RIPK2 inhibitors and their medical uses

Abstract

The present disclosure relates to a RIPK2 inhibitor represented by structural formula (I). The present disclosure further relates to pharmaceutical compositions comprising the RIPK2 inhibitor and methods of treating conditions such as inflammatory diseases, autoimmune diseases, granulomatous diseases, neurodegenerative diseases, and cancer.

Description

[Technical Field]

[0001] Related Applications This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 544,884, filed October 19, 2023, U.S. Provisional Patent Application No. 63 / 468,591, filed May 24, 2023, U.S. Provisional Patent Application No. 63 / 443,760, filed February 7, 2023, and U.S. Provisional Patent Application No. 63 / 427,317, filed November 22, 2022, the entire teachings of which are incorporated herein by reference. [Background technology]

[0002] 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.

[0003] NOD1 and NOD2 (nucleotide-binding oligomerization domains 1 and 2) are members of the NOD-like receptor (NLR) family, which are important components of the mammalian innate immune system and serve 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. Genetic polymorphisms in the genes encoding NOD1 and NOD2 are associated with inflammatory disorders. Upon activation, NOD signaling leads to the activation of NF-kB and MAP kinases, resulting in the transcription of proinflammatory kinases and the induction of autophagy.

[0004] NOD1 and NOD2 require RIPK2 as a common scaffolding (adapter) protein to propagate downstream signals that lead to aberrant proinflammatory innate immune activation. In particular, RIPK2 is required for NF-kB activation and subsequent cytokine production. Inhibition of RIPK2 ameliorates abnormal inflammatory conditions, such as intestinal inflammation. Therefore, RIPK2 inhibitors may act as therapeutic agents for reducing or ameliorating inflammation in 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.

[0005] In relation to malignant transformation, knockdown of RIPK2 downregulated the RNA expression of E-cadherin and vimentin, proteins involved in promoting epithelial-mesenchymal transition (EMT) and the metastatic phenotype, indicating that RIPK2 is involved in cell migration and metastasis. Summary of the Invention [Problem to be solved by the invention]

[0006] Therefore, there is a need for inhibitors of RIPK2 activity that can block RIPK2-dependent proinflammatory signaling and thereby provide therapeutic benefit in autoinflammatory diseases and other disorders characterized by increased and / or dysregulated RIPK2 activity. [Means for solving the problem]

[0007] A description of example embodiments of the present invention follows.

[0008] In a first embodiment, the present invention provides a compound of structural formula (I): [ka] (In the formula, R 1a , R 1b and R 1c are each independently H, halogen, CN, and C 1~6 alkyl, R 2 is H or C 1~3 is alkyl, R 3 is halogen, 4-10 membered heterocyclyl, 5-12 membered heteroaryl, S(=O)2R 5 , S(=O)(=NR 6 )(R 7 ), QR 7 , C(=O)NR 8 R 9 , NH(C=O)R 5 , C.N., N.R. 8 R 9 , P(=O)R 8a R 9a is selected from R 4 H, halogen, C 1~6 Alkyl and C 1~6 alkoxy; R 5 is NR 10 R 11 , C 1~6 Alkyl, C 3~6 selected from cycloalkyl and 4- to 10-membered heterocyclyl; R 6 are H, CN and C 1~6 alkyl, R 7 is C 1~6 Alkyl, C 3~6 cycloalkyl and 4- to 10-membered heterocyclyl, 5- to 12-membered heteroaryl; or R 6 and R 7 together with the nitrogen and sulfur atoms to which they are attached form a 4- to 10-membered heterocyclyl; Q is selected from O, S, -S(=O)- and -C(=O)-; R 8 and R 9 are independently H, C 1~6 Alkyl, C 1~6 Deuterated alkyl, C 3~6 selected from cycloalkyl and 4- to 10-membered heterocyclyl; or R 8 and R 9together with the nitrogen atom to which they are attached form a 4- to 10-membered heterocyclyl; R 8a and R 9b are each independently 1~6 alkyl, or R 8a and R 9a together with the phosphorus atom to which they are attached form a 4- to 10-membered heterocyclyl, R 10 and R 11 are each independently H or C 1~6 alkyl, or R 10 and R 11 together with the nitrogen to which they are attached form a 4- to 10-membered heterocyclyl; W, O, NR 2 , O(C 1~2 alkylene), NH(C 1~2 alkylene), C 1~2 Alkylene, C 3~6 selected from cycloalkylene and a bond; X has the following structural formula: [ka] is the part represented by one of Y 1 is CH or N, Y 2 and Y 3 are each independently 4 or N, U is for CR 12b or N, Z is CR 1b or N, L, M, and J are each independently selected from N, O, or S, provided that two of L, M, and J are N; R 12 is C 3~6 Alkyl, C 3~6 Cycloalkyl, C 5~12 selected from bridged bicyclic carbocyclyl and 4- to 10-membered heterocyclyl; R12a is C 1~6 Alkyl, C 1~6 Deuterated alkyl, C 3~6 Cycloalkyl, C 5~12 selected from bridged bicyclic carbocyclyl and 4- to 10-membered heterocyclyl; R 12b and R 13 are each independently H or C 1~6 is alkyl, and [ka] is a single or double bond, Each C 1~6 Alkyl, C 1~3 Alkyl, C 1~2 Alkylene, C 3~6 Alkyl, C 3~6 Cycloalkyl, C 1~6 Alkoxy, C 5~12 Bridged bicyclic carbocyclyl, 5- to 12-membered heteroaryl and 4- to 10-membered heterocyclyl are substituted with deuterium, oxo, F, Cl, Br, CN, OR 14 , S.R. 15 , N.R. 16 R 17 , S(O)R 18 , S(O)2R 18a , N.R. 19 S(=O)R 20 , C(=O)OR 20a , C(=O)NR 21 R 22 , N.R. 23 C(=O)R 24 , C(=S)NR 25 R 26 , C(=O)R 27 , C 1~6 Alkyl, C 1~6 Deuterated alkyl, C 3~8 Cycloalkyl, C 2~6 Alkenyl, halo(C 1~6 ) Alkyl, C 1~3 Alkyl sulfonyl amino alkyl, hydroxy (C 1~6 ) alkyl, amino (C 1~6 ) alkyl, (C 1~6 ) Alkylamino(C 1~6) alkyl, cyano (C 1~6 ) Alkyl, C 1~3 Alkylcarbonylamino (C 1~6 ) Alkyl, C 1~3 Alkoxy, Halo(C 1~3 ) Alkoxy, C 1~6 Alkoxy (C 1~3 ) Alkyl, C 6~12 optionally substituted with 1 to 3 substituents independently selected from aryl, 4- to 8-membered heterocyclyl, and 5- to 12-membered heteroaryl; R 14 , R 15 , R 18 , R 18a , R 20 , R 20a , R 24 and R 27 are each independently hydrogen or C 1~6 is alkyl, R 16 and R 17 are each independently hydrogen, C 1~6 Alkyl, hydroxy (C 1~6 ) alkyl and halo(C 1~6 ) alkyl; R 19 and R 23 are each independently 1~6 Alkyl or halo(C 1~6 ) alkyl, R 21 , R 22 , R 25 and R 26 are independently H, C 1~6 Alkyl, C 1~3 Alkoxy (C 1~6 ) alkyl, hydroxy (C 1~6 ) alkyl, cyano (C 1~6 ) alkyl, amino (C 1~6 ) Alkyl, C 1~3 Alkylamino (C 1~6 ) alkyl and di(C 1~3 ) Alkylamino(C 1~6 ) alkyl, or R 21 and R 22 or R25 and R 26 together with the nitrogen to which they are attached, deuterium, oxo, F, Cl, Br, CN, OR 14 , S.R. 15 , N.R. 16 R 17 , S(O)R 18 , S(O)2R 18a , N.R. 19 S(=O)R 20 , C(=O)OR 20a , C(=O)NR 21 R 22 , N.R. 23 C(=O)R 24 , C(=S)NR 25 R 26 , C(=O)R 27 , C 1~6 Alkyl, C 3~8 Cycloalkyl, C 2~6 Alkenyl, halo(C 1~6 ) Alkyl, C 1~3 Alkyl sulfonyl amino alkyl, hydroxy (C 1~6 ) alkyl, amino (C 1~6 ) alkyl, cyano (C 1~6 ) Alkyl, C 1~3 Alkylcarbonylamino (C 1~6 ) Alkyl, C 1~3 Alkoxy, Halo(C 1~3 ) Alkoxy, C 1~6 Alkoxy (C 1~3 ) Alkyl, C 6~12 forming a 3- to 8-membered ring optionally substituted with 1 to 3 substituents independently selected from aryl, 4- to 10-membered heterocyclyl, and 5- to 12-membered heteroaryl; However, Y 2 But R 4 CH substituted with, and R 4 optionally replaced by C 1~6 If it is alkoxy, WR 3 is CN or optionally substituted C 1~6 shall not be alkoxy, and Y 1 , Y 2 and Y 3If each is CH, then WR 3 is not F) or a pharmaceutically acceptable salt thereof.

[0009] In a second embodiment, the present invention relates to a pharmaceutical composition comprising a compound as described herein in connection with the first embodiment and its various aspects, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0010] In a third embodiment, the present invention relates to a method of treating a disease or disorder, comprising administering a therapeutically effective amount of a compound described herein in connection with the first embodiment and various aspects thereof or a pharmaceutically acceptable salt of a compound (e.g., a compound of Formula (I) or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition described herein in connection with the second embodiment and various aspects thereof, to a subject in need thereof, wherein the disease or disorder is selected from an inflammatory disease, an autoimmune disease, a granulomatous disease, cancer, and a neurodegenerative disease.

[0011] In a fourth embodiment, the present invention relates to a method of treating a RIP2 kinase-mediated disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound described herein in connection with the first embodiment and various aspects thereof (e.g., a compound of Formula (I) or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition described herein in connection with the second embodiment and various aspects thereof. In one aspect, the RIP2 kinase-mediated disease or disorder is a disease or disorder in which inhibition of RIP2 kinase would provide benefit. In certain aspects, the disease or disorder is selected from an inflammatory disease, an autoimmune disease, a granulomatous disease, cancer, and a neurodegenerative disease.

[0012] In a fifth embodiment, the present invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the treatment of a RIP2 kinase-mediated disease or disorder (e.g., an inflammatory disease, an autoimmune disease, a granulomatous disease, cancer, or a neurodegenerative disease).

[0013] In a sixth embodiment, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of RIP2 kinase-mediated diseases and disorders (e.g., inflammatory diseases, autoimmune diseases, granulomatous diseases, cancer, or neurodegenerative diseases). [Brief explanation of the drawings]

[0014] [Figure 1] FIG. 1 is a schematic showing how RIPK2 scaffold inhibitors lock RIPK2 in an inactive conformation, preventing its interaction with XIAP and leading to complete pathway inhibition. DETAILED DESCRIPTION OF THE INVENTION

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

[0016] Among the protein kinase family, a particular example is the receptor-interacting serine / threonine kinases, including RIPK2. RIPK2 consists of an N-terminal kinase domain and a C-terminal caspase recruitment domain (CARD) connected via an intermediate (IM) region. The CARD domain of RIP2 kinase mediates interactions with other CARD-containing proteins, such as NOD1 and NOD2. NOD1 and NOD2 are cytoplasmic receptors activated by specific bacterial peptidoglycan motifs and play important roles in innate immune surveillance. Upon intracellular bacterial exposure, NOD1 or NOD2 binds to RIPK2. It regulates cytokine responses mediated by NF-kB (nuclear factor kB). Upon binding to NOD1 / 2, RIPK2 undergoes autophosphorylation at Tyr 474 (Y474) and functions as a molecular scaffold that recruits other kinases (TAK1, IKKb, and MAPK activation involved in NF-kB).

[0017] Both NOD1 / 2 and RIPK2 are NF-kB-regulated genes; therefore, their activation creates a positive feedback loop in which activation of NOD1 / 2:RIPK2 stimulates further activation and inflammation. Additionally, NOD1 / 2 and RIPK2 expression is stimulated by a variety of inflammatory mediators, including tumor necrosis factor (TNF) and interferon (IFN). In addition to NF-kB pathway activation, the NOD1 / 2:RIPK2 complex stimulates autophagy, bacterial activity, MHC class II presentation, and MAPK (mitogen-activated protein kinase) activation. Overall, this pathway regulates the innate immune system and orchestrates the adaptive immune response to eradicate causative pathogens.

[0018] Dysregulation of RIPK2-dependent signaling has been linked to autoinflammatory diseases. Patients with loss-of-function NOD2 alleles are prone to developing Crohn's disease (CD), an inflammatory disorder of the gastrointestinal tract. The 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 and pediatric populations with ulcerative colitis (UC). Selective RIPK2 inhibitors have been shown to block spontaneous proinflammatory cytokine secretion from biopsies of UC / CD patients. These results highlight that activation of RIPK2 in the mucosa of UC / CD patients leads to the proinflammatory state of these biopsies.

[0019] Rheumatoid arthritis (RA) is a disease in which NOD2 / RIPK2 plays a role. The NOD2 / RIPK2 pathway has been shown to be upregulated in immune cells of RA patients, suggesting that RIPK2 inhibition may 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 granulomatous disease characterized by uveitis, dermatitis, and arthritis. Extensive genotyping of young patients with allergic rhinitis and atopic dermatitis highlighted that NOD2 polymorphisms shared with Crohn's disease may be a major cause of the observed excessive immune response to skin tissue. Mutations in NOD1 have been associated with asthma and early-onset and extraintestinal inflammatory bowel disease. Genetic and functional studies have also suggested a role for RIP2-dependent signaling in a variety of other granulomatous disorders, such as sarcoidosis.

[0020] Metabolic syndrome, a condition closely associated with obesity and overweight, is caused by chronic inflammation and characterized by hypertension, hyperglycemia, and lipolysis dysfunction. Activation of the immune system via the NOD1 pathway has been observed in patients with metabolic syndrome. Recent functional studies highlighting the influence of RIPK2 on lipolysis suggest a role for RIP2-dependent signaling in dysglycemia and lipolysis.

[0021] In cardiac hypertrophy, a complex and multifactorial pathology, inflammation has been shown to be a key feature of the disease, particularly through activation of NF-kB signaling. RIPK2 knockout studies in a mouse model of hypertrophic heart suggested a role for RIPK2 in regulating inflammation and subsequent tissue fibrosis and hypertrophy.

[0022] Besides immune-inflammatory diseases, RIPK2 regulation has also been described in several cancers. In triple-negative breast cancer (TNBC), high RIPK2 expression was associated with worse progression-free survival and overall survival. RIPK2 knockdown has been shown to increase docetaxel sensitivity and reduce tumor and lung metastasis. Another study focused on a novel oncogene cassette on chromosome 8 in breast cancer patients, and found that other tested oncogenes ( RIPK2 co-amplification with other kinases, such as MYC, has been found. In TNBC biopsies performed to discover potentially druggable kinases other than HER2, RIPK2 was shown to be hyperphosphorylated in basal-like and luminal B breast cancer biopsies, suggesting that this pathway may be activated in this type of TNBC. More recently, phosphorylated RIPK2 levels and NF-kB activity were shown to be elevated in inflammatory breast cancer biopsies. 34 Head and neck squamous cell carcinoma cell lines showed that RIPK2 knockdown resulted in cell death, indicating the protein's central role in cell survival. RIPK2 has been proposed to promote glioma cell proliferation by regulating TRAF3 and activating the NF-kB pathway and p38 signaling.

[0023] A novel role for RIPK2 in osteosarcoma invasion was demonstrated when gefitinib prevented the progression of lung metastasis via RIPK2 inhibition. Furthermore, non-canonical NF-kB plays a pivotal role in non-Hodgkin's lymphoma. Finally, using three-dimensional lymphatic endothelial cell tube formation, RIPK2 was identified as a kinase involved in lymphatic vessel remodeling, a key factor in cancer metastatic spread. Collectively, these data strongly support the development of RIPK2 inhibitors in oncology.

[0024] RIPK2 and RIP2 kinase are used interchangeably herein to refer to receptor-interacting protein kinase 2.

[0025] XIAP (X-linked inhibitor of apoptosis protein) ubiquitinates RIPK2 after NOD2 stimulation, and the interaction between the XIAP BIR2 domain and the RIPK2 kinase domain is required for NOD2 signaling (Figure 1). Although the kinase function of RIPK2 is dispensable for downstream signaling, its ability to recruit and activate XIAP is required for RIPK2 ubiquitination and signaling. Therefore, inhibition of RIPK2 with scaffolding inhibitors that bind to RIPK2 and prevent its interaction with XIAP can block proinflammatory responses in vitro and in vivo.

[0026] The compounds described herein have been shown to be RIPK2 scaffold inhibitors. Figure 1 shows that RIPK2 scaffold inhibitors can lock RIPK2 in an inactive conformation, preventing its interaction with XIAP and resulting in complete pathway inhibition. Blocking the scaffold is beneficial for inhibiting RIPK2 activation in response to bacterial flora. The disclosed RIPK2 scaffold inhibitors can be used to eliminate pathogenic responses to bacterial flora, which can cause inflammatory bowel disease and rheumatic diseases.

[0027] definition Definitions of specific functional groups and chemical terms are described in more detail below. Chemical elements are listed in the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 th Ed., inside cover, and specific functional groups are generally defined as described therein. In addition, general principles of organic chemistry and specific functional moieties and reactivities are described in Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito, 1999; Smith and March,March's Advanced Organic Chemistry,5 thEdition, 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, 3 rd Edition, Cambridge University Press, Cambridge, 1987 There are.

[0028] The compounds described herein may contain one or more asymmetric centers and therefore may exist in various stereoisomeric forms, such as enantiomers and / or diastereomers. For example, the compounds described herein may be in the form of individual enantiomers, diastereomers, or geometric isomers, or may be in the form of mixtures of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high-performance liquid chromatography (HPLC) and the formation and crystallization of chiral salts, or preferred isomers can be prepared by asymmetric synthesis. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions, Wiley Interscience, New York, 1981; Wilen et al., Tetrahedron 33:2725 (1977); Eliel, ELStereochemistry of Carbon Compounds, McGraw-Hill, NY, 1962, and Wilen, SH, Tables of Resolving Agents and Optical Resolutions p. 268, ELS Eliel, Ed., University of Notre Dame Press, Notre Dame, IN 1972. The present invention further encompasses compounds as individual isomers substantially free of other isomers or as mixtures of various isomers.

[0029] In the formula, [ka] is a single bond with no specific stereochemistry of the moiety directly attached thereto, --- is absent or a single bond, [ka] or [ka] is a single or double bond. An asterisk ( * ) indicates that the atom is a stereocenter of unknown absolute configuration. For example, in a pair of enantiomers, each has an asterisk ( * ), which indicates that the absolute configuration about a stereocenter of a given enantiomer is not defined.

[0030] Unless otherwise stated, structures depicted herein are also intended to include all isomeric forms of the structure (e.g., enantiomeric, diastereomeric, and geometric (or conformational) forms, e.g., 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, the replacement of hydrogen by deuterium or tritium; 18 By F 19 F replacement or 13 C or 14 By C 12 Compounds having this structure except for the replacement of C are within the scope of this disclosure. Such compounds are useful as analytical tools or probes in biological assays.

[0032] When a range of values ​​is listed, it is intended to encompass each value and subrange within the range. For example, "C 1~6 "Alkyl" refers to C1, C2, C3, C4, C5, C6, C1 ~6 , C 1~5 , C 1~4 , C 1~3 , C 1~2 , C 2~6 , C 2~5 , C 2~4 , C 2~3 , C 3~6 , C 3~5 , C 3~4 , C 4~6 , C 4~5 and C 5~6 Alkyl is intended to be included.

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

[0034] The term "alkyl" refers to the radical of a straight-chain or branched saturated hydrocarbon group having 1 to 10 carbon atoms ("C 1~10 In some embodiments, an alkyl group has 1 to 9 carbon atoms ("C 1~9 In some embodiments, an alkyl group has 1 to 8 carbon atoms ("C 1~8 In some embodiments, the alkyl group has 1 to 7 carbon atoms ("C alkyl"). In some embodiments, the alkyl group has 1 to 6 carbon atoms ("C 1~6 In some embodiments, an alkyl group has 1 to 5 carbon atoms ("C 1~5 In some embodiments, an alkyl group has 1 to 4 carbon atoms ("C 1~4 In some embodiments, an alkyl group has 1 to 3 carbon atoms ("C 1~3In some embodiments, the alkyl group has 1 to 2 carbon atoms ("C 1~2 In some embodiments, the alkyl group has one carbon atom ("C alkyl"). In some embodiments, the alkyl group has two to six carbon atoms ("C 2~6 alkyl). C 1~6 Examples of alkyl groups include methyl (C1), ethyl (C2), propyl (C3) (e.g., n-propyl, isopropyl), butyl (C4) (e.g., n-butyl, tert-butyl, sec-butyl, 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 with one or more substituents (e.g., a halogen, such as F) (a "substituted alkyl"). In certain embodiments, an alkyl group is an unsubstituted C1 to 10 Alkyl (unsubstituted C 1~6 Alkyl, for example, -CH3 (Me), unsubstituted ethyl (Et), unsubstituted propyl (Pr, for example, unsubstituted n-propyl (n-Pr), unsubstituted isopropyl (i-Pr)), unsubstituted butyl (Bu, for example, 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 to 10 Alkyl (substituted C 1~6 alkyl, for example, -CF3, Bn, etc.

[0035] The term "haloalkyl" refers to a substituted alkyl group in which one or more of the hydrogen atoms is independently replaced with a halogen, such as fluoro, bromo, chloro, or iodo. In some embodiments, the haloalkyl moiety has 1 to 8 carbon atoms ("C 1~8In some embodiments, the haloalkyl moiety has 1 to 6 carbon atoms ("C 1~6 In some embodiments, the haloalkyl moiety has 1 to 4 carbon atoms ("C 1~4 In some embodiments, the haloalkyl moiety has 1 to 3 carbon atoms ("C 1~3 In some embodiments, the haloalkyl moiety has 1 to 2 carbon atoms ("C 1~2 Examples of haloalkyl groups include -CHF2, -CH2F, -CF3, -CH2CF3, -CF2CF3, -CF2CF2CF3, -CCl3, -CFCl2, -CF2Cl, and the like.

[0036] The term "deuteroalkyl" refers to a group in which one or more hydrogen atoms are independently replaced with deuterium. In some embodiments, a deuterated alkyl moiety has 1 to 8 carbon atoms ("C 1~8 In some embodiments, the deuterium alkyl moiety has 1 to 6 carbon atoms ("C 1~6 In some embodiments, the deuterium alkyl moiety has 1 to 4 carbon atoms ("C 1~4 In some embodiments, the deuterium alkyl moiety has 1 to 3 carbon atoms ("C 1~3 In some embodiments, the deuterium alkyl moiety has 1 to 2 carbon atoms ("C 1~2 In some embodiments, the deuterium alkyl moiety is a C1, C2, C3, C4, C5, or C6 deuterium alkyl. A deuterium alkyl moiety having n carbon atoms can have 1 to 2n+1 deuterium atoms. Examples of deuterium alkyl groups include -CHD2, -CH2D, -CD3, -CH2CD3, -CD2CD3, -CD2CD2CD3, -CH(CD3)2, -CD(CD3)2, -C(CD3)3, and the like.

[0037] The term "hydroxyalkyl" refers to a substituted alkyl group in which one or more of the hydrogen atoms are independently replaced with a hydroxyl. In some embodiments, the hydroxyalkyl moiety has 1 to 8 carbon atoms ("C 1~8 In some embodiments, the hydroxyalkyl moiety has 1 to 6 carbon atoms ("C 1~6 In some embodiments, the hydroxyalkyl moiety has 1 to 4 carbon atoms ("C 1~4 In some embodiments, the hydroxyalkyl moiety has 1 to 3 carbon atoms ("C 1~3 In some embodiments, the hydroxyalkyl moiety has 1 to 2 carbon atoms ("C 1~2 hydroxyalkyl).

[0038] The term "alkoxy" refers to an alkyl group, as defined herein, attached to the parent molecular moiety through an oxygen atom. In some embodiments, the alkoxy moiety has 1 to 8 carbon atoms ("C 1~8 In some embodiments, the alkoxy moiety has 1 to 6 carbon atoms ("C 1~6 In some embodiments, the alkoxy moiety has 1 to 4 carbon atoms ("C 1~4 In some embodiments, the alkoxy moiety has 1 to 3 carbon atoms ("C 1~3 In some embodiments, the alkoxy moiety has 1 to 2 carbon atoms ("C 1~2 Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, and tert-butoxy.

[0039] The term "haloalkoxy" refers to a haloalkyl group, as defined herein, attached to the parent molecular moiety through an oxygen atom. In some embodiments, the alkoxy moiety has 1 to 8 carbon atoms ("C 1~8In some embodiments, the alkoxy moiety has 1 to 6 carbon atoms ("C 1~6 In some embodiments, the alkoxy moiety has 1 to 4 carbon atoms ("C 1~4 In some embodiments, the alkoxy moiety has 1 to 3 carbon atoms ("C 1~3 In some embodiments, the alkoxy moiety has 1 to 2 carbon atoms ("C 1~2 Representative examples of haloalkoxy include, but are not limited to, difluoromethoxy, trifluoromethoxy, and 2,2,2-trifluoroethoxy.

[0040] The term "alkoxyalkyl" refers to a substituted alkyl group in which one or more of the hydrogen atoms is independently replaced with an alkoxy group, as defined herein. In some embodiments, the alkoxyalkyl moiety has 1 to 8 carbon atoms ("C 1~8 In some embodiments, the alkoxyalkyl moiety has 1 to 6 carbon atoms ("C 1~6 In some embodiments, the alkoxy group is The alkyl moiety has 1 to 4 carbon atoms ("C 1~4 In some embodiments, the alkoxyalkyl moiety has 1 to 3 carbon atoms ("C 1~3 In some embodiments, the alkoxyalkyl moiety has 1 to 2 carbon atoms ("C 1~2 alkoxyalkyl").

[0041] The term "heteroalkyl" refers to an alkyl group that further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within the parent chain (i.e., inserted between adjacent carbon atoms of the parent chain) and / or disposed at one or more terminal positions of the parent chain. In certain embodiments, a heteroalkyl group is a saturated group having 1 to 20 carbon atoms and one or more heteroatoms within the parent chain ("heteroC1~20 In some embodiments, a heteroalkyl group refers to a saturated group having 1 to 18 carbon atoms and one or more heteroatoms in the parent chain ("heteroC 1~18 In some embodiments, a heteroalkyl group is a saturated group having 1 to 16 carbon atoms and one or more heteroatoms in the parent chain ("heteroC 1~16 In some embodiments, a heteroalkyl group is a saturated group having 1 to 14 carbon atoms and one or more heteroatoms in the parent chain ("heteroC 1~14 In some embodiments, a heteroalkyl group is a saturated group having 1 to 12 carbon atoms and one or more heteroatoms in the parent chain ("heteroC 1~12 In some embodiments, a heteroalkyl group is a saturated group having 1 to 10 carbon atoms and one or more heteroatoms in the parent chain ("heteroC 1~10 In some embodiments, a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and one or more heteroatoms in the parent chain ("heteroC 1~8 In some embodiments, a heteroalkyl group is a saturated group having 1 to 6 carbon atoms and one or more heteroatoms in the parent chain ("heteroC 1~6 In some embodiments, heteroalkyl groups are saturated groups having 1 to 4 carbon atoms and 1 or 2 heteroatoms in the parent chain ("heteroC 1~4 In some embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom in the parent chain ("heteroC 1~3 In some embodiments, heteroalkyl groups are saturated groups having 1 to 2 carbon atoms and 1 heteroatom in the parent chain ("heteroC 1~2In some embodiments, a heteroalkyl group is a saturated group having one carbon atom and one heteroatom ("heteroC alkyl"). In some embodiments, a heteroalkyl group, as defined herein, is a partially unsaturated group having one or more heteroatoms and at least one unsaturated carbon in the parent chain, e.g., a carbonyl group. For example, a heteroalkyl group can include an amide or ester functionality in its parent chain such that one or more carbon atoms is an unsaturated carbonyl group. Unless otherwise specified, each instance of a heteroalkyl group is independently unsubstituted ("unsubstituted heteroalkyl") or substituted with one or more substituents ("substituted heteroalkyl"). In certain embodiments, a heteroalkyl group is an unsubstituted heteroC 1~20 In certain embodiments, the heteroalkyl group is an unsubstituted heteroC1-C1 alkyl. 10 In certain embodiments, the heteroalkyl group is a substituted heteroC 1~20 In certain embodiments, the heteroalkyl group is an unsubstituted heteroC1-C1 alkyl. 10 It is alkyl.

[0042] The term "alkenyl" refers to the radical of a straight-chain or branched hydrocarbon group having 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 ("C 2~9 In some embodiments, an alkenyl group has 2 to 8 carbon atoms ("C 2~8 In some embodiments, an alkenyl group has 2 to 7 carbon atoms ("C 2~7 In some embodiments, an alkenyl group has 2 to 6 carbon atoms ("C 2~6 In some embodiments, an alkenyl group has 2 to 5 carbon atoms ("C 2~5 In some embodiments, an alkenyl group has 2 to 4 carbon atoms ("C 2~4 Arke In some embodiments, an alkenyl group has 2 to 3 carbon atoms (“C 2~3 In some embodiments, the alkenyl group has two carbon atoms ("C2 alkenyl"). The one or more carbon-carbon double bonds can be internal (e.g., in 2-butenyl) or terminal (e.g., in 1-butenyl). C 2~4 Examples of alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. 2~6 Examples of alkenyl groups include the above-mentioned C 2~4 Alkenyl groups include pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like. Unless otherwise specified, each instance of an alkenyl group is independently unsubstituted ("unsubstituted alkenyl") or substituted with one or more substituents ("substituted alkenyl"). In certain embodiments, an alkenyl group is an unsubstituted C 2~10 In certain embodiments, the alkenyl group is a substituted C 2~10 Alkenyl groups have a C=C double bond with unspecified stereochemistry (e.g., -CH=CHCH3, or [ka] ) can be an (E)- or a (Z)-double bond.

[0043] The term "heteroalkenyl" refers to an alkenyl group that further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within the parent chain (i.e., inserted between adjacent carbon atoms of the parent chain) and / or disposed at one or more terminal positions of the parent chain. In certain embodiments, a heteroalkenyl group is a group having 2 to 10 carbon atoms, at least one double bond, and one or more heteroatoms within the parent chain ("heteroalkenyl"). 2~10In some embodiments, heteroalkenyl groups have 2 to 9 carbon atoms, at least one double bond, and one or more heteroatoms in the parent chain ("heteroC 2~9 alkenyl).

[0044] In some embodiments, heteroalkenyl groups have 2 to 8 carbon atoms, at least one double bond, and one or more heteroatoms in the parent chain ("heteroC"). 2~8 In some embodiments, heteroalkenyl groups have 2 to 7 carbon atoms, at least one double bond, and one or more heteroatoms in the parent chain ("heteroC"). 2~7 In some embodiments, heteroalkenyl groups have 2 to 6 carbon atoms, at least one double bond, and one or more heteroatoms in the parent chain ("heteroC"). 2~6 In some embodiments, heteroalkenyl groups have 2 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms in the parent chain ("heteroC 2~5 In some embodiments, heteroalkenyl groups have 2 to 4 carbon atoms, at least one double bond, and 1 or 2 heteroatoms in the parent chain ("heteroC 2~4 In some embodiments, heteroalkenyl groups have 2 to 3 carbon atoms, at least one double bond, and one heteroatom in the parent chain ("heteroC 2~3 In some embodiments, heteroalkenyl groups have 2 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms in the parent chain ("heteroC 2~6 Unless otherwise specified, each instance of a heteroalkenyl group is independently unsubstituted (an "unsubstituted heteroalkenyl") or substituted (a "substituted heteroalkenyl") with one or more substituents. In certain embodiments, a heteroalkenyl group is an unsubstituted heteroC 2~10 In certain embodiments, the heteroalkenyl group is a substituted heteroC 2~10 It is alkenyl.

[0045] The term "alkynyl" refers to an alkyl group having 2 to 10 carbon atoms and one or more carbon-carbon triple bonds (e.g., refers to the radical of a linear or branched hydrocarbon group having, for example, 1, 2, 3 or 4 triple bonds ("C 2~10 In some embodiments, an alkynyl group has 2 to 9 carbon atoms ("C 2~9 In some embodiments, an alkynyl group has 2 to 8 carbon atoms ("C 2~8 In some embodiments, an alkynyl group has 2 to 7 carbon atoms ("C 2~7 In some embodiments, an alkynyl group has 2 to 6 carbon atoms ("C 2~6 In some embodiments, an alkynyl group has 2 to 5 carbon atoms ("C 2~5 In some embodiments, an alkynyl group has 2 to 4 carbon atoms ("C 2~4 In some embodiments, an alkynyl group has 2 to 3 carbon atoms ("C 2~3 In some embodiments, the alkynyl group has two carbon atoms ("C2 alkynyl"). The one or more carbon-carbon triple bonds can be internal (e.g., in 2-butynyl) or terminal (e.g., in 1-butynyl). C 2~4 Examples of alkynyl groups include, but are not limited to, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. 2~6 Examples of alkenyl groups include the above-mentioned C 2~4 Alkynyl groups include pentynyl (C5), hexynyl (C6), and the like. Additional examples of alkynyl include heptynyl (C7), octynyl (C8), and the like. Unless otherwise specified, each instance of an alkynyl group is independently unsubstituted ("unsubstituted alkynyl") or substituted with one or more substituents ("substituted alkynyl"). In certain embodiments, an alkynyl group is an unsubstituted C 2~10 In certain embodiments, the alkynyl group is a substituted C 2~10It is alkynyl.

[0046] The term "heteroalkynyl" refers to an alkynyl group that further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within the parent chain (i.e., inserted between adjacent carbon atoms of the parent chain) and / or disposed at one or more terminal positions of the parent chain. In certain embodiments, a heteroalkynyl group is a group having 2 to 10 carbon atoms, at least one triple bond, and one or more heteroatoms within the parent chain ("heteroalkynyl"). 2~10 In some embodiments, heteroalkynyl groups have 2 to 9 carbon atoms, at least one triple bond, and one or more heteroatoms in the parent chain ("heteroC"). 2~9 In some embodiments, heteroalkynyl groups have 2 to 8 carbon atoms, at least one triple bond, and one or more heteroatoms in the parent chain ("heteroC"). 2~8 In some embodiments, heteroalkynyl groups have 2 to 7 carbon atoms, at least one triple bond, and one or more heteroatoms in the parent chain ("heteroC"). 2~7 In some embodiments, heteroalkynyl groups have 2 to 6 carbon atoms, at least one triple bond, and one or more heteroatoms in the parent chain ("heteroC 2~6 In some embodiments, heteroalkynyl groups have 2 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms in the parent chain ("heteroC 2~5 In some embodiments, heteroalkynyl groups have 2 to 4 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms ("heteroC 2~4 In some embodiments, heteroalkynyl groups have 2 to 3 carbon atoms, at least one triple bond, and one heteroatom in the parent chain ("heteroC 2~3 In some embodiments, heteroalkynyl groups have 2 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms in the parent chain ("heteroC 2~6Unless 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, a heteroalkynyl group is an unsubstituted heteroC 2~10 In certain embodiments, the heteroalkynyl group is a substituted heteroC 2~10 It is alkynyl.

[0047] The term "carbocyclyl" or "carbocyclic" refers to a ring system having 3 to 14 ring carbon atoms. ("C 3~14 "Carbocyclyl" refers to the radical of a non-aromatic cyclic hydrocarbon group having 3 to 10 ring carbon atoms ("C 3~10 In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms ("C 3~8 In some embodiments, a carbocyclyl group has 3 to 7 ring carbon atoms ("C 3~7 In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms ("C 3~6 In some embodiments, a carbocyclyl group has 4 to 6 ring carbon atoms ("C 4~6 In some embodiments, the carbocyclyl group has 5 to 6 ring carbon atoms ("C 5~6 In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms ("C 5~10 carbocyclyl). Exemplary C 3~6 Carbocyclyl groups include, but are not limited to, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like.

[0048] Exemplary C 3~8The carbocyclyl group includes, but is not limited to, the above-mentioned C 3~8 Examples of carbocyclyl groups include cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), and the like. 3~10 The carbocyclyl group includes, but is not limited to, the above-mentioned C 3~8 Carbocyclyl groups and cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C 10 ), spiro[4.5]decanyl (C 10 As the foregoing examples illustrate, in certain embodiments, a carbocyclyl group is either monocyclic ("monocyclic carbocyclyl") or polycyclic (including, for example, fused, bridged, or spiro ring systems such as a bicyclic ring system ("bicyclic carbocyclyl") or a tricyclic ring system ("tricyclic carbocyclyl")) and may be saturated or contain one or more carbon-carbon double or triple bonds. "Carbocyclyl" also includes ring systems in which a carbocyclyl ring, as defined above, is fused to one or more aryl or heteroaryl groups, the point of attachment being on the carbocyclyl ring; in such cases, the carbon numbering continues as designating the number of carbons in the carbocyclyl ring system. Unless otherwise specified, each instance of a carbocyclyl group is independently unsubstituted ("unsubstituted carbocyclyl") or substituted with one or more substituents ("substituted carbocyclyl"). In certain embodiments, a carbocyclyl group is an unsubstituted C 3~14 In certain embodiments, the carbocyclyl group is a substituted C 3~14 It is a carbocyclyl.

[0049] In some embodiments, a "carbocyclyl" has 3 to 14 ring carbon atoms ("C 3~14 In some embodiments, a cycloalkyl group has 3 to 10 ring carbon atoms ("C3~10 In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms ("C 3~8 In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms ("C 3~6 In some embodiments, a cycloalkyl group has 4 to 6 ring carbon atoms ("C 4~6 In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms ("C 5~6 In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms ("C 5~10 Cycloalkyl). C 5~6 Examples of cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C6). 3~6 Examples of cycloalkyl groups include the aforementioned C 5~6 Cycloalkyl groups include cyclopropyl (C3) and cyclobutyl (C4). 3~8 Examples of cycloalkyl groups include the aforementioned C 3~6 Cycloalkyl groups and cycloheptyl (C7) and cyclo and octyl (C8). Unless otherwise specified, each instance of a cycloalkyl group is independently unsubstituted ("unsubstituted cycloalkyl") or substituted with one or more substituents ("substituted cycloalkyl"). In certain embodiments, a cycloalkyl group is an unsubstituted C 3~14 In certain embodiments, the cycloalkyl group is a substituted C 3~14 It is cycloalkyl.

[0050] The terms "heterocyclyl" or "heterocyclic" refer to the radical of a 3- to 14-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, each independently selected from nitrogen, oxygen, and sulfur ("3- to 14-membered heterocyclyl"). In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment may be at a carbon or nitrogen atom, where valence permits. Heterocyclyl groups may be either monocyclic ("monocyclic heterocyclyl") or polycyclic (e.g., fused, bridged, or spiro ring systems such as bicyclic ring systems ("bicyclic heterocyclyl") or tricyclic ring systems ("tricyclic heterocyclyl")), and may be saturated or contain one or more carbon-carbon double or triple bonds. Heterocyclyl polycyclic ring systems may contain one or more heteroatoms in one or both rings. "Heterocyclyl" also includes ring systems in which a heterocyclyl ring as defined above is fused to one or more carbocyclyl groups (the point of attachment is on either the carbocyclyl or heterocyclyl ring) or to one or more aryl or heteroaryl groups (the point of attachment is on the heterocyclyl ring); in such cases, the numbering of ring members continues to designate the number of ring members in the heterocyclyl ring system. Unless otherwise specified, each instance of heterocyclyl is independently unsubstituted (an "unsubstituted heterocyclyl") or substituted with one or more substituents (a "substituted heterocyclyl"). In certain embodiments, a heterocyclyl group is an unsubstituted 3- to 14-membered heterocyclyl. In certain embodiments, a heterocyclyl group is a substituted 3- to 14-membered heterocyclyl.

[0051] In some embodiments, a heterocyclyl group is a 4- to 10-membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, each independently selected from nitrogen, oxygen, and sulfur (a "4- to 10-membered heterocyclyl"). In some embodiments, a heterocyclyl group is a 4- to 8-membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, each independently selected from nitrogen, oxygen, and sulfur (a "5- to 8-membered heterocyclyl"). In some embodiments, a heterocyclyl group is a 5- to 6-membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, each independently selected from nitrogen, oxygen, and sulfur (a "5- to 6-membered heterocyclyl"). In some embodiments, a 5- to 6-membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5- to 6-membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heterocyclyl has one ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0052] Exemplary 3-membered heterocyclyl groups containing one heteroatom include, but are not limited to, aziridinyl, oxiranyl, and thiiranyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxathiolanyl, and dithiolanyl. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Examples of heterocyclyl groups include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazinyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azocanyl, oxecanyl, and thiocanyl. Exemplary bicyclic heterocyclyl groups include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl, decahydronaphthyridinyl, decahydro-1,8-naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole, indolinyl, phthalimidyl, naphthalimidyl, chromanyl, chromenyl, 1H-benzo[e][1,4]diazepin ... Examples include 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, and 1,2,3,4-tetrahydro-1,6-naphthyridinyl.

[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 pi electrons shared within the cyclic array) having 6 to 14 ring carbon atoms and 0 heteroatoms provided in the aromatic ring system ("C 6~14In some embodiments, an aryl group has 6 ring carbon atoms ("C aryl", e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms ("C 10 aryl," e.g., naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms ("C 14 "Aryl," e.g., anthracyl). "Aryl" also includes ring systems in which an aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups, where the radical or point of attachment is on the aryl ring, and in such cases the carbon numbering continues to designate the number of carbons in the aryl ring system. Unless otherwise specified, each instance of an aryl group is independently unsubstituted ("unsubstituted aryl") or substituted with one or more substituents ("substituted aryl"). In certain embodiments, an aryl group is an unsubstituted C 6~14 In certain embodiments, the aryl group is a substituted C 6~14 It is aryl.

[0054] "Aralkyl" is a subset of "alkyl" and refers to an alkyl group substituted with an aryl group, where the point of attachment is on the alkyl portion.

[0055] The term "heteroaryl" refers to the radical of a 5- to 14-membered monocyclic or polycyclic (e.g., bicyclic, tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared within the cyclic array) having ring carbon atoms and 1 to 4 ring heteroatoms provided in the aromatic ring system, each heteroatom being independently selected from nitrogen, oxygen, and sulfur ("5- to 14-membered heteroaryl"). In heteroaryl groups containing one or more nitrogen atoms, the point of attachment may be at a carbon or nitrogen atom, valence permitting. Heteroaryl polycyclic ring systems may contain one or more heteroatoms in one or both rings. "Heteroaryl" includes ring systems in which a heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups, the point of attachment being on the heteroaryl ring; in such cases, the numbering of the ring members continues to designate the numbering of the ring members within the heteroaryl ring system. "Heteroaryl" also includes ring systems in which a heteroaryl ring, as defined above, is fused to one or more aryl groups, and the point of attachment is either the aryl or may be located anywhere on the heteroaryl ring, and in such cases the ring member numbering continues to designate the numbering of ring members in a fused polycyclic (aryl / heteroaryl) ring system. In polycyclic heteroaryl groups in which one ring does not contain heteroatoms (e.g., indolyl, quinolinyl, carbazolyl, etc.), the point of attachment may be on either ring, i.e., on either the ring with a heteroatom (e.g., 2-indolyl) or the ring without a heteroatom (e.g., 5-indolyl).

[0056] In some embodiments, heteroaryl groups are 5- to 12-membered aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms provided to the aromatic ring system, each heteroatom being independently selected from nitrogen, oxygen, and sulfur ("5- to 12-membered heteroaryl"). In some embodiments, heteroaryl groups are 5- to 10-membered aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms provided to the aromatic ring system, each heteroatom being independently selected from nitrogen, oxygen, and sulfur ("5- to 10-membered heteroaryl"). In some embodiments, heteroaryl groups are 5- to 8-membered aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms provided to the aromatic ring system, each heteroatom being independently selected from nitrogen, oxygen, and sulfur ("5- to 8-membered heteroaryl"). In some embodiments, heteroaryl groups are 5- to 6-membered aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms provided to the aromatic ring system, each heteroatom being independently selected from nitrogen, oxygen, and sulfur ("5- to 6-membered heteroaryl"). In some embodiments, a 5- to 6-membered heteroaryl has 1 to 3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5- to 6-membered heteroaryl has 1 to 2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5- to 6-membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each instance of a heteroaryl group is independently unsubstituted ("unsubstituted heteroaryl") or substituted with one or more substituents ("substituted heteroaryl"). In certain embodiments, a heteroaryl group is an unsubstituted 5- to 14-membered heteroaryl. In certain embodiments, a heteroaryl group is a substituted 5- to 14-membered heteroaryl.

[0057] Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pterinidyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. Exemplary tricyclic heteroaryl groups include, but are not limited to, phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl, and phenazinyl. can be.

[0058] "Heteroaralkyl" is a subset of "alkyl" and refers to an alkyl group substituted with a heteroaryl group, where the point of attachment is on the alkyl portion.

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

[0060] The terms "unsaturated" or "partially unsaturated" refer to a moiety that contains at least one double or triple bond.

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

[0062] The suffix "-ene" added to a group indicates that the group is a divalent moiety, for example, alkylene is a divalent moiety of alkyl, alkenylene is a divalent moiety of alkenyl, alkynylene is a divalent moiety of alkynyl, heteroalkylene is a divalent moiety of heteroalkyl, heteroalkenylene is a divalent moiety of heteroalkenyl, heteroalkynylene is a divalent moiety of heteroalkynyl, carbocyclylene is a divalent moiety of carbocyclyl, heterocyclylene is a divalent moiety of heterocyclyl, arylene is a divalent moiety of aryl, and heteroarylene is a divalent moiety of heteroaryl.

[0063] A group is optionally substituted unless expressly specified otherwise. The term "optionally substituted" refers to 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 that can 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 atom present on a group is replaced with an acceptable substituent, e.g., a substituent that, upon substitution, results in a stable compound, e.g., a compound that does not spontaneously undergo transformation, such as by rearrangement, cyclization, elimination, or other reaction. Unless otherwise specified, a "substituted" group has a substituent at one or more substitutable positions of the group; when more than one position in any given structure is substituted, the substituents may be the same or different at each position. The term "substituted" includes substitution with all permissible substituents of organic compounds and is intended to include any of the substituents described herein that result in the formation of a stable compound. The present invention contemplates any and all such combinations to arrive at a stable compound. For purposes of this invention, heteroatoms, such as nitrogen, may have hydrogen substituents and / or any suitable substituents, as described herein, that satisfy the valence of the heteroatom and result in the formation of a stable moiety. The present invention is in no way limited by the exemplary substituents described herein.

[0064] Exemplary carbon atom substituents are halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR aa , -ON(Rbb )2、-N(R bb )2、-N(R bb )3 + X - 、-N(OR cc )R bb 、-SH、-SR aa 、-SSR cc 、-C(=O)R aa 、-CO2H、-CHO、-C(OR cc )3、-CO2R aa 、-OC(=O) R aa 、-OCO2R aa 、-C(=O)N(R bb )2、-OC(=O)N(R bb )2、-NR bb C(=O)R aa 、-NR bb CO2R aa 、-NR bb C(=O)N(R bb )2、-C(=NR bb )R aa 、-C(=NR bb )OR aa 、-OC(=NR bb )R aa 、-OC(=NR bb )OR aa 、-C(=NR bb )N(R bb )2、-OC(=NR bb )N(R bb )2、-NR bb C(=NR bb )N(R bb )2、-C(=O)NR bb SO2R aa 、-NR bb SO2R aa 、-SO2N(R bb )2、-SO2R aa 、-SO2OR aa 、-OSO2R aa 、-S(=O)R aa 、-OS(=O)R aa 、-Si(R aa )3、-OSi(R aa )3、-C(=S)N(R bb )2、-C(=O)SRaa , -C(=S)SR aa , -SC(=S)SR aa , -SC(=O)SR aa , -OC(=O)SR aa , -SC(=O)OR aa , -SC(=O)R aa , -P(=O)(R aa )2, -P(=O)(OR cc )2, -OP(=O)(R aa )2, -OP(=O)(OR cc )2, -P(=O)(N(R bb )2)2, -OP(=O)(N(R bb )2)2, -NR bb P(=O)(R aa )2, -NR bb P(=O)(OR cc )2, -NR bb P(=O)(N(R bb )2)2, -P(R cc )2, -P(OR cc )2, -P(R cc )3 + X - , -P(OR cc )3 + X - , -P(R cc )4, -P(OR cc )2, -OP(R cc )2, -OP(R cc )3 + X - , -OP(OR cc )2, -OP(OR cc )3 + X - , -OP(R cc )4, -OP(OR cc )4, -B(R aa )2, -B(OR cc )2, -BR aa (OR cc ), C 1~10 Alkyl, C 1~10 Perhaloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, Hetero C 1~10 Alkyl, Hetero C 2~10 Alkenyl, Hetero C2~10 Alkynyl, C 3~10 Carbocyclyl, 3- to 14-membered heterocyclyl, C 6~14 Each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl may have 0, 1, 2, 3, 4, or 5 R dd are independently substituted with groups, and X - is a counterion, or the two geminal hydrogens on the carbon atom are =O, =S, =NN(R bb )2, =NNR bb C(=O)R aa , =NNR bb C(=O)OR aa , =NNR bb S(=O)2R aa , =NR bb or =NOR cc is substituted with an R aa Each example of C 1~10 Alkyl, C 1~10 Perhaloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, Hetero C 1~10 Alkyl, Hetero C 2~10 Alkenyl, Hetero C 2~10 Alkynyl, C 3~10 Carbocyclyl, 3- to 14-membered heterocyclyl, C 6~14 aryl and 5- to 14-membered heteroaryl, or two R aa The groups may be joined to form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, and each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl may have 0, 1, 2, 3, 4, or 5 R dd groups, and R bb Examples of each are hydrogen, -OH, -OR aa , -N(R cc )2, -CN, -C(=O)R aa , -C(=O)N(R cc )2, -CO2R aa, -SO2R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc , -P(=O)(R aa )2, -P(=O)(OR cc )2, -P(=O)(N(R cc )2)2, C 1~10 Alkyl, C 1~10 Perhaloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, Hetero C 1~10 Alkyl, Hetero C 2~10 Alkenyl, Hetero C 2~10 Alkynyl, C 3~10 Carbocyclyl, 3- to 14-membered heterocyclyl, C 6~14 aryl and 5- to 14-membered heteroaryl, or two R bb The groups may be joined to form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, and each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl may have 0, 1, 2, 3, 4, or 5 R dd are independently substituted with groups, and X - is the counterion and R cc Each example of is independently hydrogen, C 10 Alkyl, C1~ 10 Perhaloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, hetero C1~ 10 Alkyl, Hetero C 2~10 Alkenyl, Hetero C 2~10 Alkynyl, C 3~10 Carbocyclyl, 3- to 14-membered heterocyclyl, C 6~14aryl and 5- to 14-membered heteroaryl, or two R cc The groups may be joined to form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, and each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl may have 0, 1, 2, 3, 4, or 5 R dd groups, and R dd Each example is independently a halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR ee , -ON(R ff )2, -N(R ff )2, -N(R ff )3 + X - , -N(OR ee )R ff , -SH, -SR ee , -SSR ee , -C(=O)R ee , -CO2H, -CO2R ee , -OC(=O)R ee , -OCO2R ee , -C(=O)N(R ff )2, -OC(=O)N(R ff )2, -NR ff C(=O)R ee , -NR ff CO2R ee , -NR ff C(=O)N(R ff )2, -C(=NR ff ) OR ee , -OC(=NR ff )R ee , -OC(=NR ff ) OR ee , -C(=NR ff )N(R ff )2, -OC(=NR ff )N(R ff )2, -NR ff C(=NR ff )N(R ff )2, -NR ff SO2R ee , -SO2N(R ff )2, -SO2Ree , -SO2OR ee , -OSO2R ee , -S(=O)R ee , -Si(R ee )3, -OSi(R ee )3, -C(=S)N(R ff )2, -C(=O)SR ee , -C(=S)SR ee , -SC(=S)SR ee , -P(=O)(OR ee )2, -P(=O)(R ee )2, -OP(=O)(R ee )2, -OP(=O)(OR ee )2, C 1~6 Alkyl, C 1~6 Perhaloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, Hetero C 1~6 Alkyl, Hetero C 2~6 Alkenyl, Hetero C 2~6 Alkynyl, C 3~10 Carbocyclyl, 3-10 membered heterocyclyl, C 6~10 aryl, and 5- to 10-membered heteroaryl, and each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl may have 0, 1, 2, 3, 4, or 5 R gg groups or two geminal R dd The substituents can be linked to form =O or =S, and X - is the counterion and R ee Each example of C 1~6 Alkyl, C 1~6 Perhaloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, Hetero C 1~6 Alkyl, Hetero C 2~6 Alkenyl, Hetero C 2~6 Alkynyl, C 3~10 Carbocyclyl, C 6~10aryl, 3- to 10-membered heterocyclyl, and 3- to 10-membered heteroaryl, and each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is selected from 0, 1, 2, 3, 4, or 5 R gg groups, and R ff Each instance of is independently hydrogen, C 1~6 Alkyl, C 1~6 Perhaloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, Hetero C 1~6 Alkyl, Hetero C 2~6 Alkenyl, Hetero C 2~6 Alkynyl, C 3~10 Carbocyclyl, 3-10 membered heterocyclyl, C 6~10 aryl and 5- to 10-membered heteroaryl, or two R ff groups are joined to form a 3- to 10-membered heterocyclyl or 5- to 10-membered heteroaryl ring, and each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl may have 0, 1, 2, 3, 4, or 5 R gg groups, and R gg Each example is independently a halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC 1~6 Alkyl, -ON(C 1~6 alkyl)2, -N(C 1~6 alkyl)2, -N(C 1~6 Alkyl)3 + X - , -NH(C 1~6 alkyl)2 + X - , -NH2(C 1~6 alkyl) + X - , -NH3 + X - , -N(OC 1~6 Alkyl)(C 1~6 alkyl), -N(OH)(C 1~6 alkyl), -NH(OH), -SH, -SC 1~6Alkyl, -SS(C 1~6 alkyl), -C(=O)(C 1~6 alkyl), -CO2H, -CO2(C 1~6 alkyl), -OC(=O)(C 1~6 alkyl), -OCO2(C 1~6 alkyl), -C(=O)NH2, -C(=O)N(C 1~6 alkyl)2, -OC(=O)NH(C 1~6 alkyl), -NHC(=O)(C 1~6 alkyl), -N(C 1~6 alkyl)C(=O)(C1 ~6 alkyl), -NHCO2(C 1~6 alkyl), -NHC(=O)N(C 1~6 alkyl)2, -NHC(=O)NH(C 1~6 alkyl), -NHC(=O)NH2, -C(=NH)O(C 1~6 alkyl), -OC(=NH)(C 1~6 alkyl), -OC(=NH)OC 1~6 Alkyl, -C(=NH)N(C 1~6 alkyl)2, -C(=NH)NH(C 1~6 alkyl), -C(=NH)NH2, -OC(=NH)N(C 1~6 alkyl)2, -OC(=NH)NH(C 1~6 alkyl), -OC(=NH)NH2, -NHC(=NH)N(C 1~6 alkyl)2, -NHC(=NH)NH2, -NHSO2(C 1~6 alkyl), -SO2N(C 1~6 alkyl)2, -SO2NH(C 1~6 alkyl), -SO2NH2, -SO2(C 1~6 alkyl), -SO2O(C 1~6 alkyl), -OSO2(C 1~6 alkyl), -SO(C 1~6 alkyl), -Si(C 1~6 alkyl)3, -OSi(C 1~6 alkyl)3, -C(=S)N(C 1~6 alkyl)2, -C(=S)NH(C 1~6 alkyl), -C(=S)NH2, -C(=O)S(C1~6 alkyl), -C(=S)SC 1~6 Alkyl, -SC(=S)SC 1~6 Alkyl, -P(=O)(OC 1~6 alkyl)2, -P(=O)(C 1~6 alkyl)2, -OP(=O)(C 1~6 alkyl)2, -OP(=O)(OC 1~6 Alkyl)2, C 1~6 Alkyl, C 1~6 Perhaloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, Hetero C 1~6 Alkyl, Hetero C 2~6 Alkenyl, Hetero C 2~6 Alkynyl, C 3~10 Carbocyclyl, C 6~10 aryl, 3- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, or two geminal R gg The substituents can be linked to form =O or =S, and X - is the counter ion.

[0065] The term "halo" or "halogen" refers to fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br) or iodine (iodo, -I).

[0066] The term "hydroxyl" or "hydroxy" refers to an -OH group. By extension, the term "substituted hydroxyl" or "substituted hydroxyl" refers to a hydroxyl group in which the oxygen atom directly attached to the parent molecule has been replaced with a group other than hydrogen, OR aa , -ON(R bb )2, -OC(=O)SR aa , -OC(=O)R aa , -OCO2R aa , -OC(=O)N(R bb )2, -OC(=NR bb )R aa , -OC(=NR bb ) OR aa , -OC(=NR bb )N(R bb )2, -OS(=O)R aa , -OSO2Raa , -OSi(R aa )3, -OP(R cc )2, -OP(R cc )3 + X - , -OP(OR cc )2, -OP(OR cc )3 + X - , -OP(=O)(R aa )2, -OP(=O)(OR cc )2 and -OP(=O)(N(R bb )2)2(wherein, X - , R aa , R bb and R cc is as described herein).

[0067] The term "amino" refers to the group -NH. By extension, the term "substituted amino" refers to a mono-, di-, or tri-substituted amino. In certain embodiments, a "substituted amino" is a mono- or di-substituted amino group.

[0068] The term "monosubstituted amino" refers to an amino group in which the nitrogen atom directly attached to the parent molecule is replaced with one hydrogen and one non-hydrogen group, and includes -NH(R bb ), -NHC(=O)R aa , -NHCO2R aa , -NHC(=O)N(R bb )2, -NHC(=NR bb )N(R bb )2, -NHSO2R aa , -NHP(=O)(OR cc )2 and -NHP(=O)(N(R bb )2)2(wherein, R aa , R bb and R cc is as described herein, and —NH(R bb )R bb is not hydrogen).

[0069] The term "disubstituted amino" refers to an amino group in which the nitrogen atom directly attached to the parent molecule is replaced with two groups other than hydrogen, -N(R bb )2, -NR bb C(=O)R aa , -NR bb CO2R aa , -NR bb C(=O)N(R bb )2, -NR bb C(=NR bb )N(R bb )2, -NR bb SO2R aa , -NR bb P(=O)(OR cc )2 and -NR b b P(=O)(N(R bb )2)2(wherein, R aa , R bb and R cc is as described herein, except that the nitrogen atom directly attached to the parent molecule is not replaced with a hydrogen.

[0070] The term "trisubstituted amino" refers to an amino group in which the nitrogen atom directly attached to the parent molecule is substituted with three groups, -N(R bb )2 and -N(R bb )3 + X - , (where R bb and X - is as defined herein.

[0071] The term "sulfonyl" refers to -SO2N(R bb )2, -SO2R aa and SO2OR aa (In the formula, R aa and R bb refers to a group selected from:

[0072] The term "sulfinyl" refers to -S(=O)R aa group (in the formula, R aa refers to a compound as defined herein.

[0073] The term "acyl" refers to a group having the general formula -C(=O)R X1 , -C(=O)OR X1 , -C(=O)-OC(=O)R X1 , -C(=O)SR X1 , -C(=O)N(R X1 )2, -C(=S)R X1 , -C(=S)N(R X1 )2, -C(=S)O(R X1 ), -C(=S)S(R X1 ), -C(=NR X1 )R X1 , -C(=NR X1 ) OR X1 , -C(=NR X1 )SR X1 and -C(=NR X1 )N(R X1 )2, and R X1 is hydrogen, halogen, substituted or unsubstituted hydroxyl, substituted or unsubstituted thiol, substituted or unsubstituted amino, substituted or unsubstituted acyl, cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic, cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic, cyclic or acyclic, substituted or unsubstituted, branched or unbranched alkyl, cyclic or acyclic, substituted or unsubstituted, branched or unbranched alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, aliphaticoxy, heteroaliphaticoxy, alkyloxy, heteroalkyloxy, aryloxy, heteroaryloxy, aliphaticthioxy, heteroaliphaticthioxy, alkylthioxy, heteroalkylthioxy, arylthioxy, heteroarylthioxy, mono- or di-aliphaticamino, mono- or di-heteroaliphaticamino, mono- or di-alkylamino, mono- or di-heteroalkylamino, mono- or di-arylamino, or mono- or di-heteroarylamino, or two R X1 The groups taken together form a 5- to 6-membered heterocyclic ring.

[0074] Exemplary acyl groups include aldehydes (-CHO), carboxylic acids (-COH), ketones, acyl halides, esters, amides, imines, carbonates, carbamates, and ureas. Acyl substituents include, but are not limited to, any of the substituents described herein that result in the formation of a stable moiety (e.g., aliphatic, alkyl, alkenyl, alkynyl, heteroaliphatic, heterocyclic, aryl, heteroaryl, acyl, oxo, imino, thioxo, cyano, isocyano, amino, azido, nitro, hydroxyl, thiol, halo, aliphatic amino, heteroaliphatic amino, alkylamino, heteroalkylamino, arylamino, heteroarylamino, alkylaryl, arylalkyl, aliphaticoxy, heteroaliphaticoxy, alkyloxy, heteroalkyloxy, aryloxy, heteroaryloxy, aliphaticthioxy, heteroaliphaticthioxy, alkylthioxy, heteroalkylthioxy, arylthioxy, heteroarylthioxy, acyloxy, etc., each of which may or may not be further substituted).

[0075] The term "carbonyl" refers to the carbon directly attached to the parent molecule being sp 2 Groups that are hybridized and substituted with oxygen, nitrogen or sulfur atoms, such as ketones (e.g., -C(=O)R aa ), carboxylic acids (e.g., -COH), aldehydes (CHO), esters (e.g., -COR aa , -C(=O)SR aa , -C(=S)SR aa ), amides (e.g., -C(=O)N(R bb )2, C(=O)NR bb SO2R aa , -C(=S)N(R bb )2 and imines (e.g., -C(=NR bb )R aa , -C(=NR bb ) OR aa ), C(=NR bb )N(R bb )2(wherein, R aa and R bbrefers to a group selected from:

[0076] The term "oxo" refers to the group =O and the term "thiooxo" refers to the group =S.

[0077] Nitrogen atoms can be substituted or unsubstituted, where valence allows, and include primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents are hydrogen, -OH, -OR aa , -N(R cc )2, -CN, -C(=O)R aa , -C(=O)N(R cc )2, -CO2R aa , -SO2R aa , -C(=NR bb )R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc , -P(=O)(OR cc )2, -P(=O)(R aa )2, -P(=O)(N(R cc )2)2, C 1~10 Alkyl, C 1~10 Perhaloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, hetero C1 10 Alkyl, Hetero C 2~10 Alkenyl, Hetero C 2~10 Alkynyl, C 3~10 Carbocyclyl, 3- to 14-membered heterocyclyl, C 6~14 including, but not limited to, aryl and 5-14 membered heteroaryl, or two R ccThe groups are joined to form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, and each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl may have 0, 1, 2, 3, 4, or 5 R dd groups, and R aa , R bb , R cc and R dd is as described herein.

[0078] In certain embodiments, the substituent present on a nitrogen atom is a nitrogen protecting group (also referred to herein as an "amino protecting group"). Nitrogen protecting groups include -OH, -OR aa , -N(R cc h, -C(=O)R aa , -C(=O)N(R cc )2, -CO2R aa , -SO2R aa , -C(=NR cc )R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc , C 1~10 Alkyl (e.g., aralkyl, heteroaralkyl), C 2~10 Alkenyl, C 2~10 Alkynyl, Hetero C 1~10 Alkyl, Hetero C 2~10 Alkenyl, Hetero C 2~10 Alkynyl, C 3~10 Carbocyclyl, 3- to 14-membered heterocyclyl, C 6~14Each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aralkyl, aryl, and heteroaryl may have 0, 1, 2, 3, 4, or 5 R dd groups, and R aa , R bb , R cc and R dd are as described 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. Butts, 3rd edition, John Wiley & Sons, 1999 (incorporated herein by reference).

[0079] For example, a nitrogen protecting group such as an amide group (e.g., —C(═O)R aa ) are formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropanamide, picolinamide, 3-pyridylcarboxamide, N-benzoylphenylalanyl derivatives, benzamide, p-phenylbenzamide, o-nitrophenylacetamide, o-nitrophenoxyacetamide, acetoacetamide, (N'-dithiobenzyloxyacylaminoacetamide, These include, but are not limited to, 3-(p-hydroxyphenyl)propanamide, 3-(o-nitrophenyl)propanamide, 2-methyl-2-(o-nitrophenoxy)propanamide, 2-methyl-2-(o-phenylazophenoxy)propanamide, 4-chlorobutanamide, 3-methyl-3-nitrobutanamide, o-nitrocinamide, N-acetylmethionine derivatives, o-nitrobenzamide and o-(benzoyloxymethyl)benzamide.

[0080] Nitrogen protecting groups such as carbamate groups (e.g., -C(=O)OR aa) are methyl carbamate, ethyl carbamate, 9-fluorenylmethyl carbamate (Fmoc), 9-(2-sulfa)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluorenylmethyl 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 (Troc), Teoc, 2-phenylethyl carbamate (hZ), 1-(1-adamantyl)-1-methylethyl carbamate (Adpoc), 1,1-dimethyl-2-haloethyl carbamate, 1,1-dimethyl-2,2-dibromoethyl carbamate (DB-t-BOC), 1,1-dimethyl-2,2,2-trichloroethyl carbamate (TCBOC), 1-methyl-1-(4-biphenylyl)ethyl carbamate (Bpoc), 1-(3,5-di-t-butylphenyl)-1-methylethyl carbamate (t-Bumeoc) , 2-(2'- and 4'-pyridyl)ethyl carbamate (Pyoc), 2-(N,N-dicyclohexylcarboxamido)ethyl carbamate, t-butyl carbamate (BOC or Boc), 1-adamantyl carbamate (Adoc), vinyl carbamate (Voc), allyl carbamate (Alloc), 1-isopropyl allyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc), 8-quinolyl carbamate, N-hydroxypiperidinyl carbamate, alkyl Dithiocarbamates, 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-methylthiophenylcarbamate (Mtpc), 2,4-dimethylthiophenylcarbamate (Bmpc), 2-phosphonioethyl carbamate (Peoc), 2-triphenylphosphonioisopropylcarbamate (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 Carbamates, t-amyl carbamate, S-benzylthiocarbamate, p-cyanobenzyl carbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentyl carbamate, cyclopropylmethyl carbamate, p-decyloxybenzyl carbamate, 2,2-dimethoxyacylvinyl carbamate, 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-methyl, Examples of suitable carbamates include, but are not limited to, cyclobutyl 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.

[0081] Sulfonamide groups (e.g., -S(=O)R aa Nitrogen protecting groups such as 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), and 2,4,6-trimethylbenzenesulfonamide (Mts) , 2,6-dimethoxy-4-methylbenzenesulfonamide (iMds), 2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide (Ms), -trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide, 4-(4',8'-dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS), benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide.

[0082] Other nitrogen protecting groups include phenothiazinyl-(10)-acyl derivatives, N'-p-toluenesulfonylaminoacyl derivatives, N'-phenylaminothioacyl derivatives, N-benzoylphenylalanyl derivatives, N-acetylmethionine derivatives, 4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dithiasuccinimide (Dts), N-2,3-diphenylmaleimide, N-2,5-dimethylpyrrole, and N-1,1,4,4-tetramethyldisilylazacyclo Pentane adducts (STA bases), 5-substituted 1,3-dimethyl-1,3,5-triazacyclohexane-2-ones, 5-substituted 1,3-dibenzyl-1,3,5-triazacyclohexane-2-ones, 1-substituted 3,5-dinitro-4-pyridones, N-methylamines, N-allylamines, N-[2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine, N-(1-isopropyl-4-nitro-2-oxo-3-pyrrolin-3-yl)amine, Quaternary ammonium salts, N-benzylamine, N-di(4-methoxyphenyl)methylamine, N-5-dibenzosuberylamine, N-triphenylmethylamine (Tr), N-[(4-methoxyphenyl)diphenylmethyl]amine (MMTr), N-9-phenylfluorenylamine (PhF), N-2,7-dichloro-9-fluorenylmethyleneamine, N-ferrocenylmethylamino (Fern), N-2-picolylamino N'-oxide, N-1,1-dimethylthiomethylamine N-Benzylideneamine, Np-Methoxybenzylideneamine, N-Diphenylmethyleneamine, N-[(2-pyridyl)mesityl]methyleneamine, N-(N',N'-Dimethylaminomethylene)amine, N,N'-Isopropylidenediamine, Np-Nitrobenzylideneamine, N-Salicylideneamine, N-5-Chlorsalicylideneamine, N-(5-Chloro-2-hydroxyphenyl)phenylmethyleneamine, N-Cyclohexylideneamine, N-(5,5-dimethyl-3-oxo-1-cyclohexenyl)amine, N-borane derivatives, N-diphenylborinic acid derivatives, N-[phenyl(pentaacychromium- or tungsten)acyl]amine, N-copper chelate, N-zinc chelate, N-nitroamine, N-nitrosamine, amine N-oxide, diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt), diphenylthiophosphinamide (Ppt), dialkylphosphoramidate, dibenzylphosphoramidate, diphenylphosphoramidate, benzenesulfenamide, o-di, In certain embodiments, the nitrogen protecting group is benzyl (Bn), tert-butyloxycarbonyl (BOC), carbobenzyloxy (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).

[0083] In certain embodiments, the substituent present on the oxygen atom is an oxygen protecting group (also referred to herein as a "hydroxyl protecting group"). An oxygen protecting group is -R aa , -N(R bb )2, -C(=O)SR aa , -C(=O)R aa , -CO2R aa , -C(=O)N(R bb )2, -C(=NR bb )R aa , -C(=NR bb ) OR aa , -C(=NRbb )N(R bb )2, -S(=O)R aa , -SO2R aa , -Si(R aa )3, -P(R cc )2, -P(R cc )3 + X - , -P(OR cc )2, -P(OR cc )3 + X - , -P(=O)(R aa )2, -P(=O)(OR cc )2 and -P(=O)(N(R bb )2)2, including but not limited to, X - , R aa , R bb and R cc is as described herein. Oxygen protecting groups are well known in the art and are Groups in Organic Synthesis, TW Greene and PG M Butts, 3rd edition, John Wiley & Sons, 1999 (incorporated herein by reference).

[0084] Exemplary oxygen protecting groups are methyl, methoxylmethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM), t-butoxymethyl, 4-pentenyloxymethyl (POM), siloxymethyl, 2-methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl, bis(2 -chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl (SEMOR), tetrahydropyranyl (THP), 3-bromotetrahydropyranyl, tetrahydrothiopyranyl, 1-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-oxide, diphenylmethyl, p,p'-dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl, α-naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl, triphenylmethyl (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 Benzisothiazolyl S,S-dioxide, 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, dichloroacetic acid, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate acetate, 3-phenylpropionate, 4-oxopentanoate (levulinate), 4,4-(ethylenedithio)pentanoate (levulinoyl dithioacetal), pivaloate, adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate, 2,4,6-trimethylbenzoate (mesitoate), methyl carbonate, 9-fluorenylmethyl carbonate (Fmoc), ethyl carbonate, 2,2,2-Trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate (TMSEC), 2-(phenylsulfonyl)ethyl carbonate (Psec), 2-(triphenylphosphonio)ethyl carbonate (Peoc), isobutyl carbonate, vinyl carbonate, allyl carbonate, t-butyl carbonate (BOC or Boc), p-nitrophenyl carbonate, benzyl carbonate, p- Methoxybenzyl carbonate, 3,4-dimethoxybenzyl carbonate, o-nitrobenzyl carbonate, p-nitrobenzyl carbonate, S-benzylthiocarbonate, 4-ethoxy-1-naphthotyl carbonate, methyl dithiocarbonate, 2-iodobenzoate, 4-azidobutyrate, 4-nitro-4-methylpentanoate, o-(dibromomethyl)benzoate, 2-formylbenzenesulfonate, 2- These include, but are not limited to, (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, a-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, the oxygen protecting group is silyl. In certain embodiments, the oxygen protecting group is t-butyldiphenylsilyl (TBDPS), t-butyldimethylsilyl (TBDMS), triisopropylsilyl (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-methoxy-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).

[0085] In certain embodiments, the substituent present on the sulfur atom is a sulfur protecting group (also referred to as a "thiol protecting group"). A sulfur protecting group is a -R aa , -N(R bb )2, -C(=O)SR aa , -C(=O)R aa , -CO2R aa , -C(=O)N(R bb )2, -C(=NR bb )R aa , -C(=NR bb ) OR aa , -C(=NR bb )N(R bb )2, -S(=O)R aa , -SO2R aa , -Si(R aa )3, -P(R cc )2, -P(R cc )3 + X - , -P(OR cc )2, -P(OR cc )3 + X - , -P(=O)(R aa )2, -P(=O)(OR cc )2 and -P(=O)(N(R bb )2)2, including but not limited to, R aa , R bb and R ccare as described herein. Sulfur protecting groups are well known in the art and are described in Protecting Groups in Organic Synthesis, T.W. Greene and P.G.M. Buts, 3rd edition, John Wiley & Sons, 1999, incorporated herein by reference. In certain embodiments, the sulfur protecting group is acetamidomethyl, t-Bu, 3-nitro-2-pyridinesulfenyl, 2-pyridinesulfenyl, or triphenylmethyl.

[0086] As used herein, a "counterion" can be an anionic counterion or a cationic counterion.

[0087] An "anionic counterion" is a negatively charged group that combines with a positively charged group to maintain electronic neutrality. Anionic counterions can be monovalent (i.e., contain one formal negative charge). Anionic counterions can also be multivalent (i.e., contain two or more formal negative charges), such as divalent or trivalent. Exemplary anionic counterions include halide ions (e.g., F -- , Cl - , Br - , I - ), NO3 - , ClO4 - , O.H. - , H2PO4 - , HCO3 - , HSO4 - , sulfonate ions (e.g., methanesulfonate, trifluoromethanesulfonate, p-toluenesulfonate, benzenesulfonate, 10-camphorsulfonate, naphthalene-2-sulfonate, naphthalene-1-sulfonic acid-5-sulfonate, ethane-1-sulfonic acid-2-sulfonate, etc.), carboxylate ions (e.g., acetate, propanoate, benzoate, glycerate, lactate, tartrate, glycolate, gluconate, etc.), BF4 - , PF4 - , PF6 - , AsF6 -, SbF6 - , B[3,5-(CF3)2C6H3]4 - , B(C6F5)4 - , BPh4 - , Al(OC(CF3)3)4 - and carborane anions (e.g., CB 11 H 12 - or (HCB 11 Me5Br6) - Exemplary anionic counterions, which may be multivalent, include CO3 2- , HPO4 2- , PO4 3- , B4O7 2- , SO4 2- , S2O3 2- , carboxylate anions (e.g., tartrate, citrate, fumarate, maleate, malate, malonate, gluconate, succinate, glutarate, adipate, pimelate, suberate, azelate, sebacate, salicylate, phthalate, aspartate, glutamate, etc.), and carboranes.

[0088] A "cationic counterion" is a positively charged group that combines with a negatively charged group to maintain electronic neutrality. A cationic counterion can be monovalent (i.e., contains one formal positive charge). A cationic counterion can also be multivalent (i.e., contains two or more formal positive charges), such as divalent or trivalent. Exemplary cationic counterions include, for example, cations of metals such as alkali metals and alkaline earth metals, and NH4 + , NH3(C 1~6 alkyl) + , NH2(C 1~6 alkyl)2 + , NH(C 1~6 Alkyl)3 + and N + (C 1~6 alkyl)4 cations, and C 1~6 Alkyl, as discussed above, Representative cations of alkali and alkaline earth metals are Li + , Na+ , K. + , Mg 2+ and Ca 2+ Includes:

[0089] Formulation and Administration Another embodiment of the present invention is a composition comprising a compound of the present invention (e.g., a compound of Formula (I)) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, adjuvant, or vehicle. In certain embodiments, the compositions of the present invention are formulated for administration to a patient in need thereof. In some embodiments, the compositions of the present invention are formulated for oral, intravenous, subcutaneous, intraperitoneal, or dermatological administration to a patient in need thereof.

[0090] As used herein, the term "subject" is intended to include human and non-human animals. Exemplary human subjects include human patients with a disorder, e.g., a disorder described herein, or normal subjects. The term "non-human animal" of the present invention includes all vertebrates, e.g., non-mammals (e.g., chickens, amphibians, reptiles, etc.), and mammals, e.g., non-human primates, domesticated and / or agriculturally useful animals, e.g., sheep, cows, pigs, etc., and companion animals (e.g., dogs, cats, horses, etc.). In certain embodiments, the subject includes a human, e.g., an adult male or female, or a male or female child.

[0091] As used herein, the amount of a compound described herein (e.g., a compound of Formula (I)) effective to treat a disorder, i.e., a "therapeutically effective amount," refers to the amount of compound that is effective, upon single or multiple dose administration to a subject or cell, in curing, alleviating, or ameliorating one or more symptoms of the disorder.

[0092] As used herein, an amount of a compound effective to prevent a disorder, i.e., a "prophylactically effective amount" of a compound, refers to an amount effective, upon administration in single or multiple doses to a subject, to prevent or delay the onset or recurrence of a disorder, or one or more symptoms of a disorder.

[0093] For administration to human subjects, the total daily dose of a compound of Formula (I) typically ranges from about 0.1 mg to about 3000 mg, depending on the route of administration. For example, oral administration may require a total daily dose of about 1 mg to about 3000 mg, while intravenous administration may require only a total daily dose of about 0.1 mg to about 300 mg. The total daily dose may be administered as a single or divided dose (e.g., 2, 3, 4, 5, or 6 times per day at equal or random intervals) or as needed. Typical daily doses may fall outside the above ranges, based on the discretion of the physician or drug prescriber. These dosages are based on an average human subject having a mass of about 60 kg to 70 kg, although a physician may determine appropriate doses for subjects (e.g., infants) whose mass falls outside this weight range.

[0094] As used herein, the term "treating" 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, having a disorder (e.g., a disorder described herein), a symptom of a disorder, or a predisposition to a disorder, or to isolated tissue or cells, e.g., a cell line, from a subject, e.g., a patient, in order to cure, heal, alleviate, relieve, alter, cure, ameliorate, improve, or affect the disorder, one or more symptoms of the disorder, or a predisposition to a disorder (e.g., to prevent at least one symptom of the disorder or delay the onset of at least one symptom of the disorder).

[0095] "Pharmaceutically or pharmacologically acceptable" includes molecular entities and compositions that do not produce adverse allergic or other untoward reactions when administered to animals or humans, as appropriate. For human administration, preparations should meet sterility, pyrogenicity, and general safety and purity standards as required by FDA Office of Biologics standards.

[0096] As used herein, the term "pharmaceutically acceptable salt" refers to a salt that is suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, etc., within the scope of sound medical judgment, and 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 the present invention include salts derived from appropriate inorganic and organic acids and bases compatible with the treatment of patients.

[0097] Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by other methods used in the art, for example, by use of ion exchange. Other pharmaceutically acceptable acid addition salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, and the like. Examples of the salts include sulfonate, 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, and valerate.

[0098] In some embodiments, exemplary inorganic acids that form suitable salts include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid, as well as acid metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate. Exemplary organic acids that form suitable salts include mono-, di-, and tricarboxylic acids. Examples of such acids include acetic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, hydroxymalic acid, benzoic acid, hydroxybenzoic acid, phenylacetic acid, cinnamic acid, salicylic acid, 2-phenoxybenzoic acid, p-toluenesulfonic acid, and other sulfonic acids such as methanesulfonic acid and 2-hydroxyethanesulfonic acid. Either mono- or di-acid salts can be formed, and such salts can exist in either hydrated, solvated, or substantially anhydrous form. In general, acid addition salts of these compounds are more soluble in water and various hydrophilic organic solvents and generally exhibit higher melting points compared to their free base forms.

[0099] In some embodiments, acid addition salts of compounds of formula I are most suitably formed from pharmaceutically acceptable acids, including those formed with inorganic acids such as hydrochloric acid, sulfuric acid, or phosphoric acid, and organic acids such as succinic acid, maleic acid, acetic acid, or fumaric acid.

[0100] Other pharmaceutically unacceptable salts, such as oxalates, can be used, for example, in the isolation of compounds of Formula I for laboratory use, or for subsequent conversion to pharmaceutically acceptable acid addition salts. Base addition salts (such as sodium, potassium, and ammonium salts), solvates, and hydrates of the compounds of the present invention are also included within the scope of the present invention. Conversion of a given compound salt to a desired compound salt can be achieved by applying standard techniques well known in the art.

[0101] A "pharmaceutically acceptable base addition salt" is any non-toxic organic or inorganic base addition salt of an acid compound of Formula I, or any of its intermediates. Exemplary inorganic bases that form suitable salts include, but are not limited to, lithium, sodium, potassium, calcium, magnesium, or barium hydroxide. Exemplary organic bases that form suitable salts include aliphatic, alicyclic, or aromatic organic amines, such as methylamine, trimethylamine, and picoline or ammonia. The selection of an appropriate salt can be important so that ester functionality (if present) elsewhere in the molecule is not hydrolyzed. The criteria for selecting an appropriate salt are known to those skilled in the art.

[0102] Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1~4 Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Further pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed, where appropriate, using counterions such as halides, hydroxides, carboxyls, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.

[0103] The term "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 non-toxic when administered in a dose sufficient to deliver a therapeutic amount of the compound. Pharmaceutically acceptable carriers, adjuvants, or vehicles that can be used in the compositions of the present invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphate, 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, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylate, wax, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and wool fat.

[0104] Compositions of the invention can be administered orally, parenterally (including subcutaneously, intramuscularly, intravenously, and intradermally), by inhalation spray, topically, rectally, nasally, buccally, vaginally, or via an implanted reservoir. In some embodiments, provided compounds or compositions can be administered intravenously and / or intraperitoneally.

[0105] The term "parenteral" as used herein includes subcutaneous, intradermal, intravenous, intramuscular, intraocular, intravitreal, intra-articular, intra-arterial, intra-synovial, intrasternal, intrathecal, intralesional, intrahepatic, intraperitoneal and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, subcutaneously, intraperitoneally or intravenously.

[0106] The pharmaceutically acceptable composition of the present invention can be orally administered in any orally acceptable dosage form, including, but not limited to, capsules, tablets, aqueous suspensions, dispersions, and solutions. For tablets for oral use, commonly used carriers include lactose and corn starch. Lubricants such as magnesium stearate are also commonly used. For oral administration in capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions and / or emulsions are required for oral use, the active ingredient can be suspended or dissolved in an oil phase and combined with emulsifying and / or suspending agents. If desired, certain sweeteners, flavorings, or coloring agents can be added.

[0107] In some embodiments, the oral formulations are formulated for immediate release or sustained / delayed release. do.

[0108] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and / or a) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders, such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarders 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.

[0109] 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.

[0110] Solid compositions of a similar type can also be used as fillers in soft and hard gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols. Solid dosage forms such as 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 can optionally contain opacifying agents and can also be of a composition that they release the active ingredient 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.

[0111] The compounds of the present invention can also be microencapsulated with one or more excipients, as described above. In such solid dosage forms, the compounds of the present invention can be mixed with at least one inert diluent, such as sucrose, lactose, or starch. Such dosage forms can also contain, as is normal practice, additional substances other than inert diluents, such as tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose.

[0112] Compositions for oral administration may be designed to protect the active ingredient from degradation as it passes through the gastrointestinal tract, for example by an outer coating of the formulation on a tablet or capsule.

[0113] In another embodiment, the compounds of the present invention can be provided in an extended (or "delayed" or "sustained") release composition. This delayed release composition comprises a compound of the present invention combined with a delayed release component. Such a composition allows for targeted release of the provided compound into the lower gastrointestinal tract, e.g., the small intestine, large intestine, colon, and / or rectum. In certain embodiments, the delayed release composition comprising the compounds of the present invention further comprises an enteric or pH-dependent coating, such as cellulose acetate phthalate and other phthalates (e.g., polyvinyl acetate phthalate, methacrylates (Eudragits)). Alternatively, the delayed release composition provides controlled release in the small intestine and / or colon by providing a pH-sensitive methacrylate coating, pH-sensitive polymer microspheres, or polymers that undergo hydrolytic degradation. The delayed release composition can be formulated with hydrophobic or gelling excipients or coatings. Colonic delivery can be achieved using coatings digested by bacterial enzymes, such as amylose or pectin, pH-dependent polymers, hydrogel plugs that expand over time (Pulsincap), time-dependent It may further be provided by an acrylic acid bonded to the hydrogel coating and / or the azoaromatic bonded coating.

[0114] In certain embodiments, the delayed-release composition of the present invention comprises hypromellose, microcrystalline cellulose, and a lubricant. The mixture of the compound of the present invention, hypromellose, and microcrystalline cellulose can be formulated into tablets or capsules for oral administration. In certain embodiments, the mixture is granulated and pressed into tablets.

[0115] Alternatively, the pharmaceutically acceptable composition of the present invention can be administered in the form of suppositories for rectal administration. These can be prepared by mixing the compound of the present invention with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature, and therefore melts in the rectum to release the drug. Such materials include cocoa butter, beeswax, and polyethylene glycol.

[0116] The pharmaceutically acceptable compositions of this invention may also be administered topically, particularly 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.

[0117] Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topical-transdermal patches can also be used.

[0118] For other topical applications, the pharmaceutically acceptable compositions of the present invention can be formulated in a suitable ointment containing the active ingredient suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of the present invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying wax, and water, as well as penetration enhancers. Alternatively, the pharmaceutically acceptable compositions of the present invention can be formulated in a suitable lotion or cream containing the active ingredient suspended or dissolved in one or more pharmaceutically acceptable carriers. Alternatively, the pharmaceutical composition can be formulated in a suitable lotion or cream containing the active compound suspended or dissolved in a carrier with a suitable emulsifier. 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.

[0119] For ophthalmic use, the pharmaceutically acceptable compositions of the present invention may be formulated as a micronized suspension in isotonic, pH-adjusted, sterile saline or, preferably, as a solution in isotonic, pH-adjusted, sterile saline, with or without a preservative such as benzylalkonium chloride. Alternatively, for ophthalmic use, the pharmaceutically acceptable compositions may be formulated into an ointment such as petrolatum.

[0120] The pharmaceutically acceptable compositions of this invention may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation and may be prepared as solutions in saline using benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents.

[0121] In some embodiments, the pharmaceutically acceptable compositions of the present invention are formulated for oral administration. can be.

[0122] In some embodiments, pharmaceutically acceptable compositions of this invention are formulated for intravenous administration.

[0123] In some embodiments, the pharmaceutically acceptable compositions of this invention are formulated for topical administration.

[0124] The amount of the compounds of the present invention that can be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated, the particular mode of administration, and the activity of the compound used. Preferably, the compositions should be formulated so that a dosage of 0.01 to 100 mg / kg body weight / day of the inhibitor can be administered to a patient receiving the composition.

[0125] It will be understood that the specific dosage and treatment regimen for any particular patient will depend on a variety of factors, including the activity of the specific compound used, age, body weight, general health, sex, diet, time of administration, excretion rate, drug combination, the judgment of the treating physician, and the severity of the particular disease being treated. The amount of a compound of the invention in a composition will also depend on the particular compound in the composition.

[0126] Other pharmaceutically acceptable carriers, adjuvants and vehicles that can be used in the pharmaceutical compositions of the present invention 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, polyvinylpyrrolidone, 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 hydroxyalkyl cyclodextrins, including 2- and 3-hydroxypropyl-β-cyclodextrin, or other solubilizing derivatives, may also be advantageously used to enhance delivery of the compounds described herein.

[0127] The pharmaceutical composition of the present invention is preferably administered orally or by injection.The pharmaceutical composition of the present invention can contain any conventional non-toxic pharmaceutically acceptable carrier, adjuvant or vehicle.In some cases, the pH of the formulation can be adjusted with pharmaceutically acceptable acid, base or buffer to enhance the stability of the formulated compound or its delivery form.

[0128] The pharmaceutical compositions may be in the form of a sterile injectable preparation, for example, as a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (e.g., Tween 80, etc.) and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol. Acceptable vehicles and solvents that may be used include mannitol, water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally used as solvents or suspending media. For this purpose, any bland, fixed oil may be used, including synthetic mono- or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives, as well as pharmaceutically acceptable natural oils, such as olive oil or castor oil, are also suitable, particularly their polyoxyethylated versions. These oil solutions or suspensions are useful in preparing injectable solutions. These oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants, or carboxymethylcellulose or similar dispersants, commonly used in formulating pharmaceutically acceptable dosage forms such as emulsions and / or suspensions. Other commonly used surfactants, such as Tweens or Spans, and / or other similar emulsifiers or bioavailability enhancers commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for formulation purposes.

[0129] When the compositions of the invention comprise a combination of a compound of the formulae described herein with one or more additional therapeutic or prophylactic agents, both the compound and the additional agents should be present at dosage levels that are about 1-100%, more preferably about 5-95%, of the dosage normally administered in a monotherapy regimen. The additional agents may be administered separately from the compounds of the invention as part of a multiple dose regimen. Alternatively, the additional agents may be part of a single dosage form that is mixed together with the compounds of the invention into a single composition.

[0130] The compounds described herein can be administered, for example, by injection, intravenous, intraarterial, intraocular, intravitreal, subcutaneous, oral, buccal, intranasal, transmucosal, topical, in ophthalmic formulations, or by inhalation, at doses ranging from about 0.5 to about 100 mg / kg body weight, or alternatively, from about 1 mg to about 1000 mg / dose, every 4 to 120 hours, or as required by the particular drug. The methods herein contemplate administration of an effective amount of a compound of the present invention or a composition thereof to achieve the desired or stated effect. Typically, pharmaceutical compositions of the present invention 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 carrier materials to produce a single dosage form will vary depending on the host treated and the particular mode of administration. Typical formulations will contain from about 5% to about 95% active compound (w / w). Alternatively, formulations may contain from about 20% to about 80% active compound.

[0131] Lower or higher doses than those recited above may be necessary. The specific dosage and treatment regimen for any particular patient will depend on a variety of factors, including the activity of the specific compound used, the age, body weight, general health, sex, diet, time of administration, excretion rate, drug combination, the severity and course of the disease, condition or symptom, the patient's predisposition to the disease, condition or symptom, and the judgment of the treating physician.

[0132] Once the patient's condition has improved, a maintenance dose of a compound, composition or combination of the present invention may be administered, if necessary. Subsequently, when the symptoms have been alleviated to a desired level, the dosage or frequency of administration, or both, may be reduced as a function of the symptoms, to a level at which the improved condition is maintained. However, the patient may require intermittent treatment on a long-term basis upon recurrence of disease symptoms.

[0133] Uses of the Compounds and Pharmaceutically Acceptable Compositions As used herein, a "RIPK2-mediated" disease, disorder, or condition refers to any disease or other deleterious condition in which RIPK2 plays a role. Accordingly, another embodiment of the present invention relates to, for example, treating, e.g., reducing 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 described in detail below. The compounds provided by the present invention are also useful, for example, as tools for studying RIPK2 regulation in biological and pathological phenomena, studying cancer, or identifying and / or comparatively evaluating RIPK2 modulators. Accordingly, in certain embodiments, the present invention provides a method for studying the effect of a compound or a salt or composition thereof described herein on a sample, the method comprising contacting cells in culture or a sample containing RIPK2 with the compound or a salt or composition; and and measuring the effect of the compound or a salt or composition thereof on the activity of RIPK2. For example, the compounds described herein can be used as standards or controls in binding assays (e.g., competitive binding assays) to identify or evaluate RIPK2 modulators, or as discovery tools to explore 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.

[0134] In certain embodiments, the present invention relates to a method of treating a disease or disorder comprising administering a therapeutically effective amount of a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, to a subject in need thereof, wherein the disease or disorder is selected from an inflammatory disease, an autoimmune disease, a granulomatous disease, cancer, and a neurodegenerative disease.

[0135] In some embodiments, the compounds and compositions described herein are useful for treating an inflammatory disorder in a subject in need thereof. Accordingly, in certain embodiments, the present invention provides a method for treating an inflammatory disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the present invention (e.g., a compound of Formula (I)) or a pharmaceutically acceptable salt or composition thereof.

[0136] In certain aspects, inflammatory diseases include, but are not limited to, uveitis, interleukin-1 converting enzyme fever syndrome, dermatitis, acute lung injury, type 2 diabetes, arthritis, inflammatory bowel disorder (IBD), ischemia-reperfusion injury in solid organ transplants, sepsis, liver disease, allergic diseases, and graft-versus-host disease.

[0137] In certain cases, the inflammatory disease is IBD, for example, the IBD is selected from ulcerative colitis, Crohn's disease, early-onset IBD, and extraintestinal IBD.

[0138] Alternatively, the inflammatory disease may include, but is not limited to, rheumatoid arthritis, inflammatory arthritis, peritonitis, ischemia-reperfusion injury in kidney transplants, non-alcoholic steatohepatitis, alcoholic steatohepatitis, insulin-resistant type 2 diabetes, allergic rhinitis, asthma, atopic dermatitis, Sjogren's syndrome, ankylosing spondylitis, pemphigus vulgaris, idiopathic plasma cell lymphadenopathy, atherosclerosis, myocardial infarction, thrombosis, alpha-synucleinopathies, Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, Alzheimer's disease, amyotrophic lateral sclerosis, and chronic obstructive pulmonary disease.

[0139] In certain embodiments, the disease or disorder is an autoimmune disease, including, but not limited to, systemic lupus erythematosus, lupus nephritis, psoriasis, type 1 diabetes, Goodpasture's syndrome, Guillain-Barré syndrome, Hashimoto's disease, Graves' disease, immune thrombocytopenic purpura, and multiple sclerosis (including relapsing-remitting MS, secondary progressive MS, primary progressive MS, and progressive relapsing MS).

[0140] In further embodiments, the disease or disorder is a granulomatous disease, e.g., the granulomatous disease is selected from sarcoidosis, Blau syndrome, Wegener's granulomatosis, Behcet's disease, and interstitial pulmonary disease.

[0141] In another embodiment, the disease or disorder is a neurodegenerative disorder, e.g., the neurological disease is selected from Alzheimer's disease, amyotrophic lateral sclerosis (ALS / Lou Gehrig's disease), Parkinson's disease, multiple sclerosis, diabetic neuropathy, polyglutamine (polyQ) disease, stroke, Fahr's disease, Menkes disease, Wilson's disease, cerebral ischemia, prion disorders, dementia, corticobasal degeneration, progressive supranuclear palsy, spinocerebellar atrophy, brain injury, and spinal cord injury.

[0142] In yet another embodiment, the disease or disorder is cancer. For example, the cancer is selected from blood cancers such as leukemia (e.g., acute myeloid leukemia, chronic myeloid 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, gastric cancer, bone cancer, ovarian cancer, uterine cancer, renal cancer, liver cancer, and lung cancer. The cancer may be a soft tissue cancer, including, but not limited to, a sarcoma selected from the group consisting of fibrosarcoma and liposarcoma (e.g., dedifferentiated liposarcoma and pleomorphic liposarcoma).

[0143] 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 below.

[0144] The compounds of the present invention can be used alone or in combination with other therapeutic agents. Combination therapy according to the present invention includes the administration of a therapeutically effective amount of at least one compound of the present invention and a therapeutically effective amount of at least one other therapeutically active agent (second agent). For example, combination therapy according to the present invention includes the administration of at least one compound of the present invention and at least one other therapeutically active agent to a subject in need of treatment for a given disease or disorder, such as inflammatory diseases, autoimmune diseases, granulomatous diseases, cancer, and neurodegenerative diseases described herein.

[0145] The compound of the present invention and other therapeutically active agents can be administered together in a single pharmaceutical composition or separately. When administered separately, they can be administered simultaneously or sequentially in any order. The amount and relative timing of administration of the compound of the present invention and other therapeutically active agents can be selected to achieve the desired combined therapeutic effect.Therefore, in a further aspect, a combination is provided that comprises the compound of the present invention together with one or more other therapeutically active agents.

[0146] In certain embodiments, the present invention relates to a method of treating a subject suffering from an inflammatory disorder described herein, comprising administering to the subject effective amounts of a compound represented by Formula (I) or a pharmaceutically acceptable salt thereof and an anti-inflammatory agent and / or an anti-TNF agent.

[0147] In certain embodiments, the present invention 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 represented by Formula (I) or a pharmaceutically acceptable salt thereof, and optionally an anti-inflammatory agent and / or an anti-TNF agent.

[0148] In another embodiment, the present invention relates to a method of treating a subject suffering from an autoimmune disorder described herein, comprising administering to the subject therapeutically effective amounts of a compound represented by Formula (I) or a pharmaceutically acceptable salt thereof and an autoimmune agent, such as, but not limited to, an anti-TNF agent.

[0149] Suitable anti-inflammatory / autoimmune agents include 5-aminosalicylic acid and mesalamine preparations, sulfasalazine, hydroxychloroquine, thiopurines (azathioprine, mercaptopurine), methotrexate, cyclophosphamide, cyclosporine, 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 and / or IL23 biologics (ustekinumab (Stelara®)), anti-IL 17 biologics (secukinumab), anti-CD22 (epratuzumab), anti-integrin agents (natalizumab (Tysabri®)), vedolizumab (Entyvio®)), anti-IFNa (sifalimumab), anti-CD20 These include mAbs (rituximab (Rituxan®) and ofatumumab (Arzerra®)) and other agents such as abatacept (Orencia®), anakinra (Kineret®), canakinumab (Ilaris®), rilonacept (Arcalyst®), secukinumab, epratuzumab, sifalimumab, and belimumab (Benlysta®), CD4 biologics, and other cytokine inhibitors or biologics directed against T-cell or B-cell receptors or interleukins.

[0150] Examples of suitable anti-TNF agents include anti-TNF biologics such as Enbrel® (etaneserpt), Humira® (adalimumab), Remicade® (infliximab), Cimzia® (certolizumab), and Simponi® (golimumab).

[0151] In some embodiments, the second agent and the compound represented by structural formula (I) are administered simultaneously. If administered simultaneously, the second agent and the compound can be administered in the same formulation or in different formulations. Alternatively, the compound and the additional anti-inflammatory / autoimmune agent can be administered separately.

[0152] In certain embodiments, the present invention relates to a method of treating a subject suffering from a neurodegenerative disease described herein, e.g., Parkinson's disease, comprising administering to the subject an effective amount of a compound represented by Formula (I) or a pharmaceutically acceptable salt thereof, and optionally one or more additional therapeutic agents typically used to treat Parkinson's disease. 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.

[0153] In certain embodiments, the present invention relates to a method of treating a subject suffering from a neurodegenerative disease described herein, e.g., Alzheimer's disease, comprising administering to the subject an effective amount of a compound represented by Formula (I) 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, anti-Abeta (amyloid beta) therapies including donepezil, galantamine, memantine, rivastigmine, aducanumab, crenezumab, solanezumab, and gantenerumab, small molecule inhibitors of BACEl or anti-tau therapies including verubecestat, AZD3293 (LY3314814), elenbecestat (E2609), LY2886721, PF-05297909, JNJ-54861911, TAK-070, VTP-37948, HPP854, CTS-21166, for example, LMTM (leuco-methylthioninium-bis(hydromethanesulfonate)) or a pharmaceutically acceptable salt thereof.

[0154] In certain embodiments, the present invention relates to a method of treating a subject with cancer, comprising administering to the subject an effective amount of a compound represented by Formula (I) or a pharmaceutically acceptable salt thereof and an anti-cancer agent. An "anti-cancer agent" is a compound that, when administered in an effective amount to a subject with cancer, can partially or substantially accomplish one or more of the following: arrest the growth of the cancer. , reducing the extent of cancer (e.g., reducing tumor size), inhibiting the rate of cancer growth, and ameliorating or improving clinical symptoms or cancer-related indicators (such as tissue or serum components), or extending the lifespan of a subject.

[0155] Anti-cancer agents suitable for use in the methods described herein include any anti-cancer agent approved for the treatment of cancer, hi one embodiment, anti-cancer agents include, but are not limited to, targeted antibodies, angiogenesis inhibitors, alkylating agents, antimetabolites, vinca alkaloids, taxanes, podophyllotoxins, topoisomerase inhibitors, hormonal antineoplastic agents, and other antineoplastic agents.

[0156] In one embodiment, anti-cancer agents that can be used in the 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 combinations thereof.

[0157] In one embodiment, the anti-cancer agent and the compound represented by Structural Formula (I) are administered simultaneously. When administered simultaneously, 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.

[0158] In a first embodiment, the present invention provides a compound of structural formula (I): [ka] (In the formula, R 1a , R 1b and R 1c are each independently H, halogen, CN, and C 1~6 alkyl, R 2 is H or C 1~3 is alkyl, R 3 is halogen, 4-10 membered heterocyclyl, 5-12 membered heteroaryl, S(=O)2R 5 , S(=O)(=NR 6 )(R 7 ), QR 7 , C(=O)NR 8 R 9 , NH(C=O)R 5 , C.N., N.R. 8 R 9 , P(=O)R8a R 9a is selected from R 4 H, halogen, C 1~6 Alkyl and C 1~6 alkoxy; R 5 is NR 10 R 11 , C 1~6 Alkyl, C 3~6 selected from cycloalkyl and 4- to 10-membered heterocyclyl; R 6 are H, CN and C 1~6 alkyl, R 7 is C 1~6 Alkyl, C 3~6 cycloalkyl and 4- to 10-membered heterocyclyl, 5- to 12-membered heteroaryl; or R 6 and R 7 together with the nitrogen and sulfur atoms to which they are attached form a 4- to 10-membered heterocyclyl; Q is selected from O, S, -S(=O)- and -C(=O)-; R 8 and R 9 are independently H, C 1~6 Alkyl, C 1~6 Deuterated alkyl, C 3~6 selected from cycloalkyl and 4- to 10-membered heterocyclyl; or R 8 and R 9 together with the nitrogen atom to which they are attached form a 4- to 10-membered heterocyclyl; R 8a and R 9b are each independently 1~6 alkyl, or R 8a and R 9a together with the phosphorus atom to which they are attached form a 4- to 10-membered heterocyclyl, R 10 and R 11 are each independently H or C 1~6 alkyl, or R 10 and R 11 together with the nitrogen to which they are attached form a 4- to 10-membered heterocyclyl; W, O, NR 2 , O(C 1~2 alkylene), NH(C 1~2 alkylene), C 1~2 Alkylene, C 3~6 selected from cycloalkylene and a bond; X has the following structural formula: [ka] is the part represented by one of Y 1 is CH or N, Y 2 and Y 3 are each independently 4 or N, U is for CR 12b or N, Z is CR 1b or N, L, M, and J are each independently selected from N, O, or S, provided that two of L, M, and J are N; R 12 is C 3~6 Alkyl, C 3~6 Cycloalkyl, C 5~12 selected from bridged bicyclic carbocyclyl and 4- to 10-membered heterocyclyl; R 12a is C 1~6 Alkyl, C 1~6 Deuterated alkyl, C 3~6 Cycloalkyl, C 5~12 selected from bridged bicyclic carbocyclyl and 4- to 10-membered heterocyclyl; R 12b and R 13 are each independently H or C 1~6 is alkyl, and [ka] is a single or double bond, Each C 1~6 Alkyl, C 1~3 Alkyl, C 1~2 Alkylene, C 3~6 Alkyl, C 3~6 Cycloalkyl, C 1~6 Alkoxy, C 5~12 Bridged bicyclic carbocyclyl, 5- to 12-membered heteroaryl and 4- to 10-membered heterocyclyl are substituted with deuterium, oxo, F, Cl, Br, CN, OR 14 , S.R. 15 , N.R. 16 R 17 , S(O)R 18 , S(O)2R 18a , N.R. 19 S(=O)R 20 , C(=O)OR 20a , C(=O)NR 21 R 22 , N.R. 23 C(=O)R 24 , C(=S)NR 25 R 26 , C(=O)R 27 , C 1~6 Alkyl, C 1~6 Deuterated alkyl, C 3~8 Cycloalkyl, C 2~6 Alkenyl, halo(C 1~6 ) Alkyl, C 1~3 Alkyl sulfonyl amino alkyl, hydroxy (C 1~6 ) alkyl, amino (C 1~6 ) alkyl, (C 1~6 ) Alkylamino(C 1~6 ) alkyl, cyano (C 1~6 ) Alkyl, C 1~3 Alkylcarbonylamino (C 1~6 ) Alkyl, C 1~3 Alkoxy, Halo(C 1~3 ) Alkoxy, C 1~6 Alkoxy (C 1~3 ) Alkyl, C 6~12 optionally substituted with 1 to 3 substituents independently selected from aryl, 4- to 8-membered heterocyclyl, and 5- to 12-membered heteroaryl; R 14 , R 15 , R18 , R 18a , R 20 , R 20a , R 24 and R 27 are each independently hydrogen or C 1~6 is alkyl, R 16 and R 17 are each independently hydrogen, C 1~6 Alkyl, hydroxy (C 1~6 ) alkyl and halo(C 1~6 ) alkyl; R 19 and R 23 are each independently 1~6 Alkyl or halo(C 1~6 ) alkyl, R 21 , R 22 , R 25 and R 26 are independently H, C 1~6 Alkyl, C 1~3 Alkoxy (C 1~6 ) alkyl, hydroxy (C 1~6 ) alkyl, cyano (C 1~6 ) alkyl, amino (C 1~6 ) Alkyl, C 1~3 Alkylamino (C 1~6 ) alkyl and di(C 1~3 ) Alkylamino(C 1~6 ) alkyl, or R 21 and R 22 or R 25 and R 26 together with the nitrogen to which they are attached, deuterium, oxo, F, Cl, Br, CN, OR 14 , S.R. 15 , N.R. 16 R 17 , S(O)R 18 , S(O)2R 18a , N.R. 19 S(=O)R 20 , C(=O)OR 20a , C(=O)NR 21 R 22 , N.R. 23 C(=O)R 24, C(=S)NR 25 R 26 , C(=O)R 27 , C 1~6 Alkyl, C 3~8 Cycloalkyl, C 2~6 Alkenyl, halo(C 1~6 ) Alkyl, C 1~3 Alkyl sulfonyl amino alkyl, hydroxy (C 1~6 ) alkyl, amino (C 1~6 ) alkyl, cyano (C 1~6 ) Alkyl, C 1~3 Alkylcarbonylamino (C 1~6 ) Alkyl, C 1~3 Alkoxy, Halo(C 1~3 ) Alkoxy, C 1~6 Alkoxy (C 1~3 ) Alkyl, C 6~12 forming a 3- to 8-membered ring optionally substituted with 1 to 3 substituents independently selected from aryl, 4- to 10-membered heterocyclyl, and 5- to 12-membered heteroaryl; However, Y 2 But R 4 CH substituted with, and R 4 optionally replaced by C 1~6 If it is alkoxy, WR 3 is CN or optionally substituted C 1~6 shall not be alkoxy, and Y 1 , Y 2 and Y 3 If each is CH, then WR 3 is not F) or a pharmaceutically acceptable salt thereof.

[0159] For example, the present invention provides compounds of structural formula (I): [ka] (In the formula, R 1a , R 1b and R 1c are each independently H, halogen, CN, and C1~6 alkyl, R 2 is H or C 1~3 is alkyl, R 3 is halogen, 4-10 membered heterocyclyl, 5-12 membered heteroaryl, S(=O)2R 5 , S(=O)(=NR 6 )(R 7 ), QR 7 , C(=O)NR 8 R 9 , NH(C=O)R 5 , C.N., N.R. 8 R 9 , P(=O)R 8a R 9a is selected from R 4 H, halogen, C 1~6 Alkyl and C 1~6 alkoxy; R 5 is NR 10 R 11 , C 1~6 Alkyl, C 3~6 selected from cycloalkyl and 4- to 10-membered heterocyclyl; R 6 are H, CN and C 1~6 alkyl, R 7 is C 1~6 Alkyl, C 3~6 cycloalkyl and 4- to 10-membered heterocyclyl, 5- to 12-membered heteroaryl; or R 6 and R 7 together with the nitrogen and sulfur atoms to which they are attached form a 4- to 10-membered heterocyclic group. Forming a cyclyl Q is selected from O, S, -S(=O)- and -C(=O)-; R 8 and R 9 are independently H, C 1~6 Alkyl, C 3~6 selected from cycloalkyl and 4- to 10-membered heterocyclyl; or R 8and R 9 together with the nitrogen atom to which they are attached form a 4- to 10-membered heterocyclyl; R 8a and R 9b are each independently 1~6 alkyl, or R 8a and R 9a together with the phosphorus atom to which they are attached form a 4- to 10-membered heterocyclyl, R 10 and R 11 are each independently H or C 1~6 alkyl, or R 10 and R 11 together with the nitrogen to which they are attached form a 4- to 10-membered heterocyclyl; W, O, NR 2 , O(C 1~2 alkylene), NH(C 1~2 alkylene), C 1~2 selected from alkylene and a bond; X has the following structural formula: [ka] is the part represented by one of Y 1 is CH or N, Y 2 and Y 3 are each independently 4 or N, U is for CR 12b or N, Z is CR 1b or N, L, M, and J are each independently selected from N, O, or S, provided that two of L, M, and J are N; R 12 is C 3~6 Alkyl, C 3~6 Cycloalkyl, C 5~12 selected from bridged bicyclic carbocyclyl and 4- to 10-membered heterocyclyl; R 12ais C 1~6 Alkyl, C 3~6 Cycloalkyl, C 5~12 selected from bridged bicyclic carbocyclyl and 4- to 10-membered heterocyclyl; R 12b and R 13 are each independently H or C 1~6 is alkyl, and [ka] is a single or double bond, Each C 1~6 Alkyl, C 1~3 Alkyl, C 1~2 Alkylene, C 3~6 Alkyl, C 3~6 Cycloalkyl, C 1~6 Alkoxy, C 5~12 Bridged bicyclic carbocyclyl, 5- to 12-membered heteroaryl and 4- to 10-membered heterocyclyl are substituted with deuterium, oxo, F, Cl, Br, CN, OR 14 , S.R. 15 , N.R. 16 R 17 , S(O)R 18 , S(O)2R 18a , N.R. 19 S(=O)R 20 , C(=O)OR 20a , C(=O)NR 21 R 22 , N.R. 23 C(=O)R 24 , C(=S)NR 25 R 26 , C(=O)R 27 , C 1~6 Alkyl, C 3~8 Cycloalkyl, C 2~6 Alkenyl, halo(C 1~6 ) Alkyl, C 1~3 Alkyl sulfonyl amino alkyl, hydroxy (C 1~6 ) alkyl, amino (C 1~6 ) alkyl, cyano (C 1~6 ) Alkyl, C 1~3 Alkylcarbonylamino (C 1~6 ) Alkyl, C 1~3Alkoxy, Halo(C 1~3 ) Alkoxy, C 1~6 Alkoxy (C 1~3 ) Alkyl, C 6~12 optionally substituted with 1 to 3 substituents independently selected from aryl, 4- to 8-membered heterocyclyl, and 5- to 12-membered heteroaryl; R 14 , R 15 , R 18 , R 18a , R 20 , R 20a , R 24 and R 27 are each independently hydrogen or C 1~6 is alkyl, R 16 and R 17 are each independently hydrogen, C 1~6 Alkyl, hydroxy (C 1~6 ) alkyl and halo(C 1~6 ) alkyl; R 19 and R 23 are each independently 1~6 Alkyl or halo(C 1~6 ) alkyl, R 21 , R 22 , R 25 and R 26 are independently H, C 1~6 Alkyl, C 1~3 Alkoxy (C 1~6 ) alkyl, hydroxy (C 1~6 ) alkyl, cyano (C 1~6 ) alkyl, amino (C 1~6 ) Alkyl, C 1~3 Alkylamino (C 1~6 ) alkyl and di(C 1~3 ) Alkylamino(C 1~6 ) alkyl, or R 21 and R 22 or R 25 and R 26 together with the nitrogen to which they are attached, deuterium, oxo, F, Cl, Br, CN, OR 14 , S.R. 15, N.R. 16 R 17 , S(O)R 18 , S(O)2R 18a , N.R. 19 S(=O)R 20 , C(=O)OR 20a , C(=O)NR 21 R 22 , N.R. 23 C(=O)R 24 , C(=S)NR 25 R 26 , C(=O)R 27 , C 1~6 Alkyl, C 3~8 Cycloalkyl, C 2~6 Alkenyl, halo(C 1~6 ) Alkyl, C 1~3 Alkyl sulfonyl amino alkyl, hydroxy (C 1~6 ) alkyl, amino (C 1~6 ) alkyl, cyano (C 1~6 ) Alkyl, C 1~3 Alkylcarbonylamino (C 1~6 ) Alkyl, C 1~3 Alkoxy, Halo(C 1~3 ) Alkoxy, C 1~6 Alkoxy (C 1~3 ) Alkyl, C 6~12 forming a 3- to 8-membered ring optionally substituted with 1 to 3 substituents independently selected from aryl, 4- to 10-membered heterocyclyl, and 5- to 12-membered heteroaryl; However, Y 2 But R 4 CH substituted with, and R 4 optionally replaced by C 1~6 If it is alkoxy, WR 3 is CN or optionally substituted C 1~6 Y is not an alkoxy group. 1 , Y 2 and Y 3 If each is CH, then WR 3 is not F) or a pharmaceutically acceptable salt thereof.

[0160] In a first aspect of the first embodiment, R 3 is a 4- to 10-membered heterocyclyl, a 5- to 10-membered heteroaryl, S(=O)R 5 , -S(=O)(=NR 6 )(R 7 ) and C(=O)NR 8 R 9 For example, R 3 is 4-10 membered heterocyclyl, S(=O)2R 5 and C(=O)NR 8 R 9 is selected from.

[0161] In a second aspect of the first embodiment, W is NH, N(C 1~2 alkylene), O(C 1~2 alkylene) and C 1~2 alkylene. For example, W is O. Alternatively, W is a bond. Further alternatively, W is C 3~6 The remaining features and example features of the second aspect are as described above for the first aspect of the first embodiment.

[0162] In a third aspect of the first embodiment, R 3 Deuterium, oxo, F, Cl, Br, CN, OR 14 , S.R. 15 , N.R. 16 R 17 , S(O)R 18 , S(O)2R 18a , N.R. 19 S(=O)R 20 , C(=O)OR 20a , C(=O)NR 21 R 22 , N.R. 23 C(=O)R 24 , C(=S)NR 25 R 26 , C(=O)R 27 , C 1~6 Alkyl, C 3~8 Cycloalkyl, C 2~6 Alkenyl, halo(C 1~6 ) Alkyl, C 1~3Alkyl sulfonyl amino alkyl, hydroxy (C 1~6 ) alkyl, amino (C 1~6 ) alkyl, cyano (C 1~6 ) Alkyl, C 1~3 Alkylcarbonylamino (C 1~6 ) Alkyl, C 1~3 Alkoxy, Halo(C 1~3 ) Alkoxy, C 1~6 Alkoxy (C 1~3 ) Alkyl, C 6~12 a 4- to 6-membered heterocyclyl optionally substituted with 1 to 3 substituents independently selected from aryl, 4- to 8-membered heterocyclyl, and 5- to 12-membered heteroaryl; R 14 , R 15 , R 18 , R 18a , R 20 , R 20a , R 24 and R 27 are respectively independently hydrogen or C 1~6 is alkyl, R 16 and R 17 are each independently hydrogen, C 1~6 Alkyl, hydroxy (C 1~6 ) alkyl and halo(C 1~6 ) alkyl; R 19 and R 23 are each independently 1~6 Alkyl or halo(C 1~6 ) alkyl, R 21 , R 22 , R 25 and R 26 are independently H, C 1~6 Alkyl, C 1~3 Alkoxy (C 1~6 ) alkyl, hydroxy (C 1~6 ) alkyl, cyano (C 1~6 ) alkyl, amino (C 1~6 ) Alkyl, C 1~3 Alkylamino (C 1~6 ) alkyl and di(C1~3 ) Alkylamino(C 1~6 ) alkyl, or R 21 and R 22 or R 25 and R 26 together with the nitrogen to which they are attached, deuterium, oxo, F, Cl, Br, CN, OR 14 , S.R. 15 , N.R. 16 R 17 , S(O)R 18 , S(O)2R 18a , N.R. 19 S(=O)R 20 , C(=O)OR 20a , C(=O)NR 21 R 22 , N.R. 23 C(=O)R 24 , C(=S)NR 25 R 26 , C(=O)R 27 , C 1~6 Alkyl, C 3~8 Cycloalkyl, C 2~6 Alkenyl, halo(C 1~6 ) Alkyl, C 1~3 Alkyl sulfonyl amino alkyl, hydroxy (C 1~6 ) alkyl, amino (C 1~6 ) alkyl, cyano (C 1~6 ) Alkyl, C 1~3 Alkylcarbonylamino (C 1~6 ) Alkyl, C 1~3 Alkoxy, Halo(C 1~3 ) Alkoxy, C 1~6 Alkoxy (C 1~3 ) Alkyl, C 6~12 Forms a 3- to 8-membered ring optionally substituted with 1 to 3 substituents independently selected from aryl, 4- to 10-membered heterocyclyl, and 5- to 12-membered heteroaryl. For example, R 3 is a substituted 4- to 6-membered heterocyclyl. Alternatively, R 3 is oxo, F, Cl, Br, CN, OR 14 , S.R. 15 , N.R. 16 R 17 , 4- to 10-membered heterocyclyl and C1~6 and 4- to 6-membered heterocyclyl substituted with 1 to 3 substituents independently selected from alkyl. For example, R 3 is substituted with oxo. In some embodiments, R 3 is a saturated 4-6 membered heterocyclyl. For example, R 3 is the structural formula [ka] is the part represented by A is O or NR 28 and R 28 is H, C 1~6 Alkyl, C 3~6 selected from cycloalkyl and 4- to 6-membered heterocyclyl; Each C 1~6 Alkyl, C 3~6 Cycloalkyl and 4- to 6-membered heterocyclyl are substituted with deuterium, oxo, F, Cl, Br, CN, OR 14 , S.R. 15 , N.R. 16 R 17 , S(O)R 18 , S(O)2R 18a , N.R. 19 S(=O)R 20 , C(=O)OR 20a , C(=O)NR 21 R 22 , N.R. 23 C(=O)R 24 , C(=S)NR 25 R 26 , C(=O)R 27 , C 1~6 Alkyl, C 3~8 Cycloalkyl, C 2~6 Alkenyl, halo(C 1~6 ) Alkyl, C 1~3 Alkyl sulfonyl amino alkyl, hydroxy (C 1~6 ) alkyl, amino (C 1~6 ) alkyl, cyano (C 1~6 ) Alkyl, C 1~3 Alkylcarbonylamino (C 1~6 ) Alkyl, C 1~3 Alkoxy, Halo(C1~3 ) Alkoxy, C 1~6 Alkoxy (C 1~3 ) Alkyl, C 6~12 optionally substituted with 1 to 3 substituents independently selected from aryl, 4- to 8-membered heterocyclyl, and 5- to 12-membered heteroaryl; R 14 , R 15 , R 18 , R 18a , R 20 , R 20a , R 24 and R 27 are each independently hydrogen or C 1~6 is alkyl, R 16 and R 17 are each independently hydrogen, C 1~6 Alkyl, hydroxy (C 1~6 ) alkyl and halo(C 1~6 ) alkyl; R 19 and R 23 are each independently 1~6 Alkyl or halo(C 1~6 ) alkyl, R 21 , R 22 , R 25 and R 26 are independently H, C 1~6 Alkyl, C 1~3 Alkoxy (C 1~6 ) alkyl, hydroxy (C 1~6 ) alkyl, cyano (C 1~6 ) alkyl, amino (C 1~6 ) Alkyl, C 1~3 Alkylamino (C 1~6 ) alkyl and di(C 1~3 ) Alkylamino(C 1~6 ) alkyl, or R 21 and R 22 or R 25 and R 26 together with the nitrogen to which they are attached, deuterium, oxo, F, Cl, Br, CN, OR 14 , S.R. 15, N.R. 16 R 17 , S(O)R 18 , S(O)2R 18a , N.R. 19 S(=O)R 20 , C(=O)OR 20a , C(=O)NR 21 R 22 , N.R. 23 C(=O)R 24 , C(=S)NR 25 R 26 , C(=O)R 27 , C 1~6 Alkyl, C 3~8 Cycloalkyl, C 2~6 Alkenyl, halo(C 1~6 ) Alkyl, C 1~3 Alkyl sulfonyl amino alkyl, hydroxy (C 1~6 ) alkyl, cyano (C 1~6 ) Alkyl, C 1~3 Alkylcarbonylamino (C 1~6 ) Alkyl, C 1~3 Alkoxy, Halo(C 1~3 ) Alkoxy, C 1~6 Alkoxy (C 1~3 ) Alkyl, C 6~12 In some embodiments, R forms a 3-8 membered ring optionally substituted with 1-3 substituents independently selected from aryl, 4- to 10-membered heterocyclyl, and 5- to 12-membered heteroaryl. 3 has the following structural formula: [ka] is the part represented by one of R 28 is H or C 1~3 The remaining features and example features of the third aspect are as described above for the first and second aspects of the first embodiment.

[0163] In a fourth aspect of the first embodiment, R 3 is S(=O)2R 5 For example, R 5 is C 1~6 Alkyl, e.g., C1~3 It is alkyl. R 5 can be methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl, or hexyl. 5 is C 3~6 cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, R 5 is an optionally substituted 4-6 membered heterocyclyl. In some embodiments, R 5 is NR 10 R 11 For example, R 10 and R 11 are each independently 1~6 alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl or hexyl. 10 is H, and R 11 is C 1~6 alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl or hexyl. 10 and R 11 and are each H. The remaining features and example features of the fourth aspect are as described above with respect to the first to third aspects of the first embodiment.

[0164] In a fifth aspect of the first embodiment, R 3 is (R 7 )S(=O)(NR 6 ) For example, R 7 is C 1~6 Alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl or hexyl or C 3~6 cycloalkyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. Alternatively, R 6 and R 7together with the nitrogen and sulfur atoms to which they are attached form a 4- to 10-membered heterocyclyl. The remaining features and example features of the fifth aspect are as described above for the first to fourth aspects of the first embodiment.

[0165] In a sixth aspect of the first embodiment, R 3 is C(=O)NR 8 R 9 For example, R 8 is H, and R 9 is C 1~3 alkyl, such as methyl, ethyl, propyl, or isopropyl. Alternatively, R 8 and R 9 are each independently 1~3 alkyl, for example methyl, ethyl, propyl or isopropyl. 8 and R 9 is H. The remaining features and example features of the sixth aspect are as described above with respect to the first to fifth aspects of the first embodiment.

[0166] In a seventh aspect of the first embodiment, R 3 is QR 7 , NH(C=O)R 5 , CN and NR 8 R 9 For example, R 3 is QR 7 For example, R 7 is C 1~6

[0023] Q is alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl, or hexyl. Alternatively, Q is O. Alternatively, Q is S. In some embodiments, Q is -C(=O)-. The remaining features and example features of the seventh aspect are as described above with respect to the first through sixth aspects of the first embodiment.

[0167] In an eighth aspect of the first embodiment, R 3 is a halogen. For example, R 3 is Cl. Instead, R3 is F. The remaining features and example features of the eighth aspect are as described above with respect to the first to seventh aspects of the first embodiment.

[0168] In a ninth aspect of the first embodiment, R 3 is P(=O)R 8a R 9a For example, R 8a and R 9b are each independently 1~3 alkyl, such as methyl, ethyl, propyl, or isopropyl. In some embodiments, R 8a and R 9b are methyl or ethyl, respectively. Alternatively, R 8a and R 9a together with the phosphorus atom to which they are attached form a 4- to 10-membered heterocyclyl. In a ninth aspect of the first embodiment, the compound has structural formula (Ia): [ka] The remaining features and example features of the ninth aspect are as described above with respect to the first to eighth aspects of the first embodiment.

[0169] In a tenth aspect of the first embodiment, the compound has structural formula (Ib): [ka] The remaining features and example features of the tenth aspect are as described above with respect to the first to ninth aspects of the first embodiment.

[0170] In an eleventh aspect of the first embodiment, the compound has structural formula (Ic): [ka] The remaining features and example features of the eleventh aspect are as described above with respect to the first to ninth and tenth aspects of the first embodiment.

[0171] In a twelfth aspect of the first embodiment, the compound has structural formula (Id): [ka] The remaining features and example features of the twelfth aspect are as described above with respect to the first to eleventh aspects of the first embodiment.

[0172] In a thirteenth aspect of the first embodiment, the compound has structural formula (Ie): [ka] The remaining features and example features of the thirteenth aspect are as described above with respect to the first to twelfth aspects of the first embodiment.

[0173] In a fourteenth aspect of the first embodiment, the compound has the structural formula (If): [ka] The remaining features and example features of the fourteenth aspect are as described above with respect to the first to thirteenth aspects of the first embodiment.

[0174] In a fifteenth aspect of the first embodiment, R 4 is H. The remaining features and example features of the fourteenth aspect are as described above for the first to fourteenth aspects of the first embodiment.

[0175] In a sixteenth aspect of the first embodiment, R 4 is C 1~6 Alkoxy, e.g. C 1~4 Alkoxy. For example, R 4 is methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, or tert-butoxy, e.g., methoxy. The remaining features and example features of the sixteenth aspect are as described above for the first to fifteenth aspects of the first embodiment.

[0176] In a seventeenth aspect of the first embodiment, X has the following structural formula: [ka] For example, R 13 is H. Instead, R 13 is C 1~6 and alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl, or hexyl. The remaining features and example features of the seventeenth aspect are as described above for the first through sixteenth aspects of the first embodiment.

[0177] In an eighteenth aspect of the first embodiment, X has the following structural formula: [ka] For example, R 13 is H. Instead, R 13 is C 1~6 and alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl, or hexyl. The remaining features and example features of the eighteenth aspect are as described above for the seventeenth aspect of the first embodiment.

[0178] In a nineteenth aspect of the first embodiment, X has the following structural formula: [ka] The remaining features and example features of the nineteenth aspect are as described above with respect to the first to eighteenth aspects of the first embodiment.

[0179] In a twentieth aspect of the first embodiment, X has the following structural formula: [ka] For example, X is a moiety represented by one of the structural formulas [ka] Alternatively, X is a moiety represented by the structural formula [ka] In some embodiments, X is a moiety represented by the structural formula [ka] In some embodiments, X is a moiety represented by the following structural formula: [ka] The remaining features and example features of the twentieth aspect are as described above with respect to the first through nineteenth aspects of the first embodiment.

[0180] In a twenty-first aspect of the first embodiment, R 12 is an optionally substituted C 3~6 alkyl, such as propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl or hexyl. For example, R 12 is propyl, isopropyl, butyl, isobutyl, tert-butyl. In some embodiments, R 12 is tert-butyl. In some embodiments, R 12 is unsubstituted tert-butyl. In some embodiments, R 12 are deuterium, CF3, F, Cl, Br, CN, O R 14 , S.R. 15 , N.R. 16 R 17 , S(O)R 18 , S(O)2R 18a , N.R. 19 S(=O)R 20 , C(=O)OR 20a , C(=O)NR 21 R 22 , N.R. 23 C(=O)R 24 , C(=S)NR 25 R 26 , C(=O)R 27, C 1~6 Alkyl, C 3~8 Cycloalkyl, C 2~6 Alkenyl, halo(C 1~6 ) Alkyl, C 1~3 Alkyl sulfonyl amino alkyl, hydroxy (C 1~6 ) alkyl, amino (C 1~6 ) alkyl, cyano (C 1~6 ) Alkyl, C 1~3 Alkylcarbonylamino (C 1~6 ) Alkyl, C 1~3 Alkoxy, Halo(C 1~3 ) Alkoxy, C 1~6 Alkoxy (C 1~3 ) Alkyl, C 6~12 and isopropyl substituted with 1 to 3 substituents independently selected from aryl, 4 to 10-membered heterocyclyl, and 5 to 12-membered heteroaryl. The remaining features and example features of the 21st aspect are as described above for the first to 20th aspects of the first embodiment.

[0181] In a twenty-second aspect of the first embodiment, R 12 has the following structural formula: [ka] For example, R 12 has the following structural formula: [ka] The remaining features and example features of the twenty-second aspect are as described above with respect to the first to twenty-first aspects of the first embodiment.

[0182] In a twenty-third aspect of the first embodiment, R 1a is a halogen or C 1~3 alkyl. For example, R 1a is C 1~3 alkyl, such as methyl, ethyl, propyl, or isopropyl. Alternatively, R 1a is halogen. In some embodiments, R 1ais selected from H, F, Cl, CH3, CHF2, CF3 and CD3. For example, R 1a is selected from F, CH3 and CHF2. Values ​​and example values ​​for the remainder of the variables of the 23rd aspect are as described above in relation to the first through 22nd aspects of the first embodiment.

[0183] In a twenty-fourth aspect of the first embodiment, R 1b is a halogen or C 1~3 alkyl. For example, R 1b is C 1~3 alkyl, such as methyl, ethyl, propyl, or isopropyl. Alternatively, R 1b is halogen. In some embodiments, R 1b is selected from H, F, Cl, CH3, CHF2, CF3 and CD3. For example, R 1b is selected from F, CH3 and CHF2. Values ​​and example values ​​for the remainder of the variables of the 24th aspect are as described above in relation to the first to 23rd aspects of the first embodiment.

[0184] In a twenty-fifth aspect of the first embodiment, R 1c is H or halogen. For example, R 1 c is H. Instead, R 1c is a halogen. For example, R 1c is F. The remaining values ​​and example values ​​of the variables of the 25th aspect are as described above in relation to the first to 24th aspects of the first embodiment.

[0185] In a twenty-fifth aspect of the first embodiment, the compound has the structural formula (Ig): [ka] The remaining values ​​and example values ​​of the variables of the 25th aspect are as described above in relation to the first to 24th aspects of the first embodiment.

[0186] In a twenty-seventh aspect of the first embodiment, the compound has structural formula (Ih), (Ii), or (Ij): [ka] For example, the compound may be represented by the structural formula (Ih). The compound is represented by structural formula (Ii): Alternatively, the compound is represented by structural formula (Ij): The remaining values ​​and example values ​​of the variables of the 27th aspect are as described above with respect to the first through 26th aspects of the first embodiment.

[0187] In a twenty-eighth aspect of the first embodiment, Y 1 is CH. Instead, Y 1 is N. The remaining values ​​and example values ​​of the variables of the 28th aspect are as described above in relation to the first to 27th aspects of the first embodiment.

[0188] In a 29th aspect of the first embodiment, Z is CH. Alternatively, Z is N. The remaining values ​​and example values ​​of the variables of the 29th aspect are as described above with respect to the first through 28th aspects of the first embodiment.

[0189] In a thirtieth aspect of the first embodiment, R 2 is H. Instead, R 2 is C 1~3 alkyl. For example, R 2 is methyl, ethyl, propyl, or isopropyl. Values ​​and example values ​​for the remainder of the variables of the thirtieth aspect are as described above in relation to the first through twenty-ninth aspects of the first embodiment.

[0190] In a thirty-first aspect of the first embodiment, the compound has the structural formula (Ik): [ka] (In the formula, R 5 is C 1~3 alkyl) For example, R 5 is methyl, ethyl, propyl, or isopropyl. Values ​​and example values ​​for the remainder of the variables of the thirty-first aspect are as described above in relation to the first through thirtieth aspects of the first embodiment.

[0191] In a thirty-second aspect of the first embodiment, the compound has structural formula (II): [ka] (In the formula, R 9 is C 1~3 alkyl) For example, R 9 is methyl, ethyl, propyl, or isopropyl. Values ​​and example values ​​for the remainder of the variables of the thirty-second aspect are as described above in relation to the first through thirtieth aspects of the first embodiment.

[0192] In a thirty-third aspect of the first embodiment, the compound has the structural formula (Im): [ka] (In the formula, R 29 is C 1~3 alkyl) For example, R 29 is methyl, ethyl, propyl, or isopropyl. Values ​​and example values ​​for the remainder of the variables of the thirty-third aspect are as described above in relation to the first through thirtieth aspects of the first embodiment.

[0193] In a thirty-fourth aspect of the first embodiment, the compound is selected from the compounds of Table 1.

[0194] [Table 1]

[0195] [Table 2]

[0196] [Table 3]

[0197] Table 4

[0198] Table 5

[0199] Table 6

[0200] Table 7

[0201] Table 8

[0202] Table 9

[0203] Table 10

[0204] Table 11

[0205] Table 12

[0206] Table 13

[0207] Table 14

[0208] Table 15

[0209] Table 16

[0210] Table 17

[0211] Table 18

[0212] Table 19

[0213] Table 20

[0214] Table 21

[0215] Table 22

[0216] Table 23

[0217] Table 24

[0218] Table 25

[0219] Table 26

[0220] Table 27

[0221] Table 28

[0222] Table 29

[0223] Table 30

[0224] Table 31

[0225] Table 32

[0226] Table 33

[0227] Table 34

[0228] Table 35

[0229] Table 36

[0230] Table 37

[0231] Table 38

[0232] Table 39

[0233] Table 40

[0234] Table 41

[0235] Table 42

[0236] Table 43

[0237] Table 44

[0238] Table 45

[0239] Table 46

[0240] Table 47

[0241] Table 48

[0242] Table 49

[0243] Table 50

[0244] Table 51

[0245] Table 52

[0246] Table 53

[0247] Table 54

[0248] Table 55

[0249] In a thirty-fifth aspect of the first embodiment, the compound is selected from the compounds of Table 2.

[0250] [Table 56]

[0251] [Table 57]

[0252] [Table 58]

[0253] [Table 59]

[0254] [Table 60]

[0255] [Table 61]

[0256] [Table 62]

[0257] [Table 63]

[0258] [Table 64]

[0259] [Table 65]

[0260] Table 66

[0261] Table 67

[0262] Table 68

[0263] Table 69

[0264] Table 70

[0265] Table 71

[0266] Table 72

[0267] Table 73

[0268] Table 74

[0269] Table 75

[0270] Table 76

[0271] Table 77

[0272] Table 78

[0273] Table 79

[0274] Table 80

[0275] Table 81

[0276] Table 82

[0277] Table 83

[0278] Table 84

[0279] Table 85

[0280] Table 86

[0281] In a thirty-sixth aspect of the first embodiment, the compound is selected from the compounds of Table 3.

[0282] [Table 87]

[0283] [Table 88]

[0284] [Table 89]

[0285] [Table 90]

[0286] [Table 91]

[0287] In a thirty-sixth aspect of the first embodiment, the compound has the structural formula (In): [ka] (In the formula, R 1a is C 1~3 nR is selected from alkyl, halogen, and H; 1b and R 4 are each independently halogen or H, and R 1c is C 1~3 and R is selected from haloalkyl, halogen, and H. 9 is H or C 1~3 alkyl) The remaining features and example features of the thirty-sixth aspect are as described above with respect to the first to thirty-second aspects of the first embodiment.

[0288] In a second embodiment, the present invention relates to a pharmaceutical composition comprising a compound described herein in relation to the first embodiment and its various aspects, and a pharmaceutically acceptable excipient.

[0289] In a third embodiment, the present invention relates to a method of treating a disease or disorder, comprising administering a therapeutically effective amount of a compound described herein in connection with the first embodiment and its various aspects, or a pharmaceutical composition described herein in connection with the second embodiment and its various aspects, to a subject in need thereof, wherein the disease or disorder is selected from an inflammatory disease, an autoimmune disease, a granulomatous disease, cancer, and a neurodegenerative disease.

[0290] In a first aspect of the third embodiment, 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, arthritis, inflammatory bowel disorder (IBD), ischemia-reperfusion injury in solid organ transplants, sepsis, liver disease, allergic disease, and graft-versus-host disease. For example, the inflammatory disease is IBD. For example, the IBD is selected from ulcerative colitis, Crohn's disease, early-onset IBD, and extraintestinal IBD. Alternatively, the inflammatory disease is selected from rheumatoid arthritis, inflammatory arthritis, peritonitis, ischemia-reperfusion injury in kidney grafts, non-alcoholic steatohepatitis, alcoholic steatohepatitis, insulin-resistant type 2 diabetes, allergic rhinitis, asthma, atopic dermatitis, Sjogren's syndrome, ankylosing spondylitis, pemphigus vulgaris, idiopathic plasma cell lymphadenopathy, atherosclerosis, myocardial infarction, thrombosis, alpha-synucleinopathies, Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, Alzheimer's disease, amyotrophic lateral sclerosis, and chronic obstructive pulmonary disease.

[0291] In a second aspect of the third embodiment, the disease or disorder is an autoimmune disease, for example, the autoimmune disease is selected from systemic lupus erythematosus, lupus nephritis, psoriasis, immune thrombocytopenic purpura, and multiple sclerosis.

[0292] In a third aspect of the third embodiment, the disease or disorder is a granulomatous disease, e.g., the granulomatous disease is selected from sarcoidosis, Blau syndrome, Wegener's granulomatosis, Behcet's disease, and interstitial pulmonary disease.

[0293] In a fourth aspect of the third embodiment, the disease or disorder is cancer, for example, 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.

[0294] In a fifth aspect of the third embodiment, the disease or disorder is a neurodegenerative disease. For example, the neurodegenerative disease is Alzheimer's disease, amyotrophic lateral sclerosis (ALS / Lou Gehrig's disease), , Parkinson's disease, multiple sclerosis, diabetic neuropathy, polyglutamine (polyQ) disease, stroke, Fahr's disease, Menkes disease, Wilson's disease, cerebral ischemia, prion disorders, dementia, corticobasal degeneration, progressive supranuclear palsy, spinocerebellar atrophy, brain injury, and spinal cord injury.

[0295] In a sixth aspect of the third embodiment, the method further comprises administering a therapeutically effective amount of a second agent. In some embodiments, the second agent is an anti-inflammatory agent or an anti-autoimmune agent. For example, in certain embodiments, the second agent is selected from an anti-TNF agent, an anti-IL-23 agent, an anti-integrin agent, and a JAK inhibitor. In some embodiments, the second agent is an anti-TNF agent. In some embodiments, the second agent is an anti-IL-23 agent. In some embodiments, the second agent is an anti-integrin agent. In some embodiments, the second agent is a JAK inhibitor. The remaining features and example features of the sixth aspect are as described above with respect to the first through fifth aspects of the third embodiment.

[0296] In a sixth aspect of the third embodiment, the second agent and the compound are administered together in a single pharmaceutical composition. The remaining features and example features of the seventh aspect are as described above for the first through sixth aspects of the third embodiment.

[0297] In a sixth aspect of the third embodiment, the second agent and the compound are administered separately. In some embodiments, the second agent and the compound are administered separately at the same time. In some embodiments, the second agent and the compound are administered separately at different times. The remaining features and example features of the seventh aspect are as described above with respect to the first through sixth aspects of the third embodiment. [Example]

[0298] The invention having been generally described will be more readily understood with reference to the following examples, which are included solely for the purpose of illustrating certain aspects and embodiments of the invention and are not intended to limit the invention. Starting materials described herein can be obtained from commercial sources or can be readily prepared from commercially available materials using transformations known to those skilled in the art.

[0299] The following general scheme shows the synthetic sequence for Examples 1-47.

[0300] General Scheme 1 [ka]

[0301] General Scheme 2 [ka]

[0302] General Scheme 3 [ka]

[0303] General Scheme 4 [ka]

[0304] General Scheme 5 [ka]

[0305] General Scheme 6 [ka]

[0306] General Scheme 7 [ka]

[0307] General Scheme 8 [ka]

[0308] General Scheme 9 [ka]

[0309] General Scheme 10 [ka]

[0310] General Scheme 11 [ka]

[0311] General Scheme 12 [ka]

[0312] General Scheme 13 [ka]

[0313] General Scheme 14 [ka]

[0314] General Scheme 15 [ka]

[0315] General Scheme 16 [ka]

[0316] General Scheme 17 [ka]

[0317] General Scheme 18 [ka]

[0318] General Scheme 19 [ka]

[0319] General Scheme 20 [ka]

[0320] General Scheme 21 [ka]

[0321] General Scheme 22 [ka]

[0322] General Scheme 23 [ka]

[0323] General Scheme 24 [ka]

[0324] General Scheme 25 [ka]

[0325] Example 1 - Synthesis of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(4-((6-(dimethylphosphoryl)quinolin-4-yl)oxy)-2-fluorophenyl)acetamide (Compound 36); prepared according to general scheme 18 [ka] Part I - Synthesis of (4-chloroquinolin-6-yl)dimethylphosphine oxide [ka] Xantphos (1.7 g, 2.94 mmol, 0.20 equiv.), Pd(dba) (2.69 g, 2.94 mmol, 0.20 equiv.), and triethylamine (9.5 g, 73.5 mmol, 5.00 equiv.) were added to a solution of 6-bromo-4-chloroquinoline (commercially available, 4.0 g, 14.7 mmol, 1.00 equiv.) and dimethylphosphine oxide (1.72 g, 22.1 mmol, 1.50 equiv.) in 1,4-dioxane (40 mL) under an inert atmosphere of nitrogen. The reaction mixture was then heated to 110 °C overnight. The solvent was removed under reduced pressure, and the crude product was purified by reverse-phase flash chromatography (column: C18 silica gel; mobile phase A: water, mobile phase B: ACN, gradient: 0–30% B in 30 min; wavelength: 210 nm). The title compound was obtained as an off-white solid (500 mg, 12%).

[0326] Part II - N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(4-((6-(dimethylphosphoryl)quinolin-4-yl)oxy)-2-fluoro Synthesis of (phenyl)acetamide (compound 36) [ka] (4-Chloroquinolin-6-yl)dimethylphosphine oxide (164.5 mg, 0.687 mmol, 1.00 equiv.), CsCO (447.4 mg, 1.37 mmol, 2.00 equiv.), copper(I) iodide (52.3 mg, 0.275 mmol, 0.40 equiv.), and N,N-dimethylglycine (42.5 mg, 0.412 mmol, 0.60 equiv.) were added to a solution of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(2-fluoro-4-hydroxyphenyl)acetamide (200 mg, 0.687 mmol, 1.00 equiv., which can be synthesized as described in Part II of Example 9) in 1,4-dioxane (2 mL) under an inert atmosphere of nitrogen. The reaction mixture was then heated to 100° C. overnight. The solvent was removed under reduced pressure and the crude product was purified by reverse-phase flash chromatography (column: C18 silica gel; mobile phase A: water, mobile phase B: ACN, gradient: 10-60% B in 50 min; wavelength: 210 nm). The title compound was obtained as an off-white solid (77.7 mg, 23%). LCMS (ESI) C 26 H 29 FN4O3P(M+H) + Calculated value: 495.2, measured value: 495.1. 1H NMR(400MHz,DMSO-d6)δ 10.23(s,1H),8.82(d,J=5.2Hz,1H),8.75(dd,J=12.6,1.4Hz,1H),8.15-8.13(m,2H),7.94(s,1H),7.55(t,J=8.5Hz,1H),7.45(s,1H) ),7.34(dd,J=10.4,2.4Hz,1H),7.18(dd,J=8.4,2.4Hz,1H),6.75(d,J=5.2Hz,1H),3.71(s,2H),1.76(d,J=13.4Hz,6H),1.49(s,9H).

[0327] Example 2 - Preparation of additional phosphine oxide compounds The compounds in the following table were prepared based on the experimental procedures described in Example 1 and the detailed description.

[0328] [Table 92]

[0329] [Table 93]

[0330] [Table 94]

[0331] Example 3 - Synthesis of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(2-fluoro-4-((6-(S-methylsulfonimidoyl)quinolin-4-yl)oxy)phenyl)acetamide (Compounds 69 and 70); Prepared according to General Scheme 13 [ka] (Diacetoxyiodo)benzene (1.29 g, 4.01 mmol, 3.00 equiv.) and (NH)CO (384.7 mg, 4.01 mmol, 3.00 equiv.) were added to a solution of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(2-fluoro-4-((6-(methylthio)quinolin-4-yl)oxy)phenyl)acetamide (620 mg, 1.34 mmol, 1.00 equiv., which can be synthesized according to Parts I and II of Example 32) in MeOH (6.2 mL) under an inert atmosphere of nitrogen. The reaction mixture was stirred at room temperature for 10 min. The crude product was subsequently purified by reverse-phase flash chromatography (column: C18 silica gel; mobile phase A: water, mobile phase B: ACN, gradient: 10–50% B in 60 min; wavelength: 210 nm). The racemic title compound was obtained as an off-white solid (180 mg, 27%). The two enantiomers were separated by chiral chromatography (column: CHIRALPAK IA-3, 4.6 × 50 mm, 3 μm; mobile phase A: MTBE (0.1% DEA), mobile phase B: MeOH:DCM (1:1), 20% B). The title compounds (Compound 69 (Enantiomer 1): 48.8 mg, 7.6%; Compound 70 (Enantiomer 2): 50.4 mg, 7.8%) were obtained as off-white solids (retention time (Enantiomer 1): 3.14 min, retention time (Enantiomer 2): 3.59 min, column: Chiral Cellulose-SB, 4.6 x 100 mm, 3 μm; mobile phase A: MTBE (0.1% DEA), mobile phase B: MeOH / DCM (1:1), 20% B, flow rate: 1.0 mL / min, wavelength: 254 nm). LCMS (ESI)C 25 H 27 FN5O3S(M+H) +Calculated for: 496.2, found: 495.9. 1H NMR (400 MHz, DMSO-d6) δ 10.23 (s, 1H), 8.91-8.82 (m, 2H), 8.31-8.20 (m, 2H), 7.94 (d, J = 0.8 Hz, 1H), 7.57 (t, J = 8.5 Hz, 1H), 7.46 (s, 1H), 7.36 (dd, J = 10.4, 2.4 Hz, 1H), 7.20 (dd, J = 8.4, 2.4 Hz, 1H), 6.81 (d, J = 5.2 Hz, 1H), 4.52-4.44 (m, 1H), 3.72 (s, 2H), 3.20 (d, J = 1.2 Hz, 3H), 1.49 (s, 9H).

[0332] Example 4 - Synthesis of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(2-fluoro-4-((6-(N-methylethylsulfonimidoyl)quinolin-4-yl)oxy)phenyl)acetamide (Compound 74); prepared according to General Scheme 13 [ka] Part I - Synthesis of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(4-((6-(ethylthio)quinolin-4-yl)oxy)-2-fluorophenyl)acetamide [ka] Sodium ethanethiolate (0.25 g, 3.02 mmol, 1.50 equiv.), triethylamine (1.02 g, 10.1 mmol, 5.00 equiv.), Pd(dba) (0.37 g, 0.402 mmol, 0.20 equiv.), and Xantphos (0.23 g, 0.402 mmol, 0.20 equiv.) were added to a solution of 2-(4-((6-bromoquinolin-4-yl)oxy)-2-fluorophenyl)-N-(1-(tert-butyl)-1H-pyrazol-4-yl)acetamide (1.0 g, 2.01 mmol, 1.00 equiv., which can be synthesized according to Part I of Example 32) in 1,4-dioxane (10 mL) under an inert atmosphere of nitrogen. The mixture was then heated to 80° C. overnight. The solvent was removed under reduced pressure and the crude product was purified by column chromatography (petroleum ether / EtOAc 1:1) to give the title compound as a yellow solid (780 mg, 81%).

[0333] Part II - Synthesis of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(4-((6-(ethylsulfonimidoyl)quinolin-4-yl)oxy)-2-fluorophenyl)acetamide [ka] (Diacetoxyiodo)benzene (606 mg, 1.88 mmol, 3.00 equiv.) and (NH)CO (181 mg, 1.88 mmol, 3.00 equiv.) were added to a solution of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(4-((6-(ethylthio)quinolin-4-yl)oxy)-2-fluorophenyl)acetamide (300 mg, 0.627 mmol, 1.00 equiv.) in MeOH (6.2 mL) under an inert atmosphere of nitrogen. The reaction mixture was stirred at room temperature for 10 min. The crude product was subsequently purified by reverse-phase flash chromatography (column: C18 silica gel; mobile phase A: water, mobile phase B: ACN, gradient: 10–50% B in 50 min; wavelength: 210 nm). The title compound was obtained as a pale yellow solid (21.3 mg, 6.5%).

[0334] Part III - Synthesis of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(2-fluoro-4-((6-(N-methylethylsulfonimidoyl)quinolin-4-yl)oxy)phenyl)acetamide (Compound 74) [ka] A solution of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(4-((6-(ethylsulfonimidoyl)quinolin-4-yl)oxy)-2-fluorophenyl)acetamide (185 mg, 0.363 mmol, 1.00 equiv.) and paraformaldehyde (65.4 mg, 0.726 mmol, 2.00 equiv.) in formic acid (2 mL) was heated to 120 °C for 6 h under an inert atmosphere of nitrogen. The solvent was then removed under reduced pressure and the crude product was purified by reverse-phase flash chromatography (column: C18 silica gel; mobile phase A: water, mobile phase B: ACN, gradient: 10-50% B in 60 min; wavelength: 210 nm). The title compound was obtained as a pale yellow solid (24.6 mg, 12%). LCMS (ESI) C 27 H 31 FN5O3S(M+H) + Calculated for: 524.2, Found: 524.0. 1H NMR (400 MHz, DMSO-d6) δ 10.21 (s, 1H), 8.88 (d, J = 5.2 Hz, 1H), 8.73 (d, J = 2.0 Hz, 1H), 8.25 (d, J = 8.9 Hz, 1H), 8.10 (dd, J = 8.9, 2.1 Hz, 1H), 7.94 (s, 1H), 7.55 (t, J = 8.5 Hz, 1H). H),7.45(s,1H),7.42-7.35(m,1H),7.21(dd,J=8.3,2.4Hz,1H),6.82(d,J=5.3Hz,1 H),3.71(s,2H),3.39-3.65(m,2H),2.54(s,3H),1.49(s,9H),1.13(t,J=7.4Hz,3H).

[0335] Example 5 - Synthesis of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(4-((6-(N-cyano-S-methylsulfonimidoyl)quinolin-4-yl)oxy)-2-fluorophenyl)acetamide (Compound 71); prepared according to the synthesis of Compound 19B in General Scheme 19 [ka] Cyanamide (52.7 mg, 1.25 mmol, 2.00 equiv.), potassium tert-butoxide (140.7 mg, 1.25 mmol, 2.00 equiv.), and N-chlorosuccinimide (167.4 mg, 1.25 mmol, 2.00 equiv.) were added to a solution of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(2-fluoro-4-((6-(methylsulfinyl)quinolin-4-yl)oxy)phenyl)acetamide (300 mg, 0.627 mmol, 1.00 equiv., can be prepared according to Example 32) in THF / water (1:1, 6 mL), and the reaction mixture was stirred at room temperature overnight. The crude product was then purified by reverse-phase flash chromatography (column: C18 silica gel; mobile phase A: water, mobile phase B: ACN; gradient: 20-50% B in 30 min; wavelength: 210 nm). The title compound was obtained as an off-white solid (11 mg, 3.4%). LCMS (ESI) C 26 H 26 FN6O3S(M+H) + Calculated for: 521.2, found: 521.2. 1H NMR (300 MHz, DMSO-d6) δ 10.23 (s, 1H), 9.01-8.90 (m, 2H), 8.42-8.35 (m, 2H), 7.94 (d, J = 0.8 Hz, 1H), 7.58 (t, J = 8.5 Hz, 1H), 7.46 (d, J = 0.7 Hz, 1H), 7.41 (dd, J = 10.4, 2.4 Hz, 1H), 7.28-7.19 (m, 1H), 6.88 (d, J = 5.3 Hz, 1H), 3.90 (s, 3H), 3.72 (s, 2H), 1.49 (s, 9H).

[0336] Example 6 - Synthesis of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(4-((6-(cyclopropanesulfonimidoyl)quinolin-4-yl)oxy)-2-fluoro-3-methylphenyl)acetamide (Compounds 441 and 442); Prepared according to General Scheme 13 [ka] Part I - Synthesis of (4-bromo-2-fluoro-3-methylphenyl)methanol [ka] A solution of borane in THF (1 M, 388 mL, 388 mmol, 3.00 equiv.) was added to a solution of 4-bromo-2-fluoro-3-methylbenzoic acid (30.0 g, 129 mmol, 1.00 equiv.) in THF (600 mL) at 0 °C. The mixture was then stirred at room temperature overnight. Hydrochloric acid (1 M, 600 mL) was added, and the product was extracted with EtOAc (3 × 300 mL). The combined organic phases were washed with a saturated aqueous solution of NaHCO and brine, dried over NaSO, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography (petroleum ether / EtOAc 3:1). The title compound was obtained as a white solid (24.8 g, 88%).

[0337] Part II - Synthesis of 1-Bromo-4-(bromomethyl)-3-fluoro-2-methylbenzene [ka] Tetrabromomethane (45.2 g, 136 mmol, 1.20 equiv.) was added to a solution of (4-bromo-2-fluoro-3-methylphenyl)methanol (24.8 g, 114 mmol, 1.00 equiv.) and triphenylphosphine (44.7 g, 171 mmol, 1.50 equiv.) in DCM (500 mL) at 0 °C. The mixture was then stirred at room temperature for 1 h. Water was added, and the product was extracted with DCM (3 × 300 mL). The combined organic phases were washed with brine, dried over Na SO , and the solvent was removed under reduced pressure. The crude product was purified by column chromatography (petroleum ether / EtOAc 80:1). The title compound was obtained as a yellow solid (29.6 g, 93%).

[0338] Part III - Synthesis of 2-(4-bromo-2-fluoro-3-methylphenyl)acetonitrile [ka] A solution of 1-bromo-4-(bromomethyl)-3-fluoro-2-methylbenzenemethylbenzene (29.6 g, 106 mmol, 1.00 equiv.) and potassium cyanide (10.3 g, 158 mmol, 1.50 equiv.) in DMA (100 mL) and water (50 mL) was heated to 90 °C for 1.5 h. Subsequently, a saturated aqueous solution of NaHCO was added, and the product was extracted with EtOAc (3 × 300 mL). The combined organic phases were washed with brine, dried over NaSO, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography (petroleum ether / EtOAc 50:1). The title compound was obtained as a yellow solid (19.33 g, 80%).

[0339] Part IV - Synthesis of 2-(4-bromo-2-fluoro-3-methylphenyl)acetic acid [ka] Potassium hydroxide (14.7 g, 262 mmol, 3.10 equiv.) was added to a solution of 2-(4-bromo-2-fluoro-3-methylphenyl)acetonitrile (19.3 g, 84.6 mmol, 1.00 equiv.) in EtOH (135 mL) and water (58 mL), and the mixture was heated to 90° C. for 2 h. The pH of the solution was then adjusted to 4 with hydrochloric acid, and the product was extracted with EtOAc (3×200 mL). The combined organic phases were washed with brine, dried over NaSO, and the solvent was removed under reduced pressure. The title compound (18.9 g) was used in the next reaction without further purification.

[0340] Part V - Synthesis of 2-(4-bromo-2-fluoro-3-methylphenyl)-N-(1-(tert-butyl)-1H-pyrazol-4-yl)acetamide [ka] HATU (43.6 g, 115 mmol, 1.50 equiv.) was added to a solution of 2-(4-bromo-2-fluoro-3-methylphenyl)acetic acid (18.9 g, 76.5 mmol, 1.00 equiv.), 1-(tert-butyl)-1H-pyrazol-4-amine (10.7 g, 76.5 mmol, 1.00 equiv.), and DIPEA (29.7 g, 229 mmol, 3.00 equiv.) in DMF (378 mL) at 0 °C. The reaction mixture was then stirred at room temperature for 2 h. Water (100 mL) was added, and the product was extracted with EtOAc (3 × 300 mL). The combined organic phases were washed with brine (3 × 150 mL), dried over NaSO, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography (petroleum ether / EtOAc 1:1). The title compound was obtained as a red solid (24 g, 85%).

[0341] Part VI - Synthesis of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(2-fluoro-4-hydroxy-3-methylphenyl)acetamide [ka] A solution of 2-(4-bromo-2-fluoro-3-methylphenyl)-N-(1-(tert-butyl)-1H-pyrazol-4-yl)acetamide (24.0 g, 65.2 mmol, 1.00 equiv.), bis(pinacolato)diboron (33.1 g, 130 mmol, 2.00 equiv.), Pd(dppf)Cl (4.77 g, 6.52 mmol, 0.10 equiv.), and potassium acetate (12.8 g, 130 mmol, 2.00 equiv.) in 1,4-dioxane (240 mL) was heated to 90 °C for 16 h under an inert atmosphere of nitrogen. Subsequently, a solution of hydrogen peroxide (30%, 72 mL, 3.09 mol, 47.5 equiv.) was added dropwise at 0 °C. The mixture was stirred at room temperature for 1 h. Water (150 mL) was added and the product was extracted with EtOAc (3 x 250 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 (petroleum ether / EtOAc The title compound was obtained as a green solid (17 g, 85%).

[0342] Part VII - Synthesis of 4-chloro-6-(cyclopropylthio)quinoline [ka] A solution of 6-bromo-4-chloroquinoline (20.0 g, 82.5 mmol, 1.00 equiv.), sodium cyclopropanethiolate (9.51 g, 99.0 mmol, 1.20 equiv.), Xantphos (9.54 g, 16.5 mmol, 0.20 equiv.), Pd(dba) (15.1 g, 16.5 mmol, 0.20 equiv.), and triethylamine (41.7 g, 412 mmol, 5.00 equiv.) in 1,4-dioxane (200 mL) was heated to 80 °C for 3 h under an inert atmosphere of nitrogen. The solvent was then removed under reduced pressure, and the crude product was purified by column chromatography (petroleum ether / EtOAc 10:1). The title compound was obtained as a yellow oil (11.6 g, 56%).

[0343] Part VIII - (4-chloroquinolin-6-yl)(cyclopropyl)(imino)-λ 6 -Synthesis of sulfanone [ka] A solution of 4-chloro-6-(cyclopropylthio)quinoline (3.00 g, 12.7 mmol, 1.00 equiv.), (diacetoxyiodo)benzene (12.3 g, 38.2 mmol, 3.00 equiv.), and (NH4)2CO3 (3.67 g, 38.2 mmol, 3.00 equiv.) in methanol (60 mL) was stirred at room temperature for 2 h. Subsequently, water (50 mL) was added, and the product was extracted with EtOAc (3 × 100 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 reverse-phase flash chromatography (column: C18 silica gel; mobile phase A: water, mobile phase B: ACN, gradient: 35–65% B in 30 min; wavelength: 210 nm). The title compound was obtained as a yellow solid (1.7 g, 50%).

[0344] Part IX—Synthesis of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(4-((6-(cyclopropanesulfonimidoyl)quinolin-4-yl)oxy)-2-fluoro-3-methylphenyl)acetamide (Compounds 441 and 442) [ka] N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(2-fluoro-4-hydroxy-3-methylphenyl)acetamide (572 mg, 1.87 mmol, 1.00 equiv.), (4-chloroquinolin-6-yl)(cyclopropyl)(imino)-λ 6A solution of α-sulfanone (500 mg, 1.87 mmol, 1.00 equiv.), CsCO (285 mg, 3.75 mmol, 2.00 equiv.), CuI (285 mg, 1.50 mmol, 0.8 equiv.), and N,N-dimethylglycine (116 mg, 1.12 mmol, 0.6 equiv.) in 1,4-dioxane (10 mL) was heated to 100 °C for 16 h under an inert atmosphere of nitrogen. Subsequently, water (10 mL) was added, and the product was extracted with EtOAc (3 × 10 mL). The combined organic phases were washed with brine, dried over NaSO, and the solvent was removed under reduced pressure. The crude product was purified by reverse-phase flash chromatography (column: C18 silica gel; mobile phase A: water, mobile phase B: ACN, gradient: 25–55% B in 40 min; wavelength: 210 nm). The racemic title compound was obtained as a white solid (350 mg, 35%). The two enantiomers were separated by chiral chromatography (column: CHIRAL ART Cellulose-SC, 20 × 250 mm, 5 μm; mobile phase A: n-hexane / DCM (3:1), mobile phase B: isopropanol, 35% B isocratic separation). The title compound (compound 441 (enantiomer 1): 130.0 mg, 13%; compound 442 (enantiomer 2): 103.2 mg, 10%) was obtained as a brown solid (retention time (enantiomer 1): 5.08 min, retention time (enantiomer 2): 6.70 min, column: CHIRALPAK IC-3, 4.6 × 50 nm, 3.5 μm; mobile phase A: hexane / DCM (3:1, 0.1% DEA), mobile phase B: isopropanol, 50% B). Isocratic separation using B, flow rate: 1.0 mL / min, wavelength: 254 nm. LCMS (ESI) C 28 H 31 FN5O3S(M+H) + Calculated value: 536.2, measured value: 536.1. 1H NMR(300MHz,DMSO-d6)δ10.23(s,1H),8.92-8.80(m,2H),8.25-8.23(m,2H),7.95(s,1H),7.46(s,1H),7.40(t,J=8.4Hz,1H),7.15 (d,J=8.4Hz,1H),6.62(d,J=5.2Hz,1H),4.54(s,1H),3.72(s,2H),2.90-2.79(m,1H),2.08(s,3H),1.49(s,9H),1.28-0.90(m,4H).

[0345] Example 7 - N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(2-fluoro-4-((6-(1-oxido-3,4,5,6-tetrahydro-1λ) 6 Synthesis of 2-thiazin-1-yl)quinolin-4-yl)oxy)phenyl)acetamide (compound 67); prepared according to general scheme 20 [ka] Part I - Synthesis of S-(4-(4-(2-((1-(tert-butyl)-1H-pyrazol-4-yl)amino)-2-oxoethyl)-3-fluorophenoxy)quinolin-6-yl)ethanethioate [ka] A solution of 2-(4-((6-bromoquinolin-4-yl)oxy)-2-fluorophenyl)-N-(1-(tert-butyl)-1H-pyrazol-4-yl)acetamide (1.40 g, 2.82 mmol, 1.00 equiv.), potassium thioacetate (643 mg, 5.63 mmol, 2.00 equiv.), Pd(dba) (129 mg, 0.141 mmol, 0.05 equiv.), Xantphos (163 mg, 0.282 mmol, 0.10 equiv.), and DIPEA (2.91 g, 22.5 mmol, 8.00 equiv.) in 1,4-dioxane (10 mL) was heated to 120 °C for 15 min under an inert atmosphere of nitrogen. The crude product was subsequently purified by column chromatography (petroleum ether / EtOAc 5:1). The title compound was obtained as a yellow solid (1.33 g, 96%).

[0346] Part II - Synthesis of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(2-fluoro-4-((6-((4-iodobutyl)thio)quinolin-4-yl)oxy)phenyl)acetamide [ka] 1,4-Diiodobutane (629 mg, 2.03 mmol, 2.00 equiv.) and K2CO3 (302 mg, 3.05 mmol, 3.00 equiv.) were added to a solution of S-(4-(4-(2-((1-(tert-butyl)-1H-pyrazol-4-yl)amino)-2-oxoethyl)-3-fluorophenoxy)quinolin-6-yl)ethanethioate (500.0 mg, 1.02 mmol, 1.00 equiv.) in DMF (10 mL), and the mixture was stirred at room temperature for 30 minutes. Subsequently, water was added, and the product was extracted with EtOAc (2 x 20 mL). The combined organic phases were dried over MgSO4, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography (petroleum ether / EtOAc 1:1). Title compound was obtained as a pale yellow solid (405 mg, 63%).

[0347] Part III - N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(2-fluoro-4-((6-(1-oxido-3,4,5,6-tetrahydro-1λ) 6 Synthesis of 1,2-thiazin-1-yl)quinolin-4-yl)oxy)phenyl)acetamide (Compound 67) [ka] (Diacetoxyiodo)benzene (764 mg, 2.37 mmol, 5.00 equiv.) and (NH)CO (137 mg, 1.42 mmol, 3.00 equiv.) were added to a solution of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(2-fluoro-4-((6-((4-iodobutyl)thio)quinolin-4-yl)oxy)phenyl)acetamide (300 mg, 0.474 mmol, 1.00 equiv.) in MeOH (3 mL), and the mixture was stirred at room temperature overnight. The crude product was subsequently purified by reverse-phase flash chromatography (column: C18 silica gel; mobile phase A: water, mobile phase B: ACN, gradient: 20–50% B in 30 min; wavelength: 210 nm). The title compound was obtained as a white solid (12.1 mg, 4.5%). LCMS (ESI) C 28 H 31 FN5O3S(M+H) + Calculated for: 536.2, found: 536.2. 1H NMR (300 MHz, DMSO-d6) δ 10.22 (s, 1H), 8.94-8.85 (m, 2H), 8.35-8.19 (m, 2H), 7.94 (s, 1H), 7.56 (t, J = 8.5 Hz, 1H), 7.45 (s, 1H), 7.38 (dd, J = 10.5, 2.1 Hz, 1H), 7.21 (dd ,J=7.6,2.2Hz,1H),6.81(d,J=5.2Hz,1H),3.72(s,2H),3.54-3.39(m,2H),3.29-3 .16(m,2H),2.34-2.24(m,1H),2.23-2.12(m,1H),1.79-1.62(m,2H),1.49(s,9H).

[0348] Example 8 – Preparation of additional sulfoximine compounds The compounds in the following table were prepared according to the experimental procedures described in Examples 3, 4 and 5 and in the detailed description.

[0349] [Table 95]

[0350] [Table 96]

[0351] Table 97

[0352] Table 98

[0353] Table 99

[0354] Table 100

[0355] Table 101

[0356] Table 102

[0357] Table 103

[0358] Table 104

[0359] Table 105

[0360] Table 106

[0361] [Table 107]

[0362] [Table 108]

[0363] [Table 109]

[0364] [Table 110]

[0365] [Table 111]

[0366] [Table 112]

[0367] Example 9 - Synthesis of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(4-((6-(tert-butylsulfonyl)-7-methoxyquinazolin-4-yl)oxy)-2-fluorophenyl)acetamide (Compound 2); Prepared according to General Scheme 11 [ka] Part I - Synthesis of 6-bromo-7-methoxyquinazolin-4(3H)-one [ka] A solution of 2-amino-5-bromo-4-methoxybenzoic acid (4.80 g, 19.5 mmol, 1.00 equiv.) and ammonium acetate (30.1 g, 390 mmol, 20.0 equiv.) in trimethyl orthoformate (100 mL) was heated to 100° C. overnight. The solvent was then removed under reduced pressure, and the product was extracted with EtOAc (3×100 mL). The solvent was removed under reduced pressure. The title compound was obtained as a gray solid (4.09 g, 82% yield), which was used in the next reaction without further purification.

[0368] Part II - Synthesis of 6-(tert-butylsulfonyl)-7-methoxyquinazolin-4(3H)-one [ka] A solution of 6-bromo-7-methoxyquinazolin-4(3H)-one (4.09 g, 16.1 mmol, 1.00 equiv.), 2-methylpropane-2-thiol (3.6 mL, 31.9 mmol, 2.00 equiv.), NaCO (3.37 g, 30.8 mmol, 1.90 equiv.), and Pd(PPh) (0.6 g, 0.483 mmol, 0.03 equiv.) in DMF (56 mL) was heated to 100 °C under an inert atmosphere of nitrogen for 6 h. Insoluble by-products were removed by filtration. Water was added, and the precipitated product was removed by filtration and washed with petroleum ether.

[0369] The thioether intermediate was dissolved in MeOH (140 mL), EtOAc (140 mL), and water (140 mL), and oxone (22.5 g, 134 mmol, 8.70 equiv.) was added. After stirring at room temperature for 16 h, the mixture was filtered and washed with a saturated aqueous solution of NaHCO3. The pH of the aqueous solution was adjusted to 7-8 by adding NaHCO3, and the product was extracted with EtOAc. The combined organic phases were washed with a saturated aqueous solution of NaHCO3, dried over MgSO4, and the solvent was removed under reduced pressure. The title compound was obtained as a pale yellow solid (2.57 g, 54% yield), which was used in the next reaction without further purification.

[0370] Part III - Synthesis of 6-(tert-butylsulfonyl)-4-chloro-7-methoxyquinazoline [ka] POCl3 (56.9 mg, 0.371 mmol, 1.10 equiv.) was dissolved in 6-(tert- To a solution of (butylsulfonyl)-7-methoxyquinazolin-4(3H)-one (100.0 mg, 0.337 mmol, 1.00 equiv.) and triethylamine (51.2 mg, 0.506 mmol, 1.50 equiv.) in toluene (1 mL) was added dropwise at room temperature. The reaction mixture was then heated to 80° C. for 2 hours. After cooling to room temperature, the reaction mixture was used directly in the next reaction.

[0371] Part IV - Synthesis of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(2-fluoro-4-hydroxyphenyl)acetamide [ka] DIPEA (2.28 g, 17.6 mmol, 3.00 equiv.) was added dropwise to a solution of (2-fluoro-4-hydroxyphenyl)acetic acid (1.0 g, 5.88 mmol, 1.00 equiv.) and 1-(tert-butyl)-1H-pyrazol-4-amine (1.23 g, 8.82 mmol, 1.10 equiv.) in DMF (10 mL) at 0 °C. Subsequently, propylphosphonic anhydride (0.71 g, 17.6 mmol, 3.00 equiv.) was added dropwise to the solution, and the reaction mixture was stirred at this temperature for 4 h. The solvent was removed under reduced pressure, and the crude product was purified by column chromatography (hexane / EtOAc 3:1). The title compound was obtained as a yellow solid (500 mg, 29% yield).

[0372] Part V - Synthesis of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(4-((6-(tert-butylsulfonyl)-7-methoxyquinazolin-4-yl)oxy)-2-fluorophenyl)acetamide (Compound 2) [ka] KCO (132.0 mg, 0.954 mmol, 3.00 equiv) was added to a solution of 6-(tert-butylsulfonyl)-4-chloro-7-methoxyquinazoline (100.0 mg, 0.318 mmol, 1.00 equiv) and N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(2-fluoro-4-hydroxyphenyl)acetamide (102.0 mg, 0.350 mmol, 1.10 equiv) in DMF (2 mL). The reaction mixture was heated to 80° C. overnight. The crude product was then purified by preparative HPLC (column: Xselect CSH C18 OBD; 30 x 150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; 13 min isocratic separation with 35% B; wavelength: 220 nm; RT1: 11 min). The title compound was obtained as a white solid (10.3 mg, 5.2%). LCMS (ESI) C 28 H 33 FN5O5S(M+H) + Calculated value: 570.2, measured value: 570.1. 1 H NMR(400MHz,DMSO-d6)δ 10.26(d,J=8.1Hz,1H),9.04-8.56(m,2H),7.94(t,J=9.9Hz,1H),7.65(t,J=6.8Hz,1H),7.57-7.41(m,2H),7.40-7. 30(m,1H),7.21(d,J=8.3Hz,1H),4.20-3.95(m,3H),3.69(d,J=8.2Hz,2H),1.61-1.42(m,9H),1.41-1.21(m,9H).

[0373] Example 10 - Synthesis of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(4-((6-(tert-butylsulfonyl)-7-methoxyquinolin-4-yl)oxy)-2-fluorophenyl)acetamide (Compound 3); Prepared according to General Scheme 11 [ka] Part I - Synthesis of 6-(tert-butylthio)-4-chloro-7-methoxyquinoline [ka] A solution of 6-bromo-4-chloro-7-methoxyquinoline (commercially available, 5.0 g, 18.3 mmol, 1.00 equiv.), 2-methylpropane-2-thiol (1.99 g, 22.0 mmol, 1.20 equiv.), Pd(PPh3)4 (0.64 g, 0.550 mmol, 0.03 equiv.), and Na2CO3 (3.89 g, 36.7 mmol, 2.00 equiv.) in DMF (50 mL) was heated at 100 °C for 6 h under an inert atmosphere of nitrogen. The crude product was then purified by reverse-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 (3 g, 58%).

[0374] Part II - Synthesis of 6-(tert-butylsulfonyl)-4-chloro-7-methoxyquinoline [ka] A solution of 6-(tert-butylthio)-4-chloro-7-methoxyquinoline (3.0 g, 10.6 mmol, 1.00 equiv) and oxone (7.26 g, 42.6 mmol, 4.00 equiv) in MeOH (90 mL), water (90 mL), and EtOAc (90 mL) was heated at room temperature. The mixture was stirred at rt for 16 h. The product was extracted with EtOAc (3 × 300 mL), and the combined organic phases were washed with brine and dried over NaSO. The solvent was removed under reduced pressure, and the crude product was purified by reverse-phase flash chromatography (column: C18 silica gel; mobile phase A: water (10 mmol / L NHHCO), mobile phase B: ACN, gradient: 40–70% B in 30 min; wavelength: 210 nm). The title compound was obtained as a yellow solid (1.5 g, 45%).

[0375] Part III - Synthesis of methyl 2-(4-((6-(tert-butylsulfonyl)-7-methoxyquinolin-4-yl)oxy)-2-fluorophenyl)acetate [ka] A solution of 6-(tert-butylsulfonyl)-4-chloro-7-methoxyquinoline (500.0 mg, 1.59 mmol, 1.00 equiv) and methyl 2-(2-fluoro-4-hydroxyphenyl)acetate (293.4 mg, 1.59 mmol, 1.00 equiv) in chlorobenzene (5 mL) was heated to 130 °C for 12 h. The reaction mixture was allowed to cool to room temperature, and the crude product was purified by reverse-phase flash chromatography (column: C18 silica gel; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN, gradient: 60 to 90% B in 30 min; wavelength: 210 nm). The title compound was obtained as a yellow solid (300 mg, 41%).

[0376] Part IV - Synthesis of 2-(4-((6-(tert-butylsulfonyl)-7-methoxyquinolin-4-yl)oxy)-2-fluorophenyl)acetic acid [ka] A solution of methyl 2-(4-((6-(tert-butylsulfonyl)-7-methoxyquinolin-4-yl)oxy)-2-fluorophenyl)acetate (384.5 mg, 0.867 mmol, 1.00 equiv.) and LiOH (41.5 mg, 1.73 mmol, 2.00 equiv.) in THF (4 mL) and water (4 mL) was stirred at room temperature for 2 h. The crude product was then purified by reverse-phase flash chromatography (column: C18 silica gel; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN, gradient: 20 to 50% B in 30 min; wavelength: 210 nm). The title compound was obtained as a yellow solid (260 mg, 67%).

[0377] Part V - Synthesis of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(4-((6-(tert-butylsulfonyl)-7-methoxyquinolin-4-yl)oxy)-2-fluorophenyl)acetamide (Compound 3) [ka] Propylphosphonic anhydride (106.7 mg, 0.336 mmol, 3.00 equiv.) was added dropwise to a solution of 2-(4-((6-(tert-butylsulfonyl)-7-methoxyquinolin-4-yl)oxy)-2-fluorophenyl)acetic acid (50.0 mg, 0.112 mmol, 1.00 equiv.), 1-(tert-butyl)-1H-pyrazol-4-amine (15.6 mg, 0.112 mmol, 1.00 equiv.), and DIPEA (43.3 mg, 0.336 mmol, 3.00 equiv.) in DMF (0.5 mL). The reaction mixture was stirred at room temperature for 4 hours. The crude product was then purified by preparative HPLC (column: Xselect CSH C18 Purification was performed by OBD, 30 x 150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 38-43% B in 13 min; wavelength: 220 nm; RT: 11 min. The title compound was obtained as a white solid (15 mg, 23%). LCMS (ESI) C 29 H 34 FN4O5S(M+H) + Calculated value: 569.2, measured value: 569.0. 1 H NMR(400MHz,DMSO-d6)δ 10.23(s,1H),8.81(d,J=5.3Hz,1H),8.74(d,J=1.5Hz,1H),7.97-7.92(m,1H),7.68(s,1H),7.54(t,J=8.5Hz,1H),7.48-7.43(m,1H), 7.36(dd,J=10.4,2.4Hz,1H),7.20(dd,J=8.2,2.4Hz,1H),6.64(d,J=5.3Hz,1H),4.03(s,3H),3.71(s,2H),1.49(s,9H),1.32(s,9H).

[0378] Example 10a - Synthesis of 4-(4-(2-((1-(tert-butyl)-1H-pyrazol-4-yl)amino)-2-oxoethyl)-2-methylphenoxy)-7-fluoro-N-methylquinoline-6-carboxamide (Compound 490); prepared according to general scheme 8. [ka] Part I - Synthesis of methyl 4-(((2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-ylidene)methyl)amino)-2-fluorobenzoate [ka] A solution of Meldrum's acid (22.0 g, 153 mmol, 1.00 equiv.) and methyl 4-amino-2-fluorobenzoate (29.7 g, 176 mmol, 1.15 equiv.) in triethyl orthoformate (220 mL) was heated to 105° C. for 2 h. The precipitated product was then filtered off, washed with MeOH (3×20 mL), and dried under reduced pressure. The title compound was obtained as a brown solid (44 g, 89%), which was used in the next reaction without further purification.

[0379] Part II – Synthesis of methyl 7-fluoro-4-oxo-1,4-dihydroxyquinoline-6-carboxylate [ka] A solution of methyl 4-(((2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-ylidene)methyl)amino)-2-fluorobenzoate (20.0 g, 61.9 mmol, 1.00 equiv) in diphenyl ether (100 mL) was heated to 230° C. for 1 h. The precipitated product was then filtered off, washed with hexane (3×100 mL), and dried under reduced pressure. The title compound was obtained as a brown solid (12 g, 88%), which was used in the next reaction without further purification.

[0380] Part III – Synthesis of methyl 4-chloro-7-fluoroquinoline-6-carboxylate [ka] A solution of methyl 7-fluoro-4-oxo-1,4-dihydroxyquinoline-6-carboxylate (10.0 g, 45.2 mmol, 1.00 equiv.) in phosphoryl chloride (30 mL) was heated to 110 °C for 1 h. Subsequently, the reaction mixture was carefully quenched with water, and the pH of the solution was adjusted to 8 by adding saturated aqueous Na2CO3. The product was extracted with EtOAc (3 × 200 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 column chromatography (petroleum ether / EtOAc 10:1). The title compound was obtained as a yellow solid (1.2 g, 11% yield).

[0381] Part IV - Synthesis of methyl 4-(4-(2-((1-(tert-butyl)-1H-pyrazol-4-yl)amino)-2-oxoethyl)-2-methylphenoxy)-7-fluoroquinoline-6-carboxylate [ka] A solution of methyl 4-chloro-7-fluoroquinoline-6-carboxylate (1.00 g, 4.17 mmol, 1.00 equiv.), N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(4-hydroxy-3-methylphenyl)acetamide (1.20 g, 4.17 mmol, 1.00 equiv.), and CsCO (7.72 g, 8.35 mmol, 2.00 equiv.) in DMA (10 mL) was stirred at room temperature for 5 h. The crude product was subsequently purified by reverse-phase flash chromatography (column: C18 silica gel; mobile phase A: water (0.1% TFA), mobile phase B: ACN, gradient: 10–80% B in 50 min; wavelength: 254 nm). The title compound was obtained as a yellow solid (1.5 g, 73%).

[0382] Part V - Synthesis of 4-(4-(2-((1-(tert-butyl)-1H-pyrazol-4-yl)amino)-2-oxoethyl)-2-methylphenoxy)-7-fluoro-N-methylquinoline-6-carboxamide (Compound 490) [ka] A solution of methylamine in MeOH (30%, 1.75 mL) was added to a solution of methyl 4-(4-(2-((1-(tert-butyl)-1H-pyrazol-4-yl)amino)-2-oxoethyl)-2-methylphenoxy)-7-fluoroquinoline-6-carboxylate (350 mg, 714 μmol, 1.00 equiv.) in MeOH (1.75 mL), and the mixture was stirred at room temperature for 3 h. The crude product was subsequently purified by reverse-phase flash chromatography (column: C18 silica gel; mobile phase A: water (0.1% TFA), mobile phase B: ACN, gradient: 10-50% B in 30 min; wavelength: 254 nm). The title compound was obtained as a white solid (137 g, 39%). LCMS (ESI) C 27 H 29 FN5O3(M+H) + Calculated value: 490.2, measured value: 490.2. 1 H NMR (300 MHz, DMSO-d6) δ 10.20(s,1H),8.72(d,J=5.2Hz,1H),8.62(d,J=7.8Hz,1H),8.56(d,J=4.8Hz, 1H),7.95(d,J=0.7Hz,1H),7.86(d,J=11.8Hz,1H),7.46(d,J=0.7Hz,1H),7.3 8(d,J=2.1Hz,1H),7.30(dd,J=8.2,2.2Hz,1H),7.19(d,J=8.2Hz,1H),6.42(d ,J=5.2Hz,1H),3.61(s,2H),2.85(d,J=4.6Hz,3H),2.12(s,3H),1.49(s,9H).

[0383] Example 11 – Preparation of additional 7-substituted quinoline and quinazoline compounds The compounds in the following table were prepared according to the experimental procedures described in Examples 9, 10 and 10a and in the detailed description.

[0384] [Table 113]

[0385] [Table 114]

[0386] Table 115

[0387] Table 116

[0388] Table 117

[0389] Table 118

[0390] Table 119

[0391] Table 120

[0392] Table 121

[0393] Table 122

[0394]

Table 123

[0395] Example 12 - Synthesis of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(3-(difluoromethyl)-4-((6-(methylsulfonyl)quinolin-4-yl)oxy)phenyl)acetamide (Compound 92); Prepared according to General Scheme 7 [ka] Part I - Synthesis of methyl 2-(3-(1,3-dioxolan-2-yl)-4-hydroxyphenyl)acetate [ka] Ethylene glycol (6.39 g, 103 mmol, 4.00 equiv.), triethyl orthoformate (3.01 g, 28.3 mmol, 1.10 equiv.), and tetrabutylammonium tribromide (0.12 g, 0.257 mmol, 0.01 equiv.) were added to a solution of methyl 2-(3-formyl-4-hydroxyphenyl)acetate (5.0 g, 25.7 mmol, 1.0 equiv.) in toluene (50 mL), and the mixture was stirred at room temperature overnight. The reaction was then quenched with water / ice (50 mL), and the product was extracted with EtOAc (3 × 10 mL). The combined organic phases were dried over NaSO, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography. The residue was purified by chromatography (petroleum ether / EtOAc 5:1) to give the title compound as a yellow oil (2.8 g, 46%).

[0396] Part II - Synthesis of methyl 2-(3-(1,3-dioxolan-2-yl)-4-((6-(methylsulfonyl)quinolin-4-yl)oxy)phenyl)acetate [ka] 4-Chloro-6-(methylsulfonyl)quinoline (1.00 g, 4.18 mmol, 1.00 equiv., can be synthesized as shown in Part II of Example 30) and CsCO (2.74 g, 8.39 mmol, 2.00 equiv.) were added to a solution of methyl 2-(3-(1,3-dioxolan-2-yl)-4-hydroxyphenyl)acetate (1.0 g, 4.20 mmol, 1.00 equiv.) in NMP (10 mL), and the mixture was stirred at room temperature for 4 h. Subsequently, the reaction was quenched with water / ice (50 mL), and the product was extracted with EtOAc (3 × 10 mL). The combined organic phases were dried over NaSO, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography (petroleum ether / EtOAc 1:1). The title compound was obtained as a yellow solid (600 mg, 32%).

[0397] Part III - Synthesis of methyl 2-(3-formyl-4-((6-(methylsulfonyl)quinolin-4-yl)oxy)phenyl)acetate [ka] Iron(III) chloride (1.26 g, 4.66 mmol, 2.50 equiv) was added to a solution of 2-(3-(1,3-dioxolan-2-yl)-4-((6-(methylsulfonyl)quinolin-4-yl)oxy)phenyl)acetate (590 mg, 1.33 mmol, 1.00 equiv) in DCM (12 mL), and the mixture was stirred at room temperature overnight. Subsequently, the reaction was quenched with water / ice (50 mL), and the pH of the solution was adjusted to 8 with saturated aqueous NaHCO. The product was extracted with EtOAc (3 × 5 mL), the combined organic phases were dried over NaSO, and the solvent was removed under reduced pressure. The title compound (480 mg) was used in the next reaction without further purification.

[0398] Part IV - Synthesis of methyl 2-(3-(difluoromethyl)-4-((6-(methylsulfonyl)quinolin-4-yl)oxy)phenyl)acetate [ka] Bis(2-methoxyethyl)aminosulfur trifluoride (1.04 g, 4.71 mmol, 4.00 equiv.) was added to a solution of methyl 2-(3-formyl-4-((6-(methylsulfonyl)quinolin-4-yl)oxy)phenyl)acetate (470 mg, 1.18 mmol, 1.00 equiv.) and EtOH (10.8 mg, 0.235 mmol, 0.20 equiv.) in DCM (10 mL) at 0 °C. The mixture was then stirred overnight at room temperature. The reaction was then quenched with water / ice, and the pH of the solution was adjusted to 8 with saturated aqueous NaHCO3. The product was extracted with EtOAc (3 × 10 mL), the combined organic phases were dried over Na2SO4, and the solvent was removed under reduced pressure. The crude product was purified by reverse-phase flash chromatography (column: C18 silica gel; mobile phase A: water, mobile phase B: ACN, gradient: 30-60% B in 30 min; wavelength: 210 nm) to give the title compound as a white solid (210 mg, 42%).

[0399] Part V - Synthesis of 2-(3-(difluoromethyl)-4-((6-(methylsulfonyl)quinolin-4-yl)oxy)phenyl)acetic acid [ka] LiOH (20.5 mg, 0.854 mmol, 2.00 equiv.) was added to a solution of 2-(3-(difluoromethyl)-4-((6-(methylsulfonyl)quinolin-4-yl)oxy)phenyl)acetate (180 mg, 0.427 mmol, 1.00 equiv.) in THF (2 mL) and water (2 mL) at 0 °C. The mixture was then stirred at room temperature for 2 h. The pH of the solution was adjusted to 4 with hydrochloric acid, and the crude product was purified by reverse-phase flash chromatography (column: C18 silica gel; mobile phase A: water, mobile phase B: ACN, gradient: 35–65% B in 30 min; wavelength: 210 nm). The title compound was obtained as a white solid (150 mg, 86%).

[0400] Part VI - Synthesis of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(3-(difluoromethyl)-4-((6-(methylsulfonyl)quinolin-4-yl)oxy)phenyl)acetamide (Compound 92) [ka] 1-(tert-Butyl)-1H-pyrazol-4-amine (41.0 mg, 0.295 mmol, 1.00 equiv), DIPEA (114 mg, 0.885 mmol, 3.00 equiv), and HATU (168 mg, 0.443 mmol, 1.50 equiv) were added to a solution of 2-(3-(difluoromethyl)-4-((6-(methylsulfonyl)quinolin-4-yl)oxy)phenyl)acetic acid (120 mg, 0.295 mmol, 1.00 equiv) in DMF (1.2 mL) at 0 °C. The mixture was then stirred at room temperature for 2 h. The reaction was quenched with water / ice (5 mL), and the product was extracted with EtOAc (3 × 2 mL). The combined organic phases were dried over Na2SO4, and the solvent was removed under reduced pressure. The crude product was purified by reverse-phase flash chromatography (column: C18 silica gel; mobile phase A: water (0.1% ammonia), mobile phase B: ACN, gradient: 20-50% B in 30 min; wavelength: 210 nm). The title compound was obtained as a white solid (108 mg, 69%). LCMS (ESI) C 26 H 27 F2N4O4(M+H) + Calculated value: 529.2, measured value: 529.0. 1 H NMR(300MHz,DMSO-d6)δ 10.26(s,1H),8.89-8.87(m,2H),8.30-8.28(m,2H),7.95(s,1H),7.75(d,J=2.0Hz,1H),7.64(d,J=8.3Hz,1 H),7.48-7.42(m,2H),7.24(t,J=54.0Hz,1H),6.73(d,J=5.2Hz,1H),3.73(s,2H),3.38(s,3H),1.49(s,9H).

[0401] Example 13 – Preparation of additional difluoromethylphenylene compounds The compounds in the following table were prepared according to the experimental procedures described in Example 12 and the detailed description.

[0402] [Table 124]

[0403] [Table 125]

[0404] [Table 126]

[0405] [Table 127]

[0406] Example 14 - Synthesis of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(3-fluoro-5-((6-((1-methylpiperidin-4-yl)oxy)quinazolin-4-yl)oxy)pyridin-2-yl)acetamide (Compound 20); prepared according to general scheme 15 [ka] Part I - Synthesis of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(3-fluoro-5-hydroxypyridin-2-yl)acetamide [ka] EDC (19.7 g, 127 mmol, 1.50 equiv.) was added to a solution of 2-(3-fluoro-5-hydroxypyridin-2-yl)acetic acid (14.5 g, 84.7 mmol, 1.00 equiv.), 1-(tert-butyl)-1H-pyrazol-4-amine (11.8 g, 84.7 mmol, 1.00 equiv.), HOBt (17.2 g, 127 mmol, 1.50 equiv.), and DIPEA (32.9 g, 254 mmol, 3.00 equiv.) in THF (145 mL) and DCM (145 mL) at 0 °C, and the mixture was stirred at room temperature overnight. Water (200 mL) was added, and the product was extracted with a mixture of EtOAc and 2-methyltetrahydrofuran (1:1, 5 × 150 mL). The combined organic phase was washed with brine, dried over Na SO , and the solvent was removed under reduced pressure. The crude product was purified by column chromatography (DCM / MeOH 10:1) to give the title compound as a brown solid (17.3 g, 70%).

[0407] Part II - Synthesis of 2-(5-((6-bromoquinazolin-4-yl)oxy)-3-fluoropyridin-2-yl)-N-(1-(tert-butyl)-1H-pyrazol-4-yl)acetamide [ka] K2CO3 (3.92 g, 28.3 mmol, 3.00 equiv.) was added to a solution of 6-bromo-4-chloroquinazoline (2.3 g, 9.45 mmol, 1.00 equiv.) and N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(3-fluoro-5-hydroxypyridin-2-yl)acetamide (2.76 g, 9.45 mmol, 1.00 equiv., which can be prepared as described in Part I of Example 15) in DMF (23 mL) under an inert atmosphere of nitrogen. The mixture was stirred at room temperature overnight. Subsequently, EtOAc (200 mL) was added, and the mixture was washed with water (2 x 100 mL). The organic phase was dried over Na2SO4, and the solvent was removed under reduced pressure. The title compound was obtained as a yellow solid (5.5 g), which was used in the next reaction without further purification.

[0408] Part III - Synthesis of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(3-fluoro-5-((6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-4-yl)oxy)pyridin-2-yl)acetamide [ka] A solution of 2-(5-((6-bromoquinazolin-4-yl)oxy)-3-fluoropyridin-2-yl)-N-(1-(tert-butyl)-1H-pyrazol-4-yl)acetamide (5.0 g, 10.0 mmol, 1.00 equiv.) and bis(pinacolato)diboron (3.05 g, 12.0 mmol, 1.20 equiv.), KOAc (2.95 g, 30.0 mmol, 3.00 equiv.), and Pd(dppf)Cl (1.1 g, 1.50 mmol, 0.15 equiv.) in 1,4-dioxane (80 mL) was heated to 70 °C under an inert atmosphere of nitrogen for 2.5 h. The mixture was diluted with EtOAc (200 mL) and washed with water (2 × 100 mL). The organic phase was then dried over NaSO, and the solvent was removed under reduced pressure. The title compound was obtained as a brownish-red solid (8.5 g) which was used in the next reaction without further purification.

[0409] Part IV - Synthesis of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(3-fluoro-5-((6-hydroxyquinazolin-4-yl)oxy)pyridin-2-yl)acetamide [ka] An aqueous solution of hydrogen peroxide (30%, 8 mL) was added to a solution of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(3-fluoro-5-((6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-4-yl)oxy)pyridin-2-yl)acetamide (8.0 g, 14.6 mmol, 1.00 equiv.) in THF (80 mL). The mixture was stirred at room temperature for 1.5 h. Subsequently, the mixture was filtered and the solvent was removed under reduced pressure. The crude product was purified by reverse-phase flash chromatography (column: C18 silica gel; mobile phase A: water (0.1% NH4HCO3), mobile phase B: ACN, gradient: 30–70% B in 20 min; wavelength: 210 nm). The title compound was obtained as a yellowish-brown solid (2 g, 48% over three steps).

[0410] Part V - Synthesis of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(3-fluoro-5-((6-((1-methylpiperidin-4-yl)oxy)quinazolin-4-yl)oxy)pyridin-2-yl)acetamide (Compound 20) [ka] Di-tert-butyl azodicarboxylate (844.1 mg, 3.67 mmol, 2.00 equiv.) was added to a solution of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(3-fluoro-5-((6-hydroxyquinazolin-4-yl)oxy)pyridin-2-yl)acetamide (800 mg, 1.83 mmol, 1.00 equiv.), 1-methylpiperidin-4-ol (316.7 mg, 2.75 mmol, 1.50 equiv.), and PPh3 (961.6 mg, 3.67 mmol, 2.00 equiv.) in THF (16 mL) at 0 °C. The mixture was then stirred at room temperature for 1.5 h. EtOAc (50 mL) was added, and the solution was washed with water (2 × 20 mL). The organic phase was dried over Na2SO4, and the solvent was removed under reduced pressure. The crude product was purified by preparative HPLC (column: Xselect CSH C18 Purification was performed by OBD; 19 x 150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient 25-30% B in 16 min; wavelength: 220 nm). The title compound was obtained as a white solid (130 mg, 13%). LCMS (ESI) C 28 H 33 FN7O3(M+H) + Calculated value: 534.3, measured value: 534.3. 1 H NMR(400MHz,DMSO-d6)δ10.32(s,1H),8.64(s,1H),8.50(d,J=1.9Hz,1H),8.00(dd,J= 10.1,2.2Hz,1H),7.97(d,J=9.1Hz,1H),7.93(d,J=0.7Hz,1H),7.75-7.66(m,2H),7.4 5(d,J=0.7Hz,1H),4.70(dt,J=8.1,4.2Hz,1H),3.91(d,J=2.3Hz,2H),2.68-2.57(m,2 H),2.30-2.21(m,2H),2.19(s,3H),2.07-1.96(m,2H),1.81-1.68(m,2H),1.49(s,9H).

[0411] Example 15 - Synthesis of N-(5-(tert-butyl)-1-methyl-1H-pyrazol-3-yl)-2-(3-fluoro-5-((6-(methylsulfonyl)quinolin-4-yl)oxy)pyridin-2-yl)acetamide (Compound 41); Prepared according to General Scheme 2 [ka] Part I - Synthesis of 1-(tert-butyl) 3-ethyl 2-(5-bromo-3-fluoropyridin-2-yl)malonate [ka] Sodium hydride (60% wt, 124 g, 3.09 mol, 1.20 equiv.) was added to a solution of tert-butyl ethyl malonate (485 g, 2.58 mol, 1.00 equiv.) in DMF (5 L) at 0 °C. The reaction mixture was then stirred at room temperature for 1 h. 5-Bromo-2,3-difluoropyridine (500 g, 2.58 mol, 1.00 equiv.) was added, and the mixture was heated at 80 °C overnight. The mixture was cooled to 0 °C, and saturated aqueous NH4Cl was added. The product was extracted with EtOAc (3 × 5 L), and the combined organic phases were washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure. The title compound (1.1 kg) was used in the next reaction without further purification.

[0412] Part II - Synthesis of ethyl 2-(5-bromo-3-fluoropyridin-2-yl)acetate [ka] TFA (5 L) was added to a solution of 1-(tert-butyl) 3-ethyl 2-(5-bromo-3-fluoropyridin-2-yl)malonate (1.1 kg, 3.04 mol, 1.00 equiv.) in DCM (5 L), and the mixture was stirred at room temperature for 2 h. The solvent was removed under reduced pressure. Water was added, and the pH of the solution was adjusted to 7 by adding a saturated aqueous solution of NaHCO3. The product was extracted with EtOAc (3 x 3 L), and the combined organic phases were dried over MgSO4. The solvent was removed under reduced pressure, and the crude product was purified by column chromatography (petroleum ether / EtOAc 95:5) to give the title compound as a yellow oil (520 g, 65% over two steps).

[0413] Part III - Synthesis of ethyl 2-(3-fluoro-5-hydroxypyridin-2-yl)acetate [ka] A solution of ethyl 2-(5-bromo-3-fluoropyridin-2-yl)acetate (470 g, 1.79 mol, 1.00 equiv.), Pd(dppf)Cl (131 g, 179 mmol, 0.10 equiv.), bis(pinacolato)diboron (911 g, 3.59 mol, 2.00 equiv.), and potassium acetate (352 g, 3.59 mol, 2.00 equiv.) in 1,4-dioxane (4.7 L) was heated to 85 °C for 24 h under an inert atmosphere of nitrogen. Subsequently, an aqueous solution of hydrogen peroxide (30%, 470 mL, 20.2 mol, 13.3 equiv.) was added dropwise at 0 °C, and the mixture was stirred at room temperature for 3 h. Water (2 L) was added, and the product was extracted with EtOAc (3 × 1.5 L). 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 (petroleum ether / EtOAc 1:1). The title compound was obtained as a colorless oil (271.1 g, 70% over two steps). was obtained as.

[0414] Part IV - Synthesis of 2-(3-fluoro-5-hydroxypyridin-2-yl)acetic acid [ka] Lithium hydroxide (8.57 g, 358 mmol, 2.50 equiv.) was added to a solution of ethyl 2-(3-fluoro-5-hydroxypyridin-2-yl)acetate (28.5 g, 143 mmol, 1.00 equiv.) in THF (140 mL) and water (140 mL), and the mixture was stirred at room temperature overnight. Hydrochloric acid (3 M, 500 mL) was added, and the product was extracted with a mixture of EtOAc and 2-methyltetrahydrofuran (1:1, 6 × 200 mL). The combined organic phase was washed with brine, dried over Na2SO4, and the solvent was removed under reduced pressure. The title compound (14.5 g) was used in the next reaction without further purification.

[0415] Part V - Synthesis of N-(5-(tert-butyl)-1-methyl-1H-pyrazol-3-yl)-2-(3-fluoro-5-hydroxypyridin-2-yl)acetamide [ka] HATU (9.33 g, 24.5 mmol, 1.50 equiv.) was added to a solution of 2-(3-fluoro-5-hydroxypyridin-2-yl)acetic acid (2.80 g, 16.3 mmol, 1.00 equiv.), 5-(tert-butyl)-1-methyl-1H-pyrazol-3-amine (2.76 g, 18.0 mmol, 1.10 equiv.), and triethylamine (3.31 g, 32.7 mmol, 2.00 equiv.) in DMF (28 mL), and the mixture was stirred at room temperature for 1 h. The solvent was then removed under reduced pressure, and the crude product was purified by reverse-phase flash chromatography (column: C18 silica gel; mobile phase A: water, mobile phase B: ACN, gradient: 30–60% B in 30 min; wavelength: 210 nm). The title compound was obtained as a pale yellow solid (0.51 g, 10%).

[0416] Part VI - Synthesis of N-(5-(tert-butyl)-1-methyl-1H-pyrazol-3-yl)-2-(3-fluoro-5-((6-(methylsulfonyl)quinolin-4-yl)oxy)pyridin-2-yl)acetamide (Compound 41) [ka] N-(5-(tert-butyl)-1-methyl-1H-pyrazol-3-yl)-2-(3-fluoro-5-hydroxypyridin-2-yl)acetamide (200 mg, 0.653 mmol, 1.00 equiv.), 4-chloro-6-(methylsulfonyl)quinoline (158 mg, 0.653 mmol, 1.00 equiv.), CsCO (425 mg, 1.31 mmol, 2.00 equiv.), CuI (49.7 mg, 0.261 mmol, 0.40 equiv.) A solution of N,N-dimethylglycine (40.4 mg, 0.392 mmol, 0.60 equiv.) in 1,4-dioxane (4 mL) was heated to 100 °C for 16 h under an inert atmosphere of nitrogen. Subsequently, insoluble by-products were filtered off and the solvent was removed under reduced pressure. The crude product was purified by reverse-phase flash chromatography (column: C18 silica gel; mobile phase A: water, mobile phase B: ACN, gradient: 30-60% B in 30 min; wavelength: 210 nm). The title compound was obtained as a white solid (33.3 mg, 10%). LCMS (ESI) C 25 H 27 FN5O4S(M+H) + Calculated value: 512.2, measured value: 512.1. 1 H NMR(300MHz,DMSO-d6)δ10.64(s,1H),8.93(d,J=5.2Hz,1H),8.87(s,1H),8.54(d,J=2.1Hz,1H),8.31(s,2H), 8.03(d,J=9.0Hz,1H),6.93(d,J=5.2Hz,1H),6.30(s,1H),3.95(s,2H),3.81(s,3H),3.38(s,3H),1.31(s,9H).

[0417] Example 16 – Preparation of additional pyridine compounds The compounds in the following table were prepared based on the experimental procedures described in Example 15 and in the detailed description.

[0418] [Table 128]

[0419] [Table 129]

[0420] [Table 130]

[0421] [Table 131]

[0422] [Table 132]

[0423] [Table 133]

[0424] [Table 134]

[0425] [Table 135]

[0426] [Table 136]

[0427] [Table 137]

[0428] [Table 138]

[0429] [Table 139]

[0430] Example 17 - Synthesis of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(3-methyl-4-((6-(methylsulfonyl)quinolin-4-yl)oxy)phenyl)propanamide (Compound 215); prepared according to general scheme 21 [ka] Part I - Synthesis of tert-butyl 2-(4-bromo-3-methylphenyl)propanoate [ka] Trimethylsilyl chloride (0.52 g, 4.78 mmol, 0.05 equiv.) was added to a suspension of zinc (9.38 g, 143 mmol, 1.50 equiv.) in THF (150 mL), and the mixture was stirred at room temperature for 15 minutes under an inert atmosphere of nitrogen. Subsequently, a solution of tert-butyl 2-bromopropanoate (20.0 g, 95.7 mmol, 1.00 equiv.) in THF (50 mL) was added dropwise at a temperature of 50 °C. After cooling to room temperature, the resulting organozinc reagent was used in the next reaction without further purification. 1-Bromo-4-iodo-2-methylbenzene (10.8 mL, 36.4 mmol, 1.00 equiv.), Pd2(dba)3 (3.34 g, 3.64 mmol, 0.10 equiv.), and Xantphos (2.11 g, 3.64 mmol, 0.10 equiv.) were added to a solution of the organozinc reagent in THF (120 mL, 43.7 mmol, 1.20 equiv.), and the reaction mixture was heated at 65 °C overnight under an inert atmosphere of nitrogen. Water (150 mL) was added, and the product was extracted with EtOAc (3 × 200 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 (petroleum ether / EtOAc 100:1). The title compound was obtained as a pale yellow liquid (5.3 g, 49%).

[0431] Part II - Synthesis of tert-butyl 2-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate [ka] A solution of tert-butyl 2-(4-bromo-3-methylphenyl)propanoate (5.30 g, 17.7 mmol, 1.00 equiv.), bis(pinacolato)diboron (9.03 g, 35.4 mmol, 2.00 equiv.), Pd(dppf)Cl (1.30 g, 1.77 mmol, 0.10 equiv.), and potassium acetate (5.22 g, 53.1 mmol, 3.00 equiv.) in 1,4-dioxane (53 mL) was heated at 100 °C overnight under an inert atmosphere of nitrogen. Water (70 mL) was added, and the product was extracted with EtOAc (3 × 100 mL). The combined organic phases were washed with brine, dried over NaSO, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography (petroleum ether / EtOAc 100:1). The title compound was obtained as a pale yellow liquid (4.9 g, 80%).

[0432] Part III - Synthesis of tert-butyl 2-(4-hydroxy-3-methylphenyl)propanoate [ka] A solution of hydrogen peroxide in water (1.89 g, 55.4 mmol, 4.00 equiv.) was added to a solution of tert-butyl 2-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate (4.8 g, 13.9 mmol, 1.00 equiv.) in THF (33.6 mL), and the mixture was stirred at room temperature for 5 h. Subsequently, water (70 mL) was added, and the product was extracted with EtOAc (3 × 100 mL). The combined organic phases were washed with brine, dried over NaSO, and the solvent was removed under reduced pressure. The title compound was obtained as a brown oil (4.4 g), which was used in the next reaction without further purification.

[0433] Part IV - Synthesis of tert-butyl 2-(3-methyl-4-((6-(methylsulfonyl)quinolin-4-yl)oxy)phenyl)propanoate [ka] A solution of tert-butyl 2-(4-hydroxy-3-methylphenyl)propanoate (1.0 g, 4.23 mmol, 1.00 equiv.), 4-chloro-6-(methylsulfonyl)quinoline (1.02 g, 4.23 mmol, 1.00 equiv.), and CsCO (2.76 g, 8.46 mmol, 2.00 equiv.) in NMP (20 mL) was stirred overnight at room temperature. Insoluble by-products were then filtered off, and the crude product was purified by reverse-phase flash chromatography (column: C18 silica gel; mobile phase A: water (0.1% NH4HCO3), mobile phase B: ACN, gradient: 45–75% B in 30 min; wavelength: 210 nm). The title compound was obtained as a colorless oil (1.0 g, 54%).

[0434] Part V - Synthesis of 2-(3-methyl-4-((6-(methylsulfonyl)quinolin-4-yl)oxy)phenyl)propanoic acid [ka] A solution of HCl in 1,4-dioxane (4 M, 9.5 mL) was added to a solution of tert-butyl 2-(3-methyl-4-((6-(methylsulfonyl)quinolin-4-yl)oxy)phenyl)propanoate (950 mg, 2.15 mmol, 1.00 equiv) in 1,4-dioxane (9.5 mL), and the mixture was heated at 70° C. overnight. Water (15 mL) was added, and the product was extracted with EtOAc (3×20 mL). The combined organic phase was washed with brine and Na After drying over 2SO4, the solvent was removed under reduced pressure to give the title compound as a white solid (800 mg, 96%), which was used in the next reaction without further purification.

[0435] Part VI - Synthesis of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(3-methyl-4-((6-(methylsulfonyl)quinolin-4-yl)oxy)phenyl)propanamide (Compound 215) [ka] TCFH (1.02 g, 3.63 mmol, 2.00 equiv.) was added to a solution of 2-(3-methyl-4-((6-(methylsulfonyl)quinolin-4-yl)oxy)phenyl)propanoic acid (700 mg, 1.82 mmol, 1.00 equiv.), 1-(tert-butyl)-1H-pyrazol-4-amine (379 mg, 2.72 mmol, 1.50 equiv.), and NMI (447 mg, 5.45 mmol, 3.00 equiv.) in ACN (7 mL), and the mixture was stirred at room temperature for 4 h. The crude product was subsequently purified by reverse-phase flash chromatography (column: C18 silica gel; mobile phase A: water (0.1% NH4HCO3), mobile phase B: ACN, gradient: 20–60% B in 40 min; wavelength: 210 nm). The racemic title compound was obtained as a white oil (700 mg, 76%). The two enantiomers were separated by chiral chromatography (column: CHIRAL ART Amylose-SC, 20 × 250 mm, 5 μm; mobile phase A: MTBE (0.5% of a 2 M solution of ammonia in MeOH), mobile phase B: EtOH). The title compound (72.4 mg, 7.9%, Enantiomer 1, retention time: 1.57 min; column: CHIRALPAK IA-3, 4.6 × 50 mm, 3 μm; mobile phase A: MTBE (0.1% DEA), mobile phase B: EtOH, 10% Isocratic separation using HPLC with HPLC-MS (Flow rate: 1.0 mL / min, Wavelength: 254 nm) gave the compound as a white solid. 27 H 29 N4O4S(MH) - Calculated value: 505.2, measured value: 505.1. 1 H NMR(400MHz,DMSO-d6)δ 10.15(s,1H),8.89(dd,J=1.9,0.9Hz,1H),8.83(d,J=5.2Hz,1H),8.32-8.23(m,2H),7.97(s,1H),7.45-7.43(m,2H),7.36(dd,J=8.3,2.2 Hz,1H),7.24(d,J=8.3Hz,1H),6.55(d,J=5.2Hz,1H),3.80(q,J=7.0Hz,1H),3.38(s,3H),2.15(s,3H),1.48(s,9H),1.45(d,J=7.0Hz,3H).

[0436] Example 18 – Preparation of additional arylpropionic acid compounds The compounds in the following table were prepared based on the experimental procedures described in Example 17 and the detailed description.

[0437] [Table 140]

[0438] Example 19 - Synthesis of N-(6-(tert-butyl)pyrimidin-4-yl)-2-(2-fluoro-4-((6-methoxyquinazolin-4-yl)oxy)phenyl)acetamide (Compound 32); prepared according to general scheme 4 [ka] Propylphosphonic anhydride (581.5 mg, 1.83 mmol, 2.00 equiv.) was added to a solution of 2-(2-fluoro-4-((6-methoxyquinazolin-4-yl)oxy)phenyl)acetic acid (300.0 mg, 0.914 mmol, 1.00 equiv., which can be prepared according to Part VI of Example 20), 6-(tert-butyl)pyrimidin-4-amine (140.9 mg, 0.932 mmol, 1.02 equiv.), and DIPEA (590.5 mg, 4.57 mmol, 5.00 equiv.) in DMF (3 mL) at 0 °C. The reaction mixture was then stirred at room temperature for 1 h. The crude product was purified by reverse-phase flash chromatography (column: C18 silica gel; mobile phase A: water (1% NaHCO), mobile phase B: ACN, gradient: 30–60% B in 30 min; wavelength: 210 nm). The title compound was obtained as a yellow solid (190 mg, 44%). 25 H 25 FN5O3(M+H) + Calculated value: 462.2, measured value: 462.2. 1H NMR(400MHz,DMSO-d6)δ 11.19(bs,1H),8.85(d,J=1.2Hz,1H),8.64(s,1H),8.15(d,J=1.2Hz,1H),7.95(d,J=9.1Hz,1H),7.69(dd,J=9.1,2.9Hz,1H),7.6 2(d,J=2.8Hz,1H),7.51(t,J=8.5Hz,1H),7.35(dd,J=10.5,2.4Hz,1H),7.23-7.17(m,1H),3.98(s,3H),3.93(s,2H),1.28(s,9H).

[0439] Example 20 - Synthesis of 2-(2-fluoro-4-((6-methoxyquinazolin-4-yl)oxy)phenyl)-N-(4-(1-(trifluoromethyl)cyclopropyl)pyridin-2-yl)acetamide (Compound 34); prepared according to general scheme 4 [ka] Part I - Synthesis of 2-chloro-4-(3,3,3-trifluoroprop-1-en-2-yl)pyridine [ka] A solution of (2-chloropyridin-4-yl)boronic acid (2.00 g, 12.7 mmol, 1.00 equiv.), 2-bromo-3,3,3-trifluoroprop-1-ene (2.67 g, 15.3 mmol, 1.20 equiv.), Pd(dppf)Cl (929 mg, 1.27 mmol, 0.10 equiv.), and KCO (6.19 g, 44.5 mmol, 3.50 equiv.) in THF (20 mL) and water (10 mL) was heated at 70 °C overnight under an inert atmosphere of nitrogen. Subsequently, water was added, and the product was extracted with EtOAc (3 × 20 mL). The combined organic phase was washed with brine, dried over MgSO, and the solvent was removed under reduced pressure. The crude product was purified by reverse-phase flash chromatography (column: C18 silica gel; mobile phase A: water (1% NH4HCO3), mobile phase B: ACN, gradient: 50 to 80% B in 30 min; wavelength: 210 nm) to give the title compound as a yellow oil (500 mg, 19%).

[0440] Part II - Synthesis of tert-butyl (4-(3,3,3-trifluoroprop-1-en-2-yl)pyridin-2-yl)carbamate [ka] A solution of 2-chloro-4-(3,3,3-trifluoroprop-1-en-2-yl)pyridine (1.00 g, 4.82 mmol, 1.00 equiv.), tert-butyl carbamate (1.13 g, 9.63 mmol, 2.00 equiv.), CsCO (1.87 g, 9.63 mmol, 2.00 equiv.), Pd(dba) (0.44 g, 0.482 mmol, 0.10 equiv.), and XPhos (0.46 g, 0.963 mmol, 0.20 equiv.) in 1,4-dioxane (10 mL) was heated to 90 °C for 1 h under an inert atmosphere of nitrogen. EtOAc was added, the organic phase was washed with brine, dried over MgSO, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography (petroleum ether / EtOAc 50:1). The title compound was obtained as a yellow solid.

[0441] Part III - Synthesis of tert-butyl (4-(1-(trifluoromethyl)cyclopropyl)pyridin-2-yl)carbamate [ka] Sodium bis(trimethylsilyl)amide (1.02 g, 5.55 mmol, 1.60 equiv.) and methyl(diphenyl)sulfonium tetrafluoroborate (1.30 g, 4.50 mmol, 1.30 equiv.) were added to a solution of tert-butyl (4-(3,3,3-trifluoroprop-1-en-2-yl)pyridin-2-yl)carbamate (1.00 g, 3.47 mmol, 1.00 equiv.) in THF (10 mL) at 0 °C under an inert atmosphere of nitrogen. The mixture was stirred at this temperature for 1 h. Subsequently, the solvent was removed under reduced pressure, and the crude product was purified by reverse-phase flash chromatography (column: C18 silica gel; mobile phase A: water (0.1% NH4HCO3), mobile phase B: ACN, gradient: 15–45% B in 30 min; wavelength: 210 nm). The title compound was obtained as a yellow solid (250 mg, 24%).

[0442] Part IV - Synthesis of 4-(1-(trifluoromethyl)cyclopropyl)pyridin-2-amine [ka] A solution of HCl in 1,4-dioxane (4 M, 3.00 mL, 12.0 mmol, 18.1 equiv.) was added to a solution of tert-butyl (4-(1-(trifluoromethyl)cyclopropyl)pyridin-2-yl)carbamate (200 mg, 0.662 mmol, 1.00 equiv.) in 1,4-dioxane (1 mL), and the mixture was stirred at room temperature for 1 h. The solvent was removed under reduced pressure, and the crude product was purified by reverse-phase flash chromatography (column: C18 silica gel; mobile phase A: water (0.1% NH4HCO3), mobile phase B: ACN, gradient: 10–50% B in 30 min; wavelength: 210 nm). The title compound was obtained as a yellow solid (120 mg, 90%).

[0443] Part V - Synthesis of methyl 2-(2-fluoro-4-((6-methoxyquinazolin-4-yl)oxy)phenyl)acetate [ka] 4-chloro-6-methoxyquinazoline (10.0 g, 51.4 mmol, 1.00 equiv.) A solution of 2-(2-fluoro-4-hydroxyphenyl)acetate (10.4 g, 56.5 mmol, 1.10 equiv.) and KCO (21.3 g, 154 mmol, 3.00 equiv.) in DMF (104 mL) was heated to 60 °C for 2 h. Subsequently, EtOAc (300 mL) was added, and the organic phase was washed with brine (3 × 100 mL) and dried over NaSO. The solvent was removed under reduced pressure, and the crude product was purified by column chromatography (petroleum ether / EtOAc 1:1). The title compound was obtained as an off-white solid (16 g, 90%).

[0444] Part VI - Synthesis of 2-(2-fluoro-4-((6-methoxyquinazolin-4-yl)oxy)phenyl)acetic acid [ka] A solution of lithium hydroxide monohydrate (2.75 g, 65.4 mmol, 1.40 equiv) in water (16 mL) was added to a solution of methyl 2-(2-fluoro-4-((6-methoxyquinazolin-4-yl)oxy)phenyl)acetate (16.0 g, 46.7 mmol, 1.00 equiv) in THF (160 mL), and the mixture was stirred at room temperature for 6 hours. The precipitated product was filtered off, washed with water (50 mL), and dried under reduced pressure. The compound was obtained as an off-white solid (12.3 g), which was used in the next reaction without further purification.

[0445] Part VII - Synthesis of 2-(2-fluoro-4-((6-methoxyquinazolin-4-yl)oxy)phenyl)-N-(4-(1-(trifluoromethyl)cyclopropyl)pyridin-2-yl)acetamide (34) [ka] Propylphosphonic anhydride (260 mg, 0.816 mmol, 1.50 equiv.) was added to a solution of 2-(2-fluoro-4-((6-methoxyquinazolin-4-yl)oxy)phenyl)acetic acid (179 mg, 0.544 mmol, 1.00 equiv.), 4-(1-(trifluoromethyl)cyclopropyl)pyridin-2-amine (110 mg, 0.544 mmol, 1.00 equiv.), and DIPEA (352 mg, 2.72 mmol, 5.00 equiv.) in DMF (1.1 mL) at 0 °C. The mixture was then stirred overnight at room temperature. The crude product was purified by reverse-phase flash chromatography (column: C18 silica gel; mobile phase A: water (0.1% NaHCO), mobile phase B: ACN, gradient: 35–65% B in 17 min; wavelength: 210 nm). The title compound was obtained as a white solid (7.5 mg, 2.5%). LCMS (ESI) C 26 H 21 F4N4O3(M+H) + Calculated value: 513.2, measured value: 513.0. 1 H NMR(300MHz,DMSO-d6)δ 10.96(s,1H),8.64(s,1H),8.36(d,J=5.2Hz,1H),8.24(s,1H),7.96(d,J=9 .1Hz,1H),7.72-7.61(m,2H),7.50(d,J=8.7Hz,1H),7.35(d,J=10.8Hz,1H) ,7.20(d,J=8.7Hz,2H),3.98(s,3H),3.89(s,2H),1.24(s,2H),1.20(s,2H).

[0446] Example 21 – Preparation of Amino Heteroaryl Compounds The compounds in the following table were prepared according to the experimental procedures described in Examples 19 and 20 and in the detailed description.

[0447] [Table 141]

[0448] [Table 142]

[0449] [Table 143]

[0450] [Table 144]

[0451] [Table 145]

[0452] Example 22 - Synthesis of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(2-fluoro-4-((6-(2-hydroxyethoxy)quinazolin-4-yl)oxy)phenyl)acetamide (Compound 16); Prepared according to General Scheme 16 [ka] Part I - Synthesis of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(2-fluoro-4-((6-methoxyquinazolin-4-yl)oxy)phenyl)acetamide [ka] Copper(I) iodide (0.69 g, 3.60 mmol, 1.00 equiv.) was added to a solution of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(2-fluoro-4-hydroxyphenyl)acetamide (1.05 g, 3.60 mmol, 1.00 equiv., can be synthesized as described in Part II of Example 9), CsCO (2.34 g, 7.19 mmol, 2.00 equiv.), N,N-dimethylglycine (0.56 g, 5.40 mmol, 1.50 equiv.), and 4-chloro-6-methoxyquinazoline (commercially available, 0.7 g, 3.60 mmol, 1.00 equiv.) in 1,4-dioxane (14 mL) under an inert atmosphere of nitrogen. The reaction mixture was heated to 100 °C for 3 h. Subsequently, the reaction mixture was filtered, and EtOAc (30 mL) was added to the solution. The organic phase was washed with water (2 x 20 mL) and dried over Na2SO4. The solvent was removed under reduced pressure and the crude product was purified by column chromatography (petroleum ether / EtOAc 4:1). The title compound was obtained as a brown solid (1.2 g, 74% yield).

[0453] Part II - Synthesis of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(2-fluoro-4-((6-hydroxyquinazolin-4-yl)oxy)phenyl)acetamide [ka] A solution of boron tribromide (1 M, 13.3 mL, 13.3 mmol, 12.0 equiv) was slowly added to a solution of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(2-fluoro-4-((6-methoxyquinazolin-4-yl)oxy)phenyl)acetamide (500.0 mg, 1.11 mmol, 1.00 equiv) in chloroform (10 mL) at 0 °C. The reaction mixture was then stirred overnight at room temperature. The solution was slowly poured into a saturated aqueous solution of NaHCO3 (10 mL), and the product was extracted with EtOAc (20 mL). The combined The organic phase was washed with water (2 x 10 mL) and dried over Na2SO4. The solvent was removed under reduced pressure to give the title compound as a brown solid (190 mg), which was used in the next reaction without further purification.

[0454] Part III - Synthesis of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(4-((6-(2-((tert-butyldimethylsilyl)oxy)ethoxy)quinazolin-4-yl)oxy)-2-fluorophenyl)acetamide [ka] (2-Bromoethoxy)(tert-butyl)dimethylsilane (127.7 mg, 0.534 mmol, 1.50 equiv) and K2CO3 (73.8 mg, 0.534 mmol, 1.50 equiv) were added to a solution of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(2-fluoro-4-((6-hydroxyquinazolin-4-yl)oxy)phenyl)acetamide (155.0 mg, 0.356 mmol, 1.00 equiv) in ACN (4.5 mL), and the mixture was heated to 80 °C for 2 h. Subsequently, the reaction mixture was diluted with EtOAc (10 mL), washed with water (2 × 5 mL), and dried over Na2SO4. The solvent was removed under reduced pressure. The title compound was obtained as a yellow solid (270 mg), which was used in the next reaction without further purification.

[0455] Part IV - Synthesis of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(2-fluoro-4-((6-(2-hydroxyethoxy)quinazolin-4-yl)oxy)phenyl)acetamide (Compound 16) [ka] Ammonium fluoride (389.8 mg, 10.5 mmol, 25.0 equiv) was added to a solution of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(4-((6-(2-((tert-butyldimethylsilyl)oxy)ethoxy)quinazolin-4-yl)oxy)-2-fluorophenyl)acetamide (250.0 mg, 0.421 mmol, 1.00 equiv) in MeOH (2.5 mL) and the mixture was heated to 50° C. for 2 h. The solution was then filtered and the crude product was purified by preparative HPLC (column: Xselect CSH C18 OBD, 30 x 150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 27-31% B in 13 min, wavelength: 220 nm, RT: 11 min). The title compound was obtained as an off-white solid (25 mg, 14% over two steps). LCMS (ESI) C 25 H 27 FN5O4(M+H) + Calculated value: 480.2, measured value: 480.0. 1 H NMR(400MHz,DMSO-d6)δ 10.25(s,1H),8.63(s,1H),7.97-7 .95(m,2H),7.70(dd,J=9.2,2.8Hz,1H),7.63(d,J=2.9Hz,1H),7.55-7.44(m,2H),7.33(dd,J=10.5,2.3Hz,1H),7.1 9(dd,J=8.3,2.4Hz,1H),5.01-4.93(m,1H),4.22(t,J=4.8Hz,2H),3.81(q,J=5.1Hz,2H),3.70(s,2H),1.49(s,9H).

[0456] Example 23 - Synthesis of 2-(4-((6-(((1r,4r)-4-aminocyclohexyl)oxy)quinolin-4-yl)oxy)-3-methylphenyl)-N-(1-(tert-butyl)-1H-pyrazol-4-yl)acetamide (Compound 122); prepared according to General Scheme 15 [ka] Part I – Synthesis of 4-chloroquinolin-6-ol [ka] A solution of boron tribromide in DCM (1 M, 233 mL, 233 mmol, 3.00 equiv.) was added to a solution of 4-chloro-6-methoxyquinoline (commercially available, 15.0 g, 77.5 mmol, 1.00 equiv.) in DCM (150 mL) at 0 °C over 15 min. The reaction mixture was then stirred at room temperature overnight. The mixture was slowly poured into a saturated aqueous solution of NaHCO (200 mL), and the product was extracted with EtOAc (200 mL). The organic phase was washed with water (2 × 100 mL), dried over NaSO, and the solvent was removed under reduced pressure. The title compound was obtained as an off-white solid (12.4 g), which was used in the next reaction without further purification.

[0457] Part II - Synthesis of tert-butyl ((1r,4r)-4-((4-chloroquinolin-6-yl)oxy)cyclohexyl)carbamate [ka] A solution of DEAD (0.97 g, 5.57 mmol, 2.00 equiv.) in THF (5 mL) was added to a solution of 4-chloroquinolin-6-ol (500 mg, 2.79 mmol, 1.00 equiv.), tert-butyl ((1s,4s)-4-hydroxycyclohexyl)carbamate (1.80 g, 8.34 mmol, 3.00 equiv., commercially available), and triphenylphosphine (3.65 g, 13.9 mmol, 5.00 equiv.) in THF (5 mL) at 0 °C. The mixture was stirred at room temperature for 12 h. EtOAc (40 mL) was added, and the mixture was washed with water (3 × 20 mL) and dried over NaSO. The solvent was removed under reduced pressure, and the product was purified by reverse-phase flash chromatography (column: C18 silica gel; mobile phase A: water (0.1% NHHCO), mobile phase B: ACN, gradient: 40–90% B in 20 min; wavelength: 210 nm). The title compound was obtained as a white solid (570 mg, 73%).

[0458] Part III - Synthesis of tert-butyl ((1r,4r)-4-((4-(4-(2-((1-(tert-butyl)-1H-pyrazol-4-yl)amino)-2-oxoethyl)-2-methylphenoxy)quinolin-6-yl)oxy)cyclohexyl)carbamate [ka] A solution of tert-butyl ((1r,4r)-4-((4-chloroquinolin-6-yl)oxy)cyclohexyl)carbamate (500 mg, 1.33 mmol, 1.00 equiv.), N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(4-hydroxy-3-methylphenyl)acetamide (381 mg, 1.33 mmol, 1.00 equiv., which can be synthesized as shown in Part III of Example 30), and DMAP (162 mg, 1.33 mmol, 1.00 equiv.) in chlorobenzene (5 mL) was heated to 130 °C for 20 h. The solvent was removed under reduced pressure, and the crude product was purified by reverse-phase flash chromatography (column: C18 silica gel; mobile phase A: water (0.1% NH4HCO3), mobile phase B: ACN, gradient: 40–80% B in 30 min; wavelength: 210 nm). The title compound was obtained as a white solid (400 mg, 50%).

[0459] Part IV - Synthesis of 2-(4-((6-(((1r,4r)-4-aminocyclohexyl)oxy)quinolin-4-yl)oxy)-3-methylphenyl)-N-(1-(tert-butyl)-1H-pyrazol-4-yl)acetamide (Compound 122) [ka] A solution of HCl in 1,4-dioxane (1 mL) was added to a solution of tert-butyl ((1r,4r)-4-((4-(4-(2-((1-(tert-butyl)-1H-pyrazol-4-yl)amino)-2-oxoethyl)-2-methylphenoxy)quinolin-6-yl)oxy)cyclohexyl)carbamate (200 mg, 0.319 mmol, 1.00 equiv) in 1,4-dioxane (1 mL), and the mixture was stirred at room temperature for 30 min. The reaction was quenched by the addition of saturated aqueous NaHCO3 (5 mL), and the product was extracted with EtOAc. The resulting mixture was extracted with Ac (3 x 10 mL). The combined organic phases were dried over Na2SO4 and the solvent was removed under reduced pressure. The title compound was obtained as a white solid (75 mg, 44%). LCMS (ESI) C 31 H 38 N5O3(M+H) + Calculated value: 528.3, measured value: 528.2. 1 H NMR(400MHz,DMSO-d6)δ10.24(s,1H),8.49(d,J=5.1Hz,1H),7.97-7.91(m,2H),7.60(d,J=2.8Hz,1H),7 .50-7.44(m,2H),7.36(d,J=2.2Hz,1H),7.28(dd,J=8.2,2.2Hz,1H),7.15(d,J=8.2Hz,1H),6.40(d,J=5 .1Hz,1H),4.50(td,J=10.2,4.9Hz,1H),3.60(s,2H),2.76(ddd,J=10.5,6.6,3.9Hz,1H),2.14-2.10(m, 5H),1.92-1.80(m,2H),1.53(td,J=7.2,3.6Hz,1H),1.49(s,9H),1.47-1.42(m,1H),1.36-1.21(m,2H).

[0460] Example 24 - Synthesis of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(2-fluoro-3-methyl-4-((6-((1-methylpiperidin-4-yl)oxy)quinolin-4-yl)oxy)phenyl)acetamide (Compound 103); prepared according to general scheme 15 [ka] Part I - Synthesis of 4-chloro-6-((1-methylpiperidin-4-yl)oxy)quinoline [ka] Di-tert-butyl azodicarboxylate (1.28 g, 5.57 mmol, 2.00 equiv.) was added to a solution of 4-chloroquinolin-6-ol (500 mg, 2.78 mmol, 1.00 equiv.), 1-methylpiperidin-4-ol (321 mg, 2.78 mmol, 1.00 equiv.), and triphenylphosphine (1.46 g, 5.57 mmol, 2.00 equiv.) in THF (10 mL) at 0 °C. The mixture was then stirred overnight at room temperature. Water was added, and the product was extracted with EtOAc (3 × 10 mL). The combined organic phases were washed with brine, dried over Na SO , and the solvent was removed under reduced pressure. The crude product was purified by column chromatography (DCM / MeOH 10:1). The title compound was obtained as a yellow liquid (480 mg, 62%).

[0461] Part II—Synthesis of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(2-fluoro-3-methyl-4-((6-((1-methylpiperidin-4-yl)oxy)quinolin-4-yl)oxy)phenyl)acetamide (Compound 103) [ka] A solution of 4-chloro-6-((1-methylpiperidin-4-yl)oxy)quinoline (300 mg, 1.08 mmol, 1.00 equiv.), N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(2-fluoro-4-hydroxy-3-methylphenyl)acetamide (330 mg, 1.08 mmol, 1.00 equiv.), CsCO (706 mg, 2.17 mmol, 2.00 equiv.), CuI (82.6 mg, 0.434 mmol, 0.40 equiv.), and N,N-dimethylglycine (67.1 mg, 0.650 mmol, 0.60 equiv.) in 1,4-dioxane (3 mL) was heated at 100 °C overnight under an inert atmosphere of nitrogen. Subsequently, water (10 mL) was added, and the product was extracted with EtOAc (3 × 10 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 reverse-phase flash chromatography (column: C18 silica gel; mobile phase A: water, mobile phase B: ACN, gradient: 35-55% B in 40 min; wavelength: 210 nm). The title compound was obtained as a white solid (17.0 mg, 2.8%). LCMS (ESI) C 31 H 37 FN5O3(M+H) + Calculated value: 546.3, measured value: 546.2. 1 H NMR(300MHz,DMSO-d6)δ 10.23(s,1H),8.54(d,J=5.0Hz,1H),8.27(s,1H),8.00-7.91(m,2H),7.60(d,J=2.8 Hz,1H),7.50(dd,J=9.1,2.7Hz,1H),7.46(s,1H),7.34(t,J=8.5Hz,1H),7.05(d,J=8 .3Hz,1H),6.49(d,J=5.2Hz,1H),4.66-4.57(m,1H),3.70(s,2H),2.68-2.59(m,2H) ,2.29-2.24(m,2H),2.20(s,3H),2.02-1.97(m,2H),1.81-1.70(m,5H),1.49(s,9H).

[0462] Example 25 – Preparation of additional 6-alkoxy substituted quinoline and quinazoline compounds The compounds in the following table were prepared according to the experimental procedures described in Examples 22, 23 and 24 and in the detailed description.

[0463] [Table 146]

[0464] [Table 147]

[0465] [Table 148]

[0466] [Table 149]

[0467] [Table 150]

[0468] [Table 151]

[0469] [Table 152]

[0470] [Table 153]

[0471] [Table 154]

[0472] [Table 155]

[0473] Table 156

[0474] Table 157

[0475] Table 158

[0476] Table 159

[0477] Table 160

[0478] Table 161

[0479] Table 162

[0480] Table 163

[0481] Table 164

[0482] Table 165

[0483] [Table 166]

[0484] [Table 167]

[0485] [Table 168]

[0486] [Table 169]

[0487] [Table 170]

[0488] [Table 171]

[0489] Example 26 - Synthesis of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(2-fluoro-4-((6-morpholinoquinazolin-4-yl)oxy)phenyl)acetamide (Compound 14); prepared according to general scheme 17 [ka] Part I - Synthesis of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(2-fluoro-4-((6-iodoquinazolin-4-yl)oxy)phenyl)acetamide [ka] A solution of 4-chloro-6-iodoquinazoline (commercially available, 10.0 g, 34.4 mmol, 1.00 equiv.), N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(2-fluoro-4-hydroxyphenyl)acetamide (10.0 g, 34.4 mmol, 1.00 equiv., can be synthesized as described in Part II of Example 9), and KPO (21.92 g, 103 mmol, 3.00 equiv.) in 1,4-dioxane (200 mL) was heated to 60° C. for 3 h. Water (100 mL) was then added, and the product was purified to E. Extraction with tOAc (3 x 30 mL) was performed. The combined organic phases were washed with brine (50 mL), dried over Na2SO4, and the solvent was removed under reduced pressure. The title compound was obtained as a yellow solid, which was used in the next reaction without further purification.

[0490] Part II - Synthesis of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(2-fluoro-4-((6-morpholinoquinazolin-4-yl)oxy)phenyl)acetamide (Compound 14) [ka] RuPhos Pd G3 (30.7 mg, 0.037 mmol, 0.10 equiv.) was added to a solution of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(2-fluoro-4-((6-iodoquinazolin-4-yl)oxy)phenyl)acetamide (200 mg, 0.367 mmol, 1.00 equiv.), CsCO3 (239.7 mg, 0.734 mmol, 2.00 equiv.), morpholine (63.9 mg, 0.734 mmol, 2.00 equiv.), and RuPhos (17.1 mg, 0.037 mmol, 0.10 equiv.) in 1,4-dioxane (4 mL) under an inert atmosphere of nitrogen, and the mixture was heated to 90 °C for 16 h. Subsequently, water (100 mL) was added, and the product was extracted with EtOAc (3 × 30 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 reverse-phase flash chromatography (column: C18 silica gel; mobile phase A: water (1% formic acid), mobile phase B: ACN, gradient: 10-40% B in 30 min; wavelength: 214 nm). The title compound was obtained as an off-white solid (75.1 mg, 41%). LCMS (ESI) C 27 H 30 FN6O3(M+H) + Calculated value: 505.2, measured value: 505.3. 1 H NMR(300MHz,DMSO-d6)δ 8.47(s,1H),8.01(s,1H),7.86(d,J=2.1Hz,2H),7.57(s,1H),7.53(s,1H),7.49(t,J=8.4Hz,1 H),7.18-7.12(m,2H),3.89(t,J=4.8Hz,4H),3.77(s,2H),3.36(t,J=4.9Hz,4H),1.56(s,9H).

[0491] Example 27 - Synthesis of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(2-fluoro-4-((6-(methylsulfonamido)quinolin-4-yl)oxy)phenyl)acetamide (Compound 68); prepared according to General Scheme 17 [ka] Methanesulfonamide (68.8 mg, 0.724 mmol, 1.20 equiv.), triflate Sodium fluoroacetate (98.4 mg, 0.724 mmol, 1.20 equiv.), DBU (110.2 mg, 0.724 mmol, 1.20 equiv.), and [Pd(tBuBrettPhos)(allyl)]OTf (23.5 mg, 0.030 mmol, 0.05 equiv.) were added to a solution of -(4-((6-bromoquinolin-4-yl)oxy)-2-fluorophenyl)-N-(1-(tert-butyl)-1H-pyrazol-4-yl)acetamide (300 mg, 0.603 mmol, 1.00 equiv., which can be synthesized according to Part I of Example 32) in 2-methyltetrahydrofuran (3 mL) under an inert atmosphere of nitrogen. The reaction mixture was then heated to 60° C. overnight. The solvent was removed under reduced pressure and the crude product was purified by reverse-phase flash chromatography (column: C18 silica gel; mobile phase A: water, mobile phase B: ACN, gradient: 20-50% B in 30 min; wavelength: 210 nm). The title compound was obtained as a white solid (27.9 mg, 8.9%). LCMS (ESI) C 25 H 27 FN5O4S(M+H) + Calculated value: 512.2, measured value: 512.1. 1 H NMR(300MHz,DMSO-d6)δ 10.22(s,2H),8.64(d,J=5.1Hz,1H),8.04-8.01(m,2H),7.94(s,1H),7.70(d,J=9.5Hz,1H),7.52(t,J=8.5Hz,1H),7.4 5(s,1H),7.28(d,J=10.5Hz,1H),7.12(d,J=8.4Hz,1H),6.68(d,J=5.2Hz,1H),3.70(s,2H),3.07(s,3H),1.49(s,9H).

[0492] Example 28 – Preparation of additional 6-nitrogen substituted quinoline and quinazoline compounds The compounds in the following table were prepared according to the experimental procedures described in Examples 26 and 27 and in the detailed description.

[0493] [Table 172]

[0494] Table 173

[0495] Table 174

[0496] Table 175

[0497] Table 176

[0498] Table 177

[0499] Table 178

[0500] Table 179

[0501] Table 180

[0502] Table 181

[0503] Table 182

[0504] [Table 183]

[0505] [Table 184]

[0506] Example 29 - Synthesis of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(2-fluoro-4-((6-(methylsulfonyl)quinolin-4-yl)oxy)phenyl)acetamide (Compound 38); prepared according to general scheme 11 [ka] CsCO (671.0 mg, 2.06 mmol, 2.00 equiv.), 4-chloro-6-(methylsulfonyl)quinoline (221 mg, 1.03 mmol, 1.00 equiv., which can be synthesized as described in Part II of Example 30), copper(I) iodide (78.5 mg, 0.412 mmol, 0.40 equiv.), and N,N-dimethylglycine (63.7 mg, 0.618 mmol, 0.60 equiv.) were added to a solution of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(2-fluoro-4-hydroxyphenyl)acetamide (300 mg, 1.03 mmol, 1.00 equiv., which can be synthesized according to the synthesis described in Part II of Example 9) in 1,4-dioxane (5 mL) under an inert atmosphere of nitrogen. The reaction mixture was then heated to 100° C. overnight. The solvent was removed under reduced pressure and the crude product was purified by reverse-phase flash chromatography (column: C18 silica gel; mobile phase A: water, mobile phase B: ACN, gradient: 10-50% B in 50 min; wavelength: 210 nm). The title compound was obtained as an off-white solid (133.4 mg, 25%). LCMS (ESI) C25H 26 FN4O4S(M+H) + Calculated value: 497.2, measured value: 497.1. 1H NMR(300MHz,DMSO-d6)δ10.23(s,1H),8.91(d,J=5.2Hz,1H),8.85(t,J=1.4Hz,1H),8.29(s,1H),8.28(s,1H),7.94(s,1H),7.56(t,J=8.5Hz,1H) ,7.45(d,J=0.7Hz,1H),7.37(dd,J=10.5,2.4Hz,1H),7.21(dd,J=8.5,2.4Hz,1H),6.83(d,J=5.2Hz,1H),3.72(s,2H),3.38(s,3H),1.49(s,9H).

[0507] Example 30 - Synthesis of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(3-methyl-4-((6-(methylsulfonyl)quinolin-4-yl)oxy)phenyl)acetamide (Compound 86); prepared according to general scheme 11 [ka] Part I - Synthesis of 4-chloro-6-(methylthio)quinoline [ka] A 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.), Pd(dba) (4.72 g, 5.15 mmol, 0.025 equiv.), Xantphos (5.97 g, 10.3 mmol, 0.05 equiv.), and triethylamine (143 mmol, 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 the insoluble material was filtered off. The organic phase was then washed with water and brine, dried over NaSO, 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, then the silica gel was filtered off and washed with EtOAc / hexane (1:1). The solvent was removed under reduced pressure to give the desired product as a red solid (43.5 g), which was used in the next reaction without further purification.

[0508] Part II - Synthesis of 4-chloro-6-(methylsulfonyl)quinoline [ka] Oxone (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 K2CO3 and extracted with EtOAc. The combined organic phase was washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure. The resulting material was treated with DCM (200 mL) and hexane (400 mL) to remove impurities. The product was then filtered off, washed with a small amount of EtOAc (approximately 40–50 mL) and hexane, and dried under reduced pressure. The desired product was obtained as a slightly yellowish solid (34.4 g, 69% yield), which was used in the next reaction without further purification.

[0509] Part III - Synthesis of 2-(4-hydroxy-3-methylphenyl)acetic acid [ka] A 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 desired product was obtained as a white solid (26.3 g, quantitative yield), which was It was used in the next reaction without further purification.

[0510] Part IV - Synthesis of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(4-hydroxy-3-methylphenyl)acetamide [ka] 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 aqueous NaOH. The pH was then 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 desired product was obtained as a white solid (27.1 g, 60%), which was used in the next reaction without further purification.

[0511] Part V - Synthesis of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(3-methyl-4-((6-(methylsulfonyl)quinolin-4-yl)oxy)phenyl)acetamide (Compound 86) [ka] A solution of 4-chloro-6-methylsulfonylquinoline (22.8 g, 94.3 mmol, 1.00 equiv.), N-(1-tert-butylpyrazol-4-yl)-2-(4-hydroxy-3-methylphenyl)acetamide (27.1 g, 94.3 mmol, 1.00 equiv.), DMAP (1.15 g, 9.43 mmol, 0.10 equiv.), and KCO (19.5 g, 141 mmol, 1.50 equiv.) in DMF (90 mL) was heated to 120 °C for 3.5 h. Additional 4-chloro-6-methylsulfonylquinoline (2.28 g, 9.43 mmol, 0.10 equiv.) and KCO (1.95 g, 14.1 mmol, 0.15 equiv.) were added, and heating was continued for an additional 1.5 h. Water and EtOAc were added, and the organic phase was separated. The organic phase was washed with water, and the product was extracted with aqueous HCl (pH 1). The aqueous phase was washed with EtOAc, and the pH was adjusted to 5-7. The product was extracted with EtOAc, and the organic phase was washed with water, brine, dried over Na2SO4, and the solvent was removed under reduced pressure. The crude product was dissolved in DCM, and the organic solution was washed with aqueous NaOH (pH 11-12) to remove any remaining phenol starting material impurities. The organic phase was washed with brine, dried over Na2SO4, and the solvent was removed under reduced pressure. The residue was purified via column chromatography (DCM / MeOH 95:5). The desired product was obtained as a slightly yellowish solid (17.3 g, 37% yield). LCMS (ESI) C 26 H 29 N4O4S(M+H) + Calculated value: 493.2, measured value: 493.1. 1 H NMR (400 MHz, DMSO- d6)δ 10.20(s,1H),8.91(dd,J=1.9,0.9Hz,1H),8.84(d,J=5.3Hz,1H),8.29-8.27(m,2H),7.95(s,1H),7.46(s,1H),7.39(d,J=2.1Hz,1 H),7.32(dd,J=8.3,2.2Hz,1H),7.23(d,J=8.3Hz,1H),6.55(d,J=5.2Hz,1H),3.62(s,2H),3.39(s,3H),2.14(s,3H),1.49(s,9H).

[0512] Example 31 - Synthesis of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(3-methyl-4-((6-((1-methylazetidin-3-yl)sulfonyl)quinolin-4-yl)oxy)phenyl)acetamide (Compound 149); prepared according to General Scheme 11 [ka] Part I - Synthesis of tert-butyl 3-((4-(4-(2-((1-(tert-butyl)-1H-pyrazol-4-yl)amino)-2-oxoethyl)-2-methylphenoxy)quinolin-6-yl)thio)azetidine-1-carboxylate [ka] A solution of 2-(4-((6-bromoquinolin-4-yl)oxy)-3-methylphenyl)-N-(1-(tert-butyl)-1H-pyrazol-4-yl)acetamide (1.00 g, 2.03 mmol, 1.00 equiv.), tert-butyl 3-mercaptoazetidine-1-carboxylate (767 mg, 4.05 mmol, 2.00 equiv., can be prepared according to the synthesis described in Part II of Example 43), triethylamine (1.03 g, 10.1 mmol, 5.00 equiv.), Pd(dba) (371 mg, 0.405 mmol, 0.20 equiv.), and Xantphos (234.5 mg, 0.405 mmol, 0.2 equiv.) in 1,4-dioxane (10 mL) was heated to 80° C. for 1 hour under an inert atmosphere of nitrogen. The solvent was removed under reduced pressure and the crude product was purified by column chromatography (petroleum ether / EtOAc 1:1) to give the title compound as a yellow solid (770 mg, 63%).

[0513] Part II - Synthesis of 2-(4-((6-(azetidin-3-ylthio)quinolin-4-yl)oxy)-3-methylphenyl)-N-(1-(tert-butyl)-1H-pyrazol-4-yl)acetamide [ka] A solution of HCl in 1,4-dioxane (4 M, 7 mL) was added to a solution of tert-butyl 3-((4-(4-(2-((1-(tert-butyl)-1H-pyrazol-4-yl)amino)-2-oxoethyl)-2-methylphenoxy)quinolin-6-yl)thio)azetidine-1-carboxylate (700 mg, 1.16 mmol, 1.00 equiv) in DCM (7 mL), and the mixture was stirred at room temperature for 30 min. Subsequently, the solvent was removed under reduced pressure. The title compound was obtained as a yellow solid (560 mg, 96%), which was used in the next reaction without further purification.

[0514] Part III - Synthesis of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(3-methyl-4-((6-((1-methylazetidin-3-yl)thio)quinolin-4-yl)oxy)phenyl)acetamide [ka] A solution of 2-(4-((6-(azetidin-3-ylthio)quinolin-4-yl)oxy)-3-methylphenyl)-N-(1-(tert-butyl)-1H-pyrazol-4-yl)acetamide (560 mg, 1.12 mmol, 1.00 equiv.), sodium acetate (458 mg, 5.58 mmol, 5.00 equiv.), formaldehyde (35% in water, 0.08 mL, 2.23 mmol, 2.00 equiv.), and palladium on carbon (119 mg, 20 wt.%) in MeOH (12 mL) was stirred under an atmosphere of hydrogen gas at room temperature for 60 hours. The heterogeneous catalyst was then filtered off and washed with MeOH (4 × 10 mL). The solvent was removed under reduced pressure, and the crude product was purified by column chromatography (DCM / MeOH 10:1). The title compound was obtained as a yellow oil (330 mg, 57%).

[0515] Part IV—Synthesis of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(3-methyl-4-((6-((1-methylazetidin-3-yl)sulfonyl)quinolin-4-yl)oxy)phenyl)acetamide (Compound 149) [ka] A solution of oxone (1.91 g, 3.11 mmol, 5.00 equiv) in water (3.2 mL) was added to N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(3-methyl- A solution of 4-((6-((1-methylazetidin-3-yl)thio)quinolin-4-yl)oxy)phenyl)acetamide (320 mg, 0.621 mmol, 1.00 equiv) in MeOH (3.2 mL) was added, and the mixture was stirred at room temperature for 10 min. The insoluble product was filtered off and washed with MeOH (2 × 2 mL). The solvent was removed under reduced pressure, and the crude product was purified by reverse-phase flash chromatography (column: C18 silica gel; mobile phase A: water, mobile phase B: ACN, gradient: 20-60% B in 50 min; wavelength: 210 nm). The title compound was obtained as an off-white solid (77.6 mg, 23%). LCMS (ESI) C 29 H 34 N5O4S(M+H) + Calculated value: 548.2, measured value: 548.3. 1 H NMR(300MHz,DMSO-d6)δ 10.20(s,1H),8.92-8.80(m,2H),8.32-8.11(m,2H),7.95(s,1H),7.46(s,1H),7.40(s,1H),7.35-7.23(m,2H),6.58 (d,J=5.2Hz,1H),4.57(t,J=7.3Hz,1H),3.62(s,2H),3.58(d,J=7.9Hz,4H),2.31(s,3H),2.14(s,3H),1.49(s,9H).

[0516] Example 32 - Synthesis of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(2-fluoro-4-((6-(methylsulfinyl)quinolin-4-yl)oxy)phenyl)acetamide (Compound 45); Prepared according to General Scheme 19 [ka] Part I - Synthesis of 2-(4-((6-bromoquinolin-4-yl)oxy)-2-fluorophenyl)-N-(1-(tert-butyl)-1H-pyrazol-4-yl)acetamide [ka] N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(2-fluoro-4-hydroxyphenyl)acetamide (2.88 g, 9.90 mmol, 1.20 equiv., can be synthesized according to the synthesis described in Part II of Example 9), copper(I) iodide (22.0 mg, 0.115 mmol, 0.014 equiv.), CsCO (5.37 g, 16.5 mmol, 2.00 equiv.), and 2,2,6,6-tetramethyl-3,5-heptanedione (21.3 mg, 0.115 mmol, 0.014 equiv.) were added to a solution of 6-bromo-4-chloroquinoline (commercially available, 2.00 g, 8.25 mmol, 1.00 equiv.) in DMF (20 mL) under an inert atmosphere of nitrogen. The reaction mixture was then heated to 100° C. for 3 h. The reaction was quenched with water and the product was extracted with EtOAc (3 x 50 mL). The combined organic phases were washed with brine (3 x 10 mL), dried over MgSO4 and the solvent was removed under reduced pressure. The crude product was purified by column chromatography (petroleum ether / EtOAc 1:1). The title compound was obtained as a pale yellow solid (2.0 g, 46%).

[0517] Part II - Synthesis of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(2-fluoro-4-((6-(methylthio)quinolin-4-yl)oxy)phenyl)acetamide [ka] Sodium thiomethoxide (0.36 g, 5.13 mmol, 1.50 equiv.), Pd(dba) (0.63 g, 0.684 mmol, 0.20 equiv.), Xantphos (0.4 g, 0.684 mmol, 0.20 equiv.), and triethylamine (1.73 g, 17.1 mmol, 5.00 equiv.) were added to a solution of 2-(4-((6-bromoquinolin-4-yl)oxy)-2-fluorophenyl)-N-(1-(tert-butyl)-1H-pyrazol-4-yl)acetamide (1.7 g, 3.42 mmol, 1.00 equiv.) in 1,4-dioxane (17 mL) under an inert atmosphere of nitrogen. The reaction mixture was then heated to 80 °C for 3 h. The reaction was quenched with water, and the product was extracted with EtOAc (3 × 50 mL). The combined organic phases were washed with brine (10 mL), dried over MgSO4 and the solvent was removed under reduced pressure. The crude product was purified by column chromatography (petroleum ether / EtOAc 1:1). The title compound was obtained as a pale yellow solid (1.43 g, 86%).

[0518] Part III - Synthesis of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(2-fluoro-4-((6-(methylsulfinyl)quinolin-4-yl)oxy)phenyl)acetamide (Compound 45) [ka] A solution of NaIO4 (276.3 mg, 1.29 mmol, 2.00 equiv.) in water (3 mL) was added to a solution of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(2-fluoro-4-((6-(methylthio)quinolin-4-yl)oxy)phenyl)acetamide (300 mg, 0.646 mmol, 1.00 equiv.) in THF (3 mL) at room temperature. The reaction mixture was subsequently stirred at room temperature for 60 hours. The crude product was then purified by reverse-phase flash chromatography (column: C18 silica gel; mobile phase A: water, mobile phase B: ACN, gradient: 20-50% B in 30 min; wavelength: 210 nm). The title compound was obtained as a white solid (98.9 mg, 31%). LCMS (ESI) C 25 H 25 FN4NaO3S(M+Na)+ Calculated value: 503.2, measured value: 503.0. 1 H NMR(400MHz,DMSO-d6)δ10.23(s,1H),8.83(d,J=5.2Hz,1H),8.62(d,J=2.0Hz,1H),8.21(d,J=8.8Hz,1H),8.07(dd,J=8.9,2.0Hz,1H),7.95(s, 1H),7.55(t,J=8.5Hz,1H),7.46(s,1H),7.35(dd,J=10.5,2.4Hz,1H),7.19(dd,J=8.4,2.4Hz,1H),6.79(d,J=5.2Hz,1H),3.72(s,2H),2.88(s, 3H), 1.49(s,9H)

[0519] Example 33 - Synthesis of N-(1-cyclopentyl-1H-pyrazol-4-yl)-2-(3-methyl-4-((6-(methylsulfonyl)quinolin-4-yl)oxy)phenyl)acetamide (Compound 214); Prepared according to General Scheme 3 [ka] Part I - Synthesis of 1-cyclopentyl-4-nitro-1H-pyrazole [ka] DEAD (6.01 g, 34.5 mmol, 1.30 equiv.) was added to a solution of 4-nitro-1H-pyrazole (3.00 g, 26.5 mmol, 1.00 equiv.), triphenylphosphine (8.35 g, 31.8 mmol, 1.20 equiv.), and cyclopentanol (2.51 g, 29.2 mmol, 1.10 equiv.) in THF (60 mL) at 0 °C, and the mixture was stirred at this temperature for 2 h. Subsequently, a saturated aqueous solution of ammonium chloride (60 mL) was added, and the product was extracted with DCM (3 × 20 mL). The combined organic phases were dried over NaSO, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography (petroleum ether / EtOAc 100:1). The title compound was obtained as a yellow oil (3.6 g, 74%).

[0520] Part II – Synthesis of 1-cyclopentyl-1H-pyrazol-4-amine [ka] Palladium on carbon (30 mg, 10 wt%) was added to a solution of 1-cyclopentyl-4-nitro-1H-pyrazole (300 mg, 1.66 mmol, 1.0 equiv.) in isopropanol (6 mL), and the mixture was stirred overnight at room temperature under a hydrogen atmosphere. The heterogeneous catalyst was then filtered off, and the solvent was removed under reduced pressure. The crude product was used in the next reaction without further purification.

[0521] Part III - Synthesis of methyl 2-(3-methyl-4-((6-(methylsulfonyl)quinolin-4-yl)oxy)phenyl)acetate [ka] A solution of methyl 2-(4-hydroxy-3-methylphenyl)acetate (1.49 g, 8.28 mmol, 1.00 equiv.), 4-chloro-6-(methylsulfonyl)quinoline (2.0 g, 8.28 mmol, 1.00 equiv., which can be synthesized as described in Part II of Example 30), and CsCO (5.39 g, 16.6 mmol, 2.00 equiv.) in NMP (22 mL) was stirred at room temperature for 4 h. The mixture was then filtered, and the crude product was purified by reverse-phase flash chromatography (column: C18 silica gel; mobile phase A: water (0.1% NHHCO), mobile phase B: ACN, gradient: 35–55% B in 40 min; wavelength: 210 nm). The title compound was obtained as a white solid (1.5 g, 47%).

[0522] Part IV - Synthesis of 2-(3-methyl-4-((6-(methylsulfonyl)quinolin-4-yl)oxy)phenyl)acetic acid [ka] LiOH (0.15 g, 6.26 mmol, 2.00 equiv.) was added to a solution of methyl 2-(3-methyl-4-((6-(methylsulfonyl)quinolin-4-yl)oxy)phenyl)acetate (1.2 g, 3.11 mmol, 1.00 equiv.) in THF (12 mL) and water (12 mL) at 0° C., and the mixture was stirred at this temperature for 2 h. Subsequently, the pH of the solution was adjusted to 5 by adding hydrochloric acid (1 M), and the product was extracted with EtOAc (3×20 mL). The combined organic phases were washed with brine, dried over NaSO, and the solvent was removed under reduced pressure. The title compound was obtained as a white solid (1.1 g, 95%), which was used in the next reaction without further purification.

[0523] Part V - Synthesis of N-(1-cyclopentyl-1H-pyrazol-4-yl)-2-(3-methyl-4-((6-(methylsulfonyl)quinolin-4-yl)oxy)phenyl)acetamide (Compound 214) [ka] Propylphosphonic anhydride (257 mg, 0.807 mmol, 1.50 equiv.) was dissolved in 2-(3-methyl-4-((6-(methylsulfonyl)quinolin-4-yl)oxy)phenyl)acetic acid (200 mg, 0.538 mmol, 1.00 equiv.), 1-cyclopentyl-1 A solution of H-pyrazol-4-amine (111 mg, 0.807 mmol, 1.50 equiv.) and DIPEA (348 mg, 2.69 mmol, 5.00 equiv.) in DMF (4 mL) was added at 0 °C, and the mixture was stirred at this temperature for 1 h. The crude product was then purified by reverse-phase flash chromatography (column: C18 silica gel; mobile phase A: water (0.05% (NH4)2CO3), mobile phase B: ACN, gradient: 25-55% B in 30 min; wavelength: 210 nm). The title compound was obtained as a white solid (48.4 mg, 17%). LCMS (ESI) C 27 H 27 N4O4S(MH) - Calculated value: 503.2, measured value: 503.1. 1H NMR (400 MHz, DMSO-d6) δ 10.21(s,1H),8.90(s,1H),8.83(d,J=5.2Hz,1H),8.28-8.26(m,2H),7.90(s, 1H),7.43(s,1H),7.39(s,1H),7.31(d,J=8.1Hz,1H),7.23(d,J=8.2Hz,1H),6 .55(d,J=5.2Hz,1H),4.69-4.57(m,1H),3.61(s,2H),3.38(s,3H),2.14(s,3H) ),2.09-1.97(m,2H),1.93-1.82(m,2H),1.81-1.68(m,2H),1.67-1.54(m,2H).

[0524] Example 34 - Synthesis of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(4-((6-(cyclobutylsulfonyl)quinolin-4-yl)oxy)-3-methylphenyl)acetamide (Compound 280); prepared according to general scheme 12 [ka] Part I - Synthesis of S-(4-chloroquinolin-6-yl)ethanethioate [ka] A solution of 6-bromo-4-chloroquinoline (50.0 g, 206 mmol, 1.00 equiv., commercially available), potassium thioacetate (47.1 g, 412 mmol, 2.00 equiv.), DIPEA (213 g, 1.65 mol, 8.00 equiv.), Pd(dba) (5.93 g, 10.3 mmol, 0.05 equiv.), and XPhos (9.83 g, 20.6 mmol, 0.10 equiv.) in 1,4-dioxane (500 mL) was heated to 100 °C for 1 h under an inert atmosphere of nitrogen. Subsequently, EtOAc (300 mL) was added, and insoluble by-products were filtered off. The organic phase was washed with water (3 × 300 mL), dried over NaSO, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography (petroleum ether gradient to petroleum ether / EtOAc 9:1). The title compound was obtained as a white solid (11 g, 22%).

[0525] Part II - Synthesis of 4-chloro-6-(cyclobutylthio)quinoline [ka] Iodocyclobutane (768 mg, 4.21 mmol, 1.00 equiv.) was added to a solution of S-(4-chloroquinolin-6-yl)ethanethioate (1.00 g, 4.21 mmol, 1.00 equiv.) and K2CO3 (1.16 g, 8.42 mmol, 2.00 equiv.) in MeOH (10 mL), and the mixture was stirred at room temperature for 1 h. Subsequently, insoluble by-products were filtered off, and the solvent was removed under reduced pressure. The crude product was purified by preparative HPLC (column: XB-C18; 50 × 250 mm, 10 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 100 mL / min; gradient: 35–55% B in 30 min; wavelength: 210 nm). The title compound was obtained as a yellow solid (512 mg, 49%).

[0526] Part III - Synthesis of 4-chloro-6-(cyclobutylsulfonyl)quinoline [ka] mCPBA (311 mg, 3.60 mmol, 2.00 equiv.) was added to a solution of 4-chloro-6-(cyclobutylthio)quinoline (450 mg, 1.80 mmol, 1.00 equiv.) in DCM (9 mL), and the mixture was stirred at room temperature for 2 h. The crude product was then purified by preparative HPLC (column: XBridge Prep OBD C18; 30 × 150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 100 mL / min; gradient: 55–65% B in 20 min; wavelength: 220 nm). The title compound was obtained as a white solid (470 mg, 93%).

[0527] Part IV - Synthesis of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(4-((6-(cyclobutylsulfonyl)quinolin-4-yl)oxy)-3-methylphenyl)acetamide (Compound 280) [ka] 4-Chloro-6-(cyclobutylsulfonyl)quinoline (100 mg, 0.355 mmol, 1.00 equiv.), N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(4-hydroxy-3-methylphenyl)acetamide (102 mg, 0.355 mmol, 1.00 equiv.), CsCO (232 mg, 0.710 mmol, 2.00 equiv.), CuI (67.6 mg, 0.355 mmol, 1.00 equiv.), and N,N-dichloro-2-(4-hydroxy-3-methylphenyl)acetamide (102 mg, 0.355 mmol, 1.00 equiv.). A solution of methylglycine (54.9 mg, 0.532 mmol, 1.50 equiv) in 1,4-dioxane (5 mL) was heated to 100 °C overnight under an inert atmosphere of nitrogen. Subsequently, insoluble by-products were filtered off, and the crude product was purified by preparative HPLC (column: XB-C18; 50 × 250 mm, 10 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 100 mL / min; gradient: 55–75% B in 30 min; wavelength: 210 nm). The title compound was obtained as a yellow solid (35.7 mg, 19%). LCMS (ESI) C 29 H 33 N4O4S(M+H) + Calculated value: 533.2, measured value: 533.2. 1 H NMR(400MHz,DMSO-d6)δ 10.21(s,1H),8.87-8.82(m,2H),8.26(d,J=8.9Hz,1H),8.18(dd,J=8.8,2.1Hz, 1H),7.95(s,1H),7.46(s,1H),7.39(s,1H),7.32(d,J=8.2Hz,1H),7.25(d,J=8.2 Hz,1H),6.57(d,J=5.3Hz,1H),4.37-4.25(m,1H),3.62(s,2H),2.47-2.34(m,2H) ,2.16(ddd,J=7.1,4.7,2.2Hz,2H),2.13(s,3H),2.02-1.86(m,2H),1.49(s,9H).

[0528] Example 35 - Preparation of additional sulfone compounds The compounds in the following table were prepared according to the experimental procedures described in Examples 30-34 and the detailed description.

[0529] [Table 185]

[0530] [Table 186]

[0531] [Table 187]

[0532] [Table 188]

[0533] [Table 189]

[0534] [Table 190]

[0535] [Table 191]

[0536] [Table 192]

[0537] [Table 193]

[0538] [Table 194]

[0539] Table 195

[0540] Table 196

[0541] Table 197

[0542] Table 198

[0543] Table 199

[0544] Table 200

[0545] Table 201

[0546] Table 202

[0547] Table 203

[0548] Table 204

[0549] Table 205

[0550] Table 206

[0551] Table 207

[0552] Table 208

[0553] Table 209

[0554] Table 210

[0555] Table 211

[0556] Table 212

[0557] Table 213

[0558] Table 214

[0559] [Table 215]

[0560] [Table 216]

[0561] [Table 217]

[0562] [Table 218]

[0563] [Table 219]

[0564] Example 36 - Synthesis of 4-(4-(2-((1-(tert-butyl)-1H-pyrazol-4-yl)amino)-2-oxoethyl)-3-fluorophenoxy)-N,N-dimethylquinazoline-6-carboxamide (Compound 26); prepared according to General Scheme 10 [ka] Part I - Synthesis of methyl 4-(4-(2-((1-(tert-butyl)-1H-pyrazol-4-yl)amino)-2-oxoethyl)-3-fluorophenoxy)quinazoline-6-carboxylate [ka] A solution of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(2-fluoro-4-hydroxyphenyl)acetamide (400 mg, 1.37 mmol, 1.00 equiv., can be synthesized as described in Part II of Example 9), methyl 4-chloroquinazoline-6-carboxylate (306 mg, 1.37 mmol, 1.00 equiv., commercially available), and DMAP (252 mg, 2.06 mmol, 1.50 equiv.) in chlorobenzene (4 mL) was heated to 150° C. for 3 h. The solvent was then removed under reduced pressure, and the crude product was purified by column chromatography (DCM / MeOH 10:1). The title compound was obtained as a pale yellow solid (211 mg, 31%).

[0565] Part II - Synthesis of 4-(4-(2-((1-(tert-butyl)-1H-pyrazol-4-yl)amino)-2-oxoethyl)-3-fluorophenoxy)quinazoline-6-carboxylic acid [ka] A solution of lithium hydroxide (15.1 mg, 0.628 mmol, 2.00 equiv.) in water (0.3 mL) was added to a solution of 4-(4-(2-((1-(tert-butyl)-1H-pyrazol-4-yl)amino)-2-oxoethyl)-3-fluorophenoxy)quinazoline-6-carboxylate (150 mg, 0.314 mmol, 1.00 equiv.) in THF (3 mL), and the mixture was stirred at room temperature for 1 h. The crude product was subsequently purified by reverse-phase flash chromatography (column: C18 silica gel; mobile phase A: water, mobile phase B: ACN, gradient: 10–50% B in 40 min; wavelength: 210 nm). The title compound was obtained as a white solid (58 mg, 39%).

[0566] Part III - Synthesis of 4-(4-(2-((1-(tert-butyl)-1H-pyrazol-4-yl)amino)-2-oxoethyl)-3-fluorophenoxy)-N,N-dimethylquinazoline-6-carboxamide (Compound 26) [ka] Dimethylamine (35.0 mg, 0.776 mmol, 1.20 equiv.), HATU (295 mg, 0.776 mmol, 1.20 equiv.), and DIPEA (251 mg, 1.94 mmol, 3.00 equiv.) were added to a solution of 4-(4-(2-((1-(tert-butyl)-1H-pyrazol-4-yl)amino)-2-oxoethyl)-3-fluorophenoxy)quinazoline-6-carboxylic acid (300 mg, 0.647 mmol, 1.00 equiv.) in DMF (3 mL), and the reaction mixture was stirred at room temperature for 2 h. Subsequently, water (15 mL) was added, and the product was extracted with EtOAc (3 × 5 mL). The combined organic phases were washed with brine (6 × 5 mL), dried over NaSO, and the solvent was removed under reduced pressure. The crude product was purified by reverse-phase flash chromatography (column: C18 silica gel; mobile phase A: water (1% NH4HCO3), mobile phase B: ACN, gradient: 35-65% B in 30 min; wavelength: 210 nm). The title compound was obtained as an off-white solid (80.5 mg, 25%). LCMS (ESI) C 26 H 28 FN6O3(M+H) + Calculated value: 491.2, measured value: 491.3. 1 H NMR(400MHz,DMSO-d6)δ 10.25(s,1H),8.80(s,1H),8.36(t,J=1.3Hz,1H),8.08-8.04(m,2H),7.94(d,J=0.8Hz,1H),7.50(t,J=8.5Hz,1H),7.45(d,J =0.7Hz,1H),7.36(dd,J=10.5,2.3Hz,1H),7.21(dd,J=8.4,2.3Hz,1H),3.70(s,2H),3.06(s,3H),2.99(s,3H),1.49(s,9H).

[0567] Example 37 - 4-(4-(2-((1-(tert-butyl)-1H-pyrazol-4-yl)amino)-2-oxoethyl)-5-fluoro-2-methylphenoxy)-N Synthesis of -methylquinoline-6-carboxamide (compound 360); prepared according to general scheme 6 [ka] Part I - Synthesis of methyl 2-(2-fluoro-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate [ka] A solution of methyl 2-(4-bromo-2-fluoro-5-methylphenyl)acetate (26.0 g, 99.6 mmol, 1.00 equiv.), bis(pinacolato)diboron (50.6 g, 199 mmol, 2.00 equiv.), potassium acetate (29.3 g, 299 mmol, 3.00 equiv.), and Pd(dppf)Cl (3.64 g, 4.98 mmol, 0.05 equiv.) in 1,4-dioxane (208 mL) was heated at 130 °C overnight under an inert atmosphere of nitrogen. The reaction mixture was used in the next reaction without purification.

[0568] Part II - Synthesis of methyl 2-(2-fluoro-4-hydroxy-5-methylphenyl)acetate [ka] An aqueous solution of hydrogen peroxide (30%, 52 mL, 2.23 mol, 23.0 equiv.) was added dropwise to a solution of crude methyl 2-(2-fluoro-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate (99.6 mmol, 1.00 equiv.) in 1,4-dioxane (208 mL) at 0° C. The mixture was then stirred at room temperature for 1 h. The reaction was quenched by adding a saturated aqueous solution of sodium thiosulfate. EtOAc (500 mL) was added, and the organic phase was washed with water (2×150 mL) and dried over Na2SO4. The solvent was removed under reduced pressure, and the crude product was purified by column chromatography (petroleum ether / EtOAc 97:3). The title compound was obtained as a yellow oil (30 g).

[0569] Part III - Synthesis of 2-(2-fluoro-4-hydroxy-5-methylphenyl)acetic acid [ka] Lithium hydroxide (7.27 g, 303 mmol, 2.00 equiv.) dissolved in water (150 mL) The resulting solution was added to a solution of methyl 2-(2-fluoro-4-hydroxy-5-methylphenyl)acetate (30.0 g, 152 mmol, 1.00 equiv.) in THF (150 mL) at 0° C. Subsequently, the reaction mixture was stirred at room temperature for 1 h. The pH of the solution was adjusted to 2 by adding citric acid solution, and the product was extracted with EtOAc (500 mL). The organic phase was washed with water (2×200 mL), dried over NaSO, and the solvent was removed under reduced pressure. The title compound was obtained as a yellow solid (20 g), which was used in the next reaction without further purification.

[0570] Part IV - Synthesis of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(2-fluoro-4-hydroxy-5-methylphenyl)acetamide [ka] PyBOP (10.2 g, 19.5 mmol, 1.50 equiv.) was added to a solution of 2-(2-fluoro-4-hydroxy-5-methylphenyl)acetic acid (2.40 g, 13.0 mmol, 1.00 equiv.), 1-(tert-butyl)-1H-pyrazol-4-amine (2.00 g, 14.3 mmol, 1.10 equiv.), and DIPEA (8.42 g, 65.2 mmol, 5.00 equiv.) in DMF (25 mL) at 0 °C. The mixture was then stirred at room temperature for 1 h. EtOAc (200 mL) was added, and the organic phase was washed with water (3 × 50 mL). The solvent was removed under reduced pressure and the crude product was purified by reverse-phase flash chromatography (column: C18 silica gel; mobile phase A: water (0.1% NH4HCO3), mobile phase B: ACN, gradient: 30 to 70% B in 20 min; wavelength: 210 nm) to give the title compound as a white solid (1.94 g, 53% over four steps).

[0571] Part V - Synthesis of 4-chloro-N-methylquinoline-6-carboxamide [ka] Methyl 4-chloroquinoline-6-carboxylate (1.50 g, 6.77 mmol, 1.00 equiv.) was added to a solution of methylamine in EtOH (33 wt%, 30 mL), and the mixture was stirred at room temperature overnight. The crude product was purified by reverse-phase flash chromatography (column: C18 silica gel; mobile phase A: water (0.1% NH4HCO3), mobile phase B: ACN, gradient: 10 to 50% B in 20 min; wavelength: 210 nm). The title compound was obtained as a white solid (900 mg, 60%).

[0572] Part VI - Synthesis of 4-(4-(2-((1-(tert-butyl)-1H-pyrazol-4-yl)amino)-2-oxoethyl)-5-fluoro-2-methylphenoxy)-N-methylquinoline-6-carboxamide (Compound 360) [ka] A solution of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(2-fluoro-4-hydroxy-5-methylphenyl)acetamide (150 mg, 0.489 mmol, 1.00 equiv), 4-chloro-N-methylquinoline-6-carboxamide (108 mg, 0.489 mmol, 1.00 equiv), CsCO (319 mg, 0.978 mmol, 2.00 equiv), CuI (37.3 mg, 0.196 mmol, 0.40 equiv), and N,N-dimethylglycine (30.3 mg, 0.293 mmol, 0.60 equiv) in 1,4-dioxane (1.5 mL) was heated to 90 °C under an inert atmosphere of nitrogen for 6 h. The crude product was then purified by preparative HPLC (column: XSelect CSH Fluorophenyl; 30 x 150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; 13 min isocratic separation with 36% B; wavelength: 220 nm, RT 1:11 min). The title compound was obtained as a yellow solid (70 mg, 29%). LCMS (ESI) C 27 H 29 FN5O3(M+H) + Calculated value: 490.2, measured value: 490.1.1 H NMR(400MHz,DMSO-d6)δ 10.23(s,1H),8.89(d,J=2.0Hz,1H),8.83(d,J=4.9Hz,1H),8.76(s,1H),8.25(dd,J=8.8,2.0Hz,1H),8.10(d,J=8.8Hz,1H),7.95(s, 1H),7.48-7.43(m,2H),7.27(d,J=10.0Hz,1H),6.54(d,J=5.2Hz,1H),3.69(s,2H),2.87(d,J=4.5Hz,3H),2.11(s,3H),1.49(s,9H).

[0573] Example 38 - Preparation of additional amide compounds The compounds in the following table were prepared according to the experimental procedures described in Examples 36 and 37 and in the detailed description.

[0574] [Table 220]

[0575] [Table 221]

[0576] [Table 222]

[0577] [Table 223]

[0578] [Table 224]

[0579] [Table 225]

[0580] Table 226

[0581] Table 227

[0582] Table 228

[0583] Table 229

[0584] Table 230

[0585] Table 231

[0586] Table 232

[0587] Table 233

[0588] Table 234

[0589] Table 235

[0590] Table 236

[0591] Table 237

[0592] Table 238

[0593] Table 239

[0594] Table 240

[0595] Table 241

[0596] Table 242

[0597] Table 243

[0598] Table 244

[0599] Table 245

[0600] Table 246

[0601] Table 247

[0602] Table 248

[0603] Table 249

[0604] Table 250

[0605] Table 251

[0606] Table 252

[0607] Table 253

[0608] Table 254

[0609] Table 255

[0610] Example 39 - Synthesis of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(2-fluoro-4-((6-((methylsulfonyl)methyl)quinolin-4-yl)oxy)phenyl)acetamide (Compound 75); Prepared according to General Scheme 8 [ka] Part I - Synthesis of Methyl(4-nitrobenzyl)sulfane [ka] Sodium thiomethoxide (24.33 g, 347 mmol, 1.50 equiv.) was added to a solution of 1-(bromomethyl)-4-nitrobenzene (50.0 g, 231 mmol, 1.00 equiv.) in EtOH (500 mL), and the mixture was stirred at room temperature overnight. Subsequently, water was added, and the product was extracted with EtOAc. The organic phase was then washed with water, dried over MgSO4, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography (petroleum ether / EtOAc 100:1). The title compound was obtained as a pale yellow oil (29.1 g, 65%).

[0611] Part II - Synthesis of 4-((methylthio)methyl)aniline [ka] A solution of methyl(4-nitrobenzyl)sulfane (28.0 g, 153 mmol, 1.00 equiv.) and Pd / C (2.8 g, 10% w / w) in MeOH (280 mL) was heated to 30° C. overnight under an atmosphere of hydrogen. Subsequently, the solution was filtered and the residue was washed with MeOH. The solvent was removed under reduced pressure and the crude product was purified by column chromatography (petroleum ether / EtOAc 2:1). The title compound was obtained as a pale yellow oil (20 g, 77%). .

[0612] Part III - Synthesis of 2,2-dimethyl-5-(((4-((methylthio)methyl)phenyl)amino)methylene)-1,3-dioxane-4,6-dione [ka] A solution of 4-((methylthio)methyl)aniline (25.0 g, 163 mmol, 1.00 equiv.), triethyl orthoformate (29.0 g, 196 mmol, 1.20 equiv.), and Meldrum's acid (28.22 g, 196 mmol, 1.20 equiv.) in EtOH (250 mL) was heated to 80° C. for 2 h under an inert atmosphere of nitrogen. After cooling to room temperature, the precipitated product was filtered off, washed with EtOH, and dried under reduced pressure. The crude title compound (35 g) was used in the next reaction without further purification.

[0613] Part IV - Synthesis of 6-((methylthio)methyl)quinolin-4-ol [ka] A solution of 2,2-dimethyl-5-(((4-((methylthio)methyl)phenyl)amino)methylene)-1,3-dioxane-4,6-dione (37.0 g, 120 mmol, 1.00 equiv) in diphenyl ether (370 mL) was heated at 150° C. overnight under an inert atmosphere of nitrogen. Subsequently, water (100 mL) was added and the organic phase was separated. The aqueous phase was extracted with MTBE (3×100 mL) and the solvent of the combined organic phase was removed under reduced pressure. The crude title compound (1.6 g) was used in the next reaction without further purification.

[0614] Part V - Synthesis of 4-chloro-6-((methylthio)methyl)quinoline [ka] A solution of 6-((methylthio)methyl)quinolin-4-ol (1.5 g, 7.31 mmol, 1.00 equiv.) in phosphoryl chloride (15 mL) was heated to 100 °C for 2 h under an inert atmosphere of nitrogen. The solvent was then removed under reduced pressure, and the crude product was purified by reverse-phase flash chromatography (column: C18 silica gel; mobile phase A: water, mobile phase B: ACN, gradient: 10-50% B in 40 min; wavelength: 210 nm). The title compound was obtained as a pale yellow solid. (680 mg, 1.9% over three steps).

[0615] Part VI - Synthesis of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(2-fluoro-4-((6-((methylthio)methyl)quinolin-4-yl)oxy)phenyl)acetamide [ka] DMAP (491.5 mg, 4.02 mmol, 1.50 equiv.) and N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(2-fluoro-4-hydroxyphenyl)acetamide (859.5 mg, 2.95 mmol, 1.10 equiv., can be synthesized according to the synthesis described in Part II of Example 9) were added to a solution of 4-chloro-6-((methylthio)methyl)quinoline (600 mg, 2.68 mmol, 1.00 equiv.) in chlorobenzene (6 mL) under an inert atmosphere of nitrogen. The mixture was then heated to 150 °C for 1 h. The solvent was removed under reduced pressure, and the crude product was purified by reverse-phase flash chromatography (column: C18 silica gel; mobile phase A: water, mobile phase B: ACN, gradient: 10 to 50% B in 40 min; wavelength: 210 nm). The title compound was obtained as a white solid (610 mg, 45%).

[0616] Part VII - Synthesis of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(2-fluoro-4-((6-((methylsulfonyl)methyl)quinolin-4-yl)oxy)phenyl)acetamide (Compound 75) [ka] A solution of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(2-fluoro-4-((6-((methylthio)methyl)quinolin-4-yl)oxy)phenyl)acetamide (100 mg, 0.209 mmol, 1.00 equiv.) and oxone (105.4 mg, 0.627 mmol, 3.00 equiv.) in water / MeOH (1:1, 2 mL) was stirred at room temperature for 1 h. The crude product was then purified by reverse-phase flash chromatography (column: C18 silica gel; mobile phase A: water, mobile phase B: ACN, gradient: 10-50% B in 40 min; wavelength: 210 nm). The title compound was obtained as a white solid (60.7 mg, 57%). LCMS (ESI) C 26 H 27 FN4NaO4S(M+H) + Calculated value: 533.2, measured value: 533.2. 1 H NMR(300MHz,DMSO-d6)δ 10.23(s,1H),8.75(d,J=5.1Hz,1H),8.37(d,J=2.0Hz,1H),8.07(d,J=8.7Hz,1H),7.94(d,J=0.7Hz,1H),7.85(dd,J =8.7,2.0Hz,1H),7.53(t,J=8.5Hz,1H),7.45(d,J=0.7Hz,1H),7.32(dd,J=10.5,2.4Hz,1H),7.16(dd,J=8.5,2.4Hz ,1H),6.71(d,J=5.1Hz,1H),4.79(s,2H),3.70(s,2H),2.97(s,3H),1.49(s,9H).

[0617] Example 40 - Synthesis of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(2-fluoro-5-methyl-4-((6-(piperidin-4-ylmethyl)quinolin-4-yl)oxy)phenyl)acetamide (Compound 408); prepared according to General Scheme 22 [ka] Part I - Synthesis of tert-butyl 4-((4-chloroquinolin-6-yl)methyl)piperidine-1-carboxylate [ka] A solution of 6-bromo-4-chloroquinoline (1.00 g, 4.12 mmol, 1.00 equiv.), tert-butyl 4-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)piperidine-1-carboxylate (1.61 g, 4.95 mmol, 1.20 equiv.), Pd(dppf)Cl (0.30 g, 0.412 mmol, 0.10 equiv.), and KPO (1.75 g, 8.25 mmol, 2.00 equiv.) in 1,4-dioxane was heated at 90 °C overnight under an inert atmosphere of nitrogen. The solvent was removed under reduced pressure, and the crude product was purified by column chromatography (petroleum ether / EtOAc 5:1). The title compound was obtained as a yellow solid (1.3 g, 87%).

[0618] Part II - Synthesis of tert-butyl 4-((4-(4-(2-((1-(tert-butyl)-1H-pyrazol-4-yl)amino)-2-oxoethyl)-5-fluoro-2-methylphenoxy)quinolin-6-yl)methyl)piperidine-1-carboxylate [ka] A solution of tert-butyl 4-((4-chloroquinolin-6-yl)methyl)piperidine-1-carboxylate (355 mg, 0.983 mmol, 1.50 equiv.), N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(2-fluoro-4-hydroxy-5-methylphenyl)acetamide (200 mg, 0.655 mmol, 1.00 equiv., which can be synthesized according to Part IV of Example 37), and CsCO (640 mg, 1.97 mmol, 3.00 equiv.) in NMP (4 mL) was heated to 130 °C for 3 h. The crude product was then purified by reverse-phase flash chromatography (column: C18 silica gel; mobile phase A: water, mobile phase B: ACN, gradient: 10 to 50% B in 10 min; wavelength: 210 nm). The title compound was obtained as an off-white solid (103 mg, 24%).

[0619] Part III—Synthesis of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(2-fluoro-5-methyl-4-((6-(piperidin-4-ylmethyl)quinolin-4-yl)oxy)phenyl)acetamide (Compound 408) [ka] A solution of HCl in 1,4-dioxane (4 M, 2 mL) was added to a solution of tert-butyl 4-((4-(4-(2-((1-(tert-butyl)-1H-pyrazol-4-yl)amino)-2-oxoethyl)-5-fluoro-2-methylphenoxy)quinolin-6-yl)methyl)piperidine-1-carboxylate (200 mg, 0.318 mmol, 1.00 equiv.) in DCM (2 mL), and the mixture was stirred at room temperature for 30 min. Subsequently, the solvent was removed under reduced pressure. Water was added, and the pH of the solution was adjusted to 8 by adding saturated aqueous NaHCO3. The crude product was purified by reverse-phase flash chromatography (column: C18 silica gel; mobile phase A: water, mobile phase B: ACN, gradient: 10–50% B in 40 min; wavelength: 210 nm). The title compound was obtained as an off-white solid (102.2 mg, 60%). LCMS(ESI)C 31 H 37 FN5O2(M+H) + Calculated value: 530.3, measured value: 530.2.

[0620] Example 41 – Preparation of additional 6-alkyl substituted quinoline and quinazoline compounds The compounds in the following table were prepared based on the experimental procedures described in Example 40 and in the detailed description.

[0621] [Table 256]

[0622] [Table 257]

[0623] [Table 258]

[0624] [Table 259]

[0625] [Table 260]

[0626] [Table 261]

[0627] [Table 262]

[0628] [Table 263]

[0629] [Table 264]

[0630] [Table 265]

[0631] Example 42 - Synthesis of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(2-fluoro-5-methyl-4-((6-(4-methylpyridazin-3-yl)quinolin-4-yl)oxy)phenyl)acetamide (Compound 460); prepared according to General Scheme 14 [ka] Part I - Synthesis of 4-chloro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline [ka] A solution of 6-bromo-4-chloroquinoline (commercially available, 5.0 g, 20.6 mmol, 1.0 equiv.), bis(pinacolato)diboron (6.28 g, 24.7 mmol, 1.20 equiv.), potassium acetate (4.05 g, 41.2 mmol, 2.00 equiv.), and Pd(dppf)Cl (754 mg, 1.03 mmol, 0.05 equiv.) in 1,4-dioxane (50 mL) was heated to 80 °C for 3 h. The solvent was removed under reduced pressure, and the crude product was purified by column chromatography (petroleum ether / EtOAc 1:1). The title compound was obtained as a brown solid (5.0 g, 84%).

[0632] Part II - Synthesis of 4-chloro-6-(4-methylpyridazin-3-yl)quinoline [ka] A solution of 4-chloro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline (1.0 g, 3.45 mmol, 1.00 equiv.), 3-chloro-4-methylpyridazine (0.53 g, 4.14 mmol, 1.20 equiv.), CsCO (2.25 g, 6.91 mmol, 2.00 equiv.), and Pd(dppf)Cl (126 mg, 0.173 mmol, 0.05 equiv.) in 1,4-dioxane (10 mL) and water (2 mL) was heated to 80 °C for 2 h. The crude product was subsequently purified by reverse-phase flash chromatography (column: C18 silica gel; mobile phase A: water (0.1% formic acid), mobile phase B: ACN, gradient: 10–80% B in 10 min; wavelength: 254 nm). The resulting material was extracted with diethyl ether (3 x 150 mL), and the organic phase was washed with water (150 mL) and dried over Na2SO4. The solvent was removed under reduced pressure to give the title compound as a brown solid (600 mg, 68%).

[0633] Part III—Synthesis of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(2-fluoro-5-methyl-4-((6-(4-methylpyridazin-3-yl)quinolin-4-yl)oxy)phenyl)acetamide (Compound 460) [ka] A solution of 4-chloro-6-(4-methylpyridazin-3-yl)quinoline (200 mg, 0.782 mmol, 1.00 equiv.), N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(2-fluoro-4-hydroxy-5-methylphenyl)acetamide (287 mg, 0.938 mmol, 1.20 equiv., which can be synthesized according to Part IV of Example 37), and CsCO (119 mg, 1.56 mmol, 2.00 equiv.) in DMA (2 mL) was heated to 100 °C for 3 h. The crude product was then purified by reverse-phase flash chromatography (column: C18 silica gel; mobile phase A: water (0.1% formic acid), mobile phase B: ACN, gradient: 10 to 80% B in 20 min; wavelength: 254 nm). The title compound was obtained as a pink solid (198 mg, 48%). LCMS(ESI)C 30 H 30 FN6O2(M+H) + Calculated value: 525.2, measured value: 525.4. 1 H NMR(300MHz,DMSO-d6)δ 10.20(s,1H),9.15(d,J=5.2Hz,1H),8.78(d,J=5.2Hz,1H),8.58(d,J=1.9Hz,1H),8.19(d,J=8.7Hz,1H) ,8.11(dd,J=8.7,2.0Hz,1H),7.94(d,J=0.7Hz,1H),7.76-7.68(m,1H),7.49-7.39(m,2H),7.26(d,J=10. 1Hz,1H),6.59(d,J=5.2Hz,1H),3.68(s,2H),2.49(s,3H),2.11(s,3H),1.49(s,9H).

[0634] Example 43 - Synthesis of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(3-methyl-4-((6-(4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)quinolin-4-yl)oxy)phenyl)acetamide (Compound 461); prepared according to General Scheme 14 [ka] Part I - Synthesis of 3-chloro-1-methylpyrazin-2(1H)-one [ka] Dimethyl sulfate (724 mg, 5.75 mmol, 1.50 equiv.) was added to a solution of 3-chloropyrazin-2(1H)-one (500 mg, 3.83 mmol, 1.00 equiv.) and KCO (1.06 g, 7.66 mmol, 2.00 equiv.) in ACN (10 mL), and the mixture was heated to 70 °C for 3 h. Subsequently, insoluble by-products were filtered off, and the crude product was purified by column chromatography (petroleum ether gradient to petroleum ether / EtOAc 1:1). The title compound was obtained as an off-white solid (450 mg, 81%).

[0635] Part II - Synthesis of 2-(4-((6-bromoquinolin-4-yl)oxy)-3-methylphenyl)-N-(1-(tert-butyl)-1H-pyrazol-4-yl)acetamide [ka] A solution of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(4-hydroxy-3-methylphenyl)acetamide (2.0 g, 6.96 mmol, 1.00 equiv., can be synthesized as shown in Part II of Example 30), 6-bromo-4-chloroquinoline (commercially available, 1.69 g, 6.96 mmol, 1.00 equiv.), CsCO (4.54 g, 13.9 mmol, 2.00 equiv.), CuI (0.27 g, 1.39 mmol, 0.20 equiv.), and N,N-dimethylglycine (0.22 g, 2.09 mmol, 0.30 equiv.) in DMF (20 mL) was heated to 80° C. under an inert atmosphere of nitrogen for 3 h. The crude product was then purified by reverse-phase flash chromatography (column: C18 silica gel; mobile phase A: water (0.1% NH4HCO3), mobile phase B: ACN, gradient: 20 to 60% B in 30 min; wavelength: 210 nm) to give the title compound as a brown oil (1.98 g, 55%).

[0636] Part III - Synthesis of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(3-methyl-4-((6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-4-yl)oxy)phenyl)...

Claims

1. Structural formula (I): 【Chemistry 1】 (In the formula, R １ａ , R １ｂ and R １ｃ are each independently H, C １～６ selected from alkyl, halogen, CN, and R ２ is H or C １～３ is alkyl, R ３ is S(=O) ２ R ５ , halogen, 4- to 10-membered heterocyclyl, 5- to 12-membered heteroaryl, S(═O)(═NR ６ ) (R ７ ), QR ７ , C(═O)NR ８ R ９ , NH(C═O)R ５ , C.N., N.R. ８ R ９ , P(=O)R ８ａ R ９ａ is selected from R ４ is H, halogen, C １～６ Alkyl and C １～６ alkoxy; R ５ is C １～６ Alkyl, NR １０ R １１ , C ３～６ selected from cycloalkyl and 4- to 10-membered heterocyclyl; R ６ is H, CN and C １～６ alkyl, R ７ is C １～６ Alkyl, C ３～６ selected from cycloalkyl and 4- to 10-membered heterocyclyl, 5- to 12-membered heteroaryl; or R ６ and R ７ together with the nitrogen and sulfur atoms to which they are attached form a 4- to 10-membered heterocyclyl; Q is selected from O, S, —S(═O)— and —C(═O)—; R ８ and R ９ are each independently H, C １～６ Alkyl, C １～６ Deuterated alkyl, C ３～６ selected from cycloalkyl and 4- to 10-membered heterocyclyl; or R ８ and R ９ together with the nitrogen atom to which they are attached form a 4- to 10-membered heterocyclyl; R ８ａ and R ９ｂ are each independently C １～６ alkyl, or R ８ａ and R ９ａ together with the phosphorus atom to which they are attached form a 4- to 10-membered heterocyclyl; R １０ and R １１ are each independently H or C １～６ alkyl, or R １０ and R １１ together with the nitrogen to which they are attached form a 4- to 10-membered heterocyclyl; W is a bond, O, NR ２ , O(C １～２ alkylene), NH(C １～２ alkylene), C １～２ Alkylene and C ３～６ cycloalkylene; X has the following structural formula: 【Chemistry 2】 and Y １ is CH or N, Y ２ and Y ３ are each independently CR ４ or N, U is CR １２ｂ or N, Z is CR １ｂ or N, L, M, and J are each independently selected from N, O, or S, provided that two of L, M, and J are N; R １２ is C ３～６ Alkyl, C ３～６ Cycloalkyl, C ５～１２ selected from bridged bicyclic carbocyclyl and 4- to 10-membered heterocyclyl; R １２ａ is C １～６ Alkyl, C １～６ Deuterated alkyl, C ３～６ Cycloalkyl, C ５～１２ selected from bridged bicyclic carbocyclyl and 4- to 10-membered heterocyclyl; R １２ｂ and R １３ are each independently H or C １～６ is alkyl, and 【Transformation 3】 is a single or double bond, Each C １～６ Alkyl, C １～３ Alkyl, C １～２ Alkylene, C ３～６ Alkyl, C ３～６ Cycloalkyl, C １～６ Alkoxy, C ５～１２ Bridged bicyclic carbocyclyl, 5- to 12-membered heteroaryl and 4- to 10-membered heterocyclyl are substituted with deuterium, oxo, F, Cl, Br, CN, OR １４ , S.R. １５ , N.R. １６ R １７ , S(O)R １８ , S(O) ２ R １８ａ , N.R. １９ S(=O)R ２０ , C(=O)OR ２０ａ , C(═O)NR ２１ R ２２ , N.R. ２３ C(=O)R ２４ , C(=S)NR ２５ R ２６ , C(=O)R ２７ , C １～６ Alkyl, C １～６ Deuterated alkyl, C ３～８ Cycloalkyl, C ２～６ Alkenyl, halo(C １～６ ) alkyl, C １～３ Alkyl sulfonyl amino alkyl, hydroxy (C １～６ ) alkyl, amino (C １～６ ) alkyl, (C １～６ ) alkylamino (C １～６ ) alkyl, cyano (C １～６ ) alkyl, C １～３ Alkylcarbonylamino (C １～６ ) alkyl, C １～３ Alkoxy, halo (C １～３ ) alkoxy, C １～６ Alkoxy (C １～３ ) alkyl, C ６～１２ optionally substituted with 1 to 3 substituents independently selected from aryl, 4- to 8-membered heterocyclyl, and 5- to 12-membered heteroaryl; R １４ , R １５ , R １８ , R １８ａ , R ２０ , R ２０ａ , R ２４ and R ２７ are each independently hydrogen or C １～６ is alkyl, R １６ and R １７ are each independently hydrogen, C １～６ Alkyl, hydroxy (C １～６ ) alkyl and halo(C １～６ ) alkyl; R １９ and R ２３ are each independently C １～６ Alkyl or halo(C １～６ ) alkyl, R ２１ , R ２２ , R ２５ and R ２６ are each independently H, C １～６ Alkyl, C １～３ Alkoxy (C １～６ ) alkyl, hydroxy (C １～６ ) alkyl, cyano (C １～６ ) alkyl, amino (C １～６ ) alkyl, C １～３ Alkylamino (C １～６ ) alkyl and di(C １～３ ) alkylamino (C １～６ ) alkyl, or R ２１ and R ２２ or R ２５ and R ２６ together with the nitrogen to which they are attached, deuterium, oxo, F, Cl, Br, CN, OR １４ , S.R. １５ , N.R. １６ R １７ , S(O)R １８ , S(O) ２ R １８ａ , N.R. １９ S(=O)R ２０ , C(=O)OR ２０ａ , C(═O)NR ２１ R ２２ , N.R. ２３ C(=O)R ２４ , C(=S)NR ２５ R ２６ , C(=O)R ２７ , C １～６ Alkyl, C ３～８ Cycloalkyl, C ２～６ Alkenyl, halo(C １～６ ) alkyl, C １～３ Alkyl sulfonyl amino alkyl, hydroxy (C １～６ ) alkyl, amino (C １～６ ) alkyl, cyano (C １～６ ) alkyl, C １～３ Alkylcarbonylamino (C １～６ ) alkyl, C １～３ Alkoxy, halo (C １～３ ) alkoxy, C １～６ Alkoxy (C １～３ ) alkyl, C ６～１２ forming a 3- to 8-membered ring optionally substituted with 1 to 3 substituents independently selected from aryl, 4- to 10-membered heterocyclyl, and 5- to 12-membered heteroaryl; However, Y ２ But, R ４ and R ４ is optionally substituted C １～６ When it is alkoxy, W—R ３ is CN or optionally substituted C １～６ shall not be alkoxy, and Y １ , Y ２ and Y ３ If each is CH, then W-R ３ is not F) or a pharmaceutically acceptable salt thereof.

2. Structural formula (I): 【Chemistry 4】 (In the formula, R １ａ , R １ｂ and R １ｃ are each independently H, C １～６ selected from alkyl, halogen and CN; R ２ is H or C １～３ is alkyl, R ３ is S(=O) ２ R ５ , halogen, 4- to 10-membered heterocyclyl, 5- to 12-membered heteroaryl, S(═O)(═NR ６ ) (R ７ ), QR ７ , C(═O)NR ８ R ９ , NH(C═O)R ５ , C.N., N.R. ８ R ９ , P(=O)R ８ａ R ９ａ is selected from R ４ is H, halogen, C １～６ Alkyl and C １～６ alkoxy; R ５ is C １～６ Alkyl, NR １０ R １１ , C ３～６ selected from cycloalkyl and 4- to 10-membered heterocyclyl; R ６ is H, CN and C １～６ alkyl, R ７ is C １～６ Alkyl, C ３～６ selected from cycloalkyl and 4- to 10-membered heterocyclyl, 5- to 12-membered heteroaryl; or R ６ and R ７ together with the nitrogen and sulfur atoms to which they are attached form a 4- to 10-membered heterocyclyl; Q is selected from O, S, —S(═O)— and —C(═O)—; R ８ and R ９ are each independently H, C １～６ Alkyl, C ３～６ selected from cycloalkyl and 4- to 10-membered heterocyclyl; or R ８ and R ９ together with the nitrogen atom to which they are attached form a 4- to 10-membered heterocyclyl; R ８ａ and R ９ｂ are each independently C １～６ alkyl, or R ８ａ and R ９ａ together with the phosphorus atom to which they are attached form a 4- to 10-membered heterocyclyl; R １０ and R １１ are each independently H or C １～６ alkyl, or R １０ and R １１ together with the nitrogen to which they are attached form a 4- to 10-membered heterocyclyl; W is a bond, O, NR ２ , O(C １～２ alkylene), NH(C １～２ alkylene) and C １～２ alkylene; X has the following structural formula: 【Transformation 5】 and Y １ is CH or N, Y ２ and Y ３ are each independently CR ４ or N, U is CR １２ｂ or N, Z is CR １ｂ or N, L, M, and J are each independently selected from N, O, or S, provided that two of L, M, and J are N; R １２ is C ３～６ Alkyl, C ３～６ Cycloalkyl, C ５～１２ selected from bridged bicyclic carbocyclyl and 4- to 10-membered heterocyclyl; R １２ａ is C １～６ Alkyl, C ３～６ Cycloalkyl, C ５～１２ selected from bridged bicyclic carbocyclyl and 4- to 10-membered heterocyclyl; R １２ｂ and R １３ are each independently H or C １～６ is alkyl, and 【Transformation 6】 is a single or double bond, Each C １～６ Alkyl, C １～３ Alkyl, C １～２ Alkylene, C ３～６ Alkyl, C ３～６ Cycloalkyl, C １～６ Alkoxy, C ５～１２ Bridged bicyclic carbocyclyl, 5- to 12-membered heteroaryl and 4- to 10-membered heterocyclyl are substituted with deuterium, oxo, F, Cl, Br, CN, OR １４ , S.R. １５ , N.R. １６ R １７ , S(O)R １８ , S(O) ２ R １８ａ , N.R. １９ S(=O)R ２０ , C(=O)OR ２０ａ , C(═O)NR ２１ R ２２ , N.R. ２３ C(=O)R ２４ , C(=S)NR ２５ R ２６ , C(=O)R ２７ , C １～６ Alkyl, C ３～８ Cycloalkyl, C ２～６ Alkenyl, halo(C １～６ ) alkyl, C １～３ Alkyl sulfonyl amino alkyl, hydroxy (C １～６ ) alkyl, amino (C １～６ ) alkyl, cyano (C １～６ ) alkyl, C １～３ Alkylcarbonylamino (C １～６ ) alkyl, C １～３ Alkoxy, halo (C １～３ ) alkoxy, C １～６ Alkoxy (C １～３ ) alkyl, C ６～１２ optionally substituted with 1 to 3 substituents independently selected from aryl, 4- to 8-membered heterocyclyl, and 5- to 12-membered heteroaryl; R １４ , R １５ , R １８ , R １８ａ , R ２０ , R ２０ａ , R ２４ and R ２７ are each independently hydrogen or C １～６ is alkyl, R １６ and R １７ are each independently hydrogen, C １～６ Alkyl, hydroxy (C １～６ ) alkyl and halo(C １～６ ) alkyl; R １９ and R ２３ are each independently C １～６ Alkyl or halo(C １～６ ) alkyl, R ２１ , R ２２ , R ２５ and R ２６ are each independently H, C １～６ Alkyl, C １～３ Alkoxy (C １～６ ) alkyl, hydroxy (C １～６ ) alkyl, cyano (C １～６ ) alkyl, amino (C １～６ ) alkyl, C １～３ Alkylamino (C １～６ ) alkyl and di(C １～３ ) alkylamino (C １～６ ) alkyl, or R ２１ and R ２２ or R ２５ and R ２６ together with the nitrogen to which they are attached, deuterium, oxo, F, Cl, Br, CN, OR １４ , S.R. １５ , N.R. １６ R １７ , S(O)R １８ , S(O) ２ R １８ａ , N.R. １９ S(=O)R ２０ , C(=O)OR ２０ａ , C(═O)NR ２１ R ２２ , N.R. ２３ C(=O)R ２４ , C(=S)NR ２５ R ２６ , C(=O)R ２７ , C １～６ Alkyl, C ３～８ Cycloalkyl, C ２～６ Alkenyl, halo(C １～６ ) alkyl, C １～３ Alkyl sulfonyl amino alkyl, hydroxy (C １～６ ) alkyl, amino (C １～６ ) alkyl, cyano (C １～６ ) alkyl, C １～３ Alkylcarbonylamino (C １～６ ) alkyl, C １～３ Alkoxy, halo (C １～３ ) alkoxy, C １～６ Alkoxy (C １～３ ) alkyl, C ６～１２ forming a 3- to 8-membered ring optionally substituted with 1 to 3 substituents independently selected from aryl, 4- to 10-membered heterocyclyl, and 5- to 12-membered heteroaryl; However, Y ２ But, R ４ and R ４ is optionally substituted C １～６ When it is alkoxy, W—R ３ is CN or optionally substituted C １～６ shall not be alkoxy, and Y １ , Y ２ and Y ３ If each is CH, then W-R ３ is not F) or a pharmaceutically acceptable salt thereof.

3. R ３ is a 4- to 10-membered heterocyclyl, a 5- to 10-membered heteroaryl, S(═O) ２ R ５ , -S(=O)(=NR ６ ) (R ７ ) and C(═O)NR ８ R ９ 2. The compound of claim 1 selected from:

4. W is NH, N(C １～２ alkylene), O(C １～２ alkylene) and C １～２ The compound according to any one of claims 1 to 3, selected from alkylene.

5. The compound of any one of claims 1 to 3, wherein W is O.

6. The compound of any one of claims 1 to 3, wherein W is a bond.

7. W is C ３～６ The compound according to any one of claims 1 to 3, which is a cycloalkylene.

8. R ３ is deuterium, oxo, F, Cl, Br, CN, OR １４ , S.R. １５ , N.R. １６ R １７ , S(O)R １８ , S(O) ２ R １８ａ , N.R. １９ S(=O)R ２０ , C(=O)OR ２０ａ , C(═O)NR ２１ R ２２ , N.R. ２３ C(=O)R ２４ , C(=S)NR ２５ R ２６ , C(=O)R ２７ , C １～６ Alkyl, C ３～８ Cycloalkyl, C ２～６ Alkenyl, halo(C １～６ ) alkyl, C １～３ Alkyl sulfonyl amino alkyl, hydroxy (C １～６ ) alkyl, amino (C １～６ ) alkyl, cyano (C １～６ ) alkyl, C １～３ Alkylcarbonylamino (C １～６ ) alkyl, C １～３ Alkoxy, halo (C １～３ ) alkoxy, C １～６ Alkoxy (C １～３ ) alkyl, C ６～１２ a 4- to 6-membered heterocyclyl optionally substituted with 1 to 3 substituents independently selected from aryl, 4- to 8-membered heterocyclyl, and 5- to 12-membered heteroaryl; R １４ , R １５ , R １８ , R １８ａ , R ２０ , R ２０ａ , R ２４ and R ２７ are each independently hydrogen or C １～６ is alkyl, R １６ and R １７ are each independently hydrogen, C １～６ Alkyl, hydroxy (C １～６ ) alkyl and halo(C １～６ ) alkyl; R １９ and R ２３ are each independently C １～６ Alkyl or halo(C １～６ ) alkyl, R ２１ , R ２２ , R ２５ and R ２６ are each independently H, C １～６ Alkyl, C １～３ Alkoxy (C １～６ ) alkyl, hydroxy (C １～６ ) alkyl, cyano (C １～６ ) alkyl, amino (C １～６ ) alkyl, C １～３ Alkylamino (C １～６ ) alkyl and di(C １～３ ) alkylamino (C １～６ ) alkyl, or R ２１ and R ２２ or R ２５ and R ２６ together with the nitrogen to which they are attached, deuterium, oxo, F, Cl, Br, CN, OR １４ , S.R. １５ , N.R. １６ R １７ , S(O)R １８ , S(O) ２ R １８ａ , N.R. １９ S(=O)R ２０ , C(=O)OR ２０ａ , C(═O)NR ２１ R ２２ , N.R. ２３ C(=O)R ２４ , C(=S)NR ２５ R ２６ , C(=O)R ２７ , C １～６ Alkyl, C ３～８ Cycloalkyl, C ２～６ Alkenyl, halo(C １～６ ) alkyl, C １～３ Alkyl sulfonyl amino alkyl, hydroxy (C １～６ ) alkyl, amino (C １～６ ) alkyl, cyano (C １～６ ) alkyl, C １～３ Alkylcarbonylamino (C １～６ ) alkyl, C １～３ Alkoxy, halo (C １～３ ) alkoxy, C １～６ Alkoxy (C １～３ ) alkyl, C ６～１２ 1 to 3 independently selected from aryl, 4- to 10-membered heterocyclyl, and 5- to 12-membered heteroaryl; The compound according to any one of claims 1 to 7, which forms a 3- to 8-membered ring optionally substituted with substituents.

9. R ３ The compound of claim 8, wherein is a saturated 4- to 6-membered heterocyclyl.

10. R ３ is substituted with oxo.

11. R ３ is the structural formula 【Transformation 7】 is the part represented by A is O or NR ２８ and R ２８ is H, C １～６ Alkyl, C ３～６ selected from cycloalkyl and 4- to 6-membered heterocyclyl; Each C １～６ Alkyl, C ３～６ Cycloalkyl and 4- to 6-membered heterocyclyl are substituted with deuterium, oxo, F, Cl, Br, CN, OR １４ , S.R. １５ , N.R. １６ R １７ , S(O)R １８ , S(O) ２ R １８ａ , N.R. １９ S(=O)R ２０ , C(=O)OR ２０ａ , C(═O)NR ２１ R ２２ , N.R. ２３ C(=O)R ２４ , C(=S)NR ２５ R ２６ , C(=O)R ２７ , C １～６ Alkyl, C ３～８ Cycloalkyl, C ２～６ Alkenyl, halo(C １～６ ) alkyl, C １～３ Alkyl sulfonyl amino alkyl, hydroxy (C １～６ ) alkyl, amino (C １～６ ) alkyl, cyano (C １～６ ) alkyl, C １～３ Alkylcarbonylamino (C １～６ ) alkyl, C １～３ Alkoxy, halo (C １～３ ) alkoxy, C １～６ Alkoxy (C １～３ ) alkyl, C ６～１２ optionally substituted with 1 to 3 substituents independently selected from aryl, 4- to 8-membered heterocyclyl, and 5- to 12-membered heteroaryl; R １４ , R １５ , R １８ , R １８ａ , R ２０ , R ２０ａ , R ２４ and R ２７ are each independently hydrogen or C １～６ is alkyl, R １６ and R １７ are each independently hydrogen, C １～６ Alkyl, hydroxy (C １～６ ) alkyl and halo(C １～６ ) alkyl; R １９ and R ２３ are each independently C １～６ Alkyl or halo(C １～６ ) alkyl, R ２１ , R ２２ , R ２５ and R ２６ are each independently H, C １～６ Alkyl, C １～３ Alkoxy (C １～６ ) alkyl, hydroxy (C １～６ ) alkyl, cyano (C １～６ ) alkyl, amino (C １～６ ) alkyl, C １～３ Alkylamino (C １～６ ) alkyl and di(C １～３ ) alkylamino (C １～６ ) alkyl, or R ２１ and R ２２ or R ２５ and R ２６ together with the nitrogen to which they are attached, deuterium, oxo, F, Cl, Br, CN, OR １４ , S.R. １５ , N.R. １６ R １７ , S(O)R １８ , S(O) ２ R １８ａ , N.R. １９ S(=O)R ２０ , C(=O)OR ２０ａ , C(═O)NR ２１ R ２２ , N.R. ２３ C(=O)R ２４ , C(=S)NR ２５ R ２６ , C(=O)R ２７ , C １～６ Alkyl, C ３～８ Cycloalkyl, C ２～６ Alkenyl, halo(C １～６ ) alkyl, C １～３ Alkyl sulfonyl amino alkyl, hydroxy (C １～６ ) alkyl, cyano (C １～６ ) alkyl, C １～３ Alkylcarbonylamino (C １～６ ) alkyl, C １～３ Alkoxy, halo (C １～３ ) alkoxy, C １～６ Alkoxy (C １～３ ) alkyl, C ６～１２ The compound according to any one of claims 1 to 7, which forms a 3-8 membered ring optionally substituted with 1 to 3 substituents independently selected from aryl, 4- to 10-membered heterocyclyl, and 5- to 12-membered heteroaryl.

12. R ３ has the following structural formula: 【Transformation 8】 (In the formula, R ２８ is H or C １～３ alkyl) The compound of any one of claims 1 to 7, which is a moiety represented by one of:

13. R ３ is S(=O) ２ R ５ The compound according to any one of claims 1 to 7,

14. R ５ is C １～６ 14. The compound of claim 13, wherein the compound is alkyl.

15. R ５ is C １～３ 14. The compound of claim 13, wherein the compound is alkyl.

16. R ５ is C ３～６ 14. The compound of claim 13, which is cycloalkyl.

17. R ５ is deuterium, oxo, F, Cl, Br, CN, OR １４ , S.R. １５ , N.R. １６ R １７ , S(O)R １８ , S(O) ２ R １８ａ , N.R. １９ S(=O)R ２０ , C(=O)OR ２０ａ , C(═O)NR ２１ R ２２ , N.R. ２３ C(=O)R ２４ , C(=S)NR ２５ R ２６ , C(=O)R ２７ , C １～６ Alkyl, C ３～８ Cycloalkyl, C ２～６ Alkenyl, halo(C １～６ ) alkyl, C １～３ Alkyl sulfonyl amino alkyl, hydroxy (C １～６ ) alkyl, amino (C １～６ ) alkyl, cyano (C １～６ ) alkyl, C １～３ Alkylcarbonylamino (C １～６ ) alkyl, C １～３ Alkoxy, halo (C １～３ ) alkoxy, C １～６ Alkoxy (C １～３ ) alkyl, C ６～１２ a 4- to 6-membered heterocyclyl optionally substituted with 1 to 3 substituents independently selected from aryl, 4- to 10-membered heterocyclyl, and 5- to 12-membered heteroaryl; R １４ , R １５ , R １８ , R １８ａ , R ２０ , R ２０ａ , R ２４ and R ２７ are each independently hydrogen or C １～６ is alkyl, R １６ and R １７ are each independently hydrogen, C １～６ Alkyl, hydroxy (C １～６ ) alkyl or halo(C １～６ ) alkyl, R １９ and R ２３ are each independently C １～６ Alkyl or halo(C １～６ ) alkyl, R ２１ , R ２２ , R ２５ and R ２６ are each independently H, C １～６ Alkyl, C １～３ Alkoxy (C １～６ ) alkyl, hydroxy (C １～６ ) alkyl, cyano (C １～６ ) alkyl, amino (C １～６ ) alkyl, C １～３ Alkylamino (C １～６ ) alkyl or di(C １～３ ) alkylamino (C １～６ ) alkyl, or R ２１ and R ２２ or R ２５ and R ２６ together with the nitrogen to which they are attached, deuterium, oxo, F, Cl, Br, CN, OR １４ , S.R. １５ , N.R. １６ R １７ , S(O)R １８ , S(O) ２ R １８ａ , N.R. １９ S(=O)R ２０ , C(=O)OR ２０ａ , C(═O)NR ２１ R ２２ , N.R. ２３ C(=O)R ２４ , C(=S)NR ２５ R ２６ , C(=O)R ２７ , C １～６ Alkyl, C ３～８ Cycloalkyl, C ２～６ Alkenyl, halo(C １～６ ) alkyl, C １～３ Alkyl sulfonyl amino alkyl, hydroxy (C １～６ ) alkyl, amino (C １～６ ) alkyl, cyano (C １～６ ) alkyl, C １～３ Alkylcarbonylamino (C １～６ ) alkyl, C １～３ Alkoxy, halo (C １～３ ) alkoxy, C １～６ Alkoxy (C １～３ ) alkyl, C ６～１２ 14. The compound of claim 13, which forms a 3-8 membered ring optionally substituted with 1 to 3 substituents independently selected from aryl, 4- to 10-membered heterocyclyl, and 5- to 12-membered heteroaryl.

18. R ５ is NR １０ R １１ 14. The compound of claim 13, wherein:

19. R １０ and R １１ are each independently C １～６ 19. The method of claim 18, wherein the aryl group is alkyl. Compound.

20. R １０ is H, and R １１ is C １～６ 20. The compound of claim 18, wherein the compound is alkyl.

21. R １０ and R １１ 19. The compound of claim 18, wherein each is H.

22. R ３ is (R ７ )S(=O)(NR ６ 8. The compound according to claim 1, wherein

23. R ６ is H, and R ７ is C １～６ Alkyl or C ３～６ 23. The compound of claim 22, which is cycloalkyl.

24. R ６ and R ７ The compound of claim 22, wherein: together with the nitrogen and sulfur atoms to which they are attached form a 4- to 10-membered heterocyclyl.

25. R ３ is C(=O)NR ８ R ９ The compound according to any one of claims 1 to 7,

26. R ８ is H, and R ９ is C １～３ 26. The compound of claim 25, wherein the compound is alkyl.

27. R ８ and R ９ is H.

28. R ８ and R ９ are each independently C １～３ 26. The compound of claim 25, wherein the compound is alkyl.

29. R ３ is QR ７ , NH(C═O)R ５ , CN and NR ８ R ９ The compound according to any one of claims 1 to 7, selected from:

30. R ３ is QR ７ 30. The compound of claim 29, wherein:

31. 31. The compound of claim 30, wherein Q is O.

32. 31. The compound of claim 30, wherein Q is S.

33. 31. The compound of claim 30, wherein Q is -C(=O)-.

34. R ７ is C １～６ The compound of any one of claims 29 to 33, which is alkyl.

35. R ３ The compound according to any one of claims 1 to 7, wherein is a halogen.

36. R ３ is F.

37. R ３ 36. The compound of claim 35, wherein is Cl.

38. R ３ is P(=O)R ８ａ R ９ａ The compound according to any one of claims 1 to 7,

39. R ８ａ and R ９ｂ are each independently C １～３ 39. The compound of claim 38, which is alkyl.

40. R ８ａ and R ９ａ and R 1 and R 2 together with the phosphorus atom to which they are attached form a 4- to 10-membered heterocyclyl.

41. Structural formula (Ia): 【Chemistry 9】 3. The compound of claim 1 or 2, represented by:

42. Structural formula (Ib): 【Chemistry 10】 3. The compound of claim 1 or 2, represented by:

43. Structural formula (Ic): 【Chemistry 11】 3. The compound of claim 1 or 2, represented by:

44. Structural formula (Id): 【Chemistry 12】 3. The compound of claim 1 or 2, represented by:

45. Structural formula (Ie): 【Chemistry 13】 wherein Hal is a halogen.

3. The compound of claim 1 or 2, represented by:

46. Structural formula (If): 【Chemistry 14】 3. The compound of claim 1 or 2, represented by:

47. R ４ The compound of any one of claims 1 to 45, wherein is H.

48. R ４ is C １～６ 46. ​​The compound of any one of claims 1 to 33 or 35 to 45, which is alkoxy.

49. X has the following structural formula: 【Chemistry 15】 49. The compound of any one of claims 1 to 48, wherein the compound is a moiety represented by:

50. R １３ is H.

51. R １３ is C １～６ 50. The compound of claim 49, which is alkyl.

52. X has the following structural formula: 【Chemistry 16】 49. The compound of any one of claims 1 to 48, wherein the compound is a moiety represented by:

53. R １３ is H.

54. R １３ is C １～６ 53. The compound of claim 52, which is alkyl.

55. X has the following structural formula: 【Chemistry 17】 49. The compound of any one of claims 1 to 48, wherein the compound is a moiety represented by:

56. X has the following structural formula: [Chemistry 18] 49. The compound of any one of claims 1 to 48, which is a moiety represented by one of:

57. X has the following structural formula: 【Chemistry 19】 49. The compound of any one of claims 1 to 48, which is a moiety represented by one of:

58. R １２ is deuterium, oxo, F, Cl, Br, CN, OR １４ , S.R. １５ , N.R. １６ R １７ , S(O)R １８ , S(O) ２ R １８ａ , N.R. １９ S(=O)R ２０ , C(=O)OR ２０ａ , C(═O)NR ２１ R ２２ , N.R. ２３ C(=O)R ２４ , C(=S)NR ２５ R ２６ , C(=O)R ２７ , C １～６ Alkyl, C ３～８ Cycloalkyl, C ２～６ Al Kenyl, Halo (C １～６ ) alkyl, C １～３ Alkyl sulfonyl amino alkyl, hydroxy (C １～６ ) alkyl, amino (C １～６ ) alkyl, cyano (C １～６ ) alkyl, C １～３ Alkylcarbonylamino (C １～６ ) alkyl, C １～３ Alkoxy, halo (C １～３ ) alkoxy, C １～６ Alkoxy (C １～３ ) alkyl, C ６～１２ C optionally substituted with 1 to 3 substituents independently selected from aryl, 4- to 10-membered heterocyclyl, and 5- to 12-membered heteroaryl ３～６ is alkyl, R １４ , R １５ , R １８ , R １８ａ , R ２０ , R ２０ａ , R ２４ and R ２７ are each independently hydrogen or C １～６ is alkyl, R １６ and R １７ are each independently hydrogen, C １～６ Alkyl, hydroxy (C １～６ ) alkyl or halo(C １～６ ) alkyl, R １９ and R ２３ are each independently C １～６ Alkyl or halo(C １～６ ) alkyl, R ２１ , R ２２ , R ２５ and R ２６ are each independently H, C １～６ Alkyl, C １～３ Alkoxy (C １～６ ) alkyl, hydroxy (C １～６ ) alkyl, cyano (C １～６ ) alkyl, amino (C １～６ ) alkyl, C １～３ Alkylamino (C １～６ ) alkyl or di(C １～３ ) alkylamino (C １～６ ) alkyl, or R ２１ and R ２２ or R ２５ and R ２６ together with the nitrogen to which they are attached, deuterium, oxo, F, Cl, Br, CN, OR １４ , S.R. １５ , N.R. １６ R １７ , S(O)R １８ , S(O) ２ R １８ａ , N.R. １９ S(=O)R ２０ , C(=O)OR ２０ａ , C(═O)NR ２１ R ２２ , N.R. ２３ C(=O)R ２４ , C(=S)NR ２５ R ２６ , C(=O)R ２７ , C １～６ Alkyl, C ３～８ Cycloalkyl, C ２～６ Alkenyl, halo(C １～６ ) alkyl, C １～３ Alkyl sulfonyl amino alkyl, hydroxy (C １～６ ) alkyl, amino (C １～６ ) alkyl, cyano (C １～６ ) alkyl, C １～３ Alkylcarbonylamino (C １～６ ) alkyl, C １～３ Alkoxy, halo (C １～３ ) alkoxy, C １～６ Alkoxy (C １～３ ) alkyl, C ６～１２ 58. The compound of any one of claims 1 to 57, which forms a 3-8 membered ring optionally substituted with 1 to 3 substituents independently selected from aryl, 4- to 10-membered heterocyclyl, and 5- to 12-membered heteroaryl.

59. R １２ has the following structural formula: 【Chemistry 20】 58. The compound of any one of claims 1 to 57, which is a moiety represented by one of:

60. R １２ has the following structural formula: 【Chemistry 21】 58. The compound of any one of claims 1 to 57, which is a moiety represented by one of:

61. R １２ is the structural formula 【Chemistry 22】 61. The compound of claim 60, wherein the moiety is represented by:

62. R １ａ The compound of any one of claims 1 to 61, wherein is halogen.

63. R １ａ is C １～３ 62. The compound of any one of claims 1 to 61, which is alkyl.

64. R １ａ are H, F, Cl, CH ３ , CHF ２ , C.F. ３ and CDs ３ 62. The compound of any one of claims 1 to 61, selected from:

65. R １ａ is F, CH ３ and CHF ２ 65. The compound of claim 64, selected from:

66. R １ｂ The compound of any one of claims 1 to 65, wherein is halogen.

67. R １ｂ is C １～３ 66. The compound of any one of claims 1 to 65, which is alkyl.

68. R １ｂ are H, F, Cl, CH ３ , CHF ２ , C.F. ３ and CDs ３ 66. The compound of any one of claims 1 to 65, selected from:

69. R １ｂ is F, CH ３ and CHF ２ 69. The compound of claim 68, selected from:

70. R １ｃ is H or halogen.

71. R １ｃ The compound of any one of claims 1 to 69, wherein is F.

72. Structural formula (Ig): 【Chemistry 23】 3. The compound of claim 1 or 2, represented by:

73. Structural Formula (Ih), (Ii) or (Ij): 【Chemistry 24】 3. The compound of claim 1 or 2, represented by:

74. Y １ The compound of any one of claims 1 to 73, wherein is CH.

75. Y １ The compound of any one of claims 1 to 73, wherein is N.

76. 73. The compound of any one of claims 1 to 72, wherein Z is CH.

77. 73. The compound of any one of claims 1 to 72, wherein Z is N.

78. R ２ The compound of any one of claims 1 to 77, wherein is H.

79. R ２ is C １～３ 78. The compound of any one of claims 1 to 77, which is alkyl.

80. Structural formula (Ik): 【Chemistry 25】 (In the formula, R ５ is C １～３ alkyl) 3. The compound of claim 1 or 2, represented by:

81. Structural formula (Il): 【Chemistry 26】 (In the formula, R ９ is H or C １～３ alkyl) 3. The compound of claim 1 or 2, represented by:

82. Structural formula (Im): 【Chemistry 27】 (In the formula, R ２９ is H or C １～３ alkyl) 3. The compound of claim 1 or 2, represented by:

83. Structural formula (In): 【Chemistry 28】 (In the formula, R １ａ is C １～３ selected from alkyl, halogen and H; R １ｂ and R ４ are each independently halogen or H; R １ｃ is C １～３ selected from haloalkyl, halogen and H, and R ９ is H or C １～３ alkyl) 3. The compound of claim 1 or 2, represented by:

84. 3. The compound of claim 1 or 2, selected from the compounds of Table 1.

85. 3. The compound of claim 1 or 2, selected from the compounds of Table 2.

86. 3. The compound of claim 1 or 2, selected from the compounds of Table 3.

87. 87. A pharmaceutical composition comprising a compound according to any one of claims 1 to 86 and a pharmaceutically acceptable excipient.

88. 88. 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 to 86 or a pharmaceutical composition of claim 87, wherein the disease or disorder is selected from an inflammatory disease, an autoimmune disease, a granulomatous disease, cancer, and a neurodegenerative disease.

89. 89. The method of claim 88, wherein the disease or disorder is an inflammatory disease.

90. 90. The method of claim 89, wherein the inflammatory disease is selected from uveitis, interleukin-1 converting enzyme fever syndrome, dermatitis, acute lung injury, type 2 diabetes, arthritis, inflammatory bowel disorder (IBD), ischemia-reperfusion injury in solid organ transplants, sepsis, liver disease, allergic disease, and graft-versus-host disease.

91. 90. The method of claim 89, wherein the inflammatory disease is IBD.

92. 92. The method of claim 91, wherein the IBD is selected from ulcerative colitis, Crohn's disease, early-onset IBD, and extraintestinal IBD.

93. 90. The method of claim 89, wherein the inflammatory disease is selected from rheumatoid arthritis, inflammatory arthritis, peritonitis, ischemia-reperfusion injury in kidney grafts, non-alcoholic steatohepatitis, alcoholic steatohepatitis, insulin-resistant type 2 diabetes, allergic rhinitis, asthma, atopic dermatitis, Sjogren's syndrome, ankylosing spondylitis, pemphigus vulgaris, idiopathic plasma cell lymphadenopathy, atherosclerosis, myocardial infarction, thrombosis, alpha-synucleinopathies, Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, Alzheimer's disease, amyotrophic lateral sclerosis, and chronic obstructive pulmonary disease.

94. 89. The method of claim 88, wherein the disease or disorder is an autoimmune disease.

95. 95. The method of claim 94, wherein the autoimmune disease is selected from systemic lupus erythematosus, lupus nephritis, psoriasis, immune thrombocytopenic purpura, and multiple sclerosis.

96. 89. The method of claim 88, wherein the disease or disorder is a granulomatous disease.

97. 97. The method of claim 96, wherein the granulomatous disease is selected from sarcoidosis, Blau syndrome, Wegener's granulomatosis, Behcet's disease, and interstitial pulmonary disease.

98. 89. The method of claim 88, wherein the disease or disorder is cancer.

99. 99. The method of claim 98, 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.

100. 89. The method of claim 88, wherein the disease or disorder is a neurodegenerative disease.

101. 101. The method of claim 100, wherein the neurodegenerative disease is selected from Alzheimer's disease, amyotrophic lateral sclerosis (ALS / Lou Gehrig's disease), Parkinson's disease, multiple sclerosis, diabetic neuropathy, polyglutamine (polyQ) disease, stroke, Fahr's disease, Menkes disease, Wilson's disease, cerebral ischemia, prion disorders, dementia, corticobasal degeneration, progressive supranuclear palsy, spinocerebellar atrophy, brain injury, and spinal cord injury.

102. 102. The method of any one of claims 88-101, further comprising administering a therapeutically effective amount of a second agent.

103. 103. The method of claim 102, wherein the second agent is an anti-inflammatory agent or an anti-autoimmune agent.

104. 103. The method of claim 102, wherein the second agent is selected from an anti-TNF agent, an anti-IL-23 agent, an anti-integrin agent, and a JAK inhibitor.

105. 105. The method of claim 104, wherein the second agent is an anti-TNF agent.

106. 105. The method of claim 104, wherein the second agent is an anti-IL-23 agent.

107. 105. The method of claim 104, wherein the second agent is an anti-integrin agent.

108. 105. The method of claim 104, wherein the second agent is a JAK inhibitor.

109. 109. The method of any one of claims 102 to 108, wherein the second agent and the compound are administered together in a single pharmaceutical composition.

110. 109. The method of any one of claims 102 to 108, wherein the second agent and the compound are administered separately.

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