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 / 182,734, filed April 30, 2021, which is incorporated by reference herein in its entirety. [Background technology]

[0002] Glucocerebrosidase (EC 3.2.1.45), also known as β-glucocerebrosidase, β-glucosidase, D-glucosyl-N-acylsphingosine glucohydrolase, 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 gene for glucocerebrosidase (GBA1) are associated with abnormal accumulation of lipids in lysosomes.

[0003] Genetic diseases caused by mutations in GBA1 include neurodegenerative diseases such as Gaucher disease and Parkinson's disease. Current treatment of diseases such as type 1 Gaucher disease is limited to enzyme replacement therapy (ERT) administered every two weeks. ERT is very expensive and is not effective for the neuropathic form of Gaucher disease. Efforts to discover and use small molecule compounds to activate Gcase have met with limited success. Thus, there is a need for novel compounds that effectively activate Gcase and are useful in the treatment of neurodegenerative diseases (e.g., Gaucher disease and Parkinson's disease). Summary of the Invention

[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's disease and Parkinson's disease).

[0005] In one embodiment, the compound of formula (I): [ka] and pharma- ceutically acceptable salts, co-crystals, tautomers, stereoisomers, solvates, hydrates, polymorphs, isotopically enriched derivatives, or prodrugs thereof, In the formula, R 1 is substituted or unsubstituted alkyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted aryl; A 1 teeth [ka] and L is a bond or -C(=O)-; A is, [ka] and R 2 and R 3 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 2 and R 3 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; Each R 4 are independently halogen, substituted or unsubstituted alkyl, or R 4 In the two cases, it forms a carbonyl with that carbon, m is 0, 1, 2, 3 or 4.

[0006] In certain embodiments, the compound of formula (I) has formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io) or (Ip): [ka] TIFF2024517789000005.tif191159, or a pharma- ceutically acceptable salt thereof.

[0007] Exemplary compounds of formula (I) include, but are not limited to, the following: [Table 1] TIFF2024517789000007.tif203153 and pharma- ceutically acceptable salts thereof.

[0008] In another aspect, there is provided a pharmaceutical composition comprising a compound of formula (I) or a pharma- ceutically acceptable salt thereof, and optionally a pharma- ceutically acceptable excipient.

[0009] In another aspect, there is provided a method of treating a disease or disorder in a subject in need thereof, comprising administering to the subject a compound of formula (I) or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I).

[0010] 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.

[0011] In another aspect, a method of activating glucocerebrosidase is provided, comprising contacting glucocerebrosidase with an effective amount of a compound of formula (I) or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I).

[0012] In another aspect, a kit is provided that comprises a compound of formula (I) or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I) or a pharma- ceutically acceptable salt thereof. In certain embodiments, the kit further comprises instructions for administration (e.g., human administration).

[0013] 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. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0014] definition chemical definition Definitions of certain functional groups and chemical terms are described 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, and 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.

[0015] 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 a mixture 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., Univ. of Notre Dame Press, Notre Dame, IN 1972). The present invention further encompasses the compounds as individual isomers substantially free of other isomers, and alternatively as mixtures of various isomers.

[0016] 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] is a single bond or a double bond.

[0017] 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 with 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.

[0018] 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" is C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , 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.

[0019] The term "aliphatic" refers to alkyl, alkenyl, alkynyl, and carbocyclic groups. Similarly, the term "heteroaliphatic" refers to heteroalkyl, heteroalkenyl, heteroalkynyl, and heterocyclic groups.

[0020] The term "alkyl" refers to the radical of a linear 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, an alkyl group has 1 to 8 carbon atoms ("C 1~8 In some embodiments, an 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, an alkyl group has 1 to 3 carbon atoms ("C 1~3 In some embodiments, an alkyl group has 1 to 2 carbon atoms ("C 1~2 In some embodiments, an alkyl group has one carbon atom ("C 1 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 (C 1 ), ethyl (C 2 ), Propyl (C 3 ) (e.g., n-propyl, isopropyl), butyl (C 4 ) (e.g., n-butyl, tert-butyl, sec-butyl, iso-butyl), pentyl (C 5 ) (e.g., n-pentyl, 3-pentanyl, amyl, neopentyl, 3-methyl-2-butanyl, tertiary amyl) and hexyl (C 6 ) (e.g., n-hexyl). Further examples of alkyl groups include n-heptyl (C 7 ), n-octyl (C 8) and the like. Unless otherwise specified, each instance of an alkyl group is independently unsubstituted ("unsubstituted alkyl") or substituted ("substituted alkyl") with one or more substituents (e.g., halogen, such as F). In certain embodiments, an alkyl group is an unsubstituted C 1~10 Alkyl (e.g., unsubstituted C 1~6 Alkyl, e.g., -CH 3 (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, e.g. -CF 3 , Bn).

[0021] 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 An example of a haloalkyl group is -CHF 2 , -CH 2 F, -CF 3 , -CH 2 CF 3 , -CF 2 CF 3 , -CF 2 CF2 CF 3 , -CCl 3 , -CFCl 2 , -CF 2 Cl and the like.

[0022] 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 ("C 1~4 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.

[0023] 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").

[0024] The term "heteroalkyl" refers to an alkyl group that further comprises 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 heteroalkyl group is a saturated group 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 1~18 In 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, a heteroalkyl group is a saturated group having 1 to 14 carbon atoms and one or more heteroatoms in the parent chain ("heteroC 1-14 In some embodiments, a heteroalkyl group is a saturated group 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, a heteroalkyl group is a saturated group having 1 to 6 carbon atoms and one or more heteroatoms in the parent chain ("heteroC 1~6 In some embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and 1 or 2 heteroatoms in the parent chain ("heteroC 1~4 In some embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom in the parent chain ("heteroC 1-3In some embodiments, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom in the parent chain ("heteroC 1~2 In some embodiments, a heteroalkyl group is a saturated group having one carbon atom and one heteroatom ("heteroC 1 In some embodiments, heteroalkyl groups as defined herein are partially unsaturated groups having one or more heteroatoms and at least one unsaturated carbon in the parent chain, such as 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 heteroalkyl group. 1~20 In certain embodiments, the heteroalkyl group is an unsubstituted heteroC 1~10 It is an alkyl.

[0025] 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 2~5In 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 2~3 In some embodiments, the alkenyl group has two carbon atoms ("C 2 alkenyl). The one or more carbon-carbon double bonds can be internal (e.g., 2-butenyl) or terminal (e.g., 1-butenyl). 2~4 Examples of alkenyl groups include ethenyl (C 2 ), 1-propenyl (C 3 ), 2-propenyl (C 3 ), 1-butenyl (C 4 ), 2-butenyl (C 4 ), butadienyl (C 4 ) etc. 2~6 Examples of alkenyl groups include the above-mentioned C 2~4 Alkenyl groups, as well as pentenyl (C 5 ), pentadienyl (C 5 ), hexenyl (C 6 Further examples of alkenyl include heptenyl (C 7 ), octenyl (C 8 ), octatrienyl (C 8 Unless otherwise specified, each instance of an alkenyl group is independently unsubstituted ("unsubstituted alkenyl") or substituted with one or more substituents ("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 Alkenyl. In an alkenyl group, a C=C double bond where the stereochemistry is not specified (e.g., -CH=CHCH 3 or [ka] ) may be an (E)- or a (Z)-double bond.

[0026] The term "heteroalkenyl" refers to an alkenyl group that further comprises 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 ("heteroC 2~10 In some embodiments, a heteroalkenyl group has 2 to 9 carbon atoms, at least one double bond, and one or more heteroatoms in the parent chain ("heteroC 2~9 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 2~6Unless otherwise specified, each instance of a heteroalkenyl group is independently unsubstituted ("unsubstituted heteroalkenyl") or substituted with one or more substituents ("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.

[0027] 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) (see "C 2~10 In 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 ("C 2 The one or more carbon-carbon triple bonds can be internal (e.g., 2-butynyl) or terminal (e.g., 1-butynyl). 2~4 Examples of alkynyl groups include ethynyl (C 2 ), 1-propynyl (C 3 ), 2-propynyl (C 3 ), 1-butynyl (C 4 ), 2-butynyl (C 4 ) and the like, but are not limited to these.2~6 Examples of alkenyl groups include the above-mentioned C 2~4 Alkynyl groups, as well as pentynyl (C 5 ) and hexynyl (C 6 Further examples of alkynyl include heptynyl (C 7 ), Octynyl (C 8 Unless otherwise specified, each instance of an alkynyl group is independently unsubstituted ("unsubstituted alkynyl") or substituted with one or more substituents ("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.

[0028] The term "heteroalkynyl" refers to an alkynyl group that further comprises 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 2~6In 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 2~6 Unless otherwise specified, each instance of a heteroalkynyl group is independently unsubstituted ("unsubstituted heteroalkynyl") or substituted with one or more substituents ("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.

[0029] 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 4~6In 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 3 ), cyclopropenyl (C 3 ), cyclobutyl (C 4 ), cyclobutenyl (C 4 ), cyclopentyl (C 5 ), cyclopentenyl (C 5 ), cyclohexyl (C 6 ), cyclohexenyl (C 6 ), cyclohexadienyl (C 6 ) and others. 3~8 The carbocyclyl group includes, but is not limited to, the above-mentioned C 3~6 Carbocyclyl groups, as well as cycloheptyl (C 7 ), cycloheptenyl (C 7 ), cycloheptadienyl (C 7 ), cycloheptatrienyl (C 7 ), cyclooctyl (C 8 ), cyclooctenyl (C 8 ), bicyclo[2.2.1]heptanyl (C 7 ), bicyclo[2.2.2]octanyl (C 8 ) and others. 3~10 The carbocyclyl group includes, but is not limited to, the above-mentioned C 3~8 Carbocyclyl groups, as well as cyclononyl (C 9 ), cyclononenyl (C 9 ), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C 9 ), decahydronaphthalenyl (C 10 ), spiro[4.5]decanyl (C 10As 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 bicyclic ("bicyclic carbocyclyl") or tricyclic ("tricyclic carbocyclyl") ring systems) and may be saturated or may 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 system. 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.

[0030] In some embodiments, "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 3~10 In 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 (C 5 ) are listed. C 3~6 Examples of cycloalkyl groups include the above-mentioned C 5~6 Cycloalkyl groups and cyclopropyl groups (C 3 ) and cyclobutyl (C 4 ) are listed. C 3~8 Examples of cycloalkyl groups include the above-mentioned C 3~6 Cycloalkyl groups and cycloheptyl (C 7 ) and cyclooctyl (C 8 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.

[0031] The term "heterocyclyl" or "heterocyclic" refers to the radical of a 3- to 14-membered non-aromatic ring system having ring carbon atoms and one to four ring heteroatoms, each heteroatom being independently selected from nitrogen, oxygen, and sulfur ("3- to 14-membered heterocyclyl"). In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment may be at a carbon atom or at a nitrogen atom, where valence permits. Heterocyclyl groups may be either monocyclic ("monocyclic heterocyclyl") or polycyclic (e.g., fused, bridged, or spiro ring systems, such as bicyclic ("bicyclic heterocyclyl") or tricyclic ("tricyclic heterocyclyl") ring systems), may be saturated or may contain one or more carbon-carbon double or triple bonds. Heterocyclyl polycyclic ring systems may 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, with the point of attachment being on either the carbocyclyl or heterocyclyl ring, or in which a heterocyclyl ring as defined above is fused to one or more aryl or heteroaryl groups, with the point of attachment being on the heterocyclyl ring, in which case the number of ring members continues to specify the number of ring members of 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, the heterocyclyl group is an unsubstituted 3-14 membered heterocyclyl. In certain embodiments, the heterocyclyl group is a substituted 3-14 membered heterocyclyl.

[0032] In some embodiments, a heterocyclyl group is a 5- to 10-membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, each heteroatom being independently selected from nitrogen, oxygen, and sulfur ("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 1-4 ring heteroatoms, each heteroatom being independently selected from nitrogen, oxygen, and sulfur ("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 1-4 ring heteroatoms, each heteroatom being independently selected from nitrogen, oxygen, and sulfur ("5- to 6-membered heterocyclyl"). In some embodiments, a 5- to 6-membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5- to 6-membered heterocyclyl has 1-2 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.

[0033] 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, 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, 1,2,3,4-tetrahydro-1,6-naphthyridinyl, and the like.

[0034] 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 (e.g., having 6, 10, or 14 pi electrons shared within the cyclic array). 6~14 In some embodiments, an aryl group has six ring carbon atoms ("C 6 aryl"; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms ("C 10 Aryl"; for example, 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 which case 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.

[0035] "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.

[0036] The term "heteroaryl" refers to a radical of a 5-14 membered monocyclic or polycyclic (e.g., bicyclic, tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared within the cyclic array) in which the aromatic ring system is provided with ring carbon atoms and 1-4 ring heteroatoms, each heteroatom being independently selected from nitrogen, oxygen, and sulfur ("5-14 membered heteroaryl"). In heteroaryl groups containing one or more nitrogen atoms, the point of attachment can be at a carbon atom or at a nitrogen atom, as valence permits. 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 with one or more carbocyclyl or heterocyclyl groups, and the point of attachment is on the heteroaryl ring, in which case the number of ring members continues to specify the number of ring members of 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 or heteroaryl ring, where the number of ring members indicates the number of ring members of 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 in either ring, i.e., either the ring with a heteroatom (e.g., 2-indolyl) or the ring without a heteroatom (e.g., 5-indolyl).

[0037] In some embodiments, the heteroaryl group is a 5-10 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, each heteroatom being independently selected from nitrogen, oxygen, and sulfur ("5-10 membered heteroaryl"). In some embodiments, the heteroaryl group is a 5-8 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, each heteroatom being independently selected from nitrogen, oxygen, and sulfur ("5-8 membered heteroaryl"). In some embodiments, the heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, each heteroatom being independently selected from nitrogen, oxygen, and sulfur ("5-6 membered heteroaryl"). In some embodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- 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, the heteroaryl group is an unsubstituted 5- to 14-membered heteroaryl. In certain embodiments, the heteroaryl group is a substituted 5- to 14-membered heteroaryl.

[0038] 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, benzoisofuranyl, 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.

[0039] "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.

[0040] The term "unsaturated bond" refers to a double bond or a triple bond.

[0041] The terms "unsaturated" or "partially unsaturated" refer to a moiety that contains at least one double or triple bond.

[0042] The term "saturated" refers to a moiety that does not contain any double or triple bonds, i.e., the moiety contains only single bonds.

[0043] 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 an alkyl, alkenylene is a divalent moiety of an alkenyl, alkynylene is a divalent moiety of an alkynyl, heteroalkylene is a divalent moiety of a heteroalkyl, heteroalkenylene is a divalent moiety of a heteroalkenyl, heteroalkynylene is a divalent moiety of a heteroalkynyl, carbocyclylene is a divalent moiety of a carbocyclyl, heterocyclylene is a divalent moiety of a heterocyclyl, arylene is a divalent moiety of an aryl, and heteroarylene is a divalent moiety of a heteroaryl.

[0044] Groups are optionally substituted unless otherwise specified. The term "optionally substituted" refers to being substituted or unsubstituted. In certain embodiments, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted. "Optionally substituted" refers to a group that may be substituted or unsubstituted (e.g., "substituted" or "unsubstituted" alkyl, "substituted" or "unsubstituted" alkenyl, "substituted" or "unsubstituted" alkynyl, "substituted" or "unsubstituted" heteroalkyl, "substituted" or "unsubstituted" heteroalkenyl, "substituted" or "unsubstituted" heteroalkynyl, "substituted" or "unsubstituted" carbocyclyl, "substituted" or "unsubstituted" heterocyclyl, "substituted" or "unsubstituted" aryl, or "substituted" or "unsubstituted" heteroaryl group). In general, the term "substituted" means that at least one hydrogen present on a group is replaced with an acceptable substituent, e.g., a substituent that upon replacement 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 indicated, a "substituted" group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituents may be the same or different at each position. The term "substituted" is considered to include substitution with all acceptable 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 to arrive at a stable compound. For purposes of this disclosure, heteroatoms such as nitrogen may 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.

[0045] When substituted, exemplary carbon atom substituents include halogen, -CN, -NO 2 , -N 3 , -SO 2 H, -SO 3 H, -OH, -OR aa、-ON(R bb ) 2 、-N(R bb ) 2 、-N(R bb ) 3 + X - 、-N(OR cc )R bb 、-SH、-SR aa 、-SSR cc 、-C(=O)R aa 、-CO 2 H、-CHO、-C(OR cc ) 3 、-CO 2 R aa 、-OC(=O)R aa 、-OCO 2 R aa 、-C(=O)N(R bb ) 2 、-OC(=O)N(R bb ) 2 、-NR bb C(=O)R aa 、-NR bb CO 2 R 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 SO 2 R aa 、-NR bb SO 2 R aa 、-SO 2 N(Rbb ) 2 、-SO 2 R aa 、-SO 2 OR aa 、-OSO 2 R 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 3~10 Carbocyclyl, 3-14 membered heterocyclyl, C 6~14 aryl and 5-14 membered heteroaryl, where 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 the two geminal hydrogens on a carbon atom are groups =O, =S, =NN(R bb ) 2 , =NNR bb C(=O)R aa , =NNR bb C(=O)OR aa , =NNR bb S(=O)2 R 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, 3-14 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 a 5- to 14-membered heteroaryl ring, and each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl may be selected from 0, 1, 2, 3, 4, or 5 R dd is independently substituted with R bb Each instance of is independently hydrogen, -OH, -OR aa , -N(R cc ) 2 , -CN, -C(=O)R aa , -C(=O)N(R cc ) 2 , -CO 2 R aa , -SO 2 R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc ) 2 , -SO 2 N(R cc ) 2 , -SO 2 R cc , -SO 2 OR 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, 3-14 membered heterocyclyl, C 6~14 Aryl and 5-14 membered heteroaryl, or two R bb groups are linked to form a 3- to 14-membered heterocyclyl or a 5- to 14-membered heteroaryl ring, and each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl may be selected from 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 3~10 Carbocyclyl, 3-14 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 a 5- to 14-membered heteroaryl ring, and each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl may be selected from 0, 1, 2, 3, 4, or 5 R ddis independently substituted with R dd Each instance of is independently a halogen, -CN, -NO 2 , -N 3 , -SO 2 H, -SO 3 H, -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 , -CO 2 H, -CO 2 R ee , -OC(=O)R ee , -OCO 2 R ee , -C(=O)N(R ff ) 2 , -OC(=O)N(R ff ) 2 , -NR ff C(=O)R ee , -NR ff CO 2 R 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 SO 2 Ree , -SO 2 N(R ff ) 2 , -SO 2 R ee , -SO 2 OR ee , -OSO 2 R 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, and 5- to 10-membered heteroaryl, each of alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl may have 0, 1, 2, 3, 4, or 5 R gg groups or two geminal R dd The substituents may combine to form =O or =S, where X - is the counterion, R ee Each instance of 1~6 Alkyl, C 1~6 Perhaloalkyl, C 2~6Alkenyl, 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, 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 is independently substituted with 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 5-10 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 selected from 0, 1, 2, 3, 4, or 5 R gg is independently substituted with R gg Each instance of is independently a halogen, -CN, -NO 2 , -N 3 , -SO 2 H, -SO 3 H, -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 - , -NH 2 (C 1~6 Alkyl) + X - , -NH 3 + X - , -N(OC 1~6 Alkyl)(C 1~6 alkyl), -N(OH)(C 1~6 alkyl), -NH(OH), -SH, -SC 1~6 Alkyl, -SS(C 1~6 alkyl), -C(=O)(C 1~6 Alkyl), -CO 2 H, -CO 2 (C 1~6 alkyl), -OC(=O)(C 1~6 Alkyl), -OCO 2 (C 1~6 alkyl), -C(=O)NH 2 , -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), -NHCO 2 (C 1~6 alkyl), -NHC(=O)N(C 1~6 Alkyl) 2 , -NHC(=O)NH(C 1~6 alkyl), -NHC(=O)NH 2 , -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)NH 2 , -OC(=NH)N(C 1~6 Alkyl) 2, -OC(=NH)NH(C 1~6 alkyl), -OC(=NH)NH 2 , -NHC(=NH)N(C 1~6 Alkyl) 2 , -NHC(=NH)NH 2 , -NHSO 2 (C 1~6 Alkyl), -SO 2 N(C 1~6 Alkyl) 2 , -SO 2 NH(C 1~6 Alkyl), -SO 2 NH 2 , -SO 2 (C 1~6 Alkyl), -SO 2 O(C 1~6 alkyl), -OSO 2 (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 1~6 alkyl), C(=S)NH 2 , -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 3~10Carbocyclyl, C 6-10 aryl, 3- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, or two geminal R gg The substituents may combine to form =O or =S, where X - is the counter ion.

[0046] The term "halo" or "halogen" refers to fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br) or iodine (iodo, -I).

[0047] The term "hydroxyl" or "hydroxy" refers to an -OH group. The term "substituted hydroxyl" or "substituted hydroxyl" refers, by extension, 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 , -OCO 2 R 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 , -OSO 2 R 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)(ORcc ) 2 , and -OP(=O)(N(R bb ) 2 ) 2 wherein X - , R aa , R bb , and R cc is as defined herein.

[0048] The term "amino" means -NH 2 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.

[0049] 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 , -NHCO 2 R aa , -NHC(=O)N(R bb ) 2 , -NHC(=NR bb )N(R bb ) 2 , -NHSO 2 R aa , -NHP(=O)(OR cc ) 2 , and -NHP(=O)(N(R bb ) 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.

[0050] 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, -N(R bb ) 2 , -NR bb C(=O)Raa , -NR bb CO 2 R aa , -NR bb C(=O)N(R bb ) 2 , -NR bb C(=NR bb )N(R bb ) 2 , -NR bb SO 2 R aa , -NR bb P(=O)(OR cc ) 2 , and -NR bb P(=O)(N(R bb ) 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 hydrogen.

[0051] 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 - R bb and X - is as defined herein.

[0052] The term "sulfonyl" means -SO 2 N(R bb ) 2 , -SO 2 R aa , and -SO 2 OR aa wherein R aa and R bb is as defined herein.

[0053] The term "sulfinyl" refers to the group -S(=O)Raa R aa is as defined herein.

[0054] 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 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 (-CO 2 H), 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.

[0055] The term "oxo" refers to the group =O and the term "thioxo" refers to the group =S.

[0056] Nitrogen atoms may be substituted or unsubstituted, where valence permits, 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 , -CO 2 R aa , -SO 2 R aa , -C(=NR bb )R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc ) 2, -SO 2 N(R cc ) 2 , -SO 2 R cc , -SO 2 OR cc , -SOR aa , -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, 3-14 membered heterocyclyl, C 6~14 Aryl and 5-14 membered heteroaryl, or two R attached to the N atom cc groups combine to form a 3- to 14-membered heterocyclyl or a 5- to 14-membered heteroaryl ring, and each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl may be selected from 0, 1, 2, 3, 4, or 5 R dd is independently substituted with R aa , R bb , R cc and R dd is defined herein.

[0057] 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 , -CO 2 R aa , -SO 2 R aa , -C(=NR cc )R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc ) 2 , -SO 2 N(R cc ) 2 , -SO 2 R cc , -SO 2 OR 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, 3-14 membered heterocyclyl, C 6~14 and aryl and 5-14 membered heteroaryl groups, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aralkyl, aryl, and heteroaryl may have 0, 1, 2, 3, 4, or 5 R dd is independently substituted with 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, TW Greene and PG M Huts, 3, incorporated herein by reference. rdedition, John Wiley & Sons, 1999.

[0058] For example, an amide group (e.g., -C(=O)R aa Nitrogen protecting groups such as 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.

[0059] Carbamate groups (e.g., -C(=O)OR aaExamples 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 carbamates (Cbz), p-methoxybenzyl carbamates (Moz), p-nitrile benzyl carbamates, p-bromobenzyl carbamates, p-chlorobenzyl carbamates, 2,4-dichlorobenzyl carbamates, 4-methylsulfinylbenzyl carbamates (Msz), 9-anthrylmethyl carbamates, diphenylmethyl carbamates, 2-methylthioethyl carbamates, 2-methylsulfonylethyl carbamates, 2-(p-toluenesulfonyl)ethyl carbamates, [2-(1,3-dithianyl)]methyl carbamate (Dmoc), 4-methylthiophenyl carbamate (Mtpc), 2,4-dimethylthiophenyl carbamate (Bmpc), 2-phosphonioethyl carbamate (Peoc), 2-triphenylphosphonioisopropyl carbamate (Ppoc), 1,1-dimethyl-2-cyanoethyl carbamate, m-chloro-p-acyloxybenzyl carbamate, p-(dihydroxyboryl)benzyl carbamate, 5-benzisoxazolylmethyl carbamate, 2-(trifluoromethyl)-6-chloro methyl 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, cyclopropyl methyl carbamate, p-decyloxybenzyl carbamate, 2 ,2-Dimethoxyacylvinylcarbamate, 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 1-methyl-1-cyclohexyl carbamate, 1-methyl-1-cyclopropyl methyl 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-trimethylbenzyl carbamate.

[0060] Sulfonamide groups (e.g., -S(=O) 2 R aa ), and nitrogen protecting groups such as 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 phenacylsulfonamide.

[0061] 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-tetramethyldisilylazane. 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 salt, 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(pentaacylcromium- 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 phosphoramidates, diphenyl phosphoramidates, benzenesulfenamides, 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-fluorenylmethyloxycarbonyl (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).

[0062] 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 , -CO 2 R aa , -C(=O)N(R bb ) 2 , -C(=NR bb )R aa , -C(=NRbb ) OR aa , -C(=NR bb )N(R bb ) 2 , -S(=O)R aa , -SO 2 R 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, TW Greene and PG M Huts, 3, incorporated herein by reference. rd edition, John Wiley & Sons, 1999.

[0063] Exemplary oxygen protecting groups include methyl, methoxylmethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM), t-butoxymethyl, 4-pentenyloxymethyl (POM), siloxymethyl, 2-methoxyethoxymethyl (MEM), 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'-Dinitrobenzidryl, 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), diethylisopropylsilyl (IPDMS), 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 ester, phenoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4-oxopentanoate (levulinate), 4,4-(ethylenedithio)pentanoate (levulinoyldithioacetal), pivaloate, adamantate, 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, methyldithiocarbonate, 2-indobenzoate, 4-azidobutyrate, 4-nitro-4-methylpentanoate, o-(dibromomethyl)benzoate, 2-formylbenzenesulfonate, 2-(methyl) Examples of alkyl aryl groups include, but are not limited to, alkyl aryl groups ... 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).

[0064] 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 , -CO 2 R 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 , -SO 2 R 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 cc is 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. Huts, 3rd Edition, 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.

[0065] 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., containing one formal negative charge). Anionic counterions can also be multivalent (i.e., containing two or more formal negative charges), such as divalent or trivalent. Exemplary counterions include halide ions (e.g., F - , Cl - , Br - , I - ), NO 3 - , ClO 4 - , O.H. - , H 2 PO 4 - , HCO 3 - , HSO 4 -, 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.), BF 4 - , P.F. 4 - , P.F. 6 - , AsF 6 - , SbF 6 - , B[3,5-(CF 3 ) 2 C 6 H 3 ] 4 ] - , B(C 6 F 5 ) 4 - , B.P.h. 4 - , Al(OC(CF 3 ) 3 ) 4 - , and carborane anions (e.g., CB 11 H 12 - or (HCB 11 Me 5 Br 6 ) - Exemplary counterions, which may be multivalent, include CO 3 2- , H.P.O. 4 2- , P.O. 4 3- 、 B 4 O 7 2- , S.O. 4 2- , S 2 O 3 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.

[0066] These and other exemplary substituents are described in further detail in the detailed description, examples, and claims. The invention is not intended to be limited in any manner by the above exemplary recitation of substituents.

[0067] Other definitions The following definitions are of more general terms used throughout this application.

[0068] As used herein, the term "salts" refers to any and all salts, including pharma- ceutically acceptable salts.

[0069] The term "pharmaceutically acceptable salt" refers to a salt that is suitable for use in contact with human and / or animal tissues without undue toxicity, irritation, allergic reaction, etc., within the scope of sound medical judgment, and 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 pharma- ceutically 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 alkali metal, alkaline earth metal, ammonium and N-terminated salts such as 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, and the like. + (C 1~4 Alkyl) 4 -Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Further pharma- ceutically 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.

[0070] The term "solvate" refers to a form of a compound or its salt that is associated with a solvent, usually by a solvolysis reaction. This physical association may include hydrogen bonding. Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, and the like. The compounds described herein may be prepared, 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 will be capable of isolation, 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.

[0071] The term "hydrate" refers to a compound associated with water molecules. Typically, the number of water molecules in a hydrate of a compound is in a fixed ratio to the number of compound molecules in the hydrate. Thus, a hydrate of a compound may be, for example, a compound of the general formula R xH 2 O, where R is a compound and x is a number greater than 0. A given compound may be, 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 0.5H 2 O), and polyhydrates (x is a number greater than 1, e.g., dihydrates (R 2H 2 O) and hexahydrate (R 6H 2 O)) may form two or more types of hydrates.

[0072] The term "tautomer" or "tautomerism" refers to two or more interconvertible compounds resulting from at least one formal migration of a 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 that gives the 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.

[0073] 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 referred to as "isomers." Isomers that differ in the arrangement of their atoms in space are referred to as "stereoisomers."

[0074] Stereoisomers that are not mirror images of one another are called "diastereomers" and stereoisomers that are non-superimposable mirror images of one another are called "enantiomers". When a compound has an asymmetric center, e.g., 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 called 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".

[0075] The term "polymorph" refers to a crystalline form of a compound (or its salts, hydrates or solvates). Many compounds can take on 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 solvents, crystallization rate, storage temperature, and other factors may cause one crystalline form to dominate a given preparation. Various polymorphs of a compound can be prepared by crystallization under different conditions.

[0076] 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.

[0077] The term "prodrug" refers to a compound having a cleavable group that is removed under solvolysis or physiological conditions to provide a compound described herein that is pharma- ceutically active in vivo. Examples of such 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 a suitable alcohol, or amides prepared by reacting the parent acid compound with a substituted or unsubstituted amine or acid anhydride or mixed anhydride. Simple aliphatic or aromatic esters, amides, and anhydrides derived from the acid groups pendant to the compounds described herein are particular prodrugs. In some cases, it is desirable to prepare double ester type prodrugs, such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)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.

[0078] The terms "composition" and "formulation" are used interchangeably.

[0079] The term "modulate" refers to decreasing or inhibiting activity and / or increasing or enhancing activity. For example, modulating glucocerebrosidase activity refers to 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.

[0080] 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, a child, or an adolescent) or an adult subject (e.g., a young adult, a middle-aged adult, or an elderly person)) or a non-human animal. In certain embodiments, the non-human animal is a mammal (e.g., a primate (e.g., a cynomolgus or rhesus monkey), a commercially relevant mammal (e.g., a cow, a pig, a horse, a sheep, a goat, a cat, or a dog), or an avian (e.g., a commercially relevant bird, e.g., a chicken, a duck, a goose, or a turkey)). In certain embodiments, the non-human animal is a fish, a reptile, or an amphibian. The non-human animal may be male or female at any stage of development. The non-human animal may 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, such as a soybean plant. In some embodiments, the plant is a tree or shrub.

[0081] The term "biological sample" refers to any sample, including tissue samples (such as tissue sections and needle biopsies of tissue); 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 (such as buccal swabs), or any material containing biomolecules derived from a first biological sample.

[0082] 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.

[0083] The terms "treatment", "treat" and "treating" refer to reversing, alleviating, or inhibiting the progression of a disease as described herein. In some embodiments, therapy may be administered after one or more signs or symptoms of a disease have developed or been observed. Treatment may also be continued after symptoms have resolved, for example to delay or prevent recurrence.

[0084] The terms "condition," "disease," and "disorder" are used interchangeably.

[0085] 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 combined amount of a compound described herein in multiple doses.

[0086] A "therapeutically effective amount" of a compound described herein is an amount sufficient to provide a therapeutic benefit in the treatment of a condition or to delay or minimize one or more symptoms associated with a condition. A therapeutically effective amount of a compound refers to an amount of a therapeutic agent that alone or in combination with other treatments provides a therapeutic benefit in the treatment of a condition. The term "therapeutically effective amount" can include 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 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 the enzymatic activity of GCase). 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).

[0087] 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 an 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 efficacy of another prophylactic agent. In certain embodiments, a prophylactically effective amount is an amount sufficient for GCase activation. In certain embodiments, a prophylactically effective amount is an amount sufficient for treating a disease or disorder (e.g., a neurological disorder). In certain embodiments, a prophylactically effective amount is an amount sufficient for GCase activation and treatment of a disease or disorder (e.g., a neurological disorder).

[0088] 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 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 an initial level, which may be, for example, a baseline level of enzyme activity.

[0089] The term "immunotherapy" refers to a therapeutic agent that promotes the treatment of disease by inducing, enhancing, or suppressing an immune response. Immunotherapies designed to induce or amplify an immune response are classified as activating immunotherapies, while immunotherapies that decrease or suppress an immune response are classified as suppressing immunotherapies. Immunotherapies are typically, but not always, biological therapeutic agents. 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.

[0090] 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) and may be produced by biotechnological and other techniques.

[0091] The term "small molecule" or "small molecule therapeutic agent" 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, etc.). 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 the appropriate government or regulatory agency.For example, drugs approved for human use are listed by the FDA under 21 C.FR §§ 330.5, 331 to 361, and 440 to 460, which are incorporated herein by reference, and drugs for veterinary use are listed by the FDA under 21 C.FR §§ 500 to 589, which are incorporated herein by reference. All of the drugs listed are considered acceptable for use in accordance with the present invention.

[0092] 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.

[0093] Detailed Description of Specific Embodiments Provided herein are compounds that are modulators of GCase (e.g., GCase activators). In one aspect, the GCase modulators provided are compounds of formula (I) and their pharma- ceutically acceptable salts, solvates, hydrates, polymorphs, cocrystals, tautomers, stereoisomers, isotopically labeled derivatives, prodrugs, and pharmaceutical compositions. Thus, the compounds are useful for treating and / or preventing diseases and disorders associated with GCase activity (e.g., neurological diseases and disorders) in subjects in need thereof.

[0094] The compounds described herein interact with GCase. As described herein, the therapeutic effect may be the result of the regulation (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 pharma- ceutically acceptable salts, cocrystals, tautomers, stereoisomers, solvates, hydrates, polymorphs, isotopically enriched derivatives or prodrugs.

[0095] Compounds of formula (I) In one embodiment, the compound of formula (I): [ka] or a pharma- ceutically acceptable salt thereof is disclosed. In the formula, R 1 is substituted or unsubstituted alkyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted aryl; A 1 teeth, [ka] and L is a bond or -C(=O)-; A is, [ka] and R 2 and R 3 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 2 and R 3 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; Each R 4 are independently halogen, substituted or unsubstituted alkyl, or R 4 In the two cases, it forms a carbonyl with that carbon, m is 0, 1, 2, 3 or 4.

[0096] In one embodiment, a compound of formula (Ia): [ka] or a pharma- ceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, is provided, In the formula, R 1is substituted or unsubstituted alkyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted aryl; L is a bond or -C(=O)-; A is, [ka] and R 2 and R 3 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 2 and R 3 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; Each R 4 are independently halogen, substituted or unsubstituted alkyl, or R 4 In the two cases, it forms a carbonyl with that carbon, m is 0, 1, 2, 3 or 4.

[0097] R 1 As described herein, R 1 is substituted or unsubstituted alkyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted aryl. 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. In certain embodiments, R 1 is substituted or unsubstituted pyridinyl, substituted or unsubstituted pyrimidinyl, or substituted or unsubstituted aryl.

[0098] In certain embodiments, R 1 is substituted or unsubstituted pyridinyl, substituted or unsubstituted pyrimidinyl, 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 substituted pyridinyl, substituted or unsubstituted pyrimidinyl, or substituted or unsubstituted phenyl. In certain embodiments, R 1 is a substituted pyridinyl, or a substituted or unsubstituted phenyl.

[0099] In certain embodiments, R 1 is substituted or unsubstituted pyrimidinyl. In certain embodiments, R 1 is substituted pyrimidinyl. In certain embodiments, R 1 is pyrimidinyl substituted with alkoxy. In certain embodiments, R 1 is C 1~4 It is pyrimidinyl substituted with alkoxy.

[0100] In certain embodiments, R 1 is pyridinyl substituted with halogen, haloalkyl, or haloalkoxy; pyrimidinyl substituted with alkoxy; 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 Haloalkoxy-substituted pyridinyl; C 1~4 Pyrimidinyl substituted with alkoxy; unsubstituted phenyl; or halogen, C 1~4 Haloalkyl or C 1~4 It is phenyl substituted with alkyl.

[0101] In certain embodiments, R 1is 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.

[0102] In certain embodiments, R 1 is pyridinyl substituted with halogen or haloalkyl; unsubstituted phenyl; or phenyl substituted with halogen or haloalkyl. In certain embodiments, R 1 is halogen or C 1~4 pyridinyl substituted with haloalkyl; unsubstituted phenyl; or halogen or C 1~4 It is phenyl substituted with haloalkyl.

[0103] In certain embodiments, R 1 is pyridinyl substituted with halogen or haloalkyl; unsubstituted phenyl; or phenyl substituted with halogen, haloalkoxy, or haloalkyl. In certain embodiments, R 1 is halogen or C 1~4 pyridinyl substituted with haloalkyl; unsubstituted phenyl; or halogen, C 1~4 Haloalkoxy or C 1~4 It is phenyl substituted with haloalkyl.

[0104] In certain embodiments, R 1 is pyridinyl substituted with fluoro or fluoroalkyl; unsubstituted phenyl; or phenyl substituted with fluoro or fluoroalkyl. In certain embodiments, R 1 Fluoro or C 1~4 Pyridinyl substituted with fluoroalkyl; unsubstituted phenyl; or fluoro or C 1~4 It is a phenyl substituted with a fluoroalkyl.

[0105] In certain embodiments, R 1 is pyridinyl substituted with fluoro or fluoroalkyl; unsubstituted phenyl; or phenyl substituted with fluoro, fluoroalkoxy, or fluoroalkyl. In certain embodiments, R 1 Fluoro or C 1~4 pyridinyl substituted with fluoroalkyl; unsubstituted phenyl; or fluoro, C 1~4 Fluoroalkoxy or C 1~4 It is a phenyl substituted with a fluoroalkyl.

[0106] In certain embodiments, R 1 is pyridinyl substituted with halogen or haloalkyl. In certain embodiments, R 1 is halogen or C 1~4 It is pyridinyl substituted with haloalkyl.

[0107] In certain embodiments, R 1 is pyridinyl substituted with fluoro or fluoroalkyl. In certain embodiments, R 1 Fluoro or C 1~4 It is a pyridinyl substituted with a fluoroalkyl.

[0108] In certain embodiments, R 1 is pyridinyl substituted with haloalkyl. In certain embodiments, R 1 is C 1~4 In certain embodiments, R is pyridinyl substituted with haloalkyl. 1 is pyridinyl substituted with fluoroalkyl. In certain embodiments, R 1 is C 1~4 It is a pyridinyl substituted with a fluoroalkyl.

[0109] In certain embodiments, R 1 is substituted or unsubstituted pyrimidinyl. In certain embodiments, R 1 is substituted pyrimidinyl. In certain embodiments, R1 is pyrimidinyl substituted with alkoxy. In certain embodiments, R 1 is C 1~4 It is pyrimidinyl substituted with alkoxy.

[0110] In certain embodiments, R 1 is unsubstituted phenyl.

[0111] In certain embodiments, R 1 is phenyl substituted with halogen or haloalkyl. In certain embodiments, R 1 is halogen or C 1~4 In certain embodiments, R 1 is phenyl substituted with fluoro or fluoroalkyl. In certain embodiments, R 1 Fluoro or C 1~4 It is a phenyl substituted with a fluoroalkyl.

[0112] In certain embodiments, R 1 is phenyl substituted with halogen, haloalkoxy, or haloalkyl. In certain embodiments, R 1 is a halogen, C 1~4 Haloalkoxy or C 1~4 In certain embodiments, R 1 is phenyl substituted with fluoro, fluoroalkoxy, or fluoroalkyl. In certain embodiments, R 1 Fluoro, C 1~4 Fluoroalkoxy or C 1~4 It is a phenyl substituted with a fluoroalkyl.

[0113] In certain embodiments, R 1 is phenyl substituted with halogen. In certain embodiments, R 1 is phenyl substituted with fluoro.

[0114] In certain embodiments, R 1is phenyl substituted with haloalkyl. In certain embodiments, R 1 is C 1~4 In certain embodiments, R 1 is phenyl substituted with fluoroalkyl. In certain embodiments, R 1 is C 1~4 It is a phenyl substituted with a fluoroalkyl.

[0115] In certain embodiments, R 1 is phenyl substituted with haloalkoxy. In certain embodiments, R 1 is C 1~4 In certain embodiments, R is phenyl substituted with haloalkoxy. 1 is phenyl substituted with fluoroalkoxy. In certain embodiments, R 1 is C 1~4 It is a phenyl substituted with a fluoroalkoxy.

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

[0117] In certain embodiments, R 1 is substituted or unsubstituted alkyl. In certain embodiments, R 1 is unsubstituted alkyl. In certain embodiments, R 1 is unsubstituted C 1~4 In certain embodiments, R 1 is methyl.

[0118] In certain embodiments, R 1 is methyl, [ka] It is.

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

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

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

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

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

[0124] In certain embodiments, R 1 teeth, [ka] It is.

[0125] In certain embodiments, R 1 teeth, [ka] It is.

[0126] In certain embodiments, R 1 teeth, [ka] In certain embodiments, R 1 teeth, [ka] In certain embodiments, R 1 teeth, [ka] In certain embodiments, R 1 teeth, [ka] In certain embodiments, R 1 teeth, [ka] It is.

[0127] In certain embodiments, R 1 teeth, [ka] In certain embodiments, R 1 teeth, [ka] In certain embodiments, R 1 teeth, [ka] In certain embodiments, R 1 teeth, [ka] In certain embodiments, R 1 teeth, [ka] It is.

[0128] L As described herein, L is a bond or -C(=O)-. In certain embodiments, L is a bond. In certain embodiments, L is -C(=O)-. In certain embodiments, when L is -C(=O)-, A is [ka] In certain embodiments, L is [ka] When the formula is -C(=O)-, only -C(=O)- is used.

[0129] A As described herein, A is [ka] where R 2 and R 3 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 2 and R 3 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.

[0130] In certain embodiments, A is [ka] It is.

[0131] In certain embodiments, A is [ka] It is.

[0132] In certain embodiments, A is [ka] It is.

[0133] In certain embodiments, A is [ka] It is.

[0134] In certain embodiments, A is [ka] It is.

[0135] In certain embodiments, A is [ka] It is.

[0136] In certain embodiments, R 2 and R 3 are each independently hydrogen or substituted or unsubstituted heteroaryl, or R 2 and R 3 together with the atom to which they are attached form a substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.

[0137] In certain embodiments, R 2 is substituted or unsubstituted heteroaryl. In certain embodiments, R 2 is unsubstituted heteroaryl. In certain embodiments, R 2 is substituted or unsubstituted thiadiazole. In certain embodiments, R 2 is unsubstituted thiadiazolyl.

[0138] In certain embodiments, R 3 is hydrogen.

[0139] In certain embodiments, R 2 is a substituted or unsubstituted heteroaryl; R3 is hydrogen. In certain embodiments, R 2 is unsubstituted heteroaryl, and R 3 is hydrogen. In certain embodiments, R 2 is a substituted or unsubstituted thiadiazaolyl; R 3 is hydrogen. In certain embodiments, R 2 is unsubstituted thiadiazaolyl, R 3 is hydrogen.

[0140] In certain embodiments, R 2 and R 3 together with the atom to which they are attached form a substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.

[0141] In certain embodiments, R 2 and R 3 taken together with the atom to which they are attached form a substituted or unsubstituted aryl. In certain embodiments, R 2 and R 3 taken together with the atom to which they are attached form a substituted or unsubstituted phenyl. In certain embodiments, R 2 and R 3 taken together with the atom to which they are attached form a substituted phenyl. In certain embodiments, R 2 and R 3 together with the atom to which they are attached form an unsubstituted phenyl.

[0142] In certain embodiments, R 2 and R 3 taken together with the atom to which they are attached form a substituted or unsubstituted heteroaryl. In certain embodiments, R 2 and R 3 together with the atom to which they are attached form a substituted or unsubstituted imidazolyl, substituted or unsubstituted pyrrolyl, or substituted or unsubstituted pyrazolyl. In certain embodiments, R 2 and R 3taken 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 2 and R 3 taken together with the atom to which they are attached form a substituted imidazolyl, substituted pyrrolyl, or substituted pyrazolyl. In certain embodiments, R 2 and R 3 taken together with the atom to which they are attached form a substituted pyrrolyl or substituted pyrazolyl. In certain embodiments, R 2 and R 3 together with the atom 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. 2 and R 3 taken together with the atom 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. In certain embodiments, R 2 and R 3 together with the atom to which they are attached form a substituted pyrrolyl or a substituted pyrazolyl, where the pyrrolyl or pyrazolyl is substituted with substituted or unsubstituted alkyl, or substituted or unsubstituted heterocyclyl. 2 and R 3 together with the atom 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 2 and R 3 together with the atom 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, heterocyclylalkyl, heterocyclyl, or haloalkyl. 2 and R 3taken together with the atom 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. 2 and R 3 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. In certain embodiments, R 2 and R 3 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. 2 and R 3 together with the atom to which they are attached form a substituted imidazolyl, substituted pyrrolyl, or substituted pyrazolyl, where the imidazolyl, pyrrolyl, or pyrazolyl is an unsubstituted C 1~4 Alkyl, 4-5 membered heterocyclylC 1~4 Alkyl, 4-5 membered heterocyclyl or C 1~4 In certain embodiments, R 2 and R 3 together with the atom to which they are attached form a substituted imidazolyl, substituted pyrrolyl, or substituted pyrazolyl, where the imidazolyl, pyrrolyl, or pyrazolyl is an unsubstituted C 1~4 Alkyl or C 1~4 In certain embodiments, R 2 and R 3 together with the atom to which they are attached form a substituted pyrrolyl or substituted pyrazolyl, where the pyrrolyl or pyrazolyl is an unsubstituted C 1~4 Alkyl, 4-5 membered heterocyclylC 1~4 Alkyl, 4-5 membered heterocyclyl or C 1~4 In certain embodiments, R 2 and R 3together with the atom to which they are attached form a substituted pyrrolyl or substituted pyrazolyl, where the pyrrolyl or pyrazolyl is an unsubstituted C 1~4 Alkyl or C 1~4 In certain embodiments, R 2 and R 3 together with the atom to which they are attached form a substituted imidazolyl, substituted pyrrolyl, or substituted pyrazolyl, where the imidazolyl, pyrrolyl, or pyrazolyl is an unsubstituted C 1~4 In certain embodiments, R 2 and R 3 together with the atom to which they are attached form a substituted pyrrolyl or substituted pyrazolyl, where the pyrrolyl or pyrazolyl is an unsubstituted C 1~4 In certain embodiments, R 2 and R 3 together with the atom to which they are attached form a substituted imidazolyl, substituted pyrrolyl, or substituted pyrazolyl, where the imidazolyl, pyrrolyl, or pyrazolyl is C 1~4 In certain embodiments, R 2 and R 3 together with the atom to which they are attached form a substituted pyrrolyl or substituted pyrazolyl, where pyrrolyl or pyrazolyl is C 1~4 In certain embodiments, R 2 and R 3 together with the atom to which they are attached form a substituted imidazolyl, substituted pyrrolyl or substituted pyrazolyl, where the imidazolyl, pyrrolyl or pyrazolyl is a 4- to 5-membered heterocyclylC 1~4 In certain embodiments, R 2 and R 3 together with the atom to which they are attached form a substituted pyrrolyl or substituted pyrazolyl, where pyrrolyl or pyrazolyl is a 4- to 5-membered heterocyclylC 1~4 In certain embodiments, R 2 and R 3together with the atom 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. 2 and R 3 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.

[0143] In certain embodiments, R 2 and R 3 taken together with the atom to which they are attached form a substituted or unsubstituted pyrazolyl. In certain embodiments, R 2 and R 3 taken together with the atom to which they are attached form a substituted pyrazolyl. In certain embodiments, R 2 and R 3 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 2 and R 3 taken together with the atom to which they are attached form a substituted pyrazolyl, which is substituted with substituted or unsubstituted alkyl. In certain embodiments, R 2 and R 3 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 2 and R 3 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 2 and R 3 together with the atom to which they are attached form a substituted pyrazolyl, where the pyrazolyl is an unsubstituted C 1~4 Alkyl, 4-5 membered heterocyclylC1~4 Alkyl, 4-5 membered heterocyclyl or C 1~4 In certain embodiments, R 2 and R 3 together with the atom 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 2 and R 3 together with the atom to which they are attached form a substituted pyrazolyl, where the pyrazolyl is an unsubstituted C 1~4 In certain embodiments, R 2 and R 3 together with the atom to which they are attached form a substituted pyrazolyl, which is C 1~4 In certain embodiments, R 2 and R 3 taken together with the atom to which they are attached form a substituted pyrazolyl, where the pyrazolyl is substituted with 4-5 membered heterocyclyl. In certain embodiments, R 2 and R 3 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.

[0144] In certain embodiments, R 2 and R 3 together with the atom to which they are attached form a substituted or unsubstituted pyrrolyl. In certain embodiments, R 2 and R 3 taken together with the atom to which they are attached form a substituted pyrrolyl. In certain embodiments, R 2 and R 3 taken together with the atom to which they are attached form a substituted, where pyrrolyl is substituted with substituted or unsubstituted heterocyclyl or substituted or unsubstituted alkyl. In certain embodiments, R 2 and R 3together with the atom to which they are attached form a substituted, where pyrrolyl is substituted with substituted or unsubstituted alkyl. In certain embodiments, R 2 and R 3 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 2 and R 3 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 2 and R 3 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 2 and R 3 together with the atom 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 2 and R 3 together with the atom to which they are attached form a substituted pyrrolyl, where the pyrrolyl is an unsubstituted C 1~4 In certain embodiments, R 2 and R 3 together with the atom to which they are attached form a substituted pyrrolyl, where pyrrolyl is C 1~4 In certain embodiments, R 2 and R 3 together with the atom to which they are attached form a substituted pyrrolyl, where the pyrrolyl is substituted with a 4-5 membered heterocyclyl.

[0145] In certain embodiments, A is of the formula: [ka] where X is N or CH; R a is substituted or unsubstituted alkyl, or substituted or unsubstituted heterocyclyl.

[0146] 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 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 1~4 In 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 ais haloalkyl or alkyl. In certain embodiments, X is N and R a is 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 a is 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 4-5 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 4-membered heterocyclyl C 1~4 Alkyl, 4-membered heterocyclyl, C 1~4 Fluoroalkyl or C1~4 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.

[0147] In certain embodiments, A is [ka] It is.

[0148] In certain embodiments, A is [ka] It is.

[0149] In certain embodiments, A is [ka] It is.

[0150] In certain embodiments, A is [ka] It is.

[0151] 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] It is.

[0152] 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] It is.

[0153] A 1 As described herein, A 1 teeth [ka] It is.

[0154] In certain embodiments, A 1 teeth, [ka] In certain embodiments, A 1 teeth, [ka] In certain embodiments, A 1 teeth, [ka] It is.

[0155] In certain embodiments, A 1 teeth, [ka] In certain embodiments, A 1 teeth, [ka] In certain embodiments, A 1 teeth, [ka] It is.

[0156] R 4 As described herein, each R 4 are independently halogen, substituted or unsubstituted alkyl, or R 4In the two cases, m is 0, 1, 2, 3, or 4, and m is 0, 1, 2, 3, or 4.

[0157] In certain embodiments, R 4 is a halogen or R on the same carbon 4 In two cases, R 4 is fluoro or R on the same carbon 4 In two cases, R 4 is halogen. In certain embodiments, R 4 is fluoro. In certain embodiments, R 4 In two cases, 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.

[0158] 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 and m is 2. In certain embodiments, R 4 is fluoro and m is 2. In certain embodiments, R 4 In the two cases above, it forms a carbonyl with that carbon and m is 2.

[0159] Specific Embodiments In certain embodiments, the compound of formula (I) has formula (Ia): [ka] or a pharma- ceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein R 1 , R 4 , m, L and A are as defined herein.

[0160] In certain embodiments, the compound of formula (I) has formula (Ib): [ka] or a pharma- ceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein R 1 , R 2 , R 3 , R 4 and m is as defined herein.

[0161] In certain embodiments, the compound of formula (Ib) has the formula (Ib-1): [ka] or a pharma- ceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein R 1 , R 2 , R 3 , R 4 and m is as defined herein.

[0162] In certain embodiments, the compound of formula (Ia) has the formula (Ib-2): [ka] or a pharma- ceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein R 1 , R 2 , R3 , R 4 and m is as defined herein.

[0163] In certain embodiments, the compound of formula (I) has formula (Ic): [ka] or a pharma- ceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein R 1 , R 2 , and R 3 is as defined herein.

[0164] In certain embodiments, the compound of formula (Ic) has the formula (Ic-1): [ka] or a pharma- ceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein R 1 , R 2 , and R 3 is as defined herein.

[0165] In certain embodiments, the compound of formula (Ic) has the formula (Ic-2): [ka] or a pharma- ceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein R 1 , R 2 , and R 3 is as defined herein.

[0166] In certain embodiments, the compound of formula (I) has the formula (Id): [ka] or a pharma- ceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein R 1 , R 2 , and R 3 is as defined herein.

[0167] In certain embodiments, the compound of formula (Id) has the formula (Id-1): [ka] or a pharma- ceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein R 1 , R 2 , and R 3 is as defined herein.

[0168] In certain embodiments, the compound of formula (Id) has the formula (Id-2): [ka] or a pharma- ceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein R 1 , R 2 , and R 3 is as defined herein.

[0169] In certain embodiments, the compound of formula (I) has the formula (Ie): [ka] or a pharma- ceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein R 1 , R 4 and m is as defined herein, X is N or CH, and R a is substituted or unsubstituted alkyl, or substituted or unsubstituted heterocyclyl.

[0170] In certain embodiments, X is N or CH, and R a is substituted or unsubstituted alkyl.

[0171] 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 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 1~4 In 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 ais 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 a is 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 4-5 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 4-membered heterocyclyl C 1~4 Alkyl, 4-membered heterocyclyl, C 1~4 Fluoroalkyl or C 1~4 In certain embodiments, X is CH and Ra 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.

[0172] In certain embodiments, the compound of formula (Ie) has the formula (Ie-1): [ka] or a pharma- ceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0173] In certain embodiments, the compound of formula (Ie) has the formula (Ie-2): [ka] or a pharma- ceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0174] In certain embodiments, the compound of formula (I) has the formula (If): [ka] or a pharma- ceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein R 1 , R 4 and m is as defined herein; R a is substituted or unsubstituted alkyl, or substituted or unsubstituted heterocyclyl.

[0175] In certain embodiments, R a is substituted or unsubstituted alkyl.

[0176] In certain embodiments, R is 4-5 membered heterocyclylalkyl, 4-5 membered heterocyclyl, haloalkyl, or alkyl. a is haloalkyl or alkyl. In certain embodiments, R a is 4-5 membered heterocyclylalkyl, 4-5 membered heterocyclyl, fluoroalkyl, or alkyl. In certain embodiments, R a is fluoroalkyl or alkyl. In certain embodiments, R a 4-5 membered heterocyclyl C 1~4 Alkyl, 4-5 membered heterocyclyl, C 1~4 Haloalkyl or C 1~4 In certain embodiments, R a is C 1~4 Haloalkyl or C 1~4 In certain embodiments, R a is a 4- to 5-membered heterocyclyl C 1~4 Alkyl, 4-5 membered heterocyclyl, C 1~4 Fluoroalkyl or C 1~4 In certain embodiments, R a is C 1~4 Fluoroalkyl or C 1~4 In certain embodiments, R a is C 1~4 In certain embodiments, R a is C 1~4 In certain embodiments, R a is 2,2-difluoroethyl. In certain embodiments, R a is C 1~4 In certain embodiments, R a is ethyl. In certain embodiments, R a is a 4- to 5-membered heterocyclyl C 1~4 In certain embodiments, R a is a 4-membered heterocyclyl C1~4 In certain embodiments, R a is oxetanylmethyl. In certain embodiments, R a is 4-5 membered heterocyclyl. In certain embodiments, R a is a 4-membered heterocyclyl. In certain embodiments, R a is oxetanyl.

[0177] In certain embodiments, the compound of formula (If) has the formula (If-1): [ka] or a pharma- ceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0178] In certain embodiments, the compound of formula (If) has the formula (If-2): [ka] or a pharma- ceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0179] In certain embodiments, the compound of formula (I) has the formula (Ig): [ka] or a pharma- ceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein R 1 is as defined herein, and R a is substituted or unsubstituted alkyl, or substituted or unsubstituted heterocyclyl. In certain embodiments, R a is substituted or unsubstituted alkyl.

[0180] In certain embodiments, R is 4-5 membered heterocyclylalkyl, 4-5 membered heterocyclyl, haloalkyl, or alkyl. a is haloalkyl or alkyl. In certain embodiments, R a is 4-5 membered heterocyclylalkyl, 4-5 membered heterocyclyl, fluoroalkyl, or alkyl. In certain embodiments, R a is fluoroalkyl or alkyl. In certain embodiments, R a 4-5 membered heterocyclyl C 1~4 Alkyl, 4-5 membered heterocyclyl, C 1~4 Haloalkyl or C 1~4 In certain embodiments, R a is C 1~4 Haloalkyl or C 1~4 In certain embodiments, R a is a 4- to 5-membered heterocyclyl C 1~4 Alkyl, 4-5 membered heterocyclyl, C 1~4 Fluoroalkyl or C 1~4 In certain embodiments, R a is C 1~4 Fluoroalkyl or C 1~4 In certain embodiments, R a is C 1~4 In certain embodiments, R a is C 1~4 In certain embodiments, R a is 2,2-difluoroethyl. In certain embodiments, R a is C 1~4 In certain embodiments, R a is ethyl. In certain embodiments, R a is a 4- to 5-membered heterocyclyl C 1~4 In certain embodiments, R a is a 4-membered heterocyclyl C 1~4 In certain embodiments, R a is oxetanylmethyl. In certain embodiments, R ais 4-5 membered heterocyclyl. In certain embodiments, R a is a 4-membered heterocyclyl. In certain embodiments, R a is oxetanyl.

[0181] In certain embodiments, the compound of formula (Ig) has the formula (Ig-1): [ka] or a pharma- ceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0182] In certain embodiments, the compound of formula (Ig) has the formula (Ig-2): [ka] or a pharma- ceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0183] In certain embodiments, the compound of formula (I) has the formula (Ih): [ka] or a pharma- ceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein R 1 , R 4 and m is as defined herein; R a is substituted or unsubstituted alkyl, or substituted or unsubstituted heterocyclyl. In certain embodiments, R a is substituted or unsubstituted alkyl.

[0184] In certain embodiments, R is 4-5 membered heterocyclylalkyl, 4-5 membered heterocyclyl, haloalkyl, or alkyl. ais haloalkyl or alkyl. In certain embodiments, R a is 4-5 membered heterocyclylalkyl, 4-5 membered heterocyclyl, fluoroalkyl, or alkyl. In certain embodiments, R a is fluoroalkyl or alkyl. In certain embodiments, R a 4-5 membered heterocyclyl C 1~4 Alkyl, 4-5 membered heterocyclyl, C 1~4 Haloalkyl or C 1~4 In certain embodiments, R a is C 1~4 Haloalkyl or C 1~4 In certain embodiments, R a is a 4- to 5-membered heterocyclyl C 1~4 Alkyl, 4-5 membered heterocyclyl, C 1~4 Fluoroalkyl or C 1~4 In certain embodiments, R a is C 1~4 Fluoroalkyl or C 1~4 In certain embodiments, R a is C 1~4 In certain embodiments, R a is C 1~4 In certain embodiments, R a is 2,2-difluoroethyl. In certain embodiments, R a is C 1~4 In certain embodiments, R a is ethyl. In certain embodiments, R a is a 4- to 5-membered heterocyclyl C 1~4 In certain embodiments, R a is a 4-membered heterocyclyl C 1~4 In certain embodiments, R a is oxetanylmethyl. In certain embodiments, R a is 4-5 membered heterocyclyl. In certain embodiments, R a is a 4-membered heterocyclyl. In certain embodiments, R ais oxetanyl.

[0185] In certain embodiments, the compound of formula (Ig) has the formula (Ih-1): [ka] or a pharma- ceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0186] In certain embodiments, the compound of formula (Ih) has the formula (Ih-2): [ka] or a pharma- ceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0187] In certain embodiments, the compound of formula (I) has the formula (Ii): [ka] or a pharma- ceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein R 1 is as defined herein, and R a is substituted or unsubstituted alkyl, or substituted or unsubstituted heterocyclyl. In certain embodiments, R a is substituted or unsubstituted alkyl.

[0188] In certain embodiments, R is 4-5 membered heterocyclylalkyl, 4-5 membered heterocyclyl, haloalkyl, or alkyl. a is haloalkyl or alkyl. In certain embodiments, R a is 4-5 membered heterocyclylalkyl, 4-5 membered heterocyclyl, fluoroalkyl, or alkyl. In certain embodiments, Ra is fluoroalkyl or alkyl. In certain embodiments, R a 4-5 membered heterocyclyl C 1~4 Alkyl, 4-5 membered heterocyclyl, C 1~4 Haloalkyl or C 1~4 In certain embodiments, R a is C 1~4 Haloalkyl or C 1~4 In certain embodiments, R a is a 4- to 5-membered heterocyclyl C 1~4 Alkyl, 4-5 membered heterocyclyl, C 1~4 Fluoroalkyl or C 1~4 In certain embodiments, R a is C 1~4 Fluoroalkyl or C 1~4 In certain embodiments, R a is C 1~4 In certain embodiments, R a is C 1~4 In certain embodiments, R a is 2,2-difluoroethyl. In certain embodiments, R a is C 1~4 In certain embodiments, R a is ethyl. In certain embodiments, R a is a 4- to 5-membered heterocyclyl C 1~4 In certain embodiments, R a is a 4-membered heterocyclyl C 1~4 In certain embodiments, R a is oxetanylmethyl. In certain embodiments, R a is 4-5 membered heterocyclyl. In certain embodiments, R a is a 4-membered heterocyclyl. In certain embodiments, R a is oxetanyl.

[0189] In certain embodiments, the compound of formula (Ii) has the formula (Ii-1): [ka] or a pharma- ceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0190] In certain embodiments, the compound of formula (Ii) has the formula (Ii-2): [ka] or a pharma- ceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

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

[0192] In certain embodiments, the compound of formula (Ij) has the formula (Ij-1): [ka] or a pharma- ceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0193] In certain embodiments, the compound of formula (Ij) has the formula (Ij-2): [ka] or a pharma- ceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0194] In certain embodiments, the compound of formula (I) has the formula (Ik): [ka] or a pharma- ceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein R 1 is as defined herein.

[0195] In certain embodiments, the compound of formula (Ik) has the formula (Ik-1): [ka] or a pharma- ceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0196] In certain embodiments, the compound of formula (Ik) has the formula (Ik-2): [ka] or a pharma- ceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

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

[0198] In certain embodiments, the compound of formula (Il) has the formula (Il-1): [ka] or a pharma- ceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0199] In certain embodiments, the compound of formula (Il) has the formula (Il-2): [ka] or a pharma- ceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0200] In certain embodiments, the compound of formula (I) has the formula (Im): [ka] or a pharma- ceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein R 1 is as defined herein.

[0201] In certain embodiments, the compound of formula (Im) has the formula (Im-1): [ka] or a pharma- ceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0202] In certain embodiments, the compound of formula (Im) has the formula (Im-2): [ka] or a pharma- ceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0203] In certain embodiments, the compound of formula (I) has the formula (In): [ka] or a pharma- ceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein R 1 , R 4 and m is as defined herein; R a is substituted or unsubstituted alkyl, or substituted or unsubstituted heterocyclyl.

[0204] In certain embodiments, R a is substituted or unsubstituted alkyl.

[0205] In certain embodiments, R is 4-5 membered heterocyclylalkyl, 4-5 membered heterocyclyl, haloalkyl, or alkyl. a is haloalkyl or alkyl. In certain embodiments, R a is 4-5 membered heterocyclylalkyl, 4-5 membered heterocyclyl, fluoroalkyl, or alkyl. In certain embodiments, R a is fluoroalkyl or alkyl. In certain embodiments, R a 4-5 membered heterocyclyl C 1~4 Alkyl, 4-5 membered heterocyclyl, C 1~4 Haloalkyl or C 1~4 In certain embodiments, R a is C 1~4 Haloalkyl or C 1~4 In certain embodiments, R a is a 4- to 5-membered heterocyclyl C 1~4 Alkyl, 4-5 membered heterocyclyl, C 1~4 Fluoroalkyl or C 1~4 In certain embodiments, R a is C 1~4 Fluoroalkyl or C 1~4 In certain embodiments, R a is C1~4 In certain embodiments, R a is C 1~4 In certain embodiments, R a is 2,2-difluoroethyl. In certain embodiments, R a is C 1~4 In certain embodiments, R a is ethyl. In certain embodiments, R a is a 4- to 5-membered heterocyclyl C 1~4 In certain embodiments, R a is a 4-membered heterocyclyl C 1~4 In certain embodiments, R a is oxetanylmethyl. In certain embodiments, R a is 4-5 membered heterocyclyl. In certain embodiments, R a is a 4-membered heterocyclyl. In certain embodiments, R a is oxetanyl.

[0206] In certain embodiments, the compound of formula (I) has the formula (Io): [ka] or a pharma- ceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein R 1 is as defined herein, and R a is substituted or unsubstituted alkyl, or substituted or unsubstituted heterocyclyl.

[0207] In certain embodiments, R a is substituted or unsubstituted alkyl.

[0208] In certain embodiments, R is 4-5 membered heterocyclylalkyl, 4-5 membered heterocyclyl, haloalkyl, or alkyl. a is haloalkyl or alkyl. In certain embodiments, R ais 4-5 membered heterocyclylalkyl, 4-5 membered heterocyclyl, fluoroalkyl, or alkyl. In certain embodiments, R a is fluoroalkyl or alkyl. In certain embodiments, R a 4-5 membered heterocyclyl C 1~4 Alkyl, 4-5 membered heterocyclyl, C 1~4 Haloalkyl or C 1~4 In certain embodiments, R a is C 1~4 Haloalkyl or C 1~4 In certain embodiments, R a is a 4- to 5-membered heterocyclyl C 1~4 Alkyl, 4-5 membered heterocyclyl, C 1~4 Fluoroalkyl or C 1~4 In certain embodiments, R a is C 1~4 Fluoroalkyl or C 1~4 In certain embodiments, R a is C 1~4 In certain embodiments, R a is C 1~4 In certain embodiments, R a is 2,2-difluoroethyl. In certain embodiments, R a is C 1~4 In certain embodiments, R a is ethyl. In certain embodiments, R a is a 4- to 5-membered heterocyclyl C 1~4 In certain embodiments, R a is a 4-membered heterocyclyl C 1~4 In certain embodiments, R a is oxetanylmethyl. In certain embodiments, R a is 4-5 membered heterocyclyl. In certain embodiments, R a is a 4-membered heterocyclyl. In certain embodiments, R a is oxetanyl.

[0209] In certain embodiments, the compound of formula (I) has the formula (Ip): [ka] or a pharma- ceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein R 1 is as defined herein, and R a is substituted or unsubstituted alkyl, or substituted or unsubstituted heterocyclyl.

[0210] In certain embodiments, R a is substituted or unsubstituted alkyl.

[0211] In certain embodiments, R is 4-5 membered heterocyclylalkyl, 4-5 membered heterocyclyl, haloalkyl, or alkyl. a is haloalkyl or alkyl. In certain embodiments, R a is 4-5 membered heterocyclylalkyl, 4-5 membered heterocyclyl, fluoroalkyl, or alkyl. In certain embodiments, R a is fluoroalkyl or alkyl. In certain embodiments, R a 4-5 membered heterocyclyl C 1~4 Alkyl, 4-5 membered heterocyclyl, C 1~4 Haloalkyl or C 1~4 In certain embodiments, R a is C 1~4 Haloalkyl or C 1~4 In certain embodiments, R a is a 4- to 5-membered heterocyclyl C 1~4 Alkyl, 4-5 membered heterocyclyl, C 1~4 Fluoroalkyl or C 1~4 In certain embodiments, R a is C 1~4 Fluoroalkyl or C 1~4 In certain embodiments, R a is C 1~4In certain embodiments, R a is C 1~4 In certain embodiments, R a is 2,2-difluoroethyl. In certain embodiments, R a is C 1~4 In certain embodiments, R a is ethyl. In certain embodiments, R a is a 4- to 5-membered heterocyclyl C 1~4 In certain embodiments, R a is a 4-membered heterocyclyl C 1~4 In certain embodiments, R a is oxetanylmethyl. In certain embodiments, R a is 4-5 membered heterocyclyl. In certain embodiments, R a is a 4-membered heterocyclyl. In certain embodiments, R a is oxetanyl.

[0212] In certain embodiments, the compound of formula (I) is one of the following compounds, or a pharma- ceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof: [Table 2] TIFF2024517789000110.tif202151

[0213] In certain embodiments, the compound of formula (I) is one of the following compounds, or a pharma- ceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof: [Table 3] TIFF2024517789000112.tif89148

[0214] 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.

[0215] Pharmaceutical Compositions, Kits, and Administration The present disclosure provides pharmaceutical compositions comprising a disclosed compound (e.g., a compound of formula (I)), or a pharma- ceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, and optionally a pharma- ceutically acceptable excipient. In certain embodiments, the pharmaceutical compositions described herein comprise a compound of formula (I) or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient.

[0216] 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 of such treatment. In certain embodiments, the effective amount is an amount effective to treat a neurological disease or disorder in a subject in need of such treatment. In certain embodiments, the effective amount is an amount effective to prevent a neurological disease or disorder in a subject in need of such treatment.

[0217] 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.

[0218] In certain embodiments, an effective amount is an amount effective to increase the activity of GCase in a subject, tissue, biological sample, or cell.

[0219] In certain embodiments, the subject treated or administered with the compounds described herein is an animal. The animal may be of either sex 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 another embodiment, 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 mouse and transgenic pig). In certain embodiments, the subject is a fish or reptile.

[0220] 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 a percentage recited in this paragraph and another percentage recited in this paragraph, inclusive.

[0221] The present disclosure provides pharmaceutical compositions comprising a compound that interacts with (e.g., activates) GCase for use in treating a GCase-related disease or disorder in a subject in need of such treatment.The present disclosure provides pharmaceutical compositions comprising a compound that interacts with (e.g., activates) GCase for use in treating a disease or disorder associated with abnormal activity of GCase in a subject in need of such treatment.The present disclosure provides pharmaceutical compositions comprising a compound that interacts with (e.g., activates) GCase for use in treating a disease or disorder associated with mutant GCase in a subject in need of such treatment.

[0222] 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.

[0223] 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 disease treatment, preventing a disease in a subject in need of disease prevention, and / or reducing the risk of developing a disease in a subject in need of disease prevention), improve bioavailability, improve safety, reduce drug resistance, reduce and / or modify metabolism, inhibit excretion, and / or modify distribution in a subject or cell. It will also be understood that the treatments used can achieve the desired effect on the same disorder and / or can achieve different effects. In certain embodiments, the pharmaceutical compositions described herein that include the compounds described herein and the additional pharmaceutical agents exhibit synergistic effects that are not present in pharmaceutical compositions that include one of the compounds and the additional pharmaceutical agents but not both.

[0224] The compound or composition may be administered simultaneously, 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 cells, and other organic small molecules. 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 may 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 together with each other and / or with the compounds or compositions described herein, or may be administered separately in different doses. The particular combination to be used in the regimen will take into account the 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.

[0225] 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 make a solution. In certain embodiments, the compound or pharmaceutical composition is dissolved in water to make 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).

[0226] After formulation with appropriate pharma- ceutically acceptable excipients in desired dosages, the pharmaceutical compositions of the present disclosure can be administered orally, parenterally, intracisternally, intraperitoneally, topically, buccally, etc. to humans and other animals depending on the disease or condition being treated.

[0227] In certain embodiments, pharmaceutical compositions containing a compound of formula (I) are administered orally or parenterally at dosage levels of each pharmaceutical composition sufficient to deliver about 0.001 mg / kg to about 200 mg / kg in one or more dose administrations over a day or several 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, 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 obtain the desired therapeutic and / or prophylactic effect. In certain embodiments, the compounds described herein may be 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, more preferably about 1 mg / kg to about 25 mg / kg of the subject's body weight per day, once or multiple times per day, to obtain the desired therapeutic and / or prophylactic effect. The desired dosage may be delivered three times per day, twice per day, once per day, every other day, every third day, every week, 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 non-specific effects.

[0228] 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.

[0229] The pharmaceutical compositions described herein can be prepared by any method known in the art of pharmacology.In general, such preparation methods include the steps of bringing into association a composition containing a compound of formula (I) with the carrier and / or one or more other accessory ingredients, and then, if necessary and / or desired, shaping and / or packaging the product into the desired single or multiple dosage unit.

[0230] Pharmaceutical compositions can be prepared, packaged, and / or sold in bulk, as single unit doses, and / or as a plurality of single unit doses. As used herein, a "unit dose" is a discrete amount of pharmaceutical composition that contains a predetermined amount of active ingredient. The amount of 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, such as half or one-third of such a dosage.

[0231] The relative amounts of active ingredient, pharma- ceutically 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 on the route by which the composition is administered. By way of example, the composition may contain from 0.1% to 100% (w / w) active ingredient.

[0232] Pharmaceutically acceptable excipients used in the manufacture 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.

[0233] 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.

[0234] Exemplary granulating and / or dispersing agents include potato starch, corn starch, tapioca starch, sodium starch glycolate, clays, 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.

[0235] 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), carrageenans, 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 (Myrj45), polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan monooleate (Span 80)), Riethoxylated 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.

[0236] Exemplary binders include starches (e.g., corn starch and starch paste), gelatin, sugars (e.g., sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, and the like), 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.

[0237] 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.

[0238] 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.

[0239] Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA) and its salts and hydrates (e.g., sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, 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.

[0240] Exemplary antifungal preservatives include butylparaben, methylparaben, ethylparaben, propylparaben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid.

[0241] Exemplary alcohol preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoates, and phenylethyl alcohol.

[0242] 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.

[0243] 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.

[0244] Exemplary buffers 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.

[0245] 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.

[0246] 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, linseed, geraniol, gaoud, grape seed, hazelnut, hyssop, isopropyl myristate, jojoba, kuku peanut, lavandin, lavender, and the like. Exemplary synthetic oils include, but are not limited to, butyl stearate, caprylic triglyceride, capric triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyldodecyl ester, oleyl alcohol, silicone oil, and mixtures thereof.

[0247] Liquid dosage forms for oral and parenteral administration include, but are not limited to, pharma- ceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active agent, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing and emulsifying agents, 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 aromatic 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.

[0248] 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 as sterile injectable solutions, suspensions or emulsions in non-toxic parenterally acceptable diluents or solvents, for example, solutions in 1,3-butanediol. Among the acceptable vehicles and solvents that can be used are water, Ringer's solution, USP and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally used as solvents or suspending media. For this purpose, any sterile fixed oil can be used, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

[0249] 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 prior to use.

[0250] 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 pharma- ceutically 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 retarding agents, 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 forms may also comprise buffering agents.

[0251] 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 of 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 can 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.

[0252] The active agent may also be in microencapsulated form with one or more excipients as described above. The solid dosage forms of 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 normal practice, additional substances other than the inert diluent, 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 may be used include polymeric substances and waxes.

[0253] Formulations suitable for topical administration include liniments, lotions, gels, applications, oil-in-water or water-in-oil emulsions, liquid or semi-liquid formulations such as creams, ointments or pastes; or solutions or suspensions such as drops. Formulations for topical administration to skin surfaces can be prepared by dispersing the drug with a dermatologically acceptable carrier such as lotions, creams, ointments or soaps. 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, hydroxypropylcellulose 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 to be within the scope of the present invention. Additionally, the present disclosure contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of the 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.

[0254] Furthermore, the carrier for topical formulations can be in the form of an aqueous alcohol system (e.g., liquid and gel), anhydrous oil or silicone system, or emulsion system, 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 semi-solids (such as gels and sticks) and aqueous-based mousse systems.

[0255] Kits (e.g., pharmaceutical packs) are also included in the present disclosure. The kits provided 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 kits provided may further include a second container, optionally including a pharmaceutical excipient for diluting or suspending the pharmaceutical composition or compound described herein. In some embodiments, the pharmaceutical composition or compound provided in the first container and the second container are combined to form one unit dosage form.

[0256] Thus, in one aspect, a kit is provided that includes a first container that includes a compound or pharmaceutical composition described herein. In certain embodiments, the kit is useful for treating a disease in a subject in need of such treatment (e.g., a neurological disease or disorder). In certain embodiments, the kit is useful for preventing a disease in a subject in need of such prevention (e.g., a neurological disease or disorder). In certain embodiments, the kit is useful for reducing the risk of developing a disease in a subject in need of such reduction (e.g., a neurological disease or disorder). In certain embodiments, the kit is useful for increasing the activity of GCase in a subject or cell.

[0257] In certain embodiments, the kits described herein further comprise instructions for using the kit. The kits described herein may also comprise information required by a regulatory agency, 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 kits and instructions provide for treatment of a disease in a subject in need of such treatment (e.g., a neurological disease or disorder). In certain embodiments, the kits and instructions provide for prevention of a disease in a subject in need of such prevention (e.g., a neurological disease or disorder). In certain embodiments, the kits and instructions provide for reduction of onset of a disease in a subject in need of such reduction of onset of a disease (e.g., a neurological disease or disorder). In certain embodiments, the kits and instructions provide for increasing the activity of GCase in a subject or cell. The kits described herein may comprise one or more additional pharmaceutical agents described herein as separate compositions.

[0258] Treatment 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.

[0259] The present disclosure provides methods of activating GCase. The present disclosure provides methods of increasing GCase activity. In certain embodiments, the present application provides methods of activating GCase in vitro (e.g., increasing GCase activity). In certain embodiments, the present application provides methods of activating GCase in vivo (e.g., increasing GCase activity). In certain embodiments, the present application provides methods of increasing GCase activity in a cell. In certain embodiments, the present application provides methods of increasing GCase activity in a human cell.

[0260] In certain embodiments, the method includes administering to a subject in need thereof (e.g., a subject having a neurological disease or disorder) a compound that interacts with GCase, such as 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 includes administering to a subject in need thereof a compound of the present disclosure (e.g., a compound of formula (I)), or a pharma- ceutically acceptable salt, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug, or composition thereof. In some embodiments, the method includes 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 pharma-ceutically acceptable salt, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug, or composition thereof.

[0261] 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. EXAMPLES

[0262] 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.

[0263] Synthesis method The compound of formula (I) was prepared according to the synthesis scheme 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 that are 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); TW Greene and PG M Huts, Protective Groups in Organic Synthesis, 2d. Ed., John Wiley and Sons (1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) and subsequent editions are representative and useful. Methods for optimizing reaction conditions, and if necessary, minimizing competition with products, are known in the art. 2-[3-(5-phenyl-1,3,4-thiadiazol-2-yl)piperidin-1-yl]-6-(1,3,4-thiadiazol-2-yl)pyrazine (1) [ka]

[0264] 2-[3-(5-phenyl-1,3,4-thiadiazol-2-yl)piperidin-1-yl]-6-(1,3,4-thiadiazol-2-yl)pyrazine: To a stirred solution of 3-(5-phenyl-1,3,4-thiadiazol-2-yl)piperidine hydrochloride (102 mg, 0.362 mmol, 1.2 equiv.) and 2-chloro-6-(1,3,4-thiadiazol-2-yl)pyrazine (60.0 mg, 0.302 mmol, 1.00 equiv.) in DMF (1 mL) was added Na 2 CO 3 (96.0 mg, 0.906 mmol, 3 equiv.) was added. The resulting mixture was stirred at 100 °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, gradient 10% to 60% in 15 min; detector, UV 254 nm. This afforded 2-[3-(5-phenyl-1,3,4-thiadiazol-2-yl)piperidin-1-yl]-6-(1,3,4-thiadiazol-2-yl)pyrazine (34.0 mg, 27.62%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 )δ 9.70(s,1H),8.65-8.62(m,2H),8.08-7.88(m,2H),7.59-7.54(m,3H),4.67-4.58(m,1H),4.25-4.21 (m,1H),3.68-3.51(m,2H),3.44-3.36(m,1H),2.25(s,1H),2.09-1.83(m,2H),1.77-1.69(m,1H).MS m / z:407.8[M+H] + . 2-(5-{1-[1-(2,2-difluoroethyl)pyrazolo[3,4-b]pyrazin-6-yl]piperidin-3-yl}-1,3,4-thiadiazol-2-yl)-6-(trifluoromethyl)pyridine (2) [ka]

[0265] Step 1: tert-Butyl 3-({[6-(trifluoromethyl)pyridin-2-yl]formohydrazide}carbonyl)piperidine-1-carboxylate: To a stirred solution of 6-(trifluoromethyl)pyridine-2-carboxylic acid and HATU (656 mg, 1.70 mmol, 1.1 equiv) in DCM (10 mL) was added DIEA (405 mg, 3.10 mmol, 2 equiv) and tert-butyl 3-(hydrazinecarbonyl)piperidine-1-carboxylate (458 mg, 1.80 mmol, 1.2 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 EtOAc (25 mL×2). The combined organic phase was washed with water (20 mL), brine (20 mL) and diluted with anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated to dryness in vacuo to give the crude product which was purified by chromatography on silica gel (Flash 40 g, 30-60% EA:PE) to give tert-butyl 3-({[6-(trifluoromethyl)pyridin-2-yl]formohydrazide}carbonyl)piperidine-1-carboxylate (450 mg, 99.0%) as a pale yellow oil. MS m / z: 417 [M+H] + .

[0266] Step 2: tert-Butyl 3-{5-[6-(trifluoromethyl)pyridin-2-yl]-1,3,4-thiadiazol-2-yl}piperidine-1-carboxylate: A solution of tert-butyl 3-({[6-(trifluoromethyl)pyridin-2-yl]formohydrazide}carbonyl)piperidine-1-carboxylate and Lawesson Reagent (233 mg, 0.570 mmol, 0.6 equiv) in toluene (5 mL) was stirred at 60° C. for 2 h. The reaction mixture was purified by chromatography on silica gel (Flash 40 g, 40-60% EtOAc:PE) to give 3-{5-[6-(trifluoromethyl)pyridin-2-yl]-1,3,4-thiadiazol-2-yl}piperidine-1-carboxylate (450 mg, 99.0%) as a white solid. MSm / z: 415[M+H] + .

[0267] Step 3: 2-[5-(piperidin-3-yl)-1,3,4-thiadiazol-2-yl]-6-(trifluoromethyl)pyridine hydrochloride: To a stirred solution of tert-butyl 3-{5-[6-(trifluoromethyl)pyridin-2-yl]-1,3,4-thiadiazol-2-yl}piperidine-1-carboxylate (240 mg, 0.579 mmol, 1.00 equiv) in DCM (4 mL) was added HCl (gas) in 1,4-dioxane (4 M, 2 mL) dropwise at 0° C. The resulting mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated to dryness under vacuum. This afforded 2-[5-(piperidin-3-yl)-1,3,4-thiadiazol-2-yl]-6-(trifluoromethyl)pyridine hydrochloride (150 mg, 92.0%) as a white solid. MS m / z: 315 [M+H] + .

[0268] Step 4: 2-(5-{1-[1-(2,2-difluoroethyl)pyrazolo[3,4-b]pyrazin-6-yl]piperidin-3-yl}-1,3,4-thiadiazol-2-yl)-6-(trifluoromethyl)pyridine: A stirred solution of 2-[5-(piperidin-3-yl)-1,3,4-thiadiazol-2-yl]-6-(trifluoromethyl)pyridine hydrochloride (114 mg, 0.326 mmol, 1.2 equiv.) and 6-chloro-1-(2,2-difluoroethyl)pyrazolo[3,4-b]pyrazine (50.0 mg, 0.272 mmol, 1.00 equiv.) in DMF (1 mL) was diluted with Na 2 CO 3 (86.3 mg, 0.816 mmol, 3 equiv.) was added. The resulting mixture was stirred at 100 °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, gradient 0% to 100% in 30 min; detector, UV 254 nm. This afforded 2-(5-{1-[1-(2,2-difluoroethyl)pyrazolo[3,4-b]pyrazin-6-yl]piperidin-3-yl}-1,3,4-thiadiazol-2-yl)-6-(trifluoromethyl)pyridine (73.0 mg, 54.1%) as a yellow solid. 1H NMR (400 MHz, DMSO-d 6 )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:497.2[M+H] + . 2-(1-(5-ethyl-5H-pyrrolo[2,3-b]pyrazin-3-yl)piperidin-3-yl)-5-phenyl-1,3,4-thiadiazole (3) [ka]

[0269] Step 1: tert-Butyl 3-(2-benzoylhydrazine-1-carbonyl)piperidine-1-carboxylate: To a stirred solution of 1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid and HATU (656 mg, 1.70 mmol, 1.1 equiv) in DCM (10 mL) was added DIEA (406 mg, 3.10 mmol, 2 equiv) and benzohydrazide (458 mg, 1.80 mmol, 1.2 equiv) 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 EtOAc (25 mL×2). The combined organic phase was washed with water (20 mL), brine (20 mL) and diluted with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated in vacuo to give the crude product which was purified by silica gel chromatography (Flash 40 g, 40-60% EtOAc:PE) to give tert-butyl 3-(2-benzoylhydrazine-1-carbonyl)piperidine-1-carboxylate (450 mg, 99.0%) as a pale yellow oil. MS m / z: 347 [M+H] + .

[0270] Step 2: tert-Butyl 3-(5-phenyl-1,3,4-thiadiazol-2-yl)piperidine-1-carboxylate: A solution of tert-butyl 3-(2-benzoylhydrazine-1-carbonyl)piperidine-1-carboxylate and Lawesson's reagent (233.12 mg, 0.57 mmol, 0.6 equiv) in toluene (5 mL) was stirred at 60° C. for 2 h. The reaction mixture was purified by chromatography on silica gel (Flash 40 g, 40-60% EtOAc:PE) to give tert-butyl 3-(5-phenyl-1,3,4-thiadiazol-2-yl)piperidine-1-carboxylate (450.2 mg, 99.0%) as a white solid. MS m / z: 346 [M+H] + .

[0271] Step 3: 2-Phenyl-5-(piperidin-3-yl)-1,3,4-thiadiazole: To a stirred solution of tert-butyl 3-(5-phenyl-1,3,4-thiadiazol-2-yl)piperidine-1-carboxylate (240 mg, 0.579 mmol, 1.00 equiv) in DCM (4 mL) was added HCl (gas) in 1,4-dioxane (4 M, 2 mL) dropwise at 0° C. The resulting mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated to dryness under vacuum. This afforded 2-phenyl-5-(piperidin-3-yl)-1,3,4-thiadiazole (150 mg, 95.0%) as a white solid. MS m / z: 246 [M+H] + .

[0272] Step 4: 2-(1-(5-ethyl-5H-pyrrolo[2,3-b]pyrazin-3-yl)piperidin-3-yl)-5-phenyl-1,3,4-thiadiazole: To a stirred solution of 3-chloro-5-methyl-6-phenylpyrrolo[2,3-b]pyrazine (50.0 mg, 0.205 mmol, 1.00 equiv) and 3-(2-methylphenoxymethyl)piperidine (54.8 mg, 0.267 mmol, 1.3 equiv) in dioxane (1 mL) was added Pd-PEPPSI-IPentCl-methylpyridine (17.26 mg, 0.021 mmol, 0.1 equiv) and Cs 2 CO 3(200 mg, 0.615 mmol, 3 equiv.) 2 The mixture was added at room temperature under N 2 The mixture was stirred at 100° C. under atmospheric pressure 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 0% to 100% in 30 min; detector, UV 254 nm. This gave 2-(1-(5-ethyl-5H-pyrrolo[2,3-b]pyrazin-3-yl)piperidin-3-yl)-5-phenyl-1,3,4-thiadiazole (14.0 mg, 16.5%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 )δ 8.35(s,1H),8.04-8.01(m,2H),7.64-7.53(m,4H),6.51-6.50(d,J=4.8 Hz,1H),4.59-4.55(m,1H),4.26-4.16(m,3H),3.65-3.50(m,2H),3.39-3.37(m,1H),2.35-1.81(m,4H),1.47-1.43(m,3H).MS m / z:391.0[M+H] + . 2-(2-fluorophenyl)-5-(1-(quinoxalin-2-yl)piperidin-3-yl)-1,3,4-thiadiazole (4) [ka]

[0273] Step 1: tert-Butyl 3-(2-(2-fluorobenzoyl)hydrazine-1-carbonyl)piperidine-1-carboxylate: To a stirred solution of 2-fluorobenzoic acid (202 mg, 1.44 mmol, 1.0 equiv) and HATU (547 mg, 1.44 mmol, 1.0 equiv) in DMF (5 mL) was added DIEA (557 mg, 4.32 mmol, 4 equiv) and tert-butyl 3-(hydrazinecarbonyl)piperidine-1-carboxylate (350 mg, 1.44 mmol, 1.0 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 EtOAc (25 mL×2). The combined organic phase was washed with water (40 mL), brine (40 mL) and diluted with anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated to dryness in vacuo to give the crude product which was purified by chromatography on silica gel (Flash 40 g, 40-60% EA:PE) to give tert-butyl 3-(2-(2-fluorobenzoyl)hydrazine-1-carbonyl)piperidine-1-carboxylate (250 mg, 47.6%) as a pale yellow oil. MS m / z: 310 [M-tBu+H] + .

[0274] Step 2: tert-Butyl 3-(5-phenyl-1,3,4-thiadiazol-2-yl)piperidine-1-carboxylate: A solution of tert-butyl 3-(2-(2-fluorobenzoyl)hydrazine-1-carbonyl)piperidine-1-carboxylate (250 mg, 0.685 mmol, 1 equiv) and Lawesson's reagent (168 mg, 0.410 mmol, 0.6 equiv) in toluene (5 mL) was stirred at 100° C. for 16 h. The reaction mixture was purified by chromatography on silica gel (Flash 40 g, 40-60% EtOAc:PE) to give tert-butyl 3-(5-phenyl-1,3,4-thiadiazol-2-yl)piperidine-1-carboxylate (120 mg, 50.1%) as a white solid. MS m / z: 290 [M-tBu+H] + .

[0275] Step 3: 2-(2-fluorophenyl)-5-(piperidin-4-yl)-1,3,4-thiadiazole hydrochloride: To a stirred solution of tert-butyl 3-(5-phenyl-1,3,4-thiadiazol-2-yl)piperidine-1-carboxylate (120 mg, 0.347 mmol, 1.00 equiv) in DCM (1 mL) was added HCl (gas) in 1,4-dioxane (4 M, 1 mL) dropwise at 0° C. The resulting mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated to dryness under vacuum. This afforded 2-[5-(piperidin-3-yl)-1,3,4-thiadiazol-2-yl]-6-(trifluoromethyl)pyridine hydrochloride (100 mg, 96.0%) as a white solid. MS m / z: 264 [M+H] + .

[0276] Step 4: 2-(2-fluorophenyl)-5-(1-(quinoxalin-2-yl)piperidin-3-yl)-1,3,4-thiadiazole: To a stirred solution of 2-[5-(piperidin-3-yl)-1,3,4-thiadiazol-2-yl]-6-(trifluoromethyl)pyridine hydrochloride (90.0 mg, 0.300 mmol, 1.2 equiv.) and 2-chloroquinoxaline (41.0 mg, 0.250 mmol, 1.00 equiv.) in DMF (1 mL) was added Na 2 CO 3 (79.5 mg, 0.750 mmol, 3 equiv.) was added. The resulting mixture was stirred at 100° C. under nitrogen atmosphere for 3 h. The resulting mixture was diluted with water (20 mL) and extracted with EtOAc (15 mL×3). The combined organic layers were washed with brine (30 mL) and extracted with anhydrous Na 2 SO 4The mixture was dried at 37° C. 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 reversed-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: UV254 / 220 nm). The pure fractions were concentrated under vacuum to give 2-(2-fluorophenyl)-5-(1-(quinoxalin-2-yl)piperidin-3-yl)-1,3,4-thiadiazole (50.0 mg, 51.2%) as a white solid. 1 H NMR(300 MHz,DMSO-d6)δ 8.93(s,1H),8.25(td,J=7.6,1.8 Hz,1H),7.84(d,J=8.1 Hz,1H),7.72-7.54(m,3H),7.55-7.32(m,3H),4.79(q,J=9.7,9.3 Hz,1H),4.41(dd,J=9.7,3.6 Hz,1H),3.79-3.52(m,2H),3.50-3.35(m,1H),2.40-2.22(m,1H),2.14-1.82(m,2H),1.82-1.62(m,1H).MS m / z:392.0[M+H] + . 2-(1-(1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)piperidin-3-yl)-5-(2-(trifluoromethyl)pyridin-4-yl)-1,3,4-thiadiazole (5) [ka]

[0277] Step 1: tert-Butyl 4-(2-(2-(trifluoromethyl)isonicotinoyl)hydrazine-1-carbonyl)piperidine-1-carboxylate: To a solution of tert-butyl 4-(hydrazinecarbonyl)piperidine-1-carboxylate (231 mg, 0.952 mmol, 1.00 equiv), HATU (434 mg, 1.14 mmol, 1.2 equiv) and DIPEA (246 mg, 1.90 mmol, 2.0 equiv) in DCM (10 mL) was added tert-butyl 3-(hydrazinecarbonyl)piperidine-1-carboxylate (458.3 mg, 1.8 mmol, 1.2 equiv) dropwise at 0° C. The resulting mixture was stirred at room temperature overnight. 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) and anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated to dryness in vacuo to give the crude product which was purified by silica gel chromatography (Flash 40 g, 30-60% EA:PE) to give tert-butyl 4-(2-(2-(trifluoromethyl)isonicotinoyl)hydrazine-1-carbonyl)piperidine-1-carboxylate (350 mg, 88.3%) as a white solid. MS m / z: 417 [M+H] + .

[0278] Step 2: tert-Butyl 3-(5-(2-(trifluoromethyl)pyridin-4-yl)-1,3,4-thiadiazol-2-yl)piperidine-1-carboxylate: A solution of tert-butyl 4-(2-(2-(trifluoromethyl)isonicotinoyl)hydrazine-1-carbonyl)piperidine-1-carboxylate (350 mg, 0.841 mmol, 1.00 equiv) and Lawesson's reagent (203.98 mg, 0.505 mmol, 0.6 equiv) in toluene (5 mL) was stirred at 100° C. for 3 h. The resulting mixture was concentrated to dryness under reduced pressure. The reaction mixture was purified by chromatography on silica gel (Flash 40 g, 40-60% EtOAc:PE) to give tert-butyl 3-(5-(2-(trifluoromethyl)pyridin-4-yl)-1,3,4-thiadiazol-2-yl)piperidine-1-carboxylate (150 mg, 43.1%) as a white solid. MS m / z: 415 [M+H] + .

[0279] Step 3: 2-(piperidin-3-yl)-5-(2-(trifluoromethyl)pyridin-4-yl)-1,3,4-thiadiazole: A stirred solution of tert-butyl 3-{5-[2-(trifluoromethyl)pyridin-4-yl]-1,3,4-thiadiazol-2-yl}piperidine-1-carboxylate (150 mg, 0.362 mmol, 1.00 equiv) in 4M HCl(g) / dioxane (5 mL) was stirred at 0° C. overnight. The resulting mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated to dryness under reduced pressure. This afforded 2-(piperidin-3-yl)-5-(2-(trifluoromethyl)pyridin-4-yl)-1,3,4-thiadiazole (150 mg, 93.0%) as a white solid. MS m / z: 315 [M+H] + .

[0280] Step 4: 2-(1-(1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)piperidin-3-yl)-5-(2-(trifluoromethyl)pyridin-4-yl)-1,3,4-thiadiazole: 6-chloro-1-(oxetan-3-ylmethyl)pyrazolo[3,4-b]pyrazine (65.0 mg, 0.289 mmol, 1.00 equiv), Na 2 CO 3 A solution of 2-(1-(1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)piperidin-3-yl)-5-(2-(trifluoromethyl)pyridin-4-yl)-1,3,4-thiadiazole (60.0 mg, 46.2%) was stirred at 100° C. for 1 h. The reaction mixture 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 afforded 2-(1-(1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)piperidin-3-yl)-5-(2-(trifluoromethyl)pyridin-4-yl)-1,3,4-thiadiazole (60.0 mg, 46.2%) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 )δ 8.96(d,J=5.1 Hz,1H),8.56(s,1H),8.35(s,1H),8.26(dd,J=5.1,1.6 Hz,1H),8.16(s,1H),6.59-6.28(m,1H),4.78-4.65(m,3H),4.31(d,J=13.5 Hz,1H),3.72-3.65(m,2H),3.53-3.41(m,1H),2.36-2.29(m,1H),2.06-1.96(m,1H),1.95-1.84(m,1H),1.79-1.69(m,1H).MS m / z:497.2[M+H] + . 2-(3-fluoro-1-(1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)piperidin-3-yl)-5-(6-(trifluoromethyl)pyridin-2-yl)-1,3,4-thiadiazole (6) [ka]

[0281] Step 1: tert-Butyl 4-fluoro-4-(2-(6-(trifluoromethyl)picolinoyl)hydrazine-1-carbonyl)piperidine-1-carboxylate: To a stirred mixture of 1-(tert-butoxycarbonyl)-4-fluoropiperidine-4-carboxylic acid (500 mg, 2.02 mmol, 1.00 equiv.) and 6-(trifluoromethyl)pyridine-2-carbohydrazide (456 mg, 2.22 mmol, 1.10 equiv.) in DMF (8 mL) was added HATU (922 mg, 2.42 mmol, 1.2 equiv.) and DIPEA (784 mg, 6 mmol, 3 equiv.). The resulting mixture was stirred at room temperature for 2 h. The resulting mixture was diluted with water (30 mL). The resulting mixture was extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine (2×30 mL) and diluted with anhydrous Na 2 SO 4 The mixture was dried at 4° C. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by back-flash with the following conditions: column, C18 gel; mobile phase, MeCN in water, gradient 5% to 95% in 20 min; detector, UV 254 nm. This gave tert-butyl 4-fluoro-4-(2-(6-(trifluoromethyl)picolinoyl)hydrazine-1-carbonyl)piperidine-1-carboxylate (850 mg, 96.7%) as an off-white solid. MS m / z: 379 [M-tBu+H] + .

[0282] Step 2: tert-Butyl 3-fluoro-3-(5-(6-(trifluoromethyl)pyridin-2-yl)-1,3,4-thiadiazol-2-yl)piperidine-1-carboxylate: To a stirred solution of tert-butyl 4-fluoro-4-(2-(6-(trifluoromethyl)picolinoyl)hydrazine-1-carbonyl)piperidine-1-carboxylate (900 mg, 2.07 mmol, 1.00 equiv) in toluene (12 mL) was added Lawesson's reagent (670 mg, 1.65 mmol, 0.80 equiv). The resulting mixture was stirred at 80° C. for 3 h. The reaction was cooled to 0° C. with saturated NaHCO 3 (aqueous). The resulting mixture was extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine (2×40 mL) and anhydrous Na 2 SO 4 The mixture was dried at 4° C. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by back-flash with the following conditions: column, C18 gel; mobile phase, MeCN in water (0.1% FA), gradient 5-95% in 20 min; detector, UV 254 nm. This gave tert-butyl 3-fluoro-3-(5-(6-(trifluoromethyl)pyridin-2-yl)-1,3,4-thiadiazol-2-yl)piperidine-1-carboxylate (480 mg, 53.5%) as a pale yellow solid. MS m / z: 377 [M-tBu+H] + .

[0283] Step 3: 2-(3-fluoropiperidin-3-yl)-5-(6-(trifluoromethyl)pyridin-2-yl)-1,3,4-thiadiazole hydrochloride: To a stirred solution of tert-butyl 3-fluoro-3-(5-(6-(trifluoromethyl)pyridin-2-yl)-1,3,4-thiadiazol-2-yl)piperidine-1-carboxylate (480 mg, 1.110 mmol, 1.00 equiv.) in DCM (3 mL) was added HCl (gas) in 1,4-dioxane (3 mL). The resulting mixture was stirred at room temperature for 2 h. The resulting mixture was concentrated under vacuum. The crude product 2-(3-fluoropiperidin-3-yl)-5-(6-(trifluoromethyl)pyridin-2-yl)-1,3,4-thiadiazole hydrochloride (450 mg) was used directly in the next step without further purification. MS m / z: 333 [M+H] + .

[0284] Step 4: 2-(3-fluoro-1-(1-(2,2,2 trifluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)piperidin-3-yl)-5-(6-(trifluoromethyl)pyridin-2-yl)-1,3,4-thiadiazole: To a stirred mixture of 6-chloro-1-(2,2,2 trifluoroethyl)pyrazolo[3,4-b]pyrazine (50 mg, 0.211 mmol, 1.00 equiv) and 2-(3-fluoropiperidin-3-yl)-5-(6-(trifluoromethyl)pyridin-2-yl)-1,3,4-thiadiazole hydrochloride (81.8 mg, 0.222 mmol, 1.05 equiv) in DMF (3 mL) was added Na 2 CO 3 (67.2 mg, 0.633 mmol, 3.00 equiv.) was added. The resulting mixture was stirred at 100° C. overnight. The resulting mixture was diluted with water (15 mL). The resulting mixture was extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (2×10 mL) and washed with anhydrous Na 2 SO 4The mixture was dried at 37° C. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE / EA 1:1) to give the crude product. The crude product was purified by back-flash with the following conditions: column, C18 gel; mobile phase, aqueous MeCN (0.1% FA), gradient 40% to 95% in 16 min; detector, UV 254 nm. This gave 2-(3-fluoro-1-(1-(2,2,2 trifluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)piperidin-3-yl)-5-(6-(trifluoromethyl)pyridin-2-yl)-1,3,4-thiadiazole (57.8 mg, 51.3%) as a white solid. 1 H NMR (300 MHz, DMSO-d 6 ):δ 8.63(s,1H),8.62-8.56(m,1H),8.38(t,J=8.1 Hz,1H),8.22(s,1H),8.20-8.12(m,1H),5.19(dd,J=18.3,9.0 Hz,2H),5.10-4.94(m,1H),4.64-4.51(m,1H),4.03(dd,J=32.4,14.4 Hz,1H),3.50-3.39(m,1H),2.46-2.39(m,2H),2.02-1.81(m,2H).MS m / z:533.2[M+H] + . 2-(1-(1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)piperidin-3-yl)-5-(2-(trifluoromethyl)pyridin-3-yl)-1,3,4-thiadiazole (7) [ka]

[0285] Step 1: tert-Butyl 3-(2-(2-(trifluoromethyl)nicotinoyl)hydrazine-1-carbonyl)piperidine-1-carboxylate: To a stirred solution of 2-(trifluoromethyl)pyridine-3-carboxylic acid (300 mg, 1.57 mmol, 1.00 equiv) and HATU (656 mg, 1.73 mmol, 1.1 equiv) in DCM (10 mL) was added DIEA (405 mg, 3.14 mmol, 2 equiv) and tert-butyl 3-(hydrazinecarbonyl)piperidine-1-carboxylate (458 mg, 1.88 mmol, 1.2 equiv) dropwise at 0° C. The resulting mixture was stirred at room temperature for 3 h. The residue was purified by silica gel column chromatography eluting with PE / EA (1:1) to give tert-butyl 3-(2-(2-(trifluoromethyl)nicotinoyl)hydrazine-1-carbonyl)piperidine-1-carboxylate as a pale yellow oil. MS m / z: 417 [M+H] + .

[0286] Step 2: tert-Butyl 3-(5-(2-(trifluoromethyl)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)piperidine-1-carboxylate: A solution of tert-butyl 3-(2-(2-(trifluoromethyl)nicotinoyl)hydrazine-1-carbonyl)piperidine-1-carboxylate (400 mg, 0.961 mmol, 1.00 equiv) and Lawesson's reagent (233 mg, 0.577 mmol, 0.6 equiv) in toluene (5 mL) was stirred at 60° C. for 2 h. The residue was purified by silica gel column chromatography eluting with PE / EA (1:2) to give tert-butyl 3-(5-(2-(trifluoromethyl)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)piperidine-1-carboxylate (230 mg, 57.8%) as a white solid. MSm / z: 415[M+H] + .

[0287] Step 3: 3-[5-(piperidin-3-yl)-1,3,4-thiadiazol-2-yl]-2-(trifluoromethyl)pyridine hydrochloride: To a stirred solution of tert-butyl 3-(5-(2-(trifluoromethyl)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)piperidine-1-carboxylate (230 mg, 0.555 mmol, 1.00 equiv) in DCM (2 mL) was added HCl (gas) in 1,4-dioxane (2 mL) dropwise at 0° C. The resulting mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated under vacuum. This afforded 3-[5-(piperidin-3-yl)-1,3,4-thiadiazol-2-yl]-2-(trifluoromethyl)pyridine hydrochloride (180 mg) as a white solid. MS m / z: 315 [M+H] +

[0288] Step 4: 2-(1-(1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)piperidin-3-yl)-5-(2-(trifluoromethyl)pyridin-3-yl)-1,3,4-thiadiazole: To a stirred solution of 3-[5-(piperidin-3-yl)-1,3,4-thiadiazol-2-yl]-2-(trifluoromethyl)pyridine hydrochloride (95.3 mg, 0.272 mmol, 1.00 equiv.) and 1-(2,2-difluoroethyl)pyrazolo[3,4-b]pyrazine (50 mg, 0.272 mmol, 1.00 equiv.) in DMF (1 mL) was added Na 2 CO 3 (86.3 mg, 0.816 mmol, 3 equiv.) was added. The resulting mixture was stirred at 100 °C 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, gradient 0% to 100% in 30 min; detector, UV 254 nm. This gave 2-(1-(1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)piperidin-3-yl)-5-(2-(trifluoromethyl)pyridin-3-yl)-1,3,4-thiadiazole (73 mg, 54.1%) as a yellow solid. 1 H NMR (300 MHz, DMSO-d 6)δ 9.04(d,J=5.1 Hz,1H),8.63(s,1H),8.42(d,J=1.2 Hz,1H),8.37-8.31(m,1H),8.23(s,1H),6.73-6.30(m,1H),4.84-4.73(m,3H),4.41-4.36(m,1H),3.81-3.7 5(m,2H),3.61-3.46(m,1H),2.36-2.31(m,1H),2.14-2.07(m,1H),1.97-1.93(m,1H),1.86-1.80(m,1H).MS m / z:497.2[M+H] + . 2-(3-fluoro-3-{5-[6-(trifluoromethyl)pyridin-2-yl]-1,3,4-thiadiazol-2-yl}piperidin-1-yl)-6-(1,3,4-thiadiazol-2-yl)pyrazine (8) [ka]

[0289] To a stirred mixture of 2-chloro-6-(1,3,4-thiadiazol-2-yl)pyrazine (90 mg, 0.453 mmol, 1.00 equiv) and 2-(3-fluoropiperidin-3-yl)-5-(6-(trifluoromethyl)pyridin-2-yl)-1,3,4-thiadiazole hydrochloride (175 mg, 0.476 mmol, 1.05 equiv) in DMF (4 mL) was added Na 2 CO 3 (144 mg, 1.36 mmol, 3.00 equiv.) was added. The resulting mixture was stirred at 100° C. overnight. The resulting mixture was diluted with water (15 mL). The resulting mixture was extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (2×10 mL) and washed with anhydrous Na 2 SO 4The mixture was dried at 37° C. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE / EA 1:1) to give the crude product. The crude product was purified by back-flash with the following conditions: column, C18 gel; mobile phase, aqueous MeCN (0.1% FA), gradient 40% to 95% in 16 min; detector, UV 254 nm. This gave 2-(1-(6-(1,3,4-thiadiazol-2-yl)pyrazin-2-yl)-3-fluoropiperidin-3-yl)-5-(6-(trifluoromethyl)pyridin-2-yl)-1,3,4-thiadiazole (56.3 mg, 25.1%) as a pale yellow solid. 1 H NMR (300 MHz, DMSO-d 6 ):δ 9.70(s,1H),8.68(s,1H),8.65(s,1H),8.61-8.54(m,1H),8.38(t,J=8.1 Hz,1H),8.18-8.12(m,1H),4.87(dd,J=14.7,9.0 Hz,1H),4.50-4.34(m,1H),4.00(dd,J=31.5,14.4 Hz,1H),3.50-3.37(m,1H),2.66-2.52(m,1H),2.47-2.41(m,1H),2.03-1.83(m,2H).MS m / z:495.1[M+H] + . (1H-indol-6-yl)(3-(5-(2-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)piperidin-1-yl)methanone (9) [ka]

[0290] Step 1: tert-Butyl 3-(2-(2-(trifluoromethyl)benzoyl)hydrazine-1-carbonyl)piperidine-1-carboxylate: To a stirred mixture of tert-butyl 3-(hydrazinecarbonyl)piperidine-1-carboxylate (350 mg, 1.43 mmol, 1 equiv.) and 2-(trifluoromethyl)benzoic acid (218 mg, 1.15 mmol, 0.8 equiv.) in DMF (3 mL) was added HATU (546 mg, 1.43 mmol, 1 equiv.) and DIEA (557 mg, 4.31 mmol, 3 equiv.). The resulting mixture was stirred at room temperature under an argon atmosphere for 1 h. The resulting mixture was diluted with water (20 mL). The resulting mixture was extracted with EtOAc (3×30 mL). The combined organic layers were washed with anhydrous Na 2 SO 4 The mixture was dried at 40° C. 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, gradient 10% to 50% in 10 min; detector, UV 254 nm. This gave tert-butyl 3-(2-(2-(trifluoromethyl)benzoyl)hydrazine-1-carbonyl)piperidine-1-carboxylate (280 mg, 47.2%) as a white solid. MS m / z: 416 [M+H] + .

[0291] Step 2: tert-Butyl 3-(5-(2-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)piperidine-1-carboxylate: To a stirred solution of tert-butyl 3-(2-(2-(trifluoromethyl)benzoyl)hydrazine-1-carbonyl)piperidine-1-carboxylate (280 mg, 0.675 mmol, 1 equiv.) in toluene (2 mL) was added Lawesson's reagent (164 mg, 0.405 mmol, 0.6 equiv.). The resulting mixture was stirred at 60° C. overnight. The desired product could be detected by LCMS. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (1:2) to give tert-butyl 3-(5-(2-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)piperidine-1-carboxylate (140 mg, 50.2%) as a yellow solid. MS m / z: 414 [M+H] + .

[0292] Step 3: 2-(piperidin-3-yl)-5-(2-(trifluoromethyl)phenyl)-1,3,4-thiadiazole hydrochloride: A solution of tert-butyl 3-(5-(2-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)piperidine-1-carboxylate (140 mg, 0.339 mmol, 1 eq.) and HCl (gas) in 1,4-dioxane (1 mL) in DCM (1 mL) was stirred at room temperature for 2 h. After removal of the solvent, the crude product 2-(piperidin-3-yl)-5-(2-(trifluoromethyl)phenyl)-1,3,4-thiadiazole hydrochloride (130 mg) was used in the next step without further purification. MS m / z: 314 [M+H] + .

[0293] Step 4: (1H-indol-6-yl)(3-(5-(2-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)piperidin-1-yl)methanone: To a stirred mixture of 2-(piperidin-3-yl)-5-(2-(trifluoromethyl)phenyl)-1,3,4-thiadiazole hydrochloride (80 mg, 0.229 mmol, 1 equiv.) and 1H-indole-6-carboxylic acid (36.9 mg, 0.229 mmol, 1 equiv.) in DMF (2 mL) was added HATU (104 mg, 0.275 mmol, 1.2 equiv.) and DIEA (88.6 mg, 0.687 mmol, 3 equiv.). The resulting mixture was stirred at room temperature under argon atmosphere for 1 h. The resulting mixture was diluted with water (20 mL). The resulting mixture was extracted with EtOAc (3×30 mL). The combined organic layers were washed with anhydrous Na 2 SO 4 The mixture was dried at 40° C. 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, gradient 10% to 90% in 10 min; detector, UV 254 nm. This gave (1H-indol-6-yl)(3-(5-(2-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)piperidin-1-yl)methanone (60 mg, 67.4%) as a white solid. 1 H NMR (300 MHz, DMSO-d 6 )δ 11.32(s,1H),8.02-7.94(m,1H),7.88-7.73(m,3H),7.59(d,J=8.2 Hz,1H),7.52-7.43(m,2H),7.07(dd,J=8.2,1.4 Hz,1H),6.52-6.46(m,1H),4.70-4.0(m,1H),3.61-3.55(m,1H),3.24-3.07(m,1H),2.00-1.57(m,3H).MS m / z:457.0[M+H] + . 2-(2-Fluorophenyl)-5-(1-(quinazolin-2-yl)piperidin-3-yl)-1,3,4-thiadiazole (10) [ka]

[0294] Step 1: 2-Bromo-5-(2-fluorophenyl)-1,3,4-thiadiazole: dioxane (10 mL) / H 2 To a stirred mixture of dibromo-1,3,4-thiadiazole (2 g, 8.20 mmol, 1.00 equiv.) and 2-(2-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.82 g, 8.20 mmol, 1.00 equiv.) in 2 mL of HO was added Pd(PPh 3 ) 4 (0.95 g, 0.820 mmol, 0.10 equiv.) and K 2 CO 3 (2.27 g, 16.4 mmol, 2.00 equiv) was added. The resulting mixture was stirred at 80° C. under nitrogen atmosphere for 4 h. The residue was purified by silica gel column chromatography eluting with PE / EA (8:1) to give 2-bromo-5-(2-fluorophenyl)-1,3,4-thiadiazole (540 mg, 25.4%) as an off-white solid. MS m / z: 259 [M-tBu+H] + .

[0295] Step 2: tert-Butyl 5-(5-(2-fluorophenyl)-1,3,4-thiadiazol-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate: dioxane (2.5 mL) / H 2 To a stirred mixture of 2-bromo-5-(2-fluorophenyl)-1,3,4-thiadiazole (200 mg, 0.772 mmol, 1.00 equiv) and tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-2H-pyridine-1-carboxylate (477 mg, 1.54 mmol, 2.00 equiv) in 2H2O (0.5 mL) was added Pd(dtbpf)Cl 2 (50.3 mg, 0.077 mmol, 0.10 equiv.) and K 3 PO 4(327 mg, 1.54 mmol, 2.00 equiv) was added. The resulting mixture was stirred at 60° C. overnight under nitrogen atmosphere. The residue was purified by silica gel column chromatography eluting with PE / EA (3:1) to give tert-butyl 5-(5-(2-fluorophenyl)-1,3,4-thiadiazol-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (170 mg, 60.9%) as a pale yellow solid. MS m / z: 306 [M-tBu+H] + .

[0296] Step 3: tert-Butyl 3-(5-(2-fluorophenyl)-1,3,4-thiadiazol-2-yl)piperidine-1-carboxylate: To a stirred solution of tert-butyl 5-(5-(2-fluorophenyl)-1,3,4-thiadiazol-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (170 mg, 0.470 mmol, 1.00 equiv) in MeOH (5 mL) was added Pd / C (20 mg, 10% Pd on carbon, wet with water). The resulting mixture was stirred under hydrogen atmosphere at room temperature for 3 h. The resulting mixture was filtered and the filter cake was washed with MeOH (3×10 mL). The filtrate was concentrated under reduced pressure. This gave tert-butyl 3-(5-(2-fluorophenyl)-1,3,4-thiadiazol-2-yl)piperidine-1-carboxylate (170 mg, 99.4%) as a pale yellow solid. MS m / z: 308 [M-tBu+H] + .

[0297] Step 4: 2-(2-fluorophenyl)-5-(piperidin-3-yl)-1,3,4-thiadiazole: To a stirred solution of tert-butyl 4-[5-(2-fluorophenyl)-1,3,4-thiadiazol-2-yl]piperidine-1-carboxylate (170 mg, 0.468 mmol, 1.00 equiv) in DCM (2 mL) was added HCl (gas) in 1,4-dioxane (2 mL). The resulting mixture was stirred at room temperature for 2 h. The resulting mixture was concentrated under vacuum and used directly in the next step without further purification. MS m / z: 264 [M+H] + .

[0298] Step 5: 2-(2-fluorophenyl)-5-(1-(quinazolin-2-yl)piperidin-3-yl)-1,3,4-thiadiazole: To a stirred mixture of 2-chloroquinoxaline (50 mg, 0.304 mmol, 1.00 equiv) and 2-(2-fluorophenyl)-5-(piperidin-3-yl)-1,3,4-thiadiazole (109 mg, 0.365 mmol, 1.20 equiv) in DMF (2 mL) was added K 2 CO 3 (126 mg, 0.912 mmol, 3.00 equiv) was added. The resulting mixture was stirred at 80° C. for 4 h. The resulting mixture was diluted with water (10 mL). The resulting mixture was extracted with EtOAc (3×15 mL). The combined organic layers were washed with brine (2×10 mL) and diluted with anhydrous Na 2 SO 4 The mixture was dried at 4° C. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase Combi-Flash using the following conditions: column, C18 gel; mobile phase, MeCN in water, gradient 5% to 95% in 20 min; detector, UV 254 nm. This gave 2-(2-fluorophenyl)-5-(1-(quinazolin-2-yl)piperidin-3-yl)-1,3,4-thiadiazole (46.1 mg, 38.8%) as a pale yellow solid. 1 H NMR (300 MHz, DMSO-d 6 ):δ 9.25(s,1H),8.31-8.21(m,1H),7.90-7.83(m,1H),7.79-7.70(m,1H),7.70-7.60(m,1H),7.58-7.39(m,3H),7.35-7.24(m,1H),5.09 -4.98(m,1H),4.74-4.59(m,1H),3.64-3.45(m,2H),3.43-3.33(m,1H),2.39-2.24(m,1H),2.207-1.82(m,2H),1.79-1.56(m,1H).MS m / z:392.10[M+H] + . 2-Phenyl-5-(1-(quinoxalin-2-yl)piperidin-3-yl)-1,3,4-thiadiazole (11) [ka]

[0299] Step 1: 2-phenyl-5-(1-(quinoxalin-2-yl)piperidin-3-yl)-1,3,4-thiadiazole: To a stirred solution of 2-phenyl-5-(piperidin-3-yl)-1,3,4-thiadiazole (70 mg, 0.286 mmol, 1 equiv) and 2-chloroquinoxaline (46.8 mg, 0.286 mmol, 1.00 equiv) in DMF (1 mL) was added Na 2 CO 3 (90.9 mg, 0.858 mmol, 3 equiv.) was added. The resulting mixture was stirred at 100° C. for 2 h. The residue was purified by reverse-phase flash chromatography using the following conditions (column, C18 gel; mobile phase, B phase: MeCN, A phase: water; gradient from 5% to 95% B in 20 min; detector: UV254 / 220 nm). This gave 2-phenyl-5-(1-(quinoxalin-2-yl)piperidin-3-yl)-1,3,4-thiadiazole (15 mg, 14.1%) as a white solid. MS m / z: 374.1 [M+H] + . 1 H NMR (300 MHz, DMSO-d 6 )δ 8.92(s,1H),8.02-7.90(m,2H),7.88-7.79(m,1H),7.68-7.49(m,5H),7.49-7.35(m,1H),4.79(q,J=9.1 Hz,1H),4.40(d,J=13.5 Hz,1H),3.65-3.50(m,2H),3.48-3.33(m,3H),2.34-2.23(m,1H),2.02-1.83(m,2H),1.82-1.64(m,1H). (1H-indol-6-yl)(3-(5-phenyl-1,3,4-thiadiazol-2-yl)piperidin-1-yl)methanone (12) [ka]

[0300] Step 1: Benzyl 3-(2-benzoylhydrazine-1-carbonyl)piperidine-1-carboxylate: To a stirred mixture of 1-((benzyloxy)carbonyl)piperidine-3-carboxylic acid (1 g, 3.79 mmol, 1.00 equiv.) and benzohydrazide (0.775 g, 5.69 mmol, 1.5 equiv.) in DMF (6 mL), HATU (1.73 g, 4.56 mmol, 1.2 equiv.) and DIEA (0.981 g, 7.59 mmol, 2 equiv.) were added. The resulting mixture was stirred at room temperature under argon atmosphere for 1 h. The resulting mixture was diluted with water (20 mL). The resulting mixture was extracted with EtOAc (3×30 mL). The combined organic layers were washed with anhydrous Na 2 SO 4 The mixture was dried at 4° C. 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, gradient 10% to 90% in 10 min; detector, UV 254 nm. This gave benzyl 3-(2-benzoylhydrazine-1-carbonyl)piperidine-1-carboxylate (1.02 g, 70.4%) as a white solid. MS m / z: 382 [M+H] + .

[0301] Step 2: Benzyl 3-(5-phenyl-1,3,4-thiadiazol-2-yl)piperidine-1-carboxylate: To a stirred solution of benzyl 3-(2-benzoylhydrazine-1-carbonyl)piperidine-1-carboxylate (500 mg, 1.31 mmol, 1 equiv.) in toluene (5 mL) was added Lawesson's reagent (318 mg, 0.787 mmol, 0.6 equiv.). The resulting mixture was stirred at 110° C. overnight. The desired product could be detected by LCMS. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / EA (1:2) to give benzyl 3-(5-phenyl-1,3,4-thiadiazol-2-yl)piperidine-1-carboxylate (50 mg, 10.0%) as a yellow solid. MS m / z: 380 [M+H] + .

[0302] Step 3: 2-Phenyl-5-(piperidin-3-yl)-1,3,4-thiadiazole: To a solution of benzyl 3-(5-phenyl-1,3,4-thiadiazol-2-yl)piperidine-1-carboxylate (50 mg, 0.132 mmol, 1 eq.) in MeOH (1 mL) was added Pd / C (5 mg, 10% Pd on carbon, wet with water). The resulting mixture was hydrogenated at room temperature overnight. The desired product could be detected by LCMS. The reaction was filtered through celite and the filtrate was concentrated. The crude product 2-phenyl-5-(piperidin-3-yl)-1,3,4-thiadiazole (30 mg) was used directly in the next step. MS m / z: 246 [M+H] + .

[0303] Step 4: (1H-indol-6-yl)(3-(5-phenyl-1,3,4-thiadiazol-2-yl)piperidin-1-yl)methanone: To a stirred mixture of 1H-indole-6-carboxylic acid (7.88 mg, 0.049 mmol, 0.8 equiv) and 3-(5-phenyl-1,3,4-thiadiazol-2-yl)piperidine (15 mg, 0.061 mmol, 1.00 equiv) in DMF (1 mL) was added EDCI (12.8 mg, 0.067 mmol, 1.1 equiv) and DMAP (8.22 mg, 0.067 mmol, 1.1 equiv) and the resulting mixture was stirred at room temperature under argon atmosphere for 1 h. The resulting mixture was diluted with water (10 mL). The resulting mixture was extracted with EtOAc (3×10 mL). The combined organic layers were washed with anhydrous Na 2 SO 4 The mixture was dried at 4° C. 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, gradient 10% to 50% in 10 min; detector, UV 254 nm. This gave (1H-indol-6-yl)(3-(5-phenyl-1,3,4-thiadiazol-2-yl)piperidin-1-yl)methanone (7.2 mg, 29.0%) as a white solid. 1H NMR(400 MHz,DMSO-d6)δ 11.30(s,1H),7.94(s,2H),7.64-7.54(m,4H),7.51-7.45(m,2H),7.16-6.98(m,1H),6.48(d,J=2.7 Hz,1H),4.42(s,2H),3.58-3.48(m,1H),3.40(d,J=12.1 Hz,1H),3.16(s,1H),2.28(d,J=13.4 Hz,1H),1.91(d,J=11.6 Hz,1H),1.80(s,1H),1.65(s,1H).MS m / z:389.0[M+H] + . 2-(3-Fluoro-3-{5-[6-(trifluoromethyl)pyridin-2-yl]-1,3,4-thiadiazol-2-yl}piperidin-1-yl)quinoxaline (13) [ka]

[0304] To a stirred mixture of 2-chloroquinoxaline (50 mg, 0.304 mmol, 1.00 equiv) and 2-(3-fluoropiperidin-3-yl)-5-(6-(trifluoromethyl)pyridin-2-yl)-1,3,4-thiadiazole hydrochloride (117 mg, 0.319 mmol, 1.05 equiv) in DMF (3 mL) was added Na 2 CO 3 (96.6 mg, 0.912 mmol, 3.00 equiv.) was added. The resulting mixture was stirred at 100° C. overnight. The resulting mixture was diluted with water (15 mL). The resulting mixture was extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (2×10 mL) and diluted with anhydrous Na 2 SO 4The mixture was dried at 37° C. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE / EA=2:3) to give the crude product. The crude product was purified by back-flash with the following conditions: column, C18 gel; mobile phase, aqueous MeCN (0.1% FA), gradient 40% to 95% in 16 min; detector, UV 254 nm. This gave 2-(3-fluoro-1-(quinoxalin-2-yl)piperidin-3-yl)-5-(6-(trifluoromethyl)pyridin-2-yl)-1,3,4-thiadiazole (27.9 mg, 19.9%) as a white solid. 1 H NMR (300 MHz, DMSO-d 6 ):δ 8.98(s,1H),8.63-8.53(m,1H),8.38(t,J=8.1 Hz,1H),8.19-8.08(m,1H),7.89-7.81(m,1H),7.68-7.56(m,2H),7.48-7.38(m,1H),5.08(dd,J=14.4,9.6 Hz,1H),4.72-4.57(m,1H),4.00(dd,J=32.7,14.4 Hz,1H),3.49-3.35(m,1H),2.65-2.52(m,1H),2.47-2.40(m,1H),2.04-1.82(m,2H).MS m / z:461.1[M+H] + . 2-Phenyl-5-(1-(quinazolin-2-yl)piperidin-3-yl)-1,3,4-thiadiazole (14) [ka]

[0305] To a stirred mixture of 2-chloroquinoxaline (50 mg, 0.304 mmol, 1.00 equiv) and 2-phenyl-5-(piperidin-3-yl)-1,3,4-thiadiazole (89.4 mg, 0.365 mmol, 1.20 equiv) in DMF (2 mL) was added K 2 CO 3(126 mg, 0.912 mmol, 3.00 equiv.) was added. The resulting mixture was stirred at 80° C. for 4 h. The resulting mixture was diluted with water (10 mL). The resulting mixture was extracted with EtOAc (3×15 mL). The combined organic layers were washed with brine (2×10 mL) and diluted with anhydrous Na 2 SO 4 The mixture was dried at 4° C. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase Combi-Flash using the following conditions: column, C18 gel; mobile phase, MeCN in water, gradient 5% to 95% in 20 min; detector, UV 254 nm. This gave 2-phenyl-5-(1-(quinazolin-2-yl)piperidin-3-yl)-1,3,4-thiadiazole (24 mg, 21.1%) as a pale yellow solid. 1 H NMR (300 MHz, DMSO-d 6 )δ 9.25(d,J=0.8 Hz,1H),8.02-7.90(m,2H),7.86(dd,J=8.1,1.5 Hz,1H),7.74(ddd,J=8.5,6.9,1.6 Hz,1H),7.63-7.49(m,4H),7.29(ddd,J=8.0,6.8,1.1 Hz,1H),5.05(d,J=9.4 Hz,1H),4.68(d,J=13.2 Hz,1H),3.59-3.41(m,2H),3.39-3.24(m,1H),2.35-2.28(m,1H),1.94-1.88(m,1H),1.76-1.62(m,1H).MS m / z: 374.1 [M+H] + . 2-(1-(1-ethyl-1H-pyrazolo[3,4-b]pyrazin-6-yl)piperidin-3-yl)-5-phenyl-1,3,4-thiadiazole (15) [ka]

[0306] To a stirred solution of 2-phenyl-5-(piperidin-3-yl)-1,3,4-thiadiazole (120 mg, 0.585 mmol, 1.00 equiv) and 6-chloro-1-ethyl-1H-pyrazolo[3,4-b]pyrazine (153 mg, 0.702 mmol, 1.2 equiv) in DMF (2 mL) was added Na2 CO 3 (381 mg, 1.17 mmol, 2 equiv.) was added at 0° C. The resulting mixture was stirred at 100° C. for 2 h. The mixture 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 gave 2-(1-(1-ethyl-1H-pyrazolo[3,4-b]pyrazin-6-yl)piperidin-3-yl)-5-phenyl-1,3,4-thiadiazole (20.1 mg, 7.25%) as a yellow oil. 1 H NMR (400 MHz, DMSO-d 6 )δ:8.50(s,1H),8.04(s,1H),7.94-7.96(m,2H),7.80-7.85(m,3H),4.74-4,78(m,1H),4.34-4.44(m, 3H),3.57-3.60(m,2H),3.39-3.41(m,1H),2.33-2.36(m,1H),2.03-1.55(m,3H),1.45-1.47(m,3H).MS m / z:392.2[M+H] + . 2-Methyl-5-(1-(quinazolin-2-yl)piperidin-3-yl)-1,3,4-thiadiazole (16) [ka]

[0307] Step 1: tert-Butyl 5-(5-methyl-1,3,4-thiadiazol-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate: 1,4-dioxane (4 mL) / H 2 To a stirred mixture of 2-bromo-5-methyl-1,3,4-thiadiazole (100 mg, 0.559 mmol, 1.00 equiv) and tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (224 mg, 0.727 mmol, 1.30 equiv) in 2H2O (1 mL) was added Pd(dppf)Cl 2 (40.87 mg, 0.056 mmol, 0.10 equiv.) and K2 CO 3 (231.58 mg, 1.677 mmol, 3.00 equiv.) was added. The resulting mixture was stirred at 80° C. under nitrogen atmosphere for 3 h. The resulting mixture was concentrated in vacuo. The residue was purified by Prep-TLC (PE / EA 2:1) to give tert-butyl 5-(5-methyl-1,3,4-thiadiazol-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (150 mg, 95.4%) as a pale yellow solid. MS m / z: 226 [M-tBu+H] + .

[0308] Step 2: tert-Butyl 3-(5-methyl-1,3,4-thiadiazol-2-yl)piperidine-1-carboxylate: To a stirred solution of tert-butyl 5-(5-methyl-1,3,4-thiadiazol-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (150 mg, 0.533 mmol, 1.00 equiv) in MeOH (5 mL) was added Pd / C (15 mg, 10% Pd on carbon, wet with water). The resulting mixture was stirred under hydrogen atmosphere at room temperature for 3 h. The resulting mixture was filtered and the filter cake was washed with MeOH (3×8 mL). The filtrate was concentrated under reduced pressure. This afforded tert-butyl 3-(5-methyl-1,3,4-thiadiazol-2-yl)piperidine-1-carboxylate (150 mg, 99.29%) as a pale yellow solid. MS m / z: 228 [M-tBu+H] + .

[0309] Step 3: 2-Methyl-5-(piperidin-3-yl)-1,3,4-thiadiazole hydrochloride: To a stirred solution of tert-butyl 3-(5-methyl-1,3,4-thiadiazol-2-yl)piperidine-1-carboxylate (150 mg, 0.529 mmol, 1.00 equiv) in DCM (1 mL) was added HCl (gas) in 1,4-dioxane (1 mL). The resulting mixture was stirred at room temperature for 3 h. The resulting mixture was concentrated under vacuum and used directly in the next step without further purification. MS m / z: 184 [M+H] + .

[0310] Step 4: 2-Methyl-5-(1-(quinazolin-2-yl)piperidin-3-yl)-1,3,4-thiadiazole: To a stirred mixture of 2-chloroquinoxaline (50 mg, 0.304 mmol, 1.00 equiv) and 2-methyl-5-(piperidin-3-yl)-1,3,4-thiadiazole hydrochloride (80.1 mg, 0.365 mmol, 1.20 equiv) in DMF (3 mL) was added K 2 CO 3 (1256 mg, 0.912 mmol, 3.00 equiv.) was added. The resulting mixture was stirred at 80° C. for 4 h. The resulting mixture was diluted with water (10 mL). The resulting mixture was extracted with EtOAc (3×15 mL). The combined organic layers were washed with brine (2×10 mL) and diluted with anhydrous Na 2 SO 4 The mixture was dried at 4° C. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase Combi-Flash using the following conditions: column, C18 gel; mobile phase, MeCN in water, gradient 5% to 95% in 16 min; detector, UV 254 nm. This gave 2-methyl-5-(1-(quinazolin-2-yl)piperidin-3-yl)-1,3,4-thiadiazole (30 mg, 31.7%) as a pale yellow solid. 1 H NMR (300 MHz, DMSO-d 6 )δ 9.23(d,J=0.8 Hz,1H),7.85(dd,J=8.1,1.5 Hz,1H),7.74(ddd,J=8.4,6.9,1.5 Hz,1H),7.52(dd,J=8.5,1.0 Hz,1H),7.29(ddd,J=8.0,6.9,1.1 Hz,1H),5.00-4.90(m,1H),4.63(d,J=13.1 Hz,1H),3.52-3.41(m,1H),3.40-3.35(m,1H),3.32-3.23(m,1H),2.70(s,3H),2.25-2.15(m,1H),1.96-1.75(m,2H),1.72-1.58(m,1H).MS m / z:312.15[M+H] + . (1H-indol-6-yl)(3-(5-(2-(trifluoromethyl)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)piperidin-1-yl)methanone (17) [ka]

[0311] Step 1: tert-Butyl 3-(2-(2-(trifluoromethyl)nicotinoyl)hydrazine-1-carbonyl)piperidine-1-carboxylate: To a stirred mixture of tert-butyl 3-(hydrazinecarbonyl)piperidine-1-carboxylate (350 mg, 1.43 mmol, 1 equiv.) and 2-(trifluoromethyl)nicotinic acid (219 mg, 1.15 mmol, 0.8 equiv.) in DMF (3 mL) was added HATU (546 mg, 1.43 mmol, 1 equiv.) and DIEA (557 mg, 4.31 mmol, 3 equiv.) and the resulting mixture was stirred at room temperature under argon atmosphere for 1 h. The resulting mixture was diluted with water (20 mL). The resulting mixture was extracted with EtOAc (3×30 mL). The combined organic layers were washed with anhydrous Na 2 SO 4 The mixture was dried at 40° C. 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, gradient 10% to 50% in 10 min; detector, UV 254 nm. This gave tert-butyl 3-(2-(2-(trifluoromethyl)nicotinoyl)hydrazine-1-carbonyl)piperidine-1-carboxylate (230 mg, 38.4%) as a white solid. MS m / z: 417 [M+H] + .

[0312] Step 2: tert-Butyl 3-(5-(2-(trifluoromethyl)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)piperidine-1-carboxylate: To a stirred solution of tert-butyl 3-(2-(2-(trifluoromethyl)nicotinoyl)hydrazine-1-carbonyl)piperidine-1-carboxylate (230 mg, 0.552 mmol, 1 equiv.) in toluene (2 mL) was added Lawesson's reagent (134 mg, 0.331 mmol, 0.6 equiv.). The resulting mixture was stirred at 60° C. overnight. The desired product could be detected by LCMS. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (1:2) to give tert-butyl 3-(5-(2-(trifluoromethyl)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)piperidine-1-carboxylate (110 mg, 48.0%) as a yellow solid. MS m / z: 415 [M+H] + .

[0313] Step 3: 2-(piperidin-3-yl)-5-(2-(trifluoromethyl)pyridin-3-yl)-1,3,4-thiadiazole hydrochloride: A solution of tert-butyl 3-(5-(2-(trifluoromethyl)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)piperidine-1-carboxylate (110 mg, 0.265 mmol, 1 eq.) and HCl (gas) in 1,4-dioxane (1 mL) in DCM (1 mL) was stirred at room temperature for 2 h. After removal of the solvent, the crude product 2-(piperidin-3-yl)-5-(2-(trifluoromethyl)pyridin-3-yl)-1,3,4-thiadiazole hydrochloride (60 mg) was used in the next step without further purification. MS m / z: 315 [M+H] + .

[0314] Step 4: (1H-indol-6-yl)(3-(5-(2-(trifluoromethyl)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)piperidin-1-yl)methanone: To a stirred mixture of 2-(piperidin-3-yl)-5-(2-(trifluoromethyl)pyridin-3-yl)-1,3,4-thiadiazole hydrochloride (130 mg, 0.371 mmol, 1 equiv.) and 1H-indole-6-carboxylic acid (59.7 mg, 0.371 mmol, 1 equiv.) in DMF (2 mL), HATU (169 mg, 0.445 mmol, 1.2 equiv.) and DIEA (143 mg, 1.11 mmol, 3 equiv.) were added and the resulting mixture was stirred at room temperature under argon atmosphere for 1 h. The resulting mixture was diluted with water (20 mL). The resulting mixture was extracted with EtOAc (3×30 mL). The combined organic layers were washed with anhydrous Na 2 SO 4 The mixture was dried at 40° C. 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, gradient 10% to 90% in 10 min; detector, UV 254 nm. This gave (1H-indol-6-yl)(3-(5-(2-(trifluoromethyl)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)piperidin-1-yl)methanone (59.3 mg, 34.0%) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 )δ 11.31(s,1H),9.02-8.88(m,1H),8.27(d,J=8.0 Hz,1H),8.00-7.79(m,1H),7.59(d,J=8.1 Hz,1H),7.51-7.44(m,2H),7.14-6.91(m,1H),6.56-6.36(m,1H),4.11(d,J=249.8 Hz,2H),3.59(d,J=10.7 Hz,1H),3.51-3.39(m,1H),3.18(s,1H),2.36-2.23(m,1H),1.94(d,J=11.7 Hz,1H),1.80(s,1H),1.66(s,1H).MS m / z: 458.1 [M+H] + . 2-(4-Methoxypyrimidin-5-yl)-5-(1-(quinoxalin-2-yl)piperidin-3-yl)-1,3,4-thiadiazole (18) [ka]

[0315] Step 1: Ethyl 1-(quinoxalin-2-yl)piperidine-3-carboxylate: A stirred solution of 2-chloroquinoxaline (500 mg, 3.04 mmol, 1.00 equiv) and ethyl piperidine-3-carboxylate (478 mg, 3.04 mmol, 1 equiv) in DMF (12 mL) was treated with Cs 2 CO 3 (1980 mg, 6.08 mmol, 2 equiv.) was added. The resulting mixture was stirred at 100° C. for 1 h. The resulting mixture was diluted with water (10 mL). The residue was extracted with EtOAc (2×10 mL). The combined organic layers were washed with brine (3×10 mL) and diluted with anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure to give ethyl 1-(quinoxalin-2-yl)piperidine-3-carboxylate (600 mg, 48.4%) as a brown solid. MS m / z: 286 [M+H] + .

[0316] Step 2: 1-(quinoxalin-2-yl)piperidine-3-carbohydrazide: To a stirred solution of ethyl 1-(quinoxalin-2-yl)piperidine-3-carboxylate (600 mg, 2.10 mmol, 1.00 equiv) in EtOH (6 mL) was added hydrazine (202 mg, 6.31 mmol, 3 equiv). The resulting mixture was stirred at 80° C. for 1 h. The resulting mixture was diluted with water (10 mL). The residue was extracted with EtOAc (2×10 mL). The combined organic layers were washed with brine (3×10 mL) and diluted with anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure to give 1-(quinoxalin-2-yl)piperidine-3-carbohydrazide (500 mg, 78.9%) as a dark gray solid. MS m / z: 272 [M+H]+ .

[0317] Step 3: 4-Methoxy-N'-(1-(quinoxalin-2-yl)piperidine-3-carbonyl)pyrimidine-5-carbohydrazide: To a stirred solution of 1-(quinoxalin-2-yl)piperidine-3-carbohydrazide (500 mg, 1.84 mmol, 1.00 equiv) and 4-methoxypyrimidine-5-carboxylic acid (284 mg, 1.84 mmol, 1 equiv) in DMF (7 mL) was added HATU (770 mg, 2.03 mmol, 1.1 equiv) and DIPEA (714 mg, 5.53 mmol, 3 equiv) dropwise at 0°C. The resulting mixture was stirred at room temperature for 2 h. The resulting mixture was diluted with water (10 mL). The residue was extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine (3 x 10 mL) and diluted with anhydrous Na 2 SO 4 The mixture was dried at 400 rpm. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel and eluted with PE / EA (1 / 1). This gave 4-methoxy-N'-(1-(quinoxalin-2-yl)piperidine-3-carbonyl)pyrimidine-5-carbohydrazide (400 mg, 37.3%) as a dark yellow solid. MS m / z: 408 [M+H] + .

[0318] Step 4: 2-(4-Methoxypyrimidin-5-yl)-5-(1-(quinoxalin-2-yl)piperidin-3-yl)-1,3,4-thiadiazole: To a stirred solution of 4-methoxy-N-(1-(quinoxalin-2-yl)piperidine-3-carbonyl)pyrimidine-5-carbohydrazide acid (400 mg, 0.982 mmol, 1.00 equiv) and Lawesson's reagent (238 mg, 0.589 mmol, 0.6 equiv) in toluene (6 mL) was added dropwise at 100° C. for 2 h. The resulting mixture was extracted with water (3×15 mL). The combined organic layers were washed with EtOAc (3×15 mL) and washed with anhydrous Na 2 SO 4The mixture was dried at 4° C. After filtration, the filtrate was concentrated 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), gradient 5% to 70% in 20 min; detector, UV 220 nm. This gave 2-(4-methoxypyrimidin-5-yl)-5-(1-(quinoxalin-2-yl)piperidin-3-yl)-1,3,4-thiadiazole (27.5 mg, 6.87%) as a yellow-green solid. 1 H NMR (400 MHz, DMSO-d 6 )δ:9.34(s,1H),8.98(s,1H),8.92(s,1H),7.86-7.73(m,1H),7.64-7.49(m,2H),7.41-7.38(m,1H),4.77-4.40(m,1H),4.39(d,J=13.3 Hz,1H),4.11(s,3H),3.68-3.52(m,2H),3.43-3.34(m,1H),2.34-2.26(m,1H),2.02(t,J=10.4 Hz,1H),1.87-1.84(m,1H),1.75-1.74(m,1H).MS m / z:406.1[M+H] + . 2-(1-(1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)piperidin-3-yl)-5-phenyl-1,3,4-thiadiazole (19) [ka]

[0319] To a stirred solution of 6-chloro-1-(2,2-difluoroethyl)pyrazolo[3,4-b]pyrazine (107 mg, 0.490 mmol, 1.2 equiv) and 3-(5-phenyl-1,3,4-thiadiazol-2-yl)piperidine (100 mg, 0.408 mmol, 1.00 equiv) in DMF (2 mL) was added Na 2 CO 3(129 mg, 1.22 mmol, 3 equiv.) was added. The resulting mixture was stirred at 100 °C 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, gradient 5% to 95% in 30 min; detector, UV 254 nm. This gave 2-(1-(1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)piperidin-3-yl)-5-phenyl-1,3,4-thiadiazole (36.1 mg, 20.2%) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 )δ 8.55(s,1H),8.16(s,1H),7.97-7.92(m,2H),7.61-7.52(m,3H),6.60-6.28(m,1H),4.81-4.63(m,3H),4.43-4.26(m,1H) ),3.65-3.54(m,2H),3.45-3.36(m,1H),2.31-2.23(m,1H),2.04-1.92(m,1H),1.92-1.83(m,1H),1.78-1.65(m,1H).MS m / z:428.1[M+H] + . 2-(1-(1-ethyl-1H-imidazo[4,5-b]pyrazin-6-yl)piperidin-3-yl)-5-phenyl-1,3,4-thiadiazole (20) [ka]

[0320] To a stirred solution of 2-phenyl-5-(piperidin-3-yl)-1,3,4-thiadiazole (64.8 mg, 0.264 mmol, 1.2 equiv.) and 6-bromo-1-ethyl-1H-imidazo[4,5-b]pyrazine (50 mg, 0.220 mmol, 1.00 equiv.) in dioxane (1 mL) was added 1612891-29-8 (18.5 mg, 0.022 mmol, 0.1 equiv.) and Cs 2 CO 3(143 mg, 0.440 mmol, 2 equiv.) was added. The resulting mixture was stirred at 100° C. for 2 h. The residue was purified by reverse-phase flash chromatography using the following conditions (column, C18 gel; mobile phase, B phase: MeCN, A phase: water; gradient from 0% to 100% B in 20 min; detector: UV254 / 220 nm). This gave 2-(1-(1-ethyl-1H-imidazo[4,5-b]pyrazin-6-yl)piperidin-3-yl)-5-phenyl-1,3,4-thiadiazole (16.7 mg, 19.1%) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 )δ 8.32(d,J=7.5 Hz,2H),8.02-7.87(m,2H),7.64-7.45(m,3H),4.54(d,J=13.1 Hz,1H),4.22-4.12(m,3H),3.63-3.45(m,2H),2.30-2.20(m,1H),2.01- 1.90(m,1H),1.89-1.80(m,1H),1.78-1.66(m,1H),1.48-1.40(m,3H).MS m / z:392.2[M+H] + . 2-(1-(1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)piperidin-3-yl)-5-(6-(trifluoromethyl)pyridin-3-yl)-1,3,4-thiadiazole (21) [ka]

[0321] Step 1: tert-Butyl 3-(2-(6-(trifluoromethyl)nicotinoyl)hydrazine-1-carbonyl)piperidine-1-carboxylate: To a stirred solution of 6-(trifluoromethyl)pyridine-3-carboxylic acid (300 mg, 1.57 mmol, 1.00 equiv) and HATU (656 mg, 1.72 mmol, 1.1 equiv) in DMF (5 mL) was added DIEA (406 mg, 3.14 mmol, 2 equiv) and tert-butyl 3-(hydrazinecarbonyl)piperidine-1-carboxylate (458 mg, 1.88 mmol, 1.20 equiv) dropwise at 0° C. The resulting mixture was stirred at room temperature for 16 h. The resulting mixture was diluted with water (20 mL). The resulting mixture was extracted with EtOAc (3×40 mL). The combined organic layers were washed with anhydrous Na 2 SO 4 The mixture was dried at 400 rpm. 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 5% to 95% in 20 min; detector, UV 254 nm. This gave tert-butyl 3-(2-(6-(trifluoromethyl)nicotinoyl)hydrazine-1-carbonyl)piperidine-1-carboxylate (400 mg, 61.2%) as a yellow solid. MS m / z: 417 [M+H] + .

[0322] Step 2: tert-Butyl 3-(5-(6-(trifluoromethyl)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)piperidine-1-carboxylate: A solution of tert-butyl 3-(2-(6-(trifluoromethyl)nicotinoyl)hydrazine-1-carbonyl)piperidine-1-carboxylate (200 mg, 0.48 mmol, 1.00 equiv) and Lawesson's reagent (117 mg, 0.288 mmol, 0.6 equiv) in toluene (2 mL) was stirred at 60° C. for 2 h. The residue was purified by silica gel column chromatography eluting with PE / EA (1:1) to give tert-butyl 3-(5-(6-(trifluoromethyl)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)piperidine-1-carboxylate (130 mg, 65.3%) as a white solid. MSm / z: 415[M+H] + .

[0323] Step 3: 2-(piperidin-3-yl)-5-(6-(trifluoromethyl)pyridin-3-yl)-1,3,4-thiadiazole hydrochloride: To a stirred solution of tert-butyl 3-(5-(6-(trifluoromethyl)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)piperidine-1-carboxylate (130 mg, 0.314 mmol, 1.00 equiv) in DCM (2 mL) was added HCl (gas) in 1,4-dioxane (2 mL) dropwise at 0° C. The resulting mixture was concentrated under vacuum. This afforded 2-(piperidin-3-yl)-5-(6-(trifluoromethyl)pyridin-3-yl)-1,3,4-thiadiazole hydrochloride (130 mg, crude) as a white solid. MS m / z: 315 [M+H] +

[0324] Step 4: 2-(1-(1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)piperidin-3-yl)-5-(6-(trifluoromethyl)pyridin-3-yl)-1,3,4-thiadiazole: 2-(piperidin-3-yl)-5-(6-(trifluoromethyl)pyridin-3-yl)-1,3,4-thiadiazole hydrochloride (115 mg, 0.329 mmol, 1.2 equiv.) and Na 2 CO 3 To a stirred solution of (87.3 mg, 0.822 mmol, 3 equiv) in DMF (1 mL) was added 6-chloro-1-(2,2-difluoroethyl)pyrazolo[3,4-b]pyrazine (60 mg, 0.274 mmol, 1.00 equiv). The resulting mixture was stirred at 100 °C for 2 h. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water, gradient 40% to 70% in 15 min; detector, UV 254 nm. This gave 2-(1-(1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)piperidin-3-yl)-5-(6-(trifluoromethyl)pyridin-3-yl)-1,3,4-thiadiazole (30 mg, 22.0%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 )δ 9.34-9.33(m,1H),8.65-8.63(m,1H),8.56(s,1H),8.16(s,1H),8.10(d,J=8.1 Hz,1H),6.59-6.30(m,1H),4.80-4.63(m,3H),4.35-4.32(m,1H),3.72-3.60(m,2H),3.51- 3.38(m,1H),2.30-2.27(m,1H),2.09-1.95(m,1H),1.94-1.83(m,1H),1.79-1.66(m,1H).MS m / z:497.2[M+H] + . 2-(1-(6-(1,3,4-thiadiazol-2-yl)pyrazin-2-yl)piperidin-3-yl)-5-(2-(trifluoromethoxy)phenyl)-1,3,4-thiadiazole (22) [ka]

[0325] Step 1: tert-Butyl 3-(2-(2-(trifluoromethoxy)benzoyl)hydrazine-1-carbonyl)piperidine-1-carboxylate: To a stirred solution of 2-(trifluoromethoxy)benzoic acid (300 mg, 1.45 mmol, 1.00 equiv) and HATU (553 mg, 1.45 mmol, 1 equiv) in DCM (10 mL) was added DIEA (282 mg, 2.18 mmol, 1.5 equiv) and tert-butyl 3-(hydrazinecarbonyl)piperidine-1-carboxylate (425 mg, 1.74 mmol, 1.2 equiv) dropwise at 0° C. The resulting mixture was stirred at room temperature for 16 h. The residue was purified by silica gel column chromatography eluting with PE / EA (1:1) to give tert-butyl 3-(2-(2-(trifluoromethoxy)benzoyl)hydrazine-1-carbonyl)piperidine-1-carboxylate (500 mg, 79.6%) as a pale yellow oil. MS m / z: 432 [M+H] + .

[0326] Step 2: tert-Butyl 3-(5-(2-(trifluoromethoxy)phenyl)-1,3,4-thiadiazol-2-yl)piperidine-1-carboxylate: A solution of tert-butyl 3-(2-(2-(trifluoromethoxy)benzoyl)hydrazine-1-carbonyl)piperidine-1-carboxylate (400 mg, 0.93 mmol, 1.00 equiv) and Lawesson's reagent (225 mg, 0.556 mmol, 0.6 equiv) in toluene (4 mL) was stirred at 60° C. for 3 h. The residue was purified by silica gel column chromatography eluting with PE / EA (1:1) to give tert-butyl 3-(5-(2-(trifluoromethoxy)phenyl)-1,3,4-thiadiazol-2-yl)piperidine-1-carboxylate as a pale yellow oil. MS m / z: 430 [M+H] + .

[0327] Step 3: 2-(piperidin-3-yl)-5-(2-(trifluoromethoxy)phenyl)-1,3,4-thiadiazole hydrochloride: To a stirred solution of tert-butyl 3-(5-(2-(trifluoromethoxy)phenyl)-1,3,4-thiadiazol-2-yl)piperidine-1-carboxylate (180 mg, 0.410 mmol, 1.00 equiv) in DCM (1 mL) was added HCl in dioxane (1 mL) dropwise at 0° C. The resulting mixture was stirred at room temperature for 16 h. The resulting mixture was concentrated under vacuum. This afforded 2-(piperidin-3-yl)-5-(2-(trifluoromethoxy)phenyl)-1,3,4-thiadiazole hydrochloride (140 mg, crude) as a white solid. MS m / z: 315 [M+H] +

[0328] Step 4: 2-(1-(6-(1,3,4-thiadiazol-2-yl)pyrazin-2-yl)piperidin-3-yl)-5-(2-(trifluoromethoxy)phenyl)-1,3,4-thiadiazole: 2-chloro-6-(1,3,4-thiadiazol-2-yl)pyrazine (60 mg, 0.302 mmol, 1.00 equiv.) and Na 2 CO 3 To a stirred solution of (96.05 mg, 0.906 mmol, 3 equiv) in DMF (1 mL) was added 2-(piperidin-3-yl)-5-(2-(trifluoromethoxy)phenyl)-1,3,4-thiadiazole hydrochloride (132 mg, 0.362 mmol, 1.2 equiv). The resulting mixture was stirred at 100° C. for 2 h. 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 2-(1-(6-(1,3,4-thiadiazol-2-yl)pyrazin-2-yl)piperidin-3-yl)-5-(2-(trifluoromethoxy)phenyl)-1,3,4-thiadiazole (19 mg, 12.8%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6)δ 9.71(s,1H),8.66-8.62(m,2H),8.31-8.28(m,1H),7.75-7.71(m,1H),7.66-7.57(m,2H),4.58-4.53(m,1H),4.18-4.15(m MS m / z:492.1[M+H] + . 2-(1-(6-(1,3,4-thiadiazol-2-yl)pyrazin-2-yl)-3-fluoropiperidin-3-yl)-5-(2-(trifluoromethoxy)phenyl)-1,3,4-thiadiazole (29) [ka]

[0329] Step 1: 2-(trifluoromethoxy)benzohydrazide: Methyl 2-(trifluoromethoxy)benzoate (1 g, 4.54 mmol, 1 equiv.) and hydrazine (0.44 g, 13.6 mmol, 3 equiv.) were added in EtOH (10 mL) at 80° C. The residual product was purified by reverse phase flash using the following conditions (MeCN in water (0.1% FA), gradient 40% to 95% in 16 min; detector, UV 254 nm.) to give 2-(trifluoromethoxy)benzohydrazide (900 mg, 90.0%) as a yellow oil. MS m / z: 221 [M+H] + .

[0330] Step 2: tert-Butyl 3-fluoro-3-(2-(2-(trifluoromethoxy)benzoyl)hydrazine-1-carbonyl)piperidine-1-carboxylate: To a stirred mixture of 1-(tert-butoxycarbonyl)-3-fluoropiperidine-3-carboxylic acid (500 mg, 2.02 mmol, 1 equiv.) and 2-(trifluoromethoxy)benzohydrazide (490 mg, 2.22 mmol, 1.1 equiv.) in DMF (8 mL), HATU (923 mg, 2.43 mmol, 1.2 equiv.) and DIPEA (314 mg, 2.43 mmol, 1.2 equiv.) were added. The resulting mixture was stirred at room temperature for 2 h. The resulting mixture was diluted with water (30 mL). The resulting mixture was extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine (2×30 mL) and washed with anhydrous Na 2 SO 4 The mixture was dried at 40° C. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by back-flash with the following conditions: column, C18 gel; mobile phase, MeCN in water, gradient 5% to 95% in 20 min; detector, UV 254 nm. This gave tert-butyl 3-fluoro-3-(2-(2-(trifluoromethoxy)benzoyl)hydrazine-1-carbonyl)piperidine-1-carboxylate (900 mg, 90.3%) as an off-white solid. MS m / z: 450 [M+H] + .

[0331] Step 3: tert-Butyl 3-fluoro-3-(5-(2-(trifluoromethoxy)phenyl)-1,3,4-thiadiazol-2-yl)piperidine-1-carboxylate: To a stirred solution of tert-butyl 3-fluoro-3-(2-(2-(trifluoromethoxy)benzoyl)hydrazine-1-carbonyl)piperidine-1-carboxylate (900 mg, 2.5 mmol, 1 equiv.) in toluene (12 mL) was added Lawesson's reagent (670 mg, 1.6 mmol, 0.80 equiv.). The resulting mixture was stirred at 80° C. for 3 h. The reaction was cooled to 0° C. with saturated NaHCO 3 (aqueous). The resulting mixture was extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine (2×40 mL) and anhydrous Na2 SO 4 The mixture was dried at 4° C. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by back-flash with the following conditions: column, C18 gel; mobile phase, MeCN in water (0.1% FA), gradient 5% to 95% in 20 min; detector, UV 254 nm. This gave tert-butyl 3-fluoro-3-(5-(2-(trifluoromethoxy)phenyl)-1,3,4-thiadiazol-2-yl)piperidine-1-carboxylate (150 mg, 16.4%) as a pale yellow solid. MS m / z: 448 [M+H] +.

[0332] Step 4: 2-(3-fluoropiperidin-3-yl)-5-(2-(trifluoromethoxy)phenyl)-1,3,4-thiadiazole hydrochloride: To a stirred solution of tert-butyl 3-fluoro-3-(5-(2-(trifluoromethoxy)phenyl)-1,3,4-thiadiazol-2-yl)piperidine-1-carboxylate (150 mg, 0.335 mmol, 1 equiv.) in DCM (2 mL) was added HCl (gas) in 1,4-dioxane (2 mL). The resulting mixture was stirred at room temperature for 2 h. The resulting mixture was concentrated under vacuum. The crude product 2-(3-fluoropiperidin-3-yl)-5-(2-(trifluoromethoxy)phenyl)-1,3,4-thiadiazole hydrochloride (120 mg) was used directly in the next step without further purification. MS m / z: 348 [M+H] + .

[0333] Step 5: 2-(1-(6-(1,3,4-thiadiazol-2-yl)pyrazin-2-yl)-3-fluoropiperidin-3-yl)-5-(2-(trifluoromethoxy)phenyl)-1,3,4-thiadiazole: To a stirred mixture of 2-(3-fluoropiperidin-3-yl)-5-(2-(trifluoromethoxy)phenyl)-1,3,4-thiadiazole hydrochloride (120 mg, 0.314 mmol, 1 equiv.) and methyl 2-(6-chloropyrazin-2-yl)-1,3,4-thiadiazole (62.2 mg, 0.314 mmol, 1.2 equiv.) in DMF (1 mL) was added Na 2 CO 3(66.6 mg, 0.628 mmol, 2 equiv.) was added. The resulting mixture was stirred at 80° C. overnight. The resulting mixture was diluted with water (15 mL). The resulting mixture was extracted with EtOAc (3×10 mL). The combined organic layers were washed with water (2×10 mL) and brine (1×10 mL) and extracted with anhydrous Na 2 SO 4 The mixture was dried at 37° C. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE / EA 1:1) to give the crude product. The crude product was purified by back-flash with the following conditions: column, C18 gel; mobile phase, aqueous MeCN (0.1% FA), gradient 40% to 95% in 16 min; detector, UV 254 nm. This gave 2-(1-(6-(1,3,4-thiadiazol-2-yl)pyrazin-2-yl)-3-fluoropiperidin-3-yl)-5-(2-(trifluoromethoxy)phenyl)-1,3,4-thiadiazole (15 mg, 8.83%) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 )δ 9.72(s,1H),8.66(d,J=6.0 Hz,2H),8.33(dd,J=8.0,1.6 Hz,1H),7.82-7.74(m,1H),7.71-7.62(m,2H),4.88(dd,J=14.4,9.0 Hz,1H),4.47-4.36(m,1H),4.01(dd,J=31.6,14.4 Hz,1H),3.50-3.38(m,1H),2.48-2.40(m,2H),2.01-1.81(m,2H).MS m / z:510.1[M+H] + . 2-(3-Fluoro-1-(1-(oxetan-3-ylmethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)piperidin-3-yl)-5-(6-(trifluoromethyl)pyridin-2-yl)-1,3,4-thiadiazole (27) [ka]

[0334] To a stirred mixture of 6-chloro-1-(oxetan-3-ylmethyl)pyrazolo[3,4-b]pyrazine (60 mg, 0.267 mmol, 1 equiv.) and 2-(3-fluoropiperidin-3-yl)-5-(6-(trifluoromethyl)pyridin-2-yl)-1,3,4-thiadiazole hydrochloride (106 mg, 0.320 mmol, 1.2 equiv.) in DMF (2 mL) was added Na 2 CO 3 (56.6 mg, 0.534 mmol, 2 equiv.) was added. The resulting mixture was stirred at 80° C. overnight. The resulting mixture was diluted with water (15 mL). The resulting mixture was extracted with EtOAc (3×10 mL). The combined organic layers were washed with water (2×10 mL) and brine (1×10 mL) and extracted with anhydrous Na 2 SO 4 The mixture was dried at 37° C. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE / EA 1:1) to give the crude product. The crude product was purified by back-flash with the following conditions: column, C18 gel; mobile phase, aqueous MeCN (0.1% FA), gradient 40% to 95% in 16 min; detector, UV 254 nm. This gave 2-(3-fluoro-1-(1-(oxetan-3-ylmethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)piperidin-3-yl)-5-(6-(trifluoromethyl)pyridin-2-yl)-1,3,4-thiadiazole (30 mg, 20.50%) as a white solid. 1 H NMR (300 MHz, DMSO-d 6 )δ 8.58(d,J=8.6 Hz,2H),8.38(t,J=7.9 Hz,1H),8.15(d,J=7.9 MS m / z:520.9[M+H] + . 2-(3-Fluoro-1-(1-(oxetan-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)piperidin-3-yl)-5-(6-(trifluoromethyl)pyridin-2-yl)-1,3,4-thiadiazole (24) [ka]

[0335] To a stirred mixture of 6-chloro-1-(oxetan-3-yl)pyrazolo[3,4-b]pyrazine (60 mg, 0.285 mmol, 1 equiv.) and 2-(3-fluoropiperidin-3-yl)-5-(6-(trifluoromethyl)pyridin-2-yl)-1,3,4-thiadiazole hydrochloride (113 mg, 0.342 mmol, 1.2 equiv.) in DMF (2 mL) was added Na 2 CO 3 (56.6 mg, 0.534 mmol, 2 equiv.) was added. The resulting mixture was stirred at 80° C. overnight. The resulting mixture was diluted with water (15 mL). The resulting mixture was extracted with EtOAc (3×10 mL). The combined organic layers were washed with water (2×10 mL) and brine (1×10 mL) and extracted with anhydrous Na 2 SO 4 The mixture was dried at 37° C. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE / EA 1:1) to give the crude product. The crude product was purified by back-flash with the following conditions: column, C18 gel; mobile phase, aqueous MeCN (0.1% FA), gradient 40% to 95% in 16 min; detector, UV 254 nm. This gave 2-(3-fluoro-1-(1-(oxetan-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)piperidin-3-yl)-5-(6-(trifluoromethyl)pyridin-2-yl)-1,3,4-thiadiazole (27.2 mg, 17.49%) as a white solid. 1 H NMR (300 MHz, DMSO-d 6)δ 8.59(t,J=3.9 Hz,2H),8.39(t,J=7.9 Hz,1H),8.22(s,1H),8.16(d,J=7.5 Hz,1H),5.93(t,J=6.9 Hz,1H),5.11-4.74(m,5H),4.55(d,J=12.9 Hz,1H),4.00(d,J=17.7 Hz,1H),3.42(s,1H),2.43(s,2H),1.91(s,2H).MS m / z:506.9[M+H] + . (3-Fluoro-3-(5-(6-(trifluoromethyl)pyridin-2-yl)-1,3,4-thiadiazol-2-yl)piperidin-1-yl)(1-(oxetan-3-ylmethyl)-1H-indol-6-yl)methanone (25) [ka]

[0336] To a stirred mixture of 1-(oxetan-3-ylmethyl)-1H-indole-6-carboxylic acid (60 mg, 0.260 mmol, 1 equiv.) in DMF (1 mL) was added HATU (98.8 mg, 0.260 mmol, 1 equiv.) in portions at 0° C. The mixture was stirred at this temperature for 10 min. To the above mixture were added DIEA (101 mg, 0.780 mmol, 3 equiv.) and 2-(3-fluoropiperidin-3-yl)-5-(6-(trifluoromethyl)pyridin-2-yl)-1,3,4-thiadiazole hydrochloride (95.7 mg, 0.260 mmol, 1 equiv.) successively at 0° C. The resulting mixture was stirred at room temperature for another 1 h. The reaction was quenched with water (10 mL) at 0° C. The resulting mixture was extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (1×20 mL) and anhydrous Na 2 SO 4The mixture was dried at 37° C. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (EtOAc / PE=1 / 1) to give the crude product. The crude product was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water, gradient 35% to 65% in 10 min; detector, UV 254 nm. This gave (3-fluoro-3-(5-(6-(trifluoromethyl)pyridin-2-yl)-1,3,4-thiadiazol-2-yl)piperidin-1-yl)(1-(oxetan-3-ylmethyl)-1H-indol-6-yl)methanone (50.0 mg, 35.2%) as a white solid. 1 H NMR (300 MHz, DMSO-d 6 )δ 8.56(d,J=8.1 Hz,1H),8.36(t,J=7.8 Hz,1H),8.14(d,J=7.8 Hz,1H),7.67-7.52(m,3H),7.08(dd,J=8.1,1.2 Hz,1H),6.49(d,J=3.0 Hz,1H),4.60(t,J=6.9 Hz,2H),4.53(d,J=7.5 Hz,2H),4.40(td,J=6.0,2.4 Hz,2H),4.18-3.60(m,2H),3.54-3.35(m,2H),3.30-3.06(m,1H),2.49-2.19(m,2H),2.04-1.67(m,2H).MS m / z:546.2[M+H] + . (3-Fluoro-3-(5-(6-(trifluoromethyl)pyridin-2-yl)-1,3,4-thiadiazol-2-yl)piperidin-1-yl)(1-(oxetan-3-yl)-1H-indol-6-yl)methanone (26) [ka]

[0337] Step 1: 6-(trifluoromethyl)picolinohydrazide: Methyl 6-(trifluoromethyl)picolinate (2.5 g, 12.2 mmol, 1 equiv.) and hydrazine (1.83 g, 36.5 mmol, 3 equiv.) were added in EtOH (15 mL) at 80° C. The resulting mixture was purified by reverse phase flash under the following conditions (MeCN in water (0.1% FA), gradient 40% to 95% in 16 min; detector, UV 254 nm.) to give 6-(trifluoromethyl)picolinohydrazide (2000 mg, 79.6%) as a yellow oil. MS m / z: 206 [M+H] + .

[0338] Step 2: tert-Butyl 3-fluoro-3-(2-(6-(trifluoromethyl)picolinoyl)hydrazine-1-carbonyl)piperidine-1-carboxylate: To a stirred mixture of 1-(tert-butoxycarbonyl)-3-fluoropiperidine-3-carboxylic acid (842 mg, 3.41 mmol, 1 equiv.) and 6-(trifluoromethyl)picolinohydrazide (700 mg, 3.41 mmol, 1.0 equiv.) in DMF (8 mL) was added HATU (1.29 g, 3.41 mmol, 1.0 equiv.) and DIPEA (1.32 g, 10.2 mmol, 3 equiv.). The resulting mixture was stirred at room temperature for 2 h. The resulting mixture was diluted with water (30 mL). The resulting mixture was extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine (2×30 mL) and diluted with anhydrous Na 2 SO 4 The mixture was dried at 4° C. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by back-flash with the following conditions: column, C18 gel; mobile phase, MeCN in water, gradient 5% to 95% in 20 min; detector, UV 254 nm. This gave tert-butyl 3-fluoro-3-(2-(6-(trifluoromethyl)picolinoyl)hydrazine-1-carbonyl)piperidine-1-carboxylate (1.29 g, 87.0%) as an off-white solid. MS m / z: 435 [M+H] + .

[0339] Step 3: tert-Butyl 3-fluoro-3-(5-(6-(trifluoromethyl)pyridin-2-yl)-1,3,4-thiadiazol-2-yl)piperidine-1-carboxylate: To a stirred solution of tert-butyl 3-fluoro-3-(2-(6-(trifluoromethyl)picolinoyl)hydrazine-1-carbonyl)piperidine-1-carboxylate (1.29 g, 2.97 mmol, 1 equiv.) in toluene (12 mL) was added Lawesson's reagent (1.20 g, 2.97 mmol, 1.0 equiv.). The resulting mixture was stirred at 80° C. for 3 h. The reaction was cooled to 0° C. with saturated NaHCO 3 (aqueous). The resulting mixture was extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine (2×40 mL) and anhydrous Na 2 SO 4 The mixture was dried at 4° C. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by back-flash with the following conditions: column, C18 gel; mobile phase, MeCN in water (0.1% FA), gradient 5% to 95% in 20 min; detector, UV 254 nm. This gave tert-butyl 3-fluoro-3-(5-(6-(trifluoromethyl)pyridin-2-yl)-1,3,4-thiadiazol-2-yl)piperidine-1-carboxylate (450 mg, 35.1%) as a pale yellow solid. MS m / z: 433 [M+H] +.

[0340] Step 4: 2-(3-fluoropiperidin-3-yl)-5-(6-(trifluoromethyl)pyridin-2-yl)-1,3,4-thiadiazole hydrochloride: To a stirred solution of tert-butyl 3-fluoro-3-(5-(6-(trifluoromethyl)pyridin-2-yl)-1,3,4-thiadiazol-2-yl)piperidine-1-carboxylate (450 mg, 1.04 mmol, 1 equiv.) in DCM (2 mL) was added HCl (gas) in 1,4-dioxane (2 mL). The resulting mixture was stirred at room temperature for 2 h. The resulting mixture was concentrated under vacuum. The crude product 2-(3-fluoropiperidin-3-yl)-5-(6-(trifluoromethyl)pyridin-2-yl)-1,3,4-thiadiazole hydrochloride (400 mg) was used directly in the next step without further purification. MS m / z: 333 [M+H] + .

[0341] Step 5: (3-Fluoro-3-(5-(6-(trifluoromethyl)pyridin-2-yl)-1,3,4-thiadiazol-2-yl)piperidin-1-yl)(1-(oxetan-3-yl)-1H-indol-6-yl)methanone: To a stirred mixture of 1-(oxetan-3-yl)indole-6-carboxylic acid (65.4 mg, 0.301 mmol, 1 equiv.) in DMF (1 mL) was added HATU (114 mg, 0.301 mmol, 1 equiv.) in portions at 0° C. The mixture was stirred at this temperature for 10 min. To the above mixture, DIEA (117 mg, 0.903 mmol, 3 equiv.) and 2-(3-fluoropiperidin-3-yl)-5-(6-(trifluoromethyl)pyridin-2-yl)-1,3,4-thiadiazole hydrochloride (111 mg, 0.301 mmol, 1.00 equiv.) were added successively at 0° C. The resulting mixture was stirred at room temperature for another 1 h. The reaction was quenched with water (10 mL) at 0° C. The resulting mixture was extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (1×20 mL) and washed with anhydrous Na 2 SO 4The mixture was dried at 37° C. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (EtOAc / PE=1 / 1) to give the crude product. The crude product was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water, gradient 35% to 65% in 10 min; detector, UV 254 nm. This gave (3-fluoro-3-(5-(6-(trifluoromethyl)pyridin-2-yl)-1,3,4-thiadiazol-2-yl)piperidin-1-yl)(1-(oxetan-3-yl)-1H-indol-6-yl)methanone (57.3 mg, 34.1%) as a white solid. 1 H NMR(400 MHz,DMSO-d6)δ 8.55(s,1H),8.36(t,J=8.0 Hz,1H),8.13(d,J=7.8 Hz,1H),7.89(d,J=3.3 Hz,1H),7.68(s,1H),7.63(d,J=8.0 Hz,1H),7.14-7.09(m,1H),6.62(d,J=3.2 Hz,1H),5.84(d,J=7.4 Hz,1H),5.05(t,J=7.2 Hz,2H),4.98-4.87(m,2H),4.38(d,J=75.2 Hz,1H),3.85(s,2H),2.48-2.32(m,2H),1.97-1.75(m,2H).MS m / z:532.0[M+H] + . 2-((1R,5S,6r)-3-(1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-3-azabicyclo[3.1.0]hexan-6-yl)-5-(2-(trifluoromethyl)pyridin-3-yl)-1,3,4-thiadiazole (23) [ka]

[0342] Step 1: tert-Butyl (1R,5S,6r)-6-(2-(2-(trifluoromethyl)nicotinoyl)hydrazine-1-carbonyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate: To a stirred solution of (1R,5S,6r)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexane-6-carboxylic acid (500 mg, 2.20 mmol, 1.0 equiv.) and DMAP (672 mg, 5.50 mmol, 2.50 equiv.) in DCM (5 mL), EDCI (632 mg, 3.30 mmol, 1.5 equiv.) and 2-(trifluoromethyl)nicotinohydrazide (451 mg, 2.20 mmol, 1.0 equiv.) were added. The resulting mixture was stirred at room temperature overnight. The resulting mixture was concentrated under vacuum. The residue was purified by reversed-phase flash chromatography using the following conditions (column, C18 gel; mobile phase, B phase: MeCN, A phase: water; gradient from 0% to 100% B in 20 min; detector: UV254 / 220 nm). This gave tert-butyl (1R,5S,6r)-6-(2-(2-(trifluoromethyl)nicotinoyl)hydrazine-1-carbonyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (600 mg, 65.8%) as a red solid. MS m / z: 415 [M+H] + .

[0343] Step 2: tert-Butyl (1R,5S,6r)-6-(5-(2-(trifluoromethyl)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate: A solution of tert-butyl (1R,5S,6r)-6-(2-(2-(trifluoromethyl)nicotinoyl)hydrazine-1-carbonyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (600 mg, 1.45 mmol, 1.00 equiv) and Lawesson's reagent (352 mg, 0.870 mmol, 0.6 equiv) in toluene (3 mL) was stirred at 60° C. for 2 h. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with PE / EA (1 / 1) to give (1R,5S,6r)-6-(5-(2-(trifluoromethyl)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate tert-butyl (300 mg, 40.2%) as a yellow oil. MS m / z: 413 [M+H] + .

[0344] Step 3: 2-((1R,5S,6r)-3-azabicyclo[3.1.0]hexane-6-yl)-5-(2-(trifluoromethyl)pyridin-3-yl)-1,3,4-thiadiazol hydrochloride: A solution of tert-butyl (1R,5S,6r)-6-(5-(2-(trifluoromethyl)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (200 mg, 0.485 mmol, 1 equiv) in 1,4-dioxane (1.00 mL) in DCM (2.00 mL) and HCl (gas) was stirred at room temperature for 2 h. After removal of the solvent, the crude product 2-((1R,5S,6r)-3-azabicyclo[3.1.0]hexan-6-yl)-5-(2-(trifluoromethyl)pyridin-3-yl)-1,3,4-thiadiazole hydrochloride (100 mg) was used in the next step without further purification. MS m / z: 313 [M+H] + .

[0345] Step 4: 2-((1R,5S,6r)-3-(1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-3-azabicyclo[3.1.0]hexan-6-yl)-5-(2-(trifluoromethyl)pyridin-3-yl)-1,3,4-thiadiazole: 2-((1R,5S,6r)-3-azabicyclo[3.1.0]hexane To a stirred solution of 6-chloro-1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazine (50.0 mg, 0.229 mmol, 1.00 equiv) in DMF (1.00 mL) was added Na 2 CO 3 (72.7 mg, 0.687 mmol, 3.00 equiv.) was added. The resulting mixture was stirred at 100° C. for 3 h. The residue was purified by reverse-phase flash chromatography using the following conditions (column, C18 gel; mobile phase, B phase: MeCN, A phase: water; gradient from 0% to 100% B in 20 min; detector: UV254 / 220 nm). This gave 2-((1R,5S,6r)-3-(1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-3-azabicyclo[3.1.0]hexan-6-yl)-5-(2-(trifluoromethyl)pyridin-3-yl)-1,3,4-thiadiazole (5 mg, 4.42%) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 )δ 8.94-8.93(m,1H),8.28-8.26(m,1H),8.17-8.13(m,2H),7.93-7.90(m,1H),6.61-6.32(m,1H),4 .75-4.67(m,2H),4.16-4.13(m,2H),3.77-3.74(m,2H),2.69-2.67(m,1H),2.61-2.59(m,2H).MS m / z:495.1[M+H] + . 2-((1R,5S,6R)-3-(1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-3-azabicyclo[3.1.0]hexan-6-yl)-5-phenyl-1,3,4-thiadiazole (28) [ka]

[0346] Step 1: tert-Butyl (1R,5S,6r)-6-(2-benzoylhydrazine-1-carbonyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate: To a stirred mixture of (1R,5S,6r)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexane-6-carboxylic acid (500 mg, 2.20 mmol, 1.00 equiv.) and benzohydrazide (360 mg, 2.64 mmol, 1.2 equiv.) in DMF (11 mL), HATU (921 mg, 2.42 mmol, 1.10 equiv.) and DIEA (427 mg, 3.30 mmol, 1.50 equiv.) were added. The resulting mixture was stirred at room temperature for 2 h. The resulting mixture was diluted with EtOAc (50 mL). The organic layer was washed with water (2×45 mL) and brine (45 mL) and then diluted with anhydrous Na 2 SO 4 The mixture was dried at 40° C. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, ACN in water, gradient 5% to 100% in 20 min; detector, UV 254 nm. This gave tert-butyl (1R,5S,6r)-6-(2-benzoylhydrazine-1-carbonyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (600 mg, 79.0%) as a white oil. MS m / z: 346 [M+H] + .

[0347] Step 2: tert-Butyl (1R,5S,6r)-6-(5-phenyl-1,3,4-thiadiazol-2-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate: To a stirred mixture of tert-butyl (1R,5S,6r)-6-(2-benzoylhydrazine-1-carbonyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (500 mg, 1.45 mmol, 1.00 equiv.) and Lawsson reagent (352 mg, 0.869 mmol, 0.600 equiv.) in toluene. The resulting mixture was stirred at 100° C. for 3 hours. The mixture was cooled to room temperature. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (5:1) to give (1R,5S,6r)-tert-butyl 6-(5-phenyl-1,3,4-thiadiazol-2-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (350 mg, 70.4%) as a white oil. MS m / z: 344 [M+H] + .

[0348] Step 3: 2-((1R,5S,6r)-3-azabicyclo[3.1.0]hexan-6-yl)-5-phenyl-1,3,4-thiadiazole hydrochloride: A solution of tert-butyl tert-butyl (1R,5S,6r)-6-(5-phenyl-1,3,4-thiadiazole-2-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (300 mg, 0.873 mmol, 1.00 equiv.) in DCM (2.00 mL) and HCl (gas) in 1,4-dioxane (2.00 mL) was stirred at room temperature for 2 h. After removal of the solvent, the crude product 2-((1R,5S,6r)-3-azabicyclo[3.1.0]hexan-6-yl)-5-phenyl-1,3,4-thiadiazole hydrochloride (100 mg) was used in the next step without further purification. MSm / z: 244[M+H] + .

[0349] Step 4: 2-((1R,5S,6r)-3-(1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-3-azabicyclo[3.1.0]hexan-6-yl)-5-phenyl-1,3,4-thiadiazole: A stirred solution of 2-((1R,5S,6r)-3-azabicyclo[3.1.0]hexan-6-yl)-5-phenyl-1,3,4-thiadiazole hydrochloride (90.0 mg, 0.370 mmol, 1.00 equiv) and 6-chloro-1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazine (60.0 mg, 0.274 mmol, 0.740 equiv) in DMF (1.50 mL) was added with Na 2 CO 3 (118 mg, 1.11 mmol, 3.00 equiv.) was added. The resulting mixture was stirred at 100° C. for 2 h. The residue was purified by reverse-phase flash chromatography using the following conditions (column, C18 gel; mobile phase, B phase: MeCN, A phase: water; gradient from 5% to 100% B in 20 min; detector: UV254 / 220 nm). This gave 2-((1R,5S,6r)-3-(1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-3-azabicyclo[3.1.0]hexan-6-yl)-5-phenyl-1,3,4-thiadiazole (92.0 mg, 58.4%) as a white solid. 1 H NMR (300 MHz, DMSO-d 6 )δ 8.16(d,J=6.5 Hz,2H),7.98-7.87(m,2H),7.61-7.51(m,3H),6.47(tt,J=54.9,3.8 Hz,1H),4.71(td,J=15.0,3.8 Hz,2H),4.14(d,J=11.4 Hz,2H),3.79-3.69(m,2H),2.62-2.58(m,1H),2.57-2.53(m,2H).MS m / z:426.1[M+H] + .

[0350] Biological Assay Data and Procedures Exemplary compounds were evaluated for activation of GCase in a live cell PFB assay in HELA cells (essentially as described in Ysselstein et al., "LRRK2 kinase activity regulates lysosomal glucocerebrosidase in neurons derived from Parkinson's disease patients" Nature Communications (2019) 10:5570). The results in Table 3 demonstrate that the compounds of the present disclosure are potent activators of GCase. EC 50 Range: A: <10 μM; B: >10~50 μM; C: >50~100 μM; D: >100 μM. [Table 4]

[0351] Equivalence and Scope In the claims, articles such as "a," "an," and "the" may mean one or more, unless indicated to the contrary or clear from the context. A claim or description containing "or" between one or more members of a group is deemed to be satisfied if one, more than one, or all of the group members are present in, used in, or otherwise relevant to a given product or process, unless indicated to the contrary or clear from the context. The invention includes embodiments in which exactly one member of a group is present in, used in, or otherwise relevant to a given product or process. The invention includes embodiments in which more than one, or all of the group members are present in, used in, or otherwise relevant to a given product or process.

[0352] Furthermore, the present invention encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the enumerated claims are introduced into another claim. For example, any claim that is dependent on another claim can be amended to include one or more limitations found in any other claim that is dependent on the same base claim. When elements are presented as a list, for example in Markush group format, each subgroup of elements is also disclosed, and any element(s) can be removed from the group. In general, when the invention or aspects of the invention are referred to as comprising certain elements and / or features, it is to be understood that certain embodiments of the invention or aspects of the invention consist of or consist essentially of such elements and / or features. For simplicity, these embodiments have not been specifically set forth herein. It should also be noted that the terms "comprising" and "containing" are intended to be open, allowing for the inclusion of additional elements or steps. When ranges are given, the endpoints are included. Furthermore, unless otherwise indicated or clear from the context and the understanding of one of ordinary skill in the art, values ​​expressed as ranges can contemplate in different embodiments of the invention any specific value or subrange within the stated range, down to one tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.

[0353] This application refers to various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. In the event of a conflict between any of the incorporated references and this specification, this specification shall control. Furthermore, any particular embodiment of the present invention that falls within the prior art may be expressly excluded from any one or more of the claims. Such embodiments may be excluded even if the exclusion is not expressly set forth herein, since they are deemed to be known to those skilled in the art. Any particular embodiment of the present invention may be excluded from any claim for any reason, whether related to the existence of prior art or not.

[0354] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments described herein. The scope of the embodiments described herein is not limited to the above description, but is instead set forth in the appended claims. Those skilled in the art will appreciate that various changes and modifications to this description can be made without departing from the spirit or scope of the invention, as defined in the following claims.

[0355] For completeness, various aspects of the disclosure are set forth in the following numbered clauses.

[0356] Clause 1. Formula (I): [ka] or a pharma- ceutically acceptable salt thereof, R 1 is substituted or unsubstituted alkyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted aryl; L is a bond or -C(=O)-; A is, [ka] and R 2 and R 3 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 2 and R 3 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; Each R 4 are independently halogen, substituted or unsubstituted alkyl, or R 4 In the two cases, it forms a carbonyl with that carbon, m is 0, 1, 2, 3 or 4; A compound of formula (I) or a pharma- ceutically acceptable salt thereof.

[0357] Article 2.R 1 is substituted or unsubstituted pyridinyl, or substituted or unsubstituted phenyl; 2. A compound according to claim 1 or a pharma- ceutically acceptable salt thereof.

[0358] Article 3.R 1 3. The compound according to clause 1 or 2, wherein is substituted pyridinyl, or substituted or unsubstituted phenyl, or a pharma- ceutically acceptable salt thereof.

[0359] Article 4.R 1 The compound according to any one of clauses 1 to 3, wherein is pyridinyl substituted with halogen or haloalkyl, phenyl substituted with halogen or haloalkyl, or unsubstituted phenyl, or a pharma- ceutically acceptable salt thereof.

[0360] Article 5.R 1 is pyridinyl substituted with halogen or haloalkyl, or a pharma- ceutically acceptable salt thereof.

[0361] Article 6.R 1 is pyridinyl substituted with haloalkyl, or a pharma- ceutically acceptable salt thereof.

[0362] Article 7.R 1 is unsubstituted phenyl, or a pharma- ceutically acceptable salt thereof.

[0363] Article 8.R 1 is phenyl substituted with halogen or haloalkyl, or a pharma- ceutically acceptable salt thereof.

[0364] Article 9.R 1is phenyl substituted with halogen, or a pharma- ceutically acceptable salt thereof.

[0365] Article 10.R 1 is phenyl substituted with haloalkyl, or a pharma- ceutically acceptable salt thereof.

[0366] Article 11.R 1 is methyl, [ka] That is, 5. The compound according to any one of claims 1 to 4, or a pharma- ceutically acceptable salt thereof.

[0367] Article 12.R 1 teeth, [ka] That is, 5. The compound according to any one of claims 1 to 4, or a pharma- ceutically acceptable salt thereof.

[0368] Article 13.R 1 teeth, [ka] That is, 5. The compound according to any one of claims 1 to 4, or a pharma- ceutically acceptable salt thereof.

[0369] Article 14.R 1 teeth, [ka] That is, 5. The compound according to any one of claims 1 to 4, or a pharma- ceutically acceptable salt thereof.

[0370] Clause 15.A [ka] That is, 15. The compound according to any one of claims 1 to 14, or a pharma- ceutically acceptable salt thereof.

[0371] Clause 16.A [ka] That is, 15. The compound according to any one of claims 1 to 14, or a pharma- ceutically acceptable salt thereof.

[0372] Clause 17.A [ka] That is, 15. The compound according to any one of claims 1 to 14, or a pharma- ceutically acceptable salt thereof.

[0373] Clause 18.A [ka] That is, 15. The compound according to any one of claims 1 to 14, or a pharma- ceutically acceptable salt thereof.

[0374] Clause 19.A [ka] That is, 15. The compound according to any one of claims 1 to 14, or a pharma- ceutically acceptable salt thereof.

[0375] Clause 20.A [ka] That is, 15. The compound according to any one of claims 1 to 14, or a pharma- ceutically acceptable salt thereof.

[0376] Article 21.R 2 and R 3 are each independently hydrogen or substituted or unsubstituted heteroaryl, or R 2 and R3 or a pharma- ceutically acceptable salt thereof, wherein, together with the atom to which they are attached, form a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl.

[0377] Article 22.R 2 is heteroaryl; or a pharma- ceutically acceptable salt thereof.

[0378] Article 23.R 2 23. The compound according to any one of clauses 1 to 22, wherein is thiadiazolyl, or a pharma- ceutically acceptable salt thereof.

[0379] Article 24.R 3 24. The compound according to any one of clauses 1 to 23, or a pharma- ceutically acceptable salt thereof, wherein: is hydrogen.

[0380] Article 25.R 2 and R 3 or a pharma- ceutically acceptable salt thereof, wherein, together with the atom to which they are attached, form a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl.

[0381] Article 26.R 2 and R 3 or a pharma- ceutically acceptable salt thereof. The compound according to any one of clauses 1 to 21, wherein, together with the atom to which they are attached, form a substituted or unsubstituted aryl; or a pharma- ceutically acceptable salt thereof.

[0382] Article 27.R 2 and R 3 or a pharma- ceutically acceptable salt thereof. The compound according to any one of clauses 1 to 21, wherein, together with the atom to which they are attached, form a substituted or unsubstituted phenyl; or a pharma- ceutically acceptable salt thereof.

[0383] Article 28.R 2 and R 3or a pharma- ceutically acceptable salt thereof. The compound according to any one of clauses 1 to 21, wherein: together with the atom to which they are attached, form a substituted or unsubstituted heteroaryl; or a pharma- ceutically acceptable salt thereof.

[0384] Article 29.R 2 and R 3 or a pharma- ceutically acceptable salt thereof. The compound according to any one of clauses 1 to 21, wherein, together with the atom to which they are attached, form a substituted or unsubstituted imidazolyl, a substituted or unsubstituted pyrrolyl, or a substituted or unsubstituted pyrazolyl.

[0385] Article 30.R 2 and R 3 or a pharma- ceutically acceptable salt thereof. The compound according to any one of clauses 1 to 21, wherein: together with the atom to which they are attached form a substituted or unsubstituted pyrazolyl; or a pharma- ceutically acceptable salt thereof.

[0386] Clause 31.A: [ka] That is, 31. The compound according to any one of claims 1 to 30, or a pharma- ceutically acceptable salt thereof.

[0387] Article 32.R 4 is a halogen or R on the same carbon 4 In the above two cases, a carbonyl is formed together with the carbon atom, or a pharma- ceutically acceptable salt thereof, according to any one of clauses 1 to 31.

[0388] Article 33.R 4 is fluoro or R on the same carbon 4 In the above two cases, a carbonyl is formed together with the carbon atom, or a pharma- ceutically acceptable salt thereof, according to any one of clauses 1 to 32.

[0389] Article 34.R 4 34. The compound according to any one of clauses 1 to 33, or a pharma- ceutically acceptable salt thereof, wherein is fluoro.

[0390] Clause 35. The compound according to any one of clauses 1 to 34, wherein m is 0, or a pharma- ceutically acceptable salt thereof.

[0391] Clause 36. The compound according to any one of clauses 1 to 35, wherein m is 2, or a pharma- ceutically acceptable salt thereof.

[0392] Clause 37. The compound according to any one of clauses 1 to 35, wherein m is 1, or a pharma- ceutically acceptable salt thereof.

[0393] Clause 38. A compound according to any one of clauses 1 to 37, or a pharma- ceutically acceptable salt thereof, wherein L is a bond.

[0394] Clause 39. A compound according to any one of clauses 1 to 37, or a pharma- ceutically acceptable salt thereof, wherein L is -C(=O)-.

[0395] Clause 40. The compound of formula (Ia): [ka] or a pharma- ceutically acceptable salt thereof.

[0396] Clause 41. The compound of formula (Ib) [ka] or a pharma- ceutically acceptable salt thereof.

[0397] Clause 42. The compound of formula (Ic): [ka] or a pharma- ceutically acceptable salt thereof.

[0398] Clause 43. The compound of formula (Id): [ka] or a pharma- ceutically acceptable salt thereof, wherein X is N or CH; and R a is substituted or unsubstituted alkyl.

[0399] Clause 44. The compound of formula (Ie): [ka] or a pharma- ceutically acceptable salt thereof, a is substituted or unsubstituted alkyl.

[0400] Clause 45. The compound has the formula (If): [ka] or a pharma- ceutically acceptable salt thereof, a is substituted or unsubstituted alkyl.

[0401] Article 46.R a 46. ​​The compound according to any one of clauses 43 to 45, or a pharma- ceutically acceptable salt thereof, wherein is unsubstituted alkyl or haloalkyl.

[0402] Clause 47. The compound of formula (Ig): [ka] or a pharma- ceutically acceptable salt thereof.

[0403] Clause 48. The compound of formula (Ih): [ka] or a pharma- ceutically acceptable salt thereof.

[0404] Clause 49. The compound of formula (Ii): [ka] or a pharma- ceutically acceptable salt thereof.

[0405] Clause 50. The compound of formula (Ij): [ka] or a pharma- ceutically acceptable salt thereof.

[0406] Article 51. The compound is [Table 5] TIFF2024517789000167.tif90150 or a pharma- ceutically acceptable salt thereof; 2. A compound as defined in clause 1.

[0407] Clause 52. A pharmaceutical composition comprising a compound according to any one of clauses 1 to 51 or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient.

[0408] Clause 53. A kit comprising a compound according to any one of clauses 1 to 51, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to clause 52, and instructions for administering the compound or pharmaceutical composition to a subject in need thereof.

[0409] Clause 54. A method of treating a disease or disorder in a subject in need thereof, comprising administering an effective amount of a compound according to any one of clauses 1 to 51, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to clause 52.

[0410] Clause 55. The method according to clause 54, wherein the disease or disorder is associated with glucocerebrosidase activity.

[0411] Clause 56. The method according to clause 54 or 55, wherein the disease or disorder is a neurological disease or disorder.

[0412] Clause 57. The method according to clause 56, wherein the neurological disease or disorder is Parkinson's disease or Gaucher's disease.

[0413] Clause 58. A method for activating glucocerebrosidase, comprising contacting glucocerebrosidase with an effective amount of a compound according to any one of clauses 1 to 51, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to clause 52.

[0414] Clause 59. The method of clause 58, wherein the contacting is in vitro.

[0415] Clause 60. The method of clause 58, wherein the contacting is in vivo.

[0416] Further various aspects of the present disclosure are described in the following numbered embodiments.

[0417] Embodiment 1. Formula (I): [ka] or a pharma- ceutically acceptable salt thereof, R 1 is substituted or unsubstituted alkyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted aryl; A 1 teeth, [ka] and L is a bond or -C(=O)-; A is, [ka] and R 2 and R 3are 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 2 and R 3 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; Each R 4 are independently halogen, substituted or unsubstituted alkyl, or R 4 In the two cases, it forms a carbonyl with that carbon, m is 0, 1, 2, 3 or 4; A compound of formula (I) or a pharma- ceutically acceptable salt thereof.

[0418] Embodiment 2.R 1 is substituted or unsubstituted pyridinyl, or substituted or unsubstituted phenyl; 2. The compound of embodiment 1, or a pharma- ceutically acceptable salt thereof.

[0419] Embodiment 3.R 1 is substituted pyridinyl, or substituted or unsubstituted phenyl; or a pharma- ceutically acceptable salt thereof.

[0420] Embodiment 4.R 1 is pyridinyl substituted with halogen or haloalkyl, unsubstituted phenyl, or phenyl substituted with halogen, haloalkoxy, or haloalkyl; or a pharma- ceutically acceptable salt thereof.

[0421] Embodiment 5.R 1 is pyridinyl substituted with halogen or haloalkyl; or a pharma- ceutically acceptable salt thereof.

[0422] Embodiment 6.R 1is pyridinyl substituted with haloalkyl; or a pharma- ceutically acceptable salt thereof.

[0423] Embodiment 7.R 1 is unsubstituted phenyl; or a pharma- ceutically acceptable salt thereof.

[0424] Embodiment 8.R 1 The compound according to any one of embodiments 1-4, wherein is phenyl substituted with halogen, haloalkoxy, or haloalkyl, or a pharma- ceutically acceptable salt thereof.

[0425] Embodiment 9.R 1 is phenyl substituted with halogen; or a pharma- ceutically acceptable salt thereof.

[0426] Embodiment 10.R 1 is phenyl substituted with haloalkyl; or a pharma- ceutically acceptable salt thereof.

[0427] Embodiment 11.R 1 But methyl, [ka] or a pharma- ceutically acceptable salt thereof.

[0428] Embodiment 12.R 1 but [ka] or a pharma- ceutically acceptable salt thereof.

[0429] Embodiment 13.R 1 but [ka] or a pharma- ceutically acceptable salt thereof.

[0430] Embodiment 14.R 1 but [ka] or a pharma- ceutically acceptable salt thereof.

[0431] In embodiment 15.A [ka] 15. The compound according to any one of embodiments 1 to 14, wherein:

[0432] In embodiment 16.A [ka] 15. The compound according to any one of embodiments 1 to 14, wherein:

[0433] In embodiment 17.A [ka] 15. The compound according to any one of embodiments 1 to 14, wherein:

[0434] In embodiment 18.A [ka] 15. The compound according to any one of embodiments 1 to 14, wherein:

[0435] In embodiment 19.A [ka] 15. The compound according to any one of embodiments 1 to 14, wherein:

[0436] In embodiment 20.A [ka] 15. The compound according to any one of embodiments 1 to 14, wherein:

[0437] Embodiment 21.R 2 and R 3 are each independently hydrogen or substituted or unsubstituted heteroaryl, or R 2 and R 3 or a pharma- ceutically acceptable salt thereof, according to any one of embodiments 1-20, wherein, together with the atom to which they are attached, form a substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.

[0438] Embodiment 22.R 2 is heteroaryl; or a pharma- ceutically acceptable salt thereof.

[0439] Embodiment 23.R 2 is thiadiazolyl; or a pharma- ceutically acceptable salt thereof.

[0440] Embodiment 24.R 3 24. The compound of any one of embodiments 1-23, or a pharma- ceutically acceptable salt thereof, wherein is hydrogen.

[0441] Embodiment 25.R 2 and R 3 or a pharma- ceutically acceptable salt thereof, of any one of embodiments 1-21, wherein, together with the atom to which they are attached, form a substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.

[0442] Embodiment 26.R 2 and R 3or a pharma- ceutically acceptable salt thereof. The compound of any one of embodiments 1-21, wherein: together with the atom to which they are attached, form a substituted or unsubstituted aryl; or a pharma- ceutically acceptable salt thereof.

[0443] Embodiment 27.R 2 and R 3 or a pharma- ceutically acceptable salt thereof. The compound of any one of embodiments 1-21, wherein: combined with the atom to which they are attached form a substituted or unsubstituted phenyl; or a pharma- ceutically acceptable salt thereof.

[0444] Embodiment 28.R 2 and R 3 or a pharma- ceutically acceptable salt thereof. The compound of any one of embodiments 1-21, wherein: together with the atom to which they are attached, form a substituted or unsubstituted heteroaryl; or a pharma- ceutically acceptable salt thereof.

[0445] Embodiment 29.R 2 and R 3 or a pharma- ceutically acceptable salt thereof.

[0446] Embodiment 30.R 2 and R 3 or a pharma- ceutically acceptable salt thereof. The compound of any one of embodiments 1-21, wherein: together with the atom to which they are attached form a substituted or unsubstituted pyrazolyl; or a pharma- ceutically acceptable salt thereof.

[0447] In embodiment 31.A [ka] or a pharma- ceutically acceptable salt thereof.

[0448] Embodiment 32.R 4 is a halogen or R on the same carbon 4In the two cases above, the carbon atom is joined to the carbon atom to form a carbonyl.

[0449] Embodiment 33.R 4 is fluoro or R on the same carbon 4 In the two cases above, the carbon atom is joined to the carbon atom to form a carbonyl.

[0450] Embodiment 34.R 4 or a pharma- ceutically acceptable salt thereof, according to any one of embodiments 1-33, wherein is fluoro.

[0451] Embodiment 35. A compound according to any one of embodiments 1 to 34, or a pharma- ceutically acceptable salt thereof, wherein m is 0.

[0452] Embodiment 36. A compound according to any one of embodiments 1 to 35, or a pharma- ceutically acceptable salt thereof, wherein m is 2.

[0453] Embodiment 37. A compound according to any one of embodiments 1 to 35, or a pharma- ceutically acceptable salt thereof, wherein m is 1.

[0454] Embodiment 38. A compound according to any one of embodiments 1 to 37, or a pharma- ceutically acceptable salt thereof, wherein L is a bond.

[0455] Embodiment 39. A compound according to any one of embodiments 1 to 37, or a pharma- ceutically acceptable salt thereof, wherein L is -C(=O)-.

[0456] Embodiment 40.A 1 but [ka] or a pharma- ceutically acceptable salt thereof.

[0457] Embodiment 41.A 1 but [ka] or a pharma- ceutically acceptable salt thereof.

[0458] Embodiment 42. The compound has the formula (Ia): [ka] or a pharma- ceutically acceptable salt thereof.

[0459] Embodiment 43. The compound has the formula (Ib): [ka] or a pharma- ceutically acceptable salt thereof.

[0460] Embodiment 44. The compound has the formula (Ic): [ka] or a pharma- ceutically acceptable salt thereof.

[0461] Embodiment 45. The compound has the formula (Id): [ka] or a pharma- ceutically acceptable salt thereof.

[0462] Embodiment 46. The compound has the formula (Ie): [ka] or a pharma- ceutically acceptable salt thereof, wherein X is N or CH; and R a is substituted or unsubstituted alkyl, or substituted or unsubstituted heterocyclyl.

[0463] Embodiment 47. The compound has the formula (If): [ka] or a pharma- ceutically acceptable salt thereof, a is substituted or unsubstituted alkyl, or substituted or unsubstituted heterocyclyl.

[0464] Embodiment 48. The compound has the formula (Ig): [ka] or a pharma- ceutically acceptable salt thereof, a is substituted or unsubstituted alkyl, or substituted or unsubstituted heterocyclyl.

[0465] Embodiment 49. The compound has the formula (Ih): [ka] or a pharma- ceutically acceptable salt thereof, wherein R a is hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heterocyclyl.

[0466] Embodiment 50. The compound has the formula (Ii): [ka] or a pharma- ceutically acceptable salt thereof, wherein R a is hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heterocyclyl.

[0467] Embodiment 51.R a or a pharma- ceutically acceptable salt thereof.

[0468] Embodiment 52. The compound has the formula (Ij): [ka] or a pharma- ceutically acceptable salt thereof.

[0469] Embodiment 53. The compound has the formula (Ik): [ka] or a pharma- ceutically acceptable salt thereof.

[0470] Embodiment 54. The compound has the formula (II): [ka] or a pharma- ceutically acceptable salt thereof.

[0471] Embodiment 55. The compound has the formula (Im): [ka] or a pharma- ceutically acceptable salt thereof.

[0472] Embodiment 56. The compound has the formula (In): [ka] or a pharma- ceutically acceptable salt thereof, wherein R a is hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heterocyclyl.

[0473] Embodiment 57. The compound has the formula (Io): [ka] or a pharma- ceutically acceptable salt thereof.

[0474] Embodiment 58. The compound has the formula (Ip): [ka] or a pharma- ceutically acceptable salt thereof.

[0475] Embodiment 59. The compound is [Table 6] TIFF2024517789000201.tif202156 or a pharma- ceutically acceptable salt thereof; The compound of embodiment 1.

[0476] Embodiment 60. A pharmaceutical composition comprising a compound according to any one of embodiments 1 to 59 or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient.

[0477] Embodiment 61. A kit comprising a compound according to any one of embodiments 1 to 59, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to embodiment 60, and instructions for administering the compound or pharmaceutical composition to a subject in need thereof.

[0478] Embodiment 62. A method of treating a disease or disorder in a subject in need thereof, comprising administering an effective amount of a compound described in any one of embodiments 1 to 59, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition described in embodiment 60.

[0479] Embodiment 63. The method of embodiment 62, wherein the disease or disorder is associated with glucocerebrosidase activity.

[0480] Embodiment 64. The method of embodiment 62 or 63, wherein the disease or disorder is a neurological disease or disorder.

[0481] Embodiment 65. The method of embodiment 64, wherein the neurological disease or disorder is Parkinson's disease or Gaucher's disease.

[0482] Embodiment 66. A method for activating glucocerebrosidase, comprising contacting glucocerebrosidase with an effective amount of a compound according to any one of embodiments 1 to 59, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to embodiment 60.

[0483] Embodiment 67 The method of embodiment 66, wherein the contacting is in vitro.

[0484] Embodiment 68 The method of embodiment 66, wherein the contacting is in vivo.

Claims

1. Formula (I): 【Chemistry 1】 or a pharma- ceutically acceptable salt thereof, wherein R １ is substituted or unsubstituted alkyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted aryl; A １ teeth, 【Chemistry 2】 and L is a bond or -C(=O)-; A is, 【Chemistry 3】 and R ２ and R ３ 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 ２ and R ３ 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; Each R ４ are independently halogen, substituted or unsubstituted alkyl, or R ４ In the two cases, it forms a carbonyl with that carbon, m is 0, 1, 2, 3 or 4; A compound or a pharma- ceutically acceptable salt thereof.

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

3. R １ 2. The compound of claim 1, wherein: is pyridinyl substituted with halogen or haloalkyl, unsubstituted phenyl, or phenyl substituted with halogen, haloalkoxy, or haloalkyl, or a pharma- ceutically acceptable salt thereof.

4. R １ is methyl, 【Chemistry 4】 That is, 2. The compound of claim 1 or a pharma- ceutically acceptable salt thereof.

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

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

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

8. R ２ and R ３ are each independently hydrogen or a substituted or unsubstituted heteroaryl, or R ２ and R ３ together with the atom to which they are attached form a substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; 2. The compound of claim 1 or a pharma- ceutically acceptable salt thereof.

9. R ２ and R ３ or a pharma- ceutically acceptable salt thereof, wherein: R is 0 or 1; and R is 1 or 2; and R is 2 or 3. The compound of claim 1, wherein: R is 0 or 1; and R is 1 or 2.

10. R ２ and R ３ or a pharma- ceutically acceptable salt thereof, wherein: R 1 is substituted or unsubstituted imidazolyl, R 2 is substituted or unsubstituted pyrrolyl, or R 3 is substituted or unsubstituted pyrazolyl, together with the atom to which they are attached;

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

12. R ４ is a halogen or R on the same carbon ４ In the two cases, it forms a carbonyl with that carbon.

2. The compound of claim 1 or a pharma- ceutically acceptable salt thereof.

13. 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein L is a bond.

14. A １ teeth, 【Chemistry 9】 2. The compound of claim 1, wherein:

15. The compound has the formula: 【Chemistry 10】 is a compound of the formula X is N or CH; R a is substituted or unsubstituted alkyl, or substituted or unsubstituted heterocyclyl, or R a is hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heterocyclyl; 2. The compound of claim 1 or a pharma- ceutically acceptable salt thereof.

16. The compound is 【Table 1】 2. The compound of claim 1, wherein:

17. A pharmaceutical composition comprising a compound according to any one of claims 1 to 16 or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient.

18. 17. A kit comprising a compound according to any one of claims 1 to 16, or a pharma- ceutically acceptable salt thereof, and instructions for administering said compound or a pharma- ceutically acceptable salt thereof to a subject in need thereof.

19. 17. 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 16, or a pharma- ceutically acceptable salt thereof.

20. The composition of claim 19, wherein the disease or disorder is associated with glucocerebrosidase activity.

21. 20. The composition of claim 19, wherein the disease or disorder is a neurological disease or disorder.

22. 22. The composition of claim 21, wherein the neurological disease or disorder is Parkinson's disease or Gaucher's disease.

23. 17. 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 16, or a pharma- ceutically acceptable salt thereof.

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