Sulfonylurea derivatives and uses thereof

Abstract

The present disclosure relates to compounds of formula (I) and their prodrugs, pharmaceutically acceptable salts, pharmaceutical compositions, methods of use, and methods for their preparation. The compounds disclosed herein are useful in inhibiting inflammasomes to prevent the maturation of IL-1 family cytokines and can be used to treat disorders implicating inflammasome activity, such as inflammatory, autoinflammatory, and autoimmune diseases, and cancer. TIFF2022536160000626.tif21128

Description

[Technical Field]

[0001] Related Applications This application claims priority to and the benefit of U.S. Provisional Application No. 62 / 860,664, filed June 12, 2019, the entire contents of which are incorporated herein by reference.

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

[0003] background 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. et 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. Several NLR family members are involved in inflammasome formation.

[0005] Although inflammasome activation likely evolved as a critical component of host immunity against pathogens, the NLRP3 inflammasome is unique in its ability to activate in response to endogenous sterile danger signals. Numerous such sterile signals have been characterized, and their formation is associated with specific disease states. For example, uric acid crystals, found in patients with gout, are potent 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 association of IL-1 and IL-18 with a wide range of pathophysiological conditions, including metabolic, physiological, inflammatory, hematological, and immune disorders.

[0006] The present disclosure arises from a need to provide additional compounds that specifically regulate NLRP3-dependent cellular processes, particularly compounds that have improved physicochemical, pharmacological, and pharmaceutical properties compared to existing compounds. [Prior art documents] [Non-patent literature]

[0007] [Non-Patent Document 1] Seth L. al. Rev. Immunol. 2009. 27:621-68 Summary of the Invention

[0008] overview In some aspects, the present disclosure provides, inter alia, compounds of formula (I): TIFF0007661248000001.tif21128, or a prodrug, solvate, or pharmaceutically acceptable salt thereof, wherein: R1 is one or more R 1S is a 5- to 12-membered heterocycloalkyl or 5- to 12-membered heteroaryl optionally substituted with Each R 1Sare independently C1-C6 alkyl, C1-C6 haloalkyl, -O(C1-C6 alkyl), -O(C1-C6 haloalkyl), -(C1-C6 alkyl)-O(C1-C6 alkyl), cyano, halo, C3-C8 cycloalkyl, C3-C8 aryl, 3- to 8-membered heterocycloalkyl, or 3- to 8-membered heteroaryl; R2 is -(CX2X2) n -R 2S wherein n is 0, 1, or 2, and each X2 is independently H, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, wherein the C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is optionally substituted with one or more halo, —CN, —OH, —O(C1-C6 alkyl), —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, or oxo; R 2S is C1-C6 alkyl, C3-C 16 cycloalkyl, or 4-8 membered heterocycloalkyl, C1-C6 alkyl, C3-C 16 The cycloalkyl or 4-8 membered heterocycloalkyl may be optionally substituted with one or more C-C alkyl, C-C alkenyl, C-C alkynyl, C-C haloalkyl, halo, -CN, -OH, -O(C-C alkyl), -NH, -NH(C-C alkyl), -N(C-C alkyl), or oxo; and R3 is one or more R 3S and each R is a 5- to 12-membered heterocycloalkyl or a 5- or 6-membered heteroaryl optionally substituted with 3S are independently C-C alkyl, C-C haloalkyl, C-C cycloalkyl, halo, or C-C heterocycloalkyl, wherein the C-C alkyl, C-C haloalkyl, C-C cycloalkyl, or C-C heterocycloalkyl is optionally substituted with —O(C-C alkyl), —N(C-C alkyl), halo, or —CN.

[0009] In some aspects, the present disclosure provides compounds obtainable by or obtained by a method for preparing a compound described herein (e.g., a method comprising one or more steps described in Schemes 1-6).

[0010] In some aspects, 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 aspects, the present disclosure provides intermediates described herein that are suitable for use in the methods for preparing the compounds described herein (e.g., the intermediates are selected from the intermediates described in Examples 1-17).

[0012] 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.

[0013] In some aspects, the present disclosure provides a method of treating or preventing a disease or disorder disclosed herein 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.

[0014] In some aspects, the present disclosure provides a method of treating a disease or disorder disclosed herein 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.

[0015] In some aspects, 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 aspects, 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 aspects, 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 aspects, 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 aspects, 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 aspects, 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 disease or disorder disclosed herein.

[0021] In some aspects, the disclosure provides methods of preparing the compounds of the disclosure.

[0022] In some aspects, the disclosure provides methods of preparing compounds, comprising one or more of the 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 the plural unless the context clearly dictates otherwise. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference. 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 the event of a conflict between a chemical structure and the name of a compound disclosed herein, the chemical structure will control.

[0024] [The present invention 1001] Formula (I): TIFF0007661248000002.tif21128 or a prodrug, solvate, or pharmaceutically acceptable salt thereof, During the ceremony: R 1 is one or more R 1S is a 5- to 12-membered heterocycloalkyl or 5- to 12-membered heteroaryl optionally substituted with Each R 1S independently, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, -O(C 1 -C 6 alkyl), -O(C 1 -C 6 haloalkyl), -(C 1 -C 6 alkyl)-O(C 1 -C 6 Alkyl), Cyano, Halo, C 3 -C 8 Cycloalkyl, C 3 -C 8 aryl, 3-8 membered heterocycloalkyl, or 3-8 membered heteroaryl; R 2 is -(CX 2 X 2 ) n -R 2S wherein n is 0, 1, or 2, and each X 2 are independently H, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, or C 2 -C 6 alkynyl, 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, or C 2 -C 6 Alkynyl is a group consisting of 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 optionally substituted with oxo; R 2S is C 1 -C 6 Alkyl, C 3 -C 16 cycloalkyl, or 4- to 8-membered heterocycloalkyl, 1 -C 6 Alkyl, C 3 -C 16 A cycloalkyl or 4- to 8-membered heterocycloalkyl may have one or more C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, 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 R 3 is one or more R 3S and each R is a 5- to 12-membered heterocycloalkyl or a 5- or 6-membered heteroaryl optionally substituted with 3S independently, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 3 -C 8 Cycloalkyl, halo, or C 3 -C 8 heterocycloalkyl, wherein C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 3 -C 8 Cycloalkyl, or C 3-C 8 Heterocycloalkyl is —O(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 , halo, or -CN, The compound, or a prodrug, solvate, or pharmaceutically acceptable salt thereof. [The present invention 1002] R 1 is one or more R 1S is a 5- to 12-membered heterocycloalkyl or 5- to 12-membered heteroaryl optionally substituted with Each R 1S independently, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, -O(C 1 -C 6 alkyl), -O(C 1 -C 6 haloalkyl), -(C 1 -C 6 alkyl)-O(C 1 -C 6 Alkyl), Cyano, Halo, C 3 -C 8 Cycloalkyl, C 3 -C 8 aryl, 3-8 membered heterocycloalkyl, or 3-8 membered heteroaryl; R 2 is -(CX 2 X 2 ) n -R 2S wherein n is 0, 1, or 2, and each X 2 are independently H, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, or C 2 -C 6 alkynyl, 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, or C 2 -C 6 Alkynyl is a group consisting of 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 optionally substituted with oxo; R 2S is C 1 -C 6 Alkyl, C 3 -C16 cycloalkyl, or 4- to 8-membered heterocycloalkyl, 1 -C 6 Alkyl, C 3 -C 16 A cycloalkyl or 4- to 8-membered heterocycloalkyl may have one or more C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, 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 R 3 is one or more R 3S and each R is a 7- to 12-membered heterocycloalkyl or a 5- or 6-membered heteroaryl optionally substituted with 3S independently, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 3 -C 8 Cycloalkyl, halo, or C 3 -C 8 heterocycloalkyl, wherein C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 3 -C 8 Cycloalkyl, or C 3 -C 8 Heterocycloalkyl is —O(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 , halo, or -CN, 1001 compounds of the present invention. [The present invention 1003] R 1 is a 5- to 12-membered heterocycloalkyl or a 5- to 12-membered heteroaryl, wherein at least one heteroatom of said 5- to 12-membered heterocycloalkyl or 5- to 12-membered heteroaryl is O or S, and said 5- to 12-membered heterocycloalkyl or 5- to 12-membered heteroaryl is selected from the group consisting of one or more R 1S may be substituted with; Each R 1S independently, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, -O(C 1 -C 6 Alkyl), Cyano, Halo, C 3 -C 8 Cycloalkyl, or C 3 -C 8 is aryl; R 2 is -(CH 2 ) n -R 2S where n is 0, 1, or 2; R 2S is C 1 -C 6 Alkyl, C 3 -C 16 cycloalkyl, or 4- to 8-membered heterocycloalkyl, 1 -C 6 Alkyl, C 3 -C 16 A cycloalkyl or 4- to 8-membered heterocycloalkyl may have one or more C 1 -C 6 Alkyl, halo, -OH, -O(C 1 -C 6 alkyl), -NH 2 , -NH(C 1 -C 6 alkyl), or -N(C 1 -C 6 alkyl) 2 and R 3 is a 5- to 6-membered heterocycloalkyl or a 5- or 6-membered heteroaryl, and the 5- to 12-membered heterocycloalkyl or the 5- or 6-membered heteroaryl is selected from the group consisting of one or more C 1 -C 6 Alkyl, C 3 -C 8 optionally substituted with cycloalkyl or halo; 1001 compounds of the present invention. [The present invention 1004] R 1 is a 5- to 12-membered heterocycloalkyl or a 5- to 12-membered heteroaryl, wherein at least one heteroatom of said 5- to 12-membered heterocycloalkyl or 5- to 12-membered heteroaryl is O or S, and said 5- to 12-membered heterocycloalkyl or 5- to 12-membered heteroaryl is selected from the group consisting of one or more R 1S may be substituted with; Each R 1S independently, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, -O(C 1 -C 6 Alkyl), Cyano, Halo, C 3 -C 8 Cycloalkyl, or C 3 -C 8 is aryl; R 2 is -(CH 2 ) n -R 2S where n is 0, 1, or 2; R 2S is C 1 -C 6 Alkyl, C 3 -C 16 cycloalkyl, or 4- to 8-membered heterocycloalkyl, 1 -C 6 Alkyl, C 3 -C 16 A cycloalkyl or 4- to 8-membered heterocycloalkyl may have one or more C 1 -C 6 Alkyl, halo, -OH, -O(C 1 -C 6 alkyl), -NH 2 , -NH(C 1 -C 6 alkyl), or -N(C 1 -C 6 alkyl) 2 and R 3 is one or more C 1 -C 6 Alkyl, C 3 -C 8 cycloalkyl, or 5- or 6-membered heteroaryl optionally substituted with halo; 1001 compounds of the present invention. [The present invention 1005] R 1 but one or more R 1S Any of the preceding compounds of the invention, wherein R is a 5-12 membered heterocycloalkyl optionally substituted with R. [The present invention 1006] R 1 but one or more R 1S Any of the preceding compounds of the present invention, wherein R is a 5-12 membered heteroaryl optionally substituted with R. [The present invention 1007] R 1 but, TIFF0007661248000003.tif228165TIFF0007661248000004.tif86165 Any compound of the preceding invention, wherein [The present invention 1008] At least one R 1S But C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, -O(C 1 -C 6 alkyl), -O(C 1 -C 6 haloalkyl), or halo. [The present invention 1009] At least one R 1S But C 1 -C 6 Any of the preceding compounds of the invention which is alkyl or halo. [The present invention 1010] R 2 But R 2S Any compound of the preceding invention, wherein [The present invention 1011] R 2 But -(CX 2 ) n -R 2S wherein n is 1 or 2. [The present invention 1012] R 2S is one or more C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, 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 a 6-membered heterocycloalkyl optionally substituted with oxo. [The present invention 1013] R 2 but, TIFF0007661248000005.tif178165TIFF0007661248000006.tif60165 Any compound of the preceding invention, wherein [The present invention 1014] R 2 but TIFF0007661248000007.tif109165 Any compound of the preceding invention, wherein [The present invention 1015] R 2 but, TIFF0007661248000008.tif18128 Any compound of the preceding invention, wherein [The present invention 1016] R 3 is a 5- to 6-membered heterocycloalkyl or a 5-membered heteroaryl, and the 5- to 6-membered heterocycloalkyl or the 5-membered heteroaryl is selected from the group consisting of one or more R 3S Any of the preceding compounds of the invention optionally substituted with [The present invention 1017] R 3 but one or more R 3S Any of the preceding compounds of the invention, wherein R is a 5-6 membered heterocycloalkyl optionally substituted with R. [The present invention 1018] R 3 but, TIFF0007661248000009.tif19130 Any compound of the preceding invention, wherein [The present invention 1019] R 3 but one or more R 3S Any of the preceding compounds of the invention, wherein R is a 5-membered heteroaryl optionally substituted with R. [The present invention 1020] R 3 but, TIFF0007661248000010.tif18133 Any compound of the preceding invention, wherein [The present invention 1021] R 3 but, TIFF0007661248000011.tif12128 Any compound of the preceding invention, wherein [The present invention 1022] At least one R 3S But C 1 -C 6 Any of the preceding compounds of the invention, wherein: [The present invention 1023] At least one R 3S is methyl. [The present invention 1024] Formula (II-a) or (II-b): TIFF0007661248000012.tif59128 or a prodrug, solvate, or pharmaceutically acceptable salt thereof, wherein n 1 is an integer ranging from 0 to 3. [The present invention 1025] Formulas (II-c), (II-d), (II-e): TIFF0007661248000013.tif91128 or a prodrug, solvate, or pharmaceutically acceptable salt thereof, wherein n 1 is 0 or 1. [The present invention 1026] Formula (III): TIFF0007661248000014.tif21128 or a prodrug, solvate, or pharmaceutically acceptable salt thereof. [The present invention 1027] Formula (III-a) or (III-b): TIFF0007661248000015.tif59128 or a prodrug, solvate, or pharmaceutically acceptable salt thereof, wherein n 1 is an integer ranging from 0 to 3. [The present invention 1028] Formulas (III-c), (III-d), (III-e): TIFF0007661248000016.tif91128 or a prodrug, solvate, or pharmaceutically acceptable salt thereof, wherein n 1 is 0 or 1. [The present invention 1029] Formula (IV): TIFF0007661248000017.tif23128 or a prodrug, solvate, or pharmaceutically acceptable salt thereof, wherein n 1 is an integer ranging from 0 to 3. [The present invention 1030] Formula (IV-a): TIFF0007661248000018.tif23128 or a prodrug, solvate, or pharmaceutically acceptable salt thereof. [The present invention 1031] Any of the compounds of the preceding invention selected from Compound Nos. 1 to 131 and prodrugs and pharmaceutically acceptable salts thereof. [The present invention 1032] Any of the compounds of the preceding invention selected from Compound Nos. 1 to 131 and pharmaceutically acceptable salts thereof. [The present invention 1033] Any compound of the preceding invention selected from compound numbers 1 to 131. [The present invention 1034] A compound that is an isotopic derivative of any of the preceding compounds of the invention. [This invention 1035] 1077 compounds of the present invention, which are any one of deuterium-labeled compounds of Compound Nos. 1 to 131, and prodrugs and pharmaceutically acceptable salts thereof. [The present invention 1036] Compound 1077 of the present invention or compound 1078 of the present invention, which is a compound labeled with deuterium of any one of compound numbers 1 to 131. [This invention 1037] A compound obtainable by or obtained by a process described herein, optionally wherein said process comprises one or more of the steps set out in Schemes 1 to 6. [The present invention 1038] A compound or intermediate obtained by a process for preparing any of compounds 1001 to 1079 of the present invention, wherein optionally said intermediate is selected from the intermediates described in Examples 1 to 107. [This invention 1039] A pharmaceutical composition comprising any one of the compounds of the present invention 1001 to 1079 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable diluent or carrier. [The present invention 1040] The pharmaceutical composition of the present invention 1082, wherein the compound is selected from compound numbers 1 to 131. [The present invention 1041] A method for inhibiting inflammasome activity, comprising a step of contacting cells with an effective amount of any of the compounds of the present invention 1001 to 1079 or a pharmaceutically acceptable salt thereof, wherein optionally the inflammasome is the NLRP3 inflammasome and the activity is in vitro or in vivo. [The present invention 1042] A method for treating or preventing a disease or disorder in a subject in need thereof, comprising the step of administering to the subject a therapeutically effective amount of any of the compounds of the present inventions 1001 to 1079 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present invention 1082 or 1083. [This invention 1043] A compound of any of claims 1001 to 1079, or a pharmaceutical composition of claim 1082 or claim 1083, for use in inhibiting inflammasome activity, wherein optionally the inflammasome is an NLRP3 inflammasome and the activity is in vitro or in vivo. [This invention 1044] A compound of any one of Inventions 1001 to 1079, or a pharmaceutical composition of Invention 1082 or Invention 1083 for use in treating or preventing a disease or disorder. [This invention 1045] Use of any of the compounds of the present invention 1001 to 1079 or a pharmaceutically acceptable salt thereof in the manufacture of a pharmaceutical for inhibiting inflammasome activity, wherein optionally the inflammasome is an NLRP3 inflammasome and the activity is in vitro or in vivo. [The present invention 1046] Use of any of the compounds of the present invention 1001 to 1079 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing a disease or disorder. [This invention 1047] Any of the methods, compounds, pharmaceutical compositions, or uses of the preceding inventions, wherein said disease or disorder is associated with associated inflammasome activity, and optionally said disease or disorder is a disease or disorder in which inflammasome activity is implicated. [This invention 1048] The method, compound, pharmaceutical composition, or use of any of the preceding inventions, wherein said disease or disorder is an inflammatory disorder, an autoinflammatory disorder, an autoimmune disorder, a neurodegenerative disease, or cancer. [This invention 1049]

[0023] Any of the methods, compounds, pharmaceutical compositions, or uses of the preceding inventions, wherein 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 autoinflammatory syndromes (CAPS, e.g., familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), chronic infantile neurological, cutaneous, and 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). [The present invention 1050] The method, compound, pharmaceutical composition, or use of any of the preceding inventions, wherein said disease or disorder is a neurodegenerative disease, optionally wherein said disease or disorder is Parkinson's disease or Alzheimer's disease. [This invention 1051]

[0023] Any of the methods, compounds, pharmaceutical compositions, or uses of the preceding inventions, wherein said disease or disorder is cancer, and optionally said cancer is metastatic cancer, brain cancer, gastrointestinal cancer, skin cancer, non-small cell lung cancer, head and neck squamous cell carcinoma, or colorectal adenocarcinoma. Other features and advantages of the present disclosure will become apparent from the following detailed description, and from the claims. DETAILED DESCRIPTION OF THE INVENTION

[0025] Detailed Description Autoimmune diseases are associated with the overproduction of inflammatory factors, one of which 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. et al. Rev. Immunol. 2009. 27:621-68).

[0026] Autoimmune diseases are associated with the overproduction of inflammatory factors, one of which 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. et al. Rev. Immunol. 2009. 27:621-68).

[0027] IL-1 family cytokines are highly active and, as important inflammatory mediators, are primarily associated with acute and chronic inflammation (Sims J. et al. Nature Reviews Immunology 10, 89-102 (February 2010)). Excessive production of IL-1 is thought to be a mediator of some autoimmune and autoinflammatory diseases. Autoinflammatory diseases are characterized by recurrent and spontaneous inflammation in the absence of autoantibodies, infections, or antigen-specific T lymphocytes.

[0028] The IL-1 superfamily of proinflammatory cytokines, including IL-1α, IL-1β, IL-18, and IL-36α, β, and λ, are produced as part of the host innate immune response in response to pathogens and other cellular stressors. Unlike many other secreted cytokines, which are processed and released through the standard cellular secretory apparatus consisting of the endoplasmic reticulum and Golgi apparatus, IL-1 family members lack leader sequences required for endoplasmic reticulum translocation and are therefore retained intracellularly after translation. Furthermore, IL-1β, IL-18, and IL-36α, β, and λ are synthesized as procytokines that require proteolytic activation to become optimal ligands for binding to their cognate receptors on target cells.

[0029] In the cases of IL-1α, IL-1β, and IL-18, it is now recognized that a multimeric protein complex known as the inflammasome is responsible for the activation of the proforms of IL-1β and IL-18 and the extracellular release of these cytokines. In general, the inflammasome complex consists of a sensor molecule, such as an NLR (nucleotide oligomerization domain (NOD)-like receptor), an adaptor molecule, ASC (apoptosis-associated speck-like protein containing a caspase recruitment domain (CARD)), and procaspase-1. In response to various "danger signals," including pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs), inflammasome subunits oligomerize to form intracellular supramolecular structures. 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. The assembly of the inflammasome platform promotes the autocatalytic activity of procaspase-1, generating a highly active cysteine ​​protease responsible for the activation and release of pro-IL-1β and pro-IL-18. Thus, the release of these proinflammatory cytokines is only realized in response to inflammasome sensors that detect and respond to specific molecular danger signals.

[0030] 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. Several NLR family members, including NLRP1, NLRP3, NLRP6, NLRP7, NLRP12, and NLRC4 (IPAF), are involved in inflammasome formation.

[0031] Two other structurally distinct inflammasome structures containing PYHIN domains (pylin and HIN domain-containing proteins), namely, Absent in Melanoma 2 (AIM2) and IFNλ-inducible protein 16 (IFI16) (Latz et al., Nat Rev Immunol 2013 13(6) 397-311), act as intracellular DNA sensors. Pylin (encoded by the MEFV gene) is another type of inflammasome platform involved in proIL-1β activation (Chae et al., Immunity 34, 755-768, 2011).

[0032] The activation and release of IL-1β and IL-18 from monocytes and macrophages requires the assembly of an inflammasome platform, carefully orchestrating their production through a two-step process. First, cells must encounter a priming ligand (e.g., the TLR4 receptor ligand LPS or a proinflammatory cytokine such as TNFα), leading to NFkB-dependent transcription of NLRP3, pro-IL-1β, and pro-IL-18. The newly translated procytokines remain intracellularly and inactive unless the producing cell encounters a second signal, resulting in activation of the inflammasome scaffold and maturation of pro-caspase-1.

[0033] In addition to the proteolytic activation of pro-IL-1β and pro-IL-18, active caspase-1 also leads to 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 (compounds that promote inflammation and stimulate innate and adaptive immunity), such as high-mobility group box 1 protein (HMGB1), IL-33, and IL-1α.

[0034] Inflammasome activation appears to have evolved as a critical component of host immunity against pathogens; however, the NLRP3 inflammasome is unique in its ability to activate in response to endogenous and exogenous sterile danger signals. Numerous such sterile signals have been characterized, and their formation is associated with specific disease states. For example, uric acid crystals, found in patients with gout, are potent 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 association of IL-1 and IL-18 with a wide range of pathophysiological conditions, including metabolic, physiological, inflammatory, hematological, and immune disorders.

[0035] The relevance to human disease is best exemplified by the discovery that gain-of-function mutations in the NLRP3 gene lead to a series of autoinflammatory conditions collectively known as cryopyrin-associated periodic syndromes (CAPS), including 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, sterile mediator-induced activation of NLRP3 has been implicated 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), pulmonary disorders (chronic obstructive pulmonary disease (COPD), asthma, idiopathic pulmonary fibrosis), and liver disorders (fibrosis, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis (NASH)). Furthermore, NLRP3 activation is thought to promote renal inflammation and, therefore, contribute to chronic kidney disease (CKD).

[0036] Current treatment options for diseases in which IL-1 is implicated as a contributing factor in the pathogenesis include the IL-1 receptor antagonist anakinra, an Fc-containing fusion construct of the extracellular domains of the IL-1 receptor and IL-1 receptor accessory protein (rilonacept), and the anti-IL-1β monoclonal antibody canakinumab. For example, canakinumab is 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.

[0037] Some small molecules have been reported to inhibit NLRP3 inflammasome function. For example, glyburide is a specific inhibitor of NLRP3 activation, even at micromolar concentrations 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 limited because they share a common structural feature consisting of an olefin that becomes activated upon substitution with an electron-withdrawing group; this substitution results in the undesired formation of covalent adducts with protein-bearing thiol groups. Several 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, including agonists of the G protein-coupled receptor TGR5, inhibitors of sodium-glucose cotransport (epigliflozin), the dopamine receptor antagonist A-68930, the serotonin reuptake inhibitor fluoxetine, fenamate nonsteroidal anti-inflammatory drugs, and the beta-adrenergic receptor blocker nebivolol. The usefulness of these molecules as therapeutic agents for the long-term treatment of NLRP3-dependent inflammatory disorders remains to be established. A series of sulfonylurea-containing molecules have already been identified as potent and selective inhibitors of post-translational processing of pro-IL-1β (Perregaux et al., J. Pharmacol. Exp. Ther. 299, 187-197, 2001). Recently, the exemplary molecule in this study, CP-456,773, was characterized as a specific inhibitor of NLRP3 activation (Coll et al., Nat Med 21.3 (2015): 248-255.).

[0038] The present disclosure relates to compounds useful for specifically modulating NLRP3-dependent cellular processes. In particular, there is a need for compounds that have improved physicochemical, pharmacological, and pharmaceutical properties compared to existing NLRP3-modulating compounds.

[0039] definition Unless otherwise stated, the following terms used in the specification and claims have the meanings set forth below.

[0040] As used herein, "alkyl," "C1, C2, C3, C4, C5, or C6 alkyl," or "C1-C6 alkyl" is intended to include C1, C2, C3, C4, C5, or C6 straight-chain (straight-chain) saturated aliphatic hydrocarbon groups, and C3, C4, C5, or C6 branched saturated aliphatic hydrocarbon groups. For example, C1-C6 alkyl is intended to include C1, C2, C3, C4, C5, or C6 alkyl groups. Examples of alkyl include moieties having 1 to 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., C1-C6 for straight chain, C3-C6 for branched chain), and in other embodiments, a straight-chain or branched alkyl has 4 or fewer carbon atoms.

[0041] As used herein, the term "optionally substituted alkyl" refers to an unsubstituted alkyl or an alkyl having specified substituents replacing one or more hydrogen atoms on 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, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

[0042] As used herein, the term "alkenyl" includes unsaturated aliphatic groups analogous in length and possible substitution to alkyl, as defined above, but which contain 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, a straight-chain or branched alkenyl group has six or fewer carbon atoms in its backbone (e.g., C2-C6 for straight chain, C3-C6 for branched chain). The term "C2-C6" includes alkenyl groups containing 2 to 6 carbon atoms. The term "C3-C6" includes alkenyl groups containing 3 to 6 carbon atoms.

[0043] As used herein, the term "optionally substituted alkenyl" means an unsubstituted alkenyl or an alkenyl having specified substituents replacing 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, sulfonamido, nitro, trifluoromethyl, cyano, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

[0044] As used herein, the term "alkynyl" includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but which contain 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, a straight-chain or branched alkynyl group has six or fewer carbon atoms in its backbone (e.g., C2-C6 for straight chain, C3-C6 for branched chain). The term "C2-C6" includes alkynyl groups containing 2 to 6 carbon atoms. The term "C3-C6" includes alkynyl groups containing 3 to 6 carbon atoms. As used herein, a "C2-C6 alkenylene linker" or "C2-C6 alkynylene linker" is intended to include a C2, C3, C4, C5, or C6 (straight or branched) diunsaturated aliphatic hydrocarbon group. For example, a C2-C6 alkenylene linker is intended to include C2, C3, C4, C5, and C6 alkenylene linker groups.

[0045] As used herein, the term "optionally substituted alkynyl" means an unsubstituted alkynyl or an alkynyl having specified substituents replacing 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, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

[0046] Other optionally substituted moieties (such as optionally substituted cycloalkyl, heterocycloalkyl, aryl, or heteroaryl) include both unsubstituted moieties and moieties having one or more of the specified 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.

[0047] As used herein, the term "cycloalkyl" refers to a group having 3 to 30 carbon atoms (e.g., C3-C 12 , C3-C 10, or C3-C8) saturated or partially unsaturated mono- or polycyclic (e.g., fused, bridged, or spirocyclic) hydrocarbon systems. 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 need be non-aromatic.

[0048] The term "heterocycloalkyl," as used herein, unless otherwise specified, means a saturated or partially unsaturated 3-8 membered monocyclic ring system, a 7-12 membered bicyclic ring system (fused, bridged, or spirocyclic), or an 11-14 membered tricyclic ring system (fused, bridged, or spirocyclic) having one or more heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur (e.g., O, N, S, P, or Se), e.g., 1, or 1-2, or 1-3, or 1-4, or 1-5, or 1-6 heteroatoms, or e.g., 1, 2, 3, 4, 5, or 6 heteroatoms.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-oxa- Zepanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2-oxa-6-azaspiro[3.3]heptanyl, 2,6-diazaspiro[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[cyclohe cyclohexane-1,5'-furo[3,4-b]pyridin]-yl, 3'H-spiro[cyclohexane-1,1'-furo[3,4-c]pyridin]-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 Examples include, but are not limited to, [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, and 5,6-dihydro-4H-cyclopenta[b]thiophenyl. In the case of polycyclic cycloalkyls, only one of the rings of the heterocycloalkyl need be non-aromatic (e.g., 4,5,6,7-tetrahydrobenzo[c]isoxazolyl).In some embodiments, heterocycloalkyl is 5,6-dihydro-4H-cyclopenta[b]thiophenyl. TIFF0007661248000019.tif21128. In some embodiments, heterocycloalkyl is 4,5,6,7-tetrahydrobenzofuranyl TIFF0007661248000020.tif23128. In some embodiments, heterocycloalkyl is 4,5,6,7-tetrahydrobenzo[b]thiophenyl The file is TIFF0007661248000021.tif24128.

[0049] As used herein, the term "aryl" includes "conjugated" or polycyclic ring systems having one or more aromatic rings, and includes groups that do not contain heteroatoms in the ring structure and have aromatic character. The term aryl includes both monovalent and divalent species. Examples of aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, and the like. Conveniently, the aryl is phenyl.

[0050] As used herein, the term "heteroaryl" is intended to include a stable 5-, 6-, or 7-membered monocyclic aromatic heterocycle or a 7-, 8-, 9-, 10-, 11-, 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, e.g., 1, or 1-2, or 1-3, or 1-4, or 1-5, or 1-6 heteroatoms, or e.g., 1, 2, 3, 4, 5, or 6 heteroatoms. The nitrogen atom can be substituted or unsubstituted (i.e., N or NR, where R is H or other substituent as defined). The nitrogen and sulfur heteroatoms can optionally 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, isothiazole, pyridine, pyrazine, pyridazine, pyrimidine, and the like. Heteroaryl groups can be fused or bridged with alicyclic or heterocyclic rings that are not aromatic to form polycyclic systems (e.g., 4,5,6,7-tetrahydrobenzo[c]isoxazolyl). In some embodiments, heteroaryl is thiophenyl or benzothiophenyl. In some embodiments, heteroaryl is thiophenyl. In some embodiments, heteroaryl is benzothiophenyl.

[0051] Furthermore, the terms "aryl" and "heteroaryl" include polycyclic aryl and heteroaryl groups, e.g., tricyclic, bicyclic, such as naphthalene, benzoxazole, benzodioxazole, benzothiazole, benzimidazole, benzothiophene, quinoline, isoquinoline, naphthyridine, indole, benzofuran, purine, benzofuran, deazapurine, and indolizine.

[0052] The cycloalkyl ring, heterocycloalkyl ring, aryl ring, or heteroaryl ring may have, at one or more ring positions (e.g., a ring-forming carbon atom or a heteroatom such as N), a substituent as described above, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminocarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl The aryl and heteroaryl groups may be substituted with aryl, 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, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or aromatic or heteroaromatic moieties. Aryl and heteroaryl groups may also be fused or bridged with alicyclic or heterocyclic rings that are not aromatic to form polycyclic ring systems (e.g., tetralin, methylenedioxyphenyl such as benzo[d][1,3]dioxol-5-yl).

[0053] As used herein, the term "substituted" means replacing any one or more hydrogen atoms at a specified atom with one selected from the indicated group, provided that the normal valence of the specified atom is not exceeded and that the substitution results in a stable compound. If the substituent is oxo or keto (i.e., =0), it replaces two hydrogen atoms at the atom. Keto substituents are not present in aromatic moieties. As used herein, a ring double bond refers to 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 that is sufficiently robust to enable isolation to a useful degree of purity from a reaction mixture and formulation into an efficacious therapeutic agent.

[0054] When a bond to a substituent is shown to cross the bond connecting two atoms in a ring, then such substituent may be bonded to any atom in the ring. When a substituent is listed without indicating through which atom of the substituent it is bonded to the remainder of the compound of a given formula, then the substituent may be bonded through any atom of the formula. Combinations of substituents and / or variables are permissible, but only if such combinations result in stable compounds.

[0055] When any variable (e.g., R) occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is indicated as substituted with 0 to 2 R moieties, that group may be substituted with up to two R moieties, and each occurrence of R is independently selected from the definitions of R. Also, combinations of substituents and / or variables are permissible, but only if such combinations result in stable compounds.

[0056] As used herein, the term "hydroxy" or "hydroxyl" refers to -OH or -O - The group includes a group having the formula:

[0057] The term "halo" or "halogen" as used herein means fluoro, chloro, bromo, and iodo.

[0058] The term "haloalkyl" or "haloalkoxyl" means an alkyl or alkoxyl substituted with one or more halogen atoms.

[0059] As used herein, the term "optionally substituted haloalkyl" refers to an unsubstituted haloalkyl having specified substituents replacing 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, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

[0060] As used herein, the term "alkoxy" or "alkoxyl" includes substituted and unsubstituted alkyl, alkenyl, and alkynyl groups covalently linked to an oxygen atom. Examples of alkoxy groups or alkoxyl radicals include, but are not limited to, methoxy, ethoxy, isopropyloxy, propoxy, butoxy, and pentoxy groups. Examples of substituted alkoxy groups include halogenated alkoxy groups. Alkoxy groups can 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, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. Examples of halogen substituted alkoxy groups include, but are not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy, and trichloromethoxy.

[0061] Unless otherwise indicated, the expressions used herein "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. are used interchangeably and all mean a selection from the group consisting of A, B, and / or C, i.e., one or more A, one or more B, one or more C, or any combination thereof.

[0062] It is 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 schemes below and the schemes shown in the Examples.

[0063] It should be understood that throughout this specification, when compositions are described as having, including, or comprising particular components, it is also contemplated that these compositions consist essentially of, or consist of, the recited components. Similarly, when methods or processes are described as having, including, or comprising particular processing steps, these processes also consist essentially of, or consist of, the recited processing steps. Furthermore, it should be understood that the order of steps or order for performing certain actions is immaterial so long as the invention functions. Moreover, two or more steps or actions can be conducted simultaneously.

[0064] It will be understood that the synthetic processes of the present disclosure can tolerate a wide variety of functional groups and, therefore, can employ a variety of substituted starting materials. While the processes generally provide the desired final compound at or near the end of the overall process, in certain instances it may be desirable to further convert the compound to its pharmaceutically acceptable salt.

[0065] It will be understood that the compounds of the present disclosure can be prepared in a variety of ways, using commercially available starting materials, using compounds known in the literature, or from readily prepared intermediates, using any standard synthetic methods and procedures known to those of skill in the art or that will be apparent to those skilled in the art in light of the teachings herein. Standard synthetic methods and procedures for the preparation of organic molecules, and standard transformations and manipulations of functional groups, can be obtained from the relevant scientific literature or from standard textbooks in the field. See, but not limited to, one or more sources, Smith, MB, March, J., March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5, incorporated herein by reference. th edition, John Wiley & Sons: New York, 2001, Greene, TW, Wuts, PGM, Protective Groups in Organic Synthesis, 3 rd Classic texts such as R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989), edition, John Wiley & Sons: New York, 1999; L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995), are known to those skilled in the art and are useful and generally recognized reference texts for organic synthesis.

[0066] Those skilled in the art will note that the order of certain steps, such as the introduction and removal of protecting groups, may be varied during the reaction sequences and synthetic schemes described herein. Those skilled in the art will recognize that certain groups may require protection from reaction conditions due to the use of protecting groups. Protecting groups may be used to distinguish similar functional groups within a molecule. A list of protecting groups, as well as methods for introducing and removing these groups, can be found in Greene, TW, Wuts, PGM, Protective Groups in Organic Synthesis, 3 rd edition, John Wiley & Sons: New York, 1999.

[0067] Unless otherwise specified, it will be understood that any reference to a method of treatment or prevention includes the use of the compounds to provide the treatment or prevention described herein. It will be further understood that, unless otherwise specified, any reference to a method of treatment or prevention includes the use of the compounds for the preparation of a medicament to treat or prevent such condition. Treatment or prevention includes treatment or prevention in humans or non-human animals, such as rodents and other disease models.

[0068] Unless otherwise specified, it is understood that any reference to a method of treatment includes the use of a compound to provide the treatment described herein. It is further understood that unless otherwise specified, any reference to a method of treatment includes the use of a compound to prepare a medicament to treat such a condition. Treatment includes the treatment of humans or non-human animals, such as rodents and other disease models. As used herein, the term "subject" is used interchangeably with "subject in need thereof," both of which refer to a subject having a disease or at risk of developing a disease. "Subject" includes mammals. A 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. The subject can also be a bird or poultry. In some embodiments, the mammal is a human. A subject in need thereof can be a subject already diagnosed or identified as having a disease or disorder disclosed herein. A subject in need thereof can also be a subject having a disease or disorder described herein. Alternatively, the subject in need thereof can be a subject at increased risk for developing such a disease or disorder compared to the general population (i.e., a subject who is more susceptible to developing such a disorder compared to the general population). The subject in need thereof can 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 can exhibit resistance at the start of treatment or can acquire resistance during treatment. In some embodiments, the subject in need thereof has undergone all known effective treatments for the disease or disorder disclosed herein with unsatisfactory results. In some embodiments, the subject in need thereof has undergone at least one conventional treatment.

[0069] As used herein, the term "treating" or "treat" describes the management and care of a patient to combat a disease, condition, or disorder, and includes the administration of a compound of the present disclosure, or a pharmaceutically acceptable salt, polymorph, or solvate thereof, to alleviate the symptoms or complications of the disease, condition, or disorder, or to eliminate the disease, condition, or disorder. The term "treat" can also include treatment of cells in vitro or animal models. It should be recognized that "treating" or "treatment" includes the alleviation of pre-existing symptoms of a condition. Thus, "treating" or "treatment" in relation to a condition, disorder, or condition includes (1) preventing or delaying the onset of clinical symptoms of the condition, disorder, or condition in a person who may be afflicted with or susceptible to the condition, disorder, or condition but who has not yet experienced or manifested clinical or subclinical symptoms of the condition, disorder, or condition; (2) inhibiting the condition, disorder, or condition, i.e., arresting, suppressing, or delaying the onset of the disease or its recurrence (in the case of maintenance treatment), or at least one clinical or subclinical symptom thereof; or (3) palliating or attenuating the disease, i.e., causing regression of the condition, disorder, or condition, or at least one clinical or subclinical symptom thereof.

[0070] It is to be understood that the compounds of the present disclosure, or pharmaceutically acceptable salts, polymorphs, or solvates thereof, can or may be used to prevent the relevant disease, condition, or disorder, or to identify suitable candidates for such purposes.

[0071] As used herein, the terms "preventing," "prevent," or "protecting against" are intended to describe inhibiting or eliminating the onset of symptoms or complications of a disease, condition, or disorder.

[0072] It should be understood that those skilled in the art can refer to general references for detailed descriptions of the known techniques described herein or equivalent techniques, such as 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), Colligan et al., Current Protocols in Immunology, John Wiley & Sons, NY, Enna et al., Current Protocols in Pharmacology, John Wiley & Sons, NY, Fingl et al., The Pharmacological Basis of Therapeutics (1975), Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, 18 th edition (1990). It will be appreciated that these documents may be consulted in making or using an aspect of the present disclosure.

[0073] It should also be understood that the present disclosure provides pharmaceutical compositions comprising any of the compounds described herein in combination with 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 some embodiments, the pharmaceutical composition is in bulk or unit dosage form. The unit dosage form may be in any of a variety of forms, such as a capsule, an infusion bag, a tablet, a single pump on an aerosol inhaler, or a vial. The amount of active ingredient (e.g., a formulation of the disclosed compound or a salt, hydrate, solvate, or isomer thereof) in a unit dosage form of the composition is an effective amount and will vary depending on the specific treatment involved. Those skilled in the art will recognize that it may sometimes be necessary to routinely modify the dosage depending on the age and condition of the patient. The dosage also depends on the route of administration. Various routes of administration are contemplated, such as oral, intrapulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalation, buccal, sublingual, intrapleural, intrathecal, and intranasal. Dosage forms for topical or transdermal administration of a compound of this 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 required 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, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals and that offer a reasonable benefit / risk ratio without excessive toxicity, irritation, allergic response, or other problem or complication.

[0076] As used herein, the term "pharmaceutically acceptable excipient" generally refers to an excipient that is safe, non-toxic, and biologically or otherwise desirable and useful in preparing pharmaceutical compositions, and includes excipients that are acceptable for veterinary and human pharmaceutical use. As used in the specification and claims, "pharmaceutically acceptable excipient" includes both one such excipient and more than one such excipient.

[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, e.g., intravenous administration, intradermal administration, subcutaneous administration, oral (e.g., ingestion), inhalation administration, transdermal (topical) administration, and transmucosal administration. Solutions or suspensions used for parenteral, intradermal, or subcutaneous application can contain the following components: a sterile diluent such as water for injection, saline, fixed oils, polyethylene glycol, glycerin, propylene glycol, or other synthetic solvents; an antibacterial agent such as benzyl alcohol or methylparaben; an antioxidant such as ascorbic acid or sodium bisulfite; a chelating agent such as ethylenediaminetetraacetic acid; a buffer such as acetate, citrate, or phosphate; and an agent for adjusting tonicity such as sodium chloride or glucose. pH can be adjusted with acids or bases such as hydrochloric acid or sodium hydroxide. Parenteral formulations can be enclosed in glass or plastic ampoules, disposable syringes, or multiple dose vials.

[0078] It should be understood that the compounds or pharmaceutical compositions of the present disclosure can be administered to subjects using many well-known chemotherapeutic treatments currently in use.For example, the compounds of the present disclosure can be injected into the bloodstream or body cavity, or taken orally, or applied through the skin with a patch.The selected dosage is sufficient to constitute effective treatment, but not so high as to cause unacceptable side effects.It is preferable to carefully monitor the status of the disease condition (e.g., the diseases or disorders described herein) and the health of the patient during and for a considerable period after treatment.

[0079] As used herein, the term "therapeutically effective amount" refers to an amount of a pharmaceutical agent that treats, ameliorates, or prevents an identified disease or condition, or that exhibits a detectable therapeutic or inhibitory effect. This effect can be detected by any assay known in the art. The precise effective amount for a subject will depend on the subject's weight, size, and health, the nature and extent of the condition, and the therapeutic agent or combination of therapeutic agents selected for administration. The therapeutically effective amount for a given situation can be determined by routine experimentation that is within the skill and judgment of the clinician.

[0080] As used herein, the term "therapeutically effective amount" refers to an amount of a pharmaceutical agent that treats or ameliorates, or exhibits a detectable therapeutic or inhibitory effect on, an identified disease or condition. This effect can be detected by any assay known in the art. The precise effective amount for a subject will depend on the subject's weight, size, and health, the nature and extent of the condition, and the therapeutic agent or combination of therapeutic agents selected for administration. The therapeutically effective amount for a given situation can be determined by routine experimentation that is within the skill and judgment of the clinician.

[0081] It will be appreciated that for any compound, the therapeutically effective amount can be estimated initially either in cell culture assays, e.g., neoplastic cell assays, or in animal models, usually rats, mice, rabbits, dogs, or pigs. Animal models may also be used to determine appropriate concentration ranges and routes of administration. This information can then be used to determine useful doses and routes of administration for administration in humans. Therapeutic / prophylactic efficacy and toxicity can be assessed using standard formulation procedures in cell cultures or experimental animals, e.g., ED 50 (therapeutic effective dose in 50% of the population) and LD 50 The dose ratio between toxic and therapeutic effects is known as the therapeutic index, which is the LD 50 / ED 50 Pharmaceutical compositions with large therapeutic indices are preferred. The dosage can vary within this range depending on the dosage form used, sensitivity of the patient, and the route of administration.

[0082] Dosage and administration are adjusted to provide sufficient levels of the active agent(s) or to maintain the desired effect. Factors that may be taken into consideration include the severity of the disease state, the subject's overall health, the subject's age, weight, and sex, diet, administration time and frequency, drug combination(s), reaction sensitivities, and tolerance / response to treatment. Long-acting pharmaceutical compositions may be administered every 3-4 days, every week, or once every two weeks, depending on the half-life and clearance rate of the particular formulation.

[0083] The pharmaceutical composition comprising the active compound of the present disclosure can be prepared by generally known methods, for example, conventional mixing, dissolving, granulating, sugar-coating, wet grinding, emulsifying, encapsulating, encapsulating or lyophilizing process.The pharmaceutical composition can be prepared by conventional methods using one or more pharmaceutically acceptable carriers, including excipients and / or adjuvants that facilitate the introduction of active compound into pharmaceutically acceptable preparations.Of course, the suitable preparation varies depending on the selected administration route.

[0084] Pharmaceutical compositions suitable for injection include sterile aqueous solutions (where water soluble) or aqueous dispersions, and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL™ (BASF, Parsippany, NJ), or phosphate-buffered saline (PBS). In all cases, the composition must be sterile and must be fluid to the extent that easy syringability exists. The composition must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol), and suitable mixtures thereof. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. Prevention of microbial action can be achieved by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, etc. In most cases, it is preferable to include isotonic agents, such as sugars, polyalcohols such as mannitol and sorbitol, and sodium chloride in the composition. Prolonged absorption of injectable compositions can be achieved by including agents that delay absorption, such as aluminum monostearate and gelatin in the composition.

[0085] Sterile injection solution can be prepared by adding the required amount of active compound to a suitable solvent, and then adding one or a combination of the above-mentioned components as needed, and then sterilizing by filtration.Generally, dispersion solution is prepared by adding active compound to a sterile medium that contains a basic dispersion medium and other necessary components as mentioned above.In the case of sterile powder for preparing sterile injection solution, preparation methods include vacuum drying and freeze-drying, and by drying, powder of active compound and other desired components is produced from the solution containing these components that has been previously sterilized and filtered.

[0086] Oral compositions generally contain an inert diluent or a pharmaceutically acceptable edible carrier. Oral compositions can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be combined with an excipient and used in the form of tablets, lozenges, or capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash; the fluid carrier containing the compound is given orally, rinsed, and then expectorated or swallowed. Pharmaceutically compatible binding agents and / or adjuvant materials can be included as part of the composition. Tablets, pills, capsules, troches and the like may contain any of the following ingredients: a binder such as microcrystalline cellulose, gum tragacanth, or gelatin; an excipient such as starch or lactose; a disintegrating agent such as alginic acid, Primogel, or cornstarch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetener such as sucrose or saccharin; or a flavoring such as peppermint, methyl salicylate, or orange flavor, or compounds of a similar nature.

[0087] For administration by inhalation, the compounds are delivered in the form of an aerosol spray from pressured container or dispenser which contains a suitable propellant, eg, a gas such as carbon dioxide, or a nebulizer.

[0088] Systemic administration can be via transmucosal or transdermal means. For transmucosal or transdermal administration, a penetrant suitable for the barrier to be permeated is used in the formulation. Such penetrants are generally known in the art, and for example, for transmucosal administration, surfactants, bile salts, and fusidic acid derivatives are used. Transmucosal administration can be achieved through the use of nasal sprays or suppositories. For transdermal administration, the active compound is formulated into ointments, salves, gels, or creams that are generally known in the art.

[0089] The active compounds can be prepared using pharmaceutically acceptable carriers that protect the compound against rapid elimination from the body, such as controlled-release formulations, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparing these formulations are readily apparent to those skilled in the art. Materials are also commercially available from Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions (including liposomes targeted to infected cells with monoclonal antibodies against viral antigens) can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Pat. No. 4,522,811.

[0090] It is particularly advantageous to prepare oral or parenteral compositions in unit dosage form because of easy administration and uniform dosage.The unit dosage form used herein refers to a physically discrete unit suitable for a unit dosage form for a subject to be treated, each unit containing a predetermined amount of active compound calculated to achieve a desired therapeutic effect in association with a required pharmaceutical carrier.The specification of the unit dosage form of the present disclosure is determined by and directly depends on the inherent properties of active compound and the specific therapeutic effect to be achieved.

[0091] For therapeutic applications, dosages of pharmaceutical compositions used in accordance with the present disclosure will vary depending on the agent, the age, weight, and clinical condition of the recipient patient, and the experience and judgment of the treating clinician or practitioner, among other factors that will affect the selected dosage. Generally, dosages should be sufficient to delay, and preferably cause regression of, the symptoms of the diseases or disorders described herein, preferably resulting in complete regression of the disease or disorder. Doses can range from about 0.01 mg / kg / day to about 5000 mg / kg / day. In preferred embodiments, dosages can range from about 1 mg / kg / day to about 1000 mg / kg / day. In certain embodiments, the dose ranges from 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 / day to about 3 g / day, or about 0.1 mg / day to about 1 g / day (this dose is based on the patient's weight in kg, body area in m2) in a single dose, divided doses, or continuous dose. 2 (and may be adjusted according to age). An effective amount of a pharmaceutical is that amount that is recognized by a clinician or other qualified observer, i.e., that produces an objectively identifiable improvement. Improved survival and growth rates indicate regression. As used herein, the term "dosage effective manner" refers to the amount of an active compound that produces a desired biological effect in a subject or cell.

[0092] It will be appreciated that the pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration.

[0093] For compounds of the present disclosure that are capable of further forming salts, it is understood that all of these forms are also intended to be within the scope of the present claimed disclosure.

[0094] As used herein, the term "pharmaceutically acceptable salts" refers to derivatives of the compounds of the present disclosure in which the parent compound is modified by forming its acid or base salts. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, alkali or organic salts of acidic residues such as carboxylic acids, etc. Pharmaceutically acceptable salts include conventional non-toxic salts or, for example, quaternary ammonium salts of the parent compound formed from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include 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, hexylresorcylic acid, hydrabamic acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, hydroxymaleic acid, hydroxynaphthoic acid, isethionic acid, lactic acid, and lactobionic acid. , laurylsulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, napsylic 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, and the like.

[0095] In some embodiments, the pharmaceutically acceptable salt is a sodium salt, a potassium salt, a calcium salt, a magnesium salt, a diethylamine salt, a choline salt, a meglumine salt, a benzathine salt, a tromethamine salt, an ammonia salt, an arginine salt, or a 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, etc. The present disclosure also includes salts formed when an acidic proton present in the parent compound is replaced with a metal ion, e.g., an alkali metal ion, alkaline earth ion, or aluminum ion, or is coordinated to an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like. It is understood that in the 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, for example, 3:1, 2:1, 1:2, or 1:3.

[0097] It should be understood that any reference to a pharmaceutically acceptable salt includes the solvent addition forms (solvates) or crystal forms (polymorphs), as defined herein, of the same salt.

[0098] The compound or its pharmaceutically acceptable salt is administered orally, intranasally, transdermally, intrapulmonary, inhaled, buccal, sublingually, intraperitoneally, subcutaneously, intramuscularly, intravenously, rectally, intrapleurally, intrathecally, and parenterally. In some embodiments, the compound is administered orally. Those skilled in the art will recognize the advantages of certain administration routes.

[0099] The dosing regimen utilizing the compound is selected according to various factors, including the type, species, age, weight, sex, and medical condition of the patient, the severity of the condition being treated, the route of administration, the patient's renal and hepatic function, and the particular compound or salt thereof used. A physician or veterinarian of ordinary skill can readily determine and prescribe the effective amount of medication required to prevent, counter, or halt the progression of the condition. A physician or veterinarian of ordinary skill can readily determine and prescribe the effective amount of medication required to counter or halt the progression of the condition.

[0100] Techniques for formulation and administration of the compounds disclosed in this disclosure are described in Remington: The Science and Practice of Pharmacy, 1999. 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 diluents, and sterile aqueous or organic solutions. The compounds will be present in such pharmaceutical compositions in an amount sufficient to provide the desired dosage in the range described herein.

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

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

[0103] All publications and patent documents cited herein are hereby incorporated by reference to the same extent as if each individual publication or document was specifically and individually indicated to be incorporated by reference. The citation of publications and patent documents is not intended as an admission that any is pertinent prior art, nor is it an admission as to the contents or date thereof. Having described and illustrated the invention herein, those skilled in the art will recognize that the invention can be practiced in various embodiments, and that the foregoing description and the following examples are intended to be illustrative and not limiting of the scope of the claims which follow.

[0104] As used herein, the phrase "compounds of the present disclosure" refers to both the compounds disclosed generally and the compounds specifically disclosed herein.

[0105] Compounds of the Disclosure In some aspects, the present disclosure provides, inter alia, compounds of formula (I): TIFF0007661248000022.tif21128, or a prodrug, solvate, or pharmaceutically acceptable salt thereof, wherein: R1 is one or more R 1S is a 5- to 12-membered heterocycloalkyl or 5- to 12-membered heteroaryl optionally substituted with Each R 1Sare independently C1-C6 alkyl, C1-C6 haloalkyl, -O(C1-C6 alkyl), -O(C1-C6 haloalkyl), -(C1-C6 alkyl)-O(C1-C6 alkyl), cyano, halo, C3-C8 cycloalkyl, C3-C8 aryl, 3- to 8-membered heterocycloalkyl, or 3- to 8-membered heteroaryl; R2 is -(CX2X2) n -R 2S wherein n is 0, 1, or 2, and each X2 is independently H, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, wherein the C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is optionally substituted with one or more halo, —CN, —OH, —O(C1-C6 alkyl), —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, or oxo; R 2S is C1-C6 alkyl, C3-C 16 cycloalkyl or 4-8 membered heterocycloalkyl, C1-C6 alkyl, C3-C 16 The cycloalkyl or 4-8 membered heterocycloalkyl may be optionally substituted with one or more C-C alkyl, C-C alkenyl, C-C alkynyl, C-C haloalkyl, halo, -CN, -OH, -O(C-C alkyl), -NH, -NH(C-C alkyl), -N(C-C alkyl), or oxo; and R3 is one or more R 3S and each R is a 5- to 12-membered heterocycloalkyl or a 5- or 6-membered heteroaryl optionally substituted with 3S are independently C-C alkyl, C-C haloalkyl, C-C cycloalkyl, halo, or C-C heterocycloalkyl, wherein the C-C alkyl, C-C haloalkyl, C-C cycloalkyl, or C-C heterocycloalkyl is optionally substituted with —O(C-C alkyl), —N(C-C alkyl), halo, or —CN.

[0106] In some aspects, the present disclosure provides, inter alia, compounds of formula (I): TIFF0007661248000023.tif21128, or a prodrug, solvate, or pharmaceutically acceptable salt thereof, wherein: R1 is one or more R 1S is a 5- to 12-membered heterocycloalkyl or 5- to 12-membered heteroaryl optionally substituted with Each R 1S are independently C1-C6 alkyl, C1-C6 haloalkyl, -O(C1-C6 alkyl), -O(C1-C6 haloalkyl), -(C1-C6 alkyl)-O(C1-C6 alkyl), cyano, halo, C3-C8 cycloalkyl, C3-C8 aryl, 3- to 8-membered heterocycloalkyl, or 3- to 8-membered heteroaryl; R2 is -(CX2X2) n -R 2S wherein n is 0, 1, or 2, and each X2 is independently H, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, wherein the C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is optionally substituted with one or more halo, —CN, —OH, —O(C1-C6 alkyl), —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, or oxo; R 2S is C1-C6 alkyl, C3-C 16 cycloalkyl, or 4-8 membered heterocycloalkyl, C1-C6 alkyl, C3-C 16 The cycloalkyl or 4-8 membered heterocycloalkyl may be optionally substituted with one or more C-C alkyl, C-C alkenyl, C-C alkynyl, C-C haloalkyl, halo, -CN, -OH, -O(C-C alkyl), -NH, -NH(C-C alkyl), -N(C-C alkyl), or oxo; and R3 is one or more R 3S and each R is a 7- to 12-membered heterocycloalkyl or a 5- or 6-membered heteroaryl optionally substituted with 3Sare independently C-C alkyl, C-C haloalkyl, C-C cycloalkyl, halo, or C-C heterocycloalkyl, wherein the C-C alkyl, C-C haloalkyl, C-C cycloalkyl, or C-C heterocycloalkyl is optionally substituted with —O(C-C alkyl), —N(C-C alkyl), halo, or —CN.

[0107] In some embodiments, the compound is a compound of formula (I), or a prodrug, solvate, or pharmaceutically acceptable salt thereof, wherein: R1 is a 5-12 membered heterocycloalkyl or a 5-12 membered heteroaryl, wherein at least one heteroatom in the 5-12 membered heterocycloalkyl or the 5-12 membered heteroaryl is O or S, and the 5-12 membered heterocycloalkyl or the 5-12 membered heteroaryl is substituted with one or more R 1S may be substituted with; Each R 1S is independently C1-C6 alkyl, C1-C6 haloalkyl, —O(C1-C6 alkyl), cyano, halo, C3-C8 cycloalkyl, or C3-C8 aryl; R2 is -(CH2) n -R 2S where n is 0, 1, or 2; R 2S is C1-C6 alkyl, C3-C 16 cycloalkyl, or 4-8 membered heterocycloalkyl, C1-C6 alkyl, C3-C 16 The cycloalkyl or 4- to 8-membered heterocycloalkyl may be optionally substituted with one or more C1-C6 alkyl, halo, —OH, —O(C1-C6 alkyl), —NH2, —NH(C1-C6 alkyl), or —N(C1-C6 alkyl)2; and R3 is a 5- to 6-membered heterocycloalkyl or a 5- or 6-membered heteroaryl, and the 5- to 12-membered heterocycloalkyl or 5- or 6-membered heteroaryl is optionally substituted with one or more C1-C6 alkyl, C3-C8 cycloalkyl, or halo.

[0108] In some embodiments, the compound is a compound of formula (I), or a prodrug, solvate, or pharmaceutically acceptable salt thereof, wherein: R1 is a 5-12 membered heterocycloalkyl or a 5-12 membered heteroaryl, wherein at least one heteroatom in the 5-12 membered heterocycloalkyl or the 5-12 membered heteroaryl is O or S, and the 5-12 membered heterocycloalkyl or the 5-12 membered heteroaryl is substituted with one or more R 1S may be substituted with; Each R 1S is independently C1-C6 alkyl, C1-C6 haloalkyl, —O(C1-C6 alkyl), cyano, halo, C3-C8 cycloalkyl, or C3-C8 aryl; R2 is -(CH2) n -R 2S where n is 0, 1, or 2; R 2S is C1-C6 alkyl, C3-C 16 cycloalkyl, or 4-8 membered heterocycloalkyl, C1-C6 alkyl, C3-C 16 The cycloalkyl or 4- to 8-membered heterocycloalkyl may be optionally substituted with one or more C1-C6 alkyl, halo, —OH, —O(C1-C6 alkyl), —NH2, —NH(C1-C6 alkyl), or —N(C1-C6 alkyl)2; and R3 is a 5-6 membered heteroaryl optionally substituted with one or more C1-C6 alkyl, C3-C8 cycloalkyl, or halo.

[0109] In some embodiments, the compound is a compound of formula (I), or a prodrug, solvate, or pharmaceutically acceptable salt thereof, wherein: R1 is one or more R 1S is a 5- to 12-membered heteroaryl optionally substituted with Each R 1Sis independently C1-C6 alkyl, C1-C6 haloalkyl, -O(C1-C6 alkyl), -O(C1-C6 haloalkyl), or halo; R2 is -(CX2X2) n -R 2S wherein n is 0, 1, or 2, and each X2 is independently H, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, wherein the C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is optionally substituted with one or more halo, —CN, —OH, —O(C1-C6 alkyl), —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, or oxo; R 2S is C1-C6 alkyl, C3-C 16 cycloalkyl, or 4-8 membered heterocycloalkyl, C1-C6 alkyl, C3-C 16 The cycloalkyl or 4-8 membered heterocycloalkyl may be optionally substituted with one or more C-C alkyl, C-C alkenyl, C-C alkynyl, C-C haloalkyl, halo, -CN, -OH, -O(C-C alkyl), -NH, -NH(C-C alkyl), -N(C-C alkyl), or oxo; and R3 is one or more R 3S and each R is a 7- to 12-membered heterocycloalkyl or a 5- or 6-membered heteroaryl optionally substituted with 3S are independently C-C alkyl, C-C haloalkyl, C-C cycloalkyl, halo, or C-C heterocycloalkyl, wherein the C-C alkyl, C-C haloalkyl, C-C cycloalkyl, or C-C heterocycloalkyl is optionally substituted with —O(C-C alkyl), —N(C-C alkyl), halo, or —CN.

[0110] In some embodiments, the compound is a compound of formula (I), or a prodrug, solvate, or pharmaceutically acceptable salt thereof, wherein: R1 is one or more R 1Swherein at least one heteroatom in the 5-12 membered heteroaryl is S; Each R 1S is independently C1-C6 alkyl, C1-C6 haloalkyl, -O(C1-C6 alkyl), -O(C1-C6 haloalkyl), or halo; R2 is -(CX2X2) n -R 2S wherein n is 0, 1, or 2, and each X2 is independently H, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, wherein the C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is optionally substituted with one or more halo, —CN, —OH, —O(C1-C6 alkyl), —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, or oxo; R 2S is C1-C6 alkyl, C3-C 16 cycloalkyl, or 4-8 membered heterocycloalkyl, C1-C6 alkyl, C3-C 16 The cycloalkyl or 4-8 membered heterocycloalkyl may be optionally substituted with one or more C-C alkyl, C-C alkenyl, C-C alkynyl, C-C haloalkyl, halo, -CN, -OH, -O(C-C alkyl), -NH, -NH(C-C alkyl), -N(C-C alkyl), or oxo; and R3 is one or more R 3S and each R is a 7- to 12-membered heterocycloalkyl or a 5- or 6-membered heteroaryl optionally substituted with 3S are independently C-C alkyl, C-C haloalkyl, C-C cycloalkyl, halo, or C-C heterocycloalkyl, wherein the C-C alkyl, C-C haloalkyl, C-C cycloalkyl, or C-C heterocycloalkyl is optionally substituted with —O(C-C alkyl), —N(C-C alkyl), halo, or —CN.

[0111] In some embodiments, the compound is a compound of formula (I), or a prodrug, solvate, or pharmaceutically acceptable salt thereof, wherein: R1 is one or more R 1S is a 5- to 12-membered heteroaryl optionally substituted with Each R 1S is independently C1-C6 alkyl, C1-C6 haloalkyl, -O(C1-C6 alkyl), -O(C1-C6 haloalkyl), or halo; R2 is -(CX2X2) n -R 2S wherein n is 0, 1, or 2, and each X2 is independently H, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, wherein the C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is optionally substituted with one or more halo, —CN, —OH, —O(C1-C6 alkyl), —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, or oxo; R 2S is a 4-8 membered heterocycloalkyl optionally substituted with one or more C-C alkyl, C-C alkenyl, C-C alkynyl, C-C haloalkyl, halo, -CN, -OH, -O(C-C alkyl), -NH, -NH(C-C alkyl), -N(C-C alkyl) or oxo; and R3 is one or more R 3S and each R is a 7- to 12-membered heterocycloalkyl or a 5- or 6-membered heteroaryl optionally substituted with 3S are independently C-C alkyl, C-C haloalkyl, C-C cycloalkyl, halo, or C-C heterocycloalkyl, wherein the C-C alkyl, C-C haloalkyl, C-C cycloalkyl, or C-C heterocycloalkyl is optionally substituted with —O(C-C alkyl), —N(C-C alkyl), halo, or —CN.

[0112] In some embodiments, the compound is a compound of formula (I), or a prodrug, solvate, or pharmaceutically acceptable salt thereof, wherein: R1 is one or more R 1S wherein at least one heteroatom in the 5-12 membered heteroaryl is S; Each R 1S is independently C1-C6 alkyl, C1-C6 haloalkyl, -O(C1-C6 alkyl), -O(C1-C6 haloalkyl), or halo; R2 is -(CX2X2) n -R 2S wherein n is 0, 1, or 2, and each X2 is independently H, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, wherein the C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is optionally substituted with one or more halo, —CN, —OH, —O(C1-C6 alkyl), —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, or oxo; R 2S is a 4-8 membered heterocycloalkyl optionally substituted with one or more C-C alkyl, C-C alkenyl, C-C alkynyl, C-C haloalkyl, halo, -CN, -OH, -O(C-C alkyl), -NH, -NH(C-C alkyl), -N(C-C alkyl) or oxo; and R3 is one or more R 3S and each R is a 7- to 12-membered heterocycloalkyl or a 5- or 6-membered heteroaryl optionally substituted with 3S are independently C-C alkyl, C-C haloalkyl, C-C cycloalkyl, halo, or C-C heterocycloalkyl, wherein the C-C alkyl, C-C haloalkyl, C-C cycloalkyl, or C-C heterocycloalkyl is optionally substituted with —O(C-C alkyl), —N(C-C alkyl), halo, or —CN.

[0113] In some embodiments, the compound is a compound of formula (I), or a prodrug, solvate, or pharmaceutically acceptable salt thereof, wherein: R1 is one or more R 1S is a 5- to 12-membered heteroaryl optionally substituted with Each R 1S is independently C1-C6 alkyl, C1-C6 haloalkyl, -O(C1-C6 alkyl), -O(C1-C6 haloalkyl), or halo; R2 is R 2S is; R 2S is a 4-8 membered heterocycloalkyl optionally substituted with one or more C-C alkyl, C-C alkenyl, C-C alkynyl, C-C haloalkyl, halo, -CN, -OH, -O(C-C alkyl), -NH, -NH(C-C alkyl), -N(C-C alkyl) or oxo; and R3 is one or more R 3S and each R is a 7- to 12-membered heterocycloalkyl or a 5- or 6-membered heteroaryl optionally substituted with 3S are independently C-C alkyl, C-C haloalkyl, C-C cycloalkyl, halo, or C-C heterocycloalkyl, wherein the C-C alkyl, C-C haloalkyl, C-C cycloalkyl, or C-C heterocycloalkyl is optionally substituted with —O(C-C alkyl), —N(C-C alkyl), halo, or —CN.

[0114] In some embodiments, the compound is a compound of formula (I), or a prodrug, solvate, or pharmaceutically acceptable salt thereof, wherein: R1 is thiophenyl or benzothiophenyl, and the thiophenyl or benzothiophenyl is one or more R 1S may be substituted with; Each R 1Sis independently C1-C6 alkyl, C1-C6 haloalkyl, -O(C1-C6 alkyl), -O(C1-C6 haloalkyl), or halo; R2 is R 2S is; R 2S is a 4-8 membered heterocycloalkyl optionally substituted with one or more C-C alkyl, C-C alkenyl, C-C alkynyl, C-C haloalkyl, halo, -CN, -OH, -O(C-C alkyl), -NH, -NH(C-C alkyl), -N(C-C alkyl) or oxo; and R3 is one or more R 3S and each R is a 7- to 12-membered heterocycloalkyl or a 5- or 6-membered heteroaryl optionally substituted with 3S are independently C-C alkyl, C-C haloalkyl, C-C cycloalkyl, halo, or C-C heterocycloalkyl, wherein the C-C alkyl, C-C haloalkyl, C-C cycloalkyl, or C-C heterocycloalkyl is optionally substituted with —O(C-C alkyl), —N(C-C alkyl), halo, or —CN.

[0115] In some embodiments, the compound is a compound of formula (I), or a prodrug, solvate, or pharmaceutically acceptable salt thereof, wherein: R1 is thiophenyl or benzothiophenyl, and the thiophenyl or benzothiophenyl is one or more R 1S may be substituted with; Each R 1S is C1-C6 alkyl or halo; R2 is R 2S is; R 2Sis a 4-8 membered heterocycloalkyl optionally substituted with one or more C-C alkyl, C-C alkenyl, C-C alkynyl, C-C haloalkyl, halo, -CN, -OH, -O(C-C alkyl), -NH, -NH(C-C alkyl), -N(C-C alkyl) or oxo; and R3 is one or more R 3S and each R is a 7- to 12-membered heterocycloalkyl or a 5- or 6-membered heteroaryl optionally substituted with 3S are independently C-C alkyl, C-C haloalkyl, C-C cycloalkyl, halo, or C-C heterocycloalkyl, wherein the C-C alkyl, C-C haloalkyl, C-C cycloalkyl, or C-C heterocycloalkyl is optionally substituted with —O(C-C alkyl), —N(C-C alkyl), halo, or —CN.

[0116] For compounds of formula (I), R, R 1S , R2, R 2S , R3, R 3S and X2 can each be selected from the groups described herein, where applicable; R1, R 1S , R2, R 2S , R3, R 3S Any groups described herein with respect to any of R, R, and X, if applicable, may be added to the remaining R, R 1S , R2, R 2S , R3, R 3S and X2 may be combined with any of the groups described for one or more of X2.

[0117] In some embodiments, the compound of Formula I is not N-(4,6-dimethoxy-1,3,5-triazin-2-yl)-N'-[[(4,6-dimethyl-2-pyrimidinyl)methylamino]sulfonyl]-urea, N-[[(4,6-dimethyl-2-pyrimidinyl)methylamino]sulfonyl]-N'-(4-methoxy-6-methyl-1,3,5-triazin-2-yl)-urea, N-(4,6-dimethoxy-2-pyrimidinyl)-N'-[(methyl-1H-pyrrol-1-ylamino)sulfonyl]-urea, or N-(4,6-dimethoxy-2-pyrimidinyl)-N'-[[(4,6-dimethyl-2-pyrimidinyl)methylamino]sulfonyl]-urea.

[0118] In some embodiments, the compound of Formula I is not N-(4,6-dimethoxy-1,3,5-triazin-2-yl)-N'-[[(4,6-dimethyl-2-pyrimidinyl)methylamino]sulfonyl]-urea, N-[[(4,6-dimethyl-2-pyrimidinyl)methylamino]sulfonyl]-N'-(4-methoxy-6-methyl-1,3,5-triazin-2-yl)-urea, N-(4,6-dimethoxy-2-pyrimidinyl)-N'-[(methyl-1H-pyrrol-1-ylamino)sulfonyl]-urea, N-(4,6-dimethoxy-2-pyrimidinyl)-N'-[[(4,6-dimethyl-2-pyrimidinyl)methylamino]sulfonyl]-urea, or a prodrug, solvate, or pharmaceutically acceptable salt thereof.

[0119] In some embodiments, R is a 5-12 membered heterocycloalkyl or a 5-12 membered heteroaryl, wherein at least one heteroatom in the 5-12 membered heterocycloalkyl or the 5-12 membered heteroaryl is O or S, and the 5-12 membered heterocycloalkyl or the 5-12 membered heteroaryl is selected from the group consisting of one or more R 1S may be substituted with.

[0120] In some embodiments, R1 is a 5-12 membered heterocycloalkyl or a 5-12 membered heteroaryl, and the 5-12 membered heterocycloalkyl or 5-12 membered heteroaryl is selected from the group consisting of one or more R 1S and R1 is attached to the remainder of formula (I) through a carbon atom of R1.

[0121] In some embodiments, R is a 5-12 membered heterocycloalkyl or a 5-12 membered heteroaryl, wherein at least one heteroatom in the 5-12 membered heterocycloalkyl or the 5-12 membered heteroaryl is O or S, and the 5-12 membered heterocycloalkyl or the 5-12 membered heteroaryl is selected from the group consisting of one or more R 1S and R1 is attached to the remainder of formula (I) through a carbon atom of R1.

[0122] In some embodiments, R1 is attached to the remainder of Formula (I) through a carbon atom of R1.

[0123] In some embodiments, R is one or more R 1S and optionally substituted 5-12 membered heterocycloalkyl.

[0124] In some embodiments, R is one or more R 1S R1 is a 5- to 12-membered heterocycloalkyl optionally substituted with C5-C 12 The heterocycloalkyl is bonded to the remainder of formula (I) through a carbon atom.

[0125] In some embodiments, R1 is a 5-12 membered heterocycloalkyl optionally substituted with one or more C1-C6 alkyl or halo.

[0126] In some embodiments, R1 is a 5-12 membered heterocycloalkyl optionally substituted with one or more C1-C6 alkyl (eg, methyl, ethyl, or propyl).

[0127] In some embodiments, R1 is a 5-12 membered heterocycloalkyl optionally substituted with one or more halo (eg, Cl).

[0128] In some embodiments, R1 is a 5-12 membered heterocycloalkyl.

[0129] In some embodiments, R is one or more R 1S is a 5- to 12-membered heterocycloalkyl substituted with

[0130] In some embodiments, R1 is a 5-12 membered heterocycloalkyl substituted with one or more C1-C6 alkyl or halo.

[0131] In some embodiments, R1 is a 5-12 membered heterocycloalkyl substituted with one or more C1-C6 alkyl (eg, methyl, ethyl, or propyl).

[0132] In some embodiments, R1 is a 5-12 membered heterocycloalkyl substituted with one or more halo (eg, Cl).

[0133] In some embodiments, R is one or more R 1S wherein at least one heteroatom in the 5- to 12-membered heterocycloalkyl is N, O, or S.

[0134] In some embodiments, R is one or more R 1S and at least one heteroatom in the 5- to 12-membered heterocycloalkyl is S.

[0135] In some embodiments, R is one or more R 1S and the 5- to 12-membered heterocycloalkyl contains one heteroatom.

[0136] In some embodiments, R is one or more R 1S and optionally substituted 5- to 9-membered monocyclic heterocycloalkyl.

[0137] In some embodiments, R is one or more R 1S and optionally substituted 5- to 6-membered monocyclic heterocycloalkyl.

[0138] In some embodiments, R is one or more R 1S and optionally substituted 8-12 membered bicyclic heterocycloalkyl.

[0139] In some embodiments, R is one or more R 1S and optionally substituted 8-10 membered bicyclic heterocycloalkyl.

[0140] In some embodiments, R is one or more R 1S and optionally substituted 8-9 membered bicyclic heterocycloalkyl.

[0141] In some embodiments, R is one or more R 1S and at least one heteroatom in the 8- to 9-membered bicyclic heterocycloalkyl is O or S.

[0142] In some embodiments, R is one or more R 1S and at least one heteroatom in the 8- to 9-membered bicyclic heterocycloalkyl is O.

[0143] In some embodiments, R is one or more R 1S and at least one heteroatom in the 8- to 9-membered bicyclic heterocycloalkyl is S.

[0144] In some embodiments, R is one or more R 1Sand optionally substituted 8-membered bicyclic heterocycloalkyl.

[0145] In some embodiments, R is one or more R 1S wherein at least one heteroatom in the 8-membered bicyclic heterocycloalkyl is O or S.

[0146] In some embodiments, R is one or more R 1S and wherein at least one heteroatom in the 8-membered bicyclic heterocycloalkyl is O.

[0147] In some embodiments, R is one or more R 1S wherein at least one heteroatom in the 8-membered bicyclic heterocycloalkyl is S.

[0148] In some embodiments, R is one or more R 1S and 5,6-dihydro-4H-cyclopenta[b]thiophenyl, optionally substituted with

[0149] In some embodiments, R is one or more R 1S and R1 is attached to the remainder of formula (I) through a carbon atom in the 5,6-dihydro-4H-cyclopenta[b]thiophenyl.

[0150] In some embodiments, R1 is 5,6-dihydro-4H-cyclopenta[b]thiophenyl.

[0151] In some embodiments, R1 is The file is TIFF0007661248000024.tif21128.

[0152] In some embodiments, R is one or more R 1Ssubstituted 5,6-dihydro-4H-cyclopenta[b]thiophenyl.

[0153] In some embodiments, R1 is The file is TIFF0007661248000025.tif17128.

[0154] In some embodiments, R1 is The file is TIFF0007661248000026.tif23128.

[0155] In some embodiments, R1 is 5,6-dihydro-4H-cyclopenta[b]thiophenyl substituted with one or more C1-C6 alkyl, C1-C6 haloalkyl, -O(C1-C6 alkyl), or halo.

[0156] In some embodiments, R1 is 5,6-dihydro-4H-cyclopenta[b]thiophenyl substituted with one or more C1-C6 alkyl, C1-C6 haloalkyl, or -O(C1-C6 alkyl).

[0157] In some embodiments, R1 is 5,6-dihydro-4H-cyclopenta[b]thiophenyl substituted with one or more C1-C6 alkyl (eg, methyl, ethyl, propyl, or butyl).

[0158] In some embodiments, R1 is 5,6-dihydro-4H-cyclopenta[b]thiophenyl substituted with one or more C1-C6 haloalkyl (eg, -CF3).

[0159] In some embodiments, R1 is 5,6-dihydro-4H-cyclopenta[b]thiophenyl substituted with one or more -O(C1-C6 alkyl) (e.g., -OCH3).

[0160] In some embodiments, R1 is 5,6-dihydro-4H-cyclopenta[b]thiophenyl substituted with one or more halo (eg, Cl).

[0161] In some embodiments, R1 is The file is TIFF0007661248000027.tif123165.

[0162] In some embodiments, R1 is TIFF0007661248000028.tif58128.

[0163] In some embodiments, R is one or more R 1S and optionally substituted 9-membered bicyclic heterocycloalkyl.

[0164] In some embodiments, R is one or more R 1S and wherein at least one heteroatom in the 8-membered bicyclic heterocycloalkyl is O or S.

[0165] In some embodiments, R is one or more R 1S and wherein at least one heteroatom in the 8-membered bicyclic heterocycloalkyl is O.

[0166] In some embodiments, R is one or more R 1S and 4,5,6,7-tetrahydrobenzofuranyl optionally substituted by

[0167] In some embodiments, R is one or more R 1S and R1 is attached to the remainder of formula (I) through a carbon atom of the 4,5,6,7-tetrahydrobenzofuranyl.

[0168] In some embodiments, R1 is 4,5,6,7-tetrahydrobenzofuranyl.

[0169] In some embodiments, R1 is The file is TIFF0007661248000029.tif23128.

[0170] In some embodiments, R is one or more R 1S and 4,5,6,7-tetrahydrobenzofuranyl substituted with

[0171] In some embodiments, R1 is The file is TIFF0007661248000030.tif19128.

[0172] In some embodiments, R1 is The file is TIFF0007661248000031.tif26128.

[0173] In some embodiments, R1 is 4,5,6,7-tetrahydrobenzofuranyl substituted with one or more C1-C6 alkyl.

[0174] In some embodiments, R1 is TIFF0007661248000032.tif28128.

[0175] In some embodiments, R is one or more R 1S and at least one heteroatom in the 8-membered bicyclic heterocycloalkyl is S.

[0176] In some embodiments, R is one or more R 1S and 4,5,6,7-tetrahydrobenzo[b]thiophenyl optionally substituted by

[0177] In some embodiments, R is one or more R 1S wherein R1 is attached to the remainder of formula (I) through a carbon atom in the 4,5,6,7-tetrahydrobenzo[b]thiophenyl.

[0178] In some embodiments, R1 is 4,5,6,7-tetrahydrobenzo[b]thiophenyl.

[0179] In some embodiments, R1 is The file is TIFF0007661248000033.tif23128.

[0180] In some embodiments, R is one or more R 1S substituted 4,5,6,7-tetrahydrobenzo[b]thiophenyl.

[0181] In some embodiments, R1 is The file is TIFF0007661248000034.tif19128.

[0182] In some embodiments, R1 is The file is TIFF0007661248000035.tif26128.

[0183] In some embodiments, R1 is 4,5,6,7-tetrahydrobenzo[b]thiophenyl substituted with one or more C1-C6 alkyl.

[0184] In some embodiments, R1 is The file is TIFF0007661248000036.tif27128.

[0185] In some embodiments, R1 is The file is TIFF0007661248000037.tif58147.

[0186] In some embodiments, R is one or more R 1S and 5-12 membered heteroaryl optionally substituted with

[0187] In some embodiments, R is one or more R 1S R1 is a 5- to 12-membered heteroaryl optionally substituted with C5-C 12It is attached to the remainder of formula (I) through a carbon atom of the heteroaryl.

[0188] In some embodiments, R1 is a 5-12 membered heteroaryl optionally substituted with one or more C1-C6 alkyl or halo.

[0189] In some embodiments, R1 is a 5-12 membered heteroaryl optionally substituted with one or more C1-C6 alkyl (eg, methyl, ethyl, or propyl).

[0190] In some embodiments, R1 is a 5-12 membered heteroaryl optionally substituted with one or more halo (eg, Cl).

[0191] In some embodiments, R1 is a 5-12 membered heteroaryl.

[0192] In some embodiments, R is one or more R 1S is a 5- to 12-membered heteroaryl substituted with

[0193] In some embodiments, R1 is a 5-12 membered heteroaryl substituted with one or more C1-C6 alkyl or halo.

[0194] In some embodiments, R1 is a 5-12 membered heteroaryl substituted with one or more C1-C6 alkyl (eg, methyl, ethyl, or propyl).

[0195] In some embodiments, R1 is a 5-12 membered heteroaryl substituted with one or more halo (eg, Cl).

[0196] In some embodiments, R is one or more R 1S and at least one heteroatom in the 5-12 membered heteroaryl is N, O, or S.

[0197] In some embodiments, R is one or more R 1S and at least one heteroatom in the 5- to 12-membered heteroaryl is S.

[0198] In some embodiments, R is one or more R 1S and the 5-12 membered heteroaryl contains one heteroatom.

[0199] In some embodiments, R is one or more R 1S and optionally substituted 5- to 9-membered monocyclic heteroaryl.

[0200] In some embodiments, R is one or more R 1S and optionally substituted 5-6 membered monocyclic heteroaryl.

[0201] In some embodiments, R is one or more R 1S is a 5-membered monocyclic heteroaryl optionally substituted with

[0202] In some embodiments, R is one or more R 1S and at least one heteroatom in the C5 monocyclic heteroaryl is O.

[0203] In some embodiments, R is one or more R 1S and at least one heteroatom in the C5 monocyclic heteroaryl is S.

[0204] In some embodiments, R is one or more R 1S and wherein at least one heteroatom in the C5 monocyclic heteroaryl is S and at least one heteroatom in the C5 monocyclic heteroaryl is N.

[0205] In some embodiments, R is one or more R 1S and C5 monocyclic heteroaryl optionally substituted with C5 monocyclic heteroaryl, wherein C5 monocyclic heteroaryl contains one heteroatom.

[0206] In some embodiments, R is one or more R 1S and C5 monocyclic heteroaryl optionally substituted with C5, wherein the C5 monocyclic heteroaryl contains one heteroatom which is O.

[0207] In some embodiments, R is one or more R 1S and furanyl optionally substituted by:

[0208] In some embodiments, R is one or more R 1S and R1 is attached to the remainder of formula (I) through a carbon atom in the furanyl.

[0209] In some embodiments, R1 is furanyl.

[0210] In some embodiments, R1 is TIFF0007661248000038.tif15128.

[0211] In some embodiments, R is one or more R 1S and furanyl substituted with .

[0212] In some embodiments, R1 is TIFF0007661248000039.tif44128.

[0213] In some embodiments, R1 is The file is TIFF0007661248000040.tif49128.

[0214] In some embodiments, R1 is The file is TIFF0007661248000041.tif25128.

[0215] In some embodiments, R1 is furanyl substituted with one or more C1-C6 alkyl or halo.

[0216] In some embodiments, R1 is furanyl substituted with one or more C1-C6 alkyl (eg, methyl, ethyl, or propyl).

[0217] In some embodiments, R1 is furanyl substituted with one or more halo (eg, Cl).

[0218] In some embodiments, R1 is The file is TIFF0007661248000042.tif24128.

[0219] In some embodiments, R is one or more R 1S and C5 monocyclic heteroaryl optionally substituted with C5, wherein the C5 monocyclic heteroaryl contains one heteroatom which is S.

[0220] In some embodiments, R is one or more R 1S and thiophenyl optionally substituted by

[0221] In some embodiments, R is one or more R 1S wherein R1 is attached to the remainder of formula (I) through a carbon atom on the thiophenyl.

[0222] In some embodiments, R1 is thiophenyl.

[0223] In some embodiments, R1 is The file is TIFF0007661248000043.tif15128.

[0224] In some embodiments, R is one or more R 1S and thiophenyl substituted with .

[0225] In some embodiments, R1 is The file is TIFF0007661248000044.tif44128.

[0226] In some embodiments, R1 is The file is TIFF0007661248000045.tif49128.

[0227] In some embodiments, R1 is The file is TIFF0007661248000046.tif25128.

[0228] In some embodiments, R1 is thiophenyl substituted with one or more C1-C6 alkyl or halo.

[0229] In some embodiments, R1 is thiophenyl substituted with one or more C1-C6 alkyl (eg, methyl, ethyl, or propyl).

[0230] In some embodiments, R1 is thiophenyl substituted with one or more halo (eg, Cl).

[0231] In some embodiments, R1 is The file is TIFF0007661248000047.tif110165.

[0232] In some embodiments, R1 is TIFF0007661248000048.tif55128.

[0233] In some embodiments, R1 is The file is TIFF0007661248000049.tif228165.

[0234] In some embodiments, R is one or more R 1S and C5 monocyclic heteroaryl optionally substituted with C5, wherein the C5 monocyclic heteroaryl contains two heteroatoms.

[0235] In some embodiments, R is one or more R 1S and the C5 monocyclic heteroaryl contains two heteroatoms, one heteroatom is S and the other heteroatom is N.

[0236] In some embodiments, R is one or more R 1S and optionally substituted thiazolyl.

[0237] In some embodiments, R is one or more R 1S wherein R1 is attached to the remainder of formula (I) through a carbon atom in the thiazolyl.

[0238] In some embodiments, R1 is thiazolyl.

[0239] In some embodiments, R1 is The file is TIFF0007661248000050.tif15128.

[0240] In some embodiments, R is one or more R 1S and thiazolyl substituted with

[0241] In some embodiments, R1 is The file is TIFF0007661248000051.tif19128.

[0242] In some embodiments, R1 is The file is TIFF0007661248000052.tif20128.

[0243] In some embodiments, R1 is thiazolyl substituted with one or more C1-C6 alkyl or halo.

[0244] In some embodiments, R1 is thiazolyl substituted with one or more C1-C6 alkyl (eg, methyl, ethyl, or propyl).

[0245] In some embodiments, R1 is thiazolyl substituted with one or more halo (eg, Cl).

[0246] In some embodiments, R1 is The file is TIFF0007661248000053.tif23128.

[0247] In some embodiments, R is one or more R 1S isothiazolyl optionally substituted by

[0248] In some embodiments, R is one or more R 1S wherein R1 is attached to the remainder of formula (I) through a carbon atom in the isothiazolyl.

[0249] In some embodiments, R1 is isothiazolyl.

[0250] In some embodiments, R1 is The file is TIFF0007661248000054.tif15128.

[0251] In some embodiments, R is one or more R 1S isothiazolyl substituted with

[0252] In some embodiments, R1 is The file is TIFF0007661248000055.tif20158.

[0253] In some embodiments, R1 is The file is TIFF0007661248000056.tif26128.

[0254] In some embodiments, R1 is isothiazolyl substituted with one or more C1-C6 alkyl or halo.

[0255] In some embodiments, R1 is isothiazolyl substituted with one or more C1-C6 alkyl (eg, methyl, ethyl, or propyl).

[0256] In some embodiments, R1 is isothiazolyl substituted with one or more halo (eg, Cl).

[0257] In some embodiments, R1 is The file is TIFF0007661248000057.tif29128.

[0258] In some embodiments, R is one or more R 1S and optionally substituted 9-12 membered bicyclic heteroaryl.

[0259] In some embodiments, R is one or more R 1S and optionally substituted 9-10 membered bicyclic heteroaryl.

[0260] In some embodiments, R is one or more R 1S is a 9-membered bicyclic heteroaryl optionally substituted with

[0261] In some embodiments, R is one or more R 1S wherein at least one heteroatom in the 9-membered bicyclic heteroaryl is S.

[0262] In some embodiments, R is one or more R 1S and benzothiophenyl optionally substituted by

[0263] In some embodiments, R is one or more R 1S wherein R1 is attached to the remainder of formula (I) through a carbon atom of the benzothiophenyl.

[0264] In some embodiments, R1 is benzothiophenyl.

[0265] In some embodiments, R1 is TIFF0007661248000058.tif23128.

[0266] In some embodiments, R is one or more R 1S and benzothiophenyl substituted with .

[0267] In some embodiments, R1 is TIFF0007661248000059.tif26128.

[0268] In some embodiments, R1 is benzothiophenyl substituted with one or more C1-C6 alkyl or halo.

[0269] In some embodiments, R1 is benzothiophenyl substituted with one or more C1-C6 alkyl (eg, methyl, ethyl, or propyl).

[0270] In some embodiments, R1 is benzothiophenyl substituted with one or more halo (eg, Cl).

[0271] In some embodiments, R1 is The file is TIFF0007661248000060.tif24128.

[0272] In some embodiments, R1 is The file is TIFF0007661248000061.tif22128.

[0273] In some embodiments, R1 is TIFF0007661248000062.tif58165TIFF0007661248000063.tif194165TIFF0007661248000064.tif60165

[0274] In some embodiments, at least one R 1Sis C1-C6 alkyl, C1-C6 haloalkyl, -O(C1-C6 alkyl), -O(C1-C6 haloalkyl), -(C1-C6 alkyl)-O(C1-C6 alkyl), cyano, or halo.

[0275] In some embodiments, at least one R 1S is C1-C6 alkyl, C1-C6 haloalkyl, -O(C1-C6 alkyl), -O(C1-C6 haloalkyl), -(C1-C6 alkyl)-O(C1-C6 alkyl), or halo.

[0276] In some embodiments, at least one R 1S is C1-C6 alkyl, C1-C6 haloalkyl, -O(C1-C6 alkyl), -O(C1-C6 haloalkyl), or -(C1-C6 alkyl)-O(C1-C6 alkyl).

[0277] In some embodiments, at least one R 1S is C1-C6 alkyl, C1-C6 haloalkyl, -O(C1-C6 alkyl), -O(C1-C6 haloalkyl), or halo.

[0278] In some embodiments, at least one R 1S is C1-C6 alkyl, C1-C6 haloalkyl, —O(C1-C6 alkyl), or halo.

[0279] In some embodiments, at least one R 1S is C1-C6 alkyl, C1-C6 haloalkyl, or halo.

[0280] In some embodiments, at least one R 1S is C1-C6 alkyl (e.g., methyl, ethyl, or propyl), or halo (e.g., Cl).

[0281] In some embodiments, at least one R 1S is methyl, ethyl, propyl, or Cl.

[0282] In some embodiments, at least one R 1S is C1-C6 alkyl or C1-C6 haloalkyl.

[0283] In some embodiments, at least one R 1S is C1-C6 alkyl (e.g., linear or branched).

[0284] In some embodiments, at least one R 1S is methyl, ethyl, or propyl.

[0285] In some embodiments, at least one R 1S is methyl. In some embodiments, at least one R 1S is ethyl. In some embodiments, at least one R 1S is propyl. In some embodiments, at least one R 1S is butyl. In some embodiments, at least one R 1S is pentyl. In some embodiments, at least one R 1S is hexyl. In some embodiments, at least one R 1S is isopropyl. In some embodiments, at least one R 1S is isobutyl. In some embodiments, at least one R 1S is isopentyl. In some embodiments, at least one R 1S is isohexyl. In some embodiments, at least one R 1S is secbutyl. In some embodiments, at least one R 1S is secpentyl. In some embodiments, at least one R 1S is sexhexyl.

[0286] In some embodiments, at least one R 1Sis C1-C6 haloalkyl (eg, methyl, ethyl, propyl, butyl, pentyl, or hexyl substituted with one or more halogens).

[0287] In some embodiments, at least one R 1S are -CH2F, -CHF2, and -CF3.

[0288] In some embodiments, at least one R 1S is -CHF. In some embodiments, at least one R 1S is -CHF. In some embodiments, at least one R 1S is -CF3.

[0289] In some embodiments, at least one R 1S is —O(C1-C6 alkyl), or —O(C1-C6 haloalkyl).

[0290] In some embodiments, at least one R 1S is —O(C1-C6 alkyl).

[0291] In some embodiments, at least one R 1S is methoxy. In some embodiments, at least one R 1S is ethoxy. In some embodiments, at least one R 1S is propoxy. In some embodiments, at least one R 1S is butoxy. In some embodiments, at least one R 1S is pentoxy. In some embodiments, at least one R 1S is hexoxy.

[0292] In some embodiments, at least one R 1S is —O(C 1 -C 6 haloalkyl) (e.g., methoxy, ethoxy, propoxy, butoxy, pentoxy, or hexoxy substituted with one or more halogens).

[0293] In some embodiments, at least one R 1S is halomethoxy. In some embodiments, at least one R 1S is haloethoxy. In some embodiments, at least one R 1S is halopropoxy. In some embodiments, at least one R 1S is halobutoxy. In some embodiments, at least one R 1S is halopentoxy. In some embodiments, at least one R 1S is halohexoxy.

[0294] In some embodiments, at least one R 1S is -OCF3.

[0295] In some embodiments, at least one R 1S is -OCH2CF3.

[0296] In some embodiments, at least one R 1S is —(C1-C6 alkyl)-O(C1-C6 alkyl).

[0297] In some embodiments, at least one R 1S is cyano or halo.

[0298] In some embodiments, at least one R 1S is cyano.

[0299] In some embodiments, at least one R 1S is a halo.

[0300] In some embodiments, at least one R 1S is F, Cl, Br, or I.

[0301] In some embodiments, at least one R 1S is F or Cl.

[0302] In some embodiments, at least one R 1S is F.

[0303] In some embodiments, at least one R 1S is Cl.

[0304] In some embodiments, at least one R 1S is methyl, ethyl, isopropyl, isobutyl, secbutyl, methoxy, ethoxy, -CF3, -OCF3, -OCH2CF3, F, or Cl.

[0305] In some embodiments, at least one R 1S is a C3-C8 cycloalkyl, a C3-C8 aryl, a 3- to 8-membered heterocycloalkyl, or a 3- to 8-membered heteroaryl.

[0306] In some embodiments, at least one R 1S is C3-C8 cycloalkyl.

[0307] In some embodiments, at least one R 1S is a C3-C8 aryl.

[0308] In some embodiments, at least one R 1S is a C5-C6 aryl.

[0309] In some embodiments, at least one R 1S is phenyl.

[0310] In some embodiments, at least one R 1S is a 3- to 8-membered heterocycloalkyl.

[0311] In some embodiments, at least one R 1S is a 3- to 8-membered heteroaryl.

[0312] In some embodiments, R2 is R 2S is.

[0313] In some embodiments, R2 is -(CX2X2) n -R 2S and n is 1 or 2.

[0314] In some embodiments, R2 is -(CX2X2)-R 2S is.

[0315] In some embodiments, R2 is -(CX2X2)2-R 2S is.

[0316] In some embodiments, R2 is -(CH2) n -R 2S and n is 1. In some embodiments, R2 is -(CH2) n -R 2S and n is 2.

[0317] In some embodiments, at least one X2 is H.

[0318] In some embodiments, each X2 is H.

[0319] In some embodiments, at least one X2 is a C1-C6 alkyl, a C2-C6 alkenyl, or a C2-C6 alkynyl, wherein the C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is optionally substituted with one or more halo, -CN, -OH, -O(C1-C6 alkyl), -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, or oxo.

[0320] In some embodiments, at least one X2 is a C1-C6 alkyl or a C2-C6 alkenyl, wherein the C1-C6 alkyl or C2-C6 alkenyl is optionally substituted with one or more halo, -CN, -OH, -O(C1-C6 alkyl), -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, or oxo.

[0321] In some embodiments, at least one X2 is C1-C6 alkyl (e.g., methyl, ethyl, propyl, butyl, pentyl, or hexyl) optionally substituted with one or more halo, -CN, -OH, -O(C1-C6 alkyl), -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, or oxo.

[0322] In some embodiments, at least one X2 is C1-C6 alkyl (eg, methyl, ethyl, propyl, butyl, pentyl, or hexyl).

[0323] In some embodiments, at least one X2 is a C2-C6 alkenyl (e.g., ethenyl, propenyl, butenyl, pentenyl, or hexenyl) optionally substituted with one or more halo, -CN, -OH, -O(C1-C6 alkyl), -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, or oxo.

[0324] In some embodiments, at least one X2 is a C2-C6 alkenyl (eg, ethenyl, propenyl, butenyl, pentenyl, or hexenyl).

[0325] In some embodiments, at least one X2 is a C2-C6 alkynyl (e.g., ethynyl, propynyl, butynyl, pentynyl, or hexynyl) optionally substituted with one or more halo, -CN, -OH, -O(C1-C6 alkyl), -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, or oxo.

[0326] In some embodiments, at least one X2 is a C2-C6 alkynyl (e.g., ethynyl, propynyl, butynyl, pentynyl, or hexynyl) optionally substituted with one or more halo, —CN, —O(C1-C6 alkyl), —NH2, —NH(C1-C6 alkyl), or —N(C1-C6 alkyl)2.

[0327] In some embodiments, at least one X2 is a C2-C6 alkynyl (e.g., ethynyl, propynyl, butynyl, pentynyl, or hexynyl) optionally substituted with one halo, -CN, -OH, -O(C1-C6 alkyl), -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, or oxo.

[0328] In some embodiments, at least one X2 is a C2-C6 alkynyl (e.g., ethynyl, propynyl, butynyl, pentynyl, or hexynyl) optionally substituted with one halo, -CN, -O(C1-C6 alkyl), -NH2, -NH(C1-C6 alkyl), or -N(C1-C6 alkyl)2.

[0329] In some embodiments, at least one X2 is a C2-C6 alkynyl (eg, ethynyl, propynyl, butynyl, pentynyl, or hexynyl).

[0330] In some embodiments, n is 0.

[0331] In some embodiments, n is 1 or 2.

[0332] In some embodiments, n is 1.

[0333] In some embodiments, n is 2.

[0334] In some embodiments, R 2S is C-C alkyl optionally substituted with one or more C-C alkyl, C-C alkenyl, C-C alkynyl, C-C haloalkyl, halo, -CN, -OH, -O(C-C alkyl), -NH, -NH(C-C alkyl), -N(C-C alkyl) or oxo.

[0335] In some embodiments, R 2Sis C1-C6 alkyl optionally substituted with one or more C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 haloalkyl.

[0336] In some embodiments, R 2S is C1-C6 alkyl optionally substituted with one or more C1-C6 haloalkyl.

[0337] In some embodiments, R 2S is C1-C6 alkyl optionally substituted with one or more halo, -CN, or -OH.

[0338] In some embodiments, R 2S is C1-C6 alkyl optionally substituted with one or more halo. In some embodiments, R 2S is C1-C6 alkyl optionally substituted with one or more F, Cl, Br, or I. In some embodiments, R 2S is C1-C6 alkyl optionally substituted with one or more F or Cl. In some embodiments, R 2S is C1-C6 alkyl optionally substituted with one or more F. In some embodiments, R 2S is C1-C6 alkyl optionally substituted with one or more Cl.

[0339] In some embodiments, R 2S is C1-C6 alkyl optionally substituted with one or more -CN. In some embodiments, R 2S is C1-C6 alkyl optionally substituted with one or more -OH.

[0340] In some embodiments, R 2S is C1-C6 alkyl optionally substituted with one or more -O(C1-C6 alkyl), -NH2, -NH(C1-C6 alkyl), or -N(C1-C6 alkyl)2.

[0341] In some embodiments, R 2Sis C1-C6 alkyl optionally substituted with one or more -O(C1-C6 alkyl).

[0342] In some embodiments, R 2S is C1-C6 alkyl optionally substituted with one or more -NH2, -NH(C1-C6 alkyl), or -N(C1-C6 alkyl)2.

[0343] In some embodiments, R 2S is C1-C6 alkyl optionally substituted with one or more -NH2.

[0344] In some embodiments, R 2S is C1-C6 alkyl optionally substituted with one or more -NH(C1-C6 alkyl).

[0345] In some embodiments, R 2S is C1-C6 alkyl optionally substituted with one or more -NH (methyl).

[0346] In some embodiments, R 2S is C1-C6 alkyl optionally substituted with one or more -N(C1-C6 alkyl)2.

[0347] In some embodiments, R 2S is a C1-C6 alkyl optionally substituted with one or more -N(methyl)2.

[0348] In some embodiments, R 2S is C1-C6 alkyl optionally substituted with one or more oxo.

[0349] In some embodiments, R 2S is C1-C6 alkyl (e.g., methyl, ethyl, propyl, butyl, pentyl, or hexyl).

[0350] In some embodiments, R 2S is C3-C 16cycloalkyl or 4-8 membered heterocycloalkyl, C3-C 16 The cycloalkyl or 4-8 membered heterocycloalkyl may be substituted with one or more C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, halo, -CN, -OH, -O(C1-C6 alkyl), -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, or oxo.

[0351] In some embodiments, R 2S is a C3-C alkyl optionally substituted with one or more C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, halo, -CN, -OH, -O(C1-C6 alkyl), -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, or oxo. 16 It is cycloalkyl.

[0352] In some embodiments, R 2S is a C3-C alkyl group optionally substituted with one or more C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 haloalkyl. 16 It is cycloalkyl.

[0353] In some embodiments, R 2S is a C3-C alkyl group optionally substituted with one or more C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl groups. 16 It is cycloalkyl.

[0354] In some embodiments, R 2S is a C3-C alkyl group optionally substituted with one or more C1-C6 alkyl groups. 16 In some embodiments, R 2S is a C3-C alkyl group optionally substituted with one or more C2-C6 alkenyl groups; 16 In some embodiments, R 2S is a C3-C alkyl group optionally substituted with one or more C2-C6 alkynyl groups; 16 It is cycloalkyl.

[0355] In some embodiments, R 2S is a C3-C alkyl group optionally substituted with one or more C1-C6 haloalkyl groups 16 It is cycloalkyl.

[0356] In some embodiments, R 2S C3-C, optionally substituted with one or more halo, -CN, or -OH 16 It is cycloalkyl.

[0357] In some embodiments, R 2S C3-C optionally substituted with one or more halo 16 In some embodiments, R 2S is a C3-C group optionally substituted with one or more F, Cl, Br, or I; 16 In some embodiments, R 2S is C3-C optionally substituted with one or more F or Cl 16 In some embodiments, R 2S C3-C optionally substituted with one or more F 16 In some embodiments, R 2S C3-C optionally substituted with one or more Cl 16 It is cycloalkyl.

[0358] In some embodiments, R 2S C3-C optionally substituted with one or more -CN 16 In some embodiments, R 2S C3-C optionally substituted with one or more -OH 16 It is cycloalkyl.

[0359] In some embodiments, R 2S is a C3-C alkyl optionally substituted with one or more -O(C1-C6 alkyl), -NH2, -NH(C1-C6 alkyl), or -N(C1-C6 alkyl)2. 16 It is cycloalkyl.

[0360] In some embodiments, R 2S is a C3-C alkyl group optionally substituted with one or more -O(C1-C6 alkyl) 16 It is cycloalkyl.

[0361] In some embodiments, R 2S is a C3-C alkyl optionally substituted with one or more -NH2, -NH(C1-C6 alkyl), or -N(C1-C6 alkyl)2. 16 It is cycloalkyl.

[0362] In some embodiments, R 2S is a C3-C optionally substituted with one or more -NH2 16 It is cycloalkyl.

[0363] In some embodiments, R 2S is a C3-C alkyl group optionally substituted with one or more -NH(C1-C6 alkyl) 16 It is cycloalkyl.

[0364] In some embodiments, R 2S is a C3-C optionally substituted with one or more -NH (methyl) 16 It is cycloalkyl.

[0365] In some embodiments, R 2S is a C3-C alkyl group optionally substituted with one or more -N(C1-C6 alkyl)2 groups. 16 It is cycloalkyl.

[0366] In some embodiments, R 2S is a C3-C optionally substituted with one or more -N(methyl)2 16 It is cycloalkyl.

[0367] In some embodiments, R 2S C3-C optionally substituted with one or more oxo 16 It is cycloalkyl.

[0368] In some embodiments, R 2S is C3-C 16 It is cycloalkyl.

[0369] In some embodiments, at least one R 2S is C3-C8 cycloalkyl.

[0370] In some embodiments, at least one R 2S is a C3-C8 cycloalkyl optionally substituted with -O(C1-C6 alkyl), -N(C1-C6 alkyl)2, halo, or -CN.

[0371] In some embodiments, at least one R 2S is C-C cycloalkyl. In some embodiments, at least one R 2S is C-C cycloalkyl. In some embodiments, at least one R 2S is C-C cycloalkyl. In some embodiments, at least one R 2S is C3-C4 cycloalkyl.

[0372] In some embodiments, at least one R 2S is cyclopropyl.

[0373] In some embodiments, at least one R 2S is cyclobutyl.

[0374] In some embodiments, at least one R 2S is cyclobutyl optionally substituted with one or more C-C alkyl, C-C alkenyl, C-C alkynyl, C-C haloalkyl, halo, -CN, -OH, -O(C-C alkyl), -NH, -NH(C-C alkyl), -N(C-C alkyl), or oxo.

[0375] In some embodiments, at least one R 2S is cyclopentyl.

[0376] In some embodiments, at least one R 2S is cyclopentyl optionally substituted with one or more C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, halo, —CN, —OH, —O(C1-C6 alkyl), —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, or oxo.

[0377] In some embodiments, at least one R 2S is cyclopentyl optionally substituted with one or more -O(C1-C6 alkyl).

[0378] In some embodiments, R 2S is a 4-8 membered heterocycloalkyl optionally substituted with one or more C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, halo, -CN, -OH, -O(C1-C6 alkyl), -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, or oxo.

[0379] In some embodiments, R 2S is a 4-8 membered heterocycloalkyl optionally substituted with one or more C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, halo, -CN, -OH, -NH2, or oxo.

[0380] In some embodiments, R 2S is a 4-8 membered heterocycloalkyl optionally substituted with one or more C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, halo, or oxo.

[0381] In some embodiments, R 2S is a 4-8 membered heterocycloalkyl optionally substituted with one or more C1-C6 alkyl, C1-C6 haloalkyl, or oxo.

[0382] In some embodiments, R 2S is a 4-8 membered heterocycloalkyl.

[0383] In some embodiments, R 2S is a 5-8 membered heterocycloalkyl.

[0384] In some embodiments, R 2S is a 5- to 7-membered heterocycloalkyl.

[0385] In some embodiments, R 2S is a 5-6 membered heterocycloalkyl.

[0386] In some embodiments, R 2S is a 5- or 6-membered heterocycloalkyl having one or more heteroatoms selected from N and O.

[0387] In some embodiments, R 2S is a 5- or 6-membered heterocycloalkyl having one heteroatom selected from N and O.

[0388] In some embodiments, R 2S is a 5- or 6-membered heterocycloalkyl having two heteroatoms selected from N or O.

[0389] In some embodiments, R 2S is a 6-membered heterocycloalkyl.

[0390] In some embodiments, R 2S is a 6-membered heterocycloalkyl optionally substituted with one or more C-C alkyl, C-C alkenyl, C-C alkynyl, C-C haloalkyl, halo, -CN, -OH, -O(C-C alkyl), -NH, -NH(C-C alkyl), -N(C-C alkyl), or oxo.

[0391] In some embodiments, R 2Sis a 6-membered heterocycloalkyl optionally substituted with one or more C1-C6 alkyl, C1-C6 haloalkyl, or oxo.

[0392] In some embodiments, R 2S is a 6-membered heterocycloalkyl optionally substituted with one or more C1-C6 alkyl or oxo.

[0393] In some embodiments, R 2S is a 6-membered heterocycloalkyl optionally substituted with one or more C1-C6 alkyl or C1-C6 haloalkyl.

[0394] In some embodiments, R 2S is a 6-membered heterocycloalkyl optionally substituted with one or more C1-C6 alkyls.

[0395] In some embodiments, R 2S is tetrahydropyranyl optionally substituted with one or more C1-C6 alkyl, C1-C6 haloalkyl, or oxo.

[0396] In some embodiments, R 2S is tetrahydropyranyl optionally substituted with one or more C1-C6 alkyl or oxo.

[0397] In some embodiments, R 2S is tetrahydropyranyl optionally substituted with one or more C1-C6 alkyl or C1-C6 haloalkyl.

[0398] In some embodiments, R 2S is tetrahydropyranyl optionally substituted with one or more C1-C6 alkyl.

[0399] In some embodiments, R 2S is tetrahydropyranyl optionally substituted with one or more methyl. In some embodiments, R 2Sis tetrahydropyranyl optionally substituted with one or more ethyl. In some embodiments, R 2S is tetrahydropyranyl optionally substituted with one or more propyl. In some embodiments, R 2S is tetrahydropyranyl optionally substituted with one or more butyl. In some embodiments, R 2S is tetrahydropyranyl optionally substituted with one or more pentyls. In some embodiments, R 2S is tetrahydropyranyl optionally substituted with one or more hexyls.

[0400] In some embodiments, R 2S is tetrahydropyranyl optionally substituted with one or more oxo.

[0401] In some embodiments, R 2S is tetrahydropyranyl optionally substituted with one or more C1-C6 haloalkyl (e.g., methyl, ethyl, propyl, butyl, pentyl, or hexyl optionally substituted with one or more halo).

[0402] In some embodiments, R 2S teeth, The file is TIFF0007661248000065.tif19128.

[0403] In some embodiments, R 2S teeth, TIFF0007661248000066.tif17128.

[0404] In some embodiments, R 2S is piperidinyl optionally substituted with one or more C1-C6 alkyl, C1-C6 haloalkyl, or oxo.

[0405] In some embodiments, R 2S is piperidinyl optionally substituted with one or more C1-C6 alkyl or oxo.

[0406] In some embodiments, R 2S is piperidinyl optionally substituted with one or more C1-C6 alkyl or C1-C6 haloalkyl.

[0407] In some embodiments, R 2S is piperidinyl optionally substituted with one or more C1-C6 alkyl.

[0408] In some embodiments, R 2S is piperidinyl optionally substituted with one or more methyl. In some embodiments, R 2S is piperidinyl optionally substituted with one or more ethyl. In some embodiments, R 2S is piperidinyl optionally substituted with one or more propyl. In some embodiments, R 2S is piperidinyl optionally substituted with one or more butyl. In some embodiments, R 2S is piperidinyl optionally substituted with one or more pentyls. In some embodiments, R 2S is piperidinyl optionally substituted with one or more hexyls.

[0409] In some embodiments, R 2S is piperidinyl optionally substituted with one or more oxo.

[0410] In some embodiments, R 2S is piperidinyl optionally substituted with one or more C1-C6 haloalkyl (e.g., methyl, ethyl, propyl, butyl, pentyl, or hexyl optionally substituted with one or more halo).

[0411] In some embodiments, R 2S is piperidinyl optionally substituted with one or more -CH2F, -CHF2, -CF3, -(CH)2CH2F, -(CH)2CHF2, or -(CH)2CF3.

[0412] In some embodiments, R 2S teeth, The file is TIFF0007661248000067.tif58138.

[0413] In some embodiments, R 2S teeth, TIFF0007661248000068.tif24128.

[0414] In some embodiments, R 2S is morpholinyl.

[0415] In some embodiments, R 2S is morpholinyl optionally substituted with one or more C1-C6 alkyl, C1-C6 haloalkyl, or oxo.

[0416] In some embodiments, R 2S is morpholinyl optionally substituted with one or more C1-C6 alkyl or oxo.

[0417] In some embodiments, R 2S is morpholinyl optionally substituted with one or more C1-C6 alkyl or C1-C6 haloalkyl.

[0418] In some embodiments, R 2S is morpholinyl optionally substituted with one or more C1-C6 alkyl.

[0419] In some embodiments, R 2S is morpholinyl optionally substituted with one or more methyl. In some embodiments, R 2S is morpholinyl optionally substituted with one or more ethyl. In some embodiments, R 2S is morpholinyl optionally substituted with one or more propyl. In some embodiments, R 2S is morpholinyl optionally substituted with one or more butyl. In some embodiments, R 2Sis morpholinyl optionally substituted with one or more pentyls. In some embodiments, R 2S is morpholinyl optionally substituted with one or more hexyls.

[0420] In some embodiments, R 2S is morpholinyl optionally substituted with one or more oxo.

[0421] In some embodiments, R 2S is morpholinyl optionally substituted with one or more C1-C6 haloalkyl (e.g., methyl, ethyl, propyl, butyl, pentyl, or hexyl optionally substituted with one or more halo).

[0422] In some embodiments, R 2S teeth, TIFF0007661248000069.tif18128.

[0423] In some embodiments, R2 is -(CH2) n -R 2S where n is 0 and R 2S is a 6-membered heterocycloalkyl.

[0424] In some embodiments, R2 is -(CH2) n -R 2S where n is 0 and R 2S is a 6-membered heterocycloalkyl optionally substituted with one or more C1-C6 alkyl, C1-C6 haloalkyl, or oxo.

[0425] In some embodiments, R2 is -(CH2) n -R 2S where n is 0 and R 2S is tetrahydropyranyl optionally substituted with one or more C1-C6 alkyl, C1-C6 haloalkyl, or oxo.

[0426] In some embodiments, R2 is -(CH2) n-R 2S where n is 0 and R 2S is piperidinyl optionally substituted with one or more C1-C6 alkyl, C1-C6 haloalkyl, or oxo.

[0427] In some embodiments, R2 is -(CH2) n -R 2S where n is 0 and R 2S is morpholinyl optionally substituted with one or more C1-C6 alkyl, C1-C6 haloalkyl, or oxo.

[0428] In some embodiments, R2 is -(CH2) n -R 2S where n is 1 and R 2S is a 6-membered heterocycloalkyl.

[0429] In some embodiments, R2 is -(CH2) n -R 2S where n is 1 and R 2S is a 6-membered heterocycloalkyl optionally substituted with one or more C1-C6 alkyl, C1-C6 haloalkyl, or oxo.

[0430] In some embodiments, R2 is -(CH2) n -R 2S where n is 1 and R 2S is tetrahydropyranyl optionally substituted with one or more C1-C6 alkyl, C1-C6 haloalkyl, or oxo.

[0431] In some embodiments, R2 is -(CH2) n -R 2S where n is 1 and R 2S is piperidinyl optionally substituted with one or more C1-C6 alkyl, C1-C6 haloalkyl, or oxo.

[0432] In some embodiments, R2 is -(CH2) n -R 2Swhere n is 1 and R 2S is morpholinyl optionally substituted with one or more C1-C6 alkyl, C1-C6 haloalkyl, or oxo.

[0433] In some embodiments, R2 is -(CH2) n -R 2S where n is 2 and R 2S is a 6-membered heterocycloalkyl.

[0434] In some embodiments, R2 is -(CH2) n -R 2S where n is 2 and R 2S is a 6-membered heterocycloalkyl optionally substituted with one or more C1-C6 alkyl, C1-C6 haloalkyl, or oxo.

[0435] In some embodiments, R2 is -(CH2) n -R 2S where n is 2 and R 2S is tetrahydropyranyl optionally substituted with one or more C1-C6 alkyl, C1-C6 haloalkyl, or oxo.

[0436] In some embodiments, R2 is -(CH2) n -R 2S where n is 2 and R 2S is piperidinyl optionally substituted with one or more C1-C6 alkyl, C1-C6 haloalkyl, or oxo.

[0437] In some embodiments, R2 is -(CH2) n -R 2S where n is 2 and R 2S is morpholinyl optionally substituted with one or more C1-C6 alkyl, C1-C6 haloalkyl, or oxo.

[0438] In some embodiments, R 2S is a 5-membered heterocycloalkyl.

[0439] In some embodiments, R 2S is a 5-membered heterocycloalkyl optionally substituted with one or more C-C alkyl, C-C alkenyl, C-C alkynyl, C-C haloalkyl, halo, -CN, -OH, -O(C-C alkyl), -NH, -NH(C-C alkyl), -N(C-C alkyl), or oxo.

[0440] In some embodiments, R 2S is a 5-membered heterocycloalkyl optionally substituted with one or more C1-C6 alkyl, C1-C6 haloalkyl, or oxo.

[0441] In some embodiments, R 2S is a 5-membered heterocycloalkyl optionally substituted with one or more C1-C6 alkyl or oxo.

[0442] In some embodiments, R 2S is a 5-membered heterocycloalkyl optionally substituted with one or more C1-C6 alkyl or C1-C6 haloalkyl.

[0443] In some embodiments, R 2S is a 5-membered heterocycloalkyl optionally substituted with one or more C1-C6 alkyls.

[0444] In some embodiments, R 2S is tetrahydrofuranyl optionally substituted with one or more C1-C6 alkyl, C1-C6 haloalkyl, or oxo.

[0445] In some embodiments, R 2S is tetrahydrofuranyl optionally substituted with one or more C1-C6 alkyl or oxo.

[0446] In some embodiments, R 2Sis tetrahydrofuranyl optionally substituted with one or more C1-C6 alkyl or C1-C6 haloalkyl.

[0447] In some embodiments, R 2S is tetrahydrofuranyl optionally substituted with one or more C1-C6 alkyl.

[0448] In some embodiments, R 2S is tetrahydrofuranyl optionally substituted with one or more methyl. In some embodiments, R 2S is tetrahydrofuranyl optionally substituted with one or more ethyl. In some embodiments, R 2S is tetrahydrofuranyl optionally substituted with one or more propyls. In some embodiments, R 2S is tetrahydrofuranyl optionally substituted with one or more butyl. In some embodiments, R 2S is tetrahydrofuranyl optionally substituted with one or more pentyls. In some embodiments, R 2S is tetrahydrofuranyl optionally substituted with one or more hexyls.

[0449] In some embodiments, R 2S is tetrahydrofuranyl optionally substituted with one or more oxo.

[0450] In some embodiments, R 2S is tetrahydrofuranyl optionally substituted with one or more C1-C6 haloalkyl (e.g., methyl, ethyl, propyl, butyl, pentyl, or hexyl optionally substituted with one or more halo).

[0451] In some embodiments, R 2S teeth, The file is TIFF0007661248000070.tif15128.

[0452] In some embodiments, R 2Sis pyrrolidinyl optionally substituted with one or more C1-C6 alkyl, C1-C6 haloalkyl, or oxo.

[0453] In some embodiments, R 2S is pyrrolidinyl optionally substituted with one or more C1-C6 alkyl or oxo.

[0454] In some embodiments, R 2S is pyrrolidinyl optionally substituted with one or more C1-C6 alkyl or C1-C6 haloalkyl.

[0455] In some embodiments, R 2S is pyrrolidinyl optionally substituted with one or more C1-C6 alkyl.

[0456] In some embodiments, R 2S is pyrrolidinyl optionally substituted with one or more methyl. In some embodiments, R 2S is pyrrolidinyl optionally substituted with one or more ethyl. In some embodiments, R 2S is pyrrolidinyl optionally substituted with one or more propyl. In some embodiments, R 2S is pyrrolidinyl optionally substituted with one or more butyl. In some embodiments, R 2S is pyrrolidinyl optionally substituted with one or more pentyls. In some embodiments, R 2S is pyrrolidinyl optionally substituted with one or more hexyls.

[0457] In some embodiments, R 2S is pyrrolidinyl optionally substituted with one or more oxo.

[0458] In some embodiments, R 2S is pyrrolidinyl optionally substituted with one or more C1-C6 haloalkyl (e.g., methyl, ethyl, propyl, butyl, pentyl, or hexyl optionally substituted with one or more halo).

[0459] In some embodiments, R 2S teeth, The file is TIFF0007661248000071.tif73165.

[0460] In some embodiments, R2 is -(CH2) n -R 2S where n is 0 and R 2S is a 5-membered heterocycloalkyl.

[0461] In some embodiments, R2 is -(CH2) n -R 2S where n is 0 and R 2S is a 5-membered heterocycloalkyl optionally substituted with one or more C1-C6 alkyl, C1-C6 haloalkyl, or oxo.

[0462] In some embodiments, R2 is -(CH2) n -R 2S where n is 0 and R 2S is tetrahydrofuranyl optionally substituted with one or more C1-C6 alkyl, C1-C6 haloalkyl, or oxo.

[0463] In some embodiments, R2 is -(CH2) n -R 2S where n is 0 and R 2S is pyrrolidinyl optionally substituted with one or more C1-C6 alkyl, C1-C6 haloalkyl, or oxo.

[0464] In some embodiments, R2 is -(CH2) n -R 2S where n is 1 and R 2S is a 5-membered heterocycloalkyl.

[0465] In some embodiments, R2 is -(CH2) n -R 2S where n is 1 and R 2Sis a 5-membered heterocycloalkyl optionally substituted with one or more C1-C6 alkyl, C1-C6 haloalkyl, or oxo.

[0466] In some embodiments, R2 is -(CH2) n -R 2S where n is 1 and R 2S is tetrahydrofuranyl optionally substituted with one or more C1-C6 alkyl, C1-C6 haloalkyl, or oxo.

[0467] In some embodiments, R2 is -(CH2) n -R 2S where n is 1 and R 2S is pyrrolidinyl optionally substituted with one or more C1-C6 alkyl, C1-C6 haloalkyl, or oxo.

[0468] In some embodiments, R2 is -(CH2) n -R 2S where n is 2 and R 2S is a 5-membered heterocycloalkyl.

[0469] In some embodiments, R2 is -(CH2) n -R 2S where n is 2 and R 2S is a 5-membered heterocycloalkyl optionally substituted with one or more C1-C6 alkyl, C1-C6 haloalkyl, or oxo.

[0470] In some embodiments, R2 is -(CH2) n -R 2S where n is 2 and R 2S is tetrahydrofuranyl optionally substituted with one or more C1-C6 alkyl, C1-C6 haloalkyl, or oxo.

[0471] In some embodiments, R2 is -(CH2) n -R 2S where n is 2 and R 2Sis pyrrolidinyl optionally substituted with one or more C1-C6 alkyl, C1-C6 haloalkyl, or oxo.

[0472] In some embodiments, R 2S is a 4-membered heterocycloalkyl.

[0473] In some embodiments, R 2S is a 4-membered heterocycloalkyl optionally substituted with one or more C-C alkyl, C-C alkenyl, C-C alkynyl, C-C haloalkyl, halo, -CN, -OH, -O(C-C alkyl), -NH, -NH(C-C alkyl), -N(C-C alkyl), or oxo.

[0474] In some embodiments, R 2S is a 4-membered heterocycloalkyl optionally substituted with one or more C1-C6 alkyl, C1-C6 haloalkyl, or oxo.

[0475] In some embodiments, R 2S is a 4-membered heterocycloalkyl optionally substituted with one or more C1-C6 alkyl or oxo.

[0476] In some embodiments, R 2S is a 4-membered heterocycloalkyl optionally substituted with one or more C1-C6 alkyl or C1-C6 haloalkyl.

[0477] In some embodiments, R 2S is a 4-membered heterocycloalkyl optionally substituted with one or more C1-C6 alkyls.

[0478] In some embodiments, R 2S is oxetanyl optionally substituted with one or more C1-C6 alkyl, C1-C6 haloalkyl, or oxo.

[0479] In some embodiments, R 2Sis oxetanyl optionally substituted with one or more C1-C6 alkyl or oxo.

[0480] In some embodiments, R 2S is oxetanyl optionally substituted with one or more C1-C6 alkyl or C1-C6 haloalkyl.

[0481] In some embodiments, R 2S is oxetanyl optionally substituted with one or more C1-C6 alkyls.

[0482] In some embodiments, R 2S is oxetanyl optionally substituted with one or more methyl. In some embodiments, R 2S is oxetanyl optionally substituted with one or more ethyl. In some embodiments, R 2S is oxetanyl optionally substituted with one or more propyls. In some embodiments, R 2S is oxetanyl optionally substituted with one or more butyl. In some embodiments, R 2S is oxetanyl optionally substituted with one or more pentyls. In some embodiments, R 2S is oxetanyl optionally substituted with one or more hexyls.

[0483] In some embodiments, R 2S is oxetanyl optionally substituted with one or more oxo.

[0484] In some embodiments, R 2S is oxetanyl optionally substituted with one or more C1-C6 haloalkyl (e.g., methyl, ethyl, propyl, butyl, pentyl, or hexyl optionally substituted with one or more halo).

[0485] In some embodiments, R 2S teeth, The file is TIFF0007661248000072.tif15128.

[0486] In some embodiments, R 2S is azetidinyl optionally substituted with one or more C1-C6 alkyl, C1-C6 haloalkyl, or oxo.

[0487] In some embodiments, R 2S is azetidinyl optionally substituted with one or more C1-C6 alkyl or oxo.

[0488] In some embodiments, R 2S is azetidinyl optionally substituted with one or more C1-C6 alkyl or C1-C6 haloalkyl.

[0489] In some embodiments, R 2S is azetidinyl optionally substituted with one or more C1-C6 alkyl.

[0490] In some embodiments, R 2S is azetidinyl optionally substituted with one or more methyl. In some embodiments, R 2S is azetidinyl optionally substituted with one or more ethyl. In some embodiments, R 2S is azetidinyl optionally substituted with one or more propyl. In some embodiments, R 2S is azetidinyl optionally substituted with one or more butyl. In some embodiments, R 2S is azetidinyl optionally substituted with one or more pentyls. In some embodiments, R 2S is azetidinyl optionally substituted with one or more hexyls.

[0491] In some embodiments, R 2S is azetidinyl optionally substituted with one or more oxo.

[0492] In some embodiments, R 2Sis azetidinyl optionally substituted with one or more C1-C6 haloalkyl (e.g., methyl, ethyl, propyl, butyl, pentyl, or hexyl optionally substituted with one or more halo).

[0493] In some embodiments, R 2S teeth, The file is TIFF0007661248000073.tif24128.

[0494] In some embodiments, R2 is -(CH2) n -R 2S where n is 0 and R 2S is a 4-membered heterocycloalkyl.

[0495] In some embodiments, R2 is -(CH2) n -R 2S where n is 0 and R 2S is a 4-membered heterocycloalkyl optionally substituted with one or more C1-C6 alkyl, C1-C6 haloalkyl, or oxo.

[0496] In some embodiments, R2 is -(CH2) n -R 2S where n is 0 and R 2S is oxetanyl optionally substituted with one or more C1-C6 alkyl, C1-C6 haloalkyl, or oxo.

[0497] In some embodiments, R2 is -(CH2) n -R 2S where n is 0 and R 2S is azetidinyl optionally substituted with one or more C1-C6 alkyl, C1-C6 haloalkyl, or oxo.

[0498] In some embodiments, R2 is -(CH2) n -R 2S where n is 1 and R 2S is a 4-membered heterocycloalkyl.

[0499] In some embodiments, R2 is -(CH2) n -R 2S where n is 1 and R 2S is a 4-membered heterocycloalkyl optionally substituted with one or more C1-C6 alkyl, C1-C6 haloalkyl, or oxo.

[0500] In some embodiments, R2 is -(CH2) n -R 2S where n is 1 and R 2S is oxetanyl optionally substituted with one or more C1-C6 alkyl, C1-C6 haloalkyl, or oxo.

[0501] In some embodiments, R2 is -(CH2) n -R 2S where n is 1 and R 2S is azetidinyl optionally substituted with one or more C1-C6 alkyl, C1-C6 haloalkyl, or oxo.

[0502] In some embodiments, R2 is -(CH2) n -R 2S where n is 2 and R 2S is a 4-membered heterocycloalkyl.

[0503] In some embodiments, R2 is -(CH2) n -R 2S where n is 2 and R 2S is a 4-membered heterocycloalkyl optionally substituted with one or more C1-C6 alkyl, C1-C6 haloalkyl, or oxo.

[0504] In some embodiments, R2 is -(CH2) n -R 2S where n is 2 and R 2S is oxetanyl optionally substituted with one or more C1-C6 alkyl, C1-C6 haloalkyl, or oxo.

[0505] In some embodiments, R2 is -(CH2) n -R 2S where n is 2 and R 2S is azetidinyl optionally substituted with one or more C1-C6 alkyl, C1-C6 haloalkyl, or oxo.

[0506] In some embodiments, R 2S is a 7-membered heterocycloalkyl.

[0507] In some embodiments, R 2S is a 7-membered heterocycloalkyl optionally substituted with one or more C-C alkyl, C-C alkenyl, C-C alkynyl, C-C haloalkyl, halo, -CN, -OH, -O(C-C alkyl), -NH, -NH(C-C alkyl), -N(C-C alkyl), or oxo.

[0508] In some embodiments, R 2S is a 7-membered heterocycloalkyl optionally substituted with one or more C1-C6 alkyl, C1-C6 haloalkyl, or oxo.

[0509] In some embodiments, R 2S is a 7-membered heterocycloalkyl optionally substituted with one or more C1-C6 alkyl or oxo.

[0510] In some embodiments, R 2S is a 7-membered heterocycloalkyl optionally substituted with one or more C1-C6 alkyl or C1-C6 haloalkyl.

[0511] In some embodiments, R 2S is a 7-membered heterocycloalkyl optionally substituted with one or more C1-C6 alkyls.

[0512] In some embodiments, R 2Sis oxepanyl optionally substituted with one or more C1-C6 alkyl, C1-C6 haloalkyl, or oxo.

[0513] In some embodiments, R 2S is oxepanyl optionally substituted with one or more C1-C6 alkyl or oxo.

[0514] In some embodiments, R 2S is oxepanyl optionally substituted with one or more C1-C6 alkyl or C1-C6 haloalkyl.

[0515] In some embodiments, R 2S is oxepanyl optionally substituted with one or more C1-C6 alkyl.

[0516] In some embodiments, R 2S is oxepanyl optionally substituted with one or more methyl. In some embodiments, R 2S is oxepanyl optionally substituted with one or more ethyl. In some embodiments, R 2S is oxepanyl optionally substituted with one or more propyls. In some embodiments, R 2S is oxepanyl optionally substituted with one or more butyl. In some embodiments, R 2S is oxepanyl optionally substituted with one or more pentyls. In some embodiments, R 2S is oxepanyl optionally substituted with one or more hexyls.

[0517] In some embodiments, R 2S is oxepanyl optionally substituted with one or more oxo.

[0518] In some embodiments, R 2S is oxepanyl optionally substituted with one or more C1-C6 haloalkyl (e.g., methyl, ethyl, propyl, butyl, pentyl, or hexyl optionally substituted with one or more halo).

[0519] In some embodiments, R 2S is azepanyl optionally substituted with one or more C1-C6 alkyl, C1-C6 haloalkyl, or oxo.

[0520] In some embodiments, R 2S is azepanyl optionally substituted with one or more C1-C6 alkyl or oxo.

[0521] In some embodiments, R 2S is azepanyl optionally substituted with one or more C1-C6 alkyl or C1-C6 haloalkyl.

[0522] In some embodiments, R 2S is azepanyl optionally substituted with one or more C1-C6 alkyl.

[0523] In some embodiments, R 2S is azepanyl optionally substituted with one or more methyl. In some embodiments, R 2S is azepanyl optionally substituted with one or more ethyl. In some embodiments, R 2S is azepanyl optionally substituted with one or more propyls. In some embodiments, R 2S is azepanyl optionally substituted with one or more butyl. In some embodiments, R 2S is azepanyl optionally substituted with one or more pentyls. In some embodiments, R 2S is azepanyl optionally substituted with one or more hexyls.

[0524] In some embodiments, R 2S is azepanyl optionally substituted with one or more oxo.

[0525] In some embodiments, R 2Sis azepanyl optionally substituted with one or more C1-C6 haloalkyl (e.g., methyl, ethyl, propyl, butyl, pentyl, or hexyl optionally substituted with one or more halo).

[0526] In some embodiments, R 2S teeth, The file is TIFF0007661248000074.tif20128.

[0527] In some embodiments, R2 is -(CH2) n -R 2S where n is 0 and R 2S is a 7-membered heterocycloalkyl.

[0528] In some embodiments, R2 is -(CH2) n -R 2S where n is 0 and R 2S is a 7-membered heterocycloalkyl optionally substituted with one or more C1-C6 alkyl, C1-C6 haloalkyl, or oxo.

[0529] In some embodiments, R2 is -(CH2) n -R 2S where n is 0 and R 2S is oxepanyl optionally substituted with one or more C1-C6 alkyl, C1-C6 haloalkyl, or oxo.

[0530] In some embodiments, R2 is -(CH2) n -R 2S where n is 0 and R 2S is azepanyl optionally substituted with one or more C1-C6 alkyl, C1-C6 haloalkyl, or oxo.

[0531] In some embodiments, R2 is -(CH2) n -R 2S where n is 1 and R 2S is a 7-membered heterocycloalkyl.

[0532] In some embodiments, R2 is -(CH2) n -R 2S where n is 1 and R 2S is a 7-membered heterocycloalkyl optionally substituted with one or more C1-C6 alkyl, C1-C6 haloalkyl, or oxo.

[0533] In some embodiments, R2 is -(CH2) n -R 2S where n is 1 and R 2S is oxepanyl optionally substituted with one or more C1-C6 alkyl, C1-C6 haloalkyl, or oxo.

[0534] In some embodiments, R2 is -(CH2) n -R 2S where n is 1 and R 2S is azepanyl optionally substituted with one or more C1-C6 alkyl, C1-C6 haloalkyl, or oxo.

[0535] In some embodiments, R2 is -(CH2) n -R 2S where n is 2 and R 2S is a 7-membered heterocycloalkyl.

[0536] In some embodiments, R2 is -(CH2) n -R 2S where n is 2 and R 2S is a 7-membered heterocycloalkyl optionally substituted with one or more C1-C6 alkyl, C1-C6 haloalkyl, or oxo.

[0537] In some embodiments, R2 is -(CH2) n -R 2S where n is 2 and R 2S is oxepanyl optionally substituted with one or more C1-C6 alkyl, C1-C6 haloalkyl, or oxo.

[0538] In some embodiments, R2 is -(CH2) n -R 2S where n is 2 and R 2S is azepanyl optionally substituted with one or more C1-C6 alkyl, C1-C6 haloalkyl, or oxo.

[0539] In some embodiments, R 2S is an 8-membered heterocycloalkyl.

[0540] In some embodiments, R 2S is an 8-membered heterocycloalkyl optionally substituted with one or more C-C alkyl, C-C alkenyl, C-C alkynyl, C-C haloalkyl, halo, -CN, -OH, -O(C-C alkyl), -NH, -NH(C-C alkyl), -N(C-C alkyl), or oxo.

[0541] In some embodiments, R 2S is an 8-membered heterocycloalkyl optionally substituted with one or more C1-C6 alkyl, C1-C6 haloalkyl, or oxo.

[0542] In some embodiments, R 2S is an 8-membered heterocycloalkyl optionally substituted with one or more C1-C6 alkyl or oxo.

[0543] In some embodiments, R 2S is an 8-membered heterocycloalkyl optionally substituted with one or more C1-C6 alkyl or C1-C6 haloalkyl.

[0544] In some embodiments, R 2S is an 8-membered heterocycloalkyl optionally substituted with one or more C1-C6 alkyls.

[0545] In some embodiments, R 2Sis oxocanyl optionally substituted with one or more C1-C6 alkyl, C1-C6 haloalkyl, or oxo.

[0546] In some embodiments, R 2S is oxocanyl optionally substituted with one or more C1-C6 alkyl or oxo.

[0547] In some embodiments, R 2S is oxocanyl optionally substituted with one or more C1-C6 alkyl or C1-C6 haloalkyl.

[0548] In some embodiments, R 2S is oxocanyl optionally substituted with one or more C1-C6 alkyl.

[0549] In some embodiments, R 2S is oxocanyl optionally substituted with one or more methyl. In some embodiments, R 2S is oxocanyl optionally substituted with one or more ethyl. In some embodiments, R 2S is oxocanyl optionally substituted with one or more propyl. In some embodiments, R 2S is oxocanyl optionally substituted with one or more butyl. In some embodiments, R 2S is oxocanyl optionally substituted with one or more pentyls. In some embodiments, R 2S is oxocanyl optionally substituted with one or more hexyls.

[0550] In some embodiments, R 2S is oxocanyl optionally substituted by one or more oxo.

[0551] In some embodiments, R 2S is oxocanyl optionally substituted with one or more C1-C6 haloalkyl (e.g., methyl, ethyl, propyl, butyl, pentyl, or hexyl optionally substituted with one or more halo).

[0552] In some embodiments, R 2S is azocanyl optionally substituted with one or more C1-C6 alkyl, C1-C6 haloalkyl, or oxo.

[0553] In some embodiments, R 2S is azocanyl optionally substituted with one or more C1-C6 alkyl or oxo.

[0554] In some embodiments, R 2S is azocanyl optionally substituted with one or more C1-C6 alkyl or C1-C6 haloalkyl.

[0555] In some embodiments, R 2S is azocanyl optionally substituted with one or more C1-C6 alkyl.

[0556] In some embodiments, R 2S is azocanyl optionally substituted with one or more methyl. In some embodiments, R 2S is azocanyl optionally substituted with one or more ethyl. In some embodiments, R 2S is azocanyl optionally substituted with one or more propyl. In some embodiments, R 2S is azocanyl optionally substituted with one or more butyl. In some embodiments, R 2S is azocanyl optionally substituted with one or more pentyls. In some embodiments, R 2S is azocanyl optionally substituted with one or more hexyls.

[0557] In some embodiments, R 2S is azocanyl optionally substituted by one or more oxo.

[0558] In some embodiments, R 2Sis azocanyl optionally substituted with one or more C1-C6 haloalkyl (e.g., methyl, ethyl, propyl, butyl, pentyl, or hexyl optionally substituted with one or more halo).

[0559] In some embodiments, R2 is -(CH2) n -R 2S where n is 0 and R 2S is an 8-membered heterocycloalkyl.

[0560] In some embodiments, R2 is -(CH2) n -R 2S where n is 0 and R 2S is an 8-membered heterocycloalkyl optionally substituted with one or more C1-C6 alkyl, C1-C6 haloalkyl, or oxo.

[0561] In some embodiments, R2 is -(CH2) n -R 2S where n is 0 and R 2S is oxocanyl optionally substituted with one or more C1-C6 alkyl, C1-C6 haloalkyl, or oxo.

[0562] In some embodiments, R2 is -(CH2) n -R 2S where n is 0 and R 2S is azocanyl optionally substituted with one or more C1-C6 alkyl, C1-C6 haloalkyl, or oxo.

[0563] In some embodiments, R2 is -(CH2) n -R 2S where n is 1 and R 2S is an 8-membered heterocycloalkyl.

[0564] In some embodiments, R2 is -(CH2) n -R 2S where n is 1 and R 2Sis an 8-membered heterocycloalkyl optionally substituted with one or more C1-C6 alkyl, C1-C6 haloalkyl, or oxo.

[0565] In some embodiments, R2 is -(CH2) n -R 2S where n is 1 and R 2S is oxocanyl optionally substituted with one or more C1-C6 alkyl, C1-C6 haloalkyl, or oxo.

[0566] In some embodiments, R2 is -(CH2) n -R 2S where n is 1 and R 2S is azocanyl optionally substituted with one or more C1-C6 alkyl, C1-C6 haloalkyl, or oxo.

[0567] In some embodiments, R2 is -(CH2) n -R 2S where n is 2 and R 2S is an 8-membered heterocycloalkyl.

[0568] In some embodiments, R2 is -(CH2) n -R 2S where n is 2 and R 2S is an 8-membered heterocycloalkyl optionally substituted with one or more C1-C6 alkyl, C1-C6 haloalkyl, or oxo.

[0569] In some embodiments, R2 is -(CH2) n -R 2S where n is 2 and R 2S is oxocanyl optionally substituted with one or more C1-C6 alkyl, C1-C6 haloalkyl, or oxo.

[0570] In some embodiments, R2 is -(CH2) n -R 2S where n is 2 and R 2Sis azocanyl optionally substituted with one or more C1-C6 alkyl, C1-C6 haloalkyl, or oxo.

[0571] In some embodiments, R 2S is spiroheterocycloalkyl optionally substituted with one or more C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, halo, -CN, -OH, -O(C1-C6 alkyl), -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, or oxo.

[0572] In some embodiments, R 2S is a spiroheterocycloalkyl optionally substituted with one or more C1-C6 alkyl, C1-C6 haloalkyl, or oxo.

[0573] In some embodiments, R2 is -(CH2) n -R 2S where n is 0 and R 2S is a spiroheterocycloalkyl optionally substituted with one or more C1-C6 alkyl, C1-C6 haloalkyl, or oxo.

[0574] In some embodiments, R2 is -(CH2) n -R 2S where n is 1 and R 2S is a spiroheterocycloalkyl optionally substituted with one or more C1-C6 alkyl, C1-C6 haloalkyl, or oxo.

[0575] In some embodiments, R2 is -(CH2) n -R 2S where n is 2 and R 2S is a spiroheterocycloalkyl optionally substituted with one or more C1-C6 alkyl, C1-C6 haloalkyl, or oxo.

[0576] In some embodiments, R 2Sis a spiro 7-membered heterocycloalkyl optionally substituted with one or more C1-C6 alkyl, C1-C6 haloalkyl, or oxo.

[0577] In some embodiments, R 2S is a spiro 7-membered heterocycloalkyl optionally substituted with one or more C1-C6 alkyls.

[0578] In some embodiments, R 2S is a spiro 7-membered heterocycloalkyl optionally substituted with one or more C1-C6 haloalkyl.

[0579] In some embodiments, R 2S is 2-azaspiro[3.3]heptane, optionally substituted with one or more C1-C6 alkyl, C1-C6 haloalkyl, or oxo. In some embodiments, R 2S is 2-oxaspiro[3.3]heptane optionally substituted with one or more C1-C6 alkyl, C1-C6 haloalkyl, or oxo.

[0580] In some embodiments, R 2S teeth, The file is TIFF0007661248000075.tif32128.

[0581] In some embodiments, R 2S is a bridged heterocycloalkyl optionally substituted with one or more C-C alkyl, C-C alkenyl, C-C alkynyl, C-C haloalkyl, halo, -CN, -OH, -O(C-C alkyl), -NH, -NH(C-C alkyl), -N(C-C alkyl) or oxo.

[0582] In some embodiments, R 2S is a bridged heterocycloalkyl optionally substituted with one or more C1-C6 alkyl, C1-C6 haloalkyl, or oxo.

[0583] In some embodiments, R2 is -(CH2) n -R 2S where n is 0 and R 2S is a bridged heterocycloalkyl optionally substituted with one or more C1-C6 alkyl, C1-C6 haloalkyl, or oxo.

[0584] In some embodiments, R2 is -(CH2) n -R 2S where n is 1 and R 2S is a bridged heterocycloalkyl optionally substituted with one or more C1-C6 alkyl, C1-C6 haloalkyl, or oxo.

[0585] In some embodiments, R2 is -(CH2) n -R 2S where n is 2 and R 2S is a bridged heterocycloalkyl optionally substituted with one or more C1-C6 alkyl, C1-C6 haloalkyl, or oxo.

[0586] In some embodiments, R 2S is an 8-membered bridged heterocycloalkyl optionally substituted with one or more C1-C6 alkyl, C1-C6 haloalkyl, or oxo.

[0587] In some embodiments, R 2S is a bridged quinuclidinyl optionally substituted with one or more C1-C6 alkyl, C1-C6 haloalkyl, or oxo.

[0588] In some embodiments, R 2S teeth, TIFF0007661248000076.tif10128.

[0589] In some embodiments, R2 is The file is TIFF0007661248000077.tif187170.

[0590] In some embodiments, R2 is TIFF0007661248000078.tif178165TIFF0007661248000079.tif60165

[0591] In some embodiments, R2 is The file is TIFF0007661248000080.tif89165.

[0592] In some embodiments, R2 is The file is TIFF0007661248000081.tif18128.

[0593] In some embodiments, R3 is one or more R 3S and 5-6 membered heterocycloalkyl optionally substituted with

[0594] In some embodiments, R3 is The file is TIFF0007661248000082.tif19140.

[0595] In some embodiments, R3 is one or more R 3S and 7-12 membered heterocycloalkyl optionally substituted with

[0596] In some embodiments, R3 is a 7-12 membered heterocycloalkyl.

[0597] In some embodiments, R3 is one or more R 3S and 8-11 membered heterocycloalkyl optionally substituted with

[0598] In some embodiments, R3 is an 8-11 membered heterocycloalkyl.

[0599] In some embodiments, R3 is one or more R 3S and optionally substituted 9- or 10-membered heterocycloalkyl.

[0600] In some embodiments, R3 is a 9- or 10-membered heterocycloalkyl.

[0601] In some embodiments, R3 is one or more R 3S is a 9-membered heterocycloalkyl optionally substituted with

[0602] In some embodiments, R3 is a 9-membered heterocycloalkyl.

[0603] In some embodiments, R3 is The file is TIFF0007661248000083.tif14128.

[0604] In some embodiments, R3 is The file is TIFF0007661248000084.tif14128.

[0605] In some embodiments, R3 is one or more R 3S and each R is a 5- or 6-membered heteroaryl optionally substituted with 3S are independently C-C alkyl, C-C haloalkyl, C-C cycloalkyl, halo, or C-C heterocycloalkyl, wherein the C-C alkyl, C-C haloalkyl, C-C cycloalkyl, or C-C heterocycloalkyl is optionally substituted with —O(C-C alkyl), —N(C-C alkyl), or —CN.

[0606] In some embodiments, R3 is one or more R 3S and each R is a 5- or 6-membered heteroaryl optionally substituted with 3S is independently C-C alkyl, C-C haloalkyl, C-C cycloalkyl, halo, or C-C heterocycloalkyl, wherein the C-C alkyl is optionally substituted with —O(C-C alkyl), —N(C-C alkyl), halo, or —CN.

[0607] In some embodiments, R3 is one or more R 3S and each R is a 5- or 6-membered heteroaryl optionally substituted with 3S are independently C-C alkyl, C-C haloalkyl, C-C cycloalkyl, halo, or C-C heterocycloalkyl, wherein the C-C alkyl is optionally substituted with —O(C-C alkyl), or —N(C-C alkyl).

[0608] In some embodiments, R3 is one or more R 3S and each R is a 5- or 6-membered heteroaryl optionally substituted with 3S is independently C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, halo, or C3-C8 heterocycloalkyl.

[0609] In some embodiments, R3 is one or more R 3S and each R is a 5- or 6-membered heteroaryl optionally substituted with 3S is independently C1-C6 alkyl or C1-C6 haloalkyl.

[0610] In some embodiments, R3 is a 5- or 6-membered heteroaryl having 1, 2, or 3 heteroatoms.

[0611] In some embodiments, R3 is a 5- or 6-membered heteroaryl having 1, 2, or 3 heteroatoms selected from N and O.

[0612] In some embodiments, R3 is a 5- or 6-membered heteroaryl having one heteroatom selected from N and O.

[0613] In some embodiments, R3 is a 5- or 6-membered heteroaryl having two heteroatoms selected from N and O.

[0614] In some embodiments, R3 is one or more R 3Sand each R is a 5-membered heteroaryl optionally substituted with 3S are independently C-C alkyl, C-C haloalkyl, C-C cycloalkyl, halo, or C-C heterocycloalkyl, wherein the C-C alkyl, C-C haloalkyl, C-C cycloalkyl, or C-C heterocycloalkyl is optionally substituted with —O(C-C alkyl), —N(C-C alkyl), halo, or —CN.

[0615] In some embodiments, R3 is one or more R 3S and each R is a 5-membered heteroaryl optionally substituted with 3S is independently C-C alkyl, C-C haloalkyl, C-C cycloalkyl, halo, or C-C heterocycloalkyl, wherein the C-C alkyl is optionally substituted with —O(C-C alkyl), —N(C-C alkyl), halo, or —CN.

[0616] In some embodiments, R3 is one or more R 3S and each R is a 5-membered heteroaryl optionally substituted with 3S is independently C-C alkyl, C-C haloalkyl, C-C cycloalkyl, halo, or C-C heterocycloalkyl, wherein the C-C alkyl is optionally substituted with —O(C-C alkyl) or —N(C-C alkyl).

[0617] In some embodiments, R3 is one or more R 3S and each R is a 5-membered heteroaryl optionally substituted with 3S is independently C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, halo, or C3-C8 heterocycloalkyl.

[0618] In some embodiments, R3 is one or more R 3S and each R is a 5-membered heteroaryl optionally substituted with 3Sis independently C1-C6 alkyl, C1-C6 haloalkyl, or C3-C8 cycloalkyl.

[0619] In some embodiments, R3 is one or more R 3S and each R is a 5-membered heteroaryl optionally substituted with 3S is independently C1-C6 alkyl or C1-C6 haloalkyl.

[0620] In some embodiments, R3 is one or more R 3S and each R is a 5-membered heteroaryl optionally substituted with 3S is independently C1-C6 alkyl.

[0621] In some embodiments, R3 is one or more R 3S and each R is a 6-membered heteroaryl optionally substituted with 3S are independently C-C alkyl, C-C haloalkyl, C-C cycloalkyl, halo, or C-C heterocycloalkyl, wherein the C-C alkyl, C-C haloalkyl, C-C cycloalkyl, or C-C heterocycloalkyl is optionally substituted with —O(C-C alkyl), —N(C-C alkyl), halo, or —CN.

[0622] In some embodiments, R3 is one or more R 3S and each R is a 6-membered heteroaryl optionally substituted with 3S is independently C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, halo, or C3-C8 heterocycloalkyl.

[0623] In some embodiments, R3 is one or more R 3S and each R is a 6-membered heteroaryl optionally substituted with 3S is independently C1-C6 alkyl.

[0624] In some embodiments, R3 is one or more R3S is a 5- or 6-membered heteroaryl optionally substituted with

[0625] In some embodiments, R3 is one or more R 3S is a 5-membered heteroaryl optionally substituted with

[0626] In some embodiments, R3 is one or more R 3S and pyrrolyl optionally substituted with

[0627] In some embodiments, R3 is The file is TIFF0007661248000085.tif95170.

[0628] In some embodiments, R3 is The file is TIFF0007661248000086.tif22128.

[0629] In some embodiments, R3 is The file is TIFF0007661248000087.tif19128.

[0630] In some embodiments, R3 is one or more R 3S and optionally substituted pyrazolyl.

[0631] In some embodiments, R3 is The file is TIFF0007661248000088.tif68165.

[0632] In some embodiments, R3 is The file is TIFF0007661248000089.tif20165.

[0633] In some embodiments, R3 is The file is TIFF0007661248000090.tif69165.

[0634] In some embodiments, R3 is The file is TIFF0007661248000091.tif18141.

[0635] In some embodiments, R3 is TIFF0007661248000092.tif12128.

[0636] In some embodiments, R3 is The file is TIFF0007661248000093.tif12128.

[0637] In some embodiments, R3 is one or more R 3S and imidazolyl optionally substituted by:

[0638] In some embodiments, R3 is The file is TIFF0007661248000094.tif45128.

[0639] In some embodiments, R3 is The file is TIFF0007661248000095.tif10128.

[0640] In some embodiments, R3 is The file is TIFF0007661248000096.tif10128.

[0641] In some embodiments, R3 is one or more R 3S and optionally substituted triazolyl.

[0642] In some embodiments, R3 is The file is TIFF0007661248000097.tif37133.

[0643] In some embodiments, R3 is TIFF0007661248000098.tif18128.

[0644] In some embodiments, R3 is The file is TIFF0007661248000099.tif19128.

[0645] In some embodiments, R3 is one or more R 3S and tetrazolyl optionally substituted by

[0646] In some embodiments, R3 is The file is TIFF0007661248000100.tif12128.

[0647] In some embodiments, R3 is The file is TIFF0007661248000101.tif12128.

[0648] In some embodiments, R3 is one or more R 3S is an isoxazolyl optionally substituted by

[0649] In some embodiments, R3 is The file is TIFF0007661248000102.tif41151.

[0650] In some embodiments, R3 is The file is TIFF0007661248000103.tif18128.

[0651] In some embodiments, R3 is The file is TIFF0007661248000104.tif39128.

[0652] In some embodiments, R3 is one or more R 3S and furanyl optionally substituted by:

[0653] In some embodiments, R3 is The file is TIFF0007661248000105.tif71165.

[0654] In some embodiments, R3 is The file is TIFF0007661248000106.tif18128.

[0655] In some embodiments, R3 is The file is TIFF0007661248000107.tif19128.

[0656] In some embodiments, R3 is one or more R 3S and optionally substituted oxazolyl.

[0657] In some embodiments, R3 is The file is TIFF0007661248000108.tif49128.

[0658] In some embodiments, R3 is The file is TIFF0007661248000109.tif18128.

[0659] In some embodiments, R3 is The file is TIFF0007661248000110.tif19128.

[0660] In some embodiments, R3 is one or more R 3S and 4,5,6,7-tetrahydrobenzo[c]isoxazole, optionally substituted by

[0661] In some embodiments, R3 is The file is TIFF0007661248000111.tif14128.

[0662] In some embodiments, R3 is The file is TIFF0007661248000112.tif14128.

[0663] In some embodiments, R3 is one or more R 3S isothiazolyl optionally substituted by

[0664] In some embodiments, R3 is The file is TIFF0007661248000113.tif18128.

[0665] In some embodiments, R3 is The file is TIFF0007661248000114.tif11128.

[0666] In some embodiments, R3 is one or more R 3S and optionally substituted thiazolyl.

[0667] In some embodiments, R3 is The file is TIFF0007661248000115.tif36167.

[0668] In some embodiments, R3 is The file is TIFF0007661248000116.tif13128.

[0669] In some embodiments, R is one R 3S and optionally substituted thiadiazolyl.

[0670] In some embodiments, R3 is The file is TIFF0007661248000117.tif13128.

[0671] In some embodiments, R3 is TIFF0007661248000118.tif12128.

[0672] In some embodiments, R3 is one or more R 3S is a 6-membered heteroaryl optionally substituted with

[0673] In some embodiments, R3 is one or more R 3S In some embodiments, R is pyridinyl optionally substituted with one or more R 3S In some embodiments, R is diazinyl optionally substituted with one or more R 3SIn some embodiments, R is pyridazinyl optionally substituted with one or more R 3S In some embodiments, R is pyrimidinyl optionally substituted with one or more R 3S In some embodiments, R is pyrazinyl optionally substituted with one or more R 3S In some embodiments, R is triazinyl optionally substituted with one R 3S In some embodiments, R3 is pentadinyl.

[0674] In some embodiments, R3 is The file is TIFF0007661248000119.tif20157.

[0675] In some embodiments, R3 is The file is TIFF0007661248000120.tif20128.

[0676] In some embodiments, R3 is The file is TIFF0007661248000121.tif18128.

[0677] In some embodiments, R3 is The file is TIFF0007661248000122.tif44128.

[0678] In some embodiments, R3 is The file is TIFF0007661248000123.tif16128.

[0679] In some embodiments, R3 is The file is TIFF0007661248000124.tif13128.

[0680] In some embodiments, at least one R 3S is C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, halo, or C3-C8 heterocycloalkyl.

[0681] In some embodiments, at least one R 3S is C1-C6 alkyl, C1-C6 haloalkyl, or C3-C8 cycloalkyl.

[0682] In some embodiments, at least one R 3S is C1-C6 alkyl or C1-C6 haloalkyl.

[0683] In some embodiments, at least one R 3S is C1-C6 alkyl (e.g., linear or branched).

[0684] 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 secbutyl. In some embodiments, at least one R 3S is secpentyl. In some embodiments, at least one R 3S is sexhexyl.

[0685] In some embodiments, at least one R 3Sis C-C alkyl, C-C haloalkyl, C-C cycloalkyl, or C-C heterocycloalkyl, wherein the C-C alkyl, C-C haloalkyl, C-C cycloalkyl, or C-C heterocycloalkyl is optionally substituted with —O(C-C alkyl), —N(C-C alkyl), halo, or —CN.

[0686] In some embodiments, at least one R 3S is C1-C6 alkyl optionally substituted with -O(C1-C6 alkyl), -N(C1-C6 alkyl)2, halo, or -CN.

[0687] In some embodiments, at least one R 3S is —O(C1-C6 alkyl), or C1-C6 alkyl optionally substituted with —N(C1-C6 alkyl)2.

[0688] In some embodiments, at least one R 3S is C1-C6 alkyl optionally substituted with -O(C1-C6 alkyl) (e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl).

[0689] In some embodiments, at least one R 3S is methyl optionally substituted with —O(C1-C6 alkyl). In some embodiments, at least one R 3S is ethyl optionally substituted with —O(C1-C6 alkyl). In some embodiments, at least one R 3S is propyl optionally substituted with —O(C1-C6 alkyl). In some embodiments, at least one R 3S is butyl optionally substituted with —O(C1-C6 alkyl). In some embodiments, at least one R 3S is pentyl optionally substituted with —O(C1-C6 alkyl). In some embodiments, at least one R 3S is hexyl optionally substituted with —O(C1-C6 alkyl).

[0690] In some embodiments, at least one R 3S is C1-C6 alkyl optionally substituted with -N(C1-C6 alkyl)2 (e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl).

[0691] In some embodiments, at least one R 3S is methyl optionally substituted with —N(C-C alkyl). In some embodiments, at least one R 3S is ethyl optionally substituted with —N(C-C alkyl). In some embodiments, at least one R 3S is propyl optionally substituted with —N(C-C alkyl). In some embodiments, at least one R 3S is butyl optionally substituted with —N(C-C alkyl). In some embodiments, at least one R 3S is pentyl optionally substituted with —N(C-C alkyl). In some embodiments, at least one R 3S is hexyl optionally substituted with —N(C1-C6 alkyl)2.

[0692] In some embodiments, at least one R 3S is C1-C6 alkyl optionally substituted with -CN.

[0693] In some embodiments, at least one R 3S is methyl optionally substituted with —CN. In some embodiments, at least one R 3S is ethyl optionally substituted with —CN. In some embodiments, at least one R 3S is propyl optionally substituted with —CN. In some embodiments, at least one R 3S is butyl optionally substituted with —CN. In some embodiments, at least one R 3Sis pentyl optionally substituted with -CN. In some embodiments, at least one R 3S is hexyl optionally substituted with -CN.

[0694] In some embodiments, at least one R 3S is C1-C6 haloalkyl (eg, methyl, ethyl, propyl, butyl, pentyl, or hexyl substituted with one or more halogens).

[0695] In some embodiments, at least one R 3S is a C1-C6 haloalkyl optionally substituted with -O(C1-C6 alkyl), -N(C1-C6 alkyl)2, halo, or -CN.

[0696] In some embodiments, at least one R 3S is -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, or -CH2CF3.

[0697] In some embodiments, at least one R 3S is -CHF. In some embodiments, at least one R 3S is —CH2CHF2. In some embodiments, at least one R 3S is -CH2CF3.

[0698] In some embodiments, at least one R 3S is C3-C8 cycloalkyl.

[0699] In some embodiments, at least one R 3S is a C3-C8 cycloalkyl optionally substituted with -O(C1-C6 alkyl), -N(C1-C6 alkyl)2, halo, or -CN.

[0700] In some embodiments, at least one R 3S is C-C cycloalkyl. In some embodiments, at least one R 3Sis C-C cycloalkyl. In some embodiments, at least one R 3S is C-C cycloalkyl. In some embodiments, at least one R 3S is C3-C4 cycloalkyl.

[0701] In some embodiments, at least one R 3S is cyclopropyl.

[0702] In some embodiments, at least one R 3S is cyclobutyl.

[0703] In some embodiments, at least one R 3S is a C3-C8 heterocycloalkyl.

[0704] In some embodiments, at least one R 3S is a C3-C8 heterocycloalkyl optionally substituted with -O(C1-C6 alkyl), -N(C1-C6 alkyl)2, halo, or -CN.

[0705] In some embodiments, at least one R 3S is C-C heterocycloalkyl. In some embodiments, at least one R 3S is C-C heterocycloalkyl. In some embodiments, at least one R 3S is C-C heterocycloalkyl. In some embodiments, at least one R 3S is C-C heterocycloalkyl. In some embodiments, at least one R 3S is a C4-C5 heterocycloalkyl.

[0706] In some embodiments, at least one R 3S is oxetanyl.

[0707] In some embodiments, at least one R 3S teeth, The file is TIFF0007661248000125.tif16128.

[0708] In some embodiments, at least one R 3S is methyl, ethyl, isopropyl, -CH2OCH3, -CH2CF3, -CH2CH2OCH3, -CH2CN, CH2CF2, or -CH2CH2N(CH3)2.

[0709] In some embodiments, at least one R 3S is a halo.

[0710] In some embodiments, at least one R 3S is F, Cl, Br, or I.

[0711] In some embodiments, at least one R 3S is F or Cl.

[0712] In some embodiments, at least one R 3S is F.

[0713] In some embodiments, at least one R 3S is Cl.

[0714] In some embodiments, the compound has formula (II-a) or (II-b): TIFF0007661248000126.tif59128, or a prodrug, solvate, or pharmaceutically acceptable salt thereof, wherein n1 is an integer ranging from 0 to 3 (e.g., 0, 1, 2, or 3).

[0715] In some embodiments, the compound is a compound of Formula (II-a), or a prodrug, solvate, or pharmaceutically acceptable salt thereof.

[0716] In some embodiments, the compound is a compound of Formula (II-b), or a prodrug, solvate, or pharmaceutically acceptable salt thereof.

[0717] In some embodiments, the compound has formula (II-c), (II-d), (II-e): TIFF0007661248000127.tif91128, or a prodrug, solvate, or pharmaceutically acceptable salt thereof, wherein n1 is 0 or 1.

[0718] In some embodiments, the compound is a compound of Formula (II-c), or a prodrug, solvate, or pharmaceutically acceptable salt thereof.

[0719] In some embodiments, the compound is a compound of Formula (II-d), or a prodrug, solvate, or pharmaceutically acceptable salt thereof:

[0720] In some embodiments, the compound is a compound of Formula (II-e), or a prodrug, solvate, or pharmaceutically acceptable salt thereof:

[0721] In some embodiments, the compound has formula (III): TIFF0007661248000128.tif21128, or a prodrug, solvate, or pharmaceutically acceptable salt thereof.

[0722] In some embodiments, the compound has formula (III-a) or (III-b): TIFF0007661248000129.tif59128, or a prodrug, solvate, or pharmaceutically acceptable salt thereof, wherein n1 is an integer ranging from 0 to 3 (e.g., 0, 1, 2, or 3).

[0723] In some embodiments, the compound is a compound of Formula (III-a), or a prodrug, solvate, or pharmaceutically acceptable salt thereof.

[0724] In some embodiments, the compound is a compound of Formula (III-b), or a prodrug, solvate, or pharmaceutically acceptable salt thereof.

[0725] In some embodiments, the compound has formula (III-c), (III-d), (III-e): TIFF0007661248000130.tif91128, or a prodrug, solvate, or pharmaceutically acceptable salt thereof, wherein n1 is 0 or 1.

[0726] In some embodiments, the compound is a compound of Formula (III-c), or a prodrug, solvate, or pharmaceutically acceptable salt thereof.

[0727] In some embodiments, the compound is a compound of Formula (III-d), or a prodrug, solvate, or pharmaceutically acceptable salt thereof:

[0728] In some embodiments, the compound is a compound of Formula (III-e), or a prodrug, solvate, or pharmaceutically acceptable salt thereof:

[0729] In some embodiments, the compound has formula (IV): TIFF0007661248000131.tif23128, or a prodrug, solvate, or pharmaceutically acceptable salt thereof, wherein n1 is an integer ranging from 0 to 3 (e.g., 0, 1, 2, or 3).

[0730] In some embodiments, the compound has formula (IV-a): TIFF0007661248000132.tif23128, or a prodrug, solvate, or pharmaceutically acceptable salt thereof.

[0731] For a compound of any one of the formulas described herein, R, R 1S , R2, R 2S , R3, R 3S and X2 can each be selected from the groups described herein, where applicable; R1, R 1S , R2, R 2S , R3, R3S Any groups described herein with respect to either R, R 1S , R2, R 2S , R3, R 3S and any of the groups described herein for one or more of the remainder of X2.

[0732] In some embodiments, the compound is selected from the compounds set forth in Table 1, and prodrugs and pharmaceutically acceptable salts thereof.

[0733] In some embodiments, the compound is selected from the compounds set forth in Table 1, and pharmaceutically acceptable salts thereof.

[0734] In some embodiments, the compound is selected from prodrugs of the compounds set forth in Table 1, and pharmaceutically acceptable salts thereof.

[0735] In some embodiments, the compound is selected from the compounds listed in Table 1. (Table 1) TIFF0007661248000133.tif116128TIFF0007661248000134.tif22891TIFF000766 1248000135.tif20491TIFF0007661248000136.tif20591TIFF0007661248000137. tif20691TIFF0007661248000138.tif22391TIFF0007661248000139.tif20391TIF F0007661248000140.tif22191TIFF0007661248000141.tif21591TIFF0007661248 000142.tif22391TIFF0007661248000143.tif20291TIFF0007661248000144.tif2 1091TIFF0007661248000145.tif20091TIFF0007661248000146.tif22891TIFF000 7661248000147.tif20991TIFF0007661248000148.tif22791TIFF00076612480001 49.tif22391TIFF0007661248000150.tif20991TIFF0007661248000151.tif32128

[0736] In some embodiments, the compound is a pharmaceutically acceptable salt of any one of the compounds set forth in Table 1.

[0737] In some embodiments, the compound is a lithium, sodium, potassium, calcium, or magnesium salt of any one of the compounds listed in Table 1.

[0738] In some embodiments, the compound is a sodium or potassium salt of any one of the compounds listed in Table 1.

[0739] In some embodiments, the compound is the sodium salt of any one of the compounds listed in Table 1. For example, the sodium salt of Compound No. 131 is It could be TIFF0007661248000152.tif32128.

[0740] In some embodiments, the compound is the potassium salt of any one of the compounds listed in Table 1.

[0741] In some aspects, the present disclosure provides compounds that are isotopic derivatives (eg, isotopically labeled compounds) of a compound of any one of the formulas disclosed herein.

[0742] In some embodiments, the compound is an isotopic derivative of any one of the compounds set forth in Table 1, and prodrugs and pharmaceutically acceptable salts thereof.

[0743] In some embodiments, the compound is an isotopic derivative of any one of the compounds set forth in Table 1, and pharmaceutically acceptable salts thereof.

[0744] In some embodiments, the compound is an isotopic derivative of any one of the prodrugs of the compounds listed in Table 1, and pharmaceutically acceptable salts thereof.

[0745] In some embodiments, the compound is an isotopic derivative of any one of the compounds listed in Table 1.

[0746] It will be understood that isotopic derivatives can be prepared using any of a variety of art-recognized techniques. For example, isotopic derivatives can generally be prepared by following the procedures disclosed in the schemes and / or examples set forth herein, substituting isotopically labeled reagents for non-isotopically labeled reagents.

[0747] In some embodiments, the isotopic derivative is a deuterium-labeled compound.

[0748] In some embodiments, an isotopic derivative is a deuterium-labeled compound of any one of the compounds of the formulae disclosed herein.

[0749] 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 with one or more isotopes compared to the corresponding compound of formula (I). In some embodiments, an isotopic derivative is 2 H, 13 C. 14 C. 15 N, 18 O. 29 Si, 31 P, and 34 In some embodiments, the isotopic derivative is a deuterium-labeled compound (i.e., one or more atoms thereof are deuterium-labeled). 2 (concentrated with H).

[0750] In some embodiments, the compound is a deuterium-labeled compound of any one of the compounds set forth in Table 1, and prodrugs and pharmaceutically acceptable salts thereof.

[0751] In some embodiments, the compound is a deuterium-labeled compound of any one of the compounds set forth in Table 1, and pharmaceutically acceptable salts thereof.

[0752] In some embodiments, the compound is a deuterium-labeled compound of a prodrug of any one of the compounds set forth in Table 1, and pharmaceutically acceptable salts thereof.

[0753] In some embodiments, the compound is a deuterium-labeled compound of any one of the compounds set forth in Table 1.

[0754] It is understood that a deuterium-labeled compound comprises deuterium atoms that exhibit a deuterium abundance substantially in excess of the natural abundance of deuterium, which is 0.015%.

[0755] In some embodiments, the deuterium-labeled compound exhibits a deuterium enrichment factor for each deuterium atom of at least 3500 (52.5% deuterium incorporation at 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). As used herein, the term "deuterium enrichment factor" refers to the ratio between the deuterium abundance and the natural abundance of deuterium.

[0756] It will be appreciated that deuterium-labeled compounds can be prepared using any of a variety of art-recognized techniques. For example, deuterium-labeled compounds can generally be prepared by following the procedures disclosed in the schemes and / or examples described herein, substituting deuterium-labeled reagents for non-deuterium-labeled reagents.

[0757] Compounds of the present invention, or pharmaceutically acceptable salts or solvates thereof, containing the above-mentioned deuterium atom(s) are within the scope of the present invention. 2 H) may result in certain therapeutic advantages resulting from increased metabolic stability, such as increased in vivo half-life or reduced dosage requirements.

[0758] In some embodiments, the compound is 18 F-labeled compound.

[0759] In some embodiments, the compound is 123 I-labeled compound, 124 I-labeled compound, 125 I-labeled compound, 129 I-labeled compound, 131 I-labeled compound, 135I-labeled compounds, or any combination thereof.

[0760] In some embodiments, the compound is 33 S-labeled compound, 34 S-labeled compound, 35 S-labeled compound, 36 S-labeled compounds, or any combination thereof.

[0761] 18 F, 123 I, 124 I, 125 I, 129 I, 131 I, 135 I, 32 S, 34 S, 35 S, and / or 36 It will be appreciated that S-labeled compounds can be prepared using any of a variety of art-recognized techniques. For example, deuterium-labeled compounds can generally be prepared by reacting a non-isotopically labeled reagent with a methyl group, following the procedures disclosed in the schemes and / or examples set forth herein. 18 F, 123 I, 124 I, 125 I, 129 I, 131 I, 135 I, 32 S, 34 S, 35 S, and / or 36 It can be prepared by substituting S-labeled reagents.

[0762] The above 18 F, 123 I, 124 I, 125 I, 129 I, 131 I, 135 I, 32 S, 34 S, 35 S, and 36 Compounds of the present invention or pharmaceutically acceptable salts or solvates thereof containing one or more S atom(s) are within the scope of the present invention. 18 F, 123I, 124 I, 125 I, 129 I, 131 I, 135 I, 32 S, 34 S, 35 S, and / or 36 S) substitution may result in certain therapeutic advantages resulting from increased metabolic stability, such as increased in vivo half-life or reduced dosage requirements.

[0763] For the avoidance of doubt, when a group is described herein as being "described herein," it is to be understood that the group includes the single broadest definition and any specific definitions within that group.

[0764] The various functional groups and substituents that make up the compounds of formula (I) are typically selected so that the molecular weight of the compound does not exceed 1000 daltons. More typically, the molecular weight of the compound is less than 900 daltons, e.g., less than 800 daltons, or less than 750 daltons, or less than 700 daltons, or less than 650 daltons. More conveniently, the molecular weight is less than 600 daltons, e.g., 550 daltons or less.

[0765] Suitable pharmaceutically acceptable salts of the compounds of the present disclosure are, for example, acid addition salts of compounds of the present disclosure that are sufficiently basic, such as inorganic or organic acids, such as 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 compounds of the present disclosure that are sufficiently acidic are alkali metal salts, such as sodium or potassium salts, alkaline earth metal salts, such as calcium or magnesium salts, ammonium salts, or salts with organic bases that provide pharmaceutically acceptable cations, such as methylamine, dimethylamine, diethylamine, trimethylamine, piperidine, morpholine, or tris-(2-hydroxyethyl)amine.

[0766] It is to be understood that the compounds of any one of the formulas disclosed herein, as well as the pharmaceutically acceptable salts thereof, include stereoisomers, mixtures of stereoisomers, and polymorphs of all isomeric forms of the compounds.

[0767] As used herein, the term "isomerism" refers to compounds that have identical molecular formulae but differ in the sequence of bonding of their atoms or the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are termed "stereoisomers." Stereoisomers that are not mirror images of one another are termed "diastereoisomers." Stereoisomers that are non-superimposable mirror images of each other are sometimes termed "enantiomers," or optical isomers. A mixture containing equal amounts of individual enantiomeric forms of opposite chirality is termed a "racemic mixture."

[0768] As used herein, the term "chiral center" refers to a carbon atom bonded to four nonidentical substituents.

[0769] As used herein, the term "chiral isomer" refers to a compound having at least one chiral center. Compounds having more than one chiral center can exist as individual diastereomers or as a mixture of diastereomers, termed a "diastereomeric mixture." When one chiral center is present, a stereoisomer can be characterized by the absolute configuration (R or S) of that chiral center. Absolute configuration refers to the arrangement in space of the substituents attached to the chiral center. The substituents attached to the chiral center under consideration are ranked according to the ranking rules of Cahn, Ingold and Prelog (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).

[0770] As used herein, the term "geometric isomer" refers to diastereomers that exist due to restricted rotation about a double bond or a cycloalkyl linker (e.g., 1,3-cyclobutyl). These configurations are distinguished in the designations by the prefixes cis and trans, or Z and E, which indicate that groups are on the same or opposite sides of a double bond in a molecule, according to the Cahn-Ingold-Prelog rules.

[0771] It is understood that the compounds of the present disclosure may be represented as different chiral or geometric isomers, and when a compound has chiral or geometric isomeric forms, it should be understood that all isomeric forms are intended to be included within the scope of the disclosure, and that the naming of the compound does not exclude any isomeric form, and it is understood that not all isomers may have the same level of activity.

[0772] It is understood that the structures and other compounds described in this disclosure include all atropisomers thereof, and it is also understood that not all atropisomers may exhibit the same level of activity.

[0773] 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 restricted rotation caused by hindrance of rotation of large groups around a central bond. These atropisomers generally exist as mixtures, but recent advances in chromatographic techniques have made it possible, in limited cases, to separate mixtures of two atropisomers.

[0774] As used herein, the term "tautomer" refers to one of two or more structural isomers that exist in equilibrium and readily convert from one isomeric form to another. This conversion involves the formal migration 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 solutions where tautomerization is possible, a chemical equilibrium of tautomers is reached. The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH. The concept that tautomers can be interconverted by tautomerization is called tautomerism. Two of the various possible types of tautomerism are commonly recognized: keto-enol tautomerism involves the simultaneous migration of an electron and a hydrogen atom. As demonstrated by glucose, ring-chain tautomerism occurs when an aldehyde group (-CHO) in a sugar molecule reacts with a hydroxyl group (-OH) in the same molecule, resulting in a cyclic (annular) form of the molecule.

[0775] It is understood that the compounds of the present disclosure may be represented as different tautomeric forms. It is also understood that, where a compound has tautomeric forms, all tautomeric forms are intended to be included within the scope of the present disclosure, and the naming of the compound does not exclude any tautomeric form. It is understood that certain tautomers may exhibit a higher level of activity than other tautomers.

[0776] Compounds that have the same molecular formula but differ in the nature or bonding sequence of their atoms or the spatial arrangement of their atoms are called "isomers." Isomers that differ in the spatial arrangement of their atoms are called "stereoisomers." Stereoisomers that are not mirror images of each other are called "diastereomers," and stereoisomers that are non-superimposable mirror images of each other are called "enantiomers." For example, if a compound has an asymmetric center, the asymmetric center may be attached to four different groups, resulting in a pair of enantiomers. Enantiomers can be characterized by the absolute configuration of the asymmetric center and described by the R- and S-sequencing rules of Cahn and Prelog or by the way the molecule rotates the plane of polarized light and are designated as 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."

[0777] The compounds of the present disclosure may have one or more asymmetric centers, and therefore, 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 the specification and claims is intended to include both individual enantiomers and their racemic or other mixtures. Methods for determining the stereochemical configuration and separating stereoisomers, for example, by synthesis from optically active starting materials or by resolution of racemates, are well known in the art (see Chapter 4 of "Advanced Organic Chemistry," 4th edition, J. March, John Wiley and Sons, New York, 2001). Some compounds of the present disclosure may have geometric isomerism centers (E- and Z-isomers). It is understood that the present disclosure includes all optical isomers, diastereoisomers, and geometric isomers, and mixtures thereof, that have inflammasome inhibitory activity.

[0778] The present disclosure also includes compounds of the present disclosure, as defined herein, that contain one or more isotopic substitutions.

[0779] It should be understood that the compounds of any formula described herein include the compound itself, as well as, where appropriate, their salts and solvates. For example, salts can be formed between an anion and a positively charged group (e.g., amino) in the substituted compounds disclosed herein. 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).

[0780] As used herein, the term "pharmaceutically acceptable anion" refers to an anion suitable for forming pharmaceutically acceptable salts. Similarly, salts can also be formed between a cation and a negatively charged group (e.g., carboxylate) in the substituted compounds disclosed herein. Suitable cations include sodium, potassium, magnesium, calcium, and ammonium cations such as tetramethylammonium or diethylamine. The substituted compounds disclosed herein also include salts containing quaternary nitrogen atoms.

[0781] It should be understood that the compounds of the present disclosure, for example, salts of the compounds, can exist in hydrated or non-hydrated (anhydrous) form, or as solvates with other solvent molecules.Examples of hydrates include, but are not limited to, monohydrates, dihydrates, etc.Examples of solvates include, but are not limited to, ethanol solvates, acetone solvates, etc.

[0782] The term "solvate" as used herein refers to a solvent adduct containing a stoichiometric or non-stoichiometric amount of solvent. Some compounds tend to form solvates by trapping a fixed molar ratio of solvent molecules in a crystalline solid. When the solvent is water, the solvate that forms is a hydrate, and when the solvent is alcohol, the solvate that forms is an alcoholate. A hydrate is formed by combining one or more molecules of water with one molecule of a substance, and the water retains its molecular state as H2O.

[0783] As used herein, the term "analog" refers to a compound that is structurally similar to another compound but differs slightly in composition (e.g., one atom is replaced with an atom of a different element, or a particular functional group is present, i.e., one functional group is replaced with another functional group). Thus, an analog is a compound that is similar or equivalent in function and appearance to a reference compound, but not in structure or origin.

[0784] The term "derivative," as used herein, refers to compounds that share a common core structure, but are substituted with various groups as described herein.

[0785] As used herein, the term "bioisostere" refers to a compound obtained by replacing an atom or group of atoms with another broadly similar atom or group of atoms. The purpose of bioisosteric substitution is to create a new compound with similar biological properties to the parent compound. Bioisosteric substitutions can be physicochemical or topological. Examples of carboxylic acid bioisosteres include, but are not limited to, acylsulfonamides, tetrazoles, sulfonates, and phosphonates. See, e.g., Patani and LaVoie, Chem. Rev. 96, 3147-3176, 1996.

[0786] It should also be understood that a particular compound of any one of the formulas disclosed herein can exist in solvated as well as unsolvated forms, such as, for example, hydrated forms. For example, suitable pharmaceutically acceptable solvates are hydrates, such as hemihydrate, monohydrate, dihydrate, or trihydrate. It should be understood that the present disclosure encompasses all of these solvated forms that have inflammasome inhibitory activity.

[0787] It should also be understood that a particular compound of any one of the formulas disclosed herein may exhibit polymorphism, and the present disclosure encompasses all of these forms, or mixtures thereof, that have inflammasome inhibitory activity. It is generally known that crystalline materials can be analyzed using conventional techniques, such as X-ray powder diffraction analysis, differential scanning calorimetry, thermogravimetry, diffuse reflectance infrared Fourier transform (DRIFT) spectroscopy, near-infrared (NIR) spectroscopy, and solution and / or solid-state nuclear magnetic resonance spectroscopy. The water content of these crystalline materials can be determined by Karl Fischer analysis.

[0788] Compounds of any one of the formulas disclosed herein can exist in a number of different tautomeric forms, and reference to a compound of formula (I) includes all these forms. For the avoidance of doubt, if a compound can exist in one of several tautomeric forms and only one is specifically named or shown, all other tautomeric forms are still included in formula (I). Examples of tautomeric forms include keto, enol, and enolate forms, such as the following tautomeric pairs: keto / enol (shown below), imine / enamine, amide / iminoalcohol, amidine / amidine, nitroso / oxime, thioketone / enethiol, and nitro / aci-nitro. TIFF0007661248000153.tif18128

[0789] Compounds of any one of the formulas disclosed herein that contain an amine functional group can also form N-oxides. References herein to compounds of formula (I) that contain an amine functional group also include N-oxides. When a compound contains several amine functional groups, one or more nitrogen atoms can be oxidized to form N-oxides. Specific examples of N-oxides include the N-oxides of tertiary amines or nitrogen atoms of nitrogen-containing heterocycles. 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, pages 1977-1980. More specifically, N-oxides can be produced by the procedure of LW 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.

[0790] The compounds of any one of the formulas disclosed herein may be administered in the form of a prodrug, which breaks down in the human or animal body to release the compound of the present disclosure. The prodrug may be used to modify the physical and / or pharmacokinetic properties of the compound of the present disclosure. A prodrug can be formed when the compound of the present disclosure contains a suitable group or substituent to which a property-modifying group can be attached. Examples of prodrugs include derivatives of the ester or amide group of any one of the formulas disclosed herein that contain an alkyl or acyl substituent that can be cleaved in vivo.

[0791] Thus, the present disclosure includes compounds of any one of the formulas disclosed herein as defined above when they are made available by organic synthesis and when they are made available in the human or animal body by cleavage of a prodrug thereof. Thus, the present disclosure includes compounds of any one of the formulas disclosed herein produced by organic synthetic means, as well as those compounds produced in the human or animal body by metabolism of a precursor compound, i.e., compounds of any one of the formulas disclosed herein can be synthetically produced compounds or metabolically produced compounds.

[0792] Suitable pharmaceutically acceptable prodrugs of a compound of any one of the formulae disclosed herein are those prodrugs that, based on sound medical judgment, are suitable for administration to the human or animal body, are not associated with undesirable pharmacological activity, and are not associated with undue toxicity. Various forms of prodrugs are described, for example, in the following documents: a) Methods in Enzymology, Vol. 42, pp. 309-396, edited by K. Widder, et al. (Academic Press, 1985); b) Design of Prodrugs, 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 Prodrugs”, by H. Bundgaard, pp. 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”, ACS Symposium Series, Volume 14, and h) E. Roche (editor), “Bioreversible Carriers in Drug Design”, Pergamon Press, 1987.

[0793] Suitable pharmaceutically acceptable prodrugs of the compounds of any one of the formulae disclosed herein having a hydroxy group are, for example, in vivo cleavable esters or ethers thereof. The in vivo cleavable esters or ethers of the compounds of any one of the formulae disclosed herein containing a hydroxy group are, for example, pharmaceutically acceptable esters or ethers that are cleaved in the human or animal body to generate the parent hydroxy compound. Suitable pharmaceutically acceptable ester-forming groups for the hydroxy group include inorganic esters such as phosphate esters (including phosphoramidate cyclic esters). Further suitable pharmaceutically acceptable ester-forming groups for the hydroxy group include C1-C 10 Alkanoyl groups, such as acetyl, benzoyl, phenylacetyl, and substituted benzoyl and phenylacetyl groups, C-C 10 Alkoxycarbonyl groups include, for example, ethoxycarbonyl, N,N-(C1-C6 alkyl)2 carbamoyl, 2-dialkylaminoacetyl, and 2-carboxyacetyl. Examples of ring substituents for phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl, and 4-(C1-C4 alkyl)piperazin-1-ylmethyl. Suitable pharmaceutically acceptable ether-forming groups for hydroxy groups include α-acyloxyalkyl groups, for example, acetoxymethyl and pivaloyloxymethyl.

[0794] Suitable pharmaceutically acceptable prodrugs of a compound of any one of the formulae disclosed herein having a carboxy group are, for example, in vivo cleavable amides thereof, e.g., amines, e.g., ammonia, C 1-4Alkylamines, such as methylamine, (C1-C4 alkyl)2 amines, such as dimethylamine, N-ethyl-N-methylamine, or diethylamine, C1-C4 alkoxy-C2-C4 alkylamines, such as 2-methoxyethylamine, phenyl-C1-C4 alkylamines, such as benzylamine, and amides formed with amino acids, such as glycine, or esters thereof.

[0795] It is understood that a compound of any one of the formulas disclosed herein, wherein R3 is not H, can be used as a prodrug of the corresponding compound where R3 is H. For example, a compound of any one of the formulas disclosed herein, wherein R is C-C alkyl, C-C alkenyl, or C-C alkynyl; and the C-C alkyl, C-C alkenyl, or C-C alkynyl can be selected from one or more of C-C alkyl, C-C alkenyl, C-C alkynyl, C-C cycloalkyl, C-C aryl, 5- or 6-membered heteroaryl, C-C heterocycloalkyl, C-C haloalkyl, —O(C-C alkyl), —O(C-C haloalkyl), halo, —CN, —OH, —NH, —NH(C-C alkyl), —N(C-C alkyl), oxo, or R 3S Compounds optionally substituted with can be used as prodrugs of the corresponding compounds where R3 is H.

[0796] Suitable pharmaceutically acceptable prodrugs of compounds of any one of the formulae disclosed herein having an amino group are, for example, in vivo cleavable amide derivatives thereof. Suitable pharmaceutically acceptable amides derived from an amino group include, for example, C1-C2 acetyl groups, such as acetyl, benzoyl, phenylacetyl, and substituted benzoyl and phenylacetyl groups. 10Examples of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl, and 4-(C1-C4 alkyl)piperazin-1-ylmethyl.

[0797] The in vivo effects of a compound of any one of the formulas disclosed herein may be mediated in part by one or more metabolic products formed in the human or animal body after administration of a compound of any one of the formulas disclosed herein. As noted above, the in vivo effects of a compound of any one of the formulas disclosed herein may also be mediated by metabolism of a precursor compound (prodrug).

[0798] Preferably, the present disclosure excludes any individual compound that does not exhibit biological activity as defined herein.

[0799] Synthesis method In some aspects, the disclosure provides methods of preparing the compounds of the disclosure.

[0800] In some aspects, the disclosure provides methods of preparing compounds comprising one or more steps described herein.

[0801] In some aspects, the disclosure provides compounds that can be obtained by, are obtained by, or are obtained directly from the processes for preparing the compounds described herein.

[0802] In some aspects, the present disclosure provides intermediates described herein that are suitable for use in the methods for preparing the compounds described herein.

[0803] The compounds of the present disclosure can be prepared by any suitable technique known in the art. Specific methods for the preparation of these compounds are further illustrated in the Examples below.

[0804] In describing the synthetic methods described herein, and any referenced synthetic methods used to prepare starting materials, it is understood that one of ordinary skill in the art can select all proposed reaction conditions, including the choice of solvents, reaction atmospheres, reaction temperatures, experimental times, and work-up procedures.

[0805] One skilled in the art of organic synthesis understands that the functionality present on various portions of the molecule must be compatible with the reagents and reaction conditions employed.

[0806] It is recognized that during the synthesis of compounds of the present disclosure in the methods defined herein, or during the synthesis of certain starting materials, it may be desirable to protect certain substituents to prevent their undesired reactions. Experienced chemists will know when such protection is necessary and how these protecting groups can be placed and subsequently 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 removal of the protecting group in question, the protecting group can be removed, as appropriate, by methods described in the literature or by any convenient method known to experienced chemists, which are selected to perform the removal of the protecting group while minimizing interference with groups elsewhere in the molecule. Thus, when a reactant contains a group such as amino, carboxy, or hydroxy, it may be desirable to protect the group in some of the reactions described herein.

[0807] For example, suitable protecting groups for amino or alkylamino groups include, for example, acyl groups, such as alkanoyl groups, for example, acetyl; alkoxycarbonyl groups, for example, methoxycarbonyl, ethoxycarbonyl, or t-butoxycarbonyl; arylmethoxycarbonyl groups, for example, benzyloxycarbonyl; or aroyl groups, for example, benzoyl. The deprotection conditions for the above-mentioned protecting groups necessarily vary with the selection of the protecting group. Thus, for example, acyl groups, such as alkanoyl groups, alkoxycarbonyl groups, or aroyl groups, can be removed by hydrolysis with a suitable base, such as an alkali metal hydroxide, for example, lithium hydroxide or sodium hydroxide. Alternatively, an acyl group such as a tert-butoxycarbonyl group may be removed by treatment with a suitable acid, for example, hydrochloric acid, sulfuric acid, or phosphoric acid, or trifluoroacetic acid, and an arylmethoxycarbonyl group, for example a benzyloxycarbonyl group, may be removed by hydrogenation over a catalyst such as palladium on carbon, or by treatment with a Lewis acid, for example borontris(trifluoroacetate).A suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group, which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or hydrazine.

[0808] Suitable protecting groups for hydroxy groups include, for example, acyl groups, such as alkanoyl groups, e.g., acetyl, aroyl groups, e.g., benzoyl, or arylmethyl groups, e.g., benzyl. The deprotection conditions for the above-mentioned protecting groups necessarily vary with the choice of protecting group. Thus, for example, acyl groups, such as alkanoyl or aroyl groups, can be removed by hydrolysis with a suitable base, such as an alkali metal hydroxide, e.g., lithium hydroxide, sodium hydroxide, or ammonia. Alternatively, arylmethyl groups, such as benzyl groups, can be removed by hydrogenation over a catalyst, e.g., palladium on carbon.

[0809] A suitable protecting group for a carboxy group is, for example, an esterifying group such as a methyl or ethyl group which may be removed, for example, by hydrolysis with a base such as sodium hydroxide, or, for example, a tert-butyl group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or, for example, a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium on carbon.

[0810] When a compound of formula (I) is synthesized by any one of the methods defined herein, the process may further comprise the further steps of: (i) removing any protecting groups present; (ii) converting the compound of formula (I) to another compound of formula (I); (iii) forming a pharmaceutically acceptable salt, hydrate, or solvate thereof; and / or (iv) forming a prodrug thereof.

[0811] The resulting compound of formula (I) can be isolated and purified using techniques well known in the art.

[0812] The reaction of the compounds is advantageously carried out in the presence of a suitable solvent, which is preferably inert under the respective reaction conditions. Examples of suitable solvents include hydrocarbons such as hexane, petroleum ether, benzene, toluene, or xylene; chlorinated hydrocarbons such as trichloroethylene, 1,2-dichloroethane, tetrachloromethane, 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; glycols such as methyl methyl ether (MLME), methyl tert-butyl ether (MTBE), or dioxane; 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.

[0813] The reaction temperature is preferably about -100°C to 300°C, depending on the reaction step and conditions used.

[0814] Generally, the reaction time ranges from less than 1 minute to several days, depending on the reactivity of each compound and the 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 reaction temperatures described above, suitable reaction times generally range from 10 minutes to 48 hours.

[0815] Moreover, by utilizing the procedures described herein, in combination with ordinary skill in the art, additional compounds of the present disclosure can be readily prepared. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds.

[0816] As those skilled in the art of organic synthesis will understand, the compounds of the present disclosure are readily accessible via a variety of synthetic routes, some of which are illustrated in the examples below. Those skilled in the art will readily recognize what types of reagents and reaction conditions should be used in any particular case, whenever necessary or useful, to obtain the compounds of the present disclosure, as well as how to utilize and apply them. Furthermore, by reacting other compounds of the present disclosure under suitable conditions, applying standard synthetic methods well known to those skilled in the art, such as reduction, oxidation, addition, or substitution reactions, one specific functional group present in the compounds of the present disclosure or a suitable precursor molecule thereof can be easily converted to another functional group to synthesize some of the compounds of the present disclosure. Similarly, those skilled in the art will utilize synthetic protecting groups (protective groups) whenever necessary or useful. Suitable protecting groups and methods for introducing and removing them are well known to those skilled in the art of chemical synthesis and are described in more detail, for example, in PGM Wuts, TW Greene, "Greene's Protective Groups in Organic Synthesis," 4th edition (2006) (John Wiley & Sons).

[0817] General routes for the preparation of compounds of the present application are illustrated in Schemes 1-6 herein.

[0818] Scheme 1 TIFF0007661248000154.tif20128 Compound 1a (R2 substituent containing an aldehyde or ketone functional group) is reacted with compound 1b in a solvent (e.g., dichloromethane) in the presence of a reducing agent (e.g., sodium triacetoxyborohydride) and, optionally, an acid catalyst (e.g., acetic acid) to produce compound 1c.

[0819] Scheme 2 TIFF0007661248000155.tif21128 Compound 2a is reacted with compound 2b (R3 substituent where X is a leaving group such as bromide, iodide, or mesylate) in the presence of a base (e.g., sodium tert-butoxide or cesium carbonate), a precatalyst (e.g., tris(dibenzylideneacetone)dipalladium(0)), and a ligand (e.g., 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl) in a solvent (e.g., toluene or 1,4-dioxane) at elevated temperature (e.g., 100°C) to produce compound 2c.

[0820] Scheme 3 TIFF0007661248000156.tif23128 Compound 3a is reacted with compound 3b in the presence of a solvent (e.g., dichloromethane) containing a base (e.g., triethylamine), and optionally at a low temperature (e.g., 0°C) to produce compound 3c.

[0821] Scheme 4 TIFF0007661248000157.tif22128 Compound 4a is reacted with an acid (e.g., hydrochloric acid or trifluoroacetic acid) in a suitable solvent (e.g., dichloromethane, 1,4-dioxane, or ethyl acetate), and optionally at a low temperature (e.g., 0°C), to produce compound 4b.

[0822] Scheme 5 TIFF0007661248000158.tif17128 Compound 5a is reacted with a suitable isocyanate-forming reagent (e.g., diphosgene or triphosgene) in a solvent (e.g., dichloromethane or 1,4-dioxane), and optionally in the presence of a base (e.g., triethylamine), to produce compound 5b.

[0823] Scheme 6 TIFF0007661248000159.tif25128 Compound 6a is reacted with compound 6b in a solvent (e.g., tetrahydrofuran) in the presence of a base (e.g., sodium hydroxide or sodium hydride), and optionally at a low temperature (e.g., 0°C) to produce compound 6c.

[0824] Biological assays Once generated, compounds designed, selected, and / or optimized using the methods described above can be characterized using a variety of assays known to those of skill in the art to determine whether the compounds have biological activity. For example, molecules can be characterized using conventional assays, including but not limited to, the assays described below, to determine whether they have the expected activity, binding activity, and / or binding specificity.

[0825] Furthermore, high-throughput screening can be used to speed up analysis using these assays. As a result, it is 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. High-throughput assays can use one or more different assay techniques, including, but not limited to, those described below.

[0826] A variety of in vitro or in vivo biological assays may be suitable for detecting the effects of the compounds of the present disclosure, including, but not limited to, enzyme activity assays, electrophoretic mobility shift assays, reporter gene assays, in vitro cell viability assays, and assays described herein.

[0827] In some embodiments, compounds of the present disclosure may be tested for inhibitory activity in various cell lines (e.g., peripheral blood mononuclear cells). In some embodiments, compounds of the present disclosure may be tested for inhibitory activity in peripheral blood mononuclear cells. In some embodiments, compounds of the present disclosure may be tested for their inhibitory activity against IL-1β release upon NLRP3 activation.

[0828] In some embodiments, the PBMC IC 50 Determinant assays may be used to characterize the compounds of the present disclosure.

[0829] PBMCs can be isolated, seeded into wells of a plate, and incubated with sugars. Following a medium change, a compound of the present disclosure can be added to the wells and incubated. The cells can be stimulated, and the cell culture medium can be collected for analysis.

[0830] PBMCs can be separated by density gradient centrifugation, seeded into wells of a plate, and incubated with sugars. Compounds of the present disclosure can be added to the wells and incubated. Cells can be stimulated, and cell culture medium can be collected for analysis.

[0831] 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).

[0832] In some embodiments, IL-1β release can be determined using Homogenous Time-Resolved Fluorescence (HTRF®) for quantitative detection of IL-1β. A microplate spectrophotometer can be used to detect the signal (e.g., at 655 nm and 620 nm).

[0833] In some embodiments, the biological assays are those described in the Examples herein.

[0834] Pharmaceutical Composition In some aspects, the present disclosure provides pharmaceutical compositions comprising a compound of the present disclosure as an active ingredient. In some embodiments, the present disclosure provides pharmaceutical compositions 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 pharmaceutical compositions comprising at least one compound selected from Table 1.

[0835] As used herein, the term "composition" is intended to include a product comprising the specified ingredients in the specified amounts, and any product obtained, directly or indirectly, by combining the specified ingredients in the specified amounts.

[0836] The compounds of the present disclosure can be formulated for oral administration in forms such as tablets, capsules (all including sustained or time-release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups, emulsions, and the like. 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, all using forms well known to those of ordinary skill in the pharmaceutical arts.

[0837] The formulation of the present disclosure may be in the form of an aqueous solution containing an aqueous vehicle. The aqueous vehicle component may include water and at least one pharmaceutically acceptable excipient. Suitable acceptable excipients include those selected from the group consisting of solubility enhancers, chelating agents, preservatives, tonicity agents, viscosity adjusters / suspending agents, buffers, and pH adjusters, and mixtures thereof.

[0838] Any suitable solubility enhancer can be used. Exemplary solubility enhancers include cyclodextrins such as cyclodextrins selected from the group consisting of hydroxypropyl-β-cyclodextrin, methyl-β-cyclodextrin, randomly methylated-β-cyclodextrin, ethylated-β-cyclodextrin, triacetyl-β-cyclodextrin, peracetylated-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 mixtures thereof.

[0839] Any suitable chelating agent may be used, examples of suitable chelating agents include those selected from the group consisting of ethylenediaminetetraacetic acid and its metal salts, edetate disodium, edetate trisodium, and edetate tetrasodium, and mixtures thereof.

[0840] Any suitable preservative may be used, including, for example, a preservative selected from the group consisting of quaternary ammonium salts such as benzalkonium halides (preferably benzalkonium chloride), chlorhexidine gluconate, benzethonium chloride, cetylpyridinium chloride, benzyl bromide, phenylmercuric nitrate, phenylmercuric acetate, phenylmercuric neodecanoate, merthiolate, 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.

[0841] The aqueous vehicle may contain a tonicity agent to adjust the tonicity (osmotic pressure), which may 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.

[0842] The aqueous vehicle may also contain a viscosity modifier / suspending agent. Suitable viscosity modifiers / suspending agents include those selected from the group consisting of cellulose derivatives such as methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, polyethylene glycols (e.g., polyethylene glycol 300, polyethylene glycol 400), carboxymethyl cellulose, hydroxypropyl methyl cellulose, and crosslinked acrylic acid polymers (carbomers), such as acrylic acid polymers crosslinked with polyalkenyl ethers or divinyl glycols (Carbopols, such as Carbopol 934, Carbopol 934P, Carbopol 971, Carbopol 974, and Carbopol 974P), and mixtures thereof.

[0843] To adjust the formulation to an acceptable pH (generally, a 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. Typically, the pH adjuster is a mineral acid or a metal hydroxide base, selected from the group consisting of potassium hydroxide, sodium hydroxide, and hydrochloric acid, and mixtures thereof, preferably sodium hydroxide and / or hydrochloric acid. The addition of these acidic and / or basic pH adjusters adjusts the formulation to a target acceptable pH range. Therefore, it is not always necessary to use both an acid and a base. Depending on the formulation, adding either an acid or a base may be sufficient to adjust the mixture to the desired pH range.

[0844] The aqueous vehicle may also contain a buffer to stabilize the pH. If 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 a salt thereof, including disodium tetraborate), citrate buffers (e.g., citric acid or a salt thereof, including sodium citrate), and ε-aminocaproic acid, and mixtures thereof.

[0845] The formulation may further comprise a wetting agent. A suitable class of wetting agents is one 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.

[0846] Oral compositions generally contain an inert diluent or a pharmaceutically acceptable edible carrier. Oral compositions can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with an excipient and used in the form of tablets, lozenges, or capsules. Oral compositions for use as mouthwashes can also be prepared using fluid carriers. For use as mouthwashes, oral compositions can be prepared using fluid carriers, and the fluid carrier containing the compound is orally applied, then rinsed and expectorated or swallowed. Pharmaceutically compatible binders and / or adjuvants can be included as part of the composition. Tablets, pills, capsules, troches and the like may contain any of the following ingredients: a binder such as microcrystalline cellulose, gum tragacanth, or gelatin; an excipient such as starch or lactose; a disintegrating agent such as alginic acid, Primogel, or cornstarch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetener such as sucrose or saccharin; or a flavoring such as peppermint, methyl salicylate, or orange flavor, or compounds of a similar nature.

[0847] According to a further aspect of the present disclosure, there is provided a pharmaceutical composition comprising a compound of the present disclosure as defined above, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, in combination with a pharmaceutically acceptable diluent or carrier.

[0848] Compositions of the disclosure may 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), a form suitable for topical use (e.g., creams, ointments, gels, or aqueous or oily solutions or suspensions), a form suitable for inhaled administration (e.g., finely divided powders or liquid aerosols), a form suitable for insufflation administration (e.g., finely divided powders), or a form suitable for parenteral administration (e.g., sterile aqueous or oily solutions for intravenous, subcutaneous, intramuscular, intraperitoneal, or intramuscular administration, or a suppository for rectal administration).

[0849] The compositions of the present disclosure can be obtained by conventional procedures using conventional pharmaceutical excipients that are well known in the art. Thus, compositions intended for oral use may contain, for example, one or more coloring agents, sweeteners, flavoring agents, and / or preservatives.

[0850] An effective amount of a compound of the present disclosure for use in therapy is an amount sufficient to treat or prevent, slow the progression of, and / or alleviate the symptoms associated with an inflammasome-associated condition described herein.

[0851] An effective amount of a compound of the present disclosure used for treatment is an amount sufficient to treat, slow the progression of, and / or alleviate the symptoms associated with an inflammasome-associated condition described herein.

[0852] The size of a therapeutic or prophylactic dose of a compound of formula (I) will, of course, vary according to well-known medical principles depending on the nature and severity of the condition, the age and sex of the animal or patient, and the route of administration.

[0853] How to 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.

[0854] In some aspects, the present disclosure provides a method of treating or preventing a disease or disorder disclosed herein 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.

[0855] In some aspects, the present disclosure provides a method of treating a disease or disorder disclosed herein 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.

[0856] In some embodiments, the disease or disorder is associated with inflammasome activity. In some embodiments, the disease or disorder is a disease or disorder in which inflammasome activity is implicated.

[0857] In some embodiments, the disease or disorder is an inflammatory disorder, an autoinflammatory disorder, an autoimmune disorder, a neurodegenerative disease, or cancer.

[0858] In some embodiments, the disease or disorder is an inflammatory disorder, an autoinflammatory disorder, and / or an autoimmune disorder.

[0859] In some embodiments, the disease or disorder is selected from cryopyrin-associated autoinflammatory syndromes (CAPS; e.g., familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), chronic infantile neurological, cutaneous, and 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).

[0860] In some embodiments, the disease or disorder is a neurodegenerative disease.

[0861] In some embodiments, the disease or disorder is Parkinson's disease or Alzheimer's disease.

[0862] In some embodiments, the disease or disorder is a skin disease.

[0863] In some embodiments, the skin disease is acne.

[0864] In some embodiments, the disease or disorder is cancer.

[0865] In some embodiments, the cancer is metastatic cancer, gastrointestinal cancer, skin cancer, non-small cell lung cancer, brain cancer (e.g., glioblastoma), or colon adenocarcinoma.

[0866] In some aspects, the present disclosure provides a method of treating or preventing an autoinflammatory disorder, an autoimmune disorder, a neurodegenerative disease, or cancer 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.

[0867] In some aspects, the present disclosure provides a method of treating an autoinflammatory disorder, an autoimmune disorder, a neurodegenerative disease, or cancer 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.

[0868] In some aspects, the present disclosure provides a method for treating cryopyrin-associated autoinflammatory syndromes (CAPS; e.g., familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), chronic infantile neurological 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 pulmonary disease (COPD), chronic pulmonary disease (COPD), chronic pulmonary arthritis (CPD), chronic pulmonary disease ... and a method of treating or preventing an inflammatory, autoinflammatory, and / or autoimmune disorder selected from neuroinflammation occurring in 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.

[0869] In some aspects, the present disclosure provides a method for treating cryopyrin-associated autoinflammatory syndromes (CAPS; e.g., familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), chronic infantile neurological 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), and other conditions. and a method of treating an inflammatory, autoinflammatory, and / or autoimmune disorder selected from neuroinflammation occurring in 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.

[0870] In some aspects, the present disclosure provides a method of treating or preventing a neurodegenerative disease (e.g., Parkinson's disease or Alzheimer's disease) 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.

[0871] In some aspects, the present disclosure provides a method of treating a neurodegenerative disease (e.g., Parkinson's disease or Alzheimer's disease) 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.

[0872] In some aspects, the present disclosure provides a method of treating or preventing cancer 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.

[0873] In some aspects, the present disclosure provides a method of treating cancer 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.

[0874] In some aspects, 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).

[0875] In some aspects, 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.

[0876] In some aspects, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in treating a disease or disorder disclosed herein.

[0877] In some aspects, 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.

[0878] In some aspects, 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.

[0879] In some aspects, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in treating or preventing an inflammatory, autoinflammatory, and / or autoimmune disorder selected from cryopyrin-associated autoinflammatory syndromes (CAPS; e.g., familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), chronic infantile neurological, cutaneous, and 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.

[0880] In some aspects, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in treating an inflammatory, autoinflammatory, and / or autoimmune disorder selected from cryopyrin-associated autoinflammatory syndromes (CAPS; e.g., familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), chronic infantile neurological, cutaneous, and 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.

[0881] In some aspects, 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.

[0882] In some aspects, 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.

[0883] In some aspects, 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.

[0884] In some aspects, 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.

[0885] In some aspects, 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).

[0886] In some aspects, the disclosure provides the use of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein.

[0887] In some aspects, 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 disease or disorder disclosed herein.

[0888] In some aspects, the present disclosure provides 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.

[0889] In some aspects, the present disclosure provides 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.

[0890] In some aspects, the present disclosure provides 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, autoinflammatory, and / or autoimmune disorder selected from cryopyrin-associated autoinflammatory syndromes (CAPS; e.g., familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), chronic infantile neurological, cutaneous, and 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.

[0891] In some aspects, the present disclosure provides use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating an inflammatory, autoinflammatory, and / or autoimmune disorder selected from cryopyrin-associated autoinflammatory syndromes (CAPS; e.g., familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), chronic infantile neurological, cutaneous, and 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.

[0892] In some aspects, the present disclosure provides 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.

[0893] In some aspects, 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 neurodegenerative disease (e.g., Parkinson's disease or Alzheimer's disease) in a subject in need thereof.

[0894] In some aspects, the disclosure provides the use of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing cancer in a subject in need thereof.

[0895] In some aspects, the disclosure provides the use of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating cancer in a subject in need thereof.

[0896] The present disclosure provides compounds that function as inhibitors of inflammasome activity. Accordingly, the present disclosure provides a method for inhibiting inflammasome activity in vitro or in vivo, comprising contacting a cell with an effective amount of a compound as defined herein or a pharmaceutically acceptable salt thereof.

[0897] The efficacy of the compounds of the present disclosure can be determined in industry-accepted assays / disease models according to standard practices for determining such efficacy as described in the art and recognized in the current general knowledge.

[0898] The present disclosure also provides a method of treating a disease or disorder involving inflammasome activity in a subject in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0899] At a general level, compounds of the present disclosure that inhibit the maturation of cytokines of the IL-1 family are effective in all therapeutic indications that mediate or are associated with increased levels of active forms of cytokines belonging to the IL-1 family of cytokines (Sims J. et al. Nature Reviews Immunology 10, 89-102 (February 2010)).

[0900] Exemplary diseases and corresponding references are listed below: inflammatory, autoinflammatory, and autoimmune diseases such as CAPS (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 (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), such as 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.

[0901] The compounds of the present disclosure can be suitably used to treat a disease selected from the group consisting of inflammatory diseases, autoinflammatory diseases, autoimmune diseases, neurodegenerative diseases, and cancer, including cryopyrin-associated autoinflammatory syndromes (CAPS, e.g., familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), chronic infantile neurological, cutaneous, and articular (CINCA) syndrome / neonatal-onset multisystem inflammatory disease (NOMID)), familial Mediterranean fever (FMF), nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), chronic kidney disease (CKD), gout, rheumatoid arthritis, osteoarthritis, Crohn's disease, COPD, fibrosis, obesity, type 2 diabetes, multiple sclerosis, skin diseases (e.g., acne), and neuroinflammation occurring in protein misfolding diseases such as prion diseases. Such neurodegenerative diseases include, but are not limited to, Parkinson's disease and Alzheimer's disease.

[0902] Thus, the compounds of the present disclosure can be used to treat a disease selected from the group consisting of cryopyrin-associated autoinflammatory syndromes (CAPS, e.g., familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), chronic infantile neurological, cutaneous, and 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 (e.g., acne), and neuroinflammation occurring in protein misfolding diseases such as prion diseases, neurodegenerative diseases (e.g., Parkinson's disease, Alzheimer's disease), and oncological disorders.

[0903] Cancer treatment: Linking inflammasomes It has long been recognized that chronic inflammatory responses are associated with various types of cancer. During malignant transformation or cancer treatment, inflammasomes can become activated in response to danger signals, and this activation can be either beneficial or detrimental in cancer.

[0904] IL-1β expression is elevated in various cancers (such as breast cancer, prostate cancer, colon cancer, lung cancer, head and neck cancer, and melanoma), and patients with IL-1β-producing tumors generally have a relatively poor prognosis (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).

[0905] Cancers derived from epithelial cells (carcinomas) or glandular epithelium (adenocarcinomas) are heterogeneous and comprise numerous different cell types. These may include fibroblasts, immune cells, adipocytes, endothelial cells, and pericytes, among others, all of which may secrete cytokines and chemokines (Grivennikov, Sergei I., Florian R. Greten, and Michael Karin. “Immunity, inflammation, and cancer.” Cell 140.6 (2010): 883-899). This leads to cancer-associated inflammation through immune cell infiltration. While the presence of leukocytes in tumors is known, it has only recently become clear that an inflammatory microenvironment is an essential component of all tumors. Most tumors (over 90%) are the result of somatic mutations or environmental factors rather than germline mutations, and many environmental causes of cancer are related to chronic inflammation (20% of cancers are related to chronic infections, 30% to smoking / inhaled pollutants, and 35% to dietary factors (20% of all cancers are related to obesity)) (Aggarwal, Bharat B., RV 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).

[0906] Gastrointestinal 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 may 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).

[0907] In 19% of gastric cancer cases, caspase-1 expression is decreased, which correlates with stage, lymph node metastasis, and survival time (Jee et al., 2005). Mycoplasma hyorhinis is associated with the development of gastric cancer, and activation of the NLRP3 inflammasome therein may be related to the promotion of gastric cancer metastasis (Xu et al., 2013).

[0908] skin cancer Ultraviolet radiation is the greatest environmental risk for skin cancer, which is promoted by DNA damage, immunosuppression, and inflammation. Melanoma, the most aggressive form of skin cancer, is characterized by upregulation of inflammatory cytokines that can 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 in vivo induces enhanced metastasis and proliferation of melanoma cells through IL-1-dependent mechanisms. Using thymoquinone, inhibition of metastasis in the B16F10 mouse melanoma model was shown to depend on 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).

[0909] Glioblastoma NLRP3 contributes to radiotherapy resistance in gliomas. Ionizing radiation can upregulate NLRP3, and NLRP3 inhibition suppresses tumor growth and prolongs mouse survival after radiation therapy. Therefore, NLRP3 inflammasome inhibition may be a therapeutic strategy for radioresistant 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).

[0910] metastasis More broadly, the applicants believe that NLRP3 is involved in promoting metastasis, and therefore, modulation of NLRP3 should likely 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).

[0911] The IL-1 gene is often expressed in metastases in patients with several types of human cancer. For example, IL-1 mRNA was highly expressed in more than half of all metastatic human tumor samples tested, including tumor samples from non-small cell lung cancer, colon 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 exhibit antiproliferative effects in vitro.

[0912] Furthermore, IL-1 signaling is a biomarker for predicting breast cancer patients at high risk for developing bone metastasis. In mouse models, IL-1β and its receptors are upregulated in breast cancer cells that metastasize to bone compared with cells that do not. In mouse models, the IL-1 receptor antagonist anakinra reduced bone metabolism markers IL-1β and TNFα, thereby significantly affecting the tumor environment, as well as suppressing proliferation and angiogenesis (Holen, Ingunn, et al. "IL-1 drives breast cancer growth and bone metastasis in vivo." Oncotarget (2016)).

[0913] IL-18 induced the production of MMP-9 in the human leukemia cell line HL-60, promoting extracellular matrix degradation and cancer cell migration and invasion (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 support the development of tumor metastasis in the liver by inducing VCAM-1 expression on the hepatic sinusoidal endothelium (Carrascal, Maria Teresa, et al. "Interleukin-18 binding protein reduces b16 melanoma hepatic metastasis by neutralizing adhesion and growth factors of sinusoidal endothelium." Cancer Research 63.2 (2003): 491-497).

[0914] CD36 The fatty acid scavenger receptor CD36 plays a dual role: priming the gene transcription of pro-IL-1β and inducing the assembly of the NLRP3 inflammasome complex. CD36 and TLR4-TLR6 heterodimer recognize oxLDL, which initiates a signaling pathway leading to transcriptional upregulation of NLRP3 and pro-IL-1β (signal 1). CD36 also mediates the internalization of oxLDL into the lysosomal compartment, where it forms crystals that induce lysosomal rupture and NLRP3 inflammasome activation (signal 2) (Kagan, J. and Horng T., "NLRP3 inflammasome activation: CD36 serves double duty." Nature Immunology 14.8 (2013): 772-774).

[0915] A subpopulation of human oral cancer cells expressing high levels of the fatty acid scavenger receptor CD36 is unique in its ability to initiate metastasis. Palmitic acid or a high-fat diet enhanced the transcriptional potential of CD36+ cells. Neutralizing anti-CD36 antibodies blocked metastasis in an orthotopic mouse model of human oral cancer. The presence of CD36+ metastasis-initiating cells correlates with poor prognosis in numerous cancer types. 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).

[0916] In hepatocellular carcinoma, exogenous palmitic acid activated an epithelial-mesenchymal transition (EMT)-like program and induced migration, which was inhibited by sulfo-N-succinimidyl 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)). Body mass index was not associated with the degree of EMT, highlighting that CD36 and free fatty acids are actually important.

[0917] Cancer stem cells (CSCs) use CD36 to promote their maintenance. In glioblastoma, oxidized phospholipids, which are CD36 ligands, are present, and exposure to oxidized LDL promoted the proliferation of CSCs, but not non-CSCs. Furthermore, CD36 expression correlated with patient prognosis.

[0918] Chemotherapy resistance In addition to their direct cytotoxic effects, chemotherapeutic agents exploit the host immune system to contribute to their antitumor activity. However, gemcitabine and 5-FU have been shown to activate NLRP3 in myeloid-derived suppressor cells, resulting in the production of IL-1β, which reduces their antitumor efficacy. Mechanistically, these agents activate NLRP3 by destabilizing lysosomes and releasing cathepsin B. IL-1β stimulates the production of IL-17 from CD4+ T cells, and IL-17 attenuates the efficacy of chemotherapy. When tumors were established in NLRP3- / - or Caps1- / - mice or wild-type mice treated with IL-1RA, both gemcitabine and 5-FU exhibited relatively high antitumor efficacy. Therefore, 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.). Therefore, the compounds of the present disclosure may be useful in chemotherapy for treating a range of cancers.

[0919] The compounds of the present disclosure, or pharmaceutically acceptable salts thereof, may be administered alone as monotherapy or in combination with one or more other substances and / or therapeutic agents, which may be achieved by simultaneous, sequential or separate administration of the individual components of the treatment.

[0920] For example, administration of an adjunct agent may improve therapeutic efficacy (i.e., an adjunct agent may have minimal therapeutic effect on its own, but in combination with another therapeutic agent, improves the overall therapeutic effect on the individual). Alternatively, by way of example only, administration of a compound of formula (I) with another therapeutic agent (including a treatment regimen) that also has a therapeutic effect may enhance the effect experienced by an individual.

[0921] When the compound of the present disclosure is administered in combination with other therapeutic agents, the compound of the present disclosure does not need to be administered by the same route as the other therapeutic agents, and can be administered by different routes due to different physical and chemical properties.For example, the compound of the present disclosure can be administered orally to generate and maintain a good blood level, while the other therapeutic agents can be administered intravenously.The initial administration can be carried out according to a predetermined protocol known in the art, and then the dosage, administration mode and administration time can be adjusted by a specialist based on the observed effect.

[0922] The selection of other specific therapeutic agents will depend on the diagnosis of the attending physician and their judgment regarding the individual's condition and the appropriate treatment protocol. According to this aspect of the disclosure, there is provided a combination for use in treating a disease involving inflammasome activity, the combination comprising a compound of the disclosure, as defined above, or a pharmaceutically acceptable salt thereof, and another suitable agent.

[0923] 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, in combination with a suitable pharmaceutically acceptable diluent or carrier.

[0924] In addition to their use in therapeutic medicine, the compounds of formula (I), and their pharmaceutically acceptable salts, are also useful as pharmacological tools in the development and standardization of in vitro and in vivo test systems, i.e., as tools for assessing the effects of inflammasome inhibitors in laboratory animals such as dogs, rabbits, monkeys, rats, and mice, as part of the search for new therapeutic agents.

[0925] Any of the above-described pharmaceutical composition, process, method, use, pharmaceutical, and manufacturing features of the present disclosure also apply to any of the alternative embodiments of the polymers of the present disclosure described herein.

[0926] Administration route The compounds of the present disclosure or pharmaceutical compositions containing these compounds may be administered to a subject by any convenient route of administration, whether systemic / peripheral or local (ie, at the site of the desired effect).

[0927] Routes of administration include, but are not limited to, oral (e.g., ingestion), buccal, sublingual, transdermal (including, e.g., patches, plasters, etc.), transmucosal (including, e.g., patches, plasters, etc.), intranasal (e.g., nasal drops), intraocular (e.g., eye drops), intrapulmonary (e.g., by inhalation or insufflation therapy (e.g., using an aerosol, e.g., through the mouth or nose)), rectal (e.g., suppository or enema), intravaginal (e.g., pessary), parenteral, e.g., by injection, e.g., subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, and intrasternal injection, and by implantation of a depot or reservoir, e.g., subcutaneous or intramuscular implantation.

[0928] Illustrative Embodiments Embodiment 1: Formula (I): TIFF0007661248000160.tif21128, or a prodrug, solvate, or pharmaceutically acceptable salt thereof, wherein: R1 is one or more R 1S is a 5- to 12-membered heterocycloalkyl or 5- to 12-membered heteroaryl optionally substituted with Each R 1S are independently C1-C6 alkyl, C1-C6 haloalkyl, -O(C1-C6 alkyl), -O(C1-C6 haloalkyl), -(C1-C6 alkyl)-O(C1-C6 alkyl), cyano, halo, C3-C8 cycloalkyl, C3-C8 aryl, 3- to 8-membered heterocycloalkyl, or 3- to 8-membered heteroaryl; R2 is -(CX2X2) n -R 2Swherein n is 0, 1, or 2, and each X2 is independently H, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, wherein said C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is optionally substituted with one or more halo, —CN, —OH, —O(C1-C6 alkyl), —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, or oxo; R 2S is C1-C6 alkyl, C3-C 16 cycloalkyl, or 4-8 membered heterocycloalkyl, and the C1-C6 alkyl, C3-C 16 The cycloalkyl or 4-8 membered heterocycloalkyl may be optionally substituted with one or more C-C alkyl, C-C alkenyl, C-C alkynyl, C-C haloalkyl, halo, -CN, -OH, -O(C-C alkyl), -NH, -NH(C-C alkyl), -N(C-C alkyl), or oxo; and R3 is one or more R 3S and each R is a 5- to 12-membered heterocycloalkyl or a 5- or 6-membered heteroaryl optionally substituted with 3S are independently C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, halo, or C3-C8 heterocycloalkyl, wherein said C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, or C3-C8 heterocycloalkyl is optionally substituted with -O(C1-C6 alkyl), -N(C1-C6 alkyl)2, halo, or -CN, or a prodrug, solvate, or pharmaceutically acceptable salt thereof.

[0929] Embodiment 2: R1 is one or more R 1S is a 5- to 12-membered heterocycloalkyl or 5- to 12-membered heteroaryl optionally substituted with Each R 1Sare independently C1-C6 alkyl, C1-C6 haloalkyl, -O(C1-C6 alkyl), -O(C1-C6 haloalkyl), -(C1-C6 alkyl)-O(C1-C6 alkyl), cyano, halo, C3-C8 cycloalkyl, C3-C8 aryl, 3- to 8-membered heterocycloalkyl, or 3- to 8-membered heteroaryl; R2 is -(CX2X2) n -R 2S wherein n is 0, 1, or 2, and each X2 is independently H, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, wherein said C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is optionally substituted with one or more halo, —CN, —OH, —O(C1-C6 alkyl), —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, or oxo; R 2S is C1-C6 alkyl, C3-C 16 cycloalkyl, or 4-8 membered heterocycloalkyl, and the C1-C6 alkyl, C3-C 16 The cycloalkyl or 4-8 membered heterocycloalkyl may be optionally substituted with one or more C-C alkyl, C-C alkenyl, C-C alkynyl, C-C haloalkyl, halo, -CN, -OH, -O(C-C alkyl), -NH, -NH(C-C alkyl), -N(C-C alkyl), or oxo; and R3 is one or more R 3S and each R is a 7- to 12-membered heterocycloalkyl or a 5- or 6-membered heteroaryl optionally substituted with 3S are independently C-C alkyl, C-C haloalkyl, C-C cycloalkyl, halo, or C-C heterocycloalkyl, wherein said C-C alkyl, C-C haloalkyl, C-C cycloalkyl, or C-C heterocycloalkyl is optionally substituted with —O(C-C alkyl), —N(C-C alkyl), halo, or —CN.

[0930] Embodiment 3: R1 is a 5- to 12-membered heterocycloalkyl or a 5- to 12-membered heteroaryl, wherein at least one heteroatom of said 5- to 12-membered heterocycloalkyl or said 5- to 12-membered heteroaryl is O or S, and said 5- to 12-membered heterocycloalkyl or said 5- to 12-membered heteroaryl is selected from the group consisting of one or more R 1S may be substituted with; Each R 1S is independently C1-C6 alkyl, C1-C6 haloalkyl, —O(C1-C6 alkyl), cyano, halo, C3-C8 cycloalkyl, or C3-C8 aryl; R2 is -(CH2) n -R 2S wherein n is 0, 1, or 2; R 2S is C1-C6 alkyl, C3-C 16 cycloalkyl, or 4-8 membered heterocycloalkyl, and the C1-C6 alkyl, C3-C 16 The cycloalkyl or 4- to 8-membered heterocycloalkyl may be optionally substituted with one or more C1-C6 alkyl, halo, —OH, —O(C1-C6 alkyl), —NH2, —NH(C1-C6 alkyl), or —N(C1-C6 alkyl)2; and

[0023] The compound of any one of the preceding embodiments, wherein R3 is a 5-6 membered heterocycloalkyl or a 5- or 6 membered heteroaryl, wherein said 5-12 membered heterocycloalkyl or 5- or 6 membered heteroaryl is optionally substituted with one or more C1-C6 alkyl, C3-C8 cycloalkyl, or halo.

[0931] Embodiment 4: R1 is a 5- to 12-membered heterocycloalkyl or a 5- to 12-membered heteroaryl, wherein at least one heteroatom of said 5- to 12-membered heterocycloalkyl or said 5- to 12-membered heteroaryl is O or S, and said 5- to 12-membered heterocycloalkyl or said 5- to 12-membered heteroaryl is selected from the group consisting of one or more R 1S may be substituted with; Each R 1S is independently C1-C6 alkyl, C1-C6 haloalkyl, —O(C1-C6 alkyl), cyano, halo, C3-C8 cycloalkyl, or C3-C8 aryl; R2 is -(CH2) n -R 2S where n is 0, 1, or 2; R 2S is C1-C6 alkyl, C3-C 16 cycloalkyl, or 4-8 membered heterocycloalkyl, and the C1-C6 alkyl, C3-C 16 The cycloalkyl or 4- to 8-membered heterocycloalkyl may be optionally substituted with one or more C1-C6 alkyl, halo, —OH, —O(C1-C6 alkyl), —NH2, —NH(C1-C6 alkyl), or —N(C1-C6 alkyl)2; and The compound of any one of the preceding embodiments, wherein R3 is a 5- or 6-membered heteroaryl optionally substituted with one or more C1-C6 alkyl, C3-C8 cycloalkyl, or halo.

[0932] Embodiment 5: R1 is one or more R 1S and at least one heteroatom in said 5-12 membered heteroaryl is S; Each R 1S is independently C1-C6 alkyl, C1-C6 haloalkyl, -O(C1-C6 alkyl), -O(C1-C6 haloalkyl), or halo; R2 is -(CX2X2) n -R 2S wherein n is 0, 1, or 2, and each X2 is independently H, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, wherein said C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is optionally substituted with one or more halo, —CN, —OH, —O(C1-C6 alkyl), —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, or oxo; R 2S is C1-C6 alkyl, C3-C 16 cycloalkyl, or 4-8 membered heterocycloalkyl, and the C1-C6 alkyl, C3-C 16 The cycloalkyl or 4-8 membered heterocycloalkyl may be optionally substituted with one or more C-C alkyl, C-C alkenyl, C-C alkynyl, C-C haloalkyl, halo, -CN, -OH, -O(C-C alkyl), -NH, -NH(C-C alkyl), -N(C-C alkyl), or oxo; and R3 is one or more R 3S and each R is a 7- to 12-membered heterocycloalkyl or a 5- or 6-membered heteroaryl optionally substituted with 3S are independently C-C alkyl, C-C haloalkyl, C-C cycloalkyl, halo, or C-C heterocycloalkyl, wherein said C-C alkyl, C-C haloalkyl, C-C cycloalkyl, or C-C heterocycloalkyl is optionally substituted with -O(C-C alkyl), -N(C-C alkyl), halo, or -CN.

[0933] Embodiment 6: R1 is one or more R 1S and at least one heteroatom in said 5-12 membered heteroaryl is S; Each R 1S is independently C1-C6 alkyl, C1-C6 haloalkyl, -O(C1-C6 alkyl), -O(C1-C6 haloalkyl), or halo; R2 is -(CX2X2) n -R 2Swherein n is 0, 1, or 2, and each X2 is independently H, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, wherein said C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is optionally substituted with one or more halo, —CN, —OH, —O(C1-C6 alkyl), —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, or oxo; R 2S is C1-C6 alkyl, C3-C 16 cycloalkyl, or 4-8 membered heterocycloalkyl, and the C1-C6 alkyl, C3-C 16 The cycloalkyl or 4-8 membered heterocycloalkyl may be optionally substituted with one or more C-C alkyl, C-C alkenyl, C-C alkynyl, C-C haloalkyl, halo, -CN, -OH, -O(C-C alkyl), -NH, -NH(C-C alkyl), -N(C-C alkyl), or oxo; and R3 is one or more R 3S and each R is a 7- to 12-membered heterocycloalkyl or a 5- or 6-membered heteroaryl optionally substituted with 3S are independently C-C alkyl, C-C haloalkyl, C-C cycloalkyl, halo, or C-C heterocycloalkyl, wherein said C-C alkyl, C-C haloalkyl, C-C cycloalkyl, or C-C heterocycloalkyl is optionally substituted with -O(C-C alkyl), -N(C-C alkyl), halo, or -CN.

[0934] Embodiment 7: R1 is one or more R 1S is a 5- to 12-membered heteroaryl optionally substituted with Each R 1S is independently C1-C6 alkyl, C1-C6 haloalkyl, -O(C1-C6 alkyl), -O(C1-C6 haloalkyl), or halo; R2 is -(CX2X2) n -R 2S wherein n is 0, 1, or 2, and each X2 is independently H, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, wherein said C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is optionally substituted with one or more halo, —CN, —OH, —O(C1-C6 alkyl), —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, or oxo; R 2S is a 4-8 membered heterocycloalkyl optionally substituted with one or more C-C alkyl, C-C alkenyl, C-C alkynyl, C-C haloalkyl, halo, -CN, -OH, -O(C-C alkyl), -NH, -NH(C-C alkyl), -N(C-C alkyl) or oxo; and R3 is one or more R 3S and each R is a 7- to 12-membered heterocycloalkyl or a 5- or 6-membered heteroaryl optionally substituted with 3S are independently C-C alkyl, C-C haloalkyl, C-C cycloalkyl, halo, or C-C heterocycloalkyl, wherein said C-C alkyl, C-C haloalkyl, C-C cycloalkyl, or C-C heterocycloalkyl is optionally substituted with -O(C-C alkyl), -N(C-C alkyl), halo, or -CN.

[0935] Embodiment 8: R1 is one or more R 1S a 5- to 12-membered heteroaryl optionally substituted with, said heteroaryl containing at least one S; Each R 1S is independently C1-C6 alkyl, C1-C6 haloalkyl, -O(C1-C6 alkyl), -O(C1-C6 haloalkyl), or halo; R2 is -(CX2X2) n -R 2Swherein n is 0, 1, or 2, and each X2 is independently H, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, wherein said C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is optionally substituted with one or more halo, —CN, —OH, —O(C1-C6 alkyl), —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, or oxo; R 2S is a 4-8 membered heterocycloalkyl optionally substituted with one or more C-C alkyl, C-C alkenyl, C-C alkynyl, C-C haloalkyl, halo, -CN, -OH, -O(C-C alkyl), -NH, -NH(C-C alkyl), -N(C-C alkyl) or oxo; and R3 is one or more R 3S and each R is a 7- to 12-membered heterocycloalkyl or a 5- or 6-membered heteroaryl optionally substituted with 3S are independently C-C alkyl, C-C haloalkyl, C-C cycloalkyl, halo, or C-C heterocycloalkyl, wherein said C-C alkyl, C-C haloalkyl, C-C cycloalkyl, or C-C heterocycloalkyl is optionally substituted with -O(C-C alkyl), -N(C-C alkyl), halo, or -CN.

[0936] Embodiment 9: R1 is one or more R 1S C5-C optionally substituted with 12 is heteroaryl; Each R 1S is independently C1-C6 alkyl, C1-C6 haloalkyl, -O(C1-C6 alkyl), -O(C1-C6 haloalkyl), or halo; R2 is R 2S is; R 2Sis a 4-8 membered heterocycloalkyl optionally substituted with one or more C-C alkyl, C-C alkenyl, C-C alkynyl, C-C haloalkyl, halo, -CN, -OH, -O(C-C alkyl), -NH, -NH(C-C alkyl), -N(C-C alkyl) or oxo; and R3 is one or more R 3S and each R is a 7- to 12-membered heterocycloalkyl or a 5- or 6-membered heteroaryl optionally substituted with 3S are independently C-C alkyl, C-C haloalkyl, C-C cycloalkyl, halo, or C-C heterocycloalkyl, wherein said C-C alkyl, C-C haloalkyl, C-C cycloalkyl, or C-C heterocycloalkyl is optionally substituted with -O(C-C alkyl), -N(C-C alkyl), halo, or -CN.

[0937] Embodiment 10: R1 is thiophenyl or benzothiophenyl, and said thiophenyl or benzothiophenyl is selected from the group consisting of one or more R 1S may be substituted with; Each R 1S is independently C1-C6 alkyl, C1-C6 haloalkyl, -O(C1-C6 alkyl), -O(C1-C6 haloalkyl), or halo; R2 is R 2S is; R 2S is a 4-8 membered heterocycloalkyl optionally substituted with one or more C-C alkyl, C-C alkenyl, C-C alkynyl, C-C haloalkyl, halo, -CN, -OH, -O(C-C alkyl), -NH, -NH(C-C alkyl), -N(C-C alkyl) or oxo; and R3 is one or more R 3S and each R is a 7- to 12-membered heterocycloalkyl or a 5- or 6-membered heteroaryl optionally substituted with3S are independently C-C alkyl, C-C haloalkyl, C-C cycloalkyl, halo, or C-C heterocycloalkyl, wherein said C-C alkyl, C-C haloalkyl, C-C cycloalkyl, or C-C heterocycloalkyl is optionally substituted with -O(C-C alkyl), -N(C-C alkyl), halo, or -CN.

[0938] Embodiment 11: R1 is thiophenyl or benzothiophenyl, and said thiophenyl or benzothiophenyl is selected from the group consisting of one or more R 1S may be substituted with; Each R 1S is C1-C6 alkyl or halo; R2 is R 2S is; R 2S is a 4-8 membered heterocycloalkyl optionally substituted with one or more C-C alkyl, C-C alkenyl, C-C alkynyl, C-C haloalkyl, halo, -CN, -OH, -O(C-C alkyl), -NH, -NH(C-C alkyl), -N(C-C alkyl) or oxo; and R3 is one or more R 3S and each R is a 7- to 12-membered heterocycloalkyl or a 5- or 6-membered heteroaryl optionally substituted with 3S are independently C-C alkyl, C-C haloalkyl, C-C cycloalkyl, halo, or C-C heterocycloalkyl, wherein said C-C alkyl, C-C haloalkyl, C-C cycloalkyl, or C-C heterocycloalkyl is optionally substituted with -O(C-C alkyl), -N(C-C alkyl), halo, or -CN.

[0939] Embodiment 12: R1 is one or more R 1SThe compound of any one of the preceding embodiments, wherein R is a 5-12 membered heterocycloalkyl optionally substituted with R.

[0940] Embodiment 13: R1 is one or more R 1S The compound of any one of the preceding embodiments, wherein the compound is 5,6-dihydro-4H-cyclopenta[b]thiophenyl, optionally substituted with

[0941] Embodiment 14: R1, The compound of any one of the preceding embodiments, wherein the compound is TIFF0007661248000161.tif19128.

[0942] Embodiment 15: R1 is one or more R 1S The compound of any one of the preceding embodiments, wherein R is 5-12 membered heteroaryl optionally substituted with R.

[0943] Embodiment 16: R1 is one or more R 1S wherein R is a 5- to 12-membered heteroaryl optionally substituted with R, and R is attached to the remainder of Formula (I) through a carbon atom of R.

[0944] Embodiment 17: The compound of any one of the preceding embodiments, wherein R1 is a 5-12 membered heteroaryl optionally substituted with one or more C1-C6 alkyl or halo.

[0945] Embodiment 18: R1 is one or more R 1S and the C5-C 12 The compound according to any one of the preceding embodiments, wherein at least one heteroatom in the heteroaryl is S.

[0946] Embodiment 19: R1 is one or more R 1S wherein said C5 monocyclic heteroaryl contains one heteroatom that is O.

[0947] Embodiment 20: R1 is one or more R 1S The compound of any one of the preceding embodiments, wherein N is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63

[0948] Embodiment 21: R1, The compound of any one of the preceding embodiments, wherein the compound is TIFF0007661248000162.tif22128.

[0949] Embodiment 22: R1 is one or more R 1S wherein at least one heteroatom in said C5 monocyclic heteroaryl is S.

[0950] Embodiment 23: R1 is one or more R 1S The compound of any one of the preceding embodiments, wherein R is 1 or 2, and R is 2 or 3.

[0951] Embodiment 24: R1, The compound of any one of the preceding embodiments, wherein the compound is TIFF0007661248000163.tif150170.

[0952] Embodiment 25: R1, TIFF0007661248000164.tif196165TIFF0007661248000165.tif120165.

[0953] Embodiment 26: R1, The compound of any one of the preceding embodiments, wherein the compound is TIFF0007661248000166.tif60165.

[0954] Embodiment 27: R1, The compound of any one of the preceding embodiments, wherein the compound is TIFF0007661248000167.tif24133.

[0955] Embodiment 28: R1, TIFF0007661248000168.tif168165TIFF0007661248000169.tif51170.

[0956] Embodiment 29: R1, The compound of any one of the preceding embodiments, wherein the compound is TIFF0007661248000170.tif29128.

[0957] Embodiment 30: R1, The compound of any one of the preceding embodiments, wherein the compound is TIFF0007661248000171.tif22128.

[0958] Embodiment 31: R1 is one or more R 1S wherein the C5 monocyclic heteroaryl contains two heteroatoms, one heteroatom is S and the other heteroatom is N.

[0959] Embodiment 32: R1 is one or more R 1S The compound according to any one of the preceding embodiments, wherein the compound is thiazolyl optionally substituted with

[0960] Embodiment 33: R1, The compound of any one of the preceding embodiments, wherein the compound is TIFF0007661248000172.tif20128.

[0961] Embodiment 34: R1, The compound of any one of the preceding embodiments, wherein the compound is TIFF0007661248000173.tif23128.

[0962] Embodiment 35: R1 is one or more R 1S The compound according to any one of the preceding embodiments, wherein the compound is isothiazolyl optionally substituted with

[0963] Embodiment 36: R1, The compound of any one of the preceding embodiments, wherein the compound is TIFF0007661248000174.tif26128.

[0964] Embodiment 37: R1, The compound of any one of the preceding embodiments, wherein the compound is TIFF0007661248000175.tif29128.

[0965] Embodiment 38: R1 is one or more R 1S wherein at least one heteroatom in said 9-membered bicyclic heteroaryl is S.

[0966] Embodiment 39: R1 is one or more R 1S The compound of any one of the preceding embodiments, wherein the compound is benzothiophenyl optionally substituted with

[0967] Embodiment 40: R1, The compound of any one of the preceding embodiments, wherein the compound is TIFF0007661248000176.tif26128.

[0968] Embodiment 41: R1, The compound of any one of the preceding embodiments, wherein the compound is TIFF0007661248000177.tif24128.

[0969] Embodiment 42: At least one R 1S

[0023] The compound of any one of the preceding embodiments, wherein is C1-C6 alkyl, C1-C6 haloalkyl, -O(C1-C6 alkyl), -O(C1-C6 haloalkyl), or halo.

[0970] Embodiment 43: At least one R 1S

[0023] The compound of any one of the preceding embodiments, wherein is C1-C6 alkyl or halo.

[0971] Embodiment 44: R2 is R 2S The compound of any one of the preceding embodiments, wherein

[0972] Embodiment 45: R2 is -(CX2) n -R 2S and n is 1 or 2.

[0973] Embodiment 46: R 2Sis a 6-membered heterocycloalkyl optionally substituted with one or more C-C alkyl, C-C alkenyl, C-C alkynyl, C-C haloalkyl, halo, —CN, —OH, —O(C-C alkyl), —NH, —NH(C-C alkyl), —N(C-C alkyl), or oxo.

[0974] Embodiment 47: R 2S is C-C alkyl optionally substituted with one or more C-C alkyl, C-C alkenyl, C-C alkynyl, C-C haloalkyl, halo, —CN, —OH, —O(C-C alkyl), —NH, —NH(C-C alkyl), —N(C-C alkyl) or oxo.

[0975] Embodiment 48: R 2S is a C3-C alkyl group optionally substituted with one or more C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, halo, -CN, -OH, -O(C1-C6 alkyl), -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, or oxo; 16 The compound of any one of the preceding embodiments, wherein the compound is cycloalkyl.

[0976] Embodiment 49: R 2S

[0023] The compound of any one of the preceding embodiments, wherein is a 6-membered heterocycloalkyl optionally substituted with one or more C1-C6 alkyl.

[0977] Embodiment 50: R 2S but, The compound of any one of the preceding embodiments, wherein the compound is TIFF0007661248000178.tif18128.

[0978] Embodiment 51: R2, TIFF0007661248000179.tif183165TIFF0007661248000180.tif60165.

[0979] Embodiment 52: R2, The compound of any one of the preceding embodiments, wherein the compound is TIFF0007661248000181.tif89165.

[0980] Embodiment 53: R2, The compound of any one of the preceding embodiments, wherein the compound is TIFF0007661248000182.tif21128.

[0981] Embodiment 54: R2, The compound of any one of the preceding embodiments, wherein the compound is TIFF0007661248000183.tif20128.

[0982] Embodiment 55: R2, The compound of any one of the preceding embodiments, wherein the compound is TIFF0007661248000184.tif40165.

[0983] Embodiment 56: R2, The compound of any one of the preceding embodiments, wherein the compound is TIFF0007661248000185.tif44165.

[0984] Embodiment 57: R2, The compound of any one of the preceding embodiments, wherein the compound is TIFF0007661248000186.tif18128.

[0985] Embodiment 58: R3 is a 5- to 6-membered heterocycloalkyl or a 5-membered heteroaryl, and the 5- to 6-membered heterocycloalkyl or the 5-membered heteroaryl is selected from the group consisting of one or more R 3S

[0023] The compound of any one of the preceding embodiments, optionally substituted with:

[0986] Embodiment 59: R3 is one or more R 3S The compound of any one of the preceding embodiments, wherein R is a 5-6 membered heterocycloalkyl optionally substituted with R.

[0987] Embodiment 60: R3, The compound of any one of the preceding embodiments, wherein the compound is TIFF0007661248000187.tif19131.

[0988] Embodiment 61: R3 is one or more R 3S The compound of any one of the preceding embodiments, wherein R is 5-membered heteroaryl optionally substituted with R.

[0989] Embodiment 62: R3 is one or more R 3S The compound according to any one of the preceding embodiments, wherein the compound is pyrazolyl optionally substituted with

[0990] Embodiment 63: R3, The compound of any one of the preceding embodiments, wherein the compound is TIFF0007661248000188.tif18132.

[0991] Embodiment 64: R3, The compound of any one of the preceding embodiments, wherein the compound is TIFF0007661248000189.tif12128.

[0992] Embodiment 65: At least one R3S

[0023] The compound of any one of the preceding embodiments, wherein is C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, halo, or C3-C8 heterocycloalkyl.

[0993] Embodiment 66: At least one R 3S is C1-C6 alkyl.

[0994] Embodiment 67; At least one R 3S The compound of an...

Claims

1. below: or a pharma- ceutically acceptable salt thereof, or a deuterium-labeled compound thereof.

2. The compound according to claim 1, selected from compound numbers 1 to 4, 6 to 16, 18 to 29, 32 to 67, 70 to 123, and 125 to 131.

3. The compound according to claim 1, which is a deuterium-labeled compound of any one of compound numbers 1 to 4, 6 to 16, 18 to 29, 32 to 67, 70 to 123, and 125 to 131.

4. 10. A pharmaceutical composition comprising a compound of claim 1 or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable diluent or carrier.

5. 5. The pharmaceutical composition of claim 4 for use in inhibiting inflammasome activity, wherein the inflammasome is the NLRP3 inflammasome and the activity is in vitro or in vivo.

6. 5. The pharmaceutical composition of claim 4 for use in the treatment or prevention of a disease or disorder mediated by NLRP3.

7. Use of the compound described in claim 1 or a pharma- ceutically acceptable salt thereof in the manufacture of a medicament for inhibiting inflammasome activity, wherein the inflammasome is the NLRP3 inflammasome and the activity is in vitro or in vivo.

8. 13. Use of a compound of claim 1, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing a disease or disorder mediated by NLRP3.

9. The pharmaceutical composition of claim 6, wherein the disease or disorder is associated with inflammasome activity mediated by NLRP3.

10. 7. The pharmaceutical composition of claim 6, wherein the disease or disorder is an NLRP3-mediated inflammatory disorder, an NLRP3-mediated autoinflammatory disorder, an NLRP3-mediated autoimmune disorder, an NLRP3-mediated neurodegenerative disease, or an NLRP3-mediated cancer.

11. 11. The pharmaceutical composition of claim 10, wherein the NLRP3-mediated inflammatory disorder, NLRP3-mediated autoinflammatory disorder, or NLRP3-mediated autoimmune disorder is selected from cryopyrin-associated autoinflammatory syndrome (CAPS), familial Mediterranean fever (FMF), nonalcoholic fatty liver disease (NAFLD), nonalcoholic 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.

12. The pharmaceutical composition of claim 10, wherein the neurodegenerative disease mediated by NLRP3 is Parkinson's disease or Alzheimer's disease.

13. The pharmaceutical composition of claim 10, wherein the cancer mediated by NLRP3 is metastatic cancer, brain cancer, gastrointestinal cancer, skin cancer, non-small cell lung cancer, head and neck squamous cell carcinoma, or colorectal adenocarcinoma.

14. The pharmaceutical composition of claim 11, wherein the cryopyrin-associated autoinflammatory syndrome is familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), chronic infantile neurological cutaneous articular (CINCA) syndrome, or neonatal-onset multisystem inflammatory disease (NOMID).

15. The pharmaceutical composition of claim 11, wherein the skin disease is acne.

16. The pharmaceutical composition of claim 11, wherein the protein misfolding disease is a prion disease.

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