	US 11,871,772 B2
	Antagonists of T2R54 and compositions and uses thereof
Joseph R. Fotsing, San Diego, CA (US); Andrew Patron, San Diego, CA (US); Guy Servant, San Diego, CA (US); Lan Zhang, San Diego, CA (US); Mark Williams, San Diego, CA (US); Qing Chen, San Diego, CA (US); Kenneth Simone, San Diego, CA (US); Vincent Darmohusodo, San Diego, CA (US); Chad Priest, San Diego, CA (US); Melissa S. Wong, San Diego, CA (US); and Thomas Brady, San Diego, CA (US)
Assigned to Firmenich Incorporated, Plainsboro, NJ (US)
Appl. No. 17/265,722
Filed by Firmenich Incorporated, Plainsboro, NJ (US)
PCT Filed Aug. 8, 2019, PCT No. PCT/US2019/045684 § 371(c)(1), (2) Date Feb. 3, 2021, PCT Pub. No. WO2020/033669, PCT Pub. Date Feb. 13, 2020.
Claims priority of provisional application 62/717,121, filed on Aug. 10, 2018.
Prior Publication US 2022/0330591 A1, Oct. 20, 2022
Int. Cl. A23L 27/00 (2016.01); C07D 317/66 (2006.01); C07D 401/04 (2006.01); C07D 405/12 (2006.01); C07D 405/14 (2006.01); C07D 407/12 (2006.01); C07D 409/14 (2006.01); C07D 413/12 (2006.01); C07D 413/14 (2006.01)

CPC A23L 27/86 (2016.08) [C07D 317/66 (2013.01); C07D 401/04 (2013.01); C07D 405/12 (2013.01); C07D 405/14 (2013.01); C07D 407/12 (2013.01); C07D 409/14 (2013.01); C07D 413/12 (2013.01); C07D 413/14 (2013.01)]

12 Claims

1. A compound of formula (I)

or a salt thereof, wherein:

X¹and X²are each an oxygen atom;

X³is a direct bond or >CH₂;

X⁴is >CH₂;

R^Ais a halogen atom, —CN, nitro, —OH, —NH₂, —C(O)H, —O—C(O)H, —C(O)—OH, —NH—C(O)H, —C(O)—NH₂, —O—(C_1-6alkyl), —NH—(C_1-6alkyl), —N(C_1-6alkyl)₂, —C(O)—(C_1-6alkyl), —O—C(O)—(C_1-6alkyl), —NH—C(O)—(C_1-6alkyl), —N(C_1-6alkyl)-C(O)—(C_1-6alkyl), —C(O)—O—(C_1-6alkyl), —C(O)—NH—(C_1-6alkyl), —C(O)—N(C_1-6alkyl)₂, —S(O)₂—(C_1-6alkyl), —O—S(O)₂—(C_1-6alkyl), —NH—S(O)₂—(C_1-6), —N(C_1-6alkyl)-S(O)₂—(C_1-6alkyl), —S(O)₂—(C_1-6alkyl), —S(O)₂—NH—(C_1-6alkyl), —S(O)₂—N(C_1-6alkyl)₂, C_3-10cycloalkyl, C_2-14heterocyclyl, C_6-14aryl, C_2-14heteroaryl, C_1-6alkyl, C_2-6alkenyl, C_1-6haloalkyl, C_2-6haloalkenyl, C_1-6haloalkoxy, C_2-6haloalkenyloxy, or (C_1-6alkoxy)-C_1-6alkyl;

R¹is —C(O)—R^1A;

R^1Ais C_1-6alkyl, which is optionally substituted one or more times by substituents selected independently from R^1Y;

R^1Yis a halogen atom, oxo, —CN, nitro, —OH, —NH₂, —C(O)H, —O—C(O)H, —C(O)—OH, —NH—C(O)H, —C(O)—NH₂, —O—(C_1-6alkyl), —NH—(C_1-6alkyl), —N(C_1-6alkyl)₂, —C(O)—(C_1-6alkyl), —O—C(O)—(C_1-6alkyl), —NH—C(O)—(C_1-6alkyl), —C(O)—O—(C_1-6alkyl), —C(O)—NH—(C_1-6alkyl), —C(O)—N(C_1-6alkyl)₂, —S(O)₂—(C_1-6alkyl), —O—S(O)₂—(C_1-6alkyl), —NH—S(O)₂—(C_1-6alkyl), —S(O)₂—O—(C_1-6alkyl), —S(O)₂—NH—(C_1-6alkyl), —S(O)₂—N(C_1-6alkyl)₂, C_3-10cycloalkyl, C_2-14heterocyclyl, C_6-14aryl, C_2-14heteroaryl, C_1-6alkyl, C_2-6alkenyl, C_1-6haloalkyl, C_2-6haloalkenyl, C_1-6haloalkoxy, C_2-6haloalkenyloxy, or (C_1-6alkoxy)-C_1-6alkyl;

R²is

X⁵is >NR^2G;

X⁶is C_1-6alkylene, which is optionally substituted one or more times by substituents selected independently from R^1Y;

X⁷is >N—R^2L;

X⁸, X⁹, X¹⁰, and X¹¹are each independently >C(R^2M)(R^2N);

R^2Mand R^2Nare each independently a hydrogen atom, a halogen atom, —CN, nitro, —OH, —NH₂, —C(O)H, —O—C(O)H, —C(O)—OH, —NH—C(O)H, —C(O)—NH₂, —O—(C_1-6alkyl), —NH—(C_1-6alkyl), —N(C_1-6alkyl)₂, —C(O)—(C_1-6alkyl), —O—C(O)—(C_1-6alkyl), —NH—C(O)—(C_1-6alkyl), —NH—C(O)—O—(C_1-6alkyl), —C(O)—O—(C_1-6alkyl), —C(O)—NH—(C_1-6alkyl), —C(O)—N(C_1-6alkyl)₂, —S(O)₂—(C_1-6alkyl), —O—S(O)₂—(C_1-6alkyl), —NH—S(O)₂—(C_1-6alkyl), —S(O)₂—O—(C_1-6alkyl), —S(O)₂—NH—(C_1-6alkyl), —S(O)₂—N(C_1-6alkyl)₂, C_3-10cycloalkyl, C_2-14heterocyclyl, C_6-14aryl, C_2-14heteroaryl, C_1-6alkyl, C_2-6alkenyl, C_1-6haloalkyl, C_2-6haloalkenyl, C_1-6haloalkoxy, C_2-6haloalkenyloxy, or (C_1-6alkoxy)-C_1-6alkyl; or R^2Mand R^2Noptionally combine to form an oxo group; or any two of R^2Mand R^2Nattached to adjacent carbon atoms of the piperazine ring defined by R²optionally combine to form a fused ring selected from the group consisting of phenyl, C_2-5heteroaryl, C_4-8cycloalkyl, and C_2-5heterocyclyl, wherein each of the fused rings is optionally substituted one or more times by substituents selected independently from R^1Z;

R^1Zis a halogen atom, oxo, —CN, nitro, —OH, —NH₂, —C(O)H, —O—C(O)H, —C(O)—OH, —NH—C(O)H, —C(O)—NH₂, —O—(C_1-6alkyl), —NH—(C_1-6alkyl), —N(C_1-6alkyl)₂, —C(O)—(C_1-6alkyl), —O—C(O)—(C_1-6alkyl), —NH—C(O)—(C_1-6alkyl), —C(O)—O—(C_1-6alkyl), —C(O)—NH—(C_1-6alkyl), —C(O)—N(C_1-6alkyl)₂, —S(O)₂—(C_1-6alkyl), —O—S(O)₂—(C_1-6alkyl), —NH—S(O)₂—(C_1-6alkyl), —S(O)₂—O—(C_1-6alkyl), —S(O)₂—NH—(C_1-6alkyl), —S(O)₂—N(C_1-6alkyl)₂, C_3-10cycloalkyl, C_2-14heterocyclyl, C_6-14aryl, C_2-14heteroaryl, C_1-6alkyl, C_2-6alkenyl, C_1-6haloalkyl, C_2-6haloalkenyl, C_1-6haloalkoxy, C_2-6haloalkenyloxy, (C_1-6alkoxy)-C_1-6alkyl, C_1-6alkyl, or C_2-6alkenyl;

R^2Gis a hydrogen atom, C_1-6alkyl, C_1-6haloalkyl, or (C_1-6alkoxy)-C_1-6alkyl;

R^2Lis —C(O)—R³or —C(O)—X¹⁴—R⁴;

X¹⁴is C_1-8alkylene, which is optionally substituted by one or more times by substituents selected independently from R^1Y;

R³is a hydrogen atom, —OH, —NH₂, —O—R^3B, —NH—R^3B, —N(R^3B)(R^3C), —O—C(O)—R^3B, —NH—C(O)—R^3B, —N(R^3C)—C(O)—R^3B, C_3-10carbocyclyl, C_2-14heterocyclyl, C_6-14aryl, or C_2-14heteroaryl, wherein the carbocyclyl, heterocyclyl, aryl, and heteroaryl are each optionally substituted one or more times by substituents selected independently from R^3A, wherein any two R^3Aattached to adjacent carbon atoms of the carbocyclyl, heterocyclyl, aryl, and heteroaryl groups to which they are attached optionally combine to form a fused ring selected from the group consisting of phenyl, C_2-5heteroaryl, C_4-8cycloalkyl, and C_2-5heterocyclyl, wherein each of the fused rings is optionally substituted one or more times by substituents selected independently from R^1Z, and wherein, when R^3Band R^3Care attached to the same nitrogen atom, R^3Band R^3Coptionally combine with the nitrogen atom to which they are attached to form a nitrogen-containing C_2-6heterocyclic ring, which is optionally substituted by C_1-4alkyl;

R^3Ais a halogen atom, —CN, nitro, oxo, —OH, —NH₂, —C(O)H, —O—C(O)H, —C(O)—OH, —NH—C(O)H, —C(O)—NH₂, —O—R^3D, —NH—R^3D, —N(R^3D)(R^3E), —C(O)—R^3D, —O—C(O)—R^3D, —NH—C(O)—R^3D, —C(O)—O—R^3D, —C(O)—NH—R^3D, —C(O)—N(R^3D)(R^3E), —S(O)₂—R^3D, —O—S(O)₂—R^3D, —NH—S(O)₂—R^3D, —S(O)₂—O—R^3D, —S(O)₂—NH—R^3D, —S(O)₂—N(R^3D)(R^3E), C_1-8alkyl, C_2-8alkenyl, C_3-10carbocyclyl, C_2-14heterocyclyl, C_6-14aryl, or C_2-14heteroaryl, wherein the alkyl and alkenyl are each optionally substituted one or more times by substituents selected independently from R^3Y, and wherein the carbocyclyl, heterocyclyl, aryl, and heteroaryl are each optionally substituted one or more times by substituents selected independently from R^3Z;

R^3B, R^3C, R^3D, and R^3Eare each independently C_1-8alkyl, C_2-8alkenyl, C_3-10carbocyclyl, C_2-14heterocyclyl, C_6-14aryl, or C_2-14heteroaryl, wherein the alkyl and alkenyl are each optionally substituted one or more times by substituents selected independently from R^3Y, and wherein the carbocyclyl, heterocyclyl, aryl, and heteroaryl are each optionally substituted one or more times by substituents selected independently from R^3Z;

R^3Yis a halogen atom, —CN, nitro, oxo, —OH, —NH₂, —C(O)H, —O—C(O)H, —C(O)—OH, —NH—C(O)H, —C(O)—NH₂, —O—(C_1-6alkyl), —NH—(C_1-6alkyl), —N(C_1-6alkyl)₂, —C(O)—(C_1-6alkyl), —O—C(O)—(C_1-6alkyl), —NH—C(O)—(C_1-6alkyl), —N(C_1-6alkyl)-C(O)—(C_1-6alkyl), —C(O)—O—(C_1-6alkyl), —C(O)—NH—(C_1-6alkyl), —C(O)—N(C_1-6alkyl)₂, —S(O)₂—(C_1-6alkyl), —O—S(O)₂—(C_1-6alkyl), —NH—S(O)₂—(C_1-6alkyl), —N(C_1-6alkyl)-S(O)₂—(C_1-6alkyl), —S(O)₂—O—(C_1-6alkyl), —S(O)₂—NH—(C_1-6alkyl), —S(O)₂—N(C_1-6alkyl)₂, —O—(C_1-6alkylene)-O—(C_1-6alkyl), C_3-10cycloalkyl, C_2-14heterocyclyl, C_6-14aryl, or C_2-14heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are each optionally substituted one or more times by substituents selected independently from R^1Z;

R^3Zis a halogen atom, —CN, nitro, oxo, —OH, —NH₂, —C(O)H, —O—C(O)H, —C(O)—OH, —NH—C(O)H, —C(O)—NH₂, —O—(C_1-6alkyl), —NH—(C_1-6alkyl), —N(C_1-6alkyl)₂, —C(O)—(C_1-6alkyl), —O—C(O)—(C_1-6alkyl), —NH—C(O)—(C_1-6alkyl), —N(C_1-6alkyl)-C(O)—(C_1-6alkyl), —C(O)—O—(C_1-6alkyl), —C(O)—NH—(C_1-6alkyl), —C(O)—N(C_1-6alkyl)₂, —S(O)₂—(C_1-6alkyl), —O—S(O)₂—(C_1-6alkyl), —NH—S(O)₂—(C_1-6alkyl), —N(C_1-6alkyl)-S(O)₂—(C_1-6alkyl), —S(O)₂—O—(C_1-6alkyl), —S(O)₂—NH—(C_1-6alkyl), —S(O)₂—N(C_1-6alkyl)₂, C_1-6alkyl, C_2-6alkenyl, C_1-6haloalkyl, C_2-6haloalkenyl, C_1-6haloalkoxy, C_2-6haloalkenyloxy, (C_1-6alkoxy)-C_1-6alkyl, C_3-10cycloalkyl, C_2-14heterocyclyl, C_6-14aryl, or C_2-14heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are each optionally substituted one or more times by substituents selected independently from R^1Z;

R⁴is a hydrogen atom, a halogen atom, —CN, nitro, oxo, —OH, —NH₂, —O—R^4B, —NH—R^4B, —N(R^4B)(R^4C), C(O)—R^4B, —O—C(O)—R^4B, —NH—C(O)—R^4B, —N(R^4C)—C(O)—R^4B, —C(O)—O—R^4B, —C(O)—NH—R^4B, —C(O)N(R^4B)(R^4C), —S(O)₂—R^4D, —O—S(O)₂—R^4D, —NH—S(O)₂—R^4D, —S(O)₂—O—R_4D, —S(O)₂—NH—^4D, —S(O)₂—N(R^4D)(R^4E), C_3-10carbocyclyl, C_2-14heterocyclyl, C_6-14aryl, or C_2-14heteroaryl, wherein the carbocyclyl, heterocyclyl, aryl, and heteroaryl are each optionally substituted one or more times by substituents selected independently from R^4A, wherein any two R^4Aattached to adjacent carbon atoms of the carbocyclyl, heterocyclyl, aryl, and heteroaryl groups to which they are attached optionally combine to form a fused ring selected from the group consisting of phenyl, C_2-5heteroaryl, C_4-8cycloalkyl, or C_2-5heterocyclyl, wherein each of the fused rings is optionally substituted one or more times by substituents selected independently from R^1Z, and wherein, when R^4Band R^4Care attached to the same nitrogen atom, R^4Band R^4Coptionally combine with the nitrogen atom to which they are attached to form a nitrogen-containing C_2-6heterocyclic ring, which is optionally substituted by C_1-4alkyl;

R^4Ais a halogen atom, —CN, nitro, oxo, —OH, —NH₂, —C(O)H, —O—C(O)H, —C(O)—OH, —NH—C(O)H, —C(O)—NH₂, —O—R^4D, —NH—R^4D, —N(R^4D)(R^4E), —C(O)—R^4D, —O—C(O)—R^4D, —NH—C(O)—R^4D, —N(R^4E)—C(O)—R^4D, —C(O)—O—R^4D, —C(O)—NH—R^4D, —C(O)—N(R^4D)(R^4E), C_1-8alkyl, C_2-8alkenyl, C_3-10carbocyclyl, C_2-14heterocyclyl, C_6-14aryl, or C_2-14heteroaryl, wherein the alkyl and alkenyl are each optionally substituted one or more times by substituents selected independently from R^4Y, and wherein the carbocyclyl, heterocyclyl, aryl, and heteroaryl are each optionally substituted one or more times by substituents selected independently from R^4Z;

R^4B, R^4C, R^4D, and R^4Eare each independently C_1-8alkyl, C_2-8alkenyl, C_3-10carbocyclyl, C_2-14heterocyclyl, C_6-14aryl, or C_2-14heteroaryl, wherein the alkyl and alkenyl are each optionally substituted one or more times by substituents selected independently from R″, and wherein the carbocyclyl, heterocyclyl, aryl, and heteroaryl are each optionally substituted one or more times by substituents selected independently from R^4Z;

R^4Yis a halogen atom, —CN, nitro, oxo, —OH, —NH₂, —C(O)H, —O—C(O)H, —C(O)—OH, —NH—C(O)H, —C(O)—NH₂, —O—(C_1-6alkyl), —NH—(C_1-6alkyl), —N(C_1-6alkyl)₂, —C(O)—(C_1-6alkyl), —O—C(O)—(C_1-6alkyl), —NH—C(O)—(C_1-6alkyl), —N(C_1-6alkyl)-C(O)—(C_1-6alkyl), —C(O)—O—(C_1-6alkyl), —C(O)—NH—(C_1-6alkyl), —C(O)—N(C_1-6alkyl)₂, —S(O)₂—(C_1-6alkyl), —O—S(O)₂—(C_1-6alkyl), —NH—S(O)₂—(C_1-6alkyl), —N(C_1-6alkyl)-S(O)₂—(C_1-6alkyl), —S(O)₂—O—(C_1-6alkyl), —S(O)₂—NH—(C_1-6alkyl), —S(O)₂—N(C_1-6alkyl)₂, —O—(C_1-6alkylene)-O—(C_1-6alkyl), C_3-10cycloalkyl, C_2-14heterocyclyl, C_6-14aryl, or C_2-14heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are each optionally substituted one or more times by substituents selected independently from R^1Z;

R^4Zis a halogen atom, —CN, nitro, oxo, —OH, —NH₂, —C(O)H, —O—C(O)H, —C(O)—OH, —NH—C(O)H, —C(O)—NH₂, —O—(C_1-6alkyl), —NH—(C_1-6alkyl), —N(C_1-6alkyl)₂, —C(O)—(C_1-6alkyl), —O—C(O)—(C_1-6alkyl), —NH—C(O)—(C_1-6alkyl), —N(C_1-6alkyl)-C(O)—(C_1-6alkyl), —C(O)—O—(C_1-6alkyl), —C(O)—NH—(C_1-6alkyl), —C(O)—N(C_1-6alkyl)₂, —S(O)₂—(C_1-6alkyl), —O—S(O)₂—(C_1-6alkyl), —NH—S(O)₂—(C_1-6alkyl), —N(C_1-6alkyl)-S(O)₂—(C_1-6alkyl), —S(O)₂—O—(C_1-6alkyl), —S(O)₂—NH—(C_1-6alkyl), —S(O)₂—N(C_1-6alkyl)₂, (C_1-6alkoxy)-C_1-6alkyl, C_3-10cycloalkyl, C_2-14heterocyclyl, C_6-14aryl, C_2-14heteroaryl, C_1-6alkyl, C_2-6alkenyl, C_1-6haloalkyl, C_2-6haloalkenyl, C_1-6haloalkoxy, or C_2-6haloalkenyloxy, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are each optionally substituted one or more times by substituents selected independently from R^1Z; and

n is 0, 1, or 2.