N-(1-(tert-butyl)-1 h-pyrazol-4-yl)-2-(4-((6-(quinolin-4-yl)oxy)-phenyl)acet amide derivatives as RIPK2 inhibitors for the treatment of inflammatory diseases

Abstract

The present disclosure relates to RIPK2 inhibitors of the formulae (I) or (II) for the treatment of e.g. inflammatory diseases, autoimmune diseases, granulomatous disease, neurodegenerative diseases or cancer, and, more specifically, for the treatment of inflammatory bowel disease, such as Crohn's disease or ulcerative colitis, 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, spondyloarthritis, ankylosing spondylitis, pemphigus vulgaris, idiopathic plasmacytic lymphadenopathy, atherosclerosis, myocardial infarction, thrombosis, alpha-synucleinopathy, Parkinson's disease, dementia with Lewy body, multiple system atrophy, Alzheimer's disease, amyotrophic lateral sclerosis, and chronic obstructive pulmonary disease.

Description

PATENT APPLICATION Docket No. OTQ-00725 - 1 - INHIBITORS OF RIPK2 AND USES THEREOF RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 653,119, filed May 29, 2024, and U.S. Provisional Patent Application No.63 / 722,813, filed November 20, 2024. The entire teachings of the above applications are incorporated herein by reference. BACKGROUND OF THE INVENTION

[0001] Autoinflammatory disorders are diseases characterized by systemic and organ- specific 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.

[0002] NOD1 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. NOD1 and NOD2 detect the presence of intracellular bacteria by binding to PGN fragments. Heredity polymorphisms in the genes encoding NOD1 and NOD2 have been associated with inflammatory disorders. Once activated, NOD signalingleads to activation of NF- B and MAP kinases, resulting in the transcription of pro-inflammatory kinases and the induction of autophagy.

[0003] NOD1 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- B 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 FH12897804.1OTQ-00725 reduce or resolve inflammation for 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.

[0004] 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.

[0005] 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.

[0006] A description of example embodiments of the invention follows. SUMMARY OF THE INVENTION

[0007] In some embodiments, the present disclosure relates to a compound represented by structural formula (I) or a pharmaceutically acceptable salt thereof:wherein: Y is CH or N; R1ais C1-3alkyl; R1band R1cis each independently H or halogen; R2is selected from -S(=O)2R3, -NHC(=O)R4, -NHS(=O)2R5, -N=S(=O)R6R7, -S(=O)(=NH)R8, - P(=O)R9R10, -C(=O)NHR11, -S(=O)2(NHR12), and -C1-3alkylene-S(=O)2R13; R3is selected from C1-3 alkyl, C6-12 aryl, 5- to 12-membered heteroaryl, and 4- to 10-membered heterocyclyl, wherein the C1-3alkyl is substituted with 1 to 3 substituents independently selected from halogen, C(=O)NR21R22, C6-12aryl, and 5- to 12-membered heteroaryl; FH12897804.1OTQ-00725 and wherein the 4- to 10-membered heterocyclyl is substituted with 2 to 3 substituents independently selected from C1-3alkyl, halogen, and 4- to 10-membered heterocyclyl; R4is selected from C1-6alkyl, C1-6haloalkyl, and C3-6cycloalkyl; R5is selected from C2-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C6-12aryl, and 5- to 12-membered heteroaryl; R6and R9is C1-3alkyl; R7is C1-3alkyl or C6-12aryl; R8and R11is selected from C1-3alkyl, C6-12aryl, and 5- to 12-membered heteroaryl, wherein the C1-3alkyl is substituted with 1 to 3 substituents independently selected from C6-12aryl and 5- to 12-membered heteroaryl; and R10, R12, and R13is C6-12aryl or 5- to 12-membered heteroaryl; wherein each C1-3alkyl, C1-6alkyl, C2-6alkyl, C6-12aryl, C1-6haloalkyl, C3-6cycloalkyl, 4- to 10- membered heterocyclyl, and 5- to 12-membered heteroaryl is optionally, unless indicated otherwise, substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, C(=O)NR21R22, NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, C1-6alkyl, C1-6deuteroalkyl, C3-8cycloalkyl, C2-6alkenyl, halo(C1-6)alkyl, C1-3alkylsulfonylaminoalkyl, hydroxy(C1-6)alkyl, amino(C1-6)alkyl, (C1-6) alkylamino(C1-6)alkyl, cyano(C1-6)alkyl, C1-3alkylcarbonylamino(C1-6)alkyl, C1-3alkoxy, halo(C1-3)alkoxy, C1-6alkoxy(C1-3)alkyl, C6-12aryl, 4- to 10-membered heterocyclyl, and 5- to 12-membered heteroaryl, whereinalkyl; R16and R17is each independently selected from H, C1-6alkyl, hydroxy(C1-6)alkyl, and halo(C1-6)alkyl; R19and R23is each independently C1-6alkyl or halo(C1-6)alkyl; R21, R22, R25and R26is each independently selected from H, C1-6alkyl, C1-3alkoxy(C1-6)alkyl, hydroxy(C1-6)alkyl, cyano(C1-6)alkyl, amino(C1-6)alkyl, C1-3alkylamino(C1-6)alkyl, and di(C1-3)alkylamino(C1-6)alkyl; or FH12897804.1OTQ-00725 R21and R22or R25and R26, together with the nitrogen to which they are attached, form a 3-8 membered ring optionally substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, C(=O)NR21R22, NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, C1-6alkyl, C3-8cycloalkyl, C2-6alkenyl, halo(C1-6)alkyl, C1-3alkylsulfonylaminoalkyl, hydroxy(C1-6)alkyl, amino(C1-6)alkyl, cyano(C1-6)alkyl, C1-3alkylcarbonylamino(C1-6)alkyl, C1-3alkoxy, halo(C1-3)alkoxy, C1-6alkoxy(C1-3)alkyl, C6-12aryl, 4- to 10-membered heterocyclyl, and 5- to 12-membered heteroaryl.

[0008] In some embodiments, the present disclosure relates to a compound represented by structural formula (II) or a pharmaceutically acceptable salt thereof:wherein: R1ais C1-3alkyl; R1bis H or halogen; and G is a 4- to 10-membered heterocyclyl, wherein each C1-3 alkyl and 4- to 10-membered heterocyclyl is optionally substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, C(=O)NR21R22, NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, C1-6alkyl, C1-6deuteroalkyl, C3-8cycloalkyl, C2-6alkenyl, halo(C1-6)alkyl, C1-3alkylsulfonylaminoalkyl, hydroxy(C1-6)alkyl, amino(C1-6)alkyl, (C1-6) alkylamino(C1-6)alkyl, cyano(C1-6)alkyl, C1-3alkylcarbonylamino(C1-6)alkyl, C1-3alkoxy, halo(C1-3)alkoxy, C1-6alkoxy(C1-3)alkyl, C6-12 aryl, 4- to 8-membered heterocyclyl, and 5- to 12-membered heteroaryl, whereinindependently H or C1-6alkyl; R16and R17are each independently selected from H, C1-6alkyl, hydroxy(C1-6)alkyl, and halo(C1-6)alkyl; FH12897804.1OTQ-00725 R19and R23are each independently C1-6 alkyl or halo(C1-6)alkyl; R21, R22, R25and R26are each independently selected from H, C1-6alkyl, C1-3alkoxy(C1-6)alkyl, hydroxy(C1-6)alkyl, cyano(C1-6)alkyl, amino(C1-6)alkyl, C1-3alkylamino(C1-6)alkyl, and di(C1-3)alkylamino(C1-6)alkyl; or R21and R22or R25and R26, together with the nitrogen to which they are attached, form a 3-8 membered ring optionally substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, C(=O)NR21R22, NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, C1-6alkyl, C3-8cycloalkyl, C2-6alkenyl, halo(C1-6)alkyl, C1-3alkylsulfonylaminoalkyl, hydroxy(C1-6)alkyl, amino(C1-6)alkyl, cyano(C1-6)alkyl, C1-3alkylcarbonylamino(C1-6)alkyl, C1-3alkoxy, halo(C1-3)alkoxy, C1-6alkoxy(C1-3)alkyl, C6-12aryl, 4- to 10-membered heterocyclyl, and 5- to 12-membered heteroaryl.

[0009] In some embodiments, the present disclosure relates to a compound represented by one of the following structural formulas or a pharmaceutically acceptable salt thereof: ,,FH12897804.1OTQ-00725 - 6 C29H33N5O5S ,,, FH12897804.1OTQ-00725 - 7 - , ,,, FH12897804.1OTQ-00725 - 8 - , F3N6O3 , ,, FH12897804.1OTQ-00725 9 , ,,, FH12897804.1OTQ-00725 - 10 - , ,,, FH12897804.1OTQ-00725 , ,,, FH12897804.1OTQ-00725 , ,,, FH12897804.1OTQ-00725 , ,,, FH12897804.1OTQ-00725 - 14 - , ,,,FH12897804.1OTQ-00725 - 15 -FH12897804.1OTQ-00725 , ,,,FH12897804.1OTQ-00725 , ,,, FH12897804.1OTQ-00725 , ,,,FH12897804.1OTQ-00725 ,,,,FH12897804.1OTQ-00725 , ,,, FH12897804.1OTQ-00725 ,,,,FH12897804.1OTQ-00725 , , ,,FH12897804.1OTQ-00725 - 23 - , ,,, FH12897804.1OTQ-00725 24 , , ,, FH12897804.1OTQ-00725 , , ,, FH12897804.1OTQ-00725 , ,,,FH12897804.1OTQ-00725 , ,,, FH12897804.1OTQ-00725 , , ,,FH12897804.1OTQ-00725 , ,,, FH12897804.1OTQ-00725 ,,,,FH12897804.1OTQ-00725 ,,,, FH12897804.1OTQ-00725 , ,,, FH12897804.1OTQ-00725 , , ,, FH12897804.1OTQ-00725 , , ,, FH12897804.1OTQ-00725 , , ,, FH12897804.1OTQ-00725 , ,,FH12897804.1OTQ-00725 ,, FH12897804.1OTQ-00725 , , ,,FH12897804.1OTQ-00725 , ,,, FH12897804.1OTQ-00725 ,,,,FH12897804.1OTQ-00725 , , ,,FH12897804.1OTQ-00725 , ,,, FH12897804.1OTQ-00725 ,,,, FH12897804.1OTQ-00725 , , ,, FH12897804.1OTQ-00725 , ,,, FH12897804.1OTQ-00725 , ,,, FH12897804.1OTQ-00725 , ,,, FH12897804.1OTQ-00725 , ,,, FH12897804.1OTQ-00725 , ,,, FH12897804.1OTQ-00725 ,,,,FH12897804.1OTQ-00725 ,,,,FH12897804.1OTQ-00725 - 52 - , ,,,FH12897804.1OTQ-00725 ,,,,FH12897804.1OTQ-00725 ,,,,FH12897804.1OTQ-00725 , ,,, FH12897804.1OTQ-00725 ,,,,FH12897804.1OTQ-00725 ,,,,FH12897804.1OTQ-00725 , ,,, FH12897804.1OTQ-00725 , ,,, FH12897804.1OTQ-00725 , ,,, FH12897804.1OTQ-00725 - 61 -, , , FH12897804.1OTQ-00725.

[0010] 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 (II) or a pharmaceutically acceptable salt thereof) and various aspects thereof, and a pharmaceutically acceptable excipient.

[0011] 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 therapeutically effective FH12897804.1OTQ-00725 amount of a compound or a pharmaceutically acceptable salt of the compound described herein (e.g., a compound represented by structural formula (I) or (II) 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.

[0012] 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 therapeutically effective amount of a compound described herein (e.g., a compound represented by structural formula (I) or (II) 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.

[0013] 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 (II) 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).

[0014] In some embodiments, the present disclosure relates to a compound described herein (e.g., a compound represented by structural formula (I) or (II) 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

[0015] RIP Kinases

[0016] 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 FH12897804.1OTQ-00725 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.

[0017] 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 NOD1 and NOD2. NOD1 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, NOD1 or NOD2 binds to RIPK2 to coordinate NF-κB (nuclear factor κ 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-κB, and MAPK activation).

[0018] Both NOD1 / 2 and RIPK2 are NF-κB 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 are stimulated by a variety of mediators of inflammation, including TNF (Tumor Necrosis Factor) and IFN (Interferon). In addition to NF-κB 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.

[0019] Dysregulation of RIPK2-dependent signaling has been linked to autoinflammatory diseases. Patients with loss-of-function NOD2 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 NOD2 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- FH12897804.1OTQ-00725 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.

[0020] 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 NOD2 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 NOD2 polymorphism with Crohn’s as probable leading cause of the excessive immune response against skin tissues observed. Mutations in NOD1 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.

[0021] 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 NOD1 pathway was observed in patients suffering from metabolic syndrome. A recent functional study highlighting the impact of RIPK2 inhibitors on lipolysis suggested a role for RIPK2-dependent signaling in dysglycemia and lipolysis.

[0022] In cardiac hypertrophy, a complex and multifactorial pathology, inflammation was shown as important hallmark of the disease, notably through the activation of NF-κB 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.

[0023] 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). FH12897804.1OTQ-00725 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-κB 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-κB pathway and p38 signaling.

[0024] A new role for RIPK2 in osteosarcoma invasion was demonstrated when Gefitinib, via RIPK2 inhibition, prevented progression of pulmonary metastasis. Further, non-canonical NF-κB 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.

[0025] RIPK2 and RIP2 kinase are used interchangeably herein and refer to Receptor- interacting protein kinase 2.

[0026] DEFINITIONS

[0027] Definitions of specific functional groups and chemical terms are described in more detail below. The chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5thEdition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3rdEdition, Cambridge University Press, Cambridge, 1987.

[0028] 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, FH12897804.1OTQ-00725 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 et al., Tetrahedron 33:2725 (1977); Eliel, E.L. Stereochemistry of Carbon Compounds, McGraw-Hill, NY, 1962; and Wilen, S.H., Tables of Resolving Agents and Optical Resolutions p.268, E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972. The invention additionally encompasses compounds as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

[0029] In a formula,is a single bond where the stereochemistry of the moietiesimmediately attached thereto is not specified, --- is absent or a single bond, and or is asingle 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.

[0030] 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, single 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.

[0031] 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. FH12897804.1OTQ-00725

[0032] When a range of values is listed, it is intended to encompass each value and sub- range within the range. For example, "C1-6alkyl" is intended to encompass C1, C2, C3, C4, C5, C6, C1-6, C1-5, C1-4, C1-3, C1-2, C2-6, C2-5, C2-4, C2-3, C3-6, C3-5, C3-4, C4-6, C4-5, and C5-6alkyl.

[0033] The term "aliphatic" refers to alkyl, alkenyl, alkynyl, and carbocyclic groups. Likewise, the term "heteroaliphatic" refers to heteroalkyl, heteroalkenyl, heteroalkynyl, and heterocyclic groups.

[0034] The term "alkyl" refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 10 carbon atoms ("C1-10alkyl"). In some embodiments, an alkyl group has 1 to 9 carbon atoms ("C1-9alkyl"). In some embodiments, an alkyl group has 1 to 8 carbon atoms ("C1-8alkyl"). In some embodiments, an alkyl group has 1 to 7 carbon atoms ("C1-7alkyl"). In some embodiments, an alkyl group has 1 to 6 carbon atoms ("C1-6alkyl"). In some embodiments, an alkyl group has 1 to 5 carbon atoms ("C1-5alkyl"). In some embodiments, an alkyl group has 1 to 4 carbon atoms ("C1-4alkyl"). In some embodiments, an alkyl group has 1 to 3 carbon atoms ("C1-3alkyl"). In some embodiments, an alkyl group has 1 to 2 carbon atoms ("C1-2 alkyl"). In some embodiments, an alkyl group has 1 carbon atom ("C1 alkyl"). In some embodiments, an alkyl group has 2 to 6 carbon atoms ("C2-6alkyl"). Examples of C1-6alkyl groups include methyl (C1), 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 (C6) (e.g., n-hexyl). Additional examples of alkyl groups include n-heptyl (C7), n-octyl (C8), and the like. Unless otherwise specified, each instance of an alkyl group is independently unsubstituted (an "unsubstituted alkyl") or substituted (a "substituted alkyl") with one or more substituents (e.g., halogen, such as F). In certain embodiments, the alkyl group is an unsubstituted C1-10alkyl (such as unsubstituted C1-6alkyl, 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 C1-10alkyl (such as substituted C1-6alkyl, e.g., -CF3, Bn).

[0035] 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 FH12897804.1OTQ-00725 some embodiments, the haloalkyl moiety has 1 to 8 carbon atoms ("C1-8 haloalkyl"). In some embodiments, the haloalkyl moiety has 1 to 6 carbon atoms ("C1-6haloalkyl"). In some embodiments, the haloalkyl moiety has 1 to 4 carbon atoms ("C1-4haloalkyl"). In some embodiments, the haloalkyl moiety has 1 to 3 carbon atoms ("C1-3haloalkyl"). In some embodiments, the haloalkyl moiety has 1 to 2 carbon atoms ("C1-2haloalkyl"). Examples of haloalkyl groups include -CHF2, -CH2F, -CF3, -CH2CF3, -CF2CF3, -CF2CF2CF3, -CCl3, -CFCl2, -CF2Cl, and the like.

[0036] 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 ("C1-8deuteroalkyl"). In some embodiments, the deuteroalkyl moiety has 1 to 6 carbon atoms ("C1-6deuteroalkyl”). In some embodiments, the deuteroalkyl moiety has 1 to 4 carbon atoms ("C1-4deuteroalkyl "). In some embodiments, the deuteroalkyl moiety has 1 to 3 carbon atoms ("C1-3deuteroalkyl "). In some embodiments, the deuteroalkyl moiety has 1 to 2 carbon atoms ("C1-2deuteroalkyl"). In some embodiments, the deuteroalkyl moiety is C1, C2, C3, C4, C5, or C6 deuteroalkyl. A deuteroalkyl moiety having n carbon atoms can have from 1 to 2n+1 deuterium atoms. Examples of deuteroalkyl groups include -CHD2, -CH2D, -CD3, -CH2CD3, -CD2CD3, -CD2CD2CD3, -CH(CD3)2, -CD(CD3)2, - C(CD3)3, and the like.

[0037]

[0038] 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 ("C1-8hydroxyalkyl"). In some embodiments, the hydroxyalkyl moiety has 1 to 6 carbon atoms ("C1-6hydroxyalkyl"). In some embodiments, the hydroxyalkyl moiety has 1 to 4 carbon atoms ("C1-4hydroxyalkyl"). In some embodiments, the hydroxyalkyl moiety has 1 to 3 carbon atoms ("C1-3hydroxyalkyl"). In some embodiments, the hydroxyalkyl moiety has 1 to 2 carbon atoms ("C1-2hydroxyalkyl").

[0039] 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 ("C1-8alkoxy"). In some embodiments, the alkoxy moiety has 1 to 6 carbon atoms ("C1-6alkoxy"). In some embodiments, the alkoxy moiety has 1 to 4 carbon atoms ("C1-4FH12897804.1OTQ-00725 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 ("C1-2alkoxy"). Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy and tert-butoxy.

[0040] 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 ("C1-8haloalkoxy"). In some embodiments, the alkoxy moiety has 1 to 6 carbon atoms ("C1-6haloalkoxy"). In some embodiments, the alkoxy moiety has 1 to 4 carbon atoms ("C1-4haloalkoxy"). In some embodiments, the alkoxy moiety has 1 to 3 carbon atoms ("C1-3haloalkoxy"). In some embodiments, the alkoxy moiety has 1 to 2 carbon atoms ("C1-2haloalkoxy"). Representative examples of haloalkoxy include, but are not limited to, difluoromethoxy, trifluoromethoxy, and 2,2,2-trifluoroethoxy.

[0041] 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 ("C1-8 alkoxyalkyl"). In some embodiments, the alkoxyalkyl moiety has 1 to 6 carbon atoms ("C1-6alkoxyalkyl"). In some embodiments, the alkoxyalkyl moiety has 1 to 4 carbon atoms ("C1-4alkoxyalkyl"). In some embodiments, the alkoxyalkyl moiety has 1 to 3 carbon atoms ("C1-3alkoxyalkyl"). In some embodiments, the alkoxyalkyl moiety has 1 to 2 carbon atoms ("C1-2alkoxyalkyl").

[0042] 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 ("heteroC1-20alkyl"). 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 ("heteroC1-18alkyl"). 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 ("heteroC1-16alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to14 carbon atoms and 1 or more heteroatoms within the parent chain ("heteroC1-14alkyl"). In some embodiments, a heteroalkyl group is a FH12897804.1OTQ-00725 saturated group having 1 to12 carbon atoms and 1 or more heteroatoms within the parent chain ("heteroC1-12alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1to 10 carbon atoms and 1 or more heteroatoms within the parent chain ("heteroC1-10alkyl"). 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 ("heteroC1-8alkyl"). 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 ("heteroC1-6alkyl"). 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 ("heteroC1-4alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom within the parent chain ("heteroC1-3alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom within the parent chain ("heteroC1-2alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom ("heteroC1alkyl"). 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 more substituents. In certain embodiments, the heteroalkyl group is an unsubstituted heteroC1-20alkyl. In certain embodiments, the heteroalkyl group is an unsubstituted heteroC1-10alkyl. In certain embodiments, the heteroalkyl group is a substituted heteroC1-20alkyl. In certain embodiments, the heteroalkyl group is an unsubstituted heteroC1-10alkyl.

[0043] 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 ("C2-9alkenyl"). In some embodiments, an alkenyl group has 2 to 8 carbon atoms ("C2-8alkenyl"). In some embodiments, an alkenyl group has 2 to 7 carbon atoms ("C2-7alkenyl"). In some embodiments, an alkenyl group has 2 to 6 carbon atoms ("C2-6alkenyl"). In some embodiments, an alkenyl group has 2 to 5 carbon atoms ("C2-5alkenyl"). In some embodiments, an alkenyl FH12897804.1OTQ-00725 group has 2 to 4 carbon atoms ("C2-4 alkenyl"). In some embodiments, an alkenyl group has 2 to 3 carbon atoms ("C2-3alkenyl"). In some embodiments, an alkenyl group has 2 carbon atoms ("C2alkenyl"). The one or more carbon-carbon double bonds can be internal (such as in 2- butenyl) or terminal (such as in 1-butenyl). Examples of C2-4alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. Examples of C2-6alkenyl groups include the aforementioned C2-4alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like. Unless otherwise specified, each instance of an alkenyl group is independently unsubstituted (an "unsubstituted alkenyl") or substituted (a "substituted alkenyl") with one or more substituents. In certain embodiments, the alkenyl group is an unsubstituted C2-10alkenyl. In certain embodiments, the alkenyl group is a substituted C2-10alkenyl. In an alkenyl group, a C=C double bond for which the stereochemistry is not specified (e.g., -CH=CHCH3or) may be an (E)- or (Z)-double bond.

[0044] 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 within the parent chain ("heteroC2-10alkenyl"). 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 ("heteroC2-9alkenyl").

[0045] 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 ("heteroC2-8alkenyl"). 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 ("heteroC2-7alkenyl"). 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 ("heteroC2-6alkenyl"). 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 ("heteroC2-5alkenyl"). In some embodiments, a heteroalkenyl group has FH12897804.1OTQ-00725 2 to 4 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain ("heteroC2-4alkenyl"). In some embodiments, a heteroalkenyl group has 2 to 3 carbon atoms, at least one double bond, and 1 heteroatom within the parent chain ("heteroC2-3alkenyl"). 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 ("heteroC2-6alkenyl"). 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. Incertain embodiments, the heteroalkenyl group is an unsubstituted heteroC2-10alkenyl. In certainembodiments, the heteroalkenyl group is a substituted heteroC2-10alkenyl.

[0046] 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) ("C2-10alkynyl"). In some embodiments, an alkynyl group has 2 to 9 carbon atoms ("C2-9alkynyl"). In some embodiments, an alkynyl group has 2 to 8 carbon atoms ("C2-8alkynyl"). In some embodiments, an alkynyl group has 2 to 7 carbon atoms ("C2-7alkynyl"). 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 ("C2-5alkynyl"). In some embodiments, an alkynyl group has 2 to 4 carbon atoms ("C2-4alkynyl"). In some embodiments, an alkynyl group has 2 to 3 carbon atoms ("C2-3alkynyl"). In some embodiments, an alkynyl group has 2 carbon atoms ("C2alkynyl"). The one or more carbon-carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl). Examples of C2-4alkynyl groups include, without limitation, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. Examples of C2-6alkynyl groups include the aforementioned C2-4alkynyl groups as well as pentynyl (C5), hexynyl (C6), and the like. Additional examples of alkynyl include heptynyl (C7), octynyl (C8), and the like. Unless otherwise specified, each instance of an alkynyl group is independently unsubstituted (an "unsubstituted alkynyl") or substituted (a "substituted alkynyl") with one or more substituents. In certain embodiments, the alkynyl group is an unsubstituted C2-10alkynyl. In certain embodiments, the alkynyl group is a substituted C2-10alkynyl.

[0047] 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 FH12897804.1OTQ-00725 (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 ("heteroC2-10alkynyl"). 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 ("heteroC2-9alkynyl"). 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 ("heteroC2-8alkynyl"). 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 ("heteroC2-7alkynyl"). 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 ("heteroC2-6alkynyl"). 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 ("heteroC2-5alkynyl"). In some embodiments, a heteroalkynyl group has 2 to 4 carbon atoms, at least one triple bond, and l 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 ("heteroC2-3alkynyl"). 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 ("heteroC2-6alkynyl"). Unless otherwise specified, each instance of a heteroalkynyl group is independently unsubstituted (an "unsubstituted heteroalkynyl") or substituted (a "substituted heteroalkynyl") with one or more substituents. In certain embodiments, the heteroalkynyl group is an unsubstituted heteroC2-10alkynyl. In certain embodiments, the heteroalkynyl group is a substituted heteroC2-10alkynyl.

[0048] The term "carbocyclyl" or "carbocyclic" refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 14 ring carbon atoms ("C3-14carbocyclyl") and zero heteroatoms in the non-aromatic ring system. In some embodiments, a carbocyclyl group has 3 to 10 ring carbon atoms ("C3-10carbocyclyl"). In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms ("C3-8carbocyclyl"). In some embodiments, a carbocyclyl group has 3 to 7 ring carbon atoms ("C3-7carbocyclyl"). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms ("C3-6carbocyclyl"). In some embodiments, a carbocyclyl group has 4 to 6 ring carbon atoms ("C4-6carbocyclyl"). In some embodiments, a carbocyclyl group has 5 to 6 FH12897804.1OTQ-00725 ring carbon atoms ("C5-6 carbocyclyl"). In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms ("C5-10carbocyclyl"). Exemplary C3-6carbocyclyl groups include, without limitation, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like. Exemplary C3-8carbocyclyl groups include, without limitation, the aforementioned C3-8carbocyclyl groups as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), and the like. Exemplary C3-10carbocyclyl groups include, without limitation, the aforementioned C3-8carbocyclyl groups as well as cyclononyl (C9), cyclononenyl(C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-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 carbocyclic 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 C3-14carbocyclyl. In certain embodiments, the carbocyclyl group is a substituted C3-14carbocyclyl.

[0049] In some embodiments, "carbocyclyl" is a monocyclic, saturated carbocyclyl group having from 3 to 14 ring carbon atoms ("C3-14cycloalkyl"). In some embodiments, a cycloalkyl group has 3 to 10 ring carbon atoms ("C3-10cycloalkyl"). In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms ("C3-8cycloalkyl"). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms ("C3-6cycloalkyl"). In some embodiments, a cycloalkyl group has 4 to 6 ring carbon atoms ("C4-6cycloalkyl"). In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms ("C5-6cycloalkyl"). In some embodiments, a cycloalkyl FH12897804.1OTQ-00725 group has 5 to 10 ring carbon atoms ("C5-10 cycloalkyl"). Examples of C5-6 cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C6). Examples of C3-6cycloalkyl groups include the aforementioned C5-6cycloalkyl groups as well as cyclopropyl (C3) and cyclobutyl (C4). Examples of C3-8cycloalkyl groups include the aforementioned C3-6cycloalkyl groups as well as cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise specified, each instance of a cycloalkyl group is independently unsubstituted (an "unsubstituted cycloalkyl") or substituted (a "substituted cycloalkyl") with one or more substituents. In certain embodiments, the cycloalkyl group is an unsubstituted C3-14cycloalkyl. In certain embodiments, the cycloalkyl group is a substituted C3-14cycloalkyl.

[0050] 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 defined 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. FH12897804.1OTQ-00725

[0051] 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.

[0052] 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, and dithiolanyl. Exemplary 5-membered heterocyclyl groups containing 3 heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing 1 heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing 2 heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing 3 heteroatoms include, without limitation, 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, FH12897804.1OTQ-00725 indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl, decahydronaphthyridinyl, decahydro-1,8-naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole, indolinyl, phthalimidyl, naphthalimidyl, chromanyl, chromenyl, lH-benzo[e][1,4]diazepinyl, 1,4,5,7-tetrahydropyrano[3,4-b]pyrrolyl, 5,6-dihydro-4H-furo[3,2-b]pyrrolyl, 6,7-dihydro-5H- furo[3,2-b]pyranyl, 5,7-dihydro-4H-thieno[2,3-c]pyranyl, 2,3-dihydro-1H-pyrrolo[2,3- b]pyridinyl, 2,3-dihydrofuro[2,3-b]pyridinyl, 4,5,6,7-tetrahydro-1H-pyrrolo[2,3-b]pyridinyl, 4,5,6,7-tetrahydrofuro[3,2-c]pyridinyl, 4,5,6,7-tetrahydrothieno[3,2-b]pyridinyl, 1,2,3,4- tetrahydro-1,6-naphthyridinyl, and the like.

[0053] 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 electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system ("C6-14aryl"). In some embodiments, an aryl group has 6 ring carbon atoms ("C6aryl"; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms ("C10 aryl"; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms ("C14aryl"; e.g., anthracyl). "Aryl" also includes 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. Unless otherwise specified, each instance of an aryl group is independently unsubstituted (an "unsubstituted aryl") or substituted (a "substituted aryl") with one or more substituents. In certain embodiments, the aryl group is an unsubstituted C6-14aryl. In certain embodiments, the aryl group is a substituted C6-14aryl.

[0054] "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.

[0055] 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 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, FH12897804.1OTQ-00725 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).

[0056] 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 sulfur ("5-10 membered heteroaryl"). In some embodiments, a heteroaryl group is a 5-8 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-8 membered heteroaryl"). In some embodiments, a heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-6 membered heteroaryl"). In some embodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1 ring FH12897804.1OTQ-00725 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.

[0057] Exemplary 5-membered heteroaryl groups containing 1 heteroatom include, without limitation, pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing 2 heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing 3 heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5- membered heteroaryl groups containing 4 heteroatoms include, without limitation, tetrazolyl. Exemplary 6- membered heteroaryl groups containing 1 heteroatom include, without limitation, pyridinyl. Exemplary 6-membered heteroaryl groups containing 2 heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing 3 or 4 heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively. Exemplary 7- membered heteroaryl groups containing 1 heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6- bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. Exemplary tricyclic heteroaryl groups include, without limitation, phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl, and phenazinyl.

[0058] "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.

[0059] The term "unsaturated bond" refers to a double or triple bond.

[0060] The term "unsaturated" or "partially unsaturated" refers to a moiety that includes at least one double or triple bond. FH12897804.1OTQ-00725

[0061] The term "saturated" refers to a moiety that does not contain a double or triple bond, i.e., the moiety only contains single bonds.

[0062] 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.

[0063] 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 does 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 FH12897804.1OTQ-00725 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, -ORaa, -ON(Rbb)2, -N(Rbb)2, -N(Rbb)3+X-, -N(ORcc)Rbb, -SH, -SRaa, -SSRcc, -C(=O)Raa, -CO2H, -CHO, -C(ORcc)3, -CO2Raa, -OC(=O)Raa, -OCO2Raa, -C(=O)N(Rbb)2, - OC(=O)N(Rbb)2, -NRbbC(=O)Raa, -NRbbCO2Raa, -NRbbC(=O)N(Rbb)2, -C(=NRbb)Raa, - C(=NRbb)ORaa, -OC(=NRbb)Raa, -OC(=NRbb)ORaa, -C(=NRbb)N(Rbb)2, -OC(=NRbb)N(Rbb)2, - NRbbC(=NRbb)N(Rbb)2, -C(=O)NRbbSO2Raa, -NRbbSO2Raa, -SO2N(Rbb)2, -SO2Raa, -SO2ORaa, - OSO2Raa, -S(=O)Raa, -OS(=O)Raa, -Si(Raa)3, -OSi(Raa)3, -C(=S)N(Rbb)2, -C(=O)SRaa, - C(=S)SRaa, -SC(=S)SRaa, -SC(=O)SRaa, -OC(=O)SRaa, -SC(=O)ORaa, -SC(=O)Raa, - P(=O)(Raa)2, -P(=O)(ORcc)2, -OP(=O)(Raa)2, -OP(=O)(ORcc)2, -P(=O)(N(Rbb)2)2,- OP(=O)(N(Rbb)2)2, -NRbbP(=O)(Raa)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, - OP(ORcc)3+X–, -OP(Rcc)4, -OP(ORcc)4, -B(Raa)2, -B(ORcc)2, -BRaa(ORcc), C1-10 alkyl, C1-10 perhaloalkyl, C2-10alkenyl, C2- 10alkynyl, heteroC1-10alkyl, heteroC2-10alkenyl, heteroC2-10alkynyl, C3-10carbocyclyl, 3-14 membered heterocyclyl, C6-14aryl, 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 =O, =S, =NN(Rbb)2, =NNRbbC(=O)Raa, =NNRbbC(=O)ORaa, =NNRbbS(=O)2Raa, =NRbbor =NORcc; each instance of Raais, independently, selected from C1-10alkyl, C1-10perhaloalkyl, C2-10alkenyl, C2-10alkynyl, heteroC1-10alkyl, heteroC2-10alkenyl, heteroC2-10alkynyl, C3-10carbocyclyl, 3-14 membered heterocyclyl, C6-14aryl, 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, -ORaa, -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, - FH12897804.1OTQ-00725 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, C2-10alkynyl, heteroC1-10alkyl, heteroC2-10alkenyl, heteroC2-10alkynyl, C3-10carbocyclyl, 3-14 membered heterocyclyl, C6-14aryl, 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, C1-10alkyl, C1-10perhaloalkyl, C2-10alkenyl, C2-10alkynyl, heteroC1-10alkyl, heteroC2-10alkenyl, heteroC2-10alkynyl, C3-10carbocyclyl, 3-14 membered heterocyclyl, C6-14aryl, 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, -ON(Rff)2, -N(Rff)2, -N(Rff)3+X–, -N(ORee)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, C1-6alkyl, C1-6perhaloalkyl, C2-6alkenyl, C2-6alkynyl, heteroC1-6alkyl, heteroC2-6alkenyl, heteroC2-6alkynyl, C3-10carbocyclyl, 3-10 membered heterocyclyl, C6-10aryl, 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 =O or =S; wherein X–is a counterion; each instance of Reeis, independently, selected from C1-6alkyl, C1-6perhaloalkyl, C2-6alkenyl, C2-6alkynyl, heteroC1-6alkyl, heteroC2-6alkenyl, heteroC2-6alkynyl, C3-10carbocyclyl, C6-10aryl, 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, C1-6FH12897804.1OTQ-00725 alkyl, C1-6 perhaloalkyl, C2-6 alkenyl, C2-6 alkynyl, heteroC1-6 alkyl, heteroC2-6 alkenyl, heteroC2-6alkynyl, C3-10carbocyclyl, 3-10 membered heterocyclyl, C6-10aryl 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, -OC1-6alkyl, -ON(C1-6alkyl)2, -N(Cl-6alkyl)2, -N(Cl-6alkyl)3+X–, - NH(Cl-6alkyl)2+X–, -NH2(C1-6alkyl)+X–, -NH3+X–, -N(OC1-6alkyl)(Cl-6alkyl), -N(OH)(Cl-6alkyl), -NH(OH), -SH, -SC1-6alkyl, -SS(Cl-6alkyl), -C(=O)(Cl-6alkyl), -CO2H, -CO2(C1-6alkyl), -OC(=O)(Cl-6alkyl), -OCO2(C1-6alkyl), -C(=O)NH2, -C(=O)N(C1-6alkyl)2, -OC(=O)NH(C1-6alkyl), -NHC(=O)(Cl-6alkyl), -N(Cl-6alkyl)C(=O)( C1-6alkyl), -NHCO2(C1-6alkyl), - NHC(=O)N(Cl-6alkyl)2, -NHC(=O)NH(Cl-6alkyl), -NHC(=O)NH2, -C(=NH)O(Cl-6alkyl), - OC(=NH)(Cl-6alkyl), -OC(=NH)OCl-6alkyl, -C(=NH)N(Cl-6alkyl)2, -C(=NH)NH(Cl-6alkyl), - C(=NH)NH2, -OC(=NH)N(C1-6alkyl)2, -OC(=NH)NH(C1-6alkyl), -OC(=NH)NH2, - NHC(=NH)N(C1-6 alkyl)2, -NHC(=NH)NH2, -NHSO2(C1-6 alkyl), -SO2N(C1-6 alkyl)2, - SO2NH(C1-6alkyl), -SO2NH2, -SO2(C1-6alkyl), -SO2O(C1-6alkyl), -OSO2(C1-6alkyl), -SO(C1-6alkyl), -Si(Cl-6alkyl)3, -OSi(Cl-6alkyl)3, -C(=S)N(Cl-6alkyl)2, -C(=S)NH(Cl-6alkyl), - C(=S)NH2, -C(=O)S(Cl-6alkyl), -C(=S)SC1-6alkyl, -SC(=S)SC1-6alkyl, -P(=O)(OC1-6alkyl)2, - P(=O)(C1-6alkyl)2, -OP(=O)(Cl-6alkyl)2, -OP(=O)(OCl-6alkyl)2, C1-6alkyl, C1-6perhaloalkyl, C2-6alkenyl, C2-6alkynyl, heteroC1-6alkyl, heteroC2-6alkenyl, heteroC2-6alkynyl, C3-10carbocyclyl, C6-10aryl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl; or two geminal Rggsubstituents can be joined to form =O or =S; wherein X–is a counterion.

[0064] The term "halo" or "halogen" refers to fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), or iodine (iodo, -I).

[0065] 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, -ON(Rbb)2, -OC(=O)SRaa, -OC(=O)Raa, - OCO2Raa, -OC(=O)N(Rbb)2, -OC(=NRbb)Raa, -OC(=NRbb)ORaa, -OC(=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–, - FH12897804.1OTQ-00725 OP(=O)(Raa)2, -OP(=O)(ORcc)2, and -OP(=O)(N(Rbb)2)2, wherein X–, Raa, Rbband Rccare as defined herein.

[0066] 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.

[0067] 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.

[0068] 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)2and -N(Rbb)3+X–, wherein Rbband X–are as defined herein.

[0069] The term "sulfonyl" refers to a group selected from -SO2N(Rbb)2, -SO2Raa, and- SO2ORaa, wherein Raaand Rbbare as defined herein.

[0070] The term "sulfinyl" refers to the group -S(=O)Raa, wherein Raais as defined herein.

[0071] 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 FH12897804.1OTQ-00725 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- or di-heteroarylamino; or two RX1groups taken together form a 5- to 6-membered heterocyclic ring.

[0072] 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, heteroalkylthioxy, arylthioxy, heteroarylthioxy, acyloxy, and the like, each of which may or may not be further substituted).

[0073] 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., -CO2Raa, -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.

[0074] The term "oxo" refers to the group =O, and the term "thiooxo" refers to the group =S.

[0075] Nitrogen atoms can be substituted or unsubstituted as valency permits, and include primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom FH12897804.1OTQ-00725 substituents include, but are not limited to, hydrogen, -OH, -ORaa, -N(Rcc)2, -CN, -C(=O)Raa, - C(=O)N(Rcc)2, -CO2Raa, -SO2Raa, -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, C1-10alkyl, C1-10perhaloalkyl, C2-10alkenyl, C2-10alkynyl, heteroC1-10alkyl, heteroC2-10alkenyl, heteroC2-10alkynyl, C3-10carbocyclyl, 3-14 membered heterocyclyl, C6-14aryl, 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.

[0076] 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, -ORaa, -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, C1-10 alkyl (e.g., aralkyl, heteroaralkyl), C2-10alkenyl, C2-10alkynyl, heteroC1-10alkyl, heteroC2-10alkenyl, heteroC2-10alkynyl, C3-10carbocyclyl, 3-14 membered heterocyclyl, C6-14aryl, and 5-14 membered heteroaryl groups, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aralkyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups, and wherein Raa, 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.

[0077] 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, (N'- dithiobenzyloxyacylamina)acetamide, 3-(p-hydroxyphenyl)propanamide, 3-(o- nitrophenyl)propanamide, 2-methyl-2-(o-nitrophenoxy)propanamide, 2-methyl-2-(o- FH12897804.1OTQ-00725 phenylazophenoxy )propanamide, 4-chlorobutanamide, 3-methyl-3-nitrobutanamide, o-nitrocinnamide, N-acetylmethionine derivative, o-nitrobenzamide and o-(benzoyloxymethyl)benzamide.

[0078] 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), 1-(1-adamantyl)-1- methylethyl carbamate (Adpoc), 1,1-dimethyl-2-haloethyl carbamate, 1,1-dimethyl-2,2- dibromoethyl carbamate (DB-t-BOC), 1,1-dimethyl-2,2,2-trichloroethyl carbamate (TCBOC), 1-methyl-1-(4-biphenylyl)ethyl carbamate (Bpoc), 1-(3,5-di-t-butylphenyl)-1-methylethyl carbamate (t-Bumeoc), 2-(2'- and 4'-pyridyl)ethyl carbamate (Pyoc), 2-(N,N- dicyclohexylcarboxamido)ethyl carbamate, t-butyl carbamate (BOC or Boc), 1-adamantyl carbamate (Adoc), vinyl carbamate (Voc), allyl carbamate (Alloc), 1-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- 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-(1,3-dithianyl)]methyl carbamate (Dmoc), 4-methylthiophenyl carbamate (Mtpc), 2,4-dimethylthiophenyl carbamate (Bmpc), 2-phosphonioethyl carbamate (Peoc), 2-triphenylphosphonioisopropyl carbamate (Ppoc), 1,1-dimethyl-2-cyanoethyl carbamate, m-chloro-p-acyloxybenzyl carbamate, p- (dihydroxyboryl)benzyl carbamate, 5-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, FH12897804.1OTQ-00725 o-(N,N-dimethylcarboxamido )benzyl carbamate, 1,1-dimethyl-3-(N,N- dimethylcarboxamido)propyl carbamate, 1,1-dimethylpropynyl carbamate, di(2-pyridyl)methyl carbamate, 2-furanylmethyl carbamate, 2-iodoethyl carbamate, isobornyl carbamate, isobutyl carbamate, isonicotinyl carbamate, p-(p'-methoxyphenylazo )benzyl carbamate, 1- methylcyclobutyl carbamate, 1-methylcyclohexyl carbamate, 1-methyl-1-cyclopropylmethyl carbamate, 1-methyl-1-(3,5- dimethoxyphenyl)ethyl carbamate, 1-methyl-1-(p- phenylazophenyl)ethyl carbamate, 1-methyl-1-phenylethyl carbamate, 1-methyl-1-(4- pyridyl)ethyl carbamate, phenyl carbamate, p-(phenylazo)benzyl carbamate, 2,4,6-tri-t- butylphenyl carbamate, 4-(trimethylammonium)benzyl carbamate, and 2,4,6-trimethylbenzyl carbamate.

[0079] 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- anthracenesulfonamide, 4-(4',8'-dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS ), benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide.

[0080] Other nitrogen protecting groups include, but are not limited to, phenothiazinyl- (10)-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-1,1,4,4-tetramethyldisilylazacyclopentane adduct (STABASE), 5- substituted 1,3-dimethyl-1,3,5-triazacyclohexan- 2-one, 5-substituted 1,3-dibenzyl-1,3,5- triazacyclohexan-2-one, 1-substituted 3,5-dinitro-4-pyridone, N-methylamine, N-allylamine, N- [2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine, N-(1-isopropyl-4- nitro-2-oxo-3-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- FH12897804.1OTQ-00725 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-1- 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- trichloroethyloxycarbonyl (Troc), triphenylmethyl (Tr), tosyl (Ts), brosyl (Bs), nosyl (Ns), mesyl (Ms), triflyl (Tf), or dansyl (Ds).

[0081] 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, -Raa, -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.

[0082] Exemplary oxygen protecting groups include, but are not limited to, methyl, methoxylmethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl, FH12897804.1OTQ-00725 (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-methoxycyclohexyl, 4-methoxytetrahydropyranyl (MTHP), 4- methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranyl S,S-dioxide, 1-[(2-chloro-4- methyl)phenyl]-4-methoxypiperidin-4-yl (CTMP), 1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl, 2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl, 1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl, 1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl, 2,2,2-trichloroethyl, 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, α- naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl, tri(p-methoxyphenyl)methyl, 4-(4'-bromophenacyloxyphenyl)diphenylmethyl, 4,4',4"-tris(4,5- dichlorophthalimidophenyl)methyl, 4,4',4"-tris(levulinoyloxyphenyl)methyl, 4,4',4"- tris(benzoyloxyphenyl)methyl, 3-(imidazol-1-yl)bis(4',4"-dimethoxyphenyl)methyl, 1,1-bis(4- methoxyphenyl)-1'-pyrenylmethyl, 9-anthryl, 9-(9-phenyl)xanthenyl, 9-(9-phenyl-10- oxo)anthryl, 1,3-benzodithiolan-2-yl, benzisothiazolyl S,S- 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 FH12897804.1OTQ-00725 (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-1-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-(1,1,3,3-tetramethylbutyl)phenoxyacetate, 2,4-bis( 1,1- dimethylpropyl)phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinoate, (E)-2- methyl-2-butenoate, o-(methoxyacyl)benzoate, α-naphthoate, nitrate, alkyl N,N,N',N'- tetramethylphosphorodiamidate, alkyl N-phenylcarbamate, borate, dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulfenate, sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate (Ts). 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- trichloroethyl 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).

[0083] 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, -Raa, -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. FH12897804.1OTQ-00725 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.

[0084] A "counterion" as used herein can be an anionic counterion or a cationic counterion.

[0085] 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–, ClO4–, 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–, Al(OC(CF3)3)4–, and carborane anions (e.g., CB11H12–or (HCB11Me5Br6)–). 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, succinate, glutarate, adipate, pimelate, suberate, azelate, sebacate, salicylate, phthalates, aspartate, glutamate, and the like), and carboranes.

[0086] 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 NH4+, NH3(C1-6alkyl)+, NH2(C1-6alkyl)2+, NH (C1-6alkyl)3+, and N+(C1–6alkyl)4cations, where the C1-6alkyl 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. FH12897804.1OTQ-00725 Formulation and Administration

[0087] Another embodiment of the invention is a composition comprising a compound of the disclosure (e.g, a compound represented by structural formula (I) or (II) 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.

[0088] 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.

[0089] As used herein, an amount of a compound described herein (e.g., a compound represented by structural formula (I) or (II) or a pharmaceutically acceptable salt thereof) that is effective to treat a disorder, or a “therapeutically effective amount” refers to an amount of the 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.

[0090] 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.

[0091] 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 FH12897804.1OTQ-00725 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.

[0092] 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).

[0093] “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 Biologics standards.

[0094] 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.

[0095] Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, FH12897804.1OTQ-00725 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.

[0096] 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-hydroxyethanesulfonic acid. Either 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.

[0097] 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.

[0098] 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 FH12897804.1OTQ-00725 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.

[0099] 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.

[0100] Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(C1–4 alkyl)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.

[0101] 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- FH12897804.1OTQ-00725 based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.

[0102] 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.

[0103] 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.

[0104] 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 and combined with emulsifying and / or suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.

[0105] In some embodiments, an oral formulation is formulated for immediate release or sustained / delayed release.

[0106] 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, FH12897804.1OTQ-00725 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.

[0107] 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.

[0108] 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.

[0109] 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 disclosure 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.

[0110] 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.

[0111] In another embodiment, a compound of the disclosure can be provided in an extended (or “delayed” or “sustained”) release composition. This delayed-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 FH12897804.1OTQ-00725 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.

[0112] 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.

[0113] Alternatively, pharmaceutically acceptable compositions of this disclosure can be administered in the form of suppositories for rectal administration. These can be prepared by 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.

[0114] 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.

[0115] 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. FH12897804.1OTQ-00725

[0116] 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.

[0117] 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.

[0118] 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.

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

[0120] In some embodiments, pharmaceutically acceptable compositions of this disclosure are formulated for intravenous administration. FH12897804.1OTQ-00725

[0121] In some embodiments, pharmaceutically acceptable compositions of this disclosure are formulated for topical administration.

[0122] 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.

[0123] 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.

[0124] 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-α-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, 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 α-, β-, and γ-cyclodextrin, or chemically modified derivatives such as hydroxyalkylcyclodextrins, including 2- and 3- hydroxypropyl- β-cyclodextrins, or other solubilized derivatives can also be advantageously used to enhance delivery of compounds described herein.

[0125] The pharmaceutical compositions of this disclosure are preferably administered by oral administration or by injection. The pharmaceutical compositions of this disclosure can FH12897804.1OTQ-00725 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.

[0126] 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 used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms can also be used for the purposes of formulation.

[0127] 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. FH12897804.1OTQ-00725

[0128] 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.

[0129] 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.

[0130] 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 long- term basis upon recurrence of disease symptoms. Uses of Compounds and Pharmaceutically Acceptable Compositions As 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 FH12897804.1OTQ-00725 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.

[0131] 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.

[0132] 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 therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition described herein, wherein the disease or disorder is selected from inflammatory diseases, autoimmune diseases, granulomatous diseases, cancer and neurodegenerative diseases.

[0133] 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 therapeutically effective amount of a compound of the present disclosure (e.g., a compound represented by structural formula (I) or (II) or a pharmaceutically acceptable salt thereof), or pharmaceutically acceptable salt or composition thereof. FH12897804.1OTQ-00725

[0134] 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.

[0135] 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.

[0136] 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, spondyloarthritis, ankylosing spondylitis, pemphigus vulgaris, idiopathic plasmacytic lymphadenopathy, atherosclerosis, myocardial infarction, thrombosis, -synucleinopathy, Parkinson’s disease, dementia with Lewy body, multiple system atrophy, Alzheimer’s disease, amyotrophic lateral sclerosis, and chronic obstructive pulmonary disease.

[0137] 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).

[0138] 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.

[0139] In another embodiment, the disease or disorder is a neurodegenerative 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. FH12897804.1OTQ-00725

[0140] 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)

[0141] 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.

[0142] The compounds of this disclosure (e.g., a compound represented by structural formula (I) or (II) 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 disease or disorder, for example, the inflammatory diseases, autoimmune diseases, granulomatous diseases, cancers and neurodegenerative diseases described herein.

[0143] The compounds of the disclosure (e.g., a compound represented by structural formula (I) or (II) 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. FH12897804.1OTQ-00725

[0144] 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.

[0145] 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.

[0146] In a particular embodiment, the invention relates to a method of treating a subject suffering from Ulcerative Colitis (e.g., moderately or severely active Ulcerative Colitis) as described herein comprising administering to the subject an effective amount a compound disclosed herein or a pharmaceutically acceptable salt thereof and optionally an anti- inflammatory agent and / or an anti-TNF agent. In a particular aspect, the anti-inflammatory agent is an anti-integrin agent (e.g., vedolizumab (Entyvio®)).

[0147] 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.

[0148] Suitable anti-inflammatory / autoimmune agents include 5-aminosalicyclic acid an dmesalamine 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 biologics such as anti-IL6R mAbs (Actemra® (tocilizumab)), anti-IL6 biologics, anti-IL I (anakinra (Kineret®), canakinumab (Ilaris®), rilonacept (Arcalyst®)), anti-IL12 or / and IL23 biologics (ustekinumab (Stelara®)), anti-IL17 biologics (secukinumab), anti-CD22 (epratuzumab), anti-integrin agents (natalizumab (Tysabri®)), vedolizumab (Entyvio®), anti-IFN-α (sifalimumab), anti-CD20 mAbs (rituximab (Rituxan®) and ofatumumab (Arzerra®)), and other agents, such as abatacept FH12897804.1OTQ-00725 (Orencia®), anakinra (Kineret®), canakinumab (Ilaris®), rilonacept (Arcalyst®), secukinumab, epratuzumab, sifalimumab, and belimumab (Benlysta®), CD4 biologics and other cytokine inhibitors or biologics to T-cell or B-cell receptors or interleukins.

[0149] Examples of suitable anti-TNF agents include the anti-TNF biologics such as Enbrel® (etanecerpt), Humira® (adalimumab), Remicade® (infliximab), Cimzia® (certolizumab), and Simponi® (golimumab).

[0150] In some embodiments, the anti-inflammatory / autoimmune agent is an aminosalicylate. Examples of aminosalicylates include mesalamine (Apriso®, Asacol HD®, Canasa®, Delzicol®, Lialda®, Pentasa®, Rowasa®), balsalazide (Colazal®), olsalazine (Dipentum®), and sulfasalazine (Azulfidine®). In some embodiments, the JAK inhibitors is selected from tofacitinib (Xeljan®) and upadacitinib (Rinvoq®).

[0151] 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.

[0152] 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. FH12897804.1OTQ-00725

[0153] 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.

[0154] 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.

[0155] 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.

[0156] 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.

[0157] In some embodiments, the present disclosure relates to a compound selected from the compounds in Table 1 or a pharmaceutically acceptable salt thereof. Table 1. FH12897804.1OTQ-00725FH12897804.1OTQ-00725FH12897804.1OTQ-00725FH12897804.1OTQ-00725FH12897804.1OTQ-00725FH12897804.1OTQ-00725FH12897804.1OTQ-00725FH12897804.1OTQ-00725FH12897804.1OTQ-00725FH12897804.1OTQ-00725FH12897804.1OTQ-00725FH12897804.1OTQ-00725FH12897804.1OTQ-00725FH12897804.1OTQ-00725FH12897804.1OTQ-00725FH12897804.1OTQ-00725FH12897804.1OTQ-00725FH12897804.1OTQ-00725FH12897804.1OTQ-00725FH12897804.1OTQ-00725FH12897804.1OTQ-00725FH12897804.1OTQ-00725FH12897804.1OTQ-00725FH12897804.1OTQ-00725FH12897804.1OTQ-00725FH12897804.1OTQ-00725FH12897804.1OTQ-00725FH12897804.1OTQ-00725FH12897804.1OTQ-00725FH12897804.1OTQ-00725FH12897804.1OTQ-00725FH12897804.1OTQ-00725FH12897804.1OTQ-00725FH12897804.1OTQ-00725FH12897804.1OTQ-00725FH12897804.1OTQ-00725 - 146 -FH12897804.1OTQ-00725FH12897804.1OTQ-00725FH12897804.1OTQ-00725FH12897804.1OTQ-00725FH12897804.1OTQ-00725FH12897804.1OTQ-00725FH12897804.1OTQ-00725FH12897804.1OTQ-00725FH12897804.1OTQ-00725FH12897804.1OTQ-00725FH12897804.1OTQ-00725FH12897804.1OTQ-00725FH12897804.1OTQ-00725

[0158] In some embodiments, the present disclosure relates to a compound represented by structural formula (I) or a pharmaceutically acceptable salt thereof:wherein: Y is CH or N; R1ais C1-3alkyl; R1band R1cis each independently H or halogen; R2is selected from -S(=O)2R3, -NHC(=O)R4, -NHS(=O)2R5, -N=S(=O)R6R7, -S(=O)(=NH)R8, - P(=O)R9R10, -C(=O)NHR11, -S(=O)2(NHR12), and -C1-3alkylene-S(=O)2R13; R3is selected from C1-3alkyl, C6-12aryl, 5- to 12-membered heteroaryl, and 4- to 10-membered heterocyclyl, wherein the C1-3alkyl is substituted with 1 to 3 substituents independently FH12897804.1OTQ-00725 selected from halogen, C(=O)NR21R22, C6-12 aryl, and 5- to 12-membered heteroaryl; and wherein the 4- to 10-membered heterocyclyl is substituted with 2 to 3 substituents independently selected from C1-3alkyl, halogen, and 4- to 10-membered heterocyclyl; R4is selected from C1-6alkyl, C1-6haloalkyl, and C3-6cycloalkyl; R5is selected from C2-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C6-12aryl, and 5- to 12-membered heteroaryl; R6and R9is C1-3alkyl; R7is C1-3alkyl or C6-12aryl; R8and R11is selected from C1-3alkyl, C6-12aryl, and 5- to 12-membered heteroaryl, wherein the C1-3alkyl is substituted with 1 to 3 substituents independently selected from C6-12aryl and 5- to 12-membered heteroaryl; and R10, R12, and R13is C6-12aryl or 5- to 12-membered heteroaryl; wherein each C1-3alkyl, C1-6alkyl, C2-6alkyl, C6-12aryl, C1-6haloalkyl, C3-6cycloalkyl, 4- to 10- membered heterocyclyl, and 5- to 12-membered heteroaryl is optionally, unless indicated otherwise, substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, C(=O)NR21R22, NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, C1-6alkyl, C1-6deuteroalkyl, C3-8cycloalkyl, C2-6alkenyl, halo(C1-6)alkyl, C1-3alkylsulfonylaminoalkyl, hydroxy(C1-6)alkyl, amino(C1-6)alkyl, (C1-6) alkylamino(C1-6)alkyl, cyano(C1-6)alkyl, C1-3alkylcarbonylamino(C1-6)alkyl, C1-3alkoxy, halo(C1-3)alkoxy, C1-6alkoxy(C1-3)alkyl, C6-12aryl, 4- to 10-membered heterocyclyl, and 5- to 12-membered heteroaryl, whereinalkyl; R16and R17is each independently selected from H, C1-6alkyl, hydroxy(C1-6)alkyl, and halo(C1-6)alkyl; R19and R23is each independently C1-6alkyl or halo(C1-6)alkyl; R21, R22, R25and R26is each independently selected from H, C1-6alkyl, C1-3alkoxy(C1-6)alkyl, hydroxy(C1-6)alkyl, cyano(C1-6)alkyl, amino(C1-6)alkyl, C1-3alkylamino(C1-6)alkyl, and di(C1-3)alkylamino(C1-6)alkyl; or FH12897804.1OTQ-00725 R21and R22or R25and R26, together with the nitrogen to which they are attached, form a 3-8 membered ring optionally substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, C(=O)NR21R22, NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, C1-6alkyl, C3-8cycloalkyl, C2-6alkenyl, halo(C1-6)alkyl, C1-3alkylsulfonylaminoalkyl, hydroxy(C1-6)alkyl, amino(C1-6)alkyl, cyano(C1-6)alkyl, C1-3alkylcarbonylamino(C1-6)alkyl, C1-3alkoxy, halo(C1-3)alkoxy, C1-6alkoxy(C1-3)alkyl, C6-12aryl, 4- to 10- membered heterocyclyl, and 5- to 12-membered heteroaryl.

[0159] In some embodiments, Y is CH. In some embodiments, Y is N.

[0160] In some embodiments, R1ais methyl.

[0161] In some embodiments, R1bis H. In some embodiments, R1bis F. In some embodiments, R1bis Cl.

[0162] In some embodiments, R1cis H. In some embodiments, R1cis F.

[0163] In some embodiments, the compound is represented by structural formula (Ia):

[0164] In some embodiments, R3is C6-12aryl.

[0165] In some embodiments, R3is 5- to 12-membered heteroaryl.

[0166] In some embodiments, R3is C1-3alkyl substituted with 1 to 3 substituents independently selected from halogen, C(=O)NR21R22, C6-12aryl, and 5- to 12-membered heteroaryl. For example, in some embodiments, R3is C1-3alkyl substituted with 1 substituent independently selected from halogen, C(=O)NR21R22, C6-12aryl, and 5- to 12-membered heteroaryl. In some embodiments, R3is C1alkyl substituted with C6-12aryl. In some embodiments, R3is C1alkyl substituted with 5- to 12-membered heteroaryl. FH12897804.1OTQ-00725

[0167] In some embodiments, R3is 5- to 7-membered heterocyclyl substituted with 2 substituents independently selected from C1-3alkyl, halogen, and 4- to 10-membered heterocyclyl.

[0168] In some embodiments, the compound is represented by structural formula (Ib):

[0169] In some embodiments, R4is C1-3alkyl. For example, R4is methyl.

[0170] In some embodiments, R4is C1-6haloalkyl.

[0171] In some embodiments, R4is C3-6cycloalkyl.

[0172] In some embodiments, the compound is represented by structural formula (Ic):

[0173] In some embodiments, R5is C2-6alkyl.

[0174] In some embodiments, R5is C1-6haloalkyl.

[0175] In some embodiments, R5is C3-6cycloalkyl.

[0176] In some embodiments, R5is C6-12aryl.

[0177] In some embodiments, R5is 5- to 12-membered heteroaryl.

[0178] In some embodiments, the compound is represented by structural formula (Id): FH12897804.1OTQ-00725

[0179] In some embodiments, R7is C1-3alkyl.

[0180] In some embodiments, R7is C6-12aryl.

[0181] In some embodiments, the compound is represented by structural formula (Ie):

[0182] In some embodiments, R8is C6-12aryl.

[0183] In some embodiments, R8is 5- to 12-membered heteroaryl.

[0184] In some embodiments, R8is C1-3alkyl substituted with a substituent selected from C6-12aryl and 5- to 12-membered heteroaryl.

[0185] In some embodiments, the compound is represented by structural formula (If):

[0186] In some embodiments, R10is C6-12aryl.

[0187] In some embodiments, R10is phenyl and R9is methyl.

[0188] In some embodiments, the compound is represented by structural formula (Ig): FH12897804.1OTQ-00725

[0189] In some embodiments, R11is C6-12aryl.

[0190] In some embodiments, R11is 5- to 12-membered heteroaryl.

[0191] In some embodiments, R11is C1-3alkyl substituted with a substituent selected from C6-12 aryl and 5- to 12-membered heteroaryl.

[0192] In some embodiments, the compound is represented by structural formula (Ih):

[0193] In some embodiments, R12is C6-12aryl.

[0194] In some embodiments, R12is 5- to 12-membered heteroaryl.

[0195] In some embodiments, the compound is represented by structural formula (Ii):wherein n is 1, 2, or 3.

[0196] In some embodiments, R13is C6-12aryl.

[0197] In some embodiments, R13is 5- to 12-membered heteroaryl.

[0198] In some embodiments, n is 1. FH12897804.1OTQ-00725

[0199] In some embodiments, the compound is represented by one of the following structural formulas: , ,, FH12897804.1OTQ-00725 - 166 - , , ,, FH12897804.1OTQ-00725 - 167 - , , ,, FH12897804.1OTQ-00725 - 168 - , , ,, FH12897804.1OTQ-00725 1 , , ,, FH12897804.1OTQ-00725 , , ,, FH12897804.1OTQ-00725 , , ,, FH12897804.1OTQ-00725 , , ,, FH12897804.1OTQ-00725 173 , , ,, FH12897804.1OTQ-00725 , , ,, FH12897804.1OTQ-00725 , , ,,FH12897804.1OTQ-00725 , , ,,FH12897804.1OTQ-00725 - 177 - , , , ,FH12897804.1OTQ-00725 , , ,, FH12897804.1OTQ-00725 , , ,, FH12897804.1OTQ-00725 , , ,, FH12897804.1OTQ-00725 , , ,, FH12897804.1OTQ-00725 , , ,, FH12897804.1OTQ-00725 , , ,,FH12897804.1OTQ-00725 , , ,,FH12897804.1OTQ-00725 , , ,,FH12897804.1OTQ-00725 , , ,, FH12897804.1OTQ-00725 , , ,, FH12897804.1OTQ-00725 , , ,, FH12897804.1OTQ-00725 - 189 -FH12897804.1OTQ-00725 , , ,,FH12897804.1OTQ-00725 , , ,,FH12897804.1OTQ-00725 , , ,,FH12897804.1OTQ-00725 , , ,,FH12897804.1OTQ-00725 , , ,,FH12897804.1OTQ-00725 , , ,, FH12897804.1OTQ-00725 , , ,, FH12897804.1OTQ-00725 , , ,, FH12897804.1OTQ-00725 , , ,, FH12897804.1OTQ-00725 - 199 -, , , FH12897804.1OTQ-00725 , , ,,FH12897804.1OTQ-00725 , , ,,FH12897804.1OTQ-00725 , , ,,FH12897804.1OTQ-00725 , , ,, FH12897804.1OTQ-00725 , , ,,FH12897804.1OTQ-00725 , , ,,FH12897804.1OTQ-00725 , , ,,FH12897804.1OTQ-00725 , , ,,FH12897804.1OTQ-00725 , , ,,FH12897804.1OTQ-00725 , , ,, FH12897804.1OTQ-00725 , , ,, or is a pharmaceutically acceptable salt thereof. FH12897804.1OTQ-00725

[0200] In some embodiments, the present disclosure relates to a compound represented by structural formula (II) or a pharmaceutically acceptable salt thereof:wherein: R1ais C1-3alkyl; R1bis H or halogen; and G is a 4- to 10-membered heterocyclyl, wherein each C1-3alkyl and 4- to 10-membered heterocyclyl is optionally substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, C(=O)NR21R22, NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, C1-6alkyl, C1-6deuteroalkyl, C3-8cycloalkyl, C2-6alkenyl, halo(C1-6)alkyl, C1-3alkylsulfonylaminoalkyl, hydroxy(C1-6)alkyl, amino(C1-6)alkyl, (C1-6) alkylamino(C1-6)alkyl, cyano(C1-6)alkyl, C1-3alkylcarbonylamino(C1-6)alkyl, C1-3alkoxy, halo(C1-3)alkoxy, C1-6alkoxy(C1-3)alkyl, C6-12aryl, 4- to 8-membered heterocyclyl, and 5- to 12-membered heteroaryl, whereinalkyl; R16and R17are each independently selected from H, C1-6alkyl, hydroxy(C1-6)alkyl, and halo(C1-6)alkyl; R19and R23are each independently C1-6alkyl or halo(C1-6)alkyl; R21, R22, R25and R26are each independently selected from H, C1-6alkyl, C1-3alkoxy(C1-6)alkyl, hydroxy(C1-6)alkyl, cyano(C1-6)alkyl, amino(C1-6)alkyl, C1-3alkylamino(C1-6)alkyl, and di(C1-3)alkylamino(C1-6)alkyl; or R21and R22or R25and R26, together with the nitrogen to which they are attached, form a 3-8 membered ring optionally substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, C(=O)NR21R22, NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, FH12897804.1OTQ-00725 C1-6 alkyl, C3-8 cycloalkyl, C2-6 alkenyl, halo(C1-6)alkyl, C1-3 alkylsulfonylaminoalkyl, hydroxy(C1-6)alkyl, amino(C1-6)alkyl, cyano(C1-6)alkyl, C1-3alkylcarbonylamino(C1-6)alkyl, C1-3alkoxy, halo(C1-3)alkoxy, C1-6alkoxy(C1-3)alkyl, C6-12aryl, 4- to 10- membered heterocyclyl, and 5- to 12-membered heteroaryl.

[0201] In some embodiments, R1ais methyl.

[0202] In some embodiments, R1bis H. In some embodiments, R1bis F.

[0203] In some embodiments, G comprises N. In some embodiments, G comprises S.

[0204] In some embodiments, G is substituted with 1 or 2 oxo substituents.

[0205] In some embodiments, the compound is represented by structural formula (IIa) or is a pharmaceutically acceptable salt thereof:wherein RNis H or C1-3 alkyl; and n is 1, 2, or 3.

[0206] In some embodiments, n is 1. In some embodiments, n is 2.

[0207] In some embodiments, RNis H. In some embodiments, RNis C1-3alkyl.In some embodiments, the compound is represented by structural formula (IIb) or is a pharmaceutically acceptable salt thereof:(IIb), FH12897804.1OTQ-00725 wherein m is 0, 1, or 2; and k is 1, 2, or 3.

[0208] In some embodiments, m is 0 or 1.

[0209] In some embodiments, wherein k is 1 or 2.

[0210] In some embodiments, the compound is represented by one of the following structural formulas:, or is a pharmaceutically acceptable salt thereof.

[0211] In some embodiments, the present disclosure relates to a compound represented by one of the following structural formulas or a pharmaceutically acceptable salt thereof: FH12897804.1OTQ-00725 ,,,, FH12897804.1OTQ-00725 - 215 - , ,,, FH12897804.1OTQ-00725 - 216 - , , 3N6O3 ,, FH12897804.1OTQ-00725 , ,,, FH12897804.1OTQ-00725 218 , ,,, FH12897804.1OTQ-00725 , ,,, FH12897804.1OTQ-00725 , ,,, FH12897804.1OTQ-00725 , ,,, FH12897804.1OTQ-00725 - 222 -, FH12897804.1OTQ-00725 ,,,,FH12897804.1OTQ-00725 , , ,,FH12897804.1OTQ-00725 , ,,, FH12897804.1OTQ-00725 22 , ,,, FH12897804.1OTQ-00725 ,,,,FH12897804.1OTQ-00725 ,,,,FH12897804.1OTQ-00725 , ,,, FH12897804.1OTQ-00725 ,,,,FH12897804.1OTQ-00725 21 ,,,, FH12897804.1OTQ-00725 232 , , ,,FH12897804.1OTQ-00725 , , ,, FH12897804.1OTQ-00725 , ,,, FH12897804.1OTQ-00725 ,,,,FH12897804.1OTQ-00725 ,,,,FH12897804.1OTQ-00725 2 , , ,,FH12897804.1OTQ-00725 , ,,, FH12897804.1OTQ-00725 ,,,, FH12897804.1OTQ-00725 , ,,, FH12897804.1OTQ-00725 , , ,, FH12897804.1OTQ-00725 , , ,, FH12897804.1OTQ-00725 , ,,, FH12897804.1OTQ-00725 , ,,, FH12897804.1OTQ-00725 24, FH12897804.1OTQ-00725 - 246 -, FH12897804.1OTQ-00725 , , ,,FH12897804.1OTQ-00725 , ,,, FH12897804.1OTQ-00725 ,,,,FH12897804.1OTQ-00725 , , ,,FH12897804.1OTQ-00725 , ,,, FH12897804.1OTQ-00725 , , ,, FH12897804.1OTQ-00725 , ,,, FH12897804.1OTQ-00725 , ,,, FH12897804.1OTQ-00725 , ,,, FH12897804.1OTQ-00725 , ,,, FH12897804.1OTQ-00725 , ,,,FH12897804.1OTQ-00725 , ,,, FH12897804.1OTQ-00725 ,,,,FH12897804.1OTQ-00725 ,,,,FH12897804.1OTQ-00725 , ,,, FH12897804.1OTQ-00725 ,,,,FH12897804.1OTQ-00725 ,,,,FH12897804.1OTQ-00725 , ,,, FH12897804.1OTQ-00725 ,,,,FH12897804.1OTQ-00725 ,,,, FH12897804.1OTQ-00725 2 ,,,, FH12897804.1OTQ-00725 , ,,, FH12897804.1OTQ-00725 , , ,, FH12897804.1OTQ-00725 , , ,, or a pharmaceutically acceptable salt thereof. FH12897804.1OTQ-00725

[0212] In some embodiments, the compound is represented by one of the following structural formulas: , , ,, FH12897804.1OTQ-00725 272 , , , ,, FH12897804.1OTQ-00725 273 , , , ,, FH12897804.1OTQ-00725 274 , , , ,, FH12897804.1OTQ-00725 - 275 - , , , ,, FH12897804.1OTQ-00725 , , , ,, FH12897804.1OTQ-00725 - 277 - , , , ,, FH12897804.1OTQ-00725 , , ,,FH12897804.1OTQ-00725 2 , , ,, FH12897804.1OTQ-00725 280 , , , ,, FH12897804.1OTQ-00725 - 281 - , , , ,, FH12897804.1OTQ-00725 , , ,, FH12897804.1OTQ-00725 , ,,,,FH12897804.1OTQ-00725 , , ,, FH12897804.1OTQ-00725 285 , , , ,, FH12897804.1OTQ-00725 , , , ,, FH12897804.1OTQ-00725 , , , ,, FH12897804.1OTQ-00725 - 288 - , , ,, FH12897804.1OTQ-00725 , , , ,, FH12897804.1OTQ-00725 290 , , , ,, FH12897804.1OTQ-00725 , , , ,,FH12897804.1OTQ-00725 , , , ,, FH12897804.1OTQ-00725 , , , ,, FH12897804.1OTQ-00725 , , ,, FH12897804.1OTQ-00725 , , , ,, FH12897804.1OTQ-00725 , , , ,, FH12897804.1OTQ-00725 , , , ,, FH12897804.1OTQ-00725 2 , , , ,, FH12897804.1OTQ-00725 2 , , , ,, FH12897804.1OTQ-00725 , , ,, FH12897804.1OTQ-00725 ,,or is a pharmaceutically acceptable salt thereof.

[0213] In some embodiments, the compound is represented by one of the following structural formulas:, FH12897804.1OTQ-00725 - 302 - , , ,, FH12897804.1OTQ-00725 , , ,, FH12897804.1OTQ-00725 4 , , ,, FH12897804.1OTQ-00725 , , ,, FH12897804.1OTQ-00725 , , ,, FH12897804.1OTQ-00725 , ,,FH12897804.1OTQ-00725 , , ,,FH12897804.1OTQ-00725 , , ,,FH12897804.1OTQ-00725 , , ,, FH12897804.1OTQ-00725 , , ,, FH12897804.1OTQ-00725 , , ,,FH12897804.1OTQ-00725 , , ,, FH12897804.1OTQ-00725 , , ,, FH12897804.1OTQ-00725 , , ,, FH12897804.1OTQ-00725 , , ,, FH12897804.1OTQ-00725 , , ,, FH12897804.1OTQ-00725 ,, or is a pharmaceutically acceptable salt thereof.

[0214] In some embodiments, the compound is represented by one of the following structural formulas:, FH12897804.1OTQ-00725 1 , , ,,FH12897804.1OTQ-00725 , , ,, FH12897804.1OTQ-00725 , , ,,FH12897804.1OTQ-00725 , , ,, FH12897804.1OTQ-00725 ,, or is a pharmaceutically acceptable salt thereof. FH12897804.1OTQ-00725

[0215] 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 (II) or a pharmaceutically acceptable salt thereof) and a pharmaceutically acceptable excipient.

[0216] In some embodiments, the present disclosure relates to method of treating a disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of 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.

[0217] 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, inflammatory 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 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, spondyloarthritis, ankylosing spondylitis, pemphigus vulgaris, idiopathic plasmacytic lymphadenopathy, atherosclerosis, myocardial infarction, thrombosis, - 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. FH12897804.1OTQ-00725

[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, corticobasal 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 a particular aspect, the second agent is anti- TNF agent. In some embodiments, the second agent is selected from anti-TNF agent, anti-IL-23 agent, anti-TL1a antibody (e.g., tulisokibart), a small molecule targeting TL1a, anti-integrin agent, and JAK inhibitor. 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. In some embodiments, the JAK inhibitors is selected from tofacitinib and upadacitinib.

[0224] In some embodiments, the second agent is selected from infliximab (Remicade®), adalimumab (Humira®), golimumab (Simponi®), vedolizumab (Entyvio®), ustekinumab (Stelara®), and mirikizumab (Omvoh®). In some embodiments, the second agent is vedolizumab. FH12897804.1OTQ-00725

[0225] In some embodiments, the second agent is sphingosine 1-phosphate (S1P) receptor modulator. In some embodiments, the second agent is ozanimod (Zeposia®).

[0226] In some embodiments, the second agent is selected from mesalamine, balsalazide, olsalazine, and sulfasalazine.

[0227] 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.

[0228] In some embodiments, the second agent and the compound are administered separately. In a particlur aspect, the second agent and the compound are administered separately at different times. In a particlur aspect, the second agent and the compound are administered separately at the same time.

[0229] 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 therapeutically effective amount of a compound described herein (e.g., a compound represented by structural formula (I) or (II) 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.

[0230] 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 (II) 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).

[0231] 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 FH12897804.1OTQ-00725 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, spondyloarthritis, ankylosing spondylitis, pemphigus vulgaris, idiopathic plasmacytic lymphadenopathy, atherosclerosis, myocardial infarction, thrombosis, -synucleinopathy, Parkinson’s disease, dementia with Lewy body, multiple system atrophy, Alzheimer’s disease, amyotrophic lateral sclerosis, and chronic obstructive pulmonary disease.

[0232] 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.

[0233] 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.

[0234] 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.

[0235] 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. FH12897804.1OTQ-00725

[0236] In some embodiments, the present disclosure relates to a compound described herein (e.g., a compound represented by structural formula (I) or (II) 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).

[0237] 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, spondyloarthritis, ankylosing spondylitis, pemphigus vulgaris, idiopathic plasmacytic lymphadenopathy, atherosclerosis, myocardial infarction, thrombosis, -synucleinopathy, Parkinson’s disease, dementia with Lewy body, multiple system atrophy, Alzheimer’s disease, amyotrophic lateral sclerosis, and chronic obstructive pulmonary disease.

[0238] 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.

[0239] 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.

[0240] 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 FH12897804.1OTQ-00725 cancer, colorectal cancer, head and neck cancer, melanoma, pancreatic cancer, prostate cancer, ovarian cancer, renal cancer, and lung cancer.

[0241] 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.

[0242] 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.

[0243] 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.

[0244] 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. In some embodiments, the second agent and the compound are administered separately. In a particlur aspect, the second agent and the compound are administered separately at different times. In a particlur aspect, the second agent and the compound are administered separately at the same time.

[0245] 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. FH12897804.1OTQ-00725 EXAMPLES

[0246] The following General Schemes depict synthetic sequences for Examples 1-36. General Scheme 1General Scheme 2General Scheme 3 FH12897804.1OTQ-00725General Scheme 5 FH12897804.1OTQ-00725General Scheme 7General Scheme 8 FH12897804.1OTQ-00725General Scheme 10 FH12897804.1OTQ-00725General Scheme 11General Scheme 12 FH12897804.1OTQ-00725General Scheme 15 FH12897804.1OTQ-00725General Scheme 17General Scheme 18 FH12897804.1OTQ-00725FH12897804.1OTQ-00725 Example 1 – Synthesis of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(4-((6- ((difluoromethyl)sulfonyl)quinolin-4-yl)oxy)-3-methylphenyl)acetamide (Compound 176); Prepared according to General Scheme 6Part I – Synthesis of S-(4-chloroquinolin-6-yl) ethanethioateA solution of 6-bromo-4-chloroquinoline (10.0 g, 41.2 mmol, 1.00 equiv.), potassium thioacetate (5.65 g, 49.5 mmol, 1.20 equiv.), tris(dibenzylideneacetone)dipalladium(0) (7.55 g, 8.25 mmol, 0.20 equiv.), Xantphos (4.77 g, 8.245 mmol, 0.20 equiv.), and triethylamine (12.5 g, 124 mmol, 3.00 equiv.) in 1,4-dioxane (200 mL) was heated to 80 °C for 3 h. Water was added and the product was extracted with EtOAc (3 x 100 mL). The combined organic phases were washed with brine (3 x 100 mL), dried over Na2SO4, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography (gradient of 0- 30% EtOAc in petroleum ether in 60 min). The title compound was obtained as a white solid (6.0 g, 61%). Part II – Synthesis of 4-chloro-6-((difluoromethyl)thio)quinolineFH12897804.1OTQ-00725 Potassium hydroxide (9.44 g, 168 mmol, 20.0 equiv.) was added to a solution of S-(4- chloroquinolin-6-yl) ethanethioate (2.00 g, 8.41 mmol, 1.00 equiv.) in ACN (8.8 mL) and water (3.0 mL) at 0 °C and the mixture was stirred at this temperature for 30 min. Subsequently, diethyl (bromodifluoromethyl)phosphonate (4.49 g, 16.8 mmol, 2.00 equiv.) was added dropwise and stirring was continued for another 30 min at 0 °C. The solution was filtered, and the product was extracted with EtOAc (3 x 50 mL). The combined organic phases were washed with brine (3 x 50 mL), dried over Na2SO4, 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 (0.1% formic acid), mobile phase B: ACN, gradient: 30- 70% B in 40 min; wavelength: 210 nm). The title compound was obtained as a brown solid (500 mg, 24%). Part III – Synthesis of 2-(4-hydroxy-3-methylphenyl)acetic acidA solution of methyl 2-(4-hydroxy-3-methylphenyl)acetate (28.4 g, 158 mmol, 1.00 equiv.) and lithium hydroxide (9.44 g, 394 mmol, 2.50 equiv.) in THF (200 mL) and water (100 mL) was stirred at room temperature for 2 h. Subsequently, water was added, and the aqueous solution was washed with DCM. The pH was adjusted to 1-2 and the product was extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2SO4, and the solvent was removed under reduced pressure. The intended product was obtained as a white solid (26.3 g, quantitative yield), which was used in the next reaction without further purification. Part IV – Synthesis of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(4-hydroxy-3- methylphenyl)acetamideFH12897804.1OTQ-00725 HATU (72.2 g, 190 mmol, 1.20 equiv.) was added to a solution of 2-(4-hydroxy-3- methylphenyl)acetic acid (26.3 g, 158 mmol, 1.00 equiv.), 1-tert-butylpyrazol-4-amine hydrochloride (30.6 g, 174 mmol, 1.10 equiv.), and DIPEA (82.7 mL, 474 mmol, 3.00 equiv.) in DMF (140 mL) and the mixture was stirred at room temperature for 2 h. Subsequently, water and EtOAc were added, and the organic phase was separated. The product was extracted with an aqueous NaOH solution. Subsequently, the pH was adjusted to 5-6 with HCl and the product was extracted with EtOAc. The organic phase was washed with brine, dried over Na2SO4, and the solvent was removed under reduced pressure. The residue was washed with EtOAc and dried under reduced pressure. The intended product was obtained as a white solid (27.1 g, 60%), which was used in the next reaction without further purification. Part V – Synthesis of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(4-((6- ((difluoromethyl)thio)quinolin-4-yl)oxy)-3-methylphenyl)acetamideA solution of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(4-hydroxy-3-methylphenyl)acetamide (643 mg, 2.24 mmol, 1.10 equiv.), 4-chloro-6-((difluoromethyl)thio)quinoline (500 mg, 2.04 mmol, 1.00 equiv.), DMAP (24.9 mg, 204 μmol, 0.10 equiv.), and K2CO3(563 mg, 4.07 mmol, 2.00 equiv.) in DMF (3.15 mL) was heated to 120 °C for 2 h. Subsequently, water was added, and the product was extracted with EtOAc (3 x 20 mL). The combined organic phases were washed with brine (3 x 10 mL), dried over Na2SO4, and the solvent was removed under reduced pressure. The title compound was obtained as a brown solid (1 g), which was used in the next reaction without further purification. Part VI – Synthesis of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(4-((6- ((difluoromethyl)sulfonyl)quinolin-4-yl)oxy)-3-methylphenyl)acetamide (Compound 176) FH12897804.1OTQ-00725A solution of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(4-((6-((difluoromethyl)thio)quinolin-4- yl)oxy)-3-methylphenyl)acetamide (500 mg, 1.01 mmol, 1.00 equiv.) and 3-chloroperbenzoic acid (348 mg, 2.01 mmol, 2.00 equiv.) in DCM (1.28 mL) was stirred at room temperature for 1 h. Subsequently, water was added, and the product was extracted with DCM (3 x 10 mL). The combined organic phases were washed with brine (3 x 10 mL), dried over Na2SO4, and the solvent was removed under reduced pressure. The crude product was purified by preparative HPLC (column: Xselect CSH C18 OBD, 30 × 150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3+ 0.05% ammonia solution), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 21-51% B in 10 min; wavelength: 220 nm; RT1: 7.9 min). The title compound was obtained as a light-yellow solid (42.4 mg, 7.8% over 2 steps). LCMS (ESI) calculated for C26H27F2N4O4S (M+H)+: 529.2, found: 529.3.1H NMR (400 MHz, DMSO-d6) 10.20 (bs, 1H), 8.83 – 8.77 (m, 2H), 8.50 (d, J = 7.0 Hz, 1H), 8.21 (dd, J = 9.1, 1.8 Hz, 1H), 7.94 (s, 1H), 7.45 (s, 1H), 7.39 – 7.08 (m, 4H), 6.51 (d, J = 6.9 Hz, 1H), 3.59 (s, 2H), 2.16 (s, 3H), 1.48 (s, 9H). Example 2 – Synthesis of 2-((4-(4-(2-((1-(tert-butyl)-1H-pyrazol-4-yl)amino)-2-oxoethyl)-2- methylphenoxy)quinolin-6-yl)sulfonyl)-2-methylpropanamide (Compound 2); Prepared according to General Scheme 5Part I – Synthesis of 2-((4-chloroquinolin-6-yl)thio)-2-methylpropanamide FH12897804.1OTQ-00725A solution of S-(4-chloroquinolin-6-yl) ethanethioate (2.00 g, 8.41 mmol, 1.00 equiv., which can be synthesized according to the synthesis described in Part I of Example 1), 2-bromo-2- methylpropanamide (6.98 g, 42.1 mmol, 5.00 equiv.), and K2CO3(2.33 g, 16.8 mmol, 2.0 equiv.) in DMF (40 mL) was stirred at room temperature overnight. Subsequently, water was added, and the product was extracted with EtOAc (3 x 50 mL). The combined organic phases were washed with brine (3 x 150 mL), dried over Na2SO4, 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: 40-70% B in 30 min; wavelength: 210 nm). The title compound was obtained as a brown solid (500 mg, 21%). Part II – Synthesis of 2-((4-(4-(2-((1-(tert-butyl)-1H-pyrazol-4-yl)amino)-2-oxoethyl)-2- methylphenoxy)quinolin-6-yl)thio)-2-methylpropanamideA solution of 2-((4-chloroquinolin-6-yl)thio)-2-methylpropanamide (480 mg, 1.71 mmol, 1.00 equiv.), N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(4-hydroxy-3-methylphenyl)acetamide (590 mg, 2.05 mmol, 1.20 equiv., can be synthesized according to the synthesis described in Part IV of Example 1), DMAP (20.9 mg, 171 μmol, 0.10 equiv.), and K2CO3(473 mg, 3.42 mmol, 2.00 equiv.) in DMF (9.6 mL) was heated to 120 °C overnight. Subsequently, the crude product was purified by reversed-phase flash chromatography (column: C18 silica gel; mobile phase A: FH12897804.1OTQ-00725 water (10 mmol / L NH4HCO3), mobile phase B: ACN, gradient: 20-50% B in 30 min; wavelength: 210 nm). The title compound was obtained as an orange solid (650 mg, 71%). Part III – Synthesis of 2-((4-(4-(2-((1-(tert-butyl)-1H-pyrazol-4-yl)amino)-2-oxoethyl)-2- methylphenoxy)quinolin-6-yl)sulfonyl)-2-methylpropanamide (Compound 2)Oxone (977 mg, 3.18 mmol, 2.60 equiv.) was added to a solution of 2-((4-(4-(2-((1-(tert-butyl)- 1H-pyrazol-4-yl)amino)-2-oxoethyl)-2-methylphenoxy)quinolin-6-yl)thio)-2- methylpropanamide (650 mg, 1.22 mmol, 1.00 equiv.) in THF (6.5 mL) and water (6.5 mL) and the mixture was stirred at room temperature for 90 min. 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: 30-60% B in 30 min; wavelength: 210 nm). The title compound was obtained as an off-white solid (268 mg, 39%). LCMS (ESI) calculated for C29H34N5O5S (M+H)+: 564.2, found: 564.2.1H NMR (400 MHz, DMSO-d6) 10.19 (s, 1H), 8.88 – 8.77 (m, 2H), 8.23 (d, J = 8.9 Hz, 1H), 8.10 – 8.06 (m, 1H), 7.95 (d, J = 1.8 Hz, 1H), 7.60 (s, 1H), 7.53 – 7.45 (m, 2H), 7.40 – 7.37 (m, 1H), 7.34 – 7.22 (m, 2H), 6.59 (dd, J = 5.2, 1.7 Hz, 1H), 3.62 (s, 2H), 2.13 (s, 3H), 1.54 (s, 6H), 1.49 (s, 9H). Example 3 – Synthesis of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(4-((6-((3-fluoro-1-(oxetan-3- yl)piperidin-4-yl)sulfonyl)quinolin-4-yl)oxy)-3-methylphenyl)acetamide (Compounds 187 and188 trans); Prepared according to General Scheme 5FH12897804.1OTQ-00725Part I – Synthesis of tert-butyl 3-fluoro-4-(tosyloxy)piperidine-1-carboxylatep-Toluenesulfonyl chloride (17.4 g, 91.2 mmol, 1.00 equiv.) was added to a solution of tert- butyl 3-fluoro-4-hydroxypiperidine-1-carboxylate (20.0 g, 91.2 mmol, 1.00 equiv.), DMAP (11.4 g, 91.2 mmol, 1.00 equiv.), and triethylamine (9.23 g, 91.2 mmol, 1.00 equiv.) in DCM (200 mL) at 0 °C. Subsequently, the mixture was stirred at room temperature for 2 h. Water was added, and the product was extracted with DCM (3 x 100 mL). The combined organic phases were washed with brine (100 mL), dried over Na2SO4, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography (33% EtOAc in petroleum ether). The title compound was obtained as a white solid (7 g, 21%). Part II – Synthesis of tert-butyl 4-(acetylthio)-3-fluoropiperidine-1-carboxylate (relative stereochemistry: trans)A solution of tert-butyl 3-fluoro-4-(tosyloxy)piperidine-1-carboxylate (7.00 g, 18.7 mmol, 1.00 equiv.) and potassium thioacetate (4.28 g, 37.5 mmol, 2.00 equiv.) in DMF was heated to 80 °C overnight. Subsequently, water was added, and the product was extracted with EtOAc (3 x 100 FH12897804.1OTQ-00725 mL). The combined organic phases were washed with brine (100 mL), dried over Na2SO4, and the solvent was removed under reduced pressure. The title compound was obtained as a brown oil (5.3 g, relative stereochemistry: trans), which was used in the next reaction without further purification. Part III – Synthesis of 2-(4-((6-bromoquinolin-4-yl)oxy)-3-methylphenyl)-N-(1-(tert-butyl)- 1H-pyrazol-4-yl)acetamideA solution of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(4-hydroxy-3-methylphenyl)acetamide (2.00 g, 6.96 mmol, 1.00 equiv., can be synthesized according to the synthesis described in Part IV of Example 1), 6-bromo-4-chloroquinoline (2.03 g, 8.35 mmol, 1.20 equiv.), copper(I) iodide (20 mg, 97 μmol, 0.014 equiv.), 2,2,6,6-tetramethylheptane-3,5-dione (20 mg, 97 μmol, 0.014 equiv.), and Cs2CO3(4.54 g, 13.9 mmol, 2.00 equiv.) in DMF (40 mL) was heated to 100 °C for 1 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 (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 brown solid (3.2 g, 93%). Part IV – Synthesis of tert-butyl 4-((4-(4-(2-((1-(tert-butyl)-1H-pyrazol-4-yl)amino)-2- oxoethyl)-2-methylphenoxy)quinolin-6-yl)thio)-3-fluoropiperidine-1-carboxylate (relative stereochemistry: trans) FH12897804.1OTQ-00725A solution of 2-(4-((6-bromoquinolin-4-yl)oxy)-3-methylphenyl)-N-(1-(tert-butyl)-1H-pyrazol- 4-yl)acetamide (2.00 g, 4.05 mmol, 1.00 equiv.), tert-butyl 4-(acetylthio)-3-fluoropiperidine-1- carboxylate (1.35 g, 4.86 mmol, 1.20 equiv., relative stereochemistry: trans), tris(dibenzylideneacetone)dipalladium(0) (740 mg, 811 μmol, 0.20 equiv.), Xantphos (470 mg, 811 μmol, 0.20 equiv.), and triethylamine (2.05 g, 20.3 mmol, 5.00 equiv.) in DMF (40 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: C18 silica gel; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN, gradient: 50-80% B in 30 min; wavelength: 210 nm). The title compound was obtained as a yellow solid (670 mg, 26%, relative stereochemistry: trans). Part V – Synthesis of tert-butyl 4-((4-(4-(2-((1-(tert-butyl)-1H-pyrazol-4-yl)amino)-2- oxoethyl)-2-methylphenoxy)quinolin-6-yl)sulfonyl)-3-fluoropiperidine-1-carboxylate (relative stereochemistry: trans)Oxone tetrabutylammonium salt (3.27 g, 2.01 mmol, 2.00 equiv.) was added to a solution of tert-butyl 4-((4-(4-(2-((1-(tert-butyl)-1H-pyrazol-4-yl)amino)-2-oxoethyl)-2- methylphenoxy)quinolin-6-yl)thio)-3-fluoropiperidine-1-carboxylate (650 mg, 1.00 mmol, 1.00 FH12897804.1OTQ-00725 equiv.) in THF (5.2 mL) and water (5.2 mL) and the mixture was stirred at room temperature for 1 h. Subsequently, the product was extracted with EtOAc (3 x 30 mL), and the combined organic phases were washed with brine (10 mL), dried over Na2SO4, and the solvent was removed under reduced pressure. The title compound was obtained as a yellow solid (734 mg, relative stereochemistry: trans), which was used in the next reaction without further purification. Part VI – Synthesis of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(4-((6-((3-fluoropiperidin-4- yl)sulfonyl)quinolin-4-yl)oxy)-3-methylphenyl)acetamide (relative stereochemistry: trans)A solution of tert-butyl 4-((4-(4-(2-((1-(tert-butyl)-1H-pyrazol-4-yl)amino)-2-oxoethyl)-2- methylphenoxy)quinolin-6-yl)sulfonyl)-3-fluoropiperidine-1-carboxylate (734 mg, 1.08 mmol, 1.00 equiv., relative stereochemistry: trans) in HCl in 1,4-dioxane (4.0 M, 14 mL) was stirred at room temperature for 1 h. Subsequently, the solvent was removed under reduced pressure. The title compound was obtained as a yellow solid (780 mg, relative stereochemistry: trans), which was used in the next reaction without further purification. Part VII – Synthesis of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(4-((6-((3-fluoro-1-(oxetan-3- yl)piperidin-4-yl)sulfonyl)quinolin-4-yl)oxy)-3-methylphenyl)acetamide (Compounds 187and 188 trans)FH12897804.1OTQ-00725A solution of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(4-((6-((3-fluoropiperidin-4- yl)sulfonyl)quinolin-4-yl)oxy)-3-methylphenyl)acetamide (370 mg, 638 μmol, 1.00 equiv.), 3- oxetanone (92.0 mg, 1.28 mmol, 2.00 equiv.), and acetic acid (57.5 mg, 957 μmol, 1.50 equiv.) in DMF (7 mL) was stirred at room temperature for 1 h. Subsequently, sodium triacetoxyborohydride (271 mg, 1.28 mmol, 2.00 equiv.) was added and the mixture was stirred at room temperature for another hour. Water was added and the product was extracted with EtOAc (3 x 30 mL). The combined organic phases were washed with brine (10 mL), dried over Na2SO4, 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: 20-50% B in 30 min; wavelength: 210 nm). The racemic title compound was obtained as a white solid (35 mg, 1.3% over 3 steps). The two enantiomers were separated by chiral chromatography (column: (S,S)-WHELK-O 1, 20 × 250 mm, 5 μm; mobile phase A: n-hexane (0.5% 2 M ammonia in MeOH), mobile phase B: MeOH / DCM (1:1), isocratic separation with 50% B). The title compounds (compound 187 (enantiomer 1): 8.5 mg, 0.3%; compound 188 (enantiomer 2): 9.0 mg, 0.3%) were obtained as white solids (retention time (enantiomer 1): 4.11 min, retention time (enantiomer 2): 4.54 min, column: (S,S)-WHELK-O 1, 20 × 250 mm, 5 μm, mobile phase A: n-hexane (0.5% 2 M ammonia in MeOH), mobile phase B: MeOH / DCM (1:1), isocratic separation with 50% B, flow rate: 1.0 mL / min, wavelength: 254 nm). LCMS (ESI) calculated for C33H39FN5O5S (M+H)+: 636.3, found: 636.4.1H NMR (400 MHz, DMSO-d6) 10.22 (s, 1H), 8.88 – 8.84 (m, 2H), 8.27 (d, J = 8.8 Hz, 1H), 8.17 (dd, J = 9.1, 2.1 Hz, 1H), 7.95 (s, 1H), 7.46 (s, 1H), 7.39 (s, 1H), 7.32 (d, J = 8.7 Hz, 1H), 7.25 (d, J = 8.2 Hz, 1H), 6.57 (d, J = 5.2 Hz, 1H), 5.20 (d, J = 48.6 Hz, 1H), 4.48 (t, J = 6.5 Hz, 2H), 4.38 (q, J = 6.6, 6.1 Hz, 1H), 4.30 (t, J = 6.1 Hz, 1H), 3.85 (d, J = 33.9 FH12897804.1OTQ-00725 Hz, 1H), 3.62 (s, 2H), 3.42 (q, J = 6.4 Hz, 1H), 2.98 (t, J = 11.9 Hz, 1H), 2.80 – 2.76 (m, 1H), 2.16 – 2.10 (m, 4H), 1.90 (d, J = 7.3 Hz, 3H), 1.49 (s, 9H). Example 4 – Preparation of Additional Sulfone Compounds Compounds in the table below were prepared based on experimental procedures described in Examples 1, 2, and 3 and the detailed description.FH12897804.1OTQ-00725FH12897804.1OTQ-00725FH12897804.1OTQ-00725FH12897804.1OTQ-00725 - 353 -FH12897804.1OTQ-00725FH12897804.1OTQ-00725FH12897804.1OTQ-00725 - 356 -FH12897804.1OTQ-00725FH12897804.1OTQ-00725FH12897804.1OTQ-00725FH12897804.1OTQ-00725 - 360 -FH12897804.1OTQ-00725 - 361 -FH12897804.1OTQ-00725 - 362 -FH12897804.1OTQ-00725FH12897804.1OTQ-00725FH12897804.1OTQ-00725FH12897804.1OTQ-00725 - 366 -FH12897804.1OTQ-00725 - 367 -FH12897804.1OTQ-00725FH12897804.1OTQ-00725 - 369 -FH12897804.1OTQ-00725FH12897804.1OTQ-00725 - 371 -FH12897804.1OTQ-00725FH12897804.1OTQ-00725FH12897804.1OTQ-00725FH12897804.1OTQ-00725FH12897804.1OTQ-00725FH12897804.1OTQ-00725FH12897804.1OTQ-00725FH12897804.1OTQ-00725FH12897804.1OTQ-00725FH12897804.1OTQ-00725FH12897804.1OTQ-00725FH12897804.1OTQ-00725FH12897804.1OTQ-00725FH12897804.1OTQ-00725FH12897804.1OTQ-00725FH12897804.1OTQ-00725FH12897804.1OTQ-00725 - 388 -FH12897804.1OTQ-00725FH12897804.1OTQ-00725FH12897804.1OTQ-00725 - 391 -FH12897804.1OTQ-00725FH12897804.1OTQ-00725FH12897804.1OTQ-00725Example 5 – Synthesis of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(4-((6- (cyclopropanesulfonimidoyl)quinolin-4-yl)oxy)-3-fluoro-5-methylphenyl)acetamide (Compounds 37 and 39); Prepared according to General Schemes 5 and 7 FH12897804.1OTQ-00725Part I – 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 mL) 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 Na2SO4, and the solvent was removed under reduced pressure. The title compound was obtained as a colorless liquid, which was used in the next reaction without further purification. Part II – Synthesis of sodium cyclopropanethiolateSodium 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 III – Synthesis of 4-chloro-6-(cyclopropylthio)quinoline FH12897804.1OTQ-00725A solution of 6-bromo-4-chloroquinoline (25.0 g, 103 mmol, 1.00 equiv.), sodium cyclopropanethiolate (11.9 g, 124 mmol, 1.20 equiv.), tris(dibenzylideneacetone)dipalladium(0) (18.9 g, 20.6 mmol, 0.20 equiv.), Xantphos (11.9 g, 20.6 mmol, 0.20 equiv.), and triethylamine (52.2 g, 515 mmol, 3.00 equiv.) in 1,4-dioxane (500 mL) was heated to 80 °C for 3 h under an inert atmosphere of nitrogen. Subsequently, the crude product was purified by column chromatography (50% EtOAc in petroleum ether). The title compound was obtained as a yellow solid (5.82 g, 24%).Part IV – Synthesis of (4-chloroquinolin-6-yl)(cyclopropyl)(imino)- 6-sulfanone(Diacetoxyiodo)benzene (1.23 g, 3.82 mmol, 3.00 equiv.) was added to a solution of 4-chloro-6- (cyclopropylthio)quinoline (300 mg, 1.27 mmol, 1.00 equiv.) in MeOH (6 mL) at room temperature. Subsequently, ammonium carbonate (367 mg, 3.812 mmol.3.00 equiv.) was added and the mixture was stirred at room temperature for 2 h. 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: 30-60% B in 30 min; wavelength: 210 nm). The racemic title compound was obtained as an orange solid (110 mg, 32%). Part V – Synthesis of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(4-((6- (cyclopropanesulfonimidoyl)quinolin-4-yl)oxy)-3-fluoro-5-methylphenyl)acetamide (Compounds 37 and 39) FH12897804.1OTQ-00725A solution of (4-chloroquinolin-6-yl)(cyclopropyl)(imino)- 6-sulfanone (110 mg, 412 μmol,1.00 equiv.), N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(3-fluoro-4-hydroxy-5- methylphenyl)acetamide (126 mg, 412 μmol, 1.00 equiv., can be synthesized according to the synthesis described in Part XII of Example 19), DMAP (5.0 mg, 41 μmol, 0.10 equiv.), and K2CO3 (114 mg, 824 μmol, 2.00 equiv.) in DMF (2.2 mL) was heated to 120 °C for 2 h. 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: 20-50% B in 30 min; wavelength: 210 nm). The racemic title compound was obtained as a white solid (70 mg, 32%). The two enantiomers were separated by chiral chromatography (column: CHIRALPAK IG, 20 × 250 mm, 5 μm; mobile phase A: EtOH, mobile phase B: MeOH / DCM (1:1), isocratic separation with 30% B). The title compounds (compound 37 (enantiomer 1): 21.4 mg, 31%; compound 39 (enantiomer 2): 22.3 mg, 32%) were obtained as white solids (retention time (enantiomer 1): 4.03 min, retention time (enantiomer 2): 6.45 min, column: CHIRALPAK IG-2, 4.6 × 50 mm, 3 μm, mobile phase A: n-hexane (0.2% DEA), mobile phase B: MeOH / DCM (1:1), isocratic separation with 30% B, flow rate: 1.0 mL / min, wavelength: 254 nm). LCMS (ESI) calculated for C28H31FN5O3S (M+H)+: 536.2, found: 536.2.1H NMR (400 MHz, DMSO-d6) 10.21 (s, 1H), 8.90 (d, J = 1.8 Hz, 1H), 8.83 (d, J = 5.3 Hz, 1H), 8.29 – 8.19 (m, 2H), 7.95 (s, 1H), 7.46 (s, 1H), 7.34 – 7.28 (m, 1H), 7.23 (s, 1H), 6.62 (dd, J = 5.3, 1.2 Hz, 1H), 4.55 (s, 1H), 3.65 (s, 2H), 2.86 (tt, J = 8.1, 4.7 Hz, 1H), 2.19 (s, 3H), 1.49 (s, 9H), 1.25 – 1.18 (m, 1H), 1.10 – 1.04 (m, 1H), 1.01 – 0.93 (m, 1H).Example 6 – Synthesis of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(4-((6-((dimethyl(oxo)- 6-sulfaneylidene)amino)quinolin-4-yl)oxy)-3-fluoro-5-methylphenyl)acetamide (Compound 60); Prepared according to General Scheme 15 FH12897804.1OTQ-00725Part I – Synthesis of 2-(4-((6-bromoquinolin-4-yl)oxy)-3-fluoro-5-methylphenyl)-N-(1-(tert- butyl)-1H-pyrazol-4-yl)acetamideA solution of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(3-fluoro-4-hydroxy-5- methylphenyl)acetamide (630 mg, 2.06 mmol, 1.00 equiv., can be synthesized according to the synthesis described in Part XII of Example 19), 6-bromo-4-chloroquinoline (500 mg, 2.06 mmol, 1.00 equiv.), copper(I) iodide (5.5 mg, 29 μmol, 0.014 equiv.), 2,2,6,6- tetramethylheptane-3,5-dione (5.3 mg, 29 μmol, 0.014 equiv.), and Cs2CO3(1.34 g, 4.12 mmol, 1.00 equiv.) in DMF (5 mL) was heated to 100 °C for 1 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: 50-80% B in 30 min; wavelength: 210 nm). The title compound was obtained as a brown solid (600 mg, 57%).Part II – Synthesis of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(4-((6-((dimethyl(oxo)- 6-sulfaneylidene)amino)quinolin-4-yl)oxy)-3-fluoro-5-methylphenyl)acetamide (Compound 60) FH12897804.1OTQ-00725A solution of 2-(4-((6-bromoquinolin-4-yl)oxy)-3-fluoro-5-methylphenyl)-N-(1-(tert-butyl)-1H- pyrazol-4-yl)acetamide (100 mg, 196 μmol, 1.00 equiv.), iminodimethyl-λ6-sulfanone (18.2 mg, 196 μmol, 1.00 equiv.), tris(dibenzylideneacetone)dipalladium(0) (9.0 mg, 10 μmol, 0.05 equiv.), Xantphos (11.3 mg, 20 μmol, 0.10 equiv.), and sodium tert-butoxide in 1,4-dioxane (2 mL) 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 (0.1% formic acid), mobile phase B: ACN, gradient: 10-40% B in 30 min; wavelength: 210 nm). The title compound was obtained as a white solid (51.6 mg, 50%). LCMS (ESI) calculated for C27H31FN5O3S (M+H)+: 524.2, found: 524.3.1H NMR (400 MHz, DMSO-d6) 10.20 (s, 1H), 8.46 (d, J = 5.1 Hz, 1H), 7.95 (s, 1H), 7.88 (d, J = 9.0 Hz, 1H), 7.77 (d, J = 2.5 Hz, 1H), 7.48 – 7.42 (m, 2H), 7.26 (d, J = 11.1 Hz, 1H), 7.19 (s, 1H), 6.36 (d, J = 5.0 Hz, 1H), 3.63 (s, 2H), 3.32 (s, 6H), 2.16 (s, 3H), 1.49 (s, 9H). Example 7 – Preparation of Additional Sulfoximine Compounds Compounds in the table below were prepared based on experimental procedures described in Examples 5 and 6 and the detailed description.FH12897804.1OTQ-00725FH12897804.1OTQ-00725FH12897804.1OTQ-00725FH12897804.1OTQ-00725FH12897804.1OTQ-00725FH12897804.1OTQ-00725FH12897804.1OTQ-00725FH12897804.1OTQ-00725FH12897804.1OTQ-00725FH12897804.1OTQ-00725 - 409 -FH12897804.1OTQ-00725FH12897804.1OTQ-00725FH12897804.1OTQ-00725FH12897804.1OTQ-00725FH12897804.1OTQ-00725FH12897804.1OTQ-00725FH12897804.1OTQ-00725Example 8 – Synthesis of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(7-((6- (methylsulfonyl)quinolin-4-yl)oxy)-2,3-dihydro-1H-inden-4-yl)acetamide (Compound 186); Prepared according to General Scheme 3FH12897804.1OTQ-00725 A solution of bromine (6.25 g, 39.1 mmol, 1.05 equiv.) in carbon tetrachloride (20 mL) was added dropwise to a solution of 2,3-dihydro-1H-inden-4-ol (5.00 g, 37.3 mmol, 1.00 equiv.) in DCM (100 mL) and the mixture was stirred at room temperature for 1 h. Subsequently, the reaction was quenched through the addition of an aqueous solution of sodium thiosulfate. The product was extracted with DCM (100 mL) and the combined organic phases were washed with brine (100 mL), and the solvent was removed under reduced pressure. The crude product was used in the next reaction without further purification. Part II – Synthesis of 4-chloro-6-(methylthio)quinolineA solution of 6-bromo-4-chloroquinoline (commercially available, 50 g, 206 mmol, 1.00 equiv.), sodium thiomethoxide (28.9 g, 412 mmol, 2.00 equiv.), tris(dibenzylideneacetone)dipalladium(0) (4.72 g, 5.15 mmol, 0.025 equiv.), Xantphos (5.97 g, 10.3 mmol, 0.05 equiv.), and triethylamine (143 mL, 1.03 mol, 5 equiv.) in 1,4-dioxane (300 mL) was heated to 80 °C for 5 h under an inert atmosphere of nitrogen. EtOAc was added and insoluble materials were filtered off. Next, the organic phase was washed with water and brine, dried over Na2SO4, and the solvent was removed under reduced pressure. EtOAc and hexanes were added (100 mL each), followed by silica gel (20 g). The slurry was stirred at room temperature for 30 min and the silica gel was subsequently filtered off and washed with EtOAc / hexanes (1:1). The solvent was removed under reduced pressure. The intended product was obtained as a red solid (43.5 g), which was used in the next reaction without further purification. Part III – Synthesis of 4-chloro-6-(methylsulfonyl)quinoline FH12897804.1OTQ-00725Oxone (139 g, 227 mmol, 1.1 equiv.) was added to a solution of 4-chloro-6- (methylthio)quinoline (43.2 g, 206 mmol, 1.00 equiv.) in THF (350 mL) and water (350 mL). The reaction mixture was stirred at room temperature for 2 h. Subsequently, water and EtOAc were added, and the organic phase was separated. The aqueous solution was neutralized with K2CO3and extracted with EtOAc. The combined organic phases were washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure. The obtained material was treated with DCM (200 mL) and hexanes (400 mL) to remove impurities. Next, the product was filtered off, washed with a small amount of EtOAc (ca. 40-50 mL) and hexanes and dried under reduced pressure. The intended product was obtained as a slightly yellowish solid (34.4 g, 69% yield), which was used in the next reaction without further purification. Part IV – Synthesis of 4-((7-bromo-2,3-dihydro-1H-inden-4-yl)oxy)-6- (methylsulfonyl)quinolineA solution of 7-bromo-2,3-dihydro-1H-inden-4-ol (3.2 g, 9.01 mmol, 1.00 equiv.), 4-chloro-6- (methylsulfonyl)quinoline (3.05 g, 12.6 mmol, 1.40 equiv.), DMAP (110 mg, 901 μmol, 0.10 equiv.), and K2CO3(1.87 g, 13.5 mmol, 1.50 equiv.) in DMF (60 mL) was heated to 120 °C for 5 h. Subsequently, water (300 mL) was added, and the product was extracted with EtOAc (2 x 200 mL). The combined organic phases were washed with brine (400 mL), dried over Na2SO4, and the solvent was removed under reduced pressure. The crude product was purified by FH12897804.1OTQ-00725 column chromatography (40% EtOAc in petroleum ether). The title compound was obtained as a yellow solid (1.7 g, 11% over 2 steps). Part V – Synthesis of ethyl 2-(7-((6-(methylsulfonyl)quinolin-4-yl)oxy)-2,3-dihydro-1H- inden-4-yl)acetateA solution of 4-((7-bromo-2,3-dihydro-1H-inden-4-yl)oxy)-6-(methylsulfonyl)quinoline (1.60 g, 3.83 mmol, 1.00 equiv.), ethyl potassium malonate (980 mg, 5.74 mmol, 1.50 equiv.), allylpalladium(II) chloride dimer (28.0 mg, 76.0 μmol, 0.02 equiv.), BINAP (143 mg, 230 μmol, 0.06 equiv.), and DMAP (46.7 mg, 383 μmol, 0.10 equiv.) in p-xylene (16 mL) was heated to 140 °C overnight under an inert atmosphere of nitrogen. Subsequently, water (100 mL) was added, and the product was extracted with EtOAc (100 mL). The combined organic phases were washed with brine (100 mL), dried over Na2SO4, and the solvent was removed under reduced pressure. The crude product was used in the next reaction without further purification. Part VI – Synthesis of 2-(7-((6-(methylsulfonyl)quinolin-4-yl)oxy)-2,3-dihydro-1H-inden-4-Lithium hydroxide monohydrate (410 mg, 9.87 mmol, 5.00 equiv.) was added to a solution of ethyl 2-(7-((6-(methylsulfonyl)quinolin-4-yl)oxy)-2,3-dihydro-1H-inden-4-yl)acetate (1.40 g, FH12897804.1OTQ-00725 1.97 mmol, 1.00 equiv.) in THF (15 mL) and the mixture was heated to 80 °C overnight. Water (20 mL) was added, and the solution was washed with EtOAc (20 mL). The pH of the aqueous solution was adjusted to 1 with hydrochloric acid and the product was extracted with EtOAc (30 mL). The organic phase was washed with brine, dried over Na2SO4, 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: 30-60% B in 30 min; wavelength: 210 nm). The title compound was obtained as a yellow solid (400 mg, 26% over 2 steps). Part VII – Synthesis of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(7-((6- (methylsulfonyl)quinolin-4-yl)oxy)-2,3-dihydro-1H-inden-4-yl)acetamide (Compound 186)A solution of 2-(7-((6-(methylsulfonyl)quinolin-4-yl)oxy)-2,3-dihydro-1H-inden-4-yl)acetic acid (190 mg, 478 μmol, 1.00 equiv.), 1-(tert-butyl)-1H-pyrazol-4-amine (79.9 mg, 574 μmol, 1.20 equiv.), PyBOP (373 mg, 717 μmol, 1.50 equiv.), and DIPEA (309 mg, 2.39 mmol, 5.00 equiv.) in DMF (4 mL) was stirred at room temperature for 1 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: 20-50% B in 30 min; wavelength: 210 nm). The title compound was obtained as a white solid (65 mg, 26%). LCMS (ESI) calculated for C28H31N4O4S (M+H)+: 519.2, found: 519.3.1H NMR (400 MHz, DMSO-d6) 10.19 (s, 1H), 8.91 – 8.83 (m, 2H), 8.30 – 8.26 (m, 2H), 7.95 (s, 1H), 7.46 (s, 1H), 7.28 (d, J = 8.2 Hz, 1H), 7.10 (d, J = 8.2 Hz, 1H), 6.63 (d, J = 5.2 Hz, 1H), 3.64 (s, 2H), 3.39 (s, 3H), 3.00 (t, J = 7.5 Hz, 2H), 2.71 (t, J = 7.5 Hz, 2H), 2.07 – 1.97 (m, 2H), 1.49 (s, 9H). FH12897804.1OTQ-00725 Example 9 – Synthesis of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(3-(difluoromethoxy)-4-((6- (methylsulfonyl)quinolin-4-yl)oxy)phenyl)acetamide (Compound 185); Prepared according to General Scheme 9Part I – Synthesis of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(3-hydroxy-4- methoxyphenyl)acetamideA solution of 2-(3-hydroxy-4-methoxyphenyl)acetic acid (5.00 g, 27.4 mmol, 1.00 equiv.), 1- (tert-butyl)-1H-pyrazol-4-amine (4.58 g, 32.9 mmol, 1.20 equiv.), DIPEA (10.6 g, 82.3 mmol, 3.00 equiv.), and HATU (15.7 g, 41.2 mmol, 1.50 equiv.) in DMF (50 mL) was stirred at room temperature for 2 h. Subsequently, the mixture was diluted with EtOAc (400 mL) and washed with brine (2 x 200 mL). The organic phase was dried over Na2SO4, and the solvent was removed under reduced pressure. The title compound was obtained as a brown oil (7 g), which was used in the next reaction without further purification. Part II – Synthesis of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(3-(difluoromethoxy)-4- methoxyphenyl)acetamideFH12897804.1OTQ-00725 Diethyl (bromodifluoromethyl)phosphonate (5.28 g, 19.8 mmol, 2.00 equiv.) was added dropwise to a solution of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(3-hydroxy-4- methoxyphenyl)acetamide (3.00 g, 9.89 mmol, 1.00 equiv.) and potassium hydroxide (11.1 g, 198 mmol, 20.0 equiv.) in ACN (45 mL) and water (45 mL) at 0 °C. Subsequently, the mixture was stirred at room temperature for 1 h. 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: 50-90% B in 30 min; wavelength: 210 nm). The title compound was obtained as a yellow oil (1.6 g, 39% over 2 steps). Part III – Synthesis of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(3-(difluoromethoxy)-4- hydroxyphenyl)acetamideA solution of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(3-(difluoromethoxy)-4- methoxyphenyl)acetamide (600 mg, 1.70 mmol, 1.00 equiv.) and sodium thiomethoxide (357 mg, 5.09 mmol, 3.00 equiv.) in DMF (12 mL) was heated to 100 °C for 4 h. Subsequently, the mixture was diluted with EtOAc (100 mL) and washed with brine (2 x 50 mL). The organic phase was dried over Na2SO4, and the solvent was removed under reduced pressure. The title compound was obtained as a brown solid (200 mg), which was used in the next reaction without further purification. Part IV – Synthesis of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(3-(difluoromethoxy)-4-((6- (methylsulfonyl)quinolin-4-yl)oxy)phenyl)acetamide (Compound 185) FH12897804.1OTQ-00725A solution of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(3-(difluoromethoxy)-4- hydroxyphenyl)acetamide (200 mg, 589 μmol, 1.00 equiv.), 4-chloro-6- (methylsulfonyl)quinoline (143 mg, 589 μmol, 1.00 equiv., can be synthesized according to the synthesis described in Part III of Example 8) and Cs2CO3(384 mg, 1.18 mmol, 2.00 equiv.) in DMF (4 mL) was heated to 40 °C for 5 h. Subsequently, the crude product was purified by preparative HPLC (column: Xselect CSH C18 OBD, 30 × 150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3+ 0.05% ammonia solution), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 26-56% B in 10 min; wavelength: 220 nm; RT1: 8.3 min). The title compound was obtained as a white solid (17.4 mg, 1.9% over 2 steps). LCMS (ESI) calculated for C26H27F2N4O5S (M+H)+: 545.2, found: 545.3.1H NMR (400 MHz, DMSO-d6) 10.26 (s, 1H), 8.91 – 8.85 (m, 2H), 8.31 – 8.27 (m, 2H), 7.96 (d, J = 0.9 Hz, 1H), 7.54 – 7.44 (m, 3H), 7.39 – 7.36 (m, 1H), 7.22 (t, J = 73.2 Hz, 1H), 6.70 (d, J = 5.3 Hz, 1H), 3.70 (s, 2H), 3.39 (s, 3H), 1.49 (s, 9H). Example 10 – Preparation of Additional Substituted Benzene Compounds Compounds in the table below were prepared based on experimental procedures described in Examples 8 and 9 and the detailed description.FH12897804.1OTQ-00725Example 11 – Synthesis of 2-(3-methyl-4-((6-(methylsulfonyl)quinolin-4-yl)oxy)phenyl)-N-(1- (tert-pentyl)-1H-pyrazol-4-yl)acetamide (Compound 14); Prepared according to General Scheme 1FH12897804.1OTQ-00725 Part I – Synthesis of 4-nitro-1-(tert-pentyl)-1H-pyrazoleA solution of 4-nitro-1H-pyrazole (500 mg, 4.42 mmol, 1.00 equiv.), 2-bromo-2-methylbutane (2.00 g, 13.3 mmol, 3.00 equiv.), and K2CO3(3.06 g, 22.1 mmol, 5.00 equiv.) in DMF (10 mL) was heated to 90 °C overnight. Subsequently, 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 Na2SO4, and the solvent was removed under reduced pressure. The title compound was obtained as a brown solid (800 mg), which was used in the next reaction without further purification. Part II – Synthesis of 1-(tert-pentyl)-1H-pyrazol-4-amine4,4’-Bipyridine (12.8 mg, 82.0 μmol, 0.05 equiv.) and tetrahydroxydiboron (440 mg, 4.91 mmol, 3.00 equiv.) were added to a solution of 4-nitro-1-(tert-pentyl)-1H-pyrazole (300 mg, 1.64 mmol, 1.00 equiv.) in DMF (3 mL) at 0 °C. Subsequently, the mixture was stirred at this temperature for 10 min. Water (5 mL) was added 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: 15-45% B in 30 min; wavelength: 210 nm). The title compound was obtained as a brown oil (17 mg, 6.7% over 2 steps). Part III – Synthesis of methyl 2-(3-methyl-4-((6-(methylsulfonyl)quinolin-4- yl)oxy)phenyl)acetate FH12897804.1OTQ-00725A solution of methyl 2-(4-hydroxy-3-methylphenyl)acetate (3.00 g, 16.6 mmol, 1.00 equiv.), 4- chloro-6-(methylsulfonyl)quinoline (4.43 g, 18.3 mmol, 1.10 equiv., can be synthesized according to the synthesis described in Part III of Example 8), DMAP (200 mg, 1.67 mmol, 0.10 equiv.), and K2CO3(4.60 g, 33.3 mmol, 2.00 equiv.) in DMF (30 mL) was heated to 120 °C for 2 h. Subsequently, water was added, and the product was extracted with EtOAc (3 x 30 mL). The combined organic phases were washed with brine (2 x 30 mL), dried over Na2SO4, and the solvent was removed under reduced pressure. The title compound was obtained as a brown solid (7.4 g), which was used in the next reaction without further purification. Part IV – Synthesis of 2-(3-methyl-4-((6-(methylsulfonyl)quinolin-4-yl)oxy)phenyl)acetic acidA solution of methyl 2-(3-methyl-4-((6-(methylsulfonyl)quinolin-4-yl)oxy)phenyl)acetate (7.40 g, 19.2 mmol, 1.00 equiv.) and lithium hydroxide (9.20 g, 384 mmol, 20.0 equiv.) in methanol (140 mL) and water (14 mL) was heated to 60 °C for 1 h. The mixture was diluted with water (50 mL) and EtOAc (50 mL), and the precipitated product was filtered off and washed with EtOAc (3 x 10 mL). The title compound was obtained as a white solid (4.6 g, obtained as lithium carboxylate), which was used in the next reaction without further purification. Part V – Synthesis of 2-(3-methyl-4-((6-(methylsulfonyl)quinolin-4-yl)oxy)phenyl)-N-(1- (tert-pentyl)-1H-pyrazol-4-yl)acetamide (Compound 14) FH12897804.1OTQ-00725A solution of propylphosphonic anhydride in EtOAc (50%, 116 mg, 365 μmol, 5.00 equiv.) was added to a solution of 2-(3-methyl-4-((6-(methylsulfonyl)quinolin-4-yl)oxy)phenyl)acetic acid (27.0 mg, 73.0 μmol, 1.00 equiv.), 1-(tert-pentyl)-1H-pyrazol-4-amine (16.7 mg, 109 μmol, 1.50 equiv.), and DIPEA (56.4 mg, 438 μmol, 6.00 equiv.) in DMF (0.4 mL) and the mixture was stirred at room temperature for 2 h. 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: 25-55% B in 30 min; wavelength: 210 nm). The title compound was obtained as a white solid (9.4 mg, 26%). LCMS (ESI) calculated for C27H31N4O4S (M+H)+: 507.2, found: 507.2.1H NMR (400 MHz, DMSO-d6) 10.18 (s, 1H), 8.91 (d, J = 1.8 Hz, 1H), 8.83 (d, J = 5.2 Hz, 1H), 8.31 – 8.25 (m, 2H), 7.92 (s, 1H), 7.46 (s, 1H), 7.39 (d, J = 2.1 Hz, 1H), 7.31 (dd, J = 8.3, 2.2 Hz, 1H), 7.23 (d, J = 8.2 Hz, 1H), 6.56 (d, J = 5.3 Hz, 1H), 3.62 (s, 2H), 3.38 (s, 3H), 2.14 (s, 3H), 1.79 (q, J = 7.4 Hz, 2H), 1.46 (s, 6H), 0.59 (t, J = 7.4 Hz, 3H). Example 12 – Synthesis of N-(1-(bicyclo[1.1.1]pentan-1-yl)-1H-pyrazol-4-yl)-2-(3,5-dimethyl- 4-((6-(methylsulfonyl)quinolin-4-yl)oxy)phenyl)acetamide (Compound 18); Prepared according to General Scheme 3Part I – Synthesis of 4-(4-bromo-2,6-dimethylphenoxy)-6-(methylsulfonyl)quinoline FH12897804.1OTQ-00725A solution of 4-bromo-2,6-dimethylphenol (2.00 g, 9.95 mmol, 1.00 equiv.), 4-chloro-6- (methylsulfonyl)quinoline (2.63 g, 11.9 mmol, 1.20 equiv., can be synthesized according to the synthesis described in Part III of Example 8), and DMAP (3.65 g, 29.8 mmol, 3.00 equiv.) in chlorobenzene (20 mL) was heated to 130 °C overnight. Subsequently, the crude product was purified by reversed-phase flash chromatography (column: C18 silica gel; mobile phase A: water (0.1% formic acid), mobile phase B: ACN, gradient: 30-60% B in 30 min; wavelength: 210 nm). The title compound was obtained as a yellow solid (300 mg, 7.8%). Part II – Synthesis of ethyl 2-(3,5-dimethyl-4-((6-(methylsulfonyl)quinolin-4- yl)oxy)phenyl)acetateA solution of 4-(4-bromo-2,6-dimethylphenoxy)-6-(methylsulfonyl)quinoline (300 mg, 779 μmol, 1.00 equiv.), ethyl potassium malonate (265 mg, 1.56 mmol, 2.00 equiv.), allylpalladium(II) chloride dimer (5.7 mg, 16 μmol, 0.02 equiv.), BINAP (29.1 mg, 47 μmol, 0.06 equiv.), and DMAP (9.5 mg, 78 μmol, 0.10 equiv.) in p-xylene (6 mL) was heated to 140 °C for 3 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 (0.1% formic acid), mobile phase B: ACN, gradient: 20-50% B in 30 min; wavelength: 210 nm). The title compound was obtained as a yellow solid (100 mg, 33%). FH12897804.1OTQ-00725 Part III – Synthesis of 2-(3,5-dimethyl-4-((6-(methylsulfonyl)quinolin-4- yl)oxy)phenyl)acetic acidA solution of ethyl 2-(3,5-dimethyl-4-((6-(methylsulfonyl)quinolin-4-yl)oxy)phenyl)acetate (100 mg, 255 μmol, 1.00 equiv.) and potassium hydroxide (143 mg, 2.55 mmol, 10.0 equiv.) in THF (2 mL) and water (0.2 mL) was stirred at room temperature overnight. Subsequently, water was added, and the aqueous phase was washed with EtOAc (3 x 20 mL). The pH of the aqueous phase was adjusted to 3 through the addition of hydrochloric acid and the product was extracted with EtOAc (3 x 20 mL). The combined organic phases were washed with brine (10 mL), dried over Na2SO4, and the solvent was removed under reduced pressure. The title compound was obtained as a yellow solid (134 mg), which was used in the next reaction without further purification. Part IV – Synthesis of 1-(bicyclo[1.1.1]pentan-1-yl)-4-nitro-1H-pyrazoleA solution of bicyclo[1.1.1]pentan-1-ylhydrazine dihydrochloride (14.3 g, 83.8 mmol, 2.00 equiv.) and 2-nitromalonaldehyde (5.75 g, 41.9 mmol, 1.00 equiv.) in EtOH (50 mL) and hydrochloric acid (37%, 18.4 mL) was heated to 80 °C for 3 h. Subsequently, the pH of the solution was adjusted to 8 through the addition of a saturated aqueous solution of Na2CO3. The product was extracted with EtOAc (2 x 100 mL) and the combined organic phases were washed with brine (2 x 100 mL), dried over Na2SO4, 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 brown solid (3.3 g, 44%). FH12897804.1OTQ-00725 Part V – Synthesis of 1-(bicyclo[1.1.1]pentan-1-yl)-1H-pyrazol-4-amine Palladium on carbon (20 wt.%, 210 mg) was added to a solution of 1-(bicyclo[1.1.1]pentan-1- yl)-4-nitro-1H-pyrazole (3.30 g, 18.2 mmol, 1.00 equiv.) in MeOH (33 mL) and the mixture was stirred at room temperature overnight under an atmosphere of hydrogen. Subsequently, the solution was filtered, and the residue was washed with MeOH (2 x 50 mL). The solvent was removed under reduced pressure. The title compound was obtained as a brown solid (2.3 g, 84%), which was used in the next reaction without further purification. Part VI – Synthesis of N-(1-(bicyclo[1.1.1]pentan-1-yl)-1H-pyrazol-4-yl)-2-(3,5-dimethyl-4- ((6-(methylsulfonyl)quinolin-4-yl)oxy)phenyl)acetamide (Compound 18)PyBOP (150 mg, 288 μmol, 1.50 equiv.) was added to a solution of 2-(3,5-dimethyl-4-((6- (methylsulfonyl)quinolin-4-yl)oxy)phenyl)acetic acid (70.0 mg, 192 μmol, 1.00 equiv.), 1- (bicyclo[1.1.1]pentan-1-yl)-1H-pyrazol-4-amine (32.0 mg, 230 μmol, 1.20 equiv.), and DIPEA (124 mg, 960 μmol, 5.00 equiv.) in DMF (1.4 mL) and the mixture was stirred at room temperature overnight. Subsequently, the crude product was purified by preparative HPLC (column: XBridge Prep Shield RP18 OBD, 30 × 150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 20-50% B in 12 min; wavelength: 220 nm; RT1: 9.3 min). The title compound was obtained as a white solid (62.5 mg, 47% over 2 steps). LCMS (ESI) calculated for C28H29N4O4S (M+H)+: 517.2, found: 517.3.1H NMR (400 MHz, DMSO-d6) 10.27 (s, 1H), 8.96 (s, 1H), 8.83 (d, J = 5.2 Hz, 1H), FH12897804.1OTQ-00725 8.34 – 8.24 (m, 2H), 7.91 (s, 1H), 7.47 (s, 1H), 7.21 (s, 2H), 6.45 (d, J = 5.2 Hz, 1H), 3.60 (s, 2H), 3.40 (s, 3H), 2.60 (s, 1H), 2.20 (s, 6H), 2.08 (s, 6H). Example 13 – Synthesis of 2-(3-methyl-4-((6-(methylsulfonyl)quinolin-4-yl)oxy)phenyl)-N-(1- (1,1,1-trifluoro-2-methylpropan-2-yl)-1H-pyrazol-4-yl)acetamide (Compound 16); Prepared according to General Scheme 12Part I – Synthesis of N'-(propan-2-ylidene)benzohydrazideA solution of benzhydrazide (10.0 g, 73.4 mmol, 1.00 equiv.) and acetone (80.0 g, 1.38 mol, 18.8 equiv.) in acetic acid (2 mL) and DCM (200 mL) was stirred at room temperature for 30 min. Subsequently, hexane (300 mL) was added, and the precipitated product was filtered off and washed with hexane (3 x 10 mL). The title compound was obtained as a light-yellow solid (9 g), which was used in the next reaction without further purification. Part II – Synthesis of N'-(1,1,1-trifluoro-2-methylpropan-2-yl)benzohydrazideBoron trifluoride diethyl etherate (6.04 g, 42.6 mmol, 1.50 equiv.) was added to a solution of N'- (propan-2-ylidene)benzohydrazide (5.00 g, 28.4 mmol, 1.00 equiv.), and allyltrimethylsilane (4.86 g, 42.6 mmol, 1.50 equiv.) in 1,2-dichloroethane (75 mL) and the mixture was heated to 80 °C for 30 min. Subsequently, the solvent was removed under reduced pressure. The residue FH12897804.1OTQ-00725 was dissolved in DMF (75 mL) and trimethyl(trifluoromethyl)silane (8.07 g, 56.7 mmol, 2.00 equiv.) and sodium acetate (9.31 g, 113 mmol, 4.00 equiv.) were added. The mixture was stirred at room temperature for 2 h. An aqueous saturated solution of Na2CO3(100 mL) was added, and the product was extracted with EtOAc (3 x 100 mL). The combined organic phases were washed with brine (100 mL), dried over Na2SO4, and the solvent was removed under reduced pressure. The title compound was obtained as a brown oil (4 g), which was used in the next reaction without further purification. Part III – Synthesis of (1,1,1-trifluoro-2-methylpropan-2-yl)hydrazineA solution of N'-(1,1,1-trifluoro-2-methylpropan-2-yl)benzohydrazide (1.50 g, 6.09 mmol, 1.00 equiv.) in hydrochloric acid (6 M, 15 mL) was heated to 100 °C overnight. Subsequently, the solvent was removed und reduced pressure and the residue was triturated with hexane (20 mL). The title compound was obtained as a white solid (1.15 g, 35% over 3 steps, obtained as a dihydrochloride), which was used in the next reaction without further purification. Part IV – Synthesis of 4-nitro-1-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-pyrazoleA solution of (1,1,1-trifluoro-2-methylpropan-2-yl)hydrazine (1.15 g, 5.35 mmol, 2.00 equiv.) and 2-nitromalonaldehyde (310 mg, 2.67 mmol, 1.00 equiv.) in EtOH (12 mL) and hydrochloric acid (12 M, 3 mL) was heated to 80 °C for 3 h. Subsequently, the pH of the solution was adjusted to 8 through the addition of a saturated aqueous solution of Na2CO3. The product was extracted with EtOAc (3 x 30 mL), and the combined organic phases were washed with brine (2 x 30 mL), dried over Na2SO4, and the solvent was removed under reduced pressure. The title FH12897804.1OTQ-00725 compound was obtained as a brown oil (700 mg), which was used in the next reaction without further purification. Part V – Synthesis of 1-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-pyrazol-4-amine4,4’-Bipyridine (20 mg, 157 μmol, 0.05 equiv.) and tetrahydroxydiboron (840 mg, 9.41 mmol, 3.00 equiv.) were added to a solution of 4-nitro-1-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H- pyrazole (700 mg, 3.14 mmol, 1.00 equiv.) in DMF (7 mL) at 0 °C. Subsequently, the mixture was stirred at this temperature for 10 min. Water was added 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: 30-60% B in 30 min; wavelength: 210 nm). The title compound was obtained as a brown solid (30 mg, 2.9% over 2 steps). Part VI – Synthesis of 2-(3-methyl-4-((6-(methylsulfonyl)quinolin-4-yl)oxy)phenyl)-N-(1- (1,1,1-trifluoro-2-methylpropan-2-yl)-1H-pyrazol-4-yl)acetamide (Compound 16)A solution of propylphosphonic anhydride in EtOAc (50%, 154 mg, 485 μmol, 5.00 equiv.) was added to a solution of 2-(3-methyl-4-((6-(methylsulfonyl)quinolin-4-yl)oxy)phenyl)acetic acid (36.0 mg, 97.0 μmol, 1.00 equiv., can be synthesized according to the synthesis described in Part IV of Example 11), 1-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-pyrazol-4-amine (28.1 mg, 146 μmol, 1.50 equiv.), and DIPEA (75.2 mg, 582 μmol, 6.00 equiv.) in DMF (0.7 mL) and the mixture was stirred at room temperature for 2 h. Subsequently, the crude product was purified FH12897804.1OTQ-00725 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 title compound was obtained as a white solid (16.7 mg, 32%). LCMS (ESI) calculated for C26H26F3N4O4S (M+H)+: 547.2, found: 547.3.1H NMR (400 MHz, DMSO-d6) 10.32 (s, 1H), 8.91 (s, 1H), 8.84 (d, J = 5.2 Hz, 1H), 8.30 – 8.24 (m, 2H), 8.14 (s, 1H), 7.59 (s, 1H), 7.39 (d, J = 2.1 Hz, 1H), 7.32 (dd, J = 8.2, 2.2 Hz, 1H), 7.23 (d, J = 8.2 Hz, 1H), 6.56 (d, J = 5.2 Hz, 1H), 3.64 (s, 2H), 3.38 (s, 3H), 2.14 (s, 3H), 1.79 (s, 6H). Example 14 – Preparation of Additional Substitute Pyrazole Compounds Compounds in the table below were prepared based on experimental procedures described in Examples 11, 12, and 13 and the detailed description.FH12897804.1OTQ-00725Example 15 – Synthesis of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(4-((6- (cyclopropanesulfonamido)quinolin-4-yl)oxy)-3-methylphenyl)acetamide (Compound 19); Prepared according to General Scheme 11Part I – Synthesis of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(3-methyl-4-((6-nitroquinolin-4- yl)oxy)phenyl)acetamide FH12897804.1OTQ-00725A solution of 4-chloro-6-nitroquinoline (3.00 g, 14.4 mmol, 1.00 equiv.), N-(1-(tert-butyl)-1H- pyrazol-4-yl)-2-(4-hydroxy-3-methylphenyl)acetamide (4.13 g, 14.4 mmol, 1.00 equiv., can be synthesized according to the synthesis described in Part IV of Example 1), DMAP (180 mg, 1.44 mmol, 0.10 equiv.), and K2CO3(3.98 g, 28.8 mmol, 2.00 equiv.) in DMF (60 mL) was heated to 120 °C for 2 h. Subsequently, water was added, and the product was extracted with EtOAc (3 x 100 mL). The combined organic phases were washed with brine (100 mL), dried over Na2SO4, and the solvent was removed under reduced pressure. The title compound was obtained as a black oil (7.3 g), which was used in the next reaction without further purification. Part II – Synthesis of 2-(4-((6-aminoquinolin-4-yl)oxy)-3-methylphenyl)-N-(1-(tert-butyl)- 1H-pyrazol-4-yl)acetamide4,4’-Bipyridine (120 mg, 794 μmol, 0.05 equiv.) and tetrahydroxydiboron (4.27 g, 47.7 mmol, 3.00 equiv.) were added to a solution of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(3-methyl-4-((6- nitroquinolin-4-yl)oxy)phenyl)acetamide (7.3 g, 15.9 mmol, 1.00 equiv.) in DMF (73 mL) at 0 °C. Subsequently, the mixture was stirred at this temperature for 10 min. Water was added and the product was extracted with EtOAc (3 x 100 mL). The combined organic phases were washed with brine (100 mL), dried over Na2SO4, and the solvent was removed under reduced pressure. The title compound was obtained as a yellow solid (6.2 g), which was used in the next reaction without further purification. FH12897804.1OTQ-00725 Part III – Synthesis of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(4-((6- (cyclopropanesulfonamido)quinolin-4-yl)oxy)-3-methylphenyl)acetamide (Compound 19)Cyclopropanesulfonyl chloride (655 mg, 4.66 mmol, 4.00 equiv.) was added to a solution of 2- (4-((6-aminoquinolin-4-yl)oxy)-3-methylphenyl)-N-(1-(tert-butyl)-1H-pyrazol-4-yl)acetamide (500 mg, 1.16 mmol, 1.00 equiv.) and pyridine (276 mg, 3.49 mmol, 3.00 equiv.) in DCM (7.5 mL) and the mixture was stirred at room temperature overnight. 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: 25-55% B in 30 min; wavelength: 210 nm). The title compound was obtained as a white solid (157 mg, 25% over 3 steps). LCMS (ESI) calculated for C28H32N5O4S (M+H)+: 534.2, found: 534.3.1H NMR (400 MHz, DMSO-d6) 10.22 (s, 1H), 10.18 (s, 1H), 8.58 (d, J = 5.2 Hz, 1H), 8.17 (d, J = 2.4 Hz, 1H), 8.02 (d, J = 9.0 Hz, 1H), 7.95 (s, 1H), 7.75 (dd, J = 9.1, 2.5 Hz, 1H), 7.46 (s, 1H), 7.37 (d, J = 2.3 Hz, 1H), 7.29 (dd, J = 8.4, 2.0 Hz, 1H), 7.18 (d, J = 8.2 Hz, 1H), 6.43 (d, J = 5.2 Hz, 1H), 3.61 (s, 2H), 2.80 – 2.67 (m, 1H), 2.12 (s, 3H), 1.49 (s, 9H), 1.06 – 0.92 (m, 4H). Example 16 – Preparation of Additional Amide and Sulfonamide Compounds Compounds in the table below were prepared based on experimental procedures described in Example 15 and the detailed description.FH12897804.1OTQ-00725 - 438 -FH12897804.1OTQ-00725FH12897804.1OTQ-00725 - 440 -FH12897804.1OTQ-00725FH12897804.1OTQ-00725FH12897804.1OTQ-00725FH12897804.1OTQ-00725 - 444 -FH12897804.1OTQ-00725FH12897804.1OTQ-00725Example 17 – Synthesis of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(4-((7,7-dioxido-6,8- dihydrothieno[3,4-g]quinolin-4-yl)oxy)-3-methylphenyl)acetamide (Compound 175); Prepared according to General Scheme 4Part I – Synthesis of 5-(((2,2-dioxido-1,3-dihydrobenzo[c]thiophen-5-yl)amino)methylene)- 2,2-dimethyl-1,3-dioxane-4,6-dioneA solution of 5-amino-1,3-dihydrobenzo[c]thiophene 2,2-dioxide (1.40 g, 7.64 mmol, 1.00 equiv.) and 5-(methoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (1.56 g, 8.41 mmol, 1.10 equiv.) in EtOH (30 mL) was stirred at room temperature for 30 min. Subsequently, the FH12897804.1OTQ-00725 precipitated product was filtered off, washed with EtOH (2 x 5 mL), and dried under reduced pressure. The title compound was obtained as a light-yellow solid (2.3 g), which was used in the next reaction without further purification. Part II – Synthesis of 4-hydroxy-6,8-dihydrothieno[3,4-g]quinoline 7,7-dioxideA solution of 5-(((2,2-dioxido-1,3-dihydrobenzo[c]thiophen-5-yl)amino)methylene)-2,2- dimethyl-1,3-dioxane-4,6-dione (2.3 g, 6.82 mmol, 1.00 equiv.) in diphenyl ether (40 mL) was heated to 220 °C for 90 min. Et2O (50 mL) was added and the precipitated product was filtered off, washed with Et2O (3 x 20 mL), and dried under reduced pressure. The title compound was obtained as a brown solid (1.7 g), which was used in the next reaction without further purification. Part III – Synthesis of 4-chloro-6,8-dihydrothieno[3,4-g]quinoline 7,7-dioxideA solution of 4-hydroxy-6,8-dihydrothieno[3,4-g]quinoline 7,7-dioxide (1.7 g, 7.23 mmol, 1.00 equiv.) in phosphoryl chloride (17 mL) was heated to 90 °C for 1 h. Subsequently, the solvent was removed under reduced pressure. The title compound (1.3 g) was obtained as a brown solid, which was used in the next reaction without further purification. Part IV – Synthesis of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(4-((7,7-dioxido-6,8- dihydrothieno[3,4-g]quinolin-4-yl)oxy)-3-methylphenyl)acetamide (Compound 175) FH12897804.1OTQ-00725A solution of 4-chloro-6,8-dihydrothieno[3,4-g]quinoline 7,7-dioxide (768 mg, 3.03 mmol, 3.00 equiv.), N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(4-hydroxy-3-methylphenyl)acetamide (290 mg, 1.01 mmol, 1.00 equiv., can be synthesized according to the synthesis described in Part IV of Example 1), DMAP (24.7 mg, 202 μmol, 0.20 equiv.), and K2CO3(837 mg, 6.05 mmol, 6.00 equiv.) in DMF (12 mL) was heated to 150 °C for 2 h in a microwave oven. Subsequently, the solution was filtered, and the remaining solids were washed with MeOH (3 x 5 mL). The organic phases were combined, 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: 25-55% B in 30 min; wavelength: 210 nm). The title compound was obtained as a yellow solid (60 mg, 12%). LCMS (ESI) calculated for C27H29N4O4S (M+H)+: 505.2, found: 505.2.1H NMR (400 MHz, DMSO- d6) 10.19 (s, 1H), 8.67 (d, J = 5.2 Hz, 1H), 8.05 (d, J = 8.6 Hz, 1H), 7.95 (s, 1H), 7.80 (d, J = 8.7 Hz, 1H), 7.46 (s, 1H), 7.37 (d, J = 2.1 Hz, 1H), 7.30 (dd, J = 8.3, 2.2 Hz, 1H), 7.22 (d, J = 8.2 Hz, 1H), 6.46 (d, J = 5.1 Hz, 1H), 5.11 (s, 2H), 4.70 (s, 2H), 3.61 (s, 2H), 2.14 (s, 3H), 1.49 (s, 9H). Example 18 – Synthesis of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(4-((1,1-dioxido-3,4-dihydro- 2H-thiopyrano[2,3-g]quinolin-9-yl)oxy)-3-methylphenyl)acetamide (Compound 179); Prepared according to General Scheme 4FH12897804.1OTQ-00725 Part I – Synthesis of 6-bromothiochromaneA solution of 6-bromothiochroman-4-one (15.0 g, 61.7 mmol, 1.00 equiv.) and triethylsilane (46.6 g, 401 mmol, 6.50 equiv.) in TFA (150 mL) was heated to 70 °C for 4 h. Subsequently, the mixture was poured into ice water and the product was extracted with EtOAc (2 x 300 mL). The combined organic phases were washed with a saturated aqueous solution of NaHCO3and water, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography (10% EtOAc in petroleum ether). The title compound was obtained as a colorless oil (13.3 g, 94%). Part II – Synthesis of tert-butyl thiochroman-6-ylcarbamateA solution of 6-bromothiochromane (13.0 g, 56.7 mmol, 1.00 equiv.), tert-butyl carbamate (13.3 g, 113 mmol, 2.00 equiv.), tris(dibenzylideneacetone)dipalladium(0) (5.20 g, 5.67 mmol, 0.10 equiv.), Xantphos (6.57 g, 11.3 mmol, 0.20 equiv.), and Cs2CO3(73.9 g, 227 mmol, 4.00 equiv.) in 1,4-dioxane (260 mL) and the mixture was heated to 100 °C for 16 h under an inert atmosphere of nitrogen. Subsequently, water was added, and the product was extracted with EtOAc (2 x 500 mL). The combined organic phases were washed with brine (2 x 300 mL), dried over Na2SO4, and the solvent was removed under reduced pressure. The title compound was obtained as a black solid (23 g), which was used in the next reaction without further purification. Part III – Synthesis of thiochroman-6-amine FH12897804.1OTQ-00725 A solution of hydrogen chloride in 1,4-dioxane (4.0 M, 230 mL) was added to tert-butyl thiochroman-6-ylcarbamate (23.0 g, 86.7 mmol, 1.00 equiv.) and the mixture was stirred at room temperature for 1 h. Subsequently, the mixture was poured into ice water and the solution was neutralized with a saturated aqueous solution of NaHCO3. The product was extracted with EtOAc (2 x 300 mL), and the combined organic phases were washed with a saturated aqueous solution of NaHCO3and water. The solvent was removed under reduced pressure and the crude product was purified by column chromatography (10% EtOAc in petroleum ether). The title compound was obtained as a brown oil (2.0 g, 21% over 2 steps). Part IV – Synthesis of 2,2-dimethyl-5-((thiochroman-6-ylamino)methylene)-1,3-dioxane- 4,6-dioneA solution of thiochroman-6-amine (2.00 g, 12.1 mmol, 1.00 equiv.) and 5- (methoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (2.48 g, 13.3 mmol, 1.10 equiv.) in EtOH (20 mL) was stirred at room temperature for 30 min. Subsequently, the precipitated product was filtered off, washed with cold EtOH (40 mL), and dried under reduced pressure. The title compound was obtained as a yellow solid (3 g), which was used in the next reaction without further purification. Part V – Synthesis of 3,4-dihydro-2H-thiopyrano[2,3-g]quinolin-9-ol FH12897804.1OTQ-00725A solution of 2,2-dimethyl-5-((thiochroman-6-ylamino)methylene)-1,3-dioxane-4,6-dione (2.00 g, 6.26 mmol, 1.00 equiv.) in diphenyl ether (60 mL) was heated to 190 °C for 1 h. 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: 25-55% B in 30 min; wavelength: 210 nm). The title compound was obtained as a yellow solid (240 mg, 14% over 2 steps). Part VI – Synthesis of 9-chloro-3,4-dihydro-2H-thiopyrano[2,3-g]quinolineA solution of 3,4-dihydro-2H-thiopyrano[2,3-g]quinolin-9-ol (240 mg, 1.01 mmol, 1.00 equiv.) in phosphoryl chloride (2.4 mL) was heated to 90 °C for 1 h. Subsequently, the solvent was removed under reduced pressure. The crude product was dissolved in DCM (100 mL) and the organic phase was washed with a saturated aqueous solution of NaHCO3 and water. The solvent was removed under reduced pressure. The title compound was obtained as a brown oil (200 mg), which was used in the next reaction without further purification. Part VII – Synthesis of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(4-((3,4-dihydro-2H- thiopyrano[2,3-g]quinolin-9-yl)oxy)-3-methylphenyl)acetamideFH12897804.1OTQ-00725 A solution of 9-chloro-3,4-dihydro-2H-thiopyrano[2,3-g]quinoline (200 mg, 848 μmol, 1.00 equiv.), N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(4-hydroxy-3-methylphenyl)acetamide (268 mg, 933 μmol, 1.10 equiv., can be synthesized according to the synthesis described in Part IV of Example 1), DMAP (10.4 mg, 85 μmol, 0.10 equiv.), and K2CO3(235 mg, 1.70 mmol, 2.00 equiv.) in DMF (4 mL) was heated to 120 °C for 12 h. 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: 50-80% B in 30 min; wavelength: 210 nm). The title compound was obtained as a yellow solid (220 mg, 45% over 2 steps). Part VIII – Synthesis of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(4-((1,1-dioxido-3,4-dihydro- 2H-thiopyrano[2,3-g]quinolin-9-yl)oxy)-3-methylphenyl)acetamide (Compound 179)Oxone (306 mg, 996 μmol, 2.20 equiv.) was added to a solution of N-(1-(tert-butyl)-1H- pyrazol-4-yl)-2-(4-((3,4-dihydro-2H-thiopyrano[2,3-g]quinolin-9-yl)oxy)-3- methylphenyl)acetamide (220 mg, 452 μmol, 1.00 equiv.) in THF (2.2 mL) and water (2.2 mL) and the mixture was stirred at room temperature for 2 h. 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: 25-55% B in 30 min; wavelength: 210 nm). The title compound was obtained as an off-white solid (87.4 mg, 37%). LCMS (ESI) calculated for C28H31N4O4S (M+H)+: 519.2, found: 519.3.1H NMR (400 MHz, DMSO-d6) 10.19 (s, 1H), 8.71 (d, J = 5.2 Hz, 1H), 8.15 – 8.04 (m, 2H), 7.94 (s, 1H), 7.45 (s, 1H), 7.37 (d, J = 2.2 Hz, 1H), 7.29 (dd, J = 8.4, 2.1 Hz, 1H), 7.17 (d, J = 8.2 Hz, 1H), 6.54 (d, J = 5.2 Hz, 1H), 3.80 (t, J = 6.2 Hz, 2H), 3.65 – 3.56 (m, 4H), 2.48 – 2.39 (m, 2H), 2.15 (s, 3H), 1.48 (s, 9H). FH12897804.1OTQ-00725 Example 19 – Synthesis of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(3-fluoro-5-methyl-4-((6-oxo- 6,7,8,9-tetrahydropyrido[3,4-g]quinolin-4-yl)oxy)phenyl)acetamide (Compound 180); Prepared according to General Scheme 4Sodium hydride (1.59 g, 66.3 mmol, 1.5 equiv.) was added to a solution of 6-bromo-3,4- dihydroisoquinolin-1(2H)-one (10.0 g, 44.2 mmol, 1.00 equiv.) in DMF (150 mL) at 0 °C. Subsequently, the mixture was stirred for 30 min at this temperature.1-(Chloromethyl)-4- methoxybenzene (7.62 g, 48.7 mmol, 1.1 equiv.) was added and the mixture was stirred for 1 h at room temperature. The reaction was quenched through the addition of water and the product was extracted with EtOAc (3 x 200 mL). The combined organic phases were washed with brine (3 x 400 mL), dried over Na2SO4, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography (12% EtOAc in petroleum ether). The title compound was obtained as a yellow solid (14 g, 91%). Part II – Synthesis of 6-((diphenylmethylene)amino)-2-(4-methoxybenzyl)-3,4- dihydroisoquinolin-1(2H)-one FH12897804.1OTQ-00725A solution of 6-bromo-2-(4-methoxybenzyl)-3,4-dihydroisoquinolin-1(2H)-one (14.0 g, 40.4 mmol, 1.00 equiv.), benzophenone imine (8.79 g, 48.5 mmol, 1.2 equiv.), potassium tert- butoxide (13.6 g, 121 mmol, 3.00 equiv.), tris(dibenzylideneacetone)dipalladium(0) (3.70 g, 4.04 mmol, 0.10 equiv.), and BINAP (5.04 g, 8.09 mmol, 0.20 equiv.) in 1,4-dioxane (280 mL) was heated to 90 °C for 3 h under an inert atmosphere of nitrogen. Subsequently, water was added, and the product was extracted with EtOAc (3 x 100 mL). The combined organic phases were washed with brine (150 mL), dried over Na2SO4, and the solvent was removed under reduced pressure. The title compound was obtained as a black oil (30 g), which was used in the next reaction without further purification. Part III – Synthesis of 6-amino-2-(4-methoxybenzyl)-3,4-dihydroisoquinolin-1(2H)-oneA solution of 6-((diphenylmethylene)amino)-2-(4-methoxybenzyl)-3,4-dihydroisoquinolin- 1(2H)-one (30 g) in THF (300 mL) and hydrochloric acid (2 M, 150 mL) was stirred at room temperature for 2 h. Subsequently, the solvent was removed under reduced pressure. Water was added and the aqueous phase was washed with EtOAc (2 x 200 mL). The pH of the aqueous FH12897804.1OTQ-00725 phase was adjusted to 8 through the addition of a saturated solution of Na2CO3. The product was extracted with EtOAc (3 x 200 mL). The combined organic phases were washed with brine (3 x 400 mL), dried over Na2SO4, and 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 IV – Synthesis of 5-(((2-(4-methoxybenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6- yl)amino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dioneA solution of 6-amino-2-(4-methoxybenzyl)-3,4-dihydroisoquinolin-1(2H)-one (30 g) and 5- (methoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (21.8 g, 117 mmol, 1.10 equiv.) in EtOH (300 mL) was stirred at room temperature for 30 min. Subsequently, the precipitated product was filtered off, washed with cold EtOH (2 x 30 mL), and dried under reduced pressure. The title compound was obtained as a yellow solid (15.5 g, 88% over 3 steps), which was used in the next reaction without further purification. Part V – Synthesis of 4-hydroxy-7-(4-methoxybenzyl)-8,9-dihydropyrido[3,4-g]quinolin- 6(7H)-one FH12897804.1OTQ-00725A solution of 5-(((2-(4-methoxybenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6- yl)amino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (10.0 g, 22.9 mmol, 1.00 equiv.) in diphenyl ether (100 mL) was heated to 200 °C for 1 h. Subsequently, the mixture was poured into diethyl ether (200 mL) and stirred at room temperature for 90 min. The precipitated product was filtered off, washed with diethyl ether (6 x 20 mL), and dried under reduced pressure. The title compound was obtained as a yellow solid (4.0 g, 52%), which was used in the next reaction without further purification. Part VI – Synthesis of 4-chloro-7-(4-methoxybenzyl)-8,9-dihydropyrido[3,4-g]quinolin- 6(7H)-oneA solution of 4-hydroxy-7-(4-methoxybenzyl)-8,9-dihydropyrido[3,4-g]quinolin-6(7H)-one (1.7 g) in phosphoryl chloride (17 mL) was heated to 90 °C for 1 h. Subsequently, the solvent was removed under reduced pressure. An aqueous saturated solution of Na2CO3(50 mL) was added and the product was extracted with EtOAc (3 x 30 mL). The combined organic phases were washed with brine (2 x 100 mL), dried over Na2SO4, and the solvent was removed under reduced pressure. The title compound was obtained as a brown solid (2.6 g), which was used in the next reaction without further purification. FH12897804.1OTQ-00725 Part VII – Synthesis of 4-bromo-2-fluoro-6-methylphenolN-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 (1 L) was added, and the product was extracted with EtOAc (500 mL). The organic phase was washed with an aqueous saturated solution of NaHCO3and brine and dried over Na2SO4. The solvent was removed under reduced pressure. The title compound (65 g) was used in the next reaction without further purification. Part VIII – Synthesis of 2-(benzyloxy)-5-bromo-1-fluoro-3-methylbenzeneA solution of 4-bromo-2-fluoro-6-methylphenol (65.0 g, 317 mmol, 1.00 equiv.), benzyl bromide (59.7 g, 349 mmol, 1.10 equiv.), and K2CO3(65.7 g, 476 mmol, 1.50 equiv.) in DMF (650 mL) was stirred for 3 h at room temperature. Subsequently, water (2 L) was added, and the product was extracted with EtOAc (2 x 500 mL). 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 IX – Synthesis of ethyl 2-(4-(benzyloxy)-3-fluoro-5-methylphenyl)acetateA solution of 2-(benzyloxy)-5-bromo-1-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 FH12897804.1OTQ-00725 dimer (1.34 g, 3.66 mmol, 0.02 equiv.), BINAP (6.84 g, 11.0 mmol, 0.06 equiv.), and DMAP (2.24 g, 18.3 mmol, 0.10 equiv.) in p-xylene (540 mL) was heated to 140 °C overnight under an inert atmosphere of nitrogen. Subsequently, water (1 L) was added, and the product was extracted with EtOAc (500 mL). 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 red oil (30 g, 54%). Part X – Synthesis of ethyl 2-(3-fluoro-4-hydroxy-5-methylphenyl)acetatePalladium 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 mL) 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 XI – Synthesis of 2-(3-fluoro-4-hydroxy-5-methylphenyl)acetic acidA 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 mL) and water (120 mL) 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. FH12897804.1OTQ-00725 Part XII – Synthesis of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(3-fluoro-4-hydroxy-5- methylphenyl)acetamidePyBOP (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)-1H-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 (1 L) was added, and the product was extracted with EtOAc (500 mL). 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 (20% EtOAc in petroleum ether). The title compound was obtained as a white solid (10 g, 86%). Part XIII – Synthesis of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(3-fluoro-4-((7-(4- methoxybenzyl)-6-oxo-6,7,8,9-tetrahydropyrido[3,4-g]quinolin-4-yl)oxy)-5- methylphenyl)acetamideA solution of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(3-fluoro-4-hydroxy-5- methylphenyl)acetamide (500 mg, 1.64 mmol, 1.00 equiv.), 4-chloro-7-(4-methoxybenzyl)-8,9- dihydropyrido[3,4-g]quinolin-6(7H)-one (1.16 g, 3.28 mmol, 2.00 equiv.), DMAP (40.0 mg, 327 μmol, 0.20 equiv.), and K2CO3in DMF (10 mL) was heated to 120 °C for 1 h. FH12897804.1OTQ-00725 Subsequently, water was added, and the product was extracted with EtOAc (3 x 20 mL). The combined organic phases were washed with brine (30 mL), dried over Na2SO4, 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, isocratic separation with 50% B; wavelength: 210 nm). The title compound was obtained as a light-yellow solid (800 mg, 79%). Part XIV – Synthesis of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(3-fluoro-5-methyl-4-((6-oxo- 6,7,8,9-tetrahydropyrido[3,4-g]quinolin-4-yl)oxy)phenyl)acetamide (Compound 180)A solution of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(3-fluoro-4-((7-(4-methoxybenzyl)-6-oxo- 6,7,8,9-tetrahydropyrido[3,4-g]quinolin-4-yl)oxy)-5-methylphenyl)acetamide (400 mg, 643 μmol, 1.00 equiv.) in TFA (8 mL) was heated to 70 °C overnight. 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: 25-55% B in 30 min; wavelength: 210 nm). The title compound was obtained as a light-yellow solid (74.6 mg, 23%). LCMS (ESI) calculated for C28H29FN5O3(M+H)+: 502.2, found: 502.3.1H NMR (400 MHz, DMSO-d6) 10.18 (s, 1H), 8.70 (d, J = 5.2 Hz, 1H), 8.27 (d, J = 8.9 Hz, 1H), 8.15 (s, 1H), 8.01 – 7.93 (m, 2H), 7.46 (s, 1H), 7.28 (d, J = 11.0 Hz, 1H), 7.21 (s, 1H), 6.55 (d, J = 5.1 Hz, 1H), 3.75 (t, J = 6.7 Hz, 2H), 3.64 (s, 2H), 3.51 – 3.45 (m, 2H), 2.19 (s, 3H), 1.49 (s, 9H). Example 20 – Synthesis of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(4-((2-fluoro-6- (methylsulfonyl)quinolin-4-yl)oxy)-3-methylphenyl)acetamide (Compound 183); Prepared according to General Scheme 13 FH12897804.1OTQ-00725Part I – Synthesis of 2-(4-((6-bromo-2-chloroquinolin-4-yl)oxy)-3-methylphenyl)-N-(1- (tert-butyl)-1H-pyrazol-4-yl)acetamideA solution of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(4-hydroxy-3-methylphenyl)acetamide (3.11 g, 10.8 mmol, 1.00 equiv., can be synthesized according to the synthesis described in Part IV of Example 1), 6-bromo-2,4-dichloroquinoline (3.00 g, 10.8 mmol, 1.00 equiv.), DMAP (260 mg, 2.17 mmol, 0.20 equiv.), and K2CO3(4.52 g, 32.5 mmol, 3.00 equiv.) in DMF (60 mL) was heated to 120 °C for 2 h. Subsequently, water was added, and the product was extracted with EtOAc (3 x 50 mL). The combined organic phases were washed with brine (3 x 100 mL), dried over Na2SO4, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography (35% EtOAc in petroleum ether). The title compound was obtained as a white solid (2.5 g, 44%). Part II – Synthesis of 2-(4-((6-bromo-2-fluoroquinolin-4-yl)oxy)-3-methylphenyl)-N-(1- (tert-butyl)-1H-pyrazol-4-yl)acetamideFH12897804.1OTQ-00725 A solution of 2-(4-((6-bromo-2-chloroquinolin-4-yl)oxy)-3-methylphenyl)-N-(1-(tert-butyl)- 1H-pyrazol-4-yl)acetamide (1.00 g, 1.89 mmol, 1.00 equiv.), cesium fluoride (860 mg, 5.68 mmol, 3.00 equiv.), tetramethylammonium chloride (20 mg, 190 μmol, 0.10 equiv.), and 1,4,7,10,13,16-hexaoxacyclooctadecane (50 mg, 190 μmol, 0.10 equiv.) in ACN (15 mL) was heated to 120 °C for 2 h inside a microwave oven. 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: 45-90% B in 45 min; wavelength: 210 nm). The title compound was obtained as a yellow solid (240 mg, 25%). Part III – Synthesis of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(4-((2-fluoro-6- (methylthio)quinolin-4-yl)oxy)-3-methylphenyl)acetamideA solution of 2-(4-((6-bromo-2-fluoroquinolin-4-yl)oxy)-3-methylphenyl)-N-(1-(tert-butyl)-1H- pyrazol-4-yl)acetamide (240 mg, 469 μmol, 1.00 equiv.), sodium thiomethoxide (39.5 mg, 563 μmol, 1.20 equiv.), tris(dibenzylideneacetone)dipalladium(0) (86 mg, 94 μmol, 0.20 equiv.), Xantphos (54.3 mg, 94 μmol, 0.20 equiv.), and triethylamine (143 mg, 1.41 mmol, 3.00 equiv.) in 1,4-dioxane (4.8 mL) was heated to 80 °C for 2 h under an inert atmosphere of nitrogen. Subsequently, water was added, and the product was extracted with EtOAc (3 x 10 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 brown oil (370 mg), which was used in the next reaction without further purification. Part IV – Synthesis of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(4-((2-fluoro-6- (methylsulfonyl)quinolin-4-yl)oxy)-3-methylphenyl)acetamide (Compound 183) FH12897804.1OTQ-00725A solution of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(4-((2-fluoro-6-(methylthio)quinolin-4- yl)oxy)-3-methylphenyl)acetamide (350 mg, 731 μmol, 1.00 equiv.) and 3-chloroperbenzoic acid (252 mg, 1.46 mmol, 2.00 equiv.) in DCM (7 mL) was stirred at room temperature for 1 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: 40-70% B in 30 min; wavelength: 210 nm). The title compound was obtained as a white solid (32.4 mg, 14% over 2 steps). LCMS (ESI) calculated for C26H28FN4O4S (M+H)+: 511.2, found: 511.2.1H NMR (400 MHz, DMSO- d6) 10.18 (s, 1H), 8.88 (s, 1H), 8.34 (d, J = 8.9 Hz, 1H), 8.14 (d, J = 8.9 Hz, 1H), 7.95 (s, 1H), 7.46 (s, 1H), 7.41 (s, 1H), 7.34 – 7.28 (m, 2H), 6.25 (s, 1H), 3.63 (s, 2H), 3.40 (s, 3H), 2.18 (s, 3H), 1.50 (s, 9H). Example 21 – Synthesis of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(4-((1,1-dioxido-2,3- dihydrothieno[2,3-g]quinolin-8-yl)oxy)-3-methylphenyl)acetamide (Compound 178); Prepared according to General Scheme 4Part I – Synthesis of 5-nitrobenzo[b]thiophene 1,1-dioxide FH12897804.1OTQ-007253-Chloroperbenzoic acid (14.5 g, 83.7 mmol, 3.00 equiv.) was added to a solution of 5- nitrobenzo[b]thiophene (5.00 g, 27.9 mmol, 1.00 equiv.) in DCM (100 mL) and the mixture was stirred at room temperature overnight. Subsequently, water was added, and the product was extracted with DCM (3 x 20 mL). The combined organic phases were washed with water (3 x 20 mL), dried over Na2SO4, and the solvent was removed under reduced pressure. The title compound was obtained as a yellow solid (10 g), which was used in the next reaction without further purification. Part II – Synthesis of 5-aminobenzo[b]thiophene 1,1-dioxide4,4’-Bipyridine (180 mg, 1.14 mmol, 0.03 equiv.) and tetrahydroxydiboron (10.0 g, 114 mmol, 3.00 equiv.) were added to a solution of 5-nitrobenzo[b]thiophene 1,1-dioxide (8.00 g, 37.9 mmol, 1.00 equiv.) in DMF (80 mL) at 0 °C. Subsequently, the mixture was stirred at this temperature for 10 min. Water was added and the product was extracted with EtOAc (3 x 100 mL). The combined organic phases were washed with water (3 x 100 mL), dried over Na2SO4, and the solvent was removed under reduced pressure. The title compound was obtained as a brown oil (10 g), which was used in the next reaction without further purification. Part III – Synthesis of 5-(((1,1-dioxidobenzo[b]thiophen-5-yl)amino)methylene)-2,2- dimethyl-1,3-dioxane-4,6-dione FH12897804.1OTQ-00725A solution of 5-aminobenzo[b]thiophene 1,1-dioxide (10.0 g, 55.2 mmol, 1.00 equiv.) and 5- (methoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (11.3 g, 60.7 mmol, 1.10 equiv.) in EtOH (100 mL) was stirred at room temperature for 30 min. Subsequently, the solution was filtered, and the remaining solids were washed with EtOH (100 mL). The solvent was removed under reduced pressure. The title compound was obtained as a yellow solid (5.2 g), which was used in the next reaction without further purification. Part IV – Synthesis of 8-hydroxythieno[2,3-g]quinoline 1,1-dioxideA solution of 5-(((1,1-dioxidobenzo[b]thiophen-5-yl)amino)methylene)-2,2-dimethyl-1,3- dioxane-4,6-dione (3.00 g, 8.95 mmol, 1.00 equiv.) in diphenyl ether (60 mL) was heated to 220 °C for 30 min. Subsequently, diethyl ether (200 mL) was added, and the precipitated product was filtered off and dried under reduced pressure. The title compound was obtained as a brown solid (1.2 g), which was used in the next reaction without further purification. Part V – Synthesis of 8-chlorothieno[2,3-g]quinoline 1,1-dioxide FH12897804.1OTQ-00725A solution of 8-hydroxythieno[2,3-g]quinoline 1,1-dioxide (800 mg, 3.00 mmol, 1.00 equiv.) in phosphoryl chloride (8 mL) was heated to 90 °C for 1 h. Subsequently, the solvent was removed under reduced pressure. An aqueous saturated solution of Na2CO3(50 mL) was added and the product was extracted with EtOAc (3 x 30 mL). The combined organic phases were washed with water (20 mL), dried over Na2SO4, and the solvent was removed under reduced pressure. The title compound was obtained as a brown solid, which was used in the next reaction without further purification. Part VI – Synthesis of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(4-((1,1-dioxidothieno[2,3- g]quinolin-8-yl)oxy)-3-methylphenyl)acetamide (35)A solution of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(4-hydroxy-3-methylphenyl)acetamide (300 mg, 1.04 mmol, 1.00 equiv., can be synthesized according to the synthesis described in Part IV of Example 1), 8-chlorothieno[2,3-g]quinoline 1,1-dioxide (394 mg, 1.57 mmol, 1.50 equiv.), DMAP (12.8 mg, 104 μmol, 0.10 equiv.), and K2CO3(433 mg, 3.13 mmol, 3.00 equiv.) in DMF (6 mL) was heated to 120 °C for 1 h. Subsequently, water was added, and the product was extracted with EtOAc (3 x 20 mL). 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 title compound was obtained as a white solid (41 mg, 7.8%). FH12897804.1OTQ-00725 Part VII – Synthesis of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(4-((1,1-dioxido-2,3- dihydrothieno[2,3-g]quinolin-8-yl)oxy)-3-methylphenyl)acetamide (Compound 178)Palladium on carbon (10 wt.%, 5 mg) was added to a solution of N-(1-(tert-butyl)-1H-pyrazol- 4-yl)-2-(4-((1,1-dioxidothieno[2,3-g]quinolin-8-yl)oxy)-3-methylphenyl)acetamide (50.0 mg, 99.0 μmol, 1.00 equiv.) in MeOH (4 mL) and the mixture was heated to 50 °C for 3 h under hydrogen (20 atm). 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: 25-55% B in 30 min; wavelength: 210 nm). The title compound was obtained as a white solid (6.5 mg, 13%). LCMS (ESI) calculated for C27H29N4O4S (M+H)+: 505.2, found: 505.3.1H NMR (400 MHz, DMSO-d6) 10.19 (s, 1H), 8.79 (d, J = 5.2 Hz, 1H), 8.67 (s, 1H), 8.18 (s, 1H), 7.95 (s, 1H), 7.46 (s, 1H), 7.38 (d, J = 2.1 Hz, 1H), 7.31 (dd, J = 8.3, 2.2 Hz, 1H), 7.23 (d, J = 8.2 Hz, 1H), 6.51 (d, J = 5.2 Hz, 1H), 3.76 (t, J = 6.9 Hz, 2H), 3.64 – 3.58 (m, 4H), 2.14 (s, 3H), 1.49 (s, 9H). Example 22 – Synthesis of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(3-fluoro-5-methyl-4-((7- methyl-6-(methylsulfonyl)quinolin-4-yl)oxy)phenyl)acetamide (Compound 29); Prepared according to General Schemes 4 and 5Part I – Synthesis of 5-(((4-bromo-3-methylphenyl)amino)methylene)-2,2-dimethyl-1,3- dioxane-4,6-dione FH12897804.1OTQ-00725A solution of 4-bromo-3-methylaniline (8.00 g, 43.0 mmol, 1.00 equiv.) and 5- (methoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (8.81 g, 47.3 mmol, 1.10 equiv.) in EtOH (160 mL) was stirred at room temperature for 30 min. Subsequently, the precipitated product was filtered off, washed with EtOH (2 x 30 mL), and dried under reduced pressure. The title compound was obtained as a white solid (13.5 g, 92%), which was used in the next reaction without further purification. Part II – Synthesis of 6-bromo-7-methylquinolin-4-olA solution of 5-(((4-bromo-3-methylphenyl)amino)methylene)-2,2-dimethyl-1,3-dioxane-4,6- dione (7.50 g, 22.0 mmol, 1.00 equiv.) in diphenyl ether (150 mL) was heated to 200 °C for 90 min. Subsequently, diethyl ether (300 mL) was added. The precipitated product was filtered off, washed with diethyl ether (3 x 20 mL), and dried under reduced pressure. The title compound was obtained as a brown solid (3.2 g, 61%), which was used in the next reaction without further purification. Part III – Synthesis of 6-bromo-4-chloro-7-methylquinolineFH12897804.1OTQ-00725 A solution of 6-bromo-7-methylquinolin-4-ol (3.20 g, 13.4 mmol, 1.00 equiv.) in phosphoryl chloride (64 mL) was heated to 90 °C for 1 h. Subsequently, the solvent was removed under reduced pressure. An aqueous saturated solution of Na2CO3(50 mL) was added and the product was extracted with EtOAc (3 x 50 mL). The combined organic phases were washed with brine (2 x 100 mL), dried over Na2SO4, and the solvent was removed under reduced pressure. The title compound was obtained as a brown solid (3.4 g), which was used in the next reaction without further purification. Part IV – Synthesis of 4-chloro-7-methyl-6-(methylthio)quinolineA solution of 6-bromo-4-chloro-7-methylquinoline (3.40 g, 13.3 mmol, 1.00 equiv.), sodium thiomethoxide (1.39 g, 19.9 mmol, 1.50 equiv.), tris(dibenzylideneacetone)dipalladium(0) (2.43 g, 2.65 mmol, 0.20 equiv.), Xantphos (1.53 g, 2.65 mmol, 0.20 equiv.), and triethylamine (4.02 g, 39.8 mmol, 3.00 equiv.) in 1,4-dioxane (68 mL) was heated to 80 °C for 2 h under an inert atmosphere of nitrogen. Subsequently, water was added, and the product was extracted with EtOAc (3 x 100 mL). The combined organic phases were washed with brine (200 mL), dried over Na2SO4, 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: 65-95% B in 30 min; wavelength: 210 nm). The title compound was obtained as a white solid (200 mg, 6.7% over 2 steps). Part V – Synthesis of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(3-fluoro-5-methyl-4-((7-methyl- 6-(methylthio)quinolin-4-yl)oxy)phenyl)acetamide FH12897804.1OTQ-00725A solution of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(3-fluoro-4-hydroxy-5- methylphenyl)acetamide (150 mg, 491 μmol, 1.00 equiv., can be synthesized according to the synthesis described in Part XII of Example 19), 4-chloro-7-methyl-6-(methylthio)quinoline (132 mg, 589 μmol, 1.20 equiv.), DMAP (12 mg, 98 μmol, 0.20 equiv.), and K2CO3(204 mg, 1.47 mmol, 3.00 equiv.) in DMF (3 mL) was heated to 120 °C for 1 h. 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: 60-90% B in 30 min; wavelength: 210 nm). The title compound was obtained as a white solid (95 mg, 39%). Part VI – Synthesis of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(3-fluoro-5-methyl-4-((7- methyl-6-(methylsulfonyl)quinolin-4-yl)oxy)phenyl)acetamide (Compound 29)Oxone (117 mg, 380 μmol, 2.20 equiv.) was added to a solution of N-(1-(tert-butyl)-1H- pyrazol-4-yl)-2-(3-fluoro-5-methyl-4-((7-methyl-6-(methylthio)quinolin-4- yl)oxy)phenyl)acetamide (85.0 mg, 173 μmol, 1.00 equiv.) in THF (850 μL) and water (850 μL) and the mixture was stirred at room temperature for 1 h. 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 white solid (29.6 mg, 33%). LCMS (ESI) calculated for C27H30FN4O4S (M+H)+: 525.2, found: 525.2.1H NMR (400 MHz, DMSO- d6) 10.20 (s, 1H), 8.96 (s, 1H), 8.82 (d, J = 5.2 Hz, 1H), 8.13 (s, 1H), 7.95 (s, 1H), 7.47 (s, FH12897804.1OTQ-00725 1H), 7.29 (d, J = 11.0 Hz, 1H), 7.23 (s, 1H), 6.57 (d, J = 5.2 Hz, 1H), 3.65 (s, 2H), 3.40 (s, 3H), 2.86 (s, 3H), 2.19 (s, 3H), 1.50 (s, 9H). Example 23 – Preparation of Additional Modified Quinoline Compounds Compound in the table below was prepared based on experimental procedures described in Examples 17-22 and the detailed description.Example 24 – Synthesis of 4-(4-(2-((1-(tert-butyl)-1H-pyrazol-4-yl)amino)-2-oxoethyl)-2- fluoro-6-methylphenoxy)-N-phenylquinoline-6-carboxamide (Compound 61); Prepared according to General Scheme 14 FH12897804.1OTQ-00725Part I – Synthesis of methyl 4-(4-(2-((1-(tert-butyl)-1H-pyrazol-4-yl)amino)-2-oxoethyl)-2- fluoro-6-methylphenoxy)quinoline-6-carboxylateA solution of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(3-fluoro-4-hydroxy-5- methylphenyl)acetamide (500 mg, 1.64 mmol, 1.00 equiv., can be synthesized according to the synthesis described in Part XII of Example 19), methyl 4-chloroquinoline-6-carboxylate (436 mg, 1.96 mmol, 1.20 equiv.), DMAP (20.0 mg, 164 μmol, 0.10 equiv.), and K2CO3(679 mg, 4.91 mmol, 3.00 equiv.) in DMF (10 mL) was heated to 120 °C for 2 h. Subsequently, water was added, and the product was extracted with EtOAc (3 x 30 mL). The combined organic phases were washed with brine (3 x 50 mL), dried over Na2SO4, and the solvent was removed under reduced pressure. The title compound was obtained as a brown solid (1.1 g), which was used in the next reaction without further purification. Part II – Synthesis of 4-(4-(2-((1-(tert-butyl)-1H-pyrazol-4-yl)amino)-2-oxoethyl)-2-fluoro- 6-methylphenoxy)quinoline-6-carboxylic acidFH12897804.1OTQ-00725 Lithium hydroxide monohydrate (470 mg, 11.2 mmol, 5.00 equiv.) was added to a solution of methyl 4-(4-(2-((1-(tert-butyl)-1H-pyrazol-4-yl)amino)-2-oxoethyl)-2-fluoro-6- methylphenoxy)quinoline-6-carboxylate (1.10 g, 2.24 mmol, 1.00 equiv.) in THF (11 mL) and the mixture was heated to 80 °C overnight. Subsequently, the pH of the solution was adjusted to 3 with hydrochloric acid and the product was extracted with EtOAc (3 x 30 mL). The combined organic phases were washed with brine (3 x 50 mL), dried over Na2SO4, and the solvent was removed under reduced pressure. The crude product was purified by reversed-phase flashchromatography (column: C18 silica gel; mobile phase A: water (10 mmol / L NH4HCO3),mobile phase B: ACN, gradient: 35-60% B in 30 min; wavelength: 210 nm). The title compound was obtained as a white solid (480 mg, 61% over 2 steps). Part III – Synthesis of 4-(4-(2-((1-(tert-butyl)-1H-pyrazol-4-yl)amino)-2-oxoethyl)-2-fluoro- 6-methylphenoxy)-N-phenylquinoline-6-carboxamide (Compound 61)HATU (115 mg, 302 μmol, 1.20 equiv.) was added to a solution of 4-(4-(2-((1-(tert-butyl)-1H- pyrazol-4-yl)amino)-2-oxoethyl)-2-fluoro-6-methylphenoxy)quinoline-6-carboxylic acid (120 mg, 252 μmol, 1.00 equiv.), aniline (25.8 mg, 277 μmol, 1.10 equiv.), and DIPEA (97.6 mg, 756 μmol, 3.00 equiv.) in DMF (2.4 mL) and the mixture was stirred at room temperature for 2 h. Subsequently, the crude product was purified by reversed-phase flash chromatography (column: C18 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 title compound was obtained as a white solid (17.0 mg, 12%). LCMS (ESI) calculated for C32H31FN5O3(M+H)+: 552.2, found: 552.2.1H NMR (400 MHz, DMSO-d6) 10.64 (s, 1H), 10.26 (d, J = 6.8 Hz, 1H), 9.04 (d, J = 2.0 Hz, 1H), 8.78 (d, J = 5.2 Hz, 1H), 8.37 (dd, J = 8.8, 2.1 Hz, 1H), 8.17 (d, J = 8.8 Hz, 1H), 7.95 (s, 1H), 7.87 – 7.80 (m, 2H), 7.47 (s, 1H), 7.43 – 7.34 (m, 2H), 7.30 (dd, J = 11.0, 2.0 Hz, FH12897804.1OTQ-00725 1H), 7.23 (s, 1H), 7.18 – 7.09 (m, 1H), 6.57 (dd, J = 5.1, 1.2 Hz, 1H), 3.65 (s, 2H), 2.20 (s, 3H), 1.49 (s, 9H). Example 25 – Preparation of Additional Quinoline-6-carboxamide Compounds Compounds in the table below were prepared based on experimental procedures described in Examples 24 and the detailed description.FH12897804.1OTQ-00725Example 26 – Synthesis of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(3-methyl-4-((6- (methyl(phenyl)phosphoryl)quinolin-4-yl)oxy)phenyl)acetamide (Compounds 55 and 58); Prepared according to General Scheme 16Part I – Synthesis of (4-chloroquinolin-6-yl)(methyl)(phenyl)phosphine oxideA solution of 6-bromo-4-chloroquinoline (1.04 g, 4.28 mmol, 1.00 equiv.), methyl(phenyl)phosphine oxide (600 mg, 4.28 mmol, 1.00 equiv.), tris(dibenzylideneacetone)dipalladium(0) (392 mg, 428 μmol, 0.10 equiv.), Xantphos (496 mg, 856 μmol, 0.20 equiv.), and triethylamine (1.30 g, 12.8 mmol, 3.00 equiv.), in 1,4-dioxane (12 FH12897804.1OTQ-00725 mL) was heated to 90 °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: 40-70% B in 30 min; wavelength: 210 nm). The racemic title compound was obtained as a brown oil (750 mg, 58%). Part II – Synthesis of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(3-methyl-4-((6- (methyl(phenyl)phosphoryl)quinolin-4-yl)oxy)phenyl)acetamide (Compound 55 and 58)A solution of (4-chloroquinolin-6-yl)(methyl)(phenyl)phosphine oxide (200 mg, 663 μmol, 1.00 equiv.), N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(4-hydroxy-3-methylphenyl)acetamide (191 mg, 663 μmol, 1.00 equiv., can be synthesized according to the synthesis described in Part IV of Example 1), DMAP (8.1 mg, 66 μmol, 0.10 equiv.), and K2CO3(183 mg, 1.33 mmol, 2.00 equiv.) in DMF (4 mL) was heated to 120 °C for 2 h. 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: 25-55% B in 30 min; wavelength: 210 nm). The racemic title compound was obtained as a white solid (240 mg, 66%). The two enantiomers were separated by chiral chromatography (column: Chiral ART Cellulose-SZ, 30 × 250 mm, 5 μm; mobile phase A: supercritical CO2, mobile phase B: MeOH, isocratic separation with 40% B, flow rate 100 mL / min). The title compounds (compound 55 (enantiomer 1): 56.5 mg, 16%; compound 58 (enantiomer 2): 41.5 mg, 11%) were obtained as white solids (retention time (enantiomer 1): 2.18 min, retention time (enantiomer 2): 2.34 min, column: Chiral ART Cellulose-SZ, 4.6 × 50 mm, 3 μm, mobile phase A: supercritical CO2, mobile phase B: MeOH (0.5% 2 M ammonia in MeOH, gradient of 10-50% B in 2.0 min, followed by isocratic separation with 50% B, flow rate: 4.0 mL / min, wavelength: 220 nm). LCMS (ESI) calculated for C32H34N4O3P (M+H)+: 553.2, found: 553.3.1H NMR (400 MHz, FH12897804.1OTQ-00725 DMSO-d6) δ 10.18 (s, 1H), 8.82 (d, J = 13.0 Hz, 1H), 8.74 (d, J = 5.1 Hz, 1H), 8.13 – 8.04 (m, 2H), 7.94 (s, 1H), 7.89 – 7.81 (m, 2H), 7.60 – 7.50 (m, 3H), 7.45 (s, 1H), 7.37 (s, 1H), 7.29 (d, J = 8.3 Hz, 1H), 7.20 (d, J = 8.2 Hz, 1H), 6.48 (d, J = 5.1 Hz, 1H), 3.60 (s, 2H), 2.17 (d, J = 13.7 Hz, 3H), 2.12 (s, 3H), 1.48 (s, 9H). Example 27 – Preparation of Additional Phosphine Oxide Compounds Compounds in the table below were prepared based on experimental procedures described in Example 26 and the detailed description.FH12897804.1OTQ-00725FH12897804.1OTQ-00725Example 28 – Synthesis of 4-((4-(2-((1-(tert-butyl)-1H-pyrazol-4-yl)amino)-2-oxoethyl)-2- methylphenyl)amino)-N-methylquinoline-6-carboxamide (Compound 182); Prepared according to General Scheme 8Part I – Synthesis of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(3-methyl-4- nitrophenyl)acetamideA solution of 2-(3-methyl-4-nitrophenyl)acetic acid (1.00 g, 5.12 mmol, 1.00 equiv.), 1-(tert- butyl)-1H-pyrazol-4-amine (0.71 g, 5.12 mmol, 1.00 equiv.), DIPEA (3.31 g, 25.6 mmol, 5.00 equiv.), and PyBOP (5.33 g, 10.2 mmol, 2.00 equiv.) in DMF (20 mL) was stirred at room FH12897804.1OTQ-00725 temperature for 2 h. 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: 40-70% B in 30 min; wavelength: 210 nm). The title compound was obtained as a yellow solid (900 mg, 55%). Part II – Synthesis of 2-(4-amino-3-methylphenyl)-N-(1-(tert-butyl)-1H-pyrazol-4- yl)acetamideA solution of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(3-methyl-4-nitrophenyl)acetamide (900 mg, 2.85 mmol, 1.00 equiv.), tetrahydroxydiboron (765 mg, 8.54 mmol, 3.00 equiv.), and 4,4’- bipyridine (22.2 mg, 142 μmol, 0.05 equiv.) in DMF (9 mL) was stirred at 0 °C for 10 min. Subsequently, the reaction was quenched through the addition of water and the product was extracted with EtOAc (3 x 20 mL). The combined organic phases were washed with brine (10 mL), dried over Na2SO4, 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: 30-60% B in 30 min; wavelength: 210 nm). The title compound was obtained as a pink solid (550 mg, 67%). Part III – Synthesis of 4-chloro-N-methylquinoline-6-carboxamideA solution of propylphosphonic anhydride in EtOAc (50%, 38.3 g, 120 mmol, 5.00 equiv.) was added to a solution of 4-chloroquinoline-6-carboxylic acid (5.00 g, 24.1 mmol, 1.00 equiv.), methylamine hydrochloride (2.44 g, 36.1 mmol, 1.50 equiv.), and DIPEA (18.7 g, 145 mmol, 6.00 equiv.) in DMF (100 mL). The mixture was stirred overnight at room temperature. FH12897804.1OTQ-00725 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: 30-60% B in 30 min; wavelength: 210 nm). The title compound was obtained as a yellow solid (4.7 g, 88%). Part IV – Synthesis of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(3-methyl-4- nitrophenyl)acetamide (Compound 182)A solution of 2-(4-amino-3-methylphenyl)-N-(1-(tert-butyl)-1H-pyrazol-4-yl)acetamide (130 mg, 453 μmol, 1.00 equiv.) and 4-chloro-N-methylquinoline-6-carboxamide (100 mg, 453 μmol, 1.00 equiv.) was heated to 80 °C overnight. Subsequently, the crude product was purified by preparative HPLC (column: XBridge Prep OBD C18, 30 × 150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3+ 0.05% ammonia solution), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 18-48% B in 10 min; wavelength: 220 nm; RT1: 8.2 min). The title compound was obtained as a white solid (61.1 mg, 28%). LCMS (ESI) calculated for C27H31N6O2(M+H)+: 471.3, found: 471.3.1H NMR (400 MHz, DMSO-d6) 10.21 (s, 1H), 9.01 – 8.87 (m, 2H), 8.51 – 8.47 (m, 1H), 8.37 (d, J = 5.3 Hz, 1H), 8.04 (dd, J = 8.8, 1.8 Hz, 1H), 7.96 (s, 1H), 7.87 (d, J = 8.7 Hz, 1H), 7.46 (s, 1H), 7.32 (s, 1H), 7.28 – 7.19 (m, 2H), 6.08 (d, J = 5.3 Hz, 1H), 3.59 (s, 2H), 2.87 (d, J = 4.5 Hz, 3H), 2.16 (s, 3H), 1.49 (s, 9H). Example 29 – Synthesis of 3-(4-(2-((1-(tert-butyl)-1H-pyrazol-4-yl)amino)-2-oxoethyl)-2- methylphenoxy)-N-methylimidazo[1,2-a]pyridine-6-carboxamide (Compound 184); Prepared according to General Scheme 10 FH12897804.1OTQ-00725Part I – Synthesis of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(4-(2,2-diethoxyethoxy)-3- methylphenyl)acetamideA solution of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(4-hydroxy-3-methylphenyl)acetamide (3.00 g, 10.4 mmol, 1.00 equiv., can be synthesized according to the synthesis described in Part IV of Example 1), bromoacetaldehyde diethyl acetal (3.09 g, 15.7 mmol, 1.50 equiv.), and K2CO3(2.89 g, 28.9 mmol, 2.00 equiv.) in DMF (30 mL) was heated to 110 °C for 48 h. Subsequently, water was added, and the product was extracted with EtOAc (3 x 60 mL). The combined organic phases were washed with brine (3 x 30 mL), dried over Na2SO4, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography (gradient of 0-60% EtOAc in petroleum ether in 90 min). The title compound was obtained as a brown solid (2.1 g, 50%). Part II – Synthesis of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(3-methyl-4-(2- oxoethoxy)phenyl)acetamideA solution of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(4-(2,2-diethoxyethoxy)-3- methylphenyl)acetamide (2.10 g, 5.20 mmol, 1.00 equiv.) in hydrochloric acid (12 M, 3.05 mL) and THF (4 mL) was stirred at room temperature for 1 h. Subsequently, the pH was adjusted to FH12897804.1OTQ-00725 8 through the addition of an aqueous saturated solution of NaHCO3 and the product was extracted with DCM (3 x 10 mL). The combined organic phases were washed with brine (10 mL), dried over Na2SO4, and the solvent was removed under reduced pressure. The title compound was obtained as a brown oil (2 g), which was used in the next reaction without further purification. Part III – Synthesis of 3-(4-(2-((1-(tert-butyl)-1H-pyrazol-4-yl)amino)-2-oxoethyl)-2- methylphenoxy)imidazo[1,2-a]pyridine-6-carboxylic acidA solution of 6-aminonicotinic acid (500 mg, 3.62 mmol, 1.00 equiv.), N-(1-(tert-butyl)-1H- pyrazol-4-yl)-2-(3-methyl-4-(2-oxoethoxy)phenyl)acetamide (3.58 g, 10.9 mmol, 3.00 equiv.), and iodine (1.84 g, 7.24 mmol, 2.00 equiv.) in 1,2-dichloroethane (10 mL) was heated to 80 °C for 30 min. 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: 20-50% B in 30 min; wavelength: 210 nm). The title compound was obtained as a brown oil (200 mg, 12%). Part IV – Synthesis of 3-(4-(2-((1-(tert-butyl)-1H-pyrazol-4-yl)amino)-2-oxoethyl)-2- methylphenoxy)-N-methylimidazo[1,2-a]pyridine-6-carboxamide (Compound 184)PyBOP (349 mg, 670 μmol, 1.50 equiv.) was added to a solution of 3-(4-(2-((1-(tert-butyl)-1H- pyrazol-4-yl)amino)-2-oxoethyl)-2-methylphenoxy)imidazo[1,2-a]pyridine-6-carboxylic acid FH12897804.1OTQ-00725 (200 mg, 447 μmol, 1.00 equiv.), methylamine (16.7 mg, 536 μmol, 1.20 equiv.), and DIPEA (289 mg, 2.24 μmol, 5.00 equiv.) in DMF (690 μL) and the mixture was stirred at room temperature for 2 h. 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: 25-55% B in 30 min; wavelength: 210 nm). The title compound was obtained as a white solid (14.3 mg, 6.9%). LCMS (ESI) calculated for C25H29N6O3(M+H)+: 461.2, found: 461.3.1H NMR (400 MHz, DMSO-d6) 10.12 (s, 1H), 8.66 – 8.62 (m, 1H), 8.57 (s, 1H), 7.90 (s, 1H), 7.67 – 7.59 (m, 2H), 7.41 (s, 1H), 7.33 (s, 1H), 7.28 (d, J = 2.2 Hz, 1H), 7.06 (dd, J = 8.4, 2.2 Hz, 1H), 6.67 (d, J = 8.4 Hz, 1H), 3.50 (s, 2H), 2.77 (d, J = 4.4 Hz, 3H), 2.40 (s, 3H), 1.46 (s, 9H). Example 30 – Synthesis of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(3-methyl-4-((6- (methylsulfonyl)quinolin-4-yl)methyl)phenyl)acetamide (Compound 41); Prepared according to General Schemes 5 and 17Part I – Synthesis of 4-iodo-6-(methylthio)quinolineA solution of 4-chloro-6-(methylthio)quinoline (2.00 g, 9.54 mmol, 1.00 equiv., can be synthesized according to the synthesis described in Part II of Example 8), sodium iodide (2.86 g, 19.1 mmol, 2.00 equiv.), and iodotrimethylsilane (380 mg, 1.91 mmol, 0.20 equiv.) in ACN was heated to 100 °C overnight. Subsequently, water (30 mL) was added, and the product was extracted with DCM (2 x 20 mL). The combined organic phases were washed with brine (50 FH12897804.1OTQ-00725 mL), dried over Na2SO4, 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 (0.1% formic acid), mobile phase B: ACN, gradient: 45-75% B in 30 min; wavelength: 210 nm). The title compound was obtained as a yellow solid (1.5 g, 52%). Part II – Synthesis of 4-bromo-N-methoxy-N,2-dimethylbenzamideA solution of 4-bromo-2-methylbenzoic acid (10.0 g, 46.5 mmol, 1.00 equiv.), N,O-dimethylhydroxylamine hydrochloride (13.6 g, 140 mmol, 3.00 equiv.), and 1,1 -carbonyldiimidazole (11.3 g, 69.8 mmol, 1.50 equiv.) in DCM (200 mL) was stirred at room temperature overnight. Subsequently, water (200 mL) was added, and the product was extracted with DCM (200 mL). The combined organic phases were washed with brine (50 mL), dried over Na2SO4, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography (45% EtOAc in petroleum ether). The title compound was obtained as a colorless oil (10 g, 83%). Part III – Synthesis of (4-bromo-2-methylphenyl)(6-(methylthio)quinolin-4-yl)methanoneA solution of n-butyllithium in n-hexane (2.5 M, 2.00 mL, 5.00 mmol, 1.50 equiv.) was slowly added to a solution of 4-iodo-6-(methylthio)quinoline (1.50 g, 4.98 mmol, 1.50 equiv.) in THF (15 mL) at -78 °C. The mixture was stirred for 1 h at this temperature. Subsequently, a solution of 4-bromo-N-methoxy-N,2-dimethylbenzamide (861 mg, 3.34 mmol, 1.00 equiv.) in THF (15 mL) was slowly added to the mixture and the solution was stirred for 1 h at -78 °C. After warming to room temperature, water (20 mL) was added, and the product was extracted with EtOAc (2 x 30 mL). The combined organic phases were washed with brine, dried over Na2SO4, FH12897804.1OTQ-00725 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 (0.1% formic acid), mobile phase B: ACN, gradient: 30-60% B in 30 min; wavelength: 254 nm). The title compound was obtained as a yellow solid (650 mg, 52%). Part IV – Synthesis of ethyl 2-(3-methyl-4-(6-(methylthio)quinoline-4- carbonyl)phenyl)acetateA solution of (4-bromo-2-methylphenyl)(6-(methylthio)quinolin-4-yl)methanone (500 mg, 1.34 mmol, 1.00 equiv.), ethyl potassium malonate (343 mg, 2.01 mmol, 1.50 equiv.), allylpalladium(II) chloride dimer (9.8 mg, 27 μmol, 0.02 equiv.), BINAP (50 mg, 81 μmol, 0.06 equiv.), and DMAP (16.4 mg, 134 μmol, 0.10 equiv.) in p-xylene (10 mL) was heated to 140 °C for 2 h under an inert atmosphere of nitrogen. Subsequently, water (10 mL) was added, and the product was extracted with EtOAc (20 mL). 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 reversed-phase flash chromatography (column: C18 silica gel; mobile phase A: water (0.1% formic acid), mobile phase B: ACN, gradient: 20-50% B in 30 min; wavelength: 254 nm). The title compound was obtained as a yellow solid (300 mg, 59%). Part V – Synthesis of ethyl 2-(4-(hydroxy(6-(methylthio)quinolin-4-yl)methyl)-3- methylphenyl)acetateFH12897804.1OTQ-00725 A solution of ethyl 2-(3-methyl-4-(6-(methylthio)quinoline-4-carbonyl)phenyl)acetate (300 mg, 791 μmol, 1.00 equiv.), tetrahydroxydiboron (156 mg, 1.74 mmol, 2.20 equiv.), and palladium on carbon (10 wt.%, 100 mg) in THF (3 mL) was heated to 60 °C overnight under an inert atmosphere of nitrogen. Subsequently, the solution was filtered, and the residue was washed with THF (2 x 5 mL). The solvent was removed under reduced pressure. The title compound was used in the next reaction without further purification. Part VI – Synthesis of ethyl 2-(3-methyl-4-((6-(methylthio)quinolin-4- yl)methyl)phenyl)acetateZinc (386 mg, 5.90 mmol, 10.0 equiv.) was added to a solution of ethyl 2-(4-(hydroxy(6- (methylthio)quinolin-4-yl)methyl)-3-methylphenyl)acetate (450 mg, 590 μmol, 1.00 equiv.) in acetic acid (9 mL) and the mixture was heated to 120 °C for 2 h. Subsequently, the solution was filtered, and the residue was washed with THF (20 mL). 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 (0.1% formic acid), mobile phase B: ACN, gradient: 20-50% B in 30 min; wavelength: 254 nm). The title compound was obtained as a white solid (50 mg, 17% over 2 steps). Part VII – Synthesis of 2-(3-methyl-4-((6-(methylthio)quinolin-4-yl)methyl)phenyl)acetic acidFH12897804.1OTQ-00725 Lithium hydroxide monohydrate (57.4 mg, 1.37 mmol, 10.0 equiv.) was added to a solution of ethyl 2-(3-methyl-4-((6-(methylthio)quinolin-4-yl)methyl)phenyl)acetate (50.0 mg, 137 μmol, 1.00 equiv.) in THF (1 mL) and the mixture was stirred at room temperature for 4 h. Subsequently, water (10 mL) was added, and the pH of the solution was brought to 1 with concentrated hydrochloric acid. The product was extracted with EtOAc (10 mL) and the organic phase was washed with brine, dried over Na2SO4, and the solvent was removed under reduced pressure. The title compound was used in the next reaction without further purification. Part VIII – Synthesis of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(3-methyl-4-((6- (methylthio)quinolin-4-yl)methyl)phenyl)acetamide(Benzotriazol-1-ylox)tripyrrolidinophosphonium hexafluorophosphate (148 mg, 285 μmol, 3.00 equiv.) was added to a solution of 2-(3-methyl-4-((6-(methylthio)quinolin-4- yl)methyl)phenyl)acetic acid (40.0 mg, 95.0 μmol, 1.00 equiv.), 1-tert-butylpyrazol-4-amine (15.9 mg, 114 μmol, 1.20 equiv.), and DIPEA (61.3 mg, 475 μmol, 5.00 equiv.) in DMF (800 μL) and the mixture was stirred at room temperature for 1 h. Subsequently, water (5 mL) was added, and the product was extracted with EtOAc (5 mL). The combined organic phases were washed with brine, dried over Na2SO4, and the solvent was removed under reduced pressure. The title compound was used in the next reaction without further purification. FH12897804.1OTQ-00725 - 489 - Part IX – Synthesis of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(3-methyl-4-((6- (methylsulfonyl)quinolin-4-yl)methyl)phenyl)acetamide (Compound 41) Oxone (15.0 mg, 43.0 μmol, 1.10 equiv.) was added to a solution of N-(1-(tert-butyl)-1H- pyrazol-4-yl)-2-(3-methyl-4-((6-(methylthio)quinolin-4-yl)methyl)phenyl)acetamide (36.0 mg, 39.0 μmol, 1.00 equiv.) in THF (360 μL) and water (360 μL) and the mixture was stirred at room temperature for 30 min. 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: 25-55% B in 30 min; wavelength: 210 nm). The title. compound was obtained as a white solid (1.3 mg, 1.9% over 3 steps). LCMS (ESI) calculated for C27H31N4O3S (M+H)+: 491.2, found: 491.3.1H NMR (400 MHz, DMSO-d6) δ 10.16 (s, 1H), 8.94 (d, J = 4.5 Hz, 1H), 8.77 (d, J = 1.9 Hz, 1H), 8.29 (d, J = 8.8 Hz, 1H), 8.22 (dd, J = 8.8, 1.9 Hz, 1H), 7.92 (s, 1H), 7.44 (s, 1H), 7.22 (s, 1H), 7.11 (d, J = 8.2 Hz, 1H), 7.04 (d, J = 4.5 Hz, 1H), 7.00 (d, J = 7.7 Hz, 1H), 4.57 (s, 2H), 3.53 (s, 2H), 3.34 (s, 3H), 2.23 (s, 3H), 1.48 (s, 9H).

[0247] Example 31 Preparation of Additional Diarylmethane Compounds Compound in the table below was prepared based on experimental procedures described in Example 30 and the detailed description.FH12897804.1OTQ-00725Example 32 – Synthesis of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(3-fluoro-5-methyl-4-((6-(N- (pyridin-2-yl)sulfamoyl)quinolin-4-yl)oxy)phenyl)acetamide (Compound 106); prepared according to General Scheme 18Part I – Synthesis of 4-chloroquinoline-6-sulfonyl chlorideAn aqueous solution of hydrochloric acid (3.2 mL) was added dropwise to a solution of N- chlorosuccinimide (1.80 g, 13.5 mmol, 4.00 equiv.) in ACN (32 mL) at 0 °C. Subsequently, the mixture was stirred at this temperature for 5 min and a solution of S-(4-chloroquinolin-6-yl) ethanethioate (800 mg, 3.37 mmol, 1.00 equiv., can be synthesized according to the synthesis described in Part I of Example 1) in ACN (16 mL) was added dropwise at 0 °C. The mixture was stirred at this temperature for 40 min and the solvent was removed under reduced pressure. The title compound was obtained as an off-white solid (2.1 g), which was used in the next reaction without further purification. FH12897804.1OTQ-00725 Part II – Synthesis of 4-chloro-N-(pyridin-2-yl)quinoline-6-sulfonamide2-Aminopyridine (216 mg, 2.29 mmol, 1.50 equiv.) was added to a solution of 4- chloroquinoline-6-sulfonyl chloride (1.00 g, 1.53 mmol, 1.00 equiv.) and pyridine (483 mg, 6.10 mmol, 4.00 equiv.) in DCM (20 mL) and the mixture was stirred at room temperature for 1 h. Subsequently, the crude product was purified by reversed-phase flash chromatography (column: C18 silica gel; mobile phase A: water (0.1% formic acid), mobile phase B: ACN, gradient: 10-100% B in 20 min; wavelength: 210 nm). The title compound was obtained as a white solid (150 mg, 31%). Part III – Synthesis of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(3-fluoro-5-methyl-4-((6-(N- (pyridin-2-yl)sulfamoyl)quinolin-4-yl)oxy)phenyl)acetamide (Compound 106)A solution of 4-chloro-N-(pyridin-2-yl)quinoline-6-sulfonamide (105 mg, 327 μmol, 1.00 equiv.), N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(3-fluoro-4-hydroxy-5-methylphenyl)acetamide (100 mg, 327 μmol, 1.00 equiv., can be synthesized according to the synthesis described in Part XII of Example 19), copper(I) iodide (6.3 mg, 33 μmol, 0.10 equiv.), 2,2,6,6- tetramethylheptane-3,5-dione (12.1 mg, 65 μmol, 0.20 equiv.), and Cs2CO3(213 mg, 654 μmol, 2.00 equiv.) in DMF (2 mL) was heated to 100 °C for 3 h under an inert atmosphere of nitrogen. Water (50 mL) was added, and the product was extracted with EtOAc (3 x 60 mL). The FH12897804.1OTQ-00725 combined organic phases were washed with brine (2 x 30 mL), dried over Na2SO4, 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 (0.1% formic acid), mobile phase B: ACN, gradient: 30-60% B in 30 min; wavelength: 210 nm). The title compound was obtained as a white solid (24.9 mg, 13%). LCMS (ESI) calculated for C30H30FN6O4S (M+H)+: 589.2, found: 589.3.1H NMR (400 MHz, DMSO-d6) δ 10.22 (s, 1H), 8.88 (s, 1H), 8.78 (d, J = 5.2 Hz, 1H), 8.23 – 8.13 (m, 2H), 7.97 – 7.93 (m, 2H), 7.75 (t, J = 8.1 Hz, 1H), 7.46 (s, 1H), 7.33 – 7.20 (m, 3H), 6.84 (bs, 1H), 6.59 (d, J = 5.1 Hz, 1H), 3.64 (s, 2H), 2.17 (s, 3H), 1.49 (s, 9H). Example 33 – Preparation of Additional Sulfonamide Compounds Compound in the table below was prepared based on experimental procedures described in Example 32 and the detailed description..Example 34-Synthesis of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(2-fluoro-3-methyl-4-((6- ((phenylsulfonyl)methyl)quinolin-4-yl)oxy)phenyl)acetamide (Compound 113); prepared according to General Scheme 19 FH12897804.1OTQ-00725Part I – Synthesis of 1-bromo-2-fluoro-4-(methoxymethoxy)-3-methylbenzeneSodium hydride (2.34 g, 97.5 mmol, 2.00 equiv.) was added in portions to a solution of 4- bromo-3-fluoro-2-methylphenol (10.0 g, 48.8 mmol, 1.00 equiv.) in DMF (100 mL) and the reaction mixture was stirred at room temperature for 1 h. Subsequently, bromomethyl methyl ether (9.14 g, 73.2 mmol, 1.50 equiv.) was added and the mixture was stirred at room temperature for 2 h. The crude product was purified by column chromatography (50% EtOAc in petroleum ether). The title compound was obtained as a colorless liquid (10.0 g, 82%). Part II – Synthesis of ethyl 2-(2-fluoro-4-(methoxymethoxy)-3-methylphenyl)acetateA solution of 1-bromo-2-fluoro-4-(methoxymethoxy)-3-methylbenzene (5.00 g, 20.1 mmol, 1.00 equiv.), ethyl potassium malonate (5.13 g, 30.1 mmol, 1.50 equiv.), allylpalladium(II) chloride dimer (730 mg, 2.01 mmol, 0.10 equiv.), BINAP (1.25 g, 2.01 mmol, 0.10 equiv.), and DMAP (250 mg, 2.01 mmol, 0.10 equiv.) in p-xylene (50 mL) was heated to 140 °C for 6 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: 10-100% B in 10 min; wavelength: 210 nm). The title compound was obtained as a brown oil (5.0 g). FH12897804.1OTQ-00725 Part III – Synthesis of 2-(2-fluoro-4-(methoxymethoxy)-3-methylphenyl)acetic acidA solution of ethyl 2-(2-fluoro-4-(methoxymethoxy)-3-methylphenyl)acetate (5.00 g, 19.5 mmol, 1.00 equiv.) and lithium hydroxide monohydrate (1.64 g, 39.0 mmol, 2.00 equiv.) in EtOH (50 mL) was stirred at room temperature for 2 h. Subsequently, the crude product was purified by column chromatography (50% EtOAc in petroleum ether). The title compound was obtained as a yellow solid (2.50 g, 22% over 2 steps). Part IV – Synthesis of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(2-fluoro-4-(methoxymethoxy)- 3-methylphenyl)acetamideA solution of 2-(2-fluoro-4-(methoxymethoxy)-3-methylphenyl)acetic acid (400 mg, 1.75 mmol, 1.00 equiv.), 1-(tert-butyl)-1H-pyrazol-4-amine (366 mg, 2.63 mmol, 1.50 equiv.), 1-hydroxybenzotriazole (355 mg, 2.63 mmol, 1.50 equiv.), N-(3-dimethylaminopropyl)-N -ethylcarbodiimide (544 mg, 3.51 mmol. 2.00 equiv.), and DIPEA (680 mg, 5.26 mmol, 3.00 equiv.) in DMF (4 mL) was stirred at room temperature for 4 h. Subsequently, the crude product was purified by column chromatography (50% EtOAc in petroleum ether). The title compound was obtained as a brown solid (400 mg, 65%). Part V – Synthesis of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(2-fluoro-4-hydroxy-3- methylphenyl)acetamideFH12897804.1OTQ-00725 A solution of hydrochloric acid in 1,4-dioxane (4.0 M, 2 mL) was added to N-(1-(tert-butyl)- 1H-pyrazol-4-yl)-2-(2-fluoro-4-(methoxymethoxy)-3-methylphenyl)acetamide (400 mg, 1.15 mmol, 1.00 equiv.) and the mixture was stirred at room temperature for 4 h. Subsequently, the crude product was purified by column chromatography (50% EtOAc in petroleum ether). The title compound was obtained as a yellow solid (300 mg, 86%). Part VI – Synthesis of 6-(bromomethyl)-4-chloroquinolineAIBN (370 mg, 2.25 mmol, 0.10 equiv.) was added to a solution of 4-chloro-6-methylquinoline (4.00 g, 22.5 mmol, 1.00 equiv.) and N-bromosuccinimide (4.41 g, 24.8 mmol, 1.10 equiv.) in carbon tetrachloride (200 mL) and the mixture was heated to 80 °C for 16 h. Subsequently, water (200 mL) was added, and the product was extracted with EtOAc (3 x 200 mL). The combined organic phases were washed with brine (2 x 200 mL), dried over Na2SO4, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography (10% EtOAc in petroleum ether). The title compound was obtained as a white solid (2.10 g, 36%). Part VII – Synthesis of 4-chloro-6-((phenylsulfonyl)methyl)quinolineA solution of 6-(bromomethyl)-4-chloroquinoline (2.10 g, 8.19 mmol, 1.00 equiv.), sodium benzenesulfinate (1.68 g, 10.2 mmol, 1.25 equiv.), and tetra-n-butylammonium iodide (605 mg, 1.64 mmol. 0.20 equiv.) in THF (21 mL) was heated to 50 °C for 1 h. Subsequently, water (50 mL) was added, and the product was extracted with EtOAc (3 x 100 mL). The combined FH12897804.1OTQ-00725 organic phases were washed with brine (2 x 50 mL), dried over Na2SO4, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography (35% EtOAc in petroleum ether). The title compound was obtained as a yellow solid (2.20 g, 85%). Part VIII – Synthesis of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(2-fluoro-3-methyl-4-((6- ((phenylsulfonyl)methyl)quinolin-4-yl)oxy)phenyl)acetamide (Compound 113)A solution of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(2-fluoro-4-hydroxy-3- methylphenyl)acetamide (100 mg, 327 μmol, 1.00 equiv.), 4-chloro-6- ((phenylsulfonyl)methyl)quinoline (104 mg, 327 μmol, 1.00 equiv.), copper(I) iodide (6.3 mg, 33 μmol, 0.10 equiv.), 2,2,6,6-tetramethylheptane-3,5-dione (12.1 mg, 65 μmol, 0.20 equiv.), and Cs2CO3(213 mg, 654 μmol, 2.00 equiv.) in DMF (2 mL) was heated to 100 °C for 3 h under an inert atmosphere of nitrogen. Water (50 mL) was added, and the product was extracted with EtOAc (3 x 60 mL). The combined organic phases were washed with brine (2 x 30 mL), dried over Na2SO4, and the solvent was removed under reduced pressure. The crude product was purified by preparative HPLC (column: XBridge Shield RP18 OBD, 30 × 150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 45-75% B in 20 min; wavelength: 220 nm; RT1: 8.2 min). The title compound was obtained as a white solid (117 mg, 61%). LCMS (ESI) calculated for C32H32FN4O4S (M+H)+: 587.2, found: 587.3.1H NMR (400 MHz, DMSO-d6) δ 10.23 (s, 1H), 8.67 (d, J = 5.1 Hz, 1H), 8.02 – 7.92 (m, 3H), 7.75 – 7.66 (m, 4H), 7.60 – 7.54 (m, 2H), 7.46 (s, 1H), 7.36 (t, J = 8.4 Hz, 1H), 7.03 (d, J = 8.5 Hz, 1H), 6.44 (d, J = 5.1 Hz, 1H), 5.01 (s, 2H), 3.70 (s, 2H), 1.96 (d, J = 1.2 Hz, 3H), 1.49 (s, 9H). FH12897804.1OTQ-00725 Example 35 – Preparation of Additional Sulfonylmethylquinoline Compounds Compounds in the table below were prepared based on experimental procedures described in Example 34 and the detailed description.Example 36 – Preparation of compounds 67, 68, 131, 132, 152, 159, and 170. Compounds 67, 68, 131, 132, and 152 can be prepared according to the synthetic protocol in Example 4. Compounds 159 and 170 can be prepared according to the synthetic protocol in Example 7. Example 37 - RIPK2 Inhibition

[0248] RIPK2 inhibition was measured as follows: FH12897804.1OTQ-00725

[0249] Materials: RIPK2 enzyme was purchased from Carna (catlogue 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 SignalChem 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%), DTT (final concentration of 2 mM), BSA (0.05%), EGTA (final concentration of 1 mM), and HEPE (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 μM) and MBP (final concentration of 0.02 μg / μL) 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 2. Example 38 - Inhibition of human NOD2 signaling

[0250] 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 consistsed of DMEM (Giboc, 21063- 029), heat inactivated FBS, penicillin (100 U / mL), streptomycin (100 μg / mL), Normocin (100 μg / mL), Blasticidin (30 μg / mL), and Zeocin (100 μg / mL). HEK-Blue™-hNOD2 cells were FH12897804.1OTQ-00725 transferred to assay medium consisting of DMEM (Giboc, 21063-029), heat inactivated FBS, penicillin (100 U / mL) and streptomycin (100 μg / mL) prior to stimulation. Stimulation with aNOD2 ligand, L18-MDP (Invivogen, catalogue number: tlrl-lmdp) activated NF- B and AP-1which 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- 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 EVO200.

[0251] 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 μL 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 CO2incubator for 24 hours. After the 24-hour incubation, 5 μL of the induced HEK-Blue hNOD2 cell supernatant was transferred to a new 384-well plate, centrifuged, and 45 μL 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 2. Example 39 - Inhibition of PDGFR-beta

[0252] Materials: PDGFR-beta enzyme was purchased from Carna (catalogue number 08- 158). The V9102 ADP-Glo Kinase Assay (including ultrapure ATP, 10 mM) was purchased from Promega. Kinase peptide substrate 30 (FL30) was used as the substrate for the reaction and was purchased from Perkin Elmer (catalogue number 760430). Assay buffer used for the assay consists of the following components: MgCl2(final concentration of 10 mM), Brij-35 FH12897804.1OTQ-00725 (0.01%), DTT (final concentration of 2 mM), BSA (0.05%), EGTA (final concentration of 1 mM), and HEPE (pH 7.5 at final concentration of 50 mM).

[0253] Method: In a 384-well plate, 10 nL of test compound was dispensed using Echo550 and mixed with PDGFR-beta enzyme (final concentration of 1.25 nM) in assay buffer for 30 minutes at room temperature. Subsequently, ATP (final concentration of 50 mM) and FL30 (final concentration of 1.5 mM) were dissolved in assay buffer, added, and the mixture was incubated for 90 min at room temperature. Then the ADP-Glo reagent was added and incubated for 60 min at room temperature. Lastly, 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 PDGFR-beta enzyme as reference for low control (100% kinase inhibition). Data was 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). A 4- parametric curve fit was used to determine the test compound concentration that results in 50% of PDGFR-beta kinase inhibition.

[0254] The results and PDGFR-beta / RIPK2 selectivity ratios are shown in Table 2. Table 2.FH12897804.1OTQ-00725FH12897804.1OTQ-00725FH12897804.1OTQ-00725FH12897804.1OTQ-00725FH12897804.1OTQ-00725FH12897804.1OTQ-00725

[0255] The teachings of all patents, published applications and references cited herein are incorporated by reference in their entirety.

[0256] 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. FH12897804.1

Claims

1. OTQ-00725 What is claimed is:

1. A compound represented by structural formula (I) or a pharmaceutically acceptable salt thereof: wherein: Y is CH or N; R1ais C1-3alkyl; R1band R1cis each independently H or halogen; R2is selected from -S(=O)2R3, -NHC(=O)R4, -NHS(=O)2R5, -N=S(=O)R6R7, -S(=O)(=NH)R8, - P(=O)R9R10, -C(=O)NHR11, -S(=O)2(NHR12), and -C1-3alkylene-S(=O)2R13; R3is selected from C1-3alkyl, C6-12aryl, 5- to 12-membered heteroaryl, and 4- to 10-membered heterocyclyl, wherein the C1-3alkyl is substituted with 1 to 3 substituents independently selected from halogen, C(=O)NR21R22, C6-12aryl, and 5- to 12-membered heteroaryl; and wherein the 4- to 10-membered heterocyclyl is substituted with 2 to 3 substituents independently selected from C1-3 alkyl, halogen, and 4- to 10-membered heterocyclyl; R4is selected from C1-6alkyl, C1-6haloalkyl, and C3-6cycloalkyl; R5is selected from C2-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C6-12aryl, and 5- to 12-membered heteroaryl; R6and R9is C1-3alkyl; R7is C1-3alkyl or C6-12aryl; R8and R11is selected from C1-3alkyl, C6-12aryl, and 5- to 12-membered heteroaryl, wherein the C1-3 alkyl is substituted with 1 to 3 substituents independently selected from C6-12 aryl and 5- to 12-membered heteroaryl; and R10, R12, and R13is C6-12aryl or 5- to 12-membered heteroaryl; wherein FH12897804.1 OTQ-00725 each C1-3 alkyl, C1-6 alkyl, C2-6 alkyl, C6-12 aryl, C1-6 haloalkyl, C3-6 cycloalkyl, 4- to 10- membered heterocyclyl, and 5- to 12-membered heteroaryl is optionally, unless indicated otherwise, substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, C(=O)NR21R22, NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, C1-6alkyl, C1-6deuteroalkyl, C3-8cycloalkyl, C2-6alkenyl, halo(C1-6)alkyl, C1-3alkylsulfonylaminoalkyl, hydroxy(C1-6)alkyl, amino(C1-6)alkyl, (C1-6) alkylamino(C1-6)alkyl, cyano(C1-6)alkyl, C1-3alkylcarbonylamino(C1-6)alkyl, C1-3alkoxy, halo(C1-3)alkoxy, C1-6alkoxy(C1-3)alkyl, C6-12aryl, 4- to 10-membered heterocyclyl, and 5- to 12-membered heteroaryl, wherein independently H or C1-6alkyl; R16and R17is each independently selected from H, C1-6alkyl, hydroxy(C1-6)alkyl, and halo(C1-6)alkyl; R19and R23is each independently C1-6alkyl or halo(C1-6)alkyl; R21, R22, R25and R26is each independently selected from H, C1-6alkyl, C1-3alkoxy(C1-6)alkyl, hydroxy(C1-6)alkyl, cyano(C1-6)alkyl, amino(C1-6)alkyl, C1-3 alkylamino(C1-6)alkyl, and di(C1-3)alkylamino(C1-6)alkyl; or R21and R22or R25and R26, together with the nitrogen to which they are attached, form a 3-8 membered ring optionally substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, C(=O)NR21R22, NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, C1-6alkyl, C3-8cycloalkyl, C2-6alkenyl, halo(C1-6)alkyl, C1-3alkylsulfonylaminoalkyl, hydroxy(C1-6)alkyl, amino(C1-6)alkyl, cyano(C1-6)alkyl, C1-3alkylcarbonylamino(C1-6)alkyl, C1-3alkoxy, halo(C1-3)alkoxy, C1-6alkoxy(C1-3)alkyl, C6-12aryl, 4- to 10- membered heterocyclyl, and 5- to 12-membered heteroaryl.

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

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

4. The compound of any one of claims 1-3, wherein R1ais methyl. FH12897804.1 OTQ-00725 5. The compound of any one of claims 1-4, wherein R1bis H.

6. The compound of any one of claims 1-4, wherein R1bis F.

7. The compound of any one of claims 1-6, wherein R1cis H.

8. The compound of any one of claims 1-6, wherein R1c is F.

9. The compound of any one of claims 1-6, wherein the compound is represented by structural formula (Ia):

10. The compound of claim 9, wherein R3is C6-12aryl.

11. The compound of claim 9, wherein R3is 5- to 12-membered heteroaryl.

12. The compound of claim 9, wherein R3is C1-3alkyl substituted with 1 to 3 substituents independently selected from halogen, C(=O)NR21R22, C6-12aryl, and 5- to 12-membered heteroaryl.

13. The compound of claim 9, wherein R3is C1alkyl substituted with C6-12aryl.

14. The compound of claim 9, wherein R3is C1alkyl substituted with 5- to 12-membered heteroaryl. FH12897804.1 OTQ-00725 15. The compound of claim 9, wherein R3is 5- to 7-membered heterocyclyl substituted with 2 substituents independently selected from C1-3alkyl, halogen, and 4- to 10-membered heterocyclyl.

16. The compound of any one of claims 1-6, wherein the compound is represented by structural formula (Ib):

17. The compound of claim 16, wherein R4is C1-3alkyl.

18. The compound of claim 16, wherein R4is C1-6haloalkyl.

19. The compound of claim 16, wherein R4is C3-6cycloalkyl.

20. The compound of any one of claims 1-6, wherein the compound is represented by structural formula (Ic):

21. The compound of claim 20, wherein R5is C2-6alkyl.

22. The compound of claim 20, wherein R5is C1-6haloalkyl. FH12897804.1 OTQ-00725 23. The compound of claim 20, wherein R5is C3-6cycloalkyl.

24. The compound of claim 20, wherein R5is C6-12aryl.

25. The compound of claim 20, wherein R5is 5- to 12-membered heteroaryl.

26. The compound of any one of claims 1-6, wherein the compound is represented by structural formula (Id):

27. The compound of claim 26, wherein R7is C1-3alkyl.

28. The compound of claim 26, wherein R7is C6-12aryl.

29. The compound of any one of claims 1-6, wherein the compound is represented by structural formula (Ie):

30. The compound of claim 29, wherein R8is C6-12aryl. FH12897804.1 OTQ-00725 31. The compound of claim 29, wherein R8is 5- to 12-membered heteroaryl.

32. The compound of claim 29, wherein R8is C1-3alkyl substituted with a substituent selected from C6-12aryl and 5- to 12-membered heteroaryl.

33. The compound of any one of claims 1-8, wherein the compound is represented by structural formula (If):

34. The compound of claim 33, wherein R10is C6-12aryl.

35. The compound of claim 33, wherein R10is phenyl and R9is methyl.

36. The compound of any one of claims 1-6, wherein the compound is represented by structural formula (Ig):

37. The compound of claim 36, wherein R11is C6-12aryl.

38. The compound of claim 36, wherein R11is 5- to 12-membered heteroaryl. FH12897804.1 OTQ-00725 39. The compound of claim 36, wherein R11is C1-3 alkyl substituted with a substituent selected from C6-12aryl and 5- to 12-membered heteroaryl.

40. The compound of any one of claims 1-6, wherein the compound is represented by structural formula (Ih):

41. The compound of claim 40, wherein R12is C6-12 aryl.

42. The compound of claim 40, wherein R12is 5- to 12-membered heteroaryl.

43. The compound of any one of claims 1-6, wherein the compound is represented by structural formula (Ii): wherein n is 1, 2, or 3.

44. The compound of claim 43, wherein R13is C6-12aryl.

45. The compound of claim 43, wherein R13is 5- to 12-membered heteroaryl.

46. The compound of claim 43, wherein n is 1. FH12897804.1 OTQ-00725 47. The compound of claim 1, wherein the compound is represented by one of the following structural formulas: , , , FH12897804.1 OTQ-00725 , , , , FH12897804.1 OTQ-00725 , , , , FH12897804.1 OTQ-00725 517 , , , , FH12897804.1 OTQ-00725 , , , , FH12897804.1 OTQ-00725 , , , , FH12897804.1 OTQ-00725 , , , , FH12897804.1 OTQ-00725 , , , , FH12897804.1 OTQ-00725 , , , , FH12897804.1 OTQ-00725 , , , , FH12897804.1 OTQ-00725 , , , , FH12897804.1 OTQ-00725 , , , ,FH12897804.1 OTQ-00725 , , , , FH12897804.1 OTQ-00725 , , , , FH12897804.1 OTQ-00725 , , , , FH12897804.1 OTQ-00725 , , , , FH12897804.1 OTQ-00725 , , , , FH12897804.1 OTQ-00725 , , , ,FH12897804.1 OTQ-00725 , , , ,FH12897804.1 OTQ-00725 , , , , FH12897804.1 OTQ-00725 , , , , FH12897804.1 OTQ-00725 , , , , FH12897804.1 OTQ-00725 , , , , FH12897804.1 OTQ-00725 , , , , FH12897804.1 OTQ-00725 , , , , FH12897804.1 OTQ-00725 , , , , FH12897804.1 OTQ-00725 , , , , FH12897804.1 OTQ-00725 , , , , FH12897804.1 OTQ-00725 , , , , FH12897804.1 OTQ-00725 - 543 - , , , FH12897804.1 OTQ-00725 , , , , FH12897804.1 OTQ-00725 , , , , FH12897804.1 OTQ-00725 , , , , FH12897804.1 OTQ-00725 , , , , FH12897804.1 OTQ-00725 , , , , FH12897804.1 OTQ-00725 , , , , FH12897804.1 OTQ-00725 , , , , FH12897804.1 OTQ-00725 , , , , FH12897804.1 OTQ-00725 , , , , FH12897804.1 OTQ-00725 , , , , FH12897804.1 OTQ-00725 , , , , FH12897804.1 OTQ-00725 , , , , FH12897804.1 OTQ-00725 - 556 - , , , FH12897804.1 OTQ-00725 , , , , FH12897804.1 OTQ-00725 , , , , FH12897804.1 OTQ-00725 , , or is a pharmaceutically acceptable salt thereof.

48. A compound represented by structural formula (II) or a pharmaceutically acceptable salt thereof: wherein: R1ais C1-3alkyl; R1bis H or halogen; and G is a 4- to 10-membered heterocyclyl, wherein each C1-3alkyl and 4- to 10-membered heterocyclyl is optionally substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, OR14, SR15, FH12897804.1 OTQ-00725 NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, C(=O)NR21R22, NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, C1-6alkyl, C1-6deuteroalkyl, C3-8cycloalkyl, C2-6alkenyl, halo(C1-6)alkyl, C1-3alkylsulfonylaminoalkyl, hydroxy(C1-6)alkyl, amino(C1-6)alkyl, (C1-6) alkylamino(C1-6)alkyl, cyano(C1-6)alkyl, C1-3alkylcarbonylamino(C1-6)alkyl, C1-3alkoxy, halo(C1-3)alkoxy, C1-6alkoxy(C1-3)alkyl, C6-12aryl, 4- to 8-membered heterocyclyl, and 5- to 12-membered heteroaryl, wherein independently H or C1-6alkyl; R16and R17are each independently selected from H, C1-6alkyl, hydroxy(C1-6)alkyl, and halo(C1-6)alkyl; R19and R23are each independently C1-6alkyl or halo(C1-6)alkyl; R21, R22, R25and R26are each independently selected from H, C1-6alkyl, C1-3alkoxy(C1-6)alkyl, hydroxy(C1-6)alkyl, cyano(C1-6)alkyl, amino(C1-6)alkyl, C1-3alkylamino(C1-6)alkyl, and di(C1-3)alkylamino(C1-6)alkyl; or R21and R22or R25and R26, together with the nitrogen to which they are attached, form a 3-8 membered ring optionally substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, C(=O)NR21R22, NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, C1-6alkyl, C3-8cycloalkyl, C2-6alkenyl, halo(C1-6)alkyl, C1-3alkylsulfonylaminoalkyl, hydroxy(C1-6)alkyl, amino(C1-6)alkyl, cyano(C1-6)alkyl, C1-3alkylcarbonylamino(C1-6)alkyl, C1-3alkoxy, halo(C1-3)alkoxy, C1-6alkoxy(C1-3)alkyl, C6-12aryl, 4- to 10- membered heterocyclyl, and 5- to 12-membered heteroaryl.

49. The compound of claim 48, wherein R1ais methyl.

50. The compound of claim 48 or 49, wherein R1bis H.

51. The compound of claim 48 or 49, wherein R1bis F.

52. The compound of any one of claims 48-51, wherein G comprises N. FH12897804.1 OTQ-00725 53. The compound of any one of claims 48-51, wherein G comprises S.

54. The compound of any one of claims 48-53, wherein G is substituted with 1 or 2 oxo substituents.

55. The compound of claim 48, wherein the compound is represented by structural formula (IIa) or is a pharmaceutically acceptable salt thereof: wherein RNis H or C1-3alkyl; and n is 1, 2, or 3.

56. The compound of claim 55, wherein n is 1.

57. The compound of claim 55, wherein n is 2.

58. The compound of claim 48, wherein the compound is represented by structural formula (IIb) or is a pharmaceutically acceptable salt thereof: FH12897804.1 OTQ-00725 wherein m is 0, 1, or 2; and k is 1, 2, or 3.

59. The compound of claim 58, wherein m is 0 or 1.

60. The compound of claim 58 or 59, wherein k is 1 or 2.

61. The compound of claim 48, wherein the compound is represented by one of the following structural formulas: , FH12897804.1 OTQ-00725 , or is a pharmaceutically acceptable salt thereof.

62. A compound represented by one of the following structural formulas or a pharmaceutically acceptable salt thereof: , , FH12897804.1 OTQ-00725 4 , ,, , FH12897804.1 OTQ-00725 565 , ,, , FH12897804.1 OTQ-00725 5F3N6O3 , ,, , FH12897804.1 OTQ-00725 , ,, , FH12897804.1 OTQ-00725 - 568 - , FH12897804.1 OTQ-00725 , ,, , FH12897804.1 OTQ-00725 , ,, , FH12897804.1 OTQ-00725 , ,, , FH12897804.1 OTQ-00725 - 572 - , FH12897804.1 OTQ-00725 , ,, , FH12897804.1 OTQ-00725 ,,, , FH12897804.1 OTQ-00725 , ,, , FH12897804.1 OTQ-00725 576 , ,, ,FH12897804.1 OTQ-00725 , ,, , FH12897804.1 OTQ-00725 ,,, ,FH12897804.1 OTQ-00725 ,,, ,FH12897804.1 OTQ-00725 , ,, , FH12897804.1 OTQ-00725 , ,, , FH12897804.1 OTQ-00725 , , , , FH12897804.1 OTQ-00725 , ,, , FH12897804.1 OTQ-00725 , , , , FH12897804.1 OTQ-00725 , ,, ,FH12897804.1 OTQ-00725 , ,, , FH12897804.1 OTQ-00725 ,,, ,FH12897804.1 OTQ-00725 , , , ,FH12897804.1 OTQ-00725 , ,, , FH12897804.1 OTQ-00725 , , , , FH12897804.1 OTQ-00725 , , , , FH12897804.1 OTQ-00725 , , , , FH12897804.1 OTQ-00725 , , , , FH12897804.1 OTQ-00725 , , FH12897804.1 OTQ-00725 ,, , FH12897804.1 OTQ-00725 , ,, , FH12897804.1 OTQ-00725 ,,, ,FH12897804.1 OTQ-00725 , , , ,FH12897804.1 OTQ-00725 - 599 - , , , FH12897804.1 OTQ-00725 ,,, ,FH12897804.1 OTQ-00725 , , , , FH12897804.1 OTQ-00725 , ,, , FH12897804.1 OTQ-00725 , ,, , FH12897804.1 OTQ-00725 , ,, , FH12897804.1 OTQ-00725 , ,, , FH12897804.1 OTQ-00725 , ,, , FH12897804.1 OTQ-00725 ,,, ,FH12897804.1 OTQ-00725 ,,, ,FH12897804.1 OTQ-00725 , ,, , FH12897804.1 OTQ-00725 ,,, ,FH12897804.1 OTQ-00725 ,,, ,FH12897804.1 OTQ-00725 , ,, , FH12897804.1 OTQ-00725 ,,, ,FH12897804.1 OTQ-00725 ,,, ,FH12897804.1 OTQ-00725 , ,, , FH12897804.1 OTQ-00725 , , , , FH12897804.1 OTQ-00725 617 , ,, , FH12897804.1 OTQ-00725 1 , ,, , FH12897804.1 OTQ-00725 , , , , FH12897804.1 OTQ-00725 , .

63. The compound of claim 62, wherein the compound is represented by one of the following structural formulas: , FH12897804.1 OTQ-00725 - 621 - , , , , FH12897804.1 OTQ-00725 - 622 - , , , , FH12897804.1 OTQ-00725 - 623 - , , , , FH12897804.1 OTQ-00725 - 624 - , , , , FH12897804.1 OTQ-00725 - 625 - , , , , FH12897804.1 OTQ-00725 , , , , FH12897804.1 OTQ-00725 , , , , FH12897804.1 OTQ-00725 , , , , FH12897804.1 OTQ-00725 , , , ,FH12897804.1 OTQ-00725 , , , ,FH12897804.1 OTQ-00725 , , , , FH12897804.1 OTQ-00725 , , , ,FH12897804.1 OTQ-00725 , , , ,FH12897804.1 OTQ-00725 , , , , FH12897804.1 OTQ-00725 , , , ,FH12897804.1 OTQ-00725 , , , ,FH12897804.1 OTQ-00725 , , , , FH12897804.1 OTQ-00725 , , , , FH12897804.1 OTQ-00725 , , , , FH12897804.1 OTQ-00725 , , , , FH12897804.1 OTQ-00725 , , , , FH12897804.1 OTQ-00725 , , , , FH12897804.1 OTQ-00725 , , , ,FH12897804.1 OTQ-00725 44 , , , ,FH12897804.1 OTQ-00725 , , , ,FH12897804.1 OTQ-00725 , , , , FH12897804.1 OTQ-00725 , , , , FH12897804.1 OTQ-00725 , , , , FH12897804.1 OTQ-00725 , , , , FH12897804.1 OTQ-00725 , , , , FH12897804.1 OTQ-00725 , , , , FH12897804.1 OTQ-00725 , , , , FH12897804.1 OTQ-00725 , , , , FH12897804.1 OTQ-00725 , , , , FH12897804.1 OTQ-00725 , , , , FH12897804.1 OTQ-00725 , , , , or is a pharmaceutically acceptable salt thereof. FH12897804.1 OTQ-00725 64. The compound of claim 62, wherein the compound is represented by one of the following structural formulas: , , , FH12897804.1 OTQ-00725 - 658 - , , , , FH12897804.1 OTQ-00725 , , , , FH12897804.1 OTQ-00725 - 660 - , , , FH12897804.1 OTQ-00725 , , , , FH12897804.1 OTQ-00725 , , , , FH12897804.1 OTQ-00725 , , , FH12897804.1 OTQ-00725 , , , , FH12897804.1 OTQ-00725 , , , ,FH12897804.1 OTQ-00725 , , , , FH12897804.1 OTQ-00725 , , , , FH12897804.1 OTQ-00725 , , , ,FH12897804.1 OTQ-00725 , , , , FH12897804.1 OTQ-00725 , , , , FH12897804.1 OTQ-00725 , , , , FH12897804.1 OTQ-00725 , , , , FH12897804.1 OTQ-00725 , , , , or is a pharmaceutically acceptable salt thereof. FH12897804.1 OTQ-00725 65. The compound of claim 62, wherein the compound is represented by one of the following structural formulas: , , , FH12897804.1 OTQ-00725 - 675 - , , , ,FH12897804.1 OTQ-00725 , , , ,FH12897804.1 OTQ-00725 , , , , FH12897804.1 OTQ-00725 , , FH12897804.1 OTQ-00725 , , or is a pharmaceutically acceptable salt thereof.

66. A pharmaceutical composition comprising a compound of any one of claims 1-65 and a pharmaceutically acceptable excipient.

67. A method of treating a disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1-65 or a pharmaceutical composition of claim 66, wherein the disease or disorder is selected from an inflammatory disease, autoimmune disease, granulomatous disease, cancer, and neurodegenerative disease.

68. The method of claim 67, wherein the disease or disorder is an inflammatory disease.

69. The method of claim 68, wherein the inflammatory disease is selected from uveitis, interleukin-1 converting enzyme fever syndrome, dermatitis, acute lung injury, type 2 diabetes FH12897804.1 OTQ-00725 mellitus, arthritis, inflammatory bowel disorder (IBD), ischemia reperfusion injury in a solid organ transplant, sepsis, liver disease, allergic disease, and graft versus host disease.

70. The method of claim 68, wherein the inflammatory disease is an IBD.

71. The method of claim 70, wherein the IBD is selected from ulcerative colitis, Crohn's disease, early-onset IBD, and extraintestinal IBD.

72. The method of claim 68, 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, spondyloarthritis, ankylosing spondylitis, pemphigus vulgaris, idiopathic plasmacytic lymphadenopathy, atherosclerosis, myocardial infarction, thrombosis, -synucleinopathy, Parkinson’s disease, dementia with Lewy body, multiple system atrophy, Alzheimer’s disease, amyotrophic lateral sclerosis, and chronic obstructive pulmonary disease.

73. The method of claim 67, wherein the disease or disorder is an autoimmune disease.

74. The method of claim 73, wherein the autoimmune disease is selected from systemic lupus erythematosus, lupus nephritis, psoriasis, immune thrombocytopenic purpura, and multiple sclerosis.

75. The method of claim 67, wherein the disease or disorder is a granulomatous disease.

76. The method of claim 75, wherein the granulomatous disease is selected from sarcoidosis, Blau syndrome, Wegner’s granulomatosis, Behcet’s disease, and interstitial pulmonary disease.

77. The method of claim 67, wherein the disease or disorder is a cancer. FH12897804.1 OTQ-00725 78. The method of claim 77, 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.

79. The method of claim 67, wherein the disease or disorder is a neurodegenerative disease.

80. The method of claim 79, wherein the neurodegenerative disease is selected from Alzheimer’s disease, amyotrophic lateral sclerosis (ALS / Lou Gehrig’s Disese), 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.

81. The method of any one of claims 67-80, further comprising administering a therapeutically effective amount of a second agent.

82. The method of claim 81, wherein the second agent is an anti-inflammatory agent or an anti-autoimmune agent.

83. The method of claim 81, wherein the second agent is selected from anti-TNF agent, anti- IL-23 agent, anti-integrin agent, and JAK inhibitor.

84. The method of claim 83, wherein the second agent is anti-TNF agent.

85. The method of claim 83, wherein the second agent is anti-IL-23 agent.

86. The method of claim 83, wherein the second agent is anti-integrin agent.

87. The method of claim 83, wherein the second agent is JAK inhibitor. FH12897804.1 OTQ-00725 88. The method of any one of claims 81-87, wherein the second agent and the compound are administered together in a single pharmaceutical composition.

89. The method of any one of claims 81-87, wherein the second agent and the compound are administered separately. FH12897804.1

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