Tetrahydropyrido[3,4-b]indoleestrogen receptor modulator and its use

Abstract

The present invention provides compounds having estrogen receptor modulation activity or function. [Solution] (i) Compound of formula (340): TIFF2026067858000180.tif40170 (ii) a pharmaceutically acceptable salt thereof, and a medicament for treating ER-positive breast cancer is provided.

Description

[Technical Field]

[0001] Cross-references to related applications This non-provisional application, filed under 37 CFR §1.53(b), claims the benefit under 35 U.S.C §119(e) of U.S. Provisional Application No. 62 / 093929 filed December 18, 2014, U.S. Provisional Application No. 62 / 110998 filed February 2, 2015, and U.S. Provisional Application No. 62 / 142077 filed April 2, 2015 (these are incorporated herein by reference in their entirety).

[0002] Field of Invention This specification describes compounds (including pharmaceutically acceptable salts, solvates, metabolites, and prodrugs thereof), pharmaceutical compositions comprising such compounds, and methods of using such compounds in combination with other therapeutic agents for the treatment, prevention, or diagnosis of estrogen-sensitive, estrogen receptor-dependent, or estrogen receptor-mediated diseases or conditions. [Background technology]

[0003] The estrogen receptor ("Er") is a ligand-activated transcriptional regulatory protein that mediates the induction of various biological effects through interaction with endogenous estrogen. Endogenous estrogen includes 17b (beta)-estradiol and estrone. It has been discovered that ER has two isoforms, ER-a (alpha) and ER-b (beta). Estrogen and the estrogen receptor are involved in various diseases or conditions, including breast cancer, lung cancer, ovarian cancer, colon cancer, prostate cancer, endometrial cancer, and uterine cancer, as well as other diseases or conditions. Novel ER-a targeted agents that are active in metastatic disease and acquired resistance are needed. [Overview of the project]

[0004] The present invention generally has the structure of formula I: JPEG2026067858000001.jpg4075I This invention relates to tetrahydropyrido[3,4-b]indole-1-yl compounds having estrogen receptor modulation activity or function, and stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, having the substituents and structural features described herein.

[0005] One aspect of the present invention is a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable carrier, lubricant, diluent, or excipient. One aspect of the present invention is a method for producing a compound of formula I or a pharmaceutical composition containing a compound of formula I. One aspect of the present invention is a method for treating an ER-related disease or disorder in a patient, comprising administering a therapeutically effective amount of a pharmaceutical composition to the patient having the ER-related disease or disorder. One aspect of the present invention is a kit for treating estrogen receptor-mediated conditions, a) A pharmaceutical composition containing a compound of formula I; and b) Instructions for use This is a kit that includes [the following items]. [Modes for carrying out the invention]

[0006] References relating to specific embodiments of the present invention are made in detail here. Examples of such embodiments are shown in the attached structures and formulas. The present invention is described in combination with numerous embodiments, but it is not intended to limit the present invention to those embodiments. Rather, the present invention is intended to cover all alternative forms, modifications, and equivalents, which may be included within the scope of the present invention as defined by the claims. Those skilled in the art will recognize many methods and substances that are similar or equivalent to the methods and substances described herein and may be used in the practice of the present invention. The present invention is by no means limited to the methods and substances described herein. If one or more prior art documents, patents, and similar substances have any difference or inconsistency with the definitions, usages, techniques described herein, etc., the present application shall prevail. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which the present invention pertains. Methods and substances similar or equivalent to those described herein may be used in the practice or testing of the present invention, but suitable methods and substances are listed below. All publications, patent applications, patents, and other references referred herein are incorporated by reference in their entirety. The nomenclature used in this application is based on the systematic nomenclature of IUPAC, unless otherwise specified.

[0007] definition When indicating the number of substituents, the term "one or more" means from one substituent to as many substitutions as possible, i.e., from the substitution of one hydrogen atom by a substituent to the substitution of all hydrogen atoms. The term "substituent" means an atom or group of atoms that substitutes for a hydrogen atom on the parent molecule. The term "substituted" means that a particular group has one or more substituents. Any group can have multiple substituents, and if various possible substituents are provided, the substituents are independently selected and do not have to be the same. The term "unsubstituted" means that a particular group has no substituents. The term "optionally substituted" means that a particular group is either unsubstituted or substituted with one or more substituents independently selected from the group of possible substituents. When indicating the number of substituents, the term "one or more" means from one substituent to as many substitutions as possible, i.e., from the substitution of one hydrogen atom by a substituent to the substitution of all hydrogen atoms.

[0008] As used herein, the term "alkyl" refers to a group of 1 to 12 carbon atoms (C1-C1). 12) refers to a saturated linear or branched monovalent hydrocarbon group, and the alkyl group may be independently and optionally substituted with one or more substituents listed below. In another embodiment, the alkyl group is 1 to 8 carbon atoms (C1-C8) or 1 to 6 carbon atoms (C1-C6). Examples of alkyl groups are, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1-propyl (n-Pr, n-propyl, -CH2CH2CH3), 2-propyl (i-Pr, i-propyl, -CH(CH3)2), 1-butyl (n-Bu, n-butyl, -CH2CH2CH2CH3), 2-methyl-1-propyl (i-Bu, i-butyl, -CH2CH(CH3)2), 2-butyl (s-Bu, s-butyl, -CH(CH3)CH2CH3), 2-methyl-2-propyl(t-Bu, t-butyl, -C(CH3)3), 1-pentyl(n-pentyl, -CH2CH2CH2CH2CH3), 2-pentyl(-CH(CH3)CH2CH2CH3), 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)C This includes H(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, etc.

[0009] As used herein, the term "alkyldiyl" refers to a group of about 1 to 12 carbon atoms (C1-C1). 12) refers to a saturated linear or branched divalent hydrocarbon group, and the alkyldiyl group may be independently and optionally substituted with one or more substituents as described below. In another embodiment, the alkyldiyl group is 1 to 8 carbon atoms (C1-C8) or 1 to 6 carbon atoms (C1-C6). Examples of alkyldiyl groups include, but are not limited to, methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), etc. The alkyldiyl group is also called an "alkylene" group.

[0010] The term "alkenyl" implies at least one unsaturated site, i.e., carbon-carbon sp 2 This refers to a monovalent hydrocarbon group having a double bond and consisting of 2 to 8 carbon atoms (C2-C8), either linear or branched, where the alkenyl group may be independently and selectively substituted with one or more substituents as described herein, and includes groups having "cis" and "trans" orientations, or "E" and "Z" orientations. Examples, but not limited to, include ethyleneyl or vinyl (-CH=CH2), allyl (-CH2CH=CH2), etc.

[0011] The terms "alkenylene" or "alkenyldiyl" indicate at least one unsaturated site, i.e., carbon-carbon sp 2 This refers to a straight or branched divalent hydrocarbon group having a double bond and comprising 2 to 8 carbon atoms (C2-C8), where the alkenylene group may be independently and selectively substituted with one or more substituents as described herein, and includes groups having "cis" and "trans" orientations, or "E" and "Z" orientations. Examples, but not limited to, include ethyleneylene or vinylene (-CH=CH-), allyl (-CH2CH=CH-), etc.

[0012] The term "alkynyl" refers to a monovalent hydrocarbon group consisting of 2 to 8 carbon atoms (C2-C8) with at least one unsaturated site, i.e., a carbon-carbon sp triple bond, where the alkynyl group may be independently and optionally substituted with one or more substituents as described herein. Examples include, but are not limited to, ethynyl (-C≡CH) and propynyl (propargyl, -CH2C≡CH).

[0013] The terms "alkynylene" or "alkynyldiyl" refer to a linear or branched divalent hydrocarbon group of 2 to 8 carbon atoms (C2-C8) having at least one unsaturated site, i.e., a carbon-carbon sp triple bond, where the alkynylene group may be independently and optionally substituted with one or more substituents as described herein. Examples include, but are not limited to, ethynylene (-C≡C-), propynylene (propargylene, -CH2C≡C-), and others.

[0014] The terms "carbocycle," "carbocyclyl," "carbocyclic ring," and "cycloalkyl" refer to a monocyclic ring consisting of 3 to 12 carbon atoms (C3-C3). 12), or a monovalent, non-aromatic saturated or partially unsaturated ring having 7 to 12 carbon atoms as a bicyclic ring. Bicyclic carbocyclic rings having 7 to 12 atoms may be arranged, for example, as bicyclo[4,5], [5,5], [5,6], or [6,6] systems, and bicyclic carbocyclic rings having 9 or 10 ring atoms may be arranged as bicyclo[5,6] or [6,6] systems, or as bridging systems, for example, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, and bicyclo[3.2.2]nonane. Spirocarbocyclyl moieties are also included within the scope of this definition. Examples of spirocarbocyclyl moieties include, but are not limited to, [2.2]pentanyl, [2.3]hexanyl, and [2.4]heptanyl. Examples of monocyclic carbocyclic groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopenta-1-enyl, 1-cyclopenta-2-enyl, 1-cyclopenta-3-enyl, cyclohexyl, 1-cyclohexa-1-enyl, 1-cyclohexa-2-enyl, 1-cyclohexa-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, and the like. The carbocyclyl group is independently and optionally substituted with one or more substituents as described herein.

[0015] The term "carbocyclyldiyl" refers to a monocyclic ring consisting of 3 to 12 carbon atoms (C3-C3). 12 ), or a divalent non-aromatic saturated or partially unsaturated ring having 7 to 12 carbon atoms as a bicyclic ring.

[0016] "Aryl" refers to a group of 6-20 carbon atoms (C6-C) that is derived by removing one hydrogen atom from a single carbon atom in a hydrophilic aromatic ring system. 20This refers to a monovalent aromatic hydrocarbon group consisting of aryl groups. Some aryl groups are represented structurally as "Ar". Aryls include bicyclic groups containing saturated, partially unsaturated, or aromatic rings fused to aromatic carbocyclic rings. Typical aryl groups include, but are not limited to, groups derived from benzene (phenyl), substituted benzenes, naphthalenes, anthracenes, biphenyls, indenyl, indanyl, 1,2-dihydronaphthalene, and 1,2,3,4-tetrahydronaphthyl. The aryl groups are independently and optionally substituted with one or more substituents as described herein.

[0017] The term "arylene" or "aryldiyl" is derived by removing two hydrogen atoms from two carbon atoms in a hydrophilic aromatic ring system, consisting of 6-20 carbon atoms (C6-C6). 20 This refers to a divalent aromatic hydrocarbon group consisting of aryldiyl. Some aryldiyl groups are represented as "Ar" in exemplary structures. Aryldiyls include bicyclic groups containing an aromatic ring fused to a saturated, partially unsaturated, or aromatic carbocyclic ring. Typical aryldiyl groups include, but are not limited to, groups derived from benzene (phenyldiyl), substituted benzenes, naphthalene, anthracene, biphenylene, indenylene, indanylene, 1,2-dihydronaphthalene, 1,2,3,4-tetrahydronaphthyl, etc. Aryldiyl groups are also called "arylenes" and are optionally substituted with one or more substituents as described herein.

[0018] The terms “heterocycle,” “heterocyclyl,” and “heterocyclic ring” are used interchangeably herein and refer to a saturated or partially unsaturated (i.e., having one or more double and / or triple bonds in the ring) carbocyclic group comprising 3 to about 20 ring atoms, wherein at least one ring atom is a heteroatom selected from nitrogen, oxygen, phosphorus, and sulfur, and the remaining ring atoms are carbon, wherein one or more ring atoms may be independently and optionally substituted with one or more substituents as described below. The heterocycle may be a monocycle having 3 to 7 ring members (2 to 6 carbon atoms and 1 to 4 heteroatoms selected from N, O, P, and S), or a dicycle having 7 to 10 ring members (4 to 9 carbon atoms and 1 to 6 heteroatoms selected from N, O, P, and S), e.g., bicyclo[4,5], [5,5], [5,6], or [6,6] systems). Heterocyclic compounds are described in Paquette, Leo A.; "Principles of Modern Heterocyclic Chemistry" (WABenjamin, New York, 1968), especially chapters 1, 3, 4, 6, 7 and 9; "The Chemistry of Heterocyclic Compounds, A series of Monographs" (John Wiley & Sons, New York, 1950 to present), especially volumes 13, 14, 16, 19 and 28; and J.Am.Chem.Soc. (1960) 82:5566. "Heterocyclic" also includes groups in which the heterocyclic group is fused to a saturated or partially unsaturated ring or an aromatic carbocyclic or heterocyclic ring.Examples of heterocyclic rings include, but are not limited to, morpholin-4-yl, piperidine-1-yl, piperazinyl, piperazine-4-yl-2-one, piperazine-4-yl-3-one, pyrrolidine-1-yl, thiomorpholin-4-yl, S-dioxothiomorpholin-4-yl, azocan-1-yl, azetidine-1-yl, octahydropyrido[1,2-a]pyrazine-2-yl, [1,4]diazepan-1-yl, pyrrolidinyl, tetrahydrofuranil, dihydrofuranil, tetrahydrothienyl, tetrahydropyranil, dihydropyranil, tetrahydrothiopyranil, piperidino, morpholinino, thiomorpholino, thiooxanil, piperazinyl, ho This includes mopiperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinylimidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, azabicyclo[2.2.2]hexanyl, 3H-indollyquinolidinyl, and N-pyridylurea. Spiroheterocyclyl moieties are also included within this definition. Examples of spiroheterocyclyl moieties include, but are not limited to, [2.5]octanyl and azaspiro[2.4]heptanyl. Examples of heterocyclic groups in which two ring atoms are substituted with oxo (=O) moieties are pyrimidinonyl and 1,1-dioxo-thiomorpholinyl. Heterocyclic groups as used herein may be independently and selectively substituted with one or more substituents as described herein.

[0019] The term "heterocyclyldiyl" refers to a divalent saturated or partially unsaturated (i.e., having one or more double and / or triple bonds in the ring) carbocyclic group consisting of 3 to about 20 ring atoms, where at least one ring atom is a heteroatom selected from nitrogen, oxygen, phosphorus, and sulfur, and the remaining ring atoms are carbon, where one or more ring atoms are independently and optionally substituted with one or more substituents as described.

[0020] The term "heteroaryl" refers to a monovalent aromatic group of a 5-membered, 6-membered, or 7-membered ring, and includes a condensed ring system of 5-20 atoms (at least one of which is aromatic) containing one or more heteroatoms independently selected from nitrogen, oxygen, and sulfur. Examples of heteroaryl groups include pyridinyl (e.g., including 2-hydroxypyridinyl), imidazolyl, imidazopyridinyl, pyrimidinyl (e.g., including 4-hydroxypyridinyl), pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxadiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, sinnolinyl, indazolyl, indolidinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, triazolyl, thiadiazolyl, thiadiazolyl, flazanyl, benzofuranyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthilidinyl, and flopyridinyl. The heteroaryl group is independently and optionally substituted with one or more substituents as described herein.

[0021] The term "heteroaryldiyl" refers to a divalent aromatic group of a 5-membered, 6-membered, or 7-membered ring, and includes a condensed ring system of 5-20 atoms (at least one of which is aromatic) containing one or more heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0022] The heterocyclic or heteroaryl group may, where possible, be carbon (carbon-linked) or nitrogen (nitrogen-linked) bonded. For example, but are not limited to, carbon-linked heterocyclic or heteroaryl groups may be bonded at positions 2, 3, 4, 5, or 6 of pyridine, positions 3, 4, 5, or 6 of pyridazine, positions 2, 4, 5, or 6 of pyrimidine, positions 2, 3, 5, or 6 of pyrazine, positions 2, 3, 5, or 5 of furan, tetrahydrofuran, thiofuran, thiophene, pyrrole, or tetrahydropyrrole, positions 2, 3, 4, or 5 of oxazole, imidazole, or thiazole, positions 3, 4, or 5 of isoxazole, pyrazole, or isothiazole, positions 2 or 3 of aziridine, positions 2, 3, or 4 of azetidine, positions 2, 3, 4, 5, 6, 7, or 8 of quinoline, or positions 1, 3, 4, 5, 6, 7, or 8 of isoquinoline.

[0023] For example, though not limited to, nitrogen-bonded heterocycles or heteroaryls are bonded at position 1 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, position 2 of isoindole or isoindoline, position 4 of morpholine, and position 9 of carbazole or β-carbolin.

[0024] The terms “to treat” and “treatment” refer to therapeutic treatments aimed at delaying (reducing) undesirable physiological changes or impairments, such as the onset or spread of arthritis or cancer. In this invention, beneficial or desired clinical outcomes include, but are not limited to, symptom relief, reduction of disease severity, stabilization of the disease state (i.e., no worsening), delay or slowing of disease progression, improvement or mitigation of the condition, and (partial or complete) remission, whether detectable or undetectable. “Treatment” may also mean extending survival compared to the expected survival time without treatment. Persons requiring treatment include those with a disease or impairment.

[0025] The expression "therapeutic effective dose" means the amount of the compound of the present invention that (i) treats a particular disease, condition, or disorder, (ii) alleviates, remits, or eliminates one or more symptoms of a particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of a particular disease, condition, or disorder as described herein. In the case of cancer, a therapeutic effective dose of the drug may reduce the number of cancer cells; reduce the size of the tumor; inhibit (i.e., delay, preferably halt) the invasion of cancer cells into peripheral organs; inhibit (i.e., delay, preferably halt) tumor metastasis; inhibit tumor growth to some extent; and / or alleviate to some extent one or more symptoms associated with cancer. The drug may be cell division inhibitory and / or cytotoxic to the extent that it can prevent growth and / or kill existing cancer cells. In the case of cancer treatment, effectiveness can be determined, for example, by evaluating the time to disease progression (TTP) and / or by determining the response rate (RR).

[0026] The term "cancer" refers to a physiological condition in mammals typically characterized by uncontrolled cell proliferation. "Tumor" includes one or more cancer cells. Examples of cancer include, but are not limited to, carcinomas, lymphomas, blastomas, sarcomas, and leukemias or lymphoid neoplasms. More specific examples of such cancers include squamous cell carcinoma (e.g., epithelial squamous cell carcinoma), small cell lung cancer, non-small cell lung cancer ("NSCLC"), lung cancer including adenocarcinoma and squamous cell carcinoma of the lung, peritoneal cancer, hepatocellular carcinoma, 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 cancer, salivary gland carcinoma, kidney or renal cancer, prostate cancer, vulvar cancer, thyroid cancer, hepatocellular carcinoma, anal cancer, penile cancer, and head and neck cancer.

[0027] "Hematological malignancies" (spelled "Haematological" malignancies in British English) are types of cancer that affect the blood, bone marrow, and lymph nodes. Since these three are closely interconnected via the immune system, diseases that affect one of the three will usually affect the other two as well. That is, lymphoma is a disease of the lymph nodes but usually spreads to the bone marrow and affects the blood. Hematological malignancies are malignant neoplasms (cancers) and are generally treated by specialists in hematology and / or oncology. In some settings, "hematology / oncology" is a subspecialty of internal medicine, while elsewhere it is considered an independent department (there are also surgeons and radiation oncologists). Not all blood diseases are malignant (cancerous), and such other blood conditions can also be managed by hematologists. Hematological malignancies can originate from either of two major blood cell lineages, namely the myeloid and lymphoid cell lines. The myeloid cell line normally produces granulocytes, erythrocytes, platelets, macrophages, and mast cells, and the lymphoid cell line produces B, T, NK, and plasma cells. Acute and chronic myeloid leukemia, myelodysplastic syndromes, and myeloproliferative disorders are of myeloid origin, while lymphoma, lymphocytic leukemia, and myeloma are of lymphoid origin. Leukemias include acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute monocytic leukemia (AMOL), and small lymphocytic lymphoma (SLL). Lymphomas include Hodgkin lymphoma (all four subtypes) and non-Hodgkin lymphoma (NHL, all subtypes).

[0028] "Chemotherapeutic agents" are chemical compounds useful in the treatment of cancer, regardless of their mechanism of action. Types of chemotherapeutic agents include, but are not limited to, alkylating agents, antimetabolites, plant alkaloids that are spindle poisons, cytotoxic / antineoplastic antibiotics, topoisomerase inhibitors, antibodies, photosensitizers, and kinase inhibitors. Chemotherapeutic agents include compounds used in "targeted therapy" as well as conventional chemotherapy. Examples of chemotherapeutic agents include ibrutinib (Imbruvica TMAPCI-32765, Pharmacyclics Inc. / Janssen Biotech Inc.; CAS Registry No. 936563-96-1, US 7514444), Idelalisib (ZYDELIG® CAL-101, GS 1101, GS-1101, Gilead Sciences Inc.; CAS Registry No. 1146702-54-6), Erlotinib (Tarceva®, Genentech / OSI Pharm.), docetaxel (Taxotere®, Sanofi-Aventis), 5-FU (fluorouracil, 5-fluorouracil, CAS registry number 51-21-8), gemcitabine (Gemzar®, Lilly), PD-0325901 (CAS number 391210-10-9, Pfizer), cisplatin (Platinol®, (SP-4-2)-diaminedichloroplatinum(II), cis-diamine, dichloroplatinum(II), CAS number 15663-27-1), carboplatin (CAS number 41575-94-4), paclitaxel (Taxol®, Bristol-Myers Squibb, Princeton, New Jersey) Oncology), trastuzumab (Herceptin®, Genentech), temozolomide (4-methyl-5-oxo-2,3,4,6,8-pentazabicyclo[4.3.0]nona-2,7,9-triene-9-carboxamide, CAS number 85622-93-1, Temodar®, Temodar®, Schering This includes Plough), tamoxifen ((Z)-2-[4-(1,2-diphenylbuta-1-enyl)phenoxy]-N,N-dimethylethaneamine, Nolvadex®, ISTUBAL®, VALODEX®, and doxorubicin (Adriamycin®, CAS number 23214-92-8), Akti-1 / 2, HPPD, and rapamycin.

[0029] Chemotherapy agents include inhibitors of B cell receptors, such as BTK, Bcl-2, and JAK inhibitors.

[0030] Further examples of chemotherapy agents include oxaliplatin (ELOXATIN®, Sanofi), bortezomib (Velcade®, Millennium Pharm.), sunitinib® (SU11248, Pfizer), letrozole (FEMARA®, Novartis), imatinib mesylate (Gleevec®, Novartis), XL-518 (Mek inhibitor, Exelixis, International Publication No. 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), and PTK787 / ZK. 222584 (Novartis), fulvestrant (FASLODEX®, AstraZeneca), leucovorin (folic acid), rapamycin (sirolimus, Rapammune®, Wyeth), lapatinib (TYKERB®, GSK572016, Glaxo Smith Kline), ronafarnib (Salazar) TM (SCH 66336, Schering Plough), sorafenib (Nexavar®, BAY43-9006, Bayer Labs), gefitinib (Iressa®, AstraZeneca), irinotecan (Camptosar®, CPT-11, Pfizer), tipifanib (Zarnestra) TM Johnson & Johnson, Abraxane TM(Cremophor-free), albumin-modified nanoparticle formulations of paclitaxel (American Pharmaceutical Partners, Schonburg, Illinois), vandetanib (rINN, ZD6474, ZACTIMA®, AstraZeneca), chlorambucil, AG1478, AG1571 (SU 5271; Sugen), temsirolimus (Torisel®, Wyeth), pazopanib (GlaxoSmithKline), camphospamide (Telcita®, Telik), thiotepa and cyclophosphamide (Citoxane®, Neosaal®); alkyl sulfonates such as busulfan, improsulfan, and biposulfan; benzodopa, carbocon, meturedopa, and uredopa Ethylenes and methylamelamines such as aziridine; altoretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylolmelamine; acetogenins (especially bratacin and bratacinone); camptothecin (including its synthetic analog topotecan); bryostatin; callistatin; CC-1065 (including its synthetic analogs adzeresin, calzelsin, and biceresin); cryptophycin (especially cryptophycin 1 and cryptophycin 8); dorastatin; duocalmycin (including its synthetic analogs KW-2189 and CB1-TM1); eryuterobin; pancratistatin ; Sarcodicin; Spongestatins; Chlorambucil, Chlornafadin, Chlorophosphamide, Estramustine, Ifosfamide, Mechloretamine, Mechloretamine Oxide Hydrochloride, Melphalan, Novembichin, Phenesterine, Prednimustine, Trophosphamide, Nitrogen Mustards such as Uracil Mustard; Nitrosoureas such as Carmustine, Chlorozotosine, Fotemustine, Lomustine, Nimustine and Ranimustine;Endiine antibiotics (e.g., calicheamicin, calicheamicin gamma 1I, calicheamicin omega I1 (Angew Chem. Intl. Ed. Engl. (1994) 33:183-186); dynemicin, dynemicin A; bisphosphonates such as clodronate; esperamycin; and neocardinostatin chromophores and related pigment proteins; endiine antibiotic chromophores), aclasinomycin, actinomycin, anthramycin, azaserin, bleomycin, kakutinomycin, carabicin, carminomycin, cardinophilin, chromomycinis, Dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, nemorubicin, marcelomycin, mitomycin such as mitomycin C, mycophenolate, nogaramycin, olibomycin, peplomycin, porphyromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidine, ubenimex, d Antibiotics such as nostatin and zolubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pteropterin, and trimethrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, and thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, and phloxuridine; androgens such as carsterone, dromostanolone propionate, epithiostanol, mepitiostane, and testolactone; antiadrenal agents such as aminoglutethimide, mitotane, and trilostane; folic acid supplements such as frolinic acid; acegraton and aldofamide glycoside;Aminolevulinic acid; Enyluracil; Amsacrine; Bestrabusil; Bisantrene; Edatrexate; Defofamine; Demecoltin; Diadiquan; Elfornithine; Erliptinium acetate; Epotilon; Etoglucide; Gallium nitrate; Hydroxyurea; Lentinan; Lonidamine; Maytansinoids such as Maytansine and Ansamitosine; Mitoguazone; Mitoxantrone; Mopidanmol; Nitracrine; Pentostatin; Phenamet; Pirarubicin; Rosoxantrone; Podophyllic acid; 2-Ethylhydrazide; Procarbazine; PSK (Registered Trademark) Polysaccharide Complex (JHS Natural, Eugene, Oregon) Products); Lazoxane; Rhizoxin; Schizophyllan; Spirogermanium; Tenuazonic acid; Triadicone; 2,2',2”-Trichlorotriethylamine; Trichothecene (especially T-2 toxin, verracurin A) , Loridine A and Anguidine); Urethane; Vindesine; Dacarbazine; Mannomustine; Mitobronitol; Mitractol; Pipobroman; Gacytosine; Arabinoside ("Ara-C"); Cyclophosphamide; Thiotepa; 6-Thiogunine; Mercaptopurine; Methotrexate; Platinum analogs such as 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; includes difluoromethylornithine (DMFO); retinoids such as retinoic acid; and pharmaceutically acceptable salts, acids, and derivatives of any of the above.

[0031] The definition of "chemotherapeutic agents" also includes the following: (i) anti-estrogens and selective estrogen receptor modulators (SERMs) and selective estrogen receptor modulators (SERDs) (e.g., fulvestrant (Faslodex®, Astra Zeneca)) that work to regulate or inhibit the hormonal effects on tumors, including, for example, tamoxifen (Nolvadex®; including tamoxifen citrate), raloxifene, droloxifene, 4-hydroxytamoxifen, trioxyfen, keoxyfen, LY117018, onapristone and Fareston® (toremifene citrate); (ii) aromatase inhibitors that inhibit aromatase, an enzyme that regulates estrogen production in the adrenal gland, such as 4(5)-imidazole, aminoglutethimide, MEGASE® (megestrol acetate), Aromasin® (exemestane; Pfizer), and formestane (formestanie). (iii) Antiandrogens, such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; and troxacitabine (1,3-dioxolane nucleoside cytosine analog); (iv) Protein kinase inhibitors, such as cobimetinib (International Publication No. 2007 / 044515) and other MEK inhibitors; (v) Lipid kinase inhibitors, such as taselicib (GDC-0032, Genentech Inc.); (vi) Antisense oligonucleotides, particularly those that inhibit the expression of genes (PKC-alpha, Raf, and H-Ras, etc.) in signaling pathways involved in abnormal cell proliferation, such as oblimersen (GENASENSE®, Genta Inc.).(vii) Ribozymes, e.g., VEGF expression inhibitors (e.g., ANGIOZYME®) and HER2 expression inhibitors; (viii) Vaccines, such as gene therapy vaccines, e.g., allovectin®, leubectin®, and VAXID®; proleukin® rIL-2; topoisomerase 1 inhibitors, e.g., raltotecan®; avalerix® rmRH; (ix) Anti-angiogenic agents, e.g., bevacizumab (avastin®, Genentech); and pharmaceutically acceptable salts, acids, and derivatives of any of the above.

[0032] The definition of "chemotherapeutic agents" also includes alemtuzumab (Campus), bevacizumab (Avastin®, Genentech); cetuximab (Erbitux®, Imclone); panitumumab (Vectibix®, Amgen); rituximab (Rituxan®, Genentech / Biogen Idec); pertuzumab (PERJETA TM, This also includes therapeutic antibodies such as 2C4 (Genentech), trastuzumab (Herceptin®, Genentech), trastuzumab emtansine (KADCYLA®, Genentech Inc.), and tositumomab (Bexal, Corixia).

[0033] A “metabolite” is a product produced by the metabolism of a particular compound or a salt thereof in the body. Metabolites of a compound can be identified using conventional techniques known in the art, and their activity can be determined by tests such as those described herein. Such products can be obtained, for example, from oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic cleavage, etc. of the administered compound. Accordingly, the present invention includes metabolites of the compounds of the present invention produced by a method comprising contacting a compound of formula I of the present invention with a mammal for a period of time sufficient to obtain its metabolites.

[0034] The term "package insert" is used to refer to the instructions that are typically included in the product packaging of a therapeutic product, and includes information regarding instructions, usage, dosage, administration, contraindications, and / or precautions for the use of such therapeutic product.

[0035] The term "chiral" refers to a molecule that has the property of being a mirror image partner that it cannot be superimposed on, while the term "achiral" refers to a molecule that can be superimposed on its mirror image partner.

[0036] The term "stereoisomer" refers to compounds that have the same chemical structure but differ in the arrangement of atoms or groups in space.

[0037] A "diastereomer" is a stereoisomer containing multiple chiral centers, where the molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting point, boiling point, spectral properties, and reactivity. Mixtures of diastereomers can be separated using high-resolution analytical procedures such as electrophoresis and chromatography.

[0038] An "enantiomer" refers to two stereoisomers of a compound that are mirror images of each other and cannot be superimposed.

[0039] The stereochemical definitions and conventions used herein generally follow SP. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984), McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds," John Wiley & Sons, Inc., New York, 1994. The compounds of the present invention may contain a chiral or asymmetric center and therefore may exist in different stereoisomeric forms. All stereoisomeric forms of the compounds of the present invention, including but not limited to diastereomers, enantiomers, and atropisomers, and mixtures thereof (e.g., racemic mixtures), are intended to form part of the present invention. Many organic compounds exist in an optically active form; that is, they can rotate the plane of plane-polarized light. When describing optically active compounds, the prefixes D and L, or R and S, are used to indicate the absolute configuration of the molecule around its chiral center. The prefixes d and l, or (+) and (-), are used to indicate the sign of the rotation of plane-polarized light by the compound, where (-) or 1 means the compound is levorotatory. Compounds prefixed with (+) or d are dextrorotatory. With respect to a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. Certain stereoisomers are also called enantiomers, and mixtures of such isomers are often called enantiomer mixtures. A 50:50 mixture of enantiomers is called a racemic mixture or racemate and can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process. The terms “racemic mixture” and “racemate” refer to an equimolar mixture of two enantiomer species that are not optically active. Enantiomers can be separated from racemic mixtures by chiral separation methods such as supercritical fluid chromatography (SFC). The assignment of stereochemistry at the chiral center in the separated enantiomers is provisional, and the structures shown in Table 1 are for illustrative purposes only, while the stereochemistry is ultimately determined by, for example, X-ray crystallography.

[0040] The term "tautomer" or "tautomer" refers to structural isomers of different energies that can interconvert across a low-energy barrier. For example, proton tautomers (also known as proton tautomers) include interconversions by proton transfer, such as keto-enol and imine-enamine isomerization. Valence tautomers include interconversions by rearrangement of some of the bonding electrons.

[0041] The term "pharmaceutically acceptable salt" refers to a salt that is not biologically or otherwise undesirable. pharmaceutically acceptable salts include both acid-addition salts and base-addition salts. The expression "pharmaceutically acceptable" indicates that the substance or composition must be chemically and / or toxicologically compatible with the other components of the formulation and / or the mammals treated with it.

[0042] The term "pharmaceutically acceptable acid addition salt" refers to a salt formed by an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, or phosphoric acid, and an organic acid selected from aliphatic, alicyclic, aromatic, arylaliphatic, heterocyclic carboxylic acids and sulfonic acids, such as formic acid, acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic 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 "mesylate", ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid, which is pharmaceutically acceptable.

[0043] The term "pharmaceutically acceptable base addition salt" refers to a salt formed from an organic or inorganic base that is pharmaceutically acceptable. Examples of acceptable inorganic bases include sodium salts, potassium salts, ammonium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts, and aluminum salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines (including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins), such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, trimamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, and polyamine resins.

[0044] A "solvate" refers to an association or complex of one or more solvent molecules with the compound of the present invention. Examples of solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate (RINKAN), acetic acid (AcOH), and ethanolamine.

[0045] The term “EC 50 "Median effect concentration" refers to the plasma concentration of a particular compound required to obtain 50% of the maximum effect of that particular compound in vivo.

[0046] The term "Ki" is an inhibition constant that indicates the absolute binding affinity of a particular inhibitor to a receptor. It is measured using a competitive binding assay and is equal to the concentration at which the particular inhibitor accounts for 50% of the receptor's capacity in the absence of a competing ligand (e.g., a radioactive ligand). The Ki value can be logarithmically converted to a pKi value (-log Ki), with higher values ​​indicating exponentially greater potency.

[0047] The term “IC 50IC refers to the median inhibitory concentration, which indicates the concentration of a particular compound required to achieve 50% inhibition of a biological process in vivo. 50 The value is pIC 50 It can be converted logarithmically to a value (-log IC). 50 ), the higher the value, the greater the effect exponentially. IC 50 The value is not an absolute value and depends on experimental conditions such as the concentration used, but it can be converted to an absolute inhibitory constant (Ki) using the Cheng-Prusoff equation ((Biochem.Pharmacol.(1973)22:3099).IC 70 ,I C 90 Other percentage inhibition parameters, such as those mentioned above, may also be calculated.

[0048] The terms “compound of the present invention” and “compound of formula (I)” include the compound of formula (I), the specific compounds described herein and their stereoisomers, geometric isomers, tautomers, solvates, metabolites, and pharmaceutically acceptable salts and prodrugs.

[0049] Furthermore, any formula or structure shown herein that includes the compound of formula (I) is also intended to represent hydrates, solvates, and polymorphs of such compounds, as well as mixtures thereof.

[0050] Any formula or structure shown herein, including the compound of formula (I), is also intended to represent both the unlabeled and isotope-labeled forms of the compound. The isotope-labeled compound has the structure represented by the formula shown herein, except that one or more atoms are substituted with atoms having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into the compounds of the present invention include, but are not limited to, isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as 2H (deuterium, D), 3H (tritium), 11C, 13C, 14C, 15N, 18F, 31P, 32P, 35S, 36Cl, and 125I. Various isotope-labeled compounds of the present invention, for example, compounds incorporating radioactive isotopes such as 3H, 13C, and 14C. Such isotope-labeled compounds may be useful in metabolic studies, reaction kinetic studies, detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT), including drug or substrate tissue distribution assays, or in radiotherapy for patients. Therapeutic compounds of the present invention labeled or substituted with deuterium may have improved DMPK (drug metabolism and pharmacokinetics) with respect to distribution, metabolism and excretion (ADME). Substitution with heavy isotopes such as deuterium may result in certain therapeutic advantages, such as higher metabolic stability, e.g., extended in vivo half-life or reduced required dose. Compounds labeled with 18F may be useful in PET or SPECT studies. The isotope-labeled compounds and their prodrugs of the present invention can generally be prepared by carrying out the methods disclosed in the following schemes or examples and preparations, by using readily available isotope-labeling reagents in place of non-isotope-labeling reagents. Furthermore, substitution with heavier isotopes, particularly deuterium (i.e., 2H or D), can result in specific therapeutic benefits arising from greater metabolic stability, such as an extended in vivo half-life, reduced required dose, or improved therapeutic index. In this context, deuterium is considered a substituent of the compound of formula (I). The concentration of such heavy isotopes, particularly deuterium, can be defined by the isotopic enrichment factor. In the compounds of the present invention, any atom not specifically designated as a particular isotope represents any stable isotope of that atom.Unless otherwise specified, when a position is specifically designated as "H" or "hydrogen," it is understood that the position contains hydrogen in its natural abundance isotopic composition. Therefore, in the compounds of the present invention, any atom specifically designated as deuterium (D) represents deuterium.

[0051] Estrogen receptor Estrogen receptor alpha ((ER-a; NR3A1)) and estrogen receptor beta (ER-b; NR3A2) are steroid hormone receptors and are members of the large nuclear receptor superfamily. Nuclear receptors share a common modular structure that contains minimal DNA-binding domains (DBDs) and ligand-binding domains (LBDs). Steroid hormone receptors are soluble intracellular proteins that act as ligand-regulating transcription factors. Vertebrates contain five closely related steroid hormone receptors (estrogen receptor, androgen receptor, progesterone receptor, glucocorticoid receptor, and mineralocorticoid receptor), which regulate a wide range of reproductive, metabolic, and developmental activities. ER activity is regulated by the binding of endogenous estrogens, including 17-β-estradiol and estrone.

[0052] The ER-a (alpha) gene is located on chromosome 6q25.1 and encodes the 595 AA protein. The ER-b gene is located on chromosome 14q23.3 and produces the 530 AA protein. However, due to alternative splicing and translation 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 also contain an N-terminal (A / B) domain, a hinge (D) domain that connects the C and E domains, and a C-terminal extension (F domain) (Gronemeyer and Laudet; Protein Profile 2:1173-1308, 1995). While the C and E domains of ER-a and ER-b are fully conserved (95% and 55% amino acid identity, respectively), the A / B, D, and F domains are poorly conserved (less than 30% amino acid identity). Both receptors are involved in the regulation and development of the female reproductive system, as well as playing various roles in the central nervous system, cardiovascular system, and bone metabolism.

[0053] The ligand-binding pocket of steroid hormone receptors is deeply embedded within the ligand-binding domain. Upon binding, the ligand becomes part of the hydrophobic core of this domain. As a result, most steroid hormone receptors are unstable in the absence of the hormone and require assistance from chaperones such as Hsp90 to maintain hormone-binding ability. Interaction with Hsp90 also controls the nuclear translocation of these receptors. Ligand binding stabilizes the receptor and initiates a series of structural changes, which in turn release chaperones, alter the interactions between various receptor domains, and translocate these receptors to the nucleus, where DNA binds and a protein interaction surface is reconfigured to participate in interactions with chromatin remodeling complexes and transcription mechanisms. While the ER can interact with Hsp90, this interaction is not required for hormone binding, and depending on the cellular context, the apo-ER can be located in either the cytoplasm or the nucleus. Biophysical studies have shown that DNA binding, rather than ligand binding, contributes more to receptor stability (Greenfield et al., Biochemistry 40: 6646-6652, 2001).

[0054] ER can interact with DNA either by directly binding to specific DNA sequence motifs called estrogen response elements (EREs) (classical pathway) or indirectly via protein-protein interactions (non-classical pathway) (Welboren et al., Endocrine-Related Cancer 16: 1073-1089, 2009). In the non-classical pathway, ER has been shown to be linked to other transcription factors, including SP-1, AP-1, and NF-B. These interactions appear to play a crucial role in ER's ability to regulate cell proliferation and differentiation.

[0055] Both types of ER-DNA interactions can lead to gene activation or repression depending on transcriptional coregulators replenished by their respective ER-ERE complexes (Klinge, Steroid 65: 227-251, 2000). Coregulatory replenishment is primarily mediated by two protein interaction surfaces, AF2 and AF1. AF2 is located in the ER E domain, and its conformation is directly regulated by ligands (Brzozowski et al., (1997) Nature 389: 753-758). Full agonists appear to promote coregulatory replenishment, while weak agonists and antagonists promote corepressor binding. Protein regulation using AF1 is not well understood, but it may be regulated by serine phosphorylation (Ward and Weigel, (2009) Biofactors 35: 528-536). One of the phosphorylation sites involved (S118) appears to regulate the transcriptional activity of the ER in the presence of antagonists such as tamoxifen, which play a crucial role in the treatment of breast cancer. While full agonists appear to halt the ER at specific conformations, weak agonists tend to maintain the ER in equilibrium between various conformations, thereby allowing cell-dependent differences in the co-regulatory repertoire to modulate ER activity in a cell-dependent manner (Tamrazi et al., Mol. Endocrinol. 17: 2593-2602, 2003). DNA-ER interactions are dynamic and not limited to proteasome-mediated degradation of the ER (Reid et al., Mol Cell 11: 695-707, 2003). Ligand-mediated degradation of the ER offers an attractive therapeutic strategy for estrogen-sensitive and / or resistant anti-hormone 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, and cancer. 70% of breast cancers express ER-a (ER-a-positive) and are estrogen-dependent in terms of growth and survival.Other cancers, such as ovarian cancer and endometrial cancer, are also thought to depend on ER-a signaling for growth and survival. Tamoxifen, an ER-a antagonist, is used to treat early and advanced ER-a positive breast cancer in women around menopause. Fulvestrant (Faslodex) is a steroid-based ER antagonist. TM) is used to treat breast cancer in women that has progressed despite treatment with tamoxifen (Howell A. (2006) Endocr Relat Cancer; 13:689-706; U.S. Patent No. 6,774,122; U.S. Patent No. 7,456,160; U.S. Patent No. 8,329,680; U.S. Patent No. 8,466,139). Steroidal and non-steroidal aromatase inhibitors are also used to treat cancer in humans. In some embodiments, steroidal and non-steroidal aromatase inhibitors block the production of estrogen from androstenedione and testosterone in postmenopausal women, thereby blocking ER-dependent growth in cancer. In addition to these antihormone agents, advanced ER-positive breast cancer may in some cases be treated with various chemotherapeutic agents such as anthracyclines, platinum, and taxanes. In some cases, ER-positive breast cancer with ERB-B / HER2 tyrosine kinase receptor gene amplification is treated with the monoclonal antibody trastuzumab (Herceptin®, Genentech Inc.) or the small molecule pan-ERB-B inhibitor lapatinib (Tykerb®, GlaxoSmith Kline Corp.). Despite this range of antihormone, chemotherapy, and small molecule and antibody-based targeted therapies, many women with ER-a-positive breast develop progressive metastatic disease and require new treatments. Importantly, most ER-positive tumors that progress on existing antihormone and other therapies are thought to remain ER-a-dependent for growth and survival. Therefore, there is a need for novel ER-a-targeted agents that are active in the context of metastatic disease and acquired resistance. In one embodiment, the compounds described herein are selective estrogen receptor modulators (SERMs). In certain embodiments, the SERMs described herein are selective estrogen receptor degraders (SERDs).In some embodiments, the compounds described herein are useful in cell-based assays for the treatment of estrogen-sensitive diseases or conditions and / or diseases or conditions that result in a decrease in steady-state ERa- levels (i.e., ER degradation) and resistance to anti-hormone therapy.

[0056] Most breast cancer patients are treated with drugs that block estrogen synthesis (e.g., aromatase inhibitors; AIs) or drugs that antagonize the action of estradiol via competing ER binding (e.g., tamoxifen) (Puhalla S, et al Mol Oncol 2012; 6(2):222-236). Despite the well-documented therapeutic efficacy of these drugs at various stages of the disease, many ER-+ breast cancers recur, and patients ultimately die. In recent years, next-generation whole-genome and targeted sequencing has identified ESR1 (estrogen receptor α gene) mutations in up to 20% of tumors from patients with advanced breast cancer who have progressed to endocrine therapy (mostly aromatase inhibitors) (Li S, et al. Cell Rep (2013); 4(6): 1116-1130; Merenbakh-Lamin K, et al. Cancer Res (2013); 73(23): 6856-6864; Robinson DR, et al. Nat Genet (2013); 45(12): 1446-1451; Toy W, et al. Nat Genet (2013); 45(12): 1439-1445; Jeselsohn R, et al. Clin Cancer Res (2014); 20: 1757-1767). Such ligand-binding domain (LBD) mutations confer high basal activity to the apo- receptor, making it ligand-independent and thus active in low-estradiol conditions. In the context of progressive disease following AI or tamoxifen treatment, including a subset of patients with ESR1-mutated tumors, there is a need for therapies that target ER signaling with potent activity.

[0057] In some embodiments, the compounds of formula I disclosed herein are used in a method for treating hormone-resistant estrogen receptor (ER)-positive breast cancer in patients characterized by mutations in the ESR1 gene, comprising administering a therapeutically effective amount of the compound of formula I. In some embodiments, the mutation in the ESR1 gene 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 mutations result in ER polypeptides having amino acid substitutions 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 embodiments, the patient has two or more mutations in the ESR1 gene.

[0058] Given the central role of ER-a in the development and progression of breast cancer, the compounds disclosed herein are useful for the treatment of breast cancer, either alone or in combination with other agents (but not limited to) that modulate other important pathways in breast cancer, such as IGF1R, EGFR, CDK 4 / 6, erB-B2 and 3, PI3K / AKT / mTOR axis, HSP90, PARP, or histone deacetylases.

[0059] Given the central role of ER-a in the development and progression of breast cancer, the compounds of formula I disclosed herein are useful for the treatment of breast cancer, either alone or in combination with other agents (but not limited to) used to treat breast cancer, including aromatase inhibitors, anthracyclines, platins, nitrogen mustard alkylating agents, and taxanes. Exceptional drugs used to treat breast cancer include, but are not limited to, PI3K inhibitors such as taselicib (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), ixabepirone, and others described herein.

[0060] ER-related diseases or conditions include cancer (bone cancer, breast cancer, lung cancer, colorectal cancer, endometrial cancer, prostate cancer, ovarian and uterine cancer), central nervous system (CNS) disorders (alcoholism, migraines), cardiovascular disorders (aortic aneurysm, increased susceptibility to myocardial infarction, aortic valve sclerosis, cardiovascular disease, coronary artery disease, hypertension), hematological disorders (deep vein thrombosis), and immune and inflammatory diseases (Graves' disease, arthritis, multiple sclerosis, cirrhosis). This includes ER-a dysfunction associated with increased susceptibility to infection (hepatitis B, chronic liver disease), metabolic disorders (bone density, cholestasis, hypospadias, obesity, osteoarthritis, osteopenia, osteoporosis), neurological disorders (Alzheimer's disease, Parkinson's disease, migraines, dizziness), psychiatric disorders (anorexia nervosa, attention deficit hyperactivity disorder (ADHD), dementia, major depressive disorder, psychosis), and reproductive disorders (age of menarche, endometriosis, infertility).

[0061] In some embodiments, the compounds disclosed herein are used to treat estrogen receptor-dependent or estrogen receptor-mediated diseases or conditions in mammals. In some embodiments, the compounds disclosed herein are used to treat cancer in mammals. 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 hormone-dependent cancer. In some embodiments, the cancer is estrogen receptor-dependent cancer. In some embodiments, the cancer is estrogen-sensitive cancer. In some embodiments, the cancer is resistant to anti-hormone therapy. In some embodiments, the cancer is estrogen-sensitive cancer or estrogen receptor-dependent cancer resistant to anti-hormone therapy. In some embodiments, the cancer is hormone-sensitive cancer or hormone receptor-dependent cancer resistant to anti-hormone therapy. In some embodiments, the anti-hormone therapy includes treatment with at least one agent selected from tamoxifen, fulvestrant, steroidal aromatase inhibitors, and nonsteroidal aromatase inhibitors. In some embodiments, the compounds disclosed herein are used to treat hormone receptor-positive metastatic breast cancer in postmenopausal women with disease progression after anti-estrogen therapy. In some embodiments, the compounds disclosed herein are used to treat hormone-dependent benign or malignant diseases of the milk or reproductive system of mammals. In some embodiments, the benign or malignant disease is breast cancer. In some embodiments, the compounds used in any of the methods described herein are estrogen receptor degraders; estrogen receptor antagonists; have minimal or very slight estrogen receptor agonist activity; or a combination thereof. In some embodiments, a therapeutic method using the compounds described herein includes a therapeutic regimen that involves administering radiotherapy to a mammal. In some embodiments, a therapeutic method using the compounds described herein includes administering the compounds before or after surgery. In some embodiments, a therapeutic method using the compounds described herein includes administering at least one additional anticancer agent. In some embodiments, the compounds described herein are used to treat cancer in mammals that have not received chemotherapy. In some embodiments, the compounds disclosed herein are used to treat cancer in mammals. In some embodiments, the compounds disclosed herein are used to treat cancer in mammals that are being treated with at least one anticancer agent. In one embodiment, the cancer is hormone-resistant cancer. In some embodiments, the compounds disclosed herein are used in the treatment or prevention of diseases or conditions of the uterus in mammals. In some embodiments, the diseases or conditions of the uterus are leiomyoma, uterine leiomyoma, endometrial hyperplasia, or endometriosis. In some embodiments, the diseases or conditions of the uterus are cancerous diseases or conditions of the uterus. In some other embodiments, the diseases or conditions of the uterus are non-cancerous diseases or conditions of the uterus. In some embodiments, the compounds disclosed herein are used for the treatment of endometriosis in mammals. In some embodiments, the compounds disclosed herein are used to treat leiomyomas in mammals. In some embodiments, the leiomyomas are uterine leiomyomas, esophageal leiomyomas, cutaneous leiomyomas, or small intestinal leiomyomas. In some embodiments, the compounds disclosed herein are used to treat fibroids in mammals. In some embodiments, the compounds disclosed herein are used to treat uterine fibroids in mammals.

[0062] Another embodiment of the present invention relates to the compounds described herein for use as therapeutically active substances. Another embodiment of the present invention relates to the compounds disclosed herein for use in the treatment of ER-related diseases or disorders. Another embodiment of the present invention relates to the use of the compounds disclosed herein for use in the treatment of ER-related diseases or disorders. Another embodiment of the present invention relates to the use of the compounds disclosed herein for the preparation of pharmaceuticals useful in the treatment of ER-related diseases or disorders.

[0063] Tetrahydropyrido[3,4-b]indole-1-yl compounds The present invention provides tetrahydropyrido[3,4-b]indole-1-yl compounds of formula I, including formula Ia-If, and pharmaceutical formulations thereof, which may be useful in the treatment of diseases, conditions, and / or disorders modulated by the estrogen receptor alpha (ERa).

[0064] The compound of formula I has the following structure: JPEG2026067858000002.jpg4075I and its stereoisomers, tautomers, or pharmaceutically acceptable salts [in the above formula, Y 1 CR b or N; Y 2 These are -(CH2)-, -(CH2CH2)-, or NR a and; Y 3 , NR a or C(R b )2; Here, Y 1 , Y 2 and Y 3 One of them is N or NR a and; R a It is selected from H, C1-C6 alkyl, C2-C8 alkenyl, propargyl, C3-C6 cycloalkyl and C3-C6 heterocyclyl, which are optionally substituted with one or more groups independently selected from F, Cl, Br, I, CN, OH, OCH3 and SO2CH3; R bH, -O(C1-C3 alkyl), C1-C6 alkyl, C2-C8 alkenyl, propargyl, -(C1-C6 alkyldiyl)-(C3-C6 cycloalkyl), C3-C6 cycloalkyl and C3-C6 heterocyclyl are independently selected from H, -O(C1-C3 alkyl), C1-C6 alkyl, C2-C8 alkenyl, propargyl, -(C1-C6 alkyldiyl)-(C3-C6 cycloalkyl), C3-C6 cycloalkyl and C3-C6 heterocyclyl, and are optionally substituted with one or more groups independently selected from F, Cl, Br, I, CN, -CH2F, -CHF, -CF3, -CH2CF3, -CH2CHF2, -CH2CH2F, OH, OCH3 and SO2CH3; R c It is selected from H, C1-C6 alkyl, allyl, and propargyl groups that are optionally substituted with one or more groups independently selected from F, Cl, Br, I, CN, OH, OCH3, and SO2CH3; Z 1 CR a R b Selected from C(O) and bonds; Cy is C6-C 20 Alylzil, C3-C 12 Carbocyclyldiyl, C2-C 20 Heterocyclyldiyl and C1-C 20 Selected from heteroaryldiyl; Z 2 O, S, NR a Selected from C1-C6 alkyldiyl, C1-C6 fluoroalkyldiyl, O-(C1-C6 alkyldiyl), O-(C1-C6 fluoroalkyldiyl), C(O), and bond; R 1 , R 2 , R 3 and R 4are 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, -CH2NHCH 3, -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)2CH3, -N(CH3)C(CH3)2CONH2, -N(CH3)CH2CH2S(O)2CH3, -NO2, =O, -OH , -OCH3, -OCH2CH3, -OCH2CH2OCH3, -OCH2CH2OH, -OCH2CH2N(CH3)2, -OP(O)(OH)2, -S(O)2N(CH3)2, -SCH3, -S(O)2CH 3, independently selected from -S(O)3H, cyclopropyl, cyclopropylamide, cyclobutyl, oxetanyl, azetidinyl, 1-methylazetidine-3-yl)oxy, N-methyl-N-oxetane-3-ylamino, azetidine-1-ylmethyl, benzyloxyphenyl, pyrrolidine-1-yl, pyrrolidine-1-ylmethanone, piperazine-1-yl, morpholinomethyl, morpholinomethanone and morpholino; R 5 Halogen, CN, OR a , N(R a )2, C1-C9 alkyl, C3-C9 cycloalkyl, C3-C9 heterocyclic, C6-C9 aryl, C6-C9 heteroaryl, C(O)R b , C(O)NR a SO2R a and SO2NR aH, C1-C9 alkyl, C3-C9 cycloalkyl, C3-C9 heterocyclic, C6-C9 aryl, C6-C9 heteroaryl, -(C1-C6 alkyldiyl)-(C3-C9 cycloalkyl), -(C1-C6 alkyldiyl)-(C3-C9 heterocyclic), C(O)R b , C(O)NR a SO2R a and SO2NR a Selected from; R 6is 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)2CH3, -N(CH3)C(CH3)2CONH2, -N(CH3)CH2CH2S(O)2CH3, -NO2, =O, -OH , -OCH3, -OCH2CH3, -OCH2CH2OCH3, -OCH2CH2OH, -OCH2CH2N(CH3)2, -OP(O)(OH)2, -S(O)2N(CH3)2, -SCH3, -S(O)2C Selected from H3, -S(O)3H, cyclopropyl, cyclopropylamide, cyclobutyl, oxetanyl, azetidinyl, 1-methylazetidine-3-yl)oxy, N-methyl-N-oxetane-3-ylamino, azetidine-1-ylmethyl, benzyloxyphenyl, pyrrolidine-1-yl, pyrrolidine-1-ylmethanone, piperazine-1-yl, morpholinomethyl, morpholinomethanone and morpholino; m is selected from 0, 1, 2, 3, and 4; Here, alkyldiyl, fluoroalkyldiyl, aryldiyl, carbocycryldiyl, heterocyclyldiyl and heteroaryldiyl are 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, -CF3, -CH2CF3, -CH2CHF2, -CH2CH2F, -CH(CH3)CN, -C(CH3)2CN, -CH2CN, -CH2NH2, -CH2NHSO2CH3, -CH2N HCH3, -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, -NO2, =O , -OH, -OCH3, -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, oxetanyl, azetidinyl, 1-methylazetidine-3-yl)oxy, N-methyl-N-oxetan-3-ylamino, azetidine-1-ylmethyl, benzyloxyphenyl, pyrrolidine-1-yl, pyrrolidine-1-ylmethanone, piperazine-1-yl, morpholinomethyl, morpholinomethanone, and morpholino are optionally substituted with one or more groups independently selected from these groups.] It holds.

[0065] The compound of formula Ia-k has the following structure: JPEG2026067858000003.jpg4279Ia; JPEG2026067858000004.jpg5278Ib; [In the above formula, R 7 is F, Cl, Br, I, -CN, -CH3, -CH2CH3, -CH(CH3)2, -CH2CH(CH3)2, -CH2OH, -CH2OCH3, -CH2CH2OH, -C(CH3)2OH, -CH(O H)CH(CH3)2, -C(CH3)2CH2OH, -CH2CH2SO2CH3, -CH2OP(O)(OH)2, -CH2F, -CHF2, -CH2NH2, -CH2NHSO2CH3, -CH2NHCH 3, -CH2N(CH3)2, -CF3, -CH2CF3, -CH2CHF2, -CH(CH3)CN, -C(CH3)2CN, -CH2CN, -CO2H, -COCH3, -CO2CH3, -CO2C(CH 3)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, =O, -OH, -OCH3, -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, oxetanyl, azetidinyl, 1-methylazetidine-3-yl)oxy, N-methyl-N-oxetane-3-ylamino, azetidine-1-ylmethyl, benzyloxyphenyl, pyrrolidine-1-yl, pyrrolidine-1-ylmethanone, piperazine-1-yl, morpholinomethyl, morpholinomethanone and morpholino; n is selected from 0, 1, 2, 3, and 4; JPEG2026067858000005.jpg4079Ic; JPEG2026067858000006.jpg3979Id; JPEG2026067858000007.jpg5584Ie; JPEG2026067858000008.jpg5787If [In the above formula, R 8 [is H or -CH3]; JPEG2026067858000009.jpg4176Ig; JPEG2026067858000010.jpg5176Ih; JPEG2026067858000011.jpg5176Ii; JPEG2026067858000012.jpg5176Ij; and JPEG2026067858000013.jpg4876Ik It holds.

[0066] Exemplary embodiments of the compound of formula I are shown in Y 1 CR b Y 3 NR a This includes things that are. Exemplary embodiments of the compound of formula I are shown in Y 1 N is Y 3 is C(R b This includes those that are 2. Exemplary embodiments of the compound of formula I are shown in Y 2 This includes those that are -(CH2)-. Exemplary embodiments of the compound of formula I are shown in Y 2 This includes those that are -(CH2CH2)-. Exemplary embodiments of the compound of formula I are shown in R c This includes those where H is the value. An exemplary embodiment of the compound of formula I is one in which Cy is C6-C 20 It is an aryldiyl, C6-C 20 This includes aryldiyl, which is phenyldiyl, and in which the phenyldiyl is substituted with one or more fluorine atoms. Exemplary embodiments of the compound of formula I are shown in R 1 and R 2 This includes those where H is the value. Exemplary embodiments of the compound of formula I are shown in R 3 H is R 4 This includes those where -CH3 is present. Exemplary embodiments of the compound of formula I are shown in R 5including those in which it is C1-C6 fluoroalkyl. Exemplary embodiments of the compound of formula I include those in which m is 0.

[0067] The present invention also provides a tetrahydro-pyrido[3,4-b]indol-1-yl compound of formula XI including formula XIa, and its pharmaceutical formulations, which may be useful in the treatment of diseases, conditions and / or disorders modulated by estrogen receptor alpha (ERa).

[0068] In some embodiments, the compounds of the present invention are of the following formula (XI): JPEG2026067858000014.jpg3793 Formula (XI); [In the above formula: Z 1 and Z 2 are independently selected from -O-, -(CH2)-, -C(O)- or a bond; Cy is C6-C 20 aryl, C3-C 12 carbocyclic, C2-C 20 heterocyclic or C1-C 20 heteroaryl; X is -(CH2)- or -(CH2CH2)-; R 1 is H, F, Cl, -CN, -CH2OH, -CH(CH3)OH, -C(CH3)2OH, -CH(CF3)OH, -CH2F, -CHF2, -CH2CHF2, -CF3, -CH3, -C(O)NH2, -C(O)NHCH3 and -C(O)N(CH3)2; Each R 2 is halogen, -CN, -OR 10 -, -NR 13 R 14 is C1-C6 alkyl, C3-C8 carbocyclic, -C1-C6 alkyl-OH, C3-C8 carbocyclic-OH, -OC2-C6 alkyl-OH, C1-C6 fluoroalkyl, C3-C8 fluorocarbocyclic, -C(=O)OR 12 -, -NHC(=O)R 11 -, -C(=O)NHR 12, -SO2R 11 , -NHSO2R 11 and -SO2NHR 12 is independently selected from; R 4 and R 5 are each independently selected from C1-C6 alkyl, C3-C8 carbocyclyl, -C1-C6 alkyl-OH, C3-C8 carbocyclyl-OH, C1-C6 fluoroalkyl, C3-C8 fluorocarbocyclyl, -C(=O)OR 12 ; R 9 is independently selected from C1-C6 alkyl, C3-C8 carbocyclyl, -C1-C6 alkyl-OH, C3-C8 carbocyclyl-OH, C1-C6 fluoroalkyl, C3-C8 fluorocarbocyclyl, C2-C9 heterocyclyl, C6-C 10 aryl and C1-C 10 heteroaryl; R 19 is H, C1-C6 alkyl, C3-C8 carbocyclyl, -C1-C6 alkyl-OH, C3-C8 carbocyclyl-OH, C1-C6 fluoroalkyl, C3-C8 fluorocarbocyclyl, -C(=O)OR 12 , -C(=O)NHR 12 , -SO2R 11 , -NHSO2R 11 , -SO2NHR 12 , C6-C 10 aryl and C1-C 10 heteroaryl; Each R 10 is independently selected from H, C1-C4 alkyl and C1-C4 fluoroalkyl; Each R 11 is independently selected from C1-C4 alkyl and C1-C4 fluoroalkyl; Each R 12 is independently selected from H, C1-C4 alkyl and C1-C4 fluoroalkyl; Each R 13 and each R 14 is independently selected from H and C1-C4 alkyl; m is 0, 1, 2 or 3 It has the structure of, or comprises a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0069] In some embodiments, the compound of formula (XI) is formula (XIa): JPEG2026067858000015.jpg53101 formula (XIa); [In the above formula, R 2a is independently H or F, n is 0, 1 or 2, and R 4 and R 5 [is independently H or methyl] It has the structure of [the object].

[0070] In some embodiments, the compound of formula (XI) is Z 1 This is a bond. In some embodiments, the compound of formula (XI) is Z 1 is -O-. In some embodiments, the compound of formula (XI) is Z 1 is -(CH2)-. In some embodiments, the compound of formula (XI) is Z 1 is -C(O)-. In some embodiments, the compound of formula (XI) is Z 2 This is a bond. In some embodiments, the compound of formula (XI) is Z 2 is -O-. In some embodiments, the compound of formula (XI) is Z 2 is -(CH2)-. In some embodiments, the compound of formula (XI) is Z 2 is -C(O)-. In some embodiments, the compound of formula (XI) is C6-C 20 It is aryl. In some embodiments, the compound of formula (XI) has Cy as phenyl. In some embodiments, the compound of formula (XI) has Cy as C3-C 12 It is a carbocyclyl. In some embodiments, the compound of formula (XI) has Cy as cyclohexyl. In some embodiments, the compound of formula (XI) has Cy as C2-C 20It is a heterocyclyl. In some embodiments, the compound of formula (XI) has pyrazinyl as Cy. In some embodiments, the compound of formula (XI) has piperidinyl as Cy. In some embodiments, the compound of formula (XI) has C1-C 20 It is a heteroaryl compound. In some embodiments, the compound of formula (XI) has thiazolyl as Cy. In some embodiments, the compound of formula (XI) has oxazolyl as Cy. In some embodiments, the compound of formula (XI) has pyridyl as Cy. In some embodiments, the compound of formula (XI) has R 1 is H. In some embodiments, the compound of formula (XI) is R 1 is -CH3. In some embodiments, the compound of formula (XI) is -(CH2)-. In some embodiments, the compound of formula (XI) is -(CH2)-, and R 1 is H. In some embodiments, the compound of formula (XI) is -(CH2CH2)-. In some embodiments, the compound of formula (XI) is -(CH2CH2)-, and R 1 is H. In some embodiments, the compound of formula (XI) is such that X is -(CH2CH2)- and R 1 It is -CH3.

[0071] In some embodiments, the compound of formula (XI) is Z 1 The bond is Z 2 is -O-, Cy is phenyl, X is -(CH2)-, R 1 is H. In some embodiments, the compound of formula (XI) is Z 1 The bond is Z 2 is -O-, Cy is phenyl, X is -(CH2CH2)-, R 1 is H. In some embodiments, the compound of formula (XI) is Z 1 The bond is Z 2 is -O-, Cy is phenyl, X is -(CH2CH2)-, R 1 It is -CH3.

[0072] Biological evaluation The relative potency of the compounds of formula I as inhibitors of enzyme activity (or other biological activity) can be determined by determining the concentration at which each compound inhibits activity to a predetermined degree and comparing the results. Typically, a preferred determination is the concentration at which 50% of the activity is inhibited in a biochemical assay, i.e., the 50% inhibitory concentration or "IC". 50 " IC 50 The determination of the value can be achieved using conventional methods well known in the art. Generally, IC 50 This can be determined by measuring the activity of a given enzyme in the presence of an inhibitor within the test concentration range. The experimentally obtained value of enzyme activity is then plotted against the inhibitor concentration used. The concentration of the inhibitor showing 50% enzyme activity (compared to the activity in the absence of any inhibitor) is defined as IC50. 50 This value is used. Similarly, other inhibitory concentrations can also be defined by appropriately determining the activity. For example, in some situations, the 90% inhibitory concentration, i.e., IC50, is defined as the IC50. 90 It may be desirable to establish such things.

[0073] The cell proliferation, cytotoxicity, and cell viability of compounds of formula I can be measured by the CellTiter-Glo® Luminescent Cell Viability Assay (Promega Corp.). The CellTiter-Glo® Luminescent Cell Viability Assay is a homogeneous method for determining the number of viable cells in a culture based on the quantification of present ATP, an indicator of metabolically active cells. The CellTiter-Glo® Assay is designed for use in multi-well formats and is ideal for automated high-throughput screening (HTS), cell proliferation, and cytotoxicity assays. The homogeneous assay procedure requires the direct addition of a single reagent (CellTiter-Glo® Reagent) to cells cultured in serum-supplemented medium. Cell washing, medium removal, and multiple pipetting steps are not required. The system detects only 15 cells per well in a 384-well format within 10 minutes of adding the reagent and mixture.

[0074] Prepare all exemplary compounds of formula I in Tables 1 and 2, and perform LCMS[M+H] with detection of the parent ion. + Characterized by liquid chromatography-mass spectrometry. All exemplary compounds of formula I in Tables 1 and 2 were tested for binding to ERa (estrogen receptor alpha) and biological activity according to the assays, protocols, and procedures of Examples 901-907. Table 1 ERa Alpha MCF7 HCS S inf The (%) values ​​were measured by the Breast Cancer Cell ERa High Content Fluorescence Imaging Degradation Assay of Example 901. ER alpha MCF7 HCS EC in Tables 1 and 2. 50(μM) values ​​were measured by the in vitro cell proliferation assays described in Examples 902 and 903. The rat uterine wet weight assays of Examples 906 and 907 allow for rapid determination of the antagonist activity of the compound in ER-responsive tissue (uterus of immature rats) while competing with the innate ER ligand estradiol (i.e., in antagonist mode) (Ashby, J.; et al (1997) Regulatory toxicology and pharmacology: RTP, 25 (3):226-31). The exemplary compounds of formula I in Tables 1 and 2 have the following structures, corresponding names (ChemBioDraw, version 12.0.2, CambridgeSoft Corp., Cambridge, Massachusetts) and biological activities. Where multiple names are associated with a compound or intermediate of formula I, the chemical structure shall define the compound. TIFF2026067858000016.tif200170TIFF2026067858000017.tif225170TIFF2026067858000018.tif225170TIFF2026067858000019.tif187170TIFF2026067858000020.tif220170TIFF2026067858000021.tif214170TIFF2026067858000022.tif214170TIFF2026067858000023.tif220170TIFF2026067858000024.tif219170TIFF2026067858000025.tif194170TIFF2026067858000026.tif229170TIFF2026067858000027.tif246170TIFF2026067858000028.tif252170TIFF2026067858000029.tif213170TIFF2026067858000030.tif246170TIFF2026067858000031.tif212170TIFF2026067858000032.tif253170TIFF2026067858000033.tif216170TIFF2026067858000034.tif213170TIFF2026067858000035.tif220170TIFF2026067858000036.tif228170TIFF2026067858000037.tif231170TIFF2026067858000038.tif241170TIFF2026067858000039.tif213170TIFF2026067858000040.tif215170TIFF2026067858000041.tif211170TIFF2026067858000042.tif207170TIFF2026067858000043.tif223170TIFF2026067858000044.tif231170TIFF2026067858000045.tif224170TIFF2026067858000046.tif228170TIFF2026067858000047.tif215170TIFF2026067858000048.tif228170TIFF2026067858000049.tif226170TIFF2026067858000050.tif184170TIFF2026067858000051.tif234170TIFF2026067858000052.tif185170TIFF2026067858000053.tif217170TIFF2026067858000054.tif205170TIFF2026067858000055.tif220170TIFF2026067858000056.tif251170TIFF2026067858000057.tif226170TIFF2026067858000058.tif217170TIFF2026067858000059.tif224170TIFF2026067858000060.tif250170TIFF2026067858000061.tif239170TIFF2026067858000062.tif240170TIFF2026067858000063.tif247170TIFF2026067858000064.tif209170TIFF2026067858000065.tif228170TIFF2026067858000066.tif217170TIFF2026067858000067.tif214170TIFF2026067858000068.tif249170TIFF2026067858000069.tif220170TIFF2026067858000070.tif210170TIFF2026067858000071.tif228170TIFF2026067858000072.tif234170TIFF2026067858000073.tif236170TIFF2026067858000074.tif199170TIFF2026067858000075.tif248170TIFF2026067858000076.tif211170TIFF2026067858000077.tif253170TIFF2026067858000078.tif243170TIFF2026067858000079.tif210170TIFF2026067858000080.tif211170TIFF2026067858000081.tif218170TIFF2026067858000082.tif213170TIFF2026067858000083.tif240170TIFF2026067858 000084.tif231170TIFF2026067858000085.tif221170TIFF2026067858000086.tif253170TIFF2026 067858000087.tif219170TIFF2026067858000088.tif208170TIFF2026067858000089.tif200170T IFF2026067858000090.tif209170TIFF2026067858000091.tif200170TIFF2026067858000092.tif2 44170TIFF2026067858000093.tif205170TIFF2026067858000094.tif209170TIFF20260678580000 95.tif250170TIFF2026067858000096.tif208170TIFF2026067858000097.tif200170TIFF20260678 58000098.tif245170TIFF2026067858000099.tif210170TIFF2026067858000100.tif206170TIFF20 26067858000101.tif253170TIFF2026067858000102.tif227170TIFF2026067858000103.tif71170.

[0075] Administration of the compound of formula (I) The compounds of the present invention may be administered by any route appropriate to the condition being treated. Appropriate routes include oral, parenteral (including subcutaneous, intramuscular, intravenous, intra-arterial, intradermal, intrathecal, and epidural), percutaneous, rectal, nasal, topical (including oral and sublingual), vaginal, intraperitoneal, intrapulmonary, and intranasal. In the case of topical immunosuppressive therapy, the compounds may be administered intralesion, including perfusion or other contact of the graft with the inhibitor prior to implantation. It will be understood that preferred routes may vary, for example, depending on the recipient's condition. When the compounds are administered orally, they may be formulated as pills, capsules, tablets, etc., with pharmaceutically acceptable carriers or excipients. When the compounds are administered parenterally, they may be formulated in injectable forms of unit doses with pharmaceutically acceptable parenteral vehicles, as detailed below.

[0076] Doses for treating human patients range from approximately 10 mg to approximately 1000 mg of the compound of formula I. Typical doses are approximately 100 mg to approximately 300 mg of the compound. Doses may be administered once daily (QID), twice daily (BID), or more frequently, depending on the pharmacokinetic and pharmacodynamic properties of the particular compound, including absorption, distribution, metabolism, and excretion. Furthermore, the toxicity factor may influence the drug administration regimen. When administered orally, pills, capsules, or tablets may be taken daily or less frequently over a specified period. The regimen may be repeated over several treatment cycles.

[0077] Treatment method using the compound of formula I The compounds of Formula I of the present invention are useful for treating human or animal patients suffering from diseases or disorders resulting from abnormal cell proliferation, function, or behavior associated with USP7, such as immunodeficiency, cardiovascular disease, viral infection, inflammation, metabolic / endocrine disorders, or neurological disorders, and can therefore be treated by methods comprising administering the compounds of the present invention described above to such patients. Human or animal patients suffering from cancer can also be treated by methods comprising administering the compounds of the present invention described above to them. This can improve or induce remission of the patient's condition.

[0078] The method of the present invention also applies to the breast, ovary, cervix, prostate, testicle, genitourinary tract, esophagus, larynx, glioblastoma, neuroblastoma, stomach, skin, keratosinus acanthoma, lung, epidermoid carcinoma, large cell carcinoma, non-small cell lung cancer (NSCLC), small cell carcinoma, lung adenocarcinoma, bone, colon, adenoma, pancreas, adenocarcinoma, thyroid, follicular adenocarcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, sarcoma, bladder cancer, liver cancer, and bile duct cancer, kidney cancer, pancreatic cancer, myeloid diseases, lymphoma, hairy cells, oral cavity, nasopharynx, pharynx, lips, tongue, mouth, This includes treating cancers selected from the small intestine, colorectal, large intestine, rectum, brain and central nervous system, Hodgkin's leukemia, bronchi, thyroid, liver and intrahepatic bile ducts, hepatocellular carcinoma, gastric cancer, glioma / glioblastoma, endometrial cancer, melanoma, kidney and renal pelvis, bladder, uterine body, cervix, multiple myeloma, acute myeloid leukemia, chronic myeloid leukemia, lymphocytic leukemia, chronic lymphocytic leukemia (CLL), myeloid leukemia, oral cavity and pharynx, non-Hodgkin's lymphoma, melanoma and choriocolonic adenoma.

[0079] Pharmaceutical preparations For use in the therapeutic treatment of mammals, including humans, the compounds of formula (I) of the present invention are typically formulated as pharmaceutical compositions according to standard pharmaceutical regulations. According to this aspect of the present invention, a pharmaceutical composition is provided containing the compounds of the present invention together with a pharmaceutically acceptable diluent or carrier.

[0080] Typical formulations are prepared by mixing the compound of the present invention with a carrier, diluent, or excipient. Suitable carriers, diluents, and excipients are well known to those skilled in the art and include, for example, carbohydrates, waxes, water-soluble and / or swelling polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, and water. The specific carrier, diluent, or excipient used will depend on the means and purpose to which the compound of the present invention is applied. Solvents are usually selected based on solvents that are recognized by those skilled in the art as safe to administer to mammals (GRAS; Safe Foods Certified). Generally, safe solvents are non-toxic aqueous solvents, such as water, and other non-toxic solvents that are soluble in or miscible with water. Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycol (e.g., PEG400, PEG300), and mixtures thereof. The formulation may also include one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, lubricants, processing aids, colorants, sweeteners, flavorings, and other known additives for providing a drug (i.e., the compound of the present invention or its pharmaceutical composition) in an appealing manner, or for assisting in the manufacture of a pharmaceutical product (i.e., a medicine).

[0081] These formulations can be prepared using conventional dissolution and mixing methods. For example, the bulk active pharmaceutical ingredient (i.e., the compound of the present invention or a stabilized form of the compound (e.g., a cyclodextrin derivative or a complex with another known complex-forming agent) is dissolved in a suitable solvent in the presence of one or more of the above excipients. The compounds of the present invention are typically formulated into pharmaceutical dosage forms to provide easily controllable doses of the drug, enabling patients to adhere to their prescribed regimens.

[0082] Pharmaceutical compositions (or preparations) for application can be packaged in various ways depending on the method of drug administration. Generally, articles for distribution include containers in which the pharmaceutical preparation is placed in an appropriate form. Suitable containers are well known to those skilled in the art and include materials such as bottles (plastic and glass), pouches, ampoules, plastic bags, and metal cylinders. Containers may also include tamper-evident devices to prevent unauthorized access to the contents of the package. In addition, containers may be adorned with labels indicating the contents of the container. Labels may also include appropriate warnings.

[0083] 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 purity may be optionally mixed with a pharmaceutically acceptable diluent, carrier, excipient, or stabilizer (Remington's Pharmaceutical Sciences (1980) 16th edition, Osol, A. Ed.) in the form of a lyophilized formulation, crushed powder, or aqueous solution. Formulation is carried out at room temperature, at an appropriate pH, and with the desired purity, by mixing with a physiologically acceptable carrier (i.e., a carrier that is non-toxic to the recipient at the dose and concentration used). The pH of the formulation is mainly in the range of about 3 to about 8, depending on the specific use and concentration of the compound. Formulation in acetate buffer at pH 5 is a suitable embodiment.

[0084] Compounds can typically be stored as solid compositions, lyophilized formulations, or aqueous solutions.

[0085] The pharmaceutical formulations of the present invention are to be formulated, administered, and given in a certain manner, namely in amounts, concentrations, schedules, courses, vehicles, and routes of administration in accordance with good medical practice. Factors to be considered in this context include the specific disorder being treated, the specific mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of drug delivery, the method of administration, the administration schedule, and other factors known to the physician. The "therapeutic effective dose" of the compound to be administered shall be determined by these considerations and shall be the minimum amount necessary to induce remission or treat the hyperproliferative disorder.

[0086] As a general proposition, the initial pharmacokinetic dose per parenterally administered inhibitor is approximately 0.01–100 mg / kg, or about 0.1 to 20 mg / kg of patient body weight per day, and the typical initial range for the compounds used is approximately 0.3 to 15 mg / kg / day.

[0087] Acceptable carriers, diluents, carriers, excipients and stabilizers are non-toxic to the recipient at the dosage and concentration used and include buffers such as phosphates, citrates and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (e.g., octadecyl dimethiolbenzylammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl or benzyl alcohol; alkylparabens, e.g., methyl or propylparaben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m -Cresol; low molecular weight (less than about 10 residues) polypeptides; proteins, e.g., serum albumin, gelatin, or immunoglobulin; hydrophilic polymers, e.g., polyvinylpyrrolidone; amino acids, e.g., glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates, including glucose, mannose, or dextrin; chelating agents, e.g., EDTA; sugars, e.g., sucrose, mannitol, trehalose, or sorbitol; salt-forming counterions such as sodium; metal complexes (e.g., Zn-protein complexes); and / or TWEEN TM PLURONICS TM Alternatively, it may contain a nonionic surfactant such as polyethylene glycol (PEG). Furthermore, the active pharmaceutical ingredient may be encapsulated in a colloidal drug delivery system (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles, and nanocapsules) or in a macroemulsion, in microcapsules prepared by, for example, coacervation technology or interfacial polymerization, such as hydroxymethylcellulose or gelatin microcapsules and poly-(methyl methacrylate) microcapsules, respectively. These technologies are disclosed in Remington's Pharmaceutical Sciences, 16th edition, edited by Osol, A. (1980).

[0088] Sustained-release preparations of compounds of formula I can be prepared. Suitable examples of sustained-release preparations include a semipermeable matrix of a solid hydrophobic polymer containing a compound of formula I, the matrix being in the form of a molded article, e.g., a film or microcapsules. Examples of sustained-release matrices include polyesters, hydrogels (e.g., poly(2-hydroxyethyl methacrylate) or poly(vinyl alcohol)), polylactic acid (US Patent No. 3773919), copolymers of L-glutamic acid and gamma-ethyl-L-glutamate, non-degradable ethylene vinyl acetate, and LUPRON DEPOT. TM It contains a degradable lactic acid-glycolic acid copolymer and poly-D-(-)-3-hydroxybutyric acid, such as (injectable microspheres consisting of lactic acid-glycolic acid copolymer and leuprolide acetate).

[0089] The formulations include those suitable for the routes of administration detailed herein. The formulations are conveniently provided in unit dosage forms and can be prepared by any method well known in the pharmaceutical field. The techniques and formulations are extensively described in Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, Pennsylvania). Such methods involve the step of associating an active ingredient with a carrier comprising one or more auxiliary components. Formulations are typically prepared by homogeneously and closely associating the active ingredient with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product.

[0090] Formulations of the compound of formula I suitable for oral administration may be prepared as separate units such as pills, capsules, cachets, or tablets, each containing a predetermined amount of the compound of formula I. Compressed formulations can be prepared by compressing the active ingredient in an easily flowable form (such as powder or granules) optionally mixed with a binder, lubricant, inert diluent, preservative, surfactant, or dispersant using appropriate machinery. Molded tablets can be produced by molding a mixture of the powdered active ingredient moistened with an inert liquid diluent using appropriate machinery. Tablets may optionally be coated or notched, and may be formulated to provide sustained or controlled release of the active ingredient. Tablets, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, and hard or soft capsules (e.g., gelatin capsules, syrups, or elixirs) may be prepared for oral use. Formulations of compounds of formula I intended for oral use can be prepared according to any method known in the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents, including sweeteners, flavoring agents, coloring agents and preservatives, to provide a palatable preparation. Tablets containing the active ingredient in a mixture with non-toxic, pharmaceutically acceptable excipients suitable for the manufacture of tablets are acceptable. Such excipients may be, for example, inert diluents such as calcium carbonate or sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents such as corn starch or alginic acid; binders such as starch, gelatin or acacia; and lubricants such as magnesium stearate, stearic acid or talc. Tablets may not be coated, or they may be coated by known techniques, including microencapsulation, to delay disintegration and adsorption in the gastrointestinal tract, thereby providing a longer-lasting effect. For example, time-delaying substances such as glyceryl monostearate or glyceryl distearate may be used alone or with wax.

[0091] For the treatment of the eyes or other external tissues, such as the mouth and skin, the formulation is preferably applied as a topical ointment or cream containing the active ingredient in an amount of, for example, 0.075 to 20% w / w. When formulated as an ointment, the active ingredient may be used with either paraffin or a water-miscible ointment base. Alternatively, the active ingredient may be formulated as a cream with an oil-in-water cream base. If necessary, the aqueous phase of the cream base may contain polyhydric alcohols, i.e., propylene glycol, butane 1,3-diol, mannitol, sorbitol, glycerol, and polyethylene glycol (including PEG400, which have two or more hydroxyl groups) and mixtures thereof. The topical formulation preferably contains compounds that promote the absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such skin penetration enhancers include dimethyl sulfoxide and related analogues. The oil phase of the emulsion of the present invention can be composed of well-known components in well-known ways. This phase may contain only emulsifiers, but preferably contains at least one emulsifier and a mixture of fats or oils, or a mixture of both fats and oils. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier that acts as a stabilizer. It is also preferable to include both oils and fats. In summary, the emulsifier, with or without a stabilizer, constitutes a so-called emulsifying wax, which together with the oils and fats forms a so-called emulsifying ointment base that forms the oily dispersion phase of the cream formulation. Examples of emulsifiers and emulsifying stabilizers suitable for use in the formulations of the present invention include Tween® 60, Span® 80, cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl monostearate, and sodium lauryl sulfate.

[0092] The aqueous suspension of the compound of formula I contains an active material mixed with an excipient suitable for the preparation of an aqueous suspension. Such excipients include suspending agents such as sodium carboxymethylcellulose, croscarmellose, povidone, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth gum, and acacia gum, as well as dispersants or wetting agents such as natural phospholipids (e.g., lecithin), condensation products of alkylene oxides and fatty acids (e.g., polyoxyethylene stearate), condensation products of ethylene oxides and long-chain aliphatic alcohols (e.g., heptadecaethyleneoxycetanol), and condensation products of ethylene oxides and partial esters derived from fatty acids and anhydrous hexitol (e.g., polyoxyethylene sorbitan monooleate). The aqueous suspension may also contain one or more preservatives such as ethyl or n-propyl p-hydroxybenzoate, one or more colorants, one or more flavoring agents, and one or more sweeteners such as sucrose or saccharin.

[0093] The pharmaceutical composition of the compound of formula I may be in the form of a sterile injectable formulation, such as an aqueous or oily suspension for sterile injection. This suspension can be formulated according to the prior art using the preferred dispersants or wetting agents and suspending agents described above. The sterile injectable formulation may also be a sterile injection solution or suspension in a parenterally administered, non-toxic diluent or solvent, such as a solution in 1,3-butanediol, or it may be prepared as a lyophilized powder. Acceptable vehicles and solvents that can be used include water, Ringer's solution, and isotonic saline. In addition, sterile non-volatile oils may be conventionally used as solvents or suspensions. For this purpose, any sterile non-volatile oil, including synthetic mono or diglycerides, can be used. Furthermore, fatty acids such as oleic acid can also be similarly used in the preparation of injectable formulations.

[0094] The amount of active ingredient that can be combined with a carrier material to form a single dosage form will vary depending on the host being treated and the specific method of administration. For example, a sustained-release formulation intended for oral administration to humans may contain approximately 1 to 1000 mg of the active substance, combined with an appropriate and convenient amount of carrier material that can vary in the range of approximately 5 to 95% (weight:weight) of the total composition. Pharmaceutical compositions can be prepared to provide easily measurable doses. For example, an aqueous solution intended for intravenous infusion may contain approximately 3 to 500 μg of the active ingredient per milliliter of solution, allowing for the infusion of an appropriate volume at a rate of approximately 30 mL / hour.

[0095] Preparations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions that may contain antioxidants, buffers, bacteriostatic agents, and solutes that make the preparation isotonic with the blood of the target recipient; and aqueous and non-aqueous sterile suspensions that may contain suspending agents and thickeners.

[0096] Suitable formulations for topical administration to the eye include eye drops in which the active ingredient is dissolved or suspended in an aqueous solvent for a suitable carrier. The active ingredient is preferably present in such formulations at a concentration of about 0.5 to 20% w / w, for example, about 0.5 to 10% w / w, or for example, about 1.5% w / w.

[0097] Suitable formulations for local oral administration include lozenges containing the active ingredient in a flavored base (usually sucrose and acacia or tragacanth); lozenges containing the active ingredient in an inert base such as gelatin and glycerin, or sucrose and acacia; and mouthwashes containing the active ingredient in a suitable liquid carrier.

[0098] Preparations for rectal administration may be provided as suppositories using a suitable base containing, for example, cocoa butter or salicylate.

[0099] Formulations suitable for intrapulmonary or intranasal administration have particle sizes ranging from 0.1 to 500 microns (including particle sizes in micron units ranging from 0.1 to 500 microns, such as 0.5, 1, 30, 35 microns), and are administered by rapid inhalation through the nasal cavity or by inhalation through the oral cavity, reaching the alveolar sacs. Suitable formulations include aqueous or oily solutions of the active ingredient. Formulations suitable for aerosol or dry powder administration can be prepared according to conventional methods and can be delivered together with other therapeutic agents, such as compounds conventionally used in the treatment or prevention of the disorders described below.

[0100] Formulations suitable for vaginal administration may be provided as pessaries, tampons, creams, gels, pastes, foams, or sprays, containing, in addition to the active ingredient, a carrier known to be suitable in the art.

[0101] The formulations may be contained in unit-dose or multi-dose containers, such as sealed ampoules and vials, or stored in a freeze-dried state where only a sterile liquid carrier for injection (e.g., water) is added immediately before use. Immediate injection solutions and suspensions are prepared from the aforementioned types of sterile powders, granules, and tablets. Preferred unit-dose formulations contain the active ingredient in a daily dose or unit daily sub-dose or an appropriate fraction thereof, as described herein.

[0102] The present invention further provides veterinary compositions comprising at least one active ingredient as described above, together with a veterinary carrier. The veterinary carrier may be a solid, liquid, or gaseous substance useful for administering the composition, which is otherwise inert or acceptable in the veterinary field and is compatible with the active ingredient. These veterinary compositions may be administered parenterally, orally, or via any other desired route.

[0103] Combination therapy Compounds of formula I may be used alone or in combination with additional therapeutic agents to treat diseases or disorders described herein, such as inflammatory or hyperproliferative disorders (e.g., cancer). In certain embodiments, compounds of formula I are combined in combination pharmaceutical formulations or in combination therapy regimens with an additional second therapeutic compound that has anti-inflammatory or anti-hyperproliferative properties or is useful for treating inflammation, immune response disorders, or hyperproliferative disorders (e.g., cancer). The additional therapeutic agent may be a Bcl-2 inhibitor, a JAK inhibitor, a PI3K inhibitor, an mTOR inhibitor, an anti-inflammatory agent, an immunomodulator, a chemotherapeutic agent, an apoptosis promoter, a neurotrophic factor, a cardiovascular disease treatment agent, a liver disease treatment agent, an antiviral agent, a hematological disease treatment agent, a diabetes treatment agent, or an immunodeficiency disease treatment agent. The second therapeutic agent may be an NSAID anti-inflammatory agent. The second therapeutic agent may be a chemotherapeutic agent. The second compound in the combination pharmaceutical formulation or regimen preferably has complementary activity to the compound of formula I so as not to adversely affect each other. Such compounds are preferably present in combination in amounts effective for the intended purpose. In one embodiment, the composition of the present invention comprises a compound of formula I or its stereoisomers, tautomers, solvates, metabolites, or pharmaceutically acceptable salts or prodrugs, and is combined with a therapeutic agent such as an NSAID.

[0104] Combination therapy may be administered as a simultaneous or sequential regimen. When administered sequentially, the combination may be administered in two or more doses. Combination therapy includes co-administration using separate formulations or a single pharmaceutical formulation, and sequential administration in either order, preferably with a period during which both (or all) activators exert their biological activity simultaneously.

[0105] The appropriate dosage of the above-mentioned co-administered agents is currently in use and may be reduced due to the combined effects (synergistic effects) of newly identified drugs with other therapeutic agents or treatments.

[0106] Combination therapy can produce a "synergistic effect," meaning that the effect achieved when the active ingredients are used together exceeds the sum of the effects achieved when the compounds are used separately. Synergistic effects can be achieved when the active ingredients are (1) co-formulated and administered or delivered simultaneously as a combined unit-dose formulation; (2) delivered alternately or in parallel as separate formulations; or (3) delivered by some other regimen. In the case of alternating therapy, synergistic effects can also be obtained when the compounds are administered or delivered sequentially, for example, by different injections in separate syringes, separate pills or capsules, or separate infusions. Generally, during alternating therapy, the effective dose of each active ingredient is administered sequentially, i.e., consecutively, whereas in combination therapy, two or more active ingredients are administered together.

[0107] In certain embodiments of the treatment, the compound of formula I or its stereoisomers, tautomers, solvates, metabolites, or pharmaceutically acceptable salts or prodrugs may be combined with other therapeutic agents, hormones, or antibody agents as described herein, and similarly with surgical and radiotherapy. Accordingly, the combination therapy according to the present invention comprises the administration of at least one compound of formula I or its stereoisomers, tautomers, solvates, metabolites, or pharmaceutically acceptable salts or prodrugs, and the use of at least one other cancer treatment method. The amounts of the compound of formula I and other pharmaceutically active therapeutic agents, as well as the relative timing of administration, will be selected to obtain the desired combination therapeutic effect.

[0108] In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof is used 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, chemotherapy, or any combination thereof.

[0109] In some embodiments, a pharmaceutical composition comprising 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 ixabepirone.

[0110] In some embodiments, the compounds of formula I)(II) or pharmaceutically acceptable salts thereof are used in combination with hormone block therapy, chemotherapy, radiotherapy, monoclonal antibodies, or combinations thereof.

[0111] Hormone block therapy involves the use of agents that block estrogen production or block estrogen receptors. In some embodiments, hormone block therapy involves the use of estrogen receptor modulators and / or aromatase inhibitors. Estrogen receptor modulators include triphenylethylene derivatives (e.g., tamoxifen, toremifene, droloxifen, 3-hydroxytamoxifen, doxifen, TAT-59 (phosphorylated derivative of 4-hydroxytamoxifen) and GW5638 (carboxylic acid derivative of tamoxifen)); nonsteroidal estrogen receptor modulators (e.g., raloxifene, LY353381 (SERM3) and LY357489); and 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, such exemestanes. Nonsteroidal aromatase inhibitors include, but are not limited to, anastrozole and letrozole.

[0112] In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof is administered in combination with a CDK4 / 6 inhibitor. In some embodiments, the CDK4 / 6 inhibitor is palbociclib (PD-0332991), ribociclib (LEE011), or LY283519. In some embodiments, the CDK4 / 6 inhibitor is LEE011. In some embodiments, ribociclib (LEE011) is administered in doses ranging from approximately 10 mg to approximately 1000 mg per day. In some embodiments, LEE011 is administered in doses ranging from approximately 400 mg, approximately 500 mg, or approximately 600 mg per day. In some embodiments, the daily dose of LEE011 is administered orally. In some embodiments, the daily dose of LEE011 is administered orally once daily for three weeks, followed by a one-week drug-free period during which ribociclib (LEE011) is not administered.

[0113] In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof is administered in combination with a phosphoinositide 3-kinase (PI3K) / mTOR pathway inhibitor. In some embodiments, the phosphoinositide 3-kinase (PI3K) / mTOR pathway inhibitor is everolimus, temsirolimus, BEZ235 (dactricib), BYL719 (alperisib), GDC0032 (tasericib), BKM120 (buparlicib), BGT226, GDC0068 (ipatasertib), GDC-0980 (apitricib), GDC0941 (pictilicib), INK128 (MLN0128), IN These include K1117, 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 in doses ranging from approximately 1 mg to approximately 20 mg per day. In some embodiments, everolimus is administered in doses of approximately 2.5 mg, 5 mg, or 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 in doses ranging from approximately 5 mg to 500 mg per day. In some embodiments, BKM120 is administered in doses ranging from approximately 50 mg to 100 mg per day. In some embodiments, BKM120 is administered in doses ranging from approximately 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 BYL719.In some embodiments, BYL719 is administered in doses ranging from approximately 25 mg to approximately 1000 mg per day. In some embodiments, BYL719 is administered in doses ranging from approximately 250 mg to approximately 350 mg per day. In some embodiments, the daily dose of BYL719 is administered once daily.

[0114] Metabolites of the compound of formula I The endogenous metabolites of formula I described herein are also included within the scope of the present invention. Such products may arise, for example, from oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic cleavage, etc. of the administered compound. Accordingly, the present invention includes metabolites of compounds of formula I, including compounds produced by a method comprising contacting the compound of the present invention with a mammal for a certain period of time sufficient to produce its metabolites.

[0115] Metabolites are typically radiolabeled compounds of the present invention (e.g., 14 C or 3 H) The isotopes are prepared and parenterally administered to animals such as rats, mice, guinea pigs, monkeys, or humans in a detectable dose (e.g., greater than approximately 0.5 mg / kg). The metabolites are then isolated from urine, blood, or other biological samples after allowing sufficient time for metabolism to occur (typically from approximately 30 seconds to 30 hours). Such products are readily isolated because they are labeled (otherwise, they are isolated by using antibodies that can bind to the epitopes remaining in the metabolites). The structure of the metabolites is determined by conventional methods, such as MS, LC / MS, or NMR analysis. Generally, the analysis of metabolites is carried out in the same manner as in conventional drug metabolism studies well known to those skilled in the art. Unless otherwise found in vivo, the metabolites are useful in diagnostic assays for the therapeutic administration of the compounds of the present invention.

[0116] manufactured goods In another embodiment of the present invention, a product or “kit” containing a material useful for treating the above-mentioned diseases and disorders is provided. In one embodiment, the kit comprises a container containing a compound of formula I or its stereoisomers, tautomers, solvates, metabolites, or pharmaceutically acceptable salts or prodrugs. The kit may further include a label or accompanying information affixed to or attached to the container. The term “accompanying information” is used to mean instructions typically included in the product packaging of a therapeutic product, including information on the use of such therapeutic product, instructions, usage, dosage, administration, contraindications, and / or precautions. Preferred containers include, for example, bottles, vials, syringes, blister packs, etc. Containers may be formed from a variety of materials, such as glass or plastic. Containers may hold a compound of formula I or a formulation thereof that is effective in treating a condition and may have a sterile access port (for example, the container may be a vial or intravenous solution bag with a stopper that can be punctured by a subcutaneous needle). At least one activator in the composition is a compound of formula I. The label or accompanying information indicates that the composition is used to treat a selected condition, such as cancer. Furthermore, the label or accompanying information may indicate that the patient being treated has a disorder such as hyperproliferative disorder, neurodegeneration, cardiac hypertrophy, pain, migraine, or neurotraumatic disease or event. In one embodiment, the label or accompanying information indicates that a composition comprising a compound of formula I can be used to treat a disorder resulting from abnormal cell proliferation. The label or accompanying information may also indicate that the composition can be used to treat other disorders. Alternatively or additionally, the product may further comprise a second container containing pharmaceutically acceptable buffers, such as bacteriostatic water for injection (BWFI), phosphate-buffered saline, Ringer's solution, and dextrose solution. The product may further comprise other materials desirable from a commercial and user perspective, including other buffers, diluents, filters, needles, and syringes.

[0117] The kit may further include instructions for administering the compound of formula I and (if present) a second pharmaceutical formulation. For example, if the kit comprises a first composition containing the compound of formula I and a second pharmaceutical formulation, the kit may further include instructions for administering the first and second pharmaceutical compositions simultaneously, sequentially, or individually to a patient requiring them.

[0118] In another embodiment, the kit is suitable for the delivery of a solid oral form of a compound of formula I, such as a tablet or capsule. Such a kit preferably contains multiple unit doses. Such a kit may include a card indicating the dosages arranged in the order of its intended use. An example of such a kit is a "blister pack," which is well-known in the packaging industry and widely used for packaging pharmacokinetic dosage forms. If necessary, a memory aid may be provided, for example, in the form of numbers, letters, or other markings, or with a calendar insert indicating the dates in the treatment schedule on which the doses can be administered.

[0119] According to one embodiment, the kit may further comprise (a) a first container containing a compound of formula I; and optionally (b) a second container containing a second pharmaceutical preparation, wherein the second pharmaceutical preparation comprises a second compound having anti-overgrowth activity. Alternatively or additionally, the kit may further comprise a third container containing pharmaceutically acceptable buffers, such as bacteriostatic water for injection (BWFI), phosphate-buffered saline, Ringer's solution, and dextrose solution. The kit may further comprise other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, and syringes.

[0120] In certain other embodiments in which the kit comprises the composition of Formula I and a second therapeutic agent, the kit may include containers for housing the individual compositions, such as separate bottles or separate foil packets, although the individual compositions may also be housed in a single, undivided container. Generally, the kit includes instructions for administering the individual components. This kit configuration is particularly advantageous when it is preferred to administer the individual components in different dosage forms (e.g., orally and parenterally), at different dosing intervals, or when titration of the individual components of a combination is desired by the prescribing physician.

[0121] Preparation of the compound of formula I The compounds of formula I can be synthesized by synthetic routes that involve processes similar to those well known in the art of chemistry, particularly in light of the descriptions contained herein, and processes similar to those for other heterocyclic compounds described in Comprehensive Heterocyclic Chemistry II, Editors Katritzky and Rees, Elsevier, 1997, e.g., Vol. 3; Liebigs Annalen der Chemie, (9):1910-16, (1985); Helvetica Chimica Acta, 41:1052-60, (1958); Arzneimittel-Forschung, 40(12):1328-31, (1990) (each cited by attribution). Starting materials are generally available from commercial sources such as Aldrich Chemicals (Milwaukee, Wisconsin) or can be readily prepared using methods well known to those skilled in the art (e.g., by methods outlined in Louis F. Fieser and Mary Fieser, Reagents for Organic Synthesis, v. 1-23, Wiley, NY (1967-2006 ed.), or Beilsteins Handbuch der organischen Chemie, 4, Aufl. ed. Springer-Verlag, Berlin, including the appendix (also available via the Beilstein online database)).

[0122] Methodologies for synthetic chemical transformations and protecting groups (protection and deprotection), as well as necessary reagents and intermediates, that are useful for synthesizing compounds of formula I are known in the art, and are described, for example, in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); TW. Greene and PG. MWuts, Protective Groups in Organic Synthesis, 3rd edition, John Wiley and Sons (1999); and L. Paquette (ed.), Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) and subsequent editions thereof.

[0123] The compounds of formula I can be prepared individually or as a compound library containing at least two, for example, 5 to 1000 compounds or 10 to 100 compounds. The library of compounds of formula I can be prepared by methods known to those skilled in the art, such as by combinatorial "split and mix" methods or by multiple parallel synthesis using either solution-phase or solid-phase chemistry. Accordingly, according to further aspects of the present invention, a compound library containing at least two compounds or pharmaceutically acceptable salts thereof is provided.

[0124] The examples provide exemplary methods for preparing compounds of formula I. Those skilled in the art will understand that compounds of formula I can be synthesized using other synthetic routes. While specific starting materials and reagents are shown and discussed in the figures and examples, other starting materials and reagents can be readily substituted to result in various derivatives and / or reaction conditions. In addition, many of the exemplary compounds prepared by the described methods can be further modified in light of this disclosure using conventional chemistry well known to those skilled in the art.

[0125] When preparing compounds of formula I, protection of the remote functional group (e.g., primary or secondary amine) of the intermediate may be necessary. The need for such protection depends on the properties of the remote functional group and the conditions of the preparation method. Suitable amino protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBz), and 9-fluorenylmethyleneoxycarbonyl (Fmoc). The need for such protection can be easily determined by those skilled in the art. For a general description of protecting groups and their use, see TW Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991.

[0126] In methods for preparing compounds of formula I, it may be advantageous to 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 to a desired degree of homogeneity by techniques common in the art. Typically, such separations include multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography. Chromatography may include any number of methods, such as reversed-phase and normal-phase; size exclusion; ion exchange; high, medium, and low-pressure liquid chromatography methods and apparatus; small-scale analysis; pseudo-moving bed (SMB), preparative thin or thick-layer chromatography, and small-scale thin-layer and flash chromatography.

[0127] Another type of separation method involves treating a mixture with a reagent selected to bind to or otherwise separate the desired product, unreacted starting materials, reaction by-products, etc. Such reagents include adsorbents or absorbents, such as activated carbon, molecular sieves, and ion exchange media. Alternatively, the reagent may be an acid in the case of basic substances, a base in the case of acidic substances, a binding reagent (e.g., an antibody), a binding protein, a selective chelate (e.g., a crown ether), or a liquid / liquid ion extraction reagent (LIX). The selection of an appropriate separation method depends on the properties of the substances involved, such as the boiling point and molecular weight in distillation and sublimation, the presence or absence of polar functional groups in chromatography, and the stability of the substances in acidic and basic media in multiphase extraction.

[0128] Diastereomer mixtures can be separated into individual diastereomers based on 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 enantiomer mixture into a diastereomer mixture by reaction with a suitable optically active compound (e.g., a chiral auxiliary such as a chiral alcohol or Mosher acid chloride), separating the diastereomers, and converting the individual diastereomers back into their corresponding pure enantiomers (e.g., by hydrolysis). Some of the compounds of the present invention may also be atropisomers (e.g., substituted biaryls) and are considered part of the present invention. Enantiomers can also be separated by the use of a chiral HPLC column.

[0129] A single stereoisomer substantially free of the stereoisomer, such as an enantiomer, can be obtained by the resolution of a racemic mixture using methods such as the formation of a diastereomer using an optically active resolving agent (Eliel, E. and Wilen, S. "Stereochemistry of Organic Compounds," John Wiley & Sons, Inc., New York, 1994; Lochmuller, CH, (1975) J. Chromatogr., 113(3):283-302). The racemic mixture of the chiral compound of the present invention can be separated and isolated by any suitable method including (1) the formation of an ionic diastereomer salt by the chiral compound and separation by fractional crystallization or other methods, (2) the formation of a diastereomer compound by a chiral derivatization reagent, separation of the diastereomer, and conversion to a pure stereoisomer, and (3) the direct separation of a substantially pure or concentrated stereoisomer under chiral conditions. See "Drug Stereochemistry, Analytical Methods and Pharmacology," edited by Irving W. Wainer, Marcel Dekker, Inc., New York (1993).

[0130] Under method (1), diastereomers can be formed by the reaction of enantiomerically pure chiral bases such as brucine, quinine, ephedrine, strychnine, and α-methyl-β-phenylethylamine (amphetamine) with asymmetric compounds having acidic functional groups such as carboxylic acids and sulfonic acids. Diastereomers can be separated by fractional crystallography or ion chromatography. In the case of separating optical isomers of amino compounds, the addition of chiral carboxylic acids or sulfonic acids such as camphor sulfonic acid, tartaric acid, mandelic acid, or lactic acid may result in the formation of diastereomers.

[0131] Alternatively, by method (2), the substrate to be separated is reacted with one enantiomer of a chiral compound to form a pair of diastereomers (E. and Wilen, S. "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., 1994, p. 322). Diastereomer compounds can be formed by reacting an asymmetric compound with an enantiomerically pure chiral derivatizing reagent, such as a menthyl derivative, and then the diastereomers can be separated and hydrolyzed to obtain pure or concentrated enantiomers. Methods for determining optical purity include, for example, menthyl esters (in the presence of a base), such as (-)menthyl chloroformate, or Mosher esters of racemic mixtures, and the preparation of chiral esters such as α-methoxy-α-(trifluoromethyl)phenyl acetate (Jacob III. Chem., (1982) 47:4165), and the presence of two atropisomerous enantiomers or diastereomers. 1 This includes analyzing the 1H NMR spectrum. Stable diastereomers of atropisomerous compounds can be separated and isolated by normal-phase and reverse-phase chromatography according to the separation method for atropisomerous naphthyl-isoquinoline (International Publication No. 96 / 15111). By method (3), a racemic mixture of the two enantiomers can be separated by chromatography using a chiral stationary phase ("Chiral Liquid Chromatography" (1989) WJ Lough, Ed., Chapman and Hall, New York; Okamoto, J. Chromatogr., (1990) 513:375-378). The concentrated or purified enantiomers can be identified by methods used to identify other chiral molecules having an asymmetric carbon atom, such as optical rotation and circular dichroism.

[0132] The compound of formula I can be prepared by the general procedure shown in scheme 1-7. Scheme 1: Scheme 1 of TIFF2026067858000104.tif137170 shows that the para-hydroxybenzaldehyde intermediate 1 is reacted with tert-butyl 3-iodoazetidine-1-carboxylate to obtain exemplary tert-butyl 3-(4-formylphenoxy)azetidine-1-carboxylate intermediate 2. Exemplary intermediate 1 is 2,6-difluoro-4-hydroxybenzaldehyde. Cyclochemical addition of 2 with bicyclic amine 3 yields tricyclic, tetrahydropyrido[3,4-b]indole-1-yl azetidine intermediate 4. Acid deprotection of 4 and alkylation of 5 yield tricyclic, tetrahydropyrido[3,4-b]indole-1-yl azetidine 6. Scheme 2: Scheme 2 shows that a para-iodobenzaldehyde intermediate 7, for example 2,6-difluoro-4--iodobenzaldehyde, is cyclized with a bicyclic amine 3 to obtain a tricyclic, tetrahydropyrido[3,4-b]indole-1-yliodophenyl intermediate 8. The reaction of 8 with alcohol 9 yields a tricyclic, tetrahydropyrido[3,4-b]indole-1-yl intermediate 10. Scheme 3: Scheme 3 of TIFF2026067858000106.tif98170 shows the reaction of amine 11 with an alkylating reagent, where the leaving group is iodide, bromide, or triflate, yielding intermediate 12. Alternatively, amine 11 can also be reacted with an aldehyde or ketone to obtain intermediate 12 by reductive amination. Intermediate 12 was condensed with an aldehyde, then to produce intermediate 13. Then, the X of Cy 1Target 14 could be obtained by coupling the iodide or bromide on the group with an alcohol, amine, sulfide, or olefin via a Pd or Cu-catalyzed Ullman, Buchwald, or Heck reaction. Alternatively, the protected phenol (OP) on the Cy group could be deprotected, and the resulting phenol could be further coupled with an alcohol via the Mitsunobu reaction. Alternatively, the phenol could be alkylated with iodide, bromide, chloride, triflate, or mesylate to obtain a tricyclic, tetrahydropyrido[3,4-b]indole-1-yl intermediate 14. Scheme 4: TIFF2026067858000107.tif106170 Scheme 4 involves the Pictet-Spengler cyclization of amine 11 using an aldehyde X 1 This shows that this yields an intermediate 15 which is an iodide or bromide. The reaction of amine 15 with the acid chloride produces an amide 16. Then, iodide or bromide X on Cy 1 The group could be coupled with an alcohol, amine, sulfide, or olefin via a Pd or Cu-catalyzed Ullman, Buchwald, or Heck reaction to obtain intermediate 17. Alternatively, the protected phenol (OP) on the Cy group of 16 could be deprotected, and the resulting phenol could be further coupled with an alcohol via the Mitsunobu reaction to obtain 17. Alternatively, the phenol (OH) could be alkylated with iodide, bromide, chloride, triflate, or mesylate to obtain the tricyclic, tetrahydropyrido[3,4-b]indole-1-ylamide intermediate 17. Scheme 5: Scheme 5 of TIFF2026067858000108.tif97170 shows that amine 15 can react with sulfonyl chloride to obtain sulfonamide 18, which can be converted to a tricyclic, tetrahydropyrido[3,4b]indole-1-yl sulfonamide intermediate 19 by a Pd or Cu catalyzed Ullman, Buchwald, or Heck reaction, or by a Mitsunobu or alkylation reaction. Scheme 6: TIFF2026067858000109.tif43170 Scheme 6 is an alkylating agent (R 5 This shows that intermediate 13 can be obtained by reacting with -X). Alternatively, intermediate 13 can be obtained by reacting amine 15 with an aldehyde or ketone and a reducing agent such as sodium cyanoborohydride. Scheme 7: Scheme 7 shows a typical synthetic route for tryptamine 23. Under Vilsmeier reaction conditions, substituted indole 20 is converted to aldehyde 21. Compound 22 is obtained by aldol reaction of aldehyde 21 with nitroethane. After reduction of 22 with lithium aluminum hydride, tryptamine 23 is obtained. [Examples]

[0133] Example 101 (1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidine-3-yl)oxy)phenyl)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole 101 Step 1: 3-(3,5-difluoro-4-formyl-phenoxy)-azetidine-1-carboxylate tert-butyl ester 101c Under argon, cesium carbonate (3.09 g, 9.48 mmol) and 1-Boc-3-iodoazetidine 101b (CAS number: 254454-54-1, 2.68 g, 9.48 mmol) were added to a solution of 2,6-difluoro-4-hydroxybenzaldehyde 101a (CAS number: 532967-21-8, 600 mg, 3.79 mmol) in N,N-dimethylformamide (25 mL). The resulting mixture was heated under microwave heating at 150 °C for 1 hour. The reaction mixture was cooled to ambient temperature, the solid was removed by filtration, the filtration cake was washed with toluene, and the filtrate was concentrated under vacuum. The residue was partitioned into siRNA and water, the organic phase was separated, washed with brine, dried over Na₂SO₄, filtered, and concentrated under vacuum. The crude product was adsorbed onto HMN diatomaceous earth (Isolute®, Biotage) and purified by silica gel chromatography (mobile phase: cyclohexane / ethyl acetate, gradient 0% to 30%) to obtain 101c as a yellow oily substance (1.10 g, 93%). 1 H NMR(300 MHz, CDCl3): d10.20 (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).

[0134] Step 2: (2-fluoro-2-methyl-propyl)-[(R)-2-(1H-indole-3-yl)-1-methyl-ethyl]amine 101d Compound 101d was prepared according to International Publication No. 2014 / 191726, page 78. (JPEG2026067858000112.jpg3542)

[0135] Step 3: 3-{3,5-difluoro-4-[(1R,3R)-2-(2-fluoro-2-methyl-propyl)-3-methyl-2,3,4,9-tetrahydro-1H-beta-carbolin-1-yl]phenoxy}azetidine-1-carboxylate tert-butyl ester 101e JPEG2026067858000113.jpg3876 Under argon, (2-fluoro-2-methyl-propyl)-[(R)-2-(1H-indole-3-yl)-1-methyl-ethyl]amine 101d (540 mg, 2.17 mmol) was prepared in toluene (8 mL) according to International Publication No. 2014 / 191726, p. 78. To this solution, 3-(3,5-difluoro-4-formyl-phenoxy)-azetidine-1-carboxylic acid tert-butyl ester 101c (818 mg, 2.61 mmol) and acetic acid (249 μL, 4.34 mmol) were added. The mixture was heated in a sealed tube at 80°C for 4 hours and protected from light. The reaction mixture was cooled to room temperature (RT) and concentrated under vacuum. The residue was partitioned into ethyl acetate (siRNA) and saturated sodium bicarbonate solution. The organic phase was separated, washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was adsorbed onto HMN diatomaceous earth and purified by silica gel chromatography (mobile phase: cyclohexane / ethyl acetate, gradient 0% to 20%) to obtain 101e as an off-white solid (1.10 g, 90%). 1 H NMR (300 MHz, CDCl3): d7.54 - 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); LCMS: 544.5 [M+H] + .

[0136] Step 4: (1R,3R)-1-[4-(azetidine-3-yloxy)-2,6-difluorophenyl]-2-(2-fluoro-2-methyl-propyl)-3-methyl-2,3,4,9-tetrahydro-1H-beta-carboline 101f Under argon, a mixture containing 3-{3,5-difluoro-4-[(1R,3R)-2-(2-fluoro-2-methyl-propyl)-3-methyl-2,3,4,9-tetrahydro-1H-beta-carbolin-1-yl]phenoxy}azetidine-1-carboxylic acid tert-butyl ester 101e (840 mg, 1.54 mmol) in dichloromethane (10 mL) was added dropwise with TFA (1.75 mL, 23.1 mmol), and the mixture was stirred at room temperature for 3 hours and protected from light. The reaction mixture was concentrated under vacuum and purified using an SCX-2 cartridge (mobile phase: dichloromethane / methanol 1:1, then 2N ammonia in methanol). The appropriate fractions were combined and evaporated to obtain 101f as an off-white solid (54 mg, 8%). 1 H NMR (300 MHz, CDCl3): d7.54 - 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 (br. s, 1H), 1.27 - 1.07 (m, 9H); LCMS: 442.5 [MH] - .

[0137] Step 5: Under argon, a mixture containing (1R,3R)-1-[4-(azetidine-3-yloxy)-2,6-difluorophenyl]-2-(2-fluoro-2-methyl-propyl)-3-methyl-2,3,4,9-tetrahydro-1H-beta-carbolin 101f (54 mg, 0.12 mmol) in N,N-dimethylformamide (2 mL) was mixed with 1-bromo-3-fluoropropane (16 μL, 0.16 mmol; CAS No. 352-91-0) and ethyldiisopropylamine (12 μL, 0.24 mmol). The reaction mixture was stirred at room temperature for 48 hours and protected from light. The reaction mixture was poured into a mixture of ethyl acetate and water. The organic layer was separated, washed with water and brine, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified using silica gel chromatography (mobile phase: dichloromethane / methanol, gradient 0% to 5%), followed by purification using a C18 cartridge (acetonitrile, water, formic acid). Appropriate fractions were combined and evaporated to obtain 101 as a yellow solid (27 mg, 8%). 1 H NMR (400 MHz, CDCl3): d11.12 (br s., 1H), 8.27 (s, 1.3H, formic acid), 7.53 - 7.47 (m, 2H), 7.24 - 7.20 (m, 1H), 7.13 - 7.08 (m, 2H), 6.31 - 6.25 (m, 2H), 5.20 (s, 1H), 4.96 - 4.89 (m, 1H), 4.56 (dd, J = 5.6, 5.6 Hz, 1H), 4.44 (dd, J = 5.6, 5.6 Hz, 1H), 4.33 - 4.24 (m, 2H), 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); LCMS: 504.3 [M+H] + .

[0138] Example 102 (1R,3R)-1-(2,6-difluoro-4-(2-(3-(fluoromethyl)azetidine-1-yl)ethoxy)phenyl)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole 102 Step 1: (1R,3R)-1-(2,6-difluoro-4-iodophenyl)-2-(2-fluoro-2-methyl-propyl)-3-methyl-2,3,4,9-tetrahydro-1H-beta-carboline 102b JPEG2026067858000115.jpg3658 Under argon, (2-fluoro-2-methyl-propyl)-[(R)-2-(1H-indole-3-yl)-1-methyl-ethyl]amine 101d (50 mg, 0.20 mmol) was prepared in toluene (170 μL) according to International Publication No. 2014 / 191726, p. 78. To this solution, 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). The resulting mixture was stirred in a sealed tube at 80°C and then cooled to room temperature. The mixture was purified using an SCX-2 cartridge (mobile phase: dichloromethane / methanol 9:1, followed by 2N ammonia in methanol). The appropriate fractions were combined, evaporated, and the crude product was purified by silica gel chromatography (mobile phase: cyclohexane / ethyl acetate, gradient 0% to 30%) to obtain 102b as a yellow solid (89 mg, 89%). 1H NMR (400 MHz, CDCl3): d7.54 - 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, 24.0Hz, 1H), 1.29 - 1.15 (m, 6H), 1.10 (d, J = 6.4 Hz, 3H); LCMS: 497.0 [MH] - .

[0139] Step 2: A mixture containing (1R,3R)-1-(2,6-difluoro-4-iodophenyl)-2-(2-fluoro-2-methyl-propyl)-3-methyl-2,3,4,9-tetrahydro-1H-beta-carbolin 102b (82 mg, 0.16 mmol), 2-(3-fluoromethyl-azetidine-1-yl)-ethanol 102c (prepared according to International Publication No. 2013 / 090836, p. 124) (44 mg, 0.33 mmol; CAS number: 1443984-69-7, International Publication No. 2013 / 090836), copper iodide (6.2 mg, 0.03 mmol), and potassium carbonate (68 mg, 0.49 mmol) in butyronitrile (600 μL) was degassed by three vacuum / argon cycles. The reaction mixture was heated at 135°C for 24 hours, cooled to room temperature, and diluted with ethyl acetate. The solid was removed from the reaction mixture by filtration through Celite, and the solid was washed with ethyl acetate. The combined filtrate was washed with water (three times) and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (mobile phase: 0-7% methanol / dichloromethane). Appropriate fractions were collected and evaporated to obtain 102 as a yellow solid (17.2 mg, 21%). 1H NMR (400 MHz, DMSO-d6): d10.51 (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, partially under DMSO-d6), 2.40 - 2.27 (m, 2H), 1.25 - 1.09 (m, 6H), 1.04 (d, J = 6.4 Hz, 3H); LCMS: 502.3 [MH] - .

[0140] Example 103 1-((1R,3R)-1-(2,6-difluoro-4-(2-(3-(fluoromethyl)azetidine-1-yl)ethoxy)phenyl)-3-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-yl)-2-methylpropan-1-one 103 Step 1: (1R,3R)-1-(2,6-difluoro-4-iodophenyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole 103b (2R)-1-(1H-indole-3-yl)propan-2-amine 103a (710 mg, 3.67 mmol), followed by 2,6-difluoro-4-iodobenzaldehyde (1.1 g, 4.03 mmol) and acetonitrile (2.6 mL) were added to a microwave vial. 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 in a microwave to 130°C for 1 hour, and then quenched with saturated NaHCO3 aqueous solution. The mixture was extracted by DCM (3 × 100 mL), dried over MgSO4, filtered, and concentrated. The crude product was purified by flash column chromatography on silica gel (0-100% siRNA / hexane) to obtain 103b (450 mg, 29%). 1 ¹H NMR (400 MHz, deuterochlorofor-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).

[0141] Step 2: 1-((1R,3R)-1-(2,6-difluoro-4-iodophenyl)-3-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-yl)-2-methylpropan-1-one 103c JPEG2026067858000117.jpg3954 In a round-bottom flask (RBF), (1R,3R)-1-(2,6-difluoro-4-iodophenyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole 103b (50 mg, 0.12 mmol), 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 to 45°C for 1 hour. Diisopropylethylamine (Hünig base, 0.1 mL, 0.59 mmol) was added, and the reaction mixture was stirred until LC-MS indicated that the starting materials had been consumed. A saturated aqueous solution of sodium bicarbonate (10 mL) was added. Next, the reaction mixture was extracted with DCM (3 × 50 mL), dried on MgSO4, filtered, and concentrated. The crude product was purified by flash column chromatography (0-100% toluene / hexane) on silica gel to obtain 103c (51 mg, 88%). 1 H NMR (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 = 15.2Hz, 1H), 1.12 (d, J = 6.5 Hz, 2H), 1.06 - 0.92 (m, 6H).

[0142] Step 3: 1-[(1R,3R)-1-(2,6-difluoro-4-iodophenyl)-3-methyl-1,3,4,9-tetrahydropyrido[3,4-b]indole-2-yl]-2-methyl-propan-1-one 103c (51 mg, 0.10 mmol), followed by 2-[3-(fluoromethyl)azetidine-1-yl]ethanol 102c (prepared according to International Publication No. 2013 / 090836, p. 124) (27 mg, 0.21 mmol), copper iodide (8 mg, 0.04 mmol), and potassium carbonate (43 mg, 0.31 mmol). The vial was sealed and butyronitrile (0.7 mL) was added. The reaction mixture was then heated overnight at 135°C and then cooled to room temperature. Next, the reaction mixture was filtered through Celite and eluted with dimethyl acetate. The combined filtrate was then concentrated and purified by reverse-phase HPLC to obtain 103 (16 mg, 31%). 1 H NMR (400 MHz, DMSO-d6): 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); LCMS: 500.3 [M+H] +

[0143] Example 104 1-((1R,3R)-1-(2,6-difluoro-4-(2-(3-(fluoromethyl)azetidine-1-yl)ethoxy)phenyl)-3-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-yl)-2-fluoro-2-methylpropan-1-one 104 Step 1: 1-((1R,3R)-1-(2,6-difluoro-4-iodophenyl)-3-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-yl)-2-fluoro-2-methylpropan-1-one 104a In a round-bottom flask, (1R,3R)-1-(2,6-difluoro-4-iodophenyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole 103b (100 mg, 0.24 mmol), followed by 2-fluoro-2-methyl-propanoyl chloride (prepared from the reaction of the corresponding acid with oxalyl chloride in a 1 M CHCl3 (0.59 mL) solution), sodium bicarbonate (99 mg, 1.2 mmol), and chloroform (1.6 mL). The reaction was then heated to 45°C for 1 hour, followed by the addition of Hünig base (0.2 mL, 1.2 mmol). The reaction was monitored by LC-MS, and the reaction was stirred until it was indicated that all starting materials had been consumed. The reaction was quenched with a saturated aqueous solution of sodium bicarbonate. Next, the mixture was extracted with DCM (3 × 50 mL), dried over MgSO4, filtered, and concentrated. The resulting crude product was purified by silica gel column chromatography (0-100% EtOAC / hexane) to obtain 104a (95 mg, 79%). 1H NMR (400 MHz, DMSO-d6): 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); LCMS: 513.0 [M+H] + .

[0144] Step 2: 1-[(1R,3R)-1-(2,6-difluoro-4-iodophenyl)-3-methyl-1,3,4,9-tetrahydropyrido[3,4-b]indole-2-yl]-2-fluoro-2-methyl-propan-1-one 104a (29 mg, 0.056 mmol), followed by 2-[3-(fluoromethyl)azetidine-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). The solution was degassed for 5 minutes and then heated overnight to 135°C. The reaction was monitored by LC-MS, and once it was indicated that all starting materials had been consumed, the crude mixture was cooled to room temperature and filtered through Cerite®. The Celite plug was further washed with Â, and the combined filtrate was concentrated and purified by reverse-phase HPLC to obtain 104 (9 mg, 31%). 1H NMR (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); LCMS: 518.2 [M+H] + .

[0145] Example 105 (1R,3R)-1-(4-(2-(3-(difluoromethyl)azetidine-1-yl)ethoxy)-2,6-difluorophenyl)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole 105 Step 1: 2-(3,5-difluoro-4-formylphenoxy)ethyl acetate 105a A solution containing 2,6-difluoro-4-hydroxybenzaldehyde (CAS No.: 532967-21-8, 300 mg, 1.89 mmol) and 2-bromo-ethyl 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 hours. A portion of 2-bromo-ethyl acetate (0.11 mL, 1 mmol) was added, and heating was continued at 80°C for a further 30 hours. The reaction mixture was allowed to cool to ambient temperature. The residue was partitioned into a saturated solution of ethyl acetate and sodium bicarbonate. The aqueous layer was extracted with a further portion of ethyl acetate. The combined organic layers were separated, dried over MgSO4, filtered, and concentrated under vacuum. The crude product was purified by silica gel column chromatography (mobile phase: cyclohexane / ethyl acetate, gradient 0% to 33%) to obtain 105a as a white powder (213 mg, 45%). 1 H NMR (300 MHz, CDCl3): 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, 2H), 2.11 (s, 3H).

[0146] Step 2: 2-(3,5-difluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl)phenoxy)ethyl acetate 105b Under argon, (2-fluoro-2-methyl-propyl)-[(R)-2-(1H-indole-3-yl)-1-methyl-ethyl]amine 101d (213 mg, 0.86 mmol) and 2-(3,5-difluoro-4-formylphenoxy)ethyl acetate 105a (210 mg, 0.86 mmol) were dissolved in toluene (1 mL), to which glacial acetic acid (0.1 mL, 1.72 mmol) was added. The container was sealed, and the reaction mixture was heated at 80 °C for 16 hours. The reaction mixture was allowed to cool to ambient temperature. The residue was partitioned into a saturated solution of dichloromethane and sodium bicarbonate. The aqueous layer was further extracted with a portion of the dichloromethane. The combined organic layers were separated, dried over MgSO4, filtered, and concentrated under vacuum. The crude product was purified by silica gel chromatography (mobile phase: cyclohexane / ethyl acetate, gradient 0% to 20%) to obtain 105b as a white foamy substance (232 mg, 80%). 1 H NMR (300 MHz, CDCl3): 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).

[0147] Step 3: 2-(3,5-difluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl)phenoxy)ethanol 105c JPEG2026067858000121.jpg36612-(3,5-difluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl)phenoxy)ethyl acetate 105b (320 mg, 0.675 mmol) was added to a THF / MeOH solution (2 / 1, 6 mL) with sodium hydroxide (1N, 4 mL). The reaction mixture was heated at 70°C for 4 minutes. The reaction mixture was allowed to cool to ambient temperature, and the solvent was removed under vacuum. The residue was partitioned into dichloromethane and water. The organic layer was separated, dried over MgSO4, filtered, and concentrated under vacuum to obtain 105c as a white foam (264 mg, 91%). LCMS 431.2 [MH].

[0148] Step 4: (1R,3R)-1-(4-(2-bromoethoxy)-2,6-difluorophenyl)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole 105d JPEG2026067858000122.jpg36582-(3,5-difluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl)phenoxy)ethanol 105c (130 mg, 0.3 mmol) was dissolved in DCM (2.5 mL) and triphenylphosphine (94 mg, 0.36 mmol) and carbon tetrabromide (120 mg, 0.36 mmol) were added. The reaction mixture was stirred at room temperature for 1 hour, and then the solvent was removed under vacuum. The crude product was purified by silica gel column chromatography (mobile phase: cyclohexane / ethyl acetate, gradient 0% to 20%) to obtain 105d as a white foam (142 mg, 95%). 1H NMR (300 MHz, CDCl3): 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).

[0149] Step 5: To a solution of (1R,3R)-1-(4-(2-bromoethoxy)-2,6-difluorophenyl)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole 105d (62 mg, 0.125 mmol) in acetonitrile (1 mL), N,N-diisopropylethylamine (0.064 mL, 0.375 mmol) and 3-(difluoromethyl)azetidine hydrochloride (CAS 1354792-76-9, 27 mg, 0.187 mmol) were added. The reaction mixture was stirred at room temperature for 1 hour, then at 45°C for 4 hours. The reaction mixture was allowed to cool to ambient temperature. The residue was partitioned into ethyl acetate and water. The aqueous layer was extracted with a further portion of ethyl acetate. The combined organic layers were separated, dried over MgSO4, filtered, and concentrated under vacuum. The crude product was purified by silica gel column chromatography (mobile phase: dichloromethane / methanol, gradient 0% to 2.5%) to obtain 105 as an off-white solid (40 mg, 62%). 1H NMR (300 MHz, CDCl3): 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 = 13.3, 3 Hz, 2H), 6.17 - 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), 3.46 (t, J = 7.8 Hz, 2H), 3.27 (t, J = 6.7 Hz, 2H), 3.13 - 3.04 (m, 1H), 2.92 - 2.79 (m, 3H), 2.64 - 2.55 (m, 1H), 2.45 - 2.30 (dd, J = 25.6, 14.9 Hz, 1H), 1.23 (d, J = 10.3 Hz, 3H), 1.16 (d, J = 12 Hz, 3H), 1.09 (d, J = 6.5 Hz, 3H); LCMS: 520.4 [MH] - .

[0150] Compounds 106 and 125 were prepared according to the procedure described herein, and the following LCMS[M+H] + It was characterized by the following. TIFF2026067858000123.tif181170

[0151] Example 126 (1R,3R)-1-(2,6-difluoro-4-(2-(3-(fluoromethyl)azetidine-1-yl)ethoxy)phenyl)-3-methyl-2-(methylsulfonyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole 126 Step 1: (1R,3R)-1-(2,6-difluoro-4-iodophenyl)-3-methyl-2-(methylsulfonyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (1R,3R)-1-(2,6-Difluoro-4-iodo-phenyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (50 mg, 0.12 mmol) and chloroform (0.15 M, 0.8 mL) were added to a 353650 mL round-bottom flask. Subsequently, N,N-diisopropylethylamine (0.06 mL, 0.35 mmol) and methanesulfonyl chloride (0.014 mL, 0.18 mmol) were added sequentially. Then, the reaction mixture was heated to 45 °C and monitored until LCMS indicated complete consumption of the starting material. The reaction mixture was cooled to room temperature, quenched by the addition of saturated NH4Cl aqueous solution, extracted with DCM (3 × 50 mL), dried over MgSO4, filtered, and concentrated. The crude product was purified by flash column chromatography on silica gel eluting with 0 - 50% iPrOAc / heptane to afford the title compound (40 mg, 68%). 1 H NMR (400 MHz, DMSO-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). LCMS: 503.0 [M+H] + .

[0152] Step 2: (1R,3R)-1-(2,6-difluoro-4-iodophenyl)-3-methyl-2-methylsulfonyl-1,3,4,9-tetrahydropyrido[3,4-b]indole (40 mg, 0.08 mmol), 2-[3-(fluoromethyl)azetidine-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) were added to a 5 mL vial. The solution was degassed for 5 minutes and then heated overnight to 135°C. The reaction was monitored by LC-MS, and once the reaction was complete, the reaction mixture was filtered through Celite and eluted with ethyl acetate. The filtrate was concentrated and purified by reverse-phase HPLC to obtain 126 (6 mg, yield 15%). 1 H NMR (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).LCMS 508.2 [MH].

[0153] Example 145 N-(3,5-difluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl)phenyl)-1-(3-fluoropropyl)azetidine-3-amine 145 Project 1: (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 JPEG2026067858000125.jpg3336(R)-N-(1-(1H-Indol-3-yl)propan-2-yl)-2-fluoro-2-methylpropan-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 h. After cooling to room temperature, the solution was concentrated, and the residue was diluted with EtOAc (40 mL) and washed with saturated aqueous NaHCO3 (10 mL) and water (20 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated. The residue was purified by chromatography on silica (solvent gradient: 0 - 6% EtOAc in petroleum ether) to give the title compound (800 mg, 88%) as a light yellow solid. 1 1H NMR (400 MHz, CDCl3) 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), 2.4, 7 - 2.33 (m, 1H), 1.30 - 1.17 (m, 6H), 1.11 (d, J = 6.4 Hz, 3H).

[0154] Project 2: tert-Butyl 3-((3,5-difluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)amino)azetidine-1-carboxylate Under an N2 atmosphere, a mixture containing (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) was stirred at 110°C for 16 hours. The reaction mixture was concentrated and purified using a silica gel column (0-5% methanol in DCM) to obtain the title compound (900 mg, 94%) as a brown solid. 1 H NMR (400 MHz, CDCl3) 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)

[0155] Step 3: N-(3,5-difluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl)phenyl)azetidine-3-amine A mixture containing t-butyl 3-((3,5-difluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl)phenyl)amino)azetidine-1-carboxylate (from step 2, 0.9 g, 1.66 mmol) in JPEG2026067858000127.jpg3642DCM (5 mL) is mixed with -20 o TFA of C (1.8 mL, 24.88 mmol) was added. The resulting mixture was stirred at 0°C for 16 hours. An aqueous solution of NaHCO3 (80 mL) was slowly added to the reaction mixture, and the reaction mixture was then extracted with DCM (100 mL x 2). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated to obtain the title compound (700 mg, 95%) as a brown solid. The crude product was used in the next step without further purification.

[0156] Step 4: To a mixture containing N-(3,5-difluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl)phenyl)azetidine-3-amine (from Step 3, 700.0 mg, 1.58 mmol) and N,N-diisopropylethylamine (613.3 mg, 4.75 mmol) in 10 mL of N,N-dimethylformamide, 1-bromo-3-fluoropropane (223.0 mg, 1.58 mmol) was added, and the reaction mixture was stirred at 10°C for 16 hours. The reaction mixture was purified by column chromatography (0-10% MeOH in DCM), and further purified by reverse-phase chromatography (in water, 66-96% acetonitrile / 0.05% NH4OH) to obtain 145 (280 mg, 35%) as a white solid. 1H NMR (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 = 6.8 Hz, 3H).

[0157] Example 154 (S)-3-((1R,3R)-1-(2,6-difluoro-4-(2-(3-(fluoromethyl)azetidine-1-yl)ethoxy)phenyl)-3-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-yl)-2-fluoro-2-methylpropan-1-ol 154 Step 1: Dimethyl 2-fluoro-2-methylmalonate JPEG2026067858000128.jpg1426 Sodium hydride (1.15 equivalents, 21 mmol) was added to a 500 mL round-bottom flask that had been oven-dried. The reaction mixture was placed under a nitrogen atmosphere and cooled to 0°C. Then, THF (63 mL) was added. Dimethyl 2-methylpropanediote (5.0 g, 34.2 mmol) was added dropwise to this mixture, and the reaction mixture was stirred for 30 minutes. Then, n-fluorobenzenesulfonimide (1.05 equivalents, 19.2 mmol) was added all at once. The reaction mixture was warmed to room temperature and allowed to solidify, and an additional 50 mL of THF was added. After 1.5 hours, the reaction mixture was quenched with 2N aqueous HCl, diluted with HCl (500 mL), and washed with 2N HCl (3 × 200 mL). The organic matter was separated, dried over MgSO4, filtered, and concentrated. Next, the crude white solid was transferred to 200 mL of heptane, sonicated, and filtered through Celite. Then, the filtered solid was washed with 3 × 200 mL of heptane. The combined filtrate was then concentrated to obtain the desired crude product (3 g, yield 53%) as a yellow oil. 1 H NMR (400 MHz, DMSO-d6) δ 3.32 (s, 6H), 1.18 (d, J = 6.3 Hz, 3H).

[0158] Step 2: 2-Fluoro-2-methylpropane-1,3-diol JPEG2026067858000129.jpg1414 Dimethyl 2-fluoro-2-methyl-propanediate (3 g, 18.3 mmol) and THF (90 mL) were added to an oven-dried 500 mL round-bottom flask. The reaction mixture was placed under a nitrogen atmosphere and then cooled to 0°C. Next, lithium aluminum hydride solution (1 M, 2.75 equivalents, 50.3 mmol in THF) was added dropwise, and the reaction mixture was heated to room temperature for 1 hour. The reaction mixture was then recooled to °C and quenched by adding water (2 mL), followed by 15% NaOH aqueous solution (2 mL) and water (4 mL). The slurry was stirred for 15 minutes, filtered, and concentrated to obtain the crude product (1.4 g, yield 71%). 1H 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).

[0159] Step 3: 3-(tert-butyldiphenylsilyloxy)-2-fluoro-2-methylpropane-1-ol JPEG2026067858000130.jpg1422 In an oven-dried 500 mL round-bottom flask, 2-fluoro-2-methyl-propane-1,3-diol (1.47 g, 1.25 equivalents, 13.6 mmol), followed by imidazole (1.11 g, 1.5 equivalents, 16.4 mmol), tert-butylchlorodiphenylsilane (3.0 g, 10.9 mmol), and chloroform (136 mL) were added. The reaction mixture was stirred overnight and quenched by adding saturated NH4Cl solution (100 mL). The mixture was then extracted with DCM (100 mL), dried over MgSO4, filtered, and concentrated. The crude mixture was purified by flash silica gel column chromatography (0-100% iPrOAc / heptane) to obtain the desired product (1.26 g, yield 33%). 1 H 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).

[0160] Step 4: 3-(tert-butyldiphenylsilyloxy)-2-fluoro-2-methylpropyl trifluoromethanesulfonate JPEG2026067858000131.jpg1422 In a 500 mL oven-dried round-bottom flask, 1.3 g (3.8 mmol) of 3-[tert-butyl(diphenyl)silyl]oxy-2-fluoro-2-methyl-propan-1-ol and 63 mL of dichloromethane were added under a nitrogen atmosphere. The reaction mixture was then cooled to 0°C, and trifluoromethanesulfonic anhydride (1.27 g, 1.2 equivalents, 4.5 mmol) was added dropwise. The reaction mixture was then stirred for 2 hours, followed by washing with 2N HCl and then saturated NaHCO3 solution. The organic matter was separated, dried over MgSO4, filtered through a silica gel plug, and eluted with DCM. The filtrate was then concentrated to dryness to obtain the desired crude product (1.8 g, 100% yield), which was used in the next step without further purification. 1 H NMR (400 MHz, DMSO-d6) 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).

[0161] Step 5: N-((R)-1-(1H-indole-3-yl)propan-2-yl)-3-(tert-butyldiphenylsilyloxy)-2-fluoro-2-methylpropan-1-amine JPEG2026067858000132.jpg2251 In an oven-dried 250 mL round-bottom flask, (2R)-1-(1H-indole-3-yl)propan-2-amine (600 mg, 3.1 mmol), N,N-diisopropylethylamine (0.81 mL, 1.5 equivalents, 4.65 mmol), and 1,4-dioxane (6 mL) were added, and the reaction mixture was placed under a nitrogen atmosphere. Then, [3-[tert-butyl(diphenyl)silyloxy-2-fluoro-2-methyl-propyl]trifluoromethanesulfonate (1.95 g, 1.25 equivalents, 3.9 mmol) was added, and the reaction mixture was heated to 90°C. When LC-MS showed consumption of the starting materials, the reaction mixture was quenched with saturated NaHCO3 aqueous solution, and the mixture was extracted with RINKAN (3 x 200 mL). The combined organic matter was dried over MgSO4, filtered, and concentrated. The compound was purified by flash silica gel column chromatography (0-100% siRNA / hexane) to obtain the title compound (1.2 g, 77% yield). LCMS 503.3 [MH] + .

[0162] Step 6: 3-((R)-1-(1H-indole-3-yl)propane-2-ylamino)-2-fluoro-2-methylpropane-1-ol JPEG2026067858000133.jpg22463-[tert-butyl(diphenyl)silyl]oxy-2-fluoro-N-[(1R)-2-(1H-indole-3-yl)-1-methyl-ethyl]-2-methyl-propan-1-amine (1.2 g, 2.4 mmol) was added to an oven-dried 250 mL round-bottom flask, followed by the addition of THF (9.6 mL) and tetrabutylammonium fluoride hydrate (3 mL of 1 M THF solution). The reaction mixture was stirred at room temperature until LC-MS showed complete consumption of the starting material. The reaction mixture was quenched by the addition of water and extracted with 25% IPA in 5 × 100 mL of DCM. The combined organic matter was then dried over MgSO4, filtered, and concentrated. The compound was purified by flash column chromatography on silica gel (0-30% 2N NH3 / DCM in MeOH) to obtain the title compound (332 mg, 53% yield). LCMS: 265.1 [M+H] + .

[0163] Step 7: 3-((1R,3R)-1-(2,6-difluoro-4-iodophenyl)-3-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-yl)-2-fluoro-2-methylpropane-1-ol JPEG2026067858000134.jpg3850 In a 100 mL round-bottom flask, 2-fluoro-3-[[(1R)-2-(1H-indole-3-yl)-1-methyl-ethyl]amino]-2-methyl-propan-1-ol (332 mg, 1.26 mmol), 2,6-difluoro-4-iodobenzaldehyde (370 mg, 1.1 equivalents, 1.38 mmol), and toluene (5.5 mL) were added. The reaction mixture was placed under a nitrogen atmosphere and acetic acid (2 M) was added. The reaction mixture was then heated to 90 °C for 48 hours. Next, it was quenched with a saturated aqueous solution of NaHCO3 and vigorously extracted with iPrOAc (5 x 100 ml). The organic matter was then dried over MgSO4, filtered, and concentrated. The title compound (475 mg, 74% yield) was obtained by purification by flash column chromatography (0-100% iPrOAc / heptane) on silica gel. LCMS: 515.1 [M+H] +.

[0164] Step 8: 3-[(1R,3R)-1-(2,6-difluoro-4-iodophenyl)-3-methyl-1,3,4,9-tetrahydropyrido[3,4-b]indole-2-yl]-2-fluoro-2-methyl-propan-1-ol (400 mg, 0.78 mmol), 2-[3-(fluoromethyl)azetidine-1-yl]ethanol (518 mg, 5 equivalents, 3.9 mmol), cuprous iodide (74 mg, 0.5 equivalents, 0.39 mmol), and potassium carbonate (644 mg, 6 equivalents, 4.7 mmol) were added to a 20 mL microwave vial. The vial was capped and the mixture was placed under a nitrogen atmosphere. Then, butyronitrile (5.2 mL) was added and the mixture was degassed for 10 minutes. Next, the reaction mixture was heated to 135°C for 16 hours, filtered through Celite, and purified by chiral reverse-phase HPLC to obtain two diastereomers. 154 was the second diastereomer to elute (90 mg, 22% yield). 154: 1H NMR (400 MHz, DMSO-d6) 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 (dtd, J = 20.1, 7.2, 1.3 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), 3.92 (t, J = 5.4 Hz, 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), 2.45 - 2.30 (m, 1H), 1.15 - 0.96 (m, 6H). Two protons were obscured by the water peak. Chiral SFC: Column OX UPC2, isocratic 25% MeOH containing 0.1% NH4OH, 25 minutes. Retention time 1.35 minutes. LCMS: 520.3 [M+H] + .

[0165] Example 155 (2R)-3-[(1R,3R)-1-[2,6-difluoro-4-[2-[3-(fluoromethyl)azetidine-1-yl]ethoxy]phenyl]-3-methyl-1,3,4,9-tetrahydropyrido[3,4-b]indole-2-yl]-2-fluoro-2-methyl-propan-1-ol 155 Following the procedure of Example 154, 155 was the first diastereomer to elute (110 mg, 27% yield). 155: 1H 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). Two protons were obscured by the water peak. Chiral SFC: Column OX UPC2, isocratic 25% MeOH containing 0.1% NH4OH, 25 minutes. Retention time 0.55 minutes. LCMS: 520.2 [M+H] + .

[0166] Example 174 (1R,3R)-1-[2,6-difluoro-4-[2-[3-(fluoromethyl)azetidine-1-yl]ethoxy]phenyl]-3-methyl-2-(2,2,2-trifluoroethyl)-1,3,4,9-tetrahydropyrido[3,4-b]indole 174 Step 1: (R)-1-(1H-indole-3-yl)-N-(2,2,2-trifluoroethyl)propan-2-amine A mixture containing (2R)-1-(1H-indole-3-yl)propan-2-amine (100 mg, 0.574 mmol), 2,2,2-trifluoroethyl trifluoromethanesulfonate (151 mg, 0.6313 mmol), and N,N-diisopropylethylamine (371 mg, 2.87 mmol) in 1,4-dioxane (3.8261 mL) was heated at 50°C for 6 hours. The mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate (2x). The combined organic matter was dried (Na2SO4), filtered, and concentrated. The crude product was purified by silica flash chromatography (0-50% iPrOAc / heptane) to obtain the title compound (89 mg, yield 60.5%) as a colorless oil. 1 H NMR (chloroform-d) 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).LCMS (ESI) m / z 257 [M+H + ].

[0167] Step 2: (1R,3R)-1-(2,6-difluoro-4-iodophenyl)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole A mixture containing (2R)-1-(1H-indole-3-yl)-N-(2,2,2-trifluoroethyl)propan-2-amine (54 mg, 0.211 mmol), 2,6-difluoro-4-iodobenzaldehyde (62 mg, 0.232 mmol), and acetic acid (110 mg, 1.84 mmol) in toluene (1 mL) was heated at 90°C for 5 hours. The mixture was then concentrated. The residue was partitioned into ethyl acetate and saturated NaHCO3. The aqueous layer was extracted with ethyl acetate (2x). The combined organic matter was dried (Na2SO4), filtered, and concentrated to obtain the title compound as a white solid, which was used without purification. LCMS (ESI) m / z 507 [M+H + ].

[0168] Step 3: A mixture containing (1R,3R)-1-(2,6-difluoro-4-iodophenyl)-3-methyl-2-(2,2,2-trifluoroethyl)-1,3,4,9-tetrahydropyrido[3,4-b]indole (107 mg, 0.211 mmol), 2-[3-(fluoromethyl)azetidine-1-yl]ethanol (84 mg, 0.632 mmol), CuI (16 mg, 0.0843 mmol), and K2CO3 (87 mg, 0.632 mmol) in butyronitrile (1.4 mL) was purged with N2 for 5 minutes, then sealed and heated at 135°C for 23 hours. The mixture was filtered through Celite, concentrated, and purified by preparative HPLC to obtain 174 (51 mg, yield 47%) as a yellow solid. 11H NMR (400 MHz, DMSO-d6) 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). LCMS (ESI) m / z 512 [M+H + .

[0169] Example 286 3-[(1R,3R)-1-[2,6-difluoro-4-[2-[3-(fluoromethyl)azetidin-1-yl]ethoxy]phenyl]-3-methyl-1,3,4,9-tetrahydropyrido[3,4-b]indol-2-yl]-2,2-difluoro-propan-1-ol 286 Step 1: 3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropan-1-ol JPEG2026067858000137.jpg10332,2-difluoropropane-1,3-diol (200 mg, 1.78 mmol) was mixed with THF (4 mL) and NaH (60% in mineral oil, 71 mg, 1.78 mmol) was added on an ice bath. The reaction mixture was stirred for 30 minutes. TBDPSCl (490 mg, 1.78 mmol) was added dropwise to the reaction mixture. The reaction mixture was then heated to 20°C and stirred for 3 hours. Water (10 mL) was slowly added to the reaction mixture, and the resulting mixture was extracted with RINKAN (10 mL x 2). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated. The crude residue was purified by silica gel column chromatography (20% petroleum ether in RINKAN) to obtain the title compound (450 mg, 1.28 mmol, yield 72%) as a bright yellow oil. 1 H NMR (400 MHz, CDCl3) 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).

[0170] Step 2: 3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropyl trifluoromethanesulfonate JPEG2026067858000138.jpg 8343-[tert-butyl(diphenyl)silyl]oxy-2,2-difluoropropan-1-ol (from step 1, 400 mg, 1.14 mmol) and 2,6-lutidine (0.39 mL, 3.42 mmol) were stirred in DCM (8 mL), to which Tf2O (0.38 mL, 2.28 mmol) was added dropwise on an ice bath. The reaction mixture was stirred at 20°C for 2 hours. The reaction mixture was then slowly poured into ice water (20 mL) and extracted with DCM (20 mL x 2). The combined organic layers were washed with 1N HCl (20 mL), saturated NaHCO3 (20 mL), and brine. The organic layers were dried over anhydrous Na2SO4, filtered, and concentrated. The crude residue was purified by silica gel column chromatography (10% petroleum ether in dimethyl phosphate) to obtain the title compound (500 mg, 1.04 mmol, 91%) as a light yellow oily substance. 1H NMR (400 MHz, CDCl3) 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).

[0171] Step 3: (R)-N-(1-(1H-indole-3-yl)propan-2-yl)-3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropan-1-amine A mixture containing [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), and (2R)-1-(1H-indole-3-yl)propan-2-amine (3 g, 17.22 mmol) in 60 mL of dioxane was stirred at 90°C for 12 hours. After cooling to room temperature, the reaction mixture was diluted with water (100 mL) and washed with siRNA (100 mL x 2). The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated. The crude residue was purified by silica gel column chromatography (20% siRNA in petroleum ether) to obtain the title compound (7.6 g, 87%) as a yellow oily substance. LCMS: 507.2 [M+H] + .

[0172] Step 4: (R)-3-((1-(1H-indole-3-yl)propane-2-yl)amino)-2,2-difluoropropane-1-ol JPEG2026067858000140.jpg1844(R)-N-(1-(1H-indole-3-yl)propan-2-yl)-3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropan-1-amine (from step 3, 7.6 g, 15 mmol) was mixed in 100 mL of THF, to which TBAF (1.0 M in THF, 30 mL, 30 mmol) was added. The reaction mixture was stirred at 25°C for 4 hours, then diluted with water (200 mL), and then diluted with siRNA (200 mL x 3). The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated. The crude residue was purified by silica gel column chromatography (70% siRNA in petroleum ether) to obtain the title compound (3.5 g, 87%) as a yellow oil. LCMS: 268.9 [M+H] + .

[0173] Step 5: 3-((1R,3R)-1-(2,6-difluoro-4-iodophenyl)-3-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-yl)-2,2-difluoropropane-1-ol A mixture containing (R)-3-((1-(1H-indole-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), and 2,6-difluoro-4-iodobenzaldehyde (2 g, 7.45 mmol) in toluene (30 mL) was stirred at 90 °C for 12 hours. After cooling to room temperature, the reaction mixture was diluted with water (50 mL) and washed with siRNA (100 mL x 2). The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated. The crude residue was purified by silica gel column chromatography (20% petroleum ether in siRNA) to obtain the title compound (2.8 g, 73%) as a bright yellow solid. 1H NMR (400 MHz, CDCl3) 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).

[0174] Step 6: A mixture containing 3-((1R,3R)-1-(2,6-difluoro-4-iodophenyl)-3-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-yl)-2,2-difluoropropan-1-ol (from Step 5, 1.5 g, 2.89 mmol), 2-[3-(fluoromethyl)azetidine-1-yl]ethanol (1.93 g, 14.47 mmol), CuI (1.65 g, 8.68 mmol), and K2CO3 (1.2 g, 8.68 mmol) in n-PrCN (20 mL) was stirred at 135 °C for 3 hours under an N2 atmosphere. After cooling to room temperature, the reaction mixture was 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 (in water, 50-80% acetonitrile / 0.05% NH4OH) to obtain 286 (170 mg, 11%) as a white solid. 1 H NMR (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 = 6.0 Hz, 3H).LCMS 524.1 [MH].

[0175] Example 303 (1R,3R)-2-(2,2-difluoroethyl)-1-[2,6-difluoro-4-[1-(3-fluoropropyl)azetidine-3-yl]oxyphenyl]-3-methyl-1,3,4,9-tetrahydropyrido[3,4-b]indole 303 Prepared according to the procedures of Examples 305 and 303. LCMS: 494.2 [M+H] + .

[0176] Example 304 N-(3,5-difluoro-4-((1R,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl)phenyl)-1-(3-fluoropropyl)azetidine-3-amine 304 Step 1: (R)-1-(1H-indole-3-yl)-N-(2,2,2-trifluoroethyl)propan-2-amine JPEG2026067858000142.jpg1938(2R)-1-(1H-indole-3-yl)propan-2-amine (10.0 g, 57.39 mmol) was dissolved in 1,4-dioxane (100 mL) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (13.3 g, 57.39 mmol) and DIPEA (22.2 g, 172.18 mmol) were added. The resulting mixture was stirred at 80°C for 15 hours. The reaction mixture was concentrated and purified by column chromatography eluting with 0-30% siRNA in hexane to obtain the title compound (14 g, 95.2%) as a bright yellow oily substance. 1 H NMR (400MHz, CDCl3) δ 8.02 (br. 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).

[0177] Step 2: (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 A mixture containing (R)-1-(1H-indole-3-yl)-N-(2,2,2-trifluoroethyl)propan-2-amine (from step 1, 14.0 g, 54.63 mmol), 4-bromo-2,6-difluorobenzaldehyde (11.5 g, 51.9 mmol), and acetic acid (6.25 mL, 109.26 mmol) in 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 (0-5% ethyl acetate in petroleum ether) to obtain the title compound and its cis isomer (24 g, yield 95.7%) (trans:cis = 4:1) as a yellow solid. 1 H NMR (400MHz, CDCl3) 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, 2.4 H).

[0178] Step 3: tert-butyl 3-((3,5-difluoro-4-((1R,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl)phenyl)amino)azetidine-1-carboxylate JPEG2026067858000144.jpg36481,4-Dioxane (250 mL) containing (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), Pd(dba)3 (4.59 g, 5.01 mmol), tert-butyl A mixture containing 3-aminoazetidine-1-carboxylate (12.9 g, 75.12 mmol), xanthophos (5.8 g, 10.02 mmol), and Cs2CO3 (48.9 g, 150.25 mmol) was stirred at 115°C for 16 hours under an N2 atmosphere. The reaction mixture was filtered through Celite, the filtrate was concentrated, and the mixture was purified by column chromatography (petroleum ether 0-30% siRNA) to obtain the title compound (25 g, 90.7% yield) (trans:cis = 4:1) as a light brown solid. 1 H NMR (400MHz, CDCl3) 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).

[0179] Step 4: N-(3,5-difluoro-4-((1R,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl)phenyl)azetidine-3-amine JPEG2026067858000145.jpg3642 To a solution of tert-butyl 3-((3,5-difluoro-4-((1R,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-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), sulfuric acid (4.87 mL, 90.82 mmol) was added at 0°C. The reaction mixture was stirred at 0°C for 0.5 hours. The reaction mixture was poured into a saturated NaHCO3 aqueous solution (250 mL), and the mixture was extracted with ELISA (200 mL x 2). The combined organic layers were dried over Na2SO4 and concentrated to obtain 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.

[0180] Step 5: To a mixture containing N-(3,5-difluoro-4-((1R,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl)phenyl)azetidine-3-amine (from Step 4, trans;cis=4:1, 8.0 g, 17.76 mmol) and DIPEA (8.83 mL, 53.28 mmol) in DMF (80 mL), 1-fluoro-3-iodopropane (3.34 g, 17.76 mmol) was added dropwise. The reaction mixture was stirred at 20°C for 16 hours. The reaction mixture was diluted with ELISA (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% siRNA in DCM) to obtain the target product (7g, 77.2% yield) as a brown solid. This product was combined with another batch (total 12.3g) and preparative HPLC (Phenomenex Synergi Max-RP 250) was used. * 80mm *The product was purified in 10 μm water with acetonitrile 50-80 / 10 mM NH4HCO3, and 10 g of the product (trans:cis = 4:1, inseparable by HPLC) was obtained as a white solid. Next, this product (trans:cis = 44:1) was subjected to SFC (AD(250 mm) * The solution was purified using a 30 mm, 10 μm (base-EtOH 40%) assay to obtain 304 (5.9 g, yield 59%) as a white solid. 1 H NMR (400MHz, 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).

[0181] Example 305 (1R,3R)-2-(2,2-difluoroethyl)-1-[2,6-difluoro-4-[2-[3-(fluoromethyl)azetidine-1-yl]ethoxy]phenyl]-3-methyl-1,3,4,9-tetrahydropyrido[3,4-b]indole 305 Step 1: (R)-N-(2,2-difluoroethyl)-1-(1H-indole-3-yl)propan-2-amine A mixture of (2R)-1-(1H-indole-3-yl)propan-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 iPrOAc (150 mL), washed with water and brine, dried over sodium sulfate, filtered, and concentrated. The crude product was purified by flash column chromatography on silica gel eluted with 0-5% MeOH / DCM to obtain the title compound (5.6 g, 97% yield). 1 H NMR (400 MHz, Chloroform-d) 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, LCMS: 239.15 [M+H] + .

[0182] Step 2: (1R,3R)-2-(2,2-difluoroethyl)-1-(2,6-difluoro-4-iodophenyl)-3-methyl-1,3,4,9-tetrahydropyrido[3,4-b]indole JPEG2026067858000147.jpg3640(R)-N-(2,2-difluoroethyl)-1-(1H-indole-3-yl)propan-2-amine (5.0 g, 21 mmol) and 2,6-difluoro-4-iodobenzaldehyde (5.2 g, 19 mmol) were dissolved in toluene (70 ml), to which acetic acid (2.4 mL) was added, and the mixture was heated at 90 °C for 20 hours under a nitrogen atmosphere. The reaction mixture was cooled and concentrated. The residue was dissolved in iPrOAc, washed with saturated sodium bicarbonate solution, water, and brine, dried on sodium sulfate, and concentrated. Purification by flash chromatography (silica gel, 0-15% iPrOAc / heptane) yielded the title compound (7.8 g, 76%) as a 3:1 mixture of trans and cis isomers. LCMS: 489.0 [M+H] + The mixture was then transferred directly to the next step.

[0183] Step 3: A mixture of (1R,3R)-2-(2,2-difluoroethyl)-1-(2,6-difluoro-4-iodophenyl)-3-methyl-1,3,4,9-tetrahydropyrido[3,4-b]indole (8.0 g, 16.4 mmol), 2-[3-(fluoromethyl)azetidine-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 minutes and then heated overnight to 140°C. The reaction mixture was filtered through Celite and eluted with iPrOAc. The filtrate was concentrated and purified by reverse-phase HPLC, and the cis:trans isomers were separated by chiral SFC to obtain 305 (3.77 g, yield 44%). 1H 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)..LCMS: 494.2 [M+H] + .

[0184] Example 306 (1S,3R)-2-(2,2-difluoroethyl)-1-[2,6-difluoro-4-[2-[3-(fluoromethyl)azetidine-1-yl]ethoxy]phenyl]-3-methyl-1,3,4,9-tetrahydropyrido[3,4-b]indole 306 Prepared according to the procedures of Examples 305 and 306. LCMS: 494.2 [M+H] + .

[0185] Example 340 3-[(1R,3R)-1-[2,6-difluoro-4-[[1-(3-fluoropropyl)azetidine-3-yl]amino]phenyl]-3-methyl-1,3,4,9-tetrahydropyrido[3,4-b]indole-2-yl]-2,2-difluoro-propan-1-ol 340 Step 1: (R)-N-(1-(1H-indole-3-yl)propan-2-yl)-3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropan-1-amine A mixture containing (2R)-1-(1H-indole-3-yl)propan-2-amine (29 g, 166.44 mmol), [3-[tert-butyl(diphenyl)silyl]oxy-2,2-difluoropropyl]trifluoromethanesulfonate (80.31 g, 166.44 mmol), and DIPEA (55.01 mL, 332.87 mmol) in 1,4-dioxane (600 mL) was stirred at 90°C for 12 hours. The reaction mixture was diluted with water (600 mL) and extracted with ethyl acetate (600 mL x 2). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated. The crude residue was purified by silica gel column chromatography (40% ethyl acetate in petroleum ether) to obtain the title compound (69 g, 82%) as a bright yellow oil. 1 H NMR (400MHz, CDCl3) 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, MS: [M+H] + 507.1.

[0186] Step 2: (R)-3-((1-(1H-indole-3-yl)propane-2-yl)amino)-2,2-difluoropropane-1-ol JPEG2026067858000149.jpg1844(R)-N-(1-(1H-indole-3-yl)propan-2-yl)-3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropan-1-amine (from step 1, 69 g, 136.18 mmol) was added to a stirred THF (690 mL) solution to which a 1 M THF solution of TBAF (272.35 mL, 272.35 mmol) was added. The mixture was stirred at 25°C for 4 hours. The reaction mixture was diluted with water (800 mL) and extracted with siRNA (800 mL x 3). The combined organic layer was concentrated, and the crude residue was purified by silica gel column chromatography (50% siRNA in petroleum ether) to obtain the title compound (29 g, 79%) as a bright yellow oily substance.

[0187] Step 3: 3-((1R,3R)-1-(4-bromo-2,6-difluorophenyl)-3-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-yl)-2,2-difluoropropan-1-ol A mixture containing (R)-3-((1-(1H-indole-3-yl)propan-2-yl)amino)-2,2-difluoropropan-1-ol (from step 2, 20 g, 4.54 mmol), acetic acid (12.91 mL, 223.63 mmol), and 4-bromo-2,6-difluorobenzaldehyde (16.47 g, 74.54 mmol) in toluene (400 mL) was stirred at 90°C for 12 hours. The reaction mixture was diluted with water (500 mL) and extracted with ethyl acetate (500 mL x 2). The combined organic layers were dried over anhydrous sodium 2 SO4, filtered, and concentrated. The crude residue was purified by silica gel column chromatography (20% phenylethylamine in petroleum ether) to obtain the title compound (24.8 g, 71%, trans / cis = 20 / 1) as a bright yellow oily substance. MS: [M+H] + 470.9.

[0188] Step 4: tert-butyl 3-((4-((1R,3R)-2-(2,2-difluoro-3-hydroxypropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl)-3,5-difluorophenyl)amino)azetidine-1-carboxylate JPEG2026067858000151.jpg36481,4-Dioxane (300 mL) contains 3-((1R,3R)-1-(4-bromo-2,6-difluorophenyl)-3-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-yl)-2,2-difluoropropan-1-ol (from step 3, 24.8 g, 52.62 mmol), Pd2(dba)3 (4.82 g, 5.26 mmol), xanthophos (6.09 g, 10.52 mmol), Cs2CO3 (51.44 g, 157.86 mmol), and tert-butyl A mixture containing 3-aminoazetidine-1-carboxylate (13.59 g, 78.93 mmol) was stirred at 110°C for 3 hours under an N2 atmosphere. The reaction mixture was cooled to 25°C, diluted with water (500 mL), and extracted with toluene (500 mL x 2). The combined organic layers were dried over anhydrous sodium ethanol (Na2SO4), filtered, and concentrated. The crude residue was purified by silica gel column chromatography (20% petroleum ether in toluene) to obtain the title compound (20.5 g, 69%, trans / cis = 20 / 1) as a yellow solid. MS: [M+H] + 563.0.

[0189] Step 5: 3-((1R,3R)-1-(4-(azetidine-3-ylamino)-2,6-difluorophenyl)-3-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-yl)-2,2-difluoropropane-1-ol JPEG2026067858000152.jpg3644tert-butyl 3-((4-((1R,3R)-2-(2,2-difluoro-3-hydroxypropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl)-3,5-difluorophenyl)amino)azetidine-1-carboxylate (from step 4, 20.5 g, 36.44 mmol) was dissolved in 1,4-dioxane (194 mL) and sulfuric acid (19.42 mL, 364.38 mmol) was added dropwise on an ice bath. The reaction mixture was stirred at 25°C for 0.5 hours. The reaction mixture was then poured into saturated NaHCO3 aqueous solution (800 mL) and extracted with ELISA (600 mL x 2). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated to obtain 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.

[0190] Step 6: A mixture containing 3-((1R,3R)-1-(4-(azetidine-3-ylamino)-2,6-difluorophenyl)-3-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-yl)-2,2-difluoropropan-1-ol (from Step 5, 18 g, 38.92 mmol), DIPEA (19.3 mL, 116.76 mmol), and 1-fluoro-3-iodopropane (7.32 g, 38.92 mmol) in DMF (180 mL) was stirred at 25°C for 12 hours. The reaction mixture was diluted with ELISA (500 mL) and washed with brine (500 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated. The crude residue was purified by silica gel column chromatography (10% MeOH in DCM) to obtain the target compound (7.1 g, purity 85%) as a yellow oily substance. The obtained residue was subjected to reverse-phase chromatography (in water, acetonitrile 40-75 / NH4OH 0.05%) and chiral SFC (AD 250 mm). * Further purification was performed using a 50mm, 10μm supercritical CO2 / EtOH (0.1% NH3H2O) solution (40 / 40 at 200 mL / min), yielding 340 (2.85 g, 14%) as a bright yellow solid.1 H NMR (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); MS: [M+H] + 523.2.

[0191] Example 365 3-((1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidine-3-yl)amino)phenyl)-6-fluoro-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indole-2-yl)-2,2-difluoropropan-1-ol 365 Step 1: ([3-(tert-butyl-diphenyl-silanyloxy)-2,2-difluoropropyl]-[2-(5-fluoro-1H-indole-3-yl)-1-methylethyl]amine A mixture containing [3-[tert-butyl(diphenyl)silyl]oxy-2,2-difluoropropyl]trifluoromethanesulfonate (from Example 286, Step 2, 43.22 g, 89.6 mmol), DIPEA (19.5 mL, 112.0 mmol), and 2-(5-fluoro-1H-indole-3-yl)-1-methylethylamine (CAS No.: 712-08-3, 14.7 g, 74.7 mmol) in 140 mL of dioxane was stirred at 90°C for 3 hours. The mixture was cooled to room temperature, diluted with siRNA, washed with water (x2) and brine, dried over anhydrous Na2SO4, filtered, and concentrated. The crude residue was purified by silica gel column chromatography (mobile phase: DCM) to obtain the title compound (32.8 g, 96%) as a yellow oil. 1H NMR (400 MHz, CDCl3):d 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).LCMS: 525.3 [M+H] + .

[0192] Step 2: 2-[3-(tert-butyl-diphenyl-silanyloxy)-2,2-difluoropropyl]-1-(2,6-difluoro-4-iodophenyl)-6-fluoro-3-methyl-2,3,4,9-tetrahydro-1H-beta-carboline [3-(tert-butyl-diphenyl-silanyloxy)-2,2-difluoropropyl]-[2-(5-fluoro-1H-indole-3-yl)-1-methyl-ethyl]amine (32.8 g, 62.5 mmol) was dissolved in toluene (65 mL) and 4-iodo-2,6-difluorobenzaldehyde (20.1 g, 75.0 mmol) and acetic acid (7.2 mL, 125.0 mmol) were added. After the addition was complete, the reaction mixture was stirred at 90°C for 14 hours. The mixture was cooled to room temperature, diluted with siRNA, washed with saturated NaHCO3 aqueous solution (×3) and brine, dried on anhydrous Na2SO4, and concentrated. The residue was purified by chromatography on silica (mobile phase: toluene in cyclohexane, gradient 10-50%) to obtain the title compound (34.9 g, 72%) as an off-white foam. 1 H NMR (400 MHz, CDCl3): 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), 1.14 (d, J = 6.6 Hz, 3H), 1.05 (s, 9H).LCMS: 775.2 [M+H] + .

[0193] Step 3: 3-(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-difluorophenylamino)-azetidine-1-carboxylic acid tert-butyl ester A mixture containing 1,4-dioxane (192 mL), 2-[3-(tert-butyl-diphenyl-silanyloxy)-2,2-difluoropropyl]-1-(2,6-difluoro-4-iodophenyl)-6-fluoro-3-methyl-2,3,4,9-tetrahydro-1H-beta-carbolin (30.8 g, 39.8 mmol), xanthophos (4.60 g, 7.9 mmol), Pd2(dba)3 (3.64 g, 4.0 mmol), Cs2CO3 (25.9 g, 79.4 mmol), and t-butyl 3-aminoazetidine-1-carboxylate (10.3 g, 59.6 mmol) was stirred under argon in a sealed container at 115°C for 1.5 hours. The reaction mixture was cooled to room temperature, filtered through a Cerite® pad to remove residual solids, and the filtrate was concentrated. The resulting residue was purified by flash chromatography on silica gel (mobile phase: siRNA in DCM, gradient 0-5%) to obtain the title compound (27.9 g, 76%) as a beige foam. 1 H NMR (400 MHz, CDCl3): 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), 4.26 - 4.09 (m, 2H), 4.03 - 3.91 (m, 2H), 3.69 - 3.50 (m, 3H), 3.26 - 3.14 (m, 1H), 2.95 - 2.90 (m, 1H), 2.83 - 2.70 (m, 1H), 2.50 (dd, J = 3.3, 15.1 Hz, 1H), 1.44 (s, 9H), 1.13 (d, J = 6.5 Hz, 3H), 1.04 (s, 9H).LCMS: 819.4 [M+H] + .

[0194] Step 4: Azethidine-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-difluorophenyl)amine A pre-mixed concentrated sulfuric acid (9.1 mL, 170.2 mmol) ice-cold solution of dioxane (100 mL) was slowly added to a solution of 3-(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-difluorophenylamino)-azetidine-1-carboxylic acid tert-butyl ester (27.9 g, 34.0 mmol) in dioxane (275 mL) under nitrogen at room temperature. After the addition was complete, the reaction mixture was left at room temperature for 1 hour. ELISA and water were added, and the pH of the aqueous phase was adjusted to 9 by adding solid Na2CO3. The organic layer was separated, washed with brine (x3), dried over Na2SO4, filtered, concentrated under vacuum, and the title compound (a mixture of (R,R) and (S,S) diastereomers) was obtained as a pale orange foam (26.6 g, ~ (Quantitative) obtained. LCMS: 719.4 [M+H] + .

[0195] Step 5: (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-difluorophenyl)-[1-(3-fluoropropyl)-azetidine-3-yl]amine Following the procedure outlined for the preparation of Example 101, the title compound was prepared from azetidine-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-difluorophenyl)-amine (26.6 g, 34.0 mmol) and 1-iodo-3-fluoropropane (9.60 g, 51.1 mmol; CAS number: 462-40-8). The crude product was purified by silica gel chromatography (mobile phase: dichloromethane / methanol, gradient 0% to 5%) to obtain the title compound as a light brown foam (14.9 g, 56%). 1 H NMR (400 MHz, CDCl3): 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).LCMS: 779.4 [M+H] + .

[0196] Step 6: 3-(1-{2,6-difluoro-4-[1-(3-fluoro-propyl)-azetidine-3-ylamino]-phenyl}-6-fluoro-3-methyl-1,3,4,9-tetrahydro-beta-carbolin-2-yl)-2,2-difluoro-propane-1-ol Under argon, a mixture containing (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-difluorophenyl)-[1-(3-fluoropropyl)-azetidine-3-yl]amine (12.1 g, 15.5 mmol) in THF (150 mL) was added, and the reaction mixture was stirred at room temperature for 5 hours. The reaction mixture was diluted with ELISA and washed with water (x4). The organic layer was dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by silica gel chromatography (mobile phase: 2M ammonia in methanol / TBME, gradient 0.5% to 5%) to obtain a mixture of (R,R) and (S,S)3-(1-{2,6-difluoro-4-[1-(3-fluoro-propyl)-azetidine-3-ylamino]-phenyl}-6-fluoro-3-methyl-1,3,4,9-tetrahydro-beta-carbolin-2-yl)-2,2-difluoro-propan-1-ol). The diastereomer pair was separated by chiral HPLC (ChiralPak IB, 15% EtOH + 0.1% diethylamine in heptane). Peak 365 was the second peak isolated by chiral HPLC (1.90 g, 23%). Peak 2 rt=15 min 1H NMR (400 MHz, CDCl3): δ7.46 (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).LCMS: 541.4 [M+H] + .

[0197] Example 366 3-((1S,3S)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidine-3-yl)amino)phenyl)-6-fluoro-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indole-2-yl)-2,2-difluoropropan-1-ol 366 Following the procedure of Example 365, the first peak isolated by chiral HPLC was 366: (1.95 g, 24%). Peak 1 rt=12 min 1H NMR (400 MHz, CDCl3): δ7.46 (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).LCMS: 541.4 [M+H] + .

[0198] Example 368 3-((1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidine-3-yl)oxyphenyl)-6-fluoro-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indole-2-yl)-2-fluoro-2-methylpropan-1-ol 368 Step 1: [3-(tert-butyl-diphenyl-silanyloxy)-2-fluoro-2-methyl-propyl]-[2-(5-fluoro-1H-indole-3-yl)-1-methyl-ethyl]amine [3-(tert-butyl-diphenyl-silanyloxy)-2-fluoro-2-methyl-propyl]-[2-(5-fluoro-1H-indole-3-yl)-1-methyl-ethyl]amine Under argon, 2-(5-fluoro-1H-indole-3-yl)-1-methylethylamine (CAS No.: 712-08-3, 3.61 g, 18.7 mmol) and DIPEA (4.9 mL, 28.1 mmol) were dissolved in dioxane (43 mL), to which 3-(tert-butyl-diphenyl-silanyloxy)-2-fluoro-2-methyl-propyl trifluoromethanesulfonic acid, intermediate XX (3.09 g, 9.48 mmol) was added. The resulting mixture was stirred at 90°C for 6 hours. The reaction mixture was partitioned into siRNA and water. The organic phase was separated, washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by silica gel chromatography (mobile phase: dichloromethane / methanol, gradient 0% to 5%) to obtain a mixture of diastereomers of the title compound as a yellow oil (8.0 g, 82%). 1 H NMR (300 MHz, CDCl3): d 7.82 (br. 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 LCMS: 521.3 [M+H] + .

[0199] Step 2: 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-difluorophenoxy)-azetidine-1-carboxylic acid tert-butyl ester The title compound was prepared from [3-(tert-butyl-diphenyl-silanyloxy)-2-fluoro-2-methyl-propyl]-[2-(5-fluoro-1H-indole-3-yl)-1-methyl-ethyl]amine, intermediate 1a (8 g, 15.3 mmol), and 3-(3,5-difluoro-4-formyl-phenoxy)-azetidine-1-carboxylic acid tert-butyl ester 101c (5.6 g, 18.1 mmol). The crude product was purified by silica gel chromatography (mobile phase: cyclohexane / ethyl acetate, gradient 0% to 20%) to obtain a mixture of diastereomers of the title compound as a white foam (8.0 g, 64%). 1 H NMR (300 MHz, CDCl3): d7.65 - 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); LCMS: 816.5 [M+H] + .

[0200] Step 3: 1-[4-(azetidine-3-yloxy)-2,6-difluorophenyl]-2-[3-(tert-butyl-diphenyl-silanyloxy)-2-fluoro-2-methyl-propyl]-6-fluoro-3-methyl-2,3,4,9-tetrahydro-1H-beta-carboline Under argon at 0°C, a mixture containing 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-difluorophenoxy)-azetidine-1-carboxylic acid tert-butyl ester and intermediate 2a (8.0 g, 9.80 mmol) in dioxane (80 mL) was added dropwise to a solution of dioxane (27 mL) in concentrated sulfuric acid (2.62 mL, 49.0 mmol). The mixture, protected from light, was warmed to room temperature and stirred for 3.5 hours. The reaction mixture was diluted with siRNA and saturated NaHCO3, stirred for 10 minutes, and the layers were separated. The organic layer was further washed with saturated NaHCO3 and brine, dried over Na2SO4, filtered, and concentrated under vacuum to obtain a pale yellow foam (7.05 g, ~ It was obtained as a quantitative result. 1 1H NMR (300 MHz, CDCl3): 1 H NMR (300 MHz, CDCl3): d 7.66 - 7.54 (m, 4H), 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); LCMS: 716.4 [M+H] + .

[0201] Step 4: 2-[3-(tert-butyl-diphenyl-silanyloxy)-2-fluoro-2-methyl-propyl]-1-{2,6-difluoro-4-[1-(3-fluoro-propyl)-azetidine-3-yloxy]-phenyl}-6-fluoro-3-methyl-2,3,4,9-tetrahydro-1H-beta-carboline The title compound was prepared from 1-[4-(azetidine-3-yloxy)-2,6-difluorophenyl]-2-[3-(tert-butyl-diphenyl-silanyloxy)-2-fluoro-2-methyl-propyl]-6-fluoro-3-methyl-2,3,4,9-tetrahydro-1H-beta-carbolin, intermediate 3a (7.05 g, 9.84 mmol), and 1-iodo-3-fluoropropane (2.77 g, 14.7 mmol; CAS number: 462-40-8) according to the procedure outlined for the preparation of Example 101. The crude product was purified by silica gel chromatography (mobile phase: dichloromethane / methanol, gradient 0% to 3%) to obtain the title compound as a white foam (5.7 g, 75%). LCMS: 776.4 [M+H] + .

[0202] Step 5: Racemic 3-(1-{2,6-difluoro-4-[1-(3-fluoro-propyl)-azetidine-3-yloxy]-phenyl}-6-fluoro-3-methyl-1,3,4,9-tetrahydro-beta-carbolin-2-yl)-2-fluoro-2-methyl-propane-1-ol Under argon, a mixture containing 2-[3-(tert-butyl-diphenyl-silanyloxy)-2-fluoro-2-methyl-propyl]-1-{2,6-difluoro-4-[1-(3-fluoro-propyl)-azetidine-3-yloxy]-phenyl}-6-fluoro-3-methyl-2,3,4,9-tetrahydro-1H-beta-carboline intermediate 4a (5.17 g, 6.66 mmol) in THF (80 mL) was added, and the reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was poured into a mixture of water and brine and extracted with ethyl acetate. The aqueous layer was further extracted with ethyl acetate, and the combined organic layers were further washed with water and brine, dried over Na2SO4, filtered, and dried under vacuum. The crude product was purified by silica gel chromatography (mobile phase: dichloromethane / methanol, gradient 0% to 6%) to obtain two pairs of diastereomers (diastereomer pair 1 and diastereomer pair 2). The pair of diastereomer pair 1 was further purified by chiral HPLC (ChiralPak IC, 25% IPA in heptane and 0.1% diethylamine). The first isolated peak (rt=8.2 min) = 368 was isolated as a white solid (467 mg, 13%). 1 H NMR (400 MHz, CDCl3): 7.32 (br 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, LCMS: 538.3 [M+H] + .

[0203] Example 369 3-((1S,3S)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidine-3-yl)oxy)phenyl)-6-fluoro-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indole-2-yl)-2-fluoro-2-methylpropan-1-ol 369 Following the procedure of Example 368, the second peak, 369, isolated by chiral HPLC (rt=15.5 min), was isolated as a white solid (480 mg, 13.5%).

[0204] Example 370 3-((1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidine-3-yl)oxy)phenyl)-6-fluoro-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indole-2-yl)-2-fluoro-2-methylpropan-1-ol 370 Following the procedure of Example 368, pairs of diastereomers were purified by chiral HPLC (ChiralPak IC, 35% IPA in heptane, 0.1% diethylamine). The first isolated peak was further purified by chiral HPLC (ChiralPak IA, 35% IPA in heptane, 0.1% diethylamine). The first isolated peak (rt=8.5 min) = 370 was isolated as a white solid (165 mg, 5%). 1H NMR (400 MHz, CDCl3): 7.53 (br. 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), 3.85 - 3.54 (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); LCMS: 538.3 [M+H] + .

[0205] Example 371 3-((1S,3S)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidine-3-yl)oxy)phenyl)-6-fluoro-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indole-2-yl)-2-fluoro-2-methylpropan-1-ol 371 Following the procedure of Example 368, two pairs of diastereomers were purified by chiral HPLC (ChiralPak IC, 35% IPA in heptane and 0.1% diethylamine). The isolated second peak (rt=14 min) = 371 was isolated as a white solid (180 mg, 5%).

[0206] Further exemplary compounds of formula I shown in Table 2a have the following structures, corresponding names (CambridgeSoft Corp., ChemBioDraw version 12.0.2, Cambridge, Massachusetts), and biological activity. Where multiple names are associated with a formula I compound or intermediate, the chemical structure shall define the compound. TIFF2026067858000164.tif234170

[0207] Example 431 (R)-3-((1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidine-3-yl)amino)phenyl)-6-fluoro-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indole-2-yl)-2-fluoro-2-methylpropan-1-ol 431 Step 1: 3-((tert-butyldiphenylsilyl)oxy)-2-fluoro-N-(1-(5-fluoro-1H-indole-3-yl)propan-2-yl)-2-methylpropan-1-amine JPEG2026067858000165.jpg3053 In Example 154, following Step 5, a solution of 1-(5-fluoro-1H-indole-3-yl)propan-2-amine (5.30 g, 26.2 mmol, 95%, prepared according to Yeung, et al, J. Med. Chem. 2010, 53, 5155-5164) cooled in an ice bath was mixed with 1,4-dioxane (105 mL) solution of N,N-diisopropylethylamine (6.85 mL), followed by a solution of [3-[tert-butyl(diphenyl)silyl]oxy-2-fluoro-2-methyl-propyl]trifluoromethanesulfonate (13.80 g, 28.8 mmol) in dioxane (10 mL). The mixture was heated (in a bath) at 90°C for 18 hours. The mixture was concentrated. Dilute Na2CO3 was added. The contents were extracted by DCM (2x). The combined extracts were dried with (Na2SO4) and concentrated. The crude product was purified by flash chromatography (containing 1% TEA, 0-50% iPrOAc / heptane) to obtain the product (10.38 g, 76%).

[0208] Steps 2-5: N-(4-(2-(3-((tert-butyldiphenylsilyl)oxy)-2-fluoro-2-methylpropyl)-6-fluoro-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl)-3,5-difluorophenyl)-1-(3-fluoropropyl)azetidine-3-amine The compound was prepared in the same manner as in Example 145. (JPEG2026067858000166.jpg4257)

[0209] Step 6: Racemic 3-(1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidine-3-yl)amino)phenyl)-6-fluoro-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indole-2-yl)-2-fluoro-2-methylpropane-1-ol JPEG2026067858000167.jpg2855N-[4-[(1R,3R)-2-[3-[tert-butyl(diphenyl)silyl]oxy-2-fluoro-2-methyl-propyl]-6-fluoro-3-methyl-1,3,4,9-tetrahydropyrido[3,4-b]indole-1-yl]-3,5-difluorophenyl]-1-(3-fluoropropyl)azetidine-3-amine (2.231 g, 2.879 mmol) in THF (14.4 mL) was mixed with a solution of TBAF in THF (1.0 M, 4.6 mL). The mixture was heated at 50°C for 24 hours. The mixture was concentrated. Diluted with iPrOAc, the contents were washed with dilute Na2CO3 (2x) and brine, dried, and concentrated in (Na2SO4). The composition was purified by flash chromatography (0-60% B / A, A: DCM B: 20% NH3 in MeOH). The recovered product was subjected to chiral separation. The stereochemistry assigned to compounds 431-434 in Table 2 is unknown and arbitrary. Step 1: Isolation of enantiomers 1 and 4. Enantiomers 2 and 3 remained in the mixture. 0.1% NH4OH in 32.5% isocratic isopropanol, Chiralpak AD (250x30.0, 5μm), 150g / min, UV-254nm, BPR 100bar, temperature 40°C, cycle time 5 minutes, total time 200 minutes. Step 2: Separation of enantiomers 2 and 3. 0.1% NH4OH in 30% isocratic methanol, Chiralpak OX (150x30.0, 5μm), 150g / min, UV-250nm, BPR 100bar, temperature 40°C, cycle time 3 minutes, total time 48 minutes. Compounds 431-434 were characterized as follows: Enantiomer 1: 324.8 mg. 1H NMR (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, 0H), 3.99 - 3.87 (m, 1H), 3.82 - 3.72 (m, 0H), 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).LCMS: 537.3 [M+H] + .エナンチオマー2: 251.7 mg. 1 H NMR (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).LCMS: 537.3 [M+H] + .エナンチオマー3: 105.5 mg. 1H NMR (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).LCMS: 537.3 [M+H] + .エナンチオマー4: 151.1 mg. 1 H NMR (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).LCMS: 537.3 [M+H] + .

[0210] Example 432 (S)-3-((1S,3S)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidine-3-yl)amino)phenyl)-6-fluoro-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indole-2-yl)-2-fluoro-2-methylpropan-1-ol 432 Enantiomer 432 was isolated according to the procedure of Example 431.

[0211] Example 433 (S)-3-((1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidine-3-yl)amino)phenyl)-6-fluoro-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indole-2-yl)-2-fluoro-2-methylpropan-1-ol 433 Enantiomer 433 was isolated according to the procedure of Example 431.

[0212] Example 434 (R)-3-((1R,3S)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidine-3-yl)amino)phenyl)-6-fluoro-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indole-2-yl)-2-fluoro-2-methylpropan-1-ol 434 Enantiomer 434 was isolated according to the procedure of Example 431.

[0213] Example 901: Fluorescence imaging degradation assay of breast cancer cells with high ERa content On day 1, MCF7 breast cancer cells were seeded at a density of 10,000 cells per well in 50 μL / well of L-glutamine-containing, 10% FBS (charcoal strip) RPMI (phenol red-free) in a 384-well poly-lysine-coated tissue culture plate (Greiner #T-3101-4). On day 2, 10 μL / well of two compound sources at concentrations of 100 μM and 1 μM (ultimately yielding two overlapping titration curves) were added to Labcyte low-dead-volume plates, along with 10 μL of DMSO in a designated well for backfill and 5 μM fulvestrant (control compound) in a designated well. The compounds and controls were dispensed using a Labcyte echo acoustic dispenser, and the compounds were dispensed in predetermined serial dilutions (1.8x, 10 points, 2-row) along with appropriate backfill and control compounds (final total volume transferred was 417.5 nL, compound dispensing volume from 2.5 nL to 417.5 nL; final 0.84% ​​DMSO (v / v)), resulting in a final concentration range of 0.05 nM to 835 nM. The cell plates were incubated at 37°C for 4 hours. Immobilization and permeabilization were performed using a Biotek EL406 plate washer and dispenser as follows. Cells were fixed by adding 15 μL of 16% paraformaldehyde (Electron Microscopy Sciences #15710-S) directly to 50 μL of cell culture medium in each well using a Biotek EL406 plate washer and dispenser (final formaldehyde concentration was 3.7% w / v). The samples were incubated for 30 minutes. The well contents were aspirated, and 50 μL / well of phosphate-buffered saline (PBS) containing 0.5% w / v bovine serum albumin (albumen) and 0.5% v / v Triton X-100 (Antibody Dilution Buffer) was added to each well. The samples were incubated for 30 minutes. The well contents were aspirated, and the plates were washed three times with 100 μL / well of PBS. Immunostaining for estrogen receptor alpha (ESR1) was performed using a Biotek EL406 plate washer and dispenser as follows.The supernatant was aspirated from the wells, and 25 μL / well of anti-ESR1 mAb (F10) (Santa Cruz sc-8002), diluted 1:1000 in Antibody Dilution Buffer, was dispensed. The samples were incubated at room temperature for 2 hours. The samples were washed four times with 100 μL / well PBS. Secondary antibody solutions (Alexafluor 488 conjugate anti-mouse IgG (LifeTechnologies#A21202), diluted 1:1000, and Hoechst 33342 1 μg / ml, diluted in Antibody Dilution Buffer) were dispensed into each well at a rate of 25 μL / well. The samples were incubated at room temperature for 2 hours. The samples were washed three times with 100 μL / well PBS using Biotek EL406. Quantitative fluorescence imaging of ESR1 was performed using Cellomics Arrayscan V (Thermo). Fluorescence images of the samples (Channel 1: XF53 Hoechst (DNA staining); Channel 2: XF53 FITC (ESR1 staining)) were acquired using Cellomics VTI Arrayscan with Bioapplication "Compartmental Analysis," which uses automated exposure (based on DMSO control wells) with the "peak target percentile" set to a 25% target saturation for both channels. The nuclear region (Circ) was defined using Channel 1 (DNA staining). The Alexafluor 488 fluorescence intensity (ESR1), "Mean_CircAvgIntCh2," within the nuclear region was measured for each cell, and the average of all measured cells was taken. Data analysis was performed using Genedata Screener Software with DMSO and 5nM fulvestrant-treated samples used to determine 0% and 100% ESR1 changes. The inflection point (EC50) and the plateau of maximum effect (Sinf) of the curve were defined using the "robust fit" method. Decomposition data for the exemplary compound of formula I is shown in Table 1, ER alpha MCF7 HCS S. inf It is reported as a percentage value (%).

[0214] Example 902: In Vitro Cell Proliferation Assay The efficacy of estrogen receptor modulator compounds and chemotherapeutic compounds is measured by a cell proliferation assay using the following protocol (Mendoza et al (2002) Cancer Res. 62:5485-5488). The CellTiter-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 present, which signals the presence of metabolically active cells. The CellTiter-Glo® Assay is designed for use in multi-well plate formats and is ideal for automated high-throughput screening (HTS), cell proliferation, and cytotoxicity assays. The homogeneous assay procedure requires the direct addition of a single reagent (CellTiter-Glo® Reagent) to cells cultured in serum-supplemented medium. Cell washing, medium removal, or multiple pipetting steps are not required. The CellTiter-Glo® Luminescent Cell Viability Assay, including reagents and protocol, is commercially available (Technical Bulletin TB288, Promega Corp., Madison, Wisconsin). The assay evaluates the ability of a compound to enter cells and inhibit cell proliferation. The principle of the assay is based on determining the number of viable cells present by quantifying the amount of ATP present in a homogeneous assay in which the addition of Cell Titer-Glo® reagent induces cell lysis and generates a luminescence signal via a luciferase reaction. The luminescence signal is proportional to the amount of ATP present. Procedure: Day 1 - Seed cells into a Cell Plate (Falcon #353962 384-well black, clear bottom, Microclear, lidded TC plate), collect cells, and seed cells at 1000 cells / 54 μl / well in a 384-well Cell Plate over 3 days for the assay. Cell medium: RPMI or DMEM high glucose, 10% fetal bovine serum, 2 mM L-glutamine, P / S. Incubate O / N (overnight) at 37°C, 5% CO2. Day 2 - Add the drug to the cells, compound diluent, and DMSO Plate (9-point 1:2 serial dilution). Add 20 μl of the compound at 10 mM to the second column of the 96-well plate. Using a Nunc Precision Media Plate 96-well cone-bottom polypropylene plate (catalog no. 249946), perform a total of 9-point 1:2 serial dilutions (1:50 dilution) across the entire plate (10 μl + 20 μl 100% DMSO). Add 147 μl of medium to all wells. Using Rapidplate® (manufactured by Caliper, a subsidiary of Perkin-Elmer Co.), transfer 3 μl of the DMSO+ compound from each well of the Media Plate to the corresponding well of the Media Plate. To test the combination of two drugs, transfer 1.5 μl of one drug, which is the DMSO+ compound, from each well of the DMSO Plate to the corresponding well of the Media Plate using Rapidplate. Next, transfer 1.5 μl of the other drug to the culture plate. Adding the drug to cells and cell plates (1:10 dilution): Add 6 μl of medium + compound directly to the cells (54 μl of medium already on the cells). Incubate for 3 days at 37°C with 5% CO2 in an incubator that will not be opened frequently. Day 5 - Develop the plate and thaw the Cell Titer Glo Buffer at room temperature: Remove the cell plate from 37°C and allow it to equilibrate at room temperature for approximately 30 minutes. Add Cell Titer-Glo® Buffer to Cell Titer-Glo® Substrate (from bottle to bottle). Add 30 μl of Cell Titer-Glo® Reagent (Promega catalog number G7572) to each cell well. Place on a plate shaker for approximately 30 minutes. Read the luminescence with an Analyst HT Plate Reader (0.5 seconds per well). Cell viability assay and combination assay: 1000–2000 cells per well were seeded in a 384-well plate over 16 hours. On day 2, the compound was subjected to nine 1:2 serial dilutions with DMSO in a 96-well plate. The compound was further diluted in growth medium using a Rapidplate® robot (Zymark Corp., Hopkinton, Massachusetts). The diluted compound was then added to four wells of a 384-well cell plate and incubated at 37°C and 5% CO2. After 4 days, the relative number of viable cells was measured by luminescence using Cell Titer-Glo® (Promega) according to the manufacturer's instructions and read with a Wallac Multilabel Reader® (PerkinElmer, Foster City). EC50 values ​​were calculated using Prism® 4.0 software (GraphPad, San Diego). In the combination assay, the drug was subjected to 4XEC 50 Drug administration was initiated at a specified concentration. If the drug's EC50 was >2.5 μM, the maximum concentration used was 10 μM. In all assays, the estrogen receptor preparation compound and the chemotherapeutic agent were added simultaneously or with a 4-hour interval (one before the other). Further exemplary in vitro cell proliferation assays include the following steps: 1. Approximately 10 4Aliquots of 100 μl of cell culture containing individual cells (see Table 3 for cell line and tumor type) were placed in each well of a 384-well opaque-walled plate. 2. A control well containing culture medium but without cells was prepared. 3. The compound was added to the experimental wells and incubated for 3-5 days. 4. The plate was allowed to equilibrate at room temperature for approximately 30 minutes. 5. CellTiter-Glo® Reagent was added to each well in a volume equal to the volume of cell culture medium present. 6. The contents were mixed in an orbital shaker for 2 minutes to induce cell lysis. 7. The plates were incubated at room temperature for 10 minutes to stabilize the luminescence signal. 8. Light emission was recorded, and a graph was drawn using RLU (Relative Luminous Unit). 9. To obtain the combination index, we performed an analysis using the Chou and Talalay combination method and dose-effect analysis with CalcuSyn® software (Biosoft, Cambridge, UK). Alternatively, cells were seeded at optimal density in 96-well plates and incubated for 4 days in the presence of the test compound. Subsequently, Alamar Blue... TM The reagent was added to the assay medium, and the cells were incubated for 6 hours, after which readings were taken using 544 nm excitation and 590 nm emission. Using sigmoid dose-response curve fitting, the EC was measured. 50 The value was calculated. Alternatively, growth / survival rates were analyzed 48 hours after drug treatment using Cell Titer-Glo® reagent (Promega Inc., Madison, Wisconsin). DMSO treatment was used as a control in all survival assays. IC was analyzed using XL Fit software (IDBS, Alameda, California). 50 The value was calculated. Cell lines were obtained from ATCC (American Type Culture Collection, Manassas, Virginia) or DSMZ (Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH, Braunschweig, Germany). Cells were cultured at 37°C under 5% CO2 in RPMI 1640 medium (Life Technology, Grand Island, New York) supplemented with 10% fetal bovine serum, 100 units / ml penicillin, 2 mM L-glutamine, and 100 mg / ml streptomycin.

[0215] Example 903: MCF7 in vitro cell proliferation assay MCF7 cells were washed with PBS and plated at 25,000 cells / ml and 40 μl / well in RPMI 1640 (Gibco 11835-030 [-phenol + glutamine]) and 10% charcoal strip FBS (Gibco 12676-029) in polylysine-coated 384-well tissue culture plates (Greiner), and incubated overnight. Compounds were prepared by serial dilution in DMSO 500-fold to the final target concentration using Biomek-FX, and then diluted 50-fold in RPMI 1640. The control compound fulvestrant and the negative control dimethyl sulfoxide were prepared in the same manner. Individual compound concentrations and 5 μl of each control compound were transferred to cell plates. Fulvestrant was added to the control wells at a final concentration of 100 nM. DMSO was added to the negative control wells (0.2% v / v). Five microliters (5 μl) of phenol red-free RPMI 1640 (Gibco 11835-030) containing 1 nM estradiol was added to each well of a cell plate (excluding the control well without estradiol). After incubating the cells for 72 hours, they were lysed with 40 μl / well of Cell TiterGlo reagent (Promega #G7572), and luminescence was measured using an Envision (Perkin Elmer) plate reader. Data were analyzed using Geneda Screener software, which defines 0% and 100% inhibition using samples treated with DMSO and fulvestrant, and EC50 values ​​were calculated using robust curve fitting.

[0216] Example 904 ERa Co-activator Peptide Antagonist Assay The test compounds were prepared in 1 mM DMSO and serially diluted in a 384-well transparent V-bottom polypropylene plate (Greiner catalog no. 781280) using Biomek FX at 12 points, with dose settings ranging from 1 to 3 times. Three intermediate dilutions of the compound were prepared by mixing 1 mL of each serial dilution with 32.3 mL of TR-FRET Coregulator Buffer E (Life Technologies PV4540). Two mL of each intermediate dilution was transferred to a 1536-well plate (Aurora Biotechnologies MaKO 1536 Black Plate, #00028905) using Biomek FX. Using a Bioraptr Dispenser® (Beckman Coulter), 2 mL of "3xERa solution" per well was dispensed, i.e., TR-FRET Coregulator Buffer E containing 7.5 mM dithiothreitol (DTT) and 22 nM ERa (human estrogen receptor alpha, GST-tagged ESR1 ligand-binding domain, residues spanning S282-V595, wild-type sequence or Y537S or D538G mutation); and 2 mL of 3x assay mixture (750 nM fluorescein-PGC1a peptide sequence; Life Technologies PV4421), 12 nM estradiol, and 15 nM anti-GST Tb-labeled antibody in TR-FRET Coregulator Buffer E (containing 7.5 mM DTT). The "receptor-free" control well contained a buffer that did not contain GST-ERa protein. The plate was centrifuged in a V-spin centrifuge at 1800 rpm for 20 seconds, then covered and incubated at room temperature for 2 hours.Measurements were performed using a Perkin Elmer EnVision Fluorescence Reader with TR-FRET settings (Top mirror: Perkin Elmer Lance / DELFIA Dual emission (PE#2100-4160); Excitation filter: Perkin Elmer UV (TFR) 340nm (PE#2100-5010); Emission filter: Chroma 495nm / 10nm and 520nm / 25nm (Chroma#PV003 filter for LanthaScreen, 25mm diameter for EnVision); Excitation light: 100%; Delay: 100μs; Window time: 200; Number of sequential windows: 1; Flash interval: 2000μs; Number of flashes: 100; Number of flashes (second detector): 100). Inhibition rates were calculated by comparing with a control without compound (DMSO only) and a "control without ERα". Curve fitting and IC were performed. 50 The calculations were performed using Genedata Screener software.

[0217] Example 905: Efficacy of xenograft in vivo mouse tumors Mice: Severely combined immunodeficient female mice (Fox Chase SCID®, CB-17 / IcrHsd, Harlan) or nude mice (Taconic Farms, Harlan) were 8 to 9 weeks old, and the body weight (BW) ranged from 15.1 to 21.4 grams on day 0 of the study. The animals were given ad libitum water (reverse osmosis, 1 ppm Cl) and NIH 31 Modified and Irradiated Lab Diet® consisting of 18.0% crude protein, 5.0% crude fat, and 5.0% crude fiber. The mice were housed in a static pressure micro-isolator on irradiated ALPHA-Dri® bed-o'cobs® laboratory animal bedding at 21-22°C (70-72°F) and 40-60% humidity for a 12-hour photocycle. The PRC strictly adheres to the recommendations of the Guide for Care and Use of Laboratory Animals regarding restraint, rearing, surgical procedures, feed and water control, and veterinary care. The PRC's animal care and use program is accredited by the Association for Accreditation of Laboratory Animal Care International (AALAC International), ensuring compliance with recognized standards for the care and use of laboratory animals. Tumor transplantation: Xenografting is initiated with cancer cells. Cells are cultured in RPMI 1640 medium supplemented with 0% fetal bovine serum, 2 mM glutamine, 100 units / mL penicillin, 100 μg / mL streptomycin sulfate, and 25 μg / mL gentamicin. Cells are harvested during exponential growth and divided into 5x10⁶ cells according to the doubling time of the cell line. 6 or 10x10 6 The tumor cells are resuspended in phosphate-buffered saline (PBS) at a concentration of cells / mL. The tumor cells are transplanted subcutaneously into the right flank, with an average size of 100 to 150 mm. 3 Tumor growth is monitored as it approaches the target range. The day of tumor transplantation is considered day 0 of the experiment, and 21 days later, the individual tumor volumes are measured at 75-172 mm². 3 The study consisted of 10 mice within the specified range, with a group-average tumor volume of 120-121 mm². 3 The mice are divided into four groups (see Appendix A). The volume is calculated using the following formula: Tumor volume (mm 3 )=(w 2 x(l) / 2 [where w = tumor width (mm), l = tumor length (mm)]. Tumor weight is calculated as 1 mg = 1 mm of tumor volume. 3 It can be estimated by assuming that it corresponds to [this]. Therapeutic agents: Estrogen receptor modulator compounds and chemotherapeutic agents are typically prepared from dry powder, stored at room temperature, and protected from light. Drug doses are prepared weekly in a deionized aqueous solution of 0.5% methylcellulose:0.2% Tween 80 ("Vehicle") and stored at 4°C. Vehicle(+) is a solvent / buffer containing 0.1 mg / kg of ethinylestradiol (ethinylestradiol, EE2). Vehicle(-) is a solvent / buffer that does not contain ethinylestradiol. Doses of the compound are prepared each day of administration by diluting aliquots of the stock with sterile saline (0.9% NaCl). All doses are prescribed to deliver the indicated mg / kg dose in volumes of 0.2 mL per 20 g of body weight (10 mL / kg). Treatment: All dosages are adjusted to the individual animal's body weight and administered via the prescribed route. Endpoint: Tumor volume was measured in two dimensions (length and width) using an Ultra Cal IV caliper (Model 54 10 111; Fred V. Fowler Company), as follows: Tumor volume (mm 3 ) = (length x width) 2The ratio is )x0.5, and the analysis is performed using Excel version 11.2 (Microsoft Corporation). Repeated measurements of tumor volume over time from the same animals are analyzed using a linear mixed-effects (LME) modeling technique. This technique addresses both repeated measurements and small dropouts due to non-treatment-related deaths of animals before the end of the study. A cubic regression spline is used to fit a nonlinear profile to the time course of log2 tumor volume at each dose level. These nonlinear profiles then explain the relationship with dose within the mixed model. Tumor growth inhibition (TGI%) as a percentage of vehicle control is given by the formula: TGI% = 100 × (1 - AUC 用量 / AUC ビヒクル The TGI was calculated as the percentage of the area under the approximate curve (AUC) per day for each dose group relative to the vehicle, using the formula ). Using this formula, a TGI of 100% indicates tumor quiescence, a TGI of more than 1% but less than 100% indicates delayed tumor growth, and a TGI of more than 100% indicates tumor reduction. Partial remission (PR) in animals was defined as a tumor reduction of more than 50% but less than 100% of the baseline tumor volume. Complete remission (CR) was defined as 100% tumor reduction (i.e., no measurable tumor) on any day during the study. Toxicity: Animal weight will be measured daily for the first five days of the study, and twice a week thereafter. Animal weight will be measured using the Adventurer Pro® AV812 scale (Ohaus Corporation). The percentage change in body weight will be calculated as follows: Percentage change in body weight (%) = [(New body weight - Initial body weight) / Initial body weight] × 100. Mice will be frequently observed for obvious signs of adverse side effects related to the treatment, and clinical signs of toxicity will be recorded if observed. Acceptable toxicity is defined as a decrease of less than 20% of the mean body weight (BW) of the group during the study, and no more than one treatment-related (TR) death in 10 treated animals. Any drug regimen that results in higher toxicity is considered to exceed the maximum tolerated dose (MTD). Deaths will be classified as TR if they are due to adverse side effects as evidenced by clinical signs and / or autopsy, or if the cause of death is unknown during the treatment period or within 10 days of the last dose. If there is no evidence that the death was related to adverse side effects, the death will be classified as NTR. In-vivo xenograft breast cancer model (MCF-7; tamoxifen sensitive): A sustained-release pellet containing 0.72 mg of 17-β-estradiol was subcutaneously transplanted into nu / nu mice. MCF-7 cells were grown in RPMI containing 10% FBS at 5% CO2 and 37°C. Trypsin-treated cells were pelletized and incubated in 50% RPMI (serum-free) and 50% Matrigel at 1x10⁻¹⁶ doses. 7 Resuspend cells / mL. Two to three days after pellet transplantation, subcutaneously inject MCF-7 cells into the right flank (100 μL / animal). Tumor volume (length x width) 2 Monitor the tumor every other week (bi-weekly). ~ 200mm 3 Once the average volume is reached, animals will be randomized and treatment will be initiated. Animals will be treated with the vehicle or compound daily for 4 weeks. Tumor volume and body weight will be monitored every other week throughout the study period. In-vivo xenograft breast cancer model (tamoxifen resistance model 1): Carries MCF-7 tumors (average tumor volume 200 mm²) 3)nu / nu female mice (17-β estradiol pellet; 0.72 mg; supplemented with 60-day slow-release formula) are treated with tamoxifen (citrate) via oral enteral nutrition. Tumor volume (length x width) 2 / 2) and body weight are monitored twice a week. After a significant antitumor response with no change in tumor volume, obvious tumor growth is first observed after approximately 100 days of treatment. After 120 days of treatment, the dose of tamoxifen is increased. Rapidly growing tumors are considered tamoxifen resistant and are selected for in vivo passage into new host animals. Tumor fragments derived from tamoxifen-resistant tumors ( ~ 100mm 3 The / animal) is subcutaneously transplanted into the right flank of female nu / nu mice (17-β estradiol pellet (0.72 mg; supplemented with 60-day slow-release)). The passaged tumor is maintained under a specific tamoxifen selection, and the tumor volume (length x width) is measured. 2 Monitor / 2) weekly. Tumor volume ~ 150-250mm 3 Once the target is reached, the animals are treated (average tumor volume 200 mm). 3 Randomize the animals and discontinue tamoxifen treatment. Treat the animals with the vehicle or compound daily for 4 weeks. Monitor tumor volume and body weight twice a week during the study period.

[0218] Example 906: Wet Weight Assay of Immature Uterus Immature female CD-IGS rats (21 days old) will be treated for 3 days. The animals will be administered the drug daily for 3 days. In antagonist mode, Vehicle or the compound will be administered via oral enteral nutrition, followed 15 minutes later by oral administration of 0.1 mg / kg of ethinylestradiol. In agonist mode, Vehicle or the test compound will be administered via oral enteral nutrition. On day 4, 24 hours after administration, plasma will be collected for pharmacokinetic analysis. Immediately after plasma collection, the animals will be euthanized, their uteruses removed, and their body weight measured. Uteruses and ovaries from two animals per group are fixed in 10% neutral buffered formalin, embedded in paraffin, sectioned, and stained with H&E (SDPath). The stained tissues are analyzed and interpreted by a committee-certified pathologist. For transcriptional analysis, uteri and ovaries from four animals per group are rapidly frozen in liquid N2 to examine a selection of genes modulated by the estrogen receptor. Compounds of formula I: (1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidine-3-yl)oxy)phenyl)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole 101 and (1R,3R)-1-(2,6-difluoro-4-(2-(3-(fluoromethyl)azetidine-1-yl)ethoxy)phenyl)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole Mice were treated with compound 102, tamoxifen, fulvestrant, AZD9496 (International Publication No. 2014 / 191726, Example 1, p. 74; U.S. Patent No. 9155727), and two controls: Vehicle and / or Vehicle + ethinylestradiol (EE). All compounds were administered orally (PO) once daily for 3 days (QDx3). Uterine wet weight (UWW):body weight ratio was calculated. The mean endometrial height of the uterine cross-section was measured histologically. The height of endometrial cells was measured from the basement membrane to the apical (lumen) surface using a slide viewer at 20x magnification. Obliquely cut areas were avoided. In the agonist-mode UWW assay, compounds 101 and 102 of formula I are antagonists, while AZD9496 is a partial agonist.

[0219] Example 907: Adult uterine weight - 10-day assay Female CD-IGS rats (69 days old, Charles River Laboratories) were purchased and divided into groups. Group 1 had their ovaries removed at 60 days of age by the supplier (Charles River Laboratories), and the study began two weeks after the surgery. Groups 2-8 were untreated. Vehicle or the test compound was administered orally for 10 days. Two hours after the 10th and final dose, cardiac puncture was performed, and serum was collected for pharmacokinetic and estradiol analysis. Immediately after serum collection, the animals were euthanized, their uteruses and ovaries were removed, and their body weight was measured.

[0220] Although the invention described above is explained in some detail by examples and embodiments for the sake of clear understanding, the explanation and embodiments should not be construed as limiting the scope of the invention. All disclosures of patents and scientific literature cited herein are incorporated herein by reference in their entirety with due attribution.

Claims

1. Compounds selected from Formula I: I [In the above formula: Y １ CR ｂ or N; Y ２ is, -(CH ２ )-,-(CH ２ CH ２ ) - or NR ａ And; Y ３ is NR ａ or C(R ｂ ) ２ and; Here, Y １ , Y ２ and Y ３ One of them is N or NR ａ And; R ａ F, Cl, Br, I, CN, OH, OCH ３ and SO ２ CH ３ H, C are optionally substituted with one or more groups independently selected from the above. １ -C ６ Alkyl, C ２ -C ８ Alkenyl, propargyl, C ３ -C ６ Cycloalkyl and C ３ -C ６ Selected from heterocyclines; R ｂ F, Cl, Br, I, CN, -CH ２ F, -CHF, -CF ３ ,-CH ２ CF ３ ,-CH ２ CHF ２ ,-CH ２ CH ２ F, OH, OCH ３ and SO ２ CH ３ H,-O(C) is optionally substituted with one or more groups independently selected from the above. １ -C ３ Alkyl), C １ -C ６ Alkyl, C ２ -C ８ Alkenyl, propargyl, -(C １ -C ６ (Alkyldiyl)-(C ３ -C ６ Cycloalkyl), C ３ -C ６ Cycloalkyl and C ３ -C ６ Independently selected from heterocyclines; R ｃ F, Cl, Br, I, CN, OH, OCH ３ and SO ２ CH ３ H, C are optionally substituted with one or more groups independently selected from the above. １ -C ６ Selected from alkyl, allyl, and propargyl; Z １ CR ａ R ｂ Selected from C(O) and bond; Cy is C ６ -C ２０ Alylziyl, C ３ -C １２ Carbocyclyldiyl, C ２ -C ２０ Heterocyclyldiyl and C １ -C ２０ Selected from heteroaryldiyl; Z ２ O, S, NR ａ , C １ -C ６ Alkyldiyl, C １ -C ６ Fluoroalkyldiyl, O-(C １ -C ６ Alkyldiyl), O-(C １ -C ６ Selected from fluoroalkyldiyl, C(O), and bond; R １ 、R ２ 、R ３ and R ４ are H, F, Cl, Br, I, -CN, -CH ３ 、-CH ２ CH ３ 、-CH(CH ３ ) ２ 、-CH ２ CH(CH ３ ) ２ 、-CH ２ OH、-CH ２ OCH ３ 、-CH ２ CH ２ OH、-C(CH ３ ) ２ OH、-CH(OH)CH(CH ３ ) ２ 、-C(CH ３ ) ２ CH ２ OH、-CH ２ CH ２ SO ２ CH ３ 、-CH ２ OP(O)(OH) ２ (OH) ２ 、-CH ２ F、-CHF ２ 、-CH ２ NH ２ 、-CH ２ NHSO ３ CH ２ 、-CH ３ NHCH ２ 、-CH ３ N(CH ２ ) ３ 、-CF ２ 、-CH ３ CF ２ 、-CH ２ CHF ３ 、-CH(CH ３ ) ２ CN、-C(CH ２ ) ２ CN、-CH ２ CN、-CO ２ H、-COCH ３ 、-CO ２ CH ３ 、-CO ２ C(CH ３ ) ３ 、-COCH(OH)CH ３ 、-CONNH ２ 、-CONNHCH ３ 、-CONNHCH ２ CH ３ 、-ANNHCH(CH ３ ) ２ 、-CONN(CH ３ ) ２ 、-C(CH ３ ) ２ CON ２ 、-NH ２ 、-NXCH ３ 、-N(CH ３ ) ２ 、-NHCOCH ３ 、-N(CH ３ )RED ３ 、-NHS(O) ２ CH ３ 、-N(CH ３ )C(CH ３ ) ２ CON ２ 、-N(CH ３ )CH ２ CH ２ S (O) ２ CH ３ 、-NO ２ 、=O、-OH、-OCH ３ 、-OCH ２ CH ３ 、-OCH ２ CH ２ OCH ３ 、-OCH ２ CH ２ OH、-OCH ２ CH ２ N (CH ３ ) ２ 、-OP(O)(OH) ２ 、-S(O) ２ N (CH ３ ) ２ 、-SCH ３ 、-S(O) ２ CH ３ 、-S(O) ３ H, cyclopropyl, cyclopropylamide, cyclobutyl, oxetanyl, azetidinyl, 1-methylazetidine-3-yl)oxy, N-methyl-N-oxetan-3-ylamino, azetidine-1-ylmethyl, benzyloxyphenyl, pyrrolidine-1-yl, pyrrolidine-1-ylmethanone, piperazine-1-yl, morpholinomethyl, morpholinomethanone and morpholino, independently selected from: R ５ is halogen, CN, OR ａ , N(R ａ ) ２ , C １ -C ９ Alkyl, C ３ -C ９ Cycloalkyl, C ３ -C ９ Heterogeneous algebras, C ６ -C ９ Ariel, C ６ -C ９ Heteroaryl, C(O)R ｂ , C(O)NR ａ SO ２ R ａ and SO ２ NR ａ H, C are arbitrarily substituted with one or more of the above. １ -C ９ Alkyl, C ３ -C ９ Cycloalkyl, C ３ -C ９ Heterogeneous algebras, C ６ -C ９ Ariel, C ６ -C ９ Heteroaryl, -(C １ -C ６ (Alkyldiyl)-(C ３ -C ９ Cycloalkyl), -(C １ -C ６ (Alkyldiyl)-(C ３ -C ９ Heterogenetic algebras), C(O)R ｂ , C(O)NR ａ SO ２ R ａ and SO ２ NR ａ Selected from; R ６ は、F、Cl、Br、I、-CN、-CH ３ -CH ２ CH ３ 、-CH(CH ３ ) ２ -CH ２ CH(CH ３ ) ２ -CH ２ OH-CH ２ OCH ３ -CH ２ CH ２ OH,-C(CH) ３ ) ２ OH、-CH(OH)CH(CH ３ ) ２ -C(CH) ３ ) ２ CH ２ OH-CH ２ CH ２ SO ２ CH ３ -CH ２ OP(O)(OH) ２ -CH ２ F, -CHF ２ -CH ２ NH ２ -CH ２ NHSO ２ CH ３ -CH ２ NHCH ３ -CH ２ N(CH) ３ ) ２ -CF ３ -CH ２ CF ３ -CH ２ CHF ２ -CH ２ CH ２ F, -CH(CH) ３ )CN,-C(CH) ３ ) ２ CN-CH ２ CN-CO ２ H-COCH ３ -CO ２ CH ３ -CO ２ C(CH) ３ ) ３ 、-COCH(OH)CH ３ 、-CONNH ２ 、-CONNHCH ３ 、-CONNHCH ２ CH ３ 、-ANNHCH(CH ３ ) ２ 、-CONN(CH ３ ) ２ 、-C(CH ３ ) ２ CON ２ 、-NH ２ 、-NXCH ３ 、-N(CH ３ ) ２ 、-NHCOCH ３ 、-N(CH ３ )RED ３ 、-NHS(O) ２ CH ３ 、-N(CH ３ )C(CH ３ ) ２ CON ２ 、-N(CH ３ )CH ２ CH ２ S (O) ２ CH ３ 、-NO ２ 、=O、-OH、-OCH ３ 、-OCH ２ CH ３ 、-OCH ２ CH ２ OCH ３ 、-OCH ２ CH ２ OH、-OCH ２ CH ２ N (CH ３ ) ２ 、-OP(O)(OH) ２ 、-S(O) ２ N (CH ３ ) ２ 、-SCH ３ 、-S(O) ２ CH ３ 、-S(O) ３ Selected from H, cyclopropyl, cyclopropylamide, cyclobutyl, oxetanyl, azetidinyl, 1-methylazetidine-3-yl)oxy, N-methyl-N-oxetan-3-ylamino, azetidine-1-ylmethyl, benzyloxyphenyl, pyrrolidine-1-yl, pyrrolidine-1-ylmethanone, piperazine-1-yl, morpholinomethyl, morpholinomethylmethanone, and morpholino; m is selected from 0, 1, 2, 3, and 4; Here, alkyldiyl, fluoroalkyldiyl, aryldiyl, carbocycryldiyl, heterocyclyldiyl, and heteroaryldiyl are F, Cl, Br, I, -CN, -CH ３ ,-CH ２ CH ３ ,-CH(CH ３ ) ２ ,-CH ２ CH (CH ３ ) ２ ,-CH ２ OH, -CH ２ OCH ３ ,-CH ２ CH ２ OH, -C(CH ３ ) ２ OH, -CH(OH)CH(CH ３ ) ２ , -C (CH ３ ) ２ CH ２ OH, -CH ２ CH ２ SO ２ CH ３ ,-CH ２ OP(O)(OH) ２ ,-CH ２ F, -CHF ２ , -CF ３ ,-CH ２ CF ３ ,-CH ２ CHF ２ ,-CH ２ CH ２ F, -CH(CH ３ )CN, -C(CH ３ ) ２ CN, -CH ２ CN, -CH ２ NH ２ ,-CH ２ NHSO ２ CH ３ ,-CH ２ NHCH ３ ,-CH ２ N(CH ３ ) ２ , -CO ２ H, -COCH ３ , -CO ２ CH ３ , -CO ２ C(CH) ３ ) ３ 、-COCH(OH)CH ３ -CONH ２ -CONCH ３ 、-CON(CH) ３ ) ２ -C(CH) ３ ) ２ CONG ２ 、-NH ２ 、-NHCH ３ 、-N(CH ３ ) ２ -NHCOCH ３ 、-N(CH ３ COCH ３ -NHS(O) ２ CH ３ 、-N(CH ３ )C(CH ３ ) ２ CONG ２ 、-N(CH ３ )CH ２ CH ２ S(O) ２ CH ３ -NO ２ 、=O、-OH、-OCH ３ -OCH ２ CH ３ -OCH ２ CH ２ OCH ３ -OCH ２ CH ２ OH,-OCH ２ CH ２ N(CH) ３ ) ２ 、-OP(O)(OH) ２ -S(O) ２ N(CH) ３ ) ２ -SCH ３ -S(O) ２ CH ３ -S(O) ３ H, cyclopropyl, cyclopropylamide, cyclobutyl, oxetanyl, azetidinyl, 1-methylazetidine-3-yl)oxy, N-methyl-N-oxetan-3-ylamino, azetidine-1-ylmethyl, benzyloxyphenyl, pyrrolidine-1-yl, pyrrolidine-1-ylmethanone, piperazine-1-yl, morpholinomethyl, morpholinomethanone, and morpholino are optionally substituted with one or more groups independently selected from these. and its stereoisomers, tautomers, or pharmaceutically acceptable salts.

2. Equation Ia: Ia The compound according to claim 1, having the following characteristics.

3. Formula Ib: Ib [In the above formula, R ７ is F, Cl, Br, I, -CN, -CH ３ , -CH ２ CH ３ , -CH(CH ３ ), ２ , -CH ２ CH(CH ３ ), ２ , -CH ２ OH, -CH ２ OCH ３ , -CH ２ CH ２ OH, -C(CH ３ ), ２ OH, -CH(OH)CH(CH ３ ), ２ , -C(CH ３ ), ２ CH ２ OH, -CH ２ CH ２ SO ２ CH ３ , -CH ２ OP(O)(OH) ２ , -CH ２ F, -CHF ２ , -CH ２ NH ２ , -CH ２ NHSO ２ CH ３ , -CH ２ NHCH ３ , -CH ２ N(CH ３ ), ２ , -CF ３ , -CH ２ CF ３ , -CH<"0000487">CHF ２ , -CH(CH<000"0489">), -CN, -C(CH ３ ), ２ , -CH ２ CN, -CO ２ H, -COCH ３ , -CO ２ CH ３ , -CO ２ C(CH ３ ), ３ , -COCH(OH)CH ３ , -CONH ２ 、-CONNHCH ３ 、-CONNHCH ２ CH ３ 、-ANNHCH(CH ３ ) ２ 、-CONN(CH ３ ) ２ 、-C(CH ３ ) ２ CON ２ 、-NH ２ 、-NXCH ３ 、-N(CH ３ ) ２ 、-NHCOCH ３ 、-N(CH ３ )RED ３ 、-NHS(O) ２ CH ３ 、-N(CH ３ )C(CH ３ ) ２ CON ２ 、-N(CH ３ )CH ２ CH ２ S (O) ２ CH ３ 、-NO ２ 、=O、-OH、-OCH ３ 、-OCH ２ CH ３ 、-OCH ２ CH ２ OCH ３ 、-OCH ２ CH ２ OH、-OCH ２ CH ２ N (CH ３ ) ２ 、-OP(O)(OH) ２ 、-S(O) ２ N (CH ３ ) ２ 、-SCH ３ 、-S(O) ２ CH ３ 、-S(O) ３ H, cyclopropyl, cyclopropylamide, cyclobutyl, oxetanyl, azetidinyl, 1-methylazetidine-3-yl)oxy, N-methyl-N-oxetan-3-ylamino, azetidine-1-ylmethyl, benzyloxyphenyl, pyrrolidine-1-yl, pyrrolidine-1-ylmethanone, piperazine-1-yl, morpholinomethyl, morpholinomethanone, and morpholino; n is selected from 0, 1, 2, 3, and 4. The compound according to claim 2, having the following characteristics.

4. Formula Ic: Ic The compound according to claim 1, having the following characteristics.

5. Formula Id: Id The compound according to claim 4, having the following characteristics.

6. Formula Ie: Ie [In the above formula, R ８ is H or -CH ３ [is] The compound according to claim 5, having the following characteristics.

7. Formula If: If [In the above formula, R ８ is H or -CH ３ [is] The compound according to claim 4, having the following characteristics.

8. Formula Ig: Ig The compound according to claim 1, having the following characteristics.

9. Formula Ih: Ih The compound according to claim 8, having the following characteristics.

10. Formula Ii: II The compound according to claim 9, having the following characteristics.

11. Formula Ij: Ij The compound according to claim 10, having the following characteristics.

12. Formula Ik: Ik The compound according to claim 11, having the following characteristics.

13. Y １ CR ｂ Y ３ NR ａ The compound according to claim 1.

14. Y １ N is Y ３ is C(R ｂ ) ２ The compound according to claim 1.

15. Y ２ ga- (CH ２ The compound according to claim 1, wherein the compound is:

16. Y ２ ga- (CH ２ CH ２ The compound according to claim 1, wherein the compound is:

17. R ｃ The compound according to claim 1, wherein is H.

18. Cy is C ６ -C ２０ The compound according to claim 1, wherein it is an aryldiyl.

19. C ６ -C ２０ The compound according to claim 18, wherein the aryldiyl is phenyldiyl.

20. The compound according to claim 19, wherein the phenyldiyl group is substituted with one or more F atoms.

21. R １ and R ２ The compound according to claim 1, wherein is H.

22. R ３ H is R ４ ga-CH ３ The compound according to claim 1.

23. R ５ C １ -C ６ The compound according to claim 1, wherein it is a fluoroalkyl compound.

24. The compound according to claim 1, wherein m is 0.

25. A compound according to claim 1, selected from Table 1.

26. A compound according to claim 1, selected from Table 2.

27. A pharmaceutical composition comprising the compound described in claim 1 and a pharmaceutically acceptable carrier, lubricant, diluent, or excipient.

28. The pharmaceutical composition according to claim 27, further comprising a therapeutic agent.

29. A method for producing a pharmaceutical composition, comprising combining the compound described in claim 1 with a pharmaceutically acceptable carrier, lubricant, diluent, or excipient.

30. A method for treating an ER-related disease or disorder in a patient, comprising administering a therapeutically effective amount of the pharmaceutical composition described in claim 27 to the patient having an ER-related disease or condition.

31. The method according to 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 according to claim 31, wherein the cancer is breast cancer.

33. The method according to claim 31, further comprising administering an additional therapeutic agent selected from anti-inflammatory agents, immunomodulators, chemotherapeutic agents, apoptosis promoters, neurotrophic factors, cardiovascular disease treatment agents, liver disease treatment agents, antiviral agents, hematological disease treatment agents, diabetes treatment agents, and immunodeficiency disease treatment agents.

34. The method according to 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 ixabepirone.

35. The method according to claim 30, wherein the pharmaceutical composition is administered in combination with a CDK4 / 6 inhibitor.

36. The method according to claim 35, wherein the CDK4 / 6 inhibitor is selected from palbociclib (PD-0332991), ribociclib (LEE011), and LY283519.

37. The pharmaceutical compositions are everolimus, temsirolimus, BEZ235 (dactricib), BYL719 (alperisib), GDC0032 (tasericib), BKM120 (buparlicib), BGT226, GDC0068 (ipatasertib), GDC-0980 (apitricib), GDC0941 (pictilicib), INK128 (MLN0128), INK1117, OSI-027, CC-223, AZD8055, SAR245408, and SAR245409. The method according to claim 30, administered in combination with a phosphoinositide 3-kinase (PI3K) / mTOR pathway inhibitor selected from PF04691502, WYE125132, GSK2126458, GSK-2636771, BAY806946, PF-05212384, SF1126, PX866, AMG319, ZSTK474, Cal101 (idelalisib), PWT33597, CU-906, AZD-2014, and CUDC-907.

38. a) The pharmaceutical composition according to claim 27; and b) Instructions for use A kit for treating estrogen receptor-mediated conditions, including [mention specific condition].

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 ER-related diseases or disorders.

41. Use of the compound according to any one of claims 1 to 26 for the treatment of ER-related diseases or disorders.

42. Use of a compound according to any one of claims 1 to 26 for the preparation of a pharmaceutical product useful in the treatment of ER-related diseases or disorders.

43. The present invention as described above.

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