Methods for Treating Central Nervous System Disorders

Abstract

The present invention relates to a method of treating central nervous system (CNS) disorders using a compound of formula (I)-(III), or a salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof. A method of treating CNS disorders using a composition comprising such a compound is also provided herein. The present disclosure also provides a compound of formula (A), or a salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

Description

[Background technology]

[0001] The central nervous system (CNS) includes the brain and spinal cord. The CNS is vulnerable to a variety of disorders caused by a variety of factors including trauma, infection, degeneration, structural defects and / or damage, tumors, disruptions to blood flow, and autoimmune disorders. Symptoms of CNS disorders vary depending on the area of ​​the nervous system involved and the cause of the disorder.

[0002] Due to the complexity of CNS disorders and the lack of efficient techniques to deliver therapeutic agents through the blood-brain barrier, the development of effective therapies for CNS disorders has lagged behind other therapeutic areas, so there is great interest in developing new treatment approaches for CNS disorders.

[0003] Protein kinases represent a large family of proteins that play a central role in the control of a wide variety of cellular processes and the maintenance of cellular function. A partial, non-limiting list of these kinases includes: non-receptor tyrosine kinases, such as the Janus kinase family (JAK1, JAK2, JAK3 and TYK2); receptor tyrosine kinases, such as platelet-derived growth factor receptor kinase (PDGFR); and serine / threonine kinases, such as b-RAF. Abnormalities in kinase activity have been observed in disorders resulting from inappropriate activation of the nervous system. Compounds of the present disclosure selectively inhibit the activity of one or more protein kinases compared to other related kinases, and are therefore expected to be useful in the treatment of disorders mediated by the selectively inhibited kinases, while avoiding the undesirable side effects associated with the inhibition of related kinases.

[0004] In particular, the Janus kinase family is composed of four known family members: JAK1, 2, 3, and tyrosine kinase 2 (TYK2). These cytoplasmic tyrosine kinases are associated with membrane cytokine receptors, such as the common gamma chain receptor and glycoprotein 130 (gp 130) transmembrane protein (Murray, J. Immunol. 178(5):2623-2629, 2007). Nearly 40 cytokine receptors signal through a combination of these four JAK family members and their seven downstream substrates, namely, signal transducer and activator 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 phosphorylate cytokine receptor residues, creating binding sites for sarcoma homology 2 (SH2)-containing proteins, such as STAT factors and other regulators, which are then activated by JAK phosphorylation. Activated STATs enter the nucleus and initiate the expression of survival factors, cytokines, chemokines, and molecules that promote cellular trafficking in leukocytes (Schindler et al., J. Biol. Chem. 282(28):20059-20063, 2007). JAK activation also leads to cell proliferation via pathways mediated by phosphoinositide 3-kinase (PI3K) and protein kinase B.

[0005] JAK3 and JAK1 are components of the common gamma chain cytokine receptor complex, and blocking either one inhibits signaling by inflammatory cytokines (interleukin (IL)-2, 4, 7, 9, 15, and 21) (Ghoreschi et al., Immunol. Rev. 228(1):273-287, 2009). In contrast, other pathologically relevant cytokines, such as IL-6, are specifically dependent on JAK1. Therefore, blocking JAK1 inhibits signaling by many proinflammatory cytokines (Guschin et al., EMBO J. 14(7):1421-1429, 1995).

[0006] No humans have been reported to be deficient in JAK1 or JAK2. JAK1-deficient mice die perinatally (Schindler et al., J. Biol Chem. 282(28):20059-20063, 2007). JAK2 deficiency in mice is also lethal; - / - Embryos die between the 12th and 13th day after conception due to lack of erythropoiesis (Neubauer et al., Cell 93(3):397-409, 1998). JAK3 deficiency has also been reported in humans, who exhibit severe combined immunodeficiency within the first few months of life, with symptoms including failure to thrive, severe and recurrent infections, thrush, and diarrhea. JAK3-deficient infants have no circulating T cells and NK cells, and abnormal B cell function. TYK2 deficiency has also been reported in humans, who exhibit impaired antibacterial responses, elevated serum IgE, and atopic dermatitis (Minegishi et al., Immunity 25(5):745-755, 2006).

[0007] Due to the high 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 (Incyte Corp. press release, 10 Nov. 2010; Changelian et al., Science 302(5646):875-878, 2003). Recently, two JAK1-selective compounds, upadacitinib and abrocitinib, have been approved by the FDA. A TYK2-selective inhibitor, deucravacitinib, is pending FDA approval.

[0008] Alzheimer's disease (AD) is the most common neurodegenerative disease and is estimated to account for 60-70% of all cases of dementia worldwide. According to the prevailing amyloid cascade hypothesis, the deposition of amyloid-β (Aβ) in the brain is an early symptom of AD, but accumulating evidence indicates that this hypothesis is insufficient to explain many aspects of AD pathogenesis. The discovery of elevated levels of inflammatory markers in AD patients and the identification of AD risk genes related to innate immune function suggest that neuroinflammation plays a key role in AD pathogenesis (Leng and Edison, Nat Rev Neurol. 2021 Mar;17(3):157-172). Many inflammatory markers, e.g., IL-6, are associated with the JAK-STAT pathway, which is controlled by JAK1 / TYK2. Recent studies in animal models suggest that microglial activation, rather than simply an inflammatory epiphenomenon, promotes tau pathology (Hopp et al. J. Neuroinflammation 2018, 15, 269).

[0009] Recently, JAK1 inhibitors have been shown to reduce or prevent neuronal cell death and may have potential applications in the treatment of amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD) and Alzheimer's disease (AD) (Rodriguez, S. et al. 2021 Feb 15;12(1):1033; Rodriguez, S. et al. Med. 2021, 13, eaaz4699). Increased activity of TYK2 and JAK1 is involved in the pathophysiology of AD (Wan et al., J. Neurosci. 2010, 30, 6873-81; Nevado-Holgado et al., Cells 2019, 8, 425).

[0010] Previously, novel 1H-furo[3,2-b]imidazo[4,5-d]pyridine derivatives have been described as selective dual TYK2 / JAK1 inhibitors for systemic inflammatory diseases such as rheumatoid arthritis and psoriasis ( WO 2018 / 067422 A1 , WO 2020 / 244348 A1 , WO 2020 / 244349 A1 ). Summary of the Invention

[0011] In view of the recent report of the important role of neuroinflammation in general, and TYK2 / JAK1 in particular, in CNS diseases, the present invention discloses selected compounds with excellent brain penetration and anti-neuroinflammatory activity. Thus, these compounds and compositions containing the disclosed compounds are useful for treating diseases associated with TYK2 and JAK1 activity, such as CNS diseases including multiple sclerosis, Parkinson's disease, Alzheimer's disease, or amyotrophic lateral sclerosis / frontotemporal dementia (ALS / FTD).

[0012] The present disclosure provides a 1H-furo[3,2-b]imidazo[4,5-d]pyridine pyridine compound or a salt, solvate, hydrate, polymorph, cocrystal, tautomer, isotopically labeled derivative or prodrug thereof, having such advantageous properties suitable for use as a selective dual TYK2 / JAK1 kinase inhibitor with good ability to cross the blood-brain barrier and in treating central nervous system (CNS) disorders. The present disclosure also provides a composition comprising the compound of the present disclosure or a salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative or prodrug thereof. The disclosure further provides methods of using such compounds or salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives or prodrugs, or such compositions, to treat disorders associated with TYK2 and JAK1, including central nervous system (CNS) disorders such as multiple sclerosis, Parkinson's disease, Alzheimer's disease or amyotrophic lateral sclerosis / frontotemporal dementia (ALS / FTD).

[0013] In one embodiment, a compound of formula (I): [ka] (I) or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative or prodrug thereof is provided.

[0014] In another embodiment, a compound of formula (II): [ka] (II) or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative or prodrug thereof is provided.

[0015] In another embodiment, a compound of formula (III): [ka] (III) or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative or prodrug thereof is provided.

[0016] The compounds of the present invention and compositions comprising same are useful for treating or lessening the severity of a disease, disorder or symptom thereof modulated by TYK2 and JAK1.

[0017] Accordingly, one aspect of the present disclosure relates to a method of treating a CNS disorder, comprising administering to a subject in need thereof an effective amount of a compound of Formulas (I)-(III) herein, or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative or prodrug thereof, which may be formulated into a composition. In some examples, the composition may be a pharmaceutical composition further comprising a pharma- ceutically acceptable carrier.

[0018] In some embodiments, the CNS disorder is neurotoxicity and / or neurotrauma, stroke, multiple sclerosis, spinal cord injury, epilepsy, psychiatric disorders, sleep conditions, movement disorders, nausea and / or vomiting, amyotrophic lateral sclerosis, Alzheimer's disease, and drug addiction.

[0019] In some embodiments, the CNS disorder can be any of those regulated by TYK2 and JAK1.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.

[0020] Also within the scope of the disclosure is: (i) a pharmaceutical composition for use in treating a targeted CNS disorder as described herein, comprising a compound of Formula (I)-(III) or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative or prodrug thereof, and a pharma- ceutically acceptable carrier; (ii) the use of a compound of Formula (I)-(III) 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.

[0021] The recitation of a list of chemical groups in a definition of a variable herein includes a definition of that variable as any single group or combination of the listed groups. The recitation of an embodiment of a variable herein includes that embodiment in any single embodiment or in combination with any other embodiment or portion thereof. The recitation of an embodiment herein includes that embodiment in any single embodiment or in combination with any other embodiment or portion thereof.

[0022] The details of one or more embodiments of the invention are set forth in the following description. Other features and advantages of the invention will become apparent from the following drawings and detailed description of certain embodiments, as well as the appended claims. [Brief description of the drawings]

[0023] [Figure 1] FIG. 1 shows that the compound of formula (II) reduced HT22 neuronal cell death induced by LPS activation of BV2 microglia (FIG. 1A), but did not affect the viability of HT22 cells in the presence of LPS but in the absence of BV2 microglia (FIG. 1B).

[0024] [Diagram 2] FIG. 2 shows that the compound of formula (II) inhibited the production of IL-6, TNF and MCP-1 in LPS-stimulated BV2 cells.

[0025] [Diagram 3] FIG. 3 shows the change in Disease Activity Index over time in each treatment group.

[0026] [Figure 4] 4A-4B show the changes in disease activity index for individual mice receiving vehicle treatment (FIG. 4A) or 30 mg / kg BID of a compound of formula (II) (FIG. 4B).

[0027] Unless otherwise defined, all technical and scientific terms used herein have the meanings commonly understood by those skilled in the art to which the present invention belongs. The following references provide those skilled in the art with general definitions of many terms used in the present 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 Harper Collins Dictionary of Biology (1991). The following terms used herein have the meanings ascribed to them unless otherwise specified.

[0028] Definitions of certain chemical terms are detailed below. Chemical elements are identified according to the Periodic Table of Elements, CAS edition, Handbook of Chemistry and Physics, 75th edition, inside cover, and certain functional groups are generally defined as described therein. In addition, general principles of organic chemistry, as well as certain functional groups and reactivity, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Michael B. Smith, March's Advanced Organic Chemistry, 7th Edition, John Wiley & Sons, Inc., New York, 2013; Richard C. Larock, Comprehensive Organic Transformations, John Wiley & Sons, Inc., New York, 2018; and Carruthers, Some Modern Methods of Organic Synthesis, 3rd Edition, Cambridge University Press, Cambridge, 1987.

[0029] The compounds described herein may contain one or more asymmetric centers and therefore may exist in various stereoisomeric forms, such as enantiomers and / or diastereomers.For example, the compounds described herein may be in the form of individual enantiomers, diastereomers or geometric isomers, or may be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers.Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric synthesis. See, e.g., Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, EL Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, SH, Tables of Resolving Agents and Optical Resolutions p. 268 (EL Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). The present invention further encompasses the compounds as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

[0030] The compounds herein may also include bonds (e.g., carbon-carbon bonds) whose bond rotation is restricted with respect to restrictions resulting from the presence of that particular bond, e.g., a ring or a double bond. Thus, all cis / trans and E / Z isomers are expressly included in the present disclosure. The compounds herein may also be represented in multiple tautomers, and in such cases, the present disclosure expressly includes all tautomers of the compounds described herein, even if only a single tautomeric form may be represented. All isomeric forms of such compounds herein are expressly included in the present disclosure. The term "isomer" is intended to include diastereoisomers, enantiomers, regioisomers, structural isomers, rotamers, tautomers, and the like. In the case of compounds containing one or more stereocenters, e.g., chiral compounds, the methods of the present disclosure may be carried out with enantiomerically enriched compounds, racemates, or mixtures of diastereomers. All isomers of the compounds defined herein are expressly included in the present disclosure.

[0031] In the formula, the bond: [ka] is a single bond, Dashed line: [ka] is a single bond or absent, Join: [ka] is a single bond or a double bond.

[0032] Unless otherwise specified, 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., the replacement of hydrogen with deuterium or tritium; 19 F 18 F or carbon 13 C- or 14Compounds having this structure except for the substitution of C-enriched carbons are within the scope of this disclosure. Such compounds are useful, for example, as analytical tools or probes in biological assays.

[0033] The term "isotope" refers to variants of a particular chemical element in which each atom of the element all contains the same number of protons but different numbers of neutrons.

[0034] When a range of values ​​("range") is listed, each value and subrange within the range is encompassed. A range includes both ends of the range unless otherwise stated. For example, "C 1-6 Alkyl" is C1, C2, C3, C4, C5, C6, C 1-6 , C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-5 , C 2-4 , C 2-3 , C 3-6 , C 3-5 , C 3-4 , C 4-6 , C 4-5 and C 5-6 Includes alkyl.

[0035] The term "aliphatic" refers to alkyl, alkenyl, alkynyl, and carbocyclic groups. Similarly, the term "heteroaliphatic" refers to heteroalkyl, heteroalkenyl, heteroalkynyl, and heterocyclic groups.

[0036] 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, the alkyl group refers to one containing 1 to 12 carbon atoms ("C 1-12 In some embodiments, the alkyl group is one that contains 1 to 10 carbon atoms ("C 1-10In some embodiments, the alkyl group is one that contains 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 is one having 1 carbon atom ("C alkyl"). In some embodiments, the alkyl group is one having 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), n-hexyl (C10), n-hexyl (C11), n-hexyl (C12), n-hexyl (C13), n-hexyl (C14), n-hexyl (C15), n-hexyl (C16), n-hexyl (C17), n-hexyl (C18), n-hexyl (C19), n-hexyl (C20), n-hexyl (C21), n-hexyl (C22), n-hexyl (C23), n-hexyl (C24), n-hexyl (C25), n-hexyl (C26), n-hexyl (C27), n-hexyl (C28), n-hexyl (C29), n-hexyl (C30), n-hexyl (C31), n-hexyl (C32), n-hexyl (C33), n-hexyl (C34), n-hexyl (C35), n-hexyl (C36), n-hexyl (C37), n-hexyl (C38), n-hexyl (C39), n-hexyl (C31), n-hexyl (C32), n-hexyl (C33), n-hexyl (C34), n-hexyl (C35), n-hexyl (C36), n-hexyl (C37), n-hexyl (C38 12 Unless otherwise specified, each instance of an alkyl group is independently unsubstituted ("unsubstituted alkyl") or substituted ("substituted alkyl") with one or more substituents (e.g., halogen, e.g., F). In certain embodiments, an alkyl group is an unsubstituted C1-12 Alkyl (e.g., unsubstituted C 1-6 Alkyl, e.g., -CH3 (Me), unsubstituted ethyl (Et), unsubstituted propyl (Pr, e.g., unsubstituted n-propyl (n-Pr), unsubstituted isopropyl (i-Pr), unsubstituted butyl (Bu, e.g., unsubstituted n-butyl (n-Bu), unsubstituted tert-butyl (tert-Bu or t-Bu), unsubstituted sec-butyl (sec-Bu or s-Bu), unsubstituted isobutyl (i-Bu)). In certain embodiments, the alkyl group is a substituted C 1-12 Alkyl (e.g., substituted C 1-6 alkyl, for example, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3 or benzyl (Bn).

[0037] The term "haloalkyl" refers to a substituted alkyl group in which one or more hydrogen atoms are independently replaced by a halogen, such as fluoro, bromo, chloro, or iodo. "Perhaloalkyl" is a subset of haloalkyl and refers to an alkyl group in which all of the hydrogen atoms are independently replaced by a halogen, such as 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 1-7 In 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 ("C1-5 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 of the hydrogen atoms of the haloalkyl are independently replaced by fluoro to provide a "perfluoroalkyl." In some embodiments, all of the hydrogen atoms of the haloalkyl are independently replaced by chloro to provide a "perchloroalkyl" group. Examples of haloalkyl groups include -CHF2, -CH2F, -CF3, -CH2CF3, -CF2CF3, -CF2CF2CF3, -CCl3, -CFCl2, -CF2Cl, and the like.

[0038] 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 backbone (e.g., inserted between adjacent carbon atoms) and / or at one or more terminal positions of the backbone. In certain embodiments, a heteroalkyl group is a saturated group having 1 to 20 carbon atoms and one or more heteroatoms ("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 backbone ("heteroC 1-12 In some embodiments, a heteroalkyl group refers to a saturated group containing 1 to 11 carbon atoms and one or more heteroatoms in the backbone ("heteroC 1-11 In some embodiments, a heteroalkyl group is a saturated group having 1 to 10 carbon atoms and one or more heteroatoms in the backbone ("heteroC 1-10In some embodiments, a heteroalkyl group is a saturated group having 1 to 9 carbon atoms and one or more heteroatoms in the backbone ("heteroC 1-9 In some embodiments, a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and one or more heteroatoms in the backbone ("heteroC 1-8 In some embodiments, a heteroalkyl group is a saturated group having 1 to 7 carbon atoms and one or more heteroatoms in the backbone ("heteroC 1-7 In some embodiments, a heteroalkyl group is a saturated group having 1 to 6 carbon atoms and one or more heteroatoms in the backbone ("heteroC 1-6 In some embodiments, a heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms in the backbone ("heteroC 1-5 In some embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and 1 to 2 heteroatoms in the backbone ("heteroC 1-4 In some embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom in the backbone ("heteroC 1-3 In some embodiments, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom in the backbone ("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 2-6 carbon atoms and 1 or 2 heteroatoms in the main chain ("heteroC 2-6 Unless otherwise specified, each example of a heteroalkyl group is independently unsubstituted ("unsubstituted heteroalkyl") or substituted ("substituted heteroalkyl") with one or more substituents. In certain embodiments, a heteroalkyl group is an unsubstituted heteroC 1-12In certain embodiments, the heteroalkyl group is a substituted heteroalkyl group. 1-12 It is an alkyl.

[0039] 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, an alkenyl group is one 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 2-4 In some embodiments, the alkenyl group is one having 2 to 3 carbon atoms ("C 2-3In some embodiments, the alkenyl group has two carbon atoms ("C2 alkenyl"). The one or more carbon-carbon double bonds can be internal (e.g., 2-butenyl) or terminal (e.g., 1-butenyl). 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 example of an alkenyl group is independently unsubstituted ("unsubstituted alkenyl") or substituted ("substituted alkenyl") with one or more substituents. 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] ) may be in either the (E)-configuration or the (Z)-configuration.

[0040] The term "heteroalkenyl" refers to an alkenyl group that includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur, located within the backbone (e.g., inserted between adjacent carbon atoms) and / or at one or more terminal positions of the backbone. In certain embodiments, heteroalkenyl groups are those having 2 to 20 carbon atoms, at least one double bond, and one or more heteroatoms in the backbone ("heteroC 2-20In certain embodiments, heteroalkenyl groups refer to those having 2 to 12 carbon atoms, at least one double bond, and one or more heteroatoms in the main chain ("heteroC 2-12 In certain embodiments, heteroalkenyl groups refer to those having 2 to 11 carbon atoms, at least one double bond, and one or more heteroatoms in the main chain ("heteroC 2-11 In certain embodiments, heteroalkenyl groups refer to those having 2 to 10 carbon atoms, at least one double bond, and one or more heteroatoms in the main 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 main chain ("heteroC 2-9 In some embodiments, heteroalkenyl groups have 2 to 8 carbon atoms in the main chain, at least one double bond, and one or more heteroatoms ("heteroC 2-8 In some embodiments, heteroalkenyl groups have 2 to 7 carbon atoms in the main chain, at least one double bond, and one or more heteroatoms ("heteroC 2-7 In some embodiments, heteroalkenyl groups have 2 to 6 carbon atoms in the main chain, at least one double bond, and one or more heteroatoms ("heteroC 2-6 In some embodiments, heteroalkenyl groups have 2 to 5 carbon atoms in the main chain, at least one double bond, and 1 or 2 heteroatoms ("heteroC 2-5 In some embodiments, heteroalkenyl groups have 2 to 4 carbon atoms in the main chain, at least one double bond, and 1 or 2 heteroatoms ("heteroC 2-4 In some embodiments, heteroalkenyl groups have 2 to 3 carbon atoms, at least one double bond, and one heteroatom in the main chain ("heteroC2-3 In some embodiments, heteroalkenyl groups are those having 2 carbon atoms, at least one double bond, and one heteroatom in the main chain ("heteroC2 alkenyl"). In some embodiments, heteroalkenyl groups are those having 2-6 carbon atoms, at least one double bond, and one or two heteroatoms in the main chain ("heteroC 2-6 Unless otherwise specified, each instance of a heteroalkenyl group is independently unsubstituted ("unsubstituted heteroalkenyl") or substituted ("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.

[0041] The term "alkynyl" refers to the radical of a straight-chain or branched hydrocarbon group having 2 to 20 carbon atoms and one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 triple bonds) ("C 1-20 In some embodiments, the alkynyl group refers to one having 2 to 10 carbon atoms ("C 2-10 In some embodiments, the alkynyl group is one having 2 to 9 carbon atoms ("C 2-9 In some embodiments, the alkynyl group is one having 2 to 8 carbon atoms ("C 2-8 In some embodiments, the alkynyl group is one having 2 to 7 carbon atoms ("C 2-7 In some embodiments, the alkynyl group is one having 2 to 6 carbon atoms ("C 2-6 In some embodiments, the alkynyl group is one having 2 to 5 carbon atoms ("C 2-5 In some embodiments, the alkynyl group is one 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"). One or more of the carbon-carbon triple bonds may be internal (such as, for example, 2-butynyl) or may be terminal (such as, for example, 1-butynyl). 2-4 Examples of alkynyl groups include, but are not limited to, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), 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 example of an alkynyl group is independently unsubstituted ("unsubstituted alkynyl") or substituted ("substituted alkynyl") with one or more substituents. 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.

[0042] The term "heteroalkynyl" refers to an alkynyl group that includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur, located within the backbone (e.g., inserted between adjacent carbon atoms) and / or at one or more terminal positions of the backbone. In certain embodiments, heteroalkynyl groups are those having 2 to 20 carbon atoms, at least one triple bond, and one or more heteroatoms in the backbone ("heteroalkynyl groups"). 2-20 In certain embodiments, heteroalkynyl groups refer to those having 2 to 10 carbon atoms, at least one triple bond, and one or more heteroatoms in the main 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 main 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 main 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 main chain ("heteroC 2-7 In some embodiments, heteroalkynyl groups have 2 to 6 carbon atoms, at least one triple bond, and one or more heteroatoms in the main chain ("heteroC 2-6 In some embodiments, heteroalkynyl groups have 2 to 5 carbon atoms in the main chain, at least one triple bond, and 1 or 2 heteroatoms ("heteroC 2-5 In some embodiments, heteroalkynyl groups have 2 to 4 carbon atoms in the main chain, at least one triple bond, and 1 or 2 heteroatoms ("heteroC 2-4 In some embodiments, heteroalkynyl groups have 2 to 3 carbon atoms, at least one triple bond, and one heteroatom in the main chain ("heteroC 2-3 In some embodiments, heteroalkynyl groups are those having 2 carbon atoms, at least one triple bond, and 1 heteroatom in the main chain ("heteroC2 alkynyl"). In some embodiments, heteroalkynyl groups are those having 2-6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms in the main chain ("heteroC 2-6Unless otherwise specified, each instance of a heteroalkynyl group is independently unsubstituted ("unsubstituted heteroalkynyl") or substituted ("substituted heteroalkynyl") with one or more substituents. In certain embodiments, a heteroalkynyl group is an unsubstituted heteroC 2-20 In certain embodiments, the heteroalkynyl group is a substituted heteroC 2-20 It is alkynyl.

[0043] The term "carbocyclyl" or "carbocyclic" refers to a ring system having 3 to 14 ring carbon atoms ("C 3-14 In some embodiments, carbocyclyl groups refer to those having 3 to 14 ring carbon atoms ("C 3-14 In some embodiments, the carbocyclyl group is one having 3 to 13 ring carbon atoms ("C 3-13 In some embodiments, the carbocyclyl group is one having 3 to 12 ring carbon atoms ("C 3-12 In some embodiments, the carbocyclyl group is one having 3 to 11 ring carbon atoms ("C 3-11 In some embodiments, the carbocyclyl group is one having 3 to 10 ring carbon atoms ("C 3-10 In some embodiments, the carbocyclyl group is one having 3 to 8 ring carbon atoms ("C 3-8 In some embodiments, the carbocyclyl group is one having 3 to 7 ring carbon atoms ("C 3-7 In some embodiments, the carbocyclyl group is one 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, the carbocyclyl group is one 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 as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C 10 ), spiro[4.5]decanyl (C 10 ) and other examples. 3-8 The carbocyclyl group includes the above-mentioned C 3-10 Carbocyclyl and cycloundecyl (C 11 ), spiro[5.5]undecanyl (C 11 ), cyclododecyl (C 12 ), cyclododecenyl (C 12 ), cyclotridecane (C 13 ), cyclotetradecane (C 14As the foregoing examples illustrate, in certain embodiments, carbocyclyl groups are either monocyclic ("monocyclic carbocyclyl") or polycyclic (including, for example, fused, bridged, or spiro ring systems such as bicyclic ("bicyclic carbocyclyl") or tricyclic ("tricyclic carbocyclyl") systems), and may be saturated or contain one or more carbon-carbon double or triple bonds. "Carbocyclyl" also includes ring systems in which the carbocyclyl ring, as defined above, is fused to one or more aryl or heteroaryl groups whose points of attachment are on the carbocyclyl ring, in which case the number of carbons continues to indicate the number of carbons in the carbocyclyl 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.

[0044] 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, the cycloalkyl groups are those having 3 to 6 ring carbon atoms ("C 3-6 In some embodiments, the cycloalkyl groups are those having 4 to 6 ring carbon atoms ("C 4-6 In some embodiments, the cycloalkyl groups are those having 5 to 6 ring carbon atoms ("C 5-6 In some embodiments, the cycloalkyl groups are those having 5 to 10 ring carbon atoms ("C5-10 Cycloalkyl). 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 example of a cycloalkyl group is independently unsubstituted ("unsubstituted cycloalkyl") or substituted ("substituted cycloalkyl") with one or more substituents. 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 valence allows, 0, 1 or 2 C=C double bonds in the carbocyclic ring system.

[0045] The term "heterocyclyl" or "heterocyclic" refers to a radical of a 3-14 membered non-aromatic ring system having ring carbon atoms and one to four ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("3-14 membered heterocyclyl"). In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment can be a carbon atom or a nitrogen atom, where valence permits. Heterocyclyl groups can be monocyclic ("monocyclic heterocyclyl") or polycyclic (e.g., fused, bridged, or spiro ring systems, such as bicyclic ("bicyclic heterocyclyl") or tricyclic ("tricyclic heterocyclyl") systems), saturated or containing one or more carbon-carbon double or triple bonds. Heterocyclyl polycyclic ring systems can contain one or more heteroatoms in one or both rings. "Heterocyclyl" also includes ring systems in which the heterocyclyl ring as defined above is fused to one or more carbocyclyl groups, with the point of attachment being on either the carbocyclyl or heterocyclyl ring, or the heterocyclyl ring as defined above is fused to one or more aryl or heteroaryl groups, with the point of attachment being on the heterocyclyl ring, and in such instances, the number of ring members continues to designate the number of ring members in the heterocyclyl ring system. Unless otherwise specified, each instance of heterocyclyl is independently unsubstituted ("unsubstituted heterocyclyl") or substituted by one or more substituents ("substituted heterocyclyl"). In certain embodiments, the heterocyclyl group is an unsubstituted 3-14 membered heterocyclyl. In certain embodiments, the heterocyclyl group is a substituted 3-14 membered heterocyclyl. In certain embodiments, the heterocyclyl is a substituted or unsubstituted 3-7 membered monocyclic heterocyclyl wherein one, two, or three atoms in the heterocyclic ring system are independently oxygen, nitrogen, or sulfur, where valences permit.

[0046] In some embodiments, the heterocyclyl group is a 5-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, each heteroatom being independently selected from nitrogen, oxygen, and sulfur ("5-10 membered heterocyclyl"). In some embodiments, the heterocyclyl group is a 5-8 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, each heteroatom being independently selected from nitrogen, oxygen, and sulfur ("5-8 membered heterocyclyl"). In some embodiments, the heterocyclyl group is a 5-6 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, each heteroatom being independently selected from nitrogen, oxygen, and sulfur ("5-6 membered heterocyclyl"). In some embodiments, the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0047] Exemplary 3-membered heterocyclyl groups containing one heteroatom include azirdinyl, 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, tetra-hydro-benzo-thienyl, tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl, decahydronaphthyridinyl, decahydro-1,8-naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole, indolinyl, phthalimidyl, naphthalimidyl, chromanyl, chromenyl, 1H-benzo[e][1,4]diazepin ... ,4,5,7-tetrahydro-pyrano[3,4-b]pyrrolyl, 5,6-dihydro-4H-furo[3,2-b]pyrrolyl, 6,7-dihydro-5H-furo-[3,2-b]pyranyl, 5,7-dihydro-4H-thieno[2,3-c]pyranyl, 2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, 2,3-dihydrofuro[2,3-b]pyridinyl, 4,5,6,7-tetrahydro-1H-pyrrolo-[2,3-b]pyridinyl, 4,5,6,7-tetrahydro-furo[3,2-c]pyridinyl, 4,5,6,7-tetrahydro-thieno[3,2-b]pyridinyl, and 1,2,3,4-tetrahydro-1,6-naphthyridinyl.

[0048] The term "aryl" refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 pi electrons shared in a cyclic arrangement) having 6 to 14 ring carbon atoms, with zero heteroatoms provided to the aromatic ring system ("C 6-14 In some embodiments, aryl groups are those having 6 ring carbon atoms ("C6 aryl"; e.g., phenyl). In some embodiments, aryl groups are those having 10 ring carbon atoms ("C 10 aryl"; for example, naphthyl, such as 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 the 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 instances the number of carbon atoms continues to designate the number of carbon atoms in the aryl ring system. Unless otherwise specified, each instance of an aryl group is independently unsubstituted ("unsubstituted aryl") or substituted by 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.

[0049] "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.

[0050] The term "heteroaryl" refers to a radical of a 5-14 membered monocyclic or polycyclic (e.g., bicyclic, tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10 or 14 pi electrons shared in a cyclic arrangement) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, each heteroatom being independently selected from nitrogen, oxygen and sulfur ("5-14 membered heteroaryl"). In heteroaryl groups containing one or more nitrogen atoms, the point of attachment may be a carbon atom or a nitrogen atom, as valence permits. Heteroaryl polycyclic ring systems may 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, the point of attachment being on the heteroaryl ring, in which case the number of ring members continues to indicate the number of ring members in the heteroaryl ring system. "Heteroaryl also includes ring systems in which a heteroaryl ring, as defined above, is fused to one or more aryl groups, and the point of attachment is either on the aryl ring or on the heteroaryl ring, in which case the number of ring members refers to the number of ring members in the fused polycyclic (aryl / heteroaryl) ring system. Polycyclic heteroaryl groups in which one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, etc.) are not limited to rings in which the point of attachment is either on a ring with a heteroatom (e.g., 2-indolyl) or on a ring with no heteroatoms (e.g., 5- In certain embodiments, the heteroaryl is a substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl, in which 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, in which one, two, three or four atoms in the heteroaryl ring system are independently oxygen, nitrogen or sulfur.

[0051] In some embodiments, the heteroaryl group is a 5-10 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided on the aromatic ring system, each heteroatom being independently selected from nitrogen, oxygen, and sulfur ("5-10 membered heteroaryl"). In some embodiments, the heteroaryl group is a 5-8 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided on the aromatic ring system, each heteroatom being independently selected from nitrogen, oxygen, and sulfur ("5-8 membered heteroaryl"). In some embodiments, the heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided on the aromatic ring system, each heteroatom being independently selected from nitrogen, oxygen, and sulfur ("5-6 membered heteroaryl"). In some embodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 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 5-14 membered heteroaryl.In certain embodiments, the heteroaryl group is a substituted 5-14 membered heteroaryl.

[0052] 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, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl and quinazolinyl. Exemplary tricyclic heteroaryl groups include phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl and phenazinyl.

[0053] "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.

[0054] The term "unsaturated bond" means a double bond or a triple bond.

[0055] The terms "unsaturated" or "partially unsaturated" mean a moiety that contains at least one double or triple bond.

[0056] The terms "saturated" or "fully saturated" refer to a moiety that does not contain any double or triple bonds, e.g., a moiety that contains only single bonds.

[0057] The addition of "-ene" to a group suffix indicates that the group is a divalent moiety, for example, alkylene is a divalent alkyl moiety, alkenylene is a divalent alkenyl moiety, alkynylene is a divalent alkynyl moiety, heteroalkylene is a divalent heteroalkyl moiety, heteroalkenylene is a divalent heteroalkenyl moiety, heteroalkynylene is a divalent heteroalkynyl moiety, carbocyclylene is a divalent carbocyclyl moiety, heterocyclylene is a divalent heterocyclyl moiety, arylene is a divalent aryl moiety, and heteroarylene is a divalent heteroaryl moiety.

[0058] A group may be optionally substituted unless expressly stated otherwise. The term "optionally substituted" means 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 substituted or unsubstituted groups (e.g., "substituted" or "unsubstituted" alkyl, "substituted" or "unsubstituted" alkenyl, "substituted" or "unsubstituted" alkynyl, "substituted" or "unsubstituted" heteroalkyl, "substituted" or "unsubstituted" heteroalkenyl, "substituted" or "unsubstituted" heteroalkynyl, "substituted" or "unsubstituted" carbocyclyl, "substituted" or "unsubstituted" heterocyclyl, "substituted" or "unsubstituted" aryl or "substituted" or "unsubstituted" heteroaryl groups). In general, the term "substituted" means that at least one hydrogen present on a group is replaced with an acceptable substituent, e.g., a substituent that upon 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 structure is substituted, the substituents are either the same or different at each position. The term "substituted" is intended to include substitution with all acceptable substituents of organic compounds, including any of the substituents described herein that result in the formation of a stable compound. The present 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 manner by the exemplary substituents described herein.

[0059] Exemplary carbon atom substituents include: halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR. aa、-ON(R bb )2、-N(R bb )2、-N(R bb )3 + X - 、-N(OR cc )R bb 、-SH、-SR aa 、-SSR cc 、-C(=O)R aa 、-CO2H、-CHO、-C(OR cc )2、-CO2R aa 、-OC(=O)R aa 、-OCO2R aa 、-C(=O)N(R bb )2、-OC(=O)N(R bb )2、-NR bb C(=O)R aa 、-NR bb CO2R aa 、-NR bb C(=O)N(R bb )2、-C(=NR bb )R aa 、-C(=NR bb )OR aa 、-OC(=NR bb )R aa 、-OC(=NR bb )OR aa 、-C(=NR bb )N(R bb )2、-OC(=NR bb )N(R bb )2、-NR bb C(=NR bb )N(R bb )2、-C(=O)NR bb SO2R aa 、-NR bb SO2R aa 、-SO2N(R bb )2、-SO2R aa 、-SO2OR aa 、-OSO2R aa 、-S(=O)R aa 、-OS(=O)R aa 、-Si(R aa )3、-OSi(R aa )3-C(=S)N(R bb )2、-C(=O)SR aa, -C(=S)SR aa , -SC(=S)SR aa , -SC(=O)SR aa , -OC(=O)SR aa , -SC(=O)OR aa , -SC(=O)R aa , -P(=O)(R aa )2, -P(=O)(OR cc )2, -OP(=O)(R aa )2, -OP(=O)(OR cc )2, -P(=O)(N(R bb )2)2, -OP(=O)(N(R bb )2)2, -NR bb P(=O)(R aa )2, -NR bb P(=O)(OR cc )2, -NR bb P(=O)(N(R bb )2)2, -P(R cc )2, -P(OR cc )2, -P(R cc )3 + X - , -P(OR cc )3 + X - , -P(R cc )4, -P(OR cc ) 4, -OP(R cc )2, -OP(R cc )3 + X - , -OP(OR cc )2, -OP(OR cc )3 + X - , -OP(R cc ) 4, -OP(OR cc )4, -B(R aa )2, -B(OR cc )2, -BR aa (OR cc ), C 1-20 Alkyl, C 1-20 Perhaloalkyl, C 1-20 Alkenyl, C 1-20 Alkynyl, Hetero C 1-20 Alkyl, Hetero C 1-20 Alkenyl, Hetero C1-20 Alkynyl, C 3-10 Carbocyclyl, 3-14 membered heterocyclyl, C 6-14 Aryl and 5-14 membered heteroaryl, where each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently represents 0, 1, 2, 3, 4, or 5 R dd substituted by a group; - is the counterion); Or, the two geminal hydrogens on the carbon atom are bonded to the groups =O, =S, =NN(R bb )2, =NNR bb C(=O)R aa , =NNR bb C(=O)OR aa , =NNR bb S(=O)2R aa , =NR bb OR =NOR cc Replaced by (where: R aa Each instance of 1-20 Alkyl, C 1-20 Perhaloalkyl, C 1-20 Alkenyl, C 1-20 Alkynyl, Hetero C 1-20 Alkyl, Hetero C 1-20 Alkenyl, Hetero C 1-20 Alkynyl, C 3-10 Carbocyclyl, 3-14 membered heterocyclyl, C 6-14 aryl and 5-14 membered heteroaryl, or two R aa the groups combine to form a 3- to 14-membered heterocyclyl or a 5- to 14-membered heteroaryl ring, where alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl each independently represent 0, 1, 2, 3, 4, or 5 R dd is substituted by a group; R bbEach instance of is independently hydrogen, -OH, -OR aa , -N(R cc )2, -CN, -C(=O)R aa , -C(=O)N(R cc )2, -CO2R aa , -SO2R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc , -P(=O)(R aa )2, -P(=O)(OR cc )2, -P(=O)(N(R cc )2)2, C 1-20 Alkyl, C 1-20 Perhaloalkyl, C 1-20 Alkenyl, C 1-20 Alkynyl, Hetero C 1-20 Alkyl, Hetero C 1-20 Alkenyl, Hetero C 1-20 Alkynyl, C 3-10 Carbocyclyl, 3-14 membered heterocyclyl, C 6-14 aryl and 5-14 membered heteroaryl, or two R bb the groups combine to form a 3- to 14-membered heterocyclyl or a 5- to 14-membered heteroaryl ring, where alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl each independently represent 0, 1, 2, 3, 4, or 5 R dd is substituted by a group; R cc Each instance of is independently hydrogen, C 1-20 Alkyl, C 1-20 Perhaloalkyl, C 1-20 Alkenyl, C1-20 Alkynyl, Hetero C 1-20 Alkyl, Hetero C 1-20 Alkenyl, Hetero C 1-20 Alkynyl, C 3-10 Carbocyclyl, 3-14 membered heterocyclyl, C 6-14 aryl and 5-14 membered heteroaryl, or two R cc the groups combine to form a 3- to 14-membered heterocyclyl or a 5- to 14-membered heteroaryl ring, where alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl each independently represent 0, 1, 2, 3, 4, or 5 R dd is substituted by a group; R dd Each example is independently a halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR ee , -ON(R ff )2, -N(R ff )2, -N(R ff )3 + X - , -N(OR ee )R ff , -SH, -SR ee , -SSR ee , -C(=O)R ee , -CO2H, -CO2R ee , -OC(=O)R ee , -OCO2R ee , -C(=O)N(R ff )2, -OC(=O)N(R ff )2, -NR ff C(=O)R ee , -NR ff CO2R ee , -NR ff C(=O)N(R ff )2, -C(=NR ff ) OR ee , -OC(=NR ff )R ee , -OC(=NR ff ) OR ee , -C(=NR ff )N(R ff)2, -OC(=NR ff )N(R ff )2, -NR ff C(=NR ff )N(R ff )2, -NR ff SO2R ee , -SO2N(R ff )2, -SO2R ee , -SO2OR ee , -OSO2R ee , -S(=O)R ee , -Si(R ee )3, -OSi(R ee )3, -C(=S)N(R ff )2, -C(=O)SR ee , -C(=S)SR ee , -SC(=S)SR ee , -P(=O)(OR ee )2, -P(=O)(R ee )2, -OP(=O)(R ee )2, -OP(=O)(OR ee )2, C 1-10 Alkyl, C 1-10 Perhaloalkyl, C 1-10 Alkenyl, C 1-10 Alkynyl, Hetero C 1-10 Alkyl, Hetero C 1-10 Alkenyl, Hetero C 1-10 Alkynyl, C 3-10 Carbocyclyl, 3-10 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, wherein alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl each independently represent 0, 1, 2, 3, 4, or 5 R gg or substituted by two geminal R dd The substituents combine to form =O or =S; where X - is the counterion; R ee Each instance of 1-10 Alkyl, C 1-10Perhaloalkyl, C 1-10 Alkenyl, C 1-10 Alkynyl, Hetero C 1-10 Alkyl, Hetero C 1-10 Alkenyl, Hetero C 1-10 Alkynyl, C 3-10 Carbocyclyl, C 6-10 aryl, 3- to 10-membered heterocyclyl, and 3- to 10-membered heteroaryl, wherein alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl each independently represent 0, 1, 2, 3, 4, or 5 R gg is substituted by a group; R ff Each instance is independently hydrogen, C 1-10 Alkyl, C 1-10 Perhaloalkyl, C 1-10 Alkenyl, C 1-10 Alkynyl, Hetero C 1-10 Alkyl, Hetero C 1-10 Alkenyl, Hetero C 1-10 Alkynyl, C 3-10 Carbocyclyl, 3-10 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, or two R ff the groups combine to form a 3-10 membered heterocyclyl or a 5-10 membered heteroaryl ring, where alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl each independently represent 0, 1, 2, 3, 4, or 5 R gg is substituted by a group; R gg Each example is independently a halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC 1-6 Alkyl, -ON(C 1-6 Alkyl)2, -N(C 1-6 Alkyl)2, -N(C 1-6 Alkyl)3 + X- , -NH(C 1-6 Alkyl)2 + X - , -NH2(C 1-6 Alkyl) + X - , -NH3 + X - , -N(OC 1-6 Alkyl)(C 1-6 alkyl), -N(OH)(C 1-6 alkyl), -NH(OH), -SH, -SC 1-6 Alkyl, -SS(C 1-6 alkyl), -C(=O)(C 1-6 alkyl), -CO2H, -CO2(C 1-6 alkyl), -OC(=O)(C 1-6 alkyl), -OCO2(C 1-6 alkyl), -C(=O)NH2, -C(=O)N(C 1-6 alkyl)2, -OC(=O)NH(C 1-6 alkyl), -NHC(=O)(C 1-6 alkyl), -N(C 1-6 Alkyl)C(=O)(C 1-6 alkyl), -NHCO2(C 1-6 alkyl), -NHC(=O)N(C 1-6 alkyl)2, -NHC(=O)NH(C 1-6 alkyl), -NHC(=O)NH2, -C(=NH)O(C 1-6 alkyl), -OC(=NH)(C 1-6 alkyl), -OC(=NH)OC 1-6 Alkyl, -C(=NH)N(C 1-6 alkyl)2, -C(=NH)NH(C 1-6 alkyl), -C(=NH)NH2, -OC(=NH)N(C 1-6 alkyl)2, -OC(NH)NH(C 1-6 alkyl), -OC(NH)NH2, -NHC(NH)N(C 1-6 alkyl)2, -NHC(=NH)NH2, -NHSO2(C 1-6 Alkyl), -SO2N(C 1-6 Alkyl)2, -SO2NH(C 1-6Alkyl), -SO2NH2, -SO2C 1-6 Alkyl, -SO2OC 1-6 Alkyl, -OSO2C 1-6 Alkyl, -SOC 1-6 Alkyl, -Si(C 1-6 alkyl)3, -OSi(C 1-6 Alkyl)3-C(=S)N(C 1-6 alkyl)2, C(=S)NH(C 1-6 alkyl), C(=S)NH2, -C(=O)S(C 1-6 Alkyl), -C(=S)SC 1-6 Alkyl, -SC(=S)SC 1-6 Alkyl, -P(=O)(OC 1-6 alkyl)2, -P(=O)(C 1-6 alkyl)2, -OP(=O)(C 1-6 Alkyl)2, -OP(=O)(OC 1-6 Alkyl)2, C 1-10 Alkyl, C 1-10 Perhaloalkyl, C 1-10 Alkenyl, C 1-10 Alkynyl, Hetero C 1-10 Alkyl, Hetero C 1-10 Alkenyl, Hetero C 1-10 Alkynyl, C 3-10 Carbocyclyl, C 6-10 aryl, 3- to 10-membered heterocyclyl, or 5- to 10-membered heteroaryl; or two geminal R gg the substituents may combine to form =O or =S; and each X - is the counterion).

[0060] In certain embodiments, the substituents on each carbon atom are independently halogen, substituted (e.g., substituted with one or more halogens) or unsubstituted C 1-6 Alkyl, -OR aa , -SR aa , -N(R bb )2, -CN, -SCN, -NO2, -C(=O)R aa , -CO2R aa , -C(=O)N(R bb)2, -OC(=O)R aa , -OCO2R aa , -OC(=O)N(R bb )2, -NR bb C(=O)R aa , -NR bb CO2R aa or -NR bb C(=O)N(R bb In certain embodiments, the substituents on each carbon atom are independently halogen, substituted (e.g., substituted with one or more halogens) or unsubstituted C 1-10 Alkyl, -OR aa , -SR aa , -N(R bb )2, -CN, -SCN, -NO2, -C(=O)R aa , -CO2R aa , -C(=O)N(R bb )2, -OC(=O)R aa , -OCO2R aa , -OC(=O)N(R bb )2, -NR bb C(=O)R aa , -NR bb CO2R aa or -NR bb C(=O)N(R bb )2, where R aa is hydrogen, substituted (e.g., substituted by one or more halogens) or unsubstituted C 1-10 alkyl, an oxygen protecting group when attached to an oxygen atom (e.g., silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl), or a sulfur protecting group when attached to a sulfur atom (e.g., acetamidomethyl, t-Bu, 3-nitro-2-pyridinesulfenyl, 2-pyridinesulfenyl, or triphenylmethyl); bb are independently hydrogen, substituted (e.g., substituted by one or more halogens) or unsubstituted C 1-10In certain embodiments, the substituents of each carbon atom are independently halogen, substituted (e.g., substituted with one or more halogens) or unsubstituted C 1-6 Alkyl, -OR aa , -SR aa , -N(R bb In certain embodiments, the substituents on each carbon atom are independently halogen, substituted (e.g., a moiety substituted with one or more halogens) or unsubstituted C 1-10 Alkyl, -OR aa , -SR aa , -N(R bb )2, -CN, -SCN or -NO2, where R aa is hydrogen, substituted (e.g., substituted by one or more halogens) or unsubstituted C 1-10 alkyl, an oxygen protecting group when attached to an oxygen atom (e.g., silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl), or a sulfur protecting group when attached to a sulfur atom (e.g., acetamidomethyl, t-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl); bb are independently hydrogen, substituted (e.g., substituted by one or more halogens) or unsubstituted C 1-10 alkyl, or a nitrogen protecting group (eg, Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts).

[0061] In certain embodiments, the molecular weight of the carbon atom substituent is less than 250 g / mol, less than 200 g / mol, less than 150 g / mol, less than 100 g / mol, or less than 50 g / mol.In certain embodiments, the carbon atom substituent is composed of carbon, hydrogen, fluorine, chlorine, bromine, iodine, oxygen, sulfur, nitrogen, and / or silicon atoms.In certain embodiments, the carbon atom substituent is composed of carbon, hydrogen, fluorine, chlorine, bromine, iodine, oxygen, sulfur, and / or nitrogen atoms.In certain embodiments, the carbon atom substituent is composed of carbon, hydrogen, fluorine, chlorine, bromine, and / or iodine atoms.In certain embodiments, the carbon atom substituent is composed of carbon, hydrogen, fluorine, chlorine, bromine, and / or iodine atoms.

[0062] The term "halo" or "halogen" means fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br) or iodine (iodo, -I).

[0063] 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 by 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.

[0064] The term "amino" refers to the group -NH2. The term "substituted amino" in turn refers to mono-, di- or tri-substituted amino. In certain embodiments, the "substituted amino" is a mono- or di-substituted amino group.

[0065] The term "monosubstituted amino" refers to an amino group in which the nitrogen atom directly attached to the parent molecule is replaced by one hydrogen and one non-hydrogen group, and includes -NH(R bb ), -NHC(=O)R aa , -NHCO2R aa , -NHC(=O)N(R bb )2, -NHC(=NR bb )N(R bb )2, -NHSO2R aa , -NHP(=O)(OR cc )2 and -NHP(=O)(N(R bb 2)2)2, wherein R aa , R bb and R cc is as defined herein, and -NH(R bb ) group R bb is not hydrogen.

[0066] "Disubstituted amino" refers to an amino group in which the nitrogen atom directly attached to the parent molecule is replaced by two groups other than hydrogen, -N(R bb )2, -NR bb C(=O)R aa , -NR bb CO2R aa , -NR bb C(=O)N(Rbb )2, -NR bb C(=NR bb )N(R bb )2, -NR bb SO2R aa , -NR bb P(=O)(OR cc )2 and -NR bb P(=O)(N(R bb 2)2)2, wherein R aa , R bb and R cc is as defined herein, except that the nitrogen atom directly attached to the parent molecule is not replaced with a hydrogen.

[0067] "Trisubstituted amino" refers to an amino group in which the nitrogen atom directly attached to the parent molecule is replaced by three groups, -N(R bb )3 and -N(R bb )3 + X - where R bb and X - is as defined herein.

[0068] 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 X1is hydrogen; halogen; substituted or unsubstituted hydroxyl; substituted or unsubstituted thiol; substituted or unsubstituted amino; substituted or unsubstituted acyl, cyclic or acyclic substituted or unsubstituted branched or unbranched aliphatic; cyclic or acyclic substituted or unsubstituted branched or unbranched heteroaliphatic; cyclic or acyclic, substituted or unsubstituted branched or unbranched alkyl; cyclic or acyclic substituted or unsubstituted branched or unbranched alkenyl; substituted or unsubstituted alkynyl; substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, aliphaticoxy, heteroaliphaticoxy, alkyloxy. , heteroalkyloxy, aryloxy, heteroaryloxy, aliphatic thioxy, heteroaliphatic thioxy, alkylthioxy, heteroalkylthioxy, arylthioxy, heteroarylthioxy, monoaliphatic amino or dialiphatic amino, monoheteroaliphatic amino or diheteroaliphatic amino, monoalkylamino or dialkylamino, monoheteroalkylamino or diheteroalkylamino, monoarylamino or diarylamino, or monoheteroarylamino or di-heteroarylamino; or two R X1wherein the groups taken together form a six-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, heteroaryl amino, 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).

[0069] The term "carbonyl" refers to a carbon that is directly attached to the parent molecule and has a sp 2 Groups that are hybridized and substituted with oxygen, nitrogen or sulfur atoms, such as ketones (-C(=O)R aa ), carboxylic acids (-CO2H), aldehydes (-CHO), esters (-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 imines (-C(=NR bb )R aa , -C(=NR bb ) OR aa ), -C(=NR bb )N(R bb )2) [where R aa and R bbis as defined herein.

[0070] The term "oxo" means the group ═O and the term "thioxo" means the group ═S.

[0071] Nitrogen atoms may be substituted or unsubstituted, where valence permits, and include primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents include hydrogen, -OH, -OR. aa , -N(R cc )2, -CN, -C(=O)R aa , -C(=O)N(R cc )2, -CO2R aa , -SO2R aa , -C(=NR bb )R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc , -P(=O)(OR cc )2, -P(=O)(R aa )2, -P(=O)(N(R cc )2)2, C 1-20 Alkyl, C 1-20 Perhaloalkyl, C 1-20 Alkenyl, C 1-20 Alkynyl, Hetero C 1-20 Alkyl, Hetero C 1-20 Alkenyl, Hetero C 1-20 Alkynyl, C 3-10 Carbocyclyl, 3-14 membered heterocyclyl, C 6-14 Aryl and 5-14 membered heteroaryl, or two R attached to N atom ccand R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 29 , R 30 , R 31 , R 32 , R 33 , R 34 , R 35 , R 36 , R 37 , R 38 , R 39 , R 40 , R 41 , R 42 , R 43 , R 44 , R 45 , R 46 , R 47 , R 48 , R 49 , R 50 , R 51 , R 52 , R 53 , R 54 , R 45 , R 46 dd is substituted by R aa , R bb , R cc and R dd is as defined above.

[0072] In certain embodiments, each nitrogen atom substituent is independently a substituted (e.g., substituted with one or more halogens) or unsubstituted C 1-6 Alkyl, -C(=O)R aa , -CO2R aa , -C(=O)N(R bb )2 or a nitrogen protecting group. In certain embodiments, each nitrogen atom substituent is independently a substituted (e.g., substituted with one or more halogens) or unsubstituted C 1-10 Alkyl, -C(=O)R aa , -CO2R aa , -C(=O)N(R bb )2 or a nitrogen protecting group, where R aa is hydrogen, substituted (e.g., substituted by one or more halogens) or unsubstituted C 1-10 alkyl, or an oxygen protecting group when bonded to an oxygen atom; bb are independently hydrogen, substituted (e.g., substituted by one or more halogens) or unsubstituted C 1-10 In certain embodiments, each nitrogen atom substituent is independently a substituted (e.g., substituted with one or more halogens) or unsubstituted C 1-6 alkyl, or a nitrogen protecting group.

[0073] In certain embodiments, the substituent present on the nitrogen atom is a nitrogen protecting group (also referred to herein as an "amino protecting group"). Nitrogen protecting groups include -OH, -ORaa , -N(R cc )2, -C(=O)R aa , -C(=O)N(R cc )2, -CO2R aa , -SO2R aa , -C(=NR cc )R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc , C 1-10 Alkyl (e.g., aralkyl, heteroaralkyl), C 1-20 Alkenyl, C 1-20 Alkynyl, Hetero C 1-20 Alkyl, Hetero C 1-20 Alkenyl, Hetero C 1-20 Alkynyl, C 3-10 Carbocyclyl, 3-14 membered heterocyclyl, C 6-14 and aryl and 5-14 membered heteroaryl groups, where alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aralkyl, aryl, and heteroaryl each independently represent 0, 1, 2, 3, 4, or 5 R dd is substituted by R aa , R bb , R cc and R dd is as defined herein. Nitrogen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, TW Greene and PGM Wuts, 3rd edition, John Wiley & Sons, 1999, incorporated herein by reference.

[0074] For example, in certain embodiments, at least one nitrogen protecting group is an amide group (e.g., a nitrogen protecting group (e.g., —C(═O)R aa In certain such embodiments, each nitrogen protecting group, together with the nitrogen atom to which it is attached, is independently formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropanamide, picolinamide, 3-pyridylcarboxamide, N-benzoylphenylalanyl derivatives, benzamide, p-phenylbenzamide, o-nitrophenylacetamide, o-nitrophenoxyacetamide, acetoacetamide, ( N'-dithiobenzyloxyacylamino)acetamide, 3-(p-hydroxyphenyl)propanamide, 3-(o-nitrophenyl)propanamide, 2-methyl-2-(o-nitrophenoxy)propanamide, 2-methyl-2-(o-phenylazophenoxy)propanamide, 4-chlorobutanamide, 3-methyl-3-nitrobutanamide, o-nitrocinnamide, N-acetylmethionine derivatives, o-nitrobenzamide and o-(benzoyloxymethyl)benzamide.

[0075] In certain embodiments, at least one nitrogen protecting group is a carbamate group (e.g., a nitrogen protecting group (e.g., —C(═O)OR aaIn certain such embodiments, each nitrogen protecting group, together with the nitrogen atom to which it is attached, is independently selected from methyl carbamate, ethyl carbamate, 9-fluorenylmethyl carbamate (Fmoc), 9-(2-sulfo)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluoroenylmethyl carbamate (9-(2,7-dibromo) fluoroenylmethyl carbamate), 2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyi)]methyl carbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl carbamate (Teoc), 2-phenylethyl carbamate (hZ), 1-(1-adamantyl)-1-methylethyl carbamate (Adpoc), 1,1-dimethyl-2-haloethyl carbamate, 1,1-dimethyl-2,2-dibromoethyl carbamate (DB-t-BOC), 1,1-dimethyl-2,2,2-trichloroethyl carbamate (TCBOC), 1-methyl-1-(4-biphenylyl)ethyl carbamate ( Bpoc), 1-(3,5-di-t-butylphenyl)-1-methylethyl carbamate (t-Bumeoc), 2-(2'- and 4'-pyridyl)ethyl carbamate (Pyoc), 2-(N,N-dicyclohexylcarboxamido)ethyl carbamate, t-butyl carbamate (BOC or Boc), 1-adamantyl carbamate (Adoc), vinyl carbamate (Voc), allyl carbamate (Alloc), 1-isopropyl allyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc), 8-quinolyl carbamate, N-hydroxypiperidinyl carbamate, alkyl dithiocarbamate, benzyl carbamate (Cbz), p-methoxybenzyl carbamate (Moz), p-nitrobenzyl Carbamates, p-bromobenzyl carbamates, p-chlorobenzyl carbamates, 2,4-Dichlorobenzyl carbamate, 4-methylsulfinylbenzyl carbamate (Msz), 9-anthrylmethyl carbamate, diphenylmethyl carbamate, 2-methylthioethyl carbamate, 2-methylsulfonylethyl carbamate, 2-(p-toluenesulfonyl)ethyl carbamate, [2-(1,3-dithianyl)]methyl carbamate (Dmoc), 4-methylthiophenyl carbamate (Mtpc), 2,4-dimethylthiophenyl carbamate (Bmpc), 2-phosphonioethyl carbamate (Peoc), 2-triphenylphosphonioisopropyl carbamate (Ppoc), 1,1-dimethyl-2-cyanoethyl carbamate, m-chloro-p-acyloxybenzyl carbamate, p-(dihydroxyboryl)benzyl carbamate, 5-benzoisoxazolylmethyl carbamate, 2-(trifluoromethyl)-6-chromonylmethyl carbamate (Tcroc), m-nitrophenyl carbamate, 3 ,5-Dimethoxybenzyl carbamate, o-nitrobenzyl carbamate, 3,4-dimethoxy-6-nitrobenzyl carbamate, phenyl (o-nitrophenyl) methyl carbamate, t-amyl carbamate, S-benzyl thiocarbamate, p-cyanobenzyl carbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentyl carbamate, cyclopropyl methyl carbamate, p-decyloxybenzyl carbamate, 2,2-dimeth 1,1-dimethyl-3-(N,N-dimethylcarboxamido)propyl carbamate, 1,1-dimethylpropynyl carbamate, di(2-pyridyl)methyl carbamate, 2-furanylmethyl carbamate, 2-iodoethyl carbamate, isobornyl carbamate, isobutyl carbamate, isonicotinyl carbamate, p-(p'-methoxyphenylazo)benzyl carbamate, 1-methylcyclobutyl carbamate, 1-methylcyclohexyl carbamate, 1-methyl-1-cyclopropylmethyl carbamate, 1-methyl-1-(3,5-dimethoxyphenyl)ethyl carbamate, 1-methyl-1-(p-phenylazophenyl)ethyl carbamate, 1-methyl-1-phenylethyl carbamate, 1-methyl-1-(4-pyridyl)ethyl carbamate, phenyl carbamate, p-(phenylazo)benzyl carbamate, 2,4,6-tri-t-butylphenyl carbamate, 4-(trimethylammonium)benzyl carbamate and 2,4,6-trimethylbenzyl carbamate.

[0076] In certain embodiments, at least one nitrogen protecting group is a sulfonamide group (e.g., a nitrogen protecting group (e.g., -S(=O)R aa In certain such embodiments, each nitrogen protecting group, together with the nitrogen atom to which it is attached, is selected from the group consisting of p-toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6-trimethyl-4-methoxybenzenesulfonamide (Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb), 2,6-dimethyl-4-methoxybenzenesulfonamide (Pme), 2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte), 4-methoxybenzenesulfonamide (Mbs), 2,4 ...methyl-4-methoxybenzenesulfonamide (Mtb), 2,6-dimethyl-4-methoxybenzenesulfonamide (Pme), 2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte), 4-methoxybenzenesulfonamide (Mbs), 2,4,6-trimethyl-4-methoxybenzenesulfonamide (Mtb), 2,4,6-trimethyl-4-methoxybenzenesulfonamide (Mtb), 2,4,6-trimethyl-4-methoxybenzenesulfonamide (Mtb), 2,4,6-trimethyl-4-methoxybenzenesulfonamide (Mtb), 2,4,6-trimethyl-4-methoxybenzenesulfonamide (Mtb), 2,4,6-trimethyl-4-methoxybenzenesulfonamide (Mtb), 2,4,6-trimethyl-4-methoxybenzenesulfonamide (Mtb), 2,4,6 trimethylbenzenesulfonamide (Mts), 2,6-dimethoxy-4-methylbenzenesulfonamide (iMds), 2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide (Ms), β-trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide, 4-(4',8'-dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS), benzylsulfonamide, trifluoromethylsulfonamide and phenacylsulfonamide.

[0077] In certain embodiments, each nitrogen protecting group, together with the nitrogen atom to which it is attached, is selected from the group consisting of phenothiazinyl-(10)-acyl derivatives, N'-p-toluenesulfonylaminoacyl derivatives, N'-phenylaminothioacyl derivatives, N-benzoylphenylalanyl derivatives, N-acetylmethionine derivatives, 4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dithiasuccinimide (Dts), N-2,3-diphenylmaleimide, N-2,5-dimethylphenylphenylamine derivatives, N-phenyl ... Lupyrrole, N-1,1,4,4-tetramethyldisilylazacyclopentane adduct (STABASE), 5-substituted 1,3-dimethyl-1,3,5-triazacyclohexan-2-one, 5-substituted 1,3-dibenzyl-1,3,5-triazacyclohexan-2-one, 1-substituted 3,5-dinitro-4-pyridone, N-methylamine, N-allylamine, N-[2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine, N-(1-isopropyl- 4-Nitro-2-oxo-3-pyrrolin-3-yl)amine, quaternary ammonium salts, N-benzylamine, N-di(4-methoxyphenyl)methylamine, N-5-dibenzosuberylamine, N-triphenylmethylamine (Tr), N-[(4-methoxyphenyl)diphenylmethyl]amine (MMTr), N-9-phenylfluorenylamine (PhF), N-2,7-dichloro-9-fluorenylmethyleneamine, N-ferrocenylmethylamino (Fcm), N-2-picolyla amine N'-oxide, N-1,1-dimethylthiomethyleneamine, N-benzylideneamine, Np-methoxybenzylideneamine, N-diphenylmethyleneamine, N-[(2-pyridyl)mesityl]methyleneamine, N-(N',N'-dimethylaminomethylene)amine, Np-nitrobenzylideneamine, N-salicylideneamine, N-5-chlorosalicylideneamine, N-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine, N-cyclohexylideneamine, N-(5,5-dimethyl-3-oxo-1-cyclohexenyl)amine, N-borane derivatives, N-diphenylboronic acid derivatives, N-[phenyl(pentaacylchromium- or tungsten)acyl]amine, N-copper chelates, N-zinc chelates, N-nitroamines, N-nitrosamines, amine N-oxides, diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt), diphenylthiophosphinamide (Ppt), dialkyl phosphoramidates, dibenzyl phosphoramidates, diphenyl phosphoramidates, benzenesulfenamides, o-nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide, triphenylmethylsulfenamide and 3-nitropyridine sulfenamide (Npys). In some embodiments, two examples of nitrogen protecting groups, together with the nitrogen atom to which the nitrogen protecting groups are attached, are N,N'-isopropylidenediamine.

[0078] In certain embodiments, at least one nitrogen protecting group is Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts.

[0079] In certain embodiments, each oxygen atom substituent is independently a substituted (e.g., substituted with one or more halogens) or unsubstituted C 1-10 Alkyl, -C(=O)R aa , -CO2R aa , -C(=O)N(R bb )2 or an oxygen protecting group. In certain embodiments, each oxygen atom substituent is independently a substituted (e.g., substituted with one or more halogens) or unsubstituted C 1-6 Alkyl, -C(=O)R aa , -CO2R aa , -C(=O)N(R bb )2 or an oxygen protecting group, where R aa is hydrogen, substituted (e.g., substituted by one or more halogens) or unsubstituted C1-10 alkyl, or an oxygen protecting group when attached to an oxygen atom; bb are independently hydrogen, substituted (e.g., substituted by one or more halogens) or unsubstituted C 1-10 In certain embodiments, each oxygen atom substituent is independently a substituted (e.g., substituted with one or more halogens) or unsubstituted C 1-6 alkyl, or oxygen protecting groups.

[0080] In certain embodiments, the substituent present on the oxygen atom is an oxygen protecting group (also referred to herein as a "hydroxyl protecting group"). Oxygen protecting groups include -R aa , -N(R bb )2, -C(=O)SR aa , -C(=O)R aa , -CO2R aa , -C(=O)N(R bb )2, -C(=NR bb )R aa , -C(=NR bb ) OR aa , -C(=NR bb )N(R bb )2, -S(=O)R aa , -SO2R aa , -Si(R aa )3, -P(R cc )2, -P(R cc )3 + X - , -P(OR cc )2, -P(OR cc )3 + X - , -P(=O)(R aa )2, -P(=O)(OR cc )2 and -P(=O)(N(R bb )2)2, where X - , R aa , R bb and R ccis as defined herein. Oxygen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, TW Greene and PGM Wuts, 3rd edition, John Wiley & Sons, 1999, incorporated herein by reference.

[0081] In certain embodiments, each oxygen protecting group, together with the oxygen atom to which it is attached, is selected from the group consisting of methyl, methoxymethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM), t-butoxymethyl, 4-pentenyloxymethyl (POM), silyloxymethyl (SHM), methyloxymethyl (MTM), t-butylthiomethyl, phenyldimethylsilyloxymethyl (SMOM), benzyloxymethyl (BOM), p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM), t-butoxymethyl, 4-pentenyloxymethyl (POM), methyloxymethyl (MTM), methyloxymethyl (MTM), t-butylthiomethyl, phenyldimethylsilyloxymethyl (SMOM), methyloxymethyl (MTM), t-butylthiomethyl, phenyldimethylsilyloxymethyl (SMOM), benzyloxymethyl (BOM), p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), methyloxymethyl (MOM), methyloxymethyl (MTM), t-butylthiomethyl, phenyldimethylsilyloxymethyl (PMB), methyloxymethyl (M ... 2-Methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl (SEMOR), tetrahydropyranyl (THP), 3-bromotetrahydropyranyl, tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl (MTHP), 4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranyl S,S-dioxide, 1-[ (2-chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl (CTMP), 1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl, 2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl, 1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl, 1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoro Ethyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl, t-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, benzyl (Bn), p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2-picolyl, 4-picolyl, 3-methyl-2-picolyl N-oxide, diphenylmethyl, p,p'-Dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl, α-naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl, tri(p-methoxyphenyl)methyl, 4-(4'-bromophenacyloxyphenyl)diphenylmethyl, 4,4',4''-tris(4,5-dichlorophthalimidophenyl)methyl, 4,4',4''-tris(levulinoyloxyphenyl)methyl, 4,4',4''-tris(benzo 4,4'-dimethoxy-3'''-[N-(imidazolylmethyl)carbamoyl]trityl ether (IDTr-OR), 4,4'-dimethoxy-3'''-[N-(imidazolylethyl)carbamoyl]trityl ether (IETr-OR), 1,1-bis(4-methoxyphenyl)-1'-pyrenylmethyl, 9-anthryl, 9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl, 1,3-benzodithiolan-2-yl, benzisothiazolyl S,S-dioxide, trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS), dimethyl-t-hexylsilyl, t-butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl (TBDPS), tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl (DPMS), t-butylmethoxyphenylsilyl (TBMPS), formate, benzoylformate, Acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4-oxopentanoate (levulinate), 4,4-(ethylenedithio)pentanoate (levulinoyl dithioacetal), pivaloate, adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate, 2,4,6-Trimethylbenzoate (mesitoate), methyl carbonate, 9-fluorenylmethyl carbonate (Fmoc), ethyl carbonate, 2,2,2-trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate (TMSEC), 2-(phenylsulfonyl)ethyl carbonate (Psec), 2-(triphenylphosphonio)ethyl carbonate (Peoc), isobutyl carbonate, vinyl carbonate, allyl carbonate, t-butyl Carbonate (BOC or Boc), p-nitrophenyl carbonate, benzyl carbonate, p-methoxybenzyl carbonate, 3,4-dimethoxybenzyl carbonate, o-nitrobenzyl carbonate, p-nitrobenzyl carbonate, S-benzylthiocarbonate, 4-ethoxy-1-naphthyl carbonate, methyldithiocarbonate, 2-iodobenzoate, 4-azidobutyrate, 4-nitro-4-methylpentanoate, o-(dibromomethyl)benzoate , 2-formylbenzenesulfonate, 2-(methylthiomethoxy)ethyl carbonate (MTMEC-OR), 4-(methylthiomethoxy)butyrate, 2-(methylthiomethoxymethyl)benzoate, 2,6-dichloro-4-methylphenoxyacetate, 2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetate, 2,4-bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinoate monosuccinoate, (E)-2-methyl-2-butenoate, o-(methoxyacyl)benzoate, α-naphthoate, nitrate, alkyl N,N,N',N'-tetramethylphosphorodiamidate, alkyl N-phenylcarbamate, borate, dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulfenate, sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate (Ts).

[0082] In certain embodiments, at least one oxygen protecting group is silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl or benzoyl.

[0083] In certain embodiments, each sulfur atom substituent is independently a substituted (e.g., substituted with one or more halogens) or unsubstituted C 1-10 Alkyl, -C(=O)R aa , -CO2R aa , -C(=O)N(R bb )2, or a sulfur protecting group. In certain embodiments, each sulfur atom substituent is independently a substituted (e.g., substituted with one or more halogens) or unsubstituted C 1-10 Alkyl, -C(=O)R aa , -CO2R aa , -C(=O)N(R bb )2, or a sulfur protecting group, where R aa is hydrogen, substituted (e.g., substituted by one or more halogens) or unsubstituted C 1-10 alkyl, or an oxygen protecting group when attached to an oxygen atom; bb are independently hydrogen, substituted (e.g., substituted by one or more halogens) or unsubstituted C 1-10 In certain embodiments, each sulfur atom substituent is independently a substituted (e.g., substituted with one or more halogens) or unsubstituted C 1-6 alkyl, or sulfur protecting groups.

[0084] In certain embodiments, the molecular weight of the substituent is less than 250 g / mol, less than 200 g / mol, less than 150 g / mol, less than 100 g / mol, or less than 50 g / mol. In certain embodiments, the substituent is composed of carbon, hydrogen, fluorine, chlorine, bromine, iodine, oxygen, sulfur, nitrogen, and / or silicon atoms. In certain embodiments, the substituent is composed of carbon, hydrogen, fluorine, chlorine, bromine, iodine, oxygen, sulfur, and / or nitrogen atoms. In certain embodiments, the substituent is composed of carbon, hydrogen, fluorine, chlorine, bromine, and / or iodine atoms. In certain embodiments, the substituent is composed of carbon, hydrogen, fluorine, and / or chlorine atoms. In certain embodiments, the substituent comprises 0, 1, 2, or 3 hydrogen bond donors. In certain embodiments, the substituent comprises 0, 1, 2, or 3 hydrogen bond acceptors.

[0085] A "counterion" or "anionic counterion" is a negative charge associated with a positive charge to maintain electronic neutrality. Anionic counterions can be monovalent (e.g., containing one formal negative charge). Anionic counterions can also be multivalent (e.g., containing more than one formal negative charge), 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.

[0086] The phrase "at least one example" means 1, 2, 3, 4 or more examples, but also includes ranges such as 1-4, 1-3, 1-2, 2-4, 2-3, or 3-4.

[0087] "Non-hydrogen group" means a group defined for a particular variable that is not hydrogen.

[0088] These and other exemplary substituents are described in further detail in the detailed description, examples, and claims. The present invention is not limited in any way by the above list of exemplary substituents.

[0089] As used herein, the term "salt" refers to any salt, including pharma- ceutically acceptable salts. Salts include ionic compounds resulting from the neutralization reaction of an acid with a base. A salt is composed of one or more cations (positively charged ions) and one or more anions (negatively charged ions), such that the salt 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, perchloric acid, or organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, malonic acid, or formed 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, hemisulfonate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactate, and glycerol. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N-terminated salts. + (C 1-4Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Additionally, there are ammonium salts, quaternary ammonium salts, and amine cation salts formed with counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.

[0090] The term "pharmaceutically acceptable salt" refers to a salt that is suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic reaction, etc., within the scope of sound medical judgment, and is commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe soluble acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, which are 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 include salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, perchloric acid, and the like, organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, malonic acid, and the like, or formed using other methods known in the art, such as ion exchange. Other pharma- ceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfonate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, and 2-hydroxy-ethanesulfonate. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, N-phenylene sulfonate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. + (C1-4 Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium salts, etc. Pharmaceutically acceptable salts further 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, aryl sulfonates, and the like.

[0091] The term "solvate" refers to a form of a compound or its salt that is combined with a solvent, usually by solvolysis. This physical association may include hydrogen bonding. Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, and the like. The compounds described herein may be prepared, for example, in crystalline form, and may be solvated. Suitable solvates include pharmaceutically acceptable solvates, and further include both stoichiometric and non-stoichiometric solvates. In certain embodiments, the solvate is isolable, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. "Solvate" encompasses both solution-phase and isolable solvates. Representative solvates include hydrates, ethanolates, methanolates, and the like.

[0092] The term "hydrate" refers to a compound that is 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 may be represented, for example, by the general formula R·xH2O, where R is a compound and x is a number greater than 0. A given compound may form multiple types of hydrates, including, for example, monohydrates (x is 1), lower hydrates (x is a number greater than 0 and less than 1, e.g., hemihydrates (R·0.5H2O)), and polyhydrates (x is a number greater than 1, e.g., dihydrates (R·2H2O) and hexahydrates (R·6H2O)).

[0093] The term "tautomer" or "tautomeric" refers to two or more interconvertible compounds resulting from at least one formal migration of a hydrogen atom and at least one change in valence (e.g., from a single bond to a double bond, a triple bond to a single bond, or vice versa). The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH. Tautomerization (i.e., the reaction that provides the tautomeric pair) can be catalyzed by acid or base. Exemplary tautomerizations include keto to enol, amide to imide, lactam to lactim, enamine to imine, and enamine to (different enamine) tautomerization.

[0094] 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."

[0095] Stereoisomers that are not mirror images of one another are called "diastereomers" and stereoisomers that are non-superimposable mirror images of one another are called "enantiomers". When a compound has an asymmetric center, for example when it is bonded to four different groups, a pair of enantiomers is possible. Enantiomers are characterized by the absolute configuration of their asymmetric center. Enantiomers are described by the R- and S-sequencing rules of Cahn and Prelog, or by the way in which the molecule rotates the plane of polarized light and exhibits dextrorotatory or levorotatory properties (i.e., as (+) or (-)-isomers, respectively). Chiral compounds can exist as individual enantiomers or as mixtures of them. A mixture containing equal proportions of enantiomers is called a "racemic mixture".

[0096] The term "polymorph" refers to a crystalline form of a compound (or its salts, hydrates or solvates). All polymorphs have the same elemental composition. Different crystalline forms usually 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.

[0097] The term "co-crystal" refers to a crystal structure that includes 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, none of the components is a solvent. In certain embodiments, at least one of the components is a solvent. A co-crystal of a compound and an acid is different from a salt formed from a compound and an acid. In a salt, the compound is complexed with an acid in such a way that proton transfer from the acid to the compound (e.g., complete proton transfer) occurs easily at room temperature. However, in a co-crystal, the compound is complexed with an acid in such a way that proton transfer from the acid to the compound herein does not occur easily at room temperature. In certain embodiments, in a co-crystal, there is substantially no proton transfer from the acid to the compound. In certain embodiments, in a co-crystal, there is partial proton transfer from the acid to the compound. Co-crystals can be useful for improving the properties of a compound (e.g., solubility, stability, and ease of formulation).

[0098] The term "prodrug" refers to a compound that has a cleavable group and is pharma- ceutically active in vivo, which becomes the compound described herein by solvolysis or under physiological conditions. Examples of such include, but are not limited to, N-alkylmorpholine esters, such as choline ester derivatives. Other derivatives of the compounds described herein are active in both their acid and acid derivative forms, but the acid-sensitive form often offers 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, for example, esters prepared by reacting the parent acid with a suitable alcohol, or amides prepared by reacting the parent acid compound with a substituted or unsubstituted amine, or acid anhydrides, or mixed anhydrides. Simple aliphatic or aromatic esters, amides, and anhydrides derived from acid groups pendant on the compounds described herein are particularly 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 C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, C7-C12 substituted aryl and C7-C12 arylalkyl esters of the compounds described herein.

[0099] The terms "composition" and "formulation" are used interchangeably.

[0100] A "subject" to which administration is contemplated means a human (i.e., male or female of any age, e.g., a pediatric subject (e.g., an infant, a child, or an adolescent) or an adult subject (e.g., a young adult, a middle-aged adult, or an elderly adult)) or a non-human animal. In certain embodiments, the non-human animal is a mammal (e.g., a primate (e.g., a cynomolgus or rhesus monkey), a commercially relevant mammal (e.g., a cow, a pig, a horse, a sheep, a goat, a cat, or a dog), or a bird (e.g., a commercially relevant bird, e.g., a chicken, a duck, a goose, or a turkey)). In certain embodiments, the non-human animal is a fish, a reptile, or an amphibian. The non-human animal may be male or female at any stage of development. The non-human animal may be a transgenic or genetically modified animal. The term "patient" means a human subject in need of treatment for a disorder or disease.

[0101] The terms "administer," "administering," or "administration" refer to implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing a compound described herein, or a composition thereof, into or onto a subject.

[0102] The terms "treatment", "treat" and "treating" refer to reversing, alleviating, delaying the onset, or inhibiting the progression of a disorder or disease described herein. In some embodiments, treatment may be administered after one or more signs or symptoms of a disease have developed or been observed. In other embodiments, treatment may be administered 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 disappeared, e.g., to delay or prevent recurrence.

[0103] The terms "condition", "disease" and "disorder" are used interchangeably. An "effective amount" of a compound described herein means an amount sufficient to elicit a desired biological response. An effective amount of a compound described herein may vary depending on factors such as the desired biological endpoint, the severity of side effects, the disease or disorder, the identity of the particular compound, the pharmacokinetics and pharmacodynamics, the condition being treated, the mode, route and frequency of administration desired or required, 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 a compound described herein in multiple administrations. 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).

[0104] A "therapeutically effective amount" of a compound described herein is an amount sufficient to provide a therapeutic benefit in the treatment of a condition or to delay or minimize one or more symptoms associated with a condition. A therapeutically effective amount of a compound refers to an amount of a therapeutic agent that, alone or in combination with other therapies, provides a therapeutic benefit in the treatment of a condition. The term "therapeutically effective amount" can include an amount that improves overall treatment, reduces or avoids symptoms, signs or causes of a condition, and / or enhances the therapeutic efficacy 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.

[0105] 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 a subject who had the disorder but who does not have the disorder and is at risk of regression of the disorder. In certain embodiments, the subject is at a higher risk of developing the disorder or at a higher risk of regression of the disorder than the average healthy member of the population.

[0106] As used herein, the term "inhibit" or "inhibition" in the context of an enzyme refers to a decrease in the activity of the enzyme, for example, in the context of a Janus family kinase. In some embodiments, the term refers to decreasing the level of enzyme activity, for example, a 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 decreasing the level of enzyme activity, for example, a 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.

[0107] As used herein, the term "dual TYK2 / JAK1 inhibition" or "dual TYK2 / JAK1 kinase inhibition" in the context of enzymes refers to reducing TYK2 kinase activity and JAK1 kinase activity. In some embodiments, the term refers to reducing the level of enzyme activity, e.g., TYK2 kinase activity and JAK1 kinase activity, to a level that is statistically significantly lower than the initial level of TYK2 kinase activity and the initial level of JAK1 kinase activity, which may be, for example, a baseline level of enzyme activity. In some embodiments, the term refers to reducing the level of enzyme activity, e.g., TYK2 kinase activity and JAK1 kinase activity, to a level of 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, the baseline level of enzyme activity.

[0108] As used herein, the term "dual TYK2 / JAK1 inhibitor" or "dual TYK2 / JAK1 kinase inhibitor" in the context of enzymes refers to a compound that can reduce TYK2 kinase activity and JAK1 kinase activity. In some embodiments, this term refers to a compound that can reduce the level of enzyme activity, e.g., TYK2 kinase activity and JAK1 kinase activity, to a level that is statistically significantly lower than the initial level of TYK2 kinase activity and the initial level of JAK1 kinase activity, which may be, for example, the baseline level of enzyme activity. In some embodiments, the term refers to a compound that can reduce the level of enzyme activity, e.g., TYK2 kinase activity and JAK1 kinase activity, to a level of 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% of the initial level of TYK2 kinase activity and the initial level of JAK1 kinase activity, which may be, for example, a baseline level of enzyme activity.

[0109] 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 described in this section and another percentage described in this section.

[0110] A "kinase" is a type of enzyme that transfers a phosphate group from a high-energy donor molecule, such as ATP, to a specific substrate (a process called phosphorylation). Kinases are part of a larger family of phosphotransferases. One of the largest groups of kinases are protein kinases, which act on specific proteins to modify their activity. Kinases are widely used in signal transduction and the control of complex processes within cells. A variety of other kinases act on small molecules, such as lipids, carbohydrates, amino acids, and nucleotides, to signal or direct metabolic pathways. Kinases are often named after their substrates. More than 500 protein kinases have been identified in humans. These exemplary human protein kinases include, but are not limited to, AAK1, ABL, ACK, ACTR2, ACTR2B, AKT1, AKT2, AKT3, ALK, ALK1, ALK2, ALK4, ALK7, AMPKa1, AMPKa2, ANKRD3, ANPa, ANPb, ARAF, ARAFps, ARG, AurA, AurAps1, AurAps2, AurB, AurBps1, AurC, AXL, BARK1, BARK2, BIKE, BLK, BMPR1A, BMPR1Aps1, BMPR1Aps2, BMPR1B, BMPR2, BMX, BRAF, BRAFps, BRK, BRSK1, BRSK2, BTK, BUB1, BUBR1, CaMK1a, CaMK1b, CaMK1d, CaMK1g, CaMK2a, CaMK2b, CaMK2d, CaMK2g, CaMK4, CaMKK1, CaMKK2, caMLCK, CASK, CCK4, CCRK, CDC2, CDC7, CDK10, CDK11, CDK2, CDK3, CDK4, C DK4ps, CDK5, CDK5ps, CDK6, CDK7, CDK7ps, CDK8, CDK8ps, CDK9, CDKL1, CDKL2, CDKL3, CDKL4, CDKL5, CGDps , CHED, CHK1, CHK2, CHK2ps1, CHK2ps2, CK1a, CK1a2, CK1aps1, CK1aps2, CK1aps3, CK1d, CK1e, CK1g1, CK1g 2, CK1g2ps, CK1g3, CK2a1, CK2a1-rs, CK2a2, CLIK1, CLIK1L, CLK1, CLK2, CLK2ps, CLK3, CLK3ps, CLK4, COT,CRIK、CRK7、CSK、CTK、CYGD、CYGF、DAPK1、DAPK2、DAPK3、DCAMKL1、DCAMKL2、DCAMKL3、DDR1、DDR2、DLK、DMPK1、DMPK2、DRAK1、DRAK2、DYRK1A、DYRK1B、DYRK2、DYRK3、DYRK4、EGFR、EphA1、EphA10、EphA2、EphA3、EphA4、EphA5、EphA6、EphA7、EphA8、EphB1、EphB2、EphB3、EphB4、EphB6、Erk1、Erk2、Erk3、Erk3ps1、Erk3ps2、Erk3ps3、Erk3ps4、Erk4、Erk5、Erk7、FAK、FER、FERps、FES、FGFR1、FGFR2、FGFR3、FGFR4、FGR、FLT1、FLT1ps、FLT3、FLT4、FMS、FRK、Fused、FYN、GAK、GCK、GCN2、GCN22、GPRK4、GPRK5、GPRK6、GPRK6ps、GPRK7、GSK3A、GSK3B、Haspin、HCK、HER2 / ErbB2、HER3 / ErbB3、HER4 / ErbB4、HH498、HIPK1、HIPK2、HIPK3、HIPK4、HPK1、HRI、HRIps、HSER、HUNK、ICK、IGF1R、IKKa、IKKb、IKKe、ILK、INSR、IRAK1、IRAK2、IRAK3、IRAK4、IRE1、IRE2、IRR、ITK、JAK1、JAK2、JAK3、JNK1、JNK2、JNK3、KDR、KHS1、KHS2、KIS、KIT、KSGCps、KSR1、KSR2、LATS1、LATS2、LCK、LIMK1、LIMK2、LIMK2ps、LKB1、LMR1、LMR2、LMR3、LOK、LRRK1、LRRK2、LTK、LYN、LZK、MAK、MAP2K1、MAP2K1ps、MAP2K2、MAP2K2ps、MAP2K3、MAP2K4、MAP2K5、MAP2K6、MAP2K7、MAP3K1、MAP3K2、MAP3K3、MAP3K4、MAP3K5、MAP3K6、MAP3K7、MAP3K8、MAPKAPK2、MAPKAPK3、MAPKAPK5、MAPKAPKps1、MARK1、MARK2、MARK3、MARK4、MARKps01、MARKps02、MARKps03、MARKps04、MARKps05、MARKps07、MARKps08、MARKps09、MARKps10、MARKps11、MARKps12、MARKps13、MARKps15、MARKps16、MARKps17、MARKps18、MARKps19、MARKps20 、MARKps21、MARKps22、MARKps23、MARKps24、MARKps25、MARKps26、MARKps27、MARKps28、MARKps29、MARKps30、MAST1、MAST2、MAST3、MAST4、MASTL、MELK 、MER、MET、MISR2、MLK1、MLK2、MLK3、MLK4、MLKL、MNK1、MNK1ps、MNK2、MOK、MOS、MPSK1、MPSK1ps、MRCKa、MRCKb、MRCKps、MSK1、MSK12、MSK2、MSK22、MSSK1 、MST1、MST2、MST3、MST3ps、MST4、MUSK、MYO3A、MYO3B、MYT1、NDR1、NDR2、NEK1、NEK10、NEK11、NEK2、NEK2ps1、NEK2ps2、NEK2ps3、NEK3、NEK4、NEK4ps、NEK1 K5、NEK6、NEK7、NEK8、NEK9、NIK、NIM1、NLK、NRBP1、NRBP2、NuaK1、NuaK2、Obscn、Obscn2、OSR1、p38a、p38b、p38d、p38g、p70S6K、p70S6Kb、p70S6Kps1、p7 0S6Kps2、PAK1、PAK2、PAK2ps、PAK3、PAK4、PAK5、PAK6、PASK、PBK、PCTAIRE1、PCTAIRE2、PCTAIRE3、PDGFRa、PDGFRb、PDK1、PEK、PFTAIRE1、PFTAIRE2、PHK g1、PHKg1ps1、PHKg1ps2、PHKg1ps3、PHKg2、PIK3R4、PIM1、PIM2、PIM3、PINK1、PITSLRE、PKACa、PKACb、PKACg、PKCa、PKCb、PKCd、PKCe、PKCg、PKCh、PKCi PKCips、PKCt、PKCz、PKD1、PKD2、PKD3、PKG1、PKG2、PKN1、PKN2、PKN3、PKR、PLK1、PLK1ps1、PLK1ps2、PLK2、PLK3、PLK4、PRKX、PRKXps、PRKY、PRP4、PRP4psPRPK, PSKH1, PSKH1ps, PSKH2, PYK2, QIK, QSK, RAF1, RAF1ps, RET, RHOK, RIPK1, RIPK2, RIPK3, RNAseL, ROCK1, ROCK2, RON, ROR1, ROR2, ROS, RSK1, RSK12, RSK2, RSK22, RSK3, RSK32, RSK4, RSK42, RSKL1, RSKL2, RYK, RYKps, SAKps, SBK, SCYL1, SCYL2, SCYL2ps, SCYL3, SGK, SgK050ps, SgK069, SgK071, SgK085, SgK110, SgK196, SGK2, SgK223, SgK269, SgK288, SGK3, SgK307, SgK384ps, SgK396, SgK424, SgK493, SgK494, SgK495, SgK496, SIK (for example, SIK1, SIK2), skMLCK, SLK, Slob, smMLCK, SNRK, SPEG, SPEG2, SRC, SRM, SRPK1, SRPK2, SRPK2ps, SSTK, STK33, STK33ps, STLK3, STLK5, STLK6, STLK6ps1, STLK6-rs, SuRTK106, SYK, TAK1, TAO1, TAO2, TAO3, TBCK, TBK1, TEC, TESK1, TESK2, TGFbR1, TGFbR2, TIE1, TIE2, TLK1, TLK1ps, TLK2, TLK2ps1, TLK2ps2, TNK1, Trad, Trb1, Trb2, Trb3, Trio, TRKA, TRKB, TRKC, TSSK1, TSSK2, TSSK3, TSSK4, TSSKps1, TSSKps2, TTBK1, TTBK2, TTK, TTN, TXK, TYK2, TYK22, TYRO3, TYRO3ps, ULK1, ULK2, ULK3, ULK4, VACAMKL, VRK1, VRK2, VRK3, VRK3ps, Wee1, Wee1B, Wee1Bps, Wee1ps1, Wee1ps2, Wnk1, Wnk2, Wnk3, Wnk4, YANK1, YANK2, YANK3, YES, YESps, YSK1, ZAK, ZAP70, ZC1 / HGK, ZC2 / TNIK, ZC3 / MINK, and ZC4 / NRK are present.,

[0111] Detailed Description of the Invention The present disclosure is based, at least in part, on the unexpected finding that the compounds of Formulae (I)-(III) are selective dual TYK2 / JAK1 kinase inhibitors that have good ability to penetrate the blood-brain barrier.

[0112] In one embodiment, a compound of formula (I): [ka] (I) or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative or prodrug thereof is provided.

[0113] In another embodiment, a compound of formula (II): [ka] (II) or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative or prodrug thereof is provided.

[0114] In another embodiment, a compound of formula (III): [ka] (III) or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative or prodrug thereof is provided.

[0115] Thus, described are methods of treating CNS disorders as described herein using an effective amount of a compound of Formula (I)-(III) 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)-(III) or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative or prodrug thereof.

[0116] composition The present disclosure provides a pharmaceutical composition comprising a compound of Formula (I)-(III) or a salt, solvate, hydrate, polymorph, cocrystal, 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)-(III) or a salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative or prodrug thereof, and a pharmaceutically acceptable excipient.

[0117] 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 disorder in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for preventing CNS disorder in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for reducing the risk of developing CNS disorder in a subject in need thereof. 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.

[0118] The pharmaceutical compositions described herein can be prepared by any method known in the pharmaceutical art. In general, such preparation methods include bringing into association a compound described herein (i.e., "active ingredient") with a carrier or excipient, and / or one or more other accessory ingredients, and then, if necessary and / or desired, shaping and / or packaging the product into a desired single or multi-dosage unit.

[0119] 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 that contains a predetermined amount of active ingredient. The amount of active ingredient is generally equal to the dosage of the active ingredient administered to a subject and / or a convenient fraction of such a dosage, such as 1 / 2 or 1 / 3 of such a dosage.

[0120] The relative amounts of active ingredient, pharma- ceutically acceptable excipient, and / or any additional ingredients in the pharmaceutical compositions described herein will vary depending on the identity, body type, and / or condition of the subject being treated, as well as the route by which the composition is to be administered. The compositions may contain from 0.1% to 100% (w / w) active ingredient.

[0121] Pharmaceutically acceptable excipients used in the manufacture of the provided pharmaceutical compositions include inert diluents, dispersing and / or granulating agents, surfactants and / or emulsifying agents, disintegrating agents, binders, preservatives, buffers, lubricants, and / or oils. Excipients such as cocoa butter and suppository waxes, colorants, coating agents, sweeteners, flavorings, and perfumes may also be present in the composition.

[0122] Liquid dosage forms for oral and parenteral administration include pharma- ceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.In addition to active ingredients, liquid dosage forms can contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (such as cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol and fatty acid esters of sorbitan, and mixtures thereof.In addition to inert diluents, oral compositions can contain adjuvants, such as wetting agents, emulsifiers and suspending agents, sweeteners, seasonings and perfumes. In certain embodiments for parenteral administration, the conjugates described herein are mixed with a solubilizing agent such as Cremophor®, alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers and mixtures thereof.

[0123] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions, can be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations can be sterile injectable solutions, suspensions or emulsions in non-toxic parenterally acceptable diluents or solvents, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be used are water, Ringer's solution, USP and isotonic sodium chloride solution. In addition, sterile fixed oils are 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.

[0124] The injectable preparations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0125] In order 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 accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug depends on its rate of dissolution, which in turn depends on the size and crystalline form of the crystals. Alternatively, delayed absorption of a parenterally administered drug form can be accomplished by dissolving or suspending the drug in an oil vehicle.

[0126] 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 pharma- ceutically 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, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, (e) solution retarding agents, such as paraffin, (f) absorption enhancers, such as quaternary ammonium compounds, (g) They are mixed with release controlling 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 glycols, sodium lauryl sulfate and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may contain buffering agents.

[0127] Solid compositions of a similar type can be used as fillers in soft and hard filled gelatin capsules using excipients such as lactose or milk sugar, and high molecular weight polyethylene glycols. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmacological arts. They can optionally contain opacifying agents, and can be of a composition that releases the active ingredient only, or preferentially, in a certain part of the intestinal tract, optionally in a delayed manner. Examples of encapsulating compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type can be used as fillers in soft and hard filled gelatin capsules using excipients such as lactose or milk sugar, and high molecular weight polyethylene glycols.

[0128] The active ingredient may be in microencapsulated form with one or more excipients as described above. The solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells, such as enteric coatings, release-controlling coatings and other coatings well known in the pharmaceutical formulation art. In such solid dosage forms, the active ingredient may be mixed with at least one inert diluent, such as sucrose, lactose or starch. Such dosage forms may contain additional substances other than the inert diluent, as is common practice, such as tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may contain buffering agents. They may optionally contain opacifying agents and may be of a composition that releases 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.

[0129] Although the description of pharmaceutical compositions provided herein is directed primarily to pharmaceutical compositions suitable for administration to humans, it should be understood by those skilled in the art that such compositions are generally suitable for administration to any type of animal. Modifications of pharmaceutical compositions suitable for administration to humans to make the compositions suitable for administration to various animals are well understood, and a veterinary pharmacologist of ordinary skill can design and / or perform such modifications with routine experimentation.

[0130] The compounds provided herein are typically formulated in dosage unit form for ease of administration and uniformity of dosage.However, it is understood that the total daily use amount of the compositions described herein is determined by a physician within the scope of sound medical judgment.The specific therapeutically effective dose level for a specific subject or organism depends on various factors, including the disorder and severity of the disorder to be treated; the activity of the specific active ingredient used; the specific composition used; the age, weight, health condition, sex, diet of the subject; the administration timing, administration route and excretion rate of the specific active ingredient used; the duration of treatment; the drugs used in combination with or simultaneously with the specific active ingredient used; and factors well known in medicine.

[0131] 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 thereof, preventing a disorder in a subject in need thereof, reducing the risk of developing a disorder in a subject in need thereof, and / or inhibiting the activity of a protein kinase in a subject or cell), improve bioavailability, improve safety, reduce drug resistance, reduce and / or modify metabolism, inhibit excretion, and / or modify distribution in a subject or cell. It will also be understood that the therapies used may achieve a desired effect on the same disorder and / or may achieve different effects. In certain embodiments, the pharmaceutical compositions described herein that include the compounds described herein and the additional agents exhibit synergistic effects that are not present in pharmaceutical compositions that include one of the compounds and the additional agents but not both. In certain embodiments, the additional agents achieve a desired effect on the same disorder. In some embodiments, the additional agents achieve different effects.

[0132] The compound or composition may be administered simultaneously with, prior to, or after one or more additional agents that may be useful, for example, as a combination therapy. Pharmaceutical agents include therapeutically active agents. Pharmaceuticals also include prophylactically effective 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, small organic molecules such as steroids, nucleic acids, DNA, RNA, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins, and cells. In certain embodiments, the additional agent is an agent useful for treating and / or preventing CNS disorders. Each additional agent may be administered at a dose and / or time schedule determined for that agent. The additional agents may also be administered in a single dose or composition with each other and / or with the compounds or compositions described herein, or may be administered separately in different doses or compositions. The specific combination used in the regimen takes into consideration the compatibility of the compound described herein with the additional agent and / or the desired treatment and / or prophylactic effect to be achieved.In general, it is expected that the additional agent to be combined is used at a level that does not exceed the level at which they are used individually.In some embodiments, the level used in combination is lower than the level used individually.

[0133] The additional agent includes, but is not limited to, antiproliferative agents, anticancer agents, antiangiogenic agents, steroidal or nonsteroidal antiinflammatory agents, immunosuppressants, antibacterial agents, antiviral agents, cardiovascular agents, cholesterol-lowering agents, antidiabetic agents, antiallergic agents, contraceptives, pain relievers, anesthetics, anticoagulants, enzyme inhibitors, steroids, steroid or antihistamines, antigens, vaccines, antibodies, decongestants, sedatives, opioids, analgesics, antipyretics, hormones, and prostaglandins.In certain embodiments, the additional agent is an antiproliferative agent.In certain embodiments, the additional agent is an anticancer agent.In certain embodiments, the additional agent is an antiviral agent.In certain embodiments, the additional agent 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 drugs (e.g., taxanes and vinca alkaloids), hormone receptor modulators (e.g., estrogen receptor modulators and androgen receptor modulators), cell signaling pathway inhibitors (e.g., tyrosine protein kinase inhibitors), protein stability modulators (e.g., proteasome inhibitors), Hsp90 inhibitors, glucocorticoids, all-trans retinoic acid, and other agents that promote differentiation. In certain embodiments, the compounds or pharmaceutical compositions described herein can be administered in combination with 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 as specified in the Code of Federal Regulations (CFR)), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleic acid proteins, 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.

[0134] The present disclosure also includes kits (e.g., pharmaceutical packs). The kits provided may include pharmaceutical compositions or compounds described herein and containers (e.g., vials, ampoules, bottles, syringes and / or dispenser packages, or other suitable containers). In some embodiments, the kits provided may optionally further include a second container that includes pharmaceutical excipients for diluting or suspending the pharmaceutical compositions or compounds described herein. In some embodiments, the pharmaceutical compositions or compounds provided in the first container and the second container are combined to form one unit dosage form.

[0135] Thus, in one embodiment, a kit is provided that comprises a first container that comprises a compound or pharmaceutical composition as described herein.In certain embodiments, the kit is useful for treating CNS disorder in a subject in need thereof.In certain embodiments, the kit is useful for preventing CNS disorder in a subject in need thereof.In certain embodiments, the kit is useful for reducing the risk of developing CNS disorder in a subject in need thereof.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.

[0136] In certain embodiments, the kit described herein further comprises instructions for using the kit. The kit described herein may also comprise information required by regulatory agencies such as the US Food and Drug Administration (FDA). In certain embodiments, the information included in the kit is prescription information. In certain embodiments, the kit and instructions provide for treating a CNS disorder in a subject in need thereof. In certain embodiments, the kit and instructions provide for preventing a CNS disorder in a subject in need thereof. In certain embodiments, the kit and instructions provide for reducing the risk of developing a CNS disorder in a subject in need thereof. In certain embodiments, the kit and instructions provide for inhibiting the activity (e.g., abnormal activity, such as increased activity) of a protein kinase in a subject or cell. The kit described herein may comprise one or more additional agents described herein as separate compositions.

[0137] Treatment As generally described herein, the present disclosure provides a method of treating a CNS disorder (or a symptom thereof), comprising administering to a subject in need thereof an effective amount of a compound of the present disclosure, or a salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically 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, isotopically 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., upon contact with a tissue or cell culture). As used herein, "treatment" includes therapeutic treatment. In certain embodiments, the subject is identified as one in need thereof. In certain embodiments, the method further comprises treating the subject, i.e., improving the disease, disorder, or symptom.

[0138] In certain embodiments, the effective amount is a therapeutically effective amount.For example, in certain embodiments, the method slows the progression of CNS disorder in the subject.In certain embodiments, the method improves the pathology of the subject suffering from CNS disorder.In certain embodiments, the subject is suspected or confirmed to have CNS disorder.

[0139] In certain embodiments, effective amount is prophylactically effective amount.For example, in certain embodiments, the method is to prevent or reduce the possibility of CNS disorder, for example, in certain embodiments, the method comprises administering to the subject in need thereof the compound of the present disclosure in an amount sufficient to prevent or reduce the possibility of CNS disorder.In certain embodiments, the subject is at risk of developing CNS disorder.

[0140] Exemplary CNS disorders include, but are not limited to, neurotoxicity and / or neurotrauma, stroke, multiple sclerosis, spinal cord injury, epilepsy, psychiatric disorders, sleep conditions, movement disorders, nausea and / or vomiting, amyotrophic lateral sclerosis, Alzheimer's disease, and drug addiction.

[0141] In certain embodiments, the CNS disorder is neurotoxicity and / or neurotrauma, for example, as a result of acute neurological injury (e.g., traumatic brain injury (TBI), stroke, epilepsy) or chronic neurodegenerative disorder (e.g., multiple sclerosis, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, Alzheimer's disease).In certain embodiments, the compounds of the present invention provide neuroprotective effects, for example, against acute neurological injury or chronic neurodegenerative disorder.

[0142] In certain embodiments, the CNS disorder is stroke (eg, ischemic stroke).

[0143] In certain embodiments, the CNS disorder is multiple sclerosis.

[0144] In certain embodiments, the CNS disorder is a spinal cord injury.

[0145] In certain embodiments, the CNS disorder is epilepsy.

[0146] In certain embodiments, the CNS disorder is a psychiatric disorder, such as depression, anxiety or an anxiety-related condition, a learning disability or schizophrenia.

[0147] In certain embodiments, the CNS disorder is depression. "Depression" includes, but is not limited to, depressive disorders or conditions, such as major depressive disorder (e.g., unipolar depression), dysthymic disorder (e.g., chronic mild depression), bipolar disorder (e.g., manic depression), seasonal affective disorder, and / or depression associated with drug addiction (e.g., withdrawal). Depression may be clinical or subclinical. Depression may be associated with premenstrual tension and / or premenstrual dysphoric disorder.

[0148] In certain embodiments, the CNS disorder is anxiety." Anxiety "includes but is not limited to anxiety and anxiety-related conditions, such as clinical anxiety, panic disorder, agoraphobia, generalized anxiety disorder, specific phobia, social phobia, obsessive-compulsive disorder, acute stress disorder, post-traumatic stress disorder, adjustment disorder with anxiety features, anxiety disorder associated with depression, anxiety disorder due to general medical condition, substance-induced anxiety disorder, anxiety associated with drug dependency (e.g., withdrawal, dependence, relapse) and anxiety associated with nausea and / or vomiting.The treatment can be for inducing or promoting sleep in a subject (e.g., an anxious subject).

[0149] In certain embodiments, the CNS disorder is a learning disorder (eg, attention deficit hyperactivity disorder (ADHD)).

[0150] In certain embodiments, the CNS disorder is schizophrenia.

[0151] In certain embodiments, the CNS disorder is a sleep condition. "Sleep condition" includes, but is not limited to, insomnia, narcolepsy, sleep apnea, restless legs syndrome (RLS), delayed sleep phase syndrome (DSPS), periodic limb movement disorder (PLMD), hypopnea syndrome, rapid eye movement behavior disorder (RBD), shift work sleep condition (SWSD) and sleep disorders (e.g., parasomnia), such as nightmares, night terrors, sleep talking, head banging, snoring and clenched jaw and / or bruxism.

[0152] In certain embodiments, the CNS disorder is a movement disorder, for example, a basal ganglia disorder, such as Parkinson's disease, levodopa-induced dyskinesia, Huntington's disease, Gilles de la Tourette syndrome, tardive dyskinesia, and dystonia.

[0153] In certain embodiments, the CNS disorder is Alzheimer's disease.

[0154] In certain embodiments, the CNS disorder is amyotrophic lateral sclerosis (ALS).

[0155] In certain embodiments, the CNS disorder is frontotemporal dementia (FTD).

[0156] In certain embodiments, the CNS disorder is Parkinson's disease.

[0157] In certain embodiments, the CNS disorder is nausea and / or vomiting.

[0158] In certain embodiments, the CNS disorder is drug addiction (eg, addiction to opiates, nicotine, cocaine, psychostimulants, or alcohol).

[0159] In certain embodiments, the CNS disorder is regulated by the JAK-STAT pathway.In certain embodiments, the CNS disorder is regulated by JAK1.In certain embodiments, the CNS disorder is regulated by TYK2.In certain embodiments, the CNS disorder is regulated by TYK2 and JAK1.

[0160] 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.

[0161] In certain embodiments, the CNS disorder is amyotrophic lateral sclerosis / frontotemporal dementia (ALS / FTD).

[0162] In certain embodiments, the subject is an animal. The animal may be of either sex and at any stage of development. In certain embodiments, the subject described herein is a human. In certain embodiments, the subject is a non-human animal. In certain embodiments, the subject is a mammal. In certain embodiments, the subject is a non-human mammal. In certain embodiments, the subject is a livestock animal, such as a dog, cat, cow, pig, horse, sheep or goat. In certain embodiments, the subject is a companion animal, such as a dog or cat. In certain embodiments, the subject is a farm animal, such as a cow, pig, horse, sheep or goat. In certain embodiments, the subject is a companion animal, such as a dog or cat. In certain embodiments, the subject is a livestock animal, such as a cow, pig, horse, sheep or goat. In certain embodiments, the subject is a zoo animal. In another embodiment, the subject is a research animal, such as a rodent (mouse, rat, etc.), a dog, a pig, or a non-human primate. In certain embodiments, the animal is a genetically modified animal. In certain embodiments, the animal is a transgenic animal (such as a transgenic mouse or a transgenic pig). In certain embodiments, the subject is a fish or reptile.

[0163] Any of the methods described herein may further include administering to the subject an additional agent that may be an anti-CNS disorder. Examples include, butyrophenones, phenothiazines, fluphenazine, perphenazine, prochlorperazine, thioridazine, trifluoperazine, mesoridazine, promazine, triflupromazine, levomepromazine, promethazine, thioxanthenes, chlorprothixene, flupentixol, thiothixene, zuclopenthixol, clozapine, olanzapine, risperidone, quetiapine, ziprasidone, amisulpride, asenapine, paliperidone, aripiprazole, dopamine, riboflavin ... antipsychotics selected from partial agonists, lamotrigine, memantine, tetrabenazine, cannabidiol, LY2140023, droperidol, pimozide, butaperazine, carphenazine, remoxipride, piperacetazine, sulpiride, acamprosate and tetrabenazine; fluoxetine, paroxetine, escitalopram, citalopram, seriraline, fluvoxamine, venlafaxine, milnacipran, 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, phenelzine, lamotrigine, lithium, topiramate, gabapentin, carbamazepine, oxca Antidepressants or mood stabilizers selected from levazepine, valporate, maprotiline, mirtazapine, brofaromine, gepirone, moclobemide, isoniazid and iproniazid; medicines for improving cognition and / or inhibiting neurodegeneration selected from aricept, donepezil, tacrine, rivastigmine, memantine, physostigmine, nicotine, arecoline, huperzine alfa, selegiline, riluzole, vitamin C, vitamin E, carotenoids, 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.

[0164] 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, intravaginal, intraperitoneal, topical (by powder, ointment, cream, and / or eye drop), 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 contemplated. In general, the most suitable administration route depends on various factors, including the nature of the agent (e.g., its stability in the environment of the gastrointestinal tract) and / or the condition of the subject (e.g., whether the subject can tolerate oral administration). In certain embodiments, the compounds or pharmaceutical compositions described herein are suitable for topical administration to the eye of the subject.

[0165] The exact amount of compound required to achieve an effective dose varies from subject to subject, depending on, for example, the subject's race, age and general condition, the severity of side effects or disorders, the characteristics of the specific compound, the method of administration, etc. An effective amount may be contained in a single dose (e.g., a single oral dose) or multiple doses (e.g., multiple oral doses). In certain embodiments, when multiple doses are administered to a subject or applied to a tissue or cell, any two doses of the multiple doses contain different or substantially the same amount of the compound described herein. In certain embodiments, when multiple doses are administered to a subject or applied to a tissue or cell, the frequency of administering multiple doses to a subject or applying multiple doses to a tissue or cell 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 administering multiple doses to a subject or applying multiple doses to tissue or cell is 1 dose per day.In certain embodiments, the frequency of administering multiple doses to a subject or applying multiple doses to tissue or cell is 2 doses per day.In certain embodiments, the frequency of administering multiple doses to a subject or applying multiple doses to tissue or cell is 3 doses per day.In certain embodiments, when multiple doses are administered to a subject or applied to tissue or cell, the period between the first dose and the last dose of the multiple doses 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 a subject, tissue or cell.In certain embodiments, the period between the first dose and the last dose of the multiple doses is 3 months, 6 months, or 1 year. In certain embodiments, the period between the first dose and the last dose of the multiple administrations is the lifespan of the subject, tissue, or cell.In certain embodiments, the dose (e.g., a single dose, or any of multiple doses) comprises 0.1 μg to 1 μg, 0.001 mg to 0.01 mg, 0.01 mg to 0.1 mg, 0.1 mg to 1 mg, 1 mg to 3 mg, 3 mg to 10 mg, 10 mg to 30 mg, 30 mg to 100 mg, 100 mg to 300 mg, 300 mg to 1,000 mg, or 1 g to 10 g (including per se) of a compound described herein. In certain embodiments, the dose described herein independently comprises 1 mg to 3 mg (including per se) of a compound described herein. In certain embodiments, the dose described herein comprises 3 mg to 10 mg (including per se) of a compound described herein. In certain embodiments, the dose described herein comprises 10 mg to 30 mg (including per se) of a compound described herein. In certain embodiments, the doses described herein comprise between 30 mg and 100 mg, inclusive, of the compounds described herein.

[0166] In certain embodiments, an effective amount of a compound for administration to a 70 kg adult human one or more times per day comprises from about 0.0001 mg to about 3000 mg, from about 0.0001 mg to about 2000 mg, from about 0.0001 mg to about 1000 mg, from about 0.001 mg to about 1000 mg, from about 0.01 mg to about 1000 mg, from about 0.1 mg to about 1000 mg, from about 1 mg to about 1000 mg, from about 1 mg to about 100 mg, from about 10 mg to about 1000 mg, or from about 100 mg to about 1000 mg of the compound per unit dosage form.

[0167] In certain embodiments, the compounds of the invention are administered orally or parenterally at a dosage level sufficient to deliver about 0.001 mg / kg to about 100 mg / kg, about 0.01 mg / kg to about 50 mg / kg, preferably about 0.1 mg / kg to about 40 mg / kg, preferably about 0.5 mg / kg to about 30 mg / kg, about 0.01 mg / kg to about 10 mg / kg, about 0.1 mg / kg to about 10 mg / kg, and more preferably about 1 mg / kg to about 25 mg / kg of subject body weight per day, one or more times per day to obtain the desired therapeutic effect.

[0168] It will be understood that the dosage ranges described herein are intended as guidance 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 that administered to an adult, as determined by a physician or person skilled in the art. EXAMPLES

[0169] Example 1: Preparation of compounds of formula (III) [ka] Step 1: To a 250 mL three-neck flask was added IIIa (3.4 g, 0.0126 mol, 1.0 eq), DCM (100 mL), EDCI (4.9 g, 0.0254 mol, 2.0 eq), HOBT (3.4 g, 0.0254 mol, 2.0 eq) and acetic acid (1.2 g 0.02 mol, 1.59 eq). The resulting mixture was stirred for 3 min, then TEA (2.56 g, 0.0254 mol, 2.0 eq) was added. The reaction was stirred at room temperature overnight. TLC showed the reaction was complete. The reaction mixture was concentrated, saturated sodium bicarbonate was added and extracted twice with EA. The combined organic layers were washed with brine, dried, concentrated and purified by column chromatography to give IIIb (2.9 g) as a light brown powder. Yield: 73.7%. MS-ESI: [M+H]+: 313.3.

[0170] Step 2: To a 100 mL flask was added IIIb (2.9 g, 9.3 mmol, 1.0 eq), p-toluenesulfonic acid (0.2 g) and diphenyl ether (30 mL). The reaction was heated at 190° C. for 1 h. TLC showed the reaction was complete, the reaction was cooled to room temperature and saturated NaHCO3 (50 mL) was added. The resulting mixture was extracted twice with EA. The organic layers were combined, washed with brine, concentrated, dried and purified by column chromatography. The purified residue was triturated with MTBE to give compound III (1.1 g) as a white solid. Yield: 40.2%. MS-ESI: [M+H] + : 295.2. 1H NMR(300MHz, CDCl3): 8.94(s, 1H), 7.85(d, 1H), 7.14(d, 1H), 4.25-4.33(m, 1H), 2.69(s, 3H), 2.42-2.54(m, 4H), 1.99-2.17(m, 5H), 1.43-1.52(m, 2H).

[0171] Example 2: Biochemical testing of TYK2, JAK1, JAK2, and JAK3 Testing was performed at Reaction Biology, Malvern, PA (Anastassiadis et al. Nat Biotechnol. 2011; 29(11):1039-45). The steps are briefly described as follows: Basic reaction buffer: 20 mM Hepes (pH 7.5), 10 mM MgCl2, 1 mM EGTA, 0.02% Brij35, 0.02 mg / ml BSA, 0.1 mM Na3VO4, 2 mM DTT, and 1% DMSO were used. Required cofactors were added to each kinase reaction. Each reaction was carried out according to the following reaction steps: 1) prepare the specified substrate in freshly prepared basic reaction buffer; 2) transfer the necessary cofactors to the matrix solution described above; 3) transfer the specified kinase to the substrate solution and mix slightly well; 4) transfer the compound of formula (I) in DMSO to the kinase reaction mixture by sonication (Echo550; nanoliter range) and incubate at room temperature for 20 minutes; 5) transfer the reaction mixture to 100 mM NaCl; 33 ) Induce the reaction by introducing P-ATP (specific activity: 10 μCi / μl); 6) Incubate at room temperature and perform the kinase reaction for 2 hours; 7) Plot the reaction on P81 ion exchange paper; 8) Examine the kinase activity by filter binding assay. The results shown in Table 1 indicate that the compounds of formulae (I)-(III) are potent and selective TYK2 / JAK1 inhibitors. [Table 1]

[0172] Example 3. TYK2 cell ELISA assay using NK92 cells This test was carried out to test the cellular TYK2 activity using IL-12 and IL-18 stimulated IFNγ excretion assay in NK92 cells. The test was carried out according to the following procedure: 1) NK92 cell medium containing IL-2 was replaced with medium without IL-2 and maintained overnight; 2) NK92 cells were seeded in a 96-well plate at a density of about 150,000 cells / well; 3) different concentrations of test substances were added to the wells and maintained in an incubator at 37°C and 5% CO2 for 1 hour; 4) IL-12 (final concentration: 2ng / ml) and IL-18 (final concentration: 5ng / ml) were added and stimulated in the above incubator for 24 hours; 5) After 24 hours, the mixture was centrifuged at 2000 rpm for 5 minutes, and the supernatant was collected and analyzed according to the instructions of the ELISA kit. In this assay, the compounds of formula (II) and (III) were found to have an IC 50 <100nM.

[0173] Example 4. JAK1 Cellular ELISA Assay Using PBMC Cells This test was carried out to test cellular JAK1 activity using IL-6 stimulated STAT3 phosphorylation assay in PBMC cells. The test was carried out according to the following procedure: 1) PBMC cells were seeded in 96-well plates at a density of about 300,000 cells / well; 2) different concentrations of test substances were added to the wells and maintained in an incubator at 37°C and 5% CO2 for 1 hour; 3) IL-6 (final concentration: 100ng / ml) was added and stimulated for 25 minutes in the above incubator; 4) After stimulation, the suspension was transferred to a 1.5mL tube, centrifuged at 200g for 5 minutes, cells were collected, 100μL of 1X lysis solution was added, and lysed on ice for 1 hour; 5) Centrifuged at 4°C and 12000rpm for 10 minutes, and the supernatant was collected and analyzed according to the ELISA kit instructions. In this assay, compounds of formula (II) and (III) were found to have an IC 50 <300nM.

[0174] Example 5: Inhibition of LPS-induced neuronal cell death and inflammatory cytokine production This study was carried out to test the ability of the compounds to reduce the damage of HT22 cells induced by LPS-activated BV2 cells. The study was carried out according to the following procedure: 1) microglial BV2 cells were co-cultured with HT22 hippocampal neuronal cells on transwell inserts; BV2 cells were treated with 1.7 μM of the compound of formula (II) and then stimulated with LPS (200 ng / ml) for 96 hours; 2) HT22 cells were pretreated with 1.7 μM of the compound of formula (II) for 30 minutes and then stimulated with LPS (200 ng / ml) for 96 hours; 3) BV2 cells were treated with LPS. The production of IL-6, TNF, and MCP-1 in the cell supernatant was measured using the CBA assay.

[0175] The protective effect of compound of formula (II) against microglia activation-induced neuronal cell death was evaluated in BV2 microglia / HT22 neuronal cell co-cultures. After stimulation of BV2 microglia with LPS (200 ng / mL), the viability of co-cultured HT22 cells was significantly reduced. Pretreatment of BV2 microglia with 1.7 μM compound of formula (II) significantly reduced the toxicity of LPS-stimulated BV2 microglia to HT22 cells (Figure 1A). Treatment with compound of formula (II) had no effect on the viability of HT22 cells with or without LPS (Figure 1B).

[0176] LPS-treated BV2 cells significantly increased the production of IL-6, TNF and MCP-1 compared to unstimulated cells. Pretreatment with the compound of formula (II) reduced the production of these cytokines in a dose-dependent manner. Compound of formula (II) at 1.7 μM, 5 μM and 15 μM inhibited the production of IL-6 by 49.1%, 72.4% and 83.6%, respectively. Inhibition of TNF production at the three doses was 39.9%, 81.2% and 118.5%, and inhibition of MCP-1 production was 56.9%, 83.3% and 110.6% (Figure 2).

[0177] Example 6: Brain penetration in rats This study was conducted to test the ability of the compounds to penetrate the blood-brain barrier in rats. The study was carried out according to the following procedure: 1) For each compound, three male rats weighing 217-228 g were taken and the compound was formulated at a concentration of 1 mg / ml using a 0.5% HPMC / water suspension; 2) After overnight fasting, 10 mg / kg of the compound was administered by oral administration; 3) Plasma samples were collected at 1 h, 2 h, 4 h, and 8 h after administration; 4) At 8 h after administration, brain tissue and cerebrospinal fluid (CSF) were also collected; 5) The compound concentrations in plasma, brain tissue, and CSF were analyzed using LC-MS / MS methods. Table 2 shows that the compounds of formula (II) and (III) penetrate the blood-brain barrier in rats. [Table 2]

[0178] Example 7: Brain penetration in mice This study was performed to test the ability of the compounds to penetrate the blood-brain barrier in mice. The study was performed according to the following procedure: 1) For each compound, take three male C57BL / 6 mice weighing 17-18 g and prepare the compound at a concentration of 3 mg / ml using a 0.5% HPMC / water suspension; 2) After overnight fasting, administer 30 mg / kg of the compound by oral administration; 3) Collect plasma samples at 1, 2, and 4 hours after administration; 4) At 4 hours after administration, also collect brain tissue and cerebrospinal fluid (CSF) fluid; 5) Analyze the compound concentration in plasma, brain tissue, and CSF fluid using LC-MS / MS method. Table 3 shows that the compounds of formula (II) and (III) penetrate the blood-brain barrier in mice. [Table 3]

[0179] Example 8: Myelin oligodendrocyte glycoprotein (MOG35-55)-induced experimental autoimmune encephalomyelitis (MOG) in female C57BL / 6 mice 35-55 -In vivo efficacy evaluation in EAE models MOG-EAE is one of the most common and widely used animal models of multiple sclerosis, a chronic inflammatory disease of the central nervous system characterized by axonal demyelination and degeneration. In this mouse model, animals were first immunized with myelin oligodendrocyte glycoprotein (MOG) peptide in complete Freund's adjuvant (CFA) and then boosted with pertussis toxin. After immunization, mice developed chronic inflammation in the central nervous system, leading to axonal dysfunction, and associated motor deficits and paralysis. Disease development typically begins on day 10 and lasts for 20–30 days. This model allows for the specific investigation of neuroinflammatory signaling pathways and the evaluation of the efficacy of novel anti-inflammatory therapies.

[0180] Female C57BL / 6 mice weighing 19–22 g were subcutaneously injected with 200 μl of MOG35-55 / CFA emulsion containing 100 μg of MOG-EAE35-55 (100 μl in the flank of each leg). Two hours later, 100 μl of pertussis toxin (200 ng / mouse) was injected intraperitoneally. On the second day, a second injection of 100 μl of pertussis toxin (200 ng / mouse) was administered. After MOG induction, animals were examined daily for morbidity and mortality. During routine monitoring, animals were examined for the effects of MOG35-55-EAE disease and treatment on behavior, such as mobility, food and water intake, weight gain / loss, eye / hair tangles, and other abnormalities. Mortality and observed clinical signs were recorded in detail for individual animals. Body weight and disease activity index (DAI) were measured twice weekly after disease induction and then every other day from day 10 until the end of the study. DAI was scored according to a scoring scale: 0 = normal, 1 = loss of tail tone, 2 = loss of tail tone and hind limb weakness, 3 = severe weakness of both limbs / hemiplegia, 4 = paralysis of 2 or more limbs, 5 = death. Disease score and body weight measurements were performed in a laminar flow cabinet. Body weight and disease score were measured using StudyDirectorTM software (version 3.1.399.19).

[0181] Test substances were formulated as 0.5% HPMC / water suspensions at a concentration of 3 mg / ml and oral treatment was initiated on day 10 when disease onset began. Compared to the vehicle control group, mice receiving compound of formula (II) at 30 mg / kg twice daily (BID) had reduced disease activity from days 10 to 26 (Figure 3). Figures 4A and 4B show that more mice treated with compound of formula (II) had lower DAI than mice treated with vehicle. Treatment with compound of formula (II) significantly reduced weight loss in mice with experimental autoimmune encephalomyelitis (EAE).

[0182] Inclusion by Reference This application cites various issued patents, published patent applications, scientific journal articles, and other publications, all of which are incorporated herein by reference. 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, figures, examples, and claims.

[0183] Equivalence and Scope In the claims, articles such as "a," "an," "the," etc. may mean one or more, unless indicated to the contrary or clear from the context. A claim or description containing "or" between one or more members of a group is deemed to be satisfied if one, more than one, or all of the group members are present in, used in, or otherwise relevant to a particular product or process, unless indicated to the contrary or clear from the context. The present disclosure includes embodiments in which only one member of a group is present in, used in, or otherwise relevant to a particular product or process. The present disclosure includes embodiments in which one or more, or all of the group members are present in, used in, or otherwise relevant to a particular product or process.

[0184] Furthermore, the disclosure encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the enumerated claims are introduced into another claim. For example, a claim that is dependent on another claim can be modified to include one or more limitations found in other claims that are dependent on the same base claim. When elements are presented as a list, e.g., when presented in Markush group format, each subgroup of elements is also disclosed, and any element can be removed from the group. In general, when the disclosure or aspects of the disclosure are referred to as comprising certain elements and / or features, it should be understood that a particular embodiment of the disclosure or aspects of the disclosure consists of or consists essentially of such elements and / or features. For the sake of brevity, these embodiments have not been specifically described verbatim herein. It should also be noted that the terms "comprising" and "containing" are intended to be open and allow for the inclusion of additional elements or steps. When ranges are presented, the endpoints are included. Further, 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 particular value or subrange within the ranges set forth in the various embodiments of this disclosure, down to one-tenth of the unit of the lower limit of the range, unless the context clearly indicates otherwise.

[0185] This application cites various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. In the event of a conflict between any of the incorporated citations and this specification, the specification shall control. Furthermore, certain embodiments of the present disclosure that fall within the prior art may be expressly excluded from one or more claims. Such embodiments may be excluded even if the exclusion is not expressly set forth herein, because they are deemed known to those of ordinary skill in the art. Certain embodiments of the present disclosure may be excluded from any claim for any reason, whether or not related to the existence of prior art.

[0186] Those skilled in the art will recognize or be able to ascertain, using no more than routine experimentation, numerous equivalents to the specific embodiments described herein. The scope of the embodiments of the invention described herein is not intended to be limited to the above description, but is as defined in the appended claims. Those skilled in the art will appreciate that various changes and modifications can be made to this description without departing from the spirit or scope of the present disclosure, as defined in the following claims.

[0187] Implementation Embodiments of the present disclosure include the following. Embodiment 1. A method for treating a central nervous system (CNS) disorder, comprising administering to a subject in need thereof an effective amount of a compound represented by formula (I)-(III): [ka] or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative or prodrug thereof. Embodiment 2. The method of embodiment 1, wherein the compound is a dual TYK2 / JAK1 kinase inhibitor. Embodiment 3. The method of embodiment 1, wherein the CNS disorder is neurotoxicity and / or neurotrauma, stroke, multiple sclerosis, spinal cord injury, epilepsy, psychiatric disorders, sleep conditions, movement disorders, nausea and / or vomiting, amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease or drug addiction. Embodiment 4. The method of embodiment 3, wherein the neurotoxicity and / or neurotrauma is traumatic brain injury (TBI), stroke, epilepsy, multiple sclerosis, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis or Alzheimer's disease. Embodiment 5. The method of embodiment 3, wherein the psychiatric disorder is depression, anxiety or an anxiety-related condition, a learning disability or schizophrenia. Embodiment 6. The method of embodiment 3, wherein the sleep condition is insomnia, narcolepsy, sleep apnea, restless legs syndrome (RLS), delayed sleep phase syndrome (DSPS), periodic limb movement disorder (PLMD), hypopnea syndrome, rapid eye movement behavior disorder (RBD), shift work sleep state (SWSD) or a sleep disorder (e.g., parasomnia), such as nightmares, night terrors, talking in one's sleep, head banging, snoring or clenched jaw and / or bruxism. Embodiment 7. The method of embodiment 3, wherein the movement disorder is Parkinson's disease, levodopa-induced dyskinesia, Huntington's disease, Gilles de la Tourette's syndrome, tardive dyskinesia or dystonia. Embodiment 8. The method of embodiment 1, wherein the CNS disorder is regulated by TYK2 and JAK1. Embodiment 9. The method of embodiment 1, wherein the CNS disorder is Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, dementia, frontotemporal dementia, mild cognitive impairment (MCI) or neuroinflammation. Embodiment 10. 2. The method of embodiment 1, wherein the CNS disorder is Alzheimer's disease. Embodiment 11. 2. The method of embodiment 1, wherein the CNS disorder is Parkinson's disease. Embodiment 12. The method of embodiment 1, wherein the CNS disorder is amyotrophic lateral sclerosis. Embodiment 13. 2. The method of embodiment 1, further comprising administering to the subject an additional agent. Embodiment 14. A method for inhibiting a central nervous system (CNS) disorder, comprising administering to a subject in need thereof (I) to (III): [ka] or a salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative or prodrug thereof, and a pharma- ceutically acceptable excipient. Embodiment 15. The method of embodiment 14, wherein the compound is a dual TYK2 / JAK1 kinase inhibitor. EMBODIMENT 16. The method of embodiment 14, wherein the CNS disorder is neurotoxicity and / or neurotrauma, stroke, multiple sclerosis, spinal cord injury, epilepsy, psychiatric disorders, sleep conditions, movement disorders, nausea and / or vomiting, amyotrophic lateral sclerosis, Alzheimer's disease and drug addiction. EMBODIMENT 17. The method of embodiment 16, wherein the neurotoxicity and / or neurotrauma is traumatic brain injury (TBI), stroke, epilepsy, multiple sclerosis, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis or Alzheimer's disease. EMBODIMENT 18. The method of embodiment 16, wherein the psychiatric disorder is depression, anxiety or an anxiety-related condition, a learning disability or schizophrenia. Embodiment 19. The method of embodiment 16, wherein the sleep condition is insomnia, narcolepsy, sleep apnea, restless legs syndrome (RLS), delayed sleep phase syndrome (DSPS), periodic limb movement disorder (PLMD), hypopnea syndrome, rapid eye movement behavior disorder (RBD), shift work sleep state (SWSD) or a sleep disorder (e.g., parasomnia), such as nightmares, night terrors, talking in one's sleep, head banging, snoring or clenched jaw and / or bruxism. Embodiment 20. 17. The method of embodiment 16, wherein the movement disorder is Parkinson's disease, levodopa-induced dyskinesia, Huntington's disease, Gilles de la Tourette's syndrome, tardive dyskinesia or dystonia. 21. The method of embodiment 14, wherein the CNS disorder is regulated by TYK2 and JAK1. 22. The method of embodiment 14, wherein the CNS disorder is Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, dementia, frontotemporal dementia, mild cognitive impairment (MCI) or neuroinflammation. 23. 15. The method of embodiment 14, wherein the CNS disorder is Alzheimer's disease. 24. The method of embodiment 14, wherein the CNS disorder is Parkinson's disease. 25. The method of embodiment 14, wherein the CNS disorder is amyotrophic lateral sclerosis. 26. 15. The method of embodiment 14, wherein the composition further comprises an additional agent. 27. Formula (A): [ka] [In the formula, R 1 is C1-C6 alkyl; X is CH2 or O. or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative or prodrug thereof. 28. R 1 is unsubstituted C1-C6 alkyl, or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof. 29. R 1 is methyl or ethyl; and X is CH2; or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof. EMBODIMENT 30. R 128. The compound of embodiment 27, wherein: EMBODIMENT 31. R 1 is methyl and X is CH2, or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

Claims

1. A pharmaceutical for treating a central nervous system (CNS) disorder, comprising a compound represented by formula (I) to (III): 【Chemical 1】 or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative or prodrug thereof.

2. The pharmaceutical of claim 1, wherein the compound is a dual TYK2 / JAK1 kinase inhibitor.

3. 2. The method of claim 1, wherein the CNS disorder is neurotoxicity and / or neurotrauma, stroke, multiple sclerosis, spinal cord injury, epilepsy, psychiatric disorders, sleep conditions, movement disorders, nausea and / or vomiting, amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease or drug addiction.

4. 4. The method of claim 3, wherein the neurotoxicity and / or neurotrauma is traumatic brain injury (TBI), stroke, epilepsy, multiple sclerosis, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis or Alzheimer's disease.

5. 4. The method of claim 3, wherein the psychiatric disorder is depression, anxiety or an anxiety-related condition, a learning disability, or schizophrenia.

6. 4. The pharmaceutical composition of claim 3, wherein the sleep condition is insomnia, narcolepsy, sleep apnea, restless legs syndrome (RLS), delayed sleep phase syndrome (DSPS), periodic limb movement disorder (PLMD), hypopnea syndrome, rapid eye movement behavior disorder (RBD), shift work sleep disorder (SWSD), or a sleep disorder (e.g., parasomnia) such as nightmares, night terrors, sleep talking, head banging, snoring, or clenched jaw and / or teeth grinding.

7. 4. The pharmaceutical composition according to claim 3, wherein the movement disorder is Parkinson's disease, levodopa-induced dyskinesia, Huntington's disease, Gilles de la Tourette's syndrome, tardive dyskinesia, or dystonia.

8. The pharmaceutical of claim 1, wherein the CNS disorder is regulated by TYK2 and JAK1.

9. The pharmaceutical composition of claim 1, wherein the CNS disorder is Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, dementia, frontotemporal dementia, mild cognitive impairment (MCI), or neuroinflammation.

10. The method of claim 1, wherein the CNS disorder is Alzheimer's disease.

11. The method of claim 1, wherein the CNS disorder is Parkinson's disease.

12. The pharmaceutical composition of claim 1, wherein the CNS disorder is amyotrophic lateral sclerosis.

13. The pharmaceutical composition of claim 1, further comprising an additional drug, wherein the compound is administered simultaneously with, before, or after the additional drug.

14. A pharmaceutical for treating a central nervous system (CNS) disorder, comprising a compound represented by formula (I) to (III): 【Chemistry 2】 or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative or prodrug thereof, and a pharmaceutically acceptable excipient.

15. The pharmaceutical of claim 14, wherein the compound is a dual TYK2 / JAK1 kinase inhibitor.

16. 15. The pharmaceutical of claim 14, wherein the CNS disorder is neurotoxicity and / or neurotrauma, stroke, multiple sclerosis, spinal cord injury, epilepsy, psychiatric disorders, sleep conditions, movement disorders, nausea and / or vomiting, amyotrophic lateral sclerosis, Alzheimer's disease and drug addiction.

17. 17. The medicament of claim 16, wherein the neurotoxicity and / or neurotrauma is traumatic brain injury (TBI), stroke, epilepsy, multiple sclerosis, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis or Alzheimer's disease.

18. 17. The pharmaceutical composition of claim 16, wherein the psychiatric disorder is depression, anxiety or an anxiety-related condition, a learning disability or schizophrenia.

19. 17. The medicament of claim 16, wherein the sleep condition is insomnia, narcolepsy, sleep apnea, restless legs syndrome (RLS), delayed sleep phase syndrome (DSPS), periodic limb movement disorder (PLMD), hypopnea syndrome, rapid eye movement behavior disorder (RBD), shift work sleep syndrome (SWSD), or a sleep disorder (e.g., parasomnia) such as nightmares, night terrors, sleep talking, head banging, snoring, or clenched jaw and / or teeth grinding.

20. 17. The pharmaceutical composition of claim 16, wherein the movement disorder is Parkinson's disease, levodopa-induced dyskinesia, Huntington's disease, Gilles de la Tourette's syndrome, tardive dyskinesia, or dystonia.

21. The pharmaceutical of claim 14, wherein the CNS disorder is regulated by TYK2 and JAK1.

22. 15. The pharmaceutical composition of claim 14, wherein the CNS disorder is Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, dementia, frontotemporal dementia, mild cognitive impairment (MCI), or neuroinflammation.

23. The method of claim 14, wherein the CNS disorder is Alzheimer's disease.

24. The method of claim 14, wherein the CNS disorder is Parkinson's disease.

25. The pharmaceutical composition of claim 14, wherein the CNS disorder is amyotrophic lateral sclerosis.

26. The pharmaceutical composition of claim 14, wherein the composition further comprises an additional agent.

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