Alkynyl tyrosine kinase 2 inhibitors and uses thereof

Abstract

The present disclosure relates to compounds of Formula (I): and pharmaceutically acceptable salts thereof, wherein R1, X, G1, G2, G3, W, Ring D, RD, and d 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 thereof, in the treatment or prevention of TYK2-mediated conditions, diseases, and disorders.

Description

[0001] ALKYNYL TYROSINE KINASE 2 INHIBITORS AND USES THEREOF

[0002] RELATED APPLICATIONS

[0003] [1] The present application claims priority under 35 U.S.C. § 119(e) to United States Provisional Patent Application, U.S.S.N. 63 / 549,762, filed February 5, 2024 and United States Provisional Patent Application, U.S.S.N. 63 / 655,915, filed June 4, 2024, the entire contents of each of which are incorporated herein by reference.

[0004] BACKGROUND

[0005] [2] 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] [3] 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 p19 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] [4] 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.202L 639353. 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

[0008] (5): 891-908.e8), and neuromyelitis optica (NMO) (see, e.g, Agasing, et al., Nature Communications (2020) 11 (1): 2856).

[0009] [5] 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. 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. Thus, TYK2 presents the optimal target to selectively inhibit these specific pro- inflammatory pathways while minimizing off-target effects.

[0010] [6] 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. [7] 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 TYK2 inhibitors that target the JH2 pseudokinase domain.

[0011] SUMMARY

[0012] [8] Provided herein are TYK2 inhibitors of Formula (I): and pharmaceutically acceptable salts thereof, wherein R1, X, G1, G2, G3, W, Ring D, RD, and d are as described herein.

[0013] [9] 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]

[0011] 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]

[0012] 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.

[0018]

[0013] When a range of values is listed, it is intended to encompass each value and sub-range within the range. For example, “C1-6alkyl” is intended to encompass, C1, C2, C3, C4, C5, C6, C1-6, C1-5, C1-4, C1-3, C1-2, C2-6, C2-5, C2-4, C2-3, C3-6, C3-4, C3-4, C4-5, C4-5, and C5-6alkyl.

[0019]

[0014] “Alkyl” refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 10 carbon atoms (“C1-10alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms (“C1-9alkyl”). 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 (“C1-7alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“C1-6alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C1-5alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms (“C1-4alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“C1-3alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“C1-2alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“C1alkyl”). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“C2-6alkyl”).

[0020] Examples of C1-6alkyl groups include methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), iso-butyl (C4), n-pentyl (C5), 3-pentanyl (C5), amyl (C5), neopentyl (C5), 3-methyl-2-butanyl (C5), tertiary amyl (C5), and n-hexyl (C6). Additional examples of alkyl groups include n-heptyl (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 C1-10alkyl (e.g., - CH3). In some embodiments, the alkyl group is a substituted C1-10alkyl.

[0021]

[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.

[0022] “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 (“C1-6haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 4 carbon atoms (“C1-4haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 3 carbon atoms (“C1-3 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 2 carbon atoms (“C1-2haloalkyl”). 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, -CFCl3, -CF2CI, and the like.

[0023]

[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) (“C2-10alkenyl”). In some embodiments, an alkenyl group has 2 to 9 carbon atoms (“C2-9alkenyl”). In some embodiments, an alkenyl group has 2 to 8 carbon atoms (“C2-8alkenyl”). In some embodiments, an alkenyl group has 2 to 7 carbon atoms (“C2-7alkenyl”). In some embodiments, an alkenyl group has 2 to 6 carbon atoms (“C2-6alkenyl”). In some embodiments, an alkenyl group has 2 to 5 carbon atoms (“C2-5alkenyl”). In some embodiments, an alkenyl group has 2 to 4 carbon atoms (“C2-4alkenyl”). In some embodiments, an alkenyl group has 2 to 3 carbon atoms (“C2-3alkenyl”). In some embodiments, an alkenyl group has 2 carbon atoms (“C2alkenyl”). 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 C2-4alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. Examples of C2-6alkenyl groups include the aforementioned C2-4alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like. Unless otherwise specified, each instance of an alkenyl group is independently unsubstituted (an “unsubstituted alkenyl”) or substituted (a “substituted alkenyl”) with one or more substituents. In some embodiments, the alkenyl group is an unsubstituted C210 alkenyl. In some embodiments, the alkenyl group is a substituted C2-10alkenyl.

[0024]

[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) (“C2-10alkynyl”). 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 (“C2-6alkynyl”). In some embodiments, an alkynyl group has 2 to 5 carbon atoms (“C2-5alkynyl”). In some embodiments, an alkynyl group has 2 to 4 carbon atoms (“C2-4alkynyl”). In some embodiments, an alkynyl group has 2 to 3 carbon atoms (“C2-3alkynyl”). In some embodiments, an alkynyl group has 2 carbon atoms (“C2alkynyl”). 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 C2-4alkynyl groups include, without limitation, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. Examples of C2-6alkenyl groups include the aforementioned C2-4alkynyl groups as well as pentynyl (C5), hexynyl (C6), and the like. Additional examples of alkynyl include heptynyl (C7), octynyl (C8), and the like. Unless otherwise specified, each instance of an alkynyl group is independently unsubstituted (an “unsubstituted alkynyl”) or substituted (a “substituted alkynyl”) with one or more substituents. In some embodiments, the alkynyl group is an unsubstituted C2-10alkynyl. In some embodiments, the alkynyl group is a substituted C2-10alkynyl.

[0025]

[0018] “Carbocyclyl” or “carbocyclic” refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 14 ring carbon atoms (“C3-14carbocyclyl”) and zero heteroatoms in the non-aromatic ring system. In some embodiments, a carbocyclyl group has 3 to 10 ring carbon atoms (“C3-10carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 9 ring carbon atoms (“C3-9carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms (“C3-8carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 7 ring carbon atoms (“C3-7carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (“C3-6carbocyclyl”). In some embodiments, a carbocyclyl group has 4 to 6 ring carbon atoms (“C4-6carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 6 ring carbon atoms (“C5-6carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (“C5-10carbocyclyl”). Exemplary C3-6carbocyclyl groups include, without limitation, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like. Exemplary C3-8carbocyclyl groups include, without limitation, the aforementioned C3-6carbocyclyl 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 C3-10carbocyclyl groups include, without limitation, the aforementioned C3-8carbocyclyl groups as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro- IH-indenyl (C9), 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 C3-14carbocyclyl. In some embodiments, the carbocyclyl group is a substituted C3-14carbocyclyl.

[0026]

[0019] In some embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 14 ring carbon atoms (“C3-14cycloalkyl”). In some embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 10 ring carbon atoms (“C3-10cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms (“C3-8cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms (“C3-6cycloalkyl”). In some embodiments, a cycloalkyl group has 4 to 6 ring carbon atoms (“C4-6cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms (“C5-6cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms (“C5-10cycloalkyl”). Examples of C5-6cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). Examples of C3-6cycloalkyl groups include the aforementioned C5-6cycloalkyl groups as well as cyclopropyl (C3) and cyclobutyl (C4). Examples of C3-8cycloalkyl groups include the aforementioned C3-6cycloalkyl 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 C3-14cycloalkyl. In some embodiments, the cycloalkyl group is a substituted C3-14cycloalkyl.

[0027]

[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 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.

[0028]

[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.

[0029]

[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, l,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.

[0030]

[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 (“C6-14aryl”). In some embodiments, an aryl group has 6 ring carbon atoms (“C6aryl”; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms (“C10aryl”; 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 C6-14aryl. In some embodiments, the aryl group is a substituted C6-14aryl.

[0031]

[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).

[0032]

[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.

[0033]

[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.

[0034]

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

[0035]

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

[0036]

[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 C1-6alkylene, which may be linear or branched. An alkylene may further be a C1-4alkylene. Exemplary C1-4alkylene groups include, but are not limited to, -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH2CH(CH3)-, -CH2C(CH3)2-, -CH2CH2CH2-, - CH2CH2CH2CH2-, and the like.

[0037]

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

[0038]

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

[0039]

[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, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2- hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like.

[0040] Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(C1-4alkyl)4salts. 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.

[0041]

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

[0042]

[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), t-butyl carbamate (BOC), 1- adamantyl carbamate (Adoc), and benzyl carbamate (Cbz); protect the amine as a sulfonamide such as p-toluenesulfonamide (Ts), benzenesulfonamide, methanesulfonamide (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.

[0043]

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

[0044]

[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 some embodiments, the patient or subject is a human.

[0045]

[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.

[0046]

[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 some 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).

[0047]

[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.

[0048]

[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.

[0049]

[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).

[0050]

[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.

[0051] BRIEF DESCRIPTION OF THE DRAWINGS

[0052]

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

[0053]

[0044] FIGs. 2A-2D show molecular modeling of Comparative Example G (FIG. 2A), Compound 1 (FIG. 2B), Compound 14 (FIG. 2C), and Compound 76 (FIG. 2D) bound within the JH2 domain of Tyk2. DETAILED DESCRIPTION

[0054] (i) Compounds

[0055]

[0045] Provided herein are compounds of Formula (I): and pharmaceutically acceptable salts thereof, wherein: each X is independently selected from H and halogen;

[0056] R1is C3-4carbocyclyl 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 C1-3alkyl, C1-3haloalkyl, halogen, or -OR', or two R1Agroups attached to the same carbon atom are joined to form a C3-6carbocyclyl or 3-6 membered heterocyclyl, or two R1Agroups attached to vicinal atoms are joined to form a C3-6carbocyclyl or 3-6 membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is substituted with 0, 1 , 2, or 3 substituents independently selected from C1-3alkyl, C1-3haloalkyl, halogen, -C(=O)OR', and -OR';

[0057] G1is CRG1or N, G2is CRG2or N, and G3is CRG3or N, provided no more than one of G1, G2, and G3is N; each of RG1, RG2and RG3is independently H, halogen, C1-6alkyl, C1-6haloalkyl, -(L1)-C3-4carbocyclyl, -(L1)-O-(CH2CH2O)m-R', -(L1)-N(R')2, or -(L1)-CN, or wherein L1is absent, C1-3alkylene, or C1-3haloalkylene; m is 0, 1 or 2; and provided no more than one of RG1, RG2and RG3is each instance of W is independently absent, -C(RCW)2-, -O-, or -N(RNW)-; each instance of Ring D is independently 4-8 membered heterocyclyl; each instance of RDis independently halogen, C1-6alkyl, C1-6haloalkyl, -(L2)-(Y)-C3-10carbocyclyl, -(L2)-(Y)-(4-10 membered heterocyclyl), -(L2)-(Y)-C6-10aryl, -(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, or -(L2)-(Y)-S(=O)2N(RA)2, or two RDattached to the same carbon atom are joined to form a C3-6carbocyclyl or 3-6 membered heterocyclyl, or two RDattached to the same carbon atom are taken together to form =O, wherein L2is absent, C1-3alkylene, or C1-3haloalkylene; 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 d is independently 0, 1, 2, 3, 4, 5, or 6, as valency permits; each instance of RAis independently H, C1-6alkyl, C1-6haloalkyl, -(L3)-(Z)-C3-10carbocyclyl, - (L3)-(Z)-(3-10 membered heterocyclyl), -(L3)-(Z)-C6-10aryl, or -(L3)-(Z)-(5-10 membered heteroaryl), or two RAgroups attached to the same nitrogen atom are joined to form a 4-6 membered heterocyclyl, wherein L3is absent, C1-3alkylene, or C1-3haloalkylene; 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, C1-6alkyl, C1-6haloalkyl, C3-10carbocyclyl, -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 =O; wherein each alkyl and haloalkyl is independently substituted with 0 or 1 instances of =O, and each carbocyclyl is independently substituted with 0, 1, 2, or 3 instances of RC; each instance of RCis independently halogen, C1-6alkyl, or C1-6haloalkyl, or two RCattached to the same carbon atom are taken together to form =O; each instance of RCWis independently H, halogen, or C1-6alkyl, or two instances of RCWare taken together to form =O, or wherein one RCWis joined with RG2or RG3to form a C5-6carbocyclyl or C6aryl, wherein the alkyl, carbocyclyl, or aryl is substituted with 0, 1, 2, or 3 instances of R"; each instance of R' and RNWis independently H, C1-6alkyl, or C1-6haloalkyl, or two R' groups attached to the same nitrogen atom are joined to form a 4-6 membered heterocyclyl, or RNWis joined with RG2or RG3to form a 5-6 membered heterocyclyl or 5-6 membered heteroaryl, wherein the alkyl, haloalkyl, heterocyclyl, or heteroaryl is substituted with 0, 1, 2, or 3 instances of R"; each instance of R" is independently halogen, C1-3alkyl, C1-3haloalkyl, -CN, -OR'", -N(R'")2, or -SR'", or two R" attached to the same carbon atom are taken together to form =O; and each instance of R'" is independently H, C1-3alkyl, or C1-3haloalkyl, 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 substituents independently selected from halogen.

[0058]

[0046] In some embodiments of Formula (I): each X is independently selected from H and halogen;

[0059] R1is C3-4carbocyclyl 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 C1-3alkyl, C1-3haloalkyl, halogen, or -OR', or two R1Agroups attached to the same carbon atom are joined to form a C3-6carbocyclyl or 3-6 membered heterocyclyl, or two R1Agroups attached to vicinal atoms are joined to form a C3-6carbocyclyl or 3-6 membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is substituted with 0, 1 , 2, or 3 substituents independently selected from C1-3alkyl, C1-3haloalkyl, halogen, -C(=O)0R', and -OR'; G1is CRG1or N, G2is CRG2or N, and G3is CRG3or N, provided no more than one of G1, G2, and

[0060] G3is N; each of RG1, RG2and RG3is independently H, halogen, C1-6alkyl, C1-6haloalkyl, -(L1)-C3-4carbocyclyl, -(L1)-O-(CH2CH2O)m-R', -(L1)-N(R')2, or -(L1)-CN, or wherein L1is absent, C1-3alkylene, or C1-3haloalkylene; m is 0, 1 or 2; and provided no more than one of RG1, RG2and RG3is each instance of W is independently absent, -C(RCW)2-, -O-, or -N(RNW)-; each instance of Ring D is independently 4-8 membered heterocyclyl; each instance of RDis independently halogen, C1-6alkyl, C1-6haloalkyl, -(L2)-(Y)-C3-10carbocyclyl, -(L2)-(Y)-(4-10 membered heterocyclyl), -(L2)-(Y)-C6-10aryl, -(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, or -(L2)-(Y)-S(=O)2N(RA)2, or two RDattached to the same carbon atom are joined to form a C3-6carbocyclyl or 3-6 membered heterocyclyl, or two RDattached to the same carbon atom are taken together to form =O, wherein L2is absent, C1-3alkylene, or C1-3haloalkylene; 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 d is independently 0, 1, 2, or 3; each instance of RAis independently H, C1-6alkyl, C1-6haloalkyl, -(L3)-(Z)-C3-10carbocyclyl, - (L3)-(Z)-(3-10 membered heterocyclyl), -(L3)-(Z)-C6-10aryl, or -(L3)-(Z)-(5-10 membered heteroaryl), or two RAgroups attached to the same nitrogen atom are joined to form a 4-6 membered heterocyclyl, wherein L3is absent, C1-3alkylene, or C1-3haloalkylene; 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, C1-6alkyl, C1-6haloalkyl, C3-10carbocyclyl, -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 =O; wherein each alkyl and haloalkyl is independently substituted with 0 or 1 instances of =O, and each carbocyclyl is independently substituted with 0, 1, 2, or 3 instances of RC; each instance of RCis independently halogen, C1-6alkyl, or C1-6haloalkyl, or two RCattached to the same carbon atom are taken together to form =O; each instance of RCWis independently H, halogen, or C1-6alkyl, or two instances of RCWare taken together to form =O, or wherein one RCWis joined with RG2or RG3to form a C5-6carbocyclyl or C6aryl, wherein the alkyl, carbocyclyl, or aryl is substituted with 0, 1, 2, or 3 instances of R"; each instance of R' and RNWis independently H, C1-6alkyl, or C1-6haloalkyl, or two R' groups attached to the same nitrogen atom are joined to form a 4-6 membered heterocyclyl, or RNWis joined with RG2or RG3to form a 5-6 membered heterocyclyl or 5-6 membered heteroaryl, wherein the alkyl, haloalkyl, heterocyclyl, or heteroaryl is substituted with 0, 1, 2, or 3 instances of R"; each instance of R" is independently halogen, C1-3alkyl, C1-3haloalkyl, -CN, -OR'", -N(R'")2, or -SR'", or two R" attached to the same carbon atom are taken together to form =O; and each instance of R'" is independently H, C1-3alkyl, or C1-3haloalkyl, 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 substituents independently selected from halogen.

[0061]

[0047] In some embodiments of Formula (I): each X is independently selected from H and halogen;

[0062] R1is C3-4carbocyclyl 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 C1-3alkyl, C1-3haloalkyl, halogen, or -OR', or two R1Agroups attached to the same carbon atom are joined to form a C3-5carbocyclyl or 3-5 membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is substituted with 0, 1 , 2, or 3 substituents independently selected from C1-3alkyl, C1-3haloalkyl, halogen, and -OR';

[0063] G1is CRG1or N, G2is CRG2or N, and G3is CRG3or N, provided no more than one of G1, G2, and G3is N; each of RG1, RG2and RG3is independently H, halogen, C1-6alkyl, C1-6haloalkyl, -(L1)- C3-4carbocyclyl, -(L1)-O-(CH2CH2O)m-R', -(L1)-N(R')2, or -(L1)-CN, or wherein L1is absent, C1-3alkylene, or C1-3haloalkylene; m is 0, 1 or 2; and provided no more than one of RG1, RG2 each instance of W is independently absent, -C(RCW)2-, -O-, or -N(RNW)-; each instance of Ring D is independently 4-8 membered heterocyclyl; each instance of RDis independently halogen, C1-6alkyl, C1-6haloalkyl, -(L2)-(Y)-C3-10carbocyclyl, -(L2)-(Y)-(4-10 membered heterocyclyl), -(L2)-(Y)-C6-10aryl, -(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, or -(L2)-(Y)-S(=O)2N(RA)2, or two RDattached to the same carbon atom are joined to form a C3-6carbocyclyl or 3-6 membered heterocyclyl, or two RDattached to the same carbon atom are taken together to form =O, wherein L2is absent, C1-3alkylene, or C1-3haloalkylene; 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 d is independently 0, 1, 2, or 3; each instance of RAis independently H, C1-6alkyl, Cm haloalkyl, -(L3)-(Z)-C3-10carbocyclyl, - (L3)-(Z)-(3-10 membered heterocyclyl), -(L3)-(Z)-C6-10aryl, or -(L3)-(Z)-(5-10 membered heteroaryl), or two RAgroups attached to the same nitrogen atom are joined to form a 4-6 membered heterocyclyl, wherein L3is absent, C1-3alkylene, or C1-3haloalkylene; 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, C1-6alkyl, C1-6haloalkyl, C3-10carbocyclyl, -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 =O; wherein each alkyl and haloalkyl is independently substituted with 0 or 1 instances of =O, and each carbocyclyl is independently substituted with 0, 1, 2, or 3 instances of RC; each instance of RCis independently halogen, C1-6alkyl, or C1-6haloalkyl, or two RCattached to the same carbon atom are taken together to form =O; each instance of RCWis independently H, halogen, or C1-6alkyl, or two instances of RCWare taken together to form =O, or wherein one RCWis joined with RG2or RG3to form a C5-6carbocyclyl or C6aryl, wherein the alkyl, carbocyclyl, or aryl is substituted with 0, 1, 2, or 3 instances of R"; each instance of R' and RNWis independently H, C1-6alkyl, or C1-6haloalkyl, or two R' groups attached to the same nitrogen atom are joined to form a 4-6 membered heterocyclyl, or RNWis joined with RG2or RG3to form a 5-6 membered heterocyclyl or 5-6 membered heteroaryl, wherein the alkyl, haloalkyl, heterocyclyl, or heteroaryl is substituted with 0, 1, 2, or 3 instances of R"; each instance of R" is independently halogen, C1-3alkyl, C1-3haloalkyl, -CN, -OR'", -N(R'")2, or -SR'", or two R" attached to the same carbon atom are taken together to form =O; and each instance of R'" is independently H, C1-3alkyl, or C1-3haloalkyl, 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 substituents independent selected from halogen.

[0064]

[0048] In any of the aforementioned embodiments of Formula (I), -CX3is -CH3or -CHF2.

[0065]

[0049] For example, in some embodiments of Formula (I):

[0066] CX3is -CH3or -CHF2;

[0067] R1is C3-4carbocyclyl 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 C1-3alkyl, C1-3haloalkyl, halogen, or -OR', or two R1Agroups attached to the same carbon atom are joined to form a Cm carbocyclyl or 3-6 membered heterocyclyl, or two R1Agroups attached to vicinal atoms are joined to form a Cm carbocyclyl or 3-6 membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is substituted with 0, 1 , 2, or 3 substituents independently selected from C1-3alkyl, C1-3haloalkyl, halogen, -C(=O)OR', and -OR';

[0068] G1is CRG1or N, G2is CRG2or N, and G3is CRG3or N, provided no more than one of G1, G2, and G3is N; each of RG1, RG2and RG3is independently H, halogen, C1-6alkyl, C1-6haloalkyl, -(L1)-C3-4carbocyclyl, -(L1)-O-(CH2CH2O)m-R', -(L1)-N(R')2, or -(L1)-CN, or wherein L1is absent, C1-3alkylene, or C1-3haloalkylene; m is 0, 1 or 2; and provided no more than one of RG1, RG2and RG3is each instance of W is independently absent, -C(RCW)2-, -O-, or -N(RNW)-; each instance of Ring D is independently 4-8 membered heterocyclyl; each instance of RDis independently halogen, C1-6alkyl, C1-6haloalkyl, -(L2)-(Y)-C3-10carbocyclyl, -(L2)-(Y)-(4-10 membered heterocyclyl), -(L2)-(Y)-C6-10aryl, -(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, or -(L2)-(Y)-S(=O)2N(RA)2, or two RDattached to the same carbon atom are joined to form a C3-6carbocyclyl or 3-6 membered heterocyclyl, or two RDattached to the same carbon atom are taken together to form =O, wherein L2is absent, C1-3alkylene, or C1-3haloalkylene; 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 d is independently 0, 1, 2, 3, 4, 5, or 6, as valency permits; each instance of RAis independently H, C1-6alkyl, C1-6haloalkyl, -(L3)-(Z)-C3-10carbocyclyl, -(L3)-(Z)-(3-10 membered heterocyclyl), -(L3)-(Z)-C6-10aryl, or -(L3)-(Z)-(5-10 membered heteroaryl), or two RAgroups attached to the same nitrogen atom are joined to form a 4-6 membered heterocyclyl, wherein L3is absent, C1-3alkylene, or C1-3haloalkylene; 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, C1-6alkyl, C1-6haloalkyl, C3-10carbocyclyl, -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 =O; wherein each alkyl and haloalkyl is independently substituted with 0 or 1 instances of =O, and each carbocyclyl is independently substituted with 0, 1, 2, or 3 instances of RC; each instance of RCis independently halogen, C1-6alkyl, or C1-6haloalkyl, or two RCattached to the same carbon atom are taken together to form =O; each instance of RCWis independently H, halogen, or C1-6alkyl, or two instances of RCWare taken together to form =O, or wherein one RCWis joined with RG2or RG3to form a C5-6carbocyclyl or C6aryl, wherein the alkyl, carbocyclyl, or aryl is substituted with 0, 1, 2, or 3 instances of R"; each instance of R' and RNWis independently H, C1-6alkyl, or C1-6haloalkyl, or two R' groups attached to the same nitrogen atom are joined to form a 4-6 membered heterocyclyl or RNWis joined with RG2or RG3to form a 5-6 membered heterocyclyl or 5-6 membered heteroaryl, wherein the alkyl, haloalkyl, heterocyclyl, or heteroaryl is substituted with 0, 1, 2, or 3 instances of R"; each instance of R" is independently halogen, C1-3alkyl, C1-3haloalkyl, -CN, -OR'", -N(R'")2, or -SR'", or two R" attached to the same carbon atom are taken together to form =O; and each instance of R'" is independently H, C1-3alkyl, or C1-3haloalkyl, 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.

[0069]

[0050] In some embodiments of Formula (I):

[0070] CX3is -CH3or -CHF2;

[0071] R1is C3-4carbocyclyl 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 C1-3alkyl, C1-3haloalkyl, halogen, or -OR', or two R1Agroups attached to the same carbon atom are joined to form a C3-6carbocyclyl or 3-6 membered heterocyclyl, or two R1Agroups attached to vicinal atoms are joined to form a C3-6carbocyclyl or 3-6 membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is substituted with 0, 1 , 2, or 3 substituents independently selected from C1-3alkyl, C1-3haloalkyl, halogen, -C(=O)OR', and -OR';

[0072] G1is CRG1or N, G2is CRG2or N, and G3is CRG3or N, provided no more than one of G1, G2, and G3is N; each of RG1, RG2and RG3is independently H, halogen, C1-6alkyl, C1-6haloalkyl, -(L1)-C3-4carbocyclyl, -(L1)-O-(CH2CH2O)m-R', -(L1)-N(R')2, or -(L1)-CN, or wherein L1is absent, C1-3alkylene, or C1-3haloalkylene; m is 0, 1 or 2; and provided no more than one of RG1, RG2and each instance of W is independently absent, -C(RCW)2-, -O-, or -N(RNW)-; each instance of Ring D is independently 4-8 membered heterocyclyl; each instance of RDis independently halogen, C1-6alkyl, C1-6haloalkyl, -(L2)-(Y)-C3-10carbocyclyl, -(L2)-(Y)-(4-10 membered heterocyclyl), -(L2)-(Y)-C6-10aryl, -(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, or -(L2)-(Y)-S(=O)2N(RA)2, or two RDattached to the same carbon atom are joined to form a C3-6carbocyclyl or 3-6 membered heterocyclyl, or two RDattached to the same carbon atom are taken together to form =O, wherein L2is absent, C1-3alkylene, or C1-3haloalkylene; 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 d is independently 0, 1, 2, 3, 4, 5, or 6, as valency permits; each instance of RAis independently H, C1-6alkyl, C1-6haloalkyl, -(L3)-(Z)-C3-10carbocyclyl, -(L3)-(Z)-(3-10 membered heterocyclyl), -(L3)-(Z)-C6-10aryl, or -(L3)-(Z)-(5-10 membered heteroaryl), or two RAgroups attached to the same nitrogen atom are joined to form a 4-6 membered heterocyclyl, wherein L3is absent, C1-3alkylene, or C1-3haloalkylene; 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, C1-6alkyl, C1-6haloalkyl, C3-10carbocyclyl, -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 =O; wherein each alkyl and haloalkyl is independently substituted with 0 or 1 instances of =O, and each carbocyclyl is independently substituted with 0, 1, 2, or 3 instances of RC; each instance of RCis independently halogen, C1-6alkyl, or C1-6haloalkyl, or two RCattached to the same carbon atom are taken together to form =O; each instance of RCWis independently H, halogen, or C1-6alkyl, or two instances of RCWare taken together to form =O, or wherein one RCWis joined with RG2or RG3to form a C5-6carbocyclyl or C6aryl, wherein the alkyl, carbocyclyl, or aryl is substituted with 0, 1, 2, or 3 instances of R"; each instance of R' and RNWis independently H, C1-6alkyl, or C1-6haloalkyl, or two R' groups attached to the same nitrogen atom are joined to form a 4-6 membered heterocyclyl; each instance of R" is independently halogen, C1-3alkyl, C1-3haloalkyl, -CN, -OR'", -N(R'")2, or -SR'", or two R" attached to the same carbon atom are taken together to form =O; and each instance of R'" is independently H, C1-3alkyl, or C1-3haloalkyl, 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]

[0051] In some embodiments of Formula (I): each X is independently selected from H and halogen;

[0074] R1is C3-4carbocyclyl 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 C1-3alkyl, C1-3haloalkyl, halogen, or -OR', or two R1Agroups attached to the same carbon atom are joined to form a C3-5carbocyclyl or 3-5 membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is substituted with 0, 1 , 2, or 3 substituents independently selected from C1-3alkyl, C1-3haloalkyl, halogen, and -OR';

[0075] G1is CRG1or N, G2is CRG2or N, and G3is CRG3or N, provided no more than one of G1, G2, and G3is N; each of RG1, RG2and RG3is independently H, halogen, C1-6alkyl, C1-6haloalkyl, -(L1)- C3-4carbocyclyl, -(L1)-O-(CH2CH2O)m-R', -(L1)-N(R')2, or -(L1)-CN, or wherein L1is absent, C1-3alkylene, or C1-3haloalkylene; m is 0, 1 or 2; and provided no more than one of RG1, RG2and each instance of W is independently absent, -C(RCW)2-, -O-, or -N(RNW)-; each instance of Ring D is independently 4-8 membered heterocyclyl; each instance of RDis independently halogen, C1-6alkyl, C1-6haloalkyl, -(L2)-(Y)-C3-10carbocyclyl, -(L2)-(Y)-(4-10 membered heterocyclyl), -(L2)-(Y)-C6-10aryl, -(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, or -(L2)-(Y)-S(=O)2N(RA)2, or two RDattached to the same carbon atom are joined to form a C3-6carbocyclyl or 3-6 membered heterocyclyl, or two RDattached to the same carbon atom are taken together to form =O, wherein L2is absent, C1-3alkylene, or C1-3haloalkylene; 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 d is independently 0, 1, 2, or 3; each instance of RAis independently H, C1-6alkyl, C1-6haloalkyl, -(L2)-(Z)-C3-10carbocyclyl, - (L2)-(Z)-(3-10 membered heterocyclyl), -(L2)-(Z)-C6 10 aryl, or -(L2)-(Z)-(5- 10 membered heteroaryl), or two RAgroups attached to the same nitrogen atom are joined to form a 4-6 membered heterocyclyl, wherein L3is absent, C1-3alkylene, or C1-3haloalkylene; 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, C1-6alkyl, C1-6haloalkyl, C3-10carbocyclyl, -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 =O; wherein each alkyl and haloalkyl is independently substituted with 0 or 1 instances of =O, and each carbocyclyl is independently substituted with 0, 1, 2, or 3 instances of RC; each instance of RCis independently halogen, C1-6alkyl, or C1-6haloalkyl, or two RCattached to the same carbon atom are taken together to form =O; each instance of RCWis independently H, halogen, or C1-6alkyl, or two instances of RCWare taken together to form =O, or wherein one RCWis joined with RG2or RG3to form a C5-6carbocyclyl or C6aryl, wherein the alkyl, carbocyclyl, or aryl is substituted with 0, 1, 2, or 3 instances of R"; each instance of R' and RNWis independently H, C1-6alkyl, or C1-6haloalkyl, or two R' groups attached to the same nitrogen atom are joined to form a 4-6 membered heterocyclyl, or RNWis joined with RG2or RG3to form a 5-6 membered heterocyclyl or 5-6 membered heteroaryl, wherein the alkyl, haloalkyl, heterocyclyl, or heteroaryl is substituted with 0, 1, 2, or 3 instances of R", each instance of R" is independently halogen, C1-3alkyl, C1-3haloalkyl, -CN, -OR'", -N(R'")2, or -SR'", or two R" attached to the same carbon atom are taken together to form =O; and each instance of R'" is independently H, C1-3alkyl, or C1-3haloalkyl, 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 substituents independently selected from halogen.

[0076]

[0052] In some embodiments, when W para to the Ring C point of attachment to the alkynyl linker is absent, the compound of Formula (I) is of Formula (II):

[0077] or a pharmaceutically acceptable salt thereof.

[0078]

[0053] In some embodiments, when W para to the Ring C point of attachment to the alkynyl linker is not absent, the compound of Formula (I) is of Formula (III): or a pharmaceutically acceptable salt thereof, wherein W is -C(RCW)2-, -O-, or -N(RNW)-.

[0079]

[0054] Additional embodiments are further described below and herein.

[0080] (a) R1, R1A, and X

[0081]

[0055] As generally described herein, R1is C3-4carbocyclyl or 3-4 membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is substituted with 0, 1, 2 or 3 instances of R1A.

[0082]

[0056] As generally described herein, each instance of R1Ais independently C1-3alkyl, C1-3haloalkyl, halogen, or -OR', or two R1Agroups attached to the same carbon atom are joined to form a C3-6carbocyclyl or 3-6 membered heterocyclyl, or two R1Agroups attached to vicinal atoms are joined to form a C3-6carbocyclyl or 3-6 membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is substituted with 0, 1, 2, or 3 substituents independently selected from C1-3alkyl, C1-3haloalkyl, halogen, - C(=O)OR', and -OR'.

[0083]

[0057] In some embodiments, each instance of R1Ais independently C1-3alkyl, C1-3haloalkyl, halogen, or - OR', or two R1Agroups attached to the same carbon atom are joined to form a C3-5carbocyclyl or 3-5 membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is substituted with 0, 1 , 2, or 3 substituents independently selected from C1-3alkyl, C1-3haloalkyl, halogen, and -OR'.

[0084]

[0058] In some embodiments, R1is C3-4carbocyclyl 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 C1-3alkyl, C1-3haloalkyl, halogen, or -OR', or two R1Agroups attached to the same carbon atom are joined to form a C3-6carbocyclyl or 3-6 membered heterocyclyl, or two R1Agroups attached to vicinal atoms are joined to form a C3-6carbocyclyl or 3-6 membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is substituted with 0, 1, 2, or 3 substituents independently selected from C1-3alkyl, C1-3haloalkyl, halogen, -C(=O)OR', and -OR'.

[0085]

[0059] In some embodiments, R1is C3-4carbocyclyl 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 C1-3alkyl, C1-3haloalkyl, halogen, or -OR', or two R1Agroups attached to the same carbon atom are joined to form a C3-5carbocyclyl or 3-5 membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is substituted with 0, 1, 2, or 3 substituents independently selected from C1-3alkyl, C1-3haloalkyl, halogen, and -OR'.

[0086]

[0060] In some embodiments, R1is C3-4carbocyclyl substituted with 0, 1, 2, or 3 instances of R1A. In some embodiments, R1is C3-4carbocyclyl substituted with 2 instances of R1A. In some embodiments, R1is C3-4carbocyclyl substituted with 0 or 1 instances of R1A. In some embodiments, R1is C3-4carbocyclyl substituted with 0 instances of R1A. In some embodiments, R1is C3-4carbocyclyl substituted with 1, 2, or 3 instances of R1A.

[0087]

[0061] In some embodiments, R1is C3-4carbocyclyl substituted with 1, 2, or 3 instances of R1A, wherein each instance of R1Ais independently halogen. In some embodiments, R1is C3-4carbocyclyl 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 C3-4carbocyclyl substituted with 1, 2, or 3 instances of R1A, wherein each instance of R1Ais independently -F.

[0088]

[0062] In some embodiments, R1is C3carbocyclyl (cyclopropyl) substituted with 0, 1, 2, or 3 instances of R1A. In some embodiments, R1is C3carbocyclyl substituted with 0 or 1 instances of R1A. In some embodiments, R1is C3carbocyclyl substituted with 0 instances of R1A. In some embodiments, R1is C3carbocyclyl substituted with 1, 2, or 3 instances of R1A.

[0089]

[0063] In some embodiments, R1is C3carbocyclyl substituted with 1, 2, or 3 instances of R1A, wherein each instance of R1Ais independently halogen. In some embodiments, R1is C3carbocyclyl 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 C3carbocyclyl substituted with 1, 2, or 3 instances of R1A, wherein each instance of R1Ais independently -F.

[0090]

[0064] 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). In some embodiments, R1is cyclopropyl substituted with 0, 1, or 2 instances of R1A. In some embodiments, R1is cyclopropyl substituted with 0 or 1 instance of R1A, wherein R1Ais fluoro.

[0091]

[0065] 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 C1-3alkyl and C1-3haloalkyl.

[0066] In some embodiments, R1is of the formula: wherein n is 0, 1, 2, or 3.

[0092]

[0067] In some embodiments, R1is of formula (y-1), wherein n is 0.

[0093]

[0068] 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 -E

[0094]

[0069] 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 -E

[0095]

[0070] In some embodiments, R1is of the formula:

[0096]

[0097]

[0072] In some embodiments, R1is C4carbocyclyl substituted with 0, 1, 2, or 3 instances of R1A. In some embodiments, R1is C4carbocyclyl substituted with 0 instances of R1A. In some embodiments, R1is C4carbocyclyl substituted with 1, 2, or 3 instances of R1A.

[0098]

[0073] In some embodiments, R1is 3-4 membered heterocyclyl substituted with 0, 1, 2, or 3 instances of

[0099] 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.

[0100]

[0074] In some embodiments, at least one instance of R1Ais C1-3alkyl.

[0101]

[0075] In some embodiments, at least one instance of R1Ais C1-3haloalkyl.

[0102]

[0076] 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.

[0103]

[0077] 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.

[0078] In some embodiments, at least one instance of R1Ais -OR'.

[0104]

[0079] In some embodiments, two R1Agroups attached to the same carbon atom are joined to form a C3-6carbocyclyl substituted with 0, 1, 2, or 3 substituents independently selected from C1-3alkyl, C1-3haloalkyl, halogen, -C(=O)OR', and -OR'. In some embodiments, two R1Agroups attached to the same carbon atom are joined to form unsubstituted C3-6carbocyclyl.

[0105]

[0080] In some embodiments, two R1Agroups attached to the same carbon atom are joined to form a C3-5carbocyclyl substituted with 0, 1, 2, or 3 substituents independently selected from C1-3alkyl, C1-3haloalkyl, halogen, and -OR'. In some embodiments, two R1Agroups attached to the same carbon atom are joined to form unsubstituted C3-5carbocyclyl. In some embodiments, two R1Agroups attached to the same carbon atom are joined to form unsubstituted C3carbocyclyl (cyclopropyl).

[0106]

[0081] 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 C1-3alkyl, C1-3haloalkyl, 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.

[0107]

[0082] 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 C1-3alkyl, C1-3haloalkyl, halogen, and -OR'. In some embodiments, two R1Agroups attached to the same carbon atom are joined to form unsubstituted 3-5 membered heterocyclyl.

[0108]

[0083] 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 C1-3alkyl and C1-3haloalkyl. 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 C1-3alkyl and C1-3haloalkyl. 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

[0109]

[0084] In some embodiments, two R1Agroups attached to the same carbon atom are joined to form In some embodiments, two R1Agroups attached to the same carbon atom are joined to form

[0085] In some embodiments, two R1Agroups attached to the same carbon atom are joined to form

[0110]

[0086] In some embodiments, two R1Agroups attached to vicinal atoms are joined to form a C3-6carbocyclyl substituted with 0, 1, 2, or 3 substituents independently selected from C1-3alkyl, C1-3haloalkyl, halogen, -C(=O)OR', and -OR'. In some embodiments, two R1Agroups attached to vicinal atoms are joined to form unsubstituted C3-6carbocyclyl.

[0111]

[0087] 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 C1-3alkyl, C1-3haloalkyl, halogen, -C(=O)OR', and -OR'. In some embodiments, two R1Agroups attached to vicinal atoms are joined to form unsubstituted 3-6 membered heterocyclyl.

[0112]

[0088] In some embodiments, two R1Agroups attached to vicinal atoms are joined to form:

[0113]

[0089] As generally described herein, each X is independently selected from H and halogen.

[0114]

[0090] 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.

[0115]

[0091] In some embodiments, at least one X is H. In some embodiments, at least two X are H.

[0116]

[0092] In some embodiments, -CX3is -CH3.

[0117]

[0093] In some embodiments, at least one X is halogen. In some embodiments, at least two X are halogen.

[0118] In some embodiments, each X is halogen. In some embodiments, one or two X are halogen.

[0119]

[0094] In some embodiments, at least one X is selected from the group consisting of -F, -Cl, and -Br.

[0120]

[0095] 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.

[0121]

[0096] In some embodiments, -CX3is -CH3, -CHF2, or -CH2F.

[0122]

[0097] In some embodiments, -CX3is -CH3or -CHF2.

[0123]

[0098] In some embodiments, -CX3is -CF3.

[0124]

[0099] In some embodiments, -CX3is -CHF2or -CH2F. In some embodiments, -CX3is -CHF2. In some embodiments, -CX3is -CH2F.

[0125] (b) G1, G2, G3, W, Ring D, R°, and d

[0126]

[0100] As generally described herein, G1is CRG1or N, G2is CRG2or N, and G3is CRG3or N, provided no more than one of G1, G2, and G3is N; and each of RG1, RG2and RG3is independently H, halogen, C1-6alkyl, C1-6haloalkyl, -(L1)-C3-4carbocyclyl, -(L1)-O-(CH2CH2O)m-R', -(L1)-N(R')2, -(L1)-CN, or wherein L1is absent, C1-3alkylene, or C1-3haloalkylene; m is 0, 1 or 2; and provided no more than one of RG1, RG2and RG3is wherein W, Ring D, RD, and d are as defined herein. For clarity, the RG1, RG2and RG3group may also be referred to herein as the “-W-(Ring D) substituent”, when referring to the Ring D group present therein, the “Ring D substituent”, and when referring to the W group present therein, the “W substituent”.

[0127]

[0101] In some embodiments, G1is CRG1. In some embodiments, G1is CH. In some embodiments, G1is CRG1, wherein RG1is not H. In some embodiments, G1is CRG1, wherein RG1is not H or halogen (e.g., fluoro). In some embodiments, G1is N.

[0128]

[0102] In some embodiments, G2is CRG2. In some embodiments, G2is CH. In some embodiments, G2is CRG2, wherein RG2is not H. In some embodiments, G2is CRG2, wherein RG2is not H or halogen (e.g., fluoro). In some embodiments, G2is N.

[0129]

[0103] In some embodiments, G3is CRG3. In some embodiments, G3is CH. In some embodiments, G3is CRG3, wherein RG3is not H. In some embodiments, G3is CRG3, wherein RG3is not H or halogen (e.g., fluoro). In some embodiments, G3is N.

[0130]

[0104] In some embodiments, G1is N, G2is CRG2, and G3is CRG3. In some embodiments, G1is CRG1, G2is N, and G3is CRG3. In some embodiments, G1is CRG1, G2is CRG2, and G3is N.

[0131]

[0105] In some embodiments, G1is CRG1, G2is CRG2, and G3is CRG3. In some embodiments, G1is CH, G2is CH, and G3is CH. In some embodiments, G1is CRG1, G2is CH, and G3is CH, wherein RG1is not H. In some embodiments, G1is CH, G2is CRG2, and G3is CH, wherein RG2is not H. In some embodiments, G1is CH, G2is CRG2, and G3is CH, wherein RG2is not H or halogen (e.g., fluoro). In some embodiments, G1is CH, G2is CH, and G3is CRG3, wherein RG3is not H.

[0132]

[0106] In some embodiments, Ring C is a group of formula: wherein * indicates attachment to W.

[0107] In some embodiments, Ring C is a group of formula: wherein * indicates attachment to W. In some embodiments, RG1is not H. In some embodiments, RG1is not H or halogen (e.g., fluoro).

[0133]

[0108] In some embodiments, Ring C is a group of formula: wherein * indicates attachment to W. In some embodiments, RG2is not H. In some embodiments, RG2is not H or halogen (e.g., fluoro).

[0134]

[0109] In some embodiments, Ring C is a group of formula: wherein * indicates attachment to W. In some embodiments, RG3is not H. In some embodiments, RG3is not H or halogen (e.g., fluoro).

[0135]

[0110] In some embodiments, Ring C is a group of formula: wherein * indicates attachment to W. In some embodiments, RG1and RG2are not H. In some embodiments, RG1and RG2are not H or halogen (e.g. , fluoro).

[0136]

[0111] In some embodiments, Ring C is a group of formula: wherein * indicates attachment to W. In some embodiments, RG1and RG3are not H. In some embodiments, RG1and RG3are not H or halogen (e.g. , fluoro).

[0137]

[0112] In some embodiments, Ring C is a group of formula: (C-1-vi), wherein * indicates attachment to W. In some embodiments, RG2and RG3are not H. In some embodiments, RG2and RG3are not H or halogen (e.g. , fluoro).

[0138]

[0113] As described herein, RG1is selected from H, halogen, C1-6alkyl, C1-6haloalkyl, -(L1)-C3-4carbocyclyl, -(L1)-O-(CH2CH2O)m-R', -(L1)-N(R')2, -(L1)-CN, or wherein L1is absent, C1-3alkylene, or C1-3haloalkylene; m is 0, 1 or 2; and W, Ring D, RD, and d are as defined herein.

[0139]

[0114] In some embodiments, RG1is H.

[0140]

[0115] In some embodiments, RG1is halogen.

[0141]

[0116] In some embodiments, RG1is C1-3alkyl. In some embodiments, RG1is C1-3alkyl.

[0142]

[0117] In some embodiments, RG1is C1-3haloalkyl. In some embodiments, RG1is C1-3haloalkyl. In some embodiments, RG1is C1haloalkyl.

[0143]

[0118] In some embodiments, RG1is -(L1)-C3-4carbocyclyl. In some embodiments, RG1is C3-4carbocyclyl. In some embodiments, RG1is cyclopropyl.

[0144]

[0119] In some embodiments, RG1is

[0145]

[0120] In some embodiments, RG1is -(L1)-O-(CH2CH2O)m-R'- In some embodiments, RG1is -(L1)-OR'. In some embodiments, RG1is -CH2-OR'. In some embodiments, RG1is -OR'.

[0146]

[0121] In some embodiments, RG1is -(L1)-N(R')2. In some embodiments, RG1is -N(R')2-

[0147]

[0122] In some embodiments, RG1is -(L1)-CN. In some embodiments, RG1is and -CN.

[0148]

[0123] In some embodiments, RG1is selected from H, Cl, F, methyl, ethyl, -OH, -OCH3, -CH2OCH3, -

[0149] N(H)CH3, -CHF2, and cyclopropyl.

[0150]

[0124] As described herein, RG2is selected from H, halogen, C1-6alkyl, C1-6haloalkyl, -(L1)-C3-4carbocyclyl, -(L1)-O-(CH2CH2O)m-R', -(L1)-N(R')2, -(L1)-CN, or wherein L1is absent, C1-3alkylene, or C1-3haloalkylene; m is 0, 1 or 2; and W, Ring D, RD, and d are as defined herein.

[0151]

[0125] In some embodiments, RG2is H.

[0152]

[0126] In some embodiments, RG2is halogen. In some embodiments, RG2is fluoro. In some embodiments, RG2is H or fluoro.

[0153]

[0127] In some embodiments, RG2is C1-6alkyl. In some embodiments, RG2is C1-3alkyl.

[0154]

[0128] In some embodiments, RG2is C1-6haloalkyl. In some embodiments, RG2is C1-3haloalkyl. In some embodiments, RG2is C1haloalkyl.

[0129] In some embodiments, RG2is -(L1)-C3-4carbocyclyl. In some embodiments, RG2is C3-4carbocyclyl. In some embodiments, RG2is cyclopropyl.

[0155]

[0130] In some embodiments, RG2is

[0156]

[0131] In some embodiments, RG2is -(L1)-O-(CH2CH2O)m-R'- In some embodiments, RG2is -(L1)-OR'. In some embodiments, RG2is -CH2-OR'. In some embodiments, RG2is -OR'.

[0157]

[0132] In some embodiments, RG2is -(L1)-N(R')2. In some embodiments, RG2is -N(R')2.

[0158]

[0133] In some embodiments, RG2is and -(L1)-CN. In some embodiments, RG2is and -CN.

[0159]

[0134] In some embodiments, RG2is selected from H, -OCH3, -CH2OH, -CH2OCH3, -CN, and -CHF2.

[0160]

[0135] As described herein, RG3is selected from H, halogen, C1-6alkyl, C1-6haloalkyl, -(L1)-C3-4carbocyclyl, -(L1)-O-(CH2CH2O)m-R', -(L1)-N(R')2, -(L1)-CN, or wherein L1is absent, C1-3alkylene, or C1-3haloalkylene; m is 0, 1 or 2; and W, Ring D, RD, and d are as defined herein.

[0161]

[0136] In some embodiments, RG3is H.

[0162]

[0137] In some embodiments, RG3is halogen.

[0163]

[0138] In some embodiments, RG3is C1-6alkyl. In some embodiments, RG3is C1-3alkyl.

[0164]

[0139] In some embodiments, RG3is C1-6haloalkyl. In some embodiments, RG3is C1-3haloalkyl. In some embodiments, RG3is C1haloalkyl.

[0165]

[0140] In some embodiments, RG3is -(L1)-C3-4carbocyclyl. In some embodiments, RG3is C3-4carbocyclyl. In some embodiments, RG3is cyclopropyl.

[0166]

[0141] In some embodiments, RG3is

[0167]

[0142] In some embodiments, RG3is -(L1)-O-(CH2CH2O)m-R'- In some embodiments, RG3is -(L1)-OR'. In some embodiments, RG3is -CH2-OR'. In some embodiments, RG3is -OR'.

[0168]

[0143] In some embodiments, RG3is -(L1)-N(R')2. In some embodiments, RG3is -N(R')2-

[0169]

[0144] In some embodiments, RG3is and -(L1)-CN. In some embodiments, RG3is and -CN.

[0170]

[0145] In some embodiments, RG3is selected from H, methyl, -OCH3, -CH2OH, -CH2OCH3, -CN, and - CHF2.

[0171]

[0146] In some embodiments, each instance of RG1, RG2, and RG3is independently selected from H, Cl, F, methyl, ethyl, -OH, -OCH3, -CH2OCH3, -CH2OH, -N(H)CH3, -CN, -CHF2, cyclopropyl, and

[0172]

[0147] In some embodiments, RG2and RG3are H or F; and RG1is selected from H, Cl, F, methyl, ethyl, -

[0173] OH, -OCH3, -CH2OCH3, -N(H)CH3, -CHF2, cyclopropyl, and

[0174]

[0148] In some embodiments, RG1and RG3are H or F; and RG2is selected from H, -OCH3, -CH2OH, - CH2OCH3, -CN, -CHF2, and

[0175]

[0149] In some embodiments, RG1and RG2are H or F; and RG3is selected from H, methyl, -OCH3, -

[0176] CH2OH, -CH2OCH3, -CN, and -CHF2.

[0177]

[0150] In some embodiments, each of RG1, RG2and RG3is H.

[0178]

[0151] As described herein, each instance of L1is independently absent, C1-3alkylene, or C1-3haloalkylene. In some embodiments, at least one instance of L1is independently absent. In some embodiments, at least one instance of L1is independently C1-3alkylene. In some embodiments, at least one instance of L1is independently -CH2-. In some embodiments, at least one instance of L1is independently C1-3haloalkylene.

[0179]

[0152] As described herein, each instance of m is independently 0, 1, or 2. In some embodiments, at least one instance of m is independently 0. In some embodiments, at least one instance of m is independently

[0180] 1. In some embodiments, at least one instance of m is independently 2.

[0181]

[0153] In some embodiments, Ring C is a group of formula:

[0182] wherein * indicates attachment to W.

[0183]

[0154] In some embodiments, Ring C is a group of formula: wherein * indicates attachment to W.

[0184]

[0155] As generally described herein, each instance of W is independently absent, -C(RCW)2-, -O-, or -N(RNW)-.

[0185]

[0156] In some embodiments, at least one instance of W is absent.

[0186]

[0157] In some embodiments, at least one instance of W is -C(RCW)2-. In some embodiments, at least one instance of W is -C(RCW)(H)-. In some embodiments, at least one instance of W is -CH2-.

[0187]

[0158] In some embodiments, at least one instance of W is -O-.

[0188]

[0159] In some embodiments, at least one instance of W is -N(RNW)-. In some embodiments, at least one instance of W is -N(H)-. In some embodiments, at least one instance of W is -N(Me)-.

[0189]

[0160] As generally described herein, each instance of RCWis independently H, halogen, or C1-6alkyl, or two instances of RCWare taken together to form =O, or wherein one RCWis joined with RG2or RG3to form a C5-6carbocyclyl or C6aryl, wherein the alkyl, carbocyclyl, or aryl is substituted with 0, 1 , 2, or 3 instances of R".

[0190]

[0161] In some embodiments, at least one instance of RCWis independently H.

[0162] In some embodiments, at least one at least one instance of instance of RCWis independently halogen.

[0191]

[0163] In some embodiments, at least one instance of RCWis independently C1-6alkyl substituted with 0, 1, 2, or 3 instances of R". In some embodiments, at least one instance of RCWis independently C1-6alkyl substituted with 0 R".

[0192]

[0164] In some embodiments, two instances of RCWare taken together to form =O

[0193]

[0165] In some embodiments, one RCWis joined with RG2or RG3to form a C5-6carbocyclyl or C6aryl, wherein the carbocyclyl or aryl is substituted with 0, 1, 2, or 3 instances of R". In some embodiments, one RCWis joined with RG2or RG3to form a C5-6carbocyclyl or C6aryl, wherein the carbocyclyl or aryl is substituted with 0 R".

[0194]

[0166] In some embodiments, one RCWis joined with RG2or RG3to form a C5carbocyclyl, wherein the carbocyclyl is substituted with 0, 1, 2, or 3 instances of R". In some embodiments, one RCWis joined with RG2or RG3to form a C5carbocyclyl, wherein the carbocyclyl is substituted with 0 R".

[0195]

[0167] As generally described herein, each instance of RNWis independently H, C1-6alkyl, or C1-6haloalkyl, or RNWis joined with RG2or RG3to form a 5-6 membered heterocyclyl or 5-6 membered heteroaryl, wherein the alkyl, haloalkyl, heterocyclyl, or heteroaryl is substituted with 0, 1 , 2, or 3 instances of R".

[0196]

[0168] In some embodiments, at least one instance of RNWis H.

[0197]

[0169] In some embodiments, at least one instance of RNWis C1-6alkyl substituted with 0, 1, 2, or 3 instances of R". In some embodiments, at least one instance of RNWis C1-6alkyl substituted with 0 R". In some embodiments, at least one instance of RNWis C1-3alkyl substituted with 0, 1, 2, or 3 instances of R". In some embodiments, at least one instance of RNWis C1-3alkyl substituted with 0 R". In some embodiments, RNWis methyl.

[0198]

[0170] In some embodiments, at least one instance of RNWis C1-6haloalkyl substituted with 0, 1, 2, or 3 instances of R". In some embodiments, at least one instance of RNWis C1-6haloalkyl substituted with 0 R".

[0199]

[0171] In some embodiments, RNWis joined with RG2or RG3to form a 5-6 membered heterocyclyl or 5-6 membered heteroaryl, wherein the heterocyclyl or heteroaryl is substituted with 0, 1 , 2, or 3 instances of R". In some embodiments, at least one instance of RNWis joined with RG2or RG3to form a 5-6 membered heterocyclyl or 5-6 membered heteroaryl, wherein the heterocyclyl or heteroaryl is substituted with 0 R".

[0200]

[0172] In some embodiments, RNWis joined with RG2or RG3to form a 5-membered heterocyclyl or 5- membered heteroaryl, wherein the heterocyclyl or heteroaryl is substituted with 0, 1 , 2, or 3 instances of R". In some embodiments, RNWis joined with RG2or RG3to form a 5-membered heterocyclyl or 5- membered heteroaryl, wherein the heterocyclyl or heteroaryl is substituted with 0 R".

[0173] In some embodiments, the group of the formula: wherein W" is C, CH, or N as valency permits; s is 1 or 2; each in Ring E is independently a single or double bond; and e is 0, 1, 2, or 3.

[0201]

[0174] In some embodiments, W" is C. In some embodiments, W" is CH. In some embodiments, W" is N.

[0202]

[0175] In some embodiments, s is 1. In some embodiments, s is 2.

[0203]

[0176] In some embodiments, W is -N(RNW)-; RNWis joined with RG2or RG3to form a 5-6 membered heterocyclyl or 5-6 membered heteroaryl; and the group of formula: wherein e is 0, 1, 2, or 3

[0204]

[0177] In some embodiments, W is -C(RCW)2-; one RCWis joined with RG2or RG3to form a C5-6carbocyclyl or C6aryl; and the group of formula: is of formula: wherein each in Ring E is independently a single or double bond; and e is 0, 1, 2, or 3.

[0205]

[0178] As generally described herein, each instance of Ring D is independently 4-8 membered heterocyclyl.

[0206]

[0179] It is understood that, in some embodiments, at least one of RG1, RG2, and RG3is provided no more than one of RG1, RG2and RG3is and in such instances, there exists two independent instances of such a group in the compound. Such a group of RG1, RG2and RG3may also be referred to herein as the “-W-(Ring D) substituent”, and when referring to the Ring D group present therein, the “Ring D substituent”, and when referring to the W group present therein, the “W substituent”. The language “at least one Ring D” and “at least one W”, as provided below, respectively refers to either Ring D (of the two instances) which may be present, and refers to either W (of the two instances) which may be present.

[0207]

[0180] In some embodiments, at least one Ring D is 7-8 membered, monocyclic or bicyclic (e.g., bridged, fused, spirocyclic) heterocyclyl. In some embodiments, at least one Ring D is 7-8 membered, monocyclic or bicyclic (e.g., bridged, fused, spirocyclic) heterocyclyl having 1 or 2 ring heteroatoms independently selected from N, O, and S. In some embodiments, at least one Ring D is 7-8 membered, monocyclic or bicyclic (e.g., bridged, fused, spirocyclic) heterocyclyl having 1 or 2 ring heteroatoms independently selected from N and O.

[0208]

[0181] In some embodiments, at least one Ring D is 7-8 membered, monocyclic or bicyclic (e.g., bridged) heterocyclyl. In some embodiments, at least one Ring D is 7-8 membered, monocyclic or bicyclic (e.g., bridged) heterocyclyl having 1 or 2 ring heteroatoms independently selected from N, O, and S. In some embodiments, at least one Ring D is 7-8 membered, monocyclic or bicyclic (e.g., bridged) heterocyclyl having 1 or 2 ring heteroatoms independently selected from N and O.

[0209]

[0182] In some embodiments, at least one Ring D is 4-6 membered heterocyclyl. In some embodiments, at least one Ring D is 4-6 membered heterocyclyl having 1 or 2 ring heteroatoms independently selected from N, O, and S. In some embodiments, at least one Ring D is 4-6 membered heterocyclyl having 1 or 2 ring heteroatoms independently selected from N and O.

[0210]

[0183] In some embodiments, at least one Ring D is 4-membered heterocyclyl. In some embodiments, at least one Ring D is 4-membered heterocyclyl having 1 ring heteroatom selected from N, O, and S. In some embodiments, at least one Ring D is 4-membered heterocyclyl having 1 ring nitrogen atom. In some embodiments, at least one Ring D is 4-membered heterocyclyl having 1 ring oxygen atom.

[0211]

[0184] In some embodiments, at least one Ring D is 5-membered heterocyclyl. In some embodiments, at least one Ring D is 5 -membered heterocyclyl having 1 or 2 ring heteroatoms independently selected from N, O, and S. In some embodiments, at least one Ring D is 5-membered heterocyclyl having 1 or 2 ring heteroatoms independently selected from N and O. In some embodiments, at least one Ring D is 5- membered heterocyclyl having 1 ring heteroatom selected from N and O. In some embodiments, at least one Ring D is 5 -membered heterocyclyl having 1 ring nitrogen atom. In some embodiments, at least one Ring D is 5 -membered heterocyclyl having 1 ring oxygen atom.

[0212]

[0185] In some embodiments, at least one Ring D is 6-membered heterocyclyl. In some embodiments, at least one Ring D is 6-membered heterocyclyl having 1 or 2 ring heteroatoms independently selected from N, O, and S. In some embodiments, at least one Ring D is 6-membered heterocyclyl having 1 or 2 ring heteroatoms independently selected from N and O.

[0213]

[0186] In some embodiments, at least one Ring D is 6-membered heterocyclyl having 1 ring heteroatom selected from N and O. In some embodiments, at least one Ring D is 6-membered heterocyclyl having 1 ring nitrogen atom. In some embodiments, at least one Ring D is 6-membered heterocyclyl having 1 ring oxygen atom.

[0214]

[0187] In some embodiments, at least one Ring D is 6-membered heterocyclyl having 2 ring heteroatoms independently selected from N and O. In some embodiments, at least one Ring D is 6-membered heterocyclyl having 2 ring nitrogen atoms. In some embodiments, at least one Ring D is 6-membered heterocyclyl having 2 ring oxygen atoms. In some embodiments, at least one Ring D is 6-membered heterocyclyl having 1 ring nitrogen atom and 1 ring oxygen atom.

[0215]

[0188] In some embodiments, at least one Ring D is selected from one of the following formulae: wherein z is 0, 1, 2, or 3, as valency permits.

[0216]

[0189] In some embodiments, at least one Ring D is selected from one of the following formulae: (D-2), (D-3), (D-5), (D-9), (D-13), (D-16), (D-19), (D-20), (D-22), (D-26), (D-38), (D-39), and (D-54).

[0217]

[0190] In some embodiments, at least one Ring D is selected from one of the following formulae: (D-9), (D-16), (D-17), (D-18), (D-19), (D-21), (D-22), (D-23), (D-24), (D-25), (D-26), (D-27), (D-28), (D-29), (D-30), (D-38), (D-39), (D-54), (D-57), (D-59), (D-60), (D-61), and (D-62).

[0218]

[0191] In some embodiments, at least one Ring D is selected from one of the following formulae: (D-9), (D-16), (D-38), (D-39), and (D-54).

[0219]

[0192] In some embodiments, at least one Ring D is selected from one of the following formulae: (D-9), (D-17), (D-18), (D-19), (D-57).

[0220]

[0193] In some embodiments, at least one Ring D is selected from one of the following formulae: (D-21), (D-22), (D-23), (D-24), (D-25), (D-26), (D-27), (D-28), (D-29), (D-30), (D-59), (D-60), (D-61), and (D- 62).

[0221]

[0194] In some embodiments, at least one Ring D is selected from one of the following formulae: (D-9), (D-16), and (D-22).

[0222]

[0195] In some embodiments, at least one W is absent. In some embodiments, at least one W is -C(RCW)2-, -O-, or -N(RNW)-. In some embodiments, at least one W is -N(RNW)-.

[0223]

[0196] For example, in some embodiments, at least one W is absent and at least one Ring D is selected from one of the following formulae:

[0224]

[0225]

[0197] In some embodiments, at least one W is absent and at least one Ring D is selected from one of the following formulae: (D-9), (D-16), (D-19), (D-20), (D-22), and (D-26).

[0226]

[0198] In some embodiments, at least one W is absent and at least one Ring D is selected from one of the following formulae: (D-9), (D-16), and (D-22).

[0227]

[0199] In some embodiments, at least one W is absent and at least one Ring D is selected from one of the following formulae: (D-9), (D-16), (D-17), (D-18), (D-19), (D-21), (D-22), (D-23), (D-24), (D-25), (D- 26), (D-27), (D-28), (D-29), (D-30), (D-38), (D-39), (D-54), (D-57), (D-59), (D-60), (D-61), and (D-62).

[0228]

[0200] In some embodiments, at least one W is absent and at least one Ring D is selected from one of the following formulae: (D-9), (D-16), (D-38), (D-39), and (D-54).

[0229]

[0201] In some embodiments, at least one W is absent and at least one Ring D is selected from one of the following formulae: (D-9), (D-17), (D-18), (D-19), (D-57).

[0202] In some embodiments, at least one W is absent and at least one Ring D is selected from one of the following formulae: (D-21), (D-22), (D-23), (D-24), (D-25), (D-26), (D-27), (D-28), (D-29), (D-30), (D- 59), (D-60), (D-61), and (D-62).

[0230]

[0203] In some embodiments, at least one W is absent and at least one Ring D is of formula: some embodiments, at least one Ring D is of formula: In some embodiments, each instance of RDis C1-6alkyl or C1-6haloalkyl. In some embodiments, each instance of RDis -CH3.

[0231]

[0204] In some embodiments, at least one W is absent and at least one Ring D is of formula: In some embodiments, RDis C1-6alkyl or C1-6haloalkyl. In some embodiments, RDis -CH3. In some embodiments, two RDattached to the same carbon atom are joined to form =O.

[0232]

[0205] In some embodiments, at least one W is absent and at least one Ring D is of formula:

[0206] In some embodiments, at least one W is absent and at least one Ring D is of formula:

[0233]

[0207] In some embodiments, at least one W is absent and at least one Ring D is of formula:

[0234]

[0208] In some embodiments, at least one W is absent and at least one Ring D is of formula:

[0235]

[0209] In some embodiments, at least one W is absent and at least one Ring D is of formula: In some embodiments, Ring D is of formula

[0236]

[0210] In some embodiments, at least one W is -C(RCW)2-, -O-, or -N(RNW)-, and at least one Ring D is selected from one of the following formulae:

[0237]

[0238]

[0211] In some embodiments, at least one W is -C(RCW)2-, -O-, or -N(RNW)-, and at least one Ring D is selected from one of the following formulae: (D-2), (D-3), (D-5), (D-16), (D-38), (D-39), and (D-54).

[0239]

[0212] In some embodiments, at least one W is -C(RCW)2-, -O-, or -N(RNW)- and at least one Ring D is of formula In some embodiments, Ring D is of formula (D-3), and W is -N(RNW)-. In some embodiments, Ring D is of formula (D-3), and W is -O-.

[0240]

[0213] In some embodiments, at least one W is -C(RCW)2-, -O-, or -N(RNW)- and at least one Ring D is of formula: In some embodiments. Ring D is of formula (D-4). and W is -N(RNW)-.

[0241] In some embodiments, Ring D is of formula (D-4), and W is -O-.

[0242]

[0214] In some embodiments, at least one W is -C(RCW)2-, -O-, or -N(RNW)- and at least one Ring D is of formula: In some embodiments, Ring D is of formula (D-5), and W is -

[0243] N(RNW)-. In some embodiments, Ring D is of formula (D-5), and W is -O-.

[0244]

[0215] In some embodiments, at least one W is -C(RCW)2-, -O-, or -N(RNW)- and at least one Ring D is of formula: In some embodiments, Ring D is of formula: In some embodiments, Ring D is of formula (D-38), and W is -N(RNW)-. In some embodiments, Ring D is of formula (D-38), and W is -O-.

[0245]

[0216] In some embodiments, at least one W is -C(RCW)2-, -O-, or - N(RNW)- and at least one Ring D is of formula: In some embodiments, Ring D is of formula (D-12), and W is -N(RNW)-.

[0246] In some embodiments, Ring D is of formula (D-12), and W is -O-.

[0247]

[0217] In some embodiments, at least one W is -C(RCW)2-, -O-, or - N(RNW)- and at least one Ring D is of formula: In some embodiments, Ring D is of formula (D-13), and W is -

[0248] N(RNW)-. In some embodiments, Ring D is of formula (D-13), and W is -O-.

[0249]

[0218] In some embodiments, at least one W is -C(RCW)2-, -O-, or -N(RNW)- and at least one Ring D is of formula: In some embodiments, Ring D is of formula (D-16), and W is - N(RNW)-.

[0250] In some embodiments, Ring D is of formula (D-16), and W is -O-.

[0251]

[0219] In some embodiments, at least one W is -C(RCW)2-, -O-, or -N(RNW)- and at least one Ring D is of formula: In some embodiments, Ring D is of formula (D-41), and W is -

[0252] N(RNW)-. In some embodiments, Ring D is of formula (D-41), and W is -O-.

[0253]

[0220] In some embodiments, at least one W is -C(RCW)2-, -O-, or -N(RNW)- and at least one Ring D is of formula: In some embodiments, Ring D is of formula (D-42), and W is -

[0254] N(RNW)-. In some embodiments, Ring D is of formula (D-42), and W is -O-.

[0255]

[0221] In some embodiments, at least one W is -C(RCW)2-, -O-, or -N(RNW)- and at least one Ring D is of formula: In some embodiments, Ring D is of formula (D-10), and W is -

[0256] N(RNW)-. In some embodiments, Ring D is of formula (D-10), and W is -O-.

[0257]

[0222] In some embodiments, at least one W is -C(RCW)2-, -O-, or -N(RNW)- and at least one Ring D is of formula: In some embodiments, Ring D is of formula (D-ll), and W is -

[0258] N(RNW)-. In some embodiments, Ring D is of formula (D-ll), and W is -O-.

[0259]

[0223] In some embodiments, at least one W is -C(RCW)2-, -O-, or -N(RNW)- and at least one Ring D is of formula:

[0260]

[0224] In some embodiments, Ring D is of formula (D-39), and W is -N(RNW)-. In some embodiments, Ring D is of formula (D-39), and W is -O-.

[0261]

[0225] In some embodiments, at least one W is -C(RCW)2-, -O-, or -N(RNW)- and at least one Ring D is of formula: In some embodiments, Ring D is of formula (D-54), and W is -N(RNW)-.

[0262]

[0226] In some embodiments, two RDattached to the same carbon atom are joined to form a C3-6carbocyclyl or 3-6 membered heterocyclyl, and Ring D is selected from one of the following formulae:

[0263] wherein z is 0, 1, 2, or 3, as valency permits.

[0264]

[0227] In some embodiments, Ring C is a group of formula (C-l), wherein RG2is as provided in the following formula:

[0265] (C-1-Ring D). In some embodiments of (C-1-Ring D), the Ring D substituent is a group of formula:

[0266] wherein z is 0, 1, 2, or 3, as valency permits.

[0267]

[0228] In some embodiments of (C-1-Ring D), the Ring D substituent is a group of formula (D-9), (D-13),

[0268] (D-16), (D-22), or (D-38).

[0269]

[0229] In some embodiments the W substituent is absent, and W (of Formula (III), attached at the para position of Ring C) is NH.

[0270]

[0230] In some embodiments the W substituent is absent, and W (of Formula (III), attached at the para position of Ring C) is O.

[0271]

[0231] In some embodiments, the following combinations of compounds of Formula (III), and subgenera thereof, are provided wherein W is not absent, G2is CRG2, and RG2is

[0232] In some embodiments, W is NH or O, Ring D is (D-5) or (D-38), G2is CRG2, CRG2is the group wherein the W of said group is absent and the Ring D substituent of said group is

[0272] (D-9), (D-22), (D-38), (D-13) or (D-16).

[0273] In some embodiments of compounds of Formula (III), and subgenera thereof, RG2is , and W, Ring D, W substituent, and Ring D substituent combinations are as set forth below in Table 1A:

[0274]

[0233] As generally described herein, each instance of d is independently 0, 1, 2, 3, 4, 5, or 6, as valency permits. In some embodiments, each instance of d is independently 0, 1, 2, 3, 4, 5, or 6. In some embodiments, each instance of d is independently 0, 1, 2, or 3, as valency permits. In some embodiments, each instance of d is independently 0, 1, 2, or 3. In some embodiments, at least one d is 0. In some embodiments, at least one d is 1. In some embodiments, at least one d is 2. In some embodiments, at least one d is 3. In some embodiments, at least one d is 4. In some embodiments, at least one d is 5. In some embodiments, at least one d is 6.

[0275]

[0234] As generally described herein, each instance of RDis independently halogen, C1-6alkyl, C1-6haloalkyl, -(L2)-(Y)-C3-10carbocyclyl, -(L2)-(Y)-(4-10 membered heterocyclyl), -(L2)-(Y)-C6-10aryl, - (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, or -(L2)-(Y)- S(=O)2N(RA)2, or two RDattached to the same carbon atom are joined to form a C3-6carbocyclyl or 3-6 membered heterocyclyl, or two RDattached to the same carbon atom are taken together to form =O, wherein L2is absent, C1-3alkylene, or C1-3haloalkylene; 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, C1-6alkyl, C1-6haloalkyl, -(L3)-(Z)-C3-10carbocyclyl, - (L3)-(Z)-(3-10 membered heterocyclyl), -(L3)-(Z)-C6-10aryl, or -(L3)-(Z)-(5-10 membered heteroaryl), or two RAgroups attached to the same nitrogen atom are joined to form a 4-6 membered heterocyclyl, wherein L3is absent, C1-3alkylene, or C1-3haloalkylene; 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, C1-6alkyl, C1-6haloalkyl, C3-10carbocyclyl, -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 =O; wherein each alkyl and haloalkyl is independently substituted with 0 or 1 instances of =O, and each carbocyclyl is independently substituted with 0, 1, 2, or 3 instances of RC; and each instance of RCis independently halogen, C1-6alkyl, or C1-6haloalkyl, or two RCattached to the same carbon atom are taken together to form =O.

[0276]

[0235] In some embodiments, at least one instance of RDis independently halogen. In some embodiments, at least one instance of RDis independently -F.

[0277]

[0236] In some embodiments, at least one instance of RDis independently C1-6alkyl substituted with 0, 1,

[0278] 2, or 3 instances of RB. In some embodiments, at least one instance of RDis independently C1-6alkyl substituted with 0 RB. In some embodiments, at least one instance of RDis independently C1-3alkyl substituted with 0, 1, 2, or 3 instances of RB. In some embodiments, at least one instance of RDis independently C1-3alkyl substituted with 0 RB. In some embodiments, at least one instance of RDis independently methyl. In some embodiments, at least one instance of RDis independently ethyl. In some embodiments, at least one instance of RDis independently isopropyl.

[0279]

[0237] In some embodiments, at least one instance of RDis independently C1-6haloalkyl substituted with 0, 1, 2, or 3 instances of RB. In some embodiments, at least one instance of RDis independently C1-6haloalkyl substituted with 0 RB. In some embodiments, at least one instance of RDis independently C1-3haloalkyl substituted with 0, 1, 2, or 3 instances of RB. In some embodiments, at least one instance of RDis independently C1-3haloalkyl substituted with 0 RB. In some embodiments, at least one instance of RDis independently -CF2H, -CF3, -CH2CF2H, or -CH2CF3,

[0280]

[0238] In some embodiments, at least one instance of RDis independently -(L2)-(Y)-C3-10carbocyclyl, wherein the carbocyclyl is substituted with 0, 1, 2, or 3 instances of RB. In some embodiments, at least one instance of RDis independently C3-10carbocyclyl, wherein the carbocyclyl is substituted with 0, 1, 2, or 3 instances of RB.

[0281]

[0239] In some embodiments, at least one instance of RDis independently -(L2)-(Y)-(4-10 membered heterocyclyl), wherein the heterocyclyl is substituted with 0, 1, 2, or 3 instances of RB. In some embodiments, at least one instance of RDis independently 4-10 membered heterocyclyl, wherein the heterocyclyl is substituted with 0, 1, 2, or 3 instances of RB. In some embodiments, at least one instance of R is independently

[0282]

[0240] In some embodiments, at least one instance of RDis independently -(L2)-(Y)-C6-10aryl, wherein the aryl is substituted with 0, 1, 2, or 3 instances of RB. In some embodiments, at least one instance of RDis independently C6-10aryl, wherein the aryl is substituted with 0, 1, 2, or 3 instances of RB.

[0283]

[0241] In some embodiments, at least one instance of RDis independently -(L2)-(Y)-(5-10 membered heteroaryl), wherein the heteroaryl is substituted with 0, 1, 2, or 3 instances of RB. In some embodiments, at least one instance of RDis independently 5-10 membered heteroaryl, wherein the heteroaryl is substituted with 0, 1, 2, or 3 instances of RB.

[0284]

[0242] In some embodiments, at least one instance of RDis independently -(L2)-ORA. In some embodiments, at least one instance of RDis independently -ORA. In some embodiments, at least one instance of RDis independently -OH or -OMe.

[0285]

[0243] In some embodiments, at least one instance of RDis independently -(L2)-N(RA)2. In some embodiments, at least one instance of RDis independently -N(RA)2. In some embodiments, at least one instance of RDis independently -NMe2.

[0286]

[0244] In some embodiments, at least one instance of RDis independently -(L2)-SRA. In some embodiments, at least one instance of RDis independently -SRA.

[0287]

[0245] In some embodiments, at least one instance of RDis independently -(L2)-CN. In some embodiments, at least one instance of RDis independently -CN.

[0288]

[0246] In some embodiments, at least one instance of RDis independently -(L2)-(Y)-C(=O)RA. In some embodiments, at least one instance of RDis independently -C(=O)RA.

[0289]

[0247] In some embodiments, at least one instance of RDis independently -(L2)-(Y)-C(=O)ORA. In some embodiments, at least one instance of RDis independently -C(=O)ORA. In some embodiments, at least one instance of RDis independently -CO2t-Bu.

[0290]

[0248] In some embodiments, at least one instance of RDis independently -(L2)-(Y)-C(=O)N(RA)2. In some embodiments, at least one instance of RDis independently -C(=O)N(RA)2.

[0291]

[0249] In some embodiments, at least one instance of RDis independently -(L2)-S(=O)2RA. In some embodiments, at least one instance of RDis independently -S(=O)2RA.

[0292]

[0250] In some embodiments, at least one instance of RDis independently -(L2)-S(=O)2ORA. In some embodiments, at least one instance of RDis independently -S(=O)2ORA.

[0293]

[0251] In some embodiments, at least one instance of RDis independently or -(L2)-(Y)-S(=O)2N(RA)2. In some embodiments, at least one instance of RDis independently or -S(=O)2N(RA)2.

[0294]

[0252] In some embodiments, two RDattached to the same carbon atom are joined to form a C3-6carbocyclyl or 3-6 membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is substituted with 0,

[0295] 1, 2, or 3 instances of RB. In some embodiments, two RDattached to the same carbon atom are joined to form a C3-6carbocyclyl or 3-6 membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is substituted with 0 instances of RB. In some embodiments, two RDattached to the same carbon atom are joined to form a C3-6carbocyclyl or 3-6 membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is substituted with 1 instance of RB.

[0296]

[0253] In some embodiments, two RDattached to the same carbon atom are taken together to form =O.

[0297]

[0254] In some embodiments, at least one instance of RAis independently H.

[0298]

[0255] In some embodiments, at least one instance of RAis independently C1-6alkyl substituted with 0, 1,

[0299] 2, or 3 instances of RB. In some embodiments, at least one instance of RAis independently C1-6alkyl substituted with 0 RB. In some embodiments, at least one instance of RAis independently C1-3alkyl substituted with 0, 1, 2, or 3 instances of RB. In some embodiments, at least one instance of RAis independently C1-3alkyl substituted with 0 RB. In some embodiments, at least one instance of RAis independently methyl.

[0300]

[0256] In some embodiments, at least one instance of RAis independently C1-6haloalkyl substituted with 0, 1, 2, or 3 instances of RB. In some embodiments, at least one instance of RAis independently C1-6haloalkyl substituted with 0 RB.

[0301]

[0257] In some embodiments, at least one instance of RAis independently -(L3)-(Z)-C3-10carbocyclyl, wherein the carbocyclyl is substituted with 0, 1, 2, or 3 instances of RB. In some embodiments, at least one instance of RAis independently C3-10carbocyclyl, wherein the carbocyclyl is substituted with 0, 1, 2, or 3 instances of RB.

[0302]

[0258] In some embodiments, at least one instance of RAis independently -(L3)-(Z)-(3-10 membered heterocyclyl), wherein the heterocyclyl is substituted with 0, 1, 2, or 3 instances of RB. In some embodiments, at least one instance of RAis independently 3-10 membered heterocyclyl, wherein the heterocyclyl is substituted with 0, 1, 2, or 3 instances of RB.

[0303]

[0259] In some embodiments, at least one instance of RAis independently -(L3)-(Z)-C6-10aryl, wherein the aryl is substituted with 0, 1, 2, or 3 instances of RB. In some embodiments, at least one instance of RAis independently C6-10aryl, wherein the aryl is substituted with 0, 1, 2, or 3 instances of RB.

[0304]

[0260] In some embodiments, at least one instance of RAis independently or -(L3)-(Z)-(5-10 membered heteroaryl), wherein the heteroaryl is substituted with 0, 1, 2, or 3 instances of RB. In some embodiments, at least one instance of RAis independently or 5-10 membered heteroaryl, wherein the heteroaryl is substituted with 0, 1, 2, or 3 instances of RB.

[0305]

[0261] In some embodiments, two RAgroups 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 instances of RB.

[0306]

[0262] In some embodiments, at least one instance of RBis independently halogen.

[0307]

[0263] In some embodiments, at least one instance of RBis independently C1-6alkyl substituted with 0 or 1 instances of =O. In some embodiments, at least one instance of RBis independently C1-6alkyl substituted with 0 instances of =O.

[0308]

[0264] In some embodiments, at least one instance of RBis independently C1-6haloalkyl substituted with 0 or 1 instances of =O. In some embodiments, at least one instance of RBis independently C1-6haloalkyl substituted with 0 instances of =O.

[0309]

[0265] In some embodiments, at least one instance of RBis independently C3-10carbocyclyl substituted with 0, 1, 2, or 3 instances of RC.

[0310]

[0266] In some embodiments, at least one instance of RBis independently -CN.

[0311]

[0267] In some embodiments, at least one instance of RBis independently -OR'.

[0312]

[0268] In some embodiments, at least one instance of RBis independently -N(R')2.

[0313]

[0269] In some embodiments, at least one instance of RBis independently -SR'.

[0314]

[0270] In some embodiments, at least one instance of RBis independently -C(=O)R'.

[0315]

[0271] In some embodiments, at least one instance of RBis independently -C(=O)OR'.

[0316]

[0272] In some embodiments, at least one instance of RBis independently -C(=O)N(R')2.

[0317]

[0273] In some embodiments, two RBattached to the same carbon atom are taken together to form =O.

[0274] In some embodiments, at least one instance of RCis independently halogen.

[0318]

[0275] In some embodiments, at least one instance of RCis independently C1-6alkyl.

[0319]

[0276] In some embodiments, at least one instance of RCis independently C1-6haloalkyl.

[0320]

[0277] In some embodiments, two RCattached to the same carbon atom are taken together to form =O.

[0321]

[0278] In some embodiments, each instance of RDis independently halogen, C1-6alkyl, C1-6haloalkyl, - 0RA, -N(RA)2, 4-5 membered heterocyclyl, or -C(=O)ORA, or two RDattached to the same carbon atom are joined to form a 3-6 membered heterocyclyl, or two RDattached to the same carbon atom are taken together to form =O; and each alkyl, haloalkyl, or heterocyclyl is independently substituted 0 instances of RB; and each instance of RAis independently H or C1-6alkyl, and each alkyl is independently substituted with 0 instances of RB.

[0322]

[0279] In some embodiments, at least one instance of RDis independently selected from F, methyl, ethyl, isopropyl, -CF2H, -CF3, -CH2CF2H, -CH2CF3, -OH, -OMe, -NMe2, -CO2t-Bu, , two RDattached to the same carbon atom are joined to form and / or two RDattached to the same carbon atom are taken together to form =O. In some embodiments, at least one instance of RDis independently selected from F, methyl, isopropyl, -CF2H, -CF3, -CH2CF2H, -CH2CF3, -OH, -OMe, - NMe2, -CO2t-Bu, and / or two RDattached to the same carbon atom are taken together to form =O.

[0323]

[0280] In some embodiments, at least one Ring D is selected from:

[0324] In some embodiments, W is absent, and Ring D is selected from one of the foregoing.

[0325]

[0281] In some embodiments, at least one Ring D is selected from:

[0326] In some embodiments, at least one W is -C(RCW)2-, -O-, or -N(RNW)-, and Ring D is selected from one of the foregoing. In some embodiments, at least one W is -C(RCW)2-, and Ring D is selected from one of the foregoing. In some embodiments, at least one W is -CH2-, and Ring D is selected from one of the foregoing. In some embodiments, at least one W is -O-, and Ring D is selected from one of the foregoing. In some embodiments, at least one W is -N(RNW)-, and Ring D is selected from one of the foregoing. In some embodiments, at least one W is -N(H)-, and Ring D is selected from one of the foregoing. In some embodiments, at least one W is -N(Me)-, and Ring D is selected from one of the foregoing.

[0327] (c) R', R", and R'"

[0328]

[0282] As generally described herein, each instance of R' is independently H, C1-6alkyl, or C1-6haloalkyl, or two R' groups attached to the same nitrogen atom are joined to form a 4-6 membered heterocyclyl, wherein the alkyl, haloalkyl, heterocyclyl, or heteroaryl is substituted with 0, 1, 2, or 3 instances of R".

[0329]

[0283] In some embodiments, at least one instance of R' is independently H.

[0330]

[0284] In some embodiments, at least one instance of R' is independently C1-6alkyl substituted with 0, 1, 2, or 3 instances of R". In some embodiments, at least one instance of R' is independently C1-6alkyl substituted with 0 R". In some embodiments, at least one instance of R' is independently C1-3alkyl substituted with 0, 1, 2, or 3 instances of R". In some embodiments, at least one instance of R' is independently C1-3alkyl substituted with 0 R".

[0285] In some embodiments, at least one instance of R' is independently C1-6haloalkyl substituted with 0, 1, 2, or 3 instances of R". In some embodiments, at least one instance of R' is independently C1-6haloalkyl substituted with 0 R". In some embodiments, at least one instance of R' is independently C1-3haloalkyl substituted with 0, 1, 2, or 3 instances of R". In some embodiments, at least one instance of R' is independently C1-3haloalkyl substituted with 0 R". In some embodiments, at least one instance of R' is independently C1haloalkyl substituted with 0, 1, 2, or 3 instances of R". In some embodiments, at least one instance of R' is independently C1haloalkyl substituted with 0 R".

[0331]

[0286] In some embodiments, two R' groups attached to the same nitrogen atom are joined to form a 4-6 membered heterocyclyl substituted with 0, 1, 2, or 3 instances of R". In some embodiments, two R' groups attached to the same nitrogen atom are joined to form a 4-6 membered heterocyclyl substituted with O R".

[0332]

[0287] As generally described herein, each instance of R" is independently halogen, C1-3alkyl, C1-3haloalkyl, -CN, -OR'", -N(R"')2, or -SR'", or two R" attached to the same carbon atom are taken together to form =O.

[0333]

[0288] In some embodiments, at least one instance of R" is independently halogen.

[0334]

[0289] In some embodiments, at least one instance of R" is independently C1-3alkyl.

[0335]

[0290] In some embodiments, at least one instance of R" is independently C1-3haloalkyl.

[0336]

[0291] In some embodiments, at least one instance of R" is independently -CN.

[0337]

[0292] In some embodiments, at least one instance of R" is independently -OR'".

[0338]

[0293] In some embodiments, at least one instance of R" is independently -N(R'")2.

[0339]

[0294] In some embodiments, at least one instance of R" is independently -SR'".

[0340]

[0295] In some embodiments, two R" attached to the same carbon atom are taken together to form =O.

[0341]

[0296] As generally described herein, each instance of R'" is independently H, C1-3alkyl, or C1-3haloalkyl, 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 substituents independently selected from halogen.

[0342]

[0297] In some embodiments, at least one instance of R'" is independently H.

[0343]

[0298] In some embodiments, at least one instance of R'" is independently C1-3alkyl.

[0344]

[0299] In some embodiments, at least one instance of R'" is independently C1-3haloalkyl.

[0345]

[0300] In some embodiments, 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 substituents independently selected from halogen.

[0346] (d) Subgenera

[0347]

[0301] It is understood that, for a compound of the present disclosure, variables R1, R1A, X, G1, G2, G3, RG1, RG2, RG3, W, W", RCW, RNW, Ring D, RD, d, RA, RB, RC, R', R", R'", L1. L2, L3, Z, Y, n, m, e, s, 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, G3, RG1, RG2, RG3, W, W", RCW, R™, Ring D, RD, d, RA, RB, RC, R', R", R'", L1, L2, L3, Z, Y, m, e, s, 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, G3, RG1, RG2, RG3, W, W", RCW, RNW, Ring D, RD, d, RA, RB, RC, R', R", R'", L1, L2, L3, Z, Y, m, e, s, and z. Additional exemplary combinations of the above described embodiments are further contemplated herein.

[0348]

[0302] In some embodiments, when W para to the Ring C point of attachment to the alkynyl linker is absent, the compound of Formula (I) is of Formula (II): or a pharmaceutically acceptable salt thereof. In some embodiments -CX3is -CH3or -CHF2. In some embodiments, Ring C is of formula (C-l). In some embodiments, Ring C is of formula (C-1-i). In some embodiments, Ring C is of formula (C-1-ii). In some embodiments, Ring C is of formula (C-1-iv). In some embodiments, Ring C is of formula (C-1-Ring D). In some embodiments, G1is CRG1, G2is CRG2, and G3is CRG3. In some embodiments, G1is CH, G2is CRG2, and G3is CH. In some embodiments, G1is CH, G2is CF, and G3is CH. In some embodiments, G1is CH, G2is CRG2, and G3is CH, wherein RG2is not H or halogen (e.g., fluoro). In some embodiments, G1is CH, G2is and G3is

[0349] CH. In some embodiments, at least one Ring D is of formula (D-9) (e.g., (D-9-vii) or (D-9-viii)). In some embodiments, at least one Ring D is of formula (D-9-vii) or (D-9-viii). In some embodiments, at least one Ring D is of formula (D-16), (e.g., (D-16-ix) or (D-16-xi)). In some embodiments, at least one Ring D is of formula (D-16-ix) or (D-16-xi). In some embodiments, at least one Ring D is of formula (D- 20). In some embodiments, at least one Ring D is of formula (D-22) (e.g., (D-22-vi) or (D-22-vii)). In some embodiments, at least one Ring D is of formula (D-22-vi) or (D-22-vii). In some embodiments, at least one Ring D is of formula (D-25). In some embodiments, at least one Ring D is of formula (D-26). In some embodiments, R1is a group of formula (y-2), (y-4), (y-7), (y-8), (y-9), or (y-11). In some embodiments, R1is a group of formula (y-2), (y-4-i), or (y-4-iv). In some embodiments, R1is a group of formula (y-4-i). In some embodiments, R1is a group of formula (y-4-iv). In some embodiments, R1is a group of formula (y-2). In some embodiments, R1is a group of formula (y-7).

[0350]

[0303] In some embodiments, when W para to the Ring C point of attachment to the alkynyl linker is not absent, the compound of Formula (I) is of Formula (III):

[0351] or a pharmaceutically acceptable salt thereof, wherein W is -C(RCW)2-, -O-, or -N(RNW)-. In some embodiments -CX3is -CH3or -CHF2. In some embodiments, Ring C is of formula (C-l). In some embodiments, Ring C is of formula (C-1-i). In some embodiments, Ring C is of formula (C-1-ii). In some embodiments, Ring C is of formula (C-1-iv). In some embodiments, Ring C is of formula (C-1- Ring D). In some embodiments, G1is CRG1, G2is CRG2, and G3is CRG3. In some embodiments, G1is CH, G2is CRG2, and G3is CH. In some embodiments, G1is CH, G2is CF, and G3is CH. In some embodiments, G1is CH, G2is CRG2, and G3is CH, wherein RG2is not H or halogen (e.g., fluoro). In some embodiments, G1is CH, G2is and G3is CH. In some embodiments, at least one Ring D is of formula (D-3). In some embodiments, at least one Ring D is of formula (D-4). In some embodiments, at least one Ring D is of formula (D-5). In some embodiments, at least one Ring D is of formula (D-38). In some embodiments, at least one Ring D is of formula (D-41). In some embodiments, at least one Ring D is of formula (D-42). In some embodiments, at least one Ring D is of formula (D-16). In some embodiments, at least one Ring D is of formula (D-12). In some embodiments, at least one Ring D is of formula (D-13). In some embodiments, at least one Ring D is of formula (D-10). In some embodiments, at least one Ring D is of formula (D-ll). In some embodiments, at least one Ring D is of formula (D-39). In some embodiments, at least one Ring D is of formula (D-54). In some embodiments,

[0352] Ring C is of formula (C-1-Ring D), wherein G2is CRG2, CRG2is and W, Ring

[0353] D, W substituent, and Ring D substituent are selected from those recited in Table 1A. In some embodiments, the Ring D substituent is of formula (D-9). In some embodiments, the Ring D substituent is of formula (D-13). In some embodiments, the Ring D substituent is of formula (D-16). In some embodiments, the Ring D substituent is of formula (D-22). In some embodiments, the Ring D substituent is of formula (D-38). In some embodiments, R1is a group of formula (y-2), (y-4), (y-7), (y-8), (y-9), or (y-11). In some embodiments, R1is a group of formula (y-2), (y-4-i), or (y-4-iv). In some embodiments, R1is a group of formula (y-4-i). In some embodiments, R1is a group of formula (y-4-iv). In some embodiments, R1is a group of formula (y-2). In some embodiments, R1is a group of formula (y-7).

[0304] In some embodiments, the compound of Formula (II) is of Formula: or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, 2, or 3. In some embodiments, n is 0. In some embodiments, n is 1 or 2, wherein R1Ais fluoro. In some embodiments, n is 1, wherein R1Ais fluoro. In some embodiments, n is 2 and two R1Agroups are joined to form In some embodiments, Ring C is of formula (C-l). In some embodiments, Ring C is of formula (C-1-i). In some embodiments, Ring C is of formula (C-1-ii). In some embodiments, Ring C is of formula (C-1-iv). In some embodiments, Ring C is of formula (C-1-Ring D). In some embodiments, G1is CRG1, G2is CRG2, and G3is CRG3. In some embodiments, G1is CH, G2is CRG2, and G3is CH. In some embodiments, G1is CH, G2is CF, and G3is CH. In some embodiments, G1is CH, G2is CRG2, and G3is CH, wherein RG2is not H or halogen (e.g., fluoro). In some embodiments, G1is CH, G2is and G3is

[0354] CH. In some embodiments, at least one Ring D is of formula (D-9) (e.g., (D-9-vii) or (D-9-viii)). In some embodiments, at least one Ring D is of formula (D-9-vii) or (D-9-viii). In some embodiments, at least one Ring D is of formula (D-20). In some embodiments, at least one Ring D is of formula (D-22) (e.g., (D-22-vi) or (D-22-vii)). In some embodiments, at least one Ring D is of formula (D-22-vi) or (D- 22-vii). In some embodiments, at least one Ring D is of formula (D-25). In some embodiments, at least one Ring D is of formula (D-26). In some embodiments, at least one Ring D is of formula (D-16) (e.g.,

[0355] (D-16-ix) or (D-16-xi)). In some embodiments, at least one Ring D is of formula (D-16-ix) or (D-16-xi).

[0356] In some embodiments, at least one Ring D is of formula (D-19).

[0357]

[0305] In some embodiments, the compound of Formula (II) is of Formula: or a pharmaceutically acceptable salt thereof. In some embodiments, G2is CH. In some embodiments, Ring D is of formula (D-9) (e.g., (D-9-vii) or (D-9-viii)). In some embodiments, at least one Ring D is of formula (D-9-vii) or (D-9-viii). In some embodiments, Ring D is of formula (D-20). In some embodiments, Ring D is of formula (D-22) (e.g., (D-22-vi) or (D-22-vii)). In some embodiments, at least one Ring D is of formula (D-22-vi) or (D-22-vii). In some embodiments, Ring D is of formula (D-25). In some embodiments, Ring D is of formula (D-26). In some embodiments, Ring D is of formula (D-16) (e.g., (D-16-ix) or (D-16-xi)). In some embodiments, at least one Ring D is of formula (D-16-ix) or (D- 16-xi). In some embodiments, Ring D is of formula (D-19). In some embodiments, d is 0. In some embodiments, d is 2 and two RDattached to the same carbon atom are taken together to form =O.

[0358]

[0306] In some embodiments, the compound of Formula (II) is of Formula: or a pharmaceutically acceptable salt thereof. In some embodiments, G2is CH. In some embodiments, Ring D is of formula (D-9) (e.g., (D-9-vii) or (D-9-viii)). In some embodiments, at least one Ring D is of formula (D-9-vii) or (D-9-viii). In some embodiments, Ring D is of formula (D-20). In some embodiments, Ring D is of formula (D-22) (e.g., (D-22-vi) or (D-22-vii)). In some embodiments, at least one Ring D is of formula (D-22-vi) or (D-22-vii). In some embodiments, Ring D is of formula (D-25). In some embodiments, Ring D is of formula (D-26). In some embodiments, Ring D is of formula (D-16) (e.g., (D-16-ix) or (D-16-xi)). In some embodiments, at least one Ring D is of formula (D-16-ix) or (D- 16-xi). In some embodiments, Ring D is of formula (D-19). In some embodiments, d is 0. In some embodiments, d is 2 and two RDattached to the same carbon atom are taken together to form =O.

[0359]

[0307] In some embodiments, the compound of Formula (II) is of Formula:

[0360] or a pharmaceutically acceptable salt thereof. In some embodiments, G2is CH. In some embodiments, d is 0, as valency permits. In some embodiments, d is 1, as valency permits. In some embodiments, d is 1, as valency permits, and RDis -OH. In some embodiments, d is 2 and two RDattached to the same carbon atom are taken together to form =O. In some embodiments, d is 3, one RDis methyl, and two RDattached to the same carbon atom are taken together to form =O.

[0361]

[0308] In some embodiments, the compound of Formula (II) is of Formula: or a pharmaceutically acceptable salt thereof. In some embodiments, G2is CH. In some embodiments, d is 0, as valency permits. In some embodiments, d is 1, as valency permits. In some embodiments, d is 1, as valency permits, and RDis -OH. In some embodiments, d is 2 and two RDattached to the same carbon atom are taken together to form =O. In some embodiments, d is 3, one RDis methyl, and two RDattached to the same carbon atom are taken together to form =O.

[0362]

[0309] In some embodiments, the compound of Formula (II) is of Formula: or a pharmaceutically acceptable salt thereof. In some embodiments, G2is CH. In some embodiments, d is 0, as valency permits. In some embodiments, d is 1, as valency permits. In some embodiments, d is 1, as valency permits, and RDis -OH. In some embodiments, d is 2 and two RDattached to the same carbon atom are taken together to form =O. In some embodiments, d is 3, one RDis methyl, and two RDattached to the same carbon atom are taken together to form =O.

[0363]

[0310] In some embodiments, the compound of Formula (III) is of Formula: or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, 2, or 3, wherein W is -C(RCW)2-, -O-, or - N(RNW)-. In some embodiments, n is 0. In some embodiments, n is 1 or 2, wherein R1Ais fluoro. In some embodiments, n is 1, wherein R1Ais fluoro. In some embodiments, n is 2 and two R1Agroups are joined to form In some embodiments, Ring C is of formula (C-l). In some embodiments, Ring C is of formula (C-1-i). In some embodiments, Ring C is of formula (C-1-ii). In some embodiments, Ring C is of formula (C-1-iv). In some embodiments, Ring C is of formula (C-1-Ring D). In some embodiments, G1is CRG1, G2is CRG2, and G3is CRG3. In some embodiments, G1is CH, G2is CRG2, and G3is CH. In some embodiments, G1is CH, G2is CF, and G3is CH. In some embodiments, G1is CH, G2is CRG2, and G3is CH, wherein RG2is not H or halogen (e.g., fluoro). In some embodiments, G1is CH, G2is and G3is CH. In some embodiments, at least one Ring D is of formula (D-4). In some embodiments, at least one Ring D is of formula (D-5). In some embodiments, at least one Ring D is of formula (D-38). In some embodiments, at least one Ring D is of formula (D-41). In some embodiments, at least one Ring D is of formula (D-42). In some embodiments, at least one Ring D is of formula (D-16). In some embodiments, at least one Ring D is of formula (D-12). In some embodiments, at least one Ring D is of formula (D-13). In some embodiments, at least one Ring D is of formula (D-10). In some embodiments, at least one Ring D is of formula (D-ll). In some embodiments, at least one Ring D is of formula (D-39). In some embodiments, at least one Ring D is of formula (D-54). In some embodiments, Ring C is of formula (C-1-Ring D), wherein G2is CRG2, CRG2is and W, Ring D, W substituent, and Ring D substituent are selected from those recited in Table 1A. In some embodiments, the Ring D substituent is of formula (D-9). In some embodiments, the Ring D substituent is of formula (D-13). In some embodiments, the Ring D substituent is of formula (D-16). In some embodiments, the Ring D substituent is of formula (D-22). In some embodiments, the Ring D substituent is of formula (D-38).

[0364]

[0311] In some embodiments, the compound of Formula (III) is of Formula: or a pharmaceutically acceptable salt thereof. In some embodiments, G2is CH. In some embodiments, G2is CRG2, wherein RG2is -(L1)-N(R')2. In some embodiments, G2is CRG2, wherein RG2is -N(R')2. In some embodiments, Ring D is of formula (D-4). In some embodiments, Ring D is of formula (D-5). In some embodiments, Ring D is of formula (D-38). In some embodiments, Ring D is of formula (D-41). In some embodiments, Ring D is of formula (D-42). In some embodiments, Ring D is of formula (D-16). In some embodiments, Ring D is of formula (D-12). In some embodiments, Ring D is of formula (D-13). In some embodiments, Ring D is of formula (D-10). In some embodiments, Ring D is of formula (D-ll). In some embodiments, Ring D is of formula (D-39). In some embodiments, Ring D is of formula (D-54). In some embodiments of formula (III-e-NH) or (III-f-NH), Ring D is of formula (D-38). In some embodiments of formula (III-e-O) or (III-f-O), Ring D is of formula (D-5).

[0365]

[0312] In some embodiments, the compound of Formula (III) is of Formula:

[0366] or a pharmaceutically acceptable salt thereof. In some embodiments, G2is CH. In some embodiments, G2is CRG2, wherein RG2is -(L1)-N(R')2. In some embodiments, G2is CRG2, wherein RG2is -N(R')2. In some embodiments, Ring D is of formula (D-4). In some embodiments, Ring D is of formula (D-5). In some embodiments, Ring D is of formula (D-38). In some embodiments, Ring D is of formula (D-41). In some embodiments, Ring D is of formula (D-42). In some embodiments, Ring D is of formula (D-16). In some embodiments, Ring D is of formula (D-12). In some embodiments, Ring D is of formula (D-13). In some embodiments, Ring D is of formula (D-10). In some embodiments, Ring D is of formula (D-ll). In some embodiments, Ring D is of formula (D-39). In some embodiments, Ring D is of formula (D-54). In some embodiments of formula (III-g-NH-a) or (III-h-NH-a), Ring D is of formula (D-38). In some embodiments of formula (III-g-O-a) or (III-h-O-a), Ring D is of formula (D-5). In some embodiments of formula (III-g-NH-b), (III-h-NH-b), (III-g-NH-c) or (III-h-NH-c), Ring D is of formula (D-38). In some embodiments of formula (III-g-O-b), (III-h-O-b), (III-g-O-c) or (III-h-O-c), Ring D is of formula

[0367] (D-5)

[0368]

[0313] In some embodiments, the compound of Formula (I) is of Formula (IV) or (V): or a pharmaceutically acceptable salt thereof, wherein W" is C, CH, or N as valency permits; s is 1 or 2; each in Ring E is independently a single or double bond; and e is 0, 1, 2, or 3.

[0369]

[0314] In some embodiments, the compound of Formula (I) is of Formula: or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, 2, or 3; W" is C, CH, or N as valency permits; s is 1 or 2; each in Ring E is independently a single or double bond; and e is 0, 1, 2, or 3.

[0370]

[0315] In some embodiments, the compound of Formula (I) is of Formula: or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, 2, or 3; W" is C, CH, or N as valency permits; s is 1 or 2; each in Ring E is independently a single or double bond; and e is 0, 1, 2, or 3.

[0371]

[0316] In some embodiments, the compound of Formula (I) is selected from any one of the compounds of Tables 2A-2C or Tables 3A-3C, or a pharmaceutically acceptable salt of any one of the foregoing.

[0372]

[0317] In some embodiments, the compound of Formula (I) is selected from a pharmaceutically acceptable salt of any one of the compounds of Tables 2A-2C or Tables 3A-3C.

[0373]

[0318] In some embodiments, the compound of Formula (I) is a free base selected from any one of the compounds of Tables 2A-2C or Tables 3A-3C.

[0374]

[0319] The below Tables 2A-2C and Tables 3A-3C also provide the location of the Compound (#) in the Examples (Ex) by Example Number or Table A (TA). 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. Table 2A. Compounds of Formula (I) wherein W para to the alkynyl linker is absent Table 2A. Compounds of Formula (I) wherein W para to the alkynyl linker is absent Table 2C. Compounds of Formula (I) wherein W para to the a kynyl linker is absent Table 2C. Compounds of Formula (I) wherein W para to the a kynyl linker is absent Table 2C. Compounds of Formula (I) wherein W para to the a kynyl linker is absent Table 2C. Compounds of Formula (I) wherein W para to the a kynyl linker is absent

[0375]

[0376]

[0377] (ii) Pharmaceutical Compositions

[0378]

[0320] The present disclosure provides pharmaceutical compositions comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In some embodiments, a compound described herein is provided in an effective amount in the pharmaceutical composition. In some embodiments, the effective amount is a therapeutically effective amount. In some embodiments, the effective amount is a prophylactically effective amount.

[0321] 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 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.

[0379]

[0322] Relative amounts of the compound of Formula (I), or a pharmaceutically acceptable salt 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.

[0380]

[0323] 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.

[0381]

[0324] 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).

[0382]

[0325] 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.

[0383]

[0326] 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.

[0384]

[0327] 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 some 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.

[0385]

[0328] A compound or composition, as described herein, can be administered in combination with one or more additional pharmaceutical agents (e.g., therapeutically and / or prophylactically active agents). The compounds or compositions can be administered in combination with additional pharmaceutical agents, 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.

[0386] (iii) Methods of Treatment and Prevention

[0387]

[0329] 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 thereof, or a pharmaceutical composition thereof. In some embodiments, a compound described herein is provided in an effective amount. In some embodiments, the effective amount is a therapeutically effective amount. In some embodiments, the effective amount is a prophylactically effective amount.

[0388]

[0330] In some aspects, the present disclosure provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in treating or preventing a condition, disease, or disorder.

[0389]

[0331] In some aspects, the present disclosure provides use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for treating or preventing a condition, disease, or disorder.

[0390]

[0332] In some 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”).

[0333] 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 thereof, or a pharmaceutical composition thereof. In some embodiments, a compound described herein is provided in an effective amount. In some embodiments, the effective amount is a therapeutically effective amount. In some embodiments, the effective amount is a prophylactically effective amount.

[0391]

[0334] In some aspects, the present disclosure provides compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in inhibiting TYK2 activity (e.g., in vitro or in vivo).

[0392]

[0335] In some aspects, the present disclosure provides use of compound of Formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for inhibiting TYK2 activity (e.g., in vitro or in vivo).

[0393]

[0336] In some embodiments, the condition, disease, or disorder is an inflammatory or neurodegenerative disorder. In some embodiments, the condition, disease, or disorder is an autoimmune disorder. In some 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.

[0394]

[0337] In some embodiments, the condition, disease or disorder is an inflammatory skin disorder. Exemplary inflammatory skin disorders include but are not limited to psoriasis and dermatomyositis.

[0395]

[0338] In some 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 some embodiments, the IBD is Crohn’s Disease. In some embodiments, the IBD is ulcerative colitis.

[0396]

[0339] In some 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 some embodiments, the joint inflammatory disorder is peripheral. In some embodiments, the joint inflammatory disorder is axial.

[0397]

[0340] In some 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.

[0398]

[0341] In some 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).

[0399]

[0342] In some 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).

[0343] In some 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.

[0400]

[0344] In some embodiments, the condition, disease or disorder is a systemic disorder, which is an 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.

[0401]

[0345] In some 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.

[0402] (iv) Methods of Preparation

[0403]

[0346] Compounds of Formula (I) may be synthesized following the General Schemes A-F. as described and provided below. The Examples further described non-limiting examples of these general syntheses and other preparations.

[0404]

[0347] 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), (B2), (B4), or (B5), or salt thereof, to provide a compound of Formula (C), or salt thereof, wherein each R is independently C1-6alkyl and LG1is bromo or iodo, and LGs is chloro, bromo, or iodo, and wherein R2is -W-(Ring D)-(RD)d as defined herein. In some embodiments, the Step 1 coupling is a Sonogashira cross coupling reaction, e.g., wherein (B4) is used as the coupling reagent. See, e.g., Chinchilla et al. Chem. Rev. / 2007) 107(3): 874-922 and the Examples for exemplary coupling 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, wherein R2is -W-(Ring D)-(RD)d as defined herein. In some embodiments, the Step 2 coupling is a Buchwald-Hartwig palladium -catalyzed amination reaction. See, e.g., Ruiz- Castillo, etal., Chem. Rev. (2016) 116(19): 12564-12649 and the Examples for exemplary amination reaction conditions.

[0405]

[0348] Alternatively, as depicted in General Scheme A, Steps 3-4, 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, wherein each R is independently C1-6alkyl or C1-6alkylC6aryl 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 1, 2, 3, or 4 C1-6alkyl, and wherein R2is -W-(Ring D)-(RD)d as defined herein, with a compound of Formula (B3), or salt thereof, wherein LG2 is bromo or iodo and wherein R2is -W-(Ring D)-(RD)das defined herein, to provide the compound of Formula (C), or salt thereof. Both (A2) and (A3), and salts thereof, may be prepared by treating the compound of Formula (Al), or salt thereof with a tin reagent of formula LG4-SnR3(to provide A2, or salt thereof) or a boronic ester reagent of formula LG5-B(OR)2(to provide A3, or salt thereof), wherein LG4 is chloro, bromo, or chloro, and LG5 is -OR or -B(0R)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. See, e.g., Stille et al., Org. Synth. (1993) 71:97 or the Examples for exemplary tin reagent preparation and coupling reaction conditions.

[0406] General Scheme A

[0407]

[0349] As depicted in General Scheme B. Step 1 involves coupling of a compound of Formula (F1A) or (FIB), or salt thereof, with a compound of Formula (Bl), (B2), (B4), or (B5), or salt thereof, to provide a compound of Formula (I), or salt thereof, wherein each R is independently C1-6alkyl, and LG3is chloro, bromo, or iodo, and wherein R2is -W-(Ring D)-(RD)d as defined herein. In some embodiments, the Step

[0408] 1 coupling is a Sonogashira cross coupling reaction, e.g., wherein (B4) is used as the coupling reagent. See, e.g., Chinchilla et al. Chem. Rev. (2007) 107(3): 874-922 and / or the Examples for exemplary coupling reaction conditions. The compound of Formula (F1A) or (FIB), or salt thereof, may be prepared from 6-chloro-2,7-naphthyridin-1-ol, as described in the Examples section.

[0409]

[0350] Alternatively, as depicted in General Scheme B. Steps 2-3, 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, wherein each R is independently C1-6alkyl or C1-6alkylC6aryl 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 1, 2, 3, or 4 C1-6alkyl, with a compound of Formula (B3), or salt thereof, wherein LG2 is bromo or iodo, to provide the compound of Formula (I), or salt thereof. Both (F2) and (F3), and salts thereof, may be prepared by treating the compound of Formula (Fl), or salt thereof, with a tin reagent of formula LG4-SnR3(to provide F2, or salt thereof) or a boronic ester reagent of formula LG5-B(OR)2(to provide F3, or salt thereof), wherein LG4is chloro, bromo, or chloro, and

[0410] LG5is -OR or -B(0R)2. See, e.g., Miyaura et al., Chem. Rev. (1995) 95 :2457-2483; Martin et al., Acc.

[0411] 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.

[0412] General Scheme B

[0413]

[0351] As depicted in General Scheme C. Step 1 involves coupling of a compound of Formula (G), or salt thereof, wherein Hal is bromo or iodo, with a compound of Formula (Bl), (B2), (B4), or (B5), or salt thereof, to provide a compound of Formula (H), or salt thereof, wherein PG1is an amino protecting group. In some embodiments, PG1is a paramethoxybenzyl (PMB) group. In some embodiments, the Step 1 coupling is a Sonogashira cross coupling reaction, e.g., wherein (B4) is used as the coupling reagent. See, e.g., Chinchilla et al. Chem. Rev. (2007) 107(3): 874-922 for exemplary coupling 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 or acylation of the amine moiety of the compound of Formula (J), or salt thereof, with a compound of Formula (K), or salt thereof, wherein LG6is -OH or chloro, 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.

[0414] General Scheme C

[0415]

[0352] Alternatively, as depicted in General Scheme D, Step 1 involves peptide coupling or acylation of the amine moiety of a compound of Formula (L), or salt thereof, wherein Hal is bromo or iodo, with a compound of Formula (K), or salt thereof, wherein LG6is -OH or chloro, 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. Step 2 involves coupling of the compound of Formula (M), or salt thereof, with a compound of Formula (Bl), (B2), (B4), or (B5), or salt thereof, to provide a compound of Formula (I), or salt thereof. In some embodiments, the Step 2 coupling is a Sonogashira cross coupling reaction, e.g., wherein (B4) is used as the coupling reagent. See, e.g., Chinchilla et al. Chem. Rev. (2007) 107(3): 874-922 for exemplary coupling reaction conditions.

[0416] General Scheme D

[0417]

[0353] Installing the -W-(Ring D)-(RD)d group at any step in the above described syntheses is further contemplated herein. For example, as depicted in General Scheme E, group R2of any intermediate compound of General Schemes A-D, or salt thereof, may instead be a chloro, bromo, or iodo group (fragment (i), shown below), and coupling of such a group with an H-W-(Ring D)-(RD)d reagent may provide a compound of General Schemes A-D, or salt thereof, wherein R2is -W-(Ring D)-(RD)d (fragment (ii), shown below). Alternatively, as depicted in General Scheme F, group R2of any intermediate compound of General Schemes A-D, or salt thereof, may instead be fragment (i) (shown below), and coupling of such a group with an cyclic ketone reagent, i.e., O=(Ring D)-(RD)d shown below, may provide a compound of General Schemes A-D, or salt thereof, wherein R2is a directly attached Ring D (wherein W is absent) substituted with a tertiary alcohol at the point of attachment to Ring C, i.e., -(Ring D)(OH)-(RD)d-1(fragment (iii), shown below).

[0418] General Scheme E

[0419] General Scheme F

[0420] (v) Biological Assays

[0421]

[0354] 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.

[0422]

[0355] 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.

[0423]

[0356] 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.

[0424]

[0357] 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.

[0425]

[0358] 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 (PBMCs), 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-STAT5). The levels of phospho- STAT in cell lysates may then be determined by electrochemiluminescence. If a compound shows activity at inhibiting the phosphorylation of STAT4 in the IFN alpha assay (i.e. TYK2 / JAK1) but shows minimal activity at inhibiting the phosphorylation of STAT5 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: IC50in IL-7 assay divided by the IC50in IFN alpha assay. The TYK2 fold-selectivity over JAK2 may be calculated as follows: IC50in GM-CSF assay divided by the IC50in IFN alpha assay. See also the Assay Methods section of the Examples.

[0426]

[0359] 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.

[0427]

[0360] 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-life 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-life 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-life 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.

[0428]

[0361] In addition, from the hepatocyte stability assay data, the following parameters may be calculated: (i) the in vitro intrinsic clearance (CLintin μL / 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-level clearance prediction, bridging the gap between in vitro results and real- world pharmacokinetics, and (iii) the predicted hepatic clearance (Clhin mL / min / kg), which can be predicted from the scaled CLintby taking into account the liver physiology and blood flow, using a pharmacokinetic model such as the well-stirred model. Clh= (Qhx CLint) / (Qh+ CLint) where Qhis the liver blood flow). Predicted hepatic clearance (Clh 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.

[0429]

[0362] 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 μM 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 uM in PBS, such as >50 uM or > 100 uM in PBS, may be a desirable solubility profile. See also the Assay Methods section of the Examples.

[0430]

[0363] 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 (Clu) following known procedures, such as described in Miller et al., J. Med. Chem. (2020) 63: 12156-12170. For example, unbound clearance (Clu) 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.

[0431]

[0364] 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 10-6cm / 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-gly coprotein (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 10-6cm / s. 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.; Kerns, E. H. Drug-like properties: Concepts, Structure Design and methods,' Academic Press, 2008. See also the Assay Methods section of the Examples.

[0432]

[0365] 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 μM; b) Moderate: 10 μM < IC50< 30 μM; c) High: IC50< 10 μM. 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.

[0433] (vi) Additional Embodiments

[0434]

[0366] Embodiments of the present disclosure further include:

[0435]

[0367] Embodiment 1. A compound of Formula (I): or a pharmaceutically acceptable salt thereof, wherein: each X is independently selected from H and halogen;

[0436] R1is C3-4carbocyclyl 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 C1-3alkyl, C1-3haloalkyl, halogen, or -OR', or two R1Agroups attached to the same carbon atom are joined to form a C3-6carbocyclyl or 3-6 membered heterocyclyl, or two R1Agroups attached to vicinal atoms are joined to form a C3-6carbocyclyl or 3-6 membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is substituted with 0, 1, 2, or 3 substituents independently selected from C1-3alkyl, C1-3haloalkyl, halogen, -C(=O)OR', and -OR';

[0437] G1is CRG1or N, G2is CRG2or N, and G3is CRG3or N, provided no more than one of G1, G2, and G3is N; each of RG1, RG2and RG3is independently H, halogen, C1-6alkyl, C1-6haloalkyl, -(L1)-C3-4carbocyclyl, -(L1)-O-(CH2CH2O)m-R', -(L1)-N(R')2, -(L1)-CN, or wherein L1is absent, C1-3alkylene, or C1-3haloalkylene; m is 0, 1 or 2; and provided no more than one of RG1, RG2and each instance of W is independently absent, -C(RCW)2-, -O-, or -N(RNW)-; each instance of Ring D is independently 4-8 membered heterocyclyl; each instance of RDis independently halogen, C1-6alkyl, C1-6haloalkyl, -(L2)-(Y)-C3-10carbocyclyl, -(L2)-(Y)-(4- 10 membered heterocyclyl), -(L2)-(Y)-C6-10aryl, -(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, or -(L2)-(Y)-S(=O)2N(RA)2, or two RDattached to the same carbon atom are joined to form a C3-6carbocyclyl or 3-6 membered heterocyclyl, or two RDattached to the same carbon atom are taken together to form =O, wherein L2is absent, C1-3alkylene, or C1-3haloalkylene; 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 d is independently 0, 1, 2, or 3; each instance of RAis independently H, C1-6alkyl, C1-6haloalkyl, -(L3)-(Z)-C3-10carbocyclyl, - (L3)-(Z)-(3- 10 membered heterocyclyl), -(L3)-(Z)-C6-10aryl, or -(L3)-(Z)-(5- 10 membered heteroaryl), or two RAgroups attached to the same nitrogen atom are joined to form a 4-6 membered heterocyclyl, wherein L3is absent, C1-3alkylene, or C1-3haloalkylene; 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, C1-6alkyl, C1-6haloalkyl, C3-10carbocyclyl, -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 =O; wherein each alkyl and haloalkyl is independently substituted with 0 or 1 instances of =O, and each carbocyclyl is independently substituted with 0, 1, 2, or 3 instances of RC; each instance of RCis independently halogen, C1-6alkyl, or C1-6haloalkyl, or two RCattached to the same carbon atom are taken together to form =O; each instance of RCWis independently H, halogen, or C1-6alkyl, or two instances of RCWare taken together to form =O, or wherein one RCWis joined with RG2or RG3to form a C5-6carbocyclyl or Ce aryl, wherein the alkyl, carbocyclyl, or aryl is substituted with 0, 1, 2, or 3 instances of R"; each instance of R' and RNWis independently H, C1-6alkyl, or C1-6haloalkyl, or two R' groups attached to the same nitrogen atom are joined to form a 4-6 membered heterocyclyl, or RNWis joined with RG2or RG3to form a 5-6 membered heterocyclyl or 5-6 membered heteroaryl, wherein the alkyl, haloalkyl, heterocyclyl, or heteroaryl is substituted with 0, 1, 2, or 3 instances of R"; each instance of R" is independently halogen, C1-3alkyl, C1-3haloalkyl, -CN, -OR'", -N(R'")2, or -SR'", or two R" attached to the same carbon atom are taken together to form =O; and each instance of R'" is independently H, C1-3alkyl, or C1-3haloalkyl, 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 substituents independently selected from halogen.

[0438]

[0368] Embodiment 2. The compound of embodiment 1, wherein when W para to the Ring C point of attachment to the alkynyl linker is absent, the compound is of Formula (II): or a pharmaceutically acceptable salt thereof.

[0439]

[0369] Embodiment 3. The compound of embodiment 1, wherein when W para to the Ring C point of attachment to the alkynyl linker is not absent, the compound is of the Formula (III): or a pharmaceutically acceptable salt thereof, wherein W is -C(RCW)2-, -O-, or -N(RNW)-.

[0440]

[0370] Embodiment 4. The compound of embodiment 1, wherein the compound is of the Formula (IV) or (V): or a pharmaceutically acceptable salt thereof, wherein W" is C, CH, or N as valency permits; s is 1 or 2; each in Ring E is independently a single or double bond; and e is 0, 1, 2, or 3.

[0441]

[0371] Embodiment 5. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R1is C3carbocyclyl substituted with 0, 1, 2 or 3 instances of R1A.

[0442]

[0372] Embodiment 6. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R1is cyclopropyl substituted with 0 instances of R1A.

[0443]

[0373] Embodiment 7. 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 R1A, wherein each instance of R1Ais fluoro.

[0444]

[0374] Embodiment 8. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein at least one X is H.

[0445]

[0375] Embodiment 9. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein -CX3is -CH3.

[0446]

[0376] Embodiment 10. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein at least one X is halogen.

[0447]

[0377] Embodiment 11. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein -CX3is -CHF2, -CH2F, or -CF3.

[0448]

[0378] Embodiment 12. The compound of any one of embodiments 1-11, wherein the compound is of Formula:

[0449] or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, 2, or 3.

[0450]

[0379] Embodiment 13. The compound of any one of embodiments 1-11, wherein the compound is of

[0451] Formula: or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, 2, or 3.

[0452]

[0380] Embodiment 14. The compound of any one of embodiments 1-11, wherein the compound is of Formula:

[0453] or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, 2, or 3; W" is C, CH, or N as valency permits; s is 1 or 2; each in Ring E is independently a single or double bond; and e is 0, 1, 2, or 3.

[0381] Embodiment 15. The compound of any one of embodiments 1-11, wherein the compound is of

[0454] Formula:

[0455] or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, 2, or 3; W" is C, CH, or N as valency permits; s is 1 or 2; each in Ring E is independently a single or double bond; and e is 0, 1, 2, or 3.

[0382] Embodiment 16. The compound of any one of embodiments 1-11, wherein the compound is of or a pharmaceutically acceptable salt thereof.

[0456]

[0383] Embodiment 17. The compound of any one of embodiments 1-11, wherein the compound is of

[0457] Formula:

[0458] or a pharmaceutically acceptable salt thereof.

[0459]

[0384] Embodiment 18. The compound of any one of embodiments 1-5 and 8-11, 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 C1-3alkyl and C1-3haloalkyl.

[0460]

[0385] Embodiment 19. The compound of any one of embodiments 1-5, 8-11, and 18, wherein the compound is of Formula: or a pharmaceutically acceptable salt thereof.

[0461]

[0386] Embodiment 20. The compound of any one of embodiments 1-5, 8-11, and 18, wherein the compound is of Formula: or a pharmaceutically acceptable salt thereof.

[0462]

[0387] Embodiment 21. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein G1is CRG1, G2is CRG2, and G3is CRG3.

[0463]

[0388] Embodiment 22. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein each instance of RG1, RG2, and RG3is independently selected from H, Cl, F, methyl, ethyl, -OH, -OCH3, -CH2OCH3, -CH2OH, -N(H)CH3, -CN, -CHF2, cyclopropyl, and

[0464]

[0389] Embodiment 23. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein RG2and RG3are H or F; and RG1is selected from H, Cl, F, methyl, ethyl, -

[0465] OH, -OCH3, -CH2OCH3, -N(H)CH3, -CHF2, cyclopropyl,

[0466]

[0390] Embodiment 24. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein RG1and RG3are H or F; and RG2is selected from H, -OCH3, -CH2OH, -

[0467] CH2OCH3, -CN, -CHF2, and

[0468]

[0391] Embodiment 25. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein RG1and RG2are H or F; and RG3is selected from H, methyl, -OCH3, - CH2OH, -CH2OCH3, -CN, and -CHF2.

[0469]

[0392] Embodiment 26. The compound of any one of embodiments 1-21, or a pharmaceutically acceptable salt thereof, wherein one of RG1, RG2and RG3is

[0470]

[0393] Embodiment 27. The compound of any one of embodiments 1-21, or embodiment 24, or a pharmaceutically acceptable salt thereof, wherein RG2is

[0394] Embodiment 28. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein at least one Ring D is independently selected from one of the following formulae: wherein z is 0, 1, 2, or 3.

[0471]

[0395] Embodiment 29. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein at least one W is absent and at least one Ring D is independently selected from one of the following formulae:

[0396] Embodiment 30. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein at least one W is -C(RCW)2-, -O-, or -N(RNW)-, and at least one Ring D is independently selected from one of the following formulae:

[0472]

[0397] Embodiment 31. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein each instance of RDis independently halogen, C1-6alkyl, C1-6haloalkyl, - ORA, -N(RA)2, 4-5 membered heterocyclyl, or -C(=O)ORA, or two RDattached to the same carbon atom are joined to form a 3-6 membered heterocyclyl, or two RDattached to the same carbon atom are taken together to form =O; and each alkyl, haloalkyl, or heterocyclyl is independently substituted 0 instances of RB

[0473]

[0398] Embodiment 32. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein each instance of RAis independently H or C1-6alkyl, and each alkyl is independently substituted with 0 instances of RB.

[0474]

[0399] Embodiment 33. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein at least one Ring D is independently selected from one of the following formulae:

[0475] wherein z is 0, 1, 2, or 3.

[0476]

[0400] Embodiment 34. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein at least one Ring D is independently selected from:

[0477]

[0478]

[0401] Embodiment 35. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein at least one Ring D is independently selected from:

[0479]

[0480]

[0402] Embodiment 36. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein at least one W is absent.

[0481]

[0403] Embodiment 37. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein at least one W is O, -N(H)-, or -N(Me)-, or wherein W" is N.

[0482]

[0404] Embodiment 38. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein W is NH or O, Ring D is (D-5) or (D-38), G2is CRG2, CRG2is the group wherein the W substituent of said group is absent and the Ring D substituent of said group is (D-9), (D-22), (D-38), (D-13) or (D-16).

[0483]

[0405] Embodiment 39. The compound of embodiment 38, or a pharmaceutically acceptable salt thereof, wherein the combinations of W, Ring D, W substituent of said group, and Ring D substituent of said group are as set forth in Table 1A.

[0484]

[0406] Embodiment 40. The compound of any one of the preceding embodiments, wherein the compound is selected from those in Tables 2A-B or Tables 3A-B, and pharmaceutically acceptable salts thereof.

[0485]

[0407] Embodiment 41. A pharmaceutical composition comprising the compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0486]

[0408] Embodiment 42. 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 1-40, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of embodiment 41.

[0487]

[0409] Embodiment 43. 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 1-40, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of embodiment 41.

[0488]

[0410] Embodiment 44. 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 1 and / or General Method Scheme 2.

[0489] EXEMPLIFICATION

[0490]

[0411] In order that this disclosure may be more fully understood, the following Examples are set forth. 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.

[0491] Analytical Methods

[0492]

[0412] 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-d6) and deuterated methanol (CD3OD).

[0493]

[0413] 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 (acetonitrile) may contain a modifier (typically 0.01 - 0.04 %) such as trifluoroacetic acid (trifluoroacetic acid), formic acid (FA), or ammonium carbonate. ESI or ES = electrospray ionization; m / z = mass / charge; RT = retention time (minutes).

[0494]

[0414] 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. TLC = thin layer chromatography.

[0495] Synthetic Methods

[0496]

[0415] 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 “may be” prepared or synthesized language (or the like) in the Examples signifies prophetic procedures.

[0497] (i) Intermediates

[0498] Intermediate Example 1: Synthesis of 4-bromo-6-chloro-1-methyl-2,7-naphthyridine (Intermediate 1)

[0499]

[0416] Step 1 : To a solution of 6-chloro-2,7-naphthyridin-l(2H)-one (11.0 g, 57.9 mmol, 1.0 equiv) in acetic acid (289 mL) was added bromine (5.93 mL, 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-l(2H)-one. The crude product was used for the next step without any further purification. LCMS: m / z [M+H]+= 261.0, RT = 0.83 min.

[0500]

[0417] Step 2 : To a suspension of 4-bromo-6-chloro-2.7-naphthyridin- 1 (2H)-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 mL, 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 NaHCO3(200 mL) was added, and the mixture was extracted with ethyl acetate (EtOAc) (3 X 350 mL). The combined organic layers were dried over anhydrous Na2SO4and were concentrated in vacuo. The residue was triturated with heptanes (160 ml, 10 mL / lg of pyridine) and filtered to obtain 4-bromo-6-chloro-2,7-naphthyridin-1-yl trifluoromethane sulfonate (15.8 g, 70 % over two steps). LCMS: non-ionized, RT = 1.57 min.

[0501]

[0418] Step 3 : To a solution of 4-bromo-6-chloro-2,7-naphthyridin-1-yl trifluoromethane sulfonate (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 (DCM) (3 x 200 mL). The organic phase was combined, dried, and concentrated to give 4-bromo-6-chloro-l -methyl -2, 7-naphthyridine (Intermediate 1) (8 g, 77 % yield). LCMS: m / z [M+H]+= 259.0, RT = 1.11 min.1HNMR (400 MHz, CDCl3) 5 9.34 (s, 1H), 8.73 (s, 1H), 7.97 (s, 1H), 3.00 (s, 3H).

[0502] Intermediate Example 2: Synthesis of 4-bromo-6-chloro-1-(difluoromethyl)-2, 7-naphthyridine (Intermediate 2)

[0419] Step 1 : To a solution of Intermediate 1 (100 mg, 388 nmol, 1 equiv) in 1,4-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 (EtOAc) in heptanes. Pure fractions were concentrated to provide 4-bromo-6-chloro-2,7-naphthyridine-1-carbaldehyde (43.0 mg, 41% yield).

[0503]

[0420] Step 2 : To the solution of 4-bromo-6-chloro-2,7-naphthyridine-1-carbaldehyde (43.0 mg, 158 umol, 1 equiv) in dichloromethane (396 uL) under nitrogen at 0 °C was added ethanol (ethanol) (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 (EtOAc) in heptanes. Pure fractions were concentrated to provide 4-bromo-6-chloro-1-(difluoromethyl)- 2,7-naphthyridine (Intermediate 2) (35.0 mg, 75% yield). LCMS: m / z [M+H]+= no ionization, RT = 1.30 min.1H NMR (400 MHz, CDCI3) δ 9.71 (s, 1H), 8.87 (s, 1H), 8.10 (s, 1H), 6.91 (t, J = 53.9 Hz, 1H).

[0504] Intermediate Example 3: Synthesis of N-(5-iodo-8-methyl-2,7-naphthyridin-3- yl)cyclopropanecarboxamide (Intermediate 3)

[0505]

[0421] 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 1,4-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 (EtOAc) / CH2Cl2(v / v=10: 1) at 20 °C for 30 min and filtered to afford N-(8-hydroxy -2,7-naphthyridin-3-yl)cyclopropanecarboxamide (389 g, 90% purity by1H NMR, 92% yield).

[0422] Step 2 : A mixture ofN-(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 (Note 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 (MeOH) (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 N-(8-hydroxy-5-iodo-2.7- naphthyridine-3-yl)cyclopropanecaroxamide (> 85% by1H NMR) which was used in the next step directly.

[0506]

[0423] Step 3 : A mixture of N-(8-hydroxy-5-iodo-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (75 g, 211.18 mmol, 1 eq) and N,N-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. POCI3(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 ice / H2O (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 N-(8-chloro-5-iodo-2.7-naphthyridin-3-yl) cyclopropane carboxamide. LCMS: m / z [M+H]+= 373.9.

[0507]

[0424] Step 4 : A mixture of N-(8-chloro-5-iodo-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (36.5 g, 97.70 mmol, 1 eq) and IM potassium tert-butoxide (KOtBu) in tetrahydrofuran (THF) (488.52 mL, 5 eq) in THF) (650 mL) 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 mL, 4.2 eq) in THF (650 mL) was added dropwise and stirred at 65 °C for 2 h under N2atmosphere. To the mixture was added ethyl acetate (EtOAc)ZHCl (4 M) until pH reached approximately 5. Solid precipitated from the mixture, which was filtered then purified by column chromatography (SiO2, 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, 253.11mmol, 21.4 % yield over two steps).

[0508]

[0425] 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 (trifluoroacetic acid) (500 mL) 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 L) where a solid crashed. The mixture was filtered, and the filter cake was dissolved in 2-methyltetrahydrofuran (2-MeTHF) (9 L). Solution was adjusted to pH=10 by adding a saturated solution of Na2CO3(aq.). The organic layers were dried by Na2SO4, filtered, and concentrated under reduced pressure. The residue was then purified by column chromatography (SiO2, CH2Cl2 / tetrahydrofuran = 1 / 0 to 3 / 1) to afford N-(5-iodo-8-methyl-2,7-naphthyridin-3- yl)cyclopropanecarboxamide (Intermediate 3) (51.3 g, >99 % purity).1HNMR: (400 MHz, DMSO-d6) δ 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. Intermediate Example 4: Synthesis of 5-iodo-8-methyl-2,7-naphthyridin-3-amine (Intermediate 4)

[0509]

[0426] Step 1 : To a solution of N-(8-chloro-5-iodo-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (2 g, 5.35 mmol, 1 eq) (product of Intermediate Example 3, steps 1 to 3) in tetrahydrofuran (THF) (100 mL) was added ditert-butyl propanedioate (4.86 g, 22.49 mmol, 5.03 mL, 4.2 eq) and potassium tert- butoxide (t-BuOK) (2.40 g, 21.41 mmol, 4 eq). The mixture was stirred at 25 °C for 12 h. The reaction mixture was used for next step directly.

[0510]

[0427] Step 2 : To the above reaction mixture was added HC1 (4 M, 200 mL) and the mixture was stirred at 60 °C for 4 h. The mixture was adjusted pH = 8 with solid Na2CO3, filtered and washed with ethyl acetate (EtOAc) (200 mL). The filtrate organic and aqueous phases were separated and the aqueous phase was re-extracted with ethyl acetate (100 mL x 2). The combined organic layers were combined, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (Petroleum ether / Ethyl acetate=2 / 3 to 0 / 1 and then 100% tetrahydrofuran) to give N-(5-iodo-8-methyl-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (Intermediate 3) (500 mg, 88% purity) and 5-iodo-8-methyl-2,7-naphthyridin-3-amine (Intermediate 4) (580 mg). Intermediate 4:1H NMR (400 MHz, MeOD-d4) δ 9.10 (s, 1H), 8.47 (s, 1H), 6.76 (s, 1H), 2.85 (s, 3H).

[0511] Intermediate Example 5: Synthesis of 6-chloro-1-methyl-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-2,7-naphthyridine (Intermediate 5)

[0512]

[0428] Step 1 : A mixture of Intermediate 1 (1 g, 3.88 mmol, 1 eq), 4,4,5,5-tetramethyl-2-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (1.28 g, 5.05 mmol, 1.3 eq), potassium acetate (KOAc) (1.14 g, 11.65 mmol, 3 eq) and [ 1, 1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (Pd(dppf)Cl2) (284.14 mg, 388.33 μmol, 0.1 eq) in 1,4-dioxane (10 mL) was degassed and purged with N23 times before being stirred at 90 °C for 12 hr under N2atmosphere (exemplary “Suzuki reaction conditions”; see also Farhang et al., Polyhedron (2022) 227: 116124 for other Suzuki reaction conditions). The mixture was then concentrated under reduced pressure and the crude mixture was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1 to 3 / 1) to afford 6- chloro-1-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2,7-naphthyridine (Intermediate 5) (3.5 g, 79% yield, 80% purity).1HNMR: (400 MHz, DMSO-d6) δ 9.57 (s, 1H), 8.83 (s, 1H), 8.38 (s, 1H), 3.02 (s, 3H), 1.38 (s, 12H).

[0513] Intermediate Example 6: Synthesis of N-(8-methyl-5-(trimethylstannyl)-2,7-naphthyridin-3- yl)cyclopropanecarboxamide (Intermediate 6)

[0514]

[0429] Step 1: N-(5-iodo-8-methyl-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (Intermediate 3) (200 mg, 566.32 μmol, 1 eq), trimethyl(trimethylstannyl)stannane (222.65 mg, 679.58 μmol, 140.92 μL, 1.2 eq), LiCl (24.01 mg, 566.32 μmol, 11.61 μL, 1 eq), tetrakis(triphenylphosphine)palladium (0) (Pd(PPh3)4) (65.44 mg, 56.63 μmol, 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 (EtOAc) (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 (SiCL, petroleum ether / ethyl acetate=5 / 1 to 3 / 1) to afford N-(8-methyl-5- (trimethylstannyl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (Intermediate 6) (60 mg, 27% yield).1H NMR: (400 MHz, DMSO-d6) 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).

[0515] Intermediate Example 7: Synthesis of (1R,2R)-2-fluoro-N-(5-iodo-8-methyl-2,7-naphthyridin-3- yl)cyclopropane-1-carboxamide (Intermediate 7)

[0430] Step 1 : To a solution of 5-iodo-8-methyl-2,7-naphthyridin-3-amine (Intermediate 4) (0.16 g, 561.24 μmol, 1 eq) and commercially available (1R,2R)-2-fluorocyclopropanecarboxylic acid (75.94 mg, 729.61 μmol, 1.3 eq) in pyridine (1.6 mL) and dichloromethane (DCM) (8 mL) was added POCI3(172.11 mg, 1.12 mmol, 104.63 μL, 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 mL x 3). The combined organic phases were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate=10 / l to 1 / 1) to afford (1R,2R)-2-fluoro-N-(5-iodo-8-methyl-2,7-naphthyridin-3-yl)cyclopropane-1-carboxamide (Intermediate 7) (0.1 g, 269.43 μmol, 48% yield). LCMS: (M+H+): 371.9 at 0.354 min (10-100% acetonitrile in H2O, 1 min).1HNMR: (400 MHz, DMSO-d6) 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).

[0516] Intermediate Example 8: Synthesis of (1S,2S)-2-fluoro-N-(5-iodo-8-methyl-2,7-naphthyridin-3- yl)cyclopropane-1-carboxamide (Intermediate 8)

[0517]

[0431] Step 1 : To a solution of 5-iodo-8-methyl-2,7-naphthyridin-3-amine (Intermediate 4) (0.15 g, 526.16 μmol, 1 eq) and commercially available (1S,2S)-2-fluorocyclopropanecarboxylic acid (71.19 mg, 684.01 μmol, 1.3 eq) in pyridine (1.5 mL) and dichloromethane (DCM) (7.5 mL) was added POCI3(161.35 mg, 1.05 mmol, 98.09 μL, 2 eq) at 0 °C under N2atmosphere. The mixture was stirred at

[0518] 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 / 1 to 1 / 1) to provide (1S,2S)-2-fluoro-N-(5-iodo-8- methyl-2,7-naphthyridin-3-yl)cyclopropane-1-carboxamide (Intermediate 8) (200 mg). LCMS: (M+H+): 372.1 at 0.344 min (10-100% acetonitrile in H2O, 1 min).1H NMR: (400 MHz, DMSO-d6) 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).

[0519] Intermediate Example 9: Synthesis of (1S,2R)-2-fluoro-N-(5-iodo-8-methyl-2,7-naphthyri din-3- yl)cyclopropane-1-carboxamide (Intermediate 9)

[0520]

[0432] Step 1 : To a solution of 5-iodo-8-methyl-2,7-naphthyridin-3-amine (Intermediate 4) (0.25 g, 876.94 μmol, 1 eq) and commercially available (1S,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 POCl3(269 mg, 1.75 mmol, 163.48 μL, 2 eq) at 0 °C under N2atmosphere. The mixture was stirred at

[0521] 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 (1S,2R)-2-fluoro-N-(5-iodo-8- methyl-2,7-naphthyridin-3-yl)cyclopropane-1-carboxamide (Intermediate 9) (180 mg). LCMS: (M+H+): 371.9 at 0.374 min (10-100% acetonitrile in H2O, 1 min).1H NMR: (400 MHz, DMSO-d6) 5 = 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).

[0522] Intermediate Example 10: Synthesis of (1R,2S)-2-fluoro-N-(5-iodo-8-methyl-2,7-naphthyridin-3- yl)cyclopropane-1-carboxamide (Intermediate 10)

[0523]

[0433] Step 1 : To a solution of 5-iodo-8-methyl-2,7-naphthyridin-3-amine (Intermediate 4) (0.25 g, 876.94 μmol, 1 eq) and commercially available (1R,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 POCI3(269 mg, 1.75 mmol, 163.48 μL, 2 eq) at 0 °C under N2atmosphere. The mixture was stirred at

[0524] 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 (1R,2S)-2-fluoro-N-(5-iodo-8- methyl-2,7-naphthyridin-3-yl)cyclopropane-1-carboxamide (Intermediate 10) (180 mg). LCMS: (M+H+): 371.9 at 0.380 min (10-100% acetonitrile in H2O, 1 min).

[0525] Intermediate Example 11: Synthesis of N-(5-bromo-8-(difluoromethyl)-2,7-naphthyridin-3- yl)cyclopropanecarboxamide (Intermediate 11)

[0526]

[0434] Step 1 : To a 100 mL flask equipped with a stir bar was added 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)3) (550 mg, 582 umol), 1, 1'-bis(di-tert- butylphosphino)ferrocene (dtbpf) (576 mg, 1.16 mmol) and anhydrous 1,4-dioxane (48.5 mL). The reaction mixture was degassed with nitrogen for 5 minutes before heating at 60 °C for 2h. The reaction was concentrated to 1 / 2 volume followed by the addition of water (100 mL). The mixture was filtered and the residue washed with 100 mL of heptanes to procure the crude N-(5-bromo-8-methyl-2,7- naphthyridin-3-yl)cyclopropanecarboxamide which was carried forward the next step without further purification. LCMS: m / z [M+H]+= 308.0.

[0527]

[0435] Step 2 : The crude N-(5-bromo-8-methyl-2,7-naphthyridin-3-yl)cyclopropanecarboxamide was dissolved in 1,4-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 room temperature, 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.

[0528]

[0436] Step 3 : The crude N-(5-bromo-8-formyl-2,7-naphthyridin-3-yl)cyclopropanecarboxamide was dissolved in dichloromethane (19.4 mL) and the solution was cooled to 0 °C followed by the addition of ethanol (1 drop) and (diethylamino) sulfur trifluoride (1.11 mL, 8.74 mmol) dropwise. The reaction was stirred at room temperature for 3 h. The mixture was concentrated and directly purified by normal phase chromatography (25g silica gel) eluting with a gradient of 100% heptanes to 100% of a mixture of 20% MeOH in 80% dichloromethane (DCM). Pure fractions were concentrated to give N-(5-bromo-8- (difluoromethyl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (Intermediate 11) (500 mg, 25% yield over 3 steps). LCMS: m / z [M+H]+= 344.0.

[0529] Intermediate Example 12: Synthesis of N-(5-((5-bromopyridin-2-yl)ethynyl)-8-methyl-2,7- naphthyridin-3-yl)cyclopropanecarboxamide (Intermediate 12)

[0530]

[0437] Step 1 : A mixture of commercially available 5 -bromo-2-ethynyl -pyridine (2.06 g, 11.33 mmol, 2 eq), N-(5-iodo-8-methyl-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (Intermediate 3) (2 g, 5.66 mmol, 1 eq), [1, 1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl2) (207.19 mg, 283.16 μmol, 0.05 eq), Cui (107.86 mg, 566.32 μmol, 0.1 eq) and diisopropylethylamine (3.66 g, 28.32 mmol, 4.93 mL, 5 eq) in dimethylformamide (20 mL) was degassed and purged with N23 times before being stirred at 80 °C for 2 h under N2atmosphere. The reaction mixture was diluted with H2O (20 mL), filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 0% to 100% of ethyl acetate in petroleum ether) to afford N-(5-((5-bromopyridin-2-yl)ethynyl)-8- methyl-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (Intermediate 12 ) (1.3 g, 2.24 mmol, 40% yield, 70.2% purity).1H NMR: (400MHz, DMSO-d6) δ 11.40-11.24 (m, 1H), 9.60-9.53 (m, 1H), 8.85- 8.72 (m, 3H), 8.25-8.16 (m, 1H), 7.75-7.68 (m, 1H), 2.99 (s, 3H), 2.17-2.08 (m, 1H), 0.95-0.83 (m, 4H). LCMS: m / z [M+H]+= 407.0, 409.0 at 0.425 min (10-100% acetonitrile in H2O, 1 min).

[0531] Intermediate Example 13: Synthesis of l-(6-ethynylpyridin-3-yl)-4-methylpiperazin-2-one

[0532] (Intermediate 13)

[0533]

[0438] Step 1 : To a 250 mL round-bottom flask was added 5-bromo-2-chloropyridine (5 g, 25.982 mmol, 1 equiv), 4-methylpiperazin-2-one (3.56 g, 31.178 mmol, 1.2 equiv), (1R,2R)-N1,N2- dimethylcyclohexane-l,2-diamine (0.74 g, 5.196 mmol, 0.2 equiv), Cui (0.49 g, 2.598 mmol, 0.1 equiv), K3PO4(16.55 g, 77.946 mmol, 3 equiv) and 1,4-dioxane (50 mL) at room temperature. The mixture was stirred at 100°C for 12 hours under a nitrogen atmosphere. Upon completion of the reaction, the crude mixture was concentrated under reduced pressure and the resulting crude material purified by silica gel column chromatography, eluting with a 12: 1 mixture of dichloromethane (DCM) and methanol (MeOH), to afford l-(6-chloropyridin-3-yl)-4-methylpiperazin-2-one (3.2 g, 55% yield). LCMS (ES, m / z): 226.1[M+H]+.

[0534]

[0439] Step 2 : To a 100 mL round-bottom flask was added l-(6-chloropyridin-3-yl)-4-methylpiperazin-2- one (3.2 g, 14.179 mmol, 1 equiv), trimethyl [2-(tributylstannyl)ethynyl] silane (6.59 g, 17.015 mmol, 1.2 equiv), [1, 1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (Pd(dppf)Cl2)·CH2Cl2(1.16 g, 1.418 mmol, 0.1 equiv) and 1,4-dioxane (30 mL) at room temperature. The mixture was stirred at

[0535] 100 °C for one hour under a nitrogen atmosphere. Upon completion of the reaction, the crude material was purified by silica gel column chromatography, eluting with a 12: 1 mixture of dichloromethane (DCM) and methanol (MeOH), to afford 4-methyl-1-{6-[2-(trimethylsilyl)ethynyl]pyridin-3- yl}piperazin-2-one (3 g, 74% yield). LCMS (ES, m / z): 288.1[M+H]+.

[0536]

[0440] Step 3 : To a 40 mL round-bottom flask was added 4-methyl-1-{6-[2- (trimethylsilyl)ethynyl]pyridin-3-yl}piperazin-2-one (1 g, 3.479 mmol, 1 equiv), K2CO3(0.58 g, 4.175 mmol, 1.2 equiv) and methanol (10 mL) at room temperature. The mixture was stirred at room temperature for Ih. Upon completion of the reaction, the crude mixture was concentrated under reduced pressure and the resulting crude material was purified by silica gel column chromatography, eluting with a 12: 1 mixture of dichloromethane (DCM) and methanol (MeOH), to afford l-(6-ethynylpyridin-3-yl)-4- methylpiperazin-2-one (Intermediate 13) (500 mg, 67% yield). LCMS (ES, m / z): 216.1[M+H]+.

[0537] Intermediate Example 14. Synthesis of 4-(6-((6-chloro-1-methyl-2,7-naphthyridin-4- yl)ethynyl)pyridin-3-yl)morpholine (Intermediate 14)

[0538]

[0441] Synthesis of 4-(6-((6-chloro-l -methyl -2, 7-naphthyridin-4-yl)ethynyl)pyridin-3-yl)morpholine (Intermediate 14) is described in Example 3.

[0539] Intermediate Example 15. 4-bromo-6-chloro-1-(trifluoromethyl)-2,7-naphthyridine (Intermediate

[0540]

[0442] Step 1 : To a stirred solution of 4-bromo-6-chloro-2,7-naphthyridin-1-yl trifluoromethanesulfonate (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. NaHCCf. 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.

[0541]

[0443] 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. Copper(I) iodide (155 mg, 812 umol) and methyl 2,2-difhroro-2-(fluorosulfonyl)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 ethyl acetate (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 dimethylsulfoxide (DMSO) and purified by reverse phase column (C18 using a gradient of 10% acetonitrile 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 15) (225 mg, quantitative yield).1H 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).

[0542] (ii) Final products

[0543] Example 1: Synthesis of N-(8-methyl-5-((5-morpholinopyridin-2-yl)ethynyl)-2,7-naphthyridin-3- yl)cyclopropanecarboxamide (Compound 1)

[0544]

[0444] Step 1 : To a solution of 2-bromo-5 -iodo-pyridine (1 g, 3.52 mmol, 1 eq), morpholine (368.25 mg, 4.23 mmol, 371.97 μL, 1.2 eq) and sodium tertbutoxide (tBuONa) (677.04 mg, 7.04 mmol, 2 eq) in toluene (30 mL) was added tris(dibenzylideneacetone)dipalladium(0) (Pd3(dba)3) (322.56 mg, 352.25 μmol, 0.1 eq) and 9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane (Xantphos) (203.82 mg, 352.25 μmol, 0.1 eq). The reaction was stirred at 25 °C for 12 hours under N2atmosphere. The mixture was filtered on celite and the filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (petroleum ether / ethyl acetate=10 / l to 5 / 1) to afford 4-(6-bromo-3- pyridyl)morpholine (460 mg, 47% yield, 87% purity).

[0545]

[0445] Step 2: A solution of ethynyl(trimethyl)silane (2.14 g, 21.80 mmol, 3.02 mL, 2 eq), 4-(6-bromo-3- pyridyl)morpholine (2.65 g, 10.90 mmol, 1 eq), N.N-diisopropylethylamine (7.04 g, 54.50 mmol, 9.49 mL, 5 eq), Cui (415.21 mg, 2.18 mmol, 0.2 eq) and bis(triphenylphosphine)palladium chloride (Pd(PPh3)2Cl2) (1.53 g, 2.18 mmol, 0.2 eq) in tetrahydrofuran (THF) (25 mL) was degassed and purged with N23 times before being stirred at 60 °C for 2 hours under N2atmosphere. The reaction mixture was diluted with H2O (25mL) and extracted with ethyl acetate (EtOAc) (3 x 15 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by flash silica gel chromatography (ISCO 12 g SepaFlash Silica Flash Column, Eluent of 0~7% ethyl acetate / petroleum ether, gradient at 80 mL / min) to afford trimethyl- [2-(5-morpholino-2 -pyridyl) ethynyl] silane (1.67 g, 59% yield).

[0546]

[0446] Step 3 : A solution oftrimethyl-[2-(5-morpholino-2-pyridyl)ethynyl]silane (147.47 mg, 566.32 μmol. 2 eq.), N-(5-iodo-8-methyl-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (Intermediate 3) (0.1 g, 283.16 μmol, 1 eq.), potassium benzoate (68.05 mg, 424.74 μmol, 1.5 eq.), CuCl (14.02 mg, 141.58 μmol, 3.39 μL, 0.5 eq.) and triphenylphosphine (PPh3) (22.28 mg, 84.95 μmol, 0.3 eq.) in N- methyl pyrrolidone (NMP) (2 mL) was degassed and purged with N23 times before being stirred at 80 °C for 1 hours under N2atmosphere. The mixture (combined with another 10 mg scale batch) was purified by column chromatography (SiCL, dichloromethane / methanol=l / 0 to 10 / 1), and then further purified by prep-HPLC (Waters Xbridge BEH C18 100 x 25mm x 10um; mobile phase A: H2O (10mM NH4HCO3); mobile phase B: acetonitrile; gradient: 25%-55% B over 8.0 min) to provide N-(8-methyl-5- ((5-morpholinopyridin-2-yl)ethynyl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (Compound 1) (68.9 mg).1HNMR: (400 MHz, DMSO-d6) δ 11.33 (s, 1H), 9.54 (s, 1H), 8.83 (s, 1H), 8.70 (s, 1H), 8.40 (d, J= 2.5 Hz, 1H), 7.59 (d, J= 8.6 Hz, 1H), 7.45 - 7.36 (m, 1H), 3.82 - 3.72 (m, 4H), 3.33 - 3.28 (m, 4H), 2.99 (s, 3H), 2.19 - 2.10 (m, 1H), 0.97 - 0.83 (m, 4H). LCMS: m / z [M+H]+= 414.2 at 1.903 min (5- 95% acetonitrile in H2O, 6 min).

[0547] Example 2: Synthesis of N-(5-((5-(2-oxa-5-azabicyclo [2.2.2] octan-5-yl)-3-fluoropyridin-2- yl)ethynyl)-8-methyl-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (Compound 2, rac-2), N-(5- ((5-((1S,4S)-2-oxa-5-azabicyclo[2.2.2]octan-5-yl)-3-fluoropyridin-2-yl)ethynyl)-8-methyl-2,7- naphthyridin-3-yl)cyclopropanecarboxamide (Compound 2A*) and N-(5-((5-((1R,4R)-2-oxa-5- azabicyclo[2.2.2]octan-5-yl)-3-fluoropyridin-2-yl)ethynyl)-8-methyl-2,7-naphthyridin-3- yl)cyclopropanecarboxamide (Compound 2B*)

[0548]

[0447] Step 1 : To a solution of commercially available 5 -bromo-2-chloro-3 -fluoro-pyridine (1 g, 4.75 mmol, 1 eq), 2-oxa-5-azabicyclo[2.2.2]octane (902.00 mg, 5.70 mmol, 1.2 eq, 0.5 oxalic acid) and sodium tert-butoxide (NaOtBu) (1.37 g, 14.26 mmol, 3 eq) in toluene (10 mL) was added tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)3) (87.03 mg, 95.04 μmol, 0.02 eq) and 9,9-dimethyl- 9H-xanthene-4,5-diyl)bis(diphenylphosphane (Xantphos) (164.98 mg, 285.13 μmol, 0.06 eq) in one portion under N2. The mixture was stirred at 100 °C for 3 hours, cooled to room temperature, diluted with water (25 mL) and extracted with ethyl acetate (EtOAc) (2 x 35 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by flash silica gel chromatography (ISCO; 12 g SepaFlash Silica Flash Column, eluent of 0-15% ethyl acetate / petroleum ether, gradient at 45 mL / min) to afford 5-(6-chloro-5-fluoro-3-pyridyl)-2-oxa-5- azabicyclo [2.2.2] octane (650 mg, 55% yield, 97% purity). LCMS: m / z [M+H]+= 243.0 at 0.505 min (10- 100% acetonitrile in H2O, 1 min).

[0549]

[0448] Step 2: In a sealed tube in a glovebox was combined 5-(6-chloro-5-fluoro-3-pyridyl)-2-oxa-5- azabicyclo[2.2.2]octane (650 mg, 2.68 mmol, 1 eq) and trimethyl(2-tributylstannylethynyl)silane (1.24 g, 3.21 mmol, 1.2 eq) in dimethylformamide (DMF) (6 mL), [1, 1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (Pd(dppf)Cl2)·CH2Cl2(218.73 mg, 267.85 μmol, 0.1 eq) was added to the mixture which was stirred at 110 °C for 3 hours under N2. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude material was purified by flash silica gel chromatography (ISCO; 4 g SepaFlash Silica Flash Column, eluent of 0-25% ethyl acetate / petroleum ether, gradient at 45 mL / min) to afford 2-[3-fluoro-5-(2-oxa-5- azabicyclo[2.2.2]octan-5-yl)-2-pyridyl]ethynyl-trimethyl-silane (450 mg, 52% yield, 95% purity). LCMS: m / z [M+H]+= 305.2 at 0.591 min (10-100% acetonitrile in H2O, 1 min).

[0550]

[0449] Step 3 : To a solution of 2-[3-fluoro-5-(2-oxa-5-azabicyclo[2.2.2]octan-5-yl)-2-pyridyl]ethynyl- trimethyl-silane (80 mg, 262.78 μmol, 2 eq), N-(5-iodo-8-methyl-2,7-naphthyridin-3- yl)cyclopropanecarboxamide (Intermediate 3) (46.40 mg, 131.39 μmol, 1 eq) and potassium benzoate (31.58 mg, 197.09 μmol, 1.5 eq) in dimethylimidazolidinone (1 mL) was added CuCl (6.50 mg, 65.70 μmol, 0.5 eq) and triphenylphosphine (PPh3) (10.34 mg, 39.42 μmol, 0.3 eq) in one portion under N2. The mixture was stirred at 80 °C for 1 hour under N2before being filtered on celite. The filtrate was concentrated under reduced pressure and was then purified by prep-HPLC (Waters Xbridge BEH C18 100 X 30mm X 10um; mobile phase A: H2O (10 mM NH4HCO3); mobile phase B: acetonitrile; gradient: 30%-65% B over 8.0 min) to afford N-(5-((5-(2-oxa-5-azabicyclo[2.2.2]octan-5-yl)-3- fluoropyridin-2-yl)ethynyl)-8-methyl-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (Compound 2, rac-2) (24 mg, 39% yield, 98% purity) as a mixture of two stereoisomers.1H NMR: (400 MHz, MeOD) 59.49 (s, 1H), 8.86 (s, 1H), 8.61 (s, 1H), 7.95 (s, 1H), 7.01 (dd, J = 2.3, 12.2 Hz, 1H), 4.22 - 4.02 (m, 4H), 3.91 - 3.79 (m, 1H), 3.50 (d, J = 10.8 Hz, 1H), 3.02 (s, 3H), 2.27 - 2.16 (m, 1H), 2.14 - 2.02 (m, 2H), 2.02 - 1.93 (m, 1H), 1.88 - 1.79 (m, 1H), 1.07 - 1.01 (m, 2H), 0.96 - 0.90 (m, 2H). LCMS: m / z [M+H]+= 458.2 at 2.237 min (5-95% acetonitrile in H2O, 6 min).

[0551]

[0450] Step 4: The mixture of step 3 (20 mg) was separated by SFC (ChiralPak IH, 250 X 30mm, 10um; mobile phase A: CO2; mobile phase B: methanol (0.1% NH3-H2O); B%: 40%, isocratic elution mode) to provide N-(5-((5-((1S,4S)-2-oxa-5-azabicyclo[2.2.2]octan-5-yl)-3-fluoropyridin-2-yl)ethynyl)-8-methyl- 2,7-naphthyridin-3-yl)cyclopropanecarboxamide (Compound 2A*) ( 8.5 mg, 43% yield) as the first eluting peak and N-(5 -((5 -(( lR,4R)-2-oxa-5 -azabicyclo [2.2 ,2]octan-5 -y 1) - 3 -fluoropyridin-2-yl)ethynyl)- 8-methyl-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (Compound 2B*) (8 mg, 40% yield) as the second eluting peak. * Stereochemistry arbitrarily assigned.

[0552]

[0451] Compound 2A*:1HNMR: (400 MHz, MeOD) δ 9.49 (s, 1H), 8.86 (s, 1H), 8.61 (s, 1H), 7.95 (s, 1H), 7.02 (dd, J = 2.4, 12.1 Hz, 1H), 4.19 - 4.07 (m, 4H), 3.88 - 3.82 (m, 1H), 3.53 - 3.47 (m, 1H), 3.03 - 3.00 (m, 3H), 2.26 - 2.16 (m, 1H), 2.14 - 2.02 (m, 2H), 2.01 - 1.94 (m, 1H), 1.90 - 1.79 (m, 1H), 1.07 - 1.02 (m, 2H), 0.93 (qd, J = 3.7, 7.4 Hz, 2H). LCMS: m / z [M+H]+= 458.2 at 2.250 min (5-95% acetonitrile in H2O, 6 min). SFC: >99.9 % ee at 1.642 min.

[0553]

[0452] Compound 2B*:1HNMR: (400 MHz, MeOD-d4) δ 9.49 (s, 1H), 8.86 (s, 1H), 8.61 (s, 1H), 7.95 (s, 1H), 7.06 - 6.97 (m, 1H), 4.19 - 4.05 (m, 4H), 3.88 - 3.81 (m, 1H), 3.50 (d, J = 10.0 Hz, 1H), 3.02 (s, 3H), 2.28 - 2.16 (m, 1H), 2.14 - 1.93 (m, 3H), 1.89 - 1.77 (m, 1H), 1.07 - 1.01 (m, 2H), 0.96 - 0.90 (m, 2H). LCMS: m / z [M+H]+= 458.2 at 2.248 min (5-95% acetonitrile in H2O, 6 min). SFC: 99.3% ee at 2.421 min.

[0554] Example 3: Synthesis of (1S,2S)-2-fluoro-N-(8-methyl-5-((5-morpholinopyridin-2-yl)ethynyl)-2,7- naphthyridin-3-yl)cyclopropane-1-carboxamide (Compound 3A), (1R,2S)-2-fluoro-N-(8-methyl-5- ((5-morpholinopyridin-2-yl)ethynyl)-2,7-naphthyridin-3-yl)cyclopropane-1-carboxamide (Compound 3B), (1S,2R)-2-fluoro-N-(8-methyl-5-((5-morpholinopyridin-2-yl)ethynyl)-2,7- naphthyridin-3-yl)cyclopropane-1-carboxamide (Compound 3C), and (1R,2R)-2-fluoro-N-(8- methyl-5-((5-morpholinopyridin-2-yl)ethynyl)-2,7-naphthyridin-3-yl)cyclopropane-1-carboxamide (Compound 3D)

[0555] Scheme 3A.

[0556] Scheme 3B. Scheme 3C.

[0557]

[0453] Step 1 : To a solution of 5-fluoropyridine-2-carbaldehyde (1.8 g, 14.39 mmol,

[0558] 1 eq.) and morpholine (2.51 g, 28.78 mmol, 2.53 mL, 2 eq.) in dimethylformamide (DMF) (18 mL) was added Cs2CO3(9.38 g, 28.78 mmol, 2 eq.). The mixture was stirred at 100 °C for 12 hours. The mixture (combined with another batch at 200 mg scale) was filtered through celite and the filtrate was concentrated under reduced pressure. The crude material was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=10 / l to 1 / 1) to provide 5-morpholinopyridine-2-carbaldehyde (98% purity, 1.1 g).

[0559]

[0454] Step 2: To a solution of 5-morpholinopyridine-2-carbaldehyde (1 g, 5.20 mmol, 1 eq.) and K2CO3(1.44 g, 10.41 mmol, 2 eq.) in methanol (MeOH) (10 mL) was added a solution of 1-diazo-1- dimethoxyphosphoryl-propan-2-one (1.20 g, 6.24 mmol, 1.2 eq.) in MeOH (10 mL). The mixture was stirred at 20 °C for 2 hours followed by solvent removal under reduced pressure. The crude material was diluted with water (10 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic phases were dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure to provide 4-(6- ethynyl-3-pyridyl)morpholine (800 mg, 78% yield, 96% purity).

[0560]

[0455] Step 3: To a solution of 4-(6-ethynyl-3-pyridyl)morpholine (700 mg, 3.72 mmol,

[0561] 1 eq.) in tetrahydrofuran (THF) (8 mL) was added n-butyl lithium (n-BuLi) (2.5 M, 1.79 mL, 1.2 eq.) at - 60 °C. The mixture was then stirred at -60 °C for 0.5 h followed by 0.5 h at 0 °C before being brought back to -60 °C. Tributyl(chloro)stannane (1.45 g, 4.46 mmol, 1.20 mL, 1.2 eq.) was added dropwise to the mixture at -60 °C which was then warmed up to room temp. The mixture was stirred at 20 °C for 1 hours. The reaction was quenched with ethanol (ethanol) (3 mL) and diluted with petroleum ether (50 mL). The mixture was purified directly by column chromatography (SiCL, petroleum ether / ethyl acetate = 50 / 1 to 10 / 1) to provide tributyl-[2-(5-morpholino-2-pyridyl)ethynyl]stannane (1 g, 53% yield, 94% purity).

[0562]

[0456] Step 4: Tributyl-[2-(5-morpholino-2-pyridyl)ethynyl]stannane (0.95 g, 1.99 mmol, 1.2 eq.), 4- bromo-6-chloro-1-methyl-2,7-naphthyridine (Intermediate 1) (427.15 mg, 1.66 mmol, 1 eq.) and tetrakis(triphenylphosphine)palladium(0) (Pd(PPh3)4) (191.68 mg, 165.87 μmol, 0.1 eq.) were placed in 1,4-dioxane (9.5 mL) before being stirred at 100 °C for 2 hours under N2atmosphere. The mixture (combined with another batch at 50 mg scale) was filtered through Celite and the filtrate was concentrated under reduced pressure. The crude material was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 5 / 1 to 0 / 1) to afford 4-(6-((6-chloro-1-methyl-2,7-naphthyridin-4- yl)ethynyl)pyridin-3-yl)morpholine (Intermediate 14) (300 mg, 85% purity). LCMS: m / z [M+H]+= 364.12 at 2.471 min.

[0563]

[0457] Step 5 : A solution of commercially available (1S,2S)-2-fluorocyclopropanecarboxamide (28.26 mg, 274.10 μmol, 2 eq.), Intermediate 14 (50 mg, 137.05 μmol, 1 eq.), Cs2CO3(89.31 mg, 274.10 μmol, 2 eq.), 9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane (Xantphos) (15.86 mg, 27.41 μmol, 0.2 eq.) and tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)3) (12.55 mg, 13.71 μmol, 0.1 eq.) in 1,4- dioxane (1 mL) was stirred at 120 °C for 4 hours under N2atmosphere. The mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The crude material was purified by prep- HPLC (Waters Xbridge BEH C18 100 x 30mm x 10um; mobile phase A: H2O (10mM NH4HCO3); mobile phase B: acetonitrile; gradient: 30%-60% B over 8.0 min) to afford (1S,2S)-2-fluoro-N-(8- methyl-5 -((5 -morpholinopyridin-2-yl)ethynyl)-2,7-naphthyridin-3 -yl)cyclopropane- 1 -carboxamide (Compound 3A) (6.4 mg, 10% yield, 95% purity).1HNMR: (400 MHz, CD3CN) δ 9.40 (s, 1H), 9.37 (br s, 1H), 8.80 (s, 1H), 8.67 (s, 1H), 8.33 (d, J= 2.9 Hz, 1H), 7.54 (d, J= 8.8 Hz, 1H), 7.27 (dd, J= 3.1, 8.7 Hz, 1H), 5.03 - 4.82 (m, 1H), 3.83 - 3.78 (m, 4H), 3.29 - 3.25 (m, 4H), 2.97 (s, 3H), 2.47 - 2.35 (m, 1H), 1.61 - 1.48 (m, 1H), 1.41 (qd, J= 6.5, 13.0 Hz, 1H). LCMS: m / z [M+H]+= 432.1 at 2.032 min (5- 95% acetonitrile in H2O, 6 min). SFC: >99.9 % ee at 1.279 min.

[0564]

[0458] Step 6 : A solution of commercially available (1R,2S)-2-fluorocyclopropane-1-carboxamide (28.26 mg, 274.10 μmol, 2 eq.), Intermediate 14 (50 mg, 137.05 μmol, 1 eq.), Cs2CO3(89.31 mg, 274.10 μmol, 2 eq.), 9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane (Xantphos) (15.86 mg, 27.41 μmol, 0.2 eq.) and tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)3) (12.55 mg, 13.71 μmol, 0.1 eq.) in 1,4- dioxane (1 mL) was stirred at 120 °C for 4 hours under N2atmosphere. The mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The crude material was purified by prep- HPLC (Waters Xbridge BEH C18 100 x 30mm x 10um; mobile phase A: H2O (10 mM NH4HCO3); mobile phase B: acetonitrile; gradient: 30%-60% B over 8.0 min) to afford (1R,2S)-2-fluoro-N-(8- methyl-5-((5-morpholinopyridin-2-yl)ethynyl)-2,7-naphthyridin-3-yl)cyclopropane-1-carboxamide (Compound 3B) (1.2 mg, 2.5% yield). LCMS: m / z [M+H]+= 432.2 at 2.039 min (5-95% acetonitrile in H2O, 6 min).

[0565]

[0459] Step 7: A solution of commercially available (1S,2R)-2 -fluorocyclopropane- 1 -carboxamide (28.26 mg, 274.10 μmol, 2 eq.), Intermediate 14 (50 mg, 137.05 μmol, 1 eq.), Cs2CO3(89.31 mg, 274.10 μmol, 2 eq.), 9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane (Xantphos) (15.86 mg, 27.41 μmol, 0.2 eq.) and tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)3) (12.55 mg, 13.71 μmol, 0.1 eq.) in 1,4- dioxane (1 mL) was stirred at 120 °C for 4 hours under N2atmosphere. The mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The crude material was purified by prep- HPLC (Waters Xbridge BEH C18 100 x 30mm x 10um; mobile phase A: H2O (10 mM NH4HCO3); mobile phase B: acetonitrile; gradient: 30%-60% B over 8.0 min) to afford (1S,2R)-2-fluoro-N-(8- methyl-5-((5-morpholinopyridin-2-yl)ethynyl)-2,7-naphthyridin-3-yl)cyclopropane-1-carboxamide (Compound 3C) (10.7 mg, 17% yield). LCMS: m / z [M+H]+= 432.1 at 2.038 min (5-95% acetonitrile in H2O, 6 min).

[0566]

[0460] Step 8 : A solution of commercially available (1R,2R)-2-fluorocyclopropane-l -carboxamide (28.26 mg, 274.10 μmol, 2 eq.), Intermediate 14 (50 mg, 137.05 μmol, 1 eq.), Cs2CO3(89.31 mg, 274.10 μmol, 2 eq.), 9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane (Xantphos) (15.86 mg, 27.41 μmol, 0.2 eq.) and tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)3) (12.55 mg, 13.71 μmol, 0.1 eq.) in 1,4- dioxane (1 mL) was stirred at 120 °C for 4 hours under N2atmosphere. The mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The crude material was purified by prep- HPLC (Waters Xbridge BEH C18 100 x 30mm x 10um; mobile phase A: H2O (10 mM NH4HCO3); mobile phase B: acetonitrile; gradient: 30%-60% B over 8.0 min) to afford (1R,2R)-2-fluoro-N-(8- methyl-5-((5-morpholinopyridin-2-yl)ethynyl)-2,7-naphthyridin-3-yl)cyclopropane-1-carboxamide (Compound 3D) (3.0 mg, 4.6% yield). LCMS: m / z [M+H]+= 432.2 at 2.503 min (5-95% acetonitrile in H2O, 6 min).

[0567] Example 4: Synthesis of N-(5-((5-(4-hydroxypiperidin-1-yl)pyridin-2-yl)ethynyl)-8-methyl-2,7- naphthyridin-3-yl)cyclopropanecarboxamide (Compound 4)

[0461] Step 1 : To a solution of 2-bromo-5 -iodopyridine (3 g, 10.6 mmol, 1 eq), l,4-dioxa-8- azaspiro[4.5]decane (1.51 g, 10.6 mmol, 2 eq) and sodium tert-butoxide (NaOtBu) (2.03 g, 21.1 mmol, 2 eq) in 1,4-dioxane (30 mL) was added tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)3) (967 mg, 1.06 mmol, 0.1 eq) and 9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane (Xantphos) (611 mg, 1.06 mmol, 0.1 eq). The reaction mixture was stirred at 25 °C for 1 hours under N2. The reaction mixture was concentrated under reduced pressure and crude material was purified by silica gel flash chromatography (eluent of 0-30% ethyl acetate / petroleum ether) to give 8-(6-bromopyridin-3-yl)-l,4- dioxa-8-azaspiro[4.5]decane (1.5 g, 47% yield).

[0568]

[0462] Step 2 : To a solution of 8-(6-bromopyridin-3-yl)-l,4-dioxa-8-azaspiro[4.5]decane (1.20 g, 4.01 mmol, 1 eq) in 1,4-dioxane (20 mL) was added 3N HC1 (aq) (30 mL). The reaction mixture was stirred at 25 °C for 2 hours to give a yellow solution. It was then concentrated under reduced pressure. The mixture was adjusted to pH=10 with a saturated sodium carbonate aqueous solution and extracted with ethyl acetate (EtOAc) (3 X 100 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give crude l-(6-bromopyridin-3- yl)piperidin-4-one (1.1 g) which was used directly without further purification. LCMS: m / z [M+H]+= 254.7, 256.7 at 0.298 min (5-95% acetonitrile in H2O, 0.8 min).

[0569]

[0463] Step 3: To a solution of l-(6-bromopyridin-3-yl)piperidin-4-one (1.10 g, 4.31 mmol, 1 eq) in tetrahydrofuran (THF) (10 mL) and methanol (MeOH) (2 mL) was added NaBH4(390 mg, 10.3 mmol, 2.39 eq) portionwise. The reaction mixture was stirred at 25 °C for 2 hours under N2. The reaction mixture was then quenched with water (100 mL) and extracted with CH2Cl2(2 X 100 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4. filtered, and concentrated under reduced pressure to give l-(6-bromopyridin-3-yl)piperidin-4-ol (980 mg, 88% yield), which was used directly without further purification.1H NMR: (400 MHz, CDCl3) δ 7.99 (d, J= 3.2 Hz, 1H), 7.25 (d, J= 2.4 Hz, 1H), 7.06 (dd, J= 3.2, 8.8 Hz, 1H), 3.93 -3.83 (m, 1H), 3.58 - 3.44 (m, 2H), 3.01 - 2.91 (m, 2H), 2.02 - 1.94 (m, 2H), 1.71 - 1.63 (m, 2H). LCMS: m / z [M+H]+= 256.8, 258.8 at 0.268 min (5- 95% acetonitrile in H2O, 0.8 min).

[0570]

[0464] Step 4 : To a solution of l-(6-bromopyridin-3-yl)piperidin-4-ol (830 mg, 3.23 mmol, 1 eq) and trimethyl((tributylstannyl)ethynyl)silane (1.50 g, 3.87 mmol, 1.2 eq) in 1,4-dioxane (8 mL) was added [1, 1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (Pd(dppf)Cl2)·CH2Cl2(263 mg, 322 μmol. 0.1 eq). The reaction was stirred at 100 °C for 1 hours under N2before being concentrated under reduced pressure. The crude material was purified by silica gel flash chromatography (eluent of 0-60% ethyl acetate / petroleum ether) to afford l-(6-((trimethylsilyl)ethynyl)pyridin-3-yl)piperidin-4-ol (580 mg, 65% yield).1H NMR (400 MHz, CDCl3) δ 8.25 (d, J = 2.8 Hz, 1H), 7.32 (d, J = 8.8 Hz, 1H), 7.08 (dd, J = 3.2, 8.8 Hz, 1H), 3.92 (br s, 1H), 3.67 - 3.58 (m, 2H), 3.09 - 2.98 (m, 2H), 2.07 - 1.97 (m, 2H), 1.73 - 1.63 (m, 2H), 1.58 - 1.53 (m, 1H), 0.26 (s, 9H).

[0571]

[0465] Step 5 : To a solution of l-(6-((trimethylsilyl)ethynyl)pyridin-3-yl)piperidin-4-ol (45.46 mg, 165.65 μmol. 1.3 eq), N-(5-iodo-8-methyl-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (Intermediate 3) (45 mg, 127.42 μmol, 1 eq) and potassium benzoate (30.62 mg, 191.13 μmol. 1.5 eq) in N-methyl pyrrolidone (NMP) (0.5 mL), was added triphenylphosphine (PPh3) (10.03 mg, 38.23 μmol, 0.3 eq) and CuCl (3.78 mg, 38.23 μmol. 0.3 eq). The reaction mixture was stirred at 80 °C for 1 hours before being diluted with water (15 mL) and extracted with CH2CI2(2 x 10 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by silica gel flash chromatography (eluent of 0~7% methanol / ClLCl2). then purified again by prep-HPLC (Phenomenex luna C18 150 x 25mm x 10um; mobile phase A: H2O (0.2% formic acid); mobile phase B: acetonitrile; gradient:7%-37% B over 10 min) to afford N-(5-((5-(4- hydroxypiperidin-1- yl)pyridin-2-yl)ethynyl)-8-methyl-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (Compound 4) (9.2 mg, 13% yield).1HNMR: (400 MHz, DMSO-d6) δ 11.29 (s, 1H), 9.52 (s, 1H), 8.81 (s, 1H), 8.67 (s, 1H), 8.36 (d, J = 2.8 Hz, 1H), 7.51 (d, J = 8.8 Hz, 1H), 7.37 (dd, J = 8.8, 3.2 Hz, 1H), 4.74 (br d, J = 4.0 Hz, 1H), 3.76 - 3.65 (m, 3H), 3.10 - 3.01 (m, 2H), 2.98 (s, 3H), 2.17 - 2.07 (m, 1H), 1.88 - 1.76 (m, 2H), 1.52 - 1.39 (m, 2H), 0.94 - 0.81 (m, 4H). LCMS: m / z [M+H]+= 428.2 at 1.851 min (5-95% acetonitrile in H2O, 6 min).

[0572] Example 5: Synthesis of N-(8-methyl-5-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)ethynyl)-2,7- naphthyridin-3-yl)cyclopropanecarboxamide (Compound 5)

[0573]

[0466] Step 1 : A solution of 2-bromo-5 -iodo-pyridine (5 g, 17.61 mmol, 1 eq.), 1 -methylpiperazine (1.94 g, 19.37 mmol, 2.15 mL, 1.1 eq.), sodium tert-butoxide (NaOtBu) (4.23 g, 44.03 mmol, 2.5 eq.), 9,9- dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane (Xantphos) (1.02 g, 1.76 mmol,

[0574] 0.1 eq.) and tris(dibenzylideneacetone)dipalladium(0) (Pd3(dba)3) (806.39 mg, 880.62 μmol, 0.05 eq.) in toluene (50 mL) was stirred at 60 °C for 12 hours under N2atmosphere. The mixture was filtered through celite and the filtrate was concentrated under reduced pressure. The crude material was purified by column chromatography (SiO3. petroleum ether / ethyl acetate = 10 / 1 to 0 / 1) to afford l-(6- bromo-3-pyridyl)-4-methyl-piperazine (3 g, 67% yield).

[0575]

[0467] Step 2 : To a solution of l-(6-bromo-3-pyridyl)-4-methyl -piperazine (2.9 g, 11.32 mmol,

[0576] 1 eq ), bis(triphenylphosphine)palladium chloride (Pd(PPh3)2Cl3) (794.68 mg, 1.13 mmol, 0.1 eq ), Cui (215.62 mg, 1.13 mmol, 0.1 eq.) and triethylamine (5.73 g, 56.61 mmol, 7.88 mL,

[0577] 5 eq.) in tetrahydrofuran (THF) (30 mL), was added ethynyl(trimethyl)silane (2.22 g, 22.64 mmol, 3.14 mL, 2 eq ). The mixture was stirred at 60 °C for 1 hour. The mixture (combined with another batch at 100 mg scale) was filtered through celite and the filtrate was concentrated under reduced pressure. The crude material was purified by column chromatography (SiCL, petroleum ether / ethyl acetate = 10 / 1 to 0 / 1) to afford trimethyl-[2-[5-(4-methylpiperazin-1-yl)-2-pyridyl]ethynyl]silane (2.2 g).

[0578]

[0468] Step 3 : A solution of trimethyl-[2-[5-(4-methylpiperazin-1-yl)-2-pyridyl]ethynyl]silane (600 mg, 2.19 mmol, 1.5 eq.), N-(5-iodo-8-methyl-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (Intermediate 3) (516.60 mg, 1.46 mmol, 1 eq.), potassium;benzoate (351.54 mg, 2.19 mmol, 1.5 eq.), triphenylphosphine (PPh3) (115.10 mg, 438.84 μmol, 0.3 eq.) and CuCl (43.44 mg, 438.84 μmol, 0.3 eq.) in N-methyl pyrrolidone (NMP) (6 mL) was stirred at 80 °C for 1 hours under N2atmosphere. The mixture (combined with another batch at 20 mg scale) was purified by column chromatography (SiO2, ethyl acetate / methanol = 1 / 0 to 10 / 1) to obtain impure product, which was further purified by prep-HPLC (Waters Xbridge Prep OBD C18 150 x 40mm x 10um; mobile phase A: H2O (10mM NH4HCO3); mobile phase B: acetonitrile; gradient: 25%-55% B over 8.0 min) to afford N-[8- methyl-5 - [2 - [ 5 -(4-methylpiperazin- 1 -yl)-2 -pyridyl] ethynyl] -2,7-naphthyridin-3 - yl]cyclopropanecarboxamide (Compound 5) (234.8 mg, 96% purity).1HNMR: (400 MHz, CD3CN) δ 9.38 (s, 1H), 9.27 (br s, H), 8.84 (s, 1H), 8.65 (s, 1H), 8.33 (d, J= 2.9 Hz, 1H), 7.52 (d, J= 8.8 Hz, 1H), 7.26 (dd, J= 3.0, 8.8 Hz, 1H), 3.34 - 3.28 (m, 4H), 2.96 (s, 3H), 2.53 - 2.48 (m, 4H), 2.27 (s, 3H), 1.92 - 1.87 (m, 1H), 1.03-0.99 (m, 2H), 0.94 - 0.88 (m, 2H). LCMS: m / z [M+H]+= 427.1 atl.737 min (5-95% acetonitrile in H2O, 6 min).

[0579] Example 6: Synthesis of tert-butyl 3-((6-((6-(cyclopropanecarboxamido)-1-methyl-2,7- naphthyridin-4-yl)ethynyl)pyridin-3-yl)amino)azetidine-1-carboxylate (Compound 6-Boc)

[0580]

[0469] Step 1: NaBH(OAc)3(1.47 g, 6.94 mmol, 1.2 eq) was added to the solution of 6-bromopyridin-3- amine (1 g, 5.78 mmol, 1 eq), tert-butyl 3 -oxoazetidine -1 -carboxylate (1.09 g, 6.36 mmol, 1.1 eq) and trifluoroacetic acid (1.32 g, 11.56 mmol, 858.68 μL, 2 eq) in i-PrOAc (10 mL) under N2. The reaction was stirred at 20 °C for 1 h before being quenched by the addition of H2O (20 mL) at 20 °C. The mixture was then extracted with ethyl acetate (EtOAc) (3 x 10 mL) and the combined organic layers were washed with brine (20 mL), dried over Na2SO4. filtered, and concentrated under reduced pressure. The crude material was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 3 / 1) to afford tert-butyl 3-[(6-bromo-3-pyridyl)amino]azetidine-1-carboxylate (1.8 g, 95% yield).

[0581]

[0470] Step 2: Tetrakis(triphenylphosphine)palladium(0) (Pd(PPh3)4) (633.75 mg, 548.44 μmol, 0.1 eq) was added to the mixture of tert-butyl 3-[(6-bromo-3-pyridyl)amino]azetidine-1-carboxylate (1.8 g, 5.48 mmol, 1 eq), trimethyl(2-tributylstannylethynyl)silane (2.55 g, 6.58 mmol, 1.2 eq) and Na2CO2(1.16 g, 10.97 mmol, 2 eq) in 1,4-dioxane (18 mL) under N2. The reaction was stirred at 110 °C for 2 h, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 3 / 1) to afford tert-butyl 3-((6- ((trimethylsilyl)ethynyl)pyridin-3-yl)amino) azetidine- 1 -carboxylate (1.6 g, 84% yield).

[0582]

[0471] Step 3: N-(5-iodo-8-methyl-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (Intermediate 3) (0.2 g, 566.32 μmol, 1 eq), tert-butyl 3-((6-((trimethylsilyl)ethynyl)pyridin-3-yl)amino)azetidine-1- carboxylate (234.80 mg, 679.58 μmol, 1.2 eq), potassium benzoate (136.10 mg, 849.48 μmol, 1.5 eq), CuCl (16.82 mg, 169.90 μmol, 0.3 eq) and triphenylphosphine (PPh3) (44.56 mg, 169.90 μmol, 0.3 eq) in dimethylimidazolidinone (4 mL) was stirred at 80 °C for 1 h. The reaction mixture was quenched by the addition of H2O (50 mL) at 20 °C, and then extracted with ethyl acetate (EtOAc) (3 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 5 / 1 to 0 / 1) to afford tert-butyl 3 -((6-((6-(cyclopropanecarboxamido)-1-methyl -2,7- naphthyridin-4-yl)ethynyl)pyridin-3-yl)amino)azetidine-l -carboxylate (Compound 6-Boc) (0.1 g, 35% yield).1HNMR: (400 MHz, MeOD) δ 9.47 (s, 1H), 8.88 (s, 1H), 8.59 (s, 1H), 7.94 (d, J = 2.4 Hz, 1H), 7.63 (d, J = 8.4 Hz, 1H), 7.00-6.97 (m, 1H), 4.33 (s, 3H), 3.79 (m, 2H), 3.00 (s, 3H), 2.01-1.97 (m, 1H), 1.46 (s, 9H), 1.07-1.05 (m, 2H), 0.96-0.94 (m, 2H). LCMS: m / z [M+H]+= 499.5 at 0.640 min (5-95% acetonitrile in H2O, 2 min).

[0583] Example 7: Synthesis of N-(5-((5-(azetidin-3-ylamino)pyridin-2-yl)ethynyl)-8-methyl-2,7- naphthyridin-3-yl)cyclopropanecarboxamide (Compound 6-desBoc)

[0472] Step 1 : Tert-butyl 3-((6-((6-(cyclopropanecarboxamido)-1-methyl-2,7-naphthyridin-4- yl)ethynyl)pyridin-3-yl)amino)azetidine-l -carboxylate (Compound 6-Boc, product of Example 6) (80 mg, 160.46 μmol, 1 eq) with trifluoroacetic acid (0.2 mL) and dichloromethane (2 mL) was stirred at 25 °C for 1.5 h. The reaction mixture was quenched by slow addition of a saturated aqueous solution of NaHCO3(3 mL) at 20 °C before being concentrated under reduced pressure. The crude material was diluted with tetrahydrofuran (THE) (3 mL), filtered, and concentrated under reduced pressure to provide N-(5-((5-(azetidin-3-ylamino)pyridin-2-yl)ethynyl)-8-methyl-2,7-naphthyridin-3- yl)cyclopropanecarboxamide (Compound 6-desBoc) (0.15 g).1HNMR: (400 MHz, MeOD) δ 9.48 (s, 1H), 8.89 (s, 1H), 8.59 (s, 1H), 7.97 (d, J= 2.4 Hz, 1H), 7.66 (d, J= 8.4 Hz, 1H), 7.06-7.04 (m, 1H), 4.63-4.57 (m, 1H), 4.42-4.37 (m, 2H), 4.01-3.96 (m, 2H), 3.01 (s, 3H), 2.02-1.96 (m, 1H), 1.06-0.94 (m, 4H). LCMS: m / z [M+H]+= 399.2 at 1.686 min (5-95% acetonitrile in H2O, 6 min).

[0584] Example 8: Synthesis of N-(5-((5-((1-(2,2-difluoroethyl)azetidin-3-yl)amino)pyridin-2-yl)ethynyl)-8- methyl-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (Compound 6)

[0585]

[0473] Step 1: N-(5-((5-(azetidin-3-ylamino)pyridin-2-yl)ethynyl)-8-methyl-2,7- naphthyridin-3- yl)cyclopropanecarboxamide (Compound 6-desBoc, product of Example 7) (0.15 g, 376.45 μmol, 1 eq), 2, 2-difluoroethyl trifluoromethanesulfonate (88.66 mg, 414.09 μmol, 1.1 eq) and N,N- diisopropylethylamine (243.27 mg, 1.88 mmol, 327.85 μL, 5 eq) in ethanol (ethanol) (1.5 mL) was stirred at 25 °C for 1.5 h. The reaction was the concentrated under reduced pressure and purified by prep-HPLC (Phenomenex luna C18 100 x 40 mm x 5 um; mobile phase A: H2O (0.2% formic acid); mobile phase B: acetonitrile; gradient: 10%-50% B over 8.0 min), and then further purified by prep- HPLC (Waters Xbridge BEH C18 100 x 30 mm x 10 um; mobile phase A: H2O (10 mM NH4HCO3); mobile phase B: acetonitrile; gradient: 20%-65% B over 8.0 min) to afford N-(5-((5-(( l-(2.2- difluoroethyl)azetidin-3-yl)amino)pyridin-2-yl)ethynyl)-8-methyl-2,7-naphthyridin-3- yl)cyclopropanecarboxamide (Compound 6) (5.3 mg, 3% yield).1HNMR: (400 MHz, DMSO-d6) δ 11.28 (s, 1H), 9.52 (s, 1H), 8.78 (s, 1H), 8.64 (s, 1H), 7.98 (d, J= 2.8 Hz, 1H), 7.44 (d, J= 8.4 Hz, 1H), 6.94-6.90 (m, 2H), 6.13-5.83 (m, 1H), 4.11-4.08 (m, 1H), 3.76 (t, J= 7.2 Hz, 2H), 3.06-3.03 (m, 2H), 2.97 (s, 3H), 2.90-2.81 (m, 2H), 2.13-2.10 (m, 1H), 0.91-0.86 (m, 4H). LCMS: m / z [M+H]+= 463.2 at 1.742 min (5-95% acetonitrile in H2O, 6.0 min). Example 9: Synthesis of (1S,2S)-2-fluoro-N-(8-methyl-5-((5-((S)-2-methylmorpholino)pyridin-2- yl)ethynyl)-2,7-naphthyridin-3-yl)cyclopropane-1-carboxamide (Compound 9A), (1S,2S)-2-fluoro- N-(8-methyl-5-((5-((R)-2-methylmorpholino)pyridin-2-yl)ethynyl)-2,7-naphthyridin-3- yl)cyclopropane-1-carboxamide (Compound 9B), (1R,2R)-2-fluoro-N-(8-methyl-5-((5-((S)-2- methylmorpholino)pyridin-2-yl)ethynyl)-2,7-naphthyridin-3-yl)cyclopropane-1-carboxamide (Compound 9C), and (1R,2R)-2-fluoro-N-(8-methyl-5-((5-((R)-2-methylmorpholino)pyridin-2- yl)ethynyl)-2,7-naphthyridin-3-yl)cyclopropane-1-carboxamide (Compound 9D)

[0586] Scheme 9A.

[0587] Scheme 9B.

[0588]

[0474] Step 1 : A solution of 2-bromo-5 -iodo-pyridine (3 g, 10.57 mmol, 1 eq.), (2S)-2 -methylmorpholine (1.28 g, 12.68 mmol, 1.2 eq.), tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)3) (967.68 mg, 1.06 mmol, 0.1 eq.), 9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane (Xantphos) (611.45 mg, 1.06 mmol, 0.1 eq.) and sodium tertbutoxide (tBuONa) (2.03 g, 21.13 mmol, 2 eq.) in toluene (30 mL) was degassed and purged with N2three times before being stirred at 20 °C for 6 hours under N2atmosphere. The reaction mixture was poured into H2O (50 mL) and extracted with ethyl acetate (EtOAc) (3 x 50 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to provide a residue, which was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 9 / 1) to afford (2S)-4-(6-bromo-3-pyridyl)-2 -methylmorpholine (2.2 g, 73% yield, 90% purity).

[0589]

[0475] Step 2: A solution of (2S)-4-(6-bromo-3-pyridyl)-2-methyl-morpholine (1.7 g, 6.61 mmol,

[0590] 1 eq.), ethynyl(trimethyl)silane (1.30 g, 13.22 mmol, 1.83 mL, 2 eq.), bis(triphenylphosphine) palladium chloride (Pd(PPh3)2Cl2) (928.12 mg, 1.32 mmol, 0.2 eq ), Cui (251.83 mg, 1.32 mmol,

[0591] 0.2 eq.) and triethylamine (3.35 g, 33.06 mmol, 4.60 mL, 5 eq.) in tetrahydrofuran (THF) (25 mL) was degassed and purged with N23 times. It was then stirred at 60 °C for 1 hour under N2atmosphere. The mixture (combined with another batch at 500 mg scale) was poured into H2O (50 mL) and extracted with ethyl acetate (EtOAc) (3 x 50 mL). The combined organic phases were washed with brine (2 x 50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 9 / 1) to afford trimethyl-[2-[5- |(2S)-2-methylmorpholin-4-yl ]-2-pyridyl ]ethynyl |silanc (2g, 90% purity).

[0592]

[0476] Step 3: To a solution of trimethyl-[2-[5-[(2S)-2-methylmorpholin-4-yl |-2-pyridyl |ethynyl |silanc (1.42 g, 5.17 mmol, 1 eq.) in methanol (MeOH) (28 mL) was added K2CO3(1.43 g, 10.35 mmol, 2 eq.) and the mixture was stirred at 20 °C for Ih. It was then poured into H2O (50 mL) and extracted with ethyl acetate (EtOAc) (3 x 50 mL). The combined organic layers were washed with brine (2 X 50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 1 / 1) to afford (2S)-4-(6-ethynyl-3- pyridyl)-2-methyl-morpholine (0.84 g, 80% yield).

[0593]

[0477] Step 4: A solution of (2S)-4-(6-ethynyl-3-pyridyl)-2-methyl-morpholine (56.67 mg, 280.21 μmol, 1.3 eq.), (1S,2S)-2-fluoro-N-(5-iodo-8-methyl-2,7-naphthyridin-3-yl)cyclopropane-I-carboxamide (Intermediate 8) (0.08 g, 215.55 μmol, 1 eq.), bis(triphenylphosphine)palladium chloride (Pd(PPh3)2Cl2) (30.26 mg, 43.11 μmol, 0.2 eq.), CuI (8.21 mg, 43.11 μmol, 0.2 eq.) and triethylamine (109.06 mg, 1.08 mmol, 150.01 μL, 5 eq.) in N-methyl pyrrolidone (NMP) (2 mL) was degassed and purged with N23 times before being stirred at 80 °C for 1 hour under N2atmosphere. The mixture (combined with another batch at 10 mg scale) was purified by column chromatography (SiO2, dichloromethane / methanol =

[0594] 10 / 1 to 9 / 1) and further purified by prep-HPLC (Waters Xbridge BEH C18 100 x 25mm x 10um; mobile phase A: H2O (10 mM NH4HCO3); mobile phase B: acetonitrile; gradient: 30%-60% B over 8.0 min) to afford ( 1S,2S)-2-fluoro-N-[8-methyl-5-[2-[5-[(2S)-2-methylmorpholin-4-yl ]-2- pyridyl]ethynyl]-2,7- naphthyridin-3-yl] cyclopropanecarboxamide (Compound 9A) (39.3 mg, >99% purity).1HNMR: (400 MHz, DMSO-d6) δ 11.36 (s, 1H), 9.55 (s, 1H), 8.82 (s, 1H), 8.70 (s, 1H), 8.40 (d, J= 2.7 Hz, 1H), 7.59 (d, J= 8.8 Hz, 1H), 7.41 (dd, J= 8.8, 2.8 Hz, 1H), 5.11 - 4.87 (m, 1H), 3.99 - 3.89 (m, 1H), 3.83 (br d, J = 12.0 Hz, 1H), 3.72 (br d, J= 12.5 Hz, 1H), 3.68 - 3.60 (m, 2H), 2.99 (s, 3H), 2.81 (dt, J= 3.5, 11.9 Hz, 1H), 2.50 - 2.44 (m, 1H), 2.38 - 2.30 (m, 1H), 1.79 - 1.67 (m, 1H), 1.29 - 1.20 (m, 1H), 1.18 (d, J= 6.0 Hz, 3H). LCMS: m / z [M+H]+= 446.2 at 1.968 min (5-95% acetonitrile in H2O, 6 min). SFC: >99.9% ee at 1.284 min.

[0595]

[0478] Step 5: (1R,2R)-2-fluoro-N-(8-methyl-5-((5-((S)-2-methylmorpholino)pyridin-2-yl)ethynyl)-2,7- naphthyridin-3-yl)cyclopropane-l -carboxamide (Compound 9C) was prepared following this Example but using (1R,2R)-2-fluoro-N-(5-iodo-8-methyl-2,7-naphthyridin-3-yl)cyclopropane-1-carboxamide (Intermediate 7) instead of Intermediate 8 in step 4. LCMS: m / z [M+H]+= 446.2.

[0596]

[0479] (1S,2S)-2-fluoro-N-(8-methyl-5-((5-((R)-2-methylmorpholino)pyridin-2-yl)ethynyl)-2,7- naphthyridin-3-yl)cyclopropane-l -carboxamide (Compound 9B) may be prepared following this Example but using (2R)-2 -methylmorpholine instead of (2S)-2 -methylmorpholine in step 1.

[0597]

[0480] (1R,2R)-2-fluoro-N-(8-methyl-5-((5-((R)-2-methylmorpholino)pyridin-2-yl)ethynyl)-2,7- naphthyridin-3-yl)cyclopropane-l -carboxamide (Compound 9D) may be prepared following this Example but using (2R)-2 -methylmorpholine instead of (2S)-2 -methylmorpholine in step 1 and (1R,2R)- 2-fluoro-N-(5-iodo-8-methyl-2,7-naphthyridin-3-yl)cyclopropane-1-carboxamide (Intermediate 7) instead of Intermediate 8 in step 4.

[0598] Example 10: Synthesis of N-(8-methyl-5-((5-((tetrahydro-2H-pyran-3-yl)amino)pyridin-2- yl)ethynyl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (Compound 10, rac-10), (A)-N-(8- methyl-5-((5-((tetrahydro-2H-pyran-3-yl)amino)pyridin-2-yl)ethynyl)-2,7-naphthyridin-3- yl)cyclopropanecarboxamide (Compound 10A*) and (R)-N-(8-methyl-5-((5-((tetrahydro-2H-pyran-

[0599] 3-yl)amino)pyridin-2-yl)ethynyl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (Compound

[0600] 10B*)

[0481] Step 1 : To a solution of 6-bromopyridin-3 -amine (500 mg, 2.89 mmol, 1 eq), tetrahydropyran-3- one (318.27 mg, 3.18 mmol, 1.1 eq) and trifluoroacetic acid (659.05 mg, 5.78 mmol, 429.35 μL, 2 eq) in isopropyl acetate (3 mL) was added sodium triacetoxyborohydride (1.23 g, 5.78 mmol, 2 eq). The reaction mixture was stirred at 25 °C for Ih under N2, quenched by the addition of a saturated aqueous solution of NaHCO3(50mL) and then extracted with ethyl acetate (EtOAc) (3 x 50 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 1 / 1) to give 6-bromo-N-tetrahydropyran-3-yl-pyridin-3 -amine (560 mg, 2.18 mmol, 75% yield).

[0601]

[0482] Step 2 : A solution of 6-bromo-N-tetrahydropyran-3-yl-pyridin-3 -amine (320 mg, 1.24 mmol, 1 eq), trimethyl(2-tributylstannylethynyl)silane (674.74 mg, 1.74 mmol, 1.4 eq) and [1, 1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (Pd(dppf)Cl2)·CH2Cl2(101.63 mg, 124.45 μmol, 0. 1 eq) in 1,4-dioxane (2 mL) was degassed and purged with N2three times before being stirred at 100 °C for 1 h under N2atmosphere. The reaction mixture was concentrated under reduced pressure and was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 3 / 1) to give N-tetrahydropyran-3-yl-6-(2-trimethylsilylethynyl)pyridin-3-amine (230 mg, 67% yield).

[0602]

[0483] Step 3 : A solution of N-tetrahydropyran-3-yl-6-(2-trimethylsilylethynyl)pyridin-3 -amine (140 mg, 510.14 μmol, 1.8 eq), N-(5-iodo-8-methyl-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (Intermediate 3) (100 mg, 283.16 μmol, 1 eq), potassium benzoate (45.37 mg, 283.16 μmol, 1 eq), triphenylphosphine (PPh3) (7.43 mg, 28.32 μmol, 0.1eq) and CuCl (2.80 mg, 28.32 μmol, 0.1 eq) in N- methyl pyrrolidone (NMP) (2 mL) was degassed and purged with N2three times. The mixture was then stirred at 120 °C for 0.5 hours under N2atmosphere before being quenched by slow addition of H2O (10 mL) followed by dichloromethane extraction (3 x 10 mL). The combined organic layers were washed with brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol, from 1 / 0 to 5 / 1) and repurified by prep-HPLC (CD02-Waters Xbidge BEH C18 150 x 25 x 10um; mobile phase A: H2O (0.05% NH4OH); mobile phase B: acetonitrile; gradient: 25%-55% B over 10 min) to afford N-(8-methyl-5-((5-((tetrahydro-2H-pyran-3-yl)amino)pyridin-2-yl)ethynyl)-2,7-naphthyridin-3- yl)cyclopropanecarboxamide (Compound 10, rac-10) (29.96 mg, 25% yield, 99% purity) as a mixture of two stereoisomers.1HNMR: (400 MHz, DMSO-d6) δ 11.28 (s, 1H), 9.51 (s, 1H), 8.79 (s, 1H), 8.64 (s, 1H), 8.07 (d, J= 2.4 Hz, 1H), 7.43 (d, J= 8.4 Hz, 1H), 7.03 (dd, J= 2.8, 8.4 Hz, 1H), 6.39 (d, J= 8.0 Hz, 1H), 3.85 (br dd, J= 2.8, 10.8 Hz, 1H), 3.76 - 3.68 (m, 1H), 3.53 - 3.44 (m, 1H), 3.18 (br dd, J= 8.2, 10.8 Hz, 2H), 2.97 (s, 3H), 2.17 - 2.06 (m, 1H), 2.04 - 1.94 (m, 1H), 1.79 - 1.67 (m, 1H), 1.64 - 1.43 (m, 2H), 0.97 - 0.80 (m, 4H). LCMS: m / z [M+H]+= 428.2 at 1.883 min (5-95% acetonitrile in H2O, 6 min).

[0603]

[0484] Step 4: The mixture of step 3 (29.96 mg) was separated by SFC (DAICEL CHIRALCEL OD (250mm x 30mm, 10um); mobile phase A: CO2; mobile phase B: methanol (0.1%NH4OH); B%:50%, isocratic elution mode) to afford (S)-N-(8-methyl-5-((5-((tetrahydro-2H-pyran-3-yl)amino)pyridin-2- yl)ethynyl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (Compound 10A*) (9.9 mg, 40% yield) as the 1steluting peak and (R)-N-(8-methyl-5-((5-((tetrahydro-2H-pyran-3-yl)amino)pyridin-2-yl)ethynyl)- 2,7-naphthyridin-3-yl)cyclopropanecarboxamide (Compound 10B*) (8.5 mg, 34% yield) as the 2ndeluting peak. * Stereochemistry arbitrarily assigned.

[0604]

[0485] Compound 10A*:1HNMR: (400 MHz, DMSO-d6) δ 9.47 (s, 1H), 8.88 (s, 1H), 8.58 (s, 1H), 7.99 (s, 1H), 7.60 (d, J = 8.6 Hz, 1H), 7.09 (dd, J = 2.9, 8.6 Hz, 1H), 3.96 (dd, J = 2.3, 11.2 Hz, 1H), 3.87 - 3.77 (m, 1H), 3.63 - 3.44 (m, 3H), 3.00 (s, 3H), 2.16 - 2.05 (m, 1H), 2.03 - 1.94 (m, 1H), 1.88 - 1.78 (m, 1H), 1.77 - 1.56 (m, 2H), 1.11 - 1.04 (m, 2H), 0.99 - 0.92 (m, 2H). LCMS: m / z [M+H]+= 428.2 at 1.880 min (5-95% acetonitrile in H2O, 6 min). SFC: >99.9% ee at 2.187 min.

[0605]

[0486] Compound 10B*:1HNMR: (400 MHz, DMSO-d6) δ 9.47 (s, 1H), 8.88 (s, 1H), 8.58 (s, 1H), 7.99 (d, J = 2.8 Hz, 1H), 7.59 (d, J = 8.6 Hz, 1H), 7.09 (dd, J = 2.8, 8.8 Hz, 1H), 3.96 (dd, J = 2.3, 11.2 Hz, 1H), 3.81 (m, 1H), 3.64 - 3.38 (m, 3H), 3.00 (s, 3H), 2.14 - 2.05 (m, 1H), 2.02 - 1.94 (m, 1H), 1.87 - 1.77 (m, 1H), 1.77 - 1.54 (m, 2H), 1.10 - 1.03 (m, 2H), 0.99 - 0.91 (m, 2H). LCMS m / z [M+H]+= 428.2 at 1.881 min (5-95% acetonitrile in H2O, 6 min). SFC: 99.6% ee at 2.877 min.

[0606] Example 11: Synthesis of N-(8-methyl-5-((5-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)ethynyl)-2,7- naphthyridin-3-yl)cyclopropanecarboxamide (Compound 11)

[0607]

[0487] Step 1 :To a solution of both commercially available 4-iodotetrahydropyran (1 g, 4.72 mmol, 1 eq) and (6-bromo-3-pyridyl)boronic acid (1.90 g, 9.43 mmol, 2 eq) in isopropanol (i-PrOH) (10 mL) was added (1R,2R)-2 -aminocyclohexanol (32.59 mg, 282.98 μmol, 0.06 eq) and diiodonickel (88.43 mg, 282.98 μmol, 0.06 eq) followed by sodium bix(trimethylsilyl)amide (NaHMDS) (IM in tetrahydrofuran, 9.43 mL, 2 eq) under N2. After stirring at 25 °C for 10 min, the temperature was raised to 80 °C and solution mixture stirred for 30 min. The mixture was quenched with water (20 mL) under N2and extracted with ethyl acetate (EtOAc) (20 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=l / 0 to 10 / 1) to afford 2-bromo-5-tetrahydropyran-4-yl-pyridine (200 mg, 18% yield). LCMS: (M+H+): 242.2 at 0.463 min (10-100% acetonitrile in H2O, 1 min).

[0608]

[0488] Step 2 : A mixture of 2-bromo-5-tetrahydropyran-4-yl-pyridine (180 mg, 743.46 μmol, 1 eq), trimethyl(2-tributylstannylethynyl)silane (345.50 mg, 892.15 μmol, 1.2 eq), Na2CO3(157.60 mg, 1.49 mmol, 2 eq), tetrakis(triphenylphosphine)palladium(0) (Pd(PPh3)4) (171.82 mg, 148.69 μmol, 0.2 eq) in 1,4-dioxane (2 mL) was degassed and purged with N2three times before being stirred at 100 °C for 1 hr under N2atmosphere. The reaction mixture was concentrated under reduced pressure and the residue (combined with another batch at 20 mg scale) was purified by column chromatography ( S i O2- Petroleum ether / Ethyl acetate=1 / 0 to 5 / 1) to afford trimethyl- [2-(5-tetrahydropyran-4-yl-2- pyridyl)ethynyl] silane (60 mg, 28% yield). LCMS: (M+H+): 260.1 at 0.609 min (10-100% acetonitrile in H2O, 1 min).

[0609]

[0489] Step 3 : A mixture of trimethyl-[2-(5-tetrahydropyran-4-yl-2-pyridyl)ethynyl]silane (60 mg, 231.29 μmol, 1 eq), N-(5-iodo-8-methyl-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (Intermediate 3) (81.68 mg, 231.29 μmol, 1 eq), potassium benzoate (55.58 mg, 346.93 μmol, 1.5 eq), triphenylphosphine (PPh3) (18.20 mg, 69.39 μmol, 0.3 eq) and CuCl (6.87 mg, 69.39 μmol, 0.3 eq) in l,3-dimethvl-2- imidazolidinone (DMI) ( 1 mL) was degassed and purged with N2three times before being stirred at 80 °C for 1 hr under N2atmosphere. The mixture is filtered through Celite and the solvent is removed under reduced pressure. The residue was purified by prep-HPLC (Waters Xbridge Prep OBD C18 150 x 40mm x 10um; mobile phase A: H2O (10 mM NH4HCO3); mobile phase B: acetonitrile; gradient:20%- 55% B over 8.0 min) to give N-(8-methyl-5-((5-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)ethynyl)-2,7- naphthyridin-3-yl)cyclopropanecarboxamide (Compound 11) (10.1 mg, 11% yield).1HNMR: (400 MHz, DMSO-d6) δ = 11.32 (s, 1H), 9.55 (s, 1H), 8.81 (s, 1H), 8.74 (s, 1H), 8.59 (d, J= 1.8 Hz, 1H), 7.83 (dd, J= 2.0, 8.0 Hz, 1H), 7.69 (d, J= 8.0 Hz, 1H), 3.97 (br d, J= 10.8 Hz, 2H), 3.49 - 3.42 (m, 2H), 2.99 (s, 3H), 2.95 - 2.87 (m, 1H), 2.17 - 2.08 (m, 1H), 1.80 - 1.68 (m, 4H), 0.94 - 0.83 (m, 4H). LCMS: (M+H+): 413.2 at 2.089 min (5-95% acetonitrile in H2O, 6 min).

[0610] Example 12: Synthesis of (R)-N-(5-((5-(2,4-dimethylpiperazin-1-yl)pyridin-2-yl)ethynyl)-8-methyl- 2,7-naphthyridin-3-yl)cyclopropanecarboxamide (Compound 12A) and (S)-N-(5-((5-(2,4- dimethylpiperazin-1-yl)pyridin-2-yl)ethynyl)-8-methyl-2,7-naphthyridin-3- yl)cyclopropanecarboxamide (Compound 12B)

[0611]

[0490] (R)-N-(5-((5-(2,4-dimethylpiperazin-1-yl)pyridin-2-yl)ethynyl)-8-methyl-2,7-naphthyridin-3- yl)cyclopropanecarboxamide (Compound 12A) was synthesized following Example 5, steps 1 to 3, using commercially available (R)-l,3-dimethylpiperazine (201.11 mg, 1.76 mmol, 1 eq), as the starting material instead of 1 -methylpiperazine. The final product was purified by prep-HPLC (Waters Xbridge Prep OBD C18 150 x 40mm x 10um; mobile phase A: H2O (10 mM NH4HCO3); mobile phase B: acetonitrile; gradient:25%-55% B over 8.0 min) (37.3 mg, 98.55% purity).1H NMR: (400 MHz, DMSO- d6) δ = 11.30 (s, 1H), 9.52 (s, 1H), 8.81 (s, 1H), 8.67 (s, 1H), 8.31 (d, J = 2.9 Hz, 1H), 7.53 (d, J = 8.8 Hz, 1H), 7.32 (dd, J = 2.9, 8.8 Hz, 1H), 4.27 - 4.16 (m, 1H), 3.55 (br d, J = 12.4 Hz, 1H), 3.04 (dt, J = 3.4, 12.1 Hz, 1H), 2.97 (s, 3H), 2.90 - 2.81 (m, 1H), 2.70 (br d, J = 11.0 Hz, 1H), 2.24 - 2.17 (m, 4H), 2.16 - 2.08 (m, 1H), 2.01 (dt, J = 3.5, 11.5 Hz, 1H), 1.11 (d, J = 6.5 Hz, 3H), 0.94 - 0.82 (m, 4H) LCMS: (M+H+): 441.2 at 1.620 min (5-95% acetonitrile in H2O, 6 min). SFC: >99.9% ee at 1.598 min.

[0612]

[0491] (S)-N-(5-((5-(2,4-dimethylpiperazin-1-yl)pyridin-2-yl)ethynyl)-8-methyl-2,7-naphthyridin-3- yl)cyclopropanecarboxamide (Compound 12B) may be prepared following Example 12 but using (S)- 1,3 -dimethylpiperazine instead of (R)-l,3-dimethylpiperazine.

[0613] Example 13: Synthesis of (R)-N-(5-((5-(3,4-dimethylpiperazin-1-yl)pyridin-2-yl)ethynyl)-8-methyl- 2,7-naphthyridin-3-yl)cyclopropanecarboxamide (Compound 13A) and (S)-N-(5-((5-(3,4- dimethylpiperazin-1-yl)pyridin-2-yl)ethynyl)-8-methyl-2,7-naphthyridin-3- yl)cyclopropanecarboxamide (Compound 13B)

[0614]

[0492] (R)-N-(5-((5-(3,4-dimethylpiperazin-1-yl)pyridin-2-yl)ethynyl)-8-methyl-2,7-naphthyridin-3- yl)cyclopropanecarboxamide (Compound 13A) was synthesized following Example 5, steps 1 to 3, using commercially available (R)-l,2-dimethylpiperazine (201.11 mg, 1.76 mmol, 1 eq) as the starting material instead of 1 -methylpiperazine. Final product was purified by prep-HPLC (Waters Xbridge Prep OBD C18 150 x 40mm x 10um; mobile phase A: H2O (10 mM NH4HCO3); mobile phase B: acetonitrile; gradient: 25%-55% B over 8.0 min) to provide N-[5-[2-[5-[(3R)-3,4-dimethylpiperazin-1-yl]-2- pyridyl]ethynyl]-8-methyl-2,7-naphthyridin-3-yl]cyclopropanecarboxamide (19.4 mg, 99.8% purity).1H NMR: (400 MHz, DMSO-d6) δ = 11.30 (s, 1H), 9.53 (d, J = 0.6 Hz, 1H), 8.81 (s, 1H), 8.67 (s, 1H), 8.37 (d, J = 2.9 Hz, 1H), 7.54 (d, J = 8.8 Hz, 1H), 7.38 (dd, J = 3.0, 8.9 Hz, 1H), 3.82 - 3.68 (m, 2H), 2.98 (s, 3H), 2.93 - 2.87 (m, 1H), 2.87 - 2.80 (m, 1H), 2.54-2.50 (m, 1H), 2.27 - 2.17 (m, 4H), 2.17 - 2.07 (m, 2H), 1.06 (d, J = 6.1 Hz, 3H), 0.96 - 0.80 (m, 4H). LCMS: (M+H+): 441.2 at 1.606 min (5-95% acetonitrile in H2O, 6 min). SFC 100% ee at 1.091 min.

[0615]

[0493] (S)-N-(5-((5-(3,4-dimethylpiperazin-1-yl)pyridin-2-yl)ethynyl)-8-methyl-2,7-naphthyridin-3- yl)cyclopropanecarboxamide (Compound 13B) may be prepared following Example 13 but using (S)- 1,3 -dimethylpiperazine instead of (R)-l,3-dimethylpiperazine.

[0616] Example 14: Synthesis of N-(8-(difluoromethyl)-5-((5-morpholinopyridin-2-yl)ethynyl)-2,7- naphthyridin-3-yl)cyclopropanecarboxamide (Compound 14)

[0617]

[0494] Step 1 : The mixture of commercially available 2-bromo-5 -iodopyridine (150 mg, 528 umol, 1 equiv), morpholine (56.0 uL, 634 umol, 1.2 equiv), 9,9-dimethyl-9H-xanthene-4,5- diyl)bis(diphenylphosphane (Xantphos) (31.2 mg, 52.8 umol, 10 mol%), tris(dibenzylideneacetone)- dipalladium(O) (16.2 mg, 17.2 umol, 3.25 mol%), sodium tert-butoxide (131 mg, 1.32 mmol, 2.5 equiv) and toluene (4.23 mL) was degassed with nitrogen for 5 mins before stirring at room temperature for 4 h. After completion, the reaction was quenched with water (1 mL), concentrated, and directly purified by normal phase chromatography (25g silica gel column) eluting with a gradient of 0-100% ethyl acetate (EtOAc) in heptanes. Pure fractions were concentrated to provide to give 4-(6-bromopyridin-3- yl)morpholine (102 mg, 79 % yield). LCMS: m / z [M+H]+= 245.0, RT = 0.84 min.

[0618]

[0495] Step 2: The mixture of 4-(6-bromopyridin-3-yl)morpholine (102 mg, 420 umol, 1 equiv), Cui (8.03 mg, 42.0 umol), [1, 1'-bis(dipbenylphosphino)ferrocene]paJiadium(II) dichloride (Pd(dppf)Cl2) (15.7 mg, 21.0 umol, 5 mol%), triethyl amine (Et3N) (168 uL) in dimethylformamide (DMF) (671 uL) was purged then backfilled with nitrogen. (Trimethylsilyl)acetylene (174 uL, 1.26 mmol, 3 equiv) was added and the resulting mixture was stirred at 60 °C overnight. The reaction mixture was filtered through Celite and ethyl acetate (EtOAc) (3x15 mL) was used to wash the cake. The organic phases were combined and concentrated to give a black oil. The crude product was dissolved in tetrahydrofuran (THF) (4.20 mL) and trimethylammonium fluoride (TMAF) (80.6 mg, 839 umol, 2 equiv) was added. The mixture was stirred for 30 minutes at room temperature, concentrated under reduced pressure and purified using a silica gel flash chromatography (25g) and a elution of 0 to 100% ethyl acetate in heptanes. Pure fractions were concentrated to provide 4-(6-ethynylpyridin-3-yl)morpholine (33.0 mg, 42 % yield). LCMS: [M+H]+= 189.2, RT = 0.90 min.

[0619]

[0496] Step 3: The mixture of 4-bromo-6-chloro-1-(difluoromethyl)-2,7-naphthyridine (Intermediate 2) (35.0 mg, 119 umol, 1 equiv), [l,I'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (Pd(dppf)Cl2) (8.90 mg, 11.9 umol, 10 mol%), 4-(6-ethynylpyridin-3-yl)morpholine (29.2 mg, 155 umol, 1.3 equiv), Cui (4.54 mg, 23.9 umol, 20 mol%), triethylamine (Et3N) (239 uL) and dimethylformamide (DMF) (954 uL) was degassed by nitrogen gas for 5 mins before heating to 90 °C overnight. The reaction was concentrated under reduced pressure and directly purified by normal phase chromatography (25g silica gel column) eluting with a gradient of 5-100% ethyl acetate in heptanes. Pure fractions were concentrated to provide 4-(6-((6-chloro-1-(difluoromethyl)-2,7-naphthyridin-4- yl)ethynyl)pyridin-3-yl)morpholine (17.0 mg, 36 % yield). LCMS: m / z [M+H]+= 401.1, RT = 1.29 min.

[0620]

[0497] Step 4 : The mixture of [(2-di-cyclohexylphosphino-3,6-dimethoxy-2',4',6'- triisopropyl- 1,1'- biphenyl)-2-(2'-amino-1, 1' -biphenyl)]palladium(II) methanesulfonate (BrettPhos Pd G3) (3.84 mg, 4.24 umol, 10 mol%), 2-(di-tert-butylphosphino)-2',4',6'- triisopropyl-3,6-dimethoxy- 1,1 '-biphenyl (t- butylBrettPhos) (6.36 mg, 12.7 umol, 30 mol%), 4-(6-((6-chloro-1-(difluoromethyl)-2,7-naphthyridin-4- yl)ethynyl)pyridin-3-yl)morpholine (17.0 mg, 42.4 umol, 1 equiv), cesium carbonate (42.3 mg, 127 umol, 3 equiv), cyclopropanecarboxamide (18.0 mg, 212 umol, 5 equiv) and anhydrous degassed 1,4- dioxane (699 uL) was heated to 70 °C for 2h. The reaction was directly purified by reverse phase flash chromatography (12 g C18 column), eluting with a gradient of 5-100% acetonitrile in ammonium formate (AMF). Pure fractions were lyophilized to afford N-(8-(difluoromethyl)-5-((5- morpholinopyridin-2-yl)ethynyl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (Compound 14) (3.20 mg, 17% yield). LCMS: m / z [M+H]+= 450.3, RT = 1.49 min.1H NMR (400 MHz, DMSO-d6) 11.48 (s, 1H), 9.63 (s, 1H), 8.95 (s, 1H), 8.90 (s, 1H), 8.41 (d, J = 2.7 Hz, 1H), 7.71 - 7.39 (m, 3H), 3.87 - 3.67 (m, 4H), 3. 42 - 3.28 (m, 4 H, overlap by water peak), 2.22 - 1.97 (m, 1H), 1.03 - 0.79 (m, 4H).

[0621] Example 15: Synthesis of N-(8-methyl-5-((4-morpholino-5-((tetrahydrofuran-3-yl)amino)pyridin-

[0622] 2-yl)ethynyl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (Compound 20, rac-20), (R)-N-(8- methyl-5-((4-morpholino-5-((tetrahydrofuran-3-yl)amino)pyridin-2-yl)ethynyl)-2,7-naphthyridin-

[0623] 3-yl)cyclopropanecarboxamide (Compound 20B*) and (S)-N-(8-methyl-5-((4-morpholino-5-

[0624] ((tetrahydrofuran-3-yl)amino)pyridin-2-yl)ethynyl)-2,7-naphthyridin-3- yl)cyclopropanecarboxamide (Compound 20A*)

[0625]

[0498] Step 1 : Amixture of 2, 4-dibromo-5 -nitro-pyridine (500 mg, 1.77 mmol, 1 eq), morpholine (169.98 mg, 1.95 mmol, 171.70 μL, 1.1 eq) and triethylamine (TEA) (179.48 mg, 1.77 mmol, 246.88 μL, 1 eq) in tetrahydrofuran (THF) (5 mL) was degassed and purged with N23 times before being stirred at 20 °C for 4 hr under N2atmosphere. To the mixture was added water (5 mL) and the mixture was extracted with ethyl acetate (10 mLx 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (ISCO; 4 g SepaFlash Silica Flash Column, Eluent of 0-10% Ethyl acetate / Petroleum ether gradient at 75 mL / min) to afford 4- (2-bromo-5-nitro-4-pyridyl)morpholine (420 mg, 71% yield, 86% purity).

[0626]

[0499] Step 2: To a solution of 4-(2-bromo-5-nitro-4-pyridyl)morpholine (400 mg, 1.39 mmol, 1 eq) in ethanol (ethanol) (4 mL) and sat.aqueous NH4CI (0.8 mL) was added Fe (387.68 mg, 6.94 mmol, 5 eq). The mixture was stirred at 80 °C for 1 hr and once cooled down to room temperature, the mixture was filtered through celite. The filtrate was evaporated under reduced pressure and the residue was purified by silica gel flash chromatography (ISCO; 4 g SepaFlash Silica Flash Column, Eluent of 0-20% Ethyl acetate / Petroleum ether gradient at 75 mL / min) to afford 6-bromo-4-morpholino-pyridin-3 -amine (260 mg, 72% yield, 96% purity).

[0627]

[0500] Step 3 : To a solution of 6-bromo-4-morpholino-pyridin-3 -amine (240 mg, 929.82 μmol, 1 eq) and tetrahydrofuran-3-one (160.09 mg, 1.86 mmol, 2 eq) in isopropyl acetate (3.5 mL) was added trifluoroacetic acid (trifluoroacetic acid) (212.04 mg, 1.86 mmol, 138.14 μL, 2 eq). The mixture was stirred at 20°C for 0.5 hr and then was added NaBH(OAc)3(236.48 mg, 1. 12 mmol, 1.2 eq) to the mixture. It was stirred at 20 °C for 12 hr before being quenched with water (5 mL) and extracted with ethyl acetate (EtOAc) (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (Petroleum ether / Ethyl acetate =5 / 1 to 3 / 1) to afford 6-bromo-4-morpholino-N-tetrahydrofuran-3-yl-pyridin-3-amine (280 mg, 80% yield, 87% purity).

[0628]

[0501] Step 4: A mixture of 6-bromo-4-morpholino-N-tetrahydrofuran-3-yl-pyridin-3-amine (250 mg, 761.72 μmol, 1 eq), trimethyl(2-tributylstannylethynyl)silane (324.48 mg, 837.89 μmol, 1.1 eq), [1, 1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (Pd(dppf)Cl2) (55.74 mg, 76.17 μmol, 0.1 eq) and Na2CO3(161.47 mg, 1.52 mmol, 2 eq) in 1,4-dioxane (2.5 mL) was degassed and purged with N23 times before being stirred at 110 °C for 2 hr under N2atmosphere. The residue was purified by silica gel flash chromatography (ISCO; 4 g SepaFlash Silica Flash Column, Eluent of 0-20% Ethyl acetate / Petroleum ether gradient at 75 mL / min) to afford 4-morpholino-N-tetrahydrofuran-3-yl-6-(2- trimethylsilylethynyl)pyridin-3-amine (140 mg, 52% yield, 98% purity).

[0629]

[0502] Step 5 : A mixture of N-(5-iodo-8-methyl-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (Intermediate 3) (80 mg, 226.53 μmol, 1 eq), 4-morpholino-N-tetrahydrofuran-3-yl-6-(2- trimethylsilylethynyl) pyridin-3 -amine (93.92 mg, 271.83 μmol, 1.2 eq), potassium benzoate (36.29 mg, 226.53 μmol, 1 eq), CuCl (6.73 mg, 67.96 μmol, 0.3 eq), Cui (4.31 mg, 22.65 μmol, 0.1 eq), bis(triphenylphosphine)palladium chloride (Pd(PPh3)2Cl2) (15.90 mg, 22.65 μmol, 0.1 eq), triethylamine (TEA) (114.61 mg, 1.13 mmol, 157.65 μL, 5 eq) and triphenylphosphine (PPI13) (17.82 mg, 67.96 μmol, 0.3 eq) in N-methyl pyrrolidone (NMP) (0.8 mL) was degassed and purged with N23 times before being stirred at 80 °C for 3 hr under N2atmosphere. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by prep-HPLC (Waters xbridge 150 x 25mm 10um; mobile phase A: H2O (10mM NH2HCO3); mobile phase B: acetonitrile; gradient: 35 %-65% B over 8.0 min) to afford N-(8-methyl-5-((4-morpholino-5-((tetrahydrofuran-3-yl)amino)pyridin-2- yl)ethynyl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (Compound 20, rac-20) (42.6 mg, 37% yield, 98% purity) as a mixture of 2 stereoisomers LCMS: (M+H+): 499.2 at 1.963 min (5-95% acetonitrile in H2O, 6 min).

[0630]

[0503] Step 6: The mixture from Step 5 (42.6 mg) was separated by SFC (DAICEL CHIRALCEL OX (250mm x 30mm, 10um); mobile phase A: CO2; mobile phase B: ethanol(0.1% NH3H2O); B%:60%, isocratic elution mode) to afford (R)-N-(8-methyl-5-((4-morpholino-5-((tetrahydrofuran-3- yl)amino)pyridin-2-yl)ethynyl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (Compound 20B*) (7.3 mg, 18% yield, 99% purity) as the 1steluting peak and (S)-N-(8-methyl-5-((4- morpholino-5- ((tetrahydrofuran-3-yl)amino)pyridin-2-yl)ethynyl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (Compound 20A*) (7.6 mg, 18% yield, 96% purity) as the second eluting peak. * Stereochemistry arbitrarily assigned.

[0631]

[0504] Compound 20A*:1H NMR: (400 MHz, DMSO-d6) δ = 11.37 (s, 1H), 9.53 (s, 1H), 8.97 (s, 1H), 8.65 (s, 1H), 7.97 (s, 1H), 7.38 (s, 1H), 5.04 (d, J = 6.6 Hz, 1H), 4.30 - 4.14 (m, 1H), 3.93 (dd, J = 5.9, 8.9 Hz, 1H), 3.90 - 3.71 (m, 6H), 3.66-3.63 (m, 1H), 3.08 - 2.89 (m, 7H), 2.33 - 2.21 (m, 1H), 2.19 - 2.06 (m, 1H), 1.95 - 1.79 (m, 1H), 0.95 - 0.85 (m, 4H). LCMS: (M+H+): 499.2 at 1.951 min (5-95%aceonitrile in H2O, 6 min). SFC: 99.30% ee at 1.999 min.

[0632]

[0505] Compound 20B*:1H NMR: (400 MHz, DMSO-d6) δ = 11.35 (s, 1H), 9.52 (s, 1H), 8.97 (s, 1H), 8.65 (s, 1H), 7.97 (s, 1H), 7.38 (s, 1H), 5.03 (d, J = 6.6 Hz, 1H), 4.41-4.22 (m, 1H), 3.96-3.92 (m, 1H), 3.90 - 3.78 (m, 5H), 3.78 - 3.72 (m, 1H), 3.68 1-3.64 (m, 1H), 3.07 - 2.89 (m, 7H), 2.33 - 2.22 (m, 1H), 2.19 - 2.09 (m, 1H), 1.94 - 1.82 (m, 1H), 0.96 - 0.84 (m, 4H). LCMS: (M+H+): 499.2 at 2.954 min (5- 95% acetonitrile in H2O, 6 min). SFC: 100% ee at 1.435 min.

[0633] Example 16: Synthesis of -(5-((4-(dimethylamino)-5-((tetrahydrofuran-3-yl)amino)pyridin-2- yl)ethynyl)-8-methyl-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (Compound 21, rac-21), (R)-N-(5-((4-(dimethylamino)-5-((tetrahydrofuran-3-yl)amino)pyridin-2-yl)ethynyl)-8-methyl-2,7- naphthyridin-3-yl)cyclopropanecarboxamide (Compound 21B*) and (S)-N-(5-((4- (dimethylamino)-5-((tetrahydrofuran-3-yl)amino)pyridin-2-yl)ethynyl)-8-methyl-2,7- naphthyridin-3-yl)cyclopropanecarboxamide (Compound 21A*)

[0634]

[0635]

[0506] Steps 1-5: N-(5-((4-(dimethylamino)-5-((tetrahydrofuran-3-yl)amino)pyridin-2-yl)ethynyl)-8- methyl-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (Compound 21, rac-21) (40 mg) was synthesized as a mixture of two stereoisomers following Example 15, steps 1 to 5, using Me2NH.HCl (376.06 mg, 1.3 eq) as the starting material instead of morpholine.

[0636]

[0507] Step 6: The mixture from step 5 was separated by SFC (DAICEL CHIRALCEL OX (250mm x 30mm, 10um); mobile phase A: CO2; mobile phase B: ethanol; B%: 50%, isocratic elution mode) to afford (R)-N-(5-((4-(dimethylamino)-5-((tetrahydrofuran-3-yl)amino)pyridin-2-yl)ethynyl)- 8-methyl- 2,7-naphthyridin-3-yl)cyclopropanecarboxamide (Compound 21B*) (12.0 mg, 30% yield, 99.6% purity) as the 1steluting peak and (S)-N-(5-((4-(dimethylamino)-5- ((tetrahydrofuran-3- yl)amino)pyridin-2-yl)ethynyl)-8-methyl-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (Compound 21 A*) (8.6 mg, 22% yield, 98.9% purity) as the 2ndeluting peak. * Stereochemistry arbitrarily assigned.

[0637]

[0508] Compound 21A*:1H NMR: (400 MHz, DMSO-d6) δ = 11.35 (s, 1H), 9.52 (s, 1H), 8.95 (s, 1H), 8.65 (s, 1H), 7.91 (s, 1H), 7.32 (s, 1H), 5.19 (d, J=6.7 Hz, 1H), 4.27 - 4.15 (m, 1H), 3.95 - 3.85 (m, 2H), 3.77 - 3.72 (m, 1H), 3.70 - 3.64 (m, 1H), 2.97 (s, 3H), 2.71 (s, 6H), 2.27 - 2.22 (m, 1H), 2.15 -2.11 (s, 1H), 1.95 - 1.88 (m, 1H), 0.93 - 0.85 (m, 4H). LCMS: (M+H+): 457.2 at 1.986 min (5-95% acetonitrile in H2O, 6.0 min). SFC: 98.44% ee at 1.640 min.

[0638]

[0509] Compound 21B*:1H NMR: (400 MHz, DMSO-d6) δ = 11.32 (s, 1H), 9.52 (s, 1H), 8.94 (s, 1H), 8.64 (s, 1H), 7.91 (s, 1H), 7.32 (s, 1H), 5.16 (d, J=6.4 Hz, 1H), 4.21 (s, 1H), 3.95 - 3.85 (m, 2H), 3.77 - 3.72 (m, 1H), 3.67 - 3.64 (m, 1H), 2.97 (s, 3H), 2.71 (s, 6H), 2.25 - 2.23 (m, 1H), 2.14 -2.13 (s, 1H), 1.97 - 1.86 (m, 1H), 0.99 - 0.84 (m, 4H). LCMS: (M+H+): 457.2 at 1.989 min (5-95% acetonitrile in H2O, 6.0 min). SFC: 99.40% ee at 1.274 min.

[0639] Example 17: Synthesis of tert-butyl 3-((6-((6-(cyclopropanecarboxamido)-1-methyl-2,7- naphthyridin-4-yl)ethynyl)pyridin-3-yl)oxy)pyrrolidine-1-carboxylate (Compound 22-Boc), N-(8- methyl-5-((5-(pyrrolidin-3-yloxy)pyridin-2-yl)ethynyl)-2,7-naphthyridin-3- yl)cyclopropanecarboxamide (Compound 22-desMe), N-(8-methyl-5-((5-((1-methylpyrrolidin-3- yl)oxy)pyridin-2-yl)ethynyl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (Compound 22, rac-22), (R)-N-(8-methyl-5-((5-((1-methylpyrrolidin-3-yl)oxy)pyridin-2-yl)ethynyl)-2,7- naphthyridin-3-yl)cyclopropanecarboxamide (Compound 22B*) and (S)-N-(8-methyl-5-((5-((1- methylpyrrolidin-3-yl)oxy)pyridin-2-yl)ethynyl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide

[0640] (Compound 22A*)

[0641]

[0510] Step 1 : To a mixture of commercially available tert-butyl 3 -iodopyrrolidine- 1 -carboxylate (10 g, 33.66 mmol, 1 eq) and 6-bromopyridin-3-ol (7.03 g, 40.39 mmol, 1.2 eq) in dimethylformamide (DMF) (80 mL) was added Cs2CO3(21.93 g, 67.31 mmol, 2 eq) in one portion under N2. The mixture was stirred at 80 °C for 12 h before being filtered and concentrated in vacuum. The residue was purified by silica gel flash chromatography (ISCO; 20g SepaFlash Silica Flash Column, Eluent of 0-100% Ethyl acetate / Petroleum ethergradient at 100 mL / min) to afford tert-butyl 3-[(6-bromo-3- pyridyl)oxy]pyrrolidine- 1 -carboxylate (10 g, 43% yield).

[0642]

[0511] Step 2 : To a mixture of tert-butyl 3-[(6-bromo-3-pyridyl)oxy]pyrrolidine-1-carboxylate (5 g, 14.57 mmol, 1 eq) and trimethyl(2-tributylstannylethynyl)silane (5.08 g, 13.11 mmol, 0.9 eq) in 1,4- dioxane (50 mL) was added Na2CO3(3.09 g, 29. 14 mmol, 2 eq) and tetrakis(triphenylphosphine)palladium (0) (Pd(PPh3)4) (1.68 g, 1.46 mmol, 0.1 eq) in one portion under N2. The mixture was stirred at 100 °C for 1 h before being filtered and concentrated in vacuum. The residue was purified by silica gel flash chromatography (ISCO; 12 g SepaFlash Silica Flash Column, Eluent of 0-5% Ethyl acetate / Petroleum ethergradient at 100 mL / min) to provide tert-butyl 3- ((6-((trimethylsilyl)ethynyl)pyridin-3-yl)oxy)pyrrolidine-1-carboxylate (760 mg, 36% yield, 95% purity).

[0643]

[0512] Step 3 : To a mixture N-(5-iodo-8-methyl-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (Intermediate 3) (100 mg, 283.16 μmol, 1 eq) and tert-butyl 3-[[6-(2-trimethylsilylethynyl)-3- pyridyl]oxy] pyrrolidine -1 -carboxylate (153.13 mg, 424.74 μmol, 1.5 eq) in N-methyl pyrrolidone (NMP) (1 mL) was added potassium benzoate (68.05 mg, 424.74 μmol, 1.5 eq), triphenylphosphine (PPh3) (22.28 mg, 84.95 μmol, 0.3 eq) and CuCl (8.41 mg, 84.95 μmol, 0.3 eq) in one portion under N2. The mixture was stirred at 80 °C for 1 h before being filtered and concentrated in vacuum. The residue was purified by prep-HPLC (Waters Xbridge BEH C18 100 x 30mm x 10um; mobile phase A: H2O (10mM NH4HCO3); mobile phase B: acetonitrile; gradient: 35 %-65% B over 8.0 min) to afford tertbutyl 3-((6-((6-(cyclopropanecarboxamido)-1-methyl-2,7-naphthyridin-4-yl)ethynyl)pyridin-3- yl)oxy)pyrrolidine- 1 -carboxylate (Compound 22-Boc) (90 mg, 62% yield, 100% purity). LCMS: (M+H+): 514.3 at 2.457 min (5-95% acetonitrile in H2O, 6 min).

[0644]

[0513] Step 4 : A mixture of Compound 22-Boc of step 3 (100 mg, 194.71 μmol, 1 eq) in formic acid (2 mL) was stirred at 60 °C for 1 h. The mixture was concentrated in vacuum to provide N-(8-methyl-5- ((5-(pyrrolidin-3-yloxy)pyridin-2-yl)ethynyl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (Compound 22-desMe), which was used for next step without purification. LCMS: (M+H+): 414. 1 at 1.833 min (5-95% acetonitrile in H2O, 6 min).

[0645]

[0514] Step 5: To a mixture of Compound 22-desMe (50 mg) and NaBH(OAc)3(57.66 mg, 272.04 μmol, 2.5 eq) in dichloromethane (DCM) (0.5 mL) was added HCHO (44.15 mg, 544.07 μmol, 40.51 μL, 37% purity in H2O, 5 eq) in one portion under N2. The mixture was stirred at 25 °C for 2 h and the mixture (combined with another batch at 20 mg scale-up) was quenched with water (2 mL) and concentrated under pressure. The residue was purified by prep-HPLC (Waters Xbridge BEH C18 100 x 30mm x 10um; mobile phase A: H2O (10mM NH4HCO3); mobile phase B: acetonitrile; gradient: 25%- 55% B over 8.0 min) to afford compound N-(8-methyl-5-((5-((1-methylpyrrolidin-3-yl)oxy)pyridin-2- yl)ethynyl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (Compound 22, rac-22) (41.1 mg, 97% purity), as a mixture of two stereoisomers.1H NMR: (400 MHz, MeOD-d4) δ = 9.49 (s, 1H), 8.89 (s, 1H), 8.63 (s, 1H), 8.26 (br s, 1H), 7.80 (d, J = 8.5 Hz,lH), 7.46 (dd, J = 2.8, 8.7 Hz, 1H), 5.09 - 5.04 (m, 1H), 3.01 (s, 3H), 2.96 - 2.83 (m, 3H), 2.52 - 2.39 (m, 5H), 2.06 - 1.95 (m, 2H), 1.08 - 1.02 (m, 2H), 0.99 - 0.92 (m, 2H). LCMS: (M+H+): 428.2 at 2.488 min (5-95% acetonitrile in H2O, 6 min)

[0646]

[0515] Step 6: The mixture of step 5 (30 mg) was separated by SFC (DAICEL CHIRALPAK IG (250mm x 30mm, 10um); mobile phase A: CO2; mobile phase B: ethanol (0.1%NH3H2O)]; B%:50%, isocratic elution mode) to afford (R)-N-(8-methyl-5-((5-((1-methylpyrrolidin-3-yl)oxy)pyridin- 2- yl)ethynyl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (Compound 22B*) (9.5 mg, 30% yield, 96% purity) as the first eluting peak and (S)-N-(8-methyl-5-((5-((1-methylpyrrolidin-3- yl)oxy)pyridin- 2-yl)ethynyl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (Compound 22A*) (6.4 mg, 21% yield, 99% purity) as the second eluting peak. * Stereochemistry arbitrarily assigned.

[0647]

[0516] Compound 22A*:1H NMR: (400 MHz, MeOD-d4) δ = 9.47 (s, 1H), 8.87 (s, 1H), 8.61 (s, 1H), 8.25 (d, J = 2.8 Hz, 1H), 7.79 (d, J = 8.7 Hz, 1H), 7.45 (dd, J = 2.9, 8.7 Hz, 1H), 5.12 - 5.01 (m, 1H), 3.00 (s, 3H), 2.96 - 2.82 (m, 3H), 2.53 - 2.43 (m, 2H), 2.41 (s, 3H), 2.04 - 1.95 (m, 2H), 1.08 - 1.03 (m, 2H), 0.98 - 0.93 (m, 2H). LCMS: (M+H+): 427.8 at 2.497 min (5-95% acetonitrile in H2O, 6 min). SFC: 99.70% ee at 2.463 min.

[0648]

[0517] Compound 22B*:1H NMR: (400 MHz, MeOD-d4) δ 9.46 (s, 1H), 8.86 (s, 1H), 8.61 (s, 1H), 8.25 (d, J = 2.8 Hz, 1H), 7.79 (d, J = 8.6 Hz, 1H), 7.45 (dd, J = 2.9, 8.8 Hz, 1H), 5.05 (br d, J = 4.4 Hz, 1H), 3.00 (s, 3H), 2.96 - 2.84 (m, 3H), 2.53 - 2.44 (m, 2H), 2.42 (s, 3H), 2.04 - 1.95 (m, 2H), 1.07-1.03 (m 2H), 0.98 - 0.92 (m, 2H). LCMS: (M+H+): 428.2 at 1.734 min (5-95% acetonitrile in H2O, 6 min). SFC: 100% ee at 1.773 min.

[0649] Example 18: Synthesis of N-(8-(difluoromethyl)-5-((3-fluoro-5-morpholinopyridin-2-yl)ethynyl)-

[0650] 2,7-naphthyridin-3-yl)cyclopropanecarboxamide (Compound 19)

[0651]

[0518] Step 1 : A 30 mL pressure flask equipped with a stir bar was added 5-bromo-2-chloro-3- fluoropyridine (500 mg, 2.33 mmol), (9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) (Xantphos) (137 mg, 233 umol), sodium tert-butoxide (692 mg, 6.99 mmol), tris(dibenzylideneacetone)dipalladium (Pd2(dba)3) (76.9 mg, 81.5 umol), morpholine (617 uL, 6.99 mmol) and toluene (9.31 mL). The reaction was degassed with nitrogen for 5 mins before stirring at 60 °C overnight. The reaction was quenched with water (1 mL) and the crude was evaporated to dryness. The residue was directly purified by normal phase chromatography (dry load, 25 g silica gel) eluting with 0% to 100% ethyl acetate in heptanes. Pure fractions were combined and concentrated to give 4-(6-chloro-5-fluoropyridin-3-yl)morpholine (450 mg, 89% yield).

[0652]

[0519] Step 2: A mixture of [1,1 '-bis(diphenylphosphino)ferrocene] dichloropalladium (II) (Pd(dppf)Cl2) (77.5 mg, 104 umol), Cui (39.8 mg, 208 umol), 4-(6-chloro-5-fluoropyridin-3-yl)morpholine (450 mg, 2.08 mmol), diisopropylethylamine (1.83 mL, 10.4 mmol) in dimethylformamide (4.15 mL) at room temperature was evacuated then backfilled with nitrogen. (Trimethylsilyl)acetylene (863 uL, 6.23 mmol) was added and the resulting mixture was stirred at 80 °C for 2 h. The reaction was cooled to room temperature, filtered through a celite pad, and then washed with ethyl acetate (30 mL). The filtrate was concentrated to give a black oil which was dissolved in tetrahydrofuran (6.36 mL) followed by the addition of tetramethylammonium fluoride (399 mg, 4.15 mmol). After 30 mins, 1 mL of water was added to the reaction mixture which was concentrated to dryness. The reaction was purified by normal phase chromatography (dry load, 25g, eluting with 5% to 100% of ethyl acetate in heptanes). The fraction containing the product was concentrated to give 4-(6-ethynyl-5-fluoropyridin-3-yl)morpholine (307 mg, 61% yield). The product was used for the next step without any further purification. LCMS: m / z [M+H]+= 207.2.

[0653]

[0520] Step 3 : To a 5 mL pressure flask equipped with a stir bar was added 4-bromo-6-chloro-1- (difluoromethyl)-2,7-naphthyridine (Intermediate 2) (80.0 mg, 273 umol), [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl2) (10.2 mg, 13.6 umol), 4-(6- ethynyl-5-fluoropyridin-3-yl)morpholine (79.4 mg, 327 umol), Cui (5.19 mg, 27.3 umol), diisopropylethylamine (237 uL, 1.36 mmol) and dimethylformamide (1.36 mL). The mixture was bubbled with N2for 5 mins and heated to 80 °C for 2 h. The reaction was cooled to room temperature and purified by normal phase chromatography (dry load, 25g silica gel, eluting with 0% to 50% of (20% methanol / dichloromethane) in heptanes). The fractions containing the product were collected and concentrated to give 4-(6-((6-chloro-1-(difluoromethyl)-2,7-naphthyridin-4-yl)ethynyl)-5-fluoropyridin- 3-yl)morpholine (83.0 mg, 73% yield). LCMS: m / z [M+H]+= 419.2.

[0654]

[0521] Step 4 : To a 5 mL pressure flask equipped with a stir bar was added 4-(6-((6-chloro-1- (difluoromethyl)-2,7-naphthyridin-4-yl)ethynyl)-5-fluoropyridin-3-yl)morpholine (83.0 mg, 198 umol), [(2-di-cyclohexylphosphino-3,6-dimethoxy-2',4',6'- triisopropyl-1, 1'-biphenyl)-2-(2'-amino-1, 1' - biphenyl)]palladium(II) methane sulfonate (BrettPhos Pd G3) (18.0 mg, 19.8 umol), 2-(di-tert- butylphosphino)-2',4',6'- triisopropyl-3,6-dimethoxy-1, 1'-biphenyl (tBuBrettPhos) (29.7 mg, 59.5 umol), cesium carbonate (198 mg, 595 umol), cyclopropanecarboxamide (86.1 mg, 991 umol) and anhydrous degassed 1,4-dioxane (699 uL). The reaction was heated to 70 °C for 2h, and monitored by LC-MS. The complete conversion was detected. The reaction was filtered over celite, washed with methanol (30 mL), concentrated, and purified over reversed phase chromatography (12 g, C18, eluting with 5% to 100% of acetonitrile in 10 mM aqueous solution of ammonium formate at pH 3.8. The fractions containing the desired product were collected, concentrated to remove most acetonitrile, and lyophilized to give N-(8-(difluoromethyl)-5-((3-fluoro-5-morpholinopyridin-2-yl)ethynyl)-2,7- naphthyridin-3-yl)cyclopropanecarboxamide (Compound 19) (22.0 mg, 24% yield).1H NMR: (400 MHz, DMSO-d6) δ 11.47 (s, 1H), 9.64 (s, 1H), 8.91 (s, 1H), 8.90 (d, J= 0.7 Hz, 1H), 8.31 - 8.29 (m, 1H), 7.74 - 7.38 (m, 2H), 3.78 - 3.71 (m, 4H), 3.41 - 3.37 (m, 4H), 2.18 - 2.09 (m, 1H), 0.96 - 0.84 (m, 4H). LCMS: m / z [M+H]+= 419.2.

[0655] Example 19: Synthesis of N-(8-(difluoromethyl)-5-((5-(4-methylpiperazin-1-yl)pyridin-2- yl)ethynyl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (Compound 15)

[0656]

[0522] Step 1: To a 5 mL pressure flask equipped with a stir bar was added 4-bromo-6-chloro-1- (difluoromethyl)-2,7-naphthyridine (Intermediate 2) (80.0 mg, 273 umol), [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl2) (10.2 mg, 13.6 umol), l-(6- ethynylpyridin-3-yl)-4-methylpiperazine (71.3 mg, 354 umol, which was synthesized according to Example 3, but using 1 -methylpiperazine in Step 1 instead of morpholine), Cul (5.19 mg, 27.3 umol), diisopropylethylamine (237 uL, 1.36 mmol) and dimethylformamide (1.36 mL). The mixture was bubbled with N2for 5 mins and heated to 80 °C for 2h. The reaction was cooled to room temperature and the crude reaction was purified by normal phase chromatography (dry load, 25g silica gel, eluting with 0% to 50% of (20% methanol / dichloromethane) in heptanes). The fractions containing the product were collected and concentrated to give 6-chloro-1-(difluoromethyl)-4-((5-(4-methylpiperazin-1- yl)pyridin-2-yl)ethynyl)-2,7-naphthyridine (76.0 mg, 67% yield). LCMS: m / z [M+H]+= 414.2.

[0657]

[0523] Step 2: To a 5 mL pressure flask equipped with a stir bar was added 6-chloro-1-(difluoromethyl)- 4-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)ethynyl)-2,7-naphthyridine (83.0 mg, 198 umol), [(2-di- cyclohexylphosphino-3,6-dimethoxy-2',4',6'- triisopropyl-1, 1'-biphenyl)-2-(2'-amino-1, 1' - biphenyl)]palladium(II) methane sulfonate (BrettPhos Pd G3) (18.0 mg, 19.8 umol), 2-(di-tert- butylphosphino)-2',4',6'- triisopropyl-3,6-dimethoxy-1, 1'-biphenyl (tBuBrettPhos) (29.7 mg, 59.5 umol), cesium carbonate (198 mg, 595 umol), cyclopropanecarboxamide (86.1 mg, 991 umol) and anhydrous degassed 1,4-dioxane (699 uL). The reaction was heated to 70 °C for 2 h. It was then cooled to room temperature and filtered over celite, before being washed with methanol (30 mL). Volatiles were concentrated under reduced pressure and purified by reversed phase chromatography eluting with 5% to 100% of acetonitrile in in 10 mM aqueous solution of ammonium formate at pH 3.8. The fractions containing the desired product were collected, concentrated to remove most acetonitrile, and lyophilized to give V-(8-(difluoromethyl)-5-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)ethynyl)-2,7- naphthyridin-3-yl)cyclopropanecarboxamide (Compound 15) (22.0 mg, 24% yield).1H NMR: (400 MHz, DMSO-d6) δ 11.47 (s, 1H), 9.64 (s, 1H), 8.91 (s, 1H), 8.90 (d, J= 0.7 Hz, 1H), 8.31 - 8.29 (m, 1H), 7.74 - 7.38 (m, 2H), 3.78 - 3.71 (m, 4H), 3.41 - 3.37 (m, 4H), 2.18 - 2.09 (m, 1H), 0.96 - 0.84 (m, 4H). LCMS: m / z [M+H]+= 468.1.

[0658] Example 20: Synthesis of N-(5-((5-((1-(2,2-difluoroethyl)azetidin-3-yl)oxy)pyridin-2-yl)ethynyl)-8-

[0659] (difluoromethyl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (Compound 33)

[0660]

[0524] Step 1 : To a solution of tert-butyl 3-((6-bromopyridin-3-yl)oxy)azetidine-1-carboxylate (835 mg, 2.54 mmol, which was synthesized following Example 17, Step 1 but using l-Boc-3 -iodoazetidine instead of l-Boc-3 -iodopyrrolidine) in hexafluoro-2 -propanol (5.07 mL) was added trifluoroacetic acid (388 uL, 5.07 mmol) dropwise. The mixture was stirred at room temperature for 2h before the solution was evaporated to dryness. The crude product was redissolved in ethanol (50.7 mL) followed by the addition of diisopropylethylamine (1.33 mL, 7.61 mmol) and 2,2-difluoroethyl trifluoromethanesulfonate (1.23 g, 5.58 mmol). The mixture was stirred for 3 h before being concentrated in vacuo and directly purified by normal phase chromatography (dry load, 12g silica gel, eluting with 0% to 100% of ethyl acetate in heptanes). Pure fractions were collected and concentrated to give 2-bromo-5-((1-(2,2-difluoroethyl)azetidin-3-yl)oxy)pyridine (517 mg, 70% yield). LCMS: m / z [M+H]+= 393.0.

[0661]

[0525] Step 2: A mixture of [1,1 '-bis(diphenylphosphino)ferrocene] dichloropalladium (II) (Pd(dppf)Cl2) (8.51 mg, 11.4 umol), Cui (3.36 mg, 17.5 umol), 2-bromo-5-((1-(2,2-difluoroethyl)azetidin-3- yl)oxy)pyridine (107 mg, 300 umol) and diisopropylethylamine (216 uL, 1.23 mmol) in dimethylformamide (351 uL) at room temperature was evacuated then backfilled with nitrogen.

[0662] (Trimethylsilyl)acetylene (63.2 uL, 456 umol) was added and the resulting mixture was stirred at 80 °C for 2 h. The reaction mixture was cooled to room temperature before adding tetrabutylammonium fluoride (351 uL, 351 umol). The mixture was stirred for 30 minutes followed by the addition of a solution of N-(5-bromo-8-(difliioromethyl)-2.7-naphthyridin-3-yl)cyclopropanccarboxamide (Intermediate 11) (60.0 mg, 175 umol) in dimethylformamide (351 uL). The reaction was heated up to 80 °C for 2 hours, cooled down to room temperature, filtered over a celite pad, washed with ethyl acetate, concentrated, and directly purified by reverse phase chromatography (C18) eluting with 10% to 100% of (50%methanol / acetonitrile) in 10 mM aqueous solution of ammonium formate at pH 3.8. Pure fractions were combined and lyophilized to give N-(5-((5-((1-(2,2-difluoroethyl)azetidin-3- yl)oxy)pyridin-2-yl)ethynyl)-8-(difluoromethyl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (Compound 33) (28.0 mg, 32% yield).1H NMR: (400 MHz, DMSO-d6) δ 11.52 (s, 1H), 9.65 (s, 1H), 8.97 - 8.92 (m, 2H), 8.34 (d, J= 2.9 Hz, 1H), 7.77 - 7.40 (m, 3H), 6.00 (tt, J= 55.4, 3.9 Hz, 1H), 5.01 (p, J= 5.7 Hz, 1H), 3.86 (dd, J= 8.4, 6.1 Hz, 2H), 3.29 - 3.24 (m, 2H), 2.91 (td, J= 16.0, 4.1 Hz, 2H), 2.18 - 2.09 (m, 1H), 0.95 - 0.86 (m, 4H). LCMS: m / z [M+H]+= 500.1.

[0663] Example 21: Synthesis of (A)-N-(8-(difluoromethyl)-5-((5-(3,4-dimethylpiperazin-1-yl)pyridin-2- yl)ethynyl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (Compound 17A) and (R)-N-(8- (difluoromethyl)-5-((5-(3,4-dimethylpiperazin-1-yl)pyridin-2-yl)ethynyl)-2,7-naphthyridin-3- yl)cyclopropanecarboxamide (Compound 17B)

[0664] Scheme 21 A. Scheme 21B.

[0665]

[0526] Step 1: A mixture of [1, 1'-bis(diphenylphosphino)ferrocene] dichloropalladium (II) (Pd(dppf)Cl2) (18.0 mg, 24.1 umol), Cui (7.08 mg, 37.0 umol), (S)-4-(6-bromopyridin-3-yl)-l,2-dimethylpiperazine (130 mg, 481 umol; prepared following Example 5, Step 1 but using commercially available (S)-l,2- dimethylpiperazine as the starting material instead of 1 -methylpiperazine), diisopropylethylamine (456 uL, 2.59 mmol) in dimethylformamide (740 uL) at room temperature was evacuated then backfilled with nitrogen. (Trimethylsilyl)acetylene (133 uL, 962 umol) was added and the resulting mixture was stirred at 60 °C for 1 h. The reaction mixture was cooled to room temperature before adding tetrabutylammonium fluoride (740 uL, 740 umol). The mixture was stirred for 30 minutes followed by the addition of a solution of N-(5-bromo-8-(difluoromethyl)-2,7-naphthyridin-3- yl)cyclopropanecarboxamide (Intermediate 11) (169 mg, 370 umol) in dimethylformamide (740 uL). The reaction was heated up to 80 °C for an additional 4 hours, cooled to room temperature, filtered over a celite pad, washed with ethyl acetate, concentrated, and directly purified by reverse phase chromatography (C18) eluting with 10% to 100% of (50%methanol / acetonitrile) in in 10 mM aqueous solution of ammonium formate at pH 3.8. Pure fractions were combined and lyophilized to give (S)-N- (8-(difluoromethyl)-5-((5-(3,4-dimethylpiperazin-1-yl)pyridin-2-yl)ethynyl)-2,7-naphthyridin-3- yl)cyclopropanecarboxamide (Compound 17A) (25.0 mg, 14% yield).1H NMR: (400 MHz, DMSO- d6) δ 11.50 (s, 1H), 9.63 (d, J= 0.8 Hz, 1H), 8.95 (d, J = 0.8 Hz, 1H), 8.89 (s, 1H), 8.42 (d, J = 2.8 Hz, 1H), 7.73 - 7.40 (m, 3H), 3.83 (d, J= 12.0 Hz, 2H), 2.97 (t, J= 11.8 Hz, 2H), 2.69 - 2.55 (m, 1H), 2.44 - 2.23 (m, 5H), 2.18 - 2.11 (m, 1H), 1.11 (d, J = 6.1 Hz, 3H), 0.95 - 0.86 (m, 4H). LCMS: m / z [M+H]+= 477.3.

[0666]

[0527] Step 2: (R)-N-(8-(difluoromethyl)-5-((5-(3.4-dimethylpipcrazin-l-yl)pyridin-2-yl)ethynyl)-2.7- naphthyridin-3-yl)cyclopropanecarboxamide (Compound 17B) was prepared following the procedure described in this Example but using (R)-l,2-dimethylpiperazine instead of (S)-I,2-dimethylpiperazine.1H NMR: (400 MHz, DMSO-d6) 11.50 (s, 1H), 9.63 (s, 1H), 8.95 (d,J = 0.7 Hz, 1H), 8.89 (s, 1H), 8.40 (d,J = 2.8 Hz, 1H), 7.73 - 7.37 (m, 3H), 3.85 - 3.71 (m, 2H), 2.91 (td,J = 11.8, 2.9 Hz, 1H), 2.83 (dt,J = 11.3, 2.5 Hz, 1H), 2.54 (dd,J = 7.3, 4.9 Hz, 1H), 2.26 - 2.07 (m, 6H), 1.06 (d,J = 6.2 Hz, 3H), 0.95 - 0.85 (m, 4H). LCMS: m / z [M+H]+= 477.3. Example 22: Synthesis of (R)-N-(8-(difluoromethyl)-5-((5-(2,4-dimethylpiperazin-1-yl)pyridin-2- yl)ethynyl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (Compound 16A) and (S)-N-(8- (difluoromethyl)-5-((5-(2,4-dimethylpiperazin-1-yl)pyridin-2-yl)ethynyl)-2,7-naphthyridin-3- yl)cyclopropanecarboxamide (Compound 16B) Scheme 22A.

[0667] Scheme 22B.

[0668]

[0528] Step 1: A mixture of [1, 1'-bis(diphenylphosphino)ferrocene] dichloropalladium (II) (Pd(dppf)Cl2) (13.8 mg, 18.5 umol), Cui (5.45 mg, 28.5 umol), (R)-1-(6-bromopyridin-3-yl)-2,4-dimethylpiperazine (100 mg, 370 umol; prepared according to Example 5, Step 1 but using commercially available (R)-l,3- dimethylpiperazine as the starting material instead of 1 -methylpiperazine), diisopropylethylamine (351 uL, 1.99 mmol) in dimethylformamide (569 uL) at room temperature was evacuated then backfilled with nitrogen. (Trimethylsilyl)acetylene (103 uL, 740 umol) was added and the resulting mixture was stirred at 80 °C for 2 h. The reaction mixture was cooled to room temperature before adding tetrabutylammonium fluoride (569 uL, 569 umol). The mixture was stirred for 30 minutes followed by the addition of a solution N-(5-bromo-8-(difluoromethyl)-2,7-naphthyridin-3- yl)cyclopropanecarboxamide (Intermediate 11) (130 mg, 285 umol) in dimethylformamide (569 uL). The reaction was heated up to 80 °C for an additional 4 hours, cooled down to room temperature, filtered over a celite pad, washed with ethyl acetate, concentrated, and directly purified by reverse phase chromatography (C18) eluting with 10% to 100% of (50% methanol / acetonitrile) in 10 mM aqueous solution of ammonium formate at pH 3.8. Pure fractions were combined and lyophilized to give (R)-N- (8-(difluoromethyl)-5-((5-(2,4-dimethylpiperazin-1-yl)pyridin-2-yl)ethynyl)-2,7-naphthyridin-3- yl)cyclopropanecarboxamide (Compound 16A) (25 mg).1H NMR: (400 MHz, DMSO-d6) δ 11.50 (s, 1H), 9.63 (s, 1H), 8.95 (s, 1H), 8.89 (s, 1H), 8.43 (s, 1H, formate), 8.34 (d, J= 2.8 Hz, 1H), 7.71 - 7.31 (m, 3H), 4.28 - 4.19 (m, 1H), 3.63 - 3.55 (m, 1H), 3.05 (td, J= 11.9, 3.4 Hz, 1H), 2.90 - 2.83 (m, 1H), 2.75 - 2.68 (m, 1H), 2.24 - 2.09 (m, 5H), 2.01 (td, J= 11.5, 3.5 Hz, 1H), 1.13 (d, J= 6.5 Hz, 3H), 0.90 (qd, J= 7.6, 3.8 Hz, 4H). Missing 1H due to H exchange. LCMS: m / z [M+H]+= 477.2.

[0669]

[0529] Step 2: (S)-N-(8-(difluoromethyl)-5-((5-(2,4-dimethylpiperazin-1-yl)pyridin-2-yl)ethynyl)-2,7- naphthyridin-3-yl)cyclopropanecarboxamide (Compound 16B) may be synthesized following this Example, but using (S)-1-(6-bromopyridin-3-yl)-2,4-dimethylpiperazine (prepared according to Example 5, Step 1 but using commercially available (S)- 1,3 -dimethylpiperazine as the starting material instead of 1 -methylpiperazine) instead of (R)- l-(6-bromopyridin-3-yl)-2.4-dimethylpipcrazinc.

[0670] Example 23: Synthesis of (S)-N-(5-((3-fluoro-5-((tetrahydrofuran-3-yl)amino)pyridin-2-yl)ethynyl)- 8-methyl-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (Compound 34A*) and (R)-N-(5-((3- fluoro-5-((tetrahydrofuran-3-yl)amino)pyridin-2-yl)ethynyl)-8-methyl-2,7-naphthyridin-3- yl)cyclopropanecarboxamide (Compound ...

Claims

CLAIMSWhat is claimed is:

1. A compound of Formula (I) :or a pharmaceutically acceptable salt thereof, wherein:-CX3is -CH3or -CHF2;R1is C3-4carbocyclyl 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 C1-3alkyl, C1-3haloalkyl, halogen, or -OR', or two R1Agroups attached to the same carbon atom are joined to form a C3-4carbocyclyl or 3-6 membered heterocyclyl, or two R1Agroups attached to vicinal atoms are joined to form a C3-6carbocyclyl or 3-6 membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is substituted with 0, 1, 2, or 3 substituents independently selected from C1-3alkyl, C1-3haloalkyl, halogen, -C(=O)OR', and -OR';G1is CRG1or N, G2is CRG2or N, and G3is CRG3or N, provided no more than one of G1, G2, and G3is N; each of RG1, RG2and RG3is independently H, halogen, C1-6alkyl, C1-6haloalkyl, -(L1)-C3.4 carbocyclyl, -(L1)-O-(CH2CH2O)m-R', -(L1)-N(R')2, -(L1)-CN, orwherein L1is absent, C1-3alkylene, or C1-3haloalkylene; m is 0, 1 or 2; and provided no more than one of RG1, RG2and RG3iseach instance of W is independently absent, -C(RCW)2-, -O-, or -N(RNW)-; each instance of Ring D is independently 4-8 membered heterocyclyl; each instance of RDis independently halogen, C1-6alkyl, C1-6haloalkyl, -(L2)-(Y)-C3-10carbocyclyl, -(L2)-(Y)-(4- 10 membered heterocyclyl), -(L2)-(Y)-C6-10aryl, -(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, or -(L2)-(Y)-S(=O)2N(RA)2, or two RDattached to the same carbon atom are joined to form a C3-6carbocyclyl or 3-6 membered heterocyclyl, ortwo RDattached to the same carbon atom are taken together to form =O, wherein L2is absent, C1-3alkylene, or C1-3haloalkylene; 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 d is independently 0, 1, 2, 3, 4, 5, or 6, as valency permits; each instance of RAis independently H, C1-6alkyl, C1-6haloalkyl, -(L3)-(Z)-C3-10carbocyclyl, -(L3)-(Z)-(3-10 membered heterocyclyl), -(L3)-(Z)-C6-10aryl, or -(L3)-(Z)-(5-10 membered heteroaryl), or two RAgroups attached to the same nitrogen atom are joined to form a 4-6 membered heterocyclyl, wherein L3is absent, C1-3alkylene, or C1-3haloalkylene; 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, C1-6alkyl, C1-6haloalkyl, C3-10carbocyclyl, -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 =O; wherein each alkyl and haloalkyl is independently substituted with 0 or 1 instances of =O, and each carbocyclyl is independently substituted with 0, 1, 2, or 3 instances of RC; each instance of RCis independently halogen, C1-6alkyl, or C1-6haloalkyl, or two RCattached to the same carbon atom are taken together to form =O; each instance of RCWis independently H, halogen, or C1-6alkyl, or two instances of RCWare taken together to form =O, or wherein one RCWis joined with RG2or RG3to form a C5-6carbocyclyl or C6aryl, wherein the alkyl, carbocyclyl, or aryl is substituted with 0, 1, 2, or 3 instances of R"; each instance of R' and RNWis independently H, C1-6alkyl, or C1-6haloalkyl, or two R' groups attached to the same nitrogen atom are joined to form a 4-6 membered heterocyclyl; each instance of R" is independently halogen, C1-3alkyl, C1-3haloalkyl, -CN, -OR'", -N(R'")2, or -SR'", or two R" attached to the same carbon atom are taken together to form =O; and each instance of R'" is independently H, C1-3alkyl, or C1-3haloalkyl, 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, wherein the compound is of Formula (II):or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1, wherein the compound is of Formula (III):or a pharmaceutically acceptable salt thereof, wherein W is -C(RCW)2-, -O-, or -N(RNW)-.

4. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein R1is cyclopropyl substituted with 0, 1, or 2 instances of R1A.

5. The compound of claim 4, or a pharmaceutically acceptable salt thereof, wherein R1is cyclopropyl substituted with 0 or 1 instance of R1A, wherein R1Ais fluoro.

6. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein -CX3is -CH3.

7. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein -CX3is -CHF2.

8. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein G1is CRG1, G2is CRG2, and G3is CRG3.

9. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt thereof, wherein RG1and RG3are independently H or F; and RG2is selected from H, -OCH3, -CH2OH,-CH2OCH3, -CN, -CHF2, and10. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein each of RG1, RG2and RG3are H.

11. The compound of any one of claims 1-10, wherein the compound is of Formula:or a pharmaceutically acceptable salt thereof.

12. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt thereof, wherein at least one Ring D is independently selected from one of the following formulae:wherein z is 0, 1, 2, or 3, as valency permits.

13. The compound of claim 12, or a pharmaceutically acceptable salt thereof, wherein at least oneRing D is independently selected from one of the following formulae:

14. The compound of claim 12, or a pharmaceutically acceptable salt thereof, wherein at least oneRing D is independently selected from one of the following formulae:

15. The compound of claim 12, or a pharmaceutically acceptable salt thereof, wherein at least oneRing D is independently selected from one of the following formulae:

16. The compound of any one of claims 1-15, or a pharmaceutically acceptable salt thereof, wherein each instance of RDis independently halogen, C1-6alkyl, C1-6haloalkyl, -ORA, -N(RA)2, 4-5 membered heterocyclyl, or -C(=O)ORA, or two RDattached to the same carbon atom are joined to form a 3-6 membered heterocyclyl, or two RDattached to the same carbon atom are taken together to form =O; and each alkyl, haloalkyl, or heterocyclyl is independently substituted 0 instances of RB.

17. The compound of any one of claims 1-16, or a pharmaceutically acceptable salt thereof, wherein each instance of RAis independently H or C1-6alkyl, and each alkyl is independently substituted with 0 instances of RB.

18. The compound of any one of claims 1-17, or a pharmaceutically acceptable salt thereof, wherein at least one Ring D is independently selected from:

19. The compound of any one of claims 1-18, or a pharmaceutically acceptable salt thereof, wherein at least one Ring D is independently selected from:

20. The compound of any one of claims 1-19, wherein the compound is of Formula:or a pharmaceutically acceptable salt thereof.

21. The compound of any one of claims 1-19, wherein the compound is of Formula:or a pharmaceutically acceptable salt thereof.

22. The compound of any one of claims 1-21, wherein the compound is selected from those inTables 2A-2C or Tables 3A-3C, and pharmaceutically acceptable salts thereof.

23. A compound of Formula (I) :or a pharmaceutically acceptable salt thereof, wherein: each X is independently selected from H and halogen;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 C1-3alkyl, C1-3haloalkyl, halogen, or -OR', or two R1Agroups attached to the same carbon atom are joined to form a C3-6carbocyclyl or 3-6 membered heterocyclyl, or two R1Agroups attached to vicinal atoms are joined to form a C3-6carbocyclyl or 3-6 membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is substituted with 0, 1, 2, or 3 substituents independently selected from C1-3alkyl, C1-3haloalkyl, halogen, -C(=O)OR', and -OR';G1is CRG1or N, G2is CRG2or N, and G3is CRG3or N, provided no more than one of G1, G2, and G3is N; each of RG1, RG2and RG3is independently H, halogen, C1-6alkyl, C1-6haloalkyl, -(L1)-C3-4carbocyclyl, -(L1)-O-(CH2CH2O)m-R', -(L1)-N(R')2, -(L1)-CN, orwherein L1is absent, C1-3alkylene, or C1-3haloalkylene; m is 0, 1 or 2; and provided no more than one of RG1, RG2andeach instance of W is independently absent, -C(RCW)2-, -O-, or -N(RNW)-; each instance of Ring D is independently 4-8 membered heterocyclyl; each instance of RDis independently halogen, C1-6alkyl, C1-6haloalkyl, -(L2)-(Y)-C3-10carbocyclyl, -(L2)-(Y)-(4-10 membered heterocyclyl), -(L2)-(Y)-C6-10aryl, -(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, or -(L2)-(Y)-S(=O)2N(RA)2, or two RDattached to the same carbon atom are joined to form a C3-6carbocyclyl or 3-6 membered heterocyclyl, or two RDattached to the same carbon atom are taken together to form =O, wherein L2is absent, C1-3alkylene, or C1-3haloalkylene; 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 d is independently 0, 1, 2, 3, 4, 5, or 6, as valency permits; each instance of RAis independently H, C1-6alkyl, C1-6haloalkyl, -(L3)-(Z)-C3-10carbocyclyl, - (L3)-(Z)-(3- 10 membered heterocyclyl), -(L3)-(Z)-C6-10aryl, or -(L3)-(Z)-(5- 10 membered heteroaryl), or two RAgroups attached to the same nitrogen atom are joined to form a 4-6 membered heterocyclyl, wherein L3is absent, C1-3alkylene, or C1-3haloalkylene; 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, C1-6alkyl, C1-6haloalkyl, C3-10carbocyclyl, -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 =O; wherein each alkyl and haloalkyl is independently substituted with 0 or 1 instances of =O, and each carbocyclyl is independently substituted with 0, 1, 2, or 3 instances of RC; each instance of RCis independently halogen, C1-6alkyl, or C1-6haloalkyl, or two RCattached to the same carbon atom are taken together to form =O; each instance of RCWis independently H, halogen, or C1-6alkyl, or two instances of RCWare taken together to form =O, or wherein one RCWis joined with RG2or RG3to form a C5-6carbocyclyl or C6aryl, wherein the alkyl, carbocyclyl, or aryl is substituted with 0, 1, 2, or 3 instances of R"; each instance of R' and RNWis independently H, C1-6alkyl, or C1-6haloalkyl, or two R' groups attached to the same nitrogen atom are joined to form a 4-6 membered heterocyclyl, or RNWis joined with RG2or RG3to form a 5-6 membered heterocyclyl or 5-6 membered heteroaryl, wherein the alkyl, haloalkyl, heterocyclyl, or heteroaryl is substituted with 0, 1, 2, or 3 instances of R"; each instance of R" is independently halogen, C1-3alkyl, C1-3haloalkyl, -CN, -OR'", -N(R'")2, or-SR'", or two R" attached to the same carbon atom are taken together to form =O; and each instance of R'" is independently H, C1-3alkyl, or C1-3haloalkyl, 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 substituents independently selected from halogen.

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

25. 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 claims 1-23, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 24.

26. 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 claims 1-23, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 24.

27. A method of preparing a compound of Formula (I), or salt thereof, as defined in any one of claims 1-23, following one or more steps as set forth in General Schemes A-F.

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