LSD1 regulators

Abstract

Disclosed are compounds, compositions and methods for treating diseases, syndromes, conditions and disorders affected by modulation of LSD1. Such compounds have the formula (I): [Case 1] JPEG2026502195000449.jpg37154 where the variables are defined herein. is expressed by

Description

[Technical Field]

[0001] The present disclosure relates to novel compounds capable of modulating lysine-specific demethylase-1 (LSD1) monoamine oxidase activity. Such oxidative activity can be inhibited by the compounds described herein. The present invention further describes the synthesis of the compounds and their use as pharmaceutical agents in diseases or disorders in which modulation of LSD1 may be beneficial. [Background technology]

[0002] Gene expression can be regulated at multiple levels within cells. For example, methylation of DNA promoters is associated with repression of gene expression. Various modifications of this type have already been approved for clinical use, such as Vidaza. Additional modifications include methylation of histones, which form the protein scaffold around which DNA normally wraps. Histones are important for organizing DNA, and because coiled DNA is normally unavailable for gene transcription, regulated coiling and uncoiling are important in controlling gene expression. Histones can be modified by acetylation, lysine methylation, ubikinylation, and sumoylation, many of which alter the accessibility of histones to the associated DNA.

[0003] A group of enzymes known as histone lysine methyltransferases and histone lysine demethylases is involved in histone lysine modifications. In particular, the histone demethylase LSD1 (KDM1A), which belongs to the broad family of flavin adenine dinucleotide (FAD)-dependent monoamine oxidases, catalyzes demethylase activity. Lysine-specific demethylase 1 (LSD1) catalyzes the demethylation of histone H3 on lysine 4 (H3K4me1 / 2), resulting in a transcriptionally repressed state. However, LSD1 can also demethylate histone H3 on lysine 9 methyltransferase 1 / 2 (H3K9me1 / 2), functioning as a transcriptional activator in certain cellular contexts. Therefore, depending on which lysine is demethylated by LSD1, gene expression can be repressed or activated (Maiques-Diaz A., Somervaille TCLSD1: biologic roles and therapeutic targeting. Epigenomics. 2016;8(8):1103-1116).

[0004] The LSD1 protein structure consists of three domains. The SWIRM and Tower domains function as scaffolds for multiprotein complex formation. The amine oxidase domain (AO) contains the active site, and the catalytic lysine residue (K661) acts to deprotonate methylated histone lysines (e.g., H3K4me2) and promote hydride transfer to FAD (Kong, X., et al. Catalytic mechanism investigation of lysine-specific demethylase 1 (LSD1): A computational study. PLoS One 2011, 6(9), e25444).

[0005] Elevated levels of LSD1 have been found in various cancers and are closely related to many cellular effects, such as epithelial-mesenchymal transition (EMT), cell proliferation and differentiation, stem cell biology, and malignant transformation (Abdel-Magid AF. Lysine-specific demethylase 1 (LSD-1) inhibitors as potential treatment for different types of cancers. ACS Medicinal Chemistry Letters. 2017;8:1134-5). LSD1 inactivation also enhances antitumor immunity and inhibits checkpoint blockade (Sheng W., et al. LSD1 ablation stimulates Anti-tumor immunity and enables checkpoint blockade. Cell. 2018;174:549-63). LSD1 dysfunction is also associated with the development of acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) (Mold DP, et.al. Reversible inhibitors of LSD1 as therapeutic agents in acute myeloid leukemia: clinical significance and progress to date. Medicinal Research Reviews. 2015;35:586-618).

[0006] Furthermore, high expression levels of LSD1 have also been found in breast cancer, neuroblastoma, colon cancer, and prostate cancer. Abnormal dysregulation of LSD1 causes differentiation arrest in both hematological and solid tumors, making it a potential target for cancer therapy (P. Troyer, Medical Epigenetics (Second Edition, 2021, LSD-1 functions in activation and repression of transcription)).

[0007] Many LSD1 inhibitors have been reported to date, including TCP, ORY-1001, GSK-2879552, IMG-7289, INCB059872, CC-90011, and ORY-2001 (Vafidemstat), which have been approved or are currently undergoing clinical evaluation as cancer treatments, particularly for small cell lung cancer (SCLC) and acute myeloid leukemia (AML). However, the blood-brain barrier (BBB) ​​penetration of these drugs remains insufficient. Therefore, these therapies remain unavailable for the treatment of cancers affecting the brain or central nervous system, such as brain tumors (e.g., glioblastoma) and CNS leukemia.

[0008] To date, there are no effective and approved medical treatments with good BBB penetration properties based on the inhibition of LSD1. Summary of the Invention [Means for solving the problem]

[0009] The present invention has been devised with the above observations in mind.

[0010] Generally, provided herein are compounds and pharmaceutical compositions capable of inhibiting LSD1. Also provided are methods of treatment and therapeutic / medical uses comprising the disclosed compounds or pharmaceutical compositions for inhibiting LSD1, particularly for treating diseases, disorders, or conditions associated with LSD1.

[0011] In a first aspect of the present disclosure, a compound of formula (I): [ka] (In the formula, R 1 is nitro or cyano; R 2 and R 2’ are each independently 1~3 selected from alkyl, hydrogen or halogen; R 3 is hydrogen, C 1~3 Alkyl, C 1~3Haloalkyl, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, C3-C6 heterocycloalkyl, C4-C5 heterocycloalkenyl, C3-C5 heterocycloalkyl-C1-C3 alkyl, C5-C6 aryl, C3-C6 heteroaryl, C1-C4 alkoxyl, C3-C6 cycloalkyl-C1-C3 alkoxyl, C1-C4 haloalkoxyl, C1-C3 haloalkyl, halogen, amino, alkylamino, dialkylamino, C2-C7 cyclic amine, C2-C5 heterocyclic amine, C3-C6 unsaturated or aromatic cyclic amine, C3-C5 unsaturated or aromatic complex amine each alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, heterocycloalkylalkyl, aryl, heteroaryl, alkoxyl, cycloalkylalkoxyl, alkylamino, dialkylamino, cyclic amine, heterocyclic amine, unsaturated or aromatic cyclic amine, and unsaturated or aromatic heterocyclic amine is optionally substituted with 1 to 3 substituents selected from the group consisting of C1-C3 alkyl, C1-C3 alkoxyl, C3-C6 cycloalkyl, hydroxyl, halogen, and amino; R 4 is selected from hydrogen or halogen; R 5 is hydrogen, C 1~3 selected from the group consisting of alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, C3-C6 aryl, C3-C6 heteroaryl, halogen, amino, alkylamino, dialkylamino, C2-C7 cyclic amine, C2-C5 heterocyclic amine, C3-C6 unsaturated or aromatic cyclic amine, and C3-C5 unsaturated or aromatic heterocyclic amine, wherein each alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, alkylamino, dialkylamino, cyclic amine, heterocyclic amine, unsaturated or aromatic cyclic amine, and unsaturated or aromatic heterocyclic amine is optionally substituted with 1 to 3 substituents selected from the group consisting of C1-C3 alkyl, C1-C3 alkoxyl, C3-C6 cycloalkyl, hydroxyl, halogen, or amino; R 6is hydrogen, C1-C4 alkyl, C1-C4 alkoxyl, amino, alkylamino, aminoalkyl, dialkylamino, C8-C 11 Spirocycloalkyl, C5-C 10 Heterospirocycloalkyl, C5-C 11 Monocyclic or bicyclic aryl, monocyclic or bicyclic heteroaryl, C2-C7 cyclic amine, C2-C5 heterocyclic amine, C3-C6 unsaturated or aromatic cyclic amine, C3-C5 unsaturated or aromatic heterocyclic amine, C7-C 10 selected from the group consisting of spirocyclic amine, C4-C9 heterospirocyclic amine, C3-C6 heteroaryloxyl, or C3-C6 cycloalkoxyl, each optionally substituted with 1 to 3 substituents selected from the group consisting of hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxyl, halogen, C1-C3 haloalkyl, C1-C3 haloalkoxyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C2-C5 heterocycloalkyl, or optionally substituted C3-C6 heteroaryl, wherein the optionally substituted cycloalkyl, heterocycloalkyl, and heteroaryl may be substituted with 1 or 2 substituents selected from the group consisting of C1-C3 alkyl, C1-C3 alkoxyl, hydroxyl, halogen, or amine; L is a linker selected from the group consisting of a bond, -CH2-, -CH2-CH2-, -CH(CH3)-, -C(CH3)2-, -C≡C-, -CH2-O-, -C(O)-, -O-, -O-CH2-, -NH-CH2-, -N(CH3)-CH2-, -NH-C(O)-, -N(CH3)-C(O)-, -CH2-NH-CH2-; Q is C5-C9 cycloalkyl, C4-C8 heterocycloalkyl, C8-C 11 Spirocycloalkyl, C5-C 10 Heterospirocycloalkyl, C3-C8 cyclic amine, C3-C8 heterocyclic amine, C7-C 10a monocyclic or bicyclic ring system selected from the group consisting of spirocyclic amines or C4-C9 heterospirocyclic amines, wherein each cycloalkyl or heterocycloalkyl group can be saturated or unsaturated, and the bicyclic ring can be a fused or bridged bicyclic ring; Q is selected from the group consisting of one to three R 7 and each R 7 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkylcarbonyl, hydroxyl, oxo, halogen, C1-C6 alkylamine, or amino. or a pharmaceutically acceptable salt, solvate, prodrug, pharmaceutically active metabolite, or combination thereof.

[0012] In embodiments, each heteroaryl or heterocyclic substituent may contain 1 to 4, 1 to 3, or 1 or 2 heteroatoms independently selected from O, S, and N.

[0013] In embodiments, each heteroaryl or heterocyclic substituent may be attached to the remainder of the compound through a carbon atom or through a heteroatom, hi embodiments, a heteroaryl or heterocyclic substituent is attached to the remainder of the compound through a carbon atom or through an N atom.

[0014] Preferably, R 2 and R 2’ Can one of the groups be hydrogen and the other F? 2 and R 2’ one of R can be hydrogen and the other can be Cl; or R 2 and R 2’ In some particular embodiments, both R 2 and R 2’ One of them can be methyl and the other can be hydrogen, F or Cl.

[0015] Preferably, R 3may be selected from hydrogen, halogen, C-C cycloalkyl, C-C heterocycloalkyl, C-C aryl, C-C heteroaryl, or C-C heterocyclic amine. 3 can be hydrogen or Cl; R 3 can be an optionally substituted 5- or 6-membered heteroaryl; R 3 can be an optionally substituted 4- to 6-membered heterocycloalkyl; or R 3 can be an optionally substituted 3- to 5-membered cycloalkyl; each heteromoiety can contain one or two heteroatoms independently selected from O, S, and N; and / or the optional substituents are independently selected from one or two of the group consisting of methyl, F, and Cl. In embodiments, R 3 is an optionally substituted oxazole.

[0016] In various embodiments, R 4 can be hydrogen; R 4 can be F and R 5 and R 6 can each be hydrogen; R 4 can be F and R 5 and R 6 may each be hydrogen; or R 4 , R 5 and R 6 can all be hydrogen.

[0017] In embodiments, R 5 can be hydrogen; R 5 Can F be R? 5 can be a 4- or 5-membered heterocycloalkyl; R 5 can be C1-C3 alkyl; R 5 can be a 3-, 4-, or 5-membered cycloalkyl; or R 5 may be an optionally substituted C-C cycloalkyl, C-C cycloalkenyl, C-C heterocycloalkyl, C-C aryl, or C-C heteroaryl. In particular, R 5can be selected from hydrogen, F, methyl or pyrrolidine.

[0018] In various embodiments, R 4 , R 5 and R 6 is hydrogen.

[0019] In embodiments, R 6 can be hydrogen; R 6 can be F or Cl; R 6 can be an optionally substituted 4- or 5-membered heterocycloalkyl; R 6 may be an optionally substituted 8-, 9-, or 10-membered bicyclic or spirocyclic heterocycloalkyl; R 6 can be an optionally substituted 5- or 6-membered heteroaryl; R 6 may be an optionally substituted 4-, 5-, or 6-membered cycloalkyl or spirocycloalkyl; R 6 can be C1-C3 haloalkoxy; or R 6 may be a C2-C8 alkylamine or dialkylamine, and each heteromoiety may contain one or two heteroatoms independently selected from O, S, and N, and / or the optional substituents are independently selected from one or two substituents selected from the group consisting of C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxyl, F, Cl, and hydroxyl. In particular, R 6 may be selected from hydrogen, F, methyl or pyrrolidine.

[0020] In various embodiments, L may be suitably selected from -CH2- or -CH2-CH2-.

[0021] Suitably, Q may be selected from the group consisting of optionally substituted 5- to 7-membered heterocycloalkyl and optionally substituted 4- to 7-membered mono- or fused or bridged bicycloalkylamine; each heteromoiety may contain 1 or 2 heteroatoms independently selected from O and N; and / or the optional substituents are independently selected from 1 to 3 substituents selected from the group consisting of C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxyl, C1-C3 alkylamine, C1-C3 dialkylamine, C1-C3 carbonyl, amine, amino-C1-C3 alkyl, oxo, F, Cl, and hydroxyl.

[0022] In embodiments, R 7 may be independently selected from C1-C3 alkyl, C1-C3 haloalkyl, hydroxyl, oxo, F, C1-C3 alkylamino, C1-C3 dialkylamino, or amino; or R 7 may be independently selected from methyl, ethyl, amine, and F; optionally, one, two, or three R 7 There is a group.

[0023] In some beneficial embodiments, R 3 has the following structure: [ka] may be selected from the group consisting of:

[0024] In some beneficial embodiments, R 5 is hydrogen and the following structure: [ka] may be selected from the group consisting of:

[0025] In some beneficial embodiments, R 6 is hydrogen and the following structure: [ka] may be selected from the group consisting of:

[0026] In some advantageous embodiments, Q has the following structure: [ka] may be selected from the group consisting of:

[0027] Particularly advantageously, Q has the following structure: [ka] may be selected from the group consisting of:

[0028] In embodiments, there is provided a compound of formula (I) or a pharmaceutically acceptable salt, solvate, prodrug, pharmaceutically active metabolite, or combination thereof, wherein: R1 is cyano; and / or R2 and R2' are each independently selected from hydrogen or F; and / or R3 is selected from hydrogen, propyl, i-propyl, CHF2, cyclopropyl, -CH2-cyclopropyl, -CH2-oxetane, isothiazole, oxazole, fluorooxazole, pyridyl, methoxyl, -O-CH2-cyclopropyl, -O-CH2-CF3, -O-CF3, CF3, Cl, amino, -N(CH3)(CH2-isopropyl), pyrrolidine, cyano; and / or R4 is hydrogen or F; and / or R5 is selected from hydrogen, methyl, cyclopropyl, cyclopentenyl, F, amino, NH—CH2—CH2—N(CH3)2; and / or R6 is selected from hydrogen, -O-cyclobutyl, -O-CH2-oxane, -O-CH2-CH2-CHF2, -O-CH2-CH2-CF3, -O-CH2-CF3, -CH2-O-CHF2, amino, -N(CH3)(CH-(CH3)2, benzimidazole, pyridine; and / or L is a linker selected from a bond, —CH—, C≡C—, CH—NH—CH—; and / or Q is a C4-C8 heterocycloalkyl which may contain additional heteroatoms selected from N or O; or Q is morpholinyl; Each heteroaryl, heterocycloalkyl and / or cycloalkyl group is optionally substituted.

[0029] In embodiments, there is provided a compound of formula (I) or a pharmaceutically acceptable salt, solvate, prodrug, pharmaceutically active metabolite, or combination thereof, wherein: R1 is cyano; and / or R2 and R2' are each independently selected from hydrogen or F; and / or R3 is selected from hydrogen, isothiazole, oxazole, fluorooxazole, pyridyl; and / or R4 is hydrogen or F; and / or R5 is selected from hydrogen, methyl, F; and / or R6 is selected from hydrogen, —O-cyclobutyl, —O—CH2-oxane; and / or L is a linker selected from a bond, —CH2—, C≡C—; and / or Q is a C4-C8 heterocycloalkyl which may contain additional heteroatoms selected from N or O; or Q is morpholinyl; Each heteroaryl, heterocycloalkyl and / or cycloalkyl group is optionally substituted.

[0030] In certain embodiments, there is provided a compound of formula (I) or a pharmaceutically acceptable salt, solvate, prodrug, pharmaceutically active metabolite, or combination thereof, wherein: R1 is cyano; R2 and R2' are each independently selected from hydrogen or F; R3 is selected from hydrogen, propyl, i-propyl, CHF2, cyclopropyl, -CH2-cyclopropyl, -CH2-oxetane, isothiazole, oxazole, fluorooxazole, pyridyl, methoxyl, -O-CH2-cyclopropyl, -O-CH2-CF3, -O-CF3, CF3, Cl, amino, -N(CH3)(CH2-isopropyl), pyrrolidine, cyano; R4 is hydrogen or F; R5 is selected from hydrogen, methyl, cyclopropyl, cyclopentenyl, F, amino, NH—CH2—CH2—N(CH3)2; R6 is selected from hydrogen, -O-cyclobutyl, -O-CH2-oxane, -O-CH2-CH2-CHF2, -O-CH2-CH2-CF3, -O-CH2-CF3, -CH2-O-CHF2, amino, -N(CH3)(CH-(CH3)2, benzimidazole, pyridine; L is a linker selected from a bond, —CH—, C≡C—, CH—NH—CH—; Q is a C4-C8 heterocycloalkyl which may contain additional heteroatoms selected from N or O; or Q is morpholinyl; Each heteroaryl, heterocycloalkyl and / or cycloalkyl group is optionally substituted.

[0031] In some particular embodiments, there is provided a compound of formula (I) or a pharmaceutically acceptable salt, solvate, prodrug, pharmaceutically active metabolite, or combination thereof, wherein: R1 is cyano; R2 and R2' are each independently selected from hydrogen or F; R3 is selected from hydrogen, isothiazole, oxazole, fluorooxazole, pyridyl; and / or R4 is hydrogen or F; R5 is selected from hydrogen, methyl, and F; R6 is selected from hydrogen, —O-cyclobutyl, —O—CH2-oxane; and / or L is a linker selected from a bond, —CH2—, C≡C—; Q is a C4-C8 heterocycloalkyl which may contain additional heteroatoms selected from N or O; or Q is morpholinyl; Each heteroaryl, heterocycloalkyl and / or cycloalkyl group is optionally substituted.

[0032] The present invention also provides a compound selected from any one of the group of compounds shown in Table 1; the group of compounds in Table 1 having an IC50 of 1,000 nM or less against LSD1; the group of compounds in Table 1 having an IC50 of 250 nM or less against LSD1; the group of compounds in Table 1 having an IC50 of 100 nM or less against LSD1; the group of compounds in Table 1 having an IC50 of 50 nM or less against LSD1; the group of compounds in Table 1 having an IC50 of 25 nM or less against LSD1; or the group of compounds in Table 1 having an IC50 of 10 nM or less against LSD1, or a pharmaceutically acceptable salt, solvate, prodrug or pharmaceutically active metabolite thereof, or a combination thereof.

[0033] The present disclosure provides a compound selected from any one of Examples 1-351.

[0034] According to a second aspect of the present disclosure, there is provided a pharmaceutical composition comprising one or more compounds according to the first aspect of the present disclosure or a pharmaceutically acceptable salt, solvate, prodrug or pharmaceutically active metabolite thereof, or a combination thereof, and one or more pharmaceutically acceptable carriers.

[0035] In a third aspect, the present disclosure provides a compound according to the first aspect or a pharmaceutical composition according to the second aspect for use in medicine. In particular, the compound or pharmaceutical composition may be for use in the treatment of a disease, condition or disorder associated with LSD1, such as cancer, a neoplastic disease, an autoimmune disorder and / or an inflammatory disease.

[0036] In a fourth aspect, the present disclosure provides a method of treating a disease, disorder, or condition in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound or pharmaceutical composition according to the present disclosure.

[0037] In embodiments of the uses and methods of the present disclosure, the disease, condition, or disorder may be selected from the group consisting of breast cancer, prostate cancer, head and neck cancer, brain cancer, laryngeal cancer, oral cancer, and thyroid cancer (e.g., papillary thyroid cancer), blood cancer (e.g., non-Hodgkin's lymphoma, B-cell lymphoma, chronic myeloid leukemia), sarcoma, lung cancer, gastrointestinal cancer, genitourinary cancer, liver cancer, bone cancer, nervous system cancer, gynecological cancer, and skin cancer. In embodiments, the disease, condition, or disorder is selected from the group consisting of glioblastoma, acute myeloid leukemia (AML), and small cell lung cancer (SCLC). In embodiments, the disease, condition, or disorder is glioma. In embodiments, the disease, condition, or disorder is acute myeloid leukemia (AML). In embodiments, the disease, condition, or disorder is small cell lung cancer (SCLC).

[0038] According to various embodiments, the compounds or pharmaceutical compositions may be administered orally, topically, by inhalation, intranasally, or systemically by intravenous, intraperitoneal, subcutaneous, or intramuscular injection. In some embodiments, the compounds or pharmaceutical compositions of the present disclosure may be administered in combination with one or more additional therapeutic agents. When administered in combination with one or more additional therapeutic agents, administration may be simultaneous, sequential, or separate from the one or more additional therapeutic agents.

[0039] Preferably, the compounds or pharmaceutical compositions of the present disclosure can be administered to a subject to achieve a desired effective amount of the compound in the subject's blood or plasma. For example, an effective amount can be from about 500 μm to about 10 μm.

[0040] Within the scope of this disclosure, it is expressly intended that the various aspects, embodiments, examples, and alternatives, particularly individual features thereof, described in the preceding paragraphs, claims, and / or the following description and drawings, may be construed independently or in any combination. That is, all embodiments and / or features of any embodiment may be combined in any manner and / or combination, unless such features are incompatible. More specifically, any embodiment of any aspect may form an embodiment of any other aspect, and all such combinations are specifically intended to be encompassed within the scope of the present invention. Applicant reserves the right to modify the originally filed claims or to submit new claims accordingly, including the right to amend the originally filed claims to depend on and / or incorporate features of other claims, even if not originally claimed as such. DETAILED DESCRIPTION OF THE INVENTION

[0041] Described herein are compounds and compositions (such as organic molecules, research tools, pharmaceutical formulations, and therapeutic agents); uses (in vitro and in vivo) of the disclosed compounds and compositions; and corresponding methods, whether for diagnostic, therapeutic, or research use. Chemical synthesis and biological testing of the disclosed compounds are also described. Advantageously, the compounds, compositions, uses, and methods are useful for studying and / or treating diseases or disorders in animals, including humans. Diseases or disorders that may benefit from LSD1 modulation include cancer and / or neoplastic diseases, such as brain tumors (e.g., glioblastoma), central nervous system leukemia, cancers of hematopoietic origin, or solid tumors, including chronic myeloid leukemia, myeloid leukemia (e.g., AML-acute myeloid leukemia), small cell lung cancer (SCLC), non-Hodgkin's lymphoma, and other B-cell lymphomas. Indeed, the beneficial technical effects of the present invention, exemplified by the compounds and / or pharmaceutical compositions disclosed herein, reside in their high central nervous system (CNS) and / or blood-brain barrier (BBB) ​​penetration properties. This has the advantageous technical effect that the compounds and compositions of the present disclosure may be particularly suitable for treating conditions affecting the brain and / or central nervous system, whereas other therapies lacking suitable CNS and BBB penetration properties are less suitable, such as brain cancers (e.g., glioblastoma) and CNS leukemia.

[0042] However, the compounds may also, or alternatively, be useful as lead molecules for the selection, screening, and development of further derivatives, which may, if desired, have one or more improved beneficial drug properties. Such further selection and screening may be carried out, for example, using the proprietary computational evolution algorithm described in applicant's previously published WO 2011 / 061548, which is incorporated herein by reference in its entirety.

[0043] The present disclosure also encompasses salts, solvates, and functional derivatives of the compounds described herein, which may be useful in treating diseases or disorders that may benefit from LSD1 cancer and / or neoplastic disease.

[0044] 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 (e.g., organic, physical, or theoretical chemistry; biochemistry and molecular biology).

[0045] Unless otherwise indicated, the practice of the present invention employs conventional techniques of chemistry and chemical methods, biochemistry, molecular biology, pharmaceutical formulation, and patient delivery and treatment regimens, which are within the capabilities of those of ordinary skill in the art, and such techniques are also described in the references cited herein. All references cited in this disclosure are incorporated herein by reference in their entirety.

[0046] Before describing the invention in detail, some definitions are provided that may aid in understanding the disclosure.

[0047] In accordance with the present disclosure, the term "molecule" is used interchangeably with the term "compound," and in some cases, with the term "chemical structure." The term "drug" is typically used in reference to pharmaceuticals, pharmaceutical compositions, medicaments, and the like, that have known or predicted physiological or in vitro activity of medical significance, although such properties and qualities are not excluded by the molecules or compounds of the present disclosure. Thus, the term "drug" is used interchangeably with alternative terms and phrases such as "therapeutic," "pharmaceutical," and "active." Therapeutic agents according to the present disclosure also encompass compositions and pharmaceutical formulations comprising the compounds of the present disclosure.

[0048] As used herein, the term "compound" is intended to include all stereoisomers, geometric isomers, tautomers, and isotopically enriched variants of the depicted structure. A compound identified herein by name or structure as one particular tautomeric form is intended to include other tautomeric forms unless otherwise specified. As used herein, the term "tautomer" refers to a compound whose structure differs significantly in the arrangement of atoms but exists in easy and rapid equilibrium; it should be understood that the compounds provided herein may be represented as different tautomers, and that if a compound has tautomeric forms, all tautomeric forms are intended to be within the scope of this disclosure, and the naming of the compound does not exclude any tautomers.

[0049] It will be understood that certain compounds provided herein may contain one or more asymmetric centers and therefore may be prepared and isolated as a mixture of isomers, such as a racemic mixture, or in enantiomerically pure form.

[0050] The compounds provided herein may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. That is, particularly when reference is made to compounds of formula (I), a reference to an atom includes all isotopes and isotopic mixtures of that atom, whether naturally occurring or synthetically produced, in either natural abundance or isotopically enriched form. For example, unless expressly stated otherwise, when hydrogen is referenced, it is 1 H, 2 H, 3 H or mixtures thereof; when carbon is mentioned, it is 11 C. 12 C. 13 C. 14 C or mixtures thereof; when nitrogen is mentioned, it is 13 N, 14 N, 15 N or mixtures thereof; when oxygen is mentioned, it is 14 O. 15 O.16 O. 17 O. 18 fluorine is understood to refer to fluorine, fluorine-containing compounds, or mixtures thereof; 18 F, 19 For example, deuterated alkyl and deuterated alkoxy groups specifically refer to groups in which one or more hydrogen atoms are replaced with deuterium ( 2 Some of the aforementioned isotopes are radioactive, and therefore the compounds provided herein also include compounds having one or more isotopes of one or more atoms, and mixtures thereof, including radioactive compounds in which one or more non-radioactive atoms are replaced by one of their radioactively enriched isotopes. Radiolabeled compounds are useful as therapeutic agents, e.g., cancer therapeutic agents, research reagents, e.g., assay reagents, and diagnostic agents, e.g., in vivo imaging agents. All isotopic variants of the compounds provided herein, whether radioactive or not, are intended to be encompassed within the scope of the present disclosure.

[0051] Prodrugs and solvates of the compounds of the present disclosure are also encompassed within the scope of the present disclosure. The term "prodrug" refers to a compound (e.g., a drug precursor) that is transformed in vivo to produce a compound of the present disclosure or a pharmaceutically acceptable salt, solvate, or ester of the compound. The transformation can occur by various mechanisms (e.g., by metabolic or chemical processes), such as hydrolysis of a hydrolyzable bond, for example, in blood (Higuchi & Stella (1987), "Prodrugs as Novel Delivery Systems," vol. 14 of the ACS Symposium Series; (1987), "Bioreversible Carriers in Drug Design," Roche, ed., American Pharmaceutical Association and Pergamon Press). Thus, the compositions and medicaments of the present disclosure may include prodrugs of the compounds of the present disclosure. In some aspects and embodiments, the compounds of the present disclosure are themselves prodrugs that can be metabolized in vivo to provide therapeutically active compounds. For example, sulfoxide prodrugs can be metabolized in vivo to therapeutically active sulfones (Basarab GSet al., (2008), Bioorg Med Chem Lett, 18(16), 4716-4722; Gibhard L. et al., (2008), Antimicrobial Agents and Chemotherapy, 62(12), 00232-18).

[0052] In the context of the present disclosure, the terms "individual," "subject," or "patient" are used interchangeably to refer to an animal that may be suffering from a medical (pathological) condition and may respond to a molecule, pharmaceutical, medical treatment, or therapeutic treatment regimen of the present disclosure. The animal is preferably a mammal, such as a human, cow, sheep, pig, dog, cat, bat, mouse, or rat. In particular, the subject may be a human.

[0053] As used herein, the term "treat" or "treatment" refers to curative or palliative measures. Beneficial or desired clinical results include, but are not limited to, the total or partial alleviation of symptoms associated with a disease or disorder or condition, whether detectable or undetectable, attenuation of the extent of the disease, stabilization of the disease state (i.e., not worsening), delay or slowing of disease progression, improvement or palliation and remission (partial or total) of the disease state (e.g., one or more symptoms of the disease). "Treatment" can also mean prolonging survival as compared to expected survival if not receiving treatment.

[0054] The term "prevention", as used herein, means the total or partial prevention of the onset, recurrence or spread of a disease or condition described herein or a symptom thereof.

[0055] The term "halo" refers to one of the halogens of Group 17 of the periodic table. In particular, the term refers to fluorine, chlorine, bromine, and iodine. Preferably, the term refers to fluorine or chlorine.

[0056] The term "alkyl" refers to a monovalent, optionally substituted, saturated aliphatic hydrocarbon radical. While there can be any number of carbon atoms, typically the number of carbon atoms in an alkyl group can be 1 to about 20, 1 to about 12, 1 to about 6, or 1 to about 4. Usefully, the number of carbon atoms is indicated, for example, C1-12 alkyl (or C 1~12 "Alkyl" refers to any alkyl group containing 1 to 12 carbon atoms in the chain. Alkyl groups can be straight-chained (i.e., linear), branched, or cyclic. "Lower alkyl" refers to an alkyl having 1 to 6 carbon atoms in the chain, and can have 1 to 4 carbon atoms or 1 to 2 carbon atoms. Thus, representative examples of lower alkyl radicals include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, isobutyl, isopentyl, amyl (CH 11 ), sec-butyl, tert-butyl, sec-amyl, tert-pentyl, 2-ethylbutyl, 2,3-dimethylbutyl, and the like. "Higher alkyl" refers to alkyls having seven or more carbon atoms, including n-heptyl, n-octyl, n-nonyl, n-decyl, n-dodecyl, n-tetradecyl, n-hexadecyl, n-octadecyl, n-eicosyl, and the like, as well as branched variations thereof. For example, a linear carbon chain of 4 to 6 carbons refers to the chain length not including the carbons present on the branch, while in branched chains it refers to the total number. Optional substituents for alkyl and other groups are described below.

[0057] The term "substituted" means that one or more hydrogen atoms (attached to carbon atoms or heteroatoms) have been replaced with one selected from the specified substituents, provided that the replacement does not exceed the normal valence of the specified atom under the existing circumstances. The group may be optionally substituted with the specified substituents in a position that does not significantly interfere with the preparation of compounds within the scope of the present invention, and with the understanding that the substitution does not significantly adversely affect the biological activity or structural stability of the compound. Combinations of substituents are permissible only if such combinations result in stable compounds. A "stable compound" or "stable structure" refers to a compound that is robust enough to survive isolation to a useful degree of purity from a reaction mixture and / or formulation to yield an effective therapeutic agent. "Optionally substituted" means that the relevant group is unsubstituted, or that at least one hydrogen atom has been replaced with one of the specified substituents, radicals, or moieties.

[0058] Any radical / group / moiety described herein that can be substituted (or is optionally substituted) can be substituted with one or more (e.g., 1, 2, 3, 4, or 5) substituents independently selected from the specified group of substituents. Thus, the substituents may be selected from the following group: halogen (or "halo", e.g., F, Cl, and Br), hydroxyl (-OH), amino or aminyl (-NH), thiol (-SH), cyano (-CN), (lower) alkyl, (lower) alkoxy, (lower) alkenyl, (lower) alkynyl, aryl, heteroaryl, (lower) alkylthio, oxo, haloalkyl, hydroxyalkyl, nitro (-NO), phosphate, azido (-N), alkoxycarbonyl, carboxy, alkylcarboxy, alkylamino, dialkylamino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, thioalkyl, alkylsulfonyl, arylsulfinyl, alkylaminosulfonyl, arylaminosulfonyl, alkylsulfonylamino, arylsulfonylamino, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, arylcarbamoyl, alkylcarbonylamino, arylcarbonylamino, cycloalkyl, heterocycloalkyl. Alternatively, when the substituents are on an aryl or other cyclic ring system, two adjacent atoms may be substituted with methylenedioxy or ethylenedioxy groups.More preferably, the substituents are selected from the following: halogen, hydroxy, amino, thiol, cyano, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkenyl, (C1-C6)alkynyl, aryl, aryl(C1-C6)alkyl, aryl(C1-C6)alkoxy, heteroaryl, (C1-C6)alkylthio, oxo, halo(C1-C6)alkyl, hydroxy(C1-C6)alkyl, nitro, phosphate, azido, (C1-C6)alkoxycarbonyl, carboxy, (C1-C6)alkylcarboxy, (C1-C6)alkylamino, di(C1-C6)alkylamino, amino(C1 (C1-C6)alkyl, (C1-C6)alkylamino(C1-C6)alkyl, di(C1-C6)alkylamino(C1-C6)alkyl, thio(C1-C6)alkyl, (C1-C6)alkylsulfonyl, arylsulfinyl, (C1-C6)alkylaminosulfonyl, arylaminosulfonyl, (C1-C6)alkylsulfonylamino, arylsulfonylamino, carbamoyl, (C1-C6)alkylcarbamoyl, di(C1-C6)alkylcarbamoyl, arylcarbamoyl, (C1-C6)alkylcarbonylamino, arylcarbonylamino, (C1-C6)cycloalkyl and heterocycloalkyl. Even more preferably, the substituents are selected from one or more of the following: fluoro, chloro, bromo, hydroxy, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)aryl, 5- or 6-membered heteroaryl, (C4-C6)cycloalkyl, 4- to 6-membered heterocycloalkyl, cyano, (C1-C6)alkylthio, amino, —NH(alkyl), —NH((C1-C6)cycloalkyl), —N((C1-C6)alkyl), —OC(O)—(C1-C6)alkyl, —OC(O)—(C5-C6)aryl, —OC(O)—(C1-C6)cycloalkyl, carboxy, and —C(O)O—(C1-C6)alkyl. Most preferably, the substituents are selected from one or more of the following: fluoro, chloro, bromo, hydroxy, amino, (C1-C6) alkyl and (C1-C6) alkoxy, wherein the alkyl and alkoxy are optionally substituted with one or more chloro.Particularly preferred substituents are chloro, methyl, ethyl, methoxy and ethoxy.

[0059] The term "halo" refers to a monovalent halogen radical selected from chloro, bromo, iodo, and fluoro. A "halogenated" compound is a compound substituted with one or more halo substituents. Preferred halo groups are F, Cl, and Br, with Cl being most preferred.

[0060] As used herein, the term "cyano" refers to a -CN group. As used herein, the term "hydroxyl" or "hydroxo" refers to a -OH group. As used herein, the term "amino" or "aminyl" refers to a -NH group. As used herein, the term "oxo" refers to a "=O" group attached to a carbon atom.

[0061] The term "C1-C6 haloalkyl" refers to a hydrocarbon chain substituted with at least one independently selected halogen atom, such as fluorine, chlorine, bromine, and iodine, at each occurrence. The halogen atom may be present at any position on the hydrocarbon chain. Similarly, a C1-C3 haloalkyl group is a straight or branched hydrocarbon chain containing 1, 2, or 3 carbon atoms substituted with at least one halogen atom. For example, C1-C3 haloalkyl refers to chloromethyl, fluoromethyl, trifluoromethyl, chloroethyl (e.g., 1-chloroethyl and 2-chloroethyl), trichloroethyl (e.g., 1,2,2-trichloroethyl and 2,2,2-trichloroethyl), fluoroethyl (e.g., 1-fluoromethyl and 2-fluoroethyl), trifluoroethyl (e.g., 1,2,2-trifluoroethyl and 2,2,2-trifluoroethyl), chloropropyl, trichloropropyl, fluoropropyl, and trifluoropropyl.

[0062] As used herein, the term "geminal" refers to substituent atoms or groups that are attached to the same atom in a molecule. As used herein, the term "vicinal" refers to substituent atoms or groups that are attached to adjacent atoms in a molecule. The stereochemical relationships between substituent atoms or groups can be cis, trans, undefined, or unresolved.

[0063] As used herein, the term "independently," with respect to substitution of a parent moiety with one or more substituents, means that the parent moiety may be substituted, individually or in combination, with any of the listed substituents, and any number of chemically feasible substituents may be used. In any embodiment, when a group is substituted, it may contain up to five, up to four, up to three, or one and two substituents. As non-limiting examples, useful substituents include: phenyl or pyridine independently substituted with one or more lower alkyl, lower alkoxy, or halo substituents, such as chlorophenyl, dichlorophenyl, trichlorophenyl, tolyl, xylyl, 2-chloro-3-methylphenyl, 2,3-dichloro-4-methylphenyl, and the like.

[0064] "Alkylene" or "alkylenyl" means a difunctional group obtained by removal of a hydrogen atom from an alkyl group that is defined above. Non-limiting examples of alkylene include methylene, ethylene, and propylene. "Lower alkylene" means an alkylene having 1 to 6 carbon atoms in the chain, which can be straight or branched. Alkylene groups are optionally substituted.

[0065] The term "alkenyl" refers to a monovalent, optionally substituted, unsaturated aliphatic hydrocarbon radical. Thus, an alkenyl has at least one carbon-carbon double bond (C=C). The number of carbon atoms in an alkenyl group may be indicated as 2 to about 20, for example, C2-12 alkenyl (or C 2~12Alkenyl refers to an alkenyl group containing 2 to 12 carbon atoms in its structure. Alkenyl groups can be straight-chained (i.e., linear), branched-chained, or cyclic. "Lower alkenyl" refers to an alkenyl having 1 to 6 carbon atoms, and may have 1 to 4 carbon atoms or 1 to 2 carbon atoms. Representative examples of lower alkenyl radicals include ethenyl, 1-propenyl, 1-butenyl, 1-pentenyl, 1-hexenyl, isopropenyl, isobutenyl, and the like. Higher alkenyl refers to alkenyls having seven or more carbon atoms and branched variations thereof, such as 1-heptenyl, 1-octenyl, 1-nonenyl, 1-decenyl, 1-dodecenyl, 1-tetradecenyl, 1-hexadecenyl, 1-octadecenyl, 1-eicosenyl, and the like. Optional substituents include those described elsewhere.

[0066] "Alkenylene" means a difunctional group obtained by removal of a hydrogen from an alkenyl group that is defined above. Non-limiting examples of alkenylene include -CH=CH-, -C(CH)=CH-, and -CH=CHCH-.

[0067] "Alkynyl" and "lower alkynyl" are defined similarly to the term "alkenyl," except that they contain at least one carbon-carbon triple bond.

[0068] The term "alkoxy" (or "alkoxyl") refers to a monovalent radical of formula RO-, where R is any alkyl, alkenyl, or alkynyl as defined herein. Alkoxy groups can be optionally substituted with any of the optional substituents described herein. "Lower alkoxy" has the formula RO-, where the R group is a lower alkyl, alkenyl, or alkynyl. Representative alkoxy radicals include methoxy, ethoxy, n-propoxy, n-butoxy, n-pentyloxy, n-hexyloxy, isopropoxy, isobutoxy, isopentyloxy, amyloxy, sec-butoxy, tert-butoxy, tert-pentyloxy, and the like. Preferred alkoxy groups are methoxy and ethoxy.

[0069] The term "cycloalkoxy" (or "cycloalkoxyl") refers to a group of the formula R 1 O- refers to the monovalent radical, R 1 is any cycloalkyl as defined herein. Cycloalkoxy groups can be optionally substituted with any of the optional substituents described herein. Cycloalkoxy can incorporate a monocyclic cycloalkyl group or a bicycloalkyl group. Representative cycloalkoxy radicals include cyclohexyloxy, cyclopentyloxy, cyclobutanyloxy, and cyclopropanyloxy. Particularly suitable cycloalkoxy groups include cyclohexyloxy, cyclobutanyloxy, and cyclopropanyloxy.

[0070] The term “heteroaryloxy” (or “heteroaryloxyl”) refers to a compound of the formula R 1 O- refers to the monovalent radical, R 1 is any heteroaryl as defined herein, containing at least one heteroatom selected from the following group: N, O, S. The heteroaryloxy group may be optionally substituted with any of the optional substituents described herein. The heteroaryl group may include a monocyclic heteroaryl group or a bicyclic heteroaryl group. Representative heteroaryloxy radicals include pyridinyloxy.

[0071] As used herein, the term "aryl" refers to a substituted or unsubstituted aromatic carbocyclic radical containing 5 to about 15 carbon atoms; preferably 5 or 6 carbon atoms. An aryl group may have only one individual carbocyclic ring or may contain one or more fused rings in which at least one ring is aromatic in nature. "Phenyl" is a radical formed by removing a hydrogen atom from a benzene ring, which may be substituted or unsubstituted. Thus, a "phenoxy" group is a radical of the formula RO-, where R is a phenyl radical. "Benzyl" is a radical of the formula R-CH2-, where R is phenyl, and "benzyloxy" is a radical of the formula RO-, where R is benzyl. Non-limiting examples of aryl radicals include phenyl, naphthyl, benzyl, biphenyl, furanyl, pyridinyl, indanyl, anthraquinolyl, tetrahydronaphthyl, benzoic acid radical, furan-2-carboxylic acid radical, and the like.

[0072] As used herein, a "heteroaryl" group is defined as a substituted or unsubstituted "aryl" group in which one or more carbon atoms in the ring structure are replaced with a heteroatom such as nitrogen, oxygen, or sulfur. Typically, heteroaryl groups contain one or two heteroatoms. A preferred heteroatom is N. Exemplary heteroaryl groups include furan, benzofuran, isobenzofuran, pyrrole, indole, isoindole, thiophene, benzothiophene, benzo[c]thiophene, imidazole, benzimidazole, purine, pyrazole, indazole, oxazole, benzoxazole, isoxazole, benzisoxazole, thiazole, benzothiazole, pyridine, quinoline, isoquinoline, pyrazine, quinoxaline, acridine, pyrimidine, quinazoline, pyridazine, and cinnoline.

[0073] As used herein, the term "heterocycle" or "heterocyclic" group refers to a monovalent radical having about 4 to about 15 ring atoms, preferably 4, 5, 6, or 7 ring members. Generally, heterocyclic groups contain one, two, or three heteroatoms independently selected from nitrogen, oxygen, and sulfur. A preferred heteroatom is N. Heterocyclic groups can have only one individual carbon ring or can include one or more fused rings in which at least one ring contains a heteroatom. They can be fully saturated or partially saturated, and, as with aryl and heteroaryl groups, can be substituted or unsubstituted. Representative examples of unsaturated 5-membered heterocycles having only one heteroatom include 2- or 3-pyrrolyl, 2- or 3-furanyl, and 2- or 3-thiophenyl. Corresponding partially saturated or fully saturated radicals include 3-pyrrolin-2-yl, 2- or 3-pyrrolidinyl, 2- or 3-tetrahydrofuranyl, and 2- or 3-tetrahydrothiophenyl. Representative unsaturated 5-membered heterocyclic radicals having two heteroatoms include imidazolyl, oxazolyl, thiazolyl, pyrazolyl, and the like. Corresponding fully saturated and partially saturated radicals are also included. Representative examples of unsaturated 6-membered heterocycles having only one heteroatom include 2-, 3-, or 4-pyridinyl, 2H-pyranyl, and 4H-pyranyl. Corresponding partially saturated or fully saturated radicals include 2-, 3-, or 4-piperidinyl, and 2-, 3-, or 4-tetrahydropyranyl. Representative unsaturated 6-membered heterocyclic radicals having two heteroatoms include 3- or 4-pyridazinyl, 2-, 4-, or 5-pyrimidinyl, 2-pyrazinyl, morpholino, and the like. Also included are the corresponding fully saturated and partially saturated radicals, e.g., 2-piperazine. Heterocyclic radicals are attached to the entity directly through an available carbon atom or heteroatom in the heterocyclic ring, or through a linker such as an alkylene, e.g., methylene or ethylene.

[0074] The term "pharmaceutically acceptable" indicates that the compound or salt thereof or composition is chemically and / or toxicologically compatible with the other ingredients comprising the formulation and / or the subject being treated therewith.

[0075] Unless otherwise defined, "room temperature" is intended to mean a temperature of about 18-28° C., typically about 18-25° C., and more typically about 18-22° C. As used herein, the phrase "room temperature" may be abbreviated as "rt" or "RT."

[0076] Molecules and Compounds In some embodiments, the compounds of the present disclosure can be biaryl compounds.

[0077] As used herein, compounds of structural formula (I): [ka] (In the formula, R 1 is nitro or cyano; R 2 and R 2’ are each independently 1~3 selected from alkyl, hydrogen or halogen; R 3 is hydrogen, C 1~3 Alkyl, C 1~3Haloalkyl, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, C3-C6 heterocycloalkyl, C4-C5 heterocycloalkenyl, C3-C5 heterocycloalkyl-C1-C3 alkyl, C5-C6 aryl, C3-C6 heteroaryl, C1-C4 alkoxyl, C3-C6 cycloalkyl-C1-C3 alkoxyl, C1-C4 haloalkoxyl, C1-C3 haloalkyl, halogen, amino, alkylamino, dialkylamino, C2-C7 cyclic amine, C2-C5 heterocyclic amine, C3-C6 unsaturated or aromatic cyclic amine, C3-C5 unsaturated or aromatic complex amine each alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, heterocycloalkylalkyl, aryl, heteroaryl, alkoxyl, cycloalkylalkoxyl, alkylamino, dialkylamino, cyclic amine, heterocyclic amine, unsaturated or aromatic cyclic amine, and unsaturated or aromatic heterocyclic amine is optionally substituted with 1 to 3 substituents selected from the group consisting of C1-C3 alkyl, C1-C3 alkoxyl, C3-C6 cycloalkyl, hydroxyl, halogen, and amino; R 4 is selected from hydrogen or halogen; R 5 is hydrogen, C 1~3 selected from the group consisting of alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, C3-C6 aryl, C3-C6 heteroaryl, halogen, amino, alkylamino, dialkylamino, C2-C7 cyclic amine, C2-C5 heterocyclic amine, C3-C6 unsaturated or aromatic cyclic amine, and C3-C5 unsaturated or aromatic heterocyclic amine, wherein each alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, alkylamino, dialkylamino, cyclic amine, heterocyclic amine, unsaturated or aromatic cyclic amine, and unsaturated or aromatic heterocyclic amine is optionally substituted with 1 to 3 substituents selected from the group consisting of C1-C3 alkyl, C1-C3 alkoxyl, C3-C6 cycloalkyl, hydroxyl, halogen, or amino; R 6is hydrogen, C1-C4 alkyl, C1-C4 alkoxyl, amino, alkylamino, aminoalkyl, dialkylamino, C8-C 11 Spirocycloalkyl, C5-C 10 Heterospirocycloalkyl, C5-C 11 Monocyclic or bicyclic aryl, monocyclic or bicyclic heteroaryl, C2-C7 cyclic amine, C2-C5 heterocyclic amine, C3-C6 unsaturated or aromatic cyclic amine, C3-C5 unsaturated or aromatic heterocyclic amine, C7-C 10 selected from the group consisting of spirocyclic amine, C4-C9 heterospirocyclic amine, C3-C6 heteroaryloxyl, or C3-C6 cycloalkoxyl, each optionally substituted with 1 to 3 substituents selected from the group consisting of hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxyl, halogen, C1-C3 haloalkyl, C1-C3 haloalkoxyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C2-C5 heterocycloalkyl, or optionally substituted C3-C6 heteroaryl, wherein the optionally substituted cycloalkyl, heterocycloalkyl, and heteroaryl may be substituted with 1 or 2 substituents selected from the group consisting of C1-C3 alkyl, C1-C3 alkoxyl, hydroxyl, halogen, or amine; L is a linker selected from the group consisting of a bond, -CH2-, -CH2-CH2-, -CH(CH3)-, -C(CH3)2-, -C≡C-, -CH2-O-, -C(O)-, -O-, -O-CH2-, -NH-CH2-, -N(CH3)-CH2-, -NH-C(O)-, -N(CH3)-C(O)-, -CH2-NH-CH2-; Q is C5-C9 cycloalkyl, C4-C8 heterocycloalkyl, C8-C 11 Spirocycloalkyl, C5-C 10 Heterospirocycloalkyl, C3-C8 cyclic amine, C3-C8 heterocyclic amine, C7-C 10a monocyclic or bicyclic ring system selected from the group consisting of spirocyclic amines or C4-C9 heterospirocyclic amines, wherein each cycloalkyl or heterocycloalkyl group can be saturated or unsaturated, and the bicyclic ring can be a fused or bridged bicyclic ring; Q is selected from the group consisting of one to three R 7 and each R 7 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkylcarbonyl, hydroxyl, oxo, halogen, C1-C6 alkylamine, or amino. or a pharmaceutically acceptable salt, solvate, prodrug, or pharmaceutically active metabolite thereof, or a combination thereof.

[0078] In embodiments, each hetero substituent may contain 1 to 4, 1 to 3, 2, or 1 heteroatom independently selected from O, S, and N.

[0079] In embodiments, each heteroaryl or heterocyclic substituent may be attached to the remainder of the compound through a carbon atom or through a heteroatom, hi embodiments, a heteroaryl or heterocyclic substituent is attached to the remainder of the compound through a carbon atom or through an N atom.

[0080] Preferably, in the embodiment, R 1 is cyano.

[0081] Preferably, R 2 and R 2’ One of R may be hydrogen and the other F; alternatively, R 2 and R 2’ One of R may be hydrogen and the other may be Cl; alternatively, R 2 and R 2’ In some embodiments, both R 2 and R 2’ One of them can be methyl and the other can be hydrogen, F or Cl.

[0082] Preferably, R 2 and R 2’One of the groups may be hydrogen and the other may be F; R 2 and R 2’ One of the groups may be hydrogen and the other may be F, and R 1 is cyano. In embodiments, R 2 and R 2’ One of the groups is methyl and the other is hydrogen.

[0083] In an embodiment of the present disclosure, R 3 may be selected from C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, C5-C6 aryl, C3-C6 heteroaryl, or C2-C5 heterocyclic amine.

[0084] Instead, R 3 may be an optionally substituted 5- or 6-membered heteroaryl; alternatively, R 3 can be an optionally substituted 4- to 6-membered heterocycloalkyl; or R 3 can be an optionally substituted 3- to 5-membered cycloalkyl. In any such embodiment, each heteromoiety can contain one or two heteroatoms independently selected from O, S, and N. Preferably, the optional substituents are independently selected from one or two of the group consisting of methyl, F, and Cl.

[0085] Preferably, R 3 can be a 5-membered heteroaryl containing N and S.

[0086] Preferably, R 3 can be a 5-membered heteroaryl containing N and O substituted with F.

[0087] In various aspects and embodiments, R 3 has the following structure: [ka] may be selected from the group consisting of:

[0088] More preferably, R 3More preferably, the compound has the following structure: [ka] is selected from the group consisting of:

[0089] Typically, R 3 can be a 5-membered heteroaryl containing N and S, and R 4 , R 5 and R 6 are all hydrogen. 3 is a thiazole, especially a 1,2-thiazole.

[0090] Instead, in various embodiments, R 3 may be selected from hydrogen or halogen; for example, R 3 can be hydrogen or Cl.

[0091] In any embodiment, R 4 can be hydrogen; alternatively, R 4 can be F and R 5 and R 6 can each be hydrogen; alternatively, R 4 can be F and R 5 and R 6 may each be hydrogen; or R 4 , R 5 and R 6 can all be hydrogen.

[0092] In various embodiments, R 5 can be a 4- or 5-membered heterocycloalkyl; R 5 can be C1-C3 alkyl; R 5 can be a 3-, 4-, or 5-membered cycloalkyl; or R 5 can be an optionally substituted C3-C6 cycloalkyl, C3-C6 cycloalkenyl, C3-C6 heterocycloalkyl, C3-C6 aryl, or C3-C6 heteroaryl.

[0093] More preferably, R 5 is hydrogen and the following structure: [ka] may be selected from the group consisting of:

[0094] In a particularly advantageous embodiment, R 5 may be selected from hydrogen, F, methyl or pyrrolidine. In an alternative advantageous embodiment, R 5 can be hydrogen or R 5 can be F.

[0095] In any embodiment, R 6 can be an optionally substituted 4- or 5-membered heterocycloalkyl; R 6 may be an optionally substituted 8-, 9-, or 10-membered bicyclic or spirocyclic heterocycloalkyl; R 6 can be an optionally substituted 5- or 6-membered heteroaryl; R 6 may be an optionally substituted 4-, 5-, or 6-membered cycloalkyl or spirocycloalkyl; R 6 can be C1-C3 haloalkoxy; or R 6 may be a C2-C8 alkylamine or dialkylamine. Typically, each heteromoiety may contain one or two heteroatoms independently selected from O, S, and N. Suitably, the optional substituents may be independently selected from one or two substituents selected from the group consisting of C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxyl, F, Cl, and hydroxyl.

[0096] More preferably, in various aspects and embodiments, R 6 is hydrogen and the following structure: [ka] [ka] is selected from the group consisting of:

[0097] More specifically, in various aspects and embodiments, R 6 is hydrogen and the following structure: [ka] may be selected from the group consisting of:

[0098] In some particularly advantageous embodiments, R 6 is selected from hydrogen, F, methyl, or pyrrolidine. 6 can be hydrogen; or R 6 may be selected from F or Cl.

[0099] In various alternative aspects and embodiments, R 6 is hydrogen. For example, R 6 is hydrogen and R 5 is selected from the group of structures shown in the various embodiments above.

[0100] In certain embodiments, R 1 is cyano and R 2 and R 2’ are independently selected from hydrogen and fluorine (more specifically, R 2 and R 2’ one of which is hydrogen and the other is fluorine), R 3 is a thiazole (more specifically, 1,2-thiazole), and R 4 , R 5 and R 6 is hydrogen.

[0101] In any embodiment, L is preferably -CH2- or -CH2-CH2-.

[0102] Q may be selected from the group consisting of optionally substituted 5- to 7-membered heterocycloalkyl and optionally substituted 4- to 7-membered mono- or fused or bridged bicycloalkylamine. In any such embodiment, each heterocyclic moiety may contain one or two heteroatoms independently selected from O and N. Furthermore, the optional substituents on any such Q moiety, if present, may be independently selected from one to three substituents from the group consisting of C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxyl, C1-C3 alkylamine, C1-C3 dialkylamine, C1-C3 carbonyl, amine, amino-C1-C3 alkyl, oxo, F, Cl, and hydroxyl.

[0103] Preferably, Q has the following structure: [ka] [ka] [ka] [ka] [ka] is selected from the group consisting of:

[0104] More preferably, Q has the following structure: [ka] is selected from the group consisting of:

[0105] Advantageously, Q has the following structure: [ka] is selected from the group consisting of:

[0106] In certain embodiments, L is -CH2- and Q is morpholine.

[0107] Usefully, R 7 may be independently selected from C1-C3 alkyl, C1-C3 haloalkyl, hydroxyl, oxo, F, C1-C3 alkylamino, C1-C3 dialkylamino, or amino. Alternatively, R 7 may be independently selected from methyl, ethyl, amine, and F. In embodiments, the compounds of the present disclosure may contain one, two, or three R 7 groups may be present.

[0108] In particularly preferred compounds according to structure (I), the compounds may be defined as follows: R 1 is cyano; and / or R 2 and R 2’ are each independently selected from hydrogen or F; and / or R 3 is selected from hydrogen, propyl, i-propyl, CHF2, cyclopropyl, -CH2-cyclopropyl, -CH2-oxetane, isothiazole, oxazole, isoxazole, pyridyl, methoxyl, -O-CH2-cyclopropyl, -O-CH2-CF3, -O-CF3, CF3, Cl, amino, -N(CH3)(CH2-isopropyl), pyrrolidine, cyano; R 4 is hydrogen or F; and / or R 5 is selected from hydrogen, methyl, cyclopropyl, cyclopentenyl, F, amino, NH—CH—CH—N(CH); and / or R 6is selected from hydrogen, —O-cyclobutyl, —O-CH2-oxane, —O-CH2-CH2-CHF2, —O-CH2-CH2-CF3, —O-CH2-CF3, —CH2-O-CHF2, amino, —N(CH3)(CH—(CH3)2, benzimidazole, pyridine; and / or L is a linker selected from a bond, —CH2—, —C≡C—, —CH2-NH—CH2-; and / or Q is a C4-C8 heterocycloalkyl which may contain additional heteroatoms selected from N or O; or Q is morpholinyl. In any such embodiment, each heteroaryl, heterocycloalkyl, and / or cycloalkyl group is optionally substituted. In some particular embodiments, such groups may be optionally substituted with one or more groups selected from F, Cl, methyl, hydroxyl, and amino.

[0109] In embodiments, the compound of formula (I) may be selected from any of the compounds shown in Table 1 below. The present disclosure encompasses compounds having the structures shown below, and where stereochemistry is indicated, the present disclosure also expressly encompasses the corresponding racemic forms of those compounds. Similarly, when a compound structure is shown without specific stereochemistry, all stereoisomeric forms are encompassed herein.

[0110] [Table 1-1]

[0111] [Table 1-2]

[0112] [Table 1-3]

[0113] [Table 1-4]

[0114] Table 1-5

[0115] Table 1-6

[0116] Table 1-7

[0117] Table 1-8

[0118] Table 1-9

[0119] Table 1-10

[0120] Table 1-11

[0121] Table 1-12

[0122] Table 1-13

[0123] Table 1-14

[0124] Table 1-15

[0125] Table 1-16

[0126] Table 1-17

[0127] Table 1-18

[0128] Table 1-19

[0129] Table 1-20

[0130] Table 1-21

[0131] Table 1-22

[0132] Table 1-23

[0133] Table 1-24

[0134] Table 1-25

[0135] Table 1-26

[0136] Table 1-27

[0137] Table 1-28

[0138] Table 1-29

[0139] Table 1-30

[0140] Table 1-31

[0141] Table 1-32

[0142] Table 1-33

[0143] Table 1-34

[0144] Table 1-35

[0145] Table 1-36

[0146] Table 1-37

[0147] Table 1-38

[0148] Table 1-39

[0149] Table 1-40

[0150] Table 1-41

[0151] Table 1-42

[0152] Table 1-43

[0153] Table 1-44

[0154] Table 1-45

[0155] Table 1-46

[0156] Table 1-47

[0157] Table 1-48

[0158] Table 1-49

[0159] Table 1-50

[0160] Table 1-51

[0161] Table 1-52

[0162] Table 1-53

[0163] Table 1-54

[0164] Table 1-55

[0165] Table 1-56

[0166] Table 1-57

[0167] Table 1-58

[0168] Table 1-59

[0169] Table 1-60

[0170] Table 1-61

[0171] Table 1-62

[0172] Table 1-63

[0173] Table 1-64

[0174] Table 1-65

[0175] Table 1-66

[0176] Table 1-67

[0177] Table 1-68

[0178] Table 1-69

[0179] Table 1-70

[0180] Table 1-71

[0181] Table 1-72

[0182] Table 1-73

[0183] Table 1-74

[0184] Table 1-75

[0185] Table 1-76

[0186] Table 1-77

[0187] Table 1-78

[0188] Table 1-79

[0189] Table 1-80

[0190] Table 1-81

[0191] Table 1-82

[0192] Table 1-83

[0193] Table 1-84

[0194] Table 1-85

[0195] Table 1-86

[0196] Table 1-87

[0197] Table 1-88

[0198] Table 1-89

[0199]

Table 1-90

[0200] Table 1-91

[0201] Table 1-92

[0202] Table 1-93

[0203] Table 1-94

[0204] Table 1-95

[0205] Table 1-96

[0206] Table 1-97

[0207] Table 1-98

[0208] Table 1-99

[0209]

Table 1-100

[0210] Table 1-101

[0211] Table 1-102

[0212] Table 1-103

[0213] Table 1-104

[0214] Table 1-105

[0215] Table 1-106

[0216] Table 1-107

[0217] Table 1-108

[0218] Table 1-109

[0219]

Table 1-110

[0220] Table 1-111

[0221] Table 1-112

[0222] Table 1-113

[0223] The term "active agent" is typically used to refer to a compound according to the present disclosure that has inhibitory activity against LSD1, particularly under physiological conditions. However, in many cases, active agents can be difficult to administer or deliver to the relevant physiological site due to, for example, solubility, half-life, or many other chemical or biological reasons. Therefore, it is known to use "prodrugs" of active agents to overcome physiochemical, biological, or other barriers to drug efficacy and / or toxicity. Furthermore, prodrug strategies can be used to increase the selectivity of drugs for their intended targets. Thus, according to the present disclosure, prodrugs can be useful for targeting active agents to the desired biological site while advantageously bypassing the stomach (or lungs), for example, when adverse side effects due to local inhibition of LSD1 activity arise.

[0224] Active agents can be formed from compounds or prodrugs of the present disclosure by in vivo drug metabolism and / or chemical or enzymatic cleavage of the prodrug in vivo. Typically, prodrugs can be pharmacologically inactive compounds that require chemical or enzymatic conversion to become effective active agents in the body that are intended to have their therapeutic effect. On the other hand, prodrugs can, in some embodiments, have such close structural similarity to the active agent that they can also have activity against the LSD1 target. This can be particularly true when the active agent is formed from a prodrug compound of the present disclosure by metabolism or minor chemical conversion, resulting in a metabolite that is closely related to the parent compound / prodrug. Thus, prodrugs of the present disclosure can be active inhibitors of LSD1. However, such prodrugs can preferably be characterized by having lower inhibitory activity against LSD1 than the drug / active agent from which the prodrug of the present disclosure is derived.

[0225] On the other hand, if the therapeutic effect is derived from the release of an active agent from a larger chemical entity, the final active agent / compound / drug may have significant structural differences compared to the prodrug from which it is derived. In such cases, the prodrug may effectively "mask" a form of the active agent, and in such cases, the prodrug may be completely (or essentially) completely inactive under physiological conditions.

[0226] Dosage forms, medicines and pharmaceuticals The compounds, molecules, or agents of the present disclosure can be used to treat (e.g., cure, alleviate, or prevent) one or more diseases, infections, or disorders. Thus, in accordance with the present disclosure, the compounds and molecules can be manufactured into medicaments or incorporated or formulated into pharmaceutical compositions.

[0227] The molecules, compounds, and compositions of the present disclosure can be administered by any convenient route, for example, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, oral, sublingual, intranasal, intravaginal, transdermal, rectal, inhalation, or topical administration to the skin. Delivery systems are also known, including, for example, encapsulation in liposomes, microgels, microparticles, microcapsules, capsules, etc. Any other suitable delivery system known in the art is also contemplated for use. Administration can be systemic or local. The mode of administration can be left to the discretion of the physician.

[0228] Of course, the dosage administered will vary depending on known factors, such as the pharmacodynamic properties of the particular active agent; the selected mode and route of administration; the age, health, and weight of the recipient; the nature of the disease or disorder being treated; the severity of symptoms; any concurrent or parallel treatments; the frequency of treatment; and the desired effect. Generally, the daily dosage of the active agent can be expected to range from about 0.001 to about 1,000 mg per kg of body weight. In some applications, the dosage may suitably be within the range of about 0.01 to about 100 mg; about 0.1 to about 25 mg; or about 0.5 to 10 mg.

[0229] Depending on known factors such as those described above, the required dosage of the active agent may be administered in a single daily dose, or the total daily dosage may be administered in divided doses, for example, two, three, or four times daily. Suitably, therapeutic treatment regimens according to the present disclosure are designed for single daily administration or divided twice daily administration.

[0230] Dosage forms of pharmaceutical compositions of the present disclosure suitable for administration may contain from about 1 mg to about 2,000 mg of active ingredient per unit. Typically, the daily dosage of the compound is at least about 10 mg and up to about 1,500 mg per human dose, e.g., about 25 to 1,250 mg, preferably about 50 to 1,000 mg. Typically, the daily dosage of the compound is up to about 1,000 mg. In such compositions, the compound of the present invention is generally present in an amount of about 0.5 to 95% by weight based on the total weight of the composition.

[0231] An "effective amount" or a "therapeutically effective amount" is intended to refer to an amount of a compound or composition of the present disclosure that is effective in curing, inhibiting, alleviating, reducing, or preventing the adverse effects of the disease or disorder being treated, or the amount necessary to achieve a physiologically or biochemically detectable effect. Thus, in an effective amount, the compound or agent can produce the desired therapeutic, ameliorating, inhibitory, or preventive effect for the disease or disorder. Beneficially, an effective amount of a compound or composition of the present disclosure can have the effect of inhibiting LSD1. Diseases or disorders that can benefit from LSD1 inhibition include, for example, autoimmune disorders, inflammatory diseases, cancers and / or neoplastic diseases (such as rheumatoid arthritis, multiple sclerosis, psoriasis, Sjögren's syndrome, and systemic lupus erythematosus or vasculitic diseases), cancers of hematopoietic origin or solid tumors (including chronic myeloid leukemia, myeloid leukemia, and non-Hodgkin's lymphoma and other B-cell lymphomas). Further exemplary diseases, disorders, or conditions include: lymphomas, including diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma, non-Hodgkin's lymphoma, relapsed or refractory NHL and relapsed follicular lymphoma, Hodgkin's lymphoma; leukemias, including acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML); primary myelofibrosis (PMF), erythrocytic leukemia (YLL), erythroblastoma vera, leukemia ... myeloproliferative disorders, including pleocytosis (PV) and essential thrombocytosis (ET); myelodysplastic syndromes (MDS) and multiple myeloma; sarcomas, including chondrosarcoma, Ewing's sarcoma, osteosarcoma, rhabdomyosarcoma, angiosarcoma, fibrosarcoma, liposarcoma, myxoma, rhabdomyoma, fibroma, lipoma, hamartoma, and teratoma; lung cancer, including non-small cell lung cancer (NSCLC), small cell lung carcinoma, bronchogenic carcinoma, squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, adenocarcinoma, alveolar (bronchiolar) carcinoma, bronchial adenoma, chondroitin hamartoma, and mesothelioma;Digestive tract cancers including esophageal cancer (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), gastric cancer (carcinoma, lymphoma, leiomyosarcoma), pancreatic cancer (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vipoma), small intestine cancer (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), colon cancer (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma) and colorectal cancer; kidney cancer (adenocarcinoma, Wilms' tumor, nephroblastoma), bladder and urethral cancer (squamous cell carcinoma, Genitourinary cancers, including transitional cell carcinoma, adenocarcinoma, prostate cancer (adenocarcinoma, sarcoma) and testicular cancer (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, lipoma); liver cancer, including hepatocellular carcinoma, cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, and hemangioma; osteogenic sarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor, chordoma, osteochondroma (osteochondroma), benign cartilage bone cancers, including osteoma, chondroblastoma, chondromyxoid fibroma, osteoid osteoma, and giant cell tumor; skull cancers (osteoma, hemangioma, granuloma, xanthomatosis, osteitis deformans), meningeal cancers (meningioma, meningeal sarcoma, gliomatosis), brain cancers (astrocytoma, medulloblastoma, glioma, ependymoma, embryonal tumor (pinealoma), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal cancers (neurofibroma, meningioma, glioma, sarcoma), and cancers of the nervous system, including neuroblastoma and Lhermitte-Dacros disease; uterine cancer (endometrial cancer), cervical cancer (cervical carcinoma, premature ejaculation) Gynecological cancers, including ovarian cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa theca cell tumor, Sertoli-Leydig cell tumor, dysgerminoma, malignant teratoma), vulvar cancer (squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma, melanoma), vaginal cancer (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma) and fallopian tube carcinoma); and skin cancers, including melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, lentiloid dysplasia, lipoma, hemangioma, dermatofibroma and keloids.

[0232] For therapeutic applications, the effective or therapeutically effective amount of a compound / active agent of the present disclosure may be at least about 50 nM or at least about 100 nM; typically at least about 200 nM or at least about 300 nM in the subject's blood. The effective or therapeutically effective amount may be at most about 5 μm, at most about 3 μm, preferably at most about 2 μm, typically at most about 1 μm in the subject's blood. For example, a therapeutically effective amount may be about 500 nM, e.g., about 100 nM to 500 nM. In some embodiments, the amount of therapeutic compound is measured in the subject's serum, and the above concentration may then be applied to the serum concentration of the compound of the present disclosure. Advantageously, the advantageous high CNS and / or BBB penetration properties of the compounds of the present disclosure may enable the therapeutic use of compounds / active agents of the present disclosure at lower concentrations or lower dosages, which may beneficially allow for a lower therapeutically effective amount of compound or pharmaceutical composition per administration. This may also or alternatively allow for less frequent administration of the compounds or pharmaceutical compositions of the present disclosure over a sustained period of treatment.

[0233] When administered to a subject, the compounds of the present disclosure are suitably administered as a component of a composition comprising a pharmaceutically acceptable carrier or vehicle. One or more additional pharmaceutically acceptable carriers (such as diluents, adjuvants, excipients, or vehicles) can be combined with the compounds of the present disclosure in a pharmaceutical composition. Suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences" by EW Martin. The pharmaceutical formulations and compositions of the present disclosure are formulated in accordance with regulatory standards and in accordance with the selected route of administration.

[0234] Acceptable pharmaceutical vehicles can be liquids, such as water and oils, such as those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, etc. Pharmaceutical vehicles can be saline, gum acacia, gelatin, starch paste, talc, keratin, colloidal silica, urea, etc. Additionally, auxiliary substances, stabilizers, thickeners, lubricants, and coloring agents can be used. When administered to a subject, pharmaceutically acceptable vehicles are generally sterile. Water is a suitable vehicle when the compound is administered intravenously. Saline and aqueous dextrose and glycerol solutions can also be used as liquid vehicles, particularly for injectable solutions. Suitable pharmaceutical vehicles also include excipients such as starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk powder, glycerol, propylene, glycol, water, and ethanol. The present compositions, if desired, can also contain minor amounts of wetting or emulsifying agents, or buffers.

[0235] The medicaments and pharmaceutical compositions of the present disclosure can be in the form of solutions, suspensions, emulsions, tablets, pills, pellets, powders, gels, capsules (e.g., capsules containing a liquid or powder), modified-release formulations (e.g., slow- or sustained-release formulations), suppositories, emulsions, aerosols, sprays, suspensions, or any other form suitable for use. Other examples of suitable pharmaceutical vehicles are described in Remington's Pharmaceutical Sciences, Alfonso R. Gennaro ed., Mack Publishing Co., Easton, Pa., 19th ed., 1995, see, e.g., pages 1447-1676.

[0236] Preferably, the therapeutic compositions or medicaments of the present disclosure are formulated in accordance with routine procedures as pharmaceutical compositions adapted for oral administration, more preferably to humans. Compositions for oral delivery may be in the form of, for example, tablets, lozenges, aqueous or oily suspensions, granules, powders, emulsions, capsules, syrups, or elixirs. Thus, in one embodiment, the pharmaceutically acceptable vehicle is a capsule, tablet, or pill.

[0237] Orally administered compositions may contain one or more agents, such as sweeteners such as fructose, aspartame, or saccharin; flavoring agents such as peppermint, wintergreen oil, or cherry; coloring agents; and preservatives, to provide a pharmaceutically palatable formulation. When the composition is in tablet or pill form, the composition may be coated to delay disintegration and absorption in the gastrointestinal tract, providing sustained release of the active agent over an extended period of time. A selectively permeable membrane surrounding the osmotically active driving compound is also suitable for orally administered compositions. In these dosage forms, fluid from the environment surrounding the capsule is absorbed by the driving compound, which swells and displaces the drug or drug composition through an opening. These dosage forms can provide an essentially zero-order delivery profile, as opposed to the spiked profile of immediate-release formulations. Time-delay materials such as glycerol monostearate or glycerol stearate may also be used. Oral compositions may contain standard vehicles such as mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, etc. For oral formulations, such vehicles are preferably of pharmaceutical grade. The release location can be the stomach, the small intestine (duodenum, jejunum, or ileum), or the large intestine. Those skilled in the art can prepare formulations that do not dissolve in the stomach but release the substance in the duodenum or elsewhere in the intestine. Preferably, release avoids the deleterious effects of the gastric environment by protecting the compound (or composition) or releasing the compound (or composition) beyond the gastric environment, such as the intestine. To ensure complete gastric resistance, a coating impermeable to at least pH 5.0 may be essential. Examples of more common inactive ingredients used as enteric coatings include cellulose acetate trimellitate (CAT), hydroxypropyl methylcellulose phthalate (HPMCP), HPMCP 50, HPMC P55, polyvinyl acetate phthalate (PVAP), Eudragit L30D, Aquateric, cellulose acetate phthalate (CAP), Eudragit L, Eudragit S, and Shellac, which can be used as a mixed membrane.

[0238] For example, it may be beneficial to provide the therapeutic compositions and / or compounds of the present disclosure in a form suitable for oral administration to improve patient compliance and ease administration; however, in some embodiments, the compounds or compositions of the present disclosure may cause undesirable side effects, such as intestinal inflammation, that may lead to premature termination of the therapeutic treatment regimen. Accordingly, in some embodiments, the therapeutic treatment regimen is adapted to accommodate "treatment holidays," e.g., one or more non-administration days. For example, the treatment regimens and methods of treatment of the present disclosure may include a repetitive process of administering the therapeutic composition or compound for several consecutive days, followed by one or more consecutive treatment holidays. For example, the therapeutic regimen of the present disclosure may include a repeated cycle of administering the therapeutic composition or compound for 1 to 49 days, 2 to 42 days, 3 to 35 days, 4 to 28 days, 5 to 21 days, 6 to 14 days, or 7 to 10 days, followed by a treatment holiday of 1 to 14 days, 1 to 12 days, 1 to 10 days, or 1 to 7 days (e.g., 1, 2, 3, 4, 5, 6, or 7 days).

[0239] To aid in dissolving the therapeutic agent in the aqueous environment, a surfactant may be added as a wetting agent. Surfactants may include anionic detergents such as sodium lauryl sulfate, dioctyl sodium sulfosuccinate, and dioctyl sodium sulfonate. Cationic detergents may be used, including benzalkonium chloride or benzethonium chloride. Potential nonionic detergents that may be included in the formulation as surfactants include lauromacrogol 400, polyoxyl 40 stearate, polyoxyethylene hydrogenated castor oil 10, 50, and 60, glycerol monostearate, polysorbate 20, 40, 60, 65, and 80, sucrose fatty acid esters, methylcellulose, and carboxymethylcellulose. When used, these surfactants may be present in the compound or derivative formulation alone or as a mixture in different ratios.

[0240] Typically, compositions for intravenous administration comprise sterile isotonic aqueous buffer. Where necessary, the composition may also include a solubilizing agent.

[0241] Another suitable route of administration of the therapeutic compositions of the present disclosure is by pulmonary or nasal delivery.

[0242] Additives such as the fatty acids oleic acid, linoleic acid, and linolenic acid may be included to enhance cellular uptake of the therapeutic agents of the present disclosure.

[0243] The therapeutic agents of the present disclosure may also be formulated into compositions for topical application to the skin of a subject.

[0244] When the present invention provides two or more active compounds / drugs for use in combination, the drugs can generally be formulated separately or in a single dosage form, depending on the most suitable administration regimen prescribed for each drug involved.When the therapeutic agents are formulated separately, the pharmaceutical composition of the present invention can be used in a treatment regimen that includes simultaneous, separate, or sequential administration with one or more other therapeutic agents.The other therapeutic agents can include compounds of the present disclosure or therapeutic agents known in the art.

[0245] The compounds and / or pharmaceutical compositions of the present disclosure may be formulated and suitable for administration of the compounds to the central nervous system (CNS) and / or for crossing the blood-brain barrier (BBB).

[0246] The invention will now be illustrated by the following non-limiting examples. [Example]

[0247] chemical synthesis Tables 2 and 3 below show certain compounds of the present disclosure and the reaction steps (procedures) used in their synthesis, as well as compound yields and characterization data. Exemplary reaction steps and conditions are further exemplified below.

[0248] [Table 2-1]

[0249] [Table 2-2]

[0250] Table 2-3

[0251] Table 2-4

[0252] Table 2-5

[0253] Table 2-6

[0254] Table 2-7

[0255] Table 2-8

[0256] Table 2-9

[0257] Table 2-10

[0258] Table 2-11

[0259] Table 2-12

[0260] Table 2-13

[0261] Table 2-14

[0262] Table 2-15

[0263] Table 2-16

[0264] Table 2-17

[0265] Table 2-18

[0266] Table 2-19

[0267] Table 2-20

[0268] Table 2-21

[0269] Table 2-22

[0270] Table 2-23

[0271] Table 2-24

[0272] Table 2-25

[0273] Table 2-26

[0274] Table 2-27

[0275] Table 2-28

[0276] Table 2-29

[0277] Table 2-30

[0278] Table 2-31

[0279] Table 2-32

[0280] Table 2-33

[0281] Table 2-34

[0282] Table 2-35

[0283] Table 2-36

[0284] Table 2-37

[0285] Table 2-38

[0286] Table 2-39

[0287] Table 2-40

[0288] Table 2-41

[0289] Table 2-42

[0290] Table 2-43

[0291] Table 2-44

[0292] Table 2-45

[0293] Table 2-46

[0294] Table 2-47

[0295] Table 2-48

[0296] Table 2-49

[0297] Table 2-50

[0298] Table 2-51

[0299] Table 2-52

[0300] Table 2-53

[0301] Table 2-54

[0302] Table 2-55

[0303] Table 2-56

[0304] Table 2-57

[0305] Table 2-58

[0306] Table 2-59

[0307] Table 2-60

[0308] Table 2-61

[0309] Table 3-1

[0310] Table 3-2

[0311] Table 3-3

[0312] Table 3-4

[0313] Table 3-5

[0314] Table 3-6

[0315] Table 3-7

[0316] Table 3-8

[0317] Table 3-9

[0318] Table 3-10

[0319] Table 3-11

[0320] Table 3-12

[0321] Table 3-13

[0322] Table 3-14

[0323] Table 3-15

[0324] Table 3-16

[0325] Table 3-17

[0326] Table 3-18

[0327] Table 3-19

[0328] Table 3-20

[0329] Table 3-21

[0330] Table 3-22

[0331] Table 3-23

[0332] Table 3-24

[0333] Table 3-25

[0334] Table 3-26

[0335] Table 3-27

[0336] Table 3-28

[0337] Table 3-29

[0338] Table 3-30

[0339] Table 3-31

[0340] Table 3-32

[0341] Table 3-33

[0342] Table 3-34

[0343] Table 3-35

[0344] Table 3-36

[0345] Table 3-37

[0346] Table 3-38

[0347] Table 3-39

[0348] Table 3-40

[0349] Table 3-41

[0350] Table 3-42

[0351] Table 3-43

[0352] Table 3-44

[0353] Table 3-45

[0354] Table 3-46

[0355] Table 3-47

[0356] Table 3-48

[0357] Table 3-49

[0358] Table 3-50

[0359] Table 3-51

[0360] Table 3-52

[0361] Table 3-53

[0362] Table 3-54

[0363] Table 3-55

[0364] Table 3-56

[0365] Table 3-57

[0366] Table 3-58

[0367] Table 3-59

[0368] Table 3-60

[0369] Table 3-61

[0370] Table 3-62

[0371] Table 3-63

[0372] [Table 3-64]

[0373] Materials and Methods Abbreviation ACN Acetonitrile AcOH acetic acid AIBN 2-[({E})-(1-cyano-1-methylethyl)azo]-2-methylpropanenitrile BINAP [1,1'-binaphthalene]-2,2'-diylbis[diphenylphosphine] Boc tert-butyloxycarbonyl cataCXium® Di(1-adamantyl)-n-butylphosphine CAN Cerium Ammonium Nitrate CMBP cyanomethylene tributylphosphorane or tributylphosphoranylidene acetonitrile DCM dichloromethane DIPEA Diisopropylethylamine DMA N,N-Dimethylacetamide DME 1,2-dimethoxyethane DMSO dimethyl sulfoxide Et Ethyl EtOAc ethyl acetate Et3N Triethylamine EtOH ethanol H time H2O Water JonPhos Di-tert-butyl-(2-phenylphenyl)phosphane LiHMDS [bis(trimethylsilyl)amino]lithium m-CPBA 3-chlorobenzenecarboperoxoic acid min MeOH Methanol MS mass spectrometry NaHCO3 Sodium bicarbonate NFSI N-(benzenesulfonyl)-N-fluoro-benzenesulfonamide NH4Cl Ammonium chloride Pd2(dba)3 tris(dibenzylideneacetone)dipalladium(0) Pd(OAc)2 Palladium(II) Acetate Pd-113 Dibromobis(tri-tert-butylphosphino)dipalladium(I) QPhos 1,2,3,4,5-pentaphenyl-1'-(di-tert-butylphosphino)ferrocene rt Room temperature (18~22℃) TBAF Tetrabutylammonium Fluoride TCDI Di(imidazol-1-yl)methanethione TFA trifluoroacetic acid THF tetrahydrofuran TTMSS 1,1,1,3,3,3-hexamethyl-2-(trimethylsilyl)trisilane Xantphos 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene

[0374] Sample preparation: The powder was dissolved in DMSO-d6, vortexed vigorously until the solution was clear, and transferred to an NMR tube for data acquisition.

[0375] NMR spectroscopy: Solution NMR experiments are triple resonance 1 H, 15 N, 13 C CP-TCI 5 mm cryoprobe (Bruker Biospin, Germany) was used on a 600 MHz (14.1 Tesla) Bruker Avance III NMR spectrometer ( 1 H is 600MHz, 13 C was recorded at 151 MHz.

[0376] Solution NMR experiments were performed on a 500 MHz (11.75 Tesla) Bruker Avance I NMR spectrometer ( ) using a Dual Resonance BBI 5 mm probe (Bruker Biospin, Germany). 1 H is 500MHz, 13C was recorded at 125 MHz.

[0377] Solution NMR experiments were performed on a 400 MHz (9.4 Tesla) Bruker Avance NEO NMR spectrometer ( ) using an SEI 5 mm probe (Bruker Biospin, Germany). 1 H is 400MHz, 13 C was recorded at 100 MHz.

[0378] All experiments (1D) used in the resonance assignment procedure and product structure elucidation 1 H, 2D 1 H- 1 H-COSY, 2D 1 H- 1 H-ROESY, 2D 1 H- 13 C-HSQC, 2D 1 H- 13 C-HMBC) was recorded at 300K. 1 H chemical shifts are reported in δ (ppm) as s (singlet), d (doublet), t (triplet), q (quartet), dd (double doublet), m (multiplet) or br s (broad singlet).

[0379] LCMS Chromatography: LCMS chromatographies were recorded using the following equipment: -Waters HPLC: Alliance 2695, UV: PDA 996, MS: ZQ (Simple Quad) ZQ2 -Waters UPLC: Acquity, UV: Acquity PDA, MS: Qda -Waters UPLC: Acquity, UV: Acquity TUV, MS: Qda -Waters UPLC: Acquity, UV: Acquity PDA, MS: QDa, ELSD

[0380] The instruments were tested using a Gemini NX-C18 Phenomenex (30 × 2 mm) 3 μm column for Waters HPLC and a CSH C18 Waters (50 × 2.1 mm), 1.7 μm column for UPLC Waters, all using the following eluent combinations: HO + 0.05% TFA (v / v) and ACN + 0.035% TFA (v / v) with positive electrospray ES+ as the ionization mode. UV detection was set at 220 nm and 254 nm.

[0381] Temperatures are given in degrees Celsius (°C). The reactants used in the examples may be obtained from commercial sources or may be prepared from commercially available starting materials as described herein or by methods known in the art. All compounds of the present invention are synthesized according to the examples described herein. The progress of the reactions described herein may be conveniently followed, for example, by LC, GC, or TLC, as necessary, and reaction times and temperatures may be adjusted accordingly, as will be readily understood by one of ordinary skill in the art.

[0382] General procedure for series 1 compounds -1,2,3 substitution (showing an alternative reaction scheme in which chiral separation can be performed before or after the Suzuki reaction). [ka] -1,3,4 substitution [ka]

[0383] Building Block Synthesis: Synthesis of tert-butyl 2-[(2-bromo-3-chlorophenyl)methyl]morpholine-4-carboxylate (BB-1) [ka]

[0384] Small-scale synthesis protocol General Procedure for Allylic Addition: Method B0 To a solution of 2-bromo-1-chloro-3-iodobenzene (10 g, 30 mmol) in anhydrous THF (395 mL) were added 4,4,5,5-tetramethyl-2-(prop-2-en-1-yl)-1,3,2-dioxaborolane (6.9 g, 39 mmol, 1.30 equiv.) and cesium fluoride (11.4 g, 74.8 mmol, 2.5 equiv.). The reaction mixture was degassed with argon for 5 minutes, and palladium triphenylphosphane (0.10 equiv.) was added. The mixture was stirred at 80 °C for 6 hours and then at 50 °C overnight. The reaction mixture was cooled to room temperature, diluted with water, and the aqueous layer was extracted three times with EtOAc. The combined organic layers were dried on a phase separator and concentrated under reduced pressure. The crude material was purified on a silica gel flash chromatography column (0-100% EtOAc in heptane) to give 1-allyl-2-bromo-3-chlorobenzene (6.5 g, 64%) as a colorless oil. [ka] 1 H NMR(DMSO-d6,400MHz,)δ(ppm):7.50(dd,J=7.9,1.7Hz,1H),7.36(t,J=7.8Hz,1H),7.29(dd,J=7. 7,1.7Hz,1H),5.95(ddt,J=16.6,10.1,6.4Hz,1H),5.16-4.99(m,2H),3.54(dt,J=6.4,1.6Hz,2H).

[0385] General Procedure for Epoxidation: Method H0 To a solution of 1-allyl-2-bromo-3-chlorobenzene (6.5 g, 19.1 mmol) in anhydrous DCM (147 mL) was added 3-chlorobenzenecarboperoxyacid (14.5 g, 65 mmol, 3.4 equiv.). The reaction mixture was stirred overnight at room temperature. A saturated aqueous solution of NaSO and DCM were added, and the aqueous layer was extracted three times with DCM. The combined organic layers were washed with a saturated aqueous solution of NaHCO and brine, then dried over a phase separator and concentrated under reduced pressure. The crude product was purified by flash chromatography on a silica gel column (EtOAc in heptane). Purification by HPLC with HCl (0–30%) gave 2-[(2-bromo-3-chlorophenyl)methyl]oxirane (4.8 g, 90%) as a pale yellow oil. [ka] 1 H NMR(DMSO-d6,400MHz,)δ(ppm):7.53(dd,J=5.4,4.2Hz,1H),7.43-7.29(m,2H),3.21(tdd,J=5. 2,4.0,2.5Hz,1H),3.09-2.96(m,2H),2.76(dd,J=5.1,3.9Hz,1H),2.56(dd,J=5.1,2.6Hz,1H).

[0386] General procedure for epoxide ring opening: Method G0 To a solution of 2-[(2-bromo-3-chloro-phenyl)methyl]oxirane (4.7 g; 16.8 mmol) in anhydrous DCM (7.7 mL) was added 2-aminoethanol (7.41 mL, 117.7 mmol, 7 equiv.). The reaction mixture was stirred at room temperature overnight. Water was added, the phases were separated, and the aqueous layer was extracted three times with DCM. The combined organic layers were washed with brine, dried on a phase separator, and concentrated under reduced pressure to give 1-(2-bromo-3-chloro-phenyl)-3-(2-hydroxyethylamino)propan-2-ol (5.5 g, 93%) as a yellow solid. 1H NMR(DMSO-d6,400MHz,)δ(ppm):7.51-7.41(m,1H),7.36-7.25(m,2H),4.71(d,J=5.5Hz,1H),4.44(t,J=5.3Hz,1H),3.89-3.70(m ,1H),3.44(qd,J=5.4,3.1Hz,2H),2.96(dd,J=13.6,4.8Hz,1H),2.78(dd,J=13.6,8.1Hz,1H),2.60-2.52(m,4H);m / z=310[M+H]+. [ka]

[0387] General Procedure for N-Boc Protection: Method I1 To a solution of 1-(2-bromo-3-chlorophenyl)-3-(2-hydroxyethylamino)propan-2-ol (5.5 g, 15.7 mmol) in DCM (143 mL) was added tert-butoxycarbonyl tert-butyl carbonate (3.7 g, 17.25 mmol, 1.1 equiv.) and trimethylamine (3.3 mL, 1.5 equiv.). The reaction mixture was stirred at room temperature for 2 h. Water was added, the two phases were separated, and the aqueous layer was extracted with DCM. The combined organic layers were dried over a phase separator and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel (MeOH in DCM 0–10%) to give tert-butyl N-[3-(2-bromo-3-chloro-phenyl)-2-hydroxy-propyl]-N-(2-hydroxyethyl)carbamate (7.3 g, 93%) as a pale yellow oil. [ka] 1H NMR(DMSO-d6,400MHz,)δ(ppm):7.48(dd,J=7.1,2.4Hz,1H),7.37-7.26(m,2H),5.00(dd,J=64.5,5.9Hz,1H),4.72(t,J=5.5Hz,1H),4.06-3.86(m,1H) ,3.56-3.42(m,2H),3.42-3.33(m,2H),3.26(dt,J=13.5,6.2Hz,1H),3.21- 2.83(m,2H),2.82-2.59(m,1H),1.34(d,J=43.0Hz,9H);m / z=310[M+H-Boc] + .

[0388] General Procedure for Mitsunobu Reaction: Method G3. To a solution of tert-butyl N-[3-(2-bromo-3-chlorophenyl)-2-hydroxypropyl]-N-(2-hydroxyethyl)carbamate (7.3 g, 14.6 mmol) in anhydrous toluene (112 mL) was added triphenylphosphane (4.6 g, 17.5 mmol, 1.2 equiv.) and isopropyl (N{E})-N-isopropoxycarbonyliminocarbamate (3.5 mL, 17.5 mmol, 1.2 equiv.). The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the crude material was purified by flash chromatography on silica gel (0-50% EtOAc in heptane) to afford the title compound BB-1 (4.97 g, 87%) as a white solid. [ka] 1 H NMR(DMSO-d6,400MHz,)δ(ppm):7.52(dd,J=6.2,3.3Hz,1H),7.42-7.27(m,2H),3.86-3.46 (m,4H),3.35(dd,J=11.6,2.9Hz,2H),2.95(d,J=6.5Hz,3H),1.38(s,9H);m / z=336[M-tBu] + .

[0389] Synthesis of tert-butyl 2-[(3-bromo-4-chlorophenyl)methyl]morpholine-4-carboxylate (BB-2) [ka] The same procedure as for the synthesis of tert-butyl 2-[(2-bromo-3-chlorophenyl)methyl]morpholine-4-carboxylate (BB-1) starting from 1-bromo-2-chloro-4-iodobenzene gave 2-[(3-bromo-4-chlorophenyl)methyl]morpholine-4-carboxylate (BB-2) as a white solid. 1 H NMR(DMSO-d6,400MHz)δ(ppm):7.67(d,J=8.2Hz,1H),7.53(d,J=2.0Hz,1H),7.17(dd,J=8.2,2.0Hz,1H),3.75(d,J=10.1Hz,2 H),3.67(d,J=12.3Hz,1H),3.50(d,J=5.0Hz,1H),3.33(m,2H),2.85(s,1H),2.73(m,2H),1.38(s,9H);m / z=292[M+2H-Boc]+.

[0390] Synthesis of tert-butyl 6-[(4-bromo-3-chlorophenyl)methyl]-7-oxa-4-azaspiro[2.5]octane-4-carboxylate (BB-2A) [ka] The same procedure was used to synthesize tert-butyl 2-[(2-bromo-3-chlorophenyl)methyl]morpholine-4-carboxylate (BB-1), starting from 1-bromo-2-chloro-4-iodobenzene using (1-aminocyclopropyl)methanol for the epoxide ring opening. tert-Butyl 6-[(4-bromo-3-chlorophenyl)methyl]-7-oxa-4-azaspiro[2.5]octane-4-carboxylate (BB-2A) was obtained as a colorless oil. 1H NMR(DMSO-d6,400MHz)δ(ppm):7.52(d,J=8.2Hz,1H),7.35(d,J=2.1Hz,1H),7.00(dd ,J=8.2,2.1Hz,1H),3.99-3.84(m,2H),3.67-3.58(m,1H),3.02(d,J=11.4Hz,1H),2.9 1(dd,J=13.2,10.3Hz,1H),2.75(dd,J=14.2,7.8Hz,1H),2.66(dd,J=14.2,5.0Hz,1H) ,1.43(s,9H),0.93-0.85(m,1H),0.75-0.68(m,1H),0.67-0.59(m,1H);m / z=318[M+H] + -Boc.

[0391] Synthesis of tert-butyl 2-[(4-bromo-3-chloro-2-fluorophenyl)methyl]morpholine-4-carboxylate (BB-2B) [ka] The same procedure as for the synthesis of tert-butyl 2-[(2-bromo-3-chlorophenyl)methyl]morpholine-4-carboxylate (BB-1) starting from 1-bromo-2-chloro-3-fluoro-4-iodobenzene gave tert-butyl 2-[(4-bromo-3-chloro-2-fluorophenyl)methyl]morpholine-4-carboxylate (BB-2B) as a colorless oil. 1 H NMR(DMSO-d6,400MHz)δ(ppm):7.57(dd,J=8.3,1.5Hz,1H),7.31(t,J=7.9Hz,1H),3.84-3.61(m,3H),3.52(dddd,J=10 .3,7.7,5.2,2.6Hz,1H),3.32(td,J=11.6,2.8Hz,2H),3.02-2.70(m,3H),1.39(d,J=4.4Hz,9H);m / z=410[M+2H-Boc]+.

[0392] Synthesis of tert-butyl 2-[(3-bromo-4-chloro-5-ethylphenyl)methyl]morpholine-4-carboxylate (BB-2C) [ka] The same procedure as for the synthesis of tert-butyl 2-[(2-bromo-3-chlorophenyl)methyl]morpholine-4-carboxylate (BB-1) starting from 1,5-dibromo-2-chloro-3-ethylbenzene afforded tert-butyl 2-[(3-bromo-4-chloro-5-ethylphenyl)methyl]morpholine-4-carboxylate (BB-2C) as a colorless oil (70% yield for the final step). 1 H NMR(DMSO-d6,400MHz)δ(ppm):7.51(d,J=2.0Hz,1H),7.24(d,J=2.0Hz,1H),3.80-3.63(m,3H),3.54-3.45(m,1H),3.34 (dd,J=11.6,2.8Hz,1H),2.85(s,1H),2.77-2.66(m,4H),1.38(s,9H),1.16(t,J=7.5Hz,3H).;m / z=362[M+H-(t-Bu)]+.

[0393] Synthesis of 2-[(4-bromo-3-chlorophenyl)methyl]-4-methylmorpholine (BB-2D) [ka] The same procedure as for the synthesis of tert-butyl 2-[(2-bromo-3-chlorophenyl)methyl]morpholine-4-carboxylate (BB-1) was used starting from 2-bromo-1-chloro-3-iodobenzene and using 2-(methylamino)ethan-1-ol for the epoxide ring-opening step to afford 2-[(4-bromo-3-chlorophenyl)methyl]-4-methylmorpholine (BB-2D) as a white solid (84% yield for the final step). m / z=304[M+H]+.

[0394] Synthesis of tert-butyl 2-[2-(4-bromo-3-chlorophenyl)propan-2-yl]morpholine-4-carboxylate (BB-2E) [ka] Allylic addition: To a solution of 1-bromo-2-chloro-4-iodobenzene (150 mg, 0.473 mmol) in anhydrous THF (4.5 mL) were added 5 M potassium hydroxide (0.38 mL, 1.89 mmol, 4 equiv.) and 4,4,5,5-tetramethyl-2-(3-methylbut-2-en-1-yl)-1,3,2-dioxaborolane (95%, 0.12 mL, 0.520 mmol, 1.1 equiv.). The reaction mixture was degassed with argon for 5 minutes, and palladium triphenylphosphane (27 mg, 0.0236 mmol, 0.05 equiv.) was added. The reaction mixture was stirred at 50 °C for 12 hours and then at 80 °C for 1 hour. The reaction mixture was cooled to room temperature, and water, followed by saturated aqueous NH4Cl and DCM were added. The aqueous layer was extracted three times with DCM, and the combined organic layers were washed with water and brine, then dried on a phase separator and concentrated under reduced pressure. The crude material was purified on a silica gel flash chromatography column (0–100% EtOAc in cyclohexane) to give a (50 / 50) mixture of 1-bromo-2-chloro-4-(1,1-dimethylallyl)benzene and 1-bromo-2-chloro-4-(3-methylbut-2-enyl)benzene (79.7 mg, 65%) as a colorless oil. [ka] 1H NMR(MeOD,400MHz)δ:7.56(dd,J=15.0,8.3Hz,2H),7.46(d,J=2.3Hz,1H),7.32-7.27(m,1H),7.20(dd,J=8.5,2.3Hz,1H),7.03- 6.95(m,1H),6.07-5.94(m,1H),5.28(tdt,J=7.4,2.9,1.5Hz,1H),5.07(dd,J=7.6,1.1Hz,2H),1.80-1.66(m,6H),1.38(s,8H).

[0395] The next step followed the same procedure as for BB-1: epoxidation of the mixture, epoxide ring-opening with 2-aminoethanol separated the unreacted by-product, N-Boc protection, and Mitsunobu method gave tert-butyl 2-[1-(4-bromo-3-chloro-phenyl)-1-methyl-ethyl]morpholine-4-carboxylate (BB-2E) as a colorless oil. [ka] 1 H NMR(CDCl3,400MHz)δ:7.52(d,J=8.5Hz,1H),7.46(d,J=2.3Hz,1H),7.15(dd,J=8.5,2.3Hz,1H),3.98-3.56(m,3H),3.43(t,J=11.6Hz,1H),3.29(d, J=10.5Hz,1H),2.79(t,J=12.5Hz,1H),2.43(t,J=12.3Hz,1H),1.54(d,J= 29.9Hz,2H),1.43(s,10H),1.33(d,J=7.9Hz,6H);m / z=362[M+H-(t-Bu)]+.

[0396] Synthesis of tert-butyl 6-[(4-bromo-3-chlorophenyl)methyl]-2,2-dimethylmorpholine-4-carboxylate (BB-2F) [ka] The same procedure as for the synthesis of tert-butyl 2-[(2-bromo-3-chlorophenyl)methyl]morpholine-4-carboxylate (BB-1) starting from 1-bromo-2-chloro-4-iodobenzene, using 2-amino-2-methylpropan-1-ol for the epoxide ring-opening step, and Method G2 for the final step gave tert-butyl 6-[(4-bromo-3-chlorophenyl)methyl]-2,2-dimethylmorpholine-4-carboxylate (BB-2F) as a yellow solid (32% for final step). 1 H NMR(DMSO-d6,400MHz)δ(ppm):7.77-7.60(m,2H),7.35(dd,J=8.4,2.1Hz,1H),6.38(s,2H),4.4 5(s,1H),4.09(d,J=12.5Hz,2H),3.15(s,2H),1.39(s,J=5.9Hz,9H),1.09(s,6H);m / z=320[M+H] + -Boc.

[0397] Synthesis of tert-butyl 6-[(2-bromo-3-chlorophenyl)methyl]-2,2-dimethylmorpholine-4-carboxylate (BB-2G) [ka] For the epoxide ring-opening step, the same procedure as in the synthesis of tert-butyl 2-[(2-bromo-3-chlorophenyl)methyl]morpholine-4-carboxylate (BB-1) was used, using 1-amino-2-methylpropan-2-ol dissolved in DMF. tert-Butyl 6-[(2-bromo-3-chloro-phenyl)methyl]-2,2-dimethyl-morpholine-4-carboxylate (BB-2G) was obtained as a colorless oil (34% yield for the final step). 1H NMR(DMSO-d6,400MHz)δ(ppm):7.51(dd,J=7.5,2.1Hz,1H),7.43-7.26(m,2H),3.95-3.5 1(m,3H),2.87(q,J=6.9Hz,2H),1.35(s,9H),1.10(d,J=9.2Hz,6H);m / z=364[M+H-(tBu)] + .

[0398] Synthesis of tert-butyl 2-[(4-bromo-3-chlorophenyl)methyl]-1,4-oxazepane-4-carboxylate (BB-2H) [ka] For the epoxide ring-opening step, 3-aminopropan-1-ol was used in the same procedure as in the synthesis of tert-butyl 2-[(3-bromo-4-chlorophenyl)methyl]morpholine-4-carboxylate (BB-2). tert-Butyl 2-[(4-bromo-3-chloro-phenyl)methyl]-1,4-oxazepane-4-carboxylate (BB-2H) was obtained as a colorless oil (8% yield for the final step). 1 H NMR(DMSO-d6,400MHz)δ(ppm):7.73-7.61(d,1H),7.52(s,J=2.6Hz,1H),7.16(dd,J =8.2,2.1Hz,1H),3.90(dt,J=12.6,4.4Hz,1H),3.76-3.51(m,3H),3.28(m,J=7.8Hz, 1H),3.17(m,J=25.6,13.3,6.5Hz,1H),2.96(m,J=9.5,5.0Hz,1H),2.69(m,J=20.8, 13.5,9.2Hz,2H),1.75(m,J=12.0,6.7Hz,2H),1.35(d,J=35.1Hz,9H);m / z=306[M+H] + -Boc.

[0399] Synthesis of tert-butyl 2-[(2-bromo-3-chlorophenyl)methyl]-1,4-oxazepane-4-carboxylate (BB-2I) [ka] Starting from 2-bromo-1-chloro-3-iodobenzene, the same procedure as for the synthesis of tert-butyl 2-[(4-bromo-3-chlorophenyl)methyl]-1,4-oxazepane-4-carboxylate (BB-2H) afforded tert-butyl 2-[(2-bromo-3-chloro-phenyl)methyl]-1,4-oxazepane-4-carboxylate (BB-2I) as a pale yellow oil (9% yield for the final step). 1 H NMR(DMSO-d6,400MHz)δ(ppm):7.57-7.43(m,1H),7.41-7.24(m,2H),3.91(dt,J=12.6,4.5Hz,1H),3.71 (dd,J=27.1,13.5Hz,3H),3.13-2.80(m,4H),1.92-1.65(m,2H),1.27(d,J=14.7Hz,10H);m / z=306[M+H] + -Boc.

[0400] Synthesis of tert-butyl 2-[(4-bromophenyl)methyl]morpholine-4-carboxylate (BB-2J) [ka] The same procedure as for the synthesis of tert-butyl 2-[(2-bromo-3-chlorophenyl)methyl]morpholine-4-carboxylate (BB-1) starting from 1-bromo-4-iodobenzene gave 2-[(4-bromophenyl)methyl]morpholine-4-carboxylate (BB-2J) as a yellow oil. 1 H NMR(DMSO-d6,400MHz)δ(ppm):7.52-7.43(m,2H),7.26-7.17(m,2H),3.82-3.63(m,3H),3.54-3 .43(m,1H),3.34(dd,J=11.6,2.8Hz,1H),2.93-2.53(m,4H),1.38(s,9H);m / z=258[M+2H-Boc]+.

[0401] Synthesis of tert-butyl 2-[(4-bromophenyl)methyl]morpholine-4-carboxylate (BB-2K) [ka] For the epoxide ring-opening step, 3-aminopropan-1-ol was used in the same procedure as in the synthesis of tert-butyl 2-[(4-bromophenyl)methyl]morpholine-4-carboxylate (BB-2J). Using method G2 for the Mitsunobu reaction, tert-butyl 2-[(4-bromophenyl)methyl]morpholine-4-carboxylate (BB-2K) was obtained as an orange oil (40% yield for this step). 1 H NMR(DMSO-d6,400MHz)δ(ppm):7.46(d,J=8.0Hz,2H),7.27-7.11(m,2H),3.89(d,J=12.8Hz,1H),3.72-3.51(m,3H),3.29-3 .03(m,2H),3.01-2.85(m,1H),2.80-2.55(m,2H),1.73(dt,J=13.9,6.1Hz,2H),1.34(d,J=35.4Hz,9H);m / z=270[M-Boc]+.

[0402] Boronate formation of building blocks Synthesis of tert-butyl 2-{[3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}morpholine-4-carboxylate (BB-3) [ka] To a solution of tert-butyl 2-[(4-bromo-3-chlorophenyl)methyl]morpholine-4-carboxylate (250 mg, 0.64 mmol) in 1,4-dioxane (6.4 mL, 0.1 M), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (243 mg, 0.95 mmol, 1.5 equiv), KOAc (2 equiv), and PdCl(dppf) CHCl (52 mg, 0.0640 mmol, 0.1 equiv) were added sequentially. The reaction mixture was degassed with nitrogen for 5 minutes and stirred at 100 °C for 2 hours. The reaction mixture was cooled to room temperature, filtered through Celite, and the solid was washed with MeOH. The combined filtrate was concentrated under reduced pressure. The crude material was purified by flash chromatography column (EtOAc in heptane, 0-30%) to give the title compound BB-3 as a white solid (63% yield). 1 H NMR(DMSO-d6,400MHz)δ(ppm):7.56(d,J=7.6Hz,1H),7.32(d,J=1.5Hz,1H),7.21(dd,J=7.7,1.5Hz,1H),3.8 5-3.59(m,3H),3.55-3.45(m,1H),2.90-2.56(m,4H),1.39(s,9H),1.30(s,12H);m / z=300[M(boronic acid)+H-Boc]+.

[0403] Synthesis of tert-butyl 2-{[3-chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}morpholine-4-carboxylate (BB-4) A vial was charged with tert-butyl 2-[(2-bromo-3-chlorophenyl)methyl]morpholine-4-carboxylate (1.00 g, 2.53 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (BB-1) (99%, 1.30 g, 5.07 mmol), tricyclohexylphosphane (95%, 56 mg, 0.190 mmol), and KOAc (251 mg, 2.53 mmol) in anhydrous 1,4-dioxane (10.136 mL). The reaction was degassed to afford (1{E},4{E})-1,5-diphenylpenta-1,4-dien-3-one. Palladium (122 mg, 0.127 mmol) was added. The mixture was stirred overnight at 95°C under a nitrogen atmosphere. Water was added, and the mixture was extracted three times with AcOEt. The combined organic layers were washed with water, brine, dried through a phase separator, and concentrated to give a brown oil. The crude product was purified by flash chromatography (EtOAc in heptane, 0-20%) to give tert-butyl 2-[[3-chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]morpholine-4-carboxylate (BB-4) (571 mg, 48.4% yield) as a dark green oil. [ka] 1H NMR(400MHz,DMSO)δ(ppm):7.36-7.29(m,1H),7.26(dd,J=8.1,1.1Hz,1H),7.1 8(dd,J=7.5,1.2Hz,1H),3.78(dd,J=11.6,3.2Hz,1H),3.70(d,J=12.3Hz,2H), 3.49-3.39(m,1H),3.27(td,J=11.6,2.8Hz,1H),2.79(d,J=14.2Hz,2H),2.67( dd,J=13.6,5.9Hz,2H),1.37(s,9H),1.35(d,J=2.0Hz,12H);m / z=338[M+H-Boc] + .

[0404] Intermediate BB-4 can be separated into enantiomer 1 (E1) and enantiomer 2 (E2).

[0405] Method A: Buchwald-Hartwig General Procedure A1: To a 0.1 M solution of Ar-Br (1–1.2 equiv.) in 1,4-dioxane (0.1 M), NaOtBu (3.00 equiv.) and Xantphos (0.10 equiv.) were added. The reaction mixture was degassed with argon for 5–10 min, and Pd2dba3 (0.05–0.1 equiv.) and an amine (1–1.5 equiv.) were added. The reaction mixture was heated at 90–100 °C for 5–24 h. The reaction mixture was cooled to room temperature, diluted with DCM, and quenched with water. The two layers were separated, and the aqueous layer was extracted three times with DCM. The combined organic layers were dried through a phase separator and concentrated under reduced pressure. The crude material was purified by flash chromatography (EtOAc / heptane or MeOH / DCM) to give the desired product.

[0406] Synthesis of tert-butyl 2-{[3-chloro-4-(morpholin-4-yl)phenyl]methyl}morpholine-4-carboxylate (Intermediate 1) [ka] tert-Butyl 2-[(4-bromo-3-chlorophenyl)methyl]morpholine-4-carboxylate (BB-2) (500 mg, 1.27 mmol, 1.15 equiv.) and morpholine (97 mg, 1.11 mmol, 1 equiv.) gave tert-butyl 2-{[3-chloro-4-(morpholin-4-yl)phenyl]methyl}morpholine-4-carboxylate as a yellow oil (73% yield). 1 H NMR (DMSO-d 6,400MHz): δ(ppm)7.31(d,J=1.9Hz,1H),7.18(dd,J=8.2,2.0Hz,1H),7.09(d,J=8.2Hz,1H),3.83-3.63(m,7H),3.47(dtd,J=9.3,6.5,2. m / z=397[M+H] + .

[0407] General Procedure A2: In a sealed vial, Ar-Br (1 equiv.) and 3-(methoxymethyl)azetidine hydrochloride were dissolved in 1,4-dioxane (0.1 M). A 2 M solution of NaOtBu was added (3 equiv.). The reaction mixture was degassed with nitrogen for 5-10 min, and tBuXPhos Pd G3 (0.1 equiv.) and an amine (1-1.5 equiv.) were added. The reaction mixture was stirred at 95 °C for 2 h. The reaction mixture was cooled to room temperature, diluted with DCM, and quenched with water. The two layers were separated, and the aqueous layer was extracted three times with DCM. The combined organic layers were dried on a phase separator and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel (EtOAc in heptane). 0-50%) to give the desired product.

[0408] Synthesis of tert-butyl 2-({3-chloro-4-[3-(methoxymethyl)azetidin-1-yl]phenyl}methyl)morpholine-4-carboxylate (Intermediate 2) [ka] tert-Butyl 2-[(4-bromo-3-chlorophenyl)methyl]morpholine-4-carboxylate (BB-2) (200 mg, 0.51 mmol, 1 equiv.) and 3-(methoxymethyl)azetidine hydrochloride (114 mg, 0.76 mmol, 1.5 equiv.) gave tert-butyl 2-({3-chloro-4-[3-(methoxymethyl)azetidin-1-yl]phenyl}methyl)morpholine-4-carboxylate as a yellow oil (99% yield). 1 H NMR(DMSO-d6,500MHz)δ(ppm)7.10(d,J=2.0Hz,1H),7.02(dd,J=8.3,2.0Hz,1H ),6.51(d,J=8.3Hz,1H),4.05-3.96(m,3H),3.77(dd,J=11.4,3.2Hz,1H),3.74 -3.60(m,4H),3.51(d,J=6.6Hz,2H),3.44-3.37(m,1H),3.35-3.29(m,1H),3.2 7(s,3H),2.91-2.77(m,1H),2.59(d,J=5.6Hz,3H),1.37(s,9H);m / z=411[M+H] + .

[0409] General Procedure A3: To a 0.1 M solution of Ar-Br (1.00 equiv.) in 1,4-dioxane in a sealed tube, degassing with nitrogen was added the amine (1.0 equiv.), NaOtBu (3.00 equiv.), JonPhos or BINAP (0.05 equiv.), and diacetoxypalladium (0.5 equiv.). The reaction mixture was stirred at 90°C for 2 h. The reaction mixture was cooled to room temperature, quenched with water, and extracted three times with EtOAc. The combined organic layers were dried over a phase separator and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel (EtOAc / heptane, 0-100%) to give the desired product.

[0410] Synthesis of tert-butyl 2-[[4-(4-pyrimidin-2-yl-1-piperidyl)phenyl]methyl]morpholine-4-carboxylate (Intermediate 3) [ka] tert-Butyl 2-[(4-bromophenyl)methyl]morpholine-4-carboxylate (BB-2J) (300 mg, 0.84 mmol) and 2-(piperidin-4-yl)pyrimidine hydrochloride (212 mg, 1.01 mmol, 1.2 equiv.) gave tert-butyl 2-[[4-(4-pyrimidin-2-yl-1-piperidyl)phenyl]methyl]morpholine-4-carboxylate as a yellow solid (63% yield). 1 H NMR (DMSO-d 6, 400MHz): δ(ppm)8.75(d,J=4.9Hz,2H),7.35(t,J=4.9Hz,1H),7.07(d,J=8.6H z,2H),6.89(d,J=8.7Hz,2H),3.83-3.62(m,5H),3.47-3.31(m,2H),2.97(tt,J =11.5,3.8Hz,1H),2.80(td,J=12.2,2.5Hz,3H),2.61(ddd,J=35.7,13.8,6.4H m / z=439[M+H] + .

[0411] General Procedure A4: To a toluene solution (0.1 M) of Ar-Br (1.00 equiv.) in a sealed tube, an amine (1.1 equiv.) and NaOtBu or K0tBu (2.2 equiv.) were added sequentially. The mixture was degassed with nitrogen for 5 minutes, and Pd-113 (0.07 equiv.) was added. The reaction mixture was stirred at 100 °C for 2 hours. The reaction mixture was cooled to room temperature, quenched with water, and extracted three times with EtOAc. The combined organic layers were dried through a phase separator and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel (EtOAc in heptane, 0-100%) to give the desired product.

[0412] Synthesis of tert-butyl 2-[[4-[4-(ethoxymethyl)-4-hydroxy-1-piperidyl]phenyl]methyl]morpholine-4-carboxylate (Intermediate 4) [ka] tert-Butyl 2-[(4-bromophenyl)methyl]morpholine-4-carboxylate (BB-2J) (100 mg, 0.28 mmol) and 4-(ethoxymethyl)piperidin-4-ol (49 mg, 0.31 mmol, 1.1 equivalents) gave tert-butyl 2-[[4-[4-(ethoxymethyl)-4-hydroxy-1-piperidyl]phenyl]methyl]morpholine-4-carboxylate as a yellow oil. 1 H NMR (DMSO-d 6, 400MHz):δ(ppm)7.09-6.97(m,2H),6.91-6.80(m,2H),4.29(s,1H),3.68(m ,1H),3.46(m,J=7.0Hz,2H),3.31(s,8H),3.20(s,2H),2.99(td,J=12.0,2.8 Hz,2H),2.85(s,1H),2.60(ddd,J=37.1,13.9,6.8Hz,2H),1.68(td,J=12.6 ,4.5Hz,2H),1.48(s,1H),1.37(s,9H),1.11(t,J=7.0Hz,3H);m / z=435[M+H] + .

[0413] General Procedure A5: To a stirred solution of Ar-Br (1 equiv.) in 1,4-dioxane (0.1 M), amine (1.1 equiv.), BINAP (0.4 equiv.), and cesium carbonate (3 equiv.) were added sequentially. The reaction mixture was degassed for 5 min, and Pd2(dba)3 (0.2 equiv.) was added. The mixture was stirred at 100 °C for 12 h. DCM and water were added. The aqueous layer was extracted three times with DCM. The combined organic layers were dried over a phase separator and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel (EtOAc in heptane, 0-100%) to give the desired product.

[0414] Synthesis of tert-butyl 2-({3-chloro-4-[4-(hydroxymethyl)piperidin-1-yl]phenyl}methyl)morpholine-4-carboxylate (Intermediate 5) [ka] tert-Butyl 2-[(4-bromo-3-chlorophenyl)methyl]morpholine-4-carboxylate (300 mg, 0.768 mmol) and methyl piperidine-4-carboxylate (125 mg, 0.845 mmol, 1.1 equiv.) gave tert-butyl 2-[[3-chloro-4-(4-methoxycarbonyl-1-piperidyl)phenyl]methyl]morpholine-4-carboxylate as an orange oil (353 mg, 93% yield). 1 H NMR (DMSO-d 6, 400MHz): δ(ppm)7.29(d,J=2.0Hz,1H),7.15(dd,J=8.2,2.1Hz,1H),7.06(d,J=8 .2Hz,1H),3.84-3.65(m,3H),3.64(s,3H),3.51-3.42(m,1H),3.31(m,1H),3.20 (d,J=11.8Hz,2H),2.85(s,1H),2.74-2.54(m,5H),2.51(m,J=1.8Hz,1H),1.93( dd,J=13.3,3.6Hz,2H),1.74(qd,J=11.2,3.7Hz,2H),1.38(s,9H);m / z=453[M+H] + .

[0415] General Procedure A6: To a stirred solution of Ar-Br (1 equiv.), amine (2 equiv.), 2-(2-dicyclohexylphosphanylphenyl)-N,N-dimethylaniline (0.2 equiv.), and tripotassium phosphate (4 equiv.) in DME (0.1 M) was added (1{E},4{E})-1,5-diphenylpenta-1,4-dien-3-one palladium (0.2 equiv.). The mixture was stirred at 85 °C for 12 h, diluted with ethyl acetate, and filtered through a Celite pad. The filtrate was washed with brine. The organic layer was dried over a phase separator and evaporated under reduced pressure. The crude material was purified twice by flash column chromatography (eluting with 0–50% EtOAc in cyclohexane) to give the expected product.

[0416] Synthesis of tert-butyl 2-[[4-(2-oxa-7-azaspiro[4.4]nonan-7-yl)phenyl]methyl]morpholine-4-carboxylate (Intermediate 6) [ka] tert-Butyl 2-[(4-bromophenyl)methyl]morpholine-4-carboxylate (100 mg, 0.28 mmol) and 2-oxa-7-azaspiro[4.4]nonane (71 mg, 0.56 mmol, 2 equivalents) gave tert-butyl 2-[[4-(2-oxa-7-azaspiro[4.4]nonan-7-yl)phenyl]methyl]morpholine-4-carboxylate as a yellow oil (63 mg, 70% purity, 39% yield). m / z = 403.1 [M+H] + .

[0417] Method B: Suzuki-Miyaura coupling General Procedure B1: To a solution of Ar-Br (Ar-I or Ar-Cl) (1.00 equiv.) in 1,4-dioxane / HO (4:1, 0.1 M) was added RB(OH) (or R-Bpin or R-BF3K) (1.20 equiv.) and Na2CO3 (3.00 equiv.). The reaction mixture was degassed with argon for 5 minutes, Pd(dppf)Cl2 (DCM) (0.10 equiv.) was added, and the reaction mixture was heated at 100 °C for 1–24 h. The reaction mixture was cooled to room temperature, diluted with DCM, and quenched with water. The two layers were separated, and the aqueous layer was extracted three times with DCM. The combined organic layers were dried through a phase separator and concentrated under reduced pressure. The crude material was purified by flash chromatography (0–100% EtOAc in heptane) to give the desired product.

[0418] Synthesis of tert-butyl 2-[[3-chloro-4-[2-fluoro-4-(hydroxymethyl)phenyl]phenyl]methyl]morpholine-4-carboxylate (Intermediate 7) [ka] tert-Butyl 2-[(4-bromo-3-chloro-phenyl)methyl]morpholine-4-carboxylate (200 mg, 0.51 mmol) and [3-fluoro-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanol (162 mg, 0.62 mmol) gave tert-butyl 2-[[3-chloro-4-[2-fluoro-4-(hydroxymethyl)phenyl]phenyl]methyl]morpholine-4-carboxylate as a yellow sticky oil (220 mg, 98.6% yield). 1 H NMR (DMSO-d 6,400MHz): δ(ppm)7.48(s,J=1.1Hz,1H),7.34-7.27(m,3H),7.24(s,1H),7.23-7.20(m,1H),5.36(t,J=5.8Hz,1H),4.57(d,J=5.8Hz,2 H),3.81(d,J=12.0Hz,2H),3.70(d,J=13.1Hz,1H),3.64-3.52(m,1H),3.31(m,1H),3.01-2.55(m,4H),1.40(s,9H);m / z=336[M-Boc] + .

[0419] General Procedure B2: To a solution of Ar-Cl or Ar-Br (1.00 equiv.) in 1,4-dioxane / HO (4:1, 0.1 M) was added RB(OH) (or R-Bpin) (1.40–2.5 equiv.) and KPO or KCO (2–5 equiv.). The reaction mixture was degassed with argon for 5 min, Pd(dba) (0.1–0.5 equiv.) and PCy (0.15–1 equiv.) were added, and the reaction mixture was heated at 100 °C for 24 h. The reaction mixture was cooled to room temperature, diluted with DCM, and quenched with water. The two layers were separated, and the aqueous layer was extracted three times with DCM. The combined organic layers were dried through a phase separator and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel (0–100% EtOAc in heptane) to give the desired product.

[0420] Synthesis of tert-butyl rel-(2R)-2-[[3-(4-cyano-3-fluoro-phenyl)-2-isothiazol-5-ylphenyl]methyl]morpholine-4-carboxylate (Intermediate 8) [ka] tert-Butyl rel-(2R)-2-[(3-chloro-2-isothiazol-5-yl-phenyl)methyl]morpholine-4-carboxylate (712 mg, 1.78 mmol) and 2-fluoro-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (1.12 g, 4.46 mmol) gave tert-butyl rel-(2R)-2-[[3-(4-cyano-3-fluoro-phenyl)-2-isothiazol-5-yl-phenyl]methyl]morpholine-4-carboxylate as a sticky red oil (601 mg, 67% yield). 1 H NMR (DMSO-d 6, 400MHz): δ(ppm)8.52(d,J=1.7Hz,1H),7.80(t,J=8.0,7.0Hz,1H),7.58-7.53(m,2H),7.42-7.34(m,3H),7.19(dd,J=8.0,1.5Hz,1H),3.81-3.50( m,1H),3.40(m,1H),3.25(dt,J=11.6,2.8Hz,1H),2.82(s,1H),2.66(m,J =4.9,4.4Hz,2H),2.51(m,J=1.9Hz,1H),1.38(s,9H);m / z=424[MH-tBu]+.

[0421] General Procedure B3: To a 0.14 M solution of Ar-Br (1.00 equiv.) in DMSO, RB(OH)2 (or R-Bpin) (1–2 equiv.), Cs2CO3 (3 equiv.), and KOAc (1 equiv.) were added sequentially. The reaction mixture was degassed with argon for 5 min, PdCl2(PPh3)2 (0.1–0.5 equiv.) was added, and the mixture was stirred at 120 °C for 3–12 h. The reaction mixture was cooled to room temperature, diluted with DCM, and quenched with water. The two layers were separated, and the aqueous layer was extracted three times with DCM. The combined organic layers were dried on a phase separator and concentrated under reduced pressure. The crude product was purified by flash chromatography on a silica gel column (EtOAc in heptane) to give the desired product.

[0422] Synthesis of tert-butyl 2-[[3-chloro-2-(4-methylthiazol-5-yl)phenyl]methyl]morpholine-4-carboxylate (Intermediate 9) [ka] Tert-butyl 2-[(2-bromo-3-chloro-phenyl)methyl]morpholine-4-carboxylate (300 mg, 0.77 mmol) and 4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-thiazole (180 mg, 0.77 mmol) gave tert-butyl 2-[[3-chloro-2-(4-methylthiazol-5-yl)phenyl]methyl]morpholine-4-carboxylate as a yellow oil (120 mg, 37% yield). 1 H NMR (DMSO-d 6, 400MHz): δ(ppm)9.17(s,1H),7.51(m,J=7.2,2.3,1.1Hz,1H),7.48-7.39(m,2H),3.68(dd,J=31.0,12.4Hz,2H),3.55(s,1H),3.31(s,1H),3 .24(t,J=10.6,9.5,2.2Hz,1H),2.80(s,1H),2.67(m,J=6.0Hz,2H),2.49(s,1H),2.11(s,J=0.9Hz,3H),1.36(s,J=1.9Hz,9H);m / z=409[M+H] + .

[0423] General Procedure B4: To a stirred solution of Ar-Br (1 equiv.) in anhydrous dioxane (0.8 M) at room temperature under a nitrogen atmosphere, RB(OH) (2 equiv.), KPO (2 equiv.), and Pd(PPh) (0.05–0.1 equiv.) were added sequentially. The reaction mixture was stirred at 110 °C for 12 h. The suspension was filtered and washed with methanol, and the filtrate was concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel using a gradient of EtOAc in heptane. The desired fractions were combined and concentrated to give the expected compound.

[0424] Synthesis of tert-butyl 2-[(3-chloro-2-cyclopropyl-phenyl)methyl]morpholine-4-carboxylate (Intermediate 10) [ka] tert-Butyl 2-[(2-bromo-3-chloro-phenyl)methyl]morpholine-4-carboxylate (70 mg, 0.12 mmol) and cyclopropylboronic acid (30 mg, 0.34 mmol) gave tert-butyl 2-[(3-chloro-2-cyclopropylphenyl)methyl]morpholine-4-carboxylate as a colorless oil. 1 H NMR (DMSO-d 6, 400MHz): δ(ppm)7.26(dd,J=7.3,1.9Hz,1H),7.24-7.14(m,2H),3.83-3.54(m,4H),3.38-3.33(m,1H),3.12-2.94(m,2H),2.87(br s,1H),2.78-2.53(m,1H),1.83-1.69(m,1H),1.37(s,9H),1.09(dd,J=8.7,4.5Hz,2H),0.60(dt,J=35.3,5.7Hz,2H);m / z=252[M-Boc]+.

[0425] General Procedure B5: To a solution of Ar-Br (1.00 equiv.) in toluene / HO (5:1, 0.1 M) was added KPO (4 equiv.), RB(OH) (1.5 equiv.), and PCy (0.1 equiv.). The reaction mixture was degassed with argon for 5 minutes, and Pd(OAc) (0.1 equiv.) was added. The reaction mixture was heated at 100 °C for 12 hours. The reaction mixture was cooled to room temperature, diluted with EtOAc, and quenched with water. The two layers were separated, and the aqueous layer was extracted three times with EtOAc. The combined organic layers were dried through a phase separator and concentrated under reduced pressure. If necessary, the crude material was purified by flash chromatography on silica gel to give the desired product.

[0426] Synthesis of 5-(azetidin-3-yl)-2-cyclopropyl-pyridine (intermediate 11) [ka] 5-(Azetidin-3-yl)-2-bromopyridine, trifluoroacetic acid (200 mg, 0.61 mmol) and cyclopropylboronic acid (82 mg, 0.92 mmol) gave 5-(azetidin-3-yl)-2-cyclopropylpyridine as a sticky yellow oil (122 mg, 78%). The crude product was used in the next step. m / z=175 [M+H]+.

[0427] General Procedure B6: To a solution of Ar-Br (1.00 equiv.) in dioxane / HO (4:1, 0.12 M) was added RB(OH)2 (or R-Bpin) (1–2 equiv.) and K3PO4 (2 equiv.) sequentially. The reaction mixture was degassed with argon for 5 min, PdCl2(PPh3)2 (0.05–0.1 equiv.) was added, and the mixture was stirred at 100 °C for 3–12 h. The reaction mixture was cooled to room temperature, diluted with DCM, and quenched with water. The two layers were separated, and the aqueous layer was extracted three times with DCM. The combined organic layers were dried over a phase separator and concentrated under reduced pressure. The crude material was purified by flash chromatography on a silica gel column using a gradient of EtOAc in heptane to give the desired product.

[0428] Synthesis of tert-butyl 2-[(3-chloro-2-isothiazol-5-yl-phenyl)methyl]morpholine-4-carboxylate (Intermediate 12) [ka] tert-Butyl 2-[[3-chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]morpholine-4-carboxylate (1.1 g, 2.42 mmol) and 5-bromo-1,2-thiazole (459 mg, 2.65 mmol) gave tert-butyl 2-[(3-chloro-2-isothiazol-5-yl-phenyl)methyl]morpholine-4-carboxylate as a sticky colorless oil (334 mg, 34%). 1 H NMR (DMSO-d 6, 400MHz): δ(ppm)8.70(d,J=1.7Hz,1H),7.59-7.37(m,4H),3.73(d,J=11.5Hz,1H),3.64(d,J=13.4Hz,1H),3 .58(m,1H),3.38(m,1H),3.29-3.20(td,1H),2.80(m,1H),2.64-2.53(m,3H),1.38(s,9H);m / z=395[M+H]+.

[0429] General Procedure B7: Under an argon atmosphere, Xantphos (0.28 equiv.), sodium tert-butoxide (3 equiv.), and Pd2(dba)3 (0.1 equiv.) were added to a 0.09 M solution of Ar-Br (1.00 equiv.) in dioxane. The reaction mixture was degassed with argon for 5 minutes, and potassium cyclopropyl(trifluoro)boranide (1 equiv.) was added. The mixture was stirred at 90 °C for 12 h. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted twice with EtOAc. The combined organic layers were dried using a phase separator and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel using a gradient of EtOAc in heptane to give the desired product.

[0430] Synthesis of tert-butyl 2-[(3-chloro-4-cyclopropyl-phenyl)methyl]morpholine-4-carboxylate (Intermediate 13) [ka] tert-Butyl 2-[(4-bromo-3-chlorophenyl)methyl]morpholine-4-carboxylate (200 mg, 0.51 mmol) and potassium cyclopropyl(trifluoro)boranide (78 mg, 0.51 mmol) gave tert-butyl 2-[(3-chloro-4-cyclopropylphenyl)methyl]morpholine-4-carboxylate as a yellow oil (100 mg, 50% purity, 30% yield). m / z = 296 [M+H] + -(t-Bu).

[0431] General Procedure B8: Under an argon atmosphere, 4-bromo-1,3-oxazole hydrochloride (1.05 equiv.), disodium carbonate (3 equiv.), and Pd2(dba)3 (0.1 equiv.) were added to a 0.12 M solution of Ar-Br (1.00 equiv.) in dioxane / water. The reaction mixture was degassed with argon for 5 minutes, and triphenylphosphane palladium (0.05 equiv.) was added. The mixture was stirred at 110 °C for 6 hours. The reaction mixture was cooled to room temperature, water and DCM were added, and the aqueous layer was extracted with DCM (3 times). The combined organic layers were dried using a phase separator and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel using a gradient of EtOAc in heptane to give the desired product.

[0432] Synthesis of tert-butyl 2-[(3-chloro-2-oxazol-4-yl-phenyl)methyl]morpholine-4-carboxylate (Intermediate 14) [ka] tert-Butyl 2-[[3-chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]morpholine-4-carboxylate (100 mg, 0.22 mmol) and 4-bromo-1,3-oxazole hydrochloride (45 mg, 0.23 mmol, 1.05 equiv.) gave tert-butyl 2-[(3-chloro-2-oxazol-4-yl-phenyl)methyl]morpholine-4-carboxylate as a colorless oil (24 mg, 26% yield). 1 H NMR (DMSO-d 6, 400MHz): δ(ppm)8.55(d,J=0.9Hz,1H),8.26(d,J=0.9Hz,1H),7.45(dd,J=7.8,1.6Hz,1H),7.39(t,J=7.7Hz,1H),7.35(dd,J=7.6,1.4Hz,1H),3 .72(dd,J=11.6,2.6Hz,1H),3.67-3.54(m,2H),3.41-3.34(m,1H),3.24 (td,J=11.6,2.8Hz,1H),2.87-2.59(m,4H),1.37(s,9H);m / z=279[M+H] + -(Boc).

[0433] General Procedure B9: Under an argon atmosphere, 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (1.2 equiv.), tricyclohexylphosphane (0.75 equiv.), and potassium acetate (1 equiv.) were added to a dioxane solution (0.2 M) of Ar-BPin (1.00 equiv.) under an argon atmosphere. The reaction mixture was degassed with argon for 5 minutes, and Pd2(dba)3 (0.05 equiv.) was added. The mixture was stirred at 100 °C for 7 hours. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with EtOAc (3 times). The combined organic layers were washed with brine, dried over a phase separator, and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel using a gradient of 100% EtOAc in heptane to give the desired product.

[0434] Synthesis of tert-butyl 2-[[2-(1-methylpyrazol-4-yl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]morpholine-4-carboxylate (Intermediate 15) [ka] Tert-butyl 2-[[3-chloro-2-(1-methylpyrazol-4-yl)phenyl]methyl]morpholine-4-carboxylate (65 mg, 0.16 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (51 mg, 0.19 mmol, 1.2 equivalents) gave tert-butyl 2-[[2-(1-methylpyrazol-4-yl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]morpholine-4-carboxylate as a colorless oil (15 mg, 18.6% yield). m / z = 484.2 [M+H] + .

[0435] Method C: CH activation General Procedure C1 To a 0.2 M solution of Ar-Br (1 equiv.) in DMA was added K2CO3 (3 equiv.), cataCXium® (0.1 equiv.), and pivalic acid (0.4 equiv.). The reaction mixture was degassed with argon for 5 minutes, and Pd(OAc)2 (0.05 equiv.) was added, followed by Ar-H (1 equiv.). The reaction mixture was stirred at 110 °C for 4 hours. The reaction mixture was cooled to room temperature, filtered, and concentrated under high vacuum. The crude material was purified by flash chromatography on silica gel (0-100% EtOAc in heptane) to give the desired product.

[0436] Synthesis of tert-butyl 2-[[3-chloro-2-(2-methyloxazol-5-yl)phenyl]methyl]morpholine-4-carboxylate (Intermediate 16) [ka] tert-Butyl 2-[(2-bromo-3-chloro-phenyl)methyl]morpholine-4-carboxylate (100 mg, 0.256 mmol) with 2-methyl-1,3-oxazole (22 mg, 0.256 mmol) gave tert-butyl 2-[[3-chloro-2-(2-methyloxazol-5-yl)phenyl]methyl]morpholine-4-carboxylate as a yellow oil (69 mg, 68.6% yield). m / z=393 [M-Boc]+.

[0437] General Procedure C2 A sealed tube was charged with Pd(OAc) (0.1 equiv.), KCO (2 equiv.), 2,2-dimethylpropanoic acid (0.4 equiv.), and tricyclohexylphosphonium tetrafluoroborate (0.15). The tube was purged with argon three times.

[0438] DMA (0.2 M) was added, followed by Ar-Br (1 equivalent) and Ar-H (1.3 equivalents). The resulting mixture was stirred at 110° C. for 5 hours. Water was added, and the mixture was extracted three times with EtOAc. The combined organic layers were washed with water, brine, dried over a phase separator, and concentrated under reduced pressure. The crude material was purified by flash chromatography column (EtOAc in heptane) to give the desired product.

[0439] Synthesis of tert-butyl 2-[(3-chloro-2-thiazol-5-ylphenyl)methyl]morpholine-4-carboxylate (Intermediate 17) [ka] tert-Butyl 2-[(2-bromo-3-chloro-phenyl)methyl]morpholine-4-carboxylate (600 mg, 1.53 mmol) and 1,3-thiazole (1.3 equivalents) gave tert-butyl 2-[(3-chloro-2-thiazol-5-ylphenyl)methyl]morpholine-4-carboxylate as an orange oil (232 mg, 38.2% yield). 1 H NMR (DMSO-d 6, 400MHz): δ(ppm)9.29(d,J=0.5Hz,1H),7.84(d,J=0.6Hz,1H),7.53-7.37(m,3H),3.80-3.49(m,3H) ,3.43-3.33(m,1H),3.31-3.18(m,1H),2.81(s,1H),2.63-2.55(m,2H),1.37(s,9H);m / z=395.1[M] +

[0440] General Procedure C3: A vial was charged with Ar-H (1 equiv.), Ar-Br (1.04 equiv.), Pd(OAc)2 (0.05 equiv.), QPhos (0.075 equiv.), tetrabutylammonium chloride; and acetic acid (3 equiv.) in anhydrous dioxane (0.4 M) under an argon atmosphere. The mixture was stirred at 105 °C for 12 h. Water was added, and the mixture was extracted three times with EtOAc. The combined organic layers were washed with water, brine, dried over a phase separator, and concentrated under reduced pressure. The crude material was purified by flash chromatography using a gradient of 0-100% EtOAc in heptane to give the desired product.

[0441] Synthesis of tert-butyl 2-[[3-chloro-2-(1-methylpyrazol-4-yl)phenyl]methyl]morpholine-4-carboxylate (Intermediate 18) [ka] tert-Butyl 2-[(2-bromo-3-chloro-phenyl)methyl]morpholine-4-carboxylate (1 g, 2.53 mmol, 1.04 equiv.) and 1-methyl-1H-pyrazole (1 equiv.) gave tert-butyl 2-[[3-chloro-2-(1-methylpyrazol-4-yl)phenyl]methyl]morpholine-4-carboxylate as a brown oil (125 mg, 13% yield). 1 H NMR (DMSO-d 6,400MHz): δ(ppm)7.75(s,1H),7.42-7.38(m,2H),7.34-7.25(m,2H),3.91(s,3H),3.73(dd,J=11.6,2.5Hz,1H),3.64(d,J=13.4Hz,1H),3.56(d,J =9.4Hz,1H),3.36(ddt,J=9.2,6.6,3.1Hz,1H),3.30-3.21(m,1H),2.82 (s,1H),2.65(d,J=6.3Hz,2H),2.50(s,1H),1.38(s,10H);m / z=392[M+H] +

[0442] Method D: Deprotection -N-Boc deprotection General Procedure D1: To a solution of the Boc-N product (1.00 equiv.) in DCM (0.2 M) was added 2,2,2-trifluoroacetic acid (15–20 equiv.). The reaction mixture was stirred at room temperature for 1–24 h. The reaction mixture was diluted with DCM, and a saturated aqueous solution of NaHCO3 was added. The two layers were separated, and the aqueous layer was extracted three times with DCM. The combined organic layers were dried over a phase separator and concentrated under reduced pressure. If necessary, the crude material was purified by flash chromatography using a gradient of MeOH in DCM to give the desired product. The product was isolated as the free amine or the tartrate salt.

[0443] Tartrate salt formation: (2{R},3{R})-2,3-dihydroxybutanedioic acid (0.50 equiv.) was dissolved in HO (3 mL) and the product in ACN (0.3 mL) was added. The residue was lyophilized overnight to give the desired product as the tartrate salt.

[0444] Example 113: (2R,3R)-2,3-Dihydroxybutanedioic acid; 2-fluoro-4-[2-(5-methylisothiazol-4-yl)-3-(morpholin-2-ylmethyl)phenyl]benzonitrile [ka] Tert-butyl 2-[[3-(4-cyano-3-fluorophenyl)-2-(5-methylisothiazol-4-yl)phenyl]methyl]morpholine-4-carboxylate (64 mg, 0.12 mmol) gave (2R,3R)-2,3-dihydroxybutanedioic acid 2-fluoro-4-[2-(5-methylisothiazol-4-yl)-3-(morpholin-2-ylmethyl)phenyl]benzonitrile as a white powder (41 mg, 40% yield). 1 H NMR (500MHz, DMSO-d6): δ(ppm)8.45-8.24(m,1H),7.80-7.74(m,1H),7.56-7.46(m,2H),7.37(dt,J=6.7,2. 1Hz,1H),7.24(ddd,J=10.6,4.0,1.5Hz,1H),7.06(ddd,J=8.0,4.7,1.7Hz,1H),3.76-3.71(m,1H),3.44(br d,J=2.7Hz,2H),2.87-2.77(m,1H),2.75-2.66(m,2H),2.63-2.53(m,1H),2.48-2.31(m,2H),2.05-1.93(m,3H)m / z=394[M+H]+

[0445] General Procedure D2: To a 0.1 M solution of the Boc-N product (1.00 equiv.) in DCM (2 M, 30.0 equiv.) was added HCl (2 M, 30.0 equiv.) in 1,4-dioxane or IPA. The reaction mixture was stirred at room temperature for 1-24 h. The reaction mixture was concentrated under reduced pressure to give the desired product as the HCl salt. If necessary, the crude material was purified by flash chromatography using a gradient of 0-10% MeOH in DCM. The same procedure as for D1 was used to prepare the tartrate salt from the free amine after workup with NaHCO3 / DCM.

[0446] Example 5: 4-[2-Isothiazol-5-yl-3-[[(2R)-morpholin-2-yl]methyl]phenyl]benzonitrile hydrochloride [ka] tert-Butyl (2R)-2-[[3-(4-cyanophenyl)-2-isothiazol-5-ylphenyl]methyl]morpholine-4-carboxylate (203 mg, 0.44 mmol) gave 4-[2-isothiazol-5-yl-3-[[(2R)-morpholin-2-yl]methyl]phenyl]benzonitrile hydrochloride as a beige solid (116 mg, 63% yield). 1 H NMR(600MHz,DMSO-d6):δ(ppm)2.64-2.73(m,3H)2.91(td,J=12.51,3.89Hz,1H)3.03(br d,J=12.32Hz,1H)3.11(br d,J=12.62Hz,1H)3.59(td,J=12.43,2.27Hz,1H)3.74-3.81(m,1H)3.89(dd,J=12.62,3.52Hz,1H)7.32-7.3 6(m,4H)7.50(d,J=7.19Hz,1H)7.56(t,J=7.70Hz,1H)7.71(d,J=8.22Hz,2H)8.49(d,J=1.61Hz,1H)8.99(br s,2H);m / z=362[M+H] +

[0447] -O-TBS deprotection General Procedure D3: To a solution of R-OTBS (1 equiv.) in anhydrous THF (0.1 M) was added tetrabutylammonium fluoride (1.3 equiv.) at 0°C under argon. The reaction mixture was stirred at room temperature for 12 h and then under reflux for an additional 12 h. Water and EtOAc were added. The aqueous layer was extracted with EtOAc (x3). The combined organic layers were dried using a phase separator and concentrated under reduced pressure. The crude material was purified by flash chromatography using a gradient of 0-10% MeOH in DCM to give the desired product.

[0448] Synthesis of tert-butyl 2-[[3-(4-cyano-3-fluorophenyl)-4-(4-hydroxy-4-methyl-1-piperidyl)phenyl]methyl]morpholine-4-carboxylate (Intermediate 19) [ka] Tert-butyl 2-[[4-[4-[tert-butyl(dimethyl)silyl]oxy-4-methyl-1-piperidyl]-3-(4-cyano-3-fluorophenyl)phenyl]methyl]morpholine-4-carboxylate (64 mg, 0.10 mmol) gave tert-butyl 2-[[3-(4-cyano-3-fluorophenyl)-4-(4-hydroxy-4-methyl-1-piperidyl)phenyl]methyl]morpholine-4-carboxylate as a white solid (30 mg, 58% yield). 1 H NMR(400MHz,DMSO-d6):δ(ppm)7.95(m,1H),7.83-7.78(m,1H),7.73-7.68(m,1H),7.2 2(dd,J=8.3,2.1Hz,1H),7.17(d,J=2.1Hz,1H),7.08(d,J=8.2Hz,1H),4.18(s,1H),3. 81-3.70(m,2H),3.70-3.64(m,1H),3.55-3.46(m,1H),3.37-3.32(m,1H),2.88-2.78( m,3H),2.72-2.52(m,5H),1.42-1.38(m,4H),1.36(s,9H),1.10(s,3H);m / z=510[M+H]+

[0449] -N-PMB deprotection General Procedure D4: To a solution of CAN (6 equiv.) in ACN / water (0.05 M) was added (R2)N-PMB in ACN at 0°C. The reaction mixture was stirred at room temperature for 1 h 20 min. CAN was evaporated, and the mixture was extracted with EtOAc. The combined organic layers were dried using a phase separator and concentrated under reduced pressure. The crude was purified by flash chromatography using a gradient of 0-10% MeOH in DCM to give the desired product.

[0450] Synthesis of 2-[(3-bromo-4-iodo-5-methyl-phenyl)methyl]morpholin-3-one (Intermediate 20) [ka] 2-[(3-Bromo-4-iodo-5-methylphenyl)methyl]-4-[(4-methoxyphenyl)methyl]morpholin-3-one (796 mg, 1.08 mmol) gave 2-[(3-bromo-4-iodo-5-methylphenyl)methyl]morpholin-3-one as a white solid (342 mg, 75% yield). 1 H NMR(400MHz,DMSO-d6):δ(ppm)7.99(s,1H),7.42(d,J=1.9Hz,1H),7.19(d,J=2.0Hz,1H),4.24(dd,J=8.6,3.5Hz,1H),3.94-3.83(m,1H),3. 60(ddd,J=11.8,9.9,3.6Hz,1H),3.23(td,J=11.2,4.3Hz,1H),3.18-3.03(m,2H),2.83(dd,J=14.4,8.6Hz,1H),2.47(s,3H);m / z=411[M+H]+

[0451] -N-CBz deprotection General Procedure D5: A sealed vial was charged with RN-CBz (1 equivalent) and ammonium formate (10 equivalents) in IPA (0.12 M) and water (1% v). The reaction mixture was degassed with nitrogen for 10 minutes, palladium (10%, 0.25 equivalents) was added under argon, and the reaction mixture was stirred at 60 °C for 5 hours. The reaction mixture was cooled to room temperature and filtered through a pad of Celite, washing with IPA. The filtrate was concentrated under reduced pressure to give the expected compound.

[0452] Synthesis of 5-(azetidin-3-yl)-2-methoxy-pyridine (intermediate 21) [ka] Benzyl 3-(6-methoxy-3-pyridyl)azetidine-1-carboxylate (370 mg, 1.24 mmol) gave 5-(azetidin-3-yl)-2-methoxypyridine as a beige solid (148 mg, purity 90, yield 65%). 1 H NMR (400MHz, DMSO-d6): δ(ppm)8.38(s,1H),8.12(d,J=2.5Hz,1H),7.85(dd,J=8.5,2.5Hz,1H),6.84(d,J=8.6Hz,1H),4.05-3.76(m,7H).

[0453] General Procedure D6: To a stirred solution of (R2)N-PMB in toluene (0.10 M) was added methanesulfonic acid (5 equiv.) under N2 at room temperature. The reaction mixture was stirred at 120 °C for 2 h. The reaction mixture was basified with a saturated aqueous solution of NaHCO3 and DCM was added. The phases were separated and the aqueous phase was extracted with DCM (3 times). The reaction mixture was concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel using a gradient of 0% to 100% EtOAc in heptane to give the desired compound.

[0454] Synthesis of 3-[(2-bromo-3-chloro-phenyl)methyl]piperidin-2-one (Intermediate 22) [ka] 3-[(2-Bromo-3-chlorophenyl)methyl]-1-[(4-methoxyphenyl)methyl]piperidin-2-one (250 mg, 0.59 mmol) gave 3-[(2-bromo-3-chlorophenyl)methyl]piperidin-2-one as a white solid (131 mg, 73% yield). 1 H NMR(400MHz,DMSO-d6):δ(ppm)7.57-7.43(m,2H),7.41-7.23(m,2H),3.49(dd,J=13.6,4.4Hz,1H),3.12(t,J=6.1Hz,2H),2. 72(dd,J=13.6,10.5Hz,1H),2.54(d,J=4.7Hz,1H),1.82-1.67(m,1H),1.67-1.47(m,2H),1.47-1.29(m,1H).;m / z=304[M+H]+

[0455] Method E: Halogenation General Step E1: Aromatic bromination NH2 derivative To a 0.2 M solution of the aminoaryl product (1.00 equiv.) in DCM under a N atmosphere was added NBS (1–2 equiv.) at 0° C. or room temperature. The reaction mixture was stirred at the same temperature for 2 h, quenched with saturated aqueous NaHCO3, and extracted three times with DCM. The combined organic layers were dried over a phase separator and concentrated under reduced pressure. The crude material was purified by flash chromatography using a gradient of EtOAc in heptane to give the desired product.

[0456] Synthesis of tert-butyl 2-[[3-bromo-4-(4-pyrimidin-2-yl-1-piperidyl)phenyl]methyl]morpholine-4-carboxylate (Intermediate 23) [ka] tert-Butyl 2-[[4-(4-pyrimidin-2-yl-1-piperidyl)phenyl]methyl]morpholine-4-carboxylate (246 mg, 0.56 mmol) gave tert-butyl 2-[[3-bromo-4-(4-pyrimidin-2-yl-1-piperidyl)phenyl]methyl]morpholine-4-carboxylate as a yellow solid (254 mg, 80% yield). 1 H NMR(400MHz,DMSO-d6):δ(ppm)8.77(d,J=4.9Hz,2H),7.48(d,J=2.0Hz,1H),7.36 (t,J=4.9Hz,1H),7.21(dd,J=8.2,2.0Hz,1H),7.12(d,J=8.2Hz,1H),3.84-3.60( m,5H),3.52-3.42(m,2H),2.96(dt,J=10.3,5.2Hz,1H),2.93-2.74(m,4H),2.67( d,J=6.0Hz,3H),2.00(td,J=11.1,10.2,4.8Hz,4H),1.38(s,9H).;m / z=519[M+H]+

[0457] Alternatively, bromination (NBS) or chlorination (NCS) can be carried out in DMF at 80-100° C. for 30 minutes to 3 hours.

[0458] Synthesis of tert-butyl 2-[[4-(3-chloro-2-methyl-indazol-5-yl)-3-(4-cyano-3-fluoro-phenyl)phenyl]methyl]morpholine-4-carboxylate (Intermediate 24) [ka] tert-Butyl 2-[[3-(4-cyano-3-fluorophenyl)-4-(2-methylindazol-5-yl)phenyl]methyl]morpholine-4-carboxylate (11 mg, 0.0209 mmol) was dissolved in anhydrous DMF (1 mL). The reaction mixture was degassed under N2, and then 1-chloropyrrolidine-2,5-dione (3.1 mg, 0.0230 mmol) was added. The reaction mixture (RM) was stirred at 100 °C for 2 h 30 min and then concentrated under reduced pressure. The crude material was purified by flash column chromatography on silica gel using a MeOH gradient from 0% to 0.5% to afford the desired product as a white solid (4 mg, 34% yield). 1 H NMR(400MHz,DMSO-d6):δ(ppm)7.80-7.71(m,1H),7.51-7.34(m,6H),7.10(dd,J=8.1,1.5Hz,1H),6.89(dd,J=8.9,1.7Hz,1H),4.12(s,3H), 3.80(d,J=8.7Hz,2H),3.65(dd,J=29.0,10.1Hz,2H),3.37(td,J=11.5,2.7Hz,1H),2.85(q,J=6.7,5.2Hz,4H),1.38(s,9H);m / z=562[M+H]+

[0459] -Use DAST General Procedure E2: To a solution of the aldehyde (1.00 equiv.) in DCM (0.1 M) was added DAST (3 equiv.) under a N atmosphere at 0°C. The reaction mixture was allowed to warm to room temperature and stirred at room temperature for 2-5 h. The reaction mixture was concentrated under reduced pressure, and the crude material was purified by silica gel flash chromatography (using a gradient of EtOAc in heptane) to give the desired product.

[0460] Synthesis of tert-butyl 2-[[3-chloro-4-[4-(difluoromethyl)-1-piperidyl]phenyl]methyl]morpholine-4-carboxylate (Intermediate 25) [ka] tert-Butyl 2-[[3-chloro-4-(4-formyl-1-piperidyl)phenyl]methyl]morpholine-4-carboxylate (300 mg, 0.71 mmol) gave tert-butyl 2-[[3-chloro-4-[4-(difluoromethyl)-1-piperidyl]phenyl]methyl]morpholine-4-carboxylate as a yellow oil (139 mg, 41% yield). 1 H NMR(400MHz,DMSO-d6):δ(ppm)7.30(d,J=2.0Hz,1H),7.16(dd,J=8.2,2.0Hz,1 H),7.07(d,J=8.2Hz,1H),5.99(td,J=56.8,4.6Hz,1H),3.92-3.58(m,3H),3.55 -3.40(m,1H),3.31(m,4H),2.85(s,1H),2.74-2.55(m,4H),1.98-1.85(m,1H),1 .78(d,J=12.2Hz,2H),1.55(qd,J=12.4,4.0Hz,2H),1.38(s,9H).;m / z=445[M]+

[0461] -Use NFSI General Procedure E3: A solution of Ar-H (1.00 equiv.) in THF (0.06 M) was degassed with N (bubbling for 5 min) and then cooled to -78 °C. A 1.3 M solution of LiHMDS (2 equiv.) was added dropwise, and the mixture was stirred at -78 °C for 1 h. NFSI (2 equiv.) was added, and the mixture was stirred at -78 °C for 1 h, then warmed to room temperature and stirred for 12 h. The reaction mixture was quenched with saturated aqueous NH4Cl and extracted with MeTHF (2 x). The combined organic layers were dried through a phase separator and evaporated under reduced pressure. The crude material was purified by flash chromatography on silica gel using a gradient of EtOAc in cyclohexane to give the desired product.

[0462] Synthesis of tert-butyl rel-(2R)-2-[[3-chloro-2-(4-fluorooxazol-5-yl)phenyl]methyl]morpholine-4-carboxylate (Intermediate 26) [ka] tert-Butyl rel-(2R)-2-[(3-chloro-2-oxazol-5-ylphenyl)methyl]morpholine-4-carboxylate (596 mg, 1.55 mmol) gave tert-butyl rel-(2R)-2-[[3-chloro-2-(4-fluorooxazol-5-yl)phenyl]methyl]morpholine-4-carboxylate as a yellow oil (283 mg, 41% yield). 1 H NMR(400MHz,DMSO-d6)δ(ppm)8.53(d,J=2.1Hz,1H),7.59-7.50(m,2H),7.47(dd,J=5.4,3.7Hz,1H),3.77- 3.58(m,4H),3.26(td,J=11.6,2.8Hz,1H),2.80(s,1H),2.72-2.61(m,2H),1.37(s,9H);m / z=340[M-tBu]+

[0463] -Alkyl bromides from alcohols (Appel) General Procedure E4: To a solution of R-OH (1.00 equiv.) in DCM (0.07 M) was added triphenylphosphane (1.1 equiv.) and carbon tetrabromide (1.1). The mixture was stirred at room temperature for 1 hour and 30 minutes. DCM was added and the mixture was washed with brine. The organic layer was concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel (using a gradient of 0-100% EtOAc in cyclohexane) to give the desired product.

[0464] Synthesis of 1-bromo-5-(bromomethyl)-2-iodo-3-methyl-benzene (intermediate 27) [ka] (3-Bromo-4-iodo-5-methyl-phenyl)methanol (2.47 g, 7.5 mmol) gave 1-bromo-5-(bromomethyl)-2-iodo-3-methyl-benzene as a white solid (2.19 g, 75% yield). 1 H NMR(400MHz,DMSO-d6)δ(ppm)7.65(d,J=2.1Hz,1H),7.39(d,J=2.3Hz,1H),4.62(s,2H),2.50(s,3H);m / z=310[M-Br]+

[0465] Method F: Reduction General Procedure F1: Under a nitrogen atmosphere, NaBH4 (2-6 equiv.) was added to a solution of the ester (1.00 equiv.) in anhydrous MeOH (0.1 M) at 0 °C. The reaction mixture was stirred at room temperature for 1 h. Brine and DCM were added. The two layers were separated, and the aqueous layer was extracted three times with DCM. The combined organic layers were dried over a phase separator and concentrated under reduced pressure. The crude material was purified by flash chromatography (EtOAc in heptane) to give the desired product.

[0466] Synthesis of tert-butyl 2-[[3-chloro-4-[3-(hydroxymethyl)azetidin-1-yl]phenyl]methyl]morpholine-4-carboxylate (Intermediate 28) [ka] tert-Butyl 2-[[3-chloro-4-(3-methoxycarbonylazetidin-1-yl)phenyl]methyl]morpholine-4-carboxylate (100 mg, 0.21 mmol) gave tert-butyl 2-[[3-chloro-4-[3-(hydroxymethyl)azetidin-1-yl]phenyl]methyl]morpholine-4-carboxylate as a colorless oil (70 mg, 81%). 1 H NMR(DMSO-d6,400MHz)δ(ppm)7.10(d,J=1.9Hz,1H),7.02(dd,J=8.3,2.0Hz, 1H),6.51(d,J=8.3Hz,1H),4.71(t,J=5.3Hz,1H),4.18-3.85(m,3H),3.84-3. 61(m,5H),3.57(dd,J=6.4,5.3Hz,2H),3.45-3.32(m,2H),2.85(s,1H),2.69 (tt,J=7.8,5.9Hz,1H),2.60(d,J=6.2Hz,2H),1.38(s,9H).;m / z=397[M+H]+.

[0467] General Step F2: Under a nitrogen atmosphere, a 4M solution of LiBH4 (1-2 equiv.) was added dropwise to a solution of the ester (1.00 equiv.) in anhydrous THF (0.1 M) at 0 °C. The reaction mixture was stirred at 0 °C for 1 h and then at room temperature for 12 h. The reaction mixture was quenched with a saturated aqueous solution of NH4Cl, and DCM was added. The phases were separated, and the aqueous phase was extracted three times with DCM. The combined organic layers were dried using a phase separator and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel (using a gradient of EtOAc in cyclohexane) to give the desired product.

[0468] Synthesis of tert-butyl 2-[[3-chloro-4-[4-(hydroxymethyl)-1-piperidyl]phenyl]methyl]morpholine-4-carboxylate (Intermediate 29) [ka] tert-Butyl 2-[[3-chloro-4-(4-methoxycarbonyl-1-piperidyl)phenyl]methyl]morpholine-4-carboxylate (280 mg, 0.57 mmol) gave tert-butyl 2-[[3-chloro-4-[4-(hydroxymethyl)-1-piperidyl]phenyl]methyl]morpholine-4-carboxylate as a colorless oil (270 mg, quantitative). 1 H NMR (DMSO-d6,400MHz): δ(ppm)7.28(d,J=2.0Hz,1H),7.14(dd,J=8.2,2.0Hz,1H),7.06(d,J=8 .2Hz,1H),4.47(t,J=5.3Hz,1H),3.83-3.62(m,3H),3.46(dtd,J=9.1,6.5,2.5Hz,1H),3.31(m, 3H),3.23(d,J=11.5Hz,2H),2.85(s,1H),2.66(d,J=6.5Hz,2H),2.58(t,J=12.6,10.2Hz,3H), 1.80-1.69(dd,2H),1.55-1.42(m,1H),1.38(s,9H),1.29(m,J=12.1,3.8Hz,2H);m / z=425[M]+.

[0469] General Step F3: Under a nitrogen atmosphere, 1 M borane tetrahydrofuran (2.9 equiv.) or LiAlH4 was added dropwise to a solution (0.1 M) of the amide / lactam (1 equiv.) in anhydrous THF at 0 °C. The reaction mixture was stirred at room temperature for 1.5 h. Once the formation of the borane complex was observed, the mixture was quenched with MeOH and concentrated. The residue was diluted with MeOH, NaOH 1 M (2 equiv.) was added, and the mixture was stirred at 80 °C for 2 h. The mixture was concentrated, and water and DCM were added. The mixture was extracted with DCM, the phases were separated, and the combined organic layers were concentrated. The crude material was purified by flash chromatography on silica gel (using a gradient of EtOAc in heptane) to give the desired product.

[0470] Synthesis of rac-(8aS)-3-[(4-bromo-3-chloro-phenyl)methyl]-3,4,6,7,8,8a-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazine (Intermediate 30) [ka] rac-(8aS)-3-[(4-Bromo-3-chlorophenyl)methyl]-6,7,8,8a-tetrahydro-1H-pyrrolo[2,1-c][1,4]oxazin-4-one (200 mg, 0.58 mmol) gave rac-(8aS)-3-[(4-bromo-3-chlorophenyl)methyl]-3,4,6,7,8,8a-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazine as a colorless oil (120 mg, 61%). 1 H NMR (DMSO-d6,400MHz): δ(ppm)7.28(d,J=2.0Hz,1H),7.14(dd,J=8.2,2.0Hz,1 H),7.06(d,J=8.2Hz,1H),3.82-3.63(m,3H),3.46(dtd,J=9.1,6.5,2.5Hz,1H) ,3.38-3.32(m,1H),3.23(d,J=11.3Hz,2H),2.58(dd,J=12.6,10.2Hz,2H),1.7 9-1.69(m,2H),1.58-1.45(m,1H),1.32(td,J=12.1,3.7Hz,2H);m / z=425[M]+.

[0471] General Step F4: Under a nitrogen atmosphere, 1 M diisobutylalmane (3 equiv.) was added dropwise to a solution (0.1 M) of the ester (1 equiv.) in anhydrous THF at 0° C. The reaction mixture was stirred at room temperature for 30 minutes. Methanol was added at 0° C., and the reaction mixture was concentrated under reduced pressure. EtOAc was added, and the solution was washed with a saturated aqueous solution of Rochelle's salt. The organic layer was concentrated, and the crude material was purified by flash chromatography on silica gel (using a gradient of EtOAc in heptane) to give the desired product.

[0472] Synthesis of (3-bromo-4-iodo-5-methyl-phenyl)methanol (Intermediate 31) [ka] Methyl 3-bromo-4-iodo-5-methylbenzoate (100 mg, 0.28 mmol) gave (3-bromo-4-iodo-5-methylphenyl)methanol as a white solid (83 mg, 90% yield). 1 H NMR (DMSO-d6,400MHz):δ(ppm)7.48(dd,J=2.0,0.8Hz,1H),7.24(dq,J=1.5,0.7Hz,1H),4.42(dt,J=5.8,0.8Hz,2H),2.49(s,3H);m / z=327.9[M+H] + .

[0473] General Step F5: A vial under argon was sequentially charged with the alcohol (1 equiv.) and di(imidazol-1-yl)methanethione (2 equiv.) in anhydrous THF (0.05 M). The reaction mixture was stirred at 75 °C for 12 h and then concentrated under reduced pressure. The crude product was diluted with anhydrous toluene (0.05 M), and 1,1,1,3,3,3-hexamethyl-2-(trimethylsilyl)trisilane (3 equiv.) and AIBN (0.1 equiv.) were added. The reaction mixture was stirred at 110 °C for 2 h, cooled to room temperature, and argon was bubbled through for 5 min. Additional TTMSS (3 equiv.) and AIBN (0.1 equiv.) were added, and the mixture was stirred at 110 °C for 1 h. The reaction mixture was cooled to room temperature, quenched with water (15 mL), and DCM (15 mL) was added. The phases were separated, and the aqueous phase was extracted with DCM (3 times). The combined organic layers were dried using a phase separator and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel using a gradient of 0-100% EtOAc in cyclohexane to give the desired compound.

[0474] Synthesis of 5-[2-chloro-6-(tetrahydropyran-4-ylmethyl)phenyl]isothiazole (Intermediate 32) [ka] (3-Chloro-2-isothiazol-5-yl-phenyl)-tetrahydropyran-4-yl-methanol (150 mg, 0.45 mmol) gave 5-[2-chloro-6-(tetrahydropyran-4-ylmethyl)phenyl]isothiazole as a pale yellow oil (40 mg, 25% yield). 1 H NMR (DMSO-d6,400MHz): δ(ppm)8.71(d,J=1.7Hz,1H),7.56-7.06(m,4H),3.75(dd,J=11.9,4.0Hz,2H),3.15(td,J=11.7,2.1Hz ,2H),2.37(d,J=7.1Hz,2H),1.59(ddt,J=11.3,7.7,3.9Hz,1H),1.36-1.24(m,2H),1.08(qd,J=12.0,4.5Hz,2H);m / z=420[M+H] + .

[0475] Method G: O / N-Alkyl Formation General Procedure G0: N-Alkylation A sealed vial was charged with R-Br or epoxide (1 equiv.) and an amine was added (2-10 equiv.). The reaction mixture was stirred at room temperature for 12 h. Water was added and the aqueous layer was extracted three times with DCM. The combined organic layers were washed with brine, dried on a phase separator, and concentrated under reduced pressure to give the expected product.

[0476] Synthesis of 1-[3-chloro-4-(3-pyridyloxymethyl)phenyl]-3-(2-hydroxyethylamino)propan-2-ol (Intermediate 33) [ka] 1-Bromo-3-[3-chloro-4-(3-pyridyloxymethyl)phenyl]propan-2-ol (275 mg, 0.77 mmol) and 2-aminoethanol (462 μL, 7.7 mmol, 10 equivalents) gave 1-[3-chloro-4-(3-pyridyloxymethyl)phenyl]-3-(2-hydroxyethylamino)propan-2-ol as a beige solid (239 mg, 87% yield). m / z=337 [M+H] + .

[0477] General Procedure G1: O-Alkylation Under a nitrogen atmosphere, NaH (1-2 equiv.) was added to a solution of 1 equiv. of alcohol in anhydrous THF (0.1 M) at 0°C. The reaction mixture was stirred at room temperature for 20 min, after which 1 equiv. of halide was added. The reaction mixture was stirred at room temperature for 1-2 h. Water and EtOAc were added. The two layers were separated, and the aqueous layer was extracted three times with EtOAc. The combined organic layers were dried through a phase separator and concentrated under reduced pressure. If necessary, the crude material was purified by flash chromatography (EtOAc in heptane) to give the desired product.

[0478] Synthesis of tert-butyl 2-[[3-chloro-4-[3-(methoxymethyl)isoxazol-5-yl]phenyl]methyl]morpholine-4-carboxylate (Intermediate 34) [ka] tert-Butyl 2-[[3-chloro-4-[3-(hydroxymethyl)isoxazol-5-yl]phenyl]methyl]morpholine-4-carboxylate (115 mg, 0.27 mmol) and iodomethane (38 mg, 0.27 mmol) gave tert-butyl 2-[[3-chloro-4-[3-(methoxymethyl)isoxazol-5-yl]phenyl]methyl]morpholine-4-carboxylate as a colorless oil (118 mg, quantitative) without purification. 1H NMR (DMSO-d6,400MHz): δ(ppm)7.83(d,J=8.0Hz,1H),7.58(d,J=1.6Hz,1H),7.42(dd,J=8.1,1.7Hz,1H),7.03(s,1H),4.56(s,2H),3.86-3.74(m,2 H),3.69(d,J=13.2Hz,1H),3.63-3.51(m,1H),3.36(s,3H),3.36(t,1H), 2.98-2.72(m,2H),2.73-2.55(m,2H),1.40(s,9H).;m / z=367[M+H-tBu]+.

[0479] General Procedure G2: Mitsunobu / Kakuta Under a nitrogen atmosphere, CMBP (Tsunoda's reagent) (2.00 equiv.) was added to a toluene solution (0.07 M) of Ar-OH (1.00 equiv.) and R-OH (1.10 equiv.). The reaction mixture was stirred at 100 °C for 2 h. The reaction mixture was quenched with a saturated aqueous solution of NaHCO3, and EtOAc was added. The two layers were separated, the aqueous layer was extracted with EtOAc (x3), and the combined organic layers were dried using a phase separator and concentrated under reduced pressure. The crude product was purified using a flash chromatography column (EtOAc in heptane) to give the desired product.

[0480] Synthesis of tert-butyl 2-[(3-chloro-4-{[(3R)-oxan-3-yl]methoxy}phenyl)methyl]morpholine-4-carboxylate (Intermediate 35) [ka] tert-Butyl 2-[(3-chloro-4-hydroxyphenyl)methyl]morpholine-4-carboxylate (71 mg, 0.22 mmol) and (3S)-oxan-3-ylmethanol (28 mg, 0.24 mmol) gave tert-butyl 2-[[3-chloro-4-[[rac-(3R)-tetrahydropyran-3-yl]methoxy]phenyl]methyl]morpholine-4-carboxylate as a colorless oil (82 mg, 89% yield). 1H NMR(DMSO-d6,400MHz)δ 7.30(d,J=2.1Hz,1H),7.14(dd,J=8.4,2.1Hz,1H),7.05(d,J=8.5Hz,1H) ,3.96-3.85(m,3H),3.82-3.58(m,4H),3.50-3.41(m,1H),3.39-3.32(m,2 H),3.30-3.24(m,2H),2.84(s,1H),2.65(d,J=6.6Hz,2H),2.08-1.95(m,1 H),1.90-1.80(m,1H),1.65-1.39(m,3H),1.37(s,9H);m / z=326[M-Boc]+.

[0481] General Procedure G3: Mitsunobu using DIAD / PPH3 To a solution (0.1 M) of diol (or alcohol 1 and alcohol 2) (1 equivalent) in anhydrous toluene, triphenylphosphane (1.2 equivalents) and isopropyl (N{E})-N-isopropoxycarbonyliminocarbamate (1.2 equivalents) were added. The reaction mixture was stirred at room temperature for 1-12 hours and then concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel (0-100% EtOAc in heptane) to give the expected compound. See the synthesis in Example BB-1.

[0482] General Procedure G4: N-Alkylation To a solution of amine (1 equiv.) in anhydrous DMF (0.1 M) in a microwave vial, K2CO3 (3 equiv.) and RX (10 equiv.) were added sequentially. The mixture was stirred under microwave irradiation at 110 °C for 1 h. The mixture was diluted with EtOAc, and water was added. The aqueous layer was extracted with EtOAc, and the combined organic layers were washed with water and then brine, filtered through a phase separator, and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel (using a gradient of EtOAc in cyclohexane) to give the desired product.

[0483] Synthesis of tert-butyl 2-[[3-chloro-4-[methyl-[[(3R)-tetrahydropyran-3-yl]methyl]amino]phenyl]methyl]morpholine-4-carboxylate (Intermediate 36) [ka] Tert-butyl 2-[[3-chloro-4-[[(3R)-tetrahydropyran-3-yl]methylamino]phenyl]methyl]morpholine-4-carboxylate (196 mg, 0.461 mmol) and iodomethane (287 uL, 4.61 mmol) gave tert-butyl 2-[[3-chloro-4-[methyl-[[(3R)-tetrahydropyran-3-yl]methyl]amino]phenyl]methyl]morpholine-4-carboxylate as a colorless oil (170 mg, 84% yield). 1 H NMR(DMSO-d6,400MHz)δ 7.30-7.27(m,1H),7.15(d,J=1.1Hz,2H),3.86-3.59(m,5H),3.52-3.43(m,1H),3.39-3.23(m,2H),3.07(dd,J=11.2,9.0Hz,1H),2.93 -2.73(m,3H),2.66(d,J=6.6Hz,2H),2.63(s,3H),1.81-1.62(m,3H),1.57-1.41(m,1H),1.37(s,9H),1.26-1.11(m,2H);m / z=439[M]+.

[0484] General Procedure G5: O-Arylation / N-Arylation To a solution of alcohol or amine (1 equiv.) in anhydrous DMF or DMA (0.05 M) was added Ar-Br (2 equiv.) and CsCO (5 equiv.). The reaction mixture was degassed under N, and copper iodide (0.2 equiv.) was added, followed by 1,10-phenanthroline (2 equiv.) for amine coupling. The reaction mixture was stirred at 100 °C for 12 h or up to 180 °C (with DMA in a sealed vial). If necessary, additional reagents were added, and the mixture was stirred at 100 °C for an additional 12 h. The mixture was filtered through decalite, washed with ethyl acetate, and the filtrate was concentrated under reduced pressure. The crude material was purified by flash column chromatography on silica gel using a gradient of 0% to 100% EtOAc in heptane to give the desired product.

[0485] Synthesis of tert-butyl 2-[[3-chloro-4-[(2-methyl-4-pyridyl)oxy]phenyl]methyl]morpholine-4-carboxylate (Intermediate 37) [ka] tert-Butyl 2-[(3-chloro-4-hydroxyphenyl)methyl]morpholine-4-carboxylate (50 mg, 0.15 mmol) and 4-bromo-2-methylpyridine (53 mg, 0.305 mmol) gave tert-butyl 2-[[3-chloro-4-[(2-methyl-4-pyridyl)oxy]phenyl]methyl]morpholine-4-carboxylate as a colorless oil (23 mg, 36% yield). 1 H NMR(DMSO-d6,400MHz)δ 8.32(d,J=5.6Hz,1H),7.56(d,J=1.9Hz,1H),7.34(dd,J=8.3,2.0Hz,1H),7.26(d,J=8.3Hz,1H),6.73(d,J=2.4Hz,1H),6.64(d,J=3.4H) m / z=419[M+H] + .

[0486] General Procedure G6: Reductive Amination To a solution of amine (1 equiv.) in 10 / 1 MeOH / AcOH (0.1 M) was added an aldehyde or ketone (1–20 equiv.). The mixture was stirred for 5 min, and then supported sodium cyanoborohydride (117 mg, 0.235 mmol) was added. The mixture was stirred at room temperature for 2–12 h. The resin was filtered, washed with ethyl acetate, and the filtrate was concentrated. The residue was dissolved in EtOAc and washed with saturated aqueous bicarbonate. The aqueous phase was extracted (×3), and the combined organic layers were filtered through a separatory filter and concentrated under reduced pressure. If necessary, the crude material was purified by flash column chromatography on silica gel using a gradient of 0% to 100% EtOAc in heptane to give the desired product.

[0487] Synthesis of 4-[2-(azetidin-1-yl)-5-[(4-isopropylmorpholin-2-yl)methyl]phenyl]-2-fluorobenzonitrile (Intermediate 38) [ka] 4-[2-(azetidin-1-yl)-5-(morpholin-2-ylmethyl)phenyl]-2-fluorobenzonitrile (28 mg, 0.078 mmol) and propanone (0.116 mL, 1.56 mmol) gave 4-[2-(azetidin-1-yl)-5-[(4-isopropylmorpholin-2-yl)methyl]phenyl]-2-fluorobenzonitrile as a colorless oil (10.6 mg, 32% yield). 1 H NMR(DMSO-d6,400MHz)δ 7.93(dd,J=8.0,7.1Hz,1H),7.51(dd,J=10.7,1.5Hz,1H),7.43(dd,J=8.0 ,1.5Hz,1H),7.14(dd,J=8.3,2.1Hz,1H),6.98(d,J=2.1Hz,1H),6.56(d,J= 8.3Hz,1H),3.85-3.61(m,1H),3.61-3.36(m,6H),2.75-2.53(m,5H),2.27- 2.03(m,3H),2.03-1.81(m,1H),0.94(dd,J=6.5,3.8Hz,6H);m / z=394[M+H]+ .

[0488] General Procedure G7: O-Arylation A microwave vial was charged with Ar-Br (1 equiv.), copper bromide (0.5 equiv.), sodium methanolate (25 equiv.), and ethyl acetate (1.72 M). The reaction mixture was stirred under microwave irradiation at 120° C. for 30 minutes. The reaction mixture was quenched with water, and the resulting suspension was filtered and washed with methanol. The filtrate was concentrated under reduced pressure, and EtOAc was added. The aqueous layer was extracted with EtOAc (×3). The combined organic layers were dried using a phase separator and concentrated under reduced pressure. The crude material was purified by flash column chromatography on silica gel (using a gradient of 0% to 100% EtOAc in heptane) to give the desired product.

[0489] Synthesis of tert-butyl 2-[(3-chloro-4-methoxyphenyl)methyl]morpholine-4-carboxylate (Intermediate 39) [ka] tert-Butyl 2-[(4-bromo-3-chlorophenyl)methyl]morpholine-4-carboxylate (250 mg, 0.64 mmol) and sodium methanolate (3.7 mL, 16 mmol) gave tert-butyl 2-[(3-chloro-4-methoxyphenyl)methyl]morpholine-4-carboxylate as a colorless oil (67 mg, 27.6% yield). 1 H NMR(DMSO-d6,400MHz)δ 7.31(d,J=2.1Hz,1H),7.17(dd,J=8.4,2.2Hz,1H),7.06(d,J=8.4Hz,1H),3.83(s,3H),3.81-3.60(m,3H),3. 49-3.43(m,1H),3.34(dd,J=11.6,2.8Hz,3H),2.85(s,1H),2.66(d,J=6.5Hz,2H),1.38(s,6H);m / z=242[M+H] + -Boc.

[0490] General Procedure G8: Epoxide Ring Opening with Hydrides Under an argon atmosphere, 1 M lithium triethyl hydride (5 equiv.) was added dropwise to a solution of epoxide (1 equiv.) in anhydrous THF at 0°C. The mixture was stirred for 5 min, and supported sodium cyanoborohydride (117 mg, 0.235 mmol) was added. The reaction mixture was stirred at 50°C for 4-12 h. If necessary, additional LiEtBH was added. The reaction mixture was quenched with water, and EtOAc was added. The aqueous layer was extracted with EtOAc (x3). The combined organic layers were dried using a phase separator and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel using a gradient of 5% to 50% DCM:NH3 (9:1) in DCM to give the desired product.

[0491] Synthesis of 4-[(3-chloro-2-cyclopropyl-phenyl)methyl]-1-methyl-piperidin-4-ol (Intermediate 40) [ka] tert-Butyl 2-(3-chloro-2-cyclopropylphenyl)-1-oxa-6-azaspiro[2.5]octane-6-carboxylate (50 mg, 0.13 mmol) gave 4-[(3-chloro-2-cyclopropylphenyl)methyl]-1-methylpiperidin-4-ol as a colorless oil (15 mg, 36.7% yield). 1 H NMR(DMSO-d6,400MHz)δ 7.22(ddd,J=8.7,7.7,1.5Hz,2H),7.19-7.07(m,1H),4.08(s,1H),3.00(s,2H),2.38(d,J=11.1Hz,2H),2.17(t,J=10.6Hz,2H),2.10(s, m / z=280[M] + .

[0492] Method H: Oxidation -Epoxidation General Procedure H0: To a solution of alkene (1 equiv.) in DCM (0.1 M) in a round-bottom flask was added m-CPBA (1.5 equiv.). The mixture was stirred at room temperature for 12 h. Saturated aqueous NaSO and DCM were added. The aqueous layer was extracted with DCM (x3). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel (using a gradient of EtOAc in cyclohexane) to give the desired product.

[0493] For an example, see the synthesis of BB-1.

[0494] -Oxidation of alcohols to aldehydes or ketones General Procedure H1: DMP To a stirred solution of the aldehyde (1 equiv.) in anhydrous DCM (0.1 M) at room temperature under argon, Dess-Martin periodinane (95%, 1.3 equiv.) in anhydrous DCM (0.1 M) was added over 10 min using an addition funnel under argon. The reaction mixture was stirred at room temperature for 4 h. The reaction mixture was quenched with a saturated aqueous solution of NaSO, basified with a saturated aqueous solution of NaHCO, and DCM was added. The layers were separated, and the aqueous phase was extracted with DCM (4 times). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel using a gradient of EtOAc in cyclohexane to give the desired product.

[0495] Synthesis of tert-butyl 2-[[3-chloro-4-(4-formyl-1-piperidyl)phenyl]methyl]morpholine-4-carboxylate (Intermediate 41) [ka] tert-Butyl 2-[[3-chloro-4-[4-(hydroxymethyl)-1-piperidyl]phenyl]methyl]morpholine-4-carboxylate (876 mg, 2.06 mmol) gave tert-butyl 2-[[3-chloro-4-(4-formyl-1-piperidyl)phenyl]methyl]morpholine-4-carboxylate as a yellow solid (645 mg, 74% yield). 1 H NMR(DMSO-d6,400MHz)δ 7.93(dd,J=8.0,7.1Hz,1H),7.51(dd,J=10.7,1.5Hz,1H),7.42(dd,J=8.0,1.5Hz,1H ),7.13(dd,J=8.3,2.1Hz,1H),6.97(d,J=2.1Hz,1H),6.56(d,J=8.3Hz,1H),3.77-3.7 0(m,1H),3.55-3.48(m,1H),3.43(t,J=7.3Hz,4H),3.41-3.34(m,1H),2.68-2.52(m, 5H),2.20-2.03(m,3H),1.97-1.89(m,1H),0.94(dd,J=6.5,3.8Hz,6H);m / z=423[M]+.

[0496] General Procedure H2: Oxidative Cleavage A 500 mL round-bottom flask was charged sequentially with alkene (1 equiv.), 2,6-dimethylpyridine (2 equiv.), and tetraoxoosmium (0.02 equiv.) in 1,4-dioxane / water 10 / 1 (0.07 M). The reaction mixture was stirred at room temperature for 10 min, and sodium periodate (4 equiv.) was added. The mixture was stirred at room temperature for 12–48 h (vigorously stirred due to the appearance of a precipitate). Water was added, and the dioxane was evaporated. The aqueous layer was extracted with DCM (×3). The combined organic layers were dried through a phase separator and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel using a gradient of 0%–100% EtOAc in cyclohexane to give the desired product.

[0497] Synthesis of tert-butyl 2-[(3-chloro-2-formyl-phenyl)methyl]morpholine-4-carboxylate (Intermediate 42) [ka] tert-Butyl 2-[(3-chloro-2-vinylphenyl)methyl]morpholine-4-carboxylate (4.28 g, 12 mmol) gave tert-butyl 2-[(3-chloro-2-formylphenyl)methyl]morpholine-4-carboxylate as a white solid (2.14 g, 49% yield). 1 H NMR(DMSO-d6,400MHz)δ 10.47(s,1H),7.66-7.48(m,2H),7.36(dd,J=7.4,1.4Hz,1H),3.86-3.58(m,3H),3.49-3.38(m,1H),3.26(td,J=11 m / z=240[M-(t-Bu)] + .

[0498] Method I: Protection -N-Boc protection General Procedure I1: Under an argon atmosphere, EtN (1 eq.) was added to a solution of amine (1 eq.) in anhydrous DCM (0.1 M), followed by BocO (1 eq.). The reaction mixture was stirred at room temperature for 12 h. The solvent was removed under reduced pressure. Water was added, and the aqueous layer was extracted three times with DCM. The combined organic layers were dried over a phase separator and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel (using a gradient of MeOH in DCM) to give the desired product.

[0499] Synthesis of tert-butyl 4-hydroxy-4-methyl-piperidine-1-carboxylate (Intermediate 43) [ka] 4-Methylpiperidin-4-ol (1 g, 8.42 mmol) gave tert-butyl 4-hydroxy-4-methylpiperidine-1-carboxylate as a yellow oil (1.75 g, 96.5% yield). 1 H NMR (DMSO-d6,400MHz)4.29(s,1H),3.52(dt,J=13.2,4.3Hz,2H),3.12(s,2H),1.44-1.39(m,2H),1.38(s,9H),1.37-1.29(m,2H),1.11(s,3H).

[0500] -O-TBS protection General Procedure I2: To a stirred solution of the alcohol (1 equiv.) in anhydrous DCM (0.15 M) under an argon atmosphere was added EtN (4 equiv.) and the mixture was cooled to 0 °C. TBDMSOTf (2 equiv.) was added dropwise and the reaction was stirred at room temperature for 2 h. The solvent was removed under reduced pressure. The crude material was purified by flash chromatography on silica gel (using a gradient of EtOAc in cyclohexane) to give the desired product.

[0501] Synthesis of 4-[(tert-butyldimethylsilyl)oxy]-4-methylpiperidine (Intermediate 44) [ka] tert-Butyl 4-hydroxy-4-methylpiperidine-1-carboxylate (1 g, 4.65 mmol) gave 4-[(tert-butyldimethylsilyl)oxy]-4-methylpiperidine as a yellow solid (500 mg, 44.6% yield), which underwent spontaneous deprotection of the N-Boc group during the reaction. 1 H NMR(DMSO-d6,400MHz)δ 2.87-2.68(m,4H),1.54-1.38(m,4H),1.21(s,3H),0.87(s,9H),0.08(s,6H).

[0502] Method J: Amide Formation To a stirred solution of alcohol (1 eq.) in anhydrous DCM (0.1 M) at 0° C. under argon, acyl chloride (1.4 eq.) dissolved in DCM was added dropwise. The mixture was stirred at room temperature for 12 h. The solvent was removed under reduced pressure. The residue was suspended in diethyl ether, filtered through a frit (pore size 4), and washed with a further portion of diethyl ether. The combined ether phases were evaporated. The crude material was purified by flash chromatography on silica gel (using a gradient of MeOH in DCM) to give the desired product.

[0503] Synthesis of 2-chloro-1-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]ethenone (Intermediate 45) [ka] [(2{S})-Pyrrolidin-2-yl]methanol (200 mg, 1.94 mmol) gave 2-chloro-1-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]ethanone as a colorless oil (238 mg, 62% yield). 1 H NMR(DMSO-d6,400MHz)δ 4.34-4.27(m,4H),4.02-3.89(m,3H),3.49(ddd,J=10.5,5.6,3.6Hz,2H),2.02-1.86(m,4H);m / z=178[M+H] + .

[0504] Method K: Other AR-X Transforms -Ar-Br to Ar-OH General Procedure K1: To a stirred suspension of Ar-Br (1 equiv.) in 1,4-dioxane / water 1 / 1 (0.032 M) in a vial under an argon atmosphere, potassium hydroxide (3 equiv.) and 4-{5-[bis(adamantan-1-yl)phosphanyl]-1H-pyrazol-1-yl}-1,3,5-triphenyl-1H-pyrazole (0.15 equiv.) were added sequentially. The reaction mixture was degassed with argon for 5 minutes, and then Pd2dba3 (0.1 equiv.) was added. The mixture was stirred at 100 °C for 12 hours. 1 M aqueous HCl and DCM were added. The aqueous layer was extracted with DCM (×3). The combined organic layers were dried using a phase separator and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel using a gradient of 0% to 100% EtOAc in heptane to give the desired compound.

[0505] Synthesis of tert-butyl 2-[(3-chloro-4-hydroxy-phenyl)methyl]morpholine-4-carboxylate (Intermediate 46) [ka] tert-Butyl 2-[(4-bromo-3-chlorophenyl)methyl]morpholine-4-carboxylate (250 mg, 0.63 mmol) and KOH (119 mg, 1.91 mmol, 3 equiv.) gave tert-butyl 2-[(3-chloro-4-hydroxyphenyl)methyl]morpholine-4-carboxylate as a colorless oil (150 mg, 71% yield). 1 H NMR(DMSO-d6,400MHz)δ 9.93(s,1H),7.19(d,J=2.1Hz,1H),6.98(dd,J=8.3,2.1Hz,1H),6.86(d,J=8.3Hz,1H),3.77(d,J=11.1Hz,1H),3.68(t,J=14 m / z=228[M+H] + -Boc.

[0506] -Cyanation General Procedure K2 Under nitrogen bubbling, Ar-Br (1 equiv.), cyclopentyl(diphenyl)phosphane iron (0.3 equiv.), zinc (0.8 equiv.), and Pd2dba3 (0.15 equiv.) were sequentially introduced into a microwave vial. The mixture was heated at 50 °C under N2 bubbling, and after 10 min, zinc disyanide (0.5 equiv.) was added. The mixture was stirred at 120 °C for 12 h. The mixture was filtered and washed with EtOAc. Saturated aqueous NaHCO3 was added to the filtrate, and the mixture was extracted with EtOAc (3 times). The combined organics were filtered through a phase separator and evaporated under reduced pressure. The crude material was purified by flash column chromatography on silica gel (using a gradient of 0% to 100% AcOEt in heptane) to give the desired compound.

[0507] Synthesis of tert-butyl 2-[(3-chloro-2-cyano-phenyl)methyl]morpholine-4-carboxylate (Intermediate 47) [ka] tert-Butyl 2-[(2-bromo-3-chloro-phenyl)methyl]morpholine-4-carboxylate (50 mg, 0.12 mmol) and KOH gave tert-butyl 2-[(3-chloro-2-cyano-phenyl)methyl]morpholine-4-carboxylate as a colorless oil (7 mg, 16% yield). 1 H NMR(DMSO-d6,400MHz)δ 7.71-7.58(m,2H),7.53(dd,J=7.5,1.1Hz,1H),3.80(dd,J=25.8,13.5Hz,2H),3.67(d,J=13.8Hz,2H),3.3 4(d,J=2.8Hz,1H),3.04(dd,J=14.2,4.5Hz,1H),2.92(dd,J=14.1,8.5Hz,3H),1.39(s,9H);m / z=237[M+H] + -Boc.

[0508] -Sandmeyer General Procedure K3: Sodium nitrite (2.2 equiv.) was slowly added to a stirred solution of amine (1 equiv.) in sulfuric acid (0.97 M) in a round-bottom flask at 0 °C. The mixture was stirred at 0 °C for 5 h and then poured into ice-water with stirring. The resulting solution was slowly added to a stirred solution of potassium iodide (6 equiv.) in 200 mL of ice-water. The aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with a saturated aqueous solution of NaSO, dried using a phase separator, and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel using a gradient of 0% to 100% EtOAc in heptane to give the desired product.

[0509] Synthesis of ethyl 3-bromo-2-iodo-5-methylbenzoate (intermediate 48) [ka] Ethyl 2-amino-3-bromo-5-methylbenzoate (2 g, 7 mmol) gave ethyl 3-bromo-2-iodo-5-methylbenzoate as a yellow oil (2.35 g, 75% purity, 68% yield). 1 H NMR(DMSO-d6,400MHz)δ 7 7.73(dt,J=2.8,1.4Hz,1H),7.31(dd,J=2.0,0.8Hz,1H),4.32(q,J=7.1Hz,2H),2.31-2.25(m,3H),1.33(t,J=7.1Hz,3H).

[0510] Method L: Photoredox General Procedure L1: In a 5 mL vial, aryl halide (1 equiv.), 3-bromooxetane (97%, 17 μL, 0.195 mmol), Ir[dF(CF3)ppy]2(dtbbpy)PF6 (99%, 0.03 equiv.), TTMSS (97%, 1 equiv.), and sodium carbonate (2 equiv.) were dissolved in DME (0.1 M) under an Ar atmosphere. Nickel dichloride, 1,2-dimethoxyethane (97%, 0.015 equiv.) (×5), and 4-tert-butyl-2-(4-tert-butyl-2-pyridyl)pyridine (98%, 0.018 equiv.) (×5) were dissolved in DME (0.1 M) under an Ar atmosphere. The mixture was stirred at room temperature for 15 min. 0.1 mL of precatalyst solution was added to the solution.

[0511] The mixture was degassed by sparging with Ar for 10 min and stirred at 40 °C for 7 h under irradiation with a 34 W blue LED lamp (pale green). The mixture was quenched with air in an open flask and concentrated. The crude was purified by flash chromatography (0-50% EtOAc in cyclohexane) to give the expected product.

[0512] Synthesis of tert-butyl 2-[[3-chloro-4-(oxetan-3-yl)phenyl]methyl]morpholine-4-carboxylate (Intermediate 49) [ka] From tert-butyl 2-[(4-bromo-3-chlorophenyl)methyl]morpholine-4-carboxylate (51 mg, 1 eq.) and 3-bromooxetane (27.6 mg, 1.5 eq.) a yellow oil (48% yield). 1 H NMR (DMSO-d 6,400MHz): δ(ppm)7.35(d,J=7.9Hz,1H),7.23(d,J=1.7Hz,2H),5.05(dd,J=8.5,6.0Hz,2H),4.83(dd,J=8.5,6.0Hz,2H),3.94-3.76(m,3H) ,3.64-3.53(m,2H),3.51-3.44(m,2H),2.79(dd,J=13.9,7.5Hz,1H),2.69(dd,J=14.1,5.3Hz,2H),1.45(s,9H);m / z=312[M+H]+-(t-Bu).

[0513] General Procedure L2 (Angew.Chem.Int.Ed.2019,58,1823-1827) In a 10 mL dry Pyrex® screw-cap reaction tube equipped with an appropriate stir bar, dipotassium hydrogen phosphate (2 equiv.), Ar-Br (1 equiv.), and benzaldehyde (0.5 equiv.) were dissolved in anhydrous THF (0.1 M). In a separate flask, 1,2-dimethoxyethane-dibromonickel (1:1) (97%, 0.1 equiv.) and 4-tert-butyl-2-(4-tert-butyl-2-pyridyl)pyridine (98%, 0.1 equiv.) were dissolved in anhydrous THF (0.1 M) under N2 and placed in an ultrasonic sink for 2–3 min until the solution became homogeneous. The nickel catalyst solution was added to the reaction tube via syringe. The reaction mixture was then cooled to -78 °C, degassed by evacuation (5 min), refilled with nitrogen, and warmed to room temperature. This process was repeated three times. After the reaction was thoroughly degassed, it was stirred under UVA light (380 nm) at room temperature for 24 hours. The reaction mixture was diluted with DCM. The organic layer was washed with water, and the aqueous layer was extracted with DCM. The combined organic phases were dried over a phase separator and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel (using a gradient of 0-100% EtOAc in cyclohexane) to give the desired product.

[0514] Synthesis of tert-butyl 2-[(3-chloro-4-tetrahydrofuran-2-yl-phenyl)methyl]morpholine-4-carboxylate (Intermediate 50) [ka] tert-Butyl 2-[(4-bromo-3-chlorophenyl)methyl]morpholine-4-carboxylate (300 mg, 1 equivalent) and THF (solvent) gave tert-butyl 2-[(3-chloro-4-tetrahydrofuran-2-ylphenyl)methyl]morpholine-4-carboxylate as a colorless oil (79 mg, 25% yield). 1 H NMR (CDCl 3, 400MHz): δ(ppm)7.42(d,J=7.9Hz,1H),7.19(s,1H),7.10(d,J=8.0Hz,1H),5.17(t,J=7.0Hz,1H) ,4.13(q,J=7.1Hz,1H),3.94(q,J=7.4Hz,2H),3.89-3.77(m,3H),3.64-3.53(m,1H),3.53-3.42( m,1H),3.01-2.87(m,1H),2.78(dd,J=14.1,7.2Hz,1H),2.75-2.57(m,2H),2.48(dq,J=13.8,6.9 Hz,1H),1.96(tq,J=14.4,6.4Hz,3H),1.76-1.61(m,1H),1.44(s,9H).);m / z=312[M+H]+-(t-Bu).

[0515] Method M: General Procedure M1: Hydrogenation To a stirred solution of alkene (1.00 equiv.) in MeOH (0.1 M) under N2 atmosphere was added dioxoplatinum (0.11 equiv.). The reaction mixture was stirred under H2 atmosphere at room temperature for 24 h. The mixture was filtered, washed with MeOH, and the solvent was evaporated under high vacuum. The crude material was purified by flash chromatography column (EtOAc in DCM) to give the desired product.

[0516] Synthesis of tert-butyl 2-[(3-chloro-4-tetrahydropyran-4-yl-phenyl)methyl]morpholine-4-carboxylate (Intermediate 51) [ka] Tert-butyl 2-{[3-chloro-4-(3,6-dihydro-2H-pyran-4-yl)phenyl]methyl}morpholine-4-carboxylate (79 mg) gave tert-butyl 2-[(3-chloro-4-tetrahydropyran-4-ylphenyl)methyl]morpholine-4-carboxylate as a colorless oil (55 mg, 71% yield). m / z=296 [M+H] + -Boc.

[0517] General Procedure M2: Hydrobromination A sealed vial was charged with alkene (1 equiv.) and ammonium acetate (0.15 equiv.) in acetone (0.28 M). NBS (1.1 equiv.) and water (0.28 M) were added, and the reaction mixture was stirred at room temperature for 1 h, then quenched with a saturated solution of NaSO. A saturated solution of NaHCO was also added. The aqueous layer was extracted with DCM (x3). The combined organic layers were washed with brine, dried using a phase separator, and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel using a gradient of 0% to 100% DCM / MeOH (9:1) in DCM to give the desired product.

[0518] Synthesis of 1-bromo-3-[3-chloro-4-(3-pyridyloxymethyl)phenyl]propan-2-ol (Intermediate 52) [ka] 3-[(4-Allyl-2-chlorophenyl)methoxy]pyridine (227 mg, 0.87 mmol, 1 equiv.) gave 1-bromo-3-[3-chloro-4-(3-pyridyloxymethyl)phenyl]propan-2-ol as a beige solid (54 mg, 16% yield). 1 H NMR (DMSO-d 6,400MHz): δ(ppm)8.38(d,J=2.9Hz,1H),8.21(dd,J=4.6,1.3Hz,1H),7.56(d,J=7.8H z,1H),7.50(ddd,J=8.5,3.0,1.3Hz,1H),7.46(d,J=1.6Hz,1H),7.38(s,1H),7.30(d d,J=7.8,1.6Hz,1H),5.33(t,J=5.7Hz,1H),5.21(s,2H),4.37(dq,J=10.2,5.5Hz,1H ),3.75-3.61(m,2H),3.42-3.34(m,1H),3.00(dd,J=14.6,9.2Hz,1H);m / z=356[M+H] + .

[0519] Method N: CC bond formation General Procedure N1: Condensation with Morpholinone In a flame-dried 25 mL two-neck round-bottom flask, the lactam (1 equiv.) was dissolved in anhydrous THF (0.1 mL) under Ar and cooled to -78 °C. 1 M (diisopropylamino)lithium (1.5 equiv.) was added dropwise to the solution. The mixture was stirred at -78 °C for 30 min, and Ar-CH2-Br (1.3 equiv.) in anhydrous THF (0.1 M) was added. The mixture was stirred at -78 °C for 10 min and warmed to room temperature for 12 h. Saturated aqueous NH4Cl was added, and the mixture was extracted with ethyl acetate (3 times). The combined organic layers were concentrated in vacuo. The crude material was purified by flash chromatography using a gradient of EtOAc in heptane to give the desired product.

[0520] Synthesis of (8aS)-3-[(4-bromo-3-chloro-phenyl)methyl]-6,7,8,8a-tetrahydro-1H-pyrrolo[2,1-c][1,4]oxazin-4-one (Intermediate 53) [ka] (8aS)-3-[(4-bromo-3-chlorophenyl)methyl]-6,7,8,8a-tetrahydro-1H-pyrrolo[2,1-c][1,4]oxazin-4-one (60 mg, 0.425 mmol) gave (8aS)-3-[(4-bromo-3-chlorophenyl)methyl]-6,7,8,8a-tetrahydro-1H-pyrrolo[2,1-c][1,4]oxazin-4-one as a white solid (90 mg, 57% yield). 1 H NMR (DMSO-d6,600MHz): δ(ppm)7.65(d,J=8.2Hz,1H),7.46(d,J=2.1Hz,1H),7.14(dd,J=8.2, 2.1Hz,1H),4.18(dd,J=7.9,3.5Hz,1H),4.09(dd,J=11.3,4.0Hz,1H),3.43-3.51(m,2H),3.25 (dd,J=11.2,10.3Hz,2H),3.14(dd,J=14.4,3.5Hz,1H),2.88(dd,J=14.4,8.1Hz,1H),1.84-1 .94(m,2H),1.70(ttd,J=12.3,9.6,7.0Hz,1H),1.30(qd,J=11.6,7.4Hz,1H);m / z=346[M+H]+.

[0521] General Procedure N2: Grignard Addition A flame-dried, three-necked, round-bottom flask (250 mL) equipped with a magnetic stirrer was charged with the carbonyl (1 equiv.) dissolved in anhydrous THF (0.17 M). The solution was cooled to -20 °C (homogeneous yellow solution). 3 M (methyl)magnesium bromide (1.5 equiv.) in EtO was added. The reaction was stirred at -20 °C for 2 h. After 10 min, the reaction mixture became a beige, heterogeneous solution. The mixture was warmed to 0 °C, saturated aqueous NH Cl and ethyl acetate were added, and the mixture was extracted with ethyl acetate (2 times). The combined organic layers were dried through a phase separator and concentrated. The crude material was purified by flash chromatography on a silica gel column using a gradient of EtOAc in heptane to give the desired product.

[0522] Synthesis of tert-butyl (3aR,6aS)-5-hydroxy-5-methyl-1,3,3a,4,6,6a-hexahydrocyclopenta[c]pyrrole-2-carboxylate (Intermediate 54) [ka] tert-Butyl (3aR,6aS)-5-oxo-octahydrocyclopenta[c]pyrrole-2-carboxylate (2 g, 8.43 mmol) gave tert-butyl (3aR,6aS)-5-hydroxy-5-methyl-1,3,3a,4,6,6a-hexahydrocyclopenta[c]pyrrole-2-carboxylate (1.26 g, 55.715% yield) as a colorless oil. 1 H NMR (CDCl 3, 400MHz):δ(ppm)3.54-3.43(m,2H),3.34(dd,J=11.2,3.6Hz,2H),2.76-2.61(m,2H),1 .98-1.87(m,2H),1.73(s,1H),1.66(dd,J=13.3,4.8Hz,2H),1.44(s,9H),1.31(s,3H).

[0523] General Procedure N3: Wittig To a stirred solution of dimethylphosphonate (2 equiv.) in anhydrous THF (0.325 M) in a vial at 0 °C, sodium hydride (2 equiv.) was added portionwise. The mixture was stirred at 0 °C for 10 min, and then R-Br (1 equiv.) in anhydrous THF (0.325 M) was added. The mixture was stirred at room temperature for 1 h and then cooled to 0 °C. A solution of the ketone (2 equiv.) in anhydrous THF (2 x v / 0.325 M) was added, followed by the portionwise addition of sodium hydride (2 equiv.). The mixture was stirred at room temperature for 5 h, then quenched with a saturated aqueous solution of NH4Cl, and EtOAc was added. The aqueous layer was extracted with EtOAc (x3). The combined organic layers were dried using a phase separator and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel using a gradient of 0% to 100% EtOAc in heptane to give the desired compound.

[0524] Synthesis of tert-butyl 4-[(3-chloro-2-cyclopropyl-phenyl)methylene]piperidine-1-carboxylate (Intermediate 55) [ka] 1-(Bromomethyl)-3-chloro-2-cyclopropylbenzene (228 mg, 0.91 mmol, 1 equivalent) and tert-butyl 4-oxopiperidine-1-carboxylate (374 mg, 1.82 mmol, 2 equivalents) gave tert-butyl 4-[(3-chloro-2-cyclopropylphenyl)methylene]piperidine-1-carboxylate (249 mg, 78% yield) as a colorless oil. 1 H NMR(DMSO-d6,400MHz):δ(ppm)7.30(dd,J=7.9,1.3Hz,1H),7.20(t,J=7.8Hz,1H ),7.04(dd,J=7.4,1.2Hz,1H),6.49(s,1H),3.44(t,J=5.9Hz,2H),3.30(d,J=5.6 Hz,2H),2.42-2.25(m,2H),2.16(t,J=5.7Hz,2H),1.74(ddd,J=14.3,8.8,5.9Hz ,1H),1.41(s,9H),1.11-0.91(m,2H),0.53(td,J=6.2,4.5Hz,2H).m / z=248[M+H] + -Boc.

[0525] Method O: Stille Coupling General Procedure O1: A sealed vial under argon was charged with Ar-Br (1 equiv.), dichloropalladium triphenylphosphane (0.15 equiv.), and copper iodide (0.15 equiv.) in anhydrous 1,4-dioxane (0.128 mL). The mixture was purged with argon for 5 minutes, and stannane (2 equiv.) was added under Ar. The mixture was stirred at 150°C for 1 hour. The mixture was filtered, concentrated under reduced pressure, and purified by flash chromatography on silica gel (using a gradient of 0% to 100% EtOAc in heptane) to give the desired product.

[0526] Synthesis of tert-butyl 2-[(3-chloro-2-oxazol-2-yl-phenyl)methyl]morpholine-4-carboxylate (Intermediate 56) [ka] tert-Butyl 2-[(2-bromo-3-chlorophenyl)methyl]morpholine-4-carboxylate (250 mg, 0.64 mmol, 1 equivalent) and 2-(tributylstannanyl)-1,3-oxazole (458 mg, 1.28 mmol, 2 equivalents) gave tert-butyl 2-[(3-chloro-2-oxazol-2-yl-phenyl)methyl]morpholine-4-carboxylate (70 mg, 28% yield) as a colorless oil. 1 H NMR (DMSO-d6,400MHz): δ(ppm)8.34(d,J=0.9Hz,1H),7.54(d,J=1.7Hz,1H),7.53(s,1H),7.47(d,J=0.9Hz,1H),7.43(dd,J=5.2,3.7Hz,1H),3.7 7-3.60(m,3H),3.56(d,J=14.0Hz,1H),3.23(td,J=11.6,2.8Hz,1H),2. 79(s,1H),2.73-2.54(m,2H),2.46(s,1H),1.37(s,10H));m / z=279[M+H] + -Boc.

[0527] General Procedure O2: A sealed vial under argon was charged with Ar-Br (1 equiv.) and stannane (1.2 equiv.) in DMF (0.1 M). The reaction was purged with argon three times, and palladium triphenylphosphane (0.1 equiv.) was added. The resulting mixture was stirred at 100°C for 2 h. Water was added, and the mixture was extracted with EtOAc. The combined organic layers were washed with water, brine, dried on a phase separator, and concentrated in vacuo. The crude material was purified on a silica gel column (using a gradient of EtOAc in heptane from 0°C to 100°C) to give the expected product.

[0528] Synthesis of tert-butyl 2-[[3-chloro-2-(2-methylpyrazol-3-yl)phenyl]methyl]morpholine-4-carboxylate (Intermediate 57) [ka] tert-Butyl 2-[(2-bromo-3-chlorophenyl)methyl]morpholine-4-carboxylate (100 mg, 0.256 mmol, 1 equivalent) and 1-methyl-5-(tributylstannyl)-1H-pyrazole (114 mg, 0.307 mmol, 1.2 equivalents) gave tert-butyl 2-[[3-chloro-2-(2-methylpyrazol-3-yl)phenyl]methyl]morpholine-4-carboxylate (90 mg, 90% yield) as a yellow oil. 1 H NMR (DMSO-d6,400MHz): δ(ppm)7.56-7.36(m,4H),6.28(dd,J=10.6,1.8Hz,1H),3.76-3.67(m,1H),3.63(d,J=13.6Hz,2H),3.52(d,J=3. 5Hz,3H),3.24(tt,J=11.5,3.0Hz,2H),2.80(s,1H),2.65(ddd,J=36.7,14.1,6.9Hz,1H),2.48-2.34(m,2H),1.37(s,9H);m / z=392[M+H] + .

[0529] Method P: General Procedure P1: Negishi A dry flask was charged with a suspension of zinc (3 equiv.) in DMA (0.15 M) and heated to 65–70 °C under N2 for 5 min. A mixture of chloro(trimethyl)silane (0.3 equiv.) and 1,2-dibromoethane (0.27 equiv.) was added dropwise and stirred for 10 min. After this, alkyl-I (2 equiv.) in DMA (3 mL, 0.15 M) was slowly added. The reaction mixture was slowly cooled to room temperature and then added to a mixture of copper iodide (0.31 equiv.), bis(cyclopentyldiphenylphosphane)dichloromethane-dichloropalladium iron (0.10 equiv.), and Ar-I (1 equiv.) in DMA (3 mL) and stirred at 70 °C for 12 h. The mixture was cooled to room temperature, and water was added. The aqueous layer was extracted with DCM (×3). The combined organic layers were washed with brine (NaCl), dried using a phase separator, and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel using a gradient of DCM / 7N NH3 (9:1) from 0% to 50% in DCM to give the desired compound.

[0530] Synthesis of benzyl 3-(6-methoxy-3-pyridyl)azetidine-1-carboxylate (intermediate 58) [ka] 5-Iodo-2-methoxypyridine (250 mg, 1.04 mmol, 1 equivalent) and benzyl 3-iodoazetidine-1-carboxylate (701 mg, 2.10 mmol, 2 equivalents) gave benzyl 3-(6-methoxy-3-pyridyl)azetidine-1-carboxylate (370 mg, 99.9% yield) as an orange oil. 1 H NMR (DMSO-d6,400MHz): δ(ppm)8.10(d,J=2.5Hz,1H),7.79(dd,J=8.6,2.6Hz,1H),7.38(t,J=1.6Hz,2H),7.36-7.26(m,3H),6 .82(dd,J=8.5,0.7Hz,1H),5.06(s,2H),4.37-4.26(m,2H),3.96-3.90(m,2H),3.88-3.84(m,1H),3.83(s,3H);m / z=299[M+H]+ .

[0531] General Procedure Q1: Chan Lam To a solution of Ar-BPin or boronic acid (1 equiv.), amine (2 equiv.), and KF (2 equiv.) in acetonitrile (0.0914 M) was added diacetoxycopper (2 equiv.). The mixture was stirred at 50° C. for 12 h. The mixture was filtered through Celite, and the solvent was evaporated under reduced pressure. The crude material was purified by flash chromatography on silica gel (using a gradient of 0% to 100% EtOAc in heptane) to give the desired compound.

[0532] Synthesis of tert-butyl 2-[[3-chloro-4-(4-methoxy-3-methyl-pyrazol-1-yl)phenyl]methyl]morpholine-4-carboxylate (Intermediate 59) [ka] Tert-butyl 2-[[3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]morpholine-4-carboxylate (100 mg, 0.228 mmol, 1 equivalent) and 4-methoxy-3-methyl-1H-pyrazole (51 mg, 0.456 mmol, 2 equivalents) gave tert-butyl 2-[[3-chloro-4-(4-methoxy-3-methylpyrazol-1-yl)phenyl]methyl]morpholine-4-carboxylate (52 mg, 54% yield) as a colorless oil. 1 H NMR (DMSO-d6,400MHz): δ(ppm)7.78(s,1H),7.52(d,J=1.8Hz,1H),7.43(d,J=8.2Hz,1H),7.32(dd,J=8.3,1.9Hz,1H),3.80(dd,J=11.9,2.8Hz,2H),3. 73(s,3H),3.72-3.65(m,1H),3.55(dddd,J=10.3,7.7,5.2,2.5Hz,1H),3.4 1-3.32(m,1H),3.00-2.55(m,1H),2.14(s,3H),1.40(s,9H);m / z=366[M+H]+ -t-Bu.

[0533] Method R: Isoxazole formation General Procedure R1:1.1DMF-DMA Litt:Org.Lett.2019,21,835-839 In a sealed vial under nitrogen, the ketone (1 equivalent) was diluted with 1,1-dimethoxy-N,N-dimethyl-methanamine (54 equivalents). The mixture was stirred at 100° C. for 12 hours. The mixture was cooled to room temperature and concentrated under reduced pressure to give the crude product directly.

[0534] Synthesis of tert-butyl 2-[[3-chloro-2-[(E)-3-(dimethylamino)prop-2-enoyl]phenyl]methyl]morpholine-4-carboxylate (Intermediate 60) [ka] tert-Butyl 2-[(2-acetyl-3-chlorophenyl)methyl]morpholine-4-carboxylate (250 mg, 0.657 mmol, 1 equivalent) gave tert-butyl 2-[[3-chloro-2-[(E)-3-(dimethylamino)prop-2-enoyl]phenyl]methyl]morpholine-4-carboxylate (329 mg, quantitative, crude) as an orange oil. m / z=409 [M+H] +

[0535] 1,2-Dihydroisoxazole To a stirred solution of dimethylaminoketene (1 equiv.) in ethanol (0.26 M) in a vial was added hydroxylamine hydrochloride (1.2 equiv.). The mixture was stirred at reflux for 1 h and concentrated under reduced pressure. The crude material was used directly in the next step without purification.

[0536] Synthesis of tert-butyl 2-[[3-chloro-2-(5-hydroxy-4H-isoxazol-5-yl)phenyl]methyl]morpholine-4-carboxylate (Intermediate 61) [ka] Tert-butyl 2-[[3-chloro-2-[(E)-3-(dimethylamino)prop-2-enoyl]phenyl]methyl]morpholine-4-carboxylate (327 mg, 0.80 mmol, 1 equivalent) gave tert-butyl 2-[[3-chloro-2-(5-hydroxy-4H-isoxazol-5-yl)phenyl]methyl]morpholine-4-carboxylate (422 mg, quantitative, crude) as an orange oil. m / z=297 [M+H] + -Boc.

[0537] Isoxazole To a stirred solution of dihydroisoxazole (1 eq) in DMF (0.099 M) in a vial, sulfuric acid (20 eq) was added dropwise. The reaction mixture was stirred at room temperature for 12 h (additional sulfuric acid was added as needed to drive the reaction to completion). The mixture was slowly diluted with water at 0 °C, and DCM was added. The reaction mixture was then quenched by the dropwise addition of 50% w / w aqueous NaOH (pH = 8) while still at 0 °C. The aqueous layer was extracted with DCM (x3). The combined organic layers were dried on a phase separator and concentrated under reduced pressure to give the expected compound.

[0538] Synthesis of 2-[(3-chloro-2-isoxazol-5-yl-phenyl)methyl]morpholine (Intermediate 62) [ka] tert-Butyl 2-[[3-chloro-2-(5-hydroxy-4H-isoxazol-5-yl)phenyl]methyl]morpholine-4-carboxylate (422 mg, 0.97 mmol, 1 equivalent) gave 2-[(3-chloro-2-isoxazol-5-ylphenyl)methyl]morpholine (162 mg, 55% yield) as an orange oil. 1H NMR (DMSO-d6,400MHz): δ(ppm)8.75(d,J=1.9Hz,1H),7.53-7.49(m,2H),7.40(dd,J=5.4,3.6Hz,1H),6.74(d,J=1.8Hz, 1H),3.64(d,J=11.4Hz,2H),2.82-2.69(m,1H),2.69-2.61(m,1H),2.63-2.52(m,3H),2.37-2.19(m,2H).m / z=279[M+H] +

[0539] General procedure for series 3 compounds Method A: Suzuki-Miyaura coupling General Procedure A1: Step A1.1: Ar-Br Step A1.2: Ar-Cl To a solution of Ar-Br (or Ar-Cl) (1.00 equiv.) in 1,4-dioxane / HO (4:1, 0.1 M) was added RB(OH) (or R-Bpin or R-BF3K) (1.20 equiv.) and Na2CO3 (3.00 equiv.). The reaction mixture was degassed with argon for 5 min, Pd(dppf)Cl2 (DCM) (0.10 equiv.) was added, and the reaction mixture was heated at 100 °C for 24 h. The reaction mixture was cooled to room temperature, diluted with DCM, and quenched with water. The two layers were separated, and the aqueous layer was extracted three times with DCM. The combined organic layers were dried through a phase separator and concentrated under reduced pressure. The crude material was purified by flash chromatography (0-100% EtOAc / cyclohexane) to give the desired product.

[0540] Synthesis of 3-chloro-2-cyclopropyl-benzaldehyde (Intermediate 63) [ka] 3-Chloro-2-cyclopropylbenzaldehyde (860 mg, 68%), orange oil. General procedure A1.1 from 2-bromo-3-chlorobenzaldehyde (1.5 g, 6.70 mmol, 1.00 equiv) and cyclopropylboronic acid (700 mg, 8.15 mmol, 1.20 equiv). 1H NMR(DMSO-d6,400MHz)δ 10.68(d,J=0.8Hz,1H),7.73-7.68(m,2H),7.43(t,J=7.9Hz,1H),2.13-2.06(m,1H),1.23-1.18(m,2H),0.65-0.61(m,2H);m / z=181.2[M+H]+.

[0541] General Procedure A2: Step A2.1: Ar-Br Step A2.2: Ar-Cl To a solution of Ar-Br (or Ar-Cl) (1.00 equiv.) in 1,4-dioxane / HO (4:1, 0.1 M) was added RB(OH) (or R-Bpin) (1.40 equiv.) and KPO (2.00 equiv.). The reaction mixture was degassed with argon for 5 min, Pd(dba) (0.10 equiv.) and PCy (0.15 equiv.) were added, and the reaction mixture was heated at 100 °C for 24 h. The reaction mixture was cooled to room temperature, diluted with DCM, and quenched with water. The two layers were separated, and the aqueous layer was extracted three times with DCM. The combined organic layers were dried through a phase separator and concentrated under reduced pressure. The crude material was purified by flash chromatography (0-100% EtOAc / cyclohexane) to give the desired product.

[0542] Synthesis of 4-(2-cyclopropyl-3-formyl-phenyl)-2-fluoro-benzonitrile (Intermediate 64) [ka] 4-(2-Cyclopropyl-3-formylphenyl)-2-fluorobenzonitrile (1.32 g, 78%), pale yellow solid. General procedure A2.2 from 3-chloro-2-cyclopropylbenzaldehyde (1.28 g, 6.38 mmol, 1.00 equiv) and (4-cyano-3-fluorophenyl)boronic acid (1.50 g, 8.93 mmol, 1.40 equiv). 1H NMR(DMSO-d6,400MHz)δ 10.82(d,J=0.7Hz,1H),8.02(dd,J=8.0,7.0Hz,1H),7.84(dd,J=7.5,1.6Hz,1H),7.72(dd,J=10.6,1.5Hz,1H),7.61(dd,J m / z=266.2[M+H]+.

[0543] General Procedure A3: To a solution of Ar-Br (1.00 equiv.) in 1,4-dioxane / HO (4:1, 0.1 M) was added RB(OH)2 (or R-Bpin) (2.10 equiv.) and Na2CO3 (or K3CO4) (2.40 equiv.). The reaction mixture was degassed with argon for 5 min, Pd(PPh3)4 (0.05 equiv.) was added, and the reaction mixture was heated at 100 °C for 24 h. The reaction mixture was cooled to room temperature, diluted with DCM, and quenched with water. The two layers were separated, and the aqueous layer was extracted three times with DCM. The combined organic layers were dried through a phase separator and concentrated under reduced pressure. The crude material was purified by flash chromatography (0-100% EtOAc / cyclohexane) to give the desired product.

[0544] Synthesis of tert-butyl 2-[(3-chloro-2-oxazol-5-yl-phenyl)methyl]-2,8-diazaspiro[3.5]nonane-8-carboxylate (Intermediate 65) [ka] tert-Butyl 2-[(3-chloro-2-oxazol-5-ylphenyl)methyl]-2,8-diazaspiro[3.5]nonane-8-carboxylate (65 mg, 25%), yellow oil. General Procedure A3 from tert-butyl 2-[(2-bromo-3-chlorophenyl)methyl]-2,8-diazaspiro[3.5]nonane-8-carboxylate (160 mg, 0.37 mmol, 1.00 equiv) and 5-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-oxazole (155 mg, 0.79 mmol, 2.10 equiv). 1 H NMR(DMSO-d6,400MHz)δ 8.53(s,1H),7.65-7.47(m,3H),7.39(s,1H),3.43(br,s,4H),3.21(t,J=5.5Hz,2H),2.94-2.92(m,2 H),2.68(d,J=6.7Hz,2H),1.59(t,J=6.0Hz,2H),1.38(s,9H),1.33-1.31(m,2H);m / z=418.1[M+H]+.

[0545] General Procedure A4: To a 0.1 M solution of Ar-Br (1.00 equiv.) in toluene, R-Bpin (1.30 equiv.), KF (7.00 equiv.), and NaBr (1.80 equiv.) were added. The reaction mixture was degassed with argon for 5 minutes, Pd(PPh3)4 (0.10 equiv.) was added, and the reaction mixture was heated at 125 °C for 24 h. The reaction mixture was cooled to room temperature, diluted with EtOAc, and quenched with water. The two layers were separated, and the aqueous layer was extracted three times with EtOAc. The combined organic layers were dried through a phase separator and concentrated under reduced pressure. The crude material was purified by flash chromatography (0-20% EtOAc / cyclohexane) to give the desired product.

[0546] Synthesis of tert-butyl N-[rac-(1S,2S,4R)-7-[(3-chloro-2-isothiazol-5-yl-phenyl)methyl]-7-azabicyclo[2.2.1]heptan-2-yl]carbamate (Intermediate 66) [ka] tert-Butyl N-[rac-(1S,2S,4R)-7-[(3-chloro-2-isothiazol-5-ylphenyl)methyl]-7-azabicyclo[2.2.1]heptan-2-yl]carbamate (46 mg, 60%), white solid. General Procedure A4 from tert-butyl N-[rac-(1S,2S,4R)-7-[(2-bromo-3-chlorophenyl)methyl]-7-azabicyclo[2.2.1]heptan-2-yl]carbamate (73 mg, 0.18 mmol, 1.00 equiv.) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-thiazole (51 mg, 0.23 mmol, 1.30 equiv.). 1 H NMR(DMSO-d6,400MHz)δ 8.65(d,J=1.7Hz,1H),7.56-7.42(m,4H),6.96(d,J=6.6Hz,1H),3.64(br,s,1H),3.27-3.24(m,2H),3.09(t,J=4.2Hz,1H),2.9 6(t,J=4.4Hz,1H),1.91-1.86(m,1H),1.60-1.58(m,2H),1.46-1.29(m,11H),0.96(dd,J=11.9,4.5Hz,1H);m / z=420.0[M+H]+.

[0547] General Procedure A5: To a solution of Ar-Br (1.00 equiv.) in toluene / HO (9:1, 0.2 M) was added R-BF3K (1.10 equiv.) and Cs2CO3 (3.00 equiv.). The reaction mixture was degassed with argon for 5 minutes, Pd(OAc)2 (0.10 equiv.) and cataCXium A (0.10 equiv.) were added, and the reaction mixture was heated at 100 °C for 24 h. The reaction mixture was cooled to room temperature, diluted with DCM, and quenched with water. The two layers were separated, and the aqueous layer was extracted three times with DCM. The combined organic layers were dried through a phase separator and concentrated under reduced pressure. The crude material was purified by flash chromatography (0-100% EtOAc / cyclohexane) to give the desired product.

[0548] Synthesis of tert-butyl N-[rac-(1S,2S,4R)-7-[(3-chloro-2-cyclobutyl-phenyl)methyl]-7-azabicyclo[2.2.1]heptan-2-yl]carbamate (Intermediate 67) [ka] tert-Butyl N-[rac-(1S,2S,4R)-7-[(3-chloro-2-cyclobutylphenyl)methyl]-7-azabicyclo[2.2.1]heptan-2-yl]carbamate (118 mg, 42%), yellow sticky oil. General Procedure A5 from tert-butyl N-[rac-(1S,2S,4R)-7-[(2-bromo-3-chlorophenyl)methyl]-7-azabicyclo[2.2.1]heptan-2-yl]carbamate (300 mg, 0.71 mmol, 1.00 equiv.) and potassium cyclobutyltrifluoroboronide (131 mg, 0.79 mmol, 1.10 equiv.). 1 H NMR(DMSO-d6,400MHz)δ 7.27(dd,J=7.9,1.5Hz,1H),7.22(d,J=7.4Hz,1H),7.12(t,J=7.7Hz,1H),6.96(d,J=6.6Hz,1 H),4.22(p,J=9.6Hz,1H),3.64(br,s,1H),3.59-3.51(m,2H),3.30-3.28(m,1H),3.11(t,J=4. 3Hz,1H),3.04(t,J=4.7Hz,1H),2.78-2.66(m,2H),2.28-2.22(m,2H),1.96-1.88(m,3H),1.76 (br,s,1H),1.65-1.58(m,2H),1.36(s,10H),0.97(dd,J=12.0,4.7Hz,1H);m / z=391.3[M+H]+.

[0549] General Procedure A6: To a 0.15 M solution of Ar-I (1.00 equiv.) in THF, R-BPin (1.10 equiv.) and CsF (2.50 equiv.) were added. The reaction mixture was degassed with argon for 5 minutes and heated at 60°C. Pd(PPh3)4 (0.10 equiv.) was added, and the reaction mixture was heated at 80°C for 24 hours. The reaction mixture was cooled to room temperature, diluted with DCM, and quenched with water. The two layers were separated, and the aqueous layer was extracted three times with DCM. The combined organic layers were dried over a phase separator and concentrated under reduced pressure. The crude material was purified by flash chromatography (0-20% EtOAc / heptane) to give the desired product.

[0550] Synthesis of (2-allyl-3-bromo-phenyl)methanol (intermediate 68) [ka] (2-Allyl-3-bromophenyl)methanol (411 mg, 54%), pale yellow. General procedure A6 from 3-bromo-2-iodobenzyl alcohol (1.00 mg, 3.10 mmol, 1.00 equiv) and 2-allyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (573 mg, 3.41 mmol, 1.10 equiv). 1 H NMR(DMSO-d6,400MHz)δ 7.52(dd,J=7.9,1.3Hz,1H),7.44(dd,J=7.6,1.2Hz,1H),7.18(t,J=7.8Hz,1H),5.97-5.81(m,1H),5.27(t,J=5.5Hz ,1H),5.03(dq,J=10.1,1.7Hz,1H),4.89(dq,J=17.1,1.8Hz,1H),4.54(d,J=5.5Hz,2H),3.54(dt,J=5.9,1.8Hz,2H).

[0551] Method B: Reductive amination General Procedure B1: To a solution of the aldehyde (1.00 equiv.) in MeOH / AcOH (9:1, 0.1 M) was added the amine (1.50 equiv.). The reaction mixture was stirred at room temperature for 10 minutes, and then supported NaBH3CN (1.50 equiv.) was added. The resulting mixture was stirred at room temperature for 1-24 hours. The reaction mixture was filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography (EtOAc / cyclohexane 0-100%) to give the desired product.

[0552] Synthesis of tert-butyl 3-[[3-(4-cyano-3-fluoro-phenyl)-2-cyclopropyl-phenyl]methyl]-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (Intermediate 69) [ka] tert-Butyl-3-[[3-(4-cyano-3-fluorophenyl)-2-cyclopropylphenyl]methyl]-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (82 mg, 69%), white solid. General procedure B1 from 4-(2-cyclopropyl-3-formylphenyl)-2-fluorobenzonitrile (70 mg, 0.26 mmol, 1.00 equiv.) and tert-butyl 3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (80 mg, 0.40 mmol, 1.50 equiv.). 1 H NMR (DMSO-d6, 400 MHz) δ 7.98-7.94(m,1H),7.60(dd,J=10.7,1.3Hz,1H),7.49-7.45(m,2H),7.31(t,J =7.6Hz,1H),7.18(dd,J=7.6,1.2Hz,1H),4.00-3.95(m,4H),3.11(br,s,2H),2 .83-2.73(m,2H),2.33(q,J=6.3Hz,1H),2.11-2.03(m,1H),1.65(d,J=7.9Hz,1 H),1.41(s,9H),0.74-0.69(m,2H),-0.01(q,J=5.6Hz,2H);m / z=448.2[M+H]+.

[0553] General Procedure B2: To a solution of the amine (1.30 equiv.) in DCM (0.2 M) was added NEt3 (1.00 equiv.). The reaction mixture was stirred at room temperature for 10 minutes, and then the aldehyde (1.00 equiv.) was added. The reaction mixture was stirred at room temperature for 1 hour, and then STAB (1.80 equiv.) was added. The resulting mixture was stirred at room temperature for 1-24 hours. The reaction mixture was diluted with DCM and quenched with water. The two layers were separated, and the aqueous layer was extracted three times with DCM. The combined organic layers were dried through a phase separator and concentrated under reduced pressure. The crude material was purified by flash chromatography (MeOH / DCM 0-10%) to give the desired product.

[0554] Synthesis of tert-butyl N-[rac-(1S,2S,4R)-7-[(3-bromo-4-hydroxy-phenyl)methyl]-7-azabicyclo[2.2.1]heptan-2-yl]carbamate (Intermediate 70) [ka] tert-Butyl N-[rac-(1S,2S,4R)-7-[(3-bromo-4-hydroxyphenyl)methyl]-7-azabicyclo[2.2.1]heptan-2-yl]carbamate (376 mg, 98%), white foam. General procedure B2 starting from tert-butyl rac-(1S,2S,4R)-7-azabicyclo[2.2.1]hept-2-ylcarbamate hydrochloride (312 mg, 1.25 mmol, 1.30 equiv.) and 3-bromo-4-hydroxybenzaldehyde (97%, 200 mg, 0.97 mmol, 1.00 equiv.). 1H NMR(DMSO-d6,400MHz)δ 11.92(s,1H),10.06(s,1H),7.41(s,1H),7.13(d,J=10.3Hz,1H),6.97(s,1H),6.89(d,J=8.3Hz,1H),4.08(br,s,1H),3.68(br,s,1 H),3.41(br,s,2H),3.17-3.09(m,3H),1.99-1.90(m,1H),1.77-1.52(m,2H),1.36(s,9H),1.00(d,J=8.5Hz,1H);m / z=397.3[M+H]+.

[0555] General Procedure B3: To a toluene solution (0.05 M) of the aldehyde (1.00 equiv.) was added the amine (0.90 equiv.). The reaction mixture was degassed for 5 minutes, and then NaHCO3 (0.04 equiv.) and iridium dichloride; 1,2,3,4,5-pentamethylcyclopentane (0.04 equiv.) were added. The reaction mixture was stirred at 110 °C for 24 hours. The reaction mixture was diluted with EtOAc and quenched with saturated aqueous NaHCO3. The two layers were separated, and the aqueous layer was extracted three times with EtOAc. The combined organic layers were dried through a phase separator and concentrated under reduced pressure. The crude material was purified by flash chromatography (MeOH / DCM 0-10%) to give the desired product.

[0556] Synthesis of tert-butyl N-[(1S,4S)-2-[[3-(4-cyano-3-fluoro-phenyl)-4-(2-oxa-8-azaspiro[4.5]decan-8-yl)phenyl]methyl]-2-azabicyclo[2.2.1]heptan-4-yl]carbamate (Intermediate 71) [ka] tert-Butyl N-[(1S,4S)-2-[[3-(4-cyano-3-fluorophenyl)-4-(2-oxa-8-azaspiro[4.5]decan-8-yl)phenyl]methyl]-2-azabicyclo[2.2.1]heptan-4-yl]carbamate (32 mg, 67%), yellow gum. General procedure B3 from 2-fluoro-4-[5-(hydroxymethyl)-2-(2-oxa-8-azaspiro[4.5]decan-8-yl)phenyl]benzonitrile (38 mg, 0.10 mmol, 1.00 equiv.) and tert-butyl N-[(1S,4S)-2-azabicyclo[2.2.1]heptan-4-yl]carbamate (20 mg, 0.095 mmol, 0.90 equiv.). 1 H NMR(DMSO-d6,400MHz)δ 7.97(s,1H),7.82-7.79(m,1H),7.70(d,J=6.9Hz,1H),7.30-7.11(m,3H),3.70(t,J=7.1Hz,2H),3.57(br,s,1H),3.42(s,2H),3 .05(br,s,1H),2.73,(br,s,5H),2.30(br,s,1H),1.89(br,s,2H),1.66(t,J=7.2Hz,3H),1.44-1.35(m,17H);m / z=561.5[M+H]+.

[0557] Method C: Deprotection General Procedure C1: To a solution of the Boc-N product (1.00 equiv.) in DCM (0.2 M) was added 2,2,2-trifluoroacetic acid (15.0 equiv.). The reaction mixture was stirred at room temperature for 1-24 h. The reaction mixture was diluted with DCM and quenched with saturated aqueous NaHCO3. The two layers were separated, and the aqueous layer was extracted three times with DCM. The combined organic layers were dried over a phase separator and concentrated under reduced pressure. If necessary, the crude material was purified by flash chromatography (MeOH / DCM 0-10%) to give the desired product.

[0558] (2{R},3{R})-2,3-dihydroxybutanedioic acid (0.50 equiv.) was dissolved in HO (3 mL) and the product in ACN (0.3 mL) was added. The residue was lyophilized overnight to give the desired product as the tartrate salt.

[0559] Example 323: Synthesis of 4-[2-cyclopropyl-3-(3,6-diazabicyclo[3.1.1]heptan-3-ylmethyl)phenyl]-2-fluoro-benzonitrile. (2R,3R)-2,3-dihydroxybutanedioic acid [ka] General Procedure C1 from 4-[2-cyclopropyl-3-(3,6-diazabicyclo[3.1.1]heptan-3-ylmethyl)phenyl]-2-fluorobenzonitrile; (2R,3R)-2,3-dihydroxybutanedioic acid (62 mg, 65%), a beige solid. tert-Butyl 3-[[3-(4-cyano-3-fluorophenyl)-2-cyclopropylphenyl]methyl]-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (82 mg, 0.18 mmol, 1.00 equiv.). 1 H NMR (DMSO-d 6, 600MHz,)δ 8.00-7.93(m,1H),7.62(dd,J=10.6,1.4Hz,1H),7.52-7.44(m,2H),7.33(s,1H),7.21(dd,J=7 .7,1.2Hz,1H),4.01(s,2H),3.95(br,d,J=5.0Hz,2H),3.75(s,1H),3.25-3.20(m,1H),3.13(br d,J=11.2Hz,2H),2.92(d,J=11.3Hz,2H),2.51(br s,1H),2.20-2.03(m,2H),0.84-0.63(m,2H),0.01(dd,J=5.8,1.4Hz,2H);m / z=348.2[M+H]+.

[0560] General Procedure C2: To a solution (0.1 M) of the Boc-N product (1.00 equiv.) in DCM, HCl (2 M, 30.0 equiv.) in 1,4-dioxane was added. The reaction mixture was stirred at room temperature for 1-24 h. The reaction mixture was concentrated under reduced pressure. If necessary, the crude material was purified by flash chromatography (MeOH / DCM 0-10%) to give the desired product. The crude material was dissolved in HO (1 mL) and lyophilized overnight to give the desired product as the HCl salt.

[0561] Example 171: Synthesis of 4-[3-[[(1S,4S)-4-amino-2-azabicyclo[2.2.1]heptan-2-yl]methyl]-2-isothiazol-5-yl-phenyl]-2-fluoro-benzonitrile hydrochloride [ka] 4-[3-[[(1S,4S)-4-Amino-2-azabicyclo[2.2.1]heptan-2-yl]methyl]-2-isothiazol-5-ylphenyl]-2-fluorobenzonitrile; hydrochloride (11.2 mg, 96%), pale yellow solid. General procedure C2 from tert-butyl N-[(1S,4S)-2-[[3-(4-cyano-3-fluorophenyl)-2-isothiazol-5-ylphenyl]methyl]-2-azabicyclo[2.2.1]heptan-4-yl]carbamate (13 mg, 0.026 mmol, 1.00 equiv). 1 H NMR(DMSO-d6,T=350K,500MHz)δ 8.54(d,1H,J=1.7Hz),8.02(d,1H,J=8.1Hz),7.78(dd,1H,J=7.1,7.8Hz),7.73(t,1H,J=7.8Hz),7.58(dd,1H,J=1.1,7.7Hz),7.48(d, 1H,J=1.7Hz),7.32(dd,1H,J=1.5,10.3Hz),7.20(dd,1H,J=1.6,7.9Hz),4.1-4.4(m,2H),3.91(s,1H),3.2-3.6(m,2H),1.7-2.3(m,6H) m / z=405[M+H]+.

[0562] General Procedure C3: Under a nitrogen atmosphere, tetrabutylammonium fluoride (1 M, 1.3 equiv.) was added to a 0.1 M solution of the protected alcohol product (1.00 equiv.) in THF. The reaction mixture was stirred at room temperature for 1-24 h. The reaction mixture was diluted with DCM and quenched with saturated aqueous NH4Cl. The two layers were separated, and the aqueous layer was extracted three times with DCM. The combined organic layers were dried over a phase separator and concentrated under reduced pressure. The crude material was purified by flash chromatography (0-100% EtOAc / cyclohexane) to give the desired product.

[0563] Synthesis of 4-[2-(4-chlorothiazol-5-yl)-3-(hydroxymethyl)phenyl]-2-fluoro-benzonitrile (Intermediate 72) [ka] 4-[2-(4-chlorothiazol-5-yl)-3-(hydroxymethyl)phenyl]-2-fluorobenzonitrile (105 mg, 65%), white solid. General procedure C3 from 4-[3-[[tert-butyl(dimethyl)silyl]oxymethyl]-2-(4-chlorothiazol-5-yl)phenyl]-2-fluorobenzonitrile (214 mg, 0.47 mmol, 1.00 equiv). 1 H NMR(DMSO-d6,400MHz)δ 9.13(s,1H),7.86(dd,J=8.0,7.0Hz,1H),7.74(dd,J=7.8,1.3Hz,1H),7.66(t,J=7.7Hz,1H),7.41(dd,J=7.6,1.4Hz,1H),7.3 2(dd,J=10.4,1.5Hz,1H),7.12(dd,J=8.0,1.6Hz,1H),5.35(t,J=5.4Hz,1H),4.36(dd,J=14.2,5.2Hz,1H);m / z=345.3[M+H]+.

[0564] General Procedure C4: Under a nitrogen atmosphere, a protected alcohol derivative (1.00 equiv.) was added to a solution of Pd(OH) (20%, 0.10 equiv.) in EtOH (0.04 M). The reaction mixture was stirred at room temperature under a H atmosphere for 24 hours. The reaction mixture was filtered through a pad of Celite and washed with EtOH. The filtrate was concentrated under reduced pressure. The crude product was used in the next reaction without further purification.

[0565] Synthesis of tert-butyl N-[(1S,4S)-2-azabicyclo[2.2.1]heptan-4-yl]carbamate (Intermediate 73) [ka] tert-Butyl N-[(1S,4S)-2-azabicyclo[2.2.1]heptan-4-yl]carbamate (1.38 g, 99%), pale yellow solid. General procedure C4 from benzyl (1S,4S)-4-(tert-butoxycarbonylamino)-2-azabicyclo[2.2.1]heptane-2-carboxylate (1.59 g, 4.60 mmol, 1.00 equiv). 1 H NMR(DMSO-d6,400MHz)δ 7.05(s,1H),4.33(s,1H),3.14(s,1H),2.75(s,1H),1.69-1.46(m,6H),1.37(s,9H).

[0566] Method D: Alkylation / Substitution General Procedure D1: Under a nitrogen atmosphere, NaH (60%, 1.50 equiv.) was added to a DMF solution (0.1 M) of the N-Boc product (1.00 equiv.) at 0°C. The reaction mixture was stirred at 0°C for 30 min, and then alkyl-I (1.20 equiv.) was added. The reaction mixture was stirred at 0°C for 5-24 h. The reaction mixture was diluted with DCM and quenched with water. The two layers were separated, and the aqueous layer was extracted three times with DCM. The combined organic layers were dried through a phase separator and concentrated under reduced pressure. The crude material was purified by flash chromatography (EtOAc / cyclohexane 0-50%) to give the desired product.

[0567] Synthesis of tert-butyl N-methyl-N-[rel-(1R,2R,4S)-7-[[3-(4-cyano-3-fluoro-phenyl)-2-cyclopropyl-phenyl]methyl]-7-azabicyclo[2.2.1]heptan-2-yl]carbamate (Intermediate 74) [ka] tert-Butyl N-methyl-N-[rel-(1R,2R,4S)-7-[[3-(4-cyano-3-fluorophenyl)-2-cyclopropyl-phenyl]methyl]-7-azabicyclo[2.2.1]heptan-2-yl]carbamate (25 mg, 62%), white solid. General procedure D1 from tert-butyl N-[rel-(1R,2R,4S)-7-[[3-(4-cyano-3-fluorophenyl)-2-cyclopropylphenyl]methyl]-7-azabicyclo[2.2.1]heptan-2-yl]carbamate (39 mg, 0.084 mmol, 1.00 equiv). 1 H NMR (DMSO-d6, 400 MHz) δ 7.98-7.94(m,1H),7.62-7.59(m,2H),7.47(dd,J=8.0,1.5Hz,1H),7.32(t,J= 7.6Hz,1H),7.17(dd,J=7.7,1.4Hz,1H),4.11-4.07(m,1H),3.87-3.77(m,2H), 3.45(t,J=4.4Hz,1H),3.29(s,1H),2.82(s,3H),2.08-1.91(m,4H),1.53-1.40 (m,3H),1.38(s,9H),0.72-0.70(m,2H),0.02-0.00(m,2H);m / z=476.4[M+H]+.

[0568] General Procedure D2: Procedure D2.1: K2CO3 Step D2.2: Cs2CO3 To a solution of the phenol derivative (1.00 equiv.) was added RI (or R-Br) (1.50 equiv.) and K2CO3 (3.00 equiv.). The reaction mixture was stirred at 60 °C for 30 min, and then alkyl-I (1.20 equiv.) was added. The reaction mixture was stirred at 0 °C for 2 h. The reaction mixture was diluted with EtOAc and quenched with water. The two layers were separated, and the aqueous layer was extracted three times with EtOAc. The combined organic layers were dried through a phase separator and concentrated under reduced pressure. The crude material was purified by flash chromatography (EtOAc / cyclohexane 0-30%) to give the desired product.

[0569] Synthesis of 3-bromo-2-isopropoxy-benzaldehyde (Intermediate 75) [ka] 3-Bromo-2-isopropoxy-benzaldehyde (260 mg, quantitative), pale yellow solid. General procedure D2.1 from 3-bromo-2-hydroxybenzaldehyde (175 mg, 0.84 mmol, 1.00 equiv) and 2-iodopropane (218 mg, 1.27 mmol, 1.50 equiv). 1 H NMR(DMSO-d6,400MHz)δ 10.26(d,J=0.9Hz,1H),7.99(dd,J=7.9,1.7Hz,1H),7.75(dd,J=7.7,1.7Hz,1H ),7.24(td,J=7.8,0.8Hz,1H),4.51(hept,J=6.1Hz,1H),1.32(d,J=6.1Hz,7H).

[0570] General Procedure D3 To a solution of benzyl bromide derivative (or OM) (1.00 equiv.) was added amine (1.50 equiv.) and K2CO3 (3.00 equiv.). The reaction mixture was stirred at 60 °C for 30 min, and then alkyl-I (1.20 equiv.) was added. The reaction mixture was stirred at 0 °C for 2 h. The reaction mixture was diluted with AcOEt and quenched with water. The two layers were separated, and the aqueous layer was extracted three times with AcOEt. The combined organic layers were dried on a phase separator and concentrated under reduced pressure. The crude was purified by flash chromatography column (EtOAc / cyclohexane 0-30%) to give the desired product.

[0571] Synthesis of tert-butyl N-[rac-(1S,2S,4R)-7-[(3-bromo-2-isopropoxy-phenyl)methyl]-7-azabicyclo[2.2.1]heptan-2-yl]carbamate (Intermediate 76) [ka] tert-Butyl N-[rac-(1S,2S,4R)-7-[(3-bromo-2-isopropoxy-phenyl)methyl]-7-azabicyclo[2.2.1]heptan-2-yl]carbamate (265 mg, 91%), colorless oil. General procedure D3 from 1-bromo-3-(bromomethyl)-2-isopropoxybenzene (210 mg, 0.64 mmol, 1.00 equiv.) and tert-butyl rac-(1S,2S,4R)-7-azabicyclo[2.2.1]hept-2-ylcarbamate hydrochloride (252 mg, 0.96 mmol, 1.50 equiv.). 1 H NMR(DMSO-d6,400MHz)δ 7.51-7.47(m,2H),7.05-6.98(m,2H),4.52(p,J=6.2Hz,1H),3.69(br,s,1H),3.60-3.51(m,2H),3.20(br,s,1H),3.12(t,J=4.7Hz,1 H),1.98-1.91(m,1H),1.83-1.52(m,3H),1.37(s,9H),1.26(dd,J=6.1,2.6Hz,6H),1.00(dd,J=11.9,4.6Hz,1H);m / z=441.3[M+H]+.

[0572] Method E: Reduction General Step E1: Under a nitrogen atmosphere, NaBH4 (1.10 equiv.) was added to a solution of the aldehyde (1.00 equiv.) in MeOH (0.1 M) at 0 °C. The reaction mixture was stirred at 0 °C for 2 h. The reaction mixture was diluted with DCM and quenched with saturated aqueous NaHCO3. The two layers were separated, and the aqueous layer was extracted three times with DCM. The combined organic layers were dried over a phase separator and concentrated under reduced pressure. The crude material was purified by flash chromatography (EtOAc / cyclohexane 0-50%) to give the desired product.

[0573] Synthesis of [3-chloro-2-(4-chlorothiazol-5-yl)phenyl]methanol (Intermediate 77) [ka] [3-Chloro-2-(4-chlorothiazol-5-yl)phenyl]methanol (720 mg, quantitative), yellow solid. General procedure E1 from 3-chloro-2-(4-chlorothiazol-5-yl)benzaldehyde (433 mg, 1.68 mmol, 1.00 equiv). 1 H NMR(DMSO-d6,400MHz)δ 9.32(s,1H),7.61-7.57(m,1H),7.55-7.53(m,2H),5.38(t,J=5.3Hz,1H),4.29-4.20(m,2H);m / z=260.0[M+H]+.

[0574] General Procedure E2: Under a nitrogen atmosphere, PtO2 (0.20 equiv.) was added to a solution of alkene (1.00 equiv.) in EtOAc (0.02 M). The reaction mixture was purged with dihydrogen and stirred under a hydrogen atmosphere at room temperature for 24 h. The mixture was filtered through Celite and washed with EtOAc. The solvent was evaporated under reduced pressure. The crude material was purified by flash chromatography (5-30% EtOAc / cyclohexane) to give the desired product as a mixture with another product (60:40).

[0575] Synthesis of tert-butyl N-[rac-(1S,2S,4R)-7-[(3-chloro-2-isopropyl-phenyl)methyl]-7-azabicyclo[2.2.1]heptan-2-yl]carbamate (Intermediate 78) [ka] tert-Butyl N-[rac-(1S,2S,4R)-7-[(3-chloro-2-isopropylphenyl)methyl]-7-azabicyclo[2.2.1]heptan-2-yl]carbamate (80 mg, 60%), colorless wax. General procedure E2 from tert-butyl N-[rac-(1S,2S,4R)-7-[(3-chloro-2-isopropenylphenyl)methyl]-7-azabicyclo[2.2.1]heptan-2-yl]carbamate (80 mg, 0.21 mmol, 1.00 equiv). 1 H NMR(DMSO-d6,400MHz)δ 7.34-7.08(m,3H),6.96(d,J=6.6Hz,1H),3.90-3.73(m,1H),3.71-3.49(m,2H),3.18-3.02(m, 2H),1.92-1.49(m,4H),1.36(s,9H),1.31-1.24(m,8H),1.05-0.95(m,1H);m / z=379.3[M+H]+.

[0576] General Procedure E3: Under a nitrogen atmosphere, NaBH3CN (5.00 equiv.) was added to a solution of alkene (1.00 equiv.) in acetic acid (0.05 M) at 0 °C. The reaction mixture was stirred at room temperature for 24 h. The reaction mixture was filtered, washed with methanol, and concentrated under reduced pressure. The crude material was taken up in DCM, and saturated aqueous NaHCO3 was added. The two layers were separated, and the aqueous layer was extracted three times with DCM. The combined organic layers were dried over a phase separator and concentrated under reduced pressure. The crude material was purified by flash chromatography column (EtOAc / heptane 5-25%) to give the desired product.

[0577] Synthesis of tert-butyl 2-[(4-bromoindolin-1-yl)methyl]morpholine-4-carboxylate (Intermediate 79) [ka] tert-Butyl 2-[(4-bromoindolin-1-yl)methyl]morpholine-4-carboxylate (133 mg, 87%), colorless oil. General procedure E3 from tert-butyl 2-[(4-bromoindol-1-yl)methyl]morpholine-4-carboxylate (150 mg, 0.39 mmol, 1.00 equiv). 1 H NMR(DMSO-d6,400MHz)δ 6.92(t,J=7.9Hz,1H),6.69(d,J=7.6Hz,1H),6.48(d,J=7.8Hz,1H),3.99-3.78(m,2H),3.70(d,J=13.4Hz,1H),3.60-3.54(m,1H),3.50(dd,J=1 5.7,8.4Hz,2H),3.40(td,J=11.6,2.8Hz,1H),3.15(qd,J=14.4,5.7Hz, 2H),2.91(t,J=8.6Hz,3H),2.67(s,1H),1.41(s,9H);m / z=397.3[M+H]+.

[0578] General Procedure E4: Under a nitrogen atmosphere, borane tetrahydrofuran or DIBAL-H (1 M, 2.50 equiv.) was added to a 0.1 M solution of the amide derivative (1.00 equiv.) in THF. The reaction mixture was stirred at room temperature for 1-24 h. The reaction mixture was slowly quenched with 2 M aqueous HCl in MeOH. The reaction mixture was stirred at room temperature for 4 h. The reaction mixture was basified to pH 9 with saturated aqueous NaHCO3. The two layers were separated, and the aqueous layer was extracted three times with Et2O. The combined organic layers were dried through a phase separator and concentrated under reduced pressure. The crude material was purified by flash chromatography (5-20% EtOAc / cyclohexane) to give the desired product.

[0579] Synthesis of tert-butyl 2-[(3-bromo-2-chloro-5-methylanilino)methyl]morpholine-4-carboxylate (Intermediate 80) [ka] tert-Butyl 2-[(3-bromo-2-chloro-5-methylanilino)methyl]morpholine-4-carboxylate (77 mg, 74%), pale yellow oil. General procedure E4 from tert-butyl 2-[(3-bromo-2-chloro-5-methylphenyl)carbamoyl]morpholine-4-carboxylate (95 mg, 0.22 mmol, 1.00 equiv). m / z = 421.2 [M+H]+.

[0580] General Procedure E5: To a solution of the nitrobenzene derivative (1.00 equiv.) and zinc (10.0 equiv.) in MeOH (0.1 M) was added NH4Cl (10.0 equiv.). The reaction mixture was stirred at room temperature for 24 h. The mixture was filtered through Celite and washed with AcOEt. The solvent was evaporated under reduced pressure. The crude material was purified by flash chromatography (EtOAc / cyclohexane 5-30%) to give the desired product.

[0581] Synthesis of 3-bromo-2-chloro-5-methylaniline (Intermediate 81) [ka] 3-Bromo-2-chloro-5-methylaniline (350 mg, 60%), brown solid. General procedure E5 from 1-bromo-2-chloro-5-methyl-3-nitrobenzene (650 mg, 2.60 mmol, 1.00 equiv). 1 H NMR(DMSO-d6,400MHz)δ 6.71(dd,J=2.0,0.7Hz,1H),6.58(dd,J=1.9,0.8Hz,1H),5.56(s,2H),2.14(s,3H);m / z=222.1[M+H] + .

[0582] Method F: Alcohol Conversion General Procedure F1: Under a nitrogen atmosphere, CBr4 (1.10 equiv.) and PPh3 (1.10 equiv.) were added to a 0.1 M solution of benzyl alcohol (1.00 equiv.) in DCM. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with DCM and quenched with water. The two layers were separated, and the aqueous layer was extracted three times with DCM. The combined organic layers were dried over a phase separator and concentrated under reduced pressure. The crude material was purified by flash chromatography (EtOAc / cyclohexane 0-10%) to give the desired product.

[0583] Synthesis of 1-bromo-3-(bromomethyl)-2-isopropoxy-benzene (Intermediate 82) [ka] 1-Bromo-3-(bromomethyl)-2-isopropoxybenzene (230 mg, 92%), colorless liquid. General procedure F1 from (3-bromo-2-isopropoxyphenyl)methanol (210 mg, 0.76 mmol, 1.00 equiv). 1 H NMR(DMSO-d6,400MHz)δ 7.60(dd,J=8.0,1.6Hz,1H),7.49(dd,J=7.7,1.6Hz,1H),7.07(t,J=7.8Hz,1H),4.58(dt,J=12.3,6.2Hz,1H),1.30(d,J=6.1Hz,6H).

[0584] General Step F2: Under a nitrogen atmosphere, methanesulfonyl chloride (1.50 equiv.) was added to a DCM solution (0.03 M) of benzyl alcohol (1.00 equiv.) and NEt3 (2.00 equiv.) at 0°C. The reaction mixture was stirred at 0°C for 1 hour. The reaction mixture was diluted with DCM and quenched with saturated aqueous NaHCO3. The two layers were separated, and the aqueous layer was extracted three times with DCM. The combined organic layers were dried with a phase separator and concentrated under reduced pressure. The crude product was used in the next reaction without further purification.

[0585] Synthesis of [3-(4-cyano-3-fluoro-phenyl)-2-thiazol-5-yl-phenyl]methyl methanesulfonate (Intermediate 83) [ka] [3-(4-cyano-3-fluorophenyl)-2-thiazol-5-ylphenyl]methyl methanesulfonate (120 mg, 79%), dark orange oil. General procedure F2 from 2-fluoro-4-[3-(hydroxymethyl)-2-thiazol-5-ylphenyl]benzonitrile (90 mg, 0.29 mmol, 1.00 equiv). 1 H NMR(DMSO-d6,400MHz)δ 9.10(d,J=0.8Hz,1H),7.84-7.81(m,2H),7.76(dd,J=7.7,1.4Hz,1H),7.68(t,J=7.7Hz,1H),7.55(dd,J=7.7,1. 4Hz,1H),7.39(dd,J=10.5,1.5Hz,1H),7.18(dd,J=8.0,1.6Hz,1H),3.35(s,2H),3.11(s,3H);m / z=389.2[M+H]+.

[0586] General Step F3: Under a nitrogen atmosphere, a solution of benzyl alcohol (1.00 equiv.) and R-OH (1.10 equiv.) in toluene (0.07 M) was added with Tsunoda's reagent (2.00 equiv.). The reaction mixture was stirred at 100 °C for 1 h. The reaction mixture was diluted with DCM and quenched with saturated aqueous NaHCO3. The two layers were separated, and the aqueous layer was extracted three times with DCM. The combined organic layers were dried over a phase separator and concentrated under reduced pressure. The crude material was purified by flash chromatography (MeOH / DCM 0-10%) to give the desired product.

[0587] Synthesis of tert-butyl N-[rac-(1S,2S,4R)-7-[[3-bromo-4-[[rac-(3R)-tetrahydropyran-3-yl]methoxy]phenyl]methyl]-7-azabicyclo[2.2.1]heptan-2-yl]carbamate (Intermediate 84) [ka] tert-Butyl N-[rac-(1S,2S,4R)-7-[[3-bromo-4-[[rac-(3R)-tetrahydropyran-3-yl]methoxy]phenyl]methyl]-7-azabicyclo[2.2.1]heptan-2-yl]carbamate (118 mg, 94%), colorless liquid. General procedure F3 from tert-butyl N-[rac-(1S,2S,4R)-7-[(3-bromo-4-hydroxyphenyl)methyl]-7-azabicyclo[2.2.1]heptan-2-yl]carbamate (100 mg, 0.24 mmol, 1.00 equiv). 1 H NMR (DMSO-d6, 400 MHz) δ 7.50(d,J=2.1Hz,1H),7.28-7.26(m,1H),7.03(d,J=8.4Hz,1H),6.96(d,J=6.6 Hz,1H),3.96-3.86(m,3H),3.75(dt,J=11.3,3.9Hz,1H),3.66(br,s,1H),3.42( s,2H),3.37-3.32(m,2H),3.14(br,s,1H),3.06(br,s,1H),2.09-2.02(m,2H),1 .84-1.40(m,8H),1.36(s,9H),0.98(dd,J=12.0,4.6Hz,1H);m / z=495.4[M+H]+.

[0588] General Step F4: Under a nitrogen atmosphere, N-ethyl-N-(trifluoro-lambda-4-sulfanyl)ethanamine (1.7 equiv.) was added to a 0.1 M solution of R-OH (1.0 equiv.) in DCM. The reaction mixture was stirred at room temperature for 24 h. The reaction mixture was diluted with DCM and quenched with saturated aqueous NaHCO3. The two layers were separated, and the aqueous layer was extracted three times with DCM. The combined organic layers were dried over a phase separator and concentrated under reduced pressure. The crude product was purified by flash chromatography (AcOEt / n-heptane 0-70%) to give the desired product as a mixture with other species.

[0589] Synthesis of tert-butyl N-[rac-(1S,2S,4R)-7-[[3-chloro-2-(4-fluoro-1-piperidyl)phenyl]methyl]-7-azabicyclo[2.2.1]heptan-2-yl]carbamate (Intermediate 85) [ka] tert-Butyl N-[rac-(1S,2S,4R)-7-[[3-chloro-2-(4-fluoro-1-piperidyl)phenyl]methyl]-7-azabicyclo[2.2.1]heptan-2-yl]carbamate (55 mg, 20%), white solid. General Procedure F4 from tert-butyl N-[rac-(1S,2S,4R)-7-[[3-chloro-2-(4-hydroxy-1-piperidyl)phenyl]methyl]-7-azabicyclo[2.2.1]heptan-2-yl]carbamate (130 mg, 0.30 mmol, 1.00 equiv). 1H NMR(DMSO-d6,400MHz)δ 7.42-7.27(m,2H),7.21-7.10(m,1H),6.97(s,1H),3.81(s,1H),3.70- 3.57(m,3H),3.44(d,J=9.6Hz,1H),3.33-3.16(m,5H),3.02(d,J=50.4H z,2H),2.82(s,1H),2.30(d,J=24.5Hz,1H),2.04(t,J=15.9Hz,1H),1. 98-1.52(m,4H),1.37(s,9H),1.00(t,J=8.9Hz,1H);m / z=418.3[M+H]+.

[0590] Method G: Curtius rearrangement General Procedure G1: Under a nitrogen atmosphere, CBr4 (1.10 equiv.) and PPh3 (1.10 equiv.) were added to a 0.1 M solution of benzyl alcohol (1.00 equiv.) in DCM. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with DCM and quenched with water. The two layers were separated, and the aqueous layer was extracted three times with DCM. The combined organic layers were dried over a phase separator and concentrated under reduced pressure. The crude material was purified by flash chromatography (EtOAc / cyclohexane 0-10%) to give the desired product.

[0591] Synthesis of benzyl 4-(tert-butoxycarbonylamino)-2-azabicyclo[2.2.1]heptane-2-carboxylate (Intermediate 86) [ka] Benzyl 4-(tert-butoxycarbonylamino)-2-azabicyclo[2.2.1]heptane-2-carboxylate (10.21 g, 87%), pale yellow oil. General Procedure G1 from 2-benzyloxycarbonyl-2-azabicyclo[2.2.1]heptane-4-carboxylic acid (6.29 g, 30.1 mmol, 1.00 equiv). 1H NMR(DMSO-d6,400MHz)δ 7.39-7.27(m,5H),5.07-5.00(m,2H),4.04(d,J=14.5Hz,0H),3.25(br,s,2H) ,1.77-1.68(m,5H),1.58(br,s,1H),1.38(d,J=4.9Hz,9H);m / z=347.4[M+H]+.

[0592] Method H: Buchwald-Hartwig coupling General Procedure H1: H1.1:Ar-Br H1.2:Ar-I To a 0.1 M solution of Ar-Br (or Ar-I) (1.00 equiv.) in 1,4-dioxane was added NaOtBu (3.00 equiv.) and Xantphos (0.10 equiv.). The reaction mixture was degassed with argon for 5 minutes, and Pd2dba3 (0.05 equiv.) and an amine (1.40 equiv.) were added. The reaction mixture was heated at 100 °C for 5-24 hours. The reaction mixture was cooled to room temperature, diluted with DCM, and quenched with water. The two layers were separated, and the aqueous layer was extracted three times with DCM. The combined organic layers were dried through a phase separator and concentrated under reduced pressure. The crude material was purified by flash chromatography (MeOH / DCM 0-10%) to give the desired product.

[0593] Synthesis of [2-(azetidin-1-yl)-3-chloro-6-fluoro-phenyl]-(1-methyl-1,7-diazaspiro[3.4]octan-7-yl)methanone (Intermediate 87) [ka] [2-(Azetidin-1-yl)-3-chloro-6-fluorophenyl]-(1-methyl-1,7-diazaspiro[3.4]octan-7-yl)methanone (92 mg, 19%), orange sticky oil. General procedure H1.1 from 2(2-bromo-3-chloro-6-fluorophenyl)-(1-methyl-1,7-diazaspiro[3.4]octan-7-yl)methanone (412 mg, 1.12 mmol, 1.00 equiv) and azetidine (0.11 mL, 1.55 mmol, 1.40 equiv). 1 H NMR(DMSO-d6,400MHz)δ 7.28-7.23(m,1H),6.58(td,J=8.6,5.3Hz,1H),4.24-4.18(m,2H),4.10-4.00(m, 2H),3.59-3.35(m,3H),3.29-2.95(m,4H),2.19-1.91(m,9H);m / z=338.2[M+H]+.

[0594] General Procedure H2: To a 0.1 M solution of Ar-Br (1.00 equiv.) in toluene, the amine (1.00 equiv.) and NaOtBu (3.00 equiv.) were added. The reaction mixture was degassed with argon for 5 minutes, and Pd-113 (0.06 equiv.) was added. The reaction mixture was heated at 100°C for 24 hours. The reaction mixture was cooled to room temperature, diluted with DCM, and quenched with water. The two layers were separated, and the aqueous layer was extracted three times with DCM. The combined organic layers were dried over a phase separator and concentrated under reduced pressure. The crude material was purified by flash chromatography (0-25% EtOAc / cyclohexane) to give the desired product.

[0595] Synthesis of tert-butyl-dimethyl-[[4-(4-methyl-1-piperidyl)phenyl]methoxy]silane (Intermediate 88) [ka] tert-Butyl-dimethyl-[[4-(4-methyl-1-piperidyl)phenyl]methoxy]silane (214 mg, quantitative), colorless oil. General procedure H2 from (4-bromophenyl)methoxy-tert-butyl-dimethyl-silane (200 mg, 0.65 mmol, 1.00 equiv.) and 4-methylpiperidine (81 μL, 0.65 mmol, 1.00 equiv.). 1 H NMR(DMSO-d6,400MHz)δ 7.13-7.10(m,2H),6.90-6.86(m,2H),4.57(s,2H),3.62(d,J=12.3Hz,2H),2.61(td,J=12.3,2.6Hz,2H),1.67(d,J=12.9Hz,2H),1 .48(ddq,J=14.7,7.1,3.7Hz,1H),1.21(qd,J=12.1,4.0Hz,2H),0.93(d,J=6.5Hz,3H),0.88(s,9H),0.05(s,6H);m / z=320.4[M+H] + .

[0596] General procedure H3: To a 0.1 M solution of Ar-Br (1.00 equiv.) in toluene, amine (1.10 equiv.), Cs2CO3 (3.00 equiv.), and (rac)-BINAP (0.15 equiv.) were added. The reaction mixture was degassed with argon for 5 minutes, and Pd2dba3 (0.10 equiv.) was added. The reaction mixture was heated at 95 °C for 24 h. The reaction mixture was cooled to room temperature, diluted with EtOAc, and quenched with water. The two layers were separated, and the aqueous layer was extracted three times with EtOAc. The combined organic layers were dried through a phase separator and concentrated under reduced pressure. The crude material was purified by flash chromatography (0-30% EtOAc / cyclohexane) to give the desired product.

[0597] Synthesis of 3-chloro-2-pyrrolidin-1-yl-benzaldehyde (Intermediate 89) [ka] 3-Chloro-2-pyrrolidin-1-ylbenzaldehyde (545 mg, 53%), yellow oil. General procedure H3 from 2-bromo-3-chlorobenzaldehyde (600 mg, 2.68 mmol, 1.00 equiv) and pyrrolidine (246 μL, 2.95 mmol, 1.10 equiv). 1 H NMR(DMSO-d6,400MHz)δ 10.26(d,J=0.8Hz,1H),7.79-7.75(m,1H),7.66(dd,J=7.7,1.6Hz,1H),7.33(t d,J=7.8,0.8Hz,1H),3.34-3.31(m,4H),2.04-1.97(m,4H);m / z=210.2[M+H]+.

[0598] General Procedure H4: To a toluene solution (0.1 M) of Ar-Br (1.00 equiv.) was added [Pd(C4H9)3PBr]2 (0.06 equiv.) and NaOtBu (2.00 equiv.). The reaction mixture was degassed with argon for 5 minutes, and the amine (1.20 equiv.) was added. The reaction mixture was heated at 100 °C for 2 hours. The reaction mixture was cooled to room temperature, diluted with EtOAc, and quenched with water. The two layers were separated, and the aqueous layer was extracted three times with EtOAc. The combined organic layers were dried through a phase separator and concentrated under reduced pressure. The crude material was purified by flash chromatography (0-20% EtOAc / cyclohexane) to give the desired product.

[0599] Synthesis of tert-butyl 2-[[4-(azetidin-1-yl)-3-chloro-N-methylanilino]methyl]morpholine-4-carboxylate (Intermediate 90) [ka] tert-Butyl 2-[[4-(azetidin-1-yl)-3-chloro-N-methylanilino]methyl]morpholine-4-carboxylate (100 mg, 68%), colorless oil. General procedure H4 from tert-butyl 2-[(4-bromo-3-chloro-N-methylanilino)methyl]morpholine-4-carboxylate (149 mg, 0.36 mmol, 1.00 equiv.) and azetidine (30 μL, 0.42 mmol, 1.20 equiv.). m / z=396.4 [M+H] + . (No NMR)

[0600] General Procedure H5: Under an argon atmosphere, to a 0.2 M solution of Ar-Br (1.00 equiv.) in dioxane (3.00 equiv.), NaOtBu (4.00 equiv.), Xantphos (0.10 equiv.), and Pd2dba3 (0.05 equiv.) were added. The reaction mixture was heated at 100 °C for 1 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude material was directly purified by flash chromatography (MeOH / heptane 0-30%) to give the desired product.

[0601] Synthesis of 1-[[4-(azetidin-1-yl)-3-chlorophenyl]methyl]-4-methyl-piperazine (Intermediate 91) [ka] 1-[[4-(azetidin-1-yl)-3-chlorophenyl]methyl]-4-methylpiperazine (416 mg, 97%), brown oil. General procedure H5 from 1-[(4-bromo-3-chlorophenyl)methyl]-4-methylpiperazine (467 mg, 1.54 mmol, 1.00 equiv.) and azetidine (327 μL, 4.61 mmol, 3.00 equiv.). m / z=278.3 [M+H] + . (No NMR)

[0602] General Procedure H6: To a 0.1 M solution of Ar-Br (1.00 equiv.) in dioxane was added amine (1.25 equiv.) and NaOtBu (3.50 equiv.). The reaction mixture was degassed with argon for 5 minutes, and Pd(OAc)2 (0.50 equiv.) and JohnPhos (0.05 equiv.) were added. The reaction mixture was heated at 90 °C for 24 h. The reaction mixture was cooled to room temperature, diluted with DCM, and quenched with water. The two layers were separated, and the aqueous layer was extracted three times with DCM. The combined organic layers were dried through a phase separator and concentrated under reduced pressure. The crude material was purified by flash chromatography (EtOAc / cyclohexane 0-50%) to give the desired product.

[0603] Synthesis of tert-butyl N-[rac-(1S,2S,4R)-7-[[3-chloro-4-(1-oxa-8-azaspiro[4.5]decan-8-yl)phenyl]methyl]-7-azabicyclo[2.2.1]heptan-2-yl]carbamate (Intermediate 92) [ka] tert-Butyl N-[rac-(1S,2S,4R)-7-[[3-chloro-4-(1-oxa-8-azaspiro[4.5]decan-8-yl)phenyl]methyl]-7-azabicyclo[2.2.1]heptan-2-yl]carbamate (66 mg, 33%), yellow oil. General procedure H6 from tert-butyl N-[rac-(1S,2S,4R)-7-[(4-bromo-3-chlorophenyl)methyl]-7-azabicyclo[2.2.1]heptan-2-yl]carbamate (150 mg, 0.36 mmol, 1.00 equiv.) and 1-oxa-8-azaspiro[4.5]decane hydrochloride (84 mg, 0.45 mmol, 1.25 equiv.). 1 H NMR(DMSO-d6,400MHz)δ 7.34(d,J=2.0Hz,1H),7.27-7.20(m,1H),7.10(d,J=8.1Hz,1H),3.75(t,J=6.7Hz,2H),3.71-3.59(m,1H),3.43(br s,2H),3.20-3.04(m,2H),3.02-2.88(m,4H),1.98-1.85(m,3H),1.80-1 .51(m,6H),1.36(s,9H),0.99(dd,J=12.0,4.6Hz,1H);m / z=476.1[M+H] + .

[0604] General Procedure H7: To a solution of Ar-Br (1.00 equiv.) in dioxane (0.05 M) was added the amine (1.50 equiv.) and Pd2dba3 (0.10 equiv.). The reaction mixture was degassed with argon for 5 minutes, and NaOtBu (4.1 equiv.) was added. The reaction mixture was heated at 95 °C for 24 h. The reaction mixture was cooled to room temperature, diluted with EtOAc, and quenched with water. The two layers were separated, and the aqueous layer was extracted three times with EtOAc. The combined organic layers were dried over a phase separator and concentrated under reduced pressure. The crude material was purified by flash chromatography (EtOAc / cyclohexane 0-100%) to give the desired product.

[0605] Synthesis of tert-butyl N-[rac-(1S,2S,4R)-7-[[3-chloro-4-[4-(fluoromethyl)-1-piperidyl]phenyl]methyl]-7-azabicyclo[2.2.1]heptan-2-yl]carbamate (Intermediate 93) [ka] tert-Butyl N-[rac-(1S,2S,4R)-7-[[3-chloro-4-[4-(fluoromethyl)-1-piperidyl]phenyl]methyl]-7-azabicyclo[2.2.1]heptan-2-yl]carbamate (45 mg, 31%), yellow foam. General procedure H7 from tert-butyl N-[rac-(1S,2S,4R)-7-[(4-bromo-3-chlorophenyl)methyl]-7-azabicyclo[2.2.1]heptan-2-yl]carbamate (100 mg, 0.24 mmol, 1.00 equiv.) and 4-(fluoromethyl)piperidine hydrochloride (58 mg, 0.36 mmol, 1.50 equiv.). 1H NMR(DMSO-d6,400MHz)δ 7.24(d,J=8.3Hz,1H),7.10(d,J=8.2Hz,1H),6.97(d,J=6.6Hz,1H),4.42(d,J=5.9Hz,1H),4.30(d,J=5.6Hz,1H),3.67(br s,1H),3.52-3.41(m,2H),3.28(d,J=10.8Hz,2H),3.12(d,J=28.6Hz,2H),2.64(t,J=11.9Hz,2H),1.93(d,J=15.8Hz ,1H),1.85-1.51(m,6H),1.49-1.39(m,2H),1.36(s,9H),1.24(s,2H),0.99(dd,J=11.7,4.4Hz,1H);m / z=452.4[M+H] + .

[0606] Method I: Oxidation General Procedure I1: Under a nitrogen atmosphere, MnO (10 equiv.) was added to a solution of benzyl alcohol (1.0 equiv.) in DCM (0.05 M). The reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was filtered through dicalite, washed with DCM, and the volatiles were concentrated under reduced pressure to give the desired product. The crude product was used in the next step without further purification.

[0607] Synthesis of 4-[2-(4-chlorothiazol-5-yl)-3-formyl-phenyl]-2-fluoro-benzonitrile (Intermediate 94) [ka] 4-[2-(4-chlorothiazol-5-yl)-3-formylphenyl]-2-fluorobenzonitrile (106 mg, 94%), white solid. General procedure I1 from 4-[2-(4-chlorothiazol-5-yl)-3-(hydroxymethyl)phenyl]-2-fluorobenzonitrile (105 mg, 0.305 mmol, 1.00 equiv). 1H NMR(DMSO-d6,400MHz)δ 9.85(s,1H),9.19(s,1H),8.11(dd,J=7.0,2.2Hz,1H),7.93-7.84(m,3H),7 .42(dd,J=10.3,1.6Hz,1H),7.15(dd,J=8.0,1.6Hz,1H);m / z=343.2[M+H]+.

[0608] General Procedure I2: Under a nitrogen atmosphere, Dess-Martin periodinane (1.1 equiv.) was added to a 0.1 M solution of benzyl alcohol (1.0 equiv.) in DCM. The reaction mixture was stirred at room temperature for 24 h. The reaction mixture was diluted with DCM and quenched with saturated aqueous NaHCO3 and saturated aqueous Na2S2O3. The two layers were separated, and the aqueous layer was extracted three times with DCM. The combined organic layers were dried over a phase separator and concentrated under reduced pressure. The crude product was used in the next step without further purification.

[0609] Synthesis of 2-fluoro-4-(3-formyl-2,5-dimethyl-phenyl)benzonitrile (Intermediate 95) [ka] 2-Fluoro-4-(3-formyl-2,5-dimethylphenyl)benzonitrile (280 mg, 86%), white solid. General procedure I2 from 2-fluoro-4-[3-(hydroxymethyl)-2,5-dimethylphenyl]benzonitrile (297 mg, 1.163 mmol, 1.00 equiv). 1 H NMR(DMSO-d6,400MHz)δ 10.31(s,1H),8.02(dd,J=8.0,7.0Hz,1H),7.74(d,J=2.0Hz,1H),7.65-7.54(m,1H),7.43-7.36(m,2H),2.44(s,3H),2.39(s,3H).

[0610] General Procedure I3: Under a nitrogen atmosphere, 2,6-dimethylpyridine (2 equiv.) and tetraoxoosmium (0.02 equiv.) were added to a 0.07 M solution of alkene (1.0 equiv.) in 1,4-dioxane. The reaction mixture was stirred at room temperature for 10 minutes, and sodium periodate (4 equiv.) was added. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with DCM and quenched with water. The two layers were separated, and the aqueous layer was extracted three times with DCM. The combined organic layers were dried over a phase separator and concentrated under reduced pressure. The crude product was purified by flash chromatography (AcOEt / cyclohexane 0-20%) to give the desired product.

[0611] Synthesis of 3-chloro-4-(difluoromethoxymethyl)benzaldehyde (Intermediate 96) [ka] 3-Chloro-4-(difluoromethoxymethyl)benzaldehyde (76 mg, 72%), colorless oil. General procedure I3 from 2-chloro-1-(difluoromethoxymethyl)-4-vinylbenzene (102 mg, 0.46 mmol, 1.00 equiv). 1 H NMR(CDCl3,400MHz)δ 9.99(s,1H),7.90(d,J=1.6Hz,1H),7.82(dd,J=7.9,1.6Hz,1H),7.69(d,J=7.9Hz,1H),6.41(t,J=73.5Hz,1H),5.07(s,2H).

[0612] Method J: Additive group General Procedure J1: Under a nitrogen atmosphere, 1-bromopyrrolidine-2,5-dione (1.2 equiv.) was added to a 0.1 M solution of Ar-H (1.0 equiv.) in DCM at 0°C. The reaction mixture was stirred at 0°C for 1 h. The reaction mixture was diluted with DCM and quenched with water. The two layers were separated, and the aqueous layer was extracted three times with DCM. The combined organic layers were dried over a phase separator and concentrated under reduced pressure. The crude material was purified by flash chromatography (AcOEt / cyclohexane 0-20%) to give the desired product.

[0613] Synthesis of 1-(2-bromo-4-{[(tert-butyldimethylsilyl)oxy]methyl}phenyl)-4-methylpiperidine (Intermediate 97) [ka] 1-(2-Bromo-4-{[(tert-butyldimethylsilyl)oxy]methyl}phenyl)-4-methylpiperidine (108 mg, 63%), yellow oil. General procedure J1 from 1-(4-{[(tert-butyldimethylsilyl)oxy]methyl}phenyl)-4-methylpiperidine (111 mg, 0.340 mmol, 1.00 equiv). 1 H NMR(DMSO-d6,400MHz)δ 7.50(dd,J=1.9,0.8Hz,1H),7.27-7.22(m,1H),7.12(d,J=8.2Hz,1H),4.64(d,J=0.9Hz,2H),3.19(d,J=11.7Hz,2H),2.64-2.54(m,2H),1.69 (t,J=12.2Hz,3H),1.48(ddd,J=11.0,7.1,3.9Hz,1H),1.36-1.24(m,2H),0.97(d,J=6.5Hz,3H),0.90(s,9H),0.08(s,6H);m / z=398.4[M+H]+.

[0614] General Procedure J2: A 1 M solution of [bis(trimethylsilyl)amino]lithium (1 M, 2 equiv.) was added to a 0.05 M solution of Ar-H (1.0 equiv.) in THF at -78 °C under a nitrogen atmosphere. The reaction mixture was stirred at -78 °C for 1 h, and then N-(benzenesulfonyl)-N-fluoro-benzenesulfonamide (2 equiv.) was added. The reaction mixture was warmed to room temperature and stirred for 24 h. The reaction mixture was diluted with DCM and quenched with saturated aqueous NH4Cl. The two layers were separated, and the aqueous layer was extracted three times with DCM. The combined organic layers were dried through a phase separator and concentrated under reduced pressure. The crude material was purified by flash chromatography (EtOAc / n-heptane 0-30%) to give the desired product.

[0615] Synthesis of 5-(2-{[(tert-butyldimethylsilyl)oxy]methyl}-6-chlorophenyl)-4-fluoro-1,3-oxazole (Intermediate 98) [ka] 5-(2-{[(tert-butyldimethylsilyl)oxy]methyl}-6-chlorophenyl)-4-fluoro-1,3-oxazole (97 mg, 51%), yellow oil. General procedure J2.1 from 5-(2-{[(tert-butyldimethylsilyl)oxy]methyl}-6-chlorophenyl)-1,3-oxazole (180 mg, 0.550 mmol, 1.00 equiv). 1 H NMR(DMSO-d6,400MHz)δ 8.53(d,J=2.1Hz,1H),7.63-7.55(m,3H),4.59(s,2H),0.83(s,9H),-0.01(s,6H);m / z=342.3[M+H] + .

[0616] General Procedure J3: To a 0.05 M solution of Ar-H (1.0 equiv.) in DMF was added 1-chloropyrrolidine-2,5-dione (1 equiv.) at room temperature under an argon atmosphere. The reaction mixture was stirred at 100°C for 1 hour. The reaction mixture was concentrated under reduced pressure. The crude product was purified by flash chromatography (EtOAc / cyclohexane 0-50%) to give the desired product.

[0617] Synthesis of 4-[2-(3-chloro-2-methyl-indazol-5-yl)-5-formyl-phenyl]-2-fluoro-benzonitrile (Intermediate 99) [ka] 4-[2-(3-chloro-2-methylindazol-5-yl)-5-formylphenyl]-2-fluorobenzonitrile (62 mg, 73%), off-white solid. General procedure J3 from 2-fluoro-4-[5-formyl-2-(2-methylindazol-5-yl)phenyl]benzonitrile (67 mg, 0.189 mmol, 1.00 equiv). 1 H NMR(CDCl3,400MHz)δ 10.12(s,1H),8.01(dd,J=7.9,1.7Hz,1H),7.92(d,J=1.6Hz,1H),7.72(d,J=7.9Hz,1H),7.50 -7.43(m,4H),7.11-7.05(m,2H),6.90(dd,J=9.0,1.7Hz,1H),4.18(s,3H);m / z=390.3[M+H]+.

[0618] Method K: CH activation General Procedure K1: To a 0.2 M solution of Ar-Br (1.00 equiv.) in DMA, Ar-H (1.30 equiv.), K2CO3 (2.00 equiv.), pivalic acid (0.40 equiv.), and PCy3.HBF4 (0.15 equiv.) were added. The reaction mixture was degassed for 5 min, and then Pd(OAc)2 (0.10 equiv.) was added. The reaction mixture was stirred at 110 °C for 1-24 h. The reaction mixture was diluted with EtOAc and quenched with water. The two layers were separated, and the aqueous layer was extracted three times with EtOAc. The combined organic layers were dried over a phase separator and concentrated under reduced pressure. If necessary, the crude material was purified by flash chromatography (0-100% EtOAc / cyclohexane) to give the desired product.

[0619] Synthesis of 3-chloro-2-(4-chlorothiazol-5-yl)benzaldehyde (Intermediate 100) [ka] 3-Chloro-2-(4-chlorothiazol-5-yl)benzaldehyde (570 mg, 38%), yellow solid. General procedure K1 from 2-bromo-3-chlorobenzaldehyde (1.0 g, 4.47 mmol, 1.00 equiv) and 4-chloro-1,3-thiazole (509 μL, 5.81 mmol, 1.30 equiv). 1 H NMR (DMSO-d 6, 400MHz,)δ 9.77(d,J=0.6Hz,1H),9.38(s,1H),9.32(s,1H),7.99(ddd,J=7.8,5.6,1.3Hz,2H),7.79(td,J=7.9,0.6Hz,1H);m / z=258.0[M+H]+.

[0620] General Procedure K2: To a 0.2 M solution of Ar-Br (1.00 equiv.) in DMA, Ar-H (1.02 equiv.), K2CO3 (2.64 equiv.), pivalic acid (0.38 equiv.), and Me4tButylXphos (0.12 equiv.) were added. The reaction mixture was degassed for 5 min, and then Pd(OAc)2 (0.10 equiv.) was added. The reaction mixture was stirred at 110 °C for 1-24 h. The reaction mixture was filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography (20-80% EtOAc / cyclohexane) to give the desired product.

[0621] Synthesis of 3-chloro-6-fluoro-2-oxazol-5-yl-benzaldehyde (Intermediate 101) [ka] 3-Chloro-6-fluoro-2-oxazol-5-ylbenzaldehyde (66 mg, 37%), orange oil. General procedure K1 from 2-bromo-3-chloro-6-fluorobenzaldehyde (130 mg, 0.52 mmol, 1.00 equiv) and 1,3-oxazole (35 μL, 0.53 mmol, 1.02 equiv). 1 H NMR (DMSO-d 6,400MHz,)δ 9.91(s,1H),8.63(s,1H),7.99(dd,J=9.0,4.9Hz,1H),7.64(dd,J=10.1,9.0Hz,1H),7.53(s,1H);m / z=226.0[M+H]+.

[0622] General Procedure K3: To a 0.2 M solution of Ar-Br (1.00 equiv.) in toluene, Ar-H (2.00 equiv.), K2CO3 (3.00 equiv.), pivalic acid (0.40 equiv.), and cataCXium® (0.10 equiv.) were added. The reaction mixture was degassed for 5 min, and then Pd(OAc)2 (0.05 equiv.) was added. The reaction mixture was stirred at 110 °C for 1-24 h. The reaction mixture was diluted with DCM and quenched with water. The two layers were separated, and the aqueous layer was extracted three times with DCM. The combined organic layers were dried through a phase separator and concentrated under reduced pressure. If necessary, the crude material was purified by flash chromatography (0-30% EtOAc / cyclohexane) to give the desired product.

[0623] Synthesis of tert-butyl N-[1-(3-chloro-2-isothiazol-5-yl-phenyl)-4-piperidyl]carbamate (Intermediate 102) [ka] tert-Butyl N-[1-(3-chloro-2-isothiazol-5-ylphenyl)-4-piperidyl]carbamate (100 mg, 55%), yellow solid. General procedure K3 from tert-butyl N-[1-(2-bromo-3-chlorophenyl)-4-piperidyl]carbamate (200 mg, 0.48 mmol, 1.00 equiv) and 1,2-thiazole (84 mg, 0.96 mmol, 2.00 equiv). 1 H NMR (DMSO-d 6,400MHz,)δ 8.63(d,J=1.8Hz,1H),7.72(d,J=1.8Hz,1H),7.40(t,J=8.0Hz,1H),7.32(dd,J=8.1,1.2Hz,1H),7.24(dd,J=8.0,1.3Hz,1H), 6.84(d,J=7.6Hz,1H),2.94(d,J=12.1Hz,2H),2.63(t,J=11.2Hz,2H),1.65(d,J=12.5Hz,2H),1.37(s,10H);m / z=394.2[M+H] + .

[0624] Method L: Protection General Procedure L1: Under a nitrogen atmosphere, TBDMSCl (1.20 equiv.) and imidazole (2.00 equiv.) were added to a 0.1 M solution of benzyl alcohol (1.00 equiv.) in DMA. The reaction mixture was stirred at room temperature for 24 h. The reaction mixture was diluted with EtOAc. The organic layer was washed with saturated aqueous Na2CO3 and then with brine. The two layers were separated, and the organic layer was dried over a phase separator and concentrated under reduced pressure. The crude material was purified by flash chromatography (0-50% EtOAc / cyclohexane) to give the desired product.

[0625] Synthesis of tert-butyl-[[3-chloro-2-(4-chlorothiazol-5-yl)phenyl]methoxy]-dimethyl-silane (Intermediate 103) [ka] General procedure L1 from tert-butyl-[[3-chloro-2-(4-chlorothiazol-5-yl)phenyl]methoxy]dimethylsilane (389 mg, 35%), yellow oil. [3-chloro-2-(4-chlorothiazol-5-yl)phenyl]methanol (720 mg, 2.77 mmol, 1.00 equiv). 1H NMR(DMSO-d6,400MHz)δ 9.33(s,1H),7.57-7.55(m,3H),4.44(d,J=1.7Hz,3H),0.84(s,9H),-0.02(d,J=1.7Hz,6H);m / z=374.2[M+H]+.

[0626] General Procedure L2: To a solution of the amine (1.00 equiv.) in HO (0.1 M) was added CbzCl (1.50 equiv.). NaHCO3 (3.00 equiv.) was added portionwise, and the reaction mixture was stirred at room temperature for 24 h. The reaction mixture was diluted with Et2O and quenched with saturated aqueous NaHCO3. The aqueous layer (pH = 8-9) was washed twice with Et2O. The aqueous layer was then acidified to pH = 3-4 by dropwise addition of HCl 37% and extracted three times with Et2O. The combined organic layers were dried on a phase separator and concentrated under reduced pressure. The crude product was carried on to the next step without further purification.

[0627] Synthesis of 2-benzyloxycarbonyl-2-azabicyclo[2.2.1]heptane-4-carboxylic acid (intermediate 104) [ka] 2-Benzyloxycarbonyl-2-azabicyclo[2.2.1]heptane-4-carboxylic acid (1.27 g, 80%), white solid. General procedure L2 from 2-azabicyclo[2.2.1]heptane-4-carboxylic acid hydrochloride (1.00 g, 5.63 mmol, 1.00 equiv). 1 H NMR(DMSO-d6,400MHz)δ 12.62(s,1H),7.39-7.29(m,5H),5.08-5.00(m,2H),4.21(d,J=12.8Hz,1H),3.45(ddd,J=24.2,9.4,3.0Hz,1H),3. 19(dd,J=23.6,8.3Hz,1H),1.97(tt,J=11.1,3.4Hz,1H),1.86-1.76(m,2H),1.69-1.61(m,3H);m / z=276.2[M+H]+.

[0628] Method M: Ullmann Coupling General Procedure M1: To an aqueous solution of methanamine (2 M, 5 equiv.) was added Ar-Br (1.00 equiv.) and copper (0.10 equiv.). The reaction mixture was heated at 95° C. for 24 hours. The reaction mixture was cooled to room temperature and diluted. The two layers were separated, and the aqueous layer was extracted three times with EtOAc. The combined organic layers were dried on a phase separator and concentrated under reduced pressure. The crude product was used in the next step without further purification.

[0629] Synthesis of 2-chloro-N-methyl-4-[(4-methylpiperazin-1-yl)methyl]aniline (Intermediate 105) [ka] 2-Chloro-N-methyl-4-[(4-methylpiperazin-1-yl)methyl]aniline (35 mg, 81%), pale yellow oil. General procedure M1 from 1-[(4-bromo-3-chlorophenyl)methyl]-4-methylpiperazine (50 mg, 0.16 mmol, 1.00 equiv). 1 H NMR(CDCl3,400MHz)δ 7.22(d,J=2.1Hz,1H),7.09(dd,J=8.2,2.0Hz,1H),6.58(d,J=8.2Hz,1H),4.27(d,J=7.1Hz,1H),3.38(s,2H),2.89(d,J=5.1Hz,3H),2.44(br s,7H),2.28(s,3H),1.74(br s,1H);m / z=254.3[M+H]+.

[0630] Method N: Stille Coupling General Procedure N1: A 0.1 M solution of Ar-Br (1.00 equiv.) in toluene was degassed with argon for 5 minutes, and Ar-SnBu3 (2.00 equiv.) and Pd(PPh3)4 (0.10 equiv.) were added. The reaction mixture was heated at 120 °C for 2 hours. The reaction mixture was cooled to room temperature, diluted with DCM, and quenched with water. The two layers were separated, and the aqueous layer was extracted three times with DCM. The combined organic layers were dried over a phase separator and concentrated under reduced pressure. The crude material was purified by flash chromatography (1-50% EtOAc / cyclohexane) to give the desired product.

[0631] Synthesis of tert-butyl N-[rac-(1S,2S,4R)-7-[(3-chloro-4-thiazol-2-yl-phenyl)methyl]-7-azabicyclo[2.2.1]heptan-2-yl]carbamate (Intermediate 106) [ka] tert-Butyl N-[rac-(1S,2S,4R)-7-[(3-chloro-4-thiazol-2-ylphenyl)methyl]-7-azabicyclo[2.2.1]heptan-2-yl]carbamate (32 mg, 29%), pale yellow oil. General Procedure N1 from tert-butyl N-[rac-(1S,2S,4R)-7-[(4-bromo-3-chlorophenyl)methyl]-7-azabicyclo[2.2.1]heptan-2-yl]carbamate (100 mg, 0.24 mmol, 1.00 equiv.) and 2-(tributylstannanyl)-1,3-thiazole (151 μL, 0.48 mmol, 2.00 equiv.). 1H NMR(DMSO-d6,400MHz)δ 8.14(d,J=8.1Hz,1H),8.03(d,J=3.2Hz,1H),7.95(d,J=3.2Hz,1H),7.60(d,J=1.6H z,1H),7.47(dd,J=8.0,1.7Hz,1H),3.79-3.70(m,1H),3.23(m,1H),3.14(t,J=4.7H z,1H),2.07-1.93(m,1H),1.84-1.54(m,3H),1.37(s,9H),1.34-1.28(m,1H),1.21- 1.11(m,1H),1.03(dd,J=12.1,4.7Hz,1H),0.89(t,J=7.3Hz,3H);m / z=420.4[M+H]+.

[0632] Method O: Photoredox cross-electrophilic coupling General Procedure O1: Under a nitrogen atmosphere, a 0.01 M solution of Ar-Br (1.00 equiv.) in DME was mixed with R-Br (2.00 equiv.), Ir[dF(CF3)ppy]2(dtbbpy)PF6 (0.03 equiv.), TTMSS (1.00 equiv.), and Na2CO3 (2.00 equiv.). To a separate vial, under a nitrogen atmosphere, NiCl2·glyme (0.075 equiv.) and 4,4'-di-tert-butyl-2,2'-bipyridine (0.075 equiv.) in DME (0.01 M) were added. The precatalyst mixture was stirred at room temperature for 15 min, and then 0.2 mL (0.01 equiv.) of the precatalyst solution was added to the reaction mixture. The reaction mixture was stirred at 40 °C for 6 h under irradiation with a 34 W blue LED lamp. The reaction mixture was quenched by exposure to air and concentrated under reduced pressure. The crude was purified by flash chromatography column (MeOH / DCM 0-10%) to give the desired product.

[0633] Synthesis of tert-butyl N-[rac-(1S,2S,4R)-7-[(3-chloro-4-thiazol-2-yl-phenyl)methyl]-7-azabicyclo[2.2.1]heptan-2-yl]carbamate (Intermediate 107) [ka] tert-Butyl N-[rac-(1S,2S,4R)-7-[(3-chloro-4-thiazol-2-ylphenyl)methyl]-7-azabicyclo[2.2.1]heptan-2-yl]carbamate (32 mg, 29%), yellow oil. General procedure O1 from tert-butyl N-[rac-(1S,2S,4R)-7-[(4-bromo-3-chlorophenyl)methyl]-7-azabicyclo[2.2.1]heptan-2-yl]carbamate (83 mg, 0.20 mmol, 1.00 equiv.) and 3-(bromomethyl)oxetane (63 mg, 0.40 mmol, 2.00 equiv.). 1 H NMR(CDCl3,400MHz)δ 7.39(s,1H),7.07(m,2H),4.81(dd,J=7.7,6.0Hz,2H),4.56(br s,1H),4.49(t,J=6.1Hz,2H),4.04(br s,1H),3.66-3.50(m,3H),3.44-3.31(m,1H),3.11(d,J=7.8Hz,2H),2.36(br s,1H),1.91(br s,1H),1.59(m,5H),1.42(s,9H);m / z=407.5[M+H]+.

[0634] Method P: Peptide Coupling General Procedure P1: To a 0.1 M solution of carboxylic acid (1.00 equiv.) in DMF was added amine (1.10 equiv.), NEt3 (5.00 equiv.), and HATU (1.20 equiv.). The reaction mixture was stirred at room temperature for 24 h. The reaction mixture was diluted with EtOAc and quenched with saturated aqueous NaHCO3. The two layers were separated, and the aqueous layer was extracted three times with EtOAc. The combined organic layers were dried over a phase separator and concentrated under reduced pressure. If necessary, the crude material was purified by flash chromatography (MeOH / DCM 0-10%) to give the desired product.

[0635] Synthesis of (2-bromo-3-chloro-6-fluoro-phenyl)-(1-methyl-1,7-diazaspiro[3.4]octan-7-yl)methanone (Intermediate 108) [ka] (2-Bromo-3-chloro-6-fluorophenyl)-(1-methyl-1,7-diazaspiro[3.4]octan-7-yl)methanone (412 mg, 94%), beige foam. General procedure P1 from 2-bromo-3-chloro-6-fluorobenzoic acid (300 mg, 1.18 mmol, 1.00 equiv) and 1-methyl-1,7-diazaspiro[3.4]octane dihydrochloride (259 mg, 1.30 mmol, 1.10 equiv). 1 H NMR(DMSO-d6,400MHz)δ 7.79(dt,J=9.0,5.8Hz,1H),7.52-7.45(m,1H),3.66-3.46(m,2H),3.31(s,3H)NCH 3, 3.21-3.17(m,2H),2.36-2.11(m,6H);m / z=363.1[M+H] + .

[0636] Method Q: Cyclopropanation General Procedure Q1: Under a nitrogen atmosphere, 2,2,2-trifluoroacetic acid (2.00 equiv.) was added to a 0.1 M solution of diethylzinc (1 M, 2.00 equiv.) in DCM at 0°C. The reaction mixture was stirred at 0°C for 20 minutes, followed by the addition of diiodomethane (2.00 equiv.). The reaction mixture was stirred at 0°C for 20 minutes, followed by the addition of a 0.1 M solution of alkene (1 equiv.) in DCM. The reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was diluted with DCM and quenched with 1 M HCl solution. The two layers were separated, and the aqueous layer was extracted three times with DCM. The combined organic layers were dried through a phase separator and concentrated under reduced pressure. The crude material was purified by flash chromatography (0-20% EtOAc / cyclohexane) to give the desired product.

[0637] Synthesis of [3-bromo-2-(cyclopropylmethyl)phenyl]methanol (Intermediate 109) [ka] [3-Bromo-2-(cyclopropylmethyl)phenyl]methanol (84 mg, 30%), colorless oil. General procedure Q1 from (2-allyl-3-bromophenyl)methanol (333 mg, 1.17 mmol, 1.00 equiv). 1 H NMR(DMSO-d6,400MHz)δ 7.50(dd,J=8.0,1.3Hz,1H),7.44(dd,J=7.6,1.2Hz,1H),7.19-7.12(m,1H),5.26(t,J=5.5Hz,1H),4 .59(d,J=5.4Hz,2H),2.78(d,J=6.4Hz,2H),1.07-0.95(m,1H),0.49-0.38(m,2H),0.30-0.22(m,2H).

[0638] Method S: Boo-bo type reaction General Step S1: Under a nitrogen atmosphere, butyllithium (1.6 M, 1.30 equiv.) and N,N-dimethylformamide (1.50 equiv.) were added to a 0.1 M solution of Ar-Br (1.00 equiv.) in THF at -78 °C. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with DCM and quenched with saturated aqueous NH4Cl. The two layers were separated, and the aqueous layer was extracted three times with DCM. The combined organic layers were dried over a phase separator and concentrated under reduced pressure. The crude product was purified by flash chromatography (EtOAc / heptane 0-20%) to give the desired product.

[0639] Synthesis of 3-chloro-2-(difluoromethyl)benzaldehyde (Intermediate 110) [ka] 3-Chloro-2-(difluoromethyl)benzaldehyde (63 mg, 37%), pale yellow oil. General procedure S1 from 1-bromo-3-chloro-2-(difluoromethyl)benzene (200 mg, 0.82 mmol, 1.00 equiv). 1H NMR(CDCl3,400MHz)δ 10.35(t,J=0.6Hz,1H),7.97-7.91(m,2H),7.82-7.77(m,1H), CHF2 signal is unclear.

[0640] Example of sequences used in the general procedure of series 3 [ka] A1.1+A2.2+B1+C1 (Synthesis of Example 323) [ka] L2+G1+C4 [ka] D2.1+E1+F1+D3 [ka] E5+P1+E4 [ka] K1+E1+L1+A2.2+C3+I1

[0641] Biochemical assays LSD1 Inhibition Assay: The biochemical activity of LSD1 was measured using the HTRF® LSD1 histone H3K4 monodemethylation assay (me1->me0). Briefly, enzyme buffer was prepared by adding 50 mM Tris-HCl (Sigma catalog no. T2663-IL), 50 mM NaCl (ThermoFisher catalog no. AM9759), and 0.01% Tween 20 (ThermoFisher catalog no. J20605.AP) to distilled water (final pH 8.5). This buffer was supplemented with 10 μM FAD (Fisher Scientific catalog no. 11411838) and 1 mM DTT (Sigma catalog no. D0632). In the assay, H3K4(me1) biotinylated peptide substrate (Anaspec, catalog no. 64355) was added to a final assay concentration of 95 nM. Streptavidin XL665 (Cisbio catalog number 610SAXLA) and H3K4 me0-Eu(K) antibody cryptate (Cisbio, catalog number 61KA0KAD) detection reagents were mixed according to the manufacturer's instructions. Test compounds were diluted in DMSO at 10 half-log step doses, and 10 nL of each compound dose was dispensed into a 384-well plate. Recombinant human LSD1 was diluted in enzyme buffer to a final assay concentration of 20 nM and added to the test compounds for 15 minutes. The reaction was initiated by the addition of substrate and incubated at 25°C for 60 minutes. Detection reagent was added, and the plate was incubated in the dark for 90 minutes. Fluorescence was measured using an EnVision 2103 plate reader with an optical setup in HTRF mode with excitation at 665 nM and emission at 620 nm. The ratio of acceptor to donor emission signals was calculated for each well. The inhibition rate was calculated from the HTRF ratio at different doses and fitted to a four-parameter logistic curve to determine the IC50 value. The results of the compounds of the present disclosure in this assay are shown in Table 4 below.

[0642] Data was reported as % inhibition for each concentration tested, and IC50 values ​​were estimated using QPatch software. At least two cells were tested, and more cells were tested if results diverged. The results of compounds of the present disclosure in this assay are shown in Table 4 below.

[0643] [Table 4-1]

[0644] [Table 4-2]

[0645] [Table 4-3]

[0646] [Table 4-4]

[0647] [Table 4-5]

[0648] Some specific manifestations of the inventive concepts are set forth in the following numbered clauses.

[0649] Terms 1. Formula (I): [ka] (In the formula, R 1 is nitro or cyano; R 2 and R 2’ are each independently 1~3 selected from alkyl, hydrogen or halogen; R 3 is hydrogen, C1~3 Alkyl, C 1~3 Haloalkyl, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, C3-C6 heterocycloalkyl, C4-C5 heterocycloalkenyl, C3-C5 heterocycloalkyl-C1-C3 alkyl, C5-C6 aryl, C3-C6 heteroaryl, C1-C4 alkoxyl, C3-C6 cycloalkyl-C1-C3 alkoxyl, C1-C4 haloalkoxyl, C1-C3 haloalkyl, halogen, amino, alkylamino, dialkylamino, C2-C7 cyclic amine, C2-C5 heterocyclic amine, C3-C6 unsaturated or aromatic cyclic amine, C3-C5 unsaturated or aromatic complex amine each alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, heterocycloalkylalkyl, aryl, heteroaryl, alkoxyl, cycloalkylalkoxyl, alkylamino, dialkylamino, cyclic amine, heterocyclic amine, unsaturated or aromatic cyclic amine, and unsaturated or aromatic heterocyclic amine is optionally substituted with 1 to 3 substituents selected from the group consisting of C1-C3 alkyl, C1-C3 alkoxyl, C3-C6 cycloalkyl, hydroxyl, halogen, and amino; R 4 is selected from hydrogen or halogen; R 5 is hydrogen, C 1~3 selected from the group consisting of alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, C3-C6 aryl, C3-C6 heteroaryl, halogen, amino, alkylamino, dialkylamino, C2-C7 cyclic amine, C2-C5 heterocyclic amine, C3-C6 unsaturated or aromatic cyclic amine, and C3-C5 unsaturated or aromatic heterocyclic amine, wherein each alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, alkylamino, dialkylamino, cyclic amine, heterocyclic amine, unsaturated or aromatic cyclic amine, and unsaturated or aromatic heterocyclic amine is optionally substituted with 1 to 3 substituents selected from the group consisting of C1-C3 alkyl, C1-C3 alkoxyl, C3-C6 cycloalkyl, hydroxyl, halogen, or amino; R6 is hydrogen, C1-C4 alkyl, C1-C4 alkoxyl, amino, alkylamino, aminoalkyl, dialkylamino, C8-C 11 Spirocycloalkyl, C5-C 10 Heterospirocycloalkyl, C5-C 11 Monocyclic or bicyclic aryl, monocyclic or bicyclic heteroaryl, C2-C7 cyclic amine, C2-C5 heterocyclic amine, C3-C6 unsaturated or aromatic cyclic amine, C3-C5 unsaturated or aromatic heterocyclic amine, C7-C 10 selected from the group consisting of spirocyclic amine, C4-C9 heterospirocyclic amine, C3-C6 heteroaryloxyl, or C3-C6 cycloalkoxyl, each optionally substituted with 1 to 3 substituents selected from the group consisting of hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxyl, halogen, C1-C3 haloalkyl, C1-C3 haloalkoxyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C2-C5 heterocycloalkyl, or optionally substituted C3-C6 heteroaryl, wherein the optionally substituted cycloalkyl, heterocycloalkyl, and heteroaryl may be substituted with 1 or 2 substituents selected from the group consisting of C1-C3 alkyl, C1-C3 alkoxyl, hydroxyl, halogen, or amine; L is a linker selected from the group consisting of a bond, -CH2-, -CH2-CH2-, -CH(CH3)-, -C(CH3)2-, -C≡C-, -CH2-O-, -C(O)-, -O-, -O-CH2-, -NH-CH2-, -N(CH3)-CH2-, -NH-C(O)-, -N(CH3)-C(O)-, -CH2-NH-CH2-; Q is C5-C9 cycloalkyl, C4-C8 heterocycloalkyl, C8-C 11 Spirocycloalkyl, C5-C 10 Heterospirocycloalkyl, C3-C8 cyclic amine, C3-C8 heterocyclic amine, C7-C 10a monocyclic or bicyclic ring system selected from the group consisting of spirocyclic amines or C4-C9 heterospirocyclic amines, wherein each cycloalkyl or heterocycloalkyl group can be saturated or unsaturated, and the bicyclic ring can be a fused or bridged bicyclic ring; Q is selected from the group consisting of one to three R 7 and each R 7 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkylcarbonyl, hydroxyl, oxo, halogen, C1-C6 alkylamine, or amino. or a pharmaceutically acceptable salt, solvate, prodrug or pharmaceutically active metabolite thereof, or a combination thereof.

[0650] 2. A compound of formula (I) as defined in clause 1, or a pharmaceutically acceptable salt, solvate, prodrug or pharmaceutically active metabolite thereof, or a combination thereof, wherein each heterocyclic or heteroaryl substituent may contain from 1 to 4 heteroatoms independently selected from O, S and N.

[0651] 3. A compound of formula (I) as defined in clause 1 or clause 2, or a pharmaceutically acceptable salt, solvate, prodrug or pharmaceutically active metabolite thereof, or a combination thereof, wherein each heterocyclic or heteroaryl substituent is attached to the remainder of the compound via a carbon atom.

[0652] 4. A compound of formula (I) as defined in clause 1 or clause 2, or a pharmaceutically acceptable salt, solvate, prodrug or pharmaceutically active metabolite thereof, or a combination thereof, wherein the heterocyclic or heteroaryl substituent is attached to the remainder of the compound via a heteroatom.

[0653] 5. A compound of formula (I) according to clause 1 or clause 2, or a pharmaceutically acceptable salt, solvate, prodrug or pharmaceutically active metabolite thereof, or a combination thereof, wherein the heterocyclic or heteroaryl substituent contains at least one N atom and said heterocyclic or heteroaryl substituent is bonded to the remainder of the compound via the N atom.

[0654] 6.(i)R 2 and R 2’ one of which is hydrogen and the other is F; (ii)R 2 and R 2’ one of is hydrogen and the other is Cl; or (iii)R 2 and R 2’ and R 1 and R 2 are hydrogen. The compound of formula (I) according to any one of clauses 1 to 5, or a pharmaceutically acceptable salt, solvate, prodrug or pharmaceutically active metabolite thereof, or a combination thereof.

[0655] 7.R 3 is selected from hydrogen, halogen, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, C5-C6 aryl, C3-C6 heteroaryl or C2-C5 heterocyclic amine, or a pharmaceutically acceptable salt, solvate, prodrug or pharmaceutically active metabolite thereof, or a combination thereof.

[0656] 8.(i)R 3 is hydrogen or Cl; (ii)R 3 is an optionally substituted 5- or 6-membered heteroaryl; (iii)R 3 is an optionally substituted 4- to 6-membered heterocycloalkyl; or (iv)R 3 is an optionally substituted 3- to 5-membered cycloalkyl; Each heteromoiety may contain 1 or 2 heteroatoms independently selected from O, S, and N; The compound of formula (I) or a pharmaceutically acceptable salt, solvate, prodrug or pharmaceutically active metabolite thereof, or a combination thereof, according to clause 7, wherein said optional substituents are independently selected from one or two substituents from the group consisting of methyl, F and Cl.

[0657] 9.(i)R4 is hydrogen; (ii)R 4 is F and R 5 and R 6 are hydrogen, respectively; (iii)R 4 is F and R 5 and R 6 are each hydrogen; or (iii)R 4 , R 5 and R 6 A compound of formula (I) according to any one of clauses 1 to 8, or a pharmaceutically acceptable salt, solvate, prodrug or pharmaceutically active metabolite thereof, or a combination thereof, wherein all of R, R, R and R are hydrogen.

[0658] 10.(i)R 5 is hydrogen; (ii)R 5 is F; (iii)R 5 is a 4- or 5-membered heterocycloalkyl; (iv)R 5 is C1-C3 alkyl; (v)R 5 is a 3-, 4-, or 5-membered cycloalkyl; (vi)R 5 is an optionally substituted C3-C6 cycloalkyl, C3-C6 cycloalkenyl, C3-C6 heterocycloalkyl, C3-C6 aryl or C3-C6 heteroaryl; or a pharmaceutically acceptable salt, solvate, prodrug or pharmaceutically active metabolite thereof, or a combination thereof.

[0659] 11.R 5 is selected from hydrogen, F, methyl or pyrrolidine, or a pharmaceutically acceptable salt, solvate, prodrug or pharmaceutically active metabolite thereof, or a combination thereof.

[0660] 12.(i)R6 is hydrogen; (ii)R 6 is F or Cl; (iii)R 6 is an optionally substituted 4- or 5-membered heterocycloalkyl; (iv)R 6 is an optionally substituted 8-, 9-, or 10-membered bicyclic or spirocyclic heterocycloalkyl; (v)R 6 is an optionally substituted 5- or 6-membered heteroaryl; (vi)R 6 is an optionally substituted 4-, 5-, or 6-membered cycloalkyl or spirocycloalkyl; (vii)R 6 is C1-C3 haloalkoxy; or (viii)R 6 is a C2-C8 alkylamine or dialkylamine, Each heteromoiety may contain 1 or 2 heteroatoms independently selected from O, S, and N; 12. The compound of formula (I) according to any one of clauses 1 to 11, or a pharmaceutically acceptable salt, solvate, prodrug or pharmaceutically active metabolite thereof, or a combination thereof, wherein said optional substituents are independently selected from one or two substituents from the group consisting of C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxyl, F, Cl and hydroxyl.

[0661] 13.R 6 is selected from hydrogen, F, methyl or pyrrolidine, or a pharmaceutically acceptable salt, solvate, prodrug or pharmaceutically active metabolite thereof, or a combination thereof.

[0662] 14. A compound of formula (I) according to any one of clauses 1 to 13, or a pharmaceutically acceptable salt, solvate, prodrug or pharmaceutically active metabolite thereof, or a combination thereof, wherein L is selected from -CH2- or -CH2-CH2-.

[0663] 15. Q is selected from the group consisting of optionally substituted 5- to 7-membered heterocycloalkyl and optionally substituted 4- to 7-membered mono- or fused or bridged bicycloalkylamine; Each heterocyclic moiety may contain 1 or 2 heteroatoms independently selected from O and N; 15. The compound of formula (I) according to any one of clauses 1 to 14, or a pharmaceutically acceptable salt, solvate, prodrug or pharmaceutically active metabolite thereof, or a combination thereof, wherein said optional substituents are independently selected from one to three substituents from the group consisting of C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxyl, C1-C3 alkylamine, C1-C3 dialkylamine, C1-C3 carbonyl, amine, amino-C1-C3 alkyl, oxo, F, Cl and hydroxyl.

[0664] 16.(i)R 7 are independently selected from C1-C3 alkyl, C1-C3 haloalkyl, hydroxyl, oxo, F, C1-C3 alkylamino, C1-C3 dialkylamino or amino; (ii)R 7 is independently selected from methyl, ethyl, amine and F; 1, 2 or 3 R 7 16. A compound of formula (I) according to any one of clauses 1 to 15, or a pharmaceutically acceptable salt, solvate, prodrug or pharmaceutically active metabolite thereof, or a combination thereof, wherein a group is present.

[0665] 17.(i)R 1 is cyano; and / or (ii)R 2 and R 2’ are each independently selected from hydrogen or F; and / or (iii)R 3is selected from hydrogen, propyl, i-propyl, CHF2, cyclopropyl, -CH2-cyclopropyl, -CH2-oxetane, isothiazole, oxazole, pyridyl, methoxyl, -O-CH2-cyclopropyl, -O-CH2-CF3, -O-CF3, CF3, Cl, amino, -N(CH3)(CH2-isopropyl), pyrrolidine, cyano; and / or (iv)R 4 is hydrogen or F; and / or (v)R 5 is selected from hydrogen, methyl, cyclopropyl, cyclopentenyl, F, amino, NH—CH—CH—N(CH) and / or (vi)R 6 is selected from hydrogen, -O-cyclobutyl, -O-CH2-oxane, -O-CH2-CH2-CHF2, -O-CH2-CH2-CF3, -O-CH2-CF3, -CH2-O-CHF2, amino, -N(CH3)(CH-(CH3)2, benzimidazole, pyridine; and / or (vii) L is a linker selected from a bond, —CH—, —C≡C—, —CH—NH—CH—; and / or (viii) Q is a C4-C8 heterocycloalkyl which may contain an additional heteroatom selected from N or O; or Q is morpholinyl; A compound of formula (I) according to any one of clauses 1 to 4, or a pharmaceutically acceptable salt, solvate, prodrug or pharmaceutically active metabolite thereof, or a combination thereof, wherein each heteroaryl, heterocycloalkyl and / or cycloalkyl group is optionally substituted.

[0666] 18. A compound of formula (I) according to clause 17, or a pharmaceutically acceptable salt, solvate, prodrug or pharmaceutically active metabolite thereof, or a combination thereof, wherein each heteroaryl, heterocycloalkyl and / or cycloalkyl group is optionally substituted with one or more groups selected from F, Cl, methyl, hydroxyl and amino.

[0667] 19.R 3has the following structure: [ka] 19. A compound of formula (I) according to any one of clauses 1 to 18, or a pharmaceutically acceptable salt, solvate, prodrug or pharmaceutically active metabolite thereof, or a combination thereof, selected from the group consisting of:

[0668] 20.R 3 has the following structure: [ka] 20. A compound of formula (I) according to any one of clauses 1 to 19, or a pharmaceutically acceptable salt, solvate, prodrug or pharmaceutically active metabolite thereof, selected from the group consisting of:

[0669] 21.R 5 is hydrogen and the following structure: [ka] 21. A compound of formula (I) according to any one of clauses 1 to 20, or a pharmaceutically acceptable salt, solvate, prodrug or pharmaceutically active metabolite thereof, or a combination thereof, selected from the group consisting of:

[0670] 22.R 6 is hydrogen and the following structure: [ka] [ka] [ka] 22. A compound of formula (I) according to any one of clauses 1 to 21, or a pharmaceutically acceptable salt, solvate, prodrug or pharmaceutically active metabolite thereof, selected from the group consisting of:

[0671] 23.R 6 is hydrogen and the following structure: [ka] 23. A compound of formula (I) according to any one of clauses 1 to 22, or a pharmaceutically acceptable salt, solvate, prodrug or pharmaceutically active metabolite thereof, selected from the group consisting of:

[0672] 24.Q has the following structure: [ka] [ka] [ka] [ka] 24. A compound of formula (I) according to any one of clauses 1 to 23, or a pharmaceutically acceptable salt, solvate, prodrug or pharmaceutically active metabolite thereof, or a combination thereof, selected from the group consisting of:

[0673] 25.Q has the following structure: [ka] 25. A compound of formula (I) according to any one of clauses 1 to 24, or a pharmaceutically acceptable salt, solvate, prodrug or pharmaceutically active metabolite thereof, selected from the group consisting of:

[0674] 26.Q has the following structure: [ka] 26. A compound of formula (I) according to any one of clauses 1 to 25, or a pharmaceutically acceptable salt, solvate, prodrug or pharmaceutically active metabolite thereof, or a combination thereof, selected from the group consisting of:

[0675] 27. (i) The group of compounds shown in Table 1; (ii) a group of compounds in Table 1 having an IC50 of 1,000 nM or less against LSD1; (iii) a group of compounds in Table 1 having an IC50 of 250 nM or less against LSD1; (iv) the group of compounds in Table 1 having an IC50 of 100 nM or less against LSD1; (v) the group of compounds in Table 1 having an IC50 of 50 nM or less against LSD1; (vi) a group of compounds in Table 1 having an IC50 of 25 nM or less against LSD1; or (vii) A group of compounds in Table 1 having an IC50 of 10 nM or less against LSD1 or a pharmaceutically acceptable salt, solvate, prodrug or pharmaceutically active metabolite thereof, or a combination thereof.

[0676] 28. A compound selected from any one of Examples 1-351.

[0677] 29. A compound selected from any one of Examples 4, 8, 15, 20, 26, 28, 71, 108, 109, 173, 177, 182, 183, 185, 190, 192, 194, 197, 207, 216, 234, 263, 302, 303, 315 and 335.

[0678] 30. Examples 1, 2, 3, 5, 6, 7, 9, 10, 11, 12, 13, 14, 16, 17, 18, 19, 22, 23, 24, 25, 29, 30, 34, 36, 37, 38, 39, 48, 53, 57, 74, 79, 81, 103, 110, 112, 115, 116, 154, 169, 170, 171, 172, 174, 175, 178, 179, 181, 186, 187, 188, 189, 193, 195, 198, 199, 201, A compound selected from any one of 204, 206, 209, 210, 217, 218, 219, 222, 223, 224, 230, 231, 232, 233, 235, 237, 242, 250, 254, 255, 257, 259, 260, 262, 264, 268, 275, 279, 304, 309, 310, 311, 312, 313, 314, 316, 317, 321, 323, 324, 325, 333, 334 and 336.

[0679] 31. Examples 27, 31, 32, 33, 35, 43, 46, 47, 49, 51, 56, 60, 64, 67, 68, 70, 73, 82, 83, 91, 93, 94, 95, 100, 102, 104, 111, 128, 138, 153, 156, 176, 180, 184, 191, 196, 200, 202, 203, 205, 208 , 211, 212, 213, 215, 220, 221, 227, 229, 236, 239, 240, 243, 244, 245, 247, 249, 251, 252, 253, 256, 258, 265, 273, 277, 299, 301, 305, 308, 318, 319, 322 and 339.

[0680] 32. Examples 21, 40, 41, 42, 44, 45, 50, 52, 54, 55, 58, 59, 61, 62, 63, 66, 69, 72, 75, 76, 77, 78, 80, 85, 86, 88, 92, 96, 98, 99, 101, 105, 106, 107, 113, 114, 118, 119, 120, 121, 122, 124, 125, 126, 127, 129, 133, 137, 139, 141, 143, 147, 148, 149, 151, 152, 155, 1 63, 164, 165, 166, 168, 225, 226, 228, 238, 241, 246, 248, 261, 266, 267, 269, 270, 271, 272, 274, 276, 278, 280, 282, 283, 284, 285, 288, 289, 291, 293, 294, 297, 298, 300, 306, 307, 320, 328, 332, 340, 341, 342, 346, 347, 348 and 349.

[0681] 33. A compound selected from any one of Examples 65, 84, 87, 89, 90, 97, 117, 123, 130, 131, 132, 134, 135, 136, 140, 142, 144, 145, 146, 150, 157, 158, 159, 160, 161, 162, 167, 175, 214, 281, 286, 287, 290, 292, 295, 296, 326, 327, 329, 330, 331, 337, 338, 343, 344 and 345.

[0682] 34. A pharmaceutical composition comprising a compound according to any one of clauses 1 to 33 or a pharmaceutically acceptable salt, solvate, prodrug or pharmaceutically active metabolite thereof, or a combination thereof, and one or more pharmaceutically acceptable carriers.

[0683] 35. Formula (I): [ka] (In the formula, R 1 is nitro or cyano; R 2 and R 2’ are each independently 1~3 selected from alkyl, hydrogen or halogen; R 3 is hydrogen, C 1~3 Alkyl, C 1~3 Haloalkyl, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, C3-C6 heterocycloalkyl, C4-C5 heterocycloalkenyl, C3-C5 heterocycloalkyl-C1-C3 alkyl, C5-C6 aryl, C3-C6 heteroaryl, C1-C4 alkoxyl, C3-C6 cycloalkyl-C1-C3 alkoxyl, C1-C4 haloalkoxyl, C1-C3 haloalkyl, halogen, amino, alkylamino, dialkylamino, C2-C7 cyclic amine, C2-C5 heterocyclic amine, C3-C6 unsaturated or aromatic cyclic amine, C3-C5 unsaturated or aromatic complex amine each alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, heterocycloalkylalkyl, aryl, heteroaryl, alkoxyl, cycloalkylalkoxyl, alkylamino, dialkylamino, cyclic amine, heterocyclic amine, unsaturated or aromatic cyclic amine, and unsaturated or aromatic heterocyclic amine is optionally substituted with 1 to 3 substituents selected from the group consisting of C1-C3 alkyl, C1-C3 alkoxyl, C3-C6 cycloalkyl, hydroxyl, halogen, and amino; R 4 is selected from hydrogen or halogen; R 5 is hydrogen, C 1~3selected from the group consisting of alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, C3-C6 aryl, C3-C6 heteroaryl, halogen, amino, alkylamino, dialkylamino, C2-C7 cyclic amine, C2-C5 heterocyclic amine, C3-C6 unsaturated or aromatic cyclic amine, and C3-C5 unsaturated or aromatic heterocyclic amine, wherein each alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, alkylamino, dialkylamino, cyclic amine, heterocyclic amine, unsaturated or aromatic cyclic amine, and unsaturated or aromatic heterocyclic amine is optionally substituted with 1 to 3 substituents selected from the group consisting of C1-C3 alkyl, C1-C3 alkoxyl, C3-C6 cycloalkyl, hydroxyl, halogen, or amino; R 6 is hydrogen, C1-C4 alkyl, C1-C4 alkoxyl, amino, alkylamino, aminoalkyl, dialkylamino, C8-C 11 Spirocycloalkyl, C5-C 10 Heterospirocycloalkyl, C5-C 11 Monocyclic or bicyclic aryl, monocyclic or bicyclic heteroaryl, C2-C7 cyclic amine, C2-C5 heterocyclic amine, C3-C6 unsaturated or aromatic cyclic amine, C3-C5 unsaturated or aromatic heterocyclic amine, C7-C 10 selected from the group consisting of spirocyclic amine, C4-C9 heterospirocyclic amine, C3-C6 heteroaryloxyl, or C3-C6 cycloalkoxyl, each optionally substituted with 1 to 3 substituents selected from the group consisting of hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxyl, halogen, C1-C3 haloalkyl, C1-C3 haloalkoxyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C2-C5 heterocycloalkyl, or optionally substituted C3-C6 heteroaryl, wherein the optionally substituted cycloalkyl, heterocycloalkyl, and heteroaryl may be substituted with 1 or 2 substituents selected from the group consisting of C1-C3 alkyl, C1-C3 alkoxyl, hydroxyl, halogen, or amine; L is a linker selected from the group consisting of a bond, -CH2-, -CH2-CH2-, -CH(CH3)-, -C(CH3)2-, -C≡C-, -CH2-O-, -C(O)-, -O-, -O-CH2-, -NH-CH2-, -N(CH3)-CH2-, -NH-C(O)-, -N(CH3)-C(O)-, -CH2-NH-CH2-; Q is C5-C9 cycloalkyl, C4-C8 heterocycloalkyl, C8-C 11 Spirocycloalkyl, C5-C 10 Heterospirocycloalkyl, C3-C8 cyclic amine, C3-C8 heterocyclic amine, C7-C 10 a monocyclic or bicyclic ring system selected from the group consisting of spirocyclic amines or C4-C9 heterospirocyclic amines, wherein each cycloalkyl or heterocycloalkyl group can be saturated or unsaturated, and the bicyclic ring can be a fused or bridged bicyclic ring; Q is selected from the group consisting of one to three R 7 and each R 7 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkylcarbonyl, hydroxyl, oxo, halogen, C1-C6 alkylamine, or amino. or a pharmaceutically acceptable salt, solvate, prodrug or pharmaceutically active metabolite thereof, or a combination thereof, and one or more pharmaceutically acceptable carriers.

[0684] 36. A pharmaceutical composition according to clause 35, wherein the compound is defined according to any of clauses 2 to 33.

[0685] 37. (i) The group of compounds shown in Table 1; (ii) a group of compounds in Table 1 having an IC50 of 1,000 nM or less against LSD1; (iii) a group of compounds in Table 1 having an IC50 of 250 nM or less against LSD1; (iv) the group of compounds in Table 1 having an IC50 of 100 nM or less against LSD1; (v) the group of compounds in Table 1 having an IC50 of 50 nM or less against LSD1; (vi) a group of compounds in Table 1 having an IC50 of 25 nM or less against LSD1; or (vii) A group of compounds in Table 1 having an IC50 of 10 nM or less against LSD1 or a pharmaceutically acceptable salt, solvate, prodrug or pharmaceutically active metabolite thereof, or a combination thereof, and one or more pharmaceutically acceptable carriers.

[0686] 38. A pharmaceutical composition comprising a compound selected from any one of the compounds of Examples 1-351, or a pharmaceutically acceptable salt, solvate, prodrug, or pharmaceutically active metabolite thereof, or a combination thereof, and one or more pharmaceutically acceptable carriers.

[0687] 39. A compound according to any one of clauses 1 to 33 or a pharmaceutical composition according to any one of clauses 34 to 38 for use in medicine.

[0688] 40. The compound or pharmaceutical composition for use according to clause 39, wherein the use is in the treatment of a disease, condition or disorder associated with LSD1.

[0689] 41. A compound or pharmaceutical composition for use according to clause 39 or clause 40, wherein the use is in the treatment of cancer, a neoplastic disease, an autoimmune disorder and / or an inflammatory disease.

[0690] 42. The compound or pharmaceutical composition for use according to any of clauses 39 to 41, wherein the use is in the treatment of a disease, condition or disorder selected from the group consisting of breast cancer, prostate cancer, head and neck cancer, brain cancer, laryngeal cancer, oral cancer and thyroid cancer (e.g. papillary thyroid cancer), blood cancer (e.g. non-Hodgkin's lymphoma, B-cell lymphoma, chronic myeloid leukemia), sarcoma, lung cancer, gastrointestinal cancer, genitourinary cancer, liver cancer, bone cancer, nervous system cancer, gynecological cancer and skin cancer.

[0691] 43. Use lymphomas, including diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma, non-Hodgkin's lymphoma, relapsed or refractory NHL and relapsed follicular lymphoma, Hodgkin's lymphoma; leukemia, including acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), and chronic myeloid leukemia (CML); myeloproliferative disorders, including primary myelofibrosis (PMF), polycythemia vera (PV), and essential thrombocytosis (ET); Myelodysplastic syndromes (MDS) and multiple myeloma; Sarcomas, including chondrosarcoma, Ewing's sarcoma, osteosarcoma, rhabdomyosarcoma, angiosarcoma, fibrosarcoma, liposarcoma, myxoma, rhabdomyoma, fibroma, lipoma, hamartoma, and teratoma; Lung cancers including non-small cell lung cancer (NSCLC), small cell lung cancer, bronchogenic carcinoma, squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, adenocarcinoma, alveolar (bronchiolar) carcinoma, bronchial adenoma, chondrogenic hamartoma and mesothelioma; Gastrointestinal cancers, including esophageal cancer (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), gastric cancer (carcinoma, lymphoma, leiomyosarcoma), pancreatic cancer (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vipoma), small intestine cancer (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), colon cancer (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma) and colorectal cancer; Genitourinary cancers, including kidney cancer (adenocarcinoma, Wilms' tumor, nephroblastoma), bladder and urethral cancer (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate cancer (adenocarcinoma, sarcoma), and testicular cancer (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, lipoma); liver cancer, including hepatocellular carcinoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, and hemangioma; bone cancer, including osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochondroma (osteochondroid exostosis), benign chondroma, chondroblastoma, chondromyxoid fibroma, osteoid osteoma, and giant cell tumor; Cancers of the skull (osteoma, hemangioma, granuloma, xanthomas, osteitis deformans), meningeal cancer (meningioma, meningeal sarcoma, gliomatosis), brain cancer (astrocytoma, medulloblastoma, glioma, ependymoma, embryonal tumor (pinealoma), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal cord cancer (neurofibroma, meningioma, glioma, sarcoma), and nervous system cancers including neuroblastoma and Lhermitte-Dacros disease; uterine cancer (endometrial cancer) Gynecological cancers including cervical cancer (cervical carcinoma, preneoplastic cervical dysplasia), ovarian cancer (ovarian carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa theca cell tumor, Sertoli-Leydig cell tumor, dysgerminoma, malignant teratoma), vulvar cancer (squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma, melanoma), vaginal cancer (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma)) and fallopian tube cancer (carcinoma); Skin cancers including melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, dysplastic nevi, lipoma, hemangioma, dermatofibroma and keloids 43. The compound or pharmaceutical composition of any of clauses 39 to 42 for use in the treatment of a disease, condition or disorder selected from the group consisting of:

[0692] 44. The compound or pharmaceutical composition for use according to any of clauses 39 to 43, wherein the use is in the treatment of a disease, condition or disorder selected from the group consisting of glioblastoma and acute myeloid leukemia (AML).

[0693] 45. A compound according to any one of clauses 1 to 33, a pharmaceutical composition according to any one of clauses 34 to 38 or a compound or pharmaceutical composition for use according to any one of clauses 39 to 44, wherein the compound is an inhibitor of LSD1.

[0694] 46. ​​The compound or pharmaceutical composition for use according to any of clauses 39 to 45, wherein the use is in a method comprising administering the compound orally, topically, by inhalation, by intranasal administration or systemically by intravenous, intraperitoneal, subcutaneous or intramuscular injection.

[0695] 47. The compound or pharmaceutical composition for use according to any of clauses 39 to 46, wherein the use is in a method comprising administering a compound of formula (I) in combination with one or more additional therapeutic agents.

[0696] 48. The compound or pharmaceutical composition for use according to clause 47, wherein administering comprises administering the compound of formula (I) simultaneously, sequentially or separately with one or more additional therapeutic agents.

[0697] 49. A compound or pharmaceutical composition for use according to any of clauses 39 to 48, comprising administering to a subject an effective amount of a compound of formula (I), wherein the effective amount is from about 500 nM to about 10 μM in the subject's blood or in the subject's plasma.

[0698] 50. A method for treating a disease, disorder or condition in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to any one of clauses 1 to 33 or a pharmaceutical composition according to any one of clauses 34 to 38.

[0699] 51. The method of clause 50, wherein the disease, disorder or condition is associated with LSD1.

[0700] 52. The method of clause 50 or clause 51, wherein the disease, disorder or condition is associated with overexpression or high levels of LSD1 in the subject.

[0701] 53. A method for treating a disease, disorder or condition associated with LSD1 in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to any one of clauses 1 to 33 or a pharmaceutical composition according to any one of clauses 34 to 38.

[0702] 54. The method of any one of clauses 50 to 53, wherein the compound is an inhibitor of LSD1.

[0703] 55. The method of any of clauses 50 to 54, comprising administering the compound or pharmaceutical composition orally, topically, by inhalation, by intranasal administration or systemically by intravenous, intraperitoneal, subcutaneous or intramuscular injection.

[0704] 56. The method of any of clauses 50-55, comprising administering a compound of formula (I) in combination with one or more additional therapeutic agents.

[0705] 57. The method according to any one of clauses 50 to 56, comprising administering a compound of formula (I) simultaneously, sequentially or separately with one or more additional therapeutic agents.

[0706] 58. The method of any of clauses 50-57, comprising administering to the subject an effective amount of a compound of formula (I), wherein the effective amount is from about 500 nM to about 10 μM in the subject's blood or in the subject's plasma.

[0707] 59. The method according to any one of clauses 50 to 58, for the treatment of cancer, a neoplastic disease, an autoimmune disorder and / or an inflammatory disease.

[0708] 60. The method of any of clauses 50 to 59, for the treatment of a disease, condition or disorder selected from the group consisting of breast cancer, prostate cancer, head and neck cancer, brain cancer, laryngeal cancer, oral cancer and thyroid cancer (e.g., papillary thyroid cancer), blood cancer (e.g., non-Hodgkin's lymphoma, B-cell lymphoma, chronic myeloid leukemia), sarcoma, lung cancer, gastrointestinal cancer, genitourinary cancer, liver cancer, bone cancer, nervous system cancer, gynecological cancer and skin cancer.

[0709] 61. For the treatment of cancer, and the cancer is lymphomas, including diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma, non-Hodgkin's lymphoma, relapsed or refractory NHL and relapsed follicular lymphoma, Hodgkin's lymphoma; leukemia, including acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), and chronic myeloid leukemia (CML); myeloproliferative disorders, including primary myelofibrosis (PMF), polycythemia vera (PV), and essential thrombocytosis (ET); Myelodysplastic syndromes (MDS) and multiple myeloma; Sarcomas, including chondrosarcoma, Ewing's sarcoma, osteosarcoma, rhabdomyosarcoma, angiosarcoma, fibrosarcoma, liposarcoma, myxoma, rhabdomyoma, fibroma, lipoma, hamartoma, and teratoma; Lung cancers including non-small cell lung cancer (NSCLC), small cell lung cancer, bronchogenic carcinoma, squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, adenocarcinoma, alveolar (bronchiolar) carcinoma, bronchial adenoma, chondrogenic hamartoma and mesothelioma; Gastrointestinal cancers, including esophageal cancer (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), gastric cancer (carcinoma, lymphoma, leiomyosarcoma), pancreatic cancer (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vipoma), small intestine cancer (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), colon cancer (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma) and colorectal cancer; Genitourinary cancers, including kidney cancer (adenocarcinoma, Wilms' tumor, nephroblastoma), bladder and urethral cancer (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate cancer (adenocarcinoma, sarcoma), and testicular cancer (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, lipoma); liver cancer, including hepatocellular carcinoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, and hemangioma; bone cancer, including osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochondroma (osteochondroid exostosis), benign chondroma, chondroblastoma, chondromyxoid fibroma, osteoid osteoma, and giant cell tumor; Cancers of the skull (osteoma, hemangioma, granuloma, xanthomas, osteitis deformans), meningeal cancer (meningioma, meningeal sarcoma, gliomatosis), brain cancer (astrocytoma, medulloblastoma, glioma, ependymoma, embryonal tumor (pinealoma), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal cord cancer (neurofibroma, meningioma, glioma, sarcoma), and nervous system cancers including neuroblastoma and Lhermitte-Dacros disease; uterine cancer (endometrial cancer) Gynecological cancers including cervical cancer (cervical carcinoma, preneoplastic cervical dysplasia), ovarian cancer (ovarian carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa theca cell tumor, Sertoli-Leydig cell tumor, dysgerminoma, malignant teratoma), vulvar cancer (squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma, melanoma), vaginal cancer (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma)) and fallopian tube cancer (carcinoma); Skin cancers including melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, dysplastic nevi, lipoma, hemangioma, dermatofibroma and keloids 61. The method of any of clauses 50 to 60, selected from the group consisting of:

[0710] 62. The method of any of clauses 50 to 61, for the treatment of a disease, condition or disorder selected from the group consisting of glioblastoma and acute myeloid leukemia (AML).

[0711] Further expressions of the inventive concept are set forth in each of the following clauses. Clause A1. Formula (I): [ka] (In the formula, R 1 is nitro or cyano; R 2 and R 2’ are each independently 1~3 selected from alkyl, hydrogen or halogen; R 3 is hydrogen, C 1~3 Alkyl, C 1~3Haloalkyl, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, C3-C6 heterocycloalkyl, C4-C5 heterocycloalkenyl, C3-C5 heterocycloalkyl-C1-C3 alkyl, C5-C6 aryl, C3-C6 heteroaryl, C1-C4 alkoxyl, C3-C6 cycloalkyl-C1-C3 alkoxyl, C1-C4 haloalkoxyl, C1-C3 haloalkyl, halogen, amino, alkylamino, dialkylamino, C2-C7 cyclic amine, C2-C5 heterocyclic amine, C3-C6 unsaturated or aromatic cyclic amine, C3-C5 unsaturated or aromatic complex amine each alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, heterocycloalkylalkyl, aryl, heteroaryl, alkoxyl, cycloalkylalkoxyl, alkylamino, dialkylamino, cyclic amine, heterocyclic amine, unsaturated or aromatic cyclic amine, and unsaturated or aromatic heterocyclic amine is optionally substituted with 1 to 3 substituents selected from the group consisting of C1-C3 alkyl, C1-C3 alkoxyl, C3-C6 cycloalkyl, hydroxyl, halogen, and amino; R 4 is selected from hydrogen or halogen; R 5 is hydrogen, C 1~3 selected from the group consisting of alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, C3-C6 aryl, C3-C6 heteroaryl, halogen, amino, alkylamino, dialkylamino, C2-C7 cyclic amine, C2-C5 heterocyclic amine, C3-C6 unsaturated or aromatic cyclic amine, and C3-C5 unsaturated or aromatic heterocyclic amine, wherein each alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, alkylamino, dialkylamino, cyclic amine, heterocyclic amine, unsaturated or aromatic cyclic amine, and unsaturated or aromatic heterocyclic amine is optionally substituted with 1 to 3 substituents selected from the group consisting of C1-C3 alkyl, C1-C3 alkoxyl, C3-C6 cycloalkyl, hydroxyl, halogen, or amino; R 6is hydrogen, C1-C4 alkyl, C1-C4 alkoxyl, amino, alkylamino, aminoalkyl, dialkylamino, C8-C 11 Spirocycloalkyl, C5-C 10 Heterospirocycloalkyl, C5-C 11 Monocyclic or bicyclic aryl, monocyclic or bicyclic heteroaryl, C2-C7 cyclic amine, C2-C5 heterocyclic amine, C3-C6 unsaturated or aromatic cyclic amine, C3-C5 unsaturated or aromatic heterocyclic amine, C7-C 10 selected from the group consisting of spirocyclic amine, C4-C9 heterospirocyclic amine, C3-C6 heteroaryloxyl, or C3-C6 cycloalkoxyl, each optionally substituted with 1 to 3 substituents selected from the group consisting of hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxyl, halogen, C1-C3 haloalkyl, C1-C3 haloalkoxyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C2-C5 heterocycloalkyl, or optionally substituted C3-C6 heteroaryl, wherein the optionally substituted cycloalkyl, heterocycloalkyl, and heteroaryl may be substituted with 1 or 2 substituents selected from the group consisting of C1-C3 alkyl, C1-C3 alkoxyl, hydroxyl, halogen, or amine; L is a linker selected from the group consisting of a bond, -CH2-, -CH2-CH2-, -CH(CH3)-, -C(CH3)2-, -C≡C-, -CH2-O-, -C(O)-, -O-, -O-CH2-, -NH-CH2-, -N(CH3)-CH2-, -NH-C(O)-, -N(CH3)-C(O)-, -CH2-NH-CH2-; Q is C5-C9 cycloalkyl, C4-C8 heterocycloalkyl, C8-C 11 Spirocycloalky...

Claims

1. Formula (I): 【Chemistry 1】 (In the formula, R １ is nitro or cyano; R ２ and R ２’ are each independently C １～３ selected from alkyl, hydrogen or halogen; R ３ is hydrogen, C １～３ Alkyl, C １～３ Haloalkyl, C ３ ~C ６ Cycloalkyl, C ３ ~C ６ Cycloalkenyl, C ３ ~C ６ Heterocycloalkyl, C ４ ~C ５ Heterocycloalkenyl, C ３ ~C ５ Heterocycloalkyl C １ ~C ３ Alkyl, C ５ ~C ６ Aryl, C ３ ~C ６ Heteroaryl, C １ ~C ４ Alkoxyl, C ３ ~C ６ Cycloalkyl-C １ ~C ３ Alkoxyl, C １ ~C ４ Haloalkoxyl, C １ ~C ３ Haloalkyl, halogen, amino, alkylamino, dialkylamino, C ２ ~C ７ Cyclic amines, C ２ ~C ５ Heterocyclic amines, C ３ ~C ６ Unsaturated or aromatic cyclic amines, C ３ ~C ５ unsaturated or aromatic heterocyclic amine, cyano, wherein each alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, heterocycloalkylalkyl, aryl, heteroaryl, alkoxyl, cycloalkylalkoxyl, alkylamino, dialkylamino, cyclic amine, heterocyclic amine, unsaturated or aromatic cyclic amine, and unsaturated or aromatic heterocyclic amine is selected from C １ ~C ３ Alkyl, C １ ~C ３ Alkoxyl, C ３ ~C ６ optionally substituted with 1 to 3 substituents selected from the group consisting of cycloalkyl, hydroxyl, halogen, and amino; R ４ is selected from hydrogen or halogen; R ５ is hydrogen, C １～３ Alkyl, C ３ ~C ６ Cycloalkyl, C ３ ~C ６ Cycloalkenyl, C ３ ~C ６ Aryl, C ３ ~C ６ Heteroaryl, halogen, amino, alkylamino, dialkylamino, C ２ ~C ７ Cyclic amines, C ２ ~C ５ Heterocyclic amines, C ３ ~C ６ Unsaturated or aromatic cyclic amines, C ３ ~C ５ and unsaturated or aromatic heterocyclic amines, each alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, alkylamino, dialkylamino, cyclic amine, heterocyclic amine, unsaturated or aromatic cyclic amine, and unsaturated or aromatic heterocyclic amine is selected from the group consisting of C １ ~C ３ Alkyl, C １ ~C ３ Alkoxyl, C ３ ~C ６ optionally substituted with 1 to 3 substituents selected from the group consisting of cycloalkyl, hydroxyl, halogen, or amino; R ６ is hydrogen, C １ ~C ４ Alkyl, C １ ~C ４ Alkoxyl, amino, alkylamino, aminoalkyl, dialkylamino, C ８ ~C １１ Spirocycloalkyl, C ５ ~C １０ Heterospirocycloalkyl, C ５ ~C １１ monocyclic or bicyclic aryl, monocyclic or bicyclic heteroaryl, C ２ ~C ７ Cyclic amines, C ２ ~C ５ Heterocyclic amines, C ３ ~C ６ Unsaturated or aromatic cyclic amines, C ３ ~C ５ Unsaturated or aromatic heterocyclic amines, C ７ ~C １０ Spirocyclic amines, C ４ ~C ９ Heterospirocyclic amines, C ３ ~C ６ Heteroaryloxyl or C ３ ~C ６ cycloalkoxyl, each of which is selected from the group consisting of hydroxyl, amino, C １ ~C ６ Alkyl, C １ ~C ６ Alkoxyl, halogen, C １ ~C ３ Haloalkyl, C １ ~C ３ haloalkoxyl, optionally substituted C ３ ~C ６ Cycloalkyl, optionally substituted C ２ ~C ５ Heterocycloalkyl or optionally substituted C ３ ~C ６ and optionally substituted with 1 to 3 substituents selected from the group consisting of: cycloalkyl, heterocycloalkyl, and heteroaryl; １ ~C ３ Alkyl, C １ ~C ３ may be substituted with one or two substituents selected from the group consisting of alkoxyl, hydroxyl, halogen, or amine; L is a bond, —CH ２ -, -CH ２ -CH ２ -, -CH(CH ３ ) -, -C(CH ３ ) ２ -, -C≡C-, -CH ２ -O-, -C(O)-, -O-, -O-CH ２ --NH-CH ２ -, -N(CH ３ )-CH ２ -, -NH-C(O)-, -N(CH ３ )-C(O)-,-CH ２ -NH-CH ２ - is a linker selected from the group consisting of: Q is C ５ ~C ９ Cycloalkyl, C ４ ~C ８ Heterocycloalkyl, C ８ ~C １１ Spirocycloalkyl, C ５ ~C １０ Heterospirocycloalkyl, C ３ ~C ８ Cyclic amines, C ３ ~C ８ Heterocyclic amines, C ７ ~C １０ Spirocyclic amine or C ４ ~C ９ heterospirocyclic amines, wherein each cycloalkyl or heterocycloalkyl group can be saturated or unsaturated, and the bicyclic ring can be a fused or bridged bicyclic ring; Q is a monocyclic or bicyclic ring system selected from the group consisting of one to three R ７ and each R ７ is hydrogen, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Alkylcarbonyl, hydroxyl, oxo, halogen, C １ ~C ６ independently selected from alkylamine or amino or a pharmaceutically acceptable salt, solvate, prodrug, pharmaceutically active metabolite, or combination thereof.

2. 2. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt, solvate, prodrug, pharmaceutically active metabolite, or combination thereof, wherein each heterocyclic or heteroaryl substituent may contain 1 to 4 heteroatoms independently selected from O, S, and N.

3. 3. The compound of formula (I) of claim 1 or 2, or a pharmaceutically acceptable salt, solvate, prodrug, pharmaceutically active metabolite, or combination thereof, wherein each heterocyclic or heteroaryl substituent is attached to the remainder of the compound via a carbon atom.

4. 3. The compound of formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt, solvate, prodrug, pharmaceutically active metabolite, or combination thereof, wherein the heterocyclic or heteroaryl substituent is attached to the remainder of the compound through a heteroatom.

5. 3. The compound of formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt, solvate, prodrug, pharmaceutically active metabolite, or combination thereof, wherein the heterocyclic or heteroaryl substituent comprises at least one N atom, and the heterocyclic or heteroaryl substituent is attached to the remainder of the compound via the N atom.

6. (i) R ２ and R ２’ one of is hydrogen and the other is F; (ii) R ２ and R ２’ one of is hydrogen and the other is Cl; or (iii) R ２ and R ２’ and R are hydrogen; and R is ...

7. R ３ is hydrogen, halogen, C ３ ~C ６ Cycloalkyl, C ３ ~C ６ Heterocycloalkyl, C ５ ~C ６ Aryl, C ３ ~C ６ Heteroaryl or C ２ ~C ５ 7. The compound of formula (I) according to any one of claims 1 to 6, or a pharmaceutically acceptable salt, solvate, prodrug, pharmaceutically active metabolite, or combination thereof, selected from heterocyclic amines.

8. (i) R ３ is hydrogen or Cl; (ii) R ３ is an optionally substituted 5- or 6-membered heteroaryl; (iii) R ３ is an optionally substituted 4-6 membered heterocycloalkyl; or (iv) R ３ is an optionally substituted 3-5 membered cycloalkyl; Each heteromoiety may contain 1 or 2 heteroatoms independently selected from O, S, and N; 8. The compound of formula (I) according to claim 7, or a pharmaceutically acceptable salt, solvate, prodrug, pharmaceutically active metabolite, or combination thereof, wherein the optional substituents are independently selected from one or two substituents from the group consisting of methyl, F, and Cl.

9. (i) R ４ is hydrogen; (ii) R ４ is F and R ５ and R ６ are each hydrogen; (iii) R ４ is F and R ５ and R ６ are each hydrogen; or (iii) R ４ , R ５ and R ６ The compound of formula (I) according to any one of claims 1 to 8, or a pharmaceutically acceptable salt, solvate, prodrug, pharmaceutically active metabolite, or combination thereof, wherein all of are hydrogen.

10. (i) R ５ is hydrogen; (ii) R ５ is F; (iii) R ５ is a 4- or 5-membered heterocycloalkyl; (iv) R ５ is C １ ~C ３ Is alkyl; (v) R ５ is a 3-, 4-, or 5-membered cycloalkyl; or (vi) R ５ is an optionally substituted C ３ ~C ６ Cycloalkyl, C ３ ~C ６ Cycloalkenyl, C ３ ~C ６ Heterocycloalkyl, C ３ ~C ６ Aryl or C ３ ~C ６ 10. A compound of formula (I) according to any one of claims 1 to 9, or a pharmaceutically acceptable salt, solvate, prodrug, pharmaceutically active metabolite, or combination thereof, which is heteroaryl.

11. R ５ is selected from hydrogen, F, methyl or pyrrolidine, or a pharmaceutically acceptable salt, solvate, prodrug, pharmaceutically active metabolite, or combination thereof.

12. (i) R ６ is hydrogen; (ii) R ６ is F or Cl; (iii) R ６ is an optionally substituted 4- or 5-membered heterocycloalkyl; (iv) R ６ is an optionally substituted 8-, 9-, or 10-membered bicyclic or spirocyclic heterocycloalkyl; (v) R ６ is an optionally substituted 5- or 6-membered heteroaryl; (vi) R ６ is an optionally substituted 4-, 5-, or 6-membered cycloalkyl or spirocycloalkyl; (vii) R ６ is C １ ~C ３ haloalkoxy; or (viii) R ６ is C ２ ~C ８ an alkylamine or a dialkylamine, Each heteromoiety may contain one or two heteroatoms independently selected from O, S, and N; １ ~C ３ Alkyl, C １ ~C ３ Haloalkyl, C １ ~C ３ 12. The compound of formula (I) according to any one of claims 1 to 11, or a pharmaceutically acceptable salt, solvate, prodrug, pharmaceutically active metabolite, or combination thereof, wherein one or two substituents are independently selected from the group consisting of alkoxyl, F, Cl, and hydroxyl.

13. R ６ is selected from hydrogen, F, methyl or pyrrolidine, or a pharmaceutically acceptable salt, solvate, prodrug, pharmaceutically active metabolite, or combination thereof.

14. L is -CH ２ - or -CH ２ -CH ２ 14. A compound of formula (I) according to any one of claims 1 to 13, or a pharmaceutically acceptable salt, solvate, prodrug, pharmaceutically active metabolite thereof, or a combination thereof, selected from:

15. Q is selected from the group consisting of optionally substituted 5- to 7-membered heterocycloalkyl and optionally substituted 4- to 7-membered mono- or fused or bridged bicycloalkylamine; Each heterocyclic moiety may contain 1 or 2 heteroatoms independently selected from O and N; The optional substituents are C １ ~C ３ Alkyl, C １ ~C ３ Haloalkyl, C １ ~C ３ Alkoxyl, C １ ~C ３ Alkylamines, C １ ~C ３ Dialkylamine, C １ ~C ３ Carbonyl, amine, amino-C １ ~C ３ 15. The compound of formula (I) according to any one of claims 1 to 14, or a pharmaceutically acceptable salt, solvate, prodrug, pharmaceutically active metabolite, or combination thereof, wherein each of the substituents is independently selected from the group consisting of alkyl, oxo, F, Cl, and hydroxyl.

16. (i) R ７ is C １ ~C ３ Alkyl, C １ ~C ３ Haloalkyl, hydroxyl, oxo, F, C １ ~C ３ Alkylamino, C １ ~C ３ independently selected from dialkylamino or amino; (ii) R ７ is independently selected from methyl, ethyl, amine, and F; 1, 2 or 3 R ７ 16. The compound of formula (I) according to any one of claims 1 to 15, or a pharmaceutically acceptable salt, solvate, prodrug, pharmaceutically active metabolite, or combination thereof, wherein a group is present.

17. (i) R １ is cyano; and / or (ii) R ２ and R ２’ are each independently selected from hydrogen or F; and / or (iii) R ３ is hydrogen, propyl, i-propyl, CHF ２ , cyclopropyl, —CH ２ -cyclopropyl, -CH ２ -oxetane, isothiazole, oxazole, fluorooxazole, pyridyl, methoxyl, -O-CH ２ -cyclopropyl, -O-CH ２ -CF ３ , —O—CF ３ , C.F. ３ , Cl, amino, -N(CH ３ ) (CH ２ -isopropyl), pyrrolidine, cyano; and / or (iv) R ４ is hydrogen or F; and / or (v) R ５ is hydrogen, methyl, cyclopropyl, cyclopentenyl, F, amino, NH—CH ２ -CH ２ -N(CH ３ ) ２ and / or (vi) R ６ is hydrogen, —O-cyclobutyl, —O—CH ２ -oxane, -O-CH ２ -CH ２ -CHF ２ , —O—CH ２ -CH ２ -CF ３ , —O—CH ２ -CF ３ , -CH ２ -O-CHF ２ , amino, -N(CH ３ ) (CH-(CH ３ ) ２ , benzimidazole, pyridine; and / or (vii) L is a bond, —CH ２ -, -C≡C-, -CH ２ -NH-CH ２ and / or (viii) Q is a linker selected from C, which may contain additional heteroatoms selected from N or O. ４ ~C ８ or Q is morpholinyl; 6. The compound of formula (I) according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, solvate, prodrug, pharmaceutically active metabolite, or combination thereof, wherein each heteroaryl, heterocycloalkyl, and / or cycloalkyl group is optionally substituted.

18. 18. The compound of formula (I) according to claim 17, or a pharmaceutically acceptable salt, solvate, prodrug, pharmaceutically active metabolite, or combination thereof, wherein each heteroaryl, heterocycloalkyl, and / or cycloalkyl group is optionally substituted with one or more groups selected from F, Cl, methyl, hydroxyl, and amino.

19. R ３ has the following structure: 【Chemistry 2】 19. The compound of formula (I) according to any one of claims 1 to 18, or a pharmaceutically acceptable salt, solvate, prodrug, pharmaceutically active metabolite thereof, or a combination thereof, selected from the group consisting of:

20. R ３ has the following structure: 【Transformation 3】 20. The compound of formula (I) according to any one of claims 1 to 19, or a pharmaceutically acceptable salt, solvate, prodrug, pharmaceutically active metabolite thereof, or a combination thereof, selected from the group consisting of:

21. R ５ is hydrogen and the following structure: 【Chemistry 4】 21. The compound of formula (I) according to any one of claims 1 to 20, or a pharmaceutically acceptable salt, solvate, prodrug, pharmaceutically active metabolite thereof, or a combination thereof, selected from the group consisting of:

22. R ６ is hydrogen and the following structure: 【Transformation 5】 【Transformation 6】 【Transformation 7】 22. The compound of formula (I) according to any one of claims 1 to 21, or a pharmaceutically acceptable salt, solvate, prodrug, pharmaceutically active metabolite thereof, or a combination thereof, selected from the group consisting of:

23. R ６ is hydrogen and the following structure: 【Transformation 8】 23. The compound of formula (I) according to any one of claims 1 to 22, or a pharmaceutically acceptable salt, solvate, prodrug, pharmaceutically active metabolite thereof, or a combination thereof, selected from the group consisting of:

24. Q has the following structure: 【Chemistry 9】 【Chemistry 10】 【Chemistry 11】 【Chemistry 12】 24. The compound of formula (I) according to any one of claims 1 to 23, or a pharmaceutically acceptable salt, solvate, prodrug, pharmaceutically active metabolite thereof, or a combination thereof, selected from the group consisting of:

25. Q has the following structure: 【Chemistry 13】 25. The compound of formula (I) according to any one of claims 1 to 24, or a pharmaceutically acceptable salt, solvate, prodrug, pharmaceutically active metabolite thereof, or a combination thereof, selected from the group consisting of:

26. Q has the following structure: 【Chemistry 14】 26. The compound of formula (I) according to any one of claims 1 to 25, or a pharmaceutically acceptable salt, solvate, prodrug, pharmaceutically active metabolite thereof, or a combination thereof, selected from the group consisting of:

27. (i) R １ is cyano; and / or (ii) R ２ and R ２’ are each independently selected from hydrogen or F; and / or (iii) R ３ is selected from hydrogen, isothiazole, oxazole, fluorooxazole, pyridyl; and / or (iv) R ４ is hydrogen or F; and / or (v) R ５ is selected from hydrogen, methyl, F; and / or (vi) R ６ is hydrogen, —O-cyclobutyl, —O—CH ２ - selected from oxane; and / or (vii) L is a bond, —CH ２ -, -C≡C-; and / or (viii) Q is a C group which may contain additional heteroatoms selected from N or O. ４ ~C ８ or Q is morpholinyl; 6. The compound of formula (I) according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, solvate, prodrug, pharmaceutically active metabolite, or combination thereof, wherein each heteroaryl, heterocycloalkyl, and / or cycloalkyl group is optionally substituted.

28. (i) R １ is cyano, and / or (ii) R ２ and R ２’ one of is hydrogen and the other is F, and / or (iii) R ３ is thiazole, or R ３ is 1,2-thiazole), and / or (iv) R ４ , R ５ and R ６ is hydrogen, and / or (v) L is —CH—, and / or (vi) The compound of formula (I) or a pharmaceutically acceptable salt, solvate, prodrug, pharmaceutically active metabolite, or combination thereof according to any one of claims 1 to 5, wherein Q is morpholine.

29. (i) the group of compounds shown in Table 1; (ii) a group of compounds in Table 1 having an IC50 of 1,000 nM or less against LSD1; (iii) a group of compounds in Table 1 having an IC50 of 250 nM or less against LSD1; (iv) the group of compounds in Table 1 having an IC50 of 100 nM or less against LSD1; (v) the group of compounds in Table 1 having an IC50 of 50 nM or less against LSD1; (vi) a group of compounds in Table 1 having an IC50 of 25 nM or less against LSD1; or (vii) the group of compounds in Table 1 having an IC50 of 10 nM or less against LSD1 or a pharmaceutically acceptable salt, solvate, prodrug, pharmaceutically active metabolite, or combination thereof.

30. A compound selected from any one of Examples 1-351.

31. Any one of Examples 4, 8, 15, 20, 26, 28, 71, 108, 109, 173, 177, 182, 183, 185, 190, 192, 194, 197, 207, 216, 234, 263, 302, 303, 315 and 335; and / or a compound selected from one of Examples 4A, 8A, 15A, 26A, 28A, 173A, 177A, 182A, 183A, 185A, 190A, 192A, 194A, 197A, 207A, 216A, 234A, 263A, 302A, 303A, 315A and 335A.

32. Examples 1, 2, 3, 5, 6, 7, 9, 10, 11, 12, 13, 14, 16, 17, 18, 19, 22, 23, 24, 25, 29, 30, 34, 36, 37, 38, 39, 48, 53, 57, 74, 79, 81, 103, 110, 112, 115, 116, 154, 169, 170, 171, 172, 174, 175, 178, 179, 181, 186, 187, 188, 189, 193, 195, 196 8, 199, 201, 204, 206, 209, 210, 217, 218, 219, 222, 223, 224, 230, 231, 232, 233, 235, 237, 242, 250, 254, 255, 2 57, 259, 260, 262, 264, 268, 275, 279, 304, 309, 310, 311, 312, 313, 314, 316, 317, 321, 323, 324, 325, 333, 334 and and / or any one of Examples 2A, 3A, 5A, 6A, 7A, 9A, 11A, 13A, 14A, 17A, 22A, 23A, 30A, 37A, 169A, 170A, 171A, 172A, 174A, 175A, 178A, 179A, 181A, 186A, 187A, 188A, 189A, 193A, 195A, 201A, 204A, 206A, 209A, 217A, 218A, 219A, 220A, 221B, 222C, 223C, 224C, 225C, 226C, 227C, 228C, 229C, 230C, 231C, 232C, 233C, 234C, 235C, 236C, 237C, 238C, 239C, 240C, 241C, 242C, 243C, 244C, 245C, 246C, 247C, 248C, 249C, 250C, 251C, 252C, 253C, 254C, 255C, 256C, 257C, 258C, 259C, 260C, 261C, 262C, 263C, 264C, 265C, 266C, 267C, 268C, 269C, 270C, 2 A compound selected from any one of 22A, 223A, 224A, 230A, 231A, 232A, 233A, 235A, 237A, 242A, 250A, 254A, 255A, 257A, 259A, 260A, 262A, 264A, 268A, 275A, 279A, 304A, 309A, 310A, 311A, 312A, 313A, 314A, 316A, 317A, 321A, 324A and 334A.

33. Examples 27, 31, 32, 33, 35, 43, 46, 47, 49, 51, 56, 60, 64, 67, 68, 70, 73, 82, 83, 91, 93, 94, 95, 100, 102, 104, 111, 128, 138, 153, 156, 176, 180, 184, 191, 196, 200, 202, 203, 205, 208, 211, 212, 213, 215, 220, 221, 227, 229, 236, 239, 240, 243, 244, 245, 247, 249, 251, 252, 253, 256, 258, 265, 273, 277, 299, 301, 305, 308, 318, 319, 322 and 339; and / or a compound selected from any one of Examples 31A, 176A, 180A, 184A, 191A, 196A, 200A, 202A, 203A, 208A, 211A, 212A, 213A, 215A, 220A, 221A, 229A, 243A, 244A, 245A, 247A, 249A, 251A, 252A, 253A, 256A, 258A, 273A, 299A, 301A, 305A, 308A, 318A, 319A and 322A.

34. Examples 21, 40, 41, 42, 44, 45, 50, 52, 54, 55, 58, 59, 61, 62, 63, 66, 69, 72, 75, 76, 77, 78, 80, 85, 86, 88, 92, 96, 98, 99, 101, 105, 106, 107, 113, 114, 118, 119, 120, 121, 122, and 124 , 125, 126, 127, 129, 133, 137, 139, 141, 143, 147, 148, 149, 151, 152, 155, 163, 164, 165, 166, 168, 225, 226, 228, 238, 241, 246, 248, 261, 266, 267, 269, 270, 271, 272, 274 , 276, 278, 280, 282, 283, 284, 285, 288, 289, 291, 293, 294, 297, 298, 300, 306, 307, 320, 328, 332, 340, 341, 342, 346, 347, 348 and 349; and / or any one of Examples 41A, 54A, 76A, 11 A compound selected from any one of: 4A, 120A, 225A, 228A, 241A, 246A, 248A, 261A, 269A, 270A, 271A, 272A, 282A, 285A, 291A, 293A, 294A, 297A, 300A, 306A, 307A, 320A, 342A, 347A and 349A.

35. any one of Examples 65, 84, 87, 89, 90, 97, 117, 123, 130, 131, 132, 134, 135, 136, 140, 142, 144, 145, 146, 150, 157, 158, 159, 160, 161, 162, 167, 175, 214, 281, 286, 287, 290, 292, 295, 296, 326, 327, 329, 330, 331, 337, 338, 343, 344 and 345; and / or a compound selected from any one of Examples 87A, 131A, 144A, 175A, 326A, 329A, 330A, 331A and 337A.

36. 36. A pharmaceutical composition comprising the compound of any one of claims 1 to 35, or a pharmaceutically acceptable salt, solvate, prodrug, pharmaceutically active metabolite, or combination thereof, and one or more pharmaceutically acceptable carriers.

37. Formula (I): 【Chemistry 15】 (In the formula, R １ is nitro or cyano; R ２ and R ２’ are each independently C １～３ selected from alkyl, hydrogen or halogen; R ３ is hydrogen, C １～３ Alkyl, C １～３ Haloalkyl, C ３ ~C ６ Cycloalkyl, C ３ ~C ６ Cycloalkenyl, C ３ ~C ６ Heterocycloalkyl, C ４ ~C ５ Heterocycloalkenyl, C ３ ~C ５ Heterocycloalkyl C １ ~C ３ Alkyl, C ５ ~C ６ Aryl, C ３ ~C ６ Heteroaryl, C １ ~C ４ Alkoxyl, C ３ ~C ６ Cycloalkyl-C １ ~C ３ Alkoxyl, C １ ~C ４ Haloalkoxyl, C １ ~C ３ Haloalkyl, halogen, amino, alkylamino, dialkylamino, C ２ ~C ７ Cyclic amines, C ２ ~C ５ Heterocyclic amines, C ３ ~C ６ Unsaturated or aromatic cyclic amines, C ３ ~C ５ unsaturated or aromatic heterocyclic amine, cyano, wherein each alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, heterocycloalkylalkyl, aryl, heteroaryl, alkoxyl, cycloalkylalkoxyl, alkylamino, dialkylamino, cyclic amine, heterocyclic amine, unsaturated or aromatic cyclic amine, and unsaturated or aromatic heterocyclic amine is selected from C １ ~C ３ Alkyl, C １ ~C ３ Alkoxyl, C ３ ~C ６ optionally substituted with 1 to 3 substituents selected from the group consisting of cycloalkyl, hydroxyl, halogen, and amino; R ４ is selected from hydrogen or halogen; R ５ is hydrogen, C １～３ Alkyl, C ３ ~C ６ Cycloalkyl, C ３ ~C ６ Cycloalkenyl, C ３ ~C ６ Aryl, C ３ ~C ６ Heteroaryl, halogen, amino, alkylamino, dialkylamino, C ２ ~C ７ Cyclic amines, C ２ ~C ５ Heterocyclic amines, C ３ ~C ６ Unsaturated or aromatic cyclic amines, C ３ ~C ５ and unsaturated or aromatic heterocyclic amines, each alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, alkylamino, dialkylamino, cyclic amine, heterocyclic amine, unsaturated or aromatic cyclic amine, and unsaturated or aromatic heterocyclic amine is selected from the group consisting of C １ ~C ３ Alkyl, C １ ~C ３ Alkoxyl, C ３ ~C ６ optionally substituted with 1 to 3 substituents selected from the group consisting of cycloalkyl, hydroxyl, halogen, or amino; R ６ is hydrogen, C １ ~C ４ Alkyl, C １ ~C ４ Alkoxyl, amino, alkylamino, aminoalkyl, dialkylamino, C ８ ~C １１ Spirocycloalkyl, C ５ ~C １０ Heterospirocycloalkyl, C ５ ~C １１ monocyclic or bicyclic aryl, monocyclic or bicyclic heteroaryl, C ２ ~C ７ Cyclic amines, C ２ ~C ５ Heterocyclic amines, C ３ ~C ６ Unsaturated or aromatic cyclic amines, C ３ ~C ５ Unsaturated or aromatic heterocyclic amines, C ７ ~C １０ Spirocyclic amines, C ４ ~C ９ Heterospirocyclic amines, C ３ ~C ６ Heteroaryloxyl or C ３ ~C ６ cycloalkoxyl, each of which is selected from the group consisting of hydroxyl, amino, C １ ~C ６ Alkyl, C １ ~C ６ Alkoxyl, halogen, C １ ~C ３ Haloalkyl, C １ ~C ３ haloalkoxyl, optionally substituted C ３ ~C ６ Cycloalkyl, optionally substituted C ２ ~C ５ Heterocycloalkyl or optionally substituted C ３ ~C ６ and optionally substituted with 1 to 3 substituents selected from the group consisting of: cycloalkyl, heterocycloalkyl, and heteroaryl; １ ~C ３ Alkyl, C １ ~C ３ may be substituted with one or two substituents selected from the group consisting of alkoxyl, hydroxyl, halogen, or amine; L is a bond, —CH ２ -, -CH ２ -CH ２ -, -CH(CH ３ ) -, -C(CH ３ ) ２ -, -C≡C-, -CH ２ -O-, -C(O)-, -O-, -O-CH ２ --NH-CH ２ -, -N(CH ３ )-CH ２ -, -NH-C(O)-, -N(CH ３ )-C(O)-,-CH ２ -NH-CH ２ - is a linker selected from the group consisting of: Q is C ５ ~C ９ Cycloalkyl, C ４ ~C ８ Heterocycloalkyl, C ８ ~C １１ Spirocycloalkyl, C ５ ~C １０ Heterospirocycloalkyl, C ３ ~C ８ Cyclic amines, C ３ ~C ８ Heterocyclic amines, C ７ ~C １０ Spirocyclic amine or C ４ ~C ９ heterospirocyclic amines, wherein each cycloalkyl or heterocycloalkyl group can be saturated or unsaturated, and the bicyclic ring can be a fused or bridged bicyclic ring; Q is a monocyclic or bicyclic ring system selected from the group consisting of one to three R ７ and each R ７ is hydrogen, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Alkylcarbonyl, hydroxyl, oxo, halogen, C １ ~C ６ independently selected from alkylamine or amino or a pharmaceutically acceptable salt, solvate, prodrug or pharmaceutically active metabolite thereof, or a combination thereof; one or more pharmaceutically acceptable carriers; A pharmaceutical composition comprising:

38. The pharmaceutical composition of claim 37, wherein the compound is one of claims 2 to 35.

39. (i) the group of compounds shown in Table 1; (ii) a group of compounds in Table 1 having an IC50 of 1,000 nM or less against LSD1; (iii) a group of compounds in Table 1 having an IC50 of 250 nM or less against LSD1; (iv) the group of compounds in Table 1 having an IC50 of 100 nM or less against LSD1; (v) the group of compounds in Table 1 having an IC50 of 50 nM or less against LSD1; (vi) a group of compounds in Table 1 having an IC50 of 25 nM or less against LSD1; or (vii) the group of compounds in Table 1 having an IC50 of 10 nM or less against LSD1 or a pharmaceutically acceptable salt, solvate, prodrug or pharmaceutically active metabolite thereof, or a combination thereof, and one or more pharmaceutically acceptable carriers.

40. A pharmaceutical composition comprising a compound selected from any one of the compounds of Examples 1 to 351, or a pharmaceutically acceptable salt, solvate, prodrug, or pharmaceutically active metabolite thereof, or a combination thereof, and one or more pharmaceutically acceptable carriers.

41. A compound according to any one of claims 1 to 35 or a pharmaceutical composition according to any one of claims 36 to 40 for use in medicine.

42. 42. A compound or pharmaceutical composition for use according to claim 41, wherein said use is in the treatment of a disease, condition or disorder associated with LSD1.

43. 43. A compound or pharmaceutical composition for use according to claim 41 or 42, wherein said use is in the treatment of cancer, a neoplastic disease, an autoimmune disorder and / or an inflammatory disease.

44. 44. The compound or pharmaceutical composition for use according to any one of claims 41 to 43, wherein the use is in the treatment of a disease, condition or disorder selected from the group consisting of breast cancer, prostate cancer, head and neck cancer, brain cancer, laryngeal cancer, oral cancer and thyroid cancer (e.g. papillary thyroid cancer), blood cancer (e.g. non-Hodgkin's lymphoma, B-cell lymphoma, chronic myeloid leukemia), sarcoma, lung cancer, gastrointestinal cancer, genitourinary cancer, liver cancer, bone cancer, nervous system cancer, gynecological cancer and skin cancer.

45. The use Lymphomas, including diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma, non-Hodgkin's lymphoma, relapsed or refractory NHL and relapsed follicular lymphoma, Hodgkin's lymphoma; Leukemia, including acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), and chronic myelogenous leukemia (CML); Myeloproliferative disorders, including primary myelofibrosis (PMF), polycythemia vera (PV), and essential thrombocytosis (ET); Myelodysplastic syndromes (MDS) and multiple myeloma; Sarcomas, including chondrosarcoma, Ewing's sarcoma, osteosarcoma, rhabdomyosarcoma, angiosarcoma, fibrosarcoma, liposarcoma, myxoma, rhabdomyoma, fibroma, lipoma, hamartoma, and teratoma; Lung cancers, including non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), bronchogenic carcinoma, squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, adenocarcinoma, alveolar (bronchiolar) carcinoma, bronchial adenoma, cartilaginous hamartoma, and mesothelioma; Digestive cancers, including esophageal cancer (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), gastric cancer (carcinoma, lymphoma, leiomyosarcoma), pancreatic cancer (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vipoma), small intestine cancer (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), colon cancer (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma) and colorectal cancer; Genitourinary cancers, including kidney cancer (adenocarcinoma, Wilms' tumor, nephroblastoma), bladder and urethral cancer (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate cancer (adenocarcinoma, sarcoma) and testicular cancer (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, lipoma); liver cancer, including hepatocellular carcinoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma and hemangioma; bone cancer, including osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochondroma (osteochondroid exostosis), benign chondroma, chondroblastoma, chondromyxoid fibroma, osteoid osteoma and giant cell tumor; Cancers of the skull (osteoma, hemangioma, granuloma, xanthomas, osteitis deformans), meningeal cancer (meningioma, meningeal sarcoma, gliomatosis), brain cancer (astrocytoma, medulloblastoma, glioma, ependymoma, embryonal tumor (pinealoma), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal cancer (neurofibroma, meningioma, glioma, sarcoma), and nervous system cancers including neuroblastoma and Lhermitte-Dacros disease; uterine cancer (endometrial cancer) , gynecological cancers including cervical cancer (cervical carcinoma, preneoplastic cervical dysplasia), ovarian cancer (ovarian cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa theca cell tumor, Sertoli-Leydig cell tumor, dysgerminoma, malignant teratoma), vulvar cancer (squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma, melanoma), vaginal cancer (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma) and fallopian tube cancer (carcinoma); Skin cancers including melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, dysplastic nevi, lipoma, hemangioma, dermatofibroma and keloids 45. A compound or pharmaceutical composition for use according to any one of claims 41 to 44 in the treatment of a disease, condition or disorder selected from the group consisting of:

46. 46. ​​The compound or pharmaceutical composition for use according to any one of claims 41 to 45, wherein said use is in the treatment of a disease, condition or disorder selected from the group consisting of glioblastoma, acute myeloid leukemia (AML) and small cell lung cancer (SCLC).

47. 47. The compound or pharmaceutical composition for use according to any one of claims 41 to 46, wherein said use is in the treatment of glioblastoma.

48. 47. The compound or pharmaceutical composition for use according to any one of claims 41 to 46, wherein said use is in the treatment of acute myeloid leukemia (AML).

49. 47. The compound or pharmaceutical composition for use according to any one of claims 41 to 46, wherein said use is in the treatment of small cell lung cancer (SCLC).

50. The compound according to any one of claims 1 to 35, the pharmaceutical composition according to any one of claims 36 to 40 or the compound or pharmaceutical composition for use according to any one of claims 41 to 49, wherein the compound is an inhibitor of LSD1.

51. 51. The compound or pharmaceutical composition for use according to any one of claims 41 to 50, wherein the use is in a method comprising administering the compound orally, topically, by inhalation, by intranasal administration, intracerebroventricularly, or systemically by intravenous, intraperitoneal, subcutaneous or intramuscular injection.

52. 52. The compound or pharmaceutical composition for use according to any one of claims 41 to 51, wherein the use is in a method comprising administering to a subject the compound of formula (I) or the pharmaceutical composition of any one of claims 36 to 40 in combination with one or more additional therapeutic agents.

53. 53. The compound or pharmaceutical composition for use according to claim 52, wherein said administering comprises administering to a subject said compound of formula (I) or the pharmaceutical composition of any one of claims 36 to 40 simultaneously, sequentially or separately with said one or more additional therapeutic agents.

54. 54. The compound or pharmaceutical composition for use according to any one of claims 41 to 53, comprising administering to a subject an effective amount of the compound of formula (I), wherein the effective amount is from about 500 nM to about 10 μM in the blood of the subject or in the plasma of the subject.

55. 41. A method of treating a disease, disorder or condition in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1 to 35 or a pharmaceutical composition of any one of claims 36 to 40.

56. 56. The method of claim 55, wherein the disease, disorder or condition is associated with LSD1.

57. 57. The method of claim 55 or 56, wherein the disease, disorder or condition is associated with overexpression or high levels of LSD1 in the subject.

58. 41. A method of treating a disease, disorder or condition associated with LSD1 in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 35 or a pharmaceutical composition according to any one of claims 36 to 40.

59. 59. The method of any one of claims 55 to 58, wherein the compound is an inhibitor of LSD1.

60. 60. The method of any one of claims 55 to 59, comprising administering the compound or pharmaceutical composition orally, topically, by inhalation, by intranasal administration, or systemically by intravenous, intraperitoneal, subcutaneous, or intramuscular injection.

61. 61. The method of any one of claims 55 to 60, comprising administering the compound of formula (I) or the pharmaceutical composition of any one of claims 36 to 40 in combination with one or more additional therapeutic agents.

62. 62. The method of any one of claims 55 to 61, comprising administering said compound of formula (I) simultaneously, sequentially or separately with said one or more additional therapeutic agents.

63. 63. The method of any one of claims 55 to 62, comprising administering to a subject an effective amount of the compound of formula (I), wherein the effective amount is from about 500 nM to about 10 μM in the blood of the subject or in the plasma of the subject.

64. 64. The method according to any one of claims 55 to 63, for the treatment of cancer, a neoplastic disease, an autoimmune disorder and / or an inflammatory disease.

65. 65. The method of any one of claims 55 to 64, for the treatment of a disease, condition or disorder selected from the group consisting of breast cancer, prostate cancer, head and neck cancer, brain cancer, laryngeal cancer, oral cancer and thyroid cancer (e.g., papillary thyroid cancer), blood cancer (e.g., non-Hodgkin's lymphoma, B-cell lymphoma, chronic myeloid leukemia), sarcoma, lung cancer, gastrointestinal cancer, genitourinary cancer, liver cancer, bone cancer, nervous system cancer, gynecological cancer and skin cancer.

66. for the treatment of cancer, and said cancer is Lymphomas, including diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma, non-Hodgkin's lymphoma, relapsed or refractory NHL and relapsed follicular lymphoma, Hodgkin's lymphoma; Leukemia, including acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), and chronic myelogenous leukemia (CML); Myeloproliferative disorders, including primary myelofibrosis (PMF), polycythemia vera (PV), and essential thrombocytosis (ET); Myelodysplastic syndromes (MDS) and multiple myeloma; Sarcomas, including chondrosarcoma, Ewing's sarcoma, osteosarcoma, rhabdomyosarcoma, angiosarcoma, fibrosarcoma, liposarcoma, myxoma, rhabdomyoma, fibroma, lipoma, hamartoma, and teratoma; Lung cancer, including non-small cell lung cancer (NSCLC), small cell lung cancer, bronchogenic carcinoma, squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, adenocarcinoma, alveolar (bronchiolar) carcinoma, bronchial adenoma, cartilaginous hamartoma, and mesothelioma; Digestive cancers, including esophageal cancer (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), gastric cancer (carcinoma, lymphoma, leiomyosarcoma), pancreatic cancer (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vipoma), small intestine cancer (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), colon cancer (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma) and colorectal cancer; Genitourinary cancers, including kidney cancer (adenocarcinoma, Wilms' tumor, nephroblastoma), bladder and urethral cancer (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate cancer (adenocarcinoma, sarcoma) and testicular cancer (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, lipoma); liver cancer, including hepatocellular carcinoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma and hemangioma; bone cancer, including osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochondroma (osteochondroid exostosis), benign chondroma, chondroblastoma, chondromyxoid fibroma, osteoid osteoma and giant cell tumor; Cancers of the skull (osteoma, hemangioma, granuloma, xanthomas, osteitis deformans), meningeal cancer (meningioma, meningeal sarcoma, gliomatosis), brain cancer (astrocytoma, medulloblastoma, glioma, ependymoma, embryonal tumor (pinealoma), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal cancer (neurofibroma, meningioma, glioma, sarcoma), and nervous system cancers including neuroblastoma and Lhermitte-Dacros disease; uterine cancer (endometrial cancer) , gynecological cancers including cervical cancer (cervical carcinoma, preneoplastic cervical dysplasia), ovarian cancer (ovarian cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa theca cell tumor, Sertoli-Leydig cell tumor, dysgerminoma, malignant teratoma), vulvar cancer (squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma, melanoma), vaginal cancer (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma) and fallopian tube cancer (carcinoma); Skin cancers including melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, dysplastic nevi, lipoma, hemangioma, dermatofibroma and keloids 66. The method of any one of claims 55 to 65, selected from the group consisting of:

67. 67. The method of any one of claims 55 to 66, for the treatment of a disease, condition or disorder selected from the group consisting of glioblastoma, acute myeloid leukemia (AML) and small cell lung cancer (SCLC).

68. 68. The method of any one of claims 55 to 67, for the treatment of glioblastoma.

69. 68. The method of any one of claims 55 to 67, for the treatment of acute myeloid leukemia (AML).

70. 68. The method of any one of claims 55 to 67, for the treatment of small cell lung cancer (SCLC).

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