	US 12,234,245 B2
	Sulfonimidamide compounds as inhibitors of interleukin-1 activity
Christopher McBride, South San Francisco, CA (US); Lynnie Lin Trzoss, South San Francisco, CA (US); Amogh Boloor, South San Francisco, CA (US); Nadezda V. Sokolova, South San Francisco, CA (US); Richard M. Pastor, South San Francisco, CA (US); Steven Thomas Staben, South San Francisco, CA (US); Craig Stivala, South San Francisco, CA (US); Matthew Volgraf, South San Francisco, CA (US); and Sarah M. Bronner, South San Francisco, CA (US)
Assigned to Genentech, Inc., South San Francisco, CA (US)
Filed by Genentech, Inc., South San Francisco, CA (US)
Filed on Jan. 15, 2021, as Appl. No. 17/150,349.
Application 17/150,349 is a continuation of application No. PCT/US2019/042711, filed on Jul. 19, 2019.
Claims priority of provisional application 62/701,313, filed on Jul. 20, 2018.
Prior Publication US 2021/0253596 A1, Aug. 19, 2021
Int. Cl. C07D 498/04 (2006.01); A61P 31/04 (2006.01); A61P 31/12 (2006.01); A61P 31/14 (2006.01); A61P 31/16 (2006.01); A61P 31/18 (2006.01); C07D 231/18 (2006.01); C07D 471/04 (2006.01); C07D 487/04 (2006.01); C07D 513/04 (2006.01)

CPC C07D 498/04 (2013.01) [A61P 31/04 (2018.01); A61P 31/12 (2018.01); A61P 31/14 (2018.01); A61P 31/16 (2018.01); A61P 31/18 (2018.01); C07D 231/18 (2013.01); C07D 471/04 (2013.01); C07D 487/04 (2013.01); C07D 513/04 (2013.01)]

19 Claims

1. A compound of Formula (I-5),

or a pharmaceutically acceptable salt thereof, wherein:

R¹⁰⁰is selected from the group consisting of H, Cl, D, —CN, —NO₂, —OR^3a, —C(O)R^3b, —S(O)₂R^3b, —S(O)R^3b, C₁-C₆alkyl, C₂-C₆alkenyl, C₄-C₈cycloalkenyl, C₂-C₆alkynyl, C₃-C₁₀cycloalkyl, C₆aryl, 3-7-membered heterocyclyl, and 5-6-membered heteroaryl; wherein the C₁-C₆alkyl, C₂-C₆alkenyl, C₄-C₈cycloalkenyl, C₂-C₆alkynyl, C₃-C₁₀cycloalkyl, C₆aryl, 3-7-membered heterocyclyl, and 5-6 membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, —CN, halogen, C₁-C₆alkyl, —OR^3a, —C(O)R^3b, —P(O)R^3bR^4b, —S(O)₂R^3b, —S(O)R^3b, —NR^3aR^4a, —NR^3aC(O)R^4a, —NR^3aC(O)OR^4a, —NR^3aC(O)NR^4a, —NR^3aS(O)₂R^4a, C₃-C₁₀cycloalkyl, C₆aryl, 3-7-membered heterocyclyl, and 5-6 membered heteroaryl;

R¹is selected from the group consisting of

wherein R^1zis H, D, halogen, —CN, —NO₂, —SR^7a, —OR^7a, —C(O)R^7b, —P(O)R^7bR^8b, —S(O)₂R^7b, —S(O)R^7b, —NR^7aR^8a, —NR^7aC(O)R^8a, —NR^7aC(O)OR^8a, —NR^7aC(O)NR^8a, —NR^7aS(O)₂R^8a, C₁-C₆alkyl, C₂-C₆alkenyl, C₄-C₈cycloalkenyl, C₂-C₆alkynyl, C₃-C₁₀cycloalkyl, C₆aryl, 3-7-membered heterocyclyl, or 5-6-membered heteroaryl; wherein the C₁-C₆alkyl, C₂-C₆alkenyl, C₄-C₈cycloalkenyl, C₂-C₆alkynyl, C₃-C₁₀cycloalkyl, C₆aryl, 3-7-membered heterocyclyl, and 5-6 membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, —CN, halogen, C₁-C₆alkyl, —OR^7a, —C(O)R^7b, —P(O)R^7bR^8b, —S(O)₂R^7b, —S(O)R^7b, —NR^7aR^8a, —NR^7aC(O)R^8a, —NR^7aC(O)OR^8a, —NR^7aC(O)NR^8a, —NR^7aS(O)₂R^8a, C₃-C₁₀cycloalkyl, C₆aryl, 3-7-membered heterocyclyl, and 5-6 membered heteroaryl;

each R^1a, R^1b, R^1c, R^1d, R^1e, R^1f, R^1g, and R^1his independently selected from the group consisting of H, D, halogen, —CN, —NO₂, —SR^11a, —OR^11a, —C(O)R^11b, —P(O)R^11bR^12b, —S(O)₂R^11b, —S(O)R^11b, —NR^11aR^12a, —NR^11aC(O)R^12a, —NR^11aC(O)OR^12a, —NR^11aC(O)NR^12a, —NR^11aS(O)₂R^12a, C₁-C₆alkyl, C₂-C₆alkenyl, C₄-C₈cycloalkenyl, C₂-C₆alkynyl, C₃-C₁₀cycloalkyl, C₆aryl, 3-7-membered heterocyclyl, and 5-6-membered heteroaryl; wherein the C₁-C₆alkyl, C₂-C₆alkenyl, C₄-C₈cycloalkenyl, C₂-C₆alkynyl, C₃-C₁₀cycloalkyl, C₆aryl, 3-7-membered heterocyclyl, and 5-6 membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, —CN, halogen, C₁-C₆alkyl, —OR^11a, —C(O)R^11b, —P(O)R^11bR^12b, —S(O)₂R^11b, —S(O)R^11b, —NR^11aR^12a, —NR^11aC(O)R^12a, —NR^11aC(O)OR^12a, —NR^11aC(O)NR^12a, —NR^11aS(O)₂R^12a, C₃-C₁₀cycloalkyl, C₆aryl, 3-7-membered heterocyclyl, and 5-6 membered heteroaryl; or

two of the following groups, R^1a, R^1b, R^1c, R^1d, R^1e, R^1f, R^1g, and R^1h, when present, together with the atoms to which they are attached can form a C₃-C₁₀cycloalkyl or a 3-7-membered heterocyclyl; wherein the C₃-C₁₀cycloalkyl and 3-7-membered heterocyclyl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, —CN, halogen, C₁-C₆alkyl, —OR^13a, —C(O)R^13b, —P(O)R^13bR^14b, —S(O)₂R^13b, —S(O)R^13b, —NR^13aR^14a, —NR^13aC(O)R^14a, —NR^13aC(O)OR^14a, —NR^13aC(O)NR^14a, and —NR^13aS(O)₂R^14a, or

two geminal groups R^1aand R^1b, R^1cand R^1d, R^1eand R^1f; or R^1gand R^1h, when present, can form an oxo group;

R²is

X²is N or CR^2a;

X³is N or CR^2e;

X⁴is N or CR^2d;

X⁵is N or CR^2e;

X⁶and X⁷are independently N or CR²ⁿ, wherein at least one of X⁶and X⁷is N;

R^2ais H, D, halogen, —CN, —OR^15a, C₁-C₆alkyl, C₃-C₁₀cycloalkyl, —C(O) NR^15aR^16a, —C(O)OR^15a, —NR^15aR^16a, —NR^15aC(O)R^16a, —NR^15aC(O)OR^16a, —NR^15aC(O)NR^16a, or —NR^15aS(O)₂R^16a, wherein the C₁-C₆alkyl and C₃-C₁₀cycloalkyl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, halogen, —CN, —OR^15a, —C(O)R^15b, —NR^15aR^16a, C₃-C₁₀cycloalkyl, C₆aryl, 3-7-membered heterocyclyl, and 5-6 membered heteroaryl;

each R^2b, R^2c, R^2d, R^2e, and R^2fis independently H, D, halogen, —CN, —NO₂, —SR^17a, —OR^17a, —C(O)R^17b, —P(O)R^17bR^18b, —S(O)₂R^17b, —S(O)R^17b, —NR^17aR^18a, —NR^17aC(O)R^18a, —NR^17aC(O)OR^18a, —NR^17aC(O)NR^18a, —NR^17aS(O)₂R^18a, C₁-C₆alkyl, C₂-C₆alkenyl, C₄-C₈cycloalkenyl, C₂-C₆alkynyl, C₃-C₁₀cycloalkyl, C₆aryl, 3-7-membered heterocyclyl, or 5-6 membered heteroaryl; wherein the C₁-C₆alkyl, C₂-C₆alkenyl, C₄-C₈cycloalkenyl, C₂-C₆alkynyl, C₃-C₁₀cycloalkyl, C₆aryl, 3-7-membered heterocyclyl, and 5-6 membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, —CN, halogen, —OR^17a, —C(O)R^17b, —P(O)R^17bR^18b, —S(O)₂R^17b, —S(O)R^17b, —NR^17aR^18a, —NR^17aC(O)R^18a, —NR^17aC(O)OR^18a, —NR^17aC(O)NR^18a, —NR^17aS(O)₂R^18a, C₃-C₁₀cycloalkyl, C₆aryl, 3-7-membered heterocyclyl, and 5-6 membered heteroaryl; or

two adjacent R^2b, R^2c, R^2d, R^2e, and R^2ftogether with the atoms to which they are attached can form C₃-C₁₀cycloalkyl, C₆aryl, 3-7-membered heterocyclyl, or 5-6-membered heteroaryl; wherein the C₃-C₁₀cycloalkyl, C₆aryl, 3-7-membered heterocyclyl, and 5-6-membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, D, —CN, C₁-C₆alkyl, —OR^19a, and NR^19aR^20a;

each R^2j, R^2k, R^2m, and R²ⁿis independently H, D, halogen, —CN, —NO₂, —SR^17a, —OR^17a, —C(O)R^17b, —P(O)R^17bR^18b, —S(O)₂R^17b, —S(O)R^17b, —NR^17aR^18a, —NR^17aC(O)R^18a, —NR^17aC(O)OR^18a, —NR^17aC(O)NR^18a, —NR^17aS(O)₂R^18a, C₁-C₆alkyl, C₂-C₆alkenyl, C₄-C₈cycloalkenyl, C₂-C₆alkynyl, C₃-C₁₀cycloalkyl, C₆aryl, 3-7-membered heterocyclyl, or 5-6 membered heteroaryl; wherein the C₁-C₆alkyl, C₂-C₆alkenyl, C₄-C₈cycloalkenyl, C₂-C₆alkynyl, C₃-C₁₀cycloalkyl, C₆aryl, 3-7-membered heterocyclyl, and 5-6 membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, —CN, halogen, —OR^17a, —C(O)R^17b, —P(O)R^17bR^18b, —S(O)₂R^17b, —S(O)R^17b, —NR^17aR^18a, —NR^17aC(O)R^18a, —NR^17aC(O)OR^18a, —NR^17aC(O)NR^18a, —NR^17aS(O)₂R^18a, C₃-C₁₀cycloalkyl, C₆aryl, 3-7-membered heterocyclyl, and 5-6 membered heteroaryl; or

two adjacent R^2j, R^2k, R^2m, and R²ⁿtogether with the atoms to which they are attached can form C₃-C₁₀cycloalkyl, C₆aryl, 3-7-membered heterocyclyl, or 5-6-membered heteroaryl; wherein the C₃-C₁₀cycloalkyl, C₆aryl, 3-7-membered heterocyclyl, and 5-6-membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, D, —CN, C₁-C₆alkyl, —OR^19a, and NR^19aR^20a;

each R^2gand R^2his independently H, C₁-C₆alkyl, C₃-C₁₀cycloalkyl, 3-7-membered heterocyclyl, C₆aryl, or 5-membered heteroaryl, wherein the 3-7-membered heterocyclyl and 5-membered heteroaryl are attached to the nitrogen at a carbon on the 3-7-membered heterocyclyl or 5-membered heteroaryl, and wherein the C₁-C₆alkyl, C₃-C₁₀cycloalkyl, 3-7-membered heterocyclyl, C₆aryl, or 5-membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, —CN, halogen, C₁-C₆alkyl, —OR^21a, —C(O)R^21b, —P(O)R^21bR^22b, —S(O)₂R^21b, —S(O)R^21b, —NR^21aR^22a, —NR^21aC(O)R^22a, —NR^21aC(O)OR^22a, —NR^21aC(O)NR^22a, —NR^21aS(O)₂R^22a, C₃-C₁₀cycloalkyl, C₆aryl, 3-7-membered heterocyclyl, and 5-membered heteroaryl;

R^3a, R^4a, R^7a, R^8a, R^11a, R^12a, R^13a, R^14a, R^15a, R^16a, R^17a, R^18a, R^19a, R^20aR^21a, R^22a, R^23a, and R^24aare independently, at each occurrence, H, D, C₁-C₈alkyl, C₂-C₈alkenyl, C₂-C₈alkynyl, C₃-C₁₀cycloalkyl, C₄-C₈cycloalkenyl, C₆aryl, 3-7-membered heterocyclyl, or 5-6-membered heteroaryl; wherein the C₁-C₈alkyl, C₂-C₈alkenyl, C₂-C₈alkynyl, C₃-C₁₀cycloalkyl, C₄-C₈cycloalkenyl, C₆aryl, 3-7-membered heterocyclyl, and 5-6-membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, —CN, halogen, C₁-C₆alkyl, —OH, —O—C₁-C₆alkyl, —NH₂, —NH(C₁-C₆alkyl), —N(C₁-C₆alkyl)₂, C₃-C₁₀cycloalkyl, C₆aryl, 3-7-membered heterocyclyl, and 5-6 membered heteroaryl;

R^3b, R^4b, R^7b, R^8b, R^11b, R^12b, R^13b, R^14b, R^15b, R^17b, R^18b, R^21b, R^22b, R^23b, and R^24bare independently, at each occurrence, H, D, —OH, —O(C₁-C₆alkyl), —NH₂, —NH(C₁-C₆alkyl), —N(C₁-C₆alkyl)₂, —NHS(O)₂CH₃, C₁-C₆alkyl, C₂-C₈alkenyl, C₂-C₈alkynyl, C₃-C₁₀cycloalkyl, C₄-C₈cycloalkenyl, C₆aryl, 3-7-membered heterocyclyl, or 5-6-membered heteroaryl; wherein the C₁-C₈alkyl, C₂-C₈alkenyl, C₂-C₈alkynyl, C₃-C₁₀cycloalkyl, C₄-C₈cycloalkenyl, C₆aryl, 3-7-membered heterocyclyl, and 5-6-membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, —CN, halogen, C₁-C₆alkyl, —OH, —O—C₁-C₆alkyl, —NH₂, —NH(C₁-C₆alkyl), —N(C₁-C₆alkyl)₂, C₃-C₁₀cycloalkyl, C₆aryl, 3-7-membered heterocyclyl, and 5-6 membered heteroaryl.