Sulfonylurea derivatives and their use

Abstract

The present disclosure provides a compound of formula (I): The present invention relates to compounds of TIFF2022535956000090.tif21128 and their prodrugs, pharmaceutically acceptable salts, pharmaceutical compositions, methods of use, and methods for their preparation. The compounds disclosed herein are useful for preventing the maturation of IL-1 family cytokines by inhibiting inflammasomes, and can be used to treat disorders in which inflammasome activity is implicated, such as inflammatory, autoinflammatory, and autoimmune diseases, and cancer.

Description

Technical Field

[0001] Related Applications This application claims the benefit and priority of U.S. Provisional Application No. 62 / 860,663, filed on Jun. 12, 2019, the entire contents of which are incorporated herein by reference.

[0002] Field of the Disclosure The present disclosure relates to sulfonylurea derivatives, prodrugs thereof, and pharmaceutically acceptable salts thereof, which have inflammasome inhibitory activity and are useful in methods of treating the human or animal body. The present disclosure also relates to processes for the preparation of these compounds, pharmaceutical compositions containing them, and their use in the treatment of disorders involving inflammasome activity, such as inflammatory diseases, autoinflammatory diseases, and autoimmune diseases, and oncological diseases.

Background Art

[0003] Autoimmune diseases are associated with the overproduction of inflammatory factors. One of them is interleukin-1 (IL-1), which is produced by activated macrophages, monocytes, fibroblasts, and other components of the innate immune system, such as dendritic cells. IL-1 is involved in various cellular activities such as cell proliferation, differentiation, and apoptosis (Seth L. al. Rev. Immunol. 2009. 27:621-68 (Non-Patent Document 1)).

[0004] In humans, 22 NLR proteins are classified into four NLR subfamilies according to their N-terminal domains. NLRA contains a CARD-AT domain, NLRB (NAIP) contains a BIR domain, NLRC (including NOD1 and NOD2) contains a CARD domain, and NLRP contains a pyrin domain. Multiple NLR family members are associated with inflammasome formation.

[0005] The activation of the inflammasome appears to have evolved as an important component of host immunity against pathogens. However, the NLRP3 inflammasome is unique in that it has the ability to be activated in response to endogenous sterile danger signals. Numerous such sterile signals have been elucidated, and their formation is associated with specific disease situations. For example, uric acid crystals observed in patients with gout are effective triggers for NLRP3 activation. Similarly, cholesterol crystals observed in patients with atherosclerosis can also promote NLRP3 activation. With the recognition of the role of sterile danger signals as NLRP3 activators, IL-1 and IL-18 have been implicated in a wide range of pathophysiological manifestations, including metabolic disorders, physiological disorders, inflammatory disorders, blood disorders, and immune disorders.

[0006] The present disclosure was created due to the need to provide additional compounds that specifically modulate NLRP3-dependent cellular processes. In particular, compounds with improved physicochemical, pharmacological, and pharmaceutical properties compared to existing compounds are highly desired.

Prior Art Documents

Non-Patent Documents

[0007]

Non-Patent Document 1

Summary of the Invention

[0008] In some aspects, the present disclosure provides, inter alia, a compound of formula (I): TIFF0007682813000001.tif21128, or a prodrug, solvate, or pharmaceutically acceptable salt thereof, wherein: R 1 is C 3 -C 16 cycloalkyl or C 5 -C 10 aryl, and the C 3 -C16 Cycloalkyl or C 5 -C 10 Aryl may be substituted with one or more R 1S ; Each R 1S is independently halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 2 is C 1 -C 6 alkyl or C 3 -C 16 cycloalkyl, and the C 1 -C 6 alkyl or C 3 -C 16 cycloalkyl may be substituted with one or more R 2S ; Each R 2S is independently halo, -CN, -OH, -O(C 1 -C 6 alkyl), -NH 2 -, -NH(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 or oxo, and the C 1 -C 6 alkyl may be substituted with one or more 3- to 8-membered heterocycloalkyl; R 3 is 7- to 12-membered heterocycloalkyl or 5- or 6-membered heteroaryl, and the 7- to 12-membered heterocycloalkyl or 5- or 6-membered heteroaryl may be substituted with one or more R 3S ; and Each R 3S is independently halo, C 1 -C 6 alkyl, C 1 -C6 Haloalkyl, C 3 -C 8 ycloalkyl, or 3- to 8-membered heterocycloalkyl, wherein the C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 ycloalkyl, or 3- to 8-membered heterocycloalkyl may be substituted with one or more halo, -CN, -OH, -O(C 1 -C 6 alkyl), -NH 2 2, -NH(C 1 -C 6 alkyl), or -N(C 1 -C 6 alkyl) 2 and may be optionally substituted.

[0009] In some embodiments, the present disclosure provides compounds obtainable by a method for preparing the compounds described herein (e.g., a method comprising one or more steps described in Schemes 1 and 2), or provides the obtained compounds.

[0010] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable diluent or carrier.

[0011] In some embodiments, the present disclosure provides an intermediate described herein that is suitable for use in a method for preparing the compounds described herein (e.g., the intermediate is selected from the intermediates described in Examples 1-4).

[0012] In some embodiments, the present disclosure provides a method for inhibiting inflammasome (e.g., NLRP3 inflammasome) activity (e.g., in vitro or in vivo), the method comprising contacting a cell with an effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof.

[0013] In some embodiments, the present disclosure provides a method of doing so in a subject in need of treatment or prevention of a disease or disorder disclosed herein, the method comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0014] In some embodiments, the present disclosure provides a method of doing so in a subject in need of treatment of a disease or disorder disclosed herein, the method comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0015] In some embodiments, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in inhibiting inflammasome (e.g., NLRP3 inflammasome) activity (e.g., in vitro or in vivo).

[0016] In some embodiments, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of a disease or disorder disclosed herein.

[0017] In some embodiments, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in the treatment of a disease or disorder disclosed herein.

[0018] In some embodiments, the present disclosure provides the use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for inhibiting inflammasome (e.g., NLRP3 inflammasome) activity (e.g., in vitro or in vivo).

[0019] In some embodiments, the present disclosure provides the use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein.

[0020] In some embodiments, the present disclosure provides for the use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a disease or disorder disclosed herein.

[0021] In some embodiments, the present disclosure provides a method for preparing a compound of the present disclosure.

[0022] In some embodiments, the present disclosure provides a method for preparing a compound, comprising one or more steps described herein.

[0023] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. As used herein, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, but the preferred methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. References cited herein are not admitted to be prior art to the claimed invention. In case of conflict, the present specification, including definitions, will control. Furthermore, the materials, methods, and examples are illustrative only and not intended to be limiting. In case of conflict between a chemical structure and the name of a compound disclosed herein, the chemical structure shall prevail.

[0024] [The present invention 1001] Formula (I): TIFF0007682813000002.tif21128 a compound, or a prodrug, solvate, or pharmaceutically acceptable salt thereof, wherein: R 1 is C 3 -C 16 cycloalkyl or C 5 -C 10 aryl, and the C 3 -C 16 cycloalkyl or C5 -C 10 aryl may be substituted with one or more R 1S ; each R 1S is independently halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 2 is C 1 -C 6 alkyl or C 3 -C 16 cycloalkyl, and the C 1 -C 6 alkyl or C 3 -C 16 cycloalkyl may be substituted with one or more R 2S ; each R 2S is independently halo, -CN, -OH, -O(C 1 -C 6 alkyl), -NH 2 , -NH(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 , or oxo, and the C 1 -C 6 alkyl may be substituted with one or more 3- to 8-membered heterocycloalkyl; R 3 is 7- to 12-membered heterocycloalkyl or 5- or 6-membered heteroaryl, and the 7- to 12-membered heterocycloalkyl or 5- or 6-membered heteroaryl may be substituted with one or more R 3S; and each R 3S is independently halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, or 3- to 8-membered heterocycloalkyl, and the C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, or 3- to 8-membered heterocycloalkyl may be substituted with one or more halo, -CN, -OH, -O(C 1 -C 6 alkyl), -NH 2 , -NH(C 1 -C 6 alkyl), or -N(C 1 -C 6 alkyl) 2 , the said compound, or a prodrug, solvate, or pharmaceutically acceptable salt thereof. [The present invention 1002] R 1 is C 3 -C 16 cycloalkyl; R 2 is C 1 -C 6 alkyl or C 3 -C 16 cycloalkyl, and the C 1 -C 6 alkyl or C 3 -C 16 cycloalkyl may be substituted with one or more R 2S ; each R 2S is independently -OH, -O(C 1 -C 6 alkyl), or -N(C 1 -C 6 alkyl) 2 , and the C 1 -C 6 alkyl may be substituted with one or more 3- to 8-membered heterocycloalkyl; R 3 is a 5- or 6-membered heteroaryl which may be substituted with one or more C 1 -C 6 alkyl, the compound of the present invention 1001. [The present invention 1003] R 1 is C 3 -C 16 cycloalkyl or C 5 -C 10 aryl, and the C 3 -C 16 cycloalkyl or C 5 -C 10 aryl may be substituted with one or more R 1S ; each R 1S is independently halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 2 is C 1 -C 6is alkyl or C 3 -C 16 cycloalkyl, and the C 1 -C 6 alkyl or C 3 -C 16 cycloalkyl may be substituted with one or more R 2S ; Each R 2S is independently halo, -CN, -OH, -O(C 1 -C 6 alkyl), -NH 2 , -NH(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 , or oxo; R 3 is 7- to 12-membered heterocycloalkyl or 5- or 6-membered heteroaryl, and the 7- to 12-membered heterocycloalkyl or 5- or 6-membered heteroaryl may be substituted with one or more R 3S ; and Each R 3S is independently halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, or 3- to 8-membered heterocycloalkyl, and the C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, or 3- to 8-membered heterocycloalkyl may be substituted with one or more halo, -CN, -OH, -O(C 1 -C 6 alkyl), -NH 2 , -NH(C 1 -C6 alkyl), or -N(C 1 -C 6 alkyl) 2 , a compound of the present invention 1001. [Present Invention 1004] R 1 is C 3 -C 7 monocyclic cycloalkyl, C 9 -C 10 bicyclic cycloalkyl, or C 12 -C 16 tricyclic cycloalkyl, and the C 3 -C 7 monocyclic cycloalkyl, C 9 -C 10 bicyclic cycloalkyl, or C 12 -C 16 tricyclic cycloalkyl may be substituted with one or more R 1S , any compound of the prior present invention. [Present Invention 1005] R 1 is TIFF0007682813000003.tif36128 , wherein n and n a are each independently 0, 1, 2, or 3, any compound of the prior present invention. [Present Invention 1006] R 1 is TIFF0007682813000004.tif25128 , any compound of the prior present invention. [Present Invention 1007] R 2 is C 2S alkyl which may be substituted with one or more R 1 -C 6 , any compound of the prior present invention. [Present Invention 1008] R 2 is C 2S cycloalkyl which may be substituted with one or more R 3 -C 16 , any compound of the prior present invention. [Present Invention 1009] R 2 is TIFF0007682813000005.tif48142 , any compound of the prior present invention. [Present Invention 1010] At least one R 2S is -OH, -O(C 1 -C 6 alkyl), or -N(C 1 -C 6 alkyl) 2 , and the C 1 -C 6 alkyl may be substituted with one or more 3- to 8-membered heterocycloalkyl, any compound of the prior present invention. [Present Invention 1011] At least one R 2S is -OH, TIFF0007682813000006.tif15128 , any compound of the prior present invention. [Present Invention 1012] R 3 is 5- or 6-membered heteroaryl which may be substituted with one or more R 3S , any compound of the prior present invention. [Present Invention 1013] R 3 is one or more C 1 -C 6 Any compound of the prior invention which is a 5- or 6-membered heteroaryl optionally substituted with alkyl. [Inventive concept 1014] R 3 wherein TIFF0007682813000007.tif12128 is any compound of the prior invention. [Inventive concept 1015] at least one R 3S is C 1 -C 6 alkyl is any compound of the prior invention. [Inventive concept 1016] at least one R 3S is methyl is any compound of the prior invention. [Inventive concept 1017] wherein the compound is a compound of formula (I-a), (I-b), or (I-c): TIFF0007682813000008.tif67128 or a prodrug, solvate, or pharmaceutically acceptable salt thereof, is any compound of the prior invention. [Inventive concept 1018] wherein the compound is a compound of formula (I-d): TIFF0007682813000009.tif26128 or a prodrug, solvate, or pharmaceutically acceptable salt thereof, is any compound of the prior invention. [Inventive concept 1019] wherein the compound is a compound of formula (I-e), (I-f), or (I-g): TIFF0007682813000010.tif84128 or a prodrug, solvate, or pharmaceutically acceptable salt thereof, is any compound of the prior invention. [Inventive concept 1020] wherein the compound is a compound of formula (I-h) or (I-i): TIFF0007682813000011.tif47128 or a prodrug, solvate, or pharmaceutically acceptable salt thereof, is any compound of the prior invention. [Inventive concept 1021] wherein the compound is a compound of formula (I-j) or (I-k): TIFF0007682813000012.tif63128 or a prodrug, solvate, or pharmaceutically acceptable salt thereof, is any compound of the prior invention. [Inventive concept 1022] wherein the compound is a compound of formula (I-l), (I-m), (I-n), or (I-o): TIFF0007682813000013.tif104128 or a prodrug, solvate, or pharmaceutically acceptable salt thereof, is any compound of the prior invention. [Inventive concept 1023] wherein the compound is a compound of formula (I-p), (I-q), (I-r), or (I-s): TIFF0007682813000014.tif128128 or a prodrug, solvate, or pharmaceutically acceptable salt thereof, is any compound of the prior invention. [Inventive concept 1024] wherein the compound is a compound of formula (I-n) or (I-o): TIFF0007682813000015.tif63128 or a prodrug, solvate, or pharmaceutically acceptable salt thereof, is any compound of the prior invention. [Inventive concept 1025] Any compound of the prior invention selected from Compound Nos. 1 to 11 and their prodrugs and pharmaceutically acceptable salts. [Inventive concept 1026] Any compound of the prior invention selected from Compound Nos. 1 to 11 and pharmaceutically acceptable salts thereof. [Inventive Concept 1027] Any compound of the prior invention selected from Compound Nos. 1 to 11. [Inventive Concept 1028] A compound that is an isotope derivative of any compound of the prior invention. [Inventive Concept 1029] The compound of Inventive Concept 1028, which is a compound labeled with deuterium of any one of Compound Nos. 1 to 11 and its prodrug and pharmaceutically acceptable salts. [Inventive Concept 1030] The compound of Inventive Concept 1028, which is a compound labeled with deuterium of any one of Compound Nos. 1 to 11. [Inventive Concept 1031] A compound that can be obtained by the method described herein or has been obtained; the method optionally includes one or more steps described in Schemes 1 to 2. [Inventive Concept 1032] A compound obtained by an intermediate obtained by a method for preparing any compound of Inventive Concepts 1001 to 1030, wherein the intermediate is optionally selected from the intermediates described in Examples 1 to 11. [Inventive Concept 1033] A pharmaceutical composition comprising any compound of Inventive Concepts 1001 to 1030 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable diluent or carrier. [Inventive Concept 1034] The pharmaceutical composition of Inventive Concept 1033, wherein the compound is selected from Compound Nos. 1 to 11. [Inventive Concept 1035] A method for inhibiting inflammasome activity, comprising contacting a cell with an effective amount of any compound of Inventive Concepts 1001 to 1030 or a pharmaceutically acceptable salt thereof, optionally wherein the inflammasome is an NLRP3 inflammasome and the activity is in vitro or in vivo. [Inventive Concept 1036] A method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of any compound of Inventive Concepts 1001 to 1030 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of Inventive Concept 1033 or Inventive Concept 1034. [Inventive Concept 1037] A compound of any one of 1001 to 1030 of the present invention, or a pharmaceutical composition of the present invention 1033 or the present invention 1034 for use in inhibiting inflammasome activity, optionally wherein the inflammasome is an NLRP3 inflammasome and the activity is in vitro or in vivo, said compound or pharmaceutical composition. [The present invention 1038] A compound of any one of 1001 to 1030 of the present invention, or a pharmaceutical composition of the present invention 1033 or the present invention 1034 for use in the treatment or prevention of a disease or disorder. [The present invention 1039] Use of a compound of any one of 1001 to 1030 of the present invention or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for inhibiting inflammasome activity, optionally wherein the inflammasome is an NLRP3 inflammasome and the activity is in vitro or in vivo, said use. [The present invention 1040] Use of a compound of any one of 1001 to 1030 of the present invention or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing a disease or disorder. [The present invention 1041] Any method, compound, pharmaceutical composition, or use of the prior invention, wherein the disease or disorder is related to the inflammasome activity involved, and optionally, the disease or disorder is a disease or disorder in which inflammasome activity is involved. [The present invention 1042] Any method, compound, pharmaceutical composition, or use of the prior invention, wherein the disease or disorder is an inflammatory disorder, an autoinflammatory disorder, an autoimmune disorder, a neurodegenerative disease, or cancer. [The present invention 1043] The disease or disorder is an inflammatory disorder, an autoinflammatory disorder, or an autoimmune disorder, and optionally, the disease or disorder is selected from cryopyrin-associated periodic syndromes (CAPS, e.g., familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), chronic infantile neurologic cutaneous articular (CINCA) syndrome / neonatal-onset multisystem inflammatory disease (NOMID)), familial Mediterranean fever (FMF), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), gout, rheumatoid arthritis, osteoarthritis, Crohn's disease, chronic obstructive pulmonary disease (COPD), chronic kidney disease (CKD), fibrosis, obesity, type 2 diabetes, multiple sclerosis, skin diseases (e.g., acne), and neuroinflammation occurring in protein misfolding diseases (e.g., prion diseases), any method, compound, pharmaceutical composition, or use of the present invention prior thereto. [Inventive concept 1044] The disease or disorder is a neurodegenerative disease, and optionally, the disease or disorder is Parkinson's disease or Alzheimer's disease, any method, compound, pharmaceutical composition, or use of the present invention prior thereto. [Inventive concept 1045] The disease or disorder is cancer, and optionally, the cancer is metastatic cancer, brain cancer, gastrointestinal cancer, skin cancer, non-small cell lung cancer, head and neck squamous cell carcinoma, or colorectal adenocarcinoma, any method, compound, pharmaceutical composition, or use of the present invention prior thereto. Other features and advantages of the present disclosure will become apparent from the following detailed description and the claims.

Mode for Carrying Out the Invention

[0025] Detailed Description Autoimmune diseases are associated with the overproduction of inflammatory factors. One of them is interleukin 1 (IL-1), which is produced by activated macrophages, monocytes, fibroblasts, and other components of the innate immune system, such as dendritic cells, and is involved in various cellular activities including cell proliferation, differentiation, and apoptosis (Seth L. al. Rev. Immunol. 2009. 27:621-68).

[0026] Cytokines of the IL-1 family are highly active and, as important inflammatory mediators, are mainly associated with acute and chronic inflammation (Sims J. et al. Nature Reviews Immunology 10, 89-102 (February 2010)). The overproduction of IL-1 is thought to be a mediator of some autoimmune and autoinflammatory diseases. Autoinflammatory diseases are characterized by recurrent and idiopathic inflammation in the absence of autoantibodies, infections, or antigen-specific T lymphocytes.

[0027] As inflammatory cytokines of the IL-1 superfamily, there are IL-1α, IL-1β, IL-18, and IL-36α, β, λ, which are produced as part of the host innate immune response in response to pathogens and other cellular stressors. Unlike many other secreted cytokines that are processed and released by the standard cellular secretory organs consisting of the endoplasmic reticulum and Golgi apparatus, IL-1 family members lack the leader sequence required for endoplasmic reticulum translocation and thus remain intracellular after translation. Furthermore, IL-1β, IL-18, and IL-36α, β, λ are synthesized as pro-cytokines that require proteolytic activation in order to become optimal ligands for binding to cognate receptors on target cells.

[0028] Currently, in the cases of IL-1α, IL-1β, and IL-18, it is recognized that a multimeric protein complex known as the inflammasome is responsible for the activation of the pro-forms of IL-1β and IL-18 and the extracellular release of these cytokines. Generally, the inflammasome complex consists of a sensor molecule such as NLR (nucleotide oligomerization domain (NOD)-like receptor), an adapter molecule ASC (apoptosis-related speck-like protein containing a CARD (caspase recruitment domain)), and procaspase-1. In response to various "danger signals" including pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs), the subunits of the inflammasome oligomerize to form a supramolecular structure within the cell. Examples of PAMPs include molecules such as peptidoglycan, viral DNA or RNA, and bacterial DNA or RNA. On the other hand, DAMPs consist of a wide range of endogenous or exogenous sterile triggers including monosodium urate crystals, silica, alum, asbestos, fatty acids, ceramides, cholesterol crystals, and beta-amyloid peptide aggregates. When the inflammasome platform is constructed, the autocatalytic action of procaspase-1 is promoted, resulting in the generation of highly active cysteine proteases that are responsible for the activation and release of pro-IL-1β and pro-IL-18. Therefore, the release of these highly inflammatory cytokines is only achieved in response to the detection of specific molecular danger signals and the inflammasome sensors that respond to them.

[0029] In humans, 22 NLR proteins are classified into four NLR subfamilies according to their N-terminal domains. NLRA contains a CARD-AT domain, NLRB (NAIP) contains a BIR domain, NLRC (including NOD1 and NOD2) contains a CARD domain, and NLRP contains a pyrin domain. Multiple NLR family members including NLRP1, NLRP3, NLRP6, NLRP7, NLRP12, and NLRC4 (IPAF) are associated with inflammasome formation.

[0030] Two other structurally distinct inflammasome structures that contain the PYHIN domain (pyrin and HIN domain-containing proteins), namely, Absent in Melanoma 2 (AIM2), and Interferon lambda inducible protein 16 (IFI16) (Latz et al., Nat Rev Immunol 2013 13(6) 397 - 311), serve as intracellular DNA sensors. Pyrin (encoded by the MEFV gene) forms another type of inflammasome platform associated with proIL-1β activation (Chae et al., Immunity 34, 755 - 768, 2011).

[0031] By requiring the construction of an inflammasome platform to effect the activation and release of IL-1β and IL-18 from monocytes and macrophages, their production is carefully orchestrated in a two-step process. First, cells encounter a priming ligand (e.g., the TLR4 receptor ligand LPS, or an inflammatory cytokine such as TNFα), which results in NFkB-dependent transcription of NLRP3, pro-IL-1β, and pro-IL-18. The newly translated pro-cytokines remain intracellular and inactive unless the producing cells encounter a second signal that results in the activation of the inflammasome scaffold and the maturation of procaspase-1.

[0032] In addition to the proteolytic activation of pro-IL-1β and pro-IL-18, active caspase-1 also induces a form of inflammatory cell death known as pyroptosis through the cleavage of gasdermin-D. Pyroptosis allows the mature forms of IL-1β and IL-18 to be externalized along with the release of alarmin molecules such as high mobility group box 1 protein (HMGB1), IL-33, and IL-1α (compounds that promote inflammation and activate innate and adaptive immunity).

[0033] The activation of the inflammasome appears to have evolved as an important component of host immunity against pathogens, but the NLRP3 inflammasome is unique in that it has the ability to be activated in response to both endogenous and exogenous sterile danger signals. Numerous such sterile signals have been elucidated, and their formation is associated with specific disease situations. For example, uric acid crystals found in patients with gout are effective triggers for NLRP3 activation. Similarly, cholesterol crystals found in patients with atherosclerosis can also promote NLRP3 activation. The recognition of the role of sterile danger signals as NLRP3 activators has led to the suggestion that IL-1 and IL-18 are associated with a wide range of pathophysiological symptoms, including metabolic disorders, physiological disorders, inflammatory disorders, blood disorders, and immune disorders.

[0034] The association with human diseases is best exemplified by the finding that mutations in the NLRP3 gene that result in a gain of function cause a series of autoinflammatory conditions collectively referred to as cryopyrin-associated periodic syndromes (CAPS), such as familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and neonatal-onset multisystem inflammatory disease (NOMID) (Hoffman et al., Nat Genet. 29(3) (2001) 301-305). Similarly, the sterile mediator-induced activation of NLRP3 is involved in a wide range of disorders, including joint degeneration (gout, rheumatoid arthritis, osteoarthritis), cardiometabolic disorders (type 2 diabetes, atherosclerosis, hypertension), central nervous system disorders (Alzheimer's disease, Parkinson's disease, multiple sclerosis), gastrointestinal disorders (Crohn's disease, ulcerative colitis), lung disorders (chronic obstructive pulmonary disease (COPD), asthma, idiopathic pulmonary fibrosis), and liver (fibrosis, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis (NASH)). Furthermore, NLRP3 activation promotes kidney inflammation and is therefore thought to contribute to chronic kidney disease (CKD).

[0035] As current treatment options for diseases in which IL-1 is involved as a contributing factor to pathogenesis, there are anakinra, an IL-1 receptor antagonist, rilonacept, an Fc-containing fusion construct of the extracellular domains of the IL-1 receptor and the IL-1 receptor accessory protein, and the anti-IL-1β monoclonal antibody canakinumab. For example, canakinumab has been approved for CAPS, tumor necrosis factor receptor-associated periodic syndrome (TRAPS), hyperimmunoglobulin D syndrome (HIDS) / mevalonate kinase deficiency (MKD), familial Mediterranean fever (FMF), and gout.

[0036] Some small molecules have been reported to inhibit the function of the NLRP3 inflammasome. For example, glibride serves as a specific inhibitor of NLRP3 activation even at micromolar concentrations that are unlikely to be achievable in vivo. Nonspecific agents such as parthenolide, Bay 11-7082, and 3,4-methylenedioxy-β-nitrostyrene have been reported to impair NLRP3 activation, but their therapeutic utility is considered limited as they share a common structural feature consisting of olefins activated by electron-withdrawing group substitution; this substitution results in the undesirable formation of covalent adducts with thiol groups of proteins. Some natural products, such as β-hydroxybutyric acid, sulforaphane, quercetin, and salvianolic acid, have also been reported to suppress NLRP3 activation. Similarly, numerous effectors / modulators of other molecular targets have been reported to impair NLRP3 activation, such as agonists of the G protein-coupled receptor TGR5, inhibitors of the sodium-glucose cotransporter empagliflozin, the dopamine receptor antagonist A-68930, the serotonin reuptake inhibitor fluoxetine, fenamate nonsteroidal anti-inflammatory drugs, and the β-adrenergic receptor blocker nebivolol. The utility of these molecules as therapeutics for the long-term treatment of NLRP3-dependent inflammatory disorders has not yet been established. A series of sulfonylurea-containing molecules have already been identified as potent and selective inhibitors of the post-translational processing of pro-IL-1β (Perregaux et al., J Pharmacol. Exp. Ther. 299, 187-197, 2001). More recently, the exemplary molecule CP-456,773 of this study was characterized as a specific inhibitor of NLRP3 activation (Coll et al., Nat Med 21.3 (2015): 248-255.).

[0037] The present disclosure relates to compounds useful for the specific modulation of NLRP3-dependent cellular processes. In particular, there is a need for compounds having improved physicochemical, pharmacological, and pharmaceutical properties compared to existing NLRP3-modulating compounds.

[0038] definition Unless otherwise stated, the following terms used in the specification and claims have the meanings set forth below.

[0039] As used herein, “alkyl,” “C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 Alkyl" or "C 1 -C 6 Alkyl" is C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 Linear (straight-chain) saturated aliphatic hydrocarbon groups, and C 3 , C 4 , C 5 , or C 6 It is intended to include branched saturated aliphatic hydrocarbon groups. For example, C 1 -C 6 Alkyl is C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 It is intended to include alkyl groups. Examples of alkyl include moieties having 1-6 carbon atoms, such as, but not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, or n-hexyl. In some embodiments, a straight chain or branched alkyl has 6 or fewer carbon atoms (e.g., C for straight chain). 1 -C 6 , C for branched chains 3 -C 6 ), in another embodiment, the straight chain or branched alkyl has 4 or fewer carbon atoms.

[0040] As used herein, the term "optionally substituted alkyl" means unsubstituted alkyl or alkyl having one or more predetermined substituents that replace one or more hydrogen atoms at one or more carbons of the hydrocarbon backbone. These substituents include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (such as alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (such as alkylcarbonylamino, arylcarbonylamino, carbamoyl, and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamide, nitro, trifluoromethyl, cyano, azide, heterocyclyl, alkylaryl, or aromatic moiety, or heteroaromatic moiety.

[0041] As used herein, the term "alkenyl" includes an unsaturated aliphatic group that is similar to the above-described alkyl in length and possible substitution but contains at least one double bond. For example, "alkenyl" includes straight-chain alkenyl groups (e.g., ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl) and branched alkenyl groups. In certain embodiments, the straight-chain or branched alkenyl group has 6 or fewer carbon atoms in the main chain (e.g., C 2 -C 6 , branched C 3 -C 6 ). The term "C 2 -C 6 " includes an alkenyl group containing 2 to 6 carbon atoms. The term "C 3 -C 6 " includes an alkenyl group containing 3 to 6 carbon atoms.

[0042] As used herein, the term "optionally substituted alkenyl" means an unsubstituted alkenyl or an alkenyl having one or more predetermined substituents that replace one or more hydrogen atoms at one or more hydrocarbon backbone carbon atoms. Examples of these substituents include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (such as alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (such as alkylcarbonylamino, arylcarbonylamino, carbamoyl, and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamide, nitro, trifluoromethyl, cyano, heterocyclyl, alkylaryl, or an aromatic moiety, or a heteroaromatic moiety.

[0043] As used herein, the term "alkynyl" includes the above-described alkyl and an unsaturated aliphatic group that is similar in length and possible substitution but contains at least one triple bond. For example, "alkynyl" includes straight-chain alkynyl groups (e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl), and branched alkynyl groups. In certain embodiments, the straight-chain or branched alkynyl group has 6 or fewer carbon atoms in the main chain (e.g., C 2 -C 6 , branched C 3 -C 6 ). The term "C 2 -C 6 " includes an alkynyl group containing 2 to 6 carbon atoms. The term "C 3 -C6 " contains an alkynyl group having 3 to 6 carbon atoms. As used herein, "C" 2 -C 6 " alkenylene linker" or "C" 2 -C 6 " alkynylene linker" is intended to include C 2 , C 3 , C 4 , C 5 , or C 6 (linear or branched) divalent unsaturated aliphatic hydrocarbon group. For example, C 2 -C 6 " alkenylene linker" is intended to include C 2 , C 3 , C 4 , C 5 and C 6 " alkenylene linker group.

[0044] As used herein, the term "optionally substituted alkynyl" means unsubstituted alkynyl or alkynyl having one or more predetermined substituents that replace one or more hydrogen atoms at one or more hydrocarbon backbone carbon atoms. These substituents include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (such as alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (such as alkylcarbonylamino, arylcarbonylamino, carbamoyl, and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamide, nitro, trifluoromethyl, cyano, azide, heterocyclyl, alkylaryl, or aromatic moiety, or heteroaromatic moiety.

[0045] Other optionally substituted moieties (such as optionally substituted cycloalkyl, heterocycloalkyl, aryl, or heteroaryl) include both unsubstituted moieties and moieties having one or more predetermined substituents. For example, substituted heterocycloalkyl includes heterocycloalkyl substituted with one or more alkyl groups, such as 2,2,6,6-tetramethyl-piperidinyl, and 2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridinyl.

[0046] As used herein, the term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic (e.g., fused ring, bridged ring, or spiro ring) hydrocarbon-based having 3 to 30 carbon atoms (e.g., C 3 -C 12 、C 3 -C 10 、or C 3 -C 8 ). Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, 1,2,3,4-tetrahydronaphthalenyl, and adamantyl. In the case of polycyclic cycloalkyl, only one of the rings of the cycloalkyl needs to be non-aromatic. In some embodiments, the cycloalkyl is hexahydroindenyl. In some embodiments, the cycloalkyl is TIFF0007682813000016.tif25128.

[0047] As used herein, the term "heterocycloalkyl" means, unless otherwise specified, one or more heteroatoms (e.g., O, N, S, P, or Se) independently selected from the group consisting of nitrogen, oxygen, and sulfur, e.g., 1, or 1 to 2, or 1 to 3, or 1 to 4, or 1 to 5, or 1 to 6 heteroatoms, or e.g., 1, 2, 3, 4, 5, or 6 heteroatoms, and having a saturated or partially unsaturated monocyclic ring system of 3 to 8 members, a bicyclic ring system of 7 to 12 members (fused ring, bridged ring, or spiro ring), or a tricyclic ring system of 11 to 14 members (fused ring, bridged ring, or spiro ring).Examples of heterocycloalkyl groups include piperidinyl, piperazinyl, pyrrolidinyl, dioxanyl, tetrahydrofuranyl, isoindolinyl, indolinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, oxiranyl, azetidinyl, oxetanyl, thietanyl, 1,2,3,6-tetrahydropyridinyl, tetrahydropyranyl, dihydropyranyl, pyranyl, morpholinyl, tetrahydrothiopyranyl, 1,4-diazepanyl, 1,4-oxazepanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2-oxa-6-azaspiro[3.3]heptanyl, 2,6-azaspiro[3.3]heptanyl, 1,4-dioxa-8-azaspiro[4.5]decanyl, 1,4-dioxaspiro[4.5]decanyl, 1-oxaspiro[4.5]decanyl, 1-azaspiro[4.5]decanyl, 3’H-spiro[cyclohexane-1,1’-isobenzofuran]-yl, 7’H-spiro[cyclohexane-1,5’-furo[3,4-b]pyridine]-yl, 3’H-spiro[cyclohexane-1,1’-furo[3,4-c]pyridine]-yl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[3.1.0]hexan-3-yl, 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazolyl, 3,4,5,6,7,8-hexahydropyrido[4,3-d]pyrimidinyl, 4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridinyl, 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidinyl, 2-azaspiro[3.3]heptanyl, 2-methyl-2-azaspiro[3.3]heptanyl, 2-azaspiro[3.5]nonanyl, 2-methyl-2-azaspiro[3.5]nonanyl, 2-azaspiro[4.5]decanyl, 2-methyl-2-azaspiro[4.5]decanyl, 2-oxa-azaspiro[3.4]octanyl, 2-oxa-azaspiro[3.4]octan-6-yl, etc., but are not limited thereto. In the case of polycyclic cycloalkyl, only one of the rings of the heterocycloalkyl needs to be non-aromatic (for example, 4,5,6,7-tetrahydrobenzo[c]isoxazolyl).

[0048] As used herein, the term "aryl" includes "conjugated systems" or polycyclic systems having one or more aromatic rings, and includes groups having no heteroatoms in the ring structure and having aromaticity. The term aryl includes both monovalent and divalent species. Examples of aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, etc. Conveniently, aryl is phenyl.

[0049] As used herein, the term "heteroaryl" is intended to include a stable 5-membered, 6-membered, or 7-membered monocyclic aromatic heterocycle, or a 7-membered, 8-membered, 9-membered, 10-membered, 11-membered, or 12-membered bicyclic aromatic heterocycle consisting of carbon atoms and one or more heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, for example, 1, or 1-2, or 1-3, or 1-4, or 1-5, or 1-6 heteroatoms, or, for example, 1, 2, 3, 4, 5, or 6 heteroatoms. The nitrogen atom may or may not be substituted (i.e., N or NR, where R is H or another substituent as defined). The nitrogen and sulfur heteroatoms may be oxidized (i.e., N→O and S(O) p , where p = 1 or 2). It should be noted that the total number of S and O atoms in the aromatic heterocycle does not exceed 1. Examples of heteroaryl groups include pyrrole, furan, thiophene, thiazole, isothiazole, imidazole, triazole, tetrazole, pyrazole, oxazole, isoxazole, pyridine, pyrazine, pyridazine, pyrimidine, etc. To form a polycyclic system, the heteroaryl group may be fused or bridged with an alicyclic or heterocyclic ring that is not aromatic (e.g., 4,5,6,7-tetrahydrobenzo[c]isoxazolyl).

[0050] Furthermore, the terms "aryl" and "heteroaryl" include polycyclic aryl groups and heteroaryl groups, such as tricyclic, bicyclic, for example, naphthalene, benzoxazole, benzodioxazole, benzothiazole, benzimidazole, benzothiophene, quinoline, isoquinoline, naphthyridine, indole, benzofuran, purine, benzofuran, deazapurine, indolizine.

[0051] A cycloalkyl ring, heterocycloalkyl ring, aryl ring, or heteroaryl ring may be substituted at one or more ring positions (e.g., a carbon atom forming the ring or a heteroatom such as N) with the substituents described above, such as alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminocarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, amino (such as alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (such as alkylcarbonylamino, arylcarbonylamino, carbamoyl, and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamide, nitro, trifluoromethyl, cyano, azide, heterocyclyl, alkylaryl, or an aromatic moiety or a heteroaromatic moiety. An aryl group and a heteroaryl group may be fused or bridged with an alicyclic ring or a heterocyclic ring that is not aromatic to form a polycyclic system (e.g., methylenedioxyphenyl such as tetralin, benzo[d][1,3]dioxol-5-yl).

[0052] As used herein, the term "substituted" means that any one or more hydrogen atoms on a given atom are replaced with a selected one from the indicated groups, provided that the normal valence of the given atom is not exceeded and a stable compound is obtained by the substitution. When the substituent is oxo or keto (i.e., =O), two hydrogen atoms on the atom are replaced. A keto substituent does not exist in an aromatic moiety. As used herein, a ring double bond is a double bond formed between two adjacent ring atoms (e.g., C=C, C=N, or N=N). "Stable compound" and "stable structure" are intended to indicate a compound having sufficient strength to achieve isolation in useful purity from a reaction mixture and formulation into an effective therapeutic agent.

[0053] When a bond to a substituent is shown to cross a bond connecting two atoms within a ring, such a substituent can be bonded to any atom within the ring. When a substituent is listed without indicating whether it is bonded to the remainder of a compound of a given formula through any atom of the substituent, the substituent can be bonded through any atom of the formula. Combinations of substituents and / or variables are permitted, but only if a stable compound is obtained with such combinations.

[0054] If any component of a compound or any variable in a formula (e.g., R) appears more than once, the definition at each appearance is independent of the definition at each other appearance. Thus, for example, if a group is shown to be substituted with from 0 to 2 R moieties, the group may be substituted with up to 2 R moieties, and each R at each appearance is independently selected from the definition of R. Also, combinations of substituents and / or variables are permitted, but only if a stable compound is obtained with such combinations.

[0055] As used herein, the term "hydroxy" or "hydroxyl" includes a group having -OH or -O - therewith.

[0056] As used herein, the term "halo" or "halogen" means fluoro, chloro, bromo, and iodo.

[0057] The term "haloalkyl" or "haloalkoxyl" means alkyl or alkoxyl substituted with one or more halogen atoms.

[0058] As used herein, the term "optionally substituted haloalkyl" means unsubstituted haloalkyl having a predetermined substituent that replaces one or more hydrogen atoms at one or more hydrocarbon backbone carbon atoms. These substituents include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (such as alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (such as alkylcarbonylamino, arylcarbonylamino, carbamoyl, and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamide, nitro, trifluoromethyl, cyano, azide, heterocyclyl, alkylaryl, or aromatic moiety, or heteroaromatic moiety.

[0059] As used herein, the term "alkoxy" or "alkoxyl" includes substituted and unsubstituted alkyl, alkenyl, and alkynyl groups covalently bonded to an oxygen atom. Examples of alkoxy groups or alkoxyl radicals include, but are not limited to, methoxy, ethoxy, isopropyloxy, propoxy, butoxy, and pentyloxy groups. Examples of substituted alkoxy groups include halogenated alkoxy groups. The alkoxy group may be substituted with groups such as alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (such as alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (such as alkylcarbonylamino, arylcarbonylamino, carbamoyl, and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamide, nitro, trifluoromethyl, cyano, azide, heterocyclyl, alkylaryl, or aromatic moiety, or heteroaromatic moiety. Examples of halogen-substituted alkoxy groups include, but are not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy, and trichloromethoxy.

[0060] Unless otherwise indicated, the expressions "one or more of A, B, or C", "one or more of A, B, or C", "one or more of A, B, and C", "one or more of A, B, and C", "selected from the group consisting of A, B, and C", "selected from A, B, and C", etc. used in this specification are used interchangeably and all mean a selection from the group consisting of A, B, and / or C, that is, one or more of A, one or more of B, one or more of C, or any combination thereof.

[0061] It should be understood that the present disclosure provides methods for the synthesis of compounds of any of the formulas described herein. The present disclosure also provides detailed methods for synthesizing various disclosed compounds of the present disclosure according to the following schemes and the schemes shown in the examples.

[0062] Throughout this specification, when a composition is described as having, including, or comprising a particular component, it should be understood that these compositions are also contemplated to consist essentially of or consist of the recited components. Similarly, when a method or process is described as having, including, or comprising a particular processing step, these processes also consist essentially of or consist of the recited processing steps. Further, it should be understood that as long as the present invention functions, the order of steps, or the order for performing a particular act, is not important. Further, two or more steps or acts can be performed simultaneously.

[0063] It should be understood that the synthetic process of the present disclosure can tolerate a wide variety of functional groups and thus can use various substituted starting materials. This process generally provides the desired final compound at or near the end of the entire process, but in certain cases, it may be desirable to further convert the compound into its pharmaceutically acceptable salt.

[0064] It should be understood that the compounds of the present disclosure can be prepared in various ways using commercially available starting materials, compounds known in the literature, or readily prepared intermediates, by using any standard synthetic methods and synthetic procedures known to those skilled in the art or obvious to those skilled in the art in light of the teachings herein. Standard synthetic methods and synthetic procedures for the preparation of organic molecules, as well as standard transformations and manipulations of functional groups, can be obtained from relevant scientific literature or standard textbooks in the art. Without limiting to one or more sources, by reference, Smith, M. B., March, J., March’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5 th edition, John Wiley & Sons: New York, 2001, Greene, T.W., Wuts, P.G. M., Protective Groups in Organic Synthesis, 3 rd edition, John Wiley & Sons: New York, 1999, R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989), L. Fieser and M. Fieser, Fieser and Fieser’s Reagents for Organic Synthesis, John Wiley and Sons (1994), and classical texts such as L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) are known to those skilled in the art, useful in organic synthesis, and generally recognized reference textbooks.

[0065] Those skilled in the art will note that they can change the order of certain steps, such as the introduction and removal of protecting groups, between the reaction sequences and synthetic schemes described herein. Those skilled in the art will recognize that certain groups may require protection from the reaction conditions resulting from the use of protecting groups. Protecting groups can be used to distinguish similar functional groups within a molecule. Lists of protecting groups, as well as methods for their introduction and removal, can be found in Greene, T.W., Wuts, P.G.M., Protective Groups in Organic Synthesis, 3 rd edition, John Wiley & Sons: New York, 1999.

[0066] Unless otherwise specified, it should be understood that any description of a method of treatment or prevention includes the use of a compound for providing the treatment or prevention described herein. Unless otherwise specified, it should be further understood that any description of a method of treatment or prevention includes the use of a compound for preparing a medicament for treating or preventing such a condition. Treatment includes the treatment or prevention of humans, or non-human animals such as rodents and other disease models.

[0067] Unless otherwise specified, it should be understood that any description of a method of treatment includes the use of a compound for providing the treatment described herein. Unless otherwise specified, it should be further understood that any description of a method of treatment includes the use of a compound for preparing a medicament for treating such a condition. Treatment includes the treatment of humans, or non-human animals such as rodents.

[0068] As used herein, the term "subject" is used interchangeably with "subject in need thereof", and both mean a subject having a disease or a subject at high risk of developing a disease. "Subject" includes mammals. The mammal can be, for example, a human or a suitable non-human mammal such as a primate, mouse, rat, dog, cat, cow, horse, goat, camel, sheep, or pig. Also, the subject can be a bird or poultry. In certain embodiments, the mammal is a human. The subject in need thereof can be a subject already diagnosed or identified as having a disease or disorder disclosed herein. Also, the subject in need thereof can be a subject having a disease or disorder described herein. Alternatively, the subject in need thereof can be a subject having a greater risk of developing such a disease or disorder compared to the general population (i.e., a subject more likely to develop such a disorder compared to the general population). The subject in need thereof may have a refractory or resistant disease or disorder disclosed herein (i.e., a disease or disorder disclosed herein that does not respond or has not yet responded to treatment). The subject may exhibit resistance at the start of treatment or acquire resistance during treatment. In some embodiments, the subject in need thereof has received all known effective treatments for a disease or disorder disclosed herein, but the results have not been favorable. In some embodiments, the subject in need thereof has received at least one conventional treatment.

[0069] As used herein, the terms "treating" or "treat" are defined as taking charge of and caring for a patient in order to address a disease, medical condition, or disorder, and include administering a compound of the present disclosure, or a pharmaceutically acceptable salt, polymorph, or solvate thereof, to reduce the symptoms or complications of the disease, medical condition, or disorder, or to eliminate the disease, medical condition, or disorder. The term "treat" can also include treating cells in vitro or treating an animal model. It should be recognized that "treating" or "treatment" includes alleviating the previous symptoms of a medical condition. Thus, "treating" or "treatment" related to a condition, disorder, or disease state includes: (1) preventing or delaying the appearance of clinical symptoms of a condition, disorder, or disease state that may or is likely to be affected by, or susceptible to, the condition, disorder, or disease state, but has not yet experienced or exhibited clinical or pre-clinical symptoms of the condition, disorder, or disease state in a human; (2) inhibiting the condition, disorder, or disease state, i.e., stopping, suppressing, or delaying the development of the disease or its recurrence (in the case of maintenance therapy), or at least one of their clinical or pre-clinical symptoms; or (3) reducing or attenuating the disease, i.e., causing regression of the condition, disorder, or disease state, or at least one of their clinical or pre-clinical symptoms.

[0070] It should be understood that a compound of the present disclosure, or a pharmaceutically acceptable salt, polymorph, or solvate thereof, can be used to prevent a relevant disease, medical condition, or disorder, or to identify a suitable candidate for such purpose, or can be so used.

[0071] As used herein, the terms "preventing", "prevent", or "protecting against" are for the purpose of explaining suppressing or eliminating the onset of symptoms or complications of a disease, medical condition, or disorder.

[0072] Those skilled in the art should understand that they can refer to the well-known techniques described herein or general references regarding the detailed description of techniques equivalent thereto. Such documents include Ausubel et al., Current Protocols in Molecular Biology, John Wiley and Sons, Inc. (2005), Sambrook et al., Molecular Cloning, A Laboratory Manual (3 rd edition), Cold Spring Harbor Press, Cold Spring Harbor, New York (2000), Coligan et al., Current Protocols in Immunology, John Wiley & Sons, N.Y., Enna et al., Current Protocols in Pharmacology, John Wiley & Sons, N.Y., Fingl et al., The Pharmacological Basis of Therapeutics (1975), Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, 18 th edition (1990). Of course, these documents can be referred to in creating or using an aspect of the present disclosure.

[0073] It should also be understood that the present disclosure provides a pharmaceutical composition comprising a combination of any of the compounds described herein and at least one pharmaceutically acceptable excipient or carrier.

[0074] As used herein, the term "pharmaceutical composition" refers to a formulation containing a compound of the present disclosure in a form suitable for administration to a subject. In certain embodiments, the pharmaceutical composition is in bulk or unit dosage form. The unit dosage form can be in any of a variety of forms, for example, capsules, infusion bags, tablets, a single pump in an aerosol inhaler, or vials. The amount of the active ingredient (e.g., a formulation of the disclosed compound, or a salt, hydrate, solvate, or isomer thereof) in the unit dosage form of the composition is an effective amount and varies depending on the particular treatment involved. One of ordinary skill in the art will recognize that it is sometimes necessary to routinely vary the dosage according to the age and condition of the patient. The dosage also depends on the route of administration. A variety of routes of administration are contemplated, such as oral, intralung, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalation, buccal, sublingual, intrapleural, intrathecal, intranasal, and the like. Dosage forms for topical or transdermal administration of the compounds of the present disclosure include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. In certain embodiments, the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and any necessary preservatives, buffers, or propellants.

[0075] As used herein, the term "pharmaceutically acceptable" refers to compounds, anions, cations, materials, compositions, carriers, and / or dosage forms that are suitable for use in contact with human and animal tissues within the scope of sound medical judgment, that are not unduly toxic, irritating, allergic, or cause other problems or complications, and that provide a reasonable benefit / risk ratio.

[0076] As used herein, the term "pharmaceutically acceptable excipient" generally means an excipient that is safe, non-toxic, and useful in preparing a pharmaceutically acceptable composition that is also biologically and otherwise desirable, and includes excipients acceptable for veterinary use and pharmaceutical use in humans. As used in this specification and the claims, "pharmaceutically acceptable excipient" includes both a single such excipient and two or more such excipients.

[0077] It should be understood that the pharmaceutical compositions of the present disclosure are formulated to be compatible with the intended route of administration. Examples of routes of administration include parenteral administration, such as intravenous administration, intradermal administration, subcutaneous administration, oral (e.g., oral ingestion) administration, inhalation administration, transdermal (topical) administration, and transmucosal administration. Solutions or suspensions for parenteral, intradermal, or subcutaneous application can contain the following components: sterile diluents such as water for injection, saline, fixed oils, polyethylene glycols, glycerin, propylene glycol, or other synthetic solvents, antibacterial agents such as benzyl alcohol or methylparaben, antioxidants such as ascorbic acid or sodium bisulfite, chelating agents such as ethylenediaminetetraacetic acid, buffering agents such as acetate, citrate, or phosphate, and osmotic pressure regulators such as sodium chloride or glucose. The pH can be adjusted with an acid or base such as hydrochloric acid or sodium hydroxide. Parenteral formulations can be enclosed in ampoules, disposable syringes, or multi-dose vials made of glass or plastic.

[0078] It should be understood that the compounds or pharmaceutical compositions of the present disclosure can be administered to a subject in a number of well-known current chemotherapeutic treatment methods. For example, the compounds of the present disclosure can be injected into the bloodstream or body cavity, or orally ingested, or applied through the skin with a patch. The dose selected should be sufficient to constitute an effective treatment but not so high as to cause unacceptable side effects. It is preferred to closely monitor the disease state (e.g., the diseases or disorders described herein) and the health of the patient over a significant period during and after treatment.

[0079] As used herein, the term "therapeutically effective amount" means an amount of a medicament that treats, alleviates, or prevents an identified disease or condition, or exhibits a detectable therapeutic or inhibitory effect. This effect can be detected by any assay method known in the art. The exact effective amount for a subject depends on the subject's weight, size, and health status, the nature and extent of the condition, and the therapeutic agent or combination of therapeutic agents selected for administration. The therapeutically effective amount in a given situation can be determined by a given experiment within the skill and judgment of the clinician.

[0080] As used herein, the term "therapeutically effective amount" means an amount of a medicament that treats or alleviates an identified disease or condition, or exhibits a detectable therapeutic or inhibitory effect. This effect can be detected by any assay method known in the art. The exact effective amount for a subject depends on the subject's weight, size, and health status, the nature and extent of the condition, and the therapeutic agent or combination of therapeutic agents selected for administration. The therapeutically effective amount in a given situation can be determined by a given experiment within the skill and judgment of the clinician.

[0081] It should be understood that for any compound, first, a therapeutically effective amount can be estimated initially in cell culture assays, such as assays in neonatal cells, or in animal models, usually any of rats, mice, rabbits, dogs, or pigs. Also, the animal models can be used to determine the appropriate concentration range and route of administration. This information can then be used to determine useful dosages and routes of administration in human administration. Therapeutic / preventive efficacy, and toxicity can be determined in cell culture, or in experimental animals by standard formulation procedures, such as ED 50 (therapeutically effective dose in 50% of the population) and LD 50 (lethal dose in 50% of the population). The dose ratio between the toxic effect and the therapeutic effect is referred to as the therapeutic index, which can be expressed as the LD 50 / ED 50 ratio. Pharmaceutical compositions with a large therapeutic index are preferred. The dosage can vary within this range depending on the dosage form used, the sensitivity of the patient, and the route of administration.

[0082] The dosage and administration are adjusted to provide a sufficient level of active agent(s) or to maintain the desired effect. Factors that can be taken into consideration include the severity of the disease state, the overall health of the subject, the age, weight, and sex of the subject, diet, time and frequency of administration, drug combination(s), response sensitivity, and tolerance / response to treatment. The long-acting pharmaceutical composition can be administered once every 3 - 4 days, weekly, or once every two weeks depending on the half-life and clearance rate of the particular formulation.

[0083] The pharmaceutical composition containing the active compound of the present disclosure can be manufactured by generally known methods, for example, conventional mixing, dissolving, granulating, tablet coating, wet milling, emulsifying, encapsulating, enclosing, or freeze-drying processes. One or more pharmaceutically acceptable carriers including excipients and / or adjuvants that facilitate the introduction of the active compound into a pharmaceutically usable formulation can be used to formulate the pharmaceutical composition by conventional methods. Naturally, the appropriate formulation varies depending on the route of administration selected.

[0084] Suitable pharmaceutical compositions for injection include sterile aqueous solutions (in the case of water-soluble substances), aqueous dispersions, and sterile powders for the immediate preparation of sterile injectable solutions or dispersions. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL (trademark) (BASF, Parsippany, N.J.), or phosphate-buffered saline (PBS). In any case, the composition must be sterile and must be fluid to the extent that it allows easy injection into a syringe. The composition must be stable under the manufacturing and storage conditions and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium including, for example, water, ethanol, polyols (such as glycerin, propylene glycol, and liquid polyethylene glycol), and suitable mixtures thereof. Moderate fluidity can be maintained, for example, by the use of coatings such as lecithin, by maintaining the required particle size in the case of dispersions, and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In most cases, it is preferred to include in the composition isotonic agents such as sugars, polyhydric alcohols such as mannitol and sorbitol, and sodium chloride. Prolonged absorption of the injectable composition can be achieved by including in the composition agents that delay absorption, for example, aluminum monostearate and gelatin.

[0085] Sterile injectable solutions can be prepared by filtering the sterile required amount of the active compound into a suitable solvent, optionally with one or a combination of the above-mentioned components. Generally, dispersions are prepared by introducing the active compound into a sterile medium containing a basic dispersion medium and the other necessary components mentioned above. In the case of sterile powders for the preparation of sterile injectable solutions, methods of preparation include vacuum drying and freeze-drying, by which a powder of the active ingredient and further desired components is produced from a solution containing those components that have been pre-sterile filtered.

[0086] Oral compositions generally include an inert diluent or a pharmaceutically acceptable edible carrier. The oral compositions can be encapsulated in gelatin capsules or compressed into tablets. For the purpose of therapeutic oral administration, the active compounds can be combined with excipients and used in the form of tablets, troches, or capsules. Also, oral compositions can be prepared using a fluid carrier for use as a mouthwash, and the fluid carrier containing the compound can be orally administered, rinsed, and then spat out or swallowed. Pharmaceutically compatible binders and / or auxiliary materials can be included as part of the composition. Tablets, pills, capsules, troches, etc. can contain the following components: binders such as crystalline cellulose, tragacanth gum, or gelatin, excipients such as starch or lactose, disintegrants such as alginic acid, Primogel, or corn starch, lubricants such as magnesium stearate or Sterotes, flow promoters such as colloidal silicon dioxide, sweeteners such as sucrose or saccharin, or flavoring agents such as peppermint, methyl salicylate, or orange flavor, or any compound of similar nature.

[0087] For administration by inhalation, the compound is delivered in the form of an aerosol spray from a suitable pressurized container or dispenser containing a propellant, such as a gas like carbon dioxide, or a nebulizer.

[0088] Systemic administration can be by transmucosal or transdermal means. For transmucosal or transdermal administration, permeation enhancers suitable for the permeable barrier are used in the formulation. Such permeation enhancers are generally known in the art and include, for example, surfactants, bile salts, and fusidic acid derivatives for transmucosal administration. Transmucosal administration can be achieved through the use of nasal sprays or suppositories. For transdermal administration, the active compound is formulated as an ointment, liniment, gel, or cream generally known in the art.

[0089] The active compounds can be prepared using a pharmaceutically acceptable carrier that protects the compound against rapid elimination from the body, such as a controlled release formulation that includes a graft and a microencapsulation delivery system. Biodegradable, biocompatible polymers such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid can be used. Methods for preparing these formulations are apparent to those skilled in the art. Materials can also be obtained commercially from Alza Corporation and Nova Pharmaceuticals, Inc. Liposome suspensions (including liposomes that target infected cells having monoclonal antibodies against viral antigens) can also be used as a pharmaceutically acceptable carrier. These can be prepared by methods known to those skilled in the art, for example, according to the description in U.S. Patent No. 4,522,811.

[0090] Since administration is easy and the dosage is uniform, it is particularly advantageous to formulate an oral composition or a parenteral composition in unit dosage form. As used herein, the unit dosage form refers to a physically discrete unit suitable for unit dosage forms for the subject to be treated, and each unit is associated with the required pharmaceutical carrier and contains a predetermined amount of the active compound calculated to produce the desired therapeutic effect. The specifications of the unit dosage forms of the present disclosure are determined by, and directly dependent on, the properties inherent in the active compound and the particular therapeutic effect to be achieved.

[0091] For therapeutic use, the dosage of the pharmaceutical composition used in accordance with the present disclosure will vary according to factors that influence the dosage selected, and in particular, among other factors, the active substance, the age, weight, and clinical condition of the recipient patient, and the experience and judgment of the clinician or practitioner in charge of the treatment. Generally, the dosage should be sufficient to delay, preferably regress, and preferably cause complete regression of the symptoms of the disease or disorder described herein. The dosage can range from about 0.01 mg / kg / day to about 5000 mg / kg / day. In a preferred embodiment, the dosage can range from about 1 mg / kg / day to about 1000 mg / kg / day. In one embodiment, the dosage can be in a single dose, divided doses, or a continuous dose, in the range of about 0.1 mg / day to about 50 g / day, about 0.1 mg / day to about 25 g / day, about 0.1 mg / day to about 10 g / day, about 0.1 mg to about 3 g / day, or about 0.1 mg to about 1 g / day (this dosage can be adjusted according to the patient's body weight in kg, body surface area in m 2 2, and age). The effective amount of the medicament is the amount recognized by a clinician or other qualified observer, i.e., the amount that achieves an objectively identifiable improvement. Improvement in survival rate and growth rate indicates regression. As used herein, the term "dosage effective manner" refers to the amount of an active compound that elicits a desired biological effect in a subject or cell.

[0092] It should be understood that the pharmaceutical composition can be contained in a container, pack, or dispenser together with instructions for administration.

[0093] It should be understood that for the compounds of the present disclosure that can further form salts, all these forms are also intended to be within the scope of the claimed present disclosure.

[0094] As used herein, the term "pharmaceutically acceptable salt" means a derivative of a compound of the present disclosure in which the parent compound has been modified by forming its acidic or basic salt. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic salts of basic residues such as amines, and alkali or organic salts of acidic residues such as carboxylic acids. Pharmaceutically acceptable salts include conventional non-toxic salts, or quaternary ammonium salts of the parent compound formed from, for example, non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include salts derived from inorganic and organic acids selected from, but not limited to, 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, bicarbonate, carbonic acid, citric acid, edetic acid, ethanedisulfonic acid, 1,2-ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, glycolylarsanilic acid, hexylresorcinol, hydrabamic acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, hydroxymaleic acid, hydroxynaphthoic acid, isethionic acid, lactic acid, lactobionic acid, laurylsulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, naphthylic acid, nitric acid, oxalic acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, polygalacturonic acid, propionic acid, salicylic acid, stearic acid, subacetic acid, succinic acid, sulfamic acid, sulfanilic acid, sulfuric acid, tannic acid, tartaric acid, toluenesulfonic acid, and commonly occurring amino acids such as glycine, alanine, phenylalanine, arginine, etc.

[0095] In some embodiments, the pharmaceutically acceptable salt is a sodium salt, potassium salt, calcium salt, magnesium salt, diethylamine salt, choline salt, meglumine salt, benzathine salt, tromethamine salt, ammonia salt, arginine salt, or lysine salt.

[0096] Other examples of pharmaceutically acceptable salts include hexanoic acid, cyclopentanepropionic acid, pyruvic acid, malonic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo-[2.2.2]-oct-2-ene-1-carboxylic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, muconic acid, and the like. It is understood that the present disclosure also includes salts formed when the acidic proton present in the parent compound is replaced by a metal ion, such as an alkali metal ion, an alkaline earth ion, or an aluminum ion, or coordinated to an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like. In salt form, the ratio of the compound to the cation or anion of the salt can be 1:1 or any ratio other than 1:1, such as 3:1, 2:1, 1:2, or 1:3.

[0097] It is understood that all descriptions regarding pharmaceutically acceptable salts include solvate forms (solvates) or crystal forms (polymorphs) as defined herein for the same salt.

[0098] The compound or its pharmaceutically acceptable salt is administered orally, nasally, transdermally, intralungally, by inhalation, buccally, sublingually, intraperitoneally, subcutaneously, intramuscularly, intravenously, rectally, intrapleurally, intrathecally, and parenterally. In certain embodiments, the compound is administered orally. One of ordinary skill in the art will recognize the advantages associated with a particular route of administration.

[0099] The dosing regimen using the compound is selected according to various factors including the patient type, species, age, weight, gender, and medical condition, the severity of the condition being treated, the route of administration, the patient's renal and hepatic function, and the specific compound or its salt being used. A physician or veterinarian of ordinary skill can readily determine and prescribe an effective amount of the medicament necessary to prevent, combat, or arrest the progression of a condition. A physician or veterinarian of ordinary skill can readily determine and prescribe an effective amount of the medicament necessary to combat or arrest the progression of a condition.

[0100] The techniques for formulation and administration of the compounds disclosed in this disclosure can be found in Remington: the Science and Practice of Pharmacy, 19 th edition, Mack Publishing Co., Easton, PA (1995). In certain embodiments, the compounds described herein, and their pharmaceutically acceptable salts, are used in pharmaceutical formulations in combination with a pharmaceutically acceptable carrier or diluent. Suitable pharmaceutically acceptable carriers include inert solid fillers, or inert solid diluents, and sterile aqueous solutions or sterile organic solutions. The compound is present in such pharmaceutical compositions in an amount sufficient to provide the desired dosage within the ranges described herein.

[0101] All percentages and ratios used herein are by weight unless otherwise indicated. Other features and advantages of the disclosure will become apparent from the different examples. The provided examples illustrate different components and methodologies useful in practicing the disclosure. The examples do not limit the claimed disclosure. One of ordinary skill in the art can identify and use other components and methodologies useful in practicing the disclosure based on the disclosure.

[0102] In the synthetic schemes described herein, for the sake of simplicity, compounds may be depicted in one specific configuration. Such a specific configuration should not be construed as limiting the present disclosure to one or the other of the enantiomers, tautomers, positional isomers, or stereoisomers, nor as excluding mixtures of enantiomers, tautomers, positional isomers, or stereoisomers. However, it should be understood that a given enantiomer, tautomer, positional isomer, or stereoisomer may exhibit a higher level of activity than another enantiomer, tautomer, positional isomer, or stereoisomer.

[0103] All publications and patent documents cited herein are hereby incorporated by reference in their entirety as if each individual publication or document were specifically and individually set forth herein. In citing publications and patent documents, there is no intention to recognize any of them as relevant prior art, nor is there any intention to approve their content or date. Since the present invention is described and explained herein, those skilled in the art will recognize that the present invention is capable of being practiced in various embodiments, and that the foregoing description and the following examples are for illustrative purposes only and are not intended to limit the scope of the appended claims.

[0104] As used herein, the term "compounds of the present disclosure" means both compounds generally disclosed herein and compounds specifically disclosed herein.

[0105] Compounds of the present disclosure In some embodiments, the present disclosure provides, inter alia, compounds of formula (I): TIFF0007682813000017.tif21128 compounds, or prodrugs, solvates, or pharmaceutically acceptable salts thereof, wherein: R 1 is C 3 -C 16 cycloalkyl or C 5 -C 10 aryl, and the C 3 -C 16Cycloalkyl or C 5 -C 10 Aryl is substituted with one or more R 1S ; Each R 1S is independently halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 2 is C 1 -C 6 alkyl or C 3 -C 16 cycloalkyl, and the C 1 -C 6 alkyl or C 3 -C 16 cycloalkyl may be substituted with one or more R 2S ; Each R 2S is independently halo, -CN, -OH, -O(C 1 -C 6 alkyl), -NH 2 , -NH(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 , or oxo, and the C 1 -C 6 alkyl may be substituted with one or more 3- to 8-membered heterocycloalkyl; R 3 is 7- to 12-membered heterocycloalkyl or 5- or 6-membered heteroaryl, and the 7- to 12-membered heterocycloalkyl or 5- or 6-membered heteroaryl may be substituted with one or more R 3S ; and Each R 3S is independently halo, C 1 -C 6 alkyl, C 1 -C 6Haloalkyl, C 3 -C 8 Cycloalkyl, or 3- to 8-membered heterocycloalkyl, wherein the C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 3 -C 8 Cycloalkyl, or 3- to 8-membered heterocycloalkyl may be substituted with one or more halo, -CN, -OH, -O(C 1 -C 6 Alkyl), -NH 2 , -NH(C 1 -C 6 Alkyl), or -N(C 1 -C 6 Alkyl) 2 and may be optionally substituted.

[0106] In some embodiments, the present disclosure provides a compound of formula (I), or a prodrug, solvate, or pharmaceutically acceptable salt thereof, wherein: R 1 is C 3 -C 16 Cycloalkyl; R 2 is C 1 -C 6 Alkyl or C 3 -C 16 Cycloalkyl, wherein the C 1 -C 6 Alkyl or C 3 -C 16 Cycloalkyl may be optionally substituted with one or more R 2S ; Each R 2S is independently -OH, -O(C 1 -C 6 Alkyl), or -N(C 1 -C 6 Alkyl) 2 wherein the C 1 -C 6 Alkyl may be optionally substituted with one or more 3- to 8-membered heterocycloalkyl; R 3 is one or more C1 -C 6 is a 5- or 6-membered heteroaryl optionally substituted with alkyl.

[0107] In some embodiments, the disclosure provides a compound of formula (I), or a prodrug, solvate, or pharmaceutically acceptable salt thereof, wherein: R 1 is C 3 -C 16 cycloalkyl or C 5 -C 10 aryl, and the C 3 -C 16 cycloalkyl or C 5 -C 10 aryl may be substituted with one or more R 1S ; Each R 1S is independently halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 2 is C 1 -C 6 alkyl or C 3 -C 16 cycloalkyl, and the C 1 -C 6 alkyl or C 3 -C 16 cycloalkyl may be substituted with one or more R 2S ; Each R 2S is independently halo, -CN, -OH, -O(C 1 -C 6 alkyl), -NH 2 , -NH(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 , or oxo; R3 is a 7- to 12-membered heterocycloalkyl or a 5- or 6-membered heteroaryl, and the 7- to 12-membered heterocycloalkyl or 5- or 6-membered heteroaryl is optionally substituted with one or more R 3S ; and each R 3S is independently halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, or a 3- to 8-membered heterocycloalkyl, and the C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, or a 3- to 8-membered heterocycloalkyl is optionally substituted with one or more halo, -CN, -OH, -O(C 1 -C 6 alkyl), -NH 2 , -NH(C 1 -C 6 alkyl), or -N(C 1 -C 6 alkyl) 2 .

[0108] For the compound of formula (I), R 1 , R 1S , R 2 , R 2S , R 3 , and R 3S can each independently be selected from the groups described herein, where applicable, and for any of R 1 , R 1S , R 2 , R 2S , R 3 , and R 3S any of the groups described herein, where applicable, R 1 , R 1S , R 2 , R 2S , R 3 , and R3S It should be understood that it can be combined with any of the groups described herein with respect to one or more of the remainder.

[0109] In some embodiments, R 1 is C 3 -C 16 cycloalkyl or C 5 -C 10 aryl, and the C 3 -C 16 cycloalkyl or C 5 -C 10 aryl may be substituted with one or more R 1S .

[0110] In some embodiments, R 1 is C 3 -C 16 cycloalkyl or C 5 -C 10 aryl, and the C 3 -C 16 cycloalkyl or C 5 -C 10 aryl is substituted with one or more R 1S .

[0111] In some embodiments, R 1 is C 3 -C 16 cycloalkyl or C 5 -C 10 aryl, and the C 3 -C 16 cycloalkyl or C 5 -C 10 aryl is unsubstituted.

[0112] In some embodiments, R 1 is C 1S -C 3 -C 16 cycloalkyl which may be substituted with one or more R

[0113] In some embodiments, R 1 is C 3 -C8 A monocyclic cycloalkyl or C 8 -C 16 is a polycyclic cycloalkyl, and the C 3 -C 8 A monocyclic cycloalkyl or C 8 -C 16 The polycyclic cycloalkyl may be substituted with one or more R 1S .

[0114] In some embodiments, R 1 is a C 3 -C 7 A monocyclic cycloalkyl or C 8 -C 16 is a polycyclic cycloalkyl, and the C 3 -C 7 A monocyclic cycloalkyl or C 8 -C 16 The polycyclic cycloalkyl may be substituted with one or more R 1S .

[0115] In some embodiments, R 1 is a C 3 -C 7 A monocyclic cycloalkyl, C 9 -C 10 A bicyclic cycloalkyl, or C 12 -C 16 is a tricyclic cycloalkyl, and the C 3 -C 7 A monocyclic cycloalkyl, C 9 -C 10 A bicyclic cycloalkyl, or C 12 -C 16 The tricyclic cycloalkyl may be substituted with one or more R 1S .

[0116] In some embodiments, R 1 is a C 3 -C 7 monocyclic cycloalkyl.

[0117] In some embodiments, R 1 is a C 1S monocyclic cycloalkyl which may be substituted with one or more R3 -C 7 is a monocyclic cycloalkyl.

[0118] In some embodiments, R 1 is optionally substituted with one or more R 1S and is a monocyclic saturated cycloalkyl C 3 -C 7

[0119] In some embodiments, R 1 is optionally substituted with one or more R 1S and is a monocyclic partially saturated cycloalkyl C 5 -C 7

[0120] In some embodiments, R 1 is cyclopentyl, cyclohexyl, or cycloheptyl, and the cyclopentyl, cyclohexyl, or cycloheptyl is optionally substituted with one or more R 1S

[0121] In some embodiments, R 1 is cyclopentyl, cyclohexyl, or cycloheptyl.

[0122] In some embodiments, R 1 is C 8 -C 16 and is a polycyclic cycloalkyl.

[0123] In some embodiments, R 1 is substituted with one or more R 1S and is a polycyclic cycloalkyl C 8 -C 16

[0124] In some embodiments, R 1 is substituted with one R 1S and is a polycyclic cycloalkyl C 8 -C 16

[0125] In some embodiments, R​​​​​1 is C replaced by two Rs 1S -C 8 -C 16 which is a polycyclic cycloalkyl.

[0126] In some embodiments, R 1 is C replaced by three Rs 1S -C 8 -C 16 which is a polycyclic cycloalkyl.

[0127] In some embodiments, R 1 is unsubstituted C 6 -C 10 which is a bicyclic cycloalkyl.

[0128] In some embodiments, R 1 is C 6 -C 10 which is a bicyclic cycloalkyl.

[0129] In some embodiments, R 1 is C which may be substituted by one or more Rs 1S -C 6 -C 10 which is a bicyclic cycloalkyl.

[0130] In some embodiments, R 1 is C which may be substituted by one or more Rs 1S -C 6 -C 10 which is a bicyclic saturated cycloalkyl.

[0131] In some embodiments, R 1 is C which may be substituted by one or more Rs 1S -C 6 -C 10 which is a bicyclic partially saturated cycloalkyl.

[0132] In some embodiments, R 1 is unsubstituted C 12 -C 16 which is a tricyclic cycloalkyl.

[0133] In some embodiments, R 1 is C 12 -C 16 which is a tricyclic cycloalkyl.

[0134] In some embodiments, R 1 is C 1S -C 12 which may be substituted with one or more R 16 and is a tricyclic cycloalkyl.

[0135] In some embodiments, R 1 is C 1S -C 12 which may be substituted with one or more R 16 and is a tricyclic saturated cycloalkyl.

[0136] In some embodiments, R 1 is C 1S -C 12 which may be substituted with one or more R 16 and is a tricyclic partially unsaturated cycloalkyl.

[0137] In some embodiments, R 1 is C 1S -C 12 which is substituted with one or more R 16 and is a tricyclic cycloalkyl.

[0138] In some embodiments, R 1 is C 1S -C 12 which is substituted with one or more R 16 and is a tricyclic saturated cycloalkyl.

[0139] In some embodiments, R 1 is C 1S -C 12 which is substituted with one or more R 16 and is a tricyclic partially unsaturated cycloalkyl.

[0140] In some embodiments, R 1 is a single R 1SC replaced by 12 -C 16 is a tricyclic cycloalkyl.

[0141] In some embodiments, R 1 is C substituted with one R 1S -C 12 -C 16 is a tricyclic saturated cycloalkyl.

[0142] In some embodiments, R 1 is C substituted with one R 1S -C 12 -C 16 is a tricyclic partially unsaturated cycloalkyl.

[0143] In some embodiments, R 1 is C substituted with two Rs 1S -C 12 -C 16 is a tricyclic cycloalkyl.

[0144] In some embodiments, R 1 is C substituted with two Rs 1S -C 12 -C 16 is a tricyclic saturated cycloalkyl.

[0145] In some embodiments, R 1 is C substituted with two Rs 1S -C 12 -C 16 is a tricyclic partially unsaturated cycloalkyl.

[0146] In some embodiments, R 1 is C substituted with three Rs 1S -C 12 -C 16 is a tricyclic cycloalkyl.

[0147] In some embodiments, R 1 is C substituted with three Rs 1S -C 12 -C 16 is a tricyclic saturated cycloalkyl.

[0148] In some embodiments, R 1 is a C 1S -C 12 -C 16 tricyclic partially unsaturated cycloalkyl substituted with three Rs.

[0149] In some embodiments, R 1 is a hexahydroindenyl which may be substituted with one or more Rs. 1S

[0150] In some embodiments, R 1 is hexahydroindenyl.

[0151] In some embodiments, R 1 is TIFF0007682813000018.tif36128, where n and n a are each independently 0, 1, 2, or 3.

[0152] In some embodiments, R 1 is TIFF0007682813000019.tif36128, where n and n a are each independently 0, 1, 2, or 3.

[0153] In some embodiments, R 1 is TIFF0007682813000020.tif34128, where n and n a are each independently 0, 1, 2, or 3.

[0154] In some embodiments, R 1 is TIFF0007682813000021.tif34128, where n and n a are each independently 0, 1, 2, or 3.

[0155] In some embodiments, R 1 is TIFF0007682813000022.tif36128, where n and n a are each independently 0, 1, 2, or 3, and R 1S is halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy.

[0156] In some embodiments, R 1 is TIFF0007682813000023.tif34128, where n and n a are each independently 0, 1, 2, or 3, and R 1S is halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy.

[0157] In some embodiments, R 1 is TIFF0007682813000024.tif25128.

[0158] In some embodiments, R 1 is TIFF0007682813000025.tif26128.

[0159] In some embodiments, R 1 is TIFF0007682813000026.tif26128, where R 1S is halo, C 1 -C 6Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, or C 1 -C 6 is haloalkoxy.

[0160] In some embodiments, R 1 is TIFF0007682813000027.tif25128.

[0161] In some embodiments, R 1 is TIFF0007682813000028.tif25128, wherein R 1S is halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 is haloalkoxy.

[0162] In some embodiments, R 1 is halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 is hexahydroindenyl optionally substituted with one, two, three, or four substituents independently selected from halo, C

[0163] In some embodiments, R 1 is unsubstituted hexahydroindenyl.

[0164] In some embodiments, R 1 is TIFF0007682813000029.tif25128.

[0165] In some embodiments, R 1 is unsubstituted C 5 -C 10 aryl.

[0166] In some embodiments, R 1 is C 5 -C 10 aryl.

[0167] In some embodiments, R 1 is C 1S -C 5 -C 10 aryl which may be substituted with one or more R

[0168] In some embodiments, R 1 is C 1S -C 5 -C 10 aryl which is substituted with one or more R

[0169] In some embodiments, R 1 is C 1S -C 5 -C 10 aryl which is substituted with one R

[0170] In some embodiments, R 1 is C 1S -C 5 -C 10 aryl which is substituted with two R

[0171] In some embodiments, R 1 is C 1S -C 5 -C 10 aryl which is substituted with three R

[0172] In some embodiments, R 1 is C 1S -C 5 -C 6 monocyclic aryl which may be substituted with one or more R

[0173] In some embodiments, R 1 is a C 1S -C 5 -C 6 monocyclic aryl substituted with one or more R

[0174] In some embodiments, R 1 is phenyl which may be substituted with one or more R 1S

[0175] In some embodiments, R 1 is phenyl substituted with one or more R 1S

[0176] In some embodiments, R 1 is phenyl substituted with one R 1S

[0177] In some embodiments, R 1 is TIFF0007682813000030.tif24128

[0178] In some embodiments, R 1 is phenyl substituted with two R 1S

[0179] In some embodiments, R 1 is TIFF0007682813000031.tif57128

[0180] In some embodiments, R 1 is phenyl substituted with three R 1S

[0181] In some embodiments, R 1 is TIFF0007682813000032.tif64128

[0182] In some embodiments, R 1 ​​​​​is halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy, and is phenyl substituted with one or more substituents independently selected therefrom.

[0183] In some embodiments, R 1 is unsubstituted naphthalenyl.

[0184] In some embodiments, R 1 is naphthalenyl which may be substituted with one or more R 1S .

[0185] In some embodiments, R 1 is halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy, and is naphthalenyl substituted with one or more substituents independently selected therefrom.

[0186] In some embodiments, R 1 is TIFF0007682813000033.tif22128. In some embodiments, R 1 is TIFF0007682813000034.tif15128. In some embodiments, R 1 is TIFF0007682813000035.tif20128.

[0187] In some embodiments, at least one R 1S is independently halo, C 1 -C 6 alkyl, C 1-C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy.

[0188] In some embodiments, at least one R 1S is, independently, halo. In some embodiments, at least one R 1S is, independently, F, Cl, Br, or I. In some embodiments, at least one R 1S is, independently, F or Cl. In some embodiments, at least one R 1S is, independently, Cl. In some embodiments, at least one R 1S is, independently, F.

[0189] In some embodiments, at least one R 1S is, independently, C 1 -C 6 alkyl or C 1 -C 6 haloalkyl.

[0190] In some embodiments, at least one R 1S is, independently, C 1 -C 6 alkoxy or C 1 -C 6 haloalkoxy.

[0191] In some embodiments, at least one R 1S is, independently, C 1 -C 6 alkyl. In some embodiments, at least one R 1S is, independently, methyl. In some embodiments, at least one R 1S is, independently, ethyl. In some embodiments, at least one R 1S is, independently, propyl. In some embodiments, at least one R 1Sis independently butyl. In some embodiments, at least one R 1S is independently pentyl. In some embodiments, at least one R 1S is independently hexyl. In some embodiments, at least one R 1S is independently isopropyl. In some embodiments, at least one R 1S is independently isobutyl. In some embodiments, at least one R 1S is independently isopentyl. In some embodiments, at least one R 1S is independently isohexyl. In some embodiments, at least one R 1S is independently sec-butyl. In some embodiments, at least one R 1S is independently sec-pentyl. In some embodiments, at least one R 1S is independently sec-hexyl. In some embodiments, at least one R 1S is independently tert-butyl.

[0192] In some embodiments, at least one R 1S is independently C 1 -C 6 haloalkyl. In some embodiments, at least one R 1S is independently halomethyl. In some embodiments, at least one R 1S is independently haloethyl. In some embodiments, at least one R 1S is independently halopropyl. In some embodiments, at least one R 1S is independently halobutyl. In some embodiments, at least one R 1S is independently halopentyl. In some embodiments, at least one R 1S is independently halohexyl.

[0193] In some embodiments, at least one R 1S is independently C 1 -C6 is an alkoxy. In some embodiments, at least one R 1S is independently methoxy. In some embodiments, at least one R 1S is independently ethoxy. In some embodiments, at least one R 1S is independently propoxy. In some embodiments, at least one R 1S is independently butoxy. In some embodiments, at least one R 1S is independently pentyloxy. In some embodiments, at least one R 1S is independently hexyloxy.

[0194] In some embodiments, at least one R 1S is independently C 1 -C 6 haloalkoxy. In some embodiments, at least one R 1S is independently halomethoxy. In some embodiments, at least one R 1S is independently haloethoxy. In some embodiments, at least one R 1S is independently halopropoxy. In some embodiments, at least one R 1S is independently halobutoxy. In some embodiments, at least one R 1S is independently halopentyloxy. In some embodiments, at least one R 1S is independently halohexyloxy.

[0195] In some embodiments, R 2 is C 2S -C 1 -C 6 alkyl which may be substituted with one or more R

[0196] In some embodiments, R 2 is C 2S -C 3 -C 16 cycloalkyl which may be substituted with one or more R

[0197] In some embodiments, R 2 is C 2S -C 1 -C 6 alkyl substituted with one or more R

[0198] In some embodiments, R 2 is C 2S -C 3 -C 16 cycloalkyl substituted with one or more R

[0199] In some embodiments, R 2 is C 2S -C 1 -C 6 alkyl substituted with one R

[0200] In some embodiments, R 2 is C 2S -C 3 -C 16 cycloalkyl substituted with one R

[0201] In some embodiments, R 2 is C 2S -C 1 -C 6 alkyl substituted with two R

[0202] In some embodiments, R 2 is C 2S -C 3 -C 16 cycloalkyl substituted with two R

[0203] In some embodiments, R 2 is C 2S -C 1 -C 6 alkyl substituted with three R

[0204] In some embodiments, R 2 is C 2S -C 3 -C16 It is cycloalkyl.

[0205] In some embodiments, R 2 is unsubstituted C 1 -C 6 alkyl.

[0206] In some embodiments, R 2 is C 1 -C 6 alkyl. In some embodiments, R 2 is methyl. In some embodiments, R 2 is ethyl. In some embodiments, R 2 is propyl. In some embodiments, R 2 is butyl. In some embodiments, R 2 is pentyl. In some embodiments, R 2 is hexyl. In some embodiments, R 2 is isopropyl. In some embodiments, R 2 is isobutyl. In some embodiments, R 2 is isopentyl. In some embodiments, R 2 is isohexyl. In some embodiments, R 2 is sec-butyl. In some embodiments, R 2 is sec-pentyl. In some embodiments, R 2 is sec-hexyl. In some embodiments, R 2 is tert-butyl.

[0207] In some embodiments, R 2 is C 2S -C 1 alkyl which may be substituted with one or more R 6 . In some embodiments, R 2 is methyl which may be substituted with one or more R 2S . In some embodiments, R 2 is ethyl which may be substituted with one or more R 2S . In some embodiments, R2 is propyl which may be substituted with one or more R 2S . In some embodiments, R 2 is butyl which may be substituted with one or more R 2S . In some embodiments, R 2 is pentyl which may be substituted with one or more R 2S . In some embodiments, R 2 is hexyl which may be substituted with one or more R 2S . In some embodiments, R 2 is isopropyl which may be substituted with one or more R 2S . In some embodiments, R 2 is isobutyl which may be substituted with one or more R 2S . In some embodiments, R 2 is isopentyl which may be substituted with one or more R 2S . In some embodiments, R 2 is isohexyl which may be substituted with one or more R 2S . In some embodiments, R 2 is sec-butyl which may be substituted with one or more R 2S . In some embodiments, R 2 is sec-pentyl which may be substituted with one or more R 2S . In some embodiments, R 2 is sec-hexyl which may be substituted with one or more R 2S . In some embodiments, R 2 is tert-butyl which may be substituted with one or more R 2S .

[0208] In some embodiments, R 2 is one or more halo, -CN, -OH, -O(C 1 -C 6 alkyl), -NH 2 , -NH(C 1 -C 6 alkyl), -N(C 1 -C 6 )alkyl 2or C which may be substituted with oxo 1 -C 6 is alkyl.

[0209] In some embodiments, R 2 is one or more halo, -CN, -OH, -O(C 1 -C 6 alkyl), -NH 2 , -NH(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 or ethyl which may be substituted with oxo.

[0210] In some embodiments, R 2 is one halo, -CN, -OH, -O(C 1 -C 6 alkyl), -NH 2 , -NH(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 or ethyl which may be substituted with oxo.

[0211] In some embodiments, R 2 is ethyl which may be substituted with one or more halo. In some embodiments, R 2 is ethyl which may be substituted with one or more -CN. In some embodiments, R 2 is ethyl which may be substituted with one or more -OH. In some embodiments, R 2 is ethyl which may be substituted with one or more -NH 2 . In some embodiments, R 2 is ethyl which may be substituted with one or more -NH(C 1 -C 6 alkyl). In some embodiments, R 2 is ethyl which may be substituted with one or more oxo.

[0212] In some embodiments, R2 is ethyl which may be substituted with one halo. In some embodiments, R 2 is ethyl which may be substituted with one -CN. In some embodiments, R 2 is ethyl which may be substituted with one -OH. In some embodiments, R 2 is ethyl which may be substituted with one -NH 2 . In some embodiments, R 2 is ethyl which may be substituted with one -NH(C 1 -C 6 alkyl). In some embodiments, R 2 is ethyl which may be substituted with one oxo.

[0213] In some embodiments, R 2 is ethyl which may be substituted with one or more -O(C 1 -C 6 alkyl).

[0214] In some embodiments, R 2 is ethyl which may be substituted with one -O(C 1 -C 6 alkyl).

[0215] In some embodiments, R 2 is ethyl which may be substituted with one or more -O(methyl). In some embodiments, R 2 is ethyl which may be substituted with one or more -O(ethyl). In some embodiments, R 2 is ethyl which may be substituted with one or more -O(propyl). In some embodiments, R 2 is ethyl which may be substituted with one or more -O(butyl). In some embodiments, R 2 is ethyl which may be substituted with one or more -O(pentyl). In some embodiments, R 2 is ethyl which may be substituted with one or more -O(hexyl).

[0216] In some embodiments, R 2 is ethyl optionally substituted with one -O(methyl). In some embodiments, R 2 is ethyl optionally substituted with one -O(ethyl). In some embodiments, R 2 is ethyl optionally substituted with one -O(propyl). In some embodiments, R 2 is ethyl optionally substituted with one -O(butyl). In some embodiments, R 2 is ethyl optionally substituted with one -O(pentyl). In some embodiments, R 2 is ethyl optionally substituted with one -O(hexyl).

[0217] In some embodiments, R 2 is ethyl optionally substituted with one or more -N(C 1 -C 6 alkyl) 2 .

[0218] In some embodiments, R 2 is ethyl optionally substituted with one -N(C 1 -C 6 alkyl) 2 .

[0219] In some embodiments, R 2 is ethyl optionally substituted with one or more -N(methyl) 2 . In some embodiments, R 2 is ethyl optionally substituted with one or more -N(ethyl) 2 . In some embodiments, R 2 is ethyl optionally substituted with one or more -N(propyl) 2 . In some embodiments, R 2 is ethyl optionally substituted with one or more -N(butyl) 2 . In some embodiments, R 2 is ethyl optionally substituted with one or more -N(pentyl) 2 . In some embodiments, R2 is ethyl which may be substituted with one or more -N(hexyl) 2

[0220] In some embodiments, R 2 is ethyl which may be substituted with one -N(methyl) 2 2 is ethyl which may be substituted with one -N(ethyl) 2 2 is ethyl which may be substituted with one -N(propyl) 2 2 is ethyl which may be substituted with one -N(butyl) 2 2 is ethyl which may be substituted with one -N(pentyl) 2 2 is ethyl which may be substituted with one -N(hexyl) 2

[0221] In some embodiments, R 2 is propyl which may be substituted with one or more halo, -CN, -OH, -O(C 1 -C 6 alkyl), -NH 2 -, -NH(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2

[0222] In some embodiments, R 2 is propyl which may be substituted with one halo, -CN, -OH, -O(C 1 -C 6 alkyl), -NH 2 -, -NH(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 ​​​​​​​​​

[0223] In some embodiments, R 2 is propyl optionally substituted with two halos, -CN, -OH, -O(C 1 -C 6 alkyl), -NH 2 , -NH(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 , or propyl optionally substituted with oxo.

[0224] In some embodiments, R 2 is propyl optionally substituted with three halos, -CN, -OH, -O(C 1 -C 6 alkyl), -NH 2 , -NH(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 , or propyl optionally substituted with oxo.

[0225] In some embodiments, R 2 is propyl optionally substituted with one or more halos. In some embodiments, R 2 is propyl optionally substituted with one or more -CN. In some embodiments, R 2 is propyl optionally substituted with one or more -OH. In some embodiments, R 2 is propyl optionally substituted with one or more -NH 2 . In some embodiments, R 2 is propyl optionally substituted with one or more -NH(C 1 -C 6 alkyl). In some embodiments, R 2 is propyl optionally substituted with one or more -N(C 1 -C 6 alkyl) 2 . In some embodiments, R 2 is propyl optionally substituted with one or more oxos.

[0226] In some embodiments, R 2 is propyl which may be substituted with one or more -O(C 1 -C 6 alkyl).

[0227] In some embodiments, R 2 is propyl which may be substituted with one or more -O(methyl). In some embodiments, R 2 is propyl which may be substituted with one or more -O(ethyl). In some embodiments, R 2 is propyl which may be substituted with one or more -O(propyl). In some embodiments, R 2 is propyl which may be substituted with one or more -O(butyl). In some embodiments, R 2 is propyl which may be substituted with one or more -O(pentyl). In some embodiments, R 2 is propyl which may be substituted with one or more -O(hexyl).

[0228] In some embodiments, R 2 is isopropyl which may be substituted with one or more halo, -CN, -OH, -O(C 1 -C 6 alkyl), -NH 2 , -NH(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 , or oxo.

[0229] In some embodiments, R 2 is isopropyl which may be substituted with one or more halo. In some embodiments, R 2 is isopropyl which may be substituted with one or more -CN. In some embodiments, R 2 is isopropyl which may be substituted with one or more -OH. In some embodiments, R 2 is isopropyl which may be substituted with one or more -NH2 is isopropyl which may be substituted. In some embodiments, R 2 is isopropyl which may be substituted with one or more -NH(C 1 -C 6 alkyl). In some embodiments, R 2 is isopropyl which may be substituted with one or more -N(C 1 -C 6 alkyl) 2 In some embodiments, R 2 is isopropyl which may be substituted with one or more oxo groups.

[0230] In some embodiments, R 2 is isopropyl which may be substituted with one or more -O(C 1 -C 6 alkyl).

[0231] In some embodiments, R 2 is isopropyl which may be substituted with one or more -O(methyl). In some embodiments, R 2 is isopropyl which may be substituted with one or more -O(ethyl). In some embodiments, R 2 is isopropyl which may be substituted with one or more -O(propyl). In some embodiments, R 2 is isopropyl which may be substituted with one or more -O(butyl). In some embodiments, R 2 is isopropyl which may be substituted with one or more -O(pentyl). In some embodiments, R 2 is isopropyl which may be substituted with one or more -O(hexyl).

[0232] In some embodiments, R 2 is isopropyl which may be substituted with one or more halo, -CN, -OH, -O(C 1 -C 6 alkyl), -NH 2 , -NH(C 1 -C 6 alkyl), -N(C 1 -C6 (alkyl) 2 or isobutyl which may be substituted with oxo.

[0233] In some embodiments, R 2 is one halo, -CN, -OH, -O(C 1 -C 6 alkyl), -NH 2 , -NH(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 or isobutyl which may be substituted with oxo.

[0234] In some embodiments, R 2 is two halos, -CN, -OH, -O(C 1 -C 6 alkyl), -NH 2 , -NH(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 or isobutyl which may be substituted with oxo.

[0235] In some embodiments, R 2 is three halos, -CN, -OH, -O(C 1 -C 6 alkyl), -NH 2 , -NH(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 or isobutyl which may be substituted with oxo.

[0236] In some embodiments, R 2 is isobutyl which may be substituted with one or more halos. In some embodiments, R 2 is isobutyl which may be substituted with one or more -CNs. In some embodiments, R 2is isobutyl which may be substituted with one or more -OH. In some embodiments, R 2 is isobutyl which may be substituted with one or more -NH 2 . In some embodiments, R 2 is isobutyl which may be substituted with one or more -NH(C 1 -C 6 alkyl). In some embodiments, R 2 is isobutyl which may be substituted with one or more -N(C 1 -C 6 alkyl) 2 . In some embodiments, R 2 is isobutyl which may be substituted with one or more oxo groups. In some embodiments, R 2 is isobutyl which may be substituted with one or more -O(C 1 -C 6 alkyl).

[0237] In some embodiments, R 2 is isopentyl which may be substituted with one or more halo, -CN, -OH, -O(C 1 -C 6 alkyl), -NH 2 , -NH(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 , or oxo.

[0238] In some embodiments, R 2 is isopentyl which may be substituted with one halo, -CN, -OH, -O(C 1 -C 6 alkyl), -NH 2 , -NH(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 , or oxo.

[0239] In some embodiments, R 2is isopentyl optionally substituted with two halos, -CN, -OH, -O(C 1 -C 6 -alkyl), -NH 2 , -NH(C 1 -C 6 -alkyl), -N(C 1 -C 6 -alkyl) 2 , or isopentyl optionally substituted with oxo.

[0240] In some embodiments, R 2 is isopentyl optionally substituted with three halos, -CN, -OH, -O(C 1 -C 6 -alkyl), -NH 2 , -NH(C 1 -C 6 -alkyl), -N(C 1 -C 6 -alkyl) 2 , or isopentyl optionally substituted with oxo.

[0241] In some embodiments, R 2 is isopentyl optionally substituted with one or more halos. In some embodiments, R 2 is isopentyl optionally substituted with one or more -CNs. In some embodiments, R 2 is isopentyl optionally substituted with one or more -OHs. In some embodiments, R 2 is isopentyl optionally substituted with one or more -NH 2 . In some embodiments, R 2 is isopentyl optionally substituted with one or more -NH(C 1 -C 6 -alkyl). In some embodiments, R 2 is isopentyl optionally substituted with one or more -N(C 1 -C 6 -alkyl) 2 . In some embodiments, R 2 is isopentyl optionally substituted with one or more oxos. In some embodiments, R 2 is isopentyl optionally substituted with one or more -O(C1 -C 6 is isopentyl which may be substituted with (alkyl).

[0242] In some embodiments, R 2 is unsubstituted C 3 -C 16 cycloalkyl.

[0243] In some embodiments, R 2 is C 2S -C 3 -C 16 cycloalkyl which may be substituted with one or more R

[0244] In some embodiments, R 2 is one or more halo, -CN, -OH, -O(C 1 -C 6 alkyl), -NH 2 -, -NH(C 1 -C 6 alkyl), -N(C 1 -C 6 )(alkyl) 2 or C 3 -C 16 cycloalkyl which may be substituted with oxo.

[0245] In some embodiments, R 2 is C 3 -C 8 monocyclic cycloalkyl or C 8 -C 16 polycyclic cycloalkyl, and the C 3 -C 8 monocyclic cycloalkyl or C 8 -C 16 polycyclic cycloalkyl may be substituted with one or more R 2S .

[0246] In some embodiments, R 2 is C 3 -C 7 monocyclic cycloalkyl or C 8 -C 16It is a polycyclic cycloalkyl, and the C 3 -C 8 monocyclic cycloalkyl or C 8 -C 16 The polycyclic cycloalkyl may be substituted with one or more R 2S .

[0247] In some embodiments, R 2 is C 3 -C 7 monocyclic cycloalkyl, C 9 -C 10 bicyclic cycloalkyl, or C 12 -C 16 tricyclic cycloalkyl, and the C 3 -C 7 monocyclic cycloalkyl, C 9 -C 10 bicyclic cycloalkyl, or C 12 -C 16 tricyclic cycloalkyl may be substituted with one or more R 2S .

[0248] In some embodiments, R 2 is C 3 -C 7 monocyclic cycloalkyl.

[0249] In some embodiments, R 2 is C 2S monocyclic cycloalkyl which may be substituted with one or more R 3 -C 7 .

[0250] In some embodiments, R 2 is C 1S monocyclic cycloalkyl which may be substituted with one or more R 3 -C 7 monocyclic saturated cycloalkyl.

[0251] In some embodiments, R 2 is C 2S monocyclic cycloalkyl which may be substituted with one or more R 5 -C 7It is a monocyclic partially saturated cycloalkyl.

[0252] In some embodiments, R 2 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, and the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl may be substituted with one or more R 2S .

[0253] In some embodiments, R 2 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl.

[0254] In some embodiments, R 2 is cyclobutyl.

[0255] In some embodiments, R 2 is cyclobutyl which may be substituted with one or more R 2S .

[0256] In some embodiments, R 2 is cyclobutyl which may be substituted with one or more halo, -CN, -OH, -O(C 1 -C 6 alkyl), -NH 2 , -NH(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 , or oxo.

[0257] In some embodiments, R 2 is cyclobutyl which may be substituted with one or more halo. In some embodiments, R 2 is cyclobutyl which may be substituted with one or more -CN. In some embodiments, R 2 is cyclobutyl which may be substituted with one or more -OH. In some embodiments, R 2 is cyclobutyl which may be substituted with one or more -NH 2is cyclobutyl which may be substituted. In some embodiments, R 2 is cyclobutyl which may be substituted with one or more -NH(C 1 -C 6 alkyl). In some embodiments, R 2 is cyclobutyl which may be substituted with one or more oxo. In some embodiments, R 2 is cyclobutyl which may be substituted with one or more -O(C 1 -C 6 alkyl).

[0258] In some embodiments, R 2 is cyclobutyl which may be substituted with one or more -N(C 1 -C 6 alkyl) 2 In some embodiments, R

[0259] is cyclobutyl which may be substituted with one or more -N(methyl) 2 In some embodiments, R 2 is cyclobutyl which may be substituted with one or more -N(ethyl) 2 In some embodiments, R 2 is cyclobutyl which may be substituted with one or more -N(propyl) 2 In some embodiments, R 2 is cyclobutyl which may be substituted with one or more -N(butyl) 2 In some embodiments, R 2 is cyclobutyl which may be substituted with one or more -N(pentyl) 2 In some embodiments, R 2 is cyclobutyl which may be substituted with one or more -N(hexyl) 2 In some embodiments, R 2 is cyclobutyl which may be substituted with one or more -N(hexyl).

[0260] In some embodiments, R 2 is cyclopentyl.

[0261] In some embodiments, R2 is cyclopentyl which may be substituted with one or more R 2S s.

[0262] In some embodiments, R 2 is cyclopentyl which may be substituted with one or more halo, -CN, -OH, -O(C 1 -C 6 alkyl), -NH 2 , -NH(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 , or oxo.

[0263] In some embodiments, R 2 is cyclopentyl which may be substituted with one or more halo. In some embodiments, R 2 is cyclopentyl which may be substituted with one or more -CN. In some embodiments, R 2 is cyclopentyl which may be substituted with one or more -OH. In some embodiments, R 2 is cyclopentyl which may be substituted with one or more -NH 2 s. In some embodiments, R 2 is cyclopentyl which may be substituted with one or more -NH(C 1 -C 6 alkyl). In some embodiments, R 2 is cyclopentyl which may be substituted with one or more oxo. In some embodiments, R 2 is cyclopentyl which may be substituted with one or more -O(C 1 -C 6 alkyl).

[0264] In some embodiments, R 2 is cyclopentyl which may be substituted with one or more -N(C 1 -C 6 alkyl) 2 s.

[0265] In some embodiments, R 2 is cyclopentyl which may be substituted with one or more -N(methyl) 2 . In some embodiments, R 2 is cyclopentyl which may be substituted with one or more -N(ethyl) 2 . In some embodiments, R 2 is cyclopentyl which may be substituted with one or more -N(propyl) 2 . In some embodiments, R 2 is cyclopentyl which may be substituted with one or more -N(butyl) 2 . In some embodiments, R 2 is cyclopentyl which may be substituted with one or more -N(pentyl) 2 . In some embodiments, R 2 is cyclopentyl which may be substituted with one or more -N(hexyl) 2 .

[0266] In some embodiments, R 2 is a polycyclic cycloalkyl substituted with one or more R 2S . 8 -C 16

[0267] In some embodiments, R 2 is a bicyclic cycloalkyl 6 -C 10 .

[0268] In some embodiments, R 2 is a bicyclic cycloalkyl which may be substituted with one or more R 2S . 6 -C 10

[0269] In some embodiments, R 2 is a bicyclic saturated cycloalkyl which may be substituted with one or more R 2S . 6 -C 10

[0270] ​​​In some embodiments, R 2 is a C 2S -C 6 -C 10 bicyclic partially saturated cycloalkyl which may be substituted with one or more R

[0271] In some embodiments, R 2 is a C 12 -C 16 tricyclic cycloalkyl

[0272] In some embodiments, R 2 is a C 2S -C 12 -C 16 tricyclic cycloalkyl which may be substituted with one or more R

[0273] In some embodiments, R 2 is a C 2S -C 12 -C 16 tricyclic saturated cycloalkyl

[0274] In some embodiments, R 2 is a C 2S -C 12 -C 16 tricyclic partially unsaturated cycloalkyl

[0275] In some embodiments, R 2 is a C 8 -C 16 polycyclic cycloalkyl

[0276] In some embodiments, R 2 is a C 2S -C 8 -C 16 polycyclic cycloalkyl which is substituted with one or more R

[0277] In some embodiments, R 2 is TIFF0007682813000036.tif48128

[0278] In some embodiments, R 2 is TIFF0007682813000037.tif24136.

[0279] In some embodiments, R 2 is TIFF0007682813000038.tif21128.

[0280] In some embodiments, R 2 is TIFF0007682813000039.tif21128.

[0281] In some embodiments, R 2 is TIFF0007682813000040.tif24128.

[0282] In some embodiments, at least one R 2S is halo, -CN, -OH, -O(C 1 -C 6 alkyl), -NH 2 , -NH(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 , or oxo, and the C 1 -C 6 alkyl may be substituted with one or more 3- to 8-membered heterocycloalkyl.

[0283] In some embodiments, at least one R 2S is halo, -CN, -OH, -O(C 1 -C 6 alkyl), -NH 2 , -NH(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 , or oxo.

[0284] In some embodiments, at least one R 2S is halo, -CN, -OH, or oxo.

[0285] In some embodiments, at least one R 2S is halo. In some embodiments, at least one R 2S is F, Cl, Br, or I. In some embodiments, at least one R 2S is F or Cl. In some embodiments, at least one R 2S is Cl. In some embodiments, at least one R 2S is F.

[0286] In some embodiments, at least one R 2S is -CN. In some embodiments, at least one R 2S is -OH. In some embodiments, at least one R 2S is oxo.

[0287] In some embodiments, at least one R 2S is -O(C 1 -C 6 alkyl), -NH 2 -, -NH(C 1 -C 6 alkyl), or -N(C 1 -C 6 alkyl) 2 wherein the C 1 -C 6 alkyl may be substituted with one or more 3- to 8-membered heterocycloalkyls.

[0288] In some embodiments, at least one R 2S is -NH 2 -, -NH(C 1 -C 6 alkyl), or -N(C 1 -C 6 alkyl) 2 wherein the C 1 -C 6The alkyl may be substituted with one or more 3- to 8-membered heterocycloalkyls.

[0289] In some embodiments, at least one R 2S is i-O(C 1 -C 6 alkyl), -NH 2 , -NH(C 1 -C 6 alkyl), or -N(C 1 -C 6 alkyl) 2 .

[0290] In some embodiments, at least one R 2S is -NH 2 , -NH(C 1 -C 6 alkyl), or -N(C 1 -C 6 alkyl) 2 .

[0291] In some embodiments, at least one R 2S is -O(C 1 -C 6 alkyl), and the C 1 -C 6 alkyl may be substituted with one or more 3- to 8-membered heterocycloalkyls.

[0292] In some embodiments, at least one R 2S is -O(C 1 -C 6 alkyl). In some embodiments, at least one R 2S is -O(methyl). In some embodiments, at least one R 2S is isopropyl optionally substituted with one or more -O(ethyl). In some embodiments, at least one R 2S is isopropyl optionally substituted with one or more -O(propyl). In some embodiments, at least one R 2Sis isopropyl optionally substituted with one or more -O(butyl). In some embodiments, at least one R 2S is isopropyl optionally substituted with one or more -O(pentyl). In some embodiments, at least one R 2S is isopropyl optionally substituted with one or more -O(hexyl).

[0293] In some embodiments, at least one R 2S is i-NH(C 1 -C 6 alkyl), or -N(C 1 -C 6 alkyl) 2 wherein the C 1 -C 6 alkyl may be optionally substituted with one or more 3- to 8-membered heterocycloalkyls.

[0294] In some embodiments, at least one R 2S is -NH(C 1 -C 6 alkyl), or -N(C 1 -C 6 alkyl) 2 is.

[0295] In some embodiments, at least one R 2S is -NH 2 is.

[0296] In some embodiments, at least one R 2S is -NH(C 1 -C 6 alkyl) wherein the C 1 -C 6 alkyl may be optionally substituted with one or more 3- to 8-membered heterocycloalkyls.

[0297] In some embodiments, at least one R 2S is -NH(C 1 -C 6 alkyl).

[0298] In some embodiments, at least one R 2S is -NH(methyl). In some embodiments, at least one R 2S is isopropyl optionally substituted with one or more -NH(ethyl). In some embodiments, at least one R 2S is isopropyl optionally substituted with one or more -NH(propyl). In some embodiments, at least one R 2S is isopropyl optionally substituted with one or more -NH(butyl). In some embodiments, at least one R 2S is isopropyl optionally substituted with one or more -NH(pentyl). In some embodiments, at least one R 2S is isopropyl optionally substituted with one or more -NH(hexyl).

[0299] In some embodiments, at least one R 2S is -N(C 1 -C 6 alkyl) 2 is.

[0300] In some embodiments, at least one R 2S is ethyl optionally substituted with one or more -N(methyl) 2 . In some embodiments, at least one R 2S is ethyl optionally substituted with one or more -N(ethyl) 2 . In some embodiments, at least one R 2S is ethyl optionally substituted with one or more -N(propyl) 2 . In some embodiments, at least one R 2S is ethyl optionally substituted with one or more -N(butyl) 2 . In some embodiments, at least one R 2S is ethyl optionally substituted with one or more -N(pentyl) 2 . In some embodiments, at least one R 2S is ethyl optionally substituted with one or more -N(hexyl)2 It may be ethyl which may be replaced.

[0301] In some embodiments, at least one R 2S is -OH, It is TIFF0007682813000041.tif15128.

[0302] In some embodiments, at least one R 2S is -OH, It is TIFF0007682813000042.tif10128.

[0303] In some embodiments, at least one R 2S is -OH, or It is TIFF0007682813000043.tif8128.

[0304] In some embodiments, at least one R 2S is It is TIFF0007682813000044.tif9128.

[0305] In some embodiments, at least one R 2S is It is TIFF0007682813000045.tif14128.

[0306] In some embodiments, R 3 is 7- to 12-membered heterocycloalkyl or 5- or 6-membered heteroaryl, and the 7- to 12-membered heterocycloalkyl may be substituted with one or more R 3S and may be substituted.

[0307] In some embodiments, R 3 is 7- to 12-membered heterocycloalkyl or 5- or 6-membered heteroaryl, and the 7- to 12-membered heterocycloalkyl may be substituted with one or more R 3S and may be substituted, and each R 3S is independently halo, C 1 -C6 Alkyl, C 1 -C 6 Haloalkyl, C 3 -C 8 Cycloalkyl, or 3- to 8-membered heterocycloalkyl.

[0308] In some embodiments, R 3 is 7- to 12-membered heterocycloalkyl or 5- or 6-membered heteroaryl, and the 7- to 12-membered heterocycloalkyl may be substituted with one or more R 3S , and each R 3S is independently halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, or 3- to 8-membered heterocycloalkyl, and the C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, or 3- to 8-membered heterocycloalkyl may be substituted with one or more halo, -CN, -OH, -O(C 1 -C 6 alkyl), -NH 2 , -NH(C 1 -C 6 alkyl), or -N(C 1 -C 6 alkyl). 2 It may be substituted.

[0309] In some embodiments, R 3 is 7- to 12-membered heterocycloalkyl or 5- or 6-membered heteroaryl, and the 7- to 12-membered heterocycloalkyl may be substituted with one or more R 3S , and each R 3S is independently halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C8 Cycloalkyl, or 4- to 8-membered heterocycloalkyl, where the C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, or 4- to 8-membered heterocycloalkyl may be substituted with one or more halo, -CN, -OH, -O(C 1 -C 6 alkyl), -NH 2 , -NH(C 1 -C 6 alkyl), or -N(C 1 -C 6 alkyl). 2 It may be substituted.

[0310] In some embodiments, R 3 is 7- to 12-membered heterocycloalkyl or 5- or 6-membered heteroaryl, and the 7- to 12-membered heterocycloalkyl may be substituted with one or more R 3S , and each R 3S is independently halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, or 4- to 8-membered heterocycloalkyl, where the C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, or 4- to 8-membered heterocycloalkyl is substituted with one halo, -CN, -OH, -O(C 1 -C 6 alkyl), -NH 2 , -NH(C 1 -C 6 alkyl), or -N(C 1 -C 6 alkyl). 2 It is substituted.

[0311] In some embodiments, R 3 is a 7- to 12-membered heterocycloalkyl or a 5- or 6-membered heteroaryl, and the 7- to 12-membered heterocycloalkyl may be substituted with one or more R 3S , and each R 3S is independently halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, or a 5- to 8-membered heterocycloalkyl, and the C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, or a 5- to 8-membered heterocycloalkyl may be substituted with one or more halo, -CN, -OH, -O(C 1 -C 6 alkyl), -NH 2 , -NH(C 1 -C 6 alkyl), or -N(C 1 -C 6 alkyl) 2 .

[0312] In some embodiments, R 3 is a 7- to 12-membered heterocycloalkyl or a 5- or 6-membered heteroaryl, and the 7- to 12-membered heterocycloalkyl may be substituted with one or more R 3S , and each R 3S is independently halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, or a 5- to 7-membered heterocycloalkyl, and the C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8Cycloalkyl, or 5- to 7-membered heterocycloalkyl, may be substituted with one or more halo, -CN, -OH, -O(C 1 -C 6 -alkyl), -NH 2 , -NH(C 1 -C 6 -alkyl), or -N(C 1 -C 6 -alkyl) 2 .

[0313] In some embodiments, R 3 is 7- to 12-membered heterocycloalkyl or 5- or 6-membered heteroaryl, and the 7- to 12-membered heterocycloalkyl may be substituted with one or more R 3S , each R 3S independently being halo, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 3 -C 8 -cycloalkyl, or 5- to 6-membered heterocycloalkyl, and the C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 3 -C 8 -cycloalkyl, or 5- to 6-membered heterocycloalkyl may be substituted with one or more halo, -CN, -OH, -O(C 1 -C 6 -alkyl), -NH 2 , -NH(C 1 -C 6 -alkyl), or -N(C 1 -C 6 -alkyl) 2 .

[0314] In some embodiments, R 3 is 7- to 12-membered heterocycloalkyl or 5- or 6-membered heteroaryl, and the 5- or 6-membered heteroaryl may be substituted with one or more R 3S .

[0315] In some embodiments, R 3 is a 7- to 12-membered heterocycloalkyl or a 5- or 6-membered heteroaryl, and the 5- or 6-membered heteroaryl may be substituted with one or more R 3S . Each R 3S is independently halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, or a 3- to 8-membered heterocycloalkyl.

[0316] In some embodiments, R 3 is a 7- to 12-membered heterocycloalkyl or a 5- or 6-membered heteroaryl, and the 5- or 6-membered heteroaryl may be substituted with one or more R 3S . Each R 3S is independently halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, or a 3- to 8-membered heterocycloalkyl, and the C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, or C 3 -C 8 heterocycloalkyl is optionally substituted with one or more halo, -CN, -OH, -O(C 1 -C 6 alkyl), -NH 2 , -NH(C 1 -C 6 alkyl), or -N(C 1 -C 6 alkyl). 2 It may be substituted with

[0317] In some embodiments, R 3is a 7- to 12-membered heterocycloalkyl or a 5- or 6-membered heteroaryl, and the 5- or 6-membered heteroaryl may be substituted with one or more R 3S s, and each R 3S is independently halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, or a 3- to 8-membered heterocycloalkyl, and the C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, or a 3- to 8-membered heterocycloalkyl may be substituted with one halo, -CN, -OH, -O(C 1 -C 6 alkyl), -NH 2 , -NH(C 1 -C 6 alkyl), or -N(C 1 -C 6 alkyl) 2 .

[0318] In some embodiments, R 3 is a 7- to 12-membered heterocycloalkyl or a 5- or 6-membered heteroaryl, and the 5- or 6-membered heteroaryl may be substituted with one or more R 3S s, and each R 3S is independently halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, or a 4- to 8-membered heterocycloalkyl, and the C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8Cycloalkyl, or 4- to 8-membered heterocycloalkyl, may be substituted with one or more halo, -CN, -OH, -O(C 1 -C 6 alkyl), -NH 2 , -NH(C 1 -C 6 alkyl), or -N(C 1 -C 6 alkyl) 2 and may be substituted.

[0319] In some embodiments, R 3 is 7- to 12-membered heterocycloalkyl or 5- or 6-membered heteroaryl, and the 5- or 6-membered heteroaryl may be substituted with one or more R 3S , and each R 3S is independently halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, or 5- to 8-membered heterocycloalkyl, and the C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, or 5- to 8-membered heterocycloalkyl may be substituted with one or more halo, -CN, -OH, -O(C 1 -C 6 alkyl), -NH 2 , -NH(C 1 -C 6 alkyl), or -N(C 1 -C 6 alkyl) 2 and may be substituted.

[0320] In some embodiments, R 3 is 7- to 12-membered heterocycloalkyl or 5- or 6-membered heteroaryl, and the 5- or 6-membered heteroaryl may be substituted with one or more R 3S , and each R 3Sis, independently, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, or 5- to 7-membered heterocycloalkyl, and the C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, or 5- to 7-membered heterocycloalkyl may be substituted with one or more halo, -CN, -OH, -O(C 1 -C 6 alkyl), -NH 2 , -NH(C 1 -C 6 alkyl), or -N(C 1 -C 6 alkyl) 2 and may be optionally substituted.

[0321] In some embodiments, R 3 is 7- to 12-membered heterocycloalkyl or 5- or 6-membered heteroaryl, and the 5- or 6-membered heteroaryl may be substituted with one or more R 3S , and each R 3S is, independently, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, or 5- to 6-membered heterocycloalkyl, and the C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, or 5- to 6-membered heterocycloalkyl may be substituted with one or more halo, -CN, -OH, -O(C 1 -C 6 alkyl), -NH 2 , -NH(C 1 -C 6 alkyl), or -N(C1 -C 6 alkyl) 2 may be substituted.

[0322] In some embodiments, R 3 is a 7- to 12-membered heterocycloalkyl which may be substituted with one or more R 3S .

[0323] In some embodiments, R 3 is an unsubstituted 7- to 12-membered heterocycloalkyl.

[0324] In some embodiments, R 3 is a 7- to 12-membered heterocycloalkyl.

[0325] In some embodiments, R 3 is an 8- to 11-membered heterocycloalkyl which may be substituted with one or more R 3S .

[0326] In some embodiments, R 3 is an 8- to 11-membered heterocycloalkyl which is substituted with one or more R 3S .

[0327] In some embodiments, R 3 is an 8- to 11-membered heterocycloalkyl which is substituted with one R 3S .

[0328] In some embodiments, R 3 is an 8- to 11-membered heterocycloalkyl which is substituted with two R 3S .

[0329] In some embodiments, R 3 is an 8- to 11-membered heterocycloalkyl which is substituted with three R 3S .

[0330] In some embodiments, R 3 is an 8- to 11-membered heterocycloalkyl.

[0331] In some embodiments, R 3 is a 9- or 10-membered heterocycloalkyl which may be substituted with one or more R 3S .

[0332] In some embodiments, R 3 is a 9- or 10-membered heterocycloalkyl.

[0333] In some embodiments, R is a 7-membered heterocycloalkyl which may be substituted with one or more R 3S . In some embodiments, R is an 8-membered heterocycloalkyl which may be substituted with one or more R 3S . In some embodiments, R is a 9-membered heterocycloalkyl which may be substituted with one or more R 3S . In some embodiments, R is a 10-membered heterocycloalkyl which may be substituted with one or more R 3S . In some embodiments, R is an 11-membered heterocycloalkyl which may be substituted with one or more R 3S . In some embodiments, R is a 12-membered heterocycloalkyl which may be substituted with one or more R 3S .

[0334] In some embodiments, R 3 is a 7-membered heterocycloalkyl which is substituted with one or more R 3S . In some embodiments, R is an 8-membered heterocycloalkyl which is substituted with one or more R 3S . In some embodiments, R is a 9-membered heterocycloalkyl which is substituted with one or more R 3S . In some embodiments, R is a 10-membered heterocycloalkyl which is substituted with one or more R 3S . In some embodiments, R is an 11-membered heterocycloalkyl which is substituted with one or more R 3S . In some embodiments, R is a 12-membered heterocycloalkyl which is substituted with one or more R 3Sis a 12-membered heterocycloalkyl replaced by

[0335] In some embodiments, R 3 is a 7-membered heterocycloalkyl. In some embodiments, R 3 is an 8-membered heterocycloalkyl. In some embodiments, R 3 is a 9-membered heterocycloalkyl. In some embodiments, R 3 is a 10-membered heterocycloalkyl. In some embodiments, R 3 is an 11-membered heterocycloalkyl. In some embodiments, R 3 is a 12-membered heterocycloalkyl.

[0336] In some embodiments, R 3 is an unsubstituted 5- or 6-membered heteroaryl.

[0337] In some embodiments, R 3 is a 5- or 6-membered heteroaryl.

[0338] In some embodiments, R 3 is a 5- or 6-membered heteroaryl optionally substituted with one or more R 3S s.

[0339] In some embodiments, R 3 is a 5- or 6-membered heteroaryl substituted with one or more R 3S s.

[0340] In some embodiments, R 3 is a 5- or 6-membered heteroaryl substituted with one R 3S s.

[0341] In some embodiments, R 3 is a 5- or 6-membered heteroaryl substituted with two R 3S s.

[0342] In some embodiments, R3 is a 5- or 6-membered heteroaryl substituted with three Rs 3S

[0343] In some embodiments, R 3 is a 5- or 6-membered heteroaryl optionally substituted with one or more Rs 3S each R 3S is independently halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, or 3- to 8-membered heterocycloalkyl, and the C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, or 3- to 8-membered heterocycloalkyl is optionally substituted with one or more halo, -CN, -OH, -O(C 1 -C 6 alkyl), NH 2 , -NH(C 1 -C 6 alkyl), or -N(C 1 -C 6 alkyl) 2

[0344] In some embodiments, R 3 is a 5- or 6-membered heteroaryl optionally substituted with one or more Rs 3S each R 3S is independently halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, or 3- to 8-membered heterocycloalkyl, and the C 1 -C 6 alkyl is optionally substituted with one or more halo, -CN, -OH, -O(C 1 -C 6 alkyl), -NH​​2 、 -NH(C 1 -C 6 alkyl), or -N(C 1 -C 6 alkyl) 2 may be substituted.

[0345] In some embodiments, R 3 is a 5- or 6-membered heteroaryl optionally substituted with one or more R 3S , each R 3S independently is halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, or a 3- to 8-membered heterocycloalkyl, and the C 1 -C 6 haloalkyl may be substituted with one or more halo, -CN, -OH, -O(C 1 -C 6 alkyl), -NH 2 、 -NH(C 1 -C 6 alkyl), or -N(C 1 -C 6 alkyl) 2 may be substituted.

[0346] In some embodiments, R 3 is a 5- or 6-membered heteroaryl optionally substituted with one or more R 3S , each R 3S independently is halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, or a 3- to 8-membered heterocycloalkyl, and the C 3 -C 8 cycloalkyl may be substituted with one or more halo, -CN, -OH, -O(C 1 -C 6 alkyl), -NH 2 、 -NH(C 1-C 6 alkyl), or -N(C 1 -C 6 alkyl) 2 may be substituted.

[0347] In some embodiments, R 3 is a 5- or 6-membered heteroaryl optionally substituted with one or more R 3S s, each R 3S independently is halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, or a 3- to 8-membered heterocycloalkyl, and the 3- to 8-membered heterocycloalkyl is optionally substituted with one or more halo, -CN, -OH, -O(C 1 -C 6 alkyl), -NH 2 , -NH(C 1 -C 6 alkyl), or -N(C 1 -C 6 alkyl) 2 may be substituted.

[0348] In some embodiments, R 3 is a 5- or 6-membered heteroaryl optionally substituted with one or more R 3S s, each R 3S independently is halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, or a 4- to 8-membered heterocycloalkyl, and the 4- to 8-membered heterocycloalkyl is optionally substituted with one or more halo, -CN, -OH, -O(C 1 -C 6 alkyl), -NH 2 , -NH(C 1 -C 6 alkyl), or -N(C 1 -C 6 alkyl)2 may be replaced.

[0349] In some embodiments, R 3 is a 5- or 6-membered heteroaryl which may be substituted with one or more R 3S each R 3S is independently halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, or a 5- to 8-membered heterocycloalkyl, and the 5- to 8-membered heterocycloalkyl may be substituted with one or more halo, -CN, -OH, -O(C 1 -C 6 alkyl), -NH 2 , -NH(C 1 -C 6 alkyl), or -N(C 1 -C 6 alkyl) 2 may be replaced.

[0350] In some embodiments, R 3 is a 5- or 6-membered heteroaryl which may be substituted with one or more R 3S each R 3S is independently halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, or a 5- to 7-membered heterocycloalkyl, and the 5- to 7-membered heterocycloalkyl may be substituted with one or more halo, -CN, -OH, -O(C 1 -C 6 alkyl), -NH 2 , -NH(C 1 -C 6 alkyl), or -N(C 1 -C 6 alkyl) 2 may be replaced.

[0351] In some embodiments, R 3 is a 5- or 6-membered heteroaryl which may be substituted with one or more R 3S , and each R 3S is independently halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, or a 5- to 6-membered heterocycloalkyl, and the 5- to 6-membered heterocycloalkyl may be substituted with one or more halo, -CN, -OH, -O(C 1 -C 6 alkyl), -NH 2 , -NH(C 1 -C 6 alkyl), or -N(C 1 -C 6 alkyl) 2 .

[0352] In some embodiments, R 3 is a 5- or 6-membered heteroaryl which may be substituted with one or more R 3S , and each R 3S is independently halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, or a 3- to 8-membered heterocycloalkyl, and the C 1 -C 6 alkyl may be substituted with one or more halo or -CN.

[0353] In some embodiments, R 3 is a 5- or 6-membered heteroaryl which may be substituted with one or more R 3S , and each R 3S is independently halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8Cycloalkyl, or 3- to 8-membered heterocycloalkyl, wherein the C 1 -C 6 alkyl may be substituted with one halo or -CN.

[0354] In some embodiments, R 3 is 5- or 6-membered heteroaryl optionally substituted with one or more R 3S , each R 3S independently being halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, or 3- to 8-membered heterocycloalkyl, wherein the C 1 -C 6 alkyl may be substituted with halo.

[0355] In some embodiments, R 3 is 5- or 6-membered heteroaryl optionally substituted with one or more R 3S , each R 3S independently being halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, or 3- to 8-membered heterocycloalkyl, wherein the C 1 -C 6 alkyl may be substituted with -CN.

[0356] In some embodiments, R 3 is 5- or 6-membered heteroaryl optionally substituted with one or more R 3S , each R 3S independently being halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8Cycloalkyl, or a 3- to 8-membered heterocycloalkyl, wherein the C 1 -C 6 alkyl may be substituted with -OH or -O(C 1 -C 6 alkyl).

[0357] In some embodiments, R 3 is a 5- or 6-membered heteroaryl optionally substituted with one or more R 3S each R 3S is independently halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, or a 3- to 8-membered heterocycloalkyl, wherein the C 1 -C 6 alkyl may be substituted with -OH.

[0358] In some embodiments, R 3 is a 5- or 6-membered heteroaryl optionally substituted with one or more R 3S each R 3S is independently halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, or a 3- to 8-membered heterocycloalkyl, wherein the C 1 -C 6 alkyl may be substituted with -O(C 1 -C 6 alkyl).

[0359] In some embodiments, R 3 is a 5- or 6-membered heteroaryl optionally substituted with one or more R 3S each R 3S is independently halo, C 1 -C 6 alkyl, C 1 -C6 Haloalkyl, C 3 -C 8 Cycloalkyl, or a 3- to 8-membered heterocycloalkyl, and the C 1 -C 6 Alkyl may be substituted with -NH 2 , -NH(C 1 -C 6 Alkyl), or -N(C 1 -C 6 Alkyl) 2 and may be substituted therewith.

[0360] In some embodiments, R 3 is a 5- or 6-membered heteroaryl which may be substituted with one or more R 3S s, and each R 3S is independently halo, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 3 -C 8 Cycloalkyl, or a 3- to 8-membered heterocycloalkyl, and the C 1 -C 6 Alkyl may be substituted with -NH 2 and may be substituted therewith.

[0361] In some embodiments, R 3 is a 5- or 6-membered heteroaryl which may be substituted with one or more R 3S s, and each R 3S is independently halo, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 3 -C 8 Cycloalkyl, or a 3- to 8-membered heterocycloalkyl, and the C 1 -C 6 Alkyl may be substituted with -NH(C 1 -C 6 Alkyl) and may be substituted therewith.

[0362] In some embodiments, R 3is a 5- or 6-membered heteroaryl which may be substituted with one or more R 3S each R 3S is independently halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, or 3- to 8-membered heterocycloalkyl, and the C 1 -C 6 alkyl may be substituted with -N(C 1 -C 6 alkyl) 2 and may be substituted.

[0363] In some embodiments, R 3 is a 5- or 6-membered heteroaryl which may be substituted with one or more R 3S each R 3S is independently halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, or 3- to 8-membered heterocycloalkyl.

[0364] In some embodiments, R 3 is a 5- or 6-membered heteroaryl which may be substituted with one or more R 3S each R 3S is independently C 1 -C 6 alkyl or C 1 -C 6 haloalkyl.

[0365] In some embodiments, R 3 is a 5- or 6-membered heteroaryl which may be substituted with one or more R 3S each R 3S is independently C 1 -C 6 alkyl.

[0366] In some embodiments, R 3 is a 5- or 6-membered heteroaryl which may be substituted with one or more R 3S , and each R 3S is independently C 1 -C 6 haloalkyl.

[0367] In some embodiments, R 3 is a 5- or 6-membered heteroaryl which may be substituted with one or more R 3S , and each R 3S is independently halo, C 3 -C 8 cycloalkyl, or 3- to 8-membered heterocycloalkyl.

[0368] In some embodiments, R 3 is a 5- or 6-membered heteroaryl which may be substituted with one or more R 3S , and each R 3S is independently C 3 -C 8 cycloalkyl.

[0369] In some embodiments, R 3 is a 5- or 6-membered heteroaryl which may be substituted with one or more R 3S , and each R 3S is independently halo.

[0370] In some embodiments, R 3 is a 5- or 6-membered heteroaryl which may be substituted with one or more R 3S , and each R 3S is independently 3- to 8-membered heterocycloalkyl.

[0371] In some embodiments, R 3 is a 5- or 6-membered heteroaryl having one, two, or three heteroatoms.

[0372] In some embodiments, R3 is a 5- or 6-membered heteroaryl having one, two, or three heteroatoms selected from N and O.

[0373] In some embodiments, R 3 is a 5- or 6-membered heteroaryl having one heteroatom selected from N and O.

[0374] In some embodiments, R 3 is a 5- or 6-membered heteroaryl having two heteroatoms selected from N and O.

[0375] In some embodiments, R 3 is an unsubstituted 5-membered heteroaryl.

[0376] In some embodiments, R 3 is a 5-membered heteroaryl.

[0377] In some embodiments, R 3 is a 5-membered heteroaryl substituted with one or more R 3S .

[0378] In some embodiments, R 3 is a 5-membered heteroaryl substituted with one R 3S .

[0379] In some embodiments, R 3 is a 5-membered heteroaryl substituted with two R 3S .

[0380] In some embodiments, R 3 is a 5-membered heteroaryl substituted with three R 3S .

[0381] In some embodiments, R 3 is a 5-membered heteroaryl optionally substituted with one or more R 3S , wherein each R 3S is independently halo, C1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, or 3- to 8-membered heterocycloalkyl, wherein the C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, or 3- to 8-membered heterocycloalkyl may be substituted with one or more halo, -CN, -OH, -O(C 1 -C 6 alkyl), -NH 2 , -NH(C 1 -C 6 alkyl), or -N(C 1 -C 6 alkyl) 2 and may be optionally substituted.

[0382] In some embodiments, R 3 is a 5-membered heteroaryl which may be substituted with one or more R 3S , and each R 3S is independently halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, or 4- to 8-membered heterocycloalkyl, wherein the C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, or 4- to 8-membered heterocycloalkyl may be substituted with one or more halo, -CN, -OH, -O(C 1 -C 6 alkyl), -NH 2 , -NH(C 1 -C 6 alkyl), or -N(C 1 -C 6 alkyl) 2 and may be optionally substituted.

[0383] In some embodiments, R 3 is a 5-membered heteroaryl which may be substituted with one or more R 3S each R 3S is independently halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, or a 5- to 8-membered heterocycloalkyl, and the C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, or a 5- to 8-membered heterocycloalkyl may be substituted with one or more halo, -CN, -OH, -O(C 1 -C 6 alkyl), -NH 2 , -NH(C 1 -C 6 alkyl), or -N(C 1 -C 6 alkyl) 2 and may be substituted.

[0384] In some embodiments, R 3 is a 5-membered heteroaryl which may be substituted with one or more R 3S each R 3S is independently halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, or a 5- to 7-membered heterocycloalkyl, and the C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, or a 5- to 7-membered heterocycloalkyl may be substituted with one or more halo, -CN, -OH, -O(C 1 -C6 alkyl), -NH 2 , -NH(C 1 -C 6 alkyl), or -N(C 1 -C 6 alkyl) 2 may be substituted.

[0385] In some embodiments, R 3 is a 5-membered heteroaryl which may be substituted with one or more R 3S s, and each R 3S is independently halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, or a 5- to 6-membered heterocycloalkyl, and the C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, or a 5- to 6-membered heterocycloalkyl is optionally substituted with one or more halo, -CN, -OH, -O(C 1 -C 6 alkyl), -NH 2 , -NH(C 1 -C 6 alkyl), or -N(C 1 -C 6 alkyl) 2 may be substituted.

[0386] In some embodiments, R 3 is a 5-membered heteroaryl which may be substituted with one or more R 3S s, and each R 3S is independently halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, or a 3- to 8-membered heterocycloalkyl, and the C 1 -C6 Alkyl, C 1 -C 6 Haloalkyl, C 3 -C 8 Cycloalkyl, or 3- to 8-membered heterocycloalkyl may be substituted with one or more halo or -CN.

[0387] In some embodiments, R 3 is a 5-membered heteroaryl which may be substituted with one or more R 3S , and each R 3S is independently halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, or 3- to 8-membered heterocycloalkyl, and the C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, or 3- to 8-membered heterocycloalkyl may be substituted with one or more halo.

[0388] In some embodiments, R 3 is a 5-membered heteroaryl which may be substituted with one or more R 3S , and each R 3S is independently halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, or 3- to 8-membered heterocycloalkyl, and the C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, or 3- to 8-membered heterocycloalkyl may be substituted with one or more -CN.

[0389] In some embodiments, R 3 is a 5-membered heteroaryl which may be substituted with one or more R 3S s, and each R 3S is independently halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, or a 3- to 8-membered heterocycloalkyl, and the C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, or a 3- to 8-membered heterocycloalkyl may be substituted with one or more -OH or -O(C 1 -C 6 alkyl).

[0390] In some embodiments, R 3 is a 5-membered heteroaryl which may be substituted with one or more R 3S s, and each R 3S is independently halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, or a 3- to 8-membered heterocycloalkyl, and the C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, or a 3- to 8-membered heterocycloalkyl may be substituted with one or more -OH.

[0391] In some embodiments, R 3 is a 5-membered heteroaryl which may be substituted with one or more R 3S s, and each R 3S is independently halo, C 1 -C6 Alkyl, C 1 -C 6 Haloalkyl, C 3 -C 8 Cycloalkyl, or 3- to 8-membered heterocycloalkyl, where the C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 3 -C 8 Cycloalkyl, or 3- to 8-membered heterocycloalkyl may be substituted with one or more -O(C 1 -C 6 Alkyl).

[0392] In some embodiments, R 3 is a 5-membered heteroaryl that may be substituted with one or more R 3S , and each R 3S is independently halo, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 3 -C 8 Cycloalkyl, or 3- to 8-membered heterocycloalkyl, where the C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 3 -C 8 Cycloalkyl, or 3- to 8-membered heterocycloalkyl may be substituted with one or more -NH 2 , -NH(C 1 -C 6 Alkyl), or -N(C 1 -C 6 Alkyl). 2 is optionally substituted.

[0393] In some embodiments, R 3 is a 5-membered heteroaryl that may be substituted with one or more R 3S , and each R 3S is independently halo, C 1 -C 6 Alkyl, C 1-C 6 Haloalkyl, C 3 -C 8 Cycloalkyl, or 3- to 8-membered heterocycloalkyl, and the C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 3 -C 8 Cycloalkyl, or 3- to 8-membered heterocycloalkyl may be substituted with one or more -NH(C 1 -C 6 Alkyl) or -N(C 1 -C 6 Alkyl) 2 and may be substituted.

[0394] In some embodiments, R 3 is a 5-membered heteroaryl which may be substituted with one or more R 3S , and each R 3S is independently halo, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 3 -C 8 Cycloalkyl, or 3- to 8-membered heterocycloalkyl, and the C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 3 -C 8 Cycloalkyl, or 3- to 8-membered heterocycloalkyl may be substituted with one or more -NH 2 and may be substituted.

[0395] In some embodiments, R 3 is a 5-membered heteroaryl which may be substituted with one or more R 3S , and each R 3S is independently halo, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 3 -C 8Cycloalkyl, or 3- to 8-membered heterocycloalkyl, wherein said C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, or 3- to 8-membered heterocycloalkyl may be substituted with one or more -NH(C 1 -C 6 alkyl).

[0396] In some embodiments, R 3 is a 5-membered heteroaryl which may be substituted with one or more R 3S , and each R 3S is independently halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, or 3- to 8-membered heterocycloalkyl, wherein said C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, or 3- to 8-membered heterocycloalkyl may be substituted with one or more -N(C 1 -C 6 alkyl) 2 .

[0397] In some embodiments, R 3 is a 5-membered heteroaryl which may be substituted with one or more R 3S , and each R 3S is independently halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, or 3- to 8-membered heterocycloalkyl.

[0398] In some embodiments, R3 is a 5-membered heteroaryl which may be substituted with one or more R 3S each R 3S is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 3 -C 8 cycloalkyl.

[0399] In some embodiments, R 3 is a 5-membered heteroaryl which may be substituted with one or more R 3S each R 3S is independently a 3- to 8-membered heterocycloalkyl.

[0400] In some embodiments, R 3 is a 5-membered heteroaryl which may be substituted with one or more R 3S each R 3S is independently halo.

[0401] In some embodiments, R 3 is a 5-membered heteroaryl which may be substituted with one or more R 3S each R 3S is independently C 1 -C 6 alkyl or C 1 -C 6 haloalkyl.

[0402] In some embodiments, R 3 is a 5-membered heteroaryl which may be substituted with one or more R 3S each R 3S is independently C 1 -C 6 haloalkyl.

[0403] In some embodiments, R 3 is a 5-membered heteroaryl which may be substituted with one or more R 3S each R 3Sis, independently, C 1 -C 6 is alkyl.

[0404] In some embodiments, R 3 is a 5-membered heteroaryl substituted with one or more C 1 -C 6 alkyl.

[0405] In some embodiments, R 3 is a 5-membered heteroaryl substituted with one C 1 -C 6 alkyl.

[0406] In some embodiments, R 3 is a 5-membered heteroaryl substituted with two C 1 -C 6 alkyl.

[0407] In some embodiments, R 3 is a 5-membered heteroaryl substituted with three C 1 -C 6 alkyl.

[0408] In some embodiments, R 3 is an unsubstituted 6-membered heteroaryl.

[0409] In some embodiments, R 3 is a 6-membered heteroaryl.

[0410] In some embodiments, R 3 is a 6-membered heteroaryl substituted with one or more R 3S s.

[0411] In some embodiments, R 3 is a 6-membered heteroaryl substituted with one R 3S .

[0412] In some embodiments, R 3 is a 6-membered heteroaryl substituted with two R 3Sis a 6-membered heteroaryl replaced by

[0413] In some embodiments, R 3 is a 6-membered heteroaryl replaced by three R 3S s.

[0414] In some embodiments, R 3 is a 6-membered heteroaryl optionally substituted by one or more R 3S s, each R 3S independently being halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, or a 3- to 8-membered heterocycloalkyl, wherein the C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, or a 3- to 8-membered heterocycloalkyl is optionally substituted by one or more halo, -CN, -OH, -O(C 1 -C 6 alkyl), -NH 2 -, -NH(C 1 -C 6 alkyl), or -N(C 1 -C 6 alkyl) 2 .

[0415] In some embodiments, R 3 is a 6-membered heteroaryl optionally substituted by one or more R 3S s, each R 3S independently being halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, or a 4- to 8-membered heterocycloalkyl, wherein the C 1 -C 6 alkyl, C1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, or 4- to 8-membered heterocycloalkyl may be substituted with one or more halo, -CN, -OH, -O(C 1 -C 6 alkyl), -NH 2 -, NH(C 1 -C 6 alkyl), or -N(C 1 -C 6 alkyl) 2 and may be substituted.

[0416] In some embodiments, R 3 is a 6-membered heteroaryl which may be substituted with one or more R 3S s, and each R 3S is independently halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, or 5- to 8-membered heterocycloalkyl, and the C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, or 5- to 8-membered heterocycloalkyl may be substituted with one or more halo, -CN, -OH, -O(C 1 -C 6 alkyl), -NH 2 -, NH(C 1 -C 6 alkyl), or -N(C 1 -C 6 alkyl) 2 and may be substituted.

[0417] In some embodiments, R 3 is a 6-membered heteroaryl which may be substituted with one or more R 3S s, and each R 3S is independently halo, C 1 -C 6Alkyl, C 1 -C 6 Haloalkyl, C 3 -C 8 Cycloalkyl, or 5- to 7-membered heterocycloalkyl, where the C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 3 -C 8 Cycloalkyl, or 5- to 7-membered heterocycloalkyl may be substituted with one or more halo, -CN, -OH, -O(C 1 -C 6 Alkyl), -NH 2 -, -NH(C 1 -C 6 Alkyl), or -N(C 1 -C 6 Alkyl) 2 and may be optionally substituted.

[0418] In some embodiments, R 3 is a 6-membered heteroaryl which may be optionally substituted with one or more R 3S where each R 3S is independently halo, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 3 -C 8 Cycloalkyl, or 5- to 6-membered heterocycloalkyl, where the C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 3 -C 8 Cycloalkyl, or 5- to 6-membered heterocycloalkyl may be substituted with one or more halo, -CN, -OH, -O(C 1 -C 6 Alkyl), -NH 2 -, -NH(C 1 -C 6 Alkyl), or -N(C 1 -C 6 Alkyl) 2 and may be optionally substituted.

[0419] In some embodiments, R 3 is a 6-membered heteroaryl which may be substituted with one or more R 3S , and each R 3S is independently halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, or a 3- to 8-membered heterocycloalkyl, and the C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, or a 3- to 8-membered heterocycloalkyl may be substituted with one or more halo or -CN.

[0420] In some embodiments, R 3 is a 6-membered heteroaryl which may be substituted with one or more R 3S , and each R 3S is independently halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, or a 3- to 8-membered heterocycloalkyl, and the C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, or a 3- to 8-membered heterocycloalkyl may be substituted with one or more halo.

[0421] In some embodiments, R 3 is a 6-membered heteroaryl which may be substituted with one or more R 3S , and each R 3S is independently halo, C 1 -C 6 alkyl, C 1 -C6 Haloalkyl, C 3 -C 8 ycloalkyl, or a 3- to 8-membered heterocycloalkyl, and the C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 ycloalkyl, or a 3- to 8-membered heterocycloalkyl may be substituted with one or more -CN.

[0422] In some embodiments, R 3 is a 6-membered heteroaryl which may be substituted with one or more R 3S s, and each R 3S is independently halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 ycloalkyl, or a 3- to 8-membered heterocycloalkyl, and the C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 ycloalkyl, or a 3- to 8-membered heterocycloalkyl may be substituted with one or more -OH or -O(C 1 -C 6 alkyl).

[0423] In some embodiments, R 3 is a 6-membered heteroaryl which may be substituted with one or more R 3S s, and each R 3S is independently halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 ycloalkyl, or a 3- to 8-membered heterocycloalkyl, and the C 1 -C 6 alkyl, C 1 -C6 Haloalkyl, C 3 -C 8 Cycloalkyl, or 3- to 8-membered heterocycloalkyl may be substituted with one or more -OH.

[0424] In some embodiments, R 3 is a 6-membered heteroaryl which may be substituted with one or more R 3S , and each R 3S is independently halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, or 3- to 8-membered heterocycloalkyl, and the C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, or 3- to 8-membered heterocycloalkyl may be substituted with one or more -O(C 1 -C 6 alkyl).

[0425] In some embodiments, R 3 is a 6-membered heteroaryl which may be substituted with one or more R 3S , and each R 3S is independently halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, or 3- to 8-membered heterocycloalkyl, and the C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, or 3- to 8-membered heterocycloalkyl may be substituted with one or more -NH 2 , -NH(C 1 -C 6(alkyl), or -N(C 1 -C 6 (alkyl) 2 may be substituted.

[0426] In some embodiments, R 3 is a 6-membered heteroaryl which may be substituted with one or more R 3S s, and each R 3S is independently halo, C 1 -C 6 (alkyl), C 1 -C 6 (haloalkyl), C 3 -C 8 (cycloalkyl), or a 3- to 8-membered heterocycloalkyl, and the C 1 -C 6 (alkyl), C 1 -C 6 (haloalkyl), C 3 -C 8 (cycloalkyl), or a 3- to 8-membered heterocycloalkyl may be substituted with one or more -NH(C 1 -C 6 (alkyl), or -N(C 1 -C 6 (alkyl) 2 may be substituted.

[0427] In some embodiments, R 3 is a 6-membered heteroaryl which may be substituted with one or more R 3S s, and each R 3S is independently halo, C 1 -C 6 (alkyl), C 1 -C 6 (haloalkyl), C 3 -C 8 (cycloalkyl), or a 3- to 8-membered heterocycloalkyl, and the C 1 -C 6 (alkyl), C 1 -C 6 (haloalkyl), C 3 -C 8 (cycloalkyl), or a 3- to 8-membered heterocycloalkyl may be substituted with one or more -NH 2It may be replaced by

[0428] In some embodiments, R 3 is a 6-membered heteroaryl that may be replaced by one or more R 3S each R 3S is independently halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, or 3- to 8-membered heterocycloalkyl, and the C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, or 3- to 8-membered heterocycloalkyl may be replaced by one or more -NH(C 1 -C 6 alkyl).

[0429] In some embodiments, R 3 is a 6-membered heteroaryl that may be replaced by one or more R 3S each R 3S is independently halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, or 3- to 8-membered heterocycloalkyl, and the C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, or 3- to 8-membered heterocycloalkyl may be replaced by one or more -N(C 1 -C 6 alkyl) 2 It may be replaced by

[0430] In some embodiments, R 3 is a 6-membered heteroaryl that may be replaced by one or more R3S is a 6-membered heteroaryl which may be substituted with each R 3S is independently halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, or 3- to 8-membered heterocycloalkyl.

[0431] In some embodiments, R 3 is a 6-membered heteroaryl which may be substituted with one or more R 3S and each R 3S is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 3 -C 8 cycloalkyl.

[0432] In some embodiments, R 3 is a 6-membered heteroaryl which may be substituted with one or more R 3S and each R 3S is independently 3- to 8-membered heterocycloalkyl.

[0433] In some embodiments, R 3 is a 6-membered heteroaryl which may be substituted with one or more R 3S and each R 3S is independently halo.

[0434] In some embodiments, R 3 is a 6-membered heteroaryl which may be substituted with one or more R 3S and each R 3S is independently C 1 -C 6 alkyl or C 1 -C 6 haloalkyl.

[0435] In some embodiments, R3 is a 6-membered heteroaryl which may be substituted with one or more R 3S each R 3S is independently C 1 -C 6 haloalkyl.

[0436] In some embodiments, R 3 is a 6-membered heteroaryl which may be substituted with one or more R 3S each R 3S is independently C 1 -C 6 alkyl.

[0437] In some embodiments, R 3 is a 5- or 6-membered heteroaryl which may be substituted with one or more R 3S In some embodiments, R

[0438] is a 5-membered heteroaryl which may be substituted with one or more R 3 In some embodiments, R 3S is a 5-membered heteroaryl which may be substituted with one R

[0439] In some embodiments, R 3 is a 5-membered heteroaryl which may be substituted with one R 3S In some embodiments, R

[0440] is a 5-membered heteroaryl which may be substituted with two R 3 In some embodiments, R 3S is a 5-membered heteroaryl which may be substituted with three R

[0441] In some embodiments, R 3 is pyrazolyl which may be substituted with one or more R 3S In some embodiments, R

[0442] In some embodiments, R 3 is pyrazolyl which may be substituted with one or more R 3S In some embodiments, R

[0443] In some embodiments, R3 is TIFF0007682813000046.tif68165.

[0444] In some embodiments, R 3 is TIFF0007682813000047.tif13128.

[0445] In some embodiments, R 3 is TIFF0007682813000048.tif12128.

[0446] In some embodiments, R 3 is pyrrolyl which may be substituted with one or more R 3S . In some embodiments, R 3 is imidazolyl which may be substituted with one or more R 3S . In some embodiments, R 3 is triazolyl which may be substituted with one or more R 3S . In some embodiments, R 3 is tetrazolyl which may be substituted with one or more R 3S . In some embodiments, R 3 is isoxazolyl which may be substituted with one or more R 3S . In some embodiments, R 3 is furanyl which may be substituted with one or more R 3S . In some embodiments, R 3 is oxazolyl which may be substituted with one or more R 3S . In some embodiments, R 3 is 4,5,6,7 - tetrahydrobenzo[c]isoxazole which may be substituted with one or more R 3S . In some embodiments, R 3 is isothiazolyl which may be substituted with one or more R 3S . In some embodiments, R 3 is one or more R 3SIt may be replaced by thiazolyl. In some embodiments, R 3 is thiazolyl which may be optionally substituted with one R 3S .

[0447] In some embodiments, R 3 is pyrrolyl. In some embodiments, R 3 is imidazolyl. In some embodiments, R 3 is triazolyl. In some embodiments, R 3 is tetrazolyl. In some embodiments, R 3 is isoxazolyl. In some embodiments, R 3 is furanyl. In some embodiments, R 3 is oxazolyl. In some embodiments, R 3 is 4,5,6,7-tetrahydrobenzo[c]isoxazole. In some embodiments, R 3 is isothiazolyl. In some embodiments, R 3 is thiazolyl. In some embodiments, R 3 is thiadiazolyl.

[0448] In some embodiments, R 3 is a 6-membered heteroaryl which may be optionally substituted with one or more R 3S .

[0449] In some embodiments, R 3 is pyridinyl which may be optionally substituted with one or more R 3S . In some embodiments, R 3 is diazinyl which may be optionally substituted with one or more R 3S . In some embodiments, R 3 is pyridazinyl which may be optionally substituted with one or more R 3S . In some embodiments, R 3 is pyrimidinyl which may be optionally substituted with one or more R 3S . In some embodiments, R 3 is optionally substituted with one or more R 3SIt may be replaced by pyrazinyl. In some embodiments, R 3 is triazinyl which may be substituted with one or more R 3S In some embodiments, R 3 is tetrazinyl which may be substituted with one R 3S In some embodiments, R 3 is pentazinyl.

[0450] In some embodiments, R 3 is pyridinyl. In some embodiments, R 3 is diazinyl. In some embodiments, R 3 is pyridazinyl. In some embodiments, R 3 is pyrimidinyl. In some embodiments, R 3 is pyrazinyl. In some embodiments, R 3 is triazinyl. In some embodiments, R 3 is tetrazinyl.

[0451] In some embodiments, at least one R 3S is halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, or 3- to 8-membered heterocycloalkyl, and the C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, or 3- to 8-membered heterocycloalkyl may be substituted with one or more halo, -CN, -OH, -O(C 1 -C 6 alkyl), -NH 2 2, -NH(C 1 -C 6 alkyl), or -N(C 1 -C 6 alkyl) 2 and may be substituted.

[0452] In some embodiments, at least one R 3S is halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, or 4- to 8-membered heterocycloalkyl, and the C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, or 4- to 8-membered heterocycloalkyl may be substituted with one or more halo, -CN, -OH, -O(C 1 -C 6 alkyl), -NH 2 , -NH(C 1 -C 6 alkyl), or -N(C 1 -C 6 alkyl) 2 and may be optionally substituted.

[0453] In some embodiments, at least one R 3S is halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, or 5- to 8-membered heterocycloalkyl, and the C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, or 5- to 8-membered heterocycloalkyl may be substituted with one or more halo, -CN, -OH, -O(C 1 -C 6 alkyl), -NH 2 , -NH(C 1 -C 6 alkyl), or -N(C 1 -C 6 alkyl) 2may be replaced.

[0454] In some embodiments, at least one R 3S is halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, or 5- to 7-membered heterocycloalkyl, and the C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, or 5- to 7-membered heterocycloalkyl may be substituted with one or more halo, -CN, -OH, -O(C 1 -C 6 alkyl), -NH 2 , -NH(C 1 -C 6 alkyl), or -N(C 1 -C 6 alkyl) 2 may be replaced.

[0455] In some embodiments, at least one R 3S is halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, or 5- to 6-membered heterocycloalkyl, and the C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, or 5- to 6-membered heterocycloalkyl may be substituted with one or more halo, -CN, -OH, -O(C 1 -C 6 alkyl), -NH 2 , -NH(C 1 -C 6 alkyl), or -N(C 1 -C 6(alkyl) 2 may be substituted.

[0456] In some embodiments, at least one R 3S is halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, or 3- to 8-membered heterocycloalkyl.

[0457] In some embodiments, at least one R 3S is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 3 -C 8 cycloalkyl, or C 3 -C 8 heterocycloalkyl.

[0458] In some embodiments, at least one R 3S is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 3 -C 8 cycloalkyl, or 3- to 8-membered heterocycloalkyl, and the C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, or 3- to 8-membered heterocycloalkyl is substituted with one or more halo, -CN, -OH, -O(C 1 -C 6 alkyl), -NH 2 , -NH(C 1 -C 6 alkyl), or -N(C 1 -C 6 (alkyl) 2 may be substituted.

[0459] In some embodiments, at least one R 3S is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 3 -C 8 cycloalkyl, or 4- to 8-membered heterocycloalkyl, and the C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, or 4- to 8-membered heterocycloalkyl may be substituted with one or more halo, -CN, -OH, -O(C 1 -C 6 alkyl), -NH 2 , -NH(C 1 -C 6 alkyl), or -N(C 1 -C 6 alkyl) 2 optionally.

[0460] In some embodiments, at least one R 3S is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 3 -C 8 cycloalkyl, or 5- to 8-membered heterocycloalkyl, and the C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, or 5- to 8-membered heterocycloalkyl may be substituted with one or more halo, -CN, -OH, -O(C 1 -C 6 alkyl), -NH 2 , -NH(C 1 -C 6 alkyl), or -N(C 1 -C 6 alkyl) 2 optionally.

[0461] In some embodiments, at least one R 3S is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 3 -C 8 cycloalkyl, or 5- to 7-membered heterocycloalkyl, and the C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, or 5- to 7-membered heterocycloalkyl may be substituted with one or more halo, -CN, -OH, -O(C 1 -C 6 alkyl), -NH 2 , -NH(C 1 -C 6 alkyl), or -N(C 1 -C 6 alkyl) 2 optionally substituted.

[0462] In some embodiments, at least one R 3S is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 3 -C 8 cycloalkyl, or 5- to 6-membered heterocycloalkyl, and the C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, or 5- to 6-membered heterocycloalkyl may be substituted with one or more halo, -CN, -OH, -O(C 1 -C 6 alkyl), -NH 2 , -NH(C 1 -C 6 alkyl), or -N(C 1 -C 6 alkyl) 2may be replaced.

[0463] In some embodiments, at least one R 3S is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 3 -C 8 cycloalkyl, or 3- to 8-membered heterocycloalkyl, and the C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, or 3- to 8-membered heterocycloalkyl is unsubstituted.

[0464] In some embodiments, at least one R 3S is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 3 -C 8 cycloalkyl, or 3- to 8-membered heterocycloalkyl, and the C 1 -C 6 alkyl is optionally substituted with one or more halo, -CN, -OH, -O(C 1 -C 6 alkyl), -NH 2 , -NH(C 1 -C 6 alkyl), or -N(C 1 -C 6 alkyl) 2 may be replaced.

[0465] In some embodiments, at least one R 3S is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 3 -C 8 cycloalkyl, or 3- to 8-membered heterocycloalkyl, and the C 1 -C6 Alkyl may be substituted with one halo, -CN, -OH, -O(C 1 -C 6 -alkyl), -NH 2 -, -NH(C 1 -C 6 -alkyl), or -N(C 1 -C 6 -alkyl) 2 and may be substituted.

[0466] In some embodiments, at least one R 3S is C which may be substituted with one or more halo, -CN, -OH, -O(C 1 -C 6 -alkyl), -NH 2 -, -NH(C 1 -C 6 -alkyl), or -N(C 1 -C 6 -alkyl) 2 and is C 1 -C 6 -alkyl.

[0467] In some embodiments, at least one R 3S is C which may be substituted with one halo, -CN, -OH, -O(C 1 -C 6 -alkyl), -NH 2 -, -NH(C 1 -C 6 -alkyl), or -N(C 1 -C 6 -alkyl) 2 and is C 1 -C 6 -alkyl.

[0468] In some embodiments, at least one R 3S is C which may be substituted with one or more halo, -CN, or -OH and is 1 -C 6 -alkyl.

[0469] In some embodiments, at least one R 3S is C which may be substituted with one halo, -CN, or -OH and is1 -C 6 is alkyl.

[0470] In some embodiments, at least one R 3S may be C 1 -C 6 alkyl substituted with one or more halos. In some embodiments, at least one R 3S may be C 1 -C 6 alkyl substituted with one or more F, Cl, Br, or I. In some embodiments, at least one R 3S may be C 1 -C 6 alkyl substituted with one or more F or Cl. In some embodiments, at least one R 3S may be C 1 -C 6 alkyl substituted with one or more Cl. In some embodiments, at least one R 3S may be C 1 -C 6 alkyl substituted with one or more F.

[0471] In some embodiments, at least one R 3S may be C 1 -C 6 alkyl substituted with one halo. In some embodiments, at least one R 3S may be C 1 -C 6 alkyl substituted with one F, Cl, Br, or I. In some embodiments, at least one R 3S may be C 1 -C 6 alkyl substituted with one F or Cl. In some embodiments, at least one R 3S may be C 1 -C 6 alkyl substituted with one Cl. In some embodiments, at least one R 3S may be C 1 -C6 is alkyl.

[0472] In some embodiments, at least one R 3S is C which may be substituted with one or more -CN 1 -C 6 is alkyl. In some embodiments, at least one R 3S is C which may be substituted with one or more -OH 1 -C 6 is alkyl.

[0473] In some embodiments, at least one R 3S is C which may be substituted with one -CN 1 -C 6 is alkyl. In some embodiments, at least one R 3S is C which may be substituted with one -OH 1 -C 6 is alkyl.

[0474] In some embodiments, at least one R 3S is C which may be substituted with one or more -O(C 1 -C 6 alkyl) 1 -C 6 is alkyl.

[0475] In some embodiments, at least one R 3S is C which may be substituted with one -O(C 1 -C 6 alkyl) 1 -C 6 is alkyl.

[0476] In some embodiments, at least one R 3S is C which may be substituted with one or more -NH 2 , -NH(C 1 -C 6 alkyl), or -N(C 1 -C 6 alkyl) 2 and is C 1 -C6 is alkyl.

[0477] In some embodiments, at least one R 3S is C 2 -C 1 -C 6 alkyl), or -N(C 1 -C 6 alkyl) 2 optionally substituted with one or more -NH 1 -C 6 is alkyl.

[0478] In some embodiments, at least one R 3S is C 2 -C 1 -C 6 alkyl optionally substituted with one or more -NH

[0479] In some embodiments, at least one R 3S is C 2 -C 1 -C 6 alkyl), or -N(C 1 -C 6 alkyl) 2 optionally substituted with one or more -NH(C 1 -C 6 is alkyl.

[0480] In some embodiments, at least one R 3S is C 1 -C 6 alkyl), or -N(C 1 -C 6 alkyl) 2 optionally substituted with one or more -NH(C 1 -C 6 is alkyl.

[0481] In some embodiments, at least one R 3S is C 1 -C 6 alkyl), or -N(C 1 -C 6 alkyl)2 C which may be replaced by 1 -C 6 is alkyl.

[0482] In some embodiments, at least one R 3S is C which may be replaced by one or more -NH(C 1 -C 6 alkyl). 1 -C 6 is alkyl. In some embodiments, at least one R 3S is C which may be replaced by one or more -N(C 1 -C 6 alkyl) 2 and is alkyl. 1 -C 6 is alkyl.

[0483] In some embodiments, at least one R 3S is C which may be replaced by one -NH(C 1 -C 6 alkyl). 1 -C 6 is alkyl. In some embodiments, at least one R 3S is C which may be replaced by one -N(C 1 -C 6 alkyl) 2 and is alkyl. 1 -C 6 is alkyl.

[0484] In some embodiments, at least one R 3S is C 1 -C 6 alkyl or C 1 -C 6 haloalkyl.

[0485] In some embodiments, at least one R 3S is C 1 -C 6 alkyl (e.g., linear or branched).

[0486] In some embodiments, at least one R 3Sis unsubstituted C 1 -C 6 is alkyl (e.g., linear or branched).

[0487] In some embodiments, at least one R 3S is methyl. In some embodiments, at least one R 3S is ethyl. In some embodiments, at least one R 3S is propyl. In some embodiments, at least one R 3S is butyl. In some embodiments, at least one R 3S is pentyl. In some embodiments, at least one R 3S is hexyl. In some embodiments, at least one R 3S is isopropyl. In some embodiments, at least one R 3S is isobutyl. In some embodiments, at least one R 3S is isopentyl. In some embodiments, at least one R 3S is isohexyl. In some embodiments, at least one R 3S is sec-butyl. In some embodiments, at least one R 3S is sec-pentyl. In some embodiments, at least one R 3S is sec-hexyl.

[0488] In some embodiments, at least one R 3S is methyl which may be substituted with -OH. In some embodiments, at least one R 3S is ethyl which may be substituted with -OH. In some embodiments, at least one R 3S is propyl which may be substituted with -OH. In some embodiments, at least one R 3S is butyl which may be substituted with -OH. In some embodiments, at least one R 3S is pentyl which may be substituted with -OH. In some embodiments, at least one R 3Sis hexyl which may be substituted with -OH. In some embodiments, at least one R 3S is isopropyl which may be substituted with -OH. In some embodiments, at least one R 3S is isobutyl which may be substituted with -OH. In some embodiments, at least one R 3S is isopentyl which may be substituted with -OH. In some embodiments, at least one R 3S is isohexyl which may be substituted with -OH. In some embodiments, at least one R 3S is sec-butyl which may be substituted with -OH. In some embodiments, at least one R 3S is sec-pentyl which may be substituted with -OH. In some embodiments, at least one R 3S is sec-hexyl which may be substituted with -OH.

[0489] In some embodiments, at least one R 3S is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 3 -C 8 cycloalkyl, or C 3 -C 8 heterocycloalkyl, and the C 1 -C 6 haloalkyl may be substituted with one or more -CN, -OH, -O(C 1 -C 6 alkyl), -NH 2 , -NH(C 1 -C 6 alkyl), or -N(C 1 -C 6 alkyl) 2 and may be optionally substituted.

[0490] In some embodiments, at least one R 3S is C 1 -C 6 alkyl, C 1 -C6 Haloalkyl, or C 3 -C 8 Cycloalkyl, or C 3 -C 8 Heterocycloalkyl, and the C 1 -C 6 haloalkyl may be substituted with one -CN, -OH, -O(C 1 -C 6 alkyl), -NH 2 , -NH(C 1 -C 6 alkyl), or -N(C 1 -C 6 alkyl) 2 and may be substituted.

[0491] In some embodiments, at least one R 3S is one or more -CN, -OH, -O(C 1 -C 6 alkyl), -NH 2 , -NH(C 1 -C 6 alkyl), or -N(C 1 -C 6 alkyl) 2 and may be substituted C 1 -C 6 haloalkyl.

[0492] In some embodiments, at least one R 3S is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 3 -C 8 cycloalkyl, or C 3 -C 8 heterocycloalkyl, and the C 1 -C 6 haloalkyl may be substituted with one -CN, -OH, -O(C 1 -C 6 alkyl), -NH 2 , -NH(C 1 -C 6 alkyl), or -N(C 1 -C6 (alkyl) 2 may be substituted.

[0493] In some embodiments, at least one R 3S is C 1 -C 6 haloalkyl, which may be substituted with one or more -CN or -OH.

[0494] In some embodiments, at least one R 3S is C 2 -C 6 haloalkyl, which may be substituted with one or more -CN or -OH.

[0495] In some embodiments, at least one R 3S is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 3 -C 8 cycloalkyl, or C 3 -C 8 heterocycloalkyl, where the C 1 -C 6 haloalkyl may be substituted with one -CN, -OH, -O(C 1 -C 6 alkyl), -NH 2 , -NH(C 1 -C 6 alkyl), or -N(C 1 -C 6 alkyl). 2 may be substituted.

[0496] In some embodiments, at least one R 3S is C 1 -C 6 haloalkyl, which may be substituted with one or more -CN. In some embodiments, at least one R 3S is C 1 -C 6 haloalkyl, which may be substituted with one or more -OH. In some embodiments, at least one R3S is C optionally substituted with one or more -OH 2 -C 6 is haloalkyl.

[0497] In some embodiments, at least one R 3S is C optionally substituted with one -CN 1 -C 6 is haloalkyl. In some embodiments, at least one R 3S is C optionally substituted with one -OH 1 -C 6 is haloalkyl. In some embodiments, at least one R 3S is C optionally substituted with one -OH 2 -C 6 is haloalkyl.

[0498] In some embodiments, at least one R 3S is C optionally substituted with one or more -O(C 1 -C 6 alkyl) 1 -C 6 is haloalkyl.

[0499] In some embodiments, at least one R 3S is C optionally substituted with one -O(C 1 -C 6 alkyl) 1 -C 6 is haloalkyl.

[0500] In some embodiments, at least one R 3S is C optionally substituted with one or more -NH 2 , -NH(C 1 -C 6 alkyl), or -N(C 1 -C 6 alkyl) 2 and is C 1 -C 6 is haloalkyl.

[0501] In some embodiments, at least one R 3S is a -NH 2 -, -NH(C 1 -C 6 alkyl), or -N(C 1 -C 6 alkyl)-substituted C 2 -C 1 -C 6 haloalkyl.

[0502] In some embodiments, at least one R 3S is a C 2 -C 1 -C 6 haloalkyl optionally substituted with one or more -NH

[0503] In some embodiments, at least one R 3S is a C 2 -C 1 -C 6 haloalkyl optionally substituted with one -NH

[0504] In some embodiments, at least one R 3S is a C 2 -C 2 -C 6 haloalkyl optionally substituted with one or more -NH

[0505] In some embodiments, at least one R 3S is a C 2 -C 2 -C 6 haloalkyl optionally substituted with one -NH

[0506] In some embodiments, at least one R 3S is a C 1 -C 6 -C 1 -C 6 haloalkyl optionally substituted with one or more -NH(C 2 -C 1 -C 6 alkyl) or -N(C

[0507] In some embodiments, at least one R 3S is a -NH(C 1 -C 6 alkyl) or -N(C 1 -C 6 alkyl) 2 optionally substituted C 1 -C 6 haloalkyl.

[0508] In some embodiments, at least one R 3S is one or more -NH(C 1 -C 6 alkyl) or -N(C 1 -C 6 alkyl) 2 optionally substituted C 2 -C 6 haloalkyl.

[0509] In some embodiments, at least one R 3S is a -NH(C 1 -C 6 alkyl) or -N(C 1 -C 6 alkyl) 2 optionally substituted C 2 -C 6 haloalkyl.

[0510] In some embodiments, at least one R 3S is one or more -NH(C 1 -C 6 alkyl) optionally substituted C 1 -C 6 haloalkyl. In some embodiments, at least one R 3S is one or more -N(C 1 -C 6 alkyl) 2 optionally substituted C 1 -C 6 haloalkyl.

[0511] In some embodiments, at least one R3S is a C optionally substituted with one -NH(C 1 -C 6 alkyl). In some embodiments, at least one R 1 -C 6 is a C haloalkyl optionally substituted with one -N(C 3S -C 1 -C 6 alkyl) 2 is a C haloalkyl optionally substituted with one -NH(C 1 -C 6 alkyl).

[0512] In some embodiments, at least one R 3S is a C haloalkyl optionally substituted with one or more -NH(C 1 -C 6 alkyl). In some embodiments, at least one R 2 -C 6 is a C haloalkyl optionally substituted with one or more -N(C 3S -C 1 -C 6 alkyl) 2 is a C haloalkyl optionally substituted with one -NH(C 2 -C 6 alkyl).

[0513] In some embodiments, at least one R 3S is a C haloalkyl optionally substituted with one -NH(C 1 -C 6 alkyl). In some embodiments, at least one R 2 -C 6 is a C haloalkyl optionally substituted with one -N(C 3S -C 1 -C 6 alkyl) 2 is a C haloalkyl optionally substituted with one -NH(C 2 -C 6 alkyl).

[0514] In some embodiments, at least one R 3S is -CH 2 F, -CHF 2 -, -CF 3 -, -CH 2 CH2 F, -CH 2 CHF 2 、 or -CH 2 CF 3 is. In some embodiments, at least one R 3S is -CHF 2 is. In some embodiments, at least one R 3S is -CH 2 CHF 2 is. In some embodiments, at least one R 3S is -CH 2 CF 3 is.

[0515] In some embodiments, at least one R 3S is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 3 -C 8 cycloalkyl, or 3- to 8-membered heterocycloalkyl, and the C 3 -C 8 cycloalkyl may be substituted with one or more halo, -CN, -OH, -O(C 1 -C 6 alkyl), -NH 2 , -NH(C 1 -C 6 alkyl), or -N(C 1 -C 6 alkyl) 2 optionally.

[0516] In some embodiments, at least one R 3S is C 1 -C 6 cycloalkyl optionally substituted with one or more halo, -CN, -OH, -O(C 2 , -NH 1 -C 6 alkyl), -NH(C 1 -C 6 alkyl), or -N(C 2 alkyl) 3 -C 8 is.

[0517] In some embodiments, at least one R 3S is C which may be substituted with one or more halo, -CN, or -OH 3 -C 8 is cycloalkyl.

[0518] In some embodiments, at least one R 3S is C which may be substituted with one or more halo 3 -C 8 is cycloalkyl. In some embodiments, at least one R 3S is C which may be substituted with one or more F, Cl, Br, or I 3 -C 8 is cycloalkyl. In some embodiments, at least one R 3S is C which may be substituted with one or more F or Cl 3 -C 8 is cycloalkyl. In some embodiments, at least one R 3S is C which may be substituted with one or more Cl 3 -C 8 is cycloalkyl. In some embodiments, at least one R 3S is C which may be substituted with one or more F 3 -C 8 is cycloalkyl.

[0519] In some embodiments, at least one R 3S is C which may be substituted with one or more -CN 3 -C 8 is cycloalkyl. In some embodiments, at least one R 3S is C which may be substituted with one or more -OH 3 -C 8 is cycloalkyl.

[0520] In some embodiments, at least one R 3S is C which may be substituted with one or more -O(C 1 -C 6 alkyl)3 -C 8 is a cycloalkyl.

[0521] In some embodiments, at least one R 3S is C 2 -C 1 -C 6 which may be substituted with one or more -NH 1 -C 6 -alkyl), or -N(C 2 -C 3 -C 8 is a cycloalkyl.

[0522] In some embodiments, at least one R 3S is C 2 -C 3 -C 8 which may be substituted with one or more -NH

[0523] In some embodiments, at least one R 3S is C 1 -C 6 -C 1 -C 6 which may be substituted with one or more -NH(C 2 -C 3 -C 8 -alkyl) or -N(C

[0524] In some embodiments, at least one R 3S is C 1 -C 6 -C 3 -C 8 which may be substituted with one or more -NH(C 3S -C 1 -C 6 -alkyl). In some embodiments, at least one R 2 is C 3 -C 8 which may be substituted with one or more -N(C

[0525] In some embodiments, at least one R 3S is cyclopropyl. In some embodiments, at least one R 3S is cyclobutyl. In some embodiments, at least one R 3S is cyclopentyl. In some embodiments, at least one R 3S is cyclohexyl. In some embodiments, at least one R 3S is cycloheptyl. In some embodiments, at least one R 3S is cyclooctyl.

[0526] In some embodiments, at least one R 3S is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 3 -C 8 cycloalkyl, or 3- to 8-membered heterocycloalkyl, where the 3- to 8-membered heterocycloalkyl may be substituted with one or more halo, -CN, -OH, -O(C 1 -C 6 alkyl), -NH 2 , -NH(C 1 -C 6 alkyl), or -N(C 1 -C 6 alkyl). 2 In some embodiments, at least one R

[0527] is C 3S -C 1 alkyl, C 6 -C 1 haloalkyl, or C 6 -C 3 cycloalkyl, or 3- to 8-membered heterocycloalkyl, where the 3- to 8-membered heterocycloalkyl is substituted with one halo, -CN, -OH, -O(C 8 -C 1 -C 6 alkyl), -NH 2 , -NH(C 1 -C 6(alkyl), or -N(C 1 -C 6 (alkyl) 2 may be substituted.

[0528] In some embodiments, at least one R 3S is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 3 -C 8 cycloalkyl, or a 4- to 8-membered heterocycloalkyl, where the 4- to 8-membered heterocycloalkyl is one or more halo, -CN, -OH, -O(C 1 -C 6 (alkyl), -NH 2 , -NH(C 1 -C 6 (alkyl), or -N(C 1 -C 6 (alkyl) 2 may be substituted.

[0529] In some embodiments, at least one R 3S is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 3 -C 8 cycloalkyl, or a 5- to 8-membered heterocycloalkyl, where the 5- to 8-membered heterocycloalkyl is one or more halo, -CN, -OH, -O(C 1 -C 6 (alkyl), -NH 2 , -NH(C 1 -C 6 (alkyl), or -N(C 1 -C 6 (alkyl) 2 may be substituted.

[0530] In some embodiments, at least one R 3S is C 1 -C 6 alkyl, C 1 -C6 Haloalkyl, or C 3 -C 8 Cycloalkyl, or a 5- to 7-membered heterocycloalkyl, and the 5- to 7-membered heterocycloalkyl is substituted with one or more halos, -CN, -OH, -O(C 1 -C 6 -alkyl), -NH 2 , -NH(C 1 -C 6 -alkyl), or -N(C 1 -C 6 -alkyl) 2 and may be substituted.

[0531] In some embodiments, at least one R 3S is C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, or C 3 -C 8 -cycloalkyl, or a 5- to 6-membered heterocycloalkyl, and the 5- to 6-membered heterocycloalkyl is substituted with one or more halos, -CN, -OH, -O(C 1 -C 6 -alkyl), -NH 2 , -NH(C 1 -C 6 -alkyl), or -N(C 1 -C 6 -alkyl) 2 and may be substituted.

[0532] In some embodiments, at least one R 3S is a 3- to 8-membered heterocycloalkyl that may be substituted with one or more halos, -CN, -OH, -O(C 1 -C 6 -alkyl), -NH 2 , -NH(C 1 -C 6 -alkyl), or -N(C 1 -C 6 -alkyl) 2 and may be substituted.

[0533] In some embodiments, at least one R3S is a 3- to 8-membered heterocycloalkyl optionally substituted with one halo, -CN, -OH, -O(C 1 -C 6 -alkyl), -NH 2 , -NH(C 1 -C 6 -alkyl), or -N(C 1 -C 6 -alkyl) 2 is.

[0534] In some embodiments, at least one R 3S is a 3- to 8-membered heterocycloalkyl optionally substituted with one or more halo, -CN, or -OH.

[0535] In some embodiments, at least one R 3S is a 3- to 8-membered heterocycloalkyl optionally substituted with one halo, -CN, or -OH.

[0536] In some embodiments, at least one R 3S is a 3- to 8-membered heterocycloalkyl optionally substituted with one or more halo. In some embodiments, at least one R 3S is a 3- to 8-membered heterocycloalkyl optionally substituted with one or more F, Cl, Br, or I. In some embodiments, at least one R 3S is a 3- to 8-membered heterocycloalkyl optionally substituted with one or more F or Cl. In some embodiments, at least one R 3S is a 3- to 8-membered heterocycloalkyl optionally substituted with one or more Cl. In some embodiments, at least one R 3S is a 3- to 8-membered heterocycloalkyl optionally substituted with one or more F.

[0537] In some embodiments, at least one R 3S is a 3- to 8-membered heterocycloalkyl optionally substituted with one halo. In some embodiments, at least one R 3Sis a 3- to 8-membered heterocycloalkyl optionally substituted with one F, Cl, Br, or I. In some embodiments, at least one R 3S is a 3- to 8-membered heterocycloalkyl optionally substituted with one F or Cl. In some embodiments, at least one R 3S is a 3- to 8-membered heterocycloalkyl optionally substituted with one Cl. In some embodiments, at least one R 3S is a 3- to 8-membered heterocycloalkyl optionally substituted with one F.

[0538] In some embodiments, at least one R 3S is a 3- to 8-membered heterocycloalkyl optionally substituted with one or more -CN. In some embodiments, at least one R 3S is a 3- to 8-membered heterocycloalkyl optionally substituted with one or more -OH.

[0539] In some embodiments, at least one R 3S is a 3- to 8-membered heterocycloalkyl optionally substituted with one -CN. In some embodiments, at least one R 3S is a 3- to 8-membered heterocycloalkyl optionally substituted with one -OH.

[0540] In some embodiments, at least one R 3S is a 3- to 8-membered heterocycloalkyl optionally substituted with one or more -O(C 1 -C 6 alkyl).

[0541] In some embodiments, at least one R 3S is a 3- to 8-membered heterocycloalkyl optionally substituted with one -O(C 1 -C 6 alkyl).

[0542] In some embodiments, at least one R 3S is a 3- to 8-membered heterocycloalkyl optionally substituted with one or more -NH 2, -NH(C 1 -C 6 alkyl), or -N(C 1 -C 6 alkyl) 2 which may be a 3- to 8-membered heterocycloalkyl optionally substituted with

[0543] In some embodiments, at least one R 3S is a 3- to 8-membered heterocycloalkyl optionally substituted with one -NH 2 , -NH(C 1 -C 6 alkyl), or -N(C 1 -C 6 alkyl) 2 which may be a 3- to 8-membered heterocycloalkyl optionally substituted with

[0544] In some embodiments, at least one R 3S is a 3- to 8-membered heterocycloalkyl optionally substituted with one or more -NH 2 which may be a 3- to 8-membered heterocycloalkyl optionally substituted with

[0545] In some embodiments, at least one R 3S is a 3- to 8-membered heterocycloalkyl optionally substituted with one -NH 2 which may be a 3- to 8-membered heterocycloalkyl optionally substituted with

[0546] In some embodiments, at least one R 3S is a 3- to 8-membered heterocycloalkyl optionally substituted with one or more -NH(C 1 -C 6 alkyl) or -N(C 1 -C 6 alkyl) 2 which may be a 3- to 8-membered heterocycloalkyl optionally substituted with

[0547] In some embodiments, at least one R 3S is a 3- to 8-membered heterocycloalkyl optionally substituted with one -NH(C 1 -C 6 alkyl) or -N(C 1 -C 6 alkyl) 2 which may be a 3- to 8-membered heterocycloalkyl optionally substituted with

[0548] In some embodiments, at least one R 3S is a 3- to 8-membered heterocycloalkyl optionally substituted with one or more -NH(C 1 -C 6 alkyl). In some embodiments, at least one R 3S is a C 1 -C 6 heterocycloalkyl optionally substituted with one or more -N(C 2 alkyl) 3 -C 8 .

[0549] In some embodiments, at least one R 3S is a 3- to 8-membered heterocycloalkyl optionally substituted with one -NH(C 1 -C 6 alkyl). In some embodiments, at least one R 3S is a C 1 -C 6 heterocycloalkyl optionally substituted with one -N(C 2 alkyl) 3 -C 8 .

[0550] In some embodiments, at least one R 3S is a 3- to 7-membered heterocycloalkyl. In some embodiments, at least one R 3S is a 3- to 6-membered heterocycloalkyl. In some embodiments, at least one R 3S is a 3- to 5-membered heterocycloalkyl. In some embodiments, at least one R 3S is a 3- to 4-membered heterocycloalkyl. In some embodiments, at least one R 3S is a 4- to 5-membered heterocycloalkyl. In some embodiments, at least one R 3S is a 4- to 6-membered heterocycloalkyl. In some embodiments, at least one R 3S is a 4- to 7-membered heterocycloalkyl. In some embodiments, at least one R 3Sis a 4- to 8-membered heterocycloalkyl. In some embodiments, at least one R 3S is a 5- to 8-membered heterocycloalkyl. In some embodiments, at least one R 3S is a 5- to 7-membered heterocycloalkyl. In some embodiments, at least one R 3S is a 5- to 6-membered heterocycloalkyl. In some embodiments, at least one R 3S is a 6- to 8-membered heterocycloalkyl. In some embodiments, at least one R 3S is a 6- to 7-membered heterocycloalkyl. In some embodiments, at least one R 3S is a 7- to 8-membered heterocycloalkyl.

[0551] In some embodiments, at least one R 3S is a 3-membered heterocycloalkyl. In some embodiments, at least one R 3S is a 4-membered heterocycloalkyl. In some embodiments, at least one R 3S is a 5-membered heterocycloalkyl. In some embodiments, at least one R 3S is a 6-membered heterocycloalkyl. In some embodiments, at least one R 3S is a 7-membered heterocycloalkyl. In some embodiments, at least one R 3S is an 8-membered heterocycloalkyl.

[0552] In some embodiments, at least one R 3S is halo.

[0553] In some embodiments, at least one R 3S is F, Cl, Br, or I. In some embodiments, at least one R 3S is F or Cl. In some embodiments, at least one R 3S is F. In some embodiments, at least one R 3S is Cl.

[0554] In some embodiments, the compound is of formula (I-a), (I-b), or (I-c): the compound of TIFF0007682813000049.tif63128, or a prodrug, solvate, or pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , and R 3S are as described herein.

[0555] In some embodiments, the compound is a compound of formula (I-a), or a prodrug, solvate, or pharmaceutically acceptable salt thereof.

[0556] In some embodiments, the compound is a compound of formula (I-b), or a prodrug, solvate, or pharmaceutically acceptable salt thereof.

[0557] In some embodiments, the compound is a compound of formula (I-c), or a prodrug, solvate, or pharmaceutically acceptable salt thereof.

[0558] In some embodiments, the compound is of formula (I-d): the compound of TIFF0007682813000050.tif26128, or a prodrug, solvate, or pharmaceutically acceptable salt thereof, wherein R 2 , and R 3 are as described herein.

[0559] In some embodiments, the compound is a compound of formula (I-d), or a prodrug, solvate, or pharmaceutically acceptable salt thereof.

[0560] In some embodiments, the compound is of formula (I-e), (I-f), or (I-g): the compound of TIFF0007682813000051.tif85128, or a prodrug, solvate, or pharmaceutically acceptable salt thereof, wherein R 2 , and R3S is as described herein.

[0561] In some embodiments, the compound is a compound of formula (I-e), or a prodrug, solvate, or pharmaceutically acceptable salt thereof.

[0562] In some embodiments, the compound is a compound of formula (I-f), or a prodrug, solvate, or pharmaceutically acceptable salt thereof.

[0563] In some embodiments, the compound is a compound of formula (I-g), or a prodrug, solvate, or pharmaceutically acceptable salt thereof.

[0564] In some embodiments, the compound is of formula (I-h) or (I-i): a compound of TIFF0007682813000052.tif47128, or a prodrug, solvate, or pharmaceutically acceptable salt thereof, wherein R 1 , R 2S , and R 3 are as described herein.

[0565] In some embodiments, the compound is a compound of formula (I-h), or a prodrug, solvate, or pharmaceutically acceptable salt thereof.

[0566] In some embodiments, the compound is a compound of formula (I-i), or a prodrug, solvate, or pharmaceutically acceptable salt thereof.

[0567] In some embodiments, the compound is of formula (I-j) or (I-k): a compound of TIFF0007682813000053.tif63128, or a prodrug, solvate, or pharmaceutically acceptable salt thereof, wherein R 2S , and R 3 are as described herein.

[0568] In some embodiments, the compound is a compound of formula (I-j), or a prodrug, solvate, or pharmaceutically acceptable salt thereof.

[0569] In some embodiments, the compound is a compound of formula (I-k), or a prodrug, solvate, or pharmaceutically acceptable salt thereof.

[0570] In some embodiments, the compound is of formula (I-l), (I-m), (I-n), or (I-o): a compound of TIFF0007682813000054.tif102128, or a prodrug, solvate, or pharmaceutically acceptable salt thereof, wherein R 1 , R 2S , and R 3S are as described herein.

[0571] In some embodiments, the compound is a compound of formula (I-l), or a prodrug, solvate, or pharmaceutically acceptable salt thereof.

[0572] In some embodiments, the compound is a compound of formula (I-m), or a prodrug, solvate, or pharmaceutically acceptable salt thereof.

[0573] In some embodiments, the compound is a compound of formula (I-n), or a prodrug, solvate, or pharmaceutically acceptable salt thereof.

[0574] In some embodiments, the compound is a compound of formula (I-o), or a prodrug, solvate, or pharmaceutically acceptable salt thereof.

[0575] In some embodiments, the compound is of formula (I-p), (I-q), (I-r), or (I-s): a compound of TIFF0007682813000055.tif128128, or a prodrug, solvate, or pharmaceutically acceptable salt thereof, wherein R2S and R 3S is as described herein.

[0576] In some embodiments, the compound is a compound of formula (I-p), or a prodrug, solvate, or pharmaceutically acceptable salt thereof.

[0577] In some embodiments, the compound is a compound of formula (I-q), or a prodrug, solvate, or pharmaceutically acceptable salt thereof.

[0578] In some embodiments, the compound is a compound of formula (I-r), or a prodrug, solvate, or pharmaceutically acceptable salt thereof.

[0579] In some embodiments, the compound is a compound of formula (I-s), or a prodrug, solvate, or pharmaceutically acceptable salt thereof.

[0580] In some embodiments, the compound is of formula (I-n) or (I-o): a compound of TIFF0007682813000056.tif63128, or a prodrug, solvate, or pharmaceutically acceptable salt thereof, wherein R 2S and R 3S is as described herein.

[0581] In some embodiments, the compound is a compound of formula (I-t), or a prodrug, solvate, or pharmaceutically acceptable salt thereof.

[0582] In some embodiments, the compound is a compound of formula (I-u), or a prodrug, solvate, or pharmaceutically acceptable salt thereof.

[0583] For a compound of any one of the formulas described herein, R 1 R 1S R 2 R 2S R3 and R 3S can each, when applicable, be selected from the groups described herein, and R 1 , R 1S , R 2 , R 2S , R 3 , and R 3S any of the groups described herein with respect to any one of R 1 , R 1S , R 2 , R 2S , R 3 , and R 3S can be combined with any of the groups described herein with respect to any remaining one or more of R

[0584] In some embodiments, the compound is selected from the compounds described in Table 1, as well as prodrugs and pharmaceutically acceptable salts thereof.

[0585] In some embodiments, the compound is selected from the compounds described in Table 1 and pharmaceutically acceptable salts thereof.

[0586] In some embodiments, the compound is selected from prodrugs of the compounds described in Table 1 and pharmaceutically acceptable salts thereof.

[0587] In some embodiments, the compound is selected from the compounds described in Table 1. (Table 1) TIFF0007682813000057.tif172128TIFF0007682813000058.tif188128

[0588] In some embodiments, the compound is a pharmaceutically acceptable salt of any one of the compounds described in Table 1.

[0589] In some embodiments, the compound is a lithium salt, sodium salt, potassium salt, calcium salt, or magnesium salt of any one of the compounds described in Table 1.

[0590] In some embodiments, the compound is the sodium salt or potassium salt of any one of the compounds described in Table 1.

[0591] In some embodiments, the compound is the sodium salt of any one of the compounds described in Table 1. For example, the sodium salt of Compound No. 11 may be TIFF0007682813000059.tif23128.

[0592] In some embodiments, the compound is the potassium salt of any one of the compounds described in Table 1.

[0593] In some aspects, the present disclosure provides a compound that is an isotope derivative of a compound of any one of the formulas disclosed herein (e.g., a compound labeled with an isotope).

[0594] In some embodiments, the compound is an isotope derivative of any one of the compounds described in Table 1, as well as its prodrug and pharmaceutically acceptable salts.

[0595] In some embodiments, the compound is an isotope derivative of any one of the compounds described in Table 1 and its pharmaceutically acceptable salts.

[0596] In some embodiments, the compound is an isotope derivative of any one of the prodrugs of the compounds described in Table 1 and its pharmaceutically acceptable salts.

[0597] In some embodiments, the compound is an isotope derivative of any one of the compounds described in Table 1.

[0598] It should be understood that isotopic derivatives can be prepared using any of a variety of techniques recognized in the art. For example, generally, isotopic derivatives can be prepared by performing the procedures disclosed in the schemes and / or examples described herein using isotopically labeled reagents instead of non-isotopically labeled reagents.

[0599] In some embodiments, the isotopic derivative is a deuterium-labeled compound.

[0600] In some embodiments, the isotopic derivative is a deuterium-labeled compound of any one of the compounds of the formula disclosed herein.

[0601] As used herein, the term "isotopic derivative" refers to a derivative of a compound in which one or more atoms are isotopically enriched or labeled. For example, an isotopic derivative of a compound of formula (I) is isotopically enriched or labeled for one or more isotopes as compared to the corresponding compound of formula (I). In some embodiments, the isotopic derivative is 2 H, 13 C, 14 C, 15 N, 18 O, 29 Si, 31 P, and 34 S. In some embodiments, the isotopic derivative is a deuterium-labeled compound (i.e., enriching one or more of its atoms with 2 H).

[0602] In some embodiments, the compound is a deuterium-labeled compound of any one of the compounds described in Table 1 and its prodrugs and pharmaceutically acceptable salts.

[0603] In some embodiments, the compound is a deuterium-labeled compound of any one of the compounds described in Table 1 and its pharmaceutically acceptable salts.

[0604] In some embodiments, the compound is a deuterium-labeled compound of any one of the compounds described in Table 1 and pharmaceutically acceptable salts thereof as prodrugs.

[0605] In some embodiments, the compound is a deuterium-labeled compound of any one of the compounds described in Table 1.

[0606] It should be understood that the deuterium-labeled compound contains deuterium atoms showing a deuterium abundance ratio substantially exceeding the natural abundance ratio of deuterium which is 0.015%.

[0607] In some embodiments, the deuterium-labeled compound shows a deuterium enrichment factor of at least 3500 (52.5% deuterium incorporation in each deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation) for each deuterium atom. As used herein, the term "deuterium enrichment factor" means the ratio between the deuterium abundance ratio and the natural abundance ratio of deuterium.

[0608] It should be understood that the deuterium-labeled compound can be prepared using any of a variety of techniques recognized in the art. For example, generally, the deuterium-labeled compound can be prepared by performing the procedures disclosed in the schemes and / or examples described herein using deuterium-labeled reagents instead of non-deuterium-labeled reagents.

[0609] The compound of the present invention containing the above-described deuterium atom(s), or a pharmaceutically acceptable salt or solvate thereof, is within the scope of the present invention. Further, deuterium (i.e., 2Substitution according to (H) can lead to certain therapeutic advantages obtained by increased metabolic stability, such as an extended in vivo half-life or a reduced required dose.

[0610] In some embodiments, the compound is 18 an F-labeled compound.

[0611] In some embodiments, the compound is 123 an I-labeled compound, 124 an I-labeled compound, 125 an I-labeled compound, 129 an I-labeled compound, 131 an I-labeled compound, 135 an I-labeled compound, or any combination thereof.

[0612] In some embodiments, the compound is 33 an S-labeled compound, 34 an S-labeled compound, 35 an S-labeled compound, 36 an S-labeled compound, or any combination thereof.

[0613] 18 F, 123 I, 124 I, 125 I, 129 I, 131 I, 135 I, 32 S, 34 S, 35 S, and / or 36 It should be understood that the S-labeled compounds can be prepared using any of a variety of techniques recognized in the art. For example, generally, deuterium-labeled compounds are prepared by performing the procedures disclosed in the schemes and / or examples described herein, using non-isotope-labeled reagents with 18 F, 123 I, 124 I, 125 I, 129 I, 131 I, 135 I, 32 S, 34 S, 35 S, and / or 36It can be prepared by replacing with the S-labeling reagent.

[0614] As described above 18 F 123 I 124 I 125 I 129 I 131 I 135 I 32 S 34 S 35 S, and 36 A compound of the present invention containing one or more of S atoms (plural possible) or a pharmaceutically acceptable salt or solvate thereof is within the scope of the present invention. Further, isotopes (for example, 18 F 123 I 124 I 125 I 129 I 131 I 135 I 32 S 34 S 35 S, and / or 36 S) substitution may lead to certain therapeutic advantages obtained by increased metabolic stability, such as an extended in vivo half-life or a reduced required dose.

[0615] To avoid misunderstanding, it should be noted that in this specification, if a group is described as "described in this specification", the group should be understood to include the most general and unambiguous definition, and any specific definition within the group.

[0616] The various functional groups and substituents constituting the compound of formula (I) are usually selected such that the molecular weight of the compound does not exceed 1000 daltons. More generally, the molecular weight of the compound is less than 900 daltons, for example, less than 800 daltons, or less than 750 daltons, or less than 700 daltons, or less than 650 daltons. More preferably, the molecular weight is less than 600 daltons, for example, 550 daltons or less.

[0617] Suitable pharmaceutically acceptable salts of the compounds of the present disclosure include, for example, acid addition salts of the compounds of the present disclosure that are sufficiently basic, such as inorganic acids or organic acids, for example, acid addition salts with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, formic acid, citric acid, methanesulfonic acid, or maleic acid. In addition, suitable pharmaceutically acceptable salts of the compounds of the present disclosure that are sufficiently acidic are alkali metal salts, such as sodium salts or potassium salts, alkaline earth metal salts, such as calcium salts or magnesium salts, ammonium salts, or salts with organic bases that give pharmaceutically acceptable cations, for example, salts with methylamine, dimethylamine, diethylamine, trimethylamine, piperidine, morpholine, or tris-(2-hydroxyethyl)amine.

[0618] It should be understood that the compounds of any one of the formulas disclosed herein and their pharmaceutically acceptable salts include the stereoisomers, stereoisomer mixtures, and polymorphs of all isomeric forms of the compound.

[0619] As used herein, the term "isomer" means a compound having the same molecular formula but different bonding orders of atoms or different spatial arrangements of atoms. Isomers with different spatial arrangements of atoms are referred to as "stereoisomers". Stereoisomers that are not mirror images of each other are referred to as "diastereoisomers", and stereoisomers that are non-superimposable mirror images of each other may be referred to as "enantiomers" or optical isomers. A mixture containing equal amounts of individual enantiomeric forms with opposite chirality is referred to as a "racemic mixture".

[0620] As used herein, the term "chiral center" refers to a carbon atom bonded to four different substituents.

[0621] As used herein, the term "chiral isomer" means a compound having at least one chiral center. Compounds having two or more chiral centers can exist as individual diastereomers or as a mixture of diastereomers, which is called a "mixture of diastereomers". When there is one chiral center, the stereoisomers can be characterized by the absolute configuration (R or S) of that chiral center. The absolute configuration refers to the spatial arrangement of the substituents attached to the chiral center. The substituents attached to the chiral center under consideration are ranked according to the Cahn, Ingold and Prelog ranking rules (Cahn et al, Angew. Chem. Inter. Edit. 1966, 5, 385; errata 511; Cahn et al., Angew. Chem. 1966, 78, 413; Cahn and Ingold, J. Chem. Soc. 1951 (London), 612; Cahn et al., Experientia 1956, 12, 81; Cahn, J. Chem. Educ. 1964, 41, 116).

[0622] As used herein, the term "geometric isomer" means diastereomers that exist due to the rotational hindrance around a double bond or a cycloalkyl linker (e.g., 1,3-cyclobutyl). These configurations are distinguished by the prefixes cis and trans, or Z and E, which indicate according to the Cahn-Ingold-Prelog rules that multiple groups are present on the same side or opposite sides of the double bond of the molecule.

[0623] It should be understood that the compounds of the present disclosure can be shown as different chiral isomers or geometric isomers. It should also be understood that when a compound has chiral or geometric isomeric forms, all isomeric forms are intended to be included within the scope of the present disclosure, and the naming of the compound does not exclude any isomeric form, and it should be understood that all isomers may not have the same level of activity.

[0624] It should be understood that all of the structures and other compounds described in this disclosure include all of their atropisomers. It should also be understood that all atropisomers may not exhibit the same level of activity.

[0625] As used herein, the term "atropisomer" refers to a type of stereoisomer in which the atoms of two isomers exhibit different spatial arrangements. Atropisomers exist due to rotational restrictions caused by the rotational hindrance of large groups around the central bond. These atropisomers generally exist as mixtures, but as a result of recent advances in chromatography techniques, it has become possible to separate mixtures of two atropisomers in limited cases.

[0626] As used herein, the term "tautomer" refers to one of two or more structural isomers that exist in equilibrium and are readily convertible from one isomeric form to the other. This conversion involves a formal shift of a hydrogen atom accompanied by the switching of adjacent conjugated double bonds. Tautomers exist as a mixture of a set of tautomers in solution. In a solution where tautomerization is possible, a chemical equilibrium of tautomers is reached. The exact ratio of tautomers depends on several factors such as temperature, solvent, and pH. The concept that tautomers can interconvert by tautomerization is referred to as tautomerism. Two of the various possible types of tautomerism are generally recognized. In keto-enol tautomerism, a simultaneous shift of electrons and a hydrogen atom occurs. As shown by glucose, ring-chain tautomerism results from the reaction of an aldehyde group (-CHO) in a sugar molecule with one hydroxy group (-OH) of the same molecule, causing the molecule to assume a cyclic (ring-shaped) form.

[0627] It should be understood that the compounds of this disclosure may be shown as different tautomers. It should also be understood that when a compound has tautomeric forms, all tautomeric forms are intended to be included within the scope of this disclosure and that the naming of the compound does not exclude any tautomeric form. It should be understood that a particular tautomer may exhibit a higher level of activity than other tautomers.

[0628] Compounds that have the same molecular formula but differ in the nature of the atoms, the order of bonding, or the spatial arrangement of the atoms are called "isomers". Isomers that differ in the spatial arrangement of the atoms are called "stereoisomers". Stereoisomers that are not mirror images of each other are called "diastereomers", and stereoisomers that are mirror images that cannot be superimposed on each other are called "enantiomers". For example, when a compound has an asymmetric center, the asymmetric center is bonded to four different groups, and a pair of enantiomers is possible. Enantiomers can be characterized by the absolute configuration of the asymmetric center and are described in terms of the Cahn and Prelog R- and S-rank rules, or the manner in which the molecule rotates the plane of polarization of light, and are named dextrorotatory or levorotatory (i.e., (+) or (-)-isomers, respectively). Chiral compounds can exist as individual enantiomers or mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture".

[0629] The compounds of the present disclosure may have one or more asymmetric centers and, accordingly, the compounds can be produced as individual (R)- or (S)-stereoisomers, or mixtures thereof. Unless otherwise indicated, the description or naming of a particular compound in this specification and the claims is intended to include both the individual enantiomers and their racemic mixtures, or other mixtures. Methods for determining and separating the stereochemical configurations of stereoisomers, for example, by synthesis from optically active starting materials or by resolution of racemates, are well known in the art (see the description in Chapter 4 of "Advanced Organic Chemistry", 4th edition J. March, John Wiley and Sons, New York, 2001). Some of the compounds of the present disclosure may have geometric isomeric centers (E- and Z-isomers). It should be understood that the present disclosure includes all optical isomers, diastereoisomers, and geometric isomers having inflammasome inhibitory activity, and mixtures thereof.

[0630] The present disclosure includes compounds of the present disclosure as defined herein that contain one or more isotope substitutions.

[0631] It should be understood that compounds of any formula described herein include the compound itself, and, where appropriate, its salts and solvates. For example, salts can be formed between a disclosed substituted compound and an anion and a positively charged group (e.g., amino). Suitable anions include chloride, bromide, iodide, sulfate, bisulfate, sulfamate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, glutamate, glucuronate, glutarate, malate, maleate, succinate, fumarate, tartrate, tosylate, salicylate, lactate, naphthalenesulfonate, and acetate (e.g., trifluoroacetate).

[0632] As used herein, the term "pharmaceutically acceptable anion" refers to an anion suitable for forming a pharmaceutically acceptable salt. Similarly, salts can also be formed between a disclosed substituted compound and a cation and a negatively charged group (e.g., carboxylate). Suitable cations include sodium ion, potassium ion, magnesium ion, calcium ion, and ammonium cations such as tetramethylammonium ion or diethylamine ion. Also, the disclosed substituted compounds include salts containing a quaternary nitrogen atom.

[0633] It should be understood that the compounds of the present disclosure, e.g., salts of the compounds, can exist in hydrated or non-hydrated (anhydrous) forms, or as solvates with other solvent molecules. Examples of hydrates include, but are not limited to, monohydrate, dihydrate, etc. Examples of solvates include, but are not limited to, ethanol solvate, acetone solvate, etc.

[0634] As used herein, the term "solvate" means a solvate adduct containing a stoichiometric or non-stoichiometric amount of a solvent. Some compounds have a tendency to form solvates by the crystalline solid capturing solvent molecules in a fixed molar ratio. When the solvent is water, the solvate formed is a hydrate, and when the solvent is an alcohol, the solvate formed is an alcoholate. Hydrates are formed by combining one or more molecules of water with one molecule of a substance, and the water retains its molecular state as H 2 O.

[0635] As used herein, the term "analog" means a compound that is structurally similar to another compound but has a slightly different composition (e.g., one atom is replaced by an atom of a different element, or a particular functional group is present, i.e., one functional group is replaced by another functional group). Thus, an analog is a compound that has the same or equivalent function and appearance as a reference compound but does not have the same or equivalent structure or origin.

[0636] As used herein, the term "derivative" refers to a compound that has a common core structure but is substituted with various groups described herein.

[0637] As used herein, the term "biological equivalent" refers to a compound obtained by replacing an atom or group of atoms with another atom or group of atoms that is broadly similar. The purpose of biological equivalent substitution is to create a new compound that has biological properties similar to those of the parent compound. Biological equivalent substitution can be physical-chemical or morphological. Examples of carboxylic acid biological equivalents include, but are not limited to, acylsulfonamides, tetrazoles, sulfonates, and phosphonates. See, for example, Patani and LaVoie, Chem. Rev. 96, 3147-3176, 1996.

[0638] It should also be understood that the specific compounds of any one of the formulas disclosed herein may exist in solvated forms, as well as non-solvated forms such as, for example, hydrated forms. For example, suitable solvates acceptable as pharmaceuticals are hydrates such as hemihydrate, monohydrate, dihydrate, or trihydrate. It should be understood that the present disclosure includes all of these solvated forms having inflammasome inhibitory activity.

[0639] It should also be understood that the specific compounds of any one of the formulas disclosed herein may exhibit polymorphs, and that the present disclosure includes all of these forms having inflammasome inhibitory activity, or mixtures thereof. It is generally known that crystalline materials can be analyzed using conventional techniques such as X-ray powder diffraction analysis, differential scanning calorimetry, thermogravimetric analysis, diffuse reflectance infrared Fourier transform (DRIFT) spectroscopy, near infrared (NIR) spectroscopy, solution and / or solid state nuclear magnetic resonance spectroscopy. The water content of these crystalline materials can be determined by Karl Fischer analysis.

[0640] The compounds of any one of the formulas disclosed herein can exist in numerous different tautomeric forms, and the description of the compounds of formula (I) includes all of these forms. For the sake of clarity, if a compound can exist as one of several tautomeric forms and only one is specifically noted or illustrated, all other tautomeric forms are still included in formula (I). Examples of tautomeric forms include keto forms, enol forms, and enolate forms, such as the following tautomeric pairs: keto / enol (shown below), imine / enamine, amide / imino alcohol, amidine / amidine, nitroso / oxime, thioketone / enthiole, and nitro / acy-nitro. TIFF0007682813000060.tif18128

[0641] Any one of the compounds of any one of the formulas disclosed herein that contain an amine functional group can also form an N-oxide. The description herein regarding the compounds of formula (I) that contain an amine functional group includes N-oxides. When a compound contains several amine functional groups, one or more nitrogen atoms can be oxidized to form an N-oxide. Specific examples of N-oxides include tertiary amines of nitrogen-containing heterocycles or N-oxides of nitrogen atoms. N-oxides can be formed by treating the corresponding amine with an oxidizing agent such as hydrogen peroxide or a peracid (e.g., peroxycarboxylic acid), see, for example, Advanced Organic Chemistry, by Jerry March, 4th Edition, Wiley Interscience. More specifically, N-oxides can be produced by the procedure of L. W. Deady (Syn. Comm. 1977, 7, 509-514), which involves reacting an amine compound with meta-chloroperoxybenzoic acid (mCPBA) in an inert solvent such as dichloromethane.

[0642] Any one of the compounds of any one of the formulas disclosed herein can be administered in the form of a prodrug that decomposes in the human or animal body to release the compounds of the present disclosure. By using prodrugs, the physical properties and / or pharmacokinetic properties of the compounds of the present disclosure can be modified. When the compounds of the present disclosure contain suitable groups or substituents to which a property-modifying group can be attached, prodrugs can be formed. Examples of prodrugs include derivatives containing an alkyl or acyl substituent that is cleavable in vivo on an ester or amide group of any one of the formulas disclosed herein.

[0643] Accordingly, the present disclosure includes a compound of any one of the formulas disclosed herein as defined above when it becomes available for use in organic synthesis and when its prodrug becomes available for use in the body of a human or animal by cleavage. Accordingly, the present disclosure includes a compound of any one of the formulas disclosed herein produced by organic synthesis means, as well as the compound produced in the body of a human or animal by metabolism of a precursor compound, that is, a compound of any one of the formulas disclosed herein can be a compound produced by synthesis or a compound produced by metabolism.

[0644] A pharmaceutically acceptable suitable prodrug of a compound of any one of the formulas disclosed herein is a prodrug based on a reasonable medical judgment that it is suitable for administration to the human or animal body, is not accompanied by undesirable pharmacological activity, and is not accompanied by excessive toxicity. Various forms of prodrugs are described, for example, in the following references: a) Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al. (Academic Press, 1985), b) Design of Pro-drugs, edited by H. Bundgaard, (Elsevier, 1985), c) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 “Design and Application of Pro-drugs”, by H. Bundgaard p. 113-191 (1991), d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992), e) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988), f) N. Kakeya, et al., Chem. Pharm. Bull., 32, 692 (1984), g) T. Higuchi and V. Stella, “Pro-Drugs as Novel Delivery Systems”, A.C.S. Symposium Series, Volume 14, and h) E. Roche (editor), “Bioreversible Carriers in Drug Design”, Pergamon Press, 1987.

[0645] Suitable prodrugs that are pharmaceutically acceptable for any one of the compounds of the formulas disclosed herein having a hydroxy group are, for example, its esters or ethers cleavable in vivo. Esters or ethers cleavable in vivo of any one of the compounds of the formulas disclosed herein containing a hydroxy group are, for example, pharmaceutically acceptable esters or ethers that cleave in the body of a human or animal to produce the parent hydroxy compound. Suitable ester-forming groups that are pharmaceutically acceptable for the hydroxy group include inorganic esters such as phosphate esters (including phosphoramidate cyclic esters). Further suitable ester-forming groups for the hydroxy group that are pharmaceutically acceptable include C 1 -C 10 alkanoyl groups such as acetyl group, benzoyl group, phenylacetyl group, and substituted benzoyl groups and substituted phenylacetyl groups, C 1 -C 10 alkoxycarbonyl groups such as ethoxycarbonyl group, N,N-(C 1 -C 6 alkyl) 2 carbamoyl groups, 2-dialkylaminoacetyl groups, and 2-carboxyacetyl groups and the like. Examples of ring substituents of the phenylacetyl group and the benzoyl group include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl, and 4-(C 1 -C 4 alkyl)piperazin-1-ylmethyl. Suitable ether-forming groups that are pharmaceutically acceptable for the hydroxy group include α-acyloxyalkyl groups such as acetoxymethyl group and pivaloyloxymethyl group and the like.

[0646] Suitable prodrugs that are pharmaceutically acceptable for any one of the compounds of the formulas disclosed herein having a carboxy group are, for example, its amides cleavable in vivo, for example, amines such as ammonia, C 1-4 alkylamines such as methylamine, (C 1 -C 4 alkyl)2 Amines, such as dimethylamine, N-ethyl-N-methylamine, or diethylamine, C 1 -C 4 alkoxy-C 2 -C 4 alkylamines, such as 2-methoxyethylamine, phenyl-C 1 -C 4 alkylamines, such as benzylamine, and amino acids, such as glycine, or amides formed from their esters.

[0647] A compound of any one of the formulas disclosed herein, wherein R 3 is not H, is understood to be usable as a prodrug of the corresponding compound wherein R 3 is H. For example, R 3 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl; C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl is one or more C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 5 -C 6 aryl, 5- or 6-membered heteroaryl, C 3 -C 8 heterocycloalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, halo, -CN, -OH, -NH 2 ,-NH(C1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 , oxo, or R 3S Any compound of any one of the formulas disclosed herein, which may be substituted with, may be used as a prodrug of the corresponding compound in which R 3 is H.

[0648] Suitable pharmaceutically acceptable prodrugs of any one of the compounds of the formulas disclosed herein having an amino group are, for example, its amide derivatives cleavable in vivo. Suitable pharmaceutically acceptable amides derived from the amino group include, for example, acetyl group, benzoyl group, phenylacetyl group, and C 1 -C 10 There are amides formed with an alkanoyl group. Examples of ring substituents on the phenylacetyl group and benzoyl group include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl, and 4-(C 1 -C 4 alkyl)piperazin-1-ylmethyl.

[0649] The in vivo effect of any one of the compounds of the formulas disclosed herein may be exerted to some extent by one or more metabolites formed in the body of a human or animal after administration of any one of the compounds of the formulas disclosed herein. Also, as described above, the in vivo effect of any one of the compounds of the formulas disclosed herein may also be exerted by metabolism of the precursor compound (prodrug).

[0650] Preferably, the present disclosure excludes any individual compound that does not exhibit the biological activity defined herein.

[0651] Method of synthesis In some embodiments, the present disclosure provides a method for preparing the compounds of the present disclosure.

[0652] In some embodiments, the present disclosure provides a method of a compound, comprising one or more steps described herein.

[0653] In some embodiments, the present disclosure provides a compound obtainable, or obtained, or directly obtained by a method for preparing the compounds described herein.

[0654] In some embodiments, the present disclosure provides an intermediate described herein that is suitable for use in a method for preparing the compounds described herein.

[0655] The compounds of the present disclosure can be prepared by any suitable technique known in the art. Specific methods for preparing these compounds are further described in the examples that follow.

[0656] In the synthetic methods described herein, and in the description of any synthetic methods used to prepare the starting materials, those skilled in the art will understand that they can select all of the presented reaction conditions, including the selection of solvents, reaction atmospheres, reaction temperatures, experimental times, and work-up procedures.

[0657] Those skilled in the art of organic synthesis understand that the functional groups present in various parts of the molecule must be compatible with the reagents and reaction conditions utilized.

[0658] It is recognized that during the synthesis of the compounds of the present disclosure in the manner defined herein, or during the synthesis of certain starting materials, it may be desirable to protect certain substituents to prevent their unwanted reactions. An experienced chemist will recognize when such protection is needed and how these protecting groups can be placed and later removed. For examples of protecting groups, see one of the many general texts on the subject, such as Theodora Green's "Protective Groups in Organic Synthesis" (publisher: John Wiley & Sons). For the removal of the protecting groups in question, the protecting groups can be removed, as appropriate, by methods described in the literature or by any convenient method known to an experienced chemist, and these methods are selected to effect the removal of the protecting groups while minimizing interference with groups elsewhere in the molecule. Thus, when the reactants contain groups such as, for example, amino, carboxy, or hydroxy, it may be desirable to protect the groups in some of the reactions described herein.

[0659] As an example, suitable protecting groups for an amino group or an alkylamino group are, for example, an acyl group such as an alkanoyl group such as acetyl, an alkoxycarbonyl group such as a methoxycarbonyl group, an ethoxycarbonyl group, or a t-butoxycarbonyl group, an arylmethoxycarbonyl group such as benzyloxycarbonyl, or an aroyl group such as benzoyl. The deprotection conditions of the above-mentioned protecting groups necessarily vary depending on the selection of the protecting group. Therefore, for example, an acyl group such as an alkanoyl group, an alkoxycarbonyl group, or an aroyl group can be removed by hydrolysis with a suitable base such as an alkali metal hydroxide such as lithium hydroxide or sodium hydroxide. Alternatively, an acyl group such as a tert-butoxycarbonyl group can be removed by treatment with a suitable acid such as hydrochloric acid, sulfuric acid, or phosphoric acid, or trifluoroacetic acid, and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group can be removed by hydrogenation with a catalyst such as palladium carbon or treatment with a Lewis acid such as boron tris(trifluoroacetate). A suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group, which can be removed by treatment with an alkylamine such as dimethylaminopropylamine or hydrazine.

[0660] Suitable protecting groups for a hydroxy group are, for example, an acyl group such as an alkanoyl group such as acetyl, an aroyl group such as benzoyl, or an arylmethyl group such as benzyl. The deprotection conditions of the above-mentioned protecting groups necessarily vary depending on the selection of the protecting group. Therefore, for example, an acyl group such as an alkanoyl group or an aroyl group can be removed by hydrolysis with a suitable base such as an alkali metal hydroxide such as lithium hydroxide, sodium hydroxide, or ammonia. Alternatively, an arylmethyl group such as a benzyl group can be removed by hydrogenation with a catalyst such as palladium carbon.

[0661] Suitable protecting groups for carboxy groups are, for example, esterifying groups such as methyl group or ethyl group, which can be removed by hydrolysis with a base such as sodium hydroxide, or, for example, tert-butyl group, which can be removed by treatment with an acid such as an organic acid like trifluoroacetic acid, or, for example, benzyl group, which can be removed by hydrogenation with a catalyst such as palladium carbon.

[0662] When a compound of formula (I) is synthesized by any one of the processes defined herein, the process further comprises the additional steps of (i) removing any protecting groups present, (ii) converting the compound of formula (I) to another compound of formula (I), (iii) forming its pharmaceutically acceptable salt, hydrate, or solvate, and / or (iv) forming its prodrug.

[0663] The obtained compound of formula (I) can be isolated and purified using techniques well known in the art.

[0664] Conveniently, the reaction of the compounds is carried out under their respective reaction conditions, preferably in the presence of a suitable solvent which is preferably inert. Examples of suitable solvents include hydrocarbons such as hexane, petroleum ether, benzene, toluene, or xylene; chlorinated hydrocarbons such as trichloroethylene, 1,2-dichloroethane, carbon tetrachloride, chloroform, or dichloromethane; alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol, or tert-butanol; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF), 2-methyltetrahydrofuran, cyclopentyl methyl ether (CPME), methyl tert-butyl ether (MTBE), or dioxane; glycol ethers such as ethylene glycol monomethyl or monoethyl ether or ethylene glycol dimethyl ether (diglyme); ketones such as acetone, methyl isobutyl ketone (MIBK), or butanone; amides such as acetamide, dimethylacetamide, dimethylformamide (DMF), or N-methylpyrrolidinone (NMP); nitriles such as acetonitrile; sulfoxides such as dimethyl sulfoxide (DMSO); nitro compounds such as nitromethane or nitrobenzene; esters such as ethyl acetate or methyl acetate; or mixtures of these solvents or mixtures with water, but are not limited thereto.

[0665] The reaction temperature is preferably about -100°C to 300°C, depending on the reaction step and conditions used.

[0666] Generally, the reaction time ranges from less than 1 minute to several days, depending on the reactivity of each compound and the respective reaction conditions. Suitable reaction times can be easily determined by methods known to those skilled in the art, such as reaction monitoring. Based on the above-mentioned reaction temperature, suitable reaction times generally range from 10 minutes to 48 hours.

[0667] Furthermore, by utilizing the procedures described herein in combination with ordinary skill in the art, additional compounds of the present disclosure can be readily prepared. One of ordinary skill in the art can readily understand that these compounds can be prepared using the conditions of the following preparation procedures and known variations of the processes.

[0668] As understood by those of ordinary skill in the art of organic synthesis, the compounds of the present disclosure are readily available via various synthetic routes, some of which are exemplified in the examples provided hereinafter. One of ordinary skill in the art can always readily recognize which types of reagents and reaction conditions should be used in any particular case, as well as how to utilize and apply them, when necessary or useful, to obtain the compounds of the present disclosure. Furthermore, by reacting other compounds of the present disclosure under suitable conditions, or by applying standard synthetic methods well-known to those of ordinary skill in the art, such as reduction reactions, oxidation reactions, addition reactions, or substitution reactions, one specific functional group present in a compound of the present disclosure or a suitable precursor molecule thereof can be converted into another functional group, thereby readily synthesizing some of the compounds of the present disclosure. Similarly, one of ordinary skill in the art can always utilize synthetic protecting groups (protective groups) when necessary or useful. Suitable protecting groups and methods for introducing and removing them are well-known to those of ordinary skill in the art of chemical synthesis, and are described in more detail, for example, in P.G.M. Wuts, T.W. Greene, “Greene’s Protective Groups in Organic Synthesis”, 4th edition (2006) (John Wiley & Sons).

[0669] General routes for the preparation of the compounds of the present application are described in Schemes 1 and 2 herein.

[0670] Scheme 1 In Scheme 1, L 1 is a suitable leaving group (e.g., Cl, or another halide).

[0671] Reaction (i) can produce intermediate 3 when amine 1 is reacted with isocyanate 2 in a suitable solvent (e.g., diisopropyl ether, or dichloromethane), and optionally, at low temperature (e.g., 0 °C, or -15 °C). In some embodiments, intermediate 3 can be used directly in solution and not isolated.

[0672] Reaction (ii) can produce intermediate 6 when amine 4 is reacted with carbonyl compound 5 in a suitable solvent (e.g., methanol, or dichloromethane) in the presence of a reducing agent (e.g., sodium cyanoborohydride, or sodium triacetoxyborohydride), and optionally, in the presence of an acidic catalyst (e.g., acetic acid). Intermediate 6 can be isolated by purification (e.g., by flash column chromatography, or preparative HPLC). In some embodiments, intermediate 6 is isolated as the free amine or free salt (e.g., trifluoroacetate salt).

[0673] Reaction (iii) can produce the compound of formula (I) when intermediate 3 is reacted with intermediate 6 in a suitable solvent (e.g., tetrahydrofuran) in the presence of a base (e.g., sodium hydride, or sodium methoxide), and optionally, in the presence of a catalyst (e.g., 4-(dimethylamino)-pyridine). The compound of formula (I) can be isolated by purification (e.g., by flash column chromatography, or preparative HPLC). In some embodiments, the compound of formula (I) is isolated as the free acid or free salt (e.g., sodium salt).

[0674] Scheme 2 TIFF0007682813000062.tif75159 In Scheme 2, L 1 is a suitable leaving group (e.g., Cl, or another halide).

[0675] Reaction (i) can produce intermediate 3 when amine 1 is reacted with isocyanate 2 in a suitable solvent (e.g., diisopropyl ether or dichloromethane), and optionally at a low temperature (e.g., 0 °C or -15 °C). In some embodiments, intermediate 3 can be used directly in solution and not isolated.

[0676] Reaction (ii) can produce intermediate 6 when amine 4 is reacted with acid 5 in a suitable solvent (e.g., DMF) in the presence of a coupling reagent (e.g., HOBt and EDC) and a base (e.g., DIPEA). Intermediate 6 can be purified and isolated (e.g., by flash column chromatography or preparative HPLC).

[0677] Reaction (iii) can produce intermediate 7 when intermediate 6 is reacted with a suitable reducing agent (e.g., BH 3 .THF) in a suitable solvent (e.g., THF).

[0678] In some embodiments, intermediate 7 is isolated as a free amine or a free salt (e.g., trifluoroacetate).

[0679] Reaction (iv) can produce the compound of formula (I) when intermediate 3 is reacted with intermediate 7 in a suitable solvent (e.g., tetrahydrofuran) in the presence of a base (e.g., sodium hydride or sodium methoxide), and optionally in the presence of a catalyst (e.g., 4-(dimethylamino)-pyridine). The compound of formula (I) can be purified and isolated (e.g., by flash column chromatography or preparative HPLC). In some embodiments, the compound of formula (I) is isolated as a free acid or a free salt (e.g., sodium salt).

[0680] Biological assay Once generation is complete, the compounds designed, selected, and / or optimized by the methods described above can be characterized using various assays known to those of skill in the art to determine whether the compounds have biological activity. For example, by characterizing the molecules with conventional assays such as, but not limited to, the assays described below, it can be determined whether they have the predicted activity, binding activity, and / or binding specificity.

[0681] Furthermore, by using high-throughput screening, the rate of analysis using these assays can be increased. As a result, it becomes possible to rapidly screen the activity of the molecules described herein using techniques known in the art. General methodologies for performing high-throughput screening are described, for example, in Devlin (1998) High Throughput Screening, Marcel Dekker, and U.S. Patent No. 5,763,263. In high-throughput assays, one or more different assay techniques such as, but not limited to, the techniques described below can be used.

[0682] A variety of in vitro or in vivo biological assays may be suitable for detecting the effects of the compounds of the present disclosure. These in vitro or in vivo biological assays include, but are not limited to, enzyme activity assays, electrophoretic mobility shift assays, reporter gene assays, in vitro cell viability assays, and the assays described herein.

[0683] In some embodiments, the compounds of the present disclosure can be tested for inhibitory activity in various cell lines (e.g., peripheral blood mononuclear cells). In some embodiments, the compounds of the present disclosure can be tested for inhibitory activity in peripheral blood mononuclear cells. In some embodiments, the compounds of the present disclosure can be tested for their inhibitory activity against IL-1β release upon NLRP3 activation.

[0684] In some embodiments, PBMC IC50 The determination assay can be used for the characterization of the compounds of the present disclosure.

[0685] PBMCs can be isolated, seeded into the wells of plates, and incubated with saccharides. Following a medium change, the compounds of the present disclosure can be added to the wells and incubated. The cells can be stimulated and the cell culture medium can be harvested for analysis.

[0686] PBMCs can be separated by density gradient centrifugation, seeded into the wells of plates, and incubated with saccharides. The compounds of the present disclosure can be added to the wells and incubated. The cells can be stimulated and the cell culture medium can be harvested for analysis.

[0687] In some embodiments, the release of IL-1β can be determined by quantitative detection. In some embodiments, the release of IL-1β can be determined by quantitative detection of IL-1β using an IL-1β enzyme-linked immunosorbent assay (ELISA). A microplate spectrophotometer can be used to detect the signal (e.g., at 450 nm).

[0688] In some embodiments, the release of IL-1β can be determined by quantitative detection of IL-1β using Homogenous Time-Resolved Fluorescence (HTRF®). A microplate spectrophotometer can be used to detect the signal (e.g., at 655 nm and 620 nm).

[0689] In some embodiments, the biological assay is described in the examples herein.

[0690] Pharmaceutical composition In one aspect, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure as an active ingredient. In some embodiments, the present disclosure provides a pharmaceutical composition comprising at least one compound of each formula described herein, or a pharmaceutically acceptable salt or solvate thereof, and one or more pharmaceutically acceptable carriers or excipients. In some embodiments, the present disclosure provides a pharmaceutical composition comprising at least one compound selected from Table 1.

[0691] As used herein, the term "composition" is intended to include a product containing the specified ingredients in the specified amounts, as well as any product obtained directly or indirectly by combining the specified ingredients in the specified amounts.

[0692] The compounds of the present disclosure can be formulated for oral administration in the form of tablets, capsules (including both sustained release and timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. The compounds of the present disclosure can also be formulated for intravenous (bolus or infusion), intraperitoneal, topical, subcutaneous, intramuscular, or transdermal (e.g., patch) administration using forms well known to those skilled in the pharmaceutical art.

[0693] The formulations of the present disclosure can be in the form of an aqueous solution containing an aqueous vehicle. The aqueous vehicle component can include water and at least one pharmaceutically acceptable excipient. Suitable acceptable excipients include excipients selected from the group consisting of solubilizing agents, chelating agents, preservatives, isotonic agents, viscosity modifiers / suspending agents, buffering agents, and pH adjusting agents, and mixtures thereof.

[0694] Any suitable solubility enhancer can be used. Examples of solubility enhancers include cyclodextrins such as hydroxypropyl-β-cyclodextrin, methyl-β-cyclodextrin, randomly methylated-β-cyclodextrin, ethylated-β-cyclodextrin, triacetyl-β-cyclodextrin, peracetyl-β-cyclodextrin, carboxymethyl-β-cyclodextrin, hydroxyethyl-β-cyclodextrin, 2-hydroxy-3-(trimethylammonio)propyl-β-cyclodextrin, glucosyl-β-cyclodextrin, sulfated-β-cyclodextrin (S-β-CD), maltosyl-β-cyclodextrin, β-cyclodextrin sulfobutyl ether, branched-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, randomly methylated-γ-cyclodextrin, and trimethyl-γ-cyclodextrin, and cyclodextrins selected from the group consisting of mixtures thereof.

[0695] Any suitable chelating agent can be used. Examples of suitable chelating agents include chelating agents selected from the group consisting of ethylenediaminetetraacetic acid and its metal salts, disodium edetate, trisodium edetate, and tetrasodium edetate, and mixtures thereof.

[0696] Any suitable preservative can be used. Examples of preservatives include quaternary ammonium salts such as benzalkonium halide (preferably benzalkonium chloride), chlorhexidine gluconate, benzethonium chloride, cetylpyridinium chloride, benzyl bromide, phenylmercuric nitrate, phenylmercuric acetate, phenylmercuric neodecanoate, mercurithiolate, methylparaben, propylparaben, sorbic acid, potassium sorbate, sodium benzoate, sodium propionate, ethyl p-hydroxybenzoate, propylaminopropyl biguanide, and butyl p-hydroxybenzoate, and sorbic acid, and preservatives selected from the group consisting of mixtures thereof.

[0697] In some embodiments, examples of preservatives include quaternary ammonium salts such as benzalkonium halide (preferably benzalkonium chloride), chlorhexidine gluconate, benzethonium chloride, cetylpyridinium chloride, benzyl bromide, phenylmercuric nitrate, mercioleate, methylparaben, propylparaben, sorbic acid, potassium sorbate, sodium benzoate, sodium propionate, ethyl p-hydroxybenzoate, propylaminopropyl biguanide, and butyl-p-hydroxybenzoate, and sorbic acid, and mixtures thereof.

[0698] The aqueous vehicle may contain an isotonic agent for adjusting tonicity (osmotic pressure). The isotonic agent can be selected from the group consisting of glycols (e.g., propylene glycol, diethylene glycol, triethylene glycol), glycerol, glucose, glycerin, mannitol, potassium chloride, and sodium chloride, and mixtures thereof. In some embodiments, the isotonic agent is selected from the group consisting of glycols (e.g., propylene glycol, triethylene glycol), glycerol, dextrose, glycerin, mannitol, potassium chloride, sodium chloride, and mixtures thereof.

[0699] The aqueous vehicle may also include a viscosity modifier / suspending agent. Suitable viscosity modifiers / suspending agents include cellulose derivatives such as methylcellulose, ethylcellulose, hydroxyethylcellulose, polyethylene glycol (e.g., polyethylene glycol 300, polyethylene glycol 400), carboxymethylcellulose, hydroxypropylmethylcellulose, and cross-linked acrylic acid polymers (carbomers), such as acrylic acid polymers cross-linked with polyalkenyl ethers or divinyl glycol (Carbopol, e.g., Carbopol 934, Carbopol 934P, Carbopol 971, Carbopol 974, and Carbopol 974P, etc.), and mixtures thereof.

[0700] To adjust the formulation to an acceptable pH (generally in the pH range of about 5.0 to about 9.0, more preferably about 5.5 to about 8.5, particularly about 6.0 to about 8.5, about 7.0 to about 8.5, about 7.2 to about 7.7, about 7.1 to about 7.9, or about 7.5 to about 8.0), the formulation may contain a pH adjuster. Generally, the pH adjuster is a mineral acid or a metal hydroxide base, and is selected from the group consisting of potassium hydroxide, sodium hydroxide, and hydrochloric acid, and mixtures thereof, preferably sodium hydroxide and / or hydrochloric acid. By adding these acidic and / or basic pH adjusters, the formulation is adjusted to the target acceptable pH range. Therefore, it is not always necessary to use both an acid and a base. Depending on the formulation, it may be sufficient to add only one of an acid or a base to bring the mixture to the desired pH range.

[0701] The aqueous vehicle may also contain a buffer to stabilize the pH. When used, the buffer is selected from the group consisting of phosphate buffers (e.g., sodium dihydrogen phosphate and disodium hydrogen phosphate), borate buffers (e.g., boric acid or their salts containing disodium tetraborate), citrate buffers (e.g., citric acid or their salts containing sodium citrate), and ε-aminocaproic acid, and mixtures thereof.

[0702] The formulation may further contain a wetting agent. Suitable classes of wetting agents include wetting agents selected from the group consisting of polyoxypropylene-polyoxyethylene block copolymers (poloxamers), polyethoxylated castor oil ethers, polyoxyethylated sorbitan esters (polysorbates), oxyethylated octylphenol polymers (Tyloxapol), polyoxyl 40 stearate, fatty acid glycol esters, fatty acid glyceryl esters, sucrose fatty acid esters, and polyoxyethylene fatty acid esters, and mixtures thereof.

[0703] Oral compositions generally include an inert diluent or a pharmaceutically acceptable edible carrier. The oral compositions can be encapsulated in gelatin capsules or compressed into tablets. For the purpose of therapeutic oral administration, the active compounds can be incorporated with excipients and used in the form of tablets, troches, or capsules. Also, oral compositions for use as mouthwashes can be prepared using a fluid carrier. For use as a mouthwash, an oral composition can be prepared using a fluid carrier, the fluid carrier containing the compound is orally applied, and then rinsed and spat out or swallowed. Pharmaceutically compatible binders and / or auxiliary materials can be included as part of the composition. Tablets, pills, capsules, troches, etc. can contain the following components: binders such as crystalline cellulose, tragacanth gum, or gelatin, excipients such as starch or lactose, disintegrants such as alginic acid, Primogel, or corn starch, lubricants such as magnesium stearate or Sterotes, glidants such as colloidal silicon dioxide, sweeteners such as sucrose or saccharin, or flavoring agents such as peppermint, methyl salicylate, or orange flavor, or any compounds of similar nature.

[0704] According to a further aspect of the present disclosure, there is provided a pharmaceutical composition comprising a combination of a compound of the present disclosure as defined above or a pharmaceutically acceptable salt, hydrate, or solvate thereof and a pharmaceutically acceptable diluent or carrier.

[0705] The compositions of the present disclosure can be in a form suitable for oral use (e.g., tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups, or elixirs), in a form suitable for topical use (e.g., creams, ointments, gels, or aqueous or oily solutions or suspensions), in a form suitable for inhalation administration (e.g., fine powders or liquid aerosols), in a form suitable for insufflation administration (e.g., fine powders), or in a form suitable for parenteral administration (e.g., sterile aqueous or oily solutions for intravenous, subcutaneous, intramuscular, intraperitoneal, or intramuscular administration, or suppositories for rectal administration).

[0706] The compositions of the present disclosure can be obtained by conventional procedures using conventional pharmaceutical excipients well known in the art. Thus, compositions for oral use can include, for example, one or more colorants, sweeteners, flavorants, and / or preservatives.

[0707] An effective amount of the compounds of the present disclosure for use in therapy is an amount sufficient to treat or prevent the inflammasome-related disorders described herein, delay their progression, and / or alleviate the symptoms associated with the disorders.

[0708] An effective amount of the compounds of the present disclosure for use in therapy is an amount sufficient to treat the inflammasome-related disorders described herein, delay their progression, and / or alleviate the symptoms associated with the disorders.

[0709] The size of the dose of the compounds of formula (I) for therapeutic or prophylactic purposes will, of course, vary according to well-known medical principles, depending on the nature and severity of the disorder, the age and sex of the animal or patient, and the route of administration.

[0710] Methods of Use In some aspects, the present disclosure provides a method of inhibiting inflammasome (e.g., NLRP3 inflammasome) activity (e.g., in vitro or in vivo), the method comprising contacting a cell with an effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof.

[0711] In some aspects, the present disclosure provides a method of doing so in a subject in need of treatment or prevention of a disease or disorder disclosed herein, the method comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0712] In one aspect, the present disclosure provides a method of doing so in a subject in need of treatment of a disease or disorder disclosed herein, the method comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0713] In some embodiments, the disease or disorder is associated with involved inflammasome activity. In some embodiments, the disease or disorder is a disease or disorder in which inflammasome activity is involved.

[0714] In some embodiments, the disease or disorder is an inflammatory disorder, an autoinflammatory disorder, an autoimmune disorder, a neurodegenerative disease, or cancer.

[0715] In some embodiments, the disease or disorder is an inflammatory disorder, an autoinflammatory disorder, and / or an autoimmune disorder.

[0716] In some embodiments, the disease or disorder is selected from cryopyrin-associated periodic syndromes (CAPS; e.g., familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), chronic infantile neurologic cutaneous articular (CINCA) syndrome / neonatal-onset multisystem inflammatory disease (NOMID)), familial Mediterranean fever (FMF), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), gout, rheumatoid arthritis, osteoarthritis, Crohn's disease, chronic obstructive pulmonary disease (COPD), chronic kidney disease (CKD), fibrosis, obesity, type 2 diabetes, multiple sclerosis, skin diseases (e.g., acne), and neuroinflammation occurring in protein misfolding diseases (e.g., prion diseases).

[0717] In some embodiments, the disease or disorder is a neurodegenerative disease.

[0718] In some embodiments, the disease or disorder is Parkinson's disease, or Alzheimer's disease.

[0719] In some embodiments, the disease or disorder is a skin disease.

[0720] In some embodiments, the skin disease is acne.

[0721] In some embodiments, the disease or disorder is cancer.

[0722] In some embodiments, the cancer is metastatic cancer, gastrointestinal cancer, skin cancer, non-small cell lung cancer, brain tumor (e.g., glioblastoma), or colorectal adenocarcinoma.

[0723] In some aspects, the present disclosure provides a method of doing so in a subject in need of treatment or prevention of an autoinflammatory disorder, an autoimmune disorder, a neurodegenerative disease, or cancer, the method comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0724]

[0725] ​In some embodiments, the present disclosure provides a method of treating or preventing an inflammatory disorder, autoinflammatory disorder, and / or autoimmune disorder selected from neuroinflammation occurring in cryopyrin-associated periodic syndromes (CAPS; e.g., familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), chronic infantile neurologic cutaneous articular (CINCA) syndrome / neonatal-onset multisystem inflammatory disease (NOMID)), familial Mediterranean fever (FMF), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), gout, rheumatoid arthritis, osteoarthritis, Crohn's disease, chronic obstructive pulmonary disease (COPD), chronic kidney disease (CKD), fibrosis, obesity, type 2 diabetes, multiple sclerosis, skin diseases (e.g., acne), and protein misfolding diseases (e.g., prion diseases) in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0726] In some embodiments, the present disclosure provides a method of treating an inflammatory disorder, autoinflammatory disorder, and / or autoimmune disorder selected from neuroinflammation occurring in cryopyrin-associated periodic syndromes (CAPS; e.g., familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), chronic infantile neurologic cutaneous articular (CINCA) syndrome / neonatal-onset multisystem inflammatory disease (NOMID)), familial Mediterranean fever (FMF), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), gout, rheumatoid arthritis, osteoarthritis, Crohn's disease, chronic obstructive pulmonary disease (COPD), chronic kidney disease (CKD), fibrosis, obesity, type 2 diabetes, multiple sclerosis, skin diseases (e.g., acne), and protein misfolding diseases (e.g., prion diseases) in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0727] In some embodiments, the present disclosure provides a method of doing so in a subject in need of treatment or prevention of a neurodegenerative disease (e.g., Parkinson's disease or Alzheimer's disease), the method comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0728] In some embodiments, the present disclosure provides a method of doing so in a subject in need of treatment of a neurodegenerative disease (e.g., Parkinson's disease or Alzheimer's disease), the method comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0729] In some embodiments, the present disclosure provides a method of doing so in a subject in need of treatment or prevention of cancer, the method comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0730] In some embodiments, the present disclosure provides a method of doing so in a subject in need of treatment of cancer, the method comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0731] In some embodiments, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in inhibiting inflammasome (e.g., NLRP3 inflammasome) activity (e.g., in vitro or in vivo).

[0732] In some embodiments, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of a disease or disorder disclosed herein.

[0733] In some embodiments, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in the treatment of a disease or disorder disclosed herein.

[0734] In some embodiments, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in treating or preventing an inflammatory disorder, an autoinflammatory disorder, an autoimmune disorder, a neurodegenerative disease, or cancer in a subject in need thereof.

[0735] In some embodiments, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in treating an inflammatory disorder, an autoinflammatory disorder, an autoimmune disorder, a neurodegenerative disease, or cancer in a subject in need thereof.

[0736] In some embodiments, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in treating or preventing an inflammatory disorder, an autoinflammatory disorder, and / or an autoimmune disorder selected from the group consisting of cryopyrin-associated periodic syndromes (CAPS; e.g., familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), chronic infantile neurologic cutaneous articular (CINCA) syndrome / neonatal-onset multisystem inflammatory disease (NOMID)), familial Mediterranean fever (FMF), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), gout, rheumatoid arthritis, osteoarthritis, Crohn's disease, chronic obstructive pulmonary disease (COPD), chronic kidney disease (CKD), fibrosis, obesity, type 2 diabetes, multiple sclerosis, skin diseases (e.g., acne), and neuroinflammation occurring in protein misfolding diseases (e.g., prion diseases) in a subject in need thereof.

[0737] In some embodiments, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in treating an inflammatory disorder, autoinflammatory disorder, and / or autoimmune disorder selected from neuroinflammation occurring in cryopyrin-associated autoinflammatory syndromes (CAPS; e.g., familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), chronic infantile neurologic cutaneous articular (CINCA) syndrome / neonatal-onset multisystem inflammatory disease (NOMID)), familial Mediterranean fever (FMF), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), gout, rheumatoid arthritis, osteoarthritis, Crohn's disease, chronic obstructive pulmonary disease (COPD), chronic kidney disease (CKD), fibrosis, obesity, type 2 diabetes, multiple sclerosis, skin diseases (e.g., acne), and protein misfolding diseases (e.g., prion diseases) in a subject in need thereof.

[0738] In some embodiments, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in treating or preventing a neurodegenerative disease (e.g., Parkinson's disease or Alzheimer's disease) in a subject in need thereof.

[0739] In some embodiments, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in treating a neurodegenerative disease (e.g., Parkinson's disease or Alzheimer's disease) in a subject in need thereof.

[0740] In some embodiments, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in treating or preventing cancer in a subject in need thereof.

[0741] In some embodiments, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in treating cancer in a subject in need thereof.

[0742] In some embodiments, the present disclosure provides for the use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for inhibiting inflammasome (e.g., NLRP3 inflammasome) activity (e.g., in vitro or in vivo).

[0743] In some embodiments, the present disclosure provides for the use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein.

[0744] In some embodiments, the present disclosure provides for the use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a disease or disorder disclosed herein.

[0745] In some embodiments, the present disclosure provides for the use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing an inflammatory disorder, an autoinflammatory disorder, an autoimmune disorder, a neurodegenerative disease, or cancer in a subject in need thereof.

[0746] In some embodiments, the present disclosure provides for the use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating an inflammatory disorder, an autoinflammatory disorder, an autoimmune disorder, a neurodegenerative disease, or cancer in a subject in need thereof.

[0747] In some embodiments, the present disclosure provides for the use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing an inflammatory disorder, an autoinflammatory disorder, and / or an autoimmune disorder selected from neuroinflammation occurring in cryopyrin-associated periodic syndromes (CAPS; e.g., familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), chronic infantile neurologic cutaneous articular (CINCA) syndrome / neonatal-onset multisystem inflammatory disease (NOMID)), familial Mediterranean fever (FMF), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), gout, rheumatoid arthritis, osteoarthritis, Crohn's disease, chronic obstructive pulmonary disease (COPD), chronic kidney disease (CKD), fibrosis, obesity, type 2 diabetes, multiple sclerosis, skin diseases (e.g., acne), and protein misfolding diseases (e.g., prion diseases) in a subject in need thereof.

[0748] In some embodiments, the present disclosure provides for the use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating an inflammatory disorder, an autoinflammatory disorder, and / or an autoimmune disorder selected from neuroinflammation occurring in cryopyrin-associated periodic syndromes (CAPS; e.g., familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), chronic infantile neurologic cutaneous articular (CINCA) syndrome / neonatal-onset multisystem inflammatory disease (NOMID)), familial Mediterranean fever (FMF), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), gout, rheumatoid arthritis, osteoarthritis, Crohn's disease, chronic obstructive pulmonary disease (COPD), chronic kidney disease (CKD), fibrosis, obesity, type 2 diabetes, multiple sclerosis, skin diseases (e.g., acne), and protein misfolding diseases (e.g., prion diseases) in a subject in need thereof.

[0749] In some embodiments, the present disclosure provides for the use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing a neurodegenerative disease (e.g., Parkinson's disease or Alzheimer's disease) in a subject in need thereof.

[0750] In one aspect, the present disclosure provides the use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a subject in need thereof, such as a neurodegenerative disease (e.g., Parkinson's disease or Alzheimer's disease).

[0751] In one aspect, the present disclosure provides the use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing cancer in a subject in need thereof.

[0752] In one aspect, the present disclosure provides the use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating cancer in a subject in need thereof.

[0753] The present disclosure provides compounds that function as inflammasome activity inhibitors. Accordingly, the present disclosure provides a method of inhibiting inflammasome activity in vitro or in vivo, the method comprising contacting a cell with an effective amount of a compound as defined herein or a pharmaceutically acceptable salt thereof.

[0754] The effectiveness of the compounds of the present disclosure can be determined in industry-accepted assays / disease models according to standard practices for elucidating such effectiveness, which are described in the art and recognized in current general knowledge.

[0755] The present disclosure also provides a method for treating a subject in need of treatment for a disease or disorder involving inflammasome activity, the method comprising administering to the subject a therapeutically effective amount of a compound as defined herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition.

[0756] At a general level, the compounds of the present disclosure that inhibit the maturation of cytokines of the IL-1 family mediate an increase in the level of the active form of cytokines belonging to the IL-1 family of cytokines or are effective in all therapeutic indications associated with an increase in level (Sims J. et al. Nature Reviews Immunology 10, 89-102 (February 2010)).

[0757] Exemplary diseases and corresponding references are shown below: Inflammatory diseases such as CAPS, autoinflammatory diseases, and autoimmune diseases (Dinarello CA. Immunity. 2004 Mar;20(3):243-4, Hoffman HM. al. Reumatologia 2005;21(3)), gout, rheumatoid arthritis (Gabay C et al. Arthritis Research & Therapy 2009, 11:230, Schett G. et al. Nat Rev Rheumatol. 2016 Jan;12(1):14-24.), Crohn's disease (Jung Mogg Kim Korean J Gastroenterol Vol. 58 No. 6, 300-310), COPD (Mortaz E. et al. Tanaffos. 2011;10(2): 9-14.), fibrosis (Gasse P. et al. Am J Respir Crit Care Med. 2009 May 15;179(10):903-13), obesity, type 2 diabetes ((Dinarello CA. et al. Curr Opin Endocrinol Diabetes Obes. 2010 Aug;17(4):314-21)), multiple sclerosis (see EAE-model in Coll RC. et al. Nat Med. 2015 Mar;21(3):248-55), and numerous other diseases (Martinon F. et al. Immunol. 2009. 27:229-65), for example, Parkinson's disease or Alzheimer's disease (Michael T. et al. Nature 493, 674-678 (31 January 2013), Halle A. et al., Nat Immunol. 2008 Aug;9(8):857-65, Saresella M. et al. Mol Neurodegener. 2016 Mar 3;11:23), and some oncological disorders.

[0758] The compounds of the present disclosure can be suitably used for the treatment of diseases selected from the group consisting of inflammatory diseases, autoinflammatory diseases, autoimmune diseases, neurodegenerative diseases, and cancers. The inflammatory diseases, autoinflammatory diseases, and autoimmune diseases are appropriately selected from the group consisting of cryopyrin-associated periodic syndromes (CAPS, such as familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), chronic infantile neurologic cutaneous articular (CINCA) syndrome / neonatal-onset multisystem inflammatory disease (NOMID)), familial Mediterranean fever (FMF), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), chronic kidney disease (CKD), gout, rheumatoid arthritis, osteoarthritis, Crohn's disease, COPD, fibrosis, obesity, type 2 diabetes, multiple sclerosis, skin diseases (such as acne), and neuroinflammation occurring in protein misfolding diseases such as prion diseases. The neurodegenerative diseases include, but are not limited to, Parkinson's disease and Alzheimer's disease.

[0759] Accordingly, the compounds of the present disclosure can be used for the treatment of diseases selected from the group consisting of cryopyrin-associated periodic syndromes (CAPS, such as familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), chronic infantile neurologic cutaneous articular (CINCA) syndrome / neonatal-onset multisystem inflammatory disease (NOMID)), familial Mediterranean fever (FMF), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), chronic kidney disease (CKD), gout, rheumatoid arthritis, osteoarthritis, Crohn's disease, COPD, fibrosis, obesity, type 2 diabetes, multiple sclerosis, skin diseases (such as acne), neuroinflammation occurring in protein misfolding diseases such as prion diseases, neurodegenerative diseases (such as Parkinson's disease, Alzheimer's disease), and oncological disorders.

[0760] Cancer; Association with the inflammasome It has long been recognized that chronic inflammatory responses are associated with various types of cancer. During malignant transformation or cancer treatment, the inflammasome may be activated in response to danger signals, and this activation can be either beneficial or harmful in cancer.

[0761] IL-1β expression is elevated in various cancers such as breast cancer, prostate cancer, colon cancer, lung cancer, head and neck cancer, and melanoma. Also, in patients with IL-1β-producing tumors, the prognosis is generally relatively poor (Lewis, Anne M., et al. “Interleukin-1 and cancer progression: the emerging role of interleukin-1 receptor antagonist as a novel therapeutic agent in cancer treatment.” Journal of translational medicine 4.1 (2006): 48).

[0762] Epithelial cell-derived cancers (carcinomas) or glandular epithelial-derived cancers (adenocarcinomas) are heterogeneous and consist of many different cell types. This can particularly include fibroblasts, immune cells, adipocytes, endothelial cells, and pericytes, all of which can be cytokine / chemokine-secreting (Grivennikov, Sergei I., Florian R. Greten, and Michael Karin. “Immunity, inflammation, and cancer.” Cell 140.6 (2010): 883-899). This results in cancer-related inflammation through immune cell infiltration. The presence of leukocytes in tumors is known, but it has only recently become clear that an inflammatory microenvironment is an essential component of all tumors. Most tumors (over 90%) are rather the result of somatic mutations or environmental factors than germline mutations, and many of the environmental causes of cancer are associated with chronic inflammation (20% of cancers are associated with chronic infections, 30% with tobacco pollutants / inhaled pollutants, and 35% with dietary factors (20% of all cancers are associated with obesity)) (Aggarwal, Bharat B., R. V. Vijayalekshmi, and Bokyung Sung. “Targeting inflammatory pathways for prevention and therapy of cancer: short-term friend, long-term foe.” Clinical Cancer Research 15.2 (2009): 425-430).

[0763] GI cancer Gastrointestinal (GI) tract cancers are often associated with chronic inflammation. For example, H. pylori infection is associated with gastric cancer (Amieva, Manuel, and Richard M. Peek. “Pathobiology of Helicobacter pylori-Induced Gastric Cancer.” Gastroenterology 150.1 (2016): 64-78). Colorectal cancer is associated with inflammatory bowel disease (Bernstein, Charles N., et al. “Cancer risk in patients with inflammatory bowel disease.” Cancer 91.4 (2001): 854-862). Chronic inflammation in the stomach results in upregulation of IL-1 and other cytokines (Basso D, et al., (1996) Helicobacter pylori infection enhances mucosal interleukin-1 beta, interleukin-6, and the soluble receptor of interleukin-2. Int J Clin Lab Res 26:207-210), and polymorphisms in the IL-1β gene can increase the risk of gastric cancer (Wang P, et al., (2007) Association of interleukin-1 gene polymorphisms with gastric cancer: a meta-analysis. Int J Cancer 120:552-562).

[0764] In 19% of gastric cancer cases, caspase-1 expression, which correlates with stage, lymph node metastasis, and survival time, is decreased (Jee et al., 2005). Mycoplasma hyorhinis is associated with the development of gastric cancer, and activation of the NLRP3 inflammasome there may be associated with the promotion of gastric cancer metastasis (Xu et al., 2013).

[0765] Skin cancer Ultraviolet light is the greatest environmental risk for skin cancer, which is promoted by DNA damage, immunosuppression, and inflammation. Melanoma, the most malignant form of skin cancer, is characterized by upregulation of inflammatory cytokines that can all be controlled by IL-1β (Lazar-Molnar, Eszter, et al. “Autocrine and paracrine regulation by cytokines and growth factors in melanoma.” Cytokine 12.6 (2000): 547-554). Systemic inflammation induces enhanced metastasis and proliferation of melanoma cells by IL-1-dependent mechanisms in vivo. The use of thymoquinone has been shown to inhibit metastasis in a B16F10 mouse melanoma model, which depends on the inhibition of the NLRP3 inflammasome (Ahmad, Israr, et al. “Thymoquinone suppresses metastasis of melanoma cells by inhibition of NLRP3 inflammasome.” Toxicology and applied pharmacology 270.1 (2013): 70-76).

[0766] Glioblastoma NLRP3 contributes to radiotherapy resistance in gliomas. Ionizing radiation can express NLRP3, but NLRP3 inhibition suppressed tumor growth after radiotherapy and extended mouse survival time. Therefore, NLRP3 inflammasome inhibition can achieve a treatment strategy for radiation-resistant gliomas (Li, Lianling, and Yuguang Liu. “Aging-related gene signature regulated by Nlrp3 predicts glioma progression.” American journal of cancer research 5.1 (2015): 442).

[0767] Metastasis More broadly, the Applicants believe that NLRP3 is involved in the promotion of metastasis, and thus, the regulation of NLRP3 should probably block metastasis. IL-1 is involved in tumorigenesis, tumor invasion, tumor metastasis, tumor-host interactions (Apte, Ron N., et al. “The involvement of IL-1 in tumorigenesis, tumor invasiveness, metastasis and tumor-host interactions.” Cancer and Metastasis Reviews 25.3 (2006): 387-408), and angiogenesis (Voronov, Elena, et al. “IL-1 is required for tumor invasiveness and angiogenesis.” Proceedings of the National Academy of Sciences 100.5 (2003): 2645-2650).

[0768] The IL-1 gene is often expressed in metastasis in patients with several types of human cancer. For example, IL-1 mRNA was highly expressed in more than half of all tested metastatic human tumor samples, including tumor samples from non-small cell lung cancer, colorectal adenocarcinoma, and melanoma (Elaraj, Dina M., et al. “The role of interleukin 1 in growth and metastasis of human cancer xenografts.” Clinical Cancer Research 12.4 (2006): 1088-1096). IL-1RA inhibits xenograft growth in IL-1-producing tumors but does not show an anti-proliferative effect in vitro.

[0769] Furthermore, IL-1 signaling is a biomarker for predicting breast cancer patients at high risk of developing bone metastases. In a mouse model, IL-1β and its receptor are upregulated in breast cancer cells that metastasize to bone compared to those that do not. In a mouse model, anakinra, an IL-1 receptor antagonist, not only had a significant effect on the tumor environment by reducing the bone metabolism markers IL-1β and TNFα, but also suppressed proliferation and angiogenesis (Holen, Ingunn, et al. “IL-1 drives breast cancer growth and bone metastasis in vivo.” Oncotarget (2016)).

[0770] IL-18 induced the production of MMP-9 in the human leukemia cell line HL-60, promoting the degradation of the extracellular matrix and the migration and invasion of cancer cells (Zhang, Bin, et al. “IL-18 increases invasiveness of HL-60 myeloid leukemia cells: up-regulation of matrix metalloproteinases-9 (MMP-9) expression.” Leukemia research 28.1 (2004): 91-95). Furthermore, IL-18 can induce the expression of VCAM-1 on hepatic sinusoidal endothelium, supporting the development of tumor metastasis in the liver (Carrascal, Maria Teresa, et al. “Interleukin-18 binding protein reduces b16 melanoma hepatic metastasis by neutralizing adhesiveness and growth factors of sinusoidal endothelium.” Cancer Research 63.2 (2003): 491-497).

[0771] CD36 The fatty acid scavenger receptor CD36 plays a dual role in priming the gene transcription of pro-IL-1β and inducing the construction of the NLRP3 inflammasome complex. CD36 and the TLR4-TLR6 heterodimer recognize oxLDL, and oxLDL initiates a signaling pathway that leads to the upregulation of the transcription of NLRP3 and pro-IL-1β (Signal 1). In addition, CD36 mediates the internal translocation of oxLDL into the lysosomal compartment, where lysosomal rupture and the formation of crystals that induce NLRP3 inflammasome activation occur (Signal 2) (Kagan, J. and Horng T., “NLRP3 inflammasome activation: CD36 serves double duty.” Nature Immunology 14.8 (2013): 772-774).

[0772] Subpopulations of human oral cancer cells are unique in that they express high levels of the fatty acid scavenger receptor CD36 and have the ability to initiate metastasis. Palmitic acid or a high-fat diet enhanced the transcriptional ability of CD36+ cells. In an orthotopic mouse model of human oral cancer, neutralization with an anti-CD36 antibody blocked metastasis. The presence of CD36+ metastasis-initiating cells correlates with poor prognosis in many types of cancer. It has been suggested that dietary lipids may promote metastasis (Pasqual, G, Avgustinova, A., Mejetta, S, Martin, M, Castellanos, A, Attolini, CS-O, Berenguer, A., Prats, N, Toll, A, Hueto, JA, Bescos, C, Di Croce, L, and Benitah, SA. 2017 “Targeting metastasis-initiating cells through the fatty acid receptor CD36” Nature 541:41-45).

[0773] In hepatocellular carcinoma, exogenous palmitic acid activates an epithelial-mesenchymal transition (EMT)-like program and induces migration, which is inhibited by sulfosuccinimidyl oleate, a CD36 inhibitor (Nath, Aritro, et al. “Elevated free fatty acid uptake via CD36 promotes epithelial-mesenchymal transition in hepatocellular carcinoma.” Scientific reports 5 (2015)). The obesity index was not related to the degree of EMT. This emphasizes that what is actually important are CD36 and free fatty acids.

[0774] Cancer stem cells (CSCs) use CD36 to promote their maintenance. In glioblastoma, oxidized phospholipids, which are ligands of CD36, are present, and exposure to oxidized LDL promotes the proliferation of CSCs but not that of non-CSCs. Also, CD36 was correlated with the prognosis of patients.

[0775] Chemotherapy resistance In addition to their direct cytotoxic effects, chemotherapeutic agents utilize the host immune system, which contributes to their antitumor activity. However, gemcitabine and 5-FU have been shown to produce IL-1β, which reduces antitumor efficacy, by activating NLRP3 in myeloid-derived suppressor cells. Mechanistically, these agents activated NLRP3 by destabilizing lysosomes and releasing cathepsin B. IL-1β promoted the production of IL-17 from CD4+ T cells, and IL-17 attenuated the efficacy of chemotherapy. When tumors were established in NLRP3− / − or Caps1− / − mice, or in WT mice treated with IL-1RA, a relatively high antitumor effect was observed for both gemcitabine and 5-FU. Thus, activation of myeloid-derived suppressor cell NLRP3 limits the antitumor efficacy of gemcitabine and 5-FU (Bruchard, Melanie, et al. “Chemotherapy-triggered cathepsin B release in myeloid-derived suppressor cells activates the Nlrp3 inflammasome and promotes tumor growth.” Nature medicine 19.1 (2013): 57-64.). Accordingly, the compounds of the present disclosure may be useful in chemotherapy in the treatment of a range of cancers.

[0776] The compounds of the present disclosure, or pharmaceutically acceptable salts thereof, can be administered alone as monotherapy or in combination with one or more other substances and / or therapeutic agents. This combination therapy can be achieved by simultaneous, sequential, or separate administration of the individual components of the therapy.

[0777] For example, the administration of adjuvants can improve therapeutic efficacy (i.e., an adjuvant alone may exhibit minimal therapeutic effect, but in combination with another therapeutic agent, the overall therapeutic effect on an individual is improved). Alternatively, by way of example only, the effects experienced by an individual can be enhanced by administering a compound of formula (I) together with another therapeutic agent (including a treatment regimen) that also exhibits a therapeutic effect.

[0778] When the compounds of the present disclosure are administered in combination with other therapeutic agents, it is not necessary to administer the compounds of the present disclosure by the same route as the other therapeutic agents, and due to their different physical and chemical properties, they can be administered by different routes. For example, by oral administration of the compounds of the present disclosure, their good blood levels can be generated and maintained, while the other therapeutic agents can be administered intravenously. Initial administration can be carried out according to established protocols known in the art, and then, based on the observed effects, the treating physician can modify the dosage, mode of administration, and administration time.

[0779] The selection of other specific therapeutic agents is based on the diagnosis of the attending physician and the attending physician's judgment regarding the individual's medical condition and appropriate treatment protocol. According to this aspect of the present disclosure, a combination for use in the treatment of diseases involving inflammasome activity is provided, which combination comprises a compound of the present disclosure as previously defined or a pharmaceutically acceptable salt thereof and another suitable agent.

[0780] According to a further aspect of the present disclosure, there is provided a pharmaceutical composition comprising a compound of the present disclosure or a pharmaceutically acceptable salt thereof and a suitable pharmaceutically acceptable diluent or carrier.

[0781] In addition to their use in therapeutic medicine, the compounds of formula (I) and their pharmaceutically acceptable salts are useful as pharmacological tools in the development and standardization of in vitro and in vivo test systems, i.e., as a means of evaluating the effects of inflammasome inhibitors in experimental animals such as dogs, rabbits, monkeys, rats, and mice as part of the search for new therapeutic agents.

[0782] Any of the alternative embodiments of the polymers of the present disclosure described herein can be applied to any of the pharmaceutical compositions, processes, methods, uses, medicaments, and manufacturing aspects of the present disclosure described above.

[0783] Route of administration The compounds of the present disclosure or pharmaceutical compositions containing these compounds can be administered to a subject by any convenient route of administration, either systemically / peripherally or locally (i.e., the site where the desired action takes place).

[0784] Routes of administration include oral (e.g., oral ingestion), buccal, sublingual, transdermal (e.g., including patch, plaster, etc.), transmucosal (e.g., including patch, plaster, etc.), intranasal (e.g., nasal drops), intraocular (e.g., eye drops), intrapulmonary (e.g., by inhalation therapy or insufflation therapy (e.g., using an aerosol agent, e.g., through the mouth or nose)), rectal (e.g., suppository or enema), intravaginal (e.g., pessary), parenteral, e.g., injection, e.g., subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subepidermal, intraarticular, subarachnoid, and intrasternal injection, etc., including those by implantation of a depot or reservoir, e.g., subcutaneous or intramuscular implantation, but not limited thereto.

[0785] Exemplary embodiments Embodiment 1: Formula (I): A compound of TIFF0007682813000063.tif21128, or a prodrug, solvate, or pharmaceutically acceptable salt thereof, wherein: R 1 is C 3 -C 16 cycloalkyl or C 5 -C 10 aryl, and the C 3 -C 16 cycloalkyl or C 5 -C 10 aryl may be substituted with one or more R 1S ; Each R 1S is independently halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C6 is a haloalkoxy; R 2 is C 1 -C 6 alkyl or C 3 -C 16 cycloalkyl, and the C 1 -C 6 alkyl or C 3 -C 16 cycloalkyl may be substituted with one or more R 2S ; Each R 2S is independently halo, -CN, -OH, -O(C 1 -C 6 alkyl), -NH 2 , -NH(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 , or oxo, and the C 1 -C 6 alkyl may be substituted with one or more 3- to 8-membered heterocycloalkyls; R 3 is 7- to 12-membered heterocycloalkyl or 5- or 6-membered heteroaryl, and the 7- to 12-membered heterocycloalkyl or 5- or 6-membered heteroaryl may be substituted with one or more R 3S ; and Each R 3S is independently halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, or 3- to 8-membered heterocycloalkyl, and the C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, or 3- to 8-membered heterocycloalkyl may be substituted with one or more halo, -CN, -OH, -O(C 1 -C 6(alkyl), -NH 2 , -NH(C 1 -C 6 (alkyl), or -N(C 1 -C 6 (alkyl) 2 The compound, or its prodrug, solvate, or pharmaceutically acceptable salt, which may be substituted with

[0786] Embodiment 2: R 1 is C 3 -C 16 cycloalkyl; R 2 is C 1 -C 6 alkyl or C 3 -C 16 cycloalkyl, and the C 1 -C 6 alkyl or C 3 -C 16 cycloalkyl may be substituted with one or more R 2S ; Each R 2S is independently -OH, -O(C 1 -C 6 (alkyl), or -N(C 1 -C 6 (alkyl) 2 and the C 1 -C 6 alkyl may be substituted with one or more 3- to 8-membered heterocycloalkyl; R 3 is a 5- or 6-membered heteroaryl which may be substituted with one or more C 1 -C 6 alkyl, the compound according to Embodiment 1.

[0787] Embodiment 3: R 1 is C 3 -C 16 cycloalkyl or C 5 -C 10 aryl, and the C 3 -C 16 cycloalkyl or C5 -C 10 Aryl may be substituted with one or more Rs 1S and may be; Each R 1S is independently halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 2 is C 1 -C 6 alkyl or C 3 -C 16 cycloalkyl, and the C 1 -C 6 alkyl or C 3 -C 16 cycloalkyl may be substituted with one or more Rs 2S and may be; Each R 2S is independently halo, -CN, -OH, -O(C 1 -C 6 alkyl), -NH 2 -, -NH(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 or oxo; R 3 is 7- to 12-membered heterocycloalkyl or 5- or 6-membered heteroaryl, and the 7- to 12-membered heterocycloalkyl or 5- or 6-membered heteroaryl may be substituted with one or more Rs 3S and; Each R 3S is independently halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, or 3- to 8-membered heterocycloalkyl, and the C 1 -C6 Alkyl, C 1 -C 6 Haloalkyl, C 3 -C 8 Cycloalkyl, or 3- to 8-membered heterocycloalkyl may be substituted with one or more halo, -CN, -OH, -O(C 1 -C 6 alkyl), -NH 2 , -NH(C 1 -C 6 alkyl), or -N(C 1 -C 6 alkyl) 2 The compound according to Embodiment 1, which may be substituted with

[0788] Embodiment 4: R 1 is C 3 -C 16 cycloalkyl or C 5 -C 10 aryl, and C 3 -C 16 cycloalkyl or C 5 -C 10 aryl is substituted with one or more R 1S The compound according to any one of the preceding embodiments.

[0789] Embodiment 5: R 1 is C 3 -C 16 cycloalkyl, or C 5 -C 10 aryl, and the C 3 -C 16 cycloalkyl, or C 5 -C 10 aryl is unsubstituted. The compound according to any one of the preceding embodiments.

[0790] Embodiment 6: R 1 is C 3 -C 7 monocyclic cycloalkyl, C 9 -C 10 bicyclic cycloalkyl, or C12 -C 16 is a tricyclic cycloalkyl, and the C 3 -C 7 is a monocyclic cycloalkyl, C 9 -C 10 is a bicyclic cycloalkyl, or C 12 -C 16 The tricyclic cycloalkyl may be substituted with one or more R 1S The compound according to any one of the preceding embodiments.

[0791] Embodiment 7: R 1 is an unsubstituted C 12 -C 16 The compound according to any one of the preceding embodiments, which is a tricyclic cycloalkyl.

[0792] Embodiment 8: R 1 is a C 1S -C 12 -C 16 The compound according to any one of the preceding embodiments, which is a tricyclic cycloalkyl substituted with one or more R

[0793] Embodiment 9: R 1 is hexahydroindenyl, and the compound according to any one of the preceding embodiments.

[0794] Embodiment 10: R 1 is TIFF0007682813000064.tif36128, wherein n and n a are each independently 0, 1, 2, or 3, and the compound according to any one of the preceding embodiments.

[0795] Embodiment 11: R 1 is TIFF0007682813000065.tif36128, wherein n and n aA compound according to any one of the embodiments of the prior art, which is independently 0, 1, 2, or 3.

[0796] Embodiment 12: R 1 is TIFF0007682813000066.tif25128, a compound according to any one of the embodiments of the prior art.

[0797] Embodiment 13: R 1 is unsubstituted C 5 -C 10 aryl, a compound according to any one of the embodiments of the prior art.

[0798] Embodiment 14: R 1 is C 1S substituted with one or more R 5 -C 10 aryl, a compound according to any one of the embodiments of the prior art.

[0799] Embodiment 15: R 1 is phenyl substituted with one or more substituents independently selected from halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy, a compound according to any one of the embodiments of the prior art.

[0800] Embodiment 16: R 2 is C 2S optionally substituted with one or more R 1 -C 6 alkyl, a compound according to any one of the embodiments of the prior art.

[0801] Embodiment 17: R 2 is optionally substituted with one or more R 2S C 3 -C 16 is cycloalkyl, the compound according to any one of the preceding embodiments.

[0802] Embodiment 18: R 2 is unsubstituted C 1 -C 6 is alkyl, the compound according to any one of the preceding embodiments.

[0803] Embodiment 19: R 2 is optionally substituted with one or more R 2S C 1 -C 6 is alkyl, the compound according to any one of the preceding embodiments.

[0804] Embodiment 20: R 2 is substituted with one R 2S C 1 -C 6 is alkyl, the compound according to any one of the preceding embodiments.

[0805] Embodiment 21: R 2 is substituted with two R 2S C 1 -C 6 is alkyl, the compound according to any one of the preceding embodiments.

[0806] Embodiment 22: R 2 is TIFF0007682813000067.tif49165, the compound according to any one of the preceding embodiments.

[0807] Embodiment 23: At least one R 2Sis -OH, -O(C 1 -C 6 alkyl), or -N(C 1 -C 6 alkyl) 2 wherein the C 1 -C 6 alkyl may be substituted with one or more 3- to 8-membered heterocycloalkyls, a compound according to any one of the preceding embodiments.

[0808] Embodiment 24: At least one R 2S is -OH, TIFF0007682813000068.tif15128, a compound according to any one of the preceding embodiments.

[0809] Embodiment 25: R 2S is independently -OH, a compound according to any one of the preceding embodiments.

[0810] Embodiment 26: R 2S is independently -O(C 1 -C 6 alkyl), a compound according to any one of the preceding embodiments.

[0811] Embodiment 27: R 2S is independently -O(methyl), a compound according to any one of the preceding embodiments.

[0812] Embodiment 28: R 2S is independently -NH 2 , -NH(C 1 -C 6 alkyl), or -N(C 1 -C 6 alkyl) 2 wherein, a compound according to any one of the preceding embodiments.

[0813] Embodiment 29: R 2S is independently -N(C 1 -C 6 alkyl) 2 and is the compound according to any one of the preceding embodiments.

[0814] Embodiment 30: R 2S is independently -N(methyl) 2 and is the compound according to any one of the preceding embodiments.

[0815] Embodiment 31: R 3 is a 7- to 12-membered heterocycloalkyl optionally substituted with one or more R 3S and is the compound according to any one of the preceding embodiments.

[0816] Embodiment 32: R 3 is a 5- or 6-membered heteroaryl optionally substituted with one or more R 3S and is any one of the compound...

Claims

1. A compound of formula (I-t) or (I-u): or a solvate thereof, or a pharmaceutically acceptable salt, wherein: Each R ２Ｓ is independently —OH, —O(C １ —C ６ alkyl), or —N(C １ —C ６ alkyl) ２ and the C １ —C ６ alkyl may be substituted with one or more 3- to 8-membered heterocycloalkyl; R ３Ｓ is C １ -C ６ alkyl.

2. Or is The compound according to claim 1, wherein is

3. At least one R ２Ｓ is —OH, The compound according to claim 1 or claim 2, wherein is

4. One R is present in formula (I-u). ２Ｓ The compound according to any one of claims 1 to 3, wherein

5. In formula (I-u), The compound according to claim 1 or claim 2, wherein is cyclobutyl or cyclopentyl.

6. Compound numbers 1-11: A compound selected from, or a pharmaceutically acceptable salt thereof, or a compound labeled with deuterium thereof.

7. Compound numbers 1-11: A compound selected from.

8. Compound numbers 1-11: A pharmaceutically acceptable salt of a compound selected from.

9. A pharmaceutical composition comprising the compound according to any one of claims 1-8 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable diluent or carrier.

10. The pharmaceutical composition according to claim 9, wherein the compound is selected from compound numbers 1-11:

11. A pharmaceutical composition comprising a pharmaceutically acceptable salt of the pharmaceutical according to claim 8 and a pharmaceutically acceptable diluent or carrier.

12. The pharmaceutical composition according to any one of claims 9-11 for use in inhibiting NLRP3 inflammasome activity.

13. The pharmaceutical composition according to claim 12, wherein the NLRP3 inflammasome activity is in vitro or in vivo.

14. The pharmaceutical composition according to any one of claims 9-11 for use in the treatment or prevention of a disease or disorder, wherein the disease or disorder is related to the NLRP3 inflammasome activity involved.

15. Use of the compound according to any one of claims 1-8 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for inhibiting NLRP3 inflammasome activity.

16. The use according to claim 15, wherein the NLRP3 inflammasome activity is in vitro or in vivo.

17. Use of the compound according to any one of claims 1-8 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing a disease or disorder related to the NLRP3 inflammasome activity involved or a disease or disorder in which the NLRP3 inflammasome activity is involved.

18. Use according to claim 17, wherein the disease or disorder is an inflammatory disorder, an autoinflammatory disorder, an autoimmune disorder, a neurodegenerative disease, or cancer.

19. Use according to claim 18, wherein the inflammatory disorder, autoinflammatory disorder, or autoimmune disorder is selected from cryopyrin-associated periodic syndrome (CAPS), familial Mediterranean fever (FMF), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), gout, rheumatoid arthritis, osteoarthritis, Crohn's disease, chronic obstructive pulmonary disease (COPD), chronic kidney disease (CKD), fibrosis, obesity, type 2 diabetes, multiple sclerosis, skin diseases, and neuroinflammation occurring in protein misfolding diseases.

20. Use according to claim 19, wherein the cryopyrin-associated periodic syndrome is familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), chronic infantile neurologic cutaneous articular (CINCA) syndrome, or neonatal-onset multisystem inflammatory disease (NOMID).

21. Use according to claim 19, wherein the skin disease is acne.

22. Use according to claim 19, wherein the protein misfolding disease is a prion disease.

23. Use according to claim 18, wherein the disease or disorder is a neurodegenerative disease.

24. Use according to claim 23, wherein the neurodegenerative disease is Parkinson's disease or Alzheimer's disease.

25. Use according to claim 18, wherein the disease or disorder is cancer.

26. Use according to claim 25, wherein the cancer is metastatic cancer, brain cancer, gastrointestinal cancer, skin cancer, non-small cell lung cancer, head and neck squamous cell carcinoma, or colorectal adenocarcinoma.

27. Use of the pharmaceutical composition according to any one of claims 9 to 11 in the manufacture of a medicament for inhibiting NLRP3 inflammasome activity.

28. The pharmaceutical composition according to claim 14, wherein the disease or disorder is an inflammatory disorder, an autoinflammatory disorder, an autoimmune disorder, a neurodegenerative disease, or cancer.

29. The pharmaceutical composition according to claim 14 or claim 28, wherein the disease or disorder is an inflammatory disorder, an autoinflammatory disorder, or an autoimmune disorder.

30. The pharmaceutical composition according to claim 29, wherein the inflammatory disorder, autoinflammatory disorder, or autoimmune disorder is selected from cryopyrin-associated periodic syndrome (CAPS), familial Mediterranean fever (FMF), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), gout, rheumatoid arthritis, osteoarthritis, Crohn's disease, chronic obstructive pulmonary disease (COPD), chronic kidney disease (CKD), fibrosis, obesity, type 2 diabetes, multiple sclerosis, skin diseases, and neuroinflammation occurring in protein misfolding diseases.

31. The pharmaceutical composition according to claim 30, wherein the cryopyrin-associated periodic syndrome is familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), chronic infantile neurologic cutaneous articular (CINCA) syndrome, or neonatal-onset multisystem inflammatory disease (NOMID).

32. The pharmaceutical composition according to claim 30, wherein the skin disease is acne.

33. The pharmaceutical composition according to claim 30, wherein the protein misfolding disease is a prion disease.

34. The pharmaceutical composition according to claim 28, wherein the disease or disorder is a neurodegenerative disease.

35. The pharmaceutical composition according to claim 34, wherein the neurodegenerative disease is Parkinson's disease or Alzheimer's disease.

36. The pharmaceutical composition according to claim 28, wherein the disease or disorder is cancer.

37. The pharmaceutical composition according to claim 36, wherein the cancer is metastatic cancer, brain cancer, gastrointestinal cancer, skin cancer, non-small cell lung cancer, head and neck squamous cell carcinoma, or colorectal adenocarcinoma.

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