Small molecule modulators of glucocerebrosidase activity and uses thereof

Abstract

Provided herein are compounds that modulate glucocerebrosidase (GCase), an enzyme whose activity is associated with neurological diseases and disorders (e.g., Gaucher's disease, Parkinson's disease). Also provided are pharmaceutical compositions and kits comprising the compounds, as well as methods of treating GCase-associated diseases and disorders (e.g., Gaucher's disease, Parkinson's disease) with the compounds in a subject by administering the compounds and / or compositions described herein.

Description

[Technical Field]

[0001] Related Applications This application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Application No. 63 / 182,728, filed April 30, 2021, which is incorporated herein by reference in its entirety. [Background technology]

[0002] Glucocerebrosidase (EC 3.2.1.45), also known as β-glucocerebrosidase, β-glucosidase, D-glucosyl-N-acylsphingosine monocohydrolase, or GCase, is an enzyme with glucosylceramidase activity. Glucocerebrosidase is required to cleave the β-glucosidic bond of the chemical glucocerebroside, an intermediate in glycolipid metabolism. Glucocerebrosidase is localized in lysosomes, and dysfunctional mutations in the glucocerebrosidase (GBA1) gene are associated with abnormal lipid accumulation in lysosomes. Summary of the Invention [Problem to be solved by the invention]

[0003] Genetic diseases caused by mutations in GBA1 include neurodegenerative disorders such as Gaucher disease and Parkinson's disease. Current treatment for disorders such as type 1 Gaucher disease is limited to enzyme replacement therapy (ERT) administered every two weeks. ERT is very expensive and ineffective for the neuropathic form of Gaucher disease. Efforts to discover and use small molecule compounds to activate Gcase have met with limited success. Therefore, there is a need for novel compounds that effectively activate Gcase and are useful for treating neurodegenerative disorders (e.g., Gaucher disease and Parkinson's disease). [Means for solving the problem]

[0004] The present disclosure provides compounds that are modulators of GCase, which provide novel compositions and methods for treating diseases associated with GCase activity (e.g., neurodegenerative diseases such as Gaucher disease and Parkinson's disease).

[0005] In one embodiment, the compound of formula (I): [ka] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, is provided; R 1 is a substituted or unsubstituted heteroaryl, a substituted or unsubstituted aryl, a substituted or unsubstituted carbocyclyl, a substituted or unsubstituted heterocyclyl, pentyl, butyl, methyl, -CH2CH2CH(CH3)2, or hydrogen or heterocyclyl, optionally forming a spiro ring system with A when n is 0 and G is a bond; G is a bond, -S(O)2-, or -NR 2 -, -CH2CH2O-, -CH2O-, -O- or -CR 2 R 3 - and R 2 and R 3 are each independently hydrogen, halogen, or substituted or unsubstituted alkyl, or R on that same carbon. 2 and R 3 forms a carbonyl with carbon, n is 1 or 0, A is [ka] and Each R 4 are independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, hydroxy, or R 4 Two examples of R are linked to form a bridged ring, or R on the same carbon 4 In the two cases, it forms a carbonyl with carbon, m is 0, 1, 2, 3 or 4; L is a bond, -C(=O)-, -C(=O)CH2-, -C(=O)CF2-, -C(=O)CH(Ph)-, -C(=O)CH(iPr)-, -C(=O)CH(Et)-, -C(=O)CH(Me)-, -C(=O)C(CH3)2-, -C(=O)CH(OMe)-, -C(=O)CH2CH2-, -C(=O)CH2CH2CH2-, -C(=O)CH2CH2CH2O-, -C(=O)CH(CH3)CH2-, -C(=O)CH2O-, -C(=O)CH2OCH2-, -C(=O)CH(CH3)O-, -C(=O)C H2CH=CH-, -C(=O)NHCH2CH2CH2-, -C(=O)NHCH2CH2-, -CH2-, -CH2CH2CH2-, -CH2C(CH3)2-, -C(=O)NH-, or -CH2C(=O)NH-, R 5 is substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted aryl, methyl, ethyl, butyl, pentyl, t-butyl, —CHCHCH(CH), —SCF, or —OCHCH(CH).

[0006] In another embodiment, the compound of formula (I): [ka] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, is provided; R 1 is a substituted or unsubstituted heteroaryl, substituted or unsubstituted aryl, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl, pentyl, butyl, or -CH2CH2CH(CH3)2, G is -S(O)2-, -NR 2 -, -CH2CH2O-, -CH2O-, -O- or -CR 2 R3 - and; R 2 and R 3 are each independently hydrogen, halogen, or substituted or unsubstituted alkyl; n is 1 or 0, A is [ka] and Each R 4 are independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, or R 4 Two examples of R are linked to form a bridged ring, or R on the same carbon 4 Two examples of carbonyls with carbon: m is 0, 1, 2, 3 or 4; L is a bond, —C(═O)—, —C(═O)CH—, or —C(═O)CHO—; R 5 is substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted aryloxyalkyl.

[0007] In another embodiment, the compound of formula (I): [ka] and pharmaceutically acceptable salt co-crystals, tautomers, stereoisomers, solvates, hydrates, polymorphs, isotopically enriched derivatives or prodrugs thereof, R 1 is a substituted or unsubstituted pyridinyl, or a substituted or unsubstituted phenyl; G is -O- or -CR 2 R 3 - and R 2 and R 3 are each independently hydrogen, halogen, or substituted or unsubstituted alkyl; n is 1 or 0, A is, [ka] and Each R 4 are independently halogen, substituted or unsubstituted alkyl, or R on the same carbon. 4 Two examples of carbonyls with carbon: m is 0, 1, 2, 3 or 4; L is a bond or -C(=O)-; R 5 is a substituted or unsubstituted pyrazolopyrazinyl, a substituted or unsubstituted indolyl, a substituted or unsubstituted oxadiazolyl, a substituted or unsubstituted triazolyl, or a substituted or unsubstituted pyrazinyl.

[0008] In another embodiment, the compound of formula (I): [ka] and pharmaceutically acceptable salt co-crystals, tautomers, stereoisomers, solvates, hydrates, polymorphs, isotopically enriched derivatives or prodrugs thereof, R 1 is a substituted or unsubstituted heteroaryl or a substituted or unsubstituted aryl; G is -O- or -CR 2 R 3 - and R 2 and R 3 are each independently hydrogen, halogen, or substituted or unsubstituted alkyl; n is 1 or 0, A is, [ka] and Each R 4 are independently halogen, substituted or unsubstituted alkyl, or R on the same carbon. 4 Two examples of carbonyls with carbon: m is 0, 1, 2, 3 or 4; L is a bond or -C(=O)-; R 5 is substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted aryloxyalkyl.

[0009] In certain embodiments of formula (I), R 1 is a substituted or unsubstituted pyridinyl, or a substituted or unsubstituted phenyl; G is -O- or -CR 2 R 3 - and R 2 and R 3 are each independently hydrogen, halogen, or substituted or unsubstituted alkyl; n is 1 or 0, A is, [ka] and Each R 4 are independently halogen, substituted or unsubstituted alkyl, or R on the same carbon. 4 Two examples of carbonyls with carbon: m is 0, 1, 2, 3 or 4; L is a bond or -C(=O)-; R 5 is substituted or unsubstituted pyrazolopyrazinyl, substituted or unsubstituted chromenonyl, substituted or unsubstituted indolyl, substituted or unsubstituted oxadiazolyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted triazolyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted tetrahydropyranyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted aryloxyalkyl.

[0010] In certain embodiments, the compound of Formula (I) has the formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (II-a), (II-b), (II-c), (II-d), (III-a), (III-b), (III-c), (III-d), (IV-a), (IV-b), (IV-c), (IV-d), (IV-e), (Va), (Vb), (Vc), or (Vd): [ka] TIFF2024518000000011.tif142159, or a pharmaceutically acceptable salt thereof.

[0011] In another aspect, there is provided a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable excipient.

[0012] In another aspect, there is provided a method of treating a disease or disorder in a subject in need thereof, the method comprising administering to the subject a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I).

[0013] In certain embodiments, the disease or disorder is associated with glucocerebrosidase activity. In certain embodiments, the disease or disorder is a neurological disease or disorder. In certain embodiments, the neurological disease or disorder is Parkinson's disease or Gaucher's disease.

[0014] In another aspect, a method of activating glucocerebrosidase is provided, comprising contacting glucocerebrosidase in a subject with an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I).

[0015] In another aspect, kits are provided that comprise a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In certain embodiments, the kit further comprises instructions for administration (e.g., human administration).

[0016] Details of certain embodiments of the invention are set forth in the Detailed Description of Certain Embodiments, as set forth below. Other features, objects, and advantages of the invention will become apparent from the definition, examples, and claims.

[0017] definition chemical definition Definitions of specific functional groups and chemical terms are set out in more detail below. Chemical elements are defined in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 th Ed., inside cover, and specific functional groups are generally defined as described therein. Further, general principles of organic chemistry, as well as specific functional moieties and reactivities, are described in Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5 th Edition, John Wiley&Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3 rd Edition, Cambridge University Press, Cambridge, 1987.

[0018] The compounds described herein may contain one or more asymmetric centers and therefore may exist in various stereoisomeric forms, such as enantiomers and / or diastereomers. For example, the compounds described herein may be in the form of individual enantiomers, diastereomers, or geometric isomers, or may be in the form of mixtures of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. 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 synthesis. See, e.g., Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, ELStereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, SH, Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., University of Notre Dame Press, Notre Dame, IN 1972). The present invention further encompasses compounds as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

[0019] During the ceremony, [ka] is a single bond with unspecified stereochemistry of the moiety directly attached to it, [ka] is absent or a single bond, [ka] or [ka] is a single bond or a double bond.

[0020] Unless otherwise stated, structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms, for example, the replacement of hydrogen by deuterium or tritium. 18 By F 19 Substitution of F, or 13 C or 14 By C 12 Compounds having this structure except for the substitution at C are within the scope of this disclosure. Such compounds are useful, for example, as analytical tools or probes in biological assays.

[0021] When a range of values ​​is listed, it is intended to encompass each value and subrange within the range. For example, "C 1~6 "Alkyl" refers to C1, C2, C3, C4, C5, C6, C 1~6 , C 1~5 , C 1~4 , C 1-3 , C 1~2 , C 2~6 , C 2~5 , C 2~4 , C 2~3 , C 3~6 , C 3~5 , C 3~4 , C 4~6 , C 4~5 , and C 5~6 Alkyl is intended to be included.

[0022] The term "aliphatic" refers to alkyl, alkenyl, alkynyl, and carbocyclic groups. Similarly, the term "heteroaliphatic" refers to heteroalkyl, heteroalkenyl, heteroalkynyl, and heterocyclic groups.

[0023] The term "alkyl" refers to the radical of a straight-chain or branched saturated hydrocarbon group having 1 to 10 carbon atoms ("C 1~10In some embodiments, an alkyl group has 1 to 9 carbon atoms ("C 1~9 In some embodiments, the alkyl group has 1 to 8 carbon atoms ("C 1~8 In some embodiments, the alkyl group has 1 to 7 carbon atoms ("C 1~7 In some embodiments, an alkyl group has 1 to 6 carbon atoms ("C 1~6 In some embodiments, an alkyl group has 1 to 5 carbon atoms ("C 1~5 In some embodiments, an alkyl group has 1 to 4 carbon atoms ("C 1~4 In some embodiments, the alkyl group has 1 to 3 carbon atoms ("C 1~3 In some embodiments, the alkyl group has 1 to 2 carbon atoms ("C 1~2 In some embodiments, the alkyl group has 1 carbon atom ("C alkyl"). In some embodiments, the alkyl group has 2 to 6 carbon atoms ("C 2~6 alkyl). C 1~6 Examples of alkyl groups include methyl (C1), ethyl (C2), propyl (C3) (e.g., n-propyl, isopropyl), butyl (C4) (e.g., n-butyl, tert-butyl, sec-butyl, iso-butyl), pentyl (C5) (e.g., n-pentyl, 3-pentanyl, amyl, neopentyl, 3-methyl-2-butanyl, tertiary amyl), and hexyl (C6) (e.g., n-hexyl). Further examples of alkyl groups include n-heptyl (C7), n-octyl (C8), and the like. Unless otherwise specified, each instance of an alkyl group is independently unsubstituted (an "unsubstituted alkyl") or substituted with one or more substituents (e.g., halogen, such as F) (a "substituted alkyl"). In certain embodiments, an alkyl group is an unsubstituted C 1~10 Alkyl (e.g., unsubstituted C 1~6Alkyl, for example, -CH3(Me), unsubstituted ethyl (Et), unsubstituted propyl (Pr, e.g., unsubstituted n-propyl (n-Pr), unsubstituted isopropyl (i-Pr)), unsubstituted butyl (Bu, e.g., unsubstituted n-butyl (n-Bu), unsubstituted tert-butyl (tert-Bu or t-Bu), unsubstituted sec-butyl (sec-Bu), unsubstituted isobutyl (i-Bu)). In certain embodiments, the alkyl group is a substituted C 1~10 Alkyl (e.g., substituted C 1~6 alkyl, for example -CF3, Bn).

[0024] The term "haloalkyl" refers to a substituted alkyl group in which one or more of the hydrogen atoms are independently replaced with a halogen, such as fluoro, bromo, chloro, or iodo. In some embodiments, the haloalkyl moiety has 1 to 8 carbon atoms ("C 1~8 In some embodiments, the haloalkyl moiety has 1 to 6 carbon atoms ("C 1~6 In some embodiments, the haloalkyl moiety has 1 to 4 carbon atoms ("C 1~4 In some embodiments, the haloalkyl moiety has 1 to 3 carbon atoms ("C 1~3 In some embodiments, the haloalkyl moiety has 1 to 2 carbon atoms ("C 1~2 Examples of haloalkyl groups include -CHF2, -CH2F, -CF3, -CH2CF3, -CF2CF3, -CF2CF2CF3, -CCl3, -CFCl2, -CF2Cl, and the like.

[0025] The term "alkoxy" refers to an alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. In some embodiments, the alkoxy moiety has 1 to 8 carbon atoms ("C 1~8 In some embodiments, the alkoxy moiety has 1 to 6 carbon atoms ("C 1~6 In some embodiments, the alkoxy moiety has 1 to 4 carbon atoms ("C1~4 In some embodiments, the alkoxy moiety has 1 to 3 carbon atoms ("C 1~3 In some embodiments, the alkoxy moiety has 1 to 2 carbon atoms ("C 1~2 Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, and tert-butoxy.

[0026] The term "alkoxyalkyl" refers to a substituted alkyl group in which one or more of the hydrogen atoms are independently replaced by an alkoxy group, as defined herein. In some embodiments, the alkoxyalkyl moiety has 1 to 8 carbon atoms ("C 1~8 In some embodiments, the alkoxyalkyl moiety has 1 to 6 carbon atoms ("C 1~6 In some embodiments, the alkoxyalkyl moiety has 1 to 4 carbon atoms ("C 1~4 In some embodiments, the alkoxyalkyl moiety has 1 to 3 carbon atoms ("C 1~3 In some embodiments, the alkoxyalkyl moiety has 1 to 2 carbon atoms ("C 1~2 alkoxyalkyl").

[0027] The term "heteroalkyl" refers to an alkyl group that further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (i.e., inserted between adjacent carbon atoms) and / or located at one or more terminal positions of the parent chain. In certain embodiments, heteroalkyl groups are saturated groups having 1 to 20 carbon atoms and one or more heteroatoms within the parent chain ("heteroC 1~20 In some embodiments, a heteroalkyl group refers to a saturated group having 1 to 18 carbon atoms and one or more heteroatoms in the parent chain ("heteroC 1~18In some embodiments, a heteroalkyl group is a saturated group having 1 to 16 carbon atoms and one or more heteroatoms in the parent chain ("heteroC 1~16 In some embodiments, heteroalkyl groups are saturated groups having 1 to 14 carbon atoms and one or more heteroatoms in the parent chain ("heteroC 1-14 In some embodiments, heteroalkyl groups are saturated groups having 1 to 12 carbon atoms and one or more heteroatoms in the parent chain ("heteroC 1~12 In some embodiments, a heteroalkyl group is a saturated group having 1 to 10 carbon atoms and one or more heteroatoms in the parent chain ("heteroC 1~10 In some embodiments, a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and one or more heteroatoms in the parent chain ("heteroC 1~8 In some embodiments, heteroalkyl groups are saturated groups having 1 to 6 carbon atoms and one or more heteroatoms in the parent chain ("heteroC 1~6 In some embodiments, heteroalkyl groups are saturated groups having 1 to 4 carbon atoms and 1 or 2 heteroatoms in the parent chain ("heteroC 1~4 In some embodiments, heteroalkyl groups are saturated groups having 1 to 3 carbon atoms and 1 heteroatom in the parent chain ("heteroC 1-3 In some embodiments, heteroalkyl groups are saturated groups having 1 to 2 carbon atoms and 1 heteroatom in the parent chain ("heteroC 1~2In some embodiments, a heteroalkyl group is a saturated group having one carbon atom and one heteroatom ("heteroCi alkyl"). In some embodiments, a heteroalkyl group, as defined herein, is a partially unsaturated group having one or more heteroatoms and at least one unsaturated carbon in the parent chain, e.g., a carbonyl group. For example, a heteroalkyl group can include an amide or ester functionality in its parent chain such that one or more carbon atoms are unsaturated carbonyl groups. Unless otherwise specified, each instance of a heteroalkyl group is independently unsubstituted ("unsubstituted heteroalkyl") or substituted with one or more substituents ("substituted heteroalkyl"). In certain embodiments, a heteroalkyl group is an unsubstituted heteroC 1~20 In certain embodiments, the heteroalkyl group is an unsubstituted heteroC 1~10 In certain embodiments, the heteroalkyl group is a substituted heteroC 1~20 In certain embodiments, the heteroalkyl group is an unsubstituted heteroC 1~10 It is alkyl.

[0028] The term "alkenyl" refers to the radical of a straight- or branched-chain hydrocarbon group having 2 to 10 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 9 carbon atoms ("C 2~9 In some embodiments, the alkenyl group has 2 to 8 carbon atoms ("C 2~8 In some embodiments, the alkenyl group has 2 to 7 carbon atoms ("C 2~7 In some embodiments, the alkenyl group has 2 to 6 carbon atoms ("C 2~6 In some embodiments, the alkenyl group has 2 to 5 carbon atoms ("C 2~5 In some embodiments, the alkenyl group has 2 to 4 carbon atoms ("C 2~4 In some embodiments, the alkenyl group has 2 to 3 carbon atoms ("C 2~3In some embodiments, the alkenyl group has two carbon atoms ("C2 alkenyl"). The one or more carbon-carbon double bonds can be internal (e.g., 2-butenyl) or terminal (e.g., 1-butenyl). C 2~4 Examples of alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. 2~6 Examples of alkenyl groups include the above-mentioned C 2~4 Alkenyl groups include pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Further examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like. Unless otherwise specified, each instance of an alkenyl group is independently unsubstituted (an "unsubstituted alkenyl") or substituted with one or more substituents (a "substituted alkenyl"). In certain embodiments, an alkenyl group is an unsubstituted C 2~10 In certain embodiments, the alkenyl group is a substituted C 2~10 In an alkenyl group, a C=C double bond where the stereochemistry is not specified (e.g., -CH=CHCH3 or [ka] ) may be an (E)- or (Z)-double bond.

[0029] The term "heteroalkenyl" refers to an alkenyl group that further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (i.e., inserted between adjacent carbon atoms) and / or located at one or more terminal positions of the parent chain. In certain embodiments, a heteroalkenyl group is a group having 2 to 10 carbon atoms, at least one double bond, and one or more heteroatoms within the parent chain ("heteroalkenyl"). 2~10 In some embodiments, heteroalkenyl groups have 2 to 9 carbon atoms, at least one double bond, and one or more heteroatoms in the parent chain ("heteroC2~9 In some embodiments, heteroalkenyl groups have 2 to 8 carbon atoms, at least one double bond, and one or more heteroatoms in the parent chain ("heteroC 2~8 In some embodiments, heteroalkenyl groups have 2 to 7 carbon atoms, at least one double bond, and one or more heteroatoms in the parent chain ("heteroC 2~7 In some embodiments, heteroalkenyl groups have 2 to 6 carbon atoms, at least one double bond, and one or more heteroatoms in the parent chain ("heteroC 2~6 In some embodiments, heteroalkenyl groups have 2 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms in the parent chain ("heteroC"). 2~5 In some embodiments, heteroalkenyl groups have 2 to 4 carbon atoms, at least one double bond, and 1 or 2 heteroatoms in the parent chain ("heteroC 2~4 In some embodiments, heteroalkenyl groups have 2 to 3 carbon atoms, at least one double bond, and one heteroatom in the parent chain ("heteroC 2~3 In some embodiments, heteroalkenyl groups have 2 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms in the parent chain ("heteroC"). 2~6 Unless otherwise specified, each instance of a heteroalkenyl group is independently unsubstituted (an "unsubstituted heteroalkenyl") or substituted with one or more substituents (a "substituted heteroalkenyl"). In certain embodiments, a heteroalkenyl group is an unsubstituted heteroC 2~10 In certain embodiments, the heteroalkenyl group is a substituted heteroC 2~10 It is alkenyl.

[0030] The term "alkynyl" refers to the radical of a straight- or branched-chain hydrocarbon group having 2 to 10 carbon atoms and one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 triple bonds) ("C 2~10In some embodiments, the alkynyl group has 2 to 9 carbon atoms ("C 2~9 In some embodiments, the alkynyl group has 2 to 8 carbon atoms ("C 2~8 In some embodiments, the alkynyl group has 2 to 7 carbon atoms ("C 2~7 In some embodiments, the alkynyl group has 2 to 6 carbon atoms ("C 2~6 In some embodiments, the alkynyl group has 2 to 5 carbon atoms ("C 2~5 In some embodiments, the alkynyl group has 2 to 4 carbon atoms ("C 2~4 In some embodiments, the alkynyl group has 2 to 3 carbon atoms ("C 2~3 In some embodiments, the alkynyl group has two carbon atoms ("C2 alkynyl"). The one or more carbon-carbon triple bonds can be internal (e.g., 2-butynyl) or terminal (e.g., 1-butynyl). C 2~4 Examples of alkynyl groups include, but are not limited to, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. 2~6 Examples of alkenyl groups include the above-mentioned C 2~4 Alkynyl groups include pentynyl (C5) and hexynyl (C6), and the like. Further examples of alkynyl include heptynyl (C7), octynyl (C8), and the like. Unless otherwise specified, each instance of an alkynyl group is independently unsubstituted (an "unsubstituted alkynyl") or substituted with one or more substituents (a "substituted alkynyl"). In certain embodiments, an alkynyl group is an unsubstituted C 2~10 In certain embodiments, the alkynyl group is a substituted C 2~10 It is alkynyl.

[0031] The term "heteroalkynyl" refers to an alkynyl group that further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (i.e., inserted between adjacent carbon atoms) and / or located at one or more terminal positions of the parent chain. In certain embodiments, a heteroalkynyl group refers to a group having 2 to 10 carbon atoms, at least one triple bond, and one or more heteroatoms within the parent chain ("heteroalkynyl"). 2~10 In some embodiments, heteroalkynyl groups have 2 to 9 carbon atoms, at least one triple bond, and one or more heteroatoms in the parent chain ("heteroC 2~9 In some embodiments, heteroalkynyl groups have 2 to 8 carbon atoms, at least one triple bond, and one or more heteroatoms in the parent chain ("heteroC 2~8 In some embodiments, heteroalkynyl groups have 2 to 7 carbon atoms, at least one triple bond, and one or more heteroatoms in the parent chain ("heteroC 2~7 In some embodiments, heteroalkynyl groups have 2 to 6 carbon atoms, at least one triple bond, and one or more heteroatoms in the parent chain ("heteroC 2~6 In some embodiments, heteroalkynyl groups have 2 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms in the parent chain ("heteroC 2~5 In some embodiments, heteroalkynyl groups have 2 to 4 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms in the parent chain ("heteroC 2~4 In some embodiments, heteroalkynyl groups have 2 to 3 carbon atoms, at least one triple bond, and one heteroatom in the parent chain ("heteroC 2~3 In some embodiments, heteroalkynyl groups have 2 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms in the parent chain ("heteroC 2~6Unless otherwise specified, each instance of a heteroalkynyl group is independently unsubstituted (an "unsubstituted heteroalkynyl") or substituted with one or more substituents (a "substituted heteroalkynyl"). In certain embodiments, a heteroalkynyl group is an unsubstituted heteroC 2~10 In certain embodiments, the heteroalkynyl group is a substituted heteroC 2~10 It is alkynyl.

[0032] The term "carbocyclyl" or "carbocyclic" refers to a ring system having 3 to 14 ring carbon atoms ("C 3~14 In some embodiments, a carbocyclyl group has 3 to 10 ring carbon atoms ("C 3~10 In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms ("C 3~8 In some embodiments, a carbocyclyl group has 3 to 7 ring carbon atoms ("C 3~7 In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms ("C 3~6 In some embodiments, a carbocyclyl group has 4 to 6 ring carbon atoms ("C 4~6 In some embodiments, the carbocyclyl group has 5 to 6 ring carbon atoms ("C 5~6 In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms ("C 5~10 carbocyclyl). Exemplary C 3~6 Carbocyclyl groups include, but are not limited to, cyclopropyl (C), cyclopropenyl (C), cyclobutyl (C), cyclobutenyl (C), cyclopentyl (C), cyclopentenyl (C), cyclohexyl (C), cyclohexenyl (C), cyclohexadienyl (C), and the like. 3~8 The carbocyclyl group includes, but is not limited to, the above-mentioned C 3~6Examples include carbocyclyl groups, as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), and the like. Exemplary C 3~10 The carbocyclyl group includes, but is not limited to, the above-mentioned C 3~8 Carbocyclyl groups, as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C 10 ), spiro[4.5]decanyl (C 10 As the foregoing examples illustrate, in certain embodiments, a carbocyclyl group is either monocyclic ("monocyclic carbocyclyl") or polycyclic (including, for example, fused, bridged, or spiro ring systems such as a bicyclic ring system ("bicyclic carbocyclyl") or a tricyclic ring system ("tricyclic carbocyclyl")) and can be saturated or can contain one or more carbon-carbon double or triple bonds. "Carbocyclyl" also includes ring systems in which a carbocyclyl ring, as defined above, is fused to one or more aryl or heteroaryl groups, and the point of attachment is on the carbocyclyl ring, in which case the number of carbons continues to designate the number of carbons in the carbocyclic ring. Unless otherwise specified, each instance of a carbocyclyl group is independently unsubstituted ("unsubstituted carbocyclyl") or substituted with one or more substituents ("substituted carbocyclyl"). In certain embodiments, the carbocyclyl group is an unsubstituted C 3-14 In certain embodiments, the carbocyclyl group is a substituted C 3-14 It is a carbocyclyl.

[0033] In some embodiments, a "carbocyclyl" is a monocyclic saturated carbocyclyl group having 3 to 14 ring carbon atoms ("C 3-14 In some embodiments, a cycloalkyl group has 3 to 10 ring carbon atoms ("C 3~10In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms ("C 3~8 In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms ("C 3~6 In some embodiments, a cycloalkyl group has 4 to 6 ring carbon atoms ("C 4~6 In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms ("C 5~6 In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms ("C 5~10 Cycloalkyl). C 5~6 Examples of cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). 3~6 Examples of cycloalkyl groups include the above-mentioned C 5~6 Cycloalkyl groups include cyclopropyl (C3) and cyclobutyl (C4). 3~8 Examples of cycloalkyl groups include the above-mentioned C 3~6 Cycloalkyl groups include cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise specified, each instance of a cycloalkyl group is independently unsubstituted ("unsubstituted cycloalkyl") or substituted with one or more substituents ("substituted cycloalkyl"). In certain embodiments, a cycloalkyl group is an unsubstituted C 3-14 In certain embodiments, the cycloalkyl group is a substituted C 3-14 It is cycloalkyl.

[0034] The terms "heterocyclyl" or "heterocyclic" refer to the radical of a 3- to 14-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, each independently selected from nitrogen, oxygen, and sulfur (a "3- to 14-membered heterocyclyl"). In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment can be a carbon atom or a nitrogen atom, where valence allows. Heterocyclyl groups can be either monocyclic (a "monocyclic heterocyclyl") or polycyclic (e.g., fused, bridged, or spiro ring systems, such as bicyclic (a "bicyclic heterocyclyl") or tricyclic (a "tricyclic heterocyclyl") ring systems), saturated or containing one or more carbon-carbon double or triple bonds. Heterocyclyl polycyclic ring systems can contain one or more heteroatoms in one or both rings. "Heterocyclyl" also includes ring systems in which a heterocyclyl ring, as defined above, is fused to one or more carbocyclyl groups, and the point of attachment is on either the carbocyclyl or the heterocyclyl ring, or in which a heterocyclyl ring, as defined above, is fused to one or more aryl or heteroaryl groups, and the point of attachment is on the heterocyclyl ring, in which case the number of ring members continues to specify the number of ring members on the heterocyclyl ring system. Unless otherwise specified, each instance of heterocyclyl is independently unsubstituted ("unsubstituted heterocyclyl") or substituted with one or more substituents ("substituted heterocyclyl"). In certain embodiments, a heterocyclyl group is an unsubstituted 3- to 14-membered heterocyclyl. In certain embodiments, a heterocyclyl group is a substituted 3- to 14-membered heterocyclyl.

[0035] In some embodiments, a heterocyclyl group is a 5- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, each independently selected from nitrogen, oxygen, and sulfur (a "5- to 10-membered heterocyclyl"). In some embodiments, a heterocyclyl group is a 5- to 8-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, each independently selected from nitrogen, oxygen, and sulfur (a "5- to 8-membered heterocyclyl"). In some embodiments, a heterocyclyl group is a 5- to 6-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, each independently selected from nitrogen, oxygen, and sulfur (a "5- to 6-membered heterocyclyl"). In some embodiments, a 5- to 6-membered heterocyclyl has 1 to 3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5- to 6-membered heterocyclyl has 1 to 2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heterocyclyl has one ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0036] Exemplary 3-membered heterocyclyl groups containing one heteroatom include, but are not limited to, aziridinyl, oxiranyl, and thiiranyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxathiolanyl, and dithiolanyl. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazinyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azocanyl, oxecanyl, and thiocanyl.Exemplary bicyclic heterocyclyl groups include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, tetrahydro-benzo-thienyl, tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl, decahydronaphthyridinyl, decahydro-1,8-naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole, indolinyl, phthalimidyl, naphthalimidyl, chromanyl, chromenyl, 1H-benzo[e][1,4]diazepinyl, Examples thereof include 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-1H-pyrrolo[2,3-b]pyridinyl, 2,3-dihydrofuro[2,3-b]pyridinyl, 4,5,6,7-tetrahydro-1H-pyrrolo-[2,3-b]pyridinyl, 4,5,6,7-tetrahydro-furo[3,2-c]pyridinyl, 4,5,6,7-tetrahydro-thieno[3,2-b]pyridinyl, and 1,2,3,4-tetrahydro-1,6-naphthyridinyl.

[0037] 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 pi electrons shared within the cyclic array) having 6 to 14 ring carbon atoms and 0 heteroatoms provided to the aromatic ring system ("C 6~14 In some embodiments, an aryl group has 6 ring carbon atoms ("C aryl"; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms ("C 10 Aryl"; e.g., naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms ("C 14"Aryl"; e.g., anthracyl). "Aryl" also includes ring systems in which an aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups, and the radical or point of attachment is on the aryl ring; in such cases, the number of carbon atoms continues to designate the number of carbon atoms in the aryl ring system. Unless otherwise specified, each instance of an aryl group is independently unsubstituted ("unsubstituted aryl") or substituted with one or more substituents ("substituted aryl"). In certain embodiments, an aryl group is an unsubstituted C 6~14 In certain embodiments, the aryl group is a substituted C 6~14 It is aryl.

[0038] "Arylalkyl" is a subset of "alkyl" and refers to an alkyl group substituted with an aryl group, where the point of attachment is on the alkyl portion.

[0039] The term "heteroaryl" refers to a radical of a 5- to 14-membered monocyclic or polycyclic (e.g., bicyclic, tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π-electrons shared within the cyclic array), where the aromatic ring system is provided with ring carbon atoms and 1 to 4 ring heteroatoms, each heteroatom independently selected from nitrogen, oxygen, and sulfur ("5- to 14-membered heteroaryl"). In heteroaryl groups containing one or more nitrogen atoms, the point of attachment can be at a carbon atom or a nitrogen atom, valence permitting. Heteroaryl polycyclic ring systems can contain one or more heteroatoms in one or both rings. "Heteroaryl" includes ring systems in which a heteroaryl ring, as defined above, is fused to one or more carbocyclyl or heterocyclyl groups, and the point of attachment is on the heteroaryl ring; in such cases, the number of ring members continues to designate the number of ring members in the heteroaryl ring system. "Heteroaryl" also includes ring systems in which a heteroaryl ring, as defined above, is fused to one or more aryl groups, and the point of attachment can be on either the aryl ring or the heteroaryl ring, where the number of ring members indicates the number of ring members in the fused polycyclic (aryl / heteroaryl) ring system. For polycyclic heteroaryl groups in which one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, etc.), the point of attachment can be on either ring, i.e., either the ring containing a heteroatom (e.g., 2-indolyl) or the ring without a heteroatom (e.g., 5-indolyl).

[0040] In some embodiments, heteroaryl groups are 5-10 membered aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, each heteroatom being independently selected from nitrogen, oxygen, and sulfur ("5-10 membered heteroaryl"). In some embodiments, heteroaryl groups are 5-8 membered aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, each heteroatom being independently selected from nitrogen, oxygen, and sulfur ("5-8 membered heteroaryl"). In some embodiments, heteroaryl groups are 5-6 membered aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, each heteroatom being independently selected from nitrogen, oxygen, and sulfur ("5-6 membered heteroaryl"). In some embodiments, 5-6 membered heteroaryls have 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, 5-6 membered heteroaryls have 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5- to 6-membered heteroaryl has one ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each instance of a heteroaryl group is independently unsubstituted ("unsubstituted heteroaryl") or substituted with one or more substituents ("substituted heteroaryl"). In certain embodiments, a heteroaryl group is an unsubstituted 5- to 14-membered heteroaryl. In certain embodiments, a heteroaryl group is a substituted 5- to 14-membered heteroaryl.

[0041] Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. Exemplary tricyclic heteroaryl groups include, but are not limited to, phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl, and phenazinyl.

[0042] "Heteroarylalkyl" is a subset of "alkyl" and refers to an alkyl group substituted by a heteroaryl group, where the point of attachment is on the alkyl portion.

[0043] The term "unsaturated bond" refers to a double or triple bond.

[0044] The terms "unsaturated" or "partially unsaturated" refer to a moiety that contains at least one double or triple bond.

[0045] The term "saturated" refers to a moiety that does not contain any double or triple bonds, i.e., the moiety contains only single bonds.

[0046] The addition of the suffix "-ene" to a group indicates that the group is a divalent moiety, for example, alkylene is a divalent moiety of alkyl, alkenylene is a divalent moiety of alkenyl, alkynylene is a divalent moiety of alkynyl, heteroalkylene is a divalent moiety of heteroalkyl, heteroalkenylene is a divalent moiety of heteroalkenyl, heteroalkynylene is a divalent moiety of heteroalkynyl, carbocyclylene is a divalent moiety of carbocyclyl, heterocyclylene is a divalent moiety of heterocyclyl, arylene is a divalent moiety of aryl, and heteroarylene is a divalent moiety of heteroaryl.

[0047] Groups are optionally substituted unless otherwise specified. The term "optionally substituted" refers to 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 that can be substituted or unsubstituted (e.g., a "substituted" or "unsubstituted" alkyl, a "substituted" or "unsubstituted" alkenyl, a "substituted" or "unsubstituted" alkynyl, a "substituted" or "unsubstituted" heteroalkyl, a "substituted" or "unsubstituted" heteroalkenyl, a "substituted" or "unsubstituted" heteroalkynyl, a "substituted" or "unsubstituted" carbocyclyl, a "substituted" or "unsubstituted" heterocyclyl, a "substituted" or "unsubstituted" aryl, or a "substituted" or "unsubstituted" heteroaryl group). In general, the term "substituted" means that at least one hydrogen atom present on a group is replaced with an acceptable substituent, e.g., a substituent that, upon substitution, results in a stable compound, e.g., a compound that does not spontaneously undergo transformation, such as by rearrangement, cyclization, elimination, or other reaction. Unless otherwise specified, a "substituted" group has a substituent at one or more substitutable positions of the group; when more than one position in any given structure is substituted, the substituents can be the same or different at each position. The term "substituted" is considered to include substitution with all permissible substituents of organic compounds, including any of the substituents described herein that result in the formation of a stable compound. The present disclosure contemplates all such combinations in order to arrive at stable compounds. For purposes of this disclosure, heteroatoms such as nitrogen can have hydrogen substituents and / or any suitable substituents described herein that satisfy the valence of the heteroatom and result in the formation of a stable moiety. The present disclosure is not intended to be limited in any manner by the exemplary substituents described herein.

[0048] When substituted, exemplary carbon atom substituents include halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR aa , -ON(R bb )2, -N(R bb )2, -N(Rbb )3 + X - 、-N(OR cc )R bb 、-SH、-SR aa 、-SSR cc 、-C(=O)R aa 、-CO2H、-CHO、-C(OR cc )3、-CO2R aa 、-OC(=O)R aa 、-OCO2R aa 、-C(=O)N(R bb )2、-OC(=O)N(R bb )2、-NR bb C(=O)R aa 、-NR bb CO2R aa 、-NR bb C(=O)N(R bb )2、-C(=NR bb )R aa 、-C(=NR bb )OR aa 、-OC(=NR bb )R aa 、-OC(=NR bb )OR aa 、-C(=NR bb )N(R bb )2、-OC(=NR bb )N(R bb )2、-NR bb C(=NR bb )N(R bb )2、-C(=O)NR bb SO2R aa 、-NR bb SO2R aa 、-SO2N(R bb )2、-SO2R aa 、-SO2OR aa 、-OSO2R aa 、-S(=O)R aa 、-OS(=O)R aa 、-Si(R aa )3、-OSi(R aa )3-C(=S)N(R bb )2、-C(=O)SR aa 、-C(=S)SR aa 、-SC(=S)SR aa, -SC(=O)SR aa , -OC(=O)SR aa , -SC(=O)OR aa , -SC(=O)R aa , -P(=O)(R aa )2, -P(=O)(OR cc ) 2、 -OP(=O)(R aa )2, -OP(=O)(OR cc )2, -P(=O)(N(R bb )2)2, -OP(=O)(N(R bb )2)2, -NR bb P(=O)(R aa ) 2、 -NR bb P(=O)(OR cc )2, -NR bb P(=O)(N(R bb )2)2, -P(R cc )2, -P(OR cc )2, -P(R cc )3 + X - , -P(OR cc )3 + X - , -P(R cc )4, -P(OR cc ) 4、 -OP(R cc )2, -OP(R cc )3 + X - , -OP(OR cc )2, -OP(OR cc )3 + X - , -OP(R cc )4, -OP(OR cc )4, -B(R aa )2, -B(OR cc )2, -BR aa (OR cc ), C 1~10 Alkyl, C 1~10 Perhaloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, Hetero C 1~10 Alkyl, Hetero C 2~10 Alkenyl, Hetero C 2~10 Alkynyl, C 3~10Carbocyclyl, 3- to 14-membered heterocyclyl, C 6~14 aryl and 5- to 14-membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl may be selected from the group consisting of 0, 1, 2, 3, 4, or 5 R dd groups, wherein X - is a counterion or or two geminal hydrogens on a carbon atom can be bonded to the groups =O, =S, =NN(R bb )2, =NNR bb C(=O)R aa , =NNR bb C(=O)OR aa , =NNR bb S(=O)2R aa , =NR bb , or =NOR cc has been replaced by R aa Each instance of 1~10 Alkyl, C 1~10 Perhaloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, Hetero C 1~10 Alkyl, Hetero C 2~10 Alkenyl, Hetero C 2~10 Alkynyl, C 3~10 Carbocyclyl, 3- to 14-membered heterocyclyl, C 6~14 aryl and 5- to 14-membered heteroaryl, or two R aa groups are linked to form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, and each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl may have 0, 1, 2, 3, 4, or 5 R dd are independently substituted with groups, R bb Each instance of is independently hydrogen, -OH, -OR aa , -N(R cc )2, -CN, -C(=O)R aa , -C(=O)N(Rcc )2, -CO2R aa , -SO2R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc , -P(=O)(R aa )2, -P(=O)(OR cc )2, -P(=O)(N(R cc )2)2, C 1~10 Alkyl, C 1~10 Perhaloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, Hetero C 1~10 Alkyl, Hetero C 2~10 Alkenyl, Hetero C 2~10 Alkynyl, C 3~10 Carbocyclyl, 3- to 14-membered heterocyclyl, C 6~14 aryl and 5- to 14-membered heteroaryl, or two R bb groups are linked to form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, and each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl may be joined by 0, 1, 2, 3, 4, or 5 R dd groups, wherein X - is the counterion, R cc Each instance of 1~10 Alkyl, C 1~10 Perhaloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, Hetero C 1~10 Alkyl, Hetero C 2~10 Alkenyl, Hetero C 2~10 Alkynyl, C 3~10Carbocyclyl, 3- to 14-membered heterocyclyl, C 6~14 aryl and 5- to 14-membered heteroaryl, or two R cc groups are linked to form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, and each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl may have 0, 1, 2, 3, 4, or 5 R dd are independently substituted with groups, R dd Each instance of is independently a halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR ee , -ON(R ff )2, -N(R ff )2, -N(R ff )3 + X - , -N(OR ee )R ff , -SH, -SR ee , -SSR ee , -C(=O)R ee , -CO2H, -CO2R ee , -OC(=O)R ee , -OCO2R ee , -C(=O)N(R ff )2, -OC(=O)N(R ff )2, -NR ff C(=O)R ee , -NR ff CO2R ee , -NR ff C(=O)N(R ff )2, -C(=NR ff ) OR ee , -OC(=NR ff )R ee , -OC(=NR ff ) OR ee , -C(=NR ff )N(R ff )2, -OC(=NR ff )N(R ff )2, -NR ff C(=NR ff )N(R ff )2, -NR ff SO2Ree , -SO2N(R ff )2, -SO2R ee , -SO2OR ee , -OSO2R ee , -S(=O)R ee , -Si(R ee )3, -OSi(R ee )3, -C(=S)N(R ff )2, -C(=O)SR ee , -C(=S)SR ee , -SC(=S)SR ee , -P(=O)(OR ee )2, -P(=O)(R ee )2, -OP(=O)(R ee )2, -OP(=O)(OR ee )2, C 1~6 Alkyl, C 1~6 Perhaloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, Hetero C 1~6 Alkyl, Hetero C 2~6 Alkenyl, Hetero C 2~6 Alkynyl, C 3~10 Carbocyclyl, 3-10 membered heterocyclyl, C 6~10 aryl, 5- to 10-membered heteroaryl, and each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl may be selected from the group consisting of 0, 1, 2, 3, 4, or 5 R gg groups or two geminal R dd The substituents can be linked to form =O or =S, where X - is the counterion, R ee Each instance of 1~6 Alkyl, C 1~6 Perhaloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, Hetero C 1~6 Alkyl, Hetero C 2~6 Alkenyl, Hetero C 2~6 Alkynyl, C 3~10 Carbocyclyl, C 6~10aryl, 3- to 10-membered heterocyclyl, and 3- to 10-membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is selected from 0, 1, 2, 3, 4, or 5 R gg are independently substituted with groups, R ff Each instance of 1~6 Alkyl, C 1~6 Perhaloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, Hetero C 1~6 Alkyl, Hetero C 2~6 Alkenyl, Hetero C 2~6 Alkynyl, C 3~10 Carbocyclyl, 3-10 membered heterocyclyl, C 6~10 aryl and 5- to 10-membered heteroaryl, or two R ff groups are linked to form a 3- to 10-membered heterocyclyl or 5- to 10-membered heteroaryl ring, and each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl may be substituted with 0, 1, 2, 3, 4, or 5 R gg are independently substituted with groups, R gg Each instance of is independently a halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC 1~6 Alkyl, -ON(C 1~6 alkyl)2, -N(C 1~6 alkyl)2, -N(C 1~6 Alkyl)3 + X - , -NH(C 1~6 alkyl)2 + X - , -NH2(C 1~6 alkyl) + X - , -NH3 + X - , -N(OC 1~6 Alkyl)(C 1~6 alkyl), -N(OH)(C 1~6alkyl), -NH(OH), -SH, -SC 1~6 Alkyl, -SS(C 1~6 alkyl), -C(=O)(C 1~6 alkyl), -CO2H, -CO2(C 1~6 alkyl), -OC(=O)(C 1~6 alkyl), -OCO2(C 1~6 alkyl), -C(=O)NH2, -C(=O)N(C 1~6 alkyl)2, -OC(=O)NH(C 1~6 alkyl), -NHC(=O)(C 1~6 alkyl), -N(C 1~6 alkyl)C(=O)(C 1~6 alkyl), -NHCO2(C 1~6 alkyl), -NHC(=O)N(C 1~6 alkyl)2, -NHC(=O)NH(C 1~6 alkyl), -NHC(=O)NH2, -C(=NH)O(C 1~6 alkyl), -OC(=NH)(C 1~6 alkyl), -OC(=NH)OC 1~6 Alkyl, -C(=NH)N(C 1~6 alkyl)2, -C(=NH)NH(C 1~6 alkyl), -C(=NH)NH2, -OC(=NH)N(C 1~6 alkyl)2, -OC(=NH)NH(C 1~6 alkyl), -OC(=NH)NH2, -NHC(=NH)N(C 1~6 alkyl)2, -NHC(=NH)NH2, -NHSO2(C 1~6 alkyl), -SO2N(C 1~6 alkyl)2, -SO2NH(C 1~6 alkyl), -SO2NH2, -SO2(C 1~6 alkyl), -SO2O(C 1~6 alkyl), -OSO2(C 1~6 alkyl), -SO(C 1~6 alkyl), -Si(C 1~6 alkyl)3, -OSi(C 1~6 alkyl)3-C(=S)N(C 1~6 alkyl)2, C(=S)NH(C 1~6alkyl), C(=S)NH2, -C(=O)S(C 1~6 alkyl), -C(=S)SC 1~6 Alkyl, -SC(=S)SC 1~6 Alkyl, -P(=O)(OC 1~6 alkyl)2, -P(=O)(C 1~6 alkyl)2, -OP(=O)(C 1~6 alkyl)2, -OP(=O)(OC 1~6 Alkyl)2, C 1~6 Alkyl, C 1~6 Perhaloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, Hetero C 1~6 Alkyl, Hetero C 2~6 Alkenyl, Hetero C 2~6 Alkynyl, C 3~10 Carbocyclyl, C 6-10 aryl, 3- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, or two geminal R gg The substituents can be linked to form =O or =S, where X - is the counterion.

[0049] The term "halo" or "halogen" refers to fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br) or iodine (iodo, -I).

[0050] The term "hydroxyl" or "hydroxy" refers to an -OH group. The term "substituted hydroxyl" or "substituted hydroxyl" by extension refers to a hydroxyl group in which the oxygen atom directly attached to the parent molecule has been replaced with a group other than hydrogen, such as -OR aa , -ON(R bb )2, -OC(=O)SR aa , -OC(=O)R aa , -OCO2R aa , -OC(=O)N(R bb )2, -OC(=NR bb )R aa , -OC(=NR bb ) OR aa , -OC(=NR bb )N(R bb)2, -OS(=O)R aa , -OSO2R aa , -OSi(R aa )3, -OP(R cc )2, -OP(R cc )3 + X - , -OP(OR cc )2, -OP(OR cc )3 + X - , -OP(=O)(R aa )2, -OP(=O)(OR cc )2, and -OP(=O)(N(R bb )2)2)2, wherein X - , R aa , R bb , and R cc is as defined herein.

[0051] The term "amino" refers to the group -NH. The term "substituted amino" extends to mono-, di-, or tri-substituted amino. In certain embodiments, a "substituted amino" is a mono- or di-substituted amino group.

[0052] The term "monosubstituted amino" refers to an amino group in which the nitrogen atom directly attached to the parent molecule is replaced with one hydrogen and one non-hydrogen group, and includes -NH(R bb ), -NHC(=O)R aa , -NHCO2R aa , -NHC(=O)N(R bb )2, -NHC(=NR bb )N(R bb )2, -NHSO2R aa , -NHP(=O)(OR cc )2, and -NHP(=O)(N(R bb )2)2)2, wherein R aa , R bb and R cc is as defined herein, and the group —NH(R bb )R bb is not hydrogen.

[0053] The term "disubstituted amino" refers to an amino group in which the nitrogen atom directly attached to the parent molecule is replaced with two groups other than hydrogen, such as -N(R bb )2, -NR bb C(=O)R aa , -NR bb CO2R aa , -NR bb C(=O)N(R bb )2, -NR bb C(=NR bb )N(R bb )2, -NR bb SO2R aa , -NR bb P(=O)(OR cc )2, and -NR bb P(=O)(N(R bb )2)2)2, wherein R aa , R bb , and R cc is defined herein with the proviso that the nitrogen atom directly attached to the parent molecule is not replaced with a hydrogen.

[0054] The term "trisubstituted amino" refers to an amino group in which the nitrogen atom directly attached to the parent molecule is substituted with three groups, -N(R bb )3 and -N(R bb )3 + X - and R bb and X - is as defined herein.

[0055] The term "sulfonyl" refers to -SO2N(R bb )2, -SO2R aa , and -SO2OR aa wherein R aa and R bb is as defined herein.

[0056] The term "sulfinyl" refers to the group -S(=O)R aa refers to R aa is as defined herein.

[0057] The term "acyl" refers to a group having the general formula: -C(=O)R X1 , -C(=O)OR X1 , -C(=O)-OC(=O)R X1 , -C(=O)SR X1 , -C(=O)N(R X1 )2, -C(=S)R X1 , -C(=S)N(R X1 )2, -C(=S)O(R X1 ), -C(=S)S(R X1 ), -C(=NR X1 )R X1 , -C(=NR X1 ) OR X1 , -C(=NR X1 )SR X1 , or -C(=NR X1 )N(R X1 )2, and R X1 is hydrogen; halogen; substituted or unsubstituted hydroxyl; substituted or unsubstituted thiol; substituted or unsubstituted amino; substituted or unsubstituted acyl, cyclic or acyclic, substituted or unsubstituted branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted branched or unbranched heteroaliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched alkyl; cyclic or acyclic, substituted or unsubstituted, branched or unbranched alkenyl; substituted or unsubstituted alkynyl; substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, aliphaticoxy, heteroaliphaticoxy, alkyloxy, heteroalkyloxy, aryloxy, heteroaryloxy, aliphaticthioxy, heteroaliphaticthioxy, alkylthioxy, heteroalkylthioxy, arylthioxy, heteroarylthioxy, mono- or di-aliphaticamino, mono- or di-heteroaliphaticamino, mono- or di-alkylamino, mono- or di-heteroalkylamino, mono- or di-arylamino, or mono- or di-heteroarylamino; or two R X1The groups taken together form a 5- to 6-membered heterocyclic ring. Exemplary acyl groups include aldehydes (-CHO), carboxylic acids (-COH), ketones, acyl halides, esters, amides, imines, carbonates, carbamates, and ureas. Acyl substituents include, but are not limited to, any of the substituents described herein that result in the formation of a stable moiety (e.g., aliphatic, alkyl, alkenyl, alkynyl, heteroaliphatic, heterocyclic, aryl, heteroaryl, acyl, oxo, imino, thioxo, cyano, isocyano, amino, azido, nitro, hydroxyl, thiol, halo, aliphatic amino, heteroaliphatic amino, alkylamino, heteroalkylamino, arylamino, heteroarylamino, alkylaryl, arylalkyl, aliphaticoxy, heteroaliphaticoxy, alkyloxy, heteroalkyloxy, aryloxy, heteroaryloxy, aliphaticthioxy, heteroaliphaticthioxy, alkylthioxy, heteroalkylthioxy, arylthioxy, heteroarylthioxy, acyloxy, etc., each of which may or may not be further substituted).

[0058] The term "oxo" refers to the group =O and the term "thiooxo" refers to the group =S.

[0059] Nitrogen atoms may be substituted or unsubstituted, where valence allows, and include primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents include, but are not limited to, hydrogen, OH, -OR aa , -N(R cc )2, -CN, -C(=O)R aa , -C(=O)N(R cc )2, -CO2R aa , -SO2R aa , -C(=NR bb )R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SORaa , -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc , -P(=O)(OR cc )2, -P(=O)(R aa )2, -P(=O)(N(R cc )2)2, C 1~10 Alkyl, C 1~10 Perhaloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, Hetero C 1~10 Alkyl, Hetero C 2~10 Alkenyl, Hetero C 2~10 Alkynyl, C 3~10 Carbocyclyl, 3- to 14-membered heterocyclyl, C 6~14 Aryl and 5- to 14-membered heteroaryl, or two R attached to the N atom cc groups combine to form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, and each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl may have 0, 1, 2, 3, 4, or 5 R dd groups, and R aa , R bb , R cc and R dd is defined herein.

[0060] In certain embodiments, the substituent present on a nitrogen atom is a nitrogen protecting group (also referred to herein as an "amino protecting group"). Nitrogen protecting groups include, but are not limited to, -OH, -OR aa , -N(R cc )2, -C(=O)R aa , -C(=O)N(R cc )2, -CO2R aa , -SO2R aa , -C(=NR cc )R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc )2, -SO2N(R cc)2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc , C 1~10 Alkyl (e.g., aralkyl, heteroaralkyl), C 2~10 Alkenyl, C 2~10 Alkynyl, Hetero C 1~10 Alkyl, Hetero C 2~10 Alkenyl, Hetero C 2~10 Alkynyl, C 3~10 Carbocyclyl, 3- to 14-membered heterocyclyl, C 6~14 and aryl and 5- to 14-membered heteroaryl groups, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aralkyl, aryl, and heteroaryl may be selected from the group consisting of 0, 1, 2, 3, 4, or 5 R dd groups, and R aa , R bb , R cc and R dd is as defined herein. Nitrogen protecting groups are well known in the art and are described in Protecting Groups in Organic Synthesis, T.W. Greene and P.G.M. Buts, 3, incorporated herein by reference. rd edition, John Wiley & Sons, 1999.

[0061] For example, an amide group (e.g., —C(═O)R aa), include, but are not limited to, formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropanamide, picolinamide, 3-pyridylcarboxamide, N-benzoylphenylalanyl derivatives, benzamide, p-phenylbenzamide, o-nitrophenylacetamide, o-nitrophenoxyacetamide, acetoacetamide, (N'-dithiobenzyloxyacylamino)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, N-acetylmethionine derivatives, o-nitrobenzamide, and o-(benzoyloxymethyl)benzamide.

[0062] Carbamate groups (e.g., -C(=O)OR aa), and the like, examples of nitrogen protecting groups include 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-10,10,10,10-tetrahydrothioxanthyl)]methyl carbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2-trimethyl Teoc), 2-phenylethyl carbamate (hZ), 1-(1-adamantyl)-1-methylethyl carbamate (Adpoc), 1,1-dimethyl-2-haloethyl carbamate, 1,1-dimethyl-2,2-dibromoethyl carbamate (DB-t-BOC), 1,1-dimethyl-2,2,2-trichloroethyl carbamate (TCBOC), 1-methyl-1-(4-biphenylyl)ethyl carbamate (Bpoc), 1-(3,5-di-t-butylphenyl)-1-methylethyl carbamate (t-B umeoc), 2-(2'- and 4'-pyridyl)ethyl 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-isopropyl allyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc), 8-quinolyl carbamate, N-hydroxypiperidinyl carbamate, Alkyl dithiocarbamates, benzyl carbamate (Cbz), p-methoxybenzyl carbamate (Moz), p-nitribenzyl 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-(1,3-dithianyl)]methyl carbamate (Dmoc), 4-methylthiophenylcarbamate (Mtpc), 2,4-dimethylthiophenylcarbamate (Bmpc), 2-phosphonioethylcarbamate (Peoc), 2-triphenylphosphonioisopropylcarbamate (Ppoc), 1,1-dimethyl-2-cyanoethylcarbamate, m-chloro-p-acyloxybenzylcarbamate, p-(dihydroxyboryl)benzylcarbamate, 5-benzisoxazolylmethylcarbamate, 2-(trifluoromethyl)-6-chloro- bromonylmethyl 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-benzylthiocarbamate, p-cyanobenzyl carbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentyl carbamate, cyclopropylmethyl carbamate, p-decyloxybenzyl carbamate, 2 ,2-Dimethoxyacyl vinyl carbamate, o-(N,N-dimethylcarboxamido)benzyl carbamate, 1,1-dimethyl-3-(N,N-dimethylcarboxamido)propyl carbamate, 1,1-dimethylpropynyl carbamate, di(2-pyridyl)methyl carbamate, 2-furanylmethyl carbamate, 2-indoethyl carbamate, isoboryl carbamate, isobutyl carbamate, isonicotinyl carbamate, p-(p'-methoxyphenylazo)benzyl carbamate, 1-methylcyclobutyl carbamate, 1 -methylcyclohexyl carbamate, 1-methyl-1-cyclopropylmethyl carbamate, 1-methyl-1-(3,5-dimethoxyphenyl)ethyl carbamate, 1-methyl-1-(p-phenylazophenyl)ethyl carbamate, 1-methyl-1-phenylethyl carbamate, 1-methyl-1-(4-pyridyl)ethyl carbamate, phenyl carbamate, p-(phenylazo)benzyl carbamate, 2,4,6-tri-t-butylphenyl carbamate, 4-(trimethylammonium)benzyl carbamate, and 2,4,Examples include, but are not limited to, 6-trimethylbenzylcarbamate.

[0063] Sulfonamide groups (e.g., -S(=O)R aa ), and the like, examples of the nitrogen protecting group include p-toluenesulfonamide (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), β-trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide, 4-(4',8'-dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS), benzylsulfonamide, trifluoromethylsulfonamide, and phenanthylsulfonamide.

[0064] Other nitrogen protecting groups include phenothiazinyl-(10)-acyl derivatives, N'-p-toluenesulfonylaminoacyl derivatives, N'-phenylaminothioacyl derivatives, N-benzoylphenylalanyl derivatives, N-acetylmethionine derivatives, 4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dithiasuccinimide (Dts), N-2,3-diphenylmaleimide, N-2,5-dimethylpyrrole, and N-1,1,4,4-tetramethyldisilylazacylate. Clopentane adduct (STABASE), 5-substituted 1,3-dimethyl-1,3,5-triazacyclohexan-2-one, 5-substituted 1,3-dibenzyl-1,3,5-triazacyclohexan-2-one, 1-substituted 3,5-dinitro-4-pyridone, N-methylamine, N-allylamine, N-[2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine, N-(1-isopropyl-4-nitro-2-oxo-3-pyrrolin-3-yl)amine amine, quaternary ammonium salts, N-benzylamine, N-di(4-methoxyphenyl)methylamine, N-5-dibenzosuberylamine, N-triphenylmethylamine (Tr), N-[(4-methoxyphenyl)diphenylmethyl]amine (MMTr), N-9-phenylfluorenylamine (PhF), N-2,7-dichloro-9-fluorenylmethyleneamine, N-ferrocenylmethylamino (Fcm), N-2-picolylamino N'-oxide, N-1,1-dimethylthio Methyleneamine, N-benzylideneamine, Np-methoxybenzylideneamine, N-diphenylmethyleneamine, N-[(2-pyridyl)mesityl]methyleneamine, N-(N',N'-dimethylaminomethylene)amine, N,N'-isopropylidenediamine, Np-nitrobenzylideneamine, N-salicylideneamine, N-5-chlorosalicylideneamine, N-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine, N-cyclohexylideneamine, N-(5,These include, but are not limited to, 5-dimethyl-3-oxo-1-cyclohexenyl)amine, N-borane derivatives, N-diphenylborinic acid derivatives, N-[phenyl(pentaacychromium- or tungsten)acyl]amine, N-copper chelates, N-zinc chelates, N-nitroamines, N-nitrosamines, amine N-oxides, diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt), diphenylthiophosphinamide (Ppt), dialkyl phosphoramidates, dibenzyl phosphoramidate, diphenyl phosphoramidate, benzenesulfenamide, o-nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide, triphenylmethylsulfenamide, and 3-nitropyridine sulfenamide (Npys). In certain embodiments, the 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).

[0065] In certain embodiments, the substituent present on the oxygen atom is an oxygen protecting group (also referred to herein as a "hydroxyl protecting group"). Oxygen protecting groups include, but are not limited to, -R aa , -N(R bb )2, -C(=O)SR aa , -C(=O)R aa , -CO2R aa , -C(=O)N(R bb )2, -C(=NR bb )R aa , -C(=NR bb ) OR aa , -C(=NRbb )N(R bb )2, -S(=O)R aa , -SO2R aa , -Si(R aa )3, -P(R cc )2, -P(R cc )3 + X -、 -P(OR cc )2, -P(OR cc )3 + X - , -P(=O)(R aa )2, -P(=O)(OR cc )2, and -P(=O)(N(R bb )2)2, wherein X - , R aa , R bb and R cc is as defined herein. Oxygen protecting groups are well known in the art and are described in Protecting Groups in Organic Synthesis, T.W. Greene and P.G.M. Buts, 3, incorporated herein by reference. rd edition, John Wiley & Sons, 1999.

[0066] Exemplary oxygen protecting groups include methyl, methoxymethyl (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), and the like. ), 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-dioxide, 1-[(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-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl, 1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl, 2,2,2-trichloroethoxyethyl ethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl, t-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, benzyl (Bn), p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2-picolyl, 4-picolyl, 3-methyl-2-picolyl N-oxide, diphenylmethyl, p,p'-Dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl, α-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 ) methyl, 3-(imidazol-1-yl)bis(4',4''-dimethoxyphenyl)methyl, 1,1-bis(4-methoxyphenyl)-1'-pyrenylmethyl, 9-anthryl, 9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl, 1,3-benzodithiolan-2-yl, benzisothiazolyl S,S-dioxide, trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), diethylsilyl isopropylsilyl (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, methoxyacetate, triphenylmethoxyacetate ate, phenoxyacetate, p-chlorophenoxyacetate, 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-benzylthiocarbonate, 4-ethoxy-1-naphthyl carbonate, methyl dithiocarbonate, 2-indobenzoate, 4-azidobutyrate, 4-nitro-4-methylpentanoate, o-(dibromomethyl)benzoate, 2-formylbenzenesulfonate, 2-(methyl)benzoate Examples of alkyl esters include, but are not limited to, alkyl esters such as (ethylthiomethoxy)ethyl, 4-(methylthiomethoxy)butyrate, 2-(methylthiomethoxymethyl)benzoate, 2,6-dichloro-4-methylphenoxyacetate, 2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetate, 2,4-bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinoate, (E)-2-methyl-2-butenoate, o-(methoxyacyl)benzoate, α-naphthoate, nitrate, alkyl N,N,N',N'-tetramethylphosphorodiamidate, alkyl N-phenylcarbamate, borate, dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulfenate, sulfate, methanesulfonate (methylate), benzylsulfonate, and tosylate (Ts). In certain embodiments, the oxygen protecting group is silyl. In certain embodiments, the oxygen protecting group is t-butyldiphenylsilyl (TBDPS), t-butyldimethylsilyl (TBDMS), triisopropylsilyl (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-methoxy-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).

[0067] In certain embodiments, the substituent present on the sulfur atom is a sulfur protecting group (also called a "thiol protecting group"). Sulfur protecting groups include, but are not limited to, -R aa , -N(R bb )2, -C(=O)SR aa , -C(=O)R aa , -CO2R aa , -C(=O)N(R bb )2, -C(=NR bb )R aa , -C(=NR bb ) OR aa , -C(=NR bb )N(R bb )2, -S(=O)R aa , -SO2R aa , -Si(R aa )3, -P(R cc )2, -P(R cc )3 + X -、 -P(OR cc )2, -P(OR cc )3 + X - , -P(=O)(R aa )2, -P(=O)(OR cc )2, and -P(=O)(N(R bb )2)2, where R aa , R bb and R ccis as defined herein. Sulfur protecting groups are well known in the art and are described in Protecting Groups in Organic Synthesis, T.W. Greene and P.G.M. Buts, 3, incorporated herein by reference. rd edition, John Wiley & Sons, 1999. In certain embodiments, the sulfur protecting group is acetamidomethyl, t-Bu, 3-nitro-2-pyridinesulfenyl, 2-pyridinesulfenyl, or triphenylmethyl.

[0068] A "counterion" or "anionic counterion" is a negatively charged group associated with a positively charged group to maintain electronic neutrality. Anionic counterions can be monovalent (i.e., contain one formal negative charge). Anionic counterions can also be multivalent (i.e., contain two or more formal negative charges), such as divalent or trivalent. Exemplary counterions include halide ions (e.g., F - , Cl - , Br - , I - ), NO3 - , ClO4 - , O.H. - , H2PO4 - , HCO3 - , HSO4 - , sulfonate ions (e.g., methanesulfonate, trifluoromethanesulfonate, p-toluenesulfonate, benzenesulfonate, 10-camphorsulfonate, naphthalene-2-sulfonate, naphthalene-1-sulfonic acid-5-sulfonate, ethane-1-sulfonic acid-2-sulfonate, etc.), carboxylate ions (e.g., acetate, propanoate, benzoate, glycerate, lactate, tartrate, glycolate, gluconate, etc.), BF4 - , PF4 - , PF6 - , AsF6 - , SbF6 - , B[3,5-(CF3)2C6H3]4] - , B(C6F5)4 - , BPh4- , Al(OC(CF3)3)4 - , and carborane anions (e.g., CB 11 H 12 - or (HCB 11 Me5Br6) - Exemplary counterions, which may be multivalent, include CO3 2- , HPO4 2- , PO4 3- 、 B4O7 2- , SO4 2- , S2O3 2- , carboxylate anions (e.g., tartrate, citrate, fumarate, maleate, malate, malonate, gluconate, succinate, glutarate, adipate, pimelate, suberate, azelaate, sebacate, salicylate, phthalate, aspartate, glutamate, etc.), and carboranes.

[0069] These and other exemplary substituents are described in more detail in the detailed description, examples, and claims. The present invention is not intended to be limited in any way by the above exemplary list of substituents.

[0070] Other definitions The following definitions are of more general terms used throughout this application.

[0071] As used herein, the term "salt" refers to any and all salts, including pharmaceutically acceptable salts.

[0072] The term "pharmaceutically acceptable salt" refers to a salt that is, within the scope of sound medical judgment, suitable for use in contact with human and / or animal tissues without undue toxicity, irritation, allergic response, etc., and that is 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, which is 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 non-toxic acid addition salts are salts of amino groups 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, camphor, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, Salts derived from appropriate bases include 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, etc. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N + (C 1~4 Alkyl)4 -Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Further pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed, where appropriate, using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkylsulfonates, and arylsulfonates.

[0073] The term "solvate" refers to a form of a compound or its salt that is associated with a solvent, typically via solvolysis. This physical association may involve hydrogen bonding. Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, and the like. The compounds described herein may be prepared, for example, in crystalline form, and may be solvated. Suitable solvates include pharmaceutically acceptable solvates, and further include both stoichiometric and non-stoichiometric solvates. In certain cases, a solvate may be isolated, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. "Solvate" encompasses both solution-phase and isolatable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

[0074] The term "hydrate" refers to a compound associated with water molecules. Typically, the number of water molecules contained in a hydrate of a compound is a fixed ratio to the number of compound molecules in the hydrate. Thus, a hydrate of a compound can be represented, for example, by the general formula R·xH2O, where R is the compound and x is a number greater than 0. A given compound may form more than one type of hydrate, including, for example, a monohydrate (x is 1), a lower hydrate (x is a number greater than 0 and less than 1, e.g., a hemihydrate (R·0.5H2O)), and a polyhydrate (x is a number greater than 1, e.g., a dihydrate (R·2H2O) and a hexahydrate (R·6H2O)).

[0075] The term "tautomer" or "tautomerism" refers to two or more interconvertible compounds resulting from the formal migration of at least one hydrogen atom and at least one change in valence (e.g., from a single bond to a double bond, a triple bond to a single bond, or vice versa). The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH. Tautomerization (i.e., the reaction giving rise to a tautomeric pair) can be catalyzed by acid or base. Exemplary tautomerizations include keto-enol, amide-imide, lactam-lactim, enamine-imine, and enamine-(different enamine) tautomerizations.

[0076] It should also be understood that 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."

[0077] Stereoisomers that are not mirror images of one another are called "diastereomers," and stereoisomers that are non-superimposable mirror images of each other are called "enantiomers." When a compound has an asymmetric center, for example, when it is bonded to four different groups, a pair of enantiomers is possible. Enantiomers can be characterized by the absolute configuration of their asymmetric center and described by the R and S sequencing rules of Cahn and Prelog or by the way the molecule rotates the plane of polarized light, and are referred to as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers, respectively). Chiral compounds can exist as individual enantiomers or mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture."

[0078] The term "polymorph" refers to the crystalline form of a compound (or its salts, hydrates, or solvates). Many compounds can exist in a variety of different crystalline forms (i.e., different polymorphs). Typically, such different crystalline forms have different X-ray diffraction patterns, infrared spectra, and / or may vary in some or all of the following properties: melting point, density, hardness, crystal shape, optical and electrical properties, stability, solubility, and bioavailability. Recrystallization solvent, crystallization rate, storage temperature, and other factors can cause one crystalline form to dominate in a given preparation. Various polymorphs of a compound can be prepared by crystallization under different conditions.

[0079] The term "co-crystal" refers to a crystal structure composed of at least two components. In certain embodiments, a co-crystal includes a compound of the present disclosure and one or more other components, including, but not limited to, atoms, ions, molecules, or solvent molecules. In certain embodiments, a co-crystal includes a compound of the present disclosure and one or more solvent molecules. In certain embodiments, a co-crystal includes a compound of the present disclosure and one or more acids or bases. In certain embodiments, a co-crystal includes a compound of the present disclosure and one or more components related to the compound, including, but not limited to, isomers, tautomers, salts, solvates, hydrates, synthetic precursors, synthetic derivatives, fragments, or impurities of the compound.

[0080] The term "prodrug" refers to a compound having a cleavable group that is removed by solvolysis or under physiological conditions to provide a compound described herein that is pharmaceutically active in vivo. Examples include, but are not limited to, choline ester derivatives, N-alkylmorpholine esters, and the like. Other derivatives of the compounds described herein are active in both their acid and acid-derivative forms, but the acid-sensitive forms often offer advantages of solubility, tissue compatibility, or delayed release in mammalian organisms (see Bundgard, H., Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs include acid derivatives well known to those skilled in the art, such as esters prepared by reacting the parent acid with an appropriate alcohol, or amides prepared by reacting the parent acid compound with a substituted or unsubstituted amine, acid anhydride, or mixed anhydride. Simple aliphatic or aromatic esters, amides, and anhydrides derived from acidic groups pendant to the compounds described herein are specific prodrugs. In some cases, it is desirable to prepare double ester prodrugs such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkyl esters. 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, aryl, C 7-12 Substituted aryl and C 7-12 Aryl alkyl esters may be preferred.

[0081] The terms "composition" and "formulation" are used interchangeably.

[0082] The term "modulate" means decreasing or inhibiting activity and / or increasing or enhancing activity. For example, modulating glucocerebrosidase activity means decreasing or inhibiting glucocerebrosidase activity and / or increasing or enhancing glucocerebrosidase activity. The compounds disclosed herein can be administered, for example, as chaperones or activators, to modulate glucocerebrosidase activity.

[0083] A "subject" to which administration is contemplated refers to a human (i.e., male or female of any age, e.g., a pediatric subject (e.g., an infant, child, or adolescent) or an adult subject (e.g., a young adult, middle-aged adult, or elderly)) or a non-human animal. In certain embodiments, the non-human animal is a mammal (e.g., a primate (e.g., a cynomolgus monkey or a rhesus monkey), a commercially relevant mammal (e.g., a cow, pig, horse, sheep, goat, cat, or dog), or an avian (e.g., a commercially relevant bird, e.g., a chicken, duck, goose, or turkey)). In certain embodiments, the non-human animal is a fish, reptile, or amphibian. The non-human animal can be male or female at any stage of development. The non-human animal can be a transgenic or genetically engineered animal. The term "patient" refers to a human subject in need of treatment for a disease. The subject may be a plant. In certain embodiments, the plant is a land plant. In certain embodiments, the plant is a non-vascular land plant. In certain embodiments, the plant is a vascular plant. In certain embodiments, the plant is a seed plant. In certain embodiments, the plant is a cultivated plant. In certain embodiments, the plant is a dicotyledonous plant. In certain embodiments, the plant is a monocotyledonous plant. In certain embodiments, the plant is a flowering plant. In some embodiments, the plant is a cereal plant, such as maize, corn, wheat, rice, oats, barley, rye, or millet. In some embodiments, the plant is a legume, such as a bean plant, for example, a soybean plant. In some embodiments, the plant is a tree or shrub.

[0084] The term "biological sample" refers to any sample, including tissue samples (such as tissue sections and tissue needle biopsies); cell samples (e.g., cytological smears (e.g., Pap or blood smears) or samples of cells obtained by microdissection); whole organism samples (such as yeast or bacterial samples); or cell fractions, fragments, or organelles (e.g., obtained by lysing cells and centrifuging or otherwise separating their components). Other examples of biological samples include blood, serum, urine, semen, feces, cerebrospinal fluid, interstitial fluid, mucus, tears, sweat, pus, biopsy tissue (e.g., obtained by surgical or needle biopsy), nipple aspirate, milk, vaginal fluid, saliva, swabs (e.g., buccal swabs), or any material containing biomolecules derived from a first biological sample.

[0085] The terms "administer," "administering," or "administration" refer to implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing a compound described herein or a composition thereof into or onto a subject.

[0086] The terms "treatment," "treat," and "treating" refer to reversing, alleviating, or inhibiting the progression of a disease described herein. In some embodiments, therapy may be administered after one or more signs or symptoms of a disease have developed or are observed. Treatment may also be continued after symptoms have resolved, for example, to delay or prevent recurrence.

[0087] The terms "condition," "disease," and "disorder" are used interchangeably.

[0088] An "effective amount" of a compound described herein refers to an amount sufficient to induce a desired biological response. The effective amount of a compound described herein may vary depending on factors such as the desired biological endpoint, the pharmacokinetics of the compound, the condition being treated, the mode of administration, and the age and health of the subject. In certain embodiments, the effective amount is a therapeutically effective amount. In certain embodiments, the effective amount is a prophylactic treatment. In certain embodiments, the effective amount is the amount of a compound described herein in a single dose. In certain embodiments, the effective amount is the amount of a compound described herein in a single dose.

[0089] A "therapeutically effective amount" of a compound described herein is an amount sufficient to provide a therapeutic benefit in treating a condition or to delay or minimize one or more symptoms associated with a condition. A therapeutically effective amount of a compound refers to the amount of a therapeutic agent that, alone or in combination with other treatments, provides a therapeutic benefit in treating a condition. The term "therapeutically effective amount" can encompass an amount that improves overall treatment, reduces or avoids symptoms, signs, or causes of a condition, and / or enhances the therapeutic effectiveness of another therapeutic agent. In certain embodiments, a therapeutically effective amount is an amount sufficient to activate GCase (e.g., an increase in GCase enzymatic activity of 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%, at least 95%, at least 100%, at least 150%, at least 200%, at least 250%, at least 300%, or at least 500%). In certain embodiments, a therapeutically effective amount is an amount sufficient to treat a disease or disorder (e.g., a neurological disorder). In certain embodiments, a therapeutically effective amount is an amount sufficient to treat GCase activation and a disease or disorder (eg, a neurological disorder).

[0090] A "prophylactically effective amount" of a compound described herein is an amount sufficient to prevent a condition, or one or more signs or symptoms associated with a condition, or to prevent its recurrence. A prophylactically effective amount of a compound refers to the amount of a therapeutic agent that, alone or in combination with other agents, provides a prophylactic benefit in the prevention of a condition. The term "prophylactically effective amount" can encompass an amount that improves overall prevention or enhances the prophylactic effectiveness of another prophylactic agent. In certain embodiments, a prophylactically effective amount is an amount sufficient to activate GCase. In certain embodiments, a prophylactically effective amount is an amount sufficient to treat a disease or disorder (e.g., a neurological disorder). In certain embodiments, a prophylactically effective amount is an amount sufficient to activate GCase and treat a disease or disorder (e.g., a neurological disorder).

[0091] As used herein, the term "activate" or "activation" in the context of an enzyme, e.g., GCase, refers to an increase in the activity of the enzyme. In some embodiments, the term refers to an increase in the level of enzyme activity, e.g., GCase activity, to a level that is statistically significantly higher than an initial level, which may be, for example, a baseline level of enzyme activity (e.g., of a wild-type GCase). In some embodiments, the term refers to an increase in the level of enzyme activity, e.g., GCase activity, to a level that is more than 1%, more than 5%, more than 10%, more than 25%, more than 50%, more than 75%, more than 100%, more than 150%, more than 200%, more than 300%, more than 400%, more than 500%, or more than 1000% of the initial level, which may be, for example, a baseline level of enzyme activity.

[0092] The term "immunotherapy" refers to a therapeutic agent that promotes the treatment of disease by inducing, enhancing, or suppressing the immune response. Immunotherapies designed to induce or amplify the immune response are classified as activating immunotherapies, while immunotherapies that decrease or suppress the immune response are classified as suppressing immunotherapies. Immunotherapies are typically, but not always, biotherapeutics. Numerous immunotherapies are used to treat cancer. These include, but are not limited to, monoclonal antibodies, adoptive cell transfer, cytokines, chemokines, vaccines, and small molecule inhibitors.

[0093] The terms "biological," "biological drug," and "biological product" refer to a wide range of products, such as vaccines, blood and blood components, allergens, somatic cells, gene therapy, tissues, nucleic acids, and proteins. Biologicals may contain sugars, proteins, or nucleic acids, or complex combinations of these substances, or may be living organisms such as cells and tissues. Biologicals may be isolated from a variety of natural sources (e.g., human, animal, microbial) or may be produced by biotechnological and other techniques.

[0094] The term "small molecule" or "small molecule therapeutic" refers to a molecule having a relatively low molecular weight, whether naturally occurring or artificially created (e.g., via chemical synthesis). Typically, a small molecule is an organic compound (i.e., it contains carbon). A small molecule may contain multiple carbon-carbon bonds, stereocenters, and other functional groups (e.g., amines, hydroxyls, carbonyls, heterocycles, and the like). In certain embodiments, the molecular weight of a small molecule is about 1,000 g / mol or less, about 900 g / mol or less, about 800 g / mol or less, about 700 g / mol or less, about 600 g / mol or less, about 500 g / mol or less, about 400 g / mol or less, about 300 g / mol or less, about 200 g / mol or less, or about 100 g / mol or less. In certain embodiments, the molecular weight of the small molecule is at least about 100 g / mol, at least about 200 g / mol, at least about 300 g / mol, at least about 400 g / mol, at least about 500 g / mol, at least about 600 g / mol, at least about 700 g / mol, at least about 800 g / mol, or at least about 900 g / mol, or at least about 1,000 g / mol. Combinations of the above ranges (e.g., at least about 200 g / mol to about 500 g / mol or less) are also possible. In certain embodiments, the small molecule is a therapeutically active agent such as a drug (e.g., a molecule approved by the US Food and Drug Administration as defined in the Code of Federal Regulations (CFR)). The small molecule may also be complexed with one or more metal atoms and / or metal ions. In this case, the small molecule is also referred to as a "small organometallic molecule." Preferred small molecules are biologically active in that they produce a biological effect in animals, preferably mammals, and more preferably humans. Small molecules include, but are not limited to, radionuclides and imaging agents. In certain embodiments, the small molecule is a drug. Preferably, but not necessarily, the drug is one that has already been deemed safe and effective for use in humans or animals by an appropriate governmental or regulatory agency.For example, drugs approved for human use are listed by the FDA under 21 C.F.R. sections 330.5, 331-361, and 440-460, which are incorporated herein by reference, and drugs for veterinary use are listed by the FDA under 21 C.F.R. sections 500-589, which are incorporated herein by reference. All of the listed drugs are considered acceptable for use in accordance with the present invention.

[0095] The term "therapeutic agent" refers to any substance that has therapeutic properties that produce a desired, usually beneficial, effect. For example, a therapeutic agent can treat, ameliorate, and / or prevent a disease. A therapeutic agent can be a biologic or a small molecule therapeutic, or a combination thereof, as disclosed herein.

[0096] Detailed Description of Specific Embodiments Provided herein are compounds that are modulators of GCase (e.g., GCase activators). In one aspect, the provided GCase modulators are compounds of formula (I), as well as pharmaceutically acceptable salts, solvates, hydrates, polymorphs, cocrystals, tautomers, stereoisomers, isotopically labeled derivatives, prodrugs, and pharmaceutical compositions thereof. The compounds are therefore useful for treating and / or preventing diseases and disorders associated with GCase activity (e.g., neurological diseases and disorders) in a subject in need thereof.

[0097] The compounds described herein interact with GCase. As described herein, the therapeutic effect may be the result of the modulation (e.g., activation), binding, and / or modification of GCase by the compounds described herein. The compounds may be provided for use in any of the compositions, kits, or methods described herein as their pharmaceutically acceptable salts, cocrystals, tautomers, stereoisomers, solvates, hydrates, polymorphs, isotopically enriched derivatives, or prodrugs.

[0098] Compounds of formula (I) In one embodiment, the compound of formula (I): [ka] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof is disclosed; R 1 is a substituted or unsubstituted heteroaryl, a substituted or unsubstituted aryl, a substituted or unsubstituted carbocyclyl, a substituted or unsubstituted heterocyclyl, pentyl, butyl, methyl, -CH2CH2CH(CH3)2, or hydrogen or heterocyclyl, optionally forming a spiro ring system with A when n is 0 and G is a bond; G is a bond, -S(O)2-, or -NR 2 -, -CH2CH2O-, -CH2O-, -O- or -CR 2 R 3 - and R 2 and R 3 are each independently hydrogen, halogen, or substituted or unsubstituted alkyl, or R on that same carbon. 2 and R 3 forms a carbonyl with carbon, n is 1 or 0, A is [ka] and Each R 4 are independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, hydroxy, or R 4 Two examples of R on the same carbon may be linked to form a bridged ring, or 4 Two examples of carbonyls with carbon: m is 0, 1, 2, 3 or 4; L is a bond, -C(=O)-, -C(=O)CH2-, -C(=O)CF2-, -C(=O)CH(Ph)-, -C(=O)CH(iPr)-, -C(=O)CH(Et)-, -C(=O)CH(Me)-, -C(=O)C(CH3)2-, -C(=O)CH(OMe)-, -C(=O)CH2CH2-, -C(=O)CH2CH2CH2-, -C(=O)CH2CH2CH2O-, -C(=O)CH(CH3)CH2-, -C(=O)CH2O-, -C(=O)CH2OCH2-, -C(=O)CH(CH3)O-, -C(=O)C H2CH=CH-, -C(=O)NHCH2CH2CH2-, -C(=O)NHCH2CH2-, -CH2-, -CH2CH2CH2-, -CH2C(CH3)2-, -C(=O)NH-, or -CH2C(=O)NH-, R 5 is substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted aryl, methyl, ethyl, butyl, pentyl, t-butyl, —CHCHCH(CH), —SCF, or —OCHCH(CH).

[0099] In certain embodiments of compounds of formula (I), [ka] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, is provided; R 1 is a substituted or unsubstituted heteroaryl, substituted or unsubstituted aryl, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl, pentyl, butyl, or -CH2CH2CH(CH3)2, G is -S(O)2-, -NR 2 -, -CH2CH2O-, -CH2O-, -O- or -CR 2 R 3 - and; R 2 and R 3 are each independently hydrogen, halogen, or substituted or unsubstituted alkyl; n is 1 or 0, A is [ka] and Each R 4 are independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, or R 4 Two examples of R are linked to form a bridged ring, or R on the same carbon 4 In the two cases, it forms a carbonyl with carbon, m is 0, 1, 2, 3 or 4; L is a bond, —C(═O)—, —C(═O)CH—, or —C(═O)CHO—; R 5 is substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted aryloxyalkyl.

[0100] In certain embodiments of compounds of formula (I), [ka] or a pharmaceutically acceptable salt co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative or prodrug thereof; R 1 is a substituted or unsubstituted pyridinyl, or a substituted or unsubstituted phenyl; G is -O- or -CR 2 R 3 - and R 2 and R 3 are each independently hydrogen, halogen, or substituted or unsubstituted alkyl; n is 1 or 0, A is, [ka] and Each R 4 are independently halogen, substituted or unsubstituted alkyl, or R on the same carbon. 4 Two examples of carbonyls with carbon: m is 0, 1, 2, 3 or 4; L is a bond or -C(=O)-; R 5 is a substituted or unsubstituted pyrazolopyrazinyl, a substituted or unsubstituted indolyl, a substituted or unsubstituted oxadiazolyl, a substituted or unsubstituted triazolyl, or a substituted or unsubstituted pyrazinyl.

[0101] In certain embodiments of compounds of formula (I), [ka] or a pharmaceutically acceptable salt co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative or prodrug thereof; R 1 is a substituted or unsubstituted heteroaryl or a substituted or unsubstituted aryl; G is -O- or -CR 2 R 3 - and R 2 and R 3 are each independently hydrogen, halogen, or substituted or unsubstituted alkyl; n is 1 or 0, A is, [ka] and Each R 4 are independently halogen, substituted or unsubstituted alkyl, or R on the same carbon. 4 Two examples of carbonyls with carbon: m is 0, 1, 2, 3 or 4; L is a bond or -C(=O)-; R 5 is substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted aryloxyalkyl.

[0102] In certain embodiments of compounds of formula (I), R 1 is a substituted or unsubstituted pyridinyl, or a substituted or unsubstituted phenyl; G is -O- or -CR 2 R 3 - and R 2 and R 3 are each independently hydrogen, halogen, or substituted or unsubstituted alkyl; n is 1 or 0, A is, [ka] and Each R 4 are independently halogen, substituted or unsubstituted alkyl, or R on the same carbon. 4 Two examples of carbonyls with carbon: m is 0, 1, 2, 3 or 4; L is a bond or -C(=O)-; R 5 is substituted or unsubstituted pyrazolopyrazinyl, substituted or unsubstituted chromenonyl, substituted or unsubstituted indolyl, substituted or unsubstituted oxadiazolyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted triazolyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted tetrahydropyranyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted aryloxyalkyl.

[0103] R 1 As described herein, R 1 is substituted or unsubstituted heteroaryl, substituted or unsubstituted aryl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, pentyl, butyl, methyl, —CHCHCH(CH) or hydrogen, or optionally heterocyclyl, which forms a spiro ring system with A when n is 0 and G is a bond.

[0104] In certain embodiments, R 1 is substituted or unsubstituted heteroaryl, substituted or unsubstituted aryl, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl, pentyl, butyl, or —CH 2 CH 2 CH(CH 3 ) 2 .

[0105] In certain embodiments, R 1 is substituted or unsubstituted heteroaryl, or substituted or unsubstituted aryl. In certain embodiments, R 1 is substituted or unsubstituted heteroaryl, or substituted or unsubstituted phenyl. In certain embodiments, R 1 is substituted or unsubstituted pyridinyl, or substituted or unsubstituted aryl.

[0106] In certain embodiments, R 1 is substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyridinyl, or substituted or unsubstituted phenyl. In certain embodiments, R 1 is substituted or unsubstituted pyridinyl, or substituted or unsubstituted phenyl. In certain embodiments, R 1 is a substituted pyridinyl, or a substituted or unsubstituted phenyl.

[0107] In certain embodiments, R 1 is pyridinyl substituted with haloalkyl or haloalkoxy; unsubstituted phenyl; or phenyl substituted with halogen, haloalkyl, or alkyl. In certain embodiments, R 1 is pyridinyl substituted with halogen, haloalkyl, or haloalkoxy; unsubstituted phenyl; or phenyl substituted with halogen, haloalkyl, or alkyl. In certain embodiments, R 1 is a halogen, C 1~4 Haloalkyl or C 1~4 pyridinyl substituted with haloalkoxy; unsubstituted phenyl; or halogen, C 1~4 Haloalkyl or C 1~4 It is phenyl substituted with alkyl.

[0108] In certain embodiments, R 1 is pyridinyl substituted with fluoro, fluoroalkyl, or fluoroalkoxy; unsubstituted phenyl; or phenyl substituted with fluoro, fluoroalkyl, or alkyl. In certain embodiments, R 1 Fluorocarbons, C 1~4 Fluoroalkyl or C 1~4 pyridinyl substituted with fluoroalkoxy; unsubstituted phenyl; or halogen, C 1~4 Fluoroalkyl or C 1~4 It is phenyl substituted with alkyl.

[0109] In certain embodiments, R 1 is pyridinyl substituted with haloalkyl or haloalkoxy; unsubstituted phenyl; or phenyl substituted with haloalkyl or alkyl. In certain embodiments, R 1 is C 1~4 Haloalkyl or C 1~4 pyridinyl substituted with haloalkoxy; unsubstituted phenyl; or C 1~4 Haloalkyl or C 1~4 It is phenyl substituted with alkyl.

[0110] In certain embodiments, R 1 is pyridinyl substituted with fluoroalkyl or fluoroalkoxy; unsubstituted phenyl; or phenyl substituted with fluoroalkyl or alkyl. In certain embodiments, R 1 is C 1~4 Fluoroalkyl or C 1~4 pyridinyl substituted with fluoroalkoxy; unsubstituted phenyl; or C 1~4 Fluoroalkyl or C 1~4 It is phenyl substituted with alkyl.

[0111] In certain embodiments, R 1 is pyridinyl substituted with haloalkyl or haloalkoxy. In certain embodiments, R 1is pyridinyl substituted with haloalkyl. In certain embodiments, R 1 is C 1~4 Haloalkyl or C 1~4 In certain embodiments, R is pyridinyl substituted with haloalkoxy. 1 is C 1~4 It is pyridinyl substituted with haloalkyl.

[0112] In certain embodiments, R 1 is pyridinyl substituted with fluoroalkyl or fluoroalkoxy. In certain embodiments, R 1 is pyridinyl substituted with fluoroalkyl. In certain embodiments, R 1 is C 1~4 Fluoroalkyl or C 1~4 In certain embodiments, R is pyridinyl substituted with fluoroalkoxy. 1 is C 1~4 It is a pyridinyl substituted with a fluoroalkyl.

[0113] In certain embodiments, R 1 is pyridinyl substituted with haloalkoxy. In certain embodiments, R 1 is C 1~4 It is pyridinyl substituted with haloalkoxy.

[0114] In certain embodiments, R 1 is pyridinyl substituted with fluoroalkoxy. In certain embodiments, R 1 is C 1~4 It is pyridinyl substituted with fluoroalkoxy.

[0115] In certain embodiments, R 1 is unsubstituted phenyl. In certain embodiments, R 1 is phenyl substituted with halogen, haloalkyl, or alkyl. In certain embodiments, R 1 is phenyl substituted with haloalkyl or alkyl. In certain embodiments, R 1 is C 1~4Haloalkyl or C 1~4 In certain embodiments, R is phenyl substituted with alkyl. 1 is phenyl substituted with fluoroalkyl or alkyl. In certain embodiments, R 1 is C 1~4 Fluoroalkyl or C 1~4 It is phenyl substituted with alkyl.

[0116] In certain embodiments, R 1 is phenyl substituted with haloalkyl. In certain embodiments, R 1 is phenyl substituted with fluoroalkyl. In certain embodiments, R 1 is C 1~4 In certain embodiments, R is phenyl substituted with fluoroalkyl. 1 is phenyl substituted with fluoroalkyl. In certain embodiments, R 1 is C 1~4 It is a phenyl substituted with a fluoroalkyl.

[0117] In certain embodiments, R 1 is phenyl substituted with alkyl. In certain embodiments, R 1 is C 1~4 In certain embodiments, R is phenyl substituted with alkyl. 1 is phenyl substituted with halogen. In certain embodiments, R 1 is phenyl substituted with fluoro. In certain embodiments, R 1 is hydrogen, methyl, butyl, pentyl, -CH2CH2CH(CH3) 2,、 [ka] The file is TIFF2024518000000027.tif66159.

[0118] In certain embodiments, R 1 is butyl, pentyl, -CH2CH2CH(CH3)2, [ka] is.

[0119] In certain embodiments, R 1 teeth, [ka] is.

[0120] In certain embodiments, R 1 teeth, [ka] is.

[0121] In certain embodiments, R 1 teeth, [ka] is.

[0122] In certain embodiments, R 1 teeth, [ka] is.

[0123] In certain embodiments, R 1 teeth, [ka] is.

[0124] G As described herein, G is a bond, —S(O)—, —NR 2 -, -CH2CH2O-, -CH2O-, -O- or -CR 2 R 3 In certain embodiments, G is S(O)2-, -NR 2 -, -CH2CH2O-, -CH2O-, -O- or -CR 2 R 3In certain embodiments, G is -O- or -CR 2 R 3 -It is.

[0125] In certain embodiments, G is —NR 2 In certain embodiments, G is -CH2CH2O-. In certain embodiments, G is -CH2O-. In certain embodiments, G is -O-. In certain embodiments, G is -CR 2 R 3 In certain embodiments, G is -CH2- or -CH(CH3)-. In certain embodiments, G is -CH2-. In certain embodiments, G is -CH(CH3)-.

[0126] R 2 and R 3 As described herein, R 2 and R 3 are each independently hydrogen, halogen, or substituted or unsubstituted alkyl, or R on the same carbon. 2 and R 3 forms a carbonyl with that carbon. In certain embodiments, R 2 and R 3 are each independently hydrogen, halogen, or substituted or unsubstituted alkyl.

[0127] In certain embodiments, R 2 and R 3 are each independently hydrogen or substituted or unsubstituted alkyl. In certain embodiments, R 2 and R 3 are each independently hydrogen or substituted or unsubstituted C 1~4 In certain embodiments, R 2 and R 3 are each independently hydrogen or unsubstituted C 1~4 In certain embodiments, R 2 and R 3 are each independently hydrogen or methyl. In certain embodiments, R 2 and R3 and R are each hydrogen. In certain embodiments, R 2 and R 3 forms a carbonyl with that carbon.

[0128] In certain embodiments, R 2 is hydrogen, halogen, or substituted or unsubstituted alkyl; R 3 is hydrogen. In certain embodiments, R 2 is hydrogen or substituted or unsubstituted alkyl, and R 3 is hydrogen. In certain embodiments, R 2 is a substituted or unsubstituted alkyl, and R 3 is hydrogen. In certain embodiments, R 2 is unsubstituted alkyl, and R 3 is hydrogen. In certain embodiments, R 2 is the unsubstituted C 1~4 alkyl, and R 3 is hydrogen. In certain embodiments, R 2 is methyl and R 3 is hydrogen.

[0129] n As described herein, n is 1 or 0. In certain embodiments, n is 1. In certain embodiments, n is 0. In certain embodiments, when n is 0, A is [ka] In certain embodiments, when n is 1, A is [ka] or [ka] In certain embodiments, when n is 1, A is [ka] is.

[0130] Ring A As described herein, A is [ka] and each R 4 are independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, hydroxy, or R 4 Two examples of R are linked to form a bridged ring, or R on the same carbon 4 Two examples of the carbon atom form a carbonyl with that carbon, and m is 0, 1, 2, 3, or 4.

[0131] In certain embodiments, A is [ka] and each R 4 are independently halogen, substituted or unsubstituted alkyl, or R on the same carbon. 4 Two examples of the carbon atom form a carbonyl with that carbon, and m is 0, 1, 2, 3, or 4.

[0132] In certain embodiments, A is [ka] and each R 4 are independently halogen, substituted or unsubstituted alkyl, or R on the same carbon. 4 Two examples of the carbon atom form a carbonyl with that carbon, and m is 0, 1, 2, 3, or 4.

[0133] In certain embodiments, each R 4 are independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, hydroxy, or R 4 Two examples of R are linked to form a bridged ring, or R on the same carbon 4 Two examples of R form a carbonyl with that carbon. In certain embodiments, each R 4are independently selected from halogen, substituted or unsubstituted alkyl, R on the same carbon, 4 Two examples of carbonyls are formed with that carbon.

[0134] In certain embodiments, R 4 is a halogen or R on the same carbon 4 In certain embodiments, R 4 is fluoro or R on the same carbon 4 In certain embodiments, R 4 is halogen. In certain embodiments, R 4 is fluoro. In certain embodiments, R 4 In certain embodiments, each R 4 are independently fluoro, methyl, CHOCH, methoxy, difluoromethoxy, or R on the same carbon. 4 Two examples of R form a carbonyl with that carbon. In certain embodiments, each R 4 is independently fluoro, methyl, CH3OCH2-, methoxy, or difluoromethoxy. In certain embodiments, each R 4 is independently methyl. In certain embodiments, each R 4 is independently CH3OCH2-. In certain embodiments, each R 4 is independently methoxy. In certain embodiments, each R 4 is independently difluoromethoxy.

[0135] In certain embodiments, m is 0, 1, 2, or 3. In certain embodiments, m is 0, 1, or 2. In certain embodiments, m is 0 or 2. In certain embodiments, m is 0 or 1. In certain embodiments, m is 1 or 2. In certain embodiments, m is 0. In certain embodiments, m is 2. In certain embodiments, m is 1.

[0136] In certain embodiments, R4 is a halogen or R on the same carbon 4 In certain embodiments, R 4 is fluoro or R on the same carbon 4 In certain embodiments, R 4 is halogen and m is 2. In certain embodiments, R 4 is fluoro and m is 2. In certain embodiments, R 4 In the two cases, it forms a carbonyl with that carbon, and m is 2.

[0137] In certain embodiments, A is [ka] In certain embodiments, A is [ka] In certain embodiments, A is [ka] In certain embodiments, A is [ka] In certain embodiments, A is [ka] In certain embodiments, A is [ka] is.

[0138] In certain embodiments, A is [ka] In certain embodiments, A is [ka] In certain embodiments, A is [ka] is.

[0139] In certain embodiments, A is [ka] In certain embodiments, A is [ka] In certain embodiments, A is [ka] In certain embodiments, A is [ka] In certain embodiments, A is [ka] In certain embodiments, A is [ka] In certain embodiments, A is [ka] In certain embodiments, A is [ka] In certain embodiments, A is [ka] In certain embodiments, A is [ka] In certain embodiments, A is [ka] In certain embodiments, A is [ka] In certain embodiments, A is [ka] In certain embodiments, A is [ka] In certain embodiments, A is [ka] In certain embodiments, A is [ka] In certain embodiments, A is [ka] In certain embodiments, A is [ka] In certain embodiments, A is [ka] In certain embodiments, A is [ka] In certain embodiments, A is [ka] In certain embodiments, A is [ka] In certain embodiments, A is [ka] In certain embodiments, A is [ka] In certain embodiments, A is [ka] In certain embodiments, A is [ka] In certain embodiments, A is [ka] In certain embodiments, A is [ka] In certain embodiments, A is [ka] In certain embodiments, A is [ka] In certain embodiments, A is [ka] In certain embodiments, A is [ka] In certain embodiments, A is [ka] In certain embodiments, A is [ka] In certain embodiments, A is [ka] In certain embodiments, A is [ka] In certain embodiments, A is [ka] is.

[0140] In certain embodiments, A is [ka] In certain embodiments, A is [ka] In certain embodiments, A is [ka] In certain embodiments, A is [ka] In certain embodiments, A is [ka] In certain embodiments, A is [ka] In certain embodiments, A is [ka] In certain embodiments, A is [ka] In certain embodiments, A is [ka] In certain embodiments, A is [ka] In certain embodiments, A is [ka] In certain embodiments, A is [ka] is.

[0141] In certain embodiments, A is [ka] In certain embodiments, A is [ka] In certain embodiments, A is [ka] In certain embodiments, A is [ka] In certain embodiments, A is [ka] In certain embodiments, A is [ka] In certain embodiments, A is [ka] In certain embodiments, A is [ka] In certain embodiments, A is [ka] In certain embodiments, A is [ka] In certain embodiments, A is [ka] In certain embodiments, A is [ka] In certain embodiments, A is [ka] In certain embodiments, A is [ka] In certain embodiments, A is [ka] is.

[0142] In certain embodiments, A is [ka] In certain embodiments, A is [ka] In certain embodiments, A is [ka] In certain embodiments, A is [ka] In certain embodiments, A is [ka] In certain embodiments, A is [ka] In certain embodiments, A is [ka] In certain embodiments, A is [ka] is.

[0143] In certain embodiments, A is [ka] In certain embodiments, A is [ka] In certain embodiments, A is [ka] In certain embodiments, A is [ka] is.

[0144] In certain embodiments, A is [ka] In certain embodiments, A is [ka] is.

[0145] L As described herein, L is selected from the group consisting of a bond, —C(═O)—, —C(═O)CH—, —C(═O)CF—, —C(═O)CH(Ph)—, —C(═O)CH(iPr)—, —C(═O)CH(Et)—, —C(═O)CH(Me)—, —C(═O)C(CH)—, —C(═O)CH(OMe)—, —C(═O)CHCH—, —C(═O)CHCHCH—, and —C(═O)CHCH 2CH2O-, -C(=O)CH(CH3)CH2-, -C(=O)CH2O-, -C(=O)CH2OCH2-, -C(=O)CH(CH3)O-, -C(=O)CH2CH=CH-, -C(=O )NHCH2CH2CH2-, -C(=O)NHCH2CH2-, -CH2-, -CH2CH2CH2-, -CH2C(CH3)2-, -C(=O)NH-, or -CH2C(=O)NH-.

[0146] In certain embodiments, L is a bond, —C(═O)—, —C(═O)CH 2 —, or —C(═O)CH 2 O—.

[0147] In certain embodiments, L is a bond or -C(=O)-. In certain embodiments, L is a bond. In certain embodiments, L is -C(=O)-. In certain embodiments, L is -C(=O)CH-. In certain embodiments, L is -C(=O)CHO-.

[0148] R 5 As described herein, R 5 is substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted aryl, methyl, ethyl, butyl, pentyl, t-butyl, —CHCHCH(CH), —SCF, or —OCHCH(CH).

[0149] In certain embodiments, R 5is substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted aryloxyalkyl.

[0150] In certain embodiments, R 5 is a substituted or unsubstituted pyrazolopyrazinyl, a substituted or unsubstituted indolyl, a substituted or unsubstituted oxadiazolyl, a substituted or unsubstituted triazolyl, or a substituted or unsubstituted pyrazinyl.

[0151] In certain embodiments, R 5 is substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted aryloxyalkyl.

[0152] In certain embodiments, R 5 is substituted or unsubstituted heteroaryl. In certain embodiments, R 5 is substituted or unsubstituted heterocyclyl. In certain embodiments, R 5 is substituted or unsubstituted heteroarylalkyl. In certain embodiments, R 5 is substituted or unsubstituted carbocyclyl. In certain embodiments, R 5 is a substituted or unsubstituted aryloxyalkyl.

[0153] In certain embodiments, R 5 is substituted or unsubstituted heteroaryl, substituted or unsubstituted tetrahydropyranyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted aryloxyalkyl.

[0154] In certain embodiments, R 5is a substituted or unsubstituted pyrazolopyrazinyl, substituted or unsubstituted pyrrolopyrazinyl, substituted or unsubstituted imidazopyrazinyl, substituted or unsubstituted pyrazolopyridinyl, substituted or unsubstituted pyrrolopyridinyl, substituted or unsubstituted imidazopyridinyl, substituted or unsubstituted triazolopyridinyl, substituted or unsubstituted pyrazolopyrimidinyl, substituted or unsubstituted pyrrolopyrimidinyl, substituted or unsubstituted chromenonyl, substituted or unsubstituted isochromanyl, substituted or unsubstituted indolyl, substituted or unsubstituted substituted quinoxalinyl, substituted or unsubstituted benzofuranyl, substituted or unsubstituted benzothiophenyl, substituted or unsubstituted benzimidazolyl, substituted or unsubstituted benzoxazolyl, substituted or unsubstituted 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl, substituted or unsubstituted pyrrolo[3,2-c]pyridin-4-onyl, substituted or unsubstituted 7,8-dihydropyrrolo[1,2-a]pyrimidin-4(6H)-onyl, substituted or unsubstituted 1,5-dihydro-4H-pyrazolo [4,3-c]pyridin-4-onyl, substituted or unsubstituted 2,3-dihydrobenzo[b][1,4]dioxinyl, substituted or unsubstituted tetrahydronaphthalenyl, substituted or unsubstituted isoquinolinonyl, substituted or unsubstituted quinolinyl, substituted or unsubstituted naphthyridinyl, substituted or unsubstituted naphthyl, substituted or unsubstituted pyridazinonyl, substituted or unsubstituted pyridinonyl, substituted or unsubstituted oxadiazolyl, substituted or unsubstituted thiadiazolyl, substituted or unsubstituted thiazolyl, substituted or Unsubstituted pyrazolyl, substituted or unsubstituted triazolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted thiophenyl, substituted or unsubstituted furanyl, substituted or unsubstituted isothiazolyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted isoxazolonyl, substituted or unsubstituted 3,4-dihydro-1H-pyrrolo[2,1-c][1,4]thiazin-8-yl, substituted or unsubstituted pyrrolidinonyl, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted 1,4-diazepanyl, substituted or unsubstituted dioxolanonyl, substituted or unsubstituted pyridinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted phenyl, substituted or unsubstituted tetrahydropyranyl, substituted or unsubstituted tetrahydrofuranyl, substituted or unsubstituted morpholinyl, substituted or unsubstituted cyclooctyl, substituted or unsubstituted cyclohexyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclopent ... cyclopropyl, substituted or unsubstituted bicyclo[3.3.1]nonanyl, substituted or unsubstituted bicyclo[2.2.1]heptanyl, substituted or unsubstituted 7-oxaspiro[3.5]nin-1-en-2-yl, substituted or unsubstituted hexahydro-1H-cyclopenta[c]furan-5-yl, substituted or unsubstituted adamantyl, substituted or unsubstituted spiro[2.5]octan-4-yl, methyl, ethyl, butyl, pentyl, t-butyl, -CH2CH2CH(CH3)2, -SCF3, or -OCH2CH(CH3)2.

[0155] In certain embodiments, R 5is a substituted or unsubstituted pyrazolopyrazinyl, substituted or unsubstituted pyrrolopyrazinyl, substituted or unsubstituted imidazopyrazinyl, substituted or unsubstituted pyrazolopyridinyl, substituted or unsubstituted pyrrolopyridinyl, substituted or unsubstituted pyrazolopyrimidinyl, substituted or unsubstituted indolyl, substituted or unsubstituted quinoxalinyl, substituted or unsubstituted benzofuranyl, substituted or unsubstituted 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl, substituted or unsubstituted pyrrolo[3,2-c]pyridin-4-onyl, substituted or unsubstituted 7,8-dihydropyrrolo[1,2-a]pyrimidin-4(6H)-onyl, substituted or unsubstituted 1,5 ... 4H-pyrazolo[4,3-c]pyridin-4-onyl, substituted or unsubstituted 2,3-dihydrobenzo[b][1,4]dioxinyl, substituted or unsubstituted tetrahydronaphthalenyl, substituted or unsubstituted pyridazinonyl, substituted or unsubstituted pyridinonyl, substituted or unsubstituted oxadiazolyl, substituted or unsubstituted thiadiazolyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted triazolyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted phenyl, substituted or unsubstituted tetrahydropyranyl, substituted or unsubstituted morpholinyl, or substituted or unsubstituted cyclopentyl.

[0156] In certain embodiments, R 5 is substituted or unsubstituted pyrazolopyrazinyl, substituted or unsubstituted chromenonyl, substituted or unsubstituted indolyl, substituted or unsubstituted oxadiazolyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted triazolyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted tetrahydropyranyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted aryloxyalkyl.

[0157] In certain embodiments, R 5is substituted or unsubstituted pyrazolopyrazinyl, substituted or unsubstituted chromenonyl, substituted or unsubstituted indolyl, substituted or unsubstituted oxadiazolyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted triazolyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted aryloxyalkyl.

[0158] In certain embodiments, R 5 is substituted or unsubstituted pyrazolopyrazinyl, substituted or unsubstituted pyrrolopyrazinyl, substituted or unsubstituted chromenonyl, substituted or unsubstituted indolyl, substituted or unsubstituted oxadiazolyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted triazolyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted tetrahydropyranyl, substituted or unsubstituted pyrazolylmethyl, substituted or unsubstituted indolylmethyl, substituted or unsubstituted cyclohexyl, or substituted or unsubstituted phenyloxyalkyl.

[0159] In certain embodiments, R 5 is substituted or unsubstituted pyrazolopyrazinyl, substituted or unsubstituted pyrrolopyrazinyl, substituted or unsubstituted chromenonyl, substituted or unsubstituted indolyl, substituted or unsubstituted oxadiazolyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted triazolyl, or substituted or unsubstituted pyrazinyl. In certain embodiments, R 5 is a substituted or unsubstituted pyrazolylmethyl or a substituted or unsubstituted indolylmethyl.

[0160] In certain embodiments, R 5 is substituted or unsubstituted pyrazolopyrazinyl. In certain embodiments, R 5 is substituted or unsubstituted pyrrolopyrazinyl. In certain embodiments, R 5 is substituted or unsubstituted chromenonyl. In certain embodiments, R 5is a substituted or unsubstituted indolyl. In certain embodiments, R 5 is substituted or unsubstituted oxadiazolyl. In certain embodiments, R 5 is substituted or unsubstituted pyrazolyl. In certain embodiments, R 5 is substituted or unsubstituted triazolyl. In certain embodiments, R 5 is substituted or unsubstituted pyrazinyl. In certain embodiments, R 5 is substituted or unsubstituted tetrahydropyranyl. In certain embodiments, R 5 is substituted or unsubstituted pyrazolylmethyl. In certain embodiments, R 5 is substituted or unsubstituted indolylmethyl. In certain embodiments, R 5 is substituted or unsubstituted cyclohexyl. In certain embodiments, R 5 is a substituted or unsubstituted phenyloxyalkyl.

[0161] In certain embodiments, R 5 is a substituted pyrazolopyrazinyl, substituted pyrrolopyrazinyl, substituted chromenonyl, substituted indolyl, substituted oxadiazolyl, substituted pyrazolyl, substituted triazolyl, substituted pyrazinyl, substituted tetrahydropyranyl, substituted pyrazolylmethyl, unsubstituted indolylmethyl, substituted cyclohexyl, or substituted phenyloxypropyl.

[0162] In certain embodiments, R 5 is a substituted pyrazolopyrazinyl, substituted pyrrolopyrazinyl, substituted chromenonyl, substituted indolyl, substituted oxadiazolyl, substituted pyrazolyl, substituted triazolyl, or substituted pyrazinyl. 5 is substituted tetrahydropyranyl. In certain embodiments, R 5 is substituted pyrazolylmethyl or unsubstituted indolylmethyl. In certain embodiments, R 5 is substituted cyclohexyl. In certain embodiments, R 5 is a substituted phenyloxypropyl.

[0163] In certain embodiments, R 5 is a substituted pyrazolopyrazinyl, substituted pyrrolopyrazinyl, substituted chromenonyl, substituted indolyl, substituted oxadiazolyl, substituted pyrazolyl, substituted triazolyl, substituted pyrazinyl, substituted tetrahydropyranyl, substituted pyrazolylmethyl, unsubstituted indolylmethyl, substituted cyclohexyl, or substituted phenyloxypropyl, and each substituted R 5 is substituted with haloalkyl, cycloalkyl, heteroaryl, aryl, halogen, arylalkyl, alkoxy, alkyl, heterocyclylalkyl, or heterocyclyl.

[0164] In certain embodiments, R 5 is pyrazolopyrazinyl substituted with alkyl or haloalkyl. In certain embodiments, R 5 is pyrrolopyrazinyl substituted with alkyl or haloalkyl. In certain embodiments, R 5 is chromenonyl substituted with halogen. In certain embodiments, R 5 is indolyl substituted with heterocyclylalkyl or heterocyclyl. In certain embodiments, R 5 is oxadiazolyl substituted with cycloalkyl. In certain embodiments, R 5 is pyrazolyl substituted with arylalkyl. In certain embodiments, R 5 is triazolyl substituted with aryl. In certain embodiments, R 5 is pyrazinyl substituted with heteroaryl. In certain embodiments, R 5 is tetrahydropyranyl substituted with aryl. In certain embodiments, R 5 is pyrazolylmethyl substituted with alkyl or cycloalkyl. In certain embodiments, R 5 is unsubstituted indolylmethyl. In certain embodiments, R 5 is cyclohexyl substituted with haloalkyl. In certain embodiments, R 5 is bicyclo[2.2.1]heptanyl substituted with haloalkyl. In certain embodiments, R5 is phenyloxypropyl substituted with alkoxy.

[0165] In certain embodiments, R 5 teeth, [ka] where R 20 and R 30 are each independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or R 20 and R 30 together with the atom to which they are attached form a substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0166] In certain embodiments, A is [ka] is.

[0167] In certain embodiments, A is [ka] is.

[0168] In certain embodiments, A is [ka] is.

[0169] In certain embodiments, A is [ka] is.

[0170] In certain embodiments, A is [ka] is.

[0171] In certain embodiments, A is [ka] is.

[0172] In certain embodiments, R 20 and R 30 are each independently hydrogen or substituted or unsubstituted heteroaryl, or R 20 and R 30 together with the atom to which they are attached form a substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.

[0173] In certain embodiments, R 20 is substituted or unsubstituted heteroaryl. In certain embodiments, R 20 is unsubstituted heteroaryl. In certain embodiments, R 20 is substituted or unsubstituted thiadiazole. In certain embodiments, R 20 is unsubstituted thiadiazolyl.

[0174] In certain embodiments, R 30 is hydrogen.

[0175] In certain embodiments, R 20 is a substituted or unsubstituted heteroaryl, and R 30 is hydrogen. In certain embodiments, R 20 is unsubstituted heteroaryl, and R 30 is hydrogen. In certain embodiments, R 20 is a substituted or unsubstituted thiadiazaolyl, and R 30 is hydrogen. In certain embodiments, R 20 is unsubstituted thiadiazaolyl, and R 30 is hydrogen.

[0176] In certain embodiments, R 20 and R 30 together with the atom to which they are attached form a substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.

[0177] In certain embodiments, R 20 and R 30 taken together with the atoms to which they are attached form a substituted or unsubstituted aryl. In certain embodiments, R 20 and R 30 taken together with the atoms to which they are attached form a substituted or unsubstituted phenyl. In certain embodiments, R 20 and R 30 taken together with the atoms to which they are attached form a substituted phenyl. In certain embodiments, R 20 and R 30 together with the atoms to which they are attached form an unsubstituted phenyl.

[0178] In certain embodiments, R 20 and R 30 taken together with the atom to which they are attached form a substituted or unsubstituted heteroaryl. In certain embodiments, R 20 and R 30 together with the atoms to which they are attached form a substituted or unsubstituted imidazolyl, a substituted or unsubstituted pyrrolyl, or a substituted or unsubstituted pyrazolyl. 20 and R 30 taken together with the atom to which they are attached form a substituted or unsubstituted pyrrolyl or a substituted or unsubstituted pyrazolyl. In certain embodiments, R 20 and R 30 taken together with the atoms to which they are attached form a substituted imidazolyl, substituted pyrrolyl, or substituted pyrazolyl. In certain embodiments, R 20 and R 30 taken together with the atoms to which they are attached form a substituted pyrrolyl or a substituted pyrazolyl. In certain embodiments, R 20 and R30 taken together with the atoms to which they are attached form a substituted imidazolyl, substituted pyrrolyl, or substituted pyrazolyl, where the imidazolyl, pyrrolyl, or pyrazolyl is substituted with substituted or unsubstituted alkyl or substituted or unsubstituted heterocyclyl. 20 and R 30 taken together with the atoms to which they are attached form a substituted imidazolyl, substituted pyrrolyl, or substituted pyrazolyl, where the imidazolyl, pyrrolyl, or pyrazolyl is substituted with substituted or unsubstituted alkyl. 20 and R 30 together with the atom to which they are attached form a substituted pyrrolyl or a substituted pyrazolyl, wherein the pyrrolyl or pyrazolyl is substituted with substituted or unsubstituted alkyl, or substituted or unsubstituted heterocyclyl. 20 and R 30 taken together with the atoms to which they are attached form a substituted pyrrolyl or substituted pyrazolyl, where the pyrrolyl or pyrazolyl is substituted with substituted or unsubstituted alkyl. In certain embodiments, R 20 and R 30 together with the atoms to which they are attached form a substituted imidazolyl, substituted pyrrolyl, or substituted pyrazolyl, wherein the imidazolyl, pyrrolyl, or pyrazolyl is substituted with unsubstituted alkyl, heterocyclylalkyl, heterocyclyl, or haloalkyl. 20 and R 30 taken together with the atoms to which they are attached form a substituted imidazolyl, substituted pyrrolyl, or substituted pyrazolyl, where the imidazolyl, pyrrolyl, or pyrazolyl is substituted with unsubstituted alkyl or haloalkyl. 20 and R 30 taken together with the atom to which they are attached form a substituted pyrrolyl or substituted pyrazolyl, where the pyrrolyl or pyrazolyl is substituted with unsubstituted alkyl, heterocyclylalkyl, heterocyclyl, or haloalkyl. 20 and R 30taken together with the atom to which they are attached form a substituted pyrrolyl or substituted pyrazolyl, where the pyrrolyl or pyrazolyl is substituted with unsubstituted alkyl or haloalkyl. 20 and R 30 together with the atom to which they are attached form a substituted imidazolyl, substituted pyrrolyl, or substituted pyrazolyl, wherein the imidazolyl, pyrrolyl, or pyrazolyl is an unsubstituted C 1~4 Alkyl, 4-5 membered heterocyclylC 1~4 Alkyl, 4- to 5-membered heterocyclyl or C 1~4 In certain embodiments, R 20 and R 30 together with the atom to which they are attached form a substituted imidazolyl, substituted pyrrolyl, or substituted pyrazolyl, wherein the imidazolyl, pyrrolyl, or pyrazolyl is an unsubstituted C 1~4 Alkyl or C 1~4 In certain embodiments, R 20 and R 30 together with the atom to which they are attached form a substituted pyrrolyl or substituted pyrazolyl, wherein the pyrrolyl or pyrazolyl is an unsubstituted C 1~4 Alkyl, 4-5 membered heterocyclylC 1~4 Alkyl, 4- to 5-membered heterocyclyl or C 1~4 In certain embodiments, R 20 and R 30 together with the atom to which they are attached form a substituted pyrrolyl or substituted pyrazolyl, wherein the pyrrolyl or pyrazolyl is an unsubstituted C 1~4 Alkyl or C 1~4 In certain embodiments, R 20 and R 30 together with the atom to which they are attached form a substituted imidazolyl, substituted pyrrolyl, or substituted pyrazolyl, wherein the imidazolyl, pyrrolyl, or pyrazolyl is an unsubstituted C 1~4 In certain embodiments, R 20 and R 30together with the atom to which they are attached form a substituted pyrrolyl or substituted pyrazolyl, wherein the pyrrolyl or pyrazolyl is an unsubstituted C 1~4 In certain embodiments, R 20 and R 30 together with the atoms to which they are attached form a substituted imidazolyl, substituted pyrrolyl, or substituted pyrazolyl, wherein the imidazolyl, pyrrolyl, or pyrazolyl is C 1~4 In certain embodiments, R 20 and R 30 together with the atom to which they are attached form a substituted pyrrolyl or substituted pyrazolyl, where the pyrrolyl or pyrazolyl is C 1~4 In certain embodiments, R 20 and R 30 together with the atom to which they are attached form a substituted imidazolyl, substituted pyrrolyl, or substituted pyrazolyl, wherein the imidazolyl, pyrrolyl, or pyrazolyl is a 4- to 5-membered heterocyclylC 1~4 In certain embodiments, R 20 and R 30 together with the atom to which they are attached form a substituted pyrrolyl or substituted pyrazolyl, wherein the pyrrolyl or pyrazolyl is a 4- to 5-membered heterocyclylC 1~4 In certain embodiments, R 20 and R 30 together with the atoms to which they are attached form a substituted imidazolyl, substituted pyrrolyl, or substituted pyrazolyl, where the imidazolyl, pyrrolyl, or pyrazolyl is substituted with a 4-5 membered heterocyclyl. 20 and R 30 together with the atom to which they are attached form a substituted pyrrolyl or substituted pyrazolyl, where the pyrrolyl or pyrazolyl is substituted with a 4-5 membered heterocyclyl.

[0179] In certain embodiments, R 20 and R 30taken together with the atom to which they are attached form a substituted or unsubstituted pyrazolyl. In certain embodiments, R 20 and R 30 taken together with the atoms to which they are attached form a substituted pyrazolyl. In certain embodiments, R 20 and R 30 taken together with the atom to which they are attached form a substituted pyrazolyl, where the pyrazolyl is substituted with substituted or unsubstituted alkyl, or substituted or unsubstituted heterocyclyl. In certain embodiments, R 20 and R 30 taken together with the atom to which they are attached form a substituted pyrazolyl, where the pyrazolyl is substituted with substituted or unsubstituted alkyl. In certain embodiments, R 20 and R 30 taken together with the atom to which they are attached form a substituted pyrazolyl, where the pyrazolyl is substituted with unsubstituted alkyl, heterocyclylalkyl, heterocyclyl, or haloalkyl. In certain embodiments, R 20 and R 30 taken together with the atom to which they are attached form a substituted pyrazolyl, where the pyrazolyl is substituted with unsubstituted alkyl or haloalkyl. In certain embodiments, R 20 and R 30 together with the atoms to which they are attached form a substituted pyrazolyl, where the pyrazolyl is an unsubstituted C 1~4 Alkyl, 4-5 membered heterocyclylC 1~4 Alkyl, 4- to 5-membered heterocyclyl or C 1~4 In certain embodiments, R 20 and R 30 together with the atoms to which they are attached form a substituted pyrazolyl, where the pyrazolyl is an unsubstituted C 1~4 Alkyl or C 1~4 In certain embodiments, R 20 and R 30 together with the atoms to which they are attached form a substituted pyrazolyl, where the pyrazolyl is an unsubstituted C1~4 In certain embodiments, R 20 and R 30 together with the atom to which they are attached to form a substituted pyrazolyl, and pyrazolyl is C 1~4 In certain embodiments, R 20 and R 30 taken together with the atom to which they are attached form a substituted pyrazolyl, where the pyrazolyl is substituted with a 4-5 membered heterocyclyl. In certain embodiments, R 20 and R 30 together with the atom to which they are attached form a substituted pyrazolyl, which is a 4- to 5-membered heterocyclylC 1~4 It is substituted with alkyl.

[0180] In certain embodiments, R 20 and R 30 together with the atoms to which they are attached form a substituted or unsubstituted pyrrolyl. In certain embodiments, R 20 and R 30 taken together with the atoms to which they are attached form a substituted pyrrolyl. In certain embodiments, R 20 and R 30 taken together with the atoms to which they are attached form a substituted group, where pyrrolyl is substituted with substituted or unsubstituted heterocyclyl or substituted or unsubstituted alkyl. In certain embodiments, R 20 and R 30 together with the atoms to which they are attached form a substituted group, where pyrrolyl is substituted with substituted or unsubstituted alkyl. In certain embodiments, R 20 and R 30 taken together with the atom to which they are attached form a substituted pyrrolyl, where the pyrrolyl is substituted with heterocyclyl, unsubstituted alkyl, or haloalkyl. In certain embodiments, R 20 and R 30taken together with the atom to which they are attached form a substituted pyrrolyl, where the pyrrolyl is substituted with unsubstituted alkyl or haloalkyl. In certain embodiments, R 20 and R 30 together with the atom to which they are attached form a substituted pyrrolyl, where pyrrolyl is a 4- to 5-membered heterocyclyl, unsubstituted C 1~4 Alkyl or C 1~4 In certain embodiments, R 20 and R 30 together with the atoms to which they are attached form a substituted pyrrolyl, where the pyrrolyl is an unsubstituted C 1~4 Alkyl or C 1~4 In certain embodiments, R 20 and R 30 together with the atoms to which they are attached form a substituted pyrrolyl, where the pyrrolyl is an unsubstituted C 1~4 In certain embodiments, R 20 and R 30 together with the atoms to which they are attached to form a substituted pyrrolyl, where pyrrolyl is C 1~4 In certain embodiments, R 20 and R 30 together with the atom to which they are attached form a substituted pyrrolyl, wherein the pyrrolyl is substituted with a 4- to 5-membered heterocyclyl.

[0181] In certain embodiments, R 5 teeth, [ka] where X is N or CH and R a is substituted or unsubstituted alkyl, or substituted or unsubstituted heterocyclyl. In certain embodiments, R 5 teeth, [ka] where X is N or CH and Ra is substituted or unsubstituted heterocyclyl. In certain embodiments, R 5 teeth, [ka] where X is N or CH and R a is substituted or unsubstituted alkyl. In certain embodiments, R 5 teeth, [ka] where X is N or CH and R a is haloalkyl or alkyl. In certain embodiments, R 5 teeth, [ka] where X is N or CH and R a is C 1~4 Haloalkyl or C 1~4 In certain embodiments, R 5 teeth, [ka] where X is N and R a is substituted or unsubstituted heterocyclyl. In certain embodiments, R 5 teeth, [ka] where X is N and R a is substituted or unsubstituted alkyl. In certain embodiments, R 5 teeth, [ka] where X is N and R a is haloalkyl or alkyl. In certain embodiments, R 5 teeth, [ka] where X is N and R a is C 1~4 Haloalkyl or C 1~4 In certain embodiments, R 5 teeth, [ka] where X is CH and R a is substituted or unsubstituted alkyl. In certain embodiments, R 5 teeth, [ka] where X is CH and R a is haloalkyl or alkyl. In certain embodiments, R 5 teeth, [ka] where X is CH and R a is C 1~4 Haloalkyl or C 1~4 It is alkyl.

[0182] In certain embodiments, X is N or CH and R a is substituted or unsubstituted alkyl. In certain embodiments, X is N or CH and R a is heterocyclyl, haloalkyl, or alkyl. In certain embodiments, X is N or CH and R a is haloalkyl or alkyl. In certain embodiments, X is N or CH and R a is a 4-5 membered heterocyclyl, fluoroalkyl, or alkyl. In certain embodiments, X is N or CH and R a is fluoroalkyl or alkyl. In certain embodiments, X is N or CH and R a is 4-5 membered heterocyclyl, C 1~4 Haloalkyl or C 1~4In certain embodiments, X is N or CH and R a is C 1~4 Haloalkyl or C 1~4 In certain embodiments, X is N or CH and R a is a 4-membered heterocyclyl, C 1~4 Fluoroalkyl or C 1~4 In certain embodiments, X is N or CH and R a is C 1~4 Fluoroalkyl or C 1~4 In certain embodiments, X is N and R a is substituted or unsubstituted alkyl, or substituted or unsubstituted heterocyclyl. In certain embodiments, X is N and R a is substituted or unsubstituted alkyl. In certain embodiments, X is N and R a is heterocyclyl, haloalkyl, or alkyl. In certain embodiments, X is N and R a is haloalkyl or alkyl. In certain embodiments, X is N and R a is a 4-5 membered heterocyclyl, fluoroalkyl, or alkyl. In certain embodiments, X is N and R a is fluoroalkyl or alkyl. In certain embodiments, X is N and R a is C 1~4 Haloalkyl or C 1~4 In certain embodiments, X is N or CH and R a is a 4-membered heterocyclyl, C 1~4 Fluoroalkyl or C 1~4 In certain embodiments, X is N and R a is C 1~4 Fluoroalkyl or C 1~4 In certain embodiments, X is CH and R a is substituted or unsubstituted alkyl. In certain embodiments, X is CH and R ais 4-5 membered heterocyclylalkyl, 4-5 membered heterocyclyl, haloalkyl, or alkyl. In certain embodiments, X is CH and R a is haloalkyl or alkyl. In certain embodiments, X is CH and R a is a 4- to 5-membered heterocyclyl C 1~4 Alkyl, 4-5 membered heterocyclyl, C 1~4 Haloalkyl or C 1~4 In certain embodiments, X is CH and R a is C 1~4 Haloalkyl or C 1~4 In certain embodiments, X is CH and R a is 4-5 membered heterocyclylalkyl, 4-5 membered heterocyclyl, fluoroalkyl, or alkyl. In certain embodiments, X is CH and R a is fluoroalkyl or alkyl. In certain embodiments, X is CH and R a is a four-membered heterocyclyl C 1~4 Alkyl, 4-membered heterocyclyl, C 1~4 Fluoroalkyl or C 1~4 In certain embodiments, X is CH and R a is C 1~4 Fluoroalkyl or C 1~4 In certain embodiments, X is CH and R a is C 1~4 In certain embodiments, X is CH and R a is ethyl. In certain embodiments, X is CH and R a is oxetanyl. In certain embodiments, X is CH and R a is oxetanylmethyl.

[0183] In certain embodiments, R 5 teeth, [ka] The file is TIFF2024518000000148.tif95159.

[0184] In certain embodiments, R 5 teeth, [ka] The file is TIFF2024518000000150.tif59159.

[0185] In certain embodiments, R 5 teeth, [ka] In certain embodiments, R 5 teeth, [ka] is.

[0186] In certain embodiments, R 5 teeth, [ka] is.

[0187] In certain embodiments, R 5 teeth, [ka] is.

[0188] In certain embodiments, R 5 teeth, [ka] is.

[0189] In certain embodiments, R 5 teeth, [ka] is.

[0190] Specific Embodiments In certain embodiments, the compound of formula (I) has formula (I'): [ka] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein R 1 , R 2 , R 3 , R 4 , R 5 , G, L, m and n are as defined herein.

[0191] In certain embodiments, the compound of formula (I) has formula (Ia): [ka] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein R 1 , R 2 , R 4 , R 5 , G, L and m are as defined herein.

[0192] In certain embodiments, the compound of formula (I) has formula (Ib): [ka] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein R 1 , R 2 , R 4 , R 5 , L and m are as defined herein.

[0193] In certain embodiments, the compound of formula (I) has formula (Ic): [ka] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein R 1 , R 4 , R 5 , L and m are as defined herein.

[0194] In certain embodiments, the compound of formula (I) has the formula (Id): [ka] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein R 1 , R 4 , R 5 , and m are as defined herein.

[0195] In certain embodiments, the compound of formula (I) has formula (Ie): [ka] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein R 1 , R 4 , R 5 , L and m are as defined herein.

[0196] In certain embodiments, the compound of formula (I) has the formula (If): [ka] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein R 1 , R 4 , R 5 , and m are as defined herein.

[0197] In certain embodiments, the compound of formula (I) has the formula (Ig): [ka] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein R 1 , R 4 , R 5 , and m are as defined herein.

[0198] In certain embodiments, the compound of formula (I) has the formula (Ih): [ka] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein R 1 , R 2 , R 5 , G and L are as defined herein.

[0199] In certain embodiments, the compound of formula (I) has the formula (Ii): [ka] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein R 1 , R 2 , R 4 , R a and m is as defined herein.

[0200] In certain embodiments, the compound of formula (I) has formula (II): [ka] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein R 1 , R2 , R 3 , R 4 , R 5 , G, L, m and n are as defined herein.

[0201] In certain embodiments, the compound of formula (I) has formula (II-a): [ka] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein R 1 , R 2 , R 4 , R 5 , G, L and m are as defined herein.

[0202] In certain embodiments, the compound of formula (I) has formula (II-b): [ka] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein R 1 , R 4 , R 5 , L and m are as defined herein.

[0203] In certain embodiments, the compound of formula (I) has formula (II-c): [ka] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein R 1 , R 4 , R 5 , and m are as defined herein.

[0204] In certain embodiments, the compound of formula (I) has formula (II-d): [ka] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein R 1 and R 5 is as defined herein.

[0205] In certain embodiments, the compound of formula (I) has formula (III): [ka] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein R 1 , R 2 , R 3 , R 4 , R 5 , G, L, m and n are as defined herein.

[0206] In certain embodiments, the compound of formula (I) has formula (III-a): [ka] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein R 1 , R 4 , R 5 , G, L and m are as defined herein.

[0207] In certain embodiments, the compound of formula (I) has formula (III-b): [ka] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein R 1 , R 4 , R 5 , L and m are as defined herein.

[0208] In certain embodiments, the compound of formula (I) has formula (III-c): [ka] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein R 1 , R 4 , R 5 , and m are as defined herein.

[0209] In certain embodiments, the compound of formula (I) has formula (III-d): [ka] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein R 1 and R 5 is as defined herein.

[0210] In certain embodiments, the compound of formula (I) has formula (IV): [ka] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein R 1 , R 2 , R 3 , R 4 , R 5 , G, L, m and n are as defined herein.

[0211] In certain embodiments, the compound of formula (I) has formula (IV-a): [ka] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein R 1 , R 2 , R 4 , R 5 , G, L and m are as defined herein.

[0212] In certain embodiments, the compound of formula (I) has formula (IV-b): [ka] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein R 1 , R 4 , R 5 , L and m are as defined herein.

[0213] In certain embodiments, the compound of formula (I) has formula (IV-c): [ka] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein R 1 , R 4 , R 5 , and m are as defined herein.

[0214] In certain embodiments, the compound of formula (I) has formula (IV-d): [ka] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein R 1 and R 5 is as defined herein.

[0215] In certain embodiments, the compound of formula (I) has formula (IV-e): [ka] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein R 1 and R 5 is as defined herein.

[0216] In certain embodiments, the compound of formula (I) has the formula (Va): [ka] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein R 1 , R 2 , R 4 , R 5 , G, L and m are as defined herein.

[0217] In certain embodiments, the compound of formula (I) has formula (Vb): [ka] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein R 1 , R 4 , R 5 , L and m are as defined herein.

[0218] In certain embodiments, the compound of formula (I) has formula (Vc): [ka] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein R 1 , R 4 , R5 , and m are as defined herein.

[0219] In certain embodiments, the compound of formula (I) has the formula (Vd): [ka] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein R 1 and R 5 is as defined herein.

[0220] In certain embodiments, the compound of formula (I) is one of the following compounds, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof: [Table 1] TIFF2024518000000188.tif109147

[0221] In certain embodiments, the compound of Formula (I) is a compound of Table 1, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof. [Table 2] TIFF2024518000000190.tif247169TIFF2024518000000191.tif251166TIFF2024518 000000192.tif218167TIFF2024518000000193.tif251159TIFF2024518000000194.t if239156TIFF2024518000000195.tif253168TIFF2024518000000196.tif238163TIF F2024518000000197.tif245159TIFF2024518000000198.tif255155TIFF20245180000 00199.tif241156TIFF2024518000000200.tif174108TIFF2024518000000201.tif17 1107TIFF2024518000000202.tif245159TIFF2024518000000203.tif242162TIFF202 4518000000204.tif240159TIFF2024518000000205.tif173103TIFF20245180000002 06.tif249156TIFF2024518000000207.tif253160TIFF2024518000000208.tif240163

[0222] In certain embodiments, the compound of Formula (I) is a compound of Table 2, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof. In certain embodiments, the compound of Formula (I) is not one or more of the compounds of Table 2, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof. [Table 3] TIFF2024518000000210.tif252160TIFF2024518000000211.tif253155TIFF2024518000000212.tif172104TIFF2024518000000213.t if175104TIFF2024518000000214.tif252156TIFF2024518000000215.tif175109TIFF2024518000000216.tif171107TIFF20245180000 00217.tif253159TIFF2024518000000218.tif174108TIFF2024518000000219.tif251164TIFF2024518000000220.tif171110TIFF202 4518000000221.tif171107TIFF2024518000000222.tif174105TIFF2024518000000223.tif171107TIFF2024518000000224.tif248164

[0223] In certain embodiments, provided compounds (e.g., compounds of Formula (I)) have an EC of less than 100,000 nM, less than 50,000 nM, less than 20,000 nM, less than 10,000 nM, less than 5,000 nM, less than 2,500 nM, less than 1,000 nM, less than 900 nM, less than 800 nM, less than 700 nM, less than 600 nM, less than 500 nM, less than 400 nM, less than 300 nM, less than 200 nM, less than 100 nM, less than 90 nM, less than 80 nM, less than 70 nM, less than 60 nM, less than 50 nM, less than 40 nM, less than 30 nM, less than 20 nM, less than 10 nM, less than 5 nM, less than 4 nM, less than 3 nM, less than 2 nM, or less than 1 nM. 50 Activates GCase.

[0224] Pharmaceutical Compositions, Kits, and Administration The present disclosure provides pharmaceutical compositions comprising a disclosed compound (e.g., a compound of Formula (I)), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, and optionally a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical compositions described herein comprise a compound of Formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0225] In certain embodiments, the compound of formula (I) is provided in an effective amount in a pharmaceutical composition. In certain embodiments, the effective amount is a therapeutically effective amount. In certain embodiments, the effective amount is a prophylactically effective amount. In certain embodiments, the effective amount is an amount effective to treat a disease or disorder in a subject in need thereof. In certain embodiments, the effective amount is an amount effective to treat a neurological disease or disorder in a subject in need thereof. In certain embodiments, the effective amount is an amount effective to prevent a neurological disease or disorder in a subject in need thereof.

[0226] In certain embodiments, the effective amount is an amount effective to reduce the risk of developing a disease (e.g., a neurological disease or disorder) in a subject in need thereof.

[0227] In certain embodiments, an effective amount is an amount effective to increase the activity of GCase in a subject, tissue, biological sample, or cell.

[0228] In certain embodiments, the subject treated or administered with a compound described herein is an animal. The animal may be of either gender and at any stage of development. In certain embodiments, the subject described herein is a human. In certain embodiments, the subject is a non-human animal. In certain embodiments, the subject is a mammal. In certain embodiments, the subject is a non-human mammal. In certain embodiments, the subject is a livestock animal, such as a dog, cat, cow, pig, horse, sheep, or goat. In certain embodiments, the subject is a companion animal, such as a dog or cat. In certain embodiments, the subject is a livestock animal, such as a cow, pig, horse, sheep, or goat. In certain embodiments, the subject is a zoo animal. In other embodiments, the subject is a research animal, such as a rodent (e.g., mouse, rat), dog, pig, or non-human primate. In certain embodiments, the animal is a genetically engineered animal. In certain embodiments, the animal is a transgenic animal (e.g., transgenic mice and transgenic pigs). In certain embodiments, the subject is a fish or reptile.

[0229] In certain embodiments, an effective amount is an amount effective to increase GCase activity by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 100%, at least about 150%, at least about 200%, at least about 250%, at least about 300%, at least about 400%, at least about 500%, or at least about 1000%. In certain embodiments, an effective amount is an amount effective to increase GCase activity by a range between (inclusive) a percentage recited in this paragraph and another percentage recited in this paragraph.

[0230] The present disclosure provides pharmaceutical compositions comprising compounds that interact with (e.g., activate) GCase for use in treating a GCase-associated disease or disorder in a subject in need thereof. The present disclosure provides pharmaceutical compositions comprising compounds that interact with (e.g., activate) GCase for use in treating a disease or disorder associated with abnormal GCase activity in a subject in need thereof. The present disclosure provides pharmaceutical compositions comprising compounds that interact with (e.g., activate) GCase for use in treating a disease or disorder associated with mutant GCase in a subject in need thereof.

[0231] In certain embodiments, the composition is for use in treating a disease or disorder. In certain embodiments, the composition is for use in treating a neurological disease or disorder. In certain embodiments, the composition is for use in treating Gaucher disease or Parkinson's disease. In certain embodiments, the composition is for use in treating Gaucher disease. In certain embodiments, the composition is for use in treating Parkinson's disease.

[0232] The compounds or compositions described herein can be administered in combination with one or more additional pharmaceutical agents (e.g., therapeutically and / or prophylactically active agents). The compounds or compositions can be administered in combination with additional pharmaceutical agents that improve their activity (e.g., activity (e.g., efficacy and / or effectiveness) in treating a disease in a subject in need of such treatment, preventing a disease in a subject in need of such treatment, and / or reducing the risk of developing a disease in a subject in need of such treatment), improve bioavailability, improve safety, reduce drug resistance, reduce and / or alter metabolism, inhibit excretion, and / or alter distribution in a subject or cell. It will also be understood that the treatments used can achieve desired effects for the same disorder and / or can achieve different effects. In certain embodiments, pharmaceutical compositions described herein that include a compound described herein and an additional pharmaceutical agent exhibit a synergistic effect that is not present in pharmaceutical compositions that include one of the compound and the additional pharmaceutical agent, but not both.

[0233] The compound or composition can be administered simultaneously with, before, or after one or more additional pharmaceutical agents that may be useful, for example, as a combination therapy. Pharmaceutical agents include therapeutically active agents. Pharmaceutical agents also include prophylactically active agents. Pharmaceutical agents include drug compounds (e.g., compounds approved for human or veterinary use by the US Food and Drug Administration, as defined in the Code of Federal Regulations (CFR)), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides or proteins, small molecules linked to proteins, glycoproteins, steroids, nucleic acids, DNA, RNA, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins, and small organic molecules such as cells. In certain embodiments, the additional pharmaceutical agents are pharmaceutical agents useful for treating and / or preventing diseases (e.g., neurological diseases or disorders). Each additional pharmaceutical agent can be administered at a dose and / or time schedule determined for that pharmaceutical agent. The additional pharmaceutical agents may also be administered in a single dose with each other and / or with the compounds or compositions described herein, or may be administered separately in different doses. The particular combination to use in a regimen will take into account compatibility of the compounds described herein with the additional pharmaceutical agent(s) and / or the desired therapeutic and / or prophylactic effect to be achieved. In general, it is expected that the additional pharmaceutical agent(s) will be utilized in combination at levels that do not exceed the levels at which they are utilized individually. In some embodiments, the levels utilized in combination will be lower than the levels utilized individually.

[0234] In certain embodiments, the compound or pharmaceutical composition is a solid. In certain embodiments, the compound or pharmaceutical composition is a powder. In certain embodiments, the compound or pharmaceutical composition can be dissolved in a liquid to form a solution. In certain embodiments, the compound or pharmaceutical composition is dissolved in water to form an aqueous solution. In certain embodiments, the pharmaceutical composition is a liquid for parenteral injection. In certain embodiments, the pharmaceutical composition is a liquid for oral administration (e.g., ingestion). In certain embodiments, the pharmaceutical composition is a liquid for intravenous injection (e.g., an aqueous solution). In certain embodiments, the pharmaceutical composition is a liquid for subcutaneous injection (e.g., an aqueous solution).

[0235] After formulation with appropriate pharmaceutically acceptable excipients in the desired dosage, the pharmaceutical compositions of the present disclosure can be administered to humans and other animals orally, parenterally, intracisternally, intraperitoneally, topically, buccally, etc., depending on the disease or condition being treated.

[0236] In certain embodiments, pharmaceutical compositions comprising a compound of Formula (I) are administered orally or parenterally at a dosage level of each pharmaceutical composition sufficient to deliver about 0.001 mg / kg to about 200 mg / kg of the subject's body weight per day, in one or more doses administered over a period of one or more days (depending on the mode of administration). In certain embodiments, the effective amount per dose varies from about 0.001 mg / kg to about 200 mg / kg, about 0.001 mg / kg to about 100 mg / kg, about 0.01 mg / kg to about 100 mg / kg, about 0.01 mg / kg to about 50 mg / kg, preferably about 0.1 mg / kg to about 40 mg / kg, preferably about 0.5 mg / kg to about 30 mg / kg, about 0.01 mg / kg to about 10 mg / kg, or about 0.1 mg / kg to about 10 mg / kg of the subject's body weight per day, one or more times per day, to achieve the desired therapeutic and / or prophylactic effect. In certain embodiments, the compounds described herein may be administered at a dosage level sufficient to deliver about 0.001 mg / kg to about 200 mg / kg, about 0.001 mg / kg to about 100 mg / kg, about 0.01 mg / kg to about 100 mg / kg, about 0.01 mg / kg to about 50 mg / kg, preferably about 0.1 mg / kg to about 40 mg / kg, preferably about 0.5 mg / kg to about 30 mg / kg, about 0.01 mg / kg to about 10 mg / kg, about 0.1 mg / kg to about 10 mg / kg, and more preferably about 1 mg / kg to about 25 mg / kg of a subject's body weight per day, one or more times daily, to achieve the desired therapeutic and / or prophylactic effect. The desired dosage may be delivered three times a day, twice a day, once a day, every other day, every third day, weekly, every two weeks, every three weeks, or every four weeks. In certain embodiments, the desired dosage may be delivered using multiple administrations (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or more administrations). In certain embodiments, the compositions described herein are administered at a dose below the dose at which the agent causes nonspecific effects.

[0237] In certain embodiments, the pharmaceutical composition is administered at a dose of about 0.001 mg to about 1000 mg per unit dose. In certain embodiments, the pharmaceutical composition is administered at a dose of about 0.01 mg to about 200 mg per unit dose. In certain embodiments, the pharmaceutical composition is administered at a dose of about 0.01 mg to about 100 mg per unit dose. In certain embodiments, the pharmaceutical composition is administered at a dose of about 0.01 mg to about 50 mg per unit dose. In certain embodiments, the pharmaceutical composition is administered at a dose of about 0.01 mg to about 10 mg per unit dose. In certain embodiments, the pharmaceutical composition is administered at a dose of about 0.1 mg to about 10 mg per unit dose.

[0238] The pharmaceutical compositions described herein can be prepared by any method known in the art of pharmacology. In general, such methods include the step of bringing into association a composition comprising a compound of formula (I) with the carrier and / or one or more other accessory ingredients, and then, if necessary and / or desirable, shaping and / or packaging the product into the desired single or multi-dosage unit.

[0239] 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. As used herein, a "unit dose" is a discrete amount of a pharmaceutical composition comprising a predetermined amount of an active ingredient. The amount of the active ingredient is generally equal to the dosage of the active ingredient that would be administered to a subject and / or a convenient fraction of such a dosage, for example, one-half or one-third of such a dosage.

[0240] The relative amounts of the active ingredient, pharmaceutically acceptable excipient, and / or any additional ingredients in a pharmaceutical composition of the invention will vary depending on the identity, size, and / or condition of the subject being treated, as well as the route by which the composition is administered. By way of example, the composition may contain from 0.1% to 100% (w / w) of the active ingredient.

[0241] Pharmaceutically acceptable excipients used in the preparation of the provided pharmaceutical compositions include inert diluents, dispersing and / or granulating agents, surfactants and / or emulsifying agents, disintegrating agents, binders, preservatives, buffers, lubricants, and / or oils. Excipients such as cocoa butter and suppository waxes, coloring agents, coating agents, sweetening agents, flavoring agents, and perfuming agents may also be present in the composition.

[0242] Exemplary diluents include calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium lactose phosphate, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, corn starch, powdered sugar, and mixtures thereof.

[0243] Exemplary granulating and / or dispersing agents include potato starch, corn starch, tapioca starch, sodium starch glycolate, clay, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose and wood products, natural sponge, cation exchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked poly(vinylpyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethylcellulose, cross-linked sodium carboxymethylcellulose (croscarmellose), methylcellulose, pregelatinized starch (starch 1500), microcrystalline starch, water insoluble starch, calcium carboxymethylcellulose, magnesium aluminum silicate (Veegum), sodium lauryl sulfate, quaternary ammonium compounds, and mixtures thereof.

[0244] Exemplary surfactants and / or emulsifiers include natural emulsifiers (e.g., acacia, agar, alginic acid, sodium alginate, tragacanth, cartilage, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin), colloidal clays (e.g., bentonite (aluminum silicate) and Veegum (magnesium aluminum silicate)), long-chain amino acid derivatives, high molecular weight alcohols (e.g., stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol), carbomers (e.g., carboxypolymethylene, polyacrylic acid, acrylic acid polymers, and carboxyvinyl polymers), carrageenan, cellulose derivatives (e.g., sodium carboxymethylcellulose, powdered cellulose, hydroxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose), sorbitan fatty acid esters (e.g., poly Oxyethylene sorbitan monolaurate (Tween 20), polyoxyethylene sorbitan (Tween 60), polyoxyethylene sorbitan monooleate (Tween 80), sorbitan monopalmitate (Span 40), sorbitan monostearate (Span 60), sorbitan tristearate (Span 65), glyceryl monooleate, sorbitan monooleate (Span 80)), polyoxyethylene esters (e.g., polyoxyethylene monostearate (Myrj 45), polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan monolaurate (Tween 2 ... polyoxyethylene sorbitan monolaurate (Tween 20), polyoxyethylene sorbitan monolaurate (Tween 60), polyoxyethylene sorbitan monooleate (Tween 80)), polyoxyethylene sorbitan monolaurate (Tween 20), polyoxyethylene sorbitan monolaurate (Tween 60), polyoxyethylene sorbitan monolaurate (Tween 80), polyoxyethylene sorbitan monolaurate (Tween 80), polyoxyethylene sorbitan monolaurate (Tween 80), polyoxyethylene sorbitan monolaurate (Tween 80), polyoxyethylene sorbitan monolaurate (Tween 8 Rethoxylated castor oil, polyoxymethylene stearate and Solutol), sucrose fatty acid esters, polyethylene glycol fatty acid esters (e.g., Cremophor™), polyoxyethylene ethers, (e.g., polyoxyethylene lauryl ether (Brij30)), poly(vinyl-pyrrolidone), diethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, PluronicF-68, Poloxamer-188, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium and / or mixtures thereof.

[0245] Exemplary binders include starches (e.g., corn starch and starch paste), gelatin, sugars (e.g., sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums (e.g., acacia, sodium alginate, extract of Irish moss, panwar gum, ghatti gum, mucilage of isapol husk, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, microcrystalline cellulose, cellulose acetate, poly(vinyl-pyrrolidone), magnesium aluminum silicate (Veegum), and oat arabogalactan), alginates, polyethylene oxide, polyethylene glycol, inorganic calcium salts, silicic acid, polymethacrylates, waxes, water, alcohol, and / or mixtures thereof.

[0246] Exemplary preservatives include antioxidants, chelating agents, antibacterial preservatives, antifungal preservatives, alcohol preservatives, acidic preservatives, and other preservatives. In certain embodiments, the preservative is an antioxidant. In other embodiments, the preservative is a chelating agent.

[0247] Exemplary antioxidants include alpha tocopherol, ascorbic acid, acorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite.

[0248] Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA) and its salts and hydrates (e.g., edetate sodium, edetate disodium, edetate trisodium, edetate calcium disodium, edetate dipotassium, etc.), citric acid and its salts and hydrates (e.g., citric acid monohydrate), fumaric acid and its salts and hydrates, malic acid and its salts and hydrates, phosphoric acid and its salts and hydrates, and tartaric acid and its salts and hydrates. Exemplary antimicrobial preservatives include benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and thimerosal.

[0249] Exemplary antifungal preservatives include butylparaben, methylparaben, ethylparaben, propylparaben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid.

[0250] Exemplary alcohol preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoates, and phenylethyl alcohol.

[0251] Exemplary acidic preservatives include vitamin A, vitamin C, vitamin E, beta-carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and phytic acid.

[0252] Other preservatives include tocopherol, tocopheryl acetate, desulfoxime mesylate, cetrimide, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium bisulfite, sodium metabisulfite, potassium sulfite, potassium metabisulfite, Glydant Plus, Phenonip, methylparaben, Germall 115, Germaben II, Neolone, Kathon, and Euxyl.

[0253] Exemplary buffering agents include citrate buffer, acetate buffer, phosphate buffer, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium gluceptate, calcium gluconate, D-gluconic acid, calcium glycerophosphate, calcium lactate, propanoic acid, calcium levulinate, pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasic calcium phosphate, calcium hydroxide phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixtures, dibasic potassium phosphate, monobasic potassium phosphate, potassium phosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, dibasic sodium phosphate, monobasic sodium phosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, and mixtures thereof.

[0254] Exemplary lubricants include magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behenate, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, and mixtures thereof.

[0255] Exemplary natural oils include almond, apricot kernel, avocado, babassu, bergamot, black current seed, borage, cade, chamomile, canola, caraway, carnauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee, corn, cottonseed, em, eucalyptus, evening primrose, fish, flaxseed, geraniol, gaoud, grape seed, hazelnut, hyssop, isopropyl myristate, jojoba, kuku peanut, lavandin, lavender Oils of daffodil, lemon, taibeba, macadamia nut, mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange, coarse grain, palm, palm kernel, peach kernel, peanut, poppy seed, pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood, sasuna, savory, sea buckthorn, sesame, shea butter, silicone, soybean, sunflower, tea tree, thistle, camellia, vetiver, walnut, and wheat germ. Exemplary synthetic oils include, but are not limited to, butyl stearate, caprylic triglyceride, capric triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and mixtures thereof.

[0256] Liquid dosage forms for oral and parenteral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active ingredient, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, and mixtures thereof. In addition to inert diluents, oral compositions may also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweeteners, flavoring agents, and perfuming agents. In certain embodiments for parenteral administration, the agents of the invention are mixed with solubilizing agents such as CREMOPHOR EL® (polyethoxylated castor oil), alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers, and combinations thereof.

[0257] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions, can be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations can also be sterile injectable solutions, suspensions, or emulsions in non-toxic parenterally acceptable diluents or solvents, such as solutions in 1,3-butanediol. Acceptable vehicles and solvents that can be used include water, Ringer's solution, USP, and isotonic sodium chloride solution. Additionally, sterile fixed oils are conventionally used as solvents or suspending media. For this purpose, any sterile fixed oil can be used, including synthetic monoglycerides or diglycerides. Additionally, fatty acids such as oleic acid are used in the preparation of injectables.

[0258] Injectable preparations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium before use.

[0259] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active agent may be mixed with at least one inert pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and / or a) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders, such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants, such as glycerol, d) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retardants, such as paraffin, f) absorption accelerators, such as quaternary ammonium compounds, g) humectants, such as cetyl alcohol and glycerol monostearate, h) absorbents, such as kaolin and bentonite clay, and i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

[0260] Solid compositions of a similar type can also be used as fillers in soft and hard-filled gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols. Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulation art. They may optionally contain opacifying agents and can be of a composition that releases the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type can also be used as fillers in soft and hard-filled gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols.

[0261] The active agent may also be in microencapsulated form with one or more excipients, as described above. Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings, release-controlling coatings, and other coatings well known in the pharmaceutical formulation art. In such solid dosage forms, the active agent may be mixed with at least one inert diluent, such as sucrose, lactose, or starch. Such dosage forms may also contain, as is common practice, additional substances other than inert diluents, such as tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets, and pills, the dosage forms may also contain buffering agents. They may optionally contain opacifying agents and may be of a composition that releases the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

[0262] Formulations suitable for topical administration include liniments, lotions, gels, applications, liquid or semi-liquid preparations such as oil-in-water or water-in-oil emulsions, e.g., creams, ointments, or pastes; or solutions or suspensions such as droplets. Formulations for topical administration to the skin surface can be prepared by dispersing the drug with a dermatologically acceptable carrier such as lotion, cream, ointment, or soap. Useful carriers can form a film or layer on the skin to localize application and inhibit removal. For topical administration to internal tissue surfaces, the drug can be dispersed in a liquid tissue adhesive or other substance known to enhance adsorption to tissue surfaces. For example, hydroxypropyl cellulose or fibrinogen / thrombin solutions can be advantageously used. Alternatively, tissue-coating solutions such as pectin-containing formulations can be used. Ophthalmic formulations, ear drops, and eye drops are also considered within the scope of the present invention. Furthermore, the present disclosure contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a drug to the body. Such dosage forms can be made by dissolving or dispensing the drug in a suitable vehicle. Absorption enhancers can also be used to increase the flux of the drug across the skin. The rate can be controlled by either providing a rate-controlling membrane or dispersing the drug in a polymer matrix or gel.

[0263] Additionally, carriers for topical formulations can be in the form of aqueous alcoholic systems (e.g., liquids and gels), anhydrous oil or silicone systems, or emulsion systems, including, but not limited to, oil-in-water, water-in-oil, water-in-oil-in-water, and oil-in-water-in-silicone emulsions. Emulsions can cover a wide range of consistencies, including thin lotions (which may also be suitable for spray or aerosol delivery), creamy lotions, light creams, heavy creams, and the like. Emulsions can also include microemulsion systems. Other suitable topical carriers include anhydrous solids and semisolids (such as gels and sticks) and aqueous-based mousse systems.

[0264] Kits (e.g., pharmaceutical packs) are also included in the present disclosure. The provided kits may include a pharmaceutical composition or compound described herein and a container (e.g., a vial, an ampoule, a bottle, a syringe, and / or a dispenser package, or other suitable container). In some embodiments, the provided kits may optionally further include a second container containing a pharmaceutical excipient for diluting or suspending the 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.

[0265] Thus, in one aspect, a kit is provided comprising a first container containing a compound or pharmaceutical composition described herein. In certain embodiments, the kit is useful for treating a disease (e.g., a neurological disease or disorder) in a subject in need thereof. In certain embodiments, the kit is useful for preventing a disease (e.g., a neurological disease or disorder) in a subject in need thereof. In certain embodiments, the kit is useful for reducing the risk of developing a disease (e.g., a neurological disease or disorder) in a subject in need thereof. In certain embodiments, the kit is useful for increasing GCase activity in a subject or cell.

[0266] In certain embodiments, the kits described herein further include instructions for using the kit. The kits described herein may also include information required by regulatory agencies, such as the US Food and Drug Administration (FDA). In certain embodiments, the information included in the kit is prescribing information. In certain embodiments, the kit and instructions provide for treatment of a disease (e.g., a neurological disease or disorder) in a subject in need thereof. In certain embodiments, the kit and instructions provide for prevention of a disease (e.g., a neurological disease or disorder) in a subject in need thereof. In certain embodiments, the kit and instructions provide for reduction of onset of a disease (e.g., a neurological disease or disorder) in a subject in need thereof. In certain embodiments, the kit and instructions provide for increasing GCase activity in a subject or cell. The kits described herein may include one or more additional pharmaceutical agents described herein as separate compositions. Treatment method

[0267] The present disclosure provides methods of treating a disease or disorder in a subject in need thereof. In certain embodiments, the present disclosure provides methods of treating a disease or disorder associated with GCase activity. In certain embodiments, the present application provides methods of treating a neurological disease or disorder. In certain embodiments, the present application provides methods of treating Gaucher disease or Parkinson's disease. In certain embodiments, the present application provides methods of treating Gaucher disease. In certain embodiments, the present application provides methods of treating Parkinson's disease.

[0268] The present disclosure provides methods for activating GCase. The present disclosure provides methods for increasing GCase activity. In certain embodiments, the present application provides methods for activating GCase in vitro (e.g., increasing GCase activity). In certain embodiments, the present application provides methods for activating GCase in vivo (e.g., increasing GCase activity). In certain embodiments, the present application provides methods for increasing GCase activity in cells. In certain embodiments, the present application provides methods for increasing GCase activity in human cells.

[0269] In certain embodiments, the method comprises administering to a subject in need thereof (e.g., a subject having a neurological disease or disorder) a compound that interacts with GCase, e.g., a compound that is a modulator of GCase (e.g., an activator of GCase), a binder of GCase, or a compound that modifies GCase. In certain embodiments, the method comprises administering to a subject in need thereof a compound of the present disclosure (e.g., a compound of Formula (I)), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug, or composition thereof. In some embodiments, the method comprises administering to a subject in need thereof a pharmaceutical composition comprising a compound of the present disclosure (e.g., a compound of Formula (I)), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug, or composition thereof.

[0270] Another object of the disclosure is the use of a compound described herein (e.g., any of the formulas herein) in the manufacture of a medicament for use in treating a disorder or disease described herein. Another object of the disclosure is the use of a compound described herein (e.g., any of the formulas herein) for use in treating a disorder or disease described herein. [Example]

[0271] In order that the invention described herein may be more fully understood, the following examples are set forth. The examples described in this application are provided to illustrate the compounds, pharmaceutical compositions, and methods provided herein, and should not be construed in any way as limiting the scope thereof.

[0272] Synthesis method The compounds of formula (I) were prepared according to the synthetic schemes and procedures detailed below. The examples described in this application are provided to illustrate the compounds, pharmaceutical compositions, and methods provided herein and should not be construed as limiting the scope thereof in any way. Compounds of the present disclosure not explicitly described in the procedures below can be prepared by similar methods. Those skilled in the art will understand how to make such compounds from the disclosure provided herein and by means known in the art of organic synthesis. For example, those described in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T.W. Greene and P.G.M. Buts, Protective Groups in Organic Synthesis, 2d. Ed., John Wiley & Sons (1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley & Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley & Sons (1995) and subsequent editions are representative and useful. Methods for optimizing reaction conditions, and if necessary, minimizing competition from products, are known in the art. General Procedure A [ka]

[0273] tert-Butyl (1R,5S,6S)-6-({[2-(trifluoromethyl)pyridin-3-yl]oxy}methyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate: To a stirred mixture of 2-(trifluoromethyl)pyridin-3-ol (191 mg, 1.17 mmol, 1.00 equiv.) and tert-butyl (1R,5S,6r)-6-(hydroxymethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (250 mg, 1.17 mmol, 1.00 equiv.) in THF (10 mL) was added PPh3 (492 mg, 1.88 mmol, 1.60 equiv.) and TMAD (323 mg, 1.88 mmol, 1.6 equiv.) in portions at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. The residue was purified by silica gel column chromatography eluting with hexane / EtOAc (3:1) to give tert-butyl (1R,5S,6S)-6-({[2-(trifluoromethyl)pyridin-3-yl]oxy}methyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (390 mg, 92.8%) as a pale yellow oil. LCMS (ES, m / z): 359 [M+H] + . General Procedure B [ka]

[0274] (1R,5S,6S)-6-({[2-(trifluoromethyl)pyridin-3-yl]oxy}methyl)-3-azabicyclo[3.1.0]hexane hydrochloride: To a stirred solution of tert-butyl (1R,5S,6S)-6-({[2-(trifluoromethyl)pyridin-3-yl]oxy}methyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (390 mg, 1.09 mmol, 1.00 equiv) in DCM (5 mL) was added HCl (gas) in 1,4-dioxane (4 M, 5.4 mL). The resulting mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated to dryness in vacuo. The crude product (1R,5S,6S)-6-({[2-(trifluoromethyl)pyridin-3-yl]oxy}methyl)-3-azabicyclo[3.1.0]hexane hydrochloride (300 mg, 94%) was used directly in the next step without further purification. MS m / z: 259 [M+H] + . General Procedure C [ka]

[0275] (1R,5S,6S)-3-[1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-6-({[2-(trifluoromethyl)pyridin-3-yl]oxy}methyl)-3-azabicyclo[3.1.0]hexane: To a stirred solution of (1R,5S,6S)-6-({[2-(trifluoromethyl)pyridin-3-yl]oxy}methyl)-3-azabicyclo[3.1.0]hexane hydrochloride (16.2 mg, 0.055 mmol, 1.00 equiv) and 6-chloro-1-(2,2-difluoroethyl)pyrazolo[3,4-b]pyrazine (12.0 mg, 0.055 mmol, 1.00 equiv) in DMF (1 mL) was added KCO (15.2 mg, 0.11 mmol, 2 equiv). The resulting mixture was stirred at 60°C for 16 hours. The excess solid was filtered off through Celite, and the filtrate was concentrated under vacuum. The product was purified by silica gel column chromatography eluting with hexane / EtOAc (3:1 to 1:1) to give (1R,5S,6S)-3-[1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-6-({[2-(trifluoromethyl)pyridin-3-yl]oxy}methyl)-3-azabicyclo[3.1.0]hexane as a white powder (16 mg, 66.2%). MS m / z: 441.2 [M+H] + . General Procedure D [ka]

[0276] tert-Butyl (1R,5S,6S)-6-({[6-(trifluoromethyl)pyridin-2-yl]oxy}methyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate: To a solution of tert-butyl (1R,5S,6S)-6-(hydroxymethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (250 mg, 1.17 mmol) in DMF (3.00 mL) was added NaH (51.6 mg, 1.1 equiv., 60% w / w, 1.29 mmol) at 0° C., warmed to room temperature, and stirred for 15 minutes. 2-Bromo-6-(trifluoromethyl)pyridine (265 mg, 1.17 mmol) was added to the mixture, and the mixture was heated at 60° C. for 4 hours. The reaction was monitored by LCMS. The mixture was diluted with water and extracted with EtOAc (20 mL×2). The organic layer was washed with brine, dried, filtered, evaporated and purified by Combi-Flash to give tert-butyl (1R,5S,6S)-6-({[6-(trifluoromethyl)pyridin-2-yl]oxy}methyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (360 mg, 86) as a colorless oil. General Procedure E [ka]

[0277] (5-Methyl-6-phenyl-5H-pyrrolo[2,3-b]pyrazin-3-yl)(3-(((2-(trifluoromethyl)pyridin-3-yl)oxy)methyl)piperidin-1-yl)methanone: To a stirred solution of 5-methyl-6-phenyl-5H-pyrrolo[2,3-b]pyrazine-3-carboxylic acid (100 mg, 0.395 mmol, 1.00 equiv) and HATU (165 mg, 0.435 mmol, 1.1 equiv) in DMF (1.5 mL) was added DIEA (204 mg, 1.58 mmol, 4 equiv) and 3-(piperidin-3-ylmethoxy)-2-(trifluoromethyl)pyridine hydrochloride (140 mg, 0.474 mmol, 1.2 equiv) dropwise at 0° C. The resulting mixture was stirred at 0° C. for 3 hours. The desired product could be detected by LCMS. The reaction mixture was diluted with EtOAc (20 mL), washed with water (2 × 20 mL) and brine (1 × 20 mL), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, ACN in water, gradient 0% to 100% in 30 min; detector, UV 254 nm. This afforded (5-methyl-6-phenyl-5H-pyrrolo[2,3-b]pyrazin-3-yl)(3-(((2-(trifluoromethyl)pyridin-3-yl)oxy)methyl)piperidin-1-yl)methanone (60 mg, 29.3%) as a yellow solid. MS m / z: 496.2 [M+H] + (1R,5S,6S)-3-[1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-6-({[2-(trifluoromethyl)pyridin-3-yl]oxy}methyl)-3-azabicyclo[3.1.0]hexane (1) [ka]

[0278] General procedure C was followed using (1R,5S,6S)-6-({[2-(trifluoromethyl)pyridin-3-yl]oxy}methyl)-3-azabicyclo[3.1.0]hexane hydrochloride (16.2 mg, 0.055 mmol, 1.00 equiv) and 6-chloro-1-(2,2-difluoroethyl)pyrazolo[3,4-b]pyrazine (12.0 mg, 0.055 mmol, 1.00 equiv) to give (1R,5S,6S)-3-[1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-6-({[2-(trifluoromethyl)pyridin-3-yl]oxy}methyl)-3-azabicyclo[3.1.0]hexane as a white powder (16 mg, 66.2%). 1 H NMR(500 MHz,CDCl3)δ 8.26(dd,J=4.6,1.2 Hz,1H),8.02(s,1H),7.91(s,1H),7.43(dd,J=8.5,4.5 Hz,1H),7.34(dd,J=8.3,1.2 Hz,1H),6.21(tt,J=55.7,4.5 Hz,1H),4.64(td,J=13.4,4.5 Hz,2H),4.11(d,J=6.2 Hz,2H),3.94(d,J=10.8 Hz,2H),3.66(dt,J=10.7,2.1 Hz,2H),1.92(td,J=3.2,1.3 Hz,2H),1.23-1.20(m,1H).MS m / z:441.2[M+H] + . (1R,5S,6r)-3-[1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-6-({[2-(trifluoromethyl)pyridin-3-yl]oxy}methyl)-3-azabicyclo[3.1.0]hexane (2) [ka]

[0279] Step 1: tert-Butyl (1R,5S,6r)-6-(((6-(trifluoromethyl)pyridin-3-yl)oxy)methyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate: To a stirred mixture of 2-(trifluoromethyl)pyridin-3-ol (191 mg, 1.17 mmol, 1.00 equiv) and tert-butyl (1R,5S,6r)-6-(hydroxymethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (250 mg, 1.17 mmol, 1.00 equiv) in THF (10 mL) was added PPh3 (492 mg, 1.88 mmol, 1.60 equiv) and TMAD (323 mg, 1.88 mmol, 1.6 equiv) in portions at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. The residue was purified by silica gel column chromatography eluting with hexane / EtOAc (3:1) to give tert-butyl (1R,5S,6r)-6-(((6-(trifluoromethyl)pyridin-3-yl)oxy)methyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (390 mg, 92.8%) as a pale yellow oil. LCMS (ES, m / z): 359 [M+H] + .

[0280] Step 2: (1R,5S,6r)-6-(((6-(trifluoromethyl)pyridin-3-yl)oxy)methyl)-3-azabicyclo[3.1.0]hexane hydrochloride: To a stirred solution of tert-butyl (1R,5S,6r)-6-(((6-(trifluoromethyl)pyridin-3-yl)oxy)methyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (390 mg, 1.09 mmol, 1.00 equiv) in DCM (5 mL) was added HCl (gas) in 1,4-dioxane (4 M, 5.4 mL). The resulting mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated to dryness in vacuo. The crude product (1R,5S,6r)-6-(((6-(trifluoromethyl)pyridin-3-yl)oxy)methyl)-3-azabicyclo[3.1.0]hexane hydrochloride (300 mg, 94%) was used directly in the next step without further purification. MS m / z: 259 [M+H] + .

[0281] Step 3: (1R,5S,6r)-3-[1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-6-({[2-(trifluoromethyl)pyridin-3-yl]oxy}methyl)-3-azabicyclo[3.1.0]hexane: (1R,5S,6r)-6-(((6-(trifluoromethyl)pyridine-3 To a stirred solution of (-yl)oxy)methyl)-3-azabicyclo[3.1.0]hexane hydrochloride (16.2 mg, 0.055 mmol, 1.00 equiv) and 6-chloro-1-(2,2-difluoroethyl)pyrazolo[3,4-b]pyrazine (12.0 mg, 0.055 mmol, 1.00 equiv) was added K2CO3 (15.2 mg, 0.11 mmol, 2 equiv). The resulting mixture was stirred at 60 °C for 16 h. The reaction mixture was diluted with water (10 mL) and stirred at room temperature for 15 min. The solid that formed was filtered, washed with water, and dried to give 16 mg (66.2%) of (1R,5S,6r)-3-[1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-6-({[2-(trifluoromethyl)pyridin-3-yl]oxy}methyl)-3-azabicyclo[3.1.0]hexane as a white powder. 1 H NMR(500 MHz,CDCl3)δ 8.26(dd,J=4.6,1.2 Hz,1H),8.02(s,1H),7.91(s,1H),7.43(dd,J=8.5,4.5 Hz,1H),7.34(dd,J=8.3,1.2 Hz,1H),6.21(tt,J=55.7,4.5 Hz,1H),4.64(td,J=13.4,4.5 Hz,2H),4.11(d,J=6.2 Hz,2H),3.94(d,J=10.8 Hz,2H),3.66(dt,J=10.7,2.1 Hz,2H),1.92(td,J=3.2,1.3 Hz,2H),1.23-1.20(m,1H).MS m / z:441.2[M+H] + . (3-(phenoxymethyl)piperidin-1-yl)(5-(1-phenylcyclopentyl)-1,3,4-oxadiazol-2-yl)methanone (3) [ka]

[0282] Step 1: Ethyl 3-(2-benzoylhydrazinyl)-3-oxopropanoate: To a stirred solution of ethyl (hydrazinecarbonyl)formate (583 mg, 4.42 mmol, 1.20 equiv) and 1-phenylcyclopentane-1-carboxylic acid (700 mg, 3.68 mmol, 1.00 equiv) in DCM (12 mL) was added HATU (2.10 g, 5.52 mmol, 1.5 equiv) and DIPEA (713 mg, 5.52 mmol, 1.5 equiv) dropwise at 0 °C. The resulting mixture was stirred at room temperature for 3 h. The reaction was diluted with water (20 mL) and extracted with DCM (25 mL × 2). The combined organic phase was washed with water (20 mL), brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated to dryness in vacuo to give the crude product. This was purified by silica gel chromatography (Flash 40 g, 40-60% EtOAc:PE) to give ethyl 2-oxo-2-(2-(1-phenylcyclopentane-1-carbonyl)hydrazineyl)acetate (800 mg, 60.7%) as a pale yellow oil. MS m / z: 305 [M+H] + .

[0283] Step 2: Ethyl 5-(1-phenylcyclopentyl)-1,3,4-oxadiazole-2-carboxylate: A solution of ethyl 2-oxo-2-(2-(1-phenylcyclopentane-1-carbonyl)hydrazinyl)acetate (800 mg, 2.629 mmol, 1.00 equiv) in POCl3 (10.0 mL) was stirred at 100 °C for 2 h. The resulting mixture was concentrated to dryness in vacuo. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 5% to 95% gradient in 15 min; detector, UV 254 nm to give ethyl 5-(1-phenylcyclopentyl)-1,3,4-oxadiazole-2-carboxylate (600 mg, 71.7%) as a white solid. MS m / z: 267 [M+H] + .

[0284] Step 3: 5-(1-Phenylcyclopentyl)-1,3,4-oxadiazole-2-carboxylic acid: To a solution of ethyl 5-(1-phenylcyclopentyl)-1,3,4-oxadiazole-2-carboxylate (450 mg, 1.572 mmol, 1.00 equiv.) in MeOH (2 mL) was added NaOH (96.6 mg, 2.41 mmol, 3 equiv.) in water (1.00 mL). The mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated to dryness in vacuo. The resulting mixture was then purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 5% to 95% gradient in 15 min; detector, UV 254 nm to give 5-(1-phenylcyclopentyl)-1,3,4-oxadiazole-2-carboxylic acid (300 mg) as a white solid. MS m / z: 259 [M+H] + .

[0285] Step 4: (3-(Phenoxymethyl)piperidin-1-yl)(5-(1-phenylcyclopentyl)-1,3,4-oxadiazol-2-yl)methanone: To a stirred solution of 5-(1-phenylcyclopentyl)-1,3,4-oxadiazole-2-carboxylic acid (150 mg, 0.581 mmol, 1.00 equiv) and 3-(phenoxymethyl)piperidine (133 mg, 0.697 mmol, 1.2 equiv) in DMF (2 mL) was added dropwise HATU (331 mg, 0.871 mmol, 1.5 equiv) and DIPEA (112 mg, 0.871 mmol, 1.5 equiv) at 0° C. The resulting mixture was stirred at room temperature for an additional 3 h. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (15 mL×2). The combined organic layers were washed with brine (3 × 10 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated to dryness under reduced pressure. The residue was purified by reverse-phase Combi-Flash using the following conditions: column, C18 gel; mobile phase, aqueous MeCN (0.1% FA), 20% to 70% gradient in 16 min; detector, UV 254 nm. This afforded (3-(phenoxymethyl)piperidin-1-yl)(5-(1-phenylcyclopentyl)-1,3,4-oxadiazol-2-yl)methanone (30.0 mg, 11.49%) as a white solid.1 H NMR(400 MHz,DMSO-d6)δ 8.61-8.50(m,2H),8.36-8.32(m,1H),8.15(s,1H),8.13-8.04(m,1H),6.60-6.27(m,1H),4.75-4.66(m,3H),4.38-4.35(m MS m / z:432.2[M+H] + . 2-(1,3,4-thiadiazol-2-yl)-6-[3-({[2-(trifluoromethoxy)pyridin-3-yl]oxy}methyl)piperidin-1-yl]pyrazine (4) [ka]

[0286] Step 1: tert-Butyl 3-({[2-(trifluoromethoxy)pyridin-3-yl]oxy}methyl)piperidine-1-carboxylate: To a stirred mixture of 2-(trifluoromethoxy)pyridin-3-ol (250 mg, 1.40 mmol, 1.00 equiv) and tert-butyl 3-(hydroxymethyl)piperidine-1-carboxylate (300 mg, 1.40 mmol, 1.00 equiv) in THF (6 mL) was added PPh3 (586 mg, 2.23 mmol, 1.60 equiv) and TMAD (384 mg, 2.23 mmol, 1.6 equiv) in portions under a nitrogen atmosphere at 0° C. The resulting mixture was stirred at room temperature under a nitrogen atmosphere overnight. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (1:1) to give tert-butyl 3-({[2-(trifluoromethoxy)pyridin-3-yl]oxy}methyl)piperidine-1-carboxylate (460 mg, 87.6%) as an off-white solid. LCMS (ES, m / z): 377 [M+H] + .

[0287] Step 2: 3-(piperidin-3-ylmethoxy)-2-(trifluoromethoxy)pyridine hydrochloride: To a stirred solution of tert-butyl 3-({[2-(trifluoromethoxy)pyridin-3-yl]oxy}methyl)piperidine-1-carboxylate (460 mg, 1.22 mmol, 1.00 equiv) in DCM (8 mL) was added HCl (gas) in 1,4-dioxane (4 M, 4 mL). The resulting mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated to dryness in vacuo. The crude product, 3-(piperidin-3-ylmethoxy)-2-(trifluoromethoxy)pyridine hydrochloride (380 mg), was used directly in the next step without further purification. MS m / z: 277 [M+H] + .

[0288] Step 3: 2-(1,3,4-Thiadiazol-2-yl)-6-[3-({[2-(trifluoromethoxy)pyridin-3yl]oxy}methyl)-piperidin-1-yl]pyrazine: To a stirred mixture of 2-chloro-6-(1,3,4-thiadiazol-2-yl)-pyrazine (40.0 mg, 0.201 mmol, 1.00 equiv) and 3-(piperidin-3-ylmethoxy)-2-(trifluoromethoxy)pyridine hydrochloride (75.6 mg, 0.241 mmol, 1.20 equiv) in DMF (3 mL) was added NaCO (42.7 mg, 0.402 mmol, 2.00 equiv). The resulting mixture was stirred at 80° C. for 8 hours. The resulting mixture was diluted with water (15 mL) and extracted with EtOAc (15 mL×3). The combined organic layers were washed with brine (2 × 20 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated to dryness under reduced pressure. The residue was purified by back-flash chromatography using the following conditions: column, C18 gel; mobile phase, MeCN in water, 30% to 70% gradient in 20 min; detector, UV 254 nm. This afforded 2-(1,3,4-thiadiazol-2-yl)-6-[3-({[2-(trifluoromethoxy)pyridin-3-yl]oxy}methyl)piperidin-1-yl]pyrazine (45.1 mg, 51.1%) as a pale yellow solid. 1H NMR(300MHz,DMSO-d6):δ 9.73(s,1H),8.59(s,1H),8.48(s,1H),7.91-7.86(m,1H),7.78-7.70(m,1H),7.45-7.36(m,1H),4.48-4.35(m,1H),4.31-4. 18(m,1H),4.16-4.04(m,2H),3.23-3.01(m,2H),2.21-2.06(m,1H),2.00-1.88(m,1H),1.87-1.76(m,1H),1.70-1.39(m,2H). 19 F NMR(282 MHz,DMSO-d6):δ-54.651.MS m / z:439.10[M+H] + . 1-(2,2-difluoroethyl)-6-((S)-3-((S)-1-(2-(trifluoromethyl)phenoxy)ethyl)piperidin-1-yl)-1H-pyrazolo[3,4-b]pyrazine (5a) and 1-(2,2-difluoroethyl)-6-((R)-3-((R)-1-(2-(trifluoromethyl)phenoxy)ethyl)piperidin-1-yl)-1H-pyrazolo[3,4-b]pyrazine (5b); trans-racemic-1-(2,2-difluoroethyl)-1-(2-(trifluoromethyl)phenoxy)ethyl)piperidin-1-yl)-1H-pyrazolo[3,4-b]pyrazine (5c). [ka]

[0289] Step 1: tert-Butyl 3-(1-(2-(trifluoromethyl)phenoxy)ethyl)piperidine-1-carboxylate: To a stirred mixture of tert-butyl 3-(1-hydroxyethyl)piperidine-1-carboxylate (1.00 g, 4.65 mmol, 1.00 equiv), 2-(trifluoromethyl)phenol (758 mg, 4.65 mmol, 1 equiv), and PPh3 (1.95 g, 7.44 mmol, 1.6 equiv) in THF (10 mL) was added TMAD (1.28 g, 7.44 mmol, 1.6 equiv) in portions at 0 °C. The resulting mixture was allowed to warm to room temperature and stirred at room temperature overnight. The resulting mixture was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography eluting with EtOAc / PE (1 / 2) to give tert-butyl 3-(1-(2-(trifluoromethyl)phenoxy)ethyl)piperidine-1-carboxylate (600 mg, 49.7%) as a colorless oil. MS m / z: 318 [M-tBu+H] + .

[0290] Step 2: 3-(Piperidin-3-ylmethoxy)-2-(trifluoromethyl)pyridine hydrochloride: To a stirred solution of tert-butyl 3-(1-(2-(trifluoromethyl)phenoxy)ethyl)piperidine-1-carboxylate (500 mg, 1.38 mmol, 1.00 equiv) in DCM (2.5 mL) was added HCl (gas) in dioxane (4 M, 2.5 mL). The mixture was stirred at room temperature for 2 hours. After removal of the solvent, the crude product, 3-(1-(2-(trifluoromethyl)phenoxy)ethyl)piperidine hydrochloride (360 mg), was used directly in the next step without further purification. MS m / z: 261 [M+H] +

[0291] Step 3: 1-(2,2-Difluoroethyl)-6-(3-(1-(2-(trifluoromethyl)phenoxy)ethyl)piperidin-1-yl)-1H-pyrazolo[3,4-b]pyrazine: To a stirred solution of 3-(1-(2-(trifluoromethyl)phenoxy)ethyl)piperidine (120 mg, 0.585 mmol, 1.00 equiv) and 6-chloro-1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazine (153 mg, 0.702 mmol, 1.2 equiv) in DMF (2 mL) was added NaCO (381 mg, 1.17 mmol, 2 equiv) at 0° C. The resulting mixture was stirred at 100° C. for 2 h. The reaction mixture was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, ACN in water, 0% to 100% gradient in 30 min; detector, UV 254 nm. This gave 1-(2,2-difluoroethyl)-6-(3-(1-(2-(trifluoromethyl)phenoxy)ethyl)piperidin-1-yl)-1H-pyrazolo[3,4-b]pyrazine (150 mg, 24.2%) as a yellow oil. The mixture was purified by preparative HPLC to give the trans racemate (40.5 mg, 27.3%, postulated structure) and the cis racemate (5c, 80.0 mg, 53.3%, postulated structure). The cis racemate (80.0 mg, 53.3%, assumed structure) was purified by chiral HPLC to give 1-(2,2-difluoroethyl)-6-((S)-3-((S)-1-(2-(trifluoromethyl)phenoxy)ethyl)piperidin-1-yl)-1H-pyrazolo[3,4-b]pyrazine (5a; 20.0 mg, 25.0%, assumed structure) as a colorless oil and 1-(2,2-difluoroethyl)-6-((R)-3-((R)-1-(2-(trifluoromethyl)phenoxy)ethyl)piperidin-1-yl)-1H-pyrazolo[3,4-b]pyrazine (5b; 20.0 mg, 25.0%) as a colorless oil. 1H NMR(400 MHz,DMSO-d6)δ 8.42(s,1H),8.11(s,1H),7.62-7.58(m,2H),7.32-7.29(m,2H),7.08-7.04(m,1H),6.54-6 .26(m,1H),4.74-4.47(m,5H),3.02-2.96(m,2H),1.95-1.81(m,3H),1.30-1.29(m,3H).MS m / z:456.2[M+H] + . 3-({1-[1-(2,2-difluoroethyl)pyrazolo[3,4-b]pyrazin-6-yl]piperidin-3-yl}methoxy)-2-(trifluoromethyl)pyridine (13) [ka]

[0292] Step 1: 6-chloro-1-(2,2-difluoroethyl)pyrazolo[3,4-b]pyrazine: To a stirred mixture of 6-chloro-1H-pyrazolo[3,4-b]pyrazine (180 mg, 1.16 mmol, 1.00 equiv.) and 2,2-difluoroethyl trifluoromethanesulfonate (373 mg, 1.75 mmol, 1.5 equiv.) in DMF (2 mL) was added CsCO (1.14 g, 3.50 mmol, 3 equiv.). The resulting mixture was stirred at room temperature for 3 hours. The reaction was diluted with water (20 mL) and extracted with EtOAc (20 mL x 2). The combined organic phase was washed with water (40 mL), brine (40 mL), dried over anhydrous NaSO, filtered, and concentrated to dryness in vacuo to give the crude product. This was purified by silica gel chromatography (Flash 40 g, 40-60% EA:PE) to give 6-chloro-1-(2,2-difluoroethyl)pyrazolo[3,4-b]pyrazine (130 mg, 51.1%) as a yellow solid. LCMS (ES, m / z): 219 [M+H] + .

[0293] Step 2: 3-({1-[1-(2,2-difluoroethyl)pyrazolo[3,4-b]pyrazin-6-yl]piperidin-3-yl}methoxy)-2-(trifluoromethyl)pyridine: To a stirred solution of 6-chloro-1-(2,2-difluoroethyl)pyrazolo[3,4-b]pyrazine (50.0 mg, 0.229 mmol, 1.00 equiv) and CsCO (223 mg, 0.687 mmol, 3 equiv) in DMF (1 mL) was added 3-(piperidin-3-ylmethoxy)-2-(trifluoromethyl)pyridine hydrochloride (81.4 mg, 0.275 mmol, 1.2 equiv). The resulting mixture was stirred at 80° C. for 4 hours. The resulting mixture was diluted with water (20 mL) and extracted with EtOAc (3×15 mL). The combined organic layers were washed with brine (30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography eluting with EtOAc / PE (1:1) to give the product. The product was further purified by reverse-phase Combi-Flash chromatography using the following conditions (column: C18 gel; mobile phase: B phase: MeCN, A phase: water; gradient of 35% to 75% B in 20 min; detector: UV 254 / 220 nm). The pure fractions were concentrated under vacuum to give 3-({1-[1-(2,2-difluoroethyl)pyrazolo[3,4-b]pyrazin-6-yl]piperidin-3-yl}methoxy)-2-(trifluoromethyl)pyridine (20.0 mg, 19.8%) as a yellow solid. 1 H NMR(400 MHz,DMSO-d6)δ 8.43(s,1H),8.27-8.26(m,1H),8.12(s,1H),7.83-7.81(m,1H),7.71-7.68(m,1H),6.55-6.25(m,1H),4.78-4.56(m,3H),4.41-4.37(m MS m / z:443.05[M+H] + . 2-(6-(3-((o-tolyloxy)methyl)piperidin-1-yl)pyrazin-2-yl)-1,3,4-thiadiazole (14) [ka]

[0294] Step 1: Ethyl 2-(2-(6-chloropyrazine-2-carbonyl)hydrazinyl)-2-oxoacetate: To a stirred solution of 6-chloropyrazine-2-carboxylic acid (2.00 g, 12.6 mmol, 1.0 equiv) and HATU (4.81 g, 12.6 mmol, 1.0 equiv) in DMF (20 mL) were added DIEA (4.76 g, 37.8 mmol, 3 equiv) and ethyl 2-hydrazinyl-2-oxoacetate (1.66 g, 12.6 mmol, 1.0 equiv) sequentially at 0 °C. The resulting mixture was stirred at room temperature for 3 h. The reaction was diluted with water (100 mL) and extracted with EtOAc (60 mL × 2). The combined EtOAc phase was washed with water (100 mL), brine (100 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo to give the crude product. This was purified by chromatography on silica gel (Flash 40 g, 40-60% EtOAc:PE) to give ethyl 2-(2-(6-chloropyrazine-2-carbonyl)hydrazinyl)-2-oxoacetate (2.00 g, 58.3%) as a colorless oil. MS m / z: 273 [M+H] + .

[0295] Step 2: Ethyl 5-(6-chloropyrazin-2-yl)-1,3,4-thiadiazole-2-carboxylate: A solution of ethyl 2-(2-(6-chloropyrazine-2-carbonyl)hydrazinyl)-2-oxoacetate (1.00 g, 3.67 mmol, 1 equiv.) and Lawesson's reagent (891 mg, 2.20 mmol, 0.6 equiv.) in toluene (10 mL) was stirred at 100 °C for 16 h. The reaction mixture was purified by silica gel chromatography (Flash 40 g, 40-60% EtOAc:PE) to afford ethyl 5-(6-chloropyrazin-2-yl)-1,3,4-thiadiazole-2-carboxylate (460 mg, 46.4%) as a colorless oil. MS m / z: 271 [M+H] + .

[0296] Step 3: 2-(6-chloropyrazin-2-yl)-1,3,4-thiadiazole: To a stirred solution of ethyl 5-(6-chloropyrazin-2-yl)-1,3,4-thiadiazole-2-carboxylate (460 mg, 1.70 mmol, 1.00 equiv) in dioxane (5 mL) was added dropwise HCl concentrate (1 mL) at room temperature. The resulting mixture was stirred at 100 °C for 2 h. The resulting mixture was concentrated to dryness in vacuo. The residue was purified by silica gel chromatography (Flash 40 g, 40-60% EtOAc:PE) to afford 2-(6-chloropyrazin-2-yl)-1,3,4-thiadiazole (270 mg, 80.2%) as a white solid. MS m / z: 199 [M+H] + .

[0297] Step 4: tert-Butyl 3-((o-tolyloxy)methyl)piperidine-1-carboxylate: To a stirred mixture of tert-butyl 3-(hydroxymethyl)piperidine-1-carboxylate (1.00 g, 4.65 mmol, 1.00 equiv), o-cresol (502 mg, 4.65 mmol, 1 equiv), and PPh3 (1949 mg, 7.44 mmol, 1.6 equiv) in THF (10 mL) was added TMAD (1.280 g, 7.44 mmol, 1.6 equiv) in portions at 0 °C. The resulting mixture was allowed to warm to room temperature and stirred at room temperature overnight. The resulting mixture was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography eluting with EtOAc / PE (1 / 2) to give tert-butyl 3-((o-tolyloxy)methyl)piperidine-1-carboxylate (1.00 g, 70.5%) as a colorless oil. MS m / z: 250 [M-tBu+H] +

[0298] Step 5: 3-((o-Tolyloxy)methyl)piperidine hydrochloride: tert-Butyl 3-((o-tolyloxy)methyl)piperidine-1-carboxylate (1.00 g, 3.27 mmol, 1.00 equiv) was dissolved in DCM (5 mL) / HCl (gas) in dioxane (4 M, 5 mL). The mixture was stirred at room temperature for 1 hour. After removal of the solvent, the crude product 3-((o-tolyloxy)methyl)piperidine hydrochloride (750 mg) was used directly in the next step without further purification. MS m / z: 206 [M+H] +

[0299] Step 6: 2-(6-(3-((o-Tolyloxy)methyl)piperidin-1-yl)pyrazin-2-yl)-1,3,4-thiadiazole: To a stirred solution of 3-((o-tolyloxy)methyl)piperidine hydrochloride (90.0 mg, 0.425 mmol, 1 equiv) and 2-(6-chloropyrazin-2-yl)-1,3,4-thiadiazole (82.1 mg, 0.425 mmol, 1.00 equiv) in DMF (2 mL) was added CsCO (481 mg, 1.28 mmol, 3 equiv). The resulting mixture was stirred at 100° C. under a nitrogen atmosphere for 2 hours. The resulting mixture was diluted with water (20 mL) and extracted with EtOAc (3×15 mL). The combined organic layers were washed with brine (30 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography eluting with EtOAc / PE (1:1) to give the product. The product was further purified by reverse-phase Combi-Flash chromatography using the following conditions (column: C18 gel; mobile phase: B phase: MeCN, A phase: water; B gradient from 35% to 75% in 20 min; detector: UV 254 / 220 nm). The pure fractions were concentrated in vacuo to give 2-(6-(3-((o-tolyloxy)methyl)piperidin-1-yl)pyrazin-2-yl)-1,3,4-thiadiazole (31.0 mg, 19.7%) as a yellow-green solid. 1 H NMR(300 MHz,DMSO-d6)δ 9.73(s,1H),8.59(s,1H),8.51(s,1H),7.19-7.07(m,2H),6.93(d,J=8.0 Hz,1H),6.89-6.78(m,1H),4.63-4.53(m,1H),4.28(d,J=13.4 Hz,1H),4.05-3.84(m,2H),3.19-3.06(m,1H),3.00(dd,J=13.1,10.3 Hz,1H),2.25(s,3H),2.16-2.03(m,1H),1.98-1.87(m,1H),1.87-1.75(m,1H),1.67-1.39(m,2H).MS m / z:368.15[M+H] + . (3-(2-methylphenethyl)piperidin-1-yl)(2-phenyl-2H-1,2,3-triazol-4-yl)methanone (15) [ka]

[0300] Step 1: (2-Methylbenzyl)triphenylphosphonium: A solution of 1-(chloromethyl)-2-methylbenzene (500 mg, 3.6 mmol, 1 equiv.) and PPh3 (1.0 g, 3.9 mmol, 1.1 equiv.) in toluene (15 mL) was stirred at 100 °C for 16 h. The reaction mixture was cooled to room temperature, then filtered, and the filter cake was washed with toluene (3 × 10 mL) to give (2-methylbenzyl)triphenylphosphonium (1.01 g, 70.2%) as a white solid. MS m / z: 367 [M+H] + .

[0301] Step 2: tert-Butyl (E)-3-(2-methylstyryl)piperidine-1-carboxylate: To a stirred mixture of (2-methylbenzyl)triphenylphosphonium chloride (800.0 mg, 1.99 mmol, 1.20 equiv) in THF (20.00 mL) under a N atmosphere at −78° C. was added n-BuLi (2.5 M in THF, 0.79 mL, 1.2 equiv) dropwise. The resulting mixture was warmed to 0° C. and stirred at 0° C. under a N atmosphere for 1 hour. The reaction was then cooled to −78° C. To the stirred solution was added tert-butyl 3-formylpiperidine-1-carboxylate (353.0 mg, 1.65 mmol, 1.00 equiv) in THF (1.00 mL) dropwise at −78° C. under a N atmosphere. The resulting mixture was allowed to warm to room temperature and stirred under a N2 atmosphere at room temperature for 8 hours. The reaction was quenched with saturated aqueous NH4HCO3 at 0 °C. The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (1 x 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EtOAc / PE (1 / 3) to give (E)-tert-butyl 3-(2-methylstyryl)piperidine-1-carboxylate (350.0 mg, 70.0%) as a colorless oil. MS m / z: 302 [M+H] + .

[0302] Step 3: tert-Butyl 3-(2-methylphenethyl)piperidine-1-carboxylate: To a solution of tert-butyl (E)-3-(2-methylstyryl)piperidine-1-carboxylate (350.0 mg, 1.1 mmol, 1.00 equiv) in MeOH (5.00 mL) was added Pt / C (10% w / w, 35.0 mg). The resulting mixture was hydrogenated under H2 (1 atm) at room temperature overnight. The reaction was filtered through celite, and the filtrate was concentrated. Product tert-butyl 3-(2-methylphenethyl)piperidine-1-carboxylate (320 mg, 91.0%). MS m / z: 304 [M+H] + .

[0303] Step 4: 3-(2-Methylphenethyl)piperidine Hydrochloride: To a stirred solution of tert-butyl 3-(2-methylphenethyl)piperidine-1-carboxylate (300 mg, 0.99 mmol, 1.00 equiv) in DCM (4 mL) was added HCl (gas) in 1,4-dioxane (4 M, 4 mL) dropwise at 0 °C. The resulting mixture was stirred at room temperature for 2 h. The resulting mixture was concentrated to dryness in vacuo. This afforded 3-(2-methylphenethyl)piperidine hydrochloride (200 mg, 84.0%) as a white solid. MS m / z: 204.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ9.04(s,1H),8.81(s,1H),7.13-7.05(m,4H),3.35-3.17 (m,2H),2.74-2.53(m,4H),2.25(s,3H),1.89-1.75(m,4H),1.48-1.19(m,3H).MS m / z:204.2[M+H] + .

[0304] Step 5: (3-(2-Methylphenethyl)piperidin-1-yl)(2-phenyl-2H-1,2,3-triazol-4-yl)methanone: To a stirred solution of 2-phenyl-2H-1,2,3-triazole-4-carboxylic acid (21.6 mg, 0.11 mmol, 1.00 equiv) and HATU (47.7 mg, 0.12 mmol, 1.1 equiv) in DMF (2 mL) was added DIPEA (60 μL, 0.34 mmol, 3.0 equiv) and 3-(2-methylphenethyl)piperidine hydrochloride (27.5 mg, 0.11 mmol, 1.00 equiv) sequentially at room temperature. The resulting mixture was stirred at room temperature for an additional 16 h. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (15 mL × 2). The combined organic layers were washed with brine (3 × 10 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated to dryness under reduced pressure. The residue was purified by Combi-Flash silica gel column chromatography to give (3-(2-methylphenethyl)piperidin-1-yl)(2-phenyl-2H-1,2,3-triazol-4-yl)methanone (16.0 mg, 37.5%) as a colorless oil. 1H NMR(500 MHz,DMSO-d6)δ 8.38(d,J=2.5 Hz,1H),8.03(dd,J=8.0,5.3 Hz,2H),7.60(dt,J=11.4,7.8 Hz,2H),7.48(td,J=7.3,5.1 Hz,1H),7.20-7.00(m,4H),4.39(d,J=13.0 Hz,1H),4.27(dd,J=47.6,13.3 Hz,1H),3.31-3.02(m,1H),3.01-2.74(m,1H),2.64(t,J=7.9 Hz,1H),2.55(q,J=7.1,6.3 Hz,1H),2.23(d,J=63.8 Hz,3H),1.95(d,J=12.8 Hz,1H),1.75(tt,J=13.3,3.7 Hz,1H),1.69-1.27(m,5H).MS m / z:375.3[M+H] + . 1-{1-ethylpyrazolo[3,4-b]pyrazin-6-yl}-3-[2-(trifluoromethyl)phenoxymethyl]piperidine (16) [ka]

[0305] Step 1: 6-Chloro-1-ethylpyrazolo[3,4-b]pyrazine: To a stirred solution of 6-chloro-1H-pyrazolo[3,4-b]pyrazine (300 mg, 1.94 mmol, 1.00 equiv) and cesium carbonate (1.27 mg, 3.88 mmol, 2 equiv) in DMF (4 mL) was added ethyl iodide (454.09 mg, 2.912 mmol, 1.5 equiv) dropwise at 0 °C. The resulting mixture was stirred at room temperature for 1 h. The reaction was diluted with water (20 mL) and extracted with EtOAc (25 mL × 2). The combined organic phase was washed with water (20 mL), brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated to dryness in vacuo to give the crude product. This was purified by silica gel chromatography (Flash 40 g, 40-60% EA:PE) to give 6-chloro-1-ethylpyrazolo[3,4-b]pyrazine (320 mg, 90.4%) as a yellow solid. MS m / z: 183 [M+H] + .

[0306] Step 2: 1-{1-Ethylpyrazolo[3,4-b]pyrazin-6-yl}-3-[2-(trifluoromethyl)phenoxymethyl]piperidine: To a stirred solution of 3-[2-(trifluoromethyl)phenoxymethyl]piperidine (100 mg, 0.386 mmol, 1.00 equiv.) and 6-chloro-1-ethylpyrazolo[3,4-b]pyrazine (84.5 mg, 0.463 mmol, 1.2 equiv.) in DMF (1 mL) was added CsCO (251.33 mg, 0.772 mmol, 2 equiv.). The resulting mixture was stirred at 80 °C for 3 h. The reaction mixture was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 0% to 100% gradient in 30 min; detector, UV 254 nm. This gave 1-{1-ethylpyrazolo[3,4-b]pyrazin-6-yl}-3-[2-(trifluoromethyl)phenoxymethyl]piperidine (32.6 mg, 20.8%) as a yellow solid. LCMS (ES, m / z): 406.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.37(s,1H),8.01(s,1H),7.66-7.60(m,2H),7.29-7.26(m,1H),7.13-7.0 8(m,1H),4.72-4.67(m,1H),4.40-4.35(m,1H),4.28-4.21(m,2H),4.18-4 .13(m,1H),4.04-3.98(m,1H),3.17-3.08(m,1H),2.01-2.93(m,1H),2.18 -2.04(m,1H),1.96-1.76(m,2H),1.65-1.42(m,2H),1.37-1.33(m,3H).MS m / z:406.1[M+H] + . 2-Phenyl-5-(3-(((2-(trifluoromethyl)pyridin-3-yl)oxy)methyl)piperidin-1-yl)-1,3,4-oxadiazole (17) [ka]

[0307] Step 1: tert-Butyl 3-(((2-(trifluoromethyl)pyridin-3-yl)oxy)methyl)piperidine-1-carboxylate: To a stirred mixture of tert-butyl 3-(hydroxymethyl)piperidine-1-carboxylate (1.00 g, 4.65 mmol, 1.00 equiv), 2-(trifluoromethyl)pyridin-3-ol (758 mg, 4.65 mmol, 1 equiv), and PPh3 (1.95 g, 7.44 mmol, 1.6 equiv) in THF (10 mL) was added TMAD (1.28 g, 7.44 mmol, 1.6 equiv) in portions at 0 °C. The resulting mixture was allowed to warm to room temperature and stirred at room temperature overnight. The resulting mixture was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography eluting with EtOAc / PE (1 / 2) to give tert-butyl 3-(((2-(trifluoromethyl)pyridin-3-yl)oxy)methyl)piperidine-1-carboxylate (1.00 g, 59.7%) as a colorless oil. MS m / z: 305 [M-tBu+H] + .

[0308] Step 2: 3-(Piperidin-3-ylmethoxy)-2-(trifluoromethyl)pyridine hydrochloride: To a stirred solution of tert-butyl 3-(((2-(trifluoromethyl)pyridin-3-yl)oxy)methyl)piperidine-1-carboxylate (500 mg, 1.38 mmol, 1.00 equiv) in DCM (2.5 mL) was added HCl (g) in dioxane (4 M, 2.5 mL). The mixture was stirred at room temperature for 2 hours. After removal of the solvent, the crude product, 3-(piperidin-3-ylmethoxy)-2-(trifluoromethyl)pyridine hydrochloride (360 mg), was used directly in the next step without further purification. MS m / z: 261 [M+H] +

[0309] Step 3: 2-[5-(piperidin-3-yl)-1,3,4-thiadiazol-2-yl]-6-(trifluoromethyl)pyridine hydrochloride: To a stirred solution of 3-(piperidin-3-ylmethoxy)-2-(trifluoromethyl)pyridine hydrochloride (70.0 mg, 0.236 mmol, 1.00 equiv.) and N,N-dimethyl-1,8-diazaspiro[4.5]decane-1-carboxamide (53.0 mg, 0.236 mmol, 1.00 equiv.) in DMF (1.00 mL) was added KCO (97.7 mg, 0.927 mmol, 3 equiv.) at room temperature. The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 2 hours. The resulting mixture was diluted with water (20 mL) and extracted with EtOAc (3 × 15 mL). The combined organic layers were washed with brine (30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography eluting with EtOAc / PE (1:1) to give the product. The product was further purified by reverse-phase Combi-Flash chromatography using the following conditions (column: C18 gel; mobile phase: B phase: MeCN, A phase: water; gradient of 35% to 75% B in 20 min; detector: UV 254 / 220 nm). The pure fractions were concentrated under vacuum to give 2-phenyl-5-(3-(((2-(trifluoromethyl)pyridin-3-yl)oxy)methyl)piperidin-1-yl)-1,3,4-oxadiazole (32 mg, 33.6%) as a white solid. 1 H NMR(400 MHz,DMSO-d6)δ 8.26(d,J=2.2 Hz,1H),7.90-7.79(m,3H),7.75-7.65(m,1H),7.59-7.47(m,1H),4.26-4.17(m,1H),4.15-4.03(m,2H),3.83-3 .94(m,1H),3.21-3.02(m,2H),2.23-2.10(br,1H),1.95-1.74(m,2H),1.72-1.55(m,1H),1.50-1.35(m,1H).MS m / z:405.1[M+H] + . 1-[(oxetan-3-yl)methyl]-6-[(3S)-3-{2-[2-(trifluoromethyl)phenyl]ethyl}piperidine-1-carbonyl]-1H-indole (18) [ka]

[0310] Step 1: Benzyl (S)-3-(hydroxymethyl)piperidine-1-carboxylate: To a stirred solution of (S)-1-((benzyloxy)carbonyl)piperidine-3-carboxylic acid (1.50 g, 5.68 mmol, 1.00 equiv) in THF (15.0 mL) was added BH3-Me2S (1.7 mL, 4 M, 3.00 equiv) dropwise at 0 °C under a N2 atmosphere. The resulting mixture was stirred at 0 °C under a N2 atmosphere for 3 h. The reaction was quenched with water (30 mL) at 0 °C and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EtOAc / PE (2 / 1) to give (S)-benzyl 3-(hydroxymethyl)piperidine-1-carboxylate (1.0 g, 70.4%) as a colorless oil. MS m / z: 250 [M+H] + .

[0311] Step 2: Benzyl (S)-3-formylpiperidine-1-carboxylate: To a stirred solution of benzyl (S)-3-(hydroxymethyl)piperidine-1-carboxylate (500 mg, 2.0 mmol, 1.00 equiv.) in DCM (10 mL) was added Dess-Martin (1.0 g, 2.4 mmol, 1.2 equiv.) in portions at 0° C. The resulting mixture was stirred at room temperature for 3 hours. The resulting mixture was filtered, and the filter cake was washed with DCM (3×10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (1:20) to afford benzyl (S)-3-formylpiperidine-1-carboxylate (400.0 mg, 80.1%) as a colorless oil. MS m / z: 248 [M+H] + .

[0312] Step 3: Triphenyl(2-(trifluoromethyl)benzyl)phosphonium bromide: A solution of 1-(bromomethyl)-2-(trifluoromethyl)benzene (500 mg, 2.1 mmol, 1 equiv.) and PPh3 (608.0 mg, 2.3 mmol, 1.1 equiv.) in toluene (5 mL) was stirred at 100 °C for 16 h. The reaction mixture was cooled to room temperature, filtered, and the filter cake was washed with toluene (3 × 10 mL) to give triphenyl(2-(trifluoromethyl)benzyl)phosphonium bromide (900 mg, 81.0%) as a white solid. MS m / z: 421 [M+H] + .

[0313] Step 4: Benzyl (R,E)-3-(2-(trifluoromethyl)styryl)piperidine-1-carboxylate: To a stirred mixture of triphenyl(2-(trifluoromethyl)benzyl)phosphonium (300.0 mg, 0.65 mmol, 1.00 equiv) in THF (12.00 mL) was added n-BuLi (2.5 M in THF, 0.26 mL, 1 equiv) dropwise at −78° C. under a N atmosphere. The resulting mixture was warmed to 0° C. and stirred at 0° C. for 30 minutes under a N atmosphere. The reaction was then cooled to −78° C. To the stirred solution was added benzyl (S)-3-formylpiperidine-1-carboxylate (163.0 mg, 0.65 mmol, 1.00 equiv) in THF (1.00 mL) dropwise at −78° C. under a N atmosphere. The resulting mixture was allowed to warm to room temperature and stirred under N2 atmosphere at room temperature for 8 hours. The reaction was quenched with saturated aqueous NH4HCO3 at 1 °C. The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (1 x 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EtOAc / PE (1 / 3) to give benzyl (R,E)-3-(2-(trifluoromethyl)styryl)piperidine-1-carboxylate (100 mg, 40.0%) as a colorless oil. MS m / z: 390 [M+H] + .

[0314] Step 5: (S)-3-(2-(trifluoromethyl)phenethyl)piperidine: To a solution of benzyl (R,E)-3-(2-(trifluoromethyl)styryl)piperidine-1-carboxylate (100.00 mg, 0.333 mmol, 1.00 equiv) in MeOH (5.00 mL) was added Pd / C (20% w / w, 20.0 mg). The resulting mixture was hydrogenated under H atmosphere (1 atm) at room temperature overnight. The reaction mixture was filtered through celite, and the filtrate was concentrated to dryness. The product (S)-3-(2-(trifluoromethyl)phenethyl)piperidine (90 mg, 90.0%) was used directly in the next step. MS m / z: 258 [M+H] + .

[0315] Step 6: (S)-(1H-Indol-6-yl)(3-(2-(trifluoromethyl)phenethyl)piperidin-1-yl)methanone: To a stirred solution of 1H-indole-6-carboxylic acid (50 mg, 0.31 mmol, 1.00 equiv) and (S)-3-(2-(trifluoromethyl)phenethyl)piperidine (79.8 mg, 0.31 mmol, 1.0 equiv) in DMF (2 mL) was added dropwise HATU (129 mg, 0.34 mmol, 1.1 equiv) and DIPEA (58.5 mg, 0.46 mmol, 1.5 equiv) at 0 °C. The resulting mixture was stirred at room temperature for an additional 3 h. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (15 mL × 2). The combined organic layers were washed with brine (3 × 10 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated to dryness under reduced pressure. The residue was purified by reverse-phase Combi-Flash using the following conditions: column, C18 gel; mobile phase, aqueous MeCN (0.1% FA), 20% to 70% gradient in 16 min; detector, UV 254 nm. This afforded (S)-(1H-indol-6-yl)(3-(2-(trifluoromethyl)phenethyl)piperidin-1-yl)methanone (30.0 mg, 24.1%) as a white solid. 1H NMR(400 MHz,DMSO-d6)δ 11.25(s,1H),7.64-7.45(m,3H),7.44-7.38(m,4H),7.00-6.98(m,1H),6.47(s,1H),4.30- 3.60(m,2H),3.34-2.67(m,4H),1.92-1.89(m,1H),1.61-1.68(m,2H),1.44-1.20(m,3H).MS m / z:401.2[M+H] + .

[0316] Step 7: 1-[(Oxetan-3-yl)methyl]-6-[(3S)-3-{2-[2-(trifluoromethyl)phenyl]ethyl}piperidine-1-carbonyl]-1H-indole: To a mixture of 6-[(3S)-3-{2-[2-(trifluoromethyl)phenyl]ethyl}piperidine-1-carbonyl]-1H-indole (15.0 mg, 37.5 μmol, 1.00 equiv.) in DMF (1.00 mL) was added sodium hydride 60% w / w (1.65 mg, 41.2 μmol, 1.1 equiv.) at room temperature and stirred for 15 minutes. To the mixture was added 3-(bromomethyl)oxetane (5.66 mg, 37.5 μmol, 1.0 equiv.) dropwise. The mixture was stirred at room temperature for 16 hours. The reaction was monitored by LCMS. The mixture was diluted with water (15 mL) and extracted with EtOAc (20 mL). The organic layer was washed with brine, dried, filtered, concentrated, and purified by Combi-Flash to give 1-[(oxetan-3-yl)methyl]6-[(3S)-3-{2-[2-(trifluoromethyl)phenyl]ethyl}piperidine-1-carbonyl]-1H-indole (15 mg, 85.1%) as a pale yellow sticky oil. 1H NMR(500 MHz,DMSO-d6)δ 7.74-7.30(m,7H),7.01(ddd,J=9.8,8.0,1.4 Hz,1H),6.48(d,J=3.2 Hz,1H),4.60(dd,J=7.8,6.1 Hz,2H),4.52(d,J=7.4 Hz,2H),4.40(td,J=6.1,1.4 Hz,2H),4.37-4.09(m,1H),3.85-3.52(m,1H),3.50-3.36(m,1H),3.12- 2.60(m,4H),1.96-1.87(m,1H),1.78-1.32(m,5H),1.31-1.21(m,1H).MS m / z:471.1[M+H] + . 1-(Oxetan-3-yl)-6-[(3S)-3-{2-[2-(trifluoromethyl)phenyl]ethyl}piperidine-1-carbonyl]-1H-indole (19) [ka]

[0317] To a mixture of 6-[(3S)-3-{2-[2-(trifluoromethyl)phenyl]ethyl}piperidine-1-carbonyl]-1H-indole (15.0 mg, 37.5 μmol, 1.00 equiv.) in DMF (1.00 mL) was added sodium hydride 60% w / w (1.65 mg, 41.2 μmol, 1.1 equiv.) at room temperature and stirred for 15 minutes. 3-Bromooxetane (5.13 mg, 37.5 μmol, 1.0 equiv.) was added dropwise to the mixture. The mixture was stirred at room temperature for 16 hours. The reaction was monitored by LCMS. The mixture was diluted with water (15 mL) and extracted with EtOAc (20 mL). The organic layer was washed with brine, dried, filtered, concentrated, and purified by Combi-Flash to give 1-(oxetan-3-yl)-6-[(3S)-3-{2-[2-(trifluoromethyl)phenyl]ethyl}piperidine-1-carbonyl]-1H-indole as a pale yellow sticky oil (8.0 mg, 46.8%). 1H NMR(500 MHz,DMSO-d6)δ 7.87(d,J=3.2 Hz,1H),7.71-7.30(m,6H),7.07(dd,J=8.1,1.3 Hz,1H),6.62(d,J=3.2 Hz,1H),5.89-5.76(m,1H),5.05(td,J=7.4,3.3 Hz,2H),4.92(q,J=6.1 Hz,2H),4.46-4.24(m,1H),3.85-3.53(m,1H),3.14-2.61(m,4H),1.96-1.87(m,1H),1.82-1.20(m,6H).MS m / z:457.1[M+H]+. 3-({1-[1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-4,4-difluoropiperidin-3-yl}methoxy)-2-(trifluoromethyl)pyridine (20) [ka]

[0318] Step 1: tert-Butyl 4,4-difluoro-3-(((2-(trifluoromethyl)pyridin-3-yl)oxy)methyl)piperidine-1-carboxylate: To a stirred mixture of 2-(trifluoromethyl)pyridin-3-ol (77.9 mg, 0.48 mmol, 1.00 equiv) and tert-butyl 4,4-difluoro-3-(hydroxymethyl)piperidine-1-carboxylate (120 mg, 0.48 mmol, 1.00 equiv) in THF (3 mL) under a nitrogen atmosphere at 0° C. was added PPh3 (200 mg, 0.76 mmol, 1.60 equiv) and TMAD (132 mg, 0.76 mmol, 1.6 equiv) in portions. The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. The residue was purified by silica gel column chromatography eluting with hexane / EtOAc (4:1) to give tert-butyl 4,4-difluoro-3-(((2-(trifluoromethyl)pyridin-3-yl)oxy)methyl)piperidine-1-carboxylate (100 mg, 52.8%) as a pale yellow oil. LCMS (ES, m / z): 397 [M+H] + .

[0319] Step 2: 3-((4,4-Difluoropiperidin-3-yl)methoxy)-2-(trifluoromethyl)pyridine hydrochloride: To a stirred solution of tert-butyl 4,4-difluoro-3-(((2-(trifluoromethyl)pyridin-3-yl)oxy)methyl)piperidine-1-carboxylate (100 mg, 0.25 mmol, 1.00 equiv) in DCM (2 mL) was added HCl (gas) in 1,4-dioxane (4 M, 1.26 mL). The resulting mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated to dryness in vacuo. The crude product, 3-((4,4-difluoropiperidin-3-yl)methoxy)-2-(trifluoromethyl)pyridine hydrochloride (80 mg), was used directly in the next step without further purification. MS m / z: 297 [M+H] + .

[0320] Step 3: 3-({1-[1-(2,2-Difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-4,4-difluoropiperidin-3-yl}methoxy)-2-(trifluoromethyl)pyridine: To a stirred solution of 3-((4,4-difluoropiperidin-3-yl)methoxy)-2-(trifluoromethyl)pyridine hydrochloride (18.3 mg, 0.055 mmol, 1.00 equiv) and 6-chloro-1-(2,2-difluoroethyl)pyrazolo[3,4-b]pyrazine (12.0 mg, 0.055 mmol, 1.00 equiv) in DMF (1 mL) was added KCO (15.2 mg, 0.11 mmol, 2 equiv). The resulting mixture was stirred at 60 °C for 16 h. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (15 mL × 2). The organic layer was evaporated and purified by Combiflash (4 g silica gel column) eluting with Hex / EtOAc (1 / 1). Collected fractions were concentrated to give 4 mg (15.2%) of 3-({1-[1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-4,4-difluoropiperidin-3-yl}methoxy)-2-(trifluoromethyl)pyridine as a white powder. 1H NMR(500 MHz,CDCl3)δ 8.30(d,J=5.1 Hz,2H),8.06(s,1H),7.47(dd,J=8.5,4.5 Hz,1H),7.40(d,J=8.5 Hz,1H),6.17(tt,J=55.4,4.4 Hz,1H),4.88(dt,J=14.2,4.9 Hz,1H),4.71-4.63(m,2H),4.56(dd,J=9.2,3.6 Hz,1H),4.47-4.40(m,1H),4.08(t,J=9.6 Hz,1H),3.48(ddd,J=14.4,11.7,3.3 Hz,1H),3.33-3.25(m,1H),2.74-2.59(m,1H),2.31-2.20(m,1H),2.16-2.00(m,1H).MS m / z:479.2[M+H] + . 3-({1-[1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-5,5-difluoropiperidin-3-yl}methoxy)-2-(trifluoromethyl)pyridine (21) [ka]

[0321] Step 1: tert-Butyl 3,3-difluoro-5-({[2-(trifluoromethyl)pyridin-3-yl]oxy}methyl)piperidine-1-carboxylate: Following general procedure A using tert-butyl 3,3-difluoro-5-(hydroxymethyl)piperidine-1-carboxylate (120 mg, 0.48 mmol, 1.00 equiv.) and 2-(trifluoromethyl)pyridin-3-ol (78 mg, 0.48 mmol, 1.00 equiv.), tert-butyl 3,3-difluoro-5-({[2-(trifluoromethyl)pyridin-3-yl]oxy}methyl)piperidine-1-carboxylate (137 mg, 52.8%) was obtained as a pale yellow oil. MS m / z: 397 [M+H] + .

[0322] Step 2: 3-[(5,5-difluoropiperidin-3-yl)methoxy]-2-(trifluoromethyl)pyridine hydrochloride: General procedure B was followed using tert-butyl 3,3-difluoro-5-({[2-(trifluoromethyl)pyridin-3-yl]oxy}methyl)piperidine-1-carboxylate (120 mg, 0.3 mmol, 1.00 equiv.) to give 3-[(5,5-difluoropiperidin-3-yl)methoxy]-2-(trifluoromethyl)pyridine hydrochloride (95 mg). MS m / z: 297 [M+H] + .

[0323] Step 3: 3-({1-[1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-5,5-difluoropiperidin-3-yl}methoxy)-2-(trifluoromethyl)pyridine: 3-[(5,5-difluoropiperidin-3-yl)methoxy]-2-(trifluoromethyl)pyridine hydrochloride (18.3 mg, 0.055 mmol, 1.00 equiv) and 6-chloro-1 General procedure C was followed using -(2,2-difluoroethyl)pyrazolo[3,4-b]pyrazine (12.0 mg, 0.055 mmol, 1.00 equiv) to give 3-({1-[1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-5,5-difluoropiperidin-3-yl}methoxy)-2-(trifluoromethyl)pyridine as a white powder (4 mg, 15.2%). 1H NMR(500 MHz,CDCl3)δ 8.32(d,J=4.7 Hz,1H),8.29(s,1H),8.08(d,J=1.0 Hz,1H),7.49(dd,J=8.5,4.6 Hz,1H),7.37(d,J=8.5 Hz,1H),6.18(tt,J=55.5,4.4 Hz,1H),4.67(td,J=13.4,4.4 Hz,2H),4.56(d,J=14.0 Hz,1H),4.50-4.41(m,1H),4.18(dd,J=9.1,4.1 Hz,1H),4.06(t,J=8.1 Hz,1H),3.66(ddd,J=25.0,14.1,3.0 Hz,1H),3.41(dd,J=13.7,9.4 Hz,1H),2.63(s,1H),2.38(q,J=11.2,10.0 Hz,1H),2.21-2.08(m,1H).MS m / z:479.2[M+H] + . (2-(2-fluorophenyl)-2H-1,2,3-triazol-4-yl)(3-(phenoxymethyl)piperidin-1-yl)methanone (22) [ka]

[0324] To a solution of 3-(phenoxymethyl)-1-(2H-1,2,3-triazole-4-carbonyl)piperidine (200 mg, 0.698 mmol, 1.00 equiv.) and 1-fluoro-2-iodo-benzene (310 mg, 1.40 mmol, 2 equiv.) in DMF (3 mL, 38.8 mmol, 55.5 equiv.), CuI (13.3 mg, 0.070 mmol, 0.1 equiv.), N1-(furan-2-ylmethyl)-N2-(2-methylnaphthalen-1-yl)oxalamide (21.5 mg, 0.070 mmol, 0.1 equiv.), and Cs2CO3 (683 mg, 2.10 mmol, 3 equiv.) were added under a N2 atmosphere. The resulting mixture was heated to 90 °C and stirred overnight. The desired product could be detected by LCMS. The reaction mixture was diluted with EtOAc (20 mL), washed with water (2 × 20 mL) and brine (1 × 20 mL), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated. The residue was purified by silica gel column chromatography eluting with 1:5 EtOAc / PE to give an impure product. The impure product was further purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water, gradient from 35% to 75% in 15 min; detector, UV 254 nm. This afforded (2-(2-fluorophenyl)-2H-1,2,3-triazol-4-yl)(3-(phenoxymethyl)piperidin-1-yl)methanone (17.2 mg, 6.47%) as a white solid. 1H NMR(400 MHz,DMSO-d6)δ 8.51-8.25(d,J=20.9 Hz,1H),7.69-7.24(m,1H),7.59(t,J=11.3 Hz,2H),7.51-7.37(m,1H),7.30(t,J=7.7 Hz,1H),7.19(t,J=7.2 Hz,1H),7.02-6.83(m,2H),6.81-6.79(m,1H),4.62-4.33(m,1H),4.27(d,J=13.2 Hz,1H),4.07-3.72(m,2H),3.27-3.18(m,1H),3.12-2.78(m,1H),2.13- 1.96(m,1H),1.97-1.86(m,1H),1.84-1.69(m,1H),1.66-1.33(m,2H).MS m / z:381.2[M+H] + . 2-(6-(3-((o-tolyloxy)methyl)piperidin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-1-yl)-1,3,4-thiadiazole (23) [ka]

[0325] Step 1: 6-(3-((o-Tolyloxy)methyl)piperidin-1-yl)-1H-pyrazolo[3,4-b]pyrazine: To a stirred solution of 6-chloro-1H-pyrazolo[3,4-b]pyrazine (180 mg, 1.16 mmol, 1 equiv) and 3-((o-tolyloxy)methyl)piperidine (263 mg, 1.28 mmol, 1.1 equiv) in DMF (3 mL) was added K2CO3 (321 mg, 2.33 mmol, 2 equiv) at room temperature under an air atmosphere. The resulting mixture was stirred at 100 °C under a nitrogen atmosphere overnight. The resulting mixture was diluted with EtOAc (30 mL). The combined organic layers were washed with water (2 × 20 mL), brine (1 × 10 mL), and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (5:1) to give 6-(3-((o-tolyloxy)methyl)piperidin-1-yl)-1H-pyrazolo[3,4-b]pyrazine (120 mg, 31.8%) as an off-white solid. MS m / z: 324 [M+H] + .

[0326] Step 2: 2-(6-(3-((o-tolyloxy)methyl)piperidin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-1-yl)-1,3,4-thiadiazole: To a stirred solution of 6-(3-((o-tolyloxy)methyl)piperidin-1-yl)-1H-pyrazolo[3,4-b]pyrazine (100 mg, 0.309 mmol, 1.00 equiv.) and 2-bromo-1,3,4-thiadiazole (51.0 mg, 0.309 mmol, 1 equiv.) in dioxane (2 mL) was added CsCO (201 mg, 0.618 mmol, 2 equiv.), Pd-PEPPSI-IPentCl- Methylpyridine (o-picoline (26.0 mg, 0.031 mmol, 0.1 equiv.)) was added. The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 16 h. The desired product could be detected by LCMS. The resulting mixture was diluted with water (10 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 10% to 50% gradient in 10 min; detector, UV 254 nm. This gave 2-(6-(3-((o-tolyloxy)methyl)piperidin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-1-yl)-1,3,4-thiadiazole (12.5 mg, 9.44%). MS m / z: 407.95 [M+H]+. 1 H NMR(300 MHz,DMSO-d6)δ 9.48(d,J=1.7 Hz,1H),8.63-8.47(m,2H),7.21-7.07(m,2H),6.93(d,J=8.0 Hz,1H),6.87-6.76(m,1H),4.73-4.38(m,2H),3.98(d,J=6.2 Hz,2H),3.21(d,J=11.9 Hz,2H),2.22(s,3H),2.11(d,J=18.2 Hz,1H),2.01-1.80(m,2H),1.60(d,J=9.1 Hz,2H). (3-(phenoxymethyl)piperidin-1-yl)(5-(2-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)methanone (24) [ka]

[0327] Step 1: Ethyl 2-(2-(2-methyl-2-phenylpropanoyl)hydrazinyl)-2-oxoacetate: To a stirred solution of 2-methyl-2-phenylpropanoic acid (1 g, 6.09 mmol, 1.00 equiv) and HATU (2.55 g, 6.69 mmol, 1.1 equiv) in DCM (50 mL) was added DIEA (1.57 g, 12.1 mmol, 2 equiv) and ethyl 2-hydrazinyl-2-oxoacetate (0.97 g, 7.30 mmol, 1.2 equiv) in portions at 0 °C. The resulting mixture was stirred at room temperature for 16 h. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with PE / EA (1 / 1) to give ethyl 2-(2-(2-methyl-2-phenylpropanoyl)hydrazinyl)-2-oxoacetate (1.2 g, 70.8%) as a white solid. MS m / z: 279 [M+H] + .

[0328] Step 2: Ethyl 5-(2-phenylpropan-2-yl)-1,3,4-oxadiazole-2-carboxylate: A solution of ethyl 2-(2-(2-methyl-2-phenylpropanoyl)hydrazinyl)-2-oxoacetate (1 g, 3.59 mmol, 1.00 equiv.) in phosphorus oxychloride (10 mL) was stirred at 100°C for 2 h. The resulting mixture was diluted with EtOAc (100 mL). The organic layer was washed with Na2CO3 (100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (1:2) to give ethyl 5-(2-phenylpropan-2-yl)-1,3,4-oxadiazole-2-carboxylate (600 mg, 64.1%) as a pale yellow oil. MS m / z: 261 [M+H] + .

[0329] Step 3: 5-(2-Phenylpropan-2-yl)-1,3,4-oxadiazole-2-carboxylic acid: A solution of ethyl 5-(2-phenylpropan-2-yl)-1,3,4-oxadiazole-2-carboxylate (220 mg, 0.845 mmol, 1.00 equiv) and NaOH (135 mg, 3.38 mmol, 4 equiv) in MeOH / HO (1 mL / 1 mL) was stirred at room temperature for 3 hours. The desired product could be detected by LCMS. The mixture was acidified to pH 5 with HCl (1 mol / L). The resulting mixture was extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with water (3 × 15 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water, gradient 0% to 100% in 30 min; detector, UV 254 nm. This afforded 5-(2-phenylpropan-2-yl)-1,3,4-oxadiazole-2-carboxylic acid (140 mg, 71.3%) as a white solid. MS m / z: 233 [M+H] + .

[0330] Step 4: (3-(Phenoxymethyl)piperidin-1-yl)(5-(2-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)methanone: To a stirred solution of 5-(2-phenylpropan-2-yl)-1,3,4-oxadiazole-2-carboxylic acid (60 mg, 0.258 mmol, 1.00 equiv) and HATU (108 mg, 0.284 mmol, 1.1 equiv) in DMF (1 mL) was added DIEA (66.7 mg, 0.516 mmol, 2 equiv) and 3-(phenoxymethyl)piperidine (59.3 mg, 0.310 mmol, 1.2 equiv) in portions at 0° C. The resulting mixture was stirred at room temperature for 2 hours. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water, gradient 10% to 100% in 30 min; detector, UV 254 nm. This gave 3-(phenoxymethyl)piperidin-1-yl)(5-(2-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)methanone (35 mg, 33.11%) as a white solid. 1 H NMR(400 MHz,DMSO-d6)δ 7.43-7.22(m,7H),7.01-6.82(m,3H),4.49-4.09(m,2H),3.98-3.76(m,2H),3.38-3.24(m,1H),3 .12-2.87(m,1H),2.07-2.05(m,1H),1.93-1.85(m,1H),1.83-1.70(m,7H),1.57-1.39(m,2H).MS m / z:406.3[M+H] + . (4-chloro-7-phenylpyrazolo[1,5-a]pyridin-3-yl)(3-((o-tolyloxy)methyl)piperidin-1-yl)methanone (25) [ka]

[0331] Step 1: 7-Bromo-4-chloropyrazolo[1,5-a]pyridine-3-carbaldehyde: To a solution of 7-bromo-4-chloropyrazolo[1,5-a]pyridine (300 mg, 1.29 mmol, 1.00 equiv.) was added POCl (596 mg, 3.88 mmol, 3.00 equiv.) at 0 °C. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. The mixture was basified to pH 10 with 1 M NaOH. The resulting mixture was extracted with CHCl (3 × 30 mL). The combined organic layers were washed with water (2 × 30 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. This afforded 7-bromo-4-chloropyrazolo[1,5-a]pyridine-3-carbaldehyde (150 mg, 44.6%) as a white solid. MS m / z: 260 [M+H] + .

[0332] Step 2: 7-Bromo-4-chloropyrazolo[1,5-a]pyridine-3-carboxylic acid: To a stirred solution of 7-bromo-4-chloropyrazolo[1,5-a]pyridine-3-carbaldehyde (150 mg, 0.578 mmol, 1.00 equiv) in HO (1.00 mL) was added NaHPO (416 mg, 3.46 mmol, 6.00 equiv) under an air atmosphere at 0° C. After 5 min, t-BuOH (5.00 mL), 2,3-dimethylbut-2-ene (122 mg, 1.45 mmol, 2.50 equiv), and NaClO (78.4 mg, 0.867 mmol, 1.50 equiv) were added. After 16 hours, the reaction mixture was diluted with ethyl acetate, washed with water and brine, then dried over magnesium sulfate, filtered, and concentrated to give 7-bromo-4-chloropyrazolo[1,5-a]pyridine-3-carboxylic acid (100 mg, 62.8%) as a white solid, which was used without further purification. MS m / z: 277 [M+H] + .

[0333] Step 3: (7-Bromo-4-chloropyrazolo[1,5-a]pyridin-3-yl)(3-((o-tolyloxy)methyl)piperidin-1-yl)methanone: To a stirred mixture of 7-bromo-4-chloropyrazolo[1,5-a]pyridine-3-carboxylic acid (100 mg, 0.363 mmol, 1.00 equiv.) and 3-((o-tolyloxy)methyl)piperidine (112 mg, 0.544 mmol, 1.50 equiv.) in DMF (3.00 mL) was added HATU (207 mg, 0.544 mmol, 1.50 equiv.) and DIPEA (140 mg, 1.09 mmol, 3.00 equiv.), and the resulting mixture was stirred at room temperature under an argon atmosphere for 1 hour. The resulting mixture was diluted with water (10 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, ACN in water, 10% to 50% gradient in 10 min; detector, UV 254 nm. This afforded 1-{7-bromo-4-chloropyrazolo[1,5-a]pyridine-3-carbonyl}-3-(2-methylphenoxymethyl)piperidine (100 mg, 59.5%) as a white solid. MS m / z: 464 [M+H] + .

[0334] Step 4: (4-Chloro-7-phenylpyrazolo[1,5-a]pyridin-3-yl)(3-((o-tolyloxy)methyl)piperidin-1-yl)-methanone: To a solution of 1-{7-bromo-4-chloropyrazolo[1,5-a]pyridine-3-carbonyl}-3-(2-methylphenoxymethyl)piperidine (100 mg, 0.216 mmol, 1.00 equiv) and phenylboronic acid (39.5 mg, 0.324 mmol, 1.50 equiv) in dioxane (2.00 mL) and HO (0.50 mL) was added KCO (59.7 mg, 0.430 mmol, 2.00 equiv) and Pd(dppf)Cl (15.8 mg, 0.02 mmol, 0.100 equiv). After stirring at 80 °C under nitrogen for 2 h, the resulting mixture was concentrated under reduced pressure, and the residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, ACN in water, 10% to 50% gradient in 10 min; detector, UV 254 nm, to give 1-{4-chloro-7-phenylpyrazolo[1,5-a]pyridine-3-carbonyl}-3-(2-methylphenoxymethyl)piperidine (40 mg, 40.1%) as a white solid. 1 H NMR(300MHz,DMSO-d6):δ 8.21-8.13(m,1H),7.94-7.88(m,1H),7.64-7.43(m,4H),7.11-6.69(m,5H),4.43-4.34(m,1H),4.00-3.84(m,2H) ),3.68-3.55(m,1H),2.97(s,2H),2.32-2.22(s,1H),2.10-2.00(m,1H),1.94-1.75(m,2H),1.63-1.39(m,4H).MS m / z:459.9[M+H] + . 1-(2,2-Difluoroethyl)-6-(3-(1-((2-(trifluoromethyl)pyridin-3-yl)oxy)ethyl)piperidin-1-yl)-1H-pyrazolo[3,4-b]pyrazine (26) [ka]

[0335] Step 1: tert-butyl 3-(1-{[2-(trifluoromethyl)pyridin-3-yl]oxy}ethyl)piperidine-1-carboxylate: Following general procedure A using 2-(trifluoromethyl)pyridin-3-ol (297 mg, 1.82 mmol, 1.00 equiv.) and tert-butyl 3-(1-hydroxyethyl)piperidine-1-carboxylate (501 mg, 2.18 mmol, 1.2 equiv.), tert-butyl 3-(1-((2-(trifluoromethyl)pyridin-3-yl)oxy)ethyl)piperidine-1-carboxylate (30 mg, 4.4%) was obtained as a colorless oil. MS m / z: 375 [M+H] + .

[0336] Step 2: 3-(1-(piperidin-3-yl)ethoxy)-2-(trifluoromethyl)pyridine hydrochloride: Following general procedure B using tert-butyl 3-(1-((2-(trifluoromethyl)pyridin-3-yl)oxy)ethyl)piperidine-1-carboxylate (50 mg, 0.134 mmol, 1.00 equiv.) gave 3-(1-(piperidin-3-yl)ethoxy)-2-(trifluoromethyl)pyridine hydrochloride (50 mg). MS m / z: 275 [M+H] + .

[0337] Step 3 1-(2,2-Difluoroethyl)-6-(3-(1-((2-(trifluoromethyl)pyridin-3-yl)oxy)ethyl)piperidin-1-yl)-1H-pyrazolo[3,4-b]pyrazine: General procedure C was followed using 3-(1-(piperidin-3-yl)ethoxy)-2-(trifluoromethyl)pyridine hydrochloride (50 mg, 0.161 mmol, 1.00 equiv) and 6-chloro-1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazine (38.7 mg, 0.177 mmol, 1.1 equiv). The crude product was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, ACN in water, gradient 10% to 50% in 30 min; detector, UV 254 / 220 nm to give 1-(2,2-difluoroethyl)-6-(3-(1-((2-(trifluoromethyl)pyridin-3-yl)oxy)ethyl)piperidin-1-yl)-1H-pyrazolo[3,4-b]pyrazine (13.9 mg, 18.6%) as an off-white solid. 1 H NMR(400MHz,CD3OD):δ 8.32(s,1H),8.19-8.16(m,2H),7.97(s,1H),7.77-7.74(m,1H),7.62-7.56(m,1H),6.40-6.09(m,1H),4.78-4.72(m,1H) ),4.69-4.59(m,3H),4.54-4.48(m,1H),3.16-3.05(m,2H),2.11-1.87(m,3H),1.73-1.60(m,2H),1.41-1.38(m,3H).MS m / z:457.20[M+H] + . 5-(phenoxymethyl)-1-(quinoxalin-2-yl)piperidin-2-one (27) [ka]

[0338] Step 1: 1-benzyl-5-(phenoxymethyl)piperidin-2-one: Following general procedure A using 1-benzyl-5-(hydroxymethyl)piperidin-2-one (190 mg, 0.787 mmol, 1.00 equiv.), phenol (148 mg, 1.57 mmol, 1.5 equiv.), 1-benzyl-5-(phenoxymethyl)piperidin-2-one (140 mg, 56.0%) was obtained as a white solid. MS m / z: 296 [M+H] + .

[0339] Step 2: 5-(benzylamino)-4-(phenoxymethyl)pentanoic acid: To a solution of methyl 1-benzyl-5-(phenoxymethyl)piperidin-2-one (200 mg, 0.493 mmol, 1.00 equiv.) in MeOH (2.00 mL) was added NaOH (78.9 mg, 1.97 mmol, 4.00 equiv.) in water (1.00 mL). The mixture was stirred at 100 °C for 1 h. The mixture was concentrated with 3 M aqueous HCl, and the resulting mixture was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 5% to 95% gradient in 15 min; detector, UV 254 nm to give 5-(benzylamino)-4-(phenoxymethyl)pentanoic acid (150 mg, 77.7%) as a white solid. MS m / z: 297 [M+H] + .

[0340] Step 3: 5-Amino-4-(phenoxymethyl)pentanoic acid: To a solution of 5-(benzylamino)-4-(phenoxymethyl)pentanoic acid (100 mg, 0.333 mmol, 1.00 equiv.) in MeOH (5.00 mL) was added Pd / C (16.6 mg) along with water. The resulting mixture was hydrogenated overnight at room temperature. The desired product could be detected by LCMS. The reaction was filtered through celite, and the filtrate was concentrated. The crude product, 5-amino-4-(phenoxymethyl)pentanoic acid (103 mg, crude), was used directly in the next step. MS m / z: 214 [M+H] + .

[0341] Step 4: 5-(Phenoxymethyl)piperidin-2-one: To a stirred solution of 5-amino-4-(phenoxymethyl)pentanoic acid (200 mg, 1.83 mmol, 1.00 equiv) in DMF (5.00 mL) was added saturated Na2CO3 (1.6 mL) at 0 °C. The mixture was stirred at 100 °C for 2 h. The resulting mixture was diluted with DCM (50 mL), washed with water (2 × 50 mL) and brine (1 × 50 mL), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by reverse-phase flash chromatography using the following conditions: column, C18 gel; mobile phase, B phase: MeCN, A phase: water; 5% to 95% B gradient in 15 min; detector: UV 220 / 200 nm) to give 5-(phenoxymethyl)piperidin-2-one (640 mg, 86.0%) as a colorless syrup. MS m / z: 206 [M+H] + .

[0342] Step 5: 5-(Phenoxymethyl)-1-(quinoxalin-2-yl)piperidin-2-one: To a solution of 5-(phenoxymethyl)piperidin-2-one (50.0 mg, 0.143 mmol, 1.00 equiv.) and 2-chloroquinoxaline (44.0 mg, 0.215 mmol, 1.50 equiv.) in dioxane (3.00 mL) was added RuPhos Pd G3 (5.9 mg, 0.007 mmol, 0.05 equiv.) and K2CO3 (54.9 mg, 0.286 mmol, 2.00 equiv.) under a N2 atmosphere. The resulting mixture was heated to 60 °C and stirred overnight. The desired product could be detected by LCMS. The reaction mixture was diluted with EtOAc (20 mL), washed with water (2 × 10 mL) and brine (1 × 20 mL), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated. The residue was purified by silica gel column chromatography eluting with EtOAc / PE=1 / 10 to give 5-(phenoxymethyl)-1-(quinoxalin-2-yl)piperidin-2-one (15 mg, 86.0%) as a white solid. 1H NMR(400 MHz,DMSO-d6)δ 9.30(s,1H),8.15-8.12(m,1H),8.04-7.91(m,1H),7.89-7.81(m,2H),7.38-7.33(m,2H),7.06-6.98(m,3H),4.3 4-4.28(m,1H),4.16-4.13(m,2H),4.00-3.93(m,1H),2.80-2.61(m,3H),2.19-2.13(m,1H),1.91-1.84(m,1H).MS m / z:334.0[M+H] + . 3-(phenoxymethyl)-1-(1-phenyl-1H-1,2,3-triazol-4-yl)piperidine (28) [ka]

[0343] Step 1: 4-Bromo-1-phenyl-1H-1,2,3-triazole: To a solution of 4-bromo-2H-1,2,3-triazole (400 mg, 2.70 mmol, 1.00 equiv.) and iodophenyl (1654 mg, 8.11 mmol, 3 equiv.) in DMF (5 mL), CuI (51.5 mg, 0.270 mmol, 0.1 equiv.), (1S,2S)-1-N,2-N-dimethylcyclohexane-1,2-diamine (38.5 mg, 0.270 mmol, 0.10 equiv.), and CsCO (2642 mg, 8.11 mmol, 3 equiv.) were added under a N atmosphere. The resulting mixture was heated to 100 °C and stirred overnight. The desired product could be detected by LCMS. The reaction mixture was diluted with EtOAc (30 mL), washed with water (2 × 30 mL) and brine (1 × 30 mL), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated. The residue was purified by silica gel column chromatography eluting with EtOAc / PE = 1 / 1 to give 4-bromo-1-phenyl-1H-1,2,3-triazole (100 mg, 16.5%). MS m / z: 224 [M+H] + .

[0344] Step 2: 3-(phenoxymethyl)-1-(1-phenyl-1H-1,2,3-triazol-4-yl)piperidine: To a solution of 4-bromo-1-phenyl-1H-1,2,3-triazole (60 mg, 0.268 mmol, 1.00 equiv.) and 3-(phenoxymethyl)piperidine hydrochloride (61.0 mg, 0.268 mmol, 1 equiv.) in dioxane (2 mL) was added Ephos Pd G4 (24.6 mg, 0.027 mmol, 0.1 equiv.), Ephos (14.3 mg, 0.027 mmol, 0.1 equiv.), and CsCO3 (262 mg, 0.804 mmol, 3 equiv.) under a N2 atmosphere. The resulting mixture was heated to 90 °C and stirred overnight. The desired product could be detected by LCMS. The reaction mixture was diluted with EtOAc (20 mL), washed with water (2 × 10 mL) and brine (1 × 20 mL), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated. The residue was purified by silica gel column chromatography eluting with 1:1 EtOAc / PE to give an impure product. The impure product was further purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water, gradient from 35% to 75% in 15 min; detector, UV 254 nm. This afforded 3-(phenoxymethyl)-1-(1-phenyl-1H-1,2,3-triazol-4-yl)piperidine (10 mg, 11.2%) as a white solid. 1 H NMR(400 MHz,DMSO-d6)δ 8.20(s,1H),8.04-7.76(m,2H),7.57(t,J=7.8 Hz,2H),7.44(t,J=7.4 Hz,1H),7.39-7.21(m,2H),7.09-6.76(m,3H),4.11-3.88(m,2H),3.84(dd,J=11.7,3.8 Hz,1H),3.70-3.54(m,1H),2.76(td,J=11.6,3.1 MS m / z:335.0[M+H] + . (1H-indol-6-yl)(3-((phenylsulfonyl)methyl)piperidin-1-yl)methanone (29) [ka]

[0345] Step 1: tert-Butyl (E)-3-((phenylsulfonyl)methylene)piperidine-1-carboxylate: To a stirred mixture of diethyl ((phenylsulfonyl)methyl)phosphonate (880 mg, 3.01 mmol, 1.5 equiv) in THF (8 mL) was added NaH (60% w / z oil, 120 mg, 3.01 mmol, 1.50 equiv) dropwise under N2 atmosphere at 0°C. The resulting mixture was allowed to warm to room temperature and stirred under N2 atmosphere for 30 minutes. The reaction was then cooled to 0°C. To the stirred solution was added tert-butyl 3-oxopiperidine-1-carboxylate (399 mg, 2 mmol, 1.00 equiv) in THF (4.00 mL) dropwise under N2 atmosphere at 0°C. The resulting mixture was allowed to warm to room temperature and stirred at room temperature for 3 hours under N2 atmosphere. The desired product could be detected by LCMS. The reaction was quenched with saturated aqueous NH4HCO3 at 0 °C. The resulting mixture was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with water (2 × 20 mL) and brine (1 × 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EtOAc / PE (1 / 3) to give (E)-tert-butyl 3-((phenylsulfonyl)methylene)piperidine-1-carboxylate (200 mg, 29.5%) as a colorless oil. MS m / z: 338 [M+H] + .

[0346] Step 2: tert-Butyl 3-((phenylsulfonyl)methyl)piperidine-1-carboxylate: To a stirred solution of tert-butyl (3E)-3-[(benzenesulfonyl)methylidene]piperidine-1-carboxylate (200 mg, 0.593 mmol, 1.00 equiv) in MeOH (10 mL) was added Pd / C (20 mg, 10% Pd on carbon, wet with water). The resulting mixture was stirred overnight at room temperature under a hydrogen atmosphere. The resulting mixture was filtered, and the filter cake was washed with MeOH (3×10 mL). The filtrate was concentrated under reduced pressure. This afforded tert-butyl 3-[(benzenesulfonyl)methyl]piperidine-1-carboxylate (165 mg, 82.01%) as a yellow oil. MS m / z: 340 [M+H] + .

[0347] Step 3: 3-((phenylsulfonyl)methyl)piperidine: To a stirred solution of tert-butyl 3-[(benzenesulfonyl)methyl]piperidine-1-carboxylate (120 mg, 0.354 mmol, 1.00 equiv) in DCM (3 mL) was added HCl (g) in dioxane (1.5 mL) dropwise at 0° C. The resulting mixture was stirred at room temperature for 2 hours. After removal of the solvent, the crude product 3-[(benzenesulfonyl)methyl]piperidine (130 mg) was used in the next step without further purification. MS m / z: 240 [M+H] + .

[0348] Step 4: (1H-Indol-6-yl)(3-((phenylsulfonyl)methyl)piperidin-1-yl)methanone: A mixture of 1H-indole-6-carboxylic acid (91.8 mg, 0.570 mmol, 1.00 equiv), 3-[(benzenesulfonyl)methyl]piperidine (130 mg, 0.546 mmol, 1.1 equiv), and HATU (325 mg, 0.855 mmol, 1.5 equiv) was added to DMF (2.00 mL), followed by the addition of DIPEA (96.2 mg, 0.744 mmol, 1.5 equiv) at room temperature. The mixture was stirred at room temperature for 16 hours. The resulting mixture was diluted with water (20 mL) and extracted with EtOAc (3×15 mL). The combined organic layers were washed with brine (30 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography eluting with EtOAc / PE (1:1) to give the product. The product was further purified by reverse-phase Combi-Flash chromatography using the following conditions (column: C18 gel; mobile phase: B phase: MeCN, A phase: water; gradient of 35% to 75% B in 20 min; detector: UV 254 / 220 nm). The pure fractions were concentrated under vacuum to give (1H-indol-6-yl)(3-((phenylsulfonyl)methyl)piperidin-1-yl)methanone (19 mg, 9.96%) as a white solid. 1 H NMR(300 MHz,DMSO-d6)δ 11.28(s,1H),7.98-7.33(m,8H),6.97(d,J=8.1 Hz,1H),6.50(t,J=2.4 Hz,1H),4.22(s,2H),3.29(s,2H),2.97-2.68(m,2H),1.88(t,J=12.8 Hz,2H),1.60(d,J=11.3 Hz,1H),1.44-1.17(m,2H).MS m / z:393.1[M+H] + . 2-(1-ethyl-6-(3-((o-tolyloxy)methyl)piperidin-1-yl)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3,4-thiadiazole (30) [ka]

[0349] Step 1: Ethyl 6-bromo-1H-imidazo[4,5-b]pyrazine-2-carboxylate: A solution of 5-bromopyrazine-2,3-diamine (1 g, 5.29 mmol, 1.00 equiv.) and ethyl 2,2,2-triethoxyacetate (3.5 g, 15.8 mmol, 3.0 equiv.) in 2-methylpropan-2-ol (10 mL) was stirred at 100 °C for 3 days. The mixture was cooled to room temperature and concentrated in vacuo. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 5% to 95% gradient in 30 min; detector, UV 254 nm. This afforded ethyl 6-bromo-1H-imidazo[4,5-b]pyrazine-2-carboxylate (700 mg, 48.8%) as a yellow solid. MS m / z: 271 [M+H] + .

[0350] Step 2: Ethyl 6-bromo-1-ethyl-1H-imidazo[4,5-b]pyrazine-2-carboxylate: A solution of ethyl 6-bromo-1H-imidazo[4,5-b]pyrazine-2-carboxylate (700 mg, 2.58 mmol, 1 equiv.) and ethyl iodide (483 mg, 3.10 mmol, 1.2 equiv.) in DMF (5 mL) was stirred at room temperature overnight. The resulting mixture was diluted with EtOAc (40 mL). The combined organic layers were washed with water (3 × 20 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (2:1) to afford ethyl 6-bromo-1-ethyl-1H-imidazo[4,5-b]pyrazine-2-carboxylate (400 mg, 51.8%) as a yellow solid. MS m / z: 299 [M+H] + .

[0351] Step 3: Ethyl 1-ethyl-6-(3-((o-tolyloxy)methyl)piperidin-1-yl)-1H-imidazo[4,5-b]pyrazine-2-carboxylate: A solution of ethyl 6-bromo-1-ethyl-1H-imidazo[4,5-b]pyrazine-2-carboxylate (400 mg, 1.34 mmol, 1 equiv), 3-(2-methylphenoxymethyl)piperidine (302 mg, 1.471 mmol, 1.1 equiv), and NaCO (283 mg, 2.674 mmol, 2 equiv) in DMF (5 mL) was stirred at 100 °C for 3 h. The resulting mixture was diluted with EtOAc (30 mL). The organic layer was washed with water (3 × 20 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using the following conditions: column, silica gel; mobile phase, MeCN in water, gradient 10% to 95% in 30 min; detector, UV 254 nm. This gave ethyl 1-ethyl-6-(3-((o-tolyloxy)methyl)piperidin-1-yl)-1H-imidazo[4,5-b]pyrazine-2-carboxylate (290 mg, 51.21%) as a pale yellow solid. MS m / z: 424 [M+H] + .

[0352] Step 4: 1-Ethyl-6-(3-((o-tolyloxy)methyl)piperidin-1-yl)-1H-imidazo[4,5-b]pyrazine-2-carbohydrazide: A solution of ethyl 1-ethyl-6-(3-((o-tolyloxy)methyl)piperidin-1-yl)-1H-imidazo[4,5-b]pyrazine-2-carboxylate (290 mg, 0.685 mmol, 1 equiv.) in hydrazine (4 mL) was stirred at 80° C. for 2 hours. The resulting mixture was concentrated in vacuo. The crude product obtained was used directly in the next step without further purification. MS m / z: 410 [M+H] + .

[0353] Step 5: 1-Ethyl-N'-formyl-6-(3-((o-tolyloxy)methyl)piperidin-1-yl)-1H-imidazo[4,5-b]pyrazine-2-carbohydrazide: A solution of 1-ethyl-6-(3-((o-tolyloxy)methyl)piperidin-1-yl)-1H-imidazo[4,5-b]pyrazine-2-carbohydrazide (290 mg, 0.708 mmol, 1 equiv) in HCOOH (5 mL) was stirred at 80°C for 2 hours. The residue was purified by reverse-phase flash chromatography using the following conditions: column, silica gel; mobile phase, MeCN in water, 10% to 100% gradient in 30 minutes; detector, UV 254 nm. This gave 1-ethyl-N'-formyl-6-(3-((o-tolyloxy)methyl)piperidin-1-yl)-1H-imidazo[4,5-b]pyrazine-2-carbohydrazide (200 mg, 64.5%) as a yellow solid. MS m / z: 438 [M+H] + .

[0354] Step 6: 2-(1-Ethyl-6-(3-((o-tolyloxy)methyl)piperidin-1-yl)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3,4-thiadiazole: A solution of 1-ethyl-N'-formyl-6-(3-((o-tolyloxy)methyl)piperidin-1-yl)-1H-imidazo[4,5-b]pyrazine-2-carbohydrazide (30 mg, 0.069 mmol, 1.00 equiv) and Lawesson's reagent (16.6 mg, 0.041 mmol, 0.60 equiv) in PhCH (2 mL) was stirred at 100 °C for 3 h. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with PE / EA (2:1) to give 2-(1-ethyl-6-(3-((o-tolyloxy)methyl)piperidin-1-yl)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3,4-thiadiazole as a yellow solid. The residue was further purified by reverse-phase flash chromatography using the following conditions: column, silica gel; mobile phase, MeCN in water, 10% to 90% gradient in 30 min; detector, UV 254 nm. This gave 2-(1-ethyl-6-(3-((o-tolyloxy)methyl)piperidin-1-yl)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3,4-thiadiazole (12.2 mg, 40.0%) as a yellow solid. 1 H NMR(400 MHz,CDCl3)δ 9.18(s,1H),8.27(s,1H),7.16(t,J=7.7 Hz,2H),6.99-6.74(m,2H),4.90(q,J=7.1 Hz,2H),4.72-4.62(m,1H),4.33(d,J=12.9 Hz,1H),4.00(dd,J=9.2,4.8 Hz,1H),3.93-3.83(m,1H),3.23-3.12(m,1H),3.10-2.98(m,1H),2.31(s,3H),2.30-2.1 9(m,1H),2.05-1.96(m,1H),1.95-1.87(m,1H),1.86-1.67(m,1H),1.60-1.46(m,4H).MS m / z:435.9[M+H] + 1-(2,2-Difluoroethyl)-6-(2-methyl-5-(((2-(trifluoromethyl)pyridin-3-yl)oxy)methyl)piperidin-1-yl)-1H-pyrazolo[3,4-b]pyrazine (31) [ka]

[0355] Step 1: tert-butyl 2-methyl-5-(((2-(trifluoromethyl)pyridin-3-yl)oxy)methyl)piperidine-1-carboxylate: Following general procedure A using tert-butyl 5-(hydroxymethyl)-2-methylpiperidine-1-carboxylate (100 mg, 0.436 mmol, 1.00 equiv) and 2-(trifluoromethyl)pyridin-3-ol (64 mg, 0.392 mmol, 0.9 equiv) gave tert-butyl 2-methyl-5-(((2-(trifluoromethyl)pyridin-3-yl)oxy)methyl)piperidine-1-carboxylate (70 mg, 42.8%) as a colorless oil. MS m / z: 375 [M+H] + .

[0356] Step 2: 3-((6-methylpiperidin-3-yl)methoxy)-2-(trifluoromethyl)pyridine hydrochloride: Following general procedure B using tert-butyl 2-methyl-5-(((2-(trifluoromethyl)pyridin-3-yl)oxy)methyl)piperidine-1-carboxylate (70 mg, 0.187 mmol, 1.00 equiv.) gave 3-((6-methylpiperidin-3-yl)methoxy)-2-(trifluoromethyl)pyridine hydrochloride (50 mg). MS m / z: 275 [M+H] + .

[0357] Step 3: 1-(2,2-Difluoroethyl)-6-(2-methyl-5-(((2-(trifluoromethyl)pyridin-3-yl)oxy)methyl)piperidin-1-yl)-1H-pyrazolo[3,4-b]pyrazine: General procedure C was followed using 3-((6-methylpiperidin-3-yl)methoxy)-2-(trifluoromethyl)pyridine hydrochloride (50 mg, 0.161 mmol, 1.00 equiv) and 6-chloro-1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazine (38.7 mg, 0.177 mmol, 1.1 equiv). The crude product was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, ACN in water, gradient 10% to 50% in 30 min; detector, UV 254 / 220 nm to give 1-(2,2-difluoroethyl)-6-(2-methyl-5-(((2-(trifluoromethyl)pyridin-3-yl)oxy)methyl)piperidin-1-yl)-1H-pyrazolo[3,4-b]pyrazine (17.3 mg, 22.9%) as a white solid. 1 H NMR (400 MHz, CD3OD): δ 8.32(s,1H),8.23-8.10(m,1H),7.99(s,1H),7.77-7.72(m,1H),7.66-7.6 1(m,1H),6.40-6.09(m,1H),4.94-4.88(m,1H),4.81-4.76(m,1H),4.72-4 .62(m,2H),4.29-4.24(m,1H),4.12-4.06(m,1H),3.07-2.97(m,1H),2.23 -2.13(m,1H),2.00-1.90(m,1H),1.88-1.74(m,3H),1.35-1.29(m,3H).MS m / z:457.2[M+H] + . 5-Methyl-6-phenyl-3-(3-((o-tolyloxy)methyl)piperidin-1-yl)-5H-pyrrolo[2,3-b]pyrazine (32) [ka]

[0358] Step 1: 6-Chloro-3-(2-phenylethynyl)pyrazin-2-amine: To a stirred mixture of 3-bromo-6-chloropyrazin-2-amine (1 g, 4.79 mmol, 1.00 equiv.), ethynylbenzene (0.74 g, 7.19 mmol, 1.50 equiv.), CuI (0.09 g, 0.480 mmol, 0.1 equiv.), and PPh (2.52 g, 9.59 mmol, 2 equiv.) in DMF (10 mL) was added Pd(PPh)Cl (0.34 g, 0.480 mmol, 0.1 equiv.) and TEA (1.46 g, 14.3 mmol, 3 equiv.) at room temperature. The resulting mixture was stirred at 80 °C under a N atmosphere for 16 h. The resulting mixture was diluted with EtOAc (40 mL). The resulting mixture was washed with water (2 × 40 mL). The combined organic layers were washed with brine (40 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water, gradient 0% to 100% in 30 min; detector, UV 254 nm. This afforded 6-chloro-3-(2-phenylethynyl)pyrazin-2-amine (870 mg, 79.0%) as a yellow solid. MS m / z: 230 [M+H] + .

[0359] Step 2: 3-chloro-6-phenyl-5H-pyrrolo[2,3-b]pyrazine: A solution of 6-chloro-3-(2-phenylethynyl)pyrazin-2-amine (200 mg, 0.871 mmol, 1.00 equiv.) and t-BuOK (200 mg, 1.78 mmol, 2.05 equiv.) in NMP (3 mL) was stirred at 80 °C for 2 h. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeOH in water, gradient 0% to 100% in 30 min; detector, UV 254 nm. This afforded 3-chloro-6-phenyl-5H-pyrrolo[2,3-b]pyrazine (175 mg, 87.5%) as a yellow solid. MS m / z: 230 [M+H] + .

[0360] Step 3: 3-chloro-5-methyl-6-phenylpyrrolo[2,3-b]pyrazine: To a stirred solution of 3-chloro-6-phenyl-5H-pyrrolo[2,3-b]pyrazine (170 mg, 0.740 mmol, 1.00 equiv.) and CsCO (723 mg, 2.22 mmol, 3 equiv.) in DMF (2 mL) was added MeI (126 mg, 0.888 mmol, 1.2 equiv.) at room temperature. The resulting mixture was stirred at room temperature for 3 h. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 0% to 100% gradient in 30 min; detector, UV 254 nm. This afforded 3-chloro-5-methyl-6-phenylpyrrolo[2,3-b]pyrazine (150 mg, 83.2%) as a yellow solid. MS m / z: 244 [M+H] + .

[0361] Step 4: 5-Methyl-6-phenyl-3-(3-((o-tolyloxy)methyl)piperidin-1-yl)-5H-pyrrolo[2,3-b]pyrazine: To a stirred solution of 3-chloro-5-methyl-6-phenylpyrrolo[2,3-b]pyrazine (50 mg, 0.205 mmol, 1.00 equiv.) and 3-((o-tolyloxy)methyl)piperidine hydrochloride (54.7 mg, 0.267 mmol, 1.3 equiv.) in dioxane (1 mL) was added 1612891-29-8 (17.2 mg, 0.021 mmol, 0.1 equiv.) and CsCO (200 mg, 0.615 mmol, 3 equiv.) at room temperature under a N atmosphere. The resulting mixture was stirred at 100 °C under a N atmosphere for 2 hours. The desired product could be detected by LCMS. The reaction mixture was diluted with EtOAc (20 mL), washed with water (2 × 20 mL) and brine (1 × 20 mL), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water, gradient from 0% to 100% in 30 min; detector, UV 254 nm. This afforded 5-methyl-6-phenyl-3-(3-((o-tolyloxy)methyl)piperidin-1-yl)-5H-pyrrolo[2,3-b]pyrazine (14 mg, 16.47%) as a yellow solid.1 H NMR(400 MHz,DMSO-d6)δ 8.13(s,1H),7.62-7.53(m,2H),7.51-7.42(m,2H),7.41-7.32(m,1H),7.09-7.05(m,2H),6.94 -6.82(m,1H),6.78-6.74(m,1H),6.52(s,1H),4.51-4.46(m,1H),4.20-4.17(m,1H),3.94-3.90 (m,1H),3.85-3.81(m,1H),3.62(s,3H),3.05-2.94(m,1H),2.88-2.82(m,1H),2.17(s,3H),2. 05-2.00(m,1H),1.92-1.80(m,1H),1.75-1.70(m,1H),1.57-1.48(m,1H),1.45-1.28(m,1H).MS m / z:413.0[M+H] + . 5-Methyl-6-phenyl-3-(3-(((2-(trifluoromethyl)pyridin-3-yl)oxy)methyl)piperidin-1-yl)-5H-pyrrolo[2,3-b]pyrazine (33) [ka]

[0362] To a stirred solution of 3-(piperidin-3-ylmethoxy)-2-(trifluoromethyl)pyridine hydrochloride (94.9 mg, 0.320 mmol, 1.3 equiv.) and 3-chloro-5-methyl-6-phenyl-5H-pyrrolo[2,3-b]pyrazine (60 mg, 0.246 mmol, 1.00 equiv.) in dioxane (2 mL) was added 1612891-29-8 (20.7 mg, 0.025 mmol, 0.1 equiv.) and CsCO (160 mg, 0.492 mmol, 2 equiv.) at room temperature under a N atmosphere. The resulting mixture was stirred at 100 °C under a N atmosphere for 2 hours. The desired product could be detected by LCMS. The reaction mixture was diluted with EtOAc (20 mL), washed with water (2 × 20 mL) and brine (1 × 20 mL), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water, gradient 0% to 100% in 30 min; detector, UV 254 nm. This afforded 5-methyl-6-phenyl-3-(3-(((2-(trifluoromethyl)pyridin-3-yl)oxy)methyl)piperidin-1-yl)-5H-pyrrolo[2,3-b]pyrazine (17 mg, 14.19%) as a yellow solid. 1 H NMR(400 MHz,DMSO-d6)δ 8.26(dd,J=4.5,1.2 Hz,1H),8.19(s,1H),7.85-7.80(m,1H),7.72-7.67(m,1H),7.67-7.60(m ,2H),7.56-7.47(m,2H),7.47-7.39(m,1H),6.60(s,1H),4.54(d,J=11.1 Hz,1H),4.30-4.18(m,2H),4.15-4.07(m,1H),3.68(s,3H),3.03(t,J=11.0 Hz,1H),2.96-2.86(m,1H),2.14(s,1H),1.96-1.86(m,1H),1.86-1.76(m,1H),1.67-1.53(m,1H),1.50-1.39(m,1H).MS m / z:468.3[M+H] + . 3-(Phenoxymethyl)-1-[3-(trifluoromethyl)-5H,6H,7H,8H-[1,2,4]triazolo[4,3-a]pyrazine-7-carbonyl]piperidine (34) [ka]

[0363] Step 1: 4-Nitrophenyl 3-(trifluoromethyl)-5H,6H,7H,8H-[1,2,4]triazolo[4,3-a]pyrazine-7-carboxylate: A mixture of 3-(trifluoromethyl)-5H,6H,7H,8H-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride (100 mg, 437 μmol, 1.0 equiv.), 4-nitrophenyl carbonochloridate (97.0 mg, 1.1 equiv., 481 μmol), and TEA (122 μL, 2 equiv., 875 μmol) in THF (2.00 mL) was stirred at room temperature for 16 hours. The mixture was filtered. The filtrate was concentrated and purified by Combi-flash to give a white solid (85 mg, 54%). MS m / z: 358 [M+H] +

[0364] Step 2: 3-(Phenoxymethyl)-1-[3-(trifluoromethyl)-5H,6H,7H,8H-[1,2,4]triazolo[4,3-a]pyrazine-7-carbonyl]piperidine: A mixture of 4-nitrophenyl 3-(trifluoromethyl)-5H,6H,7H,8H-[1,2,4]triazolo[4,3-a]pyrazine-7-carboxylate (20.0 mg, 56.0 μmol), 3-(phenoxymethyl)piperidine hydrochloride (12.7 mg, 56.0 μmol), and TEA (9.36 μL, 1.2 equiv, 67.2 μmol) in DMF (1.00 mL) was heated at 70 °C overnight. Completion of the reaction was determined by LC-MS. Water (2 mL) was added to the mixture, and it was extracted with EtOAc (3 mL × 2). The organic layer was concentrated and purified by Combi-Flash to give 3-(phenoxymethyl)-1-[3-(trifluoromethyl)-5H,6H,7H,8H-[1,2,4]triazolo[4,3-a]pyrazine-7-carbonyl]piperidine as a pale yellow oil (21 mg, 92%). 1 H NMR(500 MHz,CDCl3)δ 7.30-7.26(m,2H),6.95(tt,J=7.3,1.1 Hz,1H),6.88-6.84(m,2H),4.70(d,J=1.4 Hz,2H),4.28-4.15(m,2H),3.93-3.83(m,2H),3.79(dd,J=9.4,8.1 Hz,1H),3.73-3.56(m,3H),2.95(td,J=11.8,11.3,3.0 Hz,1H),2.90-2.78(m,1H),2.17-2.07(m,1H),1.94(dq,J=13.0,4.1 Hz,1H),1.81(dt,J=13.6,3.7 Hz,1H),1.39(dtd,J=13.1,11.2,4.0 Hz,1H).MS m / z:410[M+H] + . 3-({1-[1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-3-fluoropiperidin-3-yl}methoxy)-2-(trifluoromethyl)pyridine (35) [ka]

[0365] Step 1: tert-butyl 3-fluoro-3-({[2-(trifluoromethyl)pyridin-3-yl]oxy}methyl)piperidine-1-carboxylate: Following general procedure A using tert-butyl 3-fluoro-3-(hydroxymethyl)piperidine-1-carboxylate (200 mg, 0.86 mmol, 1.00 equiv.) and 2-(trifluoromethyl)pyridin-3-ol (140 mg, 0.86 mmol, 1.0 equiv.), tert-butyl 3-fluoro-3-({[2-(trifluoromethyl)pyridin-3-yl]oxy}methyl)piperidine-1-carboxylate (190 mg, 59%) was obtained as a colorless oil. MS m / z: 379 [M+H] + .

[0366] Step 2: 3-[(3-fluoropiperidin-3-yl)methoxy]-2-(trifluoromethyl)pyridine hydrochloride: General procedure B was followed using tert-butyl 3-fluoro-3-({[2-(trifluoromethyl)pyridin-3-yl]oxy}methyl)piperidine-1-carboxylate (190 mg, 0.5 mmol, 1.00 equiv.) to give 3-[(3-fluoropiperidin-3-yl)methoxy]-2-(trifluoromethyl)pyridine hydrochloride (150 mg). MS m / z: 279 [M+H] + .

[0367] Step 3: 3-({1-[1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-3-fluoropiperidin-3-yl}methoxy)-2-(trifluoromethyl)pyridine: 3-[(3-fluoropiperidin-3-yl)methoxy]-2-(trifluoromethyl)pyridine hydrochloride (17.3 mg, 0.055 mmol, 1.00 equiv) and 6-chloro-1-( General procedure C was followed using 2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazine (12 mg, 0.055 mmol, 1.1 equiv) to give 3-({1-[1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-3-fluoropiperidin-3-yl}methoxy)-2-(trifluoromethyl)pyridine (18 mg, 71%) as a white solid. 1 H NMR(500 MHz,CDCl3)δ 8.33(dd,J=4.5,1.2 Hz,1H),8.28(s,1H),8.05(s,1H),7.49(dd,J=8.5,4.6 Hz,1H),7.40(dd,J=8.5,1.2 Hz,1H),6.21(tt,J=55.6,4.5 Hz,1H),4.74-4.58(m,3H),4.35-4.12(m,3H),3.60(dd,J=28.9,14.3 Hz,1H),3.39-3.27(m,1H),2.17-1.96(m,3H),1.88-1.75(m,1H).MS m / z:461[M+H] + . (1R,5S,6S)-3-[1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-6-({[6-(trifluoromethyl)pyridin-2-yl]oxy}methyl)-3-azabicyclo[3.1.0]hexane (36) [ka]

[0368] Step 1: tert-butyl 3-fluoro-3-({[2-(trifluoromethyl)pyridin-3-yl]oxy}methyl)piperidine-1-carboxylate: Following general procedure D using tert-butyl (1R,5S,6S)-6-(hydroxymethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (250 mg, 1.17 mmol, 1.00 equiv.) and 2-bromo-6-(trifluoromethyl)pyridine (265 mg, 1.17 mmol, 1.0 equiv.), tert-butyl (1R,5S,6S)-6-({[6-(trifluoromethyl)pyridin-2-yl]oxy}methyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (360 mg, 86%) was obtained as a colorless oil. MS m / z: 359 [M+H] + .

[0369] Step 2: (1R,5S,6S)-6-({[6-(trifluoromethyl)pyridin-2-yl]oxy}methyl)-3-azabicyclo[3.1.0]hexane hydrochloride: General procedure B was followed using tert-butyl (1R,5S,6S)-6-({[6-(trifluoromethyl)pyridin-2-yl]oxy}methyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (360 mg, 1 mmol, 1.00 equiv.) to give (1R,5S,6S)-6-({[6-(trifluoromethyl)pyridin-2-yl]oxy}methyl)-3-azabicyclo[3.1.0]hexane hydrochloride (250 mg). MS m / z: 259 [M+H] + .

[0370] Step 3: (1R,5S,6S)-3-[1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-6-({[6-(trifluoromethyl)pyridin-2-yl]oxy}methyl)-3-azabicyclo[3.1.0]hexane: (1R,5S,6S)-6-({[6-(trifluoromethyl)pyridin-2-yl]oxy}methyl)-3-azabicyclo[3.1.0]hexane hydrochloride (16.2 mg, 0.055 mmol, 1.00 equiv.) General procedure C was followed using (1R,5S,6S)-3-[1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazine (12 mg, 0.055 mmol, 1.1 equiv) to give (1R,5S,6S)-3-[1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-6-({[6-(trifluoromethyl)pyridin-2-yl]oxy}methyl)-3-azabicyclo[3.1.0]hexane (23 mg, 95%) as a white solid. 1 H NMR(500 MHz,CDCl3)δ 8.03(s,1H),7.91(s,1H),7.72(t,J=7.8 Hz,1H),7.25(s,1H),6.93(d,J=8.4 Hz,1H),6.22(tt,J=55.7,4.5 Hz,1H),4.65(td,J=13.4,4.5 Hz,2H),4.32(d,J=7.2 Hz,2H),3.95(d,J=10.7 Hz,2H),3.65(dt,J=10.7,2.1 Hz,2H),1.89(d,J=3.3 Hz,2H),1.22(tt,J=7.1,3.4 Hz,1H).MS m / z:441[M+H] + . 2-(1-ethyl-5-(3-((o-tolyloxy)methyl)piperidin-1-yl)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3,4-thiadiazole (37) [ka]

[0371] Step 1: 2-(1-Ethyl-5-(3-((o-tolyloxy)methyl)piperidin-1-yl)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3,4-thiadiazole: A solution of 1-ethyl-N'-formyl-5-[3-(2-methylphenoxymethyl)piperidin-1-yl]imidazo[4,5-b]pyrazine-2-carbohydrazide (30 mg, 0.069 mmol, 1.00 equiv) and Lawesson's reagent (16.6 mg, 0.041 mmol, 0.60 equiv) in PhCH (2 mL) was stirred at 100° C. for 3 h. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with PE / EA (2:1) to give 2-(1-ethyl-5-(3-((o-tolyloxy)methyl)piperidin-1-yl)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3,4-thiadiazole (4.5 mg, 15.1%) as a yellow solid. The residue was purified by reverse-phase flash chromatography using the following conditions: column, silica gel; mobile phase, MeCN in water, 10% to 90% gradient in 30 min; detector, UV 254 nm. This gave 2-(1-ethyl-5-(3-((o-tolyloxy)methyl)piperidin-1-yl)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3,4-thiadiazole (4.5 mg, 15.1%) as a yellow solid. 1 H NMR(400 MHz,CDCl3)δ 9.25(s,1H),8.42(s,1H),7.19-7.11(,2H),6.89-6.84(m,1H),6.83-6.78(m,1H),5.02(q,J=7.1 Hz,2H),4.39-4.21(m,2H),4.01-3.86(m,2H),3.29-3.17(m,2H),2.50-2.35(m ,1H),2.27(s,3H),2.07-1.98(m,1H),1.97-1.86(m,2H),1.63-1.51(m,4H).MS m / z:436.2[M+H] + . 1-Methyl-5-phenyl-3-(3-((o-tolyloxy)methyl)piperidine-1-carbonyl)-1,5-dihydro-4H-pyrrolo[3,2-c]pyridin-4-one (38) [ka]

[0372] Step 1: 4-Chloro-1-methyl-1H-pyrrolo[3,2-c]pyridine-3-carbaldehyde: To a solution of 4-chloro-1-methyl-1H-pyrrolo[3,2-c]pyridine (500 mg, 3.00 mmol, 1.00 equiv) in DMF (5.0 mL) was added POCl (1.38 g, 9.00 mmol, 3.0 equiv) at 0 °C. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. The mixture was basified to pH 10 with 1 M NaOH. The resulting mixture was extracted with CHCl (3 × 30 mL). The combined organic layers were washed with water (2 × 30 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. This gave 4-chloro-1-methyl-1H-pyrrolo[3,2-c]pyridine-3-carbaldehyde (350 mg, 59.9%) as a white solid. MS m / z: 195 [M+H] + .

[0373] Step 2: 4-Chloro-1-methyl-1H-pyrrolo[3,2-c]pyridine-3-carboxylic acid: To a stirred solution of 4-chloro-1-methyl-1H-pyrrolo[3,2-c]pyridine-3-carbaldehyde (300 mg, 1.54 mmol, 1 equiv.) and 2,3-dimethylbut-2-ene (324 mg, 3.85 mmol, 2.5 equiv.) in t-BuOH (5 mL) and HO (1 mL) was added NaClO (209 mg, 2.31 mmol, 1.5 equiv.) and NaHPO (1109 mg, 9.24 mmol, 6.0 equiv.) in portions at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. The resulting mixture was acidified to pH ∼3 and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with water (2 x 30 mL) and brine (30 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated in vacuo to give 4-chloro-1-methyl-1H-pyrrolo[3,2-c]pyridine-3-carboxylic acid (250 mg, 77.0%) as a white solid. MS m / z: 211 [M+H] + .

[0374] Step 3: (4-Chloro-1-methyl-1H-pyrrolo[3,2-c]pyridin-3-yl)(3-((o-tolyloxy)methyl)piperidin-1-yl)methanone: To a stirred solution of 4-chloro-1-methyl-1H-pyrrolo[3,2-c]pyridine-3-carboxylic acid (230 mg, 1.09 mmol, 1 equiv) and 3-((o-tolyloxy)methyl)piperidine (269 mg, 1.31 mmol, 1.2 equiv) in DMF (3 mL) was added HATU (622 mg, 1.63 mmol, 1.5 equiv) and DIPEA (423 mg, 3.27 mmol, 3 equiv) dropwise at 0° C. under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. The reaction was diluted with water at room temperature. The resulting mixture was extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (1x20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (5:1) to give (4-chloro-1-methyl-1H-pyrrolo[3,2-c]pyridin-3-yl)(3-((o-tolyloxy)methyl)piperidin-1-yl)methanone (300 mg, 69.0%) as a white solid. MS m / z: 398 [M+H] + .

[0375] Step 4: 1-Methyl-3-(3-((o-tolyloxy)methyl)piperidine-1-carbonyl)-1,5-dihydro-4H-pyrrolo[3,2-c]pyridin-4-one: To a stirred solution of (4-chloro-1-methyl-1H-pyrrolo[3,2-c]pyridin-3-yl)(3-((o-tolyloxy)methyl)piperidin-1-yl)methanone (150 mg, 0.377 mmol, 1 equiv.) in AcOH (2.5 mL) was added NHOAc (290 mg, 3.77 mmol, 10 equiv.) in portions at 0° C. under an air atmosphere. The resulting mixture was stirred overnight at 100° C. under a nitrogen atmosphere. The desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (2:1) to give 1-methyl-3-(3-((o-tolyloxy)methyl)piperidine-1-carbonyl)-1,5-dihydro-4H-pyrrolo[3,2-c]pyridin-4-one (100 mg, 69.91%) as a white solid. MS m / z: 380 [M+H] + .

[0376] Step 5: 1-Methyl-5-phenyl-3-(3-((o-tolyloxy)methyl)piperidine-1-carbonyl)-1,5-dihydro-4H-pyrrolo[3,2-c]pyridin-4-one: 1-Methyl-3-(3-((o-tolyloxy)methyl)piperidine-1-carbonyl)-1,5-dihydro-4H-pyrrolo[3,2-c]pyridin-4-one (100 mg, 0.26 To a stirred solution of CsCO (171 mg, 0.528 mmol, 2 equiv.), CuI (5.02 mg, 0.026 mmol, 0.1 equiv.), and iodobenzene (107.53 mg, 0.528 mmol, 2 equiv.) in DMF (3 mL) was added CsCO (171 mg, 0.528 mmol, 2 equiv.), CuI (5.02 mg, 0.026 mmol, 0.1 equiv.), and 1,10-phenanthroline (9.50 mg, 0.053 mmol, 0.2 equiv.) under an air atmosphere at room temperature. The resulting mixture was stirred overnight at 100 °C under an argon atmosphere. The reaction was diluted with water at room temperature. The resulting mixture was extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with water (2 × 20 mL) and brine (1 × 20 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water, gradient 10% to 90% in 20 min; detector, UV 254 nm. This gave 1-methyl-5-phenyl-3-(3-((o-tolyloxy)methyl)piperidine-1-carbonyl)-1,5-dihydro-4H-pyrrolo[3,2-c]pyridin-4-one (35 mg, 29.1%) as a white solid. 1 H NMR(300 MHz,DMSO-d6)δ 7.59-7.29(m,6H),7.28-6.99(m,3H),6.97-6.73(m,2H),6.69(d,J=7.4 Hz,1H),4.62-4.19(m,1H),4.01-3.81(m,2H),3.73(d,J=18.3 Hz,3H),3.61-3.48(m,1H),3.11-2.72(m,2H),2.18(s,1H),2.04(d,J=25.5 Hz,1H),1.88-1.18(m,6H).MS m / z:456.0[M+H] + . 5-Methyl-6-phenyl-3-(3-((o-tolyloxy)methyl)pyrrolidin-1-yl)-5H-pyrrolo[2,3-b]pyrazine (39) [ka]

[0377] Step 1: tert-Butyl 3-((o-tolyloxy)methyl)pyrrolidine-1-carboxylate: To a stirred mixture of o-cresol (200 mg, 1.85 mmol, 1 equiv.), tert-butyl 3-(hydroxymethyl)pyrrolidine-1-carboxylate (447 mg, 2.22 mmol, 1.2 equiv.) in THF (5 mL), and PPh3 (728 mg, 2.77 mmol, 1.5 equiv.) in THF (4 mL) was added TMAD (478 mg, 2.77 mmol, 1.5 equiv.) portionwise at 0° C. The resulting mixture was warmed to 50° C. and stirred overnight. The desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EtOAc / PE (1 / 1) to give tert-butyl 3-((o-tolyloxy)methyl)pyrrolidine-1-carboxylate (120 mg, 22.3%) as a yellow solid. MS m / z: 292 [M+H] + .

[0378] Step 2: 3-((o-Tolyloxy)methyl)pyrrolidine hydrochloride: To a stirred solution of tert-butyl 3-(2-methylphenoxymethyl)pyrrolidine-1-carboxylate (120 mg, 0.412 mmol, 1 equiv.) in DCM (2.5 mL) was added HCl (gas) in dioxane (2.5 mL). The mixture was stirred at room temperature for 2 hours. After removal of the solvent, the crude product, 3-((o-tolyloxy)methyl)pyrrolidine hydrochloride (100 mg), was used directly in the next step without further purification. MS m / z: 192 [M+H] + .

[0379] Step 3: 5-Methyl-6-phenyl-3-(3-((o-tolyloxy)methyl)pyrrolidin-1-yl)-5H-pyrrolo[2,3-b]pyrazine: To a stirred solution of 3-((o-tolyloxy)methyl)pyrrolidine (100 mg, 0.410 mmol, 1 equiv.) and 3-(2-methylphenoxymethyl)pyrrolidine (86.3 mg, 0.451 mmol, 1.1 equiv.) in DMF (1.00 mL) was added Na2CO3 (87.0 mg, 0.820 mmol, 2 equiv.) at room temperature. The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 2 h. The resulting mixture was diluted with water (20 mL) and extracted with EtOAc (3 × 15 mL). The combined organic layers were washed with brine (30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography eluting with EtOAc / PE (1:1) to give the product. The product was further purified by reverse-phase Combi-Flash chromatography using the following conditions (column: C18 gel; mobile phase: B phase: MeCN, A phase: water; gradient of 35% to 75% B in 20 min; detector: UV 254 / 220 nm). The pure fractions were concentrated in vacuo to give 5-methyl-6-phenyl-3-(3-((o-tolyloxy)methyl)pyrrolidin-1-yl)-5H-pyrrolo[2,3-b]pyrazine (13 mg, 10.40%) as a white solid. 1 H NMR(400 MHz,DMSO-d6)δ 7.87(s,1H),7.63(d,J=7.6 Hz,2H),7.51(t,J=7.5 Hz,2H),7.42(t,J=7.3 Hz,1H),7.14(d,J=7.4 Hz,2H),6.96(d,J=8.1 Hz,1H),6.84(t,J=7.4 Hz,1H),6.60(s,1H),4.06(d,J=6.5 Hz,2H),3.79(dd,J=10.5,7.5 Hz,1H),3.72(s,4H),3.56(q,J=8.2 Hz,1H),3.45(dd,J=10.6,6.6 Hz,1H),2.85(t,J=7.1 Hz,1H),2.17(s,4H),1.98(t,J=12.7,7.2 Hz,1H).MS m / z:398.9[M+H] + . (1R,5S,6S)-3-[6-(1,3,4-thiadiazol-2-yl)pyrazin-2-yl]-6-({[2-(trifluoromethyl)pyridin-3-yl]oxy}methyl)-3-azabicyclo[3.1.0]hexane (40) [ka]

[0380] General procedure C was followed using (1R,5S,6S)-6-({[2-(trifluoromethyl)pyridin-3-yl]oxy}methyl)-3-azabicyclo[3.1.0]hexane hydrochloride (16.2 mg, 0.055 mmol, 1.00 equiv) and 2-chloro-6-(1,3,4-thiadiazol-2-yl)pyrazine (11 mg, 0.055 mmol, 1.1 equiv) to give (1R,5S,6S)-3-[6-(1,3,4-thiadiazol-2-yl)pyrazin-2-yl]-6-({[2-(trifluoromethyl)pyridin-3-yl]oxy}methyl)-3-azabicyclo[3.1.0]hexane (13 mg, 56%) as a white solid. 1 H NMR(500 MHz,CDCl3)δ 9.19(s,1H),8.85(s,1H),8.28(dd,J=4.6,1.2 Hz,1H),7.97(s,1H),7.46(dd,J=8.5,4.6 Hz,1H),7.37(d,J=8.5 Hz,1H),4.13(d,J=6.2 Hz,2H),3.90(d,J=10.4 Hz,2H),3.63(dt,J=10.6,1.9 Hz,2H),1.97-1.89(m,2H),1.28-1.25(m,1H).MS m / z:421[M+H] + . 1-(4-{5-methyl-2-[3-(phenoxymethyl)piperidin-1-yl]-5H-pyrrolo[2,3-b]pyrazin6-yl}piperidin-1-yl)ethan-1-one (41) [ka]

[0381] Step 1: 1-(4-{2-Bromo-5-methyl-5H-pyrrolo[2,3-b]pyrazin-6-yl}piperidin-1-yl)ethan-1-one: 4-{2-Bromo-5-methyl-5H-pyrrolo[2,3-b]pyrazin-6-yl}piperidine (300 mg, 1.02 mmol), DIPEA (266 μL, 1.5 equiv., 1.52 mmol), and acetyl chloride (87.0 μL, 1.2 equiv., 1.22 mmol) were combined with DCM (4 mL). The reaction mixture was stirred overnight. The crude reaction mixture was concentrated in vacuo and purified by chromatography (silica gel, 12 g, 50:50 to 100:0 EtOAc / hexanes). The fractions were concentrated and dried under vacuum to give 1-(4-{2-bromo-5-methyl-5H-pyrrolo[2,3-b]pyrazin-6-yl}piperidin-1-yl)ethan-1-one as a white solid (310, 90%). MS m / z: 338 [M+H] + .

[0382] Step 2: 1-(4-{5-methyl-2-[3-(phenoxymethyl)piperidin-1-yl]-5H-pyrrolo[2,3-b]pyrazin-6-yl}piperidin-1-yl)ethan-1-one: 1-(4-{2-bromo-5-methyl-5H-pyrrolo[2,3-b]pyrazin-6-yl}piperidin-1-yl)ethan-1-one (14.8 mg, 43.9 μmol) and 1-(4-{2-bromo-5-methyl-5H-pyrrolo[2,3-b]pyrazin-6-yl}piperidin-1-yl)ethan-1-one (14.8 mg, 43.9 μmol) with diserium(1+) carbonate (42.9 mg, 3 equiv., 132 μmol), RuPhos Pd A mixture of G3 (3.67 mg, 0.1 equiv., 4.39 μmol) in 1,4-dioxane (500 μL) was heated at 70° C. overnight. The reaction was monitored by LCMS. The mixture was cooled to room temperature and filtered through Celite. The filtrate was concentrated and purified by flash chromatography (silica gel, 12 g, EtOAc / hexanes = 50:50 to 100:0) to give 1-(4-{5-methyl-2-[3-(phenoxymethyl)piperidin-1-yl]-5H-pyrrolo[2,3-b]pyrazin-6-yl}piperidin-1-yl)ethan-1-one as a colorless oil (5 mg, 25%).1 H NMR(500 MHz,DMS...

Claims

1. Compounds of formula (I): 【Chemistry 1】 or a pharma- ceutically acceptable salt thereof, R １ is a substituted or unsubstituted heteroaryl, a substituted or unsubstituted aryl, a substituted or unsubstituted carbocyclyl, a substituted or unsubstituted heterocyclyl, pentyl, butyl, methyl, -CH ２ CH ２ CH (CH ３ ) ２ or hydrogen or, when n is 0 and G is a bond, heterocyclyl which optionally forms a spiro ring system with A; G is a bond, -S(O) ２ --, --NR ２ --, --CH ２ CH ２ O-, -CH ２ O-, -O- or -CR ２ R ３ - and R ２ and R ３ are each independently hydrogen, halogen, or substituted or unsubstituted alkyl, or R ２ and R ３ forms a carbonyl with that carbon, n is 1 or 0; A is 【Chemistry 2】 or 【Chemistry 3】 and Each R ４ is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, hydroxy, or R ４ The two cases may be linked to form a bridged ring, or R ４ In the two cases, it forms a carbonyl with that carbon, m is 0, 1, 2, 3 or 4; L is a bond, -C(=O)-, -C(=O)CH ２ -, -C(=O)CF ２ -, -C(=O)CH(Ph)-, -C(=O)CH(iPr)-, -C(=O)CH(Et)-、-C(=O)CH(Me)-、-C(=O)C(CH ３ ) ２ -、-C(=O)CH(OMe)-、-C(=O)CH ２ CH ２ -、 -C(=O)CH ２ CH ２ CH ２ -, -C(=O)CH ２ CH ２ CH ２ O-, -C(=O)CH(CH ３ )CH ２ -, -C(=O)CH ２ O-, -C(=O)CH ２ OCH ２ -, -C(=O)CH(CH ３ )O-, -C(=O)CH ２ CH=CH-, -C(=O)NHCH ２ CH ２ CH ２ -, -C(=O)NHCH ２ CH ２ -, -CH ２ -, -CH ２ CH ２ CH ２ -, -CH ２ C(CH ３ ) ２ -, -C(=O)NH-, or -CH ２ C(=O)NH- and, R ５ is a substituted or unsubstituted heteroaryl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted heteroarylalkyl, a substituted or unsubstituted carbocyclyl, a substituted or unsubstituted aryl, methyl, ethyl, butyl, pentyl, t-butyl, -CH ２ CH ２ CH (CH ３ ) ２ , -SCF ３ , or -OCH ２ CH (CH ３ ) ２ That is, A compound of formula (I), or a pharma- ceutically acceptable salt thereof.

2. R １ is substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyridinyl, or substituted or unsubstituted phenyl; 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof.

3. R １ is hydrogen, methyl, butyl, pentyl, -CH ２ CH ２ CH (CH ３ ) ２ , 【Chemistry 4】 【change】 or 【Chemistry 5】 That is, 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof.

4. G is -O- or -CR 2 R 3 -; 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof.

5. A is, 【Chemistry 6】 or 【Chemistry 7】 That is, 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof.

6. A is, 【Chemistry 8】 That is, 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof.

7. A is, 【Chemistry 9】 or 【Chemistry 10】 That is, 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof.

8. L is a bond, -C(=O)-, -C(=O)CH 2 -, or -C(=O)CH 2 O-; 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof.

9. R ５ is a substituted or unsubstituted pyrazolopyrazinyl, a substituted or unsubstituted pyrrolopyrazinyl, a substituted or unsubstituted imidazopyrazinyl, a substituted or unsubstituted pyrazolopyridinyl, a substituted or unsubstituted pyrrolopyridinyl, a substituted or unsubstituted imidazopyridinyl, a substituted or unsubstituted triazolopyridinyl, a substituted or unsubstituted pyrazolopyrimidinyl, a substituted or unsubstituted pyrrolopyrimidinyl, a substituted or unsubstituted chromenonyl, a substituted or unsubstituted isochromanyl, a substituted or unsubstituted indolyl, a substituted or unsubstituted Substituted quinoxalinyl, substituted or unsubstituted benzofuranyl, substituted or unsubstituted benzothiophenyl, substituted or unsubstituted benzimidazolyl, substituted or unsubstituted benzoxazolyl, substituted or unsubstituted 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl, substituted or unsubstituted pyrrolo[3,2-c]pyridin-4-onyl, substituted or unsubstituted 7,8-dihydropyrrolo[1,2-a]pyrimidin-4(6H)-onyl, substituted or unsubstituted 1,5-dihydro-4H-pyra substituted or unsubstituted 2,3-dihydrobenzo[b][1,4]dioxinyl, substituted or unsubstituted tetrahydronaphthalenyl, substituted or unsubstituted isoquinolinonyl, substituted or unsubstituted quinolinyl, substituted or unsubstituted naphthyridinyl, substituted or unsubstituted naphthyl, substituted or unsubstituted pyridazinonyl, substituted or unsubstituted pyridinonyl, substituted or unsubstituted oxadiazolyl, substituted or unsubstituted thiadiazolyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted aryl, substituted or unsubstituted aryl, substituted or unsubstituted aryl, substituted or unsubstituted aryl, substituted or unsubstituted aryl is unsubstituted pyrazolyl, substituted or unsubstituted triazolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted thiophenyl, substituted or unsubstituted furanyl, substituted or unsubstituted isothiazolyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted 3,4-dihydro-1H-pyrrolo[2,1-c][1,4]thiazin-8-yl, substituted or unsubstituted pyrrolidinonyl, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted 1,4-diazepanyl, substituted or unsubstituted dioxolanonyl, substituted or unsubstituted pyridinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted phenyl, substituted or unsubstituted tetrahydropyranyl, substituted or unsubstituted tetrahydrofuranyl, substituted or unsubstituted morpholinyl, substituted or unsubstituted cyclooctyl, substituted or unsubstituted cyclohexyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted Unsubstituted cyclobutyl, substituted or unsubstituted cyclopropyl, substituted or unsubstituted bicyclo[3.3.1]nonanyl, substituted or unsubstituted bicyclo[2.2.1]heptanyl, substituted or unsubstituted 7-oxaspiro[3.5]non-1-en-2-yl, substituted or unsubstituted hexahydro-1H-cyclopenta[c]furan-5-yl, substituted or unsubstituted adamantyl, substituted or unsubstituted spiro[2.5]octan-4-yl, methyl, ethyl, butyl, pentyl, t-butyl, -CH ２ CH ２ CH (CH ３ ) ２ , -SCF ３ , or -OCH ２ CH (CH ３ ) ２ That is, 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof.

10. R ５ teeth, 【Chemistry 11】 or 【Chemistry 12】 and R ２０ and R ３０ are each independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R ２０ and R ３０ together with the atom to which they are attached form a substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof.

11. R ５ teeth, 【Chemistry 13】 or 【Chemistry 14】 That is, 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof.

12. The compound has the formula: 【Chemistry 15】 or a pharma- ceutically acceptable salt thereof.

13. The compound has the formula: 【Chemistry 16】 or a pharma- ceutically acceptable salt thereof.

14. The compound has the formula: 【Chemistry 17】 or a pharma- ceutically acceptable salt thereof.

15. The compound has the formula: 【Chemistry 18】 or a pharma- ceutically acceptable salt thereof.

16. The compound has the formula: 【Chemistry 19】 or a pharma- ceutically acceptable salt thereof.

17. The compound of claim 1, wherein the compound has the formula: 【Chemistry 20】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 or a pharma- ceutically acceptable salt thereof, or a compound of the formula: 【Chemistry 21】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 or a pharma- ceutically acceptable salt thereof.

18. 2. The compound of claim 1 which is not one or more of the compounds of Table 2 or a pharma- ceutically acceptable salt thereof.

19. A pharmaceutical composition comprising a compound according to any one of claims 1 to 18 or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient.

20. 20. A kit comprising a compound according to any one of claims 1 to 18, or a pharma- ceutically acceptable salt thereof, and instructions for administering said compound to a subject in need thereof.

21. 20. A composition for use in treating a disease or disorder in a subject in need thereof, comprising an effective amount of a compound according to any one of claims 1 to 18, or a pharma- ceutically acceptable salt thereof.

22. The composition of claim 21 , wherein the disease or disorder is associated with glucocerebrosidase activity.

23. 23. The composition of claim 21 or 22, wherein the disease or disorder is a neurological disease or disorder.

24. 24. The composition of claim 23, wherein the neurological disease or disorder is Parkinson's disease or Gaucher's disease.

25. 20. An in vitro method for activating glucocerebrosidase, comprising contacting glucocerebrosidase with an effective amount of a compound according to any one of claims 1 to 18, or a pharma- ceutically acceptable salt thereof.

Images