Tetrahydro-pyrido[3,4-b]indole estrogen receptor modulators and uses thereof

Abstract

To provide compounds for treating estrogen receptor mediated or dependent diseases or conditions and methods for preparing them.SOLUTION: The present invention provides a compound having the following formula Ib, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof.SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This nonprovisional 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 / 093,929, filed December 18, 2014, U.S. Provisional Application No. 62 / 110,998, filed February 2, 2015, and U.S. Provisional Application No. 62 / 142,077, filed April 2, 2015, which are incorporated herein by reference in their entireties.

[0002] FIELD OF THE INVENTION Described herein are compounds (including pharmaceutically acceptable salts, solvates, metabolites, and prodrugs thereof), pharmaceutical compositions containing such compounds, and methods of using such compounds in combination with other therapeutic agents to treat, prevent, or diagnose estrogen-sensitive, estrogen receptor-dependent, or estrogen receptor-mediated diseases or conditions. [Background technology]

[0003] Estrogen receptors ("Er") are ligand-activated transcriptional regulatory proteins that mediate the induction of various biological effects through interaction with endogenous estrogens. Endogenous estrogens include 17b (beta)-estradiol and estrone. ERs have been found to have two isoforms, ER-a (alpha) and ER-b (beta). Estrogens and estrogen receptors have been implicated in various diseases or conditions, such as breast cancer, lung cancer, ovarian cancer, colon cancer, prostate cancer, endometrial cancer, uterine cancer, and other diseases or conditions. There is a need for novel ER-a-targeting agents that are active in metastatic disease and in settings of acquired resistance. Summary of the Invention

[0004] The present invention generally relates to compounds having the structure of Formula I: JPEG0007792942000001.jpg4075I 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 of a compound of formula (I) and a pharmaceutically acceptable carrier, lubricant, diluent or excipient. One aspect of the invention is a method for preparing a compound of Formula I or a pharmaceutical composition comprising a compound of Formula I. One aspect of the present invention is a method of treating an ER-associated disease or disorder in a patient, comprising administering to the patient having the disease or disorder a therapeutically effective amount of a pharmaceutical composition. One aspect of the present invention is a kit for treating an estrogen receptor mediated condition, comprising: a) a pharmaceutical composition comprising a compound of formula I; and b) Instructions for use The kit includes: DETAILED DESCRIPTION OF THE INVENTION

[0006] Reference will now be made in detail to specific embodiments of the present invention, examples of which are illustrated in the accompanying structures and formulas. While the present invention will be described in conjunction with numerous embodiments, it is not intended that the invention be limited to those embodiments. Rather, the present invention is intended to cover all alternatives, modifications, and equivalents, which may be included within the scope of the present invention as defined by the claims. One of ordinary skill in the art will recognize many methods and materials similar or equivalent to those described herein, which could be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described. In the event of a difference or conflict with, but not limited to, the definitions, usage, and techniques of terms in this application, this application shall control. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. The nomenclature used in this application is based on the IUPAC systematic nomenclature unless otherwise specified.

[0007] definition When referring to the number of substituents, the term "one or more" refers to a range from one substituent to the maximum possible number of substitutions, i.e., from replacing one hydrogen to replacing all hydrogens with a substituent. The term "substituent" refers to an atom or group of atoms replacing a hydrogen atom on a parent molecule. The term "substituted" refers to a group having one or more substituents. Any group can have multiple substituents, and when a variety of possible substituents are provided, the substituents are independently selected and need not be the same. The term "unsubstituted" means that a particular group has no substituents. The term "optionally substituted" means that a particular group is unsubstituted or substituted with one or more substituents independently selected from a group of possible substituents. When referring to the number of substituents, the term "one or more" refers to a range from one substituent to the maximum possible number of substitutions, i.e., from replacing one hydrogen to replacing all hydrogens with a substituent.

[0008] As used herein, the term "alkyl" refers to an alkyl group containing 1 to 12 carbon atoms (C-C 12), where the alkyl group may independently be optionally substituted with one or more substituents described below. In another embodiment, the alkyl group is from 1 to 8 carbon atoms (C1-C8) or from 1 to 6 carbon atoms (C1-C6). Examples of alkyl groups include, 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, -CH2CH(CH3)2 ...butyl (s-Bu, s-butyl, -CH2CH(CH3)2), 2-methyl-1-propyl (i-Bu, i-butyl, -CH2CH(CH -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 (-CH2CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)C 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 an alkyl group having from about 1 to 12 carbon atoms (C-C 12(Alkyldiyl) refers to a saturated, straight- or branched-chain divalent hydrocarbon radical of the formula (I), which may be independently optionally substituted with one or more substituents described below. In alternative embodiments, an alkyldiyl group has from 1 to 8 carbon atoms (C1-C8) or from 1 to 6 carbon atoms (C1-C6). Examples of alkyldiyl groups include, but are not limited to, methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), and the like. An alkyldiyl group is also referred to as an "alkylene" group.

[0010] The term "alkenyl" refers to an alkyl group having at least one site of unsaturation, i.e., a carbon-carbon sp 2 "Alkenyl" refers to a straight or branched chain monovalent hydrocarbon radical of two to eight carbon atoms (C2-C8) having a double bond, where alkenyl groups may be independently optionally substituted with one or more substituents described herein, and includes radicals having "cis" and "trans" orientations, alternatively, "E" and "Z" orientations. Examples include, but are not limited to, ethylenyl or vinyl (-CH=CH2), allyl (-CH2CH=CH2), and the like.

[0011] The terms "alkenylene" or "alkenyldiyl" refer to an alkenylene having at least one site of unsaturation, i.e., a carbon-carbon sp 2 "Alkenylene" refers to a straight or branched chain divalent hydrocarbon radical of two to eight carbon atoms (C2-C8) having a double bond, where alkenylene groups may be independently optionally substituted with one or more substituents described herein, and includes radicals having "cis" and "trans" orientations, alternatively, "E" and "Z" orientations. Examples include, but are not limited to, ethylenylene or vinylene (-CH=CH-), allyl (-CHCH=CH-), and the like.

[0012] The term "alkynyl" refers to a linear or branched monovalent hydrocarbon group of two to eight carbon atoms (C-C) having at least one site of unsaturation, i.e., a carbon-carbon sp triple bond, where alkynyl groups can be independently optionally substituted with one or more substituents described herein. Examples include, but are not limited to, ethynyl (-C≡CH), propynyl (propargyl, -CHC≡CH), and the like.

[0013] The terms "alkynylene" or "alkynyldiyl" refer to a linear or branched divalent hydrocarbon radical of two to eight carbon atoms (C-C) having at least one site of unsaturation, i.e., a carbon-carbon sp triple bond, where the alkynylene group can be independently optionally substituted with one or more substituents described herein. Examples include, but are not limited to, ethynylene (-C≡C-), propynylene (propargylene, -CHC≡C-), and the like.

[0014] The terms "carbocycle", "carbocyclyl", "carbocyclic ring" and "cycloalkyl" refer to a ring of 3 to 12 carbon atoms (C3-C4) as a monocyclic ring. 12(The term "carbocyclyl" refers to a monovalent non-aromatic saturated or partially unsaturated ring having 7 to 12 carbon atoms as a bicyclic ring. Bicyclic carbocyclyl rings having 7 to 12 atoms can be arranged, for example, as bicyclo[4,5], [5,5], [5,6], or [6,6] systems, and bicyclic carbocyclyl rings having 9 or 10 ring atoms can be arranged as bicyclo[5,6] or [6,6] systems, or as bridged systems, such as 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 carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, etc. Carbocyclyl groups are independently optionally substituted with one or more substituents described herein.

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

[0016] "Aryl" means an aromatic ring system of 6-20 carbon atoms (C6-C8) derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system. 20) is a monovalent aromatic hydrocarbon group consisting of a cyclic ring, ...

[0017] The term "arylene" or "aryldiyl" refers to an aryl group of 6-20 carbon atoms (C-C) derived by removing two hydrogen atoms from two carbon atoms of a parent aromatic ring system. 20 ) divalent aromatic hydrocarbon radicals consisting of aryl, aryldiyl ...

[0018] The terms "heterocycle," "heterocyclyl," and "heterocyclic ring" are used interchangeably herein and refer to saturated or partially unsaturated (i.e., having one or more double and / or triple bonds within the ring) carbocyclic groups 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 C, and where one or more ring atoms are independently optionally substituted with one or more substituents described below. A 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 bicycle having 7 to 10 ring members (4 to 9 carbon atoms and 1 to 6 heteroatoms selected from N, O, P, and S), such as a bicyclo[4,5], [5,5], [5,6], or [6,6] system. Heterocyclic rings are described in Paquette, Leo A.; "Principles of Modern Heterocyclic Chemistry" (WA Benjamin, 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. "Heterocyclyl" also includes groups in which a 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, piperidin-1-yl, piperazinyl, piperazin-4-yl-2-one, piperazin-4-yl-3-one, pyrrolidin-1-yl, thiomorpholin-4-yl, S-dioxothiomorpholin-4-yl, azocan-1-yl, azetidin-1-yl, octahydropyrido[1,2-a]pyrazin-2-yl, [1,4]diazepan-1-yl, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino, morpholinino, thiomorpholino, thioxanyl, piperazinyl, phosphino ...

[0023] Included within this definition are 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-indolylquinolizinyl, and N-pyridylurea. Spiroheterocyclyl moieties are also included within the scope of 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. The heterocyclic groups herein may be independently optionally substituted with one or more substituents 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 within the ring) carbocyclic group 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 C, and where one or more ring atoms are independently optionally substituted with one or more substituents as described.

[0020] The term "heteroaryl" refers to a monovalent aromatic group of 5, 6, or 7 members, including fused ring systems 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 are pyridinyl (including, for example, 2-hydroxypyridinyl), imidazolyl, imidazopyridinyl, pyrimidinyl (including, for example, 4-hydroxypyrimidinyl), pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxadiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, triazolyl, thiadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. Heteroaryl groups are optionally substituted independently with one or more substituents described herein.

[0021] The term "heteroaryldiyl" refers to a divalent aromatic group of 5, 6, or 7 members, including fused ring systems 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 heterocycle or heteroaryl group may be carbon (carbon-linked) or nitrogen (nitrogen-linked) linked, where possible. By way of example and not limitation, a carbon-linked heterocycle or heteroaryl may be bonded at the 2-, 3-, 4-, 5-, or 6-position of a pyridine, the 3-, 4-, 5-, or 6-position of a pyridazine, the 2-, 4-, 5-, or 6-position of a pyrimidine, the 2-, 3-, 5-, or 6-position of a pyrazine, the 2-, 3-, 4-, or 5-position of a furan, tetrahydrofuran, thiofuran, thiophene, pyrrole, or tetrahydropyrrole, the 2-, 4-, or 5-position of an oxazole, imidazole, or thiazole, the 3-, 4-, or 5-position of an isoxazole, pyrazole, or isothiazole, the 2-, or 3-position of an aziridine, the 2-, 3-, or 4-position of an azetidine, the 2-, 3-, 4-, 5-, 6-, 7-, or 8-position of a quinoline, or the 1-, 3-, 4-, 5-, 6-, 7-, or 8-position of an isoquinoline.

[0023] By way of example, and not limitation, a nitrogen-linked heterocycle or heteroaryl can be bonded at the 1-position of aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline, 1H-indazole, 2-position of isoindole or isoindoline, 4-position of morpholine, and 9-position of carbazole or b-carboline.

[0024] The terms "treat" and "treatment" refer to therapeutic treatment, the purpose of which is to delay (lessen) an undesirable physiological change or disorder, such as the onset or spread of arthritis or cancer. In the present invention, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, reduction in the extent of disease, stabilization of the disease state (i.e., not worsening), delay or slowing of disease progression, amelioration or palliation of the pathology, and remission (partial or complete), whether detectable or undetectable. "Treatment" can also mean prolonging survival as compared to expected survival if not receiving treatment. Those in need of treatment include those with a medical condition or disorder.

[0025] The phrase "therapeutically effective amount" refers to an amount of a compound of the present invention that (i) treats a particular disease, condition, or disorder, (ii) reduces, ameliorate, 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 described herein. In the case of cancer, a therapeutically effective amount of a drug may reduce the number of cancer cells; reduce tumor size; inhibit (i.e., slow to some extent, and preferably stop) cancer cell invasion into peripheral organs; inhibit (i.e., slow to some extent, and preferably stop) tumor metastasis; inhibit tumor growth to some extent; and / or alleviate to some extent one or more symptoms associated with cancer. To the extent that a drug can prevent growth and / or kill existing cancer cells, it may be cytostatic and / or cytotoxic. In the case of cancer treatment, efficacy can be determined, for example, by assessing the time to disease progression (TTP) and / or by determining the response rate (RR).

[0026] The term "cancer" refers to the physiological condition in mammals that is typically characterized by uncontrolled cell growth. A "tumor" comprises one or more cancerous cells. Examples of cancer include, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia or lymphoid malignancies. 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 of the lung and squamous cell carcinoma of the lung, cancer of the peritoneum, 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 (or "Haematological" malignancies in the UK) are types of cancer that affect the blood, bone marrow, and lymph nodes. Because these three are closely linked through the immune system, a disease that would affect one of the three usually affects the other two as well. That is, lymphoma is a disease of the lymph nodes, but it usually spreads to the bone marrow and affects the blood. Hematological malignancies are malignant neoplasms (cancers) and are generally treated by hematology and / or oncology specialists. In some centers, hematology / oncology is a subspecialty of internal medicine, while in others it is considered a separate department (also involving surgeons and radiation oncologists). Not all blood disorders are malignant (cancerous), and these other blood conditions can also be managed by hematologists. Hematological malignancies can originate from either of the two major blood cell lineages: the myeloid and lymphoid cell lines. Myeloid cell lines typically produce granulocytes, erythrocytes, platelets, macrophages, and mast cells, while lymphoid cell lines produce B, T, NK, and plasma cells. Acute and chronic myeloid leukemias, myelodysplastic syndromes, and myeloproliferative disorders are of myeloid origin, while lymphomas, lymphocytic leukemias, and myelomas are lymphoid. Leukemias include acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), acute monocytic leukemia (AMOL), and small lymphocytic lymphoma (SLL). Lymphomas include Hodgkin's lymphoma (all four subtypes) and non-Hodgkin's lymphoma (NHL, all subtypes).

[0028] A "chemotherapeutic agent" is a chemical compound useful in the treatment of cancer, regardless of mechanism of action. Classes of chemotherapeutic agents include, but are not limited to, alkylating agents, antimetabolites, spindle poison plant alkaloids, cytotoxic / antitumor antibiotics, topoisomerase inhibitors, antibodies, photosensitizers, and kinase inhibitors. Chemotherapeutic agents include compounds used in "targeted therapy" and conventional chemotherapy. Examples of chemotherapeutic agents include ibrutinib (Imbruvica TM, APCI-32765, Pharmacyclics Inc. / Janssen Biotech Inc.; CAS Registry Number 936563-96-1, US 7514444), idelalisib (ZYDELIG® CAL-101, GS 1101, GS-1101, Gilead Sciences Inc.; CAS Registry Number 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)-diamminedichloroplatinum(II), cis-diammine, dichloroplatinum(II), CAS Number 15663-27-1), carboplatin (CAS Number 41575-94-4), paclitaxel (Taxol®, Bristol-Myers Squibb, Princeton, NJ) 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®, TEMODAL®, Schering Plough), tamoxifen ((Z)-2-[4-(1,2-diphenylbut-1-enyl)phenoxy]-N,N-dimethylethanamine, Nolvadex®, ISTUBAL®, VALODEX®, and doxorubicin (Adriamycin®, CAS number 23214-92-8), Akti-1 / 2, HPPD, and rapamycin.

[0029] Chemotherapeutic agents include inhibitors of B-cell receptor targets, such as BTK, Bcl-2 and JAK inhibitors.

[0030] Further examples of chemotherapeutic agents include oxaliplatin (ELOXATIN®, Sanofi), bortezomib (VELCADE®, Millennium Pharm.), Sutent (Sunitinib®, SU11248, Pfizer), letrozole (FEMARA®, Novartis), imatinib mesylate (Gleevec®, Novartis), XL-518 (Mek inhibitor, Exelixis, WO 2007 / 044515), ARRY-886 (Mek inhibitor, AZD6244, Array BioPharma, Astra Zeneca), SF-1126 (PI3K inhibitor, Semafore Pharmaceuticals), BEZ-235 (PI3K inhibitor, Novartis), XL-147 (PI3K inhibitor, Exelixis), PTK787 / ZK 222584 (Novartis), fulvestrant (FASLODEX®, AstraZeneca), leucovorin (folinic acid), rapamycin (sirolimus, Rapamune®, Wyeth), lapatinib (TYKERB®, GSK572016, GlaxoSmithKline), lonafarnib (Salazar TM , SCH 66336, Schering Plough), sorafenib (Nexavar®, BAY43-9006, Bayer Labs), gefitinib (Iressa®, AstraZeneca), irinotecan (Camptosar®, CPT-11, Pfizer), tipifarnib (Zahnestra®), TM Johnson & Johnson), Abraxane TM(Cremophor-free), albumin-engineered nanoparticle formulation of paclitaxel (American Pharmaceutical Partners, Schaumburg, Illinois), vandetanib (rINN, ZD6474, ZACTIMA®, AstraZeneca), chlorambucil, AG1478, AG1571 (SU 5271; Sugen), temsirolimus (Torisel®, Wyeth), pazopanib (GlaxoSmithKline), canfosfamide (Terucita®, Telik), thiotepa and cyclophosphamide (Cytoxan®, Neosar®); alkyl sulfonates such as busulfan, improsulfan, and piposulfan; benzodopa, carboquone, meturedopa, and uredopa. aziridines such as altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylolmelamine; acetogenins (especially bullatacin and bullatacinone); camptothecins (including the synthetic analogue topotecan); bryostatin; callystatin; CC-1065 (including its synthetic analogues adozelesin, carzelesin, and bisceresin); cryptophycins (especially cryptophycin 1 and cryptophycin 8); dolastatins; duocarmycins (including the synthetic analogues KW-2189 and CB1-TM1); eleutherobin; pancratistatin sarcodictine; spongistatin; nitrogen mustards such as chlorambucil, chlornaphazine, chlorophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimustine;Enediyne antibiotics (e.g., calicheamicin, calicheamicin gamma 1I, calicheamicin omega 1I (Angew Chem. Intl. Ed. Engl. (1994) 33:183-186); dynemicin, dynemicin A; bisphosphonates such as clodronate; esperamicin; and neocarzinostatin chromophores and related chromoprotein enediyne antibiotic chromophores), aclacinomycin, actinomycin, anthramycin, azaserine, bleomycin, cactinomycin, carabicin, carminomycin, carzinophilin, chromomycinis, Dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin and deoxydoxorubicin, epirubicin, esorubicin, idarubicin, nemorubicin, marcelomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycin, peplomycin, porfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, dimethicone, Antibiotics such as nostatin and zorubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pteropterin, and trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, and thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, and floxuridine; androgens such as calsterone, dromostanolone propionate, epithiostanol, mepitiostane, and testolactone; antiadrenal agents such as aminoglutethimide, mitotane, and trilostane; folic acid supplements such as folinic acid; aceglatone and aldophosphamide glycosides;Aminolevulinic acid; eniluracil; amsacrine; bestravcil; bisantrene; edatrexate; defofamine; demecolcine; diaziquone; eflornithine; elliptinium acetate; epothilone; etoglucide; gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids such as maytansine and ansamitocin; mitoguazone; mitoxantrone; mopidanmol; nitracrine; pentostatin; phenamet; pirarubicin; losoxantrone; podophyllic acid; 2-ethylhydrazide; procarbazine; PSK® polysaccharide complex (JHS Natural, Eugene, Oregon) Products); Razoxane; Rhizoxin; Sizofiran; Spirogermanium; Tenuazonic acid; Triazicon; 2,2',2"-Trichlorotriethylamine; Trichothecenes (especially T-2 toxin, verracurin A) , Roridin A and Anguidine); Urethane; Vindesine; Dacarbazine; Mannomustine; Mitobronitol; Mitolactol; Pipobroman; Gacytosine; Arabinoside ("Ara-C"); Cyclophosphamide; Thiotepa; 6-Thioguanine; Mercaptopurine; Methotrexate; Platinum analogues 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; difluoromethylornithine (DMFO); retinoids such as retinoic acid; and pharmaceutically acceptable salts, acids, and derivatives of any of the above.

[0031] Also included within the definition of "chemotherapeutic agent" are: (i) antihormonal agents that act to regulate or inhibit hormone action on tumors, such as antiestrogens and selective estrogen receptor modulators (SERMs) and selective estrogen receptor modulators (SERDs) (e.g., fulvestrant (Faslodex®, Astra Zeneca)), including, for example, tamoxifen (including Nolvadex®; tamoxifen citrate), raloxifene, droloxifene, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, and Fairston® (toremifene citrate); (ii) aromatase inhibitors, such as 4(5)-imidazole, aminoglutethimide, MEGASE® (megestrol acetate), Aromasin® (exemestane; Pfizer), formestane, which inhibit the enzyme aromatase, which regulates estrogen production in the adrenal glands. , fadrozole, RIVISOR® (vorozole), Femara® (letrozole; Novartis) and Arimidex® (anastrozole; AstraZeneca); (iii) antiandrogens, such as flutamide, nilutamide, bicalutamide, leuprolide and goserelin; and troxacitabine (1,3-dioxolane nucleoside cytosine analogue); (iv) protein kinase inhibitors, such as MEK inhibitors such as cobimetinib (WO 2007 / 044515); (v) lipid kinase inhibitors, such as taselisib (GDC-0032, Genentech Inc.); (vi) antisense oligonucleotides, particularly those that inhibit the expression of genes in signal transduction pathways involved in abnormal cell proliferation (such as PKC-alpha, Raf and H-Ras), such as oblimersen (GENASENSE®, Genta Inc.(vii) ribozymes, such as VEGF expression inhibitors (e.g., ANGIOZYME®) and HER2 expression inhibitors; (viii) vaccines, such as gene therapy vaccines, for example, Allovectin®, Leuvectin®, and VAXID®; Proleukin® rIL-2; topoisomerase 1 inhibitors, for example, Raltotecan®; Abarelix® rmRH; (ix) antiangiogenic agents, for example, bevacizumab (Avastin®, Genentech); and pharmaceutically acceptable salts, acids, and derivatives of any of the above.

[0032] Also included in the definition of "chemotherapeutic agent" are alemtuzumab (Campath), bevacizumab (Avastin®, Genentech); cetuximab (Erbitux®, Imclone); panitumumab (Vectibix®, Amgen); rituximab (Rituxan®, Genentech / Biogen Idec); pertuzumab (PERJETA®, Genentech / Biogen Idec); TM, Also included are therapeutic antibodies such as 2C4, Genentech), trastuzumab (Herceptin®, Genentech), trastuzumab emtansine (KADCYLA®, Genentech Inc.), and tositumomab (Bexar, Corixia).

[0033] A "metabolite" is a product produced by metabolism of a particular compound or 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 using tests such as those described herein. Such products result, for example, from the oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic cleavage, etc., of the administered compound. Accordingly, the present invention includes metabolites of compounds of the present invention produced by a process comprising contacting a compound of Formula I of the present invention with a mammal for a period of time sufficient to yield a metabolic product thereof.

[0034] The term "package insert" is used to refer to instructions customarily included in the commercial packaging of a therapeutic product, which contain information regarding directions, usage, dosage, administration, contraindications and / or precautions regarding the use of such therapeutic product.

[0035] The term "chiral" refers to a molecule that has the property of not being superimposable on its mirror image partner, and the term "achiral" refers to a molecule that is superimposable on its mirror image partner.

[0036] The term "stereoisomers" refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space.

[0037] "Diastereomer" refers to a stereoisomer with more than one chiral center and whose molecules are not mirror images of one another. Diastereomers have different physical properties, e.g., melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers can separate under high resolution analytical procedures such as electrophoresis and chromatography.

[0038] "Enantiomers" refer to two stereoisomers of a compound which are non-superimposable mirror images of one another.

[0039] Stereochemical definitions and conventions used herein generally follow those of S.P. 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 asymmetric or chiral centers 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 optically active forms, i.e., they are capable of rotating the plane of plane-polarized light. In describing an optically active compound, the prefixes D and L, or R and S, are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes d and l, or (+) and (-), are used to indicate the sign of rotation of plane-polarized light by a compound; (-) or 1 means the compound is levorotatory. Compounds prefixed with (+) or d are dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. Specific stereoisomers are also referred to as enantiomers, and mixtures of such isomers are often called enantiomeric mixtures. A 50:50 mixture of enantiomers is called a racemic mixture or racemate and can occur when there has been no stereoselection or stereospecificity in a chemical reaction or process. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomeric species that is optically inactive. Enantiomers can be separated from racemic mixtures by chiral separation techniques such as supercritical fluid chromatography (SFC). The assignment of configurations at the chiral centers in the separated enantiomers is tentative and is shown in the structures in Table 1 for illustrative purposes while the stereochemistry is finally determined, for example, by X-ray crystallographic data.

[0040] The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that are interconvertible via a low energy barrier. For example, proton tautomers (also known as proton tautomers) include interconversions via migration of a proton, such as keto-enol and imine-enamine isomerizations. Valence tautomers include interconversions via reorganization 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 term "pharmaceutically acceptable" indicates that a substance or composition must be chemically and / or toxicologically compatible with the other ingredients comprising the formulation and / or the mammal being treated therewith.

[0042] The term "pharmaceutically acceptable acid addition salts" refers to pharmaceutically acceptable salts formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid, and the like, and organic acids selected from the aliphatic, alicyclic, aromatic, arylaliphatic, and heterocyclic carboxylic and sulfonic classes of organic 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.

[0043] The term "pharmaceutically acceptable base addition salt" refers to a salt formed with an organic or inorganic base that is pharmaceutically acceptable. Examples of acceptable inorganic bases include sodium, potassium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, 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, trimethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, and polyamine resins.

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

[0045] The term “EC 50 " is the half maximal effective concentration, and indicates the plasma concentration of a particular compound required to obtain 50% of the maximum of a particular effect in vivo.

[0046] The term "Ki" is an inhibition constant and 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 a particular inhibitor occupies 50% of the receptor in the absence of a competing ligand (e.g., a radioligand). Ki values ​​can be logarithmically converted to pKi values ​​(-log Ki), with higher values ​​indicating exponentially greater potency.

[0047] The term “IC 50" is the half maximal inhibitory concentration, which refers to the concentration of a particular compound required to obtain 50% inhibition of a biological process in vivo. IC 50 Values ​​are pIC 50 can be converted logarithmically to a value (-log IC 50 ), with higher values ​​indicating exponentially greater potency. IC 50 The IC values ​​are not absolute and depend on experimental conditions, e.g., the concentration used, but can be converted to absolute inhibition constants (Ki) using the Cheng-Prusoff equation ((Biochem. Pharmacol. (1973) 22:3099). 70 ,I C 90 Other percent inhibition parameters may also be calculated, such as

[0048] The terms "compounds of the invention" and "compounds of Formula (I)" include compounds of Formula (I), the specific compounds described herein, and stereoisomers, geometric isomers, tautomers, solvates, metabolites, and pharmaceutically acceptable salts and prodrugs thereof.

[0049] Any formula or structure given herein containing a compound of formula (I) is also intended to represent hydrates, solvates, and polymorphs of such compound, and mixtures thereof.

[0050] Any formula or structure shown herein, including compounds of Formula (I), is also intended to represent unlabeled and isotopically labeled forms of the compound. Isotopically labeled compounds have a structure represented by the formula shown herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into 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 isotopically labeled compounds of the present invention, for example, compounds incorporating radioactive isotopes such as 3H, 13C, and 14C. Such isotopically labeled compounds may be useful in metabolic studies, 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 radiation therapy of 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 confer certain therapeutic advantages resulting from greater metabolic stability, for example, extended in vivo half-life, or reduced dosage requirements. Compounds labeled with 18F may be useful for PET or SPECT studies. The isotopically labeled compounds of the present invention and their prodrugs can generally be prepared by carrying out the methods disclosed in the following schemes or examples and preparations by substituting readily available isotopically labeled reagents for non-isotopically labeled reagents. Furthermore, substitution with heavier isotopes, particularly deuterium (i.e., 2H or D), may offer certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements or improved therapeutic index. Deuterium in this context is considered a substituent of compounds of formula (I). The concentration of such heavy isotopes, particularly deuterium, can be defined by an isotopic enrichment factor. In the compounds of the present invention, any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom.Unless otherwise specified, when a position is specifically designated as "H" or "hydrogen," the position is understood to have hydrogen at its natural abundance isotopic composition. Thus, in the compounds of the present invention, any atom specifically designated as deuterium (D) is meant to represent deuterium.

[0051] Estrogen receptor Estrogen receptor alpha (ER-a; NR3A1) and estrogen receptor beta (ER-b; NR3A2) are steroid hormone receptors and members of the large nuclear receptor superfamily. Nuclear receptors share a common modular structure, minimally containing a DNA-binding domain (DBD) and a ligand-binding domain (LBD). Steroid hormone receptors are soluble intracellular proteins that act as ligand-regulated transcription factors. Vertebrates contain five closely related steroid hormone receptors (estrogen receptor, androgen receptor, progesterone receptor, glucocorticoid receptor, and mineralocorticoid receptor), which control 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 a 595-amino acid protein. The ER-b gene is located on chromosome 14q23.3 and produces a 530-amino acid 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 (the E domain), these receptors contain an N-terminal (A / B) domain, a hinge (D) domain connecting 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 completely conserved (95% and 55% amino acid identity, respectively), the A / B, D, and F domains are less 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 diverse roles in the central nervous system, cardiovascular system and bone metabolism.

[0053] The ligand-binding pocket of steroid hormone receptors is deeply buried 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 hormone and require assistance from chaperones such as Hsp90 to maintain hormone-binding capacity. Interaction with Hsp90 also regulates the nuclear translocation of these receptors. Ligand binding stabilizes the receptor and initiates a series of conformational changes that release chaperones, alter interactions between various receptor domains, translocate these receptors to the nucleus, and remodel protein interaction surfaces that allow them to bind DNA and participate in interactions with chromatin remodeling complexes and the transcriptional machinery. While ER can interact with Hsp90, this interaction is not required for hormone binding, and apo-ER can be cytoplasmic or nuclear, depending on the cellular context. Biophysical studies have shown that DNA binding, rather than ligand binding, contributes to receptor stability (Greenfield et al., Biochemistry 40: 6646-6652, 2001).

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

[0055] Both types of ER DNA interactions can result in gene activation or repression, depending on the transcriptional coregulators recruited by each ER-ERE complex (Klinge, Steroid 65: 227-251, 2000). Coregulator recruitment is primarily mediated by two protein interaction surfaces, AF2 and AF1. AF2 resides 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 coactivator recruitment, whereas weak agonists and antagonists promote corepressor binding. Protein regulation by AF1 is less well understood but can be regulated by serine phosphorylation (Ward and Weigel, (2009) Biofactors 35: 528-536). One of the involved phosphorylation sites (S118) appears to regulate the transcriptional activity of ER in the presence of antagonists, such as tamoxifen, which plays an important role in the treatment of breast cancer. While full agonists appear to arrest the ER in a specific conformation, weak agonists tend to maintain the ER in equilibrium between various conformations, allowing cell-dependent differences in the coregulator repertoire to modulate ER activity in a cell-dependent manner (Tamrazi et al., Mol. Endocrinol. 17: 2593-2602, 2003). The interaction between DNA and ER is dynamic and includes, but is not limited to, proteasomal degradation of ER (Reid et al., Mol. Cell 11: 695-707, 2003). Ligand-induced ER degradation offers an attractive therapeutic strategy for diseases or conditions that are estrogen-sensitive and / or resistant to available antihormonal treatments. ER signaling is important for the development and maintenance of female reproductive organs, including breast, ovulation, and endometrial hyperplasia. ER signaling also plays a role in bone mass, lipid metabolism, and cancer. 70% of breast cancers express ER-α (ER-α-positive) and are estrogen-dependent for growth and survival.Other cancers, such as ovarian and endometrial cancers, are also thought to depend on ER-α signaling for growth and survival. Tamoxifen, an ER-α antagonist, is used to treat early and advanced ER-α-positive breast cancer in pre- and postmenopausal women. Fulvestrant (Faslodex), a steroid-based ER antagonist, is also used. TM) are 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 nonsteroidal aromatase inhibitors are also used to treat cancer in humans. In some embodiments, steroidal and nonsteroidal 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 antihormonal agents, advanced ER-positive breast cancers are sometimes treated with various chemotherapeutic agents, such as anthracyclines, platins, and taxanes. In some cases, ER-positive breast cancers harboring gene amplification of the ERB-B / HER2 tyrosine kinase receptor are treated with the monoclonal antibody trastuzumab (Herceptin®, Genentech Inc.) or the small molecule pan-ERB-B inhibitor lapatinib (Tykerb®, GlaxoSmithKline Corp.). Despite this range of antihormones, chemotherapy, and small molecule and antibody-based targeted therapies, many women with ER-α-positive breasts develop progressive metastatic disease and are in need of new treatments. Importantly, it is believed that most ER-positive tumors that progress with existing antihormonal and other therapies remain dependent on ER-α for growth and survival. Thus, there is a need for novel ER-α-targeted agents that are active in the setting of metastatic disease and acquired resistance. In one aspect, described herein are compounds that 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 in cell-based assays result in a decrease in steady-state ERa levels (i.e., ER degradation) and are useful in treating estrogen-sensitive diseases or conditions and / or diseases or conditions that have developed resistance to antihormonal therapy.

[0056] Most breast cancer patients are treated with drugs that block estrogen synthesis (e.g., aromatase inhibitors; AIs) or antagonize the action of estradiol through competitive ER binding (e.g., tamoxifen) (Puhalla S, et al Mol Oncol 2012; 6(2):222-236). Despite the well-documented therapeutic utility of these drugs at various stages of the disease, many ER+ breast cancers recur and patients ultimately die. Recently, next-generation whole-genome and targeted sequencing have identified ESR1 (estrogen receptor alpha 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 apo-receptors, rendering them ligand-independent and therefore active in the setting of low estradiol. Therapies targeting ER signaling with potent activity are needed in the setting of progressive disease after AI or tamoxifen treatment, including the subset of patients harboring ESR1-mutated tumors.

[0057] In some embodiments, the compounds of Formula I disclosed herein are used in methods for treating hormone-resistant estrogen receptor (ER)-positive breast cancer in patients characterized by a mutation in the ESR1 gene, comprising administering a therapeutically effective amount of a 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 among amino acid positions 6, 118, 269, 311, 341, 350, 380, 392, 394, 433, 463, 503, 534, 535, 536, 537, 538, and 555 of SEQ ID NO:2. In some embodiments, the mutation results in an ER polypeptide having an amino acid substitution selected from among 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-α 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 that may modulate other important pathways in breast cancer, including, but not limited to, IGF1R, EGFR, CDK 4 / 6, erB-B2 and 3, the PI3K / AKT / mTOR axis, HSP90, PARP, or histone deacetylases.

[0059] Given the central role of ER-α in the development and progression of breast cancer, the compounds of Formula I disclosed herein are useful in the treatment of breast cancer, either alone or in combination with other agents used to treat breast cancer, including, but not limited to, aromatase inhibitors, anthracyclines, platins, nitrogen mustard alkylating agents, and taxanes. Exemplary agents used to treat breast cancer include, but are not limited to, PI3K inhibitors such as taselisib (GDC-0032, Genentech Inc.), paclitaxel, anastrozole, exemestane, cyclophosphamide, epirubicin, fulvestrant, letrozole (Femara®, Novartis, Corp.), gemcitabine, trastuzumab, pegfilgrastim, filgrastim, tamoxifen, docetaxel, toremifene, vinorelbine, capecitabine (Xeloda®, Roche), ixabepilone, and others described herein.

[0060] ER-associated 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, migraine), cardiovascular disorders (aortic aneurysm, susceptibility to myocardial infarction, aortic valve sclerosis, cardiovascular disease, coronary artery disease, hypertension), blood system disorders (deep vein thrombosis), immune and inflammatory disorders (Graves' disease, arthritis, multiple sclerosis, cirrhosis), and ), immunocompromise (hepatitis B, chronic liver disease), metabolic disorders (bone density, cholestasis, hypospadias, obesity, osteoarthritis, osteopenia, osteoporosis), neurological disorders (Alzheimer's disease, Parkinson's disease, migraine, dizziness), psychiatric disorders (anorexia nervosa, attention deficit hyperactivity disorder (ADHD), dementia, major depressive disorder, psychosis), and reproductive disorders (age at 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 a mammal. In some embodiments, the compounds disclosed herein are used to treat cancer in a mammal. In some embodiments, the cancer is breast cancer, ovarian cancer, endometrial cancer, prostate cancer, or uterine cancer. In some embodiments, the cancer is breast cancer, lung cancer, ovarian cancer, endometrial cancer, prostate cancer, or uterine cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is a hormone-dependent cancer. In some embodiments, the cancer is an estrogen receptor-dependent cancer. In some embodiments, the cancer is an estrogen-sensitive cancer. In some embodiments, the cancer is resistant to antihormonal therapy. In some embodiments, the cancer is an estrogen-sensitive cancer or an estrogen receptor-dependent cancer that is resistant to antihormonal therapy. In some embodiments, the cancer is a hormone-sensitive cancer or a hormone receptor-dependent cancer that is resistant to antihormonal therapy. In some embodiments, the antihormonal therapy includes treatment with at least one agent selected from tamoxifen, fulvestrant, a steroidal aromatase inhibitor, and a nonsteroidal aromatase inhibitor. In some embodiments, the compounds disclosed herein are used to treat hormone receptor-positive metastatic breast cancer in postmenopausal women with disease progression following anti-estrogen therapy. In some embodiments, the compounds disclosed herein are used to treat a hormone-dependent benign or malignant disease of the breast or reproductive system in a mammal. In some embodiments, the benign or malignant disease is breast cancer. In some embodiments, the compound used in any of the methods described herein is an estrogen receptor degrader; an estrogen receptor antagonist; has minimal or negligible estrogen receptor agonist activity; or a combination thereof. In some embodiments, the methods of treatment using the compounds described herein include a treatment regimen comprising administering radiation therapy to the mammal. In some embodiments, the methods of treatment using the compounds described herein include administering the compound before or after surgery. In some embodiments, the methods of treatment using the compounds described herein include administering at least one additional anti-cancer agent. In some embodiments, the compounds described herein are used to treat cancer in a chemotherapy-naive mammal. 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 have been 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 a uterine disease or condition in a mammal. In some embodiments, the uterine disease or condition is leiomyoma, uterine leiomyoma, endometrial hyperplasia, or endometriosis. In some embodiments, the uterine disease or condition is a cancerous uterine disease or condition. In some other embodiments, the uterine disease or condition is a non-cancerous uterine disease or condition. In some embodiments, the compounds disclosed herein are used to treat endometriosis in a mammal. In some embodiments, the compounds disclosed herein are used to treat leiomyoma in a mammal. In some embodiments, the leiomyoma is a uterine leiomyoma, an esophageal leiomyoma, a cutaneous leiomyoma, or a small intestinal leiomyoma. In some embodiments, the compounds disclosed herein are used to treat fibroids in a mammal. In some embodiments, the compounds disclosed herein are used to treat uterine fibroids in a mammal.

[0062] Another embodiment of the present invention relates to a compound as described herein for use as a therapeutically active substance. Another embodiment of the present invention pertains to the compounds disclosed herein for use in the treatment of an ER-associated disease or disorder. Another embodiment of the present invention relates to the use of the compounds disclosed herein for use in the treatment of an ER-associated disease or disorder. Another embodiment of the present invention pertains to the use of a compound disclosed herein for the preparation of a medicament useful in the treatment of an ER-associated disease or disorder.

[0063] Tetrahydro-pyrido[3,4-b]indol-1-yl compounds The present invention provides tetrahydro-pyrido[3,4-b]indol-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 estrogen receptor alpha (ERa).

[0064] Compounds of formula I have the following structure: JPEG0007792942000002.jpg4075I and stereoisomers, tautomers or pharmaceutically acceptable salts thereof [wherein Y 1 is CR b or N; Y 2 is -(CH2)-, -(CH2CH2)- or NR a and; Y 3 is NR a or C(R b )2; where Y 1 , Y 2 and Y 3 One of the following is N or NR a and; R a is selected from H, C1-C6 alkyl, C2-C8 alkenyl, propargyl, C3-C6 cycloalkyl, and C3-C6 heterocyclyl optionally substituted with one or more groups independently selected from F, Cl, Br, I, CN, OH, OCH3, and SO2CH3; R bis independently selected from H, —O(C-C alkyl), C-C alkyl, C-C alkenyl, propargyl, —(C-C alkyldiyl)-(C-C cycloalkyl), C-C cycloalkyl, and C-C heterocyclyl optionally substituted with one or more groups independently selected from F, Cl, Br, I, CN, —CHF, —CHF, —CF, —CHCF, —CHCHF, —CHCHF, OH, OCH, and SOCH; R c is selected from H, C1-C6 alkyl, allyl, propargyl optionally substituted with one or more groups independently selected from F, Cl, Br, I, CN, OH, OCH3, and SO2CH3; Z 1 is CR a R b , C(O) and a bond; Cy is C6-C 20 Aryldiyl, C3-C 12 Carbocyclyldiyl, C2-C 20 Heterocyclyldiyl and C1-C 20 selected from heteroaryldiyl; Z 2 are O, S, NR a , C1-C6 alkyldiyl, C1-C6 fluoroalkyldiyl, O—(C1-C6 alkyldiyl), O—(C1-C6 fluoroalkyldiyl), C(O), and a 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, -S(O)3H, cyclopropyl, cyclopropylamido, cyclobutyl, oxetanyl, azetidinyl, 1-methylazetidin-3-yl)oxy, N-methyl-N-oxetan-3-ylamino, azetidin-1-ylmethyl, benzyloxyphenyl, pyrrolidin-1-yl, pyrrolidin-1-yl-methanone, piperazin-1-yl, morpholinomethyl, morpholino-methanone, and morpholino; R 5 is halogen, CN, OR a , N(R a )2, C1-C9 alkyl, C3-C9 cycloalkyl, C3-C9 heterocycle, 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 heterocycle, C6-C9 aryl, C6-C9 heteroaryl, -(C1-C6 alkyldiyl)-(C3-C9 cycloalkyl), -(C1-C6 alkyldiyl)-(C3-C9 heterocycle), C(O)R optionally substituted with one or more substituents selected from the group consisting of 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, cyclopropylamido, cyclobutyl, oxetanyl, azetidinyl, 1-methylazetidin-3-yl)oxy, N-methyl-N-oxetan-3-ylamino, azetidin-1-ylmethyl, benzyloxyphenyl, pyrrolidin-1-yl, pyrrolidin-1-yl-methanone, piperazin-1-yl, morpholinomethyl, morpholino-methanone, and morpholino; m is selected from 0, 1, 2, 3 and 4; Here, alkyldiyl, fluoroalkyldiyl, aryldiyl, carbocyclyldiyl, 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) optionally substituted with one or more groups independently selected from 3H, cyclopropyl, cyclopropylamido, cyclobutyl, oxetanyl, azetidinyl, 1-methylazetidin-3-yl)oxy, N-methyl-N-oxetan-3-ylamino, azetidin-1-ylmethyl, benzyloxyphenyl, pyrrolidin-1-yl, pyrrolidin-1-yl-methanone, piperazin-1-yl, morpholinomethyl, morpholino-methanone, and morpholino. It has.

[0065] Compounds of formula Ia-k have the following structure: JPEG0007792942000003.jpg4279Ia; JPEG0007792942000004.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, cyclopropylamido, cyclobutyl, oxetanyl, azetidinyl, 1-methylazetidin-3-yl)oxy, N-methyl-N-oxetan-3-ylamino, azetidin-1-ylmethyl, benzyloxyphenyl, pyrrolidin-1-yl, pyrrolidin-1-yl-methanone, piperazin-1-yl, morpholinomethyl, morpholino-methanone and morpholino; n is selected from 0, 1, 2, 3 and 4]; JPEG0007792942000005.jpg4079Ic; JPEG0007792942000006.jpg3979Id; JPEG0007792942000007.jpg5584Ie; JPEG0007792942000008.jpg5787If [In the above formula, R 8 is H or -CH3]; JPEG0007792942000009.jpg4176Ig; JPEG0007792942000010.jpg5176Ih; JPEG0007792942000011.jpg5176Ii; JPEG0007792942000012.jpg5176Ij; and JPEG0007792942000013.jpg4876Ik It has.

[0066] An exemplary embodiment of the compound of Formula I is 1 is CR b and Y 3 NR a Including those that are An exemplary embodiment of the compound of Formula I is 1 is N and Y 3 is C(R b )2. An exemplary embodiment of the compound of Formula I is 2 Includes those where is -(CH2)-. An exemplary embodiment of the compound of Formula I is 2 Includes those where is -(CH2CH2)-. An exemplary embodiment of the compound of Formula I is R c Includes those where is H. An exemplary embodiment of the compound of Formula I is a compound in which Cy is C6-C 20 Aryldiyl, C6-C 20 Aryldiyl is phenyldiyl, including those substituted with one or more F. An exemplary embodiment of the compound of Formula I is R 1 and R 2 Includes those where is H. An exemplary embodiment of the compound of Formula I is R 3 is H and R 4 Includes those where is -CH3. An exemplary embodiment of the compound of Formula I is R 5is C1-C6 fluoroalkyl. Exemplary embodiments of compounds of Formula I include those where m is 0.

[0067] The present invention also provides tetrahydro-pyrido[3,4-b]indol-1-yl compounds of formula XI, including formula XIa, and pharmaceutical formulations thereof, 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 have the following formula (XI): JPEG0007792942000014.jpg3793 formula (XI); [In the above formula: Z 1 and Z 2 are independently selected from —O—, —(CH)—, —C(O)—, or a bond; Cy is C6-C 20 Aryl, C3-C 12 Carbocyclyl, C2-C 20 Heterocyclyl or C1-C 20 is heteroaryl; X is —(CH)— or —(CHCH)—; R 1 are 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 , C1-C6 alkyl, C3-C8 carbocyclyl, -C1-C6 alkyl-OH, C3-C8 carbocyclyl-OH, -OC2-C6 alkyl-OH, C1-C6 fluoroalkyl, C3-C8 fluorocarbocyclyl, -C(=O)OR 12 , -NHC(=O)R 11 , -C(=O)NHR 12, -SO2R 11 , -NHSO2R 11 and -SO2NHR 12 are independently selected from; R 4 and R 5 is C1-C6 alkyl, C3-C8 carbocyclyl, -C1-C6 alkyl-OH, C3-C8 carbocyclyl-OH, C1-C6 fluoroalkyl, C3-C8 fluorocarbocyclyl, -C(=O)OR 12 are each independently selected from R 9 is 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 independently selected from 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 independently selected from heteroaryl; Each R 10 are independently selected from H, C1-C4 alkyl, and C1-C4 fluoroalkyl; Each R 11 are independently selected from C1-C4 alkyl and C1-C4 fluoroalkyl; Each R 12 are independently selected from H, C1-C4 alkyl, and C1-C4 fluoroalkyl; Each R 13 and each R 14 are independently selected from H and C1-C4 alkyl; m is 0, 1, 2 or 3. or a pharmaceutically acceptable salt, solvate or prodrug thereof.

[0069] In some embodiments, the compound of formula (XI) has formula (XIa): JPEG0007792942000015.jpg53101 formula (XIa); [In the above formula, R 2a are independently H or F, n is 0, 1 or 2, and R 4 and R 5 are independently H or methyl. It has the following structure.

[0070] In some embodiments, the compound of formula (XI) is Z 1 is a bond. In some embodiments, the compound of formula (XI) is 1 In some embodiments, the compound of formula (XI) is 1 is —(CH)—. In some embodiments, the compound of formula (XI) is 1 is —C(O)—. In some embodiments, the compound of formula (XI) is 2 is a bond. In some embodiments, the compound of formula (XI) is 2 In some embodiments, the compound of formula (XI) is 2 is —(CH)—. In some embodiments, the compound of formula (XI) is 2 In some embodiments, the compound of formula (XI) is a compound of formula (XI) wherein Cy is C6-C 20 In some embodiments, the compound of formula (XI) is a compound where Cy is phenyl. In some embodiments, the compound of formula (XI) is a compound where Cy is C3-C 12 In some embodiments, the compound of formula (XI) is a compound where Cy is cyclohexyl. In some embodiments, the compound of formula (XI) is a compound where Cy is C2-C 20In some embodiments, the compound of formula (XI) is a compound where Cy is pyrazinyl. In some embodiments, the compound of formula (XI) is a compound where Cy is piperidinyl. In some embodiments, the compound of formula (XI) is a compound where Cy is C1-C 20 In some embodiments, the compound of formula (XI) is a compound where Cy is thiazolyl. In some embodiments, the compound of formula (XI) is a compound where Cy is oxazolyl. In some embodiments, the compound of formula (XI) is a compound where Cy is pyridyl. In some embodiments, the compound of formula (XI) is a compound where R 1 is H. In some embodiments, the compound of formula (XI) is 1 In some embodiments, the compound of formula (XI) has X -(CH2)-. In some embodiments, the compound of formula (XI) has X -(CH2)- and R 1 is H. In some embodiments, the compound of formula (XI) has X -(CH2CH2)-. In some embodiments, the compound of formula (XI) has X -(CH2CH2)- and R 1 is H. In some embodiments, the compound of formula (XI) is 1 is -CH3.

[0071] In some embodiments, the compound of formula (XI) is Z 1 is a bond and Z 2 is —O—, Cy is phenyl, X is —(CH)—, and R 1 is H. In some embodiments, the compound of formula (XI) is 1 is a bond and Z 2 is -O-, Cy is phenyl, X is -(CH2CH2)-, and R 1 is H. In some embodiments, the compound of formula (XI) is 1 is a bond and Z 2 is -O-, Cy is phenyl, X is -(CH2CH2)-, and R 1 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 the activity to a given 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 Determining the value can be accomplished using conventional techniques well known in the art. Generally, IC 50 IC can be determined by measuring the activity of a given enzyme in the presence of a range of inhibitor concentrations. The experimentally obtained values ​​of enzyme activity are then plotted against the inhibitor concentrations used. The concentration of inhibitor that exhibits 50% enzyme activity (compared to the activity in the absence of any inhibitor) is called the IC. 50 Similarly, other inhibitory concentrations can be defined with appropriate determinations of activity. For example, in some situations, the 90% inhibitory concentration, or IC 90 It may be desirable to establish, for example:

[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 culture based on quantification of ATP present, an indicator of metabolically active cells. The CellTiter-Glo® Assay is designed for use in a multiwell format, making it 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. Washing of cells, removal of medium, and multiple pipetting steps are not required. The system detects as few as 15 cells per well in a 384-well format within 10 minutes after addition of the reagent and mixture.

[0074] All exemplary compounds of Formula I in Tables 1 and 2 were prepared and analyzed by LCMS [M+H] with detection of the parent ion. + (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 shows the ER alpha MCF7 HCS S inf The (%) values ​​were measured by the Breast Cancer Cell ERa High Content Fluorescence Imaging Degradation Assay in Example 901. ER alpha MCF7 HCS EC in Tables 1 and 2 50The (μM) values ​​were measured by the in vitro cell proliferation assay described in Examples 902 and 903. The rat uterine wet weight assay of Examples 906 and 907 allows for the rapid determination of the antagonist activity of compounds in ER-responsive tissues (immature rat uterus) in competition with the natural ER ligand estradiol (i.e., antagonist mode) (Ashby, J.; et al (1997) Regulatory toxicology and pharmacology: RTP, 25 (3):226-31). 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. When multiple names are associated with a compound or intermediate of Formula I, the chemical structure shall define the compound. TIFF0007792942000016.tif200170TIFF0007792942000017.tif225170TIFF0007792942000018.tif225170TIFF0007792942000019.tif187170TIFF0007792942000020.tif220170TIFF0007792942000021.tif214170TIFF0007792942000022.tif214170TIFF0007792942000023.tif220170TIFF0007792942000024.tif219170TIFF0007792942000025.tif194170TIFF0007792942000026.tif229170TIFF0007792942000027.tif246170TIFF0007792942000028.tif252170TIFF0007792942000029.tif213170TIFF0007792942000030.tif246170TIFF0007792942000031.tif212170TIFF0007792942000032.tif253170TIFF0007792942000033.tif216170TIFF0007792942000034.tif213170TIFF0007792942000035.tif220170TIFF0007792942000036.tif228170TIFF0007792942000037.tif231170TIFF0007792942000038.tif241170TIFF0007792942000039.tif213170TIFF0007792942000040.tif215170TIFF0007792942000041.tif211170TIFF0007792942000042.tif207170TIFF0007792942000043.tif223170TIFF0007792942000044.tif231170TIFF0007792942000045.tif224170TIFF0007792942000046.tif228170TIFF0007792942000047.tif215170TIFF0007792942000048.tif228170TIFF0007792942000049.tif226170TIFF0007792942000050.tif184170TIFF0007792942000051.tif234170TIFF0007792942000052.tif185170TIFF0007792942000053.tif217170TIFF0007792942000054.tif205170TIFF0007792942000055.tif220170TIFF0007792942000056.tif251170TIFF0007792942000057.tif226170TIFF0007792942000058.tif217170TIFF0007792942000059.tif224170TIFF0007792942000060.tif250170TIFF0007792942000061.tif239170TIFF0007792942000062.tif240170TIFF0007792942000063.tif247170TIFF0007792942000064.tif209170TIFF0007792942000065.tif228170TIFF0007792942000066.tif217170TIFF0007792942000067.tif214170TIFF0007792942000068.tif249170TIFF0007792942000069.tif220170TIFF0007792942000070.tif210170TIFF0007792942000071.tif228170TIFF0007792942000072.tif234170TIFF0007792942000073.tif236170TIFF0007792942000074.tif199170TIFF0007792942000075.tif248170TIFF0007792942000076.tif211170TIFF0007792942000077.tif253170TIFF0007792942000078.tif243170TIFF0007792942000079.tif210170TIFF0007792942000080.tif211170TIFF0007792942000081.tif218170TIFF0007792942000082.tif213170TIFF0007792942000083.tif240170TIFF0007792942 000084.tif231170TIFF0007792942000085.tif221170TIFF0007792942000086.tif253170TIFF0007 792942000087.tif219170TIFF0007792942000088.tif208170TIFF0007792942000089.tif200170T IFF0007792942000090.tif209170TIFF0007792942000091.tif200170TIFF0007792942000092.tif2 44170TIFF0007792942000093.tif205170TIFF0007792942000094.tif209170TIFF00077929420000 95.tif250170TIFF0007792942000096.tif208170TIFF0007792942000097.tif200170TIFF00077929 42000098.tif245170TIFF0007792942000099.tif210170TIFF0007792942000100.tif206170TIFF00 07792942000101.tif253170TIFF0007792942000102.tif227170TIFF0007792942000103.tif71170.

[0075] Administration of Compounds of Formula (I) The compounds of the present invention can be administered by any route appropriate to the condition being treated. Suitable routes include oral, parenteral (including subcutaneous, intramuscular, intravenous, intraarterial, intradermal, intrathecal, and epidural), transdermal, rectal, nasal, topical (including buccal and sublingual), intravaginal, intraperitoneal, intrapulmonary, and intranasal. For local immunosuppressive treatment, the compounds can be administered by intralesional administration, including perfusing or otherwise contacting the graft with the inhibitor prior to transplantation. It will be understood that the preferred route may vary, for example, depending on the condition of the recipient. When the compound is administered orally, it can be formulated as a pill, capsule, tablet, etc. with a pharmaceutically acceptable carrier or excipient. When the compound is administered parenterally, it can be formulated in a pharmaceutically acceptable parenteral vehicle and a unit-dose injectable form, as described in more detail below.

[0076] The dosage for treating a human patient ranges from about 10 mg to about 1000 mg of a compound of Formula I. A typical dosage is about 100 mg to about 300 mg of the compound. The dosage may be administered once daily (QID), twice daily (BID), or more frequently, depending on the pharmacokinetic and pharmacodynamic properties, including absorption, distribution, metabolism, and excretion, of the particular compound. Additionally, toxicity factors may influence the dosage regimen. When administered orally, pills, capsules, or tablets may be taken daily or less frequently for a specified period of time. The regimen may be repeated for several treatment cycles.

[0077] Methods of Treatment with Compounds 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 immune disorders, cardiovascular diseases, viral infections, inflammation, metabolic / endocrine disorders, or neurological disorders, and therefore can be treated by methods comprising administering the compounds of the present invention to such patients as described above. Human or animal patients suffering from cancer can also be treated by methods comprising administering the compounds of the present invention to such patients as described above, which can improve or ameliorate the patient's condition.

[0078] The methods of the present invention also include the treatment of breast, ovary, cervix, prostate, testis, urogenital tract, esophagus, larynx, glioblastoma, neuroblastoma, stomach, skin, keratoacanthoma, 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 tract cancer, kidney cancer, pancreatic cancer, myeloid disorders, lymphoma, hairy cell, oral cavity, nasopharynx, pharynx, lip, tongue, mouth, including treating cancers selected from small intestine, colorectal, large intestine, rectum, brain and central nervous system, Hodgkin's, leukemia, bronchus, thyroid, liver and intrahepatic bile duct, hepatocellular carcinoma, gastric cancer, glioma / glioblastoma, endometrial cancer, melanoma, kidney and renal pelvis, bladder, uterine corpus, 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 villous colon adenoma.

[0079] Pharmaceutical preparations In order to use the compounds of formula (I) of this invention for the therapeutic treatment of mammals, including humans, they will normally be formulated in accordance with standard pharmaceutical practice as pharmaceutical compositions. According to this aspect of the invention, there is provided a pharmaceutical composition comprising a compound of this invention together with a pharmaceutically acceptable diluent or carrier.

[0080] A typical formulation is prepared by mixing a 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 swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and other materials. The specific carrier, diluent, or excipient used will depend on the means and purpose for which the compound of the present invention is to be administered. Solvents are typically selected based on solvents recognized by those skilled in the art as safe for mammalian administration (GRAS; recognized as safe for food). Generally, safe solvents are non-toxic aqueous solvents, such as water, and other non-toxic solvents that are soluble or miscible in water. Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycol (e.g., PEG400, PEG300), etc., and mixtures thereof. The formulation may also include one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifying agents, glidants, processing aids, colorants, sweeteners, flavors, flavorings, and other known additives to present the drug (i.e., the compound of the present invention or a pharmaceutical composition thereof) in an attractive manner or to aid in the manufacture of a pharmaceutical product (i.e., a medicament).

[0081] These formulations can be prepared using conventional dissolution and mixing techniques. For example, the bulk drug substance (i.e., a compound of the invention or a stabilized form of the compound (e.g., a complex with a cyclodextrin derivative or other known complexing agent) is dissolved in a suitable solvent in the presence of one or more of the above-mentioned excipients. The compounds of the invention are typically formulated into pharmaceutical dosage forms to provide an easily controllable dose of the drug, allowing patient compliance with the prescribed regimen.

[0082] Pharmaceutical compositions (or formulations) for application can be packaged in a variety of ways depending on the method used to administer the drug. Generally, an article for distribution includes a container having disposed therein the pharmaceutical formulation in an appropriate form. Suitable containers are well known to those skilled in the art and include materials such as bottles (plastic and glass), sachets, ampoules, plastic bags, metal cylinders, etc. The container may also include a tamper-evident device to prevent indiscreet access to the contents of the package. In addition, the container may be provided with a label describing the contents of the container. The label 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 by mixing the compound at room temperature, at the appropriate pH, and at the desired purity with a physiologically acceptable carrier (i.e., a carrier that is nontoxic to recipients at the dosage and concentration used). The pH of the formulation will depend primarily on the specific application and concentration of the compound, but ranges from about 3 to about 8. Formulation in acetate buffer at pH 5 is a suitable embodiment.

[0084] The compounds can generally be stored as a solid composition, a lyophilized formulation, or an aqueous solution.

[0085] The pharmaceutical formulations of the present invention will be formulated, dosed, and administered in a certain manner, i.e., in amounts, concentrations, schedules, courses, vehicles, and routes of administration consistent with good medical practice. Factors to be considered in this context include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of drug delivery, the method of administration, the administration schedule, and other factors known to physicians. The "therapeutically effective amount" of the compound administered will be determined by such considerations and is the minimum amount necessary to ameliorate or treat the hyperproliferative disorder.

[0086] As a general rule, the initial pharmaceutically effective single dose of parenterally administered inhibitor will range from about 0.01-100 mg / kg, i.e., about 0.1 to 20 mg / kg of patient body weight per day, with a typical initial range of about 0.3 to about 15 mg / kg / day of the compound used.

[0087] Acceptable carriers, diluents, vehicles, excipients, and stabilizers are non-toxic to recipients at the dosages and concentrations employed and include buffers such as phosphate, citrate, and other organic acids; antioxidants, including ascorbic acid and methionine; preservatives (e.g., octadecyldimethylbenzylammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl, or benzyl alcohol; alkyl parabens, e.g., methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m -cresol); low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers, such as polyvinylpyrrolidone; amino acids, such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates, including glucose, mannose, or dextrins; chelating agents, such as EDTA; sugars, such as sucrose, mannitol, trehalose, or sorbitol; salt-forming counterions, such as sodium; metal complexes (e.g., Zn-protein complexes); and / or TWEEN TM , PLURONICS TM or polyethylene glycol (PEG). Active pharmaceutical ingredients may also be encapsulated in colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles, and nanocapsules), or in macroemulsions, in microcapsules prepared, for example, by coacervation techniques or interfacial polymerization, such as hydroxymethylcellulose or gelatin microcapsules and poly(methyl methacrylate) microcapsules, respectively. These techniques are disclosed in Remington's Pharmaceutical Sciences, 16th ed., Osol, A. (ed.) (1980).

[0088] Sustained-release preparations of the compounds of Formula I can be prepared. Suitable examples of sustained-release preparations include semipermeable matrices of solid hydrophobic polymers containing the compounds of Formula I, which matrices are in the form of shaped articles, e.g., films or microcapsules. Examples of sustained-release matrices include polyesters, hydrogels (e.g., poly(2-hydroxyethyl-methacrylate) or poly(vinyl alcohol)), polylactic acid (U.S. Pat. No. 3,773,919), copolymers of L-glutamic acid and gamma-ethyl-L-glutamate, non-degradable ethylene-vinyl acetate, LUPRON DEPOT TM (injectable microspheres of lactic acid-co-glycolic acid and leuprolide acetate) and poly-D-(-)-3-hydroxybutyric acid.

[0089] Formulations include those suitable for the routes of administration detailed herein. Formulations are conveniently presented in unit dosage form and can be prepared by any method well known in the art of pharmacy. Techniques and formulations are generally described in Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, PA). Such methods include the step of bringing into association the active ingredient with the carrier, which constitutes one or more accessory ingredients. The formulations are usually prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers, or both, and then, if necessary, shaping the product.

[0090] Formulations of a compound of Formula I suitable for oral administration may be prepared as discrete units such as pills, capsules, cachets, or tablets, each containing a predetermined amount of a compound of Formula I. Compressed formulations can be prepared by compressing in a suitable machine the active ingredient in a free-flowing form (such as a powder or granules), optionally mixed with a binder, lubricant, inert diluent, preservative, surface active agent, or dispersing agent. Molded tablets can be made by molding in a suitable machine a mixture of the powdered active ingredient moistened with an inert liquid diluent. Tablets may optionally be coated or scored and may be formulated to provide slow or controlled release of the active ingredient. Tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules (e.g., gelatin capsules, syrups, or elixirs) may be prepared for oral use. Formulations of a compound 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 or sodium carbonate, lactose, calcium 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 be uncoated or may be coated by known techniques, including microencapsulation, to delay disintegration and adsorption in the gastrointestinal tract, thereby providing a sustained action over a longer period. For example, time-delay materials such as glyceryl monostearate or glyceryl distearate, alone or with a wax, may be used.

[0091] For treatment of the eye or other external tissues, e.g., mouth and skin, the formulations are 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 employed with either a paraffinic or water-miscible ointment base. Alternatively, the active ingredient may be formulated into a cream with an oil-in-water cream base. If desired, the aqueous phase of the cream base may contain a polyhydric alcohol, i.e., alcohols having two or more hydroxyl groups, such as propylene glycol, butane 1,3-diol, mannitol, sorbitol, glycerol, and polyethylene glycol (including PEG 400), as well as mixtures thereof. Topical formulations desirably include a compound that enhances 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 emulsions of this invention can be constituted from known ingredients in a known manner. This phase can contain only an emulsifier, but desirably 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. Also, it is preferable to include both oils and fats. In summary, the emulsifier, with or without a stabilizer, constitutes the so-called emulsifying wax, which, together with the oil and fat, forms the oily dispersed phase of the cream formulation, the so-called emulsifying ointment base. Emulsifiers and emulsion 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] Aqueous suspensions of compounds of Formula I contain the active ingredient in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients include suspending agents such as sodium carboxymethylcellulose, croscarmellose, povidone, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth, and gum acacia, as well as dispersing or wetting agents such as natural phospholipids (e.g., lecithin), condensation products of alkylene oxides with fatty acids (e.g., polyoxyethylene stearate), condensation products of ethylene oxide with long-chain aliphatic alcohols (e.g., heptadecaethyleneoxycetanol), and condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides (e.g., polyoxyethylene sorbitan monooleate). Aqueous suspensions may also contain one or more preservatives, such as ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, 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 preparation, such as a sterile injectable aqueous or oleaginous suspension. This suspension can be formulated according to conventional techniques using suitable dispersing or wetting agents and suspending agents as described above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally administrable diluent or solvent, such as a solution in 1,3-butanediol, or may be prepared as a lyophilized powder. Acceptable vehicles and solvents that can be used include water, Ringer's solution, and isotonic saline. Additionally, sterile, fixed oils can be conventionally used as solvents or suspending media. For this purpose, any sterile, fixed oil can be used, including synthetic mono- or diglycerides. Furthermore, fatty acids such as oleic acid can also be used in the preparation of injectable solutions.

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

[0095] Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain antioxidants, buffers, bacteriostats, and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.

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

[0097] Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavored base (usually sucrose and acacia or tragacanth); pastilles comprising the active ingredient in an inert base such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.

[0098] Formulations for rectal administration may be presented as a suppository with a suitable base comprising, for example, cocoa butter or a salicylate.

[0099] Formulations suitable for pulmonary or intranasal administration have, for example, particle sizes in the range of 0.1 to 500 microns (including particle sizes in microns ranging from 0.1 to 500 microns, such as 0.5, 1, 30 microns, 35 microns, etc.) and are administered by rapid inhalation through the nasal passages or by inhalation through the oral cavity to reach 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 with other therapeutic agents, such as compounds conventionally used in the treatment or prevention of disorders described below.

[0100] Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing, in addition to the active ingredient, such carriers as are known in the art to be appropriate.

[0101] The formulations may be presented in unit-dose or multi-dose containers, for example, sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of a sterile liquid carrier for injection, e.g., water, immediately prior to use. Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules, and tablets of the type described above. Preferred unit dosage formulations are those containing a daily dose or unit daily sub-dose, as herein above recited, or an appropriate fraction thereof, of an active ingredient.

[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 material useful for the purpose of administering the composition, which is otherwise inert or acceptable in the veterinary field and compatible with the active ingredient. These veterinary compositions may be administered parenterally, orally, or via any other desired route.

[0103] Combination therapy The compounds of Formula I can 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, the compounds of Formula I are combined in a combined pharmaceutical formulation or in a combination therapy administration regimen 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 can be a Bcl-2 inhibitor, a JAK inhibitor, a PI3K inhibitor, an mTOR inhibitor, an anti-inflammatory agent, an immunomodulatory agent, a chemotherapeutic agent, a pro-apoptotic agent, a neurotrophic factor, a cardiovascular disease therapeutic agent, a liver disease therapeutic agent, an antiviral agent, a blood disorder therapeutic agent, a diabetes therapeutic agent, or an immunodeficiency disease therapeutic agent. The second therapeutic agent can be an NSAID anti-inflammatory agent. The second therapeutic agent can also be a chemotherapeutic agent. The second compound of the combined pharmaceutical formulation or administration regimen preferably has complementary activity to the compound of Formula I so as not to adversely affect each other. Such compounds are suitably present in combination in amounts effective for the intended purpose. In one embodiment, the compositions of the invention comprise a compound of Formula I, or a stereoisomer, tautomer, solvate, metabolite, or pharmaceutically acceptable salt or prodrug thereof, in combination with a therapeutic agent, such as an NSAID.

[0104] The combination therapy can be administered as a simultaneous or sequential regimen. When administered sequentially, the combination can be administered in two or more administrations. Combination administration 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) active agents simultaneously exert their biological activity.

[0105] The appropriate dosages of the co-administered agents are those currently in use and may be reduced by newly identified agents and their combined (synergistic) effects with other therapeutic agents or treatments.

[0106] Combination therapy can produce "synergistic effects" and be proven to be "synergistic," i.e., the effect achieved when the active ingredients are used together exceeds the sum of the effects achieved by using the compounds separately. Synergistic effects can be achieved when the active ingredients are (1) co-formulated and administered or delivered simultaneously in a combined unit dose formulation; (2) delivered alternately or in parallel as separate formulations; or (3) delivered by some other regimen. When delivered in alternation therapy, synergistic effects can also be achieved 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 alternation therapy, effective doses of each active ingredient are administered sequentially, i.e., consecutively, whereas in combination therapy, two or more active ingredients are administered together.

[0107] In certain embodiments of treatment, the compound of Formula I or a stereoisomer, tautomer, solvate, metabolite, or pharmaceutically acceptable salt or prodrug thereof may be combined with other therapeutic agents, hormones, or antibodies as described herein, as well as with surgical and radiotherapy. Thus, combination therapy according to the present invention involves the administration of at least one compound of Formula I or a stereoisomer, tautomer, solvate, metabolite, or pharmaceutically acceptable salt or prodrug thereof, and the use of at least one other cancer treatment method. The amounts of the compound of Formula I and the other pharmaceutically active therapeutic agent, as well as the relative timing of administration, will be selected to achieve the desired combined 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 ixabepilone.

[0110] In some embodiments, the compound of Formula I)(II) or a pharmaceutically acceptable salt thereof is used in combination with hormone blockade therapy, chemotherapy, radiation therapy, a monoclonal antibody, or a combination thereof.

[0111] Hormone blockade therapy includes the use of drugs that block the production of estrogen or block estrogen receptors. In some embodiments, hormone blockade therapy includes the use of estrogen receptor modulators and / or aromatase inhibitors. Estrogen receptor modulators include triphenylethylene derivatives (e.g., tamoxifen, toremifene, droloxifene, 3-hydroxytamoxifen, idoxifene, TAT-59 (phosphorylated derivative of 4-hydroxytamoxifen) and GW5638 (carboxylic acid derivative of tamoxifen)); non-steroidal estrogen receptor modulators (e.g., raloxifene, LY353381 (SERM3) and LY357489); steroidal estrogen receptor modulators (e.g., ICI-182, 780). Aromatase inhibitors include steroidal aromatase inhibitors and non-steroidal aromatase inhibitors. Steroidal aromatase inhibitors include, but are not limited to, exemestane. Non-steroidal 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 at a dose of about 10 mg per day to about 1000 mg per day. In some embodiments, LEE011 is administered at a dose of about 400 mg per day, about 500 mg per day, or about 600 mg per day. In some embodiments, the daily dose of LEE011 is administered orally. In some embodiments, a daily dose of LEE011 is administered orally once daily for three weeks, followed by a one-week washout period in which no ribociclib (LEE011) is 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 selected from the group consisting of everolimus, temsirolimus, BEZ235 (dactolisib), BYL719 (alpelisib), GDC0032 (taselisib), BKM120 (buparlisib), BGT226, GDC0068 (ipatasertib), GDC-0980 (apitolithib), GDC0941 (pictilisib), INK128 (MLN0128), IN 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 at a dose of about 1 mg per day to about 20 mg per day. In some embodiments, everolimus is administered at a dose of about 2.5 mg per day, about 5 mg per day, or about 10 mg per day. In some embodiments, the daily dose of everolimus is administered once daily. In some embodiments, the phosphoinositide 3-kinase (PI3K) / mTOR pathway inhibitor is BKM120 (buparlisib). In some embodiments, BKM120 (buparlisib) is administered at a dose of about 5 mg per day to about 500 mg per day. In some embodiments, BKM120 is administered at a dose of about 50 mg per day to about 100 mg per day. In some embodiments, BKM120 is administered at a dose of about 100 mg per day. In some embodiments, the daily dose of BKM120 is administered once daily. In some embodiments, the phosphoinositide 3-kinase (PI3K) / mTOR pathway inhibitor is BYL719.In some embodiments, BYL719 is administered at a dose of about 25 mg per day to about 1000 mg per day. In some embodiments, BYL719 is administered at a dose of about 250 mg per day or about 350 mg per day. In some embodiments, the daily dose of BYL719 is administered once a day.

[0114] Metabolites of the Compound of Formula I Also included within the scope of this invention are in vivo metabolic products of Formula I described herein. Such products may result, for example, from the oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic cleavage, etc. of the administered compound. Accordingly, the invention includes metabolites of compounds of Formula I, including compounds produced by a process comprising contacting a compound of this invention with a mammal for a period of time sufficient to yield a metabolic product thereof.

[0115] The metabolites are typically radiolabeled (e.g., 14 C or 3 Identification is accomplished by preparing a H isotope and parenterally administering it to animals such as rats, mice, guinea pigs, monkeys, or humans at a detectable dose (e.g., greater than about 0.5 mg / kg), allowing sufficient time for metabolism to occur (typically about 30 seconds to 30 hours), and isolating the conversion products from urine, blood, or other biological samples. Such products are easily isolated because they are labeled (otherwise isolated by using antibodies capable of binding to epitopes surviving in the metabolites). The structures of the metabolites are determined by conventional methods, such as MS, LC / MS, or NMR analysis. Metabolite analysis is generally performed in the same manner as conventional drug metabolism studies well known to those skilled in the art. Metabolites, so long as they are not otherwise found in vivo, are useful in diagnostic assays for therapeutic administration of the compounds of the invention.

[0116] manufactured goods In another embodiment of the present invention, an article of manufacture or "kit" containing materials 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 a stereoisomer, tautomer, solvate, metabolite, or pharmaceutically acceptable salt or prodrug thereof. The kit may further include a label or package insert affixed to or accompanying the container. The term "package insert" is used to refer to instructions typically included in retail packaging of therapeutic products, including information on directions, usage, dosage, administration, contraindications, and / or precautions regarding the use of such therapeutic products. Suitable containers include, for example, bottles, vials, syringes, blister packs, and the like. The container may be formed from a variety of materials, such as glass or plastic. The container may hold a compound of Formula I or a formulation thereof effective to treat a condition and may have a sterile access port (e.g., the container may be a vial or an intravenous solution bag with a stopper pierceable by a hypodermic injection needle). At least one active agent in the composition is a compound of Formula I. The label or package insert indicates that the composition is used to treat a selected condition, such as cancer. The label or package insert may further indicate that the patient to be treated is a patient with a disorder, such as a hyperproliferative disorder, neurodegeneration, cardiac hypertrophy, pain, migraine, or neurotraumatic disease or event. In one embodiment, the label or package insert 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 package insert may also indicate that the composition can be used to treat other disorders. Alternatively, or additionally, the article of manufacture may further comprise a second container containing a pharmaceutically acceptable buffer, such as bacteriostatic water for injection (BWFI), phosphate buffered saline, Ringer's solution, and dextrose solution. The article of manufacture may further include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, and syringes.

[0117] The kit may further comprise instructions for the administration of the compound of Formula I and, if present, the second pharmaceutical formulation. For example, if the kit comprises a first composition comprising a compound of Formula I and a second pharmaceutical formulation, the kit may further comprise instructions for the simultaneous, sequential, or separate administration of the first and second pharmaceutical compositions to a patient in need thereof.

[0118] In another embodiment, the kit is suitable for delivering a solid oral form of a compound of Formula I, such as a tablet or capsule. Such a kit preferably contains a plurality of unit doses. Such a kit may include a card with the dosage amounts arranged in the order of their intended use. An example of such a kit is a "blister pack." Blister packs are well known in the packaging industry and are widely used to package pharmaceutical unit dosage forms. If necessary, a memory aid can be provided, for example in the form of numbers, letters, or other markings, or with a calendar insert indicating the days in the treatment schedule on which the doses can be administered.

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

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

[0121] Preparation of Compounds of Formula I The compounds of Formula I can be synthesized by synthetic routes that include processes similar to those known in the chemical arts, particularly in light of the description contained herein, and processes similar to those for other heterocycles 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 of which is incorporated by reference). The starting materials are generally available from commercial sources such as Aldrich Chemicals (Milwaukee, Wis.) or are readily prepared using methods well known to those of skill in the art (e.g., prepared by the methods outlined in Louis F. Fieser and Mary Fieser, Reagents for Organic Synthesis, v. 1-23, Wiley, NY (1967-2006 ed.), or Beilstein's Handbuch der organischen Chemie, 4, Aufl. ed. Springer-Verlag, Berlin, including appendices (also available via the Beilstein online database)).

[0122] Synthetic chemistry transformations and protecting group methodologies (protection and deprotection), as well as the necessary reagents and intermediates, useful for synthesizing compounds of Formula I are known in the art and include, for example, those described in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T.W. Greene and P.G.M. Butts, 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] Compounds of Formula I can be prepared singly or as compound libraries comprising at least two, e.g., 5 to 1000 compounds, or 10 to 100 compounds. Libraries of compounds of Formula I can be prepared by combinatorial "split and mix" techniques or by multiple parallel synthesis using either solution-phase or solid-phase chemistry, as known to those skilled in the art. Thus, according to a further aspect of the present invention, there is provided a compound library comprising at least two compounds or pharmaceutically acceptable salts thereof.

[0124] The Examples provide exemplary methods for preparing compounds of Formula I. Those skilled in the art will recognize that other synthetic routes can be used to synthesize compounds of Formula I. 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 produce various derivatives and / or reaction conditions. In addition, many of the exemplary compounds prepared by the methods described can be further modified in light of this disclosure using conventional chemistry well known to those skilled in the art.

[0125] In preparing compounds of Formula I, protection of remote functionality (e.g., primary or secondary amines) of intermediates may be necessary. The need for such protection will vary depending on the nature of the remote functionality 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 is readily determined by one skilled in the art. For a general description of protecting groups and their use, see T.W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991.

[0126] In the processes for preparing compounds of Formula I, it may be advantageous to separate reaction products from one another and / or from starting materials. The desired product of each step or series of steps is separated and / or purified to the desired degree of homogeneity by techniques common in the art. Typically, such separation involves multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography. Chromatography can include any number of methods, including, for example, reverse-phase and normal-phase; size exclusion; ion exchange; high-, medium-, and low-pressure liquid chromatography methods and equipment; small-scale analytical; simulated moving bed (SMB), preparative thin- or thick-layer chromatography, and small-scale thin-layer and flash chromatography.

[0127] Another type of separation method involves treatment of the mixture with a reagent selected to bind or otherwise render separable the desired product, unreacted starting materials, reaction by-products, etc. Such reagents include adsorbents or absorbents, e.g., activated carbon, molecular sieves, ion exchange media, etc. Alternatively, the reagent can be an acid in the case of basic substances, a base in the case of acidic substances, a binding reagent (e.g., antibody), a binding protein, a selective chelator (e.g., crown ether), a liquid / liquid ion extraction reagent (LIX), etc. The selection of an appropriate separation method depends on the properties of the substances involved, e.g., 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] Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as chromatography and / or fractional crystallization. Enantiomers can also be separated by converting the enantiomeric mixture to a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., a chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers, and converting the individual diastereomers to the 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 using a chiral HPLC column.

[0129] A single stereoisomer, e.g., an enantiomer, substantially free of its stereoisomer can be obtained by resolution of a racemic mixture using methods such as the formation of diastereomers with an optically active resolving agent (Eliel, E. and Wilen, S. "Stereochemistry of Organic Compounds," John Wiley & Sons, Inc., New York, 1994; Lochmuller, C.H. (1975) J. Chromatogr., 113(3):283-302). Racemic mixtures of chiral compounds of the present invention can be separated and isolated by any suitable method, including (1) the formation of ionic diastereomeric salts with chiral compounds and separation by fractional crystallization or other methods, (2) the formation of diastereomeric compounds with chiral derivatizing agents, separation of diastereomers, and conversion to pure stereoisomers, and (3) the direct separation of substantially pure or enriched stereoisomers under chiral conditions. See Drug Stereochemistry, Analytical Methods and Pharmacology, Irving W. Wainer, ed., Marcel Dekker, Inc., New York (1993).

[0130] Under method (1), diastereomeric salts can be formed by the reaction of enantiomerically pure chiral bases, such as brucine, quinine, ephedrine, strychnine, a-methyl-b-phenylethylamine (amphetamine), and other asymmetric compounds bearing acidic functional groups, such as carboxylic and sulfonic acids. The diastereomeric salts can be induced to separate by fractional crystallization or ionic chromatography. For the separation of optical isomers of amino compounds, the addition of chiral carboxylic or sulfonic acids, such as camphorsulfonic acid, tartaric acid, mandelic acid, or lactic acid, can result in the formation of diastereomeric salts.

[0131] Alternatively, by method (2), the substrate to be resolved is reacted with one enantiomer of a chiral compound to form a diastereomeric pair (E. and Wilen, S. "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., 1994, p. 322). Diastereomeric compounds can be formed by reacting the asymmetric compound with an enantiomerically pure chiral derivatizing agent, such as a menthyl derivative, and then the diastereomers can be separated and hydrolyzed to obtain the pure or enriched enantiomer. A method for determining optical purity involves making a chiral ester, such as a menthyl ester (in the presence of a base), e.g., (-)menthyl chloroformate, or the Mosher ester of the racemic mixture, a-methoxy-a-(trifluoromethyl)phenylacetate (Jacob III. Chem., (1982) 47:4165), and determining the presence of two atropisomeric enantiomers or diastereomers. 1 This involves analyzing the H NMR spectrum. Stable diastereomers of atropisomeric compounds can be separated and isolated by normal-phase and reverse-phase chromatography, following the method for separating atropisomeric naphthyl-isoquinolines (WO 96 / 15111). By method (3), a racemic mixture of two enantiomers can be separated by chromatography using a chiral stationary phase ("Chiral Liquid Chromatography" (1989) WJ Lough, Ed., Chapman and Hall, New York; Okamoto, J. Chromatogr., (1990) 513:375-378). Enriched or purified enantiomers can be distinguished by methods used to distinguish other chiral molecules with asymmetric carbon atoms, such as optical rotation and circular dichroism.

[0132] Compounds of formula I can be prepared by the general procedures in Schemes 1-7. Scheme 1: TIFF0007792942000104.tif137170 Scheme 1 shows the reaction of para-hydroxybenzaldehyde intermediate 1 with tert-butyl 3-iodoazetidine-1-carboxylate to provide exemplary tert-butyl 3-(4-formylphenoxy)azetidine-1-carboxylate intermediate 2. Exemplary intermediate 1 is 2,6-difluoro-4-hydroxybenzaldehyde. Cyclization of 2 with bicyclic amine 3 provides tricyclic, tetrahydro-pyrido[3,4-b]indol-1-yl azetidine intermediate 4. Acid deprotection of 4 and alkylation of 5 provides tricyclic, tetrahydro-pyrido[3,4-b]indol-1-yl azetidine 6. Scheme 2: JPEG0007792942000105.jpg80138 Scheme 2 shows the cyclization of a para-iodobenzaldehyde intermediate 7, such as 2,6-difluoro-4-iodobenzaldehyde, with a bicyclic amine 3 to give the tricyclic, tetrahydro-pyrido[3,4-b]indol-1-yl iodophenyl intermediate 8. Reaction of 8 with alcohol 9 gives the tricyclic, tetrahydro-pyrido[3,4-b]indol-1-yl intermediate 10. Scheme 3: Scheme 3 shows the reaction of amine 11 with an alkylating reagent, where the leaving group is iodide, bromide, or triflate, to give intermediate 12. Alternatively, amine 11 can be reacted with an aldehyde or ketone to give intermediate 12 via a reductive amination reaction. Intermediate 12 is condensed with an aldehyde to give intermediate 13. X of Cy is then substituted with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 1The iodide or bromide on the group could be coupled with an alcohol, amine, sulfide, or olefin via a Pd- or Cu-catalyzed Ullman, Buchwald, or Heck reaction to give target 14. Alternatively, the protected phenol (OP) on group Cy could be deprotected, and the resulting phenol could be further coupled with an alcohol via a Mitsunobu reaction. Alternatively, the phenol could be alkylated with an iodide, bromide, chloride, triflate, or mesylate to give the tricyclic, tetrahydro-pyrido[3,4-b]indol-1-yl intermediate 14. Scheme 4: TIFF0007792942000107.tif106170 Scheme 4 shows the Pictet-Spengler cyclization of amine 11 with an aldehyde to give X. 1 The reaction of amine 15 with an acid chloride produces amide 16. The reaction of iodide or bromide X on Cy then gives intermediate 15, which is an iodide or bromide. 1 The group could be coupled with an alcohol or amine or sulfide or olefin via a Pd- or Cu-catalyzed Ullman, Buchwald, or Heck reaction to give intermediate 17. Alternatively, the protected phenol (OP) on group Cy of 16 could be deprotected, and the resulting phenol could be further coupled with an alcohol via a Mitsunobu reaction to give 17. Alternatively, the phenol (OH) could be alkylated with iodide, bromide, chloride, triflate, or mesylate to give the tricyclic, tetrahydro-pyrido[3,4-b]indol-1-yl amide intermediate 17. Scheme 5: TIFF0007792942000108.tif97170 Scheme 5 shows that amine 15 can react with a sulfonyl chloride to give sulfonamide 18, which can be converted to the tricyclic, tetrahydro-pyrido[3,4b]indol-1-yl sulfonamide intermediate 19 by Pd- or Cu-catalyzed Ullman, Buchwald, or Heck reactions, or by Mitsunobu or alkylation reactions. Scheme 6: TIFF0007792942000109.tif43170 Scheme 6 shows the reaction of amine 15 with an alkylating agent (R 5 —X) to give intermediate 13. Alternatively, amine 15 can be reacted with an aldehyde or ketone and a reducing agent such as sodium cyanoborohydride to give intermediate 13. Scheme 7: Scheme 7 shows a general synthetic route to tryptamine 23. Under Vilsmeier reaction conditions, substituted indole 20 is converted to aldehyde 21. Aldol reaction of aldehyde 21 with nitroethane gives compound 22. Reduction of 22 with lithium aluminum hydride affords tryptamine 23. [Example]

[0133] Example 101 (1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-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-carboxylic acid tert-butyl ester 101c 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) 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. The resulting mixture was heated at 150 °C for 1 h under microwave heating. The reaction mixture was cooled to ambient temperature, the solids removed by filtration, the filter cake washed with toluene, and the filtrate concentrated in vacuo. The residue was partitioned between EtOAc and water, and the organic phase was separated, washed with brine, dried over NaSO, filtered, and concentrated in vacuo. 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 give 101c as a yellow oil (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-indol-3-yl)-1-methyl-ethyl]-amine 101d JPEG0007792942000112.jpg3542 Compound 101d was prepared according to WO 2014 / 191726, p. 78.

[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-carboxylic acid tert-butyl ester 101e JPEG0007792942000113.jpg3876 Under argon, to a solution of (2-fluoro-2-methyl-propyl)-[(R)-2-(1H-indol-3-yl)-1-methyl-ethyl]-amine 101d (540 mg, 2.17 mmol) prepared according to WO 2014 / 191726, p. 78, in toluene (8 mL) was added 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). The mixture was heated in a sealed tube at 80 °C for 4 h and protected from light. The reaction mixture was cooled to room temperature (RT) and concentrated in vacuo. The residue was partitioned between ethyl acetate (EtOAc) and saturated sodium bicarbonate solution. The organic phase was separated, washed with brine, dried over NaSO, filtered, and concentrated in vacuo. 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 afford 101e (1.10 g, 90%) as an off-white solid. 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-(azetidin-3-yloxy)-2,6-difluoro-phenyl]-2-(2-fluoro-2-methyl-propyl)-3-methyl-2,3,4,9-tetrahydro-1H-beta-carboline 101f To a mixture of 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) under argon, TFA (1.75 mL, 23.1 mmol) was added dropwise, and the mixture was stirred at room temperature for 3 hours while protected from light. The reaction mixture was concentrated in vacuo and purified using an SCX-2 cartridge (mobile phase: dichloromethane / methanol 1:1, followed by 2N ammonia in methanol). The appropriate fractions were combined and evaporated to give 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: To a mixture of (1R,3R)-1-[4-(azetidin-3-yloxy)-2,6-difluoro-phenyl]-2-(2-fluoro-2-methyl-propyl)-3-methyl-2,3,4,9-tetrahydro-1H-beta-carboline 101f (54 mg, 0.12 mmol) in N,N-dimethylformamide (2 mL) under argon, 1-bromo-3-fluoropropane (16 μL, 0.16 mmol; CAS number 352-91-0) and ethyldiisopropylamine (12 μL, 0.24 mmol) were added. 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 NaSO, 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 a C18 cartridge (acetonitrile, water, formic acid). The appropriate fractions were combined and evaporated to give 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)azetidin-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-iodo-phenyl)-2-(2-fluoro-2-methyl-propyl)-3-methyl-2,3,4,9-tetrahydro-1H-beta-carboline 102b 2,6-Difluoro-4-iodobenzaldehyde 102a (CAS No.: 1160573-10-3, 65 mg, 0.24 mmol) was added to a solution of (2-fluoro-2-methyl-propyl)-[(R)-2-(1H-indol-3-yl)-1-methyl-ethyl]amine 101d (50 mg, 0.20 mmol) in toluene (170 μL) under argon, prepared according to WO 2014 / 191726, p. 78, 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 on an SCX-2 cartridge (mobile phase: dichloromethane / methanol 9:1, followed by 2N ammonia in methanol). The appropriate fractions were combined and evaporated, and the crude product was purified by silica gel chromatography (mobile phase: cyclohexane / ethyl acetate, gradient 0% to 30%) to afford 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 of (1R,3R)-1-(2,6-difluoro-4-iodo-phenyl)-2-(2-fluoro-2-methyl-propyl)-3-methyl-2,3,4,9-tetrahydro-1H-beta-carboline 102b (82 mg, 0.16 mmol), 2-(3-fluoromethyl-azetidin-1-yl)-ethanol 102c (prepared according to WO 2013 / 090836 p. 124) (44 mg, 0.33 mmol; CAS number: 1443984-69-7, WO 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 resulting 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 (3 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). The appropriate fractions were collected and evaporated to give 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)azetidin-1-yl)ethoxy)phenyl)-3-methyl-3,4-dihydro-1H-pyrido[3,4-b]indol-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 To a microwave vial was added (2R)-1-(1H-indol-3-yl)propan-2-amine 103a (710 mg, 3.67 mmol), followed by 2,6-difluoro-4-iodo-benzaldehyde (1.1 g, 4.03 mmol) and acetonitrile (2.6 mL). The reaction was placed under a nitrogen atmosphere and TFA (0.5 mL, 7.0 mmol) was added. The reaction was then heated to 130 °C in a microwave for 1 h and then quenched with saturated aqueous NaHCO3. The mixture was extracted with DCM (3 × 100 mL), dried over MgSO4, filtered, and concentrated. The crude product was purified by flash column chromatography on silica gel (0-100% EtOAc / hexanes) to give 103b (450 mg, 29%). 1 H NMR (400 MHz, deuterochloroform-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]indol-2(9H)-yl)-2-methylpropan-1-one 103c To a round-bottom flask (RBF) was added (1R,3R)-1-(2,6-difluoro-4-iodo-phenyl)-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 was heated to 45 °C for 1 h. Diisopropylethylamine (Hunig's base, 0.1 mL, 0.59 mmol) was added, and the reaction was stirred until LC-MS showed the starting material was consumed. A saturated aqueous solution of sodium bicarbonate (10 mL) was added. The reaction mixture was then extracted with DCM (3×50 mL), dried over MgSO, filtered, and concentrated. The crude product was purified by flash column chromatography on silica gel (0-100% EtOAc / hexanes) to give 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: To a 5 mL microwave vial was added 1-[(1R,3R)-1-(2,6-difluoro-4-iodo-phenyl)-3-methyl-1,3,4,9-tetrahydropyrido[3,4-b]indol-2-yl]-2-methyl-propan-1-one 103c (51 mg, 0.10 mmol), followed by 2-[3-(fluoromethyl)azetidin-1-yl]ethanol 102c (prepared according to WO 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 was then heated to 135 °C overnight and then cooled to room temperature. The reaction mixture was then filtered through Celite and eluted with EtOAc. The combined filtrate was then concentrated and purified by reverse phase HPLC to give 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)azetidin-1-yl)ethoxy)phenyl)-3-methyl-3,4-dihydro-1H-pyrido[3,4-b]indol-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]indol-2(9H)-yl)-2-fluoro-2-methylpropan-1-one 104a To a round-bottom flask was added (1R,3R)-1-(2,6-difluoro-4-iodo-phenyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole 103b (100 mg, 0.24 mmol), followed by 2-fluoro-2-methyl-propanoyl chloride (prepared from the reaction of the corresponding acid with oxalyl chloride in 1 M CHCl3 (0.59 mL)), sodium bicarbonate (99 mg, 1.2 mmol), and chloroform (1.6 mL). The reaction was then heated to 45 °C for 1 h, followed by the addition of Hunig's base (0.2 mL, 1.2 mmol). The reaction was monitored by LC-MS and stirred until all starting material was consumed. The reaction was quenched with saturated aqueous sodium bicarbonate. The mixture was then extracted with DCM (3×50 mL), dried over MgSO, filtered, and concentrated. The crude product was purified by silica gel column chromatography (0-100% EtOAc / hexanes) to give 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: To a 5 mL microwave vial was added 1-[(1R,3R)-1-(2,6-difluoro-4-iodo-phenyl)-3-methyl-1,3,4,9-tetrahydropyrido[3,4-b]indol-2-yl]-2-fluoro-2-methyl-propan-1-one 104a (29 mg, 0.056 mmol), followed by 2-[3-(fluoromethyl)azetidin-1-yl]ethanol (15 mg, 0.11 mmol), copper iodide (4 mg, 0.023 mmol), potassium carbonate (24 mg, 0.17 mmol), and butyronitrile (0.37 mL). The solution was degassed for 5 minutes and then heated to 135 °C overnight. The reaction was monitored by LC-MS, which showed that all starting material had been consumed. The crude mixture was cooled to room temperature and filtered through Celite®. The Celite plug was further washed with EtOAc and the combined filtrate was concentrated and purified by reverse phase HPLC to give 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)azetidin-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 of 2,6-difluoro-4-hydroxybenzaldehyde (CAS number: 532967-21-8, 300 mg, 1.89 mmol) and 2-bromo-ethyl acetate (CAS number: 927-68-4, 0.22 mL, 2 mmol) in acetonitrile (5 mL) and N,N-dimethylformamide (1 mL) was heated at 80° C. for 24 h. An additional portion of 2-bromo-ethyl acetate (0.11 mL, 1 mmol) was added, and heating at 80° C. was continued for an additional 30 h. The reaction mixture was allowed to cool to ambient temperature. The residue was partitioned between EtOAc and saturated sodium bicarbonate solution. The aqueous layer was extracted with another portion of EtOAc. The combined organic layers were separated, dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel column chromatography (mobile phase: cyclohexane / ethyl acetate, gradient 0% to 33%) to give 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]indol-1-yl)phenoxy)ethyl acetate 105b JPEG0007792942000120.jpg4470 Under argon, to a solution of (2-fluoro-2-methyl-propyl)-[(R)-2-(1H-indol-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) in toluene (1 mL) was added glacial acetic acid (0.1 mL, 1.72 mmol). The vessel was sealed, and the reaction mixture was heated at 80 °C for 16 h. The reaction mixture was allowed to cool to ambient temperature. The residue was partitioned between dichloromethane and a saturated solution of sodium bicarbonate. The aqueous layer was extracted with another portion of dichloromethane. The combined organic layers were separated, dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography (mobile phase: cyclohexane / ethyl acetate, gradient 0% to 20%) to give 105b as a white foam (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]indol-1-yl)phenoxy)ethanol 105c JPEG0007792942000121.jpg36612-(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)phenoxy)ethyl acetate. To a solution of 105b (320 mg, 0.675 mmol) in THF / MeOH (2 / 1, 6 mL) was added sodium hydroxide (1 N, 4 mL). The reaction mixture was heated at 70 °C for 4 min. The reaction mixture was cooled to ambient temperature and the solvent was removed in vacuo. The residue was partitioned between dichloromethane and water. The organic layer was separated, dried over MgSO4, filtered, and concentrated in vacuo to give 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 JPEG0007792942000122.jpg36582-(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)phenoxy)ethanol To a solution of 105c (130 mg, 0.3 mmol) in DCM (2.5 mL) was added triphenylphosphine (94 mg, 0.36 mmol) and carbon tetrabromide (120 mg, 0.36 mmol). The reaction mixture was stirred at room temperature for 1 h, and then the solvent was removed in vacuo. The crude product was purified by silica gel column chromatography (mobile phase: cyclohexane / ethyl acetate, gradient 0% to 20%) to give 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: (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. To a solution of 105d (62 mg, 0.125 mmol) in acetonitrile (1 mL) was added N,N-diisopropylethylamine (0.064 mL, 0.375 mmol) and 3-(difluoromethyl)azetidine hydrochloride (CAS 1354792-76-9, 27 mg, 0.187 mmol). The reaction mixture was stirred at room temperature for 1 hour and then at 45 °C for 4 hours. The reaction mixture was allowed to cool to ambient temperature. The residue was partitioned between EtOAc and water. The aqueous layer was extracted with another portion of EtOAc. The combined organic layers were separated, dried over MgSO, filtered, and concentrated in vacuo. The crude product was purified by silica gel column chromatography (mobile phase: dichloromethane / methanol, gradient 0% to 2.5%) to give 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 106-125 were prepared according to the procedures described herein and had the following LCMS [M+H] + It was characterized by. TIFF0007792942000123.tif181170

[0151] Example 126 (1R,3R)-1-(2,6-difluoro-4-(2-(3-(fluoromethyl)azetidin-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 To a 50 mL round-bottom flask was added (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). N,N-Diisopropylethylamine (0.06 mL, 0.35 mmol) and methanesulfonyl chloride (0.014 mL, 0.18 mmol) were then added sequentially. The reaction was then heated to 45 °C and monitored until LCMS indicated complete consumption of the starting material. The reaction was cooled to room temperature, quenched by the addition of saturated aqueous NH4Cl, 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 give 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 = 6.6Hz, 3H).LCMS: 503.0 [M+H] + .

[0152] Step 2: To a 5 mL vial was added (1R,3R)-1-(2,6-difluoro-4-iodo-phenyl)-3-methyl-2-methylsulfonyl-1,3,4,9-tetrahydropyrido[3,4-b]indole (40 mg, 0.08 mmol), 2-[3-(fluoromethyl)azetidin-1-yl]ethanol (21 mg, 0.16 mmol), cuprous iodide (6 mg, 0.032 mmol), potassium carbonate (33 mg, 0.24 mmol), and butyronitrile (0.5 mL). The solution was degassed for 5 minutes and then heated to 135 °C overnight. The reaction was monitored by LCMS. When the reaction was complete, the reaction mixture was filtered through Celite and eluted with EtOAc. The filtrate was concentrated and purified by reverse-phase HPLC to give 126 (6 mg, 15% yield). 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]indol-1-yl)phenyl)-1-(3-fluoropropyl)azetidin-3-amine 145 Step 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 JPEG0007792942000125.jpg3336 To a solution of (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 NaHCO (10 mL) and water (20 mL). The organic layer was dried over anhydrous NaSO 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 H 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), 2.47 - 2.33 (m, 1H), 1.30 - 1.17 (m, 6H), 1.11 (d, J = 6.4 Hz, 3H).

[0154] Step 2: 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]indol-1-yl)phenyl)amino)azetidine-1-carboxylate A mixture of (1R,3R)-1-(4-bromo-2,6-difluorophenyl)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (800.0 mg, 1.77 mmol from Step 1), BINAP (110.4 mg, 0.18 mmol), Pd(dba) (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 h under a N atmosphere. The reaction mixture was concentrated and purified on a silica gel column (0-5% methanol in DCM) to give 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]indol-1-yl)phenyl)azetidin-3-amine JPEG0007792942000127.jpg3642To a mixture of 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]indol-1-yl)phenyl)amino)azetidine-1-carboxylate (from Step 2, 0.9 g, 1.66 mmol) in DCM (5 mL), o C TFA (1.8 mL, 24.88 mmol) was added. The resulting mixture was stirred at 0 °C for 16 h. Aqueous NaHCO3 solution (80 mL) was slowly added to the reaction mixture, and then the reaction mixture was extracted with DCM (100 mL × 2). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated to give the title compound (700 mg, 95%) as a brown solid. The crude product was used in the next step without further purification.

[0156] Step 4: To a mixture of N-(3,5-difluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)azetidin-3-amine (700.0 mg, 1.58 mmol from Step 3) 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 h. The reaction mixture was purified by column (0-10% MeOH in DCM) and further purified by reverse phase chromatography (66-96% acetonitrile / 0.05% NH4OH in water) to give 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)azetidin-1-yl)ethoxy)phenyl)-3-methyl-3,4-dihydro-1H-pyrido[3,4-b]indol-2(9H)-yl)-2-fluoro-2-methylpropan-1-ol 154 Step 1: Dimethyl 2-fluoro-2-methylmalonate To an oven-dried 500 mL round-bottom flask was added sodium hydride (1.15 equiv., 21 mmol). The reaction was placed under a nitrogen atmosphere and cooled to 0 °C. THF (63 mL) was then added. To this mixture was added dimethyl 2-methylpropanedioate (5.0 g, 34.2 mmol) dropwise, and the reaction mixture was stirred for 30 minutes. n-Fluorobenzenesulfonimide (1.05 equiv., 19.2 mmol) was then added in one portion. The reaction mixture was allowed to warm to room temperature and solidify, and an additional 50 mL of THF was added. After 1.5 hours, the reaction was quenched with 2 N aqueous HCl, diluted with EtOAc (500 mL), and washed with 2 N HCl (3 × 200 mL). The organics were separated, dried over MgSO4, filtered, and concentrated. The crude white solid was then taken up in 200 mL of heptane, sonicated, and filtered through Celite. The filtered solid was then washed with 3 x 200 mL of heptane. The combined filtrate was then concentrated to give the crude desired product (3 g, 53% yield) 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 To an oven-dried 500 mL round-bottom flask was added dimethyl 2-fluoro-2-methyl-propanedioate (3 g, 18.3 mmol) and THF (90 mL). The reaction mixture was placed under a nitrogen atmosphere and then cooled to 0 °C. Lithium aluminum hydride solution (1 M in THF, 2.75 equiv., 50.3 mmol) was then added dropwise, and the reaction was allowed to warm to room temperature over 1 h. The reaction was then recooled to °C and quenched by the addition of water (2 mL), followed by 15% aqueous NaOH (2 mL) and water (4 mL). The slurry was stirred for 15 min, filtered, and concentrated to give the crude product (1.4 g, 71% yield). 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-methylpropan-1-ol To an oven-dried 500 mL round-bottom flask was added 2-fluoro-2-methyl-propane-1,3-diol (1.47 g, 1.25 equiv., 13.6 mmol), followed by imidazole (1.11 g, 1.5 equiv., 16.4 mmol), tert-butylchlorodiphenylsilane (3.0 g, 10.9 mmol), and chloroform (136 mL). The reaction was stirred overnight and quenched by the addition of 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 give the desired product (1.26 g, 33% yield). 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 3-[tert-Butyl(diphenyl)silyl]oxy-2-fluoro-2-methyl-propan-1-ol (1.3 g, 3.8 mmol) and dichloromethane (63 mL) were added to an oven-dried 500 mL round-bottom flask under a nitrogen atmosphere. The reaction mixture was then cooled to 0 °C, and trifluoromethanesulfonic anhydride (1.27 g, 1.2 equiv., 4.5 mmol) was added dropwise. The reaction mixture was then stirred for 2 h, followed by washing with 2 N HCl and then saturated NaHCO3 solution. The organics were separated, then dried over MgSO4, and filtered through a silica gel plug, eluting with DCM. The filtrate was then concentrated to dryness to give 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-indol-3-yl)propan-2-yl)-3-(tert-butyldiphenylsilyloxy)-2-fluoro-2-methylpropan-1-amine To an oven-dried 250 mL round-bottom flask were added (2R)-1-(1H-indol-3-yl)propan-2-amine (600 mg, 3.1 mmol), N,N-diisopropylethylamine (0.81 mL, 1.5 equiv., 4.65 mmol), and 1,4-dioxane (6 mL), and the reaction mixture was placed under a nitrogen atmosphere. Then, [3-[tert-butyl(diphenyl)silyloxy-2-fluoro-2-methylpropyl]trifluoromethanesulfonate (1.95 g, 1.25 equiv., 3.9 mmol) was added, and the reaction mixture was heated to 90 °C. When LC-MS showed the consumption of the starting material, the reaction mixture was quenched with saturated aqueous NaHCO3, and the mixture was extracted with EtOAc (3 x 200 mL). The combined organics were dried over MgSO4, filtered, and concentrated. Purification by flash silica gel column chromatography (0-100% EtOAc / hexanes) gave the title compound (1.2 g, 77% yield). LCMS 503.3 [M−H] + .

[0162] Step 6: 3-((R)-1-(1H-indol-3-yl)propan-2-ylamino)-2-fluoro-2-methylpropan-1-ol JPEG0007792942000133.jpg22463-[tert-Butyl(diphenyl)silyl]oxy-2-fluoro-N-[(1R)-2-(1H-indol-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 THF (9.6 mL) and tetrabutylammonium fluoride hydrate (3 mL of a 1 M THF solution). The reaction mixture was stirred at room temperature until LC-MS indicated complete consumption of the starting material. The reaction mixture was quenched by the addition of water and extracted with 5 x 100 mL of 25% IPA in DCM. The combined organics were then dried over MgSO4, filtered, and concentrated. Purification by flash column chromatography on silica gel (0-30% 2N NH3 in MeOH / DCM) gave 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]indol-2(9H)-yl)-2-fluoro-2-methylpropan-1-ol To a 100 mL round-bottom flask was added 2-fluoro-3-[[(1R)-2-(1H-indol-3-yl)-1-methyl-ethyl]amino]-2-methyl-propan-1-ol (332 mg, 1.26 mmol), 2,6-difluoro-4-iodo-benzaldehyde (370 mg, 1.1 equiv., 1.38 mmol), and toluene (5.5 mL). The reaction was placed under a nitrogen atmosphere, and acetic acid (2 M) was added. The reaction was then heated to 90 °C for 48 h. It was then quenched with a saturated aqueous solution of NaHCO and vigorously extracted with iPrOAc (5 x 100 mL). The organics were then dried over MgSO, filtered, and concentrated. Purification by flash column chromatography on silica gel (0-100% iPrOAc / heptane) afforded the title compound (475 mg, 74% yield). LCMS: 515.1 [M+H] +.

[0164] Step 8: A 20 mL microwave vial was charged with 3-[(1R,3R)-1-(2,6-difluoro-4-iodo-phenyl)-3-methyl-1,3,4,9-tetrahydropyrido[3,4-b]indol-2-yl]-2-fluoro-2-methyl-propan-1-ol (400 mg, 0.78 mmol), 2-[3-(fluoromethyl)azetidin-1-yl]ethanol (518 mg, 5 equivalents, 3.9 mmol), cuprous iodide (74 mg, 0.5 equivalents, 0.39 mmol), and potassium carbonate (644 mg, 6 equivalents, 4.7 mmol). The vial was capped, and the mixture was placed under a nitrogen atmosphere. Butyronitrile (5.2 mL) was then added, and the mixture was degassed for 10 minutes. The reaction mixture was then heated to 135° C. for 16 h, filtered through Celite, and purified by chiral reverse-phase HPLC to give two diastereomers. 154 was the second eluting diastereomer (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 with 0.1% NH4OH, 25 min. Retention time 1.35 min. LCMS: 520.3 [M+H] + .

[0165] Example 155 (2R)-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-fluoro-2-methyl-propan-1-ol 155 Following the procedure of Example 154, 155 was the first eluting diastereomer (110 mg, 27% yield). 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 with 0.1% NH4OH, 25 min. Retention time 0.55 min. LCMS: 520.2 [M+H] + .

[0166] Example 174 (1R,3R)-1-[2,6-difluoro-4-[2-[3-(fluoromethyl)azetidin-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-indol-3-yl)-N-(2,2,2-trifluoroethyl)propan-2-amine A mixture of (2R)-1-(1H-indol-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 h. The mixture was cooled to room temperature, diluted with water, and extracted with EtOAc (2x). The combined organics were dried (NaSO), filtered, and concentrated. The crude product was purified by silica flash chromatography (0-50% iPrOAc / heptane) to afford the title compound (89 mg, 60.5% yield) 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 JPEG0007792942000136.jpg3437 A mixture of (2R)-1-(1H-indol-3-yl)-N-(2,2,2-trifluoroethyl)propan-2-amine (54 mg, 0.211 mmol), 2,6-difluoro-4-iodo-benzaldehyde (62 mg, 0.232 mmol), and acetic acid (110 mg, 1.84 mmol) in toluene (1 mL) was heated at 90 °C for 5 h. The mixture was then concentrated. The residue was partitioned between EtOAc and saturated NaHCO3. The aqueous layer was extracted with EtOAc (2x). The combined organics were dried (Na2SO4), filtered, and concentrated to give the title compound as a white solid, which was used without purification. LCMS (ESI) m / z 507 [M+H + ].

[0168] Step 3: A mixture of (1R,3R)-1-(2,6-difluoro-4-iodo-phenyl)-3-methyl-2-(2,2,2-trifluoroethyl)-1,3,4,9-tetrahydropyrido[3,4-b]indole (107 mg, 0.211 mmol), 2-[3-(fluoromethyl)azetidin-1-yl]ethanol (84 mg, 0.632 mmol), CuI (16 mg, 0.0843 mmol), and KCO (87 mg, 0.632 mmol) in butyronitrile (1.4 mL) was purged with N for 5 minutes in a microwave vial, then sealed and heated at 135° C. for 23 hours. The mixture was filtered through Celite, concentrated, and purified by preparative HPLC to afford 174 (51 mg, 47% yield) as a yellow solid. 1H 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, 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 To a stirred solution of 2,2-difluoropropane-1,3-diol (200 mg, 1.78 mmol) in THF (4 mL) was added NaH (60% in mineral oil, 71 mg, 1.78 mmol) on an ice bath, and the reaction mixture was stirred for 30 min. TBDPSCl (490 mg, 1.78 mmol) was added dropwise to the reaction mixture. The reaction mixture was then warmed to 20 °C and stirred for 3 h. Water (10 mL) was slowly added to the reaction mixture, and the resulting mixture was extracted with EtOAc (10 mL × 2). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated. The crude residue was purified by silica gel column chromatography (20% petroleum ether in EtOAc) to afford the title compound (450 mg, 1.28 mmol, 72% yield) as a light 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 JPEG0007792942000138.jpg8343-[tert-Butyl(diphenyl)silyl]oxy-2,2-difluoro-propan-1-ol (from Step 1, 400 mg, 1.14 mmol) and 2,6-lutidine (0.39 mL, 3.42 mmol) in DCM (8 mL) was added dropwise to TfO (0.38 mL, 2.28 mmol) on an ice bath. The reaction mixture was stirred at 20 °C for 2 h. The reaction mixture was then slowly poured into ice water (20 mL) and extracted with DCM (20 mL × 2). The combined organic layers were washed with 1 N HCl (20 mL), saturated NaHCO (20 mL), and brine. The organic layer was dried over anhydrous NaSO, filtered, and concentrated. The crude residue was purified by silica gel column chromatography (10% petroleum ether in EtOAc) to afford the title compound (500 mg, 1.04 mmol, 91%) as a light yellow oil. 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-indol-3-yl)propan-2-yl)-3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropan-1-amine A mixture of [3-[tert-butyl(diphenyl)silyl]oxy-2,2-difluoropropyl] trifluoromethanesulfonate (from Step 2, 8.31 g, 17.22 mmol), DIPEA (6.1 mL, 34.44 mmol), and (2R)-1-(1H-indol-3-yl)propan-2-amine (3 g, 17.22 mmol) in dioxane (60 mL) was stirred at 90 °C for 12 h. After cooling to room temperature, the reaction mixture was diluted with water (100 mL) and washed with EtOAc (100 mL × 2). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated. The crude residue was purified by silica gel column chromatography (20% EtOAc in petroleum ether) to afford the title compound (7.6 g, 87%) as a yellow oil. LCMS: 507.2 [M+H] + .

[0172] Step 4: (R)-3-((1-(1H-indol-3-yl)propan-2-yl)amino)-2,2-difluoropropan-1-ol JPEG0007792942000140.jpg1844 To a stirred solution of (R)-N-(1-(1H-indol-3-yl)propan-2-yl)-3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropan-1-amine (from Step 3, 7.6 g, 15 mmol) in THF (100 mL) was added TBAF (1.0 M in THF, 30 mL, 30 mmol). The reaction mixture was stirred at 25 °C for 4 h and then diluted with water (200 mL) and EtOAc (200 mL × 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated. The crude residue was purified by silica gel column chromatography (70% EtOAc in petroleum ether) to afford 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]indol-2(9H)-yl)-2,2-difluoropropan-1-ol A mixture of (R)-3-((1-(1H-indol-3-yl)propan-2-yl)amino)-2,2-difluoropropan-1-ol (from Step 4, 2 g, 7.45 mmol), HOAc (1.29 mL, 22.36 mmol), and 2,6-difluoro-4-iodo-benzaldehyde (2 g, 7.45 mmol) in toluene (30 mL) was stirred at 90 °C for 12 h. After cooling to room temperature, the reaction mixture was diluted with water (50 mL) and washed with EtOAc (100 mL × 2). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated. The crude residue was purified by silica gel column chromatography (20% petroleum ether in EtOAc) to afford the title compound (2.8 g, 73%) as a light 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 of 3-((1R,3R)-1-(2,6-difluoro-4-iodophenyl)-3-methyl-3,4-dihydro-1H-pyrido[3,4-b]indol-2(9H)-yl)-2,2-difluoropropan-1-ol (1.5 g, 2.89 mmol from Step 5), 2-[3-(fluoromethyl)azetidin-1-yl]ethanol (1.93 g, 14.47 mmol), CuI (1.65 g, 8.68 mmol), and KCO (1.2 g, 8.68 mmol) in n-PrCN (20 mL) was stirred at 135 °C under a N atmosphere for 3 h. After cooling to room temperature, the reaction mixture was diluted with water (50 mL) and washed with DCM (50 mL × 2). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated. The resulting residue was purified by reverse phase chromatography (acetonitrile 50-80% / NH4OH 0.05% in water) to afford 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)azetidin-3-yl]oxy-phenyl]-3-methyl-1,3,4,9-tetrahydropyrido[3,4-b]indole 303 Prepared according to the procedure of Examples 305, 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]indol-1-yl)phenyl)-1-(3-fluoropropyl)azetidin-3-amine 304 Step 1: (R)-1-(1H-indol-3-yl)-N-(2,2,2-trifluoroethyl)propan-2-amine JPEG0007792942000142.jpg1938 To a solution of (2R)-1-(1H-indol-3-yl)propan-2-amine (10.0 g, 57.39 mmol) in 1,4-dioxane (100 mL) was added 2,2,2-trifluoroethyl trifluoromethanesulfonate (13.3 g, 57.39 mmol) and DIPEA (22.2 g, 172.18 mmol). The resulting mixture was stirred at 80 °C for 15 h. The reaction mixture was concentrated and purified by column chromatography eluting with 0-30% EtOAc in hexane to afford the title compound (14 g, 95.2%) as a light yellow oil. 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 of (R)-1-(1H-indol-3-yl)-N-(2,2,2-trifluoroethyl)propan-2-amine (14.0 g, 54.63 mmol from Step 1), 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 h. The reaction mixture was cooled to 25 °C, concentrated, and purified by silica gel column chromatography (0-5% EtOAc in petroleum ether) to afford the title compound and its cis isomer (24 g, 95.7% yield) (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]indol-1-yl)phenyl)amino)azetidine-1-carboxylate JPEG0007792942000144.jpg3648 In 1,4-dioxane (250 mL) was added (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 ... tert-butyl 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), tert-butyl 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), tert-butyl 2-(2,2,2-trifluoroethyl)- A mixture containing 3-aminoazetidine-1-carboxylate (12.9 g, 75.12 mmol), Xantphos (5.8 g, 10.02 mmol), and CsCO (48.9 g, 150.25 mmol) was stirred at 115 °C for 16 h under a N atmosphere. The reaction mixture was filtered through Celite, and the filtrate was concentrated and purified by column chromatography (petroleum ether 0-30% EtOAc) to give 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]indol-1-yl)phenyl)azetidin-3-amine 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]indol-1-yl)phenyl)amino)azetidine-1-carboxylate (from Step 3, 10.0 g, 18.16 mmol) (trans:cis = 4:1) in 1,4-dioxane (120 mL), sulfuric acid (4.87 mL, 90.82 mmol) was added at 0 °C. The reaction mixture was stirred at 0 °C for 0.5 h. The reaction mixture was poured into saturated aqueous NaHCO (250 mL), and the mixture was extracted with EtOAc (200 mL × 2). The combined organic layers were dried over Na2SO4 and concentrated to give the title compound (8 g, 97.8% yield) (trans:cis=4:1) as a yellow solid. The crude compound was used directly in the next step.

[0180] Step 5: To a mixture of N-(3,5-difluoro-4-((1R,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)azetidin-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) was added 1-fluoro-3-iodopropane (3.34 g, 17.76 mmol) dropwise. The reaction mixture was stirred at 20° C. for 16 hours. The reaction mixture was diluted with EtOAc (400 mL) and washed with brine (200 mL×5). The combined organic layers were dried over NaSO, filtered, concentrated, and purified by column chromatography (10-40% EtOAc in DCM) to give the desired product (7 g, 77.2% yield) as a brown solid. This product was combined with another batch (12.3 g total) and purified by preparative HPLC (Phenomenex Synergi Max-RP 250 * 80mm *Purification by acetonitrile (50-80%) / 10 mM NH₄HCO₃ in 10 μl water gave 10 g of product (trans:cis ratio 4:1, inseparable by HPLC) as a white solid. This product (trans:cis ratio 44:1) was then purified by SFC (AD (250 mm * Purification with 30 mm, 10 μm) base-EtOH (40%) gave 304 (5.9 g, 59% yield) 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)azetidin-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-indol-3-yl)propan-2-amine A mixture of (2R)-1-(1H-indol-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 h. The reaction was cooled to room temperature, diluted with iPrOAc (150 mL), washed with water, brine, dried over sodium sulfate, filtered, and concentrated. The crude product was purified by flash column chromatography on silica gel eluting with 0-5% MeOH / DCM to give 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-iodo-phenyl)-3-methyl-1,3,4,9-tetrahydropyrido[3,4-b]indole JPEG0007792942000147.jpg3640 To a solution of (R)-N-(2,2-difluoroethyl)-1-(1H-indol-3-yl)propan-2-amine (5.0 g, 21 mmol) and 2,6-difluoro-4-iodobenzaldehyde (5.2 g, 19 mmol) in toluene (70 mL) was added acetic acid (2.4 mL), and the mixture was heated at 90 °C under a nitrogen atmosphere for 20 hours. The reaction mixture was cooled and concentrated. The residue was dissolved in iPrOAc, washed with saturated sodium bicarbonate solution, water, and brine, dried over sodium sulfate, and concentrated. Purification by flash chromatography (silica gel, 0-15% iPrOAc / heptane) afforded the title compound (7.8 g, 76%) as a 3:1 mixture of trans:cis isomers. LCMS: 489.0 [M+H] + The mixture was carried on to the next step as is.

[0183] Step 3: A mixture of (1R,3R)-2-(2,2-difluoroethyl)-1-(2,6-difluoro-4-iodo-phenyl)-3-methyl-1,3,4,9-tetrahydropyrido[3,4-b]indole (8.0 g, 16.4 mmol), 2-[3-(fluoromethyl)azetidin-1-yl]ethanol (2.62 g, 19.7 mmol), cuprous iodide (0.94 g, 4.9 mmol), potassium carbonate (4.5 g, 32.8 mmol), and butyronitrile (33 mL) was degassed for 5 minutes and then heated to 140 °C overnight. The reaction mixture was filtered through Celite and eluted with iPrOAc. The filtrate was concentrated and purified by reverse-phase HPLC. The cis:trans isomers were separated by chiral SFC to give 305 (3.77 g, 44% yield). 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)azetidin-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)azetidin-3-yl]amino]phenyl]-3-methyl-1,3,4,9-tetrahydropyrido[3,4-b]indol-2-yl]-2,2-difluoro-propan-1-ol 340 Step 1: (R)—N-(1-(1H-indol-3-yl)propan-2-yl)-3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropan-1-amine A mixture of (2R)-1-(1H-indol-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 h. The reaction mixture was diluted with water (600 mL) and extracted with EtOAc (600 mL × 2). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated. The crude residue was purified by silica gel column chromatography (40% EtOAc in petroleum ether) to afford the title compound (69 g, 82%) as a light 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-indol-3-yl)propan-2-yl)amino)-2,2-difluoropropan-1-ol JPEG0007792942000149.jpg1844 To a stirred solution of (R)-N-(1-(1H-indol-3-yl)propan-2-yl)-3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropan-1-amine (from Step 1, 69 g, 136.18 mmol) in THF (690 mL) was added a 1 M THF solution of TBAF (272.35 mL, 272.35 mmol). The mixture was stirred at 25° C. for 4 hours. The reaction mixture was diluted with water (800 mL) and extracted with EtOAc (800 mL×3). The combined organic layers were concentrated, and the crude residue was purified by silica gel column chromatography (50% EtOAc in petroleum ether) to afford the title compound (29 g, 79%) as a light yellow oil.

[0187] Step 3: 3-((1R,3R)-1-(4-bromo-2,6-difluorophenyl)-3-methyl-3,4-dihydro-1H-pyrido[3,4-b]indol-2(9H)-yl)-2,2-difluoropropan-1-ol A mixture of (R)-3-((1-(1H-indol-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 h. The reaction mixture was diluted with water (500 mL) and extracted with EtOAc (500 mL × 2). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated. The crude residue was purified by silica gel column chromatography (20% EtOAc in petroleum ether) to give the title compound (24.8 g, 71%, trans / cis=20 / 1) as a light yellow oil. 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]indol-1-yl)-3,5-difluorophenyl)amino)azetidine-1-carboxylate JPEG0007792942000151.jpg3648 3-((1R,3R)-1-(4-bromo-2,6-difluorophenyl)-3-methyl-3,4-dihydro-1H-pyrido[3,4-b]indol-2(9H)-yl)-2,2-difluoropropan-1-ol (from Step 3, 24.8 g, 52.62 mmol), Pd2(dba)3 (4.82 g, 5.26 mmol), Xantphos (6.09 g, 10.52 mmol), Cs2CO3 (51.44 g, 157.86 mmol), and tert-butyl 2-(2-methyl-3-methyl-4-pyrido[3,4-b]indol-2(9H)-yl) were dissolved in 1,4-dioxane (300 mL). A mixture containing 3-aminoazetidine-1-carboxylate (13.59 g, 78.93 mmol) was stirred at 110° C. for 3 hours under a N atmosphere. The reaction mixture was cooled to 25° C., diluted with water (500 mL), and extracted with EtOAc (500 mL×2). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated. The crude residue was purified by silica gel column chromatography (20% petroleum ether in EtOAc) to give the title compound (20.5 g, 69%, trans / cis=20 / 1) as a yellow solid. MS: [M+H] + 563.0.

[0189] Step 5: 3-((1R,3R)-1-(4-(azetidin-3-ylamino)-2,6-difluorophenyl)-3-methyl-3,4-dihydro-1H-pyrido[3,4-b]indol-2(9H)-yl)-2,2-difluoropropan-1-ol JPEG0007792942000152.jpg3644 tert-butyl 3-((4-((1R,3R)-2-(2,2-difluoro-3-hydroxypropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-3,5-difluorophenyl)amino)azetidine-1-carboxylate (20.5 g, 36.44 mmol from Step 4) in 1,4-dioxane (194 mL) was added dropwise to sulfuric acid (19.42 mL, 364.38 mmol) on an ice bath. The reaction mixture was stirred for 0.5 h at 25 °C. The reaction mixture was then poured into saturated aqueous NaHCO3 (800 mL) and extracted with EtOAc (600 mL × 2). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated to give the title compound (18 g, crude, trans / cis=20 / 1) as a yellow solid. The crude residue was used directly in the next step. MS: [M+H] + 463.0.

[0190] Step 6: A mixture of 3-((1R,3R)-1-(4-(azetidin-3-ylamino)-2,6-difluorophenyl)-3-methyl-3,4-dihydro-1H-pyrido[3,4-b]indol-2(9H)-yl)-2,2-difluoropropan-1-ol (18 g, 38.92 mmol from Step 5), 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 h. The reaction mixture was diluted with EtOAc (500 mL) and washed with brine (500 mL × 3). The combined organic layer was dried over anhydrous NaSO, filtered, and concentrated. The crude residue was purified by silica gel column chromatography (10% MeOH in DCM) to give the target compound (7.1 g, purity 85%) as a yellow oil. The resulting residue was purified by reverse phase chromatography (40-75% acetonitrile / 0.05% NH4OH in water) and chiral SFC (AD 250 mm * Further purification by supercritical CO2 / EtOH (0.1% NH3H2O) = 40 / 40 at 200 mL / min) gave 340 (2.85 g, 14%) as a light 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)azetidin-3-yl)amino)phenyl)-6-fluoro-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2,2-difluoropropan-1-ol 365 Step 1: ([3-(tert-butyl-diphenyl-silanyloxy)-2,2-difluoro-propyl]-[2-(5-fluoro-1H-indol-3-yl)-1-methyl-ethyl]-amine A mixture of [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-indol-3-yl)-1-methyl-ethylamine (CAS number: 712-08-3, 14.7 g, 74.7 mmol) in dioxane (140 mL) was stirred at 90 °C for 3 h. The mixture was cooled to room temperature, diluted with EtOAc, washed with water (×2) and brine, dried over anhydrous Na SO , filtered, and concentrated. The crude residue was purified by silica gel column chromatography (mobile phase: DCM) to afford 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-difluoro-propyl]-1-(2,6-difluoro-4-iodo-phenyl)-6-fluoro-3-methyl-2,3,4,9-tetrahydro-1H-beta-carboline To a solution of 3958 [3-(tert-butyl-diphenyl-silanyloxy)-2,2-difluoro-propyl]-[2-(5-fluoro-1H-indol-3-yl)-1-methyl-ethyl]-amine (32.8 g, 62.5 mmol) in toluene (65 mL) was added 4-iodo-2,6-difluorobenzaldehyde (20.1 g, 75.0 mmol) and acetic acid (7.2 mL, 125.0 mmol). Upon completion of the addition, the reaction mixture was stirred at 90 °C for 14 h. The mixture was cooled to room temperature, diluted with EtOAc, washed with saturated aqueous NaHCO (x3) and brine, dried over anhydrous NaSO, and concentrated. The residue was purified by chromatography on silica (mobile phase: toluene in cyclohexane, gradient 10-50%) to afford 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-difluoro-propyl]-6-fluoro-3-methyl-2,3,4,9-tetrahydro-1H-beta-carbolin-1-yl}-3,5-difluoro-phenylamino)-azetidine-1-carboxylic acid tert-butyl ester A mixture of 2-[3-(tert-butyl-diphenyl-silanyloxy)-2,2-difluoro-propyl]-1-(2,6-difluoro-4-iodo-phenyl)-6-fluoro-3-methyl-2,3,4,9-tetrahydro-1H-beta-carboline (30.8 g, 39.8 mmol), Xantphos (4.60 g, 7.9 mmol), Pd(dba) (3.64 g, 4.0 mmol), CsCO (25.9 g, 79.4 mmol), and t-butyl 3-aminoazetidine-1-carboxylate (10.3 g, 59.6 mmol) in 1,4-dioxane (192 mL) was stirred at 115 °C under argon in a sealed vessel for 1.5 h. The reaction mixture was cooled to room temperature, filtered through a pad of Celite® to remove residual solids, and the filtrate was concentrated. The resulting residue was purified by flash chromatography on silica gel (mobile phase: EtOAc in DCM, gradient 0-5%) to afford 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: Azetidin-3-yl-(4-{2-[3-(tert-butyl-diphenyl-silanyloxy)-2,2-difluoro-propyl]-6-fluoro-3-methyl-2,3,4,9-tetrahydro-1H-beta-carbolin-1-yl}-3,5-difluoro-phenyl)-amine An ice-cold, premixed solution of concentrated sulfuric acid (9.1 mL, 170.2 mmol) in dioxane (100 mL) was slowly added to a solution of 3-(4-{2-[3-(tert-butyl-diphenyl-silanyloxy)-2,2-difluoro-propyl]-6-fluoro-3-methyl-2,3,4,9-tetrahydro-1H-beta-carbolin-1-yl}-3,5-difluoro-phenylamino)-azetidine-1-carboxylic acid tert-butyl ester (27.9 g, 34.0 mmol) in dioxane (275 mL) under nitrogen at room temperature. Upon complete addition, the reaction mixture was allowed to stand at room temperature for 1 h. EtOAc and water were added, and the pH of the aqueous phase was adjusted to 9 by the addition of solid Na2CO3. The organic layer was separated, washed with brine (x3), dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (a mixture of (R,R) & (S,S) diastereomers) as a pale orange foam (26.6 g, ~ LCMS: 719.4 [M+H] + .

[0195] Step 5: (4-{2-[3-(tert-butyl-diphenyl-silanyloxy)-2,2-difluoro-propyl]-6-fluoro-3-methyl-2,3,4,9-tetrahydro-1H-beta-carbolin-1-yl}-3,5-difluoro-phenyl)-[1-(3-fluoro-propyl)-azetidin-3-yl]-amine The title compound was prepared from azetidin-3-yl-(4-{2-[3-(tert-butyl-diphenyl-silanyloxy)-2,2-difluoro-propyl]-6-fluoro-3-methyl-2,3,4,9-tetrahydro-1H-beta-carbolin-1-yl}-3,5-difluoro-phenyl)-amine (26.6 g, 34.0 mmol) and 1-iodo-3-fluoropropane (9.60 g, 51.1 mmol; CAS number: 462-40-8) following 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 5%) to afford 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)-azetidin-3-ylamino]-phenyl}-6-fluoro-3-methyl-1,3,4,9-tetrahydro-beta-carbolin-2-yl)-2,2-difluoro-propan-1-ol To a mixture of (4-{2-[3-(tert-butyl-diphenyl-silanyloxy)-2,2-difluoro-propyl]-6-fluoro-3-methyl-2,3,4,9-tetrahydro-1H-beta-carbolin-1-yl}-3,5-difluoro-phenyl)-[1-(3-fluoro-propyl)-azetidin-3-yl]-amine (12.1 g, 15.5 mmol) in THF (150 mL) under argon was added a 1 M solution of TBAF in THF (23.3 mL), and the reaction mixture was stirred at room temperature for 5 h. The reaction mixture was diluted with EtOAc and washed with water (×4). The organic layer was dried over NaSO, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography (mobile phase: 2M ammonia in methanol / TBME, gradient 0.5% to 5%) to give a mixture of (R,R) and (S,S) 3-(1-{2,6-difluoro-4-[1-(3-fluoro-propyl)-azetidin-3-ylamino]-phenyl}-6-fluoro-3-methyl-1,3,4,9-tetrahydro-beta-carbolin-2-yl)-2,2-difluoro-propan-1-ol. The diastereomeric pair was separated by chiral HPLC (ChiralPak IB, 15% EtOH in heptane + 0.1% diethylamine). 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)azetidin-3-yl)amino)phenyl)-6-fluoro-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2,2-difluoropropan-1-ol 366 The first peak isolated by chiral HPLC following the procedure of Example 365 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)azetidin-3-yl)oxyphenyl)-6-fluoro-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-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-indol-3-yl)-1-methyl-ethyl]-amine [3-(tert-butyl-diphenyl-silanyloxy)-2-fluoro-2-methyl-propyl]-[2-(5-fluoro-1H-indol-3-yl)-1-methyl-ethyl]-amine JPEG0007792942000159.jpg3056 Under argon, to a solution of 2-(5-fluoro-1H-indol-3-yl)-1-methyl-ethylamine (CAS number: 712-08-3, 3.61 g, 18.7 mmol) and DIPEA (4.9 mL, 28.1 mmol) in dioxane (43 mL) was added trifluoromethanesulfonic acid 3-(tert-butyl-diphenyl-silanyloxy)-2-fluoro-2-methyl-propyl ester, Intermediate XX (3.09 g, 9.48 mmol). The resulting mixture was stirred at 90 °C for 6 h. The reaction mixture was partitioned between EtOAc and water. The organic phase was separated, further washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography (mobile phase: dichloromethane / methanol, gradient 0% to 5%) to give 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-difluoro-phenoxy)-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-indol-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) according to the procedure outlined for the preparation of Intermediate 101e. The crude product was purified by silica gel chromatography (mobile phase: cyclohexane / ethyl acetate, gradient 0% to 20%) to afford 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-(azetidin-3-yloxy)-2,6-difluoro-phenyl]-2-[3-(tert-butyl-diphenyl-silanyloxy)-2-fluoro-2-methyl-propyl]-6-fluoro-3-methyl-2,3,4,9-tetrahydro-1H-beta-carboline To a mixture of 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-difluoro-phenoxy)-azetidine-1-carboxylic acid tert-butyl ester, Intermediate 2a (8.0 g, 9.80 mmol) in dioxane (80 mL) under argon at 0° C., a solution of concentrated sulfuric acid (2.62 mL, 49.0 mmol) in dioxane (27 mL) was added dropwise, and the mixture, protected from light, was allowed to warm to room temperature and stirred for 3.5 h. The reaction mixture was diluted with EtOAc and saturated NaHCO, stirred for 10 min, and the layers were separated. The organic layer was further washed with saturated NaHCO3, brine, dried over Na2SO4, filtered and concentrated in vacuo to give a pale yellow foam (7.05 g, a mixture of diastereomers of the title compound). ~ (quantitative) was obtained. 1 H NMR (300 MHz, CDCl): 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)-azetidin-3-yloxy]-phenyl}-6-fluoro-3-methyl-2,3,4,9-tetrahydro-1H-beta-carboline The title compound was prepared from 1-[4-(azetidin-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, 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 afford 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)-azetidin-3-yloxy]-phenyl}-6-fluoro-3-methyl-1,3,4,9-tetrahydro-beta-carbolin-2-yl)-2-fluoro-2-methyl-propan-1-ol JPEG0007792942000163.jpg4073 Under argon, a 1M solution of TBAF in THF (10 mL) was added to a mixture of 2-[3-(tert-butyl-diphenyl-silanyloxy)-2-fluoro-2-methyl-propyl]-1-{2,6-difluoro-4-[1-(3-fluoro-propyl)-azetidin-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), 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 EtOAc. The aqueous layer was further extracted with EtOAc, and the combined organic layers were further washed with water and brine, dried over Na2SO4, filtered, and dried in vacuo. The crude product was purified by silica gel chromatography (mobile phase: dichloromethane / methanol, gradient 0% to 6%) to give two pairs of diastereomers (diastereomer pair 1 and diastereomer pair 2). The diastereomer pair 1 pair was further purified by chiral HPLC (ChiralPak IC, 25% IPA in heptane, 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)azetidin-3-yl)oxy)phenyl)-6-fluoro-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-fluoro-2-methylpropan-1-ol 369 Following the procedure of Example 368, a second peak isolated by chiral HPLC (rt=15.5 min) = 369 was isolated as a white solid (480 mg, 13.5%).

[0204] Example 370 3-((1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenyl)-6-fluoro-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-fluoro-2-methylpropan-1-ol 370 Following the procedure of Example 368, the diastereomeric pair 2 was purified by chiral HPLC (ChiralPak IC, 35% IPA, 0.1% diethylamine in heptane). The first peak isolated was further purified by chiral HPLC (ChiralPak IA, 35% IPA, 0.1% diethylamine in heptane). The first peak isolated (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)azetidin-3-yl)oxy)phenyl)-6-fluoro-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-fluoro-2-methylpropan-1-ol 371 The diastereomeric pair of 2 was purified by chiral HPLC (ChiralPak IC, 35% IPA, 0.1% diethylamine in heptane) according to the procedure of Example 368. The second peak isolated (rt = 14 min) = 371 was isolated as a white solid (180 mg, 5%).

[0206] Additional exemplary Formula I compounds in Table 2a have the following structures, corresponding names (CambridgeSoft Corp., Cambridge, Massachusetts, ChemBioDraw version 12.0.2), and biological activities: When multiple names are associated with a Formula I compound or intermediate, the chemical structure shall define the compound. TIFF0007792942000164.tif234170

[0207] Example 431 (R)-3-((1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-6-fluoro-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-fluoro-2-methylpropan-1-ol 431 Step 1: 3-((tert-butyldiphenylsilyl)oxy)-2-fluoro-N-(1-(5-fluoro-1H-indol-3-yl)propan-2-yl)-2-methylpropan-1-amine JPEG0007792942000165.jpg3053 According to Example 154, Step 5, to a solution of 1-(5-fluoro-1H-indol-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) in 1,4-dioxane (105 mL) cooled in an ice bath was added 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 (bath) at 90 °C for 18 hours. The mixture was concentrated. Dilute Na2CO3 was added. The contents were extracted with DCM (2x). The combined extracts were dried (NaSO) and concentrated. The crude material was purified by flash chromatography (0-50% iPrOAc / heptane with 1% TEA) to give the product (10.38 g, 76%).

[0208] Step 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]indol-1-yl)-3,5-difluorophenyl)-1-(3-fluoropropyl)azetidin-3-amine JPEG0007792942000166.jpg4257 The compound was prepared in a similar manner to Example 145.

[0209] Step 6: racemic 3-(1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-6-fluoro-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-fluoro-2-methylpropan-1-ol To a solution of N-[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]indol-1-yl]-3,5-difluoro-phenyl]-1-(3-fluoropropyl)azetidin-3-amine (2.231 g, 2.879 mmol) in THF (14.4 mL) was added a solution of TBAF in THF (1.0 M, 4.6 mL). The mixture was heated at 50 °C for 24 h. The mixture was concentrated. After dilution with iPrOAc, the contents were washed with dilute NaCO (2x) and brine, dried (NaSO), and concentrated. The product was purified by flash chromatography (0-60% B / A, A: DCM B: 2M NH3 in MeOH 20% / DCM). The collected 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 as a mixture. Chiralpak AD (250x30.0, 5 μm), 0.1% NH4OH in 32.5% isocratic isopropanol at 150 g / min, UV-254 nm, BPR 100 bar, temperature 40 °C, cycle time 5 min, total time 200 min. Step 2: Resolution of Enantiomers 2 and 3. Chiralpak OX (150x30.0, 5 μm), 150 g / min, UV-250 nm, BPR 100 bar, temperature 40 °C, cycle time 3 min, total time 48 min, 0.1% NH4OH in 30% isocratic methanol. 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)azetidin-3-yl)amino)phenyl)-6-fluoro-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-fluoro-2-methylpropan-1-ol Following the procedure of Example 431, enantiomer 432 was isolated.

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

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

[0213] Example 901: Breast cancer cell ERa high content fluorescence imaging degradation assay On day 1, MCF7 breast cancer cells were seeded at a density of 10,000 cells per well in 50 μL / well of RPMI (phenol red-free) containing L-glutamine and 10% FBS (charcoal strips) in 384-well poly-lysine-coated tissue culture plates (Greiner #T-3101-4). On day 2, 10 μL / well of compound was added to Labcyte low dead volume plates at two compound source concentrations: 100 μM and 1 μM (resulting in two duplicate titration curves). Also, 10 μL of DMSO was added to designated wells for backfill, and 5 μM fulvestrant (control compound) was added to designated wells. Compounds and controls were dispensed using a Labcyte echo acoustic dispenser to dispense predetermined serial dilutions (1.8x, 10-point, duplicate) of compounds, as well as appropriate backfill and control compounds (final total volume transferred: 417.5 nL, compound dispense volumes: 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. Cell plates were incubated at 37°C for 4 hours. Fixation 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 per well using a 5 μL peristaltic pump on a Biotek EL406 (final formaldehyde concentration was 3.7% w / v). Samples were incubated for 30 min. Well contents were aspirated, and 50 μL / well of phosphate-buffered saline (PBS) containing 0.5% w / v bovine serum albumin and 0.5% v / v Triton X-100 (Antibody Dilution Buffer) was added to each well. Samples were incubated for 30 min. Well contents were aspirated, and plates were washed three times with 100 μL / well of PBS. Fluorescent immunostaining of 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 for 2 hours at room temperature. The samples were washed four times with 100 μL / well of PBS. 25 μL / well of secondary antibody solution (Alexafluor 488-conjugated anti-mouse IgG (Life Technologies #A21202) diluted 1:1000 and Hoechst 33342 1 μg / ml diluted in Antibody Dilution Buffer) was dispensed into each well. The samples were incubated for 2 hours at room temperature. The samples were washed three times with 100 μL / well of PBS using a Biotek EL406. Quantitative fluorescence imaging of ESR1 was performed using a Cellomics Arrayscan V (Thermo). Fluorescence images of the samples (Channel 1: XF53 Hoechst (DNA stain); Channel 2: XF53 FITC (ESR1 stain)) were acquired using a Cellomics VTI Arrayscan using Bioapplication "Compartmental Analysis" with autoexposure (based on DMSO control wells) setting the "peak target percentile" to 25% target saturation for both channels. Channel 1 (DNA stain) was used to define the nuclear region (Circ). Measurements of "Mean_CircAvgIntCh2," the Alexafluor 488 fluorescence intensity (ESR1) within the nuclear region, were measured for each cell and averaged across all measured cells. Data analysis was performed using Genedata Screener Software, with DMSO- and 5 nM fulvestrant-treated samples used to determine 0% and 100% ESR1 changes. The "robust fit" method was used to define the inflection point (EC50) of the curve and the plateau of maximum effect (Sinf). Degradation data for exemplary compounds of Formula I are shown in Table 1. ER Alpha MCF7 HCS S inf The values ​​are reported as % values.

[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 culture based on quantification of ATP present, which signals the presence of metabolically active cells. The CellTiter-Glo® Assay is designed for use in a multiwell plate format, making it 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. No washing of cells, removal of medium, or multiple pipetting steps is required. The Cell Titer-Glo® Luminescent Cell Viability Assay, including the reagent and protocol, is commercially available (Technical Bulletin TB288, Promega Corp., Madison, Wisconsin). The assay evaluates the ability of compounds 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 ATP present in a homogeneous assay, in which the addition of Cell Titer-Glo® reagent causes cell lysis and the generation of a luminescent signal by luciferase reaction.The luminescent signal is proportional to the amount of ATP present. Procedure: Day 1 - Seed Cell Plates (Falcon #353962 384-well black, clear bottom, microclear, TC plates with lid), harvest cells, and seed cells at 1000 cells / 54μl / well into 384-well Cell Plates for the 3-day assay. Cell Media: RPMI or DMEM high glucose, 10% fetal bovine serum, 2mM L-glutamine, P / S. Incubate O / N (overnight) at 37°C, 5% CO2. Day 2 - Add drugs to cells, compound dilutions, and the DMSO Plate (9-point 1:2 serial dilutions). Add 20 μl of compound at 10 mM to the second column of the 96-well plate. Perform a total of 9-point 1:2 serial dilutions across the plate (10 μl + 20 μl 100% DMSO) using a Nunc Precision Media Plate 96-well conical bottom polypropylene plate (catalog number 249946) (1:50 dilution). Add 147 μl of media to all wells. Use a Rapidplate® (Caliper, a Perkin-Elmer Co.) to transfer 3 μl of DMSO + compound from each well of the Media Plate to the corresponding well of the Media Plate. To test two-drug combinations, transfer 1.5 μl of one drug (DMSO + compound) from each well of the DMSO Plate to the corresponding well of the Media Plate using the Rapidplate. Then, 1.5 μl of the other drug is transferred to the culture plate. Adding drugs to cells, Cell Plate (1:10 dilution): Add 6 μl of media + compound directly to cells (54 μl of media already on cells). Incubate for 3 days at 37°C with 5% CO2 in an incubator that will not be opened frequently. Day 5 - Spread the plate and thaw Cell Titer-Glo Buffer at room temperature: Remove the Cell Plate from 37°C and equilibrate to room temperature for approximately 30 minutes. Add Cell Titer-Glo® Buffer to the Cell Titer-Glo® Substrate (bottle to bottle). Add 30 μl of Cell Titer-Glo® Reagent (Promega catalog number G7572) to each well of cells. Place on a plate shaker for approximately 30 minutes. Read luminescence on an Analyst HT Plate Reader (0.5 seconds per well). Cell viability assay and combination assay: 1000-2000 cells per well were seeded into 384-well plates for 16 hours. On day 2, nine 1:2 serial dilutions of compounds in DMSO were performed in 96-well plates. Compounds were further diluted in growth medium using a Rapidplate® robot (Zymark Corp., Hopkinton, MA). The diluted compounds were then added to quadruplicate 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 on a Wallac Multilabel Reader® (PerkinElmer, Foster City, CA). EC50 values ​​were calculated using Prism® 4.0 software (GraphPad, San Diego, CA). In combination assays, drugs were added at 4×EC 50 Dosing was initiated at a concentration of 10 μM. If the EC50 of the drug was >2.5 μM, the highest concentration used was 10 μM. In all assays, estrogen receptor modulating compounds and chemotherapeutic agents were added simultaneously or separated by 4 hours (one before the other). A further exemplary in vitro cell proliferation assay includes the following steps. 1. Add approximately 10 4Aliquots of 100 μl of cell culture containing cells (see Table 3 for cell lines and tumor types) were placed into each well of a 384-well opaque-walled plate. 2. Control wells containing medium but no cells were prepared. 3. Compounds were added to experimental wells and incubated for 3-5 days. 4. The plate was allowed to equilibrate to room temperature for approximately 30 minutes. 5. A volume of CellTiter-Glo® Reagent equal to the volume of cell culture medium present in each well was added. 6. The contents were mixed on an orbital shaker for 2 minutes to induce cell lysis. 7. The plate was incubated at room temperature for 10 minutes to allow the luminescent signal to stabilize. 8. Luminescence was recorded and graphed as RLU = Relative Luminescence Units. 9. Combination indices were analyzed 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 in the presence of test compounds for 4 days. TM was added to the assay medium and cells were incubated for 6 hours before reading at 544 nm excitation and 590 nm emission. Sigmoidal dose-response curve fitting was used to determine the EC 50 The value was calculated. Alternatively, proliferation / viability was analyzed 48 hours after drug treatment using Cell Titer-Glo® reagent (Promega Inc., Madison, WI). DMSO treatment was used as a control in all viability assays. IC was calculated using XLfit software (IDBS, Alameda, CA). 50 The value was calculated. Cell lines were obtained from ATCC (American Type Culture Collection, Manassas, VA) or DSMZ (Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH, Braunschweig, Germany). Cells were cultured in RPMI 1640 medium (Life Technology, Grand Island, NY) supplemented with 10% fetal bovine serum, 100 units / ml penicillin, 2 mM L-glutamine, and 100 mg / ml streptomycin at 37°C under 5% CO .

[0215] Example 903 MCF7 in vitro cell proliferation assay MCF7 cells were washed with PBS and plated at 25,000 cells / ml (40 μl / well) in RPMI 1640 (Gibco 11835-030 [-phenol + glutamine]) and 10% charcoal-stripped FBS (Gibco 12676-029) in polylysine-coated 384-well tissue culture plates (Greiner) and incubated overnight. Compounds were serially diluted in DMSO at 500x the final target concentration using a Biomek-FX and then diluted 50x in RPMI 1640. The control compound fulvestrant and the negative control dimethyl sulfoxide were prepared in a similar manner. Five μl of each compound concentration and each control compound was transferred to the cell plate. Fulvestrant was added to control wells at a final concentration of 100 nM. DMSO was added to 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 the cell plate (except for the no-estradiol control wells). After 72 hours of incubation, cells 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 Genedata Screener software, which defined 0% and 100% inhibition using DMSO- and fulvestrant-treated samples, and EC50 values ​​were calculated using curve fitting with a robust method.

[0216] Example 904 ERa Coactivator Peptide Antagonist Assay Test compounds were prepared at 1 mM in DMSO and serially diluted in a 12-point, 1- to 3-fold dose series in a 384-well clear V-bottom polypropylene plate (Greiner Cat. No. 781280) using a Biomek FX. 3x compound intermediate dilutions were prepared by mixing 1 mL of each compound serial dilution with 32.3 mL of TR-FRET Coregulator Buffer E (Life Technologies PV4540). 2 mL of the 3x compound intermediate dilution was transferred to a 1536-well plate (Aurora Biotechnologies MaKO 1536 Black Plate, #00028905) using a Biomek FX. Using a Bioraptr Dispenser® (Beckman Coulter), 2 mL of "3xERa solution" was dispensed per well: TR-FRET Coregulator Buffer E containing 22 nM ERa (human estrogen receptor alpha, GST-tagged ESR1 ligand-binding domain, spanning residues S282-V595, wild-type sequence or Y537S or D538G mutations) with 7.5 mM dithiothreitol (DTT); and 2 mL of TR-FRET Coregulator Buffer E (7.5 mM DTT) containing 3x assay mix (750 nM fluorescein-PGC1a peptide sequence; Life Technologies PV4421), 12 nM estradiol, and 15 nM anti-GST Tb-labeled antibody. "No receptor" control wells contained buffer without GST-ERa protein. The plate was centrifuged at 1800 rpm for 20 seconds in a V-spin centrifuge, and the plate was 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) 340 nm (PE#2100-5010); emission filters: Chroma 495 nm / 10 nm and 520 nm / 25 nm (Chroma #PV003 filter for LanthaScreen, 25 mm diameter for EnVision); excitation light: 100%; delay: 100 μsec; window time: 200; number of sequential windows: 1; flash interval: 2000 μsec; number of flashes: 100; number of flashes (second detector): 100). Percent inhibition was calculated relative to a no-compound (DMSO only) control and a "no ERα control." Curve fitting and IC. 50 Calculations were performed using Genedata Screener software.

[0217] Example 905 In Vivo Mouse Tumor Xenograft Efficacy Mice: Severe combined immunodeficient female mice (Fox Chase SCID®, CB-17 / IcrHsd, Harlan) or nude mice (Taconic Farms, Harlan) were 8 to 9 weeks old and had a body weight range of 15.1 to 21.4 grams on study day 0. Animals received water ad libitum (reverse osmosis, 1 ppm Cl) and an NIH 31 Modified and Irradiated Lab Diet® consisting of 18.0% crude protein, 5.0% crude fat, and 5.0% crude fiber. Mice were housed on irradiated ALPHA-Dri® bed-o'cobs® laboratory bedding in static pressure microisolators on a 12-hour light cycle at 21-22°C (70-72°F) and 40-60% humidity. PRC strictly adheres to the recommendations of the Guide for Care and Use of Laboratory Animals regarding restraint, husbandry, surgical procedures, food and hydration, and veterinary care. The animal care and use program at PRC is accredited by the Association for Accreditation of Laboratory Animal Care International (AALAC International), which ensures compliance with recognized standards for the care and use of laboratory animals. Tumor Implantation: Xenografts are 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 cultured at 5x10 cells per well depending on the doubling time of the cell line. 6 or 10x10 6 The tumor cells were resuspended in phosphate-buffered saline (PBS) at a concentration of 100 cells / mL. The tumor cells were implanted subcutaneously in the right flank and grown to an average size of 100 to 150 mm. 3 Tumor growth is monitored as the tumor approaches the target range of 75-172 mm. The day of tumor implantation is considered study day 0, and 21 days later, individual tumor volumes are monitored as the tumor approaches the target range of 75-172 mm. 3 The group consisted of 10 mice with tumors ranging from 120 to 121 mm 3 Mice are divided into four groups (see Appendix A). Volume is calculated using the following formula: Tumor volume (mm 3 )=(w 2 xl) / 2 [where w = tumor width (mm), l = tumor length (mm)]. Tumor weight is calculated as 1 mg = 1 mm of tumor volume. 3 can be estimated by assuming that it corresponds to Therapeutic Agents: Estrogen receptor modulator compounds and chemotherapeutic agents are typically prepared from dry powders, stored at room temperature, and protected from light. Drug doses are prepared weekly in 0.5% methylcellulose:0.2% Tween 80 in deionized water ("Vehicle") and stored at 4°C. Vehicle (+) is a solvent / buffer containing 0.1 mg / kg ethinyl estradiol (ethinylestradiol, EE2). Vehicle (-) is a solvent / buffer without ethinyl estradiol. Compound doses are prepared each dosing day by diluting a stock aliquot with sterile saline (0.9% NaCl). All doses are formulated to deliver the indicated mg / kg dose in a volume of 0.2 mL per 20 g of body weight (10 mL / kg). Treatment: All doses are adjusted to the individual animal's weight and given by the indicated route. Endpoints: Tumor volume was measured in two dimensions (length and width) using Ultra Cal IV calipers (model 54 10 111; Fred V. Fowler Company) and is as follows: tumor volume (mm 3 )=(length x width 2) x 0.5 and analyzed using Excel version 11.2 (Microsoft Corporation). A linear mixed effects (LME) modeling approach is used to analyze repeated measurements of tumor volume from the same animal over time. This approach accounts for both repeated measurements and the small amount of attrition due to non-treatment-related death of animals before study termination. A cubic regression spline is used to fit nonlinear profiles to the time course of log2 tumor volume at each dose level. These nonlinear profiles are then described in relation to dose within the mixed model. Tumor growth inhibition (TGI%) as a percent of vehicle control is calculated using the formula: TGI% = 100 x (1 - AUC 用量 / AUC ビヒクル ) and calculated as the percentage of the area under the fitted curve (AUC) of each daily dose group relative to the vehicle. Using this formula, a TGI value of 100% indicates tumor stasis, a TGI value greater than 1% and less than 100% indicates tumor growth delay, and a TGI value greater than 100% indicates tumor shrinkage. A partial response (PR) in an animal is defined as a tumor shrinkage of greater than 50% but less than 100% of the initial tumor volume. A complete response (CR) is defined as 100% tumor shrinkage (i.e., no measurable tumor) on any day during the study. Toxicity: Animals are weighed daily for the first 5 days of the study and twice weekly thereafter. Animal weights are measured using an Adventurer Pro® AV812 scale (Ohaus Corporation). Percent weight change is calculated as follows: Percent weight change (%) = [(new weight - initial weight) / initial weight] × 100. Mice are frequently observed for overt signs of treatment-related adverse side effects, and clinical signs of toxicity are recorded if observed. Acceptable toxicity is defined as a group mean body weight (BW) loss of less than 20% during the study and treatment-related (TR) deaths of up to 1 out of 10 treated animals. Any dosing regimen resulting in greater toxicity is considered to exceed the maximum tolerated dose (MTD). Deaths are classified as TR if they are due to treatment side effects as evidenced by clinical signs and / or necropsy, or deaths of unknown cause during the dosing period or within 10 days of the final dose. Deaths are classified as NTR if there is no evidence that the death was related to treatment side effects. In vivo xenograft breast cancer model (MCF-7; tamoxifen-sensitive): A sustained-release pellet containing 0.72 mg of 17-β estradiol was implanted subcutaneously into nu / nu mice. MCF-7 cells were grown in RPMI containing 10% FBS at 37°C in 5% CO. Trypsinized cells were pelleted and resuspended in 50% RPMI (serum-free) and 50% Matrigel at 1x10 7 Resuspend the cells at 100 cells / mL. 2-3 days after pellet implantation, inject MCF-7 cells subcutaneously into the right flank (100 μL / animal). Tumor volume (length x width) was measured. 2 / 2) will be monitored bi-weekly. ~ 200mm 3 Once a mean tumor volume of 1000 mg / kg is reached, animals are randomized and treatment begins. Animals are treated daily with vehicle or compound for 4 weeks. Tumor volume and body weight are monitored biweekly throughout the study. In vivo xenograft breast cancer model (tamoxifen-resistant model): MCF-7 tumor-bearing model (mean tumor volume 200 mm) 3) Nu / nu female mice (supplemented with 17-b estradiol pellets; 0.72 mg; 60-day slow release) were treated with tamoxifen (citrate) by oral gavage. Tumor volume (length x width) 2 The tumor size ( / 2) and body weight are monitored twice weekly. After a significant antitumor response in which tumor volume remains unchanged, clear tumor growth is first observed approximately 100 days into treatment. After 120 days of treatment, the tamoxifen dose is increased. Rapidly growing tumors are considered tamoxifen-resistant and are selected for in vivo passage into new host animals. Tumor fragments ( ~ 100mm 3 Tumors (17-b / animal) are subcutaneously implanted into the right flank of female nu / nu mice (supplemented with 17-b estradiol pellets (0.72 mg; 60-day slow release)). Passaged tumors are maintained under constant tamoxifen selection and tumor volume (length x width) is measured. 2 / 2) will be monitored weekly. ~ 150-250mm 3 Once the tumor volume reached 200 mm, animals were assigned to treatment groups (mean tumor volume 200 mm). 3 ) and terminate tamoxifen treatment. Animals are treated daily with vehicle or compound for 4 weeks. Tumor volume and body weight are monitored twice weekly for the duration of the study.

[0218] Example 906 Immature Uterine Wet Weight Assay Female immature CD-IGS rats (21 days old) are treated for 3 days. Animals are dosed daily for 3 days. For antagonist mode, vehicle or compound is administered by oral gavage, followed 15 minutes later by oral administration of 0.1 mg / kg ethinyl estradiol. For agonist mode, vehicle or test compound is administered by oral gavage. On day 4, 24 hours after administration, plasma is collected for pharmacokinetic analysis. Immediately after plasma collection, animals are euthanized, the uterus is removed, and body weight is measured. Uteri and ovaries from two animals per group are fixed in 10% neutral buffered formalin, paraffin embedded, sectioned, and stained with H&E (SDPath). Stained tissues are analyzed and read by a board-certified pathologist. For transcriptional analysis, uteri and ovaries from four animals per group are snap-frozen in liquid N2 and a select set of genes modulated by the estrogen receptor are examined. Compounds of formula I (1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-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)azetidin-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 102, tamoxifen, fulvestrant, AZD9496 (WO 2014 / 191726, Example 1, p. 74; U.S. Pat. No. 9,155,727), and two controls: vehicle and / or vehicle plus ethinylestradiol (EE). All compounds were administered orally (PO) once daily for three days (QDx3). Uterine wet weight (UWW):body weight ratios were calculated. The mean endometrial height of uterine cross sections was measured by histology. Endometrial cell height was measured from the basement membrane to the apical (luminal) surface at 20x magnification using a slide viewer. 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 was ovariectomized at 60 days of age by the supplier (Charles River Laboratories), and the study began two weeks after surgery. Groups 2-8 were untreated. Vehicle or test compound was orally administered for 10 days. Two hours after the final 10th administration, cardiac puncture was performed and serum was collected for pharmacokinetic and estradiol analysis. Immediately after serum collection, the animals were euthanized, the uterus and ovaries were removed, and their weights were measured.

[0220] The foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, but the descriptions and examples should not be construed as limiting the scope of the invention. The disclosures of all patent and scientific literature cited herein are hereby incorporated by reference in their entirety.

Claims

1. Formula Ib: [In the formula, Y ２ Ha-(CH ２ )- and; R ａ is ethyl or 1-propyl; R ｂ and R ｃ are H, respectively; R １ and R ２ are H, respectively; R ３ is H and R ４ Ha-CH ３ and R ５ is C 1 -C 6 fluoroalkyl; R ６ is F or Cl; m is 0 or 1; R ７ is F or Cl; and n is 0 or 1. or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof.

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

3. 3. The compound of claim 1 or 2, wherein n is 0.

4. 3. The compound of claim 1, wherein m is 0 and n is 1.

5. R ５ is the formula and The compound according to any one of claims 1 to 4, which is a moiety of

6. R ５ is the formula or is a part of; m is 0; and The compound of claim 1 , wherein n is 0.

7. The compound has the following stereochemistry: The compound according to any one of claims 1 to 6, which is a compound having the formula:

8. Compound of formula (Ib) (Ib) [In the formula, Y ２ Ha-(CH ２ )- and; R ａ are independently F, Cl, Br, I, CN, OH, OCH ３ or SO ２ CH ３ C may be substituted with one or more groups independently selected from １ -C ６ is alkyl; R ｂ and R ｃ are H, respectively; R １ and R ２ are H, respectively; R ３ is H and R ４ Ha-CH ３ and R ５ is halogen, CN, OH, NH ２ , C １ -C ９ Alkyl, C ３ -C ９ Cycloalkyl, C ３ -C ９ Heterocycle, C ６ -C ９ Aryl, C ６ -C ９ Heteroaryl, C(O)R ｂ , C(O)NR ａ , S.O. ２ R ａ or SO ２ NR ａ C substituted with one or more of １ -C ９ is alkyl; R ６ is F or Cl; m is 0 or 1; R ７ is F or Cl; and n is 0 or 1. A method for preparing (a) Formula 12 wherein m is 0. A compound of formula [In the formula, Z １ is a bond; Cy is (R ７ ) ｎ -substituted phenyl; and X １ is I] and contacting the compound of formula 13 forming a compound of (b) reacting the compound of formula 13 from step 1 with the compound of formula with a compound of formula (Ib), thereby forming a compound of formula (Ib).

9. formula is a compound of the formula:

9. The method of claim 8, comprising:

10. 10. The method of claim 8 or 9, wherein n is 0.

11. R ７ The method of any one of claims 8 to 10, wherein is F and n is 1.

12. R ａ The method of any one of claims 8 to 11, wherein is ethyl or 1-propyl.

13. R ５ but or The method of claim 8 , wherein the moiety comprises:

Images