selected compounds could be evaluated in MCF-7 in vivo xenograft model of breast cancer.

[0174] Proliferation assay in MCF-7 and T47D cells MCF-7 and T47D cells were stripped for 3 days in phenol red-free RPMI1640 medium containing 10% charcoal-stripped fetal bovine serum (CS-FBS) and 1% penicillin / streptomycin (P / S). Cells (volume of 90 μl / well) were seeded in 96-well plates at a density of 2500 cells / well for MCF-7 cells and 1500 cells / well for T47D cells. The next day, plates were treated with test compounds (10X concentration in medium, volume added 10 μl / well) in both the absence and presence of two doses of E2 (10 pM and 1 nM). Cells were incubated with test compounds for 7 days. Cell viability was assessed using CellTiterGlo (Promega, catalog number G7573) according to the manufacturer's instructions. Growth inhibition curves and IC using GraphPadPrism 6.0 software 50 Values ​​were calculated for the data shown in Table 1 obtained using a 10 pM dose of E2.

[0175] Quantitative PCR (qPCR) to evaluate ER signaling in MCF-7 cells MCF-7 cells were detached in phenol red-free RPMI1640 medium containing 10% charcoal-treated fetal bovine serum (CS-FBS) and 1% penicillin / streptomycin (P / S) for 3 days. Cells (volume of 90 μl / well) were seeded in 96-well plates at a density of 20000 cells / well. The next day, plates were treated with test compounds (10X concentration in medium, volume added 10 μl / well) in both the absence and presence of E2 (1 nM). Cells were incubated with test compounds for 24 hours. Cell lysates were prepared using the Cells-to-CT kit (ThermoFisherScientific, catalog number A25603) according to the manufacturer's instructions. A PCR mix was prepared containing the master mix, primers for progesterone receptor (PR) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) endogenous control (ThermoFisherScientific, PR: Cat. No. Hs01556702_m1 and GAPDH: 4326317E), RNase-free water (ThermoFisherScientific, Cat. No. AM9938), and 8 μl of this mix was added to each well of a MicroAmp Optical 384-well plate. Cell lysate (2 μl) was then added to each well, and the samples were analyzed using a QuantStudio6 machine using the fast cycling conditions provided in the kit. Inhibition of PR induction was analyzed, and IC50 values ​​were calculated using GraphPadPrism 6.0 software. In general, activity in this assay was tracked similarly to the MCF-7 inhibition data shown in Table 1. Many of the compounds of the present invention potently inhibited PR induction when stimulated with 1 nM E2.

[0176] ER degradation assay in MCF-7 cells MCF-7 cells were detached in phenol red-free RPMI1640 medium containing 10% charcoal-treated fetal bovine serum (CS-FBS) and 1% penicillin / streptomycin (P / S) for 3 days. Cells were seeded in 6-well plates at a density of 4X105 cells / well (volume of 2mL / well). The next day, plates were treated with test compounds (3X concentration in medium, volume of 1ml / well added). Cells were incubated with test compounds for 48 hours. Cells were washed and lysed for 15 minutes at room temperature using 70μl / well of CelLyticM (Sigma, Cat. No. C2978) lysis buffer containing protease and phosphatase inhibitors. Lysates were centrifuged at 15000rpm for 15 minutes, supernatants were collected and analyzed for concentration using bicinchoninic acid assay (BCA). Protein (25μg) was loaded and separated on 4-15% polyacrylamide gels. Proteins were then transferred to PVDF membranes, after which the membranes were incubated with ERα primary antibody (Cell Signaling, Cat. No. 13258; 1:1000) and Vinculin primary antibody (Sigma, Cat. No. V9131, 1:1000). The membranes were incubated with the respective secondary antibodies, probed with chemiluminescent material (ThermoFisherScientific, Dura (ERα): Cat. No. 34075 and Pico (Vinculin): Cat. No. 34080), and images were taken using an Azure Biosystems c600 machine. Images were analyzed using AzureSpot software. Several tested compounds disclosed herein reduced the expression of ER.

[0177] Immature rat uterus assay Sprague-Dawley rat pups were weaned at 19 days of age and randomized into groups (n=6) to receive vehicle (aqueous 20% HPBCD, 10% PEG400 in HO), E2 (0.01 mg / kg), or test compound (0.1 mg / kg to 3 mg / kg) in combination with E2 (0.01 mg / kg) once daily for three consecutive days, either by subcutaneous injection or gavage. 24 hours after the last dose, all animals were killed by carbon dioxide inhalation. Body weight and wet uterine weight were recorded for each animal. Data were analyzed using GraphPadPrism 6.0 software. For example, compound D-105 suppressed wet uterine weight to baseline with an oral dose of 3 mg / kg.

[0178] MCF-7 xenograft model Female athymic nude mice [Crl:NU(NCr)-Foxn1nu] are used for tumor xenograft testing. Three days prior to tumor cell implantation, estrogen pellets (0.36 mg E2, 60-day release; Innovative Research of America, Sarasota, Florida, USA) are implanted subcutaneously between the shoulder blades of the test animals using a sterile trocar. MCF-7 human breast adenocarcinoma cells are cultured to mid-logarithmic phase in RPMI-1640 medium containing 10% fetal bovine serum, 100 U / ml penicillin G, 100 μg / ml streptomycin sulfate, 2 mmol / l glutamine, 10 mmol / l HEPES, 0.075% sodium bicarbonate, and 25 μg / ml gentamicin. On the day of tumor cell implantation, cells are trypsinized, pelleted, and resuspended in PBS at a concentration of 5 × 107 cells / ml. Each test mouse receives 1 × 10 7 MCF-7 cells were then administered and tumor growth was monitored using the following formula: tumor volume (mm 3 )=l×w2 / 2 (where w=width and l=length in mm of MCF-7 tumor). If necessary, add 1 mm 3Tumor weights are estimated based on the assumption that a tumor volume of 1 mg is equivalent to 1 mg of tumor wet weight. Fourteen days after tumor cell implantation (denoted as day 1 of the study), mice were 9 weeks old, weighed between 21.4 and 32.5 g, and had individual tumor volumes between 75 and 144 mm. 3 The mean tumor volume (MTV) of the group was 108 mm 3 Mice are randomized into groups of 9-15 animals each and treated with vehicle, a control SERM such as tamoxifen (1 mg / animal, every other day) and a test compound (0.3, 1, 3, 10, 30, 60, 90 and 120 mg / kg daily). Tumor volumes are assessed twice weekly. The tumor endpoint is 1500 mm in the control group. 3 The MTV is defined as the MTV of 100 mg / kg / day. Animals are also monitored for partial regression (PR) and complete regression responses. Treatment acceptability is assessed by weight measurements and frequent observations for clinical signs of treatment-related adverse effects. Animals with weight loss of more than 30% for one measurement or more than 25% for three measurements are humanely sacrificed and their deaths are classified as treatment-related deaths. Acceptable toxicity is defined as less than 20% group mean weight loss during the study and less than or equal to 1 treatment-related death or 10% of 10 treated animals. At the end of the study, animals are sacrificed by terminal cardiac puncture under isoflurane anesthesia. [Table 1] The aspects of the present invention include the following. Item 1 Formula I: [ka] (In the formula, X is hydrogen, C 1 -C 3 Alkyl, C 1 -C 3 Fluoroalkyl, CN, fluorine, chlorine or bromine; R is hydrogen, C 1 -C 3 Alkyl, C 1 -C 3 Fluoroalkyl, CN, fluorine, chlorine or bromine; Each R a are independent: H, C 1 -C 3 Alkyl, C 1 -C 3 Fluoroalkyl, OH, OC 1 - 3 Alkyl, CN, fluorine, chlorine, or fluorine, chlorine, C 1 -C 3 Alkyl, CN, OC 1 -C 3 phenyl optionally substituted with 1 to 3 groups selected from alkyl and OH; Each R b are independent: H, C 1 -C 3 Alkyl, C 1 -C 3 Fluoroalkyl, OH, OC 1 - 3 Alkyl, CN, fluorine, chlorine, or fluorine, chlorine, C 1 -C 3 Alkyl, CN, OC 1 -C 3 phenyl optionally substituted with 1 to 3 groups selected from alkyl and OH; Y and Z are each independently CR b or N; U and V are independent of each other. a or N; 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,

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Claims

1. Formula I: 【Chemistry 1】 (In the formula, X is hydrogen, C 1 -C 3 Alkyl, C 1 -C 3 fluoroalkyl, CN, fluorine, chlorine or bromine; R is hydrogen, C 1 -C 3 Alkyl, C 1 -C 3 fluoroalkyl, CN, fluorine, chlorine or bromine; Each R a are independent: H, C 1 -C 3 Alkyl, C 1 -C 3 Fluoroalkyl, OH, OC 1 - 3 Alkyl, CN, fluorine, chlorine, or fluorine, chlorine, C 1 -C 3 Alkyl, CN, OC 1 -C 3 phenyl optionally substituted with 1 to 3 groups selected from alkyl and OH; Each R b are independent: H, C 1 -C 3 Alkyl, C 1 -C 3 Fluoroalkyl, OH, OC 1 - 3 Alkyl, CN, fluorine, chlorine, or fluorine, chlorine, C 1 -C 3 Alkyl, CN, OC 1 -C 3 phenyl optionally substituted with 1 to 3 groups selected from alkyl and OH; Y and Z are each independently CR b or N; U and V are independent of each other. a or N; 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, 【Chemistry 2】 and where each R' is independently H or C 1 -C 3 (It is alkyl) or a pharma- ceutically acceptable salt thereof.

2. Wが、-CH 2 -CH 2 -NH-CH 2 -CH 2 -CH 3 ;-CH 2 -CH 2 -NH-CH 2 -CH 2 -CH 2 F; 【Chemistry 3】 2. The compound of claim 1, wherein:

3. Y and Z are CR b where U and V are CR a 2. The compound of claim 1,

4. Formula II: 【Chemistry 4】 (In the formula: X is hydrogen, C 1 -C 3 Alkyl, C 1 -C 3 fluoroalkyl, CN, fluorine, chlorine or bromine; R is hydrogen, C 1 -C 3 Alkyl, C 1 -C 3 fluoroalkyl, CN, fluorine, chlorine or bromine; Each R a are independent: H, C 1 -C 3 Alkyl, C 1 -C 3 Fluoroalkyl, OH, OC 1 - 3 Alkyl, CN, fluorine, chlorine, or fluorine, chlorine, C 1 -C 3 Alkyl, CN, OC 1 -C 3 phenyl optionally substituted with 1 to 3 groups selected from alkyl and OH; Each R b are independent: H, C 1 -C 3 Alkyl, C 1 -C 3 Fluoroalkyl, OH, OC 1 - 3 Alkyl, CN, fluorine, chlorine, or fluorine, chlorine, C 1 -C 3 Alkyl, CN, OC 1 -C 3 phenyl optionally substituted with 1 to 3 groups selected from alkyl and OH; Y and Z are each independently CR b or N; U and V are independent of each other. a or N) 2. The compound of claim 1 having the structure: or a pharma- ceutically acceptable salt thereof.

5. X is hydrogen, methyl, fluorine, chlorine or bromine; R is hydrogen, methyl, fluorine, chlorine or bromine; Y and Z are each CR b and U and V are CR a and each R a is independently selected from H, fluorine or chlorine; b 5. The compound of claim 4, or a pharma- ceutically acceptable salt thereof, wherein is independently selected from H, fluorine or chlorine.

6. Formula III: 【Chemistry 5】 (In the formula: X is hydrogen, C 1 -C 3 Alkyl, C 1 -C 3 fluoroalkyl, CN, fluorine, chlorine or bromine; R is hydrogen, C 1 -C 3 Alkyl, C 1 -C 3 fluoroalkyl, CN, fluorine, chlorine or bromine; Each R a are independent: H, C 1 -C 3 Alkyl, C 1 -C 3 Fluoroalkyl, OH, OC 1 - 3 Alkyl, CN, fluorine, chlorine, or fluorine, chlorine, C 1 -C 3 Alkyl, CN, OC 1 -C 3 phenyl optionally substituted with 1 to 3 groups selected from alkyl and OH; Each R b are independent: H, C 1 -C 3 Alkyl, C 1 -C 3 Fluoroalkyl, OH, OC 1 - 3 Alkyl, CN, fluorine, chlorine, or fluorine, chlorine, C 1 -C 3 Alkyl, CN, OC 1 -C 3 phenyl optionally substituted with 1 to 3 groups selected from alkyl and OH; U and V are independent of each other. a or N) 2. The compound of claim 1 having the structure: or a pharma- ceutically acceptable salt thereof.

7. X is hydrogen, methyl, fluorine, chlorine or bromine; R is hydrogen, methyl, fluorine, chlorine or bromine; U and V are each CR a and each R a is independently selected from H, fluorine or chlorine; b 7. The compound of claim 6, or a pharma- ceutically acceptable salt thereof, wherein is independently selected from H, fluorine or chlorine.

8. 8. The compound of claim 7, wherein X is fluorine.

9. 9. The compound of claim 8, wherein R is fluorine or chlorine.

10. Formula IV: 【Chemistry 6】 (In the formula: X is hydrogen, C 1 -C 3 Alkyl, C 1 -C 3 fluoroalkyl, CN, fluorine, chlorine or bromine; R is hydrogen, C 1 -C 3 Alkyl, C 1 -C 3 fluoroalkyl, CN, fluorine, chlorine or bromine; Each R b are independent: H, C 1 -C 3 Alkyl, C 1 -C 3 Fluoroalkyl, OH, OC 1 - 3 Alkyl, CN, fluorine, chlorine, or fluorine, chlorine, C 1 -C 3 Alkyl, CN, OC 1 -C 3 phenyl optionally substituted with 1 to 3 groups selected from alkyl and OH 2. The compound of claim 1 having the structure: or a pharma- ceutically acceptable salt thereof.

11. 11. The compound of claim 10, wherein X is hydrogen or fluorine.

12. 12. The compound of claim 11, wherein R is hydrogen, fluorine or chlorine.

13. Each R b The compound of claim 12, wherein is hydrogen, fluorine or chlorine.

14. Formula V: 【Chemistry 7】 (In the formula: X is hydrogen, C 1 -C 3 Alkyl, C 1 -C 3 fluoroalkyl, CN, fluorine, chlorine or bromine; R is hydrogen, C 1 -C 3 Alkyl, C 1 -C 3 fluoroalkyl, CN, fluorine, chlorine or bromine; R b Is: H, C 1 -C 3 Alkyl, C 1 -C 3 Fluoroalkyl, OH, OC 1 - 3 Alkyl, CN, fluorine, chlorine, or fluorine, chlorine, C 1 -C 3 Alkyl, CN, OC 1 -C 3 phenyl optionally substituted with 1 to 3 groups selected from alkyl and OH 2. The compound of claim 1 having the structure: or a pharma- ceutically acceptable salt thereof.

15. 15. The compound of claim 14, wherein X is hydrogen or fluorine.

16. 16. The compound of claim 15, wherein R is hydrogen, fluorine or chlorine.

17. Each R b 17. The compound of claim 16, wherein is hydrogen, fluorine or chlorine.

18. Formula VI: 【Chemistry 8】 (In the formula: X is hydrogen, C 1 -C 3 Alkyl, C 1 -C 3 fluoroalkyl, CN, fluorine, chlorine or bromine; R is hydrogen, C 1 -C 3 Alkyl, C 1 -C 3 fluoroalkyl, CN, fluorine, chlorine or bromine; R a Is: H, C 1 -C 3 Alkyl, C 1 -C 3 Fluoroalkyl, OH, OC 1 - 3 Alkyl, CN, fluorine, chlorine, or fluorine, chlorine, C 1 -C 3 Alkyl, CN, OC 1 -C 3 phenyl optionally substituted with 1 to 3 groups selected from alkyl and OH; R b Is: H, C 1 -C 3 Alkyl, C 1 -C 3 Fluoroalkyl, OH, OC 1 - 3 Alkyl, CN, fluorine, chlorine, or fluorine, chlorine, C 1 -C 3 Alkyl, CN, OC 1 -C 3 phenyl optionally substituted with 1 to 3 groups selected from alkyl and OH 2. The compound of claim 1 having the structure: or a pharma- ceutically acceptable salt thereof.

19. 19. The compound of claim 18, wherein X is hydrogen or fluorine.

20. 20. The compound of claim 19, wherein R is hydrogen, fluorine or chlorine.

21. Each R b 21. The compound of claim 20, wherein is hydrogen, fluorine or chlorine. 【Request 22】 【Chemical 9-1】 【Chemistry 9-2】 A compound having a structure selected from the group consisting of: or a pharma- ceutically acceptable salt thereof.

23. Formula D-105: 【Chemistry 10】 23. The compound of claim 22 having the structure: or a pharma- ceutically acceptable salt thereof.

24. Formula D-106: 【Chemistry 11】 23. The compound of claim 22 having the structure: or a pharma- ceutically acceptable salt thereof.

25. Formula D-107: 【Chemistry 12】 23. The compound of claim 22 having the structure: or a pharma- ceutically acceptable salt thereof.

26. Formula D-108: 【Chemistry 13】 23. The compound of claim 22 having the structure: or a pharma- ceutically acceptable salt thereof.

27. Formula D-109: 【Chemistry 14】 23. The compound of claim 22 having the structure: or a pharma- ceutically acceptable salt thereof.

28. Formula D-110: 【Chemistry 15】 23. The compound of claim 22 having the structure: or a pharma- ceutically acceptable salt thereof.

29. N-(4-((8-chloro-7-(o-tolyl)pyrrolo[3,2-e]indazol-6(3H)-yl)methyl)phenethyl)-3-fluoropropan-1-amine; 3-Fluoro-N-(3-fluoro-4-((1-fluoro-7-(o-tolyl)pyrrolo[3,2-e]indazol-6(3H)-yl)methyl)phenethyl)propan-1-amine; N-(4-((1,8-difluoro-7-(o-tolyl)pyrrolo[3,2-e]indazol-6(3H)-yl)methyl)phenethyl)-3-fluoropropan-1-amine; N-(3,5-difluoro-4-((8-fluoro-7-(o-tolyl)pyrrolo[3,2-e]indazol-6(3H)-yl)methyl)phenethyl)-3-fluoropropan-1-amine; 3-fluoro-N-(3-fluoro-4-((8-fluoro-7-(o-tolyl)pyrrolo[3,2-e]indazol-6(3H)-yl)methyl)phenethyl)propan-1-amine; and N-(4-((8-chloro-7-(o-tolyl)pyrrolo[3,2-e]indazol-6(3H)-yl)methyl)-3-fluorophenethyl)-3-fluoropropan-1-amine A compound selected from the group consisting of:

30. A pharmaceutical composition comprising a compound according to any one of claims 1 to 29 and a pharma- ceutically acceptable excipient.

31. A compound according to any one of claims 1 to 29 or a pharmaceutical composition according to claim 30 for treating a disease, syndrome, illness or condition associated with insufficient or excessive estrogen levels in a mammal in need of such treatment.

32. 31. A compound according to any one of claims 1 to 29 or a pharmaceutical composition according to claim 30 for treating a cancer selected from the group consisting of prostate cancer, breast cancer, endometrial cancer, lung cancer, hepatocellular carcinoma, lymphoma, multiple endocrine neoplasia, vaginal cancer, renal cancer, thyroid cancer, testicular cancer, leukemia and ovarian cancer in a mammal in need of such treatment.

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