RIPK2 inhibitor and application thereof

Abstract

The present invention relates to a RIPK2 inhibitor represented by the structural formula (I): # imgabs0 #. The invention further relates to pharmaceutical compositions comprising said RIPK2 inhibitor and methods of treating conditions such as inflammatory diseases, autoimmune diseases, granulomatous diseases, neurodegenerative diseases and cancer.

Description

[0001]

Related Applications

[0002] This application claims priority to U.S. Provisional Patent Application No. 63 / 544,884, filed Oct. 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 Feb. 7, 2023; and U.S. Provisional Patent Application No. 63 / 427,317, filed Nov. 22, 2022. The entire teachings of the above applications are incorporated herein by reference.

[0003]

Background Art

[0004] Autoinflammatory diseases are disorders characterized by systemic and organ-specific inflammation caused by abnormalities in the innate immune system. Such abnormalities are associated with many 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.

[0005] NOD1 and NOD2 (nucleotide-binding oligomerization domain 1 and 2) are members of the NOD-like receptor (NLR) family, which represent important components of the mammalian innate immune system and act as intracellular receptors for the bacterial cell wall component peptidoglycan (PGN). 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. Once activated, NOD signaling causes activation of NF-κB and MAP kinases, leading to transcription of pro-inflammatory cytokines and induction of autophagy.

[0006] NOD1 and NOD2 require RIPK2 as a common scaffold (adapter) protein to transmit downstream signals that lead to aberrant pro-inflammatory innate immune activation. Specifically, RIPK2 is required for NF-κB activation and subsequent cytokine production. Inhibition of RIPK2 abrogates aberrant inflammatory states, such as intestinal inflammation. Thus, RIPK2 inhibitors have the potential to act as therapeutic agents, for example, to reduce or abrogate 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.

[0007] In the case of malignant transformation, attenuation of RIPK2 downregulates the RNA expression of E-cadherin and vimentin, proteins involved in epithelial-to-mesenchymal transition (EMT) and promoting a metastatic phenotype, indicating that RIPK2 is involved in cell migration and cancer metastasis.

[0008] Accordingly, there is a need for inhibitors of RIPK2 activity that can block RIPK2-dependent pro-inflammatory signaling and thereby provide a therapeutic benefit in autoinflammatory diseases and other disorders characterized by increased and / or dysregulated RIPK2 activity.

[0009] A description of exemplary embodiments of the invention follows.

Summary of the Invention

[0010] In a first embodiment, the invention relates to a compound represented by structural formula (I):

[0011] or a pharmaceutically acceptable salt thereof:

[0012]

[0013] Wherein:

[0014] R 1a 、R 1b and R 1c are each independently selected from H, halogen, CN and C 1-6 alkyl;

[0015] R 2 is H or C 1-3 alkyl;

[0016] R 3 is selected from halogen, 4- to 10-membered heterocyclic group, 5- to 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 、CN、NR 8 R 9 、P(=O)R 8a R 9a ;

[0017] R 4 is selected from H, halogen, C 1-6 alkyl and C 1-6 alkoxy;

[0018] R5 Selected from NR 10 R 11 、C 1-6 alkyl, C 3-6 cycloalkyl and 4- to 10-membered heterocyclic groups;

[0019] R 6 Selected from H, CN and C 1-6 alkyl;

[0020] R 7 Selected from C 1-6 alkyl, C 3-6 cycloalkyl and 4- to 10-membered heterocyclic groups, 5- to 12-membered heteroaryl, or

[0021] 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;

[0022] Q is selected from O, S, -S(=O)- and -C(=O)-;

[0023] R 8 and R 9 are each independently selected from H, C 1-6 alkyl, C 1-6 deuterated alkyl, C 3-6 cycloalkyl and 4- to 10-membered heterocyclic groups, or

[0024] R 8 and R 9 together with the nitrogen atom to which they are attached form a 4- to 10-membered heterocyclic group;

[0025] R 8a and R 9b are each independently C 1-6 alkyl, or

[0026] R 8a and R 9a together with the phosphorus atom to which they are attached form a 4- to 10-membered heterocyclic group;

[0027] R 10 and R 11 are each independently H or C 1-6 alkyl, or

[0028] R 10 and R 11 together with the nitrogen to which they are attached form a 4- to 10-membered heterocyclic group;

[0029] W is selected from O, NR 2 , O(C 1-2 alkylene), NH(C 1-2 alkylene), C1-2 Alkylene, C 3-6 Subcycloalkylene and single bond;

[0030] X is a moiety represented by one of the following structural formulas:

[0031]

[0032] Y 1 is CH or N;

[0033] Y 2 and Y 3 are each independently CR 4 or N;

[0034] U is CR 12b or N;

[0035] Z is CR 1b or N;

[0036] L, M and J are each independently selected from N, O or S, provided that two of L, M and J are N;

[0037] R 12 is selected from C 3-6 alkyl, C 3-6 cycloalkyl, C 5-12 bridged bicyclic carbocyclic group and 4- to 10-membered heterocyclic group;

[0038] R 12a is selected from C 1-6 alkyl, C 1-6 deuterated alkyl, C 3-6 cycloalkyl, C 5-12 bridged bicyclic carbocyclic group and 4- to 10-membered heterocyclic group;

[0039] R 12b and R 13 are each independently H or C 1-6 alkyl;

[0040] and

[0041] is a single bond or a double bond,

[0042] wherein 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 carbocyclic group, 5- to 12-membered heteroaryl and 4- to 10-membered heterocyclic group are optionally substituted with 1 to 3 substituents independently selected from the following: deuterium, oxo, F, Cl, Br, CN, OR14 、 SR 15 、 NR 16 R 17 、 S(O)R 18 、 S(O)2R 18a 、 NR 19 S(=O)R 20 、 C(=O)OR 20a 、 C(=O)NR 21 R 22 、 NR 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 alkylsulfonylaminoalkyl, 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 aryl, 4- to 8-membered heterocyclic group, and 5- to 12-membered heteroaryl, where

[0043] R 14 、 R 15 、 R 18 、 R 18a 、 R 20 、 R 20a 、 R 24 and R 27 each independently is hydrogen or C 1-6 alkyl;

[0044] R 16 and R 17 each independently is selected from hydrogen, C 1-6 alkyl, hydroxy(C 1-6 )alkyl, and halo(C 1-6 )alkyl;

[0045] R 19 and R 23Each is independently C 1-6 alkyl or halo(C 1-6 )alkyl;

[0046] R 21 、R 22 、R 25 and R 26 are each independently selected from 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

[0047] R 21 and R 22 or R 25 and R 26 together with the nitrogen to which they are attached form a 3- to 8-membered ring optionally substituted with 1 to 3 substituents independently selected from the following: deuterium, oxo, F, Cl, Br, CN, OR 14 , SR 15 , NR 16 R 17 , S(O)R 18 , S(O)2R 18a , NR 19 S(=O)R 20 , C(=O)OR 20a , C(=O)NR 21 R 22 , NR 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 alkylsulfonylaminoalkyl, 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, C1-6 alkoxy(C 1-3 )alkyl, C 6-12 aryl, 4- to 10-membered heterocyclic group, and 5- to 12-membered heteroaryl,

[0048] provided that when Y 2 is CH substituted with R 4 and R 4 is optionally substituted C 1-6 alkoxy, then W-R 3 is not CN or optionally substituted C 1-6 alkoxy; and

[0049] provided that when Y 1 , Y 2 and Y 3 are each CH, then W-R 3 is not F.

[0050] In a second embodiment, the present invention relates to a pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof as described herein with respect to the first embodiment and its various aspects, and a pharmaceutically acceptable excipient.

[0051] In a third embodiment, the present invention relates to a method of treating a disease or disorder, which comprises administering to an individual in need thereof a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof as described herein with respect to the first embodiment and its various aspects (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition as described herein with respect to the second embodiment and its various aspects, wherein the disease or disorder is selected from inflammatory diseases, autoimmune diseases, granulomatous diseases, cancer, and neurodegenerative diseases.

[0052] In a fourth embodiment, the present invention relates to a method of treating a RIP2 kinase-mediated disease or disorder, which comprises administering to an individual in need thereof a therapeutically effective amount of a compound as described herein with respect to the first embodiment and its various aspects (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition as described herein with respect to the second embodiment and its various aspects. In one aspect, the RIP2 kinase-mediated disease or disorder is a disease or disorder in which inhibition of the RIP2 kinase would provide a benefit. In a particular aspect, the disease or disorder is selected from inflammatory diseases, autoimmune diseases, granulomatous diseases, cancer, and neurodegenerative diseases.

[0053] In a fifth embodiment, the present invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for 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).

[0054] In a sixth embodiment, the present invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the treatment of RIP2 kinase-mediated diseases and disorders (such as inflammatory diseases, autoimmune diseases, granulomatous diseases, cancer or neurodegenerative diseases).

BRIEF DESCRIPTION OF THE DRAWINGS

[0055] Figure 1 A schematic diagram showing how a RIPK2 backbone inhibitor locks RIPK2 in an inactive conformation, preventing interaction with XIAP and causing complete pathway inhibition.

DETAILED DESCRIPTION

[0056] RIP kinase

[0057] Protein kinases constitute a large family of structurally related enzymes responsible for controlling a variety of signal transduction processes within cells. They have been shown to be key regulators in most cellular functions, including proliferation, cell metabolism, cell survival, apoptosis, DNA damage repair, and cell motility. Uncontrolled signal transduction caused by a lack of control of protein phosphorylation has been implicated in many diseases, including, for example, cancer, inflammation, allergy, immune diseases, CNS disorders, and angiogenesis.

[0058] Among the protein kinase family, a particular example is the receptor-interacting serine / threonine kinase that includes RIPK2. RIPK2 is composed of an N-terminal kinase domain and a C-terminal caspase recruitment domain (CARD) linked via an intermediate (IM) region. The CARD domain of the RIP2 kinase mediates interaction with other CARD-containing proteins such as NOD1 and NOD2. NOD1 and NOD2 are cytoplasmic receptors that are activated by specific bacterial peptidoglycan motifs and play important roles in innate immune surveillance. After intracellular bacterial exposure, NOD1 or NOD2 binds to RIPK2 to coordinate the nuclear factor kB (NF-kB)-mediated interleukin response. After binding to NOD1 / 2, RIPK2 autophosphorylates on Tyr 474 (Y474) and serves as a molecular scaffold to recruit other kinases (TAK1, IKKb involved in NF-kB, and MAPK activation).

[0059] Both NOD1 / 2 and RIPK2 are NF-kB-regulated genes, and thus their activation causes a positive feedback loop in which activation of NOD1 / 2:RIPK2 stimulates further activation and further inflammation. In addition, NOD1 / 2 and RIPK2 are shown to be 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, bactericidal activity, MHC class II presentation, and mitogen-activated protein kinase (MAPK) activation. Overall, this pathway regulates the innate immune system to help coordinate the adaptive immune response to eradicate the offending pathogen.

[0060] Dysregulation of RIPK2-dependent signaling has been associated with autoinflammatory diseases. Patients with loss-of-function NOD2 alleles are prone to develop 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 colonic biopsies from patients with CD as well as in pediatric cohorts with ulcerative colitis (UC). Selective RIPK2 inhibitors have been shown to block spontaneous pro-inflammatory cytokine secretion in biopsies from UC / CD patients. These results emphasize that RIPK2 activation in the mucosa of UC / CD patients causes a pro-inflammatory state in these biopsies.

[0061] Rheumatoid arthritis (RA) is a disease in which NOD2 / RIPK2 plays a role. It has been shown that the NOD2 / RIPK2 pathway is upregulated in immune cells from RA patients, suggesting that RIPK2 inhibition may be beneficial in this population. Gain-of-function NOD2 mutations have been genetically associated with other inflammatory diseases, such as Blau Syndrome / early-onset sarcoidosis (EOS), a pediatric granulomatous disease characterized by uveitis, dermatitis, and arthritis. Genome-wide genotyping of young patients with allergic rhinitis and atopic dermatitis has highlighted common NOD2 polymorphisms, where Crohn's disease may be the primary cause of the observed excessive immune response against skin tissue. Mutations in NOD1 are associated with asthma and early-onset and extra-intestinal inflammatory bowel disease. Genetic and functional studies have also shown that RIP2-dependent signaling plays a role in a variety of other granulomatous disorders, such as sarcoidosis.

[0062] Metabolic syndrome, a condition closely associated with obesity and overweight, is caused by chronic inflammation and is characterized by hypertension, hyperglycemia, and abnormal lipolysis. Activation of the immune system through the NOD1 pathway has been observed in patients with metabolic syndrome. Recent functional studies highlighting the impact of RIPK2 inhibitors on lipolysis have demonstrated the role of RIP2-dependent signaling in glycemic abnormalities and lipolysis.

[0063] In cardiac hypertrophy, a complex and multifactorial condition, inflammation is particularly demonstrated as an important hallmark of the disease through activation of the NF-kB signaling pathway. Gene knockout studies of RIPK2 in a murine model of hypertrophic heart have shown the role of RIPK2 in regulating inflammation and subsequent tissue fibrosis and hypertrophy.

[0064] In addition to immune-inflammatory diseases, RIPK2 regulation has also been described in several cancers. In triple-negative breast cancer (TNBC), high expression of RIPK2 has been associated with poor progression-free survival and poor overall survival. It has been shown that RIPK2 attenuation increases docetaxel sensitivity and reduces tumor and lung cancer metastasis. Another study focusing on a new cancer gene cassette on chromosome 8 in breast cancer patients found co-amplification of RIPK2 with other tested oncogenes such as MYC. TNBC biopsies performed to identify druggable kinases other than HER2 confirmed that RIPK2 is hyperphosphorylated in basal-like and luminal B breast cancer biopsies, indicating activation of this pathway in these TNBC types. Recently, increased phospho-RIPK2 levels and NF-kB activity were shown in inflammatory breast cancer tissue sections. Thirty-four head and neck squamous cell carcinoma cell lines demonstrated that RIPK2 attenuation caused cell death, indicating the important role of the protein for cell survival. It has been proposed that RIPK2 promotes glioma cell growth by regulating TRAF3 and activating the NF-kB pathway and p38 signaling.

[0065] A new role of RIPK2 in osteosarcoma invasion was confirmed when gefitinib blocked the progression of lung cancer metastasis via RIPK2 inhibition. In addition, atypical NF-kB plays a key role in non-Hodgkin's lymphoma. Finally, using three-dimensional lymphatic endothelial cell tube formation, RIPK2 was identified as a kinase involved in lymphovascular remodeling, a key factor in cancer metastatic spread. Collectively, these data strongly support the development of RIPK2 inhibitors in the field of oncology.

[0066] RIPK2 and RIP2 kinases are used interchangeably herein and refer to receptor-interacting protein kinase 2.

[0067] XIAP (X-linked inhibitor of apoptosis protein) ubiquitinates RIPK2 following NOD2 stimulation, and the interaction between the XIAP BIR2 domain and the RIPK2 kinase domain is required for NOD2 signaling ( Figure 1 ). Although the RIPK2 kinase function is not essential for downstream signaling, RIPK2 ubiquitination and signal transduction require its ability to recruit and activate XIAP. Thus, inhibition of RIPK2 by a scaffold inhibitor that binds to RIPK2 and prevents interaction with XIAP blocks pro-inflammatory responses in vitro and in vivo.

[0068] The compounds described herein have been shown to be RIPK2 scaffold inhibitors. Figure 1 Show how RIPK2 scaffold inhibitors can lock RIPK2 in an inactive conformation, prevent interaction with XIAP and cause complete pathway inhibition. Blocking the scaffold is beneficial for inhibiting RIPK2 activation in response to the microbiota. The disclosed RIPK2 scaffold inhibitors can be used, for example, to abrogate pathogenic responses to the microbiota that can arise from inflammatory bowel diseases and rheumatic diseases.

[0069] Definitions

[0070] The definitions of specific functional groups and chemical terms are described in more detail below. Chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Edition, inside cover, and specific functional groups are generally defined as described therein. In addition, general principles of organic chemistry and specific functional moieties and reactivity are described in the following: Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5th Edition, 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, 3rd Edition, Cambridge University Press, Cambridge, 1987.

[0071] The compounds described herein may contain one or more asymmetric centers and may thus 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 separated from the 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 the 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, E.L. Stereochemistry of Carbon Compounds, McGraw-Hill, NY, 1962; and Wilen, S.H., Tables of Resolving Agents and Optical Resolutions, page 268, E.L. Eliel, ed., Univ. of Notre Dame Press, Notre Dame, IN 1972. The present invention additionally encompasses compounds as individual isomers that are substantially free of other isomers and alternatively as mixtures of various isomers.

[0072] In the formula, is a single bond, where the stereochemistry of the moiety directly attached thereto is not specified, --- is absent or is a single bond, and or is a single bond or a double bond. The asterisk (*) adjacent to an atom indicates that the atom is a stereocenter of unknown absolute configuration. For example, in a pair of enantiomers, each may be depicted by a chemical structure having an asterisk (*) adjacent to the stereocenter, which will indicate that the absolute configuration of the stereocenter of the given enantiomer is not defined.

[0073] Unless otherwise stated, the structures depicted herein are also intended to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations of each stereocenter. Thus, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the compounds of the present invention are within the scope of the present invention. Unless otherwise stated, all tautomeric forms of the compounds of the present invention are within the scope of the present invention.

[0074] Unless otherwise stated, the structures depicted herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, in addition to the replacement of hydrogen by deuterium or tritium, replacement of 18 F with 19 F, or replacement of 13 C or 14 C with 12 C, compounds having the structures of the present invention are all within the scope of the present invention. Such compounds are useful, for example, as analytical tools or probes in bioanalysis.

[0075] When listing a range of values, it is intended that each value and sub-range within the range be covered. For example, "C 1-6 alkyl" is intended to cover C1, C2, C3, C4, C5, C6, C 1-6 , 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.

[0076] The term "aliphatic" refers to alkyl, alkenyl, alkynyl, and carbocyclic groups. Similarly, the term "heteroaliphatic" refers to heteroalkyl, heteroalkenyl, heteroalkynyl, and heterocyclic groups.

[0077] The term "alkyl" refers to a group of a straight-chain or branched-chain saturated hydrocarbon group having 1 to 10 carbon atoms ("C 1-10 alkyl"). In some embodiments, the alkyl has 1 to 9 carbon atoms ("C 1-9 alkyl"). In some embodiments, the alkyl has 1 to 8 carbon atoms ("C 1-8 alkyl"). In some embodiments, the alkyl has 1 to 7 carbon atoms ("C 1-7 alkyl"). In some embodiments, the alkyl has 1 to 6 carbon atoms ("C 1-6 alkyl"). In some embodiments, the alkyl has 1 to 5 carbon atoms ("C 1-5 alkyl"). In some embodiments, the alkyl has 1 to 4 carbon atoms ("C 1-4 alkyl"). In some embodiments, the alkyl has 1 to 3 carbon atoms ("C 1-3 alkyl"). In some embodiments, the alkyl has 1 to 2 carbon atoms ("C 1-2"alkyl"). In some embodiments, the alkyl group has 1 carbon atom ("C1 alkyl"). In some embodiments, the alkyl group has 2 to 6 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, isobutyl), pentyl (C5) (e.g., n-pentyl, 3-pentyl, amyl, neopentyl, 3-methyl-2-butyl, tert-pentyl), and hexyl (C6) (e.g., n-hexyl). Other examples of alkyl groups include n-heptyl (C7), n-octyl (C8), and similar groups. Unless otherwise specified, the alkyl group is independently unsubstituted ("unsubstituted alkyl") or substituted with one or more substituents (e.g., halogen, such as F) ("substituted alkyl") in each case. In certain embodiments, the alkyl group is unsubstituted C 1-10 alkyl (such as unsubstituted C 1-6 alkyl (e.g., -CH3 (Me)), unsubstituted ethyl (Et), unsubstituted propyl (Pr, e.g., unsubstituted n-propyl (n-Pr), unsubstituted isopropyl (i-Pr)), unsubstituted butyl (Bu, e.g., unsubstituted n-butyl (n-Bu), unsubstituted tert-butyl (tert-Bu or t-Bu), unsubstituted sec-butyl (sec-Bu), unsubstituted isobutyl (i-Bu)). In certain embodiments, the alkyl group is substituted C 1-10 alkyl (such as substituted C 1-6 alkyl, e.g., -CF3, Bn).

[0078] The term "haloalkyl" refers to a substituted alkyl group in which one or more hydrogen atoms are independently replaced by a halogen, such as fluorine, bromine, chlorine, or iodine. In some embodiments, the haloalkyl moiety has 1 to 8 carbon atoms ("C 1-8 haloalkyl"). In some embodiments, the haloalkyl moiety has 1 to 6 carbon atoms ("C 1-6 haloalkyl"). In some embodiments, the haloalkyl moiety has 1 to 4 carbon atoms ("C 1-4 haloalkyl"). In some embodiments, the haloalkyl moiety has 1 to 3 carbon atoms ("C 1-3 haloalkyl"). In some embodiments, the haloalkyl moiety has 1 to 2 carbon atoms ("C 1-2 haloalkyl"). Examples of haloalkyl groups include -CHF2, -CH2F, -CF3, -CH2CF3, -CF2CF3, -CF2CF2CF3, -CCl3, -CFCl2, -CF2Cl, and similar groups.

[0079] The term "deuterated alkyl" refers to an alkyl group in which one or more hydrogen atoms are independently replaced by deuterium. In some embodiments, the deuterated alkyl moiety has 1 to 8 carbon atoms ("C 1-8 deuterated alkyl"). In some embodiments, the deuterated alkyl moiety has 1 to 6 carbon atoms ("C 1-6 deuterated alkyl"). In some embodiments, the deuterated alkyl moiety has 1 to 4 carbon atoms ("C 1-4 deuterated alkyl"). In some embodiments, the deuterated alkyl moiety has 1 to 3 carbon atoms ("C 1-3 deuterated alkyl"). In some embodiments, the deuterated alkyl moiety has 1 to 2 carbon atoms ("C 1-2 deuterated alkyl"). In some embodiments, the deuterated alkyl moiety is a C1, C2, C3, C4, C5 or C6 deuterated alkyl. A deuterated alkyl moiety having n carbon atoms may have 1 to 2n + 1 deuterium atoms. Examples of deuterated alkyls include -CHD2, -CH2D, -CD3, -CH2CD3, -CD2CD3, -CD2CD2CD3, -CH(CD3)2, -CD(CD3)2, -C(CD3)3 and similar groups.

[0080] The term "hydroxyalkyl" is a substituted alkyl group in which one or more hydrogen atoms are independently replaced by a hydroxyl group. In some embodiments, the hydroxyalkyl moiety has 1 to 8 carbon atoms ("C 1-8 hydroxyalkyl"). In some embodiments, the hydroxyalkyl moiety has 1 to 6 carbon atoms ("C 1-6 hydroxyalkyl"). In some embodiments, the hydroxyalkyl moiety has 1 to 4 carbon atoms ("C 1-4 hydroxyalkyl"). In some embodiments, the hydroxyalkyl moiety has 1 to 3 carbon atoms ("C 1-3 hydroxyalkyl"). In some embodiments, the hydroxyalkyl moiety has 1 to 2 carbon atoms ("C 1-2 hydroxyalkyl").

[0081] The term "alkoxy" refers to an alkyl group as defined herein that is 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 alkoxy"). In some embodiments, the alkoxy moiety has 1 to 6 carbon atoms ("C 1-6 alkoxy"). In some embodiments, the alkoxy moiety has 1 to 4 carbon atoms ("C 1-4 alkoxy"). In some embodiments, the alkoxy moiety has 1 to 3 carbon atoms ("C 1-3 alkoxy"). In some embodiments, the alkoxy moiety has 1 to 2 carbon atoms ("C 1-2"alkoxy"). Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, and tert-butoxy.

[0082] The term "haloalkoxy" refers to a haloalkyl group as defined herein that is 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 haloalkoxy"). In some embodiments, the alkoxy moiety has 1 to 6 carbon atoms ("C 1-6 haloalkoxy"). In some embodiments, the alkoxy moiety has 1 to 4 carbon atoms ("C 1-4 haloalkoxy"). In some embodiments, the alkoxy moiety has 1 to 3 carbon atoms ("C 1-3 haloalkoxy"). In some embodiments, the alkoxy moiety has 1 to 2 carbon atoms ("C 1-2 haloalkoxy"). Representative examples of haloalkoxy include, but are not limited to, difluoromethoxy, trifluoromethoxy, and 2,2,2-trifluoroethoxy.

[0083] As defined herein, the term "alkoxyalkyl" is a substituted alkyl group in which one or more hydrogen atoms are independently replaced by an alkoxy group. In some embodiments, the alkoxyalkyl moiety has 1 to 8 carbon atoms ("C 1-8 alkoxyalkyl"). In some embodiments, the alkoxyalkyl moiety has 1 to 6 carbon atoms ("C 1-6 alkoxyalkyl"). In some embodiments, the alkoxyalkyl moiety has 1 to 4 carbon atoms ("C 1-4 alkoxyalkyl"). In some embodiments, the alkoxyalkyl moiety has 1 to 3 carbon atoms ("C 1-3 alkoxyalkyl"). In some embodiments, the alkoxyalkyl moiety has 1 to 2 carbon atoms ("C 1-2 alkoxyalkyl").

[0084] The term "heteroalkyl" refers to an alkyl group that further includes at least one heteroatom selected from oxygen, nitrogen, or sulfur (e.g., 1, 2, 3, or 4 heteroatoms) within the parent chain (i.e., inserted between adjacent carbon atoms of the parent chain) and / or at one or more terminal positions of the parent chain. In certain embodiments, heteroalkyl refers to a saturated group having 1 to 20 carbon atoms and one or more heteroatoms within the parent chain ("heteroC 1-20 alkyl"). In some embodiments, heteroalkyl is a saturated group having 1 to 18 carbon atoms and one or more heteroatoms within the parent chain ("heteroC 1-18 alkyl"). In some embodiments, heteroalkyl is a saturated group having 1 to 16 carbon atoms and one or more heteroatoms within the parent chain ("heteroC 1-16“alkyl”). In some embodiments, a heteroalkyl is a saturated group having from 1 to 14 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC 1-14 alkyl”). In some embodiments, a heteroalkyl is a saturated group having from 1 to 12 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC 1-12 alkyl”). In some embodiments, a heteroalkyl is a saturated group having from 1 to 10 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC 1-10 alkyl”). In some embodiments, a heteroalkyl is a saturated group having from 1 to 8 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC 1-8 alkyl”). In some embodiments, a heteroalkyl is a saturated group having from 1 to 6 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC 1-6 alkyl”). In some embodiments, a heteroalkyl is a saturated group having from 1 to 4 carbon atoms and 1 or 2 heteroatoms within the parent chain (“heteroC 1-4 alkyl”). In some embodiments, a heteroalkyl is a saturated group having from 1 to 3 carbon atoms and 1 heteroatom within the parent chain (“heteroC 1-3 alkyl”). In some embodiments, a heteroalkyl is a saturated group having from 1 to 2 carbon atoms and 1 heteroatom within the parent chain (“heteroC 1-2 alkyl”). In some embodiments, a heteroalkyl is a saturated group having 1 carbon atom and 1 heteroatom (“heteroC1 alkyl”). In some embodiments, a heteroalkyl as defined herein is a partially unsaturated group having 1 or more heteroatoms and at least one unsaturated carbon within the parent chain, such as a carbonyl group. For example, a heteroalkyl can include an amide or ester functional group in its parent chain such that one or more carbon atoms are unsaturated carbonyls. Unless otherwise specified, a heteroalkyl is independently unsubstituted (“unsubstituted heteroalkyl”) or substituted with one or more substituents (“substituted heteroalkyl”) in each case. In certain embodiments, the heteroalkyl is an unsubstituted heteroC 1-20 alkyl. In certain embodiments, the heteroalkyl is an unsubstituted heteroC 1-10 alkyl. In certain embodiments, the heteroalkyl is a substituted heteroC 1-20 alkyl. In certain embodiments, the heteroalkyl is an unsubstituted heteroC 1-10 alkyl.

[0085] The term “alkenyl” refers to a group of a straight-chain or branched-chain hydrocarbyl group having from 2 to 10 carbon atoms and one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 double bonds). In some embodiments, the alkenyl has from 2 to 9 carbon atoms (“C 2-9 alkenyl”). In some embodiments, the alkenyl has from 2 to 8 carbon atoms (“C 2-8“Alkenyl”). In some embodiments, the alkenyl has 2 to 7 carbon atoms (“C 2-7 “Alkenyl”). In some embodiments, the alkenyl has 2 to 6 carbon atoms (“C 2-6 “Alkenyl”). In some embodiments, the alkenyl has 2 to 5 carbon atoms (“C 2-5 “Alkenyl”). In some embodiments, the alkenyl has 2 to 4 carbon atoms (“C 2-4 “Alkenyl”). In some embodiments, the alkenyl has 2 to 3 carbon atoms (“C 2-3 “Alkenyl”). In some embodiments, the alkenyl has 2 carbon atoms (“C2 alkenyl”). One or more carbon-carbon double bonds may be internal (such as 2-butenyl) or terminal (such as 1-butenyl). C 2-4 Examples of alkenyls include vinyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and similar groups. C 2-6 Examples of alkenyls include the aforementioned C 2-4 alkenyls and pentenyl (C5), pentadienyl (C5), hexenyl (C6), and similar groups. Additional examples of alkenyls include heptenyl (C7), octenyl (C8), octatrienyl (C8), and similar groups. Unless otherwise specified, the alkenyl is independently unsubstituted (“unsubstituted alkenyl”) or substituted with one or more substituents (“substituted alkenyl”) in each case. In certain embodiments, the alkenyl is unsubstituted C 2-10 alkenyl. In certain embodiments, the alkenyl is substituted C 2-10 alkenyl. In an alkenyl, a C═C double bond for which the stereochemistry is not specified (e.g., -CH═CHCH3 or ) can be an (E) or (Z) double bond.

[0086] The term “heteroalkenyl” refers to an alkenyl that further includes at least one heteroatom selected from oxygen, nitrogen, or sulfur within the parent chain (i.e., inserted between adjacent carbon atoms of the parent chain) and / or at one or more terminal positions of the parent chain (e.g., 1, 2, 3, or 4 heteroatoms). In certain embodiments, the heteroalkenyl refers to a group having 2 to 10 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“hetero C 2-10 alkenyl”). In some embodiments, the heteroalkenyl has 2 to 9 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“hetero C 2-9 alkenyl”).

[0087] In some embodiments, the heteroalkenyl has 2 to 8 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“hetero C 2-8"Alkenyl"). In some embodiments, the heteroalkenyl has 2 to 7 carbon atoms, at least one double bond, and 1 or more heteroatoms ("hetero C 2-7 "Alkenyl"). In some embodiments, the heteroalkenyl has 2 to 6 carbon atoms, at least one double bond, and 1 or more heteroatoms ("hetero C 2-6 "Alkenyl"). In some embodiments, the heteroalkenyl has 2 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms ("hetero C 2-5 "Alkenyl"). In some embodiments, the heteroalkenyl has 2 to 4 carbon atoms, at least one double bond, and 1 or 2 heteroatoms ("hetero C 2-4 "Alkenyl"). In some embodiments, the heteroalkenyl has 2 to 3 carbon atoms, at least one double bond, and 1 heteroatom ("hetero C 2-3 "Alkenyl"). In some embodiments, the heteroalkenyl has 2 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms ("hetero C 2-6 "Alkenyl"). Unless otherwise specified, the heteroalkenyl is independently unsubstituted ("unsubstituted heteroalkenyl") or substituted with one or more substituents ("substituted heteroalkenyl") in each case. In certain embodiments, the heteroalkenyl is unsubstituted hetero C 2-10 "Alkenyl". In certain embodiments, the heteroalkenyl is substituted hetero C 2-10 "Alkenyl".

[0088] The term "alkynyl" refers to a group of a straight-chain or branched-chain hydrocarbyl group having 2 to 10 carbon atoms and one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 triple bonds) ("C 2-10 "Alkynyl"). In some embodiments, the alkynyl has 2 to 9 carbon atoms ("C 2-9 "Alkynyl"). In some embodiments, the alkynyl has 2 to 8 carbon atoms ("C 2-8 "Alkynyl"). In some embodiments, the alkynyl has 2 to 7 carbon atoms ("C 2-7 "Alkynyl"). In some embodiments, the alkynyl has 2 to 6 carbon atoms ("C 2-6 "Alkynyl"). In some embodiments, the alkynyl has 2 to 5 carbon atoms ("C 2-5 "Alkynyl"). In some embodiments, the alkynyl has 2 to 4 carbon atoms ("C 2-4 "Alkynyl"). In some embodiments, the alkynyl has 2 to 3 carbon atoms ("C 2-3 "Alkynyl"). In some embodiments, the alkynyl has 2 carbon atoms ("C2 alkynyl"). One or more carbon-carbon triple bonds can be internal (such as 2-butyne) or terminal (such as 1-butyne). C 2-4Examples of alkynyl groups include, but are not limited to, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and similar groups. C 2-6 Examples of alkenyl groups include the aforementioned C 2-4 alkynyl groups, as well as pentynyl (C5), hexynyl (C6), and similar groups. Additional examples of alkynyl groups include heptynyl (C7), octynyl (C8), and similar groups. Unless otherwise specified, the alkynyl group is independently unsubstituted (“unsubstituted alkynyl”) or substituted with one or more substituents (“substituted alkynyl”) in each case. In certain embodiments, the alkynyl group is unsubstituted C 2-10 alkynyl. In certain embodiments, the alkynyl group is substituted C 2-10 alkynyl.

[0089] The term “heteroalkynyl” refers to an alkynyl group that further includes at least one heteroatom selected from oxygen, nitrogen, or sulfur (e.g., 1, 2, 3, or 4 heteroatoms) within the parent chain (i.e., inserted between adjacent carbon atoms of the parent chain) and / or at one or more terminal positions of the parent chain. In certain embodiments, heteroalkynyl refers to a group having 2 to 10 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“hetero C 2-10 alkynyl”). In some embodiments, heteroalkynyl has 2 to 9 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“hetero C 2-9 alkynyl”). In some embodiments, heteroalkynyl has 2 to 8 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“hetero C 2-8 alkynyl”). In some embodiments, heteroalkynyl has 2 to 7 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“hetero C 2-7 alkynyl”). In some embodiments, heteroalkynyl has 2 to 6 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“hetero C 2-6 alkynyl”). In some embodiments, heteroalkynyl has 2 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain (“hetero C 2-5 alkynyl”). In some embodiments, heteroalkynyl has 2 to 4 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain (“hetero C 2-4 alkynyl”). In some embodiments, heteroalkynyl has 2 to 3 carbon atoms, at least one triple bond, and 1 heteroatom within the parent chain (“hetero C 2-3 alkynyl”). In some embodiments, heteroalkynyl has 2 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain (“hetero C 2-6"alkynyl"). Unless otherwise specified, a heteroalkynyl is independently unsubstituted ("unsubstituted heteroalkynyl") or substituted with one or more substituents ("substituted heteroalkynyl") in each case. In certain embodiments, the heteroalkynyl is an unsubstituted hetero-C 2-10 alkynyl. In certain embodiments, the heteroalkynyl is a substituted hetero-C 2-10 alkynyl.

[0090] The term "carbocyclic group" or "carbocycle" refers to a group of a non-aromatic cycloalkyl hydrocarbon group having 3 to 14 ring carbon atoms and zero heteroatoms in a non-aromatic ring system ("C 3-14 carbocyclic group"). In some embodiments, the carbocyclic group has 3 to 10 ring carbon atoms ("C 3-10 carbocyclic group"). In some embodiments, the carbocyclic group has 3 to 8 ring carbon atoms ("C 3-8 carbocyclic group"). In some embodiments, the carbocyclic group has 3 to 7 ring carbon atoms ("C 3-7 carbocyclic group"). In some embodiments, the carbocyclic group has 3 to 6 ring carbon atoms ("C 3-6 carbocyclic group"). In some embodiments, the carbocyclic group has 4 to 6 ring carbon atoms ("C 4-6 carbocyclic group"). In some embodiments, the carbocyclic group has 5 to 6 ring carbon atoms ("C 5-6 carbocyclic group"). In some embodiments, the carbocyclic group has 5 to 10 ring carbon atoms ("C 5-10 carbocyclic group"). Exemplary C 3-6 carbocyclic 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.

[0091] Exemplary C 3-8 carbocyclic groups include, but are not limited to, the foregoing C 3-8 carbocyclic groups and cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrieneyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptyl (C7), bicyclo[2.2.2]octyl (C8), and the like. Exemplary C 3-10 carbocyclic groups include, but are not limited to, the foregoing C 3-8 carbocyclic groups and cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C 10 ), spiro[4.5]decyl (C 10) and similar groups. As illustrated by the foregoing examples, in certain embodiments, the carbocyclic group is monocyclic ("monocyclic carbocyclic group") or polycyclic (e.g., containing a fused, bridged or spiro ring system, such as a bicyclic system ("bicyclic carbocyclic group") or a tricyclic system ("tricyclic carbocyclic group")) and may be saturated or may contain one or more carbon-carbon double or triple bonds. "Carbocyclic group" also includes a ring system in which a carbocyclic group ring as defined above is fused to one or more aryl or heteroaryl groups, where the point of attachment is on the carbocyclic group ring, and in such cases, the carbon number continues to indicate the number of carbons in the carbocyclic system. Unless otherwise specified, the carbocyclic group is independently unsubstituted ("unsubstituted carbocyclic group") or substituted with one or more substituents ("substituted carbocyclic group") in each case. In certain embodiments, the carbocyclic group is unsubstituted C 3-14 carbocyclic group. In certain embodiments, the carbocyclic group is substituted C 3-14 carbocyclic group.

[0092] In some embodiments, "carbocyclic group" is a monocyclic saturated carbocyclic group having 3 to 14 ring carbon atoms ("C 3-14 cycloalkyl"). In some embodiments, the cycloalkyl has 3 to 10 ring carbon atoms ("C 3-10 cycloalkyl"). In some embodiments, the cycloalkyl has 3 to 8 ring carbon atoms ("C 3-8 cycloalkyl"). In some embodiments, the cycloalkyl has 3 to 6 ring carbon atoms ("C 3-6 cycloalkyl"). In some embodiments, the cycloalkyl has 4 to 6 ring carbon atoms ("C 4-6 cycloalkyl"). In some embodiments, the cycloalkyl has 5 to 6 ring carbon atoms ("C 5-6 cycloalkyl"). In some embodiments, the cycloalkyl has 5 to 10 ring carbon atoms ("C 5-10 cycloalkyl"). Examples of C 5-6 cycloalkyl include cyclopentyl (C5) and cyclohexyl (C6). Examples of C 3-6 cycloalkyl include the foregoing C 5-6 cycloalkyl and cyclopropyl (C3) and cyclobutyl (C4). Examples of C 3-8 cycloalkyl include the foregoing C 3-6 cycloalkyl and cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise specified, the cycloalkyl is independently unsubstituted ("unsubstituted cycloalkyl") or substituted with one or more substituents ("substituted cycloalkyl") in each case. In certain embodiments, the cycloalkyl is unsubstituted C 3-14 cycloalkyl. In certain embodiments, the cycloalkyl is substituted C 3-14 cycloalkyl.

[0093] The term "heterocyclic group" or "heterocycle" refers to a group of a 3- to 14-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("3-14 membered heterocyclic group"). In a heterocyclic group containing one or more nitrogen atoms, when the valence allows, the point of attachment can be a carbon or nitrogen atom. The heterocyclic group can be monocyclic ("monocyclic heterocyclic group") or polycyclic (e.g., a fused, bridged, or spiro ring system, such as a bicyclic system ("bicyclic heterocyclic group") or a tricyclic system ("tricyclic heterocyclic group")), and can be saturated or can contain one or more carbon-carbon double or triple bonds. The polycyclic heterocyclic group system can include one or more heteroatoms in one or two rings. "Heterocyclic group" also includes a ring system in which a heterocyclic group ring as defined above is fused with one or more carbocyclic groups, wherein the point of attachment is on the carbocyclic group or the heterocyclic group ring, or a ring system in which a heterocyclic group as defined above is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclic group ring, and in such cases, the number of ring members continues to indicate the number of ring members in the heterocyclic group ring system. Unless otherwise specified, the heterocyclic group is independently unsubstituted ("unsubstituted heterocyclic group") or substituted with one or more substituents ("substituted heterocyclic group") in each case. In certain embodiments, the heterocyclic group is an unsubstituted 3-14 membered heterocyclic group. In certain embodiments, the heterocyclic group is a substituted 3-14 membered heterocyclic group.

[0094] In some embodiments, the heterocyclic group is a 4- to 10-membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("4-10 membered heterocyclic group"). In some embodiments, the heterocyclic group is a 4- to 8-membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-8 membered heterocyclic group"). In some embodiments, the heterocyclic group is a 5- to 6-membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-6 membered heterocyclic group"). In some embodiments, the 5-6 membered heterocyclic group has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclic group has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclic group has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0095] Exemplary 3-membered heterocyclic groups containing one heteroatom include, but are not limited to, aziridinyl, oxiranyl, and thiiranyl. Exemplary 4-membered heterocyclic groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclic groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, pyrrolidinyl, dihydropyrrolyl, and pyrrol-2,5-dione. Exemplary 5-membered heterocyclic groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxathiolanyl, and dithiolanyl. Exemplary 5-membered heterocyclic groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclic groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridyl, and thianyl. Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclic groups containing three heteroatoms include, but are not limited to, triazinyl. Exemplary 7-membered heterocyclic groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Exemplary 8-membered heterocyclic groups containing one heteroatom include, but are not limited to, azocanyl, oxocanyl, and thioocanyl. Exemplary bicyclic heterocyclic 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, phthalimido, naphthalimido, chromanyl, chromenyl, 1H-benzo[e][1,4]diazepinyl, 1,4,5,7-tetrahydropyrano[3,4-b]pyrrolyl, 5,6-dihydro-4H-furo[3,2-b]pyrrolyl, 6,7-dihydro-5H-furo[3,2-b]pyranyl, 5,7-dihydro-4H-thieno[2,3-c]pyranyl, 2,3-dihydro-1H-pyrrolo[2,3-b]pyridyl, 2,3-dihydrofuro[2,3-b]pyridyl, 4,5,6,7-tetrahydro-1H-pyrrolo[2,3-b]pyridyl, 4,5,6,7-tetrahydrofuro[3,2-c]pyridyl, 4,5,6,7-tetrahydrothieno[3,2-b]pyridyl, 1,2,3,4-tetrahydro-1,6-naphthyridinyl, and the like.

[0096] The term "aryl" refers to a group of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having a total of 6, 10, or 14 π electrons in the ring array), where the aromatic ring system has 6-14 ring carbon atoms and zero heteroatoms ("C6 -14"aryl"). In some embodiments, the aryl has 6 ring carbon atoms ("C6 aryl"; e.g., phenyl). In some embodiments, the aryl has 10 ring carbon atoms ("C 10 aryl"; e.g., naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, the aryl has 14 ring carbon atoms ("C 14 aryl"; e.g., anthryl). "Aryl" also includes a ring system in which the aryl ring as defined above is fused to one or more carbocyclic or heterocyclic groups, wherein the linking group or point of attachment is on the aryl ring, and in such cases, the number of carbon atoms continues to indicate the number of carbon atoms in the aryl ring system. Unless otherwise specified, the aryl is independently unsubstituted ("unsubstituted aryl") or substituted with one or more substituents ("substituted aryl") in each case. In certain embodiments, the aryl is unsubstituted C 6-14 aryl. In certain embodiments, the aryl is substituted C 6-14 aryl.

[0097] "Aralkyl" is a subset of "alkyl" and refers to an alkyl group substituted with an aryl group, wherein the point of attachment is on the alkyl moiety.

[0098] The term "heteroaryl" refers to a group of 5-14 membered monocyclic or polycyclic (e.g., bicyclic, tricyclic) 4n+2 aromatic ring systems (e.g., having a total of 6, 10 or 14 π electrons in the ring array), the aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur ("5-14 membered heteroaryl"). In a heteroaryl containing one or more nitrogen atoms, when the valence allows, the point of attachment can be a carbon or nitrogen atom. The heteroaryl polycyclic system can include one or more heteroatoms in one or two rings. "Heteroaryl" includes a ring system in which the heteroaryl ring as defined above is fused to one or more carbocyclic or heterocyclic groups, wherein the point of attachment is on the heteroaryl ring, and in such cases, the number of ring members continues to indicate the number of ring members in the heteroaryl ring system. "Heteroaryl" also includes a ring system in which the heteroaryl ring as defined above is fused to one or more aryl groups, wherein the point of attachment is on the aryl or heteroaryl ring, and in such cases, the number of ring members indicates the number of ring members in the fused polycyclic (aryl / heteroaryl) ring system. For a polycyclic heteroaryl in which one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl and similar groups), the point of attachment can be on either ring, i.e., the ring carrying the heteroatom (e.g., 2-indolyl) or the ring without a heteroatom (e.g., 5-indolyl).

[0099] In some embodiments, the heteroaryl is a 5- to 12-membered aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, each heteroatom independently selected from nitrogen, oxygen, and sulfur (“5- to 12-membered heteroaryl”). In some embodiments, the heteroaryl is a 5- to 10-membered aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, each heteroatom independently selected from nitrogen, oxygen, and sulfur (“5- to 10-membered heteroaryl”). In some embodiments, the heteroaryl is a 5- to 8-membered aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, each heteroatom independently selected from nitrogen, oxygen, and sulfur (“5- to 8-membered heteroaryl”). In some embodiments, the heteroaryl is a 5- to 6-membered aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, each heteroatom independently selected from nitrogen, oxygen, and sulfur (“5- to 6-membered heteroaryl”). In some embodiments, the 5- to 6-membered heteroaryl has 1 to 3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heteroaryl has 1 to 2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, the heteroaryl is independently unsubstituted (“unsubstituted heteroaryl”) or substituted with one or more substituents (“substituted heteroaryl”) in each case. In certain embodiments, the heteroaryl is an unsubstituted 5- to 14-membered heteroaryl. In certain embodiments, the heteroaryl is a substituted 5- to 14-membered heteroaryl.

[0100] Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furyl, and thienyl. 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, pyridyl. 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, benzothienyl, isobenzothienyl, benzofuryl, isobenzofuryl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, 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.

[0101] "Heteroalkyl" 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 moiety.

[0102] The term "unsaturated bond" refers to a double bond or a triple bond.

[0103] The term "unsaturated" or "partially unsaturated" refers to a moiety that includes at least one double bond or triple bond.

[0104] The term "saturated" refers to a moiety that does not contain a double bond or a triple bond, i.e., the moiety contains only single bonds.

[0105] A group prefaced with "sub-" indicates that the group is a divalent moiety. For example, "sub-alkyl" is the divalent moiety of an alkyl group, "sub-alkenyl" is the divalent moiety of an alkenyl group, "sub-alkynyl" is the divalent moiety of an alkynyl group, "sub-heteroalkyl" is the divalent moiety of a heteroalkyl group, "sub-heteroalkenyl" is the divalent moiety of a heteroalkenyl group, "sub-heteroalkynyl" is the divalent moiety of a heteroalkynyl group, "sub-carbocyclic" is the divalent moiety of a carbocyclic group, "sub-heterocyclic" is the divalent moiety of a heterocyclic group, "sub-aryl" is the divalent moiety of an aryl group, and "sub-heteroaryl" is the divalent moiety of a heteroaryl group.

[0106] Unless otherwise expressly provided, groups are optionally substituted. The term "optionally substituted" means substituted or unsubstituted. In certain embodiments, alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclic, cycloalkyl, heterocyclic, aryl, and heteroaryl are optionally substituted. "Optionally substituted" refers to a group that may be substituted or unsubstituted (e.g., a "substituted" or "unsubstituted" alkyl, a "substituted" or "unsubstituted" alkenyl, a "substituted" or "unsubstituted" alkynyl, a "substituted" or "unsubstituted" heteroalkyl, a "substituted" or "unsubstituted" heteroalkenyl, a "substituted" or "unsubstituted" heteroalkynyl, a "substituted" or "unsubstituted" carbocyclic, a "substituted" or "unsubstituted" heterocyclic, a "substituted" or "unsubstituted" aryl, or a "substituted" or "unsubstituted" heteroaryl). Generally, the term "substituted" means that at least one hydrogen present on the group is replaced with an admissible substituent, e.g., a substituent that results in a stable compound (e.g., a compound that does not spontaneously undergo transformation such as rearrangement, cyclization, elimination, or other reactions). Unless otherwise specified, a "substituted" group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituents are the same or different at each position. The term "substituted" is contemplated to include substitution with all admissible substituents of an organic compound and includes any of the substituents described herein that result in the formation of a stable compound. The present invention encompasses any and all such combinations in order to obtain stable compounds. For the purposes of the present invention, a heteroatom (such as nitrogen) may have a hydrogen substituent and / or any suitable substituent described herein that satisfies the valence of the heteroatom and results in the formation of a stable moiety. The present invention is not intended to be limited in any way by the exemplary substituents described herein.

[0107] Exemplary carbon atom substituents include, but are not limited to, halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR aa , -ON(R bb )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(Rbb ) 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)SR aa , -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 C 2-10 alkynyl, C 3-10 carbocyclic group, 3 - 14 membered heterocyclic group, C 6-14 aryl and 5 - 14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclic group, heterocyclic group, aryl and heteroaryl is independently substituted by 0, 1, 2, 3, 4 or 5 R dd groups; wherein X - is a counter ion; or two geminal hydrogens on a carbon atom are replaced by the following groups: =O, =S, =NN(R bb )2, =NNR bb C(=O)R aa , =NNR bb C(=O)OR aa , =NNR bb S(=O)2R aa , =NRbb or = NOR cc ; R aa independently selected from 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 carbocyclic group, 3 - 14 membered heterocyclic group, C 6-14 aryl and 5 - 14 membered heteroaryl, or two R aa groups are joined to form a 3 - 14 membered heterocyclic group or a 5 - 14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclic group, heterocyclic group, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5 R dd groups; R bb independently selected from 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 carbocyclic group, 3 - 14 membered heterocyclic group, C 6-14 aryl and 5 - 14 membered heteroaryl, or two R bbGroups combine to form a 3- to 14-membered heterocyclic group or a 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclic group, heterocyclic group, aryl, and heteroaryl is independently substituted by 0, 1, 2, 3, 4, or 5 R dd groups; where X - is a counter ion; R cc is independently selected in each case from hydrogen, 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 carbocyclic group, 3- to 14-membered heterocyclic group, C 6-14 aryl, and 5- to 14-membered heteroaryl, or two R cc groups combine to form a 3- to 14-membered heterocyclic group or a 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclic group, heterocyclic group, aryl, and heteroaryl is independently substituted by 0, 1, 2, 3, 4, or 5 R dd groups; R dd is independently selected in each case from 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(=NRff ) 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, -SO2R ee 、 -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 carbocyclic group, 3 - 10 membered heterocyclic group, C 6-10 aryl, 5 - 10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclic group, heterocyclic group, aryl and heteroaryl is independently substituted by 0, 1, 2, 3, 4 or 5 R gg groups, or two geminal R dd substituents may combine to form =O or =S; wherein X - is a counter ion; R ee is independently selected from 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 3-10Carbocyclic group, C 6-10 alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclic group, heterocyclic group, aryl and heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclic group, heterocyclic group, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5 R gg groups; R ff is independently selected from 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 carbocyclic group, 3- to 10-membered heterocyclic group, C 6-10 aryl and 5- to 10-membered heteroaryl, or two R ff groups join to form a 3- to 10-membered heterocyclic group or a 5- to 10-membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclic group, heterocyclic group, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5 R gg groups; and R gg is independently in each case a halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC 1-6 alkyl, -ON(C 1-6 alkyl)2, -N(C l-6 alkyl)2, -N(C l-6 alkyl)3 + X - , -NH(C l-6 alkyl)2 + X - , -NH2(C 1-6 alkyl) + X - , -NH3 + X - , -N(OC 1-6 alkyl)(C l-6 alkyl), -N(OH)(C l-6 alkyl), -NH(OH), -SH, -SC 1-6 alkyl, -SS(C l-6 alkyl), -C(=O)(C l-6 alkyl), -CO2H, -CO2(C 1-6 alkyl), -OC(=O)(C l-6 alkyl), -OCO2(C 1-6 alkyl), -C(=O)NH2, -C(=O)N(C 1-6 alkyl)2, -OC(=O)NH(C1-6 alkyl), -NHC(=O)(C l-6 alkyl), -N(C l-6 alkyl)C(=O)(C 1-6 alkyl), -NHCO2(C 1-6 alkyl), -NHC(=O)N(C l-6 alkyl)2, -NHC(=O)NH(C l-6 alkyl), -NHC(=O)NH2, -C(=NH)O(C l-6 alkyl), -OC(=NH)(C l-6 alkyl), -OC(=NH)OC l-6 alkyl, -C(=NH)N(C l-6 alkyl)2, -C(=NH)NH(C l-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 l-6 alkyl)3, -OSi(C l-6 alkyl)3, -C(=S)N(C l-6 alkyl)2, -C(=S)NH(C l-6 alkyl), -C(=S)NH2, -C(=O)S(C l-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 l-6 alkyl)2, -OP(=O)(OC l-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-C2-6 Alkenyl, hetero-C 2-6 Alkynyl, C 3-10 Carbocyclic group, C 6-10 Aryl, 3- to 10-membered heterocyclic group, 5- to 10-membered heteroaryl; or two vicinal R gg The substituent may be joined to form =O or =S; wherein X - is a counter ion.

[0108] The term "halo" or "halogen" refers to fluorine (fluoro group, -F), chlorine (chloro group, -Cl), bromine (bromo group, -Br) or iodine (iodo group, -I).

[0109] The term "hydroxyl" or "hydroxy" refers to the -OH group. It can be inferred therefrom that the term "substituted hydroxyl" or "substituted hydroxy" refers to a hydroxyl group in which the oxygen atom directly attached to the parent molecule is substituted by a group other than hydrogen, and includes groups selected from: -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 , -OSO2R aa , -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 are as defined herein.

[0110] The term "amino" refers to the -NH2 group. It follows that the term "substituted amino" refers to mono-substituted amino, di-substituted amino, or tri-substituted amino. In certain embodiments, "substituted amino" is mono-substituted amino or di-substituted amino.

[0111] The term "mono-substituted amino" refers to an amino in which the nitrogen atom directly attached to the parent molecule is substituted by one hydrogen and one group other than hydrogen, and includes groups selected from: -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, where R aa , R bb and R cc are as defined herein, and where the R bb of the -NH(R bb ) group is not hydrogen.

[0112] The term "di-substituted amino" refers to an amino in which the nitrogen atom directly attached to the parent molecule is substituted by two groups other than hydrogen, and includes groups selected from: -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 bb P(=O)(N(R bb )2)2, where R aa , R bb and R cc are as defined herein, provided that the nitrogen atom directly attached to the parent molecule is not substituted by hydrogen.

[0113] The term "trisubstituted amino" refers to an amino group in which the nitrogen atom directly attached to the parent molecule is substituted by three groups, and includes groups selected from -N(R bb )2 and -N(R bb )3 + X - , where R bb and X - are as defined herein.

[0114] The term "sulfonyl" refers to groups selected from -SO2N(R bb )2, -SO2R aa and -SO2OR aa , where R aa and R bb are as defined herein.

[0115] The term "sulfinyl" refers to the -S(=O)R aa group, where R aa is as defined herein.

[0116] The term "acyl" refers to groups having the general formulas -C(=O)R X1 , -C(=O)OR X1 , -C(=O)-O-C(=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, where R X1is hydrogen; halogen; substituted or unsubstituted hydroxy; substituted or unsubstituted mercapto; 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, aliphatic oxy, heteroaliphatic oxy, alkoxy, heteroalkyloxy, aryloxy, heteroaryloxy, aliphatic mercapto, heteroaliphatic mercapto, alkyl mercapto, heteroalkyl mercapto, aryl mercapto, heteroaryl mercapto, mono- or di-aliphatic amino, mono- or di-heteroaliphatic amino, mono- or di-alkyl amino, mono- or di-heteroalkyl amino, mono- or di-aryl amino, or mono- or di-heteroaryl amino; or two R X1 groups together form a 5- to 6-membered heterocycle.

[0117] Exemplary acyl groups include aldehyde (-CHO), carboxylic acid (-CO2H), ketone, acyl halide, ester, amide, imide, carbonate, carbamate, and urea. Acyl substituents include, but are not limited to, any of the substituents described herein that cause the formation of a stable moiety (e.g., aliphatic, alkyl, alkenyl, alkynyl, heteroaliphatic, heterocyclic, aryl, heteroaryl, acyl, oxo, imino, thio, cyano, isocyano, amino, azido, nitro, hydroxy, mercapto, halo, aliphatic amino, heteroaliphatic amino, alkyl amino, heteroalkyl amino, aryl amino, heteroaryl amino, alkylaryl, arylalkyl, aliphatic oxy, heteroaliphatic oxy, alkoxy, heteroalkyloxy, aryloxy, heteroaryloxy, aliphatic mercapto, heteroaliphatic mercapto, alkyl mercapto, heteroalkyl mercapto, aryl mercapto, heteroaryl mercapto, acyloxy, and the like, each of which may or may not be further substituted).

[0118] The term "carbonyl" refers to a group in which the carbon directly attached to the parent molecule is sp 2 hybridized and substituted with an oxygen, nitrogen, or sulfur atom, such as a group selected from: ketone (e.g., -C(=O)R aa ), carboxylic acid (e.g., -CO2H), aldehyde (-CHO), ester (e.g., -CO2R aa , -C(=O)SR aa , -C(=S)SR aa ), amide (e.g., -C(=O)N(R bb )2, C(=O)NR bb SO2R aa , -C(=S)N(R bb )2), and imide (e.g., -C(=NR bb )R aa, -C(=NR bb ) OR aa ), -C(=NR bb )N(R bb )2), wherein R aa and R bb are as defined herein.

[0119] The term "oxo" refers to the =O group, and the term "thioxo" refers to the =S group.

[0120] When valency permits, the nitrogen atom may be substituted or unsubstituted and includes primary, secondary, tertiary and quaternary nitrogen atoms. Exemplary nitrogen atom substituents include, but are not limited to, 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-C 1-10 alkyl, hetero-C 2-10 alkenyl, hetero-C 2-10 alkynyl, C 3-10 carbocyclic, 3- to 14-membered heterocyclic, C 6-14 aryl and 5- to 14-membered heteroaryl, or two R cc groups attached to the N atom join to form a 3- to 14-membered heterocyclic or 5- to 14-membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclic, heterocyclic, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5 Rdd group-substituted, and wherein R aa , R bb , R cc and R dd is as defined herein.

[0121] In certain embodiments, the substituent present on the nitrogen atom is a nitrogen protecting group (also referred to herein as an "amino protecting group"). Nitrogen protecting groups include, but are not limited to, -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 carbocyclic group, 3- to 14-membered heterocyclic group, C 6-14 aryl and 5- to 14-membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclic group, heterocyclic group, aralkyl, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5 R dd groups, and wherein R aa , R bb , R cc and R dd is as defined herein. Nitrogen protecting groups are well known in the art and include those protecting groups described in detail in Protecting Groups in Organic Synthesis, T.W. Greene and P.G.M. Wuts, 3rd Edition, John Wiley & Sons, 1999, which is incorporated herein by reference.

[0122] For example, nitrogen protecting groups (such as acylamino groups (e.g., -C(=O)R aa ) include but are not limited to formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropanamide, picolinamide, 3-pyridylcarboxamide, N-benzoyl-phenylalanyl derivatives, benzamide, p-phenylbenzamide, o-nitrophenylacetamide, o-nitrophenoxyacetamide, acetoacetamide, (N'-dithiobenzyloxyacylamina)acetamide, 3-(p-hydroxyphenyl)propanamide, 3-(o-nitrophenyl)propanamide, 2-methyl-2-(o-nitrophenoxy)propanamide, 2-methyl-2-(o-phenylazophenoxy)propanamide, 4-chlorobutanamide, 3-methyl-3-nitrobutanamide, o-nitrocinnamide, N-acetylmethionine derivatives, o-nitrobenzamide and o-(benzoyloxymethyl)benzamide.

[0123] Nitrogen protecting groups (such as carbamate groups (e.g., -C(=O)OR aa)including but not limited to methyl carbamate, ethyl carbamate, 9-fluorenylmethyl carbamate (Fmoc), 9-(2-sulfa)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluorenylmethyl carbamate, 2,7-di-tert-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methyl carbamate (DBD-Tmoc), 4-methoxybenzoylmethyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl carbamate (Teoc), 2-phenylethyl carbamate (hZ), 1-(1-adamantyl)-1-methylethyl carbamate (Adpoc), 1,1-dimethyl-2-haloethyl carbamate, 1,1-dimethyl-2,2-dibromoethyl carbamate (DB-t-BOC), 1,1-dimethyl-2,2,2-trichloroethyl carbamate (TCBOC), 1-methyl-1-(4-biphenylyl)ethyl carbamate (Bpoc), 1-(3,5-di-tert-butylphenyl)-1-methylethyl carbamate (t-Bumeoc), 2-(2'- and 4'-pyridyl)ethyl carbamate (Pyoc), 2-(N,N-dicyclohexylcarbamoyl)ethyl carbamate, tert-butyl carbamate (BOC or Boc), 1-adamantyl carbamate (Adoc), vinyl carbamate (Voc), allyl carbamate (Alloc), 1-isopropylallyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc), 8-quinolyl carbamate, N-hydroxypiperidyl carbamate, alkyl dithiocarbamate, 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, dibenzyl carbamate, 2-methylthioethyl carbamate, 2-methylsulfonylethyl carbamate, 2-(p-toluenesulfonyl)ethyl carbamate, [2-(1,3-dithianyl)]methyl carbamate (Dmoc), 4-methylthiophenyl carbamate (Mtpc), 2,4-dimethylthiophenyl carbamate (Bmpc), 2-phosphonioethylcarbamate (Peoc), 2-triphenylphosphonioisopropyl carbamate (Ppoc), 1,1-dimethyl-2-cyanoethyl carbamate, m-chloro-p-acetyloxybenzyl carbamate, p-(dihydroxyboranyl)benzyl carbamate, 5-benzisoxazolylmethyl carbamate, 2-(trifluoromethyl)-6-chromonylmethyl carbamate (Tcroc), m-nitrobenzyl carbamate, 3,5-Dimethoxybenzyl, o-nitrobenzyl carbamate, 3,4-dimethoxy-6-nitrobenzyl carbamate, phenyl(o-nitrophenyl)methyl carbamate, tert-amyl carbamate, S-benzyl thiocarbamate, p-cyanobenzyl carbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentyl carbamate, cyclopropylmethyl carbamate, p-decyloxybenzyl carbamate, 2,2-dimethoxyacylvinyl carbamate, o-(N,N-dimethylformamido)benzyl carbamate, 1,1-dimethyl-3-(N,N-dimethylformamido)propyl carbamate, 1,1-dimethylpropargyl carbamate, bis(2-pyridyl)methyl carbamate, 2-furylmethyl carbamate, 2-iodoethyl carbamate, isobornyl carbamate, isobutyl carbamate, isonicotinyl carbamate, p-(p'-methoxyphenylazo)benzyl carbamate, 1-methylcyclobutyl carbamate, 1-methylcyclohexyl carbamate, 1-methyl-1-cyclopropylmethyl carbamate, 1-methyl-1-(3,5-dimethoxyphenyl)ethyl carbamate, 1-methyl-1-(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-tert-butylphenyl carbamate, 4-(trimethylammonium)benzyl carbamate and 2,4,6-trimethylphenyl carbamate.,

[0124] Nitrogen protecting groups such as sulfonamido (e.g. -S(=O)2R aa ) including but not limited to p-toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6-trimethyl-4-methoxybenzenesulfonamide (Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb), 2,6-dimethyl-4-methoxybenzenesulfonamide (Pme), 2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte), 4-methoxybenzenesulfonamide (Mbs), 2,4,6-trimethylbenzenesulfonamide (Mts), 2,6-dimethoxy-4-methylbenzenesulfonamide (iMds), 2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide (Ms), -trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide, 4-(4',8'-dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS), benzylsulfonamide, trifluoromethanesulfonamide and benzoylmethylsulfonamide.,

[0125] Other nitrogen protecting groups include but are not limited to phenothiazinyl-(10)-acyl derivatives, N'-tosylamidoacyl derivatives, N'-phenylaminothioacyl derivatives, N-benzoylphenylalanyl derivatives, N-acetylmethionine derivatives, 4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dithiosuccinimide (Dts), N-2,3-diphenylmaleimide, N-2,5-dimethylpyrrole, N-1,1,4,4-tetramethyldisilazacyclopentane adduct (STABASE), 5-substituted 1,3-dimethyl-1,3,5-triazacyclohexan-2-one, 5-substituted 1,3-dibenzyl-1,3,5-triazacyclohexan-2-one, 1-substituted 3,5-dinitro-4-pyridone, N-methylamine, N-allylamine, N-[2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine, N-(1-isopropyl-4-nitro-2-oxo-3-pyrrolin-3-yl)amine, quaternary ammonium salts, N-benzylamine, N-di(4-methoxyphenyl)methylamine, N-5-dibenzocycloheptylamine, N-triphenylmethylamine (Tr), N-[(4-methoxyphenyl)diphenylmethyl]amine (MMTr), N-9-phenylfluorenylamine (PhF), N-2,7-dichloro-9-fluorenylmethyleneamine, N-ferrocenylmethylamino (Fern), N-2-pyridylmethylamino N'-oxide, N-1,1-dimethylthio-methyleneamine, N-benzylideneamine, N-p-methoxybenzylideneamine, N-dibenzylideneamine, N-[(2-pyridyl)(mesityl)]methyleneamine, N-(N',N'-dimethylaminomethylene)amine, N,N'-isopropylidenediamine, N-p-nitrobenzylideneamine, N-salicylideneamine, N-5-chlorosalicylideneamine, N-(5-chloro-2-hydroxyphenyl)benzylideneamine, N-cyclohexylideneamine, N-(5,5-dimethyl-3-oxo-1-cyclohexenyl)amine, N-borane derivatives, N-diphenylborinic acid derivatives, N-[phenyl(pentacarbonylchromium or pentacarbonyltungsten)acyl]amine, N-copper chelates, N-zinc chelates, N-nitroamines, N-nitrosoamines, amine N-oxides, diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt), diphenylthiophosphinamide (Ppt), dialkyl aminophosphates, diphenylmethyl aminophosphate, diphenyl aminophosphate, benzenesulfinamide, o-nitrobenzenesulfinamide (Nps), 2,4-dinitrobenzenesulfinamide, pentachlorobenzenesulfinamide, 2-nitro-4-methoxybenzenesulfinamide, triphenylmethylsulfinamide and 3-nitropyridinesulfinamide (Npys).In certain embodiments, the nitrogen protecting group is benzyl (Bn), tert-butoxycarbonyl (BOC), benzyloxycarbonyl (Cbz), 9-fluorenylmethoxycarbonyl (Fmoc), trifluoroacetyl, trityl, acetyl (Ac), benzoyl (Bz), p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), 2,2,2-trichloroethoxycarbonyl (Troc), trityl (Tr), tosyl (Ts), brosyl (Bs), nosyl (Ns), mesyl (Ms), trifluoromethanesulfonyl (Tf), or dansyl (Ds).

[0126] In certain embodiments, the substituent present on the oxygen atom is an oxygen protecting group (also referred to herein as a “hydroxy protecting group”). Oxygen protecting groups include, but are not limited to, -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, where X - , R aa , R bb , and R cc are as defined herein. Oxygen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rd Edition, John Wiley & Sons, 1999, which is incorporated herein by reference.

[0127] Exemplary oxygen protecting groups include but are not limited to methyl, methoxymethyl (MOM), methylthiomethyl (MTM), tert-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM), tert-butoxymethyl, 4-pentenoxymethyl (POM), silyloxymethyl, 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, tetrahydrothiopyranyl, 2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanoisobenzofuran-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-(phenylseleno)ethyl, tert-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-pyridylmethyl, 4-pyridylmethyl, 3-methyl-2-pyridylmethyl N-oxide, diphenylmethyl, p,p'-dinitrodiphenylmethyl, 5-dibenzosuberyl, triphenylmethyl, α-naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl, bis(p-methoxyphenyl)phenylmethyl, tris(p-methoxyphenyl)methyl, 4-(4'-bromobenzoylmethyloxyphenyl)diphenylmethyl, 4,4',4''-tris(4,5-dichlorophthalimido)phenylmethyl, 4,4',4''-tris(acetylpropionyloxyphenyl)methyl, 4,4',4''-tris(benzoyloxyphenyl)methyl, 3-(imidazol-1-yl)bis(4',4''-dimethoxyphenyl)methyl, 1,1-bis(4-methoxyphenyl)-1'-pyrenylmethyl, 9-anthryl, 9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl, 1,3-benzodithiolan-2-yl, benzisothiazolyl S,S-sulfoxides, trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS), dimethyl-tert-hexylsilyl, tert-butyldimethylsilyl (TBDMS), tert-butyldiphenylsilyl (TBDPS), tritylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl (DPMS), tert-butylmethoxyphenylsilyl (TEMPS), formates, benzoylformates, acetates, chloroacetates, dichloroacetates, trichloroacetates, trifluoroacetates, methoxyacetates, triphenylmethoxyacetates, phenoxyacetates, p-chlorophenoxyacetates, 3-phenylpropionates, 4-oxopentanoates (levulinates), 4,4-(ethylenedithio)pentanoates (levulinoyl dithioacetals), pivalates, adamantates, crotonates, 4-methoxycrotonates, benzoates, p-phenylbenzoates, 2,4,6-trimethylbenzoates (mesylates), methyl carbonates, 9-fluorenylmethyl carbonates (Fmoc), ethyl carbonates, 2,2,2-trichloroethyl carbonates (Troc), 2-(trimethylsilyl)ethyl carbonates (TMSEC), 2-(phenylsulfonyl)ethyl carbonates (Psec), 2-(triphenylphosphonium)ethyl carbonates (Peoc), isobutyl carbonates, ethylene carbonates, allyl carbonates, tert-butyl carbonates (BOC or Boc), p-nitrophenyl carbonates, benzyl carbonates, p-methoxybenzyl carbonates, 3,4-dimethoxybenzyl carbonates, o-nitrobenzyl carbonates, p-nitrobenzyl carbonates, S-benzyl thiocarbonates, 4-ethoxy-1-naphthyl carbonates, methyl dithiocarbonates, 2-iodobenzoates, 4-azidobutyrates, 4-nitro-4-methylpentanoates, o-(dibromomethyl)benzoates, 2-formylbenzenesulfonates, 2-(methylthiomethoxy)ethyl, 4-(methylthiomethoxy)butyrates, 2-(methylthiomethoxymethyl)benzoates, 2,6-dichloro-4-methylphenoxyacetates, 2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetates, 2,4-bis(1,1-dimethylpropyl)phenoxyacetates, chlorodiphenylacetates, isobutyrates, monosuccinates, (E)-2-methyl-2-butenoates, o-(methoxycarbonyl)benzoates, α-naphthoates, nitrates, N,N,N',N'-tetramethyldiaminophosphoric acid alkyl esters, N-phenylcarbamic acid alkyl esters, borates, dimethylphosphinous sulfoxides, 2,4-dinitrophenylsulfinic acid alkyl esters, sulfates, methanesulfonates (mesylates), benzylsulfonates, and toluenesulfonates (Ts). In certain embodiments, the oxygen protecting group is a silyl group. In certain embodiments, the oxygen protecting group is tert-butyldiphenylsilyl (TBDPS), tert-butyldimethylsilyl (TBDMS), triisopropylsilyl (TIPS), triphenylsilyl (TPS), triethylsilyl (TES), trimethylsilyl (TMS), triisopropylsilyloxymethyl (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), tetrahydrofuryl (THF), p-methoxyphenyl (PMP), trityl (Tr), methoxytrityl (MMT), dimethoxytrityl (DMT), allyl, p-methoxybenzyl (PMB), tert-butyl, benzyl (Bn), allyl, or pivaloyl (Piv).

[0128] In certain embodiments, the substituent present on the sulfur atom is a sulfur protecting group (also referred to as a "thiol protecting group"). Sulfur protecting groups include, but are not limited to, -R 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, where R aa , R bb and R cc are as defined herein. Sulfur protecting groups are well-known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T.W. Greene and P.G.M. Wuts, 3rd Edition, John Wiley & Sons, 1999, which is incorporated herein by reference. In certain embodiments, the sulfur protecting group is acetamidomethyl, t-Bu, 3-nitro-2-pyridylsulfenyl, 2-pyridylsulfenyl or triphenylmethyl.

[0129] As used herein, a "counter ion" can be an anion counter ion or a cation counter ion.

[0130] An "anion counter ion" is a negatively charged group that associates with a positively charged group to maintain electrical neutrality. The anion counter ion can be monovalent (i.e., including one formal negative charge). The anion counter ion can also be polyvalent (i.e., including more than one formal negative charge), such as divalent or trivalent. Exemplary anion counter ions include halide ions (e.g., F - , Cl - , Br - , I - ), NO3 - , ClO4 - , OH - , H2PO4 - , HCO3 - , HSO4 - , sulfonate ions (e.g., methanesulfonate, trifluoromethanesulfonate, p-toluenesulfonate, benzenesulfonate, 10-camphorsulfonate, naphthalene-2-sulfonate, naphthalene-1-sulfonate-5-sulfonate, ethane-1-sulfonate-2-sulfonate and similar ions), carboxylate ions (e.g., acetate, propionate, benzoate, glycerate, lactate, tartrate, glycolate, gluconate and similar ions), 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 anions that can be polyvalent relative ions include CO3 2- , HPO4 2- , PO4 3- , B4O7 2- , SO4 2- , S2O3 2- , carboxylate anions (such as tartrate, citrate, fumarate, maleate, malate, malonate, gluconate, succinate, glutarate, adipate, pimelate, suberate, azelate, sebacate, salicylate, phthalate, aspartate, glutamate and similar ions) and carboranes.

[0131] A "cationic relative ion" is a positively charged group that binds to a negatively charged group to maintain electrical neutrality. The cationic relative ion can be monovalent (i.e., including one formal positive charge). The cationic relative ion can also be polyvalent (i.e., including more than one formal positive charge), such as divalent or trivalent. Exemplary cationic relative ions include, for example, metal (such as alkali metal and alkaline earth metal) cations, 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, where C 1-6 alkyl can optionally be substituted as discussed above. Representative cations of alkali metals and alkaline earth metals include Li + , Na + , K + , Mg 2+ and Ca 2+ and their similar ions.

[0132] Formulation and administration

[0133] Another embodiment of the present invention is a composition comprising a compound of the present invention (such as a compound of formula (I)) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, adjuvant or vehicle. In certain embodiments, the composition of the present invention is formulated for administration to a patient in need of the composition. In some embodiments, the composition of the present invention is formulated for oral, intravenous, subcutaneous, intraperitoneal or topical administration to a patient in need.

[0134] As used herein, the term "individual" is intended to include human and non-human animals. Exemplary human individuals include human patients or normal individuals suffering from a disorder (such as the disorders described herein). The term "non-human animal" of the present invention includes all vertebrates, such as non-mammals (such as chickens, amphibians, reptiles) and mammals, such as non-human primates, domestic and / or agriculturally useful animals (such as sheep, cows, pigs, etc.) and companion animals (dogs, cats, horses, etc.). In a particular embodiment, the individual is human, such as an adult male or female, or a boy or girl.

[0135] As used herein, the amount of a compound described herein (such as a compound of formula (I)) that is effective in treating a disorder or "therapeutically effective amount" refers to the amount of the compound that, upon single or multiple dosing to an individual or cell, is effective in curing, alleviating, reducing or ameliorating one or more symptoms of the disorder.

[0136] As used herein, the amount of a compound that is effective in preventing a disorder or "preventively effective amount" of the compound refers to the amount that, upon single or multiple dosing to an individual, is effective in preventing or delaying the onset or recurrence of a disorder or one or more symptoms of the disorder.

[0137] For administration to a human individual, depending on the route of administration, the total daily dose of the compound of formula (I) is generally in the range of about 0.1 mg to about 3000 mg. For example, oral administration may require a total daily dose of about 1 mg to about 3000 mg, while an intravenous dose may only require a total daily dose of about 0.1 mg to about 300 mg. The total daily dose can be administered as a single dose or in divided doses (such as 2, 3, 4, 5 or 6 times per day at uniform intervals or at random intervals) or as needed. The typical daily dose can be outside of the above range based on the judgment of a physician or prescriber. Although these doses are based on an average human individual weighing about 60 kg to 70 kg, a physician will be able to determine the appropriate dose for an individual outside of this weight range (such as an infant).

[0138] As used herein, the term "treat" or "treatment" is defined as administering or giving a compound, either alone or in combination with a second compound, to an individual (such as a patient), or to isolated tissue or cells (such as cell lines) from an individual (such as a patient) having a disorder (such as a disorder described herein), a symptom of the disorder or susceptibility to the disorder, so as to cure, restore, alleviate, reduce, alter, remedy, slow down, improve or affect the disorder, one or more symptoms of the disorder or susceptibility to the disorder (such as preventing at least one symptom of the disorder or delaying the onset of at least one symptom of the disorder).

[0139] "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 needed. For human administration, the preparations should meet the sterility, pyrogenicity, general safety and purity standards required by the FDA Office of Biologics standards.

[0140] As used herein, the term "pharmaceutically acceptable salt" refers to those salts that are within the scope of sound medical judgment, suitable for contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and that satisfy the appropriate benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in detail by S.M. Berge et al. 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 that are compatible with the treatment of patients and are derived from suitable inorganic and organic acids and bases.

[0141] Examples of pharmaceutically acceptable non-toxic acid addition salts are salts formed by reacting the amino groups 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 salts formed by using other methods well known in the art such as ion exchange. Other pharmaceutically acceptable salts include adipates, alginates, ascorbates, aspartates, benzenesulfonates, benzoates, bisulfates, borates, butyrates, camphorates, camphorsulfonates, citrates, cyclopentanepropionates, digluconates, dodecylsulfates, ethanesulfonates, formates, fumarates, glucoheptanoates, glycerophosphates, glucuronates, hemisulfates, heptanoates, hexanoates, hydroiodides, 2-hydroxyethanesulfonates, lactates, lactobionates, laurates, lauryl sulfates, malates, maleates, malonates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, oxalates, palmitates, pamoates, pectates, persulfates, 3-phenylpropionates, phosphates, pivalates, propionates, stearates, succinates, sulfates, tartrates, thiocyanates, p-toluenesulfonates, undecanoates, valerates, and the like.

[0142] In some embodiments, exemplary inorganic acids suitable for forming salts include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid, as well as acidic metal salts such as monosodium orthophosphate and potassium bisulfate. Illustrative organic acids suitable for forming salts include monocarboxylic acids, dicarboxylic acids, and tricarboxylic acids. Exemplary of such acids are 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, hydroxymaleic 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. Mono- or disalts can be formed, and such salts can exist in hydrated, fused, or substantially anhydrous forms. Generally, the 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.

[0143] In some embodiments, the acid addition salts of the compounds of Formula I are most preferably formed from pharmaceutically acceptable acids and include, for example, 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).

[0144] Other non-pharmaceutically acceptable salts (such as oxalates) can be used, for example, to isolate the compounds of Formula I for laboratory use or for subsequent conversion to pharmaceutically acceptable acid addition salts. Also included within the scope of the present invention are base addition salts (such as sodium salts, potassium salts, and ammonium salts), solvates, and hydrates of the compounds of the present invention. The conversion of a given compound salt to the desired compound salt is accomplished by applying standard techniques well known to those skilled in the art.

[0145] "Pharmaceutically acceptable base addition salts" are any non-toxic organic or inorganic base addition salts of the acid compounds represented by Formula I or any of its intermediates. Illustrative inorganic bases suitable for forming salts include, but are not limited to, lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, or barium hydroxide. Illustrative organic bases suitable for forming salts include aliphatic, alicyclic, or aromatic organic amines such as methylamine, trimethylamine, and picoline, or ammonia. The selection of the appropriate salt can be important such that ester functional groups elsewhere in the molecule (if present) are not hydrolyzed. The criteria for the selection of the appropriate salt will be known to those skilled in the art.

[0146] Salts derived from suitable bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and N + (C 1-4 alkyl)4 salts. Representative alkali metal or alkaline earth metal salts include sodium salts, lithium salts, potassium salts, calcium salts, magnesium salts, and their analogs. Where appropriate, other pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed with counterions such as halide ions, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

[0147] The phrase "pharmaceutically acceptable carrier, adjuvant or vehicle" refers to a non-toxic carrier, adjuvant or vehicle which, when administered in a dose sufficient to deliver a therapeutically effective amount of a compound, does not destroy the pharmacological activity of the compound formulated therewith and is non-toxic. Pharmaceutically acceptable carriers, adjuvants or vehicles which 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), buffering 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-polypropylene-block polymers, polyethylene glycol and lanolin.

[0148] The compositions of the present invention can be administered orally, parenterally (including subcutaneous, intramuscular, intravenous and intradermal), by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implantable reservoir. In some embodiments, the compounds or compositions provided can be administered intravenously and / or intraperitoneally.

[0149] As used herein, the term "parenteral" includes subcutaneous, intradermal, intravenous, intramuscular, intraocular, intravitreal, intra-articular, intra-arterial, intrasynovial, intrasternal, intrathecal, intralesional, intrahepatic, intraperitoneal-lesional and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, subcutaneously, intraperitoneally or intravenously.

[0150] The pharmaceutically acceptable compositions of the present invention can be administered orally in any orally acceptable dosage form, including but not limited to capsules, tablets, aqueous suspensions, dispersions and solutions. In the case of tablets for oral use, common carriers include lactose and corn starch. Lubricants, such as magnesium stearate, are also typically added. For oral administration in capsule form, suitable 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 sweetening, flavoring or coloring agents can also be added.

[0151] In some embodiments, the oral formulations are formulated for immediate release or sustained / delayed release.

[0152] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is admixed with at least one pharmaceutically acceptable inert excipient or carrier such as sodium citrate or calcium phosphate dibasic and / or the following: a) fillers or extenders such as starch, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia; c) humectants such as glycerin; d) disintegrants such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; e) solubilization inhibitors such as paraffin; f) absorption accelerators such as quaternary ammonium salts; g) wetting agents such as acetylated alcohols and glycerol monostearate; h) absorbents such as kaolin and bentonite; and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may also contain buffering agents.

[0153] Compositions suitable for buccal or sublingual administration include tablets, lozenges, and troches, in which the active ingredient is formulated with carriers such as sugar and acacia, tragacanth, or gelatin and glycerin.

[0154] 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 glycol and its analogs. Solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulation art. They can optionally contain opacifying agents and can also have compositions that release the active ingredient only in or preferentially in a certain part of the intestine or optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

[0155] The compounds of the present invention can also be present in microencapsulated form together with one or more of the excipients indicated above. In such solid dosage forms, the compounds of the present invention can be admixed with at least one inert diluent such as sucrose, lactose, or starch. As is normal practice, such dosage forms can also contain additional substances in addition to the inert diluent, for example, tableting lubricants and other tableting aids such as magnesium stearate and microcrystalline cellulose.

[0156] Compositions for oral administration can be designed to protect the active ingredient from degradation as it passes through the digestive tract, for example, by an outer coating of the formulation on a tablet or capsule.

[0157] In another embodiment, the compounds of the invention can be provided in an extended (or "delayed" or "sustained") release composition. Such a delayed release composition comprises a compound of the invention and a delayed release component. Such compositions allow for the targeted release of the provided compound into the lower gastrointestinal tract, such as into the small intestine, large intestine, colon, and / or rectum. In certain embodiments, the delayed release composition comprising a compound of the 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 to the small intestine and / or colon by providing a pH-sensitive methacrylate coating, pH-sensitive polymeric microspheres, or a polymer that undergoes hydrolytic degradation. The delayed release composition can be formulated with a hydrophobic or gelling excipient or coating. Colon delivery can be further provided by coatings that are degraded by bacterial enzymes (such as amylose or pectin), pH-dependent polymers, hydrogel plugs that swell over time (Pulsincap), time-dependent hydrogel coatings, and / or acrylic coatings linked by azo-aromatic bonds.

[0158] In certain embodiments, the delayed release composition of the invention comprises hydroxypropyl methylcellulose, microcrystalline cellulose, and a lubricant. A mixture of a compound of the invention, hydroxypropyl methylcellulose, and microcrystalline cellulose can be formulated into tablets or capsules for oral administration. In certain embodiments, the mixture is granulated and compressed into tablets.

[0159] Alternatively, the pharmaceutically acceptable compositions of the invention can be administered in the form of suppositories for rectal administration. Such suppositories can be prepared by mixing a compound of the invention with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and will thus melt in the rectum to release the drug. Such materials include cocoa butter, beeswax, and polyethylene glycol.

[0160] The pharmaceutically acceptable compositions of the invention can also be administered topically, particularly when the treatment target includes diseases of regions or organs that are readily accessible by topical application, including the eye, skin, or lower intestine. Suitable topical formulations for each of these regions or organs are readily prepared.

[0161] Topical administration to the lower intestine can be achieved in the form of rectal suppository formulations (see above) or in the form of suitable enema formulations. Topical transdermal patches can also be used.

[0162] For other topical administrations, the pharmaceutically acceptable compositions of the present invention can be formulated into a suitable ointment form 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 into a suitable lotion or cream form containing the active ingredient suspended or dissolved in one or more pharmaceutically acceptable carriers. Alternatively, the pharmaceutical composition can be formulated with a suitable lotion or cream containing the active compound suspended or dissolved in a carrier and 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, as well as penetration enhancers.

[0163] For ophthalmic use, the pharmaceutically acceptable compositions of the present invention can be formulated as a micron-sized suspension in isotonic pH-adjusted sterile physiological saline with or without a preservative (such as benzalkonium chloride), or preferably as a solution in isotonic pH-adjusted sterile physiological saline. Alternatively, for ophthalmic use, the pharmaceutically acceptable composition can be formulated into an ointment form (such as petrolatum).

[0164] The pharmaceutically acceptable compositions of the present invention can also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation and can be prepared as a solution in physiological saline using benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and / or other conventional solubilizers or dispersants.

[0165] In some embodiments, the pharmaceutically acceptable compositions of the present invention are formulated for oral administration.

[0166] In some embodiments, the pharmaceutically acceptable compositions of the present invention are formulated for intravenous administration.

[0167] In some embodiments, the pharmaceutically acceptable compositions of the present invention are formulated for topical administration.

[0168] The amount of the compound of the present invention that can be combined with the carrier material to produce a composition in a single dosage form will depend on the host being treated, the particular mode of administration, and the activity of the compound used. Preferably, the composition should be formulated such that an inhibitor dose between 0.01 - 100 mg / kg body weight / day can be administered to a patient receiving the composition.

[0169] It should also 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 employed, age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, the judgment of the treating physician, and the severity of the particular disease being treated. The amount of the compounds of the present invention in the composition also depends on the specific compound in the composition.

[0170] Other pharmaceutically acceptable carriers, adjuvants or vehicles that can be used in the pharmaceutical compositions of the present invention include, but are not limited to, ion exchange agents, 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 Tween or other similar polymeric delivery matrices), serum proteins (such as human serum albumin), buffering substances (such as phosphates), glycine, sorbic acid, potassium sorbate, mixtures of partial glycerides of saturated vegetable fatty acids, water, salts or electrolytes (such as protamine sulfate), disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silicon dioxide, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polypropylene oxide-block polymers, polyethylene glycol and lanolin. Cyclodextrins (such as α-cyclodextrin, β-cyclodextrin and γ-cyclodextrin) or chemically modified derivatives (such as hydroxyalkyl cyclodextrins) (including 2-hydroxypropyl-β-cyclodextrin and 3-hydroxypropyl-β-cyclodextrin or other solubilizing derivatives) can also be advantageously used to enhance the delivery of the compounds described herein.

[0171] The pharmaceutical compositions of the present invention are preferably administered orally or by injection. The pharmaceutical compositions of the present invention may 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 acids, bases or buffers to enhance the stability of the formulated compound or its delivery form.

[0172] The pharmaceutical composition can be in the form of a sterile injectable preparation, for example, as a sterile injectable aqueous or oily suspension. Such suspension can be formulated according to techniques known in the art, using suitable dispersing or wetting agents (such as Tween 80) and suspending agents. The sterile injectable preparation can also be a sterile injectable solution or suspension in a parenterally acceptable non-toxic diluent or solvent, such as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents, mannitol, water, Ringer's solution, and isotonic sodium chloride solution can be used. In addition, sterile non-volatile oils are conventionally used as solvents or suspending media. For this purpose, any mild non-volatile oil can be employed, including synthetic mono- or di-glycerides. Fatty acids such as oleic acid and their glyceride derivatives are suitable for the preparation of injectables, such as natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially in their polyoxylated forms. These oil solutions or suspensions can also contain long-chain alcohol diluents or dispersing agents or carboxymethyl cellulose or similar dispersing agents commonly used in formulating pharmaceutically acceptable dosage forms, such as emulsions and / or suspensions. For formulation purposes, other commonly used surfactants (such as Tween or Span) and / or other similar emulsifying agents or bioavailability enhancers commonly used in manufacturing pharmaceutically acceptable solid, liquid, or other dosage forms can also be used.

[0173] When the composition of the present invention contains a combination of a compound of the formula described herein with one or more additional therapeutic or prophylactic agents, both the compound and the additional agent should be present at dosage levels between about 1 to 100%, and more preferably between about 5 to 95% of the doses normally administered in a single therapy regimen. The additional agent can be administered separately from the compound of the present invention as part of a multiple dosing regimen. Alternatively, the additional agent can be part of a single dosage form, mixed with the compound of the present invention in a single composition.

[0174] The compounds described herein can be administered, for example, by injection, intravenously, intra-arterially, intravitreally, subcutaneously, orally, buccally, nasally, transmucosally, topically, in the form of an ophthalmic preparation, or by inhalation, in a dose range of about 0.5 to about 100 mg / kg body weight, or alternatively in a dose range of about 1 mg to about 1000 mg per dose every 4 to 120 hours, or according to the requirements of the specific drug. The methods herein encompass administering an effective amount of the compound or composition of the present invention to achieve the desired or stated effect. Generally, the pharmaceutical composition of the present invention will be administered about 1 to about 6 times a day, or alternatively by continuous infusion. Such administration can be used as chronic or acute therapy. The amount of the active ingredient that can be combined with the carrier material to produce a single dosage form will depend on the host being treated and the specific mode of administration. A typical formulation will contain about 5% to about 95% active compound (w / w). Alternatively, the formulation can contain about 20% to about 80% active compound.

[0175] Doses lower or higher than those described above may be required. The specific dose and treatment regimen for any particular patient will depend on a variety of factors, including the activity of the specific compound employed, age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, disease, the severity and course of the condition or symptoms, the patient's response to the disease, condition or symptoms, and the judgment of the treating physician.

[0176] After improvement of the patient's condition, a maintenance dose of the compound, composition or combination of the invention may be administered, if necessary. Subsequently, the dose or frequency or both may be reduced according to the symptoms to a level that maintains the improvement of the condition when the symptoms have been alleviated to the desired level. However, the patient may require long-term intermittent treatment when the symptoms of the disease recur.

[0177] Use of the compound and pharmaceutically acceptable compositions

[0178] As used herein, a "RIPK2-mediated" disease, disorder or condition means any disease or other adverse condition in which RIPK2 plays a role. Accordingly, another embodiment of the invention relates to treating a RIPK2-mediated disorder or condition, for example, reducing its severity. 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.

[0179] The compounds provided by the invention are also suitable for use as tools, for example, to study RIPK2 regulation of biological and pathological phenomena, to study cancer or for the identification and / or comparative evaluation of RIPK2 modulators. Accordingly, in certain embodiments, the invention provides a method for studying the effect of a compound or its salt or composition described herein on a sample, the method comprising contacting a sample comprising cells or RIPK2 in culture with the compound or its salt or composition; and measuring the effect of the compound or its salt or composition on the cells or RIPK2. For example, the compounds described herein can be used as a standard or control substance in a binding assay (e.g., a competitive binding assay) to identify or evaluate potential RIPK2 modulators, or as a discovery tool to probe the role of RIPK2 regulation in certain disorders or conditions, such as those described herein, including inflammatory disorders, autoimmune disorders and other RIPK2-mediated disorders or conditions.

[0180] In one embodiment, the present invention relates to a method for treating a disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein, wherein the disease or disorder is selected from inflammatory diseases, autoimmune diseases, granulomatous diseases, cancer, and neurodegenerative diseases.

[0181] In some embodiments, the compounds and compositions described herein are suitable for treating inflammatory disorders in a subject in need thereof. Thus, in certain embodiments, the present invention provides a method for treating an inflammatory disorder, comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound of the present invention (e.g., a compound of formula (I)), or a pharmaceutically acceptable salt thereof, or a composition.

[0182] In certain aspects, inflammatory diseases can include, but are not limited to, uveitis, interleukin-1 converting enzyme fever syndrome, dermatitis, acute lung injury, type 2 diabetes, arthritis, inflammatory bowel disease (IBD), ischemic reperfusion injury in solid organ transplantation, sepsis, liver disease, allergic diseases, and graft-versus-host disease.

[0183] In certain instances, the inflammatory disease is IBD. For example, IBD is selected from ulcerative colitis, Crohn's disease, early-onset IBD, and extraintestinal IBD.

[0184] Alternatively, inflammatory diseases can include, but are not limited to, rheumatoid arthritis, inflammatory arthritis, peritonitis, ischemic reperfusion injury in kidney transplantation, non-alcoholic steatohepatitis, alcoholic steatohepatitis, insulin-resistant type 2 diabetes, allergic rhinitis, asthma, atopic dermatitis, Sjogren's syndrome, ankylosing spondylitis, pemphigus vulgaris, idiopathic plasmacytic lymphadenopathy, atherosclerosis, myocardial infarction, thrombosis, synucleinopathy, Parkinson's disease, dementia with Lewy body, multiple system atrophy, Alzheimer's disease, amyotrophic lateral sclerosis, and chronic obstructive pulmonary disease.

[0185] In a particular embodiment, the disease or disorder is an autoimmune disease. By way of example, autoimmune diseases can include, but are not limited to, systemic lupus erythematosus, lupus nephritis, psoriasis, type 1 diabetes, Goodpasture's syndrome, Guillain-Barre Syndrome, Hashimoto's disease, Grave's disease, immune thrombocytopenic purpura, and multiple sclerosis (including relapsing-remitting MS, secondary-progressive MS, primary-progressive MS, progressive-relapsing MS).

[0186] In another embodiment, the disease or disorder is a granulomatous disease. By way of example, the granulomatous disease is selected from sarcoidosis, Blau syndrome, Wegner's granulomatosis, Behcet's disease, and interstitial lung disease.

[0187] In another embodiment, the disease or disorder is a neurodegenerative disorder. By way of example, the neurological disorders are selected from Alzheimer's disease, amyotrophic lateral sclerosis (ALS / Lou Gehrig's Disease), Parkinson's disease, multiple sclerosis, diabetic neuropathy, polyglutamine (polyQ) diseases, stroke, Fahr disease, Menke's disease, Wilson's disease, cerebral ischemia, prion disorder, dementia, corticobasal degeneration, progressive supranuclear palsy, spinocerebellar ataxia, brain injury, and spinal cord injury.

[0188] In yet another embodiment, the disease or disorder is cancer. By way of example, cancers are selected from hematological 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, kidney cancer, liver cancer, and lung cancer. The cancer can be soft tissue cancer, including but not limited to sarcomas selected from the group consisting of fibrosarcoma and liposarcoma (e.g., dedifferentiated liposarcoma and pleomorphic liposarcoma).

[0189] The compounds and compositions described herein can also be administered, for example, to cells in culture in vitro or ex vivo, or to an individual in vivo, to treat, prevent, and / or diagnose a variety of conditions, including those described below.

[0190] The compounds of the invention can be used alone or in combination with other therapeutic agents. The combination therapy according to the invention comprises administering a therapeutically effective amount of at least one compound of the invention and a therapeutically effective amount of at least one other therapeutic active agent (second agent). For example, the combination therapy according to the invention comprises administering to an individual in need of treatment for a given disease or condition (such as the inflammatory diseases, autoimmune diseases, granulomatous diseases, cancers, and neurodegenerative diseases described herein) at least one compound of the invention and at least one other therapeutic active agent.

[0191] The compounds of the invention and the other therapeutic active agents can be administered together in a single pharmaceutical composition or separately, and when administered separately, this can be done simultaneously or sequentially in any order. The amounts of the compounds of the invention and the other therapeutic active agents and the relative duration of administration can be selected to achieve the desired combined therapeutic effect. Accordingly, in another aspect, there is provided a combination comprising a compound of the invention and one or more other therapeutic active agents.

[0192] In certain embodiments, the invention relates to a method of treating an individual suffering from an inflammatory disorder as described herein, which comprises administering to the individual an effective amount of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof and an anti-inflammatory agent and / or an anti-TNF agent.

[0193] In a particular embodiment, the invention relates to a method of treating an individual suffering from Crohn's disease as described herein, which comprises administering to the individual 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.

[0194] In another embodiment, the invention relates to a method of treating an individual suffering from an autoimmune disorder as described herein, which comprises administering to the individual a therapeutically effective amount 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.

[0195] 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 mTOR inhibitors (temsirolimus, everolimus), JAK inhibitors (tofacitinib), ), Syk inhibitors (fostamatinib), corticosteroids, particularly low-dose corticosteroids (such as prednisone and budesonide) and anti-inflammatory biologics, such as anti-IL6R mAb ( (tocilizumab)), anti-IL6 biologics, anti-IL1 (anakinra canakinumab rilonacept ), anti-IL12 and IL23 biologics (ustekinumab ), anti-IL17 biologics (secukinumab), anti-CD22 (epratuzumab), anti-integrin agents (natalizumab ), vedolizumab ), anti-IFNa (sifalimumab), anti-CD20 mAb (rituximab and ofatumumab ), and other agents, such as abatacept Anakinra Canakinumab Rilonacept Secukinumab, epratuzumab, sifalimumab and belimumab CD4 biologics and other interleukin inhibitors or biologics targeting T cell or B cell receptors or interleukins.

[0196] Examples of suitable anti-TNF agents include anti-TNF biologics, such as (etanecerpt), (adalimumab), (infliximab), (certolizumab) and (golimumab).

[0197] In some embodiments, the second agent and the compound represented by structural formula (I) are administered simultaneously. When administered simultaneously, the second agent and the compound can be administered in the same formulation or in different formulation forms. Alternatively, the compound and the additional anti-inflammatory / autoimmune agent can be administered separately.

[0198] In a particular embodiment, the present invention relates to a method of treating an individual suffering from a neurodegenerative disease (such as Parkinson's disease) as described herein, which comprises administering to the individual an effective amount of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof and optionally one or more additional therapeutic agents commonly 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.

[0199] In a specific embodiment, the present invention relates to a method of treating an individual suffering from a neurodegenerative disease as described herein, such as Alzheimer's disease, comprising administering to the individual an effective amount of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof and optionally one or more additional therapeutic agents commonly used to treat Alzheimer's disease. Such additional therapeutic agents include, but are not limited to, donepezil, galantamine, memantine, rivastigmine, anti-Aβ (amyloid β) therapy (including aducanumab, crenezumab, solanezumab and gantenerumab), small molecule BACE1 inhibitors, including verubecestat, A ZD3293 (LY3314814), elenbecestat (E2609), LY2886721, PF-05297909, JNJ-54861911, TAK-070, VTP-37948, HPP854, CTS-21166 or an anti-tau therapy such as leuco-methylene blue-bis(hydromethanesulfonate) (LMTM, leuco-methylthioninium-bis(hydromethanesulfonate)), or a pharmaceutically acceptable salt thereof.

[0200] In certain embodiments, the present invention relates to a method for treating an individual suffering from cancer, comprising administering to the individual an effective amount of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof and an anticancer agent. An "anticancer agent" is a compound that, when administered in an effective amount to an individual suffering from cancer, can partially or substantially achieve one or more of the following: inhibit cancer growth, reduce the extent of cancer (e.g., reduce tumor size), inhibit cancer growth rate, and slow or improve clinical symptoms or indicators associated with cancer (such as tissue or serum components) or increase the life span of the individual.

[0201] Anticancer agents suitable for use in the methods described herein include any anticancer agent that has been approved for the treatment of cancer. In one embodiment, anticancer 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.

[0202] In one embodiment, the 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.

[0203] 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 formulation forms. Alternatively, the compound and the additional anti-cancer agent can be administered separately at different times.

[0204] In a first embodiment, the present invention relates to a compound represented by structural formula (I):

[0205] or a pharmaceutically acceptable salt thereof:

[0206]

[0207] Wherein:

[0208] R 1a 、R 1b and R 1c are each independently selected from H, halogen, CN, and C 1-6 alkyl;

[0209] R 2 is H or C 1-3 alkyl;

[0210] R 3Selected from halogen, 4- to 10-membered heterocyclic group, 5- to 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 , CN, NR 8 R 9 , P(=O)R 8a R 9a ;

[0211] R 4 is selected from H, halogen, C 1-6 alkyl and C 1-6 alkoxy;

[0212] R 5 is selected from NR 10 R 11 , C 1-6 alkyl, C 3-6 cycloalkyl and 4- to 10-membered heterocyclic group;

[0213] R 6 is selected from H, CN and C 1-6 alkyl;

[0214] R 7 is selected from C 1-6 alkyl, C 3-6 cycloalkyl and 4- to 10-membered heterocyclic group, 5- to 12-membered heteroaryl, or

[0215] 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;

[0216] Q is selected from O, S, -S(=O)- and -C(=O)-;

[0217] R 8 and R 9 are each independently selected from H, C 1-6 alkyl, C 1-6 deuterated alkyl, C 3-6 cycloalkyl and 4- to 10-membered heterocyclic group, or

[0218] R 8 and R 9 together with the nitrogen atom to which they are attached form a 4- to 10-membered heterocyclic group;

[0219] R 8a and R 9b are each independently C 1-6alkyl, or

[0220] R 8a and R 9a together with the phosphorus atom to which they are attached form a 4- to 10-membered heterocyclic group;

[0221] R 10 and R 11 are each independently H or C 1-6 alkyl, or

[0222] R 10 and R 11 together with the nitrogen to which they are attached form a 4- to 10-membered heterocyclic group;

[0223] W is selected from O, NR 2 , O(C 1-2 alkylene), NH(C 1-2 alkylene), C 1-2 alkylene, C 3-6 cycloalkylene and a single bond;

[0224] X is a moiety represented by one of the following structural formulas:

[0225]

[0226] Y 1 is CH or N;

[0227] Y 2 and Y 3 are each independently CR 4 or N;

[0228] U is CR 12b or N;

[0229] Z is CR 1b or N;

[0230] L, M and J are each independently selected from N, O or S, provided that two of L, M and J are N;

[0231] R 12 is selected from C 3-6 alkyl, C 3-6 cycloalkyl, C 5-12 bridged bicyclic carbocyclic group and 4- to 10-membered heterocyclic group;

[0232] R 12a is selected from C 1-6 alkyl, C 1-6 deuterated alkyl, C 3-6 cycloalkyl, C 5-12 bridged bicyclic carbocyclic group and 4- to 10-membered heterocyclic group;

[0233] R12b and R 13 are each independently H or C 1-6 alkyl;

[0234] and

[0235] is a single bond or a double bond,

[0236] wherein 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 carbocyclic group, 5- to 12-membered heteroaryl and 4- to 10-membered heterocyclic group are optionally substituted with 1 to 3 substituents independently selected from the following: deuterium, oxo, F, Cl, Br, CN, OR 14 , SR 15 , NR 16 R 17 , S(O)R 18 , S(O)2R 18a , NR 19 S(=O)R 20 , C(=O)OR 20a , C(=O)NR 21 R 22 , NR 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 alkylsulfonylaminoalkyl, 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 aryl, 4- to 8-membered heterocyclic group and 5- to 12-membered heteroaryl, wherein

[0237] R 14 , R 15 , R 18 , R 18a , R 20 , R 20a , R 24 and R 27 are independently hydrogen or C 1-6 alkyl;

[0238] R 16 and R 17 are each independently selected from hydrogen, C 1-6 Alkyl, hydroxyl (C 1-6 ) alkyl and halogenated (C 1-6 )alkyl;

[0239] R 19 and R 23 Each independently is C 1-6 Alkyl or halogenated (C 1-6 )alkyl;

[0240] R 21 , R 22 , R 25 and R 26 Each independently selected from H, C 1-6 Alkyl, C 1-3 Alkoxy (C 1-6 ) alkyl, hydroxyl (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

[0241] R 21 and R 22 or R 25 and R 26 Together with the nitrogen to which it is attached, it forms a 3- to 8-membered ring optionally substituted with 1 to 3 substituents independently selected from the group consisting of deuterium, oxo, F, Cl, Br, CN, OR 14 , SR 15 NR 16 R 17 、S(O)R 18 、S(O)2R 18a NR 19 S(=O)R 20 、C(=O)OR 20a 、C(=O)NR 21 R 22, NR 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 alkylsulfonylaminoalkyl, 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 aryl, 4- to 10-membered heterocyclic group, and 5- to 12-membered heteroaryl,

[0242] provided that when Y 2 is CH substituted with R 4 and R 4 is optionally substituted C 1-6 alkoxy, then W-R 3 is not CN or optionally substituted C 1-6 alkoxy; and

[0243] provided that when Y 1 , Y 2 and Y 3 are each CH, then W-R 3 is not F.

[0244] For example, the present invention relates to a compound represented by the structural formula (I):

[0245] or a pharmaceutically acceptable salt thereof:

[0246]

[0247] wherein:

[0248] R 1a , R 1b and R 1c are each independently selected from H, halogen, CN, and C 1-6 alkyl;

[0249] R 2 is H or C 1-3 alkyl;

[0250] R 3 selected from halogen, 4- to 10-membered heterocyclic group, 5- to 12-membered heteroaryl group, S(=O)2R 5 , S(=O)(=NR 6 )(R 7 ), QR 7 , C(=O)NR 8 R 9 , NH(C=O)R 5 , CN, NR 8 R 9 , P(=O)R 8a R 9a ;

[0251] R 4 is selected from H, halogen, C 1-6 alkyl group and C 1-6 alkoxy group;

[0252] R 5 is selected from NR 10 R 11 , C 1-6 alkyl group, C 3-6 cycloalkyl group and 4- to 10-membered heterocyclic group;

[0253] R 6 is selected from H, CN and C 1-6 alkyl group;

[0254] R 7 is selected from C 1-6 alkyl group, C 3-6 cycloalkyl group and 4- to 10-membered heterocyclic group, 5- to 12-membered heteroaryl group, or

[0255] 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;

[0256] Q is selected from O, S, -S(=O)- and -C(=O)-;

[0257] R 8 and R 9 are each independently selected from H, C 1-6 alkyl group, C 3-6 cycloalkyl group and 4- to 10-membered heterocyclic group, or

[0258] R 8 and R 9 together with the nitrogen atom to which they are attached form a 4- to 10-membered heterocyclic group;

[0259] R 8a and R 9b are each independently C1-6 alkyl, or

[0260] R 8a and R 9a together with the phosphorus atom to which it is attached form a 4- to 10-membered heterocyclic group;

[0261] R 10 and R 11 are each independently H or C 1-6 alkyl, or

[0262] R 10 and R 11 together with the nitrogen to which it is attached form a 4- to 10-membered heterocyclic group;

[0263] W is selected from O, NR 2 , O(C 1-2 alkylene), NH(C 1-2 alkylene), C 1-2 alkylene and a single bond;

[0264] X is a moiety represented by one of the following structural formulas:

[0265]

[0266] Y 1 is CH or N;

[0267] Y 2 and Y 3 are each independently CR 4 or N;

[0268] U is CR 12b or N;

[0269] Z is CR 1b or N;

[0270] L, M and J are each independently selected from N, O or S, provided that two of L, M and J are N;

[0271] R 12 is selected from C 3-6 alkyl, C 3-6 cycloalkyl, C 5-12 bridged bicyclic carbocyclic group and 4- to 10-membered heterocyclic group;

[0272] R 12a is selected from C 1-6 alkyl, C 3-6 cycloalkyl, C 5-12 bridged bicyclic carbocyclic group and 4- to 10-membered heterocyclic group;

[0273] R 12b and R 13 are each independently H or C1-6 alkyl; and

[0274] is a single bond or a double bond,

[0275] wherein 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 carbocyclic group, 5- to 12-membered heteroaryl group, and 4- to 10-membered heterocyclic group are optionally substituted with 1 to 3 substituents independently selected from the following: deuterium, oxo, F, Cl, Br, CN, OR 14 , SR 15 , NR 16 R 17 , S(O)R 18 , S(O)2R 18a , NR 19 S(═O)R 20 , C(═O)OR 20a , C(═O)NR 21 R 22 , NR 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 alkylsulfonylaminoalkyl, 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 aryl, 4- to 8-membered heterocyclic group, and 5- to 12-membered heteroaryl group, wherein

[0276] R 14 , R 15 , R 18 , R 18a , R 20 , R 20a , R 24 and R27 Each is independently hydrogen or C 1-6 alkyl;

[0277] R 16 and R 17 are each independently selected from hydrogen, C 1-6 alkyl, hydroxy(C 1-6 )alkyl, and halo(C 1-6 )alkyl;

[0278] R 19 and R 23 are each independently C 1-6 alkyl or halo(C 1-6 )alkyl;

[0279] R 21 , R 22 , R 25 and R 26 are each independently selected from 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

[0280] R 21 and R 22 or R 25 and R 26 together with the nitrogen to which they are attached form a 3- to 8-membered ring optionally substituted with 1 to 3 substituents independently selected from the following: deuterium, oxo, F, Cl, Br, CN, OR 14 , SR 15 , NR 16 R 17 , S(O)R 18 , S(O)2R 18a , NR 19 S(=O)R 20 , C(=O)OR 20a , C(=O)NR 21 R 22 , NR 23 C(=O)R 24 , C(=S)NR 25 R 26 , C(=O)R 27 , C 1-6 alkyl, C 3-8Cycloalkyl, C 2-6 alkenyl, halo(C 1-6 )alkyl, C 1-3 alkylsulfonylaminoalkyl, 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 aryl, 4- to 10-membered heterocyclic group, and 5- to 12-membered heteroaryl,

[0281] provided that when Y 2 is CH substituted by R 4 and R 4 is optionally substituted C 1-6 alkoxy, then W-R 3 is not CN or optionally substituted C 1-6 alkoxy; and provided that when Y 1 , Y 2 and Y 3 are each CH, then W-R 3 is not F.

[0282] In the first aspect of the first embodiment, R 3 is selected from 4- to 10-membered heterocyclic groups, 5- to 10-membered heteroaryl groups, S(=O)2R 5 , -S(=O)(=NR 6 )(R 7 ) and C(=O)NR 8 R 9 . By way of example, R 3 is selected from 4- to 10-membered heterocyclic groups, S(=O)2R 5 and C(=O)NR 8 R 9 .

[0283] In the second aspect of the first embodiment, W is selected from NH, N(C 1-2 alkylene), O(C 1-2 alkylene) and C 1-2 alkylene. By way of example, W is O. Alternatively, W is a single bond. Yet alternatively, W is C 3-6 cycloalkylene. The remaining features and exemplary features of the second aspect are as described above with respect to the first aspect of the first embodiment.

[0284] In the third aspect of the first embodiment, R3 is a 4- to 6-membered heterocyclic group optionally substituted by 1 to 3 substituents independently selected from the group consisting of deuterium, oxo, F, Cl, Br, CN, OR 14 , SR 15 NR 16 R 17 、S(O)R 18 、S(O)2R 18a NR 19 S(=O)R 20 、C(=O)OR 20a 、C(=O)NR 21 R 22 NR 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 Alkylsulfonylaminoalkyl, 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, halogenated (C 1-3 ) alkoxy, C 1-6 Alkoxy (C 1-3 ) alkyl, C 6-12 aryl, 4- to 8-membered heterocyclic group, and 5- to 12-membered heteroaryl, wherein

[0285] R 14 , R 15 , R 18 , R 18a , R 20 , R 20a , R 24 and R 27 are independently hydrogen or C 1-6 alkyl;

[0286] R 16 and R 17 are each independently selected from hydrogen, C 1-6 Alkyl, hydroxyl (C 1-6 ) alkyl and halogenated (C 1-6 )alkyl;

[0287] R 19 and R 23Each is independently C 1-6 alkyl or halo(C 1-6 )alkyl;

[0288] R 21 、R 22 、R 25 and R 26 are each independently selected from 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

[0289] R 21 and R 22 or R 25 and R 26 together with the nitrogen to which they are attached form a 3- to 8-membered ring optionally substituted with 1 to 3 substituents independently selected from the following: deuterium, oxo, F, Cl, Br, CN, OR 14 , SR 15 , NR 16 R 17 , S(O)R 18 , S(O)2R 18a , NR 19 S(=O)R 20 , C(=O)OR 20a , C(=O)NR 21 R 22 , NR 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 alkylsulfonylaminoalkyl, 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, C1-6 alkoxy(C 1-3 )alkyl, C 6-12 aryl, 4- to 10-membered heterocyclic group, and 5- to 12-membered heteroaryl. For example, R 3 is an unsubstituted 4- to 6-membered heterocyclic group. Alternatively, R 3 is a 4- to 6-membered heterocyclic group substituted with 1 to 3 substituents independently selected from: oxo, F, Cl, Br, CN, OR 14 , SR 15 , NR 16 R 17 , 4- to 10-membered heterocyclic group, and C 1-6 alkyl. For example, R 3 is substituted with oxo. In some embodiments, R 3 is a saturated 4- to 6-membered heterocyclic group. For example, R 3 is a moiety represented by the following structural formula: wherein:

[0290] A is O or NR 28 ; and

[0291] R 28 is selected from H, C 1-6 alkyl, C 3-6 cycloalkyl, and 4- to 6-membered heterocyclic group,

[0292] wherein each C 1-6 alkyl, C 3-6 cycloalkyl, and 4- to 6-membered heterocyclic group is optionally substituted with 1 to 3 substituents independently selected from: deuterium, oxo, F, Cl, Br, CN, OR 14 , SR 15 , NR 16 R 17 , S(O)R 18 , S(O)2R 18a , NR 19 S(=O)R 20 , C(=O)OR 20a , C(=O)NR 21 R 22 , NR 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 alkylsulfonylaminoalkyl, 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 )alkyl, aryl, 4- to 8-membered heterocyclic group, and 5- to 12-membered heteroaryl group, where

[0293] 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 alkyl;

[0294] R 16 and R 17 are each independently selected from hydrogen, C 1-6 alkyl, hydroxy(C 1-6 )alkyl, and halo(C 1-6 )alkyl;

[0295] R 19 and R 23 are each independently C 1-6 alkyl or halo(C 1-6 )alkyl;

[0296] 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

[0297] R 21 and R 22 or R 25 and R 26Together with the nitrogen to which it is attached, form a 3- to 8-membered ring optionally substituted with 1 to 3 substituents independently selected from the following: deuterium, oxo, F, Cl, Br, CN, OR 14 , SR 15 , NR 16 R 17 , S(O)R 18 , S(O)2R 18a , NR 19 S(=O)R 20 , C(=O)OR 20a , C(=O)NR 21 R 22 , NR 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 alkylsulfonylaminoalkyl, 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 aryl, 4- to 10-membered heterocyclic group and 5- to 12-membered heteroaryl. In some embodiments, R 3 is a moiety represented by one of the following structural formulas:

[0298] wherein R 28 is H or C 1-3 alkyl.

[0299] The remaining features and exemplary features of the third aspect are described as above with respect to the first to second aspects of the first embodiment.

[0300] In the fourth aspect of the first embodiment, R 3 is S(=O)2R 5 . For example, R 5 is C 1-6 alkyl, such as C 1-3 alkyl. R 5 can be methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl or hexyl. Alternatively, R5 is C 3-6 alkyl, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. In some embodiments, R 5 is an optionally substituted 4- to 6-membered heterocyclic group. In some embodiments, R 5 is NR 10 R 11 . For example, R 10 and R 11 are each independently C 1-6 alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl or hexyl. Alternatively, R 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. Alternatively, R 10 and R 11 are each H. The remaining features and exemplary features of the fourth aspect are as described above for the first to third aspects of the first embodiment.

[0301] In the 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 alkyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. Alternatively, 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. The remaining features and exemplary features of the fifth aspect are as described above for the first to fourth aspects of the first embodiment.

[0302] In the 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 C 1-3 alkyl, such as methyl, ethyl, propyl or isopropyl. Alternatively, R 8 and R 9is H. The remaining features and exemplary features of the sixth aspect are described as above in the first to fifth aspects of the first embodiment.

[0303] In the seventh aspect of the first embodiment, R 3 is selected from 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 alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl or hexyl. Alternatively, Q is O. Alternatively again, Q is S. In some embodiments, Q is -C(═O)-. The remaining features and exemplary features of the seventh aspect are described as above in the first to sixth aspects of the first embodiment.

[0304] In the eighth aspect of the first embodiment, R 3 is a halogen. For example, R 3 is Cl. Alternatively, R 3 is F. The remaining features and exemplary features of the eighth aspect are described as above in the first to seventh aspects of the first embodiment.

[0305] In the 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 C 1-3 alkyl, such as methyl, ethyl, propyl or isopropyl. In some embodiments, R 8a and R 9b are each methyl or ethyl. Alternatively, R 8a and R 9a together with the phosphorus atom to which they are attached form a 4- to 10-membered heterocyclic group.

[0306] In the ninth aspect of the first embodiment, the compound is represented by the structural formula (Ia):

[0307] The remaining features and exemplary features of the ninth aspect are described as above in the first to eighth aspects of the first embodiment.

[0308] In the tenth aspect of the first embodiment, the compound is represented by the structural formula (Ib):

[0309] The remaining features and exemplary features of the tenth aspect are as described above with respect to the first to ninth aspects of the first embodiment.

[0310] In the eleventh aspect of the first embodiment, the compound is represented by the structural formula (Ic): The remaining features and exemplary features of the eleventh aspect are as described above with respect to the first to ninth and tenth aspects of the first embodiment.

[0311] In the twelfth aspect of the first embodiment, the compound is represented by the structural formula (Id):

[0312] The remaining features and exemplary features of the twelfth aspect are as described above with respect to the first to eleventh aspects of the first embodiment.

[0313] In the thirteenth aspect of the first embodiment, the compound is represented by the structural formula (Ie):

[0314] The remaining features and exemplary features of the thirteenth aspect are as described above with respect to the first to twelfth aspects of the first embodiment.

[0315] In the fourteenth aspect of the first embodiment, the compound is represented by the structural formula (If): The remaining features and exemplary features of the fourteenth aspect are as described above with respect to the first to thirteenth aspects of the first embodiment.

[0316] In the fifteenth aspect of the first embodiment, R 4 is H. The remaining features and exemplary features of the fifteenth aspect are as described above with respect to the first to fourteenth aspects of the first embodiment.

[0317] In the sixteenth aspect of the first embodiment, R 4 is C 1-6 alkoxy, such as C 1-4 alkoxy. For example, R 4 is methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy or tert-butoxy, such as methoxy. The remaining features and exemplary features of the sixteenth aspect are as described above with respect to the first to fifteenth aspects of the first embodiment.

[0318] In the seventeenth aspect of the first embodiment, X is a moiety represented by the following structural formula:

[0319] For example, R 13 is H. Alternatively, R 13 is C 1-6An alkyl group, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl or hexyl. The remaining features and exemplary features of the seventeenth aspect are as described above for the first to sixteenth aspects of the first embodiment.

[0320] In the eighteenth aspect of the first embodiment, X is a moiety represented by the following structural formula:

[0321] For example, R 13 is H. Alternatively, R 13 is C 1-6 An alkyl group, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl or hexyl. The remaining features and exemplary features of the eighteenth aspect are as described above for the seventeenth aspect of the first embodiment.

[0322] In the nineteenth aspect of the first embodiment, X is a moiety represented by the following structural formula:

[0323] The remaining features and exemplary features of the nineteenth aspect are as described above for the first to eighteenth aspects of the first embodiment.

[0324] In the twentieth aspect of the first embodiment, X is a moiety represented by one of the following structural formulas:

[0325] For example, X is a moiety represented by the following structural formula: Alternatively, X is a moiety represented by the following structural formula: In some embodiments, X is a moiety represented by the following structural formula: In some embodiments, X is a moiety represented by one of the following structural formulas:

[0326] The remaining features and exemplary features of the twentieth aspect are as described above for the first to nineteenth aspects of the first embodiment.

[0327] In the twenty-first aspect of the first embodiment, R 12 is an optionally substituted C 3-6 alkyl group, 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 12An isopropyl group substituted with 1 to 3 substituents independently selected from the following: deuterium, CF3, F, Cl, Br, CN, OR 14 , SR 15 , NR 16 R 17 , S(O)R 18 , S(O)2R 18a , NR 19 S(=O)R 20 , C(=O)OR 20a , C(=O)NR 21 R 22 , NR 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 alkylsulfonylaminoalkyl, 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 aryl, 4- to 10-membered heterocyclic group, and 5- to 12-membered heteroaryl. The remaining features and exemplary features of the twenty-first aspect are as described above for the first to twentieth aspects of the first embodiment.

[0328] In the twenty-second aspect of the first embodiment, R 12 is selected from moieties represented by one of the following structural formulas:

[0329]

[0330] For example, R 12 is selected from moieties represented by one of the following structural formulas:

[0331]

[0332] The remaining features and exemplary features of the twenty-second aspect are as described above for the first to twenty-first aspects of the first embodiment.

[0333] In the 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 a halogen. In some embodiments, R 1a is selected from H, F, Cl, CH3, CHF2, CF3 and CD3. For example, R 1a is selected from F, CH3 and CHF2. The remaining values and exemplary values of the variables in the twenty-third aspect are as described above for the first to twenty-second aspects of the first embodiment.

[0334] In the 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 a 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. The remaining values and exemplary values of the variables in the twenty-fourth aspect are as described above for the first to twenty-third aspects of the first embodiment.

[0335] In the twenty-fifth aspect of the first embodiment, R 1c is H or a halogen. For example, R 1c is H. Alternatively, R 1c is a halogen. For example, R 1c is F. The remaining values and exemplary values of the variables in the twenty-fifth aspect are as described above for the first to twenty-fourth aspects of the first embodiment.

[0336] In the twenty-fifth aspect of the first embodiment, the compound is represented by the structural formula (Ig):

[0337] The remaining values and exemplary values of the variables in the twenty-fifth aspect are as described above for the first to twenty-fourth aspects of the first embodiment.

[0338] In the twenty-seventh aspect of the first embodiment, the compound is represented by the structural formula (Ih), (Ii) or (Ij):

[0339]

[0340] For example, the compound is represented by structural formula (Ih). Alternatively, the compound is represented by structural formula (Ii). Alternatively, the compound is represented by structural formula (Ij). The remaining values and exemplary values of the variables in the twenty-seventh aspect are as described above with respect to the first to twenty-sixth aspects of the first embodiment.

[0341] In the twenty-eighth aspect of the first embodiment, Y 1 is CH. Alternatively, Y 1 is N. The remaining values and exemplary values of the variables in the twenty-eighth aspect are as described above with respect to the first to twenty-seventh aspects of the first embodiment.

[0342] In the twenty-ninth aspect of the first embodiment, Z is CH. Alternatively, Z is N. The remaining values and exemplary values of the variables in the twenty-ninth aspect are as described above with respect to the first to twenty-eighth aspects of the first embodiment.

[0343] In the thirtieth aspect of the first embodiment, R 2 is H. Alternatively, R 2 is C 1-3 alkyl. For example, R 2 is methyl, ethyl, propyl or isopropyl. The remaining values and exemplary values of the variables in the thirtieth aspect are as described above with respect to the first to twenty-ninth aspects of the first embodiment.

[0344] In the thirty-first aspect of the first embodiment, the compound is represented by structural formula (Ik):

[0345] wherein R 5 is C 1-3 alkyl. For example, R 5 is methyl, ethyl, propyl or isopropyl. The remaining values and exemplary values of the variables in the thirty-first aspect are as described above with respect to the first to thirtieth aspects of the first embodiment.

[0346] In the thirty-second aspect of the first embodiment, the compound is represented by structural formula (Il):

[0347] wherein R 9 is C 1-3 alkyl. For example, R 9 is methyl, ethyl, propyl or isopropyl. The remaining values and exemplary values of the variables in the thirty-second aspect are as described above with respect to the first to thirtieth aspects of the first embodiment.

[0348] In the thirty-third aspect of the first embodiment, the compound is represented by structural formula (Im):

[0349] wherein R29 is C 1-3 alkyl. For example, R 29 is methyl, ethyl, propyl or isopropyl. The remaining values and exemplary values of the variables of the thirty-third aspect are as described above for the first to thirtieth aspects of the first embodiment.

[0350] In the thirty-fourth aspect of the first embodiment, the compound is selected from the compounds in Table 1.

[0351] Table 1.

[0352]

[0353]

[0354]

[0355]

[0356]

[0357]

[0358]

[0359]

[0360]

[0361]

[0362]

[0363]

[0364]

[0365]

[0366]

[0367]

[0368]

[0369]

[0370]

[0371]

[0372]

[0373]

[0374]

[0375]

[0376]

[0377]

[0378]

[0379]

[0380]

[0381]

[0382]

[0383]

[0384]

[0385]

[0386]

[0387]

[0388]

[0389]

[0390]

[0391]

[0392]

[0393]

[0394]

[0395]

[0396]

[0397]

[0398]

[0399]

[0400]

[0401]

[0402]

[0403]

[0404]

[0405]

[0406] In the thirty-fifth aspect of the first embodiment, the compound is selected from the compounds in Table 2.

[0407] Table 2.

[0408]

[0409]

[0410]

[0411]

[0412]

[0413]

[0414]

[0415]

[0416]

[0417]

[0418]

[0419]

[0420]

[0421]

[0422]

[0423]

[0424]

[0425]

[0426]

[0427]

[0428]

[0429]

[0430]

[0431]

[0432]

[0433]

[0434]

[0435]

[0436]

[0437]

[0438]

[0439] In the thirty-sixth aspect of the first embodiment, the compound is selected from the compounds in Table 3.

[0440] Table 3.

[0441]

[0442]

[0443]

[0444]

[0445] In the thirty-sixth aspect of the first embodiment, the compound is represented by the structural formula (In):

[0446]

[0447] Wherein: R 1a is selected from C 1-3 alkyl, halogen and H; R1b and R 4 each independently is a halogen or H; R 1c is selected from C 1-3 haloalkyl, halogen and H; and R 9 is H or C 1-3 alkyl. The remaining features and exemplary features of the thirty-sixth aspect are as described above with respect to the first to thirty-second aspects of the first embodiment.

[0448] In a second embodiment, the present invention relates to a pharmaceutical composition comprising a compound as described herein with respect to the first embodiment and its various aspects and a pharmaceutically acceptable excipient.

[0449] In a third embodiment, the present invention relates to a method of treating a disease or disorder, which comprises administering to an individual in need thereof a therapeutically effective amount of a compound as described herein with respect to the first embodiment and its various aspects, or a pharmaceutical composition as described herein with respect to the second embodiment and its various aspects, wherein the disease or disorder is selected from inflammatory diseases, autoimmune diseases, granulomatous diseases, cancers and neurodegenerative diseases.

[0450] 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 disease (IBD), ischemic reperfusion injury in solid organ transplantation, sepsis, liver disease, allergic diseases and graft-versus-host disease. For example, the inflammatory disease is IBD. For example, 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, ischemic reperfusion injury in kidney transplantation, non-alcoholic steatohepatitis, alcoholic steatohepatitis, insulin-resistant type 2 diabetes, allergic rhinitis, asthma, atopic dermatitis, Sjogren's syndrome, ankylosing spondylitis, pemphigus vulgaris, idiopathic plasmacytic lymphadenopathy, atherosclerosis, myocardial infarction, thrombosis, alpha-synucleinopathy, Parkinson's disease, Lewy body dementia, multiple system atrophy, Alzheimer's disease, amyotrophic lateral sclerosis and chronic obstructive pulmonary disease.

[0451] 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.

[0452] In a third aspect of the third embodiment, the disease or disorder is a granulomatous disease. By way of example, the granulomatous disease is selected from sarcoidosis, Blau syndrome, Wegener's granulomatosis, Behçet's disease, and interstitial lung disease.

[0453] In a fourth aspect of the third embodiment, the disease or disorder is cancer. By way of example, the cancer is selected from leukemia, breast cancer, brain cancer, colorectal cancer, head and neck cancer, melanoma, pancreatic cancer, prostate cancer, ovarian cancer, kidney cancer, and lung cancer.

[0454] In a fifth aspect of the third embodiment, the disease or disorder is a neurodegenerative disease. By way of example, 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) diseases, stroke, Fahr's disease, Menkes disease, Wilson's disease, cerebral ischemia, prion protein disorders, dementia, corticobasal degeneration, progressive supranuclear palsy, spinocerebellar ataxia, brain injury, and spinal cord injury.

[0455] 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. By way of example, in certain embodiments, the second agent is selected from anti-TNF agents, anti-IL-23 agents, anti-integrin agents, and JAK inhibitors. 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 exemplary features of the sixth aspect are as described above with respect to the first through fifth aspects of the third embodiment.

[0456] 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 exemplary features of the seventh aspect are as described above with respect to the first through sixth aspects of the third embodiment.

[0457] 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 simultaneously. In some embodiments, the second agent and the compound are administered separately at different times. The remaining features and exemplary features of the seventh aspect are as described above with respect to the first through sixth aspects of the third embodiment.

[0458] Examples

[0459] The present invention has been generally described, and it will be more readily understood with reference to the following examples, which are included only to illustrate certain aspects and embodiments of the present invention and are not intended to limit the present invention. The starting materials described herein are available from commercial sources or can be readily prepared from commercially available materials using transformations known to those skilled in the art.

[0460] The following general procedures illustrate the synthetic sequences of Examples 1 - 47.

[0461] General Procedure 1

[0462]

[0463] General Procedure 2

[0464]

[0465] General Procedure 3

[0466]

[0467] General Procedure 4

[0468]

[0469] General Procedure 5

[0470]

[0471] General Procedure 6

[0472]

[0473] General Procedure 7

[0474]

[0475] General Procedure 8

[0476]

[0477] General Procedure 9

[0478]

[0479] General Procedure 10

[0480]

[0481] General Procedure 11

[0482]

[0483] General Procedure 12

[0484]

[0485] General process 13

[0486]

[0487] General process 14

[0488]

[0489] General process 15

[0490]

[0491] General process 16

[0492]

[0493] General process 17

[0494]

[0495] General process 18

[0496]

[0497] General process 19

[0498]

[0499] General process 20

[0500]

[0501] General process 21

[0502]

[0503] General process 22

[0504]

[0505] General process 23

[0506]

[0507] General process 24

[0508]

[0509] General process 25

[0510]

[0511] 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 Procedure 18

[0512]

[0513] Part I - Synthesis of Oxidized (4-chloroquinolin-6-yl)dimethylphosphine

[0514]

[0515] Under an inert atmosphere of nitrogen, Xantphos (1.7 g, 2.94 mmol, 0.20 equiv), Pd2(dba)3 (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). Subsequently, the reaction mixture was 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%).

[0516] Part II - Synthesis of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(4-((6-(dimethylphosphoryl)quinolin-4-yl)oxy)-2-fluorophenyl)acetamide (Compound 36)

[0517]

[0518] Under an inert atmosphere of nitrogen, (4-chloroquinolin-6-yl)dimethylphosphine oxide (164.5 mg, 0.687 mmol, 1.00 equiv), Cs2CO3 (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). Subsequently, the reaction mixture was 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) for C 26 H 29 FN4O3P(M+H) + Calculated: 495.2, Found: 495.1. 1 H NMR (400 MHz, DMSO-d6) δ 10.23 (s, 1H), 8.82 (d, J = 5.2 Hz, 1H), 8.75 (dd, J = 12.6, 1.4 Hz, 1H), 8.15 - 8.13 (m, 2H), 7.94 (s, 1H), 7.55 (t, J = 8.5 Hz, 1H), 7.45 (s, 1H), 7.34 (dd, J = 10.4, 2.4 Hz, 1H), 7.18 (dd, J = 8.4, 2.4 Hz, 1H), 6.75 (d, J = 5.2 Hz, 1H), 3.71 (s, 2H), 1.76 (d, J = 13.4 Hz, 6H), 1.49 (s, 9H).

[0519] Example 2 - Preparation of Additional Phosphine Oxide Compounds

[0520] The compounds in the following table were prepared based on the experimental procedures and detailed descriptions described in Example 1.

[0521]

[0522]

[0523] Example 3 - Synthesis of N-(1-(tert-Butyl)-1H-pyrazol-4-yl)-2-(2-fluoro-4-((6-(S-methylsulfinimidoyl)quinolin-4-yl)oxy)phenyl)acetamide (Compounds 69 and 70); Prepared according to General Procedure 13

[0524]

[0525] Under an inert atmosphere of nitrogen, (di(acetoxy)iodo)benzene (1.29 g, 4.01 mmol, 3.00 eq) and (NH4)2CO3 (384.7 mg, 4.01 mmol, 3.00 eq) 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 eq, which can be synthesized according to Parts I and II of Example 32) in MeOH (6.2 mL). The reaction mixture was stirred at room temperature for 10 min. Subsequently, 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 racemic title compound was obtained as an off-white solid (180 mg, 27%). The two enantiomers were separated by chiral chromatography (column: HIRALPAK IA-3, 4.6×50 mm, 3 μm; mobile phase A: MTBE (0.1% DEA), mobile phase B: MeOH:DCM (1:1), isocratic separation with 20% B). The title compound was obtained as an off-white solid (Compound 69 (enantiomer 1): 48.8 mg, 7.6%; Compound 70 (enantiomer 2): 50.4 mg, 7.8%) (retention time (enantiomer 1): 3.14 min, retention time (enantiomer 2): 3.59 min, column: CHIRAL Cellulose-SB, 4.6×100 mm, 3 μm; mobile phase A: MTBE (0.1% DEA), mobile phase B: MeOH / DCM (1:1), isocratic separation with 20% B, flow rate: 1.0 mL / min, wavelength: 254 nm). LCMS (ESI) for C 25 H 27 FN5O3S(M+H) + Calculated value: 496.2, Experimental value: 495.9. 11H 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).

[0526] Example 4 - Synthesis of N-(1-(tert-Butyl)-1H-pyrazol-4-yl)-2-(2-fluoro-4-((6-(N-methylethanesulfonimidoyl)quinolin-4-yl)oxy)phenyl)acetamide (Compound 74); Prepared according to General Procedure 13

[0527]

[0528] Part I - Synthesis of N-(1-(tert-Butyl)-1H-pyrazol-4-yl)-2-(4-((6-(ethylthio)quinolin-4-yl)oxy)-2-fluorophenyl)acetamide

[0529]

[0530] Under an inert atmosphere of nitrogen, sodium ethanethiolate (0.25 g, 3.02 mmol, 1.50 equiv), triethylamine (1.02 g, 10.1 mmol, 5.00 equiv), Pd2(dba)3 (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). Subsequently, the mixture was 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). The title compound was obtained as a yellow solid (780 mg, 81%).

[0531] Part II - Synthesis of N-(1-(tert-Butyl)-1H-pyrazol-4-yl)-2-(4-((6-(ethylsulfonimidoyl)quinolin-4-yl)oxy)-2-fluorophenyl)acetamide

[0532]

[0533] Under an inert atmosphere of nitrogen, (di(acetoxy)iodo)benzene (606 mg, 1.88 mmol, 3.00 equiv) and (NH4)2CO3 (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). The reaction mixture was stirred at room temperature for 10 min. Subsequently, 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 a pale yellow solid (21.3 mg, 6.5%).

[0534] Part III - Synthesis of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(2-fluoro-4-((6-(N-methylethanesulfonimidoyl)quinolin-4-yl)oxy)phenyl)acetamide (Compound 74)

[0535]

[0536] Under an inert atmosphere of nitrogen, 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. 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, 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) for C 27 H 31 FN5O3S (M+H) + Calculated: 524.2, Found: 524.0. 11H 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), 7.45 (s, 1H), 7.42 - 7.35 (m, 1H), 7.21 (dd, J = 8.3, 2.4 Hz, 1H), 6.82 (d, J = 5.3 Hz, 1H), 3.71 (s, 2H), 3.39 - 3.65 (m, 2H), 2.54 (s, 3H), 1.49 (s, 9H), 1.13 (t, J = 7.4 Hz, 3H).

[0537] Example 5 - Synthesis of N-(1-(tert-Butyl)-1H-pyrazol-4-yl)-2-(4-((6-(N-cyano-S-methylsulfimido)quinolin-4-yl)oxy)-2-fluorophenyl)acetamide (Compound 71); Prepared according to the synthesis of Compound 19B in General Procedure 19

[0538]

[0539] 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, prepared according to Example 32) in THF / water (1:1, 6 mL), and the reaction mixture was stirred overnight at room temperature. Subsequently, 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 an off-white solid (11 mg, 3.4%). LCMS (ESI) for C 26 H 26 FN6O3S (M + H) + Calculated: 521.2, Found: 521.2. 11H 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).

[0540] Example 6 - Synthesis of N-(1-(tert-Butyl)-1H-pyrazol-4-yl)-2-(4-((6-(cyclopropylsulfonimidoyl)quinolin-4-yl)oxy)-2-fluoro-3-methylphenyl)acetamide (Compounds 441 and 442); Prepared according to General Procedure 13

[0541]

[0542] Part I - Synthesis of (4-Bromo-2-fluoro-3-methylphenyl)methanol

[0543]

[0544] At 0 °C, 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). Subsequently, the mixture was stirred overnight at room temperature. 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 saturated aqueous NaHCO3 and brine, dried over Na2SO4, 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%).

[0545] Part II - Synthesis of 1-Bromo-4-(bromomethyl)-3-fluoro-2-methylbenzene

[0546]

[0547] At 0 °C, carbon tetrabromide (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). Subsequently, the mixture was 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 Na2SO4, 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%).

[0548] Part III - Synthesis of 2-(4-bromo-2-fluoro-3-methylphenyl)acetonitrile

[0549]

[0550] A solution of 1-bromo-4-(bromomethyl)-3-fluoro-2-methylbenzene (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, saturated aqueous NaHCO3 was added and the product was extracted with EtOAc (3 × 300 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 50:1). The title compound was obtained as a yellow solid (19.33 g, 80%).

[0551] Part IV - Synthesis of 2-(4-bromo-2-fluoro-3-methylphenyl)acetic acid

[0552]

[0553] 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. Subsequently, the pH of the solution was 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 Na2SO4, and the solvent was removed under reduced pressure. The title compound (18.9 g) was used in the next reaction without further purification.

[0554] Part V - Synthesis of 2-(4-bromo-2-fluoro-3-methylphenyl)-N-(1-(tert-butyl)-1H-pyrazol-4-yl)acetamide

[0555]

[0556] At 0 °C, 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). Subsequently, the reaction mixture was 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 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 red solid (24 g, 85%).

[0557] Part VI - Synthesis of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(2-fluoro-4-hydroxy-3-methylphenyl)acetamide

[0558]

[0559] Under an inert atmosphere of nitrogen, 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)Cl2 (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. 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 × 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 2:1). The title compound was obtained as a green solid (17 g, 85%).

[0560] Part VII - Synthesis of 4-chloro-6-(cyclopropylthio)quinoline

[0561]

[0562] Under an inert atmosphere of nitrogen, a solution of 6-bromo-4-chloroquinoline (20.0 g, 82.5 mmol, 1.00 equiv), sodium cyclopropylthiolate (9.51 g, 99.0 mmol, 1.20 equiv), Xantphos (9.54 g, 16.5 mmol, 0.20 equiv), Pd2(dba)3 (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. Subsequently, the solvent was 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%).

[0563] Part VIII - Synthesis of (4-chloroquinolin-6-yl)(cyclopropyl)(imino)-λ 6 -sulfinyl ketone

[0564]

[0565] At room temperature, a solution of 4-chloro-6-(cyclopropylthio)quinoline (3.00 g, 12.7 mmol, 1.00 equiv), (di(acetoxy)iodo)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 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%).

[0566] Part IX - Synthesis of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(4-((6-(cyclopropylsulfinylimino)quinolin-4-yl)oxy)-2-fluoro-3-methylphenyl)acetamide (Compounds 441 and 442)

[0567]

[0568] Under an inert atmosphere of nitrogen, 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 6-Sulfolone (500 mg, 1.87 mmol, 1.00 equiv), Cs2CO3 (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 a solution of 1,4-dioxane (10 mL) was heated to 100 °C for 16 h. 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: 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: hexane / DCM (3:1), mobile phase B: isopropanol, isocratic elution at 35% B). The title compounds were obtained as brown solids (Compound 441 (enantiomer 1): 130.0 mg, 13%; Compound 442 (enantiomer 2): 103.2 mg, 10%) (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, isocratic elution at 50% B, flow rate: 1.0 mL / min, wavelength: 254 nm). LCMS (ESI) for C 28 H 31 FN5O3S(M+H) + Calculated: 536.2, Found: 536.1. 1 H NMR (300 MHz, DMSO-d6) δ 10.23 (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 = 8.4 Hz, 1H), 7.15 (d, J = 8.4 Hz, 1H), 6.62 (d, J = 5.2 Hz, 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).

[0569] Example 7 - Synthesis of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(2-fluoro-4-((6-(1-oxo-3,4,5,6-tetrahydro-1λ 6 ,2-thiazine-1-yl)quinolin-4-yl)oxy)phenyl)acetamide (Compound 67); Prepared according to General Procedure 20

[0570]

[0571] Part I - Synthesis of S-(4-(4-(2-((1-(tert-butyl)-1H-pyrazol-4-yl)amino)-2-oxoethyl)-3-fluorophenoxy)quinolin-6-yl)thioacetate

[0572]

[0573] Under an inert atmosphere of nitrogen, 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), Pd2(dba)3 (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. Subsequently, the crude product was purified by column chromatography (petroleum ether / EtOAc 5:1). The title compound was obtained as a yellow solid (1.33 g, 96%).

[0574] 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

[0575]

[0576] 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)thioacetate (500.0 mg, 1.02 mmol, 1.00 equiv) in DMF (10 mL), and the mixture was stirred at room temperature for 30 min. Subsequently, water was added, and the product was extracted with EtOAc (2 × 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). The title compound was obtained as a pale yellow solid (405 mg, 63%).

[0577] Part III - Synthesis of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(2-fluoro-4-((6-(1-oxo-3,4,5,6-tetrahydro-1λ 6 ,2-thiazin-1-yl)quinolin-4-yl)oxy)phenyl)acetamide (Compound 67)

[0578]

[0579] (Diacetoxyiodo)benzene (764 mg, 2.37 mmol, 5.00 equiv) and (NH4)2CO3 (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. Subsequently, the crude product was purified by chromatography 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) for C 28 H 31 FN5O3S (M + H) + Calculated: 536.2, Found: 536.2. 11H 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, 2.2 Hz, 1H), 6.81 (d, J = 5.2 Hz, 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).

[0580] Example 8 - Preparation of Additional Sulfoximine Compounds

[0581] The compounds in the following table were prepared based on the experimental procedures and detailed descriptions described in Examples 3, 4, and 5.

[0582]

[0583]

[0584]

[0585]

[0586]

[0587]

[0588]

[0589]

[0590]

[0591]

[0592]

[0593]

[0594]

[0595]

[0596]

[0597]

[0598] 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 Procedure 11

[0599]

[0600] Part I - Synthesis of 6-Bromo-7-methoxyquinazolin-4(3H)-one

[0601]

[0602] 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. Subsequently, the solvent was 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 grey solid (4.09 g, 82% yield) and used in the next reaction without further purification.

[0603] Part II - Synthesis of 6-(tert-Butylsulfonyl)-7-methoxyquinazolin-4(3H)-one

[0604]

[0605] Under an inert atmosphere of nitrogen, 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), Na2CO3 (3.37 g, 30.8 mmol, 1.90 equiv) and Pd(PPh3)4 (0.6 g, 0.483 mmol, 0.03 equiv) in DMF (56 mL) was heated to 100 °C for 6 hours. The insoluble by-products were filtered off. Water was added and the precipitated product was filtered off and washed with petroleum ether.

[0606] The thioether intermediate was dissolved in MeOH (140 mL), EtOAc (140 mL), and water (140 mL), and potassium peroxymonosulfate (22.5 g, 134 mmol, 8.70 equiv) was added. After stirring for 16 h at room temperature, the mixture was filtered and washed with saturated aqueous 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 saturated aqueous 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) and was used in the next reaction without further purification.

[0607] Part III - Synthesis of 6-(tert-butylsulfonyl)-4-chloro-7-methoxyquinazoline

[0608]

[0609] At room temperature, POCl3 (56.9 mg, 0.371 mmol, 1.10 equiv) was added dropwise to a solution of 6-(tert-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). Subsequently, the reaction mixture was heated to 80 °C for 2 h. After cooling to room temperature, this reaction mixture was used directly in the next reaction.

[0610] Part IV - Synthesis of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(2-fluoro-4-hydroxyphenyl)acetamide

[0611]

[0612] At 0 °C, 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). 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).

[0613] 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)

[0614]

[0615] K2CO3 (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. Subsequently, the crude product was purified by preparative HPLC (Column: Xselect CSH C18 OBD; 30×150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Isocratic elution with 35% B for 13 min; Wavelength: 220 nm; RT1: 11 min). The title compound was obtained as a white solid (10.3 mg, 5.2%). LCMS (ESI) for C 28 H 33 FN5O5S (M+H) + Calculated: 570.2, Found: 570.1. 1 1H NMR (400 MHz, DMSO-d6) δ 10.26 (d, J = 8.1 Hz, 1H), 9.04 - 8.56 (m, 2H), 7.94 (t, J = 9.9 Hz, 1H), 7.65 (t, J = 6.8 Hz, 1H), 7.57 - 7.41 (m, 2H), 7.40 - 7.30 (m, 1H), 7.21 (d, J = 8.3 Hz, 1H), 4.20 - 3.95 (m, 3H), 3.69 (d, J = 8.2 Hz, 2H), 1.61 - 1.42 (m, 9H), 1.41 - 1.21 (m, 9H).

[0616] 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 Procedure 11

[0617]

[0618] Part I - Synthesis of 6-(tert-Butylthio)-4-chloro-7-methoxyquinoline

[0619]

[0620] Under an inert atmosphere of nitrogen, a solution of 6-bromo-4-chloro-7-methoxyquinoline (commercially available, 5.0 g, 18.3 mmol, 1.00 equiv), 2-methylpropan-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 to 100 °C for 6 h. Subsequently, 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: 40 - 70% B in 30 min; wavelength: 210 nm). The title compound as a yellow solid was obtained (3 g, 58%).

[0621] Part II - Synthesis of 6-(tert-Butylsulfonyl)-4-chloro-7-methoxyquinoline

[0622]

[0623] At room temperature, 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 stirred for 16 h. The product was extracted with EtOAc (3 × 300 mL) and the combined organic phases were washed with brine and dried over Na2SO4. 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 NH4HCO3), mobile phase B: ACN, gradient: 40 - 70% B in 30 min; wavelength: 210 nm). The title compound as a yellow solid was obtained (1.5 g, 45%).

[0624] Part III - Synthesis of Methyl 2-(4-((6-(tert-Butylsulfonyl)-7-methoxyquinolin-4-yl)oxy)-2-fluorophenyl)acetate

[0625]

[0626] 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 cooled 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 - 90% B in 30 min; wavelength: 210 nm). The title compound was obtained as a yellow solid (300 mg, 41%).

[0627] Part IV - Synthesis of 2-(4-((6-(tert-butylsulfonyl)-7-methoxyquinolin-4-yl)oxy)-2-fluorophenyl)acetic acid

[0628]

[0629] At room temperature, 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 for 2 h. Subsequently, 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: 20 - 50% B in 30 min; wavelength: 210 nm). The title compound was obtained as a yellow solid (260 mg, 67%).

[0630] 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)

[0631]

[0632] 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 h. Subsequently, the crude product was purified by preparative HPLC (column: Xselect CSH C18 OBD, 30×150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 38 - 43% B in 13 min; wavelength: 220 nm; RT1: 11 min). The title compound was obtained as a white solid (15 mg, 23%). LCMS (ESI) for C 29 H 34 FN4O5S(M+H) + Calcd: 569.2, Found: 569.0. 1 H NMR (400 MHz, DMSO-d6) δ 10.23 (s, 1H), 8.81 (d, J = 5.3 Hz, 1H), 8.74 (d, J = 1.5 Hz, 1H), 7.97 - 7.92 (m, 1H), 7.68 (s, 1H), 7.54 (t, J = 8.5 Hz, 1H), 7.48 - 7.43 (m, 1H), 7.36 (dd, J = 10.4, 2.4 Hz, 1H), 7.20 (dd, J = 8.2, 2.4 Hz, 1H), 6.64 (d, J = 5.3 Hz, 1H), 4.03 (s, 3H), 3.71 (s, 2H), 1.49 (s, 9H), 1.32 (s, 9H).

[0633] 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 Procedure 8.

[0634]

[0635] Part I - Synthesis of methyl 4-(((2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-ylidene)methyl)amino)-2-fluorobenzoate

[0636]

[0637] 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. Subsequently, the precipitated product was filtered off, washed with MeOH (3 × 20 mL), and dried under reduced pressure. The title compound (44 g, 89%) was obtained as a brown solid and was used in the next reaction without further purification.

[0638] Part II - Synthesis of methyl 7-fluoro-4-oxo-1,4-dihydroquinoline-6-carboxylate

[0639]

[0640] 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. Subsequently, the precipitated product was filtered off, washed with hexane (3 × 100 mL), and dried under reduced pressure. The title compound (12 g, 88%) was obtained as a brown solid and was used in the next reaction without further purification.

[0641] Part III - Synthesis of methyl 4-chloro-7-fluoroquinoline-6-carboxylate

[0642]

[0643] A solution of methyl 7-fluoro-4-oxo-1,4-dihydroquinoline-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 (1.2 g, 11% yield) was obtained as a yellow solid.

[0644] Part IV - Synthesis of methyl 4-(4-(2-((1-(tert-butyl)-1H-pyrazol-4-yl)amino)-2-oxoethyl)-2-methylphenoxy)-7-fluoroquinoline-6-carboxylate

[0645]

[0646] At room temperature, 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 Cs2CO3 (7.72 g, 8.35 mmol, 2.00 equiv) in DMA (10 mL) was stirred for 5 h. Subsequently, the crude product was 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%).

[0647] 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)

[0648]

[0649] 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. Subsequently, the crude product was 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) for C 27 H 29 FN5O3 (M + H)+ Calcd: 490.2, Found: 490.2. 11H NMR (300 MHz, DMSO-d6) δ 10.20 (s, 1H), 8.72 (d, J = 5.2 Hz, 1H), 8.62 (d, J = 7.8 Hz, 1H), 8.56 (d, J = 4.8 Hz, 1H), 7.95 (d, J = 0.7 Hz, 1H), 7.86 (d, J = 11.8 Hz, 1H), 7.46 (d, J = 0.7 Hz, 1H), 7.38 (d, J = 2.1 Hz, 1H), 7.30 (dd, J = 8.2, 2.2 Hz, 1H), 7.19 (d, J = 8.2 Hz, 1H), 6.42 (d, J = 5.2 Hz, 1H), 3.61 (s, 2H), 2.85 (d, J = 4.6 Hz, 3H), 2.12 (s, 3H), 1.49 (s, 9H).

[0650] Example 11 - Preparation of Additional 7-Substituted Quinoline and Quinazoline Compounds

[0651] The compounds in the following table were prepared based on the experimental procedures and detailed descriptions described in Examples 9, 10, and 10a.

[0652]

[0653]

[0654]

[0655]

[0656]

[0657]

[0658]

[0659]

[0660]

[0661] 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 Procedure 7

[0662]

[0663] Part I - Synthesis of Methyl 2-(3-(1,3-Dioxolan-2-yl)-4-hydroxyphenyl)acetate

[0664]

[0665] 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 overnight at room temperature. 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 Na2SO4 and the solvent was removed under reduced pressure. The crude product was purified by column chromatography (petroleum ether / EtOAc 5:1). The title compound was obtained as a yellow oil (2.8 g, 46%).

[0666] Part II - Synthesis of methyl 2-(3-(1,3-dioxolan-2-yl)-4-((6-(methylsulfonyl)quinolin-4-yl)oxy)phenyl)acetate

[0667]

[0668] 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 Cs2CO3 (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 for 4 h at room temperature. 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 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 yellow solid (600 mg, 32%).

[0669] Part III - Synthesis of methyl 2-(3-formyl-4-((6-(methylsulfonyl)quinolin-4-yl)oxy)phenyl)acetate

[0670]

[0671] Iron(III) chloride (1.26 g, 4.66 mmol, 2.50 eq) 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 eq) in DCM (12 mL), and the mixture was stirred overnight at room temperature. Subsequently, the reaction was quenched with water / ice (50 mL), and the pH of the solution was adjusted to 8 with saturated aqueous NaHCO3. The product was extracted with EtOAc (3 × 5 mL), the combined organic phases were dried over Na2SO4, and the solvent was removed under reduced pressure. The title compound (480 mg) was used in the next reaction without any further purification.

[0672] Part IV - Synthesis of methyl 2-(3-(difluoromethyl)-4-((6-(methylsulfonyl)quinolin-4-yl)oxy)phenyl)acetate

[0673]

[0674] At 0 °C, bis(2-methoxyethyl)aminosulfur trifluoride (1.04 g, 4.71 mmol, 4.00 eq) 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 eq) and EtOH (10.8 mg, 0.235 mmol, 0.20 eq) in DCM (10 mL). Subsequently, the mixture was stirred overnight at room temperature. Then, the reaction was 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). The title compound (210 mg, 42%) was obtained as a white solid.

[0675] Part V - Synthesis of 2-(3-(difluoromethyl)-4-((6-(methylsulfonyl)quinolin-4-yl)oxy)phenyl)acetic acid

[0676]

[0677] At 0 °C, LiOH (20.5 mg, 0.854 mmol, 2.00 equiv) was added to a solution of methyl 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). Subsequently, the mixture was 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%).

[0678] 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)

[0679]

[0680] At 0 °C, 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). Subsequently, the mixture was 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) for C 26 H 27 F2N4O4 (M+H) + Calculated: 529.2, Found: 529.0. 11H NMR (300 MHz, 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 = 2.0 Hz, 1H), 7.64 (d, J = 8.3 Hz, 1H), 7.48 - 7.42 (m, 2H), 7.24 (t, J = 54.0 Hz, 1H), 6.73 (d, J = 5.2 Hz, 1H), 3.73 (s, 2H), 3.38 (s, 3H), 1.49 (s, 9H).

[0681] Example 13 - Preparation of Additional Difluoromethylphenyl Compounds

[0682] The compounds in the following table were prepared based on the experimental procedures and detailed descriptions described in Example 12.

[0683]

[0684]

[0685]

[0686]

[0687] 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 Procedure 15

[0688]

[0689] Part I - Synthesis of N-(1-(tert-Butyl)-1H-pyrazol-4-yl)-2-(3-fluoro-5-hydroxypyridin-2-yl)acetamide

[0690]

[0691] At 0 °C, EDC (19.7 g, 127 mmol, 1.50 eq) was added to a solution of 2-(3-fluoro-5-hydroxypyridin-2-yl)acetic acid (14.5 g, 84.7 mmol, 1.00 eq), 1-(tert-butyl)-1H-pyrazol-4-amine (11.8 g, 84.7 mmol, 1.00 eq), HOBt (17.2 g, 127 mmol, 1.50 eq) and DIPEA (32.9 g, 254 mmol, 3.00 eq) in THF (145 mL) and DCM (145 mL), and the mixture was stirred overnight at room temperature. 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 phases were washed with brine, dried over Na2SO4 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 brown solid (17.3 g, 70%).

[0692] Part II - Synthesis of 2-(5-((6-bromoquinazolin-4-yl)oxy)-3-fluoropyridin-2-yl)-N-(1-(tert-butyl)-1H-pyrazol-4-yl)acetamide

[0693]

[0694] Under an inert atmosphere of nitrogen, K2CO3 (3.92 g, 28.3 mmol, 3.00 eq) was added to a solution of 6-bromo-4-chloroquinazoline (2.3 g, 9.45 mmol, 1.00 eq) 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 eq, prepared as shown in Part I of Example 15) in DMF (23 mL). The mixture was stirred overnight at room temperature. Subsequently, EtOAc (200 mL) was added and the mixture was washed with water (2 × 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) and was used in the next reaction without further purification.

[0695] 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

[0696]

[0697] Under an inert atmosphere of nitrogen, 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), 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)Cl2 (1.1 g, 1.50 mmol, 0.15 equiv) in a solution of 1,4-dioxane (80 mL) were heated to 70 °C for 2.5 h. The mixture was diluted with EtOAc (200 mL) and washed with water (2 × 100 mL). Subsequently, the organic phase was dried over Na2SO4, and the solvent was removed under reduced pressure. The title compound (8.5 g) was obtained as a light brownish red solid and was used in the next reaction without further purification.

[0698] 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

[0699]

[0700] A solution of hydrogen peroxide in water (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 (2 g, 48%, over 3 steps) was obtained as a light yellowish brown solid.

[0701] 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)

[0702]

[0703] At 0 °C, 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). Subsequently, the mixture was 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 OBD; 19 × 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) for C 28 H 33 FN7O3(M+H) + Calculated: 534.3, Found: 534.3. 1 H NMR (400 MHz, DMSO-d6) δ 10.32 (s, 1H), 8.64 (s, 1H), 8.50 (d, J = 1.9 Hz, 1H), 8.00 (dd, J = 10.1, 2.2 Hz, 1H), 7.97 (d, J = 9.1 Hz, 1H), 7.93 (d, J = 0.7 Hz, 1H), 7.75 - 7.66 (m, 2H), 7.45 (d, J = 0.7 Hz, 1H), 4.70 (dt, J = 8.1, 4.2 Hz, 1H), 3.91 (d, J = 2.3 Hz, 2H), 2.68 - 2.57 (m, 2H), 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).

[0704] 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 Procedure 2

[0705]

[0706] Part I - Synthesis of Ethyl 1-(tert-butyl) 2-(5-bromo-3-fluoropyridin-2-yl)malonate

[0707]

[0708] At 0 °C, sodium hydride (60 wt.%, 124 g, 3.09 mol, 1.20 equiv) was added to a solution of ethyl tert-butyl malonate (485 g, 2.58 mol, 1.00 equiv) in DMF (5 L). Subsequently, the reaction mixture was 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 to 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 any further purification.

[0709] Part II - Synthesis of Ethyl 2-(5-bromo-3-fluoropyridin-2-yl)acetate

[0710]

[0711] TFA (5 L) was added to a solution of ethyl 1-(tert-butyl) 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 solvent was adjusted to 7 by adding saturated aqueous NaHCO3. The product was extracted with EtOAc (3 × 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). The title compound was obtained as a yellow oil (520 g, 65%, over 2 steps).

[0712] Part III - Synthesis of Ethyl 2-(3-fluoro-5-hydroxypyridin-2-yl)acetate

[0713]

[0714] Under an inert atmosphere of nitrogen, a solution of ethyl 2-(5-bromo-3-fluoropyridin-2-yl)acetate (470 g, 1.79 mol, 1.00 equiv), Pd(dppf)Cl2 (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. Subsequently, a solution of hydrogen peroxide in water (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 2 steps).

[0715] Part IV - Synthesis of 2-(3-fluoro-5-hydroxypyridin-2-yl)acetic acid

[0716]

[0717] 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 phases were 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.

[0718] Part V - Synthesis of N-(5-(tert-butyl)-1-methyl-1H-pyrazol-3-yl)-2-(3-fluoro-5-hydroxypyridin-2-yl)acetamide

[0719]

[0720] HATU (9.33 g, 24.5 mmol, 1.50 eq) was added to a solution of 2-(3-fluoro-5-hydroxypyridin-2-yl)acetic acid (2.80 g, 16.3 mmol, 1.00 eq), 5-(tert-butyl)-1-methyl-1H-pyrazol-3-amine (2.76 g, 18.0 mmol, 1.10 eq) and triethylamine (3.31 g, 32.7 mmol, 2.00 eq) in DMF (28 mL), and the mixture was stirred at room 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, 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%).

[0721] 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)

[0722]

[0723] Under an inert atmosphere of nitrogen, a solution of 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 eq), 4-chloro-6-(methylsulfonyl)quinoline (158 mg, 0.653 mmol, 1.00 eq), Cs2CO3 (425 mg, 1.31 mmol, 2.00 eq), CuI (49.7 mg, 0.261 mmol, 0.40 eq) and N,N-dimethylglycine (40.4 mg, 0.392 mmol, 0.60 eq) in 1,4-dioxane (4 mL) was heated to 100 °C for 16 h. Subsequently, the 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) for C 25 H 27 FN5O4S (M + H) + Calculated: 512.2, Found: 512.1. 11H NMR (300 MHz, DMSO-d6) δ 10.64 (s, 1H), 8.93 (d, J = 5.2 Hz, 1H), 8.87 (s, 1H), 8.54 (d, J = 2.1 Hz, 1H), 8.31 (s, 2H), 8.03 (d, J = 9.0 Hz, 1H), 6.93 (d, J = 5.2 Hz, 1H), 6.30 (s, 1H), 3.95 (s, 2H), 3.81 (s, 3H), 3.38 (s, 3H), 1.31 (s, 9H).

[0724] Example 16 - Preparation of Additional Pyridine Compounds

[0725] The compounds in the following table were prepared based on the experimental procedures and detailed descriptions described in Example 15.

[0726]

[0727]

[0728]

[0729]

[0730]

[0731]

[0732]

[0733]

[0734]

[0735]

[0736]

[0737] 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 Procedure 21

[0738]

[0739] Part I - Synthesis of tert-Butyl 2-(4-Bromo-3-methylphenyl)propionate

[0740]

[0741] Trimethylsilyl chloride (0.52 g, 4.78 mmol, 0.05 eq) was added to a suspension of zinc (9.38 g, 143 mmol, 1.50 eq) in THF (150 mL), and the mixture was stirred for 15 min at room temperature under an inert atmosphere of nitrogen. Subsequently, a solution of tert-butyl 2-bromopropionate (20.0 g, 95.7 mmol, 1.00 eq) in THF (50 mL) was added dropwise at 50 °C. After cooling to room temperature, the resulting organozinc reagent was used in the next reaction without any purification. 1-Bromo-4-iodo-2-methylbenzene (10.8 mL, 36.4 mmol, 1.00 eq), Pd2(dba)3 (3.34 g, 3.64 mmol, 0.10 eq), and Xantphos (2.11 g, 3.64 mmol, 0.10 eq) were added to a solution of the organozinc reagent in THF (120 mL, 43.7 mmol, 1.20 eq), and the reaction mixture was heated to 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%).

[0742] Part II - Synthesis of tert-butyl 2-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propionate

[0743]

[0744] Under an inert atmosphere of nitrogen, a solution of tert-butyl 2-(4-bromo-3-methylphenyl)propionate (5.30 g, 17.7 mmol, 1.00 eq), bis(pinacolato)diboron (9.03 g, 35.4 mmol, 2.00 eq), Pd(dppf)Cl2 (1.30 g, 1.77 mmol, 0.10 eq), and potassium acetate (5.22 g, 53.1 mmol, 3.00 eq) in 1,4-dioxane (53 mL) was heated to 100 °C overnight. 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 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 (4.9 g, 80%).

[0745] Part III - Synthesis of tert-butyl 2-(4-hydroxy-3-methylphenyl)propionate

[0746]

[0747] A solution of hydrogen peroxide in water (1.89 g, 55.4 mmol, 4.00 eq) was added to a solution of tert-butyl 2-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propionate (4.8 g, 13.9 mmol, 1.00 eq) 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 Na2SO4, and the solvent was removed under reduced pressure. The title compound (4.4 g) was obtained as a brown oil and was used in the next reaction without further purification.

[0748] Part IV - Synthesis of tert-butyl 2-(3-methyl-4-((6-(methylsulfonyl)quinolin-4-yl)oxy)phenyl)propionate

[0749]

[0750] At room temperature, a solution of tert-butyl 2-(4-hydroxy-3-methylphenyl)propionate (1.0 g, 4.23 mmol, 1.00 eq), 4-chloro-6-(methylsulfonyl)quinoline (1.02 g, 4.23 mmol, 1.00 eq), and Cs2CO3 (2.76 g, 8.46 mmol, 2.00 eq) in NMP (20 mL) was stirred overnight. Subsequently, the insoluble by-products were filtered off, and the crude product was purified by flash column chromatography on reverse phase (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 (1.0 g, 54%) was obtained as a colorless oil.

[0751] Part V - Synthesis of 2-(3-methyl-4-((6-(methylsulfonyl)quinolin-4-yl)oxy)phenyl)propionic acid

[0752]

[0753] 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)propionate (950 mg, 2.15 mmol, 1.00 equiv) in 1,4-dioxane (9.5 mL), and the mixture was heated to 70 °C overnight. Water (15 mL) was added, and the product was extracted with EtOAc (3 × 20 mL). The combined organic phases were washed with brine, dried over Na2SO4, and the solvent was removed under reduced pressure. The title compound was obtained as a white solid (800 mg, 96%) and was used in the next reaction without further purification.

[0754] 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)

[0755]

[0756] 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. Subsequently, 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: 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: CHIRALART Amylose-SC, 20 × 250 mm, 5 μm; mobile phase A: MTBE (0.5% of 2 M ammonia in MeOH), mobile phase B: EtOH). The title compound was obtained as a white solid (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, isocratic elution with 10% B, flow rate: 1.0 mL / min, wavelength: 254 nm). LCMS (ESI) for C 27 H 29 N4O4S (M-H) -Calculated value: 505.2, experimental value: 505.1. 1 1H NMR (400 MHz, DMSO-d6) δ 10.15 (s, 1H), 8.89 (dd, J = 1.9, 0.9 Hz, 1H), 8.83 (d, J = 5.2 Hz, 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 = 8.3 Hz, 1H), 6.55 (d, J = 5.2 Hz, 1H), 3.80 (q, J = 7.0 Hz, 1H), 3.38 (s, 3H), 2.15 (s, 3H), 1.48 (s, 9H), 1.45 (d, J = 7.0 Hz, 3H).

[0757] Example 18 - Preparation of Additional Arylpionic Acid Compounds

[0758] The compounds in the following table were prepared based on the experimental procedures and detailed descriptions described in Example 17.

[0759]

[0760] 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 Procedure 4

[0761]

[0762] At 0 °C, 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, 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). Subsequently, the reaction mixture was stirred at room temperature for 1 hour. The crude product was purified by reverse-phase flash chromatography (column: C18 silica gel; mobile phase A: water (1% NaHCO3), 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%). LCMS (ESI) for C 25 1 25 FN5O3 (M + H) + Calculated value: 462.2, experimental value: 462.2.1 1H NMR (400 MHz, DMSO-d6) δ 11.19 (bs, 1H), 8.85 (d, J = 1.2 Hz, 1H), 8.64 (s, 1H), 8.15 (d, J = 1.2 Hz, 1H), 7.95 (d, J = 9.1 Hz, 1H), 7.69 (dd, J = 9.1, 2.9 Hz, 1H), 7.62 (d, J = 2.8 Hz, 1H), 7.51 (t, J = 8.5 Hz, 1H), 7.35 (dd, J = 10.5, 2.4 Hz, 1H), 7.23 - 7.17 (m, 1H), 3.98 (s, 3H), 3.93 (s, 2H), 1.28 (s, 9H).

[0763] 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 Procedure 4

[0764]

[0765] Part I - Synthesis of 2-chloro-4-(3,3,3-trifluoroprop-1-en-2-yl)pyridine

[0766]

[0767] Under an inert atmosphere of nitrogen, 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)Cl2 (929 mg, 1.27 mmol, 0.10 equiv) and K2CO3 (6.19 g, 44.5 mmol, 3.50 equiv) in THF (20 mL) and water (10 mL) was heated to 70 °C overnight. Subsequently, water was added and the product was extracted with EtOAc (3 × 20 mL). The combined organic phases were washed with brine, dried over MgSO4 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 - 80% B in 17 min; wavelength: 210 nm). The title compound was obtained as a yellow oil (500 mg, 19%).

[0768] Part II - Synthesis of tert-butyl (4-(3,3,3-trifluoroprop-1-en-2-yl)pyridin-2-yl)carbamate

[0769]

[0770] Under an inert atmosphere of nitrogen, 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), Cs2CO3 (1.87 g, 9.63 mmol, 2.00 equiv), Pd2(dba)3 (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. EtOAc was added and the organic phase was washed with brine, dried over MgSO4, 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.

[0771] Part III - Synthesis of tert-butyl (4-(1-(trifluoromethyl)cyclopropyl)pyridin-2-yl)carbamate

[0772]

[0773] At 0 °C, under an inert atmosphere of nitrogen, 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). 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 19 min; wavelength: 210 nm). The title compound was obtained as a yellow solid (250 mg, 24%).

[0774] Part IV - Synthesis of 4-(1-(trifluoromethyl)cyclopropyl)pyridin-2-amine

[0775]

[0776] A solution of HCl in 1,4-dioxane (4 M, 3.00 mL, 12.0 mmol, 18.1 eq) was added to a solution of tert-butyl (4-(1-(trifluoromethyl)cyclopropyl)pyridin-2-yl)carbamate (200 mg, 0.662 mmol, 1.00 eq) 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 20 min; wavelength: 210 nm). The title compound was obtained as a yellow solid (120 mg, 90%).

[0777] Part V - Synthesis of methyl 2-(2-fluoro-4-((6-methoxyquinazolin-4-yl)oxy)phenyl)acetate

[0778]

[0779] A solution of 4-chloro-6-methoxyquinazoline (10.0 g, 51.4 mmol, 1.00 eq), methyl 2-(2-fluoro-4-hydroxyphenyl)acetate (10.4 g, 56.5 mmol, 1.10 eq) and K2CO3 (21.3 g, 154 mmol, 3.00 eq) 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 Na2SO4. 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%).

[0780] Part VI - Synthesis of 2-(2-fluoro-4-((6-methoxyquinazolin-4-yl)oxy)phenyl)acetic acid

[0781]

[0782] A solution of lithium hydroxide monohydrate (2.75 g, 65.4 mmol, 1.40 eq) 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 eq) in THF (160 mL), and the mixture was stirred at room temperature for 6 h. The precipitated product was filtered off, washed with water (50 mL), and dried under reduced pressure. A compound was obtained as an off-white solid (12.3 g), which was used in the next reaction without further purification.

[0783] Part VII - Synthesis of 2-(2-Fluoro-4-((6-Methoxyquinazolin-4-yl)oxy)phenyl)-N-(4-(1-(Trifluoromethyl)cyclopropyl)pyridin-2-yl)acetamide (34)

[0784]

[0785] At 0 °C, 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). Subsequently, the mixture was 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% NaHCO3), 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) for C 26 H 21 F4N4O3 (M+H) + Calculated: 513.2, Found: 513.0. 1 1H NMR (300 MHz, DMSO-d6) δ 10.96 (s, 1H), 8.64 (s, 1H), 8.36 (d, J = 5.2 Hz, 1H), 8.24 (s, 1H), 7.96 (d, J = 9.1 Hz, 1H), 7.72 - 7.61 (m, 2H), 7.50 (d, J = 8.7 Hz, 1H), 7.35 (d, J = 10.8 Hz, 1H), 7.20 (d, J = 8.7 Hz, 2H), 3.98 (s, 3H), 3.89 (s, 2H), 1.24 (s, 2H), 1.20 (s, 2H).

[0786] Example 21 - Preparation of Aminoheteroaryl Compounds

[0787] The compounds in the following table were prepared based on the experimental procedures and detailed descriptions described in Examples 19 and 20.

[0788]

[0789]

[0790]

[0791]

[0792]

[0793] 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 Procedure 16

[0794]

[0795] Part I - Synthesis of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(2-fluoro-4-((6-methoxyquinazolin-4-yl)oxy)phenyl)acetamide

[0796]

[0797] Under an inert atmosphere of nitrogen, 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, which can be synthesized as described in Part II of Example 9), Cs2CO3 (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). 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 × 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).

[0798] Part II - Synthesis of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(2-fluoro-4-((6-hydroxyquinazolin-4-yl)oxy)phenyl)acetamide

[0799]

[0800] At 0 °C, 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). Subsequently, the reaction mixture was stirred overnight at room temperature. The solution was slowly poured into a saturated solution of NaHCO3 in water (10 mL) and the product was extracted with EtOAc (20 mL). The combined organic phases were washed with water (2 × 10 mL) and dried over Na2SO4. The solvent was removed under reduced pressure. The title compound (190 mg) was obtained as a brown solid and was used in the next reaction without further purification.

[0801] 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

[0802]

[0803] (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 (270 mg) was obtained as a yellow solid and was used in the next reaction without further purification.

[0804] 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)

[0805]

[0806] Ammonium fluoride (389.8 mg, 10.5 mmol, 25.0 eq) 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 eq) in MeOH (2.5 mL), and the mixture was heated to 50 °C for 2 h. Subsequently, the solution was filtered, and the crude product was purified by preparative HPLC (column: Xselect CSH C18 OBD, 30×150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 27 - 31% B in 13 min, wavelength: 220 nm, RT1: 11 min). The title compound was obtained as an off-white solid (25 mg, 14%, over 2 steps). LCMS (ESI) for C 25 H 27 FN5O4(M+H) + Calcd: 480.2, found: 480.0. 1 H NMR (400 MHz, DMSO-d6) δ 10.25 (s, 1H), 8.63 (s, 1H), 7.97 - 7.95 (m, 2H), 7.70 (dd, J = 9.2, 2.8 Hz, 1H), 7.63 (d, J = 2.9 Hz, 1H), 7.55 - 7.44 (m, 2H), 7.33 (dd, J = 10.5, 2.3 Hz, 1H), 7.19 (dd, J = 8.3, 2.4 Hz, 1H), 5.01 - 4.93 (m, 1H), 4.22 (t, J = 4.8 Hz, 2H), 3.81 (q, J = 5.1 Hz, 2H), 3.70 (s, 2H), 1.49 (s, 9H).

[0807] 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 Procedure 15

[0808]

[0809] Part I - Synthesis of 4-chloroquinolin-6-ol

[0810]

[0811] At 0 °C, 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) over 15 min. Subsequently, the reaction mixture was stirred at room temperature overnight. The mixture was slowly poured into saturated aqueous NaHCO3 (200 mL), and the product was extracted with EtOAc (200 mL). The organic phase was washed with water (2 × 100 mL), dried over Na2SO4, and the solvent was removed under reduced pressure. The title compound was obtained as an off-white solid (12.4 g) and was used in the next reaction without any further purification.

[0812] Part II - Synthesis of tert-butyl ((1r,4r)-4-((4-chloroquinolin-6-yl)oxy)cyclohexyl)carbamate

[0813]

[0814] At 0 °C, 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). Subsequently, 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 Na2SO4. 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% NH4HCO3), 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%).

[0815] 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

[0816]

[0817] tert-Butyl ((1r,4r)-4-((4-chloroquinolin-6-yl)oxy)cyclohexyl)carbamate (500 mg, 1.33 mmol, 1.00 eq), N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(4-hydroxy-3-methylphenyl)acetamide (381 mg, 1.33 mmol, 1.00 eq, which can be synthesized as shown in Part III of Example 30), and DMAP (162 mg, 1.33 mmol, 1.00 eq) in chlorobenzene (5 mL) were 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%).

[0818] 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)

[0819]

[0820] 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 eq) in 1,4-dioxane (1 mL), and the mixture was stirred at room temperature for 30 min. The reaction was quenched by adding saturated aqueous NaHCO3 (5 mL), and 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 title compound was obtained as a white solid (75 mg, 44%). LCMS (ESI) for C 31 H 38 N5O3 (M + H) + Calculated: 528.3, Found: 528.2. 11H NMR (400 MHz, DMSO-d6) δ 10.24 (s, 1H), 8.49 (d, J = 5.1 Hz, 1H), 7.97 - 7.91 (m, 2H), 7.60 (d, J = 2.8 Hz, 1H), 7.50 - 7.44 (m, 2H), 7.36 (d, J = 2.2 Hz, 1H), 7.28 (dd, J = 8.2, 2.2 Hz, 1H), 7.15 (d, J = 8.2 Hz, 1H), 6.40 (d, J = 5.1 Hz, 1H), 4.50 (td, J = 10.2, 4.9 Hz, 1H), 3.60 (s, 2H), 2.76 (ddd, J = 10.5, 6.6, 3.9 Hz, 1H), 2.14 - 2.10 (m, 5H), 1.92 - 1.80 (m, 2H), 1.53 (td, J = 7.2, 3.6 Hz, 1H), 1.49 (s, 9H), 1.47 - 1.42 (m, 1H), 1.36 - 1.21 (m, 2H).

[0821] 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 Procedure 15

[0822]

[0823] Part I - Synthesis of 4-chloro-6-((1-methylpiperidin-4-yl)oxy)quinoline

[0824]

[0825] At 0 °C, 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). Subsequently, the mixture was 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 Na2SO4, 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%).

[0826] 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)

[0827]

[0828] Under an inert atmosphere of nitrogen, 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), Cs2CO3 (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 to 100 °C overnight. 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) for C 31 H 37 FN5O3(M+H) + Calculated: 546.3, Found: 546.2. 1 H NMR (300 MHz, DMSO-d6) δ 10.23 (s, 1H), 8.54 (d, J = 5.0 Hz, 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, 2.7 Hz, 1H), 7.46 (s, 1H), 7.34 (t, J = 8.5 Hz, 1H), 7.05 (d, J = 8.3 Hz, 1H), 6.49 (d, J = 5.2 Hz, 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).

[0829] Example 25 - Preparation of Additional 6 - Alkoxy - Substituted Quinoline and Quinazoline Compounds

[0830] The compounds in the following table were prepared based on the experimental procedures and detailed descriptions described in Examples 22, 23, and 24.

[0831]

[0832]

[0833]

[0834]

[0835]

[0836]

[0837]

[0838]

[0839]

[0840]

[0841]

[0842]

[0843]

[0844]

[0845]

[0846]

[0847]

[0848]

[0849]

[0850]

[0851]

[0852]

[0853]

[0854]

[0855]

[0856]

[0857] 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 Procedure 17

[0858]

[0859] Part I - Synthesis of N-(1-(tert-Butyl)-1H-pyrazol-4-yl)-2-(2-fluoro-4-((6-iodoquinazolin-4-yl)oxy)phenyl)acetamide

[0860]

[0861] 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, synthesized as described in Part II of Example 9), and K3PO4 (21.92 g, 103 mmol, 3.00 equiv) in 1,4-dioxane (200 mL) was heated to 60 °C for 3 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 title compound was obtained as a yellow solid and was used in the next reaction without further purification.

[0862] 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)

[0863]

[0864] Under an inert atmosphere of nitrogen, 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), Cs2CO3 (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), 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) for C 27 H 30 FN6O3(M+H) + Calculated: 505.2, Found: 505.3. 1 H NMR (300 MHz, DMSO-d6) δ 8.47 (s, 1H), 8.01 (s, 1H), 7.86 (d, J = 2.1 Hz, 2H), 7.57 (s, 1H), 7.53 (s, 1H), 7.49 (t, J = 8.4 Hz, 1H), 7.18 - 7.12 (m, 2H), 3.89 (t, J = 4.8 Hz, 4H), 3.77 (s, 2H), 3.36 (t, J = 4.9 Hz, 4H), 1.56 (s, 9H).

[0865] 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 Procedure 17

[0866]

[0867] Under an inert atmosphere of nitrogen, methanesulfonamide (68.8 mg, 0.724 mmol, 1.20 equiv), sodium trifluoroacetate (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 2-(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). Subsequently, the reaction mixture was 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) for C 25 H 27 FN5O4S(M+H) + Calculated: 512.2, Found: 512.1. 1 H NMR (300 MHz, DMSO-d6) δ 10.22 (s, 2H), 8.64 (d, J = 5.1 Hz, 1H), 8.04 - 8.01 (m, 2H), 7.94 (s, 1H), 7.70 (d, J = 9.5 Hz, 1H), 7.52 (t, J = 8.5 Hz, 1H), 7.45 (s, 1H), 7.28 (d, J = 10.5 Hz, 1H), 7.12 (d, J = 8.4 Hz, 1H), 6.68 (d, J = 5.2 Hz, 1H), 3.70 (s, 2H), 3.07 (s, 3H), 1.49 (s, 9H).

[0868] Example 28 - Preparation of Additional 6-N-Substituted Quinoline and Quinazoline Compounds

[0869] The compounds in the following table were prepared based on the experimental procedures and detailed descriptions described in Examples 26 and 27.

[0870]

[0871]

[0872]

[0873]

[0874]

[0875]

[0876]

[0877]

[0878]

[0879]

[0880]

[0881] 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 Procedure 11

[0882]

[0883] Under an inert atmosphere of nitrogen, Cs2CO3 (671.0 mg, 2.06 mmol, 2.00 eq), 4-chloro-6-(methylsulfonyl)quinoline (221 mg, 1.03 mmol, 1.00 eq, synthesized as shown in Part II of Example 30), copper(I) iodide (78.5 mg, 0.412 mmol, 0.40 eq), and N,N-dimethylglycine (63.7 mg, 0.618 mmol, 0.60 eq) 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 eq, synthesized according to the synthesis described in Part II of Example 9) in 1,4-dioxane (5 mL). Subsequently, the reaction mixture was 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) for C 25 H 26 FN4O4S (M+H) + Calculated: 497.2, Found: 497.1. 11H NMR (300 MHz, DMSO-d6) δ 10.23 (s, 1H), 8.91 (d, J = 5.2 Hz, 1H), 8.85 (t, J = 1.4 Hz, 1H), 8.29 (s, 1H), 8.28 (s, 1H), 7.94 (s, 1H), 7.56 (t, J = 8.5 Hz, 1H), 7.45 (d, J = 0.7 Hz, 1H), 7.37 (dd, J = 10.5, 2.4 Hz, 1H), 7.21 (dd, J = 8.5, 2.4 Hz, 1H), 6.83 (d, J = 5.2 Hz, 1H), 3.72 (s, 2H), 3.38 (s, 3H), 1.49 (s, 9H).

[0884] 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 Procedure 11

[0885]

[0886] Part I - Synthesis of 4-chloro-6-(methylthio)quinoline

[0887]

[0888] Under an inert atmosphere of nitrogen, a solution of 6-bromo-4-chloroquinoline (commercially available, 50 g, 206 mmol, 1.00 equiv), sodium methylthiolate (28.9 g, 412 mmol, 2.00 equiv), Pd2(dba)3 (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. EtOAc was added and the insoluble material was filtered off. Subsequently, the organic phase was washed with water and brine, dried over Na2SO4, and the solvent was removed under reduced pressure. EtOAc and hexane (100 mL each) were added, followed by silica gel (20 g). The slurry was stirred at room temperature for 30 min and then the silica gel was filtered off and washed with EtOAc / hexane (1:1). The solvent was removed under reduced pressure. The desired product (43.5 g) was obtained as a red solid and was used in the next reaction without further purification.

[0889] Part II - Synthesis of 4-chloro-6-(methylsulfonyl)quinoline

[0890]

[0891] Potassium peroxymonosulfate (139 g, 227 mmol, 1.1 eq) was added to a solution of 4-chloro-6-(methylthio)quinoline (43.2 g, 206 mmol, 1.00 eq) 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 phases were 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. Next, the product was filtered out, washed with a small amount of EtOAc (ca. 40 - 50 mL) and hexane and dried under reduced pressure. The desired product (34.4 g, 69% yield) was obtained as a pale yellow solid and was used in the next reaction without further purification.

[0892] Part III - Synthesis of 2-(4-hydroxy-3-methylphenyl)acetic acid

[0893]

[0894] At room temperature, a solution of methyl 2-(4-hydroxy-3-methylphenyl)acetate (28.4 g, 158 mmol, 1.00 eq) and lithium hydroxide (9.44 g, 394 mmol, 2.50 eq) in THF (200 mL) and water (100 mL) was stirred 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 (26.3 g, quantitative yield) was obtained as a white solid and was used in the next reaction without further purification.

[0895] Part IV - Synthesis of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(4-hydroxy-3-methylphenyl)acetamide

[0896]

[0897] 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 solution. Subsequently, the pH was adjusted to 5 - 6 with HCl and the product was extracted with EtOAc. The organic phase was washed with brine, dried over Na2SO4, and the solvent was removed under reduced pressure. The residue was washed with EtOAc and dried under reduced pressure. The desired product (27.1 g, 60%) was obtained as a white solid and was used in the next reaction without further purification.

[0898] 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)

[0899]

[0900] 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 K2CO3 (19.5 g, 141 mmol, 1.50 equiv) in DMF (90 mL) was heated to 120 °C for 3.5 h. More 4-chloro-6-methylsulfonylquinoline (2.28 g, 9.43 mmol, 0.10 equiv) and K2CO3 (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 solution (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 solution (pH 11 - 12) to remove remaining phenolic 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 by column chromatography (DCM / MeOH 95:5). The desired product (17.3 g, 37% yield) was obtained as a pale yellow solid. LCMS (ESI) for C26 H 29 N4O4S(M+H) + Calculated value: 493.2, experimental value: 493.1. 1 H NMR (400 MHz, DMSO-d6) δ 10.20 (s, 1H), 8.91 (dd, J = 1.9, 0.9 Hz, 1H), 8.84 (d, J = 5.3 Hz, 1H), 8.29 - 8.27 (m, 2H), 7.95 (s, 1H), 7.46 (s, 1H), 7.39 (d, J = 2.1 Hz, 1H), 7.32 (dd, J = 8.3, 2.2 Hz, 1H), 7.23 (d, J = 8.3 Hz, 1H), 6.55 (d, J = 5.2 Hz, 1H), 3.62 (s, 2H), 3.39 (s, 3H), 2.14 (s, 3H), 1.49 (s, 9H).

[0901] 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 Procedure 11

[0902]

[0903] 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

[0904]

[0905] Under an inert atmosphere of nitrogen, 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), Pd2(dba)3 (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. 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 yellow solid (770 mg, 63%).

[0906] 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

[0907]

[0908] 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%) and was used in the next reaction without further purification.

[0909] 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

[0910]

[0911] 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 Pd / C (119 mg, 20 wt%) in MeOH (12 mL) was stirred under a hydrogen atmosphere at room temperature for 60 h. Subsequently, the heterogeneous catalyst was 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%).

[0912] 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)

[0913]

[0914] A solution of potassium peroxymonosulfate (1.91 g, 3.11 mmol, 5.00 eq) in water (3.2 mL) was added to a solution 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 (320 mg, 0.621 mmol, 1.00 eq) in MeOH (3.2 mL), and the mixture was stirred at room temperature for 10 min. The insoluble by-products were 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) for C 29 H 34 N5O4S (M+H) + Calculated: 548.2, Found: 548.3. 1 1H NMR (300 MHz, 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 = 5.2 Hz, 1H), 4.57 (t, J = 7.3 Hz, 1H), 3.62 (s, 2H), 3.58 (d, J = 7.9 Hz, 4H), 2.31 (s, 3H), 2.14 (s, 3H), 1.49 (s, 9H).

[0915] 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 Procedure 19

[0916]

[0917] Part I - Synthesis of 2-(4-((6-bromoquinolin-4-yl)oxy)-2-fluorophenyl)-N-(1-(tert-butyl)-1H-pyrazol-4-yl)acetamide

[0918]

[0919] Under an inert atmosphere of nitrogen, N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(2-fluoro-4-hydroxyphenyl)acetamide (2.88 g, 9.90 mmol, 1.20 equiv., which 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.), Cs2CO3 (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). Subsequently, the reaction mixture was heated to 100 °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 (3 × 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%).

[0920] Part II - Synthesis of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(2-fluoro-4-((6-(methylthio)quinolin-4-yl)oxy)phenyl)acetamide

[0921]

[0922] Under an inert atmosphere of nitrogen, sodium methanethiolate (0.36 g, 5.13 mmol, 1.50 equiv.), Pd2(dba)3 (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). Subsequently, the reaction mixture was 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%).

[0923] 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)

[0924]

[0925] At room temperature, a solution of NaIO4 (276.3 mg, 1.29 mmol, 2.00 equiv) in water (3 mL) was added dropwise 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). Subsequently, the reaction mixture was stirred at room temperature for 60 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: 20 - 50% B in 30 min; wavelength: 210 nm). The title compound was obtained as a white solid (98.9 mg, 31%). LCMS (ESI) for C 25 H 25 FN4NaO3S (M+Na) + Calculated: 503.2, Found: 503.0. 1 H NMR (400 MHz, DMSO-d6) δ 10.23 (s, 1H), 8.83 (d, J = 5.2 Hz, 1H), 8.62 (d, J = 2.0 Hz, 1H), 8.21 (d, J = 8.8 Hz, 1H), 8.07 (dd, J = 8.9, 2.0 Hz, 1H), 7.95 (s, 1H), 7.55 (t, J = 8.5 Hz, 1H), 7.46 (s, 1H), 7.35 (dd, J = 10.5, 2.4 Hz, 1H), 7.19 (dd, J = 8.4, 2.4 Hz, 1H), 6.79 (d, J = 5.2 Hz, 1H), 3.72 (s, 2H), 2.88 (s, 3H), 1.49 (s, 9H)

[0926] 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 Procedure 3

[0927]

[0928] Part I - Synthesis of 1-Cyclopentyl-4-nitro-1H-pyrazole

[0929]

[0930] At 0 °C, DEAD (6.01 g, 34.5 mmol, 1.30 eq) was added to a solution of 4-nitro-1H-pyrazole (3.00 g, 26.5 mmol, 1.00 eq), triphenylphosphine (8.35 g, 31.8 mmol, 1.20 eq) and cyclopentanol (2.51 g, 29.2 mmol, 1.10 eq) in THF (60 mL), and the mixture was stirred at this temperature for 2 h. Subsequently, saturated aqueous ammonium chloride solution (60 mL) was added, and the product was extracted with DCM (3 × 20 mL). The combined organic phases were 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 yellow oil (3.6 g, 74%).

[0931] Part II - Synthesis of 1-cyclopentyl-1H-pyrazol-4-amine

[0932]

[0933] Palladium / carbon (30 mg, 10 wt.%) was added to a solution of 1-cyclopentyl-4-nitro-1H-pyrazole (300 mg, 1.66 mmol, 1.0 eq) in isopropanol (6 mL), and the mixture was stirred overnight at room temperature under a hydrogen atmosphere. Subsequently, the heterogeneous catalyst was filtered off and the solvent was removed under reduced pressure. The crude product was used in the next reaction without any further purification.

[0934] Part III - Synthesis of methyl 2-(3-methyl-4-((6-(methylsulfonyl)quinolin-4-yl)oxy)phenyl)acetate

[0935]

[0936] At room temperature, a solution of methyl 2-(4-hydroxy-3-methylphenyl)acetate (1.49 g, 8.28 mmol, 1.00 eq), 4-chloro-6-(methylsulfonyl)quinoline (2.0 g, 8.28 mmol, 1.00 eq, which can be synthesized as shown in Part II of Example 30) and Cs2CO3 (5.39 g, 16.6 mmol, 2.00 eq) in NMP (22 mL) was stirred for 4 h. Subsequently, the mixture was filtered 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: 35 - 55% B in 40 min; wavelength: 210 nm). The title compound was obtained as a white solid (1.5 g, 47%).

[0937] Part IV - Synthesis of 2-(3-methyl-4-((6-(methylsulfonyl)quinolin-4-yl)oxy)phenyl)acetic acid

[0938]

[0939] At 0 °C, LiOH (0.15 g, 6.26 mmol, 2.00 eq) 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 eq) in THF (12 mL) and water (12 mL), 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 Na2SO4, 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.

[0940] 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)

[0941]

[0942] At 0 °C, propylphosphonic anhydride (257 mg, 0.807 mmol, 1.50 eq) was added to a solution of 2-(3-methyl-4-((6-(methylsulfonyl)quinolin-4-yl)oxy)phenyl)acetic acid (200 mg, 0.538 mmol, 1.00 eq), 1-cyclopentyl-1H-pyrazol-4-amine (111 mg, 0.807 mmol, 1.50 eq), and DIPEA (348 mg, 2.69 mmol, 5.00 eq) in DMF (4 mL), and the mixture was stirred at this temperature for 1 h. Subsequently, the crude product was 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) for C 27 H 27 N4O4S (M - H) - Calculated: 503.2, Found: 503.1. 11H NMR (400 MHz, DMSO-d6) δ 10.21 (s, 1H), 8.90 (s, 1H), 8.83 (d, J = 5.2 Hz, 1H), 8.28 - 8.26 (m, 2H), 7.90 (s, 1H), 7.43 (s, 1H), 7.39 (s, 1H), 7.31 (d, J = 8.1 Hz, 1H), 7.23 (d, J = 8.2 Hz, 1H), 6.55 (d, J = 5.2 Hz, 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).

[0943] Example 34 - Synthesis of N-(1-(tert-Butyl)-1H-pyrazol-4-yl)-2-(4-((6-(cyclobutanesulfonyl)quinolin-4-yl)oxy)-3-methylphenyl)acetamide (Compound 280); Prepared according to General Procedure 12

[0944]

[0945] Part I - Synthesis of S-(4-chloroquinolin-6-yl) thioacetate

[0946]

[0947] Under an inert atmosphere of nitrogen, 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.), Pd2(dba)3 (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 hour. Subsequently, EtOAc (300 mL) was added and the insoluble by-products were filtered off. The organic phase was washed with water (3 × 300 mL), dried over Na2SO4 and the solvent was removed under reduced pressure. The crude product was purified by column chromatography (gradient from petroleum ether to petroleum ether / EtOAc 9:1). The title compound was obtained as a white solid (11 g, 22%).

[0948] Part II - Synthesis of 4-chloro-6-(cyclobutylthio)quinoline

[0949]

[0950] Iodobutane (768 mg, 4.21 mmol, 1.00 eq) was added to a solution of S-(4-chloroquinolin-6-yl) thioacetate (1.00 g, 4.21 mmol, 1.00 eq) and K2CO3 (1.16 g, 8.42 mmol, 2.00 eq) in MeOH (10 mL), and the mixture was stirred at room temperature for 1 h. Subsequently, the 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%).

[0951] Part III - Synthesis of 4-chloro-6-(cyclobutanesulfonyl)quinoline

[0952]

[0953] mCPBA (311 mg, 3.60 mmol, 2.00 eq) was added to a solution of 4-chloro-6-(cyclobutylthio)quinoline (450 mg, 1.80 mmol, 1.00 eq) in DCM (9 mL), and the mixture was stirred at room temperature for 2 h. Subsequently, the crude product was purified by preparative HPLC (column: XBridge preparative 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%).

[0954] Part IV - Synthesis of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(4-((6-(cyclobutanesulfonyl)quinolin-4-yl)oxy)-3-methylphenyl)acetamide (Compound 280)

[0955]

[0956] Under an inert atmosphere of nitrogen, a solution of 4-chloro-6-(cyclobutanesulfonyl)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), Cs2CO3 (232 mg, 0.710 mmol, 2.00 equiv), CuI (67.6 mg, 0.355 mmol, 1.00 equiv), and N,N-dimethylglycine (54.9 mg, 0.532 mmol, 1.50 equiv) in 1,4-dioxane (5 mL) was heated at 100 °C overnight. Subsequently, the 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) for C 29 H 33 N4O4S (M+H) + Calculated: 533.2, Found: 533.2. 1 H NMR (400 MHz, DMSO-d6) δ 10.21 (s, 1H), 8.87 - 8.82 (m, 2H), 8.26 (d, J = 8.9 Hz, 1H), 8.18 (dd, J = 8.8, 2.1 Hz, 1H), 7.95 (s, 1H), 7.46 (s, 1H), 7.39 (s, 1H), 7.32 (d, J = 8.2 Hz, 1H), 7.25 (d, J = 8.2 Hz, 1H), 6.57 (d, J = 5.3 Hz, 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, 2.2 Hz, 2H), 2.13 (s, 3H), 2.02 - 1.86 (m, 2H), 1.49 (s, 9H).

[0957] Example 35 - Preparation of Additional Sulfone Compounds

[0958] The compounds in the following table were prepared based on the experimental procedures and detailed descriptions described in Examples 30 - 34.

[0959]

[0960]

[0961]

[0962]

[0963]

[0964]

[0965]

[0966]

[0967]

[0968]

[0969]

[0970]

[0971]

[0972]

[0973]

[0974]

[0975]

[0976]

[0977]

[0978]

[0979]

[0980]

[0981]

[0982]

[0983]

[0984]

[0985]

[0986]

[0987]

[0988]

[0989] 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 Procedure 10

[0990]

[0991] Part I - Synthesis of Methyl 4-(4-(2-((1-(tert-Butyl)-1H-pyrazol-4-yl)amino)-2-oxoethyl)-3-fluorophenoxy)quinazoline-6-carboxylate

[0992]

[0993] 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. Subsequently, 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 pale yellow solid (211 mg, 31%).

[0994] Part II - Synthesis of 4-(4-(2-((1-(tert-Butyl)-1H-pyrazol-4-yl)amino)-2-oxoethyl)-3-fluorophenoxy)quinazoline-6-carboxylic Acid

[0995]

[0996] 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. Subsequently, 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 white solid (58 mg, 39%).

[0997] 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)

[0998]

[0999] 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 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% 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) for C 26 H 28 FN6O3 (M + H) + Calculated: 491.2, Found: 491.3. 11H NMR (400 MHz, DMSO-d6) δ 10.25 (s, 1H), 8.80 (s, 1H), 8.36 (t, J = 1.3 Hz, 1H), 8.08 - 8.04 (m, 2H), 7.94 (d, J = 0.8 Hz, 1H), 7.50 (t, J = 8.5 Hz, 1H), 7.45 (d, J = 0.7 Hz, 1H), 7.36 (dd, J = 10.5, 2.3 Hz, 1H), 7.21 (dd, J = 8.4, 2.3 Hz, 1H), 3.70 (s, 2H), 3.06 (s, 3H), 2.99 (s, 3H), 1.49 (s, 9H).

[1000] Example 37 - 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); Prepared according to General Procedure 6

[1001]

[1002] Part I - Synthesis of methyl 2-(2-fluoro-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate

[1003]

[1004] Under an inert atmosphere of nitrogen, 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)Cl2 (3.64 g, 4.98 mmol, 0.05 equiv) in 1,4-dioxane (208 mL) was heated to 130 °C overnight. The reaction mixture was used in the next reaction without any purification.

[1005] Part II - Synthesis of methyl 2-(2-fluoro-4-hydroxyphenyl)-5-methylacetate

[1006]

[1007] At 0 °C, a solution of hydrogen peroxide in water (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). Subsequently, the mixture was stirred at room temperature for 1 h. The reaction was quenched by adding saturated aqueous sodium thiosulfate solution. 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 (30 g) was obtained as a yellow oil.

[1008] Part III - Synthesis of 2-(2-Fluoro-4-hydroxy-5-methylphenyl)acetic acid

[1009]

[1010] At 0 °C, a solution of lithium hydroxide (7.27 g, 303 mmol, 2.00 equiv) in water (150 mL) 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). 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 Na2SO4, and the solvent was removed under reduced pressure. The title compound (20 g) was obtained as a yellow solid and was used in the next reaction without further purification.

[1011] Part IV - Synthesis of N-(1-(tert-Butyl)-1H-pyrazol-4-yl)-2-(2-fluoro-4-hydroxy-5-methylphenyl)acetamide

[1012]

[1013] At 0 °C, 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). Subsequently, the mixture was 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 - 70% B in 20 min; wavelength: 210 nm). The title compound was obtained as a white solid (1.94 g, 53%, over 4 steps).

[1014] Part V - Synthesis of 4-chloro-N-methylquinoline-6-carboxamide

[1015]

[1016] 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 - 50% B in 20 min; wavelength: 210 nm). The title compound was obtained as a white solid (900 mg, 60%).

[1017] 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)

[1018]

[1019] Under an inert atmosphere of nitrogen, 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), Cs2CO3 (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 a solution of 1,4-dioxane (1.5 mL) were heated to 90 °C for 6 h. Subsequently, the crude product was purified by preparative HPLC (column: XSelect CSH Fluoro Phenyl; 30×150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; isocratic elution with 36% B for 13 min; wavelength: 220 nm, RT1: 11 min). The title compound was obtained as a yellow solid (70 mg, 29%). LCMS (ESI) for C 27 H 29 FN5O3(M+H) + Calculated: 490.2, Found: 490.1. 1 H NMR (400 MHz, DMSO-d6) δ 10.23 (s, 1H), 8.89 (d, J = 2.0 Hz, 1H), 8.83 (d, J = 4.9 Hz, 1H), 8.76 (s, 1H), 8.25 (dd, J = 8.8, 2.0 Hz, 1H), 8.10 (d, J = 8.8 Hz, 1H), 7.95 (s, 1H), 7.48 - 7.43 (m, 2H), 7.27 (d, J = 10.0 Hz, 1H), 6.54 (d, J = 5.2 Hz, 1H), 3.69 (s, 2H), 2.87 (d, J = 4.5 Hz, 3H), 2.11 (s, 3H), 1.49 (s, 9H).

[1020] Example 38 - Preparation of Additional Amide Compounds

[1021] The compounds in the following table were prepared based on the experimental procedures and detailed descriptions described in Examples 36 and 37.

[1022]

[1023]

[1024]

[1025]

[1026]

[1027]

[1028]

[1029]

[1030]

[1031]

[1032]

[1033]

[1034]

[1035]

[1036]

[1037]

[1038]

[1039]

[1040]

[1041]

[1042]

[1043]

[1044]

[1045]

[1046]

[1047]

[1048]

[1049]

[1050]

[1051] 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 Procedure 8

[1052]

[1053] Part I - Synthesis of Methyl (4-nitrobenzyl)sulfane

[1054]

[1055] Sodium methanethiolate (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 overnight at room temperature. 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%).

[1056] Part II - Synthesis of 4-((Methylthio)methyl)aniline

[1057]

[1058] Under a hydrogen atmosphere, 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. 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%).

[1059] Part III - Synthesis of 2,2-Dimethyl-5-(((4-((Methylthio)methyl)phenyl)amino)methylene)-1,3-dioxane-4,6-dione

[1060]

[1061] Under an inert atmosphere of nitrogen, 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. 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.

[1062] Part IV - Synthesis of 6-((methylthio)methyl)quinolin-4-ol

[1063]

[1064] Under an inert atmosphere of nitrogen, 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 to 150 °C overnight. 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 phases was removed under reduced pressure. The crude title compound (1.6 g) was used in the next reaction without further purification.

[1065] Part V - Synthesis of 4-chloro-6-((methylthio)methyl)quinoline

[1066]

[1067] Under an inert atmosphere of nitrogen, 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. 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, 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 3 steps).

[1068] 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

[1069]

[1070] Under an inert atmosphere of nitrogen, 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, which 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). Subsequently, the mixture was heated to 150 °C for 1 hour. 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 40 min; wavelength: 210 nm). The title compound was obtained as a white solid (610 mg, 45%).

[1071] 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)

[1072]

[1073] At room temperature, 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 potassium peroxymonosulfate (105.4 mg, 0.627 mmol, 3.00 equiv) in water / MeOH (1:1, 2 mL) was stirred for 1 hour. Subsequently, 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 white solid (60.7 mg, 57%). LCMS (ESI) for C 26 H 27 FN4NaO4S (M + H) + Calculated: 533.2, Found: 533.2. 11H NMR (300 MHz, DMSO-d6) δ 10.23 (s, 1H), 8.75 (d, J = 5.1 Hz, 1H), 8.37 (d, J = 2.0 Hz, 1H), 8.07 (d, J = 8.7 Hz, 1H), 7.94 (d, J = 0.7 Hz, 1H), 7.85 (dd, J = 8.7, 2.0 Hz, 1H), 7.53 (t, J = 8.5 Hz, 1H), 7.45 (d, J = 0.7 Hz, 1H), 7.32 (dd, J = 10.5, 2.4 Hz, 1H), 7.16 (dd, J = 8.5, 2.4 Hz, 1H), 6.71 (d, J = 5.1 Hz, 1H), 4.79 (s, 2H), 3.70 (s, 2H), 2.97 (s, 3H), 1.49 (s, 9H).

[1074] 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 Procedure 22

[1075]

[1076] Part I - Synthesis of tert-Butyl 4-((4-chloroquinolin-6-yl)methyl)piperidine-1-carboxylate

[1077]

[1078] Under an inert atmosphere of nitrogen, 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)Cl2 (0.30 g, 0.412 mmol, 0.10 equiv) and K3PO4 (1.75 g, 8.25 mmol, 2.00 equiv) in 1,4-dioxane was heated to 90 °C overnight. 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%).

[1079] 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

[1080]

[1081] 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 Cs2CO3 (640 mg, 1.97 mmol, 3.00 equiv) in NMP (4 mL) was heated to 130 °C for 3 h. Subsequently, 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 10 min; wavelength: 210 nm). The title compound was obtained as an off-white solid (103 mg, 24%).

[1082] 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)

[1083]

[1084] 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 solution. 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) for C 31 H 37 FN5O2 (M + H) + Calculated: 530.3, Found: 530.2.

[1085] Example 41 - Preparation of Additional 6-Alkyl-Substituted Quinoline and Quinazoline Compounds

[1086] The compounds in the following table were prepared based on the experimental procedures and detailed descriptions described in Example 40.

[1087]

[1088]

[1089]

[1090]

[1091]

[1092]

[1093]

[1094]

[1095]

[1096] 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 Procedure 14

[1097]

[1098] Part I - Synthesis of 4-chloro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline

[1099]

[1100] 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)Cl2 (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%).

[1101] Part II - Synthesis of 4-chloro-6-(4-methylpyridazin-3-yl)quinoline

[1102]

[1103] 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), Cs2CO3 (2.25 g, 6.91 mmol, 2.00 equiv) and Pd(dppf)Cl2 (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. Subsequently, the crude product was 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 ether (3 × 150 mL), and the combined organic phases were washed with water (150 mL) and dried over Na2SO4. The solvent was removed under reduced pressure. The title compound was obtained as a brown solid (600 mg, 68%).

[1104] 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)

[1105]

[1106] 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, can be synthesized according to Part IV of Example 37) and Cs2CO3 (119 mg, 1.56 mmol, 2.00 equiv) in DMA (2 mL) was heated to 100 °C for 3 h. Subsequently, the crude product was 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 20 min; wavelength: 254 nm). The title compound was obtained as a pink solid (198 mg, 48%). LCMS (ESI) for C 30 H 30 FN6O2 (M + H) + Calculated: 525.2, Found: 525.4. 11H NMR (300 MHz, DMSO-d6) δ 10.20 (s, 1H), 9.15 (d, J = 5.2 Hz, 1H), 8.78 (d, J = 5.2 Hz, 1H), 8.58 (d, J = 1.9 Hz, 1H), 8.19 (d, J = 8.7 Hz, 1H), 8.11 (dd, J = 8.7, 2.0 Hz, 1H), 7.94 (d, J = 0.7 Hz, 1H), 7.76 - 7.68 (m, 1H), 7.49 - 7.39 (m, 2H), 7.26 (d, J = 10.1 Hz, 1H), 6.59 (d, J = 5.2 Hz, 1H), 3.68 (s, 2H), 2.49 (s, 3H), 2.11 (s, 3H), 1.49 (s, 9H).

[1107] 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 Procedure 14

[1108]

[1109] Part I - Synthesis of 3-chloro-1-methylpyrazin-2(1H)-one

[1110]

[1111] 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 K2CO3 (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, the insoluble by-products were filtered off, and the crude product was purified by column chromatography (gradient from petroleum ether to petroleum ether / EtOAc 1:1). The title compound was obtained as an off-white solid (450 mg, 81%).

[1112] Part II - Synthesis of 2-(4-((6-Bromoquinolin-4-yl)oxy)-3-methylphenyl)-N-(1-(tert-butyl)-1H-pyrazol-4-yl)acetamide

[1113]

[1114] Under an inert atmosphere of nitrogen, N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(4-hydroxy-3-methylphenyl)acetamide (2.0 g, 6.96 mmol, 1.00 equiv., which 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.), Cs2CO3 (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 a solution of DMF (20 mL) were heated to 80 °C for 3 hours. Subsequently, 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: 20 - 60% B in 30 min; wavelength: 210 nm). The title compound was obtained as a brown oil (1.98 g, 55%).

[1115] Part III - Synthesis of N-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-(3-methyl-4-((6-(4,4,5,5-tetrame...

Claims

1. A compound represented by structural formula (I) or a pharmaceutically acceptable salt thereof: Wherein: R 1a 、R 1b and R 1c each independently selected from H, C 1-6 alkyl, halogen, CN, and; R 2 is H or C 1-3 alkyl; R 3 selected from S(=O)2R 5 , halogen, 4- to 10-membered heterocyclic group, 5- to 12-membered heteroaryl, S(=O)(=NR 6 )(R 7 ), QR 7 , C(=O)NR 8 R 9 , NH(C=O)R 5 , CN, NR 8 R 9 , P(=O)R 8a R 9a ; R 4 selected from H, halogen, C 1-6 alkyl and C 1-6 alkoxy; R 5 selected from C 1-6 alkyl, NR 10 R 11 , C 3-6 cycloalkyl, and 4- to 10-membered heterocyclic group; R 6 selected from H, CN, and C 1-6 alkyl; R 7 selected from C 1-6 alkyl, C 3-6 cycloalkyl, and 4- to 10-membered heterocyclic groups, 5- to 12-membered heteroaryl groups, or R 6 and R 7 together with the nitrogen and sulfur atoms to which it is attached form a 4- to 10-membered heterocyclic group; Q is selected from O, S, -S(=O)- and -C(=O)-; R 8 and R 9 each independently selected from H, C 1-6 alkyl, C 1-6 deuterated alkyl, C 3-6 cycloalkyl and 4- to 10-membered heterocyclic group, or R 8 and R 9 together with the nitrogen atom to which it is attached form a 4- to 10-membered heterocyclic group; R 8a and R 9b each independently is C 1-6 alkyl, or R 8a and R 9a together with the phosphorus atom to which it is attached form a 4- to 10-membered heterocyclic group; R 10 and R 11 each independently is H or C 1-6 alkyl, or R 10 and R 11 together with the nitrogen atom to which it is attached form a 4- to 10-membered heterocyclic group; W is selected from a single bond, O, NR 2 , O(C 1-2 alkylene), NH(C 1-2 alkylene), C 1-2 alkylene and C 3-6 cycloalkylene; X is a moiety represented by one of the following structural formulas: Y 1 is CH or N; Y 2 and Y 3 each independently is 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 selected from C 3-6 alkyl, C 3-6 cycloalkyl, C 5-12 bridged bicyclic carbocyclic group and 4- to 10-membered heterocyclic group; R 12a selected from C 1-6 alkyl, C 1-6 deuterated alkyl, C 3-6 cycloalkyl, C 5-12 bridged bicyclic carbocyclic group, and 4- to 10-membered heterocyclic group; R 12b and R 13 each independently is H or C 1-6 alkyl; And is a single bond or a double bond, Wherein each C 1-6 alkyl group, C 1-3 alkyl group, C 1-2 alkylene group, C 3-6 alkyl group, C 3-6 cycloalkyl group, C 1-6 alkoxy group, C 5-12 bridged bicyclic carbocyclic group, 5- to 12-membered heteroaryl group, and 4- to 10-membered heterocyclic group are optionally substituted with 1 to 3 substituents independently selected from the following: deuterium, oxo, F, Cl, Br, CN, OR 14 , SR 15 , NR 16 R 17 , S(O)R 18 , S(O)2R 18a , NR 19 S(=O)R 20 , C(=O)OR 20a , C(=O)NR 21 R 22 , NR 23 C(=O)R 24 , C(=S)NR 25 R 26 , C(=O)R 27 , C 1-6 alkyl group, C 1-6 deuterated alkyl group, C 3-8 cycloalkyl group, C 2-6 alkenyl group, halo(C 1-6 )alkyl group, C 1-3 alkylsulfonylaminoalkyl group, hydroxy(C 1-6 )alkyl group, amino(C 1-6 )alkyl group, (C 1-6 )alkylamino(C 1-6 )alkyl group, cyano(C 1-6 )alkyl group, C 1-3 alkylcarbonylamino(C 1-6 )alkyl group, C 1-3 alkoxy group, halo(C 1-3 )alkoxy group, C 1-6 alkoxy(C 1-3 )alkyl group, C 6-12 aryl group, 4- to 8-membered heterocyclic group, and 5- to 12-membered heteroaryl group, wherein R 14 、R 15 、R 18 、R 18a 、R 20 、R 20a 、R 24 and R 27 each independently represents hydrogen or C 1-6 alkyl; R 16 and R 17 each independently selected from hydrogen, C 1-6 alkyl, hydroxy(C 1-6 )alkyl, and halo(C 1-6 )alkyl; R 19 and R 23 each independently is C 1-6 alkyl or halo(C 1-6 )alkyl; R 21 , R 22 , R 25 and R 26 Each independently selected from H, C 1-6 Alkyl, C 1-3 Alkoxy (C 1-6 ) alkyl, hydroxyl (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 it is attached form a 3- to 8-membered ring optionally substituted with 1 to 3 substituents independently selected from the following: deuterium, oxo, F, Cl, Br, CN, OR 14 , SR 15 , NR 16 R 17 , S(O)R 18 , S(O)2R 18a , NR 19 S(=O)R 20 , C(=O)OR 20a , C(=O)NR 21 R 22 , NR 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 alkylsulfonylaminoalkyl, 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 aryl, 4- to 10-membered heterocyclic group and 5- to 12-membered heteroaryl, Provided that when Y 2 is CH substituted by R 4 and R 4 is optionally substituted C 1-6 alkoxy, W-R 3 is not CN or optionally substituted C 1-6 alkoxy; and Provided that when Y 1 , Y 2 and Y 3 are each CH, then W-R 3 is not F.

2. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is represented by structural formula (I): Wherein: R 1a 、R 1b and R 1c each independently selected from H, C 1-6 alkyl, halogen and CN; R 2 is H or C 1-3 alkyl; R 3 selected from S(=O)2R 5 , halogen, 4- to 10-membered heterocyclic group, 5- to 12-membered heteroaryl, S(=O)(=NR 6 )(R 7 ), QR 7 , C(=O)NR 8 R 9 , NH(C=O)R 5 , CN, NR 8 R 9 , P(=O)R 8a R 9a ; R 4 selected from H, halogen, C 1-6 alkyl and C 1-6 alkoxy; R 5 selected from C 1-6 alkyl, NR 10 R 11 , C 3-6 cycloalkyl and 4- to 10-membered heterocyclic group; R 6 selected from H, CN, and C 1-6 alkyl; R 7 selected from C 1-6 alkyl, C 3-6 cycloalkyl, and 4- to 10-membered heterocyclic groups, 5- to 12-membered heteroaryl groups, or R 6 and R 7 together with the nitrogen and sulfur atoms to which it is attached form a 4- to 10-membered heterocyclic group; Q is selected from O, S, -S(=O)- and -C(=O)-; R 8 and R 9 each independently selected from H, C 1-6 alkyl, C 3-6 cycloalkyl, and a 4- to 10-membered heterocyclic group, or R 8 and R 9 which together with the nitrogen atom to which it is attached forms a 4- to 10-membered heterocyclic group; R 8a and R 9b each independently is C 1-6 alkyl, or R 8a and R 9a together with the phosphorus atom to which it is attached form a 4- to 10-membered heterocyclic group; R 10 and R 11 each independently is H or C 1-6 alkyl, or R 10 and R 11 together with the nitrogen atom to which it is attached form a 4- to 10-membered heterocyclic group; W is selected from a single bond, O, NR 2 , O(C 1-2 alkylene), NH(C 1-2 alkylene) and C 1-2 alkylene; X is a moiety represented by one of the following structural formulas: Y 1 is CH or N; Y 2 and Y 3 each independently is 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 selected from C 3-6 alkyl, C 3-6 cycloalkyl, C 5-12 bridged bicyclic carbocyclic group and 4- to 10-membered heterocyclic group; R 12a selected from C 1-6 alkyl, C 3-6 cycloalkyl, C 5-12 bridged bicyclic carbocyclic group and 4- to 10-membered heterocyclic group; R 12b and R 13 each independently is H or C 1-6 alkyl; And is a single bond or a double bond, wherein each C 1-6 alkyl group, C 1-3 alkyl group, C 1-2 alkylene group, C 3-6 alkyl group, C 3-6 cycloalkyl group, C 1-6 alkoxy group, C 5-12 bridged bicyclic carbocyclic group, 5- to 12-membered heteroaryl group, and 4- to 10-membered heterocyclic group are optionally substituted with 1 to 3 substituents independently selected from the following: deuterium, oxo, F, Cl, Br, CN, OR 14 , SR 15 , NR 16 R 17 , S(O)R 18 , S(O)2R 18a , NR 19 S(═O)R 20 , C(═O)OR 20a , C(═O)NR 21 R 22 , NR 23 C(═O)R 24 , C(═S)NR 25 R 26 , C(═O)R 27 , C 1-6 alkyl group, C 3-8 cycloalkyl group, C 2-6 alkenyl group, halo(C 1-6 )alkyl group, C 1-3 alkylsulfonylaminoalkyl group, hydroxy(C 1-6 )alkyl group, amino(C 1-6 )alkyl group, cyano(C 1-6 )alkyl group, C 1-3 alkylcarbonylamino(C 1-6 )alkyl group, C 1-3 alkoxy group, halo(C 1-3 )alkoxy group, C 1-6 alkoxy(C 1-3 )alkyl group, C 6-12 aryl group, 4- to 8-membered heterocyclic group, and 5- to 12-membered heteroaryl group, wherein R 14 、R 15 、R 18 、R 18a 、R 20 、R 20a 、R 24 and R 27 each independently represents hydrogen or a C 1-6 alkyl group; R 16 and R 17 each independently selected from hydrogen, C 1-6 alkyl, hydroxy(C 1-6 )alkyl and halo(C 1-6 )alkyl; R 19 and R 23 each independently is C 1-6 alkyl or halo(C 1-6 )alkyl; R 21 , R 22 , R 25 and R 26 Each independently selected from H, C 1-6 Alkyl, C 1-3 Alkoxy (C 1-6 ) alkyl, hydroxyl (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 it is attached form a 3- to 8-membered ring optionally substituted with 1 to 3 substituents independently selected from the following: deuterium, oxo, F, Cl, Br, CN, OR 14 , SR 15 , NR 16 R 17 , S(O)R 18 , S(O)2R 18a , NR 19 S(=O)R 20 , C(=O)OR 20a , C(=O)NR 21 R 22 , NR 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 alkylsulfonylaminoalkyl, 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 aryl, 4- to 10-membered heterocyclic group and 5- to 12-membered heteroaryl, Provided that when Y 2 is CH substituted by R 4 and R 4 is optionally substituted C 1-6 alkoxy, W-R 3 is not CN or optionally substituted C 1-6 alkoxy; and Provided that when Y 1 、Y 2 and Y 3 are each CH, then W-R 3 is not F.

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

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

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

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

7. A compound according to any one of claims 1 to 3, wherein W is C 3-6 subcycloalkyl.

8. A compound according to any one of claims 1 to 7, wherein R 3 is a 4- to 6-membered heterocyclic group optionally substituted with 1 to 3 substituents independently selected from the following: deuterium, oxo, F, Cl, Br, CN, OR 14 , SR 15 , NR 16 R 17 , S(O)R 18 , S(O)2R 18a , NR 19 S(=O)R 20 , C(=O)OR 20a , C(=O)NR 21 R 22 , NR 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 alkylsulfonylaminoalkyl, 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 aryl, 4- to 8-membered heterocyclic group and 5- to 12-membered heteroaryl, wherein R 14 、R 15 、R 18 、R 18a 、R 20 、R 20a 、R 24 and R 27 each independently represents hydrogen or C 1-6 alkyl; R 16 and R 17 each independently selected from hydrogen, C 1-6 alkyl, hydroxy(C 1-6 )alkyl, and halo(C 1-6 )alkyl; R 19 and R 23 each independently is C 1-6 alkyl or halo(C 1-6 )alkyl; R 21 , R 22 , R 25 and R 26 Each independently selected from H, C 1-6 Alkyl, C 1-3 Alkoxy (C 1-6 ) alkyl, hydroxyl (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 it is attached form a 3- to 8-membered ring optionally substituted with 1 to 3 substituents independently selected from: deuterium, oxo, F, Cl, Br, CN, OR 14 , SR 15 , NR 16 R 17 , S(O)R 18 , S(O)2R 18a , NR 19 S(=O)R 20 , C(=O)OR 20a , C(=O)NR 21 R 22 , NR 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 alkylsulfonylaminoalkyl, 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 aryl, 4- to 10-membered heterocyclic group and 5- to 12-membered heteroaryl.

9. The compound according to claim 8, wherein R 3 is a 4- to 6-membered saturated heterocyclic group.

10. A compound according to claim 8 or 9, wherein R 3 is substituted by oxo.

11. A compound according to any one of claims 1 to 7, wherein R 3 is a moiety represented by the structural formula wherein: A is O or NR 28 ; and R 28 selected from H, C 1-6 alkyl, C 3-6 cycloalkyl and 4- to 6-membered heterocyclic groups, Each C 1-6 alkyl group, C 3-6 cycloalkyl group, and 4- to 6-membered heterocyclic group are optionally substituted with 1 to 3 substituents independently selected from the following: deuterium, oxo, F, Cl, Br, CN, OR 14 , SR 15 , NR 16 R 17 , S(O)R 18 , S(O)2R 18a , NR 19 S(=O)R 20 , C(=O)OR 20a , C(=O)NR 21 R 22 , NR 23 C(=O)R 24 , C(=S)NR 25 R 26 , C(=O)R 27 , C 1-6 alkyl group, C 3-8 cycloalkyl group, C 2-6 alkenyl group, halo(C 1-6 )alkyl group, C 1-3 alkylsulfonylaminoalkyl group, hydroxy(C 1-6 )alkyl group, amino(C 1-6 )alkyl group, cyano(C 1-6 )alkyl group, C 1-3 alkylcarbonylamino(C 1-6 )alkyl group, C 1-3 alkoxy group, halo(C 1-3 )alkoxy group, C 1-6 alkoxy(C 1-3 )alkyl group, C 6-12 aryl group, 4- to 8-membered heterocyclic group, and 5- to 12-membered heteroaryl group, where R 14 、R 15 、R 18 、R 18a 、R 20 、R 20a 、R 24 and R 27 each independently represents hydrogen or C 1-6 alkyl; R 16 and R 17 each independently selected from hydrogen, C 1-6 alkyl, hydroxy(C 1-6 )alkyl and halo(C 1-6 )alkyl; R 19 and R 23 each independently is C 1-6 alkyl or halo(C 1-6 )alkyl; R 21 , R 22 , R 25 and R 26 Each independently is H, C 1-6 Alkyl, C 1-3 Alkoxy (C 1-6 ) alkyl, hydroxyl (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 which, together with the nitrogen to which it is attached, forms a 3- to 8-membered ring optionally substituted with 1 to 3 substituents independently selected from the following: deuterium, oxo, F, Cl, Br, CN, OR 14 , SR 15 , NR 16 R 17 , S(O)R 18 , S(O)2R 18a , NR 19 S(=O)R 20 , C(=O)OR 20a , C(=O)NR 21 R 22 , NR 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 alkylsulfonylaminoalkyl, 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 aryl, 4- to 10-membered heterocyclic group and 5- to 12-membered heteroaryl.

12. A compound according to any one of claims 1 to 7, wherein R 3 is a moiety represented by one of the following structural formulas: Wherein R 28 is H or C 1-3 alkyl group.

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

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

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

16. The compound of claim 13, wherein R 5 is C 3-6 cycloalkyl.

17. The compound according to claim 13, wherein R 5 is a 4- to 6-membered heterocyclic group optionally substituted with 1 to 3 substituents independently selected from the following: deuterium, oxo, F, Cl, Br, CN, OR 14 SR 15 NR 16 R 17 S(O)R 18 S(O)2R 18a NR 19 S(=O)R 20 C(=O)OR 20a C(=O)NR 21 R 22 NR 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 alkylsulfonylaminoalkyl, 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 aryl, 4- to 10-membered heterocyclic group and 5- to 12-membered heteroaryl, wherein R 14 、R 15 、R 18 、R 18a 、R 20 、R 20a 、R 24 and R 27 each independently represents hydrogen or a C 1-6 alkyl group; R 16 and R 17 each independently is hydrogen, C 1-6 alkyl, hydroxy(C 1-6 )alkyl or halo(C 1-6 )alkyl; R 19 and R 23 each independently is C 1-6 alkyl or halo(C 1-6 )alkyl; R 21 , R 22 , R 25 and R 26 Each independently is H, C 1-6 Alkyl, C 1-3 Alkoxy (C 1-6 ) alkyl, hydroxyl (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 which together with the nitrogen to which it is attached forms a 3- to 8-membered ring optionally substituted with 1 to 3 substituents independently selected from the group consisting of deuterium, oxo, F, Cl, Br, CN, OR 14 , SR 15 , NR 16 R 17 , S(O)R 18 , S(O)2R 18a , NR 19 S(=O)R 20 , C(=O)OR 20a , C(=O)NR 21 R 22 , NR 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 alkylsulfonylaminoalkyl, 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 aryl, 4- to 10-membered heterocyclic group and 5- to 12-membered heteroaryl.

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

19. The compound of claim 18, wherein R 10 and R 11 are each independently C 1-6 alkyl.

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

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

22. A compound according to any one of claims 1 to 7, wherein R 3 is (R 7 )S(=O)(NR 6 ).

23. The compound of claim 22, wherein R 6 is H, and R 7 is C 1-6 alkyl or C 3-6 cycloalkyl.

24. The compound according to claim 22, wherein 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.

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

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

27. The compound according to claim 25, wherein R 8 and R 9 is H.

28. The compound according to claim 25, wherein R 8 and R 9 are each independently C 1-3 alkyl.

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

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

31. The compound according to claim 30, wherein Q is O.

32. The compound according to claim 30, wherein Q is S.

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

34. A compound according to any one of claims 29 to 33, wherein R 7 is C 1-6 alkyl.

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

36. The compound according to claim 35, wherein R 3 is F.

37. The compound according to claim 35, wherein R 3 is Cl.

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

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

40. The compound of claim 38, wherein R 8a and R 9a together with the phosphorus atom to which they are attached form a 4- to 10-membered heterocyclic group.

41. The compound according to claim 1 or 2, wherein the compound is represented by structural formula (Ia):

42. The compound according to claim 1 or 2, wherein the compound is represented by structural formula (Ib):

43. The compound according to claim 1 or 2, wherein the compound is represented by structural formula (Ic):

44. The compound according to claim 1 or 2, wherein the compound is represented by structural formula (Id):

45. The compound according to claim 1 or 2, wherein the compound is represented by structural formula (Ie): Wherein Hal is halogen.

46. The compound according to claim 1 or 2, wherein the compound is represented by structural formula (If):

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

48. A compound according to any one of claims 1 to 33 and 35 to 45, wherein R 4 is C 1-6 alkoxy.

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

50. The compound of claim 49, wherein R 13 is H.

51. The compound of claim 49, wherein R 13 is C 1-6 alkyl.

52. The compound according to any one of claims 1 to 48, wherein X is a moiety represented by the following structural formula:

53. The compound of claim 52, wherein R 13 is H.

54. The compound of claim 52, wherein R 13 is C 1-6 alkyl.

55. The compound according to any one of claims 1 to 48, wherein X is a moiety represented by the following structural formula:

56. The compound according to any one of claims 1 to 48, wherein X is a moiety represented by one of the following structural formulas:

57. The compound according to any one of claims 1 to 48, wherein X is a moiety represented by one of the following structural formulas:

58. A compound according to any one of claims 1 to 57, wherein R 12 is a C 3-6 alkyl optionally substituted with 1 to 3 substituents independently selected from the following: deuterium, oxo, F, Cl, Br, CN, OR 14 , SR 15 , NR 16 R 17 , S(O)R 18 , S(O)2R 18a , NR 19 S(=O)R 20 , C(=O)OR 20a , C(=O)NR 21 R 22 , NR 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 alkylsulfonylaminoalkyl, 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 aryl, 4- to 10-membered heterocyclic group and 5- to 12-membered heteroaryl, wherein R 14 、R 15 、R 18 、R 18a 、R 20 、R 20a 、R 24 and R 27 each independently represents hydrogen or C 1-6 alkyl; R 16 and R 17 each independently is hydrogen, C 1-6 alkyl, hydroxy(C 1-6 )alkyl or halo(C 1-6 )alkyl; R 19 and R 23 each independently is C 1-6 alkyl or halo(C 1-6 )alkyl; R 21 , R 22 , R 25 and R 26 Each independently is H, C 1-6 Alkyl, C 1-3 Alkoxy (C 1-6 ) alkyl, hydroxyl (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 it is attached form a 3- to 8-membered ring optionally substituted with 1 to 3 substituents independently selected from the following: deuterium, oxo, F, Cl, Br, CN, OR 14 , SR 15 , NR 16 R 17 , S(O)R 18 , S(O)2R 18a , NR 19 S(=O)R 20 , C(=O)OR 20a , C(=O)NR 21 R 22 , NR 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 alkylsulfonylaminoalkyl, 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 aryl, 4- to 10-membered heterocyclic group and 5- to 12-membered heteroaryl group.

59. A compound according to any one of claims 1 to 57, wherein R 12 is selected from the moieties represented by one of the following structural formulas:

60. A compound according to any one of claims 1 to 57, wherein R 12 is selected from the moieties represented by one of the following structural formulas:

61. The compound of claim 60, wherein R 12 is a moiety represented by the following structural formula:

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

63. A compound according to any one of claims 1 to 61, wherein R 1a is C 1-3 alkyl.

64. A compound according to any one of claims 1 to 61, wherein R 1a is selected from H, F, Cl, CH3, CHF2, CF3 and CD3.

65. The compound according to claim 64, wherein R 1a is selected from F, CH3 and CHF2.

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

67. A compound according to any one of claims 1 to 65, wherein R 1b is C 1-3 alkyl.

68. A compound according to any one of claims 1 to 65, wherein R 1b is selected from H, F, Cl, CH3, CHF2, CF3 and CD3.

69. The compound according to claim 68, wherein R 1b is selected from F, CH3 and CHF2.

70. A compound according to any one of claims 1 to 69, wherein R 1c is H or halogen.

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

72. The compound according to claim 1 or 2, wherein the compound is represented by structural formula (Ig):

73. The compound according to any one of claims 1 or 2, wherein the compound is represented by structural formula (Ih), (Ii) or (Ij):

74. A compound according to any one of claims 1 to 73, wherein Y 1 is CH. A compound according to any one of claims 1 to 73, wherein Y 1 is N.

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

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

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

79. A compound according to any one of claims 1 to 77, wherein R 2 is C 1-3 alkyl.

80. The compound according to claim 1 or 2, wherein the compound is represented by structural formula (Ik): wherein R 5 is C 1-3 alkyl.

81. The compound according to claim 1 or 2, wherein the compound is represented by structural formula (Il): wherein R 9 is H or C 1-3 alkyl group.

82. The compound according to claim 1 or 2, wherein the compound is represented by structural formula (Im): wherein R 29 is H or C 1-3 alkyl group.

83. A compound according to claim 1 or 2, wherein the compound is represented by structural formula (In): Wherein: R 1a selected from C 1-3 alkyl, halogen and H; R 1b and R 4 each independently is a halogen or H; R 1c selected from C 1-3 haloalkyl, halogen and H; and R 9 is H or C 1-3 alkyl group.

84. A compound according to claim 1 or 2, wherein the compound is a compound selected from Table 1.

85. A compound according to claim 1 or 2, wherein the compound is a compound selected from Table 2.

86. A compound according to claim 1 or 2, wherein the compound is a compound selected from Table 3.

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

88. A method of treating a disease or disorder, comprising administering to an individual in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 86 or a pharmaceutical composition according to claim 87, wherein the disease or disorder is selected from inflammatory diseases, autoimmune diseases, granulomatous diseases, cancers and neurodegenerative diseases.

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

90. The method according to 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 disease (IBD), ischemic reperfusion injury in solid organ transplantation, sepsis, liver disease, allergic diseases and graft-versus-host disease.

91. The method according to claim 89, wherein the inflammatory disease is IBD.

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

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

94. The method according to claim 88, wherein the disease or disorder is an autoimmune disease.

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

96. The method according to claim 88, wherein the disease or disorder is a granulomatous disease.

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

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

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, kidney cancer, and lung cancer.

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

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) diseases, stroke, Fahr disease, Menke's disease, Wilson's disease, cerebral ischemia, prion disorder, dementia, corticobasal degeneration, progressive supranuclear palsy, spinocerebellar ataxia, brain injury, and spinal cord injury.

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

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

104. The method of claim 102, wherein the second agent is selected from anti-TNF agents, anti-IL-23 agents, anti-integrin agents, and JAK inhibitors.

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

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

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

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

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

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