Novel kinase inhibitors

Abstract

The present invention relates to compounds as kinase inhibitors, in particular TYK2 inhibitors of brain penetration, for the treatment of central nervous system (CNS) disorders. Also provided herein are methods of treating CNS disorders using compositions comprising such compounds.

Description

BACKGROUND

[0001] Protein kinases represent a large family of proteins that play a central role in regulating a variety of cellular processes and maintaining cellular function. A partial, non-limiting list of these kinases includes non-receptor tyrosine kinases, such as the Janus kinase family (JAK1, JAK2, JAK3, and TYK2); receptor tyrosine kinases, such as the platelet-derived growth factor receptor kinases (PDGFR); and serine / threonine kinases, such as b-RAF. Aberrant kinase activity has been observed in disorders resulting from inappropriate activation of the nervous system. The compounds of the present disclosure selectively inhibit the activity of one or more protein kinases (but not other related kinases) and are therefore expected to be useful in treating disorders mediated by the selectively inhibited kinases, while avoiding undesirable side effects associated with inhibition of related kinases.

[0002] In particular, the Janus kinase family comprises four known family members: JAK 1, 2, 3, and Tyrosine Kinase 2 (TYK2). These cytoplasmic tyrosine kinases are associated with membrane cytokine receptors, such as the common gamma chain receptor and the glycoprotein 130 (gp 130) transmembrane proteins (Murray, J. Immunol. 178(5):2623-2629, 2007). Almost 40 cytokine receptors signal through a combination of these four JAK family members and their seven downstream substrates, the signal transducer and activator of transcription (STAT) family members (Ghoreschi et al., Immunol Rev. 228(1):273-287, 2009). Binding of a cytokine to its receptor initiates JAK activation through trans-phosphorylation and autophosphorylation. The JAK family kinases in turn phosphorylate the cytokine receptor residues, creating binding sites for proteins containing Src homology 2 (SH2), such as STAT factors and other modulators, which are subsequently phosphorylated and activated by JAKs. The activated STATs enter the nucleus, initiating the expression of survival factors, cytokines, chemokines, and molecules that facilitate leukocyte trafficking (Schindler et al., J. Biol. Chem. 282(28):20059-20063, 2007). JAK activation also leads to cell proliferation through the phosphoinositide 3-kinase (PI3K) and protein kinase B-mediated pathways.

[0003] Given the high structural similarity between JAK1 and JAK2 (Williams et al., J. Mal. Biol. 387(1):219-232, 2009), the literature indicates that most JAK1 inhibitors also inhibit JAK2 (Incyte Corp. Press Release, November 10, 2010; Changelian et al., Science 302(5646):875-878, 2003). Recently, two JAK1 selective compounds, upadacitinib and abrocitinib, have been approved by the FDA. The TYK2 selective inhibitor deucravacitinib has been approved by the FDA for the treatment of psoriasis. Deucravacitinib is also in clinical development for lupus, ankylosing spondylitis.

[0004] Alzheimer’s disease (AD) is the most common form of neurodegenerative disease, accounting for an estimated 60-70% of all dementia cases globally. According to the prevailing amyloid cascade hypothesis, deposition of amyloid-beta (Ab) in the brain is the initiating event in AD, although increasing evidence suggests that this hypothesis is insufficient to explain many aspects of AD pathogenesis. The finding of elevated levels of inflammatory markers in patients with AD and the identification of AD risk genes related to innate immune function suggest that neuroinflammation has an important role in the pathogenesis of AD (Leng and Edison, Nat Rev Neurol. 2021 Mar;17(3):157-172). In particular, based on genetic and real-world clinical data, the JAK-STAT pathway is considered a target in AD (Nevado-Holgado et al. Cells 2019, 8(5)). Type I INF signaling, regulated by TYK2 and JAK1, has been shown to promote memory impairment associated with amyloid beta plaques (Roy et al. Immunity. 2022, 55, 879) or induce neuronal cell death (Rodriguez, S. et al. Nat Commun. 2021 Feb 15;12(1):1033; Rodriguez, S. et al. Sci. Transl. Med. 2021, 13, eaaz4699). Therefore, brain-penetrating JAK1 and / or TYK2 inhibitors can be able to treat neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Alzheimer’s disease (AD). SUMMARY

[0005] In view of recent reports of general neuroinflammation, and in particular the important role of TYK2 in CNS diseases, the present disclosure discloses TYK2 inhibitors, some of which have good brain penetration and anti-neuroinflammatory activity. Accordingly, these compounds, as well as compositions comprising the compounds of the disclosure, are useful in treating disorders associated with TYK2 activity, such as CNS disorders, including Parkinson’s disease, Alzheimer’s disease, multiple sclerosis, or amyotrophic lateral sclerosis / frontotemporal dementia (ALS / FTD), as well as systemic diseases such as psoriasis, lupus, ankylosing spondylitis, and the like.

[0006] The present disclosure provides novel compounds or salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs thereof, as selective TYK2 kinase inhibitors, some of which have good ability to penetrate the blood-brain barrier and thus have favorable properties suitable for addressing central nervous system (CNS) disorders. The present disclosure also provides compositions comprising the compounds of the disclosure or salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs thereof. The present disclosure further provides methods of using such compounds or salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs thereof, or such compositions, to treat disorders associated with TYK2, including central nervous system (CNS) disorders, such as Parkinson’s disease, Alzheimer’s disease, multiple sclerosis, or amyotrophic lateral sclerosis / frontotemporal dementia (ALS / FTD), and systemic diseases, such as psoriasis, lupus, ankylosing spondylitis.

[0007] In one aspect, provided is a compound represented by one of Formula (I), Formula (II), Formula (III), and Formula (IV):

[0008]

[0009] or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein:

[0010] X is CH or N;

[0011] Y 1 is C, Y 2 is N; or Y 1 is N, Y 2 is C;

[0012] is a single or double bond;

[0013] R 1halo, OH, CN, OR, NHR, NRR', N(R)C(O)R', N(R)C(O)(O)R', OC(O)NRR', C(O)R, C(O)NRR', N(R)S(O)2R', S(O)2R, and S(O)2NRR'; 1-3 halo, OH, CN, OR, NHR, NRR', N(R)C(O)R', N(R)C(O)(O)R', OC(O)NRR', C(O)R, C(O)NRR', N(R)S(O)2R', S(O)2R, and S(O)2NRR';

[0014] Cy is C 3-7 cycloalkyl or 3-7 membered heterocyclyl, wherein Cy is optionally substituted with 1, 2, or 3 substituents independently selected from R 2 halo, OH, CN, OR, NHR, NRR', N(R)C(O)R', N(R)C(O)(O)R', OC(O)NRR', C(O)R, C(O)NRR', N(R)S(O)2R', S(O)2R, and S(O)2NRR';

[0015] R 2 is C 1-3 alkyl, C 3-7 cycloalkyl, 3-7 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, each optionally substituted with 1, 2, or 3 substituents independently selected from halo, OH, CN, OR, NHR, NRR', N(R)C(O)R', N(R)C(O)(O)R', OC(O)NRR', C(O)R, C(O)NRR', N(R)S(O)2R', S(O)2R, and S(O)2NRR';

[0016] R, R' are each independently H, C 1-3 alkyl or C 3-6 cycloalkyl, 3-7 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, each optionally substituted with 1, 2, or 3 substituents independently selected from halo, OH, CN, OR, NHR, NRR', N(R)C(O)R', N(R)C(O)(O)R', OC(O)NRR', C(O)R, C(O)NRR', N(R)S(O)2R', S(O)2R, and S(O)2NRR';

[0017] In another aspect, provided is a compound represented by one of Formula (Ia), Formula (IIa), Formula (IIIa), and Formula (IVa):

[0018]

[0019] or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein:

[0020] X is CH or N;

[0021] R 1 is H, halo, or C 1-3alkyl, said substituents are independently selected from the group consisting of halogen, OH, CN, OR, NHR, NRR', N(R)C(O)R', N(R)C(O)OR', OC(O)NRR', C(O)R, C(O)NRR', N(R)S(O)2R', S(O)2R and S(O)2NRR';

[0022] Ring A is a 4-7 membered heterocyclyl, optionally substituted with 1, 2, or 3 substituents independently selected from R 2 , oxo, halogen, OH, CN, OR, NHR, NRR', N(R)C(O)R', N(R)C(O)(O)R', OC(O)NRR', C(O)R, C(O)NRR', N(R)S(O)2R', S(O)2R and S(O)2NRR';

[0023] R 2 is C 1-3 alkyl, C 3-7 cycloalkyl, 3-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, optionally substituted with 1, 2, or 3 substituents independently selected from halogen, OH, CN, OR, NHR, NRR', N(R)C(O)R', N(R)C(O)(O)R', OC(O)NRR', C(O)R, C(O)NRR', N(R)S(O)2R', S(O)2R and S(O)2NRR';

[0024] R, R' are each independently H, C 1-3 alkyl or C 3-6 cycloalkyl, optionally substituted with 1, 2, or 3 substituents independently selected from halogen, OH and CN.

[0025] In another aspect, there is provided a compound represented by one of formula (Ib), formula (IIb), formula (IIIb) and formula (IVb):

[0026] ,

[0027] or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein:

[0028] X is CH or N;

[0029] R 1 is H, halogen or C 1-3alkyl, said substituents are independently selected from the group consisting of halogen, OH, CN, OR, NHR, NRR', N(R)C(O)R', N(R)C(O)OR', OC(O)NRR', C(O)R, C(O)NRR', N(R)S(O)2R', S(O)2R and S(O)2NRR';

[0030] Cy is C 3-7 cycloalkyl or 3-7 membered heterocyclyl, wherein Cy is optionally substituted with 1, 2, or 3 substituents independently selected from R 2 oxo, halogen, OH, CN, OR, NHR, NRR', N(R)C(O)R', N(R)C(O)(O)R', OC(O)NRR', C(O)R, C(O)NRR', N(R)S(O)2R', S(O)2R and S(O)2NRR';

[0031] R 2 is C 1-3 alkyl, C 3-7 cycloalkyl, 3-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, optionally substituted with 1, 2, or 3 substituents independently selected from halogen, OH, CN, OR, NHR, NRR', N(R)C(O)R', N(R)C(O)(O)R', OC(O)NRR', C(O)R, C(O)NRR', N(R)S(O)2R', S(O)2R and S(O)2NRR';

[0032] R, R' are each independently H, C 1-3 alkyl or C 3-6 cycloalkyl, optionally substituted with 1, 2, or 3 substituents independently selected from halogen, OH and CN.

[0033] In another aspect, there is provided a compound represented by one of formula (Ic), formula (IIc), formula (IIIc) and formula (IVc):

[0034]

[0035] or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein:

[0036] X is CH or N;

[0037] R 1 is H, halogen or C 1-3Alkyl group, wherein the substituent is independently selected from halogen, OH, CN, OR, NHR, NRR', N(R)C(O)R', N(R)C(O)OR', OC(O)NRR', C(O)R, C(O)NRR', N(R)S(O)2R', S(O)2R and S(O)2NRR';

[0038] Ring A is a 4-7 membered heterocyclic group, which is optionally substituted by 1, 2 or 3 independent substituents selected from the following: R 2 Oxygenated, halogenated, OH, CN, OR, NHR, NRR', N(R)C(O)R', N(R)C(O)(O)R', OC(O)NRR', C(O)R, C(O)NRR', N(R)S(O)2R', S(O)2R and S(O)2NRR';

[0039] R 2 C 1-3 Alkyl, C 3-7 Cycloalkyl, 3-7-membered heterocyclic, phenyl, or 5-6-membered heteroaryl, optionally substituted by 1, 2, or 3 independently selected from the following substituents: halogen, OH, CN, OR, NHR, NRR', N(R)C(O)R', N(R)C(O)(O)R', OC(O)NRR', C(O)R, C(O)NRR', N(R)S(O)2R', S(O)2R, and S(O)2NRR';

[0040] R and R' are independently H and C, respectively. 1-3 Alkyl or C 3-6 Cycloalkyl groups, optionally substituted with one, two or three independent substituents selected from halogens, OH and CN.

[0041] In another aspect, compounds represented by one of formulas (Id), (IId), (IIId), and (IVd) are provided:

[0042] ,

[0043] Or its salts, solvates, hydrates, polymorphs, eutectics, tautomers, stereoisomers, isotopically labeled derivatives or prodrugs, wherein:

[0044] X is CH or N;

[0045] R 1 C is H, halogen, or optionally substituted with 1, 2, or 3 substituents. 1-3alkyl, said substituents are independently selected from the group consisting of halogen, OH, CN, OR, NHR, NRR', N(R)C(O)R', N(R)C(O)OR', OC(O)NRR', C(O)R, C(O)NRR', N(R)S(O)2R', S(O)2R and S(O)2NRR';

[0046] Cy is C 3-7 cycloalkyl or 3-7 membered heterocyclyl, wherein Cy is optionally substituted with 1, 2, or 3 substituents independently selected from R 2 oxo, halogen, OH, CN, OR, NHR, NRR', N(R)C(O)R', N(R)C(O)(O)R', OC(O)NRR', C(O)R, C(O)NRR', N(R)S(O)2R', S(O)2R and S(O)2NRR';

[0047] R 2 is C 1-3 alkyl, C 3-7 cycloalkyl, 3-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, optionally substituted with 1, 2, or 3 substituents independently selected from halogen, OH, CN, OR, NHR, NRR', N(R)C(O)R', N(R)C(O)(O)R', OC(O)NRR', C(O)R, C(O)NRR', N(R)S(O)2R', S(O)2R and S(O)2NRR';

[0048] R, R' are each independently H, C 1-3 alkyl or C 3-6 cycloalkyl, optionally substituted with 1, 2, or 3 substituents independently selected from halogen, OH and CN.

[0049] The compounds of the present application and compositions containing them can be used to treat or reduce the severity of a TYK2 modulated disease, disorder, or symptom thereof.

[0050] Accordingly, one aspect of the present disclosure relates to a method of treating a CNS disorder, the method comprising administering to a subject in need thereof an effective amount of a compound of Formula (I) herein, or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, which can be formulated into a composition. In some examples, the composition can be a pharmaceutical composition, which can further comprise a pharmaceutically acceptable carrier.

[0051] In some embodiments, the CNS disorder can be any of those disorders modulated by TYK2. In certain embodiments, the CNS disorder is Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, dementia, frontotemporal dementia, mild cognitive impairment (MCI), or neuroinflammation.

[0052] Also within the scope of the present disclosure are: (i) pharmaceutical compositions for treating a target CNS disorder described herein, the pharmaceutical compositions comprising a compound of Formula (I) or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, and a pharmaceutically acceptable carrier; and (ii) use of a compound of Formula (I) or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, in the manufacture of a medicament for treating any target CNS disorder.

[0053] The recitation of a list of chemical groups in any definition of a variable herein includes defining the variable as any single group or combination of listed groups. The recitation of embodiments of a variable herein includes that embodiment as any single embodiment or in combination with any other embodiment or portions thereof. The recitation of embodiments herein includes that embodiment as any single embodiment or in combination with any other embodiment or portions thereof.

[0054] The details of one or more embodiments of the application are set forth in the description below. Other features or advantages of the present application will be apparent from the following drawings and detailed description and from the appended claims.

[0055] Definitions

[0056] Unless defined otherwise, all technical and scientific terms used herein have the meaning commonly understood by one of ordinary skill in the art to which this application belongs. The following references provide one of ordinary skill with a general definition of many of the terms used in this application: Singleton et al., Dictionary of Microbiology and Molecular Biology (2nd ed. 1994); The Cambridge Dictionary of Science and Technology (Walker ed., 1988); The Glossary of Genetics, 5th Ed., R. Rieger et al. (eds.), Springer Verlag (1991); and Hale & Marham, The Harper Collins Dictionary of Biology (1991). As used herein, the following terms have the meanings ascribed to them unless specified otherwise.

[0057] The definitions of specific chemical terms are described in more detail below. Chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd. inner front cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Michael B. Smith, March’s Advanced Organic Chemistry, 7th Edition, John Wiley & Sons, Inc., New York, 2013; Richard C. Larock, Comprehensive Organic Transformations, John Wiley & Sons, Inc., New York, 2018; and Carruthers, Some Modern Methods of Organic Synthesis, 3rd Edition, Cambridge University Press, Cambridge, 1987.

[0058] The compounds described herein can contain one or more asymmetric centers and thus can exist in different stereoisomeric forms. For example, the compounds described herein can exist as single enantiomers, diastereomers or geometric isomers, or as mixtures of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. Isomers can be separated 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 the preferred isomers can be prepared by asymmetric synthesis. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel E. L., Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, S. H., Tables of Resolving Agents and Optical Resolutions p. 268 (E. L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). The present application additionally encompasses compounds as single isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

[0059] The compounds herein can also contain bonds (e.g., carbon-carbon bonds) where rotation about that particular bond is restricted, for example, by the presence of a ring or double bond. Thus, all cis / trans and E / Z isomers are expressly included in the present disclosure. The compounds herein can also be represented in multiple tautomeric forms; in such cases, the present disclosure expressly includes all tautomeric forms of the compounds described herein, even if only a single tautomeric form can be represented. All such isomeric forms of such compounds herein are expressly included in the present disclosure. The term “isomer” is intended to encompass diastereomers, enantiomers, positional isomers, structural isomers, rotamers, tautomers, and the like. For compounds containing one or more stereocenters, e.g., chiral compounds, the methods of the present disclosure can be performed with enantiomerically enriched compounds, racemates, or mixtures of diastereomers. All isomers of the compounds described herein are expressly included in the present disclosure.

[0060] In the formula, the bond is a single bond, the dashed line is a single bond or is absent, and the bond or is a single or double bond.

[0061] Unless otherwise indicated, the formulas and structures described herein include both compounds that do not include isotopically enriched atoms, and compounds that include isotopically enriched atoms. For example, in addition to hydrogen being replaced by deuterium or tritium, carbon being replaced by 18 F, or carbon being replaced by 19 F or carbon being replaced by 13 C or carbon being replaced by 14 C-enriched carbon, compounds having the structures of the present disclosure are within the scope of the present disclosure. Such compounds can be used as, for example, analytical tools or probes in biological assays.

[0062] The term “isotope” refers to a variant of a particular chemical element, such that while all isotopes of a given element share the same number of protons in each atom of that element, those isotopes differ in the number of neutrons.

[0063] When a range of values (“range”) is listed, it encompasses each value and sub-range within that range. Unless otherwise stated, the range includes the values at the ends of the range. For example, “C 1-6 “Alkyl” encompasses C1, C2, C3, C4, C5, C6, C 1-6 , C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-5 , C 2-4 , C 2-3 , C 3-6 , C 3-5 , C 3-4 , C 4-6 , C 4-5 , and C 5-6 alkyl groups.

[0064] The term “aliphatic” refers to alkyl, alkenyl, alkynyl, and carbocyclic groups. Likewise, the term “heteroaliphatic” refers to heteroalkyl, heteroalkenyl, heteroalkynyl, and heterocyclyl.

[0065] The term “alkyl” refers to a straight or branched chain saturated hydrocarbon group having from 1 to 20 carbon atoms (“C 1-20 alkyl”). In some embodiments, the alkyl group has from 1 to 12 carbon atoms (“C 1-12 alkyl”). In some embodiments, the alkyl group has from 1 to 10 carbon atoms (“C 1-10 alkyl”). In some embodiments, the alkyl group has from 1 to 9 carbon atoms (“C 1-9 alkyl”). In some embodiments, the alkyl group has from 1 to 8 carbon atoms (“C 1-8Alkyl group (“alkyl”). In some embodiments, the alkyl group has 1 to 7 carbon atoms (“C”). 1-7 Alkyl group (“alkyl”). In some embodiments, the alkyl group has 1 to 6 carbon atoms (“C”). 1-6 Alkyl group (“alkyl”). In some embodiments, the alkyl group has 1 to 5 carbon atoms (“C”). 1-5 Alkyl group (“alkyl”). In some embodiments, the alkyl group has 1 to 4 carbon atoms (“C”). 1-4 Alkyl group (“alkyl”). In some embodiments, the alkyl group has 1 to 3 carbon atoms (“C”). 1-3 Alkyl group (“alkyl”). In some embodiments, the alkyl group has 1 to 2 carbon atoms (“C”). 1-2 Alkyl group (“C1 alkyl”). In some embodiments, the alkyl group has one carbon atom (“C1 alkyl”). In some embodiments, the alkyl group has two to six carbon atoms (“C1 alkyl”). 2-6 Alkyl group). C 1-6 Examples of alkyl groups include methyl (C1), ethyl (C2), propyl (C3) (e.g., n-propyl, isopropyl), butyl (C4) (e.g., n-butyl, tert-butyl, sec-butyl, isobutyl), pentyl (C5) (e.g., n-pentyl, 3-pentyl, pentyl, neopentyl, 3-methyl-2-butyl, tert-pentyl), and hexyl (C6) (e.g., n-hexyl). Other examples of alkyl groups include n-heptyl (C7), n-octyl (C8), n-dodecyl (C9), and n-heptyl (C1). 12 ), etc. Unless otherwise stated, each instance of an alkyl group is independently unsubstituted (“unsubstituted alkyl”) or substituted (“substituted alkyl”) with one or more substituents (e.g., halogens, such as F). In some embodiments, the alkyl group is an unsubstituted C 1-12 Alkyl groups (such as unsubstituted C4) 1-6 Alkyl groups, such as -CH3 (Me), unsubstituted ethyl groups (Et), unsubstituted propyl groups (Pr, e.g., unsubstituted n-propyl (n-Pr), unsubstituted isopropyl (i-Pr)), unsubstituted butyl groups (Bu, e.g., unsubstituted n-butyl (n-Bu), unsubstituted tert-butyl (tert-Bu or t-Bu), unsubstituted sec-butyl (sec-Bu or s-Bu), unsubstituted isobutyl (i-Bu)). In some embodiments, the alkyl group is a substituted C. 1-12 Alkyl (such as substituted C) 1-6 Alkyl groups, such as -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, or benzyl (Bn)).

[0066] The term "haloalkyl" is a substituted alkyl group in which one or more hydrogen atoms are independently replaced with a halogen, such as fluorine, bromine, chlorine, or iodine. "Perhaloalkyl" is a subset of haloalkyl, referring to alkyl groups in which all hydrogen atoms are independently replaced with a halogen, such as fluorine, bromine, chlorine, or iodine. In some embodiments, the haloalkyl moiety has 1 to 20 carbon atoms ("C 1-20 haloalkyl"). In some embodiments, the haloalkyl moiety has 1 to 10 carbon atoms ("C 1-10 haloalkyl"). In some embodiments, the haloalkyl moiety has 1 to 9 carbon atoms ("C 1-9 haloalkyl"). In some embodiments, the haloalkyl moiety has 1 to 8 carbon atoms ("C 1-8 haloalkyl"). In some embodiments, the haloalkyl moiety has 1 to 7 carbon atoms ("C 1-7 haloalkyl"). In some embodiments, the haloalkyl moiety has 1 to 6 carbon atoms ("C 1-6 haloalkyl"). In some embodiments, the haloalkyl moiety has 1 to 5 carbon atoms ("C 1-5 haloalkyl"). In some embodiments, the haloalkyl moiety has 1 to 4 carbon atoms ("C 1-4 haloalkyl"). In some embodiments, the haloalkyl moiety has 1 to 3 carbon atoms ("C 1-3 haloalkyl"). In some embodiments, the haloalkyl moiety has 1 to 2 carbon atoms ("C 1-2 haloalkyl"). In some embodiments, all haloalkyl hydrogen atoms are independently replaced with fluorine to provide a "perfluoroalkyl" group. In some embodiments, all haloalkyl hydrogen atoms are independently replaced with chlorine to provide a "perchloroalkyl" group. Examples of haloalkyl groups include -CHF2, -CH2F, -CF3, -CH2CF3, -CF2CF3, -CF2CF2CF3, -CC13, -CFC12, -CF2C1, and the like.

[0067] The term "heteroalkyl" refers to an alkyl group that further comprises (e.g., is inserted between adjacent carbon atoms of) and / or bears at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur at one or more terminal positions of the parent chain. In certain embodiments, a heteroalkyl group refers to a saturated group having 1 to 20 carbon atoms and 1 or more heteroatoms in the parent chain ("heteroC 1-20 alkyl"). In certain embodiments, a heteroalkyl group refers to a saturated group having 1 to 12 carbon atoms and 1 or more heteroatoms in the parent chain ("heteroC 1-12("heteroalkyl"). In some embodiments, a heteroalkyl group is a saturated heteroatom-containing group having from 1 to 11 carbon atoms and 1 or more heteroatoms in the parent chain ("heteroC 1-11 ("heteroalkyl"). In some embodiments, a heteroalkyl group is a saturated heteroatom-containing group having from 1 to 10 carbon atoms and 1 or more heteroatoms in the parent chain ("heteroC 1-10 ("heteroalkyl"). In some embodiments, a heteroalkyl group is a saturated heteroatom-containing group having from 1 to 9 carbon atoms and 1 or more heteroatoms in the parent chain ("heteroC 1-9 ("heteroalkyl"). In some embodiments, a heteroalkyl group is a saturated heteroatom-containing group having from 1 to 8 carbon atoms and 1 or more heteroatoms in the parent chain ("heteroC 1-8 ("heteroalkyl"). In some embodiments, a heteroalkyl group is a saturated heteroatom-containing group having from 1 to 7 carbon atoms and 1 or more heteroatoms in the parent chain ("heteroC 1-7 ("heteroalkyl"). In some embodiments, a heteroalkyl group is a saturated heteroatom-containing group having from 1 to 6 carbon atoms and 1 or more heteroatoms in the parent chain ("heteroC 1-6 ("heteroalkyl"). In some embodiments, a heteroalkyl group is a saturated heteroatom-containing group having from 1 to 5 carbon atoms and 1 or 2 heteroatoms in the parent chain ("heteroC 1-5 ("heteroalkyl"). In some embodiments, a heteroalkyl group is a saturated heteroatom-containing group having from 1 to 4 carbon atoms and 1 or 2 heteroatoms in the parent chain ("heteroC 1-4 ("heteroalkyl"). In some embodiments, a heteroalkyl group is a saturated heteroatom-containing group having from 1 to 3 carbon atoms and 1 heteroatom in the parent chain ("heteroC 1-3 ("heteroalkyl"). In some embodiments, a heteroalkyl group is a saturated heteroatom-containing group having from 1 to 2 carbon atoms and 1 heteroatom in the parent chain ("heteroC 1-2 ("heteroalkyl"). In some embodiments, a heteroalkyl group is a saturated heteroatom-containing group having 1 carbon atom and 1 heteroatom ("heteroCi alkyl"). In some embodiments, a heteroalkyl group is a saturated heteroatom-containing group having from 2 to 6 carbon atoms and 1 or 2 heteroatoms in the parent chain ("heteroC 2-6 ("heteroalkyl"). Unless otherwise indicated, each instance of a heteroalkyl group is independently unsubstituted ("unsubstituted heteroalkyl") or substituted ( "substituted heteroalkyl") with one or more substituents. In certain embodiments, the heteroalkyl group is an unsubstituted heteroC 1-12 ("heteroalkyl"). In certain embodiments, the heteroalkyl group is a substituted heteroC 1-12 ("heteroalkyl"). In certain embodiments, the heteroalkyl group is a substituted heteroC

[0068] The term "alkenyl" refers to a straight-chain or branched hydrocarbon group having from 2 to 20 carbon atoms and one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 double bonds). In some embodiments, an alkenyl group has 2 to 20 carbon atoms ("C2-20 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 12 carbon atoms (“C”). 2-12 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 11 carbon atoms (“C”). 2-11 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 10 carbon atoms (“C”). 2-10 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 9 carbon atoms (“C”). 2-9 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 8 carbon atoms (“C”). 2-8 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 7 carbon atoms (“C”). 2-7 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 6 carbon atoms (“C”). 2-6 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 5 carbon atoms (“C”). 2-5 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 4 carbon atoms (“C”). 2-4 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 3 carbon atoms (“C”). 2-3 The alkenyl group has two carbon atoms (“C2 alkenyl”). The one or more carbon-carbon double bonds may be internal (e.g., in a 2-butenyl group) or terminal (e.g., in a 1-butenyl group). 2-4 Examples of alkenyl groups include vinyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), and butadienyl (C4), etc. 2-6 Examples of alkenyl groups include the C mentioned above. 2-4 Alkenyl groups include pentenyl (C5), pentadienyl (C5), hexenyl (C6), etc. Other examples of alkenyl groups include heptenyl (C7), octenyl (C8), octetrinyl (C8), etc. Unless otherwise stated, each example of an alkenyl group is independently unsubstituted (“unsubstituted alkenyl”) or substituted (“substituted alkenyl”) with one or more substituents. In some embodiments, the alkenyl group is an unsubstituted C5 group. 2-20 Alkenyl group. In some embodiments, the alkenyl group is a substituted C group. 2-20 Alkenyl group. In the alkenyl group, a stereochemically unspecified C=C double bond (e.g., -CH=CHCH3 or...) It can be in (E)- or (Z)- configuration.

[0069] The term "heteroalkenyl" refers to an alkenyl group that further comprises (e.g., is inserted between adjacent carbon atoms of) and / or bears at one or more terminal positions of the parent chain, and / or one or more heteroatoms (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur. In certain embodiments, a heteroalkenyl group refers to a group having 2 to 20 carbon atoms, at least one double bond, and 1 or more heteroatoms in the parent chain ("heteroC 2-20 alkenyl"). In certain embodiments, a heteroalkenyl group refers to a group having 2 to 12 carbon atoms, at least one double bond, and 1 or more heteroatoms in the parent chain ("heteroC 2-12 alkenyl"). In certain embodiments, a heteroalkenyl group refers to a group having 2 to 11 carbon atoms, at least one double bond, and 1 or more heteroatoms in the parent chain ("heteroC 2-11 alkenyl"). In certain embodiments, a heteroalkenyl group refers to a group having 2 to 10 carbon atoms, at least one double bond, and 1 or more heteroatoms in the parent chain ("heteroC 2-10 alkenyl"). In some embodiments, a heteroalkenyl group has 2 to 9 carbon atoms, at least one double bond, and 1 or more heteroatoms in the parent chain ("heteroC 2-9 alkenyl"). In some embodiments, a heteroalkenyl group has 2 to 8 carbon atoms, at least one double bond, and 1 or more heteroatoms in the parent chain ("heteroC 2-8 alkenyl"). In some embodiments, a heteroalkenyl group has 2 to 7 carbon atoms, at least one double bond, and 1 or more heteroatoms in the parent chain ("heteroC 2-7 alkenyl"). In some embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or more heteroatoms in the parent chain ("heteroC 2-6 alkenyl"). In some embodiments, a heteroalkenyl group has 2 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms in the parent chain ("heteroC 2-5 alkenyl"). In some embodiments, a heteroalkenyl group has 2 to 4 carbon atoms, at least one double bond, and 1 or 2 heteroatoms in the parent chain ("heteroC 2-4 alkenyl"). In some embodiments, a heteroalkenyl group has 2 to 3 carbon atoms, at least one double bond, and 1 heteroatom in the parent chain ("heteroC 2-3 alkenyl"). In some embodiments, a heteroalkenyl group has 2 carbon atoms, at least one double bond, and 1 heteroatom in the parent chain ("heteroC2alkenyl"). In some embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms in the parent chain ("heteroC 2-6("alkenyl"). Unless otherwise stated, each instance of a heteroalkenyl group is independently unsubstituted ("unsubstituted heteroalkenyl") or substituted ("substituted heteroalkenyl") with one or more substituents. In some embodiments, the heteroalkenyl group is an unsubstituted heteroalkenyl group. 2-20 Alkenyl group. In some embodiments, the heteroalkenyl group is a substituted heteroC group. 2-20 Alkenyl group.

[0070] The term "alkynyl" refers to a straight-chain or branched hydrocarbon group ("C-Hydroxy") having 2 to 20 carbon atoms and one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 triple bonds). 1-20 The alkynyl group has 2 to 10 carbon atoms (“C10”). In some embodiments, the alkynyl group has 2 to 10 carbon atoms (“C10”). 2-10 The alkynyl group (“C”) is present in some embodiments. In some embodiments, the alkynyl group has 2 to 9 carbon atoms (“C”). 2-9 The alkynyl group (“C”) is present in some embodiments. In some embodiments, the alkynyl group has 2 to 8 carbon atoms (“C”). 2-8 The alkynyl group (“C”) is present in some embodiments. In some embodiments, the alkynyl group has 2 to 7 carbon atoms (“C”). 2-7 The alkynyl group (“C”) has 2 to 6 carbon atoms in some embodiments. 2-6 The alkynyl group (“C”) is present in some embodiments. In some embodiments, the alkynyl group has 2 to 5 carbon atoms (“C”). 2-5 The alkynyl group (“C”) is present in some embodiments. In some embodiments, the alkynyl group has 2 to 4 carbon atoms (“C”). 2-4 The alkynyl group (“C”) is present in some embodiments. In some embodiments, the alkynyl group has 2 to 3 carbon atoms (“C”). 2-3 The alkynyl group (“C2-alkynyl”) is present in some embodiments. The one or more carbon-carbon triple bonds may be internal (e.g., in 2-butynyl) or terminal (e.g., in 1-butynyl). 2-4 Examples of alkynyl groups include, but are not limited to, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), etc. 2-6 Examples of alkenyl groups include the C mentioned above. 2-4 The alkynyl group includes pentyynyl (C5), hexynyl (C6), etc. Other examples of alkynyl groups include heptynyl (C7), octyynyl (C8), etc. Unless otherwise stated, each example of an alkynyl group is independently unsubstituted (“unsubstituted alkynyl”) or substituted (“substituted alkynyl”) with one or more substituents. In some embodiments, the alkynyl group is an unsubstituted C5 group. 2-20 Alkyne group. In some embodiments, the alkynyl group is a substituted C group. 2-20 Alkyne group.

[0071] The term "heteroalkynyl" refers to an alkynyl group that further comprises (e.g., is inserted between adjacent carbon atoms of) and / or bears at one or more terminal positions of the parent chain one or more heteroatoms, e.g., 1, 2, 3, or 4 heteroatoms, selected from oxygen, nitrogen, or sulfur. In certain embodiments, a heteroalkynyl group refers to a group having 2 to 20 carbon atoms, at least one triple bond, and 1 or more heteroatoms in the parent chain ("heteroC 2-20 alkynyl"). In certain embodiments, a heteroalkynyl group refers to a group having 2 to 10 carbon atoms, at least one triple bond, and 1 or more heteroatoms in the parent chain ("heteroC 2-10 alkynyl"). In some embodiments, a heteroalkynyl group has 2 to 9 carbon atoms, at least one triple bond, and 1 or more heteroatoms in the parent chain ("heteroC 2-9 alkynyl"). In some embodiments, a heteroalkynyl group has 2 to 8 carbon atoms, at least one triple bond, and 1 or more heteroatoms in the parent chain ("heteroC 2-8 alkynyl"). In some embodiments, a heteroalkynyl group has 2 to 7 carbon atoms, at least one triple bond, and 1 or more heteroatoms in the parent chain ("heteroC 2-7 alkynyl"). In some embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or more heteroatoms in the parent chain ("heteroC 2-6 alkynyl"). In some embodiments, a heteroalkynyl group has 2 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms in the parent chain ("heteroC 2-5 alkynyl"). In some embodiments, a heteroalkynyl group has 2 to 4 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms in the parent chain ("heteroC 2-4 alkynyl"). In some embodiments, a heteroalkynyl group has 2 to 3 carbon atoms, at least one triple bond, and 1 heteroatom in the parent chain ("heteroC 2-3 alkynyl"). In some embodiments, a heteroalkynyl group has 2 carbon atoms, at least one triple bond, and 1 heteroatom in the parent chain ("heteroC2alkynyl"). In some embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms in the parent chain ("heteroC 2-6 alkynyl"). Unless otherwise specified, each instance of a heteroalkynyl group is independently unsubstituted ("unsubstituted heteroalkynyl") or substituted ( "substituted heteroalkynyl") with one or more substituents. In certain embodiments, the heteroalkynyl group is unsubstituted heteroC 2-20 alkynyl. In certain embodiments, the heteroalkynyl group is substituted heteroC 2-20 alkynyl.

[0072] The term "carbocyclyl" or "carbocyclic" refers to a non-aromatic cyclic hydrocarbon group having from 3 to 14 ring carbon atoms and 0 heteroatoms in the non-aromatic ring system ("C 3-14 carbocyclyl"). In some embodiments, the carbocyclyl group has 3 to 14 ring carbon atoms ("C 3-14 carbocyclyl"). In some embodiments, the carbocyclyl group has 3 to 13 ring carbon atoms ("C 3-13 carbocyclyl"). In some embodiments, the carbocyclyl group has 3 to 12 ring carbon atoms ("C 3-12 carbocyclyl"). In some embodiments, the carbocyclyl group has 3 to 11 ring carbon atoms ("C 3-11 carbocyclyl"). In some embodiments, the carbocyclyl group has 3 to 10 ring carbon atoms ("C 3-10 carbocyclyl"). In some embodiments, the carbocyclyl group has 3 to 8 ring carbon atoms ("C 3-8 carbocyclyl"). In some embodiments, the carbocyclyl group has 3 to 7 ring carbon atoms ("C 3-7 carbocyclyl"). In some embodiments, the carbocyclyl group has 3 to 6 ring carbon atoms ("C 3-6 carbocyclyl"). In some embodiments, the carbocyclyl group has 4 to 6 ring carbon atoms ("C 4-6 carbocyclyl"). In some embodiments, the carbocyclyl group has 5 to 6 ring carbon atoms ("C 5-6 carbocyclyl"). In some embodiments, the carbocyclyl group has 5 to 10 ring carbon atoms ("C 5-10 carbocyclyl"). Exemplary C 3-6 carbocyclyl groups include cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like. Exemplary C 3-8 carbocyclyl groups include the above C 3-6 carbocyclyl groups as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptyl (C7), bicyclo[2.2.2]octyl (C8), and the like. Exemplary C 3-10 carbocyclyl groups include the above C 3-8 carbocyclyl groups as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-lH-indenyl (C9), decahydronaphthalenyl (C 10 ), spiro[4.5]decyl (C10 ), etc. Example C 3-8 The carbocyclic group includes the above-mentioned C 3-10 Carbocyclic groups and cycloundecyl (C 11 ), spiro[5.5]undecyl (C 11 ), cyclododecyl (C 12 ), cyclododecenyl (C 12 ), cyclotridecane (C 13 ), cyclotetradecane (C 14 As illustrated in the foregoing embodiments, in some embodiments, the carbocyclic group is monocyclic (“monocyclic carbocyclic”) or polycyclic (e.g., comprising fused, bridged, or spirocyclic systems, such as bicyclic systems (“bicyclic carbocyclic”) or tricyclic systems (“tricyclic carbocyclic”)) and may be saturated or may contain one or more carbon-carbon double or triple bonds. “Carbocyclic” also includes ring systems in which the carbon ring as defined above is fused with one or more aryl or heteroaryl groups, wherein the connection point is on the carbocyclic ring, and in this case, the carbon number continues to represent the number of carbon atoms in the carbocyclic system. Unless otherwise stated, each instance of a carbocyclic group is independently unsubstituted (“unsubstituted carbocyclic”) or substituted (“substituted carbocyclic”) with one or more substituents. In some embodiments, the carbocyclic group is an unsubstituted C 3-14 Carbocyclic group. In some embodiments, the carbocyclic group is a substituted C 3-14 Carbon cyclic group.

[0073] In some embodiments, "carbocyclic group" is a monocyclic, saturated carbocyclic group having 3 to 14 ring carbon atoms ("C"). 3-14 cycloalkyl group (“Cycloalkyl”). In some embodiments, the cycloalkyl group has 3 to 10 cyclic carbon atoms (“C”). 3-10 cycloalkyl group (“Cycloalkyl”). In some embodiments, the cycloalkyl group has 3 to 8 cyclic carbon atoms (“C”). 3-8 cycloalkyl group (“Cycloalkyl”). In some embodiments, the cycloalkyl group has 3 to 6 cyclic carbon atoms (“C”). 3-6 cycloalkyl group (“Cycloalkyl”). In some embodiments, the cycloalkyl group has 4 to 6 cyclic carbon atoms (“C”). 4-6 cycloalkyl group (“Cycloalkyl”). In some embodiments, the cycloalkyl group has 5 to 6 cyclic carbon atoms (“C”). 5-6 cycloalkyl group (“Cycloalkyl”). In some embodiments, the cycloalkyl group has 5 to 10 cyclic carbon atoms (“C”). 5-10 cycloalkyl). C 5-6 Examples of cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). 3-6 Examples of cycloalkyl groups include the C10 group described above. 5-6cycloalkyl groups and cyclopropyl (C3) and cyclobutyl (C4). Examples of cycloalkyl groups include the above-mentioned C 3-8 cycloalkyl groups and cyclopropyl (C3) and cyclobutyl (C4). Examples of cycloalkyl groups include the above-mentioned C 3-6 cycloalkyl groups and cyclopropyl (C3) and cyclobutyl (C4). Examples of cycloalkyl groups include the above-mentioned C 3-14 cycloalkyl groups and cyclopropyl (C3) and cyclobutyl (C4). Examples of cycloalkyl groups include the above-mentioned C 3-14 cycloalkyl groups and cyclopropyl (C3) and cyclobutyl (C4). Examples of cycloalkyl groups include the above-mentioned C

[0074] The term "heterocyclyl" or "heterocycle" refers to a 3- to 14-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("3-14 membered heterocyclyl"). In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment can be a carbon atom or a nitrogen atom, if valence permits. Heterocyclyl groups can be monocyclic ("monocyclic heterocyclyl") or polycyclic (e.g., a fused, bridged or spiro ring system, such as a bicyclic ring system ("bicyclic heterocyclyl") or a tricyclic ring system ("tricyclic heterocyclyl")), and can be saturated or can contain one or more carbon-carbon double bonds or triple bonds. Heterocyclyl polycyclic ring systems can include one or more heteroatoms in one or both rings. "Heterocyclyl" also includes ring systems in which a heterocycle as defined above is fused to one or more carbocyclic rings, wherein the point of attachment is on the carbocyclic or heterocyclyl ring, or ring systems in which a heterocyclyl ring as defined above is fused to one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in this case the number of ring members continues to designate the number of ring members in the heterocyclyl ring system. Unless otherwise specified, each instance of a heterocyclyl group is independently unsubstituted ("unsubstituted heterocyclyl") or substituted ("substituted heterocyclyl") with one or more substituents. 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. In certain embodiments, the heterocyclyl is a substituted or unsubstituted, 3- to 7- membered, monocyclic heterocyclyl, wherein 1, 2, or 3 atoms in the heterocyclic ring system are independently oxygen, nitrogen, or sulfur, as valence permits.

[0075] In some embodiments, the heterocyclyl group is a 5-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heterocyclyl”). In some embodiments, the heterocyclyl group is a 5-8 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heterocyclyl”). In some embodiments, the heterocyclyl group is a 5-6 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heterocyclyl”). In some embodiments, the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0076] Exemplary 3-membered heterocyclyl groups containing 1 heteroatom include azirdinyl, oxiranyl, and thiiranyl. Exemplary 4-membered heterocyclyl groups containing 1 heteroatom include azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing 1 heteroatom include tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing 2 heteroatoms include dioxolanyl, oxasulfurolanyl, and dithiolanyl. Exemplary 5-membered heterocyclyl groups containing 3 heteroatoms include triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing 1 heteroatom include piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing 2 heteroatoms include piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing 3 heteroatoms include triazinyl. Exemplary 7-membered heterocyclyl groups containing 1 heteroatom include azepanyl, oxepanyl, and thiepanyl. Exemplary 8-membered heterocyclyl groups containing 1 heteroatom include azocanyl, oxecanyl, and thieocanyl. Exemplary bicyclic heterocyclyl groups include indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, tetrahydrobenzothiophenyl, tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl, decahydronaphthalenyl, decahydro-l,8-naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole, indolinyl, phthalimidyl, naphthalimidyl, chromanyl, chromenyl, lH-benzo[e][l,4]diazepinyl, 1,4,5,7-tetrahydropyrano[3,4-b]pyrrolyl, 5,6-dihydro-4H-furo[3,2-b]pyrrolyl, 6,7-dihydro-5H-furo[3,2-b]pyranyl, 5,7-dihydro-4H-thieno[2,3-c]pyranyl, 2,3-dihydro-lH-pyrrolo[2,3-b]pyridinyl, 2,3-dihydrofuro[2,3-b]pyridinyl, 4,5,6,7-tetrahydro-lH-pyrrolo[2,3-b]pyridinyl, 4,5,6,7-tetrahydrofuro[3,2-c]pyridinyl, 4,5,6,7-tetrahydrothieno[3,2-b]pyridinyl, 1,2,3,4-tetrahydro-l,6-naphthyridinyl, and the like.

[0077] The term "aryl" means a monocyclic or polycyclic (such as bicyclic or tricyclic) 4n+2 aromatic ring system (such as having 6, 10, or 14 p electrons shared in a cyclic arrangement) and having 6-14 ring carbon atoms and 0 heteroatoms in the aromatic ring system ("C 6-14Aryl group (“C6 aryl”). In some embodiments, the aryl group has six ring carbon atoms (“C6 aryl”; such as phenyl). In some embodiments, the aryl group has ten ring carbon atoms (“C6 aryl”). 10 "Aryl"; such as naphthyl (e.g., 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has fourteen ring carbon atoms ("C"). 14 "Aryl" (e.g., anthracene). "Aryl" also includes ring systems in which the aryl ring, as defined above, is fused with one or more carbocyclic or heterocyclic groups, wherein a linking group or linking point is located on the aryl ring, and in this case, the number of carbon atoms continues to be specified as the number of carbon atoms in the aryl ring system. Specific aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl. Unless otherwise stated, each instance of an aryl group is independently unsubstituted ("unsubstituted aryl") or substituted ("substituted aryl") with one or more substituents. In some embodiments, the aryl group is an unsubstituted C 6-14 Aryl group. In some embodiments, the aryl group is a substituted C. 6-14 Aryl.

[0078] "Aryl" is a subset of "alkyl" and refers to an alkyl group that is replaced by an aryl group, wherein the connection point is on the alkyl portion.

[0079] The term "heteroaryl" refers to a radical providing a 5- to 14-membered monocyclic or polycyclic (e.g., bicyclic, tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic array) having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is 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 a carbon or a nitrogen atom, as valency permits. Heteroaryl polycyclic ring systems can contain one or more heteroatoms within one or both rings. "Heteroaryl" includes ring systems in which a heteroaryl ring as defined above is fused to one or more carbocyclic or heterocyclyl groups, wherein the point of attachment is on the heteroaryl ring and, in that case, the number of ring members continues to be designated as the number of ring members in the heteroaryl ring system. "Heteroaryl" also includes ring systems in which a heteroaryl ring as defined above is fused to one or more aryl groups, wherein the point of attachment is on the aryl or heteroaryl ring and, in that case, the number of ring members continues to be designated as the number of ring members in the fused polycyclic (aryl / heteroaryl) ring system. In polycyclic heteroaryl groups in which one ring does not contain a heteroatom (e.g., indolyl, quinolyl, carbazolyl, etc.), the point of attachment can be on either one of the two rings, i.e., on the ring having a heteroatom (e.g., 2-indolyl) or on the ring not containing a heteroatom (e.g., 5-indolyl). In certain embodiments, the heteroaryl group is a substituted or unsubstituted, 5- or 6-membered, monocyclic heteroaryl group in which 1, 2, 3, or 4 atoms of the heteroaryl ring system are independently oxygen, nitrogen, or sulfur. In certain embodiments, the heteroaryl group is a substituted or unsubstituted 9- or 10-membered bicyclic heteroaryl group in which 1, 2, 3, or 4 atoms of the heteroaryl ring system are independently oxygen, nitrogen, or sulfur.

[0080] In some embodiments, a heteroaryl group is a 5-10 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5-8 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heteroaryl”). In some embodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise indicated, each instance of a heteroaryl group is independently unsubstituted (“unsubstituted heteroaryl”) or substituted (“substituted heteroaryl”) with one or more substituents. In certain embodiments, the heteroaryl group is an unsubstituted 5-14 membered heteroaryl. In certain embodiments, the heteroaryl group is a substituted 5-14 membered heteroaryl.

[0081] Exemplary 5-membered heteroaryl groups containing 1 heteroatom include pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing 2 heteroatoms include imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing 3 heteroatoms include triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing 4 heteroatoms include tetrazolyl. Exemplary 6-membered heteroaryl groups containing 1 heteroatom include pyridinyl. Exemplary 6-membered heteroaryl groups containing 2 heteroatoms include pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing 3 or 4 heteroatoms include triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing 1 heteroatom include azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzoimidazolyl, benzoxazolyl, benzoisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzoisothiazolyl, benzothiadiazy, cinnolinyl, phthalazinyl, and quinazolinyl. Exemplary 6,6-bicyclic heteroaryl groups include naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. Exemplary tricyclic heteroaryl groups include phenanthridinyl, phenoxathiinyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl, and phenazinyl.

[0082] "Heteroaralkyl" is a subset of "alkyl" and refers to an alkyl radical as defined herein that is substituted with a heteroaryl radical, wherein the point of attachment is on the alkyl moiety.

[0083] The term "unsaturated" or "partially unsaturated" means a moiety that contains at least one double or triple bond.

[0084] The term "unsaturated" or "partially unsaturated" means a moiety that contains at least one double or triple bond.

[0085] The term "saturated" or "fully saturated" means a moiety that does not contain a double or triple bond, e.g., a moiety that contains only single bonds.

[0086] The suffix "-ene" appended to a group indicates that the group is a divalent moiety, e.g., alkylene is a divalent moiety of an alkyl group, alkenylene is a divalent moiety of an alkenyl group, alkynylene is a divalent moiety of an alkynyl group, heteroalkylene is a divalent moiety of a heteroalkyl group, heteroalkenylene is a divalent moiety of a heteroalkenyl group, heteroalkynylene is a divalent moiety of a heteroalkynyl group, carbocyclylene is a divalent moiety of a carbocyclic group, heterocyclylene is a divalent moiety of a heterocyclic group, arylene is a divalent moiety of an aryl group, heteroarylene is a divalent moiety of a heteroaryl group.

[0087] Unless explicitly otherwise stated, a group is optionally substituted. The term "optionally substituted" means substituted or unsubstituted. In certain embodiments, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted. "Optionally substituted" means an unsubstituted or substituted group (e.g., a "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 the group is replaced with an allowable substituent, for example, a substituent that, when substituted, generates a stable compound, for example, 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 is substituted in any given structure, the substituents can be on the same or different atoms. It is contemplated that the term "substituted" includes substitution with all allowable substituents of organic compounds and includes any substituents described herein that result in the formation of a stable compound. The present application encompasses any and all such combinations to yield stable compounds. For purposes of this application, heteroatoms such as nitrogen can have hydrogen substituents and / or any suitable substituent as described herein that satisfies valency requirements of the heteroatom and results in the formation of a stable moiety. The present application is not in any way limited to the exemplary substituents described herein.

[0088] The term "halo" or "halogen" means fluoro (fluorine, -F), chloro (chlorine, -Cl), bromo (bromine, -Br), or iodo (iodine, -I).

[0089] The term "hydroxyl" or "hydroxy" means the group -OH. By extension, the term "substituted hydroxyl" or "substituted hydroxy" means a hydroxyl group in which the oxygen atom directly attached to the parent molecule is replaced with a group other than hydrogen, and includes groups selected from: aa , -ON(R bb )2, -OC(=O)SR aa , -OC(=O)R aa , -OCO2R aa , -OC(=O)N(R bb )2, -OC(=NR bb )R aa , -OC(=NR bb )ORaa , -OC(=NR bb )N(R bb )2, -OS(=O)R aa , -OSO2R aa , -OSi(R aa )3, -OP(R cc )2, -OP(R cc )3 + X - , -OP(OR cc )2, -OP(OR cc )3 + X - , -OP(=O)(R aa )2, -OP(=O)(OR cc )2, and -OP(=O)(N(R bb ))2, wherein X - , R aa , R bb , and R cc are as defined herein.

[0090] The term "amino" refers to the group -NH2. By extension, the term "substituted amino" refers to a mono-substituted amino group, a di-substituted amino group, or a tri- substituted amino group. In certain embodiments, the "substituted amino" is a mono- substituted amino group or a di-substituted amino group.

[0091] The term "acyl" refers to a group of the general formula -C(=O)R X1 , -C(=O)OR X1 , -C(=O)-O-C(=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)S(R X1 ), -C(=NR X1 )R X1 , -C(=NR X1 )OR X1 , -C(=NR X1 )SR X1 , and -C(=NR X1 )N(R X1 )2, wherein R X1hydrogen; 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, aliphatic oxy, heteroaliphatic oxy, alkyl oxy, heteroalkyl oxy, aryl oxy, heteroaryl oxy, aliphatic thioxy, heteroaliphatic thioxy, alkyl thioxy, heteroalkyl thioxy, aryl thioxy, heteroaryl thioxy, mono- or di- aliphatic amino, mono- or di-heteroaliphatic amino, mono- or di-alkyl amino, mono- or di-heteroalkyl amino, mono- or di-aryl amino, or mono- or di-heteroaryl amino; or two R X1 groups together form a 5- to 6-membered heterocyclic ring. Exemplary acyl groups include aldehyde (-CHO), carboxylic acid (-CO2H), ketone, acyl halide, ester, amide, imine, carbonate, carbamate, and urea. Acyl substituents include, but are not limited to, any 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, thia, cyano, isocyano, amino, azido, nitro, hydroxyl, thiol, halogen, aliphatic amino, heteroaliphatic amino, alkyl amino, heteroalkyl amino, aryl amino, heteroaryl amino, alkyl aryl, aryl alkyl, aliphatic oxy, heteroaliphatic oxy, alkyl oxy, heteroalkyl oxy, aryl oxy, heteroaryl oxy, aliphatic thioxy, heteroaliphatic thioxy, alkyl thioxy, heteroalkyl thioxy, aryl thioxy, heteroaryl thioxy, acyloxy, etc., each of which can or can not be further substituted).

[0092] The term "carbonyl" refers to a group -C(=0)- in which the carbon is sp 2 hybridized and substituted with an oxygen, nitrogen, or sulfur atom, for example, a group selected from ketone (-C(=0)R aa ), carboxylic acid (-CO2H), aldehyde (-CHO), ester (-CO2R aa , -C(=0)SR aa , -C(=S)SR aa ), amide (-C(=0)N(R bb )2, -C(=0)NR bb SO2R aa , -C(=S)N(R bb )2), and imine (-C(=NR bb )R aa , -C(=NR bb)OR aa ), -C(=NR bb )N(R bb )2), wherein R aa and R bb are as defined herein.

[0093] The term“oxo” refers to the group =O, and the term“thiooxo” refers to the group =S.

[0094] Nitrogen atoms can be substituted or unsubstituted as valence allows, and include primary, secondary, tertiary, and quaternary nitrogen atoms.

[0095] A“counterion” or“anionic counterion” is a negatively charged group associated with a positively charged group to maintain charge neutrality. An anionic counterion can be monovalent (e.g., include one formal negative charge). An anionic counterion can also be multivalent (e.g., include more than one formal negative charge), such as divalent or trivalent. Exemplary counterions include halide ions (e.g., F - , Cl - , Br - , I - ), NO3 - , ClO4 - , OH - , H2PO4 - , HCO3 - , HSO4 - , sulfonate ions (e.g., methanesulfonate, trifluoromethanesulfonate, p-toluenesulfonate, benzenesulfonate, 10-camphorsulfonate, naphthalene-2-sulfonate, naphthalene-1 -sulfonic acid-5-sulfonate, ethane-1 -sulfonic acid-2-sulfonate, etc.), carboxylate ions (e.g., acetate, propionate, benzoate, glycerate, lactate, tartrate, glycolate, gluconate, etc.), BF4 - , PF4 - , PF6 - , AsF6 - , SbF6 - , B[3,5-(CF3)2C6H3]4 - , B(C6F5)4 - , BPh4 - , Al(OC(CF3)3)4 - , and carborane anions (e.g., CB 11 H 12 - or (HCB 11 Me5Br6) - ). Exemplary counterions (which can be multivalent) include CO3 2- , HPO42- PO4 3- B4O7 2- SO4 2- S2O3 2- carboxylate anions (e.g., tartrate, citrate, fumarate, maleate, malate, malonate, gluconate, succinate, glutarate, adipate, pimelate, suberate, azelate, sebacate, salicylate, phthalate, aspartate, glutamate, etc.) and carboranes.

[0096] The use of the phrase“at least one instance” means 1, 2, 3, 4, or more instances, but also encompasses ranges, for example, 1 to 4, 1 to 3, 1 to 2, 2 to 4, 2 to 3, or 3 to 4 instances, inclusive of the end values.

[0097] “Non-hydrogen group” means any group defined with respect to a particular variable that is not hydrogen.

[0098] These and other exemplary substituents are described in more detail in the detailed description, examples, and claims. The application is not in any way limited by the above list of exemplary substituents.

[0099] As used herein, the term "salt" refers to any and all salts, and encompasses pharmaceutically acceptable salts. Salts include ionic compounds that result from the neutralization reaction of an acid and a base. Salts consist of one or more cations (positively charged ions) and one or more anions (negative ions), and thus salts are electrically neutral (have no net charge). Salts of the compounds of the present application include those derived from inorganic and organic acids and bases. Examples of acid addition salts are salts of an amino group 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 salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, hippurate, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N + (C 1-4 alkyl)4 salts. Representative alkali or alkaline earth salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further salts include ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

[0100] The term "pharmaceutically acceptable salt" means those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this application include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group with inorganic acids such as hydrochloric, hydrobromic, phosphoric, sulfuric, and perchloric acid, or with organic acids such as acetic, oxalic, maleic, tartaric, citric, succinic, or malonic acids, or by using other methods known in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, besylate, benzenesulfonate, bisulfate, bisulfite, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. + (C 1-4 alkyl)4 - Salts. Representative alkali or alkaline earth salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.

[0101] The term "solvate" refers to a form of a compound or salt thereof that is associated with a solvent, typically by a solvated reaction. This physical association can include hydrogen bonding. Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, and the like. The compounds described herein can be prepared, for example, in crystalline form, and can be solvated. Suitable solvates include pharmaceutically acceptable solvates, and further include stoichiometric solvates and non-stoichiometric solvates. In certain instances, the solvate will be capable of isolation, for example, where the solvent molecule is incorporated in the crystal lattice of the solid state form of the compound. "Solvate" embraces both solution-phase and isolatable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

[0102] The term "hydrate" refers to a compound associated with water. Typically, the number of water molecules included in a hydrate of a compound has a certain ratio to the number of molecules of the compound in the hydrate. Thus, a hydrate of a compound can be represented, for example, by the general formula R x H2O, where R is the compound and x is a number greater than 0. A given compound can form more than one type of hydrate, including, for example, monohydrates (x is 1), hemihydrates (x is a number greater than 0 and less than 1, such as a hemihydrate (R 0.5 H2O)), and polyhydrates (x is a number greater than 1, such as dihydrates (R 2 H2O) and hexahydrates (R 6 H2O)).

[0103] The term "tautomer" or "tautomerism" refers to two or more compounds that are interconvertible by the formal migration of a hydrogen atom and at least one change in the valence state (e.g., single bond to double bond, triple bond to single bond, or vice versa). The exact proportion of tautomers depends on several factors, including temperature, solvent, and pH. Tautomerization (i.e., the reaction that provides a tautomeric pair) can be catalyzed by an acid or a base. Exemplary tautomerizations include keto-to-enol, amide-to-imide, lactam-to-lactim, enamine-to-imine, and enamine-to-(different enamine) tautomerizations.

[0104] It is also to be understood that a compound having the same molecular formula but differing in the arrangement of atoms in space is termed an "isomer." Isomers that differ in the arrangement of atoms in space are termed "stereoisomers."

[0105] Stereoisomers that are not mirror images of one another are called "diastereomers" those that are mirror images of one another are called "enantiomers". When a compound has an asymmetric center marked by the presence of four different groups bonded to it, then a pair of enantiomers is possible. Enantiomers can be characterized by their absolute configuration, which is designated as either R- or S-, according to the Cahn and Prelog R- and S-sequencing rules. Alternatively, they can be designated as (+) or (-) merely based on the direction which they rotate plane-polarized light and are named as (+) or (-)-isomers. Chiral compounds can exist as either individual, non-racemic enantiomers or as mixtures of their enantiomers, which are called racemates, often designated as (+ / -)-isomers.

[0106] The term "polymorph" refers to crystalline forms of a compound (or a salt, hydrate or solvate thereof). All polymorphs have the same elemental composition. Different crystalline forms often have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and solubility. Factors such as re-crystallization solvent, rate of crystallization, storage temperature, and the like can cause one crystal form to dominate over another. Various polymorphs of a compound can be prepared by crystallization under different conditions.

[0107] The term "co-crystal" refers to a crystal structure comprising at least two different components (e.g., a compound and an acid), wherein each component is independently an atom, ion, or molecule. In certain embodiments, none of the components are solvents. In certain embodiments, at least one component is a solvent. A co-crystal of a compound and an acid is different from a salt formed from the compound and the acid. In a salt, the compound and the acid are complexed in a way that proton transfer from the acid to the compound readily occurs (e.g., complete proton transfer) at room temperature. In a co-crystal, however, the compound and the acid are complexed in a way that proton transfer from the acid to the compound does not readily occur at room temperature. In certain embodiments, in a co-crystal, substantially no proton transfer from the acid to the compound occurs. In certain embodiments, in a co-crystal, some proton transfer from the acid to the compound occurs. Co-crystals can be used to improve the properties of a compound (e.g., solubility, stability, and ease of formulation).

[0108] The term "prodrug" refers to a compound having a cleavable group and becomes a compound described herein by solvolysis or under physiological conditions, which has pharmaceutical activity in vivo. Examples of such include, but are not limited to, choline ester derivatives and the like, N-alkylmorphology ester and the like. Other derivatives of the compounds described herein, which have the appropriate metabolic liabilities, can be in both their acid and acid derivative forms, but the acid sensitive form often offers advantages of solubility, tissue compatibility, or delayed release in a mammalian organism (see, Bundgaard, H., Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs include acid derivatives well known to those skilled in the art, for example, esters prepared by reaction of the parent acid with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a substituted or unsubstituted amine, or anhydride or mixed anhydride. Simple aliphatic or aromatic esters, amides and anhydrides of the acidic groups side chains on the compounds described herein are particular prodrugs. In some cases, it is desirable to make bis-ester type prodrugs, such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkyl esters. C1-C8alkyl esters, C2-C8alkenyl esters, C2-C8alkynyl esters, aryl esters, C7-C12substituted aryl esters, and C7-C12aralkyl esters of the compounds described herein can be preferred.

[0109] The terms "composition" and "formulation" are used interchangeably.

[0110] A "subject" intended for administration refers to a human (i.e., a male or female of any age group, such as a pediatric subject (e.g., an infant, a child, or an adolescent) or an adult subject (e.g., an adolescent, a middle-aged person, 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 monkey or a rhesus monkey), a commercially relevant mammal (e.g., a cow, a pig, a horse, a sheep, a goat, a cat, or a dog), or a bird (e.g., a commercially relevant bird, such as 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 can be a male or a female at any stage of development. The non-human animal can be a transgenic animal or a genetically engineered animal. The term "patient" refers to a human subject in need of treatment for a disorder or a disease.

[0111] 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.

[0112] The terms“treatment,”“treat,” and“treating” refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disorder or disease described herein. In some embodiments, treatment can be administered after one or more signs or symptoms of the disease have occurred or have been observed. In other embodiments, treatment can be administered in the absence of signs or symptoms of the disorder. For example, treatment can be administered to a susceptible subject pre-symptomatically (e.g., in light of a history of symptoms and / or in light of exposure to a pathogen). Treatment can also be continued after symptoms have resolved, for example, to delay or prevent their recurrence.

[0113] The terms“disorder,”“disease,” and“disorder” are used interchangeably. An“effective amount” of a compound described herein refers to an amount that is sufficient to elicit the desired biological response. The effective amount of a compound described herein can vary depending on such factors as the desired biological endpoint, the severity of side effects, the disease or disorder, the identity of the particular compound, pharmacokinetics and pharmacodynamics, the condition being treated, the mode, route and frequency of administration desired or required, the species, age, and health and / or general condition 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 sum of the amounts of a compound described herein in multiple doses. In certain embodiments, the desired dose is delivered three times per day, twice per day, once per day, every other day, every third day, weekly, biweekly, triweekly, or quarterly. In certain embodiments, the desired dose is delivered using multiple administrations (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or more administrations).

[0114] A“therapeutically effective amount” of a compound described herein is an amount that is sufficient to provide a therapeutic benefit in the treatment of a disorder or to delay or minimize one or more symptoms associated with the disorder. A therapeutically effective amount of a compound refers to the amount of a therapeutic agent (alone or in combination with other therapies) that is sufficient to provide a therapeutic benefit in the treatment of a disorder. The term“therapeutically effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms, signs, or causes of a disorder, and / or enhances the therapeutic efficacy of another therapeutic agent. In certain embodiments, a therapeutically effective amount is an amount sufficient to dual inhibit TYK2 / JAK1 kinase. In certain embodiments, a therapeutically effective amount is an amount sufficient to treat a CNS disorder. In certain embodiments, a therapeutically effective amount is an amount sufficient to dual inhibit TYK2 / JAK1 kinase and treat a CNS disorder.

[0115] The terms "prevent," "preventing," or "prevention" refer to prophylactic treatment of a subject who does not have the disease and who may or may not be predisposed to developing the disease, or of a subject who has previously had the disease, and who may or may not be predisposed to developing a recurrence of the disease. In certain embodiments, the subject is at a higher risk of developing the disease or at a higher risk of developing a recurrence of the disease than the average healthy member of the population.

[0116] As used herein, the term "inhibit" or "inhibition" in the context of an enzyme (e.g., in the context of a Janus family kinase) refers to a decrease in the activity of the enzyme. In some embodiments, the term refers to a decrease in the level of enzyme activity (e.g., Janus family kinase activity) to a level that is statistically significantly lower than an initial level, which can for example be a baseline level of enzyme activity. In some embodiments, the term refers to a decrease in the level of enzyme activity (e.g., Janus family kinase activity) to a level that is less than 75%, less than 50%, less than 40%, less than 30%, less than 25%, less than 20%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, less than 0.5%, less than 0.1%, less than 0.01%, less than 0.001%, or less than 0.0001% of an initial level, which can for example be a baseline level of enzyme activity.

[0117] As used herein, the term "TYK2 inhibition" or "TYK2 kinase inhibition" in the context of an enzyme refers to a decrease in the activity of a TYK2 kinase. In some embodiments, the term refers to a decrease in the level of enzyme activity (e.g., TYK2 kinase activity) to a level that is statistically significantly lower than an initial level of TYK2 kinase activity, which can for example be a baseline level of enzyme activity. In some embodiments, the term refers to a decrease in the level of enzyme activity (e.g., TYK2 kinase activity) to a level that is less than 75%, less than 50%, less than 40%, less than 30%, less than 25%, less than 20%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, less than 0.5%, less than 0.1%, less than 0.01%, less than 0.001%, or less than 0.0001% of an initial level of TYK2 kinase activity, which can for example be a baseline level of enzyme activity.

[0118] In certain embodiments, an effective amount is an amount effective to inhibit protein kinase 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%, or at least about 98%. In certain embodiments, an effective amount is an amount effective to inhibit Janus family kinase activity by no more than 10%, no more than 20%, no more than 30%, no more than 40%, no more than 50%, no more than 60%, no more than 70%, no more than 80%, no more than 90%, no more than 95%, or no more than 98%. In certain embodiments, an effective amount is an amount effective to inhibit Janus family kinase activity in a range between (including the endpoints) a percentage described in this paragraph and another percentage described in this paragraph. DETAILED DESCRIPTION

[0120] The present disclosure is based, at least in part, on the unexpected result that compounds of Formula (I) are selective TYK2 kinase inhibitors, some of which have good ability to penetrate the blood-brain barrier.

[0121] In one aspect, provided are compounds represented by one of Formula (I), Formula (II), Formula (III), and Formula (IV):

[0122]

[0123] or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein:

[0124] X is CH or N;

[0125] Y 1 is C, Y 2 is N; or Y 1 is N, Y 2 is C;

[0126] is a single or double bond;

[0127] R 1 is H, halogen, or C 1-3 alkyl optionally substituted with 1, 2, or 3 substituents independently selected from halogen, OH, CN, OR, NHR, NRR’, N(R)C(O)R’, N(R)C(O)OR’, OC(O)NRR’, C(O)R, C(O)NRR’, N(R)S(O)2R’, S(O)2R, and S(O)2NRR’;

[0128] Cy is C 3-7cycloalkyl or 3-7 membered heterocyclyl, wherein Cy is optionally substituted with 1, 2, or 3 substituents independently selected from R 2 , oxo, halogen, OH, CN, OR, NHR, NRR', N(R)C(O)R', N(R)C(O)(O)R', OC(O)NRR', C(O)R, C(O)NRR', N(R)S(O)2R', S(O)2R, and S(O)2NRR';

[0129] R 2 is H, halogen, or C 1-3 alkyl optionally substituted with 1, 2, or 3 substituents independently selected from halogen, OH, CN, OR, NHR, NRR', N(R)C(O)R', N(R)C(O)(O)R', OC(O)NRR', C(O)R, C(O)NRR', N(R)S(O)2R', S(O)2R, and S(O)2NRR'; 3-7 cycloalkyl, 3-7 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, optionally substituted with 1, 2, or 3 substituents independently selected from halogen, OH, CN, OR, NHR, NRR', N(R)C(O)R', N(R)C(O)(O)R', OC(O)NRR', C(O)R, C(O)NRR', N(R)S(O)2R', S(O)2R, and S(O)2NRR';

[0130] R, R' are each independently H, C 1-3 alkyl or C 3-6 cycloalkyl optionally substituted with 1, 2, or 3 substituents independently selected from halogen, OH, and CN.

[0131] In another aspect, provided is a compound represented by one of Formula (Ia), Formula (IIa), Formula (IIIa), and Formula (IVa):

[0132]

[0133] or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein:

[0134] X is CH or N;

[0135] R 1 is H, halogen, or C 1-3 alkyl optionally substituted with 1, 2, or 3 substituents independently selected from halogen, OH, CN, OR, NHR, NRR', N(R)C(O)R', N(R)C(O)(O)R', OC(O)NRR', C(O)R, C(O)NRR', N(R)S(O)2R', S(O)2R, and S(O)2NRR';

[0136] Ring A is 4-7 membered heterocyclyl optionally substituted with 1, 2, or 3 substituents independently selected from R2 oxo, halogen, OH, CN, OR, NHR, NRR', N(R)C(O)R', N(R)C(O)(O)R', OC(O)NRR', C(O)R, C(O)NRR', N(R)S(O)2R', S(O)2R, and S(O)2NRR';

[0137] R 2 is H, halogen, or C 1-3 alkyl optionally substituted with 1, 2, or 3 substituents independently selected from halogen, OH, CN, OR, NHR, NRR', N(R)C(O)R', N(R)C(O)OR', OC(O)NRR', C(O)R, C(O)NRR', N(R)S(O)2R', S(O)2R, and S(O)2NRR'; 3-7 cycloalkyl, 3-7 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, optionally substituted with 1, 2, or 3 substituents independently selected from halogen, OH, CN, OR, NHR, NRR', N(R)C(O)R', N(R)C(O)(O)R', OC(O)NRR', C(O)R, C(O)NRR', N(R)S(O)2R', S(O)2R, and S(O)2NRR';

[0138] R, R' are each independently H, C 1-3 alkyl or C 3-6 cycloalkyl optionally substituted with 1, 2, or 3 substituents independently selected from halogen, OH, and CN.

[0139] In another aspect, provided is a compound represented by one of Formula (Ib), Formula (IIb), Formula (IIIb), and Formula (IVb):

[0140] ,

[0141] or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein:

[0142] X is CH or N;

[0143] R 1 is H, halogen, or C 1-3 alkyl optionally substituted with 1, 2, or 3 substituents independently selected from halogen, OH, CN, OR, NHR, NRR', N(R)C(O)R', N(R)C(O)OR', OC(O)NRR', C(O)R, C(O)NRR', N(R)S(O)2R', S(O)2R, and S(O)2NRR';

[0144] Cy is C 3-7 cycloalkyl or 3-7 membered heterocyclyl, wherein Cy is optionally substituted with 1, 2, or 3 substituents independently selected from R 2Oxygenated, halogenated, OH, CN, OR, NHR, NRR', N(R)C(O)R', N(R)C(O)(O)R', OC(O)NRR', C(O)R, C(O)NRR', N(R)S(O)2R', S(O)2R and S(O)2NRR';

[0145] R 2 C 1-3 Alkyl, C 3-7 Cycloalkyl, 3-7-membered heterocyclic, phenyl, or 5-6-membered heteroaryl, optionally substituted by 1, 2, or 3 independently selected from the following substituents: halogen, OH, CN, OR, NHR, NRR', N(R)C(O)R', N(R)C(O)(O)R', OC(O)NRR', C(O)R, C(O)NRR', N(R)S(O)2R', S(O)2R, and S(O)2NRR';

[0146] R and R' are independently H and C, respectively. 1-3 Alkyl or C 3-6 Cycloalkyl groups, optionally substituted with one, two or three independent substituents selected from halogens, OH and CN.

[0147] In another aspect, compounds represented by one of formulas (Ic), (IIc), (IIIc), and (IVc) are provided:

[0148]

[0149] Or its salts, solvates, hydrates, polymorphs, eutectics, tautomers, stereoisomers, isotopically labeled derivatives or prodrugs, wherein:

[0150] X is CH or N;

[0151] R 1 C is H, halogen, or optionally substituted with 1, 2, or 3 substituents. 1-3 Alkyl group, wherein the substituent is independently selected from halogen, OH, CN, OR, NHR, NRR', N(R)C(O)R', N(R)C(O)OR', OC(O)NRR', C(O)R, C(O)NRR', N(R)S(O)2R', S(O)2R and S(O)2NRR';

[0152] Ring A is a 4-7 membered heterocyclic group, which is optionally substituted by 1, 2 or 3 independent substituents selected from the following: R 2Oxygenated, halogenated, OH, CN, OR, NHR, NRR', N(R)C(O)R', N(R)C(O)(O)R', OC(O)NRR', C(O)R, C(O)NRR', N(R)S(O)2R', S(O)2R and S(O)2NRR';

[0153] R 2 C 1-3 Alkyl, C 3-7 Cycloalkyl, 3-7-membered heterocyclic, phenyl, or 5-6-membered heteroaryl, optionally substituted by 1, 2, or 3 independently selected from the following substituents: halogen, OH, CN, OR, NHR, NRR', N(R)C(O)R', N(R)C(O)(O)R', OC(O)NRR', C(O)R, C(O)NRR', N(R)S(O)2R', S(O)2R, and S(O)2NRR';

[0154] R and R' are independently H and C, respectively. 1-3 Alkyl or C 3-6 Cycloalkyl groups, optionally substituted with one, two or three independent substituents selected from halogens, OH and CN.

[0155] In another aspect, compounds represented by one of formulas (Id), (IId), (IIId), and (IVd) are provided:

[0156] ,

[0157] Or its salts, solvates, hydrates, polymorphs, eutectics, tautomers, stereoisomers, isotopically labeled derivatives or prodrugs, wherein:

[0158] X is CH or N;

[0159] R 1 C is H, halogen, or optionally substituted with 1, 2, or 3 substituents. 1-3 Alkyl group, wherein the substituent is independently selected from halogen, OH, CN, OR, NHR, NRR', N(R)C(O)R', N(R)C(O)OR', OC(O)NRR', C(O)R, C(O)NRR', N(R)S(O)2R', S(O)2R and S(O)2NRR';

[0160] Cy is C 3-7 Cy is a cycloalkyl or 3-7 membered heterocyclic group, wherein Cy is optionally substituted by 1, 2 or 3 independent substituents selected from the following: R 2, oxo, halogen, OH, CN, OR, NHR, NRR', N(R)C(O)R', N(R)C(O)(O)R', OC(O)NRR', C(O)R, C(O)NRR', N(R)S(O)2R', S(O)2R, and S(O)2NRR';

[0161] R 2 is C 1-3 alkyl, C 3-7 cycloalkyl, 3-7 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, optionally substituted with 1, 2, or 3 substituents independently selected from halogen, OH, CN, OR, NHR, NRR', N(R)C(O)R', N(R)C(O)(O)R', OC(O)NRR', C(O)R, C(O)NRR', N(R)S(O)2R', S(O)2R, and S(O)2NRR';

[0162] R, R' are each independently H, C 1-3 alkyl, or C 3-6 cycloalkyl, optionally substituted with 1, 2, or 3 substituents independently selected from halogen, OH, and CN.

[0163] In some embodiments, the present application provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein: X is CH.

[0164] In some embodiments, the present application provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein: X is N.

[0165] In some embodiments, the present application provides a compound of Formula (Ia), or a pharmaceutically acceptable salt thereof, wherein:

[0166] Ring A is 4-7 membered heterocyclyl, optionally substituted with 1, 2, or 3 substituents independently selected from R 2 , halogen, OH, CN, OR, and N(R)S(O)2R';

[0167] R 2 is C 1-3 alkyl optionally substituted with 1, 2, or 3 substituents independently selected from halogen, OH, CN, OR, NHR, NRR', N(R)C(O)R', N(R)C(O)(O)R', OC(O)NRR', C(O)R, C(O)NRR', N(R)S(O)2R', S(O)2R, and S(O)2NRR'.

[0168] In some embodiments, the present application provides a compound of Formula (Ia), or a pharmaceutically acceptable salt thereof, wherein:

[0169] A is a 6-membered heterocyclyl group optionally substituted with R 2 ;

[0170] R 2 is C 1-3 alkyl optionally substituted with 1, 2, or 3 substituents independently selected from halo, OH, CN, OR, NHR, NRR', N(R)C(O)R', N(R)C(O)(O)R', OC(O)NRR', C(O)R, C(O)NRR', N(R)S(O)2R', S(O)2R, and S(O)2NRR'.

[0171] In some embodiments, the present application provides a compound of Formula (Ia), or a pharmaceutically acceptable salt thereof, wherein:

[0172] A is a 6-membered heterocyclyl group optionally substituted with .

[0173] In some embodiments, the present application provides a compound of Formula (Ia), or a pharmaceutically acceptable salt thereof, wherein:

[0174] A is .

[0175] In some embodiments, the present application provides a compound of Formula (Ib), or a pharmaceutically acceptable salt thereof, wherein:

[0176] Cy is C 3-7 cycloalkyl optionally substituted with 1, 2, or 3 substituents independently selected from R 2 , halo, OH, CN, OR, and N(R)S(O)2R';

[0177] R 2 is C 1-3 alkyl optionally substituted with 1, 2, or 3 substituents independently selected from halo, OH, CN, OR, NHR, NRR', N(R)C(O)R', N(R)C(O)(O)R', OC(O)NRR', C(O)R, C(O)NRR', N(R)S(O)2R', S(O)2R, and S(O)2NRR'.

[0178] In some embodiments, the present application provides a compound of Formula (Ib), or a pharmaceutically acceptable salt thereof, wherein:

[0179] Cy is cyclohexyl optionally substituted with R 2 ;

[0180] R 2 is C 1-3alkyl, said substituent is independently selected from the group consisting of halogen, OH, CN, OR, NHR, NRR', N(R)C(O)R', N(R)C(O)(O)R', OC(O)NRR', C(O)R, C(O)NRR', N(R)S(O)2R', S(O)2R, and S(O)2NRR'.

[0181] In some embodiments, the present application provides a compound of Formula (Ib), or a pharmaceutically acceptable salt thereof, wherein:

[0182] Cy is .

[0183] In some embodiments, the present application provides a compound of Formula (Ib), or a pharmaceutically acceptable salt thereof, wherein:

[0184] Cy is .

[0185] In some embodiments, the present application provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein: R 1 is H, CH3, or .

[0186] In some embodiments, the present application provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the compound is depicted in Table 1:

[0187] Table 1:

[0188]

[0189] Representative compounds of the present application are as follows:

[0190] 2-(l-(2-methyl-lH-imidazo[4,5-c]quinolin-l-yl)piperidin-4-yl)acetonitrile (1);

[0191] 2-(l-(2-methyl-lH-imidazo[4,5-c][l,5]naphthyridin-l-yl)piperidin-4-yl)acetonitrile (2);

[0192] 2-((l r,4r)-4-(imidazo[l,2-a]quinoxalin-l-yl)cyclohexyl)acetonitrile (3);

[0193] 2-((l r,4r)-4-(imidazo[l,2-a]pyrido[3,2-e]pyrazin-9-yl)cyclohexyl)acetonitrile (4).

[0194] In some embodiments, the present application provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the compound is depicted in Table 2:

[0195] Table 2:

[0196]

[0197] Representative compounds of the present application are as follows:

[0198] (R)-2-(l-(2-(l-hydroxyethyl)-lH-imidazo[4,5-c]quinolin-l-yl)piperidin-4-yl)acetonitrile (5);

[0199] (R)-2-(l-(2-(l-hydroxyethyl)-lH-imidazo[4,5-c][l,5]naphthyridin-l-yl)piperidin-4-yl)acetonitrile (6);

[0200] 2-((l r,4r)-4-(2-methylimidazo[l,2-a]quinoxalin-l-yl)cyclohexyl)acetonitrile (7);

[0201] 2-((l r,4r)-4-(8-methylimidazo[l,2-a]pyrido[3,2-e]pyrazin-9-yl)cyclohexyl)acetonitrile (8).

[0202] Accordingly, described herein are methods of treating CNS disorders, such as those described herein, using an effective amount of a compound of Formula (I), or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or a composition comprising a compound of Formula (I), or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0203] Compositions

[0204] The present disclosure provides pharmaceutical compositions comprising a compound of Formula (I), or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, and optionally a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical compositions described herein comprise a compound of Formula (I), or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, and a pharmaceutically acceptable excipient.

[0205] In certain embodiments, the compounds described herein are 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 CNS disorder in a subject in need thereof. In certain embodiments, the effective amount is an amount effective to prevent a CNS disorder in a subject in need thereof. In certain embodiments, the effective amount is an amount effective to reduce the risk of having a CNS disorder in a subject in need thereof. In certain embodiments, the effective amount is an amount effective to inhibit the activity (e.g., aberrant activity, e.g., increased activity) of a protein kinase in a subject or cell.

[0206] The pharmaceutical compositions described herein can be prepared by any of the methods known in the art of pharmaceutical science. In general, such preparative methods include the steps of bringing into association the compounds described herein (i.e., the “active ingredient”) with the carrier(s) or excipient(s) and / or one or more other accessory ingredients, and then, if necessary and / or desirable, shaping and / or packaging the product into a desired single- or multi-dose unit.

[0207] The pharmaceutical compositions can be prepared, packaged, and / or sold in bulk, as single unit dosages, and / or as a plurality of single unit dosages. A “unit dosage” is a discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient. The quantity of the active ingredient is generally equal to a dose, and / or a convenient fraction of a dose, such as a half or third of a dose.

[0208] The relative amounts of the active ingredient, the pharmaceutically acceptable excipient, and / or any additional ingredients in the pharmaceutical compositions described herein will vary, depending upon the identity, size, and / or condition of the subject being treated, further depending upon the route by which the composition is to be administered. The compositions can comprise between 0.1% and 100% (w / w) of the active ingredient.

[0209] Pharmaceutically acceptable excipients used in manufacturing the provided pharmaceutical compositions include inert diluents, dispersing and / or granulating agents, surface active agents and / or emulsifiers, disintegrants, binding agents, preservatives, buffering agents, lubricants, and / or oils. Excipients such as cocoa butter and suppository waxes, colorants, coatings, sweetening, flavoring, and perfuming agents can also be present in the composition.

[0210] Liquid dosage forms for oral and parenteral administration include pharmaceutically-acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active ingredient, the liquid dosage forms can include inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3- butylene glycol, dimethylformamide, oils (e.g., cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. ® alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers, and mixtures thereof.

[0211] Injectable preparations, for example sterile injectable aqueous or oleaginous suspensions, can be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

[0212] The injectable formulations 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.

[0213] In order to prolong the effect of a drug, it is often desirable to slow its absorption from subcutaneous or intramuscular injection. This can be accomplished by the use of a liquid suspension of crystalline or amorphous material having poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, can depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.

[0214] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active ingredient is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and / or (a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, (b) binders such as, for example, 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 retarders such as paraffin, (f) absorption accelerators such as quaternary ammonium compounds, (g) release-control polymers such as various kinds of hydroxypropylmethylcellulose (HPMC), (h) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, (i) absorbents such as kaolin and bentonite clay, and (j) lubricants such as talc, magnesium stearate, magnesium oxide, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage forms can include buffering agents.

[0215] Solid compositions of a similar type can also be employed as fillers in soft and hard filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols, and the like. The 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 formulating art. They can optionally contain opacifying agents and can be of a composition that they release 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 employed as fillers in soft and hard filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols, and the like.

[0216] The active ingredient can be in micro-encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release control coatings, and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms, the active ingredient can be admixed with at least one inert diluent such as sucrose, lactose, or starch. Such dosage forms can also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets, and pills, the dosage forms can include buffering agents. They can optionally contain opacifying agents and can be of a composition that they release 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.

[0217] While the description of pharmaceutical compositions provided herein is primarily concerned with pharmaceutical compositions that are suitable for administration to humans, it is understood that such compositions are typically suitable for administration to animals of all sorts. Modifications in the pharmaceutical compositions to adapt them to a particular kind of animal are well understood, and are within the scope of those skilled in the art. It is understood that the disclosure is applicable to both human and veterinary medicine.

[0218] The compounds provided herein are generally formulated in dosage unit form for ease of administration and uniformity of dosage. However, it should be understood that the total daily usage of the compositions described herein will be decided by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular subject or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the particular active ingredient employed; the specific composition employed; the age, body weight, general health, sex, and diet of the subject; the time of administration, route of administration, and rate of excretion of the particular active ingredient employed; the duration of the treatment; drugs used in combination or coincidental with the particular active ingredient employed; and like factors well known in the medical arts.

[0219] A compound or composition as described herein can be administered in combination with one or more additional agents (e.g., therapeutically and / or prophylactically active agents). A compound or composition can be administered in combination with an additional agent that improves its activity (e.g., activity (e.g., potency and / or efficacy) in treating a disorder in a subject in need thereof, activity (e.g., potency and / or efficacy) in preventing a disorder in a subject in need thereof, activity (e.g., potency and / or efficacy) in reducing the risk of developing a disorder in a subject in need thereof, and / or activity (e.g., potency and / or efficacy) in inhibiting protein kinase activity in a subject or cell), improves bioavailability, improves safety, reduces resistance, reduces and / or alters metabolism, inhibits excretion, and / or alters distribution in a subject or cell. It is also understood that the therapy employed can achieve a desired effect for the same disorder, and / or can achieve a different effect. In certain embodiments, a pharmaceutical composition described herein comprising a compound described herein and an additional agent exhibits a synergistic effect that is not present in a pharmaceutical composition comprising one (but not both) of the compound and the additional agent. In some embodiments, the additional agent achieves a desired effect for the same disorder. In some embodiments, the additional agent achieves a different effect.

[0220] A compound or composition can be administered simultaneously, before, or after one or more additional agents useful, for example, as combination therapy. Agents include therapeutically active agents. Agents also include prophylactically active agents. Agents include small organic molecules, such as pharmaceutical compounds (e.g., compounds approved by the U.S. Food and Drug Administration for human or veterinary use under the Code of Federal Regulations (CFR) regulations), 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. In certain embodiments, the additional agent is an agent for treating and / or preventing a CNS disorder. Each additional agent can be administered at a dose and / or schedule determined for that agent. Additional agents can also be administered together with each other and / or with a compound or composition described herein in a single dose or composition, or separately administered in different doses or compositions. The particular combination employed in a regimen will take into account the compatibility of the compound described herein with the additional agent(s) and / or the desired therapeutic and / or prophylactic effect to be achieved. Generally, it is expected that the level of additional agent(s) used in combination will not exceed the level at which they are used alone. In some embodiments, the level used in combination will be lower than that used alone.

[0221] Additional agents include, but are not limited to, anti-proliferative agents, anti-cancer agents, anti-angiogenic agents, steroidal or non-steroidal anti-inflammatory agents, immunosuppressive agents, anti-bacterial agents, anti-viral agents, cardiovascular agents, cholesterol-lowering agents, anti-diabetic agents, anti-allergic agents, contraceptive agents, analgesic agents, anesthetic agents, anti-coagulant agents, inhibitors of enzymes, steroidal agents, steroidal or antihistamine agents, antigens, vaccines, antibodies, decongestants, sedatives, opioids, analgesics, antipyretics, hormones, and prostaglandins. In certain embodiments, the additional agent is an anti-proliferative agent. In certain embodiments, the additional agent is an anti-cancer agent. In certain embodiments, the additional agent is an anti-viral agent. In certain embodiments, the additional agent is a binder or inhibitor of a protein kinase. In certain embodiments, the additional agent is selected from epigenetic or transcriptional modulators (e.g., DNA methyltransferase inhibitors, histone deacetylase inhibitors (HDAC inhibitors), lysine methyltransferase inhibitors), anti-mitotic drugs (e.g., taxanes and vinca alkaloids), hormone receptor modulators (e.g., estrogen receptor modulators and androgen receptor modulators), cell signaling pathway inhibitors (e.g., tyrosine protein kinase inhibitors), protein stability modulators (e.g., proteasome inhibitors), Hsp90 inhibitors, glucocorticoids, all-trans retinoic acid, and other agents that promote differentiation. In certain embodiments, the compounds or pharmaceutical compositions described herein can be administered in combination with an anti-cancer therapy, including but not limited to surgery, radiation therapy, transplantation (e.g., stem cell transplantation, bone marrow transplantation), immunotherapy, and chemotherapy. Additional agents include small organic molecules, such as pharmaceutical compounds (e.g., compounds approved by the U.S. Food and Drug Administration, as provided in the Code of Federal Regulations (CFR)), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides or proteins, small molecules attached to proteins, glycoproteins, steroids, nucleic acids, DNA, RNA, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins, and cells.

[0222] The present disclosure also encompasses kits (e.g., pharmaceutical packs). Provided kits can comprise a pharmaceutical composition or compound described herein and a container (e.g., a vial, an ampoule, a bottle, a syringe, and / or a dispenser pack, or other suitable container). In some embodiments, provided kits can optionally further comprise a second container comprising a pharmaceutically-acceptable excipient for diluting or suspending a pharmaceutical composition or compound described herein. In some embodiments, the pharmaceutical composition or compound described herein provided in the first and second containers are combined to form a single unit dosage form.

[0223] Accordingly, in one aspect, there is provided a kit comprising a first container comprising a compound or pharmaceutical composition described herein. In certain embodiments, the kit is useful for treating a CNS disorder in a subject in need thereof. In certain embodiments, the kit is useful for preventing a CNS disorder in a subject in need thereof. In certain embodiments, the kit is useful for reducing the risk of having a CNS disorder in a subject in need thereof. In certain embodiments, the kit is useful for inhibiting the activity (e.g., abnormal activity, e.g., increased activity) of a protein kinase in a subject or cell.

[0224] In certain embodiments, the kits described herein further comprise instructions for using the kit. The kits described herein can also comprise information required by regulatory agencies (e.g., the U.S. Food and Drug Administration (FDA)). In certain embodiments, the information included in the kit is prescription information. In certain embodiments, the kit and instructions are provided for treating a CNS disorder in a subject in need thereof. In certain embodiments, the kit and instructions are provided for preventing a CNS disorder in a subject in need thereof. In certain embodiments, the kit and instructions are provided for reducing the risk of having a CNS disorder in a subject in need thereof. In certain embodiments, the kit and instructions are provided for inhibiting the activity (e.g., abnormal activity, e.g., increased activity) of a protein kinase in a subject or cell. The kits described herein can comprise one or more additional agents described herein as separate compositions.

[0225] Therapeutic methods

[0226] As generally described herein, the disclosure provides methods of treating a CNS disorder (or a symptom thereof) comprising administering to a subject in need thereof an effective amount of a compound of the disclosure or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or a composition comprising an effective amount of a compound of the disclosure or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof. Such methods can be performed in vivo (i.e., by administration to a subject) or in vitro (e.g., after contact with a tissue or cell culture). As used herein, treatment encompasses therapeutic treatment. In certain embodiments, the subject is identified as being in need. In certain embodiments, the method further comprises wherein the subject is treated; i.e., the disease, disorder, or symptom thereof is ameliorated.

[0227] In certain embodiments, the effective amount is a therapeutically effective amount. For example, in certain embodiments, the method slows the progression of a CNS disorder in the subject. In certain embodiments, the method improves a condition in a subject having a CNS disorder. In certain embodiments, the subject has a suspected or diagnosed CNS disorder.

[0228] In certain embodiments, the effective amount is a prophylactically effective amount. For example, in certain embodiments, the method prevents or reduces the likelihood of a CNS disorder, e.g., in certain embodiments, the method comprises administering a compound of the disclosure to a subject in need thereof in an amount sufficient to prevent or reduce the likelihood of a CNS disorder. In certain embodiments, the subject is at risk of having a CNS disorder.

[0229] Exemplary CNS disorders include, but are not limited to, neurotoxicity and / or neurotrauma, stroke, multiple sclerosis, spinal cord injury, epilepsy, a psychiatric disorder, a sleep disorder, a movement disorder, nausea and / or vomiting, amyotrophic lateral sclerosis, Alzheimer’s disease, and drug addiction.

[0230] In certain embodiments, the CNS disorder is a chronic neurodegenerative disorder (e.g., Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, Alzheimer’s disease). In certain embodiments, the compounds of the present invention provide neuroprotection, e.g., against chronic neurodegenerative disorders.

[0231] In certain embodiments, the CNS disorder is Alzheimer’s disease.

[0232] In certain embodiments, the CNS disorder is amyotrophic lateral sclerosis (ALS).

[0233] In certain embodiments, the CNS disorder is frontotemporal dementia (FTD).

[0234] In certain embodiments, the CNS disorder is Parkinson’s disease.

[0235] In certain embodiments, the CNS disorder is modulated by the JAK-STAT pathway. In certain embodiments, the CNS disorder is modulated by TYK2.

[0236] In certain embodiments, the CNS disorder is Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, dementia, frontotemporal dementia, mild cognitive impairment (MCI), or neuroinflammation.

[0237] In certain embodiments, the CNS disorder is amyotrophic lateral sclerosis / frontotemporal dementia (ALS / FTD).

[0238] Any of the methods described herein can further comprise administering to the subject an additional agent, which can be an anti-CNS disorder. Examples include an antipsychotic selected from the group consisting of butyrophenones, phenothiazines, fluphenazine, chlorpromazine, prochlorperazine, thioridazine, trifluoperazine, mesoridazine, promazine, triflupromazine, levomepromazine, promethazine, thioxanthenes, chlorprothixene, thiothixene, flupenthixol, zuclopenthixol, clozapine, olanzapine, risperidone, quetiapine, ziprasidone, amisulpride, asenapine, paliperidone, aripiprazole, a dopamine partial agonist, lamotrigine, memantine, tetrabenazine, cannabadiol, LY2140023, droperidol, pimozide, burimamide, carphenazine, remoxipride, piperacetazine, sulpiride, acamprosate, and tetrabenazine; an antidepressant or mood stabilizer selected from the group consisting of fluoxetine, paroxetine, escitalopram, citalopram, seriraline, fluvoxamine, venlafaxine, milnacipram, duloxetine, mirtazapine, mianserin, reboxetine, bupropion, amitriptyline, nortriptiline, protriptyline, desipramine, trimipramine, amoxapine, bupropion, bupropion sr, s-citalopram, clomipramine, desipramine, doxepin, isocarboxazid, velafaxine xr, tranylcypromine, trazodone, nefazodone, phenelzine, lamatrogine, lithium, topiramate, gabapentin, carbamazepine, oxacarbazepine, valproic acid, maprotiline, mirtazapine, brofaromine, selegiline, moclobemide, isoniazid, and iproniazid; or a drug for improving cognition and / or inhibiting neurodegeneration selected from the group consisting of Aricept, donepezil, tacrine, rivastigmine, memantine, physostigmine, nicotine, arecoline, huperzine A, selegiline, riluzole, vitamin C, vitamin E, carotenoids, ginkgo biloba. Any anti-CNS disorder agent known in the art can be used with the compounds of Formula (I)-(III) or salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs thereof to achieve the intended therapeutic effect.

[0239] The compounds and compositions provided herein may be administered via any route, including enterally (e.g., orally), parenterally, intravenously, intramuscularly, intra-arterially, intramedullaryly, intrathecally, subcutaneously, intravenously, transdermally, intradermally, rectally, intravaginally, intraperitoneally, topically (e.g., by powder, ointment, cream, and / or drops), mucous membranes, nasal cavity, buccally, sublingually; by endotracheal instillation, bronchial instillation, and / or inhalation; and / or as oral sprays, nasal sprays, and / or aerosols. Specifically covered routes include oral administration, intravenous administration (e.g., systemic intravenous injection), administration to areas supplied by blood and / or lymph, and / or direct administration to the site of infection. Generally, the most appropriate route of administration will depend on a number of factors, including the nature of the agent (e.g., its stability in the gastrointestinal environment) and / or the condition of the subject (e.g., whether the subject can tolerate oral administration). In some embodiments, the compounds or pharmaceutical compositions described herein are suitable for topical administration to the eyes of a subject.

[0240] The exact amount of compound required to achieve an effective amount will vary from subject to subject, depending on, for example, the species, age, and general condition of the subject, the severity of the side effects or disorder, the particular compound's identity, the mode of administration and the like. The effective amount can be contained in a single dose (e.g., a single oral dose) or multiple doses (e.g., multiple oral doses). In certain embodiments, when multiple doses are administered to a subject or applied to a tissue or cell, any two doses of the multiple doses comprise different or substantially identical amounts of a compound described herein. In certain embodiments, when multiple doses are administered to a subject or applied to a tissue or cell, the frequency of the multiple doses administered to the subject or applied to the tissue or cell is three doses per day, two doses per day, one dose per day, one dose every other day, one dose every third day, one dose per week, one dose per two weeks, one dose per three weeks, or one dose per four weeks. In certain embodiments, the frequency of the multiple doses administered to the subject or applied to the tissue or cell is one dose per day. In certain embodiments, the frequency of the multiple doses administered to the subject or applied to the tissue or cell is two doses per day. In certain embodiments, the frequency of the multiple doses administered to the subject or applied to the tissue or cell is three doses per day. In certain embodiments, when multiple doses are administered to a subject or applied to a tissue or cell, the duration of time between the first dose and the last dose of the multiple doses is one day, two days, four days, one week, two weeks, three weeks, one month, two months, three months, four months, six months, nine months, one year, two years, three years, four years, five years, seven years, ten years, fifteen years, twenty years, or the lifetime of the subject, tissue, or cell. In certain embodiments, the duration of time between the first dose and the last dose of the multiple doses is three months, six months, or one year. In certain embodiments, the duration of time between the first dose and the last dose of the multiple doses is the lifetime of the subject, tissue, or cell. In certain embodiments, a dose described herein (e.g., any dose of a single dose or multiple doses) independently comprises between 0.1 pg and 1 pg, between 0.001 mg and 0.01 mg, between 0.01 mg and 0.1 mg, between 0.1 mg and 1 mg, between 1 mg and 3 mg, between 3 mg and 10 mg, between 10 mg and 30 mg, between 30 mg and 100 mg, between 100 mg and 300 mg, between 300 mg and 1,000 mg, or between 1 g and 10 g (inclusive of end values) of a compound described herein. In certain embodiments, a dose described herein independently comprises between 1 mg and 3 mg (inclusive of end values) of a compound described herein. In certain embodiments, a dose described herein independently comprises between 3 mg and 10 mg (inclusive of end values) of a compound described herein.In certain embodiments, the doses described herein independently comprise between 10 mg and 30 mg, inclusive, of a compound described herein. In certain embodiments, the doses described herein independently comprise between 30 mg and 100 mg, inclusive, of a compound described herein.

[0241] It should be understood that the dose ranges as described herein provide guidance for administration of the provided pharmaceutical compositions to adults. For example, the amount administered to a child or adolescent can be determined by a medical practitioner or one skilled in the art and can be lower than or the same as the amount administered to an adult. Examples

[0242] Example 1: Synthesis of 2-(l-(2-methyl-lH-imidazo[4,5-c]quinolin-l- yl)piperidin-4-yl)acetonitrile (1)

[0243]

[0244] Step 1: To a solution of compound la (500 mg, 2.40 mmol) in ethanol (2.0 mL) was added compound lb (401 mg, 2.88 mmol, 1.2 eq.) and sodium bicarbonate (606 mg, 7.21 mmol, 3.0 eq.). The reaction mixture was stirred at 50 °C overnight. The solvent was removed under reduced pressure. The crude residue was purified by column chromatography to afford compound lc (110 mg, 0.35 mmol, 14.7% yield) as a yellow solid. LCMS: [M+H] + : 312.

[0245] Step 2: To a 40 mL flask containing compound lc (110 mg, 0.35 mmol, 1.0 eq.) was added THF (15 mL), saturated aqueous ammonium chloride solution (5 mL) and zinc (115 mg, 1.7 mmol, 5.0 eq.) at room temperature. The resulting mixture was stirred at 60 °C for 1 h. The mixture was filtered. The filtrate was removed under reduced pressure. The crude residue was purified by column chromatography to afford compound Id (30 mg, 0.11 mmol, 30.2% yield) as a yellow solid. LCMS: [M+H] + : 282.

[0246] Step 3: A mixture of compound Id (30 mg, 0.11 mmol) and acetic anhydride (3 mL) was stirred at 110 °C for 4 h. The volatiles were removed under reduced pressure. The crude residue was purified by column chromatography to give 2-(l-(2-methyl-lH-imidazo[4,5- c]quinolin-l-yl)piperidin-4-yl)acetonitrile (1) (5.2 mg, 0.017 mmol, 16.0% yield) as a yellow solid. LCMS: [M+H] + : 306. 1 H NMR (400 MHz, Methanol-d4) δ 9.20 (dd, J = 8.3, 1.6 Hz, 1H), 9.00 (s, 1H), 8.13 (dd, J = 8.4, 1.4 Hz, 1H), 7.72 (dddd, J = 14.9, 8.4, 7.0, 1.6 Hz, 2H), 3.75 - 3.66 (m, 2H), 3.49 - 3.42 (m, 2H), 2.88 (s, 3H), 2.64 (d, J = 6.1 Hz, 2H), 2.12 - 2.06 (m, 2H), 2.05 - 1.97 (m, 1H), 1.96 - 1.84 (m, 2H).

[0247] Example 2: Synthesis of 2-(l-(2-methyl-lH-imidazo[4,5-c][l,5]naphthyridin-l- yl)piperidin-4-yl)acetonitrile (2)

[0248]

[0249] Step 1: To a solution of compound 2a (550 mg, 2.63 mmol) in ethanol (20 mL) was added compound lb (439 mg, 3.16 mmol, 1.2 eq.) and sodium bicarbonate (663 mg, 7.89 mmol, 3.0 eq.). The reaction mixture was stirred at 50 °C overnight. The solvent was removed under reduced pressure. The crude residue was purified by column chromatography to give compound 2c (100 mg, 0.32 mmol, 12.2% yield) as a yellow solid. LCMS: [M+H] + : 313.

[0250] Step 2: To a 40 mL flask containing compound 2c (100 mg, 0.32 mmol, 1.0 eq.) was added THF (15 mL), saturated aqueous ammonium chloride solution (5 mL) and zinc (104 mg, 1.60 mmol, 5.0 eq.) at room temperature. The resulting mixture was stirred at 60 °C for 1 h. The mixture was filtered. The filtrate was removed under reduced pressure. The crude residue was purified by column chromatography to give compound 2d (24 mg, 0.085 mmol, 26.6% yield) as a yellow solid. LCMS: [M+H] + : 283.

[0251] Step 3: A mixture of compound 2d (24 mg, 0.085 mmol) and acetic anhydride (3 mL) was stirred at 110 °C for 4 h. The volatiles were removed under reduced pressure. The crude residue was purified by column chromatography to give 2-(1-(2-methyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)piperidin-4-yl)acetonitrile (2) (4.3 mg, 0.014 mmol, 16.5% yield) as a yellow solid. LCMS: [M+H] + : 307. 1 H NMR (400 MHz, Methanol-d4) δ 9.16 (s, 1H), 9.12 (dd, J = 4.3, 1.7 Hz, 1H), 8.53 (dd, J = 8.5, 1.7 Hz, 1H), 7.77 (dd, J = 8.5, 4.2 Hz, 1H), 4.49 (ddd, J = 12.7, 10.4, 2.7 Hz, 2H), 3.13 - 3.06 (m, 2H), 2.75 (s, 3H), 2.59 (d, J = 6.4 Hz, 2H), 2.21 - 2.08 (m, 1H), 2.09 - 2.00 (m, 2H), 1.78 (qd, J = 12.5, 4.3 Hz, 2H).

[0252] Example 3: Synthesis of 2-((1r,4r)-4-(imidazo[1,2-a]quinoxalin-1-yl)cyclohexyl)acetonitrile (3)

[0253]

[0254] Step 1: To a solution of compound 3a’ (8.35 g, 0.05 mol, 1.0 eq) and DMF (0.2 mL) in DCM (100 mL) was added dropwise oxalyl chloride (12.7 g, 0.1 mol, 2.0 eq) at 0-10 °C. The mixture was stirred at ambient temperature for 1 hour, then concentrated under reduced pressure to give compound 3b’ (9.3 g, yield: 100%) as a yellow oil.

[0255] Step 2: To a solution of compound 3b’ (9.3 g, 0.05 mol, 1.0 eq) in THF (30 mL) and acetonitrile (30 mL) was added dropwise (trimethylsilyl)diazomethane (2 M, 30 mL, 0.06 mol, 1.2 eq) in an ice bath under nitrogen atmosphere. The reaction mixture was stirred in an ice bath for 1 hour, then further stirred at room temperature for 1 hour. The reaction solution was cooled in an ice bath, then 48% aqueous hydrobromic acid (11 g, 0.065 mmol, 1.3 eq) was added dropwise, and the mixture was stirred for 15 minutes. To the reaction mixture was added saturated aqueous sodium bicarbonate solution, followed by extraction with ethyl acetate twice. The extract was washed with brine, dried over sodium sulfate, and concentrated. The resulting residue was purified by silica gel flash column chromatography to give a mixture of compounds 3c and 3c’ (3c:3c’ = 3:1, 6.2 g) as a yellow solid.

[0256] Step 3: To a 40 mL flask was added compound 3a (1.5 g, 9.15 mmol), tert-butyl carbamate (3.13 g, 27.4 mmol, 3.0 eq.), Pd2(dba)3 (421 mg, 0.46 mmol, 0.05 eq.), Brettphos (493 mg, 0.92 mmol, 0.1 eq.), cesium carbonate (5.9 g, 18.3 mmol, 2.0 eq.) and dioxane (30 mL) under nitrogen atmosphere. The reaction mixture was stirred at 100 °C overnight. The reaction mixture was cooled to room temperature, and the solvent was removed in vacuum. The crude mixture was purified by column chromatography to give compound 3b (1.1 g, 4.5 mmol, yield 49.1%) as a yellow solid. LCMS: [M+H]: 246. + : 246.

[0257] Step 4: To a solution of compound 3b (1.1 g, 4.5 mmol) in DMF (8 mL) was added sodium hydride (198 mg, 60% in mineral oil, 4.95 mmol, 1.1 eq.) at 0 °C. The reaction mixture was stirred at 0 °C for 10 min. Then a mixture of 3c and 3c’ (1.1 g, 5.4 mmol, 1.2 eq.) in anhydrous DMF (5 mL) was added dropwise at 0 °C. The mixture was stirred at room temperature for 4 h. The mixture was quenched with methanol (2 ml). The crude mixture was purified by reverse phase column chromatography to give compound 3d (740 mg, 1.81 mmol, 40.4% yield) as a yellow solid. LCMS: [M+H] + : 409.

[0258] Step 5: To a solution of compound 3d (740 mg, 1.81 mmol) in trifluoroacetic acid (5 mL) was added trifluoroacetic anhydride (5 mL). The mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure. The crude residue was purified by column chromatography to give 2-((1r,4r)-4-(imidazo[1,2-a]quinoxalin-1-yl)cyclohexyl)acetonitrile (3) (317.6 mg, 1.09 mmol, yield 60.0%) as a yellow solid. LCMS: [M+H] + : 293. 1 H NMR (400 MHz, DMSO-d6) δ 9.04 (s, 1H), 8.27 (dd, J = 8.6, 1.3 Hz, 1H), 8.09 (dd, J = 8.1, 1.6 Hz, 1H), 7.80 (ddd, J = 8.7, 7.2, 1.7 Hz, 1H), 7.70 - 7.64 (m, 2H), 3.59 - 3.50 (m, 1H), 2.56 (d, J = 6.3 Hz, 2H), 2.29 - 2.20 (m, 2H), 1.97 - 1.90 (m, 2H), 1.84 - 1.73 (m, 1H), 1.67 - 1.55 (m, 2H), 1.54 - 1.42 (m, 2H).

[0259] Example 4: Synthesis of 2-((1r,4r)-4-(imidazo[1,2-a]pyrido[3,2- e]pyrazin-9-yl)cyclohexyl)acetonitrile (4)

[0260]

[0261] Step 1: To a 40 mL flask was added compound 4a (1 g, 6.06 mmol), tert-butyl carbamate (2.07 g, 18.18 mmol, 3.0 eq.), Pd2(dba)3 (277 mg, 0.30 mmol, 0.05 eq.), BrettPhos (325 mg, 0.61 mmol, 0.1 eq.), cesium carbonate (3.9 g, 12.0 mmol, 2.0 eq.) and dioxane (3.0 mL) under nitrogen atmosphere. The reaction mixture was stirred at 100 °C overnight. The reaction mixture was cooled to room temperature and the solvent was removed in vacuum. The crude mixture was purified by column chromatography to afford compound 4b (540 mg, 2.19 mmol, 36.2% yield) as a yellow solid. LCMS: [M+H] + : 247.

[0262] Step 2: To a solution of compound 4b (300 mg, 1.22 mmol) in DMF (5 mL) was added sodium hydride (53 mg, 60% in mineral oil, 1.34 mmol, 1.1 eq.) at 0 °C. The reaction mixture was stirred at 0 °C for 10 min. Then a solution of mixture of compounds 3c and 3c’ (256.5 mg, 1.46 mmol, 1.2 eq.) in dry DMF (2 mL) was added dropwise at 0 °C. The mixture was stirred at room temperature for 2 h. The mixture was quenched with methanol (2 mL). The crude mixture was purified by reverse phase column chromatography to afford compound 4d (230 mg, 0.56 mmol, 46.1% yield) as a yellow solid. LCMS: [M+H] + : 410.

[0263] Step 3: To a solution of compound 4d (230 mg, 0.56 mmol) in acetonitrile (5 mL) was added trifluoroacetic anhydride (2 mL). The mixture was stirred at 80 °C for 3 h. The solvent was removed under reduced pressure. The crude residue was purified by column chromatography to afford 2-((1r,4r)-4-(imidazo[1,2-a]pyrido[3,2- e]pyrazin-9-yl)cyclohexyl)acetonitrile (4) (142.4 mg, 0.48 mmol, 86% yield) as a yellow solid. LCMS: [M+H] + : 294. 1H NMR (400 MHz, Methanol-d4) δ 8.98 (s, 1H), 8.78 (dd, J = 4.6, 1.7 Hz, 1H), 8.46 (dd, J = 8.1, 1.7 Hz, 1H), 7.72 (dd, J = 8.1, 4.6 Hz, 1H), 7.68 (s, 1H), 4.18 (tt, J = 11.9, 3.3 Hz, 1H), 2.50 (d, J = 6.4 Hz, 2H), 2.42 - 2.36 (m, 2H), 2.08 - 2.01 (m, 2H), 1.91 - 1.79 (m, 1H), 1.72 - 1.58 (m, 2H), 1.54 - 1.41 (m, 2H).

[0264] Example 5. TYK2 cellular ELISA assay using NK92 cells

[0265] This test was performed to test cellular TYK2 activity in NK92 cells using IL-12 and IL-18 stimulated IFNy secretion assay. The test was performed according to the following procedure: 1) replace IL-2 containing NK92 cell medium with medium without IL-2, maintain overnight; 2) plate NK92 cells in 96-well plates at a density of ~150,000 cells / well; 3) add different concentrations of test article to the wells, maintain in an incubator at 37 °C and 5% CO2 for 1 hour; 4) add IL-12 (final concentration: 2 ng / ml) and IL-18 (final concentration: 5 ng / ml) to stimulate for 24 hours in the above incubator; 5) after 24 hours, centrifuge at 2000 rpm for 5 min, take supernatant, and analyze according to the instructions of the ELISA kit.

[0266] Test results are shown below (IC 50 Units: µM):

[0267]

[0268] Incorporated by reference

[0269] This application refers to various issued patents, published patent applications, scientific journal articles, and other publications, all of which are incorporated herein by reference. The details of one or more embodiments of the application are set forth in this disclosure. Other features, objects, and advantages of the application will be apparent from the detailed description, examples, and claims.

[0270] Equivalents and scope

[0271] In the claims, the articles "a," "an," and "the" can mean one or more than one unless indicated to the contrary or otherwise evident from the context. The use of the term "or" in any claim having two or more associated statements is intended to mean that at least one of the associated statements is true. Thus, the use of "or" in such claims will be understood to be the inclusive, and not the exclusive, sense. The disclosure encompasses all variations, combinations, and permutations of one or more limitations, elements, clauses, and descriptive terms described in any associated claim. For example, dependency of any claim on another claim can be modified to include one or more limitations, elements, clauses, and descriptive terms from any other claim. Each subcombination of the elements, limitations, clauses, and descriptive terms in any claim is also contemplated, and any element, limitation, clause, or descriptive term in any claim can be removed from that claim. It should be understood that, in general, where the disclosure or aspects of the disclosure are said to include particular elements and / or features, certain embodiments of the disclosure or aspects of the disclosure consist of or consist essentially of those elements and / or features. Those embodiments are not expressly recited in every iteration of these words. Further, it should be understood that the terms "include," "includes," and "including," are intended to be open and permitting, as opposed to limiting or exhaustive. Where ranges are given, the endpoints are included in the ranges. Further, unless otherwise indicated or otherwise apparent from context, in different embodiments of the disclosure values expressed in a range can take any particular value or sub-range within that range, to the tenth of a unit of the lower limit of the range, unless otherwise indicated or otherwise apparent from context and understood by those of ordinary skill in the art.

[0272] Further, the disclosure encompasses all variations, combinations, and permutations of one or more limitations, elements, clauses, and descriptive terms from any listed claim. For example, dependency of any claim on another claim can be modified to include one or more limitations, elements, clauses, and descriptive terms from any other claim. Each subcombination of the elements, limitations, clauses, and descriptive terms in any claim is also contemplated, and any element, limitation, clause, or descriptive term in any claim can be removed from that claim. It should be understood that, in general, where the disclosure or aspects of the disclosure are said to include particular elements and / or features, certain embodiments of the disclosure or aspects of the disclosure consist of or consist essentially of those elements and / or features. Those embodiments are not expressly recited in every iteration of these words. Further, it should be understood that the terms "include," "includes," and "including," are intended to be open and permitting, as opposed to limiting or exhaustive. Where ranges are given, the endpoints are included in the ranges. Further, unless otherwise indicated or otherwise apparent from context, in different embodiments of the disclosure values expressed in a range can take any particular value or sub-range within that range, to the tenth of a unit of the lower limit of the range, unless otherwise indicated or otherwise apparent from context and understood by those of ordinary skill in the art.

[0273] The present application makes reference to various issued patents, published patent applications, journal articles and other publications, all of which are incorporated herein by reference. In the event of any inconsistency between any of the incorporated references and the present specification, the present specification shall prevail. Further, any particular embodiment of the disclosure falling within the scope of the prior art can be expressly excluded from any one or more claims. Because such embodiments are considered to be known to those of ordinary skill in the art, they can be excluded even if not expressly recited as excluded herein. Any particular embodiment of the disclosure can be excluded from any claim for any reason, whether or not related to the existence of prior art.

[0274] 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 present embodiments described herein is not intended to be limited to the above description but is only limited as set forth in the appended claims. Various modifications can be made to the present description as well as equivalents thereof without departing from the spirit or scope of the disclosure as defined in the following claims.

Claims

1. A compound of Formula (I): (I) or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein: ， X is CH or N; 2. The compound of claim 1, having Formula (la): (la) or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein: Y 1 is C, Y 2 is N; or Y 1 is N, Y 2 is C; is a single or double bond; R 1 C is H, halogen, or optionally substituted with 1, 2, or 3 substituents. 1-3 Alkyl group, wherein the substituent is independently selected from halogen, OH, CN, OR, NHR, NRR', N(R)C(O)R', N(R)C(O)OR', OC(O)NRR', C(O)R, C(O)NRR', N(R)S(O)2R', S(O)2R and S(O)2NRR'; Cy is C 3-7 Cycloalkyl or 3-7 membered heterocyclyl, wherein Cy is optionally substituted with 1, 2, or 3 substituents independently selected from R 2 , oxo, halogen, OH, CN, OR, NHR, NRR', N(R)C(O)R', N(R)C(O)(O)R', OC(O)NRR', C(O)R, C(O)NRR', N(R)S(O)2R', S(O)2R, and S(O)2NRR'; R 2 is C 1-3 alkyl, C 3-7 cycloalkyl, 3-7 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, optionally substituted with 1, 2, or 3 substituents independently selected from halogen, OH, CN, OR, NHR, NRR', N(R)C(O)R', N(R)C(O)(O)R', OC(O)NRR', C(O)R, C(O)NRR', N(R)S(O)2R', S(O)2R, and S(O)2NRR'; R, R' are each independently H, C 1-3 alkyl or C 3-6 cycloalkyl, which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, OH, and CN. X is CH or N; ， 3. The compound of claim 1, having Formula (lb): (lb) or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein: X is CH or N; R 1 C is H, halogen, or optionally substituted with 1, 2, or 3 substituents. 1-3 Alkyl group, wherein the substituent is independently selected from halogen, OH, CN, OR, NHR, NRR', N(R)C(O)R', N(R)C(O)OR', OC(O)NRR', C(O)R, C(O)NRR', N(R)S(O)2R', S(O)2R and S(O)2NRR'; Ring A is a 4-7 membered heterocyclic group, which is optionally substituted by 1, 2 or 3 independent substituents selected from the following: R 2 Oxygenated, halogenated, OH, CN, OR, NHR, NRR', N(R)C(O)R', N(R)C(O)(O)R', OC(O)NRR', C(O)R, C(O)NRR', N(R)S(O)2R', S(O)2R and S(O)2NRR'; R 2 is C 1-3 alkyl, C 3-7 cycloalkyl, 3-7 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, optionally substituted with 1, 2, or 3 substituents independently selected from halogen, OH, CN, OR, NHR, NRR', N(R)C(O)R', N(R)C(O)(O)R', OC(O)NRR', C(O)R, C(O)NRR', N(R)S(O)2R', S(O)2R, and S(O)2NRR'; R, R' are each independently H, C 1-3 alkyl or C 3-6 cycloalkyl, which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, OH, and CN. X is CH. ， X is N.

6. The compound of claim 2, 4, or 5, or a pharmaceutically acceptable salt thereof, wherein: R 1 H, halogen or C1-6alkyl optionally substituted with 1, 2, or 3 substituents independently selected from halogen, OH, CN, OR, NHR, NRR', N(R)C(O)R', N(R)C(O)OR', OC(O)NRR', C(O)R, C(O)NRR', N(R)S(O)2R', S(O)2R, and S(O)2NRR'; and 1-3 H, halogen or C1-6alkyl optionally substituted with 1, 2, or 3 substituents independently selected from halogen, OH, CN, OR, NHR, NRR', N(R)C(O)R', N(R)C(O)OR', OC(O)NRR', C(O)R, C(O)NRR', N(R)S(O)2R', S(O)2R, and S(O)2NRR'; and Cy is C 3-7 Cycloalkyl or 3-7 membered heterocyclyl, wherein Cy is optionally substituted with 1, 2, or 3 substituents independently selected from R 2 , oxo, halogen, OH, CN, OR, NHR, NRR', N(R)C(O)R', N(R)C(O)(O)R', OC(O)NRR', C(O)R, C(O)NRR', N(R)S(O)2R', S(O)2R, and S(O)2NRR'; R 2 is C 1-3 alkyl, C 3-7 cycloalkyl, 3-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, optionally substituted with 1, 2 or 3 substituents independently selected from halogen, OH, CN, OR, NHR, NRR', N(R)C(O)R', N(R)C(O)(O)R', OC(O)NRR', C(O)R, C(O)NRR', N(R)S(O)2R', S(O)2R and S(O)2NRR'; R, R' are each independently H, C 1-3 alkyl or C 3-6 cycloalkyl, which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, OH, and CN.

4. The compound according to claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein:

7. The compound of claim 6, or a pharmaceutically acceptable salt thereof, wherein:

5. The compound according to claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein:

10. The compound of claim 3, 4, or 5, or a pharmaceutically acceptable salt thereof, wherein:

11. The compound of claim 10, or a pharmaceutically acceptable salt thereof, wherein: Ring A is a 4-7 membered heterocyclyl, optionally substituted with 1, 2, or 3 substituents independently selected from R 2 , halo, OH, CN, OR, and N(R)S(O)2R'. R 2 C1-C6alkyl optionally substituted with 1, 2, or 3 substituents independently selected from halo, OH, CN, OR, NHR, NRR', N(R)C(O)R', N(R)C(O)(O)R', OC(O)NRR', C(O)R, C(O)NRR', N(R)S(O)2R', S(O)2R, and S(O)2NRR'; and 1-3 C1-C6alkyl optionally substituted with 1, 2, or 3 substituents independently selected from halo, OH, CN, OR, NHR, NRR', N(R)C(O)R', N(R)C(O)(O)R', OC(O)NRR', C(O)R, C(O)NRR', N(R)S(O)2R', S(O)2R, and S(O)2NRR'.

15. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt thereof, wherein the compound is: Ring A is a 6-membered heterocyclyl group, which is optionally substituted by R 2 substituents; R 2 C1-C6alkyl optionally substituted with 1, 2, or 3 substituents independently selected from halo, OH, CN, OR, NHR, NRR', N(R)C(O)R', N(R)C(O)(O)R', OC(O)NRR', C(O)R, C(O)NRR', N(R)S(O)2R', S(O)2R, and S(O)2NRR'; and 1-3 C1-C6alkyl optionally substituted with 1, 2, or 3 substituents independently selected from halo, OH, CN, OR, NHR, NRR', N(R)C(O)R', N(R)C(O)(O)R', OC(O)NRR', C(O)R, C(O)NRR', N(R)S(O)2R', S(O)2R, and S(O)2NRR'.

8. The compound of claim 7, or a pharmaceutically acceptable salt thereof, wherein: Ring A is a 6-membered heterocyclyl group, which is optionally substituted by substituted.

9. The compound of claim 8, or a pharmaceutically acceptable salt thereof, wherein: Ring A is . 2-(l-(2-methyl-lH-imidazo[4,5-c]quinolin-l-yl)piperidin-4-yl)acetonitrile (1); Cy is C 3-7 cycloalkyl, optionally substituted with 1, 2, or 3 substituents independently selected from R 2 halo, OH, CN, OR, and N(R)S(O)2R'. R 2 C1-C6alkyl optionally substituted with 1, 2, or 3 substituents independently selected from halo, OH, CN, OR, NHR, NRR', N(R)C(O)R', N(R)C(O)(O)R', OC(O)NRR', C(O)R, C(O)NRR', N(R)S(O)2R', S(O)2R, and S(O)2NRR'; and 1-3 C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, C3-C6cycloalkenyl, heterocyclyl, aryl, and heteroaryl, each optionally substituted with 1, 2, or 3 substituents independently selected from halo, OH, CN, OR, NHR, NRR', N(R)C(O)R', N(R)C(O)(O)R', OC(O)NRR', C(O)R, C(O)NRR', N(R)S(O)2R', S(O)2R 2-(l-(2-methyl-lH-imidazo[4,5-c][l,5]naphthyridin-l-yl)piperidin-4-yl)acetonitrile (2); Cy is cyclohexyl, which is optionally substituted with R 2 substituted; R 2 C1-C6alkyl optionally substituted with 1, 2, or 3 substituents independently selected from halo, OH, CN, OR, NHR, NRR', N(R)C(O)R', N(R)C(O)(O)R', OC(O)NRR', C(O)R, C(O)NRR', N(R)S(O)2R', S(O)2R, and S(O)2NRR'; and 1-3 C1-C6alkyl optionally substituted with 1, 2, or 3 substituents independently selected from halo, OH, CN, OR, NHR, NRR', N(R)C(O)R', N(R)C(O)(O)R', OC(O)NRR', C(O)R, C(O)NRR', N(R)S(O)2R', S(O)2R, and S(O)2NRR'.

12. The compound or pharmaceutically acceptable salt thereof of claim 11, wherein: Cy is .

13. The compound of claim 12, or a pharmaceutically acceptable salt thereof, wherein: Cy is .

14. The compound or pharmaceutically acceptable salt thereof of any one of claims 1 to 13, wherein: R 1 H, CH3or . 2-((lr,4r)-4-(imidazo[l,2-a]quinoxalin-l-yl)cyclohexyl)acetonitrile (3); 2-((lr,4r)-4-(imidazo[l,2-a]pyrido[3,2-e]pyrazin-9-yl)cyclohexyl)acetonitrile (4).

16. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt thereof, wherein the compound is: (R)-2-(l-(2-(l-hydroxyethyl)-lH-imidazo[4,5-c]quinolin-l-yl)piperidin-4-yl)acetonitrile (5); (R)-2-(l-(2-(l-hydroxyethyl)-lH-imidazo[4,5-c][l,5]naphthyridin-l-yl)piperidin-4-yl)acetonitrile (6); 2-((lr,4r)-4-(2-methylimidazo[l,2-a]quinoxalin-l-yl)cyclohexyl)acetonitrile (7); 2-((lr,4r)-4-(8-methylimidazo[l,2-a]pyrido[3,2-e]pyrazin-9-yl)cyclohexyl)acetonitrile (8).

17. A method of treating a central nervous system (CNS) disorder, the method comprising administering to a subject in need thereof an effective amount of a compound of claims 1-16, or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

18. The method of claim 17, wherein the CNS disorder is a neurodegenerative disease. ​ ​ ​ 19. The method of claim 18, wherein the neurodegenerative disease is amyotrophic lateral sclerosis, Alzheimer’s disease, multiple sclerosis, or Parkinson’s disease.

20. A method of treating an inflammatory disorder, the method comprising administering to a subject in need thereof an effective amount of a compound of claims 1-16, or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

21. The method of claim 20, wherein the inflammatory disorder is psoriasis, lupus, ankylosing spondylitis.

22. A method of treating a central nervous system (CNS) disorder, the method comprising administering to a subject in need thereof an effective amount of a composition comprising a compound of claims 1-16, or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, and a pharmaceutically acceptable excipient.

23. The method of claim 22, wherein the neurodegenerative disease is amyotrophic lateral sclerosis, Alzheimer’s disease, multiple sclerosis, or Parkinson’s disease.

24. A method of treating an inflammatory disorder, the method comprising administering to a subject in need thereof an effective amount of a composition comprising a compound of claims 1-16, or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, and a pharmaceutically acceptable excipient.

25. The method of claim 24, wherein the inflammatory disorder is psoriasis, lupus, ankylosing spondylitis.

26. The method of claims 22-25, wherein the composition further comprises an additional agent.

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