Antagonists of T2R54 and their compositions and uses thereof

Abstract

The present disclosure generally provides compounds that antagonize certain T2R taste receptors, including related uses, methods, and compositions for reducing bitterness and / or enhancing sweetness. In certain forms, the present disclosure provides flavored products or flavored compositions comprising such compounds, and the use of such compounds to reduce the bitterness and / or enhance the sweetness of such flavored products or flavored compositions.

Description

[0001] The present invention is a divisional application of invention patent application No. 201980060635.1 filed on August 8, 2019, entitled “T2R54 antagonists, compositions thereof and uses thereof”.

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims the benefit of priority to U.S. Provisional Application No. 62 / 717,121, filed on August 10, 2018, which is incorporated herein by reference as if set forth in its entirety. Technical Field

[0004] The present disclosure generally provides compounds that antagonize certain T2R taste receptors, including related uses, methods and compositions for reducing bitterness and / or enhancing sweetness. In certain forms, the present disclosure provides flavored products or flavored compositions comprising such compounds, and uses of such compounds to reduce the bitterness and / or enhance the sweetness of such flavored products or flavored compositions. Background Art

[0005] The taste system provides sensory information about the chemical composition of the outside world. Taste transduction is one of the most sophisticated forms of chemically triggered sensation in animals. Taste signals are found throughout the animal kingdom, from simple metazoans to the most complex vertebrates. Mammals are thought to have five basic forms of taste: sweet, bitter, sour, salty, and umami.

[0006] Obesity, diabetes, and cardiovascular disease are major health problems worldwide and are growing at an alarming rate. Sugar and heat (calories) are key ingredients that can be limited to have a positive nutritional effect on health. Even so, since many foods contain ingredients that make bitter taste receptors suffer, consumers often use sugar and other sweeteners to offset the perception of bitterness in such foods. In addition, certain nutritionally useful foods such as plant proteins can make bitter taste receptors suffer. Therefore, despite their nutritional value, consumers still avoid eating such foods because of the perceived bad taste. In addition, many pharmaceutical compounds such as antibiotics have a significant bitter taste. Therefore, pharmaceutical manufacturers must use complex formulation techniques to allow subjects to orally take such drugs without discomfort.

[0007] However, the physiological basis of bitter taste perception is still not well understood. Many bitter compounds produce their bitter taste at least in part by regulating certain cell surface receptors, some of which belong to a family of seven transmembrane domain receptors that interact with intracellular G proteins. These include the family of G-coupled protein receptors (GCPRs) called T2Rs found in humans and rodents. Humans express at least dozens of different receptors belonging to the T2R family. One of these receptors found in humans is called hT2R54. It is believed that this receptor plays a key role in the perception of bitterness in humans.

[0008] Some compounds are known to antagonize hT2R54. Even so, such compounds may only antagonize the hT2R54 receptor weakly, or may interact with other taste receptors, thereby changing the taste of flavored products in a way that humans do not perceive as improving taste. Therefore, there is a continuing need to discover compounds that antagonize hT2R54, with the goal of discovering compounds that reduce the human perception of bitterness without changing the taste of the product in a way that humans tend to dislike. Summary of the invention

[0009] The present disclosure provides compounds that are found to be antagonists, such as selective antagonists, of hT2R54. These compounds provide a broad array of compounds that can be used in food products or pharmaceutical products to reduce the perception of bitterness, and in some cases, even with an enhancement of the perception of sweetness in such products.

[0010] In a first aspect, the present disclosure provides a compound of formula (I) or a salt thereof:

[0011]

[0012] in:

[0013] X 1 and X 2 Each independently is an oxygen atom or>C(R 2A )(R 2B );

[0014] X 3 Is a direct key or>C(R 2C )(R 2D );

[0015] X 4 >C(R 2E )(R 2F );

[0016] R AHalogen atoms, -CN, nitro, -OH, -NH2, -C(O)H, -OC(O)H, -C(O)-OH, -NH-C(O)H, -C(O)-NH2, -O-(C 1-6 Alkyl), -NH-(C 1-6 Alkyl), -N(C 1-6 Alkyl)2,-C(O)-(C 1-6 alkyl), -OC(O)-(C 1-6 alkyl), -NH-C(O)-(C 1-6 Alkyl), -N(C 1-6 alkyl)-C(O)-(C 1-6 alkyl), -C(O)-O-(C 1-6 alkyl), -C(O)-NH-(C 1-6 alkyl), -C(O)-N(C 1-6 alkyl)2,-S(O)2-(C 1-6 alkyl), -OS(O)2-(C 1-6 Alkyl), -NH-S(O)2-(C 1-6 Alkyl), -N(C 1-6 alkyl)-S(O)2-(C 1-6 alkyl), -S(O)2-O-(C 1-6 alkyl), -S(O)2-NH-(C 1-6 alkyl), -S(O)2-N(C 1-6 Alkyl)2,C 3-10 Cycloalkyl, C 2-14 Heterocyclyl, C 6-14 Aryl, or C 2-14 Heteroaryl, C 1-6 Alkyl, C 2-6 Alkenyl, C 1-6 Haloalkyl, C 2-6 Halogenated alkenyl, C 1-6 Haloalkoxy, C 2-6 Halogenated alkenyloxy, or (C 1-6 Alkoxy)-C 1-6 alkyl;

[0017] R 1 is a halogen atom, -C(O)-R 1A , -C(O)-OR 1A , -OR 1A ,-OC(O)-R 1A or C 1-6 Alkyl, wherein the alkyl group is optionally independently selected from R 1Y Substituents are substituted one or more times;

[0018] R1A is a hydrogen atom or C 1-6 Alkyl, wherein the alkyl group is optionally independently selected from R 1Y Substituents are substituted one or more times;

[0019] R 1Y is a halogen atom, oxo, -CN, nitro, -OH, -NH2, -C(O)H, -OC(O)H, -C(O)-OH, -NH-C(O)H, -C(O)-NH2, -O-(C 1-6 Alkyl), -NH-(C 1-6 Alkyl), -N(C 1-6 alkyl)2,-C(O)-(C 1-6 alkyl), -OC(O)-(C 1-6 alkyl), -NH-C(O)-(C 1-6 alkyl), -C(O)-O-(C 1-6 alkyl), -C(O)-NH-(C 1-6 alkyl), -C(O)-N(C 1-6 alkyl)2,-S(O)2-(C 1-6 alkyl), -OS(O)2-(C 1-6 Alkyl), -NH-S(O)2-(C 1-6 alkyl), -S(O)2-O-(C 1-6 alkyl), -S(O)2-NH-(C 1-6 alkyl), -S(O)2-N(C 1-6 Alkyl)2,C 3-10 Cycloalkyl, C 2-14 Heterocyclyl, C 6-14 Aryl, C 2-14 Heteroaryl, C 1-6 Alkyl, C 2-6 Alkenyl, C 1-6 Haloalkyl, C 2-6 Halogenated alkenyl, C 1-6 Haloalkoxy, C 2-6 haloalkenyloxy, and (C 1-6 Alkoxy)-C 1-6 alkyl;

[0020] R 1Z is a halogen atom, oxo, -CN, nitro, -OH, -NH2, -C(O)H, -OC(O)H, -C(O)-OH, -NH-C(O)H, -C(O)-NH2, -O-(C 1-6 Alkyl), -NH-(C 1-6 Alkyl), -N(C 1-6 alkyl)2,-C(O)-(C 1-6alkyl), -OC(O)-(C 1-6 alkyl), -NH-C(O)-(C 1-6 alkyl), -C(O)-O-(C 1-6 alkyl), -C(O)-NH-(C 1-6 alkyl), -C(O)-N(C 1-6 alkyl)2,-S(O)2-(C 1-6 alkyl), -OS(O)2-(C 1-6 Alkyl), -NH-S(O)2-(C 1-6 alkyl), -S(O)2-O-(C 1-6 alkyl), -S(O)2-NH-(C 1-6 alkyl), -S(O)2-N(C 1-6 Alkyl)2,C 3-10 Cycloalkyl, C 2-14 Heterocyclyl, C 6-14 Aryl, C 2-14 Heteroaryl, C 1-6 Alkyl, C 2-6 Alkenyl, C 1-6 Haloalkyl, C 2-6 Halogenated alkenyl, C 1-6 Haloalkoxy, C 2-6 Halogenated alkenyloxy, (C 1-6 Alkoxy)-C 1-6 Alkyl, C 1-6 Alkyl, and C 2-6 alkenyl;

[0021] R 2 Yes-N(R 5 )(R 6 ), where R 5 and R 6 optionally combined with the nitrogen atom to which they are attached to form a nitrogen-containing C 2-6 Heterocyclic ring, which is optionally C 1-4 Alkyl substitution; or

[0022] R 2 yes or

[0023] R 2 is a hydrogen atom, a halogen atom, C 3-10 Cycloalkyl, C 2-14 Heterocyclyl, C 6-14 Aryl, or C 2-14 heteroaryl, wherein carbocyclyl, heterocyclyl, aryl and heteroaryl are each optionally independently selected from R 1Z Substituents are substituted one or more times;

[0024] X5 Yes>NR 2G ;

[0025] X 6 It is C 1-6 Alkylene, which may be independently selected from R 1Y Substituents are substituted one or more times; or

[0026] X 7 is oxygen atom, sulfur atom, >NR 2L or>C(R 2J )(R 2K );

[0027] X 8 , X 9 , X 10 and X 11 are each independently a direct bond, an oxygen atom, a sulfur atom or >C(R 2M )(R 2N ), where X 8 , X 9 , X 10 and X 11 No more than one of them is a direct bond; and where X 8 , X 9 , X 10 and X 11 not more than one of them is an oxygen atom or a sulfur atom;

[0028] X 12 is an oxygen atom, a sulfur atom or >NR 2L ;

[0029] X 13 Is a direct key or >NR 2P ;

[0030] R 2A , R 2B , R 2C , R 2D , R 2E , R 2F , R 2K , R 2M and R 2N are each independently a hydrogen atom, a halogen atom, -CN, a nitro group, -OH, -NH2, -C(O)H, -OC(O)H, -C(O)-OH, -NH-C(O)H, -C(O)-NH2, -O-(C 1-6 Alkyl), -NH-(C 1-6 Alkyl), -N(C 1-6 Alkyl)2,-C(O)-(C 1-6 alkyl), -OC(O)-(C 1-6alkyl), -NH-C(O)-(C 1-6 alkyl), -NH-C(O)-O-(C 1-6 alkyl), -C(O)-O-(C 1-6 alkyl), -C(O)-NH-(C 1-6 alkyl), -C(O)-N(C 1-6 alkyl)2,-S(O)2-(C 1-6 alkyl), -OS(O)2-(C 1-6 Alkyl), -NH-S(O)2-(C 1-6 alkyl), -S(O)2-O-(C 1-6 alkyl), -S(O)2-NH-(C 1-6 alkyl), -S(O)2-N(C 1-6 Alkyl)2,C 3-10 Cycloalkyl, C 2-14 Heterocyclyl, C 6-14 Aryl, or C 2-14 Heteroaryl, C 1-6 Alkyl, C 2-6 Alkenyl, C 1-6 Haloalkyl, C 2-6 Halogenated alkenyl, C 1-6 Haloalkoxy, C 2-6 Halogenated alkenyloxy, (C 1-6 Alkoxy)-C 1-6 Alkyl; or, R 2A and R 2B , or R 2C and R 2D , or R 2E and R 2F , or R 2M and R 2N Alternatively, R 2M and R 2N Any two of which are optionally combined to form a fused ring selected from phenyl, C 2-5 Heteroaryl, C 4-8 Cycloalkyl and C 2-5 Heterocyclyl, wherein each fused ring is optionally independently selected from R 1Z Substituents are substituted one or more times;

[0031] R 2G and R 2P are independently hydrogen atoms, C 1-6 Alkyl, C 1-6 haloalkyl, or (C 1-6 Alkoxy)-C 1-6 alkyl;

[0032] R2J Yes-R 4 or -X 14 -R 4 ;

[0033] R 2L Yes-C(O)-R 3 , -C(O)-X 14 -R 4 , -C(S)-R 3 , -C(S)-X 14 -R 4 , -S(O)2-R 3 , -S(O)2-X 14 -R 4 or -X 14 -R 4 ;

[0034] X 14 It is C 1-8 Alkylene, which may be independently selected from R 1Y Substituents are substituted one or more times;

[0035] R 3 is a hydrogen atom, -OH, -NH2, -OR 3B , -NH-R 3B , -N(R 3B )(R 3C ), -OC(O)-R 3B , -NH-C(O)-R 3B , -N(R 3C )-C(O)-R 3B , C 3-10 Carbocyclic group, C 2-14 Heterocyclyl, C 6-14 Aryl, and C 2-14 heteroaryl, wherein carbocyclyl, heterocyclyl, aryl and heteroaryl are each optionally independently selected from R 3A Substituents are substituted one or more times, wherein any two R 3A optionally combined to form a fused ring selected from phenyl, C 2-5 Heteroaryl, C 4-8 Cycloalkyl and C 2-5 Heterocyclyl, wherein each fused ring is optionally independently selected from R 1Z The substituents are substituted one or more times, and when R 3B and R 3C When attached to the same nitrogen atom, R 3B and R 3C optionally combined with the nitrogen atom to which they are attached to form a nitrogen-containing C 2-6 Heterocyclic ring, which is optionally C1-4 Alkyl substitution;

[0036] R 3A Halogen atoms, -CN, nitro, oxo, -OH, -NH2, -C(O)H, -OC(O)H, -C(O)-OH, -NH-C(O)H, -C(O)-NH2, -OR 3D , -NH-R 3D , -N(R 3D )(R 3E ), -C(O)-R 3D ,-OC(O)-R 3D , -NH-C(O)-R 3D , -C(O)-OR 3D , -C(O)-NH-R 3D ,-C(O)-N(R 3D )(R 3E ), -S(O)2-R 3D ,-OS(O)2-R 3D , -NH-S(O)2-R 3D , -S(O)2-OR 3D , -S(O)2-NH-R 3D ,-S(O)2-N(R 3D )(R 3E ), C 1-8 Alkyl, C 2-8 Alkenyl, C 3-10 Carbocyclic group, C 2-14 Heterocyclyl, C 6-14 Aryl, and C 2-14 heteroaryl, wherein the alkyl and alkenyl are each optionally independently selected from R 3Y substituted one or more times by substituents, and wherein the carbocyclyl, heterocyclyl, aryl and heteroaryl are each optionally independently selected from R 3Z Substituents are substituted one or more times;

[0037] R 3B , R 3C , R 3D and R 3E Each independently is C 1-8 Alkyl, C 2-8 Alkenyl, C 3-10 Carbocyclic group, C 2-14 Heterocyclyl, C 6-14 Aryl, or C 2-14 Heteroaryl, wherein the alkyl and alkenyl are each optionally independently selected from R 3Y wherein the carbocyclyl, heterocyclyl, aryl and heteroaryl are each independently selected from R3Z Substituents are substituted one or more times;

[0038] R 3Y is a halogen atom, -CN, nitro, oxo, -OH, -NH2, -C(O)H, -OC(O)H, -C(O)-OH, -NH-C(O)H, -C(O)-NH2, -O-(C 1-6 Alkyl), -NH-(C 1-6 Alkyl), -N(C 1-6 alkyl)2,-C(O)-(C 1-6 alkyl), -OC(O)-(C 1-6 alkyl), -NH-C(O)-(C 1-6 Alkyl), -N(C 1-6 alkyl)-C(O)-(C 1-6 alkyl), -C(O)-O-(C 1-6 alkyl), -C(O)-NH-(C 1-6 alkyl), -C(O)-N(C 1-6 alkyl)2,-S(O)2-(C 1-6 alkyl), -OS(O)2-(C 1-6 Alkyl), -NH-S(O)2-(C 1-6 Alkyl), -N(C 1-6 alkyl)-S(O)2-(C 1-6 alkyl), -S(O)2-O-(C 1-6 alkyl), -S(O)2-NH-(C 1-6 alkyl), -S(O)2-N(C 1-6 Alkyl)2,-O-(C 1-6 Alkylene)-O-(C 1-6 Alkyl), C 3-10 Cycloalkyl, C 2-14 Heterocyclyl, C 6-14 Aryl, and C 2-14 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally independently selected from R 1Z Substituents are substituted one or more times;

[0039] R 3Z is a halogen atom, -CN, nitro, oxo, -OH, -NH2, -C(O)H, -OC(O)H, -C(O)-OH, -NH-C(O)H, -C(O)-NH2, -O-(C 1-6 Alkyl), -NH-(C 1-6 Alkyl), -N(C 1-6 alkyl)2,-C(O)-(C 1-6alkyl), -OC(O)-(C 1-6 alkyl), -NH-C(O)-(C 1-6 Alkyl), -N(C 1-6 alkyl)-C(O)-(C 1-6 alkyl), -C(O)-O-(C 1-6 alkyl), -C(O)-NH-(C 1-6 alkyl), -C(O)-N(C 1-6 alkyl)2,-S(O)2-(C 1-6 alkyl), -OS(O)2-(C 1-6 Alkyl), -NH-S(O)2-(C 1-6 Alkyl), -N(C 1-6 alkyl)-S(O)2-(C 1-6 alkyl), -S(O)2-O-(C 1-6 alkyl), -S(O)2-NH-(C 1-6 alkyl), -S(O)2-N(C 1-6 Alkyl)2,C 1-6 Alkyl, C 2-6 Alkenyl, C 1-6 Haloalkyl, C 2-6 Halogenated alkenyl, C 1-6 Haloalkoxy, C 2-6 Halogenated alkenyloxy, (C 1-6 Alkoxy)-C 1-6 Alkyl, C 3-10 Cycloalkyl, C 2-14 Heterocyclyl, C 6-14 Aryl, and C 2-14 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally independently selected from R 1Z Substituents are substituted one or more times;

[0040] R 4 It is a hydrogen atom, a halogen atom, -CN, a nitro group, an oxo group, -OH, -NH2, -OR 4B , -NH-R 4B , -N(R 4B )(R 4C ), C(O)-R 4B ,-OC(O)-R 4B , -NH-C(O)-R 4B , -N(R 4C )-C(O)-R 4B , -C(O)-OR 4B , -C(O)-NH-R 4B ,-C(O)N(R 4B )(R4C ), -S(O)2-R 4D ,-OS(O)2-R 4D , -NH-S(O)2-R 4D , -S(O)2-OR 4D , -S(O)2-NH-R 4D ,-S(O)2-N(R 4D )(R 4E ), C 3-10 Carbocyclic group, C 2-14 Heterocyclyl, C 6-14 Aryl, and C 2-14 heteroaryl, wherein the carbocyclyl, heterocyclyl, aryl and heteroaryl are each optionally independently selected from R 4A Substituents are substituted one or more times, wherein any two R 4A optionally combined to form a fused ring selected from phenyl, C 2-5 Heteroaryl, C 4-8 Cycloalkyl and C 2-5 Heterocyclyl, wherein each fused ring is optionally independently selected from R 1Z The substituents are substituted one or more times, and when R 4B and R 4C When attached to the same nitrogen atom, R 4B and R 4C optionally combined with the nitrogen atom to which they are attached to form a nitrogen-containing C 2-6 Heterocyclic ring, which is optionally C 1-4 Alkyl substitution;

[0041] R 4A Halogen atoms, -CN, nitro, oxo, -OH, -NH2, -C(O)H, -OC(O)H, -C(O)-OH, -NH-C(O)H, -C(O)-NH2, -OR 4D , -NH-R 4D , -N(R 4D )(R 4E ), -C(O)-R 4D ,-OC(O)-R 4D , -NH-C(O)-R 4D , -N(R 4E )-C(O)-R 4D , -C(O)-OR 4D , -C(O)-NH-R 4D ,-C(O)-N(R 4D )(R 4E ), C 1-8 Alkyl, C 2-8 Alkenyl, C 3-10Carbocyclic group, C 2-14 Heterocyclyl, C 6-14 Aryl, and C 2-14 Heteroaryl, wherein the alkyl and alkenyl are each optionally independently selected from R 4Y wherein the carbocyclyl, heterocyclyl, aryl and heteroaryl are each independently selected from R 4Z Substituents are substituted one or more times;

[0042] R 4B , R 4C , R 4D and R 4E Each independently is C 1-8 Alkyl, C 2-8 Alkenyl, C 3-10 Carbocyclic group, C 2-14 Heterocyclyl, C 6-14 Aryl, and C 2-14 Heteroaryl, wherein the alkyl and alkenyl are each optionally independently selected from R 4Y wherein the carbocyclyl, heterocyclyl, aryl and heteroaryl are each independently selected from R 4Z Substituents are substituted one or more times;

[0043] R 4Y is a halogen atom, -CN, nitro, oxo, -OH, -NH2, -C(O)H, -OC(O)H, -C(O)-OH, -NH-C(O)H, -C(O)-NH2, -O-(C 1-6 Alkyl), -NH-(C 1-6 Alkyl), -N(C 1-6 alkyl)2,-C(O)-(C 1-6 alkyl), -OC(O)-(C 1-6 alkyl), -NH-C(O)-(C 1-6 Alkyl), -N(C 1-6 alkyl)-C(O)-(C 1-6 alkyl), -C(O)-O-(C 1-6 alkyl), -C(O)-NH-(C 1-6 alkyl), -C(O)-N(C 1-6 alkyl)2,-S(O)2-(C 1-6 alkyl), -OS(O)2-(C 1-6 Alkyl), -NH-S(O)2-(C 1-6 Alkyl), -N(C 1-6 alkyl)-S(O)2-(C 1-6 alkyl), -S(O)2-O-(C 1-6alkyl), -S(O)2-NH-(C 1-6 alkyl), -S(O)2-N(C 1-6 Alkyl)2,-O-(C 1-6 Alkylene)-O-(C 1-6 Alkyl), C 3-10 Cycloalkyl, C 2-14 Heterocyclyl, C 6-14 Aryl, and C 2-14 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally independently selected from R 1Z Substituents are substituted one or more times;

[0044] R 4Z is a halogen atom, -CN, nitro, oxo, -OH, -NH2, -C(O)H, -OC(O)H, -C(O)-OH, -NH-C(O)H, -C(O)-NH2, -O-(C 1-6 Alkyl), -NH-(C 1-6 Alkyl), -N(C 1-6 Alkyl)2,-C(O)-(C 1-6 alkyl), -OC(O)-(C 1-6 alkyl), -NH-C(O)-(C 1-6 Alkyl), -N(C 1-6 alkyl)-C(O)-(C 1-6 alkyl), -C(O)-O-(C 1-6 alkyl), -C(O)-NH-(C 1-6 alkyl), -C(O)-N(C 1-6 alkyl)2,-S(O)2-(C 1-6 alkyl), -OS(O)2-(C 1-6 Alkyl), -NH-S(O)2-(C 1-6 Alkyl), -N(C 1-6 alkyl)-S(O)2-(C 1-6 alkyl), -S(O)2-O-(C 1-6 alkyl), -S(O)2-NH-(C 1-6 alkyl), -S(O)2-N(C 1-6 Alkyl)2, (C 1-6 Alkoxy)-C 1-6 Alkyl, C 3-10 Cycloalkyl, C 2-14 Heterocyclyl, C 6-14 Aryl, or C 2-14 Heteroaryl, C 1-6 Alkyl, C 2-6 Alkenyl, C 1-6 Haloalkyl, C2-6 Halogenated alkenyl, C 1-6 Haloalkoxy, and C 2-6 haloalkenyloxy, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally independently selected from R 1Z Substituents are substituted one or more times;

[0045] R 5 Yes-C(O)-R 3 , -C(O)-X 14 -R 4 , -C(S)-R 3 , -C(S)-X 14 -R 4 , -S(O)2-R 3 , -S(O)2-X 14 -R 4 or -X 14 -R 4 ;

[0046] R 6 is a hydrogen atom or C 1-8 Alkyl, wherein the alkyl group is optionally independently selected from R 6Y Substituents are substituted one or more times;

[0047] R 6Y is a halogen atom, -CN, nitro, oxo, -OH, -NH2, -C(O)H, -OC(O)H, -C(O)-OH, -NH-C(O)H, -C(O)-NH2, -O-(C 1-6 Alkyl), -NH-(C 1-6 Alkyl), -N(C 1-6 Alkyl)2,-C(O)-(C 1-6 alkyl), -OC(O)-(C 1-6 alkyl), -NH-C(O)-(C 1-6 Alkyl), -N(C 1-6 alkyl)-C(O)-(C 1-6 alkyl), -C(O)-O-(C 1-6 alkyl), -C(O)-NH-(C 1-6 alkyl), -C(O)-N(C 1-6 alkyl)2,-S(O)2-(C 1-6 alkyl), -OS(O)2-(C 1-6 Alkyl), -NH-S(O)2-(C 1-6 Alkyl), -N(C 1-6 alkyl)-S(O)2-(C 1-6 alkyl), -S(O)2-O-(C 1-6alkyl), -S(O)2-NH-(C 1-6 alkyl), -S(O)2-N(C 1-6 Alkyl)2,-O-(C 1-6 Alkylene)-O-(C 1-6 Alkyl), C 3-10 Cycloalkyl, C 2-14 Heterocyclyl, C 6-14 Aryl, and C 2-14 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally independently selected from R 1Z Substituents are substituted one or more times;

[0048] R 7 is a hydrogen atom, a halogen atom, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, or (C 1-6 Alkyl)-OC 1-6 alkyl; and

[0049] n is 0, 1 or 2.

[0050] In a second aspect, the present disclosure provides for use of a compound of the first aspect (including any embodiment thereof).

[0051] In the third form, the present disclosure provides the use of the compound of the first form (including any embodiment thereof) to reduce the bitterness of an edible composition or a pharmaceutical composition and / or enhance its sweetness. In some embodiments, the present disclosure provides the use of the compound of the first form (including any embodiment thereof) to reduce the bitterness of an edible composition. In some other such embodiments, the edible composition is a flavored product, such as a flavored food product. In some other embodiments, the present disclosure provides the use of the compound of the first form (including any embodiment thereof) to reduce the bitterness of a pharmaceutical composition, such as a pharmaceutical composition for oral administration (tablets, capsules, elixirs, etc.).

[0052] In a fourth aspect, the present disclosure provides the use of a compound of the first aspect (including any embodiment thereof) in the manufacture of a product for reducing bitterness and / or enhancing sweetness in the product. In some embodiments, the present disclosure provides the use of a compound of the first aspect (including any embodiment thereof) in the manufacture of a flavored product such as a flavored food or beverage product for reducing bitterness in the product. In some other embodiments, the present disclosure provides the use of a compound of the first aspect (including any embodiment thereof) in the preparation of a medicament for reducing bitterness in the medicament.

[0053] In a fifth aspect, the disclosure provides for use of a compound of the first aspect (including any embodiment thereof) for antagonizing one or more human T2R taste receptors, such as one or more human T2R54 taste receptors.

[0054] In the sixth form, the present disclosure provides a method for reducing the bitterness of a flavored composition or a pharmaceutical composition and / or enhancing its sweetness, the method comprising introducing a certain amount (e.g., an effective amount) of one or more compounds of the first form (including any embodiment thereof) into the flavored composition or pharmaceutical composition. In some embodiments, the present disclosure provides a method for reducing the bitterness of a flavored composition, the method comprising introducing a certain amount (e.g., an effective amount) of one or more compounds of the first form (including any embodiment thereof) into the flavored composition. In some such embodiments, the flavored composition is a food or beverage product. In some other embodiments, the present disclosure provides a method for reducing the bitterness of a pharmaceutical composition, the method comprising introducing a certain amount (e.g., an effective amount) of one or more compounds of the first form (including any embodiment thereof) into the pharmaceutical composition.

[0055] In the seventh aspect, the present disclosure provides a method for antagonizing a human T2R receptor, the method comprising contacting a human T2R receptor with one or more compounds of the first aspect (including any embodiment thereof). In some embodiments thereof, the method comprises contacting a human T2R54 receptor with one or more compounds of the first aspect (including any embodiment thereof). In some embodiments, contacting comprises oral ingestion of a composition comprising one or more compounds of the first aspect (including any embodiment thereof). In some such embodiments, the composition is a flavored composition, such as a food or beverage product. In some other such embodiments, the composition is a pharmaceutical composition.

[0056] In the eighth aspect, the present disclosure provides a composition comprising a certain amount of one or more compounds of the first aspect (including any embodiment thereof). In some embodiments, the composition comprises one or more bitter compounds and one or more compounds of the first aspect (including any embodiment thereof) that reduce the bitterness in an effective amount. In some other embodiments, the composition is a pharmaceutical composition, and the bitter compound is one or more pharmaceutical compounds, such as an active pharmaceutical ingredient (API). In some other embodiments, the composition is a flavored composition, such as a food or beverage product, and the bitter compound is an artificial sweetener, caffeine, protein (such as plant protein), amino acid, a compound derived from a natural plant extract, etc.

[0057] Further aspects and embodiments thereof are defined in the following detailed description, drawings, abstract and claims. BRIEF DESCRIPTION OF THE DRAWINGS

[0058] The following figures are provided to illustrate various embodiments of the compositions and methods disclosed herein. The figures are provided for illustration purposes only and are not intended to describe any preferred compositions or preferred methods, nor as a source of any limitation on the scope of the claimed invention.

[0059] Figure 1 Shown are dose-response graphs for acetaminophen on a cell line expressing hT2R54 and a host cell line (which does not express the bitter taste receptor).

[0060] Figure 2 A graph showing the effect of increasing concentrations of test compound on the dose-response (DR) of acetaminophen on cells expressing hT2R54. The dose-dependency of the test compound shifts the DR curve to the right, but also results in a decrease in the efficacy of acetaminophen, indicating that the test compound behaves as a non-competitive antagonist of hT2R54. Each increase in dose shifts the curve to the right and downward. The DR curves correspond from left to right to 0, 50 μM, 200 μM, 400 μM and 800 μM of the test compound, respectively. DETAILED DESCRIPTION

[0061] The following detailed description sets forth various aspects and embodiments provided herein. This description should be read from the perspective of a person of ordinary skill in the relevant art. Therefore, it does not necessarily include information known to such a person of ordinary skill.

[0062] definition

[0063] Unless otherwise provided herein, the following terms and phrases have the meanings indicated below. The present disclosure may employ other terms and phrases not expressly defined herein. Such other terms and phrases have the meanings they have in the context of the present disclosure for those of ordinary skill in the art. In some cases, a term or phrase may be defined in the singular or in the plural. In this case, it is to be understood that any term in the singular may include its plural form, and vice versa, unless expressly indicated to the contrary.

[0064] As used herein, "solvate" refers to a compound formed by the interaction of one or more solvent molecules with one or more compounds described herein. In some embodiments, the solvate is a physiologically acceptable solvate, such as a hydrate.

[0065] As used herein, "C" wherein "a" and "b" are integers a To C b ” or “C a-b " refers to the number of carbon atoms in the specified group. That is, the group can contain carbon atoms from "a" to "b" (including the end values). Thus, for example, "C1 to C4 alkyl" or "C1-4 "Alkyl" refers to all alkyl groups having 1 to 4 carbons, i.e., CH3-, CH3CH2-, CH3CH2CH2-, (CH3)2CH-, CH3CH2CH2CH2-, CH3CH2CH(CH3)- and (CH3)3C-.

[0066] As used herein, "halogen" or "halo" refers to any of the radiation stable atoms in column 7 of the periodic table, such as fluorine, chlorine, bromine or iodine. In some embodiments, "halogen" or "halo" refers to fluorine or chlorine.

[0067] As used herein, "alkyl" refers to a fully saturated straight or branched hydrocarbon chain (i.e., containing no double or triple bonds). In some embodiments, the alkyl group has 1 to 20 carbon atoms (when appearing herein, a numerical range such as "1 to 20" refers to each integer in the given range; for example, "1 to 20 carbon atoms" means that the alkyl group can be composed of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms, although this definition also covers the occurrence of the term "alkyl" in which no numerical range is specified). The alkyl group can also be a medium-sized alkyl group having 1 to 9 carbon atoms. The alkyl group can also be a low-sized alkyl group having 1 to 4 carbon atoms. The alkyl group can be referred to as a "C 1-4 Alkyl" or similar designation. For example only, "C 1-4 "Alkyl" means that there are 1 to 4 carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl. Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, and the like. Unless otherwise indicated, the term "alkyl" refers to a group that is not further substituted.

[0068] As used herein, "substituted alkyl" refers to an alkyl group substituted with one or more substituents independently selected from the group consisting of C1-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C3-C7 carbocyclyl (optionally substituted with halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), 3- to 10-membered heterocyclyl (optionally substituted with halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), aryl (optionally substituted with halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), 5- to 10-membered heteroaryl (optionally substituted with halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), halogen, cyano, hydroxy, C1-C6 alkoxy, aryloxy (optionally substituted with halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), C3-C7 carbocyclyl (optionally substituted with halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), 3- to 10-membered heterocyclyl-oxy (optionally substituted with halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), 5- to 10-membered heteroaryl-oxy (optionally substituted with halogen , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), C3-C7-carbocyclyl-C1-C6 alkoxy (optionally substituted with halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), 3- to 10-membered heterocyclyl-C1-C6-alkoxy (optionally substituted with halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), aryl(C1-C6)alkoxy (optionally substituted with halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), 5- to 10-membered heteroaryl(C1-C6) Alkoxy (optionally substituted with halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), sulfhydryl (mercapto), halo (C1-C6) alkyl (e.g. -CF3), halo (C1-C6) alkoxy (e.g. -OCF3), C1-C6 alkylthio, arylthio (optionally substituted with halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), C3-C7 carbocyclic sulfhydryl (optionally substituted with halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), 3 to 10 membered heterocyclyl-sulfhydryl (optionally substituted with halogen, C1-C6 alkyl,C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), 5- to 10-membered heteroaryl-thio (optionally substituted with halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), C3-C7-carbocyclyl-C1-C6-alkylthio (optionally substituted with halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), 3- to 10-membered heterocyclyl-C1-C6 alkylthio (optionally substituted with halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), aryl(C1-C6)alkyl thio (optionally substituted with halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), 5- to 10-membered heteroaryl (C1-C6) alkylthio (optionally substituted with halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), amino, nitro, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, acyl, cyanate, isocyanate, thiocyanate, isothiocyanate, sulfinyl, sulfonyl, and oxo (=O). ,

[0069] As used herein, "alkoxy" refers to a radical of the formula -OR, wherein R is an alkyl radical as defined above, e.g., "C 1-9 "Alkoxy" includes, but is not limited to, methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy, isobutoxy, sec-butoxy and tert-butoxy, etc.

[0070] As used herein, "alkylthio" refers to a radical of the formula -SR, wherein R is an alkyl radical as defined above, e.g., "C 1-9 "Alkylthio" and the like, including but not limited to methylmercapto, ethylmercapto, n-propylmercapto, 1-methylethylmercapto (isopropylmercapto), n-butylmercapto, isobutylmercapto, sec-butylmercapto, tert-butylmercapto and the like.

[0071] As used herein, "alkenyl" refers to a straight or branched hydrocarbon chain containing one or more double bonds. In some embodiments, the alkenyl group has 2 to 20 carbon atoms, although this definition also covers the occurrence of the term "alkenyl" in which no numerical range is specified. The alkenyl group can also be a medium-sized alkenyl group having 2 to 9 carbon atoms. The alkenyl group can also be a low-sized alkenyl group having 2 to 4 carbon atoms. The alkenyl group can be referred to as a "C 2-4 "C 2-4"Alkenyl" means that there are 2 to 4 carbon atoms in the alkenyl chain, i.e., the alkenyl chain is selected from the group consisting of ethenyl, propen-1-yl, propen-2-yl, propen-3-yl, buten-1-yl, buten-2-yl, buten-3-yl, buten-4-yl, 1-methylpropen-1-yl, 2-methylpropen-1-yl, 1-ethylethen-1-yl, 2-methylpropen-3-yl, buta-1,3-dienyl, buta-1,2-dienyl and buta-1,2-dien-4-yl. Typical alkenyl groups include, but are in no way limited to, ethenyl, propenyl, butenyl, pentenyl and hexenyl, etc. Unless otherwise indicated, the term "alkenyl" refers to a group that is not further substituted.

[0072] As used herein, "alkynyl" refers to a straight or branched hydrocarbon chain containing one or more triple bonds. In some embodiments, an alkynyl group has 2 to 20 carbon atoms, although this definition also encompasses occurrences of the term "alkynyl" where no numerical range is specified. An alkynyl group may also be a medium-sized alkynyl group having 2 to 9 carbon atoms. An alkynyl group may also be a low-sized alkynyl group having 2 to 4 carbon atoms. An alkynyl group may be referred to as a "C 2-4 Alkynyl" or similar designation. By way of example only, "C 2-4 "Alkynyl" means that there are 2 to 4 carbon atoms in the alkynyl chain, i.e., the alkynyl chain is selected from the group consisting of ethynyl, propyn-1-yl, propyn-2-yl, butyn-1-yl, butyn-3-yl, butyn-4-yl, and 2-butynyl. Typical alkynyl groups include, but are by no means limited to, ethynyl, propynyl, butynyl, pentynyl, and hexynyl, etc. Unless otherwise indicated, the term "alkynyl" refers to a group that is not further substituted.

[0073] As used herein, "heteroalkyl" refers to a straight or branched hydrocarbon chain containing one or more heteroatoms, i.e., elements other than carbon, in the backbone of the chain, including, but not limited to, nitrogen, oxygen, and sulfur. In some embodiments, a heteroalkyl group has from 1 to 20 carbon atoms, although this definition also encompasses occurrences of the term "heteroalkyl" where no numerical range is specified. A heteroalkyl group may also be a medium-sized heteroalkyl group having from 1 to 9 carbon atoms. A heteroalkyl group may also be a low-sized heteroalkyl group having from 1 to 4 carbon atoms. A heteroalkyl group may be referred to as a "C 1-4 Heteroalkyl" or similar designations. A heteroalkyl group may contain one or more heteroatoms. By way of example only, "C 1-4 "Heteroalkyl" means that there are from one to four carbon atoms in the heteroalkyl chain and one or more additional heteroatoms in the backbone of the chain. Unless otherwise indicated, the term "heteroalkyl" refers to a group that is not further substituted.

[0074] As used herein, "alkylene" refers to a fully saturated branched or straight chain diradical chemical group containing only carbon and hydrogen, which is connected to the rest of the molecule (i.e., alkanediyl) by two points of attachment. In some embodiments, alkylene has 1 to 20 carbon atoms, although this definition also encompasses occurrences of the term alkylene where no numerical range is specified. Alkylene can also be a medium-sized alkylene having 1 to 9 carbon atoms. Alkylene can also be a low-sized alkylene having 1 to 4 carbon atoms. Alkylene can be referred to as "C 1-4 Alkylene" or similar designations. For example only, "C 1-4 "Alkylene" means that there are 1 to 4 carbon atoms in the alkylene chain, i.e., the alkylene chain is selected from the group consisting of methylene, ethylene, ethane-1,1-diyl, propylene, propylene-1,1-diyl, propylene-2,2-diyl, 1-methyl-ethylene, butylene, butane-1,1-diyl, butane-2,2-diyl, 2-methylpropylene-1,1-diyl, 1-methyl-propylene, 2-methyl-propylene, 1,1-dimethyl-ethylene, 1,2-dimethyl-ethylene and 1-ethyl-ethylene. Unless otherwise indicated, the term "alkylene" refers to a group that is not further substituted.

[0075] As used herein, "alkenylene" refers to a straight or branched diradical chemical group containing only carbon and hydrogen and containing at least one carbon-carbon double bond connected to the rest of the molecule by two points of attachment. In some embodiments, alkenylene has 2 to 20 carbon atoms, although this definition also encompasses occurrences of the term alkenylene where no numerical range is specified. Alkenylene can also be a medium-sized alkenylene having 2 to 9 carbon atoms. Alkenylene can also be a low-sized alkenylene having 2 to 4 carbon atoms. Alkenylene groups can be referred to as "C 2-4 "C 2-4 The term "alkenylene" means that there are 2 to 4 carbon atoms in the alkenylene chain, i.e., the alkenylene chain is selected from the group consisting of vinylene, ethylene-1,1-diyl, propenylene, propen-1,1-diyl, prop-2-ene-1,1-diyl, 1-methylvinylene, but-1-enylidene, but-2-enylidene, buta-1,3-dienyl, butene-1,1-diyl, buta-1,3-diene-1,1-diyl, but-2-ene-1,1-diyl, buta-3-ene-1,3-diene-1,1-diyl, buta-2-ene-1,1-diyl, buta-3-ene-1,3-diene-1,3-diene-1,3-diene-1,3-diene-1,3-diene-1,3-diene-1,3-diene-1,3-diene-2,3- ... 1-ene-1,1-diyl, 1-methyl-prop-2-ene-1,1-diyl, 2-methyl-prop-2-ene-1,1-diyl, 1-ethyl-vinylene, 1,2-dimethylvinylene, 1-methyl-propenylene, 2-methyl-propenylene, 3-methyl-propenylene, 2-methyl-propenylene-1,1-diyl and 2,2-dimethyl-ethylene-1,1-diyl. Unless otherwise indicated, the term "alkenylene" refers to a group that is not further substituted.

[0076] As used herein, "aromatic" refers to a ring or ring system having a conjugated π electron system, and includes carbocyclic aromatic groups (e.g., phenyl) and heterocyclic aromatic groups (e.g., pyridine). The term includes monocyclic or fused-ring polycyclic (i.e., rings that share adjacent pairs of atoms) groups, provided that the entire ring system is aromatic.

[0077] As used herein, "aryl" refers to an aromatic ring or ring system (i.e., two or more fused rings that share two adjacent carbon atoms) that contains only carbon in the ring backbone. When aryl is a ring system, each ring in the system is aromatic. In some embodiments, aryl has 6 to 18 carbon atoms, although this definition also covers the occurrence of the term "aryl" where no numerical range is specified. In some embodiments, aryl has 6 to 10 carbon atoms. Aryl can be referred to as "C 6-10 Aryl", "C6-C 10 Examples of aryl groups include, but are not limited to, phenyl, naphthyl, azulenyl, and anthracenyl. In some embodiments, the term "aryl" refers to phenyl. Unless otherwise indicated, the term "aryl" refers to a group that is not further substituted.

[0078] As used herein, "aryloxy" and "arylthio" refer to moieties of the formula RO- and RS-, respectively, wherein R is an aryl group as defined above, e.g., "C 6-10 Aryloxy" or "C 6-10 "Arylthio" and the like, including but not limited to phenoxy and phenylthio.

[0079] As used herein, "aralkyl" or "arylalkyl" refers to an aryl group attached as a substituent through an alkylene group, for example, "C 7-14 "Aralkyl" and the like, including but not limited to benzyl, 2-phenylethyl, 3-phenylpropyl, etc. In some embodiments, the alkylene group is a lower alkylene group (i.e., C 1-4 alkylene).

[0080] As used herein, "heteroaryl" refers to an aromatic ring or ring system (i.e., two or more fused rings sharing two adjacent atoms) containing one or more heteroatoms, i.e., elements other than carbon (including but not limited to nitrogen, oxygen and sulfur) in the ring skeleton. When heteroaryl is a ring system, each ring in the system is aromatic. In some embodiments, heteroaryl has 5 to 18 ring members (i.e., the number of atoms constituting the ring skeleton, including carbon atoms and heteroatoms), although the present definition also encompasses the occurrence of the term "heteroaryl" in which no numerical range is specified. In some embodiments, heteroaryl has 5 to 10 ring members or 5 to 7 ring members. Heteroaryl may be referred to as "5 to 7-membered heteroaryl", "5 to 10-membered heteroaryl" or similar names. Examples of heteroaryl rings include, but are not limited to, furanyl, thienyl, phthalazinyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, quinolyl, isoquinolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, indolyl, isoindolyl and benzothienyl. Unless otherwise indicated, the term "heteroaryl" refers to a group that is not further substituted.

[0081] As used herein, "heteroaralkyl" or "heteroarylalkyl" refers to a heteroaryl group attached as a substituent via an alkylene group. Examples include, but are not limited to, 2-thienylmethyl, 3-thienylmethyl, furanylmethyl, thienylethyl, pyrrolylalkyl, pyridylalkyl, isoxazolylalkyl, and imidazolylalkyl. In some cases, the alkylene group is a lower alkylene group (i.e., C 1-4 alkylene).

[0082] As used herein, "carbocyclyl" refers to a non-aromatic ring or ring system that contains only carbon atoms in the ring system backbone. When a carbocyclyl is a ring system, two or more rings may be fused, bridged, or spiro-connected. A carbocyclyl may have any degree of saturation, provided that at least one ring in the ring system is not aromatic. Thus, carbocyclyl includes cycloalkyl, cycloalkenyl, and cycloalkynyl. In some embodiments, a carbocyclyl has 3 to 20 carbon atoms, although this definition also encompasses occurrences of the term "carbocyclyl" in which no numerical range is specified. A carbocyclyl may also be a medium-sized carbocyclyl having 3 to 10 carbon atoms. A carbocyclyl may also be a carbocyclyl having 3 to 6 carbon atoms. A carbocyclic group may be referred to as a "C 3-6 Examples of carbocyclyl rings include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, 2,3-dihydroindane, bicyclo[2.2.2]octyl, adamantyl, and spiro[4.4]nonyl. Unless otherwise indicated, the term "carbocyclyl" refers to a group that is not further substituted.

[0083] As used herein, "(carbocyclyl)alkyl" refers to a carbocyclyl group attached as a substituent via an alkylene group, for example, "C 4-10 "(Carbocyclyl)alkyl" and the like, including but not limited to cyclopropylmethyl, cyclobutylmethyl, cyclopropylethyl, cyclopropylbutyl, cyclobutylethyl, cyclopropylisopropyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, cycloheptylmethyl and the like. In some cases, the alkylene group is a lower alkylene group.

[0084] As used herein, "cycloalkyl" refers to a fully saturated carbocyclyl ring or ring system according to any of the embodiments described above for carbocyclyl. Examples include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

[0085] As used herein, "cycloalkenyl" refers to a carbocyclyl ring or ring system having at least one double bond, wherein no ring in the ring system is aromatic, and according to any of the embodiments described above for carbocyclyl. An example is cyclohexenyl.

[0086] As used herein, "heterocyclic radical" refers to a non-aromatic ring or ring system containing at least one heteroatom in the ring skeleton. The heterocyclic radical can be connected together in a fused, bridged or spirally connected manner. The heterocyclic radical can have any degree of saturation, provided that at least one ring in the ring system is not aromatic. The heteroatom can be present in the non-aromatic or aromatic ring of the ring system. In some embodiments, the heterocyclic radical has 3 to 20 ring members (i.e., the number of atoms constituting the ring skeleton, including carbon atoms and heteroatoms), although the definition also covers the occurrence of the term "heterocyclic radical" in which the numerical range is not specified. The heterocyclic radical can also be a medium-sized heterocyclic radical with 3 to 10 ring members. The heterocyclic radical can also be a heterocyclic radical with 3 to 6 ring members. The heterocyclic radical can be referred to as a "3 to 6-membered heterocyclic radical" or similar names. In preferred six-membered monocyclic heterocyclyls, the heteroatoms are selected from up to three of O, N or S, and in preferred five-membered monocyclic heterocyclyls, the heteroatoms are selected from one or two heteroatoms selected from O, N or S. Examples of heterocyclyl rings include, but are not limited to, azepinyl, acridinyl, carbazolyl, cinnolinyl, dioxolanyl, imidazolinyl, imidazolidinyl, morpholinyl, oxiranyl, oxepanyl, thiepanyl, piperidinyl, piperazinyl, dioxopiperazinyl, pyrrolidonyl, pyrrolidionyl, 4-piperidonyl, pyrazolinyl, pyrazolidinyl, 1,3-dioxinyl, 1,3-dioxinyl, 1,4-dioxinyl, 1,4-dioxinyl, 1,3-oxathian ... yl), 1,4-oxathiinyl, 1,4-oxathiinyl, 2H-1,2-oxazinyl, trioxanyl, hexahydro-1,3,5-triazinyl, 1,3-dioxolyl, 1,3-dioxolanyl, 1,3-dithiolyl, 1,3-dithiolanyl, isoxazoline 1,3-oxathiolanyl, indolinyl, isoindolinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, tetrahydro-1,4-thiazinyl, thiamorpholinyl, dihydrobenzofuranyl, benzimidazolidinyl and tetrahydroquinoline.

[0087] As used herein, "(heterocyclyl)alkyl" refers to a heterocyclyl group attached via an alkylene group as a substituent. Examples include, but are not limited to, imidazolinylmethyl and indolylethyl.

[0088] "Acyl" refers to -C(=O)R, where R is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Carbocyclic group, C 6-10 Aryl, 5 to 10 membered heteroaryl and 3 to 10 membered heterocyclyl are as defined herein. Non-limiting examples include formyl, acetyl, propionyl, benzoyl and acryloyl.

[0089] "O-carboxyl" refers to a "-OC(=O)R" group, wherein R is selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Carbocyclic group, C 6-10 Aryl, 5- to 10-membered heteroaryl and 3- to 10-membered heterocyclyl are as defined herein.

[0090] "C-carboxyl" refers to a "-C(=O)OR" group, wherein R is selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Carbocyclic group, C 6-10 Aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclyl are as defined herein. Non-limiting examples include carboxyl (ie, -C(=O)OH).

[0091] A "cyano" group refers to a "-CN" group.

[0092] A "cyanate" group refers to a "-OCN" group.

[0093] An "isocyanate" group refers to a "-NCO" group.

[0094] A "thiocyanate" group refers to a "-SCN" group.

[0095] An "isothiocyanate" group refers to a "-NCS" group.

[0096] "Sulfinyl" refers to a "-S(=O)R" group, where R is selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Carbocyclic group, C 6-10 Aryl, 5- to 10-membered heteroaryl and 3- to 10-membered heterocyclyl are as defined herein.

[0097] "Sulfonyl" refers to a "-SO2R" group where R is selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Carbocyclic group, C 6-10 Aryl, 5- to 10-membered heteroaryl and 3- to 10-membered heterocyclyl are as defined herein.

[0098] "S-sulfonamide" refers to "-SO2NR A R B " group, where R A and R B are each independently selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Carbocyclic group, C 6-10 Aryl, 5- to 10-membered heteroaryl and 3- to 10-membered heterocyclyl are as defined herein.

[0099] "N-sulfonylamino" refers to "-N(R A )SO2R B ”, where R A and R B are each independently selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Carbocyclic group, C 6-10 Aryl, 5- to 10-membered heteroaryl and 3- to 10-membered heterocyclyl are as defined herein.

[0100] "O-carbamoyl" refers to "-OC(=O)NR A R B " group, where R A and R B are each independently selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Carbocyclic group, C 6-10 Aryl, 5- to 10-membered heteroaryl and 3- to 10-membered heterocyclyl are as defined herein.

[0101] "N-carbamoyl" refers to "-N(R A )C(=O)OR B " group, where R A and R B are each independently selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C3-7 Carbocyclic group, C 6-10 Aryl, 5- to 10-membered heteroaryl and 3- to 10-membered heterocyclyl are as defined herein.

[0102] "O-thiocarbamoyl" refers to "-OC(=S)NR A R B " group, where R A and R B are each independently selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Carbocyclic group, C 6-10 Aryl, 5- to 10-membered heteroaryl and 3- to 10-membered heterocyclyl are as defined herein.

[0103] "N-thiocarbamoyl" refers to "-N(R A )C(=S)OR B " group, where R A and R B are each independently selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Carbocyclic group, C 6-10 Aryl, 5- to 10-membered heteroaryl and 3- to 10-membered heterocyclyl are as defined herein.

[0104] "C-amido" refers to "-C(=O)NR A R B " group, where R A and R B are each independently selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Carbocyclic group, C 6-10 Aryl, 5- to 10-membered heteroaryl and 3- to 10-membered heterocyclyl are as defined herein.

[0105] "N-amido" refers to "-N(R A )C(=O)R B " group, where R A and R B are each independently selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Carbocyclic group, C 6-10 Aryl, 5- to 10-membered heteroaryl and 3- to 10-membered heterocyclyl are as defined herein.

[0106] "Amino" refers to "-NR A R B " group, where R A and R B are each independently selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Carbocyclic group, C 6-10 Aryl, 5- to 10-membered heteroaryl and 3- to 10-membered heterocyclyl are as defined herein. Non-limiting examples include free amino (ie, -NH2).

[0107] "Aminoalkyl" refers to an amino group attached through an alkylene group.

[0108] "Alkoxyalkyl" refers to an alkoxy group attached through an alkylene group, for example, "C 2-8 "Alkoxyalkyl" and the like.

[0109] As used herein, a substituent is derived from an unsubstituted parent group in which one or more hydrogen atoms have been exchanged with another atom or group. Unless otherwise specified, when a group is considered to be "substituted by...", it means that the group is substituted with one or more substituents independently selected from C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C3-C7 carbocyclyl (optionally substituted with halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), C3-C7-carbocyclyl-C1-C6-alkyl (optionally substituted with halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), 3 to 10 membered heterocyclyl (optionally substituted with halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), , C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), 3- to 10-membered heterocyclic-C1-C6-alkyl (optionally substituted with halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), aryl (optionally substituted with halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), aryl(C1-C6)alkyl (optionally substituted with halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), 5- to 10-membered heteroaryl (optionally substituted with halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), 5- to 10-membered heteroaryl(C1-C6)alkyl (optionally substituted with halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), halogen, cyano, hydroxy, C1-C6 alkoxy, C1-C6 alkoxy(C1-C6)alkyl (i.e. ether), aryloxy (optionally substituted with halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), C3-C7 carbocyclic group (optionally substituted with halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), C1-C6 haloalkoxy), 3- to 10-membered heterocyclyloxy (optionally substituted with halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), 5- to 10-membered heteroaryloxy (optionally substituted with halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), C3-C7-carbocyclyl-C1-C6 alkoxy (optionally substituted with halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), 3- to 10-membered heterocyclyl-C1-C6-alkoxy (optionally substituted with halogen, C1-C6 alkyl, C1-C6 alkoxy,C1-C6 haloalkyl and C1-C6 haloalkoxy), aryl(C1-C6)alkoxy (optionally substituted with halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), 5- to 10-membered heteroaryl(C1-C6)alkoxy (optionally substituted with halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), sulfhydryl (mercapto), halo(C1-C6)alkyl (e.g. -CF3), halo(C1-C6)alkoxy (e.g. -OC F3), C1-C6 alkylthio, arylthiohydrogenthio, C3-C7 carbocyclic thio (optionally substituted with halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), 3- to 10-membered heterocyclyl-thio (optionally substituted with halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), 5- to 10-membered heteroaryl-thio (optionally substituted with halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy) , C3-C7-carbocyclyl-C1-C6-alkylthio (optionally substituted with halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), 3- to 10-membered heterocyclyl-C1-C6 alkylthio (optionally substituted with halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), aryl(C1-C6)alkylthio (optionally substituted with halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), 5- to 10-membered heteroaryl(C1-C6)alkylthio (optionally substituted with halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), amino, amino(C1-C6)alkyl, nitro, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, acyl, cyanate, isocyanate, thiocyanate, isothiocyanate, sulfinyl, sulfonyl, and oxo (=O). Where a group is described as "optionally substituted with", the group may be substituted with the substituents described above. ,

[0110] It should be understood that certain basic naming conventions may include monoradicals or diradicals, depending on the context. For example, when a substituent requires two points of attachment to the rest of the molecule, it is understood that the substituent is a diradical. For example, a substituent that is identified as an alkyl group that requires two points of attachment includes a diradical, such as -CH2-, -CH2CH2-, -CH2CH(CH3)CH2-, etc. Other group naming conventions clearly indicate that the group is a diradical, such as "alkylene" or "alkenylene".

[0111] Where a substituent is described as diradical (i.e., having two points of attachment to the rest of the molecule), it is understood that the substituent may be attached in any orientation unless otherwise indicated. Thus, for example, a substituent represented by -AE- or Substituents of include those oriented such that A is attached at the left-most point of attachment in the molecule as well as those where A is attached at the right-most point of attachment in the molecule.

[0112] As used herein, "sweetener," "sweet flavoring," "sweet flavoring entity" or "sweet compound" refers to a compound or an ingestible salt thereof that induces a detectable sweet taste in a subject, such as a compound that activates T1R2 / T1R3 receptors in vitro.

[0113] As used herein, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. For example, reference to "a substituent" encompasses a single substituent as well as two or more substituents, and so forth.

[0114] As used herein, "for example," "such as," "such as," or "including" are intended to introduce examples that further illustrate a more general subject matter. Unless otherwise expressly noted, such examples are provided merely to aid in understanding the embodiments shown in the present disclosure and are not meant to be limiting in any way. Nor do these phrases indicate any kind of preference for the disclosed embodiments.

[0115] As used herein, "include," "comprising," "containing," and "comprised of" refer to open groups, meaning that the group may include other members in addition to those explicitly stated. For example, the phrase "comprising A" means that A must be present, but other members may also be present. The terms "including," "having," and "composed of" and their grammatical variants have the same meaning. In contrast, "consist of" or "composed of" or "composed of" refer to closed groups. For example, the phrase "consisting of A" means that only A is present.

[0116] As used herein, "optionally" means that the event described subsequently may or may not occur. In some embodiments, the optional event does not occur. In some other embodiments, the optional event does occur one or more times.

[0117] As used herein, "or" is to be given its broadest reasonable interpretation and is not limited to an "either / or" construction. Thus, the phrase "comprising A or B" means that A may be present and B may not be present, or B may be present and A may not be present, or both A and B may be present. Furthermore, for example, if A defines a class that may have multiple members (e.g., A1 and A2), then one or more members of the class may be present at the same time.

[0118] As used herein, certain monovalent or polyvalent groups having only a single atom may be referred to as the name of an atom. For example, in some cases, a substituent "-H" may be referred to as "hydrogen" or "hydrogen atom," or a substituent "-F" may be referred to as "fluorine" or "fluorine atom."

[0119] The point of attachment of a group is usually indicated by a dash (-) or an asterisk (*). For example, groups such as *-CH2-CH3 or -CH2-CH3 both represent ethyl groups.

[0120] Other terms are defined in other parts of this specification even if not included in this section.

[0121] Antagonists of hT2R54 and their synthesis

[0122] In a first aspect, the present disclosure provides a compound of formula (I) or a salt thereof:

[0123]

[0124] in:

[0125] X 1 and X 2 Each independently is an oxygen atom or>C(R 2A )(R 2B );

[0126] X 3 Is a direct key or>C(R 2C )(R 2D );

[0127] X 4 Yes>C(R 2E )(R 2F );

[0128] R AHalogen atoms, -CN, nitro, -OH, -NH2, -C(O)H, -OC(O)H, -C(O)-OH, -NH-C(O)H, -C(O)-NH2, -O-(C 1-6 Alkyl), -NH-(C 1-6 Alkyl), N(C 1-6 alkyl)2,-C(O)-(C 1-6 alkyl), -OC(O)-(C 1-6 alkyl), -NH-C(O)-(C 1-6 Alkyl), -N(C 1-6 alkyl)-C(O)-(C 1-6 alkyl), -C(O)-O-(C 1-6 alkyl), -C(O)-NH-(C 1-6 alkyl), -C(O)-N(C 1-6 alkyl)2,-S(O)2-(C 1-6 alkyl), -OS(O)2-(C 1-6 Alkyl), -NH-S(O)2-(C 1-6 Alkyl), -N(C 1-6 alkyl)-S(O)2-(C 1-6 alkyl), -S(O)2-O-(C 1-6 alkyl), -S(O)2-NH-(C 1-6 alkyl), -S(O)2-N(C 1-6 Alkyl)2,C 3-10 Cycloalkyl, C 2-14 Heterocyclyl, C 6-14 Aryl, or C 2-14 Heteroaryl, C 1-6 Alkyl, C 2-6 Alkenyl, C 1-6 Haloalkyl, C 2-6 Halogenated alkenyl, C 1-6 Haloalkoxy, C 2-6 Halogenated alkenyloxy, or (C 1-6 Alkoxy)-C 1-6 alkyl;

[0129] R 1 is a halogen atom, -C(O)-R 1A , -C(O)-OR 1A , -OR 1A ,-OC(O)-R 1A , or C 1-6 Alkyl, wherein the alkyl group is optionally independently selected from R 1Y Substituents are substituted one or more times;

[0130] R1A is a hydrogen atom or C 1-6 Alkyl, wherein the alkyl group is optionally independently selected from R 1Y Substituents are substituted one or more times;

[0131] R 1Y is a halogen atom, oxo, -CN, nitro, -OH, -NH2, -C(O)H, -OC(O)H, -C(O)-OH, -NH-C(O)H, -C(O)-NH2, -O-(C 1-6 Alkyl), -NH-(C 1-6 Alkyl), -N(C 1-6 alkyl)2,-C(O)-(C 1-6 alkyl), -OC(O)-(C 1-6 alkyl), -NH-C(O)-(C 1-6 alkyl), -C(O)-O-(C 1-6 alkyl), -C(O)-NH-(C 1-6 alkyl), -C(O)-N(C 1-6 alkyl)2,-S(O)2-(C 1-6 alkyl), -OS(O)2-(C 1-6 Alkyl), -NH-S(O)2-(C 1-6 alkyl), -S(O)2-O-(C 1-6 alkyl), -S(O)2-NH-(C 1-6 alkyl), -S(O)2-N(C 1-6 Alkyl)2,C 3-10 Cycloalkyl, C 2-14 Heterocyclyl, C 6-14 Aryl, or C 2-14 Heteroaryl, C 1-6 Alkyl, C 2-6 Alkenyl, C 1-6 Haloalkyl, C 2-6 Halogenated alkenyl, C 1-6 Haloalkoxy, C 2-6 haloalkenyloxy, and (C 1-6 Alkoxy)-C 1-6 alkyl;

[0132] R 1Z is a halogen atom, oxo, -CN, nitro, -OH, -NH2, -C(O)H, -OC(O)H, -C(O)-OH, -NH-C(O)H, -C(O)-NH2, -O-(C 1-6 Alkyl), -NH-(C 1-6 Alkyl), -N(C 1-6 alkyl)2,-C(O)-(C 1-6alkyl), -OC(O)-(C 1-6 alkyl), -NH-C(O)-(C 1-6 alkyl), -C(O)-O-(C 1-6 alkyl), -C(O)-NH-(C 1-6 alkyl), -C(O)-N(C 1-6 alkyl)2,-S(O)2-(C 1-6 alkyl), -OS(O)2-(C 1-6 Alkyl), -NH-S(O)2-(C 1-6 alkyl), -S(O)2-O-(C 1-6 alkyl), -S(O)2-NH-(C 1-6 alkyl), -S(O)2-N(C 1-6 Alkyl)2,C 3-10 Cycloalkyl, C 2-14 Heterocyclyl, C 6-14 Aryl, or C 2-14 Heteroaryl, C 1-6 Alkyl, C 2-6 Alkenyl, C 1-6 Haloalkyl, C 2-6 Halogenated alkenyl, C 1-6 Haloalkoxy, C 2-6 Halogenated alkenyloxy, (C 1-6 Alkoxy)-C 1-6 Alkyl, C 1-6 Alkyl, and C 2-6 alkenyl;

[0133] R 2 Yes-N(R 5 )(R 6 );or

[0134] R 2 yes or

[0135] R 2 is a hydrogen atom, a halogen atom, C 3-10 Cycloalkyl, C 2-14 Heterocyclyl, C 6-14 Aryl, or C 2-14 heteroaryl, wherein carbocyclyl, heterocyclyl, aryl and heteroaryl are each optionally independently selected from R 1Z Substituents are substituted one or more times;

[0136] X 5 Yes>NR 2G ;

[0137] X 6 It is C 1-6Alkylene, which may be independently selected from R 1Y Substituents are substituted one or more times; or

[0138] X 7 is oxygen atom, sulfur atom, >NR 2L , or>C(R 2J )(R 2K );

[0139] X 8 , X 9 , X 10 and X 11 are each independently a direct bond, an oxygen atom, a sulfur atom or >C(R 2M )(R 2N ), where X 8 , X 9 , X 10 and X 11 No more than one of them is a direct bond; and where X 8 , X 9 , X 10 and X 11 not more than one of them is an oxygen atom or a sulfur atom;

[0140] X 12 is an oxygen atom, a sulfur atom or >NR 2L ;

[0141] X 13 Is a direct key or >NR 2P ;

[0142] R 2A , R 2B , R 2C , R 2D , R 2E , R 2F , R 2K , R 2M and R 2N are each independently a hydrogen atom, a halogen atom, -CN, a nitro group, -OH, -NH2, -C(O)H, -OC(O)H, -C(O)-OH, -NH-C(O)H, -C(O)-NH2, -O-(C 1-6 Alkyl), -NH-(C 1-6 Alkyl), -N(C 1-6 alkyl)2,-C(O)-(C 1-6 alkyl), -OC(O)-(C 1-6 alkyl), -NH-C(O)-(C 1-6 alkyl), -NH-C(O)-O-(C 1-6 alkyl), -C(O)-O-(C 1-6alkyl), -C(O)-NH-(C 1-6 alkyl), -C(O)-N(C 1-6 alkyl)2,-S(O)2-(C 1-6 alkyl), -OS(O)2-(C 1-6 Alkyl), -NH-S(O)2-(C 1-6 alkyl), -S(O)2-O-(C 1-6 alkyl), -S(O)2-NH-(C 1-6 alkyl), -S(O)2-N(C 1-6 Alkyl)2,C 3-10 Cycloalkyl, C 2-14 Heterocyclyl, C 6-14 Aryl, or C 2-14 Heteroaryl, C 1-6 Alkyl, C 2-6 Alkenyl, C 1-6 Haloalkyl, C 2-6 Halogenated alkenyl, C 1-6 Haloalkoxy, C 2-6 Halogenated alkenyloxy, (C 1-6 Alkoxy)-C 1-6 Alkyl; or, R 2A and R 2B , or R 2C and R 2D , or R 2E and R 2F , or R 2M and R 2N Alternatively, R 2M and R 2N Any two of which are optionally combined to form a fused ring selected from phenyl, C 2-5 Heteroaryl, C 4-8 Cycloalkyl and C 2-5 Heterocyclyl, wherein each fused ring is optionally independently selected from R 1Z Substituents are substituted one or more times;

[0143] R 2G and R 2P are independently hydrogen atoms, C 1-6 Alkyl, C 1-6 haloalkyl, or (C 1-6 Alkoxy)-C 1-6 alkyl;

[0144] R 2J Yes-R 4 or -X 14 -R 4 ;

[0145] R2L Yes-C(O)-R 3 , -C(O)-X 14 -R 4 , -C(S)-R 3 , -C(S)-X 14 -R 4 , -S(O)2-R 3 , -S(O)2-X 14 -R 4 or -X 14 -R 4 ;

[0146] X 14 It is C 1-8 Alkylene, which may be independently selected from R 1Y Substituents are substituted one or more times;

[0147] R 3 is a hydrogen atom, -OH, -NH2, -OR 3B , -NH-R 3B , -N(R 3B )(R 3C ), -OC(O)-R 3B , -NH-C(O)-R 3B , -N(R 3C )-C(O)-R 3B , C 3-10 Carbocyclic group, C 2-14 Heterocyclyl, C 6-14 Aryl, and C 2-14 heteroaryl, wherein carbocyclyl, heterocyclyl, aryl and heteroaryl are each optionally independently selected from R 3A Substituents are substituted one or more times, wherein any two R 3A optionally combined to form a fused ring selected from phenyl, C 2-5 Heteroaryl, C 4-8 Cycloalkyl and C 2-5 Heterocyclyl, wherein each fused ring is optionally independently selected from R 1Z The substituents are substituted one or more times, and when R 3B and R 3C When attached to the same nitrogen atom, R 3B and R 3C optionally combined with the nitrogen atom to which they are attached to form a nitrogen-containing C 2-6 Heterocyclic ring, which is optionally C 1-4 Alkyl substitution;

[0148] R 3AHalogen atoms, -CN, nitro, oxo, -OH, -NH2, -C(O)H, -OC(O)H, -C(O)-OH, -NH-C(O)H, -C(O)-NH2, -OR 3D , -NH-R 3D , -N(R 3D )(R 3E ), -C(O)-R 3D ,-OC(O)-R 3D , -NH-C(O)-R 3D , -C(O)-OR 3D , -C(O)-NH-R 3D ,-C(O)-N(R 3D )(R 3E ), -S(O)2-R 3D ,-OS(O)2-R 3D , -NH-S(O)2-R 3D , -S(O)2-OR 3D , -S(O)2-NH-R 3D ,-S(O)2-N(R 3D )(R 3E ), C 1-8 Alkyl, C 2-8 Alkenyl, C 3-10 Carbocyclic group, C 2-14 Heterocyclyl, C 6-14 Aryl, and C 2-14 Heteroaryl, wherein the alkyl and alkenyl are each optionally independently selected from R 3Y wherein the carbocyclyl, heterocyclyl, aryl and heteroaryl are each independently selected from R 3Z Substituents are substituted one or more times;

[0149] R 3B , R 3C , R 3D and R 3E Each independently is C 1-8 Alkyl, C 2-8 Alkenyl, C 3-10 Carbocyclic group, C 2-14 Heterocyclyl, C 6-14 Aryl, or C 2-14 Heteroaryl, wherein the alkyl and alkenyl are each optionally independently selected from R 3Y wherein the carbocyclyl, heterocyclyl, aryl and heteroaryl are each independently selected from R 3Z Substituents are substituted one or more times;

[0150] R 3Yis a halogen atom, -CN, nitro, oxo, -OH, -NH2, -C(O)H, -OC(O)H, -C(O)-OH, -NH-C(O)H, -C(O)-NH2, -O-(C 1-6 Alkyl), -NH-(C 1-6 Alkyl), -N(C 1-6 alkyl)2,-C(O)-(C 1-6 alkyl), -OC(O)-(C 1-6 alkyl), -NH-C(O)-(C 1-6 Alkyl), -N(C 1-6 alkyl)-C(O)-(C 1-6 alkyl), -C(O)-O-(C 1-6 alkyl), -C(O)-NH-(C 1-6 alkyl), -C(O)-N(C 1-6 alkyl)2,-S(O)2-(C 1-6 alkyl), -OS(O)2-(C 1-6 Alkyl), -NH-S(O)2-(C 1-6 Alkyl), -N(C 1-6 alkyl)-S(O)2-(C 1-6 alkyl), -S(O)2-O-(C 1-6 alkyl), -S(O)2-NH-(C 1-6 alkyl), -S(O)2-N(C 1-6 Alkyl)2,-O-(C 1-6 Alkylene)-O-(C 1-6 Alkyl), C 3-10 Cycloalkyl, C 2-14 Heterocyclyl, C 6-14 Aryl and C 2-14 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally independently selected from R 1Z Substituents are substituted one or more times;

[0151] R 3Z is a halogen atom, -CN, nitro, oxo, -OH, -NH2, -C(O)H, -OC(O)H, -C(O)-OH, -NH-C(O)H, -C(O)-NH2, -O-(C 1-6 Alkyl), -NH-(C 1-6 Alkyl), -N(C 1-6 alkyl)2,-C(O)-(C 1-6 alkyl), -OC(O)-(C 1-6 alkyl), -NH-C(O)-(C 1-6 Alkyl), -N(C 1-6alkyl)-C(O)-(C 1-6 alkyl), -C(O)-O-(C 1-6 alkyl), -C(O)-NH-(C 1-6 alkyl), -C(O)-N(C 1-6 alkyl)2,-S(O)2-(C 1-6 alkyl), -OS(O)2-(C 1-6 Alkyl), -NH-S(O)2-(C 1-6 Alkyl), -N(C 1-6 alkyl)-S(O)2-(C 1-6 alkyl), -S(O)2-O-(C 1-6 alkyl), -S(O)2-NH-(C 1-6 alkyl), -S(O)2-N(C 1-6 Alkyl)2,C 1-6 Alkyl, C 2-6 Alkenyl, C 1-6 Haloalkyl, C 2-6 Halogenated alkenyl, C 1-6 Haloalkoxy, C 2-6 Halogenated alkenyloxy, (C 1-6 Alkoxy)-C 1-6 Alkyl, C 3-10 Cycloalkyl, C 2-14 Heterocyclyl, C 6-14 Aryl and C 2-14 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally independently selected from R 1Z Substituents are substituted one or more times;

[0152] R 4 It is a hydrogen atom, a halogen atom, -CN, a nitro group, an oxo group, -OH, -NH2, -OR 4B , -NH-R 4B , -N(R 4B )(R 4C ), C(O)-R 4B ,-OC(O)-R 4B , -NH-C(O)-R 4B , -N(R 4C )-C(O)-R 4B , -C(O)-OR 4B , -C(O)-NH-R 4B ,-C(O)N(R 4B )(R 4C ), -S(O)2-R 4D ,-OS(O)2-R 4D , -NH-S(O)2-R 4D, -S(O)2-OR 4D , -S(O)2-NH-R 4D ,-S(O)2-N(R 4D )(R 4E ), C 3-10 Carbocyclic group, C 2-14 Heterocyclyl, C 6-14 Aryl, and C 2-14 heteroaryl, wherein the carbocyclyl, heterocyclyl, aryl and heteroaryl are each optionally independently selected from R 4A Substituents are substituted one or more times, wherein any two R 4A optionally combined to form a fused ring selected from phenyl, C 2-5 Heteroaryl, C 4-8 Cycloalkyl and C 2-5 Heterocyclyl, wherein each fused ring is optionally independently selected from R 1Z The substituents are substituted one or more times, and when R 4B and R 4C When attached to the same nitrogen atom, R 4B and R 4C optionally combined with the nitrogen atom to which they are attached to form a nitrogen-containing C 2-6 Heterocyclic ring, which is optionally C 1-4 Alkyl substitution;

[0153] R 4A Halogen atoms, -CN, nitro, oxo, -OH, -NH2, -C(O)H, -OC(O)H, -C(O)-OH, -NH-C(O)H, -C(O)-NH2, -OR 4D , -NH-R 4D , -N(R 4D )(R 4E ), -C(O)-R 4D ,-OC(O)-R 4D , -NH-C(O)-R 4D , -N(R 4E )-C(O)-R 4D , -C(O)-OR 4D , -C(O)-NH-R 4D ,-C(O)-N(R 4D )(R 4E ), C 1-8 Alkyl, C 2-8 Alkenyl, C 3-10 Carbocyclic group, C 2-14 Heterocyclyl, C 6-14 Aryl, and C 2-14 Heteroaryl, wherein the alkyl and alkenyl are each optionally independently selected from R4Y wherein the carbocyclyl, heterocyclyl, aryl and heteroaryl are each independently selected from R 4Z Substituents are substituted one or more times;

[0154] R 4B , R 4C , R 4D and R 4E Each independently is C 1-8 Alkyl, C 2-8 Alkenyl, C 3-10 Carbocyclic group, C 2-14 Heterocyclyl, C 6-14 Aryl, and C 2-14 Heteroaryl, wherein the alkyl and alkenyl are each optionally independently selected from R 4Y wherein the carbocyclyl, heterocyclyl, aryl and heteroaryl are each independently selected from R 4Z Substituents are substituted one or more times;

[0155] R 4Y is a halogen atom, -CN, nitro, oxo, -OH, -NH2, -C(O)H, -OC(O)H, -C(O)-OH, -NH-C(O)H, -C(O)-NH2, -O-(C 1-6 Alkyl), -NH-(C 1-6 Alkyl), -N(C 1-6 Alkyl)2,-C(O)-(C 1-6 alkyl), -OC(O)-(C 1-6 alkyl), -NH-C(O)-(C 1-6 Alkyl), -N(C 1-6 alkyl)-C(O)-(C 1-6 alkyl), -C(O)-O-(C 1-6 alkyl), -C(O)-NH-(C 1-6 alkyl), -C(O)-N(C 1-6 alkyl)2,-S(O)2-(C 1-6 alkyl), -OS(O)2-(C 1-6 Alkyl), -NH-S(O)2-(C 1-6 Alkyl), -N(C 1-6 alkyl)-S(O)2-(C 1-6 alkyl), -S(O)2-O-(C 1-6 alkyl), -S(O)2-NH-(C 1-6 alkyl), -S(O)2-N(C 1-6 Alkyl)2,-O-(C 1-6Alkylene)-O-(C 1-6 Alkyl), C 3-10 Cycloalkyl, C 2-14 Heterocyclyl, C 6-14 Aryl, and C 2-14 Heteroaryl, wherein cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally independently selected from R 1Z Substituents are substituted one or more times;

[0156] R 4Z is a halogen atom, -CN, nitro, oxo, -OH, -NH2, -C(O)H, -OC(O)H, -C(O)-OH, -NH-C(O)H, -C(O)-NH2, -O-(C 1-6 Alkyl), -NH-(C 1-6 Alkyl), -N(C 1-6 Alkyl)2,-C(O)-(C 1-6 alkyl), -OC(O)-(C 1-6 alkyl), -NH-C(O)-(C 1-6 Alkyl), -N(C 1-6 alkyl)-C(O)-(C 1-6 alkyl), -C(O)-O-(C 1-6 alkyl), -C(O)-NH-(C 1-6 alkyl), -C(O)-N(C 1-6 alkyl)2,-S(O)2-(C 1-6 alkyl), -OS(O)2-(C 1-6 Alkyl), -NH-S(O)2-(C 1-6 Alkyl), -N(C 1-6 alkyl)-S(O)2-(C 1-6 alkyl), -S(O)2-O-(C 1-6 alkyl), -S(O)2-NH-(C 1-6 alkyl), -S(O)2-N(C 1-6 Alkyl)2, (C 1-6 Alkoxy)-C 1-6 Alkyl, C 3-10 Cycloalkyl, C 2-14 Heterocyclyl, C 6-14 Aryl or C 2-14 Heteroaryl, C 1-6 Alkyl, C 2-6 Alkenyl, C 1-6 Haloalkyl, C 2-6 Halogenated alkenyl, C 1-6 Haloalkoxy, and C 2-6 haloalkenyloxy, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally independently selected from R1Z Substituents are substituted one or more times;

[0157] R 5 Yes-C(O)-R 3 , -C(O)-X 14 -R 4 , -C(S)-R 3 , -C(S)-X 14 -R 4 , -S(O)2-R 3 , -S(O)2-X 14 -R 4 , or -X 14 -R 4 ;

[0158] R 6 is a hydrogen atom or C 1-8 Alkyl, wherein the alkyl group is optionally independently selected from R 6Y Substituents are substituted one or more times;

[0159] R 6Y is a halogen atom, -CN, nitro, oxo, -OH, -NH2, -C(O)H, -OC(O)H, -C(O)-OH, -NH-C(O)H, -C(O)-NH2, -O-(C 1-6 Alkyl), -NH-(C 1-6 Alkyl), -N(C 1-6 Alkyl)2,-C(O)-(C 1-6 alkyl), -OC(O)-(C 1-6 alkyl), -NH-C(O)-(C 1-6 Alkyl), -N(C 1-6 alkyl)-C(O)-(C 1-6 alkyl), -C(O)-O-(C 1-6 alkyl), -C(O)-NH-(C 1-6 alkyl), -C(O)-N(C 1-6 alkyl)2,-S(O)2-(C 1-6 alkyl), -OS(O)2-(C 1-6 Alkyl), -NH-S(O)2-(C 1-6 Alkyl), -N(C 1-6 alkyl)-S(O)2-(C 1-6 alkyl), -S(O)2-O-(C 1-6 alkyl), -S(O)2-NH-(C 1-6 alkyl), -S(O)2-N(C 1-6 Alkyl)2,-O-(C 1-6 Alkylene)-O-(C1-6 Alkyl), C 3-10 Cycloalkyl, C 2-14 Heterocyclyl, C 6-14 Aryl, and C 2-14 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally independently selected from R 1Z Substituents are substituted one or more times;

[0160] R 7 is a hydrogen atom, a halogen atom, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, or (C 1-6 Alkyl)-OC 1-6 alkyl; and

[0161] n is 0, 1 or 2.

[0162] The various subgenera of the above-identified genera, and combinations thereof, are also considered part of the present disclosure.

[0163] For example, in some of the foregoing embodiments, X 1 and X 2 In some other embodiments, X 1 and X 2 All are>C(R 2A )(R 2B In some such embodiments, R 2A and R 2B In some such embodiments, R 2A and R 2B One of them is a hydrogen atom, and R 2A and R 2B The other is a hydrogen atom, a halogen atom (such as a fluorine atom), C 1-6 Alkyl, C 1-6 Fluorinated alkyl, C 1-6 Alkoxy, C 1-6 Fluoroalkoxy, or -C(O)-(C 1-6 In some other such embodiments, R 2A and R 2B are all hydrogen atoms, so that X 1 and X 2 All are >CH2.

[0164] In some embodiments of any of the preceding embodiments, X 3 is a direct key, so that X 1 and X 4In some other embodiments of any of the foregoing embodiments, X 3 >C(R 2C )(R 2D In some such embodiments, R 2C and R 2D In some such embodiments, R 2C and R 2D One of them is a hydrogen atom, and R 2C and R 2D The other is a hydrogen atom, a halogen atom (such as a fluorine atom), C 1-6 Alkyl, C 1-6 Fluorinated alkyl, C 1-6 Alkoxy, C 1-6 Fluoroalkoxy, or -C(O)-(C 1-6 In some other such embodiments, R 2C and R 2D are all hydrogen atoms, so that X 3 is>CH2.

[0165] In some other embodiments of any of the preceding embodiments, R 2E and R 2F In some such embodiments, R 2E and R 2F One of them is a hydrogen atom, and R 2E and R 2F The other is a hydrogen atom, a halogen atom (such as a fluorine atom), C 1-6 Alkyl, C 1-6 Fluorinated alkyl, C 1-6 Alkoxy, C 1-6 Fluoroalkoxy, or -C(O)-(C 1-6 In some other such embodiments, R 2E and R 2F are all hydrogen atoms, so that X 4 is>CH2.

[0166] As mentioned above, the phenyl part of the fused ring system in formula (I) may optionally have one or two substituents R A Thus, in some embodiments of any of the preceding embodiments, n is 0. In some other embodiments of any of the preceding embodiments, n is 1. In some other embodiments of any of the preceding embodiments, n is 2.

[0167] Substituent R A Can have any suitable value as described above. In some embodiments of any of the foregoing embodiments, R Ais a halogen atom, -OH, -O-(C 1-6 Alkyl), -NH-(C 1-6 Alkyl), -N(C 1-6 Alkyl)2,-C(O)-(C 1-6 alkyl), -C(O)-O-(C 1-6 Alkyl), C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, or (C 1-6 Alkoxy)-C 1-6 In some other such embodiments, R A It is a fluorine atom, a chlorine atom, a methyl group, an ethyl group, an isopropyl group, a hydroxyl group, a methoxy group, a trifluoroalkyl group or a trifluoromethoxy group.

[0168] Substituent R 1 Can have any suitable value as described above. In some embodiments of any of the foregoing embodiments, R 1 is a halogen atom, such as a fluorine atom or a chlorine atom. 1 is a chlorine atom. In some other embodiments of any of the foregoing embodiments, R 1 -C(O)-R 1A In some other embodiments of any of the preceding embodiments, R 1 -C(O)-OR 1A In some other embodiments of any of the preceding embodiments, R 1 -OC(O)-R 1A In some other embodiments, R 1 is a halogen atom, -OR 1A In any of the preceding embodiments, R 1A C 1-6 Alkyl, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, etc. In some such embodiments, R 1A is methyl or ethyl. In some other embodiments of any of the foregoing embodiments, R 1 is -C(O)-CH3. In some other embodiments of any of the foregoing embodiments, R 1 is -C(O)-O-CH3. In some other embodiments of any of the foregoing embodiments, R 1 In some other embodiments, R 1 is a halogen atom, -O-CH3. In some other embodiments of any of the foregoing embodiments, R 1 C 1-6 Alkyl, which may be independently selected from R1Y In some other such embodiments, R 1 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl or hexyl. In some other such embodiments, R 1 is methyl, ethyl, isopropyl or propyl. In some even further such embodiments, R 1 is methyl or ethyl. In some or even other such embodiments, R 1 It is ethyl.

[0169] VARIABLE X 5 Can have any suitable value, as described above. In some embodiments of any of the foregoing embodiments, X 5 >NR 2G , where R 2G A hydrogen atom or C 1-6 In some other such embodiments, R 2G is a hydrogen atom. In some other such embodiments, R 2G It is methyl or ethyl.

[0170] As mentioned above, the variable X 6 Can have any suitable value. In some embodiments of any of the foregoing embodiments, X 6 is -CH2-. In some other embodiments of any of the foregoing embodiments, X 6 is -CH2-CH2-. In some other embodiments of any of the foregoing embodiments, X 6 is -CH(CH3)-. In some other embodiments of any of the foregoing embodiments, X 6 It is -C(CH3)2-.

[0171] In some embodiments of any of the preceding embodiments, R 2 -N(R 5 )(R 6 ). In some other such embodiments, R 6 is a hydrogen atom. In some other such embodiments, R 6 It is C 1-8 Alkyl, which may be independently selected from halogen atoms, -OH, -O-(C 1-6 Alkyl), -NH-(C 1-6 Alkyl), -N(C 1-6 Alkyl)2,-C(O)-(C 1-6 alkyl), -C(O)-O-(C 1-6 Alkyl), C 1-6 Alkyl, C 1-6 Haloalkyl, C1-6 Haloalkoxy and (C 1-6 Alkoxy)-C 1-6 The substituents of the alkyl group are substituted one or more times. In some other such embodiments, R 6 is unsubstituted C 1-8 Alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, etc. In some other embodiments, R 6 It's methyl.

[0172] In some further embodiments of any of the preceding embodiments, R 5 Yes-C(O)-R 3 , -C(O)-X 14 -R 4 or -X 14 -R 4 In some other such embodiments, R 5 -C(O)-R 3 In some other such embodiments, R 3 is not a hydrogen atom. In some other such embodiments, R 5 Yes-C(O)-X 14 -R 4 In some other such embodiments, R 4 is not a hydrogen atom. In some other such embodiments, R 5 Yes-X 14 -R 4 In some other such embodiments, R 4 is not a hydrogen atom. In some further embodiments of the embodiments set forth in this paragraph, X 14 is an unsubstituted straight chain C 1-4 Alkylene.

[0173] In some embodiments of any of the preceding embodiments, R 2 is a part of any of the following formulae: The asterisk indicates the ring and X 6 In some such embodiments, R 2 is a moiety of Formula 1. In some other embodiments is a moiety of Formula 2.

[0174] In some other embodiments of the embodiments of the preceding paragraph, X 8 , X 9 , X 10 or X 11 In some such embodiments, X 8 , X 9 , X 10 or X11 In some other such embodiments, X 8 , X 9 , X 10 or X 11 In some embodiments of each of the foregoing embodiments, each R 2M is a hydrogen atom. In some such embodiments, each R 2N It is a hydrogen atom, a halogen atom, -OH, -NH2, -C(O)-OH, -C(O)-NH2, -O-(C 1-6 Alkyl), -NH-(C 1-6 Alkyl), -N(C 1-6 Alkyl)2,-C(O)-(C 1-6 alkyl), -OC(O)-(C 1-6 alkyl), -NH-C(O)-(C 1-6 alkyl), -NH-C(O)-O-(C 1-6 alkyl), -C(O)-O-(C 1-6 alkyl), -C(O)-NH-(C 1-6 alkyl), -C(O)-N(C 1-6 Alkyl)2,C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, (C 1-6 Alkoxy)-C 1-6 Alkyl, phenyl, or C 2-5 Heteroaryl, wherein phenyl and heteroaryl are optionally independently selected from C 1-4 Alkyl and C 1-4 In some such embodiments, each R 2N It's a hydrogen atom.

[0175] In some embodiments of any of the preceding embodiments, X 7 is an oxygen atom or a sulfur atom. In some such embodiments, X 7 is an oxygen atom. In some other such embodiments, X 7 It is a sulfur atom.

[0176] In some embodiments of any of the preceding embodiments, X 7 >NR 2L In such embodiments, according to those described above, R 2L Can have any suitable value. In some embodiments, R 2L -C(O)-R 3 In some other embodiments, R 2L-C(O)-X 14 -R 4 In some other embodiments, R 2L -C(S)-R 3 In some other embodiments, R 2L -C(S)-X 14 -R 4 In some other embodiments, R 2L -S(O)2-R 3 In some other embodiments, R 2L -S(O)2-X 14 -R 4 In some other embodiments, R 2L -X 14 -R 4 In some further embodiments of any of the preceding embodiments of this paragraph, X 14 is unsubstituted C 1-8 Alkylene, such as straight chain unsubstituted C 1-4 In some further embodiments of any of the foregoing embodiments of this paragraph, R 3 is not a hydrogen atom. In some further embodiments of any of the foregoing embodiments of this paragraph, R 4 Not a hydrogen atom.

[0177] In some embodiments of any of the preceding embodiments, X 7 >C(R 2J )(R 2K ). In such an embodiment, R 2J and R 2K Can have any suitable value as described above. In some such embodiments, R 2K is a hydrogen atom. In some other such embodiments, R 2K It is C 1-6 In some other such embodiments, R 2K In some embodiments, R 2J For-R 4 In some other embodiments, R 2J -X 14 -R 4 In some further embodiments of any of the preceding embodiments of this paragraph, X 14 is unsubstituted C 1-8 Alkylene, such as straight chain unsubstituted C 1-4 In some further embodiments of any of the foregoing embodiments of this paragraph, R 4 Not a hydrogen atom.

[0178] In some embodiments of any of the preceding embodiments, R 2 is a part of any of the following formulae: The asterisk indicates 6 In some such embodiments, R 2 is a moiety of Formula 1. In some other embodiments is a moiety of Formula 2.

[0179] In some other embodiments of the embodiments of the preceding paragraph, X 8 , X 9 , X 10 or X 11 In some such embodiments, X 8 , X 9 , X 10 or X 11 In some other such embodiments, X 8 , X 9 , X 10 or X 11 In some embodiments of each of the foregoing embodiments, each R 2M is a hydrogen atom. In some such embodiments, each R 2N It is a hydrogen atom, a halogen atom, -OH, -NH2, -C(O)-OH, -C(O)-NH2, -O-(C 1-6 Alkyl), -NH-(C 1-6 Alkyl), -N(C 1-6 Alkyl)2,-C(O)-(C 1-6 alkyl), -OC(O)-(C 1-6 alkyl), -NH-C(O)-(C 1-6 alkyl), -NH-C(O)-O-(C 1-6 alkyl), -C(O)-O-(C 1-6 alkyl), -C(O)-NH-(C 1-6 alkyl), -C(O)-N(C 1-6 Alkyl)2,C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, (C 1-6 Alkoxy)-C 1-6 Alkyl, phenyl, or C 2-5 Heteroaryl, wherein phenyl and heteroaryl are optionally independently selected from C 1-4 Alkyl and C 1-4 In some such embodiments, each R 2NIt's a hydrogen atom.

[0180] In some embodiments of any of the preceding embodiments, X 12 X is an oxygen atom or a sulfur atom. 12 is an oxygen atom. In some other such embodiments, X 12 It is a sulfur atom.

[0181] In some embodiments of any of the preceding embodiments, X 12 >NR 2L In such embodiments, according to those described above, R 2L Can have any suitable value. In some embodiments, R 2L -C(O)-R 3 In some other embodiments, R 2L -C(O)-X 14 -R 4 In some other embodiments, R 2L -C(S)-R 3 In some other embodiments, R 2L -C(S)-X 14 -R 4 In some other embodiments, R 2L -S(O)2-R 3 In some other embodiments, R 2L -S(O)2-X 14 -R 4 In some other embodiments, R 2L -X 14 -R 4 In some further embodiments of any of the preceding embodiments of this paragraph, X 14 is unsubstituted C 1-8 Alkylene, such as straight chain unsubstituted C 1-4 In some further embodiments of any of the foregoing embodiments of this paragraph, R 3 is not a hydrogen atom. In some further embodiments of any of the foregoing embodiments of this paragraph, R 4 Not a hydrogen atom.

[0182] As mentioned above, the variable X 13 Can have any suitable value. In some embodiments, X 13 is a direct bond, which means that the carbon atom of the ring is directly bonded to X 6 In some other embodiments, X 13 >NR 2P As mentioned above, the variable R 2PCan have any suitable value. In some embodiments, R 2P is a hydrogen atom. In some other embodiments, R 2P It is C 1-6 In some other such embodiments, R 2P It is methyl or ethyl.

[0183] As mentioned above, the variable R 7 Can have any suitable value. In some embodiments, R 7 is a hydrogen atom. In some other embodiments, R 7 is a halogen atom, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, or (C 1-6 Alkyl)-OC 1-6 In some other embodiments, R 7 is methyl, trifluoromethyl, methoxy, trifluoromethoxy, 2-methoxyethyl or methoxymethyl.

[0184] In some embodiments, the compound is any compound of the structure listed in any one of Tables 2 to 9, or a salt thereof.

[0185] In some further embodiments of any of the preceding embodiments, the salt is an edible salt. In some other embodiments of any of the preceding embodiments, the salt is a pharmaceutically acceptable salt.

[0186] Many of the foregoing embodiments list halogen atoms as members of a particular group. In some embodiments of any of the foregoing embodiments, the halogen atom is a fluorine atom or a chlorine atom. In some other such embodiments, the halogen atom is a fluorine atom.

[0187] Many of the foregoing embodiments list aryl as a member of a particular group. In some embodiments of any of the foregoing embodiments, aryl is phenyl which is unsubstituted or substituted as indicated.

[0188] Many of the aforementioned embodiments list carbocyclyl as a member of a particular group. In some embodiments of any of the aforementioned embodiments, carbocyclyl is cycloalkyl, unsubstituted or substituted as shown, and has the same carbon number range. In some other such embodiments, any carbocyclyl or cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cyclopentyl, unsubstituted or substituted as shown.

[0189] Many of the foregoing embodiments list heteroaryl as a member of a particular group. In some other such embodiments, any such heteroaryl is pyrrol-1-yl, pyrrol-2-yl, pyrrol-3-yl, pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, imidazol-1-yl, imidazol-2-yl, imidazol-4-yl, 1,2,3-triazol-1-yl, 1,2,3-triazol-4-yl, 1,2,4-triazol-1-yl, 1,2,4-triazol-3-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, isoxazol-3-yl, isoxazol-4-yl, Thiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, furazan-3-yl, 1,2,5-oxadiazol-3-yl, 1,2,5-oxadiazol-4-yl, 1,2,5-thiadiazol-3-yl, 1,2,5-thiadiazol-4-yl, furan-2-yl, furan-3-yl, thien-2-yl, thien-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyridazin-3-yl, pyridazin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, or pyrazin-2-yl, any of which can be substituted as indicated. In some further embodiments, the optional substituents on any of the aforementioned rings are limited to substituents selected from the group consisting of: methyl, ethyl, isopropyl, hydroxyl, methoxy, fluorine atom, chlorine atom, trifluoromethyl, trifluoromethoxy, -NH2, methylamino, dimethylamino, methylcarbonyl, ethylcarbonyl, methoxycarbonyl, and ethoxycarbonyl.

[0190] Many of the foregoing embodiments list heterocyclyl as a member of a particular group. In some other such embodiments, any such heterocyclyl is pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, pyrazolidin-1-yl, pyrazolidin-2-yl, pyrazolidin-3-yl, pyrazolidin-4-yl, imidazolidin-1-yl, imidazolidin-2-yl, imidazolidin-3-yl, imidazolidin-4-yl, imidazolidin-5-yl, oxazolidin-2-yl, oxazolidin-3-yl, oxazolidin-4-yl, oxazolidin-5-yl, isoxazolidin-2-yl, isoxazolidin-3-yl, isoxazolidin-4-yl, isoxazolidin-5-yl, thiazolidin-2-yl, thiazolidin-3-yl, thiazolidin-4-yl, thiazolidin-5-yl, isothiazolidin-2-yl, Isothiazolidin-3-yl, isothiazolidin-4-yl, isothiazolidin-5-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydropyran-2-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, tetrahydrothiopyran-2-yl, tetrahydrothiopyran-3-yl, tetrahydrothiopyran-4-yl, 1,4-dioxan-2-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperazin-1-yl, piperazin-2-yl, morpholin-2-yl, morpholin-3-yl, morpholin-4-yl, thiomorpholin-2-yl, thiomorpholin-3-yl, or thiomorpholin-4-yl, any of which can be substituted as indicated. In some further embodiments, the optional substituents on any of the aforementioned rings are limited to substituents selected from the group consisting of: methyl, ethyl, isopropyl, hydroxyl, methoxy, fluorine atom, chlorine atom, trifluoromethyl, trifluoromethoxy, -NH2, methylamino, dimethylamino, methylcarbonyl, ethylcarbonyl, methoxycarbonyl, and ethoxycarbonyl. Note that in some cases, when two substituents on a common nitrogen atom are combined to form a ring, a heterocycle is formed. In certain embodiments of this case, the heterocycle is pyrrolidin-1-yl, pyrazolidin-1-yl, imidazolidin-1-yl, oxazolidin-3-yl, isoxazolidin-2-yl, thiazolidin-3-yl, isothiazolidin-2-yl, piperidin-1-yl, piperazin-1-yl, morpholin-4-yl, or thiomorpholin-4-yl, any of which can be substituted as shown. In some further embodiments, the optional substituents on any of the aforementioned rings are limited to substituents selected from the group consisting of: methyl, ethyl, isopropyl, hydroxyl, methoxy, fluorine atom, chlorine atom, trifluoromethyl, trifluoromethoxy, -NH2, methylamino, dimethylamino, methylcarbonyl, ethylcarbonyl, methoxycarbonyl, and ethoxycarbonyl.

[0191] When the compounds disclosed herein have at least one chiral center, they can exist as individual enantiomers and diastereomers or as a mixture of such isomers including racemates. The separation of each isomer or the selective synthesis of each isomer is completed by applying various methods well known to those skilled in the art. Unless otherwise specified (for example, in the case of clearly showing the stereochemistry of the chiral center), all these isomers and mixtures thereof are included in the scope of the compounds disclosed herein. In addition, the compounds disclosed herein may exist in one or more crystalline or amorphous forms. Unless otherwise specified, all these forms are included in the scope of the compounds disclosed herein, including any polymorphic form. In addition, some compounds disclosed herein can form solvates with water (i.e., hydrates) or common organic solvents. Unless otherwise specified, these solvates are included in the scope of the compounds disclosed herein.

[0192] Those skilled in the art will recognize that some structures described herein may be resonance forms or tautomers of compounds, even though they may be reasonably represented kinetically by other chemical structures. Those skilled in the art recognize that such structures may represent only a small fraction of such compound samples. Such compounds are considered to be within the scope of the described structures, even though such resonance forms or tautomers are not shown herein.

[0193] Isotopes may be present in the compound. Each chemical element represented by a compound structure may include any isotope of the element. For example, in a compound structure, a hydrogen atom may be explicitly disclosed or understood to be present in the compound. Any position where a hydrogen atom may be present in the compound may be any isotope of hydrogen, including but not limited to hydrogen-1 (protium) and hydrogen-2 (deuterium). Therefore, the compounds mentioned herein encompass all potential isotopic forms unless the context clearly indicates otherwise.

[0194] In some embodiments, the compounds disclosed herein are capable of forming acidic or basic salts due to the presence of amino or carboxyl groups or groups similar thereto. Physiologically acceptable acid addition salts can be formed with inorganic and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic 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. Physiologically acceptable salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, bases containing sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like; particularly preferred are ammonium, potassium, sodium, calcium, and magnesium salts. In some embodiments, treatment of the compounds disclosed herein with an inorganic base causes the compound to lose unstable hydrogen, thereby obtaining a compound containing an inorganic cation such as Li+ , Na + , K + ,Mg 2+ and Ca 2 + Organic bases from which salts can be derived include, for example, primary, secondary and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines, basic ion exchange resins and the like, in particular isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine and ethanolamine.

[0195] Any of the above compounds can exist in any suitable form. For example, in some embodiments, the compound is dissolved or suspended in a liquid carrier such as an aqueous composition. In some other embodiments, the compound is a crystal, semi-crystalline or amorphous solid, or can exist as a part of a crystal solvate (such as a crystal hydrate), or as a co-crystallization with another crystalline solid, such as a crystalline sweetener compound (such as erythritol, sucrose, fructose, etc.).

[0196] The above compounds can be synthesized in a manner consistent with that described in the following examples.

[0197] Uses and methods

[0198] In a second aspect, the present disclosure provides the use of the compound of the first aspect and any of the above embodiments or combinations of embodiments.

[0199] In a related third aspect, the present disclosure provides the use of the compound of the first aspect, and any embodiment or combination of embodiments described above, to reduce the bitterness or enhance the sweetness of a composition, such as an edible composition or a pharmaceutical composition.

[0200] In some embodiments, the use is used to reduce the bitterness of edible compositions. In some such embodiments, edible compositions are flavored products, such as food or beverage products. Bitterness may come from many different sources. For example, products of natural origin will usually contain bitter compounds. Common non-limiting examples of such bitter compounds are menthol, tannins in tea, coffee and wine, hop extracts in beer, etc. Bitter compounds can also be present in certain fruit and vegetable juices, such as juices of kale, beets, etc. Therefore, one or more compounds of the first form can be introduced into products containing such bitter compounds to reduce their bitterness. In turn, this leads to more consumption of such materials or reduces the amount of caloric sweeteners used to offset the bitterness in such products. Protein preparations (such as protein isolates of plant origin) usually make the taste bitter. In some embodiments, one or more compounds of the first form are combined with such compounds to reduce the bitterness of such proteins. Therefore, one or more compounds of the first form can be included in products that can use such proteins, such as protein powders, energy bars, snack foods, and various foods that use non-animal-derived products instead of cheese, meat, and other products traditionally derived from animals. Therefore, one or more compounds of the first form can be included in various cheese substitutes, meat substitutes, etc. They can also be included in products that add protein to increase the protein-to-carbohydrate ratio, where the addition of protein may bring bitterness. In addition, substitutes for salt, monosodium glutamate (MSG) and other salty compounds can be replaced with healthier substitutes such as potassium chloride (KCl). But these substitutes usually bring bitterness. Therefore, when included in low-salt or MSG-free variants of traditional salty foods (such as potato chips, soup cubes, meat-containing products, nuts, etc.), one or more compounds of the first form can be used to reduce this bitterness. Therefore, such compounds can be used in such foods together with KCl. In addition, when used as a substitute for caloric sweeteners such as sucrose or fructose, substitutes for caloric sweeteners such as various natural or synthetic sweeteners can impart bitterness. In some embodiments, one or more compounds of this first form are used in combination with one or more non-caloric or low-calorie sweeteners, such as sucralose, saccharin, acesulfame potassium, aspartame, steviol glycosides, including rebaudioside, mogroside, glycyrrhizin and flavanones, such as naringenin, hesperetin and their glucosylated derivatives. In addition, one or more compounds of the first form can be combined with any other taste enhancing compounds, including: sweetness enhancers, such as siratose; umami enhancers, such as ericamide; other bitterness reducers; and sourness reducers.

[0201] In some embodiments, the use is for reducing the bitter taste of a pharmaceutical composition. In this case, the bitter taste is caused by certain active pharmaceutical ingredients (API) or other excipients added to the formulation to enhance drug efficacy and delivery. At present, various encapsulation strategies are used to mask the taste of certain bitter ingredients in pharmaceutical formulations. However, in some cases, people can omit this isolation technology and only combine the bitter compound with one or more compounds of the first form to reduce the bitter taste of the pharmaceutical composition. Typically, such pharmaceutical compositions are pharmaceutical compositions for oral administration, such as tablets, capsules, elixirs, lozenges, etc.

[0202] In a related fourth aspect, the present disclosure provides the use of a compound of the first aspect in the manufacture of a product for reducing bitterness or enhancing sweetness in the product. In some embodiments, the present disclosure provides the use of a compound of the first aspect in the manufacture of a flavored product, such as a flavored food or beverage product, for reducing bitterness in the product. When incorporated into such a product during the manufacturing process, one or more compounds of the first aspect may be combined with other compounds in any manner described above for the third aspect. In some other embodiments, the present disclosure provides the use of a compound of the first aspect in the preparation of a medicament for reducing bitterness in the medicament. When incorporated into such a product during the manufacturing process, one or more compounds of the first aspect may be combined with other compounds in any manner described above for the third aspect.

[0203] In a related fifth aspect, the present disclosure provides the use of the compounds of the first aspect for antagonizing one or more human T2R taste receptors, such as one or more human T2R54 taste receptors. As noted above in the third and fourth aspects, according to any of the embodiments set forth in those aspects, these uses may include incorporation into various foods and pharmaceuticals.

[0204] In a related sixth form, the present disclosure provides a method for reducing the bitterness of a flavored composition or a pharmaceutical composition or enhancing its sweetness, the method comprising introducing a certain amount (e.g., an effective amount) of one or more compounds of the first form into the flavored composition or pharmaceutical composition. In some embodiments, the present disclosure provides a method for reducing the bitterness of a flavored composition, the method comprising introducing a certain amount (e.g., an effective amount) of one or more compounds of the first form into the flavored composition. In some such embodiments, the flavored composition is a food or beverage product. In some other embodiments, the present disclosure provides a method for reducing the bitterness of a pharmaceutical composition, the method comprising introducing a certain amount (e.g., an effective amount) of one or more compounds of the first form into the pharmaceutical composition. As noted above in the third and fourth forms, according to any embodiment described in those forms, these methods may include incorporation into various foods and medicines. Typically, based on the gross weight of the composition, the effective amount is 5 to 2000ppm, or 5 to 1000ppm, or 5 to 800ppm, or 5 to 500ppm, or 5 to 400ppm, or 5 to 300ppm, or 5 to 200ppm. These quantities are also closely related to the uses and methods of the aforementioned forms.

[0205] In a related seventh form, the present disclosure provides a method for antagonizing a human T2R receptor, the method comprising contacting a human T2R receptor with one or more compounds of the first form. In some embodiments thereof, the method comprises contacting a human T2R54 receptor with one or more compounds of the first form. In some embodiments, contacting comprises oral ingestion of a composition comprising one or more compounds of the first form. In some such embodiments, the composition is a flavored composition, such as a food or beverage product. In some other such embodiments, the composition is a pharmaceutical composition. As noted above in the third and fourth forms, these uses may include incorporation into various foods and medicines according to any of the embodiments set forth in those forms. Typically, the effective amount is 5 to 2000 ppm, or 5 to 1000 ppm, or 5 to 800 ppm, or 5 to 500 ppm, or 5 to 400 ppm, or 5 to 300 ppm, or 5 to 200 ppm, based on the total weight of the composition. These amounts are also closely related to the uses and methods of the aforementioned forms.

[0206] As indicated in the previous uses and methods, the first form of the compound is used in various compositions, such as edible or pharmaceutical compositions. The following details regarding compositions can be used in conjunction with any of the compositions described in the previous uses and methods.

[0207] Composition

[0208] In some forms, the present disclosure provides a composition comprising a certain amount of one or more compounds of the first form. In some embodiments, the composition comprises one or more bitter compounds and one or more compounds of the first form that reduce the bitterness effective amount. In some other embodiments, the composition is a pharmaceutical composition, and the bitter compound is one or more pharmaceutical compounds, such as an active pharmaceutical ingredient (API). In some other embodiments, the composition is a flavored composition, such as a food or beverage product, and the bitter compound is an artificial sweetener, caffeine, protein (e.g., plant protein), amino acid, a compound derived from a natural plant extract, etc.

[0209] In some embodiments, the compounds disclosed and described herein can be used alone or in combination for one or more methods, such as modifying receptor function associated with chemosensory or chemosensory-related sensations or reactions. Some embodiments provide a method of modulating a chemosensory receptor, the method comprising modulating the activity, structure, function and / or modification of a chemosensory receptor, as well as modulating, treating or preventing conditions associated with chemosensory receptors, such as physiological or pathological conditions. Typically, physiological or pathological conditions associated with chemosensory receptors include conditions, diseases or disorders associated with chemosensory receptors and / or their ligands, such as gastrointestinal diseases, metabolic diseases, functional gastrointestinal diseases, etc. In one embodiment, the method comprises increasing or enhancing sweet taste. In another embodiment, the method comprises modulating sweet taste receptors and / or their ligands expressed in body locations other than taste buds, such as internal organs.

[0210] Typically, the compounds disclosed and described herein can be provided in a composition, such as an ingestible (or edible) composition, either alone or in combination. In some embodiments, the compounds disclosed and described herein reduce the perception of bitterness associated with certain bitter compounds in the composition, either alone or in combination. In another embodiment, the compounds disclosed and described herein can contact the composition with the compounds disclosed and described herein, either alone or in combination, to form a modified composition, thereby increasing or enhancing the sweetness of the composition. In another embodiment, the compounds disclosed and described herein can be present in a composition, either alone or in combination, that modulates bitter receptors and / or their ligands expressed in the human body other than taste buds, such as human T2R receptors, such as T2R54.

[0211] Some embodiments provide an ingestible composition comprising one or more compounds of the first form and one or more bitter compounds. In some embodiments, the composition further comprises a vehicle. In some embodiments, the vehicle is water. In some other embodiments, the composition may comprise one or more natural or artificial sweeteners. In some embodiments, the compound may be present at a concentration of its sweetness recognition threshold or lower. In some embodiments, the sweetener is present in an amount of about 0.1% to about 12% by weight. In some embodiments, the sweetener is present in an amount of about 0.2% to about 10% by weight. In some embodiments, the sweetener is present in an amount of about 0.3% to about 8% by weight. In some embodiments, the sweetener is present in an amount of about 0.4% to about 6% by weight. In some embodiments, the sweetener is present in an amount of about 0.5% to about 5% by weight. In some embodiments, the sweetener is present in an amount of about 1% to about 2% by weight. In some embodiments, the sweetener is present in an amount of about 0.1% to about 5% by weight. In some embodiments, the sweetener is present in an amount of about 0.1% to about 4% by weight. In some embodiments, the sweetener is present in an amount of about 0.1% to about 3% by weight. In some embodiments, the sweetener is present in an amount of about 0.1% to about 2% by weight. In some embodiments, the sweetener is present in an amount of about 0.1% to about 1% by weight. In some embodiments, the sweetener is present in an amount of about 0.1% to about 0.5% by weight. In some embodiments, the sweetener is present in an amount of about 0.5% to about 10% by weight. In some embodiments, the sweetener is present in an amount of about 2% to about 8% by weight. In some embodiments, the sweetener can be a common carbohydrate sweetener, such as sucrose, fructose, glucose, and sweetener compositions containing natural sugars such as corn syrup (including high fructose corn syrup) or other syrups or sweetener concentrates derived from natural fruit and vegetable sources; rare natural sugars, including D-allose, D-psicose, L-ribose, D-tagatose, L-glucose, L-fucose, L-arabinose, D-turanose, and D-leucrose; semi-synthetic "sugar alcohol" sweeteners, such as erythritol, isomalt, lactitol, mannitol, sorbitol, xylitol, maltodextrin, etc.; and artificial sweeteners, such as aspartame, saccharin, acesulfame potassium, cyclamate, sucralose and alitame.In some embodiments, sweetener can be selected from the group consisting of: cyclamic acid, mogroside, tagatose, maltose, galactose, mannose, sucrose, fructose, lactose, neotame and other aspartame derivatives, glucose, D-tryptophan, glycine, maltitol, lactitol, isomalt, hydrogenated glucose syrup (HGS), hydrogenated starch hydrolysate (HSH), steviol glycosides, rebaudioside A and other sweet steviosides, guanidine sweeteners (carrelame) and other guanidine sweeteners. In some embodiments, sweetener can be a combination of two or more sweeteners as disclosed herein. In some embodiments, sweetener can be a combination of two, three, four or five sweeteners disclosed herein. In some embodiments, sweetener can be sugar. In some embodiments, sweetener can be a combination of one or more sugars and other natural and artificial sweeteners. In some embodiments, sweetener is sugar. In some embodiments, the sugar is cane sugar. In some embodiments, the sugar is beet sugar. In some embodiments, the sugar may be sucrose, fructose, glucose or a combination thereof. In some embodiments, the sugar may be sucrose. In some embodiments, the sugar may be a combination of fructose and glucose. In some embodiments, the sugar may be a combination of about 55% fructose and about 42% glucose. In some embodiments, the sugar may be a combination of about 42% fructose and about 53% glucose. In some embodiments, the sugar may be a combination of about 90% fructose and about 10% glucose. In some embodiments, the sweetener may be a rare sugar. In some embodiments, the rare sugar is selected from D-allose, D-psicose, L-ribose, D-tagatose, L-glucose, L-fucose, L-arabinose, D-turanose, D-leucrose and a combination thereof. In some embodiments, the rare sugar is D-psicose. In some embodiments, the rare sugar is D-tagatose. In some embodiments, the sweetener is an artificial sweetener. In some embodiments, the artificial sweetener can be sucralose.In some embodiments, the sweetener is rebaudioside A or other sweet steviosides, such as glucosylated steviol glycosides.

[0212] In some embodiments, the ingestible composition can be a beverage. In some embodiments, the beverage can be selected from an enhanced sparkling beverage, cola, a lemon-lime flavored sparkling beverage, an orange flavored sparkling beverage, a grape flavored sparkling beverage, a strawberry flavored sparkling beverage, a pineapple flavored sparkling beverage, ginger beer, root beer, juice, fruit-flavored juice, fruit juice drink, nectar drink, vegetable juice, vegetable-flavored juice, sports drink, energy drink, fortified water drink, vitamin-fortified water, near water drink, coconut water, tea drink, coffee, cocoa drink, a beverage containing a milk component, a beverage containing a cereal extract, and a smoothie. In some embodiments, the beverage can be a soft drink.

[0213] In some embodiments, one or more compounds described herein and one or more sweeteners described herein may be included in a food or beverage product, wherein the food or beverage product may additionally include:

[0214] Acids, including, for example, citric acid, phosphoric acid, ascorbic acid, sodium sulfate, lactic acid or tartaric acid;

[0215] bitter ingredients including, for example, caffeine, quinine, green tea, catechins, polyphenols, robusta green coffee bean extract, green coffee bean extract, protein isolate (e.g., whey protein isolate or soy protein isolate), or potassium chloride;

[0216] Coloring agents, including, for example, caramel, red #40, yellow #5, yellow #6, blue #1, red #3, purple carrot, black carrot juice, purple sweet potato, vegetable juice, fruit juice, beta-carotene, turmeric curcumin, or titanium dioxide;

[0217] preservatives, including, for example, sodium benzoate, potassium benzoate, potassium sorbate, sodium metabisulfite, sorbic acid or benzoic acid;

[0218] Antioxidants including, for example, ascorbic acid, calcium disodium EDTA, alpha-tocopherol, mixed tocopherols, rosemary extract, grape seed extract, resveratrol, or sodium hexametaphosphate;

[0219] Vitamins or functional ingredients, including, for example, resveratrol, Co-Q10, omega 3 fatty acids, theanine, choline chloride (Citcoline), inositol, inulin (chicory root), taurine, ginseng extract, guarana extract, ginger extract, L-phenylalanine, L-carnitine, L-tartrate, D-glucuronolactone, inositol, bioflavonoids, echinacea, Ginkgo Biloba, yerba mate, flaxseed oil, Garcinia cambogia peel extract, white tea extract, ribose, milk thistle thistle extract, grape seed extract, pyridoxine hydrochloride (vitamin B6), cyanocobalamin (vitamin B12), niacinamide (vitamin B3), biotin, calcium lactate, calcium pantothenate (pantothenic acid), calcium phosphate, calcium carbonate, chromium chloride, chromium polynicotinate, cupric sulfate, folic acid, ferric pyrophosphate, iron, magnesium lactate, magnesium carbonate, magnesium sulfate, monopotassium phosphate, monosodium phosphate, phosphorus, potassium iodide, potassium phosphate, riboflavin, sodium sulfate, sodium gluconate, sodium polyphosphate, sodium bicarbonate, thiamine mononitrate, vitamin D3, vitamin A palmitate, zinc gluconate, zinc lactate, or zinc sulfate;

[0220] Clouding agents, including, for example, ester gums, brominated vegetable oil (BVO) or sucrose acetate isobutyrate (SAIB);

[0221] Buffers, including, for example, sodium citrate, potassium citrate or saline;

[0222] Flavorings, including, for example, propylene glycol, ethanol, glycerin, gum arabic (acacia gum), maltodextrin, modified corn starch, dextrose, natural flavorings, natural flavorings with other natural flavorings (natural flavoring WONF), natural and artificial flavorings, artificial flavorings, silicon dioxide, magnesium carbonate, or tricalcium phosphate; and

[0223] Stabilizers include, for example, pectin, xanthan gum, carboxymethylcellulose (CMC), polysorbate 60, polysorbate 80, medium chain triglycerides, cellulose gel, cellulose gum, sodium caseinate, modified food starch, gum arabic (acacia gum), or carrageenan.

[0224] In some other embodiments, the composition may include one or more flavonones or glucosylated derivatives thereof. Non-limiting examples include blumeatin, butin, eriodictyol, hesperetin, hesperidin, homoeriodictyol, isosakuranetin, naringenin, naringin, pinocembrin, poncirin, sakuranetin, sakuranin, 7-O-methyl sterubin, pinostrobin, or glucosylated derivatives thereof.

[0225] Some embodiments provide a method for enhancing the sweetness of a sweetener, comprising combining one or more compounds of the first form with a sweetener. In some embodiments, the sweetener can be a common sugar sweetener, such as sucrose, fructose, glucose, and a sweetener composition comprising natural sugars such as corn syrup (including high fructose corn syrup) or other syrups or sweetener concentrates derived from natural fruit and vegetable sources; rare natural sugars, including D-allose, D-psicose, L-ribose, D-tagatose, L-glucose, L-fucose, L-arabinose, D-turanose, and D-leucrose; semi-synthetic "sugar alcohol" sweeteners, such as erythritol, isomalt, lactitol, mannitol, sorbitol, xylitol, maltodextrin, etc.; and artificial sweeteners, such as aspartame, saccharin, acesulfame potassium, cyclamates, sucralose and alitame. In some embodiments, sweeteners can be selected from the group consisting of: cyclamic acid, mogroside, tagatose, maltose, galactose, mannose, sucrose, fructose, lactose, neotame and other aspartame derivatives, glucose, D-tryptophan, glycine, maltitol, lactitol, isomalt, hydrogenated glucose syrup (HGS), hydrogenated starch hydrolysate (HSH), steviol glycosides, rebaudioside A and other sweet steviosides, guanidine sweeteners (carrelame) and other guanidine sweeteners. In some embodiments, sweeteners can be a combination of two or more sweeteners as disclosed herein. In some embodiments, sweeteners can be a combination of two, three, four or five sweeteners disclosed herein. In some embodiments, sweeteners can be sugar. In some embodiments, sweeteners can be a combination of one or more sugars and other natural and artificial sweeteners. In some embodiments, sweeteners are sugars. In some embodiments, sugars are cane sugars. In some embodiments, the sugar is beet sugar. In some embodiments, the sugar may be sucrose, fructose, glucose, or a combination thereof (e.g., high fructose corn syrup). In some embodiments, the sugar may be sucrose. In some embodiments, the sugar may be a combination of fructose and glucose. In some embodiments, the sugar may be a combination of about 55% fructose and about 42% glucose. In some embodiments, the sugar may be a combination of about 42% fructose and about 53% glucose. In some embodiments, the sugar may be a combination of about 90% fructose and about 10% glucose. In some embodiments, the sweetener may be a rare sugar. In some embodiments, the rare sugar is selected from D-allose, D-psicose, L-ribose, D-tagatose, L-glucose, L-fucose, L-arabinose, D-turanose, D-leucrose, and a combination thereof. In some embodiments, the rare sugar is D-psicose. In some embodiments, the rare sugar is D-tagatose. In some embodiments, the sweetener is an artificial sweetener. In some embodiments, the artificial sweetener may be sucralose.

[0226] In one embodiment, the compounds disclosed and described herein can be used alone or in combination at their ligand enhancing concentrations, e.g., very low concentrations of about a few parts per million, in combination with one or more known natural or artificial sweeteners to reduce the concentration of the known sweetener required to prepare an edible composition having a desired sweetness.

[0227] In one embodiment, the compounds disclosed and described herein, alone or in combination, can improve the sweetness of sweeteners in a wide pH range, for example, from a relatively low pH to a neutral pH. Lower and neutral pHs include, but are not limited to, about 2.5 to about 8.5; and about 3.0 to about 8.0; about 3.5 to about 7.5; about 4.0 to about 7 pH. In certain embodiments, the compounds disclosed and described herein, alone or in combination, can enhance the perceived sweetness of fixed concentration sweeteners in sweetness tests at low to neutral pH values ​​at about 500 μM, 200 μM, 100 μM, 75 μM, 50 μM, 40 μM, 30 μM, 20 μM or 10 μM compound concentrations. In certain embodiments, the enhancement factor of the compounds disclosed and described herein is substantially similar to the enhancement factor of the compounds at a relatively low pH, alone or in combination. This consistent sweetening property over a wide pH range allows the compounds disclosed and described herein to be widely used in various foods and beverages, alone or in combination. In some embodiments, the sweetener can be a common sugar sweetener, such as sucrose, fructose, glucose, and sweetener compositions containing natural sugars such as corn syrup (including high fructose corn syrup) or other syrups or sweetener concentrates derived from natural fruit and vegetable sources; rare natural sugars, including D-allose, D-psicose, L-ribose, D-tagatose, L-glucose, L-fucose, L-arabinose, D-turanose, and D-leucrose; semi-synthetic "sugar alcohol" sweeteners, such as erythritol, isomalt, lactitol, mannitol, sorbitol, xylitol, maltodextrin, etc.; and artificial sweeteners, such as aspartame, saccharin, acesulfame potassium, cyclamates, sucralose and alitame. In some embodiments, sweeteners can be selected from the group consisting of: cyclamic acid, mogroside, tagatose, maltose, galactose, mannose, sucrose, fructose, lactose, neotame and other aspartame derivatives, glucose, D-tryptophan, glycine, maltitol, lactitol, isomalt, hydrogenated glucose syrup (HGS), hydrogenated starch hydrolysate (HSH), steviol glycosides, rebaudioside A and other sweet steviosides, guanidine sweeteners (carrelame) and other guanidine sweeteners. In some embodiments, sweeteners can be a combination of two or more sweeteners as disclosed herein. In some embodiments, sweeteners can be a combination of two, three, four or five sweeteners as disclosed herein. In some embodiments, sweeteners can be sugar. In some embodiments, sweeteners can be a combination of one or more sugars and other natural and artificial sweeteners. In some embodiments, sweeteners can be sugar. In some embodiments, sugar is cane sugar. In some embodiments, the sugar is beet sugar.In some embodiments, the sweetener may be a combination of one or more sugars with other natural and artificial sweeteners.In some embodiments, the sugar may be sucrose, fructose, glucose, or a combination thereof (e.g., high fructose corn syrup). In some embodiments, the sugar may be sucrose. In some embodiments, the sugar may be a combination of fructose and glucose. In some embodiments, the sugar may be a combination of about 55% fructose and about 42% glucose. In some embodiments, the sugar may be a combination of about 42% fructose and about 53% glucose. In some embodiments, the sugar may be a combination of about 90% fructose and about 10% glucose. In some embodiments, the sweetener may be a rare sugar. In some embodiments, the rare sugar is selected from D-allose, D-psicose, L-ribose, D-tagatose, L-glucose, L-fucose, L-arabinose, D-turanose, D-leucrose, and combinations thereof. In some embodiments, the rare sugar is D-psicose. In some embodiments, the rare sugar is D-tagatose. In some embodiments, the sweetener is an artificial sweetener. In some embodiments, the artificial sweetener is sucralose.

[0228] Sweeteners have a wide range of chemically distinct structures and therefore possess various properties such as, but not limited to, aroma, flavor, mouthfeel and aftertaste.

[0229] In at least one aspect, the present disclosure provides a formulation comprising one or more compounds of the first aspect (any of any of the above embodiments, or as any individual compound of Tables 2 to 9, or a combination thereof) and one or more sweeteners, such as natural or artificial sweeteners. In some such embodiments, the formulation comprises one or more sweeteners at a concentration below the optimal sweetness concentration if used alone or without an hT2R54 antagonist disclosed herein.

[0230] Any suitable natural or artificial sweetener, or any combination thereof, may be used. Natural or artificial sweeteners used in formulations comprising sweeteners and bitterness reducing agents (i.e., T2R54 modulators disclosed herein) include, but are not limited to, natural or synthetic carbohydrates or carbohydrate analogs, including monosaccharides, disaccharides, oligosaccharides, and polysaccharides, and include rare sugars, or any sugar in the D- or L- configuration, including, for example, sucrose, fructose, glucose, L-arabinose, L-fucose, L-glucose, L-ribose, D-arabinohexose, psicose, altrose, arabinose, turanose, abequose, allose, abrinose triterpenoid glycoside A, triose, threose, xylose, xylulose, xylose oligosaccharides (such as xylotriose and xylobiose), lyxose, polydextrose, fructooligosaccharides, fucose, galacto-oligosaccharides, galactosamine, galactose, gentio-oligosaccharides (such as gentiobiose, gentiotriose and gentiobiose), ... The sweeteners may be selected from the group consisting of dextrose, cellobiose, D-leucrose, D-psicose, D-ribose, D-tagatose, trehalose (mycose), neotrehalose, isotrehalose, raffinose, idose, tagatose, melibiose, manno-oligosaccharides, rhamnose, ribose, ribulose, maltooligosaccharides (such as maltotriose, maltotetraose, maltopentaose, maltohexaose and maltoheptaose), maltose, sucrose acetate isobutyrate, dextrose, erythrose, erythrulose, deoxyribose, gulose, ketotrisaccharides, lactose, lactulose, kestose, nystose, mannose, sucralose, palatinose, polydextrose, sorbitol, sugaridextrose (mixed sugars), or talose, or a combination of any two or more of the foregoing sweeteners.

[0231] Sweeteners may also include, for example, sweetener compositions comprising one or more natural or synthetic carbohydrates, such as corn syrup, high fructose corn syrup, high maltose corn syrup, glucose syrup, sucralose syrup, hydrogenated glucose syrup (HGS), hydrogenated starch hydrolysate (HSH) or other syrups or sweetener concentrates from natural fruit and vegetable sources, or semi-synthetic "sugar alcohol" sweeteners, such as polyols. In some embodiments, non-limiting examples of polyols include erythritol, maltitol, mannitol, sorbitol, lactitol, xylitol, isomalt, propylene glycol, glycerol (glycerine), threitol, galactitol, palatinose, reduced isomaltooligosaccharides, reduced xylo-oligosaccharides, reduced gentiooligosaccharides, reduced maltose syrup, reduced glucose syrup, isomaltulose, maltodextrin, etc., and sugar alcohols or any other carbohydrates or combinations thereof that can be reduced without reducing taste.

[0232] The sweetener may be a natural or synthetic sweetener including, but not limited to, agave inulin, agave nectar, agave syrup, amazake, brazzein, brown rice syrup, coconut crystals, coconut sugar, coconut syrup, date sugar, fructans (also known as inulin fiber, fructooligosaccharides or oligofructose), green stevia powder, stevia rebaudiana, rebaudioside A, rebaudioside B, rebaudioside C, rebaudioside D, rebaudioside E, rebaudioside F, rebaudioside I, rebaudioside H, rebaudioside L, rebaudioside K, rebaudioside J, rebaudioside N, rebaudioside O, rebaudioside M and other stevia-based steviol glycosides, stevioside, stevioside extract, honey, Jerusalem artichoke (Jerusalem artichoke syrup, licorice root, monk fruit (fruit, powder or extract), lucuma (fruit, powder or extract), maple sap (including, for example, sap extracted from sugar maple (Acer saccharum), black maple (Acer nigrum), American red maple (Acer rubrum), silver maple (Acer saccharinum), Norway maple (Acer platanoides), ash maple (Acer negundo), bigleaf maple (Acer macrophyllum), roughtooth maple (Acer grandidentatum), Rocky Mountain maple (Acer glabrum), monochromatic maple (Acer mono)), maple syrup, maple sugar, walnut sap (including, for example, sap extracted from white walnut (Juglans cinerea), black walnut (Juglans nigra), ghost walnut (Juglans ailatifolia), walnut (Juglans regia)), birch sap (including, for example, sap extracted from paper birch (Betula papyrifera, yellow birch (Betula alleghaniensis), mountain birch (Betula lenta), river birch (Betula nigra), gray birch (Betula populifolia), weeping birch (Betula pendula), sycamore sap (e.g., sap extracted from Platanus occidentalis), ironwood sap (e.g., sap extracted from Ostrya virginiana), unrefined cane sugar (mascobado), molasses (e.g., blackstrap molasses), molasses sugar, monatin, monellin, cane sugar (also known as natural sugar, unrefined saccharose or sucrose),palm sugar, panocha, piloncillo, rapadura, raw sugar, rice syrup, sorghum, sorghum syrup, tapioca syrup (also called tapioca syrup), thaumatin, yacon root, maltose syrup, barley malt syrup, barley malt powder, beet sugar, cane sugar sugar, crystallized fruit juice crystals, caramel, carbitol, carob syrup, castor sugar, hydrogenated starch hydrolates, hydrolyzed canned fruit juice, hydrolyzed starch, invert sugar, anethole, arabinogalactan, concentrated grape juice, syrup, P-4000, acesulfame potassium (also known as acesulfame potassium or ace-K), alitame (also known as aclame), advantame, aspartame, baiyunosdie, neotame, benzamide derivatives, bernadame, canderel, carrelame and other guanidine sweeteners, vegetable fiber, corn sugar, coupling sugar, curculin, cyclamates, cyclocaryoside I I), demerara, dextran, dextrin, diastatic malt, dulcin, sucrol, valzin, dulcoside A, dulcoside B, emulin, enoxolone, maltodextrin, saccharin, estragole, ethyl maltol, glucin, gluconic acid, gluconolactone, glucosamine, glucuronic acid, glycerol, glycine, glycyphillin, glycyrrhizin, golden sugar, brown sugar, golden syrup, granulated sugar, gynostemma pentaphyllum, hernandulcin, isomerized liquid sugar, jallab juice, chicory Root dietary fiber, kynurenine derivatives (including N'-formyl-kynurenine, N'-acetyl-kynurenine, 6-chloro-kynurenine), galactitol, litesse, ligicane, lycasin, N-(4-cyanophenyl)-N-(2,3-methylenedioxybenzyl)guanidineacetic acid (lugduname), guanidine, falernum, mabinin I, mabinin II, maltol, crystalline maltitol (maltisorb), maltodextrin, maltotriol (maltotriol), mannosamine, miraculin, mizuame, mogrosides (including, for example, mogroside IV,mogroside V and neomogroside, mukurozioside, nano sugar, naringin dihydrochalcone, neohesperidin dihydrochalcone, nib sugar, black oligosaccharide, norbu, almond syrup, osladin, pekmez, pentadin, periandrin I, perillaldehyde, perillartine, petphyllum, phenylalanine, phloisosideside I, phlorodizin, phyllodulcin, polyglycitol syrup, polypodoside A, pterocaryoside A A), tert-butyl glycoside B, rebiana, refined syrup, rub syrup, rubusoside, selligueain A, shugr, simonoside I, siraitia grosvenorii, soy oligosaccharides, Splenda, SRIoxime V, steviol glycoside, steviol bioside, stevioside, strogins 1, 2 and 4, sucrose, sucrononate, sugar, sodium p-nitrophenylureidopropionate (suosan), phloridzin, super aspartame, tetrasaccharide, threitol, treacle, trilobtain, tryptophan and derivatives (6-trifluoromethyl-tryptophan, 6-chloro-D-tryptophan), vanilla sugar, heptyl heptol, birch syrup, aspartame-acesulfame, assugrin, and combinations or blends of any two or more thereof. ,

[0233] In other embodiments, the sweetener can be a chemically or enzymatically modified natural high-potency sweetener. Modified natural high-potency sweeteners include glycosylated natural high-potency sweeteners, such as glucosyl, galactosyl or fructosyl derivatives containing 1 to 50 glycoside residues. Glycosylated natural high-potency sweeteners can be prepared by enzymatic transglycosylation reactions catalyzed by various enzymes with transglycosylation activity. In some embodiments, the modified sweetener can be substituted or unsubstituted.

[0234] Other sweeteners also include any two or more combinations of any of the above-mentioned sweeteners. In some embodiments, the sweetener can include a combination of two, three, four or five sweeteners disclosed herein. In some embodiments, the sweetener can be sugar. In some embodiments, the sweetener can be a combination of one or more sugars and other natural and artificial sweeteners.

[0235] Those skilled in the art will recognize that any one or more of the above sweeteners may be combined in various ratios, amounts or concentrations to produce a single sweetener or a combination of two or more sweeteners and then combined with one or more flavor modifying compounds.

[0236] Those skilled in the art will recognize that the sweeteners described above for use in formulations comprising one or more sweeteners and one or more flavor modifying compounds are provided by way of example and are not intended to be limiting.

[0237] Some embodiments provide supplements, nutraceuticals, functional food products (e.g., any fresh or processed food claimed to have health and / or disease prevention properties beyond the basic nutritional function of providing nutrition), pharmaceutical products, over-the-counter (OTC) products, oral care products, cosmetics (e.g., sweetened lip balm), and other personal care products comprising the compounds disclosed and described herein, alone or in combination.

[0238] In general, over-the-counter (OTC) products and oral care products generally refer to products for home and / or personal use that are sold without a prescription and / or without seeing a doctor. Examples of OTC products include, but are not limited to, vitamins and dietary supplements; local analgesics and / or anesthetics; remedies for coughs, colds and allergies; antihistamines and / or allergy remedies; and combinations thereof. Vitamins and dietary supplements include, but are not limited to, vitamins, dietary supplements, supplements / bottled nutritional drinks, vitamins for children, dietary supplements, any other products related to nutrition or providing nutrition, and combinations thereof. Local analgesics and / or anesthetics include any topical creams / ointments / gels used to relieve superficial or deep pain such as muscle pain, teething gels; patches with analgesic ingredients; and combinations thereof. Cough, cold and allergy remedies include, but are not limited to, decongestants, cough remedies, pharyngeal preparations, medicated candies, antihistamines and remedies for coughs, colds and allergies for children; and combination products. Antihistamines and / or allergy treatments include, but are not limited to, any systemic treatment for hay fever, nasal allergies, insect bites and stings. Examples of oral care products include, but are not limited to, oral cleaning strips, toothpaste, toothbrushes, mouthwash / tooth cleaners, denture care, home mouth fresheners, teeth whiteners, dentifrice, and dental floss.

[0239] In at least one form, the present disclosure provides a formulation comprising one or more compounds of the first form (any of any of the above embodiments, or as any individual compound of Tables 2 to 9, or a combination thereof) and one or more bitter compounds. The bitter compounds can come from various sources. In some cases, the bitter compounds are components of certain natural products, such as caffeine, quinine, green tea, catechins, polyphenols, Robusta coffee bean extract, coffee bean extract, menthol and other mint compounds, etc. Therefore, in some embodiments, the composition is a beverage product, such as a tea or coffee product, which comprises one or more compounds of the first form to reduce the bitterness of such compounds in the beverage.

[0240] In some other embodiments, bitterness may come from including certain proteins (e.g., protein isolates) in food products. In some cases, plant protein isolates may be particularly bitter. Therefore, in some embodiments, the compositions disclosed herein include one or more compounds and proteins, such as protein isolates, in a first form. In some embodiments, protein isolates are made from animal products such as whey or casein. In other embodiments, protein isolates are made from plant products such as soy, chia seeds, rice, quinoa, beans, etc. In some other embodiments, the protein is an algae protein, such as spirulina. In this case, the compound in the first form can block the inherent bitterness of the protein, but can also block the astringency of the "fishy" or amine taste in the algae protein. In some other embodiments, the protein is a mycoprotein.

[0241] Compositions comprising any of the foregoing proteins can be used to prepare a variety of products. Non-limiting examples include protein mixes, energy bars, protein-based chips or crackers, cheese substitutes, meat substitutes (e.g., vegetarian chicken, vegetarian beef, etc.). Some such products may also contain heme-based synthetic additives to simulate the taste of blood in red meat. One or more compounds of the first form are added to such products to offset the bitter taste of such heme-based additives.

[0242] In some other embodiments, the bitter taste may be caused by the compound used to replace salt or monosodium glutamate (MSG). In many such cases, potassium chloride (KCl) is used. However, potassium chloride can impart a bitter taste. Therefore, in some embodiments, the composition comprises potassium chloride (KCl) in combination with one or more compounds of the first form.

[0243] In some embodiments, the compounds disclosed and described herein may be included in food or beverage products or formulations, alone or in combination. Examples of food and beverage products or formulations include, but are not limited to, sweetened coatings, frostings or icings of edible products, or any entity included in the following: soups, dry processed foods, beverages, ready-to-eat foods, canned or preserved foods, frozen processed foods, refrigerated processed foods, snack foods, baked foods, candies, dairy products, ice cream, meal replacements, pasta and noodles, and sauces, seasonings, condiments, baby food categories and / or spreads.

[0244] In general, soups refer to canned / preserved, dehydrated, instant, refrigerated, UHT and frozen soups. For the purpose of this definition, soup means a food made from meat, poultry, fish, vegetables, grains, fruit and other ingredients, cooked in a liquid that may contain visible fragments of some or all of these ingredients. It may be clear (as a stock) or thick (as a chowder), smooth, pureed or chunky, ready-to-eat, semi-concentrated or concentrated, and served hot or cold, as a first or main course or as a snack (a sipping beverage) between meals. Soup may be used as a raw material for preparing other meal ingredients, ranging from broth (consommé) to sauces (cream- or cheese-based soups).

[0245] The Dehydrated and Cooking Foods category generally refers to: (i) cooking aid products, such as powdered, granulated, paste-like, concentrated liquid products, including concentrated bouillon, bouillon and broth-like products in pressed, tableted or powdered or granulated form, sold individually as finished products or as ingredients in products, sauces and recipe mixes (regardless of technology); (ii) dietary solution products, such as dehydrated soups and freeze-dried soups, including dehydrated soup mixes, dehydrated instant soups, dehydrated ready-to-eat soups, dehydrated or self-heating preparations of ready-made dishes, meals and single-serving entrees, including pasta, potatoes and rice; and (iii) dietary garnish products, such as condiments, marinades, salad dressings, salad toppings, dips, mixes, batter mixes, shelf-stable sauces, barbecue sauces, liquid recipe mixes, concentrates, sauces or sauce mixes, including salad recipe mixes, sold as finished products or as ingredients in products, whether dehydrated, liquid or frozen.

[0246] The beverage category generally refers to beverages, beverage mixes and concentrates, including but not limited to carbonated and non-carbonated beverages, alcoholic and non-alcoholic beverages, ready-to-drink beverages, liquid concentrate preparations for preparing beverages (such as soda), and dry powder beverage precursor mixes. The beverage category also includes alcoholic beverages, soft drinks, sports drinks, isotonic beverages and hot drinks. Alcoholic beverages include but are not limited to beer, cider / perry, FABs, wine and spirits. Soft drinks include but are not limited to carbonated beverages, such as cola and non-cola carbonated beverages; fruit juices, such as fruit juices, honey drinks, juice drinks and fruit-flavored drinks; bottled water, including soda water, spring water and purified / table water; functional beverages, which can be carbonated or still beverages, including sports drinks, energy drinks or elixir drinks; concentrates, such as ready-to-drink liquids and powder concentrates. Beverages, whether hot or cold, include, but are not limited to, coffee or iced coffee, such as fresh, instant and blended coffee; tea or iced tea, such as black tea, green tea, white tea, oolong tea and flavored tea; and other beverages, including flavored, malt-based or plant-based powders, granules, blocks or tablets mixed with milk or water.

[0247] Snacks generally refer to any food that is a simple, informal meal, including but not limited to sweet and salty snacks and snack bars. Examples of snacks include but are not limited to fruit snacks, potato chips / crisps, extruded snacks, tortillas / corn chips, popcorn, pretzels, nuts and other sweet and salty snacks. Examples of snack bars include but are not limited to granola / cereal bars, breakfast bars, energy bars, fruit bars and other snack bars.

[0248] The baked goods category generally refers to any edible product whose preparation process involves exposure to heat or excessive sunlight. Examples of baked goods include, but are not limited to, bread, buns, cookies, muffins, cereals, toaster pastries, cakes, waffles, tortillas, soft cookies, pies, bagels, tarts, quiches, cakes, any baked goods, and any combination thereof.

[0249] Ice cream generally refers to frozen desserts containing cream, sugar and flavorings. Examples of ice cream include, but are not limited to: impulse ice cream; family-packed ice cream; frozen yogurt and handmade ice cream; soy, oat, bean (such as red bean and mung bean) and rice-based ice cream.

[0250] Candy generally refers to edible products that are sweet. Examples of candy include, but are not limited to, hard candy, gelatin, chocolate candy, granulated candy, chewing gum, etc. and any combination of products.

[0251] The meal replacement category generally refers to any food that is intended to replace a normal meal, especially for those who are concerned with health or fitness. Examples of meal replacements include, but are not limited to, weight loss products and recovery products.

[0252] Ready-to-eat foods are generally any food that can be consumed as a meal without extensive preparation or processing. Ready-to-eat foods include products to which the manufacturer has added recipe "skills" so that they have a high degree of readiness, completeness, and convenience. Examples of ready-to-eat foods include, but are not limited to, canned / preserved, frozen, dried, refrigerated ready meals; dinner mixes; frozen pizza; refrigerated pizza; and prepared salads.

[0253] The Pasta and Noodles category includes any pasta and / or noodles, including but not limited to canned, dried, and refrigerated / fresh pasta; as well as regular, instant, refrigerated, frozen, and snack noodles.

[0254] The canned / preserved foods category includes, but is not limited to, canned / preserved meats and meat products, fish / seafood, vegetables, tomatoes, beans, fruits, ready meals, soups, pasta and other canned / preserved foods.

[0255] The frozen processed food category includes, but is not limited to, frozen processed red meat, processed poultry, processed fish / seafood, processed vegetables, meat substitutes, processed potatoes, bakery products, desserts, ready meals, pizza, soups, noodles, and other frozen foods.

[0256] The dry processed food category includes, but is not limited to, rice, dessert mixes, dry ready meals, dehydrated soups, instant soups, dry pasta, plain noodles, and instant noodles. The refrigerated processed food category includes, but is not limited to, refrigerated processed meats, processed fish / seafood products, lunch boxes, fresh-cut fruit, ready meals, pizza, prepared salads, soups, fresh pasta, and noodles.

[0257] The Sauces, Dressings and Condiments category includes, but is not limited to, tomato sauces and purees, bouillon / stock cubes, herbs and spices, monosodium glutamate (MSG), table sauces, soy-based sauces, pasta sauces, wet / cooking sauces, dry sauces / powder mixes, ketchup, mayonnaise, mustard, salad dressings, vinaigrettes, dips, pickles and other sauces, dressings and condiments.

[0258] The baby food category includes, but is not limited to, milk- or soy-based formulas; and prepared, dry, and other baby foods.

[0259] Spreads include, but are not limited to, jams and preserves, honey, chocolate spreads, nut spreads and yeast spreads.

[0260] Dairy products generally refer to edible products produced from the milk of mammals. Examples of dairy products include, but are not limited to, drinking milk products, cheese, yogurt and sour milk drinks, and other dairy products.

[0261] Additional examples of ingestible compositions, particularly food and beverage products or formulations, are provided below. Exemplary ingestible compositions include one or more candies, chocolate candies, chocolate chips, chocolate slabs (countlines), bagged chocolate bars (selflines) / softlines, boxed assortments, standard boxed assortments, twist-wrapped miniature chocolates, flavored chocolates, chocolates with toys, sandwich cookies, other chocolate candies, mints, standard mints, strong mints, hard candies, pastilles, gums, jellies and chews, toffees, caramels and nougats, medicated candies, lollipops, liquorice, other candies, breads, packaged / industrial breads, bulk / artisan breads, pastries, cakes, packaged / industrial cakes, bulk / artisan cakes, cookies, chocolates Biscuits with coatings, Biscuits with fillings, Crackers and crackers, Bread substitutes, Breakfast cereals, Ready-to-eat cereals, Breakfast cereals for families, Flakes, Muesli, Other cereals, Children's breakfast cereals, Hot cereals, Ice cream, Ready-to-eat ice cream, Single-serve dairy ice cream, Single-serve water ice cream, Multi-serve dairy ice cream, Multi-serve water ice cream, Family-serve ice cream, Family-serve dairy ice cream, Ice cream desserts, Bulk ice cream, Family-serve water ice cream, Frozen yogurt, Artisan ice cream, Dairy products, Milk, Fresh / Pasteurised milk, Whole fat fresh / Pasteurised milk, Semi-skimmed fresh / Pasteurised milk, Extended / UHT milk, Whole fat extended / UHT milk, Semi-skimmed extended / UHT milk, Fat-free extended shelf life / UTH milk, goat's milk, condensed / evaporated milk, pure condensed / evaporated milk, flavoured, functional and other condensed milk, flavoured milk drinks, dairy only flavoured milk drinks, flavoured milk drinks with fruit juice, soy milk, yoghurt drinks, fermented milk drinks, coffee creamer, milk powder, flavoured milk drinks, cream, cheese, processed cheese, spreadable cheese, unspreadable processed cheese, unprocessed cheese, unprocessed cheese spread, hard cheese, packaged hard cheese, unpackaged hard cheese, yoghurt, plain / natural yoghurt, flavoured yoghurt, jelly yoghurt, probiotic yoghurt, drinkable yoghurt, regular drinkable yoghurt, probiotic drinkable yoghurt, frozen and shelf-stable desserts, dairy-based desserts, soy-based desserts, frozen desserts, fresh cheese and kefir Quark cheese, Fresh cheese and quark cheese, Flavored fresh cheese and quark cheese, Savory fresh cheese and quark cheese, Sweet and savory snacks, Fruit snacks, Chips / potato chips, Extruded snacks, Tortilla chips / corn chips, Popcorn, Pretzels, Nuts, Other sweet and savory snacks, Snack bars, Granola bars, Breakfast bars, Energy bars, Fruit bars, Other snack bars, Meal replacements, Weight loss products, Recovery drinks, Ready meals, Canned ready meals, Frozen ready meals, Dried ready meals, Frozen ready meals, Dinner mixes, Frozen pizza, Refrigerated pizza, Soups, Canned soups, Dehydrated soups, Instant soups, Cold soups, Hot soups, Quick frozen soups, Pasta, Canned pasta, Dry pasta, Frozen / fresh pasta, Noodles, Plain noodles, Instant noodles,Instant noodles in cups / bowls, Instant noodles in bags, Frozen noodles, Snack noodles, Canned foods, Canned meat and meat products, Canned fish / seafood, Canned vegetables, Canned tomatoes, Canned beans, Canned fruits, Canned ready-to-eat foods, Canned soups, Canned pasta, Other canned foods, Frozen foods, Frozen processed red meat, Frozen processed poultry, Frozen processed fish / seafood, Frozen processed vegetables, Frozen meat substitutes, Frozen potatoes, Oven-baked potato chips, Other oven-baked potato products, Non-oven frozen potatoes, Frozen baked foods, Frozen desserts, Frozen ready-to-eat foods, Frozen pizza, Frozen soups, Frozen noodles, Other frozen foods, Dried foods, Dessert mixes, Dried ready-to-eat foods, Dehydrated soups, Instant soups, Dried pasta, Vegetarian noodles, Instant noodles, Instant noodles in cups / bowls, Instant noodles in bags, Refrigerated foods, Refrigerated processed meats, Refrigerated fish / seafood products, Refrigerated processed fish, Refrigerated fish, Refrigerated coated fish, Refrigerated smoked fish, Refrigerated lunch packs , Refrigerated Ready-to-eat Foods, Refrigerated Pizza, Refrigerated Soups, Refrigerated / Fresh Pasta, Refrigerated Noodles, Oils and Fats, Olive Oil, Vegetable and Seed Oils, Cooking Fats, Butter, Margarine, Spreads and Fats, Functional Spreads and Fats, Seasonings, Sauces and Condiments, Tomato Pastes and Purees, Bouillon / Stock Cubes, Stock Cubes, Gravy Granules, Liquid Stocks and Stocks, Herbs and Spices, Fermented Sauces, Soy-Based Sauces, Pasta Sauces, Wet Sauces, Dry Sauces / Powder Mixes, Ketchup, Mayonnaise, Regular Mayonnaise, Mustard, Salad Dressings, Regular Salad Dressings, Reduced Fat Salad Dressings, Balsamic Vinegar, Dips, Pickles, Other Sauces, Seasonings and Condiments, Baby Food, Formula, Standard Formula, Growing-up Formula, Toddler Formula, Hypoallergenic Formula, Infant Formula Foods, Dry Baby Food, Other Baby Food, Spreads, Jams and Preserves, Honey, Chocolate Spreads, Nut-Based Spreads and Yeast-Based Spreads. Exemplary ingestible compositions also include candies, baked products, ice cream, dairy products, sweet and savory snacks, snack bars, meal replacement products, ready meals, soups, pasta, noodles, canned foods, frozen foods, dry foods, refrigerated foods, oils and fats, baby foods or spreads or mixtures thereof. Exemplary ingestible compositions also include breakfast cereals, sweetened beverages or solid or liquid concentrate compositions for preparing beverages, ideally enabling the reduction of previously known sugar sweeteners or artificial sweeteners in concentration. ,

[0262] Some embodiments provide chewable compositions that may or may not be swallowed. In some embodiments, the chewable composition may be gum, chewing gum, saccharified gum, sugarless gum, functional gum, bubble gum, which contains the compounds disclosed and described herein, alone or in combination.

[0263] Typically, a sweet receptor modulating amount, a sweet receptor ligand modulating amount, a sweet flavor modulating amount, a sweet flavor enhancing amount, or a therapeutically effective amount of at least one compound of the present invention is added to an ingestible composition, optionally in the presence of a sweetener, such that the sweet flavor-modified ingestible composition has an increased sweetness as judged generally by humans or animals, or, in the case of formulation testing, by a majority of a panel of at least eight human taste testers, as determined by procedures well known in the art, compared to an ingestible composition prepared without the compound of the present invention.

[0264] In some embodiments, the compounds disclosed and described herein regulate the sweetness or other taste properties of other natural or synthetic sweeteners, alone or in combination, and the ingestible compositions prepared therefrom. In one embodiment, the compounds disclosed and described herein can be used or provided alone or in combination with their ligand-enhanced concentrations. For example, the amount of the compounds disclosed and described herein, alone or in combination, can be about 0.001ppm to 100ppm, or a narrower alternative range of about 0.1ppm to about 10ppm, about 0.01ppm to about 30ppm, about 0.05ppm to about 10ppm, about 0.01ppm to about 5ppm, or about 0.02ppm to about 2ppm, or about 0.01ppm to about 1ppm.

[0265] Some embodiments provide sweetness enhancing compositions comprising a sweet flavor enhancing amount of a compound of the present invention in combination with a first amount of a sweetener, wherein the sweetening is greater than the sweetening provided by the first amount of the sweetener without the compound. In some embodiments, the sweetener can be a common sugar sweetener, such as sucrose, fructose, glucose, and sweetener compositions containing natural sugars such as corn syrup (including high fructose corn syrup) or other syrups or sweetener concentrates derived from natural fruit and vegetable sources; rare natural sugars, including D-allose, D-psicose, L-ribose, D-tagatose, L-glucose, L-fucose, L-arabinose, D-turanose, and D-leucrose; semi-synthetic "sugar alcohol" sweeteners, such as erythritol, isomalt, lactitol, mannitol, sorbitol, xylitol, maltodextrin, etc.; and artificial sweeteners, such as aspartame, saccharin, acesulfame potassium, cyclamates, sucralose and alitame. In some embodiments, sweeteners can be selected from the group consisting of: cyclamic acid, mogroside, tagatose, maltose, galactose, mannose, sucrose, fructose, lactose, neotame and other aspartame derivatives, glucose, D-tryptophan, glycine, maltitol, lactitol, isomalt, hydrogenated glucose syrup (HGS), hydrogenated starch hydrolysate (HSH), steviol glycosides, rebaudioside A and other sweet steviosides, guanidine sweeteners (carrelame) and other guanidine sweeteners. In some embodiments, sweeteners can be a combination of two or more sweeteners as disclosed herein. In some embodiments, sweeteners can be a combination of two, three, four or five sweeteners as disclosed herein. In some embodiments, sweeteners can be sugar. In some embodiments, sweeteners can be a combination of one or more sugars and other natural and artificial sweeteners. In some embodiments, sweeteners can be sugar. In some embodiments, sugar is cane sugar. In some embodiments, sugar is beet sugar. In some embodiments, sweeteners can be a combination of one or more sugars and other natural and artificial sweeteners. In some embodiments, sugar can be sucrose, fructose, glucose or a combination thereof (e.g., high fructose corn syrup). In some embodiments, sugar can be sucrose. In some embodiments, sugar can be a combination of fructose and glucose. In some embodiments, sugar can be a combination of about 55% fructose and about 42% glucose. In some embodiments, sugar can be a combination of about 42% fructose and about 53% glucose. In some embodiments, sugar can be a combination of about 90% fructose and about 10% glucose. In some embodiments, sweeteners can be rare sugars. In some embodiments, rare sugars are selected from D-allose, D-psicose, L-ribose, D-tagatose, L-glucose, L-fucose, L-arabinose, D-turanose, D-leucrose and combinations thereof. In some embodiments, rare sugars are D-psicose.In some embodiments, the rare sugar is D-tagatose. In some embodiments, the sweetener is an artificial sweetener. In some embodiments, the artificial sweetener can be sucralose.

[0266] In some embodiments, the compounds disclosed and described herein, alone or in combination, provide an enhancement of the potency of a sweetener at the T1R2 / T1R3 taste receptors as measured by an enhancement ratio, which is defined as the EC of the sweetener in the presence and absence of a compound described herein. 50In some embodiments, the compounds disclosed and described herein, alone or in combination, provide an enhancement ratio greater than 1 and less than 10. In some embodiments, the compounds disclosed and described herein, alone or in combination, provide an enhancement ratio of 10 to 20. In some embodiments, the compounds disclosed and described herein, alone or in combination, provide an enhancement ratio greater than 20. In some embodiments, the sweetener can be a common sugar sweetener, such as sucrose, fructose, glucose, and sweetener compositions containing natural sugars such as corn syrup (including high fructose corn syrup) or other syrups or sweetener concentrates derived from natural fruit and vegetable sources; rare natural sugars, including D-allose, D-psicose, L-ribose, D-tagatose, L-glucose, L-fucose, L-arabinose, D-turanose, and D-leucrose; semi-synthetic "sugar alcohol" sweeteners, such as erythritol, isomalt, lactitol, mannitol, sorbitol, xylitol, maltodextrin, etc.; and artificial sweeteners, such as aspartame, saccharin, acesulfame potassium, cyclamates, sucralose and alitame. In some embodiments, sweetener can be selected from the group consisting of: cyclamic acid, mogroside, tagatose, maltose, galactose, mannose, sucrose, fructose, lactose, neotame and other aspartame derivatives, glucose, D-tryptophan, glycine, maltitol, lactitol, isomalt, hydrogenated glucose syrup (HGS), hydrogenated starch hydrolysate (HSH), steviol glycosides, rebaudioside A and other sweet steviosides, guanidine sweeteners (carrelame) and other guanidine sweeteners. In some embodiments, sweetener can be a combination of two or more sweeteners as disclosed herein. In some embodiments, sweetener can be a combination of two, three, four or five sweeteners as disclosed herein. In some embodiments, sweetener can be sugar. In some embodiments, sweetener can be a combination of one or more sugars and other natural and artificial sweeteners. In some embodiments, sweetener can be sugar. In some embodiments, sweeteners can be a combination of one or more sugars and other natural and artificial sweeteners. In some embodiments, sugar can be sucrose, fructose, glucose or a combination thereof (e.g., high fructose corn syrup). In some embodiments, sugar can be sucrose. In some embodiments, sugar can be a combination of fructose and glucose. In some embodiments, sugar can be a combination of about 55% fructose and about 42% glucose. In some embodiments, sugar can be a combination of about 42% fructose and about 53% glucose. In some embodiments, sugar can be a combination of about 90% fructose and about 10% glucose. In some embodiments, sweeteners can be rare sugars. In some embodiments, rare sugars are selected from D-allose, D-psicose, L-ribose, D-tagatose, L-glucose, L-fucose, L-arabinose, D-turanose, D-leucrose and combinations thereof.In some embodiments, the rare sugar is D-psicose. In some embodiments, the rare sugar is D-tagatose. In some embodiments, the sweetener is an artificial sweetener. In some embodiments, the artificial sweetener can be sucralose.

[0267] In some embodiments, the compounds disclosed and described herein can be provided in the form of flavoring concentrate preparations, either alone or in combination, such as suitable for subsequent processing to produce ready-to-use (i.e., ready-to-eat) products. "Flavoring concentrate preparations" refer to preparations that should be reconstituted with one or more dilution media to become ready-to-use compositions. The term "ready-to-use composition" is used interchangeably with "ingestible composition" herein, which means that any substance that can be taken orally, whether alone or together with another substance, is intended for or not for consumption. In one embodiment, the ready-to-use composition includes a composition that can be directly eaten by a human or animal. The flavoring concentrate preparation is usually used by mixing or diluting with one or more dilution media, such as any edible or ingestible ingredient or product, to impart or change the dilution medium with one or more flavorings. Such a use process is generally referred to as recovery. Recovery can be carried out in a home environment or an industrial environment. For example, a consumer can recover a frozen fruit juice concentrate in a kitchen with water or other aqueous media to obtain a ready-to-use fruit juice beverage. In another example, a soft drink syrup concentrate can be recovered by a manufacturer with water or other aqueous media on a large-scale industrial scale to produce a ready-to-use soft drink. Since the flavoring concentrate formulations have a higher concentration of flavoring or seasoning than the ready-to-use composition, the flavoring concentrate formulations are generally not suitable for direct consumption without reconstitution. There are many benefits to using and producing flavoring concentrate formulations. For example, one benefit is the reduction of weight and volume in transportation, because the flavoring concentrate formulations can be reconstituted at the time of use by adding a suitable solvent, solid or liquid.

[0268] In one embodiment, the flavoring concentrate formulation comprises i) a compound disclosed and described herein, either alone or in combination; ii) a carrier; and iii) optionally at least one adjuvant. The term "carrier" refers to a generally inactive auxiliary substance, such as a solvent, adhesive, or other inert medium, which is used in combination with the compounds of the present invention and one or more optional adjuvants to form a formulation. For example, water or starch can be a carrier of the flavoring concentrate formulation. In some embodiments, the carrier is the same as the dilution medium used to reconstitute the flavoring concentrate formulation; preferably, the carrier is the same as the diluent. In other embodiments, the carrier is different from the dilution medium. As used herein, the term "carrier" includes, but is not limited to, an ingestible carrier.

[0269] The term "adjuvant" means an additive that supplements, stabilizes, maintains or enhances the expected function or efficacy of an active ingredient such as the compounds of the present invention. In one embodiment, at least one adjuvant comprises one or more flavoring agents. Flavoring agents can have any flavor known to those skilled in the art or consumers, such as chocolate, coffee, tea, mocha, French vanilla, peanut butter, chai, or the flavor of a combination thereof. In another embodiment, at least one adjuvant comprises one or more sweeteners. One or more sweeteners can be any sweetener described in the present application. In another embodiment, the at least one adjuvant comprises one or more ingredients selected from the group consisting of: emulsifiers, stabilizers, antimicrobial preservatives, antioxidants, vitamins, minerals, fats, starches, protein concentrates and isolates, salts, and combinations thereof. Examples of emulsifiers, stabilizers, antimicrobial preservatives, antioxidants, vitamins, minerals, fats, starches, protein concentrates and isolates and salts are described in U.S. Patent No. 6,468,576, the entire contents of which are incorporated herein by reference for all purposes.

[0270] In one embodiment, the flavoring concentrate preparation of the present invention can be selected from the liquid comprising solution and suspension, solid, foam material, paste, gel, emulsion and the form of their combination, for example, liquid containing a certain amount of solid content. In one embodiment, the flavoring concentrate preparation is a liquid form comprising water-based and non-aqueous. In some embodiments, the flavoring concentrate preparation of the present invention can be carbonated or non-carbonated.

[0271] The flavoring concentrate formulation may further include a freezing point depression agent, a nucleating agent or both as the at least one adjuvant. A freezing point depression agent is an ingestible compound or agent that can reduce the freezing point of a liquid or solvent to which the compound or agent has been added. That is, the freezing point of a liquid or solution containing a freezing point depression agent is lower than the freezing point of a liquid or solvent without a freezing point depression agent. In addition to reducing the initial freezing point, a freezing point depression agent can also reduce the water activity of the flavoring concentrate formulation. Examples of freezing point depressants include, but are not limited to, carbohydrates, oils, ethanol, polyols such as glycerol and combinations thereof. Nucleating agents represent ingestible compounds or agents that can promote nucleation. The presence of nucleating agents in the flavoring concentrate formulation can improve the mouthfeel of slush, and help maintain the physical properties and performance of slush at freezing temperatures by increasing the number of required ice crystal centers. Examples of nucleating agents include, but are not limited to, calcium silicate, calcium carbonate, titanium dioxide and combinations thereof.

[0272] In one embodiment, the flavoring concentrate formulation is formulated to have a low water activity to extend shelf life. Water activity is the ratio of the vapor pressure of water to the vapor pressure of pure water in the formulation at the same temperature. In one embodiment, the water activity of the flavoring concentrate formulation is less than about 0.85. In another embodiment, the water activity of the flavoring concentrate formulation is less than about 0.80. In another embodiment, the water activity of the flavoring concentrate formulation is less than about 0.75.

[0273] In one embodiment, the concentration of the compound of the present invention in the flavoring concentrate formulation is at least 2 times the concentration of the compound in the ready-to-use composition. In one embodiment, the concentration of the compound of the present invention in the flavoring concentrate formulation is at least 5 times the concentration of the compound in the ready-to-use composition. In one embodiment, the concentration of the compound of the present invention in the flavoring concentrate formulation is at least 10 times the concentration of the compound in the ready-to-use composition. In one embodiment, the concentration of the compound of the present invention in the flavoring concentrate formulation is at least 15 times the concentration of the compound in the ready-to-use composition. In one embodiment, the concentration of the compound of the present invention in the flavoring concentrate formulation is at least 20 times the concentration of the compound in the ready-to-use composition. In one embodiment, the concentration of the compound of the present invention in the flavoring concentrate formulation is at least 30 times the concentration of the compound in the ready-to-use composition. In one embodiment, the concentration of the compound of the present invention in the flavoring concentrate formulation is at least 40 times the concentration of the compound in the ready-to-use composition. In one embodiment, the concentration of the compound of the present invention in the flavoring concentrate formulation is at least 50 times the concentration of the compound in the ready-to-use composition. In one embodiment, the concentration of the compound of the present invention in the flavoring concentrate formulation is at least 60 times the concentration of the compound in the ready-to-use composition. In one embodiment, the concentration of the compound of the invention in the flavoring concentrate formulation is up to 100 times the concentration of the compound in the ready-to-use composition.

[0274] In some embodiments, the present disclosure provides a pharmaceutical composition comprising one or more compounds in a first form and one or more bitter compounds. In some embodiments, the bitter compound is a pharmaceutical API, such as an antibiotic. Children are generally much more sensitive to bitter taste than adults, and therefore, the use of bitter blockers is particularly useful in pharmaceutical compositions for pediatric administration.

[0275] In one embodiment, when applied to a patient, the compound disclosed and described herein and optional pharmaceutically acceptable carrier are sterile. In one embodiment, when the compound disclosed and described herein is administered intravenously, water is a preferred vehicle. Saline solutions and aqueous glucose solutions and glycerol solutions can also be used as liquid vehicles, particularly for injection solutions. Suitable pharmaceutical vehicles also include excipients, such as starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glyceryl monostearate, talcum powder, sodium chloride, skim milk powder, glycerol, propylene, glycol, water, ethanol, etc. If necessary, the pharmaceutical composition of the present invention may also include a small amount of wetting agent or emulsifier or pH buffer. In addition, adjuvants, stabilizers, thickeners, lubricants and colorants can be used. In some cases, the pharmaceutical composition is a liquid solution or suspension, which especially includes flavoring substances, pH regulators, natural or artificial sweeteners, etc.

[0276] Pharmaceutical compositions comprising the compounds disclosed and described herein can be prepared by conventional mixing, dissolving, granulating, dragee making, grinding, emulsifying, encapsulating, embedding or lyophilizing methods. Pharmaceutical compositions can be formulated in a conventional manner using one or more physiologically acceptable carriers, diluents, excipients or adjuvants that facilitate processing of the compounds of the invention into pharmaceutically acceptable preparations. Suitable formulations depend on the chosen route of administration.

[0277] In some embodiments, the pharmaceutical composition can take the form of a solution, suspension, emulsion, tablet, pill, granule, capsule, liquid-containing capsule, powder, sustained-release formulation, suppository, emulsion, aerosol, spray, suspension or any other suitable use. In some embodiments, the pharmaceutically acceptable carrier is a capsule.

[0278] For topical (external) administration, the compounds disclosed and described herein can be formulated into solutions, gels, ointments, creams, suspensions, etc., as is known in the art.

[0279] In some embodiments, the compounds disclosed and described herein can be formulated as pharmaceutical compositions suitable for intravenous administration to humans according to conventional procedures. Typically, the compound for intravenous administration is a solution in a sterile isotonic aqueous buffer. For injection, the compound can be formulated in an aqueous solution, preferably in a physiologically compatible buffer, such as Hanks solution, Ringer's solution or a physiological saline buffer. The solution may contain a preparatant, such as a suspending agent, a stabilizer and / or a dispersant. If necessary, the pharmaceutical composition may also include a solubilizing agent.

[0280] Pharmaceutical compositions for oral delivery can be in the form of, for example, tablets, lozenges, aqueous or oily suspensions, granules, powders, emulsions, capsules, syrups or elixirs. Pharmaceutical compositions for oral administration may contain one or more optional agents, such as sweeteners, such as fructose, aspartame or saccharin; flavoring agents, such as peppermint, wintergreen oil or cherry coloring agents and preservatives, to provide pharmaceutically acceptable preparations.

[0281] In addition, in the case of tablet or pill form, the pharmaceutical composition can be coated to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained effect over an extended period of time. The selective permeability membrane around the osmotic active driving compound is also suitable for oral administration compounds of the present invention. In these later platforms, the fluid from the capsule surrounding environment is absorbed by the driving compound, and the driving compound expands to displace the reagent or reagent composition through the hole. Contrary to the rapid increase curve of the immediate release preparation, these delivery platforms can provide a delivery curve with a degree of zero. Time-delay materials, such as glyceryl monostearate or glyceryl stearate, can also be used. Oral compositions can include standard vehicles, such as mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, etc. This type of vehicle is preferably pharmaceutical grade.

[0282] For oral liquid preparations, such as suspensions, elixirs and solutions, suitable carriers, excipients or diluents include water, saline, alkylene glycols (e.g. propylene glycol), polyalkylene glycols (e.g. polyethylene glycol) oils, alcohols, weakly acidic buffers of pH 4 to pH 6 (e.g. acetate, citrate, ascorbate at a concentration between about 5 mM and about 50 mM), etc. In addition, flavoring agents, preservatives, colorants, bile salts, acylcarnitines, etc. may be added.

[0283] Liquid drug formulations suitable for nebulizers and liquid spray devices and EHD aerosol devices generally include a compound of the invention and a pharmaceutically acceptable carrier. Preferably, the pharmaceutically acceptable carrier is a liquid, such as an alcohol, water, polyethylene glycol or a perfluorocarbon. Alternatively, another material may be added to change the aerosol properties of the solution or suspension of the compound of the invention. Preferably, the material is a liquid, such as an alcohol, a glycol, polyethylene glycol or a fatty acid. Other methods of preparing liquid drug solutions or suspensions suitable for use in aerosol devices are known to those skilled in the art.

[0284] The compounds disclosed and described herein and / or pharmaceutical compositions thereof will generally be used in an amount effective to achieve the intended purpose, i.e., bitter taste masking. Typically, based on the total weight of the composition, the effective amount is 5 to 2000 ppm, or 5 to 1000 ppm, or 5 to 800 ppm, or 5 to 500 ppm, or 5 to 400 ppm, or 5 to 300 ppm, or 5 to 200 ppm.

[0285] Another embodiment of the present invention is generally directed to a method of preventing bitter taste by using any of the compositions discussed herein.

[0286] In illustrative embodiments, compounds according to the invention will be useful for blocking / reducing / altering the bitter taste associated with compounds that activate the hT2R54 receptor and / or further activate the hT2R61, hT2R64 and / or hT2R75 taste receptors.

[0287] In certain exemplary embodiments, the compounds according to the invention will be used to block / reduce / alter the bitter taste associated with compounds that activate the hT2R54 receptor and / or the hT2R61, hT2R64 and / or hT2R75 taste receptors, such as acetaminophen, dextromethorphan, dequalinium, chloroquine and guaifenesin and their salts, hydrates, solvates or prodrug forms.

[0288] Additionally, the compounds of the present invention may be used in combination with other bitter blocker compounds such as those shown in the table below.

[0289] Table 1

[0290]

[0291]

[0292]

[0293]

[0294] In some embodiments, the composition for improving bitter taste perception may further comprise one or more compounds described in PCT Publication No. WO 2014 / 130582, which is incorporated herein by reference in its entirety.In some embodiments, the composition disclosed above may be used in combination with a cooling agent. Such cooling agents for use in combination with the compounds disclosed herein are known in the art and include those disclosed in US2013 / 0324557, WO 2014 / 130582, US 7,923,585, US2008 / 0319055, US 7,893,110, US2009 / 0105237, US2009 / 0098066, US2010 / 0035938, US 8,263,046, US 7,959,958, US2008 / 0300314, US2009 / 0312384, US 8,309,598, US 7,935,848, US2010 / 0297038, US 8,377,422, US 8,664,261, US2011 / 0091531, US2013 / 0323388, US2014 / 0341821, US2010 / 0086498, US2014 / 0186272, US 6,884,906, US2011 / 0070329, US 8,575,349, US 5,725,865, US 5,843,466, WO 2011 / 147455, US 8,007,771, WO 2004 / 037764, US6,627,233, WO 2011 / 159935, US 7,767,243, US 7,662,576, US 5,372,824, US 5,009,893, US 5,698,181, US 7,189,760, US 7,030,273, WO 02 / 091849, US 5,286,500, US 3,488,419, US 6,515,188, US 6,407,293, US 4,459,425, US 3,419,543, US2006 / 0210482, US 6,328,982, US 7,025,999, EP 1332772, US 4,157,384, WO 2014 / 090293, US2008 / 0175800, US8,344,025, US 8,927,605, US2011 / 0305657, US2013 / 0202543, and US2014 / 0335224, the entire contents of which are incorporated herein by reference.

[0295] In certain embodiments, the composition blocks the bitter taste associated with acetaminophen, dextromethorphan, dequalinium, chloroquine, and / or guaifenesin, which activate T2R54 alone or T2R54 and other receptors.

[0296] In some embodiments, the composition comprises one or two or more combinations of the compounds and compositions disclosed herein, which may be further combined with one or more acids or sour flavoring agents. Representative sour flavoring agents include, but are not limited to, ascorbic acid, benzoic acid, gallic acid, glucuronic acid, adipic acid, glutaric acid, malonic acid, succinic acid, malic acid, acetic acid, lactic acid, citric acid, tartaric acid, fumaric acid, phosphoric acid, pyrophosphoric acid, tannic acid, vinegar, lemon juice, lime juice, acidic fruit juices, and acidic fruit extracts.

[0297] In some embodiments, the compositions comprising one or a combination of two or more of the compounds and compositions disclosed herein may be further combined with one or more salts or salt flavor enhancers. Representative salts or salt flavor enhancers include, but are not limited to, inorganic salts, sodium chloride, potassium chloride, magnesium chloride, ammonium chloride, sodium gluconate, sodium phosphate, glycine, L-alanine, L-valine, L-leucine, L-isoleucine, L-phenylalanine, L-tyrosine, L-glutamine, L-glutamic acid, L-asparagine, L-aspartic acid, L-serine, L-threonine, L-cysteine, L-methionine, L-proline, L-lysine, L-arginine, L-tryptophan, L-histidine, L-pyrolysine, L-pyroglutamine, L-4-trans-hydroxyproline, L-3-cis-hydroxyproline, L-homoserine, L-homocysteine, L-cystine, L-ornithine and L-citrulline, L-glutamine, L-glutamic acid, L-asparagine, L-aspartic acid, L-valine, L-arginine and L-lysine.

[0298] In some embodiments, the composition comprises one or two or more combinations of compounds and compositions disclosed herein, which may be further combined with one or more umami flavor compounds or umami flavor enhancing compounds. Representative umami flavor compounds or umami flavor enhancing compounds include, but are not limited to, compounds identified in U.S. Patent Application Publications 2005 / 0084506A1, US2009 / 0111834A1, US2012 / 0201763A1, US2015 / 0093339A1, US 2006 / 0263411A1, US2012 / 0226047A1 and 2009 / 0220662A1. Other representative umami flavor compounds or umami flavor enhancing compounds include, but are not limited to, hydrolyzed soy protein, hydrolyzed corn protein, hydrolyzed wheat protein, anchovies, anchovy paste, fish sauce, yeast extract, nutritional yeast, hydrolyzed yeast extract, mushrooms, mushroom powder, dehydrated mushrooms, mushroom extract, kombucha, hydrolyzed vegetable protein, oyster sauce, soy sauce, soy sauce extract, tamari, miso powder, miso paste, Parmesan cheese, Parmesan cheese solids, kelp powder, kelp, dehydrated kelp, kelp paste, nori ), Nori powder, Nori paste, Laver, Dehydrated Laver, Laver powder, Laver extract, Tomato, Dehydrated Tomato, Tomato powder, Tomato extract, Vegetable powder, Vegetable extract, Whey powder, Whey solids, Whey, Collagen, Gelatin, Textured vegetable protein, Sodium caseinate, Calcium caseinate, Magnesium caseinate, Potassium caseinate, Glyoxylic acid, 3-methyl-2-oxo-butyric acid, 3-methyl-2-oxo-pentanoic acid, 4-methyl-2-oxo-pentanoic acid, 3-hydroxy-2-oxo-propionic acid, Oxaloacetic acid, 2-oxo-glutaric acid, 2-oxo-3-phenylpropionic acid, 3 -(4-hydroxyphenyl)-2-oxo-propionic acid, 2-oxo-1H-indole-3-propionic acid, 2-oxo-1H-imidazole-4-propionic acid, 4-methylthio-2-oxo-butyric acid, 3-mercapto-2-oxo-propionic acid, 3-hydroxy-2-oxo-butyric acid, 6-amino-2-oxo-hexanoic acid and 5-guanidino-2-oxo-pentanoic acid, 2-aminobutyric acid, α-alanine, glycine, norvaline, valine, aspartic acid, norleucine, leucine, isoleucine, serine, threonine, glutamic acid, phenylalanine, tyrosine, cysteine, methionine Acid, lysine, tryptophan, histidine, arginine, asparagine, glutamine, cystine, citrulline, theanine, γ-methyleneglutamic acid, isoeugenol, 2-propylphenol, p-vinylguaiacol, 2-acetylpyrazine, 2-ethyl-3,5-dimethylpyrazine, 2,3,5-trimethylpyrazine, 2,3-diethyl-5-methylpyrazine, 3-ethyl-2-methylpyrazine, dimethyl sulfide, dimethyl disulfide, dimethyl trisulfide, methylpropyl disulfide, 2-methylthiophenol, methylthiopropionaldehyde (3-methylthiopropionaldehyde), 2-octenal, 2,4-nonadienal, 2,4-decadienal, 2,4-undecadienal, 2-methoxybenzaldehyde, 2,4-dodecadienal, decenal, methyl 2-furanate, 2-ethyl-4-hydroxy-3-methyl 5(2H)-furanone, 2,6-dimethylbenzenethiol 2-nonen-1-ol, 10-undecenoic acid, undecanoic acid, isodecanoic acid and isononanoic acid, 2-oxo-butyric acid, oxaloacetic acid, 3-methyl-2-oxo-butyric acid, 3-methyl-2-oxo-pentanoic acid, 2-oxo-glutaric acid and 3-mercapto-2-oxo-propionic acid, NaCl, KCl, M SG, guanosine monophosphate (GMP), inosine monophosphate (IMP), ribonucleotides such as disodium inosinate, disodium guanylate, N-(2-hydroxyethyl)-lactamide, N-lactoyl-GMP, N-lactoyltyramine, γ-aminobutyric acid, allyl cysteine, 1-(2-hydroxy-4-methoxyphenyl)-3-(pyridin-2-yl)propan-1-one, arginine, potassium chloride, ammonium chloride, succinic acid, N-(2-methoxy-4-methylbenzyl)-N'-(2-(pyridin-2-yl)ethyl)oxalamide, N-(heptyl-4-yl)benzo(D)(1, 3) 5-dioxolecarboxamide, N-(2,4-dimethoxybenzyl)-N'-(2-(pyridin-2-yl)ethyl)oxalamide, N-(2-methoxy-4-methylbenzyl)-N'-2(2-(5-methylpyridin-2-yl)ethyl)oxalamide, cyclopropyl-E,Z-2,6-nonadienamide, glutamic acid, glutamic acid salts / esters, monosodium glutamate, monopotassium glutamate, monoammonium glutamate, calcium diglutamate, magnesium diglutamate, L-asparagine or its salt, 5'-ribonucleotide or its salt, calcium 5'-ribonucleotide, disodium 5'-ribonucleotide , 5'-ribonucleotide dipotassium, inosinic acid, guanylic acid, adenylic acid, inosinate, guanylate and adenylate, guanosine 5'-monophosphate, inosine 5'-monophosphate, 5'-adenylate, disodium guanylate, disodium inosinate, disodium adenylate; dipotassium guanylate, dipotassium inosinate, dipotassium adenylate, calcium guanylate, calcium inosinate, calcium adenylate, maltol, ethyl maltol, glycine, L-leucine, autolyzed or hydrolyzed protein (e.g., autolyzed yeast, hydrolyzed yeast, hydrolyzed vegetable protein), Koji-Aji (Ajinomoto Food Ingredients), fermented wheat gluten, glutathione, glutamylglutamic acid, (Z)-6-dodecene-4-olide, inosinic acid, dodecyl-Z6-ene-4-olide, glutamic acid, L-aconitic acid, N-(1-deoxyfructose-1-yl)glutamate, hydrolyzed vegetable protein, methyl α-D-glucoside, 2,3-dialysine, methyl α-D-glucoside 2,3-dionothine, L-asparagine, La-glutamyl-La-glutamyl-L-glutamic acid, La-aspartyl-La-glutamyl-glutamylvaline, wheat gluten hydrolyzate, aspartic acid L-,La-aspartyl-La-aspartyl-La-aspartyl-docosahexaenoic acid, and (4Z,7Z,10Z,13Z,16Z,19Z)-L-theanine, allyl cysteine, propenyl cysteine, S-(α,β-dicarboxyethyl)γ-L-glutamyl-L-cysteinyl-glycine, S-(α,β-dicarboxyethyl)cysteine, 3-(carboxyethoxy)-alanine, S-carboxymethyl-glutathione (glutaryl acid), S-carboxymethyl-cysteine-glycine, (S-carboxymethyl)-lysyl-cysteine, S-dicarboxymethyl-glutathione, S-carboxymethyl-cysteine, S-(1,2-dicarboxyethyl)-glutathione, and S-(1,2-dicarboxyethyl)-cysteine, N-acetyl GMP, N-formyl GMP, N-propionyl GMP, N-butyryl GMP, N-valeryl GMP, N-hexanoyl GMP, N-heptanoyl GMP, N-octanoyl GMP, N-oxalyl GMP, N-succinyl GMP, N-glutaryl GMP, N-fumaryl GMP, N-maleoyl GMP, N-adipoyl GMP, N-citratoyl GMP, N-galloyl GMP, N-oxaloacetyl GMP, N-feruloyl GMP, N-pyruvoyl GMP, N-benzoyl GMP, N-vanillyl GMP, N-anthryl GMP, N-caffeoyl GMP, N-cinnamoyl GMP, N-acetyl N-formyl AMP, N-propionyl AMP, N-butyryl AMP, N-valeryl AMP, N-hexanoyl AMP, N-heptanoyl AMP, N-octanoyl AMP, N-oxalyl AMP, N-succinyl AMP, N-glutaryl AMP, N-fumaryl AMP, N-maleoyl AMP, N-adipyl AMP, N-citrol AMP, N-galloyl AMP, N-oxaloacetyl AMP, N-feruloyl AMP, N-pyruvoyl AMP, N-benzoyl AMP, N-vanillyl AMP, N-anthryl AMP, N-caffeoyl AMP, N-cinnamoyl AMP, N-acetyl CMP, N-formyl CMP, N-propanoyl AMP Acyl CMP, N-butyryl CMP, N-valeryl CMP, N-hexanoyl CMP, N-heptanoyl CMP, N-octanoyl CMP, N-oxalyl CMP, N-succinyl CMP, N-glutaryl CMP, N-fumaryl CMP, N-maleoyl CMP, N-adipoyl CMP, N-citratoyl CMP, N-galloyl CMP, N-oxaloacetyl CMP, N-feruloyl CMP, N-pyruvoyl CMP, N-benzoyl CMP, N-vanillyl CMP, N-anthryl CMP, N-caffeoyl CMP, N-cinnamoyl CMP, N-acetyl GMP, N-formyl GMP, N-propionyl GMP, N-butyroyl GMP, N -Valeryl GMP, N-hexanoyl GMP, N-heptanoyl GMP, N-octanoyl GMP, N-oxalyl GMP, N-succinyl GMP, N-glutaryl GMP, N-fumaryl GMP, N-maleoyl GMP, N-adipoyl GMP, N-citratoyl GMP, N-galloyl GMP, N-oxaloacetyl GMP, N-feruloyl GMP, N-pyruvoyl GMP, N-benzoyl GMP, N-vanillyl GMP, N-anthranilyl GMP, N-caffeoyl GMP, N-cinnamoyl GMP, flavor modifier created by Maillard reaction, S-(α,β-dicarboxyethyl)γ-L-glutamyl-L-cysteine-glycine, S-(α,β-dicarboxyethyl)-cysteine, 3-(carboxymethyloxy)-alanine, S-carboxymethyl-glutathione (glutaramide acid), S-carboxymethyl-cysteinyl-glycine, (S-carboxymethyl)-lysyl-cysteine, S-dicarboxymethyl-glutathione, S-carboxymethyl-cysteine, S-(1,2-dicarboxyethyl)-glutathione and S-(1,2-dicarboxyethyl)-cysteine, γ-L-glutamyl-L-cysteine-glycine or γ-Glu-Cys-Gly, Rubemamine, rubemamide, rubescenamine, rubescenamide, zanthosine, zanthosinamide, dioxamide, dioxamine, zanthomamine and zanthomamide. ,

[0299] Umami flavor compounds or umami flavor enhancing compounds may also include peptides described in Nakata et al. Biosci. Biotechnol. Biochem. (1995) 59(4):689-93.

[0300] In some embodiments, the compounds and compositions described herein are incorporated into smoking articles or steam inhalation ("electronic cigarette") devices alone or in combination with one or more other compounds described herein. Such products and devices are well known in the art, including but not limited to cigars, cigarettes, bulk pipe tobacco, flavored cigars, flavored cigarettes, cigarette papers, pipes, hookahs, clove (kretek) cigarettes, bidis (bidis) cigarettes, mouthpieces (such as hookahs) and electronic cigarettes. In some embodiments, the compounds and compositions described herein can be further combined with one or more cooling agents, which can be directly applied directly to the smoking articles at any time during or after the manufacture of the smoking articles. In some further embodiments, the compounds and compositions described herein can be provided in the form of liquids, solids or concentrates to be applied to smoking articles or vaporizer fluids. In some other embodiments, the compounds and compositions described herein can be incorporated into vaporizer fluids. In some embodiments, the vaporizer fluid also includes propylene glycol, water, nicotine, glycerol and / or polyethylene glycol. In some embodiments, the smoking article includes tobacco. In some embodiments, the smoking article comprises tobacco, clove and / or tendu or temburni tobacco leaves.

[0301] In some embodiments, the compounds and compositions described herein, alone or in combination with one or more other compounds described herein, are incorporated into edible products, including but not limited to any ingestible and / or edible products described herein, e.g., foods and beverages.

[0302] In some embodiments, the pharmaceutical compositions disclosed herein, in addition to comprising any of the compounds disclosed herein, may be further combined with one or more cooling agents.

[0303] Preparation method

[0304] Compounds disclosed herein can be synthesized by the following methods or by improvements of these methods. The way of improving the method includes temperature, solvent, reagent, etc. known to those skilled in the art in particular. Generally, in any method for preparing compounds disclosed herein, it may be necessary or necessary to protect sensitive or reactive groups on any related molecules. This can be accomplished by conventional protecting groups, such as those described in Protective Groups in Organic Chemistry (ed. JFW McOmie, Plenum Press, 1973); and PGM Green, TW Wutts, Protecting Groups in Organic Synthesis (3rd ed.) Wiley, New York (1999), the entire contents of which are incorporated herein by reference. Protecting groups can be removed at a convenient subsequent stage using methods known in the art. Synthetic chemical transformations that can be used to synthesize applicable compounds are known in the art, including, for example, those described in R. Larock, Comprehensive Organic Transformations, VCH Publishers, 1989, or L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons, 1995, the entire contents of which are incorporated herein by reference. The routes shown and described herein are merely illustrative, and are not intended to, nor should they be interpreted as, limiting the scope of the claims in any way. Those skilled in the art will be able to recognize modifications to the disclosed synthesis, and design alternative routes based on the disclosure herein. All of these modifications and alternative routes are within the scope of the claims.

[0305] Some exemplary synthetic methods for preparing compounds of the invention are illustrated in Scheme 1 below.

[0306] Solution 1

[0307]

[0308] As described in Scheme 1, the aniline building block I can be reacted with activated carboxylic acids II and A-II under various amide coupling conditions to produce III or A-III. Species II and A-II can be generated in situ, but can also be obtained commercially or as storable intermediates. Compound III can be used as a final starting material or as an intermediate (R 5 = leaving group). Therefore, if R 5 is a leaving group (LG), III can be treated with a selected amine building block to form intermediate V. Subsequently, if the substituent R of compound V 7 If V is a protected amine group, then V can be subjected to conditions that allow for the removal of the amine protecting group to produce intermediate VI. Similarly, the amine protecting group of A-III can be removed under similar conditions to provide intermediate A-IV. These amine intermediates (VI and A-IV) can be reacted in turn with various electrophiles under coupling, substitution or addition conditions to provide VIII and AV, respectively.

[0309] However, if the substituent R 7 If it is an ester group, V can be subjected to saponification conditions to generate IX, which is then subjected to amide coupling conditions to generate compound X. Alternatively, compounds VIII and X can be prepared from intermediate III and building blocks XI and XII, respectively. In another form, compound AV can also be produced from aniline I and acid building blocks A-VI. The latter building blocks (XI, XII and A-VI) can be purchased commercially or synthesized using methods similar to those described above or in the literature.

[0310] Example 1-Synthesis of N-(6-acetylbenzo[d][1,3]dioxol-5-yl)-2-(4-(3-methylbutyryl)piperazin-1-yl)acetamide (1)

[0311]

[0312] To a suspension of N-(6-acetylbenzo[d][1,3]dioxol-5-yl)-2-(piperazine-1-yl)acetamide dihydrochloride (Example 1a) (38 mg, 0.1 mmol) and triethylamine (TEA) (40 mg, 0.4 mmol) in DMF (1 mL) was added 3-methylbutyryl chloride (12 mg, 0.1 mmol). The mixture was irradiated in a microwave at 135 ° C for 5 minutes. The solution was directly purified by reverse phase HPLC (water / acetonitrile gradient) to give the title compound (20 mg, 50% yield) as a white solid. MS 390 (M+H + ).

[0313] Example 1a. N-(6-acetylbenzo[d][1,3]dioxol-5-yl)-2-(piperazin-1-yl)acetamide dihydrochloride

[0314]

[0315] A solution of tert-butyl 4-(2-((6-acetylbenzo[d][1,3]dioxol-5-yl)amino)-2-oxoethyl)piperazine-1-carboxylate (Example 1b) (23.5 g, 58.0 mmol) in MeOH (220 mL) was treated with concentrated HCl (110 mL) and stirred at room temperature overnight. The solid was collected by filtration and washed with methanol to afford (18.2 g, 48.1 mmol, 83% yield) of the title compound as a brown solid.

[0316] Example 1b. tert-Butyl 4-(2-((6-acetylbenzo[d][1,3]dioxol-5-yl)amino)-2-oxoethyl)piperazine-1-carboxylate

[0317]

[0318] A mixture of N-(6-acetylbenzo[d][1,3]dioxol-5-yl)-2-bromoacetamide (Example 1c) (22 g, 73.3 mmol), tert-butyl piperazine-1-carboxylate (14 g, 73.3 mmol) and K2CO3 (21 g, 146.6 mmol) was heated to 85 °C in anhydrous ACN and stirred overnight under nitrogen. The reaction was diluted with EtOAc and washed with water and brine. The organic layer was dried over MgSO4, filtered and evaporated to give the title compound (23.6 g, 58.2 mmol, 79% yield).

[0319] Example 1c. (6-Acetylbenzo[d][1,3]dioxol-5-yl)-2-bromoacetamide

[0320]

[0321] A solution of 1-(6-aminobenzo[d][1,3]dioxol-5-yl)ethanone (25 g, 139.5 mmol), TEA (29.2 mL, 209.3 mmol) and DMAP (1.2 g, 9.7 mmol) in anhydrous THF (380 mL) was cooled to 0 ° C and treated dropwise with bromoacetyl chloride (17.3 g, 209.3 mmol). The ice bath was then removed and the reaction was stirred overnight under nitrogen. The mixture was concentrated to about 150 mL of THF. The residual solution was slowly diluted with water. After stirring for 30 minutes, the solid product was collected by filtration and dried to give the title compound (41.0 g, 136.5 mmol, 98% yield) as a brown solid. 1 H NMR(CDCl3,400MHz): δ2.58(s,3H),3.97(s,1H),4.16(s,1H),6.04(s,2H),7.25( d,J=14.4Hz,1H),8.34(d,J=11.6Hz,1H),12.68(brs,0.5H),12.80(bs,0.5H).MS 301(M+H + ).

[0322] Example 2-Synthesis of N-(6-acetylbenzo[d][1,3]dioxol-5-yl)-2-(4-(5-fluoro-2-methoxybenzoyl)piperazin-1-yl)acetamide (2)

[0323]

[0324] To a mixture of N-(6-acetylbenzo[d][1,3]dioxol-5-yl)-2-(piperazin-1-yl)acetamide dihydrochloride (Example 1a) (76 mg, 0.2 mmol), HOBt (30 mg, 0.2 mmol), EDC (38 mg, 0.2 mmol) and TEA (81 mg, 0.8 mmol) in DMF (1 mL) was added 5-fluoro-2-methoxybenzoic acid (34 mg, 0.2 mmol). The mixture was irradiated in a microwave at 150 °C for 5 minutes. The solution was directly purified by reverse phase HPLC (water / acetonitrile gradient) and the clean fractions were concentrated under reduced pressure and dried in vacuo to give 40 mg (44% yield) of the title compound. MS 458 (M+H+).

[0325] Example 3-Synthesis of 4-(2-((6-acetylbenzo[d][1,3]dioxol-5-yl)amino)-2-oxoethyl)piperazine-1-carboxylic acid propyl ester (3)

[0326]

[0327] In a similar manner to Example 1, 16 mg (25% yield) of the title compound was prepared from N-(6-acetylbenzo[d][1,3]dioxol-5-yl)-2-(piperazin-1-yl)acetamide dihydrochloride (Example 1a) (76 mg, 0.2 mmol), TEA (40 mg, 0.4 mmol) and phosgene (25 mg, 0.2 mmol). MS 392 (M+H + ).

[0328] Example 4-Synthesis of 4-(2-((6-acetylbenzo[d][1,3]dioxol-5-yl)amino)-2-oxoethyl)-N-isopropylpiperazine-1-carboxamide (4)

[0329]

[0330] In a similar manner to Example 1, 23 mg (30% yield) of the title compound was prepared from N-(6-acetylbenzo[d][1,3]dioxol-5-yl)-2-(piperazin-1-yl)acetamide dihydrochloride (Example 1a) (76 mg, 0.2 mmol), TEA (40 mg, 0.4 mmol) and 2-isocyanatopropane (17 mg, 0.2 mmol). MS 391 (M+H + ).

[0331] Example 5 - Synthesis of N-(6-acetylbenzo[d][1,3]dioxol-5-yl)-2-(4-(isopropylsulfonyl)piperazin-1-yl)acetamide (5)

[0332]

[0333] In a similar manner to Example 1, 42 mg (10% yield) of the title compound was prepared from N-(6-acetylbenzo[d][1,3]dioxol-5-yl)-2-(piperazin-1-yl)acetamide dihydrochloride (76 mg, 0.2 mmol), TEA (40 mg, 0.4 mmol) and propane-2-sulfonyl chloride (28 mg, 0.2 mmol). MS 412 (M+H + ).

[0334] Example 6-Synthesis of N-(6-methoxybenzo[d][1,3]dioxol-5-yl)-2-(4-(3-methylbutyryl)piperazin-1-yl)acetamide (6)

[0335]

[0336] N-(6-methoxybenzo[d][1,3]dioxol-5-yl)-2-(piperazin-1-yl)acetamide dihydrochloride (Example 6a) (73 mg, 0.2 mmol), HOBt (30 mg, 0.2 mmol), EDC (38 mg, 0.2 mmol) and TEA (81 mg, 0.8 mmol) were suspended in DMF (1 mL) and 3-methylbutyric acid (20 mg, 0.2 mmol) was added. The mixture was irradiated at 150 ° C for 5 minutes in a microwave. The solution was directly purified by reverse phase HPLC (water / acetonitrile gradient) to give 29 mg (38% yield) of the title compound. MS 378 (M+H + ).

[0337] Example 6a. N-(6-methoxybenzo[d][1,3]dioxol-5-yl)-2-(piperazin-1-yl)acetamide dihydrochloride

[0338]

[0339] In a similar manner to Example 1a, the title compound was obtained as a yellow solid (1.20 g, quantitative yield) from tert-butyl 4-(2-((6-methoxybenzo[d][1,3]dioxol-5-yl)amino)-2-oxoethyl)piperazine-1-carboxylate (Example 6b) (1.29 g, 3.28 mmol).

[0340] Example 6b. tert-Butyl 4-(2-((6-methoxybenzo[d][1,3]dioxol-5-yl)amino)-2-oxoethyl)piperazine-1-carboxylate

[0341]

[0342] The title compound was prepared in a similar manner to Example 1b from 2-bromo-N-(6-methoxybenzo[d][1,3]dioxol-5-yl)acetamide (Example 6c) (1.58 g, 5.5 mmol) and tert-butyl piperazine-1-carboxylate as a light yellow solid (1.30 g, 3.30 mmol, 60% yield).

[0343] Example 6c. 2-Bromo-N-(6-methoxybenzo[d][1,3]dioxol-5-yl)acetamide

[0344]

[0345] In a similar manner to Example 1c, 6-methoxybenzo[d][1,3]-dioxol-5-amine (0.92 g, 5.5 mmol) and bromoacetyl chloride were used to prepare the desired product (1.60 g, quantitative yield) as a gray solid. MS289 (M+H + ).

[0346] The compounds in Table 2 were prepared in a similar manner to that in Example 1, Example 2 and / or Example 6 from the corresponding amine hydrochlorides described herein and commercially available electrophiles (eg, carboxylic acids, acid chlorides, chloroformates, isocyanates and sulfonyl chlorides).

[0347] Table 2

[0348]

[0349]

[0350]

[0351]

[0352]

[0353]

[0354]

[0355]

[0356]

[0357]

[0358]

[0359]

[0360]

[0361]

[0362]

[0363]

[0364]

[0365]

[0366]

[0367]

[0368]

[0369]

[0370]

[0371]

[0372]

[0373]

[0374]

[0375]

[0376]

[0377]

[0378]

[0379] Compounds with hT2R54 IC50 of 1 μM or less were considered particularly potent.

[0380] Example 7-Synthesis of N-(6-acetylbenzo[d][1,3]dioxol-5-yl)-2-(4-benzylpiperazin-1-yl)acetamide (101)

[0381]

[0382] To a mixture of N-(6-acetylbenzo[d][1,3]dioxol-5-yl)-2-(piperazin-1-yl)acetamide dihydrochloride (Example 1a) (76 mg, 0.2 mmol), TEA (40 mg, 0.4 mmol) and Cs2CO3 (76 mg, 0.4 mmol) in DMF (1 mL) was added (chloromethyl)benzene (25 mg, 0.2 mmol). The mixture was irradiated in a microwave at 150°C for 10 minutes, diluted with methanol (1 mL), filtered, and the filtrate was purified by reverse phase HPLC (water / acetonitrile gradient) to give 20 mg of the title compound. MS 396 (M+H + ).

[0383] The compounds in Table 3 were prepared in a similar manner to that described in Example 7 from N-(6-acetylbenzo[d][1,3]dioxol-5-yl)-2-(piperazin-1-yl)acetamide dihydrochloride (Example 1a) and the corresponding commercially available electrophile.

[0384] Table 3

[0385]

[0386] Compounds with hT2R54 IC50 of 1 μM or less were considered particularly potent.

[0387] Example 8-Synthesis of N-(6-acetylbenzo[d][1,3]dioxol-5-yl)-2-morpholinoacetamide (109)

[0388]

[0389] A solution of N-(6-acetylbenzo[d][1,3]dioxol-5-yl)-2-bromoacetamide (Example 1c) (2.5 g, 8.56 mmol) and morpholine (2.3 mL, 25.7 mmol) in acetonitrile (100 mL) was heated to 90 ° C and stirred for 1 hour. The mixture was cooled to room temperature and concentrated under vacuum. The residue was stirred in a mixture of EtOAc (15 mL) and water (20 mL) for about 30 minutes, the solid product was collected by filtration, and recrystallized from EtOH / H2O to give the title compound (2.2 g, 84% yield) as a light brown solid. MS (M+H + )307.

[0390] Example 9-Synthesis of N-(6-acetylbenzo[d][1,3]dioxol-5-yl)-2-morpholinopropanamide (110)

[0391]

[0392] To a solution of N-(6-acetylbenzo[d][1,3]dioxol-5-yl)-2-bromopropionamide (Example 9a) (55 mg, 0.175 mmol) in ACN was added morpholine (45 uL, 0.525 mmol). The solution was heated at 90 °C for 2 hours and then concentrated in vacuo. The residue was purified by silica gel column chromatography (0-50% EtOAc / hexane gradient) to give the title compound as a white solid (48.9 mg, 87% yield). MS 321 (M+H + ).

[0393] Example 9a. N-(6-acetylbenzo[d][1,3]dioxol-5-yl)-2-bromopropionamide

[0394]

[0395] The title compound was prepared in a similar manner to Example 1c from 1-(6-aminobenzo[d][1,3]-dioxol-5-yl)ethan-1-one (185 mg, 1.033 mmol), TEA (288 uL, 2.065 mmol) and 2-bromopropionyl chloride (114 uL, 1.136 mmol) as an orange solid (282 mg, 87% yield). 1 H NMR (400MHz, DMSO-d6) δ1.78(d,J=6.4Hz,3H),2.59(s,3H),4.84(q,J=6.8Hz,1H),6.16(s,2H),7.63(s,1H),8.06(s,1H),12.25(s,1H).MS 314(M+H + ).

[0396] Example 10 - Synthesis of N-(6-acetylbenzo[d][1,3]dioxol-5-yl)-2-methyl-2-morpholinopropanamide (111)

[0397]

[0398] In a similar manner to Example 9, the title compound was prepared from N-(6-acetylbenzo[d][1,3]dioxol-5-yl)-2-bromo-2-methylpropanamide (Example 10a) (60 mg, 0.183 mmol) and morpholine (47 uL, 0.549 mmol) as a white solid (13.2 mg, 22% yield). MS 335 (M+H + ).

[0399] Example 10a. N-(6-acetylbenzo[d][1,3]dioxol-5-yl)-2-bromo-2-methylpropanamide

[0400]

[0401] In a similar manner to Example 1c, the title compound was prepared from 1-(6-aminobenzo[d][1,3]-dioxol-5-yl)ethan-1-one (250 mg, 1.40 mmol), TEA (389 uL, 2.79 mmol) and 2-bromo-2-methylpropanoyl chloride (285 mg, 1.54 mmol) as a yellow solid (272 mg, yield 59%). MS 329 (M+H+ ).

[0402] Example 1 Synthesis of 1-(2-((6-acetylbenzo[d][1,3]dioxol-5-yl)amino)-2-oxoethyl)-L-proline ethyl ester (112)

[0403]

[0404] In a similar manner to Example 1b, the title compound was prepared from N-(6-acetylbenzo[d][1,3]-dioxol-5-yl)-2-bromoacetamide (Example 1c) (84 mg, 0.280 mmol), L-proline ethyl ester hydrochloride (55 mg, 0.308 mmol) and K2CO3 (116 mg, 0.840 mmol) in anhydrous DMF (3 mL) at room temperature as an orange powder (47.1 mg, 46%). MS 363 (M+H + ).

[0405] Example 12-Synthesis of ethyl 1-(2-((6-acetylbenzo[d][1,3]dioxol-5-yl)amino)-2-oxoethyl)piperidine-2-carboxylate (113)

[0406]

[0407] In a similar manner to Example 1b, the title compound was prepared from N-(6-acetylbenzo[d][1,3]-dioxol-5-yl)-2-bromoacetamide (Example 1c) (75 mg, 0.250 mmol) and ethyl 2-pipecolinate hydrochloride (53 mg, 0.275 mmol) as an off-white solid (55.8 mg, 59% yield). MS 377 (M+H + ).

[0408] Example 13-Synthesis of ethyl 1-(2-((6-acetylbenzo[d][1,3]dioxol-5-yl)amino)-2-oxoethyl)pyrrolidine-3-carboxylate (114)

[0409]

[0410] In a similar manner to Example 1b, the title compound was prepared from N-(6-acetylbenzo[d][1,3]-dioxol-5-yl)-2-bromoacetamide (Example 1c) (120 mg, 0.400 mmol) and ethylpyrrolidine-3-carboxylic acid hydrochloride (79 mg, 0.440 mmol) as an orange solid (14.5 mg, 10% yield). MS 363 (M+H + ).

[0411] Example 14-Synthesis of ethyl 1-(2-((6-acetylbenzo[d][1,3]dioxol-5-yl)amino)-2-oxoethyl)piperidine-3-carboxylate (115)

[0412]

[0413] In a similar manner to Example 1b, the title compound was prepared from N-(6-acetylbenzo[d][1,3]-dioxol-5-yl)-2-bromoacetamide (Example 1c) (77 mg, 0.257 mmol) and 3-nipecotate (nipecotate) ethyl ester (44uL, 0.283 mmol) as a pale yellow solid (62.8 mg, 65% yield). MS 377 (M+H+). Alternatively, in a similar manner to Example 1b, the title compound was synthesized from N-(6-acetylbenzo[d][1,3]dioxol-5-yl)-2-chloroacetamide (Example 14a) (5.0 g, 20.0 mmol) and 3-nipecotate (3.5 g, 22.0 mmol) as a white solid (5.3 g, 70% yield). MS 377 (M+H + ).

[0414] Example 14a. N-(6-acetylbenzo[d][1,3]dioxol-5-yl)-2-chloroacetamide

[0415]

[0416] In a similar manner to Example 1c, 1-(6-aminobenzo[d][1,3]-dioxol-5-yl)ethan-1-one (3.6 g, 20 mmol) and acetyl chloride (2.4 mL, 30 mmol) and TEA (4.1 mL, 30 mmol) were used to prepare the desired product 5.6 g (quantitative yield). 1 H NMR(400MHz,DMSO-d6)δ2.58(s,3H),4.42(s,2H),6.16(s,2H),7.63(s,1H),8.13(s,1H),12.45(s,1H).MS256(M+H+ ).

[0417] Example 15-Synthesis of ethyl 1-(2-((6-acetylbenzo[d][1,3]dioxol-5-yl)amino)-2-oxoethyl)piperidine-4-carboxylate (116)

[0418]

[0419] In a similar manner to Example 1b, the title compound was prepared from N-(6-acetylbenzo[d][1,3]-dioxol-5-yl)-2-bromoacetamide (Example 1c) (75 mg, 0.250 mmol) and ethyl piperidine-4-carboxylate hydrochloride (53 mg, 0.275 mmol) as an orange solid (10.9 mg, 12% yield). MS 377 (M+H + ).

[0420] Example 16-Synthesis of ethyl 1-(2-((6-methoxybenzo[d][1,3]dioxol-5-yl)amino)-2-oxoethyl)piperidine-3-carboxylate (117)

[0421]

[0422] In a similar manner to Example 9, 2-chloro-N-(6-methoxybenzo-[d][1,3]dioxol-5-yl)acetamide (Example 16a) (100 mg, 0.4 mmol) and ethyl piperidine-3-carboxylate (63 mg, 0.4 mmol) were used to prepare 55 mg (30% yield) of the title compound as an off-white gel. MS 365 (M+H + ).

[0423] Example 16a. 2-Chloro-N-(6-methoxybenzo[d][1,3]dioxol-5-yl)acetamide

[0424]

[0425] In a similar manner to Example 1c, 6-methoxybenzo[d][1,3]-dioxol-5-amine (84 mg, 0.5 mmol) and acetyl chloride (56 mg, 0.5 mmol) were used to prepare the desired product as a gray solid (100 mg, 82% yield). MS244 (M+H + ).

[0426] Example 17-Synthesis of ethyl 1-(2-((7-acetyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)amino)-2-oxoethyl)piperidine-3-carboxylate (118)

[0427]

[0428] In a similar manner to Example 9, N-(7-acetyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-bromoacetamide (Example 17a) (200 mg, 0.64 mmol) and ethyl piperidine-3-carboxylate (148 μL, 0.96 mmol) were used to prepare the desired product as a light yellow oil (75 mg, 30% yield). MS 391 (M+H + ).

[0429] Example 17a. N-(7-acetyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-chloroacetamide

[0430]

[0431] In a similar manner to Example 1c, 1-(7-amino-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethan-1-one (11 g, 56.94 mmol) and 2-bromoacetyl chloride (7.08 mL, 85.40 mmol) were used to prepare the desired product as a brown solid (17.8 g, 99% yield). MS 315 (M+H + ).

[0432] The compounds in Table 4 were prepared in a manner analogous to Example 1b and / or Example 9 from the corresponding 2-chloro- and 2-bromo-acetamides synthesized as described herein and commercially available amine nucleophiles.

[0433] Table 4

[0434]

[0435]

[0436]

[0437]

[0438]

[0439]

[0440]

[0441]

[0442]

[0443]

[0444]

[0445]

[0446] Compounds with hT2R54 IC50 of 1 μM or less were considered particularly potent.

[0447] Example 18-Synthesis of 1-(2-((6-acetylbenzo[d][1,3]dioxol-5-yl)amino)-2-oxoethyl)-N-methylpiperidine-3-carboxamide (154)

[0448]

[0449] To a solution of 1-(2-((6-acetylbenzo[d][1,3]dioxol-5-yl]amino)-2-oxoethyl)piperidine-3-carboxylic acid (Example 18a) (0.2 g, 0.6 mmol) in DMF (5 mL) was added O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU) (0.2 g, 0.7 mmol), TEA (0.3 mL, 1.8 mmol) and methylamine HCl (0.1 g, 0.6 mmol). The mixture was stirred at room temperature overnight and purified by reverse phase HPLC using an ACN / water gradient to give the title compound (96 mg, 44% yield) as a white solid. MS 362 (M+H + ).

[0450] Example 18a. 1-(2-((6-acetylbenzo[d][1,3]dioxol-5-yl)amino)-2-oxoethyl)piperidine-3-carboxylic acid

[0451]

[0452] To a solution of ethyl 1-(2-((6-acetylbenzo[d][1,3]dioxol-5-yl)amino)-2-oxoethyl)piperidine-3-carboxylate (4.5 g, 12 mmol) in THF / MeOH (40 / 40 mL) was added LiOH (0.9 g, 42 mmol) to obtain a solution in water (40 mL) and stirred at room temperature overnight. The solution was concentrated and used without further purification. MS 349 (M+H + ).

[0453] The compounds in Table 5 were prepared in a manner analogous to Example 18 from the corresponding ester starting materials described herein and commercially available amine nucleophiles.

[0454] Table 5

[0455]

[0456]

[0457]

[0458]

[0459] Compounds with hT2R54 IC50 of 1 μM or less were considered particularly potent.

[0460] Example 19-Synthesis of 2-(4-acetamidopiperidin-1-yl)-N-(6-acetylbenzo[d][1,3]dioxol-5-yl)acetamide (166)

[0461]

[0462] Acetyl chloride (0.04 g, 5 mmol) and TEA (0.3 mL, 2 mmol) were added to a solution of N-(6-acetylbenzo[d][1,3]dioxol-5-yl)-2-(4-aminopiperidin-1-yl)acetamide dihydrochloride (Example 19a) (0.2 g, 0.5 mmol) in DCM (5 mL). The mixture was stirred at room temperature overnight and purified by reverse phase HPLC using an ACN / water gradient to give the desired product (91 mg, 50% yield) as a white solid. MS 362 (M+H + ).

[0463] Example 19a. N-(6-acetylbenzo[d][1,3]dioxol-5-yl)-2-(4-aminopiperidin-1-yl)acetamide dihydrochloride

[0464]

[0465] To anhydrous DCM (10mL) solution of tert-butyl (1- (2- ((6- acetylbenzo [d] [1,3] dioxol -5- bases) amino) -2- oxoethyl) piperidin-4-yl) carbamate (Example 19b) (3.3g, 8mmol) was added 4M HCl in dioxane (10mL) solution. The reactant was stirred at room temperature overnight. The reactant was filtered, and the solid was washed with DCM and ether successively, and dried under vacuum to give the title compound (3.1g, quantitative yield), which was a light brown solid. 1H NMR(400MHz,DMSO-d6)δ1.85-2.21(m,5H),2.58(s,3H),3.19(s,3H),4.25(s,2H) ,6.17(s,2H),7.61(s,1H),7.81(s,1H),8.45(s,3H),10.43(s,1H),11.77(s,1H).

[0466] Example 19b. tert-Butyl (1-(2-((6-acetylbenzo[d][1,3]dioxol-5-yl)amino)-2-oxoethyl)piperidin-4-yl)carbamate

[0467]

[0468] In a manner similar to Example 9, the desired product (3.3 g, 79% yield) was prepared from N-(6-acetylbenzo[d][1,3]dioxol-5-yl)-2-chloroacetamide (Example 14a) (2.5 g, 10 mmol) and tert-butyl piperidin-4-ylcarbamate (2 g, 10 mmol) as a light brown solid.

[0469] The compounds in Table 6 were prepared in a similar manner to Example 2, Example 18 and / or Example 19 from N-(6-acetylbenzo[d][1,3]dioxol-5-yl)-2-(4-aminopiperidin-1-yl)acetamide dihydrochloride (Example 19a) and the corresponding commercially available carboxylic acids and / or acid chlorides.

[0470] Table 6

[0471]

[0472]

[0473]

[0474]

[0475] Compounds with hT2R54 IC50 of 1 μM or less were considered particularly potent.

[0476] Example 20-Synthesis of N-(6-acetylbenzo[d][1,3]dioxol-5-yl)-2-((1-(furan-2-carbonyl)piperidin-4-yl)(methyl)amino)acetamide (183)

[0477]

[0478] In a similar manner to Example 19, the title compound (119 mg, 56% yield) was prepared from N-(6-acetylbenzo[d][1,3]dioxol-5-yl)-2-(methyl(piperidin-4-yl)amino)acetamide dihydrochloride (Example 20a) (0.2 g, 0.5 mmol), furan-2-carbonyl chloride (0.08 g, 0.6 mmol) and TEA (0.3 mL, 2 mmol). MS 428 (M+H + ).

[0479] Example 20a. N-(6-acetylbenzo[d][1,3]dioxol-5-yl)-2-(methyl(piperidin-4-yl)amino)acetamide dihydrochloride

[0480]

[0481] In a similar manner to Example 19a, about 1.1 g (quantitative yield) of the desired product was prepared from tert-butyl 4-((2-((6-acetylbenzo[d][1,3]dioxol-5-yl)amino]-2-oxoethyl)(methyl)amino)piperidine-1-carboxylate (Example 20b).

[0482] Example 20b. tert-Butyl 4-((2-((6-acetylbenzo[d][1,3]dioxol-5-yl)amino)-2-oxoethyl)(methyl)amino)piperidine-1-carboxylate

[0483]

[0484] In a manner similar to Example 9, about 1.2 g (60% yield) of the title compound was prepared from N-(6-acetylbenzo[d][1,3]-dioxol-5-yl)-2-chloroacetamide (Example 14a) (1.2 g, 4.7 mmol), tert-butyl 4-(methylamino)piperidine-1-carboxylate (1 g, 4.7 mmol) and TEA as a white solid. 1 H NMR (400MHz, DMSO-d6) δ1.27-1.44(m,2H),1.39(s,9H),1.80(d,J=12.4Hz,2H),2.27(s,3H),2.55(s,3H),2. 57-2.76(m,3H),3.17(s,2H),3.98(d,J=13.2Hz,2H),6.13(s,2H),7.60(s,1H),8.33(s,1H),12.68(s,1H).MS 434(M+H + ).

[0485] Example 21-Synthesis of N-(6-acetylbenzo[d][1,3]dioxol-5-yl)-2-(methyl(1-(3-methylbutyryl)piperidin-4-yl)amino)acetamide (184)

[0486]

[0487] In a similar manner to Example 19, N-(6-acetylbenzo[d][1,3]-dioxol-5-yl)-2-(methyl(piperidin-4-yl)amino)acetamide dihydrochloride (Example 20a) (0.2 g, 0.5 mmol) and 3-methylbutyryl chloride (0.07 g, 0.6 mmol) were used to prepare the desired product (118 mg, 56% yield) as a white solid. MS 418 (M+H + ).

[0488] The compounds in Table 7 were prepared in a similar manner to Example 19 from N-(6-acetylbenzo[d][1,3]dioxol-5-yl)-2-(methyl(piperidin-4-yl)amino)acetamide dihydrochloride (Example 20a) and the corresponding commercially available carboxylic acids and / or acid chlorides.

[0489] Table 7

[0490]

[0491]

[0492]

[0493] Compounds with hT2R54 IC50 of 1 μM or less were considered particularly potent.

[0494] Example 22-Synthesis of ethyl 1-(2-((6-acetylbenzo[d][1,3]dioxol-5-yl)amino)-2-oxoethyl)-4-(furan-2-carbonyl)piperazine-2-carboxylate (191, IC50=16 nM)

[0495]

[0496] In a manner similar to Example 19, the desired product (94 mg, 20% yield) was prepared from ethyl 1-(2-((6-acetylbenzo[d][1,3]dioxol-5-yl)amino)-2-oxoethyl)piperazine-2-carboxylate dihydrochloride (Example 22a) (0.45 g, 1 mmol), furan-2-carbonyl chloride (0.13 g, 1 mmol) and TEA (0.6 mL, 4 mmol) as an off-white solid. 1H NMR(400MHz,DMSO-d6)δ1.05(brs,3H),2.60(s,3H),2.65(d,J=12.2Hz,1H),3.00-3 .16(m,1H),3.35-3.54(m,2H),3.82(t,J=3.1Hz,2H),3.99(d,J=7.6Hz,2H),4.22(d ,J=13.0Hz,1H),4.64(brs,1H),6.15(s,2H),6.63(dd,J=3.5,1.8Hz,1H),7.04(d,J =3.4Hz,1H),7.64(s,1H),7.85(dd,J=1.8,0.8Hz,1H),8.37(s,1H),12.77(s,1H).MS 472(M+H + ).

[0497] Example 22a. 1-(2-((6-acetylbenzo[d][1,3]dioxol-5-yl)amino]-2-oxoethyl)-piperazine-2-carboxylic acid ethyl ester dihydrochloride

[0498]

[0499] In a similar manner to Example 19a, the desired product (1.35 g, quantitative yield) was prepared from 3-ethyl 4-(2-((6-acetylbenzo[d][1,3]dioxol-5-yl]amino)-2-oxoethyl)piperazine-1,3-dicarboxylate (Example 22b) (1.4 g, 3 mmol).

[0500] Example 22b. 1-(tert-butyl) 3-ethyl 4-(2-((6-acetylbenzo[d][1,3]dioxol-5-yl)amino)-2-oxoethyl)piperazine-1,3-dicarboxylate

[0501]

[0502] In a manner similar to Example 9, about 1.4 g (75% yield) of the desired product was prepared from N-(6-acetylbenzo[d][1,3]-dioxol-5-yl)-2-chloroacetamide (Example 14a) (1 g, 4 mmol), 1-(tert-butyl)3-ethyl piperazine-1,3-dicarboxylate (1.0 g, 4 mmol) and TEA (1.7 mL, 12 mmol) as a white solid. 1H NMR(400MHz,DMSO-d6)δ1.20(br s,3H),1.39(s,9H),2.58(s,3H),3.00-3.06(m,1H),3.39–3.59(m,2H),3.64-3.87 (m,2H),4.04-4.26(m,3H),6.14(s,2H),7.62(s,1H),8.35(s,1H),12.70(s,1H).MS 478(M+H + ).

[0503] Example 23-Synthesis of ethyl 1-(2-((6-acetylbenzo[d][1,3]dioxol-5-yl)amino)-2-oxoethyl)-4-(3-methylbutyryl)piperazine-2-carboxylate (192, IC50=57 nM)

[0504]

[0505] In a similar manner to Example 20, ethyl 1-(2-((6-acetylbenzo[d][1,3]dioxol-5-yl)amino)-2-oxoethyl)piperazine-2-carboxylate dihydrochloride (Example 22a) (0.45 g, 1 mmol) and 3-methylbutyryl chloride (0.12 g, 1 mmol) were used to prepare the desired product (82 mg, 18% yield) as a white solid. MS 462 (M+H + ).

[0506] Example 24-Synthesis of N-(6-acetylbenzo[d][1,3]dioxol-5-yl)-2-(1-(3-methylbutyryl)piperidin-3-yl)acetamide (193)

[0507]

[0508] A solution of N-(6-acetylbenzo[d][1,3]dioxol-5-yl)-2-(piperidin-3-yl)acetamide hydrochloride (53 mg, 0.156 mmol) and TEA (44 μL, 0.336 mmol) in anhydrous DCM (4 mL) was treated with isovaleryl chloride (21 uL, 0.172 mmol) and the solution was stirred at room temperature overnight. The solvent was removed in vacuo and the residue was purified by silica gel chromatography to give the title compound as a colorless oil (64.4 mg, quantitative yield). MS 389 (M+H + ).

[0509] Example 24a. N-(6-acetylbenzo[d][1,3]dioxol-5-yl)-2-(piperidin-3-yl)acetamide

[0510]

[0511] A solution of tert-butyl 3-(2-((6-acetylbenzo[d][1,3]dioxol-5-yl)amino)-2-oxoethyl)piperidine-1-carboxylate (Example 24b) (5.9 g) in 4M HCl in 1,4-dioxane (80 mL) was stirred at room temperature overnight. The precipitate was collected by filtration to give the title compound as a light yellow solid in quantitative yield.

[0512] Example 24b. 3-(2-((6-acetylbenzo[d][1,3]dioxol-5-yl)amino)-2-oxoethyl)-piperidine-1-carboxylic acid tert-butyl ester

[0513]

[0514] A mixture of 1-(6-aminobenzo[d][1,3]dioxol-5-yl)ethan-1-one (3.07 g, 17.13 mmol), 2-(1-(tert-butyloxycarbonyl)piperidin-3-ylacetic acid (5.0 g, 20.6 mmol), HATU (9.78 g, 25.70 mmol) and DIEA (8.95 mL, 51.40 mmol) in anhydrous DMF was heated to 55 °C and stirred at room temperature overnight. The reaction mixture was concentrated and the residue was diluted with EtOAc and washed with water and brine. The organic phase was dried over MgSO4, filtered and concentrated on a rotary evaporator. The residue was purified by silica gel chromatography using 20% ​​to 30% EtOAc in hexanes as eluent. The fractions were collected and dried to give the title compound as a light yellow oil (5.9 g, 14.6 mmol, 85% yield). 1 H NMR(400MHz,DMSO-d6)δ1.23(m,2H),1.35(s,9H),1.56-1.62(m,1H),1.73-1.79(m,1H),1.88(br.s,1H),2.28 (m,2H),2.57(s,3H),2.84(br.s,2H),3.71-3.83(m,2H),6.14(s,2H),7.59(s,1H),8.12(s,1H),11.83(s,1H).

[0515] Example 25-Synthesis of N-(6-acetylbenzo[d][1,3]dioxol-5-yl)-2-(1-(furan-2-carbonyl)piperidin-3-yl)acetamide (194)

[0516]

[0517] In a similar manner to Example 24, the title compound was prepared from N-(6-acetylbenzo[d][1,3]-dioxol-5-yl)-2-(piperidin-3-yl)acetamide hydrochloride (Example 24a) (42 mg, 0.123 mmol) and 2-furanoyl chloride (13 uL, 0.135 mmol) as a white solid (44.1 mg, 90% yield). MS 399 (M+H+).

[0518] Example 26-Synthesis of N-(6-acetylbenzo[d][1,3]dioxol-5-yl)-2-(1-(thiophene-2-carbonyl)piperidin-3-yl)acetamide (195)

[0519]

[0520] In a similar manner to Example 24, the title compound was prepared from N-(6-acetylbenzo[d][1,3]-dioxol-5-yl)-2-(piperidin-3-yl)acetamide hydrochloride (Example 24a) (41 mg, 0.120 mmol) and thiophene-2-carbonyl chloride (14 uL, 0.132 mmol) as a white solid (47.6 mg, 96% yield). MS 415 (M+H + ).

[0521] Example 27-Synthesis of N-(6-acetylbenzo[d][1,3]dioxol-5-yl)-2-(1-(furan-3-carbonyl)piperidin-3-yl)acetamide (196)

[0522]

[0523] A solution of 3-furancarboxylic acid (18 mg, 0.161 mmol) and DIEA (51 μL, 0.294 mmol) in anhydrous DCM (4 mL) was treated with TBTU (61 mg, 0.191 mmol), and the solution was stirred at room temperature for 1 hour. N-(6-acetylbenzo[d][1,3]dioxol-5-yl)-2-(piperidin-3-yl)acetamide hydrochloride (Example 24a) (50 mg, 0.147 mmol) was then added, and the mixture was stirred at room temperature overnight. The solvent was removed in vacuo, and the residue was purified by silica gel chromatography using 0-50% EtOAc in hexane as eluent to give the title compound as a white powder (66.5 mg, quantitative yield). MS 399 (M+H + ).

[0524] Example 28 - Synthesis of N-(6-acetylbenzo[d][1,3]dioxol-5-yl)-2-(1-(furan-2-carbonyl)piperidin-4-yl)acetamide (197)

[0525]

[0526] In a similar manner to Example 24, the title compound was prepared from N-(6-acetylbenzo[d][1,3]-dioxol-5-yl)-2-(piperidin-4-yl)acetamide hydrochloride (Example 28a) (42 mg, 0.123 mmol), TEA (34 uL, 0.246 mmol) and 2-furanoyl chloride (13 uL, 0.135 mmol) as a white solid (44 mg, 90% yield). MS399 (M+H + ).

[0527] Example 28a. N-(6-acetylbenzo[d][1,3]dioxol-5-yl)-2-(piperidin-4-yl)acetamide hydrochloride

[0528]

[0529] In a similar manner to Example 24a, the title compound was prepared from tert-butyl 4-(2-((6-acetylbenzo[d][1,3]dioxol-5-yl)amino]-2-oxoethyl)piperidine-1-carboxylate (Example 28b) (699 mg, 1.73 mmol) and 4N HCl in dioxane (4.5 mL) as a yellow solid (556 mg, 94% yield). 1 H NMR (400MHz, DMSO-d6) δ1.48–1.28(m,2H),1.82(d,J=13.9Hz,2H),1.97-2.14(m,1H),2.35(d,J=7.2Hz,2H),2.57(s,3H),2.88( q,J=11.9Hz,2H),3.26(d,J=12.8Hz,2H),6.14(s,2H),7.59(s,1H),8.08(s,1H),8.24(br.s,1H),8.54(br.s,1H),11.78(s,1H).

[0530] Example 28b. tert-Butyl 4-(2-((6-acetylbenzo[d][1,3]dioxol-5-yl)amino)-2-oxoethyl)piperidine-1-carboxylate

[0531]

[0532] The title compound was prepared in a similar manner to Example 24b from 1-(6-aminobenzo-[d][1,3]dioxol-5-yl)ethan-1-one (3.07 g, 17.13 mmol), 2-(1-(tert-butoxycarbonyl)-piperidin-4-yl)acetic acid (5.0 g, 20.6 mmol), HATU (9.78 g, 25.70 mmol) and DIEA (8.95 mL, 51.40 mmol) as a light yellow oil (6.5 g, 16.1 mmol, 94% yield). 1 H NMR (400MHz, DMSO-d6) δ1.07(qd,J=12.3,4.2Hz,2H),1.38(s,9H),1.65(d,J=11.6Hz,2H),1.87-1.99(m,1H),2.30(d,J=7.1Hz,2H) ,2.57(s,3H),2.60–2.84(m,2H),3.89(d,J=13.2Hz,2H),6.13(s,2H),7.58(d,J=0.6Hz,1H),8.11(d,J=0.6Hz,1H),11.80(s,1H).MS 305(M+H + ).

[0533] Example 29-Synthesis of N-(6-acetylbenzo[d][1,3]dioxol-5-yl)-2-(1-(3-methylbutyryl)piperidin-4-yl)acetamide (198)

[0534]

[0535] In a similar manner to Example 24, the title compound was prepared from N-(6-acetylbenzo[d][1,3]-dioxol-5-yl)-2-(piperidin-4-yl)acetamide hydrochloride (Example 28a) (40 mg, 0.117 mmol) and isovaleryl chloride (16 uL, 0.129 mmol) as a colorless oil (43 mg, 96% yield). MS 389 (M+H + ).

[0536] Example 30 - Synthesis of N-(6-acetylbenzo[d][1,3]dioxol-5-yl)-2-(1-(thiophene-2-carbonyl)piperidin-4-yl)acetamide (199)

[0537]

[0538] In a similar manner to Example 24, the title compound was prepared from N-(6-acetylbenzo[d][1,3]-dioxol-5-yl)-2-(piperidin-4-yl)acetamide hydrochloride (Example 28a) (42 mg, 0.123 mmol) and thiophene-2-carbonyl chloride (15 uL, 0.135 mmol) as a white solid (39 mg, 76% yield). MS 415 (M+H + ).

[0539] Example 31-Synthesis of N-(6-acetylbenzo[d][1,3]dioxol-5-yl)-2-(1-(furan-3-carbonyl)piperidin-4-yl)acetamide (200)

[0540]

[0541] In a similar manner to Example 18, the title compound was prepared from N-(6-acetylbenzo[d][1,3]-dioxol-5-yl)-2-(piperidin-4-yl)acetamide hydrochloride (Example 28a) (50 mg, 0.147 mmol) and 3-furancarboxylic acid (18 mg, 0.161 mmol) as a white powder (47.9 mg, 82% yield). MS 399 (M+H + ).

[0542] Example 32-Synthesis of N-(6-acetylbenzo[d][1,3]dioxol-5-yl)-2-(1-(1-methyl-1H-pyrazole-4-carbonyl)piperidin-4-yl)acetamide (201)

[0543]

[0544] In a similar manner to Example 18, the title compound was prepared from N-(6-acetylbenzo[d][1,3]-dioxol-5-yl)-2-(piperidin-4-yl)acetamide hydrochloride (Example 28a) (50 mg, 0.147 mmol) and 1-methyl-1H-pyrazole-4-carboxylic acid (19 mg, 0.147 mmol) as a white solid (40.5 mg, 67% yield). MS 413 (M+H + ).

[0545] The compounds in Table 8 were prepared in a manner analogous to Example 2 and / or Example 27 from the corresponding amine hydrochlorides described herein (eg, Examples 24a and 28a) and the corresponding commercially available carboxylic acids and / or acid chlorides.

[0546] Table 8

[0547]

[0548]

[0549]

[0550]

[0551]

[0552]

[0553]

[0554]

[0555]

[0556]

[0557]

[0558]

[0559]

[0560]

[0561]

[0562]

[0563]

[0564]

[0565]

[0566]

[0567]

[0568]

[0569]

[0570]

[0571]

[0572]

[0573]

[0574]

[0575]

[0576] Example 33-Synthesis of N-(6-acetylbenzo[d][1,3]dioxol-5-yl)-2-(tetrahydro-2H-pyran-4-yl)acetamide (270)

[0577]

[0578] In a similar manner to Example 24b, 87 mg (58% yield) of the title compound was prepared from 2-(tetrahydro-2H-pyran-4-yl)acetic acid (70 mg, 0.5 mmol), 1-(6-aminobenzo[d][1,3]dioxol-5-yl)ethan-1-one (90 mg, 0.5 mmol) and TEA (150 mg, 1.5 mmol) as a light yellow solid. Alternatively, prepared from 1-(6-aminobenzo[d][1,3]dioxol-5-yl)ethan-1-one and 2-(tetrahydro-2H-pyran-4-yl)acetyl chloride as described in Example 1c. MS 306 (M+H+).

[0579] The compounds in Table 9 were prepared in a similar manner to Examples 1c and / or 24b from 1-(6-aminobenzo[d][1,3]dioxol-5-yl)ethan-1-one and the corresponding commercially available carboxylic acids and / or acid chlorides.

[0580] Table 9

[0581]

[0582]

[0583]

[0584]

[0585]

[0586] Example 34-Synthesis of 1-(6-methyl-2-phenylpyrimidin-4-yl)piperidine-4-carboxamide (A)

[0587]

[0588] A mixture of 4-chloro-6-methyl-2-phenylpyrimidine (1 g, 4.89 mmol) and piperidine-4-carboxamide (0.627 g, 4.89 mmol) and trimethylamine (1.02 mL, 7.34 mmol) in anhydrous DMF (25 mL) was heated to reflux for 4 hours. After completion, the reaction mixture was cooled to room temperature and then concentrated to dryness. The residue was stirred in a mixed solution of EtOAc (10 mL) and water (20 mL) for about 30 minutes. The solid product was then collected by filtration to obtain 1.4 g of the compound, which was then recrystallized from EtOH / H2O. After drying, 900 mg of the title compound was obtained as a white solid with a yield of 62%. MS (MH + )297.

[0589] Other T2R54 bitter taste blockers provided by the present disclosure or suitable for use in the methods of the present disclosure include the following compounds.

[0590]

[0591] The compounds described in this application show effective bitter antagonism to T2R54 in receptor-based assays. In some cases, they also have antagonistic effects on other T2Rs. For example, in addition to T2R54, compound 1 (Table 2) exhibits significant bitter blocking effects on T2R61, T2R64, and T2R75, respectively. Table 10 shows the antagonistic activity of 1-(6-methyl-2-phenylpyrimidin-4-yl)piperidine-4-carboxamide against a group of bitter receptors, as shown in the left column, with the identity of each T2R, and the remaining percentage of activity is shown in the rightmost column.

[0592] Table 10

[0593]

[0594]

[0595] The results shown in Table 10 indicate that in this assay, in the presence of Compound 1 and a bitter compound, T2R61 activity was retained by only 61%, T2R64 activity was retained by only 42%, T2R54 activity was retained by only 15%, and T2R75 activity was retained by only 5%, compared to the activity of the receptors in the presence of the bitter compound alone.

[0596] Example 35 - Sensory Experiment

[0597] To determine the efficacy of individual antagonists in blocking bitter taste, a taste test was performed comparing epigallocatechin gallate (EGCg) alone, which is known to activate T2R54 with EGCg and the bitter blocker described herein, Compound 22 (Table 2). The results shown in Table 11 below clearly demonstrate that Compound 22 has the ability to reduce the bitter taste of EGCg.

[0598] Table 11

[0599] sample total 600uM EGCG 36 600uM EGCG + 15uM compound 22 20 total 56 600uM EGCG alone was selected as more bitter (p-value) 0.044

[0600] Example 36 - Method of Preparing Compositions

[0601] In order to manipulate or block the bitter taste associated with any application discussed herein, the compounds and compositions discussed herein can be used in combination with any product required for any of the applications. For example, the compounds and compositions of the present disclosure can be combined with any element associated with the products and / or applications discussed herein using methods known in the art for preparing such compositions.

[0602] To manipulate or block the bitter taste associated with any of the applications discussed herein, the compounds and compositions discussed herein can be used in combination with any product required for any of the applications, and can be further used in combination with one or more of the excipients and other additive compounds discussed in detail herein. For example, the compounds and compositions of the present invention can be combined with one or more such compounds using methods recognized in the art, and this mixture can then be further combined with any elements associated with the products and / or applications discussed herein using methods known in the art for preparing such compositions.

[0603] The compositions can be prepared, for example, by mixing the ingredients with any of the compounds shown in the following table:

[0604] Table 12

[0605]

[0606] Table 12 (continued)

[0607]

[0608] Table 12 (continued)

[0609]

[0610] Table 12 (continued)

[0611]

[0612] ● Refers to the ingredients usually present in the composition

[0613] Refers to ingredients that may be present in a composition

[0614] Preparations refer to any combination of pharmaceutical preparations and topical (external) preparations. Pharmaceutical ingredients refer to any combination of inactive pharmaceutical ingredients and active pharmaceutical ingredients. Flavorants refer to any combination of sweeteners, sour flavorings, umami flavorings, salty flavorings, bittering agents, and flavor enhancers. Compounds refer to a combination of one or two or more compounds of the present invention as described above.

[0615] Example 37 - Cell-based assay for measuring hT2R54 inhibition

[0616] Cells stably expressing hT2R54 and scrambled G proteins were seeded in 384-well plates 24 hours prior to the experiment. The calcium indicator Fluo4AM was loaded into the cells, washed and loaded into the FLIPR instrument with a compound plate containing quadruplicate increasing doses of acetaminophen prepared at a final concentration of 2X. A baseline was recorded for 10 seconds, then 25 μl of compound 109 (Table 4) was added to 25 μl of cells and changes in fluorescence were monitored for an additional 3 minutes. The host cell line overexpressing the G protein but not hT2R54 was treated as described above. The results of this experiment are shown in Figure 1 The results showed that in response to the bitter-tasting acetaminophen, cells expressing hT2R54, but not control cells, exhibited measurable changes in intracellular calcium.

[0617] The ability of the test compound to block bitter taste caused by hT2R54 was determined in this assay as follows. Cells stably expressing hT2R54 and promiscuous G protein were seeded in 384-well plates 24 hours prior to the experiment. The calcium indicator Fluo4AM was loaded into the cells, washed and loaded into the FLIPR instrument with a compound plate containing increasing doses of acetaminophen in buffer and increasing doses of acetaminophen with the fixed concentration of compound 109 (Table 4). The baseline was recorded for 10 seconds, then 25 μl of compound and compound mixture were added to 25 μl of cells and the changes in fluorescence were monitored for another 3 minutes. The results of this experiment are shown in Figure 2 The concentration of test compound that blocks half of the response when only the bitter compound is present is expressed as the EC50 or IC50 value.

[0618] In the above examples, the EC50 of the compound for blocking bitter taste induced by T2R54 was measured in the same manner.

Claims

1. A compound of formula (I) or a salt thereof: in: X 1 and X 2 each independently is an oxygen atom; X 3 is a direct bond or >CH2; X 4 is>CH2; R A -CN, nitro, -OH, -NH2, -C(O)H, -OC(O)H, -C(O)-OH, -NH-C(O)H, -C(O)-NH2, -O-(C 1-6 Alkyl), -NH-(C 1-6 Alkyl), -N(C 1-6 alkyl)2,-C(O)-(C 1-6 alkyl), -OC(O)-(C 1-6 alkyl), -NH-C(O)-(C 1-6 Alkyl), -N(C 1-6 alkyl)-C(O)-(C 1-6 alkyl), -C(O)-O-(C 1-6 alkyl), -C(O)-NH-(C 1-6 alkyl), -C(O)-N(C 1-6 alkyl)2,-S(O)2-(C 1-6 alkyl), -OS(O)2-(C 1-6 Alkyl), -NH-S(O)2-(C 1-6 Alkyl), -N(C 1-6 alkyl)-S(O)2-(C 1-6 alkyl), -S(O)2-O-(C 1-6 alkyl), -S(O)2-NH-(C 1-6 alkyl), -S(O)2-N(C 1-6 Alkyl)2,C 3-10 Cycloalkyl, C 2-14 Heterocyclyl, C 6-14 Aryl, C 2-14 Heteroaryl, C 1-6 Alkyl, C 2-6 Alkenyl, C 1-6 Haloalkyl, C 2-6 Halogenated alkenyl, C 1-6 Haloalkoxy, C 2-6 Halogenated alkenyloxy, or (C 1-6 Alkoxy)-C 1-6 alkyl; R 1 Yes-C(O)-R 1A ; R 1A It is C 1-6 Alkyl, wherein the alkyl group is optionally independently selected from R 1Y Substituents are substituted one or more times; R 1Y is a halogen atom, oxo, -CN, nitro, -OH, -NH2, -C(O)H, -OC(O)H, -C(O)-OH, -NH-C(O)H, -C(O)-NH2, -O-(C 1-6 Alkyl), -NH-(C 1-6 Alkyl), -N(C 1-6 alkyl)2,-C(O)-(C 1-6 alkyl), -OC(O)-(C 1-6 alkyl), -NH-C(O)-(C 1-6 alkyl), -C(O)-O-(C 1-6 alkyl), -C(O)-NH-(C 1-6 alkyl), -C(O)-N(C 1-6 alkyl)2,-S(O)2-(C 1-6 alkyl), -OS(O)2-(C 1-6 Alkyl), -NH-S(O)2-(C 1-6 alkyl), -S(O)2-O-(C 1-6 alkyl), -S(O)2-NH-(C 1-6 alkyl), -S(O)2-N(C 1-6 Alkyl)2,C 3-10 Cycloalkyl, C 2-14 Heterocyclyl, C 6-14 Aryl, C 2-14 Heteroaryl, C 1-6 Alkyl, C 2-6 Alkenyl, C 1-6 Haloalkyl, C 2-6 Halogenated alkenyl, C 1-6 Haloalkoxy, C 2-6 Halogenated alkenyloxy, or (C 1-6 Alkoxy)-C 1-6 alkyl; R 2 yes X 5 Yes>NR 2G ; X 6 It is C 1-6 Alkylene, which may be independently selected from R 1Y Substituents are substituted one or more times; X 7 Yes>NR 2L ; X 8 , X 9 , X 10 and X 11 Each independently is>C(R 2M )(R 2N ); R 2M and R 2N are each independently a hydrogen atom, a halogen atom, -CN, a nitro group, -OH, -NH2, -C(O)H, -OC(O)H, -C(O)-OH, -NH-C(O)H, -C(O)-NH2, -O-(C 1-6 Alkyl), -NH-(C 1-6 Alkyl), -N(C 1-6 alkyl)2,-C(O)-(C 1-6 alkyl), -OC(O)-(C 1-6 alkyl), -NH-C(O)-(C 1-6 alkyl), -NH-C(O)-O-(C 1-6 alkyl), -C(O)-O-(C 1-6 alkyl), -C(O)-NH-(C 1-6 alkyl), -C(O)-N(C 1-6 alkyl)2,-S(O)2-(C 1-6 alkyl), -OS(O)2-(C 1-6 Alkyl), -NH-S(O)2-(C 1-6 alkyl), -S(O)2-O-(C 1-6 alkyl), -S(O)2-NH-(C 1-6 alkyl), -S(O)2-N(C 1-6 Alkyl)2,C 3-10 Cycloalkyl, C 2-14 Heterocyclyl, C 6-14 Aryl, C 2-14 Heteroaryl, C 1-6 Alkyl, C 2-6 Alkenyl, C 1-6 Haloalkyl, C 2-6 Halogenated alkenyl, C 1-6 Haloalkoxy, C 2-6 Halogenated alkenyloxy, or (C 1-6 Alkoxy)-C 1-6 Alkyl; or, R 2M and R 2N optionally combined to form an oxo group; or, with R 2 The R atoms of the adjacent carbon atoms of the piperazine ring are defined as 2M and R 2N Any two of which are optionally combined to form a fused ring selected from phenyl, C 2-5 Heteroaryl, C 4-8 Cycloalkyl and C 2-5 Heterocyclyl, wherein each fused ring is optionally independently selected from R 1Z Substituents are substituted one or more times; R 1Z is a halogen atom, oxo, -CN, nitro, -OH, -NH2, -C(O)H, -OC(O)H, -C(O)-OH, -NH-C(O)H, -C(O)-NH2, -O-(C 1-6 Alkyl), -NH-(C 1-6 Alkyl), -N(C 1-6 alkyl)2,-C(O)-(C 1-6 alkyl), -OC(O)-(C 1-6 alkyl), -NH-C(O)-(C 1-6 alkyl), -C(O)-O-(C 1-6 alkyl), -C(O)-NH-(C 1-6 alkyl), -C(O)-N(C 1-6 alkyl)2,-S(O)2-(C 1-6 alkyl), -OS(O)2-(C 1-6 Alkyl), -NH-S(O)2-(C 1-6 alkyl), -S(O)2-O-(C 1-6 alkyl), -S(O)2-NH-(C 1-6 alkyl), -S(O)2-N(C 1-6 Alkyl)2,C 3-10 Cycloalkyl, C 2-14 Heterocyclyl, C 6-14 Aryl, C 2-14 Heteroaryl, C 1-6 Alkyl, C 2-6 Alkenyl, C 1-6 Haloalkyl, C 2-6 Halogenated alkenyl, C 1-6 Haloalkoxy, C 2-6 Halogenated alkenyloxy, (C 1-6 Alkoxy)-C 1-6 Alkyl, C 1-6 Alkyl, or C 2-6 alkenyl; R 2G is a hydrogen atom, C 1-6 Alkyl, C 1-6 haloalkyl, or (C 1-6 Alkoxy)-C 1-6 alkyl; R 2L Yes-C(O)-R 3 or -C(O)-X 14 -R 4 ; X 14 It is C 1-8 Alkylene, which may be independently selected from R 1Y Substituents are substituted one or more times; R 3 is a hydrogen atom, -OH, -NH2, -OR 3B , -NH-R 3B , -N(R 3B )(R 3C ), -OC(O)-R 3B , -NH-C(O)-R 3B , -N(R 3C )-C(O)-R 3B , C 3-10 Carbocyclic group, C 2-14 Heterocyclyl, C 6-14 Aryl, or C 2-14 heteroaryl, wherein carbocyclyl, heterocyclyl, aryl and heteroaryl are each optionally independently selected from R 3A Substituents are substituted one or more times, wherein any two R connected to adjacent carbon atoms of the carbocyclic, heterocyclic, aryl and heteroaryl groups to which they are connected 3A optionally combined to form a fused ring selected from phenyl, C 2-5 Heteroaryl, C 4-8 Cycloalkyl and C 2-5 Heterocyclyl, wherein each fused ring is optionally independently selected from R 1Z The substituents are substituted one or more times, and when R 3B and R 3C When attached to the same nitrogen atom, R 3B and R 3C optionally combined with the nitrogen atom to which they are attached to form a nitrogen-containing C 2-6 Heterocyclic ring, which is optionally C 1-4 Alkyl substitution; R 3A Halogen atoms, -CN, nitro, oxo, -OH, -NH2, -C(O)H, -OC(O)H, -C(O)-OH, -NH-C(O)H, -C(O)-NH2, -OR 3D , -NH-R 3D , -N(R 3D )(R 3E ), -C(O)-R 3D ,-OC(O)-R 3D , -NH-C(O)-R 3D , -C(O)-OR 3D , -C(O)-NH-R 3D ,-C(O)-N(R 3D )(R 3E ), -S(O)2-R 3D ,-OS(O)2-R 3D , -NH-S(O)2-R 3D , -S(O)2-OR 3D ,-S(O)2-NH-R 3D ,-S(O)2-N(R 3D )(R 3E ), C 1-8 Alkyl, C 2-8 Alkenyl, C 3-10 Carbocyclic group, C 2-14 Heterocyclyl, C 6-14 Aryl, or C 2-14 heteroaryl, wherein the alkyl and alkenyl are each optionally independently selected from R 3Y substituted one or more times by substituents, and wherein the carbocyclyl, heterocyclyl, aryl and heteroaryl are each optionally independently selected from R 3Z Substituents are substituted one or more times; R 3B , R 3C , R 3D and R 3E Each independently is C 1-8 Alkyl, C 2-8 Alkenyl, C 3-10 Carbocyclic group, C 2-14 Heterocyclyl, C 6-14 Aryl, or C 2-14 heteroaryl, wherein the alkyl and alkenyl are each optionally independently selected from R 3Y substituted one or more times by substituents, and wherein the carbocyclyl, heterocyclyl, aryl and heteroaryl are each optionally independently selected from R 3Z Substituents are substituted one or more times; R 3Y is a halogen atom, -CN, nitro, oxo, -OH, -NH2, -C(O)H, -OC(O)H, -C(O)-OH, -NH-C(O)H, -C(O)-NH2, -O-(C 1-6 Alkyl), -NH-(C 1-6 Alkyl), -N(C 1-6 alkyl)2,-C(O)-(C 1-6 alkyl), -OC(O)-(C 1-6 alkyl), -NH-C(O)-(C 1-6 Alkyl), -N(C 1-6 alkyl)-C(O)-(C 1-6 alkyl), -C(O)-O-(C 1-6 alkyl), -C(O)-NH-(C 1-6 alkyl), -C(O)-N(C 1-6 alkyl)2,-S(O)2-(C 1-6 alkyl), -OS(O)2-(C 1-6 Alkyl), -NH-S(O)2-(C 1-6 Alkyl), -N(C 1-6 alkyl)-S(O)2-(C 1-6 alkyl), -S(O)2-O-(C 1-6 alkyl), -S(O)2-NH-(C 1-6 alkyl), -S(O)2-N(C 1-6 Alkyl)2,-O-(C 1-6 Alkylene)-O-(C 1-6 Alkyl), C 3-10 Cycloalkyl, C 2-14 Heterocyclyl, C 6-14 Aryl, or C 2-14 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally independently selected from R 1Z Substituents are substituted one or more times; R 3Z is a halogen atom, -CN, nitro, oxo, -OH, -NH2, -C(O)H, -OC(O)H, -C(O)-OH, -NH-C(O)H, -C(O)-NH2, -O-(C 1-6 Alkyl), -NH-(C 1-6 Alkyl), -N(C 1-6 alkyl)2,-C(O)-(C 1-6 alkyl), -OC(O)-(C 1-6 alkyl), -NH-C(O)-(C 1-6 Alkyl), -N(C 1-6 alkyl)-C(O)-(C 1-6 alkyl), -C(O)-O-(C 1-6 alkyl), -C(O)-NH-(C 1-6 alkyl), -C(O)-N(C 1-6 alkyl)2,-S(O)2-(C 1-6 alkyl), -OS(O)2-(C 1-6 Alkyl), -NH-S(O)2-(C 1-6 Alkyl), -N(C 1-6 alkyl)-S(O)2-(C 1-6 alkyl), -S(O)2-O-(C 1-6 alkyl), -S(O)2-NH-(C 1-6 alkyl), -S(O)2-N(C 1-6 Alkyl)2,C 1-6 Alkyl, C 2-6 Alkenyl, C 1-6 Haloalkyl, C 2-6 Halogenated alkenyl, C 1-6 Haloalkoxy, C 2-6 Halogenated alkenyloxy, (C 1-6 Alkoxy)-C 1-6 Alkyl, C 3-10 Cycloalkyl, C 2-14 Heterocyclyl, C 6-14 Aryl, or C 2-14 Heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally independently selected from R 1Z Substituents are substituted one or more times; R 4 It is a hydrogen atom, a halogen atom, -CN, a nitro group, an oxo group, -OH, -NH2, -OR 4B , -NH-R 4B , -N(R 4B )(R 4C ), C(O)-R 4B ,-OC(O)-R 4B , -NH-C(O)-R 4B , -N(R 4C )-C(O)-R 4B , -C(O)-OR 4B , -C(O)-NH-R 4B ,-C(O)N(R 4B )(R 4C ), -S(O)2-R 4D ,-OS(O)2-R 4D , -NH-S(O)2-R 4D , -S(O)2-OR 4D ,-S(O)2-NH-R 4D ,-S(O)2-N(R 4D )(R 4E ), C 3-10 Carbocyclic group, C 2-14 Heterocyclyl, C 6-14 Aryl, or C 2-14 heteroaryl, wherein the carbocyclyl, heterocyclyl, aryl and heteroaryl are each optionally independently selected from R 4A Substituents are substituted one or more times, wherein any two R connected to adjacent carbon atoms of the carbocyclic, heterocyclic, aryl and heteroaryl groups to which they are connected 4A optionally combined to form a fused ring selected from phenyl, C 2-5 Heteroaryl, C 4-8 Cycloalkyl or C 2-5 Heterocyclyl, wherein each fused ring is optionally independently selected from R 1Z The substituents are substituted one or more times, and when R 4B and R 4C When attached to the same nitrogen atom, R 4B and R 4C optionally combined with the nitrogen atom to which they are attached to form a nitrogen-containing C 2-6 Heterocyclic ring, which is optionally C 1-4 Alkyl substitution; R 4A Halogen atoms, -CN, nitro, oxo, -OH, -NH2, -C(O)H, -OC(O)H, -C(O)-OH, -NH-C(O)H, -C(O)-NH2, -OR 4D , -NH-R 4D , -N(R 4D )(R 4E ), -C(O)-R 4D ,-OC(O)-R 4D , -NH-C(O)-R 4D , -N(R 4E )-C(O)-R 4D , -C(O)-OR 4D , -C(O)-NH-R 4D ,-C(O)-N(R 4D )(R 4E ), C 1-8 Alkyl, C 2-8 Alkenyl, C 3-10 Carbocyclic group, C 2-14 Heterocyclyl, C 6-14 Aryl, or C 2-14 heteroaryl, wherein the alkyl and alkenyl are each optionally independently selected from R 4Y substituted one or more times by substituents, and wherein the carbocyclyl, heterocyclyl, aryl and heteroaryl are each optionally independently selected from R 4Z Substituents are substituted one or more times; R 4B , R 4C , R 4D and R 4E Each independently is C 1-8 Alkyl, C 2-8 Alkenyl, C 3-10 Carbocyclic group, C 2-14 Heterocyclyl, C 6-14 Aryl, or C 2-14 Heteroaryl, wherein the alkyl and alkenyl are each optionally independently selected from R 4Y wherein the carbocyclyl, heterocyclyl, aryl and heteroaryl are each independently selected from R 4Z Substituents are substituted one or more times; R 4Y is a halogen atom, -CN, nitro, oxo, -OH, -NH2, -C(O)H, -OC(O)H, -C(O)-OH, -NH-C(O)H, -C(O)-NH2, -O-(C 1-6 Alkyl), -NH-(C 1-6 Alkyl), -N(C 1-6 alkyl)2,-C(O)-(C 1-6 alkyl), -OC(O)-(C 1-6 alkyl), -NH-C(O)-(C 1-6 Alkyl), -N(C 1-6 alkyl)-C(O)-(C 1-6 alkyl), -C(O)-O-(C 1-6 alkyl), -C(O)-NH-(C 1-6 alkyl), -C(O)-N(C 1-6 alkyl)2,-S(O)2-(C 1-6 alkyl), -OS(O)2-(C 1-6 Alkyl), -NH-S(O)2-(C 1-6 Alkyl), -N(C 1-6 alkyl)-S(O)2-(C 1-6 alkyl), -S(O)2-O-(C 1-6 alkyl), -S(O)2-NH-(C 1-6 alkyl), -S(O)2-N(C 1-6 Alkyl)2,-O-(C 1-6 Alkylene)-O-(C 1-6 Alkyl), C 3-10 Cycloalkyl, C 2-14 Heterocyclyl, C 6-14 Aryl, or C 2-14 Heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally independently selected from R 1Z Substituents are substituted one or more times; R 4Z is a halogen atom, -CN, nitro, oxo, -OH, -NH2, -C(O)H, -OC(O)H, -C(O)-OH, -NH-C(O)H, -C(O)-NH2, -O-(C 1-6 Alkyl), -NH-(C 1-6 Alkyl), -N(C 1-6 alkyl)2,-C(O)-(C 1-6 alkyl), -OC(O)-(C 1-6 alkyl), -NH-C(O)-(C 1-6 Alkyl), -N(C 1-6 alkyl)-C(O)-(C 1-6 alkyl), -C(O)-O-(C 1-6 alkyl), -C(O)-NH-(C 1-6 alkyl), -C(O)-N(C 1-6 alkyl)2,-S(O)2-(C 1-6 alkyl), -OS(O)2-(C 1-6 Alkyl), -NH-S(O)2-(C 1-6 Alkyl), -N(C 1-6 alkyl)-S(O)2-(C 1-6 alkyl), -S(O)2-O-(C 1-6 alkyl), -S(O)2-NH-(C 1-6 alkyl), -S(O)2-N(C 1-6 Alkyl)2, (C 1-6 Alkoxy)-C 1-6 Alkyl, C 3-10 Cycloalkyl, C 2-14 Heterocyclyl, C 6-14 Aryl, or C 2-14 Heteroaryl, C 1-6 Alkyl, C 2-6 Alkenyl, C 1-6 Haloalkyl, C 2-6 Halogenated alkenyl, C 1-6 Haloalkoxy, or C 2-6 haloalkenyloxy, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally independently selected from R 1Z substituted one or more times by a substituent; and n is 0, 1 or 2.

2. The compound according to claim 1, wherein X 3 is>CH2.

3. The compound according to claim 1, wherein n is 0.

4. The compound according to claim 1, wherein R 1A It is methyl or ethyl.

5. The compound according to claim 1, wherein R 2G It is a hydrogen atom, a methyl group or an ethyl group.

6. The compound according to claim 1, wherein X 6 It is -CH2-, -CH2-CH2-, -CH(CH3)-, or -C(CH3)2-.

7. The compound according to claim 1, wherein X 8 , X 9 , X 10 and X 11 All are >CH2.

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