Inhibitors of RIPK2 and uses thereof

Abstract

The present disclosure relates to RIPK2 inhibitors, e.g., compounds represented by structural formula (I*): The disclosure further relates to pharmaceutical composition comprising the RIPK2 inhibitors and methods of treatment of conditions such as inflammatory disease, autoimmune disease, granulomatous disease, neurodegenerative disease, and cancer.

Description

PATENT APPLICATION Docket No. OTQ-00925- 1 -INHIBITORS OF RIPK2 AND USES THEREOFRELATED APPLICATIONS

[0001] This application claims the benefit of priority to U. S. Provisional Patent Application No. 63 / 761,540, filed February 21, 2025. The entire teachings of the above application are incorporated herein by reference.BACKGROUND OF THE INVENTION

[0002] Autoinflammatory disorders are diseases characterized by systemic and organspecific inflammation due to abnormalities in the innate immune system. These abnormalities are associated with numerous inflammatory disorders such as inflammatory bowel disease (including Crohn’s disease and ulcerative colitis), sarcoidosis, inflammatory arthritis, peritonitis, multiple sclerosis, rheumatoid arthritis, and Wegener’s granulomatosis. These disorders affect millions of people.

[0003] NODI and NOD2 (nucleotide-binding oligomerization domains 1 and 2) are members of the NOD-like receptor (NLR) family, which represent important components of the mammalian innate immune system, serving as intracellular receptors for peptidoglycan (PGN), a component of bacterial cell walls. NODI and NOD2 detect the presence of intracellular bacteria by binding to PGN fragments. Heredity polymorphisms in the genes encoding NODI and NOD2 have been associated with inflammatory disorders. Once activated, NOD signaling leads to activation of NF-KB and MAP kinases, resulting in the transcription of pro-inflammatory kinases and the induction of autophagy.

[0004] NODI and NOD2 require RIPK2 as a common scaffolding (adaptor) protein to propagate downstream signals that lead to aberrant proinflammatory innate immune activation. In particular, RIPK2 is critical for NF-KB activation and subsequent cytokine production.Inhibition of RIPK2 resolves abnormal inflammation states such as intestinal inflammation. Accordingly, inhibitors of RIPK2 have potential to act as therapeutic agents, for example, to reduce or resolve inflammation for inflammatory disorders such as inflammatory bowel diseaseFH12583563.3OTQ-00925- 2 -(including Crohn’s disease and ulcerative colitis), sarcoidosis, inflammatory arthritis, peritonitis, multiple sclerosis, rheumatoid arthritis, and Wegener’s granulomatosis.

[0005] In the context of malignant transformation, knockdown of RIPK2 downregulated RNA expression of E-cadherin and vimentin, proteins involved in epithelial-to-mesenchymal transition (EMT) and the promotion of the metastatic phenotype indicating that RIPK2 is involved in cell migration and metastasis.

[0006] Accordingly inhibitors of RIPK2 activity which can block RIPK2-dependent pro-inflammatory signaling and thereby provide a therapeutic benefit in auto-inflammatory diseases and other disorders characterized by increased and / or dysregulated RIPK2 activity are needed.

[0007] A description of example embodiments of the invention follows.SUMMARY OF THE INVENTION

[0008] In some embodiments, the present disclosure relates to a compound represented by structural formula (I*) or a pharmaceutically acceptable salt thereof:wherein:Q is selected from the following moieties:OTQ-00925R35 W is 5- to 12-membered heteroaryl;X is CH or N;each Y and Z is independently selected from O, NRa, and C1-3 alkylene; Rais selected from H and C1-6 alkyl;each Rlaand Rlbis independently selected from H, C1-6 alkyl, and halogen;R2is selected from C3-6 alkyl, C3-6 deuteroalkyl, C3-12 cycloalkyl;R3is selected from C1-6 alkyl, C3-12 cycloalkyl, 4- to 10-membered heterocyclyl, 5- to 12- membered heteroaryl, S(=O)R5, S(=O)2R5, NH(C=O)R5, NH(S(=O)2)R5, S(=O)(=NR6)(R7), P(=O)R6*R7*, BR8*R9* and C(=O)NR8R9;R3* is selected from H, halogen, C1-6 alkyl, C1-6 alkoxy;R4is selected from H and C1-6 alkyl;R5is selected from C1-6 alkyl, C3-12 cycloalkyl, C6-12aryl, 4- to 10-membered heterocyclyl, 5- to 12-membered heteroaryl, and NR10Rn;R6is selected from H and C1-6 alkyl;R7is selected from C1-6 alkyl, C3-12 cycloalkyl, 4- to 10-membered heterocyclyl, 5- to 12- membered heteroaryl, and NR10Rn, orR6and R7taken together with the nitrogen and sulfur atoms to which they are attached form 4- to 10-membered heterocyclyl;OTQ-00925- 4 -each R6* and R7* is independently selected from Ci-6 alkyl, C3-12 cycloalkyl, 4- to 10-membered heterocyclyl, and 5- to 12-membered heteroaryl, orR6* and R7* taken together with the phosphorus atom to which they are attached form 4- to 10- membered heterocyclyl;each R8* and R9* is independently selected from OH, C1-6 alkyl, C3-12 cycloalkyl, 4- to 10- membered heterocyclyl, and 5- to 12-membered heteroaryl;each R8and R9is independently selected from H, C1-6 alkyl, C3-12 cycloalkyl, and 4- to 10- membered heterocyclyl, orR8and R9taken together with the nitrogen atom to which they are attached form 4- to 10- membered heterocyclyl; andeach R10and R11is independently selected from H, C1-6 alkyl, C3-12 cycloalkyl, and 4- to 10- membered heterocyclyl, orR10and R11taken together with the nitrogen atom to which they are attached form 4- to 10- membered heterocyclyl,wherein each C1-6 alkyl, C1-3 alkylene, C3-6 alkyl, C1-6 alkoxy, C3- 12 cycloalkyl, 5- to 12- membered heteroaryl, C6-12aryl, and 4- to 10-membered heterocyclyl is optionally substituted with 1 to 5 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, OC(=O)OR20b, C(=O)NR21R22, OC(=O)NR21*R22*, NRnC(=O)N(R12)(R13), NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, P(=O)Rn*R12*, B(OR13*)2, C1-6 alkyl, C2-6alkenyl, C2-6alkynyl, C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl;whereineach R11, R12, R11*, R12*, R13, R13*, R14R14* R15R15*, R16, R17, R16*, R17*, R18R18a, R19, R20R20a, R20b, R21, R22, R21*, R22*, R23, R24, R25, R26, and R27is independently selected from H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-12cycloalkyl, C6-12aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl, orone or more of the pairs of variables selected from R12and R13, R16and R17, R16* and R17*, R21and R22, R21* and R22*, and R25and R26, together with the nitrogen to which they are attached, form a 3- to 8-membered ring, andOTQ-00925- 5 -when one or more of the 1 to 5 substituents is selected from OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, OC(=O)OR20b, C(=O)NR21R22, OC(=O)NR21*R22*, NRnC(=O)N(R12)(R13), NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, P(=O)Rn*R12*, B(OR13*)2, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl, each is further optionally substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14*, SR15*, NR16*R17*, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, Ce-i2aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl.

[0009] In some embodiments, the present disclosure relates to a pharmaceutical composition comprising a compound or pharmaceutically acceptable salt thereof described herein (e.g., a compound represented by structural formula (I*) or a pharmaceutically acceptable salt thereof) and various aspects thereof, and a pharmaceutically acceptable excipient.

[0010] In some embodiments, the present disclosure relates to a method of treating a disease or disorder, comprising administering to a subject in need thereof a compound or a pharmaceutically acceptable salt of the compound described herein (e.g., a compound represented by structural formula (I*) or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition described herein with respect to the second embodiment and various aspects thereof, wherein the disease or disorder is selected from inflammatory diseases, autoimmune diseases, granulomatous diseases, cancer and neurodegenerative diseases.

[0011] In some embodiments, the present relates to a method of treating a RIPK2 kinase-mediated disease or disorder, comprising administering to a subject in need thereof a compound described herein (e.g., a compound represented by structural formula (I*) or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition described herein with respect to the second embodiment and various aspects thereof. In one aspect, the RIPK2 kinase-mediated disease or disorder is a disease or disorder wherein inhibition of RIPK2 kinase would provide benefit. In a particular aspect, the disease or disorder is selected from an inflammatory disease, autoimmune disease, granulomatous disease, cancer, and neurodegenerative disease.

[0012] In some embodiments, the present disclosure relates to the use of a compound described herein (e.g., a compound represented by structural formula (I*) or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for use in treating RIPK2 kinase-OTQ-00925- 6 -mediated diseases or disorders (e.g., inflammatory diseases, autoimmune diseases, granulomatous diseases, cancer or neurodegenerative diseases).

[0013] In some embodiments, the present disclosure relates to a compound described herein (e.g., a compound represented by structural formula (I*) or a pharmaceutically acceptable salt thereof) for use in treating RIPK2 kinase-mediated diseases and disorders (e.g., inflammatory diseases, autoimmune diseases, granulomatous diseases, cancer or neurodegenerative diseases).DETAILED DESCRIPTION OF THE INVENTION

[0014] RIP Kinases

[0015] Protein kinases constitute a large family of structurally related enzymes that are responsible for the control of a wide variety of signal transduction processes in the cell. They have been shown to be key regulators in most cellular functions including proliferation, cell metabolism, cell survival, apoptosis, DNA damage repair, and cell motility. Uncontrolled signaling due to defective control of protein phosphorylation has been implicated in a number of diseases, including, for example, cancer, inflammation, allergies, immune diseases, CNS disorders, and angiogenesis.

[0016] Amongst the families of protein kinases, one particular example is the Receptor-Interacting Serine / Threonine Kinases including RIPK2. RIPK2 is composed of an N-terminal kinase domain and a C-terminal caspase-recruitment domain (CARD) linked via an intermediate (IM) region. The CARD domain of RIPK2 kinase mediates interaction with other CARD-containing proteins, such as NODI and NOD2. NODI and NOD2 are cytoplasmic receptors which are activated by specific bacterial peptidoglycan motifs and play a key role in innate immune surveillance. Upon intracellular bacterial exposure, NODI or NOD2 binds to RIPK2 to coordinate NF-KB (nuclear factor K B)-mediated cytokine responses. Once associated with NOD1 / 2, RIPK2 undergoes autophosphorylation on Tyr 474 (Y474), and acts as a molecular scaffold to bring together other kinases (TAK1, IKKb involved in NF-KB, and MAPK activation).

[0017] Both NOD 1 / 2 and RIPK2 are NF-KB regulated genes, and as such, their activation causes a positive feedback loop in which activation of NOD1 / 2: RIPK2 stimulates further activation and further inflammation. Additionally, NOD1 / 2 and RIPK2 expression areOTQ-00925- 7 -stimulated by a variety of mediators of inflammation, including TNF (Tumor Necrosis Factor) and IFN (Interferon). In addition to NF-KB pathway activation, the NOD1 / 2: RIPK2 complex stimulates autophagy, bactericidal activity, MHC Class II presentation and MAPK (Mitogen-Activated Protein Kinase) activation. Overall, this pathway modulates the innate immune system to help tailor the adaptive immune response to eradicate the offending pathogen.

[0018] Dysregulation of RIPK2- dependent signaling has been linked to autoinflammatory diseases. Patients with loss-of-function N0D2 alleles are prone to the development of Crohn’s disease (CD), an inflammatory disorder of the gastrointestinal tract. NOD2 / RIPK2 pathway is involved in the pathogenesis of inflammatory bowel disease (IBD). Both N0D2 and RIPK2 are upregulated in colon biopsies from CD patients as well as ulcerative colitis (UC) pediatric population. A selective RIPK2 inhibitor has been shown to block the spontaneous pro-inflammatory cytokines secretion from UC / CD patient’s biopsies. This result underlines that RIPK2 activation in the UC / CD patient’s mucosa leads to the pro-inflammatory status of these biopsies.

[0019] Rheumatoid arthritis (RA) is a disease where NOD2 / RIPK2 plays a role.NOD2 / RIPK2 pathway has been shown to be upregulated in immune cells of RA patients, suggesting that RIPK2 inhibition could be beneficial in this population. Gain-of-function N0D2 mutations have been genetically linked to other inflammatory diseases, such as Blau Syndrome / Early Onset Sarcoidosis (EOS), a pediatric granulomateous disease characterized by uveitis, dermatitis, and arthritis. Broad genotyping of young patients suffering from allergic rhinitis and atopic dermatitis highlighted common N0D2 polymorphism with Crohn’s as probable leading cause of the excessive immune response against skin tissues observed.Mutations in NODI have been associated with asthma and early-onset and extra-intestinal inflammatory bowel disease. Genetic and functional studies have also suggested a role for RIPK2-dependent signaling in a variety of other granulomateous disorders, such as sarcoidosis.

[0020] Metabolic syndrome, a pathology closely related to obesity and overweight, results from a chronic inflammation and is characterized by hypertension, hyperglycemia and lipolysis dysfunction. Activation of the immune system through NODI pathway was observed in patients suffering from metabolic syndrome. A recent functional study highlighting the impact of RIPK2OTQ-00925- 8 -inhibitors on lipolysis suggested a role for RIPK2-dependent signaling in dysglycemia and lipolysis.

[0021] In cardiac hypertrophy, a complex and multifactorial pathology, inflammation was shown as important hallmark of the disease, notably through the activation of NF-KB signaling. Knockout studies of RIPK2 on hypertrophic heart mice models suggested a role of RIPK2 in the regulation of the inflammation and subsequent tissue fibrosis and hypertrophy.

[0022] Beyond immuno-inflammatory diseases, RIPK2 modulation has also been described in several cancers. In triple negative breast cancer (TNBC), RIPK2 high expression has been associated to worse progression- free survival as well as a worse overall survival. It has been shown that RIPK2 knockdown increases docetaxel sensitivity and decreases tumor and lung metastasis. Another study focusing on a new cancer gene cassette on breast cancer patients’ chromosome 8 discovered RIPK2 coamplification with other tested oncogenes (such as MYC). TNBC biopsies performed in order to find druggable kinases beyond HER2 demonstrated that RIPK2 was hyper-phosphorylated in basal-like and luminal B breast cancer biopsies suggesting that this pathway could be activated in these type of TNBC. More recently, phospho-RIPK2 levels as well as NF-KB activity were shown elevated in biopsies of Inflammatory Breast Cancer. 34 head and neck squamous cell carcinoma cell lines showed that RIPK2 knockdown led to cell death, indicating central roles of the protein for cell survival. It has been proposed that RIPK2 promotes glioma cell growth by regulating TRAF3 and activating the NF-KB pathway and p38 signaling.

[0023] A new role for RIPK2 in osteosarcoma invasion was demonstrated when Gefitinib, via RIPK2 inhibition, prevented progression of pulmonary metastasis. Further, non-canonical NF-KB plays a pivotal role in non-Hodgkin’s lymphoma. Finally, using a three-dimensional lymphatic endothelial cell tube formation, RIPK2 was identified as a kinase involved in lymphatic vessel remodeling, a key factor for the metastatic spread of cancer. Taken together these data strongly support the development of RIPK2 inhibitors in oncology.

[0024] DEFINITIONS

[0025] 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, andOTQ-00925- 9 -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 Modem Methods of Organic Synthesis, 3rdEdition, Cambridge University Press, Cambridge, 1987.

[0026] 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-performance 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 etal., Tetrahedron 33:2725 (1977); Eliel, E. L. Stereochemistry of Carbon Compounds, McGraw-Hill, NY, 1962; and Wilen, S. H., Tables of Resolving Agents and Optical Resolutions p. 268, E. L. Eliel, Ed., Univ, of Notre Dame Press, Notre Dame, IN 1972. The invention additionally encompasses compounds as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

[0027] In a formula,is a single bond where the stereochemistry of the moieties immediately attached thereto is not specified, — is absent or a single bond, and= or is a single or double bond. An asterisk (*) next to an atom indicates that the atom is a stereocenter of unknown absolute configuration. For example, in a pair of enantiomers each can be depicted by a chemical structure with an asterisk (*) next to the stereocenter, which would indicate that the absolute configuration for the stereocenter of a given enantiomer is not defined.

[0028] Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g, enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each stereocenter. Therefore, singleOTQ-00925- 10 -stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention.Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention.

[0029] Unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, replacement of19F with18F, or the replacement of12C with13C or14C are within the scope of the disclosure. Such compounds are useful, for example, as analytical tools or probes in biological assays.

[0030] When a range of values is listed, it is intended to encompass each value and subrange within the range. For example, " Ci-6 alkyl" is intended to encompass Ci, C2, C3, C4, C5, Ce, C1-6, C1-5, C1-4, C1-3, C1-2, C2-6, C2-5, C2-4, C2-3, C3-6, C3-5, C3-4, C4-6, C4-5, and C5-6 alkyl.

[0031] The term "aliphatic" refers to alkyl, alkenyl, alkynyl, and carbocyclic groups.Likewise, the term "heteroaliphatic" refers to heteroalkyl, heteroalkenyl, heteroalkynyl, and heterocyclic groups.

[0032] The term "alkyl" refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 10 carbon atoms (" C1-10 alkyl"). In some embodiments, an alkyl group has 1 to 9 carbon atoms (" C1-9 alkyl"). In some embodiments, an alkyl group has 1 to 8 carbon atoms (" Ci-s alkyl"). In some embodiments, an alkyl group has 1 to 7 carbon atoms (" C1-7 alkyl"). In some embodiments, an alkyl group has 1 to 6 carbon atoms (" C1-6 alkyl"). In some embodiments, an alkyl group has 1 to 5 carbon atoms (" C1-5 alkyl"). In some embodiments, an alkyl group has 1 to 4 carbon atoms (" C1-4 alkyl"). In some embodiments, an alkyl group has 1 to 3 carbon atoms (" C1-3 alkyl"). In some embodiments, an alkyl group has 1 to 2 carbon atoms (" C1-2 alkyl"). In some embodiments, an alkyl group has 1 carbon atom (" Ci alkyl"). In some embodiments, an alkyl group has 2 to 6 carbon atoms (" C2-6 alkyl"). Examples of C1-6 alkyl groups include methyl (Ci), ethyl (C2), propyl (C3) (e.g., n-propyl, isopropyl), butyl (C4) (e.g., n-butyl, tert-butyl, sec- butyl, iso-butyl), pentyl (C5) (e.g., n-pentyl, 3-pentanyl, amyl, neopentyl, 3- methyl-2-butanyl, tertiary amyl), and hexyl (Ce) (e.g., n-hexyl). Additional examples of alkyl groups include n-heptyl (C7), n-octyl (Cs), and the like. Unless otherwiseOTQ-00925- 11 -specified, each instance of an alkyl group is independently unsubstituted (an "unsubstituted alkyl") or substituted (a "substituted alkyl") with one or more substituents (e.g., halogen, such as F). In certain embodiments, the alkyl group is an unsubstituted Ci-io alkyl (such as unsubstituted Ci-6 alkyl, e.g., -CH3 (Me), unsubstituted ethyl (Et), unsubstituted propyl (Pr, e.g., unsubstituted n-propyl (n-Pr), unsubstituted isopropyl (i-Pr)), unsubstituted butyl (Bu, e.g., unsubstituted n-butyl (n-Bu), unsubstituted tert-butyl (tert-Bu or t-Bu), unsubstituted sec-butyl (sec-Bu), unsubstituted isobutyl (i-Bu)). In certain embodiments, the alkyl group is a substituted C1-10 alkyl (such as substituted C1-6 alkyl, e.g., -CF3, Bn).

[0033] The term "haloalkyl" refers to a substituted alkyl group, wherein one or more 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 (" Ci-s haloalkyl"). In some embodiments, the haloalkyl moiety has 1 to 6 carbon atoms (" C1-6 haloalkyl"). In some embodiments, the haloalkyl moiety has 1 to 4 carbon atoms (" C1-4 haloalkyl"). 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 (" C1-2 haloalkyl"). Examples of haloalkyl groups include -CHF2, -CH2F, -CF3, -CH2CF3, -CF2CF3, -CF2CF2CF3, -CCI3, -CFC12, -CF2C1, and the like.

[0034] The term "deuteroalkyl" refers to an alkyl group, wherein one or more of the hydrogen atoms are independently replaced by deuterium. In some embodiments, the deuteroalkyl moiety has 1 to 8 carbon atoms (" Ci-s deuteroalkyl"). In some embodiments, the deuteroalkyl moiety has 1 to 6 carbon atoms (" C1-6 deuteroalkyl”). In some embodiments, the deuteroalkyl moiety has 1 to 4 carbon atoms (" C1-4 deuteroalkyl "). In some embodiments, the deuteroalkyl moiety has 1 to 3 carbon atoms (" C1-3 deuteroalkyl "). In some embodiments, the deuteroalkyl moiety has 1 to 2 carbon atoms (" C1-2 deuteroalkyl"). In some embodiments, the deuteroalkyl moiety is Ci, C2, C3, C4, C5, or Ce deuteroalkyl. A deuteroalkyl moiety having n carbon atoms can have from 1 to 2n+l deuterium atoms. Examples of deuteroalkyl groups include -CHD2, -CH2D, -CD3, -CH2CD3, -CD2CD3, -CD2CD2CD3, -CH(CD3)2, -CD(CD3)2, -C(CD2)3, and the like.

[0035] OTQ-00925- 12 -

[0036] The term "hydroxyalkyl" is a substituted alkyl group, wherein one or more of the hydrogen atoms are independently replaced by a hydroxyl. In some embodiments, the hydroxyalkyl moiety has 1 to 8 carbon atoms (" Ci-s hydroxyalkyl"). In some embodiments, the hydroxyalkyl moiety has 1 to 6 carbon atoms (" Ci-6 hydroxyalkyl"). In some embodiments, the hydroxyalkyl moiety has 1 to 4 carbon atoms (" Ci-4 hydroxyalkyl"). In some embodiments, the hydroxyalkyl moiety has 1 to 3 carbon atoms (" C1-3 hydroxyalkyl"). In some embodiments, the hydroxyalkyl moiety has 1 to 2 carbon atoms (" C1-2 hydroxyalkyl").

[0037] The term "alkoxy" refers to an alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. In some embodiments, the alkoxy moiety has 1 to 8 carbon atoms (" C1-8 alkoxy"). In some embodiments, the alkoxy moiety has 1 to 6 carbon atoms (" C1-6 alkoxy"). In some embodiments, the alkoxy moiety has 1 to 4 carbon atoms (" C1-4 alkoxy"). In some embodiments, the alkoxy moiety has 1 to 3 carbon atoms (" C1-3 alkoxy"). In some embodiments, the alkoxy moiety has 1 to 2 carbon atoms (" C1-2 alkoxy"). Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy and tert-butoxy.

[0038] The term "haloalkoxy" refers to a haloalkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. In some embodiments, the alkoxy moiety has 1 to 8 carbon atoms (" C1-8 haloalkoxy"). In some embodiments, the alkoxy moiety has 1 to 6 carbon atoms (" C1-6 haloalkoxy"). In some embodiments, the alkoxy moiety has 1 to 4 carbon atoms (" C1-4 haloalkoxy"). In some embodiments, the alkoxy moiety has 1 to 3 carbon atoms (" C1-3 haloalkoxy"). In some embodiments, the alkoxy moiety has 1 to 2 carbon atoms (" C1-2 haloalkoxy"). Representative examples of haloalkoxy include, but are not limited to, difluoromethoxy, trifluoromethoxy, and 2,2,2-trifluoroethoxy.

[0039] The term "alkoxyalkyl" is a substituted alkyl group, wherein one or more of the hydrogen atoms are independently replaced by an alkoxy group, as defined herein. In some embodiments, the alkoxyalkyl moiety has 1 to 8 carbon atoms (" Ci-s alkoxyalkyl"). In some embodiments, the alkoxyalkyl moiety has 1 to 6 carbon atoms (" C1-6 alkoxyalkyl"). In some embodiments, the alkoxyalkyl moiety has 1 to 4 carbon atoms (" C1-4 alkoxyalkyl"). In some embodiments, the alkoxyalkyl moiety has 1 to 3 carbon atoms (" C1-3 alkoxyalkyl"). In some embodiments, the alkoxyalkyl moiety has 1 to 2 carbon atoms (" C1-2 alkoxyalkyl").OTQ-00925- 73 -

[0040] The term "heteroalkyl" refers to an alkyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (i.e., inserted between adjacent carbon atoms of) and / or placed at one or more terminal position(s) of the parent chain. In certain embodiments, a heteroalkyl group refers to a saturated group having from 1 to 20 carbon atoms and 1 or more heteroatoms within the parent chain ("heteroCi-20 alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 18 carbon atoms and 1 or more heteroatoms within the parent chain ("heteroCi-is alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 16 carbon atoms and 1 or more heteroatoms within the parent chain ("heteroCi-16 alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 14 carbon atoms and 1 or more heteroatoms within the parent chain ("heteroCi-14 alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 12 carbon atoms and 1 or more heteroatoms within the parent chain ("heteroCi-12 alkyl"). In some embodiments, a heteroalkyl group is a saturated group having Ito 10 carbon atoms and 1 or more heteroatoms within the parent chain ("heteroCi-10 alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1 or more heteroatoms within the parent chain ("heteroCi-s alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 6 carbon atoms and 1 or more heteroatoms within the parent chain ("heteroCi-6 alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and 1 or 2 heteroatoms within the parent chain ("heteroCi-4 alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom within the parent chain ("heteroCi-3 alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom within the parent chain ("heteroCi-2 alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom ("heteroCi alkyl"). In some embodiments, the heteroalkyl group defined herein is a partially unsaturated group having 1 or more heteroatoms within the parent chain and at least one unsaturated carbon, such as a carbonyl group. For example, a heteroalkyl group may comprise an amide or ester functionality in its parent chain such that one or more carbon atoms are unsaturated carbonyl groups. Unless otherwise specified, each instance of a heteroalkyl group is independently unsubstituted (an "unsubstituted heteroalkyl") or substituted (a "substituted heteroalkyl") with one or moreOTQ-00925- 14 -substituents. In certain embodiments, the heteroalkyl group is an unsubstituted heteroCi-20 alkyl. In certain embodiments, the heteroalkyl group is an unsubstituted heteroCi-10 alkyl. In certain embodiments, the heteroalkyl group is a substituted heteroCi-20 alkyl. In certain embodiments, the heteroalkyl group is an unsubstituted heteroCi-10 alkyl.

[0041] The term "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). In some embodiments, an alkenyl group has 2 to 9 carbon atoms (" C2-9 alkenyl"). In some embodiments, an alkenyl group has 2 to 8 carbon atoms (" C2-8 alkenyl"). In some embodiments, an alkenyl group has 2 to 7 carbon atoms (" C2-7 alkenyl"). In some embodiments, an alkenyl group has 2 to 6 carbon atoms (" C2-6 alkenyl"). In some embodiments, an alkenyl group has 2 to 5 carbon atoms (" C2-5 alkenyl"). In some embodiments, an alkenyl group has 2 to 4 carbon atoms (" C2-4 alkenyl"). In some embodiments, an alkenyl group has 2 to 3 carbon atoms (" C2-3 alkenyl"). In some embodiments, an alkenyl group has 2 carbon atoms (" C2 alkenyl"). The one or more carbon-carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). Examples of C2-4 alkenyl groups include ethenyl (C2), 1 -propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. Examples of C2-6 alkenyl groups include the aforementioned C2-4 alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (Ce), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (Cs), octatrienyl (Cs), 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 certain embodiments, the alkenyl group is an unsubstituted C2-10 alkenyl. In certain embodiments, the alkenyl group is a substituted C2-10 alkenyl. In an alkenyl group, a C=C double bond for which the stereochemistryis not specified (e.g., -CH=CHCH3 or) may be an (E)- or (Z)-double bond.

[0042] The term "heteroalkenyl" refers to an alkenyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (i.e., inserted between adjacent carbon atoms of) and / or placed at one or more terminal position(s) of the parent chain. In certain embodiments, a heteroalkenyl group refers to a group having from 2 to 10 carbon atoms, at least one double bond, and 1 or more heteroatoms withinOTQ-00925- 15 -the parent chain ("heteroC2-io alkenyl"). In some embodiments, a heteroalkenyl group has 2 to 9 carbon atoms at least one double bond, and 1 or more heteroatoms within the parent chain ("heteroC2-9 alkenyl").

[0043] In some embodiments, a heteroalkenyl group has 2 to 8 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain ("heteroC2-s alkenyl"). In some embodiments, a heteroalkenyl group has 2 to 7 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain ("heteroC2-7 alkenyl"). In some embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain ("heteroC2-6 alkenyl"). In some embodiments, a heteroalkenyl group has 2 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain ("heteroC2-5 alkenyl"). In some embodiments, a heteroalkenyl group has 2 to 4 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain ("heteroC2-4 alkenyl"). In some embodiments, a heteroalkenyl group has 2 to 3 carbon atoms, at least one double bond, and 1 heteroatom within the parent chain ("heteroC2-3 alkenyl"). In some embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain ("heteroC2-6 alkenyl"). Unless otherwise specified, each instance of a heteroalkenyl group is independently unsubstituted (an "unsubstituted heteroalkenyl") or substituted (a "substituted heteroalkenyl") with one or more substituents. In certain embodiments, the heteroalkenyl group is an unsubstituted heteroC2-io alkenyl. In certain embodiments, the heteroalkenyl group is a substituted heteroC2-io alkenyl.

[0044] The term "alkynyl" refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 10 carbon atoms and one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 triple bonds) (" C2-10 alkynyl"). In some embodiments, an alkynyl group has 2 to 9 carbon atoms (" C2-9 alkynyl"). In some embodiments, an alkynyl group has 2 to 8 carbon atoms (" C2-8 alkynyl"). In some embodiments, an alkynyl group has 2 to 7 carbon atoms (" C2-7 alkynyl"). In some embodiments, an alkynyl group has 2 to 6 carbon atoms (" C2-6 alkynyl"). In some embodiments, an alkynyl group has 2 to 5 carbon atoms (" C2-5 alkynyl"). In some embodiments, an alkynyl group has 2 to 4 carbon atoms (" C2-4 alkynyl"). In some embodiments, an alkynyl group has 2 to 3 carbon atoms (" C2-3 alkynyl"). In some embodiments, an alkynyl group has 2 carbon atoms (" C2 alkynyl"). The one or more carbon-carbon triple bonds can be internal (suchOTQ-00925- 16 -as in 2-butynyl) or terminal (such as in 1-butynyl). Examples of C2-4 alkynyl groups include, without limitation, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. Examples of C2-6 alkynyl groups include the aforementioned C2-4 alkynyl groups as well as pentynyl (C5), hexynyl (Ce), and the like. Additional examples of alkynyl include heptynyl (C7), octynyl (Cs), 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 certain embodiments, the alkynyl group is an unsubstituted C2-10 alkynyl. In certain embodiments, the alkynyl group is a substituted C2-10 alkynyl.

[0045] The term "heteroalkynyl" refers to an alkynyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (i.e., inserted between adjacent carbon atoms of) and / or placed at one or more terminal position(s) of the parent chain. In certain embodiments, a heteroalkynyl group refers to a group having from 2 to 10 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain ("heteroC2-io alkynyl"). In some embodiments, a heteroalkynyl group has 2 to 9 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain ("heteroC2-9 alkynyl"). In some embodiments, a heteroalkynyl group has 2 to 8 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain ("heteroC2-s alkynyl"). In some embodiments, a heteroalkynyl group has 2 to 7 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain ("heteroC2-7 alkynyl"). In some embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain ("heteroC2-6 alkynyl"). In some embodiments, a heteroalkynyl group has 2 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain ("heteroC2-5 alkynyl"). In some embodiments, a heteroalkynyl group has 2 to 4 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain ("heteroC2-4 alkynyl"). In some embodiments, a heteroalkynyl group has 2 to 3 carbon atoms, at least one triple bond, and 1 heteroatom within the parent chain ("heteroC2-3 alkynyl"). In some embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain ("heteroC2-6 alkynyl"). Unless otherwise specified, each instance of a heteroalkynyl group is independently unsubstituted (an "unsubstitutedOTQ-00925- 17 -heteroalkynyl") or substituted (a "substituted heteroalkynyl") with one or more substituents. In certain embodiments, the heteroalkynyl group is an unsubstituted heteroC2-io alkynyl. In certain embodiments, the heteroalkynyl group is a substituted heteroC2-io alkynyl.

[0046] The term "carbocyclyl" or "carbocyclic" refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 14 ring carbon atoms (" C3-14 carbocyclyl") and zero heteroatoms in the non-aromatic ring system. In some embodiments, a carbocyclyl group has 3 to 10 ring carbon atoms (" C3-10 carbocyclyl"). In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms (" C3-8 carbocyclyl"). In some embodiments, a carbocyclyl group has 3 to 7 ring carbon atoms (" C3-7 carbocyclyl"). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (" C3-6 carbocyclyl"). In some embodiments, a carbocyclyl group has 4 to 6 ring carbon atoms (" C4-6 carbocyclyl"). In some embodiments, a carbocyclyl group has 5 to 6 ring carbon atoms (" C5-6 carbocyclyl"). In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (" C5-10 carbocyclyl"). Exemplary C3-6 carbocyclyl groups include, without limitation, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (Ce), cyclohexenyl (Ce), cyclohexadienyl (Ce), and the like.Exemplary C3-8 carbocyclyl groups include, without limitation, the aforementioned C3-8 carbocyclyl groups as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (Cs), cyclooctenyl (Cs), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (Cs), and the like. Exemplary C3-10 carbocyclyl groups include, without limitation, the aforementioned C3-8 carbocyclyl 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 certain 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 continue to designate the number of carbons in the carbocyclicOTQ-00925- 18 -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 certain embodiments, the carbocyclyl group is an unsubstituted C3-14 carbocyclyl. In certain embodiments, the carbocyclyl group is a substituted C3-14 carbocyclyl.

[0047] In some embodiments, "carbocyclyl" is a monocyclic, saturated carbocyclyl group having from 3 to 14 ring carbon atoms (" C3-14 cycloalkyl"). In some embodiments, a cycloalkyl group has 3 to 10 ring carbon atoms (" C3-10 cycloalkyl"). In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms (" C3-8 cycloalkyl"). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms (" C3-6 cycloalkyl"). In some embodiments, a cycloalkyl group has 4 to 6 ring carbon atoms (" C4-6 cycloalkyl"). In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms (" C5-6 cycloalkyl"). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms (" C5-10 cycloalkyl"). Examples of C5-6 cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (Ce). Examples of C3-6 cycloalkyl groups include the aforementioned C5-6 cycloalkyl groups as well as cyclopropyl (C3) and cyclobutyl (C4).Examples of C3-8 cycloalkyl groups include the aforementioned C3-6 cycloalkyl groups as well as cycloheptyl (C7) and cyclooctyl (Cs). 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 certain embodiments, the cycloalkyl group is an unsubstituted C3-14 cycloalkyl. In certain embodiments, the cycloalkyl group is a substituted C3-14 cycloalkyl.

[0048] The term "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 heteroatom is independently selected from nitrogen, oxygen, and sulfur ("3-14 membered heterocyclyl"). 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 ring systems wherein the heterocyclyl ring, as definedOTQ-00925- 19 -above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, or 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, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system. Unless otherwise specified, each instance of heterocyclyl is independently unsubstituted (an "unsubstituted heterocyclyl") or substituted (a "substituted heterocyclyl") with one or more substituents. In certain embodiments, the heterocyclyl group is an unsubstituted 3-14 membered heterocyclyl. In certain embodiments, the heterocyclyl group is a substituted 3-14 membered heterocyclyl.

[0049] In some embodiments, a heterocyclyl group is a 4-10 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 ("4-10 membered heterocyclyl"). In some embodiments, a heterocyclyl group is a 4-8 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.

[0050] Exemplary 3 -membered heterocyclyl groups containing 1 heteroatom include, without limitation, aziridinyl, 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, andOTQ-00925- 20 -dithiolany 1. 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, triazinyl. 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-l,8-naphthyridinyl, octahydropyrrolo[3,2- / ?]pyrrole, indolinyl, phthalimidyl, naphthalimidyl, chromanyl, chromenyl, lH-benzo[e][l,4]diazepinyl, 1.4.5.7-tetrahydropyrano[3,4- / >]pyrrolyl, 5,6-dihydro-477-furo[3,2- / >]pyrrolyl, 6,7-dihydro-577-furo[3,2- / >]pyranyl, 5,7-dihydro-477-thieno[2,3-c]pyranyl, 2,3-dihydro-177-pyrrolo[2,3- / >]pyridinyl, 2,3-dihydrofuro[2,3- / >]pyridinyl, 4,5,6,7-tetrahydro-177-pyrrolo[2,3- / >]pyridinyl, 4.5.6.7-tetrahydrofuro[3,2-c]pyridinyl, 4,5,6,7-tetrahydrothieno[3,2- / >]pyridinyl, 1,2,3,4-tetrahydro-l,6-naphthyridinyl, and the like.

[0051] The term "aryl" refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 it electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (" Ce-14 aryl"). In some embodiments, an aryl group has 6 ring carbon atoms (" Ce aryl"; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms (" Cio aryl"; e.g., naphthyl such as 1 -naphthyl and 2-naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms (" Ci4 aryl"; e.g., anthracyl). " Aryl" also includes 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 continue to designate the number of carbon atoms in the aryl ring system. UnlessOTQ-00925- 21 -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 certain embodiments, the aryl group is an unsubstituted Ce-14 aryl. In certain embodiments, the aryl group is a substituted Ce-14 aryl.

[0052] " Aralkyl" is a subset of "alkyl" and refers to an alkyl group substituted by an aryl group, wherein the point of attachment is on the alkyl moiety.

[0053] The term "heteroaryl" refers to a radical of a 5-14 membered monocyclic or polycyclic (e.g., bicyclic, tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 it 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" includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heteroaryl ring system. " Heteroaryl" also includes ring systems wherein the heteroaryl ring, as defined above, 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, the number of ring members designates the number of ring members in the fused polycyclic (aryl / heteroaryl) ring system. Polycyclic heteroaryl groups wherein one ring does not contain a 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 heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl).

[0054] In some embodiments, a heteroaryl group is a 5-12 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 ("5-12 membered heteroaryl"). 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 sulfurOTQ-00925- 22 -("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 certain embodiments, the heteroaryl group is an unsubstituted 5-14 membered heteroaryl. In certain embodiments, the heteroaryl group is a substituted 5-14 membered heteroaryl.

[0055] 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-OTQ-00925- 23 -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.

[0056] " Heteroaralkyl" is a subset of "alkyl" and refers to an alkyl group substituted by a heteroaryl group, wherein the point of attachment is on the alkyl moiety.

[0057] The term "unsaturated bond" refers to a double or triple bond.

[0058] The term "unsaturated" or "partially unsaturated" refers to a moiety that includes at least one double or triple bond.

[0059] The term "saturated" refers to a moiety that does not contain a double or triple bond, i.e., the moiety only contains single bonds.

[0060] Affixing the suffix "-ene" to a group indicates the group is a divalent moiety, e.g., alkylene is the divalent moiety of alkyl, 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.

[0061] A group is optionally substituted unless expressly provided otherwise. The term "optionally substituted" refers to being substituted or unsubstituted. In certain embodiments, alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted. " Optionally substituted" refers to a group which may be substituted or unsubstituted (e.g., "substituted" or "unsubstituted" alkyl, "substituted" or "unsubstituted" alkenyl, "substituted" or "unsubstituted" alkynyl, "substituted" or "unsubstituted" heteroalkyl, "substituted" or "unsubstituted" heteroalkenyl, "substituted" or "unsubstituted" heteroalkynyl, "substituted" or "unsubstituted" carbocyclyl, "substituted" or "unsubstituted" heterocyclyl, "substituted" or "unsubstituted" aryl, or "substituted" or "unsubstituted" heteroaryl group). In general, the term "substituted" means that at least one hydrogen present on a group is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which doesOTQ-00925- 24 -not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction. Unless otherwise indicated, a "substituted" group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position. The term "substituted" is contemplated to include substitution with all permissible substituents of organic compounds, and includes any of the substituents described herein that results in the formation of a stable compound. The present invention contemplates any and all such combinations in order to arrive at a stable compound. For purposes of this invention, heteroatoms such as nitrogen may have hydrogen substituents and / or any suitable substituent as described herein which satisfy the valencies of the heteroatoms and results in the formation of a stable moiety. The invention is not intended to be limited in any manner by the exemplary substituents described herein.Exemplary carbon atom substituents include, but are not limited to, halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR33, -ON(Rbb)2, -N(Rbb)2, -N(Rbb)3+X; -N(ORcc)Rbb, -SH, -SR33, -SSRCC, -C(=O)Raa, -CO2H, -CHO, -C(ORCC)3, -CO2R33, -0C(=0)R33, -OCO2R33, -C(=O)N(Rbb)2, -OC(=O)N(Rbb)2, -NRbbC(=0)R33, -NRbbC02R33, -NRbbC(=O)N(Rbb)2, -C(=NRbb)R33, -C(=NRbb)0R33, -0C(=NRbb)R33, -0C(=NRbb)0R33, -C(=NRbb)N(Rbb)2, -OC(=NRbb)N(Rbb)2, -NRbbC(=NRbb)N(Rbb)2, -C(=0)NRbbS02R33, -NRbbS02R33, -SO2N(Rbb)2, -SO2R33, -SO2OR33, -OSO2R33, -S(=0)R33, -0S(=0)R33, -SiCR33^, -OSI(R33)3, -C(=S)N(Rbb)2, -C(=0)SR33, -C(=S)SR33, -SC(=S)SR33, -SC(=0)SR33, -0C(=0)SR33, -SC(=0)0R33, -SC(=0)R33, -P(=0)(R33)2, -P(=O)(ORCC)2, -0P(=0)(R33)2, -OP(=O)(ORCC)2, -P(=O)(N(Rbb)2)2,-OP(=O)(N(Rbb)2)2, -NRbbP(=0)(R33)2, -NRbbP(=O)(ORcc)2, -NRbbP(=O)(N(Rbb)2)2, -P(RCC)2, -P(ORCC)2, -P(RCC)3+X, -P(ORCC)3+X, -P(RCC)4, -P(ORCC)2, -OP(RCC)2, -OP(RCC)3+X, -OP(ORCC)2, -0P(0Rcc)3+X, -OP(RCC)4, -OP(ORCC)4, -B(R33)2, -B(ORCC)2, -BR33(0RCC), Ci-10 alkyl, Ci-io perhaloalkyl, C2-10 alkenyl, C2- 10 alkynyl, heteroCi-10 alkyl, heteroC2-io alkenyl, heteroC2-io alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, Ce-i4aryl, and 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups; wherein X is a counterion; or two geminal hydrogens on a carbon atom are replaced with the group =0, =S, =NN(Rbb)2, =NNRbbC(=0)R33, =NNRbbC(=0)0R33,OTQ-00925- 25 -=NNRbbS(=0)2Raa, =NRbbor =NORCC; each instance of Raais, independently, selected from Ci-10 alkyl, Ci-io perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, heteroCi-10 alkyl, heteroC2-io alkenyl, heteroC2-io alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, Ce-14 aryl, and 5-14 membered heteroaryl, or two Raagroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups; each instance of Rbbis, independently, selected from hydrogen, -OH, -OR” -N(RCC)2, -CN, -C(=O)Raa, -C(=O)N(RCC)2, -CO2Raa, -SO2Raa, -C(=NRcc)ORaa, -C(=NRCC)N(RCC)2, -SO2N(RCC)2, -SO2RCC, -SO2ORCC, -SORaa, -C(=S)N(RCC)2, -C(=O)SRCC, -C(=S)SRCC, -P(=O)(Raa)2, -P(=O)(ORCC)2, -P(=O)(N(RCC)2)2, C1-10 alkyl, C1-10 perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, heteroCi-10 alkyl, heteroC2-io alkenyl, heteroC2-io alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, Ce-14 aryl, and 5-14 membered heteroaryl, or two Rbbgroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups; wherein X is a counterion; each instance of Rccis, independently, selected from hydrogen, C1-10 alkyl, Ci-10 perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, heteroCi-10 alkyl, heteroC2-io alkenyl, heteroC2-io alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, Ce-14 aryl, and 5-14 membered heteroaryl, or two Rccgroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups; each instance of Rddis, independently, selected from halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -ORee, -0N(Rff)2, -N(Rff)2, -N(Rff)3+X, -N(0Ree)Rff, -SH, -SRee, -SSRee, -C(=O)Ree, -CO2H, -CO2Ree, -OC(=O)Ree, -OCO2Ree, -C(=O)N(Rff)2, -OC(=O)N(Rff)2, -NRffC(=O)Ree, -NRffCO2Ree, -NRffC(=O)N(Rff)2, -C(=NRff)ORee, -OC(=NRff)Ree, -OC(=NRff)ORee, -C(=NRff)N(Rff)2, -OC(=NRff)N(Rff)2, -NRffC(=NRff)N(Rff)2, -NRffSO2Ree, -SO2N(Rff)2, -SO2Ree, -SO2ORee, -OSO2Ree, -S(=O)Ree, -Si(Ree)3, -OSi(Ree)3, -C(=S)N(Rff)2, -C(=O)SRee, -C(=S)SRee, -SC(=S)SRee, -P(=O)(ORee)2, -P(=O)(Ree)2, -OP(=O)(Ree)2, -OP(=O)(ORee)2, C1-6 alkyl, C1-6 perhaloalkyl, C2-6 alkenyl, C2-6 alkynyl, heteroCi-6 alkyl, heteroC2-6 alkenyl, heteroC2-6 alkynyl, C3-10 carbocyclyl, 3-10 memberedOTQ-00925- 26 -heterocyclyl, Ce-io aryl, 5-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgggroups, or two geminal Rddsubstituents can be joined to form =0 or =S; wherein X is a counterion; each instance of Reeis, independently, selected from Ci-6 alkyl, Ci-6 perhaloalkyl, C2-6 alkenyl, C2-6 alkynyl, heteroCi-6 alkyl, heteroC2-6 alkenyl, heteroC2-6 alkynyl, C3-10 carbocyclyl, Ce-io aryl, 3-10 membered heterocyclyl, and 3-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgggroups; each instance of Rffis, independently, selected from hydrogen, C1-6 alkyl, C1-6 perhaloalkyl, C2-6 alkenyl, C2-6 alkynyl, heteroCi-6 alkyl, heteroC2-6 alkenyl, heteroC2-6 alkynyl, C3-10 carbocyclyl, 3-10 membered heterocyclyl, Ce-io aryl and 5-10 membered heteroaryl, or two Rffgroups are joined to form a 3-10 membered heterocyclyl or 5-10 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgggroups; and each instance of Rggis, independently, halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC1-6 alkyl, -ON(CI-6alkyl)2, -N(CI-6alkyl)2, -N(CI-6alkyl)3+X, -NH(CI-6alkyl)2+X, -NH2(CI-6alkyl)+X, -NH3+X, -N(OCI-6alkyl)(Ci-6alkyl), -N(0H)(CI-6alkyl), -NH(OH), -SH, -SC1-6 alkyl, -SS(Ci-6alkyl), -C(=O)(Ci-6alkyl), -CO2H, -CO2(Ci-6alkyl), -OC(=O)(Ci-6alkyl), -OCO2(Ci-6alkyl), -C(=0)NH2, -C(=O)N(CI-6alkyl)2, -OC(=O)NH(CI-6alkyl), -NHC(=O)(CI-6alkyl), -N(Ci-6alkyl)C(=O)( C1-6 alkyl), -NHCO2(CI-6alkyl), -NHC(=O)N(CI-6alkyl)2, -NHC(=O)NH(CI-6alkyl), -NHC(=0)NH2, -C(=NH)O(CI-6alkyl), -OC(=NH)(CI-6alkyl), -OC(=NH)OCi-6alkyl, -C(=NH)N(Ci-6alkyl)2, -C(=NH)NH(CI-6alkyl), -C(=NH)NH2, -OC(=NH)N(CI-6 alkyl)2, -0C(=NH)NH(CI-6alkyl), -0C(=NH)NH2, -NHC(=NH)N(CI-6 alkyl)2, -NHC(=NH)NH2, -NHSO2(CI-6alkyl), -SO2N(CI-6alkyl)2, -SO2NH(CI-6alkyl), -SO2NH2, -SO2(Ci-6alkyl), -SO2O(Ci-6alkyl), -OSO2(Ci-6alkyl), -SO(Ci-6alkyl), -Si(Ci-6alkyl)3, -OSi(Ci-6alkyl)3, -C(=S)N(CI-6alkyl)2, -C(=S)NH(CI-6alkyl), -C(=S)NH2, -C(=O)S(CI-6alkyl), -C(=S)SCi-6alkyl, -SC(=S)SCi-6alkyl, -P(=O)(OCi-6alkyl)2, -P(=O)(Ci-6alkyl)2, -OP(=O)(Ci-6alkyl)2, -OP(=O)(OCi-6alkyl)2, C1-6 alkyl, C1-6 perhaloalkyl, C2-6 alkenyl, C2-6 alkynyl, heteroCi-6 alkyl, heteroC2-6 alkenyl, heteroC2-6 alkynyl, C3-10OTQ-00925- 27 -carbocyclyl, Ce-io aryl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl; or two geminal Rggsubstituents can be joined to form =0 or =S; wherein X is a counterion.

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

[0063] The term "hydroxyl" or "hydroxy" refers to the group -OH. The term "substituted hydroxyl" or "substituted hydroxyl," by extension, refers to a hydroxyl group wherein the oxygen atom directly attached to the parent molecule is substituted with a group other than hydrogen, and includes groups selected from -ORaa, -0N(Rbb)2, -OC(=O)SRaa, -OC(=O)Raa, -OCO2Raa, -OC(=O)N(Rbb)2, -OC(=NRbb)Raa, -OC(=NRbb)ORaa, -0C(=NRbb)N(Rbb)2, -OS(=O)Raa, -OSO2Raa, -OSi(Raa)3, -OP(RCC)2, -OP(RCC)3+X, -OP(ORCC)2, -OP(ORCC)3+X, -OP(=O)(Raa)2, -OP(=O)(ORCC)2, and -OP(=O)(N(Rbb)2)2, whereinX, R^, Rbband Rccare as defined herein.

[0064] The term "amino" refers to the group -NH2. The term "substituted amino," by extension, refers to a monosubstituted amino, a disubstituted amino, or a trisubstituted amino. In certain embodiments, the "substituted amino" is a monosubstituted amino or a disubstituted amino group.The term "monosubstituted amino" refers to an amino group wherein the nitrogen atom directly attached to the parent molecule is substituted with one hydrogen and one group other than hydrogen, and includes groups selected from -NH(Rbb), -NHC(=O)Raa, -NHCO2Raa,-NHC(=O)N(Rbb)2, -NHC(=NRbb)N(Rbb)2, -NHSO2Raa, -NHP(=O)(ORCC)2, and -NHP(=O)(N(Rbb)2)2, wherein Raa, Rbb, and Rccare as defined herein, and wherein Rbbof the group -NH(Rbb) is not hydrogen.

[0065] The term "disubstituted amino" refers to an amino group wherein the nitrogen atom directly attached to the parent molecule is substituted with two groups other than hydrogen, and includes groups selected from -N(Rbb)2, -NRbbC(=O)Raa, -NRbbCO2Raa, -NRbbC(=O)N(Rbb)2, -NRbbC(=NRbb)N(Rbb)2, -NRbbSO2Raa, -NRbbP(=O)(ORcc)2, and -NRbbP(=O)(N(Rbb)2)2, wherein Raa, Rbb, and Rccare as defined herein, with the proviso that the nitrogen atom directly attached to the parent molecule is not substituted with hydrogen.OTQ-00925- 28 -

[0066] The term "trisubstituted amino" refers to an amino group wherein the nitrogen atom directly attached to the parent molecule is substituted with three groups, and includes groups selected from -N(Rbb)2 and -N(Rbb)3 X, wherein Rbband X are as defined herein.

[0067] The term "sulfonyl" refers to a group selected from -SO2N(Rbb)2, -SChR^, and-SChOR1111, wherein Raaand Rbbare as defined herein.

[0068] The term "sulfinyl" refers to the group -S(=O)Raa, wherein Raais as defined herein.

[0069] The term "acyl" refers to a group having the general formula -C(=O)RX1, -C(=O)ORX1, -C(=O)-O-C(=O)RX1, -C(=O)SRX1, -C(=O)N(RX1)2, -C(=S)RX1, -C(=S)N(RX1)2, -C(=S)O(RX1), -C(=S)S(RX1), -C(=NRX1)RX1, -C(=NRX1)ORX1, -C(=NRX1)SRX1, and -C(=NRX1)N(RX1)2, wherein RX1is hydrogen; halogen; substituted or unsubstituted hydroxyl; substituted or unsubstituted thiol; substituted or unsubstituted amino; substituted or unsubstituted acyl, cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched alkyl; cyclic or acyclic, substituted or unsubstituted, branched or unbranched alkenyl; substituted or unsubstituted alkynyl; substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, aliphaticoxy, heteroaliphaticoxy, alkyloxy, heteroalkyloxy, aryloxy, heteroaryloxy, aliphaticthioxy, heteroaliphaticthioxy, alkylthioxy, heteroalkylthioxy, arylthioxy, heteroarylthioxy, mono- or di- aliphaticamino, mono- or di- heteroaliphaticamino, mono- or di-alkylamino, mono- or di-heteroalkylamino, mono- or di-arylamino, or mono- ordi-heteroarylamino; or two RX1groups taken together form a 5- to 6-membered heterocyclic ring.

[0070] Exemplary acyl groups include aldehydes (-CHO), carboxylic acids (-CO2H), ketones, acyl halides, esters, amides, imines, carbonates, carbamates, and ureas. Acyl substituents include, but are not limited to, any of the substituents described herein, that result in the formation of a stable moiety (e.g., aliphatic, alkyl, alkenyl, alkynyl, heteroaliphatic, heterocyclic, aryl, heteroaryl, acyl, oxo, imino, thiooxo, cyano, isocyano, amino, azido, nitro, hydroxyl, thiol, halo, aliphaticamino, heteroaliphaticamino, alkylamino, heteroalkylamino, arylamino, heteroarylamino, alkylaryl, arylalkyl, aliphaticoxy, heteroaliphaticoxy, alkyloxy, heteroalkyloxy, aryloxy, heteroaryloxy, aliphaticthioxy, heteroaliphaticthioxy, alkylthioxy,OTQ-00925- 29 -heteroalkylthioxy, arylthioxy, heteroarylthioxy, acyloxy, and the like, each of which may or may not be further substituted).

[0071] The term "carbonyl" refers a group wherein the carbon directly attached to the parent molecule is sp2hybridized, and is substituted with an oxygen, nitrogen or sulfur atom, e.g., a group selected from ketones (e.g., -C(=O)Raa), carboxylic acids (e.g., -CO2H), aldehydes (-CHO), esters (e.g, -COzR^, -C(=O)SRaa, -C(=S)SRaa), amides (e.g, -C(=O)N(Rbb)2,-C(=O)NRbbSO2Raa, -C(=S)N(Rbb)2), and imines (e.g., -C(=NRbb)Raa, -C(=NRbb)ORaa), -C(=NRbb)N(Rbb)2), wherein Raaand Rbbare as defined herein.

[0072] The term "oxo" refers to the group =0, and the term "thiooxo" refers to the group =S.

[0073] Nitrogen atoms can be substituted or unsubstituted as valency permits, and include primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents include, but are not limited to, hydrogen, -OH, -OR1111, -N(RCC)2, -CN, -C(=O)Raa, -C(=O)N(RCC)2, -COIR2*, -SOZR^, -C(=NRbb)Raa, -C(=NRcc)ORaa, -C(=NRCC)N(RCC)2, -SO2N(RCC)2, -SO2RCC, -SO2ORCC, -SORaa, -C(=S)N(RCC)2, -C(=O)SRCC, -C(=S)SRCC, -P(=O)(ORCC)2, -P(=O)(Raa)2, -P(=O)(N(RCC)2)2, CI-10 alkyl, C1-10 perhaloalkyl, C2-10 alkenyl, C2.10 alkynyl, heteroCi-10 alkyl, heteroC2-io alkenyl, heteroC2-io alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, Ce-14 aryl, and 5-14 membered heteroaryl, or two Rccgroups attached to an N atom are joined to form a 3-14 membered heterocyclyl or a 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups, and wherein Raa, Rbb, Rcc, and Rddare as defined herein.

[0074] In certain embodiments, the substituent present on the nitrogen atom is an nitrogen protecting group (also referred to herein as an "amino protecting group"). Nitrogen protecting groups include, but are not limited to, -OH, -OR1111, -N(RCC)2, -C(=O)Raa, -C(=O)N(RCC)2, -CO2Raa, -SO2Raa, -C(=NRcc)Raa, -C(=NRcc)ORaa, -C(=NRCC)N(RCC)2, -SO2N(RCC)2, -SO2RCC, -SO2ORCC, -SORaa, -C(=S)N(RCC)2, -C(=O)SRCC, -C(=S)SRCC, CI-10 alkyl (e.g., aralkyl, heteroaralkyl), C2-10 alkenyl, C2-10 alkynyl, heteroCi-10 alkyl, heteroC2-io alkenyl, heteroC2-io alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, Ce-14 aryl, and 5-14 membered heteroaryl groups, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl,OTQ-00925- 30 -heteroalkynyl, carbocyclyl, heterocyclyl, aralkyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups, and wherein R^, Rbb, Rccand Rddare as defined herein. Nitrogen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rdedition, John Wiley & Sons, 1999, incorporated herein by reference.

[0075] For example, nitrogen protecting groups such as amide groups (e.g., -C(=O)Raa) include, but are not limited to, formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropanamide, picolinamide, 3-pyridylcarboxamide, N-benzoylphenylalanyl derivative, benzamide, p-phenylbenzamide, o-nitrophenylacetamide, o-nitrophenoxyacetamide, acetoacetamide, (N1-dithiobenzyloxyacylamina)acetamide, 3-(p-hydroxyphenyl)propanamide, 3-(o-nitrophenyl)propanamide, 2-methyl-2-(o-nitrophenoxy)propanamide, 2-methyl-2-(o-phenylazophenoxy )propanamide, 4-chlorobutanamide, 3-methyl-3-nitrobutanamide, o-nitrocinnamide, N-acetylmethionine derivative, o-nitrobenzamide ando-(benzoyloxymethyl)benzamide.

[0076] Nitrogen protecting groups such as carbamate groups (e.g., -C(=O)ORaa) include, but are not limited to, methyl carbamate, ethyl carbamate, 9-fluorenylmethyl carbamate (Fmoc), 9-(2-sulfa)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluoroenylmethyl carbamate, 2,7-di-t-butyl- [9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methyl carbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl carbamate (Teoc), 2-phenylethyl carbamate (hZ), l-(l-adamantyl)-l-methylethyl carbamate (Adpoc), 1, 1 -dimethyl-2-haloethyl carbamate, l,l-dimethyl-2,2-dibromoethyl carbamate (DB-t-BOC), l,l-dimethyl-2,2,2-trichloroethyl carbamate (TCBOC), 1 -methyl- l-(4-biphenylyl)ethyl carbamate (Bpoc), l-(3,5-di-t-butylphenyl)-l-methylethyl carbamate (t-Bumeoc), 2-(2'- and 4'-pyridyl)ethyl carbamate (Pyoc), 2-(N, N-dicyclohexylcarboxamido) ethyl carbamate, t-butyl carbamate (BOC or Boc), 1-adamantyl carbamate (Adoc), vinyl carbamate (Voc), allyl carbamate (Alloc), 1 -isopropylallyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc), 8-quinolyl carbamate, N-hydroxypiperidinyl carbamate, alkyldithio carbamate, benzyl carbamate (Cbz), p-methoxybenzyl carbamate (Moz), p-nitrobenzyl carbamate, p-bromobenzyl carbamate, p-OTQ-00925- 31 -chlorobenzyl carbamate, 2,4-dichlorobenzyl carbamate, 4-methylsulfinylbenzyl carbamate (Msz), 9-anthrylmethyl carbamate, diphenylmethyl carbamate, 2-methylthioethyl carbamate, 2-methylsulfonylethyl carbamate, 2-(p-toluenesulfonyl)ethyl carbamate, [2-(l,3-dithianyl)]methyl carbamate (Dmoc), 4-methylthiophenyl carbamate (Mtpc), 2,4-dimethylthiophenyl carbamate (Bmpc), 2-phosphonioethyl carbamate (Peoc), 2-triphenylphosphonioisopropyl carbamate (Ppoc), l,l-dimethyl-2-cyanoethyl carbamate, m-chloro-p-acyloxybenzyl carbamate, p-(dihydroxyboryl)benzyl carbamate, 5-benzisoxazolylmethyl carbamate, 2-(trifluoromethyl)-6-chromonylmethyl carbamate (Tcroc), m-nitrophenyl carbamate, 3, 5 -dimethoxybenzyl carbamate, o-nitrobenzyl carbamate, 3,4-dimethoxy-6-nitrobenzyl carbamate, phenyl(o-nitrophenyl)methyl carbamate, t-amyl carbamate, S-benzyl thiocarbamate, p-cyanobenzyl carbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentyl carbamate, cyclopropylmethyl carbamate, p-decyloxybenzyl carbamate, 2,2-dimethoxyacylvinyl carbamate, o-(N, N-dimethylcarboxamido )benzyl carbamate, l,l-dimethyl-3-(N, N-dimethylcarboxamido)propyl carbamate, 1, 1 -dimethylpropynyl carbamate, di(2-pyridyl)methyl carbamate, 2-furanylmethyl carbamate, 2-iodoethyl carbamate, isobornyl carbamate, isobutyl carbamate, isonicotinyl carbamate, p-(p'-methoxyphenylazo )benzyl carbamate, 1-methylcyclobutyl carbamate, 1 -methylcyclohexyl carbamate, 1 -methyl- 1 -cyclopropylmethyl carbamate, l-methyl-l-(3,5- dimethoxyphenyl)ethyl carbamate, 1 -methyl- l-(p-phenylazophenyl) ethyl carbamate, 1 -methyl- 1 -phenylethyl carbamate, 1 -methyl- 1 -(4-pyridyl)ethyl carbamate, phenyl carbamate, p-(phenylazo)benzyl carbamate, 2,4,6-tri-t-butylphenyl carbamate, 4-(trimethylammonium)benzyl carbamate, and 2,4,6-trimethylbenzyl carbamate.

[0077] Nitrogen protecting groups such as sulfonamide groups (e.g., -S(=O)2Raa) include, but are not limited to, p-toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6-trimethyl-4-methoxybenzenesulfonamide (Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb), 2,6-dimethyl-4- methoxybenzenesulfonamide (Pme), 2,3,5,6-tetramethyl-4- methoxybenzenesulfonamide (Mte), 4-methoxybenzenesulfonamide (Mbs), 2,4,6-trimethylbenzenesulfonamide (Mts), 2,6-dimethoxy-4-methylbenzenesulfonamide (iMds), 2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide (Ms), 2-trimethylsilylethanesulfonamide (SES), 9-OTQ-00925- 32 -anthracenesulfonamide, 4-(4',8'-dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS ), benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide.

[0078] Other nitrogen protecting groups include, but are not limited to, phenothiazinyl-(lO)-acyl derivative, N'-p-toluenesulfonylaminoacyl derivative, N'-phenylaminothioacyl derivative, N-benzoylphenylalanyl derivative, N-acetylmethionine derivative, 4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dithiasuccinimide (Dts), N-2,3-diphenylmaleimide, N-2,5-dimethylpyrrole, N-l,l,4,4-tetramethyldisilylazacyclopentane adduct (STABASE), 5-substituted l,3-dimethyl-l,3,5-triazacyclohexan- 2-one, 5-substituted l,3-dibenzyl-l,3,5-triazacyclohexan-2-one, 1 -substituted 3,5-dinitro-4-pyridone, N-methylamine, N-allylamine, N-[2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine, N-(l-isopropyl-4-nitro-2-oxo-3-pyroolin-3-yl)amine, quaternary ammonium salts, N-benzylamine, N-di(4-methoxyphenyl)methylamine, N-5-dibenzosuberylamine, N-triphenylmethylamine (Tr), N-[(4-methoxyphenyl)diphenylmethyl]amine (MMTr), N-9-phenylfluorenylamine (PhF), N-2,7-dichloro-9-fluorenylmethyleneamine, N-ferrocenylmethylamino (Fern), N-2-picolylamino N'-oxide, N- 1,1 -dimethylthiomethyleneamine, N-benzylideneamine, N-p-methoxybenzylideneamine, N-diphenylmethyleneamine, N-[(2-pyridyl)mesityl]methyleneamine, N-(N', N'-dimethylaminomethylene)amine, N, N'-isopropylidenediamine, N-p-nitrobenzylideneamine, N-salicylideneamine, N-5-chlorosalicylideneamine, N-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine, N-cyclohexylideneamine, N-(5,5-dimethyl-3-oxo-l- cyclohexenyl)amine, N-borane derivative, N-diphenylborinic acid derivative, N- [phenyl(pentaacylchromium- or tungsten)acyl] amine, N-copper chelate, N-zinc chelate, N- nitroamine, N-nitrosoamine, amine N-oxide, diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt), diphenylthiophosphinamide (Ppt), dialkyl phosphoramidates, dibenzyl phosphoramidate, diphenyl phosphoramidate, benzenesulfenamide, o-nitrobenzenesulfenamide (Nps ), 2,4-dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide, triphenylmethylsulfenamide, and 3-nitropyridinesulfenamide (Npys). In certain embodiments, a nitrogen protecting group is benzyl (Bn), tert-butyloxycarbonyl (BOC), carboxybenzyl (Cbz), 9-flurenylmethyloxycarbonyl (Fmoc), trifluoroacetyl, triphenylmethyl, acetyl (Ac), benzoyl (Bz), p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), 2,2,2-OTQ-00925- 33 -trichloroethyloxycarbonyl (Troc), triphenylmethyl (Tr), tosyl (Ts), brosyl (Bs), nosyl (Ns), mesyl (Ms), triflyl (Tf), or dansyl (Ds).

[0079] In certain embodiments, the substituent present on an oxygen atom is an oxygen protecting group (also referred to herein as an "hydroxyl protecting group"). Oxygen protecting groups include, but are not limited to, -R”, -N(Rbb)2, -C(=O)SRaa, -C(=O)Raa, -CO2Raa, -C(=O)N(Rbb)2, -C(=NRbb)Raa, -C(=NRbb)ORaa, -C(=NRbb)N(Rbb)2, -S(=O)Raa, -SO2Raa, -Si(Raa)3, -P(RCC)2, -P(RCC)3+X, -P(ORCC)2, -P(ORCC)3+X, -P(=O)(Raa)2, -P(=O)(ORCC)2, and -P(=O)(N(Rbb)2)2, wherein X, Raa, Rbb, and Rccare as defined herein. Oxygen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rdedition, John Wiley & Sons, 1999, incorporated herein by reference.

[0080] Exemplary oxygen protecting groups include, but are not limited to, methyl, methoxylmethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM), t-butoxymethyl, 4-pentenyloxymethyl (POM), siloxymethyl, 2-methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl (SEMOR), tetrahydropyranyl (THP), 3 -bromotetrahydropyranyl, tetrahydrothiopyranyl, 1 -methoxy cyclohexyl, 4-methoxytetrahydropyranyl (MTHP), 4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranyl S, S-dioxide, l-[(2-chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl (CTMP), l,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl, 2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl, 1 -ethoxy ethyl, 1 -(2-chloroethoxy)ethyl, 1 -methyl- 1 -methoxy ethyl, 1 -methyl- 1 -benzyloxy ethyl, 1 -methyl- 1 -benzyloxy-2-fluoroethyl, 2, 2, 2-tri chloroethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl, t-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, benzyl (Bn), p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2- picolyl, 4-picolyl, 3-methyl-2-picolyl N-oxido, diphenylmethyl, p,p'-dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl, oc-naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl, tri(p-methoxyphenyl)methyl, 4-(4'-bromophenacyloxyphenyl)diphenylmethyl, 4,4',4"-tris(4,5-OTQ-00925- 34 -dichlorophthalimidophenyl)methyl, 4,4',4"-tris(levulinoyloxyphenyl)methyl, 4, 4', 4"-tris(benzoyloxyphenyl)methyl, 3-(imidazol- 1 -yl)bis(4',4"-dimethoxyphenyl)methyl, 1, 1 -bis(4-methoxyphenyl)-l'-pyrenylmethyl, 9-anthryl, 9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl, l,3-benzodithiolan-2-yl, benzisothiazolyl S, S- dioxido, trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS), dimethylthexylsilyl, t-butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl (TBDPS), tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl (DPMS), t-butylmethoxyphenylsilyl (TEMPS), formate, benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate, 3 -phenylpropionate, 4-oxopentanoate (levulinate), 4,4-(ethylenedithio )pentanoate (levulinoyldithioacetal), pivaloate, adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate, 2,4,6-trimethylbenzoate (mesitoate), methyl carbonate, 9-fluorenylmethyl carbonate (Fmoc), ethyl carbonate, 2,2,2-trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate (TMSEC), 2-(phenylsulfonyl)ethyl carbonate (Psec), 2-(triphenylphosphonio)ethyl carbonate (Peoc), isobutyl carbonate, vinyl carbonate, allyl carbonate, t-butyl carbonate (BOC or Boc), p-nitrophenyl carbonate, benzyl carbonate, p-methoxybenzyl carbonate, 3,4-dimethoxybenzyl carbonate, o-nitrobenzyl carbonate, p-nitrobenzyl carbonate, S-benzyl thiocarbonate, 4-ethoxy-l-napththyl carbonate, methyl dithiocarbonate, 2-iodobenzoate, 4-azidobutyrate, 4-nitro-4-methylpentanoate, o-(dibromomethyl)benzoate, 2-formylbenzenesulfonate, 2-(methylthiomethoxy)ethyl, 4-(methylthiomethoxy)butyrate, 2-(methylthiomethoxymethyl)benzoate, 2,6-dichloro-4-methylphenoxyacetate, 2,6-dichloro-4-(l,l,3,3-tetramethylbutyl)phenoxyacetate, 2,4-bis( 1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinoate, (E)-2-methyl-2-butenoate, o-(methoxyacyl)benzoate, oc-naphthoate, nitrate, alkyl N, N, N', N'-tetramethylphosphorodiamidate, alkyl N-phenylcarbamate, borate, dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulfenate, sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate (Ts). In certain embodiments, an oxygen protecting group is silyl. In certain embodiments, an oxygen protecting group is t-butyldiphenylsilyl (TBDPS), t-butyldimethylsilyl (TBDMS), triisoproylsilyl (TIPS), triphenylsilyl (TPS), triethylsilyl (TES), trimethylsilyl (TMS), triisopropylsiloxymethyl (TOM), acetyl (Ac), benzoyl (Bz), allyl carbonate, 2,2,2-OTQ-00925- 35 -tri chloroethyl carbonate (Troc), 2-trimethylsilylethyl carbonate, methoxymethyl (MOM), 1-ethoxyethyl (EE), 2-methyoxy-2-propyl (MOP), 2,2,2-trichloroethoxyethyl, 2-methoxyethoxymethyl (MEM), 2- trimethylsilylethoxymethyl (SEM), methylthiomethyl (MTM), tetrahydropyranyl (THP), tetrahydrofuranyl (THF), p-methoxyphenyl (PMP), triphenylmethyl (Tr), methoxytrityl (MMT), dimethoxytrityl (DMT), allyl, p-methoxybenzyl (PMB), t-butyl, benzyl (Bn), allyl, or pivaloyl (Piv).

[0081] In certain embodiments, the substituent present on a sulfur atom is a sulfur protecting group (also referred to as a "thiol protecting group"). Sulfur protecting groups include, but are not limited to, -R^, -N(Rbb)2, -C(=O)SRaa, -C(=O)Raa, -CO2Raa, -C(=O)N(Rbb)2, -C(=NRbb)Raa, -C(=NRbb)ORaa, -C(=NRbb)N(Rbb)2, -S(=O)Raa, -SO2Raa, -Si(Raa)3, -P(RCC)2, -P(RCC)3+X, -P(ORCC)2, -P(ORCC)3+X, -P(=O)(Raa)2, -P(=O)(ORCC)2, and -P(=O)(N(Rbb)2)2, wherein Raa, Rbb, and Rccare as defined herein. Sulfur protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W.Greene and P. G. M. Wuts, 3rdedition, John Wiley & Sons, 1999, incorporated herein by reference. In certain embodiments, a sulfur protecting group is acetamidomethyl, t-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl.

[0082] A "counterion" as used herein can be an anionic counterion or a cationic counterion.

[0083] An “anionic counterion" is a negatively charged group associated with a positively charged group in order to maintain electronic neutrality. An anionic counterion may be monovalent (i.e., including one formal negative charge). An anionic counterion may also be multivalent (i.e., including more than one formal negative charge), such as divalent or trivalent. Exemplary anionic counterions include halide ions (e.g., F, Cl", Br, I"), NO3", CIO4, OH", H2PO4", HCO3, HSO4", sulfonate ions (e.g., methansulfonate, trifluoromethanesulfonate, p-toluenesulfonate, benzenesulfonate, 10-camphor sulfonate, naphthalene-2-sulfonate, naphthalene- 1 -sulfonic acid-5-sulfonate, ethan-1 -sulfonic acid-2-sulfonate, and the like), carboxylate ions (e.g., acetate, propanoate, benzoate, glycerate, lactate, tartrate, glycolate, gluconate, and the like), BF4, PF4, PF6, AsF6", SbF6", B[3,5-(CF3)2C6H3]4", B(C6F5)4, BPh4, A1(OC(CF3)3)4", and carborane anions (e.g., CBnHi2" or (HCBi iMesBre) ). Exemplary anionic counterions which may be multivalent include CO32, HPO42, PO43, B4O72, SO42, S2O32, carboxylate anions (e.g., tartrate, citrate, fumarate, maleate, malate, malonate, gluconate,OTQ-00925- 36 -succinate, glutarate, adipate, pimelate, suberate, azelate, sebacate, salicylate, phthalates, aspartate, glutamate, and the like), and carboranes.

[0084] A “cationic counterion" is a positively charged group associated with a negatively charged group in order to maintain electronic neutrality. A cationic counterion may be monovalent (i.e., including one formal positive charge). A cationic counterion may also be multivalent (i.e., including more than one formal positive charge), such as divalent or trivalent. Exemplary cationic counterions include, for example, cations of metals, such as alkali metals and alkaline earth metals, as well as NEU+, NH3(Ci-ealkyl)+, NH2(CI-6 alkyl)2+, NH (Ci-6 alkyl)s+, and N+(Ci-6 alkyl)4 cations, where the Ci-6 alkyl can be optionally substituted as discussed above. Representative cations of alkali and alkaline earth metals include Li+, Na+, K+, Mg2+, and Ca2+, and the like.Formulation and Administration

[0085] Another embodiment of the invention is a composition comprising a compound of the disclosure (e.g, a compound represented by structural formula (I*) or a pharmaceutically acceptable salt thereof), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle. In certain embodiments, a composition of the disclosure is formulated for administration to a patient in need of the composition. In some embodiments, a composition of the disclosure is formulated for oral, intravenous, subcutaneous, intraperitoneal or dermatological administration to a patient in need thereof.

[0086] As used herein, the term “subject” is intended to include human and non-human animals. Exemplary human subjects include a human patient having a disorder, e.g., a disorder described herein or a normal subject. The term “non-human animals” of the invention includes all vertebrates, e.g., non-mammals (such as chickens, amphibians, reptiles) and mammals, such as non-human primates, domesticated and / or agriculturally useful animals, e.g, sheep, cow, pig, etc., and companion animals (dog, cat, horse, etc.). In a particular embodiment the subject is a human, for example, a adult male or female or a male or female child.

[0087] As used herein, an amount of a compound described herein (e.g., a compound represented by structural formula (I*) or a pharmaceutically acceptable salt thereof) that is effective to treat a disorder, or a “therapeutically effective amount” refers to an amount of theOTQ-00925- 37 -compound which is effective, upon single or multiple dose administration to a subject or a cell, in curing, alleviating, relieving or improving one or more symptoms of a disorder.

[0088] As used herein, an amount of a compound effective to prevent a disorder, or a “prophylactically effective amount” of the compound refers to an amount effective, upon single-or multiple-dose administration to the subject, in preventing or delaying the onset or recurrence of a disorder or one or more symptoms of the disorder.

[0089] For administration to human subjects, the total daily dose of the compounds disclosed herein is typically in the range of about 0.1 mg to about 3000 mg depending on the route of administration. For example, oral administration can require a total daily dose of from about 1 mg to about 3000 mg, while an intravenous dose can only require a total daily dose of from about 0.1 mg to about 300 mg. The total daily dose may be administered in a single or divided doses (e.g., 2, 3, 4, 5 or 6 times per day at evenly spaced or randomly spaced intervals) or on an as needed basis. The typical daily dose can fall outside the ranges above based on the discretion of the physician or drug prescriber. Although these dosages are based on an average human subject having a mass of about 60 kg to 70 kg, the physician will be able to determine the appropriate dose for a subject (e.g., an infant) whose mass falls outside this weight range.

[0090] As used herein, the term “treat” or “treatment” is defined as the application or administration of a compound, alone or in combination with a second compound, to a subject, e.g., a patient, or application or administration of the compound to an isolated tissue or cell, e.g., cell line, from a subject, e.g., a patient, who has a disorder (e.g., a disorder as described herein), a symptom of a disorder, or a predisposition toward a disorder, in order to cure, heal, alleviate, relieve, alter, remedy, ameliorate, improve or affect the disorder, one or more symptoms of the disorder or the predisposition toward the disorder (e.g., to prevent at least one symptom of the disorder or to delay onset of at least one symptom of the disorder).

[0091] “Pharmaceutically or pharmacologically acceptable” includes molecular entities and compositions that do not produce an adverse, allergic or other untoward reaction when administered to an animal, or a human, as appropriate. For human administration, preparations should meet sterility, pyrogenicity, and general safety and purity standards, as required by FDA Office of Biologies standards.OTQ-00925- 38 -

[0092] As used herein, the term “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. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, the relevant teachings of which are incorporated herein by reference in their entirety. Pharmaceutically acceptable salts of the compounds of this disclosure include salts derived from suitable inorganic and organic acids and bases that are compatible with the treatment of patients.

[0093] Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable acid addition 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, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like.

[0094] In some embodiments, exemplary inorganic acids which form suitable salts include, but are not limited thereto, hydrochloric, hydrobromic, sulfuric and phosphoric acid and acid metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate. Illustrative organic acids which form suitable salts include the mono-, di- and tricarboxylic acids. Illustrative of such acids are, for example, acetic, glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, benzoic, hydroxybenzoic, phenylacetic, cinnamic, salicylic, 2-phenoxybenzoic, p-toluenesulfonic acid and other sulfonic acids such as methanesulfonic acid and 2-hydroxy ethanesulfonic acid. EitherOTQ-00925- 39 -the mono- or di-acid salts can be formed, and such salts can exist in either a hydrated, solvated or substantially anhydrous form. In general, the acid addition salts of these compounds are more soluble in water and various hydrophilic organic solvents, and generally demonstrate higher melting points in comparison to their free base forms.

[0095] In some embodiments, acid addition salts of the compounds of formula I are most suitably formed from pharmaceutically acceptable acids, and include, for example, those formed with inorganic acids, e.g., hydrochloric, sulfuric or phosphoric acids and organic acids e.g. succinic, maleic, acetic or fumaric acid.

[0096] Other non-pharmaceutically acceptable salts, e.g., oxalates can be used, for example, in the isolation of compounds disclosed herein for laboratory use, or for subsequent conversion to a pharmaceutically acceptable acid addition salt. Also included within the scope of the disclosure are base addition salts (such as sodium, potassium and ammonium salts), solvates and hydrates of compounds of the disclosure. The conversion of a given compound salt to a desired compound salt is achieved by applying standard techniques, well known to one skilled in the art.

[0097] A “pharmaceutically acceptable basic addition salt” is any non-toxic organic or inorganic base addition salt of the acid compounds represented by formula I, or any of its intermediates. Illustrative inorganic bases which form suitable salts include, but are not limited thereto, lithium, sodium, potassium, calcium, magnesium or barium hydroxides. Illustrative organic bases which form suitable salts include aliphatic, alicyclic or aromatic organic amines such as methylamine, trimethylamine and picoline or ammonia. The selection of the appropriate salt may be important so that an ester functionality, if any, elsewhere in the molecule is not hydrolyzed. The selection criteria for the appropriate salt will be known to one skilled in the art.

[0098] Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(CI-4 alky 1)4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxyl, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate.OTQ-00925- 40 -

[0099] The phrase “pharmaceutically acceptable carrier, adjuvant, or vehicle” refers to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated and is nontoxic when administered in doses sufficient to deliver a therapeutic amount of the compound. Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions of this disclosure include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.

[0100] Compositions of the present disclosure may be administered orally, parenterally (including subcutaneous, intramuscular, intravenous and intradermal), by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. In some embodiments, provided compounds or compositions are administrable intravenously and / or intraperitoneally.

[0101] The term “parenteral,” as used herein, includes subcutaneous, intracutaneous, intravenous, intramuscular, intraocular, intravitreal, intra-articular, intra-arterial, intra-synovial, intrasternal, intrathecal, intralesional, intrahepatic, intraperitoneal, intralesional and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, subcutaneously, intraperitoneally or intravenously.

[0102] Pharmaceutically acceptable compositions of this disclosure can be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions, dispersions and solutions. In the case of tablets for oral use, carriers commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions and / or emulsions are required for oral use, the active ingredient can be suspended or dissolved in an oily phase andOTQ-00925- 41 -combined with emulsifying and / or suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.

[0103] In some embodiments, an oral formulation is formulated for immediate release or sustained / delayed release.

[0104] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and / or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders, such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium salts, g) wetting agents, such as acetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

[0105] Compositions suitable for buccal or sublingual administration include tablets, lozenges and pastilles, wherein the active ingredient is formulated with a carrier such as sugar and acacia, tragacanth, or gelatin and glycerin.

[0106] Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using excipients such as lactose or milk sugar, as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

[0107] A compound of the disclosure can also be in micro-encapsulated form with one or more excipients, as noted above. In such solid dosage forms, the compound of the disclosureOTQ-00925- 42 -can be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms can also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose.

[0108] Compositions for oral administration may be designed to protect the active ingredient against degradation as it passes through the alimentary tract, for example, by an outer coating of the formulation on a tablet or capsule.

[0109] In another embodiment, a compound of the disclosure can be provided in an extended (or “delayed” or “sustained”) release composition. This delay ed-release composition comprises a compound of the disclosure in combination with a delayed-release component. Such a composition allows targeted release of a provided compound into the lower gastrointestinal tract, for example, into the small intestine, the large intestine, the colon and / or the rectum. In certain embodiments, the delayed-release composition comprising a compound of the disclosure further comprises an enteric or pH-dependent coating, such as cellulose acetate phthalates and other phthalates (e.g., polyvinyl acetate phthalate, methacrylates (Eudragits)). Alternatively, the delayed-release composition provides controlled release to the small intestine and / or colon by the provision of pH sensitive methacrylate coatings, pH sensitive polymeric microspheres, or polymers which undergo degradation by hydrolysis. The delayed-release composition can be formulated with hydrophobic or gelling excipients or coatings. Colonic delivery can further be provided by coatings which are digested by bacterial enzymes such as amylose or pectin, by pH dependent polymers, by hydrogel plugs swelling with time (Pulsincap), by time-dependent hydrogel coatings and / or by acrylic acid linked to azoaromatic bonds coatings.

[0110] In certain embodiments, the delayed-release composition of the present disclosure comprises hypromellose, microcrystalline cellulose, and a lubricant. The mixture of a compound of the disclosure, hypromellose and microcrystalline cellulose can be formulated into a tablet or capsule for oral administration. In certain embodiments, the mixture is granulated and pressed into tablets.

[0111] Alternatively, pharmaceutically acceptable compositions of this disclosure can be administered in the form of suppositories for rectal administration. These can be prepared byOTQ-00925- 43 -mixing the compound of the disclosure with a suitable non- irritating excipient that is solid at room temperature but liquid at rectal temperature and, therefore, will melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols.

[0112] Pharmaceutically acceptable compositions of this disclosure can also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.

[0113] Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically-transdermal patches can also be used.

[0114] For other topical applications, the pharmaceutically acceptable compositions of the disclosure can be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers. Carriers for topical administration of compounds of this disclosure include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water and penetration enhancers. Alternatively, pharmaceutically acceptable compositions of the disclosure can be formulated in a suitable lotion or cream containing the active component suspended or dissolved in one or more pharmaceutically acceptable carriers. Alternatively, the pharmaceutical composition can be formulated with a suitable lotion or cream containing the active compound suspended or dissolved in a carrier with suitable emulsifying agents. In some embodiments, suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water. In other embodiments, suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water and penetration enhancers.

[0115] For ophthalmic use, pharmaceutically acceptable compositions of the disclosure can be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with or without a preservative such as benzalkonium chloride. Alternatively, for ophthalmic uses, the pharmaceutically acceptable compositions can be formulated in an ointment such as petrolatum.OTQ-00925- 44 -

[0116] Pharmaceutically acceptable compositions of this disclosure can also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and can be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents.

[0117] In some embodiments, pharmaceutically acceptable compositions of this disclosure are formulated for oral administration.

[0118] In some embodiments, pharmaceutically acceptable compositions of this disclosure are formulated for intravenous administration.

[0119] In some embodiments, pharmaceutically acceptable compositions of this disclosure are formulated for topical administration.

[0120] The amount of compounds of the present disclosure that can be combined with the carrier materials to produce a composition in a single dosage form will vary depending upon the host treated, the particular mode of administration and the activity of the compound employed. Preferably, compositions should be formulated so that a dosage of between 0.01 - 100 mg / kg body weight / day of the inhibitor can be administered to a patient receiving the composition.

[0121] It should also be understood that a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, the judgment of the treating physician and the severity of the particular disease being treated. The amount of a compound of the present disclosure in the composition will also depend upon the particular compound in the composition.

[0122] Other pharmaceutically acceptable carriers, adjuvants and vehicles that can be used in the pharmaceutical compositions of this disclosure include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) such as D-oc -tocopherol polyethylene glycol 1000 succinate, surfactants used in pharmaceutical dosage forms such as Tweens or other similar polymeric delivery matrices, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids,OTQ-00925- 45 -water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat. Cyclodextrins such as a-, 0-, and y-cyclodextrin, or chemically modified derivatives such as hydroxyalkylcyclodextrins, including 2- and 3-hydroxypropyl- 0-cyclodextrins, or other solubilized derivatives can also be advantageously used to enhance delivery of compounds described herein.

[0123] The pharmaceutical compositions of this disclosure are preferably administered by oral administration or by injection. The pharmaceutical compositions of this disclosure can contain any conventional non-toxic pharmaceutically-acceptable carriers, adjuvants or vehicles. In some cases, the pH of the formulation can be adjusted with pharmaceutically acceptable acids, bases or buffers to enhance the stability of the formulated compound or its delivery form.

[0124] The pharmaceutical compositions can be in the form of a sterile injectable preparation, for example, as a sterile injectable aqueous or oleaginous suspension. This suspension can be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as, for example, Tween 80) and suspending agents. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be employed are mannitol, water, Ringer’s solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil can be employed including synthetic mono- or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions can also contain a long-chain alcohol diluent or dispersant, or carboxymethyl cellulose or similar dispersing agents which are commonly used in the formulation of pharmaceutically acceptable dosage forms such as emulsions and or suspensions. Other commonly used surfactants such as Tweens or Spans and / or other similar emulsifying agents or bioavailability enhancers which are commonly usedOTQ-00925- 46 -in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms can also be used for the purposes of formulation.

[0125] When the compositions of this disclosure comprise a combination of a compound of the formulae described herein and one or more additional therapeutic or prophylactic agents, both the compound and the additional agent should be present at dosage levels of between about 1 to 100%, and more preferably between about 5 to 95% of the dosage normally administered in a monotherapy regimen. The additional agent(s) can be administered separately, as part of a multiple dose regimen, from the compounds of this disclosure. Alternatively, the additional agent(s) can be part of a single dosage form, mixed together with the compound of this disclosure in a single composition.

[0126] The compounds described herein can, for example, be administered by injection, intravenously, intraarterially, intraocularly, intravitreally, subdermally, orally, buccally, nasally, transmucosally, topically, in an ophthalmic preparation, or by inhalation, with a dosage ranging from about 0.5 to about 100 mg / kg of body weight or, alternatively, in a dosage ranging from about 1 mg to about 1000 mg / dose, every 4 to 120 hours, or according to the requirements of the particular drug. The methods herein contemplate administration of an effective amount of a compound of the disclosure, or a composition thereof, to achieve the desired or stated effect. Typically, the pharmaceutical compositions of this disclosure will be administered from about 1 to about 6 times per day or, alternatively, as a continuous infusion. Such administration can be used as a chronic or acute therapy. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. A typical preparation will contain from about 5% to about 95% active compound (w / w). Alternatively, a preparation can contain from about 20% to about 80% active compound.

[0127] Doses lower or higher than those recited above may be required. Specific dosage and treatment regimens for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health status, sex, diet, time of administration, rate of excretion, drug combination, the severity and course of the disease, condition or symptoms, the patient’s disposition to the disease, condition or symptoms, and the judgment of the treating physician.OTQ-00925- 47 -

[0128] Upon improvement of a patient’s condition, a maintenance dose of a compound, composition or combination of this disclosure can be administered, if necessary. Subsequently, the dosage or frequency of administration, or both, can be reduced, as a function of the symptoms, to a level at which the improved condition is retained when the symptoms have been alleviated to the desired level. Patients may, however, require intermittent treatment on a longterm basis upon recurrence of disease symptoms.Uses of Compounds and Pharmaceutically Acceptable CompositionsAs used herein, “RIPK2-mediated” disease, disorder or condition means any disease or other deleterious condition in which RIPK2 plays a role. Accordingly, another embodiment of the present disclosure relates to treating, for example, lessening the severity of, a RIPK2-mediated disorder or condition. RIPK2-mediated disorders include inflammatory disorders, autoimmune disorders, granulomatous diseases, neurodegenerative disorders, and cancer. Specific examples of RIPK2-mediated disorders are set forth in detail below.

[0129] Compounds provided by this disclosure are also useful as tools, for example, to study RIPK2 modulation in biological and pathological phenomena, to study cancer or for the identification and / or comparative evaluation of RIPK2 modulators. Accordingly, in particular embodiments, the present disclosure provides a method for studying an effect of a compound described herein, or a salt or composition thereof, on a sample, the method comprising contacting a sample comprising cells in culture or RIPK2 with the compound, or the salt or composition thereof; and measuring the effect of the compound, or salt or composition thereof, on the cells or RIPK2. For example, the compounds described herein can be used as a standard or control substance in binding assays (e.g., competitive binding assays) to identify or evaluate potential RIPK2 modulators or as a discovery tool to probe the role of RIPK2 modulation in certain disorders or conditions, such as those described herein, including inflammatory disorders, autoimmune disorders, and other RIPK2-mediated disorders or conditions.

[0130] In a certain embodiment, the present disclosure relates to a method of treating a disease or disorder, comprising administering to a subject in need thereof a compound described herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition describedOTQ-00925- 48 -herein, wherein the disease or disorder is selected from inflammatory diseases, autoimmune diseases, granulomatous diseases, cancer and neurodegenerative diseases.

[0131] In some embodiments, compounds and compositions described herein are useful for treating inflammatory disorders in a subject in need thereof. Thus, in certain embodiments, the present disclosure provides a method for treating an inflammatory disorder, comprising the step of administering to a subject in need thereof a compound of the present disclosure (e.g., a compound represented by structural formula (I*) or a pharmaceutically acceptable salt thereof), or pharmaceutically acceptable salt or composition thereof.

[0132] In certain aspects, the inflammatory disease can include, but is not limited to uveitis, interleukin- 1 converting enzyme fever syndrome, dermatitis, acute lung injury, type 2 diabetes mellitus, arthritis, inflammatory bowel disease (IBD), ischemia reperfusion injury in a solid organ transplant, sepsis, liver disease, allergic disease, and graft versus host disease.

[0133] In certain instances, the inflammatory disease is an IBD. For example, the IBD is selected from ulcerative colitis, Crohn's disease, early-onset IBD, and extraintestinal IBD.

[0134] Alternatively, the inflammatory disease can include but is not limited to rheumatoid arthritis, inflammatory arthritis, peritonitis, ischemia reperfusion injury in kidney transplant, non-alcohol steatohepatitis, alcohol steatohepatitis, insulin-resistant type 2 diabetes, allergic rhinitis, asthma, atopic dermatitis, Sjogren’s syndrome, ankylosing spondylitis, pemphigus vulgaris, idiopathic plasmacytic lymphadenopathy, atherosclerosis, myocardial infarction, thrombosis, a-synucleinopathy, Parkinson’s disease, dementia with Lewy body, multiple system atrophy, Alzheimer’s disease, amyotrophic lateral sclerosis, and chronic obstructive pulmonary disease.

[0135] In a particular embodiment, the disease or disorder is an autoimmune disease. For example, the autoimmune disease can include, but is not limited to systemic lupus erythematosus, lupus nephritis, psoriasis, diabetes mellitus type 1, Goodpasture’s syndrome, Guillain-Barre Syndrome, Hashimoto’s disease, Grave’s disease, immune thrombocytopenic purpura, and multiple sclerosis (including relapsing-remitting MS, secondary-progressive MS, primary-progressive MS, progressive-relapsing MS).OTQ-00925- 49 -

[0136] In a further embodiment, the disease or disorder is a granulomatous disease. For example, the granulomatous disease is selected from sarcoidosis, Blau syndrome, Wegner’s granulomatosis, Behcet’s disease, and interstitial pulmonary disease.

[0137] In another embodiment, the disease or disorder is a neurodeg enerative disorder. For example, the neurological disorder is selected from Alzheimer’s disease, amyotrophic lateral sclerosis (ALS / Lou Gehrig’s Disease), Parkinson’s disease, multiple sclerosis, diabetic neurophathy, polyglutamine (polyQ) diseases, stroke, Fahr disease, Menke’s disease, Wilson’s disease, cerebral ischemia, a prion disorder, dementia, corticobasal degeneration, progressive supranuclear palsy, spinocerebellar atrophies, brain injury and spinal cord injury.

[0138] In yet another embodiment, the disease or disorder is cancer. For example, the cancer is selected from a hematological cancer such as leukemia (e.g., acute myeloid leukemia, chronic myelogenous leukemia), lymphoma (e.g., non-Hodgkin’s Lymphoma, Hodgkin’s Lymphoma, diffuse large B-cell lymphoma), myeloma (e.g., multiple myeloma, myelodysplastic syndrome, myelofibrosis), breast cancer, brain cancer (e.g., glioblastoma), colorectal cancer, esophageal cancer, head and neck cancer, melanoma, pancreatic cancer, prostate cancer, stomach cancer, bone cancer, ovarian cancer, uterine cancer, renal cancer, liver cancer and lung cancer. The cancer can be a soft tissue cancer, including but not limited to, a sarcoma selected from the group consisting of a fibrosarcoma and liposarcoma (e.g., a dedifferentiated liposarcoma and a pleomorphic liposarcoma)

[0139] The compounds and compositions described herein can also be administered to cells in culture, e.g., in vitro or ex vivo, or to a subject, e.g., in vivo, to treat, prevent, and / or diagnose a variety of disorders, including those described herein below.

[0140] The compounds of this disclosure (e.g., a compound represented by structural formula (I*) or a pharmaceutically acceptable salt thereof) can be used alone or in combination with other therapeutic agents. Combination therapies according to the present disclosure comprise the administration of at least one compound of the disclosure, and the use of at least one other therapeutically active agent. For example, combination therapies according to the present disclosure comprise the administration of at least one compound of the disclosure and at least one other therapeutically active agent to a subject in need of treatment for a given diseaseOTQ-00925- 50 -or disorder, for example, the inflammatory diseases, autoimmune diseases, granulomatous diseases, cancers and neurodegenerative diseases described herein.

[0141] The compounds of the disclosure (e.g., a compound represented by structural formula (I*) or a pharmaceutically acceptable salt thereof) and the other therapeutically active agent can be administered together in a single pharmaceutical composition or separately and, when administered separately this can occur simultaneously or sequentially in any order. The amounts of the compounds of the disclosure and other therapeutically active agents and the relative timings of administration can be selected in order to achieve the desired combined therapeutic effect. Thus in a further aspect, there is provided a combination comprising a compound of the disclosure together with one or more other therapeutically active agents.

[0142] In certain embodiments, the disclosure relates to a method of treating a subject suffering from an inflammatory disorder as described herein comprising administering to the subject an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof and an anti-inflammatory agent and / or an anti-TNF agent.

[0143] In a particular embodiment, the disclosure relates to a method of treating a subject suffering from Crohn's disease as described herein comprising administering to the subject an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof and optionally an anti-inflammatory agent and / or an anti-TNF agent.

[0144] In another embodiment, the disclosure relates to a method of treating a subject suffering from an autoimmune disorder as described herein comprising administering to the subject an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof and an autoimmune agent such as, but not limited to, an anti-TNF agent.

[0145] Suitable anti-inflammatory / autoimmune agents include 5-aminosalicyclic acid and mesalamine preparations, sulfasalazine, hydroxychloroquine, thiopurines (azathioprin, mercaptopurin), methotrexate, cyclophosphamide, calcineurin inhibitors (cyclosporine, pimecrolimus, tacrolimus), mycophenolic acid (CellCept®), mTOR inhibitors (temsirolimus, everolimus), JAK inhibitors (tofacitinib (Xeljan®)), Syk inhibitors (fostamatinib), corticosteroids, particularly low-dose corticosteroids (such as prednisone (Deltasone®) and bundesonide) and anti-inflammatory biologies such as anti-IL6R mAbs (Actemra® (tocilizumab)), anti-IL6 biologies, anti-ILI (anakinra (Kineret®), canakinumab (Haris®),OTQ-00925- 51 -rilonacept (Arcalyst®)), anti-IL12 or / and IL23 biologies (ustekinumab (Stelara®)), anti-IL17 biologies (secukinumab), anti-CD22 (epratuzumab), anti-integrin agents (natalizumab (Tysabri®)), vedolizumab (Entyvio®), anti-IFN-a (sifalimumab), anti-CD20 mAbs (rituximab (Rituxan®) and ofatumumab (Arzerra®)), and other agents, such as abatacept (Orencia®), anakinra (Kineret®), canakinumab (Haris®), rilonacept (Arcalyst®), secukinumab, epratuzumab, sifalimumab, and belimumab (Benlysta®), CD4 biologies and other cytokine inhibitors or biologies to T-cell or B-cell receptors or interleukins.

[0146] Examples of suitable anti-TNF agents include the anti-TNF biologies such as Enbrel® (etanecerpt), Humira® (adalimumab), Remicade® (infliximab), Cimzia® (certolizumab), and Simponi® (golimumab).

[0147] In a particular embodiment, the disclosure relates to a method of treating a subject suffering from a neurodegenerative disease as described herein such as Parkinson’s comprising administering to the subject an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof and optionally one or more additional therapeutic agents typically used in the treatment of Parkinson’s. Such additional therapeutic agents include, but are not limited to levodopa, carbodopa or a combination thereof, pramipexole, ropinirole, rotigotine, selegiline, rasagiline, entacapone, tolcapone, benztropine, trihexyphenidyl, or amantadine, or a pharmaceutically acceptable salt thereof.

[0148] In a particular embodiment, the disclosure relates to a method of treating a subject suffering from a neurodegenerative disease as described herein such as Alzheimer’s comprising administering to the subject an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof and optionally one or more additional therapeutic agents typically used in the treatment of Alzheimer’s disease. Such additional therapeutic agents include, but are not limited to donepezil, galantamine, memantine, rivastigmine, anti-Abeta (amyloid beta) therapies including aducanumab, crenezumab, solanezumab, and gantenerumab, small molecule inhibitors of BACE1 including verubecestat, AZD3293 (LY3314814), elenbecestat (E2609), LY2886721, PF-05297909, JNJ-54861911, TAK-070, VTP-37948, HPP854, CTS-21166, or anti-tau therapies such as LMTM (leuco-methylthioninium-bis(hydromethanesulfonate)), or a pharmaceutically acceptable salt thereof.OTQ-00925- 52 -

[0149] In certain embodiments, the disclosure relates to a method of treating a subject with cancer comprising administering to the subject an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof and an anti-cancer agent. An "anti-cancer agent" is a compound, which when administered in an effective amount to a subject with cancer, can achieve, partially or substantially, one or more of the following: arresting the growth, reducing the extent of a cancer (e.g., reducing size of a tumor), inhibiting the growth rate of a cancer, and ameliorating or improving a clinical symptom or indicator associated with a cancer (such as tissue or serum components) or increasing longevity of the subject.

[0150] The anti-cancer agents suitable for use in the methods described herein include any anti-cancer agents that have been approved for the treatment of cancer. In one embodiment, the anti-cancer agent includes, but is not limited to, a targeted antibody, an angiogenesis inhibitor, an alkylating agent, an antimetabolite, a vinca alkaloid, a taxane, a podophyllotoxin, a topoisomerase inhibitor, a hormonal antineoplastic agent and other antineoplastic agents.

[0151] In one embodiment, the anti-cancer agents that can be used in methods described herein include, but are not limited to, paclitaxel, docetaxel, 5 -fluorouracil, trastuzumab, lapatinib, bevacizumab, letrozole, goserelin, tamoxifen, cetuximab, panitumumab, gemcitabine, capecitabine, irinotecan, oxaliplatin, carboplatin, cisplatin, doxorubicin, epirubicin, cyclophosphamide, methotrexate, vinblastine, vincristine, melphalan, cytarabine, etoposide, daunorubicin, bleomycin, mitomycin and adriamycin and a combination thereof.

[0152] In one embodiment, the anti-cancer agent and the compound disclosed herein are administered contemporaneously. When administered contemporaneously, the anti-cancer agent and the compound can be administered in the same formulation or in different formulations. Alternatively, the compound and the additional anti-cancer agent can be administered separately at different times.

[0153] In some embodiments, the present disclosure relates to a compound represented by structural formula (I*) or a pharmaceutically acceptable salt thereof:OTQ-00925- 53 -wherein:Q is selected from the following moieties:W is 5- to 12-membered heteroaryl;X is CH or N;each Y and Z is independently selected from O, NRa, and C1-3 alkylene; Rais selected from H and C1-6 alkyl;each Rlaand Rlbis independently selected from H, C1-6 alkyl, and halogen;R2is selected from C3-6 alkyl, C3-6 deuteroalkyl, C3-12 cycloalkyl;R3is selected from C1-6 alkyl, C3-12 cycloalkyl, 4- to 10-membered heterocyclyl, 5- to 12- membered heteroaryl, S(=O)R5, S(=O)2R5, NH(C=O)R5, NH(S(=O)2)R5, S(=O)(=NR6)(R7), P(=O)R6*R7*, BR8*R9* and C(=O)NR8R9;R3* is selected from H, halogen, C1-6 alkyl, C1-6 alkoxy;R4is selected from H and C1-6 alkyl;R5is selected from C1-6 alkyl, C3-12 cycloalkyl, C6-12aryl, 4- to 10-membered heterocyclyl, 5- to 12-membered heteroaryl, and NR10Rn;OTQ-00925- 54 -R6is selected from H and Ci-6 alkyl;R7is selected from Ci-6 alkyl, C3-12 cycloalkyl, 4- to 10-membered heterocyclyl, 5- to 12- membered heteroaryl, and NR10Rn, orR6and R7taken together with the nitrogen and sulfur atoms to which they are attached form 4- to 10-membered heterocyclyl;each R6* and R7* is independently selected from C1-6 alkyl, C3-12 cycloalkyl, 4- to 10-membered heterocyclyl, and 5- to 12-membered heteroaryl, orR6* and R7* taken together with the phosphorus atom to which they are attached form 4- to 10- membered heterocyclyl;each R8* and R9* is independently selected from OH, C1-6 alkyl, C3-12 cycloalkyl, 4- to 10- membered heterocyclyl, and 5- to 12-membered heteroaryl;each R8and R9is independently selected from H, C1-6 alkyl, C3-12 cycloalkyl, and 4- to 10- membered heterocyclyl, orR8and R9taken together with the nitrogen atom to which they are attached form 4- to 10- membered heterocyclyl; andeach R10and R11is independently selected from H, C1-6 alkyl, C3-12 cycloalkyl, and 4- to 10- membered heterocyclyl, orR10and R11taken together with the nitrogen atom to which they are attached form 4- to 10- membered heterocyclyl,wherein each C1-6 alkyl, C1-3 alkylene, C3-6 alkyl, C1-6 alkoxy, C3- 12 cycloalkyl, 5- to 12- membered heteroaryl, C6-12aryl, and 4- to 10-membered heterocyclyl is optionally substituted with 1 to 5 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, OC(=O)OR20b, C(=O)NR21R22, OC(=O)NR21*R22*, NRnC(=O)N(R12)(R13), NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, P(=O)Rn*R12*, B(OR13*)2, C1-6 alkyl, C2-6alkenyl, C2-6alkynyl, C3-12 cycloalkyl, Ce-i2aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl;whereineach R11, R12, R11*, R12*, R13, R13*, R14R14*, R15, R15*, R16, R17, R16*, R17*, R18R18a, R19, R20R20a. R2011, R21, R22, R21*, R22*, R23, R24, R25, R26, and R27is independently selected fromOTQ-00925- 55 -H, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl, orone or more of the pairs of variables selected from R12and R13, R16and R17, R16* and R17*, R21and R22, R21* and R22*, and R25and R26, together with the nitrogen to which they are attached, form a 3- to 8-membered ring, andwhen one or more of the 1 to 5 substituents is selected from OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, OC(=O)OR20b, C(=O)NR21R22, OC(=O)NR21*R22*, NRnC(=O)N(R12)(R13), NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, P(=O)Rn*R12*, B(OR13’)2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl, each is further optionally substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14*, SR15*, NR16*R17*, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl.

[0154] In some embodiments, X is CH. In some embodiments, X is N.

[0155] In some embodiments, Z is O. In some embodiments, Z is NRa. In some embodiments, Rais H. In some embodiments, Rais C1-6 alkyl. In some embodiments, Rais methyl. In some embodiments, Z is C1-3 alkylene, such as CH2.

[0156] In some embodiments, Y is O. In some embodiments, Y is NRa. In some embodiments, Rais H. In some embodiments, Rais C1-6 alkyl. In some embodiments, Rais methyl. In some embodiments, Y is C1-3 alkylene. In some embodiments, Y is CH2.

[0157] In some embodiments, W is a 5- to 6-membered heteroaryl, wherein the 5- to 6-membered heteroaryl is optionally substituted with 1 to 5 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, OC(=O)OR20b, C(=O)NR21R22, OC(=O)NR21*R22*, NRnC(=O)N(R12)(R13), NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, P(=O)Rn*R12*, B(OR13*)2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl.OTQ-00925- 56 -

[0158] In some embodiments, W is selected from the following moieties:wherein each of the listed moieties is optionally substituted with 1 to 3 substituents, as valence permits, independently selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, OC(=O)OR20b, C(=O)NR21R22, OC(=O)NR21*R22*, NRUC(=O)N(R12)(R13), NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, P(=O)Rn*R12*, B(OR13*)2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl. In some embodiments, W isselected from the following moieties:

[0159] In some embodiments, R2is t-Bu.

[0160] In some embodiments, the compound is represented by structural formula (I) or a pharmaceutically acceptable salt thereof:wherein:Q is selected from the following moieties:OTQ-00925- 57 -Z is O or NH;each Rlaand Rlbis independently selected from H, Ci-6 alkyl, and halogen;R2is C3-6 alkyl;R3is selected from C1-6 alkyl, C3-12 cycloalkyl, 4- to 10-membered heterocyclyl, 5- to 12- membered heteroaryl, S(=O)2R5, NH(C=O)R5, S(=O)(=NR6)(R7), and C(=O)NR8R9; R4is selected from H and C1-6 alkyl;R5is selected from C1-6 alkyl, C3-12 cycloalkyl, 4- to 10-membered heterocyclyl, 5- to 12- membered heteroaryl, and NR10Rn;R6is selected from H and C1-6 alkyl;R7is selected from C1-6 alkyl, C3-12 cycloalkyl, 4- to 10-membered heterocyclyl, 5- to 12- membered heteroaryl, and NR10Rn, orR6and R7taken together with the nitrogen and sulfur atoms to which they are attached form 4- to 10-membered heterocyclyl;each R8and R9is independently selected from H, C1-6 alkyl, C3-12 cycloalkyl, and 4- to 10- membered heterocyclyl, orR8and R9taken together with the nitrogen atom to which they are attached form 4- to 10- membered heterocyclyl; andeach R10and R11is independently selected from H, C1-6 alkyl, C3-12 cycloalkyl, and 4- to 10- membered heterocyclyl, orR10and R11taken together with the nitrogen atom to which they are attached form 4- to 10- membered heterocyclyl,wherein each C1-6 alkyl, C3-6 alkyl, C3-12 cycloalkyl, 5- to 12-membered heteroaryl, and 4- to 10- membered heterocyclyl is optionally substituted with 1 to 5 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, OC(=O)OR20b, C(=O)NR21R22, OC(=O)NR21*R22*, NRUC(=O)N(R12)(R13), NR23C(=O)R24, C(=S)NR25R26, C(=O)R27,OTQ-00925- 58 -Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl;whereineach R11, R12, R13, R14R14* R15R15*, R16, R17, R16*, R17*, R18R18a, R19, R20R20a, R20b, R21, R22R21*, R22*, R23, R24, R25, R26, and R27is independently selected from H, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, Ce-i2aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl, orone or more of the pairs of variables selected from R12and R13, R16and R17, R16* and R17*, R21and R22, R21* and R22*, and R25and R26, together with the nitrogen to which they are attached, form a 3-8 membered ring, andwhen one or more of the 1 to 5 substituents is selected from OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, OC(=O)OR20b, C(=O)NR21R22, OC(=O)NR21*R22*, NRnC(=O)N(R12)(R13), NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, P(=O)Rn*R12*, B(OR13’)2, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, Ce-i2aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl, each is further optionally substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14*, SR15*, NR16*R17*, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, Ce-i2aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl.

[0161] In some embodiments, the compound is represented by structural formula (la) or a pharmaceutically acceptable salt thereof:

[0162] In some embodiments, R4is C1-3 alkyl, wherein the C1-3 alkyl is optionally substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, OC(=O)OR20b,OTQ-00925- 59 -C(=O)NR21R22, OC(=O)NR21*R22*, NRnC(=O)N(R12)(R13), NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3 -12 cycloalkyl, C6-12aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl.

[0163] In some embodiments, the compound is represented by structural formula (la-1) or a pharmaceutically acceptable salt thereof:1b HNNHR3(la-1).

[0164] In some embodiments, R3is S(=O)2R5.

[0165] In some embodiments, R5is C1-3 alkyl, wherein the C1-3 alkyl is optionally substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, OC(=O)OR20b,C(=O)NR21R22, OC(=O)NR21*R22*, NRHC(=O)N(R12)(R13), NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3 -12 cycloalkyl, C6-12aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl.

[0166] In some embodiments, R5is methyl.

[0167] In some embodiments, R5is C3-12 cycloalkyl or 5- to 12-membered heteroaryl.

[0168] In some embodiments, R3is S(=O)(=NR6)(R7).

[0169] In some embodiments, R6is H.

[0170] In some embodiments, R7is C1-3 alkyl, wherein the C1-3 alkyl is optionally substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, OC(=O)OR20b, C(=O)NR21R22, OC(=O)NR21*R22*, NRnC(=O)N(R12)(R13), NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3 -12 cycloalkyl, C6-12aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl.

[0171] In some embodiments, R7is C3-6 cycloalkyl, wherein the C3-6 cycloalkyl is optionally substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, CN,OTQ-00925- 60 -NO2, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, OC(=O)OR20b, C(=O)NR21R22, OC(=O)NR21*R22*, NRnC(=O)N(R12)(R13), NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3 -i2cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl.

[0172] In some embodiments, R7is cyclopropyl.

[0173] In some embodiments, R7is 5- to 6-membered heteroaryl, wherein the 5- to 6-membered heteroaryl is optionally substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, OC(=O)OR20b, C(=O)NR21R22, OC(=O)NR21*R22*, NRnC(=O)N(R12)(R13), NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, CI-6alkyl, C2.6alkenyl, C2.6alkynyl, C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl.

[0174] In some embodiments, R7is pyridyl.

[0175] In some embodiments, R3is C(=O)NR8R9.

[0176] In some embodiments, R8is H.

[0177] In some embodiments, R9is C1-3 alkyl, wherein the C1-3 alkyl is optionally substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, OC(=O)OR20b, C(=O)NR21R22, OC(=O)NR21*R22*, NRnC(=O)N(R12)(R13), NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3 -12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl.

[0178] In some embodiments, R9is methyl.

[0179] In some embodiments, Z is O.

[0180] In some embodiments, Z is NH.

[0181] In some embodiments, the compound is represented by structural formula (lb) or a pharmaceutically acceptable salt thereof:OTQ-00925- 61 -

[0182] In some embodiments, the compound is represented by structural formula (Ib-1 ) or a pharmaceutically acceptable salt thereof:

[0183] In some embodiments, the compound is represented by structural formula (Ic) or a pharmaceutically acceptable salt thereof:

[0184] In some embodiments, the compound is represented by structural formula (Ic-1) or a pharmaceutically acceptable salt thereof:OTQ-00925- 62 -

[0185] In some embodiments, the compound is represented by structural formula (Id) or a pharmaceutically acceptable salt thereof:

[0186] In some embodiments, the compound is represented by structural formula (Id-1) or a pharmaceutically acceptable salt thereof:

[0187] In some embodiments, R3is C1-3 alkyl wherein the C1-3 alkyl is optionally substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, OC(=O)OR20b, C(=O)NR21R22, OC(=O)NR21*R22*, NRHC(=O)N(R12)(R13), NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl.

[0188] In some embodiments, R3is C1-3 alkyl substituted with 1-3 substituents selected from F, CN, S(O)2R18a, C(=O)NR21R22, C(=O)R27, C1-3 alkyl, C3-12 cycloalkyl, 4- to 10-membered heterocyclyl, and 5- to 12-membered heteroaryl.

[0189] In some embodiments, R3is C3-6 cycloalkyl, wherein the C3-6 cycloalkyl is optionally substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, OC(=O)OR20b,C(=O)NR21R22, OC(=O)NR21*R22*, NRnC(=O)N(R12)(R13), NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3 -12 cycloalkyl, C6-12aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl.

[0190] In some embodiments, R3is 4- to 10-membered heterocyclyl.OTQ-00925- 63 -

[0191] In some embodiments, 4- to 6-membered heterocyclyl, wherein the 4- to 6-membered heterocyclyl is optionally substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, OC(=O)OR20b, C(=O)NR21R22, OC(=O)NR21*R22*, NRnC(=O)N(R12)(R13), NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, CI-6alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl.

[0192] In some embodiments, R3is 5- to 6-membered heterocyclyl substituted with 1 to 3 substituents independently selected from oxo, OR14, Ci-6 alkyl, halo(Ci-6)alkyl, Ci-6 alkoxy, C3-12 cycloalkyl, and 5- to 12-membered heteroaryl.

[0193] In some embodiments, R3is 5-membered heterocyclyl substituted with oxo and C1-3 alkyl.

[0194] In some embodiments, R3is 5-membered heterocyclyl substituted with oxo and 5- to 6-membered heteroaryl.

[0195] In some embodiments, R3is 5- to 12-membered heteroaryl. In some embodiments,

[0196] In some embodiments, R3is 5- to 6-membered heteroaryl, wherein the 5- to 6-membered heteroaryl is optionally substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, OC(=O)OR20b, C(=O)NR21R22, OC(=O)NR21*R22*, NRnC(=O)N(R12)(R13), NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, CI-6alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl.

[0197] In some embodiments, R3is S(=O)2R5.

[0198] In some embodiments, R3is NH(C=O)R5.

[0199] In some embodiments, R5is C1-3 alkyl or C3-6 cycloalkyl, wherein C1-3 alkyl or C3-6 cycloalkyl is optionally substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, OC(=O)OR20b, C(=O)NR21R22, OC(=O)NR21*R22*, NRnC(=O)N(R12)(R13), NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, CI-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl.OTQ-00925- 64 -

[0200] In some embodiments, Rlais C1-3 alkyl, wherein C1-3 alkyl is optionally substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, OC(=O)OR20b, C(=O)NR21R22, OC(=O)NR21*R22*, NRHC(=O)N(R12)(R13), NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3 -12 cycloalkyl, C6-12aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl.

[0201] In some embodiments, Rlais methyl.

[0202] In some embodiments, Rlais halogen.

[0203] In some embodiments, Rlais F.

[0204] In some embodiments, Rlbis H.

[0205] In some embodiments, Rlbis methyl.

[0206] In some embodiments, the compound is represented by structural formula (le) or a pharmaceutically acceptable salt thereof:

[0207] In some embodiments, the compound is represented by structural formula (Ie-1) or a pharmaceutically acceptable salt thereof:

[0208] In some embodiments, the compound is selected from compounds of Table 1 or a pharmaceutically acceptable salt thereof.Table 1Compound # StructureOTQ-00925- 65 -1? o ~\j / \ <.HA ' N'r "' VZ \ V o ii li ' ^ ' " O ’" NN2 \MH2 X < o- o~s\ ZIHN VEnantiomer 1 / H- J T li f VN 3 r v " N "0n.'■ < NH.V<■ o-sHN VEnantiomer 2H4 X '.;oriN^<,. NH / <1C^N'"HH5 ■i "i r O "NH<?-S N0OTQ-00925- 66 -H O YT1NY> 6 ' A < 0H7 A I I ii it 1’. NII 0 Ai u V-* / X 1G-b.x- d / H8rVv^-3' < tH<x'.1o' V9 O XT J 'Q U " ~ k c HN=, K'Enantiomer 110 I* n < 'Xi "■^^ A vPc='xhNEnantiomer 2OTQ-00925- 67 -H,, s -. N - 11 / AV J QII 1 H > \ •; J FO O o ^--S, N0 0 / \ \1111 / ,,<> A■ vzz50-w o( >\ / / \1 <''.' X / J 'O IZ O JZ,, / 2 z> > - 7 ''n' ~- -■ H\ \v / ---__12 \ \2 / ° Q\-- -NvQ\-- k NHF zx ZI X 1C-5. X / _\ 1 o' ' z X > 2 Az\ z \ / 1314HF i > V / orf "f " N ' V ° " 'H 15 " FHF0-<. N,HN jj 1Enantiomer 1OTQ-00925- 68 -Hx ZY N" T if V’ N 16H- KiO-" S* I'1HNTjEnantiomer 2n yy^Y> 17" Y_HFO=S*_ XHNCNEnantiomer 118J z< 0=8*HNX CNEnantiomer 2'-Y V'f\ H 1 H k''' 19lk 'Y 10=5*, ^N.HN' If JEnantiomer 1H- V- "... N.i r ji >i 'N II X 1YV q '-U6 I-N V- ' 20G~k* ^..hkHN’! LEnantiomer 2OTQ-00925- 69 -Hx, N. - 5 \ O 1 rf V ^ N '- ° ~N,.21 < > NHu- XHNCNEnantiomer 1Z.■ '-x' - V. 2 H TZ y- o V- A A X \ o M22"xHA\ yoA xHNCNEnan, a,t.iomer 2< X zV-- '_ \ O / Ho - Ho '' A "vA \ 23 A. ANA^ O -ri XoNHF X 1c ": XH24H, " f' X.,tk..25 ~ V f- r ’j ' N Av -J 0"x^NriF-A' i A 0=S. F6'OTQ-00925- 70 -P H26 A; Q; J Qo Y-s.N6z^X-u.27 _A \\ 'wZT ' / \z / / (,o Z c. V -- '\O _ H / - 0 ' - HCk, N.28 7 1 i II T n %n r NN, 1 H ) ' <.,> N / o=s.dH N X- | vx29MHzz- o=s*HN’Enantiomer 1Hk V X " -. -IK -X N Y - Yr'Y Al0 l'N.30VH / < o-s'.HNEnantiomer 2OTQ-00925- 71 -HN "1 ■' " If " IM 31 MH / = HNo oEnantiomer 1XZ.^r~ i - HN 1 d 1 / \ 7]i f, N x< - / X.. / ' o l-Nu T N ' - 32 < N Ho / X )o=7 - ( o- HN zx Enantiomer 2 / Z ■ V. ^33HN i ' "-r iiX' v ti - >:f'N-'t iTt X 1^40x, 34 N-Nz / X.ZNX°1Enantiomer 1H— Y f xr7' >ZvvV 0 =v 35 N-N / "^ - - <Y°Enantiomer 2OTQ-00925- 72 -Hv* ' '°" T 'VN- N F / v 36Q- J- ~NU - Enantiomer 1Hr 'n ' \ if "■N' NV U ° (N -N F / ■ 37 r"'*Enantiomer 2HX-X X-x N X-- T 1] T.[ t 'llSN h < ol-N \ A;V N-N / ' 38Trans-stereochemistry Enantiomer 1H39 VN K * / r \.i " CHTrans-stereochemistry Enantiomer 2Hx-,, XUf° Q. \ I H X 40 N-N_ / 1Enantiomer 1OTQ-00925- 73 -Hx...- N... - ri ' ■■ n ■■ > >, VV o, LN \ '< H V' 41 N-NM / X / 1Enantiomer 2 Z, / x• ' w f TZZ, T. - >o >OHx x ( „ x Nx- 42 C?">o QH / < O. N. ^ Z P o'7' O x>-zO7^ h Jl J.'jz z-^'? z- 'z —-- '4344pN _x«• ji < Y '\ 45 / / 7 t _N-N / X / / X?OTQ-00925- 74 -K46 v r T r IT x / J 6-‘ Ky °lLN' k-N / X / \ Z — NHO \$ '< / 47 Qs / .x zO X A \ / 'r i| i i ii **A1N 48,z\A-c-^>x °LN' \!i V^’ N-N / s ( VCN-x y..---. 1 N!..-. X 49 A ii r t ir A’ V «rV M V •,' N-W X I f ", 3NH50\;x,. XM J- NK- M / X iQOTQ-00925- 75 -- bN.-I y r [f "i. -N51 t A,.. % O'7 HN -N ■ - iKh'A V'» ''TN'V% y A, s. s 0 *•-< 52< sr Gy N-; J / '• 1\ / / > -r*r \- -^ - A - - ‘ 1 1 i1". 5 '■ 53V iiN -R>0>X' A ' R '- '-- 54 ’ *,■■ -■'. / K »NH04 - tHr; YY Y'A55vlj > 'N- N / AVcHOTQ-00925- 76 -H■H Yi Y'CN< N- r I X t U F / X 56pr~^’<N I IEnantiomer 1Hf-> Xi )i i it ii i‘ hi ‘'N x h i V- 57 N h' F / 'Y°iEnantiomer 2IIr i i ii II iN-n- X" ->VN / N-N580Enantiomer 1H• "'? Vv > NVN3 11— N / 59 (X NN MEnantiomer 2i.hT- \xr jf Tf'x '>X!> o u.N- 60 < N-N "f ' ~ / :— V ^-NHG1.OTQ-00925- 77 - H. V^-v *1€61N-N / X\H62 JjQCX\ tt V" h.'- N / * - / j- -wc‘ / H,., x < - v 2 k.,.x i '1; O i' ' / / kY 0 L-^N63 H-*: A- ' -a\Enantiomer 1N.- 'x Y-v-J- '^ Y ¥ ' ■:64 U K <' AV.h\Enantiomer 2HN p V rf r \N65 < r0' > - ^ti-NEnantiomer 1OTQ-00925- 78 -HX. <.z, J-J. - |i ixh ii M O --hf 66 \ iJvvS;-N A- r <„" " C HEnantiomer 2;l / X X X A. / X \h ' fl T ' <r if If ' M, AVol~N67 < '1 ~ V'N-h. / X / / rC~ (FH^iixf Y Y' Y 7J° - 68<tFl:Enantiomer 1, YXJ ' 5aetj-N Z^- 691-i—FI- Enantiomer 2uri\? TCi V'70 '1-N F / xbEnantiomer 1OTQ-00925- 79 -yl ¥ « ¥ VN \, A. o A\ i! i71 ■|-N('v. / ~03Enantiomer 2H YNV\ AA A 0 AV fl ° 1v>- 72 N-f* f / \7 ■<Enantiomer 1H A Y PA / -Y '-O-VUA73 N-N r / s ‘ 1 / 0 'Enantiomer 2H. N, - U' i] > ii ([ 'llSHA-. A o -AC II 3 1 - 74 N-'tw f- / ' •_* / X -KHEnantiomer 1H KAi. ' i1" ’ i?* ^A'A'A'UA_.75 F / ''■’?N"Enantiomer 2OTQ-00925- 80 -h76 ' O l H X'Xf'Q* / x ' ic iV-o' J Zv T j z?- Q 7T U ' / TZ0hNv<',> " VM' / x"''- ’ < X1’r'',' 77 J k '. '1 \ 6•XN J' V / “-N Q / \ UN o) ( 4).Z £^ \- k x >0" ' " '7879H NN - T- Y * y. 'M 807 4 X V X\?vOTQ-00925- 81 -.,,... q,,- V' '■ -c.81 N-N AA-iHt l T f f¥ A?r-O^JA,. 'N-N, A 82 / \ — \‘N y ~QAEnantiomer 1HA'] A^A''YN''AN N-N, ' X 83V- 1 / .L~— -- Enantiomer 2HXAYY''NYAV II ° 1 v N-N FZV 84iAEnantiomer 1H■J -xA-’ -..-*'.... ''i i. < 'i A '- - o '0AN. \ ’» 1 '< N -N F / ■ 85A:°AEnantiomer 2OTQ-00925- 82 - H? * "j \ ' iix. '■0 N, N-N A- 86 / / — NHo y _■^oEnantiomer 1H°, N-N / \ 87 / oA,\ '6Enantiomer 2H7r''x|rN' r^N ° '~'NV88 N- N(\ -N'"\O HN ■] V!■' '.f f Na-H 0 ~N \ IIu89_\TNt?- □NEnantiomer 1H-rv Vv<Nf r " ' ° 'A 90_\rt \-QNEnantiomer 2OTQ-00925- 83 -H7 'I Y if ', N 'Ox° ~N91 N-N / <• / ■(■.Enantiomer 1Hr i: r r Y f w 92N-N / x r^.,Enantiomer 2H K X x-x N „■ 7 ii T ii if "iiXN 93 ■ ° -«vN- N / i \* / C '•w - " 0Enantiomer 1H-x, -''x N., y IlYII if il N 94 '0"'v N- N / X i \* / ° " oEnantiomer 2H95 T^ Y Y XY >x.!< ‘> O '~-N< ifQ" \ -RN-N Y'X F" '0 -NHO' \OTQ-00925- 84 -H096 N -N / x F-' \ / T] Ti;- Ny o o \V * 1z / o / 97 a \ / CM ZI f_ _~ \ ~ i Z v '', X z H / \ YXNU~N98 z N- NZX Y NH F O V J -F\FHf,r-0^ - A - N N / ’x 99k rJA;N -’o,. F1FEnantiomer 1Hil ixn ]{11■'N \ M ' ‘IY Ou- V ° 'LN " M N-N / '.100S>c, F1FEnantiomer 2OTQ-00925- 85 -Hx i C HX-NZ x" " O' ■*< ° N 101 \ H \ - 'N- M / ' • • " o'z--, N'O " 2 x“ / 6A 2L. ' \o\V - 102 O~\C X:ZIo\H, X ' X., X N.o;| 'r r Y TO103K^AN, V o -. NMHF X> -NHdH104>-d «.o^< / NHH ATXVA< YN''A05 O YN1^6H»- Y-.rNY*°OTQ-00925- 86 -H106 j-AHJ ArZv-°iEnantiomer 1H, X ' <. / s., N. ~ v1H1107 / ■-0 F / X rJ*Z Z-‘ONiEnantiomer 2H108 y: r r YZ'fZ-o 'J° ’'VV-=N / X / \CN H Z VN''1'-O YX'-v- 'Y O i ~'N> 109 Z-N / X Ao1Enantiomer 1H N T I f M > 110A 'Enantiomer 2OTQ-00925- 87 -xN - r j u A VN111. ' 'XCD:,< N-NDJCACD:-NHX %' ‘z 0'Z! / XZ Zl‘j - rf i / \- _! s r —d\! —1 - \112 / 0-r; / _ / \N > z r H^ 11 '1 II VN113 N-N / / -Nc‘ ''i II [ '1 li i’ N114 0 •.N-N / ’N0oyHr>-YN-<%115Z:,- ' ° ' VN-N X.<)r -NHo' ‘v-OTQ-00925- 88 -116 o oN-N Y s. / -NHy - < / JYO / IZ>o Hx- X ' N -• 117 T IL J' » f 'll "« O' ° A Y A- > N -N / \ F■ s, F ' / xo 'NH O J / I \ ■”V z2 \ ’c ' ' "1 H118 YYYTNr N N\ / V-NHO119HN120e XV 1 O I A § V -X N -N / x / P'"oOTQ-00925- 89 - H121 N-N '<)r -N ' '■>C y. X - \ / fO / tr, H122 rf Trf 'Q a T y- < n ~ ' _r> NO 'H123 i IIOr T A A AJ OU<N'NN-N / X y NHC‘ 'FuX, N1.124? ';; r r " I*N 0'K, N-N X- / y -NH0125OTQ-00925- 90 -■ ':: i ’i n > rr vy0126 N -N FF,, ' O, / O, s-N''T *I' / \ ■ _ / . “■0y ( -FXJ=T- \ NH127 r'j. / N-N / ' \-NHO’ '128H1290X- N-N',-NH0bHf yAO— °l'N, 130N-N / S. <y -NH6OTQ-00925- 91 -FH- N,-X- -1. ^. N - NNx >,,x, u o s -x 131 <0v N-N X / z>- NHOvHN f -TN132 / .0" V N- N<z-NdH NMxsf X - ■ „ - X.-N' d,- N o 133Z;A0Ax o ■- N- N1<-NHcHri - T< 7i ' - x > 134 A A O Id n0T f N -N F - / xZV -NHc'v-HN '.], X rf ~',, ' N 1351'Lx11011d d dr' o V" ' r^ N -N F<-NH0'xOTQ-00925- 92 - TH136\x- o, - woT zz- O' / \ =._^ 0, x 1 J H'...? ii r / V ( '1 I? 'N 137 k ' => 6r-N1 \ 71 Y~:°' X■ H * h■ YV^NT'N0" N\,7 1 '." 138 N — F / '- / / 7 — NH° l>H..-s. N.139!' n O n > / rxo0N / >-NHO140OTQ-00925- 93 -H141 Z' N '-o- ' - ' ° Y / > / # -N. y z V 2 / J " '■ ' ' Z T IZ / \ <. L_ \142 / b, <x / / ^- / \ y / o 21 / 'i o,l C V2'j J ZZ'1 Z- J - - HN - n;r > T -j 143(• '> ' 'N^ " ° ' -N N3H / x \ / -NC1 H-N- --X T H 'r p" «144 N A0 LN 'O r H / K ■ (\ -No'v-145OTQ-00925- 94 -..-. JI..r;; i 'i g > 146 / " N' X ° N wHH\ — N - 147 L 5 > >r i.n\ AXN H' *' }<'X'A~°Hx. CR > - 148Nr ir i ' N. - <N-!^0-N > NH / < f\,>-NHO,. 7- 1 _ • H K'.,.149 V I < ii i, « 'N. -'"'■ N Nx 0~N, \ =NH / <, -N1HK x-' N.,-tirl] " I II f 11150 V / / ° V ' ^-N / x \ / ,7 -NcOTQ-00925- 95 -1 Hx.. *x N7i f li' 'if „VN;< Jx <x ^ o -N f! V 151 Y-N / ' • r-N1HN"'^ V VN'AN152VNHK<> -NH0'xHx v< x xx.. N..153 JLL -O ° YY « ■ Xr-NikH.x-. NN '.1 " I d IT " 'N 154 A A K Oc-N\Nz-N II ~ / ANHoHxX / X Nz<:1 O f V"-Z, \ <x 0 hiN155 « Y A \N-NF F' X \}r -NH0 >‘- JOTQ-00925- 96 -I l0-- °156 / N -N / 'HOZOH, z y / Z-- - \_JH xzx. x > > O:, NV,r i?157, -r- - - \ / N-N / Vb / / \ / 0 \ o / \ X ' - / 0z ■\ a,rJZxX 1 '■ b HJT 0 T f ii " N 158N-N / 'xo' b\_ / 159HN bi Y -x.f > Y] 160 M N. IIx1 I A o 1’ -M - <,r o - bNB-OHHOOTQ-00925- 97 -161f zz- O % / Z ■^' w6\d_\XT—1 / _<. A H» - \ N162 yQ ' X0( O =1-N ' U ZI V ' N -N / X / ^\ r / V-OH / \H1637 h 7' ii ■■ 7T ' N XvsA - ° / N -N / ' OHH164 T 1 L i| n ''NN-N / x y OHFjCH'.., X x. x „N.165;:! r J " 7 N N -N F / X (S--O / OTQ-00925- 98 -H' ' A / 'N'b N o -N' \- >7 i166 N -N ’ / 0 )V _ <AO / ) 7- '“l| - v 1673 <ZI / « >2 ■ '.AzM'?W AA168 A A0AJ O -N po / V-NOH169° -N, N-N\ / / >-NOH^ '.| Y\ 'YN". A A. -A. A. o S.' 170 A0 Fv N-N / \ -NH° l>OTQ-00925- 99 -HZ..Z.0A,'- 0171 N-N / / NH OH..<x ', N 172 r ii ]1 II o > o N-V <■: < ° 7N-N F / \ \)r -NHo'v-H-x. -x. „!<, N.7 ” '| T 7 " 'i I 173 N..!• -k J O k 7 / -N11 0F Q. -Nii H174i ■!. / N- N A — / ' A -NHcz xH. X' ■ <x I'L „!< 175 j-JQ v o!iX N- N HO^ ^V-(zXA -N 7o'zOTQ-00925- 100 - H, N NHN 'I i. x' d176 1 V0' / y -NFHO NH0i --J \x r'z‘ ^ / z- HZ T IZ xz> Oo V-~-1 < ■! 1 N- 177 X k JjO S X ( o\ / \--“■f\|— N '{W F 1 - y u £.. > < b AK L>-N O o / zd" 'pjO < / - X vz-' 'O z k 1. - '- ZZ1- o '178179'\ • 180 -1. NOTQ-00925- 101 -181; i / \ H TZ U_>o-z1 1 A I < s? J < if O ~' F "r 182 N-N / -N b°r~'o'v-y97 ° < ''< J! Az~A >■ ■"F H,r183 AJ.NX." & O' / -OH, X -F / FF -NO'HN, NL 184 9' I| V II if > ^1 f J O r >f-NF\ ",J0FwI. „ N, -N 1 || r II " 1 NH 185 AN V^0 NA,>’ H X i -NS>oOTQ-00925- 102 -186? >"rv- ° >' -■.fZ T. o o - \ -n-- S b }- \ / >= '187 = = n\b OX- ZTo. zz- r '□.zX 'x / \ 1 H HN M - ' >s.1 I> I I*5; '< 1 x -NX -NII > ’,, \ / '188 o “ AN -N c;\ / •y- N6VH'C- 189 N -NHO_, •NH° bHw x. > K „ N 190 7 J i ' „ n i' o €! ° “■ \ " \ _ F N-N / xx^p \> °HOTQ-00925- 103 -H Hx-x -x J- N. N. „, il f- T i, 191N' x J'x. J 0 - M <■ r o '■ ■: N-N / - \ NHo'xz x X vIZF^O— H.ex x,. ON ' - xz.. Nx xi y -T jf192N- N -x' - / ZT-No'IZ. Z -~ 'ox.'X''-<^VV"193H HM?-x. Clx.^x194 / ' N^N' °VNHX<z-N° XH H195 N ii r |. >iXNN, ' °V-N \ V\ N ‘')> -NHO'OTQ-00925- 104 -H H I X X i'tN 196 z '^V -O' ' '- ° N > O ' / X X° / - < rH HN ',| y o >- < 'N / / A \ o 197 v,\\(,H? X / A / t y - / z-Ni / ZIO kLT| / A^■Jz z?- 0U XZ': Hx J-x - 0 -, KX T T' if fi r.XN / NAZV‘0 LN 198 'L / :H / ;<< / ~Ncv-199HNXxv0 N.^.A■ ■ q!■ ■: N 200 x._ > o ^~N- V IIu / y -NVNHo 'OTQ-00925- 105 -H.. x.,< X,201 fi V y- 6 F / X )? -N?dH., C\ N...0 ' „ T;, „ £ ',\j 202 / ysA ^0WHX / # -NH° bHN '^N ' - - ir -A - 's, AANA. AFO203 > NH? X O A' NAHHCi. ^X'XXH i r jTi ii 'N 204 b °N11..^ N1H / r X ' O'> KN'Xi H205 V' y " Y ' Y Y AANA> ° -w " JHZ-, TC'^"' NH2OTQ-00925- 106 -HCl- x-xXN. x 206 ii t I 'i ■■ l! >. T V N V ° 'N F' " VHlC^'HI, R207 N K -r if ' "iiVN. ' V -N'M 0 LN' r ",. NHHlJ' '^i V" YN\PN 208p i q i v- V. NHF / < L. NH2noH, N- 209 AV; £ VM I H / r '- r - OHx:-x x, N, x 210? TVi' V 'N -. ^x o‘,. NHA O=S.dCDsOTQ-00925- 107 -211o O r-... O--l / \j' > Z / ■--_) < 2 IZ —' / / \\yP - / 'S0 o xz- f X> / , / 'V 71-. H- N212 >1,-1 k;f. r' NO£ vi r — X - U.. NHF ZIZI( O— r- (A003oz <■.H O Ou u H„ X Ch <? - 213?. j r 2 t >H i H x''CD:s' -f, JD3CCD3 O'" N' - HH,,<x D-C x- N214 ' J t if i 'N.r r tT ' ' Vs_,-. N, > o-s,o’ V215OTQ-00925- 108 -H- N0’ 216Ld ^NHF / ° Lox 1., N ”^217 " 7 V 2 f >N^NH / r7c=s.O VH, Cl / ~xN. _ 218 i: ’■ i'" ii df " Y:i ~ - y °“SUNH.x>.. „N. _v219 " | * - A - YIl 1 p i-,,. MF.^.FX'. o-s,dNH?1 H220j' I X!l3 O' „.. NHA. OdOTQ-00925- 109 - H X S Nv AN " I 111^11,N221'LNHH7 0. D ‘-- J o <5 r~ =sy6,<Dz / DD / \ ' ) < }. z - ± I =r <xV / - IZVs~n —-. > CK > - x° H\. X - 222 " " I > ',[ / > 'No=_^H1H Q- ° ' N.zxX" 'N / / x- I XO-S- 2L A / , QJx2o o11223f HM-X ^z X / Ns- 224 7 J r II J II N v ° -K, MH / < O=S,. 'o'225OTQ-00925- 110 -226oO / \u^sz \.\> Y - p iz<IZ, rz / O-""\ / _\ / / \ Xo- ( 2 227) A / ” / \ A \7yO--- ZI / A X> Z < -z xv z--z'r^ rxZ- I '>Z<>oc-xo \x~ >x-- / Z z'- - z z 0_ \ / b 1'o / —J H228 '"’i f li" V 'Y %i, X. NHH229 ii: ii " ii,N11N’ V" ~ iN.HFX^N A o^s. X0 "0H230OTQ-00925- I l l -I,. &, 231MHX o=,sxHN'i HM ' -X.. - 7 r ii j u 'N 2320’v 1X-NH2«n233;AAN. ^ A OHF1O-S, - n' N° HI H'I ' i f T " N 234X ' N '^ ' '' ° \HT HN.II0.. Txa235 Y' T nH / < HN.,,- S,O' 0OTQ-00925- 112 -Hifu u *236v - j / A o 6%« -A2 / 1 <z / z- '■ ’ z x>7- Ax> Tl -. Z T> >°=X237 f\=: ^ O- zrV / T 6 / o., / w z —ZI( IZ. tc.-- ' XH238MHrSA 1 H!.. ‘i. / b ■239F240 V 3- J| M■)XJ N,1i H k k^N, 0; S_HNOTQ-00925- 113 -241o O or—Av0 O O11 / \ / \ / JIn,^ ' zy>—- -vV z' *? A / / C \k ‘ / J- _f / y / -.>7.t / / \> __ \ / __ _\( - 242 ■’ > \ \ ■n >° / =AK o O=x- ZI ziA f rZX - J1Z '2'E"' Ox- -?zA x ~243HM-X 'x'• N, N 244 i r H i r, N. < -x__ o S~ -' iT 1' N r - <,, NMO=S, - HN HHM ' A " A ' - ' X, -N-,, I* 245 1 ■' •■ li ■", N.< r V ^. N •' ' - 1°-S-. X° uOTQ-00925- 114 -246J„ ov II Zz V-. Z T(247n;c / \r— / 'O\\uHr \~.ZI * J - O-S. ^, / r. - o y_ / \ / V; wz.— '\ O_. / io248° V' >-.... N „A - O=S,dC°3E I H249 r II II 'i o ^hi K i N Y1 H<... N HO, _^- O^S,6H NX, N., 1 II J r NH 250x<x1 " 0 ■- (lL / N *, / x,HO0OTQ-00925- 115 -251oO■ - / \li.1\ / / H- >' ^NsN 252, V I J o Q- i O—-, t; « T ZI - o-.s^Zf ' HN' ^Z v r / \ >H253 i ■ " IT ■ o k... > OlL,, NHX 0=, Sx^'HN'H254 » Y v V y V y, -c. o„ r N U P N UxH X- 1 ' ’ C-S. _..x. Y ^ 255 < 1 i;.< a u„,XN - r “xHk / I - / 1 A V 0=S,. F FHN' HOTQ-00925- 116 ->: 1 i' ii X; J 256 ■L,, NHI / A o=s. _6 «257, UX!' ° u1 H<<> N F O-S, ' * * -' _F F6 '0HHN ''1 'Y T IT T‘ 258-, U -V 'NzU -V o'k / lHk A v 'o-259b V’T‘11vV'r 'YO‘Y N~’%v '.. N CiO”S.oH260 I r i, f pVv0MHXo=s.oOTQ-00925- 117 -H261 * v i a x T r s i VHrS? / x o o _.O~-ll / \.s.O' VJZA-\TZ / / y \-n_\ / _ H HN''<, N 262 7, f II II II ), Z y N' 'f / ^ ° \,ZI -J- "v^NHCl f O.—r / V 1o=s.x„- L / / HN' ' "' xo ' \263riKl■, Cl.x- - CR -N 264 11 X f o C?s' z X 1°CS'r.HN1.0HN265 * 1 >■ 1 'VN ° ' KHO OHOTQ-00925- 118 -266 i r i! " FMU H;;< I9z ra-\v - < )ZS^=~ / V z / \ V / / , _* x■■z?' „. \ \ =■*' / \ IZ / / w / XZ \\ / / o= / AO- 267\ >\ / Y Qrvx\J - X / ' sz_. \ ZTA ZT / \ / , ozx,, / / A““. -v\ / —\f z^-z / \ \ J / - 1 LL >- U ' -268269... 1 H X.270 K Z 'x i' O >S''NL NHZ1^ "^V NOTQ-00925- 119 - HA l A. \ 6 Qr' T N ' FN271 L, NH / <jfX'VVM > '1TyVN272U H p X! VX- ' Y F, NN Y fo A Y %N273 II 1 H k " > N F / x.1 F. FN'XX 1L' ■ 1H CL..;;! T;«!! ji \N 274 X X' - A o -_I HN' I^NIrv- " / XiV1••<.,..- • —. N„ 275 j J Y < 1? >,r v BA'^° 'V 'L^N / XN< J^OTQ-00925- 120 -JI2 v,r T Y > 2760Y.,Hk VNZ =., J, - {'' 1 \ / ' \ -,kz / = A. N z) X > A4k / z / > 2zIZ( \ _ vk H TZ. x z X X „N.NA - 277 r ij < ’n / " if o^-VN YNHZT V F AG- T / / k ZI ' J \ - '' -N \H Az!z z< zC —s'278Hr.f A " YY'xrN" Y'N >k Ax AJ 0 Y 27911 1H‘\ _. NH / - YO 'N / '-" N280OTQ-00925- 121 -H281AVJ 0v VN / x1' -o.' 7HN N H L-< 1 1? K TZ L C.282VJiH / < 1T' xx Zz%L\ y v—~ ~' z \ / > / z- z = = -283HN^..7. i N 284 1 1 °L-N~ JN; N— i'jHP ''i i ii II r, 'N 0 -N 285 LNH, L" -NOTQ-00925- 122 -FHN XY oNY X-N 286V--K^ ■r°H, Cx, x. - N - * ' 1 < < |f > " N ' ' ° " N, 287 \ -|MHK 1N ■i X Y. Ox ViH. x x,x x N, N.x„,f Yi ' N 288 >TVVVS-V C, NHr- r°HN. "i r > T 7 " N 289 'N,1 I H< > N, - J., Or ' 1'l H? ' i r T * v. N 290 Y-N '■.■< N ^’Nlx. 11'CH 1OTQ-00925- 123 -H H-N' ' -XH 1 1 II II ll N° V '291KJ / 0 'N2. X y " *^ X iz: / ">o--- T Z.. Ll d292 wA / ><- -'ZI2T / 7 / ) / ..xc / - - \\ —7• ' '\ Z_OO \ _ \ / / II II 'o O -- H■ ^O. N293A a A J! 5 1?11H A 'izAGr -fci ' - H294

[0209] In some embodiments, the compound is selected from compounds of Table 2 or a pharmaceutically acceptable salt thereof.Table 2Compound # Compound # Compound # Compound #1 9 17 252 10 18 263 11 19 27OTQ-00925- 124 -5 13 21 296 14 22 307 15 23 318 16 24 32

[0210] In some embodiments, the compound is selected from compounds of Table 3 or a pharmaceutically acceptable salt thereof.Table 3Compound # Compound # Compound # Compound #203 226 249 272204 227 250 273205 228 251 274206 229 252 275207 230 253 276208 231 254 277209 232 255 278210 233 256 279211 234 257 280212 235 258 281213 236 259 282214 237 260 283215 238 261 284216 239 262 285217 240 263 286218 241 264 287219 242 265 288220 243 266 289221 244 267 290222 245 268 291223 246 269 292224 247 270 293225 248 271 294

[0211] In some embodiments, the compound is selected from compounds of Table 4 or a pharmaceutically acceptable salt thereof.Table 4Compound # Compound # Compound # Compound #33 54 75 9634 55 76 97OTQ-00925- 125 -35 56 77 9836 57 78 9937 58 79 10038 59 80 10139 60 81 10240 61 82 10341 62 83 10442 63 84 10543 64 85 10644 65 86 10745 66 87 10846 67 88 10947 68 89 11048 69 90 9349 70 91 9450 71 92 9551 72 53 7452 73

[0212] In some embodiments, the compound is selected from compounds of Table 5 or a pharmaceutically acceptable salt thereof.Table 5Compound # Compound # Compound # Compound #111 133 155 177112 134 156 178113 135 157 179114 136 158 180115 137 159 181116 138 160 182117 139 161 183118 140 162 184119 141 163 185120 142 164 186121 143 165 187122 144 166 188123 145 167 189124 146 168 190125 147 169 191126 148 170 192127 149 171 193128 150 172 194OTQ-00925- 126 -129 151 173 195 130 152 174 196 131 153 175 197 132 154 176 198200 201 202 199

[0213] In some embodiments, the compound is selected from compounds of Table 6 or a pharmaceutically acceptable salt thereof.Table 6Compound # Compound #1 345 487 588 3629 5930 383 44

[0214] In some embodiments, the present disclosure relates to a pharmaceutical composition comprising a compound described herein (e.g., a compound represented by structural formula (I*) or a pharmaceutically acceptable salt thereof) and a pharmaceutically acceptable excipient.

[0215] In some embodiments, the present disclosure relates to method of treating a disease or disorder, comprising administering to a subject in need thereof a compound described herein with respect to the first embodiment and various aspects thereof or a pharmaceutical composition described herein with respect to the second embodiment and various aspects thereof, wherein the disease or disorder is selected from inflammatory diseases, autoimmune diseases, granulomatous diseases, cancer and neurodegenerative diseases.

[0216] In some embodiments, the disease or disorder is an inflammatory disease. For example, the inflammatory disease is selected from uveitis, interleukin- 1 converting enzyme fever syndrome, dermatitis, acute lung injury, type 2 diabetes mellitus, arthritis, inflammatoryOTQ-00925- 127 -bowel disease (IBD), ischemia reperfusion injury in a solid organ transplant, sepsis, liver disease, allergic disease, and graft versus host disease. For example, the inflammatory disease is an IBD. For example, in certain embodiments, the IBD is selected from ulcerative colitis, Crohn's disease, early-onset IBD, and extraintestinal IBD. In some embodiments, the IBD is ulcerative colitis. In a particular aspect, the ulcerative colitis is moderately-to-severely active ulcerative colitis.

[0217] In some embodiments, the inflammatory disease is selected from rheumatoid arthritis, inflammatory arthritis, peritonitis, ischemia reperfusion injury in kidney transplant, non-alcohol steatohepatitis, alcohol steatohepatitis, insulin-resistant type 2 diabetes, allergic rhinitis, asthma, atopic dermatitis, Sjogren’s syndrome, ankylosing spondylitis, pemphigus vulgaris, idiopathic plasmacytic lymphadenopathy, atherosclerosis, myocardial infarction, thrombosis, a-synucleinopathy, Parkinson’s disease, dementia with Lewy body, multiple system atrophy, Alzheimer’s disease, amyotrophic lateral sclerosis, and chronic obstructive pulmonary disease.

[0218] In some embodiments, the disease or disorder is an autoimmune disease. For example, in certain embodiments, the autoimmune disease is selected from systemic lupus erythematosus, lupus nephritis, psoriasis, immune thrombocytopenic purpura, and multiple sclerosis.

[0219] In some embodiments, the disease or disorder is a granulomatous disease. For example, in certain embodiments, the granulomatous disease is selected from sarcoidosis, Blau syndrome, Wegner’s granulomatosis, Behcet’s disease, and interstitial pulmonary disease.

[0220] In some embodiments, the disease or disorder is cancer. For example, in certain embodiments, the cancer is selected from leukemia, breast cancer, brain cancer, colorectal cancer, head and neck cancer, melanoma, pancreatic cancer, prostate cancer, ovarian cancer, renal cancer, and lung cancer.

[0221] In some embodiments, the disease or disorder is a neurodegenerative disease. For example, in certain embodiments, the neurodegenerative disease is selected from Alzheimer’s disease, amyotrophic lateral sclerosis (ALS / Lou Gehrig’s Disease), Parkinson’s disease, multiple sclerosis, diabetic neurophathy, polyglutamine (polyQ) diseases, stroke, Fahr disease, Menke’s disease, Wilson’s disease, cerebral ischemia, a prion disorder, dementia, corticobasalOTQ-00925- 128 -degeneration, progressive supranuclear palsy, spinocerebellar atrophies, brain injury, and spinal cord injury.

[0222] In some embodiments, the method further comprises administering second agent. For example, in some embodiments, the second agent is an anti-inflammatory agent or an anti-autoimmune agent.

[0223] In some embodiments, the second agent is selected from anti-TNF agent, anti-IL-23 agent, anti-integrin agent, and JAK inhibitor. In some embodiments, the second agent is selected from anti-TNF agent, anti-IL-23 agent, anti-integrin agent, TL1 A inhibitor, and JAK inhibitor. In a particular aspect, the second agent is anti-TNF agent. In a particular aspect, second agent is anti-IL-23 agent. In a particular aspect, the second agent is anti-integrin agent. In some embodiments, the anti-integrin agent is vedolizumab. In a particular aspect, second agent is JAK inhibitor. In some embodiments, the JAK inhibitor is selected from filgotinib, tofacitinib, and upadacitinib. In a particular aspect, the second agent is TL1A inhibitor. In some embodiments, the TL1A inhibitor is tulisokibart.

[0224] In some embodiments, the second agent and the compound are administered contemporaneously, such as administered together in a single pharmaceutical formulation. In a particular aspect, the second agent and the compound are formulated for simultaneous administration.

[0225] In some embodiments, the second agent and the compound are administered separately. In a particular aspect, the second agent and the compound are administered separately at different times. In a particular aspect, the second agent and the compound are administered separately at the same time.

[0226] In some embodiments, the present disclosure relates to a method of treating a RIPK2 kinase-mediated disease or disorder, comprising administering to a subject in need thereof a compound described herein (e.g., a compound represented by structural formula (I*) or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition described herein with respect to the second embodiment and various aspects thereof. In one aspect, the RIPK2 kinase-mediated disease or disorder is a disease or disorder wherein inhibition of RIPK2 kinase would provide benefit. In a particular aspect, the disease or disorder is selected from anOTQ-00925- 129 -inflammatory disease, autoimmune disease, granulomatous disease, cancer, and neurodegenerative disease.

[0227] In some embodiments, the present disclosure relates to the use of a compound described herein (e.g., a compound represented by structural formula (I*) or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for use in treating RIPK2 kinase-mediated diseases or disorders (e.g., inflammatory diseases, autoimmune diseases, granulomatous diseases, cancer or neurodegenerative diseases).

[0228] In some embodiments, the RIPK2 kinase-mediated disease or disorder is an inflammatory disease. For example, in certain embodiments, the inflammatory disease is selected from uveitis, interleukin- 1 converting enzyme fever syndrome, dermatitis, acute lung injury, type 2 diabetes mellitus, arthritis, inflammatory bowel disease (IBD), ischemia reperfusion injury in a solid organ transplant, sepsis, liver disease, allergic disease, and graft versus host disease. For example, in certain embodiments, the inflammatory disease is an IBD. For example, the IBD is selected from ulcerative colitis, Crohn's disease, early-onset IBD, and extraintestinal IBD. For example, in certain embodiments, the inflammatory disease is selected from rheumatoid arthritis, inflammatory arthritis, peritonitis, ischemia reperfusion injury in kidney transplant, non-alcohol steatohepatitis, alcohol steatohepatitis, insulin-resistant type 2 diabetes, allergic rhinitis, asthma, atopic dermatitis, Sjogren’s syndrome, ankylosing spondylitis, pemphigus vulgaris, idiopathic plasmacytic lymphadenopathy, atherosclerosis, myocardial infarction, thrombosis, a-synucleinopathy, Parkinson’s disease, dementia with Lewy body, multiple system atrophy, Alzheimer’s disease, amyotrophic lateral sclerosis, and chronic obstructive pulmonary disease.

[0229] In some embodiments, the RIPK2 kinase-mediated disease or disorder is an autoimmune disease. For example, in certain embodiments, the autoimmune disease is selected from systemic lupus erythematosus, lupus nephritis, psoriasis, immune thrombocytopenic purpura, and multiple sclerosis.

[0230] In some embodiments, the RIPK2 kinase-mediated disease or disorder is a granulomatous disease. For example, in certain embodiments, the granulomatous disease is selected from sarcoidosis, Blau syndrome, Wegner’s granulomatosis, Behcet’s disease, and interstitial pulmonary disease.OTQ-00925- 130 -

[0231] In some embodiments, the RIPK2 kinase-mediated disease or disorder is cancer. For example, in certain embodiments, the cancer is selected from leukemia, breast cancer, brain cancer, colorectal cancer, head and neck cancer, melanoma, pancreatic cancer, prostate cancer, ovarian cancer, renal cancer, and lung cancer.

[0232] In some embodiments, the RIPK2 kinase-mediated disease or disorder is a neurodegenerative disease. For example, in certain embodiments, the neurodegenerative disease is selected from Alzheimer’s disease, amyotrophic lateral sclerosis (ALS / Lou Gehrig’s Disease), Parkinson’s disease, multiple sclerosis, diabetic neurophathy, polyglutamine (polyQ) diseases, stroke, Fahr disease, Menke’s disease, Wilson’s disease, cerebral ischemia, a prion disorder, dementia, corticobasal degeneration, progressive supranuclear palsy, spinocerebellar atrophies, brain injury, and spinal cord injury.

[0233] In some embodiments, the present disclosure relates to a compound described herein (e.g., a compound represented by structural formula (I*) or a pharmaceutically acceptable salt thereof) for use in treating RIPK2 kinase-mediated diseases and disorders (e.g., inflammatory diseases, autoimmune diseases, granulomatous diseases, cancer or neurodegenerative diseases).

[0234] In some embodiments, the RIPK2 kinase-mediated disease or disorder is an inflammatory disease. For example, in certain embodiments, the inflammatory disease is selected from uveitis, interleukin- 1 converting enzyme fever syndrome, dermatitis, acute lung injury, type 2 diabetes mellitus, arthritis, inflammatory bowel disease (IBD), ischemia reperfusion injury in a solid organ transplant, sepsis, liver disease, allergic disease, and graft versus host disease. For example, in certain embodiments, the inflammatory disease is an IBD. For example, the IBD is selected from ulcerative colitis, Crohn's disease, early-onset IBD, and extraintestinal IBD. For example, in certain embodiments, the inflammatory disease is selected from rheumatoid arthritis, inflammatory arthritis, peritonitis, ischemia reperfusion injury in kidney transplant, non-alcohol steatohepatitis, alcohol steatohepatitis, insulin-resistant type 2 diabetes, allergic rhinitis, asthma, atopic dermatitis, Sjogren’s syndrome, ankylosing spondylitis, pemphigus vulgaris, idiopathic plasmacytic lymphadenopathy, atherosclerosis, myocardial infarction, thrombosis, a-synucleinopathy, Parkinson’s disease, dementia with Lewy body, multiple system atrophy, Alzheimer’s disease, amyotrophic lateral sclerosis, and chronic obstructive pulmonary disease.OTQ-00925- 131 -

[0235] In some embodiments, the RIPK2 kinase-mediated disease or disorder is an autoimmune disease. For example, in certain embodiments, the autoimmune disease is selected from systemic lupus erythematosus, lupus nephritis, psoriasis, immune thrombocytopenic purpura, and multiple sclerosis.

[0236] In some embodiments, the RIPK2 kinase-mediated disease or disorder is a granulomatous disease. For example, in certain embodiments, the granulomatous disease is selected from sarcoidosis, Blau syndrome, Wegner’s granulomatosis, Behcet’s disease, and interstitial pulmonary disease.

[0237] In some embodiments, the RIPK2 kinase-mediated disease or disorder is cancer. For example, in certain embodiments, the cancer is selected from leukemia, breast cancer, brain cancer, colorectal cancer, head and neck cancer, melanoma, pancreatic cancer, prostate cancer, ovarian cancer, renal cancer, and lung cancer.

[0238] In some embodiments, the RIPK2 kinase-mediated disease or disorder is a neurodegenerative disease. For example, in certain embodiments, the neurodegenerative disease is selected from Alzheimer’s disease, amyotrophic lateral sclerosis (ALS / Lou Gehrig’s Disease), Parkinson’s disease, multiple sclerosis, diabetic neurophathy, polyglutamine (polyQ) diseases, stroke, Fahr disease, Menke’s disease, Wilson’s disease, cerebral ischemia, a prion disorder, dementia, corticobasal degeneration, progressive supranuclear palsy, spinocerebellar atrophies, brain injury, and spinal cord injury.

[0239] In some embodiments, the compound is formulated to be administered with a second agent. For example, in some embodiments, the second agent is an anti-inflammatory agent or an anti-autoimmune agent.

[0240] In some embodiments, the second agent is selected from anti-TNF agent, anti-IL-23 agent, anti-integrin agent, and JAK inhibitor. In a particular aspect, the second agent is anti-TNF agent. In a particular aspect, second agent is anti-IL-23 agent. In a particular aspect, the second agent is anti-integrin agent. In a particular aspect, second agent is JAK inhibitor.

[0241] In some embodiments, the second agent and the compound are administered contemporaneously, such as administered together in a single pharmaceutical formulation. In a particular aspect, the second agent and the compound are formulated for simultaneous administration.OTQ-00925- 132 -

[0242] In some embodiments, the second agent and the compound are administered separately. In a particular aspect, the second agent and the compound are administered separately at different times. In a particular aspect, the second agent and the compound are administered separately at the same time.

[0243] The invention now being generally described, will be more readily understood by reference to the following examples, which are included merely for purposes of illustration of certain aspects and embodiments of the present invention, and are not intended to limit the invention. Starting materials described herein can be obtained from commercial sources or may be readily prepared from commercially available materials using transformations known to those skilled in the art.EXAMPLESThe following General Schemes depict synthetic sequences for Examples 1-16.General Scheme 1OTQ-00925- 133 -NaSR15, Pd2(dba)3, XantphosGeneral Scheme 2NaSR15, Pd2(dba)3, heat XantphosPhl(OAc)2, (NH4)2CO3General Scheme 3OTQ-00925- 134 -General Scheme 6OTQ-00925- 135 -General Scheme 7(RO)2B-R3Pd catalyst Pd catalystGeneral Scheme 8General Scheme 9BrOTQ-00925- 136 - General Scheme 10(HO)2B-R4Cu catalyst R3General Scheme 11R3General Scheme 12OTQ-00925General Scheme 13OTQ-00925- 138 -H N02HCI reduction H2N'N'R2OHC^CHO R213A 13B 13DGeneral Scheme 15OTQ-00925- 139 -R6P;R7O' H Pd(PPh3)4, Br baseGeneral Scheme 16OTQ-00925- 140 -Oo p crs" R5o' o General Scheme 17OTQ-00925- 141 -NaO2S-l 18a baseGeneral Scheme 18B2(OH)4Pd catalyst BrGeneral Scheme 19OH HO'B'R3Pd catalystBrGeneral Scheme 20OTQ-00925- 142 -General Scheme 21General Scheme 22LiOH Pd2(allyl)2CI2, 22A Bl NAP, DMAP 22CH^N'W-R2amide couplingGeneral Scheme 23OTQ-00925- 143 -reduction13DGeneral Scheme 24H2N-WR2CDI, base24AGeneral Scheme 25H2N-WR2CDI, base25BGeneral Scheme 26General Scheme 27OTQ-00925- 144 -R327A 26B General Scheme 28R328A 26B General Scheme 29R329A 26B General Scheme 30 R330A 26B General Scheme 31OTQ-00925- 145 -deoxofluorinationExample 1 - Synthesis of A-(l-(tert-butyl)-l / f-pyrazol-4-yl)-2-(3-methyl-4-((6-(methylsulfonyl)-l,5-naphthyaridin-4-yl)amino)phenyl)acetamide (Compound 1); Prepared according to General Scheme 1°oSPart I - Synthesis of / V-(l-(tert-butyl)-l / / -pyiazol-4-yl)-2-(3-methyl-4-nitrophenyl)acetamideBenzotriazole- 1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (5.33 g, 10.2 mmol, 2.00 equiv.) was added to a solution of 2-(3-methyl-4-nitrophenyl)acetic acid (1.00 g, 5.12 mmol, 1.00 equiv.), 1 -(tert-butyl)- l / f-pyrazol-4-amine (710 mg, 5.12 mmol, 1.00 equiv.), and DIPEA (3.31 g, 25.6 mmol, 5.00 equiv.) in DMF (20 mL) and the mixture was stirred at room temperature for 2 h. Subsequently, the crude product was purified by reversed-phase flash chromatography (column: Cl 8 silica gel; mobile phase A: water (10 mmol / L NH4HCO3),OTQ-00925- 146 -mobile phase B: ACN, gradient: 40-70% B in 30 min; wavelength: 210 nm). The title compound was obtained as a yellow solid (900 mg, 56%).Part H- Synthesis of 2-(4-amino-3-methylphenyl)- / V-(l-(te / -butyl)-l / / -pyrazol-4-yl)acetamide4,4’ -Bipyridine (22.2 mg, 142 pmol, 0.05 equiv.) was added to a solution of A-(l -( / / 7-butyl)-l / 7-pyrazol-4-yl)-2-(3-methyl-4-nitrophenyl)acetamide (900 mg, 2.85 mmol, 1.00 equiv.) and tetrahydroxy diboron (765 mg, 8.54 mmol, 3.00 equiv.) in DMF (9 mb) at 0 °C and the mixture was stirred for 10 min at this temperature. Water was added and the product was extracted with EtOAc (3 x 20 mb). The combined organic phases were washed with brine (10 mb) and dried over Na2SC>4, and the solvent was removed under reduced pressure. The crude product was purified by reversed-phase flash chromatography (column: Cl 8 silica gel; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN, gradient: 30-60% B in 30 min; wavelength: 210 nm). The title compound was obtained as a pink solid (550 mg, 68%).Part III - Synthesis of 5-(((6-bromopyridin-3-yl)amino)methylene)-2,2-dimethyl-l,3-dioxane-4, 6-dioneA solution of 6-bromopyridin-3 -amine (10.0 g, 57.8 mmol, 1.00 equiv.) and 5-(methoxymethylene)-2,2-dimethyl-l,3-dioxane-4, 6-dione (11.8 g, 63.6 mmol, 1.10 equiv.) in EtOH (100 mb) was stirred at room temperature for 30 min. Subsequently, the precipitated product was filtered off, washed with EtOH (3 x 10 mb), and dried under reduced pressure. TheOTQ-00925- 147 -title compound was obtained as a yellow solid (15 g), which was used in the next reaction without further purification.Part IV- Synthesis of 2,2-dimethyl-5-(((6-(methylthio)pyridin-3-yl)amino)methylene)-l,3- dioxane-4, 6-dioneA solution of 5-(((6-bromopyridin-3-yl)amino)methylene)-2,2-dimethy 1-1, 3 -dioxane-4, 6-dione (5.00 g, 15.3 mmol, 1.00 equiv.), sodium thiomethoxide (1.07 g, 15.3 mmol, 1.00 equiv.), tris(dibenzylideneacetone)dipalladium(0) (700 mg, 764 pmol, 0.05 equiv.), Xantphos (880 mg, 1.53 mmol, 0.10 equiv.), and triethylamine (4.64 g, 45.8 mmol, 3.00 equiv.) in 1,4-dioxane (100 mL) was heated to 80 °C for 2 h under an inert atmosphere of nitrogen. EtOAc was added and insoluble materials were filtered off. Next, the organic phase was washed with brine, dried over Na2SO4, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography (25% EtOAc in petroleum ether). The title compound was obtained as a yellow solid (1.50 g, 8.8% over 2 steps).Part V- Synthesis of 6-(methylthio)-l,5-naphthyridin-4-olAs\A solution of 2,2-dimethyl-5-(((6-(methylthio)pyridin-3-yl)amino)methylene)-l,3-dioxane-4,6- dione (1.50 g, 5.10 mmol, 1.00 equiv.) in diphenyl ether (15 mL) was heated to 200 °C for 30 min. Subsequently, diethyl ether (30 mL) was added, and the precipitated product was filtered off. The obtained material was washed with diethyl ether (3 x 5 mL) and dried under reducedOTQ-00925- 148 -pressure. The title compound was obtained as a yellow solid (130 mg), which was used in the next reaction without further purification.Part VI - Synthesis of 8-chloro-2-(methylthio)-l,5-naphthyridineA( TCls\A solution of 6-(methylthio)-l,5-naphthyridin-4-ol (130 mg, 676 pmol, 1.00 equiv.) in phosphoryl chloride (1.3 mL) was heated to 60 °C for 2 h. Subsequently, the solvent was removed under reduced pressure. The title compound was obtained as a brown oil (300 mg), which was used in the next reaction without further purification.Part VII- Synthesis of 8-chloro-2-(methylsulfonyl)-l,5-naphthyridineClOxone (592 mg, 1.71 mmol, 1.20 equiv.) was added to a solution of 8-chloro-2-(methylthio)- 1,5-naphthyridine (300 mg, 1.42 mmol, 1.00 equiv.) in water (3 mL) and THF (3 mL) and the mixture was stirred at room temperature for 30 min. Subsequently, the crude product was purified by reversed-phase flash chromatography (column: Cl 8 silica gel; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN, gradient: 30-60% B in 30 min; wavelength: 210 nm). The title compound was obtained as a brown solid (90.0 mg, 7.3% over 3 steps).Part VIII - Synthesis of / V-(l-( / e / -butyl)-l / / -pyrazol-4-yl)-2-(3-methyl-4-((6- (methylsulfonyl)-l,5-naphthyridin-4-yl)amino)phenyl)acetamide (Compound 1)OTQ-00925- 149 -o=,s^oA solution of 8-chloro-2-(methylsulfonyl)-l,5-naphthyridine (45.0 mg, 185 pmol, 1.00 equiv.) and 2-(4-amino-3-methylphenyl)-A-(l-(tert-butyl)-177-pyrazol-4-yl)acetamide (53.1 mg, 185 pmol, 1.00 equiv.) in EtOH (1 mL) was heated to 80 °C for 5 h. Subsequently, the crude product was purified by reversed-phase flash chromatography (column: Cl 8 silica gel; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN, gradient: 25-55% B in 30 min; wavelength: 210 nm). The title compound was obtained as a yellow solid (35.3 mg, 39%). LCMS (ESI) calculated for C25H29N6O3S (M+H)+: 493.2, found: 493.3. 'H NMR (400 MHz, DMSO-d6) 810.18 (s, 1H), 9.29 (s, 1H), 8.55 - 8.49 (m, 2H), 8.25 (d, J= 8.8 Hz, 1H), 7.94 (s, 1H), 7.45 (s, 1H), 7.37 - 7.25 (m, 3H), 6.43 (d, J= 5.3 Hz, 1H), 3.65 (s, 3H), 3.60 (s 2H), 2.21 (s, 3H), 1.48 (s, 9H).Example 2 - Synthesis of A-(l-(tert-butyl)-177-pyrazol-4-yl)-2-(4-((6-(cyclopropanesulfonimidoyl)-l,5-naphthyridin-4-yl)amino)-3-methylphenyl)acetamide (Compounds 2 and 3); Prepared according to General Scheme 2Part I - Synthesis of 6-bromo-l,5-naphthyridin-4-olArT y^oHBrOTQ-00925- 150 -A solution of 5-(((6-bromopyridin-3-yl)amino)methylene)-2,2-dimethyl-l,3-dioxane-4, 6-dione (15.0 g, 45.9 mmol, 1.00 equiv., can be synthesized according to the synthesis described in Part III of Example 1) in diphenyl ether (300 mb) was heated to 220 °C for 5 min. Subsequently, diethyl ether (200 mb) was added, and the precipitated product was filtered off. The obtained material was washed with diethyl ether (3 x 10 mL) and dried under reduced pressure. The title compound was obtained as a yellow solid (8 g), which was used in the next reaction without further purification.Part II - Synthesis of 2-bromo-8-chloro-l,5-naphthyridineBrA solution of 6-bromo-l,5-naphthyridin-4-ol (8.00 g, 35.5 mmol, 1.00 equiv.), DIPEA (18.4 g, 142 mmol, 4.00 equiv.), and phosphoryl chloride (16.4 g, 107 mmol, 3.00 equiv.) in toluene (80 mL) was heated to 110 °C overnight. Subsequently, the solvent was removed under reduced pressure. The crude product was purified by column chromatography (17% EtOAc in petroleum ether). The title compound was obtained as a yellow solid (1.60 g, 14% over 2 steps).Part III - Synthesis of cyclopropanethiolCyclopropylmagnesium bromide (50.0 g, 344 mmol, 1.00 equiv.) was added to a suspension of sulfur (11.0 g, 344 mmol, 1.00 equiv.) in THF (500) and the mixture was heated to 50 °C for 3 h under an inert atmosphere of nitrogen. Subsequently, lithium aluminium hydride (6.53 g, 172 mmol, 0.50 equiv.) was added slowly and the mixture was heated to 60 °C for 30 min under an inert atmosphere of nitrogen. A solution of 5% sulfuric acid in water (10 mL) was added and the product was extracted with MTBE (3 x 20 mL). The combined organic phases were washed with brine (20 mL), dried over Na2SC>4, and the solvent was removed under reduced pressure.OTQ-00925- 151 -The title compound was obtained as a colorless liquid, which was used in the next reaction without further purification.Part IV - Synthesis of sodium cyclopropanethiolateSNaSodium hydride (16.2 g, 674 mmol, 2.00 equiv.) was added to a solution of cyclopropanethiol (25.0 g, 337 mmol, 1.00 equiv.) in THF (250 mL) and the mixture was stirred at room temperature for 2 h under an inert atmosphere of nitrogen. Subsequently, the solvent was removed under reduced pressure. The title compound was obtained as a yellow solid (30 g), which was used in the next reaction without further purification.Part V- Synthesis of 8-chloro-2-(cyclopropylthio)-l,5-naphthyridineClA solution of 2-bromo-8-chloro-l,5-naphthyridine (2.00 g, 8.21 mmol, 1.00 equiv.), sodium cyclopropanethiolate (790 mg, 8.21 mmol, 1.00 equiv.), tris(dibenzylideneacetone)dipalladium(0) (752 mg, 821 pmol, 0.10 equiv.), Xantphos (951 mg, 1.64 mmol, 0.20 equiv.), and triethylamine (2.49 g, 24.6 mmol, 3.00 equiv.) in 1,4-dioxane (20 mL) was heated to 80 °C for 2 h under an inert atmosphere of nitrogen. Subsequently, the crude product was purified by reversed-phase flash chromatography (column: Cl 8 silica gel; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN, gradient: 30-60% B in 30 min; wavelength: 210 nm). The title compound was obtained as a brown oil (700 mg, 36%).Part VI- Synthesis of V-(l-( / c / 7-butyl)-l / / -pyrazol-4-yl)-2-(4-((6-(cyclopropylthio)-1.5-naphthyridin-4-yl)amino)-3-methylphenyl)acetamideOTQ-00925- 152 -A solution of 8-chloro-2-(cyclopropylthio)-l,5-naphthyridine (150 mg, 634 pmol, 1.00 equiv.), 2-(4-amino-3-methylphenyl)-A-(l -(tert-butyl)- 177-pyrazol-4-yl)acetami de (182 mg, 634 pmol, 1.00 equiv., can be synthesized according to the synthesis described in Part II of Example 1), (SP-4- 1 )- [ 1, 3 -bis [2,6-bis( 1 -ethylpropyl)phenyl] -4, 5 -dichloro- 1,3 -dihydro-2 / f- imidazoleylidene] di chi oro(2-methylpyridine)palladium (107 mg, 127 pmol, 0.20 equiv.), and CS2CO3 (826 mg, 2.54 mmol, 4.00 equiv.) in 1,4-dioxane (3 mb) was heated to 100 °C for 2 h under an inert atmosphere of nitrogen. Subsequently, the crude product was purified by reversed-phase flash chromatography (column: C18 silica gel; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN, gradient: 35-65% B in 30 min; wavelength: 210 nm). The title compound was obtained as a yellow oil (220 mg, 71%).Part VII - Synthesis of V-( l-( / / 7-butyl)- 1 / / -pyrazol— l-yl)-2-(4-((6- (cyclopropanesulfonimidoyl)-l,5-naphthyridin-4-yl)amino)-3-methylphenyl)acetamide (Compounds 2 and 3)(Diacetoxyiodo)benzene (437 g, 1.36 mmol, 3.00 equiv.) was added to a solution of A-(l-(tert- butyl)-177-pyrazol-4-yl)-2-(4-((6-(cyclopropylthio)-l,5-naphthyridin-4-yl)amino)-3- methylphenyl)acetamide (220 mg, 452 pmol, 1.00 equiv.) in MeOH (4 mb) at room temperature. Subsequently, ammonium carbonate (130 mg, 1.36 mmol. 3.00 equiv.) was added and the mixture was stirred at room temperature for 1 h. The crude product was purified byOTQ-00925- 153 -revers ed-phase flash chromatography (column: Cl 8 silica gel; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN, gradient: 25-55% B in 30 min; wavelength: 210 nm). The racemic title compound was obtained as a white solid (80.0 mg, 34%). The two enantiomers were separated by chiral chromatography (column: CHIRALPAK IG, 20 x 250 mm, 5 pm; mobile phase A: / 7-hexane (0.5% 2 M ammonia solution in MeOH), mobile phase B: EtOH / DCM (1:1), isocratic separation with 40% B). The title compounds (compound 2 (enantiomer 1): 19.1 mg, 8.1%; compound 3 (enantiomer 2): 21.0 mg, 8.9%) were obtained as yellow solids (retention time (enantiomer 1): 11.36 min, retention time (enantiomer 2): 16.21 min, column: CHIRALPAK IG, 20 x 250 mm, 5 pm; mobile phase A: / 7-hexane (0.5% 2 M ammonia solution in MeOH), mobile phase B: EtOH / DCM (1:1), isocratic separation with 40% B, flow rate: 20 mL / min, wavelength: 254 nm). LCMS (ESI) calculated for C27H32N7O2S (M+H)+: 518.2, found: 518.3.XH NMR (400 MHz, DMSO-t / 6) 810.19 (s, 1H), 9.15 (s, 1H), 8.51 (d, J= 5.4 Hz, 1H), 8.47 (d, J= 8.8 Hz, 1H), 8.29 (d, J= 8.8 Hz, 1H), 7.94 (s, 1H), 7.45 (s, 1H), 7.38 - 7.32 (d, 2H), 7.28 (dd, J= 7.9, 2.1 Hz, 1H), 6.50 (d, J= 5.3 Hz, 1H), 4.93 (s, 1H), 3.60 (s, 2H), 3.42 (td, J = 8.0, 4.1 Hz, 1H), 2.22 (s, 3H), 1.48 (s, 9H), 1.32 - 1.23 (m, 1H), 1.09 -0.92 (m, 3H).Example 3 - Synthesis of 8-((4-(2-((l-(terZ-butyl)-177-pyrazol-4-yl)amino)-2-oxoethyl)-2-methylphenyl)amino)-A-methyl-l,5-naphthyridine-2-carboxamide (Compound 4); Prepared according to General Scheme 3N HQ> NHPart I - Synthesis of methyl 8-hydroxy-l,5-naphthyridine-2-carboxylateOTQ-00925- 154 -A solution of 6-chloro-l,5-naphthyridin-4-ol (5.00 g, 27.7 mmol, 1.00 equiv.), Pd(dppf)C12 (2.03 g, 2.77 mmol, 0.10 equiv.), and triethylamine (8.41 g, 83.1 mmol, 3.00 equiv.) in MeOH (100 mL) was heated to 80 °C overnight under an atmosphere of carbon monoxide.Subsequently, the solution was filtered, and the remaining solids were washed with MeOH (3 x 50 mL). The solvent was removed under reduced pressure. The title compound was obtained as a brown solid (5.0 g), which was used in the next reaction without further purification.Part II - Synthesis of methyl 8-chloro-l,5-naphthyridine-2-carboxylate14""%A( IClCT 'O""’A solution of methyl 8-hydroxy-l,5-naphthyridine-2-carboxylate (5.00 g, 24.5 mmol, 1.00 equiv.) and phosphoryl chloride (18.8 g, 122 mmol, 5.00 equiv.) in toluene (50 mL) was heated to 110 °C for 8 h. Subsequently, the solvent was removed under reduced pressure. The crude product was purified by column chromatography (17% EtOAc in petroleum ether). The title compound was obtained as a brown oil (1.00 g, 16% over 2 steps).Part III - Synthesis of 8-chloro- / V-methyl-l,5-naphthyridine-2-carboxamideOTQ-00925- 155 -A solution of methylamine in THF (2.0 M, 10 mL) was added to methyl 8-chloro-l,5-naphthyridine-2-carboxylate (1.00 g, 4.49 mmol, 1.00 equiv.) and CS2CO3 (2.93 g, 8.98 mmol, 2.00 equiv.) and the mixture was stirred at room temperature for 3 h. Subsequently, the solvent was removed under reduced pressure and the crude product was purified by reversed-phase flash chromatography (column: C18 silica gel; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN, gradient: 10-50% B in 20 min; wavelength: 210 nm). The title compound was obtained as a yellow solid (250 mg, 25%).Part IV- Synthesis of 8-((4-(2-((l-(tert-butyl)-TH-pyrazol-4-yl)amino)-2-oxoethyl)-2-niethylphenyl)aniino)- / V-methyl-l,5-naphthyridine-2-carboxamide (Compound 4)N NHHA solution of 8-chloro-A-methyl-l,5-naphthyridine-2-carboxamide (250 mg, 1.13 mmol, 1.00 equiv.), 2-(4-amino-3-methylphenyl)-A-( l-( / <? / 7-butyl)- l / / -pyrazol-4-yl)acetamide (323 mg, 1.13 mmol, 1.00 equiv., can be synthesized according to the synthesis described in Part II of Example 1), tris(dibenzylideneacetone)dipalladium(0) (103 mg, 110 pmol, 0.10 equiv.), Xantphos (130 mg, 230 pmol, 0.20 equiv.), and CS2CO3 (1.10 g, 3.38 mmol, 3.00 equiv.) in DMF (2.5 mb) was heated to 120 °C overnight under an inert atmosphere of nitrogen.Subsequently, the crude product was purified by reversed-phase flash chromatography (column: Cl 8 silica gel; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN, gradient: 10-50% B in 20 min; wavelength: 210 nm). The title compound was obtained as a light-brown solid (48.7 mg, 9.2%). LCMS (ESI) calculated for C26H30N7O2 (M+H)+: 472.3, found: 472.1. 'H NMR (400 MHz, DMSO-t / 6) 810.21 (s, 1H), 9.56 (s, 1H), 9.50 (s, 1H), 8.44 (d, J= 5.3 Hz, 1H), 8.40 - 8.30 (m, 2H), 7.95 (s, 1H), 7.46 (s, 1H), 7.40 - 7.25 (m, 3H), 6.35 (d, J= 5.3 Hz, 1H), 3.61 (s, 2H), 2.93 (d, J= 4.7 Hz, 3H), 2.23 (s, 3H), 1.49 (s, 9H).OTQ-00925- 156 -Example 4 - Synthesis of V-(l-(terZ-butyl)-l / f-pyrazol-4-yl)-2-(3-methyl-4-((6-(pyridin-2-ylsulfonyl)-l,5-naphthyridin-4-yl)amino)phenyl)acetamide (Compound 5), Prepared according to General Schemes 1 and 2NPart I - Synthesis of 8-chloro-2-(pyridin-2-ylthio)-l,5-naphthyridineS.1A solution of 2-bromo-8-chloro-l,5-naphthyridine (500 mg, 2.05 mmol, 1.00 equiv., can be synthesized according to the synthesis described in Part II of Example 2), pyridine-2-thiol (274 mg, 2.46 mmol, 1.20 equiv.), tris(dibenzylideneacetone)dipalladium(0) (188 mg, 205 pmol, 0.10 equiv.), Xantphos (238 mg, 411 pmol, 0.20 equiv.), and triethylamine (623 mg, 6.16 mmol, 3.00 equiv.) in 1,4-di oxane (10 mb) was heated to 80 °C for 2 h under an inert atmosphere of nitrogen. Water was added and the product was extracted with EtOAc (3 x 10 mL). The combined organic phases were washed with brine (3 x 10 mL), dried over Na2SC>4, and the solvent was removed under reduced pressure. The title compound was obtained as a brown oil, which was used in the next reaction without further purification.Part II- Synthesis of V-(l-( / c / 7-biityl)-l / / -pyrazol-4-yl)-2-(3-inethyl-4-((6-(pyridin-2-ylthio)-l,5-naphthyridin-4-yl)amino)phenyl)acetamideOTQ-00925- 157 -A solution of 8-chloro-2-(pyridin-2-ylthio)-l,5-naphthyridine (85.0 mg, 311 pmol, 1.00 equiv.), 2-(4-amino-3-methylphenyl)-A-(l -(tert-butyl)- 177-pyrazol-4-yl)acetami de (88.9 mg, 311 pmol, 1.00 equiv., can be synthesized according to the synthesis described in Part II of Example 1), (SP-4- 1 )- [ 1, 3 -bis [2,6-bis( 1 -ethylpropyl)phenyl] -4, 5 -dichloro- 1,3 -dihydro-2 / 7-im i dazol -2-ylidene]dichloro(2-methylpyridine)palladium (78.3 mg, 93 pmol, 0.30 equiv.), and CS2CO3 (405 mg, 1.24 mmol, 4.00 equiv.) in 1,4-dioxane (1.7 mb) was heated to 100 °C overnight under an inert atmosphere of nitrogen. Subsequently, the crude product was purified by revers ed-phase flash chromatography (column: Cl 8 silica gel; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN, gradient: 30-60% B in 30 min; wavelength: 210 nm). The title compound was obtained as a yellow oil (29.0 mg, 18% over 2 steps).Part III - Synthesis of V-(l-(tert-butyl)-lH-pyrazol-4-yl)-2-(3-methyl-4-((6-(pyridin-2-ylsulfonyl)-l,5-naphthyridin-4-yl)amino)phenyl)acetamide (Compound 5)Oxone (81.0 mg, 132 pmol, 3.00 equiv.) was added to a solution of A-(l-(tert-butyl)-177- pyrazol-4-yl)-2-(3-methyl-4-((6-(pyridin-2-ylthio)-l,5-naphthyridin-4-yl)amino)phenyl)acetamide (23.0 mg, 44.0 pmol, 1.00 equiv.) in water (230 pL) and THF (230 pL) and the mixture was stirred at room temperature for 2 h. Subsequently, the crude product was purified by reversed-phase flash chromatography (column: Cl 8 silica gel; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN, gradient: 20-50% B in 10 min;OTQ-00925- 158 -wavelength: 210 nm). The title compound was obtained as a yellow solid (5.0 mg, 20%). LCMS (ESI) calculated for C29H30N7O3S (M+H)+: 556.2, found: 556.3. 'H NMR (400 MHz, DMSO-d6) <510.17 (s, 1H), 8.71 (s, 1H), 8.69- 8.44 (m, 5H), 8.21 (td, = 7.8, 1.7 Hz, 1H), 7.93 (s, 1H), 7.75 (ddd, J= 7.8, 4.6, 1.1 Hz, 1H), 7.44 (s, 1H), 7.33 (d, J= 8.0 Hz, 1H), 7.28 (d, J= 1.9 Hz, 1H), 7.23 (dd, J= 8.2, 2.0 Hz, 1H), 6.62 (d, J= 5.4 Hz, 1H), 3.56 (s, 2H), 2.04 (s, 3H), 1.48 (s, 9H).Example 5 - Preparation of Additional 1,5-Naphthyridine CompoundsCompounds in the table below were prepared based on experimental procedures described in Examples 1-4, General Scheme 10 and the detailed description.No. Structure Name ’HNMR Observe d m / z 6 A-(l-( / c / 7-butyl)- (400 MHz, DMSO-d6) 507.2177-pyrazol-4-yl)-2- <510.16 (d, J= 3.4 Hz, (M+H)+(3-methyl-4- 1H), 8.70 (d, J = 5.5 Hz,°dS- (methyl(6- 1H), 8.48 (d, J = 8.8 Hz, (methylsulfonyl)- 1H), 8.07 (d, J= 8.7Hz,1,5-naphthyridin-4- 1H), 7.92 (s, 1H), 7.46- yl)amino)phenyl)ace 7.42 (m, 1H), 7.30 (d, J = tamide 2.1 Hz, 1H), 7.13 (d, J =8.0 Hz, 1H), 6.99 -6.93(m, 2H), 3.52 (s, 2H), 3.47(s, 3H), 2.73 -2.56 (m,3H), 2.19 (s, 3H), 1.48 (s,9H)7 7V-(l-(terZ-butyl)- (400 MHz, DMSO-d6) 507.20N177-pyrazol-4-yl)-2- 810.19 (s, 1H), 9.26 (s, (M+H)+((JHKO S, (4-((6- 1H), 8.56- 8.51 (m, 2H), d(ethylsulfonyl)-l,5- 8.27 (d, J = 8.8 Hz, 1H),OTQ-00925- 159 -naphthyridin-4- 7.94 (s, 1H), 7.45 (s, 1H), yl)amino)-3- 7.37- 7.31 (m, 2H), 7.28 methylphenyl)aceta (dd, J= 8.0, 2.0 Hz, 1H), mide 6.45 (d, J = 5.3 Hz, 1H),3.94 (q, J = 7.3 Hz, 2H),3.60 (s, 2H), 2.21 (s, 3H),1.49 (s, 9H), 1.22 (t, J =7.4 Hz, 3H)8 7V-(l-(terZ-butyl)- (400 MHz, DMSO-d6) 519.2177-pyrazol-4-yl)-2- <510.19 (s, 1H), 9.13 (s, (M+H)+(4-((6- 1H), 8.58 - 8.50 (m, 2H), (cyclopropylsulfonyl 8.22 (d, J = 8.8 Hz, 1H), ^^ z X Jx)- 1,5-naphthyridin- 7.94 (s, 1H), 7.45 (s, 1H),4-yl)amino)-3- 7.38 - 7.32 (m, 2H), 7.30 methylphenyl)aceta - 7.25 (m, 1H), 6.51 (d, J & mide = 5.4 Hz, 1H), 3.72 (ddd,J= 13.1, 7.9, 4.9 Hz, 1H), zW\= / O - 3.59 (s, 2H), 2.22 (s, 3H),1.48 (s, 9H), 1.25 - 1.18(m, 2H), 1.17- 1.11 (m,2H)9 7V-(l-(terZ-butyl)- (400 MHz, DMSO-d6) 492.2 JQYTTT> 177-pyrazol-4-yl)-2- <510.19 (s, 1H), 9.19 (s, (M+H)+HX(3 -methyl-4-((6-(5- 1H), 8.52- 8.45 (m, 2H), o=AHNmethylsulfonimidoyl 8.32 (d, J= 8.8 Hz, 1H), Enantiomer 1)- 1,5-naphthyridin- 7.94 (s, 1H), 7.45 (s, 1H), (retention time: 2.40 min,4- 7.37- 7.30 (m, 2H), 7.27 column: CHIRALPAKyl)amino)phenyl)ace (d, J = 8.0 Hz, 1H), 6.44IK-3, 4.6 x 50 mm, 3 pm;tamide (d, J= 5.3 Hz, 1H), 4.86 mobile phase A: hexaneOTQ-00925- 160 -(0.1% DEA), mobile (s, 1H), 3.60 (s, 2H), 3.49 phase B: EtOH / DCM (s, 3H), 2.21 (s, 3H), 1.48 (1:1), isocratic separation (s, 9H)with 40% B, flow rate: 1mL / min, wavelength: 254nm)10 A-(l-(terAbutyl)- (400 MHz, DMSOx / ) 492.2 l / f-pyrazol-4-yl)-2- <510.19 (s, 1H), 9.19 (s, (M+H)+(3 -methyl-4-((6-(5- 1H), 8.52- 8.45 (m, 2H), o=s^UNmethylsulfonimidoyl 8.32 (d, J= 8.8 Hz, 1H), Enantiomer 2)- 1,5-naphthyridin- 7.94 (s, 1H), 7.45 (s, 1H), (retention time: 2.93 min,4- 7.37- 7.30 (m, 2H), 7.27 column: CHIRALPAKyl)amino)phenyl)ace (d, J = 8.0 Hz, 1H), 6.44IK-3, 4.6 x 50 mm, 3 pm;tamide (d, J= 5.3 Hz, 1H), 4.86 mobile phase A: hexane(s, 1H), 3.60 (s, 2H), 3.49(0.1% DEA), mobile(s, 3H), 2.21 (s, 3H), 1.48 phase B: EtOH / DCM(s, 9H)(1:1), isocratic separationwith 40% B, flow rate: 1mL / min, wavelength: 254nm)Example 6 - Preparation of compounds 11-32 and 203-294Compounds 11-32 and 203-294 can be prepared according to the synthetic protocols in Examples 1-4 and the General Schemes 10-21Example 7 - Synthesis of A-(l-(terAbutyl)-l / f-pyrazol-4-yl)-2-(3-methyl-4-((2-(methylsulfonyl)-2 / / -pyrazolo[4,3- / ?]pyridin-7-yl)oxy)phenyl)acetamide (Compound 33);Prepared according to General Scheme 4OTQ-00925- 161 -Part I - Synthesis of 2-(4-hydroxy-3-methylphenyl)acetic acidHO XX IA solution of lithium hydroxide (1.00 g, 41.6 mmol, 1.50 equiv.) in water (41 mL) was added to a solution of methyl 2-(4-hydroxy-3-methylphenyl)acetate (5.00 g, 27.7 mmol, 1.00 equiv.) in THE (50 mL) and the mixture was stirred at room temperature for 1 h. Subsequently, hydrochloric acid (1 M, 10 mL) was added, and the product was extracted with EtOAc (3 x 20 mL). The combined organic phases were washed with brine (20 ml), dried over Na2SO4, and the solvent was removed under reduced pressure. The title compound was obtained as a lightyellow solid (4.0 g, 87%), which was used in the next reaction without further purification.Part II - Synthesis of N-( 1 -( / c / 7- butyl)- l / / -pyrazol-4-yl)-2-(4-hydroxy-3-methylphenyl)acetamideBenzotriazole- 1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (9.39 g, 18.1 mmol, 1.20 equiv.) was added to a solution of 2-(4-hydroxy-3-methylphenyl)acetic acid (2.50 g, 15.0 mmol, 1.00 equiv.), 1 -(tert-butyl)- l / f-pyrazol-4-amine (2.30 g, 16.5 mmol, 1.10 equiv.), and DIPEA (5.83 g, 45.1 mmol, 3.00 equiv.) in DMF (25 mL) and the mixture was stirred at room temperature for 1 h. Subsequently, water (50 mL) was added, and the product was extracted with EtOAc (3 x 20 mL). The combined organic phases were washed with brine (20 mL), dried over Na2SC>4, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography (50% EtOAc in petroleum ether). The title compound was obtained as a white solid (1.57 g, 36%).OTQ-00925- 162 -Part HI - Synthesis of 2-(4-(( l / / -pyrazol()|4.3- / j|pyridin-7-yl)oxy)-3-inethylphenyl)-V-(l-(te / 7-hutyl)- l / / -pyrazol-4-yl)acetainideHNtl< N-TNH 'aA solution of A-( l-( / / 7-butyl)- l / / -pyrazol-4-yl)-2-(4-hydroxy-3-methylphenyl)acetamide (500 mg, 1.74 mmol, 1.00 equiv.), 7-chloro-l / f-pyrazolo[4,3- / >]pyridine (267 mg, 1.74 mmol, 1.00 equiv.), copper(I) iodide (5.0 mg, 26 pmol, 0.015 equiv.), 2,2,6,6-tetramethylheptane-3,5-dione (4.8 mg, 26 pmol, 0.015 equiv.), and CS2CO3 (1.13 g, 3.48 mmol, 2.00 equiv.) inDMF (10 mb) was heated to 150 °C for 2 h in a micro wave oven under an inert nitrogen atmosphere.Subsequently, the crude product was purified by reversed-phase flash chromatography (column: Cl 8 silica gel; mobile phase A: water (0.1% formic acid), mobile phase B: ACN, gradient: 40-70% B in 30 min; wavelength: 210 nm). The title compound was obtained as a white solid (79 mg, 11%).Part TV - Synthesis of V-(l-( / c / 7-biityl)-l / / -pyiazol-4-yl)-2-(3-inethyl-4-((2-(inetliylsiilf()nyl)-2 / / -pyrazol()|4.3- / j|pyridiii-7-yl)oxy (phenyl (acetamide (Compound 33)HNr iN-NMethanesulfonyl chloride (13.6 mg, 119 pmol, 1.20 equiv.) was added to a solution of 2-(4-((l / / -pyrazolo[4,3- / ?]pyridin-7-yl)oxy)-3-methylphenyl)-A-(l -( / c77-butyl)-l / / -pyrazol-4-yl)acetamide (40.0 mg, 99 pmol, 1.00 equiv.) and triethylamine (15.0 mg, 149 pmol, 1.50 equiv.) in DCM (400 pL) and the mixture was stirred at room temperature for 2 h. The solvent was removed under reduced pressure, and the crude product was purified by reversed-phase flash chromatography (column: C18 silica gel; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN, gradient: 25-55% B in 30 min; wavelength: 210 nm). The titleOTQ-00925- 163 -compound was obtained as a white solid (10.8 mg, 23%). LCMS (ESI) calculated for C23H27N6O4S (M+H)+: 483.2, found: 483.2. 'H NMR (400 MHz, DMSO-d6) 810.20 (s, 1H), 9.24 (s, 1H), 8.44 (d, J= 4.9 Hz, 1H), 7.95 (s, 1H), 7.45 (s, 1H), 7.37 (d, J= 2.2 Hz, 1H), 7.29 (dd, J= 8.3, 2.2 Hz, 1H), 7.21 (d, J= 8.3 Hz, 1H), 6.25 (d, J= 4.9 Hz, 1H), 3.86 (s, 3H), 3.60 (s, 2H), 2.15 (s, 3H), 1.48 (s, 9H).Example 8 - Synthesis of A-(l-(tert-butyl)-177-pyrazol-4-yl)-2-(3-methyl-4-((2-(l-methyl-2-oxopyrrolidin-3-yl)-2 / 7-pyrazolo[4,3- / ?]pyridin-7-yl)oxy)phenyl)acetamide (Compounds 34 and 35); Prepared according to General Schemes 4 and 5HNriN-NA solution of 2-(4-(( l / 7-pyrazolo[4,3- / ?]pyridin-7-yl)oxy)-3-methylphenyl)-A-( l -( / / 7-butyl)-177-pyrazol-4-yl)acetamide (150 mg, 371 pmol, 1.00 equiv., can be synthesized according to the synthesis described in Part III of Example 7), 3-bromo-l-methylpyrrolidin-2-one (98.5 mg, 553 pmol, 1.50 equiv.), and K2CO3 (103 mg, 742 pmol, 2.00 equiv.) in DMF (3 mb) was heated to 60 °C for 4 h. Subsequently, the crude product was purified by reversed-phase flash chromatography (column: Cl 8 silica gel; mobile phase A: water (0.1% formic acid), mobile phase B: ACN, gradient: 20-50% B in 30 min; wavelength: 210 nm). The racemic title compound was obtained as a white solid (60 mg, 32%). The two enantiomers were separated by chiral chromatography (column: CHIRALPAK IC, 20 x 250 mm, 5 pm; mobile phase A: n-hexane (0.5% 2 M ammonia solution in MeOH), mobile phase B: EtOH / DCM (1:1), isocratic separation with 50% B). The title compounds (compound 34 (enantiomer 1): 21.1 mg, 11%; compound 35 (enantiomer 2): 20.4 mg, 11%) were obtained as white solids (retention time (enantiomer 1): 8.49 min, retention time (enantiomer 2): 12.37 min, column: CHIRALPAK IC, 20 x 250 mm, 5 pm; mobile phase A: 77-hexane (0.5% 2 M ammonia solution in MeOH), mobile phase B: EtOH / DCM (1:1), isocratic separation with 50% B, flow rate: 20 mL / min,OTQ-00925- 164 -wavelength: 254 nm). LCMS (ESI) calculated for C27H32N7O3 (M+H)+: 502.3, found: 502.3.JH NMR (400 MHz, DMSO-d6) 8 10.19 (s, 1H), 8.77 (s, 1H), 8.27 (d, J = 4.9 Hz, 1H), 7.95 (d, J= 0.7 Hz, 1H), 7.45 (d, J= 0.7 Hz, 1H), 7.34 (d, J= 2.1 Hz, 1H), 7.26 (dd, J = 8.3, 2.2 Hz, 1H), 7.14 (d, J= 8.1 Hz, 1H), 6.11 (d, = 4.9Hz, 1H), 5.54 (t, J= 8.9 Hz, 1H), 3.64- 3.54 (m, 1H), 3.59 (s, 2H), 3.49 (dt, J= 9.4, 7.7 Hz, 1H), 2.86 (s, 3H), 2.69 (td, J= 8.0, 6.1 Hz, 2H), 2.12 (s, 3H), 1.48 (s, 9H).Example 9 - Synthesis of A-(l-( / / 7-butyl)-l / 7-pyrazol-4-yl)-2-(3-fluoro-5-methyl-4-((2-(2-oxo-l-(pyridin-2-yl)pyrrolidin-3-yl)-277-pyrazolo[4,3- / >]pyridin-7-yl)oxy)phenyl)acetamide (Compounds 36 and 37); Prepared according to General Scheme 5Part I - Synthesis of 4-bromo-2-fluoro-6-methylphenolFA-Bromosuccinimide (53.3 g, 300 mmol, 1.05 equiv.) was added to a solution of 2-fluoro-6-methylphenol (36.0 g, 285 mmol, 1.00 equiv.) in acetic acid (360 ml) at 0 °C and the mixture was subsequently stirred at room temperature for 3 h. Water (I L) was added, and the product was extracted with EtOAc (500 mb). The organic phase was washed with an aqueous saturated solution of NaHCCh and brine and dried over Na2SC>4. The solvent was removed under reduced pressure. The title compound (65 g) was used in the next reaction without further purification.Part II - Synthesis of 2-(benzyloxy)-5-bromo-l-fluoro-3-methylbenzeneOTQ-00925- 165 -A solution of 4-bromo-2-fluoro-6-methylphenol (65.0 g, 349 mmol), benzyl bromide (59.7 g, 349 mmol, 1.10 equiv.), and K2CO3 (65.7 g, 476 mmol, 1.50 equiv.) in DMF (650 mb) was stirred for 3 h at room temperature. Subsequently, water (2 L) was added, and the product was extracted with EtOAc (2 x 500 mb). The combined organic phases were washed with brine, dried over Na2SO4, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography (3% EtOAc in petroleum ether). The title compound was obtained as a colorless oil (54 g, 64% over 2 steps).Part III - Synthesis of ethyl 2-(4-(benzyloxy)-3-fluoro-5-methylphenyl)acetateA solution of 2-(benzyloxy)-5-bromo-l-fluoro-3-methylbenzene (54.0 g, 183 mmol, 1.00 equiv.), ethyl potassium malonate (46.7 g, 274 mmol, 1.50 equiv.), allylpalladium(II) chloride dimer (1.34 g, 3.66 mmol, 0.02 equiv.), BINAP (6.84 g, 11.0 mmol, 0.06 equiv.), andDMAP (2.24 g, 18.3 mmol, 0.10 equiv.) in / ?-xylene (540 mb) was heated to 140 °C overnight under an inert atmosphere of nitrogen. Subsequently, water (I L) was added, and the product was extracted with EtOAc (500 mb). The combined organic phases were washed with brine, dried over Na2SC>4, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography (3% EtOAc in petroleum ether). The title compound was obtained as a red oil (30 g, 54%).Part IV - Synthesis of ethyl 2-(3-fluoro-4-hydroxy-5-methylphenyl)acetateFOTQ-00925- 166 -Palladium on carbon (10 wt.%, 1.80 g) was added to a solution of ethyl 2-(4-(benzyloxy)-3-fluoro-5-methylphenyl)acetate (18.0 g, 59.5 mmol, 1.00 equiv.) in isopropanol (200 mb) and the mixture was stirred at room temperature overnight under an atmosphere of hydrogen. The catalyst was filtered off and the solvent was removed under reduced pressure. The title compound was obtained as a red oil (13.8 g, 87%), which was used in the next reaction without further purification.Part V - Synthesis of 2-(3-fhioro-4-hydroxy-5-methylphenyl)acetic acidOHFA solution of ethyl 2-(3-fluoro-4-hydroxy-5-methylphenyl)acetate (12.0 g, 56.5 mmol, 1.00 equiv.) and lithium hydroxide (4.07 g, 170 mmol, 3.00 equiv.) in THF (60 mb) and water (120 mb) was stirred at room temperature for 10 min. Subsequently, water was added, and the pH of the aqueous phase was adjusted to 6 through the addition of hydrochloric acid. The product was extracted with EtOAc and the solvent was removed under reduced pressure. The title compound was obtained as a yellow solid (9 g, 82%), which was used in the next reaction without further purification.Part VI - Synthesis of 7V-(l-(tert-butyl)-17T-pyrazol-4-yl)-2-(3-fluoro-4-hydroxy-5-methylphenyl)acetamideHPyBOP (15.0 g, 28.8 mmol, 1.50 equiv.) was added to a solution of 2-(3-fluoro-4-hydroxy-5-methylphenyl)acetic acid (7.00 g, 19.2 mmol, 1.00 equiv.), 1 -(tert-butyl)- l / 7-pyrazol-4-amine (3.20 g, 23.0 mmol, 1.20 equiv.), and DIPEA (12.4 g, 96.0 mmol, 5.00 equiv.) in DMF (140 mL) and the mixture was stirred at room temperature overnight. Subsequently, water (I L) was added, and the product was extracted with EtOAc (500 mL). The organic phase was washedOTQ-00925- 167 -with brine, dried over Na2SC>4, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography (20% EtOAc in petroleum ether). The title compound was obtained as a white solid (10 g, 86%).Part VII- Synthesis of 7V-(l-(tert-butyl)-lH-pyrazol-4-yl)-2-(3-fluoro-5-methyl-4-((2-((2- (trimethylsilyl (ethoxy )inethyl)-2 / / -pyrazol()|4.3- / j|pyridin-7-yl)oxy (phenyl (acetamideA solution of 7V-(l-(terZ-butyl)-177-pyrazol-4-yl)-2-(3-fluoro-4-hydroxy-5-methylphenyl)acetamide (2.10 g, 6.88 mmol, 1.00 equiv.), 7-chloro-2-((2-(trimethylsilyl)ethoxy)methyl)-277-pyrazolo[4,3- / >]pyridine (2.24 g, 7.91 mmol, 1.15 equiv.), copper(I) iodide (131 mg, 688 pmol, 0.10 equiv.), 2,2,6,6-tetramethylheptane-3,5-dione (127 mg, 688 pmol, 0.10 equiv.), and CS2CO3 (4.48 g, 13.8 mmol, 2.00 equiv.) in DMF (21 mb) was heated to 100 °C for 16 h under an inert nitrogen atmosphere. Subsequently, the crude product was purified by reversed-phase flash chromatography (column: Cl 8 silica gel; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN, gradient: 10-50% B in 10 min; wavelength: 210 nm). The title compound was obtained as a yellow solid (3.6 g, 95%).Part VIII- Synthesis of 2-(4-((lH-pyrazolo[4,3-fr|pyi’idin-7-yl)oxy)-3-fluoro-5-methylphenyl)-V-( l-( / c / 7-butyl(- l / / -pyrazol-4-yl)acetamideA solution of A-(l-(terZ-butyl)-177-pyrazol-4-yl)-2-(3-fluoro-5-methyl-4-((2-((2-(trimethylsilyl)ethoxy)methyl)-277-pyrazolo[4,3- / >]pyridin-7-yl)oxy)phenyl)acetamide (3.60 g, 6.51 mmol, 1.00 equiv.) in DCM (18 mb) and TFA (18 mb) was stirred at room temperature forOTQ-00925- 168 -3 h. Subsequently, the solvent was removed under reduced pressure. The residue was dissolved in water and the pH of the solution was brought to 7 with a saturated aqueous solution of Na2CC>3. The solution was extracted with EtOAc (3 x 200 mb), and the combined organic phases were washed with brine (2 x 50 mb), dried over Na2SC>4, and the solvent was removed under reduced pressure. Ammonium hydroxide (36 mb) and THF (7.2 mb) were added, and the resulting mixture was stirred at room temperature for 2 h. Subsequently, the solvent was removed under reduced pressure, and the crude product was purified by reversed-phase flash chromatography (column: Cl 8 silica gel; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN, gradient: 10-50% B in 10 min; wavelength: 210 nm). The title compound was obtained as a yellow solid (1.3 g, 74%).Part IX - Synthesis of 3-bromo-l-(pyridin-2-yl)pyrrolidin-2-oneBrA solution of 2-aminopyridine (400 mg, 4.25 mmol, 1.00 equiv.) and 2,4-dibromobutanoyl bromide (2.62 g, 8.50 mmol, 2.00 equiv.) in DCM (4 mb) was stirred at 0 °C for 1 h.Subsequently, the mixture was allowed to warm to room temperature and stirred for an additional 2 h. A solution of sodium hydroxide (650 mg, 16.3 mmol, 3.80 equiv.) in water (4 mb) was added and the mixture was stirred for 1 h. The product was extracted with DCM (3 x 20 mb) and the combined organic phases were washed with brine (3 x 20 mb), dried over Na2SO4, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography (50% EtOAc in petroleum ether). The racemic title compound was obtained as a white solid (630 mg, 61%).Part X - Synthesis of / V-(l-( / e / -butyl)-l / / -pyrazol-4-yl)-2-(3-fluoro-5-niethyl-4-((2-(2-oxo-l-(pyridin-2-yl)pyrrolidin-3-yl)-27f-pyrazolo[4,3-6]py|’idin-7-yl)oxy)phenyl)acetamide (Compounds 36 and 37)OTQ-00925- 169 -A solution of 2-(4-((l / f-pyrazolo[4,3- / >]pyridin-7-yl)oxy)-3-fluoro-5-methylphenyl)-7V-(l-(tert-butyl)-l / f-pyrazol-4-yl)acetamide (228 mg, 539 pmol, 1.00 equiv.), 3-bromo-l-(pyridin-2-yl)pyrrolidin-2-one (130 mg, 539 pmol, 1.00 equiv.), and K2CO3 (149 mg, 1.08 mmol, 2.00 equiv.) in DMF (2.6 mb) was heated to 60 °C for 4 h. Subsequently, the crude product was purified by reversed-phase flash chromatography (column: Cl 8 silica gel; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN, gradient: 10-50% B in 10 min; wavelength: 210 nm). The racemic title compound was obtained as a white solid (144 mg, 46%). The two enantiomers were separated by chiral chromatography (column: CHIRAL ART Cellulose-SZ, 30 x 250 mm, 5 pm; mobile phase A: MTBE (0.5% 10 mM ammonia solution in MeOH), mobile phase B: EtOH, isocratic separation with 30% B). The title compounds (compound 36 (enantiomer 1): 53.3 mg, 17%; compound 37 (enantiomer 2): 50.4 mg, 16%) were obtained as white solids (retention time (enantiomer 1): 1.00 min, retention time (enantiomer 2): 1.37 min, column: CHIRAL ART Cellulose-SZ, 4.6 x 50 mm, 3 pm; mobile phase A: MTBE (0.1% DEA), mobile phase B: EtOH, isocratic separation with 30% B, flow rate: 1.67 mL / min, wavelength: 254 nm). LCMS (ESI) calculated for C31H32FN8O3 (M+H)+: 583.3, found: 583.3. 'H NMR (400 MHz, DMSO-t / 6) 8 10.20 (s, 1H), 8.93 (s, 1H), 8.51 - 8.46 (m, 1H), 8.35 - 8.26 (m, 2H), 7.94 (s, 1H), 7.93 - 7.84 (m, 1H), 7.45 (s, 1H), 7.28 - 7.19 (m, 2H), 7.17 (s, 1H), 6.22 (dd, = 4.9, 1.0 Hz, 1H), 5.95 (t, J=9.5 Hz, 1H), 4.41 -4.30 (m, 1H), 4.11 -4.09 (m, 1H), 3.61 (s, 2H), 2.93 -2.78 (m, 2H), 2.16 (s, 3H), 1.48 (s, 9H).Example 10- Synthesis of A-(l-( / / 7-butyl)-l / 7-pyrazol-4-yl)-2-(4-((2-(2-hydroxycyclopentyl)-2 / / -pyrazolo[4,3- / ?]pyridin-7-yl)oxy)-3-methylphenyl)acetamideOTQ-00925- 170 -(Compounds 38 and 39; relative stereochemistry: trans),- Prepared according to General Scheme 5HN1 1( iT°N-N* / OHPart I - Synthesis of 2-hydroxycyclopentyl 4-methylbenzenesulfonate (relative stereochemistry: cis)Triethylamine (991 mg, 9.79 mmol, 1.00 equiv.) and dibutyltin(IV) oxide (48.7 mg, 200 pmol, 0.02 equiv.) was added to a solution of cis- 1,2-cyclopentanediol (1.00 g, 9.79 mmol, 1.00 equiv.) and / ?- toluenesulfonyl chloride (1.87 g, 9.79 mmol, 1.00 equiv.) in DCM (10 mL) and the mixture was stirred at room temperature for 1 h. Subsequently, water was added, and the product was extracted with EtOAc (3 x 50 mL). The combined organic phases washed with brine, dried over Na2SC>4, and the solvent was removed under reduced pressure. The racemic title compound was obtained as a yellow oil (1.5 g), which was used in the next reaction without further purification.Part II- Synthesis of V-(l-( / c / 7-biityl)-l / / -pyrazol-4-yl)-2-(4-((2-(2-hydroxycyclopentyl)- 277-pyrazolo[4,3- / ’]pyi’idin-7-yl)oxy)-3-methylphenyl)acetamide (Compounds 38 and 39; relative stereochemistry: trans)11N-NOHOTQ-00925- 171 -A solution of 2-(4-((177-pyrazolo[4,3- / >]pyridin-7-yl)oxy)-3-methylphenyl)-7V-(l-(terZ-butyl)-177-pyrazol-4-yl)acetamide (50 mg, 120 pmol, 1.00 equiv., can be synthesized according to the synthesis described in Part in of Example 7), 2-hydroxy cyclopentyl 4-methylbenzenesulfonate (30.4 mg, 120 pmol, 1.00 equiv., relative stereochemistry: cis), and CS2CO3 (80.5 mg, 240 pmol, 2.00 equiv.) in DMF (1 mb) was heated to 70 °C for 4 h. Subsequently, the crude product was purified by reversed-phase flash chromatography (column: Cl 8 silica gel; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN, gradient: 10-50% B in 20 min; wavelength: 220 nm). The racemic title compound was obtained as a yellow solid (28.0 mg, 46%). The two enantiomers were separated by chiral chromatography (column: CHIRAL ART Cellulose-SJ, 30 x 250 mm, 5 pm; mobile phase A: 77-hexane (0.5% 10 mM ammonia solution in MeOH), mobile phase B: EtOH: ACN (5:1), isocratic separation with 12% B). The title compounds (compound 38 (enantiomer 1): 2.8 mg, 4.6%; compound 39 (enantiomer 2): 7.1 mg, 12%) were obtained as yellow solids (retention time (enantiomer 1): 3.28 min, retention time (enantiomer 2): 3.55 min, column: CHIRAL ART Cellulose-SJ, 4.6 x 50 mm, 3 pm; mobile phase A: 77-hexane (0.1% DEA), mobile phase B: EtOH / ACN (5:1), isocratic separation with 20% B, flow rate: 1.0 mL / min, wavelength: 254 nm). LCMS (ESI) calculated for C27H33N6O3 (M+H)+: 489.3, found: 489.2. 'H NMR (400 MHz, DMSO-t / 6) 8 10.18 (s, 1H), 8.70 (s, 1H), 8.23 (d,.7= 4,9 Hz, 1H), 7.94 (s, 1H), 7.45 (s, 1H), 7.34 (s, 1H), 7.26 (d, J= 9.4Hz, 1H), 7.14 (d, J= 8.3 Hz, 1H), 6.09 (d, J= 5.0 Hz, 1H), 5.23 (d, J= 5.2 Hz, 1H), 4.75 - 5.68 (m, 1H), 4.45 -4.35 (m, 1H), 3.59 (s, 2H), 2.32-2.15 (m, 2H), 2.13 (s, 3H), 2.08 - 1.95 (m, 1H), 1.88 - 1.78 (m, 2H), 1.70 - 1.56 (m, 1H), 1.48 (s, 9H).Example 11 - Synthesis of A-(l-(tert-butyl)-177-pyrazol-4-yl)-2-(3-methyl-4-((2-(l-methyl-2-oxopyrrolidin-3-yl)-277-pyrazolo[4,3-Z>]pyridin-7-yl)amino)phenyl)acetamide (Compounds 40 and 41); Prepared according to General Scheme 6OTQ-00925- 172 -Part I - Synthesis of 3-(7-chloro-2 / f-pyrazolo[4,3-^]pyi’idin-2-yl)-l-methylpyrrolidin-2-oneA solution of 7-chloro-177-pyrazolo[4,3-b]pyridine (1.00 g, 6.51 mmol, 1.00 equiv.), 3-bromo-l-methylpyrrolidin-2-one (1.28 g, 7.16 mmol, 1.10 equiv.), and K2CO3 (1.80 g, 13.0 mmol, 2.00 equiv.) in DMF (20 mb) was heated to 60 °C for 3 h. Subsequently, the crude product was purified by reversed-phase flash chromatography (column: Cl 8 silica gel; mobile phase A: water (0.1% TFA), mobile phase B: ACN, gradient: 20-100% B in 20 min; wavelength: 220 nm). The racemic title compound was obtained as a brown solid (600 mg, 37%).Part II- Synthesis of 7V-(l-(tert-butyl)-lH-pyrazol-4-yl)-2-(3-methyl-4-((2-(l-methyl-2-oxopyrrolidin-3-yl)-2 / f-pyrazolo[4,3-6]py|’idin-7-yl)amino)phenyl)acetamide (Compounds 40 and 41)A solution of 2-(4-amino-3-methylphenyl)-A-( l-( / / 7-butyl)- l / 7-pyrazol-4-yl)acetamide (300 mg, 1.04 mmol, 1.00 equiv., can be synthesized according to the synthesis described in Part II of Example 1), 3-(7-chloro-277-pyrazolo[4,3- / >]pyridin-2-yl)-l-methylpyrrolidin-2-one (289 mg,OTQ-00925- 173 -1.15 mmol, 1.10 equiv.), (SP-4-l)-[l,3-bis[2,6-bis(l-ethylpropyl)phenyl]-4,5-dichloro-l,3- dihydro-277-imidazol-2-ylidene]dichloro(2-methylpyridine)palladium (176 mg, 210 pmol, 0.20 equiv.), and CS2CO3 (1.36 g, 4.16 mmol, 4.00 equiv.) in 1,4-dioxane (6 mb) was heated to 100 °C for 2 h under an inert atmosphere of nitrogen. Subsequently, water (20 mb) was added, and the product was extracted with EtOAc (3 x 20 mL). The combined organic phases were washed with brine (10 mL), dried over Na2SC>4, and the solvent was removed under reduced pressure. The crude product was purified by reversed-phase flash chromatography (column: Cl 8 silica gel; mobile phase A: water (0.1% formic acid), mobile phase B: ACN, gradient: 5-25% B in 60 min; wavelength: 220 nm). The racemic title compound was obtained as a white solid (141 mg, 27%). The two enantiomers were separated by chiral chromatography (column: CHIRALPAK IH, 30 x 250 mm, 5 pm; mobile phase A: MTBE (0.5% 10 mM ammonia solution in MeOH), mobile phase B: MeOH, isocratic separation with 25% B). The title compounds (compound 40 (enantiomer 1): 58.0 mg, 11%; compound 41 (enantiomer 2): 59.0 mg, 11%) were obtained as white solids (retention time (enantiomer 1): 1.04 min, retention time (enantiomer 2): 1.40 min, column: CHIRALPAK IH-3, 4.6 x 50 mm, 3 pm; mobile phase A: MTBE (0.1% DEA), mobile phase B: MeOH, isocratic separation with 30% B, flow rate: 1.0 mL / min, wavelength: 254 nm). LCMS (ESI) calculated for C27H33N8O2 (M+H)+: 501.3, found: 501.3. 'H NMR (400 MHz, DMSO-d6) 8 10.24 (s, IH), 8.64 (s, IH), 8.56 (s, IH), 8.07 (d, J= 5.1 Hz, IH), 7.99 (d, J= 0.7 Hz, IH), 7.50 (d, J= 0.6 Hz, IH), 7.31 (d, J= 1.9 Hz, IH), 7.29 -7.21 (m, 2H), 5.91 (d, J= 5.1 Hz, IH), 5.54 (t, J= 9.2 Hz, IH), 3.64 - 3.51 (m, 4H), 2.90 (s, 3H), 2.84 - 2.69 (m, 2H), 2.24 (s, 3H), 1.54 (s, 9H).Example 12- Synthesis of A-(l-(tert-butyl)-177-pyrazol-4-yl)-2-(4-((2-(3-methoxy-l-methyl- 177-pyrazol-4-yl)furo[3,2- / >]pyridin-7-yl)amino)-3-methylphenyl)acetamide (Compound 42); Prepared according to General Scheme 7OTQ-00925- 174 -Part I - Synthesis of 3-methoxy-l-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l / / -pyr azoleA solution of 77-butyllithium (2.5 M in 77-hexane, 3.14 mL, 7.85 mmol, 1.50 equiv.) was added dropwise to a solution of 4-bromo-3-methoxy-l-methyl-lH-pyrazole (1.00 g, 5.24 mmol, 1.00 equiv.) in THF (20 mL) at -78 °C under an inert atmosphere of nitrogen. Subsequently, 2-isopropoxy-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (1.36 g, 7.33 mmol, 1.40 equiv.) was added dropwise over the course of 3 min at this temperature. The mixture was allowed to warm to room temperature and stirred for 1 h. The reaction was quenched through the addition of a saturated aqueous solution of NH4CI at 0 °C and the product was extracted with EtOAc (3 x 80 mL). The combined organic phases were washed with brine (50 mL), dried over Na2SC>4, and the solvent was removed under reduced pressure. The crude product was purified by reversed-phase flash chromatography (column: C18 silica gel; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN, gradient: 10-100% B in 20 min; wavelength: 210 nm). The title compound was obtained as a white solid (230 mg, 19%).Part II- Synthesis of 7-chloro-2-(3-methoxy-l-methyl-LH-pyrazol-4-yl)furo[3,2-6]pyridineA solution of 3-methoxy-l-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-177-pyrazole (230 mg, 966 pmol, 1.00 equiv.), 7-chloro-2-iodofuro[3,2- / >]pyridine (324 mg, 1.16 mmol, 1.20 equiv.), Pd(dppf)C12 (70.7 mg, 97 pmol, 0.10 equiv.), andK^CCh (267 mg, 1.93 mmol, 2.00 equiv.) in 1,4-dioxane (1.84 mL) and water (460 pL) was heated to 80 °C for 1 h under an inert atmosphere of nitrogen. Subsequently, EtOAc (50 mL) was added, and the organic phase was washed with brine (30 mL) and dried over Na2SO4. The solvent was removed under reducedOTQ-00925- 175 -pressure and the crude product was purified by column chromatography (40% EtOAc in petroleum ether). The title compound was obtained as a yellow solid (150 mg, 59%).Part III - Synthesis of 7V-(l-(ter / -butyl)-lH-pyrazol-4-yl)-2-(4-((2-(3-methoxy-l-methyl- l / / -pyrazol-4-yl)furo [3,2-6] pyridin-7-yl)amino)-3-methylphenyl)acetamide (Compound 42)A solution of 7-chloro-2-(3-methoxy-l-methyl-177-pyrazol-4-yl)furo[3,2-6]pyridine (150 mg, 569 pmol, 1.00 equiv.), 2-(4-amino-3-methylphenyl)-A-(l -(tert- butyl)- 1H- pyrazol-4-yl)acetamide (163 mg, 569 pmol, 1.00 equiv., can be synthesized according to the synthesis described in Part II of Example 1), (SP-4-l)-[l,3-bis[2,6-bis(l-ethylpropyl)phenyl]-4,5- dichloro-l,3-dihydro-277-imidazol-2-ylidene]dichloro(2-methylpyridine)palladium (47.8 mg, 57 pmol, 0.10 equiv.), and CS2CO3 (556 mg, 1.71 mmol, 3.00 equiv.) in 1,4-dioxane (3 mb) was heated to 100 °C for 1 h under an inert atmosphere of nitrogen. Subsequently, the solvent was removed under reduced pressure and the crude product was purified by preparative HPLC (column: Xselect CSH Cl 8 OBD, 30 * 150 mm, 5 pm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: MeOH; flow rate: 60 mL / min; gradient: 50-80% B in 36 min; wavelength: 220 nm). The title compound was obtained as an off-white solid (104 mg, 36%). LCMS (ESI) calculated for C28H32N7O3 (M+H)+: 514.3, found: 514.4. 'H NMR (300 MHz, DMSO-d6) < 10.17 (s, 1H), 8.34 (s, 1H), 7.97 (d, J= 5.5 Hz, 1H), 7.92 (s, 1H), 7.69 (s, 1H), 7.45 (s, 1H), 7.23 (s, 1H), 7.17- 7.13 (m, 2H), 6.66 (s, 1H), 6.31 (d, J= 5.5 Hz, 1H), 3.94 (s, 3H), 3.77 (s, 3H), 3.57 (s, 2H), 2.19 (s, 3H), 1.48 (s, 9H).Example 13- Synthesis of A-(l-( / / 7-butyl)-l / 7-pyrazol-4-yl)-2-(3-methyl-4-((2-(3-methyl-2- oxoimidazolidin-1 -yl)furo[3,2- / ?]pyridin-7-yl)amino)phenyl)acetamide (Compound 43);Prepared according to General Scheme 8OTQ-00925- 176 -1Part I - Synthesis of l-(7-chlorofuro[3,2-Z>]pyridin-2-yl)-3-methylimidazolidin-2-oneA solution of 7-chloro-2-iodofuro[3,2- / >]pyridine (500 mg, 1.79 mmol, 1.00 equiv.), 1- methylimidazolidin-2-one (358 mg, 3.58 mmol, 2.00 equiv.), copper(I) iodide (34.1 mg, 179 pmol, 0.10 equiv.), (,5)-A, A^ -dimethyl- 1,2-diaminocyclohexane (50.8 mg, 358 pmol, 0.20 equiv.), and K2CO3 (371 mg, 2.68 mmol, 1.50 equiv.) in 1,4-dioxane (5 mL) was heated to 100 °C for 3 h under an inert atmosphere of nitrogen. Subsequently, water (20 mL) was added, and the product was extracted with EtOAc (3 x 20 mL). The combined organic phases were washed with brine (2 x 20 mL), dried over Na2SO4, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography (50% EtOAc in petroleum ether). The title compound was obtained as a yellow solid (50 mg, 11%).Part II- Synthesis of V-(l-(tert-butyl)-LH-pyrazol-4-yl)-2-(3-methyl-4-((2-(3-methyl-2- oxoimidazolidin-l-yl)furo[3,2-Z>]pyridin-7-yl)amino)phenyl)acetamide (Compound 43)1A solution of l-(7-chlorofuro[3,2- / >]pyridin-2-yl)-3-methylimidazolidin-2-one (40.0 mg, 159 pmol, 1.00 equiv.), 2-(4-amino-3-methylphenyl)-A-(l-(terLbutyl)-177-pyrazol-4-yl)acetamideOTQ-00925- 177 -(45.5 mg, 159 pmol, 1.00 equiv., can be synthesized according to the synthesis described in Part II of Example 1), (SP-4-l)-[l,3-bis[2,6-bis(l-ethylpropyl)phenyl]-4,5-dichloro-l,3-dihydro-277-imidazol-2-ylidene]dichloro(2-methylpyridine)palladium (26.7 mg, 31.8 pmol, 0.20 equiv.), and CS2CO3 (104 mg, 318 pmol, 2.00 equiv.) in 1,4-dioxane (800 pL) was heated to 100 °C for 2 h under an inert atmosphere of nitrogen. Subsequently, the crude product was purified by revers ed-phase flash chromatography (column: Cl 8 silica gel; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN, gradient: 10-50% B in 10 min; wavelength: 254 nm). The title compound was obtained as a white solid (11.2 mg, 14%). LCMS (ESI) calculated for C27H32N7O3 (M+H)+: 502.3, found: 502.3. 'H NMR (300 MHz, DMSO-c / ) 810.14 (s, 1H), 8.27 (s, 1H), 7.96 - 7.87 (m, 2H), 7.44 (s, 1H), 7.21 (d, J= 1.9 Hz, 1H), 7.19 - 7.06 (m, 2H), 6.36 - 6.26 (m, 2H), 3.68 (dd, J= 9.2, 6.6 Hz, 2H), 3.53 (s, 2H), 3.39 (dd, J= 9.4, 6.7 Hz, 2H), 2.76 (s, 3H), 2.18 (s, 3H), 1.48 (s, 9H).Example 14- Synthesis of A-(l-(tert-butyl)-177-pyrazol-4-yl)-2-(3-methyl-4-((2-(3-methyl-2-oxoimidazolidin-1 -yl)pyrazolo[l,5-a]pyrimidin-7-yl)oxy)phenyl)acetamide (Compound 44); Prepared according to General Scheme 9r ^iAOPart I - Synthesis of 2-(4-((2-bromopyrazolo[l,5-a]pyrimidin-7-yl)oxy)-3-methylphenyl)- V-( l-( / c / 7-butyl(- l / / -pyrazol-4-yl (acetamideri=NA solution of A-( l-( / / 7-butyl)- l / 7-pyrazol-4-yl)-2-(4-hydroxy-3-methylphenyl)acetamide (2.00 g, 6.96 mmol, 1.00 equiv.), 2-bromo-7-chloropyrazolo[l,5-a]pyrimidine (1.62 g, 6.96 mmol,OTQ-00925- 178 -1.00 equiv.), 4-(dimethylamino)pyridine (90.0 mg, 696 pmol, 0.10 equiv.), and K2CO3 (1.92 g, 13.9 mmol, 2.00 equiv.) in DMF (40 mL) was heated to 120 °C for 1 h. Subsequently, water (150 mL) was added, and the product was extracted with EtOAc (3 x 100 mL). The combined organic phases were washed with brine (70 mL), dried over Na2SC>4, and the solvent was removed under reduced pressure. The crude product was purified by reversed-phase flash chromatography (column: Cl 8 silica gel; mobile phase A: water (0.1% formic acid), mobile phase B: ACN, gradient: 10-55% B in 20 min; wavelength: 254 nm). The title compound was obtained as a yellow solid (2.8 g, 83%)Part II- Synthesis of 7V-(l-(tert-butyl)-LH-pyrazol-4-yl)-2-(3-methyl-4-((2-(3-methyl-2-oxoimidazolidin-l-yl)pyrazolo[l,5-a]pyrimidin-7-yl)oxy)phenyl)acetamide (Compound 44)ri^N' L)A solution of 2-(4-((2-bromopyrazolo[l,5-a]pyrimidin-7-yl)oxy)-3-methylphenyl)-V-(l-(terZ-butyl)-177-pyrazol-4-yl)acetamide (250 mg, 517 pmol, 1.00 equiv.), 1 -methylimidazolidin-2-one (155 mg, 1.55 mmol, 3.00 equiv.), tris(dibenzylideneacetone)dipalladium(0) (47.4 mg, 52 pmol, 0.10 equiv.), / BuXPhos (43.9 mg, 103 pmol, 0.20 equiv.), and CS2CO3 (506 mg, 1.55 mmol, 3.00 equiv.) in 1,4-di oxane (5 mL) was heated to 100 °C for 2 h under an inert atmosphere of nitrogen. Subsequently, the crude product was purified by preparative HPLC (column: Xselect CSH Cl 8 OBD, 30 * 150 mm, 5 pm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 20-40% B in 20 min; wavelength: 220 nm). The title compound was obtained as a white solid (53.3 mg, 21%). LCMS (ESI) calculated for C26H31N8O3 (M+H)+: 503.3, found: 503.3. 'H NMR (400 MHz, DMSO-d6) 8 10.22 (s, 1H), 8.23 (d, J= 5.0 Hz, 1H), 7.94 (d, J= 0.8 Hz, 1H), 7.45 (d, J= 0.8 Hz, 1H), 7.38 (d, J= 1.7 Hz, 1H), 7.33 - 7.28 (m, 2H), 6.88 (s, 1H), 5.78 (d, J= 5.0 Hz, 1H), 3.96 (dd, J=OTQ-00925- 179 -9.3, 6.8 Hz, 2H), 3.61 (s, 2H), 3.53 (dd, J= 9.3, 6.7 Hz, 2H), 2.82 (s, 3H), 2.15 (s, 3H), 1.48 (s, 9H).Example 15 - Preparation of Additional Heteroarene CompoundsCompounds in the table below were prepared based on experimental procedures described in Examples 7-14 and the detailed description.No. Structure Name ’HNMR Observe d m / z 45 A-(l-( / c / 7-butyl)- (400 MHz, DMSO-<7,) 497.2177-pyrazol-4-yl)-2- <510.18 (d, J= 2.5 Hz, (M+H)+N-N / X(3-methyl-4-((2- 1H), 8.63 - 8.53 (m, 2H), / s'°((methylsulfonyl)me 7.95 (d, J= 1.8 Hz, 1H),thyl)-2H- 7.51 - 7.42 (m, 1H), 7.41 pyrazolo[4,3- - 7.34 (m, 1H), 7.29 (dd, J / >]pyridin-7- = 8.3, 2.2 Hz, 1H), 7.16 yl)oxy)phenyl)aceta (d, J = 8.2 Hz, 1H), 6.45mide (bs, 1H), 6.12 (s, 2H),3.60 (s, 2H), 3.09 (s, 3H),2.19 (s, 3H), 1.48 (s, 9H)46 H A-(l-( / c / 7-butyl)- (400 MHz, DMSO-<7,) 476.21 1 XT I XN177-pyrazol-4-yl)-2- <510.19 (s, 1H), 8.64 (s, (M+H)+N-N / \(3 -methyl-4-((2-(2- 1H), 8.28 - 8.21 (m, 2H), JAH(methylamino)-2- 7.94 (s, 1H), 7.45 (s, 1H),oxoethyl)-2 / 7- 7.34 (d, J =2.2 Hz, 1H), pyrazolo[4,3- 7.26 (dd, J = 8.3, 2.2 Hz, / >]pyridin-7- 1H), 7.13 (d, J = 8.2 Hz, yl)oxy)phenyl)aceta 1H), 6.12 (d, J= 4.9 Hz,mide 1H), 5.17 (s, 2H), 3.59 (s,2H), 2.66 (d, J=4.6Hz,OTQ-00925- 180 -3H), 2.13 (s, 3H), 1.48 (s,9H)47 H 2-(4-((2-(2-amino-2- (400 MHz, DMSO-d6) 462.2 i 1 LT 2 V-Noxoethyl)-2 / 7- <510.22 (s, 1H), 8.62 (s, (M+H)+N-N / \pyrazolo[4,3- 1H), 8.26 (d, J=4.9Hz, ^NH20 / >]pyridin-7-yl)oxy)- 1H), 7.94 (s, 1H), 7.75 (s,3 -methy 1 phenyl )-N- 1H), 7.46- 7.40 (m, 2H),( 1 -(tert-butyl)- 1H- 7.34 (d, J =2.2 Hz, 1H), pyrazol-4- 7.26 (dd, J = 8.3, 2.2 Hz, yl)acetamide 1H), 7.13 (d, J = 8.2 Hz,1H), 6.11 (d, J=4.9Hz,1H), 5.17 (s, 2H), 3.59 (s, 2H), 2.13 (s, 3H), 1.48 (s,9H)48 7V-(l-(terZ-butyl)- (400 MHz, DMSO-d6) 444.2177-pyrazol-4-yl)-2- <510.19 (s, 1H), 8.80 (s, (M+H)+N-N / X( (4-((2- 1H), 8.32 (d, J= 4.9 Hz,CN(cyanomethyl)-2 / 7- 1H), 7.94 (s, 1H), 7.45 (d, pyrazolo[4,3- J= 0.7Hz, 1H), 7.35 (d, J / >]pyridin-7-yl)oxy)- = 2.1 Hz, 1H), 7.27 (dd, J3- = 8.2, 2.2 Hz, 1H), 7.17 methylphenyl)aceta (d, J = 8.2 Hz, 1H), 6.17mide (d, J = 4.9 Hz, 1H), 5.92(s, 2H), 3.59 (s, 2H), 2.13(s, 3H), 1.48 (s, 9H)49 7V-(l-(terZ-butyl)- (400 MHz, DMSO-d6) 470.6 riXTTr> 177-pyrazol-4-yl)-2- <510.15 (s, 1H), 8.14 (d, J (M+H)+N'N / \(4-((2-(l- CN = 5.5 Hz, 1H), 7.93 (s, cyanocyclopropyl)- 1H), 7.44 (d, J = 8.2 Hz,OTQ-00925- 181 -277-pyrazolo[4,3- 2H), 7.19 (dd, J = 8.5, 2.2 / >]pyridin-7-yl)oxy)- Hz, 1H), 7.09-7.03 (m,3- 2H), 3.50 (s, 2H), 1.89 (s, methylphenyl)aceta 3H), 1.65 - 1.48 (m, 4H), mide 1.48 (s, 9H)50 H 7V-(1 -( / cj / V-butyl)- (400 MHz, DMSO-d6) 516.3 i i TT 1 177-pyrazol-4-yl)-2- (M+H)V <510.22 (s, 1H), 8.30 -+N N / \(3 -methyl-4-((2-(2- 8.24 (m, 2H), 7.93 (s, 1H),0 ' —1oxo-2-(pyrrolidin- 1 - 7.45 (s, 1H), 7.33 (d, J=yl)ethyl)-2 / 7- 2.1 Hz, 1H), 7.25 (dd, J= pyrazolo[4,3- 8.2, 2.2 Hz, 1H), 7.09 (d, / >]pyridin-7- J= 8.2Hz, 1H), 6.30 (d, J yl)oxy)phenyl)aceta = 5.1 Hz, 1H), 5.47 (s,mide 2H), 3.58 (s, 2H), 3.50 (t,J= 6.8 Hz, 2H), 3.26 (t, J= 6.9 Hz, 2H), 2.10 (s,3H), 1.85 (pent, J = 6.8Hz, 2H), 1.71 (q, 7 = 6.8Hz, 2H), 1.48 (s, 9H)51 2-(4-((2-((177- (400 MHz, DMSO-<7e) 485.2 imidazol-4- <510.23 (s, 1H), 9.07 (s, (M+H)+yl)methyl)-2 / 7- 1H), 8.86 (bs, 1H), 8.39N^? NH pyrazolo[4,3- (bs, 1H), 7.94 (s, 1H), / >]pyridin-7-yl)oxy)- 7.85 (s, 1H), 7.46 (s, 1H),3 -methylphenyl)-? / - 7.36 (s, 1H), 7.28 (d, J=(1 -(tert-butyl)- 177- 8.3 Hz, 1H), 7.15 (d, J = pyrazol-4- 7.2 Hz, 1H), 6.23 (s, 1H), yl)acetamide 5.90 (s, 2H), 3.60 (s, 2H),2.11 (s, 3H), 1.49 (s, 9H)OTQ-00925- 182 -52 H 2-(7-(4-(2-((l-(tert- (400 MHz, DMSO-1) 490.2 i i TT I T-Nbutyl)- l / f-pyrazol-4- 810.21 (s, 1H), 8.56 (s, (M+H)+N-N / \yl)amino)-2- 1H), 8.26 (d, J=4.9Hz,Vi0 \ oxoethyl)-2- 1H), 7.94 (s, 1H), 7.45 (s,methylphenoxy)-2 / 7- 1H), 7.34 (d, J =2.2 Hz, pyrazolo[4,3- 1H), 7.26 (dd, J = 8.2, 2.1 / >]pyridin-2-yl)-7V,7V- Hz, 1H), 7.13 (d, J = 8.2 dimethylacetamide Hz, 1H), 6.13 (d, J = 4.9Hz, 1H), 5.54 (s, 2H),3.59 (s, 2H), 3.11 (s, 3H),2.89 (s, 3H), 2.13 (s, 3H),1.48 (s, 9H)53 H.7 Z 1 / A-(l-( / <? / 7-butyl)- (400 MHz, DMSO-1) 532.2 A i xy i x / Y '0^N, 177-pyrazol-4-yl)-2- <510.19 (s, 1H), 8.58 (s, (M+H)+N N / \(3 -methyl-4-((2-(2- 1H), 8.27 (d, J=4.9Hz,0^0 morpholino-2- 1H), 7.94 (s, 1H), 7.45 (s,oxoethyl)-2 / 7- 1H), 7.34 (s, 1H), 7.26 (d, pyrazolo[4,3- J= 8.2Hz, 1H), 7.13 (d, J / >]pyridin-7- = 8.1 Hz, 1H), 6.14 (d, J = yl)oxy)phenyl)aceta 5.0 Hz, 1H), 5.59 (s, 2H), mide 3.70- 3.48 (m, 10H), 2.13(s, 3H), 1.49 (s, 9H)54 A-( / <? / 7-butyl)-2-(7- (400 MHz, DMSO-d6) 518.3 i i XT I XN(4-(2-((l-(7erZ- <510.25 (s, 1H), 8.69 (s, (M+H)+N N / \butyl)- 177-pyrazol-4- 1H), 8.37 (d, J = 5.2 Hz, l^NHyl)amino)-2- ° 1H), 8.11 (s, 1H), 7.94 (s,oxoethyl)-2- 1H), 7.46 (s, 1H), 7.37 (d, methylphenoxy)-2 / 7- J =2.1 Hz, 1H), 7.28 (dd, pyrazolo[4,3- J= 8.3, 2.1 Hz, 1H), 7.18OTQ-00925- 183 - / >]pyridin-2- (d, J = 8.2 Hz, 1H), 6.23 yl)acetamide (d, J = 5.2 Hz, 1H), 5.18(s, 2H), 3.6 (s, 2H), 2.14(s, 3H), 1.48 (s, 9H), 1.30(s, 9H)55 H 7V-(l-(terZ-butyl)- (400 MHz, DMSO-d6) 488.3 i l LT I 1CN177-pyrazol-4-yl)-2- 810.36 (d, J = 3.9 Hz, (M+H)+N'N / \(3 -methyl-4-((2-(2- 1H), 9.16 (t, J = 2.1 Hz,H oxopyrrolidin-3 -yl)- 1H), 8.75 (dd, J = 6.3, 1.7277-pyrazolo[4,3- Hz, 1H), 8.45 (s, 1H), / >]pyridin-7- 7.94 (s, 1H), 7.49 -7.41 yl)oxy)phenyl)aceta (m, 2H), 7.39- 7.28 (m, mide 2H), 6.58 (dd, J = 6.4, 1.2Hz, 1H), 5.71 (t, J = 9.1Hz, 1H), 3.64 (s, 2H),3.52- 3.40 (m, 2H) 2.88 - 2.73 (m, 2H), 2.15 (s, 3H), 1.48 (s, 9H)56 H 7V-(l-(terZ-butyl)- (400 MHz, DMSO-d6) 520.31 1 11 1 1CNf^o>T V 177-pyrazol-4-yl)-2- 810.21 (s, 1H), 8.80 (s, (M+H) N-N F / X+(3-fluoro-5-methyl- 1H), 8.29 (d, J= 5.0Hz,1 4-((2-(l-methyl-2- 1H), 7.95 (s, 1H), 7.45 (s, Enantiomer 1 oxopyrrolidin-3 -yl)- 1H), 7.24 (d, J= 11.1 Hz, (retention time: 1.14 min, 277-pyrazolo[4,3- 1H), 7.18 (d, J= 2.0 Hz, column: CHIRALPAK / >]pyridin-7- 1H), 6.20 (d, J=4.9Hz,IK-3, 4.6 x 50 mm, 3 pm; yl)oxy)phenyl)aceta 1H), 5.54 (t, J= 9.0 Hz, mobile phase A: MTBE mide 1H), 3.62 (s, 2H), 3.62- (0.1% DEA), mobile3.50 (m, 1H), 3.53 -3.44 phase B: MeOH, isocratic(m, 1H), 2.85 (s, 3H), 2.74 separation with 30% B,OTQ-00925- 184 -flow rate: 1.67 mL / min, -2.64 (m, 2H), 2.17 (s, wavelength: 254 nm) 3H), 1.49 (s, 9H)57 H 7V-(l-(terZ-butyl)- (400 MHz, DMSO-L) 520.3 i 1 lY l 13Nf^o>T V 177-pyrazol-4-yl)-2- 810.21 (s, 1H), 8.80 (s, (M+H)+N-N F / X(3-fluoro-5-methyl- 1H), 8.29 (d, J= 5.0Hz,1 4-((2-(l-methyl-2- 1H), 7.95 (s, 1H), 7.45 (s, Enantiomer 2 oxopyrrolidin-3 -yl)- 1H), 7.24 (d, J= 11.1 Hz, (retention time: 1.46 min, 277-pyrazolo[4,3- 1H), 7.18 (d, J= 2.0 Hz, column: CHIRALPAK / >]pyridin-7- 1H), 6.20 (d, J=4.9Hz,IK-3, 4.6 x 50 mm, 3 gm; yl)oxy)phenyl)aceta 1H), 5.54 (t, J= 9.0 Hz, mobile phase A: MTBE mide 1H), 3.62 (s, 2H), 3.62- (0.1% DEA), mobile3.50 (m, 1H), 3.53 -3.44 phase B: MeOH, isocratic(m, 1H), 2.85 (s, 3H), 2.74 separation with 30% B,-2.64 (m, 2H), 2.17 (s,flow rate: 1.67 mL / min,3H), 1.49 (s, 9H)wavelength: 254 nm)58 H 7V-(l-(terZ-butyl)- (400 MHz, DMSO-L) 565.3177-pyrazol-4-yl)-2- 810.19 (s, 1H), 8.89 (s, (M+H)+N" N / V(3 -methyl-4-((2-(2- 1H), 8.50- 8.46 (m, 1H), oxo-l-(pyridin-2- 8.33 - 8.26 (m, 2H), 7.94 d yl)pyrrolidin-3-yl)- (s, 1H), 7.92 -7.84 (m, Enantiomer 1 277-pyrazolo[4,3- 1H), 7.44 (s, 1H), 7.33 (d, (retention time: 0.86 min, / >]pyridin-7- J=2.3 Hz, 1H), 7.29- column: CHIRALyl)oxy)phenyl)aceta 7.20 (m, 2H), 7.15 (d, J = Cellulose-SZ, 4.6 x 50 mide 8.2 Hz, 1H), 6.12 (d, J=mm, 3 pm; mobile phase4.9 Hz, 1H), 5.94 (t, J =A: MTBE (0.1% DEA),9.5 Hz, 1H), 4.40 -4.31 mobile phase B: MeOH,(m, 1H), 4.10-4.00 (m, isocratic separation with1H), 3.58 (s, 2H), 2.91 - 30% B, flow rate: 1.67OTQ-00925- 185 -mL / min, wavelength: 254 2.80 (m, 2H), 2.12 (s, 3H), nm) 1.48 (s, 9H)59 H 7V-(l-(terZ-butyl)- (400 MHz, DMSO-L) 565.3 fi imr i> 177-pyrazol-4-yl)-2- 810.19 (s, 1H), 8.89 (s, (M+H)+N-N / \(3 -methyl-4-((2-(2- 1H), 8.50- 8.46 (m, 1H), oxo-l-(pyridin-2- 8.33 - 8.26 (m, 2H), 7.946 yl)pyrrolidin-3-yl)- (s, 1H), 7.92 -7.84 (m, Enantiomer 2 277-pyrazolo[4,3- 1H), 7.44 (s, 1H), 7.33 (d, (retention time: 1.22 min, / >]pyridin-7- J=2.3 Hz, 1H), 7.29- column: CHIRAL yl)oxy)phenyl)aceta 7.20 (m, 2H), 7.15 (d, J = Cellulose-SZ, 4.6 x 50mide 8.2 Hz, 1H), 6.12 (d, J =mm, 3 gm; mobile phase4.9 Hz, 1H), 5.94 (t, J =A: MTBE (0.1% DEA),9.5 Hz, 1H), 4.40 -4.31 mobile phase B: MeOH,(m, 1H), 4.10-4.00 (m, isocratic separation with1H), 3.58 (s, 2H), 2.91 - 30% B, flow rate: 1.672.80 (m, 2H), 2.12 (s, 3H), mL / min, wavelength: 2541.48 (s, 9H)nm)60 7V-(l-(terZ-butyl)- (400 MHz, DMSO-L) 502.2°N177-pyrazol-4-yl)-2- <510.18 (s, 1H), 8.61 (s, (M+H)+N N / \(4-((2-(2- 1H), 8.48 (s, 1H), 8.26 (d,NHO1 (cyclopropylamino)- J=4.9Hz, 1H), 7.94 (s,2-oxoethyl)-2 / 7- 1H), 7.45 (s, 1H), 7.34 (d, pyrazolo[4,3- J=2.2Hz, 1H), 7.26 (dd, / >]pyridin-7-yl)oxy)- J= 8.3, 2.2 Hz, 1H), 7.133- (d, J = 8.2 Hz, 1H), 6.12 methylphenyl)aceta (d, J = 4.9 Hz, 1H), 5.13mide (s, 2H), 3.58 (s, 2H), 2.73-2.66 (m, 1H), 2.13 (s,3H), 1.48 (s, 9H), 0.69-OTQ-00925- 186 -0.61 (m, 2H), 0.53 -0.42(m, 2H)61 H 7V-(1 -( / cj / V-butyl)- (400 MHz, DMSO-d6) 518.21 1 XT I I> 177-pyrazol-4-yl)-2- <510.18 (s, 1H), 9.17 (d, J (M+H)+N-N / \(3 -methyl-4-((2-(2- = 6.7 Hz, 1H), 8.63 (s,^NH0b (oxetan-3-ylamino)- 1H), 8.26 (d, J = 5.0 Hz,02-oxoethyl)-2 / 7- 1H), 7.94 (s, 1H), 7.45 (s, pyrazolo[4,3- 1H), 7.34 (s, 1H), 7.29- / >]pyridin-7- 7.22 (m, 1H), 7.13 (d, J = yl)oxy)phenyl)aceta 8.2 Hz, 1H), 6.12 (d, J =mide 5.0 Hz, 1H), 5.23 (s, 2H),4.90-4.80 (m, 1H), 4.78 -4.70 (m, 2H), 4.48 (t, J= 6.3 Hz, 2H), 3.58 (s,2H), 2.12 (s, 3H), 1.48 (s,9H)62 M^\ Z> / „- HN / 7V-(l-(terZ-butyl)- (400 MHz, DMSO-d6) 504.3 X i V i X^T 1 T VN177-pyrazol-4-yl)-2- <510.23 (s, 1H), 8.61 (s, (M+H)+N-N / \(4-((2-(2- 1H), 8.35 - 8.22 (m, 2H), o ^NH(isopropylamino)-2- 7.94 (s, 1H), 7.46 (s, 1H), oxoethyl)-2 / 7- 7.34 (d, J =2.1 Hz, 1H), pyrazolo[4,3- 7.29- 7.23 (m, 1H), 7.13 / >]pyridin-7-yl)oxy)- (d, J = 8.2 Hz, 1H), 6.133- (d, J = 4.9 Hz, 1H), 5.15 methylphenyl)aceta (s, 2H), 3.92 - 3.80 (m,mide 1H), 3.59 (s, 2H), 2.13 (s,3H), 1.48 (s, 9H), 1.11 (d,7 = 6.6 Hz, 6H)OTQ-00925- 187 -63 H 7V-(l-(terZ-butyl)- (400 MHz, DMSO-d6) 516.3177-pyrazol-4-yl)-2- <510.20 (s, 1H), 8.67 (s, (M+H)+N'N / \Clo (3-methyl-4-((2-(l- 1H), 8.25 (d, 7= 4.9 Hz,\ methyl-2- 1H), 7.94 (s, 1H), 7.45 (s, Enantiomer 1oxopiperidin- 3 -y 1)- 1H), 7.34 (d, 7= 2.1 Hz, (retention time: 0.81 min,277-pyrazolo[4,3- 1H), 7.29- 7.24 (m, 1H), column: Enantiocel A4-3, / >]pyridin-7- 7.14 (d, 7= 8.2 Hz, 1H),4.6 x 50 mm, 3 pm;yl)oxy)phenyl)aceta 6.08 (d, 7= 4.9 Hz, 1H), mobile phase A: hexanemide 5.47- 5.35 (m, 1H), 3.64(0.1% DEA), mobile- 3.47 (m, 3H), 3.42- phase B: EtOH: ACN3.38 (m, 1H), 2.90 (s, 3H), (5:1), isocratic separation2.65 -2.54 (m, 1H), 2.39 with 50% B, flow rate:-2.28 (m, 1H), 2.13 (s,1.67 mL / min,3H), 2.10- 1.92 (m, 2H), wavelength: 254 nm)1.48 (s, 9H)64 7V-(l-(terZ-butyl)- (400 MHz, DMSO-76) 516.3 n inVN177-pyrazol-4-yl)-2- <510.20 (s, 1H), 8.67 (s, (M+H)+N-N / X(3-methyl-4-((2-(l- 1H), 8.25 (d, 7= 4.9 Hz,\ methyl-2- 1H), 7.94 (s, 1H), 7.45 (s, Enantiomer 2oxopiperidin- 3 -y 1)- 1H), 7.34 (d, 7= 2.1 Hz, (retention time: 1.07 min, 277-pyrazolo[4,3- 1H), 7.29- 7.24 (m, 1H), column: Enantiocel A4-3, / >]pyridin-7- 7.14 (d, 7= 8.2 Hz, 1H),4.6 x 50 mm, 3 pm;yl)oxy)phenyl)aceta 6.08 (d, 7= 4.9 Hz, 1H), mobile phase A: hexanemide 5.47- 5.35 (m, 1H), 3.64(0.1% DEA), mobile- 3.47 (m, 3H), 3.42- phase B: EtOH: ACN3.38 (m, 1H), 2.90 (s, 3H), (5:1), isocratic separation2.65 -2.54 (m, 1H), 2.39 with 50% B, flow rate:-2.28 (m, 1H), 2.13 (s,1.67 mL / min,wavelength: 254 nm)OTQ-00925- 188 -3H), 2.10- 1.92 (m, 2H),1.48 (s, 9H)65 7V-(l-(terZ-butyl)- (400 MHz, DMSO-d6) 491.3 fy\Y^ ° N 177-pyrazol-4-yl)-2- <510.19 (s, 1H), 8.71 (s, (M+H)+N'N / \(4-((2-(4- 0 / '"0H 1H), 8.26 (d, J=4.9Hz,hydroxytetrahydrofu 1H), 7.94 (s, 1H), 7.45 (s, Enantiomer 1 (relativeran-3-yl)-277- 1H), 7.34 (d, J =2.1 Hz, stereochemistry: trans)pyrazolo[4,3- 1H), 7.28 - 7.24 (m, 1H), (retention time: 4.06 min, / >]pyridin-7-yl)oxy)- 7.14 (d, J = 8.2 Hz, 1H), column: Cellulose-SJ, 4.63- 6.11 (d, J =4.9 Hz, 1H), x 100 mm, 3 pm; mobilemethylphenyl)aceta 5.79 (d, J=4.5 Hz, 1H), phase A: hexane (0.1%mide 5.13 - 5.08 (m, 1H), 4.69 DEA), mobile phase B:-4.64 (m, 1H), 4.34- EtOH / ACN (5:1),4.27 (m, 1H), 4.20 -4.14 isocratic separation with(m, 2H), 3.67 (dd, J = 9.4,20% B, flow rate: 1.03.5 Hz, 1H), 3.59 (s, 2H), mL / min, wavelength: 2542.12 (s, 3H), 1.48 (s, 9H) nm66 H 7V-(l-(terZ-butyl)- (400 MHz, DMSO-d6) 491.3 / / WN, 177-pyrazol-4-yl)-2- <510.19 (s, 1H), 8.71 (s, (M+H)+N N / \(4-((2-(4- O 4 / -"'OH 1H), 8.26 (d, J=4.9Hz,hydroxytetrahydrofu 1H), 7.94 (s, 1H), 7.45 (s, Enantiomer 2 (relativeran-3-yl)-277- 1H), 7.34 (d, J =2.1 Hz, stereochemistry: trans)pyrazolo[4,3- 1H), 7.28 - 7.24 (m, 1H), (retention time: 4.61 min, / >]pyridin-7-yl)oxy)- 7.14 (d, J = 8.2 Hz, 1H), column: Cellulose-SJ, 4.63- 6.11 (d, J =4.9 Hz, 1H), x 100 mm, 3 pm; mobilemethylphenyl)aceta 5.79 (d, J=4.5 Hz, 1H), phase A: hexane (0.1%mide 5.13 - 5.08 (m, 1H), 4.69 DEA), mobile phase B:-4.64 (m, 1H), 4.34- EtOH / ACN (5:1),4.27 (m, 1H), 4.20 -4.14 isocratic separation withOTQ-00925- 189 -20% B, flow rate: 1.0 (m, 2H), 3.67 (dd, J= 9.4, mL / min, wavelength: 254 3.5 Hz, 1H), 3.59 (s, 2H), nm 2.12 (s, 3H), 1.48 (s, 9H67 H 7V-(l-(terZ-butyl)- (400 MHz, DMSO-d6) 526.3 i i TT I T-N177-pyrazol-4-yl)-2- 810.30 (s, 1H), 8.88 - (M+H)+N-N A(4-((2-(2-((2,2- 8.81 (m, 1H), 8.72 (s, 1H), VNH F0 \ _ / difluoroethyl)amino) 8.35 (d, J= 5.2 Hz, 1H),F-2-oxoethyl)-277- 7.94 (s, 1H), 7.46 (s, 1H), pyrazolo[4,3- 7.36 (d, J= 2.1 Hz, 1H), / >]pyridin-7-yl)oxy)- 7.32- 7.24 (m, 1H), 7.163- (d, J = 8.2 Hz, 1H), 6.21 - methylphenyl)aceta 5.96 (m, 2H), 5.33 (s, 2H), mide 3.64- 3.54 (m, 4H), 2.13(s, 3H), 1.48 (s, 9H)68 7V-(l-(terZ-butyl)- (300 MHz, DMSO-d6) 8 570.3 fl uri iffy^cA^0N 177-pyrazol-4-yl)-2- 10.19 (s, 1H), 8.81 (s, (M+H)+N-N A(3 -methyl-4-((2-(2- 1H), 8.29 (d, J=4.9Hz, y^F oxo- 1 -(2,2,2- 1H), 7.95 (s, 1H), 7.45 (s, Ftrifluoroethyl)pyrroli 1H), 7.35 (s, 1H), 7.27 (d, Enantiomer 1din-3 -yl)-2H- J= 8.8 Hz, 1H), 7.16 (d, J (retention time: 1.72 min,pyrazolo[4,3- = 8.3 Hz, 1H), 6.13 (d, J= column: CHIRALPAK / >]pyridin-7- 5.0 Hz, 1H), 5.72 (t, J =IK-3, 4.6 x 50 mm, 3 gm;yl)oxy)phenyl)aceta 9.2 Hz, 1H), 4.35 -4.07 mobile phase A: hexanemide (m, 2H), 3.80- 3.60 (m,(0.1% DEA), mobile2H), 3.59 (s, 2H), 2.85 - phase B: EtOH, isocratic2.74 (m, 2H), 2.13 (s, 3H), separation with 30% B,1.49 (s, 9H)flow rate: 1.67 mL / min,wavelength: 254 nm)OTQ-00925- 190 -69 7V-(l-(terZ-butyl)- (300 MHz, DMSO-L) 8 570.3 bcoc T<N177-pyrazol-4-yl)-2- 10.19 (s, 1H), 8.81 (s, (M+H)+N'N / \(3 -methyl-4-((2-(2- 1H), 8.29 (d, J=4.9Hz, oxo- 1 -(2,2,2- 1H), 7.95 (s, 1H), 7.45 (s,I^FFtrifluoroethyl)pyrroli 1H), 7.35 (s, 1H), 7.27 (d, Enantiomer 2din-3 -yY)-2H- J= 8.8 Hz, 1H), 7.16 (d, J (retention time: 2.26 min,pyrazolo[4,3- = 8.3 Hz, 1H), 6.13 (d, J= column: CHIRALPAK / >]pyridin-7- 5.0 Hz, 1H), 5.72 (t, J =IK-3, 4.6 x 50 mm, 3 pm;yl)oxy)phenyl)aceta 9.2 Hz, 1H), 4.35 -4.07 mobile phase A: hexanemide (m, 2H), 3.80- 3.60 (m,(0.1% DEA), mobile2H), 3.59 (s, 2H), 2.85 - phase B: EtOH, isocratic2.74 (m, 2H), 2.13 (s, 3H), separation with 30% B,1.49 (s, 9H)flow rate: 1.67 mL / min,wavelength: 254 nm)70 7V-(l-(terZ-butyl)- (300 MHz, DMSO-L) 8 507.3 rv^o'T 177-pyrazol-4-yl)-2- 10.20 (s, 1H), 8.66 (s, (M+H)V+N-N F / X(3-fluoro-5-methyl- 1H), 8.28 (d, J= 5.3 Hz, b° 4-((2- 1H), 7.95 (s, 1H), 7.46 (s, Enantiomer 1 ((tetrahydrofuran-2- 1H), 7.24 (d, J= 11.3 Hz, (retention time: 1.46 min, yl)methyl)-2 / 7- 1H), 7.18 (s, 1H), 6.19 (d, column: CHIRALPAK pyrazolo[4,3- J= 5.1 Hz, 1H), 4.63 - IE-3, 4.6 x 50 mm, 3 pm; / >]pyridin-7- 4.44 (m, 2H), 4.42 -4.31 mobile phase A: MTBE yl)oxy)phenyl)aceta (m, 1H), 3.85 - 3.73 (m,(0.1% DEA), mobile mide 1H), 3.71 - 3.64 (m, 1H), phase B: MeOH, isocratic 3.62 (s, 2H), 2.17 (s, 3H), separation with 10% B, 2.08 - 1.94 (m, 1H), 1.84 flow rate: 1.67 mL / min, - 1.82 (m, 2H), 1.74- wavelength: 254 nm) 1.61 (m, 1H), 1.49 (s, 9H)OTQ-00925- 191 -71 H 7V-(l-(terZ-butyl)- (300 MHz, DMSO-d6) 5 507.3 A LJ I Tb 177-pyrazol-4-yl)-2- (M+H) fVk°' T V 10.20 (s, 1H), 8.66 (s,+N-N F / X(3-fluoro-5-methyl- 1H), 8.28 (d, J= 5.3 Hz, b 4-((2- 1H), 7.95 (s, 1H), 7.46 (s, Enantiomer 2 ((tetrahydrofuran-2- 1H), 7.24 (d, J= 11.3 Hz, (retention time: 1.93 min, yl)methyl)-2 / 7- 1H), 7.18 (s, 1H), 6.19 (d, column: CHIRALPAK pyrazolo[4,3- J= 5.1 Hz, 1H), 4.63 - IE-3, 4.6 x 50 mm, 3 pm; / >]pyridin-7- 4.44 (m, 2H), 4.42 -4.31 mobile phase A: MTBE yl)oxy)phenyl)aceta (m, 1H), 3.85 - 3.73 (m,(0.1% DEA), mobile mide 1H), 3.71 - 3.64 (m, 1H), phase B: MeOH, isocratic 3.62 (s, 2H), 2.17 (s, 3H), separation with 10% B, 2.08 - 1.94 (m, 1H), 1.84 flow rate: 1.67 mL / min, - 1.82 (m, 2H), 1.74- wavelength: 254 nm) 1.61 (m, 1H), 1.49 (s, 9H)72 H 2-(7-(4-(2-((l -(tert- (400 MHz, DMSO-d6) 522.3 bb bCTbf TNbutyl)- 177-pyrazol-4- <510.20 (s, 1H), 8.77 (s, (M+H)+* N~N F / \ / yl)amino)-2- AN 1H), 8.28 (d, J= 5.0Hz, 0xoxoethyl)-2-fluoro- 1H), 7.95 (s, 1H), 7.45 (s, Enantiomer 16-methylphenoxy)- 1H), 7.24 (dd, J= 1.7 Hz, (retention time: 1.34 min,277-pyrazolo[4,3- 11.0 Hz, 1H), 7.18 (s,column: Enantiocel A4-3, / >]pyridin-2-yl)-A, A- 1H), 6.19 (d, J = 5.2 Hz,4.6 x 50 mm, 3 pm;dimethylpropanamid 1H), 6.00 (q, J = 7.3 Hz, mobile phase A: hexanee 1H), 3.62 (s, 2H), 3.13 (s,(0.1% DEA), mobile3H), 2.88 (s, 3H), 2.16 (s, phase B: EtOH, isocratic3H), 1.76 (d, J = 7.3 Hz, separation with 40% B,3H), 1.49 (s, 9H)flow rate: 1.67 mL / min,wavelength: 254 nm)OTQ-00925- 192 -73 H 2-(7-(4-(2-((l -(tert- (400 MHz, DMSOY) 522.3 fl TT l T<NfY^o^T V butyl)- 177-pyrazol-4- <510.20 (s, 1H), 8.77 (s, (M+H)+JN-N F / \yl)amino)-2- AN / 1H), 8.28 (d, J= 5.0Hz, oz xoxoethyl)-2-fluoro- 1H), 7.95 (s, 1H), 7.45 (s, Enantiomer 26-methylphenoxy)- 1H), 7.24 (dd, J= 1.7 Hz, (retention time: 1.74 min,277-pyrazolo[4,3- 11.0 Hz, 1H), 7.18 (s,column: Enantiocel A4-3, / >]pyridin-2-yl)-A, A- 1H), 6.19 (d, J = 5.2 Hz,4.6 x 50 mm, 3 pm;dimethylpropanamid 1H), 6.00 (q, J = 7.3 Hz, mobile phase A: hexanee 1H), 3.62 (s, 2H), 3.13 (s,(0.1% DEA), mobile3H), 2.88 (s, 3H), 2.16 (s, phase B: EtOH, isocratic3H), 1.76 (d, J = 7.3 Hz, separation with 40% B,3H), 1.49 (s, 9H)flow rate: 1.67 mL / min,wavelength: 254 nm)74 H 2-(7-(4-(2-((l -(tert- (300 MHz, DMSOY) 508.3 i i TT lbutyl)- 177-pyrazol-4- <510.20 (s, 1H), 8.77 (s, (M+H)+JN-N F / \yl)amino)-2- YNH 1H), 8.28 - 8.25 (m, 2H), 0xoxoethyl)-2-fluoro- 7.95 (s, 1H), 7.45 (s, 1H), Enantiomer 16-methylphenoxy)- 7.26- 7.20 (m, 1H), 7.18 (retention time: 1.83 min,277-pyrazolo[4,3- (s, 1H), 6.16 (d, J= 5.11 column: CHIRALPAK / >]pyridin-2-yl)-A- Hz, 1H), 5.37 (q, J= 7.3ID-3, 4.6 x 50 mm, 3 pm;methylpropanamide Hz, 1H), 3.62 (s, 2H),mobile phase A: MTBE2.64 (d, J =4.85 Hz, 3H),(0.1% DEA), mobile2.17 (s, 3H), 1.80 - 1.77phase B: MeOH, isocratic(d, J = 7.3 Hz, 3H), 1.48 separation with 10% B,(s, 9H)flow rate: 1.67 mL / min,wavelength: 254 nm)OTQ-00925- 193 - Z^z ^75 ^ Y^SVz^ H°7\ 0 \^\ 2-(7-(4-(2-((l -(tert- (300 MHz, DMSOY) 508.3 fl TT l T'Nbutyl)- 177-pyrazol-4- <510.20 (s, 1H), 8.77 (s, (M+H)+J fN-YN ^o^T F V / \yl)amino)-2- YNH 1H), 8.28 - 8.25 (m, 2H), 0xZI oxoethyl)-2-fluoro- 7.95 (s, 1H), 7.45 (s, 1H), Enantiomer 26-methylphenoxy)- 7.26- 7.20 (m, 1H), 7.18 (retention time: 2.35 min,277-pyrazolo[4,3- (s, 1H), 6.16 (d, J= 5.11 column: CHIRALPAK / >]pyridin-2-yl)-A- Hz, 1H), 5.37 (q, J= 7.3ID-3, 4.6 x 50 mm, 3 pm;methylpropanamide Hz, 1H), 3.62 (s, 2H),mobile phase A: MTBE2.64 (d, J =4.85 Hz, 3H),(0.1% DEA), mobile2.17 (s, 3H), 1.80 - 1.77phase B: MeOH, isocratic(d, J = 7.3 Hz, 3H), 1.48 separation with 10% B,(s, 9H)flow rate: 1.67 mL / min,wavelength: 254 nm)76 A-(l-(tert-butyl)- (400 MHz, DMSOY) 514.4177-pyrazol-4-yl)-2- <510.17 (s, 1H), 8.39 (s, (M+H)+(4-((2-(5-methoxy- 1H), 8.01 (d, J = 5.5 Hz,1 -methyl- 1H- 1H), 7.95 (s, 1H), 7.69 (s, pyrazol-4- 1H), 7.45 (s, 1H), 7.25 (d, yl)furo[3,2- J= 1.9 Hz, 1H), 7.21 - / >]pyridin-7- 7.11 (m, 2H), 6.85 (s, 1H), yl)amino)-3- 6.31 (d, J= 5.5 Hz, 1H), methylphenyl)aceta 3.89 (s, 3H), 3.67 (s, 3H), mide 3.55 (s, 2H), 2.21 (s, 3H),1.48 (s, 9H)77 2-(4-((2- (400 MHz, DMSOY) 462.2XITTTT" acetamidopyrazolo[l <511.15 (s, 1H), 10.21 (s, (M+H)+)=N / \HN,5-a]pyrimidin-7- 1H), 8.28 (d, J = 5.1 Hz,^0yl)oxy)-3- 1H), 7.93 (s, 1H), 7.44 (s, methylphenyl)-A-(l - 1H), 7.41 - 7.36 (m, 1H),OTQ-00925- 194 -(tert-butyl)- 1H- 7.35 - 7.27 (m, 2H), 6.90 pyrazol-4- (s, 1H), 5.92 (d, J = 5.1 yl)acetamide Hz, 1H), 3.60 (s, 2H),2.15 (s, 3H), 2.10 (s, 3H),1.48 (s, 9H)78 A-(7-(4-(2-((l -(tert(400 MHz, DMSO-1) 488.20N butyl)- 177-pyrazol-4- 811.45 (s, 1H), 10.21 (s, (M+H)+ / xHN yl)amino)-2- 1H), 8.27 (d, J = 5.1 Hz,oxoethyl)-2- 1H), 7.93 (s, 1H), 7.45 (s, methylphenoxy)pyra 1H), 7.38 (s, 1H), 7.36- zolo[l,5- 7.27 (m, 2H), 6.89 (s, 1H), a]pyrimidin-2- 5.92 (d, J = 5.0 Hz, 1H), yl)cyclopropanecarb 3.60 (s, 2H), 2.16 (s, 3H), oxamide 1.94- 1.85 (m, 1H), 1.48(s, 9H), 0.91 -0.77 (m,4H)Example 16 - Preparation of compounds 79-202.Compounds 79-202 can be prepared according to the synthetic protocols in Examples 7-14 and General Schemes 22-31Example 17 - RIPK2 Inhibition

[0244] RIPK2 inhibition was measured as follows:

[0245] Materials: RIPK2 enzyme was purchased from Carna (catalogue number 09-128). The V9102 ADP-Glo Kinase Assay (including ultrapure ATP, 10 mM) was purchased from Promega. Native swine MBP was used as the substrate for the reaction and was purchased from Signal Chem Biotech (catalogue number M42-51N). Assay buffer used for the assay consisted of the following components: MgCl2 (final concentration of 10 mM), Brij-35 (0.01%), DTTOTQ-00925- 195 -(final concentration of 2 mM), BSA (0.05%), EGTA (final concentration of 1 mM), and HEPES (pH 7.5 at final concentration of 50 mM).Method: In a 384-well plate, 10 nL of test compound was dispensed using Echo550 and mixed with RIPK2 enzyme (final concentration of 5 nM) in assay buffer for 30 minutes at room temperature. Subsequently, ATP (final concentration of 150 pM) and MBP (final concentration of 0.02 pg / pL) were dissolved in assay buffer, added, and the mixture was incubated for 180 min at room temperature. Then ADP-Glo reagent was added and incubated for 60 min at room temperature. Last, Kinase Detection Reagent was added to the mixture and incubated for 60 min. The resulting luminescent signal was measured with an Envision reader to determine the amount of ADP produced. All plates contained vehicle controls (10 nL DMSO only) as a reference for the high control (0% kinase inhibition), and wells with no RIPK2 enzyme as reference for low control (100% kinase inhibition). Data were analyzed to determine the percent inhibition of ADP production in the presence of test compound using both low and high controls. Percent inhibition of test compound = 100 - (test compound RLU (relative luminescence units) - low control RLU) / (high control RLU - low control RLU). 4-parametric curve fit was used to determine the test compound concentration that results in 50% of RIPK2 kinase inhibition. The results are shown in Table 6.Example 18 - Inhibition of human NOD2 signaling

[0246] Materials: Human NOD2-expressing HEK293 cells, HEK-Blue™-hNOD2 cells, were developed by Invivogen (catalogue number: hkb-hnod2) using co-transfection of the human NOD2 gene and an optimized secreted embryonic alkaline phosphatase (SEAP) reporter gene into HEK293 cells. The cell maintenance medium consisted of DMEM (Gibco, 21063-029), heat inactivated PBS, penicillin (100 U / mL), streptomycin (100 pg / mL), Normocin (100 pg / mL), Blasticidin (30 pg / mL), and Zeocin (100 pg / mL). HEK-Blue™-hNOD2 cells were transferred to assay medium consisting of DMEM (Gibco, 21063-029), heat inactivated FBS, penicillin (100 U / mL) and streptomycin (100 pg / mL) prior to stimulation. Stimulation with a NOD2 ligand, L18-MDP (Invivogen, catalogue number: tlrl-lmdp) activated NF-KB and AP-1 which induced the production of SEAP. Levels of SEAP were determined with HEK-Blue™ Detection (referred to as QUANTI-Blue solution), a cell culture medium that allows for real-OTQ-00925- 196 -time detection of SEAP. QUANTI-Blue solution was prepared by adding 1 mL of QB reagent and 1 mL of QB buffer to 98 mL of sterile H2O. Test compounds were prepared into a 10 mM DMSO solution and were serially diluted into 10 points using a 3-fold dilution in a 384-well plate using a TECAN EV0200.

[0247] Method: In a 384-well plate, 40 nL of test compound was dispensed using Echo550. HEK-Blue™-hNOD2 cells (Invivogen) were prepared into a cell suspension and 40 pL of the cell suspension (12500 cells per well) was dispensed into the 384-well plate. To activate NOD2 signaling, 40 nL of L18-MDP (final concentration of 0.5 ng / mL) was added and the plate was incubated at 37 °C in a CO2 incubator for 24 hours. After the 24-hour incubation, 5 pL of the induced HEK-Blue hNOD2 cell supernatant was transferred to a new 384-well plate, centrifuged, and 45 pL of QUANTI-Blue solution was added per well and incubated for 3 hours at 37 °C. SEAP levels were measured using an Ensight at 620 nm. Percent inhibition of NOD2 signaling was determined using the following equation: (high control - test compound signal) / (high control - low control) X 100. The reaction high control was determined using wells with DMSO, cells, L18-MDP, and QUANTI-Blue solution. The reaction low control was determined using wells with DMSO, cells, and QUANTI-Blue solution. 4-parametric curve fit was used to determine the test compound concentration that results in 50% reduction of L18-MDP-driven human NOD2 signaling. The results are shown in Table 6.Table 6RIPK2 hNOD2Compound #IC50 (nM) IC50 (nM)1 < 2.5 1.28 < 2.5 0.44 < 2.5 126 35 487 < 2.5 0.48 < 2.5 0.39 < 2.5 4.92 < 2.5 1.7OTQ-00925- 197 -RIPK2 hNOD2 Compound #IC50 (nM) IC50 (nM) 10 < 2.5 163 < 2.5 1.633 < 2.5 13.434 < 2.5 3.635 8.7 > 10045 > 100 > 10046 5.4 5147 4.0 > 10048 < 2.5 4.049 > 100 > 10050 > 100 > 10051 < 2.5 > 10052 4.0 2453 6.9 > 10054 3.9 1455 2.6 4756 < 2.5 2558 < 2.5 1.236 < 2.5 7.657 > 100 > 10059 4.8 4.337 53 8160 5.9 9161 4.9 > 10062 6.4 7838 2.9OTQ-00925- 198 -RIPK2 hNOD2Compound #IC50 (nM) IC50 (nM)39 1567 > 10040 7.9 > 10041 2.5 2544 1.977 6878 31

[0248] The teachings of all patents, published applications and references cited herein are incorporated by reference in their entirety.

[0249] While this invention has been particularly shown and described with references to example embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the scope of the invention encompassed by the appended claims.

Claims

OTQ-00925- 199 -What is claimed is:

1. A compound represented by structural formula (I*) or a pharmaceutically acceptable salt thereof:wherein:Q is selected from the following moieties:W is 5- to 12-membered heteroaryl;X is CH or N;each Y and Z is independently selected from O, NRa, and C1-3 alkylene; Rais selected from H and C1-6 alkyl;each Rlaand Rlbis independently selected from H, C1-6 alkyl, and halogen;R2is selected from C3-6 alkyl, C3-6 deuteroalkyl, C3-12 cycloalkyl;R3is selected from C1-6 alkyl, C3-12 cycloalkyl, 4- to 10-membered heterocyclyl, 5- to 12- membered heteroaryl, S(=O)R5, S(=O)2R5, NH(C=O)R5, NH(S(=O)2)R5, S(=O)(=NR6)(R7), P(=O)R6*R7*, BR8*R9* and C(=O)NR8R9;OTQ-00925- 200 -R3* is selected from H, halogen, Ci-6 alkyl, Ci-6 alkoxy;R4is selected from H and Ci-6 alkyl;R5is selected from Ci-6 alkyl, C3-12 cycloalkyl, C6-12aryl, 4- to 10-membered heterocyclyl, 5- to 12-membered heteroaryl, and NR10Rn;R6is selected from H and C1-6 alkyl;R7is selected from C1-6 alkyl, C3-12 cycloalkyl, 4- to 10-membered heterocyclyl, 5- to 12- membered heteroaryl, and NR10Rn, orR6and R7taken together with the nitrogen and sulfur atoms to which they are attached form 4- to 10-membered heterocyclyl;each R6* and R7* is independently selected from C1-6 alkyl, C3-12 cycloalkyl, 4- to 10-membered heterocyclyl, and 5- to 12-membered heteroaryl, orR6* and R7* taken together with the phosphorus atom to which they are attached form 4- to 10- membered heterocyclyl;each R8* and R9* is independently selected from OH, C1-6 alkyl, C3-12 cycloalkyl, 4- to 10- membered heterocyclyl, and 5- to 12-membered heteroaryl;each R8and R9is independently selected from H, C1-6 alkyl, C3-12 cycloalkyl, and 4- to 10- membered heterocyclyl, orR8and R9taken together with the nitrogen atom to which they are attached form 4- to 10- membered heterocyclyl; andeach R10and R11is independently selected from H, C1-6 alkyl, C3-12 cycloalkyl, and 4- to 10- membered heterocyclyl, orR10and R11taken together with the nitrogen atom to which they are attached form 4- to 10- membered heterocyclyl,wherein each C1-6 alkyl, C1-3 alkylene, C3-6 alkyl, C1-6 alkoxy, C3- 12 cycloalkyl, 5- to 12- membered heteroaryl, C6-12 aryl, and 4- to 10-membered heterocyclyl is optionally substituted with 1 to 5 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, OC(=O)OR20b, C(=O)NR21R22, OC(=O)NR21*R22*, NRnC(=O)N(R12)(R13), NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, P(=O)Rn*R12*, B(OR13*)2, Ci-6alkyl, C2-6OTQ-00925- 201 -alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl;whereineach R11, R12, R11*, R12*, R13, R13*, R14R14* R15R15*, R16, R17, R16*, R17*, R18R18a, R19, R20R20a, R20b,R2iR22R2PR22*R23R24R25R26,and R271S independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl, orone or more of the pairs of variables selected from R12and R13, R16and R17, R16* and R17*, R21and R22, R21* and R22*, and R25and R26, together with the nitrogen to which they are attached, form a 3- to 8-membered ring, andwhen one or more of the 1 to 5 substituents is selected from OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, OC(=O)OR20b, C(=O)NR21R22, OC(=O)NR21*R22*, NRnC(=O)N(R12)(R13), NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, P(=O)Rn*R12*, B(OR13’)2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl, each is further optionally substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14*, SR15*, NR16*R17*, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl.

2. The compound of claim 1, wherein X is CH.

3. The compound of claim 1, wherein X is N.

4. The compound of any one of claims 1-3, wherein Z is O.

5. The compound of any one of claims 1-3, wherein Z is NRa.

6. The compound of claim 5, wherein Rais H.

7. The compound of claim 5, wherein Rais C1-6 alkyl.OTQ-00925- 202 -8. The compound of claim 7, wherein Rais methyl.

9. The compound of any one of claims 1-3, wherein Z is C1-3 alkylene.

10. The compound of any one of claims 1-9, wherein Y is O.

11. The compound of any one of claims 1 -9, wherein Y is NRa.

12. The compound of claim 11, wherein Rais H.

13. The compound of claim 11, wherein Rais C 1-6 alkyl.

14. The compound of claim 13, wherein Rais methyl.

15. The compound of any one of claims 1-9, wherein Y is C1-3 alkylene.

16. The compound of claim 15, wherein Y is CH2.

17. The compound of any one of claims 1-16, wherein W is a 5- to 6-membered heteroaryl, wherein the 5- to 6-membered heteroaryl is optionally substituted with 1 to 5 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, OC(=O)OR20b, C(=O)NR21R22, OC(=O)NR21*R22*, NRnC(=O)N(R12)(R13), NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, P(=O)Rn*R12*, B(OR13*)2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl.OTQ-00925- 203 -18. The compound of claim 17, wherein W is selected from the following moieties:wherein each of the listed moieties is optionally substituted with 1 to 3 substituents, as valence permits, independently selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, OC(=O)OR20b, C(=O)NR21R22, OC(=O)NR21*R22*, NRUC(=O)N(R12)(R13), NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, P(=O)Rn*R12*, B(OR13*)2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl.

19. The compound of claim 18, wherein W is selected from the following moieties:

20. The compound of claim 18 or 19, wherein R2is t-Bu.

21. The compound of claim 1, wherein the compound is represented by structural formula (I) or a pharmaceutically acceptable salt thereof:wherein:Q is selected from the following moieties:OTQ-00925- 204 -Z is O or NH;each Rlaand Rlbis independently selected from H, Ci-6 alkyl, and halogen;R2is C3-6 alkyl;R3is selected from C1-6 alkyl, C3-12 cycloalkyl, 4- to 10-membered heterocyclyl, 5- to 12- membered heteroaryl, S(=O)2R5, NH(C=0)R5, S(=O)(=NR6)(R7), and C(=O)NR8R9; R4is selected from H and C1-6 alkyl;R5is selected from C1-6 alkyl, C3-12 cycloalkyl, 4- to 10-membered heterocyclyl, 5- to 12- membered heteroaryl, and NR10Rn;R6is selected from H and C1-6 alkyl;R7is selected from C1-6 alkyl, C3-12 cycloalkyl, 4- to 10-membered heterocyclyl, 5- to 12- membered heteroaryl, and NR10Rn, orR6and R7taken together with the nitrogen and sulfur atoms to which they are attached form 4- to 10-membered heterocyclyl;each R8and R9is independently selected from H, C1-6 alkyl, C3-12 cycloalkyl, and 4- to 10- membered heterocyclyl, orR8and R9taken together with the nitrogen atom to which they are attached form 4- to 10- membered heterocyclyl; andeach R10and R11is independently selected from H, C1-6 alkyl, C3-12 cycloalkyl, and 4- to 10- membered heterocyclyl, orR10and R11taken together with the nitrogen atom to which they are attached form 4- to 10- membered heterocyclyl,wherein each C1-6 alkyl, C3-6 alkyl, C3-12 cycloalkyl, 5- to 12-membered heteroaryl, and 4- to 10- membered heterocyclyl is optionally substituted with 1 to 5 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, OC(=O)OR20b, C(=O)NR21R22, OC(=O)NR21*R22*, NRUC(=O)N(R12)(R13), NR23C(=O)R24, C(=S)NR25R26, C(=O)R27,OTQ-00925- 205 -Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl;whereineach R11, R12, R13, R14R14* R15R15*, R16, R17, R16*, R17*, R18R18a, R19, R20R20aR20b, R21, R22R2!*, R22*, R23, R24, R25, R26, and R27is independently selected from H, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl, orone or more of the pairs of variables selected from R12and R13, R16and R17, R16* and R17*, R21and R22, R21* and R22*, and R25and R26, together with the nitrogen to which they are attached, form a 3-8 membered ring, andwhen one or more of the 1 to 5 substituents is selected from OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, OC(=O)OR20b, C(=O)NR21R22, OC(=O)NR21*R22*, NRUC(=O)N(R12)(R13), NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, P(=O)Rn*R12*, B(OR13’)2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-i2 aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl, each is further optionally substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14*, SR15*, NR16*R17*, Ci-6alkyl, Ci-6haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12aryl, 4- to 12-membered heterocyclyl, and 5- to 12- membered heteroaryl.

22. The compound of claim 21, wherein the compound is represented by structural formula (la) or a pharmaceutically acceptable salt thereof:OTQ-00925- 206 -23. The compound of claim 21 or 22, wherein R4is C1-3 alkyl, wherein the C1-3 alkyl is optionally substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, OC(=O)OR20b, C(=O)NR21R22, OC(=O)NR21*R22*, NRnC(=O)N(R12)(R13), NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl.

24. The compound of claim 21 or 22, wherein the compound is represented by structural formula (la-1) or a pharmaceutically acceptable salt thereof:R3(la-1).

25. The compound of any one of claims 21-24, wherein R3is S(=O)2R5.

26. The compound of claim 25, wherein R5is C1-3 alkyl, wherein the C1-3 alkyl is optionally substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, OC(=O)OR20b, C(=O)NR21R22, OC(=O)NR21*R22*, NRnC(=O)N(R12)(R13), NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl.

27. The compound of claim 26, wherein R5is methyl.

28. The compound of claim 25, wherein R5is C3-12 cycloalkyl or 5- to 12-membered heteroaryl.OTQ-00925- 207 -29. The compound of any one of claims 21-24, wherein R3is S(=O)(=NR6)(R7).

30. The compound of claim 29, wherein R6is H.

31. The compound of claim 29 or 30, wherein R7is C1-3 alkyl, wherein the C1-3 alkyl is optionally substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, OC(=O)OR20b, C(=O)NR21R22, OC(=O)NR21*R22*, NRUC(=O)N(R12)(R13), NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl.

32. The compound of claim 29 or 30, wherein R7is C3-6 cycloalkyl, wherein the C3-6 cycloalkyl is optionally substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, OC(=O)OR20b, C(=O)NR21R22, OC(=O)NR21*R22*, NRnC(=O)N(R12)(R13), NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl.

33. The compound of claim 32, wherein R7is cyclopropyl.

34. The compound of claim 29 or 30, wherein R7is 5- to 6-membered heteroaryl, wherein the 5- to 6-membered heteroaryl is optionally substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, OC(=O)OR20b, C(=O)NR21R22, OC(=O)NR21*R22*, NRnC(=O)N(R12)(R13), NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, CI-6alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl.

35. The compound of claim 33, wherein R7is pyridyl.OTQ-00925- 208 -36. The compound of any one of claims 21-24, wherein R3is C(=O)NR8R9.

37. The compound of claim 36, wherein R8is H.

38. The compound of claim 36 or 37, wherein R9is C1-3 alkyl, wherein the C1-3 alkyl is optionally substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, OC(=O)OR20b, C(=O)NR21R22, OC(=O)NR21*R22*, NRUC(=O)N(R12)(R13), NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl.

39. The compound of claim 38, wherein R9is methyl.

40. The compound of claim 21, wherein Z is O.

41. The compound of claim 21, wherein Z is NH.

42. The compound of claim 21, wherein the compound is represented by structural formula (lb) or a pharmaceutically acceptable salt thereof:

43. The compound of claim 42, wherein the compound is represented by structural formula (Ib-1) or a pharmaceutically acceptable salt thereof:OTQ-00925R3(Ib-1).

44. The compound of claim 21, wherein the compound is represented by structural formula (Ic) or a pharmaceutically acceptable salt thereof:

45. The compound of claim 42, wherein the compound is represented by structural formula (Ic-1) or a pharmaceutically acceptable salt thereof:

46. The compound of claim 21, wherein the compound is represented by structural formula (Id) or a pharmaceutically acceptable salt thereof:OTQ-00925- 210 -47. The compound of claim 42, wherein the compound is represented by structural formula (Id-1) or a pharmaceutically acceptable salt thereof:

48. The compound of any one of claims 40-47, wherein R3is C1-3 alkyl wherein the C1-3 alkyl is optionally substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, OC(=O)OR20b, C(=O)NR21R22, OC(=O)NR21*R22*, NRnC(=O)N(R12)(R13), NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl.

49. The compound of claim 48, wherein R3is C1-3 alkyl substituted with 1-3 substituents selected from F, CN, S(O)2R18a, C(=O)NR21R22, C(=O)R27, C1-3 alkyl, C3-12 cycloalkyl, 4- to 10-membered heterocyclyl, and 5- to 12-membered heteroaryl.

50. The compound of any one of claims 40-47, wherein R3is C3-6 cycloalkyl, wherein the C3-6 cycloalkyl is optionally substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, OC(=O)OR20b, C(=O)NR21R22, OC(=O)NR21*R22*, NRnC(=O)N(R12)(R13), NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl.

51. The compound of any one of claims 40-47, wherein R3is 4- to 10-membered heterocyclyl.OTQ-00925- 211 -52. The compound of claim 51, wherein R3is 4- to 6-membered heterocyclyl, wherein the 4-to 6-membered heterocyclyl is optionally substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, OC(=O)OR20b, C(=O)NR21R22, OC(=O)NR21*R22*, NRnC(=O)N(R12)(R13), NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, CI-6alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl.

53. The compound of any one of claims 40-47, wherein R3is 5- to 6-membered heterocyclyl substituted with 1 to 3 substituents independently selected from oxo, OR14, C1-6 alkyl, halo(Ci-e)alkyl, C1-6 alkoxy, C3-12 cycloalkyl, and 5- to 12-membered heteroaryl.

54. The compound of claim 53, wherein R3is 5-membered heterocyclyl substituted with oxo and Ci -3 alkyl.

55. The compound of claim 53, wherein R3is 5-membered heterocyclyl substituted with oxo and 5- to 6-membered heteroaryl.

56. The compound of any one of claims 40-47, wherein R3is 5- to 12-membered heteroaryl.

57. The compound of claim 56, wherein R3is 5- to 6-membered heteroaryl, wherein the 5-to 6-membered heteroaryl is optionally substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, OC(=O)OR20b, C(=O)NR21R22, OC(=O)NR21*R22*, NRnC(=O)N(R12)(R13), NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, CI-6alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl.

58. The compound of any one of claims 40-47, wherein R3is S(=O)2R5.OTQ-00925- 212 -59. The compound of any one of claims 40-47, wherein R3is NH(C=O)R5.

60. The compound of claim 58 or 59, wherein R5is C1-3 alkyl or C3-6 cycloalkyl, wherein Ci-3 alkyl or C3-6 cycloalkyl is optionally substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, OC(=O)OR20b, C(=O)NR21R22, OC(=O)NR21*R22*, NRnC(=O)N(R12)(R13), NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, CI-6alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl.

61. The compound of any one of claims 21-60, wherein Rlais C1-3 alkyl, wherein C1-3 alkyl is optionally substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, OC(=O)OR20b, C(=O)NR21R22, OC(=O)NR21*R22*, NRUC(=O)N(R12)(R13), NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl.

62. The compound of claim 61, wherein Rlais methyl.

63. The compound of claim 61, wherein Rlais halogen.

64. The compound of claim 61, wherein Rlais F.

65. The compound of any one of claims 61-64, wherein Rlbis H.

66. The compound of any one of claims 61-64, wherein Rlbis methyl.

67. The compound of claim 21, wherein the compound is represented by structural formula (le) or a pharmaceutically acceptable salt thereof:OTQ-00925- 213 -68. The compound of claim 67, wherein the compound is represented by structural formula (Ie-1) or a pharmaceutically acceptable salt thereof:

69. The compound of claim 1, wherein the compound is selected from compounds of Table 1 or a pharmaceutically acceptable salt thereof.

70. The compound of claim 1, wherein the compound is selected from compounds of Table 2 or a pharmaceutically acceptable salt thereof.

71. The compound of claim 1, wherein the compound is selected from compounds of Table 3 or a pharmaceutically acceptable salt thereof.

72. The compound of claim 1, wherein the compound is selected from compounds of Table 4 or a pharmaceutically acceptable salt thereof.

73. The compound of claim 1, wherein the compound is selected from compounds of Table 5 or a pharmaceutically acceptable salt thereof.

74. A pharmaceutical composition comprising a compound of any one of claims 1-73 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.OTQ-00925- 214 -75. A method of treating a disease or disorder, comprising administering to a subject in need thereof a compound of any one of claims 1-73 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of claim 74, wherein the disease or disorder is selected from an inflammatory disease, autoimmune disease, granulomatous disease, cancer, and neurodegenerative disease.

76. The method of claim 75, wherein the disease or disorder is an inflammatory disease.

77. The method of claim 76, wherein the inflammatory disease is selected from uveitis, interleukin- 1 converting enzyme fever syndrome, dermatitis, acute lung injury, type 2 diabetes mellitus, arthritis, inflammatory bowel disease (IBD), ischemia reperfusion injury in a solid organ transplant, sepsis, liver disease, allergic disease, and graft versus host disease.

78. The method of claim 76, wherein the inflammatory disease is an IBD.

79. The method of claim 76, wherein the IBD is selected from ulcerative colitis, Crohn's disease, early-onset IBD, and extraintestinal IBD.

80. The method of claim 76, wherein the inflammatory disease is selected from rheumatoid arthritis, inflammatory arthritis, peritonitis, ischemia reperfusion injury in kidney transplant, non-alcohol steatohepatitis, alcohol steatohepatitis, insulin-resistant type 2 diabetes, allergic rhinitis, asthma, atopic dermatitis, Sjogren’s syndrome, ankylosing spondylitis, pemphigus vulgaris, idiopathic plasmacytic lymphadenopathy, atherosclerosis, myocardial infarction, thrombosis, a-synucleinopathy, Parkinson’s disease, dementia with Lewy body, multiple system atrophy, Alzheimer’s disease, amyotrophic lateral sclerosis, and chronic obstructive pulmonary disease.

81. The method of claim 75, wherein the disease or disorder is an autoimmune disease.OTQ-00925- 215 -82. The method of claim 81, wherein the autoimmune disease is selected from systemic lupus erythematosus, lupus nephritis, psoriasis, immune thrombocytopenic purpura, and multiple sclerosis.

83. The method of claim 75, wherein the disease or disorder is a granulomatous disease.

84. The method of claim 83, wherein the granulomatous disease is selected from sarcoidosis, Blau syndrome, Wegner’s granulomatosis, Behcet’s disease, and interstitial pulmonary disease.

85. The method of claim 75, wherein the disease or disorder is a cancer.

86. The method of claim 85, wherein the cancer is selected from leukemia, breast cancer, brain cancer, colorectal cancer, head and neck cancer, melanoma, pancreatic cancer, prostate cancer, ovarian cancer, renal cancer, and lung cancer.

87. The method of claim 75, wherein the disease or disorder is a neurodegenerative disease.

88. The method of claim 87, wherein the neurodegenerative disease is selected from Alzheimer’s disease, amyotrophic lateral sclerosis (ALS / Lou Gehrig’s Disease), Parkinson’s disease, multiple sclerosis, diabetic neurophathy, polyglutamine (polyQ) diseases, stroke, Fahr disease, Menke’s disease, Wilson’s disease, cerebral ischemia, a prion disorder, dementia, corticobasal degeneration, progressive supranuclear palsy, spinocerebellar atrophies, brain injury, and spinal cord injury.

89. The method of any one of claims 75-88, further comprising administering a second agent.

90. The method of claim 89, wherein the second agent is an anti-inflammatory agent or an anti-autoimmune agent.OTQ-00925- 216 -91. The method of claim 90, wherein the second agent is selected from anti-TNF agent, anti-IL-23 agent, anti-integrin agent, TL1 A inhibitor, and JAK inhibitor.

92. The method of claim 89, wherein the second agent is selected from anti-TNF agent, anti-IL-23 agent, anti-integrin agent, and JAK inhibitor.

93. The method of claim 89, wherein the second agent is anti-TNF agent.

94. The method of claim 89, wherein the second agent is anti-IL-23 agent.

95. The method of claim 89, wherein the second agent is anti-integrin agent.

96. The method of claim 95, wherein the anti-integrin agent is vedolizumab.

97. The method of claim 89, wherein the second agent is TL1 A inhibitor.

98. The method of claim 97, wherein the TL1 A inhibitor is tulisokibart.

99. The method of claim 89, wherein the second agent is JAK inhibitor.

100. The method of claim 99, wherein the JAK inhibitor is selected from filgotinib, tofacitinib, and upadacitinib.

101. The method of any one of claims 89-100, wherein the second agent and the compound are administered together in a single pharmaceutical composition.

102. The method of any one of claims 89-100, wherein the second agent and the compound are administered separately.

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