NLRP3 modulators

Abstract

Described herein are NLRP3 modulators and methods of using NLRP3 modulators to treat diseases, disorders or conditions. Also described herein are pharmaceutical compositions containing such compounds.

Description

[0001] Cross-references

[0002] This application claims the benefit of U.S. Provisional Application No. 62 / 990,363, filed on March 16, 2020, the entire contents of which are incorporated herein by reference. Background Art

[0003] The NOD-like receptor (NLR) family, porphyrin domain-containing protein 3 (NLRP3) inflammasome is a key component of the innate immune response and inflammatory processes, and its aberrant activity is pathogenic in genetic disorders such as cryopyrin-associated periodic syndrome (CAPS) and complex diseases such as multiple sclerosis, type 2 diabetes, Alzheimer's disease, and atherosclerosis. Current treatments for NLRP3-related diseases include biologics targeting IL-1. Small molecule inhibitors of NLRP3 offer an attractive alternative to these biologics, given their potential to improve safety and patient comfort and compliance. Summary of the invention

[0004] In one aspect, provided herein is a compound of formula (I') or a pharmaceutically acceptable salt or solvate thereof:

[0005]

[0006] in:

[0007] X1 is O, S or N(R3);

[0008] X2 is -N(R4)- or -C(R4)2-;

[0009] X3 is -N(R5)- or -C(R5)2-;

[0010] Y1 is O, S or N(R8);

[0011] Y2 is N or C(R9);

[0012] Z1 is O, S, N(R3) or -C(R 17 )=C(R 17 )-;

[0013] Z2 is N or C (R 19 );

[0014] R1 is

[0015] R2 is

[0016] R3 is hydrogen, -OR 14, -CN, -NO2 or -S(=O)2R 15 ;

[0017] R4 is each independently selected from hydrogen, C1-C6 alkyl, -C1-C6 alkyl-OR7 and -C1-C6 alkyl-N(R7)2;

[0018] R5 is each independently selected from hydrogen, C1-C6 alkyl, -C1-C6 alkyl-OR7 and -C1-C6 alkyl-N(R7)2;

[0019] R6 are each independently selected from C1-C6 alkyl, -C1-C6 alkyl-CO2R 18 , C1-C6 haloalkyl, -C1-C6 alkyl-OR7 and -C1-C6 alkyl-N(R7)2;

[0020] R7 are each independently selected from hydrogen and C1-C6 alkyl;

[0021] R8 is hydrogen, C1-C6 alkyl, -C1-C6 alkyl-OR7, -C1-C6 alkyl-N(R7)2 or C3-C6 cycloalkyl;

[0022] R9 is hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl or C3-C6 cycloalkyl;

[0023] R 10 is hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -C1-C6 alkyl-OR7 or -C1-C6 alkyl-N(R7)2;

[0024] R 11 and R 12 independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -C1-C6 alkyl-OR7 and -C1-C6 alkyl-N(R7)2; or R 11 and R 12 Combine to form a 5- or 6-membered cycloalkyl ring;

[0025] R 13 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C5 cycloalkyl, C2-C9 heterocycloalkyl, phenyl or C2-C9 heteroaryl, wherein C3-C5 cycloalkyl, C2-C9 heterocycloalkyl, phenyl and C2-C9 heteroaryl are optionally substituted by 1, 2, 3 or 4 R 16 replace;

[0026] R 14 is hydrogen or C1-C6 alkyl;

[0027] R 15 is a C1-C6 alkyl group;

[0028] R 16 Each is independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C6 cycloalkyl, C2-C9 heterocycloalkyl, C6-C 10 Aryl, C2-C9 heteroaryl, among which C3-C6 cycloalkyl, C2-C9 heterocycloalkyl, C6-C 10 Aryl, C2-C9 heteroaryl are optionally substituted with 1, 2 or 3 groups selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy and C1-C6 haloalkoxy;

[0029] R 17 Each is independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -C1-C6 alkyl-OR7 and -C1-C6 alkyl-N(R7)2;

[0030] R 18 is hydrogen or C1-C6 alkyl;

[0031] R 19 is hydrogen, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, -C1-C6 alkyl-OR7 or -C1-C6 alkyl-N(R7)2;

[0032] m is 0, 1 or 2;

[0033] n is 1, 2 or 3;

[0034] p is 0, 1, or 2;

[0035] q is 0, 1, 2, 3, or 4;

[0036] s is 1, 2, or 3; and

[0037] t is 1, 2, or 3.

[0038] In another aspect, provided herein is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof:

[0039]

[0040] in:

[0041] X1 is O, S or N(R3);

[0042] X2 is -N(R4)- or -C(R4)2-;

[0043] X3 is -N(R5)- or -C(R5)2-;

[0044] Y1 is O, S or N(R8);

[0045] Y2 is N or C(R9);

[0046] Z1 is O, S, N(R3) or -C(R 17 )=C(R 17 )-;

[0047] Z2 is N or C (R 19 );

[0048] R1 is

[0049] R2 is

[0050] R3 is hydrogen, -OR 14 , -CN, -NO2 or -S(=O)2R 15 ;

[0051] R4 is each independently selected from hydrogen, C1-C6 alkyl, -C1-C6 alkyl-OR7 and -C1-C6 alkyl-N(R7)2;

[0052] R5 is each independently selected from hydrogen, C1-C6 alkyl, -C1-C6 alkyl-OR7 and -C1-C6 alkyl-N(R7)2;

[0053] R6 are each independently selected from C1-C6 alkyl, -C1-C6 alkyl-CO2R 18 , C1-C6 haloalkyl, -C1-C6 alkyl-OR7 and -C1-C6 alkyl-N(R7)2;

[0054] R7 are each independently selected from hydrogen and C1-C6 alkyl;

[0055] R8 is hydrogen, C1-C6 alkyl, -C1-C6 alkyl-OR7, -C1-C6 alkyl-N(R7)2 or C3-C6 cycloalkyl;

[0056] R9 is hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl or C3-C6 cycloalkyl;

[0057] R 10 is hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -C1-C6 alkyl-OR7 or -C1-C6 alkyl-N(R7)2;

[0058] R 11 and R 12 independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, -C1-C6 alkyl-OR7 and -C1-C6 alkyl-N(R7)2; or R 11 and R 12Combine to form a 5- or 6-membered cycloalkyl ring;

[0059] R 13 is phenyl or C2-C9 heteroaryl, wherein phenyl and C2-C9 heteroaryl are optionally substituted by 1, 2, 3 or 4 R 16 replace;

[0060] R 14 is hydrogen or C1-C6 alkyl;

[0061] R 15 is a C1-C6 alkyl group;

[0062] R 16 Each is independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C6 cycloalkyl, C2-C9 heterocycloalkyl, C6-C 10 Aryl, C2-C9 heteroaryl, among which C3-C6 cycloalkyl, C2-C9 heterocycloalkyl, C6-C 10 Aryl, C2-C9 heteroaryl are optionally substituted with 1, 2 or 3 groups selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy and C1-C6 haloalkoxy;

[0063] R 17 Each is independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -C1-C6 alkyl-OR7 and -C1-C6 alkyl-N(R7)2;

[0064] R 18 is hydrogen or C1-C6 alkyl;

[0065] R 19 is hydrogen, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, -C1-C6 alkyl-OR7 or -C1-C6 alkyl-N(R7)2;

[0066] m is 0, 1 or 2;

[0067] n is 1, 2 or 3;

[0068] p is 0, 1, or 2;

[0069] q is 0, 1, 2, 3, or 4;

[0070] s is 1, 2, or 3; and

[0071] t is 1, 2, or 3.

[0072] In some embodiments, it is a compound of formula (I') or (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is In some embodiments, it is a compound of formula (I') or (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is In some embodiments, it is a compound of formula (I') or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Y2 is C(R9). In some embodiments, it is a compound of formula (I') or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R9 is hydrogen or C1-C6 alkyl. In some embodiments, it is a compound of formula (I') or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R9 is hydrogen. In some embodiments, it is a compound of formula (I') or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Y2 is N. In some embodiments, it is a compound of formula (I') or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Y1 is O. In some embodiments, it is a compound of formula (I') or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Y1 is S. In some embodiments, it is a compound of formula (I') or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Y1 is N(R8). In some embodiments, it is a compound of formula (I') or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R8 is hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl. In some embodiments, it is a compound of formula (I') or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R8 is hydrogen. In some embodiments, it is a compound of formula (I') or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R8 is C1-C6 alkyl. In some embodiments, it is a compound of formula (I') or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R8 is C3-C6 cycloalkyl. In some embodiments, it is a compound of formula (I') or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is In some embodiments, it is a compound of formula (I') or (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is In some embodiments, is a compound of Formula (I') or (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 10is hydrogen. In some embodiments, it is a compound of formula (I') or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is each independently selected from C1-C6 alkyl. In some embodiments, it is a compound of formula (I') or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is each -CH3. In some embodiments, it is a compound of formula (I') or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 1. In some embodiments, it is a compound of formula (I') or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 2. In some embodiments, it is a compound of formula (I') or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 3. In some embodiments, it is a compound of formula (I') or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 0. In some embodiments, it is a compound of formula (I') or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2. In some embodiments, it is a compound of formula (I') or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1. In some embodiments, it is a compound of formula (I') or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein m is 1. In some embodiments, it is a compound of formula (I') or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 1. In some embodiments, it is a compound of formula (I') or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is In some embodiments, it is a compound of formula (I') or (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is In some embodiments, it is a compound of formula (I') or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein s is 1. In some embodiments, it is a compound of formula (I') or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein t is 1. In some embodiments, it is a compound of formula (I') or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Z2 is C(R 19 In some embodiments, a compound of formula (I') or (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 19 In some embodiments, a compound of formula (I') or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Z2 is N. In some embodiments, a compound of formula (I') or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is In some embodiments, it is a compound of formula (I') or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Z1 is S. In some embodiments, it is a compound of formula (I') or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Z1 is O. In some embodiments, it is a compound of formula (I') or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Z1 is -C(R 17 )=C(R 17 )-. In some embodiments, it is a compound of formula (I') or (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 17 In some embodiments, a compound of formula (I') or (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 11 and R 12 In some embodiments, a compound of formula (I') or (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 13 is optionally 1, 2, 3 or 4 R 16 In some embodiments, a compound of formula (I') or (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 13 is optionally 1, 2, 3 or 4 R 16 In some embodiments, it is a compound of formula (I') or (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 13 is optionally 1, 2, 3 or 4 R 16 In some embodiments, a compound of formula (I') or (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 16 Each is independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl and C1-C6 alkoxy. In some embodiments, it is a compound of formula (I') or (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 16 Each is a C1-C6 alkoxy group. In some embodiments, it is a compound of formula (I') or (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is In some embodiments, it is a compound of formula (I') or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X2 is -N(R4)-. In some embodiments, it is a compound of formula (I') or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is each hydrogen. In some embodiments, it is a compound of formula (I') or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X3 is -N(R5)-. In some embodiments, it is a compound of formula (I') or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X is -C(R5)2-. In some embodiments, it is a compound of formula (I') or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is each hydrogen. In some embodiments, it is a compound of formula (I') or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X1 is O.

[0073] In another aspect, described herein is a pharmaceutical composition comprising a compound of formula (I') or (I) or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable excipient.

[0074] In some embodiments, described herein is a method of treating a metabolic disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I') or (I), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, described herein is a method of treating a metabolic disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I') or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein the metabolic disease is selected from type 2 diabetes, atherosclerosis, obesity, and gout.

[0075] In some embodiments, described herein is a method of treating a liver disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I') or (I) or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, described herein is a method of treating a liver disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I') or (I) or a pharmaceutically acceptable salt or solvate thereof, wherein the liver disease is selected from non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis (ASH), viral hepatitis, and cirrhosis.

[0076] In some embodiments, described herein is a method of treating a pulmonary disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I') or (I), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, described herein is a method of treating a pulmonary disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I') or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein the pulmonary disease is selected from asthma, chronic obstructive pulmonary disease (COPD), and idiopathic pulmonary fibrosis.

[0077] In some embodiments, described herein is a method of treating a central nervous system disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I') or (I) or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, described herein is a method of treating a central nervous system disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I') or (I) or a pharmaceutically acceptable salt or solvate thereof, wherein the central nervous system disease is selected from Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis, and Parkinson's disease.

[0078] In some embodiments, described herein is a method of treating an inflammatory or autoimmune disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I') or (I) or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, described herein is a method of treating an inflammatory or autoimmune disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I') or (I) or a pharmaceutically acceptable salt or solvate thereof, wherein the inflammatory or autoimmune disease is selected from rheumatoid arthritis, multiple sclerosis, psoriasis, lupus, inflammatory bowel disease, Crohn's disease, and ulcerative colitis.

[0079] In some embodiments, described herein is a method of treating a cardiovascular disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I') or (I) or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, described herein is a method of treating a cardiovascular disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I') or (I) or a pharmaceutically acceptable salt or solvate thereof, wherein the cardiovascular disease is atherosclerosis or stroke.

[0080] Incorporation by reference

[0081] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. DETAILED DESCRIPTION

[0082] definition

[0083] In the context of this disclosure, a number of terms will be used.

[0084] Unless otherwise limited, all technical and scientific terms used herein have the same meaning as the commonly understood subject matter to which protection is claimed. In the case where a plurality of definitions are provided for the terms herein, the definitions in this section shall prevail. All patents, patent applications, publications and disclosed nucleotide and amino acid sequences (e.g., sequences available in GenBank or other databases) mentioned herein are incorporated herein by reference. In the case of reference URLs or other such identifiers or addresses, it should be understood that such identifiers may change, and specific information on the Internet may change back and forth, but equivalent information may be found by searching the Internet. Reference to it proves the availability and public dissemination of such information.

[0085] It should be understood that the foregoing general description and the following detailed description are merely exemplary and explanatory and are not limitations on any subject matter claimed. In this application, unless otherwise specifically stated, the use of the singular includes the plural. It must be noted that the singular forms "a, an" and "the" used in this specification and the appended claims include plural referents unless the context clearly indicates otherwise. In this application, unless otherwise stated, the use of "or" means "and / or". In addition, the use of the term "including" and other forms, such as "include, include, included" are not restrictive.

[0086] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0087] Definitions of standard chemical terms may be found in reference works including, but not limited to, Carey and Sundberg "Advanced Organic Chemistry 4th Edition" Volume A (2000) and Volume B (2001), Plenum Press, New York. Unless otherwise indicated, conventional methods of mass spectroscopy, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques, and pharmacology are used.

[0088] Unless specific definitions are provided, the nomenclature and laboratory procedures and techniques used in connection with analytical chemistry, synthetic organic chemistry, and medicine and pharmaceutical chemistry as described herein are those recognized in the art. Standard techniques can be used for chemical synthesis, chemical analysis, drug preparation, formulation and delivery, and treatment of patients. Standard techniques can be used for recombinant DNA, oligonucleotide synthesis, and tissue culture and transformation (e.g., electroporation, lipofection). Reaction and purification techniques can be performed, for example, using a kit of manufacturer's specifications or as generally implemented in the art or as described herein. The above techniques and procedures can be performed generally with conventional methods and as described in various general and more specific references cited and discussed in this specification.

[0089] It should be understood that the methods and compositions described herein are not limited to the specific methods, protocols, cell lines, constructs and reagents described herein, and can therefore vary. It should also be understood that the terms used herein are only used for the purpose of describing specific embodiments and are not intended to limit the scope of the methods, compounds, compositions described herein.

[0090] As used herein, C1-C x Including C1-C2, C1-C3...C1-C x C1-C x refers to the number of carbon atoms that make up the designated moiety (excluding optional substituents).

[0091] "Alkyl" group refers to a straight or branched hydrocarbon chain radical consisting only of carbon and hydrogen atoms that does not contain unsaturation. In some embodiments, an "alkyl" group may have 1 to 6 carbon atoms (whenever it occurs in this article, a numerical range such as "1 to 6" refers to each integer in a given range; for example, "1 to 6 carbon atoms" refers to an alkyl group that can be composed of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 6 carbon atoms, but this definition also covers the occurrence of the term "alkyl" where a numerical range is not specified). The alkyl group of the compound described herein may be designated as "C1-C6 alkyl" or a similar name. As an example only, "C1-C6 alkyl" means that there are 1-6 carbon atoms in the alkyl chain, that is, the alkyl chain is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl and hexyl. The alkyl group may be substituted or unsubstituted. Depending on the structure, the alkyl group may be a monovalent radical or a divalent radical (i.e., alkylene).

[0092] "Alkoxy" refers to an "-O-alkyl" group where alkyl is as defined herein.

[0093] The term "alkenyl" refers to a straight or branched hydrocarbon chain radical group consisting only of carbon and hydrogen atoms, containing at least one carbon-carbon double bond. Non-limiting examples of alkenyl groups include -CH=CH2, -C(CH3)=CH2, -CH=CHCH3, -CH=C(CH3)2 and -C(CH3)=CHCH3. In some embodiments, the alkenyl group may have 2 to 6 carbons. The alkenyl group may be substituted or unsubstituted. Depending on the structure, the alkenyl group may be a monovalent radical or a divalent radical (i.e., an alkenylene group).

[0094] The term "alkynyl" refers to a straight or branched hydrocarbon chain radical group consisting only of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond. Non-limiting examples of alkynyl groups include -C≡CH, -C≡CCH3, -C≡CCH2CH3 and -C≡CCH2CH2CH3. In some embodiments, the alkynyl group may have 2 to 6 carbons. The alkynyl group may be substituted or unsubstituted. Depending on the structure, the alkynyl group may be a monovalent radical or a divalent radical (i.e., an alkynylene group).

[0095] "Amino" refers to the -NH2 group.

[0096] The term "alkylamine" or "alkylamino" refers to an -N(alkyl) x H y A group wherein alkyl is as defined herein and x and y are selected from the group consisting of x=1, y=1 and x=2, y=0. When x=2, the alkyl group together with the nitrogen to which it is attached may optionally form a cyclic ring system. A "dialkylamino" group refers to a -N(alkyl)2 group wherein alkyl is as defined herein.

[0097] The term "aromatic" refers to a planar ring having a delocalized π-electron system containing 4n+2π electrons, where n is an integer. An aromatic ring can be formed by five, six, seven, eight, nine or more than nine atoms. Aromatic compounds can be optionally substituted. The term "aromatic" includes both aryl groups (e.g., phenyl, naphthyl) and heteroaryl groups (e.g., pyridyl, quinolyl).

[0098] As used herein, the term "aryl" refers to an aromatic ring in which each atom forming the ring is a carbon atom. The aryl ring can be formed by five, six, seven, eight, nine or more than nine carbon atoms. The aryl group can be optionally substituted. Examples of aryl groups include, but are not limited to, phenyl and naphthyl. Depending on the structure, the aryl group can be a monovalent radical or a divalent radical (i.e., an arylene group).

[0099] "Carboxy" refers to -CO2H. In some embodiments, the carboxyl moiety can be replaced by a "carboxylic acid bioisostere", which refers to a functional group or moiety that exhibits physical and / or chemical properties similar to a carboxylic acid moiety. Carboxylic acid bioisosteres have biological properties similar to carboxylic acid groups. Compounds having a carboxylic acid moiety can exchange the carboxylic acid moiety with a carboxylic acid bioisostere and have similar physical and / or biological properties when compared to carboxylic acid-containing compounds. For example, in one embodiment, the carboxylic acid bioisostere ionizes at physiological pH to approximately the same extent as the carboxylic acid group. Examples of bioisosteres of carboxylic acids include, but are not limited to wait.

[0100] The term "cycloalkyl" refers to a monocyclic or polycyclic non-aromatic radical in which each atom (i.e., backbone atom) forming the ring is a carbon atom. The cycloalkyl group may be saturated or partially unsaturated. The cycloalkyl group may be fused to an aromatic ring (in this case, the cycloalkyl group is bonded to a non-aromatic ring carbon atom). In some embodiments, the cycloalkyl group includes a group having from 3 to 10 ring atoms.

[0101] The term "heteroaryl" or alternatively "heteroaromatic" refers to an aryl group containing one or more ring heteroatoms selected from nitrogen, oxygen and sulfur. An N-containing "heteroaromatic" or "heteroaryl" moiety refers to an aromatic group in which at least one of the backbone atoms of the ring is a nitrogen atom.

[0102] A "heterocycloalkyl" group or a "heteroalicyclic" group refers to a cycloalkyl group in which at least one backbone ring atom is a heteroatom selected from nitrogen, oxygen and sulfur. The radical may be fused to an aryl or heteroaryl group. The term heteroalicyclic also includes all ring forms of carbohydrates, including but not limited to monosaccharides, disaccharides and oligosaccharides. Unless otherwise indicated, heterocycloalkyl has from 2 to 10 carbons in the ring. It should be understood that when referring to the number of carbon atoms in heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is different from the total number of atoms (i.e., the backbone atoms of the heterocycloalkyl ring) (including heteroatoms) constituting the heterocycloalkyl.

[0103] The term "halo" or alternatively "halogen" refers to fluorine, chlorine, bromine and iodine.

[0104] The term "haloalkyl" refers to an alkyl group substituted with one or more halogens. The halogens may be the same or they may be different. Non-limiting examples of haloalkyl include -CH2Cl, -CF3, -CHF2, -CH2CF3, -CF2CF3, etc.

[0105] The terms "fluoroalkyl" and "fluoroalkoxy" include alkyl and alkoxy groups substituted with one or more fluorine atoms, respectively. Non-limiting examples of fluoroalkyl groups include -CF3, -CHF2, -CH2F, -CH2CF3, -CF2CF3, -CF2CF2CF3, -CF(CH3)3, etc. Non-limiting examples of fluoroalkoxy groups include -OCF3, -OCHF2, -OCH2F, -OCH2CF3, -OCF2CF3, -OCF2CF2CF3, -OCF(CH3)2, etc.

[0106] The term "heteroalkyl" refers to an alkyl radical in which one or more backbone chain atoms are selected from atoms other than carbon (e.g., oxygen, nitrogen, sulfur, phosphorus, silicon, or a combination thereof). The heteroatom may be located at any internal position of the heteroalkyl group. Examples include, but are not limited to, -CH2-O-CH3, -CH2-CH2-O-CH3, -CH2-NH-CH3, -CH2-CH2-NH-CH3, -CH2-N(CH3)-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH2-S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH2-NH-OCH3, -CH2-O-Si(CH3)3, -CH2-CH=N-OCH3, and -CH=CH-N(CH3)-CH3. In addition, up to two heteroatoms may be consecutive, for example, -CH2-NH-OCH3 and -CH2-O-Si(CH3)3. In addition to the number of heteroatoms, a "heteroalkyl" group may have from 1 to 6 carbon atoms.

[0107] The term "bond" or "single bond" refers to a chemical bond between two atoms or between two moieties when the atoms connected by the bond are considered part of a larger substructure.

[0108] The term "moiety" refers to a specific fragment or functional group of a molecule. A chemical moiety is generally a recognized chemical entity embedded in or appended to a molecule.

[0109] As used herein, the substituent "R" appearing by itself and without a numerical designation refers to a substituent selected from alkyl, haloalkyl, heteroalkyl, alkenyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon), and heterocycloalkyl.

[0110] "Optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not.

[0111] The term "optionally substituted" or "substituted" means that the referenced group may be substituted with one or more additional groups selected from alkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, -OH, alkoxy, aryloxy, alkylthio, arylthio, alkyl sulfoxide, aryl sulfoxide, alkyl sulfone, aryl sulfone, -CN, alkyne, C1-C6 alkylalkyne, halo, acyl, acyloxy, -CO2H, -CO2-alkyl, nitro, haloalkyl, fluoroalkyl, and amino (including mono- and di-substituted amino groups (e.g., -NH2, -NHR, -N(R)2)) and protected derivatives thereof. For example, the optional substituent may be L s R s , where L s each independently selected from a bond, -O-, -C(=O)-, -S-, -S(=O)-, -S(=O)2-, -NH-, -NHC(O)-, -C(O)NH-, S(=O)2NH-, -NHS(=O)2, -OC(O)NH-, -NHC(O)O-, -(C1-C6 alkyl)-, or -(C2-C6 alkenyl)-; and R s Each is independently selected from H, (C1-C6 alkyl), (C3-C8 cycloalkyl), aryl, heteroaryl, heterocycloalkyl and C1-C6 heteroalkyl. Protecting groups that can form protective derivatives of the above substituents are found in sources such as Greene and Wuts above.

[0112] As used herein, the term "about" or "approximately" means within 20%, preferably within 10%, and more preferably within 5% of a given value or range.

[0113] As used herein, the term "therapeutically effective amount" refers to an amount of a NLRP3 inhibitor that is effective to at least partially improve or at least partially prevent conditions associated with skin aging when administered to a mammal in need thereof.

[0114] As used herein, the term "expression" includes the process by which a polynucleotide is transcribed into mRNA and translated into a peptide, polypeptide or protein.

[0115] The term "modulate" includes decreasing or increasing the activity or expression of a target molecule.

[0116] The term "activator" is used in this specification to denote any molecular species that results in activation of a given receptor, regardless of whether the species itself binds to the receptor when the species is topically administered or a metabolite of the species binds to the receptor. Thus, an activator may be a ligand for a receptor, or it may be an activator that is metabolized to a ligand for a receptor (i.e., a metabolite that is formed in tissue and is the actual ligand).

[0117] The term "patient" or "mammal" refers to a human, non-human primate, dog, cat, cow, sheep, pig, mouse or other veterinary or laboratory mammal. Those skilled in the art recognize that a therapy that reduces the severity of a pathology in one mammal may predict the efficacy of the therapy in another mammalian species.

[0118] "Pharmaceutically acceptable salts" include both acid addition salts and base addition salts. Pharmaceutically acceptable salts of any of the compounds described herein are intended to encompass any and all pharmaceutically suitable salt forms. Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0119] "Pharmaceutically acceptable acid addition salts" refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the like. Also included are salts formed with organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, and the like, including, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Thus, exemplary salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, octanoates, isobutyrates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, etc. Also contemplated are salts of amino acids, such as arginates, gluconates, and galacturonates (see, e.g., Berge SM et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 66: 1-19 (1997)). The acid addition salts of basic compounds are prepared by contacting the free base form with a sufficient amount of the desired acid to produce the salt.

[0120] "Pharmaceutically acceptable base addition salts" refers to those salts which retain the biological effectiveness and properties of the free acid and are not biologically or otherwise undesirable. These salts are prepared by adding an inorganic base or an organic base to the free acid. In some embodiments, pharmaceutically acceptable base addition salts are formed with metals or amines, such as alkali metals and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts, aluminum salts, and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, N,N-dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, N-methylglucamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like. See Berge et al., supra.

[0121] As used herein, "treatment," "treating," or "palliating," or "ameliorating" are used interchangeably herein. These terms refer to methods of obtaining beneficial or desired results, including but not limited to therapeutic benefit and / or preventive benefit. "Therapeutic benefit" refers to the eradication or amelioration of the underlying condition being treated. In addition, a therapeutic benefit is achieved by eradication or amelioration of one or more physiological symptoms associated with the underlying condition, such that an improvement is observed in the patient, even though the patient still suffers from the underlying condition. For preventive benefit, the composition is administered to a patient at risk of developing a particular disease, or to a patient reporting one or more physiological symptoms of a disease, even if a diagnosis of the disease has not yet been made.

[0122] NLRP3 modulators

[0123] NLRP3 is an intracellular signaling molecule that senses many pathogen-derived, environmental-derived, and host-derived factors. Upon activation, NLRP3 binds to apoptosis-associated speck-like proteins containing caspase activation and recruitment domains (ASC). ASC then polymerizes to form large aggregates called ASC specks.

[0124] Aggregated ASC binds to the cysteine ​​protease caspase-1 to form a complex called inflammasome. This leads to the activation of active caspase-1, which cleaves the precursor forms of the proinflammatory cytokines IL-1β and IL-18 (respectively called pro-IL-ιβ and pro-IL-18), thereby activating these cytokines. Caspase-1 also mediates a type of inflammatory cell death called pyroptosis. ASC speckle aggregates can recruit and activate caspase-8, which can process pro-IL-ιβ and pro-IL-18 and trigger apoptotic cell death.

[0125] Caspase-1 cleaves pro-IL-ιβ and pro-IL-18 into their active forms, which are secreted from cells. Active caspase-1 also cleaves gasdermin-D to trigger cell pyroptosis. Caspase-1 also mediates the release of alarmin molecules such as IL-33 and high mobility group box 1 protein (HMGB1) through its control of focal cell death pathways. Caspase-1 also cleaves intracellular IL-1R2, causing its degradation and allowing the release of IL-1α. In human cells, caspase-1 can also control the processing and secretion of IL-37. Many other caspase-i substrates such as components of the cytoskeleton and glycolytic pathways can lead to caspase-I-dependent inflammation.

[0126] NLRP3-dependent ASC specks are released into the extracellular environment, where they can activate caspase-1, induce processing of caspase-1 substrates, and propagate inflammation. Active cytokines derived from NLRP3 inflammasome activation are important drivers of inflammation and interact with other cytokine pathways to shape the immune response to infection and injury. For example, IL-ιβ signaling induces the secretion of proinflammatory cytokines IL-6 and TNF. IL-1β and IL-18 synergize with IL-23 to induce memory CD4 Th17 cells and γδ T cells to produce IL-17 in the absence of T cell receptor engagement. IL-18 and IL-12 also synergize to induce IFN-γ production by memory T cells and NK cells that drive Th1 responses.

[0127] The inherited CAPS diseases Muckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), and neonatal-onset multisystem inflammatory disease (NOMID) are all caused by gain-of-function mutations in NLRP3, defining NLRP3 as a key component of the inflammatory process. NLRP3 is also implicated in the pathogenesis of many complex diseases, including metabolic disorders such as type 2 diabetes, atherosclerosis, obesity, and gout, among others.

[0128] The role of NLRP3 in central nervous system diseases is emerging, and lung diseases have also been shown to be affected by NLRP3. In addition, NLRP3 plays a role in the development of liver disease, kidney disease and aging. Many of these associations were defined using NLRP3 KO mice, but insights into the specific activation of NLRP3 in these diseases have also been gained. In type 2 diabetes (T2D), deposition of amylin in the pancreas activates NLRP3 and IL-ιβ signaling, leading to cell death and inflammation.

[0129] Current treatments for NLRP3-related diseases include biologics that target IL-1. These are the recombinant IL-1 receptor antagonist anakinra, the neutralizing IL-1β antibody canakinumab, and the soluble decoy IL1 receptor rilonacept. These approaches have proven successful in treating CAPS, and these biologics have been used in clinical trials for other IL-1β-related diseases. Small molecule inhibitors of NLRP3 offer an attractive alternative to these biologics, given their potential to improve safety (minimal risk of infection and ease of withdrawal compared with biologics) and patient comfort and compliance.

[0130] The compounds of formula (I'), (I) or (Ia) described herein are NLRP3 modulators. The compounds of formula (I'), (I) or (Ia) described herein and compositions comprising these compounds can be used to treat NLRP3-related diseases, including but not limited to type 2 diabetes, atherosclerosis, obesity and gout.

[0131] In some embodiments, provided herein is a compound of formula (I') or a pharmaceutically acceptable salt or solvate thereof:

[0132]

[0133] in:

[0134] X1 is O, S or N(R3);

[0135] X2 is -N(R4)- or -C(R4)2-;

[0136] X3 is -N(R5)- or -C(R5)2-;

[0137] Y1 is O, S or N(R8);

[0138] Y2 is N or C(R9);

[0139] Z1 is O, S, N(R3) or -C(R 17 )=C(R 17 )-;

[0140] Z2 is N or C (R 19 );

[0141] R1 is

[0142] R2 is

[0143] R3 is hydrogen, -OR 14 , -CN, -NO2 or -S(=O)2R 15 ;

[0144] R4 is each independently selected from hydrogen, C1-C6 alkyl, -C1-C6 alkyl-OR7 and -C1-C6 alkyl-N(R7)2;

[0145] R5 is each independently selected from hydrogen, C1-C6 alkyl, -C1-C6 alkyl-OR7 and -C1-C6 alkyl-N(R7)2;

[0146] R6 are each independently selected from C1-C6 alkyl, -C1-C6 alkyl-CO2R 18 , C1-C6 haloalkyl, -C1-C6 alkyl-OR7 and -C1-C6 alkyl-N(R7)2;

[0147] R7 are each independently selected from hydrogen and C1-C6 alkyl;

[0148] R8 is hydrogen, C1-C6 alkyl, -C1-C6 alkyl-OR7, -C1-C6 alkyl-N(R7)2 or C3-C6 cycloalkyl;

[0149] R9 is hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl or C3-C6 cycloalkyl;

[0150] R 10 is hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -C1-C6 alkyl-OR7 or -C1-C6 alkyl-N(R7)2;

[0151] R 11 and R 12independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -C1-C6 alkyl-OR7 and -C1-C6 alkyl-N(R7)2; or R 11 and R 12 Combine to form a 5- or 6-membered cycloalkyl ring;

[0152] R 13 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C5 cycloalkyl, C2-C9 heterocycloalkyl, phenyl or C2-C9 heteroaryl, wherein C3-C5 cycloalkyl, C2-C9 heterocycloalkyl, phenyl and C2-C9 heteroaryl are optionally substituted by 1, 2, 3 or 4 R 16 replace;

[0153] R 14 is hydrogen or C1-C6 alkyl;

[0154] R 15 is a C1-C6 alkyl group;

[0155] R 16 Each is independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C6 cycloalkyl, C2-C9 heterocycloalkyl, C6-C 10 Aryl, C2-C9 heteroaryl, among which C3-C6 cycloalkyl, C2-C9 heterocycloalkyl, C6-C 10 Aryl, C2-C9 heteroaryl are optionally substituted with 1, 2 or 3 groups selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy and C1-C6 haloalkoxy;

[0156] R 17 Each is independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -C1-C6 alkyl-OR7 and -C1-C6 alkyl-N(R7)2;

[0157] R 18 is hydrogen or C1-C6 alkyl;

[0158] R 19 is hydrogen, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, -C1-C6 alkyl-OR7 or -C1-C6 alkyl-N(R7)2;

[0159] m is 0, 1 or 2;

[0160] n is 1, 2 or 3;

[0161] p is 0, 1, or 2;

[0162] q is 0, 1, 2, 3, or 4;

[0163] s is 1, 2, or 3; and

[0164] t is 1, 2, or 3.

[0165] In some embodiments, is a compound of formula (I') or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is In some embodiments, is a compound of formula (I') or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is In some embodiments, is a compound of formula (I') or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is In some embodiments, is a compound of formula (I') or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is In some embodiments, is a compound of formula (I') or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is

[0166] In some embodiments, it is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein m is 1. In some embodiments, it is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein m is 0. In some embodiments, it is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein m is 2.

[0167] In some embodiments, it is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 1. In some embodiments, it is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 0. In some embodiments, it is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 2.

[0168] In some embodiments is a compound of Formula (I') or a pharmaceutically acceptable salt or solvate thereof, wherein m is 1 and p is 1.

[0169] In some embodiments, it is a compound of formula (I') or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is independently selected from -C1-C6 alkyl, -C1-C6 alkyl-CO2R 18 , C1-C6 haloalkyl and C1-C6 heteroalkyl. In some embodiments, a compound of formula (I') or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is independently selected from C1-C6 alkyl, -C1-C6 alkyl-CO2R 18and C1-C6 haloalkyl. In some embodiments, it is a compound of formula (I') or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is independently selected from C1-C6 alkyl. In some embodiments, it is a compound of formula (I') or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is each -CH3.

[0170] In some embodiments, provided herein is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 0, 1, 2, or 3. In some embodiments, provided herein is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 0. In some embodiments, provided herein is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 1. In some embodiments, provided herein is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 2. In some embodiments, provided herein is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 3. In some embodiments, provided herein is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 4.

[0171] In some embodiments, is a compound of formula (I') or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is

[0172] In some embodiments, provided herein is a compound of formula (I') or a pharmaceutically acceptable salt or solvate thereof, wherein Y1 is O. In some embodiments, provided herein is a compound of formula (I') or a pharmaceutically acceptable salt or solvate thereof, wherein Y1 is S. In some embodiments, provided herein is a compound of formula (I') or a pharmaceutically acceptable salt or solvate thereof, wherein Y1 is N(R8). In some embodiments, provided herein is a compound of formula (I') or a pharmaceutically acceptable salt or solvate thereof, wherein Y1 is N(R8) and R8 is hydrogen or C1-C6 alkyl.

[0173] In some embodiments, provided herein is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein Y2 is N. In some embodiments, provided herein is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein Y2 is C(R9). In some embodiments, provided herein is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein Y2 is C(R9) and R9 is selected from hydrogen and C1-C6 alkyl. In some embodiments, provided herein is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein Y2 is C(R9) and R9 is hydrogen. In some embodiments, provided herein is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein Y2 is C(R9) and R9 is C1-C6 alkyl.

[0174] In some embodiments, the present invention provides a compound of formula (I') or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is In some embodiments, the present invention provides a compound of formula (I') or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is In some embodiments, the present invention provides a compound of formula (I') or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is In some embodiments, the present invention provides a compound of formula (I') or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is In some embodiments, the present invention provides a compound of formula (I') or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is In some embodiments, the present invention provides a compound of formula (I') or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is In some embodiments, the present invention provides a compound of formula (I') or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is In some embodiments, the present invention provides a compound of formula (I') or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is In some embodiments, the present invention provides a compound of formula (I') or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is In some embodiments, the present invention provides a compound of formula (I') or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is

[0175] In some embodiments, provided herein is a compound of formula (I') or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is In some embodiments, provided herein is a compound of formula (I') or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is s is 1 and t is 1. In some embodiments, provided herein is a compound of formula (I') or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is s is 1, t is 1 and Z2 is C(R 19 In some embodiments, the present invention provides a compound of formula (I') or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is s is 1, t is 1 and Z2 is C(H). In some embodiments, provided herein is a compound of formula (I') or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is s is 1, t is 1 and Z2 is N.

[0176] In some embodiments, provided herein is a compound of formula (I') or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is In some embodiments, provided herein is a compound of formula (I') or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is s is 1 and t is 1. In some embodiments, provided herein is a compound of formula (I') or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is s is 1, t is 1 and Z2 is C(R 19 In some embodiments, the present invention provides a compound of formula (I') or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is s is 1, t is 1 and Z2 is C(H). In some embodiments, provided herein is a compound of formula (I') or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is s is 1, t is 1 and Z2 is N.

[0177] In some embodiments, provided herein is a compound of formula (I') or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is In some embodiments, provided herein is a compound of formula (I') or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is and Z1 is S. In some embodiments, provided herein is a compound of formula (I') or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is and Z1 is -C(R 17 )=C(R 17 In some embodiments, provided herein are compounds of formula (I') or pharmaceutically acceptable salts or solvates thereof, wherein R2 is Z1 is -C(R 17 )=C(R 17 )-, and R 17 Each is independently selected from hydrogen and halogen. In some embodiments, provided herein is a compound of formula (I') or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is and Z1 is -C(H)=C(H)-. In some embodiments, provided herein is a compound of formula (I') or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is And R 11 and R 12 In some embodiments, the present invention provides a compound of formula (I') or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is And R 11 and R 12 In some embodiments, the present invention provides a compound of formula (I') or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is And R 11 and R 12 is independently selected from hydrogen, halogen and C1-C6 alkyl. In some embodiments, the present invention provides a compound of formula (I') or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is And R 13 1, 2 or 3 R 16 In some embodiments, the present invention provides a compound of formula (I') or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is And R 13 Optional 1 or 2 R 16 In some embodiments, the present invention provides a compound of formula (I') or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is R 13 Optional 1 or 2 R 16 substituted pyridyl, and R 16 Each is independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl and C1-C6 alkoxy. In some embodiments, the present invention provides a compound of formula (I') or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is R 13 For optional use of 1 R 16 substituted pyridyl, and R 16is selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl and C1-C6 alkoxy. In some embodiments, provided herein is a compound of formula (I') or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is R 13 For optional use of 1 R 16 substituted pyridyl, and R 16 In some embodiments, the present invention provides a compound of formula (I') or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is And R 13 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C5 cycloalkyl or C2-C9 heterocycloalkyl. In some embodiments, provided herein is a compound of formula (I') or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is And R 13 In some embodiments, the present invention provides a compound of formula (I') or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is And R 13 In some embodiments, the present invention provides a compound of formula (I') or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is And R 13 It is a C3-C5 cycloalkyl group.

[0178] In some embodiments, provided herein is a compound of formula (I') or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is In some embodiments, provided herein is a compound of formula (I') or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is In some embodiments, provided herein is a compound of formula (I') or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is In some embodiments, provided herein is a compound of formula (I') or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is In some embodiments, provided herein is a compound of formula (I') or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is In some embodiments, provided herein is a compound of formula (I') or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is In some embodiments, provided herein is a compound of formula (I') or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is In some embodiments, provided herein is a compound of formula (I') or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is In some embodiments, provided herein is a compound of formula (I') or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is In some embodiments, provided herein is a compound of formula (I') or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is

[0179] In some embodiments, provided herein is a compound of formula (I') or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is

[0180] In some embodiments, provided herein is a compound of formula (I') or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is

[0181] In some embodiments, provided herein is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein X2 is -N(R5)-. In some embodiments, provided herein is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein X2 is -N(R5)- and R5 is hydrogen. In some embodiments, provided herein is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein X2 is -N(R5)- and R5 is C1-C6 alkyl. In some embodiments, provided herein is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein X2 is -C(R5)2-. In some embodiments, provided herein is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein X2 is -C(R5)2- and R5 is each hydrogen.

[0182] In some embodiments, provided herein is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein X3 is -N(R5)-. In some embodiments, provided herein is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein X3 is -N(R5)- and R5 is hydrogen. In some embodiments, provided herein is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein X3 is -N(R5)- and R5 is C1-C6 alkyl. In some embodiments, provided herein is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein X3 is -C(R5)2-. In some embodiments, provided herein is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein X3 is -C(R5)2- and R5 is each hydrogen.

[0183] In some embodiments, provided herein is a compound of formula (I') or a pharmaceutically acceptable salt or solvate thereof, wherein X1 is O. In some embodiments, provided herein is a compound of formula (I') or a pharmaceutically acceptable salt or solvate thereof, wherein X1 is S. In some embodiments, provided herein is a compound of formula (I') or a pharmaceutically acceptable salt or solvate thereof, wherein X1 is N(R3). In some embodiments, provided herein is a compound of formula (I') or a pharmaceutically acceptable salt or solvate thereof, wherein X1 is C(NO2)(R4).

[0184] In some embodiments, provided herein is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof:

[0185]

[0186] in:

[0187] X1 is O, S or N(R3);

[0188] X2 is -N(R4)- or -C(R4)2-;

[0189] X3 is -N(R5)- or -C(R5)2-;

[0190] Y1 is O, S or N(R8);

[0191] Y2 is N or C(R9);

[0192] Z1 is O, S, N(R3) or -C(R 17 )=C(R 17 )-;

[0193] Z2 is N or C (R 19 );

[0194] R1 is

[0195] R2 is

[0196] R3 is hydrogen, -OR 14 , -CN, -NO2 or -S(=O)2R 15 ;

[0197] R4 is each independently selected from hydrogen, C1-C6 alkyl, -C1-C6 alkyl-OR7 and -C1-C6 alkyl-N(R7)2;

[0198] R5 is each independently selected from hydrogen, C1-C6 alkyl, -C1-C6 alkyl-OR7 and -C1-C6 alkyl-N(R7)2;

[0199] R6 are each independently selected from C1-C6 alkyl, -C1-C6 alkyl-CO2R 18 , C1-C6 haloalkyl, -C1-C6 alkyl-OR7 and -C1-C6 alkyl-N(R7)2;

[0200] R7 are each independently selected from hydrogen and C1-C6 alkyl;

[0201] R8 is hydrogen, C1-C6 alkyl, -C1-C6 alkyl-OR7, -C1-C6 alkyl-N(R7)2 or C3-C6 cycloalkyl;

[0202] R9 is hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl or C3-C6 cycloalkyl;

[0203] R 10 is hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -C1-C6 alkyl-OR7 or -C1-C6 alkyl-N(R7)2;

[0204] R 11 and R 12 independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, -C1-C6 alkyl-OR7 and -C1-C6 alkyl-N(R7)2; or R 11 and R 12 Combine to form a 5- or 6-membered cycloalkyl ring;

[0205] R 13 is phenyl or C2-C9 heteroaryl, wherein phenyl and C2-C9 heteroaryl are optionally substituted by 1, 2, 3 or 4 R 16 replace;

[0206] R 14is hydrogen or C1-C6 alkyl;

[0207] R 15 is a C1-C6 alkyl group;

[0208] R 16 Each is independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C6 cycloalkyl, C2-C9 heterocycloalkyl, C6-C 10 Aryl, C2-C9 heteroaryl, among which C3-C6 cycloalkyl, C2-C9 heterocycloalkyl, C6-C 10 Aryl, C2-C9 heteroaryl are optionally substituted with 1, 2 or 3 groups selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy and C1-C6 haloalkoxy;

[0209] R 17 Each is independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -C1-C6 alkyl-OR7 and -C1-C6 alkyl-N(R7)2;

[0210] R 18 is hydrogen or C1-C6 alkyl;

[0211] R 19 is hydrogen, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, -C1-C6 alkyl-OR7 or -C1-C6 alkyl-N(R7)2;

[0212] m is 0, 1 or 2;

[0213] n is 1, 2 or 3;

[0214] p is 0, 1, or 2;

[0215] q is 0, 1, 2, 3, or 4;

[0216] s is 1, 2, or 3; and

[0217] t is 1, 2, or 3.

[0218] In some embodiments, is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is In some embodiments, is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is In some embodiments, is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is In some embodiments, is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is In some embodiments, is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is

[0219] In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein m is 1. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein m is 0. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein m is 2.

[0220] In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 1. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 0. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 2.

[0221] In some embodiments is a compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein m is 1 and p is 1.

[0222] In some embodiments, it is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is independently selected from C1-C6 alkyl, -C1-C6 alkyl-CO2R 18 , C1-C6 haloalkyl and C1-C6 heteroalkyl. In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is independently selected from C1-C6 alkyl, -C1-C6 alkyl-CO2R 18 In some embodiments, it is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is independently selected from C1-C6 alkyl. In some embodiments, it is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is each -CH3.

[0223] In some embodiments, provided herein is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 0, 1, 2, or 3. In some embodiments, provided herein is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 0. In some embodiments, provided herein is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 1. In some embodiments, provided herein is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 2. In some embodiments, provided herein is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 3. In some embodiments, provided herein is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 4.

[0224] In some embodiments, is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is

[0225] In some embodiments, provided herein is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein Y1 is O. In some embodiments, provided herein is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein Y1 is S. In some embodiments, provided herein is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein Y1 is N(R8). In some embodiments, provided herein is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein Y1 is N(R8) and R8 is hydrogen or C1-C6 alkyl.

[0226] In some embodiments, provided herein is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Y2 is N. In some embodiments, provided herein is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Y2 is C(R9). In some embodiments, provided herein is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Y2 is C(R9) and R9 is selected from hydrogen and C1-C6 alkyl. In some embodiments, provided herein is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Y2 is C(R9) and R9 is hydrogen. In some embodiments, provided herein is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Y2 is C(R9) and R9 is C1-C6 alkyl.

[0227] In some embodiments, provided herein is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is In some embodiments, provided herein is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is In some embodiments, provided herein is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is In some embodiments, provided herein is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is In some embodiments, provided herein is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is In some embodiments, provided herein is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is In some embodiments, provided herein is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is In some embodiments, provided herein is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is In some embodiments, provided herein is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is In some embodiments, provided herein is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is

[0228] In some embodiments, provided herein is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is In some embodiments, provided herein is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is s is 1 and t is 1. In some embodiments, provided herein is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is s is 1, t is 1 and Z2 is C(R 19 In some embodiments, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is s is 1, t is 1 and Z2 is C(H). In some embodiments, provided herein is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is s is 1, t is 1 and Z2 is N.

[0229] In some embodiments, provided herein is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is In some embodiments, provided herein is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is and Z1 is S. In some embodiments, provided herein is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is and Z1 is -C(R 17 )=C(R 17 In some embodiments, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is and Z1 is -C(H)=C(H)-. In some embodiments, provided herein are compounds of formula (I) or pharmaceutically acceptable salts or solvates thereof, wherein R2 is And R 11 and R 12 In some embodiments, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is q is 1, and R 13 1, 2 or 3 R 16 In some embodiments, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is q is 1, and R 13 Optional 1 or 2 R 16 In some embodiments, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is R 13 Optional 1 or 2 R 16 substituted pyridyl, and R 16 Each is independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl and C1-C6 alkoxy. In some embodiments, provided herein is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is q is 1, R 13 For optional use of 1 R 16 substituted pyridyl, and R 16 is selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl and C1-C6 alkoxy. In some embodiments, provided herein is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is q is 1, R 13 is optionally replaced by 1 R 16 substituted pyridyl, and R 16 It is a C1-C6 alkoxy group.

[0230] In some embodiments, provided herein is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is In some embodiments, provided herein is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is In some embodiments, provided herein is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is In some embodiments, provided herein is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is In some embodiments, provided herein is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is In some embodiments, provided herein is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is In some embodiments, provided herein is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is In some embodiments, provided herein is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is In some embodiments, provided herein is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is In some embodiments, provided herein is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is

[0231] In some embodiments, provided herein is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein X2 is -N(R5)-. In some embodiments, provided herein is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein X2 is -N(R5)- and R5 is hydrogen. In some embodiments, provided herein is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein X2 is -N(R5)- and R5 is C1-C6 alkyl. In some embodiments, provided herein is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein X2 is -C(R5)2-. In some embodiments, provided herein is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein X2 is -C(R5)2- and R5 is each hydrogen.

[0232] In some embodiments, provided herein is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein X3 is -N(R5)-. In some embodiments, provided herein is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein X3 is -N(R5)- and R5 is hydrogen. In some embodiments, provided herein is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein X3 is -N(R5)- and R5 is C1-C6 alkyl. In some embodiments, provided herein is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein X3 is -C(R5)2-. In some embodiments, provided herein is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein X3 is -C(R5)2- and R5 is each hydrogen.

[0233] In some embodiments, provided herein is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein X1 is O. In some embodiments, provided herein is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein X1 is S. In some embodiments, provided herein is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein X1 is N(R3). In some embodiments, provided herein is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein X1 is C(NO2)(R4).

[0234] In some embodiments, provided herein is a compound of Formula (Ia) or a pharmaceutically acceptable salt or solvate thereof:

[0235]

[0236] in:

[0237] Y1 is O, S or N(R8);

[0238] Y2 is N or C(R9);

[0239] Z1 is O, S, N(R3) or -C(R 17 )=C(R 17 )-;

[0240] Z2 is N or C (R 19 );

[0241] R1 is

[0242] R2 is

[0243] R6 are each independently selected from C1-C6 alkyl, -C1-C6 alkyl-CO2R 18 , C1-C6 haloalkyl, -C1-C6 alkyl-OR7 and -C1-C6 alkyl-N(R7)2;

[0244] R7 are each independently selected from hydrogen and C1-C6 alkyl;

[0245] R8 is hydrogen, C1-C6 alkyl, -C1-C6 alkyl-OR7, -C1-C6 alkyl-N(R7)2 or C3-C6 cycloalkyl;

[0246] R9 is hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl or C3-C6 cycloalkyl;

[0247] R 10 is hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -C1-C6 alkyl-OR7 or -C1-C6 alkyl-N(R7)2;

[0248] R 11 and R 12 independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, -C1-C6 alkyl-OR7 and -C1-C6 alkyl-N(R7)2; or R 11 and R 12 Combine to form a 5- or 6-membered cycloalkyl ring;

[0249] R 13 is phenyl or C2-C9 heteroaryl, wherein phenyl and C2-C9 heteroaryl are optionally substituted by 1, 2, 3 or 4 R 16 replace;

[0250] R 16 Each is independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C6 cycloalkyl, C2-C9 heterocycloalkyl, C6-C 10 Aryl, C2-C9 heteroaryl, among which C3-C6 cycloalkyl, C2-C9 heterocycloalkyl, C6-C 10 Aryl, C2-C9 heteroaryl are optionally substituted with 1, 2 or 3 groups selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy and C1-C6 haloalkoxy;

[0251] R 17 Each is independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -C1-C6 alkyl-OR7 and -C1-C6 alkyl-N(R7)2;

[0252] R 18 is hydrogen or C1-C6 alkyl;

[0253] R 19 is hydrogen, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, -C1-C6 alkyl-OR7 or -C1-C6 alkyl-N(R7)2;

[0254] m is 0, 1 or 2;

[0255] n is 1, 2 or 3;

[0256] p is 0, 1, or 2;

[0257] q is 0, 1, 2, 3, or 4;

[0258] s is 1, 2, or 3; and

[0259] t is 1, 2, or 3.

[0260] In some embodiments, is a compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is In some embodiments, is a compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is In some embodiments, is a compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is In some embodiments, is a compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is In some embodiments, is a compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is

[0261] In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein m is 1. In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein m is 0. In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein m is 2.

[0262] In some embodiments is a compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein p is 1. In some embodiments is a compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein p is 0. In some embodiments is a compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein p is 2.

[0263] In some embodiments is a compound of Formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein m is 1 and p is 1.

[0264] In some embodiments, it is a compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is independently selected from C1-C6 alkyl, -C1-C6 alkyl-CO2R 18 , C1-C6 haloalkyl and C1-C6 heteroalkyl. In some embodiments, a compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is each independently selected from C1-C6 alkyl, -C1-C6 alkyl-CO2R 18 In some embodiments, a compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is independently selected from C1-C6 alkyl. In some embodiments, a compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is each -CH3.

[0265] In some embodiments, provided herein is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 0, 1, 2, or 3. In some embodiments, provided herein is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 0. In some embodiments, provided herein is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 1. In some embodiments, provided herein is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 2. In some embodiments, provided herein is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 3. In some embodiments, provided herein is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 4.

[0266] In some embodiments, is a compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is

[0267] In some embodiments, provided herein is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein Y1 is O. In some embodiments, provided herein is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein Y1 is S. In some embodiments, provided herein is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein Y1 is N(R8). In some embodiments, provided herein is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein Y1 is N(R8) and R8 is hydrogen or C1-C6 alkyl.

[0268] In some embodiments, provided herein is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein Y2 is N. In some embodiments, provided herein is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein Y2 is C(R9). In some embodiments, provided herein is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein Y2 is C(R9) and R9 is selected from hydrogen and C1-C6 alkyl. In some embodiments, provided herein is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein Y2 is C(R9) and R9 is hydrogen. In some embodiments, provided herein is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein Y2 is C(R9) and R9 is C1-C6 alkyl.

[0269] In some embodiments, provided herein is a compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is

[0270] In some embodiments, provided herein is a compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is In some embodiments, provided herein is a compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is In some embodiments, provided herein is a compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is In some embodiments, provided herein is a compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is In some embodiments, provided herein is a compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is In some embodiments, provided herein is a compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is In some embodiments, provided herein is a compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is In some embodiments, provided herein is a compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is In some embodiments, provided herein is a compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is

[0271] In some embodiments, provided herein is a compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is In some embodiments, provided herein is a compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is s is 1 and t is 1. In some embodiments, provided herein is a compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is s is 1, t is 1 and Z2 is C(R 19 In some embodiments, provided herein is a compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is s is 1, t is 1 and Z2 is C(H). In some embodiments, provided herein is a compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is s is 1, t is 1 and Z2 is N.

[0272] In some embodiments, provided herein is a compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is In some embodiments, provided herein is a compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is and Z1 is S. In some embodiments, provided herein is a compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is and Z1 is -C(R 17 )=C(R 17 In some embodiments, provided herein is a compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is and Z1 is -C(H)=C(H)-. In some embodiments, provided herein is a compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is And R 11 and R 12 In some embodiments, the present invention provides a compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is q is 1, and R 13 1, 2 or 3 R 16 In some embodiments, the present invention provides a compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is q is 1, and R 13 Optional 1 or 2 R 16In some embodiments, provided herein is a compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is q is 1, R 13 Optional 1 or 2 R 16 substituted pyridyl, and R 16 Each is independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl and C1-C6 alkoxy. In some embodiments, provided herein is a compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is q is 1, R 13 For optional use of 1 R 16 substituted pyridyl, and R 16 is selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl and C1-C6 alkoxy. In some embodiments, provided herein is a compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is q is 1, R 13 is optionally replaced by 1 R 16 substituted pyridyl, and R 16 It is a C1-C6 alkoxy group.

[0273] In some embodiments, provided herein is a compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is In some embodiments, provided herein is a compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is In some embodiments, provided herein is a compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is In some embodiments, provided herein is a compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is In some embodiments, provided herein is a compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is In some embodiments, provided herein is a compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is In some embodiments, provided herein is a compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is In some embodiments, provided herein is a compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is In some embodiments, provided herein is a compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is In some embodiments, provided herein is a compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is

[0274] In some embodiments, provided herein is a compound selected from the following: or a pharmaceutically acceptable salt or solvate thereof.

[0275] In some embodiments, provided herein is a compound selected from the following:

[0276]

[0277]

[0278] or a pharmaceutically acceptable salt or solvate thereof.

[0279] In some embodiments, provided herein is a compound selected from the following:

[0280]

[0281]

[0282] or a pharmaceutically acceptable salt or solvate thereof.

[0283] Any combination of the above groups for the various variables is contemplated herein. Throughout the specification, one skilled in the art can select groups and substituents thereof to provide stable moieties and compounds.

[0284] In some embodiments, the therapeutic agent (eg, a compound of Formula (I'), (I) or (Ia)) is present in the pharmaceutical composition as a pharmaceutically acceptable salt. In some embodiments, any of the compounds described above are suitable for use in any of the methods or compositions described herein.

[0285] Further forms of the compounds disclosed herein

[0286] Isomers

[0287] In addition, in some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein have one or more double bonds. The compounds provided herein include all cis isomers, trans isomers, cis isomers, antiisomers, entgegen isomers and cis isomers and their corresponding mixtures. In some cases, the compound exists as a tautomer. The compounds described herein include all possible tautomers in the formula described herein. In some cases, the compounds described herein have one or more chiral centers, and each center exists in R configuration or S configuration. The compounds described herein include all diastereomers, enantiomers and epimer forms and their corresponding mixtures. In other embodiments of the compounds and methods provided herein, the mixture of enantiomers and / or diastereomers produced by a single preparation step, combination or interconversion can be used for the applications described herein. In some embodiments, compounds described herein are prepared as optically pure enantiomers by chiral chromatography of racemic mixtures. In some embodiments, by reacting the racemic mixture of the compound with an optically active resolving agent to form a pair of diastereomeric compounds, separating diastereomers and reclaiming optically pure enantiomers, compounds described herein are prepared as their individual stereoisomers. In some embodiments, dissociable complexes (e.g., crystalline diastereoisomer salts) are preferred. In some embodiments, diastereomers have different physical properties (e.g., melting point, boiling point, solubility, reactivity, etc.) and are separated by utilizing these differences. In some embodiments, diastereomers are separated by chiral chromatography or preferably separated by separation / resolving techniques based on solubility differences. In some embodiments, then optically pure enantiomers and resolving agents are recovered by any practical method that does not result in racemization.

[0288] Labeled compounds

[0289] In some embodiments, the compounds described herein exist in their isotopically labeled form. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically labeled compounds. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically labeled compounds as pharmaceutical compositions. Therefore, in some embodiments, the compounds disclosed herein include isotopically labeled compounds that are identical to those described herein, but in fact one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number typically found in nature. Examples of isotopes incorporated into the compounds described herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, for example, respectively. 2 H. 3 H. 13 C. 14 C. l5 N. 17 O. 18 O. 31 P. 32 P. 35 S. 18 F and 36 Cl. Compounds described herein containing the above-mentioned isotopes and / or other isotopes of other atoms and pharmaceutically acceptable salts, esters, solvates, hydrates or derivatives thereof are within the scope of the present invention. Certain isotopically labeled compounds, for example, compounds incorporating radioactive isotopes such as 3 H and 14 C, can be used in drug and / or substrate tissue distribution assays. Tritiated isotopes are particularly preferred due to their ease of preparation and detectability, i.e., 3 H and carbon-14 (i.e. 14 C). In addition, heavy isotopes such as deuterium (i.e. 2 H) substitutions produce certain therapeutic advantages, such as increased in vivo half-life or reduced dosage requirements. In some embodiments, isotopically labeled compounds, their pharmaceutically acceptable salts, esters, solvates, hydrates or derivatives are prepared by any suitable method.

[0290] In some embodiments, the compounds described herein are labeled by other means, including but not limited to the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.

[0291] Pharmaceutically acceptable salts

[0292] In some embodiments, the compounds described herein exist in the form of pharmaceutically acceptable salts thereof. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions.

[0293] In some embodiments, the compounds described herein have acidic or basic groups and therefore react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form pharmaceutically acceptable salts. In some embodiments, these salts are prepared in situ during the final isolation and purification of the compounds described herein, or by reacting the purified compound in free form with a suitable acid or base separately and isolating the salt thus formed.

[0294] Solvate

[0295] In some embodiments, the compounds described herein exist as solvates. In some embodiments, methods of treating diseases by administering such solvates are provided. Methods of treating diseases by administering such solvates as pharmaceutical compositions are also described herein.

[0296] Solvates contain a stoichiometric or non-stoichiometric amount of solvent, and in some embodiments, are formed during crystallization with pharmaceutically acceptable solvents such as water, ethanol, etc. Hydrates are formed when the solvent is water or alcoholates are formed when the solvent is alcohol. Solvates of compounds described herein are conveniently prepared or formed in the methods described herein. By way of example only, hydrates of compounds described herein are conveniently prepared by recrystallization from an aqueous / organic solvent mixture using an organic solvent including but not limited to dioxane, tetrahydrofuran or MeOH. In addition, compounds provided herein exist in non-solvated and solvated forms. Generally, for the purposes of compounds and methods provided herein, solvated forms are considered to be equivalent to non-solvated forms.

[0297] Synthesis of compounds

[0298] In some embodiments, the synthesis of the compounds described herein is achieved using means described in the chemical literature, using methods described herein, or by a combination thereof. In addition, solvents, temperatures, and other reaction conditions given herein may be varied.

[0299] In other embodiments, starting materials and reagents used to synthesize compounds described herein are synthesized or obtained from commercial sources such as, but not limited to, Sigma-Aldrich, Fischer Scientific (Fischer Chemicals), and Acros Organics.

[0300] In further embodiments, the compounds described herein and other related compounds having different substituents are synthesized using the techniques and materials described herein and those recognized in the art, such as described in Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplementary Materials (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989), March, Advanced Organic Chemistry 4th Edition, (Wiley 1992); Carey and Sundberg, Advanced Organic Chemistry 4th Edition, Volumes A and B (Plenum 2000, 2001), and Green and Wuts, Protective Groups in Organic Synthesis 3rd Edition, (Wiley 1999) (all of which are incorporated herein by reference for the purposes of this disclosure). General methods for preparing the compounds disclosed herein can be derived from the reactions, and the reactions can be modified by using appropriate reagents and conditions to introduce the various moieties found in the formulas provided herein. As a guide, the following synthetic methods can be used.

[0301] Uses of Protecting Groups

[0302] In the reaction, it may be necessary to protect reactive functional groups, such as hydroxyl, amino, imino, sulfenyl or carboxyl groups, where these groups are desired in the final product to prevent them from undesirably participating in the reaction. Protective groups are used to block some or all reactive moieties and prevent these groups from participating in chemical reactions until the protective group is removed. Preferably, each protective group can be removed in different ways. Protective groups sheared under completely different reaction conditions meet the requirement of differential removal.

[0303] The protecting group can be removed by acid, base, reducing conditions (such as, for example, hydrogenolysis) and / or oxidative conditions. Groups such as trityl, dimethoxytrityl, acetal and tert-butyldimethylsilyl are acid unstable and can be used to protect carboxyl and hydroxy reactive moieties in the presence of amino groups protected with Cbz groups (which can be removed by hydrogenolysis) and Fmoc groups (which are base unstable). Carboxylic acid and hydroxy reactive moieties can be terminated with base unstable groups such as, but not limited to, methyl, ethyl and acetyl in the presence of amines terminated with acid unstable groups such as tert-butyl carbamate or carbamates that are stable to acid and base but can be removed by hydrolysis.

[0304] Carboxylic acid and hydroxyl reactive moieties may also be terminated with hydrolytically removable protecting groups such as benzyl groups, while amine groups capable of acid hydrogen bonding may be terminated with base labile groups such as Fmoc. Carboxylic acid reactive moieties may be protected by conversion to simple ester compounds exemplified herein (which include conversion to alkyl esters), or they may be terminated with oxidatively removable protecting groups such as 2,4-dimethoxybenzyl, while coexisting amino groups may be terminated with fluoride-labile silylcarbamates.

[0305] Allyl-terminated groups are useful in the presence of acid and base protecting groups because the former are stable and can be subsequently removed by metal or π-acid catalysts. For example, allyl-terminated carboxylic acids can be treated with Pd in ​​the presence of acid-labile tert-butyl carbamate or base-labile acetate amine protecting groups. 0 -catalyzed reaction deprotection. Another form of protecting group is a resin to which a compound or intermediate can be attached. As long as the residue is attached to the resin, the functional group is blocked and cannot react. Once released from the resin, the functional group is available for reaction.

[0306] Typically, the capping / protecting group may be selected from:

[0307]

[0308] A detailed description of other protecting groups, together with techniques that can be used to create protecting groups and to remove them, is described in Greene and Wuts, Protective Groups in Organic Synthesis, 3rd ed., John Wiley & Sons, New York, NY, 1999, and Kocienski, Protective Groups, Thieme Verlag, New York, NY, 1994, which are incorporated herein by reference for such disclosure).

[0309] Treatment and prevention methods

[0310] In some embodiments, a method of treating a metabolic disease in a patient in need thereof comprises administering to the patient a therapeutically effective amount of a compound of Formula (I'), (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, a method of treating a metabolic disease in a patient in need thereof comprises administering to the patient a therapeutically effective amount of a compound of Formula (I'), (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein the metabolic disease is selected from type 2 diabetes, atherosclerosis, obesity, and gout. In some embodiments, a method of treating type 2 diabetes in a patient in need thereof comprises administering to the patient a therapeutically effective amount of a compound of Formula (I'), (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, a method of treating atherosclerosis in a patient in need thereof comprises administering to the patient a therapeutically effective amount of a compound of Formula (I'), (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, a method of treating obesity in a patient in need thereof comprises administering to the patient a therapeutically effective amount of a compound of Formula (I'), (I) or (Ia) or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, a method of treating gout in a patient in need thereof comprises administering to the patient a therapeutically effective amount of a compound of Formula (I'), (I) or (Ia) or a pharmaceutically acceptable salt or solvate thereof.

[0311] In some embodiments, a method of treating a liver disease in a patient in need thereof comprises administering to the patient a therapeutically effective amount of a compound of Formula (I'), (I) or (Ia) or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, a method of treating a liver disease in a patient in need thereof comprises administering to the patient a therapeutically effective amount of a compound of Formula (I'), (I) or (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein the liver disease is selected from non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis (ASH), viral hepatitis or cirrhosis.

[0312] In some embodiments is a method of treating a pulmonary disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I'), (I) or (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein the pulmonary disease is selected from asthma, COPD and idiopathic pulmonary fibrosis.

[0313] In some embodiments, a method of treating a central nervous system disease in a patient in need thereof comprises administering to the patient a therapeutically effective amount of a compound of Formula (I'), (I) or (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein the central nervous system disease is selected from Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis and Parkinson's disease.

[0314] In some embodiments, a method of treating an inflammatory or autoimmune disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I'), (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, a method of treating an inflammatory or autoimmune disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I'), (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein the disease is rheumatoid arthritis. In some embodiments, a method of treating an inflammatory or autoimmune disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I'), (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein the disease is multiple sclerosis. In some embodiments, a method of treating an inflammatory or autoimmune disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I'), (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein the disease is psoriasis. In some embodiments, a method of treating an inflammatory or autoimmune disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I'), (I) or (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein the disease is lupus. In some embodiments, a method of treating an inflammatory or autoimmune disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I'), (I) or (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein the disease is an intestinal disease. In some embodiments, a method of treating an inflammatory or autoimmune disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I'), (I) or (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein the disease is Crohn's disease. In some embodiments, a method of treating an inflammatory or autoimmune disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I'), (I) or (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein the disease is ulcerative colitis.

[0315] In some embodiments, a method of treating a cardiovascular disease in a patient in need thereof comprises administering to the patient a therapeutically effective amount of a compound of Formula (I'), (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, a method of treating a cardiovascular disease in a patient in need thereof comprises administering to the patient a therapeutically effective amount of a compound of Formula (I'), (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein the cardiovascular disease is atherosclerosis or stroke. In some embodiments, a method of treating atherosclerosis in a patient in need thereof comprises administering to the patient a therapeutically effective amount of a compound of Formula (I'), (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, a method of treating a stroke in a patient in need thereof comprises administering to the patient a therapeutically effective amount of a compound of Formula (I'), (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof.

[0316] Pharmaceutical compositions and methods of administration

[0317] The NLRP3 inhibitors described herein are administered to a subject in a biocompatible form suitable for administration to treat or prevent a disease, disorder or condition. Administration of the NLRP3 inhibitors described herein can be in any pharmacological form, including a therapeutically effective amount of the NLRP3 inhibitor alone or in combination with a pharmaceutically acceptable carrier.

[0318] In certain embodiments, the compounds described herein are administered as pure chemicals. In other embodiments, the compounds described herein are combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, a physiologically suitable (or acceptable) excipient, or a physiologically suitable (or acceptable) carrier), which is selected based on the selected route of administration and standard pharmaceutical practices as described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 21st Edition Mack Pub. Co., Easton, PA (2005)).

[0319] Thus, provided herein is a pharmaceutical composition comprising at least one compound or pharmaceutically acceptable salt as described herein and one or more pharmaceutically acceptable carriers. A carrier (or excipient) is acceptable or suitable if it is compatible with the other ingredients of the composition and is not harmful to the recipient (i.e., subject) of the composition.

[0320] In some embodiments, a pharmaceutical composition comprises a pharmaceutically acceptable carrier and a compound of formula (I'), (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, a pharmaceutical composition comprises a pharmaceutically acceptable carrier and a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, a pharmaceutical composition comprises a pharmaceutically acceptable carrier and a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, a pharmaceutical composition comprises a pharmaceutically acceptable carrier and a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof.

[0321] Another embodiment provides a pharmaceutical composition consisting essentially of a pharmaceutically acceptable carrier and a compound of Formula (I'), (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, a pharmaceutical composition consisting essentially of a pharmaceutically acceptable carrier and a compound of Formula (I'), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, a pharmaceutical composition consisting essentially of a pharmaceutically acceptable carrier and a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, a pharmaceutical composition consisting essentially of a pharmaceutically acceptable carrier and a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof.

[0322] In certain embodiments, the compounds described herein are substantially pure in that they contain less than about 5%, or less than about 1%, or less than about 0.1% of other small organic molecules, such as contaminating intermediates or by-products produced during one or more steps of the synthetic methods.

[0323] These formulations include those suitable for oral, topical, buccal, parenteral (eg, subcutaneous, intramuscular, intradermal or intravenous) or aerosol administration.

[0324] Exemplary pharmaceutical compositions are used in the form of pharmaceutical preparations, such as solid, semisolid or liquid forms, which include one or more disclosed compounds as active ingredients, mixed with organic or inorganic carriers or excipients suitable for external, enteral or parenteral application. In some embodiments, the active ingredient is mixed with a generally non-toxic pharmaceutically acceptable carrier, such as for tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, and any other form suitable for use. The amount of active target compound contained in the pharmaceutical composition is sufficient to produce the desired effect on the course of the disease or condition.

[0325] In some embodiments, the NLRP3 inhibitors described herein are administered to a subject in a biocompatible form suitable for topical administration to treat or prevent a skin disease, disorder, or condition. "Biocompatible form suitable for topical administration" refers to a form of the NLRP3 inhibitor to be administered in which the therapeutic effects of the inhibitor outweigh any toxic effects. Administration of the NLRP3 inhibitors described herein can be in any pharmacological form, including a therapeutically effective amount of the NLRP3 inhibitor alone or in combination with a pharmaceutically acceptable carrier.

[0326] Topical administration of NLRP3 inhibitors can be in the form of aerosols, semisolid pharmaceutical compositions, powders or solutions. The term "semisolid composition" refers to ointments, creams, salves, jellies or other pharmaceutical compositions of substantially similar consistency suitable for skin. Examples of semisolid compositions are given in Chapter 17 of The Theory and Practice of Industrial Pharmacy, Lachman, Lieberman and Kanig published by Lea and Febiger (1970) and Chapter 67 of Remington's Pharmaceutical Sciences, 15th edition (1975) published by Mack Publishing Company.

[0327] Skin (dermal) or skin (skin) patch is another method for transdermal delivery of treatment or pharmaceutical composition described herein. Patch can provide absorption enhancer such as DMSO to increase the absorption of compound. Patch can include those that control the speed of drug delivery to skin. Patch can provide a variety of drug delivery systems, including reservoir system (reservoirsystem) or overall monolayer system (monolithic system) respectively. Reservoir design can, for example, have four layers: adhesive layer directly contacting skin, control film controlling drug molecule diffusion, drug molecule reservoir and waterproof backing. This design delivers a uniform amount of drug within a specified time period, and the delivery rate must be less than the saturation limit of different types of skin. Overall monolayer design, for example, usually only has three layers: adhesive layer, polymer matrix containing the compound and waterproof backing. This design brings saturated amount of drug to skin. Therefore, delivery is controlled by skin. When the amount of drug in the patch is reduced to below the saturation level, the delivery rate decreases.

[0328] In one embodiment, the topical composition may take the form of, for example, a hydrogel based on polyacrylic acid or polyacrylamide; as an ointment, for example with polyethylene glycol (PEG) as a carrier, such as the standard ointment DAB 8 (50% PEG300, 50% PEG 1500); or as an emulsion, in particular a microemulsion based on water-in-oil or oil-in-water, optionally with the addition of liposomes. Suitable penetration enhancers (entraining agents) include sulfoxide derivatives, such as dimethyl sulfoxide (DMSO) or decyl methyl sulfoxide (decyl-MSO) and carbitol (diethylene glycol monoethyl ether) or cyclodextrins; and pyrrolidones, such as 2-pyrrolidone, N-methyl-2-pyrrolidone, 2-pyrrolidone-5-carboxylic acid or biodegradable N-(2-hydroxyethyl)-2-pyrrolidone and its fatty acid esters; urea derivatives, such as dodecyl urea, 1,3-didodecyl urea and 1,3-diphenyl urea; and terpenes, such as D-limonene, menthone, α-terpineol, carvone, limonene oxide or 1,8-cineole.

[0329] Ointments, pastes, creams and gels can also contain excipients, such as starch, tragacanth, cellulose derivatives, polyethylene glycol, silicone, bentonite, silicic acid and talcum or their mixtures. Powders and sprays can also contain excipients, such as mixtures of lactose, talcum, silicic acid, aluminum hydroxide, calcium silicate and polyamide powder or these materials. The solution of nanocrystalline antimicrobial metal can be converted into aerosol or spray by conventional any known method for preparing aerosol medicine. Usually, this method comprises pressurization or is provided for the device of pressurized solution container, usually uses inert carrier gas, and pressurized gas is passed through aperture. Spray can contain conventional propellant in addition, such as chlorofluorocarbon and volatile unsubstituted hydrocarbon such as butane and propane.

[0330] The carrier may also contain other pharmaceutically acceptable excipients for changing or maintaining the pH, osmotic pressure concentration, viscosity, transparency, color, sterility, stability, dissolution rate or smell of the formulation. The anti-skin aging composition may also include antioxidants, sunscreens, natural retinoids (e.g., retinol) and other additives commonly found in skin care compositions.

[0331] In some embodiments for preparing solid compositions such as tablets, the main active ingredient is mixed with a pharmaceutical carrier (e.g., conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums and other pharmaceutical diluents such as water) to form a solid preformulation composition containing a homogenous mixture of the disclosed compound or its non-toxic pharmaceutically acceptable salt. When these preformulation compositions are referred to as homogenous, it is meant that the active ingredient is evenly dispersed throughout the composition, making the composition easily subdivided into equally effective unit dosage forms, such as tablets, pills, and capsules.

[0332] In solid dosage forms for oral administration (capsules, tablets, pills, lozenges, powders, granules, etc.), the subject compositions are mixed with one or more pharmaceutically acceptable carriers such as sodium citrate or dicalcium phosphate and / or any of the following: (1) fillers or extenders, such as starch, cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, lactose, sucrose, glucose, mannitol and / or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, hydroxypropyl methylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and / or acacia; (3) humectants, such as Such as glycerol; (4) disintegrants, such as crospovidone, cross-linked sodium carboxymethyl cellulose, sodium starch glycolate, agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; (5) solution retardants, such as paraffin; (6) absorption promoters, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, sodium docusate, cetyl alcohol and glyceryl monostearate; (8) absorbents, such as kaolin and bentonite; (9) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate and mixtures thereof; and (10) coloring agents. In the case of capsules, tablets and pills, in some embodiments, the composition includes a buffer. In some embodiments, solid compositions of similar type are also used as fillers in soft-filled and hard-filled gelatin capsules using excipients such as lactose or milk sugars and high molecular weight polyethylene glycols.

[0333] In some embodiments, tablets are prepared by optionally compressing or molding with one or more auxiliary ingredients. In some embodiments, compressed tablets are prepared using a binder (e.g., gelatin or hydroxypropyl methylcellulose), a lubricant, an inert diluent, a preservative, a disintegrant (e.g., sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), a surfactant or a dispersant. In some embodiments, molded tablets are prepared by molding a mixture of the subject composition moistened with an inert liquid diluent in a suitable machine. In some embodiments, tablets and other solid dosage forms (e.g., lozenges, capsules, pills, and granules) are formulated or prepared to have coatings and shells (e.g., enteric coatings and other coatings).

[0334] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof, and powders. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the subject composition, in some embodiments, the liquid dosage form contains an inert diluent such as, for example, water or other solvents, solubilizers and emulsifiers such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (particularly cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofuranol, polyethylene glycol, and fatty acid esters of sorbitan, cyclodextrins, and mixtures thereof.

[0335] In some embodiments, suspensions contain, in addition to the subject compositions, suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

[0336] In some embodiments, powders and sprays contain, in addition to the subject composition, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate and polyamide powder or mixtures of these substances. In some embodiments, sprays additionally contain conventional propellants such as chlorofluorocarbons and volatile unsubstituted hydrocarbons such as butane and propane.

[0337] Compositions and compounds disclosed herein may alternatively be administered by aerosol. This is achieved by preparing an aqueous aerosol, liposome preparation or solid particles containing the compound. In some embodiments, non-aqueous (e.g., fluorocarbon propellant) suspensions are used. In some embodiments, sonic nebulizers are used because they minimize the exposure of medicaments to shear, which causes the degradation of the compounds contained in the subject composition. Typically, aqueous aerosols are prepared by preparing an aqueous solution or suspension of the subject composition with a conventional pharmaceutically acceptable carrier and stabilizer. Carriers and stabilizers vary according to the requirements of the specific subject composition, but typically include nonionic surfactants (Tween, Pluronics or polyethylene glycol), harmless proteins such as serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars or sugar alcohols. Aerosols are typically prepared by isotonic solutions.

[0338] Pharmaceutical compositions suitable for parenteral administration comprise a combination of a subject composition and one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions or sterile powders for reconstitution into sterile injectable solutions or dispersions prior to use, which in some embodiments contain antioxidants, buffers, bacteriostats, solutes that render the formulation isotonic with the blood of the intended recipient, or suspending or thickening agents.

[0339] Examples of suitable aqueous and non-aqueous carriers for pharmaceutical compositions include water, ethanol, polyols (e.g., glycerol, propylene glycol, polyethylene glycol, etc.), and suitable mixtures thereof, vegetable oils (e.g., olive oil), and injectable organic esters (e.g., ethyl oleate), and cyclodextrins. Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by maintaining the required particle size in the case of dispersions, and by the use of surfactants.

[0340] The dosage of the composition comprising at least one compound described herein varies depending on the condition of the patient (eg, human), ie, the stage of the disease, general health, age, and other factors.

[0341] The pharmaceutical composition is applied in a manner suitable for the disease to be treated (or prevented). Suitable dosage and suitable duration and frequency of application will be determined by factors such as the patient's condition, the type and severity of the patient's disease, the specific form of the active ingredient and the method of administration. Typically, suitable dosage and treatment regimen provide a composition of the amount sufficient to provide treatment and / or prevention benefits (e.g., improved clinical outcomes, such as more frequent complete or partial remissions, or longer disease-free and / or overall survival, or mitigation of symptom severity). Optimal dose is typically determined using experimental models and / or clinical trials. In some embodiments, optimal dose depends on the patient's body mass, body weight or blood volume.

[0342] Oral dosages are generally from about 1.0 mg to about 1000 mg, one to four or more times a day.

[0343] Depending on the pharmacokinetic parameters of the dosage formulation and the route of administration utilized, the dosage administration may be repeated.

[0344] It is particularly advantageous to formulate the composition in a dosage unit form for ease of administration and uniform dosage. As used herein, a dosage unit form refers to physically discrete units suitable as unit doses for mammalian subjects to be treated; each unit contains a predetermined amount of active compound calculated to produce the desired therapeutic effect in combination with the desired pharmaceutical carrier. The specifications of the dosage unit form are determined by and directly depend on (a) the unique characteristics of the NLRP3 inhibitor and the specific therapeutic effect to be achieved and (b) the limitations inherent in the field of compounding such active compounds for treating individual sensitivities. The specific dose can be readily calculated by a person of ordinary skill in the art, for example, based on the approximate body weight or body surface area of ​​the patient or the volume of body space to be occupied. The dose will also be calculated based on the specific route of administration selected. A person of ordinary skill in the art generally further refines the calculations necessary to determine the appropriate dose for treatment. Such calculations can be performed by a person of ordinary skill in the art without undue experimentation based on the activity of the NLRP3 inhibitors disclosed herein in the target cell assay formulation. The exact dose is determined in conjunction with standard dose response studies. It will be understood that the actual amount of composition administered will be determined by the practitioner according to relevant circumstances, including the condition or conditions to be treated, the choice of composition to be administered, the age, weight and response of the individual patient, the severity of the patient's symptoms and the route of administration chosen.

[0345] The toxicity and therapeutic efficacy of such NLRP3 inhibitors can be determined by standard pharmaceutical procedures in cell culture or experimental animals, for example, to determine LD 50 (the dose that is lethal to 50% of the population) and ED 50 (the dose that is therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio LD 50 / ED 50 NLRP3 inhibitors that exhibit large therapeutic indices are preferred. Although NLRP3 inhibitors that exhibit toxic side effects may be used, care should be taken to design delivery systems that target such inhibitors to affected tissue sites in order to minimize potential damage to uninfected cells, thereby reducing side effects.

[0346] The data obtained from cell culture assays and animal studies can be used in formulating a range of dosage for use in humans. Dosages of such NLRP3 inhibitors are preferably within the range that includes the ED 50 The dosage may vary within this range depending on the dosage form employed and the route of administration utilized. For any NLRP3 inhibitor used in the methods described herein, the therapeutically effective dose can be estimated initially from cell culture assays. A dose can be formulated in animal models to achieve an IC including as determined in cell culture. 50(i.e., the concentration of the NLRP3 inhibitor that achieves half-maximal inhibition of symptoms). Such information can be used to more accurately determine useful doses in humans. Levels in plasma can be measured, for example, by high performance liquid chromatography.

[0347] Example

[0348] The following examples are provided for illustrative purposes and not for limiting the scope of the claims provided herein. These examples and all literature citations throughout this specification are incorporated herein by reference for all legal purposes provided. The starting materials and reagents used to synthesize the compounds described herein can be synthesized or can be obtained from commercial sources such as, but not limited to, Sigma-Aldrich, Acros Organics, Fluka, and Fischer Scientific.

[0349] This article uses the standard abbreviations and acronyms defined in J.Org.Chem.2007 72(1):23A-24A. Other abbreviations and acronyms used in this article are as follows:

[0350]

[0351] Example 1: ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)((4,6,7,8-tetrahydro-5,8-ethanofuro[3,2-c]azepine Synthesis of sodium ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)((4,6,7,8-tetrahydro-5,8-ethanofuro[3,2-c]azepin-2-yl)sulfonyl)amide)(13)

[0352]

[0353] To a solution of 1 (5.0 g, 44 mmol, 1.0 eq.) in DMF (50 mL) was added HATU (25.5 g, 67 mmol, 1.5 eq.), DIEA (23.0 g, 178 mmol, 4 eq.) and 1' (10.3 g, 67 mmol, 1.5 eq.) at 0°C. The reaction mixture was stirred at room temperature overnight. The mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with water, brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by silica gel chromatography to give compound 2 (9 g).

[0354] To a solution of 2 (9.0 g, 42 mmol, 1.0 eq.) in EtOH (190 mL) was added NaOH (5.4 g, 136 mmol, 3 eq. in 190 mL water). The reaction mixture was stirred at room temperature for 2 h. The pH was adjusted to 2 with 1N HCl. The mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with water, brine, dried over Na2SO4, and concentrated in vacuo to give compound 3 (6 g).

[0355] To a solution of 3 (5.0 g, 27 mmol, 1.0 equivalent) in MsOH (150 mL) was added 500 mL RBF, P2O5. The reaction mixture was stirred at 130 ° C overnight. The mixture was poured onto ice / water, and then the pH was adjusted to 10 with Na2CO3. The mixture was extracted with DCM, and the combined organic layers were washed with water, brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel chromatography to obtain compound 4 (2.5 g).

[0356] To a solution of 4' (12.2 g, 54 mmol, 1.5 eq.) in THF (60 mL) was added NaH (1.26 g, 54 mmol, 1.5 eq.). After stirring for 30 min, 4 (6 g, 36 mmol, 1 eq.) was added. The mixture was stirred at room temperature overnight. Water (20 mL) was added dropwise at 0 °C. The mixture was extracted with EtOAc. The combined organic layers were washed with water, brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by silica gel chromatography to give compound 5 (11.9 g).

[0357] Mg (1.2 g, 34 mmol, 4 eq.) was added to a solution of 5 (2.0 g, 8.5 mmol, 1 eq.) in MeOH / THF (100 / 10 mL). The reaction mixture was stirred at room temperature overnight. The mixture was poured into ice-cold 2N HCl (50 mL). The acidic solution was treated with Na2CO3 to pH 8.5-9. The mixture was extracted with EtOAc. The combined organic layers were washed with water and brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by silica gel chromatography to obtain compound 6 (1.7 g).

[0358] To a solution of 6 (1.7 g, 7.2 mmol, 1 eq.) in THF (100 mL) was added LAH (5.4 g, 143 mmol, 20 eq.). The reaction mixture was stirred at 70 °C overnight. The mixture was quenched with water and an aqueous NaOH solution. The mixture was filtered and the solid was washed with methanol. The solution was concentrated in vacuo and the residue was purified by silica gel chromatography to obtain compound 7 (700 mg).

[0359] To a solution of PPh3 (2.2 g, 8.3 mmol, 3 eq.) and DIAD (1.7 g, 8.3 mmol, 3 eq.) in THF (100 mL) was added 7 (500 mg, 2.7 mmol, 1 eq.) at 0°C. The reaction mixture was stirred at room temperature overnight. The solution was concentrated in vacuo, and the residue was purified by silica gel chromatography to give compound 8 (330 mg).

[0360] To a solution of 8 (326 mg, 2.0 mmol, 1 eq.) in DCM (10 mL) was added SO3DMF (918 mg, 6.0 mmol, 3 eq.) in a microwave tube. The mixture was heated at 70 °C for 1 h in a microwave. When the reaction was complete, a dark solid was precipitated. The solvent was decanted and the solid was dissolved in water (20 mL) and lyophilized to give a crude mixture of compound 9 (400 mg), which was used directly without further purification.

[0361] To a solution of 9 (670 mg, 2.76 mmol, 1 eq.) in ACN (5 mL) was added NaCO (584 mg, 5.51 mmol, 2 eq.). The mixture was stirred at room temperature for 30 min and then evaporated to dryness under reduced pressure. SOCl (10 mL) was then added. The mixture was heated to 80 °C for 40 min and then evaporated to dryness to give 10 which was used directly in the next step.

[0362] To a solution of 10 in THF (5 mL) was slowly added NH4OH (5 mL) at 0°C. The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo, and the residue was purified by silica gel chromatography to give 11 (270 mg).

[0363] To a solution of 11 (120 mg, 0.50 mmol, 1.0 eq.) in anhydrous THF (15 mL) was added t-BuONa solution (240 mg, 2.5 mmol, 5.0 eq.) at 0 °C in N2. The mixture was stirred at room temperature for 15 min. A solution of 11' (250 mg, 0.75 mmol, 1.5 eq.) was then added to the reaction mixture at 0 °C and stirred at room temperature for 3 h. The reaction mixture was concentrated in vacuo. The residue was purified by silica gel chromatography to give 12 (200 mg). LCMS: [M+1] +＝ 442.

[0364] To a NaOH aqueous solution (22.7 mL, 0.02N NaOH) was added 12 (200 mg, 0.454 mmol, 1.0 equiv) at 0°C. The reaction was stirred at room temperature for 30 min. The mixture was then lyophilized to afford compound 13 as a light yellow solid. LCMS: [M-Na+1] +＝442.15. 1 HNMR (400MHz, CD3OD) δ6.85 (s, 1H), 6.67 (s, 1H), 3.87 (s, 2H), 3.22-3.10 (m, 2H), 3.04-2.95 (m, 3H), 2.81 (t, J = 7.2Hz, 4H), 2.06-1.91 (m, 8H).

[0365] To a solution of a (3.8 g, 21.97 mmol, 1.0 eq) in anhydrous DCM (50 mL) was slowly added pyridine (10.97 mL, 136.24 mmol, 6.0 eq) and b (3.99 g, 19.77 mmol, 0.9 eq) at 0 ° C in N2. The reaction mixture was then stirred at room temperature for 2 h. The mixture was diluted with DCM (300 mL) and washed with 0.6 M HCl (300 mL). The organic phase was washed with brine, dried over Na2SO4 and concentrated in vacuo to give 11' (6.5 g), which was used without further purification.

[0366] Example 2: ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)((4,6,7,8-tetrahydro-5,8-ethanothieno[3,2-c]azepine Synthesis of sodium ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)((4,6,7,8-tetrahydro-5,8-ethanothieno[3,2-c]azepin-2-yl)sulfonyl)amide)(26)

[0367]

[0368] A mixture of 14 (2.0 g, 15.6 mmol, 1.0 eq), DIEA (8.1 g, 62.4 mmol, 4.0 eq) and HATU (9.0 g, 23.4 mmol, 1.5 eq) in DMF (30 mL) was stirred at room temperature for 30 min. Then 1' (3.6 g, 23.4 mmol, 1.5 eq) was added at 0°C, and the reaction mixture was stirred at room temperature overnight. The mixture was diluted with water (150 mL) and extracted with EtOAc (80 mL×3). The combined organic layers were washed with water (100 mL×3), brine (100 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel chromatography to give 15 (3.06 g).

[0369] To a solution of 15 (3.06 g, 13.46 mmol, 1.0 equiv) in EtOH (30 mL) and H2O (10 mL) was slowly added NaOH (1.62 g, 40.39 mmol, 3.0 equiv) at 0°C. The reaction mixture was stirred at room temperature for 2 h. The pH was adjusted to 2 with 3M HCl. The mixture was extracted with EtOAc (50 mL×3). The combined organic layers were washed with water (80 mL×3), brine (50 mL), dried over Na2SO4 and concentrated in vacuo to give compound 16 (2.4 g), which was used in the next step without further purification.

[0370] To a solution of 16 (1.94 g, 9.7 mmol, 1.0 equivalent) in MsOH (40 mL) was added P2O5 (6.9 g, 48.7 mmol, 5.0 equivalent) at room temperature. The reaction mixture was stirred overnight at 130 ° C. The reaction mixture was poured into ice water (200 mL) and extracted with DCM. The combined organic layers were concentrated in vacuo and purified by silica gel chromatography to obtain compound 17 (1.24 g).

[0371] To a solution of 4' (1.56 g, 6.95 mmol, 1.2 eq) was added NaH (1.26 g, 54 mmol, 1.5 eq) at 0°C. After stirring at 0°C for 30 min, 17 (1.05 g, 5.8 mmol, 1.0 eq) was added. The mixture was stirred at room temperature overnight. Water (40 mL) was added dropwise at 0°C. The mixture was extracted with EtOAc (30 mL×3). The combined organic layers were washed with water (40 mL×3), brine (40 mL), dried over Na2SO4 and concentrated in vacuo to give compound 18 (1.2 g), which was used in the next step without further purification.

[0372] To a solution of 5 (1.2 g, 4.78 mmol, 1.0 eq.) in MeOH (40 mL) and THF (4 mL) was added Mg (470 mg, 19.10 mmol, 4.0 eq.). The reaction mixture was stirred at room temperature overnight. The mixture was adjusted to pH 1 with 3M HCl and extracted with DCM (30 mL×3). The combined organic layers were washed with NaHCO (45 mL), brine (45 mL), dried over NaSO, and concentrated in vacuo to give 19 (1.2 g).

[0373] LAH (3.8 g, 100.29 mmol, 20.0 equiv) was added to a solution of 19 (1.2 g, 50.14 mmol, 1.0 equiv) in THF (40 mL). The reaction mixture was stirred at 80 ° C overnight. The mixture was cooled and quenched with ice water (10 mL), sodium hydroxide (3N, 5 mL) and water (30 mL). The mixture was filtered and the filtrate was extracted with EtOAc (15 mL×3). The combined organic layer was washed with brine (20 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel chromatography to obtain 20 (270 mg).

[0374] To a mixture of 7 (270 mg, 1.37 mmol, 1.0 eq.) and PPh3 (1.26 g, 4.79 mmol, 3.5 eq.) in anhydrous THF (50 mL) was slowly added DIAD (830 mg, 4.11 mmol, 3.0 eq.) at 0°C. The reaction mixture was stirred at room temperature overnight. The mixture was concentrated in vacuo, and the residue was purified by silica gel chromatography to give 21 (180 mg).

[0375] A mixture of 21 (156 mg, 0.87 mmol, 1.0 eq) and SO3.DMF (400 mg, 2.61 mmol, 3.0 eq) in DCM (5 mL) was stirred under microwave at 70° C. for 1 h. The mixture was concentrated in vacuo to give 22 (200 mg) which was used without further purification.

[0376] A solution of 22 (90 mg, 0.35 mmol, 1.0 equiv) in SOCl2 (4 mL) was stirred for 1 h at 80° C. The reaction mixture was concentrated in vacuo to give 23, which was used in the next step without further purification.

[0377] To a solution of 23 in THF (10 mL) was slowly added NH 4 OH (3 mL) at 0° C. The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo. The residue was purified by silica gel chromatography to give 24 (45 mg).

[0378] To a solution of 11 (25 mg, 0.1 mmol, 1.0 eq.) in anhydrous THF (3 mL) was added t-BuONa solution (47 mg, 0.48 mmol, 5.0 eq.) at 0 °C in N2. The mixture was stirred at room temperature for 15 min. A solution of 11' (50 mg, 0.15 mmol, 1.5 eq.) was then added to the reaction mixture at 0 °C and stirred at room temperature for 3 h. The reaction mixture was concentrated in vacuo. The residue was purified by silica gel chromatography to give 25 (36 mg). LCMS: [M+1] +＝ 458.

[0379] 25 (36 mg, 0.078 mmol, 1.0 equiv) was added to a NaOH aqueous solution (7.8 mL, 0.01 N NaOH) at 0°C. The reaction was stirred at room temperature for 30 min. The mixture was then lyophilized to give compound 26 (36 mg) as a light yellow solid. LCMS: 2.75 min, [M-Na+1] +＝ 458.1. 1 HNMR(400MHz,D2O)δ7.32(s,1H),7.09(s,1H),4.08(s,2H),3.16~3.09(m,3H),3. 20~2.95(m,2H), 2.88(t,J=7.2Hz,4H), 2.66(t,J=7.2Hz,4H), 2.07~2.01(m,8H).

[0380] Compounds 27-44 were prepared by methods analogous to those described in the previous examples.

[0381]

[0382]

[0383]

[0384] Compounds 45-54 were prepared by methods analogous to those described in the previous examples.

[0385]

[0386]

[0387] Example 3: Mouse BMDM IL-1b assay

[0388] Mouse bone marrow cells from C57BL6 tibia and femur were cultured at a density of 50 million cells / 15 cm petri dish in complete Isocov medium (BMDM medium) supplemented with 20 ng / mL MCSF. Fresh medium was replaced every 3 days, and bone marrow-derived macrophages were collected on day 7, washed and counted. Cells were plated at 5×10 per well. 4Cells were seeded at a density of 100 uL of BMDM medium in a 96-well plate and cultured overnight. Cells were stimulated with 200 ng / mL ultrapure LPS-B5 at 37°C for 3 h, and then pre-diluted compounds were added. 5 mM ATP was added for a second stimulation 30 min after compound addition for 45 min. After stimulation, the plate was briefly centrifuged and 50 μL of supernatant was collected from each well. ELISA for mouse IL-1b was performed using a pre-coated kit with 1:10 and 1:100 diluted supernatants. IL-1b concentrations were calculated based on pre-titrated standards, and compound inhibition IC50s were generated using the Levenberg Marquardt damped least squares method.

[0389] IC 50 The values ​​are shown in the following table.

[0390] Compound <![CDATA[IL-1b(IC 50 )]]> Compound <![CDATA[IL-1b(IC 50 )]]> 13 A 26 A

[0391] A:IC 50 <100nM

[0392] Example 4: Human whole blood (HWB) IL-1b assay

[0393] The assay was performed as described by Tran et al. "Whole blood assay as a model for in vitro evaluation of inflammation activation and subsequent caspase-mediated interleukin-1beta release" PLoS ONE 14(4): e0214999. https: / / doi.org / 10.1371 / journal.pone.0214999. That is, freshly drawn human whole blood with anticoagulant was incubated with the test compound at different titration points at 37°C in 5% CO2 for 0.5 h. The cells were then primed with 100 ng / mL LPS at 37°C for 3.5 h, followed by restimulation with 5 mM ATP for 45 min. The supernatant was harvested and analyzed for human IL-1b concentration using a commercially available ELISA kit.

[0394] IC 50 The values ​​are shown in the following table.

[0395]

[0396] A:IC 50 <1μM; 1μM≤B:IC 50 ≤10μM.

[0397] Example 5: Human monocyte IL-1b assay

[0398] Human PBMCs were harvested from fresh donor blood using a Ficoll gradient. 50 million PBMC cells in 10 mL RPMI were seeded onto a 15 cm non-tissue culture treated Petri dish and incubated at 37 °C for 1 h. At the end of the incubation period, the medium was gently shaken and non-adherent cells were removed. Adherent cells were harvested by gently scraping and counted. The enriched adherent cells were plated at 2 × 10 4 Cells / well were seeded into 96-well plates and stimulated with 200ng / mL ultrapure LPS-B5 for 3h before adding pre-diluted compounds. 30min after compound addition, 5mM ATP was added for a second stimulation for 45min. After stimulation, the plates were briefly centrifuged and 50μL of supernatant was collected from each well. ELISA for human IL-1b was performed using a pre-coated kit with 1:10 and 1:100 dilutions of supernatant. IL-1b concentrations were calculated based on pre-titrated standards and compound inhibition IC50s were generated using the Levenberg Marquardt damped least squares method.

[0399] The examples and embodiments described herein are for illustrative purposes only, and in some embodiments, various modifications or changes are intended to be included within the scope of the disclosure and the scope of the appended claims.

Claims

1. A compound of formula (I') or a pharmaceutically acceptable salt thereof: in: X1 is 0; X2 is -N(R4)-; X3 is -N(R5)-; R1 is R2 is Y1 is O or S; Y2 is C(R9); Z1 is -C(R 17 )=C(R 17 )-; Z2 is C(R 19 ); R4 is hydrogen; R5 is hydrogen; R9 is hydrogen; R 11 and R 12 are independently selected from hydrogen, halogen and C1-C6 alkyl; or R 11 and R 12 Combine to form a 5-membered cycloalkyl ring; R 13 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkynyl, C3-C5 cycloalkyl or C2-C9 heteroaryl, wherein the C2-C9 heteroaryl is optionally substituted by 1 R 16 replace; R 16 is a C1-C6 alkoxy group; R 17 are each independently selected from hydrogen and halogen; R 19 is hydrogen, halogen or -CN; m is 1; n is 2; p is 1; q is 0; s is 1; and t is 1.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R1 is 3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R2 is 4. The compound according to claim 3 or a pharmaceutically acceptable salt thereof, wherein R 19 For hydrogen.

5. The compound according to claim 3 or a pharmaceutically acceptable salt thereof, wherein R 19 It is a halogen.

6. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R2 is 7. The compound according to claim 6 or a pharmaceutically acceptable salt thereof, wherein R17 Each is hydrogen.

8. The compound according to claim 6 or a pharmaceutically acceptable salt thereof, wherein R 13 is optionally replaced by 1 R 16 Substituted C2-C9 heteroaryl.

9. The compound according to claim 8 or a pharmaceutically acceptable salt thereof, wherein R 13 is optionally replaced by 1 R 16 Substituted pyridinyl.

10. The compound according to claim 6 or a pharmaceutically acceptable salt thereof, wherein R 13 It is a C1-C6 alkyl group.

11. The compound according to claim 6 or a pharmaceutically acceptable salt thereof, wherein R 13 It is a C3-C5 cycloalkyl group.

12. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R2 is 13. A compound, which is: or a pharmaceutically acceptable salt thereof.

14. A compound, which is: or a pharmaceutically acceptable salt thereof.

15. A compound selected from: or a pharmaceutically acceptable salt thereof.

16. A pharmaceutical composition comprising the compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

17. Use of a compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 16 in the preparation of a medicament for treating an inflammatory or autoimmune disease in a patient.

18. Use according to claim 17, wherein the inflammatory or autoimmune disease is selected from rheumatoid arthritis, multiple sclerosis, psoriasis, lupus and inflammatory bowel disease.

19. The use according to claim 17, wherein the inflammatory or autoimmune disease is Crohn's disease.

20. The use according to claim 17, wherein the inflammatory or autoimmune disease is ulcerative colitis.

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