Bicyclic tyrosine kinase 2 inhibitors and uses thereof

Abstract

The present disclosure relates to compounds of Formula (I), and pharmaceutically acceptable salts and isotopically labeled derivatives thereof, wherein R1, X, G1, G2, G3, G4, G5, G6, and G7 are as described herein, methods of preparation, methods of treatment and prevention, and pharmaceutical compositions comprising same. The present disclosure further relates to the use of the compounds of Formula (I), and pharmaceutically acceptable salts and isotopically labeled derivatives thereof, in the treatment or prevention of TYK2-mediated diseases and disorders.

Description

[0001] BICYCLIC TYROSINE KINASE 2 INHIBITORS AND USES THEREOF

[0002] RELATED APPLICATIONS

[0003]

[0001] The present application claims priority under 35 U.S.C. § 119(e) to United States Provisional Patent Application, U.S.S.N. 63 / 623,047, filed January 19, 2024, United States Provisional Patent Application, U.S.S.N. 63 / 643,026, filed May 6, 2024, and United States Provisional Patent Application, U.S.S.N. 63 / 690,267, filed September 3, 2024, the entire contents of each of which are incorporated herein by reference.

[0004] BACKGROUND

[0005]

[0002] The Janus kinase (JAK) family is composed of four phosphotransferases, JAK1, JAK2, JAK3 and Tyrosine kinase 2 (TYK2), each of which have high homology and are composed of four main domains: Four-point-one, Ezrin, Radixin, Moesin (FERM), Src homology (SH2), pseudokinase (JH2) and kinase (JH1) domains, where the FERM and SH2 domains constitute the receptor-binding module, and where the JH2 domain negatively regulates JH1 domain kinase activity. See, e.g., Lupardus et al., PNAS (2014) 111 :8025. Each member of the JAK family associates with a distinct set of cytokine receptors, mediating a phosphorylation cascade and subsequent activation of Signal Transducer and Activator of Transcription (STAT) proteins. Activated STATs dissociate from the cytokine receptor and translocate to the cell nucleus to regulate transcription of selected STAT-dependent genes. Disruption or dysregulation of the JAK-STAT pathways, such as through genetic mutations or increased localized concentrations of inflammatory cytokines, is a key driver of various pathologies. See, e.g., Howell et al., Front. Immunol. (2019) 10:2342.

[0006]

[0003] TYK2 regulates signal transduction pathways downstream of multiple pro-inflammatory cytokines such as IL-12, IL-23, and the type I interferons, such as interferon alpha (IFN-a). See, e.g., Burke et al., Science Translational Medicine (2019) 11:502. Genetic association studies have identified TYK2 as a potential drug target for multiple inflammatory and autoimmune disorders. For example, TYK2 loss of function mutations are associated with protection from the development of psoriasis, inflammatory bowel disease, rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis, and multiple sclerosis. See, e.g., Dendrou, et al. Sci Transl Med. (2016) 8:363. This role in inflammatory disease has also been demonstrated in animal models where mice deficient in either the IL-12 / IL-23 p40 subunit or IL-23 pl9 subunit, are resistant to experimental models of colitis and psoriasis. See, e.g., Ishizaki et al., J Immunol (2011) 187:181 (colitis and psoriasis); Hue et al., J. Exp. Med. (2006) 203:2473-2483 (IBD); and Hong et al., J. Immunol. (1999) 162:7480-7491 (psoriasis). Dysregulated expression of IL-12 and / or IL-23 has been found in patients suffering from psoriasis and inflammatory bowel disease. See, e.g., Lee et al., J. Exp. Med. (2004) 199:125-130 (psoriasis); Piskin et al., J. Immunol. (2006) 176:1908-1915 (psoriasis); Piskin et al., Ex. Dermatol. (2004) 13:764-772 (psoriasis); Lee et al., J. Exp. Med. (2004) 199:125-130 (psoriasis); Duffin et al., Dermatol. Ther. (2010) 23:101-113 (psoriasis); Abraham and Cho, Annu. Rev. Med. (2009) 60:97-110 (IBD); and Yen et al., J. Clin. Invest. (2006) 116:1310-1316 (IBD). The contribution of these cytokines to inflammatory indications has also been validated in the clinic through the demonstrated efficacy of neutralizing antibodies. Biologies targeting the IL-12 / IL-23 p40 subunit or IL-23 pl9 subunit have been approved for multiple diseases, including psoriasis, psoriatic arthritis, and IBD. See, e.g., Parigi et al., J Crohns Colitis (2022) 16 (Supplement_2):ii64-ii72. The antibody anifrolumab, which targets type I interferon receptor subunit 1 to block type I IFN signalling, is approved for SLE. See, e.g., Deeks et al., Drugs (2021) 15:1795-1802.

[0007]

[0004] Furthermore, multiple evidence also suggests that blocking IL-12, IL-23, and type I interferon signalling by inhibition of TYK2 could be beneficial for neurological indications. For example, TYK2- deficient mice are protected from experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. See, e.g., Oyamada, A. et al. J Immunol (2009) 183:7539. IL-23 signaling has been linked to the pathogenesis of Alzheimer’s disease by promoting microglia activation and amyloid beta plaque formation. See, e.g., Nitsch et al., Frontiers in Neurology (2021) 12, doi:10.3389 / fneur.2021639353. Elevated type I interferon levels have been associated with Parkinson’s disease (see, e.g., Main et al., Glia (2016) 64 (9): 1590-1604), amyotrophic lateral sclerosis (ALS) (see, e.g., Wang et al., Glia (2011) 59 (6): 946-58), traumatic brain injury (see, e.g., Karve et al., eNeuro (2016) 3 (1): ENEURO.0128-15.2016), Huntington’s Disease (see, e.g., Lee, et al., Neuron (2020) 107 (5): 891-908.e8), and neuromyelitis optica (NMO) (see, e.g, Agasing, et al., Nature Communications (2020) 11 (1): 2856).

[0008]

[0005] Given the critical role of TYK2 dependent cytokines in numerous indications, the development of small molecule inhibitors to target these pathways has been of high interest to the scientific and medical community. See, e.g., Liang et al., J. Med. Chem. (2013) 56:4521-4536. JAK family members function as dimers, with IL-12 / 23 signaling mediated by TYK2 and JAK2, while the type I IFNs signal through TYK2 and JAK1. Consequently, blocking the signaling of these cytokines can be achieved by targeting either kinase. However, both JAK1 and JAK2 regulate the activity of numerous additional cytokines, and their inhibition has been associated with detrimental clinical consequences. Thus, TYK2 presents the optimal target to selectively inhibit these specific pro-inflammatory pathways while minimizing off- target effects. For example, blockade of JAK2 activity is viewed as problematic since the kinase regulates additional cytokines, such as erythropoietin, and its inhibition is associated with unwanted hematologic toxicities such as anemia, neutropenia, and thrombocytopenia. See, e.g., Liang supra; Alabdulaali, Hematology Reviews (2009) Lel056-61.

[0009]

[0006] Furthermore, given the high degree of sequence homology between JAK family kinase members, the development of selective TYK2 inhibitors, sparing JAK1, JAK2, or JAK3 inhibition, presents a significant challenge. See e.g., Liang supra. Efforts to drug TYK2 through the development of small molecules binding to the JH1 kinase domain has led to compounds with inadequate selectivity across the JAK family. See, e.g., Gerstenberger et al., J. Med. Chem. (2020) 63:13561-13577. The recent discovery of allosteric inhibitors that bind to the TYK2 JH2 pseudokinase domain provides an opportunity for greatly improved selectivity due to the unique structural features of the domain compared to the JH2 and JH1 domains of JAK1, JAK2, and JAK3. See, e.g., Wrobleski et al., J. Med. Chem. (2019) 62(20):8973. Binding of a small molecule to the TYK2 JH2 site stabilizes the enzyme in its autoinhibited state to allosterically prevent kinase activity and downstream STAT signaling.

[0010]

[0007] There is the need to develop improved small molecules that inhibit the pathway more effectively to treat a wider range of diseases. Maintaining high selectivity across the JAK family is also critical to avoid potential off-target effects and negative clinical events. Thus, there is an unmet need in the field to develop improved small molecules for inhibiting TYK2 kinase activity, particularly JH2 domain TYK2 inhibitors.

[0011] SUMMARY

[0012]

[0008] Provided herein are TYK2 inhibitors of Formula (I): and pharmaceutically acceptable salts and isotopically labeled derivatives thereof, wherein R1, X, G1, G2, G3, G4, G5, G6, and G7are as described herein.

[0013]

[0009] Further provided are methods of preparation, methods of treatment and prevention, and pharmaceutical compositions comprising same.

[0014] DEFINITIONS

[0015]

[0010] Definitions of specific functional groups and chemical terms are described in more detail below. The chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito, 1999; Smith and March, March s ’ Advanced Organic Chemistry, 5thEdition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3rdEdition, Cambridge University Press, Cambridge, 1987.

[0016] [Oil] Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various stereoisomeric forms, e.g., enantiomers and / or diastereomers. For example, the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. 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 syntheses. See, for example, Jacques et al. , Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, E.L., Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, S.H., Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ, of Notre Dame Press, Notre Dame, IN 1972). Compounds described herein can additionally encompasses individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

[0017] 1012] Unless otherwise stated, compounds described herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms (“isotopically labeled derivative”). For example, compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, replacement of19F with18F, or the replacement of a carbon by a13C- or14C-enriched carbon are within the scope of the disclosure. Such compounds are useful, for example, as a therapeutic or prophylactic agent, as analytical tools, or as probes in biological assays. In certain embodiments, the isotopically labeled derivative has 1, 2, 3, 4, 5, 6, 7, or 8 deuterium atoms in place of hydrogen atoms.

[0018]

[0013] When a range of values is listed, it is intended to encompass each value and sub-range within the range. For example, “Ci-6 alkyl” is intended to encompass alkyl.

[0019]

[0014] “Alkyl” refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 10 carbon atoms (“C1-10 alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms (“C1-9 alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“C1-8alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“C1-7 alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“C1-6 alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C1-5 alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms (“C1-4 alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“C1-3 alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“C1-2 alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“Ci alkyl”). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“C2-6 alkyl”). Examples of C1-6 alkyl groups include methyl (Ci), ethyl (C2), n-propyl (C3), isopropyl (C3), M-butyl (C4), tert-butyl (C4), sec-butyl (C4), Ao-butyl (C4), n-pentyl (C5), 3-pentanyl (C5), amyl (C5), neopentyl (C5), 3-methyl-2-butanyl (C5), tertiary amyl (C5), and n-hcxyl (Ce). Additional examples of alkyl groups include n-hcptyl (C7), n-octyl (C8) and the like. Unless otherwise specified, each instance of an alkyl group is independently unsubstituted (an “unsubstituted alkyl”) or substituted (a “substituted alkyl”) with one or more substituents. In some embodiments, the alkyl group is an unsubstituted CMO alkyl (e.g., -CH3). In some embodiments, the alkyl group is a substituted C1-10 alkyl.

[0015] “Haloalkyl” refers to a substituted alkyl group, as defined herein, wherein one or more of the hydrogen atoms are independently replaced by a halogen, e.g., fluoro, bromo, chloro, or iodo. “Perhaloalkyl” is a subset of haloalkyl and refers to an alkyl group wherein all of the hydrogen atoms are independently replaced by a halogen, e.g., fluoro, bromo, chloro, or iodo. In some embodiments, the haloalkyl moiety has 1 to 8 carbon atoms (“C1-8haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 6 carbon atoms (“Ci-6 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 4 carbon atoms (“Ci-4 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 3 carbon atoms (“Ci-3 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 2 carbon atoms (“C1-2 haloalkyl”). In some embodiments, all of the haloalkyl hydrogen atoms are replaced with fluoro to provide a perfluoroalkyl group. In some embodiments, all of the haloalkyl hydrogen atoms are replaced with chloro to provide a “perchloroalkyl” group. Examples of haloalkyl groups include -CF3, -CF2CF3, -CF2CF2CF3, -CCI3, -CFCI2, -CF2CI, and the like.

[0020]

[0016] “Alkenyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 10 carbon atoms and one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 double bonds) (“C2-10 alkenyl”). In some embodiments, an alkenyl group has 2 to 9 carbon atoms (“C2-9 alkenyl”). In some embodiments, an alkenyl group has 2 to 8 carbon atoms (“C2-8 alkenyl”). In some embodiments, an alkenyl group has 2 to 7 carbon atoms (“C2-7 alkenyl”). In some embodiments, an alkenyl group has 2 to 6 carbon atoms (“C2-6 alkenyl”). In some embodiments, an alkenyl group has 2 to 5 carbon atoms (“C2-5 alkenyl”). In some embodiments, an alkenyl group has 2 to 4 carbon atoms (”€’2 4 alkenyl”). In some embodiments, an alkenyl group has 2 to 3 carbon atoms (“C2-3 alkenyl”). In some embodiments, an alkenyl group has 2 carbon atoms (“C2 alkenyl”). The one or more carbon-carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). Examples of alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. Examples of C2-6 alkenyl groups include the aforementioned C2-4 alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (Ce), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like. Unless otherwise specified, each instance of an alkenyl group is independently unsubstituted (an “unsubstituted alkenyl”) or substituted (a “substituted alkenyl”) with one or more substituents. In some embodiments, the alkenyl group is an unsubstituted C2-10 alkenyl. In some embodiments, the alkenyl group is a substituted C2-10 alkenyl.

[0021]

[0017] “Alkynyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 10 carbon atoms and one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 triple bonds) (“C2-10 alkynyl”). In some embodiments, an alkynyl group has 2 to 9 carbon atoms (“C2-9 alkynyl”). In some embodiments, an alkynyl group has 2 to 8 carbon atoms (“C2-8 alkynyl”). In some embodiments, an alkynyl group has 2 to 7 carbon atoms (“C2-7 alkynyl”). In some embodiments, an alkynyl group has 2 to 6 carbon atoms (“C2-6 alkynyl”). In some embodiments, an alkynyl group has 2 to 5 carbon atoms (“C2-5 alkynyl”). In some embodiments, an alkynyl group has 2 to 4 carbon atoms (”C2- 4 alkynyl”). In some embodiments, an alkynyl group has 2 to 3 carbon atoms (“C2-3 alkynyl”). In some embodiments, an alkynyl group has 2 carbon atoms (“C2 alkynyl”). The one or more carbon-carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl). Examples of alkynyl groups include, without limitation, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. Examples of C2-6 alkenyl groups include the aforementioned alkynyl groups as well as pentynyl (C5), hexynyl (Ce), and the like. Additional examples of alkynyl include heptynyl (C7), octynyl (C8), and the like. Unless otherwise specified, each instance of an alkynyl group is independently unsubstituted (an “unsubstituted alkynyl”) or substituted (a “substituted alkynyl”) with one or more substituents. In some embodiments, the alkynyl group is an unsubstituted C2-10 alkynyl. In some embodiments, the alkynyl group is a substituted C2-10 alkynyl.

[0022]

[0018] “Carbocyclyl” or “carbocyclic” refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 14 ring carbon atoms (“C3-14 carbocyclyl”) and zero heteroatoms in the non-aromatic ring system. In some embodiments, a carbocyclyl group has 3 to 10 ring carbon atoms (“C3-10 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 9 ring carbon atoms (“C3-9 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms (“C3-8 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 7 ring carbon atoms (“C3-7 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (“C3-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 4 to 6 ring carbon atoms (“C4-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 6 ring carbon atoms (“C5-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (“C5-10 carbocyclyl”). Exemplary C3-6 carbocyclyl groups include, without limitation, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (Ce), cyclohexenyl (Ce), cyclohexadienyl (Ce), and the like. Exemplary C3-8 carbocyclyl groups include, without limitation, the aforementioned C3-6 carbocyclyl groups as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), and the like. Exemplary C3-10 carbocyclyl groups include, without limitation, the aforementioned C3-8 carbocyclyl groups as well as cyclononyl (C$>), cyclononenyl (C$>), cyclodecyl (C10), cyclodecenyl (C10), octahydro- 1 H-indcny I (C$>), decahydronaphthalenyl (C10), spiro[4.5]decanyl (C10), and the like. As the foregoing examples illustrate, in some embodiments, the carbocyclyl group is either monocyclic (“monocyclic carbocyclyl”) or polycyclic (e.g., containing a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) or tricyclic system (“tricyclic carbocyclyl”)) and can be saturated or can contain one or more carbon-carbon double or triple bonds. “Carbocyclyl” also includes ring systems wherein the carbocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups wherein the point of attachment is on the carbocyclyl ring, and in such instances, the number of carbons designate the number of carbons in the polycyclic ring system. Unless otherwise specified, each instance of a carbocyclyl group is independently unsubstituted (an “unsubstituted carbocyclyl”) or substituted (a “substituted carbocyclyl”) with one or more substituents. In some embodiments, the carbocyclyl group is an unsubstituted C3-14 carbocyclyl. In some embodiments, the carbocyclyl group is a substituted C3-14 carbocyclyl.

[0023]

[0019] In some embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 14 ring carbon atoms (“C3-14 cycloalkyl”). In some embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 10 ring carbon atoms (“C3-10 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms (“C3-8 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms (“C3-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 4 to 6 ring carbon atoms ("CU cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms (“C5-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms (“C5-10 cycloalkyl”). Examples of C5-6 cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). Examples of C3-6 cycloalkyl groups include the aforementioned C5-6 cycloalkyl groups as well as cyclopropyl (C3) and cyclobutyl (C4). Examples of C3-8 cycloalkyl groups include the aforementioned C3-6 cycloalkyl groups as well as cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise specified, each instance of a cycloalkyl group is independently unsubstituted (an “unsubstituted cycloalkyl”) or substituted (a “substituted cycloalkyl”) with one or more substituents. In some embodiments, the cycloalkyl group is an unsubstituted C3-14 cycloalkyl. In some embodiments, the cycloalkyl group is a substituted C3-14 cycloalkyl.

[0024]

[0020] “Heterocyclyl” or “heterocyclic” refers to a radical of a 3- to 14-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each ring heteroatom is independently selected from nitrogen, oxygen, and sulfur (“3-14 membered heterocyclyl”). It is understood that the ring sulfur or ring nitrogen may exist in an oxygenated state, such as an N-oxide (N- O), sulfonyl (S(=O)2) or sulfinyl (S=O) ring heteroatom. In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. A heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or polycyclic (e.g., a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”) or tricyclic system (“tricyclic heterocyclyl”)), and can be saturated or can contain one or more carbon-carbon double or triple bonds. Heterocyclyl polycyclic ring systems can include one or more heteroatoms in one or both rings. “Heterocyclyl” also includes (i) polycyclic ring systems wherein the heterocyclyl ring, as defined above, is fused (e.g., spiro-fused or ring fused) or bridged with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, or (ii) polycyclic ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances (i) and (ii), the number of ring members designate the number of ring members in the polycyclic ring system. Unless otherwise specified, each instance of heterocyclyl is independently unsubstituted (an “unsubstituted heterocyclyl”) or substituted (a “substituted heterocyclyl”) with one or more substituents. In some embodiments, the heterocyclyl group is an unsubstituted 3-14 membered heterocyclyl. In some embodiments, the heterocyclyl group is a substituted 3-14 membered heterocyclyl.

[0025]

[0021] In some embodiments, a heterocyclyl group is a 5-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5-8 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5- 8 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5-6 membered non- aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heterocyclyl”). In some embodiments, the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0026]

[0022] Exemplary 3-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azirdinyl, oxiranyl, and thiiranyl. Exemplary 4-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azetidinyl, oxetanyl and thietanyl. Exemplary 5-membered heterocyclyl groups containing 1 heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2, 5-dione. Exemplary 5-membered heterocyclyl groups containing 2 heteroatoms include, without limitation, dioxolanyl, oxathiolanyl and dithiolanyl. Exemplary 5-membered heterocyclyl groups containing 3 heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6- membered heterocyclyl groups containing 1 heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing 2 heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing 3 heteroatoms include, without limitation, triazinanyl. Exemplary 7-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary 8-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl. Exemplary bicyclic heterocyclyl groups include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl, decahydronaphthyridinyl, decahydro- 1 , 8-naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole, indolinyl, phthalimidyl, naphthalimidyl, chromanyl, chromenyl, 1H- benzo[e][l,4] diazepinyl, 1 ,4, 5 ,7-tetrahydropyrano [3 ,4-b] pyrrolyl, 5 , 6-dihydro-4H-furo [3 ,2- b]pyrrolyl, 6,7-dihydro-5H-furo[3,2-b]pyranyl, 5,7-dihydro-4H-thieno[2,3-c]pyranyl, 2,3-dihydro- lH-pyrrolo[2,3-b]pyridinyl, 2,3-dihydrofuro[2,3-b]pyridinyl, 4,5,6,7-tetrahydro-lH-pyrrolo[2,3- b]pyridinyl, 4,5,6,7-tetrahydrofuro[3,2-c]pyridinyl, 4,5,6,7-tetrahydrothieno[3,2-b]pyridinyl, 1, 2,3,4- tetrahydro-l,6-naphthyridinyl, and the like.

[0027]

[0023] “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 array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C6-14 aryl”). In some embodiments, an aryl group has 6 ring carbon atoms (“C14aryl”; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms (“Cioaryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms (“C14aryl”; e.g., anthracyl). “Aryl” also includes polycyclic ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms designate the number of carbon atoms in the polycyclic ring system. Unless otherwise specified, each instance of an aryl group is independently unsubstituted (an “unsubstituted aryl”) or substituted (a “substituted aryl”) with one or more substituents. In some embodiments, the aryl group is an unsubstituted C6-14 aryl. In some embodiments, the aryl group is a substituted C6-14 aryl.

[0028]

[0024] “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 array) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-14 membered heteroaryl”). In heteroaryl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Heteroaryl polycyclic ring systems can include one or more heteroatoms in one or both rings. “Heteroaryl” also includes polycyclic ring systems wherein the heteroaryl ring, as defined above, (i) is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, or (ii) is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances (i) and (ii), the number of ring members designate the number of ring members in the fused polycyclic ring system. Polycyclic heteroaryl groups wherein one ring does not contain a ring heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and the like), the point of attachment can be on either ring, i.e., either the ring bearing a ring heteroatom (e.g., 2-indolyl) or the ring that does not contain a ring heteroatom (e.g., 5- indolyl).

[0029]

[0025] In some embodiments, a heteroaryl group is a 5-10 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5-8 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heteroaryl”). In some embodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each instance of a heteroaryl group is independently unsubstituted (an “unsubstituted heteroaryl”) or substituted (a “substituted heteroaryl”) with one or more substituents. In some embodiments, the heteroaryl group is an unsubstituted 5-14 membered heteroaryl. In some embodiments, the heteroaryl group is a substituted 5-14 membered heteroaryl.

[0030]

[0026] Exemplary 5-membered heteroaryl groups containing 1 heteroatom include, without limitation, pyrrolyl, furanyl and thiophenyl. Exemplary 5-membered heteroaryl groups containing 2 heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing 3 heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing 4 heteroatoms include, without limitation, tetrazolyl. Exemplary 6-membered heteroaryl groups containing 1 heteroatom include, without limitation, pyridinyl. Exemplary 6-membered heteroaryl groups containing 2 heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing 3 or 4 heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing 1 heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, without limitation, 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, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. Exemplary tricyclic heteroaryl groups include, without limitation, phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl and phenazinyl.

[0031]

[0027] “Halo” or “halogen” refers to fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), or iodine (iodo, -I) radicals.

[0032]

[0028] “Saturated” refers to a ring moiety that does not contain a double or triple bond, i.e. , the ring contains all single bonds.

[0033]

[0029] Affixing the suffix “-ene” to a group indicates the group is a divalent moiety, e.g., alkylene is the divalent moiety of alkyl, haloalkylene is the divalent moiety of haloalkyl, alkenylene is the divalent moiety of alkenyl, alkynylene is the divalent moiety of alkynyl, heteroalkylene is the divalent moiety of heteroalkyl, heteroalkenylene is the divalent moiety of heteroalkenyl, heteroalkynylene is the divalent moiety of heteroalkynyl, carbocyclylene is the divalent moiety of carbocyclyl, heterocyclylene is the divalent moiety of heterocyclyl, arylene is the divalent moiety of aryl, and heteroarylene is the divalent moiety of heteroaryl. By way of example, alkylene may be a Ci-6 alkylene, which may be linear or branched. An alkylene may further be a Ci-4 alkylene. Exemplary Ci-4 alkylene groups include, but are not limited to, -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH2CH(CH3)-, -CH2C(CH3)2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, and the like.

[0034]

[0030] “Vicinal” refers to two substituents which are bonded to two adjacent atoms (i.e., in a 1,2- relationship).

[0035]

[0031] “Salt” refers to any and all salts, including pharmaceutically acceptable salts.

[0036]

[0032] “Pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. Examples of pharmaceutically acceptable acid addition salts include, but are not limited to, salts formed from inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid salts, or salts formed from organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethane sulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethane sulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalene sulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(Ci-4alkyl)4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

[0037]

[0033] A “free base” refers to a neutral non-ionized form of a compound which is not a salt or pharmaceutically acceptable salt.

[0038]

[0034] “Amino protecting groups” are described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rdedition, John Wiley & Sons, 1999. Exemplary amino protecting groups include, but are not limited to, those that protect the amine as an amide, such as formyl, acetyl (Ac), chloroacetyl, trichloroacetyl, trifluoroacetyl, and phenylacetyl; protect the amine as a carbamate, such as methyl carbamate, ethyl carbamante, 9-fluorenylmethyl carbamate (Fmoc), / -butyl carbamate (BOC), 1-adamantyl carbamate (Adoc), and benzyl carbamate (Cbz); protect the amine as a sulfonamide such as p-toluenesulfonamide (Ts), benzenesulfonamide, methane sulfonamide (Ms), and benzylsulfonamide; and / or protect the amine as a benzylated amine, such as benzyl (Bn), p- methoxybenzyl (PMB),p-nitobenzyl, p-bromobenzyl, p-chlorobenzyl, and 2,4-dichlorobenzyl.

[0035] “Condition,” “disease,” and “disorder” are used interchangeably herein.

[0039]

[0036] A “patient” or “subject” is used interchangeably herein, and refers to a mammal, e.g., a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate, such as a monkey, chimpanzee, baboon, or rhesus. In certain embodiments, the patient or subject is a human.

[0040]

[0037] “Administer,” “administering,” or “administration” refer to implanting, absorbing, ingesting, injecting, inhaling, providing or otherwise introducing a compound described herein, or a composition thereof, in, to or on a subject.

[0041]

[0038] “Effective amount” refers to an amount of the compound sufficient to provide a benefit in the treatment or prevention of a disease, disorder or condition in a subject in need thereof. An effective amount can therefore encompass: (i) a “therapeutically effective amount” (useful in the treatment of a disease, disorder, or condition) is an amount that reduces symptoms or causes of the disease, disorder or condition and / or enhances the therapeutic efficacy of another therapeutically active agent in the treatment of the disease, disorder or condition in said subject suffering from said disease, disorder, or condition, and (ii) a “prophylactically effective amount” (useful in the prevention of a disease, disorder, or condition) is an amount that delays or prevents the appearance of at least one symptom of a disease, disorder or condition in a subject that may have or has a predisposition for the disease, disorder or condition but has not yet experienced or displayed symptoms of the disease, disorder or condition, and / or enhances the prophylactic efficacy of another prophylactically active agent in the delay or prevention of the appearance of at least one symptom of a disease, disorder or condition, in said subject. An effective amount of a compound may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, health, and condition of the subject. In certain embodiments, an effective amount is an amount sufficient for inhibiting TYK2 activity in situ (e.g., in a cell relative to a control (e.g., a vehicle)) or in vivo (e.g., in an animal model).

[0042]

[0039] “Treating” or “treat” or “treatment” describes the therapeutic management and care of a subject for the purpose of combating established symptoms of a disease, condition, or disorder in said subject.

[0040] “Preventing,” “prevent,” or “protecting against” describes the prophylactic management and care of a subject that may have or has a predisposition for the disease, disorder or condition but has not yet experienced or displayed any symptoms of the disease, disorder or condition, for the purpose of preventing the appearance of at least one symptom of the disease, disorder or condition in said subject.

[0041] “Inhibition”, “inhibiting”, “inhibit” and “inhibitor”, and the like, refer to the ability of a compound to reduce, slow, halt or prevent activity of a particular biological process (e.g., TYK2 activity) in a cell relative to a control (e.g., a vehicle).

[0043]

[0042] The phrase “at least one” refers to one instance or more than one instance, e.g., 1, 2, 3, 4, or more instances, but also encompasses a range, e.g., for example, from 1 to 4, from 1 to 3, from 1 to 2, from 2 to 4, from 2 to 3, or from 3 to 4 instances, inclusive.

[0044] BRIEF DESCRIPTION OF THE DRAWINGS

[0045]

[0043] FIGs. 1A-1D show molecular modeling of Comparative Example A (FIG. 1A), Comparative Example B (FIG. IB), Comparative Example C (FIG. 1C), and Compound 2 (FIG. ID) bound within the JH2 domain of Tyk2.

[0046]

[0044] FIGs. 2A-2B show molecular modeling of Comparative Example D (FIG. 2A) and Compound 19 (FIG. 2B) bound within the JH2 domain of Tyk2.

[0047]

[0045] FIGs. 3A-3C show molecular modeling of Compound 7A (FIG. 3A), Compound 27A* (FIG. 3B), and Compound 85A* (FIG. 3C) bound within the JH2 domain of Tyk2. DETAILED DESCRIPTION i. Compounds

[0048]

[0046] Provided herein are compounds of Formula (I): and pharmaceutically acceptable salts and isotopically labeled derivatives thereof, wherein:

[0049] R1is C3-4 carbocyclyl or 3-4 membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is substituted with 0, 1, 2, or 3 instances of R1A; each instance of R1Ais independently C1-3 alkyl, C1-3 haloalkyl, halogen, or -OR', or two R1Agroups attached to the same carbon atom are joined to form a C3-6 carbocyclyl or 3-6 membered heterocyclyl, or two R1Agroups attached to vicinal atoms are joined to form a C3-6 carbocyclyl or 3-6 membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is substituted with 0, 1, 2, or 3 substituents independently selected from C1-3 alkyl, C1-3 haloalkyl, halogen, -C(=O)OR', and -OR'; each X is independently selected from H and halogen;

[0050] G1is CRG1or N and G2is CRG2or N; each of RG1and RG2is independently selected from H, halogen, C1-6 alkyl, C1-6 haloalkyl, and -(Li)-O-(CH2CH2O)m-R', wherein Li is absent, C1-3 alkylene, or C1-3 haloalkylene, and wherein m is 0, 1 or 2;

[0051] G3is N or CR3and G4is N or CR4, provided at least one of G3and G4is CR3or CR4, respectively, and at least one of said R3and R4is not H;

[0052] G5is O, N, S, or N-RG5, wherein RG5is H, C1-3 alkyl, or C1-3 haloalkyl;

[0053] G6is C or N;

[0054] G7is C or N;

[0055] R3and R4are each independently H, halogen, C1-6 alkyl, C1-6 haloalkyl, -(L2)-(Y)-C3-10 carbocyclyl, -(L2)-(Y)-(4- 10 membered heterocyclyl), -(L2)-(Y)-C6-10 aryl, -(L2)-(Y)-(5- 10 membered heteroaryl), -(L2)-ORA, -(L2)-N(RA)2, -(L2)-SRA, -(L2)-CN, -(L2)-(Y)-C(=O)RA, -(L2)-(Y)-C(=O)ORA, -(L2)-(Y)-C(=O)N(RA)2, -(L2)-S(=O)2RA, -(L2)-S(=O)2ORA, -(L2)-(¥)-S(=O)2N(RA)2, or -B(ORA)2, wherein L2 is absent, C1-3 alkylene, or C1-3 haloalkylene; Y is absent, -O-, or -N(RA)-; and each alkyl, haloalkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, alkylene, or haloalkylene is independently substituted with 0, 1, 2, or 3 instances of RB; each instance of RAis independently H, C1-6 alkyl, C1-6 haloalkyl, -(L3)-(Z)-C3-10 carbocyclyl, -(L3)-(Z)-(3- 10 membered heterocyclyl), -(L3)-(Z)-C6-10 aryl, or -(L3)-(Z)-(5- 10 membered heteroaryl), or two RAgroups (i) attached to the same nitrogen atom or (ii) attached to two oxygen atoms which are attached to the same boron atom are joined to form a 4-6 membered heterocyclyl; wherein L3 is absent, C1-3 alkylene, or C1-3 haloalkylene; Z is absent or -O-; and each alkyl, haloalkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, alkylene, or haloalkylene is independently substituted with 0, 1, 2, or 3 instances of RB; each instance of RBis independently halogen, C1-6 alkyl, C1-6 haloalkyl, C3-10 carbocyclyl, 4-6 membered heterocyclyl, -CN, -OR', -N(R')2, -SR', -C(=O)R', -C(=O)OR', or -C(=O)N(R')2, or two RBattached to the same carbon atom are taken together to form =0; wherein each alkyl and haloalkyl is independently substituted with 0 or 1 =0 and independently substituted with 0, 1, 2, or 3 -OR'; and each carbocyclyl and heterocyclyl is independently substituted with 0, 1, 2, or 3 instances of Rc; each instance of Rcis independently halogen, C1-6 alkyl, C1-6 haloalkyl, or -OR', or two Rcattached to the same carbon atom are taken together to form =0; each instance of R' is independently H, C1-6 alkyl, or C1-6 haloalkyl, or two R' groups attached to the same nitrogen atom are joined to form a 4-6 membered heterocyclyl, wherein the alkyl, haloalkyl, or heterocyclyl is substituted with 0, 1, 2, or 3 R"; each instance of R" is independently halogen, -CN, -OR'", -N(R'")2, or -SR'", or two R" attached to the same carbon atom are taken together to form =0; and each instance of R'" is independently H, C1-3 alkyl, or C1-3 haloalkyl, or two R'" groups attached to the same nitrogen atom are joined to form a 4-6 membered heterocyclyl, wherein the heterocyclyl is substituted with 0, 1, 2, or 3 halogen.

[0056]

[0047] In some embodiments, provided herein are compounds of Formula (I): and pharmaceutically acceptable salts and isotopically labeled derivatives thereof, wherein:

[0057] R1is C3-4 carbocyclyl or 3-4 membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is substituted with 0, 1, 2, or 3 instances of R1A; each instance of R1Ais independently C1-3 alkyl, C1-3 haloalkyl, halogen, or -OR', or two R1Agroups attached to the same carbon atom are joined to form a C3-6 carbocyclyl or 3-6 membered heterocyclyl, or two R1Agroups attached to vicinal atoms are joined to form a C3-6 carbocyclyl or 3-6 membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is substituted with 0, 1, 2, or 3 substituents independently selected from C1-3 alkyl, C1-3 haloalkyl, halogen, -C(=O)OR', and -OR';

[0058] -CX3is -CH3or -CHF2; G1is CRG1or N and G2is CRG2or N; each of RG1and RG2is independently selected from H, halogen, C1-6 alkyl, Ci-6 haloalkyl, and - (Li)-O-(CH2CH2O)m-R', wherein Li is absent, C1-3 alkylene, or C1-3 haloalkylene, and wherein m is 0, 1 or 2;

[0059] G3is N or CR3and G4is N or CR4, provided at least one of G3and G4is CR3or CR4, and at least one of said R3and R4is not H;

[0060] G5is O, N, S, or N-RG5, wherein RG5is H, C1-3 alkyl, or C1-3 haloalkyl;

[0061] G6is C or N;

[0062] G7is C or N;

[0063] R3and R4are each independently H, halogen, C1-6 alkyl, C1-6 haloalkyl, -(L2)-(Y)-C3-10 carbocyclyl, -(L2)-(Y)-(4-10 membered heterocyclyl), -(L2)-(Y)-C6-10 aryl, -(L2)-(Y)-(5-10 membered heteroaryl), -(L2)-ORA, -(L2)-N(RA)2, -(L2)-SRA, -(L2)-CN, -(L2)-(Y)-C(=O)RA, -(L2)-(Y)-C(=O)ORA, - (L2)-(Y)-C(=O)N(RA)2, -(L2)-S(=O)2RA, -(L2)-S(=O)2ORA, -(L2)-(¥)-S(=O)2N(RA)2, or -B(ORA)2, wherein L2 is absent, C1-3 alkylene, or C1-3 haloalkylene; Y is absent, -O-, or -N(RA)-; and each alkyl, haloalkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, alkylene, or haloalkylene is independently substituted with 0, 1, 2, or 3 instances of RB; each instance of RAis independently H, C1-6 alkyl, C1-6 haloalkyl, -(L3)-(Z)-C3-10 carbocyclyl, - (L3)-(Z)-(3-10 membered heterocyclyl), -(L3)-(Z)-C6-10 aryl, or -(L3)-(Z)-(5-10 membered heteroaryl), or two RAgroups (i) attached to the same nitrogen atom or (ii) attached to two oxygen atoms which are attached to the same boron atom are joined to form a 4-6 membered heterocyclyl; wherein L3 is absent, C1-3 alkylene, or C1-3 haloalkylene; Z is absent or -O-; and each alkyl, haloalkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, alkylene, or haloalkylene is independently substituted with 0, 1, 2, or 3 instances of RB; each instance of RBis independently halogen, C1-6 alkyl, C1-6 haloalkyl, C3-10 carbocyclyl, -CN, - OR', -N(R')2, -SR', -C(=O)R', -C(=O)OR', -C(=O)N(R')2, or two RBattached to the same carbon atom are taken together to form =0; wherein each alkyl and haloalkyl is independently substituted with 0 or 1 =0; and each carbocyclyl is independently substituted with 0, 1, 2, or 3 instances of Rc; each instance of Rcis independently halogen, C1-6 alkyl, or C1-6 haloalkyl, or two Rcattached to the same carbon atom are taken together to form =0; each instance of R' is independently H, C1-6 alkyl, or C1-6 haloalkyl, or two R' groups attached to the same nitrogen atom are joined to form a 4-6 membered heterocyclyl, wherein the alkyl, haloalkyl, or heterocyclyl is substituted with 0, 1, 2, or 3 R"; each instance of R" is independently halogen, -CN, -OR'", -N(R'")2, or -SR'", or two R" attached to the same carbon atom are taken together to form =0; and each instance of R'" is independently H, C1-3 alkyl, or C1-3 haloalkyl, or two R'" groups attached to the same nitrogen atom are joined to form a 4-6 membered heterocyclyl, wherein the heterocyclyl is substituted with 0, 1, 2, or 3 halogen.

[0064]

[0048] In some embodiments of Formula (I), and pharmaceutically acceptable salts and isotopically labeled derivatives thereof:

[0065] R1is C3-4 carbocyclyl or 3-4 membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is substituted with 0, 1, 2, or 3 instances of R1A; each instance of R1Ais independently Cm alkyl, C1-3 haloalkyl, halogen, or -OR', or two R1Agroups attached to the same carbon atom are joined to form a C35 carbocyclyl or 3-5 membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is substituted with 0, 1 , 2, or 3 substituents independently selected from Cm alkyl, Cm haloalkyl, halogen, and -OR';

[0066] -CX3is -CH3or -CHF2;

[0067] G1is CRG1or N and G2is CRG2or N; each of RG1and RG2is independently selected from H, halogen, Ci-6 alkyl, Cm haloalkyl, and - (Li)-O-(CH2CH2O)m-R', wherein Li is absent, Cm alkylene, or Cm haloalkylene, and wherein m is 0, 1 or 2;

[0068] G3is N or CR3and G4is N or CR4, provided at least one of G3and G4is CR3or CR4, respectively, and at least one of said R3and R4is not H;

[0069] G5is O, N, S, or N-RG5, wherein RG5is H, Cm alkyl, or Cm haloalkyl;

[0070] G6is C or N;

[0071] G7is C or N;

[0072] R3and R4are each independently H, halogen, Cm alkyl, Cm haloalkyl, -(L2)-(Y)-C3-io carbocyclyl, -(L2)-(Y)-(4-10 membered heterocyclyl), -(L2)-(Y)-C6 -10 aryl, -(L2)-(Y)-(5-10 membered heteroaryl), -(L2)-ORA, -(L2)-N(RA)2, -(L2)-SRA, -(L2)-CN, -(L2)-(Y)-C(=O)RA, -(L2)-(Y)-C(=O)ORA, - (L2)-(Y)-C(=O)N(RA)2, -(L2)-S(=O)2RA, -(L2)-S(=O)2ORA, -(L2)-(Y)-S(=O)2N(RA)2, or -B(ORA)2, wherein L2is absent, Cm alkylene, or Cm haloalkylene; Y is absent, -O-, or -N(RA)-; and each alkyl, haloalkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, alkylene, or haloalkylene is independently substituted with 0, 1, 2, or 3 instances of RB; each instance of RAis independently H, Cm alkyl, Cm haloalkyl, -(L3)-(Z)-C3-10 carbocyclyl, - (L3)-(Z)-(3-10 membered heterocyclyl), -(L3)-(Z)-Ce -10 aryl, or -(L3)-(Z)-(5-10 membered heteroaryl), or two RAgroups (i) attached to the same nitrogen atom or (ii) attached to two oxygen atoms which are attached to the same boron atom are joined to form a 4-6 membered heterocyclyl; wherein L3is absent, Cm alkylene, or Cm haloalkylene; Z is absent or -O-; and each alkyl, haloalkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, alkylene, or haloalkylene is independently substituted with 0, 1 , 2, or 3 instances of RB; each instance of RBis independently halogen, Cm alkyl, Cm haloalkyl, C3-10 carbocyclyl, -CN, - OR', -N(R')2, -SR', -C(=O)R', -C(=O)OR', -C(=O)N(R')2, or two RBattached to the same carbon atom are taken together to form =0; wherein each alkyl and haloalkyl is independently substituted with 0 or 1 =0; and each carbocyclyl is independently substituted with 0, 1 , 2, or 3 instances of Rc; each instance of Rcis independently halogen, Cm alkyl, or Cm haloalkyl, or two Rcattached to the same carbon atom are taken together to form =0; each instance of R' is independently H, Ci-6 alkyl, or Ci-6 haloalkyl, or two R' groups attached to the same nitrogen atom are joined to form a 4-6 membered heterocyclyl, wherein the alkyl, haloalkyl, or heterocyclyl is substituted with 0, 1, 2, or 3 R"; each instance of R" is independently halogen, -CN, -OR'", -N(R'")2, or -SR'", or two R" attached to the same carbon atom are taken together to form =0; and each instance of R'" is independently H, C1-3 alkyl, or C1-3 haloalkyl, or two R'" groups attached to the same nitrogen atom are joined to form a 4-6 membered heterocyclyl, wherein the heterocyclyl is substituted with 0, 1, 2, or 3 halogen.

[0073]

[0049] In some embodiments of Formula (I), each instance ofX is hydrogen to provide a methylated compound of Formula (I-a): or a pharmaceutically acceptable salt or isotopically labeled derivative thereof.

[0074]

[0050] In some embodiments of Formula (I), one instance of X is hydrogen and two instances of X are fluorine to provide a difluoromethylated compound of Formula (I-b): or a pharmaceutically acceptable salt or isotopically labeled derivatives thereof.

[0051] Additional embodiments are further described below and herein.

[0075] (a) R1, R1A, -CX3, andX

[0076]

[0052] As generally described herein, R1is C3-4 carbocyclyl or 3-4 membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is substituted with 0, 1, 2, or 3 instances of R1A.

[0077]

[0053] As generally described herein, each instance of R1Ais independently C1-3 alkyl, C1-3 haloalkyl, halogen, or -OR', or two R1Agroups attached to the same carbon atom are joined to form a C3-6 carbocyclyl or 3-6 membered heterocyclyl, or two R1Agroups attached to vicinal atoms are joined to form a C3-6 carbocyclyl or 3-6 membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is substituted with 0, 1, 2, or 3 substituents independently selected from C1-3 alkyl, C1-3 haloalkyl, halogen, -C(=O)OR', and -OR'.

[0078]

[0054] In some embodiments, each instance of R1Ais independently C1-3 alkyl, C1-3 haloalkyl, halogen, or -OR', or two R1Agroups attached to the same carbon atom are joined to form a C3-5 carbocyclyl or 3-5 membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is substituted with 0, 1, 2, or 3 substituents independently selected from C1-3 alkyl, C1-3 haloalkyl, halogen, and -OR'.

[0079]

[0055] In some embodiments, R1is C3-4 carbocyclyl or 3-4 membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is substituted with 0, 1, 2, or 3 instances of R1A, and wherein each instance of R1Ais independently C1-3 alkyl, C1-3 haloalkyl, halogen, or -OR', or two R1Agroups attached to the same carbon atom are joined to form a C3-6 carbocyclyl or 3-6 membered heterocyclyl, or two R1Agroups attached to vicinal atoms are joined to form a C3-6 carbocyclyl or 3-6 membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is substituted with 0, 1, 2, or 3 substituents independently selected from C1-3 alkyl, C1-3 haloalkyl, halogen, -C(=O)OR', and -OR'.

[0080]

[0056] In some embodiments, R1is C3-4 carbocyclyl or 3-4 membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is substituted with 0, 1, 2, or 3 instances of R1A, and wherein each instance of R1Ais independently C1-3 alkyl, C1-3 haloalkyl, halogen, or -OR', or two R1Agroups attached to the same carbon atom are joined to form a C3-5 carbocyclyl or 3-5 membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is substituted with 0, 1, 2, or 3 substituents independently selected from C1-3 alkyl, C1-3 haloalkyl, halogen, and -OR'.

[0081]

[0057] In some embodiments, R1is C3-4 carbocyclyl substituted with 0, 1, 2, or 3 instances of R1A. In some embodiments, R1is C3-4 carbocyclyl substituted with 2 instances of R1A. In some embodiments, R1is C3-4 carbocyclyl substituted with 0 or 1 instances of R1A. In some embodiments, R1is C3-4 carbocyclyl substituted with 0 instances of R1A. In some embodiments, R1is C3-4 carbocyclyl substituted with 1, 2, or 3 instances of R1A.

[0082]

[0058] In some embodiments, R1is C3-4 carbocyclyl substituted with 1, 2, or 3 instances of R1A, wherein each instance of R1Ais independently halogen. In some embodiments, R1is C3-4 carbocyclyl substituted with 1, 2, or 3 instances of R1A, wherein each instance of R1Ais independently selected from the group consisting of -F, -Cl, and -Br. In some embodiments, R1is C3-4 carbocyclyl substituted with 1, 2, or 3 instances of R1A, wherein each instance of R1Ais independently -F.

[0083]

[0059] In some embodiments, R1is C3 carbocyclyl (cyclopropyl) substituted with 0, 1, 2, or 3 instances of R1A. In some embodiments, R1is C3 carbocyclyl substituted with 0 or 1 instances of R1A. In some embodiments, R1is C3 carbocyclyl substituted with 0 instances of R1A. In some embodiments, R1is C3 carbocyclyl substituted with 1, 2, or 3 instances of R1A.

[0084]

[0060] In some embodiments, R1is C3 carbocyclyl substituted with 1, 2, or 3 instances of R1A, wherein each instance of R1Ais independently halogen. In some embodiments, R1is C3 carbocyclyl substituted with 1, 2, or 3 instances of R1A, wherein each instance of R1Ais independently selected from the group consisting of -F, -Cl, and -Br. In some embodiments, R1is C3 carbocyclyl substituted with 1, 2, or 3 instances of R1A, wherein each instance of R1Ais independently -F.

[0061] In some embodiments, R1is cyclopropyl substituted with 0, 1, 2, or 3 instances of R1A, preferably wherein R1Ais absent (0 instances of R1A) or is -F (1, 2, or 3 instances of R1A).

[0085]

[0062] In some embodiments, R1is cyclopropyl substituted with 2 instances of R1A, wherein two R1Agroups attached to the same carbon atom are joined to form a 3-6 membered heterocyclyl substituted with 0 or 1 substituents independently selected from C1-3 alkyl and C1-3 haloalkyl.

[0086] (R|2A

[0087]

[0063] In some embodiments, R1is of the formula: V (y-1), wherein n is 0, 1, 2, or 3.

[0088]

[0064] In some embodiments, R1is of formula (y-1), wherein n is 0.

[0089]

[0065] In some embodiments, R1is of formula (y-1), wherein n is 1, 2, or 3. In some embodiments, R1is of formula (y-1), wherein n is 1, 2, or 3, and each instance of R1Ais independently halogen. In some embodiments, R1is of formula (y-1), wherein n is 1, 2, or 3, and each instance of R1Ais independently - F.

[0090]

[0066] In some embodiments, R1is of formula (y-1), wherein n is 1, and R1Ais halogen. In some embodiments, R1is of formula (y-1), wherein n is 1, and R1Ais -F.

[0091]

[0067] In some embodiments, R1is of formula (y-1), wherein n is 2, and two R1Agroups attached to the same carbon atom are joined to form a C3-5 carbocyclyl or 3-5 membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is substituted with 0, 1, 2, or 3 substituents independently selected from C1-3 alkyl, C1-3 haloalkyl, halogen, and -OR'. In some embodiments, R1is of formula (y-1), wherein n is 2, and two R1Agroups attached to the same carbon atom are joined to form a C3-5 carbocyclyl or 3-5 membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is substituted with 0 or 1 substituents independently selected from C1-3 alkyl and C1-3 haloalkyl.

[0092]

[0068] In some embodiments, R1is of the formula:

[0093]

[0094]

[0070] In some embodiments, R1is C4 carbocyclyl substituted with 0, 1, 2, or 3 instances of R1A. In some embodiments, R1is C4 carbocyclyl substituted with 0 instances of R1A. In some embodiments, R1is C4 carbocyclyl substituted with 1, 2, or 3 instances of R1A.

[0095]

[0071] In some embodiments, R1is 3-4 membered heterocyclyl substituted with 0, 1, 2, or 3 instances of R1A. In some embodiments, R1is 3-4 membered heterocyclyl substituted with 0 instances of R1A. In some embodiments, R1is 3-4 membered heterocyclyl substituted with 1, 2, or 3 instances of R1A.

[0096]

[0072] In some embodiments, at least one instance of R1Ais C1-3 alkyl.

[0097]

[0073] In some embodiments, at least one instance of R1Ais C1-3 haloalkyl.

[0074] In some embodiments, at least one instance of R1Ais halogen. In some embodiments, at least two instances of R1Aare independently halogen. In some embodiments, at least three instances of R1Aare independently halogen.

[0098]

[0075] In some embodiments, at least one instance of R1Ais selected from the group consisting of -F, -Cl, and -Br. In some embodiments, at least one instance of R1Ais -F. In some embodiments, at least two instances of R1Aare independently -F. In some embodiments, at least three instances of R1Aare independently -F.

[0099]

[0076] In some embodiments, at least one instance of R1Ais -OR'.

[0100]

[0077] In some embodiments, two R1Agroups attached to the same carbon atom are joined to form a C3-6 carbocyclyl substituted with 0, 1, 2, or 3 substituents independently selected from C1-3 alkyl, C1-3 haloalkyl, halogen, -C(=O)OR', and -OR'. In some embodiments, two R1Agroups attached to the same carbon atom are joined to form unsubstituted C3-6 carbocyclyl.

[0101]

[0078] In some embodiments, two R1Agroups attached to the same carbon atom are joined to form a C3-5 carbocyclyl substituted with 0, 1, 2, or 3 substituents independently selected from C1-3 alkyl, C1-3 haloalkyl, halogen, and -OR'. In some embodiments, two R1Agroups attached to the same carbon atom are joined to form unsubstituted C3-5 carbocyclyl. In some embodiments, two R1Agroups attached to the same carbon atom are joined to form unsubstituted C3 carbocyclyl (cyclopropyl).

[0102]

[0079] In some embodiments, two R1Agroups attached to the same carbon atom are joined to form a 3-6 membered heterocyclyl substituted with 0, 1, 2, or 3 substituents independently selected from C1-3 alkyl, C1-3 haloalkyl, halogen, -C(=O)OR', and -OR'. In some embodiments, two R1Agroups attached to the same carbon atom are joined to form unsubstituted 3-6 membered heterocyclyl.

[0103]

[0080] In some embodiments, two R1Agroups attached to the same carbon atom are joined to form a 3-5 membered heterocyclyl substituted with 0, 1, 2, or 3 substituents independently selected from C1-3 alkyl, C1-3 haloalkyl, halogen, and -OR'. In some embodiments, two R1Agroups attached to the same carbon atom are joined to form unsubstituted 3-5 membered heterocyclyl.

[0104]

[0081] In some embodiments, two R1Agroups attached to the same carbon atom are joined to form a 3-6 membered heterocyclyl substituted with 0 or 1 substituents independently selected from C1-3 alkyl and C1-3 haloalkyl. In some embodiments, two R1Agroups attached to the same carbon atom are joined to form a 3-5 membered heterocyclyl substituted with 0 or 1 substituents independently selected from C1-3 alkyl and C1-3 haloalkyl. In some embodiments, two R1Agroups attached to the same carbon atom are joined to form some embodiments, two R1Agroups attached to the same carbon atom are joined to form

[0105]

[0082] In some embodiments, two R1Agroups attached to the same carbon atom are joined to form odiments, two R1groups attached to the same carbon atom are joined to form

[0106]

[0083] In some embodiments, two R1Agroups attached to the same carbon atom are joined to form

[0107]

[0084] In some embodiments, two R1Agroups attached to vicinal atoms are joined to form a C3-6 carbocyclyl substituted with 0, 1, 2, or 3 substituents independently selected from C1-3 alkyl, C1-3 haloalkyl, halogen, -C(=O)OR', and -OR'. In some embodiments, two R1Agroups attached to vicinal atoms are joined to form unsubstituted C3-6 carbocyclyl.

[0108]

[0085] In some embodiments, two R1Agroups attached to vicinal atoms are joined to form a 3-6 membered heterocyclyl substituted with 0, 1, 2, or 3 substituents independently selected from C1-3 alkyl, C1-3 haloalkyl, halogen, -C(=O)OR', and -OR'. In some embodiments, two R1Agroups attached to vicinal atoms are joined to form unsubstituted 3-6 membered heterocyclyl.

[0109] [086 J In some embodiments, two R1Agroups attached to vicinal atoms are joined to form:

[0110]

[0087] As generally described herein, each X is independently selected from H and halogen.

[0111]

[0088] In some embodiments, each X is independently selected from the group consisting of H, -F, -Cl, and -Br. In some embodiments, each X is independently selected from the group consisting of H and -F.

[0089] In some embodiments, at least one X is H. In some embodiments, at least two X are H.

[0112]

[0090] In some embodiments, -CX3 is -CH3.

[0113]

[0091] In some embodiments, at least one X is halogen. In some embodiments, at least two X are halogen. In some embodiments, each X is halogen. In some embodiments, one or two X are halogen.

[0092] In some embodiments, at least one X is selected from the group consisting of -F, -Cl, and -Br.

[0093] In some embodiments, at least one X is -F. In some embodiments, at least two X are -F. In some embodiments, each X is -F.

[0114]

[0094] In some embodiments, -CX3 is -CH3, -CHF2 or -CH2F.

[0115]

[0095] In some embodiments, -CX3 is -CH3 or -CHF2.

[0116]

[0096] In some embodiments, -CX3 is -CF3.

[0117] [097J In some embodiments, -CX3 is -CHF2 or -CH2F. In some embodiments, -CX3 is -CHF2. In some embodiments, -CX3 is -CH2F.

[0118] (b) G1, G2, Rai, and Ra2

[0119]

[0098] As generally described herein, G1is CRG1or N and G2is CRG2or N; wherein each of RG1and RG2is independently selected from H, halogen, C1-6 alkyl, Ci-6 haloalkyl, and -(Li)-O-(CH2CH2O)m-R', wherein Li is absent, C1-3 alkylene, or C1-3 haloalkylene, and wherein m is 0, 1 or 2.

[0120]

[0099] In some embodiments, G1is CRG1and G2is CRG2, wherein each of RG1and RG2is independently selected from H, halogen, C1-6 alkyl, C1-6 haloalkyl, and -(Li)-O-(CH2CH2O)m-R', wherein Li is absent, C1-3 alkylene, or C1-3 haloalkylene, and wherein m is 0, 1 or 2.

[0121]

[0100] In some embodiments, G1is CRG1and G2is CRG2, wherein each of RG1and RG2is independently selected from H, -F, -CHF2, and -OCH3.

[0122]

[0101] In some embodiments, G1is CRG1and G2is CRG2, wherein each of RG1and RG2is independently selected from H and halogen. In some embodiments, G1is CRG1and G2is CRG2, wherein each of RG1and RG2is independently selected from H and -F.

[0123]

[0102] In some embodiments, G1is CRG1and G2is CRG2, wherein each of RG1and RG2is independently selected from H and C1-6 alkyl.

[0124]

[0103] In some embodiments, G1is CRG1and G2is CRG2, wherein each of RG1and RG2is independently selected from H and C1-6 haloalkyl. In some embodiments, G1is CRG1and G2is CRG2, wherein each of RG1and RG2is independently selected from H and C1-3 haloalkyl. In some embodiments, G1is CRG1and G2is CRG2, wherein each of RG1and RG2is independently selected from H and -CHF2.

[0125]

[0104] In some embodiments, G1is CRG1and G2is CRG2, wherein each of RG1and RG2is independently selected from H and -(Li)-O-(CH2CH2O)m-R', wherein Li is absent, C1-3 alkylene, or C1-3 haloalkylene, and wherein m is 0, 1 or 2. In some embodiments, G1is CRG1and G2is CRG2, wherein each of RG1and RG2is independently selected from H and -OR'. In some embodiments, G1is CRG1and G2is CRG2, wherein each of RG1and RG2is independently selected from H and -OCH3.

[0126]

[0105] In some embodiments, G1is N.

[0127]

[0106] In some embodiments, G1is CRG1, wherein RG1is selected from H, halogen, C1-6 alkyl, C1-6 haloalkyl, and -(Li)-O-(CH2CH2O)m-R', wherein Li is absent, C1-3 alkylene, or C1-3 haloalkylene, and wherein m is 0, 1 or 2.

[0128]

[0107] In some embodiments, G1is CRG1, wherein RG1is independently selected from H, -F, -CHF2, and -OCH3.

[0129]

[0108] In some embodiments, G1is CH.

[0130]

[0109] In some embodiments, G1is CRG1, wherein RG1is halogen. In some embodiments, G1is CF.

[0131]

[0110] In some embodiments, G1is CRG1, wherein RG1is C1-6 alkyl.

[0132]

[0111] In some embodiments, G1is CRG1, wherein RG1is C1-6 haloalkyl. In some embodiments, G1is -

[0133] C(CHF2).

[0134]

[0112] In some embodiments, G1is CRG1, wherein RG1is -(Li)-O-(CH2CH2O)m-R', wherein Li is absent, C1-3 alkylene, or C1-3 haloalkylene, and wherein m is 0, 1 or 2. In some embodiments, G1is CRG1, wherein RG1is -OR'. In some embodiments, G1is -(OCH3) .

[0135]

[0113] In some embodiments, G2is N.

[0136]

[0114] In some embodiments, G2is CRG2, wherein RG2is selected from H, halogen, C1-6 alkyl, C1-6 haloalkyl, and -(Li)-O-(CH2CH2O)m-R', wherein Li is absent, C1-3 alkylene, or C1-3 haloalkylene, and wherein m is 0, 1 or 2.

[0137]

[0115] In some embodiments, G2is CRG2, wherein RG2is independently selected from H, -F, -CHF2, and -OCH3.

[0138]

[0116] In some embodiments, G2is CH.

[0139]

[0117] In some embodiments, G2is CRG2, wherein RG2is halogen. In some embodiments, G2is CF.

[0140]

[0118] In some embodiments, G2is CRG2, wherein RG2is C1-6 alkyl.

[0141]

[0119] In some embodiments, G2is CRG2, wherein RG2is C1-6 haloalkyl. In some embodiments, G1is -

[0142] C(CHF2).

[0143]

[0120] In some embodiments, G2is CRG2, wherein RG2is -(Li)-O-(CH2CH2O)m-R', wherein Li is absent, C1-3 alkylene, or C1-3 haloalkylene, and wherein m is 0, 1 or 2. In some embodiments, G2is CRG2, wherein RG2is -OR'. In some embodiments, G2is -C(OCH3).

[0144]

[0121] As generally described herein, each of RG1and RG2is independently selected from H, halogen, Ci- e alkyl, C1-6 haloalkyl, and -(Li)-O-(CH2CH2O)m-R', wherein Li is absent, C1-3 alkylene, or C1-3 haloalkylene, and wherein m is 0, 1 or 2.

[0145]

[0122] In some embodiments, at least one of RG1and RG2is H.

[0146]

[0123] In some embodiments, at least one of RG1and RG2is halogen. In some embodiments, at least one of RG1and RG2is -F.

[0147]

[0124] In some embodiments, at least one of RG1and RG2is C1-6 alkyl.

[0148]

[0125] In some embodiments, at least one of RG1and RG2is C1-6 haloalkyl. In some embodiments, at least one of RG1and RG2is C1-3 haloalkyl. In some embodiments, at least one of RG1and RG2is -CHF2.

[0149]

[0126] In some embodiments, at least one of RG1and RG2is -(Li)-O-(CH2CH2O)m-R', wherein Li is absent, C1-3 alkylene, or C1-3 haloalkylene, and wherein m is 0, 1 or 2. In some embodiments, at least one of RG1and RG2is -O-(CH2CH2O)m-R', wherein m is 0, 1 or 2. In some embodiments, at least one of RG1and RG2is -OR'. In some embodiments, at least one of RG1and RG2is -OCH3.

[0150]

[0127] In some embodiments, at least one of RG1and RG2is H, and at least one of RG1and RG2is selected from H, halogen, C1-3 alkyl, C1-3 haloalkyl, and -OR'.

[0151]

[0128] In some embodiments, at least one of RG1and RG2is H, and at least one of RG1and RG2is selected from H, -F, -CHF2, and -OCH3.

[0152]

[0129] In some embodiments, each of RG1and RG2is independently H.

[0153]

[0130] In some embodiments, at least one of RG1and RG2is H, and at least one of RG1and RG2is halogen. In some embodiments, at least one of RG1and RG2is H, and at least one of RG1and RG2is -F.

[0154]

[0131] In some embodiments, at least one of RG1and RG2is H, and at least one of RG1and RG2is C1-3 alkyl.

[0155]

[0132] In some embodiments, at least one of RG1and RG2is H, and at least one of RG1and RG2is C1-3 haloalkyl. In some embodiments, at least one of RG1and RG2is H, and at least one of RG1and RG2is -CHF2.

[0156]

[0133] In some embodiments, at least one of RG1and RG2is H, and at least one of RG1and RG2is -OR'. In some embodiments, at least one of RG1and RG2is H, and at least one of RG1and RG2is -OCH3.

[0157]

[0134] In some embodiments, RG1is selected from H, halogen, C1-3 alkyl, C1-3 haloalkyl, and -OR'.

[0158]

[0135] In some embodiments, RG1is selected from H, -F, -CHF2, and -OCH3.

[0159]

[0136] In some embodiments, RG1is H.

[0160]

[0137] In some embodiments, RG1is halogen. In some embodiments, RG1is -F.

[0161]

[0138] In some embodiments, RG1is C1-6 alkyl.

[0162]

[0139] In some embodiments, RG1is C1-6 haloalkyl. In some embodiments, RG1is C1-3 haloalkyl. In some embodiments, RG1is -CHF2.

[0163]

[0140] In some embodiments, RG1is -(Li)-O-(CH2CH2O)m-R', wherein Li is absent, C1-3 alkylene, or C1-3 haloalkylene, and wherein m is 0, 1 or 2. In some embodiments, RG1is -OR'. In some embodiments, RG1is -OCH3.

[0164]

[0141] In some embodiments, RG2is selected from H, halogen, C1-3 alkyl, C1-3 haloalkyl, and -OR'.

[0165]

[0142] In some embodiments, RG2is selected from H, -F, -CHF2, and -OCH3.

[0166]

[0143] In some embodiments, RG2is H.

[0167]

[0144] In some embodiments, RG2is halogen. In some embodiments, RG2is -F.

[0168]

[0145] In some embodiments, RG2is C1-6 alkyl.

[0169]

[0146] In some embodiments, RG2is C1-6 haloalkyl. In some embodiments, RG2is C1-3 haloalkyl. In some embodiments, RG2is -CHF2.

[0170]

[0147] In some embodiments, RG2is -(Li)-O-(CH2CH2O)m-R', wherein Li is absent, C1-3 alkylene, or C1-3 haloalkylene, and wherein m is 0, 1 or 2. In some embodiments, RG2is -OR'. In some embodiments, RG2is -OCH3.

[0171]

[0148] As generally described herein, Li is absent, C1-3 alkylene, or C1-3 haloalkylene. In some embodiments, Li is absent. In some embodiments, Li is C1-3 alkylene. In some embodiments, Li is C1-3 haloalkylene.

[0172]

[0149] As generally described herein, m is 0, 1 or 2. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2.

[0173] (c) G3, G4, R3, R4, RA. RB, and Rc

[0174]

[0150] As generally described herein, G3is N or CR3and G4is N or CR4, provided at least one of G3and G4is CR3or CR4, respectively, and at least one of said R3and R4is not H;

[0175] R3and R4are each independently H, halogen, C1-6 alkyl, C1-6 haloalkyl, -(L2)-(Y)-C3-10 carbocyclyl, -(L2)-(Y)-(4-10 membered heterocyclyl), -(L2)-(Y)-C6-10 aryl, -(L2)-(Y)-(5-10 membered heteroaryl), -(L2)-ORA, -(L2)-N(RA)2, -(L2)-SRA, -(L2)-CN, -(L2)-(Y)-C(=O)RA, -(L2)-(Y)-C(=O)ORA, - (L2)-(Y)-C(=O)N(RA)2, -(L2)-S(=O)2RA, -(L2)-S(=O)2ORA, -(L2)-(Y)-S(=O)2N(RA)2, or -B(ORA)2, wherein L2is absent, C1-3 alkylene, or C1-3 haloalkylene; Y is absent, -O-, or -N(RA)-; and each alkyl, haloalkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, alkylene, or haloalkylene is independently substituted with 0, 1, 2, or 3 instances of RB; each instance of RAis independently H, C1-6 alkyl, Ci-6 haloalkyl, -(L3)-(Z)-C3-10 carbocyclyl, - (Ls)-(Z)-(3-10 membered heterocyclyl), -(LsXZj-C6-10 aryl, or -(Ls)-(Z)-(5-10 membered heteroaryl), or two RAgroups attached to the same nitrogen or two RAgroups (i) attached to the same nitrogen atom or (ii) attached to two oxygen atoms which are attached to the same boron atom are joined to form a 4-6 membered heterocyclyl; wherein Ls is absent, C1-3 alkylene, or C1-3 haloalkylene; Z is absent or -O-; and each alkyl, haloalkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, alkylene, or haloalkylene is independently substituted with 0, 1, 2, or 3 instances of RB; each instance of RBis independently halogen, C1-6 alkyl, C1-6 haloalkyl, C3-10 carbocyclyl, 4-6 membered heterocyclyl, -CN, -OR', -N(R')2, -SR', -C(=O)R', -C(=O)OR', or -C(=O)N(R')2, or two RBattached to the same carbon atom are taken together to form =0; wherein each alkyl and haloalkyl is independently substituted with 0 or 1 =0 and independently substituted with 0, 1, 2, or 3 -OR'; and each carbocyclyl and heterocyclyl is independently substituted with 0, 1, 2, or 3 instances of Rc; each instance of Rcis independently halogen, C1-6 alkyl, C1-6 haloalkyl, or -OR', or two Rcattached to the same carbon atom are taken together to form =0.

[0176]

[0151] In some embodiments, G3is N or CR3and G4is CR4. In some embodiments, G3is N or CH and G4is CR4. In some embodiments, G3is CH and G4is CR4.

[0177]

[0152] In some embodiments, G3is CR3and G4is N or CR4. In some embodiments, G3is CR3and G4is N or CH. In some embodiments, G3is CR3and G4is CH. In some embodiments, G3is CR3and G4is CR4wherein R3is not H or halogen and R4is halogen (e.g., fluoro). In some embodiments, G3is CR3and G4is CR4wherein R4is not H or halogen and R3is halogen (e.g., fluoro).

[0178]

[0153] In some embodiments, G3is CR3and G4is CR4.

[0179]

[0154] As generally described herein, at least one of R3and R4is not H.

[0180]

[0155] In some embodiments, at least one of R3or R4is C1-6 alkyl, C1-6 haloalkyl, -(L2)-(Y)-C3-10 carbocyclyl, -(L2)-(Y)-(4-10 membered heterocyclyl), -(L2)-(Y)-C6-10 aryl, -(L2)-(Y)-(5-10 membered heteroaryl), -(L2)-ORA, -(L2)-C(=O)ORA, or -B(ORA)2, wherein L2is absent, C1-3 alkylene, or C1-3 haloalkylene; and wherein each alkyl, haloalkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, alkylene, or haloalkylene is independently substituted with 0, 1, or 2 instances of RB. In some embodiments, at least one of R3or R4is C1-6 alkyl, C1-6 haloalkyl, -(L2)-(Y)-C3-10 carbocyclyl, -(L2)-(Y)-(4-10 membered heterocyclyl), -(L2)-(Y)-C6-10 aryl, -(L2)-(Y)-(5-10 membered heteroaryl), -(L2)-ORA, -(L2)-C(=O)ORA, or -B(ORA)2, wherein L2is absent, C1-3 alkylene, or C1-3 haloalkylene; and wherein each alkyl, haloalkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, alkylene, or haloalkylene is independently substituted with 0 or 1 instances of RB. In some embodiments, Y is absent or -O-. In some embodiments, Y is absent. In some embodiments, Y is O.

[0181]

[0156] In some embodiments, at least one of R3or R4is C1-6 alkyl, -(L2)-(Y)-C3-10 carbocyclyl, -(L2)-(Y)- (4-10 membered heterocyclyl), -(L2)-(Y)-(5-10 membered heteroaryl), -(L2)-ORA, -(L2)-C(=O)ORA, or - B(ORA)2, wherein L2is absent, C1-3 alkylene, or C1-3 haloalkylene; and wherein each alkyl, carbocyclyl, heterocyclyl, heteroaryl, alkylene, or haloalkylene is independently substituted with 0, 1, or 2 instances of RB. In some embodiments, at least one of R3or R4is C1-6 alkyl, -(L2)-(Y)-C3-10 carbocyclyl, -(L2)-(Y)- (4-10 membered heterocyclyl), -(L2)-(Y)-(5-10 membered heteroaryl), -(L2)-ORA, -(L2)-C(=O)ORA, or - B(ORA)2, wherein L2 is absent, C1-3 alkylene, or C1-3 haloalkylene; and wherein each alkyl, carbocyclyl, heterocyclyl, heteroaryl, alkylene, or haloalkylene is independently substituted with 0 or 1 instances of RB. In some embodiments, Y is absent or -O-. In some embodiments, Y is absent. In some embodiments, Y is O.

[0182]

[0157] In some embodiments, at least one of R3or R4is C1-3 alkyl, -(Y)-C4-e carbocyclyl, -(Y)-4-7 membered monocyclic heterocyclyl, -(Y)-6-10 membered bridged heterocyclyl, -(Y)-7-10 membered spirocyclic heterocyclyl, -(Y)-5-6 membered heteroaryl, -(C1-3 alkylene)-ORA, -ORA, -C(=O)ORA, or - B(ORA)2, wherein each alkyl, carbocyclyl, heterocyclyl, heteroaryl, or alkylene is independently substituted with 0, 1, or 2 instances of RB. In some embodiments, at least one of R3or R4is C1-3 alkyl, - (Y)-C4-6 carbocyclyl, -(Y)-4-7 membered monocyclic heterocyclyl, -(Y)-6-10 membered bridged heterocyclyl, -(Y)-7-10 membered spirocyclic heterocyclyl, -(Y)-5-6 membered heteroaryl, -(C1-3 alkylene) -ORA, -ORA, -C(=O)ORA, or -B(ORA)2, wherein each alkyl, carbocyclyl, heterocyclyl, heteroaryl, or alkylene is independently substituted with 0 or 1 instances of RB. In some embodiments, Y is absent. In some embodiments, Y is O.

[0183]

[0158] In some embodiments, at least one of R3or R4is C1-3 alkyl, -(Y)-4-7 membered monocyclic heterocyclyl, -(Y)-6-10 membered bridged heterocyclyl, -(Y)-7-10 membered spirocyclic heterocyclyl, - (Y)-5-6 membered heteroaryl, or -(C1-3 alkylene) -ORA, wherein each alkyl, heterocyclyl, heteroaryl, or alkylene is independently substituted with 0, 1, or 2 instances of RB. In some embodiments, at least one of R3or R4is C1-3 alkyl, -(Y)-4-7 membered monocyclic heterocyclyl, -(Y)-6-10 membered bridged heterocyclyl, -(Y)-7-10 membered spirocyclic heterocyclyl, -(Y)-5-6 membered heteroaryl, or -(C1-3 alkylene) -ORA, wherein each alkyl, heterocyclyl, heteroaryl, or alkylene is independently substituted with 0 or 1 instances of RB. In some embodiments, Y is absent. In some embodiments, Y is O.

[0184]

[0159] In some embodiments, at least one of R3and R4is H, and the other is not H.

[0185]

[0160] In some embodiments, at least one of R3and R4is halogen. In some embodiments, at least one of R3and R4is chloro.

[0186]

[0161] In some embodiments, at least one of R3and R4is C1-6 alkyl substituted with 0, 1, 2, or 3 instances of RB. In some embodiments, at least one of R3and R4is C1-6 alkyl substituted with 0 or 1 instances of RB.

[0187]

[0162] In some embodiments, at least one of R3and R4is C1-3 alkyl substituted with 0, 1, 2, or 3 instances of RB. In some embodiments, at least one of R3and R4is C1-3 alkyl substituted with 0 or 1 instances of RB. In some embodiments, at least one of R3and R4is C1-3 alkyl substituted with 0 or 1 instances of RB, wherein each instance of RBis independently halogen or -OR'.

[0188]

[0163] In some embodiments, at least one of R3and R4is C1-3 alkyl substituted with 0 or 1 instances of - OR', wherein R' is H, C1-6 alkyl, or C1-6 haloalkyl, and wherein the alkyl or haloalkyl is substituted with 0, 1, 2, or 3 R".

[0164] In some embodiments, at least one of R3and R4is C1-3 alkyl substituted with 0 or 1 instances of - OR', wherein R' is H, C1-3 alkyl, or C1-3 haloalkyl, and wherein the alkyl or haloalkyl is substituted with 0 or 1 R".

[0189]

[0165] In some embodiments, at least one of R3and R4is C1-3 alkyl substituted with 0 or 1 instances of - OH or -OCH3.

[0190]

[0166] In some embodiments, at least one of R3and R4is: -OCH3,

[0191]

[0167] In some embodiments, at least one of R3and R4is: -OCH3,

[0192]

[0168] In some embodiments, at least one of R3and R4is C1-6 haloalkyl substituted with 0, 1, 2, or 3 instances of RB. In some embodiments, at least one of R3and R4is C1-6 haloalkyl substituted with 0 or 1 instances of RB.

[0193]

[0169] In some embodiments, at least one of R3and R4is C1-3 haloalkyl substituted with 0, 1, 2, or 3 instances of RB. In some embodiments, at least one of R3and R4is C1-3 haloalkyl substituted with 0 or 1 instances of RB.

[0194]

[0170] In some embodiments, at least one of R3and R4is -(L2)-(Y)-C3-10 carbocyclyl, wherein L2 is absent, C1-3 alkylene, or C1-3 haloalkylene; Y is absent, -O-, or -N(RA)-; and each carbocyclyl, alkylene, or haloalkylene is independently substituted with 0, 1, 2, or 3 instances of RB. In some embodiments, at least one of R3and R4is -(L2)-(Y)-C 3-10 carbocyclyl, wherein L2 is absent, C1-3 alkylene, or C1-3 haloalkylene; Y is absent, -O-, or -N(RA)-; and each carbocyclyl, alkylene, or haloalkylene is independently substituted with 0 or 1 instances of RB. In some embodiments, Y is absent. In some embodiments, Y is O.

[0195]

[0171] In some embodiments, at least one of R3and R4is -(L2)-(Y)-C4-e carbocyclyl, wherein L2 is absent, C1-3 alkylene, or C1-3 haloalkylene; Y is absent, -O-, or -N(RA)-; and each carbocyclyl, alkylene, or haloalkylene is independently substituted with 0, 1, 2, or 3 instances of RB. In some embodiments, at least one of R3and R4is -(L2)-(Y)-C4-e carbocyclyl, wherein L2 is absent, C1-3 alkylene, or C1-3 haloalkylene; Y is absent, -O-, or -N(RA)-; and each carbocyclyl, alkylene, or haloalkylene is independently substituted with 0 or 1 instances of RB. In some embodiments, Y is absent. In some embodiments, Y is O.

[0196]

[0172] In some embodiments, at least one of R3and R4is -(Y)-C3-10 carbocyclyl, wherein Y is absent, - O-, or -N(RA)-; and the carbocyclyl is substituted with 0, 1, 2, or 3 instances of RB. In some embodiments, at least one of R3and R4is -(Y)-C3-10 carbocyclyl, wherein Y is absent, -O-, or -N(RA)-; and the carbocyclyl is substituted with 0 or 1 instances of RB. In some embodiments, Y is absent. In some embodiments, Y is O.

[0173] In some embodiments, at least one of R3and R4is -(Y)-C4-6 carbocyclyl, wherein Y is absent, -O-, or -N(RA)-; and the carbocyclyl is substituted with 0, 1, 2, or 3 instances of RB. In some embodiments, at least one of R3and R4is -(Y)- C4-6 carbocyclyl, wherein Y is absent, -O-, or -N(RA)-; and the carbocyclyl is substituted with 0 or 1 instances of RB. In some embodiments, Y is absent. In some embodiments, Y is O.

[0197]

[0174] In some embodiments, at least one of R3and R4is C3-10 carbocyclyl substituted with 0 or 1 instances of RB.

[0198]

[0175] In some embodiments, at least one of R3and R4is C4-6 carbocyclyl substituted with 0 or 1 instances of RB. In some embodiments, at least one of R3and R4is C4-6 carbocyclyl substituted with 0 or 1 instances of -OH.

[0199]

[0176] In some embodiments, at least one of R3and R4is of the formula: wherein z is

[0200] 0, 1, 2, or 3. In some embodiments, Y is absent. In some embodiments, Y is O. rV-on

[0201]

[0177] In some embodiments, at least one of R3and R4is:

[0202]

[0178] In some embodiments, at least one of R3and R4is -(L2)-(Y)-(4-10 membered heterocyclyl), wherein L2 is absent, C1-3 alkylene, or C1-3 haloalkylene; Y is absent, -O-, or -N(RA)-; and each heterocyclyl, alkylene, or haloalkylene is independently substituted with 0, 1, 2, or 3 instances of RB. In some embodiments, at least one of R3and R4is -(L2)-(Y)-(4-10 membered heterocyclyl), wherein L2 is absent, C1-3 alkylene, or C1-3 haloalkylene; Y is absent, -O-, or -N(RA)-; and each heterocyclyl, alkylene, or haloalkylene is independently substituted with 0, 1, or 2 instances of RB. In some embodiments, at least one of R3and R4is -(L2)-(Y)-(4-10 membered heterocyclyl), wherein L2 is absent, C1-3 alkylene, or C1-3 haloalkylene; Y is absent, -O-, or -N(RA)-; and each heterocyclyl, alkylene, or haloalkylene is independently substituted with 0 or 1 instances of RB. In some embodiments, Y is absent. In some embodiments, Y is O.

[0203]

[0179] In some embodiments, at least one of R3and R4is -(Y)-(4-10 membered heterocyclyl), wherein Y is absent, -O-, or -N(RA)-; and the heterocyclyl is substituted with 0, 1, 2, or 3 instances of RB. In some embodiments, at least one of R3and R4is -(Y)-(4-10 membered heterocyclyl), wherein Y is absent, -O-, or -N(RA)-; and the heterocyclyl is substituted with 0, 1, or 2 instances of RB. In some embodiments, at least one of R3and R4is -(Y)-(4-10 membered heterocyclyl), wherein Y is absent, -O-, or -N(RA)-; and the heterocyclyl is substituted with 0 or 1 instances of RB. In some embodiments, Y is absent. In some embodiments, Y is O.

[0204]

[0180] In some embodiments, at least one of R3and R4is -(Y)-(4-10 membered heterocyclyl containing 1 or 2 ring heteroatoms independently selected from O and N), wherein Y is absent or -O-; and the heterocyclyl is substituted with 0, 1, 2, or 3 instances of RB. In some embodiments, at least one of R3and R4is -(Y)-(4-10 membered heterocyclyl containing 1 or 2 ring heteroatoms independently selected from O and N), wherein Y is absent or -O-; and the heterocyclyl is substituted with 0, 1, or 2 instances of RB. In some embodiments, at least one of R3and R4is -(Y)-(4-10 membered heterocyclyl containing 1 or 2 ring heteroatoms independently selected from O and N), wherein Y is absent or -O-; and the heterocyclyl is substituted with 0 or 1 instances of RB. In some embodiments, Y is absent. In some embodiments, Y is O.

[0205]

[0181] In some embodiments, at least one of R3and R4is -(L2)-(Y)-(4-6 membered heterocyclyl), wherein L2 is absent, C1-3 alkylene, or C1-3 haloalkylene; Y is absent, -O-, or -N(RA)-; and each heterocyclyl, alkylene, or haloalkylene is independently substituted with 0, 1, 2, or 3 instances of RB. In some embodiments, at least one of R3and R4is -(L2)-(Y)-(4-6 membered heterocyclyl), wherein L2 is absent, C1-3 alkylene, or C1-3 haloalkylene; Y is absent, -O-, or -N(RA)-; and each heterocyclyl, alkylene, or haloalkylene is independently substituted with 0, 1, or 2 instances of RB. In some embodiments, at least one of R3and R4is -(L2)-(Y)-(4-6 membered heterocyclyl), wherein L2 is absent, C1-3 alkylene, or C1-3 haloalkylene; Y is absent, -O-, or -N(RA)-; and each heterocyclyl, alkylene, or haloalkylene is independently substituted with 0 or 1 instances of RB. In some embodiments, Y is absent. In some embodiments, Y is O.

[0206]

[0182] In some embodiments, at least one of R3and R4is -(Y)-(4-6 membered heterocyclyl), wherein Y is absent, -O-, or -N(RA)-; and the heterocyclyl is substituted with 0, 1, 2, or 3 instances of RB. In some embodiments, at least one of R3and R4is -(Y)-(4-6 membered heterocyclyl), wherein Y is absent, -O-, or -N(RA)-; and the heterocyclyl is substituted with 0, 1, or 2 instances of RB. In some embodiments, at least one of R3and R4is -(Y)-(4-6 membered heterocyclyl), wherein Y is absent, -O-, or -N(RA)-; and the heterocyclyl is substituted with 0 or 1 instances of RB. In some embodiments, Y is absent. In some embodiments, Y is O. In some embodiments, Y is -N(RA)-. In some embodiments, Y is -NH- or -N(CH3)-.

[0207]

[0183] In some embodiments, at least one of R3and R4is -(Y)-(4-6 membered heterocyclyl containing 1 or 2 ring heteroatoms independently selected from O and N), wherein Y is absent, -O-, -NH-, or -N(CHs)-; and the heterocyclyl is substituted with 0, 1, 2, or 3 instances of RB. In some embodiments, at least one of R3and R4is -(Y)-(4-6 membered heterocyclyl containing 1 or 2 ring heteroatoms independently selected from O and N), wherein Y is absent, -O-, -NH-, or -N(CH3)-; and the heterocyclyl is substituted with 0 or 1 instances of RB.

[0208]

[0184] In some embodiments, at least one of R3and R4is -(Y)-(4-6 membered heterocyclyl containing 1 or 2 ring heteroatoms independently selected from O and N), wherein Y is absent or -O-; and the heterocyclyl is substituted with 0, 1, 2, or 3 instances of RB. In some embodiments, at least one of R3and R4is -(Y)-(4-6 membered heterocyclyl containing 1 or 2 ring heteroatoms independently selected from O and N), wherein Y is absent or -O-; and the heterocyclyl is substituted with 0, 1, or 2 instances of RB. In some embodiments, at least one of R3and R4is -(Y)-(4-6 membered heterocyclyl containing 1 or 2 ring heteroatoms independently selected from O and N), wherein Y is absent or -O-; and the heterocyclyl is substituted with 0 or 1 instances of RB.

[0185] In some embodiments, at least one of R3and R4is -(Y)-(4-6 membered heterocyclyl containing 1 or 2 ring heteroatoms independently selected from O and N), wherein Y is absent or -O-; and the heterocyclyl is substituted with 0, 1, or 2 instances of halogen, Ci-6 alkyl, or -OR'.

[0209]

[0186] In some embodiments, at least one of R3and R4is -(Y)-(4-7 membered monocyclic heterocyclyl containing 1 or 2 ring heteroatoms independently selected from O and N), wherein Y is absent or -O-; and the heterocyclyl is substituted with 0, 1, or 2 instances of halogen, Ci-6 alkyl, -OR', or -C(=O)OR'.

[0210]

[0187] In some embodiments, at least one of R3and R4is -(Y)-(4-6 membered monocyclic heterocyclyl containing 1 or 2 ring heteroatoms independently selected from O and N), wherein Y is absent or -O-; and the heterocyclyl is substituted with 0, 1, or 2 instances of halogen, Ci-6 alkyl, -OR', or -C(=O)OR'.

[0211]

[0188] In some embodiments, at least one of R3and R4is -(Y)-(4-7 membered monocyclic heterocyclyl containing 1 or 2 ring heteroatoms independently selected from O and N), wherein Y is absent or -O-; and the heterocyclyl is substituted with 0 or 1 instances of -OR', wherein each instance of R' is independently H, C1-3 alkyl, or C1-3 haloalkyl; and the alkyl or haloalkyl is substituted with 0, 1, 2, or 3 R". In some embodiments, at least one of R3and R4is -(Y)-( 4-7 membered monocyclic heterocyclyl containing 1 or 2 ring heteroatoms independently selected from O and N), wherein Y is absent or -O-; and the heterocyclyl is substituted with 1 instance of -OH or -OCH3.

[0212]

[0189] In some embodiments, at least one of R3and R4is -(Y)-(4-6 membered monocyclic heterocyclyl containing 1 ring N atom), wherein Y is absent or -O-; and the heterocyclyl is substituted with 0 or 1 instances of RB.

[0213]

[0190] In some embodiments, at least one of R3and R4is -(Y)-(4-6 membered monocyclic heterocyclyl containing 1 ring N atom), wherein Y is absent or -O-; and the heterocyclyl is substituted with 0, 1, or 2 instances of halogen, C1-6 alkyl, -OR', or -C(=O)OR'.

[0214]

[0191] In some embodiments, at least one of R3and R4is -(Y)-(4-6 membered monocyclic heterocyclyl containing 1 ring N atom), wherein Y is absent or -O-; and the heterocyclyl is substituted with 0 or 1 instances of C1-3 alkyl, C1-3 haloalkyl, or -C(=O)OR'.

[0215]

[0192] In some embodiments, at least one of R3and R4is -(Y)-(4-6 membered monocyclic heterocyclyl containing 1 ring N atom), wherein Y is absent or -O-; and the heterocyclyl is substituted with 0 or 1 instances of halogen. In some embodiments, at least one of R3and R4is -(Y)-(4-6 membered monocyclic heterocyclyl containing 1 ring N atom), wherein Y is absent or -O-; and the heterocyclyl is substituted with 1 instance of -F.

[0216]

[0193] In some embodiments, at least one of R3and R4is -(Y)-(4-6 membered monocyclic heterocyclyl containing 1 ring N atom), wherein Y is absent or -O-; and the heterocyclyl is substituted with 0, 1, or 2 instances of C1-3 alkyl. In some embodiments, at least one of R3and R4is -(Y)-(4-6 membered monocyclic heterocyclyl containing 1 ring N atom), wherein Y is absent or -O-; and the heterocyclyl is substituted with 1 or 2 instances of -CH3, -CH2CH3, or -CHiCHY.

[0217]

[0194] In some embodiments, at least one of R3and R4is -(Y)-(4-6 membered monocyclic heterocyclyl containing 1 ring N atom), wherein Y is absent or -O-; and the heterocyclyl is substituted with 0 or 1 instances of -OR', wherein each instance of R' is independently H, C1-3 alkyl, or C1-3 haloalkyl; and the alkyl or haloalkyl is substituted with 0, 1, 2, or 3 R". In some embodiments, at least one of R3and R4is -(Y)-(4-6 membered monocyclic heterocyclyl containing 1 ring N atom), wherein Y is absent or -O-; and the heterocyclyl is substituted with 1 instance of -OH.

[0218]

[0195] In some embodiments, at least one of R3and R4is -(Y)-(4-6 membered monocyclic heterocyclyl containing 1 ring N atom), wherein Y is absent or -O-; and the heterocyclyl is substituted with 0, 1, or 2 instances of -C(=O)OR'. In some embodiments, at least one of R3and R4is -(Y)-(4-6 membered monocyclic heterocyclyl containing 1 ring N atom), wherein Y is absent or -O-; and the heterocyclyl is substituted with 1 instance of -C(=O)O(C(CH3)3).

[0219]

[0196] In some embodiments, at least one of R3and R4is -(Y)-(4-6 membered monocyclic heterocyclyl containing 1 ring O atom), wherein Y is absent, -O-, -NH-, or -N(CH3)-; and the heterocyclyl is substituted with 0, 1, or 2 instances of RB. In some embodiments, at least one of R3and R4is -(Y)-(4-6 membered monocyclic heterocyclyl containing 1 ring O atom), wherein Y is absent, -O-, -NH-, or -N(CH3)-; and the heterocyclyl is substituted with 0 instances of RB.

[0220]

[0197] In some embodiments, at least one of R3and R4is -(Y)-(4-6 membered monocyclic heterocyclyl containing 1 ring O atom), wherein Y is absent or -O-; and the heterocyclyl is substituted with 0, 1, or 2 instances of RB. In some embodiments, at least one of R3and R4is -(Y)-(4-6 membered monocyclic heterocyclyl containing 1 ring O atom), wherein Y is absent or -O-; and the heterocyclyl is substituted with 0 instances of RB.

[0221]

[0198] In some embodiments, at least one of R3and R4is -(Y)-(4-6 membered monocyclic heterocyclyl containing 1 ring O atom), wherein Y is absent or -O-; and the heterocyclyl is substituted with 0, 1, or 2 instances of halogen, Ci-6 alkyl, or -OR', wherein R' is H, Ci-6 alkyl, or Ci-6 haloalkyl; and the alkyl or haloalkyl is substituted with 0, 1, 2, or 3 R".

[0222]

[0199] In some embodiments, at least one of R3and R4is -(Y)-(4-6 membered monocyclic heterocyclyl containing 1 ring O atom), wherein Y is absent or -O-; and the heterocyclyl is substituted with 0 or 1 instances of halogen. In some embodiments, at least one of R3and R4is -(Y)-(4-6 membered monocyclic heterocyclyl containing 1 ring O atom), wherein Y is absent or -O-; and the heterocyclyl is substituted with 1 instance of -F.

[0223]

[0200] In some embodiments, at least one of R3and R4is -(Y)-(4-6 membered monocyclic heterocyclyl containing 1 ring O atom), wherein Y is absent or -O-; and the heterocyclyl is substituted with 0, 1, or 2 instances of C1-3 alkyl. In some embodiments, at least one of R3and R4is -(Y)-(4-6 membered monocyclic heterocyclyl containing 1 ring O atom), wherein Y is absent or -O-; and the heterocyclyl is substituted with 0, 1, or 2 instances of -CH3.

[0224]

[0201] In some embodiments, at least one of R3and R4is -(Y)-(4-6 membered monocyclic heterocyclyl containing 1 ring O atom), wherein Y is absent or -O-; and the heterocyclyl is substituted with 0 or 1 instances of -OR', wherein each instance of R' is independently H, C1-3 alkyl, or C1-3 haloalkyl; and the alkyl or haloalkyl is substituted with 0, 1, 2, or 3 R". In some embodiments, at least one of R3and R4is -(Y)-(4-6 membered monocyclic heterocyclyl containing 1 ring O atom), wherein Y is absent or -O-; and the heterocyclyl is substituted with 1 instance of -OH or -OCH3.

[0202] In some embodiments, at least one of R3and R4is 4-6 membered monocyclic heterocyclyl containing 1 ring O atom substituted with 0, 1, or 2 instances of halogen, Ci-6 alkyl, or -OR', wherein R' is H, Ci-6 alkyl, or Ci-6 haloalkyl.

[0225]

[0203] In some embodiments, at least one of R3and R4is 4-6 membered monocyclic heterocyclyl containing 1 ring O atom substituted with 0, 1, or 2 instances of -F, -CHs, -OH, or -OCHs.

[0226]

[0204] In some embodiments, at least one of R3and R4is -(Y)-(4-6 membered monocyclic heterocyclyl containing 2 ring O atoms), wherein Y is absent or -O-; and the heterocyclyl is substituted with 0 or 1 instances of RB. In some embodiments, at least one of R3and R4is -(Y)-(4-6 membered monocyclic heterocyclyl containing 2 ring O atoms), wherein Y is absent or -O-; and the heterocyclyl is substituted with 0 instances of RB.

[0227]

[0205] In some embodiments, at least one of R3and R4is 4-6 membered monocyclic heterocyclyl containing 2 ring O atoms, wherein the heterocyclyl is substituted with 0 instances of RB.

[0228]

[0206] In some embodiments, at least one of R3and R4is -(Y)-(4-7 membered monocyclic heterocyclyl containing 1 ring N atom and 1 ring O atom), wherein Y is absent or -O-; and the heterocyclyl is substituted with 0, 1, or 2 instances of RB. In some embodiments, at least one of R3and R4is -(Y)-(4-7 membered monocyclic heterocyclyl containing 1 ring N atom and 1 ring O atom), wherein Y is absent or -O-; and the heterocyclyl is substituted with 0 or 1 instances of RB. In some embodiments, at least one of R3and R4is -(Y)-(4-7 membered monocyclic heterocyclyl containing 1 ring N atom and 1 ring O atom), wherein Y is absent or -O-; and the heterocyclyl is substituted with 0 instances of RB.

[0229]

[0207] In some embodiments, at least one of R3and R4is -(Y)-(4-6 membered monocyclic heterocyclyl containing 1 ring N atom and 1 ring O atom), wherein Y is absent or -O-; and the heterocyclyl is substituted with 0, 1, or 2 instances of RB. In some embodiments, at least one of R3and R4is -(Y)-(4-6 membered monocyclic heterocyclyl containing 1 ring N atom and 1 ring O atom), wherein Y is absent or -O-; and the heterocyclyl is substituted with 0 or 1 instances of RB. In some embodiments, at least one of R3and R4is -(Y)-(4-6 membered monocyclic heterocyclyl containing 1 ring N atom and 1 ring O atom), wherein Y is absent or -O-; and the heterocyclyl is substituted with 0 instances of RB.

[0230]

[0208] In some embodiments, at least one of R3and R4is -(Y)-(6-10 membered bridged heterocyclyl containing 1 or 2 ring heteroatoms independently selected from O and N), wherein Y is absent or -O-; and the heterocyclyl is substituted with 0, 1, 2, or 3 instances of RB. In some embodiments, at least one of R3and R4is -(Y)-(6-10 membered bridged heterocyclyl containing 1 or 2 ring heteroatoms independently selected from O and N), wherein Y is absent or -O-; and the heterocyclyl is substituted with 0, 1, or 2 instances of RB. In some embodiments, at least one of R3and R4is -(Y)-(6-10 membered bridged heterocyclyl containing 1 or 2 ring heteroatoms independently selected from O and N), wherein Y is absent or -O-; and the heterocyclyl is substituted with 0 or 1 instances of RB.

[0231]

[0209] In some embodiments, at least one of R3and R4is -(Y)-(6-10 membered bridged heterocyclyl containing 1 or 2 ring heteroatoms independently selected from O and N), wherein Y is absent or -O-; and the heterocyclyl is substituted with 0 instances of RB.

[0210] In some embodiments, at least one of R3and R4is -(Y)-(6-10 membered bridged heterocyclyl containing 1 ring N atom and 1 ring O atom), wherein Y is absent or -O-; and the heterocyclyl is substituted with 0, 1, 2, or 3 instances of RB. In some embodiments, at least one of R3and R4is -(Y)-(6- 10 membered bridged heterocyclyl containing 1 ring N atom and 1 ring O atom), wherein Y is absent or -O-; and the heterocyclyl is substituted with 0, 1, or 2 instances of RB. In some embodiments, at least one of R3and R4is -(Y)-(6-10 membered bridged heterocyclyl containing 1 ring N atom and 1 ring O atom), wherein Y is absent or -O-; and the heterocyclyl is substituted with 0 or 1 instances of RB.

[0232]

[0211] In some embodiments, at least one of R3and R4is -(Y)-(6-10 membered bridged heterocyclyl containing 1 ring N atom and 1 ring O atom), wherein Y is absent or -O-; and the heterocyclyl is substituted with 0 instances of RB.

[0233]

[0212] In some embodiments, at least one of R3and R4is -(Y)-(6-10 membered bridged heterocyclyl containing 1 ring N atom and 1 ring O atom), wherein Y is absent or -O-; and the heterocyclyl is substituted with 0, 1, or 2 instances of halogen, Ci-6 alkyl, -OR', or -C(=O)OR'.

[0234]

[0213] In some embodiments, at least one of R3and R4is -(Y)-(6-10 membered bridged heterocyclyl containing 1 or 2 ring N atoms), wherein Y is absent or -O-; and the heterocyclyl is substituted with 0, 1, or 2 instances of halogen, Ci-6 alkyl, -OR', or -C(=O)OR'.

[0235]

[0214] In some embodiments, at least one of R3and R4is -(Y)-7-10 membered spirocyclic heterocyclyl, wherein Y is absent or -O-; and the heterocyclyl is substituted with 0, 1, 2, or 3 instances of RB. In some embodiments, at least one of R3and R4is -(Y)-7-10 membered spirocyclic heterocyclyl, wherein Y is absent or -O-; and the heterocyclyl is substituted with 0, 1, or 2 instances of RB. In some embodiments, at least one of R3and R4is -(Y)-7-10 membered spirocyclic heterocyclyl, wherein Y is absent or -O-; and the heterocyclyl is substituted with 0 or 1 instances of RB.

[0236]

[0215] In some embodiments, at least one of R3and R4is -(Y)-(7-10 membered spirocyclic heterocyclyl containing 1, 2, or 3 ring heteroatoms independently selected from O and N), wherein Y is absent or - O-; and the heterocyclyl is substituted with 0, 1, 2, or 3 instances of RB. In some embodiments, at least one of R3and R4is -(Y)-(7-10 membered spirocyclic heterocyclyl containing 1, 2, or 3 ring heteroatoms independently selected from O and N), wherein Y is absent or -O-; and the heterocyclyl is substituted with 0, 1, or 2 instances of RB. In some embodiments, at least one of R3and R4is -(Y)-(7-10 membered spirocyclic heterocyclyl containing 1, 2, or 3 ring heteroatoms independently selected from O and N), wherein Y is absent or -O-; and the heterocyclyl is substituted with 0 or 1 instances of RB.

[0237]

[0216] In some embodiments, at least one of R3and R4is -(Y)-(7-10 membered spirocyclic heterocyclyl containing 1 ring N atom and 2 ring O atoms), wherein Y is absent or -O-; and the heterocyclyl is substituted with 0, 1, or 2 instances of RB. In some embodiments, at least one of R3and R4is -(Y)-(7-10 membered spirocyclic heterocyclyl containing 1 ring N atom and 2 ring O atoms), wherein Y is absent or -O-; and the heterocyclyl is substituted with 0 or 1 instances of RB.

[0238]

[0217] In some embodiments, at least one of R3and R4is -(Y)-(7-10 membered spirocyclic heterocyclyl containing 1 ring N atom and 1 ring O atom), wherein Y is absent or -O-; and the heterocyclyl is substituted with 0, 1, or 2 instances of RB. In some embodiments, at least one of R3and R4is -(Y)-(7-10 membered spirocyclic heterocyclyl containing 1 ring N atom and 1 ring O atom), wherein Y is absent or -O-; and the heterocyclyl is substituted with 0 or 1 instances of RB.

[0239]

[0218] In some embodiments, at least one of R3and R4is -(Y)-(7-10 membered spirocyclic heterocyclyl containing 2 ring N atoms), wherein Y is absent or -O-; and the heterocyclyl is substituted with 0, 1, or 2 instances of RB.

[0240]

[0219] In some embodiments, at least one of R3and R4is -(Y)-(7-10 membered spirocyclic heterocyclyl containing 1 ring N atom and 2 ring O atoms), wherein Y is absent or -O-; and the heterocyclyl is substituted with 0, 1, or 2 instances of halogen, Ci-6 alkyl, -OR', or -C(=O)OR'.

[0241]

[0220] In some embodiments, at least one of R3and R4is -(Y)-(7-10 membered spirocyclic heterocyclyl containing 1 ring N atom and 1 ring O atom), wherein Y is absent or -O-; and the heterocyclyl is substituted with 0, 1, or 2 instances of halogen, Ci-6 alkyl, -OR', or -C(=O)OR'.

[0242]

[0221] In some embodiments, at least one of R3and R4is -(Y)-(7-10 membered spirocyclic heterocyclyl containing 2 ring N atoms), wherein Y is absent or -O-; and the heterocyclyl is substituted with 0, 1, or 2 instances of halogen, C1-6 alkyl, -OR', or -C(=O)OR'.

[0243]

[0222] In some embodiments, at least one of R3and R4is 4-6 membered monocyclic heterocyclyl containing 1 ring N atom and 1 ring O atom, wherein the heterocyclyl is substituted with 0 instances of RB

[0244]

[0223] In some embodiments, at least one of R3and R4is 4-6 membered monocyclic heterocyclyl containing 1 ring N atom and 1 ring O atom, wherein the heterocyclyl is substituted with 1 instance of RB

[0245]

[0224] In some embodiments, at least one of R3and R4is 4-6 membered monocyclic heterocyclyl containing 1 ring N atom and 1 ring O atom, wherein the heterocyclyl is substituted with 2 instances of RB

[0246]

[0225] In some embodiments, at least one of R3and R4is 6-10 membered bridged heterocyclyl containing 1 ring N atom and 1 ring O atom, wherein the heterocyclyl is substituted with 0 instances of RB

[0247]

[0226] In some embodiments, at least one of R3and R4is of the formula:

[0248] wherein z is 0, 1, 2, or 3, as valency permits.

[0249]

[0227] In some embodiments, at least one of R3and R4is:

[0229] In some embodiments, at least one of R3and R4is -(L2)-(Y)-C6-10 aryl, wherein L2 is absent, C1-3 alkylene, or C1-3 haloalkylene; Y is absent, -O-, or -N(RA)-; and each aryl, alkylene, or haloalkylene is independently substituted with 0, 1, 2, or 3 instances of RB. In some embodiments, at least one of R3and R4is -(L2)-(Y)-C6-10 aryl, wherein L2 is absent, C1-3 alkylene, or C1-3 haloalkylene; Y is absent, -O-, or - N(RA)-; and each aryl, alkylene, or haloalkylene is independently substituted with 0 or 1 instances of RB

[0250]

[0230] In some embodiments, at least one of R3and R4is Ce aryl substituted with 0, 1, 2, or 3 instances of RB. In some embodiments, at least one of R3and R4is Ce aryl substituted with 0 or 1 instances of RB.

[0251]

[0231] In some embodiments, at least one of R3and R4is -(L2)-(Y)-(5-10 membered heteroaryl), wherein L2 is absent, C1-3 alkylene, or C1-3 haloalkylene; Y is absent, -O-, or -N(RA)-; and each heteroaryl, alkylene, or haloalkylene is independently substituted with 0, 1, 2, or 3 instances of RB. In some embodiments, at least one of R3and R4is -(L2)-(Y)-(5-10 membered heteroaryl), wherein L2 is absent, C1-3 alkylene, or C1-3 haloalkylene; Y is absent, -O-, or -N(RA)-; and each heteroaryl, alkylene, or haloalkylene is independently substituted with 0 or 1 instances of RB.

[0252]

[0232] In some embodiments, at least one of R3and R4is -(L2)-(Y)-(5-6 membered heteroaryl), wherein L2 is absent, C1-3 alkylene, or C1-3 haloalkylene; Y is absent, -O-, or -N(RA)-; and each heteroaryl, alkylene, or haloalkylene is independently substituted with 0, 1, 2, or 3 instances of RB. In some embodiments, at least one of R3and R4is -(L2)-(Y)-(5-6 membered heteroaryl), wherein L2 is absent, C1-3 alkylene, or C1-3 haloalkylene; Y is absent, -O-, or -N(RA)-; and each heteroaryl, alkylene, or haloalkylene is independently substituted with 0 or 1 instances of RB.

[0253]

[0233] In some embodiments, at least one of R3and R4is -(Y)-(5-6 membered heteroaryl), wherein Y is absent, -O-, or -N(RA)-; and the heteroaryl is substituted with 0, 1, 2, or 3 instances of RB. In some embodiments, at least one of R3and R4is -(Y)-(5-6 membered heteroaryl), wherein Y is absent, -O-, or - N(RA)-; and the heteroaryl is substituted with 0 or 1 instances of RB.

[0254]

[0234] In some embodiments, at least one of R3and R4is -(Y)-(5-6 membered heteroaryl containing 1, 2, or 3 ring heteroatoms selected from O, N, and S), wherein Y is absent, -O-, or -N(RA)-; the heteroaryl is substituted with 0, 1, 2, or 3 instances of RB. In some embodiments, at least one of R3and R4is -(Y)-( 5- 6 membered heteroaryl containing 1, 2, or 3 ring heteroatoms selected from O, N, and S), wherein Y is absent, -O-, or -N(RA)-; and the heteroaryl is substituted with 0 or 1 instances of RB.

[0255]

[0235] In some embodiments, at least one of R3and R4is -(Y)-(5-6 membered heteroaryl containing 1, 2, or 3 ring heteroatoms independently selected from O and N), wherein Y is absent, -O-, or -N(RA)-; the heteroaryl is substituted with 0, 1, 2, or 3 instances of RB. In some embodiments, at least one of R3and R4is -(Y)-(5-6 membered heteroaryl containing 1, 2, or 3 ring heteroatoms independently selected from O and N), wherein Y is absent, -O-, or -N(RA)-; and the heteroaryl is substituted with 0 or 1 instances of RB

[0256]

[0236] In some embodiments, at least one of R3and R4is 5-6 membered heteroaryl containing 1, 2, or 3 ring heteroatoms selected from O and N, wherein the heteroaryl is substituted with 0, 1, 2, or 3 instances of RB. In some embodiments, at least one of R3and R4is 5-6 membered heteroaryl containing 1, 2, or 3 ring heteroatoms selected from O and N, wherein the heteroaryl is substituted with 0 or 1 instances of RB

[0257]

[0237] In some embodiments, at least one of R3and R4is 5-6 membered heteroaryl containing 2 ring N atoms, wherein the heteroaryl is substituted with 0 or 1 instances of RB. In some embodiments, at least one of R3and R4is 5-6 membered heteroaryl containing 2 ring N atoms, wherein the heteroaryl is substituted with 0 or 1 instances of C1-3 alkyl. In some embodiments, at least one of R3and R4is 5-6 membered heteroaryl containing 2 ring N atoms, wherein the heteroaryl is substituted with 0 or 1 instances of -CH3.

[0258]

[0238] In some embodiments, at least one of R3and R4is 5-6 membered heteroaryl containing 3 ring N atoms, wherein the heteroaryl is substituted with 0 or 1 instances of RB. In some embodiments, at least one of R3and R4is 5-6 membered heteroaryl containing 3 ring N atoms, wherein the heteroaryl is substituted with 0 or 1 instances of C1-3 alkyl. In some embodiments, at least one of R3and R4is 5-6 membered heteroaryl containing 3 ring N atoms, wherein the heteroaryl is substituted with 0 or 1 instances of -CH3.

[0259]

[0239] In some embodiments, at least one of R3and R4is 5-6 membered heteroaryl containing 2 ring N atoms and 1 ring O atom, wherein the heteroaryl is substituted with 0 or 1 instances of RB. In some embodiments, at least one of R3and R4is 5-6 membered heteroaryl containing 2 ring N atoms and 1 ring O atom, wherein the heteroaryl is substituted with 0 or 1 instances of C1-3 alkyl. In some embodiments, at least one of R3and R4is 5-6 membered heteroaryl containing 2 ring N atoms and 1 ring O atom, wherein the heteroaryl is substituted with 0 or 1 instances of -CH3.

[0260]

[0240] In some embodiments, at least one of R3and R4is of the formula: valency permits.

[0261]

[0241] In some embodiments, at least one of R3and R4is:

[0262]

[0242] In some embodiments, at least one of R3and R4is -(L2)-ORA, wherein L2 is absent, C1-3 alkylene, or C1-3 haloalkylene; and each alkylene or haloalkylene is independently substituted with 0, 1, 2, or 3 instances of RB.

[0263]

[0243] In some embodiments, at least one of R3and R4is -ORA. In some embodiments, at least one of R3and R4is -ORA, wherein RAis 3-10 membered heterocyclyl substituted with 0, 1, 2, or 3 instances of RB. In some embodiments, at least one of R3and R4is -ORA, wherein RAis 4-6 membered heterocyclyl substituted with 0 or 1 instances of RB.

[0264]

[0244] In some embodiments, at least one of R3and R4is -ORA, wherein RAis C1-6 alkyl substituted with 0, 1, 2, or 3 instances of RB. In some embodiments, at least one of R3and R4is -ORA, wherein RAis C1-3 alkyl substituted with 0 or 1 instances of RB.

[0265]

[0245] In some embodiments, at least one of R3and R4is -(C1-3 alkylene)-ORA, wherein the alkylene is independently substituted with 0 or 1 instances of RB. In some embodiments, at least one of R3and R4is -(C1-3 alkylene)-ORA, wherein the alkylene is independently substituted with 0 instances of RB; and RAis H or Ci -3 alkyl.

[0266]

[0247] In some embodiments, at least one of R3and R4is: -OCHs,

[0267]

[0248] In some embodiments, at least one of R3and R4is -(L2)-N(RA)2, wherein L2 is absent, C1-3 alkylene, or C1-3 haloalkylene; and each alkylene or haloalkylene is independently substituted with 0, 1, 2, or 3 instances of RB. In some embodiments, at least one of R3and R4is -N(RA)2.

[0268]

[0249] In some embodiments, at least one of R3and R4is:

[0269]

[0251] In some embodiments, at least one of R3and R4is -(L2)-SRA, wherein L2 is absent, C1-3 alkylene, or C1-3 haloalkylene; and each alkylene or haloalkylene is independently substituted with 0, 1, 2, or 3 instances of RB. In some embodiments, at least one of R3and R4is -SRA.

[0270]

[0252] In some embodiments, at least one of R3and R4is -(L2)-CN, wherein L2 is absent, C1-3 alkylene, or C1-3 haloalkylene; and each alkylene or haloalkylene is independently substituted with 0, 1, 2, or 3 instances of RB. In some embodiments, at least one of R3and R4is -CN.

[0271]

[0253] In some embodiments, at least one of R3and R4is -(L2)-(Y)-C(=O)RA, wherein L2 is absent, C1-3 alkylene, or C1-3 haloalkylene; Y is absent, -O-, or -N(RA)-; and each alkylene or haloalkylene is independently substituted with 0, 1, 2, or 3 instances of RB. In some embodiments, at least one of R3and R4is -C(=O)RA.

[0272]

[0254] In some embodiments, at least one of R3and R4is -(L2)-(Y)-C(=O)ORA, wherein L2 is absent, C1-3 alkylene, or C1-3 haloalkylene; Y is absent, -O-, or -N(RA)-; and each alkylene or haloalkylene is independently substituted with 0, 1, 2, or 3 instances of RB. In some embodiments, at least one of R3and R4is -(L2)-(Y)-C(=O)ORA, wherein L2 is absent, C1-3 alkylene, or C1-3 haloalkylene; Y is absent, -O-, or -N(RA)-; and each alkylene or haloalkylene is independently substituted with 0 or 1 instances of RB.

[0273]

[0255] In some embodiments, at least one of R3and R4is -(L2)-C(=O)ORA, wherein L2 is absent, C1-3 alkylene, or C1-3 haloalkylene; and each alkylene or haloalkylene is independently substituted with 0, 1, 2, or 3 instances of RB. In some embodiments, at least one of R3and R4is -(L2)-C(=O)ORA, wherein L2 is absent, C1-3 alkylene, or C1-3 haloalkylene; and each alkylene or haloalkylene is independently substituted with 0 and 1 instances of RB.

[0274]

[0256] In some embodiments, at least one of R3and R4is -C(=O)ORA. In some embodiments, at least one of R3and R4is -C(=O)ORA, wherein RAis C1-6 alkyl. In some embodiments, at least one of R3and R4is -C(=O)ORA, wherein RAis C1-3 alkyl. In some embodiments, at least one of R3and R4is -C(=O)ORA, wherein RAis -CH3.

[0275]

[0257] In some embodiments, at least one of R3and R4is -(L2)-(Y)-C(=O)N(RA)2, wherein L2 is absent, C1-3 alkylene, or C1-3 haloalkylene; Y is absent, -O-, or -N(RA)-; and each alkylene or haloalkylene is independently substituted with 0, 1, 2, or 3 instances of RB. In some embodiments, at least one of R3and R4is -C(=O)N(RA)2,

[0276]

[0258] In some embodiments, at least one of R3and R4is -(L2)-S(=O)2RA, wherein L2 is absent, C1-3 alkylene, or C1-3 haloalkylene; and each alkylene or haloalkylene is independently substituted with 0, 1, 2, or 3 instances of RB. In some embodiments, at least one of R3and R4is -S(=O)2RA.

[0277] [259J In some embodiments, at least one of R3and R4is -(L2)-S(=O)2ORA, wherein L2 is absent, C1-3 alkylene, or C1-3 haloalkylene; and each alkylene or haloalkylene is independently substituted with 0, 1, 2, or 3 instances of RB. In some embodiments, at least one of R3and R4is -S(=O)2ORA.

[0260] In some embodiments, at least one of R3and R4is -(L2)-(Y)-S(=O)2N(RA)2, wherein L2 is absent, C1-3 alkylene, or C1-3 haloalkylene; Y is absent, -O-, or -N(RA)-; and each alkylene or haloalkylene is independently substituted with 0, 1, 2, or 3 instances of RB. In some embodiments, at least one of R3and R4is -S(=O)2N(RA)2.

[0278]

[0261] In some embodiments, at least one of R3and R4is -B(ORA)2.

[0279]

[0262] In some embodiments, at least one of R3or R4is: halogen, -B(ORA)2, -ORA, -(C1-3 alkylene)-ORA, wherein z is 0, 1, 2, or 3, as valency permits.

[0280]

[0263] In some embodiments, at least one of R3or R4is of the formula (z-1), (z-2), (z-3), (z-4), (z-5), (z- 6), (z-7), (z-9), (z-11), (z-17), (z-18), (z-19), (z-20), (z-21), (z-22), (z-23), (z-24), (z-25), (z-27), (z-28), (z-30), (z-31), (z-32), (z-33), (z-34), (z-35), (z-36), (z-37), (z-38), (z-39), (z-40), (z-41), (z-43), (z-44), (z-45), (z-46), (z-48), (z-49), (z-50), (z-51), (z-52), (z-53), (z-54), (z-55), (z-56), (z-57), (z-59), (z-61), (z-62), (z-63), (z-64), or (z-65), wherein z is 0.

[0281]

[0264] In some embodiments, at least one of R3or R4is of the formula (z-1), (z-2), (z-3), (z-4), (z-5), (z-

[0282] 6), (z-7), (z-8), (z-9), (z-10), (z-11), (z-12), (z-13), (z-14), (z-15), (z-16), (z-17), (z-18), (z-19), (z-20),

[0283] (z-21), (z-22), (z-23), (z-24), (z-25), (z-26), (z-27), (z-28), (z-29), (z-30), (z-31), (z-32), (z-33), (z-34),

[0284] (z-35), (z-36), (z-37), (z-38), (z-39), (z-40), (z-41), (z-42), (z-43), (z-44), (z-45), (z-46), (z-47), (z-48),

[0285] (z-49), (z-50), (z-51), (z-52), (z-53), (z-54), (z-55), (z-56), (z-57), (z-58), (z-59), (z-60), (z-61), (z-62),

[0286] (z-63), (z-64), or (z-65), wherein z is 1.

[0287]

[0265] In some embodiments, at least one of R3or R4is of the formula (z-1), (z-2), (z-3), (z-4), (z-5), (z-

[0288] 6), (z-7), (z-8), (z-9), (z-10), (z-12), (z-13), (z-14), (z-15), (z-16), (z-17), (z-20), (z-22) (z-23), (z-24),

[0289] (z-25), (z-26), (z-27), (z-28), (z-29), (z-30), (z-31), (z-32), (z-33), (z-34), (z-35), (z-36), (z-37), (z-38),

[0290] (z-39), (z-40), (z-41), (z-42), (z-43), (z-44), (z-45), (z-46), (z-47), (z-48), (z-49), (z-50), (z-51), (z-52),

[0291] (z-53), (z-54), (z-55), (z-56), (z-57), (z-58), (z-59), (z-60), (z-61), (z-62), (z-63), (z-64), or (z-65), wherein z is 2.

[0292]

[0266] In some embodiments, at least one of R3or R4is of the formula (z-1), (z-2), (z-3), (z-4), (z-5), (z- 6), (z-7), (z-8), (z-9), (z-10), (z-12), (z-15), (z-22), (z-23), (z-24), (z-25), (z-26), (z-27), (z-28), (z-29), (z-30), (z-31), (z-32), (z-33), (z-34), (z-35), (z-36), (z-37), (z-38), (z-39), (z-40), (z-41), (z-42), (z-43), (z-44), (z-45), (z-46), (z-47), (z-48), (z-49), (z-50), (z-51), (z-52), (z-53), (z-54), (z-55), (z-56), (z-57), (z-58), (z-59), (z-60), (z-61), (z-62), (z-63), (z-64), or (z-65), wherein z is 3.

[0293]

[0267] In some embodiments, at least one of R3and R4is of the formula: wherein z is 0, 1, 2, or 3, as valency permits.

[0294]

[0268] In some embodiments of formula (z-4), wherein Y is absent, at least one of R3or R4is of the formula: wherein z is 0, 1, 2, or 3, as valency permits.

[0295]

[0269] In some embodiments, at least one of R3or R4is of the formula (z-4), (z-4a), (z-4b), or (z-4c), wherein z is 0. In some embodiments, at least one of R3or R4is of the formula (z-4), (z-4a), (z-4b), (z- 4c), (z-4d), (z-4e), or (z-4f), wherein z is 1. In some embodiments, at least one of R3or R4is of the formula (z-4), (z-4a), (z-4b), (z-4c), (z-4d), (z-4e), or (z-4f), wherein z is 2. In some embodiments, at least one of R3or R4is of the formula (z-4), (z-4a), (z-4b), (z-4c), (z-4d), (z-4e), or (z-4f), wherein z is

[0296] 3.

[0297]

[0270] In some embodiments, at least one of R3and R4is of the formula: (z-6), wherein z is 0, 1, 2, or 3, as valency permits.

[0298]

[0271] In some embodiments of formula (z-6), at least one of R3or R4is of the formula: wherein z is 0, 1, 2, or 3, as valency permits.

[0299]

[0272] In some embodiments, at least one of R3or R4is of the formula (z-6), wherein z is 0. In some embodiments, at least one of R3or R4is of the formula (z-6), (z-6a), or (z-6b), wherein z is 1. In some embodiments, at least one of R3or R4is of the formula (z-6), (z-6a), (z-6b), (z-6c), (z-6d), (z-6e), or (z- 6f), wherein z is 2. In some embodiments, at least one of R3or R4is of the formula (z-6), (z-6a), (z-6b),

[0300] (z-6c), (z-6d), (z-6e), or (z-6f), wherein z is 3.

[0301]

[0273] In some embodiments, at least one of R3or R4is of the formula: some embodiments, Y is absent.

[0302]

[0274] In some embodiments of formula (z-26), wherein Y is absent, at least one of R3or R4is of the formula: wherein z is 0, 1, 2, or 3, as valency permits.

[0303]

[0275] In some embodiments, at least one of R3or R4is of the formula (z-26) wherein z is 0. In some embodiments, at least one of R3or R4is of the formula (z-6) or (z-26a), wherein z is 1. In some embodiments, at least one of R3or R4is of the formula (z-26), (z-26a), (z-26b), (z-26c), (z-26d), or (z-

[0304] 26e), wherein z is 2. In some embodiments, at least one of R3or R4is of the formula (z-26), (z-26a), (z-

[0305] 26b), (z-26c), (z-26d), or (z-26e), wherein z is 3.

[0306]

[0276] In some embodiments, at least one of R3or R4is of the formula: wherein z is 1, 2, or 3, as valency permits. In some embodiments, Y is absent.

[0307]

[0277] For example, in some embodiments of formula (z-3) wherein Y is absent, at least one of R3or R4is of the formula: valency permits.

[0308]

[0278] In some embodiments, at least one of R3or R4is of the formula (z-3), (z-3h), (z-3i), (z-3j), (z-3-i), (z-3h-i), (z-3i-i) , or (z-3j-i), wherein z is 0. In some embodiments, at least one of R3or R4is of the formula (z-3), (z-3a), (z-3b), (z-3c), (z-3d), (z-3e), (z-3f), (z-3g), (z-3h), (z-3i), (z-3j), (z-3-i), (z-3a-i), (z-3b-i), (z-3c-i), (z-3d-i), (z-3e-i), (z-3f-i), (z-3g-i), (z-3h-i), (z-3i-i), or (z-3j-i), wherein z is 1. In some embodiments, at least one of R3or R4is of the formula (z-3), (z-3a), (z-3b), (z-3c), (z-3d), (z-3e),

[0309] (z-3f), (z-3g), (z-3h), (z-3i), (z-3j), (z-3-i), (z-3a-i), (z-3b-i), (z-3c-i), (z-3d-i), (z-3e-i), (z-3f-i), (z-3g-i), (z-3h-i), (z-3i-i) , or (z-3j-i), wherein z is 2. In some embodiments, at least one of R3or R4is of the formula (z-3), (z-3a), (z-3b), (z-3c), (z-3d), (z-3e), (z-3f), (z-3g), (z-3h), (z-3i), (z-3j), (z-3-i), (z-3a-i), (z-3b-i), (z-3c-i), (z-3d-i), (z-3e-i), (z-3f-i), (z-3g-i), (z-3h-i), (z-3i-i), or (z-3j-i), wherein z is 3.

[0310]

[0279] In some embodiments, at least one of R3or R4is of the formula: wherein z is 1, 2, or 3, as valency permits.

[0311]

[0280] In some embodiments, at least one of R3or R4is of the formula (z-28), (z-28a), or (z-28b), wherein z is 0. In some embodiments, at least one of R3or R4is of the formula (z-28), (z-28a), or (z- 28b), wherein z is 1. In some embodiments, at least one of R3or R4is of the formula (z-28), (z-28a), or (z-28b), wherein z is 2. In some embodiments, at least one of R3or R4is of the formula (z-28), (z-28a), or (z-28b), wherein z is 3.

[0312]

[0281] In some embodiments, at least one of R3and R4is:

[0313]

[0314]

[0282] In some embodiments, at least one of at least one of R3and R4is selected from any of the above recited, and the other of R3and R4is H or fluoro.

[0315]

[0283] In some embodiments, at least one of R3and R4is:

[0316]

[0317]

[0284] In some embodiments, at least one of at least one of R3and R4is selected from any of the above recited, and the other of R3and R4is H or fluoro.

[0318]

[0285] In some embodiments, G3is CR3; G4is CR4; R3is:  

[0319] provided at least one of R3and R4is not H or F; optionally and further provided at least one of R3and R4is not -Cl or -B(0H)2; optionally and further provided at least one of R3and R4comprises a ring as described above and herein; optionally and further provided R3comprises a ring as described above and herein, and R4is H or F.

[0320]

[0290] In some embodiments, at least one instance of RAis H.

[0291] In some embodiments, at least one instance of RAis C1-6 alkyl, wherein the alkyl is substituted with 0, 1, 2, or 3 instances of RB. In some embodiments, at least one instance of RAis C1-3 alkyl, wherein the alkyl is substituted with 0, 1, 2, or 3 instances of RB. In some embodiments, at least one instance of RAis -CH3.

[0321]

[0292] In some embodiments, at least one instance of RAis C1-6 haloalkyl, wherein the haloalkyl is substituted with 0, 1, 2, or 3 instances of RB. In some embodiments, at least one instance of RAis C1-3 haloalkyl, wherein the haloalkyl is substituted with 0, 1, 2, or 3 instances of RB.

[0322]

[0293] In some embodiments, at least one instance of RAis -(L3)-(Z)-C3-10 carbocyclyl, wherein L3 is absent, C1-3 alkylene, or C1-3 haloalkylene; Z is absent or -O-; and each carbocyclyl, alkylene, or haloalkylene is independently substituted with 0, 1, 2, or 3 instances of RB. In some embodiments, at least one instance of RAis -(L3)-(Z)-C3-10 carbocyclyl, wherein L3 is absent, C1-3 alkylene, or C1-3 haloalkylene; Z is absent or -O-; and each carbocyclyl, alkylene, or haloalkylene is independently substituted with 0 or 1 instances of RB.

[0323]

[0294] In some embodiments, at least one instance of RAis -(L3)-(Z)-(3-10 membered heterocyclyl), wherein L3 is absent, C1-3 alkylene, or C1-3 haloalkylene; Z is absent or -O-; and each heterocyclyl, alkylene, or haloalkylene is independently substituted with 0, 1, 2, or 3 instances of RB. In some embodiments, at least one instance of RAis 3-10 membered heterocyclyl substituted with 0, 1, 2, or 3 instances of RB.

[0324]

[0295] In some embodiments, at least one instance of RAis -(L3)-(Z)-(4-6 membered heterocyclyl), wherein L3 is absent, C1-3 alkylene, or C1-3 haloalkylene; Z is absent or -O-; and each heterocyclyl, alkylene, or haloalkylene is independently substituted with 0, 1, 2, or 3 instances of RB. In some embodiments, at least one instance of RAis 4-6 membered heterocyclyl substituted with 0 or 1 instances of RB

[0325]

[0296] In some embodiments, at least one instance of RAis -(L3)-(Z)-C6-10 aryl, wherein L3 is absent, C1-3 alkylene, or C1-3 haloalkylene; Z is absent or -O-; and each aryl, alkylene, or haloalkylene is independently substituted with 0, 1, 2, or 3 instances of RB.

[0326]

[0297] In some embodiments, at least one instance of RAis or -(L3)-(Z)-(5-10 membered heteroaryl), wherein L3 is absent, C1-3 alkylene, or C1-3 haloalkylene; Z is absent or -O-; and each heteroaryl, alkylene, or haloalkylene is independently substituted with 0, 1, 2, or 3 instances of RB.

[0327]

[0298] In some embodiments, two RAgroups attached to the same nitrogen atom are optionally taken together to form a 4-6 membered heterocyclyl, wherein the heterocyclyl is substituted with 0, 1, 2, or 3 instances of RB.

[0328]

[0299] In some embodiments, at least one of R3and R4is -B(ORA)2 wherein each instance of RAis independently H, C1-6 alkyl, C1-6 haloalkyl, or two RAgroups attached to two oxygen atoms which are attached to the same boron atom are joined to form a 5-6 membered heterocyclyl, wherein the heterocyclyl is substituted with 0, 1, 2, or 3 RBgroups. In certain embodiments, at least one of R3and R4is -B(OH)2.

[0329]

[0300] In some embodiments, each instance of RBis independently halogen, C1-6 alkyl, C1-6 haloalkyl, C3- io carbocyclyl, -CN, -OR', -N(R')2, -SR', -C(=O)R', -C(=O)OR', -C(=O)N(R')2, or two RBattached to the same carbon atom are taken together to form =0; wherein each alkyl and haloalkyl is independently substituted with 0 or 1 =0; and each carbocyclyl is independently substituted with 0, 1, 2, or 3 instances of Rc.

[0330]

[0301] In some embodiments, at least one instance of RBis halogen. In some embodiments, at least one instance of RBis -F.

[0331]

[0302] In some embodiments, at least one instance of RBis C1-6 alkyl independently substituted with 0 or 1 =0 and independently substituted with 0, 1, 2, or 3 -OR'. In some embodiments, at least one instance of RBis Ci-3 alkyl independently substituted with 0 or 1 =0 and independently substituted with 0, 1, 2, or 3 -OR'.

[0332]

[0303] In some embodiments, at least one instance of RBis C1-6 alkyl substituted with 0 or 1 =0. In some embodiments, at least one instance of RBis C1-3 alkyl substituted with 0 or 1 =0. In some embodiments, at least one instance of RBis C1-6 alkyl substituted with 0, 1, 2, or 3 -OR'. In some embodiments, at least one instance of RBis C1-3 alkyl substituted with 0, 1, 2, or 3 -OR'. In some embodiments, at least one instance of RBis -CH3.

[0333]

[0304] In some embodiments, at least one instance of RBis C1-6 haloalkyl independently substituted with 0 or 1 =0 and independently substituted with 0, 1, 2, or 3 -OR'. In some embodiments, at least one instance of RBis C1-3 haloalkyl independently substituted with 0 or 1 =0 and independently substituted with 0, 1, 2, or 3 -OR'.

[0334]

[0305] In some embodiments, at least one instance of RBis C1-6 haloalkyl substituted with 0 or 1 =0. In some embodiments, at least one instance of RBis C1-3 haloalkyl substituted with 0 or 1 =0. In some embodiments, at least one instance of RBis C1-6 haloalkyl substituted with 0, 1, 2, or 3 -OR'. In some embodiments, at least one instance of RBis C1-3 haloalkyl substituted with 0, 1, 2, or 3 -OR'. In some embodiments, at least one instance of RBis -CH2CHF2.

[0335]

[0306] In some embodiments, at least one instance of RBis C3-10 carbocyclyl substituted with 0, 1, 2, or 3 instances of Rc. In some embodiments, at least one instance of RBis C3-10 carbocyclyl substituted with 0 or 1 instances of Rc.

[0336]

[0307] In some embodiments, at least one instance of RBis 4-6 membered heterocyclyl substituted with 0, 1, 2, or 3 instances of Rc. In some embodiments, at least one instance of RBis 4-6 membered heterocyclyl substituted with 0 or 1 instances of Rc.

[0337]

[0308] In some embodiments, at least one instance of RBis -CN.

[0338]

[0309] In some embodiments, at least one instance of RBis -OR'. In some embodiments, at least one instance of RBis -OR', wherein R' is H, C1-3 alkyl, or C1-3 haloalkyl. In some embodiments, at least one instance of RBis -OH or -OCH3.

[0339]

[0310] In some embodiments, at least one instance of RBis -N(R')2.

[0340]

[0311] In some embodiments, at least one instance of RBis -SR'.

[0341]

[0312] In some embodiments, at least one instance of RBis -C(=O)R'.

[0313] In some embodiments, at least one instance of RBis -C(=O)OR'. In some embodiments, at least one instance of RBis -C(=O)OR', wherein R' is H, C1-3 alkyl, or C1-3 haloalkyl. In some embodiments, at least one instance of RBis -C(=O)OC(CH3)3.

[0342]

[0314] In some embodiments, at least one instance of RBis -C(=0)N(R')2.

[0343]

[0315] In some embodiments, two RBattached to the same carbon atom are taken together to form =0.

[0344]

[0316] In some embodiments, each instance of Rcis independently halogen, C1-6 alkyl, or C1-6 haloalkyl, or two Rcattached to the same carbon atom are taken together to form =0;

[0345]

[0317] In some embodiments, at least one instance of Rcis halogen.

[0346]

[0318] In some embodiments, at least one instance of Rcis C1-6 alkyl. In some embodiments, at least one instance of Rcis C1-3 alkyl.

[0347]

[0319] In some embodiments, at least one instance of Rcis C1-6 haloalkyl. In some embodiments, at least one instance of Rcis C 1.3 haloalkyl.

[0348]

[0320] In some embodiments, at least one instance of Rcis -OR'.

[0349]

[0321] In some embodiments, two Rcattached to the same carbon atom are taken together to form =0.

[0350] (d) G5, RG5, G6, and G7, and additional embodiments ofG'-G4.

[0351]

[0322] As generally described herein, for the bicyclic ring system as provided in Formula (I) and depicted below, G5is O, N, S, or N-RG5, wherein RG5is H, C1-3 alkyl, or C1-3 haloalkyl,

[0352]

[0323] In some embodiments, G5is O.

[0353]

[0324] In some embodiments, G5is N.

[0354]

[0325] In some embodiments, G5is S.

[0355]

[0326] In some embodiments, G5is N-RG5, wherein RG5is H, C1-3 alkyl, or C1-3 haloalkyl.

[0356]

[0327] As generally described herein, G6is C or N and G7is C or N.

[0357]

[0328] In some embodiments, G6is C. In some embodiments, G6is N.

[0358]

[0329] In some embodiments, G7is C. In some embodiments, G7is N.

[0359]

[0330] In some embodiments, G5is O, and G6is C.

[0360]

[0331] In some embodiments, G5is O, and G7is C.

[0361]

[0332] In some embodiments, each of G6and G7is C.

[0362]

[0333] In some embodiments, each of G5and G6is N.

[0363]

[0334] In some embodiments, G5is N, and G7is C.

[0364]

[0335] In some embodiments, G6is N, and G7is C.

[0365]

[0336] In some embodiments, G5is S, and G6is C.

[0366]

[0337] In some embodiments, G5is S, and G7is C.

[0338] In some embodiments, G5is NRG5, and G6is C.

[0367]

[0339] In some embodiments, G5is NRG5, and G7is C.

[0368]

[0340] In some embodiments, G5is CRG5, and G6is N.

[0369]

[0341] In some embodiments, G5is CRG5, and G7is C.

[0370]

[0342] In some embodiments, G5is CRG5, and G6is C.

[0371]

[0343] In some embodiments, G5is CRG5, and G7is N.

[0372]

[0344] In some embodiments, G5is O, and each of G6and G7is C, such that the bicyclic ring system of formula:

[0373]

[0345] In some embodiments of formula (i), G3is CR3and G4is CR4, wherein R4is H.

[0374]

[0346] In some embodiments of formula (i), G3is CR3and G4is CR4, wherein R3is H.

[0375]

[0347] In some embodiments of formula (i), G3is CR3and G4is CR4, wherein R4is fluoro, and R3is not

[0376] H or fluoro.

[0377]

[0348] In some embodiments of formula (i), G3is CR3and G4is CR4, wherein R3is fluoro, and R4is not H or fluoro.

[0378]

[0349] In some embodiments of formula (i), each of G1and G2is CH.

[0379]

[0350] In some embodiments of formula (i), G1is N and G2is CH.

[0380]

[0351] In some embodiments, each of G5and G6is N, and G7is C, such that the bicyclic ring system of formula:

[0381]

[0352] In some embodiments of formula (ii), G3is CR3and G4is CR4, wherein R4is H.

[0382]

[0353] In some embodiments of formula (ii), G3is CR3and G4is CR4, wherein R3is H.

[0383]

[0354] In some embodiments of formula (ii), G3is CR3and G4is CR4, wherein R4is fluoro, and R3is not

[0384] H or fluoro.

[0385]

[0355] In some embodiments of formula (ii), G3is CR3and G4is CR4, wherein R3is fluoro, and R4is not H or fluoro.

[0386]

[0356] In some embodiments of formula (ii), each of G1and G2is CH.

[0387]

[0357] In some embodiments of formula (ii), G1is N and G2is CH.

[0358] In some embodiments, G5is S, and each of G6and G7is C, such that the bicyclic ring system of formula:

[0388]

[0359] In some embodiments of formula (iii), G3is CR3and G4is CR4, wherein R4is H.

[0389]

[0360] In some embodiments of formula (iii), G3is CR3and G4is CR4, wherein R3is H.

[0390]

[0361] In some embodiments of formula (iii), G3is CR3and G4is CR4, wherein R4is fluoro, and R3is not H or fluoro.

[0391]

[0362] In some embodiments of formula (iii), G3is CR3and G4is CR4, wherein R3is fluoro, and R4is not H or fluoro.

[0392]

[0363] In some embodiments of formula (iii), each of G1and G2is CH.

[0393]

[0364] In some embodiments of formula (iii), G1is N and G2is CH.

[0394]

[0365] In some embodiments, G5is NRG5, and each of G6and G7is C, such that the bicyclic ring system of formula:

[0395]

[0366] In some embodiments of formula (iv), G3is CR3and G4is CR4, wherein R4is H.

[0396]

[0367] In some embodiments of formula (iv), G3is CR3and G4is CR4, wherein R3is H.

[0397]

[0368] In some embodiments of formula (iv), G3is CR3and G4is CR4, wherein R4is fluoro, and R3is not

[0398] H or fluoro.

[0399]

[0369] In some embodiments of formula (iv), G3is CR3and G4is CR4, wherein R3is fluoro, and R4is not H or fluoro.

[0400]

[0370] In some embodiments of formula (iv), each of G1and G2is CH.

[0401]

[0371] In some embodiments of formula (iv), G1is N and G2is CH.

[0402]

[0372] In some embodiments, G5is CRG5, G6is N, and G7is C, such that the bicyclic ring system of formula:

[0403]

[0373] In some embodiments of formula (v), G3is CR3and G4is CR4, wherein R4is H.

[0374] In some embodiments of formula (v), G3is CR3and G4is CR4, wherein R3is H.

[0404]

[0375] In some embodiments of formula (v), G3is CR3and G4is CR4, wherein R4is fluoro, and R3is not H or fluoro.

[0405]

[0376] In some embodiments of formula (v), G3is CR3and G4is CR4, wherein R3is fluoro, and R4is not H or fluoro.

[0406]

[0377] In some embodiments of formula (v), each of G1and G2is CH.

[0407]

[0378] In some embodiments of formula (v), G1is N and G2is CH.

[0408]

[0379] In some embodiments, G5is CRG5, G6is C, and G7is N, such that the bicyclic ring system of formula:

[0409]

[0380] In some embodiments of formula (vi), G3is CR3and G4is CR4, wherein R4is H.

[0410]

[0381] In some embodiments of formula (vi), G3is CR3and G4is CR4, wherein R3is H.

[0411]

[0382] In some embodiments of formula (vi), G3is CR3and G4is CR4, wherein R4is fluoro, and R3is not

[0412] H or fluoro.

[0413]

[0383] In some embodiments of formula (vi), G3is CR3and G4is CR4, wherein R3is fluoro, and R4is not H or fluoro.

[0414]

[0384] In some embodiments of formula (vi), each of G1and G2is CH.

[0415]

[0385] In some embodiments of formula (vi), G1is N and G2is CH.

[0416] (e) R', R", andR'"

[0417]

[0386] As generally described herein, each instance of R' is independently H, C1-6 alkyl, or C1-6 haloalkyl, or two R' groups attached to the same nitrogen atom are optionally taken together to form a 4-6 membered heterocyclyl, wherein the alkyl, haloalkyl, or heterocyclyl is substituted with 0, 1, 2, or 3 R".

[0418]

[0387] In some embodiments, each instance of R' is independently H, C1-3 alkyl, or C1-3 haloalkyl, wherein the alkyl or haloalkyl is substituted with 0, 1, 2, or 3 R".

[0419]

[0388] In some embodiments, at least one instance of R' is H.

[0420]

[0389] In some embodiments, at least one instance of R' is C1-6 alkyl substituted with 0, 1, 2, or 3 R". In some embodiments, at least one instance of R' is C1-6 alkyl substituted with 0 or 1 R".

[0421]

[0390] In some embodiments, at least one instance of R' is C1-3 alkyl substituted with 0, 1, 2, or 3 R". In some embodiments, at least one instance of R' is C1-3 alkyl substituted with 0 or 1 R".

[0422]

[0391] In some embodiments, at least one instance of R' is C1-6 haloalkyl substituted with 0, 1, 2, or 3 R". In some embodiments, at least one instance of R' is C1-6 haloalkyl substituted with 0 or 1 R".

[0423]

[0392] In some embodiments, at least one instance of R' is C1-3 haloalkyl substituted with 0, 1, 2, or 3 R". In some embodiments, at least one instance of R' is C1-3 haloalkyl substituted with 0 or 1 R".

[0393] In some embodiments, two R' groups attached to the same nitrogen atom are taken together to form a 4-6 membered heterocyclyl substituted with 0, 1, 2, or 3 R". In some embodiments, two R' groups attached to the same nitrogen atom are taken together to form a 4-6 membered heterocyclyl substituted with 0 or 1 R".

[0424]

[0394] As generally described herein, each instance of R" is independently halogen, -CN, -OR'", - N(R'")2, or -SR'", or two R" attached to the same carbon atom are taken together to form =0.

[0425]

[0395] In some embodiments, each instance of R" is independently -CN, -OR'", -N(R'")2, or -SR'", or two R" attached to the same carbon atom are taken together to form =0.

[0426]

[0396] In some embodiments, at least one instance of R" is halogen.

[0427]

[0397] In some embodiments, at least one instance of R" is -CN.

[0428]

[0398] In some embodiments, at least one instance of R" is -OR'".

[0429]

[0399] In some embodiments, at least one instance of R" is -N(R'")2.

[0430]

[0400] In some embodiments, at least one instance of R" is -SR'".

[0431]

[0401] In some embodiments, two R" attached to the same carbon atom are taken together to form =0.

[0432]

[0402] As generally described herein, each instance of R'" is independently H, C1-3 alkyl, or C1-3 haloalkyl, or two R'" groups attached to the same nitrogen atom are taken together to form a 4-6 membered heterocyclyl, wherein the heterocyclyl is substituted with 0, 1, 2, or 3 halogen.

[0433]

[0403] In some embodiments, each instance of R'" is independently H, C1-3 alkyl, or C1-3 haloalkyl.

[0434]

[0404] In some embodiments, at least one instance of R'" is H.

[0435]

[0405] In some embodiments, at least one instance of R'" is C1-3 alkyl.

[0436]

[0406] In some embodiments, at least one instance of R'" is C1-3 haloalkyl.

[0437]

[0407] In some embodiments, two R'" groups attached to the same nitrogen atom are taken together to form a 4-6 membered heterocyclyl substituted with 0, 1, 2, or 3 halogen. In some embodiments, two R'" groups attached to the same nitrogen atom are taken together to form a 4-6 membered heterocyclyl substituted with 0 or 1 halogen.

[0438]

[0408] In some embodiments, each instance of R' is independently H, C1-3 alkyl, or C1-3 haloalkyl, wherein the alkyl or haloalkyl is substituted with 0, 1, 2, or 3 R"; each instance of R" is independently - CN, -OR'", -N(R'")2, or -SR'", or two R" attached to the same carbon atom are taken together to form =0; and each instance of R'" is independently H, C1-3 alkyl, or C1-3 haloalkyl.

[0439] (f) Subgenera

[0440]

[0409] It is understood that, for a compound of the present disclosure, variables R1, R1A, X, G1, G2, RG1, RG2, G3, G4, R3, R4, G5, RG5, G6, G7, RA, RB, Rc, R', R", R'", n, and z can each be, where applicable, selected from the groups described herein, and any group described herein for any of variables R1, R1A, X, G1, G2, RG1, RG2, G3, G4, R3, R4, G5, RG5, G6, G7, RA, RB, RC, R', R", R'", n, and z can be combined, where applicable, with any group described herein for one or more of the remainder of variables R1, R1A, X, G1, G2, RG1, RG2, G3, G4, R3, R4, G5, RG5, G6, G7, RA, RB, RC, R', R", R'", n, and z. Additional exemplary combinations of the above described embodiments are further contemplated herein.

[0410] For example, in some embodiments, the compound of Formula (I) is of Formula (II-a), Formula (Il-b), Formula (II-c), Formula (II-d), Formula (II-e), or Formula (Il-f): or a pharmaceutically acceptable salt or isotopically labeled derivative thereof, wherein n is 0, 1, or 2. In some embodiments, n is 0. In some embodiments, n is 1 or 2, wherein R1Ais fluoro. In some embodiments, a group of formula (y-2), (y-4), (y-7), (y-8), (y-9), or (y-11) . In some embodiments, a group of formula (y-2), (y-3-i) or (y-3-iv). In some embodiments, is a group of formula (y-2), (y-4-i) or (y-4-iv). In some embodiments, is a group of formula (y-

[0441] 2). In some embodiments, is a group of formula (y-4-i). In some embodiments, is a group of formula (y-4-iv). In some embodiments is a group of formula (y-7). In some embodiments, n is 2 and two R1Agroups are joined to form .

[0442]

[0411] In some embodiments, the compound of Formula (I) is of Formula (Il-a) or (Il-b): or a pharmaceutically acceptable salt or isotopically labeled derivative thereof, wherein n is 0, 1, or 2. In some embodiments, the compound of Formula (I) is of Formula (Il-a). In some embodiments, the compound of Formula (I) is of Formula (Il-b). In some embodiments, each of G1and G2is CH. In some embodiments, G1is N and G2is CH. In some embodiments, G3is CR3and G4is CR4, wherein R4is H. In some embodiments, G3is CR3and G4is CR4, wherein R3is H. In some embodiments, G3is CR3and G4is CR4, and one of R3and R4is halogen (e.g., fluoro) and the other of R3and R4is not H or halogen (e.g., fluoro). In some embodiments, one of R3and R4is any one of formula (z-1) to (z-65). In some embodiments, one of R3and R4is of formula (z-3), (z-4), (z-6), (z-16), or (z-26). In some embodiments, one of R3and R4is of formula (z-3), (z-4), (z-6), or (z-26). In some embodiments, one of R3and R4is of formula (z-4) or (z-6). In some embodiments, R3is of formula (z-3) and R4is H or fluoro. In some embodiments, R3is of formula (z-3b) and R4is H or fluoro. In some embodiments, R4is of formula (z- 3) and R3is H or fluoro. In some embodiments, R4is of formula (z-3b) and R3is H or fluoro. In some embodiments, R3is of formula (z-4) (e.g., (z-4a)) and R4is H or fluoro. In some embodiments, R3is of formula (z-4) (e.g., (z-4a)) and R4is H. In some embodiments, R3is of formula (z-6) (e.g., (z-6a), (z- 6b), (z-6c), or (z-6f)) and R4is H or fluoro. In some embodiments, R3is of formula (z-6) (e.g., (z-6a), (z-6b), (z-6c), or (z-6f)) and R4is H. In some embodiments, R3is of formula (z-26) (e.g., (z-26a), (z- 26d), or (z-26e)) and R4is H or fluoro. In some embodiments, R3is of formula (z-26) (e.g., (z-26a), (z- 26d), or (z-26e)) and R4is H. In some embodiments, each of G1and G2is CH, R3is of formula (z-3b), (z-4) (e.g., (z-4a)), (z-6) (e.g., (z-6a), (z-6b), (z-6c), or (z-6f)), or (z-26) (e.g., (z-26a), (z-26d), or (z- (R^ln ^

[0443] 26e)); R4is H; andvis a group of formula (y-2), (y-4) (e.g., (y-4-i) or (y-4-iv)), or (y-7). In some embodiments, is a group of formula (y-2), (y-4) (e.g., (y-4-i) or (y-4-iv)), or (y-7), each of G1and G2is CH, R3is of formula (z-4) (e.g., (z-4a)), and R4is H. In some embodiments, is a group of formula (y-2), (y-4) (e.g., (y-4-i) or (y-4-iv)), or (y-7), each of G1and G2is CH, R3is of formula (z-6) (e.g., (z-6a), (z-6b), (z-6c), or (z-6f)), and R4is H. In some embodiments, R4is of formula

[0444] (z-6) (e.g., (z-6a), (z-6b), (z-6c), or (z-6f)) and R3is H or fluoro. In some embodiments, is a group of formula (y-2), (y-4) (e.g., (y-4-i) or (y-4-iv)), or (y-7), each of G1and G2is CH, R3is of formula (z-26) (e.g., (z-26a), (z-26d), or (z-26e)), and R4is H.

[0445]

[0412] In some embodiments, the compound of Formula (I) is of Formula (II-a-1), (II-a-2), (II-a-3), (II- b-1), (II-b-2), or (II-b-3): or a pharmaceutically acceptable salt or isotopically labeled derivative thereof. In some embodiments, the compound of Formula (I) is of Formula (II-a-1). In some embodiments, the compound of Formula (I) is of Formula (II-a-2). In some embodiments, the compound of Formula (I) is of Formula (II-a-3). In some embodiments, the compound of Formula (I) is of Formula (II-b-1). In some embodiments, the compound of Formula (I) is of Formula (II-b-2). In some embodiments, the compound of Formula (I) is of Formula (II-b-3). In some embodiments, each of G1and G2is CH. In some embodiments, G1is N and G2is CH. In some embodiments, G3is CR3and G4is CR4, wherein R4is H. In some embodiments, G3is CR3and G4is CR4, wherein R3is H. In some embodiments, G3is CR3and G4is CR4, and one of R3and R4is halogen (e.g., fluoro) and the other of R3and R4is not H or halogen (e.g., fluoro). In some embodiments, one of R3and R4is any one of formula (z-1) to (z-65). In some embodiments, one of R3and R4is of formula (z-3), (z-4), (z-6), (z-16), or (z-26). In some embodiments, one of R3and R4is of formula (z-3), (z-4), (z-6), or (z-26). In some embodiments, one of R3and R4is of formula (z-4) or (z- 6). In some embodiments, R3is of formula (z-3) and R4is H or fluoro. In some embodiments, R3is of formula (z-3b) and R4is H or fluoro. In some embodiments, R3is of formula (z-4) (e.g., (z-4a)) and R4is H or fluoro. In some embodiments, R3is of formula (z-4) (e.g., (z-4a)) and R4is H. In some embodiments, R3is of formula (z-6) (e.g., (z-6a), (z-6b), (z-6c), or (z-6f)) and R4is H or fluoro. In some embodiments, R3is of formula (z-6) (e.g., (z-6a), (z-6b), (z-6c), or (z-6f)) and R4is H. In some embodiments, R3is of formula (z-26) (e.g., (z-26a), (z-26d), or (z-26e)) and R4is H or fluoro. In some embodiments, R3is of formula (z-26) (e.g., (z-26a), (z-26d), or (z-26e)) and R4is H.

[0446]

[0413] In some embodiments, the compound of Formula (I) is of Formula (Ill-a), Formula (Ill-b), Formula (III-c), Formula (Ill-d), Formula (Ill-e), or Formula (Ill-f): or a pharmaceutically acceptable salt or isotopically labeled derivative thereof, wherein n is 0, 1, or 2. In some embodiments, n is 0. In some embodiments, n is 1 or 2, wherein R1Ais fluoro. In some embodiments, a group of formula (y-2), (y-4), (y-7), (y-8), (y-9), or (y-11) . In some embodiments, a group of formula (y-2), (y-3-i) or (y-3-iv). In some embodiments,

[0447] (RjA)n <, is a group of formula (y-2), (y-4-i) or (y-4-iv). In some embodiments,vis a group of formula (y-

[0448] 2). In some embodiments, is a group of formula (y-4-i). In some embodiments, group of formula (y-4-iv). In some embodiments, a group of formula (y-7). In some embodiments, n is 2 and two R1Agroups are joined to form

[0449]

[0414] In some embodiments, the compound of Formula (I) is of Formula (Ill-a) or (Ill-b): or a pharmaceutically acceptable salt or isotopically labeled derivative thereof, wherein n is 0, 1, or 2. In some embodiments, the compound of Formula (I) is of Formula (Ill-a). In some embodiments, the compound of Formula (I) is of Formula (Ill-b). In some embodiments, each of G1and G2is CH. In some embodiments, G1is N and G2is CH. In some embodiments, G3is CR3and G4is CR4, wherein R4is H. In some embodiments, G3is CR3and G4is CR4, wherein R3is H. In some embodiments, G3is CR3and G4is CR4, and one of R3and R4is halogen (e.g., fluoro) and the other of R3and R4is not H or halogen (e.g., fluoro). In some embodiments, one of R3and R4is any one of formula (z-1) to (z-65). In some embodiments, one of R3and R4is of formula (z-3), (z-4), (z-6), (z-16), or (z-26). In some embodiments, one of R3and R4is of formula (z-3), (z-4), (z-6), or (z-26). In some embodiments, one of R3and R4is of formula (z-4) or (z-6). In some embodiments, R3is of formula (z-3) and R4is H or fluoro. In some embodiments, R3is of formula (z-3b) and R4is H or fluoro. In some embodiments, R4is of formula (z-3) and R3is H or fluoro. In some embodiments, R4is of formula (z-3b) and R3is H or fluoro. In some embodiments, R3is of formula (z-4) (e.g., (z-4a)) and R4is H or fluoro. In some embodiments, R3is of formula (z-4) (e.g., (z-4a)) and R4is H. In some embodiments, R3is of formula (z-6) (e.g., (z-6a), (z-6b), (z-6c), or (z-6f)) and R4is H or fluoro. In some embodiments, R3is of formula (z-6) (e.g., (z-6a), (z-6b), (z-6c), or (z-6f)) and R4is H. In some embodiments, R3is of formula (z-26) (e.g., (z-26a), (z-26d), or (z-26e)) and R4is H or fluoro. In some embodiments, R3is of formula (z-26) (e.g., (z-26a), (z-26d), or (z-26e)) and R4is H. In some embodiments, each of G1and G2is CH, R3is of formula (z-3b), (z-4) (e.g., (z-4a)), (z-6) (e.g., (z-6a), (z-6b), (z-6c), or (z-6f)), or (z-26) (e.g., (z-26a),

[0450] (RjA)n <,

[0451] (z-26d), or (z-26e)); R4is H; andvis a group of formula (y-2), (y-4) (e.g., y-4-i or y-4-iv), or (y-

[0452] 7). In some embodiments, is a group of formula (y-2), (y-4) (e.g., (y-4-i) or (y-4-iv)), or (y-7), each of G1and G2is CH, R3is of formula (z-4) (e.g., (z-4a)), and R4is H. In some embodiments, group of formula (y-2), (y-4) (e.g., (y-4-i) or (y-4-iv)), or (y-7), each of G1and G2is CH, R3is of formula (z-6) (e.g., (z-6a), (z-6b), (z-6c), or (z-6f)), and R4is H. In some embodiments, R4is of formula (z-6) (e.g., (z-6a), (z-6b), (z-6c), or (z-6f)) and R3is H or fluoro. In some embodiments, group of formula (y-2), (y-4) (e.g., (y-4-i) or (y-4-iv)), or (y-7), each of G1and G2is CH, R3is of formula (z-26) (e.g, (z-26a), (z-26d), or (z-26e)), and R4is H.

[0453]

[0415] In some embodiments, the compound of Formula (I) is of Formula (IV-a), Formula (IV-b), Formula (IV-c), Formula (IV-d), Formula (IV-e), or Formula (TV-f): or a pharmaceutically acceptable salt or isotopically labeled derivative thereof, wherein n is 0, 1 , or 2. In some embodiments, n is 0. In some embodiments, n is 1 or 2, wherein R1Ais fluoro. In some embodiments, a group of formula (y-2), (y-4), (y-7), (y-8), (y-9), or (y-11). In some embodiments, a group of formula (y-2), (y-3-i) or (y-3-iv). In some embodiments, is a group of formula (y-2), (y-4-i) or (y-4-iv). In some embodiments, is a group of formula (y-

[0454] 2). In some embodiments, is a group of formula (y-4-i). In some embodiments, is a group of formula (y-4-iv). In some embodiments, a group of formula (y-7) . In some embodiments, n is 2 and two R1Agroups are joined to form

[0455]

[0416] In some embodiments, the compound of Formula (I) is of Formula (IV-a) or (IV-b): or a pharmaceutically acceptable salt or isotopically labeled derivative thereof, wherein n is 0, 1, or 2. In some embodiments, the compound of Formula (I) is of Formula (IV- a). In some embodiments, the compound of Formula (I) is of Formula (IV-b). In some embodiments, each of G1and G2is CH. In some embodiments, G1is N and G2is CH. In some embodiments, G3is CR3and G4is CR4, wherein R4is H. In some embodiments, G3is CR3and G4is CR4, wherein R3is H. In some embodiments, G3is CR3and G4is CR4, and one of R3and R4is halogen (e.g., fluoro) and the other of R3and R4is not H or halogen (e.g., fluoro). In some embodiments, one of R3and R4is any one of formula (z-1) to (z-65). In some embodiments, one of R3and R4is of formula (z-3), (z-4), (z-6), (z-16), or (z-26). In some embodiments, one of R3and R4is of formula (z-3), (z-4), (z-6), or (z-26). In some embodiments, one of R3and R4is of formula (z-4) or (z-6). In some embodiments, R3is of formula (z-3) and R4is H or fluoro. In some embodiments, R3is of formula (z-3b) and R4is H or fluoro. In some embodiments, R4is of formula (z-3) and R3is H or fluoro. In some embodiments, R4is of formula (z-3b) and R3is H or fluoro. In some embodiments, R3is of formula (z-4) (e.g., (z-4a)) and R4is H or fluoro. In some embodiments, R3is of formula (z-4) (e.g., (z-4a)) and R4is H. In some embodiments, R3is of formula (z-6) (e.g., (z-6a), (z-6b), (z-6c), or (z-6f)) and R4is H or fluoro. In some embodiments, R3is of formula (z-6) (e.g., (z-6a), (z-6b), (z-6c), or (z-6f)) and R4is H. In some embodiments, R3is of formula (z-26) (e.g., (z-26a), (z-26d), or (z-26e)) and R4is H or fluoro. In some embodiments, R3is of formula (z-26) (e.g., (z-26a), (z-26d), or (z-26e)) and R4is H. In some embodiments, each of G1and G2is CH, R3is of formula (z-3b), (z-4) (e.g., (z-4a)), (z-6) (e.g., (z-6a), (z-6b), (z-6c), or (z-6f)), or (z-26) (e.g., (z-26a), group of formula (y-2), (y-4) (e.g., y-4-i or y-4-iv), or (y- 7). In some embodiments, is a group of formula (y-2), (y-4) (e.g., (y-4-i) or (y-4-iv)), or (y-7), each of G1and G2is CH, R3is of formula (z-4) (e.g., (z-4a)), and R4is H. In some embodiments, group of formula (y-2), (y-4) (e.g., (y-4-i) or (y-4-iv)), or (y-7), each of G1and G2is CH,

[0456] R3is of formula (z-6) (e.g., (z-6a), (z-6b), (z-6c), or (z-6f)), and R4is H. In some embodiments, R4is of formula (z-6) (e.g., (z-6a), (z-6b), (z-6c), or (z-6f)) and R3is H or fluoro. In some embodiments, group of formula (y-2), (y-4) (e.g., (y-4-i) or (y-4-iv)), or (y-7), each of G1and G2is CH,

[0457] R3is of formula (z-26) (e.g., (z-26a), (z-26d), or (z-26e)), and R4is H.

[0458]

[0417] In some embodiments, the compound of Formula (I) is of Formula (IV-a-1), (IV-a-2), (IV-a-3),

[0459] (IV-b-1), (IV-b-2), or (IV-b-3): or a pharmaceutically acceptable or isotopically labeled derivative salt thereof. In some embodiments, the compound of Formula (I) is of Formula (IV-a-1). In some embodiments, the compound of Formula (I) is of Formula (IV-a-2). In some embodiments, the compound of Formula (I) is of Formula (IV-a-3). In some embodiments, the compound of Formula (I) is of Formula (IV-b-1). In some embodiments, the compound of Formula (I) is of Formula (IV-b-2). In some embodiments, the compound of Formula (I) is of Formula (IV-b-3). In some embodiments, each of G1and G2is CH. In some embodiments, G1is N and G2is CH. In some embodiments, G3is CR3and G4is CR4, wherein R4is H. In some embodiments, G3is CR3and G4is CR4, wherein R3is H. In some embodiments, G3is CR3and G4is CR4, and one of R3and R4is halogen (e.g., fluoro) and the other of R3and R4is not H or halogen (e.g., fluoro). In some embodiments, one of R3and R4is any one of formula (z-1) to (z-65). In some embodiments, one of R3and R4is of formula (z-3), (z-4), (z-6), (z-16), or (z-26). In some embodiments, one of R3and R4is of formula (z-3), (z-4), (z-6), or (z-26). In some embodiments, one of R3and R4is of formula (z-4) or (z- 6). In some embodiments, R3is of formula (z-3) and R4is H or fluoro. In some embodiments, R3is of formula (z-3b) and R4is H or fluoro. In some embodiments, R3is of formula (z-4) (e.g., (z-4a)) and R4is H or fluoro. In some embodiments, R3is of formula (z-4) (e.g., (z-4a)) and R4is H. In some embodiments, R3is of formula (z-6) (e.g., (z-6a), (z-6b), (z-6c), or (z-6f)) and R4is H or fluoro. In some embodiments, R3is of formula (z-6) (e.g., (z-6a), (z-6b), (z-6c), or (z-6f)) and R4is H. In some embodiments, R3is of formula (z-26) (e.g., (z-26a), (z-26d), or (z-26e)) and R4is H or fluoro. In some embodiments, R3is of formula (z-26) (e.g., (z-26a), (z-26d), or (z-26e)) and R4is H.

[0460]

[0418] In some embodiments, the compound of Formula (I) is of Formula (V-a), Formula (V-b), Formula (V-c), Formula (V-d), Formula (V-e), or Formula (V-f): or a pharmaceutically acceptable salt or isotopically labeled derivative thereof, wherein n is 0, 1, or 2. In some embodiments, n is 0. In some embodiments, n is 1 or 2, wherein R1Ais fluoro. In some embodiments, a group of formula (y-2), (y-4), (y-7), (y-8), (y-9), or (y-11) . In some embodiments, a group of formula (y-2), (y-3-i) or (y-3-iv). In some embodiments, is a group of formula (y-2), (y-4-i) or (y-4-iv). In some embodiments, is a group of formula (y-

[0461] 2). In some embodiments, is a group of formula (y-4-i). In some embodiments, is a group of formula (y-4-iv). In some embodiments, a group of formula (y-7). In some embodiments, n is 2 and two R1Agroups are joined to form

[0462]

[0419] In some embodiments, the compound of Formula (I) is of Formula (V-a) or (V-b): or a pharmaceutically acceptable salt or isotopically labeled derivative thereof, wherein n is 0, 1, or 2. In some embodiments, the compound of Formula (I) is of Formula (V-a). In some embodiments, the compound of Formula (I) is of Formula (V-b). In some embodiments, each of G1and G2is CH. In some embodiments, G1is N and G2is CH. In some embodiments, G3is CR3and G4is CR4, wherein R4is H. In some embodiments, G3is CR3and G4is CR4, wherein R3is H. In some embodiments, G3is CR3and G4is CR4, and one of R3and R4is halogen (e.g., fluoro) and the other of R3and R4is not H or halogen (e.g., fluoro). In some embodiments, one of R3and R4is any one of formula (z-1) to (z-65). In some embodiments, one of R3and R4is of formula (z-3), (z-4), (z-6), (z-16), or (z-26). In some embodiments, one of R3and R4is of formula (z-3), (z-4), (z-6), or (z-26). In some embodiments, one of R3and R4is of formula (z-4) or (z-6). In some embodiments, R3is of formula (z-3) and R4is H or fluoro. In some embodiments, R3is of formula (z-3b) and R4is H or fluoro. In some embodiments, R4is of formula (z-3) and R3is H or fluoro. In some embodiments, R4is of formula (z-3b) and R3is H or fluoro. In some embodiments, R3is of formula (z-4) (e.g., (z-4a)) and R4is H or fluoro. In some embodiments, R3is of formula (z-4) (e.g., (z-4a)) and R4is H. In some embodiments, R3is of formula (z-6) (e.g., (z-6a), (z-6b), (z-6c), or (z-6f)) and R4is H or fluoro. In some embodiments, R3is of formula (z-6) (e.g., (z-6a), (z-6b), (z-6c), or (z-6f)) and R4is H. In some embodiments, R3is of formula (z-26) (e.g., (z-26a), (z-26d), or (z- 26e)) and R4is H or fluoro. In some embodiments, R3is of formula (z-26) (e.g., (z-26a), (z-26d), or (z- 26e)) and R4is H. In some embodiments, each of G1and G2is CH, R3is of formula (z-3b), (z-4) (e.g., (z- 4a)), (z-6) (e.g., (z-6a), (z-6b), (z-6c), or (z-6f)), or (z-26) (e.g., (z-26a), (z-26d), or (z-26e)); R4is H; and group of formula (y-2), (y-4) (e.g., y-4-i or y-4-iv), or (y-7). In some embodiments, group of formula (y-2), (y-4) (e.g., (y-4-i) or (y-4-iv)), or (y-7), each of G1and G2is CH,

[0463] R3is of formula (z-4) (e.g., (z-4a)), and R4is H. In some embodiments, is a group of formula

[0464] (y-2), (y-4) (e.g., (y-4-i) or (y-4-iv)), or (y-7), each of G1and G2is CH, R3is of formula (z-6) (e.g., (z-

[0465] 6a), (z-6b), (z-6c), or (z-6f)), and R4is H. In some embodiments, R4is of formula (z-6) (e.g., (z-6a), (z-

[0466] (RjA)n b

[0467] 6b), (z-6c), or (z-6f)) and R3is H or fluoro. In some embodiments, * is a group of formula (y-2), (y-4) (e.g., (y-4-i) or (y-4-iv)), or (y-7), each of G1and G2is CH, R3is of formula (z-26) (e.g., (z-26a), (z-26d), or (z-26e)), and R4is H.

[0468] (RjA)n <,

[0469]

[0420] In some embodiments of Formula (I), wherein R1isv, G3is CR3and R3is a group of formula (z-26a), G4is CR4and R4is H, G1and G2are each CH, and G7is C, provided is a compound of Formula (I-a-26a) (wherein G5is O and G6is C) or Formula (I-b-26a) (wherein G5and G6are each N):

[0470] or a pharmaceutically acceptable salt or isotopically labeled derivative thereof, wherein n is 0, 1, or 2. In some embodiments, the compound of Formula (I) is of Formula (I-a-z-26a). In some embodiments, the compound of Formula (I) is of Formula (I-b-z-26a). In some embodiments, -CX3 is CH3 or

[0471] -CHF2. In some embodiments, is a group of formula (y-2), (y-4-i) or (y-4-iv). In some embodiments, the RBattached to the N atom is -CH3 or -CH2CH3. In some embodiments, z is 1 (allowing for no further substitution on the R3ring). In some embodiments, z is 2 (allowing for 1 RBsubstitution on the R3ring), the group of formula (z-26a) is of formula (z-26d) or (z-26e).

[0472] (RjA)n <,

[0473]

[0421] In some embodiments of Formula (I), wherein R1isv, G3is CR3and R3is a group of formula (z-6), G4is CR4and R4is H, G1and G2are CH, G7is C, provided is a compound of Formula (I- a-z-6) (wherein G5is O and G6is C) or Formula (I-b-z-6) (wherein G5and G6are each N): or a pharmaceutically acceptable salt or isotopically labeled derivative thereof, wherein n is 0, 1, or 2. In some embodiments, the compound of Formula (I) is of Formula (I-a-z-6). In some embodiments, the compound of Formula (I) is of Formula (I-b-z-6). In some embodiments, -CX3 is CH3 or -CHF2. In some embodiments, a group of formula (y-2), (y-4-i) or (y-4-iv). In some embodiments, z is 0. In some embodiments, z is 1. In some embodiments, z is 1, and RBis -CH3. In some embodiments, z is 1, and the group of formula (z-6) is of formula (z-6a) or (z-6b). In some embodiments, z is 2. In some embodiments, z is 2, and each instance of RBis independently -CH3. In some embodiments, z is 2, and the group of formula (z-6) is of formula (z-6c). In some embodiments, z is 2, and the group of formula (z-6) is of formula (z-6f).

[0474] (RjX

[0475]

[0422] In some embodiments of Formula (I), wherein R1is * , G3is CR3and R3is a group of formula (z-4a), G4is CR4and R4is H, G1and G2are CH, G7is C, provided is a compound of Formula (I-a-z-4a) (wherein G5is O and G6is C) or Formula (I-b-z-4a) (wherein G5and G6are each N): or a pharmaceutically acceptable salt or isotopically labeled derivative thereof, wherein n is 0, 1, or 2. In some embodiments, the compound of Formula (I) is of Formula (I-a-z-4a). In some embodiments, the compound of Formula (I) is of Formula (I-b-z-4a). In some embodiments, -CX3 is -CH3 or -CHF2. In some embodiments, group of formula (y-2), (y-4-i) or (y-4-iv). In some embodiments, z is

[0476] 0. In some embodiments, z is 1. In some embodiments, z is 2.

[0477] (RjA)n <,

[0478]

[0423] In some embodiments of Formula (I), wherein R1isv, G3is CR3and R3is a group of formula (z-28), G4is CR4and R4is H, G1and G2are CH, G7is C, provided is a compound of Formula

[0479] (I-a-z-28) (wherein G5is O and G6is C) or Formula (I-b-z-28) (wherein G5and G6are each N):

[0480] or a pharmaceutically acceptable salt or isotopically labeled derivative thereof, wherein n is 0, 1, or 2. In some embodiments, the compound of Formula (I) is of Formula (I-a-z-28). In some embodiments, the compound of Formula (I) is of Formula (I-b-z-28). In some embodiments, -CX3 is CH3 or -CHF2. In some embodiments, is a group of formula (y-2), (y-4-i) or (y-4-iv). In some embodiments, z is 0. In some embodiments, z is 1. In some embodiments, the group of formula (z-28) is of formula (z-28a). In some embodiments, the group of formula (z-28) is of formula (z-28b).

[0481]

[0424] In some embodiments, the compound of Formula (I) is selected from any one of the compounds of Table 1, Table 2, Table 3, or Table 4 or a pharmaceutically acceptable salt or isotopically labeled derivative of any one of the foregoing.

[0482]

[0425] In some embodiments, the compound of Formula (I) is selected from a pharmaceutically acceptable salt of any one of the compounds of Table 1, Table 2, Table 3, or Table 4. In some embodiments, the pharmaceutically acceptable salt is also an isotopically labeled derivative thereof. In some embodiments, the pharmaceutically acceptable salt is not an isotopically labeled derivative thereof.

[0483]

[0426] In some embodiments, the compound of Formula (I) is a free base or isotopically labeled derivative thereof selected from any one of the compounds of Table 1, Table 2, Table 3, or Table 4. In some embodiments, the free base is also an isotopically labeled derivative thereof. In some embodiments, the free base is not an isotopically labeled derivative thereof.

[0484]

[0427] The below Tables 1-4 also provides the location of the Compound (#) in the Examples (Ex) by Example Number or as provided in Table A (TA) of the Examples. The Asterix (*) next to the Compound Number (#) signifies that arbitrary stereochemistry has been assigned. “Rac” indicates a mixture of two or more stereoisomers in equal or unequal proportions.

[0485]

[0486]

[0487]

[0488] Table 4. Compounds of Formula (I)

[0489]

[0490]

[0491] Table 4. Compounds of Formula (I) ii. Pharmaceutical Compositions

[0492]

[0428] The present disclosure provides pharmaceutical compositions comprising a compound of Formula (I), or a pharmaceutically acceptable salt or isotopically labeled derivative thereof, and a pharmaceutically acceptable carrier. In certain embodiments, a compound described herein is provided in an effective amount in the pharmaceutical composition. In certain embodiments, the effective amount is a therapeutically effective amount. In certain embodiments, the effective amount is a prophylactically effective amount.

[0493]

[0429] Pharmaceutical compositions described herein can be prepared by any method known in the art of pharmacology. In general, such preparatory methods include bringing the compound of Formula (I), or a pharmaceutically acceptable salt or isotopically labeled derivative thereof, into association with a carrier or excipient, and / or one or more other accessory ingredients, and then, if necessary and / or desirable, shaping, and / or packaging the product into a desired single- or multi-dose unit.

[0494]

[0430] Relative amounts of the compound of Formula (I), or a pharmaceutically acceptable salt or isotopically labeled derivative thereof, the pharmaceutically acceptable carrier, and / or any additional ingredients in a pharmaceutical composition described herein will vary, depending upon the identity, size, and / or condition of the subject treated and further depending upon the route by which the composition is to be administered.

[0495]

[0431] Pharmaceutically acceptable carriers used in the manufacture of provided pharmaceutical compositions include inert diluents, solvents, dispersing and / or granulating agents, surface active agents and / or emulsifiers, disintegrating agents, binding agents, preservatives, buffering agents, lubricating agents, oils, butters, and / or waxes. Excipients such as coloring agents, coating agents, sweetening agents, flavoring agents, and fragrances may also be present in the composition.

[0496]

[0432] The compounds and compositions provided herein can be administered by any route, including enteral (e.g., oral), parenteral, intravenous, intramuscular, intra-arterial, intramedullary, intrathecal, subcutaneous, intraventricular, transdermal, intradermal, rectal, intravaginal, intraperitoneal, topical (as by powders, ointments, creams, and / or drops), mucosal, nasal, buccal, sublingual; by intratracheal instillation, bronchial instillation, and / or inhalation; and / or as an oral spray, nasal spray, and / or aerosol. Specifically contemplated routes are oral administration, intravenous administration (e.g., systemic intravenous injection), regional administration via blood and / or lymph supply, and / or direct administration to an affected site. In general, the most appropriate route of administration will depend upon a variety of factors including the nature of the compound (e.g., its stability in the environment of the gastrointestinal tract), and / or the condition of the subject (e.g., whether the subject is able to tolerate oral administration).

[0497]

[0433] Although the descriptions of pharmaceutical compositions provided herein are principally directed to pharmaceutical compositions which are suitable for administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to animals of all sorts. Modification of pharmaceutical compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and / or perform such modification with ordinary experimentation.

[0498]

[0434] Compounds provided herein are typically formulated in dosage unit form for ease of administration and uniformity of dosage. It will be understood, however, that the total daily usage of the compositions described herein will be decided by a physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular subject or organism will depend upon a variety of factors including the disease being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex, and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific active ingredient employed; the duration of the treatment; drugs used in combination or coincidental with the specific active ingredient employed; and like factors well known in the medical arts.

[0499]

[0435] The exact amount of a compound required to achieve an effective amount will vary from subject to subject, depending, for example, on species, age, and general condition of a subject, severity of the side effects or disorder, identity of the particular compound, mode of administration, and the like. An effective amount may be included in a single dose (e.g., 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 include different or substantially the same amounts of a compound described herein.

[0500]

[0436] A compound or composition, as described herein, can be administered in combination with one or more additional pharmaceutical agents (e.g., therapeutically and / or prophy tactically active agents). The compounds or compositions can be administered in combination with additional pharmaceutical agents, for example, to improve the compound or composition activity (e.g., potency and / or efficacy) in treating a disease, disorder, or condition in a subject in need thereof, in preventing a disease, disorder, or condition in a subject in need thereof (e.g., in reducing the risk of developing a disease, disorder, or condition in a subject with such a predisposition), and / or to improve bioavailability and / or safety, reduce drug resistance, reduce and / or modify metabolism, inhibit excretion, and / or modify distribution in a subject or cell. It will also be appreciated that the treatment employed may achieve a desired effect for the same disease, disorder, or condition, and / or it may achieve different effects. iii. Methods of Treatment and Prevention

[0501]

[0437] In some aspects, the present disclosure provides a method of treating or preventing a condition, disease, or disorder in a subject in need thereof, comprising administering to the subject a compound of Formula (I), or a pharmaceutically acceptable salt or isotopically labeled derivative thereof, or a pharmaceutical composition thereof. In certain embodiments, a compound described herein is provided in an effective amount. In certain embodiments, the effective amount is a therapeutically effective amount. In certain embodiments, the effective amount is a prophylactically effective amount.

[0502]

[0438] In some aspects, the present disclosure provides a compound of Formula (I), or a pharmaceutically acceptable salt or isotopically labeled derivative thereof, or a pharmaceutical composition thereof, for use in treating or preventing a condition, disease, or disorder.

[0503]

[0439] In some aspects, the present disclosure provides use of a compound of Formula (I), or a pharmaceutically acceptable salt or isotopically labeled derivative thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for treating or preventing a condition, disease, or disorder.

[0504]

[0440] In certain embodiments, the condition, disease, or disorder is due to abnormally elevated levels of cytokines in the TYK2 -dependent pathway (“TYK2 activity” and a “TYK2 -mediated condition, disease, or disorder”).

[0505]

[0441] In some aspects, the present disclosure provides a method of inhibiting TYK2 activity in a cell (e.g., in vitro or in vivo), comprising contacting the cell with a compound of Formula (I), or a pharmaceutically acceptable salt or isotopically labeled derivative thereof, or a pharmaceutical composition thereof. In certain embodiments, a compound described herein is provided in an effective amount. In certain embodiments, the effective amount is a therapeutically effective amount. In certain embodiments, the effective amount is a prophylactically effective amount.

[0506]

[0442] In some aspects, the present disclosure provides compound of Formula (I), or a pharmaceutically acceptable salt or isotopically labeled derivative thereof, for use in inhibiting TYK2 activity (e.g., in vitro or in vivo).

[0507]

[0443] In some aspects, the present disclosure provides use of compound of Formula (I), or a pharmaceutically acceptable salt or isotopically labeled derivative thereof, in the manufacture of a medicament for inhibiting TYK2 activity (e.g., in vitro or in vivo).

[0508]

[0444] In certain embodiments, the condition, disease, or disorder is an inflammatory disorder. In certain embodiments, the condition, disease, or disorder is a neurodegenerative disorder. In certain embodiments, the condition, disease, or disorder is an autoimmune disorder. In certain embodiments, the condition, disease, or disorder is selected from the group consisting of an inflammatory skin disorder, an inflammatory gastrointestinal disorder, a joint inflammatory disorder, an autoimmune disorder, an ocular inflammatory disorder, a neurodegenerative disorder, or a demyelinating neuroinflammatory disorder.

[0509]

[0445] In certain embodiments, the condition, disease or disorder is an inflammatory skin disorder. Exemplary inflammatory skin disorders include but are not limited to psoriasis and dermatomyositis.

[0510]

[0446] In certain embodiments, the condition, disease or disorder is an inflammatory gastrointestinal disorder. Exemplary inflammatory gastrointestinal disorders include but are not limited to inflammatory bowel disease (IBD), which includes Crohn’s Disease and ulcerative colitis. In certain embodiments, the IBD is Crohn’s Disease. In certain embodiments, the IBD is ulcerative colitis.

[0511]

[0447] In certain embodiments, the condition, disease or disorder is a joint inflammatory disorder. Exemplary joint inflammatory disorders include but are not limited to psoriatic arthritis, rheumatoid arthritis juvenile idiopathic arthritis, and ankylosing spondylitis. In certain embodiments, the joint inflammatory disorder is peripheral. In certain embodiments, the joint inflammatory disorder is axial.

[0512]

[0448] In certain embodiments, the condition, disease or disorder is an autoimmune disorder. Exemplary autoimmune disorders include but are not limited to systemic lupus erythematosus (SLE), type I diabetes, type I interferonopathies, cutaneous lupus, lupus nephritis, discoid lupus, primary biliary cirrhosis, systemic sclerosis, and Sjogren’s syndrome.

[0513]

[0449] In certain embodiments, the condition, disease or disorder is an ocular inflammatory disorder. Exemplary ocular inflammatory disorders include but are not limited to uveitis and age-related macular degeneration (AMD).

[0514]

[0450] In certain embodiments, the condition, disease or disorder is a neurodegenerative disorder. Exemplary neurodegenerative disorders include but are not limited to Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, Huntington's disease, a frontotemporal disorder, and traumatic brain injury (TBI).

[0515]

[0451] In certain embodiments, the condition, disease or disorder is a demyelinating neuroinflammatory disorder. Exemplary demyelinating neuroinflammatory disorders include but are not limited to multiple sclerosis and neuromyelitis optica.

[0516]

[0452] In certain embodiments, the condition, disease or disorder is a systemic disorder, which is a disorder affecting a number of organics and tissues or affects the body as a whole. Exemplary systemic disorders include, but are not limited to, psoriasis, psoriatic arthritis, Crohn’s Disease, ulcerative colitis, systemic lupus erythematosus, cutaneous lupus, lupus nephritis, discoid lupus, ankylosing spondylitis, type I diabetes, type I interferonopathies, rheumatoid arthritis, juvenile idiopathic arthritis, uveitis, and primary biliary cirrhosis.

[0517]

[0453] In certain embodiments, the condition, disease or disorder is a central nervous system disorder (CNS) disorder, which is a neurologic disorder affecting the structure of function of the brain, spinal cord, autonomic and / or peripheral nerves. Exemplary CNS disorders include, but are not limited to, Parkinson’s disease, amyotrophic lateral sclerosis, Alzheimer’s disease, multiple sclerosis, neuromyelitis optica, traumatic brain injury, Huntington's disease, and frontotemporal disorders. iv. Methods of Preparation

[0518]

[0454] Compounds of Formula (I) may be synthesized following the General Schemes A-D, as described and provided below. The Examples further described non-1imiting examples of these general syntheses and other preparations. Isotopically labeled derivatives of the intermediates and final products are contemplated herein.

[0519]

[0455] For example, as depicted in General Scheme A, Step 1 involves coupling of a compound of Formula (Al), or salt thereof, with a compound of Formula (Bl), or salt thereof, to provide a compound of Formula (C), or salt thereof, wherein LGi is bromo or iodo. In certain embodiments, the Step 1 coupling is a CH-activation reaction. See, e.g., Zheng, et al., Tetrahedron Lett. (2019) 60(51): 151316 and the Examples for exemplary CH-activation reaction conditions. Step 2 involves coupling of a compound of Formula (C), or salt thereof, with a compound of Formula (D), or salt thereof, to provide a compound of Formula (I), or salt thereof. In certain embodiments, the Step 2 coupling is a Buchwald- Hartwig palladium-catalyzed amination reaction. See, e.g., Ruiz-Castillo, et al., Chem. Rev. (2016) 116(19): 12564-12649 and the Examples for exemplary amination reaction conditions. Alternatively, as depicted in General Scheme A, the compound of Formula (I), or salt thereof, may be prepared by coupling of a tin compound of Formula (A2), or salt thereof, or a boronic ester compound of Formula (A3), or salt thereof, with a compound of Formula (B2), wherein each R is independently C1-6alkyl or C1-6alkylCearyl or two R groups attached to the different oxygen atoms of the boronic ester are joined to form a 5-6 membered ring optionally substituted with one or two C1-6alkyl, and LG2 is bromo or iodo, to provide the compound of Formula (C), or salt thereof. Both (A2) and (A3) may be prepared by treating the compound of Formula (Al) with a tin reagent of formula LG^SnRs (to provide A2) or a boronic ester reagent of formula LG5-B(OR)2 (to provide A3), wherein LG4 is chloro, bromo, or chloro, and LG5 is -OR or -B(OR)2 See, e.g., Miyaura, et al. Chem. Rev. (1995) 95:2457-2483; Martin, et al. Acc. Chem. Res. (2008), 41(11): 1461-1473 and the Examples for exemplary boronic ester preparation and coupling (e.g., Suzuki) reaction conditions. See, e.g., Stille, et al. Org. Synth. (1993) 71:97 or the Examples for exemplary tin reagent preparation and coupling reaction conditions.

[0520] General Scheme A

[0521]

[0456] As depicted in General Scheme B. Step 1 involves coupling of a compound of Formulae (F1A)- (F1B), or salt thereof, with a compound of Formula (Bl), or salt thereof, to provide a compound of Formula (I), or salt thereof. In certain embodiments, the Step 1 coupling is a CH-activation reaction. See, e.g., Ruiz-Castillo, et al., Chem. Rev. (2016) 116(19): 12564-12649 and the Examples for exemplary amination reaction conditions. The compound of Formulae (FIA)-(FIB), or salt thereof, may be prepared from 6-chloro-2,7-naphthyridin-1-ol, as described in the Examples section. Alternatively, as depicted in General Scheme B. the compound of Formula (I), or salt thereof, may be prepared coupling of a tin compound of Formula (F2), or salt thereof, or a boronic ester compound of Formula (F3), or salt thereof, with a compound of Formula (B2), wherein each R is independently C1-6alkyl or C1-6alkylCearyl or two R groups attached to the different oxygen atoms of the boronic ester are joined to form a 5-6 membered ring optionally substituted with one or two C1-6alkyl, and LG2 is bromo or iodo, to provide the compound of Formula (I), or salt thereof. Both (F2) and (F3) may be prepared by treating the compound of Formulae (FIA)-(FIB) with a tin reagent of formula LG^SnRs (to provide F2) or a boronic ester reagent of formula LG5-B(OR)2 (to provide F3), wherein LG4 is chloro, bromo, or chloro, and LG5 is -OR or -B(OR)2, wherein R is as defined above. See, e.g., Miyaura, et al. Chem. Rev. (1995) 95:2457-2483; Martin, et al. Acc. Chem. Res. (2008), 41(11): 1461-1473 and the Examples. See, e.g., Stille, et al. Org. Synth. ( 1993) 71 : 97 or the Examples for exemplary tin reagent preparation and coupling reaction conditions. General Scheme B

[0522]

[0457] As depicted in General Scheme C. Step 1 involves coupling of a compound of Formula (G), or salt thereof, with a compound of Formula (B2), or salt thereof, to provide a compound of Formula (H), or salt thereof, wherein PG1is an amino protecting group. In certain embodiments, PG1is a paramethoxybenzyl (PMB) group. In certain embodiments, the Step 1 coupling is a Buchwald-Hartwig palladium-catalyzed amination reaction. See, e.g., Ruiz-Castillo, etal., Chem. Rev. (2016)

[0523] 116(19): 12564-12649 and the Examples for exemplary amination reaction conditions. Step 2 involves deprotecting the compound of Formula (H), or salt thereof, to provide a compound of Formula (J), or salt thereof. Step 3 involves peptide coupling of the amine moiety of the compound of Formula (J), or salt thereof, with the carboxylic acid moiety of the compound of Formula (K), or salt thereof, to provide a compound of Formula (I), or salt thereof. Exemplary peptide coupling conditions are described in El- Faham et al., Chemical Reviews (2011) 111:6557-6602, and as described in the Examples.

[0524] General Scheme C

[0525] 1458] As depicted in General Scheme I). Step 1 involves peptide coupling of the amine moiety of a compound of Formula (L), or salt thereof, wherein Hal is bromo or iodo, with the carboxylic acid moiety of a compound of Formula (K), or salt thereof, to provide a compound of Formula (M), or salt thereof. Exemplary peptide coupling conditions are described in El-Faham et al., Chemical Reviews (2011) 111:6557-6602, and as described in the Examples. Step 2 involves coupling of the compound of Formula (M), or salt thereof, with a compound of Formula (Bl), or salt thereof, to provide a compound of Formula (I), or salt thereof. In certain embodiments, the Step 2 coupling is a Buchwald-Hartwig palladium-catalyzed amination reaction. See, e.g., Ruiz-Castillo, et al., Chem. Rev. (2016) 116(19): 12564-12649 and the Examples for exemplary amination reaction conditions. v. Biological Assays

[0526]

[0459] Compounds designed, selected and / or optimized by methods described above, once produced, can be characterized using a variety of assays known to those skilled in the art to determine whether the compounds have activity against the target. For example, the compounds can be characterized by conventional assays, including but not limited to those assays described below, to determine whether they have a predicted activity, binding activity and / or binding specificity.

[0527]

[0460] Furthermore, high-throughput screening can be used to speed up analysis using such assays. As a result, it can be possible to rapidly screen the molecules described herein for activity, using techniques known in the art. General methodologies for performing high-throughput screening are described, for example, in Devlin (1998) High Throughput Screening, Marcel Dekker; and U.S. Patent No. 5,763,263. High-throughput assays can use one or more different assay techniques including, but not limited to, those described below.

[0528]

[0461] Various in vitro or in vivo biological assays may be suitable for detecting the effect of the compounds of the present disclosure. These in vitro or in vivo biological assays can include, but are not limited to, enzymatic activity assays, electrophoretic mobility shift assays, reporter gene assays, in vitro cell viability assays, binding assays, cellular assays (cell lines, primary cells and whole blood), in vitro cell viability assays, as well as assays for determining TYK2 inhibitory activity, selectivity, brain penetrance, metabolic stability, solubility, clearance, permeability and efflux, and hERG inhibition.

[0529]

[0462] Inhibitory Activity . In some embodiments, the compounds may be tested for their TYK2 inhibitory activity using known procedures, such as the methodology reported Burke et al., Science Translational Medicine (2019) 11:502. In some embodiments, the compounds of the instant disclosure may be tested for their binding to the TYK2 JH2 domain. See also the TYK2 JH2 domain binding assay described in the Assay Methods section of the Examples.

[0463] Selectivity. To determine TYK2 selectivity of test compounds over JAK1 and / or JAK2 in a physiologically relevant setting, one or more assays may be performed in human peripheral blood mononuclear cells (hPBMC8), e.g., an IFN alpha assay (TYK2 / JAK1 phospho-STAT4), an IL-7 assay (JAK1 / JAK3 phospho-STAT5) and a GM-CSF assay (JAK2 phospho-STAF5). The levels of phospho- STAF in cell lysates may then be determined by electrochemiluminescence. If a compound shows activity at inhibiting the phosphorylation of STAF4 in the IFN alpha assay (i.e. TYK2 / JAK1) but shows minimal activity at inhibiting the phosphorylation of STAF5 in the IL-7 assay (i.e. JAK1 / JAK3), it can be assumed that the inhibition of the IFNa assay is due to inhibition of TYK2, not JAK1. The GM-CSF assay may be used to determine JAK2 activity. The selectivity for TYK2 may be calculated by performing a ratio of the two IC50’ s in question, to provide the fold (increase or decrease) change. For example, the TYK2 fold-selectivity over JAK1 and / or JAK3 may be calculated as follows: IC50 in IL-7 assay divided by the IC50 in IFN alpha assay. The TYK2 fold-selectivity over JAK2 may be calculated as follows: IC50 in GM-CSF assay divided by the IC50 in IFN alpha assay. See also the Assay Methods section of the Examples.

[0530]

[0464] Brain Penetrance. In some embodiments, the compounds may be tested for brain penetrance using known procedures, such as the methodology reported in Loryan et al., Pharmaceutical Research (2022) 39: 1321-1341. For example, a Kp ratio or Kpu,u value greater than or equal to 0.3 may be considered brain penetrant (e.g., between >0.3 and 10, inclusive), and Kp ratio or a Kpu,u value of less than 0.3 (e.g., between 0. 1 to < 0.3, inclusive) may be considered not brain penetrant.

[0531]

[0465] Stability and In Vitro Clearance. In some embodiments, the stability of compounds may be determined using a hepatocyte stability assay, which is used to determine the metabolic stability of a compound in hepatocytes (liver cells) or liver microsomes. This type of assay provides valuable information about how quickly a drug is metabolized in the liver and can be used to assess its potential effectiveness and safety in drug discovery. In one exemplary assay, hepatocytes from the species of interest (e.g., mouse, rat, dog, monkey, human) are incubated with the test compound at a controlled temperature of 37 °C for different time periods (e.g. , 5, 15, 30, 60, and 120 minutes). At each time point during the incubation, samples are taken, the reaction is terminated, and the amount of test compound remaining analyzed using LC-MS / MS to monitor the disappearance of the test compound over time (Gradient). From these data, a half-1ife can be calculated (t 'A = time it takes for A of the test compound to be consumed in the hepatocyte incubation). In some embodiments, the compound is metabolically stable, e.g. , having a half-1ife in mouse, rat, dog, human, or monkey liver microsomes or hepatocytes of >20 minutes, >30 minutes, >40 minutes, >50 minutes, >60 minutes, >120 minutes, >240 minutes, >480 minutes, between about 30 minutes to about 120 minutes, between about 60 minutes to about 120 minutes, or between about 60 minutes to about 480 minutes. Metabolic stability as expressed by half-1ife in mouse, rat, dog, human, or monkey liver microsomes or hepatocytes may be indicative of improved metabolic stability in human. See, e.g., Coe et al., Methods in Pharmacology & Toxicology (2008) 151.

[0532]

[0466] In addition, from the hepatocyte stability assay data, the following parameters may be calculated: (i) the in vitro intrinsic clearance (CLmt in pL / min / million cells), which is a direct measure of the rate at which hepatocytes metabolize a compound in a controlled in vitro experiment and allows for comparison of metabolism rates across compounds in a uniform experimental setup, (ii) the scaled intrinsic clearance (scaled CLint in mL / min / kg), which is an extrapolation of the in vitro intrinsic clearance to estimate the metabolic clearance rate in a whole organism, normalized by body weight, and is calculated by multiplying the in vitro intrinsic clearance by a species-specific scaling factor which accounts for the number of hepatocytes in the liver and the liver’s size relative to the organism, and provides an organism-1evel clearance prediction, bridging the gap between in vitro results and real- world pharmacokinetics, and (iii) the predicted hepatic clearance (Qh in mL / min / kg), which can be predicted from the scaled CLmtby taking into account the liver physiology and blood flow, using a pharmacokinetic model such as the well-stirred model. Qh = (Qh x CLmt) / (Qh + CLmt) where Qh is the liver blood flow). Predicted hepatic clearance (Qh in mL / min / kg) is a useful metric confirming the in vitro hepatic clearance for each species, such as mouse, rat, dog, monkey, and human, correlate to the actual in vivo clearance measured. A good correlation across species also provides confidence in the in vitro predicted value, allowing for streamlined and efficient in vitro testing instead of in vivo testing during drug discovery.

[0533]

[0467] Solubility. In some embodiments, the solubility of compounds may be determined following known procedures, such as described in Alsenz and Kansy, Advanced Drug Delivery Reviews (2007) 59:546-567, and Wang et al. J Mass Spectrom. (2000) 35:71-76. For example, the kinetic solubility in physiologically relevant media, such as phosphate buffered solution (PBS, pH 7.4) or simulated gastric fluid (SGF), may be measured using serial dilution and two hour incubation period, followed by filtration, and reported in pM by LC-MS / MS. Thermodynamic solubility in physiologically relevant media may be measured by LC-MS / MS, after a twenty-four hour incubation, followed by filtration, and reported in mg / mL. Optimized solubility may be beneficial for manufacturing and further processing of the compound. Furthermore, optimized solubility allows for a more efficient in vitro analysis of the compound, including data collection around the compound’s safety, drug-drug interactions, potency, selectivity, metabolism and permeability. In general, a solubility of >20 mM in PBS, such as >100 mM, in PBS, may be a desirable solubility profile. See also the Assay Methods section of the Examples.

[0534]

[0468] In Vivo Clearance. In some embodiments, the clearance of compounds may be determined using a clearance assay. For example, mouse clearance may be measured by dosing C57BL6 mice via IV Bolus dose administration of 0.5 mg / kg of test compound formulized in 5% DMSO + 10% Kolliphor HS-15, with blood being drawn at different timepoints. Concentration of test compound in blood at various timepoints may be quantified using LC-MS / MS. The clearance in mL / min / kg may be determined by dividing the dose administrated by the AUC (area under the curve- Blood cone vs time). See, e.g., Smith et al., Clearance in Drug Design (2019) 62:2245-2255. In some embodiments, the compounds may be tested for unbound clearance (Qu) following known procedures, such as described in Miller et al., J. Med. Chem. (2020) 63: 12156-12170. For example, unbound clearance (Qu) may be calculated by dividing total clearance (‘CL’ in mL / min / kg) as measured in blood or plasma by the unbound fraction in plasma (fu). See also the Assay Methods section of the Examples.

[0535]

[0469] Permeability and Efflux. In some embodiments, the permeability of compounds may be determined following known procedures, such as described in Wang et al. J Mass Spectrom. (2000) 35:71-76. For example, permeability across cell membranes may be measured using either Caco-2 or MDCK-MDR1 cell lines in Transwell plates, after measuring the compound in both apical and basolateral chambers, and reported as an apparent permeability Papp A-B in IO-6cm / s. In some embodiments, the permeability of compounds may be determined using a MDCK-MDR1 permeability assay. This assay is a commonly used in vitro method to evaluate the permeability and efflux of compounds across cell monolayers. It specifically assesses the ability of a substance to be transported by the multidrug resistance protein 1 (MDR1), also known as P-glycoprotein (P-gp), which is an efflux transporter involved in the elimination of many drugs from cells. To perform the MDCK-MDR1 permeability assay, a cell line derived from Madin-Darby Canine Kidney (MDCK) cells that express the MDR1 protein is used. These modified MDCK cells form a monolayer on a permeable support, such as a Transwell® insert. The assay can be conducted by applying the test compound separately to both the apical side and basolateral side of the MDCK-MDR1 monolayer and incubating the cells at an appropriate temperature, typically 37 °C, for a specific time period (2 hours in our experiment) to allow the compound to permeate through the monolayers. At the end of the incubations, samples are collected from both the apical and basolateral compartments and the concentration of the test compound in each compartment is determined using LC-MS / MS and a flux from apical to basolateral (A-B) direction and from basolateral to apical (B-A) direction are reported as apparent permeability’s Papp in IO-6cm / s.

[0536] The efflux ratio, which represents the transport efficiency of the compound, is calculated by dividing the flux from basolateral to apical (Papp B-A) by the flux from apical to basolateral (Papp A-B). See, e.g., E. H.; Di, L.; Kems, E. H. Drug-like properties: Concepts, Structure Design and methods,' Academic Press, 2008. See also the Assay Methods section of the Examples.

[0537]

[0470] hERG inhibition. The human ether-a-go-go related gene (hERG) is associated with cardiac potassium channel inhibition leading to QT-interval prolongation, a severe cardiovascular toxicity responsible for numerous drug attrition in the clinic, and low hERG inhibition decreases the risk of cardiovascular toxicity. A generally acceptable ranking system used to identify the potency of a test compound inhibiting hERG channel is as follows: a) Low: IC50 > 30 pM; b) Moderate: 10 pM < IC50 < 30 pM; c) High: IC50 < 10 pM. An exemplary assay which may be used to evaluate the potential inhibitory effect of a test compound on the hERG channel is a manual patch-clamp system performed using a transfected HEK293 cell line with a hERG gene, and using dofetilide as a positive control. See, e.g., Roche et al., ChemBioChem. (2002) 3:455-459; Glenn et al., Journal of Pharmacological and Toxicological Methods (2004) 50:93-101; and Roger et al., Computer Methods and Programs in Biomedicine (2004) 74, 167-181. vi. Additional Embodiments

[0538]

[0471] Embodiments of the present disclosure further include:

[0472] Embodiment 1. A compound of Formula (I): or a pharmaceutically acceptable salt thereof, wherein:

[0539] R1is C3-4 carbocyclyl or 3-4 membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is substituted with 0, 1, 2, or 3 instances of R1A; each instance of R1Ais independently C1-3 alkyl, C1-3 haloalkyl, halogen, or -OR', or two R1Agroups attached to the same carbon atom are joined to form a C3-6 carbocyclyl or 3-6 membered heterocyclyl, or two R1Agroups attached to vicinal atoms are joined to form a C3-6 carbocyclyl or 3-6 membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is substituted with 0, 1, 2, or 3 substituents independently selected from C1-3 alkyl, C1-3 haloalkyl, halogen, -C(=O)OR', and -OR'; each X is independently selected from H and halogen;

[0540] G1is CRG1or N and G2is CRG2or N; each of RG1and RG2is independently selected from H, halogen, C1-6 alkyl, C1-6 haloalkyl, and -(Li)-O-(CH2CH2O)m-R', wherein Li is absent, C1-3 alkylene, or C1-3 haloalkylene, and wherein m is 0, 1 or 2;

[0541] G3is N or CR3and G4is N or CR4, provided at least one of G3and G4is CR3or CR4, and at least one of said R3and R4is not H;

[0542] G5is O, N, S, or N-RG5, wherein RG5is H, C1-3 alkyl, or C1-3 haloalkyl;

[0543] G6is C or N;

[0544] G7is C or N;

[0545] R3and R4are each independently H, halogen, C1-6 alkyl, C1-6 haloalkyl, -(L2)-(Y)-C3-10 carbocyclyl, -(L2)-(Y)-(4- 10 membered heterocyclyl), -(L2)-(Y)-C6-10 aryl, -(L2)-(Y)-(5- 10 membered heteroaryl), -(L2)-ORA, -(L2)-N(RA)2, -(L2)-SRA, -(L2)-CN, -(L2)-(Y)-C(=O)RA, -(L2)-(Y)-C(=O)ORA, -(L2)-(Y)-C(=O)N(RA)2, -(L2)-S(=O)2RA, -(L2)-S(=O)2ORA, -(L2)-(¥)-S(=O)2N(RA)2, or -B(ORA)2, wherein L2 is absent, C1-3 alkylene, or C1-3 haloalkylene; Y is absent, -O-, or -N(RA)-; and each alkyl, haloalkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, alkylene, or haloalkylene is independently substituted with 0, 1, 2, or 3 instances of RB; each instance of RAis independently H, C1-6 alkyl, C1-6 haloalkyl, -(L3)-(Z)-C3-10 carbocyclyl, -(L3)-(Z)-(3- 10 membered heterocyclyl), -(L3)-(Z)-C6-10 aryl, or -(L3)-(Z)-(5- 10 membered heteroaryl), or two RAgroups (i) attached to the same nitrogen atom or (ii) attached to two oxygen atoms which are attached to the same boron atom are joined to form a 4-6 membered heterocyclyl; wherein L3 is absent, C1-3 alkylene, or C1-3 haloalkylene; Z is absent or -O-; and each alkyl, haloalkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, alkylene, or haloalkylene is independently substituted with 0, 1, 2, or 3 instances of RB; each instance of RBis independently halogen, C1-6 alkyl, Ci-6 haloalkyl, C3-10 carbocyclyl, -CN, -OR', -N(R')2, -SR', -C(=O)R', -C(=O)OR', -C(=O)N(R')2, or two RBattached to the same carbon atom are taken together to form =0; wherein each alkyl and haloalkyl is independently substituted with 0 or 1 =0; and each carbocyclyl is independently substituted with 0, 1, 2, or 3 instances of Rc; each instance of Rcis independently halogen, C1-6 alkyl, or C1-6 haloalkyl, or two Rcattached to the same carbon atom are taken together to form =0; each instance of R' is independently H, C1-6 alkyl, or C1-6 haloalkyl, or two R' groups attached to the same nitrogen atom are joined to form a 4-6 membered heterocyclyl, wherein the alkyl, haloalkyl, or heterocyclyl is substituted with 0, 1, 2, or 3 R"; each instance of R" is independently halogen, -CN, -OR'", -N(R'")2, or -SR'", or two R" attached to the same carbon atom are taken together to form =0; and each instance of R'" is independently H, C1-3 alkyl, or C1-3 haloalkyl, or two R'" groups attached to the same nitrogen atom are joined to form a 4-6 membered heterocyclyl, wherein the heterocyclyl is substituted with 0, 1, 2, or 3 halogen.

[0546]

[0473] Embodiment 2. The compound of embodiment 1, or a pharmaceutically acceptable salt thereof, wherein G5is O, and each of G6and G7is C, such that the bicyclic ring system of formula:

[0547]

[0474] Embodiment 3. The compound of embodiment 1, or a pharmaceutically acceptable salt thereof, wherein each of G5and G6is N, and G7is C, such that the bicyclic ring system of formula:

[0548]

[0475] Embodiment 4. The compound of embodiment 1, or a pharmaceutically acceptable salt thereof, wherein G5is S, and each of G6and G7is C, such that the bicyclic ring system of formula:

[0549]

[0476] Embodiment 5. The compound of embodiment 1, or a pharmaceutically acceptable salt thereof, wherein G5is NRG5, and each of G6and G7is C, such that the bicyclic ring system of formula:

[0550]

[0477] Embodiment 6. The compound of embodiment 1, or a pharmaceutically acceptable salt thereof, wherein G5is CRG5, G6is N, and G7is C, such that the bicyclic ring system of formula:

[0551]

[0478] Embodiment 7. The compound of embodiment 1, or a pharmaceutically acceptable salt thereof, wherein G5is CRG5, G6is C, and G7is N, such that the bicyclic ring system of formula:

[0552]

[0479] Embodiment 8. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R1is C3 carbocyclyl (cyclopropyl) substituted with 0, 1, 2, or 3 instances of R1A.

[0553]

[0480] Embodiment 9. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R1is cyclopropyl substituted with 0, 1, 2, or 3 instances of -F.

[0554]

[0481] Embodiment 10. The compound of any one of embodiments 1-8, or a pharmaceutically acceptable salt thereof, wherein R1is cyclopropyl substituted with 2 instances of R1A, wherein two R1Agroups attached to the same carbon atom are joined to form a 3-6 membered heterocyclyl substituted with 0 or 1 substituents independently selected from C1-3 alkyl and C1-3 haloalkyl.

[0555]

[0482] Embodiment 11. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein at least one X is H.

[0556]

[0483] Embodiment 12. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein -CX3 is -CH3.

[0557]

[0484] Embodiment 13. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein at least one X is halogen.

[0558] [485J Embodiment 14. The compound of any one of embodiments 1-11 and 13, or a pharmaceutically acceptable salt thereof, wherein -CX3 is -CHF2 or -CH2F

[0486] Embodiment 15. The compound of any one of the preceding embodiments, wherein the compound is of Formula:

[0559] or a pharmaceutically acceptable salt thereof, wherein n is 0, 1 , or 2.

[0560]

[0487] Embodiment 16. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein G1is CRG1and G2is CRG2.

[0561]

[0488] Embodiment 17. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein at least one of RG1and RG2is H, and at least one of RG1and RG2is selected from H, halogen, C1-3 alkyl, C1-3 haloalkyl, and -OR'.

[0562]

[0489] Embodiment 18. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein at least one of RG1and RG2is H, and at least one of RG1and RG2is selected from H, -F, -CHF2, and -OCH3.

[0563]

[0490] Embodiment 19. The compound of any one of embodiments 1-18, or a pharmaceutically acceptable salt thereof, wherein G3is N or CR3and G4is CR4.

[0564]

[0491] Embodiment 20. The compound of any one of embodiments 1-18, or a pharmaceutically acceptable salt thereof, wherein G3is CR3and G4is N or CR4.

[0565]

[0492] Embodiment 21. The compound of any one of embodiments 1-18, or a pharmaceutically acceptable salt thereof, wherein G3is CR3and G4is CR4.

[0566]

[0493] Embodiment 22. The compound of any one of embodiments 1-18, or a pharmaceutically acceptable salt thereof, wherein G3is CH and G4is CR4.

[0567]

[0494] Embodiment 23. The compound of any one of embodiments 1-18, or a pharmaceutically acceptable salt thereof, wherein G3is CR3and G4is CH.

[0568]

[0495] Embodiment 24. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein at least one of R3or R4is C1-6 alkyl, C1-6 haloalkyl, - (L2)-(Y)-C3-10 carbocyclyl, -(L2)-(Y)-(4-10 membered heterocyclyl), -(L2)-(Y)-C6-10 aryl, -(L2)-(Y)-(5-10 membered heteroaryl), -(L2)-ORA, -(L2)-C(=O)ORA, or -B(ORA)2, wherein L2 is absent, C1-3 alkylene, or C1-3 haloalkylene; and wherein each alkyl, haloalkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, alkylene, or haloalkylene is independently substituted with 0 or 1 instances of RB.

[0569]

[0496] Embodiment 25. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein at least one of R3or R4is C1-6 alkyl, -(L2)-(Y)-C3-10 carbocyclyl, -(L2)-(Y)-(4-10 membered heterocyclyl), -(L2)-(Y)-(5-10 membered heteroaryl), -(L2)- ORA, -(L2)-C(=0)0RA, or -B(0RA)2, wherein L2is absent, C1-3 alkylene, or C1-3 haloalkylene; and wherein each alkyl, carbocyclyl, heterocyclyl, heteroaryl, alkylene, or haloalkylene is independently substituted with 0 or 1 instances of RB.

[0570]

[0497] Embodiment 26. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein at least one of R3or R4is C1-3 alkyl, -(Y)-C4-6 carbocyclyl, -(Y)-(4-6 membered monocyclic heterocyclyl), -(Y)-6-10 membered bridged heterocyclyl, -(Y)-(5-6 membered heteroaryl), -(C1-3 alkylene)-ORA, -ORA, -C(=O)ORA, or -B(0RA)2, wherein each alkyl, carbocyclyl, heterocyclyl, heteroaryl, or alkylene is independently substituted with 0 or 1 instances of RB.

[0571]

[0498] Embodiment 27. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein at least one of R3or R4is C1-3 alkyl, -(Y)-(4-6 membered monocyclic heterocyclyl), -(Y)-6-10 membered bridged heterocyclyl, -(Y)-(5-6 membered heteroaryl), or -(C1-3 alkylene) -ORA, wherein each alkyl, heterocyclyl, heteroaryl, or alkylene is independently substituted with 0 or 1 instances of RB.

[0572]

[0499] Embodiment 28. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein at least one of R3or R4is of the formula: halogen, - B(ORA)2, -ORA, -(C1.3 alkylene)-ORA,

[0573] wherein z is 0, 1, 2, or 3, as valency permits.

[0574]

[0500] Embodiment 29. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein at least one of R3or R4is of the formula: wherein z is 0, 1, 2, or 3, as valency permits.

[0575]

[0501] Embodiment 30. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein at least one of R3or R4is of the formula:

[0576]

[0502] Embodiment 31. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein at least one of R3or R4is of the formula:

[0577] 2, or 3, as valency permits.

[0578]

[0503] Embodiment 32. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein Y is absent or -O-.

[0579]

[0504] Embodiment 33. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein each instance of RBis independently halogen, Ci-6 alkyl, Ci-6 haloalkyl, -OR', -C(=O)R', -C(=O)OR'.

[0580]

[0505] Embodiment 34. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein: each instance of R' is independently H, C1-3 alkyl, or C1-3 haloalkyl, wherein the alkyl or haloalkyl is substituted with 0, 1, 2, or 3 R"; each instance of R" is independently -CN, -OR'", -N(R"')2, or -SR'", or two R" attached to the same carbon atom are taken together to form =0; and each instance of R'" is independently H, C1-3 alkyl, or C1-3 haloalkyl.

[0581]

[0506] Embodiment 35. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein at least one of R3and R4is:

[0582]

[0507] Embodiment 36. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein at least one of R3and R4is:

[0583]

[0584]

[0508] Embodiment 37. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein:

[0585] G3is CR3;

[0586] G4is CR4; provided at least one of R3and R4is not H or F; optionally and further provided at least one of R3and R4is not -Cl or -B(OH)2; optionally and further provided at least one of R3and R4comprises a ring as described above and herein; optionally and further provided R3comprises a ring as described above and herein, and R4is H or F.

[0587]

[0509] Embodiment 38. The compound of any of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein n is 0.

[0588]

[0510] Embodiment 39. The compound of any one of embodiments 1-37, or a pharmaceutically acceptable salt thereof, wherein n is 1 or 2, R1Ais fluoro, or wherein two R1Agroups attached to the same carbon atom are joined to form a C3-5 carbocyclyl or 3-5 membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is substituted with 0 or 1 substituents independently selected from C1-3 alkyl and Ci -3 haloalkyl.

[0589]

[0511] Embodiment 40. The compound of any of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein each of G1and G2is CH.

[0590]

[0512] Embodiment 41. The compound of any of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein G3is CR3and G4is CR4, wherein R4is H.

[0591]

[0513] Embodiment 42. The compound of any of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein G3is CR3and G4is CR4, wherein R3is H.

[0592]

[0514] Embodiment 43. The compound of any one of the of any of the preceding embodiments, wherein the compound is of Formula: or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, or 2.

[0593]

[0515] Embodiment 44. The compound of any one of the of any of the preceding embodiments, wherein the compound is of Formula:

[0594] or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, or 2.

[0595]

[0516] Embodiment 45. The compound of any one of the preceding embodiments, wherein the compound is selected from those in Table 1, Table 2, and Table 3, and pharmaceutically acceptable salts of any of the foregoing.

[0596]

[0517] Embodiment 46. A pharmaceutical composition comprising the compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0597]

[0518] Embodiment 47. A method of treating or preventing a TYK2 -mediated condition, disease, or disorder in a subject in need thereof comprising administering to the subject a compound of any one of embodiments 1-45, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of embodiment 46.

[0598]

[0519] Embodiment 48. An in vivo or in vitro method of inhibiting tyrosine kinase 2 (TYK2) activity in a cell comprising contacting the cell with a compound of any one of embodiments 1-45, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of embodiment 46.

[0599]

[0520] Embodiment 49. A method of preparing a compound of Formula (I), or salt thereof, as defined in embodiment 1, following one or more steps as set forth in General Method Scheme A and / or General Method Scheme B.

[0600] EXEMPLIFICATION

[0601]

[0521] In order that this disclosure may be more fully understood, the following Examples are set forth.

[0602] It should be understood that these examples are for illustrative purposes only and are not to be construed as limiting this disclosure in any manner.

[0603] Analytical Methods

[0604]

[0522] Nuclear magnetic resonance (NMR) spectra were recorded at 400 MHz as stated and at 300.3 K unless otherwise stated; the chemical shifts (5) are reported in parts per million (ppm). Spectra were recorded using a Bruker Avance 400 instrument with 8, 16 or 32 scans. Typical NMR solvents include deuterated dimethylsulfoxide (DMSO-t / ,) and deuterated methanol (CD3OD).

[0605]

[0523] Liquid Chromatography - Mass Spectrometry (LCMS) chromatograms and spectra were recorded using a Shimadzu LCMS-2020. Injection volumes were 0.7 - 8.0 pl and the flow rates were typically 0.8 or 1.2 mL / min. Detection methods were diode array (DAD) or evaporative light scattering (ELSD) as well as positive ion electrospray ionization. MS range was 100 - 1000 Da. Mobile phases of water and / or acetonitrile (MeCN) may contain a modifier (typically 0.01 - 0.04 %) such as trifluoroacetic acid (TFA), formic acid (FA), or ammonium carbonate. ESI or ES = electrospray ionization; m / z = mass / charge; RT = retention time (minutes). Purification / Separation Methods. The synthetic methods describe purification and / or separation chromatographic methods which have been employed in the purification and / or isolation of the exemplified compounds. Rf = retention factor; RT = retention time (minutes); Prep-HPLC = Preparative High-performance liquid chromatography. Chiral SFC = chiral supercritical fluid chromatography.

[0606] Synthetic Methods

[0607]

[0524] The Asterix (*) next to the Compound Number (#) signifies that arbitrary stereochemistry has been assigned. “Rac” indicates a mixture of two or more stereoisomers in equal or unequal proportions. Future tense language (“may be” prepared) indicates experiments not yet conducted.

[0608] (i) Intermediates

[0609] Intermediate Example 1: Synthesis of 4-bromo-6-chloro-1-methyl-2,7-naphthyridine (Intermediate 1)

[0610] Intermediate 1

[0611] 4-bromo-6-chloro-1 -methyl-2,7- naphthyridine

[0612]

[0525] Step 1: To a solution of 6-chloro-2,7-naphthyridin-1(227)-one (11.0 g, 57.9 mmol, 1.0 equiv) in acetic acid (289 mL) was added bromine (5.93 mb, 116 mmol, 2.0 equiv). The reaction mixture was stirred at room temperature for Ih. After completion, the reaction was concentrated and azeotroped with heptanes to provide 4-bromo-6-chloro-2.7-naphthyridin- 1 (2 / / )-onc. The crude product was used for the next step without any further purification. LCMS: m / z [M+H]+= 261.0, RT = 0.83 min.

[0613]

[0526] Step 2: To a suspension of 4-bromo-6-chloro-2.7-naphthyridin- 1 (2 / / )-onc. and 2,6-di-tert-butyl- 4-methylpyridine (16.5 g, 77.0 mmol, 1.33 equiv) in dichloromethane (386 mL) at -78 °C was added triflic anhydride (20.3 mb, 116 mmol, 2.0 equiv) via syringe. The cold suspension was allowed to warm to room temperature over 30 minutes and stirred for an additional Ih. After completion of the reaction, a saturated solution of NaHCOs (200 mL) was added, and the mixture was extracted with ethyl acetate (ethyl acetate) (3 X 350 mL). The combined organic layers were dried over anhydrous Na2SO4 and were concentrated in vacuo. The residue was triturated with heptanes (160 ml, 10 mb / lg of pyridine) and filtered to obtain 4-bromo-6-chloro-2,7-naphthyridin-1-yl trifluoromethanesulfonate (15.8 g, 70 % over two steps). LCMS: non-ionized, RT = 1.57 min.

[0614]

[0527] Step 3: To a solution of 4-bromo-6-chloro-2,7-naphthyridin-1-yl trifluoromethanesulfonate (15.8 g, 40.4 mmol, 1.0 equiv) and tris(acetylacetonato) iron(III) (614 mg, 1.74 mmol, 4.3 mol%) in diethyl ether (289 mL) under a nitrogen atmosphere at 0 °C was added methylmagnesium bromide (17.0 mL, 57.7 mmol, 1.43 equiv). After completion, the reaction was concentrated quenched with saturated solution of NH4CI (100 mL), extracted with dichloromethane (dichloromethane) (3 x 200 mL). The organic phase was combined, dried, and concentrated to give 4-bromo-6-chloro-1-methyl-2,7- naphthyridine (Intermediate 1) (8 g, 77 % yield). LCMS: m / z [M+H]+= 259.0, RT = 1.11 min.1H NMR (400 MHz, CDCh) δ 9.34 (s, 1H), 8.73 (s, 1H), 7.97 (s, 1H), 3.00 (s, 3H).

[0615] Intermediate Example 2: Synthesis of 5-(methoxymethyl)benzo[d] oxazole (Intermediate 2)

[0616] Intermediate 2

[0617] 5-(methoxymethyl)benzo[d|oxazole

[0618]

[0528] Step 1: To the solution of 4-(chloromethyl)-2-nitrophenol (300 mg, 1.60 mmol, 1.0 equiv) in methanol (methanol) (3.16 mL) was added sodium methoxide (160 uL, 16.0 mmol, 10 equiv). The reaction was stirred at room temperature for Ih. After completion, the reaction was then quenched with aqueous HC1 IM (1 mL) and extracted with ethyl acetate (ethyl acetate) (3 x 10 mL). The organic phase was combined, dried over anhydrous sodium sulfate, and concentrated to yield crude 4- (methoxymethyl)-2-nitrophenol. LCMS: m / z [M-H]' = 182.1, RT = 0.14 min.

[0619]

[0529] Step 2: To the solution of above product in methanol (methanol) (3.16 mL) was added Pd / C (17.0 mg, 160 umol, 10 mol%). The reaction mixture was equipped with hydrogen balloon and stirred overnight at room temperature. After completion, the reaction was filtered, and filtrate was concentrated to give 2-amino-4-(methoxymethyl)phenol. LCMS: m / z [M+H]+= 154.1, RT = 0.38 min.

[0620]

[0530] Step 3: To the solution of product from step 2 in trimethylorthoformate (2.62 mL, 24.0 mmol, 15.0 equiv) was added acetic acid (AcOH) (3 mL). The resulting mixture was stirred under microwave for 30 min at 160 °C. The reaction mixture was then concentrated to yield 5- (methoxymethyl)benzo[d] oxazole (Intermediate 2) (260 mg, 100 % yield). LCMS: not ionized, RT = 0.95 min. 'H NMR (400 MHz, CD3OD) δ 8.47 (s, IH), 7.73 (dd, J= 1.6, 0.8 Hz, IH), 7.65 (dd, J= 8.4, 0.6 Hz, IH), 7.46 - 7.41 (m, IH), 4.58 (s, 2H), 3.40 (s, 3H).

[0621] Intermediate Example 3: Synthesis of 2-(benzo[d]oxazol-5-yl)propan-2-ol (Intermediate 3)

[0622] Intermediate 3 2-(benzo[d|oxazol-5-yl)propan-2-ol

[0623]

[0531] Step 1: To a solution of lanthanum (III) chloride bis(lithium chloride) complex (26.3 mL, 15.8 mmol, 3.0 equiv, 0.6M in THF) under nitrogen atmosphere was added methylmagnesium chloride (5.26 mL, 15.8 mmol, 3.0 equiv, 3M in THF) dropwise at room temperature. After 10 min, the mixture was cooled to -40 °C. To this mixture was added the solution of methyl benzo[d]oxazole-5-carboxylate (995 uL, 5.26 mmol, 1.0 equiv) in tetrahydrofuran (THF) (2 mL). The mixture was warmed to room temperature and stirred for an additional 2h. After completion, the reaction was directly purified by normal phase flash chromatography (25g silica gel column) eluting with a gradient of 0-60% ethyl acetate (ethyl acetate) in heptanes. Pure fractions were concentrated to provide 2-(benzo[d]oxazol-5- yl)propan-2-ol (Intermediate 3) (760 mg, 82 % yield). LCMS: m / z [M+H]+= 178.3, RT = 0.91 min.

[0624] Intermediate Example 4: Synthesis of JV-(5-iodo-8-methyl-2,7-naphthyridin-3- yl)cyclopropanecarboxamide (Intermediate 4)

[0625] A / -(5-iodo-8-methyl-2,7- naphthyridin-3- yl)cyclopropanecarboxamide

[0626]

[0532] Step 1 : A mixture of commercially available 6-chloro-2,7-naphthyridin-1-ol (75 g, 416.66 mmol, 1 eq), cyclopropanecarboxamide (53.01 g, 622.95 mmol, 1.5 eq), tris(dibenzylideneacetone) dipalladium(O) (Pd2(dba)3) (38.03 g, 41.52 mmol, 0.1 eq), (9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) (Xantphos) (24.03 g, 41.52 mmol, 0.1 eq) and CS2CO3 (270.62 g, 830.60 mmol, 2 eq) in dioxane (750 mL) was degassed and purged with N23 times before being stirred at 140 °C for 12 h under N2atmosphere. The mixture was cooled to 200C and solids were filtered (4 reactions on 75 g were run in parallel and treated together). The filter cake was dried under reduced pressure to give a crude residue which was triturated with ethyl acetate (ethyl acetate) / CH2C12 (v / v=10:l) at 20 °C for 30 min and filtered to afford compound X-18-hydroxy -2,7-naphthyridin-3-yl)cyclopropanecarboxamide (389 g, 90% purity by >H NMR, 92% yield).

[0627] [533 J Step 2 : A mixture of X-(8-hydroxy-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (74 g, 322.81 mmol, 1 eq) and N-iodosuccinimide (NIS) (108.94 g, 484.21 mmol, 1.5 eq) in dimethylformamide (DMF) (800 mL) was degassed, purged with N23 times and stirred at 20 °C for 4 h (5 reactions on 74 g were run in parallel and treated together). The mixture was poured into H2O (20 L) and filtered. The filter cake was dried under reduced pressure to give a crude residue which was triturated with methanol (methanol) (4 L) at 20 °C for 30 min and filtered again. The filter cake was dried under reduced vacuum to afford 420 g of crude X-(8-hydroxy-5-iodo-2,7- naphthyridine-3-yl)cyclopropanecaroxamide (> 85% by ’H NMR) which was used in the next step directly.

[0534] Step 3: A mixture of A-(8-hydroxy-5-iodo-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (75 g, 211.18 mmol, 1 eq) and A,A-diisopropylethylamine (DIPEA) (136.47 g, 1.05 mol, 183.92 mL, 5 eq) in acetonitrile (1400 mL) was degassed and purged with N2for 3 times, and then the mixture was stirred at 20 °C for 0.5 h under N2atmosphere. POCh (323.82 g, 2.11 mol, 196.85 mL, 10 eq) was added dropwise, and then the mixture was stirred at 80 °C for 4.5 h under N2atmosphere. The mixture was poured into icc / lLO (3.5 L) and filtered to give a residue. The residue was dried by lyophilization. (Note: 5 reactions on 75 g were run in parallel and treated separately). Altogether, the 5 reactions afforded a total of 450 g of crude A-(8-chloro-5-iodo-2,7-naphthyridin-3-yl)cyclopropanecarboxamide. LCMS: m / z [M+H]+= 373.9

[0628]

[0535] Step 4: A mixture of A-(8-chloro-5-iodo-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (36.5 g, 97.70 mmol, 1 eq) and IM KOtBu in tetrahydrofuran (THF) (488.52 mL, 5 eq) in (THF) (650 mF) was degassed and purged with N23 times. The mixture was warmed to 65 °C and di-tert-butyl malonate (88.75 g, 410.36 mmol, 91.87 mF, 4.2 eq) in tetrahydrofuran (THF) (650 mF) was added dropwise and stirred at 65 °C for 2 h under N2atmosphere. To the mixture was added ethyl acetate (ethyl acetate) / HCl (4 M) until pH reached approximately 5. Solid precipitated from the mixture, which was filtered on Buchner. The solid was then purified by column chromatography (SiC>2, petroleum ether / ethyl acetate=l / 0 to 3 / 1) (12 reactions on 37 g scale were run in parallel and treated together) to afford di-tert- butyl 2-[6-(cyclopropanecarbonylamino)-4-iodo-2,7-naphthyridin-1-yl]propanedioate (140 g,

[0629] 253.1 Immol, 21.4 % yield over two steps).

[0630]

[0536] Step 5: A mixture of di-tert-butyl 2-[6-(cyclopropanecarbonylamino)-4-iodo-2,7-naphthyridin-1- yl]propanedioate (50 g, 90.37 mmol, 1 eq) in trifluoroacetic acid (TFA) (500 mF) was degassed and purged with N23 times before being stirred at 60 °C for 1 h under N2atmosphere. The mixture (combined with another 65 g reaction) was concentrated under reduced pressure and the residue was added to H2O (2.3 E) where a solid crashed. The mixture was filtered, and the filter cake was dissolved in 2-methyltetrahydrofuran (2-MeTHF) (9 F). Solution was adjusted to pH=10 by adding a saturated solution of Na2CC>3(aq.). The organic layers were dried by Na2SOr. filtered, and concentrated under reduced pressure. The residue was then purified by column chromatography (SiC>2, CH2C12 / tetrahydrofuran = 1 / 0 to 3 / 1) to afford A-(5-iodo-8-methyl-2,7-naphthyridin-3- yl)cyclopropanecarboxamide (Intermediate 4) (51.3 g, >99 % purity). ’H NMR: (400 MHz, DMSO-de) 5 11.32 (s, 1H), 9.36 (s, 1H), 8.80 (s, 1H), 8.56 (s, 1H), 2.89 (s, 3H), 2.21-2.01 (m, 1H), 0.97-0.81 (m, 4H). LCMS: m / z [M+H]+= 354.0

[0631] Intermediate Example 5: Synthesis of 6-chloro-1-methyl-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-2,7-naphthyridine (Intermediate 5)

[0632] Intermediate 1 Intermediate 5

[0633] 6-chloro-1 -methyl-4-(4, 4,5,5- tetramethyl-1 ,3,2- dioxaborolan-2-yl)-2,7- naphthyridine

[0634]

[0537] Step 1: A mixture of 4-bromo-6-chloro-1-methyl-2,7-naphthyridine (Intermediate 1) (1 g, 3.88 mmol, 1 eq), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (1.28 g, 5.05 mmol, 1.3 eq), potassium acetate (KOAc) (1.14 g, 11.65 mmol, 3 eq) and [l,r-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (Pd(dppf)C12) (284.14 mg, 388.33 pmol, 0.1 eq) in dioxane (10 mL) was degassed and purged with N23 times before being stirred at 90 °C for 12 hr under N2atmosphere. The mixture was then concentrated under reduced pressure and the crude mixture was purified by column chromatography (SiC>2, petroleum ether / ethyl acetate=50 / l to 3 / 1) to afford 6-chloro-1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,7-naphthyridine (Intermediate 5) (3.5 g, 9.15 mmol, 79% yield, 80% purity). 'H NMR: (400 MHz, DMSO- e) δ 9.57 (s, 1H), 8.83 (s, 1H), 8.38 (s, 1H), 3.02 (s, 3H), 1.38 (s, 12H).

[0635]

[0538] Pinacol boronic ester is abbreviated as Bpin herein.

[0636] Intermediate Example 6: Synthesis of / V-(8-methyl-5-(trimethylstannyl)-2,7-naphthyridin-3- yl 2,7-

[0637] Intermediate 4 yl)cyclopropanecarboxamide

[0638]

[0539] Step 1 : A mixture A-(5-iodo-8-methyl-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (Intermediate 4) (200 mg, 566.32 pmol, 1 eq), trimethyl(trimethylstannyl)stannane (222.65 mg, 679.58 pmol, 140.92 pL, 1.2 eq), LiCl (24.01 mg, 566.32 pmol, 11.61 pL, 1 eq), tetrakis(triphenylphosphine)palladium (0) (Pd(PPh3)4) (65.44 mg, 56.63 pmol, 0.1 eq) in toluene (1.5 mL) was degassed and purged with N23 times before being stirred at 100 °C for 5 hr under N2atmosphere. The reaction mixture was poured into H2O (5 mL) and extracted with ethyl acetate (ethyl acetate) (3 X 5 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography (SiC>2, petroleum ether / ethyl acetate=5 / l to 3 / 1) to afford A-(8-methyl-5-(trimethylstannyl)-2,7-naphthyridin-3- yl)cyclopropanecarboxamide (Intermediate 6) (60 mg, 153.82 pmol, 27% yield). 'H NMR: (400 MHz, DMSO-Je) δ 11.13 (s, 1 H), 9.44 (s, 1 H), 8.50 (s, 1 H), 8.36 (s, 1 H), 2.91 (s, 3 H), 2.13 - 2.08 (m, 1 H), 0.90 - 0.84 (m, 4 H), 0.48 (s, 9 H).

[0639] Intermediate Example 7: Synthesis of 4-bromo-6-chloro-1-(difluoromethyl)-2,7-naphthyridine (Intermediate 7) yridine

[0640] Intermediate 1

[0641]

[0540] Step 1: To a solution of 4-bromo-6-chloro- 1 -methyl -2, 7-naphthyridine (Intermediate 1) (100 mg, 388 umol, 1 equiv) in dioxane (777 uL) was added selenium dioxide (87.9 mg, 777 umol, 2.0 equiv). The reaction was heated to 80 °C overnight. After completion, the reaction was concentrated and directly purified by normal phase chromatography (25g silica gel column) eluting with a gradient of 5- 100% ethyl acetate (ethyl acetate) in heptanes. Pure fractions were concentrated to provide 4-bromo-6- chloro-2,7-naphthyridine-1-carbaldehyde (43.0 mg, 41 % yield).

[0642]

[0541] Step 2: To the solution of 4-bromo-6-chloro-2,7-naphthyridine-1-carbaldehyde (43.0 mg, 158 umol, 1 equiv) in dichloromethane (dichloromethane) (396 uL) under nitrogen at 0 °C was added EtOH (1 drop) and (diethylamino)sulfur trifluoride (DAST) (20.2 uL, 158 umol, 1 equiv). The reaction was stirred at room temperature overnight. After completion, the reaction was concentrated and directly purified by normal phase chromatography (25 g silica gel column) eluting with a gradient of 0-50% ethyl acetate (ethyl acetate) in heptanes. Pure fractions were concentrated to provide 4-bromo-6-chloro- l-(difluoromethyl)-2, 7-naphthyridine (Intermediate 7) (35.0 mg, 75 % yield). LCMS: [M+H]+= no ionization, RT = 1.30 min. 'H NMR (400 MHz, CDC13) δ 9.71 (s, 1H), 8.87 (s, 1H), 8.10 (s, 1H), 6.91 (t, J= 53.9 Hz, 1H).

[0643] Intermediate Example 8: N-(5-bromo-8-(difluoromethyl)-2,7-naphthyridin-3- yl)cyclopropanecarboxamide (Intermediate 8) and N-(5-bromo-8-methyl-2,7-naphthyridin-3- yl)cyclopropanecarboxamide (Intermediate 21)

[0644] Intermediate 1 Intermediate 21

[0645] / V-(5-bromo-8-methyl-2,7- naphthyridin-3- yl)cyclopropanecarboxamide

[0646] Intermediate 8

[0647] A / -(5-bromo-8-(difluoromethyl)-2,7- naphthyridin-3-yl)cyclopropanecarboxamide

[0648]

[0542] Step 1: To a 100 mL flask equipped with a stir bar was added 4-bromo-6-chloro-1-methyl-2,7- naphthyridine (Intermediate 1) (1.50 g, 5.82 mmol), CS2CO3 (5.81 g, 17.5 mmol), cyclopropanecarboxamide (1.52 g, 17.5 mmol), tris(dibenzylideneacetone)dipalladium (Pd2(dba)s) (550 mg, 582 umol), l,T -bis(di-tert-butylphosphino)ferrocene (dtbpf) (576 mg, 1.16 mmol) and anhydrous dioxane (48.5 mL). The reaction mixture was degassed with nitrogen for 5 minutes before heating at 60 °C for 2h. The reaction was then concentrated to 1 / 2 volume and added water (100 mL). The residue after filtration was then washed with 100 mL of heptanes to procure the crude N-(5-bromo-8-methyl- 2,7-naphthyridin-3-yl)cyclopropanecarboxamide (Intermediate 21), which was carried forward the next step without further purification. LCMS: m / z [M+H]+= 308.0

[0649]

[0543] Step 2: Intermediate 21 was dissolved in dioxane (29.1 mL) and selenium dioxide (857 mg, 7.57 mmol) was added. The mixture was heated at 80 °C for 3h. The reaction was cooled to rt and filtered over a Celite pad and washed with ethyl acetate (50 mL). The filtrate was concentrated to give N-(5- bromo-8-formyl-2,7-naphthyridin-3-yl)cyclopropanecarboxamide which was used for the next step without any further purification. LCMS: m / z [M+H]+= 320.0.

[0650]

[0544] Step 3: The crude N-(5-bromo-8-formyl-2,7-naphthyridin-3-yl)cyclopropanecarboxamide was dissolved in dichloromethane (19.4 mL). The solution was cooled to 0 °C before adding ethanol (EtOH) (1 drop) and (diethylamino)sulfiir trifluoride (1.11 mL, 8.74 mmol) dropwise. The reaction was stirred at room temperature for 3 h. The reaction was concentrated and directly purified by normal phase chromatography (25g silica gel) eluting with 20% methanol / dichloromethane (MeOH / DCM) in heptanes. Pure fractions were concentrated to give N-(5-bromo-8-(difluoromethyl)-2,7-naphthyridin-3- yl)cyclopropanecarboxamide (Intermediate 8) (500 mg, 25% over 3 steps). LCMS: m / z [M+H]+= 344.0.

[0651] Intermediate Example 9: N-(8-(difluoromethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 2,7-naphthyridin-3-yl)cyclopropanecarboxamide (Intermediate 9)

[0652] Intermediate 8 Intermediate 9

[0653] / V-(8-(difluoromethyl)-5-(4,4,5,54etramethyl-

[0654] / V-(5-bromo-8-(difluoromethyl)-2,7- 1 ,3,2-dioxaborolan-2-yl)-2,7-naphthyridin-3- naphthyridin-3-yl)cyclopropanecarboxamide yl)cyclopropanecarboxamide

[0655]

[0545] To a microwave vial was added N-(5-bromo-8-(difluoromethyl)-2,7-naphthyridin-3- yl)cyclopropanecarboxamide (Intermediate 8) (100 mg, 292 umol), bis(pinacolato)diboron (90.9 mg, 351 umol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,T-biphenyl)[2-(2'-amino-1,T- biphenyl)]palladium(II) (XPhos Pd G2) (24.2 mg, 29.2 umol), potassium 2-ethylhexanoate (167 mg, 877 umol) and toluene (2.06 mL). The resulting reaction mixture was purged with nitrogen, then heated to 70°C for Ih. The reaction mixture was cooled to rt, filtered on Celite, washed with dichloromethane (DCM) and concentrated in vacuo. 5 mL of heptanes was added and it was sonicated and stirred for lOmin. 5 mL of pentane was then added and it was filtered, washing with pentane to afford JV-(8- (difluoromethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,7-naphthyridin-3- yl)cyclopropanecarboxamide (Intermediate 9) (66.2 mg, 58% yield). LCMS: [M+H]+= 390.3, RT = 1.66 min. 'H NMR (400 MHz, dmso-d6) δ 11.24 (s, IH), 9.58 (s, IH), 9.21 (s, IH), 8.82 (s, IH), 7.53 (t, J = 54.0 Hz, IH), 2.15 - 2.04 (m, IH), 1.37 (s, 12H), 0.92 - 0.83 (m, 4H).

[0656] Intermediate Example 10: 6-chloro-1-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-

[0657] 2-yl)-2,7-naphthyridine (Intermediate 10)

[0658] Intermediate 7 Intermediate 10

[0659] 6-chloro-1 -(difluoromethyl)-4-(4,4,5,5-tetramethyl-

[0660] 1 ,3,2-dioxaborolan-2-yl)-2,7-naphthyridine

[0661]

[0546] To a flask was added 4-bromo-6-chloro-1-(difluoromethyl)-2,7-naphthyridine (Intermediate 7) (1.00 g, 3.41 mmol), potassium acetate (1.02 g, 10.2 mmol), l,l'-bis(diphenylphosphino)ferrocene dichloropalladium (II) (438 mg, 586 umol), bis(pinacolato)diboron (1.15 g, 4.43 mmol) and dioxane (10.0 mL). The mixture was purged with nitrogen, then heated at 90 °C for 2 h. The reaction mixture was cooled to rt, filtered over celite and washed with ethyl acetate (EtOAc). The filtrate was concentrated in vacuo. 20 ml of diethyl ether (Et20) was added and the suspension was stirred at room temperature for 30 min before filtering, washing with Et2O. The filtrate was concentrated in vacuo to obtain a residue which was triturated with Et2O to afford 6-chloro-1-(difluoromethyl)-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-2,7-naphthyridine (crop 1) (Intermediate 10) (208 mg, 17% yield). Impure filtrate was then concentrated, then 20 mb of 1: 1 Et2O:heptane was added and the suspension was stirred at room temprature for 30 min, then at 0°C for 30 min before filtering, washing with heptanes to afford 6-chloro-1-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 2,7-naphthyridine (crop 2) (Intermediate 10) (599 mg, 39% yield).1H NMR (400 MHz, dmso-d6) δ 9.67 (s, 1H), 9.03 (s, 1H), 8.54 (s, 1H), 7.63 (t, J = 53.1 Hz, 1H), 1.40 (s, 12H).

[0662] Intermediate Example 12: 5-iodo-8-methyl-2,7-naphthyridin-3-amine (Intermediate 11) and (lR,2R)-2-fluoro-N-(5-iodo-8-methyl-2,7-naphthyridin-3-yl)cyclopropane-1-carboxamide (Intermediate 12)

[0663] Intermediate 4 Intermediate 11 Intermediate 12

[0664] 5-iodo-8-methyl-2,7- (1 R,2R)-2-fluoro- N-(5-iodo-8-methyl-2,7- naphthyridin-3-amine naphthyridin-3-yl)cyclopropane-1 -carboxamide

[0665]

[0547] Step 1: To the mixture of iV-(5-iodo-8-methyl-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (Intermediate 4) (450 mg, 1.27 mmol, 1 equiv.) and sodium hydroxide (153 mg, 3.82 mmol, 3 equiv.) was added the mix of water (1.27 mL) and methanol (MeOH) (5.10 mL). The reaction was stirred at 60 °C overnight. The reaction was then concentrated to remove all MeOH and the product crashed out by adding water (20 mL). The residue was collected and filtered to give 5-iodo-8-methyl-2,7-naphthyridin- 3-amine (Intermediate 11) (363 mg, 100 % yield). LCMS: m / z [M+H]+= 286.0.

[0666]

[0548] Step 2: To a solution of 5-iodo-8-methyl-2,7-naphthyridin-3-amine (Intermediate 11) (0.16 g, 561.24 pmol, 1 eq) and commercially available (lR,2R)-2-fluorocyclopropanecarboxylic acid (75.94 mg, 729.61 pmol, 1.3 eq) in pyridine (1.6 mL) and dichloromethane (DCM) (8 mL) was added POCE (172.11 mg, 1.12 mmol, 104.63 ph, 2 eq) at 0 °C under N2atmosphere. The mixture was stirred at 20 °C for 0.5 hr. The mixture was quenched by H2O (30 mL) and extracted with DCM (30 mb x 3). The combined organic phases were dried over anhydrous Na2SO4, fdtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate=10 / l to 1 / 1) to afford (lR,2R)-2-fhioro-N-(5-iodo-8-methyl-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (Intermediate 12) (0.1 g, 269.43 pmol, 48% yield). ECMS: (M+H+): 371.9 at 0.354 min (10-100% acetonitrile in H2O, I min). ’H NMR: (400 MHz, DMSO-de) δ = 11.38 (s, 1H), 9.39 (d, J= 0.6 Hz, 1H), 8.84 (s, 1H), 8.58 (s, 1H), 5.11 - 4.88 (m, 1H), 2.91 (s, 3H), 2.38 - 2.26 (m, 1H), 1.81 - 1.65 (m, 1H), 1.28 - 1.23 (m, 1H).

[0667] Intermediate Example 13: (lS,2S)-2-fluoro-N-(5-iodo-8-methyl-2,7-naphthyridin-3- yl)cyclopropane-1-carboxamide (Intermediate 13)

[0668] Intermediate 11 Intermediate 13

[0669] (1 S,2S)-2-fluoro- A / -(5-iodo-8-methyl-2,7- naphthyridin-3-yl)cyclopropane-1 -carboxamide

[0670]

[0549] Step 1: To a solution of 5-iodo-8-methyl-2,7-naphthyridin-3-amine (Intermediate 11) (0.15 g, 526.16 pmol, 1 eq) and commercially available (lS,2S)-2-fluorocyclopropanecarboxylic acid (71.19 mg, 684.01 pmol, 1.3 eq) in pyridine (1.5 mL) and dichloromethane (DCM) (7.5 mL) was added POCh (161.35 mg, 1.05 mmol, 98.09 pL, 2 eq) at 0 °C under N2atmosphere. The mixture was stirred at

[0671] 20 °C for 0.5 hr. The mixture (combined with another 50 mg scale batch) was quenched by H2O (30 mL) and extracted with DCM (30 mL x 3). The combined organic phases were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude mixture was purified by silica gel chromatography (Petroleum ether / Ethyl acetate=10 / l to 1 / 1) to provide (lS,2S)-2-fluoro-N-(5-iodo-8- methyl-2,7-naphthyridin-3-yl)cyclopropane-1 -carboxamide (Intermediate 13) (200 mg). LCMS: (M+H+): 372.1 at 0.344 min (10-100% acetonitrile in H2O, 1 min). 'HNMR: (400 MHz, DMSO-de) δ = 11.37 (s, 1H), 9.38 (s, 1H), 8.83 (s, 1H), 8.58 (s, 1H), 5.10 - 4.87 (m, 1H), 2.91 (s, 3H), 2.36 - 2.28 (m, 1H), 1.79 - 1.66 (m, 1H), 1.28 - 1.19 (m, 1H).

[0672] Intermediate Example 14: (lS,2R)-2-fluoro-N-(5-iodo-8-methyl-2,7-naphthyridin-3- yl)cyclopropane-1-carboxamide (Intermediate 14)

[0673] Intermediate 11

[0674] Intermediate 14

[0675] (1 S,2R)-2-fluoro- A / -(5-iodo-8-methyl-2,7- naphthyridin-3-yl)cyclopropane-1 -carboxamide

[0676]

[0550] Step 1: To a solution of 5-iodo-8-methyl-2,7-naphthyridin-3-amine (Intermediate 11) (0.25 g, 876.94 pmol, 1 eq) and commercially available (lS,2R)-2-fluorocyclopropanecarboxylic acid (118.65 mg, 1.14 mmol, 1.3 eq) in pyridine (2.5 mL) and dichloromethane (DCM) (12.5 mL) was added POCI3 (269 mg, 1.75 mmol, 163.48 pL, 2 eq) at 0 °C under N2atmosphere. The mixture was stirred at

[0677] 20 °C for 0.5 hr. The mixture (combined with another 50 mg scale batch) was quenched by H2O (30 mL) and extracted with DCM (30 mL x 3). The combined organic phases were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude mixture was purified by silica gel chromatography (Petroleum ether / Ethyl acetate=10 / l to 7 / 3) to afford (lS,2R)-2-fluoro-N-(5-iodo-8- methyl-2,7-naphthyridin-3-yl)cyclopropane-1 -carboxamide (Intermediate 14) (180 mg). LCMS: (M+H+): 371.9 at 0.374 min (10-100% acetonitrile in H2O, 1 min). 'H NMR: (400 MHz, DMSO-de) δ = 11.67 (s, 1H), 9.53 (s, 1H), 8.88 (s, 1H), 8.60 (s, 1H), 5.07 (br s, 1H), 3.00 (s, 3H), 2.75 - 2.61 (m, 1H), 1.69 - 1.55 (m, 1H), 1.41-1.30 (m, 1H).

[0678] Intermediate Example 15: (lR,2S)-2-fluoro-N-(5-iodo-8-methyl-2,7-naphthyridin-3- yl)cyclopropane-1-carboxamide (Intermediate 15)

[0679] Intermediate 15

[0680] (1 R,2S)-2-fluoro- A / -(5-iodo-8-methyl-2,7- naphthyridin-3-yl)cyclopropane-1 -carboxamide

[0681]

[0551] Step 1: To a solution of 5-iodo-8-methyl-2,7-naphthyridin-3-amine (Intermediate 11) (0.25 g, 876.94 pmol, 1 eq) and commercially available (lR,2S)-2-fluorocyclopropanecarboxylic acid (118.65 mg, 1.14 mmol, 1.3 eq) in pyridine (2.5 mL) and dichloromethane (DCM) (12.5 mL) was added POCL (269 mg, 1.75 mmol, 163.48 pL, 2 eq) at 0 °C under N2atmosphere. The mixture was stirred at

[0682] 20 °C for 0.5 hr. The mixture (combined with another 50 mg scale batch) was quenched by H2O (30 mL) and extracted with DCM (30 mL x 3). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude mixture was purified by silica gel chromatography (Petroleum ether / Ethyl acetate=10 / l to 3 / 1) to afford (lR,2S)-2-fluoro-N-(5-iodo-8- methyl-2,7-naphthyridin-3-yl)cyclopropane-1 -carboxamide (Intermediate 15) (180 mg). LCMS: (M+H+): 371.9 at 0.380 min (10-100% acetonitrile in H2O, 1 min).

[0683] Intermediate Example 16: N-(8-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,7- naphthyridin-3-yl)cyclopropanecarboxamide (Intermediate 16)

[0684] Intermediate 16

[0685] / \ / -(8-methyl-5-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-2,7-naphthyridin-3- yl)cyclopropanecarboxamide

[0686]

[0552] Step 1: To a 250 mL round bottom flask was added N-(5-Iodo-8-methyl-2,7-naphthyridin-3- yl)cyclopropanecarboxamide (Intermediate 4) (3.07 g, 10.0 mmol, 1 eq) in tetrahydrofuran (THF) (5.06 mL), bis(pinacolato)diboron (3.12 g, 12.0 mmol, 1.2 eq), chloro(2-dicyclohexylphosphino-2',4',6'- triisopropyl- l . l '-biphcnyl)|2-(2'-amino- l . l '-biphcnyl)|palladium(II) (XPhos Pd G2) (830 mg, 1.00 mmol, 0.1 eq), potassium 2-ethylhexanoate (5.71 g, 30.1 mmol, 3 eq) and toluene (70.8 mL). The flask was purged with nitrogen, then heated to 70°C for 3h. The mixture was filtered on Celite, washing with dichloromethane (DCM) and evaporation in vacuo. 25 mb of heptanes was added and the suspension was stirred for 30min at room temperature, then 30 min in an ice bath before filtering to afford N-(8-methyl- 5 -(4,4,5 ,5 -tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)-2,7-naphthyridin-3 -yl)cyclopropanecarboxamide (Intermediate 16) (2.27 g, 6.4 mmol, 64 % yield, 92% purity).1H NMR: (400 MHz, DMSO-de) δ 11.02 (s, 1H), 9.44 (s, 1H), 9.05 (s, 1H), 8.63 (s, 1H), 2.93 (s, 3H), 2.13 - 2.02 (m, 1H), 1.33 (s, 12H), 0.87 - 0.80 (m, 4H). LCMS: (M+H+): 272.2 at 0.68 min (5-95% acetonitrile in ammonium formate (AMF), 3 min, boronic acid peak observed).

[0687]

[0553] Step 1 (Alternative procedure): To a vial was added X-(5-iodo-8-methyl-2,7-naphthyridin-3- yl)cyclopropanecarboxamide (Intermediate 4) (250 mg, 0.708 mmol), bis(pinacolato)diboron (B2(Pin)2) (270 mg, 1.06 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,l'-biphenyl)[2- (2'-amino-1,l'-biphenyl)]palladium(II) (XPhos Pd G2) (58.6 mg, 0.0708 mmol) and potassium 2- ethylhexanoate (403 mg, 2.12 mmol). The vial was capped, evacuated, and backfilled with argon. Degassed anhydrous toluene (5.00 mL) was then added under Ar and the mixture was heated at 100 °C for 2 hours. The reaction mixture was passed through a pad of celite and washed with ethyl acetate and 10% methanol / dichloromethane. Filtrate was concentrated under reduced pressure and the crude mixture was purified on a normal phase column (15% to 100% ethyl acetate in heptanes) to obtain A'-(8- methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,7-naphthyridin-3- yl)cyclopropanecarboxamide (Intermediate 16) (115 mg, 46% yield). LCMS: m / z [M+H]+= 272.2 (boronic acid).

[0688] Intermediate Example 17: (6-(cyclopropanecarboxamido)-1-methyl-2,7-naphthyridin-4-yl)boronic acid (Intermediate 17)

[0689] Intermediate 4 Intermediate 17

[0690] (6-(cyclopropanecarboxamido)-1 -methyl- 2,7-naphthyridin-4-yl)boronic acid

[0691]

[0554] Step 1: To a flame dried vial was added N-(5-iodo-8-methyl-2,7-naphthyridin-3- yl)cyclopropanecarboxamide (Intermediate 4) (1.00 g, 2.83 mmol), bis(pinacolato)diboron (E^Pinh) (1.08 g, 4.25 mmol), chloro(2-dicyclohexylphosphino-2', 4', 6'-triisopropyl- 1,1 '-biphenyl) [2-(2'-amino- l,r-biphenyl)]palladium(II) (XPhos Pd G2) (235 mg, 0.283 mmol), and potassium 2-ethylhexanoate (1.61 g, 8.49 mmol). The vial was capped, evacuated, and backfilled with argon. Degassed anhydrous toluene (30 mL) was added under argon and the mixture was heated at 90 °C for 2 hours. Reaction was cooled down to room temperature and concentrated under reduced pressure. Obtained crude was dissolved in 20 mb DMSO and purified on a reverse phase column using a gradient of 5-100% acetonitrile (MeCN) in 10 aq. mM ammonium formate (AMF) to provide a solid residue, which was redissolved in MeCN / MeOH (50% / 50%), which was concentrated under reduced pressure. Toluene was then added to the residue, which was dried by placing under vacuum to afford (6- (cyclopropanecarboxamido)-1-methyl-2,7-naphthyridin-4-yl)boronic acid (Intermediate 17) (820 mg, 95% yield). 'H NMR: (400 MHz, dmso) δ 11.21 (s, 1H), 9.54 (s, 1H), 9.12 (s, 1H), 9.04 (s, 2H), 8.76 (s, 1H), 7.47 (t, J= 53.5 Hz, 1H), 2.13 - 2.05 (m, 1H), 0.90 - 0.82 (m, 4H). LCMS: m / z [M+H]+= 272.2.

[0692] Intermediate Example 18: 6-chloro-1-(difluoromethyl)-4-(4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2- yl)-2,7-naphthyridine (Intermediate 18)

[0693] Intermediate 18

[0694] Intermediate 7

[0695] 6-chloro-1 -(difluoromethyl)-4- (4,4, 5,5-tetraethy 1-1 ,3,2- dioxaborolan-2-yl)-2,7-naphthyridine

[0696]

[0555] Into a 40mL sealed tube was added 4-bromo-6-chloro-1-(difluoromethyl)-2,7-naphthyridine (Intermediate 7) (1 g, 3.41 mmol, 1 equiv), 4,4,5,5-tetraethyl-2-(4,4,5,5-tetraethyl-1,3,2-dioxaborolan- 2-yl)-1,3,2-dioxaborolane (1.87 g, 5.11 mmol, 1.50 equiv), [l,r-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (Pd(dppf)C12) (747.91 mg, 1.02 mmol, 0.3 equiv), potassium acetate (1.00 g, 10.22 mmol, 3 equiv) and dioxane (13 mL) at room temperature. The resulting mixture was stirred at 100°C for 2h under nitrogen atmosphere before being cooled down to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using an elution of petroleum ether / ethyl acetate (5: 1) to afford 6-chloro-1- (difluoromethyl)-4-(4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2-yl)-2,7-naphthyridine (Intermediate 18) (800 mg, 59% yield) LCMS (ES, m / z): 397.2[M+H]+.

[0697] Intermediate Example 19: (lS,2S)-N-(5-bromo-8-(difluoromethyl)-2,7-naphthyridin-3-yl)-2- fluorocyclopropane- 1 -carboxamide (Intermediate 19)

[0698] Intermediate 7 PMB = paramethoxy benzyl

[0699] Intermediate 19

[0700] (1 S,2S)-A / -(5-bromo-8-

[0701] (difluoromethyl)-2,7-naphthyridin- 3-yl)-2-fluorocyclopropane-1 - carboxamide

[0702]

[0556] Step 1: To the solution of 4-bromo-6-chloro-1-(difluoromethyl)-2,7-naphthyridine (Intermediate 7) (800 mg, 2.73 mmol, 1 equiv.) in dioxane (5.45 mL) was added 4-methoxybenzylamine (1.09 mb, 8.18 mmol, 3 equiv) and MAMiisopropylcthylamiric (DIPEA) (2.40 mL, 13.6 mmol, 5 equiv.). The reaction was heated at 145 °C for 3h under microwave irradiation. The reaction was filtered and washed with dichloromethane (DCM) (50 mL). Filtrate was concentrated to give crude product of 5-bromo-A'- (4-methoxybenzyl)-8-methyl-2,7-naphthyridin-3-amine which was used in the next step without purification. LCMS: m / z [M+H]+= 396.1.

[0703]

[0557] Step 2: The crude product 5-bromo-A'-(4-mcthoxybcnzyl)-8-mcthyl-2.7-naphthyridin-3-aminc was dissolved in trifluoroacetic acid (TFA) (3.91 mL, 51.1 mmol, 30 equiv.). The solution was heated at 50 °C for 2h after which it was concentrated under reduced pressure. A saturated solution of NaHCOs was added until no bubbles were observed. Yellow solid precipitated out and the residue was filtered, washed with water (20 mL) and dried to give crude product of 5-bromo-8-(difluoromethyl)-2,7- naphthyridin-3-amine which was used in the next step without purification. LCMS: m / z [M+H]+= 276.0.

[0704]

[0558] Step 3: To the solution of commercially available ( I.S'.2.S)-2-fliiorocyclopropanccarboxylic acid (896 mg, 8.18 mmol, 3 equiv.) in dichloromethane (DCM) (36.3 mL) was added I -chloro-A'. A'.2- trimethyl-1 -propenylamine (1.49 mL, 10.9 mmol, 4 equiv.). The mixture was stirred for 1 h before a suspension of 5-bromo-8-(difluoromethyl)-2,7-naphthyridin-3-amine and pyridine (1.10 mL, 13.6 mmol, 5 equiv.) in dichloromethane (DCM) (18.2 mL) was added dropwise to the reaction mixture at room temperature. The reaction mixture was stirred for another 3 h before being concentrated under reduced pressure. Water (50 mL) was added, and the residue was collected by filtration, washed with water (20 mL) and further purified by normal phase chromatography using a gradient 0% to 100% of a 20% methanol (MeOH) / dichloromethane (DCM) in heptanes. Pure fractions were combined and concentrated to give (lS,2S)-A-(5-bromo-8-methyl-2,7-naphthyridin-3-yl)-2-fluorocyclopropane-1- carboxamide (Intermediate 19) (700 mg, 71 % yield over 3 steps). LCMS: m / z [M+H]+= 362.0.

[0705] Intermediate Example 20. 4-bromo-6-chloro-1-(trifluoromethyl)-2,7-naphthyridine (Intermediate

[0706] Intermediate Intermediate 20 Example 1, step 2 product 4-bromo-6-chloro-1 -

[0707] (trifluoromethyl)-2,7- naphthyridine

[0708]

[0559] Step 1: To a stirred solution of 4-bromo-6-chloro-2,7-naphthyridin-1-yl trifluoromethanesulfonate

[0709] (Intermediate Example 1, step 2 product) (500 mg, 843 umol) in acetonitrile (5 mL) was added sodium iodide (635 mg, 4.21 mmol) followed by hydrochloric acid (76.1 uL, 927 umol). The mixture was stirred at room temperature for 16 h before being quenched with aq. sat. NaHCOs. The reaction mixture was extracted with ethyl acetate (EtOAc) and the organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated to dryness. The crude mixture was purified by silica gel column, eluting with 0% to 10% EtOAc in heptanes, to give 4-bromo-6-chloro-1-iodo-2,7- naphthyridine (300 mg, 96% yield). LCMS: m / z [M+H]+= 370.8.

[0710]

[0560] Step 2: 4-Bromo-6-chloro-1-iodo-2,7-naphthyridine (250 mg, 677 umol) was stirred in anhydrous dimethylformamide (DMF) (4.02 mL) while nitrogen was bubbled through the reaction mixture.

[0711] Copper(I) iodide (155 mg, 812 umol) and methyl 2,2-difhroro-2-(fhrorosulfonyl)acetate (390 mg, 2.03 mmol) was added and the mixture was stirred at 80 °C for 4 h. The reaction was cooled back to room temperature, quenched with a saturated aqueous solution of NaCl, and the reaction mixture extracted with EtOAc (2x). The organic layers were combined, washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to provide a crude residue, which was dissolved in DMSO and purified by reverse phase column (Cl 8 using a gradient of 10% MeCN in aqueous 10 mM of ammonium formate to 100% acetonitrile), and the purified material obtained lyophilized, to provide 4- bromo-6-chloro-1-(trifluoromethyl)-2,7-naphthyridine (Intermediate 20) (225 mg, quantitative yield). 'H NMR (400 MHz, CDC13) δ = 9.55 (d, J= 0.8 Hz, 1H), 8.96 (s, 1H), 8.15 (d, J= 0.8 Hz, 1H).

[0712] Intermediate Example 21: (lS,2S)-N-(8-(difluoromethyl)-5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-2,7-naphthyridin-3-yl)-2-fluorocyclopropane-1-carboxamide (Intermediate 22)

[0713] Intermediate 22

[0714] (1 S,2S)-N-(8-(difluoromethyl)-5- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan- 2-y l)-2,7-naphthy ridin-3-y l)-2- fluorocyclopropane-1 -carboxamide

[0561] To a 150 mL round bottomed flask equipped with a condenser and N2inlet was added ( I .S',2.S')- A- (5-bromo-8-methyl-2,7-naphthyridin-3-yl)-2-fluorocyclopropane-1-carboxamide (Intermediate 19) (2.80 g, 7.77 mmol), bis(pinacolato)diboron (2.24 g, 8.55 mmol), bis(pinacolato)diboron (90.9 mg, 351 umol), chloro(2-dicyclohexylphosphino-2', 4', 6'-triisopropyl- 1,1 '-biphenyl) [2-(2'-amino- 1,1'- biphenyl)]palladium(II) (XPhos Pd G2) (312 mg, 389 umol), potassium 2-ethylhexanoate (3.69 g, 19.4 mmol) and isopropyl acetate (IPAc) (42.0 mL). The reaction mixture was bubbled with nitrogen for 2 min, then heated to 75°C for 4h. The reaction mixture was then cooled to room temperature, filtered over celite and washed with IPAc. The filtrate was then washed twice with a 5% NaHCOs aqueous solution. The combined aqueous layers were back-extracted once with IPAc. Combined IPAc organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford crude material. Heptanes (33.6 mL, 12 vol) was added to the residue and the mixture was sonicated for 5 min. The resulting slurry was stirred at rt for 18h (overnight). The precipitate was collected by vacuum filtration, washed with heptanes several times to afford (lS,2S)-N-(8-(difluoromethyl)-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,7-naphthyridin-3-yl)-2-fluorocyclopropane-1- carboxamide (Intermediate 22) (1.83 g, 58% yield). LCMS: [M+H]+ = 326.3, RT (min) = 0.94 min (boronic acid); LCMS: [M+H]+ = 408.4, 1.59 min (boronic ester). 'H NMR (400 MHz, DMSO-d6) δ 11.28 (s, 1H), 9.59 (d, J= 1.0 Hz, 1H), 9.22 (d, J= 0.9 Hz, 1H), 8.84 (s, 1H), 7.54 (t, J= 53.3 Hz, 1H), 5.10 - 4.85 (m, 1H), 2.36 - 2.25 (m, 1H), 1.77 - 1.64 (m, 1H), 1.39 (s, 12H), 1.23 - 1.16 (m, 1H).

[0715] Intermediate Example 22: (l-(difluoromethyl)-6-(N-(4- methoxybenzyl)cyclopropanecarboxamido)-2,7-naphthyridin-4-yl)boronic acid (Intermediate 23) and 8-(difluoromethyl)-N-(4-methoxybenzyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,7- naphthyridin-3-amine (Intermediate 24)

[0716] Intermediate Scheme 22A. Intermediate Scheme 22B. -

[0717] PM

[0718]

[0562] Step 1: A round bottom equipped with a condenser is charged with 4-bromo-6-chloro-1-

[0719] (difluoromethyl)-2,7-naphthyridine (Intermediate 7) (329 mg, 897 pmol), N,N-diisopropylethylamine (628 uL, 3.59 mmol), dimethylacetamide (DMAc) (5.26 mL) and 4-methoxybenzylamine (179 uL, 1.35 mmol). Reaction was allowed to stir at 120 °C for 4 hours under nitrogen atmosphere. After 24 hours, an additional amount of 4-methoxybenzylamine (59.8 uL, 448 pmol) was added. The reaction was stirred at 120°C for 4 hours under nitrogen atmosphere and it was cooled down to room temperature to provide a crude solution of 5-bromo-8-(difluoromethyl)-N-(4-methoxybenzyl)-2,7-naphthyridin-3- amine, which was carried forward in Step 2 without purification. LCMS: m / z [M+H]+= 394.1.

[0720]

[0563] Step 1 (Alternative procedure): To the solution of 4-bromo-6-chloro-1-(difluoromethyl)-2,7- naphthyridine (Intermediate 7) (500 mg, 1.70 mmol) in dioxane (3.40 mL) was added 4- methoxybenzylamine (908 uL, 6.81 mmol) and A,A-diisopropylethylamine (DIPEA) (1.50 mL, 8.52 mmol). The reaction was stirred at 120 °C for 19 h. The reaction mixture was concentrated in vacuo, diluted in dichloromethane (DCM) and washed with water. The aqueous layer was extracted with DCM (2x). The combined organic layers were washed with water (5x), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to provide 5-bromo-8-(difluoromethyl)-N-(4-methoxybenzyl)-2,7- naphthyridin-3-amine which carried forward in Step 4 without further purification. LCMS: m / z [M+H]+394.1.

[0721]

[0564] Step 2: Cyclopropane carbonyl chloride (498 uL, 5.38 mmol) was added at room temperature in one portion to the solution of 5-bromo-8-(difluoromethyl)-N-(4-methoxybenzyl)-2,7-naphthyridin-3- amine from Step 1, and reaction was stirred overnight. After 19 hours, the reaction diluted with ethyl acetate (EtOAc) and water. Organic washed with water 3x, brine, dried over sodium sulfate, filtered, and concentrated to dryness to provide the crude material. The crude was purified by silica gel using a gradient of 100% dichloromethane (DCM) to 25% EtOAc in 75% DCM. Appropriate fractions combined and concentrated to provide N-(5-bromo-8-(difluoromethyl)-2,7-naphthyridin-3-yl)-N-(4- methoxybenzyl)cyclopropanecarboxamide (74% over 2 steps). LCMS: m / z [M+H]+= 462.0, 464.0.

[0722]

[0565] Step 3: To a vial was added N-(5-bromo-8-(difluoromethyl)-2,7-naphthyridin-3-yl)-N-(4- methoxybenzyl)cyclopropanecarboxamide (197 mg, 426 pmol), bis(pinacolato)diboron (E^PinE) (168 mg, 648 pmol), potassium 2-ethylhexanoate (249 mg, 1.31 mmol) and anhydrous toluene (3.00 mL). The reaction mixture was bubbled with N2while sonicating for 5 mins before chloro(2- dicyclohexylphosphino-2',4',6'-triisopropyl-1,T-biphenyl)[2-(2'-amino-1,T-biphenyl)]palladium(II) (XPhos Pd G2) (34.6 mg, 43.0 pmol) was quickly added. The reaction vial was sealed and stirred at 70 °C for 4 h. The reaction mixture was then concentrated in-vacuo. The crude material was purified by reverse-phase chromatography eluting with a gradient of 5-95% acetonitrile in H2O (containing 10 mM ammonium formate (AmF)). Appropriate fractions were collected and concentrated in-vacuo and the resulting residue was triturated in heptanes affording (l-(difluoromethyl)-6-(N-(4- methoxybenzyl)cyclopropanecarboxamido)-2,7-naphthyridin-4-yl)boronic acid (Intermediate 23) (78.0 mg, 43 % yield). LCMS: m / z [M+H]+= 428.3.

[0723]

[0566] Step 4: To a vial was added 5-bromo-8-(difluoromethyl)-N-(4-methoxybenzyl)-2,7-naphthyridin- 3-amine solution from Alternative Step 1 (100 mg, 254 pmol), bis(pinacolato)diboron (B2(Pin)2) (99.3 mg, 383 pmol), potassium 2-ethylhexanoate (144 mg, 758 pmol) and anhydrous toluene (1.70 mL). The reaction mixture was bubbled with N2while sonicating for 5 mins before chloro(2- dicyclohexylphosphino-2',4',6'-triisopropyl-1,l'-biphenyl)[2-(2'-amino-1,l'-biphenyl)]palladium(II) (XPhos Pd G2) (20.4 mg, 25.4 pmol) was quickly added. The reaction vial was sealed and stirred at 70 °C for 3 h. The reaction mixture was then cooled back to room temperature and filtered over celite, washing with dichloromethane (DCM) and the filtrate concentrated in vacuo to provide 8- (difluoromethyl)-N-(4-methoxybenzyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,7- naphthyridin-3-amine (Intermediate 24). LCMS: m / z [M+H]+442.3.

[0724] Intermediate Example 23: Synthesis of 6-chloro-1-methyl-4-(4,4,5,5-tetraethyl-1,3,2-dioxaborolan-

[0725] 2-yl)-2,7-naphthyridine (Intermediate 25)

[0726]

[0567] Step 1: To a solution of A mixture of 4-bromo-6-chloro-1-methyl-2,7-naphthyridine (Intermediate 1) (500 mg, 1.942 mmol, 1 equiv) and 4,4,5,5-tetraethyl-2-(4,4,5,5-tetraethyl-1,3,2- dioxaborolan-2-yl)-1,3,2-dioxaborolane (1.42g, 3.884 mmol, 2 equiv) in dioxane (7.5 mL) was added ), [l,T-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (Pd(dppf)C12)-CH2C12 (159 mg, 0.194 mmol, 0.1 equiv) and potassium acetate (AcOK) (572 mg, 5.826 mmol, 3 equiv) at room temperature. The resulting mixture was stirred at 100°C for 15h under nitrogen atmosphere, then was concentrated under reduced pressure and purified by silica gel column chromatography, eluting with petroleum ether / ethyl acetate (6:4), to afford 6-chloro-1-methyl-4-(4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2-yl)-2,7- naphthyridine (Intermediate 25) (700 mg, 100% yield). LCMS (ES, m / z): 361.2 [M+H]+.

[0727] (ii) Final compounds

[0728] Example 1: A-(5-(5-(methoxymethyl)benzo[d]oxazol-2-yl)-8-methyl-2,7-naphthyridin-3- yl)cyclopropanecarboxamide (Compound 1) d|oxazol- 2-yl)-8-methyl-2,7-naphthyridin-3- yl)cyclopropanecarboxamide

[0729]

[0568] Step 1: To the mixture of 5 -(methoxymethyl)benzo[d] oxazole (Intermediate 2) (31.7 mg, 194 umol, 1.0 equiv), (9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) (Xantphos) (8.28 mg, 14.6 umol, 7.5 mol%), palladium (II) acetate (Pd(OAc)2) (2.18 mg, 9.71 umol, 5 mol%), sodium tert- butoxide (46.2 mg, 466 umol, 2.4 equiv) in dimethoxyethane (DME) (1.29 mL) was added a solution of 4-bromo-6-chloro-1-methyl-2,7-naphthyridine (Intermediate 1) (50.0 mg, 194 umol, 1.0 equiv) in DME (647 uL). The reaction was stirred at 80 °C overnight. After completion, the reaction was directly purified by normal phase flash chromatography (25g silica gel column) eluting with a gradient of 0- 100% methanol (methanol) in dichloromethane (dichloromethane). Pure fractions were concentrated and lyophilized to afford 2-(6-chloro-1-methyl-2,7-naphthyridin-4-yl)-5-

[0730] (mcthoxymcthyl)bcnzoft / | oxazole (26.0 mg, 39 % yield). LCMS: m / z [M+H]+= 340.2, RT = 1.60 min.

[0731]

[0569] Step 2: To the mixture of 2-(6-chloro-1 -methyl -2, 7-naphthyridin-4-yl)-5 -(methoxymethyl) benzo [d\ oxazole (26.0 mg, 76.5 umol, 1.0 equiv), [(2-di-cyclohexylphosphino-3,6-dimethoxy-2',4',6'- triisopropyl- 1 , 1 '-biphenyl)-2-(2'-amino- 1 , T -biphenyl)]palladium(II) methanesulfonate methanesulfonate (BrettPhos Pd G3) (6.94 mg, 7.65 umol, 10 mol%), 2-(Di- / c / 7-butylphosphino)- 2',4',6'- triisopropyl-3,6-dimethoxy-1,l'-biphenyl (tButyl BrettPhos) (11.5 mg, 23.0 umol, 30 mol%), cesium carbonate (76.3 mg, 230 umol, 3.0 equiv) and cyclopropanecarboxamide (32.6 mg, 383 umol, 5.0 equiv) was added degassed dioxane (699 uL). The reaction was heated to 90 °C for 2h. After completion, the reaction was directly purified by reverse phase flash chromatography (12 g C18 column), eluting with a gradient of 5-100% acetonitrile in ammonium bicarbonate (AMB) (lOmM in water, pH = 10). Pure fractions were lyophilized to afford A'-(5-(5-(mcthoxymcthyl)bcnzo|t / |oxazol-2- yl)-8-methyl-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (Compound 1) (3.20 mg, 11 % yield). LCMS: m / z [M+H]+= 389.3, RT = 2.40 min. 'H NMR (400 MHz, DMSO-d6) δ 11.28 (s, 1H), 9.83 (s, 1H), 9.63 (s, 1H), 9.25 (s, 1H), 7.87 - 7.77 (m, 2H), 7.49 - 7.44 (m, 1H), 4.58 (s, 2H), 3.34 (s, 3H), 3.07 (s, 3H), 2.20 - 2.11 (m, 1H), 0.99 - 0.82 (m, 4H).

[0732] Example 2: N-(5-(5-(2-hydroxypropan-2-yl)benzo[d]oxazol-2-yl)-8-methyl-2,7-naphthyridin-3- yl)cyclopropanecarboxamide (Compound 2) and N-(5-(5-(2-hydroxypropan-2-yl)benzo[d]oxazol- 2-yl)-8-(methyl-d3)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (Compound 2-CD3)

[0733] A / -(5-(5-(2-hydroxypropan-2- yl)benzo[c / ]oxazol-2-yl)-8-methyl-2,7- naphthyridin-3- yl)cyclopropanecarboxamide

[0734] Compound 2-CD3

[0735] A / -(5-(5-(2-hydroxypropan-2-

[0736] CD3OD yl)benzo[oqoxazol-2-yl)-8-(methyl-c / 3)-2,7- naphthyridin-3-yl)cyclopropanecarboxamide

[0737] S3

[0738]

[0570] Step 1: The mixture of 4-bromo-6-chloro-1-methyl-2,7-naphthyridine (Intermediate 1) (40.0 mg, 155 umol), 2-(benzo[<7]oxazol-5-yl)propan-2-ol (Intermediate 3) (35.8 mg, 202 umol, 1.3 equiv.), copper(I) iodide (5.95 mg, 31.1 umol, 20 mol%), palladium (II) acetate (Pd(OAc)2) (3.49 mg, 15.5 umol, 10 mol%), tricyclohexylphosphine tetrafluoroborate (11.8 mg, 31.1 umol, 20 mol%), 1,8- diazabicyclo[5.4.0]undec-7-ene (59.2 uL, 388 umol, 2.5 equiv) and dioxane (5.18 mL) was degassed by nitrogen for 5 mins. The reaction mixture was heated to 110 °C overnight. After completion, the reaction was directly purified by reverse phase flash chromatography (12 g C18 column) eluting with a gradient of 0-60% acetonitrile in ammonium formate (AMF) (10 mM in water, pH=3.8). Pure fractions were lyophilized to afford 2-(2-(6-chloro- l -mcthyl-2.7-naphthyridin-4-yl)bcnzoft / |oxazol-5-yl)propan-2-ol (16.0 mg, 29 % yield). LCMS: [M+H]+ = 354.3, RT = 1.47 min,.

[0739]

[0571] Step 2 : The mixture of 2-(2-(6-chloro- l -mcthyl-2.7-naphthyridin-4-yl)bcnzoft / |oxazol-5- yl)propan-2-ol (39.0 mg, 110 umol, 1.0 equiv), l,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (33.6 uL, 220 umol, 2.0 equiv), cyclopropanecarboxamide (28.7 mg, 331 umol, 3.0 equiv), sodium trifluoroacetate (20.5 uL, 220 umol, 2.0 equiv), (R)-1-[(Sp)-2- (diphenylphosphino)ferrocenyl]ethyldicyclohexylphosphine (( / ?)-(.S)-1osiphos)( 13.7 mg, 22.0 umol, 20 mol%), allylpalladium chloride dimer (4.07 mg, 11 umol, 10 mol%) and 2-methyltetrahydrofuran (2- MeTHF) (2.20 mL) was degassed with nitrogen for 5 mins. The reaction mixture was heated to 100 °C by a microwave reaction for 2h after which LC-MS confirmed complete conversion to N-(5-(5-(2- hydroxypropan-2-yl)benzo[d]oxazol-2-yl)-8-methyl-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (Compound 2). Reaction was concentrated and used for the next step without any further purification. LCMS: m / z [M+H]+= 403.4, RT = 1.32 min.

[0740]

[0572] Step 3: The above residue was re-suspended in CDsOD (1.10 mL) and stirred at room temperature overnight. After completion, the reaction was directly purified by reverse phase flash chromatography (12 g C18 column), eluting with a gradient of 0-60% acetonitrile in ammonium bicarbonate (AMB) (lOrnM in water, pH = 10). Pure fractions were lyophilized to afford A-(5-(5-(2- hydroxypropan-2-yl)benzo[d]oxazol-2-yl)-8-(methyl-d3)-2,7-naphthyridin-3- yl)cyclopropanecarboxamide (Compound 2-CD3) (2.90 mg, 6.5 % yield). LCMS: m / z [M+H]+= 406.4, RT = 2.30 min. 'H NMR (400 MHz, DMSO-d6) δ 11.28 (s, 1H), 9.83 (d, J= 0.9 Hz, 1H), 9.62 (d, J= 0.8 Hz, 1H), 9.24 (s, 1H), 7.94 (d, J= 1.4 Hz, 1H), 7.74 (d, J= 8.6 Hz, 1H), 7.61 (dd, J= 8.6, 1.8 Hz, 1H), 5.24 (s, 1H), 2.21 - 2.08 (m, 1H), 1.53 (s, 6H), 0.97 - 0.91 (m, 2H), 0.91 - 0.85 (m, 2H).

[0741] Example 3: Synthesis of N-(5-(6-(2,5-dihydrofuran-3-yl)oxazolo[5,4-c]pyridin-2-yl)-8-methyl-2,7- naphthyridin-3-yl)cyclopropanecarboxamide (Compound 3X), N-(5-(6-(3- hydroxytetrahydrofuran-3-yl)oxazolo[5,4-c]pyridin-2-yl)-8-methyl-2,7-naphthyridin-3- yl)cyclopropanecarboxamide (Compound 3, rac-3), ( R)- V-(5-(6-(3-1iydroxytetraliydrofuran-3- yl)oxazolo[5,4-c]pyridin-2-yl)-8-methyl-2,7-naphthyridin-3-yl)cyclopropanecarboxamide

[0742] (Compound 3A*) and (S)-A-(5-(6-(3-hydroxytetrahydrofuran-3-yl)oxazolo[5,4-c]pyridin-2-yl)-8- methyl-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (Compound 3B*)

[0743] Compound 3X Compound 3 (rac-3)

[0744] A / -(5-(6-(2,5-dihydrofuran-3- A / -(5-(6-(3- yl)oxazolo[5,4-c]pyridin-2-yl)-8- hyd roxytetrahyd rof u ran-3- methyl-2,7-naphthyridin-3- yl)oxazolo[5,4-c]pyridin-2-yl)-8- yl)cyclopropanecarboxamide methyl-2,7-naphthyridin-3- yl)cyclopropanecarboxamide

[0745] Compound 3A* Compound 3B*

[0746] (R)-A / -(5-(6-(3- (S)- / V-(5-(6-(3- hydroxytetrahydrofuran-3- hydroxytetrahydrofuran-3- yl)oxazolo[5,4-c]pyridin-2-yl)-8- yl)oxazolo[5,4-c]pyridin-2-yl)-8- methyl-2,7-naphthyridin-3- methyl-2,7-naphthyridin-3- yl)cyclopropanecarboxamide yl)cyclopropanecarboxamide

[0747]

[0573] Step 1: 4-Amino-6-bromopyridin-3-ol (500 mg, 3.20 mmol) was dissolved in triethyl orthoformate anhydrous (98%, 5 mL) and heated at 120 °C for 4 hours. Volatiles were evaporated under reduced pressure to afford 6-bromooxazolo[5,4-c]pyridine (610 mg, 96 % yield) and used in the next step without further purification. LCMS: m / z [M+H]+= 199.2, RT = 0.79 min.

[0748]

[0574] Step 2: To a vial was added 6-bromooxazolo[5,4-c]pyridine (300 mg, 1.51 mmol), sodium carbonate (807 mg, 7.54 mmol), [l,T-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (Pd(dppf)C12) (110 mg, 0.151 mmol), and 2-(2,5-dihydrofuran-3-yl)-4,4,5,5-tetramethyl-1,3,2- dioxaborolane (366 mg, 1.81 mmol). The tube was evacuated and back-filled with nitrogen. Degassed water (0.2 mL) and dioxane (4.00 mL) was added via syringe and the resulting reaction mixture was degassed. The reaction mixture was then heated at 105 °C for 2 h. The reaction mixture was cooled down to rt and poured into water (15 mL) and extracted with ethyl acetate (ethyl acetate). Combined organic layers was washed with brine, dried over Na2SO4 and concentrated. Obtained crude was purified on a normal phase column (1-10% methanol in dichloromethane) to give 6-(2,5-dihydrofuran-3- yl)oxazolo[5,4-c]pyridine (65.0 mg, 23 % yield). LCMS: m / z [M+H]+= 189.4, RT = 0.8 min.

[0749]

[0575] Step 3: To a flamed dried vial was added V-(5-iodo-8-methyl-2,7-naphthyridin-3- yl)cyclopropanecarboxamide (Intermediate 4) (84.5 mg, 0.239 mmol), 6-(2,5-dihydrofuran-3- yl)oxazolo[5,4-c]pyridine (45.0 mg, 0.239 mmol), triphenylphosphine (PPh,) (31.4 mg, 0.120 mmol), copper (II) acetate monohydrate (Cu(OAc)2 H2O) (9.74 mg, 0.0478 mmol), bis(triphenylphosphine)palladium (II) dichloride (Pd^hs^CL) (34.3 mg, 0.0478 mmol) and K2CO3 (99.1 mg, 0.717 mmol). The vial was capped, evacuated, and backfilled with Ar. Degassed anhydrous toluene (2.00 mL) was added under Ar and the mixture was heated at 135 °C for 45 min. Reaction was diluted with dichloromethane (dichloromethane), silica was added and volatiles were evaporated under reduced pressure. Obtained crude was purified on a normal phase column (dichloromethane / methanol, 0 to 4% methanol) to afford N-(5-(6-(2,5-dihydrofuran-3-yl)oxazolo[5,4-c]pyridin-2-yl)-8-methyl-2,7- naphthyridin-3-yl)cyclopropanecarboxamide (Compound 3X) (50.0 mg, 51 % yield). LCMS: m / z [M+H]+= 414.1, RT = 1.26 min.

[0576] Step 4: To a suspension of N-(5-(6-(2,5-dihydrofuran-3-yl)oxazolo[5,4-c]pyridin-2-yl)-8-methyl- 2,7-naphthyridin-3-yl)cyclopropanecarboxamide (Compound 3X) (50.0 mg, 0.121 mmol) and Mn(dpm)s (0.15 eq) in dichloromethane (dichloromethane) (2.50 mL) and isopropanol (iPrOH) (500 uL) was added phenylsilane (1.5 eq) under oxygen (1 atm) atmosphere. The reaction mixture was stirred at rt for 16 hours. Additional Mn(dpm)s (0.15 eq) and phenylsilane (1.5 eq) was added and the reaction mixture was stirred at rt for additional 24 hours. Dimethyl sulfoxide (DMSO) (4 mL) was added and mixture was fdtered. Volatiles were evaporated under reduced pressure and obtained DMSO solution was purified on a reverse phase column (5-100% acetonitrile in a 10 mmol ammonium formate in water solution at pH = 3.8) to obtain 18 mg of N-(5-(6-(3-hydroxytetrahydrofuran-3-yl)oxazolo[5,4-c]pyridin- 2-yl)-8-methyl-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (Compound 3, rac-3) as a mixture of two stereoisomers. LCMS: m / z [M+H]+= 432.1, RT = 1.81 min.

[0750]

[0577] Step 5: The mixture of step 4 were separated via Chiral HPLC (ChiralPak IG SFC, 5 pm, 10 x 250 mm, Daicel, Stationary phase: Amylose tris(3-chloro-5 methylphenylcarbamate); Mode: Isocratic; mobile phase A: 60% acetonitrile / ethanol; mobile phase B: 40% supercritical CO?: B%:50%; Flow rate: lOmL / min, Backpressure: 150 bar, Column temperature: 40 °C, Run time (min): 20) to afford (S)-JV-(5- (6-(3 -hydroxytetrahydrofuran-3 -yl)oxazolo [5 ,4-c]pyridin-2-yl)-8-methyl-2,7-naphthyridin-3 - yl)cyclopropanecarboxamide (Compound 3B*) (5 mg, 9% yield, first eluting peak) and (R)-N-(5-(6-(3- hydroxytetrahydrofuran-3 -yl)oxazolo [5 ,4-c]pyridin-2-yl)-8-methyl-2,7-naphthyridin-3 - yl)cyclopropanecarboxamide (Compound 3A*) (6.5 mg, 12% yield, second eluting peak).

[0751] * Stereochemistry arbitrarily assigned.

[0752]

[0578] Compound 3A*: LCMS: m / z [M+H]+= 432.1, RT = 1.82 min.1H NMR (400 MHz, DMSO-d6) 5 11.29 (s, 1H), 9.90 (s, 1H), 9.64 (s, 1H), 9.34 (s, 1H), 9.11 (d, J= 0.9 Hz, 1H), 8.16 (s, 1H), 5.81 (s, 1H), 4.13 - 4.02 (m, 3H), 3.88 - 3.85 (m, 1H), 3.09 (s, 3H), 2.63 - 2.59 (m, 1H), 2.18 - 2.11 (m, 2H), 0.99 - 0.86 (m, 4H).

[0753]

[0579] Compound 3B*: LCMS: m / z [M+H]+= 432.1, RT = 1.82 min.1H NMR (400 MHz, DMSO-d6) 5 11.29 (s, 1H), 9.88 (s, 1H), 9.63 (s, 1H), 9.32 (s, 1H), 9.10 (s, 1H), 8.14 (d, J= 0.9 Hz, 1H), 5.80 (s, 1H), 4.12 - 4.00 (m, 3H), 3.87 - 3.82 (m, 1H), 3.07 (s, 3H), 2.62 - 2.55 (m, 1H), 2.16 - 2.08 (m, 2H), 0.98 - 0.84 (m, 4H).

[0754] Example 4: N-(5-(5-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)benzo[d]oxazol-2-yl)-8-methyl-2,7- naphthyridin-3-yl)cyclopropanecarboxamide (Compound 4) Compound 4

[0755] A / -(5-(5-(8-oxa-3- azabicyclo[3.2.1]octan-3- y l)benzo[ c / ]oxazol-2-y l)-8- methyl-2,7-naphthyridin-3- yl)cyclopropanecarboxamide

[0756]

[0580] Step 1: To a flamed dried vial was added W(5-iodo-8-methyl-2,7-naphthyridin-3- yl)cyclopropanecarboxamide (Intermediate 4) (500 mg, 1.42 mmol), 5-bromo-1,3-benzoxazole (336 mg, 1.70 mmol), triphenylphosphine (PPh,) (186 mg, 0.708 mmol), copper (II) acetate monohydrate (CU(OAC)2H2O) (57.7 mg, 0.283 mmol), bis(triphenylphosphine)palladium(II) dichloride (Pd(Ph3)2Cl2) (203 mg, 0.283 mmol) and K2COs (587 mg, 4.25 mmol). The vial was capped, evacuated, and backfilled with argon gas (Ar). Degassed anhydrous toluene (10.00 mL) was added under Ar and the mixture was heated at 135 °C for 1 hour. Reaction was diluted with dichloromethane

[0757] (dichloromethane) (50 mL), silica was added, and volatiles were evaporated under reduced pressure. Obtained crude was purified on a normal phase column (dichloromethane / methanol, 0 to 4% methanol). Obtained desired product containing triphenylphosphine oxide (PPIvO) was triturated with isopropanol (iPrOH) to give / V-(5-(5-bromobenzo[d]oxazol-2-yl)-8-methyl-2,7-naphthyridin-3- yl)cyclopropanecarboxamide (295 mg, 46 % yield). LCMS : m / z [M+H]+= 423.0, 425.0, RT = 1.62 mm.

[0758]

[0581] Step 2: To a microwave (MW) vial equipped with a stir bar was added A-(5-(5- bromobenzo[d]oxazol-2-yl)-8-methyl-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (50.0 mg, 0.118 mmol), NaOtBu (58.5 mg, 0.591 mmol), 8-oxa-3-azabicyclo[3.2.1]octane hydrochloride (54.1 mg, 0.354 mmol) and [dicyclohexyl (2', 6'-diisopropoxy-2 -biphenylyl) phosphine-KP] (methanesulfonatato-KO) [2'- (methylamino-idV)-2-biphenylyl-KC2] palladium (RuPhos Pd G4) (21.1 mg, 0.0236 mmol). The mixture was capped, evacuated, and backfilled with Ar. Degassed toluene (3.00 mL) was added and the reaction was heated at 125 °C for 2 hours in microwave. The reaction mixture was passed through a pad of celite and rinsed with solvent (methanol (methanol), CH2C12, ethyl acetate (ethyl acetate) and 4 mL of dimethylsulfoxide (DMSO) at the end). Volatiles were evaporated under reduced pressure and the obtained DMSO solution was filtered (0.45 pm PTFE filter) and purified with prep-MS Prep-MS (Waters CSH C18 OBD Prep Column, 5 pm, 30 mm X 75 mm, mobile phase A = 10 mM NLLCOJT in water, pH 3.8; mobile phase B = acetonitrile; Flow = 45 mL / min; Run time = 12 min; UV Detector = Waters 2998 PDA; 198 to 360 nm. MS Detector = Waters Acquity QDa). Pure fractions were lyophilized to afford N- (5-(5-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)benzo[d]oxazol-2-yl)-8-methyl-2,7-naphthyridin-3- yl)cyclopropanecarboxamide, also referred to herein as N-(5-(5-((lR,5S)-8-oxa-3- azabicyclo[3.2.1]octan-3-yl)benzo[d]oxazol-2-yl)-8-methyl-2,7-naphthyridin-3- yl)cyclopropanecarboxamide (Compound 4) (6 mg, 11% yield). LCMS : m / z [M+H]+= 456.1, RT = 2.74 min. 'H NMR (400 MHz, CD3CN) δ 9.93 (s, 1H), 9.48 (s, 1H), 9.27 (s, 1H), 7.54 (d, J= 9.0 Hz, 1H), 7.16 (d, J= 2.4 Hz, 1H), 7.06 (dd, J= 9.0, 2.5 Hz, 1H), 4.45 - 4.42 (m, 2H), 3.46 - 3.40 (m, 2H), 3.04 (s, 3H), 2.98 - 2.94 (m, 2H), 2.11 - 2.09 (m, 2H), 1.78 - 1.75 (m, 1H), 1.06 - 1.01 (m, 2H), 0.96 - 0.85 (m, 4H).

[0759] Example 5: Synthesis of (2-(6-(cyclopropanecarboxamido)-1-methyl-2,7-naphthyridin-4- yl)benzo[d]oxazol-5-yl)boronic acid (Compound 5)

[0760] Compound 5

[0761] 2-(6-(cyclopropanecarboxamido)-1- methyl-2,7-naphthyridin-4- yl)benzo[ d|oxazol-5-yl)boronic acid

[0762]

[0582] Step 1: To a 5mL pressure flask equipped with a stir bar was added iV-(5-iodo-8-methyl-2,7- naphthyridin-3-yl)cyclopropanecarboxamide (Intermediate 4) (50 mg, 142 umol, 1.0 equiv), Cu(OAc)2H2O (5.77 mg, 28.3 umol., 20 mol%) and bis(triphenylphosphine)palladium(II) dichloride (Pd(Ph3)2Cl2) (20 mg, 28.3 umol, 20 mol%) in toluene (1.00 mL). The mixture was degassed under N2for 10 minutes. Then, triphenylphosphine (PPh3) (18.6 mg, 70.8 umol, 50 mol%), K2CO3(58.7 mg, 425 umol, 3.0 equiv) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[aQoxazole (43.4 mg, 170 umol, 1.2 equiv) were added. The reaction was then heated to 135 °C for 16 hours. The solution was then passed through a 0.45 um syringe filter and subjected to normal phase flash chromatography eluting with a gradient of 5-95% ethyl acetate (ethyl acetate) in heptanes to afford JV-(8-methyl-5-(5- (4.4.5.5-tctramcthyl- l .3.2-dioxaborolan-2-yl)bcnzo|djoxazol-2-yl)-2.7-napthyridin-3-yl). LCMS: m / z [M+H]+= 471.4, RT = 3.36 min. Bpin = pinacol boronic ester.

[0763]

[0583] Step 2: To a solution of JV-(8-methyl-5-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)bcnzo|djoxazol-2-yl)-2.7-napthyridin-3-yl) (24.0 mg, 51.0 umol, 1.0 equiv) in dichloromethane (dichloromethane) (0.8 mL) was added trimethylboroxine (19.4 mg, 153 umol, 3.0 equiv) and trifluoroacetic acid (TFA) (160 uL). The solution was stirred at room temperature for 2 hours. Then, the solution was concentrated, dissolved in minimal methanol (methanol) and purified by prep-HPLC (Waters CSH C18 OBD Prep Column, 5 pm, 30 mm X 75 mm Eluents: A = 10 mM NELCO3H in water, pH 3.8; B = acetonitrile. Flow = 45 mL / min. Gradient: 0 min = 20% B, 1 min = 20% B, 12 min = 40% B, 12. 1 min = 100% B, 5 min = 100% B. Run time = 15 min. UV Detector = Waters 2998 PDA, 198 to 360 nm. MS Detector = Waters Acquity QD) and was eluted with a gradient of 20-40% acetonitrile / water (containing 10 mM ammonium formate, pH 3.8). Pure fractions were lyophilized to afford (2-(6-(cyclopropanecarboxamido)-1-methyl-2,7-naphthyridin-4-yl)benzo[d]oxazol-5-yl)boronic acid (Compound 5) (2 mg, 10 % yield). LCMS : m / z [M+H]+= 389.0, RT = 1.89 min. 'H NMR (400 MHz, DMSO-Je) δ 11.29 (s, 1H), 9.87 (s, 1H), 9.61 (s, 1H), 9.25 (s, 1H), 8.63 (s, 2H), 8.37 (s, 1H), 8.30 (s, 1H), 7.89 (d, J= 8.2 Hz, 1H), 7.77 (d, J= 8.2 Hz, 1H), 3.05 (s, 3H), 2.21 - 2.06 (m, 1H), 0.97 - 0.80 (m, 4H).

[0764] Example 6: Synthesis of V-(5-(5-(2-1ivdi (»xypi (»pan-2-yl )benzo[d]oxazol-2-yl )-8-methyl-2,7- naphthyridin-3-yl)cyclopropanecarboxamide (Compound 2)

[0765]

[0584] Step 1 : A mixture of commercially available 3-chloro-5-iodo-2,7-naphthyridine (500 mg, 1.72 mmol, 1 equiv), methyl l,3-benzoxazole-5-carboxylate (610 mg, 3.44 mmol, 2.0 equiv), palladium (II) acetate (Pd(OAc)2) (77 mg, 0.343 mmol, 0.2 equiv), 4,6-bis(diphenylphosphanyl)-10H-phenoxazine (380 mg, 0.689 mmol, 0.4 equiv) and CS2CO3 (1682 mg, 5.16 mmol, 3.0 equiv) in 1,4-dioxane (10 mL) was stirred for 3h at 80°C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature before being quenched in water (lOOmL). The aqueous layer was extracted with ethyl acetate (ethyl acetate) (3 x 200 mL) and combined organic phases were dried, fdtered, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with CH2Q2 / ethyl acetate (7: 1) to afford methyl 2-(6-chloro-2,7-naphthyridin-4-yl)benzo[d]oxazole-5-carboxylate (250 mg, 36% yield). LCMS: m / z [M+H]+= 340.0.

[0766]

[0585] Step 2: In a 100-mL round bottom flask, to a solution of methyl 2-(6-chloro-2,7-naphthyridin-4- yl)benzo[d]oxazole-5-carboxylate (500 mg, 1.47 mmol, 1 equiv) and CeCU (750 mg, 3.04 mmol, 2.07 equiv) in tetrahydrofuran (THF) (5 mL) was added dropwise MeMgBr (4.9 mL, 14.68 mmol, 9.97 equiv) (3 M in THF) at -78 °C under N2atmosphere. The reaction mixture was stirred at -78 °C for 60 min and the reaction was quenched with a sat. aqueous solution of NH4CI (10 mL), The mixture was then extracted with ethyl acetate (ethyl acetate) (3 x 5mL) and combined organic extracts were washed with brine (10 mL), dried over anhydrous Na2SO4, fdtered, and concentrated under vacuum to yield a crude product which was directly purified by flash chromatography (ethyl acetate / petroleum ether) mixture to yield 2-(2-(6-chloro-1-methyl-2,7-naphthyridin-4-yl)benzo[d]oxazol-5-yl)propan-2-ol. LCMS: m / z [M+H]+= 356.0.

[0767]

[0586] Step 3: Into a solution of 2-(2-(6-chloro-1-methyl-2,7-naphthyridin-4-yl)benzo[d]oxazol-5- yl)propan-2-ol (30 mg, 0.085 mmol, 1 equiv) in dioxane (0.3 mL) was added cyclopropanecarboxamide (37 mg, 0.435 mmol, 5.13 equiv), tris(dibenzylideneacetone)dipalladinm(0) (Pd2(dba)3) (16 mg, 0.017 mmol, 0.21 equiv), (9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) (Xantphos) (10 mg, 0.017 mmol, 0.2 equiv) and CS2CO3 (83 mg, 0.255 mmol, 3.0 equiv). The mixture was stirred at 80°C for 2 hours under nitrogen before being purified by reverse flash chromatography with the following condition: column, C18 silica gel; mobile phase: acetonitrile in water, 5% to 100% gradient in 15min; detector, UV 220nm to afford / V-(5-(5-(2-hydroxypropan-2-yl)benzo[d]oxazol-2-yl)-8-methyl-2, 7- naphthyridin-3-yl)cyclopropanecarboxamide (Compound 2) (15.9 mg, 46% yield). LCMS: m / z [M+H]+= 403.2. ’H NMR (400 MHz, DMSO-d6) δ 11.26 (s, 1H), 9.82 (d, J = 1.2 Hz, 1H), 9.63 (d, J = 1.2 Hz, 1H), 9.24 (s, 1H), 7.95 (d, J = 1.6 Hz, 1H), 7.75 - 7.73 (d, J = 11.2 Hz, 1H), 7.63 - 7.59 (m, 1H), 5.22 (s, 1H), 3.07 (s, 3H), 2.18 - 2.13 (m, 1H), 1.54 (s, 6H), 0.98 - 0.89 (m, 4H).

[0768] Example 7: Synthesis of N-(5-(5-(3-hydroxytetrahydrofuran-3-yl)benzo[d]oxazol-2-yl)-8-methyl- 2,7-naphthyridin-3-yl)cyclopropanecarboxamide (Compound 7, rac-7), (R)- / V-(5-(5-(3- hydroxytetrahydrofuran-3-yl)benzo[d]oxazol-2-yl)-8-methyl-2,7-naphthyridin-3- yl)cyclopropanecarboxamide (Compound 7A) and (S)- / V-(5-(5-(3-hydroxytetrahydrofuran-3- yl)benzo[d]oxazol-2-yl)-8-methyl-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (Compound 7B)

[0769] M-(5-(5-(3-hydroxytetrahydrofuran- (R)-M-(5-(5-(3- (S)-N-(5-(5-(3-

[0770] 3-yl)benzo[ d]oxazol-2-yl)-8-methyl- hydroxytetrahydrofuran- hydroxytetrahydrofuran-3-

[0771] 2,7-naphthyridin-3- 3-yl)benzo[ d|oxazol-2- yl)benzo[ d]oxazol-2-yl)-8- yl)cyclopropanecarboxamide yl)-8-methyl-2,7- methyl-2, 7-napht hy ridi n-3- naphthyridin-3- yl)cyclopropanecarboxamide yl)cyclopropanecarboxa mide

[0772]

[0587] Step 1: To a solution of 5-bromo-1,3-benzoxazole (2 g, 10.10 mmol, 1 eq) in tetrahydrofuran (THF) (20 mL) cooled to -70 °C, was added n-BuLi (2.5 M, 8.08 mb, 2 eq) dropwise under N2. Stirring was continued for 1 hour before the addition of tetrahydrofuran-3-one (2.61 g, 30.30 mmol, 3 eq) as a THF (10 mL) solution. The reaction was stirred at -70 °C for another 2 hours and quenched with a sat. solution of NH4CI (40 mL) under N2. Water (30 mL) was added, and the resulting mixture was extracted with ethyl acetate (150 mLx3). The combined organic phases were dried with anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash silica gel chromatography (ISCO; 12 g SepaFlash Silica Flash Column, Eluent of 0-15% ethyl acetate / petroleum ether gradient at 50 mL / min) to afford 3-(l,3-benzoxazol-5-yl)tetrahydrofuran-3-ol (900 mg, 3.73 mmol, 37% yield, 85% purity).

[0773]

[0588] Step 2 : To a mixture of 3-(l,3-benzoxazol-5-yl)tetrahydrofuran-3-ol (900 mg, 4.39 mmol, 1 eq), 4- bromo-6-chloro-1-methyl-2,7-naphthyridine (Intermediate 1) (677.64 mg, 2.63 mmol, 0.6 eq), K2CO3 (1.21 g, 8.77 mmol, 2 eq) and triphenylphosphine ( P Ph, ) (575.16 mg, 2.19 mmol, 0.5 eq) in toluene (10 mL), was added Cu(Oac)2.H2O (175.12 mg, 877.15 pmol, 0.2 eq) and bis(triphenylphosphine)palladium(II) dichloride (Pd(PPh3)2C12) (615.67 mg, 877.15 pmol, 0.2 eq) in one portion under N2. The mixture was stirred at 140 °C for 1 hour and then concentrated in vacuum without work-up. The residue was purified by flash silica gel chromatography (ISCO; 4 g SepaFlash Silica Flash Column, Eluent of 0-50% ethyl acetate / petroleum ether gradient at 50 mL / min) to afford 3-[2-(6-chloro- l-methyl-2,7-naphthyridin-4-yl)-1,3-benzoxazol-5-yl]tetrahydrofuran-3-ol (1 g, 2.62 mmol, 30% yield).

[0774]

[0589] Step 3 : To a mixture of 3-[2-(6-chloro-1-methyl-2,7-naphthyridin-4-yl)-1,3-benzoxazol-5- yl]tetrahydrofuran-3-ol (1 g, 2.62 mmol, 1 eq), cyclopropanecarboxamide (334.34 mg, 3.93 mmol, 1.5 eq) and CS2CO3 (1.71 g, 5.24 mmol, 2 eq) in dioxane (10 mL) was added 2,2’-bis-diphenylphosphino- 1,1’ -binaphthyl (BINAP) (652.33 mg, 1.05 mmol, 0.4 eq) and [(2-di-cyclohexylphosphino-3,6- dimethoxy-2',4',6'- triisopropyl- l,l'-biphenyl)-2-(2'-amino- 1,1' -biphenyl)]palladium(II) methanesulfonate methanesulfonate (BrettPhos Pd G3) (474.84 mg, 523.82 pmol, 0.2 eq) in one portion under N2. The mixture was stirred at 120 °C for 3 hours before being concentrated in vacuum. The residue (combined with another 430 mg scale) was purified by flash silica gel chromatography (ISCO; 4 g SepaFlash Silica Flash Column, eluent of 0-65% ethyl acetate / petroleum ether gradient at 50 mL / min) to give impure final product which was further purified by prep-HPLC (Waters Xbridge BEH Cl 8 100 x 30mm x lOum; mobile phase A: H2O (lOrnM NH4HCO3); mobile phase B: acetonitrile; gradient: 25%- 50% B over 8.0 min) to afford A-[5-[5-(3-hydroxytetrahydrofuran-3-yl)-1, 3-benzoxazol-2-yl]-8-methyl- 2,7-naphthyridin-3-yl]cyclopropanecarboxamide (Compound 7, rac-7) (450 mg, 98% purity) as a mixture of 2 stereoisomers. 'H NMR: (400 MHz, DMSO-de) δ 11.29 (br s, 1H), 9.82 (s, 1H), 9.62 (s, 1H), 9.24 (s, 1H), 7.98 (d, J = 1.6 Hz, 1H), 7.79 (d, J = 8.8 Hz, 1H), 7.62 (dd, J = 1.6, 8.8 Hz, 1H), 5.61 (s, 1H), 4.09 - 4.02 (m, 2H), 3.91 - 3.83 (m, 2H), 3.06 (s, 3H), 2.40-2.37 (m, 1H), 2.25 - 2.11 (m, 2H), 0.96 - 0.84 (m, 4H).

[0775]

[0590] Step 4: The mixture (450 mg) was separated by SFC (ChiralPak IH, 250 x 30mm, lOum; mobile phase A: CO2; mobile phase B: methanol (0.1%NH4OH); B%:50%, isocratic elution mode) to afford (R)- A-(5-(5-(3-hydroxytetrahydrofuran-3-yl)benzo[d]oxazol-2-yl)-8-methyl-2,7-naphthyridin-3- yl)cyclopropanecarboxamide (Compound 7A) (180.2 mg, 414.48 pmol, 40% yield, 99% purity) as the first eluting peak and (S)-A-(5-(5-(3-hydroxytetrahydrofuran-3-yl)benzo[d]oxazol-2-yl)-8- methyl-2,7- naphthyridin-3-yl)cyclopropanecarboxamide (Compound 7B) (181.5 mg, 418.32 pmol, 40% yield, 99% purity) as the second eluting peak. Absolute stereochemistry of Compounds 7A and 7B were confirmed by X-ray crystallography.

[0776]

[0591] Compound 7A:1H NMR: (400 MHz, DMSO-de) δ 11.28 (s, IH), 9.83 (s, IH), 9.62 (s, IH), 9.24 (s, IH), 7.98 (d, J = 1.6 Hz, IH), 7.79 (d, J = 8.4 Hz, IH), 7.62 (dd, J = 1.6, 8.8 Hz, IH), 5.61 (s, IH), 4.09 - 4.02 (m, 2H), 3.90 - 3.82 (m, 2H), 3.06 (s, 3H), 2.44 - 2.33 (m, IH), 2.30 - 2.09 (m, 2H), 0.97 - 0.85 (m, 4H). LCMS: m / z [M+H]+= 431.2 at 2.032 min (5-95% acetonitrile in H2O, 6 min). SFC:99.34% ee at 1.442 min.

[0777]

[0592] Compound 7B:1H NMR: (400 MHz, DMSO-de) δ 11.28 (s, IH), 9.82 (s, IH), 9.62 (s, IH), 9.24 (s, IH), 7.98 (d, J = 1.6 Hz, IH), 7.79 (d, J = 8.8 Hz, IH), 7.62 (dd, J = 1.6, 8.8 Hz, IH), 5.61 (s, IH), 4.09 - 4.02 (m, 2H), 3.90 - 3.82 (m, 2H), 3.06 (s, 3H), 2.44 - 2.33 (m, IH), 2.25 - 2.11 (m, 2H), 0.97 - 0.85 (m, 4H). LCMS: m / z [M+H]+= 431.2 at 2.030 min (5-95% acetonitrile in H2O, 6 min). SFC: 99.21% ee at 1.860 min.

[0778] Example 8: Synthesis of N-(8-methyl-5-(5-(tetrahydrofuran-3-yl)benzo[d]oxazol-2-yl)-2,7- naphthyridin-3-yl)cyclopropanecarboxamide (Compound 8, rac-8), ( R)- V-(8-inetlivl-5-(5- (tetrahydrofuran-3-yl)benzo[d]oxazol-2-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (Compound 8A*) and (S)- / V-(8-methyl-5-(5-(tetrahydrofuran-3-yl)benzo[d]oxazol-2-yl)-2,7- naphthyridin-3-yl)cyclopropanecarboxamide (Compound 8B*)

[0779] Bpin

[0780]

[0781] (R)- / V-(8-methyl-5-(5- (S)- / V-(8-methyl-5-(5-

[0782] (tetrahydrofuran-3-yl)benzo[c / |oxazol- (tetrahydrofuran-3-yl)benzo[c / |oxazol-

[0783] 2-yl)-2,7-naphthyridin-3- 2-yl)-2,7-naphthyridin-3- yl)cyclopropanecarboxamide yl)cyclopropanecarboxam ide

[0784]

[0593] Step 1: To a mixture of 4-bromo-2-nitro-phenol (5 g, 22.94 mmol, 1 eq) in dimethylformamide (DMF) (25 mL) was added K2CO3 (3.80 g, 27.52 mmol, 1.2 eq). The reaction was stirred at 25 °C for 2 hr followed by the addition of a solution of bromomethylbenzene (4.71 g, 27.52 mmol, 3.27 mL,

[0785] 1.2 eq) in DMF (25 mL). The mixture was stirred at 85 °C for 12 hr, then quenched with water (200 mL) and extracted with ethyl acetate (3 X 100 mL). The combined organic phases were dried with anhydrous Na2SO4, fdtered, and concentrated under reduced pressure to provide l-benzyloxy-4-bromo-2- nitrobenzene (12.5 g, 40.57 mmol, 88% yield). 'H NMR: (400 MHz, DMSO-de) δ 8.12 (d, J = 2.5 Hz, 1H), 7.83 (dd, J = 2.5, 9.0 Hz, 1H), 7.47 - 7.38 (m, 5H), 7.37 - 7.31 (m, 1H), 5.31 (s, 2H).

[0786]

[0594] Step 2 : A mixture of l-benzyloxy-4-bromo-2 -nitrobenzene (5 g, 16.23 mmol, 1 eq), 2-(2,5- dihydrofuran-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (4.77 g, 24.34 mmol, 1.5 eq), Na2COs (5.16 g, 48.68 mmol, 3 eq), [l,r-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (Pd(dppf)C12)*CH2C12 (1.33 g, 1.62 mmol, 0.1 eq) in dioxane (100 mL) and H2O (10 mL) was stirred at 100 °C for 12 hr under N2atmosphere. The mixture (combined with another 5 g scale) was fdtered on celite and concentrated under reduced pressure. The crude residue was purified by column chromatography (SiC>2, petroleum ether / ethyl acetate=20 / l to 5 / 1) to afford 3-(4-benzyloxy-3- nitrophenyl)-2,5-dihydrofuran (7 g, 23.54 mmol, 73% yield).

[0787]

[0595] Step 3: To a solution of 3-(4-benzyloxy-3-nitrophenyl)-2,5-dihydrofuran (3.5 g, 11.77 mmol,

[0788] 1 eq) in methanol (methanol) (70 mL) was added Pd / C (700 mg, 10% wt, 0.66 mmol, 0.05eq) under Ar atmosphere. The mixture was then stirred under H2 (50 Psi) at 50 °C for 12 hr. The mixture was filtered on celite and concentrated under reduced pressure to afford crude 2-amino-4-tetrahydrofuran-3- yl -phenol which was directly used in the next step.

[0789]

[0596] Step 4: To a solution of 2-amino-4-tetrahydrofuran-3-yl -phenol (4 g, 22.32 mmol,

[0790] 1 eq) in diethoxymethoxyethane (40 mL) was added tosic acid monohydrate (TsOH’FLO) (1.27 g, 6.70 mmol, 0.3 eq). The mixture was stirred at 140 °C for 2 hr before being quenched with sat. solution of NaHCOs (40 mL) and extracted with ethyl acetate (3 X 40 mL). The combined organic phases were dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiCL, petroleum ether / ethyl acetate=20 / l to 1 / 1) to afford 5-tetrahydrofuran-3- yl- 1,3 -benzoxazole (3.2 g, 16.91 mmol, 76% yield).

[0791]

[0597] Step 5: To a mixture of 5-tetrahydrofuran-3-yl-1,3-benzoxazole (500 mg, 2.64 mmol,

[0792] 1 eq) and l,l,1,2,2,3,3,4,4-nonafluoro-4-iodo-butane (1.01 g, 2.91 mmol, 1.1 eq) in dimethylformamide (DMF) (10 mL) was added t-BuONa (126.98 mg, 1.32 mmol, 0.5 eq). The mixture was stirred at 25 °C for 1 hr, diluted with H2O (10 mL), and extracted with ethyl acetate (3 X 20 mL). The combined organic phases were dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure to provide crude 2-iodo-5-tetrahydrofuran-3-yl-1,3-benzoxazole (600 mg, 1.90 mmol, 72% yield) which was directly used in the next step.

[0793]

[0598] Step 6 : A mixture of 2-iodo-5-tetrahydrofuran-3-yl- 1,3 -benzoxazole (1.5 g, 4.76 mmol, 1.2 eq), 6- chloro-1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,7-naphthyridine (Intermediate 5) (1.21 g, 3.97 mmol, 1 eq), K3PO4 (2.53 g, 11.90 mmol, 3 eq), [l,l'-bis(di-fert- butylphosphino)ferrocene]dichloropalladium(II) (Pd(dtbpf)C12) (258.54 mg, 396.69 pmol,

[0794] 0. 1 eq) in tetrahydrofuran (THF) (16 mL) and H2O (4 mL) was stirred at 80 °C for 3 hr under N2atmosphere. The mixture was filtered on celite and concentrated under reduced pressure. The residue was purified by column chromatography (SiCL, petroleum ether / ethyl acetate = 20 / 1 to 1 / 1) to provide 2- (6-chloro-1-methyl-2,7-naphthyridin-4-yl)-5-tetrahydrofuran-3-yl-1,3- benzoxazole (900 mg, 2.46 mmol, 62% yield). LCMS: m / z [M+H]+= 366.2, 368.2 at 0.530 min (10-100% acetonitrile in H2O, 1 min).

[0795]

[0599] Step 7: A mixture of cyclopropanecarboxamide (314.07 mg, 3.69 mmol, 1.5 eq), 2-(6-chloro-1- methyl-2,7-naphthyridin-4-yl)-5-tetrahydrofiiran-3-yl- 1,3 -benzoxazole (900 mg, 2.46 mmol,

[0796] 1 eq), CS2CO3 (1.60 g, 4.92 mmol, 2 eq), (9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) (Xantphos) (284.71 mg, 492.06 pmol, 0.2 eq) and tris(dibenzylideneacetone)dipalladinm(0) (Pd2(dba)3) (225.29 mg, 246.03 pmol, 0. 1 eq) in dioxane (9 mL) was degassed and purged with N23 times, followed by stirring at 120 °C for 2 hr under N2atmosphere. The mixture (combined with another 330 mg scale) was filtered on celite and concentrated under reduced pressure. The crude residue was purified by prep- HPLC (Welch Xtimate C18 250 x70mm xlOum; mobile phase A: H2O (lOmM NH4HCO3); mobile phase B: acetonitrile; gradient: 30%-70% B over 20.0 min) to provide JV-[8-methyl-5-(5-tetrahydrofuran-3-yl- l,3-benzoxazol-2-yl)-2,7-naphthyridin-3-yl]cyclopropanecarboxamide (Compound 8, rac-8) (400 mg, 98% purity). 'H NMR: (400 MHz, CD3CN) δ 9.96 (s, 1H), 9.51 (s, 1H), 9.31 (s, 2H), 7.73 (s, 1H), 7.66 (d, J= 8.4 Hz, 1H), 7.44 - 7.40 (m, 1H), 4.16 (t, J= 7.8 Hz, 1H), 4.09 (dt, J= 4.4, 8.3 Hz, 1H), 3.92 (q, J = 7.7 Hz, 1H), 3.75 (t, J= 7.8 Hz, 1H), 3.67 - 3.58 (m, 1H), 3.07 (s, 3H), 2.52 - 2.42 (m, 1H), 2.10 (br dd, J= 8.3, 12.5 Hz, 2H), 1.08-1.04 (m, 2H), 0.99 - 0.92 (m, 2H).

[0797]

[0600] Step 8: JV-[8-methyl-5-(5-tetrahydrofuran-3-yl-1,3-benzoxazol-2-yl)-2,7-naphthyridin-3- yl] cyclopropanecarboxamide (400 mg) was separated by SFC (DAICEL CHIRALPAK IC (250mm x 30mm, lOum); mobile phase A: CO2; mobile phase B: ethanol (0.1% NH3H2O); B%:50%, isocratic elution mode) to provide (R)-JV-(8-methyl-5-(5-(tetrahydrofuran-3-yl)benzo[d]oxazol-2-yl)-2,7- naphthyridin-3-yl)cyclopropanecarboxamide (Compound 8A*) (155 mg, 369.01 pmol, 38% yield, >98% purity) as the first eluting peak and (S)- / V-(8-methyl-5-(5-(tetrahydrofuran-3-yl)benzo[d]oxazol-2-yl)-2,7- naphthyridin-3-yl)cyclopropanecarboxamide (Compound 8B*) (170 mg, 407.39 pmol, 42% yield, 99.3% purity) as the second eluting peak. * Stereochemisty arbitrarily assigned.

[0798]

[0601] Compound 8A*:1H NMR: (400 MHz, DMSO-de) δ 11.27 (s, 1H), 9.78 (s, 1H), 9.61 (s, 1H), 9.23 (s, 1H), 7.79 - 7.74 (m, 2H), 7.42 (dd, J= 1.6, 8.4 Hz, 1H), 4.10 (t, J= 7.4 Hz, 1H), 4.02 (dt, J= 4.4, 8.3 Hz, 1H), 3.84 (q, J= 7.8 Hz, 1H), 3.68 - 3.63 (m, 1H), 3.63 - 3.54 (m, 1H), 3.06 (s, 3H), 2.44 - 2.35 (m, 1H), 2.18 - 2.11 (m, 1H), 2.03 (qd, J= 7.9, 12.2 Hz, 1H), 0.96 - 0.85 (m, 4H). LCMS: m / z [M+H]+= 415.2 at 2.287 min (5-95% acetonitrile in H2O, 6 min).

[0799]

[0602] Compound 8B*:1H NMR: (400 MHz, DMSO-de) δ 11.26 (s, 1H), 9.77 (s, 1H), 9.61 (s, 1H), 9.22 (s, 1H), 7.81 - 7.71 (m, 2H), 7.44 - 7.39 (m, 1H), 4.10 (t, J= 7.5 Hz, 1H), 4.02 (dt, J= 4.4, 8.3 Hz, 1H), 3.84 (q, J= 7.8 Hz, 1H), 3.68 - 3.63 (m, 1H), 3.62 - 3.54 (m, 1H), 3.05 (s, 2H), 2.44 - 2.35 (m, 1H), 2.19 - 2.11 (m, 1H), 2.02 (qd, J= 8.0, 12.1 Hz, 1H), 0.96 - 0.84 (m, 4H). LCMS: m / z [M+H]+= 415.2 at 2.287 min (5-95% acetonitrile in H2O, 6 min).

[0800] Example 9: Synthesis of / V-(8-methyl-5-(5-(l-methyl-1H-1,2,4-triazol-3-yl)benzo[d]oxazol-2-yl)-2,7- naphthyridin-3-yl)cyclopropanecarboxamide (Compound 9)

[0801]

[0603] Step 1: A mixture of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-benzoxazole (1 g, 4.08 mmol, 1 eq), 3 -bromo- 1 -methyl- 1, 2, 4-triazole (793.15 mg, 4.90 mmol, 1.2 eq), K3PO4 (1.73 g, 8.16 mmol, 2 eq), dicyclohexyl[2',4',6'-tris(propan-2-yl)[l,l'-biphenyl]-2-yl]phosphane (Xphos) (389.03 mg, 816.06 pmol, 0.2 eq) and [(4,5-bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2'-amino-1,l'- biphenyl)]palladium(II) methanesulfonate (XantPhos Pd G3) (386.95 mg, 408.03 pmol,

[0802] 0.1 eq) in dioxane (10 mL) and H2O (2.5 mL) was stirred at 90 °C for 12 hr under N2atmosphere. Once cooled to rt, the reaction mixture was fdtered on celite and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=10 / l to 1 / 1) to afford 5 -(1 -methyl- 1, 2, 4-triazol-3-yl)- 1,3 -benzoxazole (350 mg, 1.68 mmol, 41% yield, 96% purity).

[0803]

[0604] Step 2: To a mixture of 5-(l-methyl-1,2,4-triazol-3-yl)-1,3-benzoxazole (300 mg, 1.50 mmol, 1 eq) and l,l,1,2,2,3,3,4,4-nonafluoro-4-iodo-butane (570.23 mg, 1.65 mmol,

[0804] 1.1 eq) in dimethylformamide (DMF) (6 mL) was added sodium t-butoxide (t-BuONa) (72.01 mg, 749.26 pmol, 0.5 eq). The mixture was stirred at 25 °C for 1 hr before being quenched with water (10 mL). The precipitated solid was collected by filtration and dried under reduced pressure to provide 2-iodo-5-(l- methyl-1, 2, 4-triazol-3-yl)- 1,3 -benzoxazole (170 mg, 521.32 pmol, 35% yield).

[0805]

[0605] Step 3: A mixture of 2-iodo-5-(l-methyl-1,2,4-triazol-3-yl)-1,3-benzoxazole (170 mg, 521.32 pmol, 1 eq), 6-chloro-1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,7-naphthyridine (Intermediate 5) (190.54 mg, 625.59 pmol, 1.2 eq), K3PO4 (331.98 mg, 1.56 mmol, 3 eq), [l,l'-bis(di- ?ert-butylphosphino)ferrocene]dichloropalladium(II) (Pd(dtbpf)C12) (33.98 mg, 52.13 pmol,

[0806] 0. 1 eq) in tetrahydrofuran (THF) (1.6 mL) and H2O (0.4 mL) was stirred at 80 °C for 3 hr under N2atmosphere. The mixture was filtered on celite and concentrated under reduced pressure. The residue was purified by column chromatography (SiCL, petroleum ether / ethyl acetate=20 / l to 1 / 1) to provide 2- (6-chloro- 1 -methyl-2,7-naphthyridin-4-yl)-5 -( 1 -methyl- 1 ,2,4-triazol-3-yl)- 1 ,3 -benzoxazole (80 mg, 200.43 pmol, 38% yield, 94% purity). LCMS: m / z [M+H]+= 377.1, 379.0 at 0.442 min (10-100% acetonitrile in H2O, 1 min).

[0807]

[0606] Step 4: A mixture of 2-(6-chloro-1-methyl-2,7-naphthyridin-4-yl)-5-(l-methyl-1,2,4-triazol-3-yl)-

[0808] 1.3 benzoxazole (70 mg, 185.78 pmol, 1 eq), cyclopropanecarboxamide (20.55 mg, 241.51 pmol,

[0809] 1.3 eq), CS2CO3 (121.06 mg, 371.55 pmol, 2 eq), (9.9-Dimcthyl-9 / / -xanthcnc-4.5-diyl)bis (diphenyl phosphane) (Xantphos) (21.50 mg, 37.16 pmol, 0.2 eq) and tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)3) (17.01 mg, 18.58 pmol, 0.1 eq) in dioxane (0.7 mL) was stirred at 120 °C for 2 hr under N2atmosphere. The mixture (combined with another batch at 10 mg scale) was fdtered on celite and concentrated under reduced pressure. The crude residue was purified by prep-HPLC (Waters Xbridge BEH C18 100 x 30mm x lOum; mobile phase A: H2O (lOmM NH4HCO3); mobile phase B: acetonitrile; gradient: 20%-50% B over 8.0 min) to provide JV-(8-methyl-5-(5-(l-methyl-1H-1,2,4-triazol-3- yl)benzo[d]oxazol-2-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (Compound 9) (6.9 mg, >99% purity). 'H NMR: (400 MHz, DMSO-d6) δ 11.29 (s, 1H), 9.89 (s, 1H), 9.63 (s, 1H), 9.27 (s, 1H), 8.58 (s, 1H), 8.38 (d, J= 1.1 Hz, 1H), 8.15 (dd, J= 1.5, 8.5 Hz, 1H), 7.92 (d, J = 8.5 Hz, 1H), 3.97 (s, 3H), 3.07 (s, 3H), 2.20 - 2.11 (m, 1H), 0.99 - 0.93 (m, 2H), 0.91 - 0.85 (m, 2H). LCMS: m / z [M+H]+= 426.2 at 2.462 min (5-95% acetonitrile in H2O, 6 min).

[0810] Example 10: Synthesis of N-(5-(5-(l-hydroxyethyl)benzo[d]oxazol-2-yl)-8-methyl-2,7-naphthyridin-

[0811] 3-yl)cyclopropanecarboxamide (Compound 10, rac-10), (R)-N-(5-(5-(l- hydroxyethyl)benzo[d]oxazol-2-yl)-8-methyl-2,7-naphthyridin-3-yl)cyclopropanecarboxamide

[0812] (Compound 10A*) and (S)-X-(5-(5-(l-hydroxyethyl)benzo[d]oxazol-2-yl)-8-methyl-2,7- naphthyridin-3-yl)cyclopropanecarboxamide (Compound 10B*)

[0813] Compound 10A* Compound 10B*

[0814] (R)-A / -(5-(5-(1 - (S)-A / -(5-(5-(1- hydroxyethyl)benzo[d|oxazol-2- hydroxyethyl)benzo[d|oxazol-2- yl)-8-methyl-2,7-naphthyridin-3- yl)-8-methyl-2,7-naphthyridin-3 yl)cyclopropanecarboxam ide yl)cyclopropanecarboxam ide

[0815]

[0607] Step 1: A mixture of 5-bromo-1,3-benzoxazole (2 g, 10.10 mmol, 1 eq), Pd(amphos)C12 (715.17 mg, 1.01 mmol, 715.17 pL, 0.1 eq) and tributyl(l-ethoxyvinyl)stannane (4.38 g, 12.12 mmol, 4.09 mb, 1.2 eq) in dioxane (20 mL) was degassed and purged with N23 times, and then stirred at 110 °C for 6 hr under N2atmosphere. To this mixture was added sat. KF (30 mL) followed by extraction with ethyl acetate (3 X 50 mL). The combined organic layers were dried over Na2SO4, fdtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography (SiCL, petroleum ether / ethyl acetate=100 / l to 20 / 1) to afford l-(l,3-benzoxazol-5-yl)ethan-1-one (660 mg, 3.40 mmol, 34% yield, 83% purity) .

[0816]

[0608] Step 2: To a solution of l-(l,3-benzoxazol-5-yl)ethan-1-one (660 mg, 4.10 mmol, 1 eq) in methanol (methanol) (6.6 mL) and CH2CI2 (2.64 mL) was added NaBFL (247.90 mg, 6.55 mmol, 1.6 eq) at 0°C under N2. The mixture was stirred at 0 °C for 0.5 hr before being quenched by the addition of a sat. solution of NH4CI (5 mL) at 0°C. The resulting mixture was stirred at 25 °C for 0.5 h followed by extraction with ethyl acetate (ethyl acetate) (3 x 10 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiC>2, petroleum ether / ethyl acetate=20 / l to 10 / 1) to afford l-(l,3-benzoxazol-5- yl)ethan-1-ol (340 mg. 80% purity).

[0817]

[0609] Step 3 : To a solution of l-(l,3-benzoxazol-5-yl)ethan-1-ol (340 mg, 2.08 mmol, 1 eq), l,LL2,2,3,3,4,4-nonafluoro-4-iodo-butane (792.89 mg, 2.29 mmol, 1.1 eq) in dimethylformamide (DMF) (17 mL) was added t-BuONa (100.12 mg, 1.04 mmol, 0.5 eq). The mixture was stirred at 25 °C for 1 hr. followed by the addition of water (10 mL) and the extraction with ethyl acetate (ethyl acetate) (3 X 20 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO; 4 g SepaFlash Silica Flash Column, eluent of 0-20% ethylacetate / petroleum ether gradient at 75 mL / min) to afford 1- (2-iodo-1,3-benzoxazol-5-yl)ethan-1-ol (130 mg, 373.27 pmol, 18% yield, 83% purity). LCMS: m / z [M+H]+= 289.9 at 0.603 min (5-95% acetonitrile in H2O, 2 min).

[0818]

[0610] Step 4 : A mixture of l-(2-iodo-1,3-benzoxazol-5-yl)ethan-1-ol (37.05 mg, 128.18 pmol, 1 eq), N- (8-methyl-5-(trimethylstannyl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (Intermediate 6) (50 mg, 128.18 pmol, 1 eq) and [l,r-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (Pd(dppf)C12) (9.38 mg, 12.82 pmol, 0.1 eq) in dioxan...

Claims

CLAIMSWhat is claimed is:

1. A compound of Formula (I) :or a pharmaceutically acceptable salt or isotopically labeled derivative thereof, wherein:R1is C3-4 carbocyclyl or 3-4 membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is substituted with 0, 1, 2, or 3 instances of R1A; each instance of R1Ais independently Cm alkyl, C1-3 haloalkyl, halogen, or -OR', or two R1Agroups attached to the same carbon atom are joined to form a C3-6 carbocyclyl or 3-6 membered heterocyclyl, or two R1Agroups attached to vicinal atoms are joined to form a C3-6 carbocyclyl or 3-6 membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is substituted with 0, 1 , 2, or 3 substituents independently selected from Cm alkyl, Cm haloalkyl, halogen, -C(=O)OR', and -OR';-CX3is -CH3or -CHF2;G1is CRG1or N and G2is CRG2or N; each of RG1and RG2is independently selected from H, halogen, Ci-6 alkyl, Cm haloalkyl, and - (Li)-O-(CH2CH2O)m-R', wherein Li is absent, Cm alkylene, or Cm haloalkylene, and wherein m is 0, 1 or 2;G3is N or CR3and G4is N or CR4, provided at least one of G3and G4is CR3or CR4, respectively, and at least one of said R3and R4is not H;G5is O, N, S, or N-RG5, wherein RG5is H, Cm alkyl, or Cm haloalkyl;G6is C or N;G7is C or N;R3and R4are each independently H, halogen, Cm alkyl, Cm haloalkyl, -(L2)-(Y)-C3-io carbocyclyl, -(L2)-(Y)-(4-10 membered heterocyclyl), -(L2)-(Y)-Ce -10 aryl, -(L2)-(Y)-(5-10 membered heteroaryl), -(L2)-ORA, -(L2)-N(RA)2, -(L2)-SRA, -(L2)-CN, -(L2)-(Y)-C(=O)RA, -(L2)-(Y)-C(=O)ORA, - (L2)-(Y)-C(=O)N(RA)2, -(L2)-S(=O)2RA, -(L2)-S(=O)2ORA, -(L2)-(Y)-S(=O)2N(RA)2, or -B(ORA)2, wherein L2is absent, Cm alkylene, or Cm haloalkylene; Y is absent, -O-, or -N(RA)-; and each alkyl, haloalkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, alkylene, or haloalkylene is independently substituted with 0, 1, 2, or 3 instances of RB; each instance of RAis independently H, Cm alkyl, Cm haloalkyl, -(L3)-(Z)-C3-10 carbocyclyl, - (L3)-(Z)-(3-10 membered heterocyclyl), -(L3)-(Z)-Ce -10 aryl, or -(L3)-(Z)-(5-10 membered heteroaryl), or two RAgroups (i) attached to the same nitrogen atom or (ii) attached to two oxygen atoms which areattached to the same boron atom are joined to form a 4-6 membered heterocyclyl; wherein L3 is absent, C1-3 alkylene, or Cm haloalkylene; Z is absent or -O-; and each alkyl, haloalkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, alkylene, or haloalkylene is independently substituted with 0, 1 , 2, or 3 instances of RB; each instance of RBis independently halogen, Ci-6 alkyl, Ci-6 haloalkyl, C3-10 carbocyclyl, 4-6 membered heterocyclyl, -CN, -OR', -N(R')2, -SR', -C(=O)R', -C(=O)OR', or -C(=O)N(R')2, or two RBattached to the same carbon atom are taken together to form =0; wherein each alkyl and haloalkyl is independently substituted with 0 or 1 =0 and independently substituted with 0, 1, 2, or 3 -OR'; and each carbocyclyl and heterocyclyl is independently substituted with 0, 1, 2, or 3 instances of Rc; each instance of Rcis independently halogen, Ci-6 alkyl, Ci-6 haloalkyl, or -OR', or two Rcattached to the same carbon atom are taken together to form =0; each instance of R' is independently H, Ci-6 alkyl, or Ci-6 haloalkyl, or two R' groups attached to the same nitrogen atom are joined to form a 4-6 membered heterocyclyl, wherein the alkyl, haloalkyl, or heterocyclyl is substituted with 0, 1, 2, or 3 R"; each instance of R" is independently halogen, -CN, -OR'", -N(R'")2, or -SR'", or two R" attached to the same carbon atom are taken together to form =0; and each instance of R'" is independently H, C1-3 alkyl, or C1-3 haloalkyl, or two R'" groups attached to the same nitrogen atom are joined to form a 4-6 membered heterocyclyl, wherein the heterocyclyl is substituted with 0, 1 , 2, or 3 halogen.

2. The compound of claim 1 , or a pharmaceutically acceptable salt or isotopically labeled derivative thereof, wherein the bicyclic ring system of formula:

3. The compound of claim 1, or a pharmaceutically acceptable salt or isotopically labeled derivative thereof, wherein the bicyclic ring system of formula:

4. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt or isotopically labeled derivative thereof, wherein R1is cyclopropyl substituted with 0, 1, or 2 instances of5. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt or isotopically labeled derivative thereof, wherein R1is cyclopropyl substituted with 0 or 1 instance of R1A, wherein R1Ais -E6. The compound of any one of claims 1-5, wherein the compound is of Formula (Il-a):or a pharmaceutically acceptable salt or isotopically labeled derivative thereof, wherein n is 0, 1 , or 2.

7. The compound of any one of claims 1-5, wherein the compound is of Formula (Il-b):or a pharmaceutically acceptable salt or isotopically labeled derivative thereof, wherein n is 0, 1 , or 2.

8. The compound of any one of claims 1-5, wherein the compound is of Formula (IV-a):or a pharmaceutically acceptable salt or isotopically labeled derivative thereof, wherein n is 0, 1 , or 2.

9. The compound of any one of claims 1-5, wherein the compound is of Formula (IV-b):or a pharmaceutically acceptable salt or isotopically labeled derivative thereof, wherein n is 0, 1 , or 2.

10. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt or isotopically labeled derivative thereof, wherein G1is CH or N and G2is CH.

11. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt or isotopically labeled derivative thereof, wherein G3is CR3and G4is CR4.

12. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt or isotopically labeled derivative thereof, wherein at least one of R3or R4is C3-10 carbocyclyl or 4-10 membered heterocyclyl, wherein each carbocyclyl or heterocyclyl is independently substituted with 0, 1, 2, or 3 instances of RB.

13. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt or isotopically labeled derivative thereof, wherein at least one of R3or R4is of the formula:wherein z is 0, 1, 2, or 3, as valency permits.

14. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt or isotopically labeled derivative thereof, wherein at least one of R3or R4is of the formula:as valency permits.

15. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt or isotopically labeled derivative thereof, wherein at least one of R3or R4is of the formula:

16. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt or isotopically labeled derivative thereof, wherein at least one of R3or R4is of the formula:wherein z is 0, 1, 2, or 3, as valency permits.

17. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt or isotopically labeled derivative thereof, wherein at least one of R3or R4is of the formula:wherein z is 0, 1, 2, or 3, as valency permits18. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt or isotopically labeled derivative thereof, wherein each instance of RBis independently halogen, Cm alkyl, Cm haloalkyl, -OR', -C(=O)R', or -C(=O)OR', or two RBattached to the same carbon atom are taken together to form =0, wherein each alkyl and haloalkyl is independently substituted with 0 or 1 =0 and independently substituted with 0, 1, 2, or 3 -OR'.

19. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt or isotopically labeled derivative thereof, wherein: each instance of R' is independently H, Cm alkyl, or Cm haloalkyl, wherein the alkyl or haloalkyl is substituted with 0, 1, 2, or 3 R"; each instance of R" is independently -CN, -OR'", -N(R"')2, or -SR'", or two R" attached to the same carbon atom are taken together to form =0; and each instance of R'" is independently H, Cm alkyl, or Cm haloalkyl.

20. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt or isotopically labeled derivative thereof, wherein at least one of R3and R4is:

21. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt or isotopically labeled derivative thereof, wherein at least one of R3and R4is:

22. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt or isotopically labeled derivative thereof, wherein:G3is CR3;G4is CR4;R3is C3io carbocyclyl or 4-10 membered heterocyclyl, wherein each carbocyclyl or heterocyclyl is independently substituted with 0, 1, 2, or 3 instances of RB, andR4is H or E23. The compound of any one of the of any of the preceding claims, wherein the compound is of Formula (I-a-z-6) or (I-b-z-6):or a pharmaceutically acceptable salt or isotopically labeled derivative thereof, wherein n is 0, 1 , or 2, and z is 0, 1, 2, or 3, as valency permits.

24. The compound of any one of the of any of the preceding claims, wherein the compound is ofFormula (I-a-z-26a) or (I-b-z-26a):or a pharmaceutically acceptable salt or isotopically labeled derivative thereof, wherein n is 0, 1 , or 2, and z is 0, 1, 2, or 3, as valency permits.

25. The compound of any one of the of any of the preceding claims, wherein the compound is ofFormula (I-a-z-4a) or (I-b-z-4a):or a pharmaceutically acceptable salt or isotopically labeled derivative thereof, wherein n is 0, 1 , or 2, and z is 0, 1, 2, or 3, as valency permits.

26. The compound of any one of the of any of the preceding claims, wherein the compound is ofFormula (II-a-1), (II-a-2), (II-a-3), (II-b-1), (II-b-2), (II-b-3), (IV-a-1), (IV-a-2), (IV-a-3), (IV-b-1),or a pharmaceutically acceptable salt or isotopically labeled derivative thereof.

27. The compound of any one of the preceding claims, wherein the compound is selected from those in Table 1, Table 2, Table 3, and Table 4, and pharmaceutically acceptable salts and isotopically labeled derivatives of any of the foregoing.

28. A compound of Formula (I) :or a pharmaceutically acceptable salt thereof, wherein:R1is C34 carbocyclyl or 3-4 membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is substituted with 0, 1, 2, or 3 instances of R1A; each instance of R1Ais independently Cm alkyl, C1-3 haloalkyl, halogen, or -OR', or two R1Agroups attached to the same carbon atom are joined to form a C3-6 carbocyclyl or 3-6 membered heterocyclyl, or two R1Agroups attached to vicinal atoms are joined to form a C3-6 carbocyclyl or 3-6 membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is substituted with 0, 1 , 2, or 3 substituents independently selected from C1-3 alkyl, C1-3 haloalkyl, halogen, -C(=O)OR', and -OR'; each X is independently selected from H and halogen;G1is CRG1or N and G2is CRG2or N; each of RG1and RG2is independently selected from H, halogen, Ci-6 alkyl, Ci-6 haloalkyl, and - (Li)-O-(CH2CH2O)m-R', wherein Li is absent, C1-3 alkylene, or C1-3 haloalkylene, and wherein m is 0, 1 or 2;G3is N or CR3and G4is N or CR4, provided at least one of G3and G4is CR3or CR4, and at least one of said R3and R4is not H;G5is O, N, S, or N-RG5, wherein RG5is H, C1-3 alkyl, or C1-3 haloalkyl;G6is C or N;G7is C or N;R3and R4are each independently H, halogen, Ci-6 alkyl, Ci-6 haloalkyl, -(L2)-(Y)-C3 -10 carbocyclyl, -(L2)-(Y)-(4-10 membered heterocyclyl), -(L2)-(Y)-Ce -10 aryl, -(L2)-(Y)-(5-10 membered heteroaryl), -(L2)-ORA, -(L2)-N(RA)2, -(L2)-SRA, -(L2)-CN, -(L2)-(Y)-C(=O)RA, -(L2)-(Y)-C(=O)ORA, - (L2)-(Y)-C(=O)N(RA)2, -(L2)-S(=O)2RA, -(L2)-S(=O)2ORA, -(L2)-(Y)-S(=O)2N(RA)2, or -B(ORA)2, wherein L2 is absent, C1-3 alkylene, or C1-3 haloalkylene; Y is absent, -O-, or -N(RA)-; and each alkyl, haloalkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, alkylene, or haloalkylene is independently substituted with 0, 1, 2, or 3 instances of RB; each instance of RAis independently H, Ci-6 alkyl, Ci-6 haloalkyl, -(LsXZj-C8 -10 carbocyclyl, - (L3)-(Z)-(3-10 membered heterocyclyl), -(L3)-(Z)-C6 -10 aryl, or -(L3)-(Z)-(5-10 membered heteroaryl), or two RAgroups (i) attached to the same nitrogen atom or (ii) attached to two oxygen atoms which are attached to the same boron atom are joined to form a 4-6 membered heterocyclyl; wherein L3 is absent, C1-3 alkylene, or Cm haloalkylene; Z is absent or -O-; and each alkyl, haloalkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, alkylene, or haloalkylene is independently substituted with 0, 1 , 2, or 3 instances of RB; each instance of RBis independently halogen, Ci-6 alkyl, Ci-6 haloalkyl, C3-10 carbocyclyl, -CN, - OR', -N(R')2, -SR', -C(=O)R', -C(=O)OR', -C(=O)N(R')2, or two RBattached to the same carbon atom are taken together to form =0; wherein each alkyl and haloalkyl is independently substituted with 0 or 1 =0; and each carbocyclyl is independently substituted with 0, 1 , 2, or 3 instances of Rc; each instance of Rcis independently halogen, Ci-6 alkyl, or Ci-6 haloalkyl, or two Rcattached to the same carbon atom are taken together to form =0; each instance of R' is independently H, Ci-6 alkyl, or Ci-6 haloalkyl, or two R' groups attached to the same nitrogen atom are joined to form a 4-6 membered heterocyclyl, wherein the alkyl, haloalkyl, or heterocyclyl is substituted with 0, 1, 2, or 3 R";each instance of R" is independently halogen, -CN, -OR'", -N(R'")2, or -SR'", or two R" attached to the same carbon atom are taken together to form =0; and each instance of R'" is independently H, C1-3 alkyl, or C1-3 haloalkyl, or two R'" groups attached to the same nitrogen atom are joined to form a 4-6 membered heterocyclyl, wherein the heterocyclyl is substituted with 0, 1 , 2, or 3 halogen.

29. A pharmaceutical composition comprising the compound of any one of the preceding claims, or a pharmaceutically acceptable salt or isotopically labeled derivative thereof, and a pharmaceutically acceptable carrier.

30. A method of treating or preventing a TYK2-mediated condition, disease, or disorder in a subject in need thereof comprising administering to the subject the compound of any one of claims 1-28, or a pharmaceutically acceptable salt or isotopically labeled derivative thereof, or the pharmaceutical composition of claim 29.

31. An in vivo or in vitro method of inhibiting tyrosine kinase 2 (TYK2) activity in a cell comprising contacting the cell with the compound of any one of claims 1-28, or a pharmaceutically acceptable salt or isotopically labeled derivative thereof, or the pharmaceutical composition of claim 29.

32. A method of preparing a compound of Formula (I), or salt or isotopically labeled derivative thereof, as defined in claim 1 , following one or more steps as set forth in General Method Scheme A and / or General Method Scheme B, and / or General Method Scheme C and / or General Method Scheme D.

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