TRPC3 inhibitors and uses thereof

Abstract

Provided herein are compounds, including compounds of any of the formulae described herein (e.g., Formula (I)), and pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, isotopically labeled derivatives, and prodrugs thereof. Compounds provided herein can inhibit transient receptor potential cation channel subfamily C (TRPC) activity (e.g., TRPC member 3 (TRPC3) activity, TRPC member 6 (TRPC6) activity) and are therefore useful in the treatment and / or prevention of diseases (e.g., Alzheimer's disease).

Description

[0001] TRPC3 INHIBITORS AND USES THEREOF

[0002] RELATED APPLICATIONS

[0003]

[0001] This application claims priority under 35 U.S.C. § 119(e) to United States Provisional Patent Application, U.S.S.N. 63 / 621,673, filed January 17, 2024, the entire contents of which is incorporated herein by reference.

[0004] BACKGROUND

[0005]

[0002] Alzheimer’ s disease (AD) is a neurodegenerative disorder characterized by both dementia and the accumulation of neuropathological amyloid plaques and tau tangles. Mutations that drive overproduction of beta-amyloid (AP) have been shown to cause early onset familial AD (FAD), leading to a model in which production and accumulation of Ap is thought to be an initiating event in a sequence leading to memory loss, neurodegeneration, gliosis, and synaptic dysfunction. Strategies to directly target amyloid for clearance have not translated into successful treatments, and the number of deaths attributable to AD as well as costs associated with the disease continue to rise. In addition, even among patients with FAD mutations, the age at first symptom onset is widely variable, with some patients exhibiting symptoms decades later than predicted based on mutation status, suggesting additional genetic factors exist that may provide protection from disease.

[0006]

[0003] In recent years, the transient receptor potential cation channel subfamily C, member 3 (TRPC3) protein has emerged as a therapeutic target for treating neurodegenerative diseases including Alzheimer’s disease. See, e.g., U.S. Patent No. 11,723,347 B2, the entire contents of which is incorporated herein by reference. Increases in TRPC3 genes and upregulation of TRPC3 proteins are associated with amyloid load and AD-related cognitive symptoms in Alzheimer’ s disease. More recently, TRPC3 inhibitors have been reported to rescue neuronal loss and improve cognitive symptoms of AD, including loss of spatial learning and memory. See, e.g., Wang et al. “A Selective TRPC3 Antagonist Rescues Neuronal Loss and Facilitates Spatial Learning and Memory in Alzheimer's Model” Journal of Pharmacology and Experimental Therapeutics 2023, 385(S3), 314.

[0007] SUMMARY

[0008]

[0004] Provided herein are compounds, including compounds of any of the formulae described herein (e.g., Formula (I)), and pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, isotopically labeled derivatives, and prodrugs thereof. Compounds provided herein can inhibit transient receptor potential cation channel subfamily C (TRPC) activity (e.g., TRPC member 3 (TRPC3) activity, TRPC member 6 (TRPC6) activity) and are therefore useful in the treatment and / or prevention of diseases (e.g., Alzheimer’s disease). Also provided herein are pharmaceutical compositions comprising the compounds provided herein, and kits comprising the same. Additionally, the disclosure provides methods of preparing the compounds and pharmaceutical compositions described herein and intermediates useful in such methods.

[0005] In one aspect, provided herein are compounds of Formula (I): and pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, isotopically labeled derivatives, and prodrugs thereof, wherein R1, R", RN1, R2, R3, R4, R5, Y, m, n, and p are as defined herein.

[0009]

[0006] In certain embodiments, for example, a compound of Formula (I) is selected from those recited in Table 1 (infra), and pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, isotopically labeled derivatives, and prodrugs thereof.

[0010]

[0007] In another aspect, provided herein are pharmaceutical compositions comprising a compound of Formula (I), or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, and one or more pharmaceutically acceptable carriers and / or excipients. In certain embodiments, a pharmaceutical composition provided herein comprises an effective amount (e.g., therapeutically effective amount) of a compound of Formula (I), or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof.

[0011]

[0008] As described, compounds and pharmaceutical compositions provided herein can inhibit TRPC (e.g., TRPC3, TRPC6) activity and are therefore useful for treating and / or preventing diseases (e.g., diseases in which TRPC3 activity is implicated, e.g., Alzheimer’s disease). Therefore, provided herein are methods and uses of the compounds and pharmaceutical compositions provided herein, including, but not limited to, the following:

[0012] (a) Methods of inhibiting TRPC e.g., TRPC3, TRPC6) activity in a subject comprising administering to the subject an effecting amount of a compound of Formula (I), or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition thereof.

[0013] (b) Methods of treating and / or preventing a disease associated with TRPC (e.g., TRPC3, TRPC6) activity in a subject in need thereof comprising administering to the subject a compound of Formula (I), or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition thereof.

[0014] (c) Methods of treating and / or preventing Alzheimer’s disease in a subject in need thereof comprising administering to the subject a compound of Formula (I), or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition thereof. (d) Methods comprising administering to a subject a compound of Formula (I), or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition thereof. In certain embodiments, the subject has or is at risk of having a disease associated with TRPC (e.g., TRPC3, TRPC6) activity (e.g., Alzheimer’s disease).

[0015] (e) Methods of inhibiting TRPC (e.g., TRPC3, TRPC6) activity in vitro comprising contacting a TRPC e.g., TRPC3, TRPC6) protein with a compound of Formula (I), or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition thereof.

[0016]

[0009] In another aspect, provided herein are compounds of Formula (I), and pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, isotopically labeled derivatives, and prodrugs thereof, and pharmaceutical compositions thereof, for use in any of the methods provided herein. In another aspect, provided herein are compounds of Formula (I), and pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, isotopically labeled derivatives, and prodrugs thereof, and pharmaceutical compositions thereof, for use as medicaments and / or in the preparation of medicaments.

[0017]

[0010] In another aspect, provided herein are kits comprising a compound of Formula (I), or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition thereof. The kits described herein may include a single dose or multiple doses of the compound or pharmaceutical composition thereof. The kits described herein are useful in any method or use provided herein, and optionally further comprise instructions for using the kit (e.g., instructions for using the compound or composition included in the kit).

[0018] [Oil] Also provided herein are methods of preparing compounds of Formula (I), and pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, isotopically labeled derivatives, and prodrugs thereof, and pharmaceutical compositions thereof. Synthetic intermediates useful in the preparation of the compounds and compositions are also provided herein.

[0019]

[0012] The details of certain embodiments of the disclosure are set forth in the Detailed Description, as described below. Other embodiments of the disclosure will be apparent from the Definitions, Examples, Abstract, and Claims.

[0020] DEFINITIONS

[0021] Chemical Definitions

[0022]

[0013] Definitions of specific functional groups and chemical terms are described in more detail below. The chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Michael B. Smith, March’s Advanced Organic Chemistry, 7thEdition, John Wiley & Sons, Inc., New York, 2013; Richard C. Larock, Comprehensive Organic Transformations, John Wiley & Sons, Inc., New York, 2018; and Carruthers, Some Modem Methods of Organic Synthesis, 3rdEdition, Cambridge University Press, Cambridge, 1987.

[0023]

[0014] Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various stereoisomeric forms, e.g., enantiomers and / or diastereomers. For example, the compounds described herein can be in the form of an individual enantiomer, diastereomer, or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, E.L. Stereochemistry of Carbon Compounds (McGraw- Hill, NY, 1962); and Wilen, S.H., Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ, of Notre Dame Press, Notre Dame, IN 1972). The present disclosure additionally encompasses compounds as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

[0024]

[0015] Unless otherwise provided, formulae and structures depicted herein include compounds that do not include isotopically enriched atoms, and also include compounds that include isotopically enriched atoms (“isotopically labeled derivatives”). For example, compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, replacement of19F with18F, or the replacement of a carbon by a13C- or14C-enriched carbon are within the scope of the disclosure. Such compounds are useful, for example, as analytical tools or probes in biological assays. The term “isotopes” refers to variants of a particular chemical element such that, while all isotopes of a given element share the same number of protons in each atom of the element, those isotopes differ in the number of neutrons.

[0025]

[0016] When a range of values (“range”) is listed, it encompasses each value and sub-range within the range. A range is inclusive of the values at the two ends of the range unless otherwise provided. For example, “Ci-6 alkyl” encompasses, Ci, C2, C3, C4, C5, Ce, Ci-6, C1-5, Ci^t, C1-3, C1-2, C2-6, C2-5, C: 4. C2-3, C3-6, C3-5, C3 4, C4-6, C4-5, and C5-6 alkyl.

[0026]

[0017] Use of the phrase “at least one instance” refers to 1, 2, 3, 4, or more instances, but also encompasses a range, e.g., for example, from 1 to 4, from 1 to 3, from 1 to 2, from 2 to 4, from 2 to 3, or from 3 to 4 instances, inclusive.

[0027]

[0018] The term “aliphatic” refers to alkyl, alkenyl, alkynyl, and carbocyclic groups.

[0028]

[0019] The term “alkyl” refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 20 carbon atoms (“Ci-20 alkyl”). In some embodiments, an alkyl group has 1 to 12 carbon atoms (“Ci-12 alkyl”). In some embodiments, an alkyl group has 1 to 10 carbon atoms (“Ci-10 alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms (“C1-9 alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“Ci-8 alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“C1-7 alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“C1-6 alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C1-5 alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms (“Ci^t alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“C1-3 alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“C1-2 alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“Ci alkyl”). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“C2-6 alkyl”). Examples of Ci-6 alkyl groups include methyl (Ci), ethyl (C2), propyl (C3) (e.g., n-propyl, isopropyl), butyl (C4) (e.g., zz-butyl, tert-butyl, sec-butyl, isobutyl), pentyl (C5) (e.g., n-pentyl, 3-pentanyl, amyl, neopentyl, 3-methyl-2-butanyl, tertamyl), and hexyl (Ce) (e.g., n-hexyl). Additional examples of alkyl groups include zz-hcptyl (C7), n-octyl (Cs), zz-dodccyl (C12), and the like. Unless otherwise specified, each instance of an alkyl group is independently unsubstituted (an “unsubstituted alkyl”) or substituted (a “substituted alkyl”) with one or more substituents (e.g., halogen, such as F). In certain embodiments, the alkyl group is an unsubstituted C1-12 alkyl (such as unsubstituted Ci-6 alkyl, e.g., -CH3 (Me), unsubstituted ethyl (Et), unsubstituted propyl (Pr, e.g., unsubstituted n-propyl (n-Pr), unsubstituted isopropyl (z'-Pr)), unsubstituted butyl (Bu, e.g., unsubstituted zz-butyl (n-Bu), unsubstituted tert-butyl (tert-Bu or t-Bu), unsubstituted .vec-butyl (sec- Bu or s-Bu), unsubstituted isobutyl (z'-Bu)). In certain embodiments, the alkyl group is a substituted Ci-12 alkyl (such as substituted Ci-6 alkyl, e.g., -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, or benzyl (Bn)).

[0029]

[0020] The term “haloalkyl” is a substituted alkyl group, wherein one or more of the hydrogen atoms are independently replaced by a halogen, e.g., fluoro, bromo, chloro, or iodo. “Perhaloalkyl” is a subset of haloalkyl and refers to an alkyl group wherein all of the hydrogen atoms are independently replaced by a halogen, e.g., fluoro, bromo, chloro, or iodo. In some embodiments, the haloalkyl moiety has 1 to 20 carbon atoms (“Ci-20 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 10 carbon atoms (“Ci-10 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 9 carbon atoms (“C1-9 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 8 carbon atoms (“Ci-8 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 7 carbon atoms (“C1-7 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 6 carbon atoms (“Ci-6 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 5 carbon atoms (“C1-5 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 4 carbon atoms (“Ci^t haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 3 carbon atoms (“C1-3 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 2 carbon atoms (“C1-2 haloalkyl”). In some embodiments, all of the haloalkyl hydrogen atoms are independently replaced with fluoro to provide a “perfluoroalkyl” group. In some embodiments, all of the haloalkyl hydrogen atoms are independently replaced with chloro to provide a “perchloroalkyl” group. Examples of haloalkyl groups include -CHF2, -CH2F, -CF3, -CH2CF3, -CF2CF3, -CF2CF2CF3, -CCI3, -CFQ2, -CF2CI, and the like.

[0030]

[0021] The term “heteroalkyl” refers to an alkyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, sulfur, silicon, boron, and phosphorous within e.g., inserted between adjacent carbon atoms of) and / or placed at one or more terminal position(s) of the parent chain. In certain embodiments, the heteroalkyl group is an alkyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, and sulfur within (e.g., inserted between adjacent carbon atoms of) and / or placed at one or more terminal position(s) of the parent chain. In certain embodiments, a heteroalkyl group refers to a saturated group having from 1 to 20 carbon atoms and 1 or more heteroatoms within the parent chain (“Ci-20 heteroalkyl”). In certain embodiments, a heteroalkyl group refers to a saturated group having from 1 to 12 carbon atoms and 1 or more heteroatoms within the parent chain (“Ci-12 heteroalkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 11 carbon atoms and 1 or more heteroatoms within the parent chain (“Ci-11 heteroalkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 10 carbon atoms and 1 or more heteroatoms within the parent chain (“Ci-10 heteroalkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 9 carbon atoms and 1 or more heteroatoms within the parent chain (“C1-9 heteroalkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1 or more heteroatoms within the parent chain (“Ci-8 heteroalkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 7 carbon atoms and 1 or more heteroatoms within the parent chain (“C1-7 heteroalkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 6 carbon atoms and 1 or more heteroatoms within the parent chain (“Ci-6 heteroalkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms within the parent chain (“C1-5 heteroalkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and 1 or 2 heteroatoms within the parent chain (“Ci^t heteroalkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom within the parent chain (“C1-3 heteroalkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom within the parent chain (“C1-2 heteroalkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom (“Ci heteroalkyl”). In some embodiments, a heteroalkyl group is a saturated group having 2 to 6 carbon atoms and 1 or 2 heteroatoms within the parent chain (“C2-6 heteroalkyl”). Unless otherwise specified, each instance of a heteroalkyl group is independently unsubstituted (an “unsubstituted heteroalkyl”) or substituted (a “substituted heteroalkyl”) with one or more substituents.

[0031]

[0022] The term “alkenyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 20 carbon atoms and one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 double bonds). In some embodiments, an alkenyl group has 2 to 20 carbon atoms (“C2-20 alkenyl”). In some embodiments, an alkenyl group has 2 to 12 carbon atoms (“C2-12 alkenyl”). In some embodiments, an alkenyl group has 2 to 11 carbon atoms (“C2-11 alkenyl”). In some embodiments, an alkenyl group has 2 to 10 carbon atoms (“C2-10 alkenyl”). In some embodiments, an alkenyl group has 2 to 9 carbon atoms (“C2-9 alkenyl”). In some embodiments, an alkenyl group has 2 to 8 carbon atoms (“C2-8 alkenyl”). In some embodiments, an alkenyl group has 2 to 7 carbon atoms (“C2-7 alkenyl”). In some embodiments, an alkenyl group has 2 to 6 carbon atoms (“C2-6 alkenyl”). In some embodiments, an alkenyl group has 2 to 5 carbon atoms (“C2-5 alkenyl”). In some embodiments, an alkenyl group has 2 to 4 carbon atoms (“C2-4 alkenyl”). In some embodiments, an alkenyl group has 2 to 3 carbon atoms (“C2-3 alkenyl”). In some embodiments, an alkenyl group has 2 carbon atom (“C2 alkenyl”). The one or more carbon-carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). Examples of C 4 alkenyl groups include ethenyl (C2), 1 -propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. Examples of C2-6 alkenyl groups include the aforementioned C2-4 alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (Ce), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (Cs), octatrienyl (Cs), and the like. Unless otherwise specified, each instance of an alkenyl group is independently unsubstituted (an “unsubstituted alkenyl”) or substituted (a “substituted alkenyl”) with one or more substituents. In an alkenyl group, a C=C double bond for which the stereochemistry is not specified (e.g., -CH=CHCH3 or may be in the (£)- or (Z)- configuration.

[0032]

[0023] The term “heteroalkenyl” refers to an alkenyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, sulfur, silicon, boron, and phosphorous within (e.g., inserted between adjacent carbon atoms of) and / or placed at one or more terminal position(s) of the parent chain. In certain embodiments, the heteroalkenyl group is an alkenyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, and sulfur within (e.g., inserted between adjacent carbon atoms of) and / or placed at one or more terminal position(s) of the parent chain. In certain embodiments, a heteroalkenyl group refers to a group having from 2 to 20 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“C2-20 heteroalkenyl”). In certain embodiments, a heteroalkenyl group refers to a group having from 2 to 12 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“C2-12 heteroalkenyl”). In certain embodiments, a heteroalkenyl group refers to a group having from 2 to 11 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“C2-11 heteroalkenyl”). In certain embodiments, a heteroalkenyl group refers to a group having from 2 to 10 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“C2-10 heteroalkenyl”). In some embodiments, a heteroalkenyl group has 2 to 9 carbon atoms at least one double bond, and 1 or more heteroatoms within the parent chain (“C2-9 heteroalkenyl”). In some embodiments, a heteroalkenyl group has 2 to 8 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“C2-8 heteroalkenyl”). In some embodiments, a heteroalkenyl group has 2 to 7 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“C2-7 heteroalkenyl”). In some embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“C2-6 heteroalkenyl”). In some embodiments, a heteroalkenyl group has 2 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“C2-5 heteroalkenyl”). In some embodiments, a heteroalkenyl group has 2 to 4 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“C2-4 heteroalkenyl”). In some embodiments, a heteroalkenyl group has 2 to 3 carbon atoms, at least one double bond, and 1 heteroatom within the parent chain (“C2-3 heteroalkenyl”). In some embodiments, a heteroalkenyl group has 2 carbon atoms, at least one double bond, and 1 heteroatom within the parent chain (“C2 heteroalkenyl”). In some embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“C2-6 heteroalkenyl”). Unless otherwise specified, each instance of a heteroalkenyl group is independently unsubstituted (an “unsubstituted heteroalkenyl”) or substituted (a “substituted heteroalkenyl”) with one or more substituents.

[0033]

[0024] The term “alkynyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 20 carbon atoms and one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 triple bonds) (“C2-20 alkynyl”). In some embodiments, an alkynyl group has 2 to 10 carbon atoms (“C2 -10 alkynyl”). In some embodiments, an alkynyl group has 2 to 9 carbon atoms (“C2-9 alkynyl”). In some embodiments, an alkynyl group has 2 to 8 carbon atoms (“C2-8 alkynyl”). In some embodiments, an alkynyl group has 2 to 7 carbon atoms (“C2 -7 alkynyl”). In some embodiments, an alkynyl group has 2 to 6 carbon atoms (“C2-6 alkynyl”). In some embodiments, an alkynyl group has 2 to 5 carbon atoms (“C2-5 alkynyl”). In some embodiments, an alkynyl group has 2 to 4 carbon atoms (“C2-4 alkynyl”). In some embodiments, an alkynyl group has 2 to 3 carbon atoms (“C2-3 alkynyl”). In some embodiments, an alkynyl group has 2 carbon atoms (“C2 alkynyl”). The one or more carbon-carbon triple bonds can be internal (such as in 2- butynyl) or terminal (such as in 1-butynyl). Examples of C2-4 alkynyl groups include, without limitation, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. Examples of C2-6 alkenyl groups include the aforementioned C24 alkynyl groups as well as pentynyl (C5), hexynyl (Ce), and the like. Additional examples of alkynyl include heptynyl (C7), octynyl (Cs), and the like. Unless otherwise specified, each instance of an alkynyl group is independently unsubstituted (an “unsubstituted alkynyl”) or substituted (a “substituted alkynyl”) with one or more substituents.

[0034]

[0025] The term “heteroalkynyl” refers to an alkynyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, sulfur, silicon, boron, and phosphorous within (e.g., inserted between adjacent carbon atoms of) and / or placed at one or more terminal position(s) of the parent chain. In certain embodiments, the heteroalkynyl group is an alkynyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, and sulfur within (e.g., inserted between adjacent carbon atoms of) and / or placed at one or more terminal position(s) of the parent chain. In certain embodiments, a heteroalkynyl group refers to a group having from 2 to 20 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“C2-20 heteroalkynyl”). In certain embodiments, a heteroalkynyl group refers to a group having from 2 to 10 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“C2-10 heteroalkynyl”). In some embodiments, a heteroalkynyl group has 2 to 9 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“C2-9 heteroalkynyl”). In some embodiments, a heteroalkynyl group has 2 to 8 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“C2-8 heteroalkynyl”). In some embodiments, a heteroalkynyl group has 2 to 7 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“C2-7 heteroalkynyl”). In some embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“C2-6 heteroalkynyl”). In some embodiments, a heteroalkynyl group has 2 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain (“C2-5 heteroalkynyl”). In some embodiments, a heteroalkynyl group has 2 to 4 carbon atoms, at least one triple bond, and lor 2 heteroatoms within the parent chain (“C 4 heteroalkynyl”). In some embodiments, a heteroalkynyl group has 2 to 3 carbon atoms, at least one triple bond, and 1 heteroatom within the parent chain (“C2-3 heteroalkynyl”). In some embodiments, a heteroalkynyl group has 2 carbon atoms, at least one triple bond, and 1 heteroatom within the parent chain (“C2 heteroalkynyl”). In some embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain (“Ci-6 heteroalkynyl”). Unless otherwise specified, each instance of a heteroalkynyl group is independently unsubstituted (an “unsubstituted heteroalkynyl”) or substituted (a “substituted heteroalkynyl”) with one or more substituents.

[0035]

[0026] The term “carbocyclyl” or “carbocyclic” refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 14 ring carbon atoms (“C3-14 carbocyclyl”) and zero heteroatoms in the non- aromatic ring system. In some embodiments, a carbocyclyl group has 3 to 14 ring carbon atoms (“C3-14 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 13 ring carbon atoms (“C3 -13 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 12 ring carbon atoms (“C3-12 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 11 ring carbon atoms (“C3 -11 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 10 ring carbon atoms (“C3 -10 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms (“C3-8 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 7 ring carbon atoms (“C3 -7 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (“C3-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 4 to 6 ring carbon atoms (“C4-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 6 ring carbon atoms (“C5-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (“C5-10 carbocyclyl”). Exemplary C3-6 carbocyclyl groups include cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (Ce), cyclohexenyl (Ce), cyclohexadienyl (Ce), and the like. Exemplary C3-8 carbocyclyl groups include the aforementioned C3-6 carbocyclyl groups as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (Cs), cyclooctenyl (Cs), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (Cs), and the like. Exemplary C3-10 carbocyclyl groups include the aforementioned C3-8 carbocyclyl groups as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro- IH-indenyl (C9), decahydronaphthalenyl (C10), spiro[4.5]decanyl (C10), and the like. Exemplary C3-8 carbocyclyl groups include the aforementioned C3-10 carbocyclyl groups as well as cycloundecyl (Cn), spiro[5.5]undecanyl (Cn), cyclododecyl (C12), cyclododecenyl (C12), cyclotridecane (C13), cyclotetradecane (C14), and the like. As the foregoing examples illustrate, in certain embodiments, the carbocyclyl group is either monocyclic (“monocyclic carbocyclyl”) or polycyclic (e.g., containing a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) or tricyclic system (“bicyclic carbocyclyl”)) and can be saturated or can contain one or more carbon-carbon double or hiple bonds. “Carbocyclyl” also includes ring systems wherein the carbocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups wherein the point of attachment is on the carbocyclyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the carbocyclic ring system. Unless otherwise specified, each instance of a carbocyclyl group is independently unsubstituted (an “unsubstituted carbocyclyl”) or substituted (a “substituted carbocyclyl”) with one or more substituents. In certain embodiments, the carbocyclyl includes 0, 1, or 2 C=C double bonds in the carbocyclic ring system, as valency permits.

[0036]

[0027] “Cycloalkyl” refers to a saturated carbocyclyl group. In some embodiments, a cycloalkyl group has from 3 to 14 ring carbon atoms (“C3-14 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 10 ring carbon atoms (“C3-10 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms (“C3-8 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 7 ring carbon atoms (“C37 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms (“C3-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 4 to 6 ring carbon atoms (“C4-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms (“C5-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms (“C5-10 cycloalkyl”). Examples of C5-6 cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). Examples of C3-6 cycloalkyl groups include the aforementioned C5-6 cycloalkyl groups as well as cyclopropyl (C3) and cyclobutyl (C4). Examples of C3-8 cycloalkyl groups include the aforementioned C3-6 cycloalkyl groups as well as cycloheptyl (C7) and cyclooctyl (Cs). Unless otherwise specified, each instance of a cycloalkyl group is independently unsubstituted (an “unsubstituted cycloalkyl”) or substituted (a “substituted cycloalkyl”) with one or more substituents.

[0037]

[0028] The term “heterocyclyl” or “heterocyclic” refers to a radical of a 3- to 14-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, silicon, boron, and phosphorous (“3-14 membered heterocyclyl”). In certain embodiments, the heterocyclyl group is a radical of a 3- to 14-membered non- aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur. The point of attachment can be either to a ring carbon atom or a ring heteroatom of the heterocyclyl group, as valency permits. For example, in heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. A heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or polycyclic (e.g., a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”) or tricyclic system (“tricyclic heterocyclyl”)), and can be saturated or can contain one or more carbon-carbon double or triple bonds. Heterocyclyl polycyclic ring systems can include one or more heteroatoms in one or both rings. “Heterocyclyl” also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system. Unless otherwise specified, each instance of heterocyclyl is independently unsubstituted (an “unsubstituted heterocyclyl”) or substituted (a “substituted heterocyclyl”) with one or more substituents. In certain embodiments, the heterocyclyl is substituted or unsubstituted, 3- to 8-membered, monocyclic heterocyclyl, wherein 1, 2, or 3 atoms in the heterocyclic ring system are independently oxygen, nitrogen, or sulfur, as valency permits.

[0029] In some embodiments, a heterocyclyl group is a 5-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5-8 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5-6 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heterocyclyl”). In some embodiments, the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0038]

[0030] Exemplary 3-membered heterocyclyl groups containing 1 heteroatom include azirdinyl, oxiranyl, and thiiranyl. Exemplary 4-membered heterocyclyl groups containing 1 heteroatom include azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing 1 heteroatom include tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2, 5-dione. Exemplary 5-membered heterocyclyl groups containing 2 heteroatoms include dioxolanyl, oxathiolanyl and dithiolanyl. Exemplary 5-membered heterocyclyl groups containing 3 heteroatoms include triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6- membered heterocyclyl groups containing 1 heteroatom include piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing 2 heteroatoms include piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing 3 heteroatoms include triazinyl. Exemplary 7-membered heterocyclyl groups containing 1 heteroatom include azepanyl, oxepanyl and thiepanyl. Exemplary 8-membered heterocyclyl groups containing 1 heteroatom include azocanyl, oxecanyl and thiocanyl. Exemplary bicyclic heterocyclyl groups include indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl, decahydronaphthyridinyl, decahydro- 1 ,8-naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole, indolinyl, phthalimidyl, naphthalimidyl, chromanyl, chromenyl, lH-benzo[e][l,4]diazepinyl, 1,4,5,7-tetrahydro- pyrano[3 ,4-b]pyrrolyl, 5 ,6-dihydro-4H-furo[3 ,2-b]pyrrolyl, 6,7 -dihydro-5H-furo[3 ,2-b]pyranyl, 5,7- dihydro-4H-thieno[2,3-c]pyranyl, 2,3-dihydro-lH-pyrrolo[2,3-b]pyridinyl, 2,3-dihydrofuro[2,3- b]pyridinyl, 4,5,6,7-tetrahydro-lH-pyrrolo[2,3-b]pyridinyl, 4,5,6,7-tetrahydrofuro[3,2-c]pyridinyl, 4,5,6,7-tetrahydrothieno[3,2-b]pyridinyl, l,2,3,4-tetrahydro-l,6-naphthyridinyl, and the like.

[0039]

[0031] The term “aryl” refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 71 electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“Ce -14 aryl”). In some embodiments, an aryl group has 6-10 ring carbon atoms (“Ce io aryl”). In some embodiments, an aryl group has 6 ring carbon atoms (“Ce aryl”; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms (“Cio aryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms (“Cu aryl”; e.g., anthracyl). “Aryl” also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system. Unless otherwise specified, each instance of an aryl group is independently unsubstituted (an “unsubstituted aryl”) or substituted (a “substituted aryl”) with one or more substituents.

[0040]

[0032] The term “heteroaryl” refers to a radical of a 5-14 membered monocyclic or polycyclic (e.g., bicyclic, tricyclic) 4n+2 aromatic ring system e.g., having 6, 10, or 14 71 electrons shared in a cyclic array) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, silicon, boron, and phosphorous (“5-14 membered heteroaryl”). In certain embodiments, the heteroaryl group is a radical of a 5-14 membered monocyclic or polycyclic (e.g., bicyclic, tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 71 electrons shared in a cyclic array) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur. The point of attachment can be either to a ring carbon atom or a ring heteroatom of the heteroaryl group, as valency permits. For example, in heteroaryl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Heteroaryl polycyclic ring systems can include one or more heteroatoms in one or both rings. “Heteroaryl” includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heteroaryl ring system. “Heteroaryl” also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused polycyclic (aryl / heteroaryl) ring system. Polycyclic heteroaryl groups wherein one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and the like) the point of attachment can be on either ring, e.g., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5 -indolyl). In certain embodiments, the heteroaryl is substituted or unsubstituted, 5- or 6-membered, monocyclic heteroaryl, wherein 1, 2, 3, or 4 atoms in the heteroaryl ring system are independently oxygen, nitrogen, or sulfur. In certain embodiments, the heteroaryl is substituted or unsubstituted, 9- or 10-membered, bicyclic heteroaryl, wherein 1, 2, 3, or 4 atoms in the heteroaryl ring system are independently oxygen, nitrogen, or sulfur.

[0041]

[0033] In some embodiments, a heteroaryl group is a 5-10 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5-8 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heteroaryl”). In some embodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each instance of a heteroaryl group is independently unsubstituted (an “unsubstituted heteroaryl”) or substituted (a “substituted heteroaryl”) with one or more substituents.

[0042]

[0034] Exemplary 5-membered heteroaryl groups containing 1 heteroatom include pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing 2 heteroatoms include imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing 3 heteroatoms include triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing 4 heteroatoms include tetrazolyl. Exemplary 6-membered heteroaryl groups containing 1 heteroatom include pyridinyl. Exemplary 6-membered heteroaryl groups containing 2 heteroatoms include pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing 3 or 4 heteroatoms include triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing 1 heteroatom include azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6- bicyclic heteroaryl groups include indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. Exemplary tricyclic heteroaryl groups include phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl, and phenazinyl.

[0035] The term “acyl” refers to a group having the general formula -C(=O)Raa, -C(=O)ORaa, -C(=O)-O-C(=O)Raa, -C(=O)SRaa, -C(=O)N(Rbb)2, -C(=S)Raa, -C(=S)N(Rbb)2, -C(=S)S(Raa), -C(=NRbb)Raa, -C(=NRbb)ORaa, -C(=NRbb)SRaa, and -C(=NRbb)N(Rbb)2, wherein Raaand Rbbare as defined herein. Exemplary acyl groups include aldehydes (-CHO), carboxylic acids (-CO2H), ketones, acyl halides, esters, amides, imines, carbonates, carbamates, and ureas.

[0043]

[0036] The term “halo” or “halogen” refers to fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), or iodine (iodo, -I).

[0044]

[0037] The term “silyl” refers to the group -Si(Raa)2, wherein Raais as defined herein.

[0045]

[0038] A group is optionally substituted unless expressly provided otherwise. The term “optionally substituted” refers to being substituted or unsubstituted. In certain embodiments, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted. “Optionally substituted” refers to a group which is substituted or unsubstituted (e.g., “substituted” or “unsubstituted” alkyl, “substituted” or “unsubstituted” alkenyl, “substituted” or “unsubstituted” alkynyl, “substituted” or “unsubstituted” heteroalkyl, “substituted” or “unsubstituted” heteroalkenyl, “substituted” or “unsubstituted” heteroalkynyl, “substituted” or “unsubstituted” carbocyclyl, “substituted” or “unsubstituted” heterocyclyl, “substituted” or “unsubstituted” aryl or “substituted” or “unsubstituted” heteroaryl group). In general, the term “substituted” means that at least one hydrogen present on a group is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction. Unless otherwise indicated, a “substituted” group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position. The term “substituted” is contemplated to include substitution with all permissible substituents of organic compounds and includes any of the substituents described herein that results in the formation of a stable compound. The present disclosure contemplates any and all such combinations in order to arrive at a stable compound. For purposes of this disclosure, heteroatoms such as nitrogen, oxygen, and sulfur may have hydrogen substituents and / or any suitable substituent as described herein which satisfy the valencies of the heteroatoms and results in the formation of a stable moiety. The embodiments described herein are not limited in any manner by the exemplary substituents described herein.

[0046]

[0039] Exemplary carbon atom substituents include halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -ORaa, -ON(Rbb)2, -N(Rbb)2, -N(Rbb)3+X“, -N(ORcc)Rbb, -SH, -SRaa, -SSRCC, -C(=O)Raa, -CO2H, -CHO, -C(ORCC)2, -CO2R", -OC(=O)Raa, -OCO2Raa, -C(=O)N(Rbb)2, -OC(=O)N(Rbb)2, -NRbbC(=O)Raa, -NRbbCO2Raa, -NRbbC(=O)N(Rbb)2, -C(=NRbb)Raa, -C(=NRbb)ORaa, -OC(=NRbb)Raa, -OC(=NRbb)ORaa, -C(=NRbb)N(Rbb)2, -OC(=NRbb)N(Rbb)2, -NRbbC(=NRbb)N(Rbb)2, -C(=O)NRbbSO2Raa, -NRbbSO2Raa, -SO2N(Rbb)2, -SO2Raa, -SO2ORaa, -OSO2Raa, -S(=O)Raa, -OS(=O)Raa, -Si(Raa)3, -OSi(Raa)3-C(=S)N(Rbb)2, -C(=O)SRaa, -C(=S)SRaa, -SC(=S)SRaa, -SC(=O)SRaa, -OC(=O)SRaa, -SC(=O)ORaa, -SC(=O)Raa, -P(=O)(Raa)2, -P(=O)(ORCC)2, -OP(=O)(Raa)2, -OP(=O)(ORCC)2, -P(=O)(N(Rbb)2)2, -OP(=O)(N(Rbb)2)2, -NRbbP(=O)(Raa)2, -NRbbP(=O)(ORcc)2, -NRbbP(=O)(N(Rbb)2)2, -P(RCC)2, -P(ORCC)2, -P(RCC)3+X-, -P(ORCC)3+X-, -P(RCC)4, -P(ORCC)4, -OP(RCC)2, -OP(RCC)3+X-, -OP(ORCC)2, -OP(ORCC)3+X-, -OP(RCC)4, -OP(ORCC)4, -B(Raa)2, -B(ORCC)2, -BRaa(ORcc), Ci-2o alkyl, Ci-2o perhaloalkyl, C2-2o alkenyl, C2-2o alkynyl, Ci-2o heteroalkyl, C2-2o heteroalkenyl, C2-2o heteroalkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, Ce i4aryl, and 5- 14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups, and wherein X“ is a counterion; or two geminal hydrogens on a carbon atom are replaced with the group =0, =S, =NN(Rbb)2, =NNRbbC(=0)Raa, =NNRbbC(=0)0Raa, =NNRbbS(=O)2Raa, =NRbb, or =NORCC; wherein: each instance of Raais, independently, selected from Ci-20 alkyl, Ci-20 perhaloalkyl, C2-2o alkenyl, C2-20 alkynyl, Ci-20 heteroalkyl, C2-20 heteroalkenyl, C2-20 heteroalkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, Ce-i4 aryl, and 5-14 membered heteroaryl, or two Raagroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each of the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups; each instance of Rbbis, independently, selected from hydrogen, -OH, -OR311, -N(RCC)2, -CN, -C(=O)Raa, -C(=O)N(RCC)2, -CO2Raa, -SO2Raa, -C(=NRcc)ORaa, -C(=NRCC)N(RCC)2, -SO2N(RCC)2, -SO2RCC, -SO2ORCC, -SORaa, -C(=S)N(RCC)2, -C(=O)SRCC, -C(=S)SRCC, -P(=O)(Raa)2, -P(=O)(ORCC)2, -P(=O)(N(RCC)2)2, C1-20 alkyl, Ci-20 perhaloalkyl, C2-20 alkenyl, C2-20 alkynyl, C 1-20 heteroalkyl, C2-20 heteroalkenyl, C2-20 heteroalkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, Ce-i4 aryl, and 5-14 membered heteroaryl, or two Rbbgroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups; each instance of Rccis, independently, selected from hydrogen, Ci-20 alkyl, Ci-20 perhaloalkyl, C2-20 alkenyl, C2-20 alkynyl, Ci-20 heteroalkyl, C2-20 heteroalkenyl, C2-20 heteroalkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, Ce -14 aryl, and 5-14 membered heteroaryl, or two Rccgroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups; each instance of Rddis, independently, selected from halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -ORee, -ON(Rff)2, -N(Rff)2, -N(Rff)3+X’, -N(ORee)Rff, -SH, -SRee, -SSRee, -C(=O)Ree, -CO2H, -CO2Ree, -OC(=O)Ree, -OCO2Ree, -C(=O)N(Rff)2, -OC(=O)N(Rff)2, -NRffC(=O)Ree, -NRffCO2Ree, -NRffC(=O)N(Rff)2, -C(=NRff)ORee, -OC(=NRff)Ree, -OC(=NRff)ORee, -C(=NRff)N(Rff)2, -OC(=NRff)N(Rff)2, -NRffC(=NRff)N(Rff)2, -NRffSO2Ree, -SO2N(Rff)2, -SO2Ree, -SO2ORee, -OSO2Ree, -S(=O)Ree, -Si(Ree)3, -OSi(Ree)3, -C(=S)N(Rff)2, -C(=O)SRee, -C(=S)SRee, -SC(=S)SRee, -P(=O)(ORee)2, -P(=O)(Ree)2, -OP(=O)(Ree)2, -OP(=O)(ORee)2, Ci-10 alkyl, Ci-10 perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, C 1-10 heteroalkyl, C2-10 heteroalkenyl, C2 10 heteroalkynyl, C3-10 carbocyclyl, 3-10 membered heterocyclyl, Ce 10 aryl, and 5-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgggroups, or two geminal Rddsubstituents are joined to form =0 or =S, and wherein X“ is a counterion; each instance of Reeis, independently, selected from Ci-10 alkyl, Ci-10 perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, Ci-10 heteroalkyl, C2-10 heteroalkenyl, C2-10 heteroalkynyl, C3-10 carbocyclyl, Ce 10 aryl, 3-10 membered heterocyclyl, and 3-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgggroups; each instance of Rffis, independently, selected from hydrogen, Ci-io alkyl, Ci-io perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, Ci-10 heteroalkyl, C2-10 heteroalkenyl, C2-10 heteroalkynyl, C3-10 carbocyclyl, 3-10 membered heterocyclyl, Ce-io aryl, and 5-10 membered heteroaryl, or two Rffgroups are joined to form a 3-10 membered heterocyclyl or 5-10 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgggroups; each instance of Rggis, independently, halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC1-6 alkyl, -ON(Ci-6 alkyl)2, -N(CI-6 alkyl)2, -N(CI-6 alkyl)3+X“, -NH(CI-6 alkyl)2+X“, -NH2(CI_6 alkyl)+X~. -NH3+X“, — NlOCi <, alkyl)(Ci-6 alkyl), -N(OH)(Ci^ alkyl), -NH(OH), -SH, -SCi^ alkyl, -SSlCiGalkyl), -C(=O)(Ci-6 alkyl), -CO2H, -CO2(CiGalkyl), -OC(=O)(C1^ alkyl), -OCO2(C,6alkyl), -C(=O)NH2, -C(=O)N(CI-6 alkyl)2, -OC(=O)NH(Ci6alkyl), -NHC(=O)( Cwalkyl), -N(Ci^ alkyl)C(=O)( Cwalkyl), -NHCO4C,Galkyl), -NHC(=O)N(Ci-6 alkyl)2, -NHC(=O)NH(CI_6alkyl), -NHC(=O)NH2, -C(=NH)O(Ci^ alkyl), -OC(=NH)(Ci-6 alkyl), — OC(=NH)OCi6alkyl, -C(=NH)N(Ci^ alkyl)2, -C(=NH)NH(CI_6alkyl), -C(=NH)NH2, -OC(=NH)N(CI_6alkyl)2, -OC(NH)NH(C,_6 alkyl), -OC(NH)NH2, -NHC(NH)N(CI_6 alkyl)2, -NHC(=NH)NH2, — NHSO2(Ci-6alkyl), -SO2N(CIGalkyl)2, -SO2NH(CI_6 alkyl), -SO2NH2, -SO2C1 <> alkyl, -SO2OC1 <> alkyl, -OSO2C1 <> alkyl, -SOCi^ alkyl, -Si(Ci_6 alkyl)3, -OSi(Ci^ alkyl)3-C(=S)N(CI-6 alkyl)2, C(=S)NH(CI_6alkyl), C(=S)NH2, -C(=O)S(C1^ alkyl), -C(=S)SCi. _6alkyl, -SC(=S)SCiGalkyl, -P(=O)(OCi^ alkyl)2, -P(=O)(Ci_6 alkyl)2, -OP(=O)(C« alkyl)2, -OP(=O)(OC« alkyl)2, Ci-10 alkyl, Ci-10 perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, Ci-10 heteroalkyl, C2-10 heteroalkenyl, C2-10 heteroalkynyl, C3-10 carbocyclyl, Ce-io aryl, 3-10 membered heterocyclyl, or 5-10 membered heteroaryl; or two geminal Rggsubstituents can be joined to form =0 or =S; and each X“ is a counterion.

[0047]

[0040] In certain embodiments, the molecular weight of a substituent (e.g., carbon atom substituent) is lower than 250, lower than 200, lower than 150, lower than 100, or lower than 50 g / mol. In certain embodiments, a substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, iodine, oxygen, sulfur, nitrogen, and / or silicon atoms. In certain embodiments, a substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, iodine, oxygen, sulfur, and / or nitrogen atoms. In certain embodiments, a substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, and / or iodine atoms. In certain embodiments, a substituent consists of carbon, hydrogen, fluorine, and / or chlorine atoms.

[0048]

[0041] In certain embodiments, exemplary carbon atom substituents include halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -ORaa, -N(Rbb)2, -N(Rbb)3+X“, -SH, -SRaa, -C(=O)Raa, -CO2H, -CHO, -CO2Raa, -OC(=O)Raa, -OCO2Raa, -C(=O)N(Rbb)2, -OC(=O)N(Rbb)2, -NRbbC(=O)Raa, -NRbbCO2Raa, -NRbbC(=O)N(Rbb)2, -NRbbSO2Raa, -SO2N(Rbb)2, -SO2Raa, -SO2ORaa, -OSO2Raa, -S(=O)Raa, -OS(=O)Raa, -Si(Raa)3, -OSi(Raa)3, -P(=O)(Raa)2, -P(=O)(ORCC)2, -OP(=O)(Raa)2, -OP(=O)(ORCC)2, -P(=O)(N(Rbb)2)2, -OP(=O)(N(Rbb)2)2, -NRbbP(=O)(Raa)2, -NRbbP(=O)(ORcc)2, -NRbbP(=O)(N(Rbb)2)2, -B(Raa)2, -B(ORCC)2, -BRaa(ORcc), Ci-io alkyl, Ci-io perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, Ci-io heteroalkyl, C2-10 heteroalkenyl, C2-10 heteroalkynyl, C3-io carbocyclyl, 3-14 membered heterocyclyl, Ce-i4 aryl, and 5-14 membered heteroaryl, wherein X“ is a counterion; or two geminal hydrogens on a carbon atom are replaced with the group =0, =S, =NN(Rbb)2, =NNRbbC(=0)Raa, =NNRbbC(=0)0Raa, =NNRbbS(=0)2Raa, =NRbb, or =NORCC; each instance of Raais, independently, selected from Ci-io alkyl, Ci-io perhaloalkyl, C2-10 alkenyl, C2-io alkynyl, Ci-io heteroalkyl, C2io heteroalkenyl, C2io heteroalkynyl, C3-io carbocyclyl, 3-14 membered heterocyclyl, Ce-i4 aryl, and 5-14 membered heteroaryl, or two Raagroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring; each instance of Rbbis, independently, selected from hydrogen, -OH, -OR311, -N(RCC)2, -CN, -C(=0)Raa, -C(=0)N(RCC)2, -C02Raa, -SO2Raa, -C(=NRcc)0Raa, -C(=NRCC)N(RCC)2, -SO2N(RCC)2, -SO2RCC, -SO2ORCC, -SORaa, -P(=O)(Raa)2, -P(=O)(ORCC)2, -P(=O)(N(RCC)2)2, Ci-io alkyl, Ci-io perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, Crio heteroalkyl, C2io heteroalkenyl, C2-10 heteroalkynyl, C3-io carbocyclyl, 3-14 membered heterocyclyl, Ce u aryl, and 5-14 membered heteroaryl, or two Rbbgroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring; and each instance of Rccis, independently, selected from hydrogen, Ci-io alkyl, Ci-io perhaloalkyl, C2io alkenyl, C2-10 alkynyl, Ci-io heteroalkyl, C2-10 heteroalkenyl, C2-10 heteroalkynyl, C3-io carbocyclyl, 3-14 membered heterocyclyl, Ce u aryl, and 5-14 membered heteroaryl, or two Rccgroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring.

[0049]

[0042] In certain embodiments, each carbon atom substituent is independently halogen, substituted (e.g., substituted with one or more halogen) or unsubstituted Ci-6 alkyl, -ORaa, -SRaa, -N(Rbb)2, -CN, -NO2, -C(=O)Raa, -CO2Raa, -C(=O)N(Rbb)2, -OC(=O)Raa, -OCO2Raa, -OC(=O)N(Rbb)2, -NRbbC(=O)Raa, -NRbbCO2Raa, or -NRbbC(=O)N(Rbb)2. In certain embodiments, each carbon atom substituent is independently halogen, substituted (e.g., substituted with one or more halogen) or unsubstituted Ci-io alkyl, -ORaa, -SRaa, -N(Rbb)2, -CN, -NO2, -C(=O)Raa, -CO2Raa, -C(=O)N(Rbb)2, -OC(=O)Raa, -OCO2Raa, -OC(=O)N(Rbb)2, -NRbbC(=O)Raa, -NRbbCO2Raa, or -NRbbC(=O)N(Rbb)2, wherein Raais hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted Ci-6 alkyl, an oxygen protecting group (e.g., silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl) when attached to an oxygen atom, or a sulfur protecting group (e.g., acetamidomethyl, t-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl) when attached to a sulfur atom; and each Rbbis independently hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted Ci-6 alkyl, or a nitrogen protecting group (e.g., Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts). In certain embodiments, each carbon atom substituent is independently halogen, substituted (e.g., substituted with one or more halogen) or unsubstituted Ci-6 alkyl, -ORaa, -SRaa, -N(Rbb)2, -CN, or -NO2. In certain embodiments, each carbon atom substituent is independently halogen, substituted (e.g., substituted with one or more halogen moieties) or unsubstituted Ci-6 alkyl, -0Raa, -SRaa, -N(Rbb)2, -CN, -SCN, or -NO2, wherein Raais hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted Ci-6 alkyl, an oxygen protecting group (e.g., silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl) when attached to an oxygen atom, or a sulfur protecting group (e.g., acetamidomethyl, t-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl) when attached to a sulfur atom; and each Rbbis independently hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted Ci-10 alkyl, or a nitrogen protecting group (e.g., Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts).

[0050]

[0043] In certain embodiments, each nitrogen atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted Ci-6 alkyl, -C(=O)Raa, -CC R^, -C(=O)N(Rbb)2, or a nitrogen protecting group. In certain embodiments, each nitrogen atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted Ci-6 alkyl, -C(=O)Raa, -CC R^, -C(=O)N(Rbb)2, or a nitrogen protecting group, wherein Raais hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted Ci-6 alkyl, or an oxygen protecting group when attached to an oxygen atom; and each Rbbis independently hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted Ci-6 alkyl, or a nitrogen protecting group. In certain embodiments, each nitrogen atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted Ci-6 alkyl or a nitrogen protecting group.

[0051]

[0044] In certain embodiments, the substituent present on the nitrogen atom is a nitrogen protecting group (also referred to herein as an “amino protecting group”). Nitrogen protecting groups include -OH, -ORaa, -N(RCC)2, -C(=O)Raa, -C(=O)N(RCC)2, -CO2Raa, -SO2Raa, -C(=NRcc)Raa, -C(=NRcc)ORaa, -C(=NRCC)N(RCC)2, -SO2N(RCC)2, -SO2RCC, -SO2ORCC, -SORaa, -C(=S)N(RCC)2, -C(=O)SRCC, -C(=S)SRCC, Ci-10 alkyl (e.g., aralkyl, heteroaralkyl), C2-20 alkenyl, C2-20 alkynyl, Ci-20 heteroalkyl, C2-20 heteroalkenyl, C2-20 heteroalkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, Ce -14 aryl, and 5-14 membered heteroaryl groups, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aralkyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups, and wherein Raa, Rbb, Rccand Rddare as defined herein. Nitrogen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rdedition, John Wiley & Sons, 1999, incorporated herein by reference.

[0052]

[0045] For example, in certain embodiments, at least one nitrogen protecting group is an amide group (e.g., a moiety that includes the nitrogen atom to which the nitrogen protecting groups (e.g., -C(=O)Raa) is directly attached). In certain such embodiments, each nitrogen protecting group, together with the nitrogen atom to which the nitrogen protecting group is attached, is independently selected from the group consisting of formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropanamide, picolinamide, 3-pyridylcarboxamide, -benzoylphenylalanyl derivatives, benzamide, p-phenylbenzamide, o-nitophenylacetamide, o-nitrophenoxyacetamide, acetoacetamide, ( ’ -dithiobenzyloxy acylamino) acetamide, 3-(p-hydroxyphenyl)propanamide, 3-(o- nitrophenyl)propanamide, 2-methyl-2-(o-nitrophenoxy)propanamide, 2-methyl-2-(o- phenylazophenoxy)propanamide, 4-chlorobutanamide, 3-methyl-3-nitrobutanamide, o-nitrocinnamide, A-acetyhnethionine derivatives, o-nitrobenzamide, and o-(benzoyloxymethyl)benzamide.

[0053]

[0046] In certain embodiments, at least one nitrogen protecting group is a carbamate group (e.g., a moiety that includes the nitrogen atom to which the nitrogen protecting groups (e.g., -C(=O)ORaa) is directly attached). In certain such embodiments, each nitrogen protecting group, together with the nitrogen atom to which the nitrogen protecting group is attached, is independently selected from the group consisting of methyl carbamate, ethyl carbamate, 9-fluorenylmethyl carbamate (Fmoc), 9-(2-sulfo)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluoroenylmethyl carbamate, 2,7-di-t-butyl- [9-( 10,10-dioxo-l 0,10,10,10- tetrahydrothioxanthyl)] methyl carbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate (Phenoc), 2,2,2- trichloroethyl carbamate (Troc), 2-trimethylsilylethyl carbamate (Teoc), 2-phenylethyl carbamate (hZ), l-(l-adamantyl)-l-methylethyl carbamate (Adpoc), l,l-dimethyl-2-haloethyl carbamate, 1,1-dimethyl- 2,2-dibromoethyl carbamate (DB-t-BOC), l,l-dimethyl-2,2,2-trichloroethyl carbamate (TCBOC), 1- methyl-l-(4-biphenylyl)ethyl carbamate (Bpoc), l-(3,5-di-t-butylphenyl)-l -methylethyl carbamate (t- Bumeoc), 2-(20- and 4e-pyridyl )cthyl carbamate (Pyoc), 2-(N,N-dicyclohexylcarboxamido)ethyl carbamate, t-butyl carbamate (BOC or Boc), 1-adamantyl carbamate (Adoc), vinyl carbamate (Voc), allyl carbamate (Alloc), 1 -isopropylallyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc), 8-quinolyl carbamate, N-hydroxypiperidinyl carbamate, alkyldithio carbamate, benzyl carbamate (Cbz), p-methoxybenzyl carbamate (Moz), p-nitobenzyl carbamate, p-bromobenzyl carbamate, p-chlorobenzyl carbamate, 2,4-dichlorobenzyl carbamate, 4-methylsulfinylbenzyl carbamate (Msz), 9-anthrylmethyl carbamate, diphenylmethyl carbamate, 2-methylthioethyl carbamate, 2- methylsulfonylethyl carbamate, 2-(p-toluenesulfonyl)ethyl carbamate, [2-(l,3-dithianyl)]methyl carbamate (Dmoc), 4-methylthiophenyl carbamate (Mtpc), 2,4-dimethylthiophenyl carbamate (Bmpc), 2- phosphonioethyl carbamate (Peoc), 2-triphenylphosphonioisopropyl carbamate (Ppoc), 1,1 -dime thyl-2- cyanoethyl carbamate, m-chloro-p-acyloxybenzyl carbamate, p-(dihydroxyboryl)benzyl carbamate, 5- benzisoxazolylmethyl carbamate, 2-(trifluoromethyl)-6-chromonylmethyl carbamate (Tcroc), m- nitrophenyl carbamate, 3,5-dimethoxybenzyl carbamate, o-nitrobenzyl carbamate, 3,4-dimethoxy-6- nitrobenzyl carbamate, phenyl(o-nitrophenyl)methyl carbamate, t-amyl carbamate, S-benzyl thiocarbamate, p-cyanobenzyl carbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentyl carbamate, cyclopropylmethyl carbamate, p-decyloxybenzyl carbamate, 2,2-dimethoxyacylvinyl carbamate, o-(A,A-dimethylcarboxamido)benzyl carbamate, I , I -dimcthyl-3-(W,A- dimethylcarboxamido)propyl carbamate, 1,1-dimethylpropynyl carbamate, di(2-pyridyl)methyl carbamate, 2-furanylmethyl carbamate, 2-iodoethyl carbamate, isoborynl carbamate, isobutyl carbamate, isonicotinyl carbamate, p-(p ’-methoxyphenylazo)benzyl carbamate, 1 -methylcyclobutyl carbamate, 1- methylcyclohexyl carbamate, 1 -methyl- 1 -cyclopropylmethyl carbamate, l-methyl-l-(3,5- dimethoxyphenyl)ethyl carbamate, 1 -methyl- l-(p-phenylazophenyl)ethyl carbamate, 1 -methyl- 1- phenylethyl carbamate, 1 -methyl- l-(4-pyridyl)ethyl carbamate, phenyl carbamate, p-(phenylazo) benzyl carbamate, 2,4,6-tri-t-butylphenyl carbamate, 4-(trimethylammonium)benzyl carbamate, and 2,4,6- trimethylbenzyl carbamate.

[0054]

[0047] In certain embodiments, at least one nitrogen protecting group is a sulfonamide group (e.g., a moiety that includes the nitrogen atom to which the nitrogen protecting groups (e.g., -S(=O)2Raa) is directly attached). In certain such embodiments, each nitrogen protecting group, together with the nitrogen atom to which the nitrogen protecting group is attached, is independently selected from the group consisting of p-tohienesulfonamide (Ts), benzenesulfonamide, 2,3,6-trimethyl-4- methoxybenzenesulfonamide (Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb), 2,6-dimethyl-4- methoxybenzenesulfonamide (Pme), 2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte), 4- methoxybenzenesulfonamide (Mbs), 2,4,6-trimethylbenzenesulfonamide (Mts), 2,6-dimethoxy-4- methylbenzenesulfonamide (iMds), 2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide (Ms), P-trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide, 4-(4',8'- dimethoxynaphthylmethyl)benzenesulfonamide (DNMB S) , benzylsulfonamide , trifluoromethylsulfonamide, and phenacylsulfonamide.

[0055]

[0048] In certain embodiments, each nitrogen protecting group, together with the nitrogen atom to which the nitrogen protecting group is attached, is independently selected from the group consisting of phenothiazinyl-(10)-acyl derivatives, A’-p-tohienesulfonylaminoacyl derivatives, N’- phenylaminothioacyl derivatives, A-bcnzoylphcnylalanyl derivatives, A-acctylmcthioninc derivatives,

[0056] 4.5-diphenyl-3-oxazolin-2-one, A-phthalimide, A-dithiasuccinimidc (Dts), A-2,3-diphcnylmalcimidc, N-

[0057] 2.5-dimethylpyrrole, N-l ,1 ,4,4-tetramethyldisilylazacyclopentane adduct (STABASE), 5-substituted 1,3- dimethyl-l,3,5-triazacyclohexan-2-one, 5-substituted l,3-dibenzyl-l,3,5-triazacyclohexan-2-one, 1- substituted 3,5-dinitro-4-pyridone, A-methylamine, A-allylamine, A-[2- (trimethylsilyl)ethoxy]methylamine (SEM), A-3-acetoxypropylamine, A-(l-isopropyl-4-nitro-2-oxo-3- pyroolin-3-yl)amine, quaternary ammonium salts, A-benzylamine, A-di(4-methoxyphenyl)methylamine, A-5-dibenzosuberylamine, A-triphenylmethylamine (Tr), A-[(4-methoxyphenyl)diphenylmethyl]amine (MMTr), A-9-phenylfluorenylamine (PhF), A-2,7-dichloro-9-fluorenylmethyleneamine, N- ferrocenylmethylamino (Fem), A-2-picolylamino N ’-oxide, N- 1 , 1 -dimethylthiomethyleneamine, N- benzylideneamine, A-p-methoxybenzylideneamine, A-diphenylmethyleneamine, N-[(2- pyridyl)mesityl]methyleneamine, A-(A’,A’-dimethylaminomethylene)amine, A-p-nitrobenzylideneamine, A-salicylideneamine, A-5-chlorosalicylideneamine, A-(5-chloro-2- hydroxyphenyl)phenylmethyleneamine, A-cyclohexylideneamine, A-(5,5-dimethyl-3-oxo-l- cyclohexenyl) amine, A-borane derivatives, A-diphenylborinic acid derivatives, A- [phenyl(pentaacylchromium- or tungsten)acyl] amine, A-copper chelate, A-zinc chelate, A-nitroamine, A- nitrosoamine, amine A-oxide, diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt), diphenylthiophosphinamide (Ppt), dialkyl phosphoramidates, dibenzyl phosphoramidate, diphenyl phosphor amidate, benzenesulfenamide, o-nitrobenzenesulfenamide (Nps), 2,4- dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide, triphenylmethylsulfenamide, and 3-nitropyridinesulfenamide (Npys). In some embodiments, two instances of a nitrogen protecting group together with the nitrogen atoms to which the nitrogen protecting groups are attached are iV, ’-isopropylidenediamine.

[0058]

[0049] In certain embodiments, a nitrogen protecting group is benzyl (Bn), tert-butyloxycarbonyl (BOC), carbobenzyloxy (Cbz), 9-flurenylmethyloxycarbonyl (Fmoc), trifluoroacetyl, triphenylmethyl, acetyl (Ac), benzoyl (Bz), p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), 2,2,2-trichloroethyloxycarbonyl (Troc), triphenylmethyl (Tr), tosyl (Ts), brosyl (Bs), nosyl (Ns), mesyl (Ms), triflyl (Tf), or dansyl (Ds).

[0059]

[0050] In certain embodiments, at least one nitrogen protecting group is Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts.

[0060]

[0051] In certain embodiments, each oxygen atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted Ci-6 alkyl, -C(=O)Raa, -CC R^, -C(=O)N(Rbb)2, or an oxygen protecting group. In certain embodiments, each oxygen atom substituents is independently substituted (e.g., substituted with one or more halogen) or unsubstituted Ci-6 alkyl, -C(=O)Raa, -CC R^, -C(=O)N(Rbb)2, or an oxygen protecting group, wherein Raais hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted Ci-6 alkyl, or an oxygen protecting group when attached to an oxygen atom; and each Rbbis independently hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted Ci-6 alkyl, or a nitrogen protecting group. In certain embodiments, each oxygen atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted Ci-6 alkyl or an oxygen protecting group.

[0061]

[0052] In certain embodiments, the substituent present on an oxygen atom is an oxygen protecting group (also referred to herein as an “hydroxyl protecting group”). Oxygen protecting groups include -Raa, rein. Oxygen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rdedition, John Wiley & Sons, 1999, incorporated herein by reference.

[0062]

[0053] In certain embodiments, each oxygen protecting group, together with the oxygen atom to which the oxygen protecting group is attached, is selected from the group consisting of methoxy, methoxylmethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM), t-butoxymethyl, 4-pentenyloxymethyl (POM), siloxymethyl, 2- methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl, 2- (trimethylsilyl)ethoxymethyl (SEMOR), tetrahydropyranyl (THP), 3-bromotetrahydropyranyl, tetrahydrothiopyranyl, 1 -methoxycyclohexyl, 4-methoxytetrahydropyranyl (MTHP), 4- methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranyl .S'..S'-dioxidc, l-[(2-chloro-4- methyl)phenyl]-4-methoxypiperidin-4-yl (CTMP), 1 ,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl, 2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl, 1- ethoxy ethyl, l-(2-chloroethoxy)ethyl, 1 -methyl- 1 -methoxy ethyl, 1 -methyl- 1 -benzyloxy ethyl, 1 -methyl- 1- benzyloxy-2-fluoroethyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl, t-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, benzyl (Bn), p-methoxybenzyl (PMB), 3,4- dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, p- phenylbenzyl, 2-picolyl, 4-picolyl, 3-methyl-2-picolyl A-oxido, diphenylmethyl, p,p’-dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl, a-naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl, di(p- methoxyphenyl)phenylmethyl, tri(p-methoxyphenyl)methyl, 4-(4’ - bromophenacyloxyphenyl)diphenylmethyl, 4,4',4"-tris(4,5-dichlorophthalimidophenyl)methyl, 4,4' ,4"- tris(levulinoyloxyphenyl)methyl, 4,4',4"-tris(benzoyloxyphenyl)methyl, 4,4’-Dimethoxy-3"’-[N- (imidazolylmethyl) ]trityl Ether (IDTr-OR), 4,4'-Dimethoxy-3"’-[N-(imidazolylethyl)carbamoyl]trityl Ether (lETr-OR), l,l-bis(4-methoxyphenyl)-l'-pyrenylmethyl, 9-anthryl, 9-(9-phenyl)xanthenyl, 9-(9- phenyl-10-oxo)anthryl, l,3-benzodithiolan-2-yl, benzisothiazolyl .S'.S-dioxido, trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS), dimethylthexylsilyl, t-butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl (TBDPS), tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl (DPMS), t-butylmethoxyphenylsilyl (TBMPS), formate, benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxy acetate, triphenylmethoxy acetate, phenoxy acetate, p-chlorophenoxy acetate, 3- phenylpropionate, 4-oxopentanoate (levulinate), 4,4-(ethylenedithio)pentanoate (levulinoyldithioacetal), pivaloate, adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate, 2,4,6- trimethylbenzoate (mesitoate), methyl carbonate, 9-fluorenylmethyl carbonate (Fmoc), ethyl carbonate, 2,2,2-trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate (TMSEC), 2-(phenylsulfonyl) ethyl carbonate (Psec), 2-(triphenylphosphonio) ethyl carbonate (Peoc), isobutyl carbonate, vinyl carbonate, allyl carbonate, t-butyl carbonate (BOC or Boc), p-nitrophenyl carbonate, benzyl carbonate, p- methoxybenzyl carbonate, 3,4-dimethoxybenzyl carbonate, o-nitrobenzyl carbonate, p-nitrobenzyl carbonate, S-benzyl thiocarbonate, 4-ethoxy-l-napththyl carbonate, methyl dithiocarbonate, 2- iodobenzoate, 4-azidobutyrate, 4-nitro-4-methylpentanoate, o-(dibromomethyl)benzoate, 2- formylbenzenesulf onate, 2-(methylthiomethoxy)ethyl carbonate (MTMEC-OR), 4- (methylthiomethoxy)butyrate, 2-(methylthiomethoxymethyl)benzoate, 2,6-dichloro-4- methylphenoxy acetate, 2,6-dichloro-4-( 1 , 1 ,3,3-tetramethylbutyl)phenoxyacetate, 2,4-bis(l , 1 - dimethylpropyl)phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinoate, (E)-2-methyl-2- butenoate, o-(methoxyacyl)benzoate, a-naphthoate, nitrate, alkyl N,N,N’,N’- tetramethylphosphorodiamidate, alkyl A-phenylcarbamate, borate, dimethylphosphinothioyl, alkyl 2,4- dinitrophenylsulfenate, sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate (Ts).

[0063]

[0054] In certain embodiments, an oxygen protecting group is silyl. In certain embodiments, an oxygen protecting group is t-butyldiphenylsilyl (TBDPS), t-butyldimethylsilyl (TBDMS), triisoproylsilyl (TIPS), triphenylsilyl (TPS), triethylsilyl (TES), trimethylsilyl (TMS), triisopropylsiloxymethyl (TOM), acetyl (Ac), benzoyl (Bz), allyl carbonate, 2,2,2-trichloroethyl carbonate (Troc), 2-trimethylsilylethyl carbonate, methoxymethyl (MOM), 1-ethoxyethyl (EE), 2-methyoxy-2-propyl (MOP), 2,2,2-trichloroethoxyethyl, 2-methoxyethoxymethyl (MEM), 2-trimethylsilylethoxymethyl (SEM), methylthiomethyl (MTM), tetrahydropyranyl (THP), tetrahydrofuranyl (THF), p-methoxyphenyl (PMP), triphenylmethyl (Tr), methoxytrityl (MMT), dimethoxytrityl (DMT), allyl, p-methoxybenzyl (PMB), t-butyl, benzyl (Bn), allyl, or pivaloyl (Piv).

[0064]

[0055] In certain embodiments, at least one oxygen protecting group is silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl.

[0065]

[0056] In certain embodiments, each sulfur atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted Ci-6 alkyl, -C(=O)Raa, -CO2Raa, -C(=O)N(Rbb)2, or a sulfur protecting group. In certain embodiments, each sulfur atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted Ci-6 alkyl, -C(=O)Raa, -CO2Raa, -C(=O)N(Rbb)2, or a sulfur protecting group, wherein Raais hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted Ci-6 alkyl, or an oxygen protecting group when attached to an oxygen atom; and each Rbbis independently hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted Ci-6 alkyl, or a nitrogen protecting group. In certain embodiments, each sulfur atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted Ci-6 alkyl or a sulfur protecting group.

[0066]

[0057] In certain embodiments, the substituent present on a sulfur atom is a sulfur protecting group (also referred to as a “thiol protecting group”). In some embodiments, each sulfur protecting group is selected from the group consisting of -Raa, -N(Rbb)2, -C(=O)SRaa, -C(=O)Raa, -CO2Raa, -C(=O)N(Rbb)2, -C(=NRbb)Raa, -C(=NRbb)ORaa, -C(=NRbb)N(Rbb)2, -S(=O)Raa, -SO2Raa, -Si(Raa)3, -P(RCC)2, -P(RCC)3+X-, -P(ORCC)2, -P(ORCC)3+X“, -P(=O)(Raa)2, -P(=O)(ORCC)2, and -P(=O)(N(Rbb) 2)2, wherein Raa, Rbb, and Rccare as defined herein. Sulfur protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rdedition, John Wiley & Sons, 1999, incorporated herein by reference.

[0067]

[0058] In certain embodiments, a sulfur protecting group is acetamidomethyl, t-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl.

[0068]

[0059] A “counterion” or “anionic counterion” is a negatively charged group associated with a positively charged group in order to maintain electronic neutrality. An anionic counterion may be monovalent (e.g., including one formal negative charge). An anionic counterion may also be multivalent (e.g., including more than one formal negative charge), such as divalent or trivalent. Exemplary counterions include halide ions e.g., F", Cl", Br , I"), NO3, CIO4 , OH , H2PO4 , HCO3“, HSO4 , sulfonate ions (e.g., methansulfonate, trifluoromethanesulfonate, p-tohienesulfonate, benzenesulfonate, 10-camphor sulfonate, naphthalene-2-sulfonate, naphthalene- 1 -sulfonic acid-5-sulfonate, ethan-1 -sulfonic acid-2- sulfonate, and the like), carboxylate ions (e.g., acetate, propanoate, benzoate, glycerate, lactate, tartrate, glycolate, gluconate, and the like), BF4~, PEp, PFe", AsFe", SbFe", B[3,5-(CF3)2CeH3]4] , B(C6F5)4~, BPtu , A1(OC(CF3)3)4-, and carborane anions (e.g., CBnHi2- or (HCBi iMesBre) ). Exemplary counterions which may be multivalent include CO32-, HPOr2-, POr3-, B4O?2-, SOr2-, S2O32-, carboxylate anions (e.g., tartrate, citrate, fumarate, maleate, malate, malonate, gluconate, succinate, glutarate, adipate, pimelate, suberate, azelate, sebacate, salicylate, phthalates, aspartate, glutamate, and the like), and carboranes. Other Definitions

[0069]

[0060] The following definitions are more general terms used throughout the present application.

[0061] As used herein, the term “salt” refers to any and all salts and encompasses pharmaceutically acceptable salts. Salts include ionic compounds that result from the neutralization reaction of an acid and a base. A salt is composed of one or more cations (positively charged ions) and one or more anions (negative ions) so that the salt is electrically neutral (without a net charge). Salts of the compounds of the present disclosure include those derived from inorganic and organic acids and bases.

[0070]

[0062] The term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of the present disclosure include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid or with organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods known in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p- toluenesulfonate, undecanoate, valerate salts, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N+(Ci-4 alkyl)4~ salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

[0071]

[0063] Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers”. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers”.

[0072]

[0064] ‘ ‘Stereoisomers” that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers”. When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+)- or (-)-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture.”

[0065] The term “tautomers” or “tautomeric” refers to two or more interconvertible compounds resulting from at least one formal migration of a hydrogen atom and at least one change in valency (e.g., a single bond to a double bond, a triple bond to a single bond, or vice versa). The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH. Tautomerizations (z.e., the reaction providing a tautomeric pair) may catalyzed by acid or base. Exemplary tautomerizations include keto-to- enol, amide-to-imide, lactam-to-lactim, enamine-to-imine, and enamine-to-(a different enamine) tautomerizations .

[0073]

[0066] The term “solvate” refers to forms of a compound, including salts thereof, that are associated with a solvent, usually by a solvolysis reaction. This physical association may include hydrogen bonding. Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, and the like. The compounds described herein may be prepared, e.g., in crystalline form, and may be solvated. Suitable solvates include pharmaceutically acceptable solvates and further include both stoichiometric solvates and non-stoichiometric solvates. In certain instances, the solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated in the crystal lattice of a crystalline solid. “Solvate” encompasses both solution-phase and isolatable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

[0074]

[0067] The term “hydrate” refers to a solvate wherein the compound is associated with water. Typically, the number of the water molecules contained in a hydrate of a compound is in a definite ratio to the number of the compound molecules in the hydrate. Therefore, a hydrate of a compound may be represented, for example, by the general formula Rxx H2O, wherein R is the compound, and x is a number greater than 0. A given compound may form more than one type of hydrate, including, e.g., monohydrates (x is 1), lower hydrates (x is a number greater than 0 and smaller than 1, e.g., hemihydrates (Rx0.5 H2O)), and polyhydrates (x is a number greater than 1, e.g., dihydrates (Rx2 H2O) and hexahydrates (Rx6 H2O)).

[0075]

[0068] The term “prodrugs” refers to compounds that have cleavable groups and become by solvolysis or under physiological conditions the compounds described herein, which are pharmaceutically active in vivo. See, e.g., Bundgard, H., Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985. Prodrugs include acid derivatives such as, for example, esters prepared by reaction of the parent acid with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a substituted or unsubstituted amine, or acid anhydrides, or mixed anhydrides. Simple aliphatic or aromatic esters, amides, and anhydrides derived from acidic groups pendant on the compounds described herein are particular prodrugs. In some cases it is desirable to prepare double ester-type prodrugs such as (acyloxy) alkyl esters or ((alkoxycarbonyl)oxy)alkylesters. Other derivatives of the compounds described herein have activity in both their acid and acid derivative forms, but in the acid sensitive form often offer advantages of solubility, tissue compatibility, or delayed release in the subject.

[0076]

[0069] Throughout the present disclosure, references to “the compound” and “a compound” provided herein are intended to encompass the compound or group of compounds, and also pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, isotopically labeled derivatives, and prodrugs thereof. Isotopically labeled derivatives are also included.

[0077]

[0070] The terms “composition” and “formulation” are used interchangeably.

[0078]

[0071] A “subject” to which administration is contemplated refers to a human (z.e., male or female of any age group, e.g., pediatric subject (e.g., infant, child, or adolescent) or adult subject (e.g., young adult, middle-aged adult, or senior adult)) or non-human animal. In certain embodiments, the non-human animal is a mammal (e.g., primate e.g., cynomolgus monkey or rhesus monkey), commercially relevant mammal (e.g., cattle, pig, horse, sheep, goat, cat, or dog), or bird (e.g., commercially relevant bird, such as chicken, duck, goose, or turkey)). In certain embodiments, the non-human animal is a fish, reptile, or amphibian. The non-human animal may be a male or female at any stage of development. The non- human animal may be a transgenic animal or genetically engineered animal. The term “patient” refers to a human subject in need of treatment of a disease, disorder, or condition.

[0079]

[0072] The term “administer,” “administering,” or “administration” refers to implanting, absorbing, ingesting, injecting, inhaling, providing or otherwise introducing a compound described herein, or a composition thereof, in, to or on a subject.

[0080]

[0073] The terms “treatment,” “treat,” and “treating” refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease described herein. In some embodiments, treatment may be administered after one or more signs or symptoms of the disease have developed or have been observed. In other embodiments, treatment may be administered in the absence of signs or symptoms of the disease. For example, treatment may be administered to a susceptible subject prior to the onset of symptoms (e.g., in light of a history of symptoms and / or in light of exposure to a pathogen). Treatment may also be continued after symptoms have resolved, for example, to delay or prevent recurrence.

[0081]

[0074] The term “prevent,” “preventing,” or “prevention” refers to a prophylactic treatment of a subject who is not and was not with a disease but is at risk of developing the disease or who was with a disease, is not with the disease, but is at risk of regression of the disease. In certain embodiments, the subject is at a higher risk of developing the disease or at a higher risk of regression of the disease than an average healthy member of a population.

[0082]

[0075] The terms “condition,” “disease,” and “disorder” are used interchangeably.

[0083]

[0076] An “effective amount” of a compound described herein refers to an amount sufficient to elicit the desired biological response. An effective amount of a compound described herein may vary depending on such factors as the desired biological endpoint, severity of side effects, disease, or disorder, the identity, pharmacokinetics, and pharmacodynamics of the particular compound, the condition being treated, the mode, route, and desired or required frequency of administration, the species, age and health or general condition of the subject. In certain embodiments, an effective amount is a therapeutically effective amount. In certain embodiments, an effective amount is a prophylactic treatment. In certain embodiments, an effective amount is the amount of a compound described herein in a single dose. In certain embodiments, an effective amount is the combined amounts of a compound described herein in multiple doses. In certain embodiments, an effective amount is an amount sufficient for inhibiting TRPC (e.g., TRPC3, TRPC6) activity (e.g., in a subject or in vitro).

[0084]

[0077] A “therapeutically effective amount” of a compound described herein is an amount sufficient to provide a therapeutic benefit in the treatment of a condition or to delay or minimize one or more symptoms associated with the condition. A therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the condition. The term “therapeutically effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms, signs, or causes of the condition, and / or enhances the therapeutic efficacy of another therapeutic agent. In certain embodiments, a therapeutically effective amount is an amount sufficient for treating a disease, disorder, or condition (e.g., a disease, disorder, or condition associated with TRPC (e.g., TRPC3, TRPC6) activity, e.g., Alzheimer’s disease) in a subject. In certain embodiments, a therapeutically effective amount is an amount sufficient for inhibiting TRPC (e.g., TRPC3, TRPC6) activity in a subject.

[0085]

[0078] A “prophylactically effective amount” of a compound described herein is an amount sufficient to prevent a condition, or one or more symptoms associated with the condition or prevent its recurrence. A prophylactically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other agents, which provides a prophylactic benefit in the prevention of the condition. The term “prophylactically effective amount” can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent. In certain embodiments, a prophylactically effective amount is an amount sufficient for preventing a disease, disorder, or condition (e.g., a disease, disorder, or condition associated with TRPC (e.g., TRPC3, TRPC6) activity, e.g., Alzheimer’s disease) in a subject. In certain embodiments, a prophylactically effective amount is an amount sufficient for inhibiting TRPC (e.g., TRPC3, TRPC6) activity in a subject.

[0086]

[0079] ‘ ‘Transient receptor potential cation channel subfamily C” (also known as “transient receptor potential canonical channel”) refers to the family of membrane proteins that includes, for example, members 1-7 (TRPC1, TRPC2, TRPC3, TRPC4, TRPC5, TRPC6, and TRPC7, respectively). For example, the TRPC member 3 (TRPC3) protein is a membrane protein that can form a non-selective channel permeable to cations, such as calcium. The TRPC3 protein is encoded by the TRPC3 gene (Gene ID: 7222). The protein may be induced to form channels in conditions of low intracellular calcium stores and / or by a receptor tyrosine kinase- activated phosphatidylinositol second messenger system or G- protein coupled receptors. Together with TRPC6 and TRPC7, TRPC3 is implicated in the regulation of vascular tone, cell growth, proliferation, and pathological hypertrophy. As described herein, increases in TRPC3 are associated with amyloid load and Alzheimer’s disease-related cognitive symptoms. Thus, increased levels of TRPC3 expression and / or activity may be indicative of Alzheimer’s disease.

[0087]

[0080] As used herein, the term “inhibit,” “inhibition,” or “inhibiting” in the context of proteins, for example, in the context of TRPC proteins (e.g. , TRPC3 proteins, TRPC6 proteins), refers to a reduction in the activity of the protein or a downstream effect. In some embodiments, the term refers to a reduction in the level of protein activity (e.g., TRPC3 activity, e.g., TRPC3 activity, TRPC6 activity) to a level that is statistically significantly lower than an initial level, which may, for example, be a baseline or reference level of activity. In some embodiments, the term refers to a reduction of the level of protein activity (e.g., TRPC3 activity, e.g., TRPC3 activity, TRPC6 activity) to a level that is less than 75%, less than 50%, less than 40%, less than 30%, less than 25%, less than 20%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, less than 0.5%, less than 0.1%, less than 0.01%, less than 0.001%, or less than 0.0001% of an initial level, which may, for example, be a baseline level of activity.

[0088] DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS

[0089]

[0081] Provided herein are compounds, including compounds of any of the formulae described herein e.g., Formula (I)), and pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, isotopically labeled derivatives, and prodrugs thereof. Compounds provided herein can inhibit transient receptor potential cation channel subfamily C (TRPC) activity (e.g., TRPC member 3 (TRPC3) activity, TRPC member 6 (TRPC6) activity) and are therefore useful in the treatment and / or prevention of diseases (e.g., Alzheimer’s disease). Also provided herein are pharmaceutical compositions comprising the compounds provided herein, and kits comprising the same. Additionally, the disclosure provides methods of preparing the compounds and pharmaceutical compositions described herein, and intermediates useful thereto.

[0090] Compounds

[0091]

[0082] Provided herein are compounds of Formula (I): and pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, isotopically labeled derivatives, and prodrugs thereof, wherein: n is 1 or 2;

[0092] R1is Ci-6 alkyl, Ci-6 haloalkyl, C3-7 carbocyclyl, 3-7 membered heterocyclyl, Ce-io aryl, 5-10 membered heteroaryl, -IJ-C3 7 carbocyclyl, -L’-(3-7 membered heterocyclyl), -L’-Ce 10 aryl, or -L’-(5-10 membered heteroaryl), wherein L1is C1-3 alkylene, and wherein each alkyl, haloalkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, or alkylene is independently optionally substituted; each instance of R" is independently H, Ci-6 alkyl, C3-7 carbocyclyl, or 3-7 membered heterocyclyl, or two R" are joined together with the intervening atoms to form C3-7 carbocyclyl or 3-7 membered heterocyclyl, wherein each alkyl, carbocyclyl, or heterocyclyl is independently optionally substituted; or R1and one instance of R" are joined together with the intervening atoms to form optionally substituted 4-7 membered heterocyclyl;

[0093] R2is H, halogen, Ci-6 alkyl, Ci-6 haloalkyl, C3-7 carbocyclyl, 3-7 membered heterocyclyl, Ci-6 acyl, -CN, -OR2a, -N(RN)2, or -SRs, wherein each alkyl, haloalkyl, carbocyclyl, heterocyclyl, or acyl is independently optionally substituted; each instance of R3is independently halogen, Ci-6 alkyl, Ci-6 haloalkyl, C3-7 carbocyclyl, 3-7 membered heterocyclyl, Ci-6 acyl, -CN, -OR0, -N(RN)2, or -SRs, wherein each alkyl, haloalkyl, carbocyclyl, heterocyclyl, or acyl is independently optionally substituted; or any two instances of R2and / or R3attached to the same carbon atom are joined together with the intervening atoms to form C3-7 carbocyclyl or 3-7 membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is optionally substituted; or any two instances of R2and / or R3attached to the same carbon atom are taken together to form =0; m 0, 1, 2, 3, 4, 5, 6, 7, or 8, as valency permits;

[0094] R4is C3-7 carbocyclyl, 3-7 membered heterocyclyl, Ce-io aryl, 5-10 membered heteroaryl, -L4-C3 7 carbocyclyl, -L4-(3-7 membered heterocyclyl), -L4-Ce 10 aryl, or -L4-(5-10 membered heteroaryl), wherein L4is C1-3 alkylene, and wherein each carbocyclyl, heterocyclyl, aryl, heteroaryl, or alkylene is independently optionally substituted;

[0095] Y is -O-, -N(RN)-, -S-, -S(=O)-, -S(=O)2-, or -C(Rc)2-; each instance of R5is independently halogen, Ci-6 alkyl, Ci-6 haloalkyl, C3-7 carbocyclyl, 3-7 membered heterocyclyl, Ci-6 acyl, -CN, -NO2, -N3, -OR0, -N(RN)2, -N=S(RS)2(=O), or -SRs, wherein each alkyl, haloalkyl, carbocyclyl, heterocyclyl, or acyl is independently optionally substituted; p is 0, 1, 2, 3, or 4; each instance of RN1and RNis independently H, Ci-6 alkyl, C3-7 carbocyclyl, Ci-6 acyl, or a nitrogen protecting group, or two RNattached to the same nitrogen atom are joined together with the intervening atoms to form 3-7 membered heterocyclyl, wherein each alkyl, carbocyclyl, acyl, or heterocyclyl is independently optionally substituted; each instance of R° and R2ais independently H, Ci-6 alkyl, Ci-6 haloalkyl, C3-7 carbocyclyl, 3-7 membered heterocyclyl, Ci-6 acyl, or an oxygen protecting group, wherein each alkyl, haloalkyl, carbocyclyl, heterocyclyl, or acyl is independently optionally substituted; each instance of Rsis independently H, Ci-6 alkyl, Ci-6 haloalkyl, C3-7 carbocyclyl, 3-7 membered heterocyclyl, Ci-6 acyl, or a sulfur protecting group, wherein each alkyl, haloalkyl, carbocyclyl, heterocyclyl, or acyl is independently optionally substituted; and each instance of Rcis independently H, halogen, Ci-6 alkyl, Ci-6 haloalkyl, C3-7 carbocyclyl, or 3- 7 membered heterocyclyl, or two Rcare joined together with the intervening atoms to form C3-7 carbocyclyl or 3-7 membered heterocyclyl, wherein each alkyl, haloalkyl, carbocyclyl, or heterocyclyl is independently optionally substituted; or two Rcare taken together to form =0.

[0083] In certain embodiments, the compound of Formula (I) is of Formula (I'): or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof.

[0096]

[0084] In certain embodiments, the compound of Formula (I) is of Formula (I-a): or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof.

[0097]

[0085] In certain embodiments, the compound of Formula (I) is of Formula (I-a'): or a pharmaceutically acceptable salt, tautomer, solvate, isotopically labeled derivative, or prodrug thereof.

[0086] In certain embodiments, the compound of Formula (I) is of Formula (I-b): or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein:

[0098] X1and X2are each independently N or CR4b; and each instance of R4aand R4bis independently H, halogen, Ci-6 alkyl, Ci-6 haloalkyl, C3-7 carbocyclyl, 3-7 membered heterocyclyl, Ci-6 acyl, -CN, -NO2, -N3, -OR0, -N(RN)2, or -SRs, wherein each alkyl, haloalkyl, carbocyclyl, heterocyclyl, or acyl is independently optionally substituted.

[0099]

[0087] In certain embodiments, the compound of Formula (I) is of Formula (I-b'): or a pharmaceutically acceptable salt, tautomer, solvate, isotopically labeled derivative, or prodrug thereof.

[0100]

[0088] In certain embodiments, the compound of Formula (I) is of Formula (I-c): or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof.

[0089] In certain embodiments, the compound of Formula (I) is of Formula (I-c'): or a pharmaceutically acceptable salt, tautomer, solvate, isotopically labeled derivative, or prodrug thereof.

[0101]

[0090] In certain embodiments, the compound of Formula (I) is of Formula (I-d): or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof.

[0102]

[0091] In certain embodiments, the compound of Formula (I) is of Formula (I-d'): or a pharmaceutically acceptable salt, tautomer, solvate, isotopically labeled derivative, or prodrug thereof.

[0092] In certain embodiments, the compound of Formula (I) is of Formula (I-e) or (I-f): or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof.

[0103]

[0093] In certain embodiments, the compound of Formula (I) is of Formula (I-e') or (I-f'): or a pharmaceutically acceptable salt, tautomer, solvate, isotopically labeled derivative, or prodrug thereof.

[0104]

[0094] In certain embodiments, a compound provided herein is a compound of Formula (I) or any subgenus or species thereof, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or solvate thereof. In certain embodiments, a compound provided herein is a compound of Formula (I) or any subgenus or species thereof, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof. In certain embodiments, a compound provided herein is a compound of Formula (I) or any subgenus or species thereof, or a pharmaceutically acceptable salt thereof. In certain embodiments, a compound provided herein is a compound of Formula (I) or any subgenus or species thereof, as a free base.

[0105]

[0095] In the various aspects and embodiments disclosed herein, express reference to a compound of Formula (I) is understood to alternatively refer to a compound of any disclosed subgenus or species thereof, for example, to a compound of Table 1.

[0106]

[0096] In certain embodiments, a compound of Formula (I) is selected from the compounds recited in Table 1, and pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, isotopically labeled derivatives, and prodrugs thereof. In certain embodiments, a compound of Formula (I) is selected from the compounds recited in Table 1, and pharmaceutically acceptable salts, stereoisomers, and tautomers thereof. In certain embodiments, a compound of Formula (I) is selected from the compounds recited in Table 1, and pharmaceutically acceptable salts thereof. In certain embodiments, a compound of Formula (I) is selected from the compounds recited in Table 1 (in free base form). Table 1

[0097] The following definitions and embodiments apply to all generic formulae comprising the relevant groups (e.g., Formula (I) or any subgeneric formula thereof) provided herein. The recitation of a listing of chemical groups in any definition of a variable herein includes definitions of that variable as any single group or combination of listed groups. The recitation of an embodiment for a variable herein includes that embodiment as any single embodiment or in combination with any other embodiments or portions thereof.

[0107]

[0098] As generally defined herein, n is 1 or 2.

[0108]

[0099] In certain embodiments, n is 1.

[0109]

[0100] In certain embodiments, n is 2.

[0110]

[0101] As generally defined herein, RN1is H, Ci-6 alkyl, C3-7 carbocyclyl, Ci-6 acyl, or a nitrogen protecting group, wherein the alkyl, carbocyclyl, or acyl is optionally substituted.

[0111]

[0102] In certain embodiments, RN1is H.

[0112]

[0103] In certain embodiments, RN1is optionally substituted Ci-6 alkyl. In certain embodiments, RN1is optionally substituted Cm alkyl. In certain embodiments, RN1is unsubstituted C1-3 alkyl. In certain embodiments, RN1is methyl.

[0113]

[0104] In certain embodiments, RN1is optionally substituted C3-7 carbocyclyl.

[0114]

[0105] In certain embodiments, RN1is optionally substituted Ci-6 acyl.

[0115]

[0106] In certain embodiments, RN1is a nitrogen protecting group.

[0116]

[0107] As generally defined herein, R1is Ci-6 alkyl, Ci-6 haloalkyl, C3-7 carbocyclyl, 3-7 membered heterocyclyl, Ce-io aryl, 5-10 membered heteroaryl, -L'-Cs -7 carbocyclyl, -L’-(3-7 membered heterocyclyl), -L’-Ce 10 aryl, or -L’-(5-10 membered heteroaryl), wherein L1is C1-3 alkylene, and wherein each alkyl, haloalkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, or alkylene is independently optionally substituted.

[0117]

[0108] In certain embodiments, R1is optionally substituted Ci-6 alkyl. In certain embodiments, R1is optionally substituted CM alkyl. In certain embodiments, R1is unsubstituted C1-4 alkyl. In certain embodiments, R1is methyl. In certain embodiments, R1is ethyl. In certain embodiments, R1is tert-butyl.

[0118]

[0109] In certain embodiments, R1is optionally substituted Ci-6 haloalkyl. In certain embodiments, R1is optionally substituted C1-3 haloalkyl. In certain embodiments, R1is unsubstituted C1-3 haloalkyl. In certain embodiments, R1is unsubstituted Ci haloalkyl.

[0119] [HO] In certain embodiments, R1is optionally substituted C3-7 carbocyclyl. In certain embodiments, R1is optionally substituted C3-6 carbocyclyl. In certain embodiments, R1is unsubstituted C3-6 carbocyclyl.

[0120]

[0111] In certain embodiments, R1is optionally substituted 3-7 membered heterocyclyl (e.g., having 1 or 2 ring heteroatoms independently selected from O, N, and S, e.g., having 1 ring O atom). In certain embodiments, R1is optionally substituted 4-6 membered heterocyclyl (e.g., having 1 or 2 ring heteroatoms independently selected from O, N, and S, e.g., having 1 ring O atom). In certain embodiments, R1is unsubstituted 4-6 membered heterocyclyl e.g., having 1 or 2 ring heteroatoms independently selected from O, N, and S, e.g., having 1 ring O atom).

[0121]

[0112] In certain embodiments, R1is optionally substituted Ce-io aryl. In certain embodiments, R1is optionally substituted Ce aryl. In certain embodiments, R1is unsubstituted Ce aryl (phenyl).

[0122]

[0113] In certain embodiments, R1is optionally substituted 5-10 membered heteroaryl (e.g., having 1 or 2 ring heteroatoms independently selected from O, N, and S, e.g., having 1 or 2 ring N atoms). In certain embodiments, R1is optionally substituted 5-6 membered heteroaryl (e.g., having 1 or 2 ring heteroatoms independently selected from O, N, and S, e.g., having 1 or 2 ring N atoms). In certain embodiments, R1is optionally substituted 5-membered heteroaryl e.g., having 1 or 2 ring heteroatoms independently selected from O, N, and S, e.g., having 1 or 2 ring N atoms). In certain embodiments, R1is 5-membered heteroaryl having 1 or 2 ring N atoms, wherein the heteroaryl is optionally substituted with one or more substituents independently selected from unsubstituted Ci-4 alkyl.

[0123]

[0114] In certain embodiments, R1is -L'-Cs -7 carbocyclyl, wherein the carbocyclyl is optionally substituted. In certain embodiments, R1is -L'-Cs e carbocyclyl, wherein the carbocyclyl is optionally substituted. In certain embodiments, R1is -(C1-3 alkylene) -C36 carbocyclyl, wherein the alkylene and carbocyclyl are independently optionally substituted. In certain embodiments, R1is -(Ci alkylene)-C36 carbocyclyl, wherein the alkylene and carbocyclyl are independently optionally substituted. In certain embodiments, R1is -CH2-C36 carbocyclyl.

[0124]

[0115] In certain embodiments, R1is -L’-(3-7 membered heterocyclyl), wherein the heterocyclyl is optionally substituted. In certain embodiments, R1is -L’-(4-6 membered heterocyclyl), wherein the heterocyclyl is optionally substituted, and wherein the heterocyclyl has 1 or 2 ring heteroatoms independently selected from O, N, and S. In certain embodiments, R1is -L’-(4-6 membered heterocyclyl), wherein the heterocyclyl is optionally substituted, and wherein the heterocyclyl has 1 or 2 ring O atoms. In certain embodiments, R1is -(C1-3 alkylene)-(4-6 membered heterocyclyl), wherein the alkylene and heterocyclyl are independently optionally substituted, and wherein the heterocyclyl has 1 or 2 ring O atoms. In certain embodiments, R1is -(Ci alkylene)-(4-6 membered heterocyclyl), wherein the alkylene and heterocyclyl are independently optionally substituted, and wherein the heterocyclyl has 1 or 2 ring O atoms. In certain embodiments, R1is -CH2-(4-6 membered heterocyclyl), wherein the heterocyclyl has 1 or 2 ring O atoms.

[0125]

[0116] In certain embodiments, R1is -L'-Ce -10 aryl, wherein the aryl is optionally substituted. In certain embodiments, R1is -L’-Cearyl, wherein the aryl is optionally substituted.

[0126]

[0117] In certain embodiments, R1is -L’-(5-10 membered heteroaryl), wherein the heteroaryl is optionally substituted. In certain embodiments, R1is -L’-(5-6 membered heteroaryl), wherein the heteroaryl is optionally substituted, and wherein the heteroaryl has 1 or 2 ring heteroatoms independently selected from O, N, and S. In certain embodiments, R1is -L’-(5-6 membered heteroaryl), wherein the heteroaryl is optionally substituted, and wherein the heteroaryl has 1 or 2 ring N atoms. In certain embodiments, R1is -(C1-3 alkylene)-(5-6 membered heteroaryl), wherein the alkylene and heteroaryl are independently optionally substituted, and wherein the heteroaryl has 1 or 2 ring N atoms. In certain embodiments, R1is -(Ci alkylene)-(5-6 membered heteroaryl), wherein the alkylene and heteroaryl are independently optionally substituted, and wherein the heteroaryl has 1 or 2 ring N atoms. In certain embodiments, R1is -CH2-(5-6 membered heteroaryl), wherein the heteroaryl has 1 or 2 ring N atoms.

[0118] As generally defined herein, L1is optionally substituted C1-3 alkylene. In certain embodiments, L1is optionally substituted Ci alkylene. In certain embodiments, L1is unsubstituted Ci alkylene (-CH2-).

[0127]

[0119] In certain embodiments, R1is R1is selected from: methyl, ethyl, tert-butyl, -CF3, -CH2CF3,

[0128]

[0120] As generally defined herein, each instance of R" is independently H, Ci-6 alkyl, C3-7 carbocyclyl, or 3-7 membered heterocyclyl, or two R" are joined together with the intervening atoms to form C3-7 carbocyclyl or 3-7 membered heterocyclyl, wherein each alkyl, carbocyclyl, or heterocyclyl is independently optionally substituted.

[0129]

[0121] In certain embodiments, at least one instance of R" is H. In certain embodiments, each instance of R" is H.

[0130]

[0122] In certain embodiments, at least one instance of R" is optionally substituted Ci-6 alkyl. In certain embodiments, at least one instance of R" is optionally substituted C1-3 alkyl. In certain embodiments, at least one instance of R" is unsubstituted C1-3 alkyl.

[0131]

[0123] In certain embodiments, at least one instance of R" is optionally substituted C3-7 carbocyclyl.

[0132]

[0124] In certain embodiments, at least one instance of R" is optionally substituted 3-7 membered heterocyclyl.

[0133]

[0125] In certain embodiments, two R" are joined together with the intervening atoms to form C3-7 carbocyclyl or 3-7 membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is optionally substituted.

[0134]

[0126] In other embodiments, R1and one instance of R" are joined together with the intervening atoms to form optionally substituted 4-7 membered heterocyclyl. In certain embodiments, R1and one instance of R" are joined together with the intervening atoms to form optionally substituted 4-6 membered heterocyclyl having 1 ring O atom. In certain embodiments, R1and one instance of R" are joined together with the intervening atoms to form unsubstituted 4-6 membered heterocyclyl having 1 ring O atom.

[0127] As generally defined herein, R2is H, halogen, Ci-6 alkyl, Ci-6 haloalkyl, C3-7 carbocyclyl, 3-7 membered heterocyclyl, Ci-6 acyl, -CN, -OR2a, -N(RN)2, or -SRs, wherein each alkyl, haloalkyl, carbocyclyl, heterocyclyl, or acyl is independently optionally substituted.

[0135]

[0128] In certain embodiments, R2is H.

[0136]

[0129] In certain embodiments, R2is halogen.

[0137]

[0130] In certain embodiments, R2is optionally substituted Ci-6 alkyl. In certain embodiments, R2is optionally substituted Cm alkyl. In certain embodiments, R2is unsubstituted C1-3 alkyl.

[0138]

[0131] In certain embodiments, R2is optionally substituted Ci-6 haloalkyl.

[0139]

[0132] In certain embodiments, R2is optionally substituted C3-7 carbocyclyl.

[0140]

[0133] In certain embodiments, R2is optionally substituted 3-7 membered heterocyclyl.

[0141]

[0134] In certain embodiments, R2is optionally substituted Ci-6 acyl.

[0142]

[0135] In certain embodiments, R2is -CN.

[0143]

[0136] In certain embodiments, R2is -OR2a. In certain embodiments, R2is -OR2a, wherein R2ais optionally substituted Ci-6 alkyl. In certain embodiments, R2is -OR2a, wherein R2ais optionally substituted C1-3 alkyl. In certain embodiments, R2is -OR2a, wherein R2'1is unsubstituted C1-3 alkyl. In certain embodiments, R2is -OR2a, wherein R2ais optionally substituted Ci-6 haloalkyl. In certain embodiments, R2is -OR2a, wherein R2ais optionally substituted C1-3 haloalkyl. In certain embodiments, R2is -OR2a, wherein R2ais trihalomethyl. In certain embodiments, R2is -OMe. In certain embodiments, R2is -OEt. In certain embodiments, R2is -OCF3.

[0144]

[0137] In certain embodiments, R2is -N(RN)2-

[0145]

[0138] In certain embodiments, R2is -SRs.

[0146]

[0139] In certain embodiments, R2is selected from H, -OMe, -OEt, -OCF3, and methyl.

[0147]

[0140] As generally defined herein, R2ais H, Ci-6 alkyl, Ci-6 haloalkyl, C3-7 carbocyclyl, 3-7 membered heterocyclyl, Ci-6 acyl, or an oxygen protecting group, wherein each alkyl, haloalkyl, carbocyclyl, heterocyclyl, or acyl is independently optionally substituted.

[0148]

[0141] In certain embodiments, R2ais H.

[0149]

[0142] In certain embodiments, R2ais optionally substituted Ci-6 alkyl. In certain embodiments, R2ais optionally substituted C1-3 alkyl. In certain embodiments, R2ais unsubstituted C1-3 alkyl. In certain embodiments, R2ais methyl. In certain embodiments, R2ais ethyl.

[0150]

[0143] In certain embodiments, R2ais optionally substituted Ci-6 haloalkyl. In certain embodiments, R2ais optionally substituted C1-3 haloalkyl. In certain embodiments, R2ais trihalomethyl. In certain embodiments, R2ais -CF3.

[0151]

[0144] In certain embodiments, R2ais optionally substituted C3-7 carbocyclyl.

[0152]

[0145] In certain embodiments, R2ais optionally substituted 3-7 membered heterocyclyl.

[0153]

[0146] In certain embodiments, R2ais optionally substituted Ci-6 acyl.

[0154]

[0147] In certain embodiments, R2ais an oxygen protecting group.

[0155]

[0148] As generally defined herein, each instance of R3is independently halogen, Ci-6 alkyl, Ci-6 haloalkyl, C3-7 carbocyclyl, 3-7 membered heterocyclyl, Ci-6 acyl, -CN, -OR0, -N(RN)2, or -SRs, wherein each alkyl, haloalkyl, carbocyclyl, heterocyclyl, or acyl is independently optionally substituted.

[0156]

[0149] In certain embodiments, at least one instance of R3is halogen.

[0157]

[0150] In certain embodiments, at least one instance of R3is optionally substituted Ci-6 alkyl.

[0158]

[0151] In certain embodiments, at least one instance of R3is optionally substituted Ci-6 haloalkyl.

[0159]

[0152] In certain embodiments, at least one instance of R3is optionally substituted C3-7 carbocyclyl.

[0160]

[0153] In certain embodiments, at least one instance of R3is optionally substituted 3-7 membered heterocyclyl.

[0161]

[0154] In certain embodiments, at least one instance of R3is optionally substituted Ci-6 acyl.

[0162]

[0155] In certain embodiments, at least one instance of R3is -CN. In certain embodiments, at least one instance of R3is -OR0. In certain embodiments, at least one instance of R3is -N(RN)2- In certain embodiments, at least one instance of R3is -SRs.

[0163]

[0156] In certain embodiments, any two instances of R2and / or R3attached to the same carbon atom are joined together with the intervening atoms to form optionally substituted C3-7 carbocyclyl or optionally substituted 3-7 membered heterocyclyl. In certain embodiments, any two instances of R2and / or R3attached to the same carbon atom are taken together to form =0.

[0164]

[0157] As generally defined herein, m 0, 1, 2, 3, 4, 5, 6, 7, or 8, as valency permits.

[0165]

[0158] In certain embodiments, m is 0.

[0166]

[0159] In certain embodiments, m is 1. In certain embodiments, m is 2. In certain embodiments, m is 3. In certain embodiments, m is 4. In certain embodiments, m is 5. In certain embodiments, m is 6. In certain embodiments, m is 7. In certain embodiments, m is 8.

[0167]

[0160] As generally defined herein, R4is C3-7 carbocyclyl, 3-7 membered heterocyclyl, Ce-io aryl, 5-10 membered heteroaryl, -L4-C3 7 carbocyclyl, -L4-(3-7 membered heterocyclyl), -L4-Ce 10 aryl, or -L4-(5-10 membered heteroaryl), wherein L4is C1-3 alkylene, and wherein each carbocyclyl, heterocyclyl, aryl, heteroaryl, or alkylene is independently optionally substituted.

[0168]

[0161] In certain embodiments, R4is optionally substituted C3-7 carbocyclyl.

[0169]

[0162] In certain embodiments, R4is optionally substituted 3-7 membered heterocyclyl (e.g., having 1 or 2 ring heteroatoms independently selected from O, N, and S, e.g., having 1 ring O atom). In certain embodiments, R4is optionally substituted 4-6 membered heterocyclyl (e.g., having 1 or 2 ring heteroatoms independently selected from O, N, and S, e.g., having 1 ring O atom). In certain embodiments, R4is optionally substituted 6 membered heterocyclyl e.g., having 1 or 2 ring heteroatoms independently selected from O, N, and S, e.g., having 1 ring O atom). In certain embodiments, R4is unsubstituted 6 membered heterocyclyl (e.g., having 1 or 2 ring heteroatoms independently selected from O, N, and S, e.g., having 1 ring O atom).

[0170]

[0163] In certain embodiments, R4is optionally substituted Ce-io aryl. In certain embodiments, R4is optionally substituted Ce aryl. In certain embodiments, R4is unsubstituted Ce aryl (phenyl).

[0171]

[0164] In certain embodiments, R4is optionally substituted 5-10 membered heteroaryl (e.g., having 1, 2, or 3 ring heteroatoms independently selected from O, N, and S, e.g., having 1 or 2 ring N atoms). In certain embodiments, R4is 5-10 membered heteroaryl (e.g., having 1, 2, or 3 ring heteroatoms independently selected from O, N, and S, e.g., having 1 or 2 ring N atoms) substituted with 0, 1, 2, 3, 4, 5, or 6 instances of R4a, as valency permits.

[0172]

[0165] In certain embodiments, R4is optionally substituted 5-6 membered heteroaryl (e.g., having 1 or 2 ring heteroatoms independently selected from O, N, and S, e.g., having 1 or 2 ring N atoms). In certain embodiments, R4is 5-6 membered heteroaryl e.g., having 1 or 2 ring heteroatoms independently selected from O, N, and S, e.g., having 1 or 2 ring N atoms) substituted with 0, 1, 2, 3, or 4 instances of R4a, as valency permits.

[0173]

[0166] In certain embodiments, R4is optionally substituted 5 -membered heteroaryl (e.g., having 1 or 2 ring heteroatoms independently selected from O, N, and S, e.g., having 1 or 2 ring N atoms). In certain embodiments, R4is 5-membered heteroaryl (e.g., having 1 or 2 ring heteroatoms independently selected from O, N, and S, e.g., having 1 or 2 ring N atoms) substituted with 0, 1, 2, or 3 instances of R4a, as valency permits.

[0174]

[0167] In certain embodiments, R4is optionally substituted 6-membered heteroaryl (e.g., having 1 or 2 ring heteroatoms independently selected from O, N, and S, e.g., having 1 or 2 ring N atoms). In certain embodiments, R4is 6-membered heteroaryl (e.g., having 1 or 2 ring heteroatoms independently selected from O, N, and S, e.g., having 1 or 2 ring N atoms) substituted with 0, 1, 2, 3, or 4 instances of R4a, as valency permits.

[0175]

[0168] In certain embodiments, R4is optionally substituted pyridyl. In certain embodiments, R4is pyridyl substituted with 0, 1, 2, 3, or 4 instances of R4a.

[0176]

[0169] In certain embodiments, R4is optionally substituted pyrazinyl. In certain embodiments, R4is pyrazinyl substituted with 0, 1 , 2 or 3 instances of R4a.

[0177]

[0170] In certain embodiments, R4is optionally substituted pyrimidinyl. In certain embodiments, R4is pyrimidinyl substituted with 0, 1 , 2 or 3 instances of R4a.

[0178]

[0171] In certain embodiments, R4is optionally substituted pyridazinyl. In certain embodiments, R4is pyridazinyl substituted with 0, 1 , 2 or 3 instances of R4a.

[0179]

[0172] In certain embodiments, R4is optionally substituted quinolinyl. In certain embodiments, R4is quinolinyl substituted with 0, 1, 2, 3, 4, 5, or 6 instances of R4a.

[0180]

[0173] In certain embodiments, R4is optionally substituted isoquinolinyl. In certain embodiments, R4is isoquinolinyl substituted with 0, 1, 2, 3, 4, 5, or 6 instances of R4a.

[0181]

[0174] In certain embodiments, R4is optionally substituted thiazolyl. In certain embodiments, R4is thiazolyl substituted with 0, 1 , 2, or 3 instances of R4a.

[0182]

[0175] In certain embodiments, R4is -L4-C37 carbocyclyl, wherein the carbocyclyl is optionally substituted.

[0183]

[0176] In certain embodiments, R4is -L4-(3-7 membered heterocyclyl), wherein the heterocyclyl is optionally substituted.

[0184]

[0177] In certain embodiments, R4is -L4-Ce 10 aryl, wherein the aryl is optionally substituted. In certain embodiments, R4is -L4-Ce aryl, wherein the aryl is optionally substituted. In certain embodiments, R4is - (C1-3 alkylene)-Ce aryl, wherein the aryl and alkylene are independently optionally substituted. In certain embodiments, R4is -CH2-C6 aryl, wherein the aryl and alkylene are independently optionally substituted.

[0185]

[0178] In certain embodiments, R4is -L4-(5-10 membered heteroaryl), wherein the heteroaryl is optionally substituted.

[0186]

[0179] As generally defined herein, L4is optionally substituted C1-3 alkylene. In certain embodiments, L4is optionally substituted Ci alkylene. In certain embodiments, L4is unsubstituted Cm alkylene. In certain embodiments, L4is -CH2-.

[0187]

[0180] In certain embodiments, R4is of the formula: , wherein X1, X2, R4b, and R4aare as defined herein.

[0188]

[0181] In certain embodiments, R4is of the formula:

[0189]

[0182] In certain embodiments, R4is of the formula:

[0190]

[0183] As generally defined herein, X1and X2are each independently N or CR4b.

[0191]

[0184] In certain embodiments, X1is N.

[0192]

[0185] In certain embodiments, X1is CR4b. In certain embodiments, X1is CH.

[0193]

[0186] In certain embodiments, X2is N.

[0194]

[0187] In certain embodiments, X2is CR4b. In certain embodiments, X2is CH.

[0195]

[0188] In certain embodiments, X1and X2are N.

[0196]

[0189] In certain embodiments, R4is selected from:

[0197]

[0190] As defined herein, each instance of R4ais independently H, halogen, Ci-6 alkyl, Ci-6 haloalkyl, C3-7 carbocyclyl, 3-7 membered heterocyclyl, Ci-6 acyl, -CN, -NO2, -N3, -OR0, -N(RN)2, or -SRs, wherein each alkyl, haloalkyl, carbocyclyl, heterocyclyl, or acyl is independently optionally substituted.

[0198]

[0191] In certain embodiments, at least one instance of R4ais H.

[0199]

[0192] In certain embodiments, at least one instance of R4ais halogen. In certain embodiments, at least one instance of R4ais F.

[0200]

[0193] In certain embodiments, at least one instance of R4ais optionally substituted Ci-6 alkyl. In certain embodiments, at least one instance of R4ais optionally substituted C1-3 alkyl. In certain embodiments, at least one instance of R4ais unsubstituted C1-3 alkyl. In certain embodiments, at least one instance of R4ais methyl.

[0201]

[0194] In certain embodiments, at least one instance of R4ais optionally substituted Ci-6 haloalkyl. In certain embodiments, at least one instance of R4ais optionally substituted C1-3 haloalkyl. In certain embodiments, at least one instance of R4ais optionally substituted Ci haloalkyl. In certain embodiments, at least one instance of R4ais unsubstituted Ci haloalkyl. In certain embodiments, at least one instance of R4ais trihalomethyl. In certain embodiments, at least one instance of R4ais -CF3. In certain embodiments, at least one instance of R4ais dihalomethyl. In certain embodiments, at least one instance of R4ais -CF2H.

[0202]

[0195] In certain embodiments, at least one instance of R4ais optionally substituted C3-7 carbocyclyl. In certain embodiments, at least one instance of R4ais optionally substituted C3-6 carbocyclyl. In certain embodiments, at least one instance of R4ais optionally substituted C3 carbocyclyl. In certain embodiments, at least one instance of R4ais unsubstituted C3 carbocyclyl.

[0196] In certain embodiments, at least one instance of R4ais optionally substituted 3-7 membered heterocyclyl.

[0203]

[0197] In certain embodiments, at least one instance of R4ais optionally substituted Ci-6 acyl.

[0204]

[0198] In certain embodiments, at least one instance of R4ais -CN.

[0205]

[0199] In certain embodiments, at least one instance of R4ais -NO2.

[0206]

[0200] In certain embodiments, at least one instance of R4ais -N3.

[0207]

[0201] In certain embodiments, at least one instance of R4ais -OR0.

[0208]

[0202] In certain embodiments, at least one instance of R4ais -N(RN)2.

[0209]

[0203] In certain embodiments, at least one instance of R4ais -SRs.

[0210]

[0204] In certain embodiments, at least one instance of R4ais selected from -CF3, -CF2H, -CN, methyl, -

[0211]

[0205] As defined herein, each instance of R4bis independently H, halogen, Ci-6 alkyl, Ci-6 haloalkyl, C3-7 carbocyclyl, 3-7 membered heterocyclyl, Ci-6 acyl, -CN, -NO2, -N3, -OR0, -N(RN)2, or -SRs, wherein each alkyl, haloalkyl, carbocyclyl, heterocyclyl, or acyl is independently optionally substituted.

[0212]

[0206] In certain embodiments, at least one instance of R4bis H. In certain embodiments, each instance of R4bis H.

[0213]

[0207] In certain embodiments, at least one instance of R4bis halogen. In certain embodiments, at least one instance of R4bis F.

[0214]

[0208] In certain embodiments, at least one instance of R4bis optionally substituted Ci-6 alkyl. In certain embodiments, at least one instance of R4bis optionally substituted Cm alkyl. In certain embodiments, at least one instance of R4bis unsubstituted Cm alkyl. In certain embodiments, at least one instance of R4bis methyl.

[0215]

[0209] In certain embodiments, at least one instance of R4bis optionally substituted Ci-6 haloalkyl. In certain embodiments, at least one instance of R4bis optionally substituted Cm haloalkyl. In certain embodiments, at least one instance of R4bis optionally substituted Ci haloalkyl. In certain embodiments, at least one instance of R4bis unsubstituted Ci haloalkyl.

[0216]

[0210] In certain embodiments, at least one instance of R4bis trihalomethyl. In certain embodiments, at least one instance of R4bis -CF3. In certain embodiments, at least one instance of R4bis dihalomethyl. In certain embodiments, at least one instance of R4bis -CF2H.

[0217]

[0211] In certain embodiments, at least one instance of R4bis optionally substituted C3-7 carbocyclyl. In certain embodiments, at least one instance of R4bis optionally substituted C3-6 carbocyclyl. In certain embodiments, at least one instance of R4bis optionally substituted C3 carbocyclyl. In certain embodiments, at least one instance of R4bis unsubstituted C3 carbocyclyl.

[0218]

[0212] In certain embodiments, at least one instance of R4bis optionally substituted 3-7 membered heterocyclyl.

[0219]

[0213] In certain embodiments, at least one instance of R4bis optionally substituted Ci-6 acyl.

[0214] In certain embodiments, at least one instance of R4bis -CN.

[0220]

[0215] In certain embodiments, at least one instance of R4bis -NO2.

[0221]

[0216] In certain embodiments, at least one instance of R4bis -Ns.

[0222]

[0217] In certain embodiments, at least one instance of R4bis -OR0.

[0223]

[0218] In certain embodiments, at least one instance of R4bis -N(RN)2.

[0224]

[0219] In certain embodiments, at least one instance of R4bis -SRs.

[0225]

[0220] In certain embodiments, at least one instance of R4bis selected from -CFs, -CF2H, -CN, methyl, -

[0226]

[0221] As generally defined herein, Y is -O-, -N(RN)-, -S-, -S(=O)-, -S(=O)2-, or -C(Rc)2-.

[0227]

[0222] In certain embodiments, Y is -O-.

[0228]

[0223] In certain embodiments, Y is -N(RN)-. In certain embodiments, Y is -NH-. In certain embodiments,

[0229] Y is -N(Me)-.

[0230]

[0224] In certain embodiments, Y is -S-.

[0231]

[0225] In certain embodiments, Y is -S(=O)-.

[0232]

[0226] In certain embodiments, Y is -S(=O)2-.

[0233]

[0227] In certain embodiments, Y is or -C(Rc)2-. In certain embodiments, Y is or -CH2-.

[0234]

[0228] As generally defined herein, each instance of R5is independently halogen, Ci-6 alkyl, Ci-6 haloalkyl, C3-7 carbocyclyl, 3-7 membered heterocyclyl, Ci-6 acyl, -CN, -NO2, -N3, -OR0, -N(RN)2, - N=S(RS)2(=O), or -SRs, wherein each alkyl, haloalkyl, carbocyclyl, heterocyclyl, or acyl is independently optionally substituted.

[0235]

[0229] In certain embodiments, at least one instance of R5is halogen. In certain embodiments, at least one instance of R5is F.

[0236]

[0230] In certain embodiments, at least one instance of R5is optionally substituted Ci-6 alkyl. In certain embodiments, at least one instance of R5is optionally substituted C1-3 alkyl. In certain embodiments, at least one instance of R5is unsubstituted C1-3 alkyl. In certain embodiments, at least one instance of R5is methyl. In certain embodiments, at least one instance of R5is ethyl.

[0237]

[0231] In certain embodiments, at least one instance of R5is optionally substituted Ci-6 haloalkyl.

[0238]

[0232] In certain embodiments, at least one instance of R5is optionally substituted C3-7 carbocyclyl. In certain embodiments, at least one instance of R5is optionally substituted C35 carbocyclyl. In certain embodiments, at least one instance of R5is optionally substituted C3 carbocyclyl. In certain embodiments, at least one instance of R5is unsubstituted C3 carbocyclyl.

[0239]

[0233] In certain embodiments, at least one instance of R5is optionally substituted 3-7 membered heterocyclyl.

[0240]

[0234] In certain embodiments, at least one instance of R5is optionally substituted Ci-6 acyl.

[0241]

[0235] In certain embodiments, at least one instance of R5is -CN.

[0242]

[0236] In certain embodiments, at least one instance of R5is -NO2.

[0237] In certain embodiments, at least one instance of R5is -N3.

[0243]

[0238] In certain embodiments, at least one instance of R5is -OR0. In certain embodiments, at least one instance of R5is -OR0, wherein R° is optionally substituted Ci-6 alkyl. In certain embodiments, at least one instance of R5is -OR0, wherein R° is optionally substituted Cm alkyl. In certain embodiments, at least one instance of R5is -OR0, wherein R° is unsubstituted C1-3 alkyl. In certain embodiments, at least one instance of R5is -OR0, wherein R° is optionally substituted Ci-6 haloalkyl. In certain embodiments, at least one instance of R5is -OR0, wherein R° is optionally substituted C1-3 haloalkyl. In certain embodiments, at least one instance of R5is -OR0, wherein R° is trihalomethyl.

[0244]

[0239] In certain embodiments, at least one instance of R5is -N(RN)2- In certain embodiments, at least one instance of R5is -N(RN)2, wherein each instance of RNis independently optionally substituted Ci-6 alkyl. In certain embodiments, at least one instance of R5is -N(RN)2, wherein each instance of RNis independently optionally substituted Cm alkyl. In certain embodiments, at least one instance of R5is - N(RN)2, wherein each instance of RNis independently unsubstituted Cm alkyl.

[0245]

[0240] In certain embodiments, at least one instance of R5is -N=S(Rs)2(=O).

[0246]

[0241] In certain embodiments, at least one instance of R5is optionally substituted -SRs.

[0247]

[0242] In certain embodiments, at least one instance of R5is selected from F, -OMe, -OEt, -Oz'-Pr -OCF3, -

[0248] NMe2, -N=S(Me)2(=O), -CN, ethyl, and cyclopropyl.

[0249]

[0243] As generally defined herein, p is 0, 1, 2, 3, or 4.

[0250]

[0244] In certain embodiments, p is 0. In certain embodiments, p is 1. In certain embodiments, p is 2. In certain embodiments, p is 3. In certain embodiments, p is 4.

[0251]

[0245] As generally defined herein, each instance of RNis independently H, Ci-6 alkyl, C3-7 carbocyclyl, C1-6 acyl, or a nitrogen protecting group, or two RNattached to the same nitrogen atom are joined together with the intervening atoms to form 3-7 membered heterocyclyl, wherein each alkyl, carbocyclyl, acyl, or heterocyclyl is independently optionally substituted.

[0252]

[0246] In certain embodiments, at least one instance of RNis H.

[0253]

[0247] In certain embodiments, at least one instance of RNis optionally substituted Ci-6 alkyl. In certain embodiments, at least one instance of RNis optionally substituted C1-3 alkyl. In certain embodiments, at least one instance of RNis unsubstituted C1-3 alkyl.

[0254]

[0248] In certain embodiments, at least one instance of RNis optionally substituted C3-7 carbocyclyl.

[0255]

[0249] In certain embodiments, at least one instance of RNis optionally substituted Ci-6 acyl.

[0256]

[0250] In certain embodiments, at least one instance of RNis a nitrogen protecting group.

[0257]

[0251] In certain embodiments, two RNattached to the same nitrogen atom are joined together with the intervening atoms to form 3-7 membered heterocyclyl.

[0258]

[0252] As generally defined herein, each instance of R° is independently H, Ci-6 alkyl, Ci-6 haloalkyl, C3-7 carbocyclyl, 3-7 membered heterocyclyl, Ci-6 acyl, or an oxygen protecting group, wherein each alkyl, haloalkyl, carbocyclyl, heterocyclyl, or acyl is independently optionally substituted.

[0259]

[0253] In certain embodiments, at least one instance of R° is H.

[0260]

[0254] In certain embodiments, at least one instance of R° is optionally substituted Ci-6 alkyl. In certain embodiments, at least one instance of R° is optionally substituted Cm alkyl. In certain embodiments, at least one instance of R° is unsubstituted Cm alkyl.

[0261]

[0255] In certain embodiments, at least one instance of R° is optionally substituted Ci-6 haloalkyl.

[0262]

[0256] In certain embodiments, at least one instance of R° is optionally substituted C3-7 carbocyclyl.

[0263]

[0257] In certain embodiments, at least one instance of R° is optionally substituted 3-7 membered heterocyclyl.

[0264]

[0258] In certain embodiments, at least one instance of R° is optionally substituted Ci-6 acyl.

[0265]

[0259] In certain embodiments, at least one instance of R° is an oxygen protecting group.

[0266]

[0260] As generally defined herein, each instance of Rsis independently H, Ci-6 alkyl, Ci-6 haloalkyl, C3-7 carbocyclyl, 3-7 membered heterocyclyl, Ci-6 acyl, or a sulfur protecting group, wherein each alkyl, haloalkyl, carbocyclyl, heterocyclyl, or acyl is independently optionally substituted.

[0267]

[0261] In certain embodiments, at least one instance of Rsis H.

[0268]

[0262] In certain embodiments, at least one instance of Rsis optionally substituted Ci-6 alkyl. In certain embodiments, at least one instance of Rsis optionally substituted Cm alkyl. In certain embodiments, at least one instance of Rsis unsubstituted Cm alkyl.

[0269]

[0263] In certain embodiments, at least one instance of Rsis optionally substituted Ci-6 haloalkyl.

[0270]

[0264] In certain embodiments, at least one instance of Rsis optionally substituted C3-7 carbocyclyl.

[0271]

[0265] In certain embodiments, at least one instance of Rsis optionally substituted 3-7 membered heterocyclyl.

[0272]

[0266] In certain embodiments, at least one instance of Rsis optionally substituted Ci-6 acyl.

[0273]

[0267] In certain embodiments, at least one instance of Rsis an oxygen protecting group.

[0274]

[0268] As generally defined herein, each instance of Rcis independently H, halogen, Ci-6 alkyl, Ci-6 haloalkyl, C3-7 carbocyclyl, or 3-7 membered heterocyclyl, or two Rcare joined together with the intervening atoms to form C3-7 carbocyclyl or 3-7 membered heterocyclyl, wherein each alkyl, haloalkyl, carbocyclyl, or heterocyclyl is independently optionally substituted; or two Rcare taken together to form =0.

[0275]

[0269] In certain embodiments, at least one instance of Rcis H.

[0276]

[0270] In certain embodiments, at least one instance of Rcis halogen.

[0277]

[0271] In certain embodiments, at least one instance of Rcis optionally substituted Ci-6 alkyl. In certain embodiments, at least one instance of Rcis optionally substituted C1-3 alkyl. In certain embodiments, at least one instance of Rcis unsubstituted C1-3 alkyl.

[0278]

[0272] In certain embodiments, at least one instance of Rcis optionally substituted Ci-6 haloalkyl.

[0279]

[0273] In certain embodiments, at least one instance of Rcis optionally substituted C3-7 carbocyclyl.

[0280]

[0274] In certain embodiments, at least one instance of Rcis optionally substituted 3-7 membered heterocyclyl.

[0281]

[0275] In certain embodiments, two Rcare joined together with the intervening atoms to form C3-7 carbocyclyl or 3-7 membered heterocyclyl. In certain embodiments, two Rcare taken together to form =0. Pharmaceutical Compositions, Kits, and Administration

[0282]

[0276] The present disclosure provides pharmaceutical compositions comprising a compound provided herein (e.g., a compound of Formula (I), or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof) and one or more pharmaceutically acceptable carriers and / or excipients. In certain embodiments, a compound described herein is provided in an effective amount in the pharmaceutical composition. In certain embodiments, the effective amount is a therapeutically effective amount. In certain embodiments, the effective amount is a prophylactically effective amount.

[0283]

[0277] Pharmaceutical compositions described herein can be prepared by any method known in the art of pharmacology. In general, such preparatory methods include bringing the compound described herein (z.e., the “active ingredient”) into association with a carrier or excipient, and / or one or more other accessory ingredients, and then, if necessary and / or desirable, shaping, and / or packaging the product into a desired single- or multi-dose unit.

[0284]

[0278] Pharmaceutical compositions can be prepared, packaged, and / or sold in bulk, as a single unit dose, and / or as a plurality of single unit doses. A “unit dose” is a discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient. The amount of the active ingredient is generally equal to the dosage of the active ingredient which would be administered to a subject and / or a convenient fraction of such a dosage, such as one-half or one-third of such a dosage.

[0285]

[0279] Relative amounts of the active ingredient, the pharmaceutically acceptable carrier or excipient, and / or any additional ingredients in a pharmaceutical composition described herein will vary, depending upon the identity, size, and / or condition of the subject treated and further depending upon the route by which the composition is to be administered.

[0286]

[0280] Pharmaceutically acceptable carriers / excipients used in the manufacture of provided pharmaceutical compositions include inert diluents, solvents, dispersing and / or granulating agents, surface active agents and / or emulsifiers, disintegrating agents, binding agents, preservatives, buffering agents, lubricating agents, oils, butters, and / or waxes. Excipients such as coloring agents, coating agents, sweetening agents, flavoring agents, and fragrances may also be present in the composition.

[0287]

[0281] The compounds and compositions provided herein can be administered by any route, including enteral (e.g., oral), parenteral, intravenous, intramuscular, intra-arterial, intramedullary, intrathecal, subcutaneous, intraventricular, transdermal, intradermal, rectal, intravaginal, intraperitoneal, topical (as by powders, ointments, creams, and / or drops), mucosal, nasal, buccal, sublingual; by intratracheal instillation, bronchial instillation, and / or inhalation; and / or as an oral spray, nasal spray, and / or aerosol. Specifically contemplated routes are oral administration, intravenous administration (e.g., systemic intravenous injection), regional administration via blood and / or lymph supply, and / or direct administration to an affected site. In general, the most appropriate route of administration will depend upon a variety of factors including the nature of the agent (e.g., its stability in the environment of the gastrointestinal tract), and / or the condition of the subject (e.g., whether the subject is able to tolerate oral administration).

[0282] Although the descriptions of pharmaceutical compositions provided herein are principally directed to pharmaceutical compositions which are suitable for administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to animals of all sorts. Modification of pharmaceutical compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and / or perform such modification with ordinary experimentation.

[0288]

[0283] Compounds provided herein are typically formulated in dosage unit form for ease of administration and uniformity of dosage. It will be understood, however, that the total daily usage of the compositions described herein will be decided by a physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular subject or organism will depend upon a variety of factors including the disease being treated and the severity of the disorder; the activity of the specific active ingredient employed; the specific composition employed; the age, body weight, general health, sex, and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific active ingredient employed; the duration of the treatment; drugs used in combination or coincidental with the specific active ingredient employed; and like factors well known in the medical arts.

[0289]

[0284] The exact amount of a compound required to achieve an effective amount will vary from subject to subject, depending, for example, on species, age, and general condition of a subject, severity of the side effects or disorder, identity of the particular compound, mode of administration, and the like. An effective amount may be included in a single dose (e.g., single oral dose) or multiple doses (e.g., multiple oral doses). In certain embodiments, when multiple doses are administered to a subject or applied to a tissue or cell, any two doses of the multiple doses include different or substantially the same amounts of a compound described herein.

[0290]

[0285] A compound or composition, as described herein, can be administered in combination with one or more additional pharmaceutical agents (e.g., therapeutically and / or prophy tactically active agents). The compounds or compositions can be administered in combination with additional pharmaceutical agents that improve their activity (e.g., activity (e.g., potency and / or efficacy) in treating a disease in a subject in need thereof, in preventing a disease in a subject in need thereof, in reducing the risk to develop a disease in a subject in need thereof), improve bioavailability, improve safety, reduce drug resistance, reduce and / or modify metabolism, inhibit excretion, and / or modify distribution in a subject or cell. It will also be appreciated that the therapy employed may achieve a desired effect for the same disorder, and / or it may achieve different effects.

[0291]

[0286] Also encompassed by the disclosure are kits (e.g., pharmaceutical packs). The kits provided may comprise a pharmaceutical composition or compound described herein and a container (e.g., a vial, ampule, bottle, syringe, and / or dispenser package, or other suitable container). In some embodiments, provided kits may optionally further include a second container comprising a pharmaceutical excipient for dilution or suspension of a pharmaceutical composition or compound described herein. In some embodiments, the pharmaceutical composition or compound described herein provided in the first container and the second container are combined to form a single unit dosage form. Thus, in one aspect, provided are kits including a first container comprising a compound or pharmaceutical composition described herein. In certain embodiments, the kits are useful for treating and / or preventing a disease, disorder, or condition in a subject in need thereof.

[0292]

[0287] In certain embodiments, a kit described herein further includes instructions for using the kit. A kit described herein may also include information as required by a regulatory agency such as the U.S. Food and Drug Administration (FDA). In certain embodiments, the information included in the kits is prescribing information. In certain embodiments, the kits provide instructions for treating a disease (e.g., cancer) in a subject in need thereof. In certain embodiments, the kits provide instructions for preventing a disease in a subject in need thereof. A kit described herein may include one or more additional pharmaceutical agents described herein as a separate composition.

[0293] Methods of Treatment and Uses

[0294]

[0288] As described, compounds provided herein can inhibit transient receptor potential cation channel subfamily C (TRPC) activity (e.g., TRPC3 activity, TRPC6 activity) and are therefore useful in the treatment and / or prevention of diseases (e.g., Alzheimer’s disease).

[0295]

[0289] In one aspect, provided herein are methods of inhibiting TRPC (e.g., TRPC3, TRPC6) activity in a subject comprising administering to the subject an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition thereof. In certain embodiments, the method is for inhibiting TRPC3 activity. In certain embodiments, the method is for inhibiting TRPC6 activity.

[0296]

[0290] Also provided herein are compounds of Formula (I), and pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, isotopically labeled derivatives, and prodrugs thereof, and pharmaceutical compositions thereof, for use in inhibiting TRPC (e.g., TRPC3, TRPC6) activity in a subject. In certain embodiments, the TRPC activity is TRPC3 activity. In certain embodiments, the TRPC activity is TRPC6 activity.

[0297]

[0291] Also provided herein are uses of compounds of Formula (I), and pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, isotopically labeled derivatives, and prodrugs thereof, and pharmaceutical compositions thereof, in the manufacture of medicaments for inhibiting TRPC (e.g., TRPC3, TRPC6) activity. In certain embodiments, the TRPC activity is TRPC3 activity. In certain embodiments, the TRPC activity is TRPC6 activity.

[0298]

[0292] In another aspect, provided herein are methods of treating a disease associated with TRPC (e.g., TRPC3, TRPC6) activity in a subject in need thereof comprising administering to the subject a therapeutically effective amount of compound of Formula (I), or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition thereof. In certain embodiments, the disease is associated with TRPC3 activity (e.g., Alzheimer's disease). In certain embodiments, the disease is associated with TRPC6 activity.

[0299]

[0293] Also provided herein are compounds of Formula (I), and pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, isotopically labeled derivatives, and prodrugs thereof, and pharmaceutical compositions thereof, for use in treating a disease associated with TRPC (e.g., TRPC3, TRPC6) activity in a subject. In certain embodiments, the disease is associated with TRPC3 activity (e.g., Alzheimer's disease). In certain embodiments, the disease is associated with TRPC6 activity.

[0300]

[0294] Also provided herein are uses of compounds of Formula (I), and pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, isotopically labeled derivatives, and prodrugs thereof, and pharmaceutical compositions thereof, in the manufacture of medicaments for treating a disease associated with TRPC e.g., TRPC3, TRPC6) activity in a subject. In certain embodiments, the disease is associated with TRPC3 activity (e.g., Alzheimer's disease). In certain embodiments, the disease is associated with TRPC6 activity.

[0301]

[0295] In another aspect, provided herein are methods of preventing a disease associated with TRPC (e.g., TRPC3, TRPC6) activity in a subject in need thereof comprising administering to the subject a prophylactically effective amount of compound of Formula (I), or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition thereof. In certain embodiments, the disease is associated with TRPC3 activity (e.g., Alzheimer's disease). In certain embodiments, the disease is associated with TRPC6 activity.

[0302]

[0296] Also provided herein are compounds of Formula (I), and pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, isotopically labeled derivatives, and prodrugs thereof, and pharmaceutical compositions thereof, for use in preventing a disease associated with TRPC (e.g., TRPC3, TRPC6) activity in a subject. In certain embodiments, the disease is associated with TRPC3 activity (e.g., Alzheimer's disease). In certain embodiments, the disease is associated with TRPC6 activity.

[0303]

[0297] Also provided herein are uses of compounds of Formula (I), and pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, isotopically labeled derivatives, and prodrugs thereof, and pharmaceutical compositions thereof, in the manufacture of medicaments for preventing a disease associated with TRPC (e.g., TRPC3, TRPC6) activity in a subject. In certain embodiments, the disease is associated with TRPC3 activity (e.g., Alzheimer's disease). In certain embodiments, the disease is associated with TRPC6 activity.

[0304]

[0298] In another aspect, provided herein are methods of treating Alzheimer’s disease in a subject in need thereof comprising administering to the subject a therapeutically effective amount of compound of Formula (I), or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition thereof.

[0305]

[0299] Also provided herein are compounds of Formula (I), and pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, isotopically labeled derivatives, and prodrugs thereof, and pharmaceutical compositions thereof, for use in treating Alzheimer’s disease in a subject.

[0306]

[0300] Also provided herein are uses of compounds of Formula (I), and pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, isotopically labeled derivatives, and prodrugs thereof, and pharmaceutical compositions thereof, in the manufacture of medicaments for treating Alzheimer’s disease.

[0307]

[0301] In another aspect, provided herein are methods of preventing Alzheimer’s disease in a subject in need thereof comprising administering to the subject a prophylactically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition thereof.

[0308]

[0302] Also provided herein are compounds of Formula (I), and pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, isotopically labeled derivatives, and prodrugs thereof, and pharmaceutical compositions thereof, for use in preventing Alzheimer’s disease in a subject.

[0309]

[0303] Also provided herein are uses of compounds of Formula (I), and pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, isotopically labeled derivatives, and prodrugs thereof, and pharmaceutical compositions thereof, in the manufacture of medicaments for preventing Alzheimer’s disease.

[0310]

[0304] In another aspect, provided herein are methods comprising administering to a subject a compound of Formula (I), or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition thereof. In certain embodiments, the subject has or is at risk of having a disease associated with TRPC (e.g. , TRPC3, TRPC6 activity). In certain embodiments, the subject has or is at risk of having a disease associated with TRPC3 activity. In certain embodiments, the subject has or is at risk of having a disease associated with TRPC6 activity. In certain embodiments, the subject has or is at risk of having Alzheimer’s disease. In certain embodiments, the subject has been diagnosed with Alzheimer’s disease.

[0311]

[0305] Also provided herein are methods of inhibiting TRPC (.e.g., TRPC3, TRPC6) activity in vitro comprising contacting a TRPC protein with a compound of Formula (I), or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition thereof. In certain embodiments, the method is for inhibiting TRPC3 activity, and the TRPC protein is a TRPC3 protein. In certain embodiments, the method is for inhibiting TRPC6 activity, and the TRPC protein is a TRPC6 protein.

[0312] Alzheimer’s Disease

[0313]

[0306] In some aspects, the present disclosure provides methods and uses for treating and / or preventing Alzheimer’s disease (AD). Alzheimer’s disease is a disorder of the brain. Manifestations of AD include abnormal structure(s), function(s), or other process(es) in the brain. AD is the most common form of dementia, a term that encompasses memory loss and other intellectual abilities series enough to interfere with the activities of daily life.

[0314]

[0307] Management of AD includes maintaining quality of life, maximizing function in daily activities, enhancing cognition / mood / behavior, fostering a safe environment, and promoting social engagement. While there is no cure for AD to this point, medications and various management strategies are used to temporarily improve symptoms and to slow the progression of the disease. Medications that may be used are directed to cognitive enhancement (e.g., improving mental function, lowering blood pressure, and balancing mood), and include Donepezil, Galantamine, Memantine, and Rivastigmine. Any of the foregoing medications may be used in combination with a compound or composition provided herein.

[0308] AD results from changing brain chemistry, for example changes in neurons. As the disease progresses, neurons throughout the brain decrease in size and number of synaptic connections, and the resulting reduction in synaptic density is particularly detrimental to cognitive function. The population of neurons also decreases. AD is further characterized by a loss of synapses and neurons in the cerebral cortex and other areas of the brain, as well as the accumulation of extracellular protein-containing deposits (amyloid plaques) and neurofibrillary tangles (tau tangles). Plaques are dense deposits of betaamyloid peptide and cellular material located outside and around neurons. Tangles comprise aggregates of microtubule-associated tau protein. The tau protein becomes hyperphosphorylated and accumulates within the neurons themselves. The neurons impacted by the plaques and tangles then lose their respective synaptic connections with other neurons and may die. Thus, in some embodiments, neurons of the cerebral cortex are contacted with a compound or composition provided herein, for example, in an amount that reduces accumulation of beta-amyloid peptide and / or tau protein.

[0315]

[0309] Symptoms of AD include decreases in cognitive function, such as decreases in processing speed (e.g., speed at which cognitive activities are performed, speed of motor responses), attention (e.g., ability to concentrate and focus on specific stimuli), memory (e.g., episodic memory, semantic memory), visuospatial constructions, and executive functioning (e.g., the ability to engage in independent, appropriate, purposive behavior). Other symptoms of AD include behavioral changes (e.g., aggression, agitation, difficulty with self-care, irritability, personality changes, restlessness, lack of restrain, wandering, becoming lost), mood changes (e.g., anger, apathy, general discontent, loneliness, mood swings), psychological changes (e.g., depression, hallucinations, paranoia), as well as several miscellaneous symptoms, including the inability to combine muscle movements, jumbled speech, and loss of appetite. Risk factors for AD, in addition to age and heritability factors, may include diabetes, mid-life obesity, mid-life hypertension, hyperlipidemia, smoking status, diet, physical activity, alcohol consumption, cognitive training, social engagement, traumatic brain injury, depression, and lack of sleep.

[0316]

[0310] In some embodiments, a subject of the present disclosure exhibits one or more symptoms and / or risk factors of AD.

[0317]

[0311] Treatment of AD includes, in some embodiments, alleviating one or more symptoms of AD. Alleviation of AD refers to the process of making the symptoms of AD less intense and / or more bearable. Treatment of AD includes, in some embodiments, alleviating symptoms of cognitive decline. In some embodiments, a compound or composition is administered in an amount effective to alleviate one or more symptoms of AD. In some embodiments, a compound or composition is administered in an amount effective to slow or stop progression of AD.

[0318]

[0312] Working memory, the capacity to simultaneously manipulate information while maintaining other information, is impaired in subjects with AD. A number of different working memory tests are available and known in the art, for example, the complex span paradigm (Daneman, 1980) and its numerous variations. In some embodiments, a compound or composition is administered in an amount effective to improve working memory performance by at least 10% compared to the subject’s working memory performance prior to delivery of the agent (e.g., within 1 week to 3 months prior). In some embodiments, an agent improves working memory performance by at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 100% (e.g., by 10%- 100%), subject’s working memory performance prior to administration of the compound or composition.

[0319]

[0313] In some embodiments, a compound or composition improves working memory performance by at least 1.5-fold, at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 6-fold, at least 7-fold, at least 8-fold, at least 9-fold, at least 10-fold, at least 11-fold, at least 12-fold, at least 13-fold, at least 14-fold, at least 15-fold, at least 16-fold, at least 17-fold, at least 18-fold, at least 19-fold, or at least 20- fold (e.g., 1.5 fold- 20- fold), relative to the subject’s working memory performance prior to delivery of the agent.

[0320]

[0314] In some embodiments, an agent is delivered in an amount effective to reduce the amount of betaamyloid plaque by at least 40% compared to the amount of beta-amyloid plaque prior to administration of the agent. In some embodiments, an agent reduces the amount of beta-amyloid plaque by at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 100% (e.g., by 20%-100%), relative to the amount beta-amyloid plaque prior to administration of the compound or composition.

[0321]

[0315] In some embodiments, a compound or composition reduces the amount of beta-amyloid plaque in a subject by at least 1.5-fold, at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 6-fold, at least 7-fold, at least 8-fold, at least 9-fold, at least 10-fold, at least 11-fold, at least 12-fold, at least 13- fold, at least 14-fold, at least 15-fold, at least 16-fold, at least 17-fold, at least 18-fold, at least 19-fold, or at least 20-fold (e.g., 1.5 fold- 20-fold), relative to the amount beta-amyloid plaque prior to administration of the agent. For an example blood test to detect plaques in the brain, see, e.g., newscientist.com / article / 2141198-blood-test-detects-alzheimers-plaques-building-up-in-brain). Magnetic resonance imaging (MRI) may also be used.

[0322] EXAMPLES Synthesis of Compounds

[0323]

[0316] General methods. All temperatures are in degrees Celsius (°C) and are uncorrected. Reagent grade chemicals and anhydrous solvents were purchased from commercial sources and unless otherwise mentioned, were used without further purification. The names of the products were determined using the naming software included in the Biovia electronic lab notebook. Silica gel chromatography was performed on Teledyne Isco instruments using pre-packaged disposable SiO stationary phase columns with eluent flow-rate ranges of 15 to 200 mL / min, UV detection (254 and 280 nm). Reverse phase purification was carried out using Cl 8 columns, UV detection (214 and 254 nm). The analytical HPLC chromatograms were performed using an Agilent 1100 series instrument with DAD detector (190 nm to 300 nm). The mass spectra were recorded with a Waters Micromass ZQ detector at 130 °C. The mass spectrometer was equipped with an electrospray ion source (ESI) operated in a positive, or negative, ion mode and was set to scan between m / z 150-750 with a scan time of 0.3 s. Products and intermediates were analyzed by HPLC / MS on a Gemini-NX (5 pM, 2.0 x 30 mm) using a high pH buffer gradient of 5 % to 100 % of MeCN in H2O (0.03 % NH4HCO3 / 0.375 % NH4OH) over 2.5 min at 1.8 mL / min for a 3.5 min run (B05) and EVO C18 (5 pM, 3.0 x 50 mm) using a low pH buffer gradient of 5 % to 100 % of MeCN in H2O (0.1 % NH4HCO2) over 2.5 min at 2.2 mL / min for a 3.5 min run (A05), and by UPLC / MS on a BEH Cl 8 (1.7 pM, 2.1 x 50 mm) using a high pH buffer gradient of 5 % to 100 % of MeCN in H2O (10 mM NH4HCO3; pH 10) over 10 min at 0.7 mL / min (BEH_AmmBicarb) and BEH C18 (1.7 pM, 2.1 x 50 mm) using a low pH buffer gradient of 5 % to 100 % of MeCN in H2O (10 mM NH4HCO2; pH 4) over 10 min at 0.7 mL / min (BEH_AmmForm), unless otherwise specified. The ’H NMR spectra were recorded on a Varian AS 400 MHz / 54 mm instrument and a Bruker UltraShield 500 MHz / 54 mm instrument (BZH 43 / 500 / 70B, D221 / 54-3209), unless otherwise specified. The chemical shifts are reported in parts-per-million and are referenced to solvent peaks, which in ’H NMR appear at 7.26 ppm for CDCI3, 2.50 for DMSO- j, and 3.31 ppm for CD3OD.

[0324] Terms and abbreviations: degree Celsius;

[0325] A angstrom;

[0326] AcOH acetic acid;

[0327] AgNCL silver nitrate;

[0328] Ag2O silver(I) oxide; aq. aqueous; Boc tert-butyloxy carbonyl;

[0329] BOC2O di-tert-butyl decarbonate;

[0330] CC14carbon tetrachloride;

[0331] CDI 1 , 1 '-carbonyldiimidazole;

[0332] CHCL chloroform;

[0333] CS2CO3 cesium carbonate;

[0334] CuBr copper(I) bromide;

[0335] Cui copper(I) iodide;

[0336] Cu(MeCN)4BF4tetrakis(acetonitrile)copper(I) tetrafluoroborate;

[0337] CU(OAC)2 copper(II) acetate;

[0338] DCC AJV'-dicyclohexy Icarbodi im ide ;

[0339] DCE 1 ,2-dichloroethane;

[0340] DCM dichloromethane ;

[0341] DIAD diisopropyl azodicarboxylate;

[0342] DIPEA N.A iisopropylcthylaminc:

[0343] DMAP 4-dimethylaminopyridine;

[0344] DMEDA N.V-dimcthylcthylcncdiaminc:

[0345] DMF N.A i methyl formamide;

[0346] DMSO dimethyl sulfoxide;

[0347] ES electrospray;

[0348] Et2O diethyl ether;

[0349] EtOAc ethyl acetate;

[0350] EtOH ethanol; g gram(s); h hour(s);

[0351] H2hydrogen;

[0352] HATU 2-( IH-benzotriazol- 1-yl)- 1 , 1 ,3,3-tetramethyluronium hexafluorophosphate;

[0353] HC1 hydrochloride;

[0354] H2O water;

[0355] HPLC high performance liquid chromatography;

[0356] Hz hertz; zPrOH isopropanol; J J-coupling;

[0357] JohnPhos (2-biphenylyl)di-tert-butylphosphine;

[0358] K2CO3potassium carbonate;

[0359] KI potassium iodide;

[0360] K3PO4potassium phosphate tribasic;

[0361] L liter(s);

[0362] M molar; mCPBA 3-chloroperbenzoic acid;

[0363] Me methyl;

[0364] MeCN / ACN acetonitrile;

[0365] MeOH methanol;

[0366] MgSO4magnesium sulfate; min minute(s); MS mass spectrometry; N2nitrogen;

[0367] NaBH(OAc)3sodium triacetoxyborohydride;

[0368] NaH sodium hydride;

[0369] NaHCO3sodium bicarbonate;

[0370] Nal sodium iodide;

[0371] NaOH sodium hydroxide;

[0372] NaOtBu sodium tert-butoxide;

[0373] Na2SO4sodium sulfate;

[0374] Na2S2O3sodium thiosulfate;

[0375] NBS A-bromosuccinimide;

[0376] NH4C1 ammonium chloride; NH4HCO2ammonium formate; NH4HCO3ammonium bicarbonate; (NH4)S2O8ammonium persulfate;

[0377] NMO 4-methylmorpholine A-oxidc:

[0378] NMR nuclear magnetic resonance;

[0379] Pd / C palladium on carbon;

[0380] Pd(OAc)2palladium(II) acetate;

[0381] Pd(dppf)Cl2[1,1 '-bis(diphenylphosphino)ferrocene] dichloropalladium (II); Pd-PEPPSI-IPent [l,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3- chloropyridyl)dichloropalladium(II);

[0382] PhMe toluene;

[0383] PMB para-m ethoxy benzyl;

[0384] PPh3triphenylphosphine;

[0385] PS-PPh3polymer-bound triphenylphosphine;

[0386] RuPhos Pd G2 chloro(2-dicyclohexylphosphino-2',6'-diisopropoxy-l,l'-biphenyl)[2-(2'-amino-

[0387] 1 , 1 '-biphenyl)] palladium (II) ;

[0388] RuPhos Pd G3 (2-dicyclohexylphosphino-2',6'-diisopropoxy- 1 , 1 '-biphenyl) [2-(2'-amino- 1,1'- biphenyl)]palladium(II) methanesulfonate; sat. saturated;

[0389] Sc(OTf)3scandium (III) triflate;

[0390] T3P propanephosphonic acid anhydride;

[0391] TEA triethylamine;

[0392] TFA trifluoroacetic acid;

[0393] THF tetrahydrofuran;

[0394] TPAP tetrapropylammonium perruthenate;

[0395] TsCl tosyl chloride;

[0396] UPLC ultra performance liquid chromatography; wt.% percentage by weight;

[0397] Xantphos Pd G3 [(4,5-bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2'-amino- 1,1'- biphenyl)]palladium(II) methanesulfonate;

[0398] ZnCl2zinc chloride; Ex. 16, 2-(cyclopropylmethoxy )- V-|(3.S)- l-(3-tetrahy d ropy ran-4-yloxy phenyl )pyrrolidin-3- yl]acetamide

[0399] Step 1: 4-(3-bromophenoxy)tetrahydropyran

[0400]

[0317] DIAD (2.60 mL, 13.2 mmol) was added dropwise to a solution of 3-bromophenol (2.00 g, 11.6 mmol), tetrahydropyran-4-ol (1.20 mL, 12.6 mmol) and PPI13 (3.94 g, 15.0 mmol) in THF (60.0 mL) at 4 °C under nitrogen. The mixture was stirred at 4 °C for 2 h, then at 22 °C for 18 h. A solution of ZnCL (1.0 M in THF, 23.0 mL, 23.0 mmol) was added to the mixture at 22 °C and was stirred for 2 h. The mixture was filtered on filter paper, the cake was washed with diethyl ether (3 x 20.0 mL), and the filtrate was concentrated. The residue was purified by silica gel chromatography (80 g cartridge) with hexanes and EtOAc (0-15%) to provide the title compound as an oil (2.44 g, 66%). ’H NMR (500 MHz, CDCL) 5 7.16 - 7.11 (m, 1H), 7.10 - 7.06 (m, 2H), 6.86 - 6.82 (m, 1H), 4.52 - 4.42 (m, 1H), 4.01 - 3.94 (m, 2H), 3.62 - 3.56 (m, 2H), 2.05 - 1.98 (m, 2H), 1.82 - 1.74 (m, 2H).

[0401] Step 2: tert-butyl V-| (3.S)-l-(3-tetrahvd ropy ran-4-vloxy phenyl )pvrrolidin-3-vl |carbamate

[0402]

[0318] NaOtBu (359 mg, 3.73 mmol) was added to a mixture 4-(3-bromophenoxy)tetrahydropyran (500 mg, 1.56 mmol), tert-butyl A-[(35)-pyrrolidin-3-yl ]carbamate (348 mg, 1.87 mmol) and RuPhos Pd G3 (130 mg, 0.156 mmol) in 1,4-dioxane (7.80 mL) at 22 °C. The mixture was stirred at 100 °C for 24 h, cooled to 22 °C, and concentrated. The residue was purified by silica gel chromatography (40 g cartridge) with hexanes and EtOAc (0-50%) to provide the title compound as a solid (358 mg, 64%). ’H NMR (500 MHz, DMSO-< / 6) 57.16 (d, J = 6.9 Hz, 1H), 7.06 - 6.99 (m, 1H), 6.23 (dd, J = 8.1, 2.3 Hz, 1H), 6.09 (dd, J = 8.0, 2.2 Hz, 1H), 6.05 - 6.00 (m, 1H), 4.55 - 4.47 (m, 1H), 4.13 - 4.06 (m, 1H), 3.85 - 3.80 (m, 2H), 3.50 - 3.44 (m, 2H), 3.44 - 3.39 (m, 1H), 3.31 - 3.28 (m, 1H), 3.21 - 3.16 (m, 1H), 3.01 - 2.97 (m, 1H), 2.16 - 2.08 (m, 1H), 1.96 - 1.90 (m, 2H), 1.89 - 1.82 (m, 1H), 1.59 - 1.51 (m, 2H), 1.39 (s, 9H). m / z (ES+) [M+H]+363.3; HPLC (A05) tR= 2.50 min.

[0403] Step 3: (3S)-l-(3-tetrahydropyran-4-yloxyphenyl)pyrrolidin-3-amine

[0404]

[0319] TFA (2.00 mL) was added to a mixture of tert-butyl A-[(35)-l-(3-tetrahydropyran-4- yloxyphenyl)pyrrolidin-3-yl]carbamate (358 mg, 0.988 mmol) in DCM (2.00 mL) at 22 °C under nitrogen. The mixture was stirred at 22 °C for 1 h and diluted with sat. aq. NaHCCL (50.0 mL). The aqueous phase was extracted with DCM (3 x 25.0 mL), and the combined organic phases were washed with brine (25.0 mL), dried (Na2SOr), filtered, and concentrated to provide the title compound as an oil (252 mg, 97%). >H NMR (300 MHz, CDCL) 57.11 (dd, J= 8.1, 8.1 Hz, 1H), 6.26 (dd, J= 8.1, 2.3 Hz, 1H), 6.18 (dd, J= 8.1, 2.3 Hz, 1H), 6.12 (dd, J= 2.3, 2.3 Hz, 1H), 4.47 (tt, J = 7.9, 3.9 Hz, 1H), 3.99 (ddd, J= 11.6, 6.0, 3.9 Hz, 2H), 3.69 (p, J = 5.8 Hz, 1H), 3.63 - 3.38 (m, 5H), 3.31 (ddd, J = 9.3, 7.9, 6.0 Hz, 1H), 3.00 (dd, 7= 9.4, 4.7 Hz, 1H), 2.21 (ddt, 7= 12.0, 7.8, 6.0 Hz, 1H), 2.13 - 1.94 (m, 3H), 1.90 - 1.71 (m, 3H). m / z (ES+) [M+H]+= 263.37; HPLC (A05) tR= 1.85 min.

[0405] Step 4: 2-(cyclopropylmethoxy)-A-[(3S)-l-(3-tetrahydropyran-4-yloxyphenyl)pyrrolidin-3- yl]acetamide

[0406]

[0320] DIPEA (196 pL, 1.14 mmol) was added to mixture of 2-(cyclopropylmethoxy)acetic acid (52.1 mg, 0.400 mmol) and HATU (159 mg, 0.419 mmol) in DCM (3.00 mL) at 0 °C under nitrogen. After 5 min, a solution of (3S -l-(3-tetrahydropyran-4-yloxyphenyl)pyrrolidin-3-amine (100 mg, 0.381 mmol, in 1.00 mL of DCM) was added to the mixture, and it was stirred at 22 °C for 1 h, and concentrated. The residue was purified by silica gel chromatography (25 g cartridge) with hexanes and EtOAc (0-100%) and by reverse phase chromatography (Cl 8, 12 g cartridge) with water (10 mM NH4HCO3) and MeCN (5- 100%) to provide the title compound as a solid (108 mg, 76%). ’H NMR (400 MHz, DMSO-cL) 57.88 (d, J = 7.3 Hz, 1H), 7.03 (dd, J= 8.1, 8.1 Hz, 1H), 6.29 - 6.20 (m, 1H), 6.15 - 6.09 (m, 1H), 6.06 (dd, 7 = 2.3, 2.3 Hz, 1H), 4.56 - 4.47 (m, 1H), 4.47 - 4.36 (m, 1H), 3.87 (s, 2H), 3.83 (dt, J= 11.5, 4.4 Hz, 2H), 3.50 - 3.41 (m, 3H), 3.37 - 3.18 (m, 4H), 3.09 (dd, J = 9.7, 5.1 Hz, 1H), 2.23 - 2.10 (m, 1H), 2.05 - 1.86 (m, 3H), 1.64 - 1.47 (m, 2H), 1.09 - 0.95 (m, 1H), 0.51 - 0.41 (m, 2H), 0.25 - 0.07 (m, 2H). m z (ES+) [M+H]+= 375.23; UPLC (BEH AmmForm) 1R = 3.96 min.

[0407] Ex. 131, A-[(3S)-l-(3-benzyloxyphenyl)pyrrolidin-3-yl]-2-(cyclopropylmethoxy)acetamide

[0408] H N-Boc

[0409] Step 1: l-benzyloxy-3-bromo-benzene

[0410]

[0321] 3-Bromophenol (1.00 g, 5.78 mmol) was added to a mixture of K2CO3 (1.20 g, 8.67 mmol), KI (96.0 mg, 0.578 mmol) and benzyl bromide (0.687 mL, 5.78 mmol) in DMF (30 mL) at 22 °C under nitrogen. The mixture was stirred at 50 °C for 16 h and diluted with H2O (50.0 mL). The aqueous phase was extracted with EtOAc (3 x 50.0 mL), and the combined organic phases were washed with brine (50.0 mL), dried (MgSCL), filtered, and concentrated. The residue was purified by silica gel chromatography (40 g cartridge) with hexanes and EtOAc (0-20%) to provide the title compound as a solid (1.20 g, 75%). 'H NMR (400 MHz, DMSO-oU 5 7.49 - 7.37 (m, 4H), 7.37 - 7.30 (m, 1H), 7.26 - 7.19 (m, 2H), 7.13 (ddd, J= 8.0, 1.8, 0.9 Hz, 1H), 7.03 (ddd, J = 8.5, 2.5, 0.9 Hz, 1H), 5.13 (s, 2H). m / z (ES)+ [M+H]+= not observed; HPLC (A05) tR = 2.66 min.

[0411] Step 2: tert-butyl A-[(3S)-l-(3-benzyloxyphenyl)pyrrolidin-3-yl]carbamate

[0412] H N-Boc

[0322] tert-Butyl A-[(3>S -pyrrolidin-3-yl ]carbamate (255 mg, 1.37 mmol) was added to a mixture of 1- bromo-3-(trifluoromethoxy)benzene (300 mg, 1.14 mmol), RuPhos Pd G3 (95.4 mg, 0.114 mmol) and NaOtBu (274 mg, 2.85 mmol) in 1,4-dioxane (5.70 mL) at 22 °C under nitrogen. The mixture was stirred at 120 °C for 16 h and concentrated. The residue was purified by silica gel chromatography (40 g cartridge) with hexanes and EtOAc (0-20%) to provide the title compound as a solid (250 mg, 57%). m / z (ES)+[M+H]+= 369.3; HPLC (A05) tR= 2.71 min.

[0413] Step 3: (3S)-l-(3-benzyloxyphenyl)pyrrolidin-3-amine hydrochloride

[0414]

[0323] tert-Butyl A-[(3S)-l-(3-benzyloxyphenyl)pyrrolidin-3-yl]carbamate (250 mg, 0.678 mmol) was added to a mixture of HC1 (4.0 M solution in 1,4-dioxane, 1.70 mL, 6.78 mmol) in DCM (1.70 mL) at 22 °C under nitrogen. The mixture was stirred at 22 °C for 16 h and concentrated to provide the title compound as a solid (240 mg, >98%), which was used in the next step without further purification, m / z. (ES)+[M+H]+= 269.2; HPLC (A05) tR= 2.03 min.

[0415] Step 4: / V-| (3S)-l-(3-benzyloxy phenyl )pyrrolidin-3-yl]-2-(cyclopropylmethoxy (acetamide

[0416]

[0324] (35)-l-(3-Benzyloxyphenyl)pyrrolidin-3-amine hydrochloride (56.2 mg, 0.183 mmol) was added to a mixture of 2- (cyclopropylmethoxy) acetic acid (20.0 mg, 0.154 mmol), T3P (50 wt.% solution in EtOAc, 183 pL, 0.307 mmol) and TEA (85.7 pL, 0.615 mmol) in DMF (850 pL) at 22 °C under nitrogen. The mixture was stirred at 22 °C for 16 h and concentrated. The residue was purified by silica gel chromatography (4 g cartridge) with DCM and MeOH (0-10%), and by reverse phase chromatography (C18, 12 g cartridge) with water and MeCN (10-60%) to provide the title compound as a solid (9.40 mg, 16%). 'H NMR (400 MHz, DMSO-76) 57.84 (d, J = 7.3 Hz, 1H), 7.40 - 7.36 (m, 2H), 7.35 - 7.30 (m, 2H), 7.28 - 7.21 (m, 1H), 7.06 - 6.94 (m, 1H), 6.22 (d, 7= 7.9 Hz, 1H), 6.11 - 6.04 (m, 2H), 5.00 (s, 2H), 4.46 - 4.28 (m, 1H), 3.82 (s, 2H), 3.44 - 3.34 (m, 1H), 3.24 - 3.19 (m, 3H), 3.19 - 3.13 (m, 1H), 3.07 - 3.01 (m, 1H), 2.10 (s, 1H), 1.92 (d, J = 7.8 Hz, 1H), 1.02 - 0.92 (m, 1H), 0.40 (d, J = 7.6 Hz, 2H), 0.11 (d, J = 5.0 Hz, 2H). m / z (ES)+[M+H]+= 381.3; UPLC (BEH_AmmForm) tR= 5.17 min. Ex. 23, 2-(cydopropylmethoxy)-iV-[(3S)-l-[3-(4-methoxyphenoxy)phenyl]-3-piperidyl]acetamide

[0417] Step 1: tert-butyl iV-[(3S)-l-[3-(4-methoxyphenoxy )phenyl]-3-piperidyl] carbamate

[0418]

[0325] A mixture of tert-butyl A-[(35)-l-(3-bromophenyl)-3-piperidyl]carbamate (250 mg, 0.704 mmol), 4-methoxyphenol (105 mg, 0.844 mmol), Pd(OAc)2 (7.90 mg, 35.2 pmol), JohnPhos (21.0 mg, 70.4 pmol) and K3PO4 (299 mg, 1.41 mmol) in PhMe (6.00 mL) was stirred at 100 °C for 72 h under nitrogen. The mixture was cooled to 22 °C, filtered through Celite® with DCM (100 mL), and concentrated. The product was purified by silica gel chromatography (25 g cartridge) with hexanes and EtOAc (0-20%) to provide the title compound as an oil (163 mg, 58%). m / z (ES+) [M+H]+= 399.30; HPLC (A05) 1R = 2.63 min.

[0419] Step 2: (3S)-l-[3-(4-methoxyphenoxy)phenyl]piperidin-3-amine

[0420]

[0326] TFA (1.00 mL) was added to a mixture of tert-butyl A-[(35)-l-[3-(4-methoxyphenoxy)phenyl]-3- piperidyl] carbamate (163 mg, 0.409 mmol) in DCM (2.00 mL) at 22 °C under nitrogen. The mixture was stirred at 22 °C for 1 h and diluted with sat. aq. NaHCCL (50.0 mL). The aqueous phase was extracted with DCM (3 x 25.0 mL), and the combined organic phases were washed with brine (25.0 mL), dried (Na2SOr), filtered, and concentrated to provide the title compound as an oil (111 mg, 91%). m / z. (ES+) [M+H]+= 299.20; HPLC (A05) tR= 2.00 min.

[0421] Step 3: 2-(cyclopropylmethoxy)-iV-[(3S)-l-[3-(4-methoxyphenoxy)phenyl]-3-piperidyl]acetamide

[0422]

[0327] DIPEA (191 pL, 1.12 mmol) was added to mixture of 2-(cyclopropylmethoxy)acetic acid (50.8 mg, 0.391 mmol) and HATU (156 mg, 0.409 mmol) in DCM (3.00 mL) at 0 °C under nitrogen. After 5 min, (35)-l-[3-(4-methoxyphenoxy)phenyl]piperidin-3-amine (111 mg, 0.372 mmol) was added to the mixture, and it was stirred at 22 °C for 1 h and concentrated. The residue was purified by silica gel chromatography (25 g cartridge) with hexanes and EtOAc (0-100%) to provide the title compound as an oil (122 mg, 80%). *H NMR (400 MHz, DMSO L) 57.54 (d, J= 8.0 Hz, 1H), 7.13 (d, J= 8.2 Hz, 1H), 7.01 - 6.89 (m, 4H), 6.64 (ddd, J= 8.3, 2.4, 0.8 Hz, 1H), 6.50 (dd, 7= 2.3, 2.3 Hz, 1H), 6.22 (ddd, J = 8.1, 2.3, 0.8 Hz, 1H), 3.86 (s, 2H), 3.85 - 3.78 (m, 1H), 3.74 (s, 3H), 3.46 (dd, J= 12.1, 3.8 Hz, 1H), 3.45 - 3.37 (m, 1H), 3.28 (d, J= 6.9 Hz, 2H), 2.85 - 2.78 (m, 1H), 2.75 (dd, J= 12.1, 9.1 Hz, 1H), 1.80 - 1.66 (m, 2H), 1.59 - 1.46 (m, 2H), 1.09 - 0.95 (m, 1H), 0.50 - 0.40 (m, 2H), 0.21 - 0.13 (m, 2H). m / z (ES+) [M+H]+= 411.23; UPLC (BEH AmmForm) tR = 5.23 min.

[0423] Ex. 24, 2-(cyclopropylmethoxy )-Af-[(3S)-l-[3-(3-methoxyphenoxy )phenyl]-3-piperidyl]acetamide

[0424] Step 1: tert-butyl tV-[(3S)-l-[3-(3-methoxyphenoxy)phenyl]-3-piperidyl]carbamate

[0425]

[0328] A mixture of tert-butyl A-[(35)-l-(3-bromophenyl)-3-piperidyl]carbamate (250 mg, 0.704 mmol), 3 -methoxyphenol (92.7 pL, 0.844 mmol), Pd(OAc)2 (7.90 mg, 35.2 pmol), JohnPhos (21.0 mg, 70.4 pmol) and K3PO4 (299 mg, 1.41 mmol) in PhMe (6.00 mL) was stirred at 100 °C for 72 h under nitrogen. The mixture was cooled to 22 °C, filtered through Celite® with DCM (100 mL), and concentrated. The product was purified by silica gel chromatography (25 g cartridge) with hexanes and EtOAc (0-20%) to provide the title compound as an oil (186 mg, 66%). m / z (ES+) [M+H]+= 399.30; HPLC (A05) tR = 2.65 min.

[0426] Step 2: (3S)-l-[3-(3-methoxyphenoxy)phenyl]piperidin-3-amine

[0427]

[0329] TFA (1.00 mL) was added to a mixture of tert-butyl A-[(3>S -l-[3-(3-methoxyphenoxy)phenyl]-3- piperidyl] carbamate (186 mg, 0.467 mmol) in DCM (2.00 mL) at 22 °C under nitrogen. The mixture was stirred at 22 °C for 1 h and diluted with sat. aq. NaHCCh (50.0 mL). The aqueous phase was extracted with DCM (3 x 25.0 mL), and the combined organic phases were washed with brine (25.0 mL), dried (Na2SOr), filtered, and concentrated to provide the title compound as an oil (139 mg, >98%). m / z (ES+) [M+H]+= 299.20; HPLC (A05) tR= 2.02 min.

[0428] Step 3: 2-(cyclopropylmethoxy)-iV-[(3S)-l-[3-(3-methoxyphenoxy)phenyl]-3-piperidyl]acetamide

[0429]

[0330] DIPEA (239 pL, 1.40 mmol) was added to mixture of 2-(cyclopropylmethoxy)acetic acid (63.7 mg, 0.489 mmol) and HATU (195 mg, 0.512 mmol) in DCM (3.00 mL) at 0 °C under nitrogen. After 5 min, (3S)-l-[3-(3-methoxyphenoxy)phenyl]piperidin-3-amine (139 mg, 0.466 mmol) was added to the mixture, and it was stirred at 22 °C for 1 h and concentrated. The residue was purified by silica gel chromatography (25 g cartridge) with hexanes and EtOAc (0-100%) to provide the title compound as an oil (133 mg, 70%). *H NMR (400 MHz, DMSO-76) 5 7.55 (d, J= 7.9 Hz, 1H), 7.25 (dd, J= 8.2, 8.2 Hz, 1H), 7.18 (dd, J= 8.2, 8.2 Hz, 1H), 6.72 (ddd, J= 8.4, 2.4, 0.8 Hz, 1H), 6.68 (ddd, J= 8.3, 2.4, 0.8 Hz, 1H), 6.57 (t, J = 2.3 Hz, 1H), 6.55 (t, J = 2.3 Hz, 1H), 6.51 (ddd, J= 8.1, 2.3, 0.9 Hz, 1H), 6.35 (ddd, 7 = 8.1, 2.3, 0.8 Hz, 1H), 3.86 (s, 2H), 3.84 - 3.80 (m, 1H), 3.72 (s, 3H), 3.53 - 3.40 (m, 2H), 3.28 (d, J= 6.9 Hz, 2H), 2.87 - 2.79 (m, 1H), 2.76 (dd, 7= 12.2, 9.1 Hz, 1H), 1.80 - 1.67 (m, 2H), 1.60 - 1.47 (m, 2H), 1.09 - 0.95 (m, 1H), 0.50 - 0.39 (m, 2H), 0.21 - 0.13 (m, 2H). m / z (ES+) [M+H]+= 411.23; UPLC (BEH_AmmForm) tR= 5.33 min.

[0430] Ex. 3, 2-methoxy-Af-[(3S)-l-[3-[[6-(trifluoromethyl)-3-pyridyl]oxy]phenyl]pyrrolidin-3- yl]acetamide

[0431] Step 1: 2-methoxy-iV-[(3S)-l-[3-[[6-(trifluoromethyl)-3-pyridyl]oxy]phenyl]pyrrolidin-3- yl]acetamide

[0432]

[0331] DIPEA (254 pL, 1.48 mmol) was added to mixture of 2-methoxyacetic acid (39.9 pL, 0.520 mmol) and HATU (207 mg, 0.544 mmol) in DCM (6.00 mL) at 0 °C under nitrogen. After 5 min, (3.S')-I-|3-||6- (trifluoromethyl)-3-pyridyl]oxy]phenyl]pyrrolidin-3-amine hydrochloride (160 mg, 0.495 mmol) was added to the mixture, and it was stirred at 22 °C for 2 h and concentrated. The residue was purified by silica gel chromatography (25 g cartridge) with DCM and MeOH (0-10%), and by reverse phase chromatography (C18, 25 g cartridge) with water (10 mM NH4HCO3) and MeCN (5-100%) to provide the title compound as a solid (130 mg, 66%). ’H NMR (400 MHz, DMSO- e) 5 8.51 (d, J = 2.8 Hz, 1H), 8.06 (d, J = 7.4 Hz, 1H), 7.87 (d, J= 8.7 Hz, 1H), 7.48 (dd, J= 8.4, 2.5 Hz, 1H), 7.24 (dd, J= 8.1, 8.1 Hz, 1H), 6.47 - 6.40 (m, 1H), 6.37 (dd, J= 8.0, 1.6 Hz, 1H), 6.32 (dd, 7= 2.2, 2.2 Hz, 1H), 4.49 - 4.39 (m, 1H), 3.80 (s, 2H), 3.46 (dd, J = 9.9, 6.9 Hz, 1H), 3.39 - 3.35 (m, 1H), 3.29 (s, 3H), 3.27 - 3.21 (m, 1H), 3.11 (dd, 7 = 9.8, 5.2 Hz, 1H), 2.22 - 2.09 (m, 1H), 2.03 - 1.91 (m, 1H). m / z (ES+) [M+H]+= 396.15; UPLC (BEH AmmBicarb) tR= 4.49 min.

[0433] Ex. 47, 2-[(3-methyloxetan-3-yl)methoxy]-iV-[(3S)-l-[3-[[6-(trifluoromethyl)-3- pyridyl]oxy]phenyl]pyrrolidin-3-yl]acetamide

[0434] Step 1: 2-[(3-methyloxetan-3-yl)methoxy]-iV-[(3S)-l-[3-[[6-(trifluoromethyl)-3- pyridyl]oxy]phenyl]pyrrolidin-3-yl]acetamide

[0435]

[0332] DIPEA (278 pL, 1.63 mmol) was added to mixture of 2-[(3-methyloxetan-3-yl)methoxy]acetic acid (91.2 mg, 0.569 mmol) and HATU (227 mg, 0.596 mmol) in DCM (10.0 mL) at 0 °C under nitrogen. After 5 min, (3S -l-[3-[[6-(trifhioromethyl)-3-pyridyl]oxy]phenyl]pyrrolidin-3-amine hydrochloride (195 mg, 0.542 mmol) was added to the mixture, and it was stirred at 22 °C for 1 h and concentrated. The residue was purified by silica gel chromatography (25 g cartridge) with DCM and MeOH (0-10%), and by reverse phase chromatography (C18, 12 g cartridge) with water (10 mM NH4HCO3) and MeCN (5- 100%) to provide the title compound as a solid (132 mg, 52%). ’H NMR (400 MHz, DMSO-c / o) 58.50 (d, J = 2.8 Hz, 1H), 7.95 (d, J = 7.2 Hz, 1H), 7.87 (d, J= 8.7 Hz, 1H), 7.48 (dd, J= 8.4, 2.6 Hz, 1H), 7.24 (dd, J = 8.1, 8.1 Hz, 1H), 6.45 (dd, 7= 8.1, 1.9 Hz, 1H), 6.37 (dd, 7 = 7.9, 1.7 Hz, 1H), 6.33 (dd, 7 = 2.2, 2.2 Hz, 1H), 4.48 - 4.41 (m, 1H), 4.39 (d, 7 = 5.6 Hz, 2H), 4.19 (d, 7 = 5.4 Hz, 2H), 3.92 (s, 2H), 3.50 (s, 2H), 3.49 - 3.45 (m, 1H), 3.40 - 3.33 (m, 1H), 3.30 - 3.23 (m, 1H), 3.11 (dd, 7 = 9.9, 4.9 Hz, 1H), 2.24 - 2.13 (m, 1H), 2.01 - 1.90 (m, 1H), 1.23 (s, 3H). m / z (ES+) [M+H]+= 466.20; UPLC (BEH_AmmBicarb) tR = 4.65 min.

[0436] Ex. 48, 2-(oxetan-3-ylmethoxy)-iV-[(3S)-l-[3-[[6-(trifluoromethyl)-3-pyridyl]oxy]phenyl]pyrrolidin- 3-yl]acetamide

[0437] Step 1: 2-(oxetan-3-ylmethoxy)-Af-[(3S)-l-[3-[[6-(trifluoromethyl)-3-pyridyl]oxy]phenyl]pyrrolidin- 3-yl]acetamide

[0438]

[0333] DIPEA (293 pL, 1.71 mmol) was added to mixture of 2-(oxetan-3-ylmethoxy)acetic acid (87.4 mg, 0.598 mmol) and HATU (238 mg, 0.627 mmol) in DCM (10.0 mL) at 0 °C under nitrogen. After 5 min, (3S)-l-[3-[[6-(trifluoromethyl)-3-pyridyl]oxy]phenyl]pyrrolidin-3-amine hydrochloride (205 mg, 0.570 mmol) was added to the mixture, and it was stirred at 22 °C for 1 h and concentrated. The residue was purified by silica gel chromatography (25 g cartridge) with DCM and MeOH (0-10%), and by reverse phase chromatography (Cl 8, 12 g cartridge) with water (10 mM NH4HCO3) and MeCN (5-100%) to provide the title compound as a solid (92.3 mg, 36%). ’H NMR (400 MHz, DMSO-cL) 58.50 (d, J = 2.8 Hz, 1H), 7.98 (d, 7 = 7.3 Hz, 1H), 7.87 (d, J= 8.7 Hz, 1H), 7.52 - 7.44 (m, 1H), 7.24 (dd, J= 8.1, 8.1 Hz, 1H), 6.45 (dd, J= 8.0, 1.9 Hz, 1H), 6.37 (dd, J= 7.9, 1.6 Hz, 1H), 6.33 (dd, J= 2.2, 2.2 Hz, 1H), 4.62 (d, J = 6.0 Hz, 1H), 4.60 (d, J = 6.0 Hz, 1H), 4.50 - 4.37 (m, 1H), 4.32 - 4.28 (m, 2H), 3.88 (s, 2H), 3.66 (d, 7= 6.8 Hz, 2H), 3.47 (dd, 7 = 9.9, 6.8 Hz, 1H), 3.39 - 3.34 (m, 1H), 3.29 - 3.24 (m, 1H), 3.21 - 3.13 (m, 1H), 3.11 (dd, 7= 10.0, 5.1 Hz, 1H), 2.24 - 2.11 (m, 1H), 2.02 - 1.89 (m, 1H). m / z (ES+) [M+H]+= 452.18; UPLC (BEH AmmBicarb) tR= 4.78 min.

[0439] Ex. 49, 2-(2-cyano-2-methyl-propoxy )-Af-[(3S)-l-[3-[[6-(trifluoromethyl)-3- pyridyl]oxy]phenyl]pyrrolidin-3-yl]acetamide

[0440] Step 1 : 2-(2-cyano-2-methyl-propoxy)-iV-[(3S)- 1- [3- [[6-(trifluoromethyl)-3- pyridyl]oxy]phenyl]pyrrolidin-3-yl]acetamide

[0441]

[0334] 3-Hydroxy-2,2-dimethyl-propanenitrile (20.1 mg, 0.203 mmol) was added to a mixture of NaH (60% dispersion in mineral oil, 8.54 mg, 0.223 mmol) in THF (1.00 mL) at 0 °C under nitrogen, and the mixture was stirred for 30 min. 2-Bromo-A-[(35)-l-[3-[[6-(trifluoromethyl)-3- pyridyl]oxy]phenyl]pyrrolidin-3-yl]acetamide (100 mg, 0.203 mmol) in THF (1.00 mL) and KI (3.36 mg, 20.3 pmol) were added to the mixture, and it was stirred at 22 °C for 18 h. The mixture was diluted with water (20.0 mL). The aqueous phase was extracted with EtOAc (3 x 50.0 mL), and the combined organic phases were washed with brine (25.0 mL), dried (MgSCL), filtered, and concentrated. The residue was purified by silica gel chromatography (4 g cartridge) with DCM and MeOH (0-10%), and by reverse phase chromatography (Cl 8, 12 g cartridge) with water and MeCN (10-100%) to provide the title compound as a solid (22.9 mg, 24%). >H NMR (400 MHz, DMSO-76) 5 8.50 (d, J = 2.8 Hz, 1H), 7.94 (d, 7 = 7.2 Hz, 1H), 7.87 (d, J= 8.7 Hz, 1H), 7.48 (dd, J= 8.6, 2.8 Hz, 1H), 7.24 (dd, 7= 8.1, 8.1 Hz, 1H), 6.49 - 6.41 (m, 1H), 6.41 - 6.35 (m, 1H), 6.33 (dd, 7 = 2.3, 2.3 Hz, 1H), 4.49 - 4.37 (m, 1H), 3.98 (s, 2H), 3.52 - 3.46 (m, 3H), 3.40 - 3.33 (m, 1H), 3.28 - 3.23 (m, 1H), 3.11 (dd, 7 = 9.9, 4.8 Hz, 1H), 2.25 - 2.13 (m, 1H), 1.99 - 1.90 (m, 1H), 1.29 - 1.28 (m, 6H). m / z (ES)+[M+H]+= 463.3; UPLC (BEH_AmmBicarb) tR = 5.05 min.

[0442] Ex. 50, 2-(tetrahydropyran-4-ylmethoxy)-iV-[(3S)-l-[3-[[6-(trifluoromethyl)-3- pyridyl]oxy]phenyl]pyrrolidin-3-yl]acetamide

[0443] Step 1: 2-(tetrahydropyran-4-ylmethoxy)-Af-[(3S)-l-[3-[[6-(trifluoromethyl)-3- pyridyl]oxy]phenyl]pyrrolidin-3-yl]acetamide

[0444]

[0335] Tetrahydropyran-4-ylmethanol (23.5 mg, 0.203 mmol) was added to a mixture of NaH (60% dispersion in mineral oil, 8.54 mg, 0.223 mmol) in THF (1.00 mL) at 0 °C under nitrogen, and the mixture was stirred for 30 min. 2-Bromo-A-[(35)-l-[3-[[6-(trifluoromethyl)-3- pyridyl]oxy]phenyl]pyrrolidin-3-yl]acetamide (100 mg, 0.203 mmol) in THF (1.00 mL) and KI (3.36 mg, 20.3 pmol) were added to the mixture, and it was stirred at 22 °C for 18 h. The mixture was diluted with water (20.0 mL). The aqueous phase was extracted with EtOAc (3 x 50.0 mL), and the combined organic phases were washed with brine (25.0 mL), dried (MgSCL), filtered, and concentrated. The residue was purified by silica gel chromatography (4 g cartridge) with DCM and MeOH (0-10%), by reverse phase chromatography (Cl 8, 12 g cartridge) with water and MeCN (10-100%), and by preparative HPLC (BEH, C18) with water (10 mM NH4HCO3) and MeCN (55-65%) to provide the title compound as a solid (7 mg, 7%). >H NMR (400 MHz, DMSO-76) 5 8.46 (d, J= 2.8 Hz, 1H), 7.85 - 7.78 (m, 2H), 7.49 - 7.42 (m, 1H), 7.20 (dd, J= 8.1, 8.1 Hz, 1H), 6.44 - 6.38 (m, 1H), 6.33 (ddd, J= 8.0, 2.3, 0.8 Hz, 1H), 6.27-6.29 (m, 1H), 4.44 - 4.34 (m, 1H), 3.80 (s, 2H), 3.79 - 3.73 (m, 2H), 3.43 (dd, J= 9.9, 6.7 Hz, 1H), 3.36 - 3.29 (m, 2H), 3.24 - 3.17 (m, 4H), 3.08 (dd, J = 9.9, 5.1 Hz, 1H), 2.18 - 2.08 (m, 1H), 1.97 - 1.88 (m, 1H), 1.82 - 1.68 (m, 1H), 1.56 - 1.46 (m, 2H), 1.19 - 1.05 (m, 2H). m / z (ES)+[M+H]+= 480.3;

[0445] UPLC (BEH_AmmBicarb) tR= 4.81 min.

[0446] Ex. 51, 2-(cyclopropylmethoxy)-Af-[(3R ,4S)-4-methoxy-l-[3-[[6-(trifluoromethyl)-3- pyridyl]oxy]phenyl]pyrrolidin-3-yl]acetamide

[0447] Step 1 : tert-butyl V-| (3 / ?,4.S )-4-H ydroxy- 1 -[ 3-| | 6-( trifhioroniethvl )-3-pyridyl ]oxy ] phenyl ] pyrrolidin- 3-yl]carbamate

[0448]

[0336] tert-Butyl N-[(3R.4S )-4-hydroxypyrrolidin-3-yl ]carbamatc (229 mg, 0.904 mmol) was added to a mixture of 5-(3-iodophenoxy)-2-(trifluoromethyl)pyridine (300 mg, 0.822 mmol), RuPhos Pd G3 (68.8 mg, 82.2 pmol) and Cs2CO3(669 mg, 2.05 mmol) in 1,4-dioxane (5.50 mL) at 22 °C under nitrogen. The mixture was stirred at 120 °C for 30 min and concentrated. The residue was purified by silica gel chromatography (12 g cartridge) with hexanes and EtOAc (0-60%) to provide the title compound as a solid (270 mg, 75%).1H NMR (300 MHz, DMSO-76) 5 8.51 (d, J= 2.8 Hz, 1H), 7.86 (d, J= 8.7 Hz, 1H), 7.48 (dd, J= 8.6, 2.8 Hz, 1H), 7.23 (dd, J= 8.1, 8.1 Hz, 1H), 6.55 (d, J = 7.8 Hz, 1H), 6.37 (dd, J = 14.1, 8.1 Hz, 2H), 6.27 (s, 1H), 5.21 (d, 7= 4.2 Hz, 1H), 4.22 (s, 1H), 4.11 - 4.05 (m, 1H), 3.45 (d, J = 7.5 Hz, 2H), 3.16 (d, J= 10.5 Hz, 1H), 3.07 (t, J = 9.0 Hz, 1H), 1.40 (s, 9H). m / z (ES)+[M+H]+= 440.3; HPLC (A05) tR= 2.48 min.

[0449] Step 2: tert-butyl N -[(3R ,4S)-4-methoxy-l-[3-[[6-(trifluoromethyl)-3-pyridyl]oxy ] phenyl] pyrrolidin- 3-yl]carbamate

[0337] lodomethane (142 pL, 2.28 mmol) was added to mixture of tert-butyl A-[(3R,45)-4-hydroxy-l-[3- [[6-(trifluoromethyl)-3-pyridyl]oxy]phenyl]pyrrolidin-3-yl]carbamate (100 mg, 0.228 mmol) and Ag2O (264 mg, 1.14 mmol) in MeCN (2.30 mL) at 22 °C under nitrogen. The mixture was stirred at 22 °C for 16 h and concentrated. The residue was purified by silica gel chromatography (12 g cartridge) with hexanes and EtOAc (0-40%) to provide the title compound as a solid (80.0 mg, 78%). ’H NMR (300 MHz, DMSO- e) 5 8.51 (d, J = 2.8 Hz, 1H), 7.86 (d, J= 8.7 Hz, 1H), 7.48 (dd, J= 8.7, 2.9 Hz, 1H), 7.24 (dd, J= 8.1, 8.1 Hz, 1H), 6.81 (d, J= 8.1 Hz, 1H), 6.45 - 6.34 (m, 2H), 6.30 (d, J= 2.3 Hz, 1H), 4.20 (s, 1H), 3.94 (d, J= 4.2 Hz, 1H), 3.49 - 3.39 (m, 1H), 3.39 - 3.35 (m, 2H), 3.30 (s, 3H), 3.11 - 3.02 (m, 1H), 1.40 (s, 9H). m / z (ES)+[M+H]+= 454.3; HPLC (A05) tR= 2.63 min.

[0450] Step 3: (31f,4S)-4-methoxy-l-[3-[[6-(trifluoromethyl)-3-pyridyl]oxy]phenyl]pyrrolidin-3-amine

[0451]

[0338] TFA (118 pL, 1.59 mmol) was added to a mixture of tert-butyl A-[(3R,45)-4-methoxy-l-[3-[[6- (trifluoromethyl)-3-pyridyl]oxy]phenyl]pyrrolidin-3-yl]carbamate (80.0 mg, 0.159 mmol) in DCM (1.00 mL) at 22 °C under nitrogen. The mixture was stirred at 22 °C for 18 h and diluted with sat. aq. NaHCCh (20.0 mL). The aqueous phase was extracted with DCM (3 x 50.0 mL), and the combined organic phases were washed with brine (25.0 mL), dried (MgSCL), filtered, and concentrated. The residue was purified by silica gel chromatography (12 g cartridge) with MeOH and DCM (0-10%) to provide the title compound as an oil (42.0 mg, 75%). m / z (ES)+[M+H]+= 354.3; HPLC (A05) 1R = 2.00 min.

[0452] Step 4: 2-(cyclopropylmethoxy)-Af-[(31f,4S)-4-methoxy-l-[3-[[6-(trifluoromethyl)-3- pyridyl]oxy]phenyl]pyrrolidin-3-yl]acetamide

[0453]

[0339] (3R,45)-4-Methoxy-l-[3-[[6-(trifluoromethyl)-3-pyridyl]oxy]phenyl]pyrrolidin-3-amine (42 mg, 0.119 mmol) was added to a mixture of 2-(cyclopropylmethoxy)acetic acid (17.0 mg, 0.131 mmol), T3P (50 wt.% solution in EtOAc, 141 pL, 0.238 mmol) and TEA (66.3 pL, 0.475 mmol) in DMF (1.00 mL) at 22 °C under nitrogen. The mixture was stirred at 22 °C for 16 h and concentrated. The residue was purified by silica gel chromatography (4 g cartridge) with DCM and MeOH (0-10%), and by reverse phase chromatography (Cl 8, 12 g cartridge) with water and MeCN (10-100%) to provide the title compound as a solid (18.7 mg, 34%). >H NMR (400 MHz, DMSO-76) 5 8.51 (d, J = 2.8 Hz, 1H), 7.87 (dd, 7= 8.8, 0.7 Hz, 1H), 7.54 - 7.43 (m, 2H), 7.25 (dd, J= 8.1, 8.1 Hz, 1H), 6.45 (ddd, J= 8.3, 2.3, 0.9 Hz, 1H), 6.38 (ddd, 7 = 8.0, 2.3, 0.8 Hz, 1H), 6.34 (dd, 7 = 2.3, 2.3 Hz, 1H), 4.57 - 4.46 (m, 1H), 4.04 - 3.98 (m, 1H), 3.92 (d, 7= 1.3 Hz, 2H), 3.55 - 3.49 (m, 1H), 3.43 - 3.40 (m, 2H), 3.31 - 3.28 (m, 5H), 3.09 (dd, 7 = 9.4, 7.8 Hz, 1H), 1.08 - 0.97 (m, 1H), 0.52 - 0.44 (m, 2H), 0.23 - 0.16 (m, 2H). m / z (ES)+[M+H]+= 466.3; UPLC (BEH AmmBicarb) 1R = 5.35 min.

[0454] Ex. 4, 2-te / t-butoxy-iV-[(35)-l-[3-[[6-(trifluoromethyl)-3-pyridyl]oxy ]phenyl]pyrrolidin-3- yl]acetamide

[0455] Step 1: 2-te / 7-butoxy-iV-[(35)-l-[3-[[6-(trifluoromethyl)-3-pyridyl]oxy]phenyl]pyrrolidin-3- yl]acetamide

[0456]

[0340] DIPEA (254 pL, 1.48 mmol) was added to mixture of 2-tert-butoxyacetic acid (67.6 pL, 0.520 mmol) and HATU (207 mg, 0.544 mmol) in DCM (6.00 mL) at 0 °C under nitrogen. After 5 min, (35)- 1- [3-[[6-(trifluoromethyl)-3-pyridyl]oxy]phenyl]pyrrolidin-3-amine hydrochloride (160 mg, 0.495 mmol) was added to the mixture, and it was stirred at 22 °C for 2 h and concentrated. The residue was purified by silica gel chromatography (25 g cartridge) with DCM and MeOH (0-10%), and by reverse phase chromatography (C18, 12 g cartridge) with water (10 mM NH4HCO3) and MeCN (5-100%) to provide the title compound as a solid (97 mg, 45%). ’H NMR (400 MHz, DMSO-cL) 5 8.50 (d, J= 2.8 Hz, 1H), 7.87 (dd, J= 8.7, 0.7 Hz, 1H), 7.64 (d, 7= 7.5 Hz, 1H), 7.52 - 7.44 (m, 1H), 7.24 (dd, J= 8.1, 8.1 Hz, 1H), 6.46 (ddd, J= 8.4, 2.4, 0.9 Hz, 1H), 6.37 (ddd, J= 8.0, 2.3, 0.8 Hz, 1H), 6.35 - 6.30 (m, 1H), 4.51 - 4.40 (m, 1H), 3.77 (s, 2H), 3.46 (dd, J = 9.8, 7.0 Hz, 1H), 3.42 - 3.31 (m, 1H), 3.27 - 3.22 (m, 1H), 3.13 (dd, 7 = 9.8, 5.6 Hz, 1H), 2.17 (dq, 7= 12.5, 6.6 Hz, 1H), 2.04 - 1.93 (m, 1H), 1.15 (s, 9H). m / z (ES+) [M+H]+= 438.20; UPLC (BEH AmmBicarb) 1R = 5.41 min.

[0457] Ex. 53, 2-ethoxy-iV-[(35)-l-[3-[[6-(trifluoromethyl)-3-pyridyl]oxy]phenyl]pyrrolidin-3-yl]acetamide

[0458] Step 1: 2-ethoxy-iV-[(3S)-l-[3-[[6-(trifluoromethyl)-3-pyridyl]oxy]phenyl]pyrrolidin-3-yl]acetamide

[0459]

[0341] DIPEA (254 pL, 1.48 mmol) was added to mixture of 2-ethoxyacetic acid (52.3 pL, 0.520 mmol) and HATU (207 mg, 0.544 mmol) in DCM (6.00 mL) at 0 °C under nitrogen. After 5 min, (3.S')- I -|3-| |6- (trifluoromethyl)-3-pyridyl]oxy]phenyl]pyrrolidin-3-amine hydrochloride (160 mg, 0.495 mmol) was added to the mixture, and it was stirred at 22 °C for 2 h and concentrated. The residue was purified by silica gel chromatography (25 g cartridge) with DCM and MeOH (0-10%), and by reverse phase chromatography (C18, 25 g cartridge) with water (10 mM NH4HCO3) and MeCN (5-100%) to provide the title compound as a solid (136 mg, 67%). ’H NMR (400 MHz, DMSO- e) 5 8.51 (d, J = 2.8 Hz, 1H), 7.97 (d, J = 7.3 Hz, 1H), 7.87 (d, J = 8.7 Hz, 1H), 7.48 (dd, J= 8.4, 2.5 Hz, 1H), 7.24 (dd, J= 8.1, 8.1 Hz, 1H), 6.44 (dd, 7 = 8.0, 2.0 Hz, 1H), 6.37 (dd, J= 7.9, 1.6 Hz, 1H), 6.33 (dd, J= 2.2, 2.2 Hz, 1H), 4.50 - 4.38 (m, 1H), 3.83 (s, 2H), 3.52 - 3.42 (m, 3H), 3.40 - 3.35 (m, 1H), 3.29 - 3.21 (m, 1H), 3.11 (dd, J = 9.9, 5.3 Hz, 1H), 2.22 - 2.10 (m, 1H), 2.03 - 1.91 (m, 1H), 1.13 (t, J = 7.0 Hz, 3H). m / z (ES+) [M+H]+= 410.17; UPLC (BEH AmmBicarb) 1R = 4.82 min.

[0460] Ex. 31, 2-methoxy-iV-[(3S)-l-[3-[5-(trifluoromethyl)pyrazin-2-yl]oxyphenyl]pyrrolidin-3- yl]acetamide

[0461] Step 1: l-benzyloxy-3-iodo-benzene

[0462]

[0342] Benzyl bromide (1.19 mL, 10.0 mmol) was added to a mixture of 3-iodophenol (1.00 mL, 9.09 mmol), CS2CO3 (3.55 g, 10.9 mmol) in DMF (45.0 mL) at 22 °C under nitrogen. The mixture was stirred at 100 °C for 16 h and concentrated. The residue was purified by silica gel chromatography (40 g cartridge) with hexanes and EtOAc (0-15%) to provide the title compound as an oil (1.40 g, 50%). ’H NMR (300 MHz, DMSO- / (1) 5 7.48 - 7.25 (m, 7H), 7.13 - 6.97 (m, 2H), 5.10 (s, 2H).

[0463] Step 2: tert-butyl iV-[(3S)-l-(3-benzyloxyphenyl)pyrrolidin-3-yl]carbamate

[0464]

[0343] tert-Butyl A-[(35)-pyrrolidin-3-yl ]carbamate (1.26 g, 5.42 mmol) was added to a mixture of 1- benzyloxy-3-iodo-benzene (1.40 g, 4.51 mmol), RuPhos Pd G3 (378 mg, 0.452 mmol) and CS2CO3 (3.68 g, 11.3 mmol) in 1,4-dioxane (23 mL) at 22 °C under nitrogen. The mixture was stirred at 120 °C for 30 min and concentrated. The residue was purified by silica gel chromatography (40 g cartridge) with hexanes and EtOAc (0-60%) to provide the title compound as a solid (1.54 g, 93%). m / z (ES)+[M+H]+= 369.3; HPLC (A05) tR= 2.82 min.

[0465] Step 3: (3S)-l-(3-benzyloxyphenyl)pyrrolidin-3-amine

[0466]

[0344] tert-Butyl N-[(3S)- l-(3-benzyloxyphenyl)pyrrolidin-3-yl ]carbamate (1.54 g, 4.18 mmol) was added to a mixture of TFA (3.10 mL, 41.8 mmol) in DCM (30.0 mL) at 22 °C under nitrogen. The mixture was stirred at 22 °C for 16 h and diluted with sat. aq. NaHCOi (50.0 mL). The aqueous phase was washed with DCM (3 x 25.0 mL). The combined organic phases were washed with brine (25.0 mL), dried (MgSCh), filtered, and concentrated to provide the title compound as an oil (1.12 g, >98%). m / z. (ES)+[M+H]+= 269.3; HPLC (A05) tR= 2.16 min.

[0467] Step 4: A-[(3S)-l-(3-benzyloxyphenyl)pyrrolidin-3-yl]-2-methoxy-acetamide

[0468]

[0345] DIPEA (2.14 mL, 12.5 mmol) was added to mixture of 2-methoxyacetic acid (456 mg, 5.06 mmol) and HATU (1.75 g, 4.60 mmol) in DCM (30.0 mL) at 22 °C under nitrogen. After 5 min, (35)-l-[3-[[6- (trifluoromethyl)-3-pyridyl]oxy]phenyl]pyrrolidin-3-amine (1.12 g, 4.17 mmol) was added to the mixture, and it was stirred at 22 °C for 1 h and concentrated. The residue was purified by silica gel chromatography (40 g cartridge) with DCM and MeOH (0-10%) to provide the title compound as an oil (1.49 g, 96%). m / z (ES)+[M+H]+= 342.3; HPLC (A05) tR= 2.60 min.

[0469] Step 5: A-[(3S)-l-(3-hydroxyphenyl)pyrrolidin-3-yl]-2-methoxy-acetamide

[0470]

[0346] A-[(35)-l-(3-benzyloxyphenyl)pyrrolidin-3-yl]-2-ethoxy-acetamide (1.49 g, 4.20 mmol) was added to a mixture of Pd / C (10 wt.%, 671 mg, 0.631 mmol) in EtOAc (21.0 mL) and MeOH (21.0 mL) at 22 °C under nitrogen. The mixture was stirred at 22 °C for 48 h under H2. The mixture was filtered through Celite® washing with EtOAc (3 x 50.0 mL). The filtrate was concentrated, and the residue was purified by silica gel chromatography (40 g cartridge) with hexanes and EtOAc (0-100%) to provide the title compound as an oil (270 mg, 25%). ’H NMR (300 MHz, DMSO-t / e) 5 8.97 (s, 1H), 7.98 (d, J= 7.3 Hz, 1H), 6.92 (dd, J = 8.0, 8.0 Hz, 1H), 6.08 - 5.94 (m, 2H), 5.92 (s, 1H), 4.47 - 4.35 (m, 1H), 3.80 (s, 2H), 3.40 (dd, J = 9.5, 6.8 Hz, 1H), 3.26 - 3.13 (m, 2H), 3.05 (dd, J = 9.5, 5.2 Hz, 1H), 2.69 (s, 3H), 2.26 - 2.08 (m, 1H), 1.97 - 1.88 (m, 1H), 1.28 - 1.21 (m, 1H). m / z (ES)+[M+H]+= 251.2; HPLC (A05) tR= 2.14 min.

[0471] Step : 2-methoxy- N- [(3S)- 1 - [3- [5-(trifluoromethyl)pyrazin-2-yl]oxyphenyl] pyrrolidin-3- yl]acetamide

[0472]

[0347] lV-[(3S)-l-(3-Hydroxyphenyl)pyrrolidin-3-yl]-2-methoxy-acetamide (40.0 mg, 160 mmol) was added to a mixture of 2-chloro-5-(trifluoromethyl)pyrazine (32.1 mg, 0.176 mmol) and CS2CO3 (57.3 mg, 0.176 mmol) in DMF (2.00 mL) at 22 °C under nitrogen. The mixture was stirred at 90 °C for 2 h and diluted with water (20.0 mL). The aqueous phase was extracted with DCM (3 x 25.0 mL), and the combined organic phases were washed with brine (25.0 mL), dried (Na2SOr), filtered, and concentrated. The residue was purified by silica gel chromatography (25 g cartridge) with DCM and MeOH (0-10%), and by reverse phase chromatography (C18, 12 g cartridge) with water (10 rnM NH4HCO3) and MeOH (5-100%) to provide the title compound as a solid (13.3 mg, 21%). ’H NMR (400 MHz, DMSO-<L 5 8.72 (s, 1H), 8.65 (s, 1H), 8.07 (d, J = 7.5 Hz, 1H), 7.23 (dd, J= 8.1, 8.1 Hz, 1H), 6.49 - 6.41 (m, 2H), 6.40 (dd, J = 2.2, 2.2 Hz, 1H), 4.49 - 4.37 (m, 1H), 3.80 (s, 2H), 3.45 (dd, J = 9.8, 6.7 Hz, 1H), 3.35 (s, 1H), 3.29 (s, 3H), 3.27 - 3.20 (m, 1H), 3.10 (dd, J = 9.5, 5.2 Hz, 1H), 2.22 - 2.09 (m, 1H), 2.04 - 1.91 (m, 1H). m / z (ES+) [M+H]+= 397.15; UPLC (BEH_AmmBicarb) 1R = 4.33 min.

[0473] Ex. 32, 2-methoxy-Af-[(3S)-l-[3-[6-(trifluoromethyl)pyridazin-3-yl]oxyphenyl ]pyrrolidin-3- yl]acetamide

[0474] Step 1 : 2-methoxy-Af-[(3S)-l-[3-[6-(trifluoromethyl)pyridazin-3-yl]oxyphenyl]pyrrolidin-3- yl]acetamide

[0475]

[0348] lV-[(3S)-l-(3-Hydroxyphenyl)pyrrolidin-3-yl]-2-methoxy-acetamide (40.0 mg, 0.160 mmol) was added to a mixture of 3-chloro-6-(trifluoromethyl)pyridazine (32.1 mg, 0.176 mmol) and CS2CO3 (57.3 mg, 0.176 mmol) in DMF (2.00 mL) at 22 °C under nitrogen. The mixture was stirred at 90 °C for 2 h and diluted with water (20.0 mL). The aqueous phase was extracted with DCM (3 x 25.0 mL), and the combined organic phases were washed with brine (25.0 mL), dried (Na2SOr), filtered, and concentrated. The residue was purified by silica gel chromatography (25 g cartridge) with DCM and MeOH (0-10%), and by reverse phase chromatography (C18, 12 g cartridge) with water (10 mM NH4HCO3) and MeOH (5-100%) to provide the title compound as a solid (20.5 mg, 32%). ’H NMR (400 MHz, DMSO-cL) 5 8.25 (d, 7 = 9.3 Hz, 1H), 8.07 (d, 7 = 7.5 Hz, 1H), 7.65 - 7.57 (m, 1H), 7.25 (dd, 7= 8.1, 8.1 Hz, 1H), 6.47 (dd, 7= 8.1, 2.2 Hz, 2H), 6.41 (dd, 7= 2.2, 2.2 Hz, 1H), 4.52 - 4.38 (m, 1H), 3.80 (s, 2H), 3.47 (dd, 7 = 9.8, 6.7 Hz, 1H), 3.40 - 3.35 (m, 1H), 3.29 (s, 3H), 3.27 - 3.21 (m, 1H), 3.11 (dd, 7 = 9.7, 5.2 Hz, 1H), 2.22 - 2.09 (m, 1H), 2.04 - 1.91 (m, 1H). m / z (ES+) [M+H]+= 397.15; UPLC (BEH_AmmBicarb) tR = 3.78 min.

[0476] Ex. 33, 2-methoxy-A-[(3S)-l-[3-[2-(trifluoromethyl)pyrimidin-5-yl]oxyphenyl]pyrrolidin-3- yl]acetamide

[0477] Step 1 : 2-methoxy- N- [(3S) - 1 - [3- [2- (trifluoromethyl)pyrimidin-5-yl]oxyphenyl] pyrrolidin-3- yl]acetamide

[0478]

[0349] A-[(3S)-l-(3-Hydroxyphenyl)pyrrolidin-3-yl]-2-methoxy-acetamide (40.0 mg, 0.160 mmol) was added to a mixture of 5-bromo-2-(trifluoromethyl)pyrimidine (39.9 mg, 0.176 mmol) and CS2CO3 (57.3 mg, 0.176 mmol) in DMF (800 pL) at 22 °C under nitrogen. The mixture was stirred at 90 °C for 16 h and concentrated. The residue was purified by silica gel chromatography (4 g cartridge) with DCM and MeOH (0-10%), and by reverse phase chromatography (C18, 12 g cartridge) with water and MeCN (10- 60%) to provide the title compound as a solid (18.9 mg, 30%). ’H NMR (400 MHz, DMSO-<() 5 8.73 (s, 2H), 8.02 (d, 7= 7.3 Hz, 1H), 7.25 (dd, J= 8.1, 8.1 Hz, 1H), 6.45 (dddd, J= 8.1, 5.8, 2.4, 0.8 Hz, 2H), 6.40 (dd, J = 2.3, 2.3 Hz, 1H), 4.51 - 4.38 (m, 1H), 3.80 (s, 2H), 3.52 - 3.43 (m, 1H), 3.40 - 3.34 (m, 1H), 3.29 (s, 3H), 3.27 - 3.22 (m, 1H), 3.15 - 3.07 (m, 1H), 2.22 - 2.10 (m, 1H), 2.04 - 1.92 (m, 1H). m / z (ES)+[M+H]+= 397.3; UPLC (BEH_AmmBicarb) 1R = 4.28 min. Ex. 6, 2-(3-methyloxetan-3-yl)oxy-iV-[(3S)-l-[3-[[6-(trifluoromethyl)-3- pyridyl]oxy]phenyl]pyrrolidin-3-yl]acetamide

[0479] Step 1: 2-(3-methyloxetan-3-yl)oxy-iV-[(3S)-l-[3-[[6-(trifluoromethyl)-3- pyridyl]oxy]phenyl]pyrrolidin-3-yl]acetamide

[0480]

[0350] 3-Methyloxetan-3-ol (10.0 pL, 0.129 mmol) was added to a mixture of NaH (60% in oil, 4.95 mg, 0.118 mmol) in THF (1.00 mL) at 0 °C under nitrogen, and the mixture was stirred for 30 min. 2-Bromo- A-[(35)-l-[3-[[6-(trifluoromethyl)-3-pyridyl]oxy]phenyl]pyrrolidin-3-yl]acetamide (58.0 mg, 0.118 mmol) in THF (1.00 mL) was added to the mixture, and it was stirred at 22 °C for 1 h. The mixture was diluted with water (20.0 mL). The aqueous phase was extracted with EtOAc (3 x 50.0 mL), and the combined organic phases were washed with brine (25.0 mL), dried (MgSCL), filtered, and concentrated. The residue was purified by silica gel chromatography (25 g cartridge) with DCM and MeOH (0-10%) and by preparative HPLC (BEH, C18) with water (10 mM NH4HCO3) and MeCN (49-59%) to provide the title compound as a solid (22.5 mg, 42%). ’H NMR (400 MHz, DMSO-cL) 5 8.46 (d, J= 2.8 Hz, 1H), 7.93 (d, J = 7.3 Hz, 1H), 7.82 (d, J= 8.7 Hz, 1H), 7.44 (dd, J= 8.7, 2.8 Hz, 1H), 7.20 (dd, J= 8.1, 8.1 Hz, 1H), 6.44 - 6.37 (m, 1H), 6.33 (dd, J= 7.7, 2.2 Hz, 1H), 6.29 (dd, J = 2.3, 2.3 Hz, 1H), 4.51 (d, J = 6.6 Hz, 2H), 4.45 - 4.36 (m, 1H), 4.24 - 4.18 (m, 2H), 3.80 (s, 2H), 3.43 (dd, J= 9.8, 6.9 Hz, 1H), 3.34 - 3.30 (m, 1H), 3.23 - 3.18 (m, 1H), 3.08 (dd, 7= 9.8, 5.3 Hz, 1H), 2.18 - 2.09 (m, 1H), 1.99 - 1.90 (m, 1H), 1.40 (s, 3H). m / z (ES+) [M+H]+= 452.18; UPLC (BEH_AmmBicarb) 1R = 4.52 min.

[0481] Ex. 34, iV-[(3S)-l-[3-[(6-cyclopropyl-3-pyridyl)oxy]phenyl]pyrrolidin-3-yl]-2-methoxy-acetamide

[0482] Step 1: 2-cyclopropyl-5-iodo-pyridine

[0483]

[0351] 5-Bromo-2-cyclopropyl-pyridine (200 mg, 1.01 mmol) was added to a mixture of Cui (38.5 mg, 0.202 mmol), Nal (151 mg, 1.01 mmol) and DMEDA (43.5 pL, 0.404 mmol) in 1,4-dioxane (2.70 mL) at 22 °C under nitrogen. The mixture was stirred at 120 °C for 18 h. The residue was concentrated and purified by reverse phase chromatography (Cl 8, 12 g cartridge) with water and MeCN (10-100%) to provide the title compound as an oil (160 mg, 65%). m / z (ES)+[M+H]+= 246. 1; HPLC (A05) 1R = 2.37 min.

[0484] Step 2: iV-[(3S)-l-[3-[(6-cyclopropyl-3-pyridyl)oxy]phenyl]pyrrolidin-3-yl]-2-methoxy-acetamide

[0485]

[0352] N-[(35)-l-(3-Hydroxyphenyl)pyrrolidin-3-yl]-2-methoxy-acetamide (63.0 mg, 0.252 mmol) was added to a mixture of 2-cyclopropyl-5-iodo-pyridine (61.7 mg, 0.252 mmol), K3PO4 (107 mg, 0.503 mmol), Cu(MeCN)4BF4 (7.92 mg, 25.2 pmol) and 2-(2-pyridyl)pyridine (7.86 mg, 50.3 pmol) in DMSO (2.60 mL) at 22 °C under nitrogen. The mixture was stirred at 80 °C for 16 h and diluted with water (50.0 mL). The aqueous phase was washed with EtOAc (3 x 25.0 mL). The combined organic phases were washed with brine (25.0 mL), dried (MgSCL), filtered, and concentrated. The residue was purified by silica gel chromatography (4 g cartridge) with DCM and MeOH (0-10%), and by reverse phase chromatography (Cl 8, 12 g cartridge) with water and MeCN (10-100%) to provide the title compound as a solid (5.80 mg, 6%). *H NMR (400 MHz, DMSO-oU 5 8.17 (dd, J = 1.8, 1.8 Hz, 1H), 8.01 (d, J = 7.3 Hz, 1H), 7.33 - 7.24 (m, 2H), 7.18 - 7.09 (m, 1H), 6.34 - 6.27 (m, 1H), 6.20 - 6.09 (m, 2H), 4.47 - 4.38 (m, 1H), 3.80 (s, 2H), 3.43 (dd, J= 9.7, 6.8 Hz, 1H), 3.36 - 3.32 (m, 1H), 3.29 (s, 3H), 3.27 - 3.17 (m, 1H), 3.08 (dd, J = 9.7, 5.2 Hz, 1H), 2.21 - 2.03 (m, 2H), 2.02 - 1.89 (m, 1H), 0.95 - 0.89 (m, 2H), 0.88 - 0.82 (m, 2H). m / z (ES)+[M+H]+= 368.3; UPLC (BEH_AmmBicarb) 1R = 4.22 min.

[0486] Ex. 58, 2-ethoxy- / V-[(3S)-l-[3-[2-(trifluoromethyl)pyrimidin-5-ylJoxyphenylJpyrrolidin-3- yl]acetamide

[0487] Step 3 yloxyphenyl)pyrrolidin-3-yl]-2-ethoxy-acetamide

[0488]

[0353] DIPEA (1.91 mL, 11.2 mmol) was added to mixture of 2-ethoxyacetic acid (370 pL, 3.91 mmol) and HATU (1.56 g, 4.10 mmol) in DCM (20.0 mL) at 22 °C under nitrogen. After 5 min, (35)-l-(3- benzyloxyphenyl)pyrrolidin-3-amine (1.00 g, 3.73 mmol) was added to the mixture, and it was stirred at 22 °C for 16 h and concentrated. The residue was purified by silica gel chromatography (40 g cartridge) with hexanes and EtOAc (0-100%) to provide the title compound as an oil (1.41 g, >98%). m / z. (ES)+[M+2H]+= 356.4; HPLC (A05) tR= 2.42 min.

[0489] Step 2: 2-ethoxy-iV-[(3S)-l-(3-hydroxyphenyl)pyrrolidin-3-yl]acetamide

[0490]

[0354] A^-[(35)-l-(3-Benzyloxyphenyl)pyrrolidin-3-yl]-2-ethoxy-acetamide (1.41 g, 3.98 mmol) was added to a mixture of Pd / C (10 wt.%, 635 mg, 0.597 mmol) in EtOAc (20.0 mL) and MeOH (20.0 mL) at 22 °C under nitrogen. The mixture was stirred at 22 °C for 16 h under H2. The mixture was filtered through Celite® washing with EtOAc (3 x 50.0 mL). The filtrate was concentrated, and the residue was purified by silica gel chromatography (40 g cartridge) with DCM and MeOH (0-10%) to provide the title compound as an oil (710 mg, 68%). m / z (ES)+[M+H]+= 265.2; HPLC (A05) tR= 1.98 min.

[0491] Step 3: 2-ethoxy-Af-[(3S)-l-[3-[2-(trifluoromethyl)pyrimidin-5-yl]oxyphenyl]pyrrolidin-3- yl]acetamide

[0492]

[0355] 2-Ethoxy-A-[(3S)-l-(3-hydroxyphenyl)pyrrolidin-3-yl]acetamide (91.0 mg, 0.344 mmol) was added to a mixture of 5-bromo-2-(trifluoromethyl)pyrimidine (86.0 mg, 0.379 mmol) and CS2CO3 (123 mg, 0.379 mmol) in DMF (2.00 mL) at 22 °C under nitrogen. The mixture was stirred at 90 °C for 16 h and diluted with water (20.0 mL). The aqueous phase was extracted with DCM (3 x 25.0 mL), and the combined organic phases were washed with brine (25.0 mL), dried (Na2SOr), filtered, and concentrated. The residue was purified by silica gel chromatography (12 g cartridge) with DCM and MeOH (0-10%). The collected fractions were concentrated and purified by reverse phase chromatography (Cl 8, 12 g cartridge) with water (10 mM NH4HCO2) and MeOH (5-100%) to provide the title compound as a solid (51 mg, 36%). 'H NMR (400 MHz, DMSO-76) 5 8.73 (s, 2H), 7.94 (d, J = 7.3 Hz, 1H), 7.25 (dd, J= 8.1, 8.1 Hz, 1H), 6.45 (ddd, 7= 7.4, 7.2, 2.3 Hz, 2H), 6.40 (dd, J = 2.2, 2.2 Hz, 1H), 4.53 - 4.37 (m, 1H), 3.83 (s, 2H), 3.51 - 3.45 (m, 3H), 3.42 - 3.33 (m, 1H), 3.30 - 3.23 (m, 1H), 3.12 (dd, J= 9.8, 5.3 Hz, 1H), 2.23 - 2.10 (m, 1H), 2.03 - 1.91 (m, 1H), 1.13 (t, J = 7.0 Hz, 3H). m / z (ES)+[M+H]+= 411.16; UPLC (BEH_AmmBicarb) tR = 4.62 min.

[0493] Ex. 35, iV-[(3S)-l-[3-[[6-(difluoromethyl)-3-pyridyl]oxy]phenyl]pyrrolidin-3-yl]-2-methoxy- acetamide

[0494] Step 1: Af-[(3S)-l-[3-[[6-(difluoromethyl)-3-pyridyl]oxy]phenyl]pyrrolidin-3-yl]-2-methoxy- acetamide

[0495]

[0356] lV-[(3S)-l-(3-Hydroxyphenyl)pyrrolidin-3-yl]-2-methoxy-acetamide (71.0 mg, 0.284 mmol) was added to a mixture of 5-bromo-2-(difluoromethyl)pyridine (64.9 mg, 0.312 mmol) and CS2CO3 (102 mg, 0.312 mmol) in DMF (1.50 mL) at 22 °C under nitrogen. The mixture was stirred at 120 °C for 18 h and diluted with water (20.0 mL). The aqueous phase was extracted with DCM (3 x 25.0 mL), and the combined organic phases were washed with brine (25.0 mL), dried (Na2SOr), filtered, and concentrated. The residue was purified by silica gel chromatography (12 g cartridge) with MeOH and DCM (0-10%). The collected fractions were concentrated and purified by reverse phase chromatography (Cl 8, 12 g cartridge) with water (10 mM NH4HCO2) and MeOH (5-100%) to provide the title compound as a solid (33 mg, 31%). 'H NMR (400 MHz, DMSO-76) 5 8.42 (d, J = 2.8 Hz, 1H), 8.02 (d, J = 7.2 Hz, 1H), 7.68 (d, 7 = 8.6 Hz, 1H), 7.48 (dd, 7= 8.6, 2.8 Hz, 1H), 7.22 (dd, 7 = 8.1, 8.1 Hz, 1H), 7.13 - 6.75 (m, 1H), 6.41 (dd, 7 = 8.1, 2.0 Hz, 1H), 6.32 (dd, 7= 7.7, 2.0 Hz, 1H), 6.28 (dd, 7= 2.3, 2.3 Hz, 1H), 4.52 - 4.32 (m, 1H), 3.80 (s, 2H), 3.46 (dd, 7 = 9.8, 6.8 Hz, 1H), 3.40 - 3.32 (m, 1H), 3.30 - 3.21 (m, 4H), 3.10 (dd, 7 = 9.8, 5.2 Hz, 1H), 2.21 - 2.09 (m, 1H), 2.03 - 1.91 (m, 1H). m / z (ES)+[M+H]+378.16; UPLC (BEH_AmmBicarb) tR = 3.96 min.

[0496] Ex. 132, 2V-[(3S)-l-[3-cyano-5-[[6-(trifluoromethyl)-3-pyridyl]oxy]phenyl]pyrrolidHi-3-yl]-2-

[0497]

[0357] DIPEA (5.51 mL, 32.3 mmol) was added to mixture of 2-methoxyacetic acid (865 pL, 11.3 mmol) and HATU (4.49 g, 11.8 mmol) in DCM (50.0 mL) at 22 °C under nitrogen. After 5 min, tert-butyl (35)- 3- aminopyrrolidine- 1 -carboxylate (2.00 g, 10.7 mmol) was added to the mixture, and it was stirred at 22 °C for 1 h and diluted with H2O (50.0 mL). The aqueous phase was extracted with EtOAc (3 x 50.0 mL), and the combined organic phases were washed with brine (50.0 mL), dried (MgSOr), filtered, and concentrated. The residue was purified by silica gel chromatography (40 g cartridge) with hexanes and EtOAc (0-100%) to provide the title compound as an oil (2.38 g, 69%). ’H NMR (300 MHz, DMSO-cL) 5 7.97 (d, 7 = 7.1 Hz, 1H), 4.29 - 4.20 (m, 1H), 3.79 (s, 2H), 3.49 - 3.33 (m, 2H), 3.26 - 3.18 (m, 1H), 3.12 - 3.02 (m, 1H), 2.69 (s, 3H), 2.04 - 1.92 (m, 1H), 1.86 - 1.78 (m, 1H), 1.39 (s, 9H).

[0498] Step 2: 2-methoxy- V-|(3.S )-pyrrolidin-3-vl|acetamide hydrochloride

[0499]

[0358] tert-Butyl (35)-3-[(2-methoxyacetyl)amino]pyrrolidine-l-carboxylate (2.38 g, 9.21 mmol) was added to a mixture of HC1 (4.0 M solution in 1,4-dioxane, 52.6 mL, 10.5 mmol) in DCM (50.0 mL) at 22 °C under nitrogen. The mixture was stirred at 22 °C for 16 h and concentrated to provide the title compound as a solid (1.20 g, 67%). >H NMR (300 MHz, DMSO-76) 59.14 (s, 2H), 8.18 (d, J = 7.2 Hz, 1H), 4.48 - 4.31 (m, 1H), 3.82 (s, 2H), 3.31 (s, 3H), 3.28 - 3.23 (m, 1H), 3.22 - 3.09 (m, 1H), 3.10 - 2.97 (m, 1H), 2.20 - 2.02 (m, 1H), 1.95 - 1.78 (m, 1H).

[0500] Step 3: 3-bromo-5-[[6-(trifluoromethyl)-3-pyridyl]oxy]benzonitrile

[0501]

[0359] 3-Bromo-5-hydroxy-benzonitrile (200 mg, 1.01 mmol) was added to a mixture of 5-fluoro-2- (trifluoromethyl)pyridine (0.134 pL, 1.11 mmol) and CS2CO3 (494 mg, 1.52 mmol) in DMF (5.00 mL) at 22 °C under nitrogen. The mixture was stirred at 80 °C for 16 h and concentrated. The residue was filtered on a pad of Celite® and rinced with EtOAc (3 x 20.0 mL). The filtrate was concentrated, and the residue was purified by silica gel chromatography (25 g cartridge) with hexanes and EtOAc (0-100%) to provide the title compound as an oil (233 mg, 67%). m / z (ES)+[M+H]+= 343.0; HPLC (A05) 1R = 2.47 min.

[0502] Step 4: Af-[(3S)-l-[3-cyano-5-[[6-(trifluoromethyl)-3-pyridyl]oxy ]phenyl]pyrrolidin-3-yl]-2- methoxy-acetamide

[0503]

[0360] 2-Methoxy-lV-[(3S)-pyrrolidin-3-yl]acetamide hydrochloride (62.4 mg, 0.321 mmol) was added to a mixture of 3-bromo-5-[[6-(trifluoromethyl)-3-pyridyl]oxy]benzonitrile (100 mg, 0.291 mmol), RuPhos Pd G3 (48.8 mg, 58.3 pmol) and NaOtBu (70.0 mg, 0.729 mmol) in 1,4-dioxane (1.50 mL) at 22 °C under nitrogen. The mixture was stirred at 100 °C for 18 h. The mixture was cooled to 22 °C, filtered on a pad of Celite®, and the filtrate was concentrated. The residue was purified by silica gel chromatography (12 g cartridge) with DCM and MeOH (0-50%), and by reverse phase chromatography (C18, 12 g cartridge) with water and MeCN (10-100%) to provide the title compound as a solid (42.2 mg, 34%). ’H NMR (400 MHz, DMSO-de) 5 8.58 - 8.52 (m, 1H), 8.07 (d, J = 7.3 Hz, 1H), 7.90 (dd, J= 8.1, 0.6 Hz, 1H), 7.63 - 7.55 (m, 1H), 6.87 - 6.82 (m, 2H), 6.65 (dd, J= 2.2, 2.2 Hz, 1H), 4.50 - 4.40 (m, 1H), 3.80 (s, 2H), 3.50 (dd, J= 10.2, 6.7 Hz, 1H), 3.44 - 3.34 (m, 1H), 3.29 - 3.25 (m, 4H), 3.15 (dd, 7 = 10.2, 5.2 Hz, 1H), 2.20 - 2.09 (m, 1H), 2.05 - 1.94 (m, 1H). m / z (ES)+[M+H]+= 421.3; UPLC (BEH_AmmBicarb) tR = 4.31 min.

[0504] Ex. 59, 2-methoxy-iV-[(3S)-l-[3-methoxy-5-[[6-(trifluoromethyl)-3-pyridyl]oxy]phenyl]pyrrolidin-3- yl]acetamide

[0505]

[0361] 3-Bromo-5-methoxy-phenol (205 mg, 1.01 mmol) was added to a mixture of 5-fluoro-2- (trifluoromethyl)pyridine (134 pL, 1.11 mmol) and CS2CO3 (493 mg, 1.51 mmol) in DMF (12.0 mL) at 22 °C under nitrogen. The mixture was stirred at 80 °C for 16 h and concentrated. The residue was filtered on a pad of Celite® and rinced with EtOAc (3 x 20.0 mL). The filtrate was concentrated, and the residue was purified by silica gel chromatography (24 g cartridge) with hexanes and EtOAc (0-100%) to provide the title compound as an oil (338 mg, 96%). m / z (ES)+[M+H]+= 348. 1; HPLC (A05) 1R = 2.59 min.

[0506] Step 2: 2-methoxy-A [(3S)-l-[3-methoxy-5-[[6-(trifluoromethyl)-3-pyridyl]oxy]phenyl]pyrrolidin-3- yl]acetamide

[0507]

[0362] 2-Methoxy-A-[(3S)-pyrrolidin-3-yl]acetamide hydrochloride (61.5 mg, 0.316 mmol) was added to a mixture of 5-(3-bromo-5-methoxy-phenoxy)-2-(trifluoromethyl)pyridine (100 mg, 0.287 mmol), RuPhos Pd G3 (48.1 mg, 57.5 pmol) and NaOtBu (69.0 mg, 0.718 mmol) in 1,4-dioxane (1.50 mL) at 22 °C under nitrogen. The mixture was stirred at 100 °C for 18 h. The mixture was cooled to 22 °C, filtered on a pad of Celite®, and the filtrate was concentrated. The residue was purified by silica gel chromatography (12 g cartridge) with DCM and MeOH (0-50%), and by reverse phase chromatography (C18, 12 g cartridge) with water and MeCN (10-100%) to provide the title compound as a solid (64.0 mg, 52%). >H NMR (400 MHz, DMSO-6) 5 8.51 (d, J = 2.8 Hz, 1H), 8.03 (d, J = 7.3 Hz, 1H), 7.87 (dd, J = 8.8, 0.6 Hz, 1H), 7.54 - 7.46 (m, 1H), 6.02 (dd, J = 2.1, 2.1 Hz, 1H), 5.94 (ddd, J= 8.8, 2.1, 2.1 Hz, 2H), 4.43 (h, J = 6.7 Hz, 1H), 3.80 (s, 2H), 3.71 (s, 3H), 3.45 (dd, J= 9.9, 6.8 Hz, 1H), 3.39 - 3.33 (m, 1H), 3.29 (s, 3H), 3.26 - 3.19 (m, 1H), 3.09 (dd, J = 9.8, 5.3 Hz, 1H), 2.20 - 2.08 (m, 1H), 2.02 - 1.90 (m, 1H). m / z (ES)+[M+H]+= 426.3; UPLC (BEH_AmmBicarb) 1R = 4.49 min.

[0508] Ex. 130, iV-[(3S)-l-[3-[[dimethyl(oxo)-lambda6-sulfanylidene]amino]-5-[[6-(trifluoromethyl)-3- pyridyl]oxy]phenyl]pyrrolidin-3-yl]-2-methoxy-acetamide

[0509] Step 1: 5-(3,5-dibromophenoxy)-2-(trifluoromethyl)pyridine

[0510]

[0363] 3,5-Dibromophenol (500 mg, 1.98 mmol) was added to a mixture of 5-fluoro-2- (trifluoromethyl)pyridine (0.263 pL, 2.18 mmol) and CS2CO3 (970 mg, 2.98 mmol) in DMF (12.0 mL) at 22 °C under nitrogen. The mixture was stirred at 80 °C for 16 h and concentrated. The residue was filtered on a pad of Celite® and rinced with EtOAc (3 x 20.0 mL). The filtrate was concentrated, and the residue was purified by silica gel chromatography (80 g cartridge) with hexanes and EtOAc (0-100%) to provide the title compound as an oil (663 mg, 84%). m / z (ES)+[M+H]+398.0; HPLC (A05) 1R = 2.68 min.

[0511] Step 2: [3-bromo-5-[[6-(trifluoromethyl)-3-pyridyl]oxy]phenyl]imino-dimethyl-oxo-lambda6- sulfane

[0512]

[0364] Dimethylsulfoximine (46.9 pL, 0.504 mmol) was added to a mixture of 5-(3,5-dibromophenoxy)-2- (trifluoromethyl)pyridine (200 mg, 0.504 mmol), Xantphos Pd G3 (95.6 mg, 0.101 mmol) and CS2CO3 (492 mg, 1.51 mmol) in 1,4-dioxane (2.50 mL) at 22 °C under nitrogen. The mixture was stirred at 120 °C for 18 h and concentrated. The residue was purified by silica gel chromatography (25 g cartridge) with hexanes and EtOAc (0-100%) to provide the title compound as an oil (99.0 mg, 48%). ’H NMR (300 MHz, DMSO-76) 5 8.57 (d, J = 2.8 Hz, 1H), 7.91 (d, J= 8.7 Hz, 1H), 7.63 (dd, J= 8.6, 2.9 Hz, 1H), 6.97 (dd, J= 1.8, 1.8 Hz, 1H), 6.91 (dd, J= 2.0, 2.0 Hz, 1H), 6.64 (dd, J = 2.1, 2.1 Hz, 1H), 3.27 (s, 6H). m z (ES)+[M+2H]+= 411.1; HPLC (A05) tR= 2.35 min.

[0513] Step 3: Af-[(3S)-l-[3-[[dimethyl(oxo)-lambda6-sulfanylidene]amino]-5-[[6-(trifluoromethyl)-3- pyridyl]oxy]phenyl]pyrrolidin-3-yl]-2-methoxy-acetamide

[0514]

[0365] 2-Methoxy-A-[(3S)-pyrrolidin-3-yl]acetamide hydrochloride (51.8 mg, 0.266 mmol) was added to a mixture of [3-bromo-5-[[6-(trifluoromethyl)-3-pyridyl]oxy]phenyl]imino-dimethyl-oxo-lambda6- sulfane (99.0 mg, 0.242 mmol), RuPhos Pd G3 (40.5 mg, 48.4 pmol) and NaOtBu (58.1 mg, 0.605 mmol) in 1,4-dioxane (1.50 mL) at 22 °C under nitrogen. The mixture was stirred at 100 °C for 18 h. The mixture was cooled to 22 °C, filtered on a pad of Celite®, and the filtrate was concentrated. The residue was purified by silica gel chromatography (12 g cartridge) with DCM and MeOH (0-10%), and by reverse phase chromatography (Cl 8, 12 g cartridge) with water and MeCN (10-100%) to provide the title compound as a solid (34.3 mg, 29%). *H NMR (400 MHz, DMSO-76) 5 8.45 (d, J = 2.8 Hz, 1H), 7.98 (d, 7 = 7.2 Hz, 1H), 7.82 (dd, 7= 8.8, 0.6 Hz, 1H), 7.46 (ddd, 7= 8.7, 2.8, 0.7 Hz, 1H), 5.94 (dd, 7 = 2.0, 2.0 Hz, 1H), 5.91 (dd, 7 = 2.0, 2.0 Hz, 1H), 5.86 (dd, 7 = 2.1, 2.1 Hz, 1H), 4.41 - 4.32 (m, 1H), 3.76 (s, 2H), 3.37 (dd, 7 = 9.7, 6.8 Hz, 1H), 3.25 (s, 3H), 3.20 - 3.17 (m, 1H), 3.15 (s, 6H), 3.02 (dd, 7= 9.8, 5.3 Hz, 1H), 2.49 - 2.47 (m, 1H), 2.13 - 2.04 (m, 1H), 1.97 - 1.86 (m, 1H). m / z (ES)+[M+H]+= 487.3; UPLC (BEH_AmmBicarb) tR= 3.40 min.

[0515] Ex. 61, 2-(l-isopropylpyrazol-4-yl)oxy-iV-[(3S)-l-[3-[2-(trifluoromethyl)pyrimidin-5- yl]oxyphenyl]pyrrolidin-3-yl]acetamide

[0516]

[0517] Step 1: iV-[(3S)-l-(3-benzyloxyphenyl)pyrrolidin-3-yl]-2-bromo-acetamide

[0518]

[0366] (35)-l-(3-Benzyloxyphenyl)pyrrolidin-3-amine (1.00 g, 3.73 mmol) was added to a mixture of TEA (1.09 mL, 7.83 mmol) in DCM (20.0 mL) at 0 °C under nitrogen. 2-Bromoacetyl chloride (341 pL, 4.10 mmol) was added dropwise to the mixture, and it was stirred at 22 °C for 2 h. The mixture was diluted with water (20.0 mL). The aqueous phase was extracted with EtOAc (3 x 50.0 mL), and the combined organic phases were washed with brine (25.0 mL), dried (MgSCL), filtered, and concentrated. The residue was purified by silica gel chromatography (40 g cartridge) with hexanes and EtOAc (0- 100%) to provide the title compound as a solid (1.05 g, 72%). ’H NMR (300 MHz, DMSO-t / e) 5 8.60 (d, 7= 6.9 Hz, 1H), 7.48 - 7.26 (m, 5H), 7.11 - 6.99 (m, 1H), 6.33 - 6.23 (m, 1H), 6.18 - 6.10 (m, 2H), 5.06 (s, 2H), 4.41 - 4.29 (m, 1H), 3.83 (s, 2H), 3.46 (dd, J= 10.0, 6.3 Hz, 1H), 3.29 - 3.20 (m, 2H), 3.05 (dd, 7= 10.0, 4.0 Hz, 1H), 2.26 - 2.09 (m, 1H), 1.93 - 1.82 (m, 1H). m / z (ES)+[M+H]+= 389.5; HPLC (A05) tR = 2.42 min.

[0519] Step 2: l-isopropylpyrazol-4-ol

[0367] lH-Pyrazol-4-ol (200 mg, 2.38 mmol) was added to mixture of CS2CO3 (853 mg, 2.62 mmol) and 2-iodopropane (238 pL, 2.38 mmol) in DMF (8.00 mL) at 22 °C under nitrogen. The mixture was stirred at 65 °C for 2 h and concentrated. The residue was purified by silica gel chromatography (12 g cartridge) with DCM and MeOH (0-10%) to provide the title compound as an oil (273 mg, 91%). ’H NMR (300 MHz, DMSO-< / 6) 5 12.29 (s, 1H), 7.40 (s, 1H), 7.20 (s, 1H), 4.15 (hept, J= 6.1 Hz, 1H), 1.20 (d, 7= 6.1 Hz, 6H). m / z (ES)+[M+H]+= 127.1; HPLC (A05) tR= 1.65 min.

[0520] Step 3: iV-[(3S)-l-(3-benzyloxyphenyl)pyrrolidin-3-yl]-2-(l-isopropylpyrazol-4-yl)oxy-acetamide l-Isopropylpyrazol-4-ol (71.3 mg, 0.565 mmol) was added to a mixture of NaH (60% dispersion in mineral oil, 21.7 mg, 0.565 mmol) in THF (3.00 mL) at 0 °C under nitrogen, and the mixture was stirred for 30 min. A-[(35)-l-(3-Benzyloxyphenyl)pyrrolidin-3-yl]-2-bromo-acetamide (200 mg, 0.514 mmol) in THF (2.00 mL) was added to the mixture, and it was stirred at 22 °C for 16 h. The mixture was diluted with water (20.0 mL). The aqueous phase was extracted with EtOAc (3 x 50.0 mL), and the combined organic phases were washed with brine (25.0 mL), dried (MgSCL), filtered, and concentrated to provide the title compound as an oil (260 mg, >98%). ’H NMR (300 MHz, DMSO-A) 5 8.42 (d, J = 6.9 Hz, 1H), 7.49 - 7.26 (m, 6H), 7.16 (d, J= 0.9 Hz, 1H), 7.11 - 6.99 (m, 1H), 6.28 (dd, J= 7.9, 2.1 Hz, 1H), 6.18 - 6.10 (m, 2H), 5.06 (s, 2H), 4.63 (s, 2H), 4.40 - 4.32 (m, 1H), 4.20 - 4.08 (m, 1H), 3.46 (dd, J = 9.9, 6.3 Hz, 1H), 3.30 - 3.18 (m, 2H), 3.06 (dd, J = 9.9, 4.1 Hz, 1H), 2.26 - 2.09 (m, 1H), 1.94 - 1.83 (m, 1H), 1.21 (d, J= 6.1 Hz, 6H). m z (ES)+[M+H]+= 435.8; HPLC (A05) tR= 2.43 min.

[0521] Step 4: iV-[(3S)-l-(3-hydroxyphenyl)pyrrolidin-3-yl]-2-(l-isopropylpyrazol-4-yl)oxy-acetamide

[0522]

[0368] A-[(35)-l-(3-Benzyloxyphenyl)pyrrolidin-3-yl]-2-(l-isopropylpyrazol-4-yl)oxy-acetamide (260 mg, 0.598 mmol) was added to a mixture of Pd / C (10 wt.%, 95.5 mg, 89.8 pmol) in EtOAc (3.00 mL) and MeOH (3.00 mL) at 22 °C under nitrogen. The mixture was stirred at 22 °C for 16 h under H2. The mixture was filtered on a pad of Celite® washing with EtOAc (3 x 50.0 mL). The filtrate was concentrated, and the residue was purified by silica gel chromatography (40 g cartridge) with DCM and MeOH (0-10%) to provide the title compound as an oil (103 mg, 50%). ’H NMR (300 MHz, DMSO-cA,) 5 8.97 (s, 1H), 8.39 (d, J = 6.8 Hz, 1H), 7.38 (d, J = 0.9 Hz, 1H), 6.91 (dd, J = 8.0, 8.0 Hz, 1H), 6.06 - 6.01 (m, 1H), 5.99 - 5.95 (m, 1H), 5.92 (dd, 7= 2.2, 2.2 Hz, 1H), 5.74 (s, 1H), 4.62 (s, 2H), 4.37 - 4.28 (m, 1H), 4.20 - 4.05 (m, 1H), 3.40 (dd, J = 9.8, 6.3 Hz, 1H), 3.29 - 3.25 (m, 1H), 3.25 - 3.13 (m, 1H), 3.01 (dd, 7 = 9.8, 4.0 Hz, 1H), 2.24 - 2.04 (m, 1H), 1.94 - 1.78 (m, 1H), 1.20 (d, 7= 6.1 Hz, 6H). m / z (ES)+[M+H]+= 345.3; HPLC (A05) tR= 2.04 min.

[0523] Step 5: 2-(l-isopropylpyrazol-4-yl)oxy-A-[(3S)-l-[3-[2-(trifluoromethyl)pyrimidin-5- yl]oxyphenyl]pyrrolidin-3-yl]acetamide

[0524]

[0369] A-[(35)-l-(3-Hydroxyphenyl)pyrrolidin-3-yl]-2-(l-isopropylpyrazol-4-yl)oxy-acetamide (50.0 mg, 0.145 mmol) was added to a mixture of 5-bromo-2-(trifluoromethyl)pyrimidine (49.4 mg, 0.218 mmol) and CS2CO3 (71.0 mg, 0.218 mmol) in DMF (1.00 mL) at 22 °C under nitrogen. The mixture was stirred at 100 °C for 16 h and concentrated. The residue was purified by silica gel chromatography (4 g cartridge) with DCM and MeOH (0-10%), and by reverse phase chromatography (Cl 8, 12 g cartridge) with water and MeCN (10-60%) to provide the title compound as a solid (19.4 mg, 27%). ’H NMR (500 MHz, DMSO-76) 5 8.73 (s, 2H), 8.43 (d, 7= 6.9 Hz, 1H), 7.39 (d, 7= 0.9 Hz, 1H), 7.26 (dd, 7= 8.1, 8.1 Hz, 1H), 7.16 (d, 7 = 0.9 Hz, 1H), 6.51 - 6.40 (m, 3H), 4.63 (d, 7 = 0.9 Hz, 2H), 4.41 - 4.34 (m, 1H), 4.18 - 4.09 (m, 1H), 3.49 (dd, 7= 10.1, 6.3 Hz, 1H), 3.42 - 3.33 (m, 1H), 3.28 - 3.26 (m, 1H), 3.09 (dd, 7= 10.1, 4.0 Hz, 1H), 2.24 - 2.14 (m, 1H), 1.96 - 1.86 (m, 1H), 1.21 (d, 7= 6.1 Hz, 6H). m / z (ES)+[M+H]+= 491.4; UPLC (BEH AmmBicarb) tR= 4.84 min.

[0525] Ex. 62, 2-(l-ethylpyrazol-4-yl)oxy-A-[(3S)-l-[3-[[6-(trifluoromethyl)-3- pyridyl]oxy]phenyl]pyrrolidin-3-yl]acetamide Step 1: l-ethylpyrazol-4-ol

[0526]

[0370] 1 H-Pyrazol-4-ol (200 mg, 2.38 mmol) was added to mixture of CS2CO3 (853 mg, 2.62 mmol) and iodoethane (163 pL, 2.38 mmol) in DMF (8.00 mL) at 22 °C under nitrogen. The mixture was stirred at 65 °C for 2 h and concentrated. The residue was purified by silica gel chromatography (12 g cartridge) with DCM and MeOH (0-10%) to provide the title compound as an oil (143 mg, 54%). ’H NMR (300 MHz, DMSO-76) 5 12.30 (s, 1H), 7.41 (s, 1H), 7.21 (s, 1H), 3.87 (q, J = 7.0 Hz, 2H), 1.26 (t, J = 7.0 Hz, 3H). m / z (ES)+[M+H]+= 113.1; HPLC (A05) tR= 1.02 min.

[0527] Step 2: 2-(l-ethylpyrazol-4-yl)oxy-A-[(3S)-l-[3-[[6-(trifluoromethyl)-3- pyridyl]oxy]phenyl]pyrrolidin-3-yl]acetamide

[0528]

[0371] 2-Bromo-A-[(3S)-l-[3-[[6-(trifluoromethyl)-3-pyridyl]oxy]phenyl]pyrrolidin-3-yl]acetamide (94.0 mg, 0.212 mmol) was added to a mixture of l-ethylpyrazol-4-ol (47.5 mg, 0.423 mmol) and K2CO3 (87.7 mg, 0.635 mmol) in MeCN (4.00 mL) at 22 °C under nitrogen. The mixture was stirred at 90 °C for 5 h and concentrated. The residue was purified by silica gel chromatography (25 g cartridge) with DCM and MeOH (0-10%). The collected fractions were concentrated and purified by reverse phase chromatography (C18, 12 g cartridge) with water (10 mM NH4HCO2) and MeOH (5-100%) and by preparative HPLC (BEH, Cl 8) with water (10 mM NH4HCO3) and MeCN (50-60%) to provide the title compound as a solid (32.5 mg, 32%). ’H NMR (400 MHz, DMSO-t / e) 5 8.51 (d, J = 2.8 Hz, 1H), 8.47 (d, J = 6.8 Hz, 1H), 7.88 (d, J = 8.7 Hz, 1H), 7.48 (dd, J = 8.7, 2.3 Hz, 1H), 7.40 (d, J = 0.9 Hz, 1H), 7.25 (dd, J = 8.1, 8.1 Hz, 1H), 7.17 (d, J = 0.9 Hz, 1H), 6.46 (dd, 7= 8.4, 1.6 Hz, 1H), 6.38 (dd, J= 7.9, 1.6 Hz, 1H), 6.35 (dd, J = 2.2, 2.2 Hz, 1H), 4.63 (s, 2H), 4.41 - 4.31 (m, 1H), 3.86 (q, J = 7.0 Hz, 2H), 3.48 (dd, 7= 10.1, 6.3 Hz, 1H), 3.42 - 3.35 (m, 1H), 3.30 - 3.24 (m, 1H), 3.08 (dd, 7= 10.0, 3.9 Hz, 1H), 2.24 - 2.13 (m, 1H), 1.95 - 1.84 (m, 1H), 1.26 (t, 7 = 7.0 Hz, 3H). m / z (ES+) [M+H]+= 476.19; UPLC (BEH_AmmBicarb) tR= 4.79 min.

[0529] Ex. 63, 2-(2-methoxyethoxy)-A-[(3S)-l-[3-[[6-(trifluoromethyl)-3-pyridyl]oxy]phenyl]pyrrolidin-3- yl]acetamide

[0530] Step 1: 2-(2-methoxyethoxy)-Af-[(3S)-l-[3-[[6-(trifluoromethyl)-3-pyridyl]oxy]phenyl]pyrrolidin-3- yl]acetamide

[0531]

[0372] DIPEA (158 pL, 0.925 mmol) was added to mixture of 2-(2-methoxyethoxy)acetic acid (36.8 pL, 0.324 mmol) and HATU (129 mg, 0.339 mmol) in DMF (2.00 mL) at 0 °C under nitrogen. After 5 min, (35)-l-[3-[[6-(trifluoromethyl)-3-pyridyl]oxy]phenyl]pyrrolidin-3-amine hydrochloride (99.7 mg, 0.308 mmol) was added to the mixture, and it was stirred at 22 °C for 1 h and concentrated. The residue was purified by silica gel chromatography (25 g cartridge) with DCM and MeOH (0-10%), by reverse phase chromatography (C18, 12 g cartridge) with water (10 mM NH4HCO3) and MeCN (5-100%), and by preparative HPLC (BEH, Cl 8) with water (10 mM NH4HCO3) and MeCN (50-60%) to provide the title compound as an oil (58.8 mg, 43%). *H NMR (400 MHz, DMSO-76) 5 8.51 (d, J = 2.8 Hz, 1H), 7.91 (d, 7 = 7.3 Hz, 1H), 7.87 (d, J= 8.5 Hz, 1H), 7.48 (dd, J= 8.4, 2.5 Hz, 1H), 7.25 (dd, J= 8.1, 8.1 Hz, 1H), 6.45 (dd, J= 8.0, 1.9 Hz, 1H), 6.37 (dd, 7= 7.9, 1.7 Hz, 1H), 6.33 (dd, 7= 2.2, 2.2 Hz, 1H), 4.52 - 4.37 (m, 1H), 3.88 (s, 2H), 3.59 - 3.54 (m, 2H), 3.52 - 3.43 (m, 3H), 3.40 - 3.34 (m, 1H), 3.31 - 3.24 (m, 1H), 3.22 (s, 3H), 3.10 (dd, 7 = 9.9, 4.9 Hz, 1H), 2.23 - 2.13 (m, 1H), 2.00 - 1.90 (m, 1H). m / z (ES+) [M+H]+= 440.18; UPLC (BEH AmmBicarb) 1R = 4.58 min.

[0532] Ex. 64, iV-[(3S)- l-[3-[ 1 -( difliioroniet lix l )-3-pyridyl ]oxy ]phenyl ]pyrrolidin-3-yl ]-2-ethoxy-acetamide

[0533] Step 1: iV-[(3S)-l-[3-[[6-(difluoromethyl)-3-pyridyl]oxy]phenyl]pyrrolidin-3-yl]-2-ethoxy-acetamide

[0534]

[0373] 2-Ethoxy-N-[(3S)-l-(3-hydroxyphenyl)pyrrolidin-3-yl]acetamide (50.0 mg, 0.189 mmol) was added to a mixture of 5-bromo-2-(difluoromethyl)pyridine (59.0 mg, 0.284 mmol) and CS2CO3 (92.5 mg, 0.284 mmol) in DMF (1.00 mL) at 22 °C under nitrogen. The mixture was stirred at 100 °C for 16 h and concentrated. The residue was purified by silica gel chromatography (4 g cartridge) with DCM and MeOH (0-10%), and by reverse phase chromatography (C18, 12 g cartridge) with water and MeCN (10- 100%) to provide the title compound as a solid (11.8 mg, 16%). ’H NMR (400 MHz, DMSO-<() 5 8.42 (d, J = 2.8 Hz, 1H), 7.96 (d, J= 7.3 Hz, 1H), 7.69 (d, J= 8.7 Hz, 1H), 7.47 (dd, J= 8.6, 2.8 Hz, 1H), 7.22 (dd, J= 8.1, 8.1 Hz, 1H), 7.10 - 6.79 (m, 1H), 6.42 (dd, J= 8.4, 2.1 Hz, 1H), 6.32 (dd, J = 7.7, 2.2 Hz, 1H), 6.28 (dd, J = 2.3, 2.3 Hz, 1H), 4.50 - 4.37 (m, 1H), 3.83 (s, 2H), 3.50 - 3.43 (m, 3H), 3.33 - 3.32 (m, 1H), 3.29 - 3.21 (m, 1H), 3.10 (dd, J= 9.8, 5.3 Hz, 1H), 2.22 - 2.10 (m, 1H), 2.03 - 1.90 (m, 1H), 1.13 (t, J= 7.0 Hz, 3H). m / z (ES)+[M+H]+= 392.3; UPLC (BEH_AmmBicarb) 1R = 4.31 min.

[0535] Ex. 65, iV-[(3S)-l-[3-[(6-cyclopropyl-3-pyridyl)oxy]phenyl]pyrrolidin-3-yl]-2-ethoxy-acetamide

[0536] Step 1: iV-[(3S)-l-[3-[(6-cyclopropyl-3-pyridyl)oxy]phenyl]pyrrolidin-3-yl]-2-ethoxy-acetamide

[0537]

[0374] 2-Ethoxy-N-[(35)-l-(3-hydroxyphenyl)pyrrolidin-3-yl]acetamide (80.0 mg, 0.303 mmol) was added to a mixture of 2-cyclopropyl-5-iodo-pyridine (111 mg, 0.454 mmol), K3PO4 (128 mg, 0.605 mmol), Cu(MeCN)4BF4 (9.52 mg, 30.3 pmol) and 2-(2-pyridyl)pyridine (9.45 mg, 60.5 pmol) in DMSO (2.00 mL) at 22 °C under nitrogen. The mixture was stirred at 100 °C for 16 h. The residue was purified by silica gel chromatography (4 g cartridge) with DCM and MeOH (0-10%), and by reverse phase chromatography (Cl 8, 12 g cartridge) with water and MeCN (10-100%) to provide the title compound as a solid (3.70 mg, 3%). 'H NMR (400 MHz, DMSO-oU 5 8.17 (dd, 7= 1.8, 1.8 Hz, 1H), 7.92 (d, J = 7.3 Hz, 1H), 7.28 (d, J= 1.8 Hz, 2H), 7.18 - 7.09 (m, 1H), 6.35 - 6.28 (m, 1H), 6.20 - 6.12 (m, 2H), 4.49 - 4.36 (m, 1H), 3.83 (s, 2H), 3.51 - 3.41 (m, 3H), 3.36 - 3.33 (m, 1H), 3.26 - 3.17 (m, 1H), 3.08 (dd, J= 9.7, 5.2 Hz, 1H), 2.21 - 2.12 (m, 1H), 2.12 - 2.04 (m, 1H), 2.02 - 1.89 (m, 1H), 1.13 (t, J = 7.0 Hz, 3H), 0.94 - 0.89 (m, 2H), 0.88 - 0.82 (m, 2H). m / z (ES)+[M+H]+= 382.3; UPLC (BEH_AmmBicarb) tR= 4.57 min.

[0538] Ex. 66, 2-ethoxy-A-[(3S)-l-[3-[[2-methyl-6-(trifluoromethyl)-3-pyridyl]oxy ]phenyl]pyrrolidin-3- yl]acetamide

[0539] Step 1: 2-ethoxy-A-[(3S)-l-[3-[[2-methyl-6-(trifluoromethyl)-3-pyridyl]oxy]phenyl]pyrrolidin-3- yl]acetamide

[0540]

[0375] 2-Ethoxy-A-[(3S)-l-(3-hydroxyphenyl)pyrrolidin-3-yl]acetamide (50.0 mg, 0.189 mmol) was added to a mixture of 3-bromo-2-methyl-6-(trifluoromethyl)pyridine (68.1 mg, 0.284 mmol) and CS2CO3 (92.5 mg, 0.284 mmol) in DMF (1.00 mL) at 22 °C under nitrogen. The mixture was stirred at 100 °C for 16 h and concentrated. The residue was purified by silica gel chromatography (4 g cartridge) with DCM and MeOH (0-10%), and by reverse phase chromatography (C18, 12 g cartridge) with water and MeCN (10-100%) to provide the title compound as a solid (12.0 mg, 15%). ’H NMR (400 MHz, DMSO-Je) 5 7.93 (d, J = 7.4 Hz, 1H), 7.67 (d, J = 8.5 Hz, 1H), 7.28 - 7.18 (m, 2H), 6.46 - 6.39 (m, 1H), 6.33 - 6.26 (m, 2H), 4.48 - 4.39 (m, 1H), 3.83 (s, 2H), 3.52 - 3.42 (m, 3H), 3.38 - 3.34 (m, 1H), 3.23 (d, J = 9.6 Hz, 1H), 3.11 (dd, J = 9.8, 5.3 Hz, 1H), 2.54 (s, 3H), 2.21 - 2.10 (m, 1H), 2.02 - 1.93 (m, 1H), 1.13 (t, J = 7.0 Hz, 3H). m / z (ES)+[M+H]+= 424.3; UPLC (BEH_AmmBicarb) 1R = 5.11 min.

[0541] Ex. 68, 2-ethoxy-A-[(3S)-l-[3-methoxy-5-[2-(trifluoromethyl)pyrimidin-5-yl]oxy-phenyl]pyrrolidin- 3-yl]acetamide

[0542] Step 1 : 5-(3-bromo-5-methoxy-phenoxy)-2-(trifluoromethyl)pyrimidine

[0543]

[0376] 3-Bromo-5-methoxy-phenol (800 mg, 3.94 mmol) was added to a mixture of 5-bromo-2- (trifluoromethyl)pyrimidine (984 mg, 4.33 mmol) and CS2CO3 (1.93 g, 5.91 mmol) in DMF (15.0 mL) at 22 °C under nitrogen. The mixture was stirred at 100 °C for 16 h and concentrated. The residue was purified by silica gel chromatography (40 g cartridge) with hexanes and EtOAc (0-100%) to provide the title compound as an oil (1.28 g, 93%). m / z (ES)+[M+H]+= 349.2; HPLC (A05) tR= 2.51 min.

[0544] Step 2: tert-butyl Af-[(3S)-l-[3-methoxy-5-[2-(trifluoromethyl)pyrimidin-5-yl]oxy- phenyl]pyrrolidin-3-yl]carbamate

[0545]

[0377] tert- Butyl A-[(35)-pyrrolidin-3-yl]carbamate (751 mg, 4.03 mmol) was added to a mixture of 5-(3- bromo-5-methoxy-phenoxy)-2-(trifluoromethyl)pyrimidine (1.28 g, 3.67 mmol), RuPhos Pd G3 (613 mg, 0.733 mmol) and CS2CO3 (2.99 g, 9.17 mmol) in 1,4-dioxane (15.0 mL) at 22 °C under nitrogen. The mixture was stirred at 120 °C for 3 h and concentrated. The residue was purified by silica gel chromatography (40 g cartridge) with hexanes and EtOAc (0-100%) to provide the title compound as a solid (1.20 g, 65%). m z (ES)+[M+H]+= 455.4; HPLC (A05) tR= 2.57 min.

[0546] Step 3: (3S)-l-[3-methoxy-5-[2-(trifluoromethyl)pyrimidin-5-yl]oxy-phenyl]pyrrolidin-3-amine hydrochloride

[0547]

[0378] tert-Butyl A-[(35)-l-[3-methoxy-5-[2-(trifluoromethyl)pyrimidin-5-yl]oxy-phenyl]pyrrolidin-3- yl]carbamate (1.20 g, 2.64 mmol) was added to a mixture of HC1 (4.0 M solution in 1,4-dioxane, 6.60 mL, 26.4 mmol) in DCM (6.00 mL) at 22 °C under nitrogen. The mixture was stirred at 22 °C for 3 h and concentrated to provide the title compound as a solid (1.00 g, 97%). ’H NMR (300 MHz, DMSO-cL) 5 8.73 (s, 2H), 8.25 (br s, 3H), 6.19 (dd, 7= 2.1, 2.1 Hz, 1H), 6.08 (dd, 7 = 2.1, 2.1 Hz, 1H), 6.01 (dd, 7 = 2.1, 2.1 Hz, 1H), 3.73 (s, 3H), 3.53 - 3.44 (m, 2H), 3.35 - 3.23 (m, 3H), 2.38 - 2.20 (m, 1H), 2.15 - 2.00 (m, 1H). m / z (ES)+[M+H-HC1]+= 356.3; HPLC (A05) tR= 1.98 min.

[0548] Step 4: 2-ethoxy- / V-[(3S)-l-[3-methoxy-5-[2-(trifluoromethyl)pyrimidin-5-yl]oxy-phenyl]pyrrolidin- 3-yl]acetamide

[0549]

[0379] DIPEA (175 pL, 1.02 mmol) was added to mixture of 2-ethoxyacetic acid (25.4 pL, 0.269 mmol) and HATU (107 mg, 0.281 mmol) in DMF (1.00 mL) at 22 °C under nitrogen. After 5 min, (35)-l-[3- methoxy-5-[2-(trifluoromethyl)pyrimidin-5-yl]oxy-phenyl]pyrrolidin-3-amine hydrochloride (100 mg, 0.256 mmol) was added to the mixture, and it was stirred at 22 °C for 16 h and concentrated. The residue was purified by silica gel chromatography (4 g cartridge) with hexanes and EtOAc (0-100%), and by reverse phase chromatography (Cl 8, 12 g cartridge) with water and MeCN (10-100%) to provide the title compound as an oil (27.1 mg, 22%). ’H NMR (400 MHz, DMSO-t / e) 5 8.73 (s, 2H), 7.92 (d, J= 7.3 Hz, 1H), 6.11 (dd, J = 2.1, 2.1 Hz, 1H), 6.02 (dd, J = 2.1, 2.1 Hz, 1H), 5.97 (dd, J = 2.1, 2.1 Hz, 1H), 4.49 - 4.36 (m, 1H), 3.83 (s, 2H), 3.72 (s, 3H), 3.52 - 3.42 (m, 3H), 3.40 - 3.32 (m, 1H), 3.28 - 3.20 (m, 1H), 3.10 (dd, 7 = 9.9, 5.4 Hz, 1H), 2.21 - 2.09 (m, 1H), 2.03 - 1.90 (m, 1H), 1.13 (t, 7= 7.0 Hz, 3H). m / z (ES)+[M+H]+= 441.3; UPLC (BEH_AmmBicarb) tR = 4.65 min.

[0550] Ex. 69, 2-methoxy- / V-[(37?,4S)-4-methoxy-l-[3-[2-(trifluoromethyl)pyrimidin-5- yl]oxyphenyl]pyrrolidin-3-yl]acetamide

[0551] Step 1: tert-butyl iV-[(31f,4S)-4-hydroxy-l-[3-[2-(trifluoromethyl)pyrimidin-5- yl]oxyphenyl]pyrrolidin-3-yl]carbamate

[0552]

[0380] tert- Butyl A-[(3R,4y)-4-hydroxypyrrolidin-3-yl]carbamate (229 mg, 0.904 mmol) was added to a mixture of 5-(3-iodophenoxy)-2-(trifluoromethyl)pyrimidine (301 mg, 0.822 mmol), RuPhos Pd G3 (68.8 mg, 82.2 pmol) and CS2CO3 (669 mg, 2.05 mmol) in 1,4-dioxane (6.00 mL) at 22 °C under nitrogen. The mixture was stirred at 120 °C for 1 h and concentrated. The residue was purified by silica gel chromatography (25 g cartridge) with hexanes and EtOAc (0-80%) to provide the title compound as a solid (246 mg, 68%). m / z (ES+) [M+H-BOC? = 340.98; HPLC (A05) tR= 2.44 min.

[0553] Step 2: tert-butyl iV-[(31f,4S)-4-methoxy-l-[3-[2-(trifluoromethyl)pyrimidin-5- yl]oxyphenyl]pyrrolidin-3-yl]carbamate

[0554]

[0381] lodomethane (348 pL, 5.59 mmol) was added to mixture of tert-butyl A / -|(3 / ?.4.S')-4-hydroxy- l -|3- [2-(trifluoromethyl)pyrimidin-5-yl]oxyphenyl]pyrrolidin-3-yl]carbamate (246 mg, 0.559 mmol) and Ag2O (647 mg, 2.79 mmol) in MeCN (6.00 mL) at 22 °C under nitrogen. The mixture was stirred at 22 °C for 18 h and concentrated. The residue was purified by silica gel chromatography (25 g cartridge) with hexanes and EtOAc (0-40%) to provide the title compound as an oil (156 mg, 62%). m / z (ES+) [M+H- Boc]+= 355.67; HPLC (A05) tR= 2.63 min.

[0555] Step 3: (31?,4S)-4-methoxy-l-[3-[2-(trifluoromethyl)pyrimidin-5-yl]oxyphenyl]pyrrolidin-3-amine hydrochloride

[0556]

[0382] tert-Butyl A-[(3R,45)-4-methoxy-l-[3-[2-(trifluoromethyl)pyrimidin-5-yl]oxyphenyl]pyrrolidin-3- yl]carbamate (156 mg, 0.343 mmol) was dissolved in HC1 (4.0 M in 1,4-dioxane, 1.72 mL, 6.87 mmol) at 22 °C under nitrogen. The mixture was stirred at 22 °C for 4 h and concentrated to provide the title compound as a solid (109 mg, 81%). m / z (ES+) [M+H-HC1]+= 355.54; HPLC (A05) tR= 2.00 min.

[0557] Step 4: 2-methoxy- / V-[(3R,4S)-4-methoxy-l-[3-[2-(trifluoromethyl)pyrimidin-5- yl]oxyphenyl]pyrrolidin-3-yl]acetamide

[0558]

[0383] DIPEA (63.9 pL, 0.373 mmol) was added to mixture of 2-methoxyacetic acid (10.0 pL, 0.131 mmol) and HATU (52.0 mg, 0.137 mmol) in DCM (3.00 mL) at 0 °C under nitrogen. After 5 min, (37?,4 )-4-methoxy-l-[3-[2-(trifluoromethyl)pyrimidin-5-yl]oxyphenyl]pyrrolidin-3-amine hydrochloride (48.6 mg, 0.124 mmol) was added to the mixture, and it was stirred at 22 °C for 1 h and concentrated. The residue was purified by silica gel chromatography (25 g cartridge) with DCM and MeOH (0-10%), by reverse phase chromatography (C18, 12 g cartridge) with water (10 mM NH4HCO2) and MeCN (5- 100%), and by preparative HPLC (BEH, Cl 8) with water (10 mM NH4HCO3) and MeCN (50-60%) to provide the title compound as an oil (42 mg, 79%). ’H NMR (400 MHz, DMSO-cA,) 5 8.74 (s, 2H), 7.53 (d, J= 8.1 Hz, 1H), 7.26 (dd, J= 8.1, 8.1 Hz, 1H), 6.47 (d, 7= 2.2 Hz, 1H), 6.45 (d, J = 2.3 Hz, 1H), 6.41 (dd, 7= 2.3, 2.3 Hz, 1H), 4.60 - 4.47 (m, 1H), 4.04 - 3.95 (m, 1H), 3.86 (s, 2H), 3.51 (dd, 7 = 9.5, 7.7 Hz, 1H), 3.46 - 3.39 (m, 2H), 3.32 (s, 3H), 3.29 (s, 3H), 3.16 - 3.07 (m, 1H). m / z (ES+) [M+H]+= 427.16; UPLC (BEH AmmBicarb) tR= 4.45 min.

[0559] Ex. 70, 2-(l-isopropylpyrazol-4-yl)oxy-iV-[(3S)-l-[3-methoxy-5-[2-(trifluoromethyl)pyrimidin-5- yl]oxy-phenyl]pyrrolidin-3-yl]acetamide

[0560] Step 1: 2-bromo-iV-[(3S)-l-[3-methoxy-5-[2-(trifluoromethyl)pyrimidin-5-yl]oxy-phenyl]pyrrolidin- 3-yl]acetamide

[0561]

[0384] (3S)-l-[3-Methoxy-5-[2-(trifluoromethyl)pyrimidin-5-yl]oxy-phenyl]pyrrolidin-3-amine hydrochloride (100 mg, 0.256 mmol) was added to a mixture of TEA (107 pL, 0.768 mmol) in DCM (2.00 mL) at 0 °C under nitrogen. 2-Bromoacetyl chloride (23.4 pL, 0.281 mmol) was added dropwise to the mixture, and it was stirred at 22 °C for 2 h. The mixture was diluted with water (20.0 mL). The aqueous phase was extracted with EtOAc (3 x 50.0 mL), and the combined organic phases were washed with brine (25.0 mL), dried (MgSCL), filtered, and concentrated. The residue was purified by silica gel chromatography (12 g cartridge) with hexanes and EtOAc (0-100%) to provide the title compound as a solid (70.0 mg, 58%). m / z (ES)+[M+2H]+= 477.3; HPLC (A05) 1R = 2.37 min.

[0562] Step 2: 2-(l-isopropylpyrazol-4-yl)oxy-Af-[(3S)-l-[3-methoxy-5-[2-(trifluoromethyl)pyrimidin-5- yl]oxy-phenyl]pyrrolidin-3-yl]acetamide

[0563]

[0385] l-Isopropylpyrazol-4-ol (20.4 mg, 0.162 mmol) was added to a mixture of NaH (60% dispersion in mineral oil, 6.21 mg, 0.162 mmol) in THF (1.00 mL) at 0 °C under nitrogen, and the mixture was stirred for 30 min. 2-Bromo-A-[(3S)-l-[3-methoxy-5-[2-(trifluoromethyl)pyrimidin-5-yl]oxy-phenyl]pyrrolidin- 3-yl]acetamide (70.0 mg, 0.147 mmol) in THF (1.00 mL) was added to the mixture, and it was stirred at 22 °C for 16 h. The mixture was diluted with z'PrOH (10.0 mL). The residue was purified by silica gel chromatography (4 g cartridge) with hexanes and EtOAc (0-100%), and by reverse phase chromatography (Cl 8, 12 g cartridge) with water and MeCN (10-100%) to provide the title compound as an oil (2.00 mg, 3%). 'H NMR (400 MHz, DMSO-76) 5 8.73 (s, 2H), 8.42 (d, J= 6.8 Hz, 1H), 7.39 (d, J = 0.9 Hz, 1H), 7.16 (d, 7= 0.9 Hz, 1H), 6.12 (dd, 7= 2.1, 2.1 Hz, 1H), 6.04 (dd, 7= 2.1, 2.1 Hz, 1H), 5.99 - 5.97 (m, 1H), 4.63 (s, 2H), 4.41 - 4.32 (m, 1H), 4.18 - 4.09 (m, 1H), 3.72 (s, 3H), 3.48 (dd, 7 = 10.1, 6.3 Hz, 1H), 3.39 - 3.34 (m, 1H), 3.29 - 3.25 (m, 1H), 3.07 (dd, 7 = 10.1, 4.1 Hz, 1H), 2.21 - 2.13 (m, 1H), 1.93 - 1.87 (m, 1H), 1.21 (d, 7 = 6.1 Hz, 6H). m / z (ES)+[M+H]+= 521.3; UPLC (BEH_AmmBicarb) tR = 4.85 min.

[0564] Ex. 71, 2-(l-ethylpyrazol-4-yl)oxy-A [(3S)-l-[3-[2-(trifluoromethyl)pyrimidin-5- yl]oxyphenyl]pyrrolidin-3-yl]acetamide Step 1: 2-bromo-iV-[(3S)-l-[3-[2-(trifluoromethyl)pyrimidin-5-yl]oxyphenyl]pyrrolidin-3- yl]acetamide

[0565]

[0386] (3S)-l-[3-[2-(Trifluoromethyl)pyrimidin-5-yl]oxyphenyl]pyrrolidin-3-amine hydrochloride (100 mg, 0.277 mmol) was added to a mixture of TEA (116 pL, 0.832 mmol) in DCM (2.00 mL) at 0 °C under nitrogen. 2-Bromoacetyl chloride (25.4 pL, 0.305 mmol) was added dropwise to the mixture, and it was stirred at 22 °C for 2 h. The mixture was diluted with water (20.0 mL). The aqueous phase was extracted with EtOAc (3 x 50.0 mL), and the combined organic phases were washed with brine (25.0 mL), dried (MgSCL), filtered, and concentrated. The residue was purified by silica gel chromatography (12 g cartridge) with hexanes and EtOAc (0-100%) to provide the title compound as a solid (50.0 mg, 41%). m / z (ES)+[M+2H]+= 448.3; HPLC (A05) tR= 2.36 min.

[0566] Step 2: 2-(l-ethylpyrazol-4-yl)oxy-iV-[(3S)-l-[3-[2-(trifluoromethyl)pyrimidin-5- yl]oxyphenyl]pyrrolidin-3-yl]acetamide

[0567]

[0387] l-Ethylpyrazol-4-ol (13.9 mg, 0.124 mmol) was added to a mixture of NaH (60% dispersion in mineral oil, 4.73 mg, 0.124 mmol) in THF (1.00 mL) at 0 °C under nitrogen, and the mixture was stirred for 30 min. 2-Bromo-A-[(35)-l-[3-[2-(trifluoromethyl)pyrimidin-5-yl]oxyphenyl]pyrrolidin-3- yl]acetamide (50.0 mg, 0.112 mmol) in THF (1.00 mL) was added to the mixture, and it was stirred at 22 °C for 16 h. The mixture was diluted with z'PrOH (10.0 mL). The residue was purified by silica gel chromatography (4 g cartridge) with hexanes and EtOAc (0-100%), and by reverse phase chromatography (Cl 8, 12 g cartridge) with water and MeCN (10-100%) to provide the title compound as an oil (15.1 mg, 24%). >H NMR (400 MHz, DMSO-zL) 5 8.68 (s, 2H), 8.39 (d, J= 6.9 Hz, 1H), 7.35 (d, J = 0.9 Hz, 1H), 7.21 (dd, J= 8.1, 8.1 Hz, 1H), 7.12 (d, J= 0.9 Hz, 1H), 6.46 - 6.36 (m, 3H), 4.58 (s, 2H), 4.36 - 4.30 (m, 1H), 3.81 (q, 7= 7.0 Hz, 2H), 3.44 (dd, 7= 10.1, 6.3 Hz, 1H), 3.38 - 3.28 (m, 1H), 3.23 - 3.21 (m, 1H), 3.04 (dd, 7= 10.1, 4.0 Hz, 1H), 2.21 - 2.08 (m, 1H), 1.92 - 1.81 (m, 1H), 1.21 (t, J = 7.0 Hz, 3H). m / z (ES)+[M+H]+= 477.3; UPLC (BEH_AmmBicarb) tR= 4.61 min.

[0568] Ex. 12, 2-ethoxy-Af-[(31?,4S)-4-methoxy-l-[3-[2-(trifluoromethyl)pyrimidin-5- yl]oxyphenyl]pyrrolidin-3-yl]acetamide

[0569] Step 1: 2-ethoxy-Af-[(31f,4S)-4-methoxy-l-[3-[2-(trifluoromethyl)pyrimidin-5- yl]oxyphenyl]pyrrolidin-3-yl]acetamide

[0570]

[0388] DIPEA (27.6 pL, 0.161 mmol) was added to mixture of 2-ethoxyacetic acid (5.58 pL, 59.1 pmol) and HATU (22.5 mg, 59.1 pmol) in DCM (1.00 mL) at 0 °C under nitrogen. After 5 min, (3R,45)-4- methoxy- 1 - [3 - [2- (trifluoromethyl)pyrimidin-5 -yl] oxyphenyl] pyrrolidin-3 -amine hydrochloride (21.0 mg, 53.7 pmol) was added to the mixture, and it was stirred at 22 °C for 1 h and concentrated. The residue was purified by preparative HPLC (BEH, C18) with water (10 mM NH4HCO3) and MeCN (53-63%) to provide the title compound as a solid (12.0 mg, 51%). ’H NMR (400 MHz, DMSO-Je) 58.74 (s, 2H), 7.49 (d, J= 8.0 Hz, 1H), 7.26 (dd, J= 8.1, 8.1 Hz, 1H), 6.47 (d, 7 = 2.3 Hz, 1H), 6.45 (d, J = 2.3 Hz, 1H), 6.41 (dd, J = 2.2, 2.2 Hz, 1H), 4.56 - 4.48 (m, 1H), 4.04 - 3.97 (m, 1H), 3.89 (d, J = 0.9 Hz, 2H), 3.56 - 3.46 (m, 3H), 3.45 - 3.39 (m, 2H), 3.32 (s, 3H), 3.16 - 3.06 (m, 1H), 1.15 (t, J = 7.0 Hz, 3H). m / z (ES)+[M+H]+= 441.3; UPLC (BEH_AmmBicarb) tR= 4.80 min.

[0571] Ex. 129, 2-(l-methylpyrazol-4-yl)oxy- / V-[(3S)-l-[3-[2-(trifluoromethyl)pyrimidin-5- yl]oxyphenyl]pyrrolidin-3-yl]acetamide

[0572] Step 1: 2-(l-methylpyrazol-4-yl)oxy-iV-[(3S)-l-[3-[2-(trifluoromethyl)pyrimidin-5- yl]oxyphenyl]pyrrolidin-3-yl]acetamide

[0573]

[0389] l-Methylpyrazol-4-ol (6.30 mg, 64.2 pmol) was added to a mixture of NaH (60% dispersion in mineral oil, 2.46 mg, 64.2 pmol) in THF (1.00 mL) at 0 °C under nitrogen, and the mixture was stirred for 30 min. 2-Bromo-A-[(3S)-l-[3-[2-(trifluoromethyl)pyrimidin-5-yl]oxyphenyl]pyrrolidin-3- yl]acetamide (26.0 mg, 58.4 pmol) in THF (1.00 mL) was added to the mixture, and it was stirred at 22 °C for 16 h. The mixture was diluted with z'PrOH (10.0 mL). The residue was purified by silica gel chromatography (4 g cartridge) with hexanes and EtOAc (0-100%), and by reverse phase chromatography (Cl 8, 12 g cartridge) with water and MeCN (10-100%) to provide the title compound as an oil (12.6 mg, 40%). *H NMR (400 MHz, DMSO-zL) 5 8.73 (s, 2H), 8.28 (d, J = 7.1 Hz, 1H), 7.42 (d, J = 0.9 Hz, 1H), 7.29 - 7.22 (m, 1H), 7.17 (d, J = 0.9 Hz, 1H), 6.46 (ddd, J= 9.8, 6.6, 2.3 Hz, 2H), 6.41 (d, 7 = 2.4 Hz, 1H), 4.49 - 4.41 (m, 1H), 4.29 (s, 2H), 3.73 - 3.69 (m, 3H), 3.48 (dd, J= 10.0, 6.7 Hz, 1H), 3.40 - 3.34 (m, 1H), 3.27 - 3.23 (m, 1H), 3.13 (dd, J = 9.9, 4.9 Hz, 1H), 2.22 - 2.14 (m, 1H), 2.02 - 1.94 (m, 1H). m / z (ES)+[M+H]+= 463.3; UPLC (BEH_AmmBicarb) 1R = 4.22 min.

[0574] Ex. 73, iV-[(3S)-l-[3-(2-cyclopropylpyrimidin-5-yl)oxyphenyl]pyrrolidin-3-yl]-2-ethoxy-acetamide

[0575] Step 1: 2-cyclopropyl-5-iodo-pyrimidine

[0576]

[0390] 5-Bromo-2-cyclopropyl-pyrimidine (500 mg, 2.51 mmol) was added to a mixture of Cui (95.7 mg, 0.502 mmol), Nal (377 mg, 2.51 mmol) and DMEDA (108 pL, 1.00 mmol) in 1,4-dioxane (5.00 mL) at 22 °C under nitrogen. The mixture was stirred at 120 °C for 18 h and diluted with H2O (50.0 mL). The aqueous phase was extracted with EtOAc (3 x 50.0 mL), and the combined organic phases were washed with brine (50.0 mL), dried (MgSCL), filtered, and concentrated to provide the title compound as a solid (574 mg, 93%). m / z (ES)+[M+H]+= 247.1; HPLC (A05) tR= 2.20 min.

[0577] Step 2: .V-[(3.S )- l-[3-(2-Cyclopropylpyrimidin-5-yl )oxy phenyl ]pyrrolidin-3-yl]-2-ethoxy-acetamide

[0578]

[0391] 2-Ethoxy-A-[(35)-l-(3-hydroxyphenyl)pyrrolidin-3-yl]acetamide (200 mg, 0.757 mmol) was added to a mixture of 2-cyclopropyl-5 -iodo-pyrimidine (279 mg, 1.13 mmol), K3PO4 (321 mg, 1.51 mmol), Cu(MeCN)4BF4 (23.8 mg, 75.7 pmol) and 2-(2-pyridyl)pyridine (23.6 mg, 0.151 mmol) in DMSO (4.00 mL) at 22 °C under nitrogen. The mixture was stirred at 100 °C for 16 h. The residue was purified by silica gel chromatography (4 g cartridge) with DCM and MeOH (0-10%), and by reverse phase chromatography (Cl 8, 12 g cartridge) with water and MeCN (10-100%) to provide the title compound as a solid (58.0 mg, 20%). >H NMR (400 MHz, DMSO-de) 5 8.41 (s, 2H), 7.93 (d, 7= 7.3 Hz, 1H), 7.20 - 7.11 (m, 1H), 6.39 - 6.31 (m, 1H), 6.25 - 6.20 (m, 2H), 4.42 (h, J= 5.9 Hz, 1H), 3.83 (s, 2H), 3.51 - 3.42 (m, 3H), 3.38 - 3.32 (m, 1H), 3.27 - 3.20 (m, 1H), 3.09 (dd, J = 9.8, 5.2 Hz, 1H), 2.25 - 2.10 (m, 2H), 2.03 - 1.90 (m, 1H), 1.13 (t, J= 7.0 Hz, 3H), 1.05 - 0.99 (m, 2H), 0.97 - 0.92 (m, 2H). m / z (ES)+[M+H]+= 383.3; UPLC (BEH AmmBicarb) tR= 4.19 min.

[0579] Ex. 74, A-[(3S)-l-[3-ethoxy-5-[2-(trifluoromethyl)pyrimidin-5-yl]oxy-phenyl]pyrrolidin-3-yl]-2- methoxy-acetamide

[0580]

[0392] 5-Bromobenzene-l,3-diol (1.00 g, 5.29 mmol) was added to a mixture of iodoethane (425 pL, 5.29 mmol) and CS2CO3 (1.90 g, 5.82 mmol) in MeCN (25.0 mL) at 22 °C under nitrogen. The mixture was stirred at 70 °C for 16 h and concentrated. The residue was purified by silica gel chromatography (40 g cartridge) with hexanes and EtOAc (0-100%) to provide the title compound as an oil (453 mg, 39%). m / z (ES) [M-H] = 217.1; HPLC (A05) tR= 2.24 min.

[0581] Step 2: 5-(3-bromo-5-ethoxy-phenoxy)-2-(trifluoromethyl)pyrimidine

[0582]

[0393] 3-Bromo-5-ethoxy-phenol (200 mg, 0.921 mmol) was added to a mixture of 5-bromo-2- (trifluoromethyl)pyrimidine (230 mg, 1.01 mmol) and CS2CO3 (450 mg, 1.38 mmol) in DMF (3.00 mL) at 22 °C under nitrogen. The mixture was stirred at 100 °C for 16 h and concentrated. The residue was purified by silica gel chromatography (24 g cartridge) with hexanes and EtOAc (0-100%) to provide the title compound as an oil (275 mg, 82%). m / z (ES)+[M+H]+= 363.1; HPLC (A05) tR= 2.62 min.

[0583] Step 3: Af-[(3S)-l-[3-ethoxy-5-[2-(trifluoromethyl)pyrimidin-5-yl]oxy-phenyl]pyrrolidin-3-yl]-2- methoxy-acetamide

[0584]

[0394] 2-Methoxy-A-[(3S)-pyrrolidin-3-yl]acetamide hydrochloride (59.0 mg, 0.303 mmol) was added to a mixture of 5-(3-bromo-5-ethoxy-phenoxy)-2-(trifluoromethyl)pyrimidine (100 mg, 0.275 mmol), RuPhos Pd G3 (46.1 mg, 55.1 pmol) and NaOtBu (66.2 mg, 0.688 mmol) in 1,4-dioxane (1.50 mL) at 22 °C under nitrogen. The mixture was stirred at 120 °C for 3 h and concentrated. The residue was purified by silica gel chromatography (24 g cartridge) with hexanes and EtOAc (0-100%), and by reverse phase chromatography (Cl 8, 12 g cartridge) with water and MeCN (10-100%) to provide the title compound as a solid (32.9 mg, 24%). >H NMR (400 MHz, DMSO-de) 5 8.69 (s, 2H), 7.96 (d, 7= 7.3 Hz, 1H), 6.05 (dd, 7= 2.1, 2.1 Hz, 1H), 5.96 (dd, 7 = 2.1, 2.1 Hz, 1H), 5.91 (dd, 7 = 2.1, 2.1 Hz, 1H), 4.43 - 4.32 (m, 1H), 3.95 (q, 7= 6.9 Hz, 2H), 3.76 (s, 2H), 3.46 - 3.37 (m, 1H), 3.34 - 3.29 (m, 1H), 3.25 (s, 3H), 3.22 - 3.16 (m, 1H), 3.05 (dd, 7= 9.9, 5.3 Hz, 1H), 2.16 - 2.04 (m, 1H), 1.99 - 1.86 (m, 1H), 1.25 (t, 7= 7.0 Hz, 3H). m / z (ES)+[M+H]+= 441.3; UPLC (BEH_AmmBicarb) tR= 4.70 min.

[0585] Ex. 75, 2-ethoxy- / V-[(3S)-l-[3-ethoxy-5-[2-(trifluoromethyl)pyrimidin-5-ylJoxy-phenyl]pyrrolidin-3- yl]acetamide

[0586]

[0587] Step 1 : tert-butyl V-| (3.8 )- 1 -[ 3-ethoxy-5-[ 2-( trifhioromethvl )py rimidin-5-y 1 ]oxy-phenyl ] pyrrolidin- 3-yl]carbamate

[0588]

[0395] tert-Butyl A-[(35)-pyrrolidin-3-yl]carbamate (95.9 mg, 0.515 mmol) was added to a mixture of 5- (3-bromo-5-ethoxy-phenoxy)-2-(trifluoromethyl)pyrimidine (170 mg, 0.468 mmol), RuPhos Pd G3 (39.2 mg, 46.8 pmol) and CS2CO3 (305 mg, 0.936 mmol) in 1,4-dioxane (8.00 mL) at 22 °C under nitrogen. The mixture was stirred at 120 °C for 3 h and concentrated. The residue was purified by silica gel chromatography (25 g cartridge) with hexanes and EtOAc (0-60%) to provide the title compound as an oil (111 mg, 51%). m / z (ES+) [M-tBu+H]+= 414.28; HPLC (A05) tR= 2.65 min.

[0589] Step 2: (3S)-l-[3-ethoxy-5-[2-(trifluoromethyl)pyrimidin-5-yl]oxy-phenyl]pyrrolidin-3-amine hydrochloride

[0590]

[0396] tert-Butyl A-[(35)-l-[3-ethoxy-5-[2-(trifluoromethyl)pyrimidin-5-yl]oxy-phenyl]pyrrolidin-3- yl]carbamate (111 mg, 0.237 mmol) was dissolved in HC1 (4.0 M in 1,4-dioxane, 1.18 mL, 4.74 mmol) at 22 °C under nitrogen. The mixture was stirred at 22 °C for 18 h and concentrated to provide the title compound as a solid (95.9 mg, >98%). m / z (ES+) [M+H-HC1]+= 369.65; HPLC (A05) tR= 2.06 min. Step 3: Af-[(3S)-l-[3-ethoxy-5-[2-(trifluoromethyl)pyrimidin-5-yl]oxy-phenyl]pyrrolidin-3-yl]-2- methoxy-acetamide

[0591]

[0397] DIPEA (122 pL, 0.711 mmol) was added to mixture of 2-ethoxyacetic acid (25.0 pL, 0.249 mmol) and HATU (99.1 mg, 0.261 mmol) in DMF (6.00 mL) at 0 °C under nitrogen. After 5 min, (35)-l-[3- ethoxy-5-[2-(trifluoromethyl)pyrimidin-5-yl]oxy-phenyl]pyrrolidin-3-amine hydrochloride (95.9 mg, 0.237 mmol) was added to the mixture, and it was stirred at 22 °C for 1 h and concentrated. The residue was purified by silica gel chromatography (25 g cartridge) with DCM and MeOH (0-10%), and by reverse phase chromatography (C18, 12 g cartridge) with water (10 mM NH4HCO2) and MeOH (5- 100%) to provide the title compound as a solid (40.1 mg, 37%). ’H NMR (400 MHz, DMSO-<() 5 8.73 (s, 2H), 7.92 (d, 7= 7.3 Hz, 1H), 6.09 (dd, J = 2.1, 2.1 Hz, 1H), 6.01 (dd, J = 2.0, 2.0 Hz, 1H), 5.95 (dd, J = 2.0, 2.0 Hz, 1H), 4.48 - 4.37 (m, 1H), 3.99 (q, J = 7.0 Hz, 2H), 3.83 (s, 2H), 3.52 - 3.41 (m, 3H), 3.38 - 3.33 (m, 1H), 3.27 - 3.20 (m, 1H), 3.09 (dd, J = 9.9, 5.3 Hz, 1H), 2.21 - 2.09 (m, 1H), 2.03 - 1.90 (m, 1H), 1.29 (t, J = 7.0 Hz, 3H), 1.13 (t, J = 7.0 Hz, 3H). m / z (ES+) [M+H]+= 455.19; HPLC (BEH_AmmBicarb) tR = 5.01 min.

[0592] Ex. 76, 2-ethoxy-iV-[(3S)-l-[3-(trifluoromethoxy)-5-[2-(trifluoromethyl)pyrimidin-5-yl]oxy- phenyl]pyrrolidin-3-yl]acetamide

[0593] Step 1: Af-[(3S)-l-benzylpyrrolidin-3-yl]-2-ethoxy-acetamide

[0398] DIPEA (1.38 mL, 8.05 mmol) was added to mixture of 2-ethoxyacetic acid (284 pL, 2.82 mmol) and HATU (1.12 g, 2.95 mmol) in DCM (25.0 mL) at 0 °C under nitrogen. After 5 min, (3.8)- 1 - benzylpyrrolidin-3-amine (445 pL, 2.68 mmol) was added to the mixture, and it was stirred at 22 °C for 4 h and concentrated. The residue was purified by silica gel chromatography (40 g cartridge) with DCM and MeOH (0-5%) to provide the title compound as an oil (728 mg, >98%). ’H NMR (300 MHz,CDCL) 57.38 - 7.27 (m, 5H), 7.03 (d, J = 7.4 Hz, 1H), 4.56 - 4.37 (m, 1H), 3.88 (s, 2H), 3.78 (s, 2H), 3.55 (q, J = 6.8 Hz, 2H), 3.05 (td, J = 9.0, 3.9 Hz, 1H), 2.88 - 2.75 (m, 2H), 2.46 - 2.33 (m, 2H), 1.82 - 1.67 (m, 1H), 1.24 (t, J = 7.0 Hz, 3H). m / z (ES+) [M+H]+= 263.29; HPLC (A05) tR= 1.12 min.

[0594] Step 2: 2-ethoxy-iV-[(3S)-pyrrolidin-3-yl]acetamide

[0595]

[0399] A solution of A-[(35)-l-benzylpyrrolidin-3-yl]-2-ethoxy-acetamide (728 mg, 2.64 mmol, in 10.0 mL of EtOAc) was added to a mixture of Pd / C (10 wt.%, 281 mg, 0.264 mmol) in MeOH (10.0 mL) at 22°C under nitrogen. The mixture was purged under 1 atm of hydrogen and stirred at 22 °C for 8 h. The mixture was filtered over a pad of Celite®, rinsed with MeOH (50.0 mL) and DCM (50.0 mL), and the filtrate was concentrated to provide the title compound as an oil (494 mg, >98%). ’H NMR (300 MHz, CDCL) 56.76 - 6.65 (m, 1H), 4.45 - 4.33 (m, 1H), 3.90 (s, 2H), 3.56 (q, J = 7.0 Hz, 2H), 3.22 - 3.13 (m, 1H), 3.13 - 3.03 (m, 1H), 3.03 - 2.88 (m, 1H), 2.81 (dd, 7= 11.5, 3.7 Hz, 1H), 2.26 - 2.10 (m, 1H), 1.73 - 1.58 (m, 1H), 1.23 (t, 7 = 7.0 Hz, 3H).

[0596] Step 3: 5-[3-bromo-5-(trifluoromethoxy)phenoxy]-2-(trifluoromethyl)pyrimidine

[0597]

[0400] 3-Bromo-5-(trifluoromethoxy)phenol (100 mg, 0.389 mmol) was added to a mixture of 5-bromo-2- (trifluoromethyl)pyrimidine (97.2 mg, 0.428 mmol) and CS2CO3 (190 mg, 0.584 mmol) in DMF (1.00 mL) at 22 °C under nitrogen. The mixture was stirred at 100 °C for 16 h and concentrated. The residue was purified by silica gel chromatography (12 g cartridge) with hexanes and EtOAc (0-100%) to provide the title compound as an oil (118 mg, 75%). m / z (ES)+[M+H]+= 403.2; HPLC (A05) tR= 2.60 min.

[0598] Step 4: 2-ethoxy-iV-[(3S)-l-[3-(trifluoromethoxy)-5-[2-(trifluoromethyl)pyrimidin-5-yl]oxy- phenyl]pyrrolidin-3-yl]acetamide

[0401] 2-Ethoxy-A-[(35)-pyrrolidin-3-yl]acetamide (61.6 mg, 0.322 mmol) was added to a mixture of 5- [3-bromo-5-(trifluoromethoxy)phenoxy]-2-(trifluoromethyl)pyrimidine (118 mg, 0.293 mmol), RuPhos Pd G3 (24.5 mg, 29.3 pmol) and CS2CO3 (238 mg, 0.732 mmol) in 1,4-dioxane (2.50 mL) at 22 °C under nitrogen. The mixture was stirred at 100 °C for 1 h and concentrated. The residue was purified by silica gel chromatography (4 g cartridge) with hexanes and EtOAc (0-100%), and by reverse phase chromatography (Cl 8, 12 g cartridge) with water and MeCN (10-100%) to provide the title compound as a solid (55.7 mg, 39%). 'H NMR (400 MHz, DMSO-de) 5 8.80 (s, 2H), 7.97 (d, 7= 7.3 Hz, 1H), 6.52 - 6.47 (m, 1H), 6.47 - 6.41 (m, 1H), 6.38 - 6.33 (m, 1H), 4.49 - 4.40 (m, 1H), 3.83 (s, 2H), 3.53 - 3.43 (m, 3H), 3.42 - 3.34 (m, 1H), 3.28 - 3.25 (m, 1H), 3.13 (dd, J= 10.1, 5.2 Hz, 1H), 2.21 - 2.11 (m, 1H), 2.05 - 1.92 (m, 1H), 1.13 (t, J = 7.0 Hz, 3H). m / z (ES)+[M+H]+= 495.3; UPLC (BEH_AmmBicarb) tR = 5.43 min.

[0599] Ex. 77, 2-ethoxy-iV-[(3S)-l-[3-fluoro-5-[2-(trifluoromethyl)pyrimidin-5-yl]oxy-phenyl]pyrrolidin-3- yl] acetamide

[0600] Step 1 : 5-(3-bromo-5-fluoro-phenoxy)-2-(trifluoromethyl)pyrimidine

[0601]

[0402] 3-Bromo-5-fluoro-phenol (74.3 mg, 0.389 mmol) was added to a mixture of 5-bromo-2- (trifluoromethyl)pyrimidine (97.2 mg, 0.428 mmol) and CS2CO3 (190 mg, 0.584 mmol) in DMF (1.00 mL) at 22 °C under nitrogen. The mixture was stirred at 100 °C for 16 h and concentrated. The residue was purified by silica gel chromatography (12 g cartridge) with hexanes and EtOAc (0-100%) to provide the title compound as an oil (120 mg, 92%). m / z (ES)+[M+H]+= 339.2; HPLC (A05) tR = 2.50 min.

[0602] Step 2: 2-ethoxy-iV-[(3S)-l-[3-fluoro-5-[2-(trifluoromethyl)pyrimidin-5-yl]oxy-phenyl]pyrrolidin-3- yl]acetamide

[0603]

[0403] 2-Ethoxy-A-[(35)-pyrrolidin-3-yl]acetamide (74.9 mg, 0.392 mmol) was added to a mixture of 5- (3-bromo-5-fluoro-phenoxy)-2-(trifluoromethyl)pyrimidine (120 mg, 0.356 mmol), RuPhos Pd G3 (29.8 mg, 35.6 pmol) and CS2CO3 (290 mg, 0.890 mmol) in 1,4-dioxane (2.50 mL) at 22 °C under nitrogen. The mixture was stirred at 100 °C for 1 h and concentrated. The residue was purified by silica gel chromatography (4 g cartridge) with hexanes and EtOAc (0-100%), and by reverse phase chromatography (Cl 8, 12 g cartridge) with water and MeCN (10-100%) to provide the title compound as a solid (40.3 mg, 26%). *H NMR (400 MHz, DMSO-de) 5 8.79 (s, 2H), 7.95 (d, 7= 7.3 Hz, 1H), 6.36 (ddd, 7= 9.7, 2.2, 2.2 Hz, 1H), 6.31 - 6.23 (m, 2H), 4.50 - 4.38 (m, 1H), 3.83 (s, 2H), 3.52 - 3.43 (m, 3H), 3.40 - 3.32 (m, 1H), 3.27 - 3.22 (m, 1H), 3.11 (dd, 7 = 10.0, 5.3 Hz, 1H), 2.22 - 2.09 (m, 1H), 2.04 - 1.91 (m, 1H), 1.13 (t, 7 = 7.0 Hz, 3H). m / z (ES)+[M+H]+= 429.3; UPLC (BEH_AmmBicarb) 1R = 4.78 min.

[0604] Ex. 78, 2-ethoxy-Af-[(31?,4S)-4-methoxy-l-[3-methoxy-5-[[6-(trifluoromethyl)-3- pyridyl]oxy]phenyl]pyrrolidin-3-yl]acetamide

[0605] Step 1: tert-butyl iV-[(31f,4S)-4-hydroxy-l-[3-methoxy-5-[[6-(trifluoromethyl)-3- pyridyl]oxy]phenyl]pyrrolidin-3-yl]carbamate

[0606]

[0404] tert-Butyl A-[(3R,4S)-4-hydroxypyrrolidin-3-yl]carbamate (149 mg, 0.736 mmol) was added to a mixture of 5-(3-bromo-5-methoxy-phenoxy)-2-(trifluoromethyl)pyridine (233 mg, 0.669 mmol), RuPhos Pd G3 (56.0 mg, 66.9 pmol) and CS2CO3 (436 mg, 1.34 mmol) in 1,4-dioxane (6.00 mL) at 22 °C under nitrogen. The mixture was stirred at 120 °C for 30 min and concentrated. The residue was purified by silica gel chromatography (25 g cartridge) with hexanes and EtOAc (0-60%) to provide the title compound as an oil (208 mg, 66%). m / z (ES+) [M-Boc+H]+= 370.33; HPLC (A05) 1R = 2.46 min.

[0607] Step 2: tert-butyl iV-[(31f,4S)-4-methoxy-l-[3-methoxy-5-[[6-(trifluoromethyl)-3- pyridyl]oxy]phenyl]pyrrolidin-3-yl]carbamate

[0608]

[0405] lodomethane (276 pL, 4.43 mmol) was added to mixture of tert-butyl A / -|(3 / .4.S')-4-hydroxy- l -|3- methoxy-5-[[6-(trifluoromethyl)-3-pyridyl]oxy]phenyl]pyrrolidin-3-yl]carbamate (208 mg, 0.443 mmol) and Ag2O (513 mg, 2.22 mmol) in MeCN (5.00 mL) at 22 °C under nitrogen. The mixture was stirred at 22 °C for 18 h and concentrated. The residue was purified by silica gel chromatography (25 g cartridge) with hexanes and EtOAc (0-60%) to provide the title compound as an oil (34 mg, 16%). m / z (ES+) [M+H-Boc]+= 384.34; HPLC (A05) tR = 2.62 min.

[0609] Step 3: (31f,4S)-4-methoxy-l-[3-methoxy-5-[[6-(trifluoromethyl)-3-pyridyl]oxy]phenyl]pyrrolidin-3- amine hydrochloride

[0610]

[0406] tert-Butyl A-[(37?,45)-4-methoxy-l-[3-methoxy-5-[[6-(trifluoromethyl)-3- pyridyl]oxy]phenyl]pyrrolidin-3-yl]carbamate (34.0 mg, 70.3 pmol) was dissolved in HC1 (4 M in 1,4- dioxane, 352 pL, 1.41 mmol) at 22 °C under nitrogen. The mixture was stirred at 22 °C for 1 h and concentrated to provide the title compound as a solid (29.5 mg, >98%). m / z (ES+) [M+H]+= 384.63; HPLC (A05) tR = 2.06 min.

[0611] Step 4: 2-ethoxy-Af-[(31f,4S)-4-methoxy-l-[3-methoxy-5-[[6-(trifluoromethyl)-3- pyridyl]oxy]phenyl]pyrrolidin-3-yl]acetamide

[0612]

[0407] DIPEA (36.1 pL, 0.211 mmol) was added to mixture of 2-ethoxyacetic acid (7.42 pL, 73.8 pmol) and HATU (29.4 mg, 77.3 pmol) in DMF (2.00 mL) at 0 °C under nitrogen. After 5 min, (37?,45)-4- methoxy- 1 - [3 -methoxy-5 - [ [6- (trifluoromethyl)- 3-pyridyl] oxy] phenyl] pyrrolidin-3 -amine hydrochloride (29.5 mg, 70.3 pmol) was added to the mixture, and it was stirred at 22 °C for 1 h and concentrated. The residue was purified by silica gel chromatography (25 g cartridge) with DCM and MeOH (0-10%), and by reverse phase chromatography (Cl 8, 12 g cartridge) with water (10 mM NH4HCO2) and MeOH (5- 100%) to provide the title compound as a solid (20.4 mg, 62%). ’H NMR (400 MHz, DMSO-<() 5 8.51 (d, J = 2.7 Hz, 1H), 7.86 (d, 7= 8.7 Hz, 1H), 7.51 (dd, 7= 8.9, 2.6 Hz, 1H), 7.48 (d, 7 = 7.9 Hz, 1H), 6.03 (dd, 7= 2.1, 2.1 Hz, 1H), 5.97 (dd, 7 = 2.1, 2.1 Hz, 1H), 5.94 (dd, 7 = 2.1, 2.1 Hz, 1H), 4.56 - 4.45 (m, 1H), 4.01 - 3.96 (m, 1H), 3.89 (d, 7 = 0.8 Hz, 2H), 3.72 (s, 3H), 3.56 - 3.46 (m, 3H), 3.43 - 3.37 (m, 2H), 3.32 (s, 3H), 3.13 - 3.04 (m, 1H), 1.15 (t, 7 = 7.0 Hz, 3H). m / z (ES+) [M+H]+= 470.19; UPLC (BEH_AmmBicarb) tR = 5.01 min.

[0613] Ex. 79, 2-ethoxy- / V-[(3S)-l-[3-ethyl-5-[2-(trifluoromethyl)pyrimidin-5-ylJoxy-phenylJpyrrolidin-3- yl]acetamide

[0614] Step 1 : 5-(3-bromo-5-chloro-phenoxy)-2-(trifluoromethyl)pyrimidine

[0615]

[0408] 3-Bromo-5-chloro-phenol (1.00 g, 4.82 mmol) was added to a mixture of 5-bromo-2- (trifluoromethyl)pyrimidine (1.09 g, 4.82 mmol) and CS2CO3 (2.36 g, 7.23 mmol) in DMF (10.0 mL) at 22 °C under nitrogen. The mixture was stirred at 100 °C for 16 h and concentrated. The residue was purified by silica gel chromatography (40 g cartridge) with hexanes and EtOAc (0-100%) to provide the title compound as an oil (1.21 g, 71%). m / z (ES)+[M+H]+= 355.0; HPLC (A05) 1R = 2.58 min.

[0616] Step 2: Af-[(3S)-l-[3-chloro-5-[2-(trifluoromethyl)pyrimidin-5-yl]oxy-phenyl]pyrrolidin-3-yl]-2- ethoxy-acetamide

[0617]

[0409] 2-Ethoxy-A-[(3S)-pyrrolidin-3-yl]acetamide (205 mg, 1.07 mmol) was added to a mixture of 5-(3- bromo-5-chloro-phenoxy)-2-(trifluoromethyl)pyrimidine (249 mg, 0.704 mmol), RuPhos Pd G3 (89.7 mg, 0.107 mmol) and CS2CO3 (873 mg, 2.68 mmol) in 1,4-dioxane (5.00 mL) at 22 °C under nitrogen. The mixture was stirred at 65 °C for 1 h and concentrated. The residue was purified by silica gel chromatography (25 g cartridge) with hexanes and EtOAc (0-40%) to provide the title compound as a solid (254 mg, 53%). m / z ES+[M+H]+= 445.7; HPLC (A05) tR = 2.45 min. Step 3: 2-ethoxy-N-[(3S)-l-[3-ethyl-5-[2-(trifluoromethyl)pyrimidin-5-yl]oxy-phenyl]pyrrolidin-3- yl]acetamide

[0618]

[0410] Pd(dppf)C12-DCM (9.18 mg, 11.2 pmol) was added to a mixture of A-[(3S)-l-[3-chloro-5-[2- (trifluoromethyl)pyrimidin-5-yl]oxy-phenyl]pyrrolidin-3-yl]-2-ethoxy-acetamide (50.0 mg, 0.112 mmol), K2CO3 (46.6 mg, 0.337 mmol) and diethylzinc (1.0 M solution in heptane, 169 pL, 0.169 mmol) in 1,4- dioxane (2.00 mL) at 22 °C under nitrogen. The mixture was stirred at 80 °C for 16 h. The residue was purified by silica gel chromatography (4 g cartridge) with hexanes and EtOAc (0-100%), and by preparative HPLC (BEH, Cl 8) with water [10 mM (NH4XHCO3)] and MeCN (61-71%) to provide the title compound as a solid (17.4 mg, 35%). ’H NMR (400 MHz, DMSO-A) 5 8.67 (s, 2H), 7.88 (d, J = 7.3 Hz, 1H), 6.27 (ddd, 7= 7.7, 1.6, 1.6 Hz, 2H), 6.18 (dd, J = 2.2, 2.2 Hz, 1H), 4.44 - 4.33 (m, 1H), 3.78 (s, 2H), 3.48 - 3.38 (m, 3H), 3.36 - 3.27 (m, 1H), 3.23 - 3.17 (m, 1H), 3.06 (dd, J = 9.8, 5.2 Hz, 1H), 2.54 - 2.47 (m, 2H), 2.17 - 2.05 (m, 1H), 1.99 - 1.86 (m, 1H), 1.16 - 1.05 (m, 6H). m / z (ES)+[M+H]+439.3; UPLC (BEH_AmmBicarb) tR = 5.35 min.

[0619] 1H NMR and13C NMR.

[0620]

[0411] ’H NMR spectra were recorded on a Bruker Avance 400 (400 MHz, ’H, 100 MHz,13C) spectrometer. Chemical shift values (5) are reported in ppm relative to residual chloroform (5 7.26 ppm for ’H; 5 78.0 ppm for13C). Multiplicities are indicated by s (singlet), d (doublet), t (triplet), q (quartet), p (pentet), h (heptet), dd-doublet of doublets, dt-doublet of triplets, dq-doublet of quartets, m (multiplet), and br (broad). The identification of ’H and13C signals was achieved using a combination of ’H,13C, DEPT, COSY, HMBC, HMQC, and NOESY experiments. Coupling constants (J) are reported in Hertz (Hz). Solvents: CDCI3, DMSO-d6, MeOD, CD3CN, and D2O.

[0621] HPLC LCMS

[0622] Purification Methods

[0623] Ex. 57, (S)-2-(cyclopropylmethoxy)-N-(l-(3-((6-methylpyridin-3-yl)oxy)phenyl)pyrrolidin-3- yl)acetamide

[0624] Step 1: 5-(3-bromophenoxy)-2- methylpyridine

[0625]

[0412] A mixture of 6-methylpyridin-3-ol (1 g, 9.16 mmol, 1 eq), 2-(3-bromophenyl)-4,4,5,5-tetramethyl- 1,3,2-dioxaborolane (3.89 g, 13.75 mmol, 1.5 eq), 4 A MS (50 mg, 1.00 eq), Cu(OAc)2 (2.50 g, 13.75 mmol, 1.5 eq) and TEA (2.78 g, 27.49 mmol, 3.83 mL, 3 eq) in DCM (20 mL) was stirred at 20 °C for 12 h under O2. The mixture was diluted with H2O (20 mL) and extracted with DCM (15 mL x 2). The combined organic phases were dried over Na2SC>4, filtered, and concentrated. The residue was purified by column chromatography (SiC>2, Petroleum ether / Ethyl acetate=100 / 0 to 0 / 1). Compound 5-(3- bromophenoxy)-2-methyl-pyridine (500 mg, 1.89 mmol, 10.33% yield) was obtained as a yellow solid. 'H NMR (400 MHz, DMSO- / (1) 5 8.23 (s, 1H), 7.19-7.05 (m, 5H), 6.85-6.83 (m, 1H), 2.49 (s, 3H). m / z (ES+) [M+H]+= 264.0.

[0626] Step 2: ( S)- / er / -butyl (l-(3-((6-methylpyridin-3-yl)oxy)phenyl)pyrrolidin-3-yl)carbamate

[0627]

[0413] A mixture of 5-(3-bromophenoxy)-2-methyl-pyridine (450 mg, 1.70 mmol, 1 eq), tert-butyl A- [(35)-pyrrolidin-3-yl]carbamate (380.80 mg, 2.04 mmol, 1.2 eq), RuPhos Pd G3 (712.49 mg, 851.89 pmol, 0.5 eq) and CS2CO3 (1.11 g, 3.41 mmol, 2 eq) in 1,4-dioxane (15 mL) was stirred at 100 °C for 12 h under N2. The mixture was diluted with H2O (20 mL) and extracted with EtOAc (30 mL x 2). The combined organic phases were dried over Na2SC>4, filtered, and concentrated. The residue was purified by column chromatography (SiC>2, Petroleum ether / Ethyl acetate= 100 / 0 to 0 / 1). Compound tert-butyl N- [(3>S -l-[3-[(6-methyl-3-pyridyl)oxy]phenyl]pyrrolidin-3-yl]carbamate (250 mg, 676.67 pmol, 19.86% yield) was obtained as a white solid, m / z (ES+) [M+H]+= 370.1.

[0628] Step 3: (S)-l-(3-((6-methylpyridin-3-yl)oxy)phenyl)pyrrolidin-3-amine

[0629]

[0414] A mixture of tert-butyl A-[(3S)-l-[3-[(6-methyl-3-pyridyl)oxy]phenyl]pyrrolidin-3-yl]carbamate (250 mg, 676.67 pmol, 1 eq) in DCM (5 mL) and TFA (1 mL) was stirred at 20 °C for 5 h under N2 and concentrated. Compound (3S)-l-[3-[(6-methyl-3-pyridyl)oxy]phenyl]pyrrolidin-3-amine (200 mg, crude, TFA) was obtained as a white solid, m / z. (ES+) [M+H]+= 270.1.

[0630] Step 4: (S)-2-(cyclopropylmethoxy)-A-(l-(3-((6-methylpyridin-3-yl)oxy)phenyl)pyrrolidin-3- yl)acetamide

[0631]

[0415] A mixture of (3>S -l-[3-[(6-methyl-3-pyridyl)oxy]phenyl]pyrrolidin-3-amine (700 mg, 1.83 mmol, 1 eq, TFA), 2-(cyclopropylmethoxy)acetic acid (285.16 mg, 2.19 mmol, 1.2 eq), HATU (1.04 g, 2.74 mmol, 1.5 eq) and DIPEA (707.97 mg, 5.48 mmol, 954.14 pL, 3 eq) in DMF (10 mL) was stirred at 20 °C for 12 h under N2. The mixture was concentrated, and the residue was purified by prep-HPLC column: (Waters Xbridge Prep OBD C18 150*40mm* 10 pM; mobile phase: [water (NH4HCO3)-ACN]; B%: 35%-65%, 8 min). Compound 2-(cyclopropylmcthoxy)-A / -|(3.S')-l-|3-|(6-mcthyl-3- pyridyl)oxy]phenyl]pyrrolidin-3-yl]acetamide (37.4 mg, 98.04 pmol, 93.96% yield) was obtained as a yellow oil. >H NMR (400 MHz, DMSO-d6) 5 8.21-8.20 (m, 1H), 7.91 (d, J = 7.2 Hz, 1H), 7.32-7.29 (m, 1H), 7.25-7.23 (m, 1H), 7.15 (t, J= 8 Hz, 1H), 6.32 (d, J= 8.4 Hz, 1H), 6.19-6.16 (m, 2H), 4.44-4.40 (m, 1H), 3.86 (s, 2H), 3.45-3.41 (m, 2H), 3.28-3.26 (m, 2H), 3.23-3.22 (m, 1H), 3.10-3.08 (m, 1H), 2.44 (s, 3H), 2.16-2.13 (m, 1H), 1.99-1.95 (m, 1H), 1.04-0.98 (m, 1H), 0.47-0.43 (m, 2H), 0.17-0.15 (m, 2H). m / z (ES+) [M+H]+= 382.3.

[0632] Ex. 36, 2-(cyclopropylmethoxy)-AL[(35)-l-[3-[[6-[[dimethyl(oxo)-X6-sulfanylidene]amino]-3- pyridyl]oxy]phenyl]pyrrolidin-3-yl]acetamide

[0633] Step 1: 2-(cyclopropylmethoxy)-X-[(35)-l-[3-[[6-[[dimethyl(oxo)-X6-sulfanylidene]amino]-3- pyridyl]oxy]phenyl]pyrrolidin-3-yl]acetamide

[0634]

[0416] A mixture of lV-[(35)-l-[3-[(6-chloro-3-pyridyl)oxy]phenyl]pyrrolidin-3-yl]-2- (cyclopropylmethoxy)acetamide (90 mg, 223.94 pmol, 1 eq), imino-dimethyl-oxo-X6-sulfane (25.03 mg, 268.73 pmol, 1.2 eq), CS2CO3 (145.93 mg, 447.89 pmol, 2 eq), Pd2(dba)3 (41.01 mg, 44.79 pmol, 0.2 eq) and Xantphos (51.83 mg, 89.58 pmol, 0.4 eq) in 1,4-dioxane (5 mL) was stirred at 120 °C for 12 h under N2. The mixture was concentrated, and the residue was purified by prep-HPLC (column: Waters Xbridge Prep OBD C18 150*40mm* 10 pM; mobile phase: [water (NH4HCO3)-ACN]; B%: 25%-55%, 8 min). Compound 2-(cyc lopropy Imcthoxy) -X- [(35)- 1 - [3- [[6- [ [ di mcthy 1 (oxo)-ZG-su Ifany 1 idcnc ] amino] -3- pyridyl]oxy]phenyl]pyrrolidin-3-yl]acetamide (37.3 mg, 81.34 pmol, 18.16% yield) was obtained as a white solid. >H NMR (400 MHz, DMSO-dj 57.92-7.89 (m, 2H), 7.28 (dd, J= 3.2 Hz, 8.8 Hz, 1H), 7.10 (t, J= 8.2 Hz, 1H), 6.65 (d, J= 8.8 Hz, 1H), 6.26 (d, J = 9.2 Hz, 1H), 6.14-6.10 (m, 2H), 4.43-4.38 (m, 1H), 3.86 (s, 2H), 3.43-3.41 (m, 1H), 3.35 (s, 6H), 3.31 (s, 1H), 3.27 (d, J = 7.2 Hz, 2H), 3.22 (s, 1H), 3.09-3.06 (m, 1H), 2.17-2.10 (m, 1H), 1.99-1.92 (m, 1H), 1.04-0.99 (m, 1H), 0.47-0.43 (m, 2H), 0.18- 0.14 (m, 2H). m / z (ES+) [M+H]+= 459.3.

[0635] Ex. 37, (S)-AHl-(3-((6-(azetidin-l-yl)pyridin-3-yl)oxy )phenyl)pyrrolidin-3-yl)-2-

[0636] (cyclopropylmethoxy)acetamide

[0637] Step 1: (S)-tert-butyl (l-(3-methoxyphenyl)pyrrolidin-3-yl)carbamate

[0638]

[0417] A mixture of l-iodo-3-methoxy-benzene (5 g, 21.36 mmol, 2.54 mL, 1 eq), tert-butyl N-\(3S)- pyrrolidin- 3 -yl] carbamate (4.38 g, 23.50 mmol, 1.1 eq), RuPhos Pd G3 (893.42 mg, 1.07 mmol, 0.05 eq) and CS2CO3 (10.44 g, 32.05 mmol, 1.5 eq) in 1,4-dioxane (100 mL) was stirred at 100 °C for 12 h under N2. The mixture was diluted with H2O (40 mL) and extracted with EtOAc (50 mL x 2). The combined organic phases were dried over Na2SC>4, filtered, and concentrated. The residue was purified by column chromatography (SiC>2, Petroleum ether / Ethyl acetate=100 / l to 0 / 1). Compound tert-butyl A-[(35)-l-(3- methoxyphenyl)pyrrolidin-3-yl]carbamate (5 g, 17.10 mmol, 80.05% yield) was obtained as a yellow oil. >H NMR (400 MHz, DMSO-of 57.17-7.15 (m, 1H), 7.03 (t, J= 8 Hz, 1H), 6.19-6.16 (m, 1H), 6.10-6.08 (m, 1H), 6.01-5.99 (m, 1H), 3.69 (s, 3H), 3.44-3.41 (m, 1H), 3.30-3.29 (m, 2H), 3.20-3.01 (m, 1H), 3.01- 2.98 (m, 1H), 2.132-2.09 (m, 1H), 1.88-1.83 (m, 1H), 1.39 (s, 9H). m / z (ES+) [M+H]+= 293.1.

[0639] Step 2: (S)-3-(3-aminopyrrolidin-l-yl)phenol

[0640]

[0418] To a solution of tert-butyl N-[(3S)- l-(3-methoxyphenyl)pyrrolidin-3-yl ]carbamate (4.5 g, 15.39 mmol, 1 eq) in DCM (70 mL) was added BBrg (7.71 g, 30.78 mmol, 2.97 mL, 2 eq) at 15 °C. The mixture was stirred at 15 °C for 1 h and concentrated. Compound 3-[(35)-3-aminopyrrolidin-l-yl]phenol (4.5 g, crude, HBr) was obtained as a yellow solid, m / z (ES+) [M+H]+= 179.0.

[0641] Step 3: (S)-2-(cyclopropylmethoxy)-Af-(l-(3-hydroxyphenyl)pyrrolidin-3-yl)acetamide

[0642]

[0419] A mixture of 3-[(35)-3-aminopyrrolidin-l-yl]phenol (4.5 g, 25.25 mmol, 1 eq), 2- (cyclopropylmethoxy)acetic acid (3.94 g, 30.30 mmol, 1.2 eq), HATU (14.40 g, 37.87 mmol, 1.5 eq) and DIPEA (9.79 g, 75.74 mmol, 13.19 mL, 3 eq) in DMF (80 mL) was stirred at 15 °C for 12 h under N2. The mixture was diluted with H2O (50 mL) and extracted with EtOAc (50 mL x 2). The combined organic phases were dried over Na2SC>4, filtered, and concentrated. The residue was purified by column chromatography (SiC>2, Petroleum ether / Ethyl acetate=100 / 0 to 0 / 1). Compound 2- (cyclopropylmethoxy)-A-[(3S)-l-(3-hydroxyphenyl)pyrrolidin-3-yl]acetamide (900 mg, 3.10 mmol, 12.28% yield) was obtained as a solid. [M+H]+= 291.0.

[0643] Step 4: (S)- / V-(l-(3-((6-chloropyridin-3-yl )oxy )phenyl )pyrrolidin-3-yl )-2- (cyclopropylmethoxy)acetamide

[0644]

[0420] A mixture of 2-(cyclopropylmethoxy)-A-[(3S)-l-(3-hydroxyphenyl)pyrrolidin-3-yl]acetamide (300 mg, 1.03 mmol, 1 eq), 2-chloro-5-fluoro-pyridine (135.90 mg, 1.03 mmol, 1 eq) and CS2CO3 (504.96 mg, 1.55 mmol, 1.5 eq) in DMF (5 mL) was stirred at 120 °C for 12 h under N2. The mixture was diluted with H2O (10 mL) and extracted with EtOAc (15 mL x 2). The combined organic phases were dried over Na2SOr, filtered, and concentrated. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=100 / 0 to 0 / 1). Compound N-[(3S)- 1 -[3-[(6-chloro-3- pyridyl)oxy]phenyl]pyrrolidin-3-yl]-2-(cyclopropylmethoxy)acetamide (170 mg, 423.01 pmol, 40.94% yield) was obtained as a yellow oil. m / z (ES+) [M+H]+= 402.0.

[0645] Step 5: (S)-Af-(l-(3-((6-(azetidin-l-yl)pyridin-3-yl)oxy)phenyl)pyrrolidin-3-yl)-2- (cyclopropylmethoxy)acetamide

[0421] A mixture of A-[(3£)-l-[3-[(6-chloro-3-pyridyl)oxy]phenyl]pyrrolidin-3-yl]-2- (cyclopropylmethoxy)acetamide (10 mg, 24.88 pmol, 1 eq), azetidine (7.10 mg, 124.41 pmol, 8.40 pL, 5 eq), CS2CO3 (16.21 mg, 49.77 pmol, 2 eq), Pd2(dba)3 (9.11 mg, 9.95 pmol, 0.4 eq) and Xantphos (11.52 mg, 19.91 pmol, 0.8 eq) in 1,4-dioxane (5 mL) was stirred at 120 °C for 12 h under N2. The mixture was diluted with H2O (10 mL) and extracted with EtOAc (20 mL x 2). The combined organic phases were dried over Na2SC>4, filtered, and concentrated. The residue was purified by prep-HPLC (column: Waters Xbridge Prep OBD C18 150*40mm* 10 pM; mobile phase: [water (NH4HCO3)-ACN] ; B%: 40%-70%, 8 min). Compound A-[(3>S -l-[3-[[6-(azetidin-l-yl)-3-pyridyl]oxy]phenyl]pyrrolidin-3-yl]-2- (cyclopropylmethoxy)acetamide (13.8 mg, 32.66 pmol, 65.63% yield) was obtained as a white solid. ’H NMR (400 MHz, DMSO- L) 5 7.91-7.87 (m, 2H), 7.28 (dd, J = 3.2 Hz, 8.8 Hz, 1H), 7.07 (t, J = 8.4 Hz, 1H), 6.38 (d, J= 8.8 Hz, 1H), 6.25-6.21 (m, 1H), 6.14-6.05 (m, 2H), 4.44-4.38 (m, 1H), 3.91 (t, J = 7.2 Hz, 4H), 3.86 (s, 2H), 3.42-3.38 (m, 1H), 3.30 (s, 1H), 3.27 (d, J = 6.8 Hz, 2H), 3.24-3.20 (m, 1H), 3.08- 3.03 (m, 1H), 2.32-2.25 (m, 2H), 2.15-2.10 (m, 1H), 1.98-1.90 (m, 1H), 1.04-0.98 (m, 1H), 0.47-0.43 (m, 2H), 0.18-0.14 (m, 2H). m / z (ES+) [M+H]+= 423.2.

[0646] Ex. 52, (S)-2-(trifluoromethoxy )-W(l-(3-((6-(trifluoromethyl)pyridin-3-yl )oxy )phenyl )pyrrolidin-3- yl)acetamide

[0647] Step 1: 5-(3-bromophenoxy)-2-(trifluoromethyl)pyridine

[0648]

[0422] A mixture of 3-bromophenol (2 g, 11.56 mmol, 1 eq), 5-fluoro-2-(trifluoromethyl)pyridine (2.10 g, 12.72 mmol, 1.1 eq) and CS2CO3 (7.53 g, 23.12 mmol, 2 eq) in DMF (20 mL) was stirred at 100 °C for 12 h under N2. The mixture was diluted with H2O (30 mL) and extracted with EtoAc (30 mL x 2). The combined organic phases were dried over Na2SC>4, filtered, and concentrated. The residue was purified by column chromatography (SiC>2, Petroleum ether / Ethyl acetate=100 / l to 0 / 1). Compound 5-(3- bromophenoxy)-2-(trifluoromethyl)pyridine (2.5 g, 7.86 mmol, 67.99% yield) was obtained as a white solid. Step 2: (S)-tert-butyl (l-(3-((6-(trifluoromethyl)pyridin-3-yl)oxy)phenyl)pyrrolidin-3-yl)carbamate

[0649]

[0423] A mixture of 5-(3-bromophenoxy)-2-(trifluoromethyl)pyridine (2.5 g, 7.86 mmol, 1 eq), tert-butyl W[(3S)-pyrrolidin-3-yl]carbamate (1.61 g, 8.65 mmol, 1.1 eq), CS2CO3 (3.84 g, 11.79 mmol, 1.5 eq) and RuPhos Pd G3 (657.34 mg, 785.94 pmol, 0.1 eq) in 1,4-dioxane (20 mF) was stirred at 100 °C for 12 h under N2. The mixture was diluted with H2O (40 mL) and extracted with EtOAc (50 mL x 2). The combined organic phases were dried over Na2SC>4, filtered, and concentrated. The residue was purified by column chromatography (SiC>2, Petroleum ether / Ethyl acetate= 100 / 1 to 0 / 1). Compound tert-butyl N- [(3S)-l-[3-[[6-(trifhioromethyl)-3-pyridyl]oxy]phenyl]pyrrolidin-3-yl]carbamate (1.4 g, 3.31 mmol, 42.07% yield) was obtained as a white solid, m / z (ES+) [M+H]+= 424.1.

[0650] Step 3: (S)-l-(3-((6-(trifluoromethyl)pyridin-3-yl)oxy)phenyl)pyrrolidin-3-amine

[0651]

[0424] A mixture of tert-butyl A-[(35)-l-[3-[[6-(trifluoromethyl)-3-pyridyl]oxy]phenyl]pyrrolidin-3- yl]carbamate (1.4 g, 3.31 mmol, 1 eq) in TFA (2 mL) and DCM (10 mL) was stirred at 15 °C for 5 h under N2 and concentrated. Compound (3S)-l-[3-[[6-(trifhroromethyl)-3-pyridyl ] oxy] phenyl] pyrrolidin- 3-amine (1.4 g, 3.20 mmol, 96.82% yield, TFA) was obtained as a white solid and used in the next step without further purification.

[0652] Step 4: (S)-2-(trifluoromethoxy)-W(l-(3-((6-(trifluoromethyl)pyridin-3-yl)oxy)phenyl)pyrrolidin-3-

[0653]

[0425] A mixture of (3S)-l-[3-[[6-(trifhioromethyl)-3-pyridyl]oxy]phenyl]pyrrolidin-3-amine (200 mg, 457.32 pmol, 1 eq, TFA), 2-(trifluoromethoxy)acetic acid (79.05 mg, 548.78 pmol, 1.2 eq), HATU (260.83 mg, 685.97 pmol, 1.5 eq) and DIPEA (177.31 mg, 1.37 mmol, 238.97 pF, 3 eq) in DMF (5 mF) was stirred at 15 °C for 12 h under N2. The mixture was concentrated, and the residue was purified by prep-HPFC (column: Waters Xbridge Prep OBD C18 150*40mm* 10 pM; mobile phase: [water (NH4HCC>3)-ACN]; B%: 60%-90%, 8 min). Compound 2-(trifluoromethoxy)-X-[(35)-l-[3-[[6- (trifluoromethyl)-3-pyridyl]oxy]phenyl]pyrrolidin-3-yl]acetamide (36.9 mg, 82.12 pmol, 71.83% yield) was obtained as a white solid. ’H NMR (400 MHz, DMSO-ofj 5 8.53-8.50 (m, 2H), 7.88 (d, J= 8.8 Hz, 1H), 7.48 (dd, J = 2.4 Hz, 8.8 Hz, 1H), 7.26 (t, J= 8 Hz, 1H), 6.48-6.45 (m, 1H), 6.39-6.34 (m, 2H), 4.53 (s, 2H), 4.47-4.40 (m, 1H), 3.51-3.47 (m, 1H), 3.39-3.30 (m, 1H), 3.29-3.25 (m, 1H) , 3.11 (dd, 7=4.4 Hz, 14.4 Hz, 1H), 2.23-2.15 (m, 1H), 1.97- 1.90 (m, lH). m / z (ES+) [M+H]+= 450.0.

[0654] Ex. 54, (S)-2-phenoxy-W(l-(3-((6-(trifluoromethyl)pyridin-3-yl)oxy)phenyl)pyrrolidin-3- yl)acetamide

[0655] Step 1 : (S)-2-phenoxy-W(l-(3-((6-(trifluoromethyl)pyridin-3-yl)oxy)phenyl)pyrrolidin-3-

[0656]

[0426] A mixture of (3S)-l-[3-[[6-(trifluoromethyl)-3-pyridyl]oxy]phenyl]pyrrolidin-3-amine (100 mg, 228.66 pmol, 1 eq, TFA), 2-phenoxyacetic acid (41.75 mg, 274.39 pmol, 1.2 eq), HATU (86.94 mg, 228.66 pmol, 1 eq) and DIPEA (29.55 mg, 228.66 pmol, 39.83 pL, 1 eq) in DMF (5 mL) was stirred at 15 °C for 12 h under N2. The mixture was concentrated, and the residue was purified by prep-HPLC (column: Waters Xbridge Prep OBD C18 150*40mm* 10 pM; mobile phase: [water (NH4HCO3)-ACN]; B%: 50%-80%, 8 min). Compound 2-phenoxy-X-[(35)-l-[3-[[6-(trifluoromethyl)-3- pyridyl]oxy]phenyl]pyrrolidin-3-yl]acetamide (35.8 mg, 78.26 pmol, 34.23% yield) was obtained as a yellow oil. >H NMR (400 MHz, DMSO-de) 5 8.51(d, J = 2.8 Hz, 1H), 8.36 (d, J = 7.2 Hz, 1H), 7.88 (d, J = 8.4 Hz, 1H), 7.40 (dd, J = 2.8 Hz, 9.6 Hz, 1H), 7.28-7.23 (m, 3H), 6.94 (d, J= 8.8 Hz, 3H), 6.47-6.45 (m, 1H), 6.39-6.37 (m, 1H), 6.35-6.32 (m, 1H), 4.48 (s, 2H), 4.47-4.44 (m, 1H), 3.52-3.50 (m, 1H), 3.49- 3.46 (m, 1H), 3.30-3.26 (m, 1H), 3.23 (dd, J = 4.8 Hz, 9.6 Hz, 1H), 2.22-2.15 (m, 1H), 2.00-1.95 (m, 1H). m / z (ES+) [M+H]+= 458.2.

[0657] Ex. 7, (S)-2-((l#-pyrazol-4-yl)oxy)-AHl-(3-((6-(trifluoromethyl)pyridin-3- yl)oxy)phenyl)pyrrolidin-3-yl)acetamide

[0658]

[0427] To a solution of 1 H-pyrazol-4-ol (500 mg, 5.95 mmol, 1 eq) in ACN (20 mL) was added TEA (2.41 g, 23.79 mmol, 3.31 mL, 4 eq) and MegSiCl (775.29 mg, 7.14 mmol, 905.72 pL, 1.2 eq) at 15 °C under N2. The mixture was stirred for 0.5 h. [Chloro(diphenyl)methyl] benzene (1.66 g, 5.95 mmol, 1 eq) was added to the mixture at 15 °C, and it was stirred at 80 °C for 11.5 h. The mixture was diluted with H2O (20 mL) and extracted with EtOAc (30 mL x 2). The combined organic phases were dried over Na^SOr. filtered, and concentrated. The residue was purified by column chromatography (SiCL. Petroleum ether / Ethyl acetate=100 / l to 0 / 1). Compound l-tritylpyrazol-4-ol (500 mg, 1.53 mmol, 64.40% yield) was obtained as a white solid. >H NMR (400 MHz, DMSO-6) 5 8.39 (s,lH), 7.22-7.18 (m, 9H), 7.07 (s,lH), 6.93-6.91 (m, 6H), 6.64 (s,lH). m z (ES+) [M+H]+= 325.0.

[0659] Step 2: (S)-Af-(l-(3-((6-(trifluoromethyl)pyridin-3-yl )oxy )phenyl )pyrrolidin-3-yl )-2-((l-trityl- H- pyrazol-4-yl)oxy)acetamide

[0660]

[0428] To a solution of l-tritylpyrazol-4-ol (480 mg, 1.47 mmol, 1 eq) in DMF (15 mL) was added NaH (117.64 mg, 2.94 mmol, 60% purity, 2 eq) at 15 °C under N2. The mixture was stirred at 15 °C for 0.5 h. 2-Bromo-A-[(3S -l-[3-[[6-(trifluoromethyl)-3-pyridyl]oxy]phenyl]pyrrolidin-3-yl]acetamide (326.66 mg, 735.32 pmol, 0.5 eq) was added at 15 °C under N2 to the mixture, and it was stirred at 15 °C for 4.5 h. Sat. aq. NH4CI (20 mL) was added to the mixture, and it was stirred for 10 min. The mixture was diluted with H2O (20 mL) and extracted with EtOAc (30 mL x 2). The combined organic phases were concentrated, and the residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=100 / l to 0 / 1). Compound N-[(3S)- 1 -[3-[ [6-(trifluoromethyl)-3-pyridyl ]oxy]phenyl ]pyrrolidin-3- yl]-2-(l-tritylpyrazol-4-yl)oxy-acetamide (250 mg, 362.46 pmol, 24.65% yield) was obtained as a white solid. Step 3: (S)-2-((l£f-pyrazol-4-yl)oxy)-Af-(l-(3-((6-(trifluoromethyl)pyridin-3- yl)oxy)phenyl)pyrrolidin-3-yl)acetamide

[0661]

[0429] A mixture of W[(3S)-l-[3-[[6-(trifluoromethyl)-3-pyridyl]oxy]phenyl]pyrrolidin-3-yl]-2-(l- tritylpyrazol-4-yl)oxy-acetamide (230 mg, 333.47 pmol, 1 eq) in TFA (1 mL) and DCM (20 mL) was stirred at 20 °C for 5 h under N2. The mixture was concentrated, and the residue was purified by prep- HPLC (column: Waters Xbridge Prep OBD C18 150*40mm* 10 pM; mobile phase: [water (NH4HCO3)- ACN]; B%: 35%-65%, 8 min). Compound 2-(lH-pyrazol-4-yloxy)-X-[(3S)-l-[3-[[6-(trifluoromethyl)-3- pyridyl]oxy]phenyl]pyrrolidin-3-yl]acetamide (25 mg, 55.88 pmol, 16.76% yield) was obtained as a gray solid. >H NMR (400 MHz, DMSO-76) 5 12.39 (s, 1H), 8.50 (d, J = 2.8 Hz, 1H), 8.28 (d, J = 7.2 Hz, 1H), 7.86 (d, J= 8.8 Hz, 1H), 7.50-7.45 (m, 2H), 7.24 (t, J= 8.2 Hz, 2H), 6.45 (d, 7= 1.6 Hz, 1H), 6.37 (d, J = 2 Hz, 1H), 6.33 (d, J = 5.6 Hz, 1H), 4.49-4.44 (m, 1H), 4.31 (s, 2H), 3.48 (dd, J= 6.8 Hz, 9.6 Hz, 2H), 3.33-3.25 (m, 1H), 3.14-3.10 (m, 1H), 2.21-2.13 (m, 1H), 1.99-1.94 (m, 1H). m / z (ES+) [M+H]+= 448.2.

[0662] Ex. 133, (S)-2-((l,3-dimethyl-lH-pyrazol-4-yl )oxy )-W(l-(3-((6-(trifluoromethyl ) pyridin-3- yl)oxy)phenyl)pyrrolidin-3-yl)acetamide

[0663] Step 1: (S)-2-((l,3-dimethyl-LH-pyrazol-4-yl)oxy )-W(l-(3-((6-(trifluoromethyl)pyridin-3- yl)oxy)phenyl)pyrrolidin-3-yl)acetamide

[0664]

[0430] To a solution of l,3-dimethylpyrazol-4-ol (50 mg, 445.91 pmol, 1 eq) in DMF (3 mL) was added NaH (53.51 mg, 1.34 mmol, 60% purity, 3 eq) at 15 °C under N2. The mixture was stirred for 0.5 h. 2- Bromo-A-[(3>S)-l-[3-[[6-(trifluoromethyl)-3-pyridyl]oxy]phenyl]pyrrolidin-3-yl]acetamide (99.05 mg, 222.96 pmol, 0.5 eq) was added to the mixture at 15°C under N2, and it was stirred at 15 °C for 1.5 h. Sat. aq. NH4CI (10 mL) was added to the mixture, and it was stirred for 10 min. The mixture was concentrated, and the residue was purified by prep-HPLC (column: Waters Xbridge Prep OBD Cl 8 150*40mm* 10 pM; mobile phase: [water (NH4HCO3)-ACN] ; B%: 40%-70%, 8 min). Compound 2-(l,3- dimethylpyrazol-4-yl)oxy-A-[(3S)-l-[3-[[6-(trifluoromethyl)-3-pyridyl]oxy]phenyl]pyrrolidin-3- yl]acetamide (24.3 mg, 51.11 pmol, 11.46% yield) was obtained as a yellow oil. ’H NMR (400 MHz, DMSO- e) 5 8.50 (d, J = 2.8 Hz, 1H), 8.22 (d, J = 7.2 Hz, 1H), 7.86 (d, J= 8.8 Hz, 1H), 7.52-7.46 (m, 1H), 7.28 (s, 1H), 7.24 (t, J= 8 Hz, 1H), 6.45 (dd, J = 2 Hz, 8.4 Hz, 1H), 6.38-6.35 (m, 1H), 6.32 (t, J = 4 Hz, 1H), 4.49-4.41 (m, 1H), 4.24 (s, 2H), 3.60 (s, 3H), 3.49-3.45 (m, 1H), 3.36-3.34 (m, 1H), 3.27-3.14 (m, 1H), 3.13-3.11 (m, 1H), 2.20-2.13 (m, 1H), 2.03 (s, 3H), 1.99-1.94 (m, 1H). m / z (ES+) [M+H]+= 476.1.

[0665] Ex. 55, (S)-2-((l-methylcyclopropyl)methoxy)-A-(l-(3-((6-(trifluoromethyl)pyridin-3- yl)oxy)phenyl)pyrrolidin-3-yl)acetamide step 1

[0666] Step 1: (S)-2-((l-methylcyclopropyl)methoxy)-A-(l-(3-((6-(trifluoromethyl)pyridin-3- yl)oxy)phenyl)pyrrolidin-3-yl)acetamide

[0667]

[0431] To a solution of (l-methylcyclopropyl)methanol (40 mg, 464.40 pmol, 45.10 pL, 1 eq) in DMF (5 mL) was added NaH (55.72 mg, 1.39 mmol, 60% purity, 3 eq) at 15 °C under N2. The mixture was stirred for 0.5 h. 2-Bromo-A-[(3S)-l-[3-[[6-(trifluoromethyl)-3-pyridyl]oxy]phenyl] pyrrolidin- 3 -yl] acetamide (103.15 mg, 232.20 pmol, 0.5 eq) was added to the mixture at 15 °C under N2, and it was stirred at 15 °C for 1.5 h. Sat. aq. NH4CI (10 mL) was added to the mixture, and it was stirred for 10 min. The mixture was concentrated, and the residue was purified by prep-HPLC (column: Waters Xbridge Prep OBD Cl 8 150*40mm* 10 pM; mobile phase: [water (NH -ICO3)-ACN] ; B%: 50%-80%, 8 min). Compound 2-[(l- methylcyclopropyl)methoxy]-A-[(3S)-l-[3-[[6-(trifluoromethyl)-3-pyridyl]oxy]phenyl]pyrrolidin-3- yl]acetamide (26.38 mg, 58.69 pmol, 12.64% yield) was obtained as a white solid. ’H NMR (400 MHz, DMSO-76) 5 8.49 (d, 7 = 2.8 Hz, 1H), 7.86 (d, 7= 9.6 Hz, 2H), 7.47 (d, 7= 11.2 Hz, 1H), 7.23 (t, 7= 8.4 Hz, 1H), 6.44 (dd, 7=2 Hz, 8.4 Hz, 1H), 6.36 (dd, 7 = 2 Hz, 9.6 Hz, 1H), 6.32 (d, 7 = 2 Hz ,1H), 4.44- 4.39 (m, 1H), 3.89 (s, 2H), 3.48-3.45 (m, 1H), 3.43-3.35 (m, 2H), 3.31 (s, 2H), 3.21-3.11(m, 1H), 2.41- 2.31 (m, 1H), 2.00-1.90 (m, 1H), 1.05 (s, 3H), 0.36-0.33 (m, 2H) , 0.26-0.23 (m, 2H). m / z (ES+) [M+H]+= 450.2.

[0668] Ex. 5, (S)-2-((l-methyl-177-pyrazol-4-yl)oxy)-A-(l-(3-((6-(trifluoromethyl)pyridin-3- yl)oxy)phenyl)pyrrolidin-3-yl)acetamide

[0669] Step 1: (S)-2-((l-methyl-lH-pyrazol-4-yl)oxy)-iV-(l-(3-((6-(trifluoromethyl)pyridin-3- yl)oxy)phenyl)pyrrolidin-3-yl)acetamide

[0670]

[0432] To a solution of l-methylpyrazol-4-ol (50 mg, 509.67 pmol, 1 eq) in DMF (5 mL) was added NaH (61.16 mg, 1.53 mmol, 60% purity, 3 eq) at 15 °C under N2. The mixture was stirred for 0.5 h. 2-Bromo- W[(35)-l-[3-[[6-(trifluoromethyl)-3-pyridyl]oxy]phenyl]pyrrolidin-3-yl]acetamide (113.21 mg, 254.83 pmol, 0.5 eq) was added to the mixture at 15 °C under N2, and it was stirred at 15 °C for 1.5 h. The mixture was concentrated, and the residue was purified by prep-HPLC (column: Waters Xbridge Prep OBD C18 150*40mm* 10 pM; mobile phase: [water (NH4HCO3)-ACN]; B%: 40%-70%, 8 min). Compound 2-( 1 -methyl pyrazol-4-yl)oxy-N- 113.S')- 1- [3-[[6-(trifluoromethyl)-3- pyridyl]oxy]phenyl]pyrrolidin-3-yl]acetamide (31 mg, 67.18 pmol, 13.18% yield) was obtained as a white solid. >H NMR (400 MHz, DMSO-76) 5 8.51 (d, J = 2.8 Hz, 1H), 8.29 (d, J= 6.8 Hz, 1H), 7.86 (d, 7= 8.8 Hz, 1H), 7.49 (dd, 7= 2.8 Hz, 8.8 Hz, 1H), 7.43 (s, 1H), 7.25 (t, 7 = 8 Hz, 1H), 7.180 (s, 1H), 6.47-6.44 (m, 1H), 6.39-6.33 (m, 1H), 6.35-6.32 (m, 1H), 4.49-4.41 (m, 1H), 4.30 (s, 2H), 3.71 (s, 3H), 3.51-3.46 (m, 1H), 3.49-3.45 (m, 1H), 3.37-3.32 (m, 1H), 3.14-3.10 (m, 1H) , 2.21-2.15 (m, 1H), 2.02- 1.95 (m, 1H). m / z (ES+) [M+H]+= 462.1. Ex. 30, (S)-2-(cyclopropylmethoxy)-Af-(l-(3-(methyl(6-(trifluoromethyl)pyridin-3- yl)amino)phenyl)pyrrolidin-3-yl)acetamide

[0671] Step 1 : N- (3-bromophenyl )- V-met li 1 -6- ( t rifluoromet hvl )py ridin-3-amine

[0672]

[0433] A mixture of 3-bromo-A-methyl-aniline (2 g, 10.75 mmol, 1.37 mL, 1 eq), 5-fluoro-2- (trifluoromethyl)pyridine (1.95 g, 11.82 mmol, 1.1 eq) and CS2CO3 (7.01 g, 21.50 mmol, 2 eq) in DMF (20 mL) was stirred at 100 °C for 12 h under N2. The mixture was diluted with H2O (20 mL) and extracted with EtOAc (30 mL x 2). The combined organic phases were dried over Na2SOr. filtered, and concentrated. The residue was purified by column chromatography (SiC>2, Petroleum ether / Ethyl acetate=100 / l to 0 / 1). Compound A-(3-bromophenyl)-A-methyl-6-(trifluoromethyl)pyridin-3-amine (600 mg, 1.81 mmol, 16.86% yield) was obtained as a white solid.

[0673] Step 2: (S)- rt-butyl (l-(3-(methyl(6-(trifluoromethyl)pyridin-3-yl)amino)phenyl)pyrrolidin-3- yl)carbamate

[0674]

[0434] A mixture of A-(3-bromophenyl)-A-methyl-6-(trifluoromethyl)pyridin-3-amine (600 mg, 1.81 mmol, 1 eq), tert-butyl A-[(35)-pyrrolidin-3-yl]carbamate (371.23 mg, 1.99 mmol, 1.1 eq), RuPhos Pd G3 (151.55 mg, 181.20 pmol, 0.1 eq) and CS2CO3 (1.18 g, 3.62 mmol, 2 eq) in 1,4-dioxane (15 mL) was stirred at 100 °C for 12 h under N2. The mixture was diluted with H2O (20 mL) and extracted with EtOAc (30 mL x 2). The combined organic phases were dried over Na^SO-i. filtered, and concentrated. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=100 / l to 0 / 1). Compound tert-butyl A-[(3S)-l-[3-[methyl-[6-(trifhioromethyl)-3-pyridyl]amino]phenyl]pyrrolidin-3- yl]carbamate (300 mg, 687.33 pmol, 37.93% yield) was obtained as a white solid. Step 3: (S)-Af-(3-(3-aminopyrrolidin-l-yl)phenyl)-Af-methyl-6-(trifluoromethyl)pyridin-3-amine

[0675]

[0435] A mixture of tert-butyl X-[(35)-l-[3-[methyl-[6-(trifluoromethyl)-3-pyridyl]amino]phenyl] pyrrolidin- 3 -yl] carbamate (300 mg, 687.33 pmol, 1 eq) in TFA (2 mL) and DCM (10 mL) was stirred at

[0676] 15 °C for 5 h under N2 and concentrated. Compound A-[3-[(35)-3-aminopyrrolidin- 1 -yl ]phenyl ]-A- methyl-6-(trifluoromethyl)pyridin-3-amine (250 mg, 555.09 pmol, 80.76% yield, TFA) was obtained as a white solid and used in the next step without further purification.

[0677] Step 4: (S)-2-(cyclopropylmethoxy)-iV-(l-(3-(methyl(6-(trifluoromethyl)pyridin-3- yl)amino)phenyl)pyrrolidin-3-yl)acetamide

[0678]

[0436] A mixture of A-[3-[(3S)-3-aminopyrrolidin-l-yl]phenyl]-A-methyl-6-(trifluoromethyl)pyridin-3- amine (250 mg, 555.09 pmol, 1 eq, TFA), 2-(cyclopropylmethoxy)acetic acid (72.24 mg, 555.09 pmol, 1 eq), HATU (211.06 mg, 555.09 pmol, 1 eq) and DIPEA (71.74 mg, 555.09 pmol, 96.69 pL, 1 eq) in DMF (10 mL) was stirred at 15 °C for 12 h under N2. The mixture was concentrated, and the residue was purified by prep-HPLC (column: Waters Xbridge Prep OBD C18 150*40mm* 10 pM; mobile phase: [water (NH4HCO3)-ACN]; B%: 50%-80%, 8 min). Compound 2-(cyclopropyhnethoxy)-tV-[(3>S -l-[3- [methyl-[6-(trifluoromethyl)-3-pyridyl]amino]phenyl]pyrrolidin-3-yl]acetamide (25.3 mg, 56.41 pmol, 7.26% yield) was obtained as a yellow oil. ’H NMR (400 MHz, DMSO- j) 5 8.14 (d, J = 2.8 Hz, 1H), 7.92 (d, J= 6.8 Hz, 1H), 7.59 (d, J= 8.8 Hz, 1H), 7.24(t, J= 8 Hz, 1H), 7.20-7.17 (m, 1H), 6.51-6.45 (m, 2H), 6.41-6.39 (m, 1H), 4.45-4.42 (m, 1H), 3.87 (s, 2H), 3.48-3.44 (m, 1H), 3.37-3.33 (m, 1H), 3.28 (s, 3H), 3.27 (s, 2H), 3.25-3.13 (m, 1H), 3.14 - 3.11 (m, 1H), 2.19-2.14 (m, 1H), 2.00-1.95 (m, 1H) , 1.03- 0.99 (m, 1H) , 0.47-0.43 (m, 2H), 0.17-0.14 (m, 2H). m / z (ES+) [M+H]+= 449.1.

[0679] Ex. 56, (S)-2-((l-isopropyl-lZ / -pyrazol-4-yl)oxy)-W(l-(3-((6-(trifluoromethyl)pyridin-3- yl)oxy)phenyl)pyrrolidin-3-yl)acetamide

[0680] Step 1: (S)-2-((l-isopropyl-LH-pyrazol-4-yl)oxy)-iV-(l-(3-((6-(trifluoromethyl)pyridin-3- yl)oxy)phenyl)pyrrolidin-3-yl)acetamide

[0681]

[0437] To a solution of l-isopropylpyrazol-4-ol (50 mg, 396.33 pmol, 1 eq) in DMF (5 mL) was added NaH (79.27 mg, 1.98 mmol, 60% purity, 5 eq) at 15 °C under N2. The mixture was stirred for 0.5 h under N2. 2-BromoW-[(3S)-l-[3-[[6-(trifluoromethyl)-3-pyridyl]oxy]phenyl]pyrrolidin-3-yl] acetamide (88.03 mg, 198.17 pmol, 0.5 eq) was added to the mixture at 15 °C under N2, and it was stirred at 15 °C for 1.5 h. Sat. aq. NH4CI (10 mL) was added to the mixture, and it was stirred for 10 min. The mixture was concentrated, and the residue was purified by prep-HPLC (column: Waters Xbridge Prep OBD Cl 8 150*40mm* 10 pM; mobile phase: [water (NFLHCC^-ACN] ; B%: 50%-80%, 8 min). Compound 2-(l- isopropylpyrazol-4-yl)oxy-A-[(3S)-l-[3-[[6-(trifluoromethyl)-3-pyridyl]oxy]phenyl]pyrrolidin-3- yl]acetamide (37.4 mg, 76.41 pmol, 19.28% yield) was obtained as a white solid. ’H NMR (400 MHz, DMSO- e) 5 8.51 (d, J = 2.8 Hz, 1H), 8.27 (d, J= 7.2 Hz, 1H), 7.87 (d, J= 8.8 Hz, 1H), 7.50-7.47 (m, 2H), 7.24 (t, J= 8.2 Hz, 1H), 7.18 (s, 1H), 6.44 (dd, 7 = 2 Hz, 10 Hz, 1H), 6.36 (dd, J= 6 Hz, 8 Hz, 1H), 6.33-6.30 (m, 1H), 4.50-4.43 (m, 1H), 4.36-4.30 (m, 1H), 4.30 (s, 2H), 3.50-3.45 (m, 1H), 3.34-3.27 (m, 2H), 3.14-3.09 (m, 1H), 2.20-2.13 (m, 1H), 2.01-1.94 (m, 1H), 1.33 (d, J= 6.8 Hz, 6H). m / z (ES+) [M+H]+= 490.1.

[0682] Ex. 67, (S)-2-((l-methoxy-2-methylpropan-2-yl)oxy )-A-(l-(3-((6-(trifluoromethyl)pyridin-3- yl)oxy)phenyl)pyrrolidin-3-yl)acetamide

[0683] Step 1: 5-(3-bromophenoxy)-2-(trifluoromethyl)pyridine

[0684]

[0438] A mixture of 3-bromophenol (5 g, 28.90 mmol, 1 eq), 5-fluoro-2-(trifluoromethyl)pyridine (5.25 g, 31.79 mmol, 1.1 eq) and CS2CO3 (11.30 g, 34.68 mmol, 1.2 eq) in DMF (50 mL) was stirred at 100 °C for 12 h under N2. The mixture was diluted with H2O (50 mL) and extracted with EtOAc (50 mL x 2). The combined organic phases were dried over Na2SC>4, filtered, and concentrated. The residue was purified by column chromatography (SiC>2, Petroleum ether / Ethyl acetate=100 / l to 0 / 1). Compound 5-(3- bromophenoxy)-2-(trifluoromethyl)pyridine (5 g, 15.72 mmol, 54.39% yield) was obtained as a white solid.

[0685] Step 2: (S) -tert-butyl (l-(3-((6-(trifluoromethyl)pyridin-3-yl)oxy)phenyl)pyrrolidin-3-yl)carbamate

[0686]

[0439] A mixture of 5-(3-bromophenoxy)-2-(trifluoromethyl)pyridine (5 g, 15.72 mmol, 1 eq), tert-butyl A^-[(35)-pyrrolidin-3-yl]carbamate (3.22 g, 17.29 mmol, 1.1 eq), RuPhos Pd G3 (1.31 g, 1.57 mmol, 0.1 eq) and CS2CO3 (10.24 g, 31.44 mmol, 2 eq) in 1,4-dioxane (20 mL) was stirred at 100 °C for 12 h under N2. The mixture was diluted with H2O (30 mL) and extracted with EtOAc (50 mL x 2). The combined organic phases were dried over Na^SO-i. filtered, and concentrated. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=100 / l to 0 / 1). Compound tert-butyl A-[(35)-l-[3- [[6-(trifluoromethyl)-3-pyridyl]oxy]phenyl]pyrrolidin-3-yl]carbamate (3.5 g, 8.27 mmol, 52.59% yield) was obtained as a white solid, m / z (ES+) [M+H]+= 424.2.

[0687] Step 3: (S)-l-(3-((6-(trifluoromethyl)pyridin-3-yl)oxy)phenyl)pyrrolidin-3-amine

[0688]

[0440] A solution of tert-butyl A-[(35)- l-[3-[[6-(trifhroromethyl)-3-pyridyl ]oxy]phenyl ]pyrrolidin-3- yl]carbamate (3.5 g, 8.27 mmol, 1 eq) in TFA (2 mL) and DCM (10 mL) was stirred at 20 °C for 2 h under N2 and concentrated. Compound (3S -l-[3-[[6-(trifhroromethyl)-3-pyridyl ] oxy] phenyl] pyrrolidin- 3-amine (4 g, 9.15 mmol, 55.33% yield, TFA) was obtained as a white solid and it was used in the next step without further purification, m / z (ES+) [M+H]+= 324.0.

[0689] Step 4: ethyl 2-((l-methoxy-2-methylpropan-2-yl)oxy)acetate

[0690]

[0441] To a solution of l-methoxy-2-methyl-propan-2-ol (5 g, 48.01 mmol, 1 eq) in THF (15 mL) was added NaH (2.88 g, 72.01 mmol, 60% purity, 1.5 eq) at 0 °C. The mixture was stirred for 0.5 h. Ethyl 2- bromoacetate (9.62 g, 57.61 mmol, 6.37 mL, 1.2 eq) was added to the mixture at 0 °C, and it was stirred at 20 °C for 4.5 h. Sat. aq. NH4CI (20 ml) was added to the mixture, and it was stirred for 10 min. The mixture was diluted with H2O (20 mL) and extracted with EtOAc (30 mL x 2). The combined organic phases were dried over Na2SC>4, filtered, and concentrated. The residue was purified by column chromatography (SiC>2, Petroleum ether / Ethyl acetate=100 / l to 0 / 1). Compound ethyl 2-(2- methoxy- 1,1- dimethyl-ethoxy)acetate (1 g, 5.26 mmol, 10.95% yield) was obtained as a white solid. ’H NMR (400 MHz, DMSO-< / 6) 5 4.20-4.18 (m, 2H), 4.13 (s, 2H), 3.25 (s, 3H), 3.20 (s, 2H), 1.21-1.17 (m, 3H), 1.10 (s, 6H).

[0691] Step 5: 2-((l-methoxy-2-methylpropan-2-yl)oxy)acetic acid

[0692]

[0442] To a solution of ethyl 2-(2-methoxy-l,l-dimethyl-ethoxy)acetate (1 g, 5.26 mmol, 1 eq) in EtOH (10 mL) and H2O (5 mL) was added NaOH (420.50 mg, 10.51 mmol, 2 eq). The mixture was stirred at 20 °C for 12 h. The mixture was acidified to pH = 3 with aq. HC1 (6 M) and extracted with EtOAc (30 mL x 2). The combined organic phases were dried over Na2SOr. filtered, and concentrated. Compound 2-(2- methoxy-l,l-dimethyl-ethoxy)acetic acid (600 mg, crude) was obtained as a white solid and used in the next step without further purification.

[0693] Step 6: (S)-2-((l-methoxy-2-methylpropan-2-yl)oxy)-Af-(l-(3-((6-(trifluoromethyl)pyridin-3- yl)oxy)phenyl)pyrrolidin-3-yl)acetamide

[0694]

[0443] A mixture of 2-(2-methoxy-l,l-dimethyl-ethoxy)acetic acid (118.67 mg, 731.70 pmol, 0.8 eq), (3S)-l-[3-[[6-(trifluoromethyl)-3-pyridyl]oxy]phenyl]pyrrolidin-3-amine (400 mg, 914.63 pmol, 1 eq, TFA), HATU (521.65 mg, 1.37 mmol, 1.5 eq) and DIPEA (354.63 mg, 2.74 mmol, 477.94 pL, 3 eq) in DMF (5 mL) was stirred at 25 °C for 12 h under N2. The mixture was concentrated, and the residue was purified by prep-HPLC (column: Phenomenex C18 80*40mm*3 pM; mobile phase: [wate^NELHCCL)- ACN]; B%: 40%-70%, 8 min). 100 mg, -85% purity by HPLC. Compound 2-(2-methoxy-l,l-dimethyl- ethoxy)-A-[(3S)-l-[3-[[6-(trifluoromethyl)-3-pyridyl] oxy]phenyl]pyrrolidin-3-yl]acetamide (20.3 mg, 43.42 pmol, 4.75% yield) was obtained as a colorless oil. ’H NMR (400 MHz, DMSO-<7>) 5 8.50 (d, J = 2.4 Hz, 1H), 7.87 (d, J = 8.8 Hz, 1H), 7.64 (d, J = 7.6 Hz, 1H), 7.47 (dd, J = 2.8 Hz, 8.8 Hz, 1H), 7.24 (t, 7= 8.0 Hz, 1H), 6.47-6.44 (m, 1H), 6.38-6.34 (m, 2H), 4.44 - 4.43 (m, 1H), 3.82 (s, 2H), 3.47 (dd, 7 = 6.8 Hz, 9.6 Hz, 1H), 3.38 - 3.36 (m, 1H), 3.34 (s, 1H), 3.22 (s, 5H), 3.12-3.08 (m, 1H), 2.21-2.14 (m, 1H), 1.98-1.93 (m, 1H), 1.097 (d, 7= 2.4 Hz, 6H). m / z (ES+) [M+H]+= 468.1.

[0695] Ex. 17, 2-(cyclopropylmethoxy )-Af-[(3S)-l-(3-phenoxyphenyl)-3-piperidyl]acetamide

[0696] Step 1: l-bromo-3-phenoxy-benzene

[0697]

[0444] To a mixture of 3-bromophenol (1 g, 5.78 mmol, 1 eq) and phenylboronic acid (1.06 g, 8.67 mmol, 1.5 eq) in DCM (50 mL) were added Cu(OAc)2 (1.57 g, 8.67 mmol, 1.5 eq), TEA (1.75 g, 17.34 mmol, 2.41 mL, 3 eq) and 4 A MS (2 g) at 25 °C. The mixture was stirred at 25 °C under O2 (15 psi) for 12 h and concentrated. The residue was purified by column chromatography (SiC>2, Petroleum ether / Ethyl acetate = 1 / 0 to 50 / 1). Compound l-bromo-3-phenoxy-benzene (0.45 g, 1.81 mmol, 31.25% yield) was obtained as a colourless oil.

[0698] Step 2: tert-butyl tV-[(3S)-l-(3-phenoxyphenyl )-3-piperidyl ]carbamate

[0699]

[0445] To a solution of l-bromo-3-phenoxy-benzene (0.45 g, 1.81 mmol, 1 eq) and tert-butyl A-[(3S)-3- piperidyl] carbamate (397.98 mg, 1.99 mmol, 1.1 eq) in...

Claims

CLAIMSWhat is claimed is:

1. A compound of Formula (I) :or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein: n is 1 or 2;R1is Ci-6 alkyl, Ci-6 haloalkyl, C3-7 carbocyclyl, 3-7 membered heterocyclyl, Ce-io aryl, 5-10 membered heteroaryl, -L'-Cs -7 carbocyclyl, -L*-(3-7 membered heterocyclyl), -L'-Ce -10 aryl, or -L’-(5-10 membered heteroaryl), wherein L1is C1-3 alkylene, and wherein each alkyl, haloalkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, or alkylene is independently optionally substituted; each instance of R" is independently H, Ci-6 alkyl, C3-7 carbocyclyl, or 3-7 membered heterocyclyl, or two R" are joined together with the intervening atoms to form C3-7 carbocyclyl or 3-7 membered heterocyclyl, wherein each alkyl, carbocyclyl, or heterocyclyl is independently optionally substituted; or R1and one instance of R" are joined together with the intervening atoms to form optionally substituted 4-7 membered heterocyclyl;R2is H, halogen, Ci-6 alkyl, Ci-6 haloalkyl, C3-7 carbocyclyl, 3-7 membered heterocyclyl, Ci-6 acyl, -CN, -OR2a, -N(RN)2, or -SRs, wherein each alkyl, haloalkyl, carbocyclyl, heterocyclyl, or acyl is independently optionally substituted; each instance of R3is independently halogen, Ci-6 alkyl, Ci-6 haloalkyl, C3-7 carbocyclyl, 3-7 membered heterocyclyl, Ci-6 acyl, -CN, -OR0, -N(RN)2, or -SRs, wherein each alkyl, haloalkyl, carbocyclyl, heterocyclyl, or acyl is independently optionally substituted; or any two instances of R2and / or R3attached to the same carbon atom are joined together with the intervening atoms to form C3-7 carbocyclyl or 3-7 membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is optionally substituted; or any two instances of R2and / or R3attached to the same carbon atom are taken together to form =0; m 0, 1, 2, 3, 4, 5, 6, 7, or 8, as valency permits;R4is C3-7 carbocyclyl, 3-7 membered heterocyclyl, Ce-io aryl, 5-10 membered heteroaryl, -L4-C3 7 carbocyclyl, -L4-(3-7 membered heterocyclyl), -L4-Ce 10 aryl, or -L4-(5-10 membered heteroaryl), wherein L4is C1-3 alkylene, and wherein each carbocyclyl, heterocyclyl, aryl, heteroaryl, or alkylene isindependently optionally substituted;Y is -O-, -N(RN)-, -S-, -S(=O)-, -S(=O)2-, or -C(Rc)2-; each instance of R5is independently halogen, Ci-6 alkyl, Ci-6 haloalkyl, C3-7 carbocyclyl, 3-7 membered heterocyclyl, Ci-6 acyl, -CN, -NO2, -N3, -OR0, -N(RN)2, -N=S(RS)2(=O), or -SRs, wherein each alkyl, haloalkyl, carbocyclyl, heterocyclyl, or acyl is independently optionally substituted; p is 0, 1, 2, 3, or 4; each instance of RN1and RNis independently H, Ci-6 alkyl, C3-7 carbocyclyl, Ci-6 acyl, or a nitrogen protecting group, or two RNattached to the same nitrogen atom are joined together with the intervening atoms to form 3-7 membered heterocyclyl, wherein each alkyl, carbocyclyl, acyl, or heterocyclyl is independently optionally substituted; each instance of R° and R2ais independently H, Ci-6 alkyl, Ci-6 haloalkyl, C3-7 carbocyclyl, 3-7 membered heterocyclyl, Ci-6 acyl, or an oxygen protecting group, wherein each alkyl, haloalkyl, carbocyclyl, heterocyclyl, or acyl is independently optionally substituted; each instance of Rsis independently H, Ci-6 alkyl, Ci-6 haloalkyl, C3-7 carbocyclyl, 3-7 membered heterocyclyl, Ci-6 acyl, or a sulfur protecting group, wherein each alkyl, haloalkyl, carbocyclyl, heterocyclyl, or acyl is independently optionally substituted; and each instance of Rcis independently H, halogen, Ci-6 alkyl, Ci-6 haloalkyl, C3-7 carbocyclyl, or 3- 7 membered heterocyclyl, or two Rcare joined together with the intervening atoms to form C3-7 carbocyclyl or 3-7 membered heterocyclyl, wherein each alkyl, haloalkyl, carbocyclyl, or heterocyclyl is independently optionally substituted; or two Rcare taken together to form =0.

2. The compound of claim 1, wherein the compound is of Formula (I'):or a pharmaceutically acceptable salt, tautomer, solvate, isotopically labeled derivative, or prodrug thereof.

3. The compound of claim 1, wherein the compound is of Formula (I-a):or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof.

4. The compound of claim 1, wherein the compound is of Formula (I-a'):or a pharmaceutically acceptable salt, tautomer, solvate, isotopically labeled derivative, or prodrug thereof.

5. The compound of claim 1, wherein the compound is of Formula (I-b):or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein:X1and X2are each independently N or CR4b; and each instance of R4aand R4bis independently H, halogen, Ci-6 alkyl, Ci-6 haloalkyl, C3-7 carbocyclyl, 3-7 membered heterocyclyl, Ci-6 acyl, -CN, -NO2, -N3, -OR0, -N(RN)2, or -SRs, whereineach alkyl, haloalkyl, carbocyclyl, heterocyclyl, or acyl is independently optionally substituted.

6. The compound of claim 5, wherein the compound is of Formula (I-b'):or a pharmaceutically acceptable salt, tautomer, solvate, isotopically labeled derivative, or prodrug thereof.

7. The compound of claim 5, wherein the compound is of Formula (I-c):or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof.

8. The compound of claim 5, wherein the compound is of Formula (I-c'):or a pharmaceutically acceptable salt, tautomer, solvate, isotopically labeled derivative, or prodrug thereof.

9. The compound of claim 5, wherein the compound is of Formula (I-d):or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof.

10. The compound of claim 5, wherein the compound is of Formula (I-d'):or a pharmaceutically acceptable salt, tautomer, solvate, isotopically labeled derivative, or prodrug thereof.

11. The compound of claim 5, wherein the compound is of Formula (I-e) or (I-f):or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof.

12. The compound of claim 5, wherein the compound is of Formula (I-e') or (I-f') :or a pharmaceutically acceptable salt, tautomer, solvate, isotopically labeled derivative, or prodrug thereof.

13. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein n is 1.

14. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein n is 2.

15. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein RN1is H.

16. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein each R" is H.

17. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R1is optionally substituted Ci-6 alkyl.

18. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R1is optionally substituted CM alkyl.

19. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R1unsubstituted Ci-4 alkyl.

20. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R1is methyl or ethyl.

21. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R1is -IJ-C3-7 carbocyclyl, wherein L1is Cm alkylene, and wherein the carbocyclyl and alkylene are independently optionally substituted.

22. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R1is -CH2- C35 carbocyclyl, wherein the carbocyclyl is optionally substituted.

23. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R1is:

24. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R1is selected25. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R2is H.

26. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R2is -OR2a.

27. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R2is -OMe.

28. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R2is selected from H, -OMe, -OEt, -OCF3, and methyl.

29. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R2ais Ci-6 alkyl or Ci-6 haloalkyl, wherein the alkyl or haloalkyl is optionally substituted.

30. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R2ais optionally substituted Ci-6 alkyl.

31. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R2ais unsubstituted C1-3 alkyl.

32. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R2ais methyl.

33. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R2ais selected from ethyl and -CF3.

34. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein m is 0.

35. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein Y is -O-.

36. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R4isoptionally substituted 5-10 membered heteroaryl.

37. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R4is optionally substituted 6-membered heteroaryl.

38. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R4is optionally substituted 6-membered heteroaryl having 1 or 2 ring N atoms.

39. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R4is of the formula:wherein:X1and X2are each independently N or CR4b; and each instance of R4aand R4bis independently H, halogen, Ci-6 alkyl, Ci-6 haloalkyl, C3-7 carbocyclyl, 3-7 membered heterocyclyl, Ci-6 acyl, -CN, -NO2, -N3, -OR0, -N(RN)2, or -SRs, wherein each alkyl, haloalkyl, carbocyclyl, heterocyclyl, or acyl is independently optionally substituted.

40. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R4is of the formula:

41. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R4is:

42. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R4is selectedfrom:

43. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein X1is N.

44. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein X2is N.

45. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt,stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R4ais optionally substituted Ci-6 haloalkyl.

46. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R4ais unsubstituted C1-3 haloalkyl.

47. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R4ais -CF3.

48. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R4ais49. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein at least one instance of R4bis H.

50. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein each instance of R4bis H.

51. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein p is 0.

52. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein p is 1.

53. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein at least one instance of R5is selected from halogen, unsubstituted Ci-6 alkyl, unsubstituted C3-7 carbocyclyl, -OR0, and -N(RN)2.

54. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt,stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein at least one instance of R5is selected from F, -OMe, -OEt, -Oz'-Pr -OCF3, -NMe2, -N=S(Me)2(=0), -CN, ethyl, and cyclopropyl.

55. The compound of claim 1, wherein the compound is selected from those in Table 1, and pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, isotopically labeled derivatives, and prodrug thereof.

56. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof.

57. A pharmaceutical composition comprising a compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof; and a pharmaceutically acceptable carrier.

58. A method of inhibiting transient receptor potential cation channel subfamily C (TRPC) activity in a subject comprising administering to the subject an effective amount of a compound of any one of claims 1-56, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition thereof.

59. A method of treating a disease associated with TRPC activity in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-56, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition thereof.

60. A method of preventing a disease associated with TRPC activity in a subject comprising administering to the subject a prophy tactically effective amount of a compound of any one of claims 1- 56, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition thereof.

61. The method of any one of claims 58-61, wherein the TRPC activity is transient receptor potential cation channel subfamily C, member 3 (TRPC3) activity.

62. The method of any one of claims 58-61, wherein the TRPC activity is transient receptor potential cation channel subfamily C, member 6 (TRPC6) activity.

63. A method of treating Alzheimer’s disease in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-56, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, orprodrug thereof, or a pharmaceutical composition thereof.

64. A method of preventing Alzheimer’s disease in a subject comprising administering to the subject a prophylactically effective amount of a compound of any one of claims 1-56, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition thereof.

65. A method comprising administering to a subject a compound of any one of claims 1-56, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition thereof.

66. The method of claim 65, wherein the subject has or is at risk of having a disease associated with TRPC activity.

67. The method of claim 65 or 66, wherein the subject has or is at risk of having a disease associated with TRPC3 activity.

68. The method of claim 65 or 66, wherein the subject has or is at risk of having a disease associated with TRPC6 activity.

69. The method of any one of claims 66-68, wherein the subject has or is at risk of having Alzheimer’s disease.

70. The method of any one of claims 58-69, wherein the subject is a human.

71. The method of any one of claims 58-69, wherein the subject is a mouse.

72. A compound of any one of claims 1-56, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition thereof, for use in treating or preventing a disease associated with TRPC activity in a subject.

73. The compound for use of claim 72, wherein the TRPC activity is TRPC3 activity.

74. The compound for use of claim 72, wherein the TRPC activity is TRPC6 activity.

75. A compound of any one of claims 1-56, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition thereof, for use in treating or preventing Alzheimer’s disease in a subject.

76. The compound for use of any one of claims 72-75, wherein the subject is a human.

77. The compound for use of any one of claims 72-75, wherein the subject is a mouse.

78. A compound of any one of claims 1-56, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition thereof, for use as a medicament.

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