Novel kinase inhibitors

Abstract

The present invention relates to compounds as kinase inhibitors, particularly brain-penetrant TYK2 inhibitors useful for treating central nervous system (CNS) disorders. Also provided herein are methods of treating CNS disorders using compositions containing such compounds.

Description

[Background technology]

[0001] Protein kinases are a large family of proteins that play a central role in regulating diverse cellular processes and maintaining cellular function. Some (but not limited to) of these kinases include non-receptor tyrosine kinases, such as the Janus kinase family (JAK1, JAK2, JAK3, and TYK2), receptor tyrosine kinases, such as platelet-derived growth factor receptor kinase (PDGFR), and serine / threonine kinases, such as b-RAF. Abnormal 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 over other related kinases, and are therefore expected to be useful in treating disorders mediated by the selectively inhibited kinases while avoiding the undesirable side effects associated with the inhibition of related kinases.

[0002] In particular, the Janus kinase family consists of four known family members: JAK1, JAK2, JAK3, and tyrosine kinase 2 (TYK2). These cytoplasmic tyrosine kinases associate with membrane cytokine receptors, such as the common gamma chain receptor and glycoprotein 130 (gp130) transmembrane protein (Murray, J. Immunol. 178(5):2623-2629, 2007). Approximately 40 cytokine receptors signal through a combination of these four JAK family members and seven downstream substrates, including signal transduction and activation of transcription (STAT) family members (Ghoreschi et al., Immunol Rev. 228(1):273-287, 2009). Cytokine binding to the receptor initiates JAK activation through transphosphorylation and autophosphorylation. JAK family kinases then phosphorylate residues on the cytokine receptor, creating binding sites for sarcoma homology 2 (SH2)-containing proteins, such as STAT factors and other regulatory factors. These proteins are then activated by phosphorylation by JAKs. Activated STATs enter the nucleus and initiate the expression of survival factors, cytokines, chemokines, and molecules that promote leukocyte intracellular migration (Schindler et al., J. Biol. Chem. 282(28):20059-20063, 2007). JAK activation also induces cell proliferation via phosphoinositide 3-kinase (PI3K) and protein kinase B-mediated pathways.

[0003] Given the close structural similarity between JAK1 and JAK2 (Williams et al., J. Mal. Biol. 387(1):219-232, 2009), literature suggests that most JAK1 inhibitors also inhibit JAK2 (lncyte Corp. press release, November 10, 2010; Changelian et al., Science 302 (5646):875-878, 2003). Recently, two JAK1-selective compounds, upadacitinib and abrocitinib, were approved by the FDA. Deuclavacitinib, a TYK2-selective inhibitor, has been approved by the FDA for the treatment of psoriasis. Deuclavacitinib is also in clinical development for systemic lupus erythematosus and ankylosing spondylitis.

[0004] Alzheimer's disease (AD) is the most common form of neurodegenerative disease, accounting for an estimated 60–70% of dementia cases worldwide. According to the prevailing amyloid cascade hypothesis, amyloid-β (Aβ) deposition in the brain is the initiating point for AD pathogenesis. However, accumulating evidence suggests that this hypothesis alone cannot explain many aspects of AD pathogenesis. The discovery of increased levels of inflammatory markers in AD patients and the identification of AD risk genes related to innate immune function suggest that neuroinflammation plays a prominent role in AD pathogenesis (Leng and Edison, Nat Rev Neurol. 2021 Mar;17(3):157-172). In particular, the JAK-STAT pathway has been implicated as a target in AD based on genetic real-world data (Nevado-Holgado et al. Cells 2019, 8(5)). Type I INF signaling regulated by TYK2 and JAK1 has been shown to promote memory dysfunction associated with amyloid-β 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-penetrant JAK1 and / or TYK2 inhibitors may be useful for treating neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Alzheimer's disease (AD). Summary of the Invention

[0005] In light of recent reports of the important role of neuroinflammation in general, and TYK2 in particular, in CNS diseases, the present invention discloses TYK2 inhibitors. Some of these inhibitors have good brain penetration and anti-neuroinflammatory activity. Therefore, these compounds and compositions containing the disclosed compounds are useful for treating disorders associated with TYK2 activity, including CNS disorders such as 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, and ankylosing spondylitis.

[0006] The present disclosure provides novel compounds or salts, solvates, hydrates, polymorphs, cocrystals, tautomers, stereoisomers, isotope-labeled derivatives, or prodrugs thereof as selective TYK2 kinase inhibitors, some of which have good ability to penetrate the blood-brain barrier and therefore have advantageous properties suitable for use in treating central nervous system (CNS) disorders. The present disclosure also provides compositions comprising the compounds of the present disclosure or salts, solvates, hydrates, polymorphs, cocrystals, tautomers, stereoisomers, isotope-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, etc.

[0007] In one embodiment, the compounds of formula (I), formula (II), formula (III) and formula (IV): [ka] [In the formula, X is CH or N; Y 1 is C and Y 2 is N; or Y 1 is N and Y 2 is C; [ka] is a single or double bond; R 1 is H, halo, or C optionally substituted by one, two, or three substituents independently selected from the group consisting of halo, 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)R', S(O)R, and S(O)NRR'; 1-3 is alkyl; Cy is C 3-7 cycloalkyl or 3- to 7-membered heterocyclyl, where Cy is R 2 , oxo, 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)R', S(O)R and S(O)NRR'; R 2 is optionally substituted by one, two, or three substituents independently selected from the group consisting of 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)R', S(O)R, and S(O)NRR' 1-3 Alkyl, C 3-7 cycloalkyl, 3- to 7-membered heterocyclyl, phenyl, or 5- to 6-membered heteroaryl; R, R' are each independently H or C optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halo, OH and CN. 1-3 Alkyl or C 3-6 cycloalkyl] or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative or prodrug thereof.

[0008] In another embodiment, the compounds of formula (Ia), formula (IIa), formula (IIIa) and formula (IVa): [ka] [In the formula, X is CH or N; R 1 is H, halo, or C optionally substituted by one, two, or three substituents independently selected from the group consisting of halo, 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)R', S(O)R, and S(O)NRR'; 1-3 is alkyl; Ring A is R 2 , oxo, 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)R', S(O)R and S(O)NRR'; R 2 is optionally substituted by one, two, or three substituents independently selected from the group consisting of 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)R', S(O)R, and S(O)NRR' 1-3 Alkyl, C 3-7 cycloalkyl, 3- to 7-membered heterocyclyl, phenyl, or 5- to 6-membered heteroaryl; R, R' are each independently H or C optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halo, OH and CN. 1-3 Alkyl or C 3-6 cycloalkyl] or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative or prodrug thereof.

[0009] In another embodiment, the compounds of formula (Ib), formula (IIb), formula (IIIb) and formula (IVb): [ka] [In the formula, X is CH or N; R 1 is H, halo, or C optionally substituted by one, two, or three substituents independently selected from the group consisting of halo, 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)R', S(O)R, and S(O)NRR'; 1-3 is alkyl; Cy is C 3-7 cycloalkyl or 3- to 7-membered heterocyclyl, where Cy is R 2 , oxo, 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)R', S(O)R and S(O)NRR'; R 2 is optionally substituted by one, two, or three substituents independently selected from the group consisting of 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)R', S(O)R, and S(O)NRR' 1-3 Alkyl, C 3-7 cycloalkyl, 3- to 7-membered heterocyclyl, phenyl, or 5- to 6-membered heteroaryl; R, R' are each independently H or C optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halo, OH and CN. 1-3 Alkyl or C 3-6 cycloalkyl] or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative or prodrug thereof.

[0010] In another embodiment, the compounds of formula (Ic), formula (IIc), formula (IIIc) and formula (IVc): [ka] [In the formula, X is CH or N; R 1 is H, halo, or C optionally substituted by one, two, or three substituents independently selected from the group consisting of halo, 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)R', S(O)R, and S(O)NRR'; 1-3 is alkyl; Ring A is R 2 , oxo, 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)R', S(O)R and S(O)NRR'; R 2 is optionally substituted by one, two, or three substituents independently selected from the group consisting of 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)R', S(O)R, and S(O)NRR' 1-3 Alkyl, C3-7 cycloalkyl, 3- to 7-membered heterocyclyl, phenyl, or 5- to 6-membered heteroaryl; R, R' are each independently H or C optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halo, OH and CN. 1-3 Alkyl or C 3-6 cycloalkyl] or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative or prodrug thereof.

[0011] In another embodiment, the compounds of formula (Id), formula (IId), formula (IIId) and formula (IVd): [ka] [In the formula, X is CH or N; R 1 is H, halo, or C optionally substituted by one, two, or three substituents independently selected from the group consisting of halo, 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)R', S(O)R, and S(O)NRR'; 1-3 is alkyl; Cy is C 3-7 cycloalkyl or 3- to 7-membered heterocyclyl, where Cy is R 2 , oxo, 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)R', S(O)R and S(O)NRR'; R 2is optionally substituted by one, two, or three substituents independently selected from the group consisting of 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)R', S(O)R, and S(O)NRR' 1-3 Alkyl, C 3-7 cycloalkyl, 3- to 7-membered heterocyclyl, phenyl, or 5- to 6-membered heteroaryl; R, R' are each independently H or C optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halo, OH and CN. 1-3 Alkyl or C 3-6 cycloalkyl] or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative or prodrug thereof.

[0012] Compounds of the present invention, and compositions comprising them, are useful for treating or lessening the severity of diseases, disorders, or symptoms thereof modulated by TYK2.

[0013] Thus, one aspect of the present disclosure relates to a method for treating a CNS disorder, comprising administering to a subject in need thereof an effective amount of a compound of formula (I) as described 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.

[0014] In some embodiments, the CNS disorder can be any of those regulated 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.

[0015] Also included within the scope of the present disclosure is (i) a pharmaceutical composition for use in treating a targeted CNS disorder described herein, 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) the use of a compound of formula (I) or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative or prodrug thereof, for the manufacture of a medicament for use in treating any of the targeted CNS disorders.

[0016] When a definition of a variable herein includes a list of chemical groups, the variable is defined as any of the listed groups alone or in combination. The description of an embodiment of a variable herein includes the practice of that embodiment as a single embodiment or in combination with other embodiments or portions thereof. The description of an embodiment herein includes the practice of that embodiment as a single embodiment or in combination with other embodiments or portions thereof.

[0017] The details of one or more embodiments of the invention are set forth in the following description. Other features or advantages of the invention will be apparent from the following drawings and detailed description of several embodiments, as well as from the appended claims.

[0018] definition Unless otherwise defined, all technical and scientific terms used herein have the meanings that are commonly understood by those skilled in the art to which this invention belongs.The following references provide those skilled in the art with many of the general definitions of the terms used in this invention: 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 HarperCollins Dictionary of Biology (1991).As used herein, the following terms have the meanings ascribed to them unless otherwise specified.

[0019] Definitions of specific chemical terms are described in more detail below. Chemical elements are identified according to the CAS Periodic Table, published inside the cover of the Handbook of Chemistry and Physics (75th ed.), and specific functional groups generally follow the definitions set forth therein. Additionally, general principles of organic chemistry, as well as specific functional groups and reactivities, are described in detail in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Michael B. Smith, March's Advanced Organic Chemistry, 7 thEdition, 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, 3 rd Edition, Cambridge University Press, Cambridge, 1987.

[0020] The compounds described herein may contain one or more asymmetric centers and therefore may exist in various stereoisomeric forms, such as enantiomers and / or diastereomers. For example, the compounds described herein may be in the form of individual enantiomers, diastereomers, or geometric isomers, or may be in the form of mixtures of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high-pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts. Alternatively, preferred isomers can be prepared by asymmetric synthesis. See, e.g., Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, 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., University of Notre Dame Press, Notre Dame, IN 1972). The present invention further encompasses the compounds as individual isomers substantially free of other isomers, or alternatively, as mixtures of various isomers.

[0021] The compounds herein may also contain bonds (e.g., carbon-carbon bonds) in which bond rotation around a particular bond is restricted, for example, due to the presence of a ring or double bond. Accordingly, all cis / trans and E / Z isomers are expressly included in the present disclosure. The compounds described herein may also be represented in multiple tautomeric forms, and in such cases, the present disclosure expressly includes all tautomeric forms of the compounds described herein, even if only a single tautomeric form may be represented. All such isomeric forms of such compounds are expressly included in the present disclosure. The term "isomer" is intended to include diastereoisomers, enantiomers, positional isomers, structural isomers, rotamers, tautomers, etc. For compounds containing one or more asymmetric centers, e.g., chiral compounds, the methods of the present disclosure can be practiced using enantiomerically enriched compounds, racemates, or mixtures of diastereomers. All isomers of the compounds described herein are expressly included in the present disclosure.

[0022] In the formula, the bond: [ka] is a single bond, dotted line: [ka] is a single bond or absent, and the bond: [ka] is a single or double bond.

[0023] Unless otherwise stated, the formulas and structures depicted herein include compounds that do not contain isotopically enriched atoms as well as compounds that contain isotopically enriched atoms, e.g., replacement of hydrogen by deuterium or tritium, 18 By F 19 Substitution of F, or 13 C or 14Compounds having this structure, except for the replacement of a carbon by a C-rich carbon, are within the scope of this disclosure. Such compounds are useful, for example, as analytical tools or probes in biological assays.

[0024] The term "isotope" refers to variants of a particular chemical element such that all isotopes of a given element share the same number of protons in each atom of that element, but the isotopes differ in the number of neutrons.

[0025] When a range of values ​​("Range") is listed, each value and subrange within the range is inclusive. Unless otherwise specified, the range includes both the end values ​​of the range. For example, "C 1-6 "Alkyl" refers to C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, C6 alkyl, C 1-6 Alkyl, C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl, C 1-2 Alkyl, C 2-6 Alkyl, C 2-5 Alkyl, C 2-4 Alkyl, C 2-3 Alkyl, C 3-6 Alkyl, C 3-5 Alkyl, C 3-4 Alkyl, C 4-6 Alkyl, C 4-5 Alkyl and C 5-6 It includes alkyl.

[0026] The term "aliphatic" refers to alkyl, alkenyl, alkynyl, and carbocyclic groups. Similarly, the term "heteroaliphatic" refers to heteroalkyl, heteroalkenyl, heteroalkynyl, and heterocyclic groups.

[0027] The term "alkyl" refers to the radical of a linear or branched saturated hydrocarbon group having 1 to 20 carbon atoms ("C 1-20 In some embodiments, alkyl groups are those having 1 to 12 carbon atoms ("C 1-12In some embodiments, the alkyl group is one having 1 to 10 carbon atoms ("C 1-10 In some embodiments, the alkyl group is one having 1 to 9 carbon atoms ("C 1-9 In some embodiments, the alkyl group is one having 1 to 8 carbon atoms ("C 1-8 In some embodiments, the alkyl group is one having 1 to 7 carbon atoms ("C 1-7 In some embodiments, the alkyl group is one having 1 to 6 carbon atoms ("C 1-6 In some embodiments, the alkyl group is one having 1 to 5 carbon atoms ("C 1-5 In some embodiments, the alkyl group is one having 1 to 4 carbon atoms ("C 1-4 In some embodiments, the alkyl group is one having 1 to 3 carbon atoms ("C 1-3 In some embodiments, the alkyl group is one having 1 to 2 carbon atoms ("C 1-2 In some embodiments, the alkyl group has 1 carbon atom ("C alkyl"). In some embodiments, the alkyl group has 2 to 6 carbon atoms ("C 2-6 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-pentanyl, amyl, neopentyl, 3-methyl-2-butanyl, tert-amyl), and hexyl (C6) (e.g., n-hexyl). Additional examples of alkyl groups include n-heptyl (C7), n-octyl (C8), n-dodecyl (C9), and hexyl (C10). 12Unless otherwise specified, each instance of an alkyl group is independently unsubstituted (an "unsubstituted alkyl") or substituted (a "substituted alkyl") with one or more substituents (e.g., halogen, e.g., F). In certain embodiments, an alkyl group is an unsubstituted C 1-12 Alkyl (e.g., unsubstituted C 1-6 Alkyl, for example, -CH3 (Me), unsubstituted ethyl (Et), unsubstituted propyl (Pr, for example, unsubstituted n-propyl (n-Pr), unsubstituted isopropyl (i-Pr)), unsubstituted butyl (Bu, for example, 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 certain embodiments, the alkyl group is substituted C 1-12 Alkyl (e.g., substituted C 1-6 alkyl, for example, —CH2F, —CHF2, —CF3, —CH2CH2F, —CH2CHF2, —CH2CF3 or benzyl (Bn).

[0028] The term "haloalkyl" refers to a substituted alkyl group in which one or more hydrogen atoms are independently replaced by a halogen, e.g., fluoro, bromo, chloro, or iodo. "Perhaloalkyl" is a subset of haloalkyl and refers to an alkyl group in which all hydrogen atoms are independently replaced by a halogen, e.g., fluoro, bromo, chloro, or iodo. In some embodiments, the haloalkyl moiety is one having 1 to 20 carbon atoms ("C 1-20 In some embodiments, the haloalkyl moiety has 1 to 10 carbon atoms ("C 1-10 In some embodiments, the haloalkyl moiety has 1 to 9 carbon atoms ("C 1-9 In some embodiments, the haloalkyl moiety has 1 to 8 carbon atoms ("C 1-8 In some embodiments, the haloalkyl moiety has 1 to 7 carbon atoms ("C 1-7In some embodiments, the haloalkyl moiety has 1 to 6 carbon atoms ("C 1-6 In some embodiments, the haloalkyl moiety has 1 to 5 carbon atoms ("C 1-5 In some embodiments, the haloalkyl moiety has 1 to 4 carbon atoms ("C 1-4 In some embodiments, the haloalkyl moiety has 1 to 3 carbon atoms ("C 1-3 In some embodiments, the haloalkyl moiety has 1 to 2 carbon atoms ("C 1-2 In some embodiments, all haloalkyl hydrogen atoms are independently replaced with fluoro to provide a "perfluoroalkyl" group. In some embodiments, all haloalkyl hydrogen atoms are independently replaced with chloro to provide a "perchloroalkyl" group. Examples of haloalkyl groups include -CHF, -CHF, -CF, -CHCF, -CFCF, -CFCF, -CFCFCF, -CCl, -CFCl, -CFCl, and the like.

[0029] The term "heteroalkyl" refers to an alkyl group that further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within the parent chain (e.g., inserted between adjacent carbon atoms) and / or at one or more terminal positions of the parent chain. In certain embodiments, a heteroalkyl group is a saturated group having 1 to 20 carbon atoms and one or more heteroatoms within the parent chain ("heteroC"). 1-20 In certain embodiments, a heteroalkyl group refers to a saturated group having 1 to 12 carbon atoms and one or more heteroatoms in the parent chain ("heteroC 1-12 In some embodiments, a heteroalkyl group refers to a saturated group having 1 to 11 carbon atoms and one or more heteroatoms in the parent chain ("heteroC 1-11In some embodiments, heteroalkyl groups are saturated groups having 1 to 10 carbon atoms and one or more heteroatoms in the parent chain ("heteroC 1-10 In some embodiments, heteroalkyl groups are saturated groups having 1 to 9 carbon atoms and one or more heteroatoms in the parent chain ("heteroC 1-9 In some embodiments, heteroalkyl groups are saturated groups having 1 to 8 carbon atoms and one or more heteroatoms in the parent chain ("heteroC 1-8 In some embodiments, heteroalkyl groups are saturated groups having 1 to 7 carbon atoms and one or more heteroatoms in the parent chain ("heteroC 1-7 In some embodiments, heteroalkyl groups are saturated groups having 1 to 6 carbon atoms and one or more heteroatoms in the parent chain ("heteroC 1-6 In some embodiments, heteroalkyl groups are saturated groups having 1 to 5 carbon atoms and 1 or 2 heteroatoms in the parent chain ("heteroC 1-5 In some embodiments, heteroalkyl groups are saturated groups having 1 to 4 carbon atoms and 1 or 2 heteroatoms in the parent chain ("heteroC 1-4 In some embodiments, heteroalkyl groups are saturated groups having 1 to 3 carbon atoms and 1 heteroatom in the parent chain ("heteroC 1-3 In some embodiments, heteroalkyl groups are saturated groups having 1 to 2 carbon atoms and 1 heteroatom in the parent chain ("heteroC 1-2 In some embodiments, the heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom ("heteroC1 alkyl"). In some embodiments, the heteroalkyl group is a saturated group having 2 to 6 carbon atoms and 1 or 2 heteroatoms in the parent chain ("heteroC 2-6Unless otherwise specified, each instance of a heteroalkyl group is independently unsubstituted (an "unsubstituted heteroalkyl") or substituted (a "substituted heteroalkyl") with one or more substituents. In certain embodiments, a heteroalkyl group is an unsubstituted heteroC 1-12 In certain embodiments, the heteroalkyl group is a substituted heteroC 1-12 It is alkyl.

[0030] The term "alkenyl" refers to the radical of a straight-chain or branched hydrocarbon group having 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, alkenyl groups are those having 2 to 20 carbon atoms ("C 2-20 In some embodiments, the alkenyl group is one having 2 to 12 carbon atoms ("C 2-12 In some embodiments, the alkenyl group is one having 2 to 11 carbon atoms ("C 2-11 In some embodiments, the alkenyl group is one having 2 to 10 carbon atoms ("C 2-10 In some embodiments, the alkenyl group is one having 2 to 9 carbon atoms ("C 2-9 In some embodiments, the alkenyl group is one having 2 to 8 carbon atoms ("C 2-8 In some embodiments, the alkenyl group is one having 2 to 7 carbon atoms (“C 2-7 In some embodiments, the alkenyl group is one having 2 to 6 carbon atoms ("C 2-6 In some embodiments, the alkenyl group is one having 2 to 5 carbon atoms ("C 2-5 In some embodiments, the alkenyl group is one having 2 to 4 carbon atoms ("C 2-4In some embodiments, the alkenyl group is one having 2 to 3 carbon atoms (“C 2-3 In some embodiments, the alkenyl group has two carbon atoms ("C2 alkenyl"). The one or more carbon-carbon double bonds can be internal (e.g., 2-butenyl) or terminal (e.g., 1-butenyl). C 2-4 Examples of alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. 2-6 Examples of the alkenyl group include the above-mentioned C 2-4 Alkenyl groups include pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like. Unless otherwise specified, each instance of an alkenyl group is independently unsubstituted ("unsubstituted alkenyl") or substituted with one or more substituents ("substituted alkenyl"). In certain embodiments, an alkenyl group is an unsubstituted C 2-20 In certain embodiments, the alkenyl group is a substituted C 2-20 In an alkenyl group, a C=C double bond with unspecified stereochemistry (e.g., -CH=CHCH3 or [ka] ) can be in the (E) or (Z) configuration.

[0031] The term "heteroalkenyl" refers to an alkenyl group that further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within the parent chain (e.g., inserted between adjacent carbon atoms) and / or at one or more terminal positions of the parent chain. In certain embodiments, a heteroalkenyl group refers to a group having 2 to 20 carbon atoms, at least one double bond, and one or more heteroatoms within the parent chain ("heteroalkenyl"). 2-20In certain embodiments, a heteroalkenyl group refers to a group having 2 to 12 carbon atoms, at least one double bond, and one or more heteroatoms in the parent chain ("heteroC"). 2-12 In certain embodiments, a heteroalkenyl group refers to a group having 2 to 11 carbon atoms, at least one double bond, and one or more heteroatoms in the parent chain ("heteroC"). 2-11 In certain embodiments, a heteroalkenyl group refers to a group having 2 to 10 carbon atoms, at least one double bond, and one or more heteroatoms in the parent chain ("heteroC"). 2-10 In some embodiments, heteroalkenyl groups refer to those having 2 to 9 carbon atoms, at least one double bond, and one or more heteroatoms in the parent chain ("heteroC"). 2-9 In some embodiments, heteroalkenyl groups refer to those having 2 to 8 carbon atoms, at least one double bond, and one or more heteroatoms in the parent chain ("heteroC"). 2-8 In some embodiments, heteroalkenyl groups have 2 to 7 carbon atoms, at least one double bond, and one or more heteroatoms in the parent chain ("heteroC 2-7 In some embodiments, heteroalkenyl groups have 2 to 6 carbon atoms, at least one double bond, and one or more heteroatoms in the parent chain ("heteroC 2-6 In some embodiments, heteroalkenyl groups have 2 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms in the parent chain ("heteroC 2-5 In some embodiments, heteroalkenyl groups have 2 to 4 carbon atoms, at least one double bond, and 1 or 2 heteroatoms in the parent chain ("heteroC 2-4 In some embodiments, heteroalkenyl groups have 2 to 3 carbon atoms in the parent chain, at least one double bond, and one heteroatom ("heteroC 2-3In some embodiments, heteroalkenyl groups have 2 carbon atoms, at least one double bond, and 1 heteroatom in the parent chain ("heteroC2 alkenyl"). In some embodiments, heteroalkenyl groups have 2 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms in the parent chain ("heteroC2 alkenyl"). 2-6 Unless otherwise specified, each instance of a heteroalkenyl group is independently unsubstituted (an "unsubstituted heteroalkenyl") or substituted (a "substituted heteroalkenyl") with one or more substituents. In certain embodiments, a heteroalkenyl group is an unsubstituted heteroC 2-20 In certain embodiments, the heteroalkenyl group is a substituted heteroC 2-20 It is alkenyl.

[0032] The term "alkynyl" refers to a straight-chain or branched hydrocarbon radical 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 In some embodiments, alkynyl groups refer to those having 2 to 10 carbon atoms ("C 2-10 In some embodiments, alkynyl groups are those having 2 to 9 carbon atoms (“C 2-9 In some embodiments, alkynyl groups are those having 2 to 8 carbon atoms (“C 2-8 In some embodiments, alkynyl groups are those having 2 to 7 carbon atoms (“C 2-7 In some embodiments, alkynyl groups are those having 2 to 6 carbon atoms (“C 2-6 In some embodiments, alkynyl groups are those having 2 to 5 carbon atoms (“C 2-5 In some embodiments, alkynyl groups are those having 2 to 4 carbon atoms (“C 2-4In some embodiments, the alkynyl group is one having 2 to 3 carbon atoms ("C 2-3 In some embodiments, the alkynyl group has two carbon atoms ("C2 alkynyl"). The one or more carbon-carbon triple bonds can be internal (e.g., 2-butynyl) or terminal (e.g., 1-butynyl). C 2-4 Examples of alkynyl groups include, but are not limited to, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. 2-6 Examples of the alkenyl group include the above-mentioned C 2-4 Alkynyl groups include pentynyl (C5), hexynyl (C6), and the like. Additional examples of alkynyl include heptynyl (C7), octynyl (C8), and the like. Unless otherwise specified, each instance of an alkynyl group is independently unsubstituted ("unsubstituted alkynyl") or substituted with one substituent ("substituted alkynyl"). In certain embodiments, an alkynyl group is an unsubstituted C 2-20 In certain embodiments, the alkynyl group is a substituted C 2-20 It is alkynyl.

[0033] The term "heteroalkynyl" refers to an alkynyl group that further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within the parent chain (e.g., inserted between adjacent carbon atoms) and / or at one or more of the terminal positions of the parent chain. In certain embodiments, a heteroalkynyl group is a group having 2 to 20 carbon atoms, at least one triple bond, and one or more heteroatoms within the parent chain ("heteroalkynyl"). 2-20 In certain embodiments, a heteroalkynyl group refers to a group having 2 to 10 carbon atoms, at least one triple bond, and one or more heteroatoms in the parent chain ("heteroC"). 2-10In some embodiments, heteroalkynyl groups have 2 to 9 carbon atoms, at least one triple bond, and one or more heteroatoms in the parent chain ("heteroC"). 2-9 In some embodiments, heteroalkynyl groups have 2 to 8 carbon atoms, at least one triple bond, and one or more heteroatoms in the parent chain ("heteroC 2-8 In some embodiments, heteroalkynyl groups have 2 to 7 carbon atoms, at least one triple bond, and one or more heteroatoms in the parent chain ("heteroC 2-7 In some embodiments, heteroalkynyl groups have 2 to 6 carbon atoms, at least one triple bond, and one or more heteroatoms ("heteroC 2-6 In some embodiments, heteroalkynyl groups have 2 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms in the parent chain ("heteroC 2-5 In some embodiments, heteroalkynyl groups have 2 to 4 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms in the parent chain ("heteroC 2-4 In some embodiments, heteroalkynyl groups have 2 to 3 carbon atoms, at least one triple bond, and one heteroatom in the parent chain ("heteroC 2-3 In some embodiments, heteroalkynyl groups have 2 carbon atoms, at least one triple bond, and 1 heteroatom in the parent chain ("heteroC2 alkynyl"). In some embodiments, heteroalkynyl groups have 2 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms in the parent chain ("heteroC 2-6Unless otherwise specified, each instance of a heteroalkynyl group is independently unsubstituted (an "unsubstituted heteroalkynyl") or substituted (a "substituted heteroalkynyl") with one or more substituents. In certain embodiments, a heteroalkynyl group is an unsubstituted heteroC 2-20 In certain embodiments, the heteroalkynyl group is a substituted heteroC 2-20 It is alkynyl.

[0034] The term "carbocyclyl" or "carbocyclic" refers to a non-aromatic ring system having 3 to 14 ring carbon atoms ("C 3-14 In some embodiments, carbocyclyl groups are those having 3 to 14 ring carbon atoms ("C 3-14 In some embodiments, carbocyclyl groups are those having 3 to 13 ring carbon atoms ("C 3-13 In some embodiments, carbocyclyl groups are those having 3 to 12 ring carbon atoms ("C 3-12 In some embodiments, carbocyclyl groups are those having 3 to 11 ring carbon atoms ("C 3-11 In some embodiments, carbocyclyl groups are those having 3 to 10 ring carbon atoms ("C 3-10 In some embodiments, carbocyclyl groups are those having 3 to 8 ring carbon atoms ("C 3-8 In some embodiments, carbocyclyl groups are those having 3 to 7 ring carbon atoms ("C 3-7 In some embodiments, carbocyclyl groups are those having 3 to 6 ring carbon atoms ("C 3-6 In some embodiments, the carbocyclyl group is one having 4 to 6 ring carbon atoms ("C 4-6In some embodiments, the carbocyclyl group is one having 5 to 6 ring carbon atoms ("C 5-6 In some embodiments, carbocyclyl groups are those having 5 to 10 ring carbon atoms ("C 5-10 carbocyclyl). 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. 3-8 The carbocyclyl group includes the above-mentioned C 3-6 Carbocyclyl groups include cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), and the like. Exemplary C 3-10 The carbocyclyl group includes the above-mentioned C 3-8 Carbocyclyl groups and cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C 10 ), spiro[4.5]decanyl (C 10 ) and other examples. 3-8 The carbocyclyl group includes the above-mentioned C 3-10 Carbocyclyl group and cycloundecyl (C 11 ), spiro[5.5]undecanyl (C 11 ), cyclododecyl (C 12 ), cyclododecenyl (C 12 ), Cyclo(C 13 ), cyclotetradecane (C 14As illustrated in the examples above, in certain embodiments, a carbocyclyl group is either monocyclic ("monocyclic carbocyclyl") or polycyclic (e.g., including fused, bridged, or spiro ring systems, such as bicyclic ("bicyclic carbocyclyl") or tricyclic ("tricyclic carbocyclyl") systems), may be saturated, and may contain one or more carbon-carbon double or triple bonds. "Carbocyclyl" also includes ring systems in which a carbocyclyl ring, as defined above, is fused to one or more aryl or heteroaryl groups, and the point of attachment is on the carbocyclyl ring; in such cases, the number of carbons continues to refer to the number of carbons in the carbocyclic ring system. Unless otherwise specified, each instance of a carbocyclyl group is independently unsubstituted ("unsubstituted carbocyclyl") or substituted with one or more substituents ("substituted carbocyclyl"). In certain embodiments, the carbocyclyl group is an unsubstituted C 3-14 In certain embodiments, the carbocyclyl group is a substituted C 3-14 It is a carbocyclyl.

[0035] In some embodiments, "carbocyclyl" refers to a monocyclic saturated carbocyclyl group having 3 to 14 ring carbon atoms ("C 3-14 In some embodiments, cycloalkyl groups are those having 3 to 10 ring carbon atoms ("C 3-10 In some embodiments, cycloalkyl groups are those having 3 to 8 ring carbon atoms ("C 3-8 In some embodiments, cycloalkyl groups are those having 3 to 6 ring carbon atoms ("C 3-6 In some embodiments, cycloalkyl groups are those having 4 to 6 ring carbon atoms ("C 4-6 In some embodiments, cycloalkyl groups are those having 5 to 6 ring carbon atoms ("C 5-6In some embodiments, cycloalkyl groups are those having 5 to 10 ring carbon atoms ("C 5-10 C 5-6 Examples of cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). 3-6 Examples of the cycloalkyl group include the above-mentioned C 5-6 Cycloalkyl groups include cyclopropyl (C3) and cyclobutyl (C4). 3-8 Examples of the cycloalkyl group include the above-mentioned C 3-6 Cycloalkyl groups include cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise specified, each instance of a cycloalkyl group is independently unsubstituted ("unsubstituted cycloalkyl") or substituted with one or more substituents ("substituted cycloalkyl"). In certain embodiments, a cycloalkyl group is an unsubstituted C 3-14 In certain embodiments, the cycloalkyl group is a substituted C 3-14 In certain embodiments, a carbocyclyl contains, where valences allow, zero, one or two C=C double bonds in the carbocyclic ring system.

[0036] The term "heterocyclyl" or "heterocyclic" refers to the radical of a 3- to 14-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, each independently selected from nitrogen, oxygen, and sulfur ("3- to 14-membered heterocyclyl"). In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment can be at a carbon atom or a nitrogen atom, where valence allows. Heterocyclyl groups can be either monocyclic ("monocyclic heterocyclyl") or polycyclic (e.g., fused, bridged, or spiro ring systems, such as bicyclic ("bicyclic heterocyclyl") or tricyclic ("tricyclic heterocyclyl") systems), which may be saturated and contain one or more carbon-carbon double or triple bonds. Heterocyclyl polycyclic ring systems can contain one or more heteroatoms in one or both rings. "Heterocyclyl" includes ring systems in which a heterocyclyl ring, as defined above, is fused to one or more carbocyclyl groups, and the point of attachment is on either the carbocyclyl ring or the heterocyclyl ring; in such cases, the number of ring members continues to refer to the number of ring members in the heterocyclyl ring system. Unless otherwise specified, each instance of heterocyclyl is independently unsubstituted (an "unsubstituted heterocyclyl") or substituted with one or more substituents (a "substituted heterocyclyl"). In certain embodiments, a heterocyclyl group is an unsubstituted 3- to 14-membered heterocyclyl. In certain embodiments, a heterocyclyl group is a substituted 3- to 14-membered heterocyclyl. In certain embodiments, a heterocyclyl is a substituted or unsubstituted 3- to 7-membered monocyclic heterocyclyl, wherein one, two, or three atoms in the heterocyclic ring system are independently oxygen, nitrogen, or sulfur, where valences allow.

[0037] In some embodiments, the heterocyclyl group is a 5- to 10-membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, each heteroatom independently selected from nitrogen, oxygen, and sulfur (a "5- to 10-membered heterocyclyl"). In some embodiments, the heterocyclyl group is a 5- to 8-membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, each heteroatom independently selected from nitrogen, oxygen, and sulfur (a "5- to 8-membered heterocyclyl"). In some embodiments, the heterocyclyl group is a 5- to 6-membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, each heteroatom independently selected from nitrogen, oxygen, and sulfur (a "5- to 6-membered heterocyclyl"). In some embodiments, the 5- to 6-membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heterocyclyl has 1 to 2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heterocyclyl has 1 heteroatom selected from nitrogen, oxygen, and sulfur.

[0038] Exemplary 3-membered heterocyclyl groups containing one heteroatom include aziridinyl, oxiranyl, and thiiranyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include dioxolanyl, oxathiolanyl, and dithiolanyl. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing three heteroatoms include triazinyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include azepanyl, oxepanyl, and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include azocanyl, oxecanyl, and thiocanyl.Exemplary bicyclic heterocyclyl groups include indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl, decahydronaphthyridinyl, decahydro-1,8-naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole, indolinyl, phthalimidyl, naphthalimidyl, chromanyl, chromenyl, and 1H-benzo[e][1,4]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-1H-pyrrolo[2,3-b]pyridinyl, 2,3-dihydrofuro[2,3-b]pyridinyl, 4,5,6,7-tetrahydro-1H-pyrrolo[2,3-b]pyridinyl, 4,5,6,7-tetrahydrofuro[3,2-c]pyridinyl, 4,5,6,7-tetrahydrothieno[3,2-b]pyridinyl, and 1,2,3,4-tetrahydro-1,6-naphthyridinyl.

[0039] The term "aryl" refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., one in which 6, 10, or 14 pi electrons are shared in a cyclic arrangement), where the aromatic ring system has 6 to 14 ring carbon atoms and 0 heteroatoms ("C 6-14 In some embodiments, aryl groups have 6 ring carbon atoms ("C aryl"; e.g., phenyl). In some embodiments, aryl groups have 10 ring carbon atoms ("C 10 aryl"; e.g., naphthyl, e.g., 1-naphthyl and 2-naphthyl). In some embodiments, aryl groups are those having 14 ring carbon atoms ("C 14"Aryl"; e.g., anthracyl). "Aryl" also includes ring systems in which an aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups, where the radical or point of attachment is on the aryl ring, and in such cases the number of carbon atoms continues to refer to the number of carbon atoms in the aryl ring system. Unless otherwise specified, each instance of an aryl group is independently unsubstituted ("unsubstituted aryl") or substituted with one or more substituents ("substituted aryl"). In certain embodiments, an aryl group is an unsubstituted C 6-14 In certain embodiments, the aryl group is a substituted C 6-14 It is aryl.

[0040] "Aralkyl" is a subset of "alkyl" and refers to an alkyl group substituted with an aryl group, where the point of attachment is on the alkyl portion.

[0041] The term "heteroaryl" refers to a radical of a 5- to 14-membered monocyclic or polycyclic (e.g., bicyclic, tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic arrangement) having ring carbon atoms and 1 to 4 ring heteroatoms, each heteroatom independently selected from nitrogen, oxygen, and sulfur ("5- to 14-membered heteroaryl"). In heteroaryl groups containing one or more nitrogen atoms, the point of attachment can be a carbon atom or a nitrogen atom, valence permitting. Heteroaryl polycyclic ring systems can contain one or more heteroatoms in one or both rings. "Heteroaryl" includes ring systems in which a heteroaryl ring, as defined above, is fused to one or more carbocyclyl or heterocyclyl groups, where the point of attachment is on the heteroaryl ring; in such cases, the number of ring members continues to refer to the number of ring members in the heteroaryl ring system. "Heteroaryl" also includes a ring system in which the heteroaryl ring defined above is fused with one or more aryl groups, and the attachment point is on either the aryl ring or the heteroaryl ring, and in such cases, the number of ring members refers to the number of ring members in the fused polycyclic (aryl / heteroaryl) ring system. In polycyclic heteroaryl groups in which one ring does not contain heteroatoms and the other contains heteroatoms (e.g., indolyl, quinolinyl, carbazolyl, etc.), the attachment point can be on either ring, for example, on the ring containing heteroatoms (e.g., 2-indolyl) or on the ring without heteroatoms (e.g., 5-indolyl). In certain embodiments, the heteroaryl is a substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently oxygen, nitrogen, or sulfur. In certain embodiments, the heteroaryl is a substituted or unsubstituted 9- or 10-membered bicyclic heteroaryl wherein one, two, three, or four atoms in the heteroaryl ring system are independently oxygen, nitrogen, or sulfur.

[0042] In some embodiments, heteroaryl groups are 5-10 membered aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms, each heteroatom independently selected from nitrogen, oxygen, and sulfur ("5-10 membered heteroaryl"). In some embodiments, heteroaryl groups are 5-8 membered aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms, each heteroatom independently selected from nitrogen, oxygen, and sulfur ("5-8 membered heteroaryl"). In some embodiments, heteroaryl groups are 5-6 membered aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms, each heteroatom independently selected from nitrogen, oxygen, and sulfur ("5-6 membered heteroaryl"). In some embodiments, 5-6 membered heteroaryls have 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, 5-6 membered heteroaryls have 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heteroaryl has one ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each instance of a heteroaryl group is independently unsubstituted ("unsubstituted heteroaryl") or substituted with one or more substituents ("substituted heteroaryl"). In certain embodiments, the heteroaryl group is an unsubstituted 5- to 14-membered heteroaryl. In certain embodiments, the heteroaryl group is a substituted 5- to 14-membered heteroaryl.

[0043] Exemplary 5-membered heteroaryl groups containing one heteroatom include pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. Exemplary tricyclic heteroaryl groups include phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl, and phenazinyl.

[0044] "Heteroaralkyl" is a subset of "alkyl" and refers to an alkyl group substituted with a heteroaryl group, where the point of attachment is on the alkyl portion.

[0045] The term "unsaturated bond" refers to a double or triple bond.

[0046] The terms "unsaturated" or "partially unsaturated" refer to a moiety that contains at least one double or triple bond.

[0047] The terms "saturated" or "fully saturated" mean a moiety that does not contain any double or triple bonds, e.g., the moiety contains only single bonds.

[0048] The addition of the suffix "-ene" to a group indicates that the group is a divalent moiety, for example, alkylene is a divalent moiety of alkyl, alkenylene is a divalent moiety of alkenyl, alkynylene is a divalent moiety of alkynyl, heteroalkylene is a divalent moiety of heteroalkyl, heteroalkenylene is a divalent moiety of heteroalkenyl, heteroalkynylene is a divalent moiety of heteroalkynyl, carbocyclylene is a divalent moiety of carbocyclyl, heterocyclylene is a divalent moiety of heterocyclyl, arylene is a divalent moiety of aryl, and heteroarylene is a divalent moiety of heteroaryl.

[0049] A group may be optionally substituted unless expressly specified otherwise. The term "optionally substituted" refers to substituted or unsubstituted. In certain embodiments, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups may be optionally substituted. "Optionally substituted" refers to a substituted or unsubstituted group (e.g., a "substituted" or "unsubstituted" alkyl, a "substituted" or "unsubstituted" alkenyl, a "substituted" or "unsubstituted" alkynyl, a "substituted" or "unsubstituted" heteroalkyl, a "substituted" or "unsubstituted" heteroalkenyl, a "substituted" or "unsubstituted" heteroalkynyl, a "substituted" or "unsubstituted" carbocyclyl, a "substituted" or "unsubstituted" heterocyclyl, a "substituted" or "unsubstituted" aryl, or a "substituted" or "unsubstituted" heteroaryl group). In general, the term "substituted" means that at least one hydrogen atom present on a group is replaced with an acceptable substituent, e.g., a substituent that, upon substitution, results in a stable compound, e.g., a compound that does not spontaneously undergo transformation, such as by rearrangement, cyclization, elimination, or other reaction. Unless otherwise specified, a "substituted" group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituents are either the same or different at each position. The term "substituted" is intended to include substitution with all permissible substituents of organic compounds, including any substituent described herein that results in the formation of a stable compound. The present invention contemplates all such combinations to arrive at a stable compound. For purposes of this invention, heteroatoms, such as nitrogen, may have hydrogen substituents and / or any suitable substituents described herein that satisfy the valence of the heteroatom and result in the formation of a stable moiety. The present invention is not limited in any way by the exemplary substituents described herein.

[0050] The term "halo" or "halogen" refers to fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br) or iodine (iodo, -I).

[0051] The term "hydroxyl" or "hydroxy" refers to an -OH group. The term "substituted hydroxyl" or "substituted hydroxyl" by extension refers to a hydroxyl group in which the oxygen atom directly attached to the parent molecule has been replaced with a group other than hydrogen, such as -OR aa , -ON(R bb )2, -OC(=O)SR aa , -OC(=O)R aa , -OCO2R aa , -OC(=O)N(R bb )2, -OC(=NR bb )R aa , -OC(=NR bb ) OR aa , -OC(=NR bb )N(R bb )2, -OS(=O)R aa , -OSO2R aa , -OSi(R aa )3, -OP(R cc )2, -OP(R cc )3 + X - , -OP(OR cc )2, -OP(OR cc )3 + X - , -OP(=O)(R aa )2, -OP(=O)(OR cc )2 and -OP(=O)(N(R bb ))2, where X - , R aa , R bb and R cc is as defined herein.

[0052] The term "amino" refers to the group -NH. The term "substituted amino" refers, by extension, to mono-, di-, or tri-substituted amino groups. In certain embodiments, the "substituted amino group" is a mono- or di-substituted amino group.

[0053] The term "acyl" refers to a group having the general formula: -C(=O)R X1 , -C(=O)OR X1, -C(=O)-OC(=O)R X1 , -C(=O)SR X1 , -C(=O)N(R X1 )2, -C(=S)R X1 , -C(=S)N(R X1 )2 and -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 X1 is hydrogen; halogen; substituted or unsubstituted hydroxyl; substituted or unsubstituted thiol; substituted or unsubstituted amino; substituted or unsubstituted acyl, cyclic or acyclic substituted or unsubstituted branched or unbranched aliphatic; cyclic or acyclic substituted or unsubstituted branched or unbranched heteroaliphatic; cyclic or acyclic substituted or unsubstituted branched or unbranched alkyl; cyclic or acyclic substituted or unsubstituted branched or unbranched alkenyl; substituted or unsubstituted alkynyl; substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, aliphaticoxy, heteroaliphaticoxy, alkyloxy, heptyloxy, hydroxyl ... or two R are aryloxy, heteroaryloxy, aliphatic thioxy, heteroaliphatic thioxy, alkylthioxy, heteroalkylthioxy, arylthioxy, heteroarylthioxy, mono-aliphatic amino or di-aliphatic amino, mono-heteroaliphatic amino or di-heteroaliphatic amino, mono-alkylamino or di-alkylamino, mono-heteroalkylamino or di-heteroalkylamino, mono-arylamino or di-arylamino, or mono-heteroarylamino or di-heteroarylamino; or two R are aryloxy, heteroaryloxy, heteroaryloxy, heteroaryloxy, heteroarylthi ... mono-heteroaliphatic amino or di-heteroaliphatic amino, mono-alkylamino or di-alkylamino, mono-heteroalkylamino or di-heteroalkylamino, mono-arylamino or X1groups taken together form a 5- to 6-membered heterocyclic ring. Exemplary acyl groups include aldehydes (-CHO), carboxylic acids (-COH), ketones, acyl halides, esters, amides, imines, carbonates, carbamates, and ureas. Acyl substituents include, but are not limited to, any of the substituents described herein that result in the formation of a stable moiety (e.g., aliphatic, alkyl, alkenyl, alkynyl, heteroaliphatic, heterocyclic, aryl, heteroaryl, acyl, oxo, imino, thioxo, cyano, isocyano, amino, azido, nitro, hydroxyl, thiol, halo, aliphatic amino, heteroaliphatic amino, alkylamino, heteroalkylamino, arylamino, heteroarylamino, alkylaryl, arylalkyl, aliphaticoxy, heteroaliphaticoxy, alkyloxy, heteroalkyloxy, aryloxy, heteroaryloxy, aliphaticthioxy, heteroaliphaticthioxy, alkylthioxy, heteroalkylthioxy, arylthioxy, heteroarylthioxy, acyloxy, etc., each of which may or may not be further substituted).

[0054] The term "carbonyl" refers to a carbon atom directly attached to the parent molecule that is sp 2 Groups that are hybridized and substituted by oxygen, nitrogen or sulfur atoms, such as ketones (-C(=O)R aa ), carboxylic acid (-CO2H), aldehyde (-CHO), ester (-CO2R aa , -C(=O)SR aa , -C(=S)SR aa ), amide (-C(=O)N(R bb )2, -C(=O)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) a group selected from the group consisting of: aa and Rbb refers to a group as defined herein.

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

[0056] Nitrogen atoms can be substituted or unsubstituted where valence allows, and include primary, secondary, tertiary and quaternary nitrogen atoms.

[0057] A "counterion" or "anionic counterion" is a negatively charged group associated with a positively charged group to maintain electron neutrality. Anionic counterions can be monovalent (e.g., containing one formal negative charge). Anionic counterions can also be multivalent (e.g., containing multiple formal negative charges), such as divalent or trivalent. Exemplary counterions include halide ions (e.g., F - , Cl - , Br - , I - ), NO3 - , ClO4 - , O.H. - , H2PO4 - , HCO3 - 、 HSO4 - , sulfonate ions (e.g., methanesulfonate, trifluoromethanesulfonate, p-toluenesulfonate, benzenesulfonate, 10-camphorsulfonate, naphthalene-2-sulfonate, naphthalene-1-sulfonic acid-5-sulfonate, ethane-1-sulfonic acid-2-sulfonate, etc.), carboxylate ions (e.g., acetate, propanoate, benzoate, glycerate, lactate, tartrate, glycolate, gluconate, etc.), BF4 - , PF4 - , PF6 - , AsF6 - , SbF6 - , B[3,5-(CF3)2C6H3]4] - , B(C6F5)4 - , BPh4 - , Al(OC(CF3)3)4 -and carborane anions (e.g., CB 11 H 12 - or (HCB 11 Me5Br6) - ) Exemplary counterions that may be multivalent include CO3 2- , HPO4 2- , PO4 3- , B4O7 2- , SO4 2- , S2O3 2- , carboxylate anions (e.g., tartrate, citrate, fumarate, maleate, malate, malonate, gluconate, succinate, glutarate, adipate, pimelate, suberate, azelate, sebacate, salicylate, phthalate, aspartate, glutamate, etc.), and carboranes.

[0058] Use of the phrase "at least one example" means 1, 2, 3, 4 or more examples, but also includes ranges including, for example, 1-4, 1-3, 1-2, 2-4, 2-3, or 3-4 examples.

[0059] "Non-hydrogen group" refers to any group defined for a particular variable that is not hydrogen.

[0060] These and other exemplary substituents are described in more detail in the detailed description, examples, and claims. The present invention is not limited in any way by the above list of exemplary substituents.

[0061] As used herein, the term "salt" refers to any and all salts, including pharmaceutically acceptable salts. Salts include ionic compounds resulting from the neutralization reaction of an acid and a base. A salt is composed of one or more cations (positively charged ions) and one or more anions (negative ions), and therefore is electrically neutral (has no net charge). Salts of the compounds of the present invention include those derived from inorganic and organic acids and bases. Examples of acid addition salts are salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or 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, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, Salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and N-methyl-N ... + (C 1-4Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further salts include ammonium, quaternary ammonium, and amine cations formed with counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.

[0062] The term "pharmaceutically acceptable salt" refers to a salt that is, 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 reaction, etc., and that is commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art; for example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, which is incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or using other methods known in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, gluconate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactate, and the like. Salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and N-methyl-N ... + (C 1-4Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Pharmaceutically acceptable salts also include non-toxic ammonium, quaternary ammonium, and amine cations formed, where appropriate, with counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.

[0063] The term "solvate" refers to a compound or its salt form combined with a solvent, usually through solvolysis. This physical association includes hydrogen bonding. Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, and the like. The compounds described herein may be prepared, for example, in crystalline form, and may be solvated. Suitable solvates include pharmaceutically acceptable solvates and further include both stoichiometric and non-stoichiometric solvates. In certain cases, solvates can be isolated, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. "Solvate" encompasses both solution-phase and isolatable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

[0064] The term "hydrate" refers to a compound combined with water. Typically, the number of water molecules contained in a hydrate of a compound is a fixed ratio to the number of compound molecules in the hydrate. Thus, a hydrate of a compound can be represented, for example, by the general formula R·xH2O, where R is the compound and x is a number greater than 0. A given compound can form one or more types of hydrates, including, for example, a monohydrate (x is 1), a lower hydrate (x is a number greater than 0 and less than 1, e.g., a hemihydrate (R·0.5H2O)), and a polyhydrate (x is a number greater than 1, e.g., a dihydrate (R·2H2O) and a hexahydrate (R·6H2O)).

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

[0066] It should also be understood that compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed "isomers." Isomers that differ in the arrangement of their atoms in space are termed "stereoisomers."

[0067] Stereoisomers that are not mirror images of one another are called "diastereomers," while stereoisomers that are non-superimposable mirror images of each other are called "enantiomers." When a compound has an asymmetric carbon atom, e.g., when it is bonded to four different groups, a pair of enantiomers can exist. Enantiomers are characterized by the absolute configuration of the asymmetric carbon atom and described by the R- and S-sequencing rules of Cahn and Prelog, or by the way the molecule rotates the plane of polarized light, referred to as dextrorotatory or levorotatory (i.e., as (+) or (-) isomers, respectively). Chiral compounds can exist as individual enantiomers or as mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture."

[0068] The term "polymorph" refers to a crystalline form of a compound (or its salt, hydrate, or solvate). All polymorphs have the same elemental composition. Different crystalline forms typically have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and solubility. Depending on the recrystallization solvent, crystallization rate, storage temperature, and other factors, one crystalline form may predominate. Various polymorphs of a compound can be prepared by crystallization under different conditions.

[0069] The term "cocrystal" refers to a crystal structure comprising at least two different components (e.g., a compound and an acid), each of which is independently an atom, ion, or molecule. In certain embodiments, neither component is a solvent. In certain embodiments, at least one of the components is a solvent. A cocrystal of a compound and an acid differs from a salt formed from the compound and an acid. In a salt, the compound forms a complex with the acid, and proton transfer from the acid to the compound (e.g., complete proton transfer) readily occurs at room temperature. In contrast, in a cocrystal, the compound forms a complex with the acid, but proton transfer from the acid to the compound does not readily occur at room temperature. In certain embodiments, in a cocrystal, there is substantially no proton transfer from the acid to the compound. In certain embodiments, there is partial proton transfer from the acid to the compound in a cocrystal. Cocrystals can be useful for improving the properties of a compound (e.g., solubility, stability, ease of formulation).

[0070] The term "prodrug" refers to a compound that has a cleavable group and becomes a compound described herein upon solvolysis or physiological conditions, and is pharmaceutically active in vivo. Examples include, but are not limited to, choline ester derivatives, N-alkylmorpholine esters, and the like. Other derivatives of the compounds described herein are active in both their acid and acid-derivative forms, but the acid-sensitive forms often offer advantages of solubility, tissue compatibility, or delayed release in mammalian organisms (see 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, such as esters prepared by reacting the parent acid with an appropriate alcohol, or amides prepared by reacting the parent acid compound with a substituted or unsubstituted amine, or acid anhydrides, or mixed anhydrides. Simple aliphatic or aromatic esters, amides, and anhydrides derived from acidic groups pendant on the compounds described herein are specific prodrugs. In some cases, it is desirable to prepare double ester type prodrugs, such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkyl esters. Preferred are C-C alkyl, C-C alkenyl, C-C alkynyl, aryl, C-C substituted aryl, and C-C arylalkyl esters of the compounds described herein.

[0071] The terms "composition" and "formulation" are used interchangeably.

[0072] The "subject" to which administration is intended refers to a human (i.e., a man or woman of any age group, for example, a pediatric subject (such as an infant, a child, or an adolescent) or an adult subject (such as a young adult, a middle-aged adult, or an elderly person)) or a non-human animal. In certain embodiments, the non-human animal is a mammal (e.g., a primate (e.g., a cynomolgus 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 important 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 may be male or female at any stage of development. The non-human animal may be a transgenic or genetically modified animal. The term "patient" refers to a human subject in need of treatment for a disorder or disease.

[0073] 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 the body of a subject.

[0074] The terms "treatment," "treat," and "treating" refer to ameliorating, alleviating, delaying the onset, or inhibiting the progression of a disorder or disease described herein. In some embodiments, treatment may be applied after one or more signs or symptoms of a disease have developed or been observed. In other embodiments, treatment may be applied in the absence of signs or symptoms of a disorder. For example, treatment may be administered to a susceptible subject prior to the onset of symptoms (e.g., in light of a history of symptoms and / or exposure to a pathogen). Treatment may also be continued after symptoms have resolved, for example, to delay or prevent recurrence.

[0075] The terms "condition," "disease," and "disorder" are used interchangeably. An "effective amount" of a compound described herein refers to an amount sufficient to induce a desired biological response. The effective amount of a compound described herein can vary depending on factors such as the desired biological endpoint, side effects, severity of the disease or disorder, the identity of the specific compound, pharmacokinetics and pharmacodynamics, the condition to be treated, the mode, route, and desired or required frequency of administration, the race, age, and health 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 administration. In certain embodiments, the effective amount is the combined amount of multiple administrations of a compound described herein. In certain embodiments, the desired dosage is delivered three times a day, twice a day, once a day, every other day, every third day, every week, every two weeks, every three weeks, or every four weeks. In certain embodiments, the desired dose is delivered using multiple administrations (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or more administrations).

[0076] A "therapeutically effective amount" of a compound described herein is an amount sufficient to provide a therapeutic benefit in the treatment of a condition or to delay or minimize one or more symptoms associated with the condition. A therapeutically effective amount of a compound refers to the amount of a therapeutic agent that, alone or in combination with other therapies, provides a therapeutic benefit in the treatment of a condition. The term "therapeutically effective amount" can include an amount that improves overall therapy, reduces or avoids symptoms, signs, or causes of a condition, and / or enhances the therapeutic effect of another therapeutic agent. In certain embodiments, a therapeutically effective amount is an amount sufficient for dual TYK2 / JAK1 kinase inhibition. In certain embodiments, a therapeutically effective amount is an amount sufficient for treating a CNS disorder. In certain embodiments, a therapeutically effective amount is an amount sufficient for dual TYK2 / JAK1 kinase inhibition and treating a CNS disorder.

[0077] The terms "prevent," "preventing," or "prevention" refer to the prophylactic treatment of a subject who does not have the disorder and who did not have the disorder but is at risk of developing the disorder, or who did have the disorder and who did not have the disorder but is at risk of the disorder's relapse. In certain embodiments, the subject is at a higher risk of developing the disorder or a higher risk of the disorder's regression than the average healthy member of the population. In certain embodiments, the subject is at a higher risk of developing the disorder or at a higher risk of the disorder's relapse compared to the average healthy member of the population.

[0078] As used herein, the term "inhibit" or "inhibition," in the context of an enzyme, for example, a Janus family kinase, refers to a reduction in the activity of the enzyme. In some embodiments, the term refers to a reduction 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 may be, for example, a baseline level of enzyme activity. In some embodiments, the term refers to a reduction 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 the initial level, which may be, for example, a baseline level of enzyme activity.

[0079] The term "TYK2 inhibition" or "TYK2 kinase inhibition" as used herein in the context of an enzyme refers to a reduction in TYK2 kinase activity. In some embodiments, this term refers to a reduction in the level of enzyme activity, e.g., TYK2 kinase activity, to a level that is statistically significantly lower than the initial level of TYK2 kinase activity, which may be, for example, the baseline level of enzyme activity. In some embodiments, this term refers to a reduction 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 the initial level of TYK2 kinase activity, which may be, for example, the baseline level of enzyme activity. In certain embodiments, an effective amount is an amount effective to inhibit the activity of a protein kinase 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 the activity of a Janus family kinase by 10% or less, 20% or less, 30% or less, 40% or less, 50% or less, 60% or less, 70% or less, 80% or less, 90% or less, 95% or less, or 98% or less. In certain embodiments, an effective amount is an amount effective to inhibit the activity of a Janus family kinase in a range between a percentage recited in this paragraph and another percentage recited in this paragraph.

[0080] Detailed Description of the Invention The present disclosure is based, at least in part, on the unexpected finding that compounds of formula (I) are selective TYK2 kinase inhibitors, some of which have good ability to penetrate the blood-brain barrier.

[0081] In one embodiment, the compounds of formula (I), formula (II), formula (III) and formula (IV): [ka] [In the formula, X is CH or N; Y 1 is C and Y 2 is N; or Y 1 is N and Y 2 is C; [ka] is a single or double bond; R 1 is H, halo, or C optionally substituted by one, two, or three substituents independently selected from the group consisting of halo, 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)R', S(O)R, and S(O)NRR'; 1-3 is alkyl; Cy is C 3-7 cycloalkyl or 3- to 7-membered heterocyclyl, where Cy is R 2 , oxo, 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)R', S(O)R and S(O)NRR'; R 2 is optionally substituted by one, two, or three substituents independently selected from the group consisting of 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)R', S(O)R, and S(O)NRR' 1-3 Alkyl, C 3-7 cycloalkyl, 3- to 7-membered heterocyclyl, phenyl, or 5- to 6-membered heteroaryl; R, R' are each independently H or C optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halo, OH and CN. 1-3 Alkyl or C 3-6 cycloalkyl] or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative or prodrug thereof.

[0082] In another embodiment, the compounds of formula (Ia), formula (IIa), formula (IIIa) and formula (IVa): [ka] [In the formula, X is CH or N; R 1 is H, halo, or C optionally substituted by one, two, or three substituents independently selected from the group consisting of halo, 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)R', S(O)R, and S(O)NRR'; 1-3 is alkyl; Ring A is R 2 , oxo, 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)R', S(O)R and S(O)NRR'; R 2 is optionally substituted by one, two, or three substituents independently selected from the group consisting of 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)R', S(O)R, and S(O)NRR' 1-3 Alkyl, C3-7 cycloalkyl, 3- to 7-membered heterocyclyl, phenyl, or 5- to 6-membered heteroaryl; R, R' are each independently H or C optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halo, OH and CN. 1-3 Alkyl or C 3-6 cycloalkyl] or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative or prodrug thereof.

[0083] In another embodiment, the compounds of formula (Ib), formula (IIb), formula (IIIb) and formula (IVb): [ka] [In the formula, X is CH or N; R 1 is H, halo, or C optionally substituted by one, two, or three substituents independently selected from the group consisting of halo, 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)R', S(O)R, and S(O)NRR'; 1-3 is alkyl; Cy is C 3-7 cycloalkyl or 3- to 7-membered heterocyclyl, where Cy is R 2 , oxo, 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)R', S(O)R and S(O)NRR'; R 2is optionally substituted by one, two, or three substituents independently selected from the group consisting of 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)R', S(O)R, and S(O)NRR' 1-3 Alkyl, C 3-7 cycloalkyl, 3- to 7-membered heterocyclyl, phenyl, or 5- to 6-membered heteroaryl; R, R' are each independently H or C optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halo, OH and CN. 1-3 Alkyl or C 3-6 cycloalkyl] or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative or prodrug thereof.

[0084] In another embodiment, the compounds of formula (Ic), formula (IIc), formula (IIIc) and formula (IVc): [ka] [In the formula, X is CH or N; R 1 is H, halo, or C optionally substituted by one, two, or three substituents independently selected from the group consisting of halo, 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)R', S(O)R, and S(O)NRR'; 1-3 is alkyl; Ring A is R 2, oxo, 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)R', S(O)R and S(O)NRR'; R 2 is optionally substituted by one, two, or three substituents independently selected from the group consisting of 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)R', S(O)R, and S(O)NRR' 1-3 Alkyl, C 3-7 cycloalkyl, 3- to 7-membered heterocyclyl, phenyl, or 5- to 6-membered heteroaryl; R, R' are each independently H or C optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halo, OH and CN. 1-3 Alkyl or C 3-6 cycloalkyl] or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative or prodrug thereof.

[0085] In another embodiment, compounds of formula (Id), (IId), (IIId) and (IVd): [ka] [In the formula, X is CH or N; R 1is H, halo, or C optionally substituted by one, two, or three substituents independently selected from the group consisting of halo, 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)R', S(O)R, and S(O)NRR'; 1-3 is alkyl; Cy is C 3-7 cycloalkyl or 3- to 7-membered heterocyclyl, where Cy is R 2 , oxo, 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)R', S(O)R and S(O)NRR'; R 2 is optionally substituted by one, two, or three substituents independently selected from the group consisting of 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)R', S(O)R, and S(O)NRR' 1-3 Alkyl, C 3-7 cycloalkyl, 3- to 7-membered heterocyclyl, phenyl, or 5- to 6-membered heteroaryl; R, R' are each independently H or C optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halo, OH and CN. 1-3 Alkyl or C 3-6 cycloalkyl] or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative or prodrug thereof.

[0086] In some embodiments, the present invention provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein X is CH.

[0087] In some embodiments, the present invention provides a compound of Formula (I), wherein X is N, or a pharmaceutically acceptable salt thereof.

[0088] In some embodiments, the present invention provides a compound of formula (Ia): [In the formula, Ring A is R 2 , a 4- to 7-membered heterocyclyl optionally substituted by 1, 2, or 3 substituents independently selected from the group consisting of halo, OH, CN, OR, and N(R)S(O)R'; R 2 is optionally substituted by one, two, or three substituents independently selected from the group consisting of 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)R', S(O)R, and S(O)NRR' 1-3 alkyl] or a pharmaceutically acceptable salt thereof.

[0089] In some embodiments, the present invention provides a compound of formula (Ia): [In the formula, Ring A is R 2 is a 6-membered heterocyclyl optionally substituted by R 2 is optionally substituted by one, two, or three substituents independently selected from the group consisting of 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)R', S(O)R, and S(O)NRR' 1-3 alkyl]. or a pharmaceutically acceptable salt thereof.

[0090] In some embodiments, the present invention provides a compound of formula (Ia): [In the formula, Ring A is [ka] and 6-membered heterocyclyl optionally substituted by or a pharmaceutically acceptable salt thereof.

[0091] In some embodiments, the present invention provides a compound represented by formula (Ia), wherein ring A is [ka] is] or a pharmaceutically acceptable salt thereof.

[0092] In some embodiments, the present invention provides a compound of formula (Ib): [In the formula, Cy is R 2 C optionally substituted by one, two or three substituents independently selected from the group consisting of halo, OH, CN, OR and N(R)S(O)R′ 3-7 is cycloalkyl; R 2 is optionally substituted by one, two, or three substituents independently selected from the group consisting of 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)R', S(O)R, and S(O)NRR' 1-3 alkyl] or a pharmaceutically acceptable salt thereof.

[0093] In some embodiments, the present invention provides a compound of formula (Ib): [In the formula, Cy is R 2 cyclohexyl optionally substituted by R 2is optionally substituted by one, two, or three substituents independently selected from the group consisting of 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)R', S(O)R, and S(O)NRR' 1-3 alkyl] or a pharmaceutically acceptable salt thereof.

[0094] In some embodiments, the present invention provides a compound represented by formula (Ib), wherein Cy is [ka] is] or a pharmaceutically acceptable salt thereof.

[0095] In some embodiments, the present invention provides a compound represented by formula (Ib), wherein Cy is [ka] is] or a pharmaceutically acceptable salt thereof.

[0096] In some embodiments, the present invention provides a compound of formula (I), wherein R 1 is H, CH3 or [ka] is] or a pharmaceutically acceptable salt thereof.

[0097] In some embodiments, the present invention provides a compound comprising: [ka] or a pharmaceutically acceptable salt thereof. Exemplary compounds of the invention are listed below: 2-(1-(2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)piperidin-4-yl)acetonitrile (1); 2-(1-(2-methyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)piperidin-4-yl)acetonitrile (2); 2-((1r,4r)-4-(imidazo[1,2-a]quinoxalin-1-yl)cyclohexyl)acetonitrile (3); 2-((1r,4r)-4-(imidazo[1,2-a]pyrido[3,2-e]pyrazin-9-yl)cyclohexyl)acetonitrile (4).

[0098] In some embodiments, the present invention provides a compound comprising: [ka] or a pharmaceutically acceptable salt thereof. Exemplary compounds of the invention are listed below: (R)-2-(1-(2-(1-hydroxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl)piperidin-4-yl)acetonitrile (5); (R)-2-(1-(2-(1-hydroxyethyl)-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)piperidin-4-yl)acetonitrile (6); 2-((1r,4r)-4-(2-methylimidazo[1,2-a]quinoxalin-1-yl)cyclohexyl)acetonitrile (7); 2-((1r,4r)-4-(8-methylimidazo[1,2-a]pyrido[3,2-e]pyrazin-9-yl)cyclohexyl)acetonitrile (8).

[0099] Thus, described herein are methods of treating a CNS disorder, as 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.

[0100] composition The present disclosure provides a pharmaceutical composition 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 composition described herein comprises 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.

[0101] In certain embodiments, the compound described herein is provided in an effective amount in a pharmaceutical composition.In certain embodiments, the effective amount is a therapeutically effective amount.In certain embodiments, the effective amount is a prophylactically effective amount.In certain embodiments, the effective amount is an amount effective for treating CNS disorders in a subject in need of treatment.In certain embodiments, the effective amount is an amount effective for preventing CNS disorders in a subject in need of prevention.In certain embodiments, the effective amount is an amount effective for reducing the risk of developing CNS disorders in a subject in need of reduction.In certain embodiments, the effective amount is an amount effective for inhibiting the activity (e.g., abnormal activity, such as increased activity) of protein kinase in a subject or cell.

[0102] The pharmaceutical compositions described herein can be prepared by any method known in the pharmaceutical art. Generally, such preparation methods involve bringing into association a compound described herein (i.e., the "active ingredient") with a carrier or excipient, and / or one or more other accessory ingredients, and then, if necessary and / or desirable, shaping and / or packaging the product into a desired single- or multi-dosage unit.

[0103] Pharmaceutical compositions can be prepared, packaged, and / or sold in bulk, as a single unit dose, and / or as a plurality of single unit doses. A "unit dose" is a discrete amount of pharmaceutical composition containing a predetermined amount of active ingredient. The amount of active ingredient is generally equal to the dosage of the active ingredient that would be administered to a subject and / or a convenient fraction of such a dosage, for example, 1 / 2 or 1 / 3 of such a dosage.

[0104] The relative amounts of active ingredient, pharmaceutically acceptable excipient, and / or any additional ingredients in the pharmaceutical compositions described herein will vary depending on the identity, size, and / or condition of the subject being treated, as well as the route by which the composition is administered. The compositions may contain from 0.1% to 100% (w / w) of the active ingredient.

[0105] Pharmaceutically acceptable excipients used in the preparation of the provided pharmaceutical compositions include inert diluents, dispersing and / or granulating agents, surfactants and / or emulsifying agents, disintegrating agents, binders, preservatives, buffers, lubricants, and / or oils. Excipients such as cocoa butter and suppository waxes, coloring agents, coating agents, sweetening agents, flavoring agents, and perfuming agents may also be present in the compositions.

[0106] Liquid dosage forms for oral and parenteral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.In addition to the active ingredient, liquid dosage forms may contain, for example, inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (e.g., cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol and fatty acid esters of sorbitan, and mixtures thereof.In addition to inert diluents, oral compositions may contain adjuvants such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents, and fragrances. In certain embodiments for parenteral administration, the conjugates described herein are mixed with a solubilizing agent such as Cremophor®, alcohol, oil, modified oil, glycol, polysorbate, cyclodextrin, polymer, and mixtures thereof.

[0107] Injectable preparations, for example, sterile injectable aqueous or oily suspensions, can be formulated according to known techniques using suitable dispersants or wetting agents and suspending agents. Sterile injectable preparations can be sterile injectable solutions, suspensions, or emulsions in non-toxic parenterally acceptable diluents or solvents, for example, as solutions in 1,3-butanediol. Acceptable vehicles and solvents that can be used include water, Ringer's solution, USP, and isotonic sodium chloride solution. In addition, sterile fixed oils are commonly used as solvents or suspending media. For this purpose, any bland fixed oil can be used, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectable preparations.

[0108] Injectable preparations can be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium before use.

[0109] To prolong the effect of a drug, it is often desirable to delay the absorption of the drug from subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug depends on the rate of dissolution, which in turn depends on the size and crystalline form of the crystals. Alternatively, delayed absorption of parenterally administered drug forms can be achieved by dissolving or suspending the drug in an oil vehicle.

[0110] 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 starch, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia; (c) humectants, such as glycerol; (d) disintegrants, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (e) solution retarders. (f) absorption enhancers, such as quaternary ammonium compounds, (g) controlled-release polymers, such as various grades of hydroxypropylmethylcellulose (HPMC), (h) wetting agents, such as cetyl alcohol and glycerol monostearate, (i) absorbents, such as kaolin and bentonite clay, and (j) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may contain buffering agents.

[0111] Solid compositions of a similar type can be used as fillers for soft and hard gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols. Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmacological arts. They may optionally contain opacifying agents and can be of a composition that releases the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally with a delayed release. Examples of encapsulating compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type can be used as fillers for soft and hard gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols.

[0112] The active ingredient may be in microencapsulated form with one or more excipients, as described above. Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings, release-controlling coatings, and other coatings well known in the pharmaceutical formulation art. In such solid dosage forms, the active ingredient can be mixed with at least one inert diluent, such as sucrose, lactose, or starch. As is common practice, such dosage forms can contain additional substances other than inert diluents, such as tableting lubricants and tableting aids, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets, and pills, the dosage form can contain a buffering agent. Optionally, opacifying agents can be included to release the active ingredient only, or preferentially, in a certain part of the intestinal tract, optionally with a delayed release. Examples of encapsulating agents that can be used include polymeric substances and waxes.

[0113] Although the description of pharmaceutical compositions provided herein primarily relates to pharmaceutical compositions suitable for administration to humans, those skilled in the art will understand that such compositions are generally suitable for administration to any type of animal. Modifications of pharmaceutical compositions suitable for administration to humans to make them suitable for administration to a variety of animals are well known, and a veterinary pharmacologist of ordinary skill can design and / or perform such modifications using routine experimentation.

[0114] The compound described herein is usually formulated in dosage unit form to ensure easy administration and uniformity of dosage.However, it goes without saying that the total daily use amount of the compositions described herein should be determined by a doctor within the scope of sound medical judgment.The specific therapeutically effective dosage level for specific subject or organism depends on various factors, including the disease to be treated and its severity, the activity of the specific active ingredient used, the specific composition used, the age, weight, general health condition, sex and diet of subject, the administration time, route of administration and excretion rate of the specific active ingredient used, treatment period, the drug used in combination with or simultaneously with the specific active ingredient used, and similar factors well known in the medical field.

[0115] The compounds or compositions described herein can be administered in combination with one or more additional agents (e.g., therapeutically and / or prophylactically active agents). The compounds or compositions can be administered in combination with additional agents that improve their activity (e.g., activity (e.g., potency and / or efficacy) in treating a disorder in a subject in need of treatment, preventing a disorder in a subject in need of prevention, reducing the risk of developing a disorder in a subject in need of reduction, and / or inhibiting the activity of a protein kinase in a subject or cell), improve their bioavailability, improve their safety, reduce drug resistance, reduce and / or alter their metabolism, inhibit their excretion, and / or alter their distribution in a subject or cell. It will also be understood that the therapies used may achieve a desired effect for the same disorder or may achieve different effects. In certain embodiments, pharmaceutical compositions described herein comprising a compound described herein and an additional agent exhibit a synergistic effect not seen in pharmaceutical compositions comprising only one compound and an additional agent. In some embodiments, the additional agents achieve a desired effect for the same disorder. In some embodiments, the additional agents achieve different effects.

[0116] The compound or composition can be administered simultaneously with, before, or after one or more additional agents, e.g., useful as a combination therapy. Agents include therapeutically active agents. Agents also include prophylactically active agents. Agents include drug compounds (e.g., compounds approved for human or veterinary use by the U.S. Food and Drug Administration, as defined in the Code of Federal Regulations (CFR)), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides or proteins, small molecules bound to proteins, glycoproteins, steroids, nucleic acids, DNA, RNA, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins, and small organic molecules such as cells. In certain embodiments, the additional agent is an agent useful for treating and / or preventing central nervous system disorders. Each additional agent can be administered at a dose and / or administration schedule determined for that agent. The additional agents can be administered together with each other and / or with the compounds or compositions described herein in a single dose or composition, or separately in different doses or compositions. The specific combination to be adopted in the regimen will take into consideration the compatibility of the compound described herein with the additional drug, and / or the desired therapeutic and / or prophylactic effect to be achieved.In general, it is expected that the additional drug pharmaceutical agent will be used in combination at a level that does not exceed the level at which it is used alone.In some embodiments, the level used in combination will be lower than the level at which it is used alone.

[0117] Additional drugs include, but are not limited to, antiproliferative agents, anticancer agents, antiangiogenic agents, steroidal or nonsteroidal anti-inflammatory agents, immunosuppressants, antibacterial agents, antiviral agents, cardiovascular therapeutic agents, cholesterol-lowering agents, antidiabetic agents, antiallergic agents, contraceptives, analgesics, anesthetics, anticoagulants, enzyme inhibitors, steroidal agents, steroidal or antihistamines, antigens, vaccines, antibodies, decongestants, sedatives, opioids, analgesics, antipyretics, hormones and prostaglandins.In certain embodiments, the additional drug is an antiproliferative agent.In certain embodiments, the additional drug is an anticancer agent.In certain embodiments, the additional drug is an antiviral agent.In certain embodiments, the additional drug is a protein kinase binder or inhibitor. In certain embodiments, the additional agent is selected from the group consisting of epigenetic or transcriptional modulators (e.g., DNA methyltransferase inhibitors, histone deacetylase inhibitors (HDAC inhibitors), lysine methyltransferase inhibitors), antimitotic agents (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 anticancer therapies, 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 drug compounds (e.g., compounds approved by the U.S. Food and Drug Administration (FDA) as defined in the Code of Federal Regulations (CFR)), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides or proteins, small molecules bound to proteins, glycoproteins, steroids, nucleic acids, DNA, RNA, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins, and cells.

[0118] The present disclosure also includes kits (e.g., pharmaceutical packs). The provided kits may include a pharmaceutical composition or compound described herein and a container (e.g., a vial, an ampoule, a bottle, a syringe, and / or a dispenser package, or other suitable container). In some embodiments, the provided kits may optionally further include a second container containing a pharmaceutical excipient for diluting or suspending the pharmaceutical composition or compound described herein. In some embodiments, the pharmaceutical composition or compound provided in the first container and the second container are combined to form a single unit dosage form.

[0119] Thus, in one aspect, a kit is provided, comprising a first container containing a compound or pharmaceutical composition described herein.In certain embodiments, the kit is useful for treating CNS disorders in a subject in need of treatment.In certain embodiments, the kit is useful for preventing CNS disorders in a subject in need of prevention.In certain embodiments, the kit is useful for reducing the risk of developing CNS disorders in a subject in need of reduction.In certain embodiments, the kit is useful for inhibiting the activity (e.g., abnormal activity, such as increased activity) of protein kinase in a subject or cell.

[0120] In certain embodiments, the kit described herein further comprises instructions for use of the kit. The kit described herein may also include information required by regulatory authorities such as the U.S. Food and Drug Administration (FDA). In certain embodiments, the information included in the kit is prescribing information. In certain embodiments, the kit and instructions provide treatment of a CNS disorder in a subject in need of treatment. In certain embodiments, the kit and instructions provide prevention of a CNS disorder in a subject in need of prevention. In certain embodiments, the kit and instructions provide a reduction in the risk of developing a CNS disorder in a subject in need of such reduction. In certain embodiments, the kit and instructions inhibit the activity (e.g., abnormal activity, such as increased activity) of a protein kinase in a subject or cell. The kit described herein may include one or more additional agents described herein as separate compositions.

[0121] Treatment method As outlined herein, the present disclosure provides a method for treating CNS (or its symptoms), comprising administering to a subject in need thereof an effective amount of a compound of the present disclosure, or a salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotope-labeled derivative or prodrug thereof, or a composition comprising an effective amount of a compound of the present disclosure, or a salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotope-labeled derivative or prodrug thereof. Such a method can be performed in vivo (i.e., by administration to a subject) or in vitro (e.g., by contact with tissue or cell culture). As used herein, "treatment" includes therapeutic treatment. In certain embodiments, the subject is identified as being in need thereof. In certain embodiments, the method further comprises treating the subject, i.e., improving the disease, disorder, or its symptoms.

[0122] In certain embodiments, effective amount is therapeutically effective amount.For example, in certain embodiments, this method delays the progression of CNS disorder in object.In certain embodiments, this method improves the condition of the object suffering from CNS disorder.In certain embodiments, object is suspected or confirmed to have CNS disorder.

[0123] In certain embodiments, effective amount is prophylactically effective amount.For example, in certain embodiments, this method is to prevent CNS disorder or reduce the likelihood of developing, for example, in certain embodiments, it comprises administering the compound of the present disclosure to the subject in need thereof with the amount that is sufficient to prevent CNS disorder or reduce the likelihood of developing.In certain embodiments, the subject is at risk of developing CNS disorder.

[0124] Exemplary CNS disorders include, but are not limited to, neurotoxicity and / or neurotrauma, stroke, multiple sclerosis, spinal cord injury, epilepsy, psychiatric disorders, sleep disorders, movement disorders, nausea and / or vomiting, amyotrophic lateral sclerosis, Alzheimer's disease, and drug addiction.

[0125] 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 neuroprotective effects against, for example, chronic neurodegenerative diseases.

[0126] In certain embodiments, the CNS disorder is Alzheimer's disease.

[0127] In certain embodiments, the CNS disorder is amyotrophic lateral sclerosis (ALS).

[0128] In certain embodiments, the CNS disorder is frontotemporal dementia (FTD).

[0129] In certain embodiments, the CNS disorder is Parkinson's disease.

[0130] In certain embodiments, the CNS disorder is regulated by the JAK-STAT pathway. In certain embodiments, the CNS disorder is regulated by TYK2.

[0131] 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.

[0132] In certain embodiments, the CNS disorder is amyotrophic lateral sclerosis / frontotemporal dementia (ALS / FTD).

[0133] Any of the methods described herein can further include administering to the subject an additional agent, which can be an anti-CNS disorder agent. Examples include butyrophenones, phenothiazines, fluphenazine, perphenazine, prochlorperazine, thioridazine, trifluoperazine, mesoridazine, promazine, triflupromazine, levomepromazine, promethazine, thioxanthenes, chlorprothixene, flupenthixol, thiothixene, zuclopenthixol, clozapine, olanzapine, risperidone, quetiapine, ziprasidone, amisulpride, asenapine, acetaminophen ... antipsychotics selected from phenanthrene, paliperidone, aripiprazole, dopamine partial agonists, lamotrigine, memantine, tetrabenazine, cannabidiol, LY2140023, droperidol, pimozide, butaperazine, carphenazine, remoxipride, piperacetazine, sulpiride, acamprosate and tetrabenazine; fluoxetine, paroxetine, escitalopram, citalopram, ceriraline, fluvoxamine, venlafexine, milnacipram, duloxetine, Mirtazapine, mianserin, reboxetine, bupropion, amitriptyline, nortriptyline, protriptyline, desipramine, trimipramine, amoxapine, bupropion, bupropion SR, s-citalopram, clomipramine, desipramine, doxepin, isocarboxazid, velafaxine XR, tranylcypromine, trazodone, nefazodone, phenezin, ramatrogine, lithium, topiramate, gabapentin, carbamazepine, oxacarbazepine, valproate an antidepressant or mood stabilizer selected from valporate, maprotiline, mirtazapine, brofaromine, gepirone, moclobemide, isoniazid, and iproniazid; or an agent for improving cognitive function and / or inhibiting neurodegeneration selected from aricept, donepezil, tacrine, rivastigmine, memantine, physostigmine, nicotine, arecoline, huperzine alfa, selegiline, riluzole, vitamin C, vitamin E, carotenoids, and ginkgo biloba.Any anti-CNS disorder agent known in the art can be used in combination with a compound of Formulas (I)-(III) or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof to achieve the intended therapeutic effect.

[0134] The compounds and compositions provided herein can be administered by any route, including enteral (e.g., oral), parenteral, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, subcutaneous, intracerebroventricular, transdermal, interdermal, rectal, vaginal, intraperitoneal, topical (by powder, ointment, cream and / or drops), mucosal, nasal, buccal, sublingual; intratracheal instillation, bronchial instillation, and / or inhalation; and / or oral spray, nasal spray, and / or aerosol.Specifically, oral administration, intravenous administration (e.g., systemic intravenous injection), local administration via blood and / or lymphatic supply, and / or direct administration to the affected area are considered.Generally, the most appropriate administration route depends on various factors, including the nature of the drug (e.g., stability in the gastrointestinal environment) and / or the condition of the subject (e.g., whether the subject can tolerate oral administration).In certain embodiments, the compounds or pharmaceutical compositions described herein are suitable for topical administration to the eye of a subject.

[0135] The exact amount of compound required to achieve an effective dose varies from subject to subject, and depends, for example, on the subject's race, age and general condition, the severity of side effects or disorders, the type of specific compound, the method of administration, etc. An effective amount can be contained in a single administration (e.g., a single oral administration) or multiple administrations (e.g., multiple oral administrations). In certain embodiments, when administered to a subject multiple times or applied to tissue or cells multiple times, any two doses of the multiple administrations contain different or substantially the same amount of the compound described herein. In certain embodiments, when administered to a subject multiple times or applied to tissue or cells multiple times, the frequency of multiple administrations to a subject or multiple application to tissue or cells is 3 times a day, 2 times a day, 1 time a day, 1 time every other day, 1 time every 3 days, 1 time every week, 1 time every 2 weeks, 1 time every 3 weeks, or 1 time every 4 weeks. In certain embodiments, the frequency of multiple administrations to a subject or multiple application to tissue or cells is 1 time a day. In certain embodiments, the frequency of multiple administrations to subject or multiple application to tissue or cell is twice a day.In certain embodiments, the frequency of multiple administrations to subject or multiple application to tissue or cell is 3 times a day.In certain embodiments, when multiple administrations to subject or multiple application to tissue or cell, the period between the first administration and the last administration of multiple administrations is 1 day, 2 days, 4 days, 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 6 months, 9 months, 1 year, 2 years, 3 years, 4 years, 5 years, 7 years, 10 years, 15 years, 20 years, or the lifespan of subject, tissue or cell.In certain embodiments, the period between the first administration and the last administration of multiple administrations is 3 months, 6 months or 1 year.In certain embodiments, the period between the first administration and the last administration of multiple administrations is the lifespan of subject, tissue or cell.In certain embodiments, the doses described herein (e.g., a single dose, or any dose in multiple administrations) independently comprise 0.1 μg to 1 μg (inclusive), 0.001 mg to 0.01 mg (inclusive), 0.01 mg to 0.1 mg (inclusive), 0.1 mg to 1 mg (inclusive), 1 mg to 3 mg (inclusive), 3 mg to 10 mg (inclusive), 10 mg to 30 mg (inclusive), 30 mg to 100 mg (inclusive), 100 mg to 300 mg (inclusive), 300 mg to 1,000 mg (inclusive), or 1 g to 10 g (inclusive) of a compound described herein. In certain embodiments, the doses described herein independently comprise 1 mg to 3 mg (inclusive) of a compound described herein. In certain embodiments, the doses described herein independently comprise 3 mg to 10 mg (inclusive) 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.

[0136] It will be understood that the dosage ranges described herein are guidelines for administering the provided pharmaceutical compositions to adults. For example, the amount administered to a child or adolescent may be less than or the same as the amount administered to an adult, as determined by a physician or person skilled in the art. [Example]

[0137] Example 1: Synthesis of 2-(1-(2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)piperidin-4-yl)acetonitrile (1) [ka] Step 1: To a solution of compound 1a (500 mg, 2.40 mmol) in ethanol (20 mL) was added compound 1b (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 give compound 1c (110 mg, 0.35 mmol, 14.7% yield) as a yellow solid. LCMS: [M+H] + :312.

[0138] Step 2: To a 40 mL flask containing compound 1c (110 mg, 0.35 mmol, 1.0 eq.) was added THF (15 mL), saturated aqueous ammonium chloride (5 mL), and zinc (115 mg, 1.77 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 1d (30 mg, 0.11 mmol, 30.2% yield) as a yellow solid. LCMS: [M+H] + : 282.

[0139] Step 3: A mixture of compound 1d (30 mg, 0.11 mmol) and acetic anhydride (3 mL) was stirred at 110° C. for 4 hours. 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]quinolin-1-yl)piperidin-4-yl)acetonitrile (1) (5.2 mg, 0.017 mmol, 16.0% yield) as a yellow solid. LCMS: [M+H] + : 306. 1H 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).

[0140] Example 2: Synthesis of 2-(1-(2-methyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)piperidin-4-yl)acetonitrile (2) [ka] Step 1: To a solution of compound 2a (550 mg, 2.63 mmol) in ethanol (20 mL) was added compound 1b (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.

[0141] 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.

[0142] Step 3: A mixture of compound 2d (24 mg, 0.085 mmol) and acetic anhydride (3 mL) was stirred at 110° C. for 4 hours. 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).

[0143] Example 3: Synthesis of 2-((1r,4r)-4-(imidazo[1,2-a]quinoxalin-1-yl)cyclohexyl)acetonitrile (3) [ka] 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 oxalyl chloride (12.7 g, 0.1 mol, 2.0 eq) dropwise at 0-10° C. The mixture was stirred at ambient temperature for 1 h and then concentrated under reduced pressure to give compound 3b' (9.3 g, yield: 100%) as a yellow oil.

[0144] Step 2: Under a nitrogen atmosphere, (trimethylsilyl)diazomethane (2M, 30 mL, 0.06 mol, 1.2 eq) was added dropwise to compound 3b' (9.3 g, 0.05 mol, 1.0 eq) in THF (30 mL) and acetonitrile (30 mL) in an ice bath. The reaction mixture was stirred in the ice bath for 1 hour and then at room temperature for another 1 hour. The reaction solution was cooled in an ice bath, and then an aqueous solution of 48% hydrobromic acid (11 g, 0.065 mmol, 1.3 eq) was added dropwise, and the mixture was stirred for 15 minutes. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, which was then extracted twice with ethyl acetate. The extracts were washed with brine, dried over sodium sulfate, and concentrated. The resulting residue was purified by flash column silica gel chromatography to give a mixture of compounds 3c and 3c' (3c:3c' = 3:1, 6.2 g) as a yellow solid.

[0145] 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 a nitrogen atmosphere. The reaction mixture was stirred at 100 °C overnight. The reaction mixture was allowed to cool to room temperature, and the solvent was removed under reduced pressure. The crude mixture was purified by column chromatography to give compound 3b (1.1 g, 4.5 mmol, 49.1% yield) as a yellow solid. LCMS: [M+H] + : 246.

[0146] 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 solution of a mixture of 3c and 3c′ (1.1 g, 5.4 mmol, 1.2 eq.) in dry 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.

[0147] 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, 60.0% yield) 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).

[0148] Example 4: Synthesis of 2-((1r,4r)-4-(imidazo[1,2-a]pyrido[3,2-e]pyrazin-9-yl)cyclohexyl)acetonitrile (4) [ka] 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 (30 mL) under a nitrogen atmosphere. The reaction mixture was stirred at 100 °C overnight. The reaction mixture was allowed to cool to room temperature, and the solvent was removed under reduced pressure. The crude mixture was purified by column chromatography to give compound 4b (540 mg, 2.19 mmol, 36.2% yield) as a yellow solid. LCMS: [M+H] + : 247.

[0149] Step 2: To a solution of compound 4b (300 mg, 1.22 mmol) in DMF (5 mL) was added sodium hydride (53 mg, 60% 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 a 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 give compound 4d (230 mg, 0.56 mmol, 46.1% yield) as a yellow solid. LCMS: [M+H] + : 410.

[0150] Step 3: To 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 hours. 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]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. 1 H 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).

[0151] Example 5. TYK2 cell ELISA assay using NK92 cells This study was conducted to examine intracellular TYK2 activity using an IFNγ excretion assay in NK92 cells stimulated with IL-12 and IL-18. The assay was performed as follows: 1) NK92 cell medium containing IL-2 was replaced with medium without IL-2 and cultured overnight; 2) NK92 cells were seeded into a 96-well plate at a density of approximately 150,000 cells / well; 3) different concentrations of test substances were added to the wells and incubated in an incubator at 37°C and 5% CO2 for 1 hour; 4) IL-12 (final concentration: 2 ng / ml) and IL-18 (final concentration: 5 ng / ml) were added and stimulated in the incubator for 24 hours; 5) After 24 hours, the cells were centrifuged at 2000 rpm for 5 minutes, and the supernatant was collected and analyzed according to the ELISA kit instructions.

[0152] The test results are as follows (IC 50 (μM)). [Table 1]

[0153] Inclusion by reference This application references 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 invention are described herein. Other features, objects, and advantages of the invention will be apparent from the detailed description, examples, and claims.

[0154] Equivalents and Scope In the claims, articles such as "a," "an," and "the" may mean one or more unless stated otherwise or clear from the context. A claim or description including "or" between one or more members of a group is deemed to be satisfied if one, more than one, or all of the group members are present in, employed in, or associated with a particular product or process, unless stated otherwise or clear from the context. The disclosure includes embodiments in which exactly one member of a group is present in, employed in, or associated with a particular product or process. The disclosure includes embodiments in which one or more, or all of the group members are present in, employed in, or associated with a particular product or process.

[0155] Furthermore, the present disclosure encompasses all variations, combinations, and permutations that introduce one or more limitations, elements, clauses, and descriptive terminology of the enumerated claims into other claims. For example, a claim that depends on another claim can be amended to include one or more limitations found in other claims that depend from the same base claim. Where elements are presented as lists (e.g., Markush group format), each subgroup of elements is also disclosed, and any element can be deleted from the group. In general, when the present disclosure or aspects of the present disclosure are referred to as comprising particular elements and / or features, it is understood that certain embodiments of the present disclosure or aspects of the present disclosure consist of, or consist essentially of, such elements and / or features. For the sake of brevity, these embodiments have not been specifically described verbatim herein. Also, note that the terms "comprising" and "containing" are intended to have an open meaning, allowing for the inclusion of additional elements or steps. Where ranges are presented, endpoints are included. Furthermore, unless otherwise stated or apparent from the context and the understanding of one of ordinary skill in the art, values ​​expressed as ranges can take any specific value or subrange within the stated range in different embodiments of this disclosure, to the nearest tenth of the lower limit of the range, unless the context clearly dictates otherwise.

[0156] This application references various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. In the event of a conflict between an incorporated reference and this specification, this specification shall control. Furthermore, certain embodiments of the present disclosure that constitute prior art may be expressly excluded from any claim. Such embodiments may be deemed known to those of skill in the art and therefore may be excluded even if not expressly excluded herein. Certain embodiments of the present disclosure may be excluded from any claim for any reason, regardless of the existence of prior art.

[0157] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, equivalents to the specific embodiments described herein. The scope of the embodiments described herein is not limited to the above description, but is as set forth in the appended claims. Those skilled in the art will recognize that various changes and modifications can be made herein without departing from the spirit or scope of the disclosure.

Claims

1. Formula (I): 【Chemistry 1】 [In the formula, X is CH or N; Y 1 is C and Y 2 is N; or Y 1 is N and Y 2 is C; 【Chemistry 2】 is a single or double bond; R 1 is H, halo, or halo, 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) 2 R', S(O) 2 R and S(O) 2 C optionally substituted with one, two or three substituents independently selected from the group consisting of NRR′ 1-3 is alkyl; Cy is C 3-7 cycloalkyl or 3- to 7-membered heterocyclyl, where Cy is R 2 , oxo, 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) 2 R', S(O) 2 R and S(O) 2 optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of NRR'; R 2 are 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) 2 R', S(O) 2 R and S(O) 2 C optionally substituted with one, two or three substituents independently selected from the group consisting of NRR′ 1-3 Alkyl, C 3-7 cycloalkyl, 3- to 7-membered heterocyclyl, phenyl, or 5- to 6-membered heteroaryl; R, R' are each independently H or C optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halo, OH and CN. 1-3 Alkyl or C 3-6 is cycloalkyl] or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative or prodrug thereof.

2. Formula (Ia): 【Transformation 3】 [In the formula, X is CH or N; R 1 is H, halo, or halo, 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) 2 R', S(O) 2 R and S(O) 2 C optionally substituted with one, two or three substituents independently selected from the group consisting of NRR′ 1-3 is alkyl; Ring A is R 2 , oxo, 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) 2 R', S(O) 2 R and S(O) 2 NRR' is a 4- to 7-membered heterocyclyl optionally substituted by 1, 2, or 3 substituents independently selected from the group consisting of: R 2 are 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) 2 R', S(O) 2 R and S(O) 2 C optionally substituted with one, two or three substituents independently selected from the group consisting of NRR′ 1-3 Alkyl, C 3-7 cycloalkyl, 3- to 7-membered heterocyclyl, phenyl, or 5- to 6-membered heteroaryl; R, R' are each independently H or C optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halo, OH and CN. 1-3 Alkyl or C 3-6 is cycloalkyl] 10. The compound of claim 1, or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative or prodrug thereof, having the formula:

3. Formula (Ib): 【Chemistry 4】 [In the formula, X is CH or N; R 1 is H, halo, or halo, 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) 2 R', S(O) 2 R and S(O) 2 C optionally substituted with one, two or three substituents independently selected from the group consisting of NRR′ 1-3 is alkyl; Cy is C 3-7 cycloalkyl or 3- to 7-membered heterocyclyl, where Cy is R 2 , oxo, 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) 2 R', S(O) 2 R and S(O) 2 optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of NRR'; R 2 are 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) 2 R', S(O) 2 R and S(O) 2 C optionally substituted with one, two or three substituents independently selected from the group consisting of NRR′ 1-3 Alkyl, C 3-7 cycloalkyl, 3- to 7-membered heterocyclyl, phenyl, or 5- to 6-membered heteroaryl; R, R' are each independently H or C optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halo, OH and CN. 1-3 Alkyl or C 3-6 is cycloalkyl] 10. The compound of claim 1, or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative or prodrug thereof, having the formula:

4. 4. The compound of claim 1, wherein X is CH, or a pharmaceutically acceptable salt thereof.

5. 4. The compound of claim 1, wherein X is N, or a pharmaceutically acceptable salt thereof.

6. Ring A is R 2 , Halo, OH, CN, OR and N(R)S(O) 2 R' is a 4- to 7-membered heterocyclyl optionally substituted by 1, 2, or 3 substituents independently selected from the group consisting of: 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) 2 R', S(O) 2 R and S(O) 2 C optionally substituted with one, two or three substituents independently selected from the group consisting of NRR′ 1-3 is alkyl, 6. The compound of claim 2, 4 or 5, or a pharmaceutically acceptable salt thereof.

7. Ring A is R 2 is a 6-membered heterocyclyl optionally substituted by 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) 2 R', S(O) 2 R and S(O) 2 C optionally substituted with one, two or three substituents independently selected from the group consisting of NRR′ 1-3 is alkyl, 7. The compound of claim 6 or a pharmaceutically acceptable salt thereof.

8. Ring A is 【Transformation 5】 8. The compound of claim 7, wherein R is a 6-membered heterocyclyl optionally substituted by: or a pharmaceutically acceptable salt thereof.

9. Ring A is 【Transformation 6】 9. The compound of claim 8, wherein:

10. Cy, R 2 , Halo, OH, CN, OR and N(R)S(O) 2 R', optionally substituted with one, two, or three substituents independently selected from the group consisting of 3-7 is cycloalkyl; 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) 2 R', S(O) 2 R and S(O) 2 C optionally substituted with one, two or three substituents independently selected from the group consisting of NRR′ 1-3 6. The compound of claim 3, 4 or 5, or a pharmaceutically acceptable salt thereof, wherein:

11. Cy, R 2 cyclohexyl optionally substituted by 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) 2 R', S(O) 2 R and S(O) 2 C optionally substituted with one, two or three substituents independently selected from the group consisting of NRR′ 1-3 is alkyl, 11. The compound of claim 10 or a pharmaceutically acceptable salt thereof.

12. Cy, 【Transformation 7】 12. The compound of claim 11, wherein:

13. Cy, 【Transformation 8】 13. The compound of claim 12, wherein:

14. R 1 But, H, CH 3 or 【Chemistry 9】 14. The compound of any one of claims 1 to 13, wherein:

15. The compound is 2-(1-(2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)piperidin-4-yl)acetonitrile (1); 2-(1-(2-methyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)piperidin-4-yl)acetonitrile (2); 2-((1r,4r)-4-(imidazo[1,2-a]quinoxalin-1-yl)cyclohexyl)acetonitrile (3); 2-((1r,4r)-4-(imidazo[1,2-a]pyrido[3,2-e]pyrazin-9-yl)cyclohexyl)acetonitrile (4) 15. The compound of any one of claims 1 to 14, wherein:

16. The compound is (R)-2-(1-(2-(1-hydroxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl)piperidin-4-yl)acetonitrile (5); (R)-2-(1-(2-(1-hydroxyethyl)-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)piperidin-4-yl)acetonitrile (6); 2-((1r,4r)-4-(2-methylimidazo[1,2-a]quinoxalin-1-yl)cyclohexyl)acetonitrile (7); 2-((1r,4r)-4-(8-methylimidazo[1,2-a]pyrido[3,2-e]pyrazin-9-yl)cyclohexyl)acetonitrile (8) 15. The compound of any one of claims 1 to 14, wherein:

17. 19. A method of treating a central nervous system (CNS) disorder, 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. 18. The method of claim 17, wherein the CNS disorder is a neurodegenerative disease.

19. 19. The method of claim 18, wherein the neurodegenerative disease is amyotrophic lateral sclerosis, Alzheimer's disease, multiple sclerosis or Parkinson's disease.

20. 19. A method of treating an inflammatory disorder, 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. 21. The method of claim 20, wherein the inflammatory disorder is psoriasis, lupus, or ankylosing spondylitis.

22. 19. A method of treating a central nervous system (CNS) disorder, comprising administering to a subject in need thereof an effective amount of a composition comprising the 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. 23. The method of claim 22, wherein the neurodegenerative disease is amyotrophic lateral sclerosis, Alzheimer's disease, multiple sclerosis or Parkinson's disease.

24. 19. A method of treating an inflammatory disorder, comprising administering to a subject in need thereof an effective amount of a composition comprising the 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. 25. The method of claim 24, wherein the inflammatory disorder is psoriasis, lupus, or ankylosing spondylitis.

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

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