Compounds for inhibition of inflammation

A method of treating or preventing a disease or condition in which inflammasome activation is implicated in pathogenesis, the method comprises administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I):

• or a pharmaceutically acceptable salt thereof, wherein:
• R1, R2, R3, and R4 are each independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, Cy1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, S(O)2Rb1, and S(O)2NRc1Rd1;
• wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2 or 3 substituents independently selected from Cy1, halo, CN, NO2, ORa1, SRa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1C(O)NRc1Rd1, NRc1S(O)2Rb1, NRc1S(O)2NRc1Rd1, S(O)2Rb1 and S(O)2NRc1Rd1;
• or R1 and R2 together with the N atom to which they are attached form a 4-12 membered heterocycloalkyl, which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from RCy2;
• or R3 and R4 together with the N atom to which they are attached form a 4-12 membered heterocycloalkyl, which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from RCy3;
• each Cy1 is independently selected from C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-12 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from RCy1;
• each RCy1, RCy2, and RCy3 is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, halo, CN, NO2, ORa2, C(O)Rb2, C(O)NRc2Rd2, C(O)ORa2, NRc2Rd2, NRc2C(O)Rb2, NRc2C(O)ORa2, NRc2C(O)NRc2Rd2, S(O)2Rb2 and S(O)2NRc2Rd2;
• Ra1, Ra2, Rc1, Rc2, Rd1, and Rd2 are each independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-4 haloalkyl, Cy1, C(O)Rb3, C(O)NRc3Rd3, C(O)ORa3, S(O)2Rb3, and S(O)2NRc3Rd3;
• wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Cy1, halo, CN, NO2, ORa3, SRa3, C(O)Rb3, C(O)NRc3Rd3, C(O)ORa3, NRc3Rd3, NRc3C(O)Rb3, NRc3C(O)ORa3, NRc3C(O)NRc3Rd3, NRc3S(O)2Rb3, NRc3S(O)2NRc3Rd3, S(O)2Rb3 and S(O)2NRc3Rd3;
• Rb1 and Rb2 are each independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-4 haloalkyl and Cy1;
• wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Cy1, halo, CN, NO2, ORa3, SRa3, C(O)Rb3, C(O)NRc3Rd3, C(O)ORa3, NRc3Rd3, NRc3C(O)Rb3, NRc3C(O)ORa3, NRc3C(O)NRc3Rd3, NRc3S(O)2Rb3, NRc3S(O)2NRc3Rd3, S(O)2Rb3 and S(O)2NRc3Rd3;
• Ra3, Rc3, and Rd3 are each independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-12 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, (4-12 membered heterocycloalkyl)-C1-4 alkylene, C(O)Rb4, C(O)NRc4Rd4, C(O)ORa4, NRc4Rd4, S(O)2Rb4, and S(O)2NRc4Rd4;
• wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-12 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-12 membered heterocycloalkyl)-C1-4 alkylene are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from oxo, C1-6 alkyl, C1-4 haloalkyl, C1-4 hydroxyalkyl, C1-6 cyanoalkyl, halo, CN, NO2, ORa4, SRa4, C(O)Rb4, C(O)NRc4Rd4, C(O)ORa4, NRc4Rd4, NRc4C(O)Rb4, NRc4C(O)ORa4, NRc4C(O)NRc4Rd4, NRc4S(O)2Rb4, NRc4S(O)2NRc4Rd4, S(O)2Rb4, and S(O)2NRc4Rd4;
• each Rb3 is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-4 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-12 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-12 membered heterocycloalkyl)-C1-4 alkylene, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-12 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-12 membered heterocycloalkyl)-C1-4 alkylene are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from C1-6 alkyl, C1-4 haloalkyl, C1-4 hydroxyalkyl, C1-6 cyanoalkyl, halo, CN, NO2, ORa4, SRa4, C(O)Rb4, C(O)NRc4Rd4, C(O)ORa4, NRc4Rd4, NRc4C(O)Rb4, NRc4C(O)ORa4, NRc4C(O)NRc4Rd4, NRc4S(O)2Rb4, NRc4S(O)2NRc4Rd4, S(O)2Rb4, and S(O)2NRc4Rd4;
• Ra4, Rc4, and Rd4 are each independently selected from H, C1-6 alkyl, C1-4haloalkyl, C1-4 hydroxyalkyl, C1-4 cyanoalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-12 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, (4-12 membered heterocycloalkyl)-C1-4 alkylene and Rg, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-12 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-12 membered heterocycloalkyl)-C1-4 alkylene are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Rg;
• each Rb4 is independently selected from C1-6 alkyl, C1-4haloalkyl, C1-4 hydroxyalkyl, C1-4 cyanoalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-12 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, (4-12 membered heterocycloalkyl)-C1-4 alkylene and Rg, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-12 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-12 membered heterocycloalkyl)-C1-4 alkylene is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Rg;
• and
• each Rg is independently selected from OH, NO2, CN, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-4 haloalkyl, C1-6alkoxy, C1-6 haloalkoxy, cyano-C1-3 alkylene, HO—C1-3 alkylene, C6-10 aryl, C6-10 aryloxy, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-12 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, (4-12 membered heterocycloalkyl)-C1-4 alkylene, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, thio, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, carbamyl, C1-6 alkylcarbamyl, di(C1-6 alkyl)carbamyl, carboxy, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, C1-6 alkylcarbonylamino, C1-6 alkylsulfonylamino, aminosulfonyl, C1-6 alkylaminosulfonyl, di(C1-6 alkyl)aminosulfonyl, aminosulfonylamino, C1-6 alkylaminosulfonylamino, di(C1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C1-6 alkylaminocarbonylamino, and di(C1-6 alkyl)aminocarbonylamino.

A method of:

• inhibiting gasdermin pore formation in a cell;
• and/or
• inhibiting inflammasome-mediated death of a cell (pyroptosis);
• and/or
• inhibiting cytokine secretion from a cell;
• and/or
• inhibiting an inflammatory caspase in a cell;
• and/or
• covalently reacting with a cysteine of a gasdermin protein in a cell;
• and/or
• covalently reacting with a cysteine of an inflammatory signaling molecule selected from:
• a sensor, an adaptor, and a transcription factor, or a regulator thereof;
• the method comprising contacting the cell with an effective amount of a compound of Formula (I):
• or a pharmaceutically acceptable salt thereof, wherein:
• R1, R2, R3, and R4 are each independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, Cy1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, S(O)2Rb1, and S(O)2NRc1Rd1;
• wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2 or 3 substituents independently selected from Cy1, halo, CN, NO2, ORa1, SRa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1C(O)NRc1Rd1, NRc1S(O)2Rb1, NRc1S(O)2NRc1Rd1, S(O)2Rb1 and S(O)2NRc1Rd1;
• or R1 and R2 together with the N atom to which they are attached form a 4-12 membered heterocycloalkyl, which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from RCy2;
• or R3 and R4 together with the N atom to which they are attached form a 4-12 membered heterocycloalkyl, which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from RCy3;
• each Cy1 is independently selected from C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-12 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from RCy1;
• each RCy1, RCy2, and RCy3 is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, halo, CN, NO2, ORa2, C(O)Rb2, C(O)NRc2Rd2, C(O)ORa2, NRc2Rd2, NRc2C(O)Rb2, NRc2C(O)ORa2, NRc2C(O)NRc2Rd2, S(O)2Rb2 and S(O)2NRc2Rd2;
• Ra1, Ra2, Rc1, Rc2, Rd1, and Rd2 are each independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-4 haloalkyl, Cy1, C(O)Rb3, C(O)NRc3Rd3, C(O)ORa3, S(O)2Rb3, and S(O)2NRc3Rd3;
• wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Cy1, halo, CN, NO2, ORa3, SRa3, C(O)Rb3, C(O)NRc3Rd3, C(O)ORa3, NRc3Rd3, NRc3C(O)Rb3, NRc3C(O)ORa3, NRc3C(O)NRc3Rd3, NRc3S(O)2Rb3, NRc3S(O)2NRc3Rd3, S(O)2Rb3 and S(O)2NRc3Rd3;
• Rb1 and Rb2 are each independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-4 haloalkyl and Cy1;
• wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Cy1, halo, CN, NO2, ORa3, SRa3, C(O)Rb3, C(O)NRc3Rd3, C(O)ORa3, NRc3Rd3, NRc3C(O)Rb3, NRc3C(O)ORa3, NRc3C(O)NRc3Rd3, NRc3S(O)2Rb3, NRc3S(O)2NRc3Rd3, S(O)2Rb3 and S(O)2NRc3Rd3;
• Ra3, Rc3, and Rd3 are each independently selected from H, C1-6 alkyl, C1-4haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-12 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, (4-12 membered heterocycloalkyl)-C1-4 alkylene, C(O)Rb4, C(O)NRc4Rd4, C(O)ORa4, NRc4Rd4, S(O)2Rb4, and S(O)2NRc4Rd4;
• wherein said Cue alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-12 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-12 membered heterocycloalkyl)-C1-4 alkylene are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from oxo, C1-6 alkyl, C1-4haloalkyl, C1-4 hydroxyalkyl, C1-6 cyanoalkyl, halo, CN, NO2, ORa4, SRa4, C(O)Rb4, C(O)NRc4Rd4, C(O)ORa4, NRc4Rd4, NRc4C(O)Rb4, NRc4C(O)ORa4, NRc4C(O)NRc4Rd4, NRc4S(O)2Rb4, NRc4S(O)2NRc4Rd4, S(O)2Rb4, and S(O)2NRc4Rd4;
• each Rb3 is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-4 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-12 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-12 membered heterocycloalkyl)-C1-4 alkylene, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-12 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-12 membered heterocycloalkyl)-C1-4 alkylene are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from C1-6 alkyl, C1-4 haloalkyl, C1-4 hydroxyalkyl, C1-6 cyanoalkyl, halo, CN, NO2, ORa4, SRa4, C(O)Rb4, C(O)NRc4Rd4, C(O)ORa4, NRc4Rd4, NRc4C(O)Rb4, NRc4C(O)ORa4, NRc4C(O)NRc4Rd4, NRc4S(O)2Rb4, NRc4S(O)2NRc4Rd4, S(O)2Rb4, and S(O)2NRc4Rd4;
• Ra4, Rc4, and Rd4 are each independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C1-4 hydroxyalkyl, C1-4 cyanoalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-12 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, (4-12 membered heterocycloalkyl)-C1-4 alkylene and Rg, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-12 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-12 membered heterocycloalkyl)-C1-4 alkylene are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Rg;
• each Rb4 is independently selected from C1-6 alkyl, C1-4 haloalkyl, C1-4 hydroxyalkyl, C1-4 cyanoalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-12 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, (4-12 membered heterocycloalkyl)-C1-4 alkylene and Rg, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-12 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-12 membered heterocycloalkyl)-C1-4 alkylene is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Rg;
• and
• each Rg is independently selected from OH, NO2, CN, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-4 haloalkyl, C1-6alkoxy, C1-6 haloalkoxy, cyano-C1-3 alkylene, HO—C1-3 alkylene, C6-10 aryl, C6-10 aryloxy, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-12 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, (4-12 membered heterocycloalkyl)-C1-4 alkylene, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, thio, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, carbamyl, C1-6 alkylcarbamyl, di(C1-6 alkyl)carbamyl, carboxy, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, C1-6 alkylcarbonylamino, C1-6 alkylsulfonylamino, aminosulfonyl, C1-6 alkylaminosulfonyl, di(C1-6 alkyl)aminosulfonyl, aminosulfonylamino, C1-6 alkylaminosulfonylamino, di(C1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C1-6 alkylaminocarbonylamino, and di(C1-6 alkyl)aminocarbonylamino.

A method of:

• inhibiting gasdermin pore formation in a cell;
• and/or
• inhibiting inflammasome-mediated death of a cell (pyroptosis);
• and/or
• inhibiting cytokine secretion from a cell;
• and/or
• inhibiting an inflammatory caspase in a cell;
• and/or
• covalently reacting with a cysteine of a gasdermin protein in a cell;
• and/or
• covalently reacting with a cysteine of an inflammatory signaling molecule selected from:
• a sensor, an adaptor, and a transcription factor, or a regulator thereof;
• and/or
• treating or preventing a disease or condition in which inflammasome activation and/or gasdermin inflammatory cell death is implicated in pathogenesis;
• the method comprising contacting the cell with an effective amount of, or administering to a subject in need thereof a therapeutically effective amount of, any one of the following compounds:
• or a pharmaceutically acceptable salt thereof.

A method of identifying a compound that:

• inhibits a gasdermin pore formation in a cell;
• and/or
• inhibits inflammasome-mediated death of a cell (pyroptosis);
• and/or
• inhibits cytokine secretion from a cell;
• and/or
• inhibits an inflammatory caspase in a cell;
• and/or
• covalently reacts with a cysteine of a gasdermin protein in a cell;
• and/or
• covalently reacts with a cysteine of an inflammatory signaling molecule selected from:
• a sensor, an adaptor, and a transcription factor, or a regulator thereof;
• the method comprising:
• i) providing a sample comprising a liposome comprising a metal cation capable of forming a complex with a chelating ligand, the chelating ligand, a test compound, and a gasdermin protein, or a fragment thereof;
• ii) contacting the gasdermin protein in the sample with a protease enzyme;
• and
• iii) determining whether the test compound inhibits leakage of the metal cation from the liposome, wherein said inhibition of the leakage of the metal cation from the liposome is an indication that the test compound:
• inhibits a gasdermin pore formation in a cell;
• and/or
• inhibits inflammasome-mediated death of a cell (pyroptosis);
• and/or
• inhibits cytokine secretion from a cell;
• and/or
• inhibits an inflammatory caspase in a cell;
• and/or
• covalently reacts with a cysteine of a gasdermin protein in a cell;
• and/or
• covalently reacts with a cysteine of an inflammatory signaling molecule selected from:
• a sensor, an adaptor, and a transcription factor, or a regulator thereof.