TETRAHYDROPYRIDO[3,4-B]INDOLS ESTROGEN RECEPTOR MODULATORS AND THEIR USES

Abstract

Tetrahydropyrido[3,4-b]indol-1-yl compounds with estrogen receptor modulating activity or function are described, having the structure of Formula I (see Formula), and pharmaceutically acceptable stereoisomers, tautomers, or salts thereof, with the substituents and structural features described herein. Pharmaceutical compositions and medicinal products comprising the compounds of Formula I are also described, as well as methods of using such estrogen receptor modulators, alone or in combination with other therapeutic agents, to treat diseases or pathological conditions that are mediated by or dependent on estrogen receptors.

Description

TETRAHYDRO-PYRIDO[3,4-B]INDOLS ESTROGEN RECEPTOR MODULATORS AND THEIR USES

[001] Cross-reference with related applications This non-provisional application filed pursuant to 37 CFR §1.53(b) claims the benefit under 35 U.S.C. §119(e) of U.S. provisional application serial number 62 / 093,929 filed on December 18, 2014, U.S. provisional application serial number 62 / 110,998 filed on February 2, 2015, and U.S. provisional application serial number 62 / 142,077 filed on April 2, 2015, all of which are incorporated herein by reference. Scope of the invention Described herein are compounds, including pharmaceutically acceptable salts, solvates, metabolites, prodrugs thereof, pharmaceutical compositions containing such compounds, and methods of using such compounds to treat, prevent, or diagnose diseases or pathological conditions that are estrogen-responsive, estrogen-receptor-dependent, or estrogen-receptor-mediated in combination with other therapeutic agents. Background of the invention The estrogen receptor (“ER”) is a ligand-activated transcriptional regulatory protein that mediates a wide variety of biological effects through its interaction with endogenous estrogens. Endogenous estrogens include estradiol-17β (beta) and estrone. The ER has been found to have two isoforms, ER-α (alpha) and ER-β (beta). Estrogens and estrogen receptors are implicated in a large number of diseases or pathological conditions, including breast cancer, lung cancer, ovarian cancer, colon cancer, prostate cancer, endometrial cancer, uterine cancer, and other diseases or pathological conditions. There is a need for novel ER-α-directed agents that have activity in limiting metastatic disease and acquired resistance. Summary of the invention The invention relates generally to tetrahydro-pyrido[3,4-b]indol-1-yl compounds with estrogen receptor modulating activity or function, having the structure of formula I: IVIA / a / ¿U¿¿ / UU fUfO and the stereoisomers, tautomers or pharmaceutically acceptable salts thereof and which have the substituents and structural characteristics described herein. One aspect of the invention is a pharmaceutical composition of a compound of formula I and a pharmaceutically acceptable carrier, lubricant, diluent or excipient. One aspect of the invention is a process for obtaining a compound of formula I or a pharmaceutical composition containing a compound of formula I. One aspect of the invention is a method of treating an ER-related disease or disorder in a patient, comprising administering a therapeutically effective amount of a pharmaceutical composition to a patient having an ER-related disease or disorder. One aspect of the invention is a kit for treating an estrogen receptor-mediated disease state, comprising: a) a pharmaceutical composition containing a compound of formula I; and b) the instructions for use. Detailed description of illustrative embodiments Reference will now be made in detail to certain embodiments of the invention, to the examples thereof illustrated in the appended structures and formulae. The invention is described in conjunction with the enumerated embodiments, but it is understood that it is not intended to limit the invention to these embodiments. On the contrary, the invention embraces all alternatives, modifications, and equivalents which may be included within the scope of the present invention as defined in the claims. Those skilled in the art will recognize many methods and materials similar or equivalent to those described herein which could be employed in practicing the present invention. The present invention is by no means limited to the methods and materials described herein.In the event that one or more of the technical literature articles, patents, and similar materials differ from or contradict this application, including but not limited to: defined terms, use of terms, techniques described, or the like, then this application shall govern. Unless otherwise defined, all technical and scientific terms used herein have the same meanings commonly ascribed to those skilled in the art within the scope of this invention. Although methods and materials similar or equivalent to those described herein may be employed in the practice or testing of the invention, appropriate methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are hereby incorporated by reference in their entirety.The nomenclature used in this application is based on the IUPAC systematic nomenclature, unless otherwise indicated. Definitions When stating the number of substituents, the term “one or more” indicates the range from one substituent to the maximum possible number of substituents, i.e., from the replacement of one hydrogen to the replacement of all hydrogen atoms by substituents. The term “substituent” indicates an atom or group of atoms that replaces a hydrogen atom in the original molecule. The term “substituted” indicates that the specified group bears one or more substituents. When any group may bear multiple substituents and a wide variety of possible substituents is provided, then the substituents are chosen independently and not IVIA / a / ¿U¿¿ / UU fUfO must necessarily be identical. The term “unsubstituted” indicates that the specified group bears no substituents. The term “optionally substituted” indicates that the specified group is unsubstituted or substituted by one or more substituents, independently chosen from the group of possible substituents. When indicating the number of substituents, the term “one or more” indicates from one substituent to the maximum possible number of substituents, that is, from the replacement of one hydrogen atom to the replacement of all hydrogen atoms by substituents. The term “alkyl” is used herein to mean a monovalent, saturated, straight or branched chain hydrocarbon moiety of one to twelve carbon atoms (Ci-C12), which alkyl moiety may be optionally substituted independently by one or more substituents described below. In another embodiment, an alkyl moiety is one having one to eight carbon atoms (Ci-C8) or one to six carbon atoms (Ci—C6). Examples of alkyl groups include, but are not limited to, methyl (Me, -CH), ethyl (Et, -CHCH), 1-propyl (n-Pr, n-propyl, CHCHCH), 2-propyl (i-Pr, i-propyl, -CH(CH)), 1-butyl (n-Bu, n-butyl, -CHCHCHCHCH), 2-methyl-1-propyl (i-Bu, i-butyl, -CHCH(CH)), 2-butyl (s-Bu, s-butyl, -CH(CH)CHCH), 2-methyl-2-propyl (t-Bu, t-butyl, -CH(CH)), 1-pentyl (n-pentyl, -CHCHCHCHCHCH), 2-pentyl (-CH(CH)CHCHCH), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2),3-methyl-1-butyl (-CH2CH2CH(CH3)2), 2-methyl-1-butyl (CH2CH(CH3)CH2CH3), 1-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3, 1-heptyl, 1-octyl and the like., The term “alkyldiyl” is used herein to mean a divalent, straight or branched chain saturated hydrocarbon moiety of about one to twelve carbon atoms (C1-C12), which alkyldiyl moiety may be optionally substituted independently by one or more substituents described below. In another embodiment, an alkyldiyl moiety has one to eight carbon atoms (C1—Cs) or one to six carbon atoms (C1-Ce). Examples of alkyldiyl groups include, but are not limited to, methylene (-CH2-), ethylene (-CH2CH2-), propylene (CH2CH2CH2-), and the like. An alkyldiyl group may also be referred to as an “alkylene” group. The term “alkenyl” denotes a monovalent, straight or branched chain hydrocarbon moiety having from two to eight carbon atoms (C2-C8) with at least one site of unsaturation, i.e., an sp2 carbon-carbon double bond, said alkenyl moiety may be optionally substituted independently by one or more substituents described herein and includes moieties having “cis” and “trans” orientations or, alternatively, “E” and “Z” orientations. Examples include, but are not limited to, ethyleneyl or vinyl (-CH=CH2), allyl (-OH2OH=OH2) and the like. The terms “alkenylene” or “alkenyldiyl” denote a divalent straight or branched chain hydrocarbon moiety having from two to eight carbon atoms (C2—C8) and at least one site of unsaturation, i.e., a sp2 type carbon-carbon double bond, said alkenylene moiety may be optionally substituted independently by one or more substituents described herein and includes moieties having “cis” and “trans” orientations or alternatively “E” and “Z” orientations. Examples include, but are not limited to, ethylene or vinyl (-CH=CH), allyl (-CH2CH=CH-) and the like. The term “alkynyl” refers to a linear or branched monovalent hydrocarbon moiety having two to eight carbon atoms (C2-C8) and at least one site of unsaturation, i.e., a carbon-carbon triple bond of the sp type, said alkynyl moiety being optionally substituted independently by one or more substituents described herein. Examples include, but are not limited to, ethynyl (-C^CH), propynyl (propargyl, -CH2C=CH), and the like. The term “alkynylene” or “alkynyldiyl” denotes a linear or branched divalent hydrocarbon moiety of two to eight carbon atoms (C2-Cs) and at least one site of unsaturation, i.e., a carbon-carbon triple bond of the sp type, said alkynylene moiety may be optionally substituted independently by one or more substituents described herein. Examples include, but are not limited to, ethynylene (-C=C-), propynylene (propargylene, -CH2C=C-) and the like. The terms “carbocycle”, “carbocyclyl”, “carbocyclic ring” and “cycloalkyl” mean a saturated or partially unsaturated, non-aromatic monovalent ring having 3 to 12 carbon atoms (C3-C12) in the form of a monocyclic ring or 7 to 12 carbon atoms in the form of a bicyclic ring. Bicyclic carbocycles having 7 to 12 carbon atoms can be present, for example, in the form of a bieldo system [4.5], [5.5], [5.6] or [6.6] and bicyclic carbocycles having 9 to 10 ring atoms can be present in the form of a bieldo system [5.6] or [6.6] or in the form of bridged systems, for example bicyclo[2.2.1]-heptane, bicyclo[2.2.2]octane and bicyclo[3.2.2]nonane. The radicals Spiro carbocyclyl moieties are also included within the scope of this definition. Examples of spiro carbocyclyl moieties include [2.2]pentanyl, [2.3]hexanyl, and [2.4]heptanyl.Examples of monocyclic carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, and the like. Carbocyclyl groups are optionally substituted independently by one or more substituents described herein. The term “carbocyclyldiyl” indicates a divalent, saturated or partially unsaturated, non-aromatic ring having 3 to 12 carbon atoms (C3-C12) in the form of a monocyclic ring or 7 to 12 carbon atoms in the form of a bicyclic ring. “Aryl” means a monovalent aromatic hydrocarbon moiety of 6 to 20 carbon atoms (Ce—C20) derived by the removal of a hydrogen atom from a single carbon atom of the parent aromatic ring system. Some aryl groups are depicted in the illustrative “Ar” type structures. Aryl includes bicyclic moieties having an aromatic ring fused to a saturated or partially unsaturated ring or to an aromatic carbocyclic ring. Typical aryl groups include, but are not limited to, moieties derived from benzene (phenyl), substituted benzenes, naphthalene, anthracene, biphenyl, indenyl, indanyl, 1,2-dihydronaphthalene, 1,2,3,4-tetrahydronaphthyl, and the like. Aryl groups are independently optionally substituted by one or more substituents described herein. The terms “arylene” or “aryldiyl” denote a divalent aromatic hydrocarbon moiety of 6 to 20 carbon atoms (Ce—C20) derived by the removal of two hydrogen atoms from two carbon atoms of the parent aromatic ring system. Some aryldiyl groups are represented in the illustrative structures as “Ar.” Aryldiyl includes bicyclic moieties containing an aromatic ring fused to a saturated or partially unsaturated ring or to an aromatic ring. Aryldiyl groups include, but are not limited to, moieties derived from benzene (phenyldiyl), substituted benzenes, naphthalene, anthracene, biphenylene, indenylene, indanylene, 1,2-dihydronaphthalene, 1,2,3,4-tetrahydronaphthyl, and the like. Aryldiyl groups are also called “arylene” and are optionally substituted by one or more substituents described herein. The terms “heterocycle”, “heterocyclyl” and “heterocyclic ring” are used interchangeably herein and denote a saturated or partially unsaturated (i.e., having one or more double and / or triple bonds within the ring) carbocyclic moiety of from 3 to about 20 ring atoms, at least one ring atom being a heteroatom selected from nitrogen, oxygen, phosphorus and sulfur, the remaining ring atoms being C, wherein one or more ring atoms are optionally substituted independently by one or more substituents described below. A heterocycle may be a monocycle having 3 to 7 members (2 to 6 carbon atoms and 1 to 4 heteroatoms chosen from N, O, P and S) or a bicycle having 7 to 10 members (4 to 9 carbon atoms and 1 to 6 heteroatoms chosen from N, O, P and S), for example: a bicycle system [4.5], [5.5], [5.6] or [6.6]. Heterocycles have been described in Paquette, Leo A.; “Principies of Modern Heterocyclic Chemistry” (W.A. Benjamin, New York, 1968), particularly Chapters 1, 3, 4, 6, 7, and 9; “The Chemistry of Heterocyclic Compounds, A Series of Monographs” (John Wiley & Sons, New York, 1950 to the present), particularly Volumes 13, 14, 16, 19, and 28; and in J. Am. Chem. Soc. 82, 5566, 1960. “Heterocyclyl” also includes moieties where such heterocyclic moieties are fused to a saturated or partially unsaturated ring, to an aromatic carbocycle, or to a heterocyclic ring.Examples of heterocyclic rings include, but are not limited to, morpholin-4-ilo, piperidin-1-ilo, piperazinilo, piperazin-4-l-2-ona, piperazin-4-l-3-ona, pyrrolidin-1-ilo, thiomorpholin-4-ilo, S-dioxotiomorpholin-4-ilo, azocan-1-ilo, azetidin-1-ilo, octahidropirido[1,2-a]-pirazin-2-ilo, [1,4]diazepan-1-ilo, pyrrolidinilo, tetra-hidrofuranilo, dihidrofuranilo, tetrahydrotienilo, tetra-hidropiranilo, dihidropiranilo, tetrahydrotiopiranilo, piperidino, morphino, tiomorpholino, tioxanilo, piperazinilo, homopiperazinilo, azetidinilo, oxetanilo, tieanilo, homo-piperidinilo, oxepanilo, tiepanilo, oxazepinilo, diazepinilo, tiazepinilo, 2-pirrolinilo, 3-pirrolinilo, indolinilo, 2H-piranilo, 4H-piranilo, dioxanilo, 1,3-dioxolanilo, pirazolinilo, ditianilo, dithiolanilo, dihidropiranilo, dihidrotienilo, dihidrofuranilo, pyrazolidinimidazolinilo, imidazolidinilo, 3azabiciclo[3.1.0]hexanilo, 3-azabiciclo-[4.1.0]heptanilo, azabiciclo[2.2.2]hexanilo, 3H-indolyl quinolizinyl and N-pyridilureas.Spiro heterocyclyl moieties are also included within the scope of this definition. Examples of spiro heterocyclyl moieties include azaspiro[2.5]octanyl and azaspiro[2.4]heptanyl. Examples of heterocyclic groups in which two ring atoms are substituted by oxo moieties (=0) are pyrimidinonyl and 1,1-dioxo-thiomorpholinyl. The heterocycle groups present are optionally substituted independently by one or more substituents described herein. The term “heterocyclyldiyl” means a divalent, saturated or partially unsaturated (i.e., having one or more double and / or triple bonds within the ring) carbocyclic moiety of from 3 to about 20 ring atoms, wherein at least one ring atom is a heteroatom selected from nitrogen, oxygen, phosphorus and sulfur, the other ring atoms being C, wherein one or more ring atoms are optionally substituted independently by one or more substituents described herein. The term “heteroaryl” means a monovalent aromatic moiety of 5, 6 or 7 ring members and includes fused ring systems (at least one of which shall be aromatic) of 5 to 20 atoms, containing one or more heteroatoms independently chosen from nitrogen, oxygen and sulfur.Examples of heteroaryl groups are pyridinyl (including, for example, 2-hydroxypyridinyl), imidazolyl, imidazopyridinyl, pyrimidinyl (including, for example, 4-hydroxypyrimidinyl), pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxadiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, triazolyl, thiadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. Heteroaryl groups are optionally substituted independently by one or more substituents described herein. The term “heteroaryldiyl” denotes a divalent aromatic moiety of 5, 6 or 7 members and includes fused ring systems (at least one of which shall be aromatic) of 5-20 atoms, containing one or more heteroatoms independently chosen from nitrogen, oxygen and sulfur. Heterocycle or heteroaryl groups will be linked through a carbon (carbon linkage) or nitrogen (nitrogen linkage) whenever possible. By way of illustration but not limitation, carbon-linked heterocycles or heteroaryls are linked via the 2, 3, 4, 5, or 6 position of pyridine, via the 3, 4, 5, or 6 position of pyridazine, via the 2, 4, 5, or 6 position of pyrimidine, via the 2, 3, 5, or 6 position of pyrazine, via the 2, 3, 4, or 5 position of furan, tetrahydrofuran, thiofuran, thiophene, pyrrole, or tetrahydropyrrole, via the 2, 4, or 5 position of oxazole, imidazole, or thiozole, via the 3, 4, or 5 position of isoxazole, pyrazole, or isothiazole, via the 2 or 3 position of aziridine, via the 2, 3, or 4 position of azetidine, via the 2, 3, or 4 position of azetidine, via the 2, 3, or 5 ... 2,3,4,5,6,7 or 8 of quinoline or by position 1,3,4,5,6,7 or 8 of isoquinoline. By way of illustration but not limitation, heterocycles or heteroaryls attached through nitrogen are attached via the 1-position of aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline, 1H-indazole, via the 2-position of isoindole or isoindoline, via the 4-position of morpholine, and via the 9-position of carbazole or β-carboline. The terms “treat” and “treatment” refer to a therapeutic approach intended to halt (slow down) an undesired physiological change or disorder, such as the development or spread of arthritis or cancer. For the purposes of this invention, beneficial or desired clinical outcomes include, but are not limited to, alleviation of symptoms, reduction in the extent of disease, stabilization (i.e., not worsening) of the disease, delay or halting of disease progression, improvement or palliation of the disease state, and remission (either partial or complete), whether detectable or not. “Treatment” also refers to prolonging survival compared to the expected survival without treatment. Those in need of treatment are all those suffering from a disease state or disorder. The term “therapeutically effective amount” refers to an amount of a compound of the present invention that (i) treats the particular disease, condition, or disorder, (i) attenuates, ameliorates, or eliminates one or more symptoms of the particular disease, condition, or disorder, or (i¡¡) prevents or delays the onset of one or more symptoms of the particular disease, condition, or disorder described herein. In the case of cancer, the therapeutically effective amount of the medicament can reduce the number of cancer cells; reduce the size of the tumor; inhibit (i.e., reduce to some extent and preferably stop) the infiltration of cancer cells into peripheral organs; inhibit (i.e., reduce to some extent and preferably stop) tumor metastasis; inhibit, to some extent, tumor growth; and / or alleviate to some extent one or more of the symptoms associated with the cancer.Depending on the extent to which a drug can prevent growth and / or kill existing cancer cells, it may be cytostatic and / or cytotoxic. In cancer therapy, efficacy can be measured, for example, by assessing the time to disease progression (TTP) and / or determining the response rate (RR). The term "cancer" indicates or describes the pathological state of a mammal, typically characterized by abnormal (dysregulated) cell growth. A "tumor" is made up of one or more cancerous cells. Examples of cancer include carcinoma, lymphoma, blastoma, sarcoma, leukemia, and lymphoid cancers. More specific examples of these types of cancer include squamous cell cancer (e.g.,epithelial squamous cell lung cancer), lung cancer, including small cell lung cancer, non-small cell lung cancer (“NSCLC”), lung adenocarcinoma and squamous cell carcinoma of the lung, peritoneal cancer, hepatocellular cancer, gastric or stomach cancer, including gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney or renal cancer, prostate cancer, vulvar cancer, thyroid cancer, hepatic carcinoma, anal carcinoma, penile carcinoma, as well as head and neck cancer. Hematological malignancies are types of cancer that affect the blood, bone marrow, and lymph nodes. Since the three are intimately connected by the immune system, a disease that affects one of the three will often affect the others as well: although lymphoma is a disease of the lymph nodes, it often spreads to the bone marrow, affecting the blood. Hematological malignancies are malignant neoplasms ("cancer") and are generally treated by hematology and / or oncology specialists. In some hospitals, "hematology-oncology" is a subspecialty of internal medicine, while in others, they are considered separate divisions (there are also surgical and radiation oncologists). Not all hematological disorders are malignant ("cancerous"); such blood-related conditions may also be treated by a hematologist.Hematologic malignancies can arise from two main blood cell lineages: myeloid and lymphoid cell lines. The myeloid cell line typically produces granulocytes, red blood cells, platelets, macrophages, and mast cells; the lymphoid cell line produces B, T, NK, and plasma cells. Lymphomas, lymphocytic leukemias, and myeloma are of lymphoid origin, whereas acute and chronic myelogenous leukemia, myelodysplastic syndromes, and myeloproliferative diseases are of myeloid origin. Leukemias include acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), acute monocytic leukemia (AMOLES), and small lymphocytic lymphoma (SLL). Lymphomas include Hodgkin lymphomas (all four subtypes) and non-Hodgkin lymphomas (NHL, all subtypes). A "chemotherapeutic agent" is a chemical compound useful for the treatment of cancer, regardless of its mechanism of action. Classes of chemotherapeutic agents include, but are not limited to: alkylating agents, antimetabolites, alkaloids of spindle-shaped poisonous plants, cytotoxic antitumor antibiotics, topoisomerase inhibitors, antibodies, photosensitizers, and kinase inhibitors. Chemotherapeutic agents include compounds used in targeted therapy and conventional chemotherapy. Examples of chemotherapeutic agents include: ibrutinib (IMBRUVICA™, APCI-32765, Pharmacyclics Inc. / Janssen Biotech Inc.; CAS Reg. No. 936563-96-1, US 7514444), idelalisib (ZYDELIG®, CAL-101, GS1101, GS-1101, Gilead Sciences Inc.; CAS Reg. No. 1146702-54-6), erlotinib (TARCEVA®, Genentech / OSI Pharm.), docetaxel (TAXOTERE®, Sanofi-Aventis), 5-FU (fluoro-uracil, 5-fluorouracil, CAS Reg.No. 51-21-8), gemcitabine (GEMZAR®, Lilly), PD-0325901 (CAS No. 391210-10-9, Pfizer), cisplatin (Platinol®, (SP-4-2)-diaminedichloroplatinum (II), cis-diamine, dichloroplatinum (II), CAS No. 15663-27-1), carboplatin (CAS No. 41575-94-4), paclitaxel (TAXOL®, BristolMyers Squibb Oncology, Princeton, NJ), trastuzumab (HERCEPTIN®, Genentech), temozolomide (4-methyl-5-oxo2,3,4,6,8-pentazabicyclo[4.3.0]none-2,7,9-tyne-9-carboxamide, CAS no. 85622-93-1, TEMODAR®, TEMODAL®, Schering Plow), tamoxifen ((Z)-2-[4-(1,2-diphenylbut-1-enyl)phenoxy]-N,N-dimethylethanamine, NOLVADEX®, ISTUBAL®, VALODEX®) and doxorubicin (ADRIAMYCIN®, CAS no. 23214-92-8), Akt¡-1 / 2, HPPD and rapamycin. Chemotherapeutic agents include inhibitors of B cell receptor targets, for example BTK, Bcl-2, and JAK inhibitors. Further examples of chemotherapeutic agents include: oxaliplatin (ELOXATIN®, Sanofi), bortezomib (VELCADE®, Millennium Pharm.), sutent (SUNITINIB®, SU11248, Pfizer), letrozol (FEMARA®, Novartis), imatinib mesylate (GLEEVEC®, Novartis), XL-518 (Mek inhibitor, Exelixis, WO 2007 / 044515), ARRY-886 (Mek inhibitor, AZD6244, Array BioPharma, Astra Zeneca), SF-1126 (PI3K inhibitor, Semafore Pharmaceuticals), BEZ-235 (PI3K inhibitor, Novartis), XL-147 (PI3K inhibitor, Exelixis), PTK787 / ZK 222584 (Novartis), fulvestrant (FASLODEX®, AstraZeneca), leucovorin (folic acid), rapamicina (sirolimus, RAPAMUNE®, Wyeth), lapatinib (TYKERB®, GSK572016, Glaxo Smith Kline), lonafarnib (SARASAR™, SCH 66336, Schering Plough), sorafenib (NEXAVAR®, BAY43-9006, Bayer Labs), gefitinib (IRESSA®, AstraZeneca), irinotecan (CAMPTOSAR®, CPT-11, Pfizer), tipifarnib (ZARNESTRA™, Johnson & Johnson), ABRAXANO™ (Cremophor-free), formulaciones de paclitaxel en nanoparticulas de ingeniería de albúmina (American Pharmaceutical Partners, Schaumberg, II.<h2 style=";text-align:left;direction:ltr">), vandetanib (rINN, ZD6474, ZACTIMA®, AstraZeneca), clorambucil, AG1478, AG1571 (SU 5271; Sugen), temsirolimus (TORISEL®, Wyeth), pazopanib (Glaxo Smith Kline), canfosfamide (TELCYTA®, Telik), tiotepa and ciclosfosfamide (CYTOXAN®,.<h2 style=";text-align:left;direction:ltr"> NEOSAR®); alkyl sulfonates, e.g., busulfan, improsulfan, and piposulfan; aziridines, e.g., benzodopa, carboquone, meturedopa, and uredopa; ethyleneimines and methylamelamines, including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylomelamine; acetogenins (especially bulatacin and bulatacinone); a camptothecin (including the synthetic analogue topotecan); bryostatin; kallistatin; CC-1065 (including its synthetic analogues adozelesin, carzelesin, and bizelesin); cryptophycins (in particular cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycin (including its synthetic analogues KW-2189 and CB1-TM1); eleutherobin; pancratistatin; a sarcodictyne; spongistatin; nitrogen mustards, e.g. chlorambucil, chlornaphazine, chlorophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembiquine, phenesterine, prednimustine, trofosfamide, uracil mustard;Nitrosoureas, e.g. carmustine, chlorozotocin, fotemustine, lomustine, nimustine and ranimnustine; antibiotics, e.g. the enediine antibiotics (e.g. calicheamicin, calicheamicin gammall, calicheamicin omegall (Angew Chem. Intl. Ed. Engl. 33,183-186, 1994); dynemycin, dynemycin A; bisphosphonates, e.g. clodronate; esperanzamycin;as well as the chromophore neocarzinostatin and related chromophores of enediine antibiotics chromoprotein), aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, carminomycin, carzinophylline, chromomycins, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, morpholinodoxorubicin, cyanomorpholinodoxorubicin, 2-pyrrolinodoxorubicin and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, nemorubicin, marcellomycin, mitomycins, e.g. mitomycin C, mycophenolic acid, noghallmycin, olivomycins, peplomycin, porfiromycin, puromycin, chelamicin, rodorubicin, Streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; antimetabolites, e.g., methotrexate and 5-fluorouracil (5-FU); folic acid analogues, e.g., denopterin, methotrexate, pteropterin, trimetrexate; purine analogues, e.g., fludarabine, 6-mercaptopurine, thiamiprine, thioguanine;pyrimidine analogues, e.g. ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens, e.g. calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; antiadrenergics, e.g. aminoglutethimide, mitotane, trilostane; folic acid replenishers, e.g. frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elfornithine; elliptinium acetate; an epothilone; ethoglucose; gallium nitrate; hydroxyurea; lentinan; lonidainine; Maytansinoids, e.g., maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidammols; nitraerin; pentostatin; phenamet; pirarubicin; losoxantrone; podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK® polysaccharide complex (JHS Natural Products, Eugene, OR); razoxane; rhizoxin; sizofiran; spirogermanium;tenuazonic acid; triaziquone; 2,2',2"-trichlorotriethylamine; trichothecenes (especially T-2 toxin, verracurin A, roridin A, and anguidine); urethane; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside (“Ara-C”); cyclophosphamide; thiotepa; 6-thioguanine; mercaptopurine; methotrexate; platinum analogues, e.g., cisplatin and carboplatin; vinblastine; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; vinorelbine (NAVELBINE®); novantrone; teniposide; edatrexate; daunomycin; aminopterin; capecitabine (XELODA®, Roche); ibandronate; CPT-11; topoisomerase inhibitor RFS 2000; difluormethylornithine (DMFO); MA / a / zuzz / uu iyio retinoids, for example retinoic acid; and pharmaceutically acceptable salts, acids and derivatives of any of the foregoing. Also included in the definition of “chemotherapeutic agent” are: (i) antihormonal agents that act to regulate or inhibit the action of hormones on tumours, for example anti-oestrogens and selective oestrogen receptor modulators (SERMs), including, for example, tamoxifen (including NOLVADEX®; tamoxifen citrate), raloxifene, droloxifene, 4-hydroxytamoxifen, trioxifen, keoxifen, LY117018, onapristone and FARESTON® (toremifine citrate) and selective oestrogen receptor modulators (SERDs), for example fulvestrant (FASLODEX®, Astra Zeneca); (i) aromatase inhibitors, which inhibit the aromatase enzyme, which regulates the production of estrogen in the adrenal glands, e.g. 4(5)-imidazoles, aminoglutethimide, MEGASE® (megestrol acetate), AROMASIN® (exemestane; Pfizer), formestanie, fadrozole, RIVISOR® (vorozole), FEMARA® (letrozole; Novartis) and ARIMIDAX® (anastrozole; AstraZeneca);(iii) antiandrogens, for example flutamide, nilutamide, bicalutamide, leuprolide and goserelin; as well as troxacitabine (a cytosine analogue of 1,3-dioxolanenucleoside); (iv) protein kinase inhibitors, for example MEK inhibitors, for example cobimetinib (WO 2007 / 044515); (v) lipid kinase inhibitors, for example taselisib (GDC-0032, Genentech Inc.); (vi) antisense oligonucleotides, in particular those that inhibit the expression of genes in signaling pathways involved in aberrant cell proliferation, for example PKC-alpha, Raf and Η-Ras, for example oblimersen (GENASENSE®, Genta Inc.); (vii) ribozymes, e.g., VEGF expression inhibitors (e.g., ANGIOZYME®) and HER2 expression inhibitors; (viii) vaccines, e.g., generic therapy vaccines, e.g., ALLOVECTIN®, LEUVECTIN®, and VAXID®; PROLEUKIN® rlL-2; topoisomerase 1 inhibitors, e.g., LURTOTECAN®;ABARELIX® rmRH; (ix) antiangiogenic agents, for example bevacizumab (AVASTIN®, Genentech); and pharmaceutically acceptable salts, acids and derivatives of any of the foregoing. Also included in the definition of “chemotherapeutic agent” are therapeutic antibodies, such as alemtuzumab (Campath), bevacizumab (AVASTIN®, Genentech); cetuximab (ERBITUX®, Imclone); panitumumab (VECTIBIX®, Amgen), rituximab (RITUXAN®, Genentech / Biogen Idee), pertuzumab (PERJETA™, 2C4, Genentech), trastuzumab (HERCEPTIN®, Genentech), trastuzumab emtansine (KADCYLA®, Genentech Inc.), and tositumomab (BEXXAR, Corixia). A “metabolite” is a product generated by the metabolism in the human body of a specified compound or a salt thereof. Metabolites of a compound can be identified using standard biological techniques, and their activities can be determined by performing assays, for example, those described herein. Such products can be generated, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic decomposition, and the like, of administered compounds. Accordingly, the invention includes metabolites of the compounds of the present invention, including compounds generated by a process comprising contacting a compound of Formula I of this invention with a mammal for a period of time sufficient to generate the metabolic product thereof. The term "leaflet" is used to indicate the instructions routinely included in commercial packaging of therapeutic products, which contain information about the indications, use, dosage, administration, contraindications and / or precautions relating to the use of such therapeutic products.

[0001] The term “chiral” indicates molecules that have the property of not being superimposable with their corresponding mirror images, while the term “achiral” indicates molecules that are superimposable on their corresponding mirror images.

[0002] The term “stereoisomers” indicates compounds that have an identical chemical constitution, but differ in the arrangement of their atoms or groups in space.

[0003] “Diastereomer” means a stereoisomer having two or more centers of chirality and whose molecules are not mirror images of one another. Diastereomers have different physical properties, e.g., melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers can be separated by high-resolution analytical methods, e.g., electrophoresis and chromatography.

[0004] “Enantiomers” indicates two stereoisomers of a compound that are non-superimposable mirror images of each other.

[0005] The stereochemical definitions and conventions employed herein are generally in accordance with S.P. Parker, ed., McGraw-Hill Dictionary of Chemical Terms, McGraw-Hill Book Company, New York, 1984; and E. Eliel and S. Wilen, “Stereochemistry of Organic Compounds,” John Wiley & Sons, Inc., New York, 1994. The compounds of the invention may contain asymmetric or chiral centers and may therefore exist in different stereoisomeric forms. All stereoisomeric forms of the compounds of the invention, including, but not limited to, diastereomers, enantiomers, and atropisomers, as well as mixtures thereof, e.g., racemic mixtures, are intended to form part of the present invention. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of polarized light.When describing an optically active compound, the prefixes D and L, or R and S, are used to indicate the absolute configuration of the molecule around its chiral center(s). The prefixes (+) and (-) or (-) are used to designate the rotation of the plane of polarized light caused by the compound, with (-) or (-) meaning that the compound is left-handed. A compound bearing the prefix (+) or (-d) is right-handed. For a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. A specific stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which can occur when a chemical reaction or process has proceeded non-stereoselectively or non-stereospecifically.The terms "racemic mixture" and "racemate" indicate an equimolar mixture of two enantiomeric compounds, devoid of optical activity. Enantiomers can be separated from the racemic mixture by a. IVIA / a / ¿U¿¿ / UU by chiral separation method, for example supercritical liquid chromatography (SFC). The assignment of configuration to the chiral centers of the separated enantiomers may be tentative and is depicted in the structures in Table 1 for illustrative purposes, while the stereochemistry can be definitively established, for example from X-ray crystallographic data.

[0006] The term “tautomer” or “tautomeric form” refers to structural isomers of different energies, which are interconvertible across a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions effected by migration of a proton, e.g., keto-enol and imine-enamine isomerizations. Valence tautomers include interconversions effected by rearrangement of some of the bond electrons. The term "pharmaceutically acceptable salts" indicates salts that are not undesirable in a biological or other sense. Pharmaceutically acceptable salts include not only acid addition salts but also base addition salts. The term "pharmaceutically acceptable" indicates that the substance or composition must be chemically and / or toxicologically compatible with the other ingredients in the formulation and / or with the mammal to be treated with it. The term “pharmaceutically acceptable acid addition salt” means pharmaceutically acceptable salts formed with inorganic acids, for example hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid or with organic acids, selected from the groups of aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic acids, for example formic acid, acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, melic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranilic acid, benzoic acid, cinnamic acid, mandelic acid, embonic acid, phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like. The term "pharmaceutically acceptable base addition salts" refers to pharmaceutically acceptable salts derived from an organic or inorganic base. Examples of acceptable inorganic bases include sodium, potassium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts. Salts derived from pharmaceutically acceptable non-toxic organic bases include salts of primary, secondary and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, for example isopropyl amine, trimethylamine, diethylamine, triethylamine, tripropyl amine, ethanolamine, 2-diethylaminoethanol, trimethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like. A “solvate” refers to the association or complex of one or more solvent molecules and a compound of the invention. Examples of solvents that can form solvates include, but are not limited to: water, isopropanol, ethanol, methanol, DMSO, ethyl acetate (EtOAc), acetic acid (AcOH), and ethanolamine. The term “EC5o” is the half-maximal effective concentration and indicates the plasma concentration of a particular compound required to obtain 50% of the maximum of a particular effect “in vivo”. The term "Ki" is the inhibition constant and indicates the absolute binding affinity of a particular inhibitor to a receptor. It is determined by performing competition binding assays and is equal to the concentration at which the particular inhibitor would occupy 50% of the receptor if no competing ligand (e.g., a radioligand) were present. Ki values ​​can be logarithmically converted to pKi values ​​(-log Ki), with higher values ​​indicating exponentially greater potency. The term “IC50” stands for half-maximal inhibitory concentration and indicates the concentration of a particular compound required to achieve 50% inhibition of an in vitro biological process. IC50 values ​​can be converted to logarithmic terms, which are called pICso (-log ICso) values; higher values ​​indicate exponentially greater potential. The IC50 value is not an absolute value but depends on the experimental conditions, e.g., the concentrations used. It can be converted into an absolute inhibition constant (Ki) by applying the Cheng-Prusoff equation (Biochem. Pharmacol. 22, 3099, 1973). Other percentage inhibition parameters, such as IC70, IC90, etc., can be calculated.

[0007] The terms “compound of this invention”, “compounds of the present invention” and “compounds of formula I” include the compounds of formula I and the stereoisomers, geometrical isomers, tautomers, solvates, metabolites and pharmaceutically acceptable salts and prodrugs thereof. Any formula or structure presented herein, which includes compounds of formula I, is assumed to also encompass hydrates, solvates, polymorphs of said compounds and mixtures thereof. Any formula or structure presented herein, which includes compounds of formula I, is assumed to also encompass the unlabeled and isotopically labeled forms of such compounds. Isotopically labeled compounds have the structures represented in the formulas given herein, except that one or more atoms have been replaced by an atom having a selected atomic mass or atomic number. Examples of isotopes that may be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, for example, but not limited to: 2H (deuterium, D), 3H (tritium), 11C, 13C, 14C, 15N, 18F, 31P, 32P, 35S, 36Cl, and 1251. Various isotopically labeled compounds of the present invention are incorporated, for example those incorporating radioactive isotopes such as 3H, 13C, and 14C.These isotope-labeled compounds may be useful for metabolic studies, reaction kinetic studies, detection techniques, or imaging techniques, such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), including drug or substrate tissue distribution assays, or for the radioactive treatment of patients. The therapeutic compounds of the invention, substituted or labeled with deuterium, have improved DMPK (drug metabolism and pharmacokinetics) properties with respect to distribution, metabolism, and excretion (ADME). Substitution with heavier isotopes, such as deuterium, may provide certain therapeutic advantages due to their greater metabolic stability, such as a longer in vivo half-life or requiring a lower dosage. An 18F-labeled compound may be useful for PET or SPECT studies.The compounds of this invention and their isotopically labeled prodrugs can generally be obtained by carrying out the procedures described in the schemes and in the examples and the preparations described below, in which a readily available isotopically labeled reagent is used instead of a non-isotopically labeled reagent. In addition, substitution with heavier isotopes, especially deuterium (i.e., 2H or D), may provide certain therapeutic advantages, derived from their greater metabolic stability, for example, a longer in vivo half-life or require a lower dosage or improve the therapeutic index. It is understood that deuterium is considered in this context as a substituent of the compound of formula (I). The concentration of such a higher isotope, specifically deuterium, can be defined as the isotopic enrichment factor.In the compounds of this invention, any atom not specifically designated as a particular isotope is assumed to represent any stable isotope of that atom. Unless otherwise indicated, when a position is specifically designated as “H” or “hydrogen,” that position is assumed to have hydrogen in its natural isotopic abundance composition. Accordingly, in the compounds of this invention, any atom specifically designated as deuterium (D) is assumed to represent deuterium. Estrogen receptor Estrogen receptor alpha (ER-α; NR3A1) and estrogen receptor beta (ER-β; NR3A2) are steroid hormone receptors, which belong to a larger group of nuclear receptors. Nuclear receptors have in common the modular structure, which at least includes a DNA-binding domain (DBD) and a ligand-binding domain (LBD). The steroid hormone receptors are soluble intracellular proteins, which act as ligand-regulated transcription factors. Vertebrates contain five closely related steroid hormone receptors (estrogen receptor, androgen receptor, progesterone receptor, glucocorticoid receptor, mineralocorticoid receptor), which regulate a wide spectrum of reproductive, metabolic, and developmental activities. ER activities are controlled by the binding of endogenous estrogens, including estradiol 17β and estrenes. The ER-α (alpha) gene is located on 6q25.1 and encodes the 595 AA protein. The ER-β gene resides on chromosome 14q23.3 and produces the 530 AA protein. However, because of alternative cleavage and translocation initiation sites, each of these genes can give rise to multiple isoforms. In addition to the DNA-binding domain (called the C domain) and the ligand-binding domain (E domain), these receptors contain an N-terminal (A / B) domain, a hinge (D) domain linking the C and E domains, and a C-terminal extension (F domain) (Gronemeyer and Laudet; Protein Profile 2,1173-1308,1995). The C and E domains of ER-α and ER-β are fully conserved (95% and 55% amino acid identity, respectively), the conservation of the A / B, D and F domains is poor (less than 30% amino acid identity).Both receptors are involved in the regulation and development of the female reproductive tract, but they also play several roles in the central nervous system, the cardiovascular system, and bone metabolism. The ligand-binding pocket of steroid hormone receptors is deeply buried within the ligand-binding domain. Once bound, the ligand becomes part of the hydrophobic core of the ligand-binding domain. Consequently, most steroid hormone receptors are unstable in the absence of hormones and require the assistance of chaperones, for example Hsp90, to maintain hormone-binding competence. Interaction with Hsp90 also controls the nuclear translocation of these receptors.Ligand binding stabilizes the receptor and initiates sequential conformational changes that release chaperones, alter interactions between receptor domains, and remodel protein interacting surfaces, allowing these receptors to relocate within the nucleus, bind DNA, and engage in interactions with chromatin remodeling complexes and the transcriptional machinery. Although ERs can interact with Hsp90, this interaction is not required for hormone binding, and depending on the cellular context, the ER-apo may be cytoplasmic or nuclear. Biophysical studies indicate that DNA binding, in preference to ligand binding, contributes to receptor stability (Greenfield et al., Biochemistry 40, 6646–6652, 2001). The ER can interact with DNA either directly by binding to a specific DNA sequence motif called the estrogen response element (ERE) (classical mechanism) or indirectly through protein-protein interactions (nonclassical mechanism) (Welboren et al., Endocrine-Related Cancer 16,1073–1089, 2009). In the nonclassical mechanism, the ER has been shown to bind to other transcription factors, including SP-1, AP-1, and NF-κΒ. These interactions appear to play a crucial role in the ER’s ability to regulate cell proliferation and differentiation. Both types of ER-DNA interactions can result in gene activation or repression depending on which transcriptional coregulators are recruited by the corresponding ERERE complex (Klinge, Steroid 65, 227-251, 2000). Recruitment of coregulators is primarily mediated by two protein interaction surfaces, AF2 and AF1. AF2 is located in the E domain of the ER and its conformation is directly regulated by the ligand (Brzozowski et al., Nature 389, 753-758, 1997). Full agonists appear to facilitate the recruitment of coactivators, whereas weak agonists and antagonists facilitate the binding of corepressors. Regulation of the protein by AF1 is less understood, but may be controlled by serine phosphorylation (Ward and Weigel, Biofactors 35, 528-536,2009).One of the phosphorylation sites (S118) involved appears to control ER transcriptional activity in the presence of antagonists, such as tamoxifen, which plays an important role in the treatment of breast cancer. Full agonists appear to lock the ER into a particular conformation, whereas weak agonists tend to maintain the ER in equilibrium between different conformations, allowing cell-dependent differences in the coregulator repertoires to modulate ER activity in a cell-dependent manner (Tamrazi et al., Mol. Endocrine 17, 2593–2602, 2003). ER interactions with DNA are dynamic and include, but are not limited to, ER degradation by the proteasome (Reid et al., Mol. Cell 11, 695–707, 2003).ER degradation with ligands provides an attractive treatment strategy for diseases or pathological conditions that are estrogen-sensitive and / or resistant to available antihormonal therapies. ER signaling is crucial for the development and maintenance of female reproductive organs, including the breast, ovulation, and endometrial thickening. ER signaling also plays a role in bone mass, lipid metabolism, cancer, and more. Approximately 70% of breast cancers express ER-α (ER-α positive) and depend on estrogen for growth and survival. Other cancers, such as ovarian and endometrial cancers, are also thought to depend on ER-α signaling for growth and survival.Tamoxifen, an ER-α antagonist, has been used to treat early and advanced ER-α-positive breast cancer in both pre- and postmenopausal women. Fulvestrant (FASLODEX®, AstraZeneca) is a steroid-based ER antagonist used to treat breast cancer in women that has progressed despite tamoxifen therapy (Howell, A., Endocr. Relat. Cancer 13, 689-706,2006; US 6774122; US 7456160; US 8329680; US 8466139). Steroidal and nonsteroidal aromatase inhibitors are also used to treat human cancer. In some embodiments, steroidal and nonsteroidal aromatase inhibitors block the production of estrogens androstenedione and testosterone in postmenopausal women, thereby blocking ER-dependent cancer growth.In addition to these antihormonal agents, progressive ER-positive breast cancer is sometimes treated with a wide variety of other chemotherapeutic agents, including anthracillins, platinums, and taxanes. In some cases, ER-positive breast cancer harboring gene amplification of the ERB-α / HER2 tyrosine kinase receptor (HER2) is treated with the monoclonal antibody trastuzumab (Herceptin®, Genentech Inc.) or the small-molecule pan-ERB-α inhibitor lapatinib (TYKERB®, Glaxo Smith Kline Corp.). Despite this arsenal of targeted therapies, including antihormonal, chemotherapeutic, small molecule, and antibody-based therapies, many women with ER-α-positive breast cancer develop progressive metastatic disease and require novel therapies.Importantly, it is thought that the majority of ER-positive tumors that progress on existing antihormonal therapies, as well as other therapies, will continue to rely on ER-α for growth or survival. Therefore, novel ER-α-targeted agents with activity to address metastatic disease and acquired resistance are needed. In one aspect, compounds that are selective estrogen receptor modulators (SERMs) are described herein. In specific embodiments, the SERMs described herein are selective estrogen receptor degraders (SERDs).In some embodiments, in cell-based assays, the compounds described herein result in a reduction of steady-state ER-α levels (i.e., ER degradation) and are useful for the treatment of estrogen-sensitive diseases or conditions and / or diseases or conditions that have developed resistance to anti-hormonal therapies. Most breast cancer patients are treated with agents that block estrogen synthesis (e.g., aromatase inhibitors; AIs) or antagonize the effects of estradiol through competitive binding to the ER (e.g., tamoxifen) (Puhalla, S. et al., Mol. Oncol. 6(2), 222–236, 2012). Despite the well-documented therapeutic utility of these agents for various stages of the disease, many ER+ breast cancers recur, and patients eventually succumb. In recent years, next-generation genome-wide targeted sequencing has identified mutations in the ESR1 (estrogen receptor alpha gene) in up to 20% of tumors from patients with advanced breast cancer who have progressed on endocrine therapies, largely with aromatase inhibitors (L¡, S. et al., Cell. Rep. 4(6), 1116-1130, 2013; Merenbakh-Lamin, K, et al., Cancer Res. 73(23), 6856-6864, 2013; Robinson, D.R. et al., Nat.Genet. 45(12), 1446-1451, 2013); Toy, W. et al., Nat. Genet. 45(12), 1439-1445, 2013; Jeselsohn, R. et al., Clin. Cancer Res. 20, 1757-1767, 2014). These ligand-binding domain (LBD) mutations confer high basal activity to the aporeceptor, rendering it ligand-independent and thus active in binding estradiol to low concentrations. New therapies targeting ER signaling with robust activity are needed to delineate progressive disease after Al- or tamoxifen treatment, including a subset of patients carrying ESR1-mutant tumors. In some embodiments, the compounds of formula I described herein are used in methods of treating estrogen receptor (ER) positive, hormone refractory breast cancer in a patient characterized by having a mutation in the ESR1 gene, which comprises administering a therapeutically effective amount of a compound of formula I. In some embodiments, the ESR1 gene mutation results in an ER polypeptide having an amino acid substitution at a position selected from amino acid positions 6, 118, 269, 311, 341, 350, 380, 392, 394, 433, 463, 503, 534, 535, 536, 537, 538 and 555 of SEQ ID NO:2. In some embodiments, the mutation results in an ER polypeptide having an amino acid substitution at a position selected from H6Y, S118P, R269C, T311M, S341L, A350E, E380Q, V392I, R394H, S433P, S463P, R503W, V534E, P535H, L536R, L536P, L536Q, Y537N, Y537C, Y537S, D538G, and R555C.In some forms of execution, the patient has two or more mutations in the ESR1 gene. Given the central role of ER-α in the development and progression of breast cancer, the compounds described herein are useful for the treatment of breast cancer, either alone or in combination with other agents that can modulate other critical mechanisms of breast cancer, including, but not limited to, those directed against IGF1R, EGFR, CDK4 / 6, erB-B2 and 3, the PI3K / AKT / mTOR axis, HSP90, PARP or histone deacetylases. Given the central role of ER-α in the development and progression of breast cancer, the compounds of formula I described herein are useful for the treatment of breast cancer, either alone or in combination with other agents used to treat breast cancer, including, but not limited to, aromatase inhibitors, anthracyclines, platinums, nitrogen mustard-type alkylating agents, taxanes. Illustrative agents used to treat breast cancer include, but are not limited to, PI3K inhibitors, e.g., taselisib (GDC-0032, Genentech Inc.), paclitaxel, anastrozole, exemestane, cyclophosphamide, epirubicin, fulvestrant, letrozole (FEMARA®, Novartis, Corp.), gemcitabine, trastuzumab, pegfilgrastim, filgrastim, tamoxifen, docetaxel, toremifene, vinorelbine, capecitabine (XELODA®, Roche), ixabepilone, as well as others described herein. ER-related diseases or pathological states include ER-α dysfunction associated with cancer (bone cancer, breast cancer, lung cancer, colorectal cancer, endometrial cancer, prostate cancer, ovarian and uterine cancer), central nervous system (CNS) disorders (alcoholism, migraine), cardiovascular system disorders (aortic aneurysm, myocardial infarction susceptibility, aortic valve sclerosis, cardiovascular disease, coronary artery disease, hypertension), hematological system disorders (deep vein thrombosis), immune and inflammatory diseases (Graves' disease, arthritis, multiple sclerosis, cirrhosis), infection susceptibility (hepatitis B, chronic hepatitis), metabolic disorders (bone density, cholestasis, hypospadias, obesity, osteoarthritis, osteopenia, osteoporosis), neurological disorders (Alzheimer's disease, Parkinson's disease, migraine, vertigo),Psychiatric disorders (anorexia nervosa, attention deficit hyperactivity disorder (ADHD), dementia, major depressive disorder, psychosis) and reproductive system disorders (age at menarche, endometriosis, infertility). In some embodiments, the compounds described herein are used for the treatment of an estrogen receptor-dependent or estrogen receptor-mediated disease or condition of a mammal. In some embodiments, the compounds described herein are used to treat cancer in a mammal. In some embodiments, the cancer is breast cancer, ovarian cancer, endometrial cancer, prostate cancer, or uterine cancer. In some embodiments, the cancer is breast cancer, lung cancer, ovarian cancer, endometrial cancer, prostate cancer, or uterine cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is a hormone-dependent cancer. In some embodiments, the cancer is an estrogen-receptor-dependent cancer. In some embodiments, the cancer is an estrogen-sensitive cancer. In some embodiments, the cancer is resistant to antihormonal therapy. In some embodiments, the cancer is an estrogen-sensitive cancer or an estrogen-receptor-dependent cancer that is resistant to antihormonal therapy.In some embodiments, the cancer is a hormone-sensitive cancer or an androgen receptor-dependent cancer that is resistant to antihormonal therapy. In some embodiments, antihormonal therapy includes treatment with at least one agent selected from tamoxifen, fulvestrant, steroidal aromatase inhibitors, or nonsteroidal aromatase inhibitors. In some embodiments, the compounds described herein are used to treat hormone receptor-positive metastatic breast cancer in a post-menopausal woman with disease progression after undergoing anti-estrogen therapy. In some embodiments, the compounds described herein are used to treat a hormone-dependent benign or malignant breast disease or a disease of the reproductive tract of a mammal. In some embodiments, the benign or malignant disease is breast cancer. In some embodiments, the compound employed in any one of the methods described herein is an estrogen receptor degrader; is an estrogen receptor antagonist; has minimal or negligible estrogen receptor agonist activity; or combinations thereof. In some embodiments, the methods of treatment with compounds described herein include a treatment regimen consisting of administering radiation therapy to the mammal. In some embodiments, the treatment methods with compounds described herein include administering the compound before or after surgery. In some embodiments, methods of treatment with compounds described herein include administering to the mammal at least one additional anticancer agent. In some embodiments, the compounds described herein are used to treat cancer in a mammal, said mammal having not previously undergone chemotherapy. In some embodiments, the compounds described herein are used to treat cancer in a mammal. In some embodiments, the compounds described herein are used to treat cancer in a mammal, the mammal being treated for cancer with at least one anticancer agent. In one embodiment, the cancer is a hormone-resistant cancer. In some embodiments, the compounds described herein are used for the treatment or prevention of diseases or conditions of the uterus of a mammal. In some embodiments, the disease or condition of the uterus is a leiomyoma, a uterine leiomyoma, endometrial hyperplasia, or endometriosis. In some embodiments, the disease or condition of the uterus is a cancerous disease or condition of the uterus. In still other embodiments, the disease or condition of the uterus is a non-cancerous disease or condition of the uterus. In some embodiments, the compounds described herein are used for the treatment of endometriosis in a mammal. In some embodiments, the compounds described herein are used for the treatment of a leiomyoma of a mammal. In some embodiments, the leiomyoma is a uterine leiomyoma, an esophageal leiomyoma, a cutaneous leiomyoma, or a small intestinal leiomyoma. In some embodiments, the compounds described herein are used for the treatment of fibroids of a mammal. In some embodiments, the compounds described herein are used for the treatment of uterine fibroids of a mammal. Another embodiment of the invention relates to a compound described herein for use as a therapeutically active substance. Another embodiment of the invention relates to a compound described herein for use in the treatment of an ER-related disease or disorder. Another embodiment of the invention relates to the use of a compound described herein for the treatment of an ER-related disease or disorder. Another embodiment of the invention relates to the use of a compound described herein for the manufacture of a medicament useful in the treatment of an ER-related disease or disorder. Tetrahydro-pyrido[3,4-b1¡ndole-1-yl compounds The present invention provides tetrahydro-pyrido[3,4-b]indole-1-yl compounds of formula I, including formulas Ia-If and pharmaceutical formulations thereof, which are potentially useful for the treatment of estrogen receptor alpha (ERa) modulated diseases, pathological states and / or disorders. Compounds of formula I have the structure: IVIA / a / ¿U¿¿ / UU fUfO and the stereoisomers, tautomers or pharmaceutically acceptable salts thereof, in which: Y1es CRbo N; Y2is -(CH2)-, -(CH2CH2)- or NRa; Y3es NRao C(Rb)2; where one of Y1, Y2 and Y3 is N or NRa; Rase is selected from H, C1-Ce alkyl, C2-C8 alkenyl, propargyl, C3-C6 cycloalkyl and C3-C6 heterocyclyl, optionally substituted with one or more groups independently selected from F, Cl, Br, I, CN, OH, OCH3 and SO2CH3; Rb is independently selected from H, -O(C1-C3 alkyl), C1—Ce alkyl, C2-C8 alkenyl, propargyl, -(C1Ce alkyldiyl)—(C3-Ce cycloalkyl), C3-C6 cycloalkyl and C3-C6 heterocyclyl, optionally substituted with one or more groups independently selected from F, Cl, Br, I, CN, -CH2F, -CHF2, -CF3, -CH2CF3, -CH2CHF2, -CH2CH2F, OH, OCH3 and SO2CH3; Rc is selected from H, C1-Ce alkyl, allyl, propargyl, optionally substituted with one or more groups independently selected from F, Cl, Br, I, CN, OH, OCH3 and SO2CH3; Z1 is chosen from CRaRb, C(O) and a bond; Cy is chosen from C6-C20 aryldiyl, C3-C12 carbocyclyldiyl, C2-C20 heterocyclyldiyl and C1-C20 heteroaryldiyl; Z2 is chosen from O, S, NRa, C1—Ce alkyldiyl, C1—Ce fluoroalkyldiyl, O—(Ci—Ce alkyldiyl), O-(Ci—Ce fluoroalkyldiyl), C(O) and a bond; R1, R2, R3 and R4 are independently selected between H, F, Cl, Br, I, -CN, -CH3, -CH2CH3, -CH(CH3)2, -CH2CH(CH3)2, -CH2OH, -CH2OCH3, -CH2CH2OH, -C(CH3)2OH, -CH(OH)CH(CH3)2, -C(CH3)2CH2OH, -CH2CH2SO2CH3, CH2OP(O)(OH)2, -CH2F, -CHF2, -CH2NH2, -CH2NHSO2CH3, -CH2NHCH3, -CH2N(CH3)2, -CF3, -CH2CF3, CH2CHF2, -CH(CH3)CN, -C(CH3)2CN, -CH2CN, -CO2H, -COCH3, -CO2CH3, -CO2C(CH3)3, -COCH(OH)CH3, CONH2, -CONHCH3, -CONHCH2CH3, -CONHCH(CH3)2, -CON(CH3)2, -C(CH3)2CONH2, -NH2i-NHCH3, -N(CH3)2, -NHCOCH3, -N(CH3)COCH3, -NHS(O)2CH3, -N(CH3)C(CH3)2CONH2, -N(CH3)CH2CH2S(O)2CH3, -no2, =0, -OH, 0CH3, -OCH2CH3, -OCH2CH2OCH3, -OCH2CH2OH, -OCH2CH2N(CH3)2, -OP(O)(OH)2, -S(O)2N(CH3)2, -sch3, S(O)2CH3, -S(O)3H, cyclopropyl, cyclopropylamide, cyclobutyl, oxetanil, azetidinil, 1-methylazetidin-3-yl)ox, N-methyl-Noxetan-3-ylamino, azetidin-1-ylmethyl, benzyloxyphenyl, pyrrolidin-1-yl, pyrrolidin-1-yl-methanone, piperazin-1-yl, morpholinomethyl, morpholino-methanone and morpholino; R5 is selected from H, C1-C9 alkyl, C3-C9 cycloalkyl, C3-Cg heterocycle, Cs-Cg aryl, Ce-Cg heteroaryl, - (C121 alkyldiyl C6)-(C3-C9 cycloalkyl), —(C1-Ce alkyldiyl)-(C3-C9 heterocycle), C(O)Rb, C(O)NRa, SO2Ray SO2NRa, optionally substituted with one or more of halogen, CN, ORa, N(Ra)2, C1-C9 alkyl, C3-C9 cycloalkyl, C3-C9 heterocycle, C6-C9 aryl, C6-C9 heteroaryl, C(O)Rb, C(O)NRa, SO2Ray SO2NRa; <h2 style=";text-align:left;direction:ltr">R6se elige entre F, Cl, Br, I, -CN, -CH3, -CH2CH3, -CH(CH3)2, -CH2CH(CH3)2, -CH2OH, -CH2OCH3, -CH2CH2OH, -C(CH3)2OH, -CH(OH)CH(CH3)2, -C(CH3)2CH2OH, -CH2CH2SO2CH3, -CH2OP(O)(OH)2, -CH2F, -CHF2, -CH2NH2, CH2NHSO2CH3, -CH2NHCH3, -CH2N(CH3)2, -CF3, -CH2CF3, -CH2CHF2, -CH(CH3)CN, -C(CH3)2CN, -ch2cn, CO2H, -COCH3, -CO2CH3, -CO2C(CH3)3, -COCH(OH)CH3, -conh2, -conhch3, -conhch2ch3, CONHCH(CH3)2, -CON(CH3)2, -C(CH3)2CONH2, -NH2i-NHCH3, -N(CH3)2, -NHCOCH3, -N(CH3)COCH3, NHS(O)2CH3, -N(CH3)C(CH3)2CONH2, -N(CH3)CH2CH2S(O)2CH3, -NO2i=0, -OH, -OCH3, -OCH2CH3, OCH2CH2OCH3, -OCH2CH2OH, -OCH2CH2N(CH3)2, -OP(O)(OH)2, -S(O)2N(CH3)2, -SCH3i-S(O)2CH3, -S(O)3H, cyclopropyl, cyclopropylamine, cyclobutyl, oxetanilo, azetidinilo, 1-metilazetidin-3-il)oxi, N-metil-N-oxetan-3-ilamino, azetidin-1-ilmetilo, benciloxifenilo, pirrolidin-1-ilo, pirrolidin-1-il-metanona, piperazin-1-ilo, morfolinometilo, morpholínometanona y morpholino; ym se elig entre 0,1,2, 3 y 4;<h2 style=";text-align:left;direction:ltr"> said alkyldiyl, fluoroalkyldiyl, aryldiyl, carbo-cyclyldiyl, heterocyclyldiyl and heteroaryldiyl are optionally substituted by one or more groups independently selected from F, Cl, Br, I, -CN, -CH3, -CH2CH3, -CH(CH3)2, CH2CH(CH3)2, -CH2OH, -CH2OCH3, -CH2CH2OH, -C(CH3)2OH, -CH(OH)CH(CH3)2i-C(CH3)2CH2OH, CH2CH2SO2CH3, -CH2OP(O)(OH)2, -ch2f, -chf2, -cf3, -ch2cf3, -ch2chf2, -ch2ch2f, CH(CH3)CN, -C(CH3)2CN, -CH2CN, -CH2NH2, -CH2NHSO2CH3, -CH2NHCH3, -CH2N(CH3)2, -co2h, -coch3, CO2CH3, -CO2C(CH3)3, -COCH(OH)CH3i-CONH2, -CONHCH3i-CON(CH3)2, -C(CH3)2CONH2, -nh2, NHCH3, -N(CH3)2, -NHCOCH3, -N(CH3)COCH3, -NHS(O)2CH3, -N(CH3)C(CH3)2CONH2, -N(CH3)CH2CH2S(O)2CH3i-NO2, =0, -OH, -0CH3, -OCH2CH3, -OCH2CH2OCH3, -OCH2CH2OH, -OCH2CH2N(CH3)2, -OP(O)(OH)2iS(O)2N(CH3)2, -SCH3, -S(O)2CH3, -S(O)3H, cyclopropyl, cyclopropylamide, cyclobutyl, oxetanyl, azetidinyl, 1methylazetidin-3-yl)oxy, N-methyl-N-oxetan-3-ylamino, azetidin-1-ylmethyl, benzyloxyphenyl, pyrrolidin-1-yl,pyrrolidin-1-ylmethanone, piperazin-1-yl, morpholinomethyl, morpholino-methanone and morpholino., Compounds of the formulas la-k have the structures: MΛ / a / ZUZZ / UU fUfO <h2 style=";text-align:left;direction:ltr">and R7es F, Cl, Br, I, -CN, -CH3, -CH2CH3, -CH(CH3)2, -CH2CH(CH3)2, -CH2OH, -CH2OCH3, -CH2CH2OH, -C(CH3)2OH, -CH(OH)CH(CH3)2, -C(CH3)2CH2OH, -CH2CH2SO2CH3i-CH2OP(O)(OH)2, -CH2F, -CHF2, -CH2NH2, CH2NHSO2CH3, -CH2NHCH3, -CH2N(CH3)2, -CF3, -CH2CF3, -CH2CHF2, -CH(CH3)CN, -C(CH3)2CN, -ch2cn, CO2H, -COCHs, -CO2CH3, -CO2C(CH3)3, -COCH(OH)CH3, -conh2, -conhch3, -conhch2ch3, CONHCH(CH3)2, -CON(CH3)2, -C(CH3)2CONH2, -NH2, -NHCH3, -N(CH3)2, -NHCOCH3, -N(CH3)COCH3, NHS(O)2CH3, -N(CH3)C(CH3)2CONH2, -N(CH3)CH2CH2S(O)2CH3i-no2, =0, -OH, -och3, -och2ch3, OCH2CH2OCH3, -OCH2CH2OH, -OCH2CH2N(CH3)2, -OP(O)(OH)2, -S(O)2N(CH3)2, -SCH3i-S(O)2CH3, -S(O)3H, cyclopropyl alcohol, cyclopropyl alcohol, oxetanilo, azetidinilo, 1 -metilazetidin-3-il)oxi, N-metil-N-oxetan-3-ilamino, azetidin-1ilmetilo, benciloxifenilo, pirrolidin-1-ilo, pirrolidin-1-il-metanona, piperazin-1-ilo, morfolinometilo, morpholino-metanona y morpholino; They are between 0,1,2, 3 and 4;<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> Id;<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> ινΐΛ / a / zuzz / uu / y Illustrative embodiments of compounds of formula I include those, wherein Y1 is CRbe and Y3 is NRa. Illustrative embodiments of compounds of formula I include those in which Y1 is N and Y3 is C(Rb)2. Illustrative embodiments of compounds of formula I include those in which Y2 is (CH2)-. Illustrative embodiments of compounds of formula I include those in which Y2 is (CH2CH2)-. Illustrative embodiments of compounds of formula I include those in which Rces H. Illustrative embodiments of compounds of formula I include those wherein Cy is C6-C20 aryldiyl, C6-C20 aryldiyl is phenyldiyl, and phenyldiyl is substituted by one or more F. Illustrative embodiments of compounds of formula I include those in which R1 and R2 are H. Illustrative embodiments of compounds of formula I include those in which R3 is H and R4 is -CH3. Illustrative embodiments of compounds of formula I include those in which R5 is fluoroalkyl Ci-Ce. Illustrative embodiments of compounds of formula I include those in which m is 0. The present invention also provides tetrahydro-pyrido[3,4-b]indol-1-yl compounds of formula XI, including formula Xla, and pharmaceutical formulations thereof, which are potentially useful for the treatment of estrogen receptor alpha (ERa) modulated diseases, conditions, and / or disorders. In some embodiments, a compound of the invention has the following structure of formula (XI): in which: Z1 and Z2 are chosen independently from -O-, -(CH2)-, -C(O)- and a bond; Cy is C6-C20 aryl, C3-C12 carbocyclyl, C2-C20 heterocyclyl, or C1-C20 heteroaryl; X is -(CH2)- or -(CH2CH2)-; R1 is chosen from H, F, Cl, -CN, -CH2OH, -CH(CH3)OH, -C(CH3)2OH, -CH(CF3)OH, -CH2F, -CHF2, -CH2CHF2, -CF3>CH3, -C(O)NH2i-C(O)NHCH3y -C(O)N(CH3)2; each R2 is independently selected from halogen, -CN, -OR10, -NR13R14, C1-C6 alkyl, C3-C8 carbocyclyl, -C1Ce alkyl-OH, -C3-C8 carbocyclyl-OH, -O-C2-C6 alkyl-OH, C1-C6 fluoroalkyl, C3-C8 fluorocarbocyclyl, -C(=O)OR12, -NHC(=O)R11, -C(=O)NHR12, -SO2R11, -NHSO2R11 and -SO2NHR12; R4 and R5 are independently selected from C1-C6 alkyl, C3-C8 carbocyclyl, -C1-C6 alkyl-OH, -C3-C8 carbocyclyl-OH, C1-Ce fluoroalkyl, C3-C8 fluorocarbocyclyl, -C(=O)OR12; R9 is independently selected from C1-C10 alkyl, C3-C8 carbocyclyl, -C1-C10 alkyl-OH, C3-C8 carbocyclyl-OH, C1-C8 fluoroalkyl, C3-C8 fluorocarbocyclyl, C2-Cg heterocyclyl, C8-C10 aryl and C1-C10 heteroaryl; R19, C6-Ci0aryl and C1-C10 heteroaryl; each R10 is independently selected from H, C1-C4 alkyl, and C1-C4 fluoroalkyl; each R11 is independently selected from C1-C4 alkyl and C1-C4 fluoroalkyl; each R12 is independently selected from H, C1-C4 alkyl, and C1-C4 fluoroalkyl; Each R13 and each R14 are independently selected from H and C1-C4 alkyl; and m is 0, 1, 2 or 3; or a pharmaceutically acceptable salt, solvate or prodrug thereof. In some embodiments, the compound of formula (XI) has the structure of formula (Xla): formula (Xla); where R2a is independently H or F, n is 0, 1 or 2 and R4 and R5 are independently H or methyl. In some embodiments there is a compound of formula (XI), wherein Z1 is a bond. In some embodiments there is a compound of formula (XI), wherein Z1 is -O-. In some embodiments there is a compound of formula (XI), wherein Z1 is -(CH2)-. In some embodiments there is a compound of formula (XI), wherein Z1 is -C(O)-. In some embodiments there is a compound of formula (XI), wherein Z2 is a bond. In some embodiments there is a compound of formula (XI), wherein Z2 is -O-. In some embodiments there is a compound of formula (XI), wherein Z2 is -(CH2)-. In some embodiments there is a compound of formula (XI), wherein Z2 is -C(O)-. In some embodiments there is a compound of formula (XI), wherein Cy is C6-C20 aryl. In some embodiments there is a compound of the formula (XI), in which Cy is phenyl.In some embodiments there is a compound of the formula (XI), wherein Cy is C3-C12 carbocyclyl. In some embodiments there is a compound of the formula (XI), wherein Cy is cyclohexyl. In some embodiments there is a compound of the formula (XI), wherein Cy is C2-C20 heterocyclyl. In some embodiments there is a compound of the formula (XI), wherein Cy is pyrazinyl. In some embodiments there is a compound of the formula (XI), wherein Cy is piperidinyl. In some embodiments there is a compound of the formula (XI), wherein Cy is C1-C20 heteroaryl. In some embodiments there is a compound of the formula (XI), wherein Cy is thiazolyl. In some embodiments there is a compound of the formula (XI), wherein Cy is oxazolyl. In some embodiments there is a compound of the formula (XI), wherein Cy is pyridyl. In some embodiments there is a compound of formula (XI), in which R1 is H.In some embodiments there is a compound of formula (XI), wherein R1 is -CH3. In some embodiments there is a compound of formula (XI), wherein X is -(CH2). In some embodiments there is a compound of formula (XI), wherein X is -(CH2)- and R1 is H. In some embodiments there is a compound of formula (XI), wherein X is -(CH2CH2)-. In some embodiments there is a compound of formula (XI), wherein X is -(CH2CH2)- and R1 is H. In some embodiments there is a compound of formula (XI), wherein X is -(CH2CH2)- and R1 is -CH3. In some embodiments there is a compound of formula (XI), wherein Z1 is a bond, Z2 is -O-, Cy is phenyl, X is -(CH2)-, and R1 is H. In some embodiments there is a compound of formula (XI), wherein Z1 is a bond, Z2 is -O-, Cy is phenyl, X is -(CH2CH2)-, and R1 is H. In some embodiments there is a compound of formula (XI), wherein Z1 is a bond, Z2 is -O-, Cy is phenyl, X is -(CH2CH2)-, and R1 is -CH3. Biological evaluation The relative efficacies of the compounds of formula I as inhibitors of enzyme (or other biological) activity can be established by determining the concentrations at which each compound inhibits activity to a predefined degree and then comparing the results. Generally, the preferred determination is the concentration that inhibits 50% of the activity in a biochemical assay, i.e., the 50% inhibitory concentration or “IC50.” Determination of IC50 values ​​can be carried out using conventional techniques well known in biology. In general, an IC50 value can be determined by measuring the activity of a given enzyme in the presence of a range of concentrations of the inhibitor under study. The experimentally obtained enzyme activity values ​​are then plotted against the inhibitor concentrations employed.The inhibitor concentration that exhibits 50% enzymatic activity (relative to the activity in the absence of inhibitor) is taken as the IC50 value. Other inhibitor concentrations can also be defined by performing appropriate activity determinations. For example, in some situations, it may be desirable to set the inhibitory concentration at 90%, i.e., IC90, etc. The cell proliferation, cytotoxicity, and cell viability of compounds of formula I can be measured by performing the CelITiter-Glo® Luminescent Cell Viability Assay (Promega Corp.). The CelITiter-Glo® Luminescent Cell Viability Assay is a homogeneous method for determining the number of viable cells in a culture based on the quantification of ATP, an indicator of metabolically active cells. The CelITiter-Glo® assay is designed for use in multi-well formats, making it ideal for automated high throughput screening (HTS) for cell proliferation and cytotoxicity assays. This homogeneous assay procedure involves adding the individual reagent (CelITiter-Glo® Reagent) directly to cultured cells in serum-supplemented medium. Cell washing, medium removal, and multiple pipetting steps are not required.The system can detect up to 15 cells per well in a 384-well format in 10 minutes after adding reagent and shaking. All exemplary compounds of formula I in Tables 1 and 2 are obtained and characterized by LCMS [M+H]+ (liquid chromatography + mass spectroscopy) with parent ion detection. All ινΐΛ / a / zuzz / uu 1 and ιΌ exemplary compounds of formula I in Tables 1 and 2 are assayed for ERa (estrogen receptor alpha) binding and biological activity according to the assays, protocols, and procedures in Examples 901-907. The ER-alpha MCF7 HCS S¡nf (%) values ​​in Table 1 are obtained by performing the assay of Example 901 high content fluorescence imaging degradation of ERa breast cancer cells. The EC5o (µM) values ​​of ER-alpha MCF7 HCS in Tables 1 and 2 are measured by performing the “in vitro” cell proliferation assays described in Examples 902 and 903.The rat uterine wet weight assays of Examples 906 and 907 allow rapid determination of antagonist compound activity in an ER-responsive tissue (immature rat uterus) when in competition with the native ER ligand estradiol, i.e., in antagonist mode (Ashby, J. et al., Regulatory toxicology and pharmacology (RTP) 25 (3), 226-31, 1997). Illustrative compounds of formula I in Tables 1 and 2 have the following structures, corresponding names (ChemBioDraw, version 12.0.2, CambridgeSoft Corp., Cambridge MA), and biological activity. Where more than one name is associated with a compound of formula I or an intermediate, then the chemical structure will be taken as the basis for defining the compound. Table 1 ινΐΛ / a / zuzz / uu / a <h2 style=";text-align:left;direction:ltr">Structure number ER-alfa MCF7 HCS EC50(pM) ER-alfa MCF7 HCS Sinf (%) 101 IZ ó (1R,3R)-1-(2,6-difluor4-((1-(3-fluorpropyl)azetidin-3-il)oxi)fenil)-2-(2-fluor-2metilpropyl)-3-met¡l2,3,4,9-tetra-hydro-1 Hpirido[3,4-b]ndol 0,000049 -100 102 _f \-F HF^( / \=\ / —N 2—\ 0- / F (1R,3R)-1-(2,6-difluor4-(2-(3-(fluormetil)azetidn-1-yl)etoxi)fenil)-2-(2-fluor-2metilpropyl)-3-metal-2,3,4,9-tetra-hydro-1Hpirido[3,4-b]ndol 0.000014 -98.9%<h2 style=";text-align:left;direction:ltr"> n° structure name ER-alpha MCF7 HCS EC50(mM) ER-alpha MCF7 HCS Sinf (%) 103 _ / ON\. QM ¿f H 0—\ / XX— N >--\ A7 F 1-((1 R,3R)-1-(2,6difluoro-4-(2-(3-(fluoromethyl)azetid¡n-1-yl)ethoxy)phenyl)-3-met¡l-3,4dihydro-1 H-pyrido[3,4b]indol-2(9H)-yl)-2-methylpropan-1-one 0.00011 -91.8% 104 F Λ νΆ ÍIh 0 H ;— / F^ / \ F 0—\ / A / vn >— 1-((1R,3R)-1-(2-(2) difluor-4-(2-(3-(fluoromethyl)azetid¡n-1-¡l)ethoxy)phenyl)-3-met¡l-3,4- dihydro-1 H-pyrido[3,4b]indol-2(9H)-yl)-2-fluor2-methylpropan-1-one 0.000.43.45% . F 0-N^AF HfO γ / f \ .nJ 0 (1R,3R)-1-(4-(2-(3(difluoromethyl)azetidine-lyl)ethoxy)-2,6-difluorophenyl)-2-(2-fluoro-2methylpropyl)-3-met¡l2,3,4,9,9-hydro-tetra-1- Hpyrido[3,4-b]¡ndol 0.000027 -94% 106 . F Λ N— Cv^.j Mo- <n-A Cl (1R,3R)-1-(4-((1-(3cloropropil)azetidin-3¡l)oxi)-2,6-d¡fluor-fenil)2-(2-fluor-2-metilpropil)3-metil-2,3,4,9- tetrah id ro-1 Hpirido[3,4-b]¡ndol 0,000142 -90,4% <h2 style=";text-align:left;direction:ltr">Structure number ER-alfa MCF7 HCS EC50(mM) ER-alfa MCF7 HCS Sinf (%) 107 χ F / N—' (1R,3R)-1-(2,6-difluor4-((1-propyl-azetidin-3l)oxy)-fenil)-2-(2-fluor-2metilpropyl)-3-metal2,3,4,9-tetrahydro-1 Hpirido[3,4-b]ndol 0,000024 -97,6% 108 \ F GA. j zrA 0—\ Λ~η / (1R,3R)-1-(2,6-difluor4-((S)-2-((R)-3(fluormetil)pyrrolidin-lil)propoxy)fenil)-2-(2fluor-2-metil-propyl)-3metil-2,3,4,9-tetrahydro1 H-pyridoxine[3,4-b]ndol 0,00011 -79,3% 109 \ F ΠA / -'i fJq OX / l (1R,3R)-1-(2,6-difluor4-(2-((R)-3(fluormetil)pyrrolidin-lil)propoxy)fenil)-2-(2-fluorometyl)pyrrolidin-lil)propoxy)fenil)-3-metil2,3,4,9-tetrahydro-1 H-pirido[3,4-b]indol 0.000050 -86.5% 110 111 __ / y—F nA í xV< zr^ H # N O-\ / X__ VN )--\ VF (1R,3R)-2-(2-fluor-2metilpropyl)-1 -(6-(2-(3(fluormetil)-azetidn-1l)etoxi)-pr¡r¡d¡n-3-l)-3-methyl-2,3,4,9-tetrahydro1 H-pir¡do[3,4-b]indol 0.000898 -96.8<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">n° estructura number ER-alfa MCF7 HCS EC50(mM) ER-alfa MCF7 HCS Sinf (%) 112 \ FHN} F 0^ / \__ / n >— (1S,3R)-2-(2-fluor-2metilpropil)-1-(3-fluor-5(2-(3-(fluormetil)azetid¡n-1-¡l)etoxi)pir¡din-2-¡l)-3metil-2,3,4,9-tetrahidro-1 H-pirido[3,4b]indol 0.000092 -93.9 113 iz í / 1 Va o V > TI (1R,3R)-2-(cyclobutilmetil)-1-(2,6-difluor-4(2-(3-(fluormetil)azetidin-1-l)etox)fenil)-3-metil-2,3,4,9tetrahedro-1 H-pyridinol[3,4-b]indol 0.00618 -94.8 114 ^2 θΛ / O \ LL \ ΤΪ . Z zi (1R,3R)-1-(2,6-di-fluor4-(2-(3-(fluormetil)azetid¡n-1-l)etoxi)fenil)-3-met¡l-2((3-metiloxetan-3-il)metil)-2,3,4,9-tetrahydro-1 H-pyridox[3,4b]indol 0,000715 -97,8 115 r° CTV-( / -' N zr< f-^Q Λν> (1R,3R)-1-(2,6-di-fluor4-(2-(3-(fluormetil)azetid¡n-1-l)etoxi)fenil)-3-met¡l-2(oxetan-3-ilmetil)- 2,3,4,9-tetrahydro-1 Hpirido[3,4-b]¡ndol 0,0231 -95,5<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">η° Structure number ER-alfa MCF7 HCS EC50(mM) ER-alfa MCF7 HCS Sinf (%) 116 —\ / ^° C TV< / V 'N iX fO (1R,3R)-1-(2,6-difluor-4-(2-(3-(fluormetil)azetidin-1-il)etoxi)fenil)-3-metil-2-(oxetan-3-il)-2,3,4,9tetrah id ro-1 H-pyridinol[3,4-b]indol 0,0414 -85 117 / \ F ^Qi. X3 o-7 (1R,3R)-1-(2,6-difluor-4-(2-(piperidin-1-l)etoxi)fenil)-2-(2-fluor2-metilpropyl)-3-metil-2,3,4,9-tetrahydro-1 Hpirido[3,4-b]ndol 0.000171 -71.7 118 rvÚ7 N / =\ FV_( ^Γθ o—' (1R,3R)-1-(2,6-difluor4-(2-(piperidin-1-l)etoxi)fenil)-2-(2-fluor2-metilpropyl)-3-metil-2,3,4,9-tetrahydro-1 Hpirido[3,4-b]ndol 0.000488 -72.2 119 * \ FN—' Γ iTV7- 7 F_jÁ J (1-(2-(3,5-difluor-4((1R,3R)-2-(2-fluor-2metilpropyl)-3-met¡l2,3,4,9-tetrahydro-1 Hpirido[3,4-b]ndol-1il)phenoxy)et¡l)azetidin-3-il)metanol 0.00198 -71.3<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> LM / a / ZUZZ / UU fíífo<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">η° estructura number ER-alfa MCF7 HCS EC5o(mM) ER-alfa MCF7 HCS Sinf (%) 120 / \ FC XV. / O \= / / 7 F (1R,3R)-2-(2-fluor-2metilpropyl)-1-(2-fluor-4(2-(3-(fluormetil)azetidn-1-l)etoxi)fenil)-3-metal-2,3,4,9-tetrahydro-1 Hpirido[3,4-b]ndol 0,0000562 -96,3 121 __7 o 'N-^\ í F %___ / H / =^ O—7 F 1-((1R,3R)-1-(2,6-difluor-4-(2-(3-(fluormetil)azetidn-1-l)etoxi)fenil)-3-metal-3,4-dihydro-1 H-pirido[3,4b]indol-2(9H)-il)etanone 0.008 -91 122 / ° ίί^νΧ2νΝ^^°Η H / =\ F —< λ '—( aN^V—Λ oy Χ / --Ά 1-((1R,3R)-1-(2,6difluor-4-(2-(3-(fluormetil)azetid¡n-1-¡l)etoxi)fenil)-3-met¡l-3,4dihydro-1 H-pirido[3,4b]indol-2(9H)-il)-2hydroxy-2-metilpropan1-ona 0.0014 -97.8 123 . * oh N-—7 Í 1H / F 'z>=< HF·^# / \ O-7 F (R)-3-((1R,3R)-1-(2,6-difluor-4-(2-(3(fluormetil)azetidin-lil)etoxi)fenil)-3-metil-3,4-dihydro-1H-pyridinol-2(9H)-il)-2metilpropan-1-ol 0.00104 -96.1<h2 style=";text-align:left;direction:ltr"> η° structure number ER-alpha MCF7 HCS EC50(mM) ER-alpha MCF7 HCS Sinf (%) 124 OH ΓΥΜ ° η 7=( F ν) ΖΧ \ λ-Ν \_, 0- / ν'λ F ((1R,3R)-1-(2,6-di-fluor4-(2-(3-(fluormethyl)azetid¡n-1yl)ethoxi)phenyl)-3-met¡l- 3,4-dihydro-1 H-pyrido[3,4-b]indol-2(9H)11)((1 s,3S)-3-hidrox¡cyclobutyl)methanone 0,135 -75 125 Ν-Ζ ίΧ>Λ \ / Η / \ FAJ rN% o—' F 1 -(1-(2,6-difluor-4-(2-(3(fluormethyl)-azetidin-1¡l)ethoxi)-phenyl)-3,3dimethyl-3,4-d¡hydro-1 Hpyrido[3,4-b]¡ndol-2(9H)yl)-2-methylpropan-1-ona 0,0744 -90 126 / 0 0 / \ ^'s— Γ^ΓΛ-( FH / ^\ F Μ / -N^ o-^ F (1R,3R)-1-(2,6-di-fluor4-(2-(3-(fluormethyl)azetid¡n-1-¡l)ethoxi)phenyl)-3-methyl-2(methylsulfonyl)-2,3,4,9tetrah id ro-1 Hpyrido[3,4-b]¡ndol 0.000469 -94.4 Table 2 n° structure name ER-alpha MCF7 HCS EC50 (µΜ) CL-EM [M+H]+ 127 N i F h 7-- / 0 F 1-[(1R,3R)-1-[2,6-difluoro-4[2-[3-(fluoromethyl)-azetidin-1yl]phenyl-xi-methyl-3]] 1,3,4,9-tetrahydropyrid[3,4-b]¡ndol-2-¡l]-2methyl-propan-2-ol 0.000641 502.6 128 0 F (1R,3R)-1-[4-[2-[3- (difluoromethyl)azetidin-l yl]ethoxy]-2,6-d¡fluoro-phen¡l]-2(2-fluoro-2-methyl-propyl)-3- methyl-1,3,4,9-tetrahydropyr¡do[3,4-b]indole 0.000064 522.3 129 o TZxxA\ τι (1R,3R)-1-[4-[1-(3- chloropropyl)azetid¡n-3-yl]oxy- 2,6-difluoro-phenyl]-2-(2-fluoro2-methyl-propyl)-3-methyl- 1,3,4,9-tetra- hydropyrido[3,4-b]indole 2,70,202 <h2 style=";text-align:left;direction:ltr">n° estructura number ER-alfa MCF7 HCS EC50 (μΜ) CL-EM [M+H]+ 130 IZ ΤΊ (1R,3R)-1-[2,6-difluor-4-(1propilazet¡d¡n-3-il)ox¡-fen¡l]2-(2-fluor-2-metil-prop¡l)-3metil-1,3,4,9- tetrahidropyr¡do[3,4-b]-¡ndol 0.0000504 486.3 131 HO\FHF\-7 7\F 0—7 v ((1S,3R)-1-(2,6-difluor-4-(2(3-(fluormetil)azetidin-1¡l)etoxi)fenil)-2-(2-fluor-2metilpropil)-2,3,4,9-tetrahydro-1 H-pyrido[3,4b]indol-3-il)metanol 0.000146 520.3 132 _Λ \-FN—' ÍTV^ / Hfa=J Vnh (1R,3R)-1-[4-(azetidin-3iloxi)-2,6-d¡fluor-fenil]-2-(2fluor-2-metil-propyl)-3-metil1,3,4,9-tetrahydropir¡do[3,4-b]indol 0.00031 444.2 133 ” 0 0 <N F—7 (1R,3R)-2-(2-fluor-2- metilpropil)-1-(2-fluor-4-(2(3-(fluormetil)azetidin-1¡l)etoxi)fenil)-3-met¡l- 2,3,4,9-tetrahidro-1 Hpirido[3,4-b]¡ndol 0,0000562 486,3 <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">n° estructura number ER-alfa MCF7 HCS EC50 (μΜ) CL-EM [M+H]+ 134 h K / F u) 0^ '—NV^ F (1R,3R)-2-ciclobutil-1-[2,6dífluor-4-[2-[3(fluormetil)azetidin-l¡l]etoxi]fen¡l]-3-met¡l1,3,4,9-tetrahidropirido[3,4-b]indol 0,000542 484,3 135 FHF \ / / \ F / — / O—' (1R,3S)-1-[2,6-difluor-4-[2- [3-(fluormetil)azetidin-1- ¡l]etoxi]fenil]-3-(fluormet¡l)- 2-(2-fluor-2-metil-propyl)-1,3,4,9-tetrahidropirido[3,4-b]-indol 0.0000973 522,3 136 > |—0 / ^\ / ~\ F-J__I N ' FH — / FF (1R,3R)-1-[2,6-difluor-4-[2[3-(fluormetil)azetidin-1¡l]etoxi]fenil]-2-[(3fluorxetan-3-il)metil]-3metil-1,3,4,9-tetrahidropirido[3,4-b]indol 0.000114 518,3 137 Q XVo L zx O cyclohexil((1R,3R)-1-(2,6- difluor-4-(2-(3-(fluormetil)azetidn-1-(l)etox)-fen-3-metil-3,4-dihydro1H-pyridinol-2(9H)IJmetanoic acid 0.028 540.4<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">Structure number ER-alfa MCF7 HCS EC50 (μΜ) CL-EM [M+H]+ 138 qcQ N í OHK / F \ ^nA f 0—' 1-[(1R,3R)-1-[2,6-difluor-4[2-[3-(fluormetil)-azet¡d¡n-1¡l]etoxi]fen¡l]-3-metil1,3,4,9-tetrahydropir¡do[3,4-b]indol-2-il]-2,2dimetil-propan-1-ona 0,000491 514,3 139 o IZ | οΆ. J s -A cyclopropyl((1R,3R)-1-(2,6difluor-4-(2-(3-(fluormetil)azetidn-1-l)etoxi)fenil)-3-metil-3,4dihydro-1H-pyridinol[3,4-b]indol-2(9H)-il)metanoic acid 0.00248 498.2 140 __. \ FN i FH j^Z f^Q o-~y~N(^·— (1R,3R)-1-[2,6-difluor-4-[2(3-metilazetdn-1-l)etoxi]fenil]-2-(2-fluor-2metil-propyl)-3-metil1,3,4,9-tetrahydropirido[3,4-b]ndol 0,00013 486,4 141 v- Γτ° ys^X ll zi O (1R,3R)-1-(2,6-difluor-4-(2((R)-3-metilpyrroldn-1-l)etoxi)fenil)-2-(2-fluor-2metilpropyl)-3-metil-2,3,4,9tetrahydropirido-1 H-pirido[3,4b]indol 0.000151 500.2<h2 style=";text-align:left;direction:ltr"> η° structure name ER-alpha MCF7 HCS EC50 (μΜ) CL-EM [M+H]+ 142 --X \ FV Ν i F Η ζ^Ζ ΡΌ ? ο^Ο (1R,3R)-1-[2,6-difluoro-4- [(2S)-2-pyrrolid¡n-1-¡l- propoxy]phenyl]-2-(2-fluoro-2- methyl-prop¡l)-3-methyl- 1,3,4,9-tetrahydro- pyrido[3,4,000-090] 500.3 143 --Ζ \ F \-^ Ν-Ζ^~ Ν ί F '-Η Ζ Ν—. ο-^ / (1R,3R)-1-[2,6-difluoro-4-[3- [3-(fluoromethyl)azetid¡n-1- ¡l]propoxy]phenyl]-2-(2-fluoro-2methyl-prop¡l)-3-methyl- 1,3,4,9-pyr-tetrahydro-4-indole, 4-b 0.000078 518.4 144 Ν i ρ η Νζ^-^ F (1R,3R)-1-[2,6-difluoro-4- [(E)-3-[3-(fluoromethyl)- azetidine-1 -yl]prop-1- enyl]phenyl]-2-(2-fluoro-2-methylpropyl)-3-methyl-1,3,4,9tetrahydro-pyr¡do[3,4-b]¡ndole 0.000144 500.1 145 CZCZ4 N i FH z^ / fO F ΗΝ^ / \ / Λ— / / N— N-(3,5-difluoro-4-((1R,3R)-2(2-fluoro-2-methylpropyl)-3methyl-2,3,4,9-tetrahyde rho-1H- p¡rido[3,4-b]¡ndol-1-¡l)phen¡l)- 1 -(3-f I uor propyl)-aminated ina 90,000. 503.3 η° structure name ER-alpha MCF7 HCS EC5o (μΜ) CL-EM [M+H]+ 146 FNFF (1R,3R)-2-[(3,3-difluor- cyclobutyl)meth¡l]-1-[2,6difluoro-4-[2-[3-(fluoromethyl)azetid¡n-1-¡l]ethoxy¡]phenyl]-3-methyl-1,3,4,9tetrahydropyr¡do[3,4-b]-¡ndol 0.01 53 1 4 1 4 4 h —H u) 0-^ F (1R,3R)-1-[2,6-difluoro-4-[2[3-(fluoromethyl)azetid¡n-1yl]ethoxy]phenyl]-2-(2,2dimethylpropyl)-3-meth¡l1,3,4,9-tetrahydropindo[3,4-b]indole 1,3,4,9-tetrahydropindo[3,4-b]50,808,806. CKÍv0 N i 0 H 5. F fO \ z-nA ,f Oγ,Λ— / cyclobutyl-[(1R,3R)-1-[2,6difluoro-4-[2-[3-(fluoromethyl)azetidine-1-¡l]ethoxy¡]phenyl]-3-methyl-1,3,4,9tetrahydropyrido[3,4-b]indol-2-yl]methanone 0.001 7217 ΜΛ / a / ZUZZ / UU fUfO η° structure name ER-alpha MCF7 HCS EC50 (μΜ) CL-EM [M+H]+ 149 N and 0 hf^f cyclopentyl-[(1R,3R)-1-[2,6difluoro-4-[2-[3(fluoromethyl)azetidine-l¡l]ethoxy]phen¡l]-3-methyl1,3,4,9-tetrahydropyrido[3,4-b]¡ndol-2-¡l]methanol 0,502,502,666 Q^- H / ^ZF~O (1R,3R)-1-[2,6-difluoro-4-[2[(3S)-3-methylpyrrolidine-1¡l]ethoxy]phenyl]-2-(2-fluoro-2methyl-prop¡l)-3-methyl1,3,4,9-tetrahydropindo[3,40,000-408] 500.2 151 r^\ \ F \-=ZC n-^z^ N i FHZ=-ZF^Q i o_anQ (1R,3R)-1-[2,6-difluoro-4[(2R)-2-pyrrolide¡n-1-¡l- propoxy]phenyl]-2-(2-fluoro-methyl-methyl-2p-¡p-3) 1,3,4,9-tetrahydropyride[3,4-b]¡ndole 0.000156 500.1 152 / S \ F \ ? VN and FH z=y / Ej O-^Z (1R,3R)-1-[2,6-difluoro-4-[(1propylazetidin-3-yl)methoxy]phenyl]-2-(2-fluoro-2methyl-prop¡l)-3-methyl- 1,3,4,9-tetrahydropyrido[3,4,b-endo[3,4] 0.000362 500.3 ΐνίΆ / Β / ^υ^ / υυ / Ufo η° structure name ER-alpha MCF7 HCS EC50 (μΜ) CL-EM [M+H]+ 153 NFHFF (1R,3R)-1-[2,6-difluoro-4-[2[3-(fluoromethyl)azetid¡n-1¡l]ethoxy]phenyl]-2-[(1fluorocyclobutyl)methyl]-3-meth¡l1,3,4,9-tetrahydropindo[3,4-b]indole 1,004,501 O -ΠIZ I íV zX (? γιι~π (S)-3-((1R,3R)-1-(2,6- difluoro-4-(2-(3-(fluoro- methyl)azetid¡n-1-¡l)ethoxy¡)- phenyl)-3-methyl-3,4-dihydro- 1H-pyrido[3,4-b]¡ndol-2(9H)- yl)-2-fluoro-2-methylpropane-1- ol 0.0000333 520.3 155 F OH Λ Ih*__ / Ν — ÍTVí / η^ο 0 Ν X (2R-R-2(1)-[1-3-R-1) difluoro-4-[2-[3-(fluoro- methyl)azetid¡n-1-¡l]ethoxy¡]- phenyl]-3-methyl-1,3,4,9- tetrahydropyrido[3,4-b]- indol-2-yl]-2-fluoro-2-met¡l- propane-1 -ol 0020.993 n° structure name ER-alpha MCF7 HCS EC5o (μΜ) CL-EM [M+H]+ 156 _Λ Vf N / H \ / 0 NF—7 (1R,3R)-1-[4-[2-[3-(fluoromethyl)azet¡d¡n-1-¡l]ethoxy¡]phenyl]-2-(2-fluoro-2-methylpropyl)-3-methyl-1,3,4,9tetrahydropyr¡do[3,4-b]-¡ndol 0083,563. LL YA Μ XV I'zx o 2-cyclopropyl-1-[(1R,3R)-1[2,6-difluoro-4-[2-[3(fluoromethyl)azetidine-lyl]ethoxy]phen¡l]-3-methyl- 1,3,4,9-tetrahropyrido[3,4-tandole] 0.005 512.4 158 c^VH 3 F FV o^ / — / 2-cyclobutyl-1-[(1R,3R)-1[2,6-difluoro-4-[2-[3(fluoromethyl)azetidin-l]ethoxy]phen¡l]-3-meth¡l1,3,4,9-tetrahydropyrido[3,4-b]indol-2-ethanone 20,15,156] QUU' N i 0 H 3 FV 1-[(1R,3R)-1-[2,6-difluoro-4[2-[3-(fluoromethyl)-azetid¡n-1¡l]ethoxy]phen¡l]-3-met¡l1,3,4,9-tetrahydropyrido[3,4-b]indol-2-diyl]-2,4-fluoro-propanone-10,000 522.3 η° structure name ER-alpha MCF7 HCS EC50 (μΜ) CL-EM [M+H]+ 160 __ __Λ \ F Ν i F Η F~Q (1R,3R)-1-[2,6-difluoro-4-[2- [3-(fluoromethyl)-3-aphenethyl-1-xie] ¡l]-2(2-fluoro-2-methyl-propyl)-3methyl-1,3,4,9-tetrahydropindo[3,4-b]indole 0.000285 518.4 161 Ζ^ ο (1R,3R)-1-[2,6-difluoro-4-(1methylazetide¡n-3-¡l)ox¡-phen¡l]2-(2-fluoro-2-methyl-propyl)-3methyl-1,3,4,9- tetrahydropyr¡do[3,4-b]-¡ndol 0.0004043624 Η %= / F^ / \ V? 0~<)ν (1R,3R)-1-[4-(1-ethylazetidine-3-yl)oxy-2,6-difluorophenyl]-2-(2-fluoro-2-methylpropyl)-3-methyl-1,3,4,9tetrahydro-pyr¡do[3,4-b]¡dol 0.000 5.8272 ΟίΑ-Ι Ν i F Η Ζ- / F—- / 'χ νζ ο~^Α .—Υ (1R,3R)-1-[2,6-difluoro-4-(1pentylazetid¡n-3-yl)oxy-phenyl]2-(2-fluoro-2-Ι-methyl-propyl-3,3,4-9,9 tetrahydropyr¡do[3,4-b]-¡ndol 0.000457 513.9 η° structure name ER-alpha MCF7 HCS EC5o (μΜ) CL-EM [M+H]+ 164 __Λ \ F y ¿ ν-~ζ Η / = / F^Z \ (1R,3R)-1-[4-[1-(cyclo- prop¡lmethyl)azet¡din-3-¡l]ox¡2,6-difluoro-phenyl]-2-(2-fluoro2-methyl-propyl)-3-meth¡l1,3,4,9-tetrahydropyr¡do[3,4-b]indole 0.000216 498.4 165 ζ ζ (1R,3R)-1-[4-[1-(cyclo- pentylmethyl)azet¡d¡n-3-¡l]ox¡2,6-difluoro-phenyl]-2-(2-fluoro2-methyl-propyl)-3-methyl1,3,4,9-tetrahydropyrido[3,4-b]l 50,605. 166 QCrZ Η Ζ== / F^Z \ V / (1R,3R)-1-[2,6-difluoro-4-[1(2-fluoroethyl)azet¡din-3-¡l]ox¡phenyl]-2-(2-fluoro-2-methylpropyl)-3-methyl-1,3,4,9-9 tetrahydro-pyr¡do[3,4-b]¡ndole 0.000175 490.4 167 hf^H (1R,3R)-1-[2,6-difluoro-4-(1prop-2-in¡lazet¡din-3-¡l)ox¡phenyl]-2-(2-fluoro-2-methylpropyl)-3-methyl-1,3,4,9tetrahydro-pindo[3,4-b]¡ndol 0.8080.33 ΜΛ / a / zuzz / uu iy ιo 6 η° structure name ER-alpha MCF7 HCS EC50 (μΜ) CL-EM [M+H]+ 168 __Λ \ F Η / WF^ / \ νγ °ΧνΥ (1R,3R)-1-[2,6-difluoro-4-(1¡sopropylazetid¡n-3-yl)ox¡phenyl]-2-(2-fluoro-2-methylpropyl)-3-methyl-1,3,4,9tetrahydro-p¡r¡do[3,4-b]indole 2,0,0,0,201,486 __Λ \ F / Γ / V > / Η Ζ== / FV \ V> °χΝ^ (1R,3R)-1-[2,6-difluoro-4-(1isobut¡lazet¡din-3-¡l)ox¡phenyl]-2-(2-fluoro-2-methylpropyl)-3-methyl-1,3,4,9tetrahydropyr¡do[3,4-b]-¡ndol 0.0004.970 QC^< Ν i F Η — / F ν) Ο^ / Λ η 3-[3,5-difluoro-4-[(1R,3R)-2(2-fluoro-2-methyl-propyl)-3methyl-1,3,4,9-tetrahydropyrido[3,4-b]¡ndole-1¡lphenylatoxico-1] of tert-butyl 0.001 544.3 171 Η Μ F~ / ) (1R,3R)-1-(2,6-difluoro-4-(2(3-(fluoromethyl)azetidine-1yl)ethoxy)phenyl)-3-ethyl-2-(2fluoro-2-methylpropyl-2-(2fluoro-2-methylpropyl)-2,3,4,19 H-pyrido[3,4b]indole 0.000471 518.3 ΜΛ / a / ZUZZ / UU fUfO n° structure name ER-alpha MCF7 HCS EC5o (μΜ) CL-EM [M+H]+ 172 HA -N'V 0— / ν'— (1R,3S)-1-(2,6-difluoro-4-(2(3-(fluoromethyl)azetid¡n-1¡l)ethoxy)phenyl)-3-ethyl-2-(2fluoro-2-methylpropyl)-2,3,4,9tetrahydro-1 H-pyrido[3,4b]indole 518, 173. FHF v) F (1R,3R)-1-[2,6-difluoro-4-[2[3-(fluoromethyl)azetidine-1¡l]ethoxy]phen¡l]-3-methyl-2-[(1methylcyclobut¡l)methyl]1,3,4,9-tetrahydropyrido[3,4,3,5,010b]indole 174 V vrX / --' FN i FHZ~~— / FV / F (1R,3R)-1-[2,6-difluoro-4-[2- [3-(fluoromethyl)azetidin-1- ¡l]ethoxy]phen¡l]-3-meth¡l-2- (2,2,2-trifluorethyl, 1,3,4) tetrahydropyr¡do[3,4-b]-¡ndol 0.000285 512.2 ινΐΛ / a / zuzz / uu furo η° structure name ER-alpha MCF7 HCS EC5o (μΜ) CL-EM [M+H]+ 175 FF Ν \ FFV? F (1S,3R)-1-[2,6-difluoro-4-[2[3-(fluoromethyl)azet¡din-1¡l]ethoxy]phen¡l]-3-methyl-2(2,2,2-trifluorote¡l)-1,3,4,9tetrahydropyr¡do[3,4-b]-1,2014-l 176 _Λ \-f ΟΛλ / HfO 0—<0Ν-^ ο— 0— (1R,3R)-1-[4-[1-(3,3dimethoxyprop¡l)azetidine-3¡l]oxy-2,6-difluoro-phen¡l]-2-(2fluoro-2-methyl-propyl)-3-methyl1,3,4,9-tetrahydropyrid[3,4-b-endol 3,040,300.30] 177 __Λ \-F 8 0— F (1R,3R)-1-[2-fluoro-4-[1-(3fluoropropyl)azetidin-3-yl]-oxyphenyl]-2-(2-fluoro-2-methylpropyl)-3-methyl-1,3,4,9tetrahydro-pyrdo[3,4,b 0.000164 486.3 178 VF __ / Ν·—' Q> < / f Ηρ-Ο °-X-O-xF 1-[2,6-difluor-4-[2-[3- (fluormetil)azetid¡n-1-il]etoxi]fenil]-2-(2-fluor-2metil-propil)-1,3,4,9tetrahidropir¡do[3,4-b]-¡ndol 0,0005 490,2 <h2 style=";text-align:left;direction:ltr">n° estructura number ER-alfa MCF7 HCS EC5o (μΜ) CL-EM [M+H]+ 179 Λ o / —\ / N-Sx\ frVC0 ζΛ 0 N (1S,3R)-1-[4-[2-[3- (fluormetil)azetid¡n-1il]etoxi]fen¡l]-3-metil-2- metilsulfonil-1,3,4,9tetrahydropyr¡do[3,4-b]-¡ndol 0.013 472.2 180 / —z / -- f 5 ~Z~m (1R,3R)-1-(4-(2-(3-(fluormetil)azetidn-1-l)etoxi)fenil)-3-metil-2(metilsulfonil)-2,3,4,9tetrahydro-1H-pyridinol[3,4b]indol 0.000222 472.2 181 / ~~\ V z0H \ Λ VN~w ZN ; 0 H i F VZ 1-((1 R,3 R)-1-(2,6-difluor-4(2-(3-(f I uormeti l)-azetid¡ n-1 - il)etoxi)fenil)-3-metil-3,4-dihydro-1 H-pyridinol-2(9H)-il)-3-hydroxy¡2-metil-propan-1-ona 0,004 516,2<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> iviA / a / ¿u¿¿ / uu iy ιo<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">n° estructura number ER-alfa MCF7 HCS EC5o (μΜ) CL-EM [M+H]+ 182 QÍÍZ N - 0 Η 1 F F-~ / \ V / \ Ζ-νΛ / o— / — / azetidin-3-¡l-[(1R,3R)-1[2,6-difluor-4-[2-[3(fluormetil)azetidin-l¡l]etoxi]fen¡l]-3-metil1,3,4,9-tetrahidropirido[3,4-b]indol-2-il]metanona >0,1 513,3 183 u- / v χγ° Τ'z:c O((1R,3R)-1-(2,6-difluor-4- (2-(3-(fluormetil)azetidin-1- ¡l)etoxi)fenil)-3-met¡l-3,4- dihidro-1 H-pirido[3,4- b]indol-2(9H)-il)(2-fluor- cyclopropil)metanona 0,004 516,3 184 __χ \ F \ ? VN ' FH 7^ / V < (1R,3R)-1-[2,6-difluor-4[(2S)-2-[(3R)-3-metilpirrolidin-1-yl]propoxy]-fenil]2-(2-fluor-2-metil-propyl)-3metil-1,3,4,9tetrahydropir¡do[3,4-b]-¡ndol 0,000494 514,4 185 N 3 OH £ FF^0 [(1R,3R)-1-[2,6-difluor-4-[2[3-(fluormetil)azet¡din-1-¡l]etoxi]fen¡l]-3-met¡l- 1,3,4,9-tetrahydro- pirido[3,4-b]ndol-2-l]-fenilmetanoate 0.014 534.2<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> MA / a / zuzz / uu iy ιo<h2 style=";text-align:left;direction:ltr"> η° structure name ER-alpha MCF7 HCS EC5o (µΜ) CL-EM [M+H]+ 186 \ on V. N % H ú F vn^f (1R,3R)-2-(cyclopropylmethyl)-1-[2,6-difluoro-4-[2-[3-(fluoromethyl-1) ¡l]ethoxy]phen¡l]-3-methyl- 1,3,4,9-tetrahydro- pyrido[3,4-b]indole 0.002 484.4 187 O IZ I ti (1R,3R)-1-[4-[1-(2-cyclopropylet¡l)azet¡din-3-¡l]ox¡2,6-difluoro-phenyl]-2-(2-fluoro- 2-methyl-propyl)-3-met¡l- 1,3,4,9-tetrahydropyrido[3,01,01b] 512.4 188 x. using (1R,3R)-1-[4-(1-allyl- azetidine-3-¡l)ox¡-2,6-d¡fluoro- phenyl]-2-(2-fluoro-2-methylpropyl)-3-methyl-1,3,4,9tetrahydro-p¡r¡do[3,4-b indole 0,80,804,804] 189 0717 H 7= / FV \ V> (1R,3R)-1-[4-[1-(cyclo- butylmethyl)azet¡din-3-yl]ox¡- 2,6-difluoro-phenyl]-2-(2-fluoro2-methyl-propyl)-3-met¡l- 1,3,4,9-tetrahydropyride[3,4-b]¡ndol 0.001 512.3 <h2 style=";text-align:left;direction:ltr">n° estructura number ER-alfa MCF7 HCS EC5o (μΜ) CL-EM [M+H]+ 190 O zz I ó 'κ z (1R,3R)-1-[2,6-difluor-4-(1¡sopentilazetid¡n-3-¡l)oxifenil]-2-(2-fluor-2-metil- propil)-3-metil-1,3,4,9tetrahidro-p¡ndo[3,4-b]indol 0,002 514,3 191 Z \ FN á FH / == / FV \ Vv (1R,3R)-1-(2,6-difluor-4- ((1 -(2-metil butil)azetid) in-3¡l)oxi)fenil)-2-(2-fluor-2metilpropyl)-3-metil-2,3,4,9tetrahydro-1 H-pirido[3,4-b]indol 0.000267 514,3 192 O IZ 1 (1R,3R)-1-(2,6-difluor-4((1 -(penta n-2-¡l)azetidi n-3¡l)oxi)fenil)-2-(2-fluor-2metilpropyl)-3-metil-2,3,4,9tetrahydro-1 H-pirido[3,4b]indol 0.001 514,3 193 __Z \ F / VN \ TH / ==¿ F-^ / / (1R,3R)-1-[4-(1-cyclo- butilazetidin-3-il)oxi-2,6- difluor-fenil]-2-(2-fluor-2metil-prop¡l)-3-metil- 1,3,4,9-tetrahidro- pírido[3,4-b]¡ndol 0,000484 498,3<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> iviA / a / ¿u¿¿ / uu iy ιo<h2 style=";text-align:left;direction:ltr"> η° structure name ER-alpha MCF7 HCS EC5o (μΜ) CL-EM [M+H]+ 194 O iz 1 Á'Á <X 'Y: Z^ (1R,3R)-1-[2,6-difluor-4-[1(oxetan-3-il)azetid¡n-3¡l]oxi-fenil]-2-(2-fluor-2metil-propil)-3-met¡l1,3,4,9-tetrahidro- pir¡do[3,4-b]indol 0,000077 500,2 195 > \ F ΓΤΜj K Ηχχ7 (1R,3R)-1-[4-(1-cyclo- propylazetid¡n-3-yl)oxi-2,6difluoro-phenyl]-2-(2-fluoro-2methyl-prop¡l)-3-methyl- 1,3,4,9-trahydro[¡¡¡¡¡¡¡-b 0.000165 484.3 196 O TZ I z^ (1R,3R)-1-[2,6-difluoro-4-[1(3-fluoropropyl)azetidine-3¡l]sulfanyl-phenyl]-2-(2-fluoro-2methyl-prop¡l)-3-methyl1,3,4,9-tetrahydropindo[3,4-b]indole 0.0207777. N and FH F-0 ον' / χ F (1R,3R)-1-[2,6-difluoro-4-[2[3-(fluoromethyl)azetidin-1yl]ethoxy]phen¡l]-2-¡sobut¡l-3methyl-1,3,4,9-tetrahydro¡r¡r¡r¡4,001-indole 486.2 <h2 style=";text-align:left;direction:ltr">n° estructura number ER-alfa MCF7 HCS EC50 (μΜ) CL-EM [M+H]+ 198 O “ s Yyp'0 í o (1R,3R)-1-(2,6-difluor-4-(2(3-(fluormetil)azetidin-1¡l)etoxi)fenil)-3-nnet¡l-2-((R)2-fenilpropil)-2,3,4,9- tetrahidro-1 H-pirido[3,4b]indol 0.002 548.1 199 050^0 N 3 FH / ¾^ F (1R,3R)-1-(2,6-difluor-4-(2(3-(fluormetil)azetidin-1¡l)etoxi)fenil)-3-metal-2-((S)2-fenilpropil)-2,3,4,9tetrahydro-1H-pyridox[3,4b]indol 0.00232 548.3 200 CL N ' F (1R,3R)-1-[2,6-difluor-4-(1propilazetidn-3-il)oxi-fenil]2-sobutil-3-metil-1,3,4,9tetrahydro-pindo[3,4-b]indol 0.000408 468.3 201 QCU N - H 5-^, o 0 N—l F— / (1R,3R)-2-(2-fluor-2-metilpropyl)-1-[4-[1-(3fluorpropyl)azetidin-3¡l]oxifen¡l]-3-metil-1,3,4,9tetrahydropir¡do[3,4-b]-ndol 0.000315<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> iviA / a / ¿u¿¿ / uu iy ιo<h2 style=";text-align:left;direction:ltr"> n° structure name ER-alpha MCF7 HCS EC5o (μΜ) CL-EM [M+H]+ 202 ,___( 0 o ÍX>Aj \an AA hf^j 0.. VN^^ F (1R,3R)-1-[2,6-difluoro-4-[1(3-fluoropropyl)azetid¡n-3¡l]oxy-phenyl]-3-meth¡l-2methylsulfonyl-1,3,4,9tetrahydropyr¡do[3,4-b]-¡ndol 0.00001 508 F-HNA 0— / \^>-- / [1-[2,6-difluoro-4-[2-[3(fluoromethyl)azetid¡n-1¡l]ethoxy]phen¡l]-3-meth¡l- 1,3,4,9-tetrahydropyrido[3,4-b]indol-2-¡l]-3-fluoromethl(40,000) 530.4 204 ___ __Λ \ FVNA^~ N i FH fO ? methyl-1,3,4,9- tetrahydropyr¡do[3,4-b]¡ndole 0.000371 536.4 205 __ __Λ \ FN i F Η λ=- / F^Q (1R,3R)-1-[2,6-difluoro-4-[2[3-fluoro-methyl-1) -yl]ethoxy]phenyl]-2(2-fluoro-2-methyl-propyl)-3methyl-1,3,4,9-tetrahydropyrido[3,4-b]¡ndol 0.000375 522.1 η° structure name ER-alpha MCF7 HCS EC50 (μΜ) CL-EM [M+H]+ 206 Ν Ί1 \ / Λ >— / Ο Ν ; Η F 4-[(1R,3R)-1-[2,6-difluoro-4[2-[3-(fluoromethyl)-azetid¡n-1¡l]ethoxy]phen¡l]-3-meth¡l- 1,3,4,9-tetrahydropyrido[3,4-b]indol-2oxo-butyl-0,031]] 511.3 207 Oíb3 Ν ; Η FX VN^F (1 R,3R)-2-(cyclohexyl-meth¡l)1-[2,6-difluoro-4-[2-[3- (fluoromethyl)azetid¡n-1yl]ethoxy]phen¡l]-3-methyl1,3,4,9-tetrahydropyrido[3,4,13-b] 526.4 208 __ / \ F / ί Ν-- / ^ hfvK (1R,3R)-1-[2,6-difluoro-4-[1[2-(oxetane-3-yl)ethyl]-azet¡d¡n3-¡l]oxy-phenyl]-2-(2-fluoro-2-methyl-promethyl-3¡¡) 1,3,4,9-tetrahydropyrido[3,4-b]¡ndole 0.000066 528.3 209 Ο ^ΙΖ J. rS O-^nkJ / / ▼ b (1R,3R)-1-[4-[1-(cyclo- hexylmeth)-1-[4-[1-(cyclo- hexylmeth)-l)¡¡n-il¡¡-l 2,6-difluoro-phenyl]-2-(2-fluoro2-methyl-propyl)-3-met¡l- 1,3,4,9-tetrahydropyrido[3,4-b]¡ndol 0.008 540.3 η° structure name ER-alpha MCF7 HCS EC5o (μΜ) CL-EM [M+H]+ 210 F / N— / UHj1 0 <N F— (1R,3R)-1-[2-cloro-4-[2-[3(fluormetil)azetid¡n-1¡l]etoxi]fenil]-2-(2-fluor-2metil-prop¡l)-3-metil1,3,4,9-tetrahidropírido[3,4-b]¡ndol 0,0001 503,2 211 F f N—' oAú / ci zH. F (1R,3R)-1-[2-cloro-4-[1-(3fluorpropil)azetidin-3-il]oxifenil]-2-(2-fluor-2-metilpropil)-3-metil-1,3,4,9tetrahidro-p¡ndo[3,4-b]indol 0,0002 503,2 212 a. OH \ 7 C n—' 0 H h F F^0 1-((1 R,3R)-1-(2,6-difluor-4(2-(3-(f I uormeti l)-azetid¡ n-1 ¡l)etoxi)fenil)-3-metil-3,4dihidro-1 H-pirido[3,4- b]indol-2(9H)-il)-3- hidroxibutan-1-ona 0,001 538,2 213 O o \ J S A; [(1R,3R)-1-[2,6-difluor-4-[2[3-(fluormetil)azetidin-1¡l]etoxi]fen¡l]-3-metil- 1,3,4,9-tetrahidropirido[3,4-b]indol-2-il](oxetan-3-il)metanona 0,004 514,2 <h2 style=";text-align:left;direction:ltr">n° estructura number ER-alfa MCF7 HCS EC50 (μΜ) CL-EM [M+H]+ 214 > i—S \ A d N ; OHF\znA F oA ^>—~y [(1R,3R)-1-[2,6-difluor-4-[2[3-(fluormetil)azetidin-1¡l]etoxi]fen¡l]-3-metil1,3,4,9-tetrahidropirido[3,4-b]indol-2-il](tietan-3-il)metanona 0,004 530,2 215 < ' xv° YZ\,A\J z:co (R)-1-((1R,3R)-1-(2,6difluor-4-(2-(3-(fluormetil)azetidn-1l)etoxi)fenil)-3-metal1,3,4,9-tetrahydro-2Hpirido[3,4-b]indol-2-yl)-3fluor-2-metilpropan-1-ona 0,000335 518,3 216 qíA N í. H i F FV\ V / °A (1 R,3R)-2-(cyclopentilmetil)-1-[2,6-difluor-4-[2-[3-(fluormetil)azetidin-1-l]etoxi]fenil]-3-metil-1,3,4,9-tetrahydro-pyrido[3,4-b]ndol 0.001 512.4 217 QíA N i F o~_^A )— / (1 R,3R)-1-[4-[1-[(4,4-difluorciclohexil)metil]azetidin-3-il]oxi-2,6-dfluor-fenil]2-(2-fluor-2-metil-propyl)-3metil-1,3,4,9- tetrah¡dropirido[3,4-b]-¡ndol 0,002 576,3<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">η° Structure number ER-alfa MCF7 HCS EC50 (μΜ) CL-EM [M+H]+ 218 Ν -- 0 HF \ / -nA / O-- / N\zZ-- / (S)-1-((1R,3R)-1-(2,6difluor-4-(2-(3-(fluormetil)azetid¡n-1-¡l)etoxi)fenil)-3-metil-1,3,4,9-tetrahydro-2H-pyridox[3,4b]indol-2-il)-3-fluor-2metilpropan-1-ona 0,000402 518,3 219 o IZ ] s A z TI ((1R,3R)-1-(2,6-difluor-4- (2-(3-(fluormetil)azetidin-1¡l)etoxi)fenil)-3-metil-1,3,4,9-tetrahydro-2Hpirido[3,4-b]indol-2il)(oxetan-2-il)metano 0.035 514,2 220 / NH CrV-ú / fJq, 0—\ / k \—ny—\ VF (1R,3R)-1-[2,6-difluor-4-[2[3-(fluormetil)azetidin-1¡l]etoxi]fen¡l]-3-metil2,3,4,9-tetrahydro-1Hpirido[3,4-b]indol 0.007 430,2 221 / \ F / n-4 O5-a ° h \ / 0 N ^^F 2-fluor-1-[(1R,3R)-1-[4-[2[3-(fluormetil)azetidin-1il]etoxi]fenil]-3-metil1,3,4,9-tetrahydrobrio[3,4-b]indol-2-l]-2metil-propan-1-ona 0.18 482.3<h2 style=";text-align:left;direction:ltr"> η° structure name ER-alpha MCF7 HCS EC50 (μΜ) CL-EM [M+H]+ 222 Λ 0 ί ΓΗ / HF \= / 0 t-'Nx^x^F 1-[(1R,3R)-1-[2,6-difluoro-4[1-(3-fluoropropyl)-azetid¡n-3¡l]oxy-phenyl]-3-methyl-1,3,4,9tetrahydro-pyr¡do[3,4b]indol-2-yl]-2-fluoro-2-methpropanol-10,040. 518.2 223 QjIzV'^ Ν ; 0 Η 5. F Fw \ / -νΛ / 0— / — / 1-[(1R,3R)-1-[2,6-difluoro-4[2-[3-(fluoromethyl)-azetidine-1¡l]ethoxy]phen¡l]-3-meth¡l1,3,4,9-tetrahydropyrido[3,4-b]indole-2-dimethyl]-2(no¡0803)ethanone 515.2 224 Ν ί F Η <.__ / V> ο^ / λ Λ \ζ F (1R,3R)-1-[2,6-difluoro-4-[1[(1-fluorocyclopropyl)- methyl]azet¡d¡n-3-yl]oxy-phen¡l]2-(2-fluoro-2-methyl-propyl)-3methyl-1,3,4,9- tetrahydropyr¡do[3,4-b]-¡ndole 0.000316 516.2 225 Ο 1 Ιο JΆ χ \(Η\Ζ\ \ \ “Π \< -ζ: [(1R,3R)-1-[2,6-difluoro-4-[1(3-fluoropropyl)azetid¡n-3¡l]oxy-phen¡l]-3-methyl-1,3,4,9tetrahydro-pyrido[3,4b]indol-2-yl]-(1fluorocyclobutyl)methanone 0.01.01 n° structure name ER-alpha MCF7 HCS EC50 (μΜ) CL-EM [M+H]+ 226 N ; OH ú FVO^ / \ F [(1R,3R)-1-[2,6-difluoro-4-[1(3-fluoropropyl)azetidine-3¡l]oxy-phen¡l]-3-methyl-1,3,4,9tetrahydro-pyrido[3,4b]indol-2-yl]-(1methylcic)metropone 512.1 227 / ^\ z—\ 'xZ FN and FHS—- / F—Z'x V / ο^ / Ά F (1R,3R)-1-[2,6-difluoro-4-[1(3-fluoropropyl)azetidin-3yl]oxy-phenyl]-2-[[1-(fluorometh¡l)cyclopropyl]meth¡l]-3methyl-1,3,4,9-tetrahydropyrido[3,4-b indole 010,510.56] 228 ¿CVZ\ o \ / TZ [1-[[(1R,3R)-1-[2,6-di-fluoro- 4-[1 -(3-f I uorpropyl)-azetide in3-¡l]oxy-phen¡l]-3-methyl- 1,3,4,9-tetrahydropyr-do[3,4,4-b methyl]cycloprop¡l]methanol 0.001 514.2 ΜΛ / a / zuzz / uu iy ιo <h2 style=";text-align:left;direction:ltr">Structure number ER-alfa MCF7 HCS EC5o (μΜ) CL-EM [M+H]+ 229 / \F / na QvC NT—\H \F \ / 0 N 2-fluor-1-[(1S,3R)-1-[2-fluor-4-[2-[3-(fluormetil)azetidin-1 -il]etoxi]fenil]-3metil-1,3,4,9-tetrahydropirido[3,4-b]ndol-2-l]-2metil-propan-1-ona 0,025 500,2 230 OEI z / s^ — ' 2-fluor-1-[(1R,3R)-1-[2-fluor-4-[2-[3-(fluormetil methyl)azetidine-1-l]etox]-fenil]-3-metil-1,3,4,9tetrahydrobindo[3,4-b]indol-2-l]-2-metil-propan-1-onan 0.000068 500.2<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> iviA / a / ¿u¿¿ / uu iy ιo<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">n° estructura number ER-alfa MCF7 HCS EC50 (μΜ) CL-EM [M+H]+ 231 fo f metilsulfonil-1,3,4,9tetrahydropyr¡do[3,4-b]-¡ndol 0,024 490,2 232 Λ o 05-4 ° H f Ό 0 N (1R,3R)-1-[2-fluor-4-[2-[3- (fluormetil)azetidin-1-¡l]etoxi]fenil]-3-met¡l-2- Metilsulfonil-1,3,4,9tetrahydropirdo[3,4-b]-ndol 0.000192 490.2 233 / ^λ f\Aoh N i FH z— / FA0 \ FO^A z— / 3-((1 R,3R)-1-(2,6-difluor-4((1 -(3-f I uorpropyl)-azetid in3-¡l)oxi)fen¡l)-3-metil-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]ndol-2-¡l)-2fluor-2-metilpropan-1-ol 0.000133 520.3<h2 style=";text-align:left;direction:ltr"> η° structure name ER-alpha MCF7 HCS EC5o (μΜ) CL-EM [M+H]+ 234 / --ζ F\ / ^OH ''' N y FH z~-ZFV / \ F 3-((1 R,3R)-1-(2,6-difluor-4((1 -(3-) in3-¡l)oxy)phenyl)-3-meth¡l- 1,3,4,9-tetrahydro-2Hpyrido[3,4-b]indol-2-yl)-2fluoro-2-methylpropan-1-ol 0.00018 520.3 235 f \F 7 n-4 QV 0< ^F ^F 2-fluoro-1-[(1S,3R)-1-[4-[2[3-(fluoromethyl)azetidine-1yl]ethoxy]phen¡l]-3-methyl- 1,3,4,9-tetrahydropyrido[3,4-b]indol-2-yl]-2-met¡lpropane-1-1-20.42-436 zw 21 (1R)-1-[2,6-difluoro-4-[2-[3(fluoromethyl)azetidin-lyl]ethoxy¡]phenyl]-2-(2-fluoro-2- methyl-propyl)-1,3,4,9tetrahydropyr¡do[3,4-b]-¡ndol 0,0182-2902-2 ÍIVC / H fO (1S)-1-[2,6-difluoro-4-[2-[3- (fluoromethyl)azetidin¡n-1- ¡l]ethoxy]phenyl]-2-(2-fluoro-2- methyl-propyl)-1,3,4,9- tetrahydropyr¡do[3,4-bndo[3,4-bndo]-4,04,904. ΜΛ / a / zuzz / uu iy ιo n° structure name ER-alpha MCF7 HCS EC5o (μΜ) CL-EM [M+H]+ 238 O ΞΓΖ | / x ó X z [(1R,3R)-1-[2,6-difluoro-4-[1(3-fluoropropyl)azetid¡n-3¡l]oxy-phenyl]-3-methyl-1,3,4,9tetrahydropyrido-[3,4b]indol-2-yl]-(1-fluorocyclone)promethane 2004.04 516.1 239 —\ / F υτλχ / HF — / \ V? °—0N—\ F (1R,3R)-6-chloro-1-(2,6- difluoro-4-((1-(3-fluoro- propyl)azetidine-3- ¡l)oxy)phenyl)-2-(2-fluoro-2methylpropyl)-3-methyl-2,3,4,9tetrahydro-1-H 0.00156 538.1 240 --\ Z^FN— XTV-íz HUj z\ f (1R,3R)-1-(2,6-difluoro-4-(2(3-(fluoromethyl)azetidin-1¡l)ethoxy)phenyl)-7-fluoro-2-(2fluoro-2-methylpropyl)-3-meth¡l2,3,4,9-tetrahydro-1 Hpyrido[3,4-20,202,200]indole 241 FK > \ CL N·— / ^ N i F °~~Ά (1R,3R)-1-(2,6-difluoro-4-(2(3-(fluoromethyl)azetid¡n-1¡l)ethoxy)phenyl)-6-fluoro-2-(2fluoro-2-methylpropyl)-3-3,4,4-tehydro Hpyrido[3,4-b]¡ndol 0.000381 522.3 ινΐΛ / a / zuzz / uu furo η° structure name ER-alpha MCF7 HCS EC50 (μΜ) CL-EM [M+H]+ 242 Λ\FY TV-iz Ν / =< HfX / F(1R,3R)-1-(2,6-difluor-4-((1-(3-f I uorpropyl)azetid¡ n-3- ¡l)oxy)phenyl)-6-fluoro-2-(2- fluoro-2-methylpropyl)-3-meth¡l- 2,3,4,9-tetrahydro-1 H- pyrido[3,4-b]¡ndole 0.00542 522.3 243 < / \ Ν^\ >-- / ^ΟΗ Ν i F Η Á— / . FV / (1-(((1R,3R)-1-(2,6-difluoro4-(2-(3-(fluoro-methyl)azetidine1-¡l)ethoxy)-phen¡l)-3-methyl- 1,3,4,9-tetrahydro-2Hpyrido[3,4-b]indol-2¡l)methyl)c¡clo-propyl)methanol 0.002 514.2 244 --- / \^F LXVá / Ν >=< Η F ο——\ F (1S,3S)-6-chloro-1-(2,6difluoro-4-((1-(3-fluoropropyl)azet¡d¡n-3-¡l)ox¡)phenyl)-2-(2-fluoro-2methylpropyl)-3-methyl-2,3,4,9tetrahydro-1 H-pyrido[3,4b]indole 0.063 538.1 245 F. , \ y—\ F \ Ν~- / ^ F Η F- / F v3 ΟΆ (1S,3S)-1-(2,6-difluoro-4-(2(3-(fluoromethyl)azetidin-1¡l)ethoxy)phenyl)-6-fluoro-2-(2fluoro-2-methylpropyl)-3-methyl2,3,4,9-tetrahydro-1 Hpyrido[3,4-b]¡ndole 0.035 522.3 ΜΛ / a / ZUZZ / UU fUfO <h2 style=";text-align:left;direction:ltr">n° estructura number ER-alfa MCF7 HCS EC5o (μΜ) CL-EM [M+H]+ 246 F Γ~° C TVí r HU / 0— F (1R,3R)-1-[2,6-difluor-4-[1(3-fluorpropil)azetid¡n-3¡l]oxi-fenil]-3-metil-2-[(3metiloxetan-3-il)met¡l]1,3,4,9-tetrahidropirido[3,4-b]indol 0.000358 536.1 247 f —ς Xf N—' í TVi,r HF—C / / \ F / >— na- o— / (1R,3R)-1-(2,6-difluor-4-(2(3-(fluormetil)azetidin-1¡l)etoxi)fenil)-5-fluor-2-(2fluor-2-metilpropyl)-3-metil2,3,4,9-tetrahydro-1 Hpirido[3,4-b]ndol 0.00434 522.2 248 --\ / “F x\7 N—' χ TVí / hf vi / °^0χ F (1R,3R)-1-(2,6-difluor-4((1 -(3-f I fluorpropyl)azetidin-3¡l)oxi)fenil)-7-fluor-2-(2fluor-2-metilpropyl)-3-metil2,3,4,9-tetrahydro-1 Hpirido[3,4-b]ndol 0.000518 522,2 249 f / —FL TYL_ / HF-( ) 0— F (1R,3R)-1-(2,6-difluor-4-((1 -(3-f I urpropyl)azetid i n-3- l)oxi)fenil)-5-fluor-2-(2-fluor-2-metilpropyl)-3-metil- 2,3,4,9-tetrahydro-1 Hpirido[3,4-b]indol 0.000511 522,2<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> iviA / a / ¿u¿¿ / uu iy ιo<h2 style=";text-align:left;direction:ltr"> η° structure name ER-alfa MCF7 HCS EC50 (μΜ) LC-MS [M+H]+ 250 __ __Λ \ F N i H O °^<ΤΧρ (1R,3R)-2-(2-fluoro-2-metilpropil)-1-[4-[2-[(3R)-3(fluorometil)-pyrrolidin-1¡l]ethoxy]phenyl]-3-metil1,3,4,9-tetrahydropyrido[3,4-b]indol 0.000275 482.2 251 I —\ / F N— C τν< / H f—C # f 7 y-N 7-- / (1S,3S)-1-(2,6-difluor-4-(2(3-(fluormetil)azetidin-1yl)ethoxi)fenil)-5-fluor-2-(2fluor-2-metilpropyl)-3-met¡l2,3,4,9-tetrahydro-1 Hpyrido[3,4-b]¡ndol 0.021 522.2 252 —X / -F N—' £ TV< τ HF-(} 0—£ν— F (1S,3S)-1-(2,6-difluor-4-((1(3-fluoropropyl)azetidin-3¡l)oxi)fenil)-7-fluor-2-(2fluor-2-metilpropyl)-3-met¡l2,3,4,9-tetrahydro-1 Hpyrido[3,4-b]¡ndol 0.05 522.3 253 F ^Lf N—Z L Xn< / HF-( 0— F (1S,3S)-1-(2,6-difluoro-4-((1(3-fluoropropyl)azetid¡n-3¡l)oxi)fenil)-5-fluor-2-(2fluor-2-metilpropil)-3-met¡l- 2,3,4,9-tetrahydro-1Hpyrido[3,4-b]¡ndol 0.035 522.2 ML / a / zuzz / uu iy io <h2 style=";text-align:left;direction:ltr">Structure number ER-alfa MCF7 HCS EC5o (μΜ) CL-EM [M+H]+ 254 > O OtXZ / '-X'Y N > FH — / F °~Λ F 2-[(1R,3R)-1-[2,6-difluor-4[2-[3-(fluormetil)-azetid-n-1- l]etoxi]fenil]-3-metal-1,3,4,9-tetrahydro-pyridox[3,4-b]indol-2-yl]-N,Ndimetil-acetamide 0,04 515,2 255 N i FH AY 0^ 3-((1 R,3R)-1-(2,6-difluor-4(2-(3-(f I fluormetil)-azetid n-1 ¡l)etoxi)fen¡l)-3-metil- 1,3,4,9-tetrahydro-2Hpíndo[3,4-b]ndol-2-il)-2fluor-2-metilpropan-1-ol 0,000010 520,2 256 L nA<7 CrV Ja F (1R,3R)-2-(2-fluor-2-metilpropyl)-1-[4-[1-(3-fluorpropyl)azetidin-3-il]oxi2-metil-fenil]-3-metil- 1,3,4,9-tetrahydropirido[3,4-b]ndol 0,00169 257 \ \ FN^ i xv-í / HX 7 z\ / \==< Γ~N / — o—l (1R)-1-[2,6-difluor-4-[2-[3- (fluormetil)azetidin-l- ¡l]etoxi]fenil]-2-(2-fluor-2metil-propil)-3,3-dimet¡l-4,9- dihidro-1 H-pirido[3,4b]indol 0.00109 518.3<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> iviA / a / ¿u¿¿ / uu iy ιo<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> O<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">η° estructura number ER-alfa MCF7 HCS EC50 (μΜ) CL-EM [M+H]+ 258 ν FL \^-Ν c Η f / 7 ζ\7 \=Ζ / —Νχ / — 0—' (S)-1-(2,6-difluor-4-(2-(3(fluormetil)azetidin-l¡l)etoxi)fenil)-2-(2-fluor-2metilpropil)-3,3-dimet¡l2,3,4,9-tetrahidro-1 Hpir¡do[3,4-b]indol 0.031 518.3 259 1 LL 21 (1R,3R)-1-[4-[1-[(3,3-dfluorciclobutyl)metil]azetidin-3-yl]ox-2,6-difluorfenil]-2-(2-fluor-2-metilpropyl)-3-metil-1,3,4,9tetrahydropirido-[3,4-b]indol 0.000444 538.3 260 F H F VV (1R,3R)-1-(2,6-difluor-4-(2(3-(fluormetil)azetidin-1¡l)etoxi)fenil)-8-fluor-2-(2fluor-2-metilpropyl)-3-metil2,3,4,9-tetrahydropirido-1¡l[3,4-b]indol 0.000881 522.3 261 / \F ÍI / Lj F HfX^ F (1R,3R)-1-(2,6-difluor-4-((1 -(3-f I urpropyl)azetidyl)n-3-(l)oxi)fenil)-8-fluor-2-(2-fluor-2-metilpropyl)-3-metil-2,3,4,9-tetrahydro-1H-pyridoxine[3,4-b]ndol 0.00028 522.3<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> I'm here<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">η° estructura number ER-alfa MCF7 HCS EC5o (μΜ) CL-EM [M+H]+ 262 --\ F / ί FF Η F ν) °7 Vn^f (1S,3S)-1-(2,6-difluor-4-(2(3-(fluormetil)azetidin-1¡l)etoxi)fenil)-8-fluor-2-(2fluor-2-metilpropil)-3-metil2,3,4,9-tetrahidro-1 Hpirido[3,4-b]indol 0.026 522.3 263 / ζ \·>ιΙΙΟΗ αΡ7 Η f— 0— F (S)-1-((1R,3R)-1-(2,6difluor-4-((1-(3-fluorpropyl)azetidin-3-il)oxi)fenil)-3-metil-1,3,4,9tetrahydro-2H-pirido[3,4b]indol-2-il)propan-2-ol 0.000359 488.3 264 hf^q 0— F (R)-1-((1R,3R)-1-(2,6difluor-4-((1-(3-fluorpropyl)azetidin-3-il)ox¡)fenil)-3-metil-1,3,4,9tetrahydro-2H-pirido[3,4b]indol-2-il)propan-2-ol 0.000969 488.3 265 i η a £ F __ / 0 <Ν Cl—' (1R,3R)-1-[4-[2-[3-(chlorometil)azetidn-1-l]etox]2,6-difluor-fenil]-2-(2-fluor2-metil-propyl)-3-metil1,3,4,9-tetrahydropirido[3,4-b]ndol 0.0017 521.2<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> I'm fine<h2 style=";text-align:left;direction:ltr"> η° structure name ER-alpha MCF7 HCS EC5o (μΜ) CL-EM [M+H]+ 266 ocA N and H Qc, F (1R,3R)-1-[3-chloro-4-[1-(3fluoropropyl)azetidin-3-yl]oxyphenyl]-2-(2-fluoro-2-methylpropyl)-3-methyl-1,3,4,9tetrahydropyr¡do-[3,4-b]¡ndol 0.01 0.01 5 — 27 — 27 \ X \ N ~ Z H , Q- O^AF (1R,3R)-1-[3-fluoro-4-[1-(3fluoropropyl)azetid¡n-3-¡l]-ox¡phenyl]-2-(2-fluoro-2-methylpropyl)-3-methyl-1,3,4,9tetrahydropyr¡do-[3,4-b-do-[3,404,040]l 486.3 268 \ -¿ez N ' FF^0 0 / F (2R)-3-[(1R,3R)-1-[2,6d¡fluoro-4-[2-[3-(fluoromethyl)azetid¡n-1-¡l]ethoxy¡]phenyl]-3-methyl-1,3,4,9tetrahydropyrido[3,4-b]indol-2-yl-1-2-0,08]-prodiol 504.2 ΜΛ / a / zuzz / uu iy ιo <h2 style=";text-align:left;direction:ltr">n° estructura number ER-alfa MCF7 HCS EC5o (μΜ) CL-EM [M+H]+ 269 N i F Η V__ / F—Z'x V / o-~ / \ Vf (1R,3R)-1-[2,6-difluor-4-[1[[(1S,2R)-2-fluor- ciclopropil]metil]azet¡d¡n-3¡l]oxi-fenil]-2-(2-fluor-2metil-propil)-3-metil- 1,3,4,9-tetrahidropirido- [3,4-b]indol 0.001 516.3 270 IZ. Jx. Y. y (1R,3R)-1-(2,6-difluor-4-(2(3-(fluormetil)azetidin-1¡l)etoxi)fenil)-2-((S)-3-fluor2-metilpropyl)-3-met¡l- 2,3,4,9-tetrahydro-1-Hpindo[3,4-b]indol 0,000459 504,3 271 OH Η F~\ 7 0—\ xN 2--- F (S)-3-((1R,3R)-1-(2,6-difluor-4-(2-(3-(fluormetil)azetidin-1-l)etoxi)fenil)-3-metil-1,3,4,9tetrahydro-2H-pyridox[3,4b]indol-2-yl)-2metilpropano-1,2-diol 0.005 518.3 272 F (1R,3R)-1-[2,6-difluor-4-[1(3-fluorpropyl)azetidin-3l]oxi-fenil]-2-(3-fluor-2,2dimetil-propyl)-3-metil1,3,4,9-tetrahydropirido[3,4-b]indol 0.000685 518.3<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> iviA / a / ¿u¿¿ / uu iy ιo<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">η° estructura number ER-alfa MCF7 HCS EC50 (μΜ) CL-EM [M+H]+ 273 O ΞΕΖ | TI\-£í>k 0.00028 502.2 274 ZF f ν' z0H N í- H z=-, F^Ó °x vn^f (S)-2-fluor-3-((1R,3R)-1-(2fluor-4-(2-(3-(fluormetil)azetidn-1-l)etox)fenil)-3-metil-1,3,4,9tetrahydro-2H-pirido[3,4b]indol-2-il)-2-metilpropan-1-ol 0.000253 524.1 275 O IZ ] z-\ / 1 (R)-2-fluor-3-((1R,3R)-1-(4(2-(3-(fluormetil)azetidn-1-l)etox)fenil)-3-metil1,3,4,9-tetrahydro-2H-pirido[3,4-b]indol-2-il)-2metilpropan-1-ol 0.000166 484,2 276 .F r^\ / —\ V z0H vtCn^^ N i Η O °Ί ^Nζ\-ΖΡ (S)-2-fluor-3-((1R,3R)-1-(4(2-(3-(fl uormeti l)-azetid¡ n-1 ¡l)etox¡)fen¡l)-3-met¡l- 1,3,4,9-tetrahydro-2Hpirido[3,4-b]ndol-2-¡l)-2metilpropan-1-ol 0.000309 484,2<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">n° estructura number ER-alfa MCF7 HCS EC50 (μΜ) CL-EM [M+H]+ 277 Qú / Á- N i FH z^ZF~OO^AF (1R,3R)-1-[2,6-difluor-4-[1(3-fluorpropyl)azetidin-3- ¡l]ox¡-fen¡l]-3-metil-2-(2,2,2- trifluoretil)-1,3,4,9- tetrahydropyr¡do[3,4-b]-¡ndol 0.000090 512.2 278 OH / V0H oíH' H / T~\ F—7 A 0 ^-NF (2R)-3-[(1R,3R)-1-[2,6difluor-4-[2-[3-(fluormetil)azetidin-1-il]etoxi]fenil]-3-metil-1,3,4,9tetrahidropirido[3,4-b]indol-2-il]-2-metil-propano1,2-diol 0.00031 518.3 279 \FN—' ίΧ>Λ \^N η—\ H # yF 0-< / \_-x (1R,3R)-2-(2-fluor-2metilpropil)-1-(3-fluor-4-(2- (3-(fluormetil)azetidin-1- ¡l)etoxi)fenil)-3-met¡l- 2,3,4,9-tetrahydro-1H- pírido[3,4-b]¡ndol 0,00016 486,3<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> iviA / a / ¿u¿¿ / uu iy ιo<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">n° estructura number ER-alfa MCF7 HCS EC5o (μΜ) CL-EM [M+H]+ 280 ΓΎ Z ht (1S,3R)-2-(2-fluor-2-metilpropi l)-1 -(3-fluor-4-(2-(3(fluormetil)azetidin-l¡l)etoxi)fenil)-3-metil2,3,4,9-tetrahidro-1 Hpirido[3,4-b]¡ndol 0.006 486,3 281 > \ F Ά í TVi / η \ / F O-\ / \_-χ (1R,3R)-1-(2,3-difluor-4-(2(3-(fluormetil)azetidin-1¡l)etoxi)fenil)-2-(2-fluor-2metilpropil)-3-metil-2,3,4,9tetrahydro-1H-pirido[3,4b]indol 0.000183 504,3 282 o ^IZ 3 6 -y (1R,3R)-1-(2,6-difluor-4- ((1-(((1S,2S)-2-fluorciclopropil)metil)azetidin-3¡l)oxi)fenil)-2-(2-fluor-2metilpropil)-3-metil-2,3,4,9tetrahydro-1H-pirido[3,4b]indol 0.001 516,3 283 o oXjT 7 / ° zx 1-[(1R,3R)-1-[2,6-difluor-4[1-(3-fluorpropyl)-azetidn-3l]oxi-fen-l]-3-metil-1,3,4,9tetrahydro-pirdo[3,4b]indol-2-il]-propan-2-ona 0.001 486.3<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> ινAL / a / zuzz / uu / y / o<h2 style=";text-align:left;direction:ltr"> η° structure name ER-alpha MCF7 HCS EC50 (μΜ) CL-EM [M+H]+ 284 0— F 3-[(1R,3R)-1-[2,6-difluoro-4[1-(3-fluoropropyl)-azetid¡n-3¡l]oxy-phenyl]-3-methyl-1,3,4,9tetrahydro-pyr¡do[3,4b]indol-2-yl]-2,2-dmethl-propanel-10-20-08 516.3 285 O IZ 7 / ti / u (1R,3R)-1-[2,6-difluoro-4-[1(3-fluoropropyl)azetidin¡n-3yl]oxy-phen¡l]-2-et¡l-sulfon¡l-3methyl-1,3,4,9tetrahydropyr-3-dob-4-b 0.002 522.1 286 LL sv Γ o 3-[(1R,3R)-1-[2,6-difluoro-4[2-[3-(fluoromethyl)-azetid¡n-1yl]ethoxy]phen¡l]-3-methyl- 1,3,4,9-tetrahydropyrido[3,4-b]indol-2-¡l]-2,2difluoro-propan-1-ol 0.0000978 524.1 287 Oíb^ N i F Η Λ— / F vJ 0—. <n^f 3-[(1R,3R)-1-[2,6-difluor-4[2-[3-(fluormetil)-azetid¡n-1¡l]etoxi]fen¡l]-3-met¡l1,3,4,9-tetrahidropindo[3,4-b]indol-2-¡l]-2,2dimetil-propan-1-ol 0,001 516,3 <h2 style=";text-align:left;direction:ltr">n° estructura number ER-alfa MCF7 HCS EC5o (μΜ) CL-EM [M+H]+ 288 . F OH Λ h^J í lV< j F Jq J HN—<3N (R)-3-((1R,3R)-1-(2,6dífluor-4-((1-(3-fluorpropil)azetid¡n-3-¡l)amino)fen¡l)-3-metil1,3,4,9-tetrahidro-2Hpirido[3,4-b]indol-2-il)-2fluor-2-metilpropan-1-ol 0,0000528 519,3 289 F OH ίΧ>Λ 7 ^h FJ (S)-3-((1R,3R)-1-(2,6difluor-4-((1-(3-fluorpropil)azetidin-3-il)amino)fen¡l)-3-metil1,3,4,9-tetrahidro-2Hpirido[3,4-b]indol-2-il)-2fluor-2-metilpropan-1-ol 0.000199 519.3 290. F OH Λ hi*__ / F Ja j mp. (R)-2-fluor-3-((1R,3R)-1-(2fluor-4-((1-(3-fluorpropyl)azetidin-3-il)amino)fen¡l)-3-metil-1,3,4,9-tetrahydro-2Hpirido[3,4-b]indol-2-il)-2metilpropan-1-ol 0.000497 501,3 291 F OH fF (S)-2-fluor-3-((1R,3R)-1-(2-fluor-4-((1-(3-fluor-propyl)azetidin-3-il)-amino)fenyl)-3-metil-1,3,4,9-tetrahydro-2Hpirido[3,4-b]indol-2-il)-2metilpropan-1-ol 0.00013 501.3<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> MA / a / zuzz / uu iy ιo<h2 style=";text-align:left;direction:ltr"> η° structure name ER-alpha MCF7 HCS EC50 (µΜ) CL-EM [M+H]+ 292 F OH Λ / / ,1__ / 'η \ p H # AJ ην-^ν^ (R)-2-fluor-3-((1R,3R)-1-(4-(1-(3-f) uzet I in3-yl)amino)phenyl)-3-met¡l1,3,4,9-tetrahydro-2Hpyrido[3,4-b]indol-2-¡l)-2methylpropan-1-ol 0.002 483.3 293 F OH n 'η X p hn-O^ (S)-2-fluoro-3-((1R,3R)-1-(4((1 -(3-f I uorpropyl)-azetide in3-¡l)amino)phen¡l)-3-methyl1,3,4,9-tetrahydro-2Hpyrido[3,4-b]indol-2-yl)-2methylpropane-10,40,538 294 \VyOH N i FH / ^ZF~x \^n— F 3-((1 R,3R)-1-(2,6-difluoro-4((1 -(3-f I uorpropyl)-azetide in3-¡l)oxy)phen¡l)-3-methyl- 1,3,4,9-tetrahydro-2Hpyrido[3,4-b]indol-2-yl)-2fluoro-2-methylpropan-1-ol 520,3 295 __ __> O In k F Η Λ=Ζ F~w 1-((1S,3R)-1-(2,6-(2,4-(1-(1)-(f) I uorpropyl)-azetide in3-¡l)oxy)phen¡l)-3-methyl- 1,3,4,9-tetrahydro-2H- pyrido[3,4-b]indole-2¡l)propan-2-one 0.021 486.2 ΜΛ / a / zuzz / uu iy ιo <h2 style=";text-align:left;direction:ltr">η° estructura number ER-alfa MCF7 HCS EC50 (μΜ) CL-EM [M+H]+ 296 __ / RFN 6 ,FH z==Z HN—, 3,5-difluor-N-(2-(3-) (fluormetil)azetidin-1-¡l)et¡l)4-((1R,3R)-3-metil-2-(2,2,2trifluoretil)-2,3,4,9tetrahidro-1 H-pirido[3,4b]indol-1-il)an¡l¡na 0.0002 511.2 297 / ^\ 7-- / 0 uj1-''! N i F / H HV F^OV^\^F (S)-3-((1R,3R)-1-(2,6difluor-4-(2-(3-(fluormetil)azetidn-1-l)etoxfenil)-3-metil-1,3,4,9-tetrahydro-2H-pyridinol[3,4b]indol-2-yl)-N,N,2trimethylpropanamide 0,018 543,3 298 F u) b^^F (R)-3-((1R,3R)-1-(2,6difluor-4-(2-(3-(fluormetil)azetidn-1-l)etoxi)fenil)-3-metal-1,3,4,9tetrahydro-2H-pyridinol-2-yl)-N,N,2trimethylpropanamide 0.005 543.3 299 F 0H H λ— / F^O o-^N(XzF acid (S)-3-((1R,3R)-1-(2,6difluor-4-(2-(3-(fluormetil)azetidn-1-l)etoxi)fenil)-3-metal- 1,3,4,9-tetrahidro-2Hpindo[3,4-b]¡ndol-2-il)-2metilpropanoico 0.003 516.2<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">n° estructura number ER-alfa MCF7 HCS EC50 (μΜ) CL-EM [M+H]+ 300 qAA HW ácido (R)-3-((1R,3R)-1(2,6-difluor-4-(2-(3- (fluormetil)azetidin-lil)etoxi)fenil)-3-metil- 1,3,4,9-tetrahidro-2Hpirido[3,4-b]indol-2-il)-2metilpropanoico 0,001 516,2 301 R / —\ / F L1OH. / hf—ζ y 0— F (1R,3S)-1-(2,6-difluor-4-((1(3-fluorpropyl)azetidin-3¡l)oxi)fenil)-2-(2-fluor-2metilpropil)-3-(fluormetil)2,3,4,9-tetrahydro-1 Hpiridol[3,4-b]ndol 0,0000881 522,2 302 y--Ρ^Γ°H N > FH z— / F 0-A\ L,nA 3-((1 R,3R)-1-(2,6-difluor-4((1 -(3-f I urpropyl)-azetidin3-¡l)oxi)fenil)-3-metil-3,4dihydro-1 H-pirido[3,4-b]indol-2(9H)-il)-2,2-difluorpropan-1-ol 0.00012 524,1 303 QíÍ-^f N i FHWA (1R,3R)-2-(2,2-difluoretyl)1-[2,6-difluor-4-[1-(3fluorpropyl)azetidin-3-il]oxifenil]-3-metil-1,3,4,9tetrahidropir¡do-[3,4-b]¡indol 0.0000482 494,2<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">Structure number ER-alfa MCF7 HCS EC50 (μΜ) CL-EM [M+H]+ 304 F\ / FV^y^N^FN % FH / A f^o ' F HNA~^ N-(3,5-difluor-4-((1R,3R)-3metil-2-(2,2,2-trifluor-etil)- 2,3,4,9-tetrahydro-1 Hpirido[3,4-b]ndol-1-l)-fen¡l)1 -(3-f I uor propil)-azetid ina3-amina 0,000224 511,2 305 > FY í FH z— / °A ^ν0ά F (1R,3R)-2-(2,2-difluoretil)1-[2,6-difluor-4-[2-[3(fluormetil)azetidin-l¡l]etoxi]fen¡l]-3-metil-1,3,4,9-tetrahidropirdo[3,4-b]indol 0.000216 494,2 306 F. / VF mU A f_q (1S,3R)-2-(2,2-difluoretil)1-[2,6-difluor-4-[2-[3(fluormetil)azetidin-l¡l]etoxi]fen¡l]-3-metil-1,3,4,9-tetrahidropirido-[3,4-b]indol 0.003 494,2 307 __Z \ FCIV n-7 > ,F hf^ ^^F (1R,3R)-1-[4-[1-(3,3difluorcyclobutyl)azetidn-3il]oxi-2,6-dfluor-phenyl]-2-(2fluor-2-metilpropyl)-3-metil1,3,4,9-tetrahydropirido[3,4-b]ndol 0.000193 534.1<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">η° estructura number ER-alfa MCF7 HCS EC5o (μΜ) CL-EM [M+H]+ 308 N i FH / ^ZF~w ' F O-- / N / == / \^N—' (1R,3R)-1-[2,6-difluor-4-[1[(E)-3-fluoral¡l]azetidin-3¡l]oxi-fenil]-2-(2-fluor-2metil-prop¡l)-3-metil1,3,4,9-tetrahidropirido[3,4-b]indol 0.000127 502.3 309 H f~C / 0— F (1R,3R)-1-(2,6-difluor-4- ((1 -(3-f I uorpropil)azetid i n-3- ¡l)oxi)fenil)-3-met¡l-2-(2- (metilsulfonil)propil)- 2,3,4,9-tetrahidro-1 H-pindo[3,4-b]indol 0.006 550,3 310 Γ\—Λ\ 0 Ulas- N Ó Η z--. OF 1-(3-fluorpropyl)-N-[4-[(1R,3R)-3-metil-2metilsulfonil-1,3,4,9-tetrahidropirido[3,4-b]indol-1-il]fenil]azetidina-3amina 0.000708 471,2 311 / \ 0 N i 0 FH __ / F^ hn^AF N-[3,5-difluor-4-[(1R,3R)-3metil-2-metilsulfonil-1,3,4,9-tetrahidropirido[3,4-b]indol-1-il]fen¡l]-1-(3fluorpropyl)azetidina-3amina 0.000248 507,2<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> I'm fine<h2 style=";text-align:left;direction:ltr"> η° structure number ER-alpha MCF7 HCS EC5o (μΜ) CL-EM [M+H]+ 312 Ν ί Ο Η > Ο (1R,3R)-1-[4-[2-[3- (fluoromethyl)azetidin-l- ¡l]etoxi]fen¡l]-3-met¡l-2vinylsulfonyl-1,3,4,9tetrahidropir¡do[3,4-b]-¡ndol 0,002 484,1 313 ζι J °~ΥΟ r-'-'V <4 ▲ / fl Yy^vT [ ζτ ο (1R,3R)-1-[4-[2-[3-(fluoromethyl)azetidin-1-yl]ethoxi]phenyl]-N,3-dimet¡l-1,3,4,9tetrahidropyrido[3,4-b]indole-2-sulfonamide 0,001 487,4 314 / ΤΑ / ι ο Υ / Υ / 'Υ Ν'^'Χ Ó Ο ΗΝ-^Α 'VNy^ F 1-(3-fluorpropyl)-N-[4- [(1S,3R)-3-methyl-2-methylsulfonyl-1,3,4,9-tetrahidropir¡do[3,4-b]¡ndol-1-¡l]phenyl]azetid¡na-3-am¡na 0.009 471.3 315 / λ ο O^N'SY Ν^ί ÓF Η V / FF v3 ην-~>Λ F N-[3,5-difluor-4-[(1S,3R)-3methyl-2-methylsulfonyl- 1,3,4,9-tetrahidropyrido[3,4-b]indole-1-yl]phen¡l]-1-(3fluorpropyl)azetidine-3amine 0.002 507.1 <h2 style=";text-align:left;direction:ltr">η° estructura number ER-alfa MCF7 HCS EC5o (μΜ) CL-EM [M+H]+ 316 ιζ ΛΚ y. Α ιι X / ζ ζ 3-[(1R,3R)-1-[2,6-difluor-4[1-(3-fluorpropil)-azetid¡n-3¡l]oxi-fenil]-3-metil-1,3,4,9tetrahidro-pirido[3,4b]indol-2-il]-2,2-d¡met¡lpropanonitrilo 0.0000724 511.2 317 Ν i F Η A=VF / =^ / \ \ F (1R,3R)-1-[4-[1-(3,3- d¡fluoral¡l)azetidin-3-il]oxi- 2,6-difluor-fenil]-2-(2-fluor- 2-metil-propil)-3-met¡l- 1,3,4,9-tetrahidro-pirido[3,4-b]¡ndol 0,000181 520,1 318 ΟΗ Ν i F Η ζ-— / F^ (S)-2-(((1R,3R)-1-(2,6difluor-4-(2-(3-(fluormetil)azetid¡n-1-¡l)etox¡)fenil)-3-metil-1,3,4,9tetrahidro-2H-pirido[3,4b]indol-2-il)met¡l)-3,3,3trifluorpropan-1-ol 0,001 556,2 319 OH AYA nA'£f 0==7 >--- F Ν i F Η ζ-- / F <3 o—, Αζ^ν (R)-2-(((1R,3R)-1-(2,6difluor-4-(2-(3-(fluormetil)azetidn-1-l)etoxfenil)-3-metil-1,3,4,9tetrahydro-2H-pyridinol-2-yl)metil)-3,3,3trifluorpropan-1-ol 0.00043 556.2<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> I'm fine<h2 style=";text-align:left;direction:ltr"> η° structure name ER-alpha MCF7 HCS EC50 (μΜ) CL-EM [M+H]+ 320 / ^Χ 7--χΓ^ΟΗ Ν i F Η %=- / F~w ΗΝ —. 3-((1 R,3R)-1-(2,6-difluoride-4((2-(3-(fluoromethyl)-azetidine1-¡l)ethyl)am¡no)-phenyl)-3methyl-1,3,4,9-tetrahydro-2Hpyrido[3,4-b]indol-methylflu-2-ylpan) 0.00027 519.2 321 k \ F / Ν—' (yy\j Η ΗΝ—\ 7\__ '—Ν / X 'Ύ F 3,5-difluoride-N-[2-[3-(fluormethyl)azetidine-1-yl]et¡l]-4[(1R,3R)-2-(2-fluor-2-methylpropyl)-3-methyl-1,3,4,09tetrahydropyride-[3,4b-2]indol]2,¡anol-2 503.2 322 ll ΖΣ 3-fluorine-N-[2-[3-(fluormethyl)azetid¡n-1-¡l]et¡l]-4- [(1R,3R)-2-(2-fluorine-2-methylpropyl)-3-methyl-1,3,4,9tetrahydropyride-[3,4b]indol-1-yl]an¡l¡na 0.0000253 485.2 323 > \ F / Ηi_ ,—\ Q N-[2-[3-(fluoromethyl)-azetidine1-yl]ethyl]-4-[(1R,3R)-2-(2fluor-2-methyl-propyl)-3-methyl1,3,4,9-tetrahydropyrido[3,4-b]indol-1-yl]aniline 2,0406072,0400 ΜΛ / a / ZUZZ / UU fUfO <h2 style=";text-align:left;direction:ltr">η° estructura number ER-alfa MCF7 HCS EC5o (μΜ) CL-EM [M+H]+ 324 0 \ / 1 N'S^ Ν 3 0 Η - Ο O^^N^^^F (1R,3R)-2-etilsulfonil-1-[4[2-[3-(fluormetil)-azetidin-1¡l]etoxi]fenil]-3-met¡l- 1,3,4,9-tetrahidropirido[3,4-b]¡ndol 0.000198 486.2 325 / ΤΑ Λλ ο \^zV / N'S- Ν 3 0 Η Α—, Ο ΗΝ—_ F N-[2-[3-(fluormetil)-azetidin1-¡l]etil]-4-[(1R,3R)-3-metil2-metilsulfonil-1,3,4,9tetrahydropyr¡do[3,4-b]¡ndol-1-il]an¡lina 0.001 471.1 326 ΓΑ / \ ο Ν 3 0 F Η ZF ΗΝ—_ F 3,5-difluor-N-[2-[3-(fluormetil)azetid¡n-1-¡l]et¡l]-4[(1 R,3R)-3-metil-2-metilsulfonil-1,3,4,9-tetrahidrop¡rido[3,4-b]¡ndol-1-il]anilina 0,000305 507,2 327 CHÍA N 3 HOvn^f 2-fluor-3-((1R,3R)-1-(2fluor-4-((2-(3-(fluormetil)azetidin-1 -il)etil)amno)fenil)-3-metil-1,3,4,9tetrahydro-2H-pyridinol-2-il)-2-metalpropan1-ol 0,000347 501,2<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> I'm fine<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">Structure number ER-alfa MCF7 HCS EC5o (μΜ) CL-EM [M+H]+ 328 5 ¿S r- / / / / 1 [ ZT o 2-fluor-3-((1R,3R)-1-(4-((2(3-(fluormetil)azetidin-1il)etil)amno)fen¡l)-3-met¡l1,3,4,9-tetrahydro-2Hpirido[3,4-b]indol-2-il)-2metilpropan-1-ol 0,000167 483,3 329 o IZ ] NALS s Xo (1R,3R)-1-[4-[2-[3(fluormetil)azetidin-l¡l]etoxi]fen¡l]-N,N,3-trimet¡l1,3,4,9-tetrahydropirido[3,4-b]indol-2sulfonamide 0.001 523,1 330 (jPLas- N i 0 H / ^\ O \ - F / —z \^N^ / (1R,3R)-1-[4-[1-(3-fluorpropyl)azetidin-3-l]oxifenil]-3-met¡l-2-methylsulfonyl-1,3,4,9-tetrahydropirido[3,4-b]-indol 0.002 472,2 331 H / == / F''C / OA^XX^OH 3-[3-[3,5-difluor-4-[(1R,3R)2-(2-fluor-2-metil-propyl)-3metil-1,3,4,9tetrahidropirido-[3,4-b]indol-1-il]phenoxy]-azetid¡n1-¡l]cyclobutanol 0.000236 514.2<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">η° Structure number ER-alfa MCF7 HCS EC50 (μΜ) CL-EM [M+H]+ 332 N > 0 HZ^\ O (1R,3R)-1 -(4-(2-(3(fluormetil)azetidn-1l)etoxi)fenil)-2-((S)isopropylsulfn-3-metil-2,3,4,9-tetrahydro-1 Hpirido[3,4-b]indol 0,008 484,2 333 o OEI ] z-\ ' (1 R,3R)-1 -(4-(2-(3(fluormetil)azetidn-1il)etoxi)fenil)-2-((R)isopropylsulfin¡l)-3-metil2,3,4,9-tetrahydro-1 H-pyridoxine¡l)-3-methyl ... 514,2 335 Criz^ N >__ / HfV) 0— <Qn— F (1R,3R)-1-[2,6-difluor-4-[1(5-fluorpentil)azetidin-3il]oxi-fenil]-2-(2-fluor-2metil-prop¡l)-3-metil1,3,4,9-tetrahidropirido[3,4-b]indol 0,000442 532,3 <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> I'm fine<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">n° estructura number ER-alfa MCF7 HCS EC5o (μΜ) CL-EM [M+H]+ 336 yy-F F (1R,3R)-1-[3,5-difluor-4-[1(3-fluorpropil)azet¡din-3il]oxi-fenil]-2-(2-fluor-2metil-propil)-3-metil1,3,4,9-tetrahidropirido[3,4-b]indol 0.000263 504.3 337 c / X «F^ °—CN / __ k—F (1R,3R)-1-[2,6-difluor-4-[1(4-fluorbutyl)azetidin-3l]oxi-fenil]-2-(2-fluor-2metil-propyl)-3-metil1,3,4,9-tetrahidropirido[3,4-b]indol 0.000387 518.3 338 -j ζι θ (1R,3R)-1-[3,5-difluor-4-[1(5-fluorpentil)azetidin-3l]oxi-fenil]-2-(2-fluor-2metil-propyl)-3-metil1,3,4,9-tetrahidropirido[3,4-b]indol 0.001 532.2 339 οΧ^4 , Η F \ / F o— <Qn-^ F (1R,3R)-1-[2,5-difluor-4-[1(3-fluorpropil)azetidin-3¡l]oxi-fenil]-2-(2-fluor-2metil-prop¡l)-3-metil1,3,4,9-tetrahidropirido[3,4-b]indol 0,001 504,2 <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> MA / a / zuzz / uu iy ιo<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">η° estructura number ER-alfa MCF7 HCS EC5o (μΜ) CL-EM [M+H]+ 340 / --{ F\f 0H N ' FH 7=- / F~o F 3-[(1R,3R)-1-[2,6-difluor-4[[1 -(3-f I uor propil)-azetidi n3-¡l]amino]fen¡l]-3-metil1,3,4,9-tetrahidropirido[3,4-b]indol-2-il]-2,2dífluor-propan-1-ol 0,000203 523,2 341 __Z\FH o F 3-[(1R,3R)-1-[2,6-difluor-4[2-[3-(fluormetil)-azetidn-1il]etilamno]-fenil]-3-metil-1,3,4,9-tetrahedropirido[3,4b]-indol-2-il]-2,2-difluor-propan-1-ol 0,000348 545,2 342 QíO N - H / =^ N NI \ . F (1S,3R)-2-(2-fluor-2metilpropyl)-1-(5-((1-(3fluorpropyl)azetidin-3-l)ox)pyrazin-2-l)-3-metil2,3,4,9-tetrahydro-1Hpirido[3,4-b]ndol 0.000619 470.3 343 CttO , N - F 7 H / θ' 1 fO ) \ / IN O-Oj (1R,3R)-1-(2,6-difluor-4- ((1-(3-fluorpropil)-3-metilazetidin-3-l)ox)fenl)-2-(2fluor-2-metilpropil)-3-metil- 2,3,4,9-tetrahydro-1Hpindo[3,4-b]indol 0.0002 518.3<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> I'm fine<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">n° estructura number ER-alfa MCF7 HCS EC5o (μΜ) CL-EM [M+H]+ 344 __Z\F CVOn~v AnL / HOF 2-[(1R,3R)-2-(2-fluor-2metil-propil)-3-met¡l1,3,4,9-tetrahidropirido[3,4-b]indol-1-il]-5-[1-(3fluorpropil)azetidin-3-¡l]ox¡benzonitrilo 0.000347 493.3 345 __ __Z R , vV-NAx N 3 H zÁY O Vn ° V 4-((1 R,3R)-2-(2-fluor-2metilprop¡l)-3-metil-2,3,4,9tetrahidro-1 H-pirido[3,4b]indol-1-il)-1-(3-(3(fluormetil)azetidin-lil)propyl)prdn-2(1 H)-ona 0.0123 483,3 346 crfX N > H ov F [4-[(1R,3R)-2-(2-fluor-2metil-propl)-3-metil1,3,4,9-tetrahidropirido[3,4-b]indol-1-il]fenl]-[1-(3fluorpropil)azetidin-3il]metanona 0.000399 480,2 347 ckPy F nh2 HV / F-0 o^nA^f (R)-3-((1R,3R)-1-(2,6difluor-4-(2-(3-(fluormetil)azetidn-1-l)etox)fenil)-3-metil-1,3,4,9tetrahydro-2H-pirdo[3,4b]indol-2-il)-2-methylpropanamide 0.014 515.3<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> iviA / a / ¿u¿¿ / uu iy ιo<h2 style=";text-align:left;direction:ltr"> η° estructura nombre ER-alfa MCF7 HCS EC50 (μΜ) CL-EM [M+H]+ 348 η w ° FW .F \^Ν ácido (R)-3-((1R,3R)-1(2,6-difluor-4-((1-(3-fluorpropil)azetid¡n-3-¡l)ox¡)fenil)-3-metil-1,3,4,9tetrahidro-2H-pirido[3,4b]indol-2-il)-2-metilpropanoico 0,001 516,2 349 O ΞΕΖ | J7”VA / Ο<Α / > / 'ιι < / ο k I ácido (S)-3-((1R,3R)-1-(2,6difluor-4-((1-(3fluorpropil)azetidin-3¡l)oxi)fen¡l)-3-metil-1,3,4,9tetrahidro-2H-pirido[3,4b]indol-2-yl)-2metilpropanoico 0,00203 515,2 350 ΟίίΆ0Η Η W ° fO __F \^.Ν— ácido 3-[1-[2,6-difluor-4-[1(3-fluorpropil)azetidin-3- il]oxi-fen¡l]-3-met¡l-1,3,4,9- tetrahidropyrido-[3,4- b]indol-2-yl]-2-methyl-propanoic acid 0.014 516.2 351 τ \ ο / Α ΐ ζι Ο ácido 3-[1-[2,6-difluor-4-[1(3-fluorpropyl)azetid¡n-3yl]oxy-phenyl]-3-meth¡l-1,3,4,9tetrahydropyrido-[3,4- b]indol-2-yl]-2-meth¡lpropanoic 0,033 516,2 n° structure name ER-alpha MCF7 HCS EC5o (μΜ) CL-EM [M+H]+ 352 * FN and FF~v HN^ (R)-3-((1R,3R)-1-(2,6difluoro-4-((2-(3-(fluoromethyl)azetide¡n-1-¡l)et¡l)amino)phen¡l)-3-methyl1,3,4,9-tetrahydro-2Hpyrido[3,4-b]indol-fluoro-2-ylpropanel-2)-2 0.000685 519.3 353 F / ~ \ x? / 0H N ' FF~v HN^ (S)-3-((1R,3R)-1-(2,6difluoro-4-((2-(3-(fluoromethyl)azetidin-1-yl)ethyl)amino)phen¡l-3-methyl-) 1,3,4,9-tetrahydro-2Hpyrido[3,4-b]¡ndol-2-¡l)-2fluoro-2-methylpropan-1-ol 0.000033 519.3 354 γ=\ / —< 5 OX—\,Z—í OH N > FHZ / H-N-Z\ X-Z. N— / acid (2R)-3-[(1R,3R)-1[2,6-difluoro-4-[[1-(3-fluoropropyl)azetidin-3-yl]- amino]phenyl]-3-met¡l-1,3,4,9- tetrahydropindo-[3,4- b]indol-2-yl-propano-2-01]-0 514.2 355 fYa / VV fl< í FHX=~ / F~0 o~z~nO-vf (1S,3S)-1-(2,6-difluoro-4-(2(3-(fluoromethyl)azetidine-1¡l)ethoxy)phen¡l)-6-fluoro-3-methyl2-(2,2,2-trifluoroethyl)-2,3,4,9tetrahydro-1 H-pyrido[3,40,202,202]indole iviA / a / ¿u¿¿ / uu iy ιo <h2 style=";text-align:left;direction:ltr">n° estructura number ER-alfa MCF7 HCS EC50 (μΜ) CL-EM [M+H]+ 356 ] sz ? (1R,3R)-1-(2,6-difluor-4-(2(3-(fluormetil)azetid¡n-1- ¡l)etoxi)fenil)-6-fluor-3-met¡l2-(2,2,2-trifluoretil)-2,3,4,9tetrahidro-1 H-pirido[3,4b]indol 0.000509 530.2 357 vbú / -- / FFH Jb / FF (1S,3S)-1-(2,6-difluor-4-((1(3-fluorpropyl)azetidin-3¡l)oxi)fenil)-6-fluor-3-met¡l2-(2,2,2-trifluoret¡l)-2,3,4,9tetrahidro-1 H-pirido[3,4b]indol 0.0261 529.5 358 N i FF~Q °- <N F (1R,3R)-1-(2,6-difluor-4((1 -(3-f I uorpropil)azetid i n-3il)oxi)fenil)-6-fluor-3-metil2-(2,2,2-trifluoretil)-2,3,4,9tetrahidro-1 H-pirido[3,4b]indol 0,000417 529,5 359 F. > F\^x / —ς OH N i FH 0^ 3-((1 R,3R)-1-(2,6-difluor-4(2-(3-(f I uormeti l)-azetid¡ n-1 ¡l)etoxi)fenil)-6-fluor-3-met¡l1,3,4,9-tetrahydro-2Hpindo[3,4-b]ndol-2-il)-2,2difluorpropan-1-ol 0,000552 541,5<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> MA / a / zuzz / uu iy ιo<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">n° estructura number ER-alfa MCF7 HCS EC5o (μΜ) CL-EM [M+H]+ 360 FF \^\ / --ξ F h Ρ~Η Aa^^f 3-((1S,3S)-1-(2,6-difluor-4(2-(3-(f I uormeti l)-azetidi n-1 - il)etoxi)fen¡l)-6-fluor-3-met¡[1,3,4,9-tetra-hydro-2Hpirido[3,4-b]-¡ndol-2-¡l)-2,2difluor-propan-1-ol 0.009 541.5 361 fw^ z^¿ \-=s< N-Av'F N i FFH — / FA / 0^ (1R,3R)-1-[2,6-difluor-4-[2[3-(fluormetil)azetidin-1il]etoxi]fen¡l]-3-metil-2(3,3,3-trifluorpropil)-1,3,4,9tetrahydropyr¡do-[3,4-b]¡ndol 0.003 525.5 362 z^¿ \-= / N—f FFH JA / F v3 °~Λ (1S,3R)-1-[2,6-difluor-4-[2- [3-(fluormetil)azetidin-1- ¡l]etoxi]fen¡l]-3-met¡l-2- (3,3,3-trifluorpropil)-1,3,4,9- tetrahydropyr¡do-[3,4-b]¡ndol >0,1 526,2 363 F\—FvLz0H \ ? ZL n—Z z N i FH 7r~~ / F v3 ο-^ / λ — / F λ^Μ-,Ζ 3-((1 R,3R)-1-(2,6-difluor-4((1 -(3-f I uorpropyl)-azetid in3-¡l)oxi)fenil)-6-fluor-3-methyl-1,3,4,9-tetrahydro-2Hpindo[3,4-b]¡ndol-2-il)-2,2difluor-propan-1-ol 0,000166 542,1<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> iviA / a / ¿u¿¿ / uu iy ιό<h2 style=";text-align:left;direction:ltr"> η° structure name ER-alpha MCF7 HCS EC50 (μΜ) CL-EM [M+H]+ 364 F SS F fJ.oh \-= / N~~z / ΙΨ k FH KZ F Ο-^Ά / ^F 3-((1S,3S)-1-(2,6-(2-4-(1)( I uorpropyl)-azetide in3-¡l)oxy)phenyl)-6-fluoro-3methyl-1,3,4,9-tetrahydro-2Hpyr¡do[3,4-b]indol-2-yl)-2,2difluoro-propan-1-ol 0.009 542.1 365 Ζζ N-ΗZ f~Z f~Q HN^ / AF 3-((1 R,3R)-1-(2,6-difluoro-4((1 -(3-f I uorpropyl )-azetide in3-¡l)amino)phenyl)-6-fluoro-3methyl-1,3,4,9-tetrahydro-2H- pyrido[3,4-b]indol-2-2-propyl-2-propyl-1 0.000233 563.2 366 XZF \===\ ζ^Λ V z0H vH / - / h A^ZF~^Q hn^AF 3-((1S,3S)-1-(2,6-difluoro-4((1 -(3-f I uorpropyl)-azetide in3-¡l)amino)phenyl)-6-fluoro-3methyl-1,3,4,9-tetrahyde rho-2Hpindo[3,4-b]¡ndol-2-yl)-2,2difluoro-propan-1-ol 0.004 563.2 367 r=\ / --\ O ^--\ O ^—\ Z~Z F~Z F~Z. hn~<)n^--'F acid (2S)-3-[(1R,3R)-1[2,6-difluoro-4-[[1-(3-fluoropropyl)azetidin-3-yl]amino]phenyl]-3-met¡l-1,3,4,9tetrahydropyrido-[3,4b]indole-promethrin-2-[3,4b] 0.008 515.3 η° structure name ER-alpha MCF7 HCS EC50 (μΜ) CL-EM [M+H]+ 368 FVa / —( f\^OH N - FHZ=ZF^O ' F 3-((1 R,3R)-1-(2,6-difluor-4((1) -(3-fluoropropyl)-azetid¡n3-¡l)oxy)phenyl)-6-fluoro-3- methyl-1,3,4,9-tetrahydro-2Hpyrido[3,4-b]indol-2-yl)-2fluoro-2-methylpropan-1-ol 0.000546 538.369 FVa.<h2 style=";text-align:left;direction:ltr"> / —\' Fy^0H \J”y,N ^''' f HFV / \F oA\ ,— / 3-((1S,3S)-1-(2,6-difluor-4((1 -(3-fluorpropil)-azetid¡n3-¡l)oxi)fenil)-6-fluor-3- metil-1,3,4,9-tetrahidro-2Hpirido[3,4-b]indol-2-il)-2fluor-2-metilpropan-1-ol 0.024 538.3 370 F\ / F y^0H C / N'' N 3 FH Ás¿ f~o \ F °Xn^ 3-((1 R,3R)-1-(2,6-difluor-4((1-(3-fluorpropyl)-azetid¡n-) 3-¡l)oxi)fenil)-6-fluor-3metil-1,3,4,9-tetrahidro-2Hpirido[3,4-b]indol-2-il)-2fluor-2-metilpropan-1-ol 0.000203 538.3 371 F\ RF / —y ry^OH F η Λ7 ' F 3-((1S,3S)-1-(2,6-difluor-4((1 -(3-f I uorpropil)-azetid in3-¡l)oxi)fenil)-6-fluor-3- metil-1,3,4,9-tetrahidro-2Hpirido[3,4-b]indol-2-¡l)-2fluor-2-metilpropan-1-ol 0.009 538,3 372 N i FHA / F~w \ F HN^ / A / — / N-(3,5-difluor-4-((1R,3R)-6fluor-3-metil-2-(2,2,2trifluoretyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]-indol1-¡l)fenil)-1-(3fluorpropyl)azetidina-3amina 0,000198 529,2.<h2 style=";text-align:left;direction:ltr"> n° structure name ER-alpha MCF7 HCS EC50 (μΜ) CL-EM [M+H]+ 373 F f -- / F fh AF~Q \ F HN^A y-- / χΝ-ν N-(3,5-difluoro-4-((1S,3S)-6fluoro-3-methyl-2-(2,2,2trifluoroethyl)-2,3,4,9-tetrahydro-1 H-pyrido[3,4-b]-indole1-¡l)phenyl)-1-(3fluoropropyl)azetidine-30,20,898 amine YY^ N—J OH C XV< J HO r^FX 0 acid 3-((1 R,3R)-1 -(2,6difluoro-4-(2-(3-(fluoromethyl)azet¡dyn-1-¡l)ethoxy¡)phenyl)-3-methyl-1,3,4,9tetrahydro-2H-pyrido[3,4b]indol-2-¡l)-2,2-dimethylpropanoic acid - 3,500 x 530. \ / 3⁄4 \~P~T~f AA FFH ζ=Α \ F (R)-2-(((1R,3R)-1-(2,6difluoro-4-((1-(3-fluoropropyl)azetidine-3-yl)oxy)phenyl)-3-methyl-1,3,4,9tetrahydro-2H-pyrido[3,4b]indol-2-yl)met¡l)-triol,3,3,3-fluoro-1-propane 0.000764 556.2 376 OH N % FHA fO ' ,F (S)-2-(((1R,3R)-1-(2,6difluoro-4-((1-(3-fluoropropyl)azetidine-3-yl)oxy)phenyl)-3-met¡l-1,3,4,9tetrahydro-2H-pyrido[3,4b]indol-2-yl)met¡l-triol,3,3-1-propane 0.001 556.2 100 η° structure name ER-alpha MCF7 HCS EC50 (μΜ) CL-EM [M+H]+ 377 ___ __ / R y N - h / V v N \ . F (1R,3R)-2-(2-fluoro-2methylpropyl)-1-(2-((1-(3fluoropropyl)azet¡din-3¡l)ox¡)pyrimid¡n-5-¡l)-3-meth¡l2,3,4,9-tetrahydro-1 Hpyrido[3,4-b 0,005] 470.3 378 r=\ / —V 0 F °HH >- / F acid 3-[(1S,3R)-1-[2,6- difluoro-4-[2-[3-(fluoro- methyl)azetidin¡n-1-¡l]ethoxy]- phenyl]-3-methyl-1,3,4,9-tetrapido-[3,4] ¡ndol-2-yl]-2,2-dimet¡l- propanoic 0.028 530.3 379 f VF vMj'- / FN 1 F ρΎχ f ,.F (1R,3R)-1-(2,6-difluoro-4-(2(3-(fluoromethyl)azetidin-1yl)ethoxy)phenyl)-2-(2,2difluoropropyl)-3-methyl2,3,4,9-tetrahydro-1 Hpyrido[3,4-b]dol 0.000.288 *2 FN—2 ( 1H H \ / HO F (S)-(4-((1R,3R)-2-(2-fluoro2-methylpropyl)-3-meth¡l- 2,3,4,9-tetrahydro-1 Hpyrido[3,4-b]indol-1yl)phenyl)(1 -(3-fluorozeropropyl-methanol-3) 0.000188 482.3 ΜΛ / a / zuzz / uu iy ιo 101 n° structure name ER-alpha MCF7 HCS EC5o (μΜ) CL-EM [M+H]+ 381 » \ FN—7 (ih ah \ / S—TyN—\__ HO F (R)-(4-((1R,3R)-2-(2-fluor2-methylpropyl)-3-meth. Hpyrido[3,4-b]¡ndol-1yl)phenyl)(1 -(3-fluoropropyl)azetidin-3-¡l)methanol 0.000605 482.3 382 / AN—' OH ίΤ\ H F- / 7 h / ^NF N'^'7 H acid 3,3(1) R(R-1) -(2,6difluor-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phen¡l)-3-methyl- 1,3,4,9-tetrahydro-2Hpyrido[3,4-b]indol-2-yl)-2,2dimethylpropanoic 0.00101 ,2 528 / F 3____. RN^ TXA / HfaJ 0. <N fA (1R,3R)-1-(2,6-difluor-4-(2(3-(fluormetil)azetid¡n-1¡l)etoxi)fenil)-2-(2,2-d¡fluoretil)-6-fluor-3-metil2,3,4,9-tetrahidro-1 Hpirido[3,4-b]indol 0,00028 512,2 384 c- F. / F R N^ TTV< / F AA-N YA HfA= / 0 rN f-A (1S,3S)-1-(2,6-difluor-4-(2- (3-(fluormetil)azetid¡n-1il)etoxi)fenil)-2-(2,2-difluoretil)-6-fluor-3-metil- 2,3,4,9-tetrahidro-1Hpirido[3,4-b]indol 0,029 512,2 MA / a / zuzz / uu iy ιo 102 <h2 style=";text-align:left;direction:ltr">η° Structure number ER-alfa MCF7 HCS EC5o (μΜ) CL-EM [M+H]+ 385 F\_ __ / FN 1 FH zY F (1R,3R)-1-(2,6-difluor-4- ((1 -(3-f I urpropyl)azetid i n-3il)oxy)fen¡l)-2-(2,2-d¡fluoretyl)-6-fluor-3-metil2,3,4,9-tetrahydro-1 Hpírido[3,4-b]ndol 0,000074 512,2 386 TI IZ vY- v (1S,3S)-1-(2,6-difluor-4-((1(3-fluorpropil)azet¡din-3il)oxi)fen¡l)-2-(2,2-difluoretil)-6-fluor-3-metil2,3,4,9-tetrahidro-1Hpir¡do[3,4-b]indol 0.023 512.2 387 F\ / Va / \o OvAsA N 3 Ó c H' / fO NH AF N-(3,5-difluor-4-((1R,3R)-6fluor-3-metil-2-(metilsulfonil)-2,3,4,9-tetrahidro1 H-pirido[3,4-b]¡ndol-1il)fenil)-1 -(3-fluorpropil)azetidina-3-amina 0.000149 525.2<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> I'm fine<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> 103<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">Structure number ER-alfa MCF7 HCS EC5o (μΜ) CL-EM [M+H]+ 388 F γAΧL 0 (JYx N^^Y °f HV / fO NH NY F N-(3,5-difluor-4-((1S,3S)-6fluor-3-metil-2-(metilsulfonil)-2,3,4,9-tetrahydro1H-pyrido[3,4-b]indol-1il)fenil)-1 -(3-fluorpropyl)azetidina-3-amina 0,019 525,2 389 / F\ _ / \-f Y YV< j zrY HfxJ NH 3 F N-(4-((1R,3R)-2-(2,2difluoretil)-6-fluor-3-met¡l- 2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-il)-3,5difluorfenil)-1-(3fluorpropyl)azetidina-3amina 0.000056 511,2 390 . F. ? / F nttVyf w^-n HfY / NH 3 F N-(4-((1S,3S)-2-(2,2-difluoretyl)-6-fluor-3-metil- 2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-il)-3,5difluorfenil)-1-(3-fluorpropyl)azetidina-3amina 0.0097 511,2<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> I'm going to go<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> 104<h2 style=";text-align:left;direction:ltr"> η° structure name ER-alpha MCF7 HCS EC50 (μΜ) CL-EM [M+H]+ 391 E , \ N- / '' N 4 F Η □? F^'' (1R,3R)-1-(2,6-difluoro-4((1-cis-(3-(fluoromethyl)cyclobutyl)azetidin-3-yl)oxy)phenyl)-2-(2-fluoro-2methylprop¡l)-3-methyl-2,3,4,9tetrahydro-1 H-pirido[3,4]indole)-2-(2-fluoro-2methylprop¡l)-3-methyl-2,3,4,9 0.00015 530.3 392 F z N 3 FH Á~— / F~Y1 (1R,3R)-1-(2,6-difluoro-4((1-trans-(3-(fluoromethyl)cyclobutyl)azetidine-3-yl)oxy)phenyl)-2-(2-fluoro-2methylpropyl)-3-methyl-2,3,4,9tetrahydro-1 H-pyrido[3,4,004,030] 393 N - FH / = / fO \ F (1R,3R)-1-(2,6-difluoro-4- ((1 -(3-f I uorpropyl)azetide i n-3- ¡l)oxy)phenyl)-2-((1-fluoro- cyclobutyl)methyl)-3-methyl- 2,3,4-trahydro, 9-1-H pyrido[3,4-b]¡ndol 0.000142 516.3 ΜΛ / a / ZUZZ / UU fUfO 105 <h2 style=";text-align:left;direction:ltr">Structure number ER-alfa MCF7 HCS EC5o (μΜ) CL-EM [M+H]+ 394 F, OH Hfax 0 rN F—' (S)-3-((1R,3R)-1-(2,6difluor-4-(2-(3-(fluormetil)azetidn-1-l)etox)fenil)-3-metal-3,4-dhdro1H-pyridox[3,4-b]indol-2(9H)il)-2-fluorpropan-1-ol 0,00023 506,2 395 F OH y nfXY. j 0 <N F—' (R)-3-((1R,3R)-1-(2,6dífluor-4-(2-(3-(fluormetil)azetidin-1-il)etox¡)fenil)-3-met¡l-3,4-dihidro1H-pirido[3,4-b]¡ndol-2(9H)il)-2-fluorpropan-1-ol 0,000053 506,2 396 rY / —( V f'AXK / n^<F N 2 F H ÁV NH F N-(3,5-difluor-4-((1R,3R)-7fluor-3-metil-2-(2,2,2trifluoretil)-2,3,4,9-tetrahidro-1 H-pirido[3,4-b]-indol1-¡l)fenil)-1-(3fluorpropil)azetidina-3amina 0,00011 529,2 <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> iviA / a / ¿u¿¿ / uu iy ιo<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> 106<h2 style=";text-align:left;direction:ltr"> η° structure name ER-alpha MCF7 HCS EC50 (µΜ) CL-EM [M+H]+ 397 / --Ζ f\ / f Ν / \ F FXj ΝΗ F N-(3,5-difluor-4-((1S,3S)-7fluor-3-methyl-2-(2,2,2trifluorethyl)-2,3,4,9-tetrahydro-1 H-pyrido[3,4-b]-¡ndol1-yl)phenyl)-1-(3fluorpropyl02,3a)amine 398 F ΓΆ / --\ \Ζ^0Η Ν 2 F Η ΖΎ ΝΗ ίϊ F (S)-3-((1R,3R)-1-(2,6difluoride-4-((1-(3-fluorpropyl)azetid¡n-3-yl)amino)phen¡l)-5-fluorine-3-methyl3,4-dihydro-1 H-pyrido[3,4- b]indol-2(9H)-yl)-2-fluorine-2methylpropane-1-ol 0.00011 537.3 399 τ Ο / U- '0 X πΖζ ΖΙ11 (R)-3-((1S,3S)-1-(2,6difluoride-4-((1-(3-fluorpropyl)azetidine-3-yl)amino)phenyl)-5-fluor-3-met¡l3,4-dihydro-1 H-pyrido[3,4b]ylpro-pn-lu-2-meth-2H) 0.0011 537.3 ΜΛ / a / zuzz / uu iy ιo 107 η° structure name ER-alpha MCF7 HCS EC5o (μΜ) CL-EM [M+H]+ 400 F / =£ / —( VOH N 1 FH 7— / NH F (R)-3-((1R,3R)-1-(2,6difluoro-4-((1-(3-fluoropropyl)azetidine-3-yl)amino)phenyl)-5-fluoro-3-methyl3,4-dihydro-1 H-pyrido[3,4b]indol-2(9H)-yl)-2-methyl-fluoro-2-propane 0.000023 537.3 401 F / r=í / --d \X~OH -- / F \ F η K / F vv NH ίϊ F (S)-3-((1S,3S)-1-(2,6difluoro-4-((1-(3-fluoropropyl)azetidine-3-yl)amino)phenyl)-5-fluoro-3-methyl3,4-dihydro-1 H-pyrido[3,4b]indol-2(9H)-yl)-2-fluoro-20-20-2 537.3 402 F ΑΑΑ^^^λ F °HH z— / ΡΎΑ f ,.P (R)-3-((1R,3R)-1-(2,6- difluoro-4-(2-(3-(fluoro- methyl)azetidine-1-yl)ethoxy)- phenyl)-3-met¡l-3,4-dih¡dro1H-pyrido[3,4-b]¡ndol-2(9H)¡l)-2-(fluoromethyl)-propan-1-ol 0.000032 520.3 ΜΛ / a / zuzz / uu iy ιo 108 n° structure name ER-alpha MCF7 HCS EC5o (μΜ) CL-EM [M+H]+ 403 F f oh HF~YJ f (S)-3-((1R,3R)-1-(2,6difluoro-4-(2-(3-(fluoromethyl)azetide¡n-1-¡l)ethoxy)phenyl)-3-meth¡l-3,4-dihydro1H-pyrido[3,4-b]¡ndol-2(9H)-yl-fluoro-propanel-2(9H) 0.00013 520.3 404 __ __ / E z N 1 FH / = / ' -x FN— / 3 / -- / / VN- / N-(3,5-difluoro-4-((1R,3R)-2(2-fluoro-2-methylpropyl)-3methyl-2,3,4,9-tetrahide ro-1Hp¡r¡do[3,4-b]indol-1-yl)phenyl)1-(3-fluoropropyl)-Nmethylazetidine-3-amine 0.000745 517.3 405 _ / Fy N 1 FH zV NH ? F (R)-N-(4-(2-(2,2-difluoroethyl)-3,3-dimethyl-2,3,4,9tetrahydro-1 H-pyrido[3,4b]indol-1-yl)-3,5-difluorophenyl)-1-(3-fluoropropyl)azetidine-3-amine 0.002377 MA / a / zuzz / uu iy ιo 109 η° structure name ER-alpha MCF7 HCS EC5o (μΜ) CL-EM [M+H]+ 406 Q <j>f η Λ- / FV / NH F (S)-N-(4-(2-(2,2-difluoro-ethyl)3,3-dimethyl-2,3,4,9tetrahydro-1 H-pyrido[3,4b]indol-1-yl)-3,5-d¡fluorophenyl)-1-(3-fluoropropyl)azetidine-3-amine 0.0018 507.3 407 F rÁ F\ / f FN 1 FH O- / NH 2 F N-(3,5-difluoro-4-((1R,3R)-5fluoro-3-methyl-2-(2,2,2trifluoroethyl)-2,3,4,9-tetrahydro-1 H-pyrido[3,4-b]-indole1-¡l)phenyl)-1-(3fluoropropyl)azetidine-3amine 0.00012 529.2 408 F oÁ — / F\ / FFH TV FV / NH / F N-(3,5-difluoro-4-((1S,3S)-5fluoro-3-methyl-2-(2,2,2trifluoroethyl)-2,3,4,9-tetrah hydro-1 H-pyrido[3,4-b]-indole1-¡l)phenyl)-1-(3fluoropropyl)azetidine-3amine 0.0063 529.2 ΜΛ / a / zuzz / uu iy ιo 110 <h2 style=";text-align:left;direction:ltr">n° estructura number ER-alfa MCF7 HCS EC5o (μΜ) CL-EM [M+H]+ 409 F fhy— / F vJ NH F N-(3,5-difluor-4-((1S,3S)-8fluor-3-metil-2-(2,2,2trifluoretil)-2,3,4,9-tetrahidro-1 H-pirido[3,4-b]-¡ndol1-¡l)fenil)-1-(3fluorpropil)azetidina-3amina 0.026 529.2 410 VF / ^N 3 FFH / — / NH 7 F N-(3,5-difluor-4-((1R,3R)-8fluor-3-metil-2-(2,2,2trífluoretil)-2,3,4,9-tetrahidro-1 H-pirido[3,4-b]-ndol1-l)fenil)-1-(3fluorpropyl)azetidine-3amin 0.00012 529.2 411 O—i 57 L (1R,3R)-1-(2,6-difluor-4-(1-(3-fluorpropyl)azetidin-3-loxi)fenil)-2-((3-fluoroxetan-3-il)metil)-3-metil-2,3,4,9-tetrahydro-1 H-pirido[3,4-b]ndol 0.00007 518.3<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> I'm fine<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> 111<h2 style=";text-align:left;direction:ltr"> η° structure name ER-alpha MCF7 HCS EC50 (μΜ) CL-EM [M+H]+ 412 / ΤΧ / —f \Ζ^0Η faJAL / AFF Η Λ— / F vJ NH AF (S)-3-((1S,3S)-1-(2,6difluoro-4-((1-(3-fluoropropyl)azetid¡n-3-¡l)amino)phenyl)-7-fluoro-3-meth¡l3,4-dihydro-1 H-pyrido[3,4b]indol-2(9H-2-methyl-propanel-2) 0.0013 537.3 413 / ΓΆ / —\ V~~0H N 3 FH z— / NH nA ? F (R)-3-((1R,3R)-1-(2,6difluoro-4-((1-(3-fluoropropyl)azetidine-3-yl)amino)phen¡l)-7-fluoro-3-methyl3,4-dihydro-1 H-pyrido[3,4b]indol-2(9H)-yl)-2-fluoro-2-propanol-2-yl 0.000018 537.3 414 / T\ / —\ \Z~~0H fXJ£n^f N 3 FH z— / F^J NH A ? F (S)-3-((1R,3R)-1-(2,6difluoro-4-((1-(3-fluoropropyl)azetidine-3-yl)amino)phenyl)-7-fluoro-3-met¡l3,4-dihydro-1 H-pyrido[3,4b]indol-2(9H)-yl)-2-methyl-2-fluoro-1-yl-propanyl 0.00012 537.3 ΜΛ / a / zuzz / uu iy ιo 112 n° structure name ER-alpha MCF7 HCS EC5o (µΜ) CL-EM [M+H]+ 415 AA / A' Voh N^XF Η Λ-Ζ F vJ NH nJ F (R)-3-((1S,3S)-1-(2,6- difluor-4-(1-(3-(1-fluor-) propyl)azetide¡n-3-¡l)- amino)phenyl)-7-fluoro-3-meth¡l- 3,4-dihydro-1 H-pyrido[3,4b]indol-2(9H)-yl)-2-fluoro-2methylpropan-1-ol 0.0095 537.3 / 4 / _ F / \-F / \-F vfLyN^FN 1 FHA / NH F 3-((1 R,3R)-1-(2,6-difluoro-4((1 -(3-f I uorpropyl)-azetide in3-yl)amino)phenyl)-5-fluoro-3methyl-3,4-d¡hydro-1 H- pyrido[3,4-l-b-l-2) 2,2-difluoropropane-1-ol 0.000024 541.2 417 FJF / =\ / —c WOH N'Z \ F Η V / F vj NH ? F 3-((1S,3S)-1-(2,6-difluoro-4((1 -(3-f I uorpropyl)-azetide in3-¡l)amino)phenyl)-5-fluoro-3methyl-3,4-dih¡dro-1 Hpindo[3,4-b]-indole-2(9H)-ylpropane-1 0.0033 541.2 iviA / a / ¿u¿¿ / uu iy ιo 113 n° structure name ER-alpha MCF7 HCS EC5o (μΜ) CL-EM [M+H]+ 418 OH \ Ώ^Χ N—ZN 3 F Η Z— / F~Yj NH ίϊ F (R)-3-((1R,3R)-1-(2,6difluoro-4-((1-(3-fluoropropyl)azetidine-3-yl)amino)phen¡l)-3-methyl-3,4dihydro-1 H-pyrido[3,4-b]indol-2(9H)-yl)-2-fluoro-2(hydroxymet¡l)propano-n¡tr¡lo 0.000033 530.3 419 OH W—¿ ' F]V^ N-~ZN 3 F Η Z—Z NH 0 · ? F (S)-3-((1R,3R)-1-(2,6difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phen¡l)-3-met¡l-3,4dihydro-1 H-pyrido[3,4-b]indol-2(9H)-yl)-2-fluoro-2(hydrox¡meth¡l)propano-n¡tr¡lo 0.000026 530.3 420 F _ / --Y \Z~~~OH (í^y^^N ^ZFN 8 FYZ F' YH? (R)-3-(1-(2,6-difluoro-4-((1(3-fluoropropyl)azetid¡n-3yl)amino)phen¡l)-3,3-d¡meth¡l3,4-dihydro-1 H-pyrido[3,4b]indol-2(9H)-yl)-2,2difluoro-propane-10,017 537.3 iviA / a / ¿u¿¿ / uu iy ιo 114 η° structure name ER-alpha MCF7 HCS EC50 (μΜ) CL-EM [M+H]+ 421 F _ \ V~0H FF hy— / F VJ NH ? F (S)-3-(1-(2,6-difluoro-4-((1(3-fluoropropyl)azetidin-3yl)amino)phen¡l)-3,3-dimeth¡l3,4-dihydro-1 H-pyrido[3,4b]indol-2(9H)-yl)-2,2difluoro-propane-10006 537.3 422 Η F / —λ \Z^OH vO- / N^F / XN'y \ FF Η WF VV NH F 3-((1S,3S)-1-(2,6-difluoro-4((1 -(3-f I uorpropyl)-azetide in3-¡l)amino)phenyl)-8-fluoro-3methyl-3,4-dih¡dro-1 Hpindo[3,4-b]-¡ndol-2(9H)-yl)2,2-difluoropropane-1-ol 0.0371 541.2 423 / F _ / —-{ \ΥOH / ΡΝΉΜ zV NH ? F 3-((1 R,3R)-1-(2,6-difluoro-4((1 -(3-f I uorpropyl)-azetide in3-¡l)amino)phenyl)-8-fluoro-3methyl-3,4-dihydro-1 Hpyrido[3,4-b]¡ndole-2(9H)-l)2,¡l-difluoro-propane-1 0.000089 541.2 115 n° structure name ER-alpha MCF7 HCS EC5o (μΜ) CL-EM [M+H]+ 424 ΊΊ IZ TI Γγ A (1R,3R)-1-(2,6-difluoro-4-(1(3-fluoropropyl)azetidin-3¡loxi)phen¡l)-6,8-difluoro-2-(2fluoro-2-methylpropyl)-3-methyl2,3,4,9-tetrahydro-1 Hpyrido[3,4-b indole 0,50,50,50] 425 / F _ rr-X / —< VZOH N - F Η λ— / NH X i F 3-((1 R,3R)-1-(2,6-difluoro-4((1 -(3-f I uorpropyl)-azetide in3-¡l)amino)phenyl)-7-fluoro-3methyl-dih Hpyrido[3,4-b]-indol-2(9H)-yl)2,2-difluoropropan-1-ol 0.000021 541.3 426 VX0H fA41 / n^f F Η Λ— / FV / NH X ? F 3-((1S,3S)-1-(2,6-difluoro-4((1 -(3-f I uorpropyl)-azetide in3-¡l)amino)phenyl)-7-fluoro-3methyl-3,4-dih¡dro-1 Hpindo[3,4-b]-¡ndol-2(9,2,2,2)-Hpino-difluoro-1) 0.00638 541.2 iviA / a / ¿u¿¿ / uu iy ιό 116 n° structure name ER-alpha MCF7 HCS EC50 (μΜ) CL-EM [M+H]+ 427 ~YF\ / \ AVN 2 FHA / (1R,3R)-1-(2,6-difluor-4- ((1-((1-(fluoromethyl)cyclo- propyl)meth¡l)azet¡din-3¡l)oxy)phenyl)-2-(2-fluoro-2methylpropyl)-3-methyl-2,3,4,9tetrahydro-1 H-pyrido[3,4b]indole 0.000278 530.3 428 F > Va / —r F\ / Y ο / Y γ,Ν A (1R,3R)-1-(2,6-difluoro-4-(1(3-fluoropropyl)azetid¡n-3¡loxy)phenyl)-6,7-d¡fluoro-2-(2fluoro-2-methylpropyl)-3-methyl2,3,4,9-tetrahydro-1Hendopido[3,4,b] 0.0007 540.3 429 / / F αV / 4N (1R,3R)-2-(2-fluoro-2methylpropyl)-1-(1-((1-(3fluoropropyl)azetidine-3¡l)methyl)-1 H-pyrazol-4-yl)-3methyl-2,3,9-trahydro,9-1-1 Hpyr¡do[3,4-b]indole 0.00099 456.3 430 e O-An-A N - FHAF NH A / F N-[4-[(1R,3R)-2-(2,2difluoroethyl)-3-meth¡l-1,3,4,9tetrahydropyrido[3,4-b]¡ndol-1-yl]-3,5-difluoro-phen¡l]1 -(3-f I uor propyl)-azetide in 3-amine 0.040.250 ΜΛ / a / zuzz / uu iy ιo 117 Administration of formula I compounds The compounds of the invention may be administered by any route appropriate to the disease state to be treated. Suitable routes include oral, parenteral (including subcutaneous, intramuscular, intravenous, intraarterial, intradermal, intrathecal, and epidural), transdermal, rectal, nasal, topical (including buccal and sublingual), vaginal, intraperitoneal, intrapulmonary, and intranasal administration. For local immunosuppressive treatment, the compounds may be administered intralesional, including by infusion, or by any other mode of contact between the graft and the inhibitor prior to transplantation. It will be appreciated that the preferred route may vary, for example, depending on the disease state of the recipient. When the compound is administered orally, it may be formulated as a pill, capsule, tablet, etc., together with a pharmaceutically acceptable carrier or excipient.When the compound is administered parenterally, it may be formulated together with a pharmaceutically acceptable parenteral vehicle and in a unit dosage injectable form, as detailed below. A dose for treating human patients may range from approximately 10 mg to 1000 mg of a compound of formula I. A typical dose may range from approximately 100 mg to 300 mg of the compound. The dose may be administered once daily (QID), twice daily (BID), or more frequently depending on the pharmacokinetic and pharmacodynamic properties, including absorption, distribution, metabolism, and excretion, of a particular compound. In addition, toxicity factors may influence the dosage and administration schedule. When administered orally, the pill, capsule, or tablet may be taken daily or less frequently for a specified period of time. The regimen may be repeated for a certain number of courses of therapy. Methods of treatment with compounds of formula I The compounds of formula I of the present invention are useful for treating a human or animal patient suffering from a disease or disorder resulting from abnormal cell growth, function, or behavior associated with USP7, for example an immune disorder, cardiovascular disease, viral infection, inflammation, metabolic or endocrine disorder, or neurological disorder, and may therefore be treated by a method comprising administering to the patient a compound of the present invention as defined above. An animal or human patient suffering from cancer may also be treated by a method comprising administering to the patient a compound of the present invention as defined above. The patient's condition may thereby be alleviated or ameliorated. The methods of the invention also include treating cancer chosen from breast cancer, ovarian cancer, cervical cancer, prostate cancer, testicular cancer, genitourinary tract cancer, esophageal cancer, laryngeal cancer, glioblastoma, neuroblastoma, stomach cancer, skin cancer, keratoacanthoma, lung cancer, squamous cell carcinoma, large cell carcinoma, non-small cell lung carcinoma (NSCLC), small cell carcinoma, lung adenocarcinoma, bone cancer, colon cancer, adenoma, pancreatic cancer, adenocarcinoma, thyroid cancer, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, sarcoma, bladder carcinoma, liver carcinoma, and bile duct cancer, kidney carcinoma, ινΐΛ / a / zuzz / uu / and ic 118 pancreatic cancer, myeloid disorders, lymphoma, hairy cell cancer, oral cavity cancer, nasopharyngeal cancer, pharynx cancer, lip cancer, tongue cancer, mouth cancer, small intestine cancer, colorectal cancer, large intestine cancer, rectum cancer, brain and central nervous system cancer, Hodgkin's cancer, leukemia, bronchial cancer, thyroid cancer, liver cancer, intrahepatic bile duct cancer, hepatocellular cancer, gastric cancer, glioma / glioblastoma, endometrial cancer, melanoma, kidney and renal pelvis cancer, urinary bladder cancer, corpus uteri cancer, cervix cancer, multiple myeloma, acute myelogenous leukemia, chronic myelogenous leukemia, lymphocytic leukemia, chronic lymphocytic leukemia (CLL), myeloid leukemia, oral cavity and pharynx cancer, non-Hodgkin's lymphoma Hodgkin, melanoma, and villous adenoma of the colon. Pharmaceutical formulations In order to employ a compound of this invention for the therapeutic treatment of mammals, including humans, it will normally be formulated according to standard pharmaceutical practice as a pharmaceutical composition. According to this aspect of the invention, there is provided a pharmaceutical composition containing a compound of this invention in association with a pharmaceutically acceptable carrier or diluent. A typical formulation is made by mixing a compound of formula I and a carrier, diluent, or excipient. Suitable carriers, diluents, or excipients are known to those of skill in the art and include materials such as carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like. The particular carrier, diluent, or excipient to be used will depend upon the media and purpose for which the compound of the present invention will be applied. Solvents are generally selected from those solvents recognized by those of skill in the art as safe (GRAS) for administration to a mammal. In general, safe solvents are nontoxic aqueous solvents, for example, water, and other nontoxic solvents that are soluble or miscible in water. Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycols (e.g. PEG 400, PEG 300), etc. and mixtures thereof.The formulations may further include one or more buffers, stabilizing agents, surfactants, humectants, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifying agents, lubricants, processing aids, colorants, sweeteners, fragrances, flavorings, and other known additives to provide the drug product with an elegant presentation (drug is the compound of the present invention or a pharmaceutical composition containing it) or to facilitate the manufacture of the pharmaceutical product (i.e., medicament). The formulations can be manufactured by conventional dissolution and mixing processes. For example, the bulk drug substance (i.e., the compound of the present invention or a stabilized form of the compound of formula I (e.g., a complex with a cyclodextrin derivative or other known complexing agent)) is dissolved in an appropriate solvent in the presence of one or more excipients described above. The compound of the present invention is normally formulated in pharmaceutical dosage forms to provide an easily controllable dosage of the drug and to allow the patient to tolerate the prescribed regimen well. The pharmaceutical composition (or formulation) for application can be packaged in many ways depending on the method used to administer the drug. In general, a commercial article includes a IVIA / a / ¿U¿¿ / UU ÍXfO 119 container, which contains the pharmaceutical formulation in an appropriate form. Suitable containers are already known to those skilled in the art, and include materials such as bottles (plastic or glass), sachets, vials, plastic bags, metal cylinders, and the like. The container may also include a secure sealing assembly that prevents indiscreet access to the contents of the container. In addition, the container will have a label affixed to it describing its contents. The label may also include relevant warnings. Pharmaceutical formulations of the compounds of the present invention can be prepared for various routes and types of administration. For example, a compound of formula I, having the desired degree of purity, can optionally be mixed with pharmaceutically acceptable diluents, carriers, excipients or stabilizers (Remington's Pharmaceutical Sciences (1980) 16th edition, Osol, A., coord.), in the form of a lyophilized formulation, ground powder or aqueous solution. The formulation can be made by mixing, at room temperature and an appropriate pH, the compound of the invention of the desired degree of purity with physiologically acceptable carriers, that is, carriers that are nontoxic to the recipients at the doses and concentrations employed. The pH of the formulation will depend primarily on the specific use and the concentration of the compound, but can be between 3 and 8. The formulation in an acetate buffer at pH 5 is a suitable embodiment.

[0008] The compound may be stored in the ordinary manner in the form of a solid composition, a lyophilized formulation or an aqueous solution.

[0009] The pharmaceutical compositions of the invention will be formulated, dosed, and administered in a manner, i.e., in amounts, concentrations, regimens, sequence, vehicles, and routes of administration, consistent with good medical practice. Factors to be considered in this context include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the agent, the method of administration, the regimen of administration, and other factors well known to medical practitioners. The “therapeutically effective amount” of the compound to be administered should be governed by these considerations and is the minimum amount necessary to ameliorate or treat the hyperproliferative disorder.

[0010] As a general proposition, the initial pharmaceutically effective amount of the inhibitor to be administered parenterally will be in the range of about 0.01-100 mg / kg, i.e. about 0.1 to 20 mg / kg of the patient's body weight per day, with the typical initial range of the compound employed being about 0.3 to 15 mg / kg / day.

[0011] Acceptable diluents, carriers, excipients, and stabilizers are non-toxic to recipients at the doses and concentrations employed and include buffers such as phosphate, citrate, and other organic acids; antioxidants, including ascorbic acid and methionine; preservatives (e.g., octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride; phenol, butyl or benzyl alcohols; alkyl parabens, e.g., methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight peptides (less than about 10 residues); proteins, e.g., serum albumin, gelatin, or immunoglobulins; hydrophilic polymers, for example polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine or lysine; and 120 monosaccharides, disaccharides, and other carbohydrates, including glucose, mannose, or dextrins; chelating agents, such as EDTA; sugars such as sucrose, mannitol, trehalose, or sorbitol; salt-forming counterions, such as sodium; metal complexes (e.g., zinc-protein complexes); and / or non-ionic surfactants, such as TWEEN™, PLURONICS™, or polyethylene glycol (PEG). The active pharmaceutical ingredients may also be occluded within microcapsules prepared, for example, by coacervation or interfacial polymerization techniques, for example, of hydroxymethylcellulose or gelatin microcapsules and poly(methyl methacrylate) microcapsules, respectively, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nanoparticles and nanocapsules) or in macroemulsions. These techniques have been described in Remington's Pharmaceutical Sciences, 16th edition, Osol, A., coord. (1980).

[0012] Sustained-release preparations of the compounds of formula I may be prepared. Suitable examples of sustained-release preparations include semipermeable matrices of solid hydrophobic polymers containing a compound of formula I, said matrices being in the form of molded articles, e.g. sheets or microcapsules. Examples of sustained release matrices include polyesters, hydrogels (e.g., poly(2-hydroxyethyl methacrylate), or polyvinyl alcohol), polylactides (US 3773919), copolymers of L-glutamic acid and gamma-ethyl L-glutamate, non-degradable ethylene-vinyl acetate copolymers, degradable lactic acid-glycolic acid copolymers, e.g., LUPRON DEPOT™ (injectable microspheres composed of lactic acid-glycolic acid copolymers and leuprolide acetate), and poly-D-(-)3-hydroxybutyric acid.

[0013] Formulations include those suitable for the routes of administration detailed herein. The formulations may conveniently be presented in unit dosage form and may be manufactured by any of the methods well known in the art of pharmacy. Techniques and formulations will generally be found in Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, PA). Such methods include the step of bringing into association the active ingredient and the carrier, which constitutes one or more accessory ingredients. In general, formulations are manufactured by bringing the active ingredient and liquid carriers or finely divided solid carriers, or both, into uniform and intimate association, and then, if necessary, molding the product.

[0014] Formulations of a compound of formula I suitable for oral administration may be manufactured in the form of discrete units, such as pills, capsules, cachets or tablets, each of which contains a predetermined amount of a compound of formula I. Compressed tablets may be manufactured in a suitable machine by compressing the active ingredient in a free-flowing form, for example powders or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface active agent or dispersing agent. Molded tablets may be manufactured by molding in a suitable machine a mixture of the powdered active ingredient moistened with a liquid inert diluent. The tablets may optionally be coated or impregnated and may optionally be formulated to provide slow or controlled release of the active ingredient therefrom.Tablets, lozenges, lozenges, aqueous suspensions or ινΐΛ / a / zuzz / uu zazo. 121 oily, dispersible powders or granules, emulsions, hard or soft capsules, e.g. gelatin capsules, syrups or elixirs may be manufactured for oral use. Formulations of compounds of formula I intended for oral use may be manufactured according to any method known in the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents, including sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide a palatable preparation. Tablets containing the active ingredient in admixture with a non-toxic pharmaceutically acceptable excipient suitable for the manufacture of tablets are acceptable.These excipients may be, for example, inert diluents, such as calcium or sodium carbonate, lactose, calcium or sodium phosphate; granulating and disintegrating agents, for example, corn starch or alginic acid; binding agents, for example, starch, gelatin, or acacia; and lubricating agents, for example, magnesium stearate, stearic acid, or talc. The tablets may be uncoated or may be coated by known techniques, including microencapsulation, to delay disintegration and absorption in the gastrointestinal tract and thus provide a sustained action over a longer period. For example, a time-delay material such as glyceryl monostearate or glyceryl distearate, alone or with a wax, may be used.

[0015] For treatment of the eyes or other external tissues, e.g. the mouth or skin, the formulations may be applied in the form of a topical ointment or cream containing the active ingredient(s) in an amount, for example, from 0.075 to 20% w / w. If formulated in an ointment, the active ingredients may be employed in a paraffinic or water-miscible ointment base. Alternatively, the active ingredients may be formulated in a cream with an oil-in-water base. If desired, the aqueous phase of the cream base may include a polyhydric alcohol, i.e., an alcohol having two or more hydroxyl groups, for example propylene glycol, butane-1,3-diol, mannitol, sorbitol, glycerol, and polyethylene glycol (including PEG 400), and mixtures thereof. Topical formulations may desirably include a compound that enhances absorption or penetration of the active ingredient through the skin or other affected areas.Examples of such dermal penetration enhancers include dimethyl sulfoxide and related analogues. The oil phase of the emulsions of this invention may be constituted from the known ingredients in a known manner. The phase may contain merely an emulsifier, but desirably it will contain a mixture of at least one emulsifier with a fat or an oil or with both the fat and the oil. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier, which acts as a stabilizer. Also preferred is the inclusion of both an oil and a fat. Together, the emulsifier(s) with or without stabilizer(s) constitute the so-called emulsifying wax, and the wax together with the oil and fat constitute the so-called emulsifying ointment, which forms the oily dispersed phase of the cream-type formulations.Emulsifiers and emulsion stabilizers suitable for use in the formulation of the invention include Tween® 60, Span® 80, cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl monostearate, and sodium lauryl sulfate.

[0016] Aqueous suspensions of the compounds of formula I contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients include ινΐΛ / a / zuzz / uu / and ιό 122 a suspending agent, for example sodium carboxymethylcellulose, croscarmellose, povidone, methylcellulose, hydroxypropyl methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia and dispersing or wetting agents, for example naturally occurring phosphatides (e.g. lecithin), a condensation product of an alkylene oxide with a fatty acid (e.g. polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g. heptadecaethyleneoxycetanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride (e.g. polyoxyethylene sorbitol monooleate). The aqueous suspension may also contain one or more preservatives, for example ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, for example sucrose or saccharin.

[0017] Pharmaceutical compositions of compounds of formula I may be presented in the form of a sterile injectable preparation, for example, a sterile injectable aqueous or oleaginous suspension. Such a suspension may be formulated according to known techniques using appropriate dispersing or wetting agents and suspending agents as mentioned above. The sterile injectable preparation may also take the form of a sterile injectable solution or suspension in a non-toxic, parenterally acceptable diluent or solvent, for example, a solution in 1,3-butanediol, or be prepared as a lyophilized powder. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils may be employed in the conventional manner as the solvent or suspending medium.Any mild fixed oil can be used for this purpose, including synthetic mono- and diglycerides. Fatty acids, such as oleic acid, can also be used for the manufacture of injectables.

[0018] The amount of active ingredient that can be combined with the carrier material to produce a unit dosage form may vary depending on the host being treated and the particular mode of administration. For example, a delayed release formulation intended for oral administration to humans may contain about 1 to 1000 mg of active material in admixture with an appropriate and convenient amount of carrier material, which may vary from about 5 to 95% of the total composition (by weight). The pharmaceutical composition may be manufactured to provide readily measurable quantities for administration. For example, an aqueous solution intended for intravenous infusion may contain about 3 to 500 µg of active ingredient per milliliter of solution so that infusion of a suitable volume may be accomplished at a rate of about 30 ml / hr.

[0019] Formulations suitable for parenteral administration include sterile aqueous and non-aqueous injectable solutions, which may contain antioxidants, buffers, bacteriostatic substances, and solutes that render the formulation isotonic with the blood of the intended recipient; and sterile aqueous and non-aqueous suspensions, which may include suspending agents and thickening agents.

[0020] Formulations suitable for topical administration to the eyes include drops, in which the active ingredient is dissolved or suspended in an appropriate vehicle, in particular a solvent. 123 aqueous for the active ingredient. The active ingredient is preferably present in such formulations in a concentration of approximately 0.5 to 20% w / w, for example 0.5 to 10% w / w, for example around 1.5% w / w.

[0021] Formulations suitable for topical oral administration include lozenges, which contain the active ingredient in a flavored base, usually sucrose and acacia or tragacanth; lozenges containing the active ingredient in an inert base, for example gelatin and glycerin or sucrose and acacia; and mouthwashes containing the active ingredient in a suitable liquid vehicle.

[0022] Formulations for rectal administration may be presented in the form of a suppository with an appropriate base containing, for example, cocoa butter or a salicylate.

[0023] Formulations suitable for intrapulmonary or nasal administration have a particle size in the range of, for example, 0.1 to 500 microns (including particle sizes within the range of 0.1 to 500 microns in micron increments such as 0.5, 1, 30 microns, 35 microns, etc.), which is administered by rapid inhalation through the nostrils or by inhalation through the mouth so as to reach the pulmonary alveoli. Suitable formulations include aqueous or oleaginous solutions of the active ingredient. Formulations suitable for aerosol or dry powder administration may be manufactured according to conventional methods and may be administered in conjunction with other therapeutic agents, such as those compounds previously used for the treatment or prophylaxis of disorders as described below.

[0024] Formulations suitable for vaginal administration may be presented in the form of lozenges, lozenges, creams, gels, pastes, foams or sprays, which in addition to the active ingredient contain the appropriate vehicles, already known in the art.

[0025] The formulations may be packaged in single-dose or multi-dose packages, for example in sealed ampoules and vials, and may be stored in a lyophilized state, requiring only the addition of the sterile liquid vehicle, for example water, for injection immediately before use. Solutions and suspensions for extemporaneous injection are manufactured from sterile powders, granules and tablets of the type described above. Preferred unit dose formulations are those containing a daily dose or a daily unit sub-dose, as mentioned above, or an appropriate fraction thereof, of the active ingredient.

[0026] The invention further provides veterinary compositions containing at least one active ingredient, as defined above, together with a veterinary carrier therefor. Veterinary carriers are materials useful for the purpose of administering the composition and may be solid, liquid or gaseous materials, which are otherwise inert or acceptable for veterinary use and are compatible with the active ingredient. These veterinary compositions may be administered parenterally, orally or by any other desired route.

[0027] Combination therapy

[0028] The compounds of formula I can be used alone or in combination with other therapeutic agents for the treatment of a disease or disorder described herein, for example an inflammation. MΛ / a / ZUZZ / UU fUfO 124 or a hyperproliferative disorder (e.g., cancer). In certain embodiments, a compound of formula I is combined in a combination pharmaceutical formulation, or in a dosage regimen as combination therapy, with a second compound that has anti-inflammatory or antiproliferative properties or is useful for treating an inflammatory, immune response, or hyperproliferative disorder (e.g., cancer). The additional therapeutic agent can be a Bcl-2 inhibitor, a JAK inhibitor, a PI3K inhibitor, an mTOR inhibitor, an anti-inflammatory agent, an immunomodulatory agent, a chemotherapeutic agent, an apoptosis enhancer, a neurotropic factor, an agent for treating cardiovascular disease, an agent for treating liver disease, an antiviral agent, an agent for treating hematological disorders, an agent for treating diabetes, and an agent for treating immunodeficiency disorders.The second therapeutic agent may be an NSAID anti-inflammatory agent. The second therapeutic agent may be a chemotherapeutic agent. The second therapeutic agent in the combination pharmaceutical formulation or dosage regimen preferably has activities complementary to those of the compound of formula I such that they do not adversely interact with each other. Such compounds are conveniently present in combination in amounts that are effective for the intended purpose. In one embodiment, a composition of this invention contains a compound of formula I or a stereoisomer, tautomer, solvate, metabolite, or a pharmaceutically acceptable salt or prodrug thereof, in combination with a therapeutic agent, for example, an NSAID.

[0029] The combination therapy may be administered in a simultaneous or sequential regimen. If administered sequentially, the combination may be administered in two or more administrations. Combined administration includes coadministration, using separate formulations or a single pharmaceutical formulation, and sequential administration in any order, preferably with a period of time during which both (or all) active agents exert their biological activities simultaneously.

[0030] The ideal doses for any of the previously co-administered agents are those currently used and may be reduced due to the action of the combination (synergism) of the newly identified agent and the other chemotherapeutic agents or treatments.

[0031] Combination therapy may provide “synergism” and demonstrate “synergistic” quality, that is, the effect achieved when the active ingredients are used concurrently is greater than the sum of the effects obtained when the compounds are used separately. A synergistic effect may be obtained when the active ingredients are: (1) co-formulated and administered or delivered simultaneously in a unit-dose combination formulation; (2) delivered alternately or in parallel as separate formulations; or (3) delivered by another regimen. If administered in alternating therapy, the synergistic effect may be achieved when the compounds are administered or delivered successively, e.g., by different injections with separate syringes, separate pills or capsules, or separate infusions.In general, during alternating therapy, an effective dose of each active ingredient is administered successively, i.e., one after the other, while in combination therapy, effective doses of two or more active ingredients are administered together. ML / a / zuzz / uu iyio 125

[0032] In a particular embodiment of the anticancer therapy, a compound of formula I, or a stereoisomer, tautomer, solvate, metabolite, or a pharmaceutically acceptable salt or prodrug thereof, may be combined with other chemotherapeutic agents, hormonal agents, or antibodies, for example those described herein, and may also be combined with surgical therapy or radiotherapy. The combination therapies according to the present invention thus consist of the administration of at least one compound of formula I, or a stereoisomer, geometrical isomer, tautomer, solvate, metabolite, or a pharmaceutically acceptable salt or prodrug thereof and the use of at least one other additional method for the treatment of cancer. The amounts of the compound(s) of formula I and the other pharmaceutically active agent(s) and the relative time regimens of administration will be chosen to achieve the desired combined therapeutic effect. In some embodiments, a compound of formula I or a pharmaceutically acceptable salt thereof is employed in combination with an aromatase inhibitor, a phosphoinositide 3-kinase (PI3K) - mTOR pathway inhibitor, a CDK 4 / 6 inhibitor, a HER-2 inhibitor, an EGFR inhibitor, a PD-1 inhibitor, a poly ADP-ribose polymerase (PARP) inhibitor, a histone deacetylase (HDAC) inhibitor, an HSP90 inhibitor, a VEGFR inhibitor, an AKT inhibitor, a chemotherapeutic agent, or any combination thereof. In some embodiments, a pharmaceutical composition containing a compound of formula I or a pharmaceutically acceptable salt thereof is administered in combination with a therapeutic agent selected from paclitaxel, anastrozole, exemestane, cyclophosphamide, epirubicin, fulvestrant, letrozole, gemcitabine, trastuzumab (HERCEPTIN®, Genentech), trastuzumab emtansine (KADCYLA®, Genentech), pegfilgrastim, filgrastim, tamoxifen, docetaxel, toremifene, vinorelbine, capecitabine, and ixabepilone. In some embodiments, a compound of formula I or a pharmaceutically acceptable salt thereof is used in combination with hormone blocking therapy, chemotherapy, radiation therapy, monoclonal antibodies, or combinations thereof. Hormone blockade therapy includes the use of agents that block estrogen production or that block estrogen receptors. In some embodiments, hormone blockade therapy includes the use of estrogen receptor modulators and aromatase inhibitors. Estrogen receptor modulators include triphenylethylene derivatives (e.g., tamoxifen, toremifene, droloxifene, 3-hydroxytamoxifen, idoxifene, TAT-59 (a phosphorylated derivative of 4-hydroxytamoxifen), and GW5638 (a carboxylic acid derivative of tamoxifen)); nonsteroidal estrogen receptor modulators (e.g., raloxifene, LY353381 (SERM3), and LY357489); steroidal estrogen receptor modulators (e.g., ICI-182,780). Aromatase inhibitors include steroidal aromatase inhibitors and nonsteroidal aromatase inhibitors. Steroidal aromatase inhibitors include, but are not limited to, exemestane.Nonsteroidal aromatase inhibitors include, but are not limited to, anastrozole and letrozole. In some embodiments, a compound of formula I or a pharmaceutically acceptable salt thereof is administered in combination with a CDK 4 / 6 inhibitor. In some embodiments, the CDK 4 / 6 inhibitor is administered in combination with a compound of formula I or a pharmaceutically acceptable salt thereof. 126 CDK 4 / 6 inhibitor is palbociclib (PD-0332991), ribociclib (LEE011), or LY283519. In some embodiments, the CDK 4 / 6 inhibitor is LEE011. In some embodiments, ribociclib (LEE011) is administered at a dose of about 10 mg / day to 1,000 mg / day. In some embodiments, LEE011 is administered at a dose of about 400 mg / day, about 500 mg / day, or about 600 mg / day. In some embodiments, the daily dose of LEE011 is administered orally. In some embodiments, the daily dose of ribociclib (LEE011) is administered orally once daily for three weeks, followed by a one-week drug-free period during which ribociclib (LEE011) is not administered. In some embodiments, a compound of formula I or a pharmaceutically acceptable salt thereof is administered in combination with an inhibitor of the phosphoinositide 3-kinase (PI3K) - mTOR pathway. In some embodiments, the phosphoinositide 3-kinase (PI3K) - mTOR pathway inhibitor is everolimus, temsirolimus, BEZ235 (dactolisib), BIL719 (alpelisib), GDC0032 (taselisib), BKM120 (buparlisib), BGT226, GDC0068 (ipatasertib), GDC-0980 (apitolisib), GDC0941 (pictilisib), INK128 (MLN0128), INK1117, OSI-027, CC-223, AZD8055, SAR245408, SAR245409, PF04691502, WYE125132, GSK2126458, GSK-2636771, BAY806946, PF-05212384, SF1126, PX866, AMG319, ZSTK474, Cal101 (idelalisib), PWT33597, CU-906, AZD-2014, or CUDC-907. In some embodiments, the phosphoinositide 3-kinase (PI3K) - mTOR pathway inhibitor is everolimus. In some embodiments, everolimus is administered at a dose of approximately 1 mg / day to 20 mg / day.In some embodiments, everolimus is administered at a dose of about 2.5 mg per day, about 5 mg per day, or about 10 mg per day. In some embodiments, the daily dose of everolimus is administered once daily. In some embodiments, the phosphoinositide 3-kinase (PI3K) - mTOR pathway inhibitor is BKM120 (buparlisib). In some embodiments, BKM120 (buparlisib) is administered at a dose of about 5 mg per day to 500 mg per day. In some embodiments, BKM120 is administered at a dose of about 50 mg per day to 100 mg per day. In some embodiments, BKM120 is administered at a dose of about 100 mg per day. In some embodiments, the daily dose of BKM120 is administered once daily. In some embodiments, the phosphoinositide 3-kinase (PI3K) - mTOR pathway inhibitor is BIL719. In some embodiments, BIL719 is administered at a dose of approximately 25 mg / day to 1000 mg / day.In some embodiments, BIL719 is administered at a dose of approximately 250 mg per day or 350 mg per day. In some embodiments, the daily dose of BIL719 is administered once a day. Metabolites of compounds of formula I

[0033] Also encompassed within the scope of this invention are “in vivo” metabolic products of formula I as described herein. Such products may result, for example, from oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic decomposition, and the like, of administered compounds. Accordingly, the invention includes metabolites of compounds of formula I, including compounds produced in a process comprising contacting a compound of this invention with a mammal for a period of time sufficient to form a metabolic product thereof. ινΐΛ / a / zuzz / uu / a 127

[0034] Metabolic products are typically identified by separating a compound of the invention labeled with a radioisotope (e.g., C14 or H3), administering it parenterally in a detectable dose (e.g., greater than about 0.5 mg / kg) to an animal such as a rat, mouse, guinea pig, ape, or man, allowing sufficient time for metabolism to occur (usually from about 30 seconds to 30 hours), and isolating its conversion products from urine, blood, or other biological samples. These products are easily isolated because they are labeled (others are isolated using antibodies capable of binding to surviving epitopes on the metabolite). Metabolic structures are determined by conventional methods, e.g., by MS, LC-MS, or NMR analysis. In general, metabolite analysis is performed by the same method as conventional drug metabolism studies, which are well known to those skilled in the art.Metabolic products, provided they are not otherwise found "in vivo", may be useful for diagnostic assays intended to determine the therapeutic dose of the compounds of the invention.

[0035] Industrially manufactured articles

[0036] In another embodiment of the invention, there is provided an article of manufacture or "kit" containing materials useful for treating the above-described diseases and disorders. In one embodiment, the kit contains a container, wherein a compound of formula I or a stereoisomer, tautomer, solvate, metabolite, or pharmaceutically acceptable salt or prodrug thereof is packaged. The kit may further have a label or package insert, affixed to or attached to the container. The term "package insert" is used herein to refer to the instructions typically included in commercially available packages of therapeutic products, containing information concerning the indications, use, dosage, administration, contraindications, and / or warnings relating to the use of such therapeutic products. Suitable packages include, for example, bottles, vials, syringes, blister packs, etc.The container or vessel may be made of a variety of materials, for example, glass or plastic. The container may hold a compound of formula I or a formulation thereof that is effective for treating a disease state and may have a sterile access port (for example, the container may be an intravenous solution bag or a vial having a stopper pierceable with a hypodermic injection needle). At least one active agent of the composition will be a compound of formula I. The label or package insert indicates that the composition is used to treat the disease state in question, for example, cancer. In addition, the label or package insert may indicate that the patient to be treated is one suffering from a disorder, for example, a hyperproliferative disorder, neurodegeneration, cardiac hypertrophy, pain, migraine, or a neurotraumatic disease or event.In one embodiment, the label or package insert indicates that the composition containing a compound of formula I can be used to treat a disorder resulting from abnormal cell growth. The label or package insert may also indicate that the composition can be used to treat other disorders. Alternatively or additionally, the article of manufacture may contain a second container or package that houses a pharmaceutically acceptable buffer, for example, bacteriostatic water for injection (BWFI), phosphate-buffered saline, Ringer's solution, and dextrose solution. It may also include other materials. MA / a / zuzz / uu iyio 128 undesirable from a commercial or user point of view, including other flasks, diluents, filters, needles and syringes.

[0037] The kit may further contain directions for administration of the compound of formula I and, if present, a second pharmaceutical formulation. For example, if the kit comprises a first composition containing a compound of formula I and a second pharmaceutical formulation, then the kit may further contain directions for simultaneous, sequential, or separate administration of the first and second pharmaceutical compositions to the patient in need thereof.

[0038] In another embodiment, kits are suitable for the provision of oral solid dosage forms of a compound of formula I, for example, tablets or capsules. Such a kit preferably includes a large number of unit doses. Such kits may include a card having the doses oriented in the order of their intended use. An example of such a kit is a "blister pack." Blister packs are well known in the packaging industry and are widely used for the packaging of unit dose dosage forms. If desired, a memory aid, for example in the form of numbers, letters, or other markings, or a calendar insert, may be provided on which the days of the treatment regimen on which the doses may be administered are noted.

[0039] In one embodiment, a kit may comprise (a) a first container containing a compound of formula I; and optionally (b) a second container containing a second pharmaceutical formulation, said second pharmaceutical formulation containing a second compound with anti-hyperproliferative activity. Alternatively or additionally, the kit may further contain a third container containing a pharmaceutically acceptable buffer, for example bacteriostatic water for injection (BWFI), phosphate buffered saline, Ringer's solution, and dextrose solution. It may also include other commercially or user desirable materials, including other bulbs, diluents, filters, needles, and syringes.

[0040] In certain further embodiments, where the kit contains a composition of formula I and a second therapeutic agent, the kit may contain a container for housing separate compositions, for example a divided bottle or a divided foil packet, however, the separate compositions may also be housed within a single undivided container. Typically, the kit contains directions for administration of the separate components. The kit form is especially advantageous when the separate components are preferably administered in different dosage forms (e.g., oral and parenteral), are administered at different dosage intervals, or when the prescribing physician desires to titrate the individual components of the combination.

[0041] Obtaining the compounds of formula I

[0042] The compounds of formula I can be obtained by synthetic methods that include processes similar to those that are well known in organic chemistry, in particular in light of the description contained herein and those of other heterocycles, which are described in: Comprehensive Heterocyclic Chemistry II, coordinated by Katritzky and Rees, Elsevier, 1997, e.g. volume 3; Liebigs Annalen der Chemie 9,1910-16,1985; Helvetica Chimica IVIA / a / ¿U¿¿ / UU ÍXfO 129 Acta 41,1052-60,1958; Arzneimittel-Forschung, 40(12), 1328-31,1990; each of which is expressly incorporated herein by reference. Starting materials are generally available from commercial suppliers, e.g., from Aldrich Chemicals (Milwaukee, WI), or are compounds obtainable by methods well known to those skilled in the art (e.g., by the general methods described by Louis F. Fieser and Mary Fieser, Reagents for Organic Synthesis, 1-23, Wiley, NY (ed. 1967-2006), or in Beilstein's Handbuch der organischen Chemie, 4th ed., Springer, Berlin, including supplements (also available through Beilstein's on-line database). Synthetic chemical transformations and protecting group methodologies (protection and deprotection) useful for the synthesis of compounds of formula I and the necessary reagents and intermediates are well known in the art and include, for example, those described in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 3rd ed., John Wiley & Sons (1999); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley & Sons (1995) and subsequent editions thereof.

[0043] The compounds of formula I may be obtained individually or in the form of compound libraries containing at least 2, for example 5 to 1,000 compounds or 10 to 100 compounds. Libraries of compounds of formula I may be obtained by a combinatorial "cut and mix" strategy or by multiple parallel syntheses, employing solution phase or solid phase chemistry, or by methods well known to those skilled in the art. Thus, according to another aspect of the invention there is provided a compound library containing at least 2 compounds or pharmaceutically acceptable salts thereof.

[0044] The examples provide illustrative methods for obtaining the compounds of formula I. Those skilled in the art will appreciate that other synthetic methods may be applied to obtain the compounds of formula I. Although the specific starting materials and reagents are depicted in the figures and examples, they may be substituted with other starting materials and reagents to obtain a wide variety of derivatives and / or reaction conditions. In addition, many of the compounds obtained by the methods described below may be further modified in light of this disclosure by applying conventional chemistry, which is well known to those skilled in the art.

[0045] In order to obtain the compounds of formula I, protection of remote functional groups (e.g., primary or secondary amines) of the intermediates may be necessary. The need for such protection may vary depending on the nature of the remote functional group and the conditions of the preparation methods. Suitable groups for protecting the amino group include acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBz), and 9-fluorenimethyleneoxycarbonyl (Fmoc). The need for such protection will be readily determined by those skilled in the art. For a general description of protecting groups and their use, see T.W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991.

[0046] In the methods of obtaining the compounds of this invention, it may be advantageous iviA / a / zuzz / uu / and / □ 130 separate the reaction products from each other and / or from the starting materials. The desired products from each step or series of steps are separated and / or purified (subsequently separated) to the desired degree of homogeneity by standard chemical techniques. Typically, separations of this type involve multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography. Chromatography encompasses a wide range of methods, including, for example, reversed-phase and normal-phase methods; size exclusion; ion exchange; high-, medium-, and low-pressure liquid chromatography methods and apparatus; small analytical scale; simulated moving bed (SMB) and thin-layer or thick-layer chromatography; as well as small-scale techniques for thin-layer chromatography and flash chromatography.

[0047] Another group of separation methods involves the treatment of a mixture with a reagent chosen to bind to or render separable a desired product, an unreacted starting material, a reaction by-product or the like. Such reagents include adsorbents and absorbents, for example activated carbon, molecular sieves, ion exchange media or the like. Alternatively, the reagents may be acids in the case of a basic material, bases in the case of an acidic material, binding reagents for example antibodies, binding proteins, selective chelators, for example crown ethers, liquid / liquid ion extraction (LIX) reagents or the like. The selection of appropriate separation methods will depend on the nature of the materials concerned.For example, boiling point and molecular weight in distillation and sublimation, the presence or absence of polar functional groups in chromatography, the stability of materials in acidic and basic media in multiphase extraction and the like.

[0048] Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physicochemical differences by methods well known to those skilled in the art, such as chromatography and / or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., a chiral auxiliary, such as a chiral alcohol or Mosher's acid chloride), by separating the diastereomers, and by converting (e.g., by hydrolysis) the individual diastereomers into the corresponding pure enantiomers. In addition, some of the compounds of the present invention may be atropisomers (e.g., substituted biaryls) and are considered as part of this invention. Enantiomers can also be separated by a chiral HPLC column.

[0049] An individual stereoisomer, e.g., an enantiomer, can be obtained substantially free of its stereoisomer by resolution of the racemic mixture using a method such as diastereomer formation with optically active resolving agents (Eliel, E. and Wilen, S. "Stereochemistry of Organic Compounds”, John Wiley & Sons, Inc., New York, 1994; Lochmuller, C.H., J. Chromatogr. 113(3), 283-302, 1975).Racemic mixtures of chiral compounds of the invention may be separated and isolated by any appropriate method, including: (1) formation of ionic diastereomeric salts with chiral compounds and separation by fractional crystallization or other methods, (2) formation of diastereomeric compounds with chiral derivatization reagents, separation of the diastereomers and conversion to the pure stereoisomers, and (3) separation of substantially pure or enriched stereoisomers directly under chiral conditions, see ινΐΛ / a / zuzz / uu / y. 131 "Drug Stereochemistry, Analytical Methods and Pharmacology”, Irving W. Wainer, coord., Marcel Dekker, Inc., New York, 1993.

[0050] By method (1) diastereomeric salts can be formed by reaction with enantiomerically pure chiral bases, for example brucine, quinine, ephedrine, strychnine, α-methyl-β-phenylethylamine (amphetamine) and the like with asymmetric compounds carrying acidic functional groups, for example carboxylic acid and sulfonic acid. The diastereomeric salts can be induced to separate by fractional crystallization or ion chromatography. For the separation of optical isomers of amino compounds, the formation of diastereomeric salts can be achieved by the addition of chiral carboxylic or sulfonic acids, for example camphorsulfonic acid, tartaric acid, mandelic acid or lactic acid.

[0051] Alternatively, in method (2) the substrate to be resolved is reacted with one enantiomer of a chiral compound to form a diastereomeric pair (E. and Wilen, S. "Stereochemistry of Organic Compounds”, John Wiley & Sons, Inc., 1994, p. 322). Diastereomeric compounds may be formed by reacting asymmetric compounds with enantiomerically pure chiral derivatizing agents, e.g. menthyl derivatives, and subsequently separating the diastereomers and hydrolyzing to form the pure or enriched enantiomer. One method for determining optical purity is to form the chiral esters, e.g. the menthyl ester, e.g. (-)menthyl chloroformate, in the presence of a base, or the Mosher ester, a-methoxy-a(trifluoromethyl)phenyl acetate (Jacob III., J. Org. Chem. 47, 4165, 1982), from the racemic mixture and analyze the 1H NMR spectrum to determine the presence of the two atropisomeric enantiomers or diastereomers.Stable diastereomers of atropisomeric compounds can be separated and isolated by normal-phase and reverse-phase chromatography according to the methods for the separation of atropisomeric naphthyl-isoquinolines (WO 96 / 15111). By method (3) a racemic mixture of two enantiomers can be separated by chromatography using a chiral stationary phase ("Chiral Liquid Chromatography", W. J. Lough, coord., Chapman and Hall, New York, 1989; Okamoto, J. Chromatogr. 513, 375-378, 1990). Enriched or purified enantiomers can be distinguished by methods used to distinguish other chiral molecules with asymmetric carbon atoms, e.g. optical rotation and circular dichroism. ινΐΛ / a / zuzz / uu zazo Compounds of formula I can be obtained by the general procedures of schemes 1-7. 132 Diagram 1 BocH(R\ o OH (R )n ON Boc ivix / a / zuzz / uu zazo RJR4 HN R52 ,6_ Acid by ' ' Rdheating R3R4 N R5(R')<> N .íR'i R·1 ON Boc r3R4 N R5' Y - N m(R^) R36O N Rb Scheme 1 depicts the reaction of para-hydroxybenzaldehyde intermediate 1 with tert-butyl 3-iodoazetidine-1-carboxylate to form exemplary intermediate 2, tert-butyl 3-(4-formylphenoxy)azetidine-1-carboxylate. An illustrative intermediate 1 is 2,6-difluoro-4-hydroxybenzaldehyde. Cyclization of compound 2 with bicyclic amines 3 yields tricyclic intermediate 4, tetrahydropyrido[3,4-b]indol-1-ylazetidine. Acid deprotection of compound 4 and alkylation of 5 yields tricyclic intermediate 6, tetrahydropyrido[3,4-b]indol-1-ylazetidine. Diagram 2: 133 MΛ / a / ZUZZ / UU fUfO Scheme 2 shows the cyclization of para-iodo-benzaldehyde intermediates 7, such as 2,6-difluoro-4-iodobenzaldehyde, with bicyclic amines 3 to form the tricyclic intermediate 8, tetrahydropyrido[3,4-b]indol-1-yl-iodophenyl. Reaction of 8 with alcohol 9 produces the tricyclic intermediate 10, tetrahydropyrido[3,4-b]indol-1-yl. Diagram 3: OHC Z'-Cy X' X'-l Br OP AcOH 'nijcno heating or redü-ion of Mitsunobu or aiqjilacion Scheme 3 depicts the reaction of amine 11 with an alkylating reagent, in which the leaving group could be an iodide, a bromide or a triflate, leading to intermediate compound 12. Alternatively, amine 11 could also react with an aldehyde or ketone to form intermediate compound 12 by a reductive amination reaction. Condensation of intermediate compound 12 with an aldehyde produces compound 134 intermediate 13. The iodide or bromide of the X1 group of Cy could then be condensed with an alcohol or an amine or a sulfide or an olefin by a Pd or Cu catalyzed Ullman or Buchwald or Heck reaction to form the desired compound 14. Alternatively, the protected phenol (OP) of the Cy group could be deprotected and the resulting phenol then condensed with an alcohol by a Mitsunobu reaction. Alternatively, the phenol could be alkylated with an iodide, a bromide, a chloride, a triflate or a mesylate to form the tricyclic intermediate 14, tetrahydro-pyrido[3,4-b]indol-1-yl. Diagram 4: ινΐΛ / a / zuzz / uu zazo OHCx Scheme 4 represents the Pictet-Spengler delatio of amine 11 with an aldehyde leading to intermediate compound 15, where X1 is iodide or bromide. By reaction of amine 15 with an acid chloride the amide 16 is formed. The iodide or bromide group X1 of Cy can then be condensed with an alcohol, amine, sulfide or olefin by a Pd or Cu catalyzed Ullman or Buchwald or Heck reaction to form intermediate 17. Alternatively, the protected phenol (OP) of the Cy group of compound 16 can be deprotected and the resulting phenol then condensed with an alcohol by a Mitsunobu reaction to form compound 17. Alternatively, the phenol (OH) can be alkylated with an iodide, bromide, chloride, triflate or mesylate to form the tricyclic intermediate 17, the tetrahydro-pyrido[3,4-b]indol-1-yl-amide. Diagram 5: 135 ινΐΛ / a / zuzz / uu Pd catalyst or heating or Mitsunobu reaction or alkylation Scheme 5 represents the reaction of amine 15 with a sulfonyl chloride to form sulfonamide 18, which by a Pd- or Cu-catalyzed Ullman or Buchwald or Heck reaction or by Mitsunobu or alkylation reactions is converted into tricyclic intermediate 19, tetrahydro-pyrido[3,4-b]indole-1-ylsulfonamide. Diagram 6: X-R5 X=l. OTf, Br or reductive amination with an aldehyde or ketone Scheme 6 represents the reaction of amine 15 with an alkylating agent (R5-X) to form intermediate compound 13. Alternatively, amine 15 can be reacted with an aldehyde or ketone and a reducing agent, for example sodium cyanoborohydride, to form intermediate compound 13. Diagram 7 iviA / a / ¿u¿z / uu iyio The general synthetic method for preparing tryptamine 23 is shown in Scheme 7. The substituted indole 20 is transformed into the aldehyde 21 under the conditions of the Vilsmeier reaction. The aldol reaction of the aldehyde 21 with nitroethane produces compound 22. Reduction of 22 with lithium aluminum hydride gives tryptamine 1523. Examples EXAMPLE 101 Step 1: 3-(3,5-difluoro-4-formyl-phenoxy¡)-azet¡d¡na-1-carboxylate tert-butyl 101c H Under an argon atmosphere, cesium carbonate (3.09 g, 9.48 mmol) and 101b Boc-3-iodoazetidine (CAS No. 254454-54-1) were added to a solution of 2,6-difluoro-4-hydroxybenzaldehyde 101a (CAS No. 532967-21) (8.600 mg, 3.79 mmol) in N,N-dimethylformamide (25 ml). The resulting mixture was heated at 150 °C in a microwave for 1 h. The reaction mixture was allowed to cool to room temperature, the solids were filtered off, the filter cake was washed with toluene, and the filtrate was concentrated in vacuo. The residue is partitioned between EtOAc and water, the organic phase is separated, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product is adsorbed onto HMN diatomaceous earth (Isolute®, Biotage) and purified by silica gel chromatography (mobile phase: cyclohexane / ethyl acetate, gradient 0% to 30%), yielding 137 compound 101c as yellow oil (1.10 g, 93%). H1NMR(300 MHz, CDCI3): δ = 10.20 (s, 1H), 6.35 (m, 2H), 4.94 - 4.86 (m, 1H), 4.34 (ddd, J = 1.1, 6.4, 9.8 Hz, 2H), 4.05 - 3.98 (m, 2H), 1.45 (s, 9H). Step 2: (2-fluor-2-methyl-prop¡l)-[(R)-2-(1H-¡ndole-3-¡l)-1-methyl-ethyl]-amine 101d ινΐΛ / a / zuzz / uu / y / o Compound 101 d is obtained according to WO 2014 / 191726, page 78. Step 3: tert-butyl 3-{3,5-difluoro-4-[(1 R,3R)-2-(2-fluor-2-methyl-propyl)-3-methyl-2,3,4,9-tetrahydro-1 H-beta-carbolin-1-II]phenoxy}-azethin-1-carboxylate 101e Under an argon atmosphere, tert-butyl 3-(3,5-difluoro-4-formylphenoxy)azetidine-1-carboxylate 101c (818 mg, 2.61 mmol) and acetic acid (249 μl, 4.34 mmol) were added to a solution of (2-fluoro-2-methylpropyl)-[(R)-2-(1H-indol-3-yl)-1-methylethyl]amine 101d obtained according to WO 2014 / 191726, page 78 (540 mg, 2.17 mmol) in toluene (8 ml). The mixture was heated at 80 °C in a sealed tube protected from light for 4 h. The reaction mixture was allowed to cool to room temperature (RT) and concentrated in vacuo. The residue is partitioned between ethyl acetate (EtOAc) and saturated sodium bicarbonate solution. The organic phase is separated, washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo.The crude product is adsorbed onto HMN diatomaceous earth and purified by chromatography on silica gel (mobile phase: cyclohexane / ethyl acetate, gradient from 0% to 20%), yielding compound 101e as an off-white solid (1.10 g, 90%). H1NMR(300 MHz, CDCI3): δ = 7.54 - 7.49 (m, 1H), 7.39 (s, 1H), 7.25 - 7.19 (m, 1H), 7.15 - 7.05 (m, 2H), 6.28 - 6.21 (m, 2H), 5.20 (s, 1H), 4.84 - 4.76 (m, 1H), 4.33 - 4.24 (m, 2H), 4.02 - 3.94 (m, 2H), 3.69 - 3.61 (m, 1H), 3.12 - 3.02 (m, 1H), 2.84 (dd, J = 15.1, 20.0 Hz, 1H), 2.65 - 2.56 (m, 1H), 2.38 (dd, J = 14.9, 24.7 Hz, 1H), 1.45 (s, 9H), 1.28 - 1.08 (m, 9H); LC-MS: 544.5 [M+H]+. Step 4: (1 R,3R)-1-[4-(azet¡din-3-¡lox¡)-2,6-difluoro-phen¡l]-2-(2-fluor-2-methyl-prop¡l)-3-methyl-2,3,4,9-tetrahydro1 H-beta-carboline 101 f 138 ινΐΛ / a / zuzz / uu / y Under argon atmosphere, TFA (1.75 ml, 23.1 mmol) was added dropwise to a mixture of tert-butyl 3-{3,5-difluoro-4-[(1 R,3R)-2-(2-fluoro-2-methyl-propyl)-3-methyl-2,3,4,9-tetra-hydro-1 H-beta-carbolin-1-yl]-phenoxy}-azetidine-1-carboxylate 101e (840 mg, 1.54 mmol) and dichloromethane (10 ml) and the mixture was stirred at room temperature for 3 h, protected from light. The reaction mixture was concentrated in vacuo and purified using an SCX-2 cartridge (mobile phase: dichloromethane / methanol = 1:1 then 2N ammonia in methanol). The appropriate fractions are combined and concentrated to give compound 101f as an off-white solid (54 mg, 8%).RMN H1(300 MHz, CDCI3): δ = 7,54 - 7,49 (m, 1H), 7,41 (s, 1H), 7,25 - 7,20 (m, 1H), 7,13 - 7,07 (m, 2H), 6,30 - 6,22 (m, 2H), 5,19 (s, 1H), 4,96 4,90 (m, 1H), 3,97 - 3,91 (m, 2H), 3,83 - 3,78 (m, 2H), 3,71 - 3,60 (m, 1H), 3,12 - 3,03 (m, 1H), 2,85 (dd, J = 15,1,19,6 Hz, 1H), 2,64 -2,55 (m, 1H), 2,38 (dd, J = 15,1,25,2 Hz, 1H), 1,82 (anchas, 1H), 1,27 - 1,07(m, 9H); CL-EM: 442,5 [M-H]-. Step 5: Under argon atmosphere, 1-bromo-3-fluoropropane (16 μl, 0.16 mmol; CAS No. 352-91-0) and ethyldiisopropylamine (12 μl, 0.24 mmol) were added to a mixture of (1R,3R)-1-[4-(azetidín-3-yloxy)-2,6-difluoro-phenyl]-2-(2-fluoro-2-methyl-propyl)-3-methyl-2,3,4,9-tetrahydro-1H-beta-carboline 101f (54 mg, 0.12 mmol) and N,N-dimethylformamide (2 ml). The reaction mixture was stirred at room temperature for 48 h, protected from light. The reaction mixture was poured into a mixture of ethyl acetate and water. The organic phase was separated, washed with water and brine, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (mobile phase: dichloromethane / methanol, gradient 0% to 5%) and then using a C18 cartridge (acetonitrile, water, formic acid). The appropriate fractions were combined and concentrated to give compound 101 as a yellow solid (27 mg, 8%).<h2 style=";text-align:left;direction:ltr">RMN H1(400 MHz, CDCI3): δ = 11.12 (ancha s, 1H), 8.27 (s, 1.3H, ácido fórmico), 7.53 - 7.47 (m, 2H), 7.24 - 7.20 (m, 1H), 7.13 - 7.08 (m, 2H), 6.31 3.64 (dd, J = 4.8, 11.1 Hz, 1H), 3.49-3.47 (m, 1H), 3.07-2.97 (m,3H),2.84 (dd, J = 15.0.20.3 Hz, 1H), 2.64-2.58 (m, 1H), 2.38 (dd, J = 15.0, 24.5 Hz, 1H), 1.99 - 1.83 (m, 2H), 1.27 - 1.08 (m, 9H); CL-EM: 504.3 [M+H]+.<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> Ejemplo 102 (1 R,3R)-1 -(2,6-difluor-4-(2-(3-(fluormet¡l)azet¡din-1 -il)etox¡)fen¡l)-2-(2-fluor-2-met¡lprop¡l)-3-met¡l-2,3,4,9tetrahidro-1 H-pirido[3,4-b]¡ndol 102<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> Paso 1: (1R,3R)-1-(2,6-difluor-4-yodo-fenil)-2-(2-fluor-2-met¡l-propil)-3-met¡l-2,3,4,9-tetrahidro-1 H-betacarbolina 102b<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> 139<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> IVIA / a / ¿U¿¿ / UU ÍXfO<h2 style=";text-align:left;direction:ltr"> Under an argon atmosphere, 2,6-difluoro-4-iodobenzaldehyde 102a (CAS No. 1160573-10-3, 65 mg, 0.24 mmol) followed by acetic acid (23 μl, 0.40 mmol) was added to a solution of (2-fluoro-2-methyl-propyl)-[(R)-2-(1H-indol-3-yl)-1-methyl-ethyl]-amine 101d, obtained according to WO 2014 / 191726, page 78, (50 mg, 0.20 mmol) in toluene (170 μl). The resulting mixture was stirred at 80 °C in a sealed tube for 5 h and then allowed to cool to room temperature. The mixture is purified on an SCX-2 cartridge (mobile phase: dichloromethane / methanol = 9:1, then 2N ammonia in methanol). The appropriate fractions are combined and concentrated, and the crude product is purified by silica gel chromatography (mobile phase: cyclohexane / ethyl acetate, gradient from 0% to 30%) to give compound 102b as a yellow solid (89 mg, 89%).RMN H1(400 MHz, CDCI3): δ = 7,54 - 7,50 (m, 1H), 7,39 (s, 1H), 7,25 - 7,21 (m, 3H), 7,16 - 7,08 (m, 2H), 5,26 (s, 1H), 3,67 - 3,60 (m, 1H), 3,06 (ddd, J = 1,5, 4,9,15,2 Hz, 1H), 2,86 (dd, J = 15,2, 21,5 Hz, 1H), 2,61 (ddd, J = 1,5, 4,4,15,2 Hz, 1H), 2,39 (dd, J = 15,2, 24,0 Hz, 1H), 1,29 -1,15 (m, 6H), 1,10 (d, J = 6,4 Hz, 3H); CL-EM: 497,0 [M-H]-. Step 2: A mixture of (1R,3R)-1-(2,6-difluoro-4-iodo-phenyl)-2-(2-fluoro-2-methyl-propyl)-3-methyl-2,3,4,9-tetrahydro-1 H-beta-carboline 102b (82 mg, 0.16 mmol), 2-(3-fluoromethyl-azetidin-1-yl)-ethanol 102c, obtained according to WO 2013 / 090836, page 124 (44 mg, 0.33 mmol; CAS No. 1443984-69-7, WO 2013 / 090836), copper iodide (6.2 mg, 0.03 mmol), potassium carbonate (68 mg, 0.49 mmol) and butyronitrile (600 mg, 0.16 mmol) is degassed. μI) with three cycles of vacuum - argon. The reaction mixture was heated at 135 °C for 24 h, allowed to cool to room temperature, and diluted with ethyl acetate. The solid was separated from the reaction mixture by filtration through Celite and washed with ethyl acetate. The combined filtrates were washed with water (three times) and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (mobile phase: 0 to 7% methanol in dichloromethane).<h2 style=";text-align:left;direction:ltr">Recover the fractions and concentrate, including 102 grams of solid amarillo formula (17.2 mg, 21%). RMN H1(400 MHz, DMSO-de): δ = 10.51 (s, 1H), 7.39 (d, J = 7.3 Hz, 1H), 7.18 (d, J = 7.8 Hz, 1H), 7.01 - 6.91 (m, 2H), 6.64 (d, J = 11.2 Hz, 2H), 5.11 (s, 1H), 4.56 (d, J = 5.9 Hz, 1H), 4.44 (d, J = 5.4 Hz, 1H), 3.92 (s, 2H), 3.54 - 3.47 (m, 2H), 3.06 - 2.66 (m, 6H), 2.59 - 2.53 (m, 2H, parcialmente Before DMSO-d6), 2.40-2.27 (m, 2H), 1.25 -1.09 (m, 6H), 1.04 (d, J = 6.4 Hz, 3H); CL-EM: 502.3 [MH]-.<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> Example 103<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> -((1 R,3R)-1 -(2,6-d¡fluor-4-(2-(3-(fluormetil)azet¡d¡n-1-¡l)etox¡)fen¡l)-3-met¡l-3,4-d¡h¡dro-1 H-pirido[3,4-b]¡ndol2(9H)-il)-2-metilpropan-1-ona 103<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> Step 1: (1R,3R)-1-(2,6-difluor-4-iodofenil)-3-metal-2,3,4,9-tetrahydro-1H-pyridoxine[3,4-b]ndol 103b<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> 140<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> 103b<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> MA / a / zuzz / uu iyio<h2 style=";text-align:left;direction:ltr"> (2R)-1-(1H-indol-3-yl)propane-2-amine 103a (710 mg, 3.67 mmol) was added to a microwave vial, followed by 2,6-difluoro-4-iodobenzaldehyde (1.1 g, 4.03 mmol) and acetonitrile (2.6 mL). The reaction mixture was placed under a nitrogen atmosphere and TFA (0.5 mL, 7.0 mmol) was added. The reaction mixture was then heated at 130 °C in a microwave for 1 h and saturated aqueous NaHCO3 solution was added. The mixture was extracted with DCM (3 x 100 mL), dried over MgSO4, filtered, and concentrated. The crude product was purified by flash column chromatography on silica gel (0 to 100% EtOAc in hexanes) to give compound 103b (450 mg, 29%). H1 NMR(400 MHz, deuterated chloroform-d): δ 7.60 - 7.48 (m, 2H), 7.27 (d, J = 7.3 Hz, 2H), 7.17 - 7.08 (m, 2H), 5.63 (s, 1H), 3.45 (dq, J = 12.7, 6.2 Hz, 1H), 2.99 (ddd, J = 15.5, 4.6, 1.3 Hz, 1H), 2.52 (ddd, J = 15.5, 7.3,1.8 Hz, 1H), 1.29 (d, J = 6.5 Hz, 3H). <h2 style=";text-align:left;direction:ltr">Step 2: 1-((1R,3R)-1-(2,6-difluor-4-iodofenil)-3-metil-3,4-dihydro-1H-pirdo[3,4-b]ndol-2(9H)-l)-2-metilpropan-1-ona 103c<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> (1R,3R)-1-(2,6-Difluoro-4-iodo-phenyl)-3-methyl-2,3,4,9-tetra-hydro-1H-pyrido[3,4-b]indole 103b (50 mg, 0.12 mmol) was added into a round-bottom flask (RBF), followed by sodium bicarbonate (50 mg, 0.59 mmol) and chloroform (0.8 mL). 2-Methylpropanoyl chloride (31 mg, 0.2947 mmol) was added, and the reaction mixture was heated at 45 °C for 1 h. Diisopropylethylamine (Hunig's base, 0.1 mL, 0.59 mmol) was added, and the reaction mixture was stirred until LC-MS indicated consumption of the starting materials. A saturated aqueous sodium bicarbonate solution (10 mL) was added. The reaction mixture was extracted with DCM (3 x 50 mL), dried over MgSO4, filtered, and concentrated. The crude product was purified by flash column chromatography on silica gel (0 to 100% EtOAc in hexanes) to give compound 103c (51 mg, 88%).RMN H1(400 MHz, DMSO-d6): δ 10,74 (s, 1H), 7,46 (d, J = 7,8 Hz, 1H), 7,39 (d, J = 9,2 Hz, 2H), 7,24 (dt, J = 8,0, 1,0 Hz, 1H), 7,01 (dddd, J = 26,4, 8,0, 7,0, 1,2 Hz, 2H), 6,10 (s, 1H), 4,88-4,71 (m, 1H), 3,17 (dd, J = 14,9, 5,6 Hz, 1H), 3,03 (p, J = 6,6 Hz, 1H), 2,84 (d, J = 15,2 Hz, 1H), 1,12 (d, J = 6,5 Hz, 2H), 1,06-0,92 (m, 6H). 141 Step 3: 1-[(1R,3R)-1-(2,6-difluoro-4-iodo-phenyl)-3-methyl1,3,4,9-tetrahydropyrido[3,4-b]indol-2-yl]-2-methyl-propan-1-one 103c (51 mg, 0.10 mmol) and then 2-[3-(fluoromethyl)azetidin-1-yl]ethanol 102c, synthesized according to WO 2013 / 090836, page 124 (27 mg, 0.21 mmol), copper iodide (8 mg, 0.04 mmol) and potassium carbonate (43 mg, 0.31 mmol) are introduced into a 5 ml microwave vial. The vial is sealed and butyronitrile (0.7 ml) is added. The reaction mixture was heated at 135 °C overnight and cooled to room temperature. The reaction mixture was filtered through Celite, eluting with EtOAc. The combined filtrates were concentrated and purified by reverse-phase HPLC to give compound 103 (16 mg, 31%).<h2 style=";text-align:left;direction:ltr">RMN H1(400 MHz, DMSOd6): δ 10.48 (s, 1H), 7.51 - 7.39 (m, 1H), 7.32 - 7.22 (m, 1H), 7.09 - 6.90 (m, 2H), 6.51 (d, J = 11.0 Hz, 2H), 6.11 (s, 1H), 4.89-4.71 (m, 1H), 4.55 (d, J = 6.1 Hz, 1H), 4.43 (d, J = 6.0 Hz, 1H), 3.94 (q, J = 5.4 Hz, 2H), 3.59 - 3.38 (m, 2H), 3.24 - 3.18 (m, 2H), 3,04 - 2.97 (m, 2H), 2.87 - 2.74 (m, 4H), 1.12 (d, J = 6.4 Hz, 3H), 0.98 (dd, J = 10.3, 6.7 Hz, 6H); CL-EM: 500.3 [M+H]+.<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> Example 104<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> 1-((1R,3R)-1-(2,6-difluor-4-(2-(3-(fluormetil)azetidin-1-l)etoxi)fenil)-3-metil-3,4-dihydro-1H-pyridinol2(9H)-l)-2-fluoro-2-methylpropan-1-ol 104<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> Step 1: 1-((1R,3R)-1-(2,6-dfluor-4-iodofen)-3-metal-3,4-dhydro-1H-pyridox[3,4-b]ndol-2(9H)-l)-2-fluor-2metilpropan-1-ona 104a<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> I am / a / zuzz / uu / y ic<h2 style=";text-align:left;direction:ltr"> (1R,3R)-1-(2,6-Difluoro-4-iodo-phenyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole 103b (100 mg, 0.24 mmol) was added to a round-bottom flask, followed by 2-fluoro-2-methylpropanoyl chloride (0.59 mL of a 1 M solution in CHCh, obtained by reacting the corresponding acid with oxalyl chloride), sodium bicarbonate (99 mg, 1.2 mmol), and chloroform (1.6 mL). The reaction mixture was heated at 45 °C for 1 h, and Hunig's base (0.2 mL, 1.2 mmol) was added. The reaction mixture was stirred until LC-MS indicated that all the starting materials were consumed. A saturated aqueous sodium bicarbonate solution was added to the reaction mixture. The mixture was extracted with DCM (3 x 50 mL), dried over MgSO4, filtered, and concentrated. The resulting crude product was purified by silica gel column chromatography (0 to 100% EtOAc in hexanes) to give compound 104a (95 mg, 79%).RMN H1(400 MHz, DMSO-de): δ = 7,54 7,31 (m, 3H), 7,28-7,21 (m, 1H), 7,04 (ddd, J = 8,1,7,1,1,3 Hz, 1H), 6,98 (td, J = 7,5, 7,0, 1,1 Hz, 1H), 6,08 (s, 1H), 5,14 (s, 1H), 3,14 (dd, J - 15,4, 4,6 Hz, 1H), 2,81 (d, J = 15,2 Hz, 1H), 1,51 (dd, J = 35,4, 21,8 Hz, 6H), 1,17 (dt, J = 3,1 Hz, 3H); CL-EM: 513,0 [M+H]+. 142 Step 2: 1-[(1R,3R)-1-(2,6-difluoro-4-iodo-phenyl)-3-methyl1,3,4,9-tetrahydropyrido[3,4-b]indol-2-yl]-2-fluoro-2-methyl-propan-1-one 104a (29 mg, 0.056 mmol) and then 2-[3-(fluoro-methyl)azetidin-1-yl]ethanol (15 mg, 0.11 mmol), copper iodide (4 mg, 0.023 mmol), potassium carbonate (24 mg, 0.17 mmol) and butyronitrile (0.37 ml) are introduced into a 5 ml microwave vial. The solution is degassed for 5 min and heated at 135 °C overnight. When LC-MS showed that all starting materials had been consumed, the crude mixture was cooled to room temperature and filtered through Celite®. The Celite pad was washed with EtOAc, and the combined filtrates were concentrated and purified by reverse-phase HPLC to give compound 104 (9 mg, 31%).<h2 style=";text-align:left;direction:ltr">RMN H1(400 MHz, DMSO-d6, 350K): δ 10.69 (s, 1H), 7.54-7.38 (m, 1H), 7.31 -7.17 (m, 1H), 7.00 (dtd, J = 24.8, 7.1.1.2 Hz, 2H), 6.55 (d, J = 12.0 Hz, 1H), 6.03 (s, 1H), 5.21 - 5.05 (m, 1H), 4.54 (d, J = 6.2 Hz, 1H), 4.42 (d, J = 6.2 Hz, 1H), 3.87 (t, J = 5.4 Hz, 2H), 3.30 - 3.25 (m, 2H), 3.15 (dd, J = 15.3, 4.7 Hz, 1H), 2.96 (t, J = 6.5 Hz, 2H), 2.79 (d, J = 15.1 Hz, 1H), 2.75-2.62 (m, 3H), 1.55 (d, J = 21.8 Hz, 2H), 1.45 (d, J = 21,8 Hz, 2H), 1,15 (d, J = 6,4 Hz, 2H); CL-EM: 518.2 [M+H]+.<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> Example 105 (1R,3R)-1-(4-(2-(3-(dfluormetl)azetdn-1-l)etox)-2,6-dfluorfenl)-2-(2-fluor-2-metlpropl)-3-metil-2,3,4,9tetrahydro-1H-prdo[3,4-b]ndol 105 ινAL / a / zuzz / uu fxfo<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> Paso 1: acetato de 2-(3,5-difluor-4-formilfenox¡)et¡lo 105a<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> A solution of 2,6-difluoro-4-hydroxybenzaldehyde (CAS No. 532967-21-8, 300 mg, 1.89 mmol) and 2-bromoethyl acetate (CAS No. 927-68-4, 0.22 mL, 2 mmol) in acetonitrile (5 mL) and N,N-dimethylformamide (1 mL) was heated at 80 °C for 24 h. Another portion of 2-bromoethyl acetate (0.11 mL, 1 mmol) was added, and heating was continued at 80 °C for another 30 h. The reaction mixture was allowed to cool to room temperature. The residue was partitioned between EtOAc and saturated sodium bicarbonate solution. The aqueous phase was extracted with additional portions of EtOAc. The organic phases are combined, separated, dried with MgSO4, filtered, and concentrated in vacuo. The crude product is purified by column chromatography on silica gel (mobile phase: cyclohexane / ethyl acetate, gradient from 0% to 33%), yielding compound 105a as a white powder (213 mg, 45%).H1 NMR (300 MHz, CDCI3): δ = 10.20 (s, 1H), 6.51 (d, J = 10.4 Hz, 2H), 4.44 (t, J = 4.7 Hz, 2H), 4.22 (t, J = 4.7 Hz 2, 2H).), (3H1). Step 2: acetate of 2-(3,5-difluoride-4-((1 R,3R)-2-(2-fluorine-2-methylpropyl)-3-met¡l-2,3,4,9-tetra¡dro-1 H-pyrido[3,4-b]indol-1-ylblo)phenox 10¡5)et 143 105b ινΐΛ / a / zuzz / uu / y Under argon atmosphere, glacial acetic acid (0.1 ml, 1.72 mmol) was added to a solution of (2-fluoro-2-methylpropyl)-[(R)-2-(1H-indol-3-yl)-1-methylethyl]-amine 101d (213 mg, 0.86 mmol) and 2-(3,5-difluoro-4-formylphenoxy)ethyl acetate 105a (210 mg, 0.86 mmol) in toluene (1 ml). The flask was sealed and the reaction mixture was heated at 80 °C for 16 h. The reaction mixture was allowed to cool to room temperature. The residue was partitioned between dichloromethane and saturated sodium bicarbonate solution. The aqueous phase was extracted with additional portions of dichloromethane. The organic phases are combined, separated, dried with MgSO4, filtered, and concentrated in vacuo. The crude product is purified by chromatography on silica gel (mobile phase: cyclohexane / ethyl acetate, gradient from 0% to 20%), yielding compound 105b as a white foam (323 mg, 80%).RMN H1(300 MHz, CDCI3): δ = 7,54 - 7,49 (m, 1H), 7,38 (s, 1H), 7,24 - 7,19 (m, 1H), 7,14 - 7,07 (m, 2 H), 6,42 (dd, J = 13, 3 Hz, 2H), 5,19 (s, 1H), 4,40 (t, J = 4,7 Hz, 2H), 4,12 (t, J = 4,7 Hz, 2H), 3,70 - 3,62 (m, 1H), 3,13 - 3,04 (m, 1H), 2,92 - 2,79 (dd, J = 19,15 Hz, 1H), 2,65 - 2,55 (m, 1H), 2,46 - 2,31 (dd, J = 25,0,15,0 Hz, 1H), 2,10 (s, 3H), 1,24 (d, J = 11,0 Hz, 3H), 1,17 (d, J = 11,3 Hz, 3H), 1,1 (d, J = 6,5 Hz, 3H). Paso 3: 2-(3,5-difluor-4-((1 R,3R)-2-(2-fluor-2-metil-prop¡l)-3-metil-2,3,4,9-tetrah¡dro-1 H-pirido[3,4-b]indol-1il)fenoxi)etanol 105c 105c To a solution of 2-(3,5-difluoro-4-((1 R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydrolH-pyrido[3,4-b]indol-1-yl)phenoxy)ethyl acetate 105b (320 mg, 0.675 mmol) in THF / MeOH (2 / 1, 6 mL) was added sodium hydroxide (1 N, 4 mL). The reaction mixture was heated at 70 °C for 45 min. The reaction mixture was allowed to cool to room temperature and the solvent was removed in vacuo. The residue was partitioned between dichloromethane and water. The organic phase was separated, dried over MgSO4, filtered and concentrated in vacuo to give compound 105c as a white foam (264 mg, 91%). CL-MS: 431.2 [MH]-. Step 4: (1 R,3R)-1-(4-(2-bromoethoxy)-2,6-difluorophenyl)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1 H144 pyrido[3,4-b]indole 105d iviA / a / zuzz / uu / and to To a solution of 2-(3,5-difluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido-[3,4b]indol-1-yl)phenoxy)ethanol 105c (130 mg, 0.3 mmol) in DCM (2.5 ml) were added triphenylphosphine (94 mg, 0.36 mmol) and carbon tetrabromide (120 mg, 0.36 mmol). The reaction mixture was stirred at room temperature for 1 h and the solvent was removed in vacuo. The crude product was purified by column chromatography on silica gel (mobile phase: cyclohexane / ethyl acetate, gradient from 0% to 20%), yielding compound 105d as a white foam (142 mg, 95%).RMN H1(300 MHz, CDCI3): δ 7,54 - 7,49 (m, 1H), 7,38 (s, 1H), 7,25 - 7,19 (m, 1H), 7,15 - 7,07 (m, 2 H), 6,42 (dd, J = 13,0, 3,0 Hz, 2H), 5,20 (s, 1H), 4,24 (t, J = 4,7 Hz, 2H), 3,72 - 3,59 (m, 3H), 3,12 3,03 (m, 1H), 2,92-2,79 (dd, J = 19,4,15,0 Hz, 1H), 2,64-2,56 (m, 1H), 2,46-2,31 (dd, J = 25,0,15,0 Hz, 1H), 1,24 (d, J = 12,1 Hz, 3H), 1,17 (d, J = 12 Hz, 3H), 1,10 (d, J = 6,5 Hz, 3H). Step 5: To a solution of (1R,3R)-1-(4-(2-bromoethoxy)-2,6-dfluorophenyl)-2-(2-fluoro-2-methylpropyl)-3-methyl2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole 105d (62 mg, 0.125 mmol) in acetonitrile (1 mL) was added N,N-diisopropylethylamine (0.064 mL, 0.375 mmol) and 3-(difluoromethyl)azetidine hydrochloride (CAS 1354792-76-9, 27 mg, 0.187 mmol). The reaction mixture was stirred at room temperature for 1 h and then at 45 °C for 4 h. The reaction mixture was allowed to cool to room temperature. The residue is partitioned between EtOAc and water. The aqueous phase is extracted with additional portions of EtOAc. The combined organic phases are separated, dried over MgSO4, filtered, and concentrated in vacuo. The crude product is purified by column chromatography on silica gel (mobile phase: dichloromethane / methanol, gradient from 0% to 2.5%) to afford compound 105 as an off-white solid (40 mg, 62%).NMR H1(300 MHz, CDCI3): δ 7.54 - 7.49 (m, 1H), 7.38 (s, 1H), 7.24 - 7.19 (m, 1H), 7.14 - 7.06 (m, 2 H), 6.38 (dd, J = 1.3, 3.6 H), z 5.76 (dt, J = 56.0, 5.1 Hz, 1H), 5.18 (s, 1H), 3.90 (t, J = 5.3 Hz, 2H), 3.71 3.63 (m, 1H), 2H), 3.13 to 3.04 (m, 1H), 2.92 to 2.79 (m, 3H), 2.64 to 2.55 (m, 1H), 2.45 to 2.30 (dd, J = 25.6,14.9 Hz, 1H), (d, J = 12 Hz, 3H), 1.09 (d, J = 6.5 Hz, 3H); CL-EM: 520.4 [MH]-. Compounds 106–125 are obtained by the procedures described herein and characterized by CL-EM [M+H]+: 106,520.1,107,486.4,108,532.4,109,518.2 145 110 111 469.2 112 487.3 113 498.3 114 514.3 115 500.3 116 486.3 117 486.1 118 500.2 119 500.2 120 48 24.27 122,516.2,123,502.3,124,528.3,125,514.3 ινΐΛ / a / zuzz / uu / y <h2 style=";text-align:left;direction:ltr">Example 126 (1R,3R)-1-(2,6-dfluor-4-(2-(3-(fluormetal)azetidin-1-l)etox)fenal)-3-metil-2-(metalsulfonal)-2,3,4,9-tetrahedro1H-pyridinol[3,4-b]ndol 126<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> Step 1: (1R,3R)-1-(2,6-difluor-4-iodofen)-3-metal-2-(metilsulfon)-2,3,4,9-tetrahydro-1H-pyridoxine[3,4-b]ndol<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> IFνΛ°<h2 style=";text-align:left;direction:ltr"> (1R,3R)-1-(2,6-Difluoro-4-iodo-phenyl)-3-methyl-2,3,4,9-tetra-hydro-1H-pyrido[3,4-b]indole (50 mg, 0.12 mmol) and chloroform (0.15 M, 0.8 ml) were then charged to a 50-ml round-bottom flask. N,N-Diisopropylethylamine (0.06 ml, 0.35 mmol) and methanesulfonyl chloride (0.014 ml, 0.18 mmol) were then added sequentially. The reaction mixture was heated at 45 °C until LC-MS monitoring indicated that the starting materials were completely consumed. The reaction mixture was cooled to room temperature, saturated aqueous NH4Cl solution was added, extracted with DCM (3 x 50 mL), dried over MgSO4, filtered, and concentrated. The crude product was purified by flash column chromatography on silica gel eluting with 0 to 50% ProAc in heptanes to give the title compound (40 mg, 68% yield). H1N NMR (400 MHz, DMSO 146 d6) δ = 10,78 (s, 1H), 7,54 (d, J = 7,9 Hz, 2H), 7,44 (d, J = 7,8 Hz, 1H), 7,22 (d, J = 8,1 Hz, 1H), 7,05 (ddd, J = 8,2, 7,1, 1,2 Hz, 1H), 7,02-6,95 (m, 1H), 6,18 (s, 1H), 4,43 (q, J = 5,6, 5,0 Hz, 1H), 3,09 - 2,99 (m, 1H), 2,83 (s, 4H), 1,31 (d, J = 6,6 Hz, 3H). CL-EM: 503,0 [M+H]+. Step 2: (1R,3R)-1-(2,6-Difluoro-4-iodo-phenyl)-3-methyl-2-methylsulfonyl1,3,4,9-tetrahydropyrido[3,4-b]indole (40 mg, 0.08 mmol), 2-[3-(fluoromethyl)azetidin-1-yl]ethanol (21 mg, 0.16 mmol), cuprous iodide (6 mg, 0.032 mmol), potassium carbonate (33 mg, 0.24 mmol), and butyronitrile (0.5 ml) are added to a 5 ml vial. The solution is degassed for 5 min and then heated at 135 °C overnight. When LC-MS monitoring indicated complete reaction, the reaction mixture was filtered through Celite, eluting with EtOAc. The filtrate was concentrated and purified by reverse-phase HPLC to give compound 126 (6 mg, 15% yield).<h2 style=";text-align:left;direction:ltr">RMN H1(400 MHz, DMSO-d6) δ = 10.74 (s, 1H), 7.43 (d, J = 7.7 Hz, 1H), 7.24 - 7.20 (m, 1H), 7.04 (ddd, J = 8.2, 7.0.1.4 Hz, 1H), 6.97 (td, J = 7.4, 1.1 Hz, 1H), 6.73 - 6.64 (m, 2H), 6.15 (s, 1H), 4.55 (d, J = 6.2 Hz, 1H), 4.45 - 4.35 (m, 2H), 3.93 (t, J = 5.4 Hz, 2H), 3.30 - 3.28 (m, 2H), 3.03 - 2.95 (m, 3H), 2.77 (s, 3H), 2.74 - 2.65 (m, 4H), 1.33 (dd, J = 6.8, 2.1 Hz, 3H). CL-EM: 508.2 [M+H]+.<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> iviA / a / zuzz / uu zazo<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> Example 145<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> N-(3,5-dfluor-4-((1R,3R)-2-(2-fluor-2-metalpropyl)-3-metal-2,3,4,9-tetrahedro-1H-prdo[3,4-b]ndol-1-il)fenyl)-1(3-fluorpropyl)azetidina-3-amina 145<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> Paso 1: (1 R,3R)-1-(4-bromo-2,6-difluorfen¡l)-2-(2-fluor-2-met¡lprop¡l)-3-metil-2,3,4,9-tetrah¡dro-1 H-pirido[3,4-b]indol<h2 style=";text-align:left;direction:ltr"> To a solution of (R)-N-(1-(1H-indol-3-yl)propan-2-yl)-2-fluoro-2-methylpropane-1-amine (500 mg, 2.01 mmol) in toluene (6 mL) was added 4-bromo-2,6-difluorobenzaldehyde (490 mg, 2.21 mmol) and acetic acid (0.58 mL, 10.2 mmol). The reaction mixture was stirred at 80 °C for 16 hours. The solution was cooled to room temperature, concentrated, and the residue was diluted with EtOAc (40 mL), washed with saturated aqueous NaHCO3 solution (10 mL) and water (20 mL). The organic phase was dried over anhydrous Na2SO4 and concentrated. The residue was purified by chromatography on silica gel (solvent gradient: 0 to 6% EtOAc in petroleum ether) to give the title compound (800 mg, 88%) as a light yellow solid.<h2 style=";text-align:left;direction:ltr">RMN H1(400 MHz, CDCh) δ = 7.53 (d, J = 7.2 Hz, 1H), 7.41 (s, 1H), 7.24 (d, J = 7.2 Hz, 1H), 7.16 - 7.09 (m, 2H), 7.06 (d, J = 8.0 Hz, 2H), 5.27 (s, 1H), 3.73-3.54 (m, 1H), 3.09-3.05 (m, 1H), 2.95-2.76 (m, 1H), 2.64-2.60 (m, 1H), 2.47 - 2.33 (m, 1H), 1.30 -1.17 (m, 6H), 1.11 (d, J = 6,4 Hz, 3H).<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> Paso 2: 3-((3,5-difluor-4-((1 R,3R)-2-(2-fluor-2-metil-propil)-3-met¡l-2,3,4,9-tetrah¡dro-1 H-pirido[3,4-b]indol-1147 ¡l)fenil)am¡no)azetidina-1 -carboxilato de t-butilo<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> NIAL / a / zuzz / uu<h2 style=";text-align:left;direction:ltr"> A mixture of (1R,3R)-1-(4-bromo-2,6-difluorophenyl)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (from step 1, 800.0 mg, 1.77 mmol), BINAP (110.4 mg, 0.18 mmol), Pd2(dba)3 (162.3 mg, 0.18 mmol), t-BuONa (511.0 mg, 5.32 mmol) and t-butyl 3-aminoazetidine-1-carboxylate (457.9 mg, 2.66 mmol) in toluene (10 ml) is stirred at 110 °C under N2 for 16 hours. The reaction mixture was concentrated and purified on a silica gel column (0 to 5% methanol in DCM) to give the title compound (900 mg, 94%) as a brown solid. H1 NMR(400 MHz, CDCI3) δ = 7.51 (d, J = 6.4 Hz, 1H), 7.43 (s, 1H), 7.22 (d, J = 8.0 Hz, 1H), 7.13-7.05 (m,2H), 5.97 (d, J = 11.2 Hz, 2H), 5.14 (s, 1H), 4.37 - 4.21 (m, 3H), 4.20 - 4.01 (m, 1H), 3.78 3.60 (m, 3H), 3.12-3.07 (m, 1H), 2.96 - 2.77 (m, 1H), 2.63-2.57 (m, 1H), 2.48 - 2.33 (m, 1H), 1.45 (s, 9H), 1.25 -1.17 (m,6H), 1.10 (d, J = 6.0 Hz, 3H) Step 3: N-(3,5-difluoro-4-((1R,3R)-2-(2-fluoro-2-methyl-propyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]ndole-1¡l)phenyl)azethina-3-amine To a mixture of 3-((3,5-difluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1 H-pyrido[3,4b]indol-1-yl)phenyl)amino)azetidine-1-carboxylic acid tert-butyl ester (from step 2, 0.9 g, 1.66 mmol) and DCM (5 mL) was added TFA (1.8 mL, 24.88 mmol) at -20 °C. The resulting mixture was stirred at 0 °C for 16 hours. Aqueous NaHCO3 solution (80 mL) was slowly added to the reaction mixture, and then the reaction mixture was extracted with DCM (100 mL χ 2). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated to give the title compound (700 mg, 95%) as a brown solid. The crude product was used for the next step without further purification. Step 4: To a mixture of N-(3,5-difluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1-Hypyrido-[3,4-b]indol-1-yl)phenyl)azetidine-3-amine (from step 3, 700.0 mg, 1.58 mmol), N,N-diisopropylethylamine (613.3 mg, 4.75 mmol) and N,N-dimethylformamide (10 mL) was added 1-bromo-3-fluoropropane (223.0 mg, 1.58 mmol) and the reaction mixture was stirred at 10 °C for 16 hours. The reaction mixture was purified by fluorescence chromatography. 148 column (0 to 10% MeOH in DCM) and then purified by reverse phase chromatography (66-96% acetonitrile / 0.05% NH4OH in water), obtaining the 145 mixture (280 mg, 35%) in white solid form. NMR H1(400 MHz, CD3OD) δ = 7.38 (d, J = 7.6 Hz, 1H), 7.17 (d, J = 7.6 Hz, 1H), 7.03 - 6.88 (m, 2H), 6.07 (d, J = 11.6 Hz, 2H), 5.10 (s, 1H), 4.54 - 4.36 (m, 2H), 4.03 - 4.01 (m, 1H), 3.79 - 3.71 (m, 2H), 3.69 - 3.65 (m, 1H), 3.04 - 3.00 (m, 1H), 2.97 - 2.91 (m, 2H), 2.87 - 2.85 (m, 1H), 2.62 (t, J = 7.6 Hz, 2H), 2.58 - 2.55 (m, 1H), 2.48 - 2.32 (m, 1H), 1.83 -1.67 (m, 2H), 1.20 -1.11 (m,6H), 1.08 (d,J = 6.8Hz, 3H). Example 154 (S)-3-((1R,3R)T(2,6-d¡fluor-4-(2-(3-(fluormeth¡l)-azetid¡n-1-¡l)ethox¡)phenyl)- 3-met¡l-3,4-d¡h¡dro-1H-p¡r¡do[3,4b]indol-2(9H)-yl)-2-fluor-2-met¡lpropan-1-ol 154 Step 1: 2-fluor-2-methylmalonate de dimethyl OO Sodium hydride (1.15 equiv., 21 mmol) was added to a 500 ml round-bottom flask, dried in an oven. The reaction mixture was placed under a nitrogen atmosphere and cooled to 0 °C. THF (63 ml) was added. To this mixture was added dimethyl 2-methylpropanedioate (5.0 g, 34.2 mmol) dropwise, and the reaction mixture was stirred for 30 min. N-Fluorbenzenesulfonimide (1.05 equiv., 19.2 mmol) was added in one portion. The reaction mixture was allowed to warm to room temperature and solidify, then another 50 ml of THF was added. After 1.5 h, a 2 N aqueous HCl solution was added to the reaction mixture, diluted with EtOAc (500 ml) and washed with 3 x 200 ml of 2 N HCl. The organic phase was separated, dried with MgSO4, filtered and concentrated. The crude white solid was taken up in 200 ml of heptane, sonicated and filtered through Celite. The filtered solids were washed with 3 x 200 ml of heptane.The filtrates were combined and concentrated to give the desired crude product (3 g, yield = 53%) as a yellow oil. H1NMR (400 MHz, DMSO-d6) δ = 3.32 (s, 6H), 1.18 (d, J = 6.3 Hz, 3H). Step 2: 2-fluoro-2-methylpropane-1,3-diol OH OH AND Into a 500 ml oven-dried round-bottom flask were charged dimethyl 2-fluoro-2-methylpropanedioate (3 g, 18.3 mmol) and THF (90 ml). The reaction mixture was placed under N2 and cooled to 0 °C. Lithium aluminum hydride solution (1 M in THF, 2.75 equiv., 50.3 mmol) was added dropwise, and the reaction mixture was warmed to room temperature over 1 h. The reaction mixture was again cooled to 0 °C, water (2 ml) followed by the addition of 15% aqueous NaOH solution (2 ml) and water (4 ml). The suspension was stirred for 15 min, filtered, and concentrated to give the crude product (1.4 g, 71% yield). H1 NMR(400 MHz, DMSO-d6) δ 4.85 (t, J = 5.9 Hz, 2H), 3.45 (d, J = 5.9 Hz, 2H), 3.41 (d, J = 5.9 Hz, 2H), 1.22-1.15 (d, 3H). Step 3:3-(tert-butyldiphenylsilyloxy¡)-2-fluor-2-methyl-propan-1-ol 149 OH OTBDPS ινΐΛ / a / zuzz / uu zazo Into a 500 ml oven-dried round-bottom flask were placed 2-fluoro-2-methyl-propane-1,3-diol (1.47 g, 1.25 equiv., 13.6 mmol) followed by imidazole (1.11 g, 1.5 equiv., 16.4 mmol), tert-butylchlorodiphenylsilane (3.0 g, 10.9 mmol) and chloroform (136 ml). The reaction mixture was stirred overnight and then saturated NH4Cl solution (100 ml) was added. The mixture was extracted with DCM (100 ml), dried over MgSO4, filtered and concentrated. The crude mixture was purified by flash column chromatography on silica gel (0-100% ProOAc in heptanes) to give the desired product (1.26 g, 33% yield). 1H NMR (400 MHz, DMSO-d6) δ = 7.68-7.60 (m, 4H), 7.51-7.40 (m, 6H), 4.97 (t, J = 5.8 Hz, 1H), 3.70 (dd, J = 19.4, 1.9 Hz, 2H), 3.52 (ddd, J = 18.5, 5.8, 1.8 Hz, 2H), 1.28 (d, J = 21.8 Hz, 3H), 1.01 (s, 9H). Step 4: 3-(tert-butyldi-phenylsilox¡)-2-fluoromethanesulfonate OTf OTBDPS ú Under a nitrogen atmosphere, 3-[tert-butyl(diphenyl)silyl]oxy-2-fluoro-2-methyl-propan-1-ol (1.3 g, 3.8 mmol) and dichloromethane (63 ml) were charged to a 500 ml round-bottom flask, dried in an oven. The reaction mixture was cooled to 0 °C and trifluoromethanesulfonic anhydride (1.27 g, 1.2 equiv., 4.5 mmol) was added dropwise. The reaction mixture was stirred for 2 h and washed with 2 N HCl and then with saturated NaHCO3 solution. The organic phase was separated, dried over MgSO4 and filtered through a silica gel cartridge eluting with DCM. The filtrate was concentrated to dryness to give the desired crude product (1.8 g, yield = 100%) which was used in the next step without further purification. 1H NMR (400 MHz, DMSO-de) δ = 7.66 - 7.58 (m, 4H), 7.56 - 7.41 (m, 6H), 5.07 - 4.81 (m, 2H), 3.88 - 3.68 (m, 2H), 1.40 (d, J = 21.6 Hz, 3H), 1.01 (s, 9H). Step 5: N-((R)-1-(1 H-indol-3-¡l)propan-2-yl)-3-(tert-but¡ld¡phen¡ls¡l¡lox¡)-2-fluoro-2-methylpropane-1 -amine To HN—. NT V—λ H \ F OTBDPS Into a 250 ml oven-dried round-bottom flask were charged (2R)-1-(1H-indol-3-yl)propane-2-amine (600 mg, 3.1 mmol), N,N-diisopropylethylamine (0.81 ml, 1.5 equiv., 4.65 mmol), and 1,4-dioxane (6 ml), and the reaction mixture was placed under a nitrogen atmosphere. [3-[tert-butyl(diphenyl)syl]oxy-2-fluoro-2-methylpropyl] trifluoromethanesulfonate (1.95 g, 1.25 equiv., 3.9 mmol) was added, and the reaction mixture was heated to 90 °C. When LC-MS analysis indicated that the starting materials had been consumed, saturated aqueous NaHCO2 solution was added to the reaction mixture, and the mixture was extracted with EtOAc (3 x 200 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated. Purification by column chromatography 150 flash through silica gel (0 to 100% EtOAc in hexanes) gave the title compound (1.2 g, 77% yield). LC-MS: 503.3 [M+H]+. Step 6: 3-((R)-1 -(1 H-índol-3-yl)propan-2-ílano)-2-fluoro-2-methylpropan-1 -ol IVIA / a / ¿U¿¿ / UU fUfO Into a 250 mL oven-dried round-bottom flask was added 3-[tert-butyl(diphenyl)syl]oxy-2-fluoro-N-[(1R)-2-(1H-indol-3-11)-1-methyl-ethyl]-2-methyl-propane-1-amine (1.2 g, 2.4 mmol), followed by THF (9.6 mL) and tetrabutylammonium fluoride hydrate (3 mL of a 1 M solution in THF). The reaction mixture was allowed to stir at room temperature until LC-MS indicated that the starting materials were completely consumed. To the reaction mixture was added water and extracted with 25% IPA in DCM 5 x 100 mL. The combined organic layers were dried over MgSO4, filtered, and concentrated. Purification by flash column chromatography on silica gel (0 to 30% NH32 N in MeOH in DCM) gave the title compound (332 mg, 53% yield). LC-MS: 265.1 [M+H]+. Step 7: 3-((1 R,3R)-1-(2,6-difluor-4-iodophenyl)-3-methyl-3,4-dihydro-1 H-pyrido[3,4-b]indol-2(9H)-yl)-2-fluor-2methylpropan-1-ol Into a 100 mL round-bottom flask were charged 2-Fluoro-3-[[(1 R)-2-(1 H-indol-3-yl)-1-methylethyl]amino]-2-methyl-propan-1-ol (332 mg, 1.26 mmol), 2,6-difluoro-4-iodo-benzaldehyde (370 mg, 1.1 equiv., 1.38 mmol), and toluene (5.5 mL). The reaction mixture was placed under a nitrogen atmosphere, and acetic acid (2 M) was added. The reaction mixture was heated at 90 °C for 48 h. To the reaction mixture was added saturated aqueous NaHCO3 solution and the mixture was vigorously extracted with µPrOAc (5 x 10 O mL). The organic layer was dried over MgSO4, filtered, and concentrated. Purification by flash column chromatography on silica gel (0-100% ProOAc in heptanes) gave the title compound (475 mg, 74% yield). LC-MS: 515.1 [M+H]+. Step 8: 3-[(1 R,3R)-1-(2,6-difluoro-4-iodo-phenyl)-3-methyl1,3,4,9-tetrahydropyrido[3,4-b]indol-2-yl]-2-fluoro-2-methyl-propan-1-ol (400 mg, 0.78 mmol), 2-[3-(fluoromethyl)azetidin-1-yl]-ethanol (518 mg, 5 equiv., 3.9 mmol), cuprous iodide (74 mg, 0.5 equiv., 0.39 mmol), and potassium carbonate (644 mg, 6 equiv., 4.7 mmol) are introduced into a 20 ml microwave vial. The vial is capped and the mixture is placed under a nitrogen atmosphere. Butyronitrile (5.2 mL) was added, and the mixture was degassed for 10 min. The reaction mixture was heated at 135 °C for 16 h, filtered through Celite, and purified by reverse-phase chiral HPLC to give two diastereomers. Compound 154 151 is the diastereomer that elute second (90 mg, yield = 22%). 154: NMR H1(400 MHz, in DMSO) δ = 10.48 (s, 1H), 7.39 (dd, J = 7.4,1.3 Hz, 1H), 7.17 (dd, J = 7.6,1.2 Hz, 1H), 6.96 (d, J = 7.6,1.2 Hz, 1H), Hz, 2H), 6.72 6.55 (m, 2H), 5.08 (s, 1H), 4.84 (t, J = 5.6 Hz, 1H), 4.56 (d, J = 6.2 Hz, 1H), 4.44 (d, J = 6.2 Hz, 1H), 2H), 3.55 (q, J = 6.0, 5.4 Hz, 1H), 3.03 - 2.83 (m, 4H), 2.72 (dt, J = 13.0, 5.6 Hz, 3H), 2.61 - 2.51 (m, 2H), 0.96 (m, 6H). 2 protons remain hidden below the water peak. Chiral SFC: UPC2 OX column, Socratic elution with 25% MeOH with 0.1% NH4OH for 2.5 min. Retention time = 1.35 min. CL-EM: 520.3 [M+H]+. Example 155 (2R)-3-[(1R,3R)-1-[2,6-d¡fluoro-4-[2-[3-(fluoromet¡l)-azet¡d¡n-1-¡l]ethoxy]phen¡l] -3-met¡l-1,3,4,9-tetrahydro-p¡r¡do[3,4b]indol-2-yl]-2-fluoro-2-methyl-propan-1-ol 155 According to the procedures of Example 154, compound 155 is the first eluting diastereomer (110 mg, yield = 27%). 155: H1 NMR(400 MHz, DMSO-d6): δ = 10.52 (s, 1H), 7.42 - 7.34 (m, 1H), 7.21 - 7.14 (m, 1H), 6.96 (dtd, J = 20.9, 7.1, 1.2 Hz, 2H), 6.69 - 6.58 (m, 2H), 5.12 (s, 1H), 4.81 (t, J = 5.8 Hz, 1H), 4.56 (d, J = 6.2 Hz, 1H), 4.44 (d, J = 6.2 Hz, 1H), 3.93 (t, J = 5.4 Hz, 2H), 3.46 (ddd, J = 18,2,11,9, 5.7 Hz, 2H), 3.14 (ddd, J = 20.4, 11.9, 5.9 Hz, 2H), 3.03 - 2.78 (m, 4H), 2.78 - 2.64 (m, 3H), 2.58 - 2.51 (m, 2H), 2.47 - 2.36 (m, 1H), 1.11 (d, J = 22.0 Hz, 3H), 1.04 (d, J = 6.5 Hz, 3H). 2 protons are hidden beneath the water peak. Chiral SFC: OX UPC2 column, isocratic elution with 25% MeOH containing 0.1% NH4OH for 2.5 min. Retention time = 0.55 min. LC-MS: 520.2 [M+H]+. EXAMPLE 174 Step 1: (R)-1-(1 H-¡ndol-3-yl)-N-(2,2,2-trifluoroethyl)-propan-2-am¡ne ινΐΛ / a / zuzz / uu / y A mixture of (2R)-1-(1H-indol-3-yl)propane-2-amine (100 mg, 0.574 mmol), 2,2,2-trifluoroethyl trifluoromethanesulfonate (151 mg, 0.6313 mmol), N,N-diisopropylethylamine (371 mg, 2.87 mmol), and 1,4-dioxane (3.8261 ml) was heated at 50 °C for 6 h. The reaction mixture was cooled to room temperature, diluted with water, and extracted with EtOAc (2x). The combined organic layers were dried (Na2SO4), filtered, and concentrated. The crude product was purified by flash chromatography on silica gel (0-50% ProOAc in heptane) to give the title compound (89 mg, 60.5% yield) as a colorless oil. H1-NMR(d-chloroform): δ = 8.10 7.92 (m, 1H), 7.62 - 7.56 (m, 1H), 7.33 (dt, J = 8.1, 0.9 Hz, 1H), 7.23 - 7.16 (m, 1H), 7.15 - 7.08 (m, 1H), 7.02 - 6.98 (m, 1H), 3.21 - 3.09 (m, 3H), 2.83 (dd, J = 6.6, 0.8 Hz, 2H), 1.12 (d, J = 6.2 Hz, 3H). LC-MS (ESI) m / z = 257 [M+H+], 152 Step 2: (1R,3R)-1 -(2,6-difluoro-4-iodophenyl)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1 H-pyrido[3,4- ινΐΛ / a / zuzz / uu / y / o A mixture of (2R)-1-(1H-indol-3-yl)-N-(2,2,2-trifluoroethyl)propane-2-amine (54 mg, 0.211 mmol), 2,6-difluoro-4-iodobenzaldehyde (62 mg, 0.232 mmol), acetic acid (110 mg, 1.84 mmol), and toluene (1 mL) was heated at 90 °C for 5 h. The mixture was concentrated. The residue was partitioned between EtOAc and saturated NaHCO3 solution. The aqueous phase was extracted with EtOAc (2x). The combined organic phases were dried (Na2SO4), filtered, and concentrated to give the title compound as a white solid which was used without purification. LC-MS (ESI) m / z 507 [M+H+]. Step 3: A mixture of (1R,3R)-1-(2,6-difluoro-4-iodo-phenyl)-3-methyl-2-(2,2,2-trifluoroethyl)-1,3,4,9-tetrahydro-pyrido[3,4-b]indole (107 mg, 0.211 mmol), 2-[3-(fluoromethyl)azetidin-1-yl]ethanol (84 mg, 0.632 mmol), Cul (16 mg, 0.0843 mmol), K2CO3 (87 mg, 0.632 mmol) and butyronitrile (1.4 ml) is purged with N2 for 5 min in a microwave vial, the vial is sealed and heated at 135 °C for 23 h. The mixture was filtered through Celite, concentrated and purified by prep. HPLC to give compound 174 (51 mg, yield = 47%) as a yellow solid. H1 NMR(400 MHz, DMSO-de) δ = 10.61 (s, 1H), 7.45 - 7.35 (m, 1H), 7.20 (dt, J = 8.0, 0.9 Hz, 1H), 7.05 -6.90 (m, 2H), 6.71 - 6.59 (m, 2H), 5.20 (s, 1H), 4.50 (dd, J = 47.6,6.2 Hz, 2H), 3.94 (t, J = 5.4 Hz, 2H), 3.57 - 3.35 (m, 2H), 3.31 - 3.22 (m, 2H), 2.97 (dt, J = 16.8, 7.9 Hz, 3H), 2.84 (ddd, J = 15,3,4,9,1.2 Hz, 1H), 2.77 - 2.66 (m, 3H), 2.64 - 2.56 (m, 1H), 1.12 (d, J = 6.6 Hz, 3H). LC-MS (ESI) m / z = 512 [M+H+], Example 286 286 Step 1: 3-((tert-butyldiphen¡ls¡l¡l)oxy)-2,2-difluoro-propan-1-ol TBDPSO FF To a stirred solution of 2,2-difluoropropane-1,3-diol (200 mg, 1.78 mmol) in THF (4 mL) was added NaH (60% in mineral oil, 71 mg, 1.78 mmol) in an oil bath, and the reaction mixture was stirred for 30 minutes. TBDPSCI (490 mg, 1.78 mmol) was added dropwise to the reaction mixture. The reaction mixture was warmed to 20 °C, and stirring was continued for 3 hours. Water (10 mL) was slowly added to the reaction mixture, and the resulting mixture was washed with EtOAc (10 mL * 2). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated. The crude residue was purified by gel column chromatography. 153 silica (20% petroleum ether in EtOAc) to give the title compound (450 mg, 1.28 mmol, 72% yield) as a light yellow oil. 1H NMR (400 MHz, CDCb) δ = 7.71-7.64 (m, 4H), 7.44-7.36 (m, 6H), 3.96-3.84 (m, 4H), 1.86 (s, 1H), 1.06 (s, 9H). Step 2: 3-((tert-butyldi-phenylsilyl)oxy)-2,2-difluoropropyl trifluoromethanesulfonate ivix / a / zuzz / uu zazo TBDPSO AND OTf FF To a stirred solution of 3-[tert-butyl(diphenyl)silyl]oxy-2,2-dfluoropropan-1-ol (from step 1, 400 mg, 1.14 mmol) and 2,6-lutidine (0.39 mL, 3.42 mmol) in DCM (8 mL) was added dropwise Tf2O (0.38 mL, 2.28 mmol) over an ice bath. The reaction mixture was stirred at 20 °C for 2 h. The reaction mixture was slowly poured into ice-water (20 mL) and extracted with DCM (20 mL χ 2). The combined organic layers were washed with 11 N HCl (20 mL), saturated NaHCO3 solution (20 mL), and brine. The organic layer was dried over anhydrous Na2SO, filtered, and concentrated. The crude residue was purified by column chromatography on silica gel (10% petroleum ether in EtOAc) to give the desired product (500 mg, 1.04 mmol, 91%) as a light yellow oil. H1NMR (400 MHz, CDCb) δ = 7.66-7.64 (m, 4H), 7.47-7.41 (m, 6H), 4.76 (t, J = 7.6 Hz, 2H), 3.89 (t, J = 7.6 Hz, 2H), 1.08 (s, 9H). Step 3: (R)-N-(1-(1H-indol-3-yl)propan-2-yl)-3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropane-1-amine F\F otbdps γΠHN^ N A mixture of [3-[tert-butyl(diphenyl)silyl]oxy-2,2-difluoropropyl] trifluoromethanesulfonate (from step 2, 8.31 g, 17.22 mmol), DIPEA (6.1 ml, 34.44 mmol), (2R)-1-(1H-indol-3-yl)propane-2-amine (3 g, 17.22 mmol), and dioxane (60 ml) was stirred at 90 °C for 12 hours. The reaction mixture was cooled to room temperature, diluted with water (100 ml), and washed with EtOAc (100 ml χ 2). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated. The crude residue was purified by column chromatography on silica gel (20% EtOAc / petroleum ether) to give the title compound (7.6 g, 87%) as a yellow oil. LC-MS: 507.2 [M+H]+. Step 4: (R)-3-((1-(1 H-indol-3-¡l)propan-2-¡l)amino)-2,2-difluoropropan-1-ol To a stirred solution of (R)-N-(1-(1H-indol-3-yl)-propan-2-yl)-3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropane-1-amine (from step 3, 7.6 g, 15 mmol) in THF (100 mL) was added TBAF (1.0 M in THF, 30 mL, 30 mmol). The reaction mixture was stirred at 25 °C for 4 h, diluted with water (200 mL), and extracted with EtOAc (200 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated. The mixture was purified by evaporation of ethyl acetate (200 mg, 1H NMR (CDCl3) δ 1.74 (d, J=8.8 Hz, 1H), 7.87 ... 154 crude residue by column chromatography on silica gel (70% EtOAc in petroleum ether) to give the title compound (3.5 g, 87%) as a light yellow oil. LC-MS: 268.9 [M+H]+. Step 5: 3-((1 R,3R)-1-(2,6-difluor-4-iodophenyl)-3-methyl-3,4-dihydro-1 H-pyrido[3,4-b]indol-2(9H)-yl)-2,2-difluoropropan-1-ol ΜΛ / a / zuzz / uu 1 and 1 oF\ Γ OH A mixture of (R)-3-((1-(1 H-indol-3-yl)propan-2-yl)amino)-2,2-difluoropropan-1-ol (from step 4.2 g, 7.45 mmol), HOAc (1.29 ml, 22.36 mmol), 2,6-difluoro-4-iodo-benzaldehyde (2 g, 7.45 mmol) and toluene (30 ml) was stirred at 90 °C for 12 hours. The reaction mixture was cooled to room temperature, diluted with water (50 ml) and washed with EtOAc (50 ml χ 2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated. The crude residue was purified by column chromatography on silica gel (20% petroleum ether in EtOAc) to give the title compound (2.8 g, 73%) as a light yellow solid. H NMR (400 MHz, CDCl) δ = 7.53-7.49 (m, 2H), 7.30-7.22 (m, 3H), 7.18-7.13 (m, 2H), 5.25 (s, 1H), 3.72-3.68 (m, 3H), 3.24-3.06 (m, 3H), 2.85-2.75 (m, 1H), 2.70-2.66 (m, 1H), 1.18 (d, J = 6.8 Hz, 3H). Step 6: A mixture of 3-((1 R,3R)-1-(2,6-difluoro-4-iodophenyl)-3-methyl-3,4-dihydro-1 H-pyrido[3,4-b]indol-2(9H)-yl)-2,2-difluoropropan-1-ol (from step 5, 1.5 g, 2.89 mmol), 2[3-(fluoromethyl)azetidin-1-yl]ethanol (1.93 g, 14.47 mmol), Cul (1.65 g, 8.68 mmol), K2CO3 (1.2 g, 8.68 mmol) and nPrCN (20 ml) is stirred under a N2 atmosphere at 135 °C for 3 hours. The reaction mixture was cooled to room temperature, diluted with water (50 mL), and washed with DCM (50 mL x 2). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated. The resulting residue was purified by reverse-phase chromatography (50-80% acetonitrile in 0.05% NH4OH in water) to give compound 286 (170 mg, 11%) as a white solid.NMR H1(400 MHz, CD3OD) δ = 7.41 (d, J = 8.0 Hz, 1H), 7.19 (d, J = 8.0 Hz, 1H), 7.03 - 6.94 (m, 2H), 6.54 (d, J = 11.2 Hz, 2H), 5.24 (s, 1H), 4.49 (dd, J = 47.6, 6.0 Hz, 2H), 4.00 - 3.98 (m, 2H), 3.83 - 3.72 (m, 1H), 3.63 - 3.45 (m, 4H), 3.22 - 3.13 (m, 3H), 3.02 - 2.60 (m, 6H), 1.17 (d, J = 6.0Hz, 3H). CL-EM: 524.1 [M+H]+. Example 303 (1R,3R)-2-(2,2-d¡fluorethyl)-1-[2,6-d¡fluor-4-[1-(3-fluorprop¡l)azet¡din-3-¡l]oxi-phenyl]-3-met¡l-1,3,4,9-tetrahidrop¡r¡do[3,4-b]¡ndol 303 By following the procedures of example 305, the calculation 303 is obtained. CL-EM: 494.2 [M+H]+. Example 304 N-(3,5-d¡fluor-4-((1R,3R)-3-met¡l-2-(2,2,2-trifluor-et¡l)-2,3,4,9-tetrahydro-1H-p¡r¡do[3,4-b]indol-1-yl)phen¡l)-1-(3fluorpropyl)azetidine-3-amine 304 155 Step 1: (R)-1-(1H-¡ndol-3-yl)-N-(2,2,2-trifluoreth¡l)-propane-2-am¡na / VfFvjOhn H ΜΛ / a / zuzz / uu 1 y 1 o To a solution of (2R)-1-(1H-indol-3-yl)propane-2-amine (10.0 g, 57.39 mmol) in 1,4-dioxane (100 ml) was added 2,2,2-trifluoroethyl trifluoromethanesulfonate (13.3 g, 57.39 mmol) and DIPEA (22.2 g, 172.18 mmol). The resulting mixture was stirred at 80 °C for 15 h. The reaction mixture was concentrated and purified by column chromatography eluting with 0 to 30% EtOAc in hexanes to give the title compound (14 g, 95.2%) as a light yellow oil. H1 NMR(400 MHz, CDCL) δ = 8.02 (broad s, 1H), 7.60 (d, J = 8.0 Hz, 1H), 7.37 (d, J = 8.0 Hz, 1H), 7.21 (t, J = 8.0Hz, 1H), 7.16-7.09 (m, 1H), 7.05 (s, 1H), 3.24 - 3.11 (m, 3H), 2.84 (d, J =6.4 Hz, 2H), 1.14 (d, J = 6.4 Hz, 3H). Step 2: (1 R,3R)-1 -(4-bromo-2,6-difluorophenyl)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1 H-pyrido[3,4-b] indole A mixture of (R)-1-(1H-indol-3-yl)-N-(2,2,2-trifluoroethyl)propane-2-amine (from step 1.14.0 g, 54.63 mmol), 4-bromo-2,6-difluorobenzaldehyde (11.5 g, 51.9 mmol), acetic acid (6.25 ml, 109.26 mmol) and toluene (150 ml) was stirred at 90 °C for 16 hours. The reaction mixture was cooled to 25 °C, concentrated, and purified by silica gel column chromatography (0 to 5% EtOAc / petroleum ether) to afford the title compound and its cis isomer (24 g, 95.7% yield) (trans:cis = 4:1) as a yellow solid. H1 NMR(400 MHz, CDCI3) δ = 7.52 (d, J = 8.4 Hz, 1H), 7.24 (d, J = 8.0 Hz, 1H), 7.19-7.05 (m, 4H), 5.69 (s, 0.2H), 5.31 (s, 0.8H), 3.64 - 3.50 (m, 1H), 3.45 - 3.17 (m, 1H), 3.10-3.06 (m, 1H), 2.98 - 2.81 (m, 1H), 2.78 - 2.59 (m, 1H), 1.41 (d, J = 6.4 Hz, 0.6 H), 1.18 (d, J = 6.4 Hz, 2.4H). Step 3: 3-((3,5-difluoro-4-((1 R,3R)-3-methyl-2-(2,2,2-trifluorote¡l)-2,3,4,9-tetrahydro-1 H-pyrido[3,4-b]indol-1-yl)phenyl)amino)azete-1-dcarboxylate-boc-box 156 A mixture of (1R,3R)-1-(4-bromo-2,6-difluorophenyl)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (trans:cis = 4:1) (from step 2, 23.0 g, 50.08 mmol), Pd2(dba)3 (4.59 g, 5.01 mmol), tert-butyl 3-aminoazetidine-1-carboxylate (12.9 g, 75.12 mmol), Xantphos (5.8 g, 10.02 mmol), Cs2CO3 (48.9 g, 150.25 mmol) and 2-(2,2,2-trifluoroethyl)-1H-pyrido[3,4-b]indole (from step 2, 23.0 g, 50.08 mmol) was stirred at 115°C under a N2 atmosphere for 16 hours. mmol) and 1,4-dioxane (250 ml). The reaction mixture was filtered through Celite, the filtrate was concentrated and purified by column chromatography (0 to 30% EtOAc in petroleum ether) to give the title compound (25 g, yield = 90.7%) (trans:cis = 4:1) as a light brown solid.<h2 style=";text-align:left;direction:ltr">RMN H1(400 MHz, CDCI3) δ = 7.56 - 7.37 (m, 1H), 7.24 - 7.19 (m, 1H), 7.15 - 7.06 (m, 2H), 6.04 - 5.94 (m, 2H), 5.57 (s, 0.2H), 5.21 (s, 0.8H), 4.50 - 4.38 (m, 1H), 4.31 - 4.21 (m, 2H), 3.74-3.72 (m, 2H), 3.61 - 3.47 (m, 1H), 3.35 - 3.17 (m, 1H), 3.10-3.07 (m, 1H), 3.02 - 2.78 (m, 1H), 2.77 - 2.55 (m, 1H), 1.44 (s, 9H), 1.39 (d, J = 6.4 Hz,0.6H), 1.16 (d, J = 6.4 Hz, 2.4H).<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> Step 4: N-(3,5-difluor-4-((1R,3R)-3-metil-2-(2,2,2-trifluoretyl)-2,3,4,9-tetrahydro-1H-pyridox[3,4-b]indol-1-yl)phenyl)azetidina-3-aminobutyric acid<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> MA / a / zuzz / uu 1 y 1 o<h2 style=";text-align:left;direction:ltr"> To a solution of tert-butyl 3-((3,5-difluoro-4-((1 R,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1 H-pyrido[3,4b]indol-1-yl)phenyl)amino)azetidine-1-carboxylate (from step 3, 10.0 g, 18.16 mmol) (trans :cis = 4:1) in 1,4-dioxane (120 ml) was added sulfuric acid (4.87 ml, 90.82 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 0.5 h. The reaction mixture was poured into saturated aqueous NaHCO3 solution (250 ml) and the mixture was extracted with EtOAc (200 ml χ 2). The combined organic phases were dried over Na2SO4 and concentrated to give the title compound (8 g, 97.8% yield) (trans:cis = 4:1) as a yellow solid. The crude compound was used directly in the next step. Step 5: To a mixture of N-(3,5-difluoro-4-((1 R,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1 H-pyrido[3,4-b]indol-1-yl)phenyl)azetidine-3-amine (from step 4, trans : cis = 4:1, 8.0 g, 17.76 mmol), DIPEA (8.83 ml, 53.28 mmol) and DMF (80 ml) was added dropwise 1-fluoro-3-iodopropane (3.34 g, 17.76 mmol). The reaction mixture was stirred at 20 °C for 16 hours. The reaction mixture was diluted with EtOAc (400 mL) and washed with brine (200 mL x 5). The combined organic layers were dried over Na2SO4, filtered, concentrated, and purified by column chromatography (10-40% EtOAc in DCM) to give the desired product (7 g, 77.2% yield) as a brown solid. This product was combined with another batch (12.3 g total) and purified by prep. HPLC (Phenomenex Synergi Max-RP 250*80mm*10 pm; 50-80% acetonitrile / 10 mM NH4HCO3 in water) to give 10 g of product (trans:cis = 4:1, inseparable by HPLC) as a white solid.By purifying this product (trans: cis = 4:1) by SFC (AD (250mm*30mm,10 pm) base-EtOH 40%), obtaining the pure 304 compound (5.9 g,. 157 yield = 59 %) in white solid form. NMR H1(400 MHz, CD3OD) δ = 7.40 (d, J = 7.6 Hz, 1H), 7.20 (d, J = 7.6 Hz, 1H), 7.05 - 6.91 (m, 2H), 6.09 (d, J = 12 Hz, 2H), 5.22 (s, 1H), 4.58 - 4.35 (m, 2H), 4.07-4.02 (m, 1H), 3.77 (t, J = 7.6 Hz, 2H), 3.62 - 3.50 (m, 1H), 3.39 - 3.32 (m, 1H), 3.06 - 2.90 (m, 4H), 2.66 - 2.55 (m, 3H), 1.87 - 1.66 (m, 2H), 1.17 (d, J = 6.4 Hz, 3H). Example 305 (1R,3R)-2-(2,2-d¡fluorethyl)-1-[2,6-difluor-4-[2-[3-(fluoromethyl)azet¡d¡n-1-¡l]ethoxi]phenyl]-3-met¡l-1,3,4,9tetrahydropyrido[3,4-b]indole 305 Step 1: (R)-N-(2,2-difluoroethyl)-1-(1H-indol-3-yl)-propane-2-amine F iviA / a / zuzz / uu / y / o A mixture of (2R)-1-(1H-indol-3-yl)propane-2-amine (4.2 g, 24.1 mmol), 2,2-difluoroethyl trifluoromethanesulfonate (5.16 g, 24.1 mmol), and diisopropylamine (8.41 mL, 48.2 mmol) was heated at 80 °C for 3 hours. The reaction mixture was cooled to room temperature, diluted with ¡PrOAc (150 mL), washed with water, brine, dried over sodium sulfate, filtered, and concentrated. The crude product was purified by flash column chromatography on silica gel eluting with 0 to 5% MeOH in DCM to give the title compound (5.6 g, 97% yield). H1 NMR(400 MHz, d-chloroform) δ = 8.03 (s, 1H), 7.63 - 7.54 (m, 1H), 7.36 (dt, J = 8.1.0.9 Hz, 1H), 7.27 - 7.17 (m, 1H), 7.12 (ddd, J = 8.0, 7.1,1.1 Hz, 1H), 5.78 (tdd, J = 56.6, 4.7, 4.1 Hz, 1H), 3.11 -2.76 (m, 5H), 1.12 (d, J = 6.2 Hz, 3H); LC-MS: 239.15 [M+H]+. Step 2: (1 R,3R)-2-(2,2-difluoroethyl)-1 -(2,6-difluoro-4-iodo-phenyl)-3-methyl-1,3,4,9-tetrahydroxindo[3,4-b]indole To a solution of (R)-N-(2,2-difluoroethyl)-1-(1H-indol-3-yl)propane-2-amine (5.0 g, 21 mmol) and 2,6-difluoro-4-iodobenzaldehyde (5.2 g, 19 mmol) in toluene (70 mL) was added acetic acid (2.4 mL), and the mixture was heated at 90 °C for 20 h under a nitrogen atmosphere. The reaction mixture was cooled and concentrated. The residue was dissolved in β-ProAc, washed with saturated sodium bicarbonate solution, water, brine, dried over sodium sulfate, and concentrated. Purification by flash chromatography (silica gel, 0-15% ProAc in heptanes) gave the title compound (7.8 g, 76%) as a 3:1 mixture of trans:cis isomers. LC-MS: 489.0 [M+H]+. The mixture was used as is for the next step. 158 Step 3: A mixture of (1R,3R)-2-(2,2-difluoroethyl)-1-(2,6-difluoro-4-iodo-phenyl)-3-methyl-1,3,4,9-tetrahydropindo[3,4-b]indole (8.0 g, 16.4 mmol), 2-[3-(fluoromethyl)azetidin-1-yl]ethanol (2.62 g, 19.7 mmol), cuprous iodide (0.94 g, 4.9 mmol), potassium carbonate (4.5 g, 32.8 mmol) and butyronitrile (33 ml) was degassed for 5 min and heated at 140 °C overnight. The reaction mixture was filtered through Celite eluting with µPrOAc. The filtrate is concentrated, purified by reverse-phase HPLC and the cis:trans isomers are separated by chiral SFC, yielding compound 305 (3.77 g, yield = 44%). H1 NMR(400 MHz, DMSO-d6) δ = 10.59 (s, 1H), 7.40 (dd, J = 7.9.1.3 Hz, 1H), 7.22 - 7.14 (m, 1H), 7.04-6.88 (m, 2H), 6.66 (d, J = 11.1 Hz, 2H), 6.05 - 5.61 (m, 1H), 5.17 (d, J = 1.7 Hz, 1H), 4.50 (dd, J = 47.6, 6.2 Hz, 2H), 3.94 (t, J = 5.3 Hz, 2H), 3.41 - 3.32 (m, 2H), 3.15 - 2.90 (m, 3H), 2.90 - 2.52 (m, 7H), 1.09 (d, J = 6.5 Hz, 3H).CL-EM: 494.2 [M+H]+. iviA / a / zuzz / uu / y to Example 306 (1S,3R)-2-(2,2-difluoroethyl)-1-[2,6-difluoro-4-[2-[3-(fluoromethyl)azet¡din-1-yl]ethoxy¡]phen¡l]-3-methyl-1,3,4,9-tetrahydro¡r¡r¡4,bdo[3,4,6-3] With arrangement to the procedures of Example 305 compound 306 is obtained. CL-EM: 494.2 [M+H]+. Example 340 3-[(1R,3R)-1-[2,6-d¡fluor-4-[[1-(3-fluoroprop¡l)-azet¡d¡n-3-¡l]am¡no]phen¡l] -3-met¡l-1,3,4,9-tetrah¡dropyr¡do-[3,4b]indol-2-yl]-2,2-d¡fluoro-propan-1-ol 340 Step 1: (R)-N-(1-(1 H-indol-3-yl)propan-2-yl)-3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropano-1-amine F\ / FOTBDPS A mixture of (2R)-1-(1H-indol-3-yl)propane-2-amine (29 g, 166.44 mmol), [3-[tert-butyl(diphenyl)silyl]oxy-2,2-dfluoropropyl] trifluoromethanesulfonate (80.31 g, 166.44 mmol), DIPEA (55.01 ml, 332.87 mmol), and 1,4-dioxane (600 ml) was stirred at 90 °C for 12 h. The reaction mixture was diluted with water (600 ml) and extracted with EtOAc (600 ml χ 2). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated. The crude residue was purified by column chromatography on silica gel (40% EtOAc in petroleum ether) to give the title compound (69 g, 82%) as a light yellow oil. H1 NMR(400 MHz, CDCI3) δ = 7.88 (s, 1H), 7.66 (d, J=7.2 Hz, 4H), 7.60 (d, J=8.0 Hz, 1H), 7.48 - 7.33 (m, 7H), 7.22 - 7.08 (m, 2H), 7.01 (s, 1H), 3.86 - 3.79 (m, 2H), 3.23 - 3.09 (m, 3H), 2.86 - 2.80 (m, 2H), 1.13 (d, J=6.4 Hz, 3H), 1.05 (s, 9H). EM = [M+H]+507.1. Step 2: (R)-3-((1-(1H-indol-3-yl)propan-2-¡l)amino)-2,2-difluoropropan-1-ol HN-V N To a stirred solution of (R)-N-(1-(1 H-indol-3-yl)propan-2-yl)-3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropane-1-amine (from step 1, 69 g, 136.18 mmol) in THF (690 ml) is added 1 M TBAF (272.35 ml, 272.35 159 mmol) in THF. The mixture was stirred at 25 °C for 4 hours. The reaction mixture was diluted with water (800 ml) and extracted with EtOAc (800 ml χ 3). The combined organic layers were concentrated, and the crude residue was purified by column chromatography on silica gel (50% EtOAc / petroleum ether) to give the title compound (29 g, 79%) as a light yellow oil. Step 3: 3-((1R,3R)-1-(4-bromo-2,6-difluorophenyl)-3-methyl-3,4-dihydro-1H-pyr¡do[3,4-b]indol-2(9H)-yl)-2,2difluoropropan-1-ol ινΐΛ / a / zuzz / uu / and ιό F\ / FOH A mixture of (R)-3-((1-(1 H-indol-3-yl)propan-2-yl)amino)-2,2-difluoropropan-1-ol (from step 2, 20 g, 74.54 mmol), acetic acid (12.91 ml, 223.63 mmol), 4-bromo-2,6-difluorobenzaldehyde (16.47 g, 74.54 mmol) and toluene (400 ml) was stirred at 90 °C for 12 hours. The reaction mixture was diluted with water (500 ml) and extracted with EtOAc (500 ml χ 2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated. The crude residue was purified by column chromatography on silica gel (20% EtOAc / petroleum ether) to give the title compound (24.8 g, 71%, trans / cis = 20 / 1) as a light yellow solid. MS = [M+H]+470.9. Step 4: tert-butyl 3-((4-((1 R,3R)-2-(2,2-difluor-3-hydroxy-propyl)-3-methyl-2,3,4,9-tetrahydro-1 H-pyrido[3,4-b]indol-1-yl)3,5-difluorophenyl)amino)azet¡dine-1-carboxylate A mixture of 3-((1R,3R)-1-(4-bromo-2,6-difluorophenyl)-3-methyl-3,4-dihydro-1H-pyrido[3,4-b]indol-2(9H)-yl)-2,2-dfluoropropan-1-ol (from step 3, 24.8 g, 52.62 mmol), Pd2(dba)3 (4.82 g, 5.26 mmol), Xantphos (6.09 g, 10.52 mmol), Cs2CO3 (51.44 g, 157.86 mmol), 3-aminoazetidine-1-carboxylic acid tert-butyl ester (13.59 g, 78.93 mmol) and 2-(2-amino-2-ol)-2-ol was stirred at 110 °C for 3 hours under a N2 atmosphere. 1,4-dioxane (300 ml). The reaction mixture was cooled to 25 °C, diluted with water (500 ml), and extracted with EtOAc (500 ml χ 2). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated. The crude residue was purified by column chromatography on silica gel (20% petroleum ether in EtOAc) to give the title compound (20.5 g, 69%, trans / cis = 20 / 1) as a yellow solid. MS = [M+H]+563.0. 160 Step 5: 3-((1 R,3R)-1 -(4-(azetidin-3-ylamino)-2,6-di-fluorophenyl)-3-methyl-3,4-dihydro-1 H-pyrido[3,4-b]indol2(9H)-yl)-2,2-difluoropropan-1-ol IVIA / a / ¿U¿¿ / UU ÍXfO To a solution of tert-butyl 3-((4-((1 R,3R)-2-(2,2-difluoro-3-hydroxypropyl)-3-methyl-2,3,4,9-tetrahydro-1 H-pyrido[3,4-b]indol-1-yl)-3,5-dfluorophenyl)amino)azetidine-1-carboxylate (from step 4, 20.5 g, 36.44 mmol) in 1,4-dioxane (194 ml) was added dropwise sulfuric acid (19.42 ml, 364.38 mmol) on an ice bath. The reaction mixture was stirred at 25 ° C for 0.5 h. The reaction mixture was poured into saturated aqueous NaHCO3 solution (800 ml) and extracted with EtOAc (600 ml χ 2). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated to give the title compound (18 g, crude, trans / cis = 20 / 1) as a yellow solid. The crude residue was used directly in the next step. MS = [M+H]+463.0. Step 6: A mixture of 3-((1R,3R)-1-(4-(azetidin-3-ylamino)-2,6-difluorophenyl)-3-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-yl)-2,2-dfluoropropan-1-ol (from step 5.18 g, 38.92 mmol), DIPEA (19.3 ml, 116.76 mmol), 1-fluoro-3-iodopropane (7.32 g, 38.92 mmol) and DMF (180 ml) was stirred at 25 °C for 12 hours. The reaction mixture was diluted with EtOAc (500 ml) and washed with brine (500 ml x 3). The organic phases were combined, dried over anhydrous Na2SO4, filtered, and concentrated. The crude residue was purified by column chromatography on silica gel (10% MeOH in DCM) to give the desired product (7.1 g, purity = 85%) as a yellow oil. The resulting residue was further purified by reverse-phase chromatography (40-75% acetonitrile in 0.05% NH4OH in water) and chiral SFC (AD 250mm*50mm, 10 pm; supercritical CO2 / EtOH (0.1% NH3H2O) = 40 / 40 at 200 ml / min) to give compound 340 (2.85 g, 14%) as a light yellow solid.<h2 style=";text-align:left;direction:ltr">RMN H1(400 MHz, CD3OD) δ = 7.39 (d, J = 7.2 Hz, 1H), 7.19 (d, J = 8.0 Hz, 1H), 7.01 - 6.93 (m, 2H), 6.11 (d, J = 12.0 Hz, 2H), 5.16 (s, 1H), 4.52 - 4.38 (m, 2H), 4.05 - 4.03 (m, 1H), 3.80 - 3.74 (m, 3H), 3.63 - 3.42 (m, 2H), 3.20 - 3.10 (m, 1H), 2.96 - 2.92 (m, 3H), 2.82 - 2,71 (m, 1H), 2.64 - 2.58 (m, 3H), 1.81 -1.68 (m, 2H), 1.14 (d, J = 6.4 Hz, 3H); EM = [M+H]+523.2.<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> Example 365<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> 3-((1 365<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> Paso 1: ([3-(tert-but¡ld¡fenil-silan¡lox¡)-2,2-d¡fluor-propil]-[2-(5-fluor-1 H-índol-3-il)-1 -metil-etil]-amína<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> iviA / a / zuzz / uu / y<h2 style=";text-align:left;direction:ltr"> A mixture of [3-[tert-butyl(diphenyl)syl]oxy-2,2-difluoropropyl] trifluoromethanesulfonate (from Example 286, Step 2, 43.22 g, 896 mmol), DIPEA (19.5 ml, 112.0 mmol), 2-(5-Fluor-1-Hindol-3-yl)-1-methylethylamine (CAS No. 712-08-3, 14.7 g, 74.7 mmol), and dioxane (140 ml) was stirred at 90 °C for 3 hours. The mixture was cooled to room temperature, diluted with EtOAc, washed with water (x 2), brine, dried over anhydrous Na2SO4, filtered, and concentrated. The crude residue was purified by column chromatography on silica gel (mobile phase: DCM) to give the title compound (32.8 g, 96%) as a yellow oil. H1 NMR(400 MHz, CDCI3): δ = 7.89 (s, 1H), 7.69-7.61 (m, 4H), 7.48 - 7.34 (m, 6H), 7.26-7.19 (m, 2H), 7.03 - 7.02 (m, 1H), 6.93 (dt, J = 2.5, 9.0 Hz, 1H), 3.88 - 3.78 (m, 2H), 3.22 - 3.03 (m, 3H), 2.84 - 2.70 (m, 2H), 1.11 (d, J = 6.2 Hz, 3H), 1.04 (s, 9H). LC-MS: 525.3 [M+H]+. <h2 style=";text-align:left;direction:ltr">Paso 2: 2-[3-(tert-but¡ld¡fenil-s¡lan¡lox¡)-2,2-d¡fluor-prop¡l]-1-(2,6-d¡fluor-4-yodo-fen¡l)-6-fluor-3-met¡l2,3,4,9-tetrahidro-1 H-beta-carbolina<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> To a solution of [3-(tert-butylphenylsilanyloxy)-2,2-difluoropropyl]-[2-(5-fluoro-1H-indole-3-yl)-1-methylethyl]amine (32.8 g, 62.5 mmol) in toluene (65 mL) was added 4-iodo-2,6-difluorobenzaldehyde (20.1 g, 75.0 mmol) and acetic acid (7.2 mL, 125.0 mmol). After complete addition, the reaction mixture was stirred at 90 °C for 14 hours. The mixture was allowed to cool to room temperature, diluted with EtOAc, washed with saturated aqueous NaHCO3 solution (3x), brine, dried over anhydrous Na2SO4, and concentrated. The residue was purified by chromatography on silica gel (mobile phase: toluene in cyclohexane, gradient 10 to 50%) to give the title compound (34.9 g, 72%) as a matte white foam.NMR H1(400 MHz, CDCI3): δ = 7.65 - 7.60 (m, 4H), 7.46 - 7.33 (m, 7H), 7.21 - 7.08 (m, 4H), 6.90 - 6.84 (m, 1H), 5.27 (s, 1H), 3.99 - 3.88 (m, 1H), 3.65 - 3.54 (m, 2H), 3.33 - 3.20 (m, 1H), 2.93 (ddd, J = 1.4, 4.9,15.2 Hz, 1H), 2.81 - 2.69 (m, 1H), 2.56 - 2.51 (m, 1H), (d, J = 6.6 Hz, 3H), 1.05(s, 9H). CL-EM: 775.2 [M+H]+. Step 3: 3-(4-{2-[3-(tert-but¡l-diphen¡ls¡lan¡lox¡)-2,2-d¡fluoro-propyl]-6-fluoro-3-methyl-2,3,4,9-tetrah¡dro-1H beta-carbolin-1-yl}-3,5-difluoro-phenylamino)-azetid¡ne-1-carboxylate de tert-butyl 162 ινΐΛ / a / zuzz / uu / y A mixture of 2-[3-(tert-butyl-diphenylsilaneoxy)-2,2-dfluoropropyl]-1-(2,6-difluoro-4-iodophenyl)-6-fluoro-3-methyl-2,3,4,9-tetrahydro-1H-beta-carboline (30.8 g, 39.8 mmol), XantPhos (4.60 g, 7.9 mmol), Pd2(dba)3 (3.64 g, 4.0 mmol), Cs2CO3 (25.9 g, 79.4 mmol), 3-aminoazetidine-1-carboxylic acid tert-butyl ester (10.3 g, 59.6 mmol) was stirred at 115 °C under an argon atmosphere in a sealed flask for 1.5 hours. and 1,4-dioxane (192 ml). The reaction mixture was allowed to cool to room temperature, the residual solid was filtered off through a pad of Celite®, and the filtrate was concentrated. The resulting residue was purified by flash chromatography on silica gel (mobile phase: EtOAc in DCM, gradient 0 to 5%) to give the title compound (27.9 g, 76%) as a beige foam.<h2 style=";text-align:left;direction:ltr">RMN H1(400 MHz, CDCI3): δ = 7.67 - 7.58 (m, 4H), 7.48 - 7.32 (m, 6H), 7.15 - 7.06 (m, 2H), 6.88 - 6.80 (m, 1H), 5.88 - 5.80 (m, 2H), 5.15 (s, 1H). (dd, J = 3.3.15.1 Hz, 1H), 1.44 (s, 9H), 1.13 (d, J = 6.5 Hz, 3H), 1.04 (s, 9H). CL-EM: 819.4 [M+H]+.<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> Paso 4: azetidin-3-¡l-(4-{2-[3-(tert-butil-difenil-silan¡lox¡)-2,2-difluor-prop¡l]-6-fluor-3-metil-2,3,4,9tetrahidro-1 H-beta-carbolin-1-il}-3,5-difluor-fen¡l)-am¡na<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> Under a nitrogen atmosphere, a solution of concentrated sulfuric acid premixed with ice (9.1 ml, 170.2 mmol) in dioxane (100 ml) is slowly added at room temperature to a solution of tert-butyl 3-(4-{2-[3-(tert-butyldiphenylsilanyloxy)-2,2-dfluoropropyl]-6-fluoro-3-methyl-2,3,4,9-tetrahydro-1H-beta-carbolin-1-yl}-3,5-dfluorophenylamino)azetidine-1-carboxylate (27.9 g, 34.0 mmol) in dioxane (275 ml) After the addition is complete, the reaction mixture is stirred at room temperature for 1 hour. EtOAc and water were added, and the pH of the aqueous phase was adjusted to 9 by the addition of solid Na2CO3. The organic phase was separated, washed with brine (x 3), dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound (mixture of (R,R) & (S,S) diastereoisomers). 163 as a pale orange foam (26.6 g, quantitative yield). LC-MS: 719.4 [M+H]+. Step 5: (4-{2-[3-(tert-but¡ld¡phenyl-s¡lanylox¡)-2,2-d¡fluorine-prop¡l]-6-fluorine-3-met¡l-2,3,4,9-tetrahydro-1H beta-carbolin-1 -yl}-3,5-difluoride-[1-phenyl)- -(3-fluoro-propyl)-azetid¡n-3-¡l]-am¡na The title compound was obtained from azetidin-3-yl-(4-{2-[3-(tert-butyl-diphenyl-silanyloxy)-2,2-difluoropropyl]-6-fluoro-3-methyl-2,3,4,9-tetrahydro-1H-beta-carbolin-1-yl}-3,5-difluoro-phenyl)-amine (26.6 g, 34.0 mmol) and 1-iodo-3-fluoropropane (9.60 g, 51.1 mmol; CAS No. 462-40-8) according to the procedure described for the preparation of the compound of Example 101. The crude product was purified by chromatography on silica gel (mobile phase: dichloromethane / methanol, gradient 0% to 5%) to afford the title compound as a pale brown foam. (14.9 g, 56%).RMN H1(400 MHz, CDCI3): δ 7,69 - 7,56 (m, 4H), 7,50 (s, 1H), 7,47 - 7,30 (m, 6H), 7,16 - 7,01 (m, 2H), 6,87-6,81 (m, 1H), 5,92 - 5,78 (m, 2H), 5,14 (s, 1H), 4,54 (t, J = 6,0 Hz, 1H), 4,42 (t, J = 6,0 Hz, 1H), 4,18 (d, J = 7,0 Hz, 1H), 4,06 - 3,86 (m, 2H), 3,74 - 3,47 (m, 4H), 3,30 - 3,10 (m, 1H), 3,00-2,70 (m, 3H), 2,56 (t, J = 7,2 Hz, 2H), 2,53-2,45 (m, 1H), 1,85- 1,50 (m, 3H), 1,12 (d, J = 6,5 Hz, 3H), 1,04 (s, 9H). CL-EM: 779,4 [M+H]+. Paso 6: 3-(1-{2,6-difluor-4-[1-(3-fluor-propil)-azet¡d¡n-3-¡lam¡no]-fen¡l}-6-fluor-3-met¡l-1,3,4,9tetrahidro-beta-carbolin-2-il)-2,2-difluor-propan-1-ol Under argon atmosphere, a mixture of (4-{2-[3-(tert-butyl-diphenylsilananyloxy)-2,2-dfluoro-propyl]-6-fluoro-3-methyl2,3,4,9-tetrahydro-1H-beta-carbolin-1-yl}-3,5-difluoro-phenyl)-[1-(3-fluoro-propyl)-azetidin-3-yl]-amine (12.1 g, 15.5 mmol) and THF (150 ml) was added with 1M solution of TBAF in THF (23.3 ml) and the reaction mixture was stirred at room temperature for 5 hours. The reaction mixture was diluted with EtOAc and washed with water (x 4). The organic phase was dried over Na2SO4, filtered and concentrated in vacuo. The crude product is purified by chromatography on silica gel (mobile phase: 2M ammonia in methanol / TBME, gradient from 0.5% to 5%), giving a mixture of 164 (R,R)- and the (S,S)-3-(1-{2,6-difluoro-4-[1-(3-fluoro-propyl)-azetidin-3-yl-annino]-phen¡l}-6-fluoro-3-methyl-1,3,4,9-tetrahydro-betacarbolin-2-yl)-2,2-d¡fluoro-propan-1-ol. The pair of diastereoisomers is separated by chiral HPLC (ChiralPak IB, 15% EtOH in heptane + 0.1% diethylamine). Compound 365 corresponds to the second peak isolated by chiral HPLC: (1.90 g, 23%); peak 2 rt = 15 min. NMR H1(400 MHz, CDCI3): δ = 7.46 (s, 1H), 7.16 - 7.08 (m, 2H), 6.86 (dt, J = 2.5, 9.0 Hz, 1H), 6.08 - 6.00 (m, 2H), 5.09 (s, 1H), 4.54 (t, J = 5.9 Hz, 1H), 4.43 (t, J = 5.9 Hz, 1H), 4.38 (d, J = 6.7 Hz, 1H), 4.07 - 3.97 (m, 1H), 3.80 - 3.56 (m, 6H), 3.28 - 3.16 (m, 1H), 3.11 - 3.02 (m, 1H), 2.97 - 2.82 (m, 3H), 2.64 - 2.55 (m, 3H), 1.82 - 1.67 (m, 2H), 1.16 (d, J = 6.5 Hz, 3H). CL-EM: 541.4 [M+H]+. Example 366 3-((1S,3S)-1-(2,6-difluoro-4-((1). -(3-fluoroprop¡l)azet¡d¡n-3-¡l)amino)phen¡l)-6-fluoro-3-methyl-1,3,4,9-tetrahydro-2Hpyrido[3,4-b]indol-2-¡l)-2,2-difluoropropan-1-ol 366 With arrangement to the procedures of Example 365, the first peak isolated by chiral HPLC corresponds to compound 366: (1.95 g, 24%). Peak 1 rt = 12 min. NMR H1(400 MHz, CDCI3): δ = 7.46 (s, 1H), 7.16 - 7.08 (m, 2H), 6.86 (dt, J = 2.5, 9.0 Hz, 1H), 6.08 - 6.00 (m, 2H), 5.09 (s, 1H), 4.54 (t, J = 5.9 Hz, 1H), 4.43 (t, J = 5.9 Hz, 1H), 4.38 (d, J = 6.7 Hz, 1H), 4.07 - 3.97 (m, 1H), 3.80 - 3.56 (m, 6H), 3.28 - 3.16 (m, 1H), 3.11 - 3.02 (m, 1H), 2.97 - 2.82 (m, 3H), 2.64 - 2.55 (m, 3H), 1.82 - 1.67 (m, 2H), 1.16 (d, J = 6.5 Hz, 3H). CL-EM: 541.4 [M+H]+. Example 368 3-((1 R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)-azetidin-3-yl)oxy)phenyl)-6-fluoro-3-met¡l-1,3,4,9-tetrahydro-2Hpyrido[3,4-b] indole-2-i I )-2-fluoro-2-methyl propan-1 -ol 368 Step 1: [3-(tert-butyl-diphenyl-silaniloxy)-2-fluoro-2-methyl-propyl]-[2-(5-fluoro-1 H-indol-3-yl)-1 -methyl-ethyl]-am¡na ΜΛ / a / zuzz / uu 1 and 1 o Under argon atmosphere, 3-(tert-butyl-diphenylsilanoloxy)-2-fluoro-2-methylpropyl 3-fluoromethanesulfonate, intermediate XX (3.09 g, 9.48 mmol) was added to a solution of 2-(5-fluoro-1H-indol-3-yl)-1-methylethylamine (CAS No. 712-08-3, 3.61 g, 18.7 mmol) and DIPEA (4.9 ml, 28.1 mmol) in dioxane (43 ml). The resulting mixture was stirred at 90 °C for 6 h. The reaction mixture was partitioned between EtOAc and water. The organic phase was separated, washed further with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by chromatography on silica gel (mobile phase: dichloromethane / methanol, gradient 0% to 5%) to give a mixture of diastereoisomers of the title compound as a yellow oil (8.0 g, 82%).<h2 style=";text-align:left;direction:ltr">RMN H1(300 MHz, CDCh): δ = 7.82 (ancha s, 1H), 7.68 - 7.63 (m, 4H), 7.52 - 7.38 (m, 6H), 7.25 - 7.18 (m, 2H), 7.02 - 6.98 (m, 1H), 6.92 (dt, J = 2.4, 9.1 Hz, 1H), 3.82 - 3.57 (m, 5H), 3.02 - 2.65 (m, 6H), 1.33 (d, J = 22.0 Hz, 3H), 1.1 - 1.0 (m, 9H); CL-EM: 521.3 [M+H]+.<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> Paso 2: 3-(4-{2-[3-(tert-butil-difenil-silaniloxi)-2-fluor-2-metil-propil]-6-fluor-3-metil-2,3,4,9-tetrahidro-1 H165 beta-carbolin-1-il}-3,5-d¡fluor-fenoxi)-azetidina-1-carboxilato de tert-butilo ivix / a / zuzz / uu / y<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> The title compound is obtained from [3-(tert-butyl-diphenylsilaneoxy)-2-fluoro-2-methylpropyl]-[2-(5-fluoro-1H-indol-3-yl)-1-methylethyl]-amine, intermediate 1a (8 g, 15.3 mmol) and tert-butyl 3-(3,5-difluoro-4-formylphenoxy)azetidine-1-carboxylate 101c (5.6 g, 18.1 mmol) according to the procedure described for the preparation of intermediate 101e. The crude product was purified by chromatography on silica gel (mobile phase: cyclohexane / ethyl acetate, gradient 0% to 20%) to give a mixture of diastereoisomers of the title compound as a white foam (8.0 g, 64%).<h2 style=";text-align:left;direction:ltr">RMN H1(300 MHz, CDCb): δ = 7.65 - 7.54 (m, 4H), 7.47 - 7.30 (m, 7H), 7.17 - 7.08 (m, 2H), 6.84 (dt, J = 2.4, 9.0 Hz, 1H), 6.23 - 6.07 (m, 2H), 5.16 (s, 1H), 4.71 -4.63 (m, 1H), 4.29 - 4.18 (m, 2H), 3.99 - 3.88 (m, 2H), 3.79 (dd, J = 11.5, 16.8 Hz, 1H), 3.64 - 3.54 (m, 1H), 3.50 - 3.29 (m, 1H), 3,10 2,83 (m, 2H), 2,69 - 2,39 (m, 2H), 1,54 (s, 3H), 1,46 - 1,40 (m, 9H), 1,29 - 0,98 (m, 12H); CL-EM: 816.5 [M+H]+.<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> Paso 3: 1-[4-(azetidin-3-ilox¡)-2,6-d¡fluor-fenil]-2-[3-(tert-butil-d¡fen¡l-silaniloxi)-2-fluor-2-metil-propil]-6-fluor3-metil-2,3,4,9-tetrahidro-1 H-beta-carbolina<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> Under an argon atmosphere, a mixture of tert-butyl 3-(4-{2-[3-(tert-butyl-diphenyl-silanyloxy)-2-fluoro-2-methyl-propyl]-6-fluoro-3-methyl-2,3,4,9-tetrahydro-1H-beta-carbolin-1-yl}-3,5-dfluoro-phenoxy)-azetidine-1-carboxylate, intermediate 2a (8.0 g, 9.80 mmol) and dioxane (80 ml) was added dropwise at 0°C a solution of concentrated sulfuric acid (2.62 ml, 49.0 mmol) in dioxane (27 ml), the mixture was allowed to warm, protected from light, to room temperature and stirred for 3.5 h. The reaction mixture was diluted with EtOAc and saturated NaHCO3 solution, stirred for 10 min, and the layers were separated. The organic layer was further washed with saturated NaHCO3 solution, brine, dried over Na2SO4, filtered, and concentrated in vacuo to give a mixture of diastereoisomers of the title compound as a pale yellow foam (7.05 g, quantitative yield). 1H NMR (300 MHz, CDCb): <h2 style=";text-align:left;direction:ltr">6 δ = 7.66 - 7.54 (m, 4Η), 7.47 - 7.30 (m, 7H), 7.17 - 7.06 (m, 2H), 6.84 (dt, J = 2.4, 9.0 Hz, 1H), 6.25 - 6.09 (m, 2H), 5.16 (s, 1H), 4.86 - 4.76 (m, 1H), 3.94 - 3.65 (m, 3H), 3.63 - 3.54 (m, 1H), 3.49 - 3.24 (m, 1H), 3.11 - 2.83 (m, 2H), 2.69 2.39 (m,2H), 1.54 (s, 3H), 1.27-1.12 (m, 3H), 1.11 -0.98 (m, 12H); CL-EM: 716.4 [M+H]+.<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> Paso 4: 2-[3-(tert-butil-d¡fenil-s¡lan¡lox¡)-2-fluor-2-met¡l-prop¡l]-1-{2,6-difluor-4-[1-(3-fluor-propil)-azetid¡n-3iloxi]-fenil}-6-fluor-3-metil-2,3,4,9-tetrah¡dro-1 H-beta-carbolina iviA / a / zuzz / uu / y ic<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> The title compound was obtained from 1-[4-(azetidín-3-yloxy)-2,6-difluoro-phenyl]-2-[3-(tert-butyldiphenyl-silanyloxy)-2-fluoro-2-methyl-propyl]-6-fluoro-3-methyl-2,3,4,9-tetrahydro-1 H-beta-carboline, intermediate 3a (7.05 g, 9.84 mmol) and 1-iodo-3-fluoropropane (2.77 g, 14.7 mmol; CAS No. 462-40-8) according to the procedure described for the preparation of example 101. The crude product was purified by chromatography on silica gel (mobile phase: dichloromethane / methanol, gradient from 0% to 3%) to yield the title compound. white foam form (5.7 g, 75%). LC-MS: 776.4 [M+H]+. Step 5: Racemic 3-(1-{2,6-difluor-4-[1-(3-fluoro-propyl)-azet¡din-3-¡lox¡]-phen¡l}-6-fluor-3-methyl-1,3,4,9-tetrahydro-beta tree in-2-yl)-2-f I uor-2-methyl-propan-1 -ol Under argon atmosphere, a mixture of 2-[3-(tert-butylphenylsilanyloxy)-2-fluoro-2-methylpropyl]-1-{2,6-difluoro-4-[1-(3-fluoropropyl)azetidin-3-yloxy]phenyl}-6-fluoro-3-methyl-2,3,4,9-tetrahydro-1H-beta-carboline intermediate 4a (5.17 g, 6.66 mmol) and THF (80 mL) was added with 1M TBAF solution in THF (10 mL) and the reaction mixture was stirred at room temperature for 24 h. The reaction mixture was poured into a mixture of water and brine and extracted with EtOAc. The aqueous phase is further extracted with EtOAc, the organic phases are combined, washed further with water and brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product is purified by chromatography on silica gel (mobile phase: dichloromethane / methanol, gradient from 0% to 6%), yielding two 167 diastereomeric pairs (diastereomers 1 and 2). Diastereomeric pair 1 is further purified by chiral HPLC (ChiralPak IC, 25% IPA in heptane + 0.1% diethylamine). The first isolated peak (rt = 8.2 min) = 368 is isolated as a white solid (467 mg, 13%). H1 NMR(400 MHz, CDCI3): 7.32 (wide s, 1H), 7.17 - 7.09 (m, 2H), 6.89 - 6.83 (m, 1H), 6.38 - 6.33 (m, 2H), 5.03 (s, 1H), 4.76 - 4.69 (m, 1H), 4.55 (t, 1H, J = 5.9 Hz), 4.47 - 4.41 (m, 2H), 4.00 (t, 1H, J = 4.9 Hz), 3.83 - 3.76 (m, 2H), 3.60 (q, 1H, J = 10.3 Hz), 3.46 - 3.34 (m, 1H), 3.23 - 3.09 (m, 4H), 2.67 - 2.57 (m, 4H), 1.84 - 1.69 (m, 2H), 1.14 -1.08 (m, 6H); LC-MS: 538.3 [M+H]+. Example 369 3-((1 S,3S)-1 -(2,6-difluor-4-((1-(3-fluoropropyl)-azetidin-3-yl)ox¡)pheníl)-6-fluor-3-methyl-1,3,4,9-tetrahydro-2Hpyrido[3,4-b]indol-2-ii)-2-fluor-2-methylpropan-1 -ol 369 According to the procedures of example 368 the second chiral HPLC peak (rt = 15.5 min) = 369 is isolated as a white solid (480 mg, 13.5%). Example 370 3-((1 R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)-azet¡din-3-yl)oxy)phenyl)-6-fluoro-3-methyl-1,3,4,9-tetrahydro-2Hpí rido[3,4-b]indol-2-i I )-2-fluor-2-methyl propan-1 -ol 370 According to the procedures of Example 368, the diastereomeric pair 2 is purified by chiral HPLC (ChiralPak IC, 35% IPA in heptane + 0.1% diethylamine). The first isolated peak is further purified by chiral HPLC (ChiralPak IC, 35% IPA in heptane + 0.1% diethylamine): the first isolated peak (rt = 8.5 min) = 370 is isolated as a white solid (165 mg, 5%). H1NMR(400 MHz, CDCI3): 7.53 (wide s, 1H), 7.16 - 7.12 (m, 2H), 6.90 6.84 (m, 1H), 6.33-6.28 (m, 2H), 5.35 (s, 1H), 4.76 - 4.68 (m, 1H), 4.55 (t, 1H, J = 5.9 Hz), 4.45 - 4.41 (m, 1H), 3.853.54 (m, 6H), 3.16 - 2.92 (m, 4H), 2.79 (t, 1H, J = 15.7 Hz), 2.68 - 2.56 (m, 3H), 1.77 (tdd, J = 6,7,19,3,19,3 Hz, 2H), 1.23 -1.15 (m, 6H); LC-MS: 538.3 [M+H]+. Example 371 3-((1S,3S)-1-(2,6-difluor-4-((1-(3-fluoropropyl)-azetidin-3-yl)oxy)phenyl)-6-fluor-3-methyl-1,3,4,9-tetrahydro-2Hpyrido[3,4-b]indol-2-i I )-2-fluor-2-methyl propan-1 -ol 371 Diastereoisomer pair 2 was purified by chiral HPLC (ChiralPak IC, 35% IPA in heptane + 0.1% diethylamine) according to the procedures of Example 368. The second isolated peak (rt = 14 min) = 371 was isolated as a white solid (180 mg, 5%). Other illustrative compounds of formula I in Table 2a have the following structures, corresponding names (ChemBioDraw, version 12.0.2, CambridgeSoft Corp., Cambridge MA), and biological activity. If a compound or intermediate of formula I has more than one name associated with it, then the chemical structure will be used to define the compound. Table 2a ινΐΛ / a / zuzz / uu fxfo 168 <h2 style=";text-align:left;direction:ltr">n° estructura number ER-alfa MCF7 HCS ECso(mM) CL-EM [M+H]+ 431 F OH RJ n-^ rrv, r H (R)-3-((1R,3R)-1-(2,6-difluor-4((1 -(3-fluorpropi l)azet id i n-3il)amino)fenil)-6-fluor-3-metil1,3,4,9-tetrah¡dro-2H-pirido[3,4b]indol-2-il)-2-fluor-2metilpropan-1-ol 0,0000943 537,3 432 F OH R f TXVá / f Hf^O hnX)n^^f (S)-3-((1S,3S)-1-(2,6-difluor-4- ((1-(3-f luorpropi) l)azet id i n-3il)amino)fenyl)-6-fluor-3-metil1,3,4,9-tetrahydro-2H-pyridoxine[3,4-b]indol-2-il)-2-fluor-2-methylpropan-1 -ol 0,00327 537,3 433 F OH R d N--^ ΥΪH ; HF \== / (S)-3-((1R,3R)-1-(2,6-difluor-4((1 -(3-f luorpropi l)azet i n-3il)amino)fenil)-6-fluor-3-metil1,3,4,9-tetrahidro-2H-pirido[3,4b]indol-2-il)-2-fluor-2metilpropan-1 -ol 0,0000209 537,3 434 F OH f n-3il)amino)fenil)-6-fluor-3-metil1,3,4,9-tetrahidro-2H-pirido[3,4b]indol-2-il)-2-fluor-2metilpropan-1 -ol 0.000706 537.3<h2 style=";text-align:left;direction:ltr"> Example 431 (R)-3-((1 R,3R)-1-(2,6-d¡fluoro-4-((1-(3-fluoropropyl)-azet¡d¡n-3-¡l)am¡no)phen¡l)-6-fluoro- 3-methl-1,3,4,9-tetra-hydro2H-pyrido[3,4-b]indole-2-l)-2-fluoro-2-methlpropane-1 -ol 431 Step 1: 3-((tert-butyldiphen¡lsilyl)ox¡)-2-fluoro-N-(1-(5-fluoro-1 H-indol-3-yl)propan-2-¡l)-2-met¡lpropano-1 amine 169 ινΐΛ / a / zuzz / uu / y / o To a solution of 1-(5-fluoro-1H-indol-3-yl)propane-2-amine (5.30 g, 26.2 mmol, 95%, synthesized according to Yeung et al., J. Med. Chem. 53,5155-5164,2010) in 1,4-dioxane (105 ml) cooled with an ice bath are added N,N-diisopropylethylamine (6.85 ml) and then [3-[tert-butyl(diphenyl)syl]oxy-2-fluoro-2-methylpropyl] trifluoromethanesulfonate (13.80 g, 28.8 mmol) in dioxane (10 ml), according to example 154, step 5. The mixture is heated at 90 °C (bath) for 18 h. The mixture is concentrated. Dilute Na2Cl3 is added. The contents are extracted with DCM (2x). The extracts are combined, dried (Na2SO4), and concentrated. The crude residue is purified by flash chromatography (0-50% ProOAc in heptane with 1% TEA) to give the product (10.38 g, 76%). Steps 2-5: N-(4-(2-(3-((tert-but¡ldiphen¡lsilyl)oxy)-2-fluoro-2-methylpropyl)-6-fluoro-3-methyl-2,3,4,9-tetrahydro1 H-pyrido[3,4-b]indol-1-l)-3,5-difluorophenyl)-1-(3-fluoropropyl)-azethina-3-amine The compound is obtained in a similar manner to example 145. Step 6: Racemic 3-(1-(2,6-difluor-4-((1-(3-fluoropropyl)-azetidin-3-yl)amino)phenyl)-6-fluor-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-fluoro-2-methylpropan-1-ol Combine solution of the N-[4-[(1 R,3R)-2-[3-[tert-butyl(diphenyl)silyl]oxy-2-fluor-2-methyl-prop¡l]-6-fluor-3-methyl-1,3,4,9tetrahydro¡dropído[3,4-b]indol-1-¡l]-3,5-difluoro-phen¡l]-1-(3-fluoroprop¡l)azeth¡na-3-amine (2.231 g, 2.879 mmol) in THE (14.4 mi) the TBAF in THF (1.0 M, 4.6 mi) is added. The mixture is heated at 50°C for 24 h. The mixture is concentrated. It is diluted with ¡PrOAc, its contents are washed with dilute Na2CÜ3 (2x) and with brine, dried (Na2SO4) and concentrated. The crude residue is purified by flash chromatography (B 0-60% in A, A: DCM, B: 20% NH3M in MeOH in DCM). The collected product is subjected to a chiral separation. The stereochemistry assigned to the 170 compounds 431-434 in Table 2 are unknown and arbitrary. Step 1: Isolation of enantiomers 1 and 4. Enantiomers 2 and 3 remain in the mixture. Chiralpak AD (250 x 30.0, 5 pm), 32.5% isocratic elution, 0.1% NH4OH in isopropanol at 150 g / min, UV-254 nm, BPR 100 bar, temp. 40°C, cycle time: 5 min, total time: 200 min. Step 2: Resolution of enantiomers 2 and 3. Chiralpak OX (150 x 30.0, 5 pm), 30% isocratic elution, 0.1% NH4OH in methanol at 150 g / min, UV-250 nm, BPR 100 bar, temp. 40°C, cycle time: 3 min, total time: 48 min. Compounds 431-434 are characterized as follows. Enantiomer 1: 324.8 mg.RMN H1(400 MHz, DMSO-d6) δ = 10,59 (s, 1H), 7,19 7,08 (m, 2H), 6,85 - 6,75 (m, 1H), 6,68 (d, J = 6,9 Hz, 1H), 6,17 - 6,06 (m, 2H), 5,01 (s, 1H), 4,81 (t, J = 5,8 Hz, 1H), 4,51 (t, J = 6,1 Hz, 1H), 4,39 (t, J = 6,0 Hz, 1H), 4,33 (d, J = 4,2 Hz, OH), 3,99 - 3,87 (m, 1H), 3,82 - 3,72 (m, OH), 3,67 - 3,56 (m, 2H), 3,55 - 3,40 (m, 2H), 3,19 - 3,05 (m, 1H), 2,95 - 2,68 (m, 4H), 1,74 - 1,56 (m, 2H), 1,14-0,99 (m, 6H). CL-EM: 537,3 [M+H]+. Enantiómero 2: 251,7 mg. RMN H1(400 MHz, DMSO-d6) δ = 10,59 (s, 1H), 7,20 - 7,07 (m, 2H), 6,86 - 6,75 (m, 1H), 6,68 (d, J = 6,8 Hz, 1H), 6,11 (d, J = 12,1 Hz, 2H), 5,01 (s, 1H), 4,81 (t, J = 5,8 Hz, 1H), 4,51 (t, J = 6,1 Hz, 1H), 4,39 (t, J = 6,0 Hz, 1H), 4,00 -3,87 (m, 1H), 3,68 - 3,57 (m, 2H), 3,55-3,41 (m, 2H), 3,20 - 3,06 (m, 1H), 2,95 - 2,69 (m, 4H), 1,73 - 1,56 (m, 2H), 1,17- 0,96 (m, 6H). CL-EM: 537,3 [M+H]+. Enantiómero 3: 105,5 mg.RMN H1(400 MHz, DMSO-d6) δ = 10,55 (s, 1H), 7,17 - 7,08 (m, 2H), 6,84 - 6,75 (m, 1H), 6,67 (d, J = 6,8 Hz, 1H), 6,14 - 6,05 (m, 2H), 4,98 (s, 1H), 4,84 (t, J = 5,7 Hz, 1H), 4,51 (t, J = 6,0 Hz, 1H), 4,39 (t, J = 6,0 Hz, 1H), 3,99 - 3,87 (m, 1H), 3,67 - 3,57 (m, 2H), 3,57 - 3,47 (m, 1H), 2,92 - 2,79 (m, 2H), 2,77 - 2,69 (m, 2H), 1,73 -1,56 (m, 2H), 1,13 - 0,96 (m, 6H). CL-EM: 537,3 [M+H]+. Enantiómero 4:151,1 mg. RMN H1(400 MHz, DMSO-d6) δ = 10,55 (s, 1H), 7,18 - 7,07 (m, 2H), 6,84 - 6,75 (m, 1H), 6,67 (d, J = 7,0 Hz, 1H), 6,10 (d, J = 12,1 Hz, 2H), 4,97 (s, 1H), 4,84 (t, J = 5,7 Hz, 1H), 4,51 (t, J = 6,1 Hz, 1H), 4,39 (t, J = 6,1 Hz, 1H), 3,98 - 3,89 (m, 1H), 3,66 - 3,58 (m, 2H), 3,57 - 3,48 (m, 1H), 2,93 - 2,79 (m, 2H), 2,79 - 2,69 (m, 2H), 1,74- 1,57 (m, 2H), 1,12- 0,96 (m, 6H). CL-EM: 537,3 [M+H]+. Example 432 (S)-3-((1 S,3S)-1-(2,6-difluor-4-((1-(3-fluoropropyl)-azetidin-3-yl)amino)phenyl)-6-fluoro-3-methyl-1,3,4,9-tetra-hydro2H-pyrido[3,4-b]indol-2-yl)-2-fluor-2-methylpropan-1-ol 432 Enantiomer 432 is isolated according to the procedures of Example 431. Example 433 (S)-3-((1 R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)-azet¡din-3-yl)amino)phenyl)-6-fluor-3-methyl-1,3,4,9-tetra-hydro2H-pyrido[3,4-b]indol-2-yl)-2-fluor-2-methylpropan-1-ol 433 Enantiomer 433 is isolated according to the procedures of Example 431. Example 434 (R)-3-((1 R,3S)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)-azetidin-3-l)amino)phenyl)-6-fluoro-3-methyl-1,3,4,9-tetra-hydro2H-pyrido[3,4-b]indole-2-l)-2-fluor-2-methylpropan-1-ol 434 Enantiomer 434 is isolated according to the procedures of Example 431. Example 901: ινΐΛ / a / zuzz / uu 171 High-content fluorescence imaging degradation assay of ERa in breast cancer cells MCF7 breast cancer cells are seeded on day 1 at a density of 10,000 cells per well in a poly-lysine coated 384-well tissue culture plate (Greiner #T-3101-4) in 50 μI / well of RPMI (phenol red free), 10% FBS (pulled through charcoal) containing L-glutamine. On day 2, compounds are prepared at 2 compound source concentrations: 100 μM and 1 μM (to ultimately achieve 2 overlapping titration curves) in a Labcyte low lost volume plate, 10 μI / well and 10 μI of DMSO in designated fill wells and 5 μM of Fulvestrant (control compound) in designated wells.Compounds and controls are dispensed using a Labcyte Echo acoustic dispenser to deliver compounds of a predefined serial dilution (1.8x, 10 points, in duplicate) and appropriate fill and control compounds (final total volume transferred 417.5 nI and compound dispensed volume ranges from 2.5 nI to 417.5 nI; 0.84% ​​final DMSO (v / v)), ultimately yielding a concentration range from 0.05 nM to 835 nM. Cell plates are incubated at 37°C for 4 hours. Fixation and permeabilization are performed using a Biotek EL406 plate washer and dispenser as follows.Cells are fixed by adding 15 μI of 16% paraformaldehyde (Electron Microscopy Sciences #15710-S) directly to 50 μI of cell culture medium in each well using the Biotek EL406 5 μI peristaltic pump cassette (final formaldehyde concentration is 3.7% w / v). Samples are incubated for 30 minutes. The contents of the wells are aspirated, and 50 μI / well of phosphate-buffered saline (PBS) containing 0.5% w / v bovine serum albumin and 0.5% v / v Triton X-100 (antibody dilution buffer) is added to each well. Samples are incubated for 30 minutes. The contents of the wells are aspirated and washed 3 times with 100 μl / well of PBS. Immunofluorescent staining for estrogen receptor alpha (ESR1) is performed using a Biotek EL406 plate washer and dispenser as follows.The supernatant fluid is aspirated from the wells and 25 μl / well of anti-ESRI mAb (F10) (Santa Cruz sc-8002) diluted 1:1000 in antibody dilution buffer is dispensed. The samples are incubated at room temperature for 2 hours. The samples are washed 4 times with 100 μl / well of PBS. 25 μl / well of secondary antibody solution (Alexafluor 488 anti-mouse IgG conjugate (LifeTechnologies #A21202) diluted 1:1000 and Hoechst 33342 1 μg / ml diluted in antibody dilution buffer) is dispensed into each well. Samples are incubated at room temperature for 2 hours. Samples are washed 3 times with 100 μl / well of PBS using a Biotek EL406. Quantitative ESR1 fluorescence imaging is performed using a Cellomics Arrayscan V (Thermo).Fluorescence images of the samples (channel 1: XF53 Hoechst (DNA staining); channel 2: XF53 FITC (ESR1 staining)) were obtained using a Cellomics VTI Arrayscan in Bioapplication "Compartmental Analysis" mode, auto-exposure (based on DMSO control wells) by setting the "peak target percentage" to 25% target saturation for both channels. Channel 1 (DNA staining) was used to define the nuclear region (Gire). "Mean_CircAvglntCh2", which is the fluorescence intensity of Alexafluor 488 iviA / a / ¿u¿z / uu iyi o, was measured. 172 (ESR1) within the nuclear region, are carried out on a cell-by-cell basis and averaged across all cells measured. Data analysis is performed using Genedata Screener Software, with samples treated with DMSO and 5 nM Fulvestrant used to define 0% and 100% change in ESR1. The "Robust Fit" method is applied to define the inflection point of the curve (EC5o) and the plateau of maximum effect (Sinf). The degradation data for compounds of formula I in the examples are presented in the values ​​in the ER-alpha MCF7 HCS S¡nf (%) column of Table 1. Example 902 In vitro cell proliferation assay The efficacy of estrogen receptor modulating compounds and chemotherapeutic compounds is determined by a cell proliferation assay using the following protocol (Mendoza et al., Cancer Res. 62, 5485-5488, 2002). The CelITer-Glo® luminescent cell viability assay is a homogeneous method for determining the number of viable cells in a culture based on the quantification of ATP, which indicates the presence of metabolically active cells. The CelITer-Glo® assay is desig...

Claims

1. A compound chosen from formula I: ινΐΛ / a / zuzz / uu zazo and pharmaceutically acceptable stereoisomers, tautomers or salts thereof, wherein: Y1 is CRb or N; Y2 is -(CH2)-, -(CH2CH2)- or NRa; Y3 is NRa or C(Rb)2; wherein one of Y1, Y2 and Y3 is N or NRa; Ra is chosen from H, Ci—Ce alkyl, C2-C8 alkenyl, propargyl, C3-C6 cycloalkyl and C3-C6 heterocyclyl, optionally substituted with one or more groups chosen independently from F, Cl, Br, I, CN, OH, OCH3 and SO2CH3; Rb is independently selected from H, -O(C1-C3 alkyl), C1—Ce alkyl, C2-C8 alkenyl, propargyl, -(C1Ce alkyldiyl)—(Cs-Ce cycloalkyl), C3-C6 cycloalkyl and C3-C6 heterocyclyl, optionally substituted with one or more groups independently selected from F, Cl, Br, I, CN, -CH2F, -CHF2, -CF3, -CH2CF3, -CH2CHF2, -CH2CH2F, OH, OCH3 and SO2CH3; Rc is independently selected from H, Ci—C6 alkyl, allyl, propargyl, optionally substituted with one or more groups independently selected from F, Cl, Br, I, CN, OH,OCH3 and SO2CH3; Z1 chooses between CRaRb, C(O) and an enlace; Cy is selected between aryldiyl C6-C20, carbocyclyldiyl C3-C12, heterocyclyldiyl C2-C20 and heteroaryldiyl C1-C20; Z2 is chosen between O, S, NRa, alkyldiyl Ci-Ce, fluoralkyldiyl Ci-Ce, O-(alkyldiyl Ci-Ce), O-(fluoralkyldiyl Ci-Ce), C(O) and an enlace; R1, R2, R3 and R4 are independently selected between H, F, Cl, Br, I, -CN, -CH3, -CH2CH3, -CH(CH3)2, -CH2CH(CH3)2, -CH2OH, -CH2OCH3, -CH2CH2OH, -C(CH3)2OH, -CH(OH)CH(CH3)2, -C(CH3)2CH2OH, -CH2CH2SO2CH3, CH2OP(O)(OH)2, -CH2F, -CHF2, -CH2NH2, -CH2NHSO2CH3, -CH2NHCH3, -CH2N(CH3)2, -CF3, -CH2CF3, CH2CHF2, -CH(CH3)CN, -C(CH3)2CN, -CH2CN, -CO2H, -COCH3, -CO2CH3, -CO2C(CH3)3, -COCH(OH)CH3, CONH2, -CONHCH3, -CONHCH2CH3, -CONHCH(CH3)2, -CON(CH3)2, -C(CH3)2CONH2, -NH2, -NHCH3, -N(CH3)2, -NHCOCH3, -N(CH3)COCH3, -NHS(O)2CH3i -N(CH3)C(CH3)2CONH2, -N(CH3)CH2CH2S(O)2CH3, -no2, =0, -OH, OCH3, -OCH2CH3, -OCH2CH2OCH3, -OCH2CH2OH, -OCH2CH2N(CH3)2, -OP(O)(OH)2, -S(O)2N(CH3)2, -SCH3, 181 S(O)2CH3,-S(O)3H, cyclopropyl, cyclopropylamide, cyclobutyl, oxetanil, azetidinyl, 1 -metilazetid¡n-3-¡l)ox¡, N-methyl-Noxetan-3-ylamino, azetidin-1-ylmetilo, benciloxyphenyl, pyrrolidin-1-ylo, pyrrolidin-1 -il-metanona, piperazin-1 -lio, morfolinometilo, morfolino-metanona y morfolino; R5 if you choose between H, alkyl C1-C9, cycloalkyl C3-C9, heterocycle C3-C9, aryl C6-C9, heteroaryl C6-C9, (alkyldiyl C1C6)—(cycloalkyl C3-C9), -(alkyldiyl Ci—C6)—(heterocycle C3-C9), C(O)Rb, C(O)NRa, SO2Ra and SO2NRa, optionally replaced with one or more halogens, CN, ORa, N(Ra)2, alkyl C1-C9, cycloalkyl C3-C9, heterocycle C3-C9, aryl CeC9, heteroaryl C6-C9, C(O)Rb, C(O)NRa, SO2Ra and SO2NRa; R6 is selected between F, Cl, Br, I, -CN, -CH3, -CH2CH3, -CH(CH3)2, -CH2CH(CH3)2, -CH2OH, -CH2OCH3, -CH2CH2OH, -C(CH3)2OH, -CH(OH)CH(CH3)2, -C(CH3)2CH2OH, -CH2CH2SO2CH3, -CH2OP(O)(OH)2, -CH2F, -chf2, -CH2NH2, CH2NHSO2CH3, -CH2NHCH3, -CH2N(CH3)2, -CF3, -CH2CF3, -CH2CHF2, -CH2CH2F, -CH(CH3)CN, C(CH3)2CN, -CH2CN,-CO2H, -COCH3, -CO2CH3, -CO2C(CH3)3, -COCH(OH)CH3, -CONH2, -CONHCH3, CONHCH2CH3, -CONHCH(CH3)2, -CON(CH3)2, -C(CH3)2CONH2, -NH2, -NHCH3, -N(CH3)2, -NHCOCH3, N(CH3)COCH3, -NHS(O)2CH3, -N(CH3)C(CH3)2CONH2, -N(CH3)CH2CH2S(O)2CH3, -NO2, =0, -OH, -0CH3, OCH2CH3, -OCH2CH2OCH3, -OCH2CH2OH, -OCH2CH2N(CH3)2i -OP(O)(OH)2, -S(O)2N(CH3)2, -sch3, S(O)2CH3, -S(O)3H, cyclopropyl, cyclopropylamide, cyclobutyl, oxetanyl, azetidinyl, 1-methylazetidin-3-yl)oxy, N-methyl-Noxetan-3-ylamino, azetidin-1-ylmethyl, benzyloxyphenyl, pyrrolidin-1-yl, pyrrolidin-1-yl-methanone, piperazin-1-yl, morpholinomethyl, morpholino-methanone and morpholino; and m is chosen between 0,1,2, 3 and 4; said alkyldiyl, fluoroalkyldiyl, aryldiyl, carbocyclyldiyl, heterocyclyldiyl and heteroaryldiyl are optionally substituted by one or more groups chosen independently from F, Cl, Br, I, -CN, -CH3, -CH2CH3, -CH(CH3)2, CH2CH(CH3)2, -CH2OH, -CH2OCH3, -CH2CH2OH, -C(CH3)2OH, -CH(OH)CH(CH3)2, -C(CH3)2CH2OH, CH2CH2SO2CH3,-CH2OP(O)(OH)2, -CH2F, -CHF2, -CF3i -CH2CF3, -CH2CHF2, -CH2CH2F, CH(CH3)CN, -C(CH3)2CN, -CH2CN, -CH2NH2, -CH2NHSO2CH3, -CH2NHCH3, -CH2N(CH3)2, -CO2H, -COCH3, CO2CH3, -CO2C(CH3)3, -COCH(OH)CH3, -CONH2, -CONHCH3, -CON(CH3)2, -C(CH3)2CONH2, -nh2, NHCH3, -N(CH3)2, -NHCOCH3, -N(CH3)COCH3, -NHS(O)2CH3, -N(CH3)C(CH3)2CONH2, -N(CH3)CH2CH2S(O)2CH3, -NO2i =0, -OH, -OCH3, -OCH2CH3, -OCH2CH2OCH3, -OCH2CH2OH, -OCH2CH2N(CH3)2i -OP(O)(OH)2, S(O)2N(CH3)2, -SCH3, -S(O)2CH3, -S(O)3H, cyclopropyl, cyclopropylamide, cyclobutyl, oxetanil, azetidinyl, 1methylazetidin-3-l)ox, N-methyl-N-oxetan-3-ylamino, azetidin-1-ylmethyl, benzyloxyphenyl, pyrrolidin-1-yl, pyrrolidin-1-ylmethanol, piperazin-1-yl, morpholinomethyl, morpholino-methanol and morpholino., 2. The content of the indication 1 which has the formula: ivix / a / zuzz / uu zazo 3. The composition of the indication 2 which has the formula Ib: ΜΛ / a / zuzz / uu iyio in which R7 is F, Cl, Br, I, -CN, -CH3, -CH2CH3, -CH(CH3)2, -CH2CH(CH3)2, -CH2OH, -CH2OCH3, -CH2CH2OH, C(CH3)2OH, -CH(OH)CH(CH3)2, -C(CH3)2CH2OH, -CH2CH2SO2CH3, -CH2OP(O)(OH)2, -ch2f, -chf2, -CH2NH2, CH2NHSO2CH3, -CH2NHCH3, -CH2N(CH3)2, -CF3, -CH2CF3, -CH2CHF2, -CH(CH3)CN, -C(CH3)2CN, -ch2cn, CO2H, -COCH3i -CO2CH3, -CO2C(CH3)3, -COCH(OH)CH3i -conh2, -conhch3, -conhch2ch3, CONHCH(CH3)2, -CON(CH3)2, -C(CH3)2CONH2, -NH2, -NHCH3, -N(CH3)2, -NHCOCH3, -N(CH3)COCH3, NHS(O)2CH3, -N(CH3)C(CH3)2CONH2, -N(CH3)CH2CH2S(O)2CH3i -NO2, =0, -OH, -OCH3, -och2ch3, OCH2CH2OCH3, -OCH2CH2OH, -OCH2CH2N(CH3)2, -OP(O)(OH)2i -S(O)2N(CH3)2, -SCH3, -S(O)2CH3, -S(O)3H, cyclopropyl, cyclopropylamide, oxetanil, azetidinyl, 1 -methylazetidin-3-yl)oxy, N-methyl-N-oxetan-3-ylamino, azetidin-1ylmethyl, benzyloxyphenyl, pyrrolidin-1-yl, pyrrolidin-1-yl-methanol, piperazin-1-yl, morpholinomethyl, morpholino-methanol and morpholino;and n is chosen between 0,1,2, 3 and 4.; 4. The compound of claim 1 having the formula le: Rb le.

5. The compound of claim 4 having formula Id:

6. The compound of claim 5 having the formula le: ινΐΛ / a / zuzz / uu / and wherein R8 is H or -CH3.

7. The compound of claim 4 having the formula If: 184 MA / a / zuzz / uu 1 and 1 or wherein R8 is H or -CH3.

8. The compound of claim 1 having the formula Ig:

10. The compound of claim 9 having formula II: 185 11. The compound of claim 10 having formula Ij:

12. The compound of claim 11 having the formula Ik: d3 ινΐΛ / a / zuzz / uu fxfo 13. The compound of claim 1, wherein Y1 is CRb and Y3 is NRa.

14. The compound of claim 1, wherein Y1 is N and Y3 is C(Rb)2.

15. The compound of claim 1, wherein Y2 is -(CH2)-.

16. The compound of claim 1, wherein Y2 is -(CH2CH2)-.

17. The compound of claim 1, wherein Rc is H.

18. The compound of claim 1, wherein Cy is a C6-C20 aryldiyl.

19. The compound of claim 18, wherein the C6-C20 aryldiyl is the phenyldiyl. 186 20. The compound of claim 19, wherein the phenyldiyl is substituted by one or more F.

21. The compound of claim 1, wherein R1 and R2 are H.

22. The compound of claim 1, wherein R3 is H and R4 is -CH3.

23. The compound of claim 1, wherein R5 is Ci-C6 fluoroalkyl.

24. The compound of claim 1, wherein m is 0.

25. The compound of claim 1 selected from Table 1.

26. The compound of claim 1 chosen from Table 2.

27. A pharmaceutical composition containing a compound of claim 1 and a pharmaceutically acceptable vehicle, lubricant, diluent or excipient.

28. The pharmaceutical composition according to claim 27, containing an additional therapeutic agent.

29. A process for manufacturing a pharmaceutical composition comprising combining a compound of claim 1 with a pharmaceutically acceptable vehicle, lubricant, diluent or excipient.

30. A method for treating a disease or disorder related to an ER in a patient comprising administering a therapeutically effective amount of a pharmaceutical composition of claim 27 to a patient suffering from a disease or pathological condition related to an ER.

31. The method of claim 30, wherein the ER-related disease or disorder is a cancer selected from breast cancer, lung cancer, ovarian cancer, endometrial cancer, prostate cancer, and uterine cancer.

32. The method of claim 31, wherein the cancer is breast cancer.

33. The method of claim 31, further comprising administering an additional therapeutic agent selected from an anti-inflammatory agent, an immunomodulatory agent, a chemotherapeutic agent, an apoptosis enhancer, a neurotrophic factor, an agent for treating cardiovascular diseases, an agent for treating liver disease, an antiviral agent, an agent for treating hematological disorders, an agent for treating diabetes, and an agent for treating immunodeficiency disorders.

34. The method of claim 30, wherein the pharmaceutical composition is administered in combination with a therapeutic agent selected from paclitaxel, anastrozole, exemestane, cyclophosphamide, epirubicin, fulvestrant, letrozole, gemcitabine, trastuzumab (HERCEPTIN®, Genentech), trastuzumab emtansine (KADCYLA®, Genentech), pegfilgrastim, filgrastim, tamoxifen, docetaxel, toremifene, vinorelbine, capecitabine, and ixabepilone.

35. The method of claim 30, wherein the pharmaceutical composition is administered in combination with a CDK 4 / 6 inhibitor.

36. The method of claim 35, wherein the CDK 4 / 6 inhibitor is selected from palbociclib (PD0332991), ribociclib (LEE011) and LY283519.

37. The method of claim 30, wherein the pharmaceutical composition is administered in combination with an inhibitor of the phosphoinositide 3-kinase (PI3K) - mTOR mechanism selected from everolimus, temsirolimus, BEZ235 (dactolisib), BIL719 (alpelisib), GDC0032 (taselisib), BKM120 (buparlisib), BGT226, GDC0068 (ipatasertib), GDC-0980 (apitolisib), GDC0941 (pictilisib), INK128 (MLN0128), INK1117, OSI-027, CC-223, AZD8055, SAR245408, SAR245409, PF04691502, WYE125132, GSK2126458, GSK-2636771, BAY806946, PF-05212384, SF1126, PX866, AMG319, ZSTK474, Cali 01 (idelalisib), PWT33597, CU-906, AZD-2014 and CUDC-907.

38. A kit for treating a pathological condition mediated by an estrogen receptor, comprising: a) a pharmaceutical composition of claim 27; and b) instructions for use.

39. A compound according to any one of claims 1 to 26 for use as a therapeutically active substance.

40. A compound according to any one of claims 1 to 26 for use in the treatment of an ER-related disease or disorder.

41. Use of a compound according to any one of claims 1 to 26 for the treatment of a disease or disorder related to rare diseases.

42. Use of a compound according to any one of claims 1 to 26 for the manufacture of a medicament useful for the treatment of a disease or disorder related to rare diseases.

43. The invention as described.