Organic compounds as nlrp3 inhibitors

A compound represented by the structure of Formula (1-II):

• or a pharmaceutically acceptable salt, solvate, isomer, atropisomer, or tautomer thereof;
• wherein ring
• is a 4-11 membered nitrogen-containing heterocycloalkyl ring or substituted heterocycloalkyl ring;
• R1 is selected from the group consisting of —CN, —H, —F, and —CF3;
• R1′ is H;
• or R1 together with R1′ form a thiophene ring;
• R2 is selected from the group consisting of H, C1-C3 alkyl, and —CF3;
• R3 is selected from the group consisting of H, C1-C3 alkyl, and —CF3;
• or R2 together with R3 form a 5- or 6-membered aromatic or non-aromatic ring, all carbon or with O or N, optionally substituted with -Me or —OH;
• Y is a bond or C1-C3 alkyl optionally substituted with 1, 2, or 3 C1-C3 alkyl or —CF3;
• R4 is selected from the group consisting of H, —F, C1-C3 alkyl, and —CF3;
• R5 is selected from the group consisting of H, Me, and —CF3;
• R6 and R6′ are independently selected from the group consisting of —H, —F, C1-C6 alkyl, C1-C6 cycloalkyl, and —CF3;
• or R6 and R6′ together with the atom they are bonded to form a C1-C6 cycloalkyl or C1-C6 heterocycloalkyl ring;
• and
• n is 2, 3, or 4.

A compound represented by the structure of Formula (1-III):

• or a pharmaceutically acceptable salt, solvate, isomer, atropisomer, or tautomer thereof,
• wherein ring
• is a 4-7 membered nitrogen-containing heterocycloalkyl ring or substituted heterocycloalkyl ring;
• ring
• is a 4-7 membered cycloalkyl ring or substituted cycloalkyl ring;
• R1 is selected from the group consisting of —CN, —H, —F, and —CF3;
• R1′ is H;
• or R1 and R1′ together form a thiophene ring;
• R2 is selected from the group consisting of H, C1-C3 alkyl, and —CF3;
• R3 is selected from the group consisting of H, C1-C3 alkyl, and —CF3;
• or R2 together with R3 form a 5- or 6-membered aromatic or non-aromatic ring, all carbon or with O or N, optionally substituted with -Me or —OH;
• R4 is selected from the group consisting of H, —F, C1-C3 alkyl, and —CF3;
• and
• Y is a bond or C1-C3 alkyl optionally substituted with 1, 2, or 3 C1-C3 alkyl or —CF3.

A compound represented by the structure of Formula (1-IV):

• or a pharmaceutically acceptable salt, solvate, isomer, atropisomer, or tautomer thereof,
• wherein ring
• is a 4-7 membered nitrogen-containing heterocycloalkyl ring or substituted heterocycloalkyl ring;
• wherein ring
• is a 4-7 membered nitrogen-containing heterocycloalkyl ring or substituted hetereocycloalkyl ring;
• R1 is selected from the group consisting of —CN, —H, —F, and —CF3;
• R1′ is H;
• or R1 and R1′ together form a thiophene ring;
• R2 is selected from the group consisting of H, C1-C3 alkyl, and —CF3;
• R3 is selected from the group consisting of H, C1-C3 alkyl, and —CF3;
• or R2 together with R3 form a 5- or 6-membered aromatic or non-aromatic ring, all carbon or with O or N within the ring, optionally substituted with -Me or —OH;
• Y is a bond or C1-C3 alkyl optionally substituted with 1, 2, or 3 C1-C3 alkyl or —CF3;
• R4 is selected from the group consisting of H, —F, C1-C3 alkyl, and —CF3;
• and
• R5 is selected from the group consisting of —H, -Me and —CF3.

A compound represented by the structure of Formula (1-V):

• or a pharmaceutically acceptable salt, solvate, isomer, atropisomer, or tautomer thereof,
• wherein ring
• is a 4-11 membered cycloalkyl heterocycloalkyl, substituted cycloalkyl, or substituted heterocycloalkyl ring;
• W is NH, N-Me, N-Et, N-iPr, or a bond;
• R1 is selected from the group consisting of —CN, —H, —F, and —CF3;
• R1′ is H;
• or R1 and R1′ together form a thiophene ring;
• R2 is selected from the group consisting of H, C1-C3 alkyl, —CF3;
• R4 is selected from the group consisting of H, —F, C1-C3 alkyl, and —CF3;
• Y is a bond or C1-C3 alkyl optionally substituted with 1, 2, or 3 C1-C3 alkyl or —CF3;
• R5 is selected from the group consisting of —H, -Me, and —CF3;
• R6 and R6′ are independently selected from the group consisting of —H, —F, C1-C6 alkyl, and —CF3,
• or R6 and R6′ together with the atom they are bonded to form a C1-C6 cycloalkyl or C1-C6 heterocycloalkyl ring;
• and
• n is 1, 2, 3, or 4.

A compound represented by the structure of Formula (1-VI):

• wherein ring
• is an optionally substituted 4-7 membered nitrogen-containing heterocycloalkyl ring or substituted heterocycloalkyl ring;
• ring
• is an optionally substituted 4-7 membered cycloalkyl ring or substituted cycloalkyl ring;
• R1 is selected from the group consisting of —CN, —H, —F, and —CF3;
• R1′ is H;
• or R1 and R1′ together form a thiophene ring;
• R2 is selected from the group consisting of —H, C1-C3 alkyl, and —CF3;
• R4 is selected from the group consisting of —H, —F, C1-C3 alkyl, and —CF3;
• R5 is selected from the group consisting of —H, -Me, and —CF3;
• and
• Y is a bond or C1-C3 alkyl optionally substituted with 1, 2, or 3 C1-C3 alkyl or —CF3.

A compound represented by the structure of Formula (1-VII):

• wherein ring
• is a 4-11 membered cycloalkyl heterocycloalkyl, substituted cycloalkyl, or substituted heterocycloalkyl ring;
• R1 is selected from the group consisting of —CN, —H, —F, and —CF3;
• R1′ is H;
• or R1 and R1′ together form a thiophene ring;
• R2 is selected from the group consisting of —H, C1-C3 alkyl, —CF3;
• R4 is selected from the group consisting of —H, —F, C1-C3 alkyl, and —CF3;
• R5 is selected from the group consisting of —H, -Me, and —CF3;
• R6 and R6′ are independently selected from the group consisting of —H, —F, C1-C6 alkyl, C1-C6 cycloalkyl, and —CF3,
• or R6 and R6′ together with the atom they are bonded to form a C1-C6 cycloalkyl or C1-C6 heterocycloalkyl ring;
• n is 0, 1, 2, 3, or 4;
• and
• Y is a bond or C1-C3 alkyl optionally substituted with 1, 2, or 3 C1-C3 alkyl or —CF3.

A compound represented by the structure of Formula (1-VIII):

• wherein ring
• is a 4-11 membered cycloalkyl, heterocycloalkyl, substituted cycloalkyl, or substituted heterocycloalkyl ring;
• R1 is selected from the group consisting of —CN, —H, —F, and —CF3;
• R1′ is H;
• or R1 and R1′ together form a thiophene ring;
• R2 is selected from the group consisting of —H, C1-C3 alkyl, and —CF3;
• R4 is selected from the group consisting of H, —F, C1-C3 alkyl, and —CF3;
• R5 is selected from the group consisting of H, Me, and —CF3;
• R6 and R6′ are independently selected from the group consisting of —H, —F, C1-C6 alkyl, and —CF3,
• or R6 and R6′ together with the atom they are bonded to form a C1-C6 cycloalkyl or C1-C6 heterocycloalkyl ring;
• n is 1, 2, 3, or 4;
• and
• Y is a bond (or C1-C3 alkyl optionally substituted with 1, 2, or 3 C1-C3 alkyl or —CF3.

A compound represented by the structure of Formula (1-IX):

• or a pharmaceutically acceptable salt, solvate, isomer, atropisomer, or tautomer thereof,
• wherein ring
• is a 4-11 membered nitrogen-containing heterocycloalkyl ring or substituted heterocycloalkyl ring,
• R1 is selected from the group consisting of —CN, —H, —F, and —CF3;
• R1′ is H;
• or R1 and R1′ together form a thiophene ring;
• R2 is selected from the group consisting of H, C1-C3 alkyl, —CF3;
• R3 is selected from the group consisting of H, C1-C3 alkyl, and —CF3;
• or R2 together with R3 form a 5- or 6-membered aromatic or non-aromatic ring, all carbon or with O or N within the ring, optionally substituted with -Me or —OH;
• R4 is selected from the group consisting of H, —F, C1-C3 alkyl, and —CF3;
• R5 is selected from the group consisting of H, Me, and —CF3;
• R6 and R6′ are independently selected from the group consisting of —H, —F, C1-C6 alkyl, C1-6 cycloalkyl, and —CF3,
• or R6 and R6′ together with the atom they are bonded to form a C1-C6 cycloalkyl or C1-C6 heterocycloalkyl ring;
• n is 2, 3, or 4;
• and
• Y is a bond (or C1-C3 alkyl optionally substituted with 1, 2, or 3 C1-C3 alkyl or —CF3.

A compound represented by the structure of Formula (2-I)

• or a pharmaceutically acceptable salt, solvate, hydrate, isomer, atropisomer, or tautomer thereof,
• wherein ring
• is a 4-11 membered cycloalkyl, substituted cycloalkyl, heterocycloalkyl, or substituted heterocycloalkyl ring;
• W is selected from the group consisting of NH, N-Me, N-Et and N-iPr, or W is a bond;
• R1 is selected from the group consisting of —CN, —H, —F, and —CF3;
• R1′ is —H;
• or R1 together with R1′ form a thiophene ring;
• each R2 and R3 is selected from the group consisting of —H, C1-C3 alkyl, and —CF3;
• or R2 together with R3 forms a 5- or 6-membered aromatic or non-aromatic ring containing all C or at least one O or N, optionally substituted with -Me or —OH;
• R4 is selected from the group consisting —H, —F, C1-C3 alkyl, and —CF3;
• Y is a bond or C1-C3 alkyl optionally substituted with 1, 2, or 3 C1-C3 alkyl or —CF3.
• R5 is selected from the group consisting of —H, -Me and —CF3;
• R6 and R6′ are independently selected from the group consisting of —H, —F, C1-C6 alkyl or cycloalkyl, and —CF3;
• or R6 and R6′ together with the atom they are bonded to form a C1-C6 cycloalkyl or C1-C6 heterocycloalkyl ring;
• n is 1, 2, 3, or 4;
• and
• R7 is selected from the group consisting of —H, C1-C6 alkyl, cycloalkyl, heterocylcoalkyl,

A compound represented by the structure of Formula (2-II)

• or a pharmaceutically acceptable salt, solvate, hydrate, isomer, atropisomer, or tautomer thereof,
• wherein ring
• is a 4-11 membered nitrogen-containing heterocycloalkyl ring or substituted heterocycloalkyl ring;
• W is selected from NH, N-Me, N-Et and N-iPr, or is a bond;
• R1 is selected from the group consisting of —CN, —H, —F, and —CF3;
• R1′ is H;
• or R1 and R1′ together form a thiophene ring;
• R2 and R3 are each independently selected from the group consisting of H, C1-C3 alkyl, and —CF3;
• or R2 together with R3 form a 5- or 6-membered aromatic or non-aromatic ring, all carbon or with O or N within the ring, optionally substituted with -Me or —OH;
• R4 is selected from the group consisting of —H, —F, C1-C3 alkyl, and —CF3;
• R5 is selected from the group consisting of —H, -Me, and —CF3;
• R6 and R6′ are independently selected from the group consisting of —H, —F, C1-C6 alkyl or cycloalkyl, and —CF3;
• or R6 and R6′ together with the atom they are bonded to form a C1-C6 cycloalkyl or C1-C6 heterocycloalkyl ring;
• and
• n is 1, 2, 3, or 4.

A compound represented by the structure of Formula (2-III)

• or a pharmaceutically acceptable salt, solvate, hydrate isomer, atropisomer, or tautomer thereof,
• wherein ring
• is a 4-11 membered heterocycloalkyl or substituted heterocycloalkyl ring;
• R1 is selected from the group consisting of —CN, —H, —F, and —CF3;
• R1′ is H;
• or R1 and R1′ together form a thiophene ring;
• R2 is selected from the group consisting of H, C1-C3 alkyl, —CF3;
• R3 is selected from the group consisting of H, C1-C3 alkyl, —CF3;
• Or R2 together with R3 form a 5- or 6-membered aromatic or non-aromatic ring, all carbon or with O or N within the ring, optionally substituted with -Me or —OH;
• R4 is selected from the group consisting of —H, —F, C1-C3 alkyl, and —CF3;
• R5 is selected from the group consisting of —H, -Me and —CF3;
• W2 is selected from the group consisting of optionally substituted —CH2—, —CH2CH2—, and —CH2CH2CH2—, or is a bond.

A compound represented by the structure of Formula (2-IV):

• or a pharmaceutically acceptable salt, solvate, hydrate, isomer, atropisomer, or tautomer thereof, wherein:
• ring
• is a 4-11 membered cycloalkyl, substituted cycloalkyl, heterocycloalkyl or substituted heterocycloalkyl ring;
• R1 is selected from the group consisting of —CN, —H, —F, and —CF3;
• R1′ is H;
• or R1 and R1′ together form a thiophene ring;
• R2 is selected from the group consisting of H, C1-C3 alkyl, —CF3;
• R3 is selected from the group consisting of H, C1-C3 alkyl, —CF3;
• or R2 together with R3 form a 5- or 6-membered aromatic or non-aromatic ring, all carbon or with O or N within the ring, optionally substituted with -Me or —OH;
• R4 is selected from the group consisting of —H, —F, C1-C3 alkyl, and —CF3;
• R5 is selected from the group consisting of —H, -Me, and —CF3;
• W3 is selected from the group consisting of optionally substituted —CH2—, —CH2CH2—, and —CH2CH2CH2—, or is a bond;
• Y is a bond or C1-C3 alkyl optionally substituted with 1, 2, or 3 C1-C3 alkyl or —CF3;
• and
• R7 is selected from the group consisting of —H, C1-C6 alkyl, cycloalkyl, heterocycloalkyl

A compound represented by the structure of Formula (2-V):

• or a pharmaceutically acceptable salt, solvate, isomer, atropisomer or tautomer thereof, wherein:
• ring
• is azetidine, pyrrolidine, piperidine, or azepane;
• R1 is selected from the group consisting of —CN, —H, —F, and —CF3;
• R1′ is H;
• or R1 and R1′ together form a thiophene ring;
• R2 is selected from the group consisting of H, C1-C3 alkyl, —CF3;
• R3 is selected from the group consisting of H, C1-C3 alkyl, —CF3;
• or R2 together with R3 form a 5- or 6-membered aromatic or non-aromatic ring, all carbon or with O or N within the ring, optionally substituted with -Me or —OH;
• R4 is selected from the group consisting of —H, —F, C1-C3 alkyl, and —CF3;
• R5 is selected from the group consisting of —H, -Me and —CF3;
• and
• R12 is selected from the group consisting of:
• wherein m is 1, 2, or 3 and each R13 is independently selected from the group consisting of —H, C1-C3 alkyl, and —CF;
• or two R13 groups connect to form a cyclopropyl or cyclobutyl ring.

A compound represented by the structure of Formula (2-VI):

• or a pharmaceutically acceptable salt, solvate, hydrate, isomer, atropisomer, or tautomer thereof,
• wherein R1 is selected from the group consisting of —CN, —H, —F, and —CF3;
• R1′ is H;
• or R1 and R1′ together form a thiophene ring;
• R2 is selected from the group consisting of H, C1-C3 alkyl, and —CF3;
• R3 is selected from the group consisting of H, C1-C3 alkyl, and —CF3;
• or R2 together with R3 form a 5- or 6-membered aromatic or non-aromatic ring, all carbon or with O or N within the ring, optionally substituted with -Me or —OH;
• R5 is selected from the group consisting of —H, -Me and —CF3;
• W4 is selected from the group consisting of —CH2—, —CH2CH2—,
• R8 and R8′ are independently selected from the group consisting of —H, C1-C5 alkyl, C1-C5 cycloalkyl, and —CF3;
• and
• R9 is selected from the group consisting of —H, C1-C6 alkyl, C1-C6 cycloalkyl, heterocycloalkyl,

A compound represented by the structure of Formula (2-VII):

• or a pharmaceutically acceptable salt, solvate, hydrate, isomer, atropisomer, or tautomer thereof, wherein:
• R1 is selected from the group consisting of —CN, —H, —F, and —CF3;
• R1′ is H;
• or R1 and R1′ together form a thiophene ring;
• R2 is selected from the group consisting of H, C1-C3 alkyl, and —CF3;
• R3 is selected from the group consisting of H, C1-C3 alkyl, and —CF3;
• or R2 together with R3 form a 5- or 6-membered aromatic or non-aromatic ring, all carbon or with O or N within the ring, optionally substituted with -Me or —OH;
• R5 is selected from—the group consisting of H, -Me and —CF3;
• R6 and R6′ are independently selected from the group consisting of —H, —F, C1-C6 alkyl, C1-C6 cycloalkyl, and —CF3,
• or R6 and R6′ together with the atom they are bonded to form a C1-C6 cycloalkyl or C1-C6 heterocycloalkyl ring;
• n is 1, 2, 3, or 4;
• R14 and R14′ are independently selected from the group consisting of H, C1-C5 alkyl (including cycloalkyl), and —CF3;
• or R14 and R14′ together with the atoms that they are bonded to form a optionally substituted C3-C6 cycloalkyl or optionally substituted C3-C6 heterocycloalkyl ring;
• R10 is selected from the group consisting of —H, C1-C7 alkyl, C1-C7 cycloalkyl, C1-C7 methylcycloalkyl),
• and
• R11 is selected from the group consisting of H, C1-C7 alkyl, C1-C7 cycloalkyl, C1-C7 methylcycloalkyl.