Anesthetic compounds and methods of making and using same to treat or prevent pain conditions - Patents.com

Abstract

The present disclosure relates to compounds of general formula (I): TIFF2025512713000244.tif2271, wherein R1 is H, -OMe, Me, or one or more electron-withdrawing groups, R2 and R3 are each independently H or alkyl, or together form a 4-8 membered heterocycle with the adjacent nitrogen atom, R4 is H or alkyl, R5 is H or one or more electron-donating groups, and n is 1 to 4. The disclosure further provides compositions comprising a therapeutically effective amount of a compound of general formula (I), and methods of treating or preventing pain in a subject by administering such compositions to the subject [e.g., applying topically].

Description

[Technical field]

[0001] Priority claim This application claims priority to U.S. Provisional Patent Application No. 63 / 317,868, filed March 8, 2022, the entire contents of which are incorporated herein by reference.

[0002] Field The present disclosure provides compounds useful as anesthetic agents, methods for their preparation, compositions containing them, and methods of using them to treat or prevent pain. [Background technology]

[0003] background Anesthetic agents are commonly used to treat or prevent pain. However, certain classes of anesthetic agents encourage overuse, abuse, and / or overprescription. Other agents are potent but offer poor bioavailability, for example when administered topically.

[0004] There remains a need for improved anesthetic agents, particularly agents that are effective when applied topically to a subject's skin. Summary of the Invention [Means for solving the problem]

[0005] overview In one embodiment, the present disclosure provides a compound of formula (I): [ka] (In the formula, R1 is H, -OMe, Me, or one or more electron withdrawing groups; R2 and R3 are each independently H or alkyl, or taken together with the adjacent nitrogen atom form a 4- to 8-membered heterocycle; R4 is H or alkyl; R5 is H or one or more electron donating groups; and and n is 1 to 4.

[0006] In other embodiments, the present disclosure provides a compound of formula (II): [ka] (In the formula, EWG is one or more electron withdrawing groups selected from the group consisting of Cl, F, CF3, and OCF3; R2 and R3 are each independently H or alkyl; Alk is an aliphatic carbon group of 1 to 6 carbon atoms, and EDG is one or more alkoxy or alkyl electron donating groups).

[0007] In other embodiments, the present disclosure provides a compound of formula (III): [ka] (In the formula, EWG is one or more electron withdrawing groups selected from the group consisting of Cl, F, CF3, and OCF3; R8 is -NH2, -N(H)Alk, -N(Alk)2, [ka] is selected from the group consisting of R7 is H or alkyl; m is 3 to 6; p is 1 to 4; q is 1 to 4; p+q is 3 to 6; each Alk is independently an aliphatic carbon group of 1 to 6 carbon atoms; and EDG is one or more alkoxy or alkyl electron donating groups).

[0008] In other embodiments, the present disclosure provides a compound of formula (IV): [ka] (In the formula, R1 is H, Cl, F, -CF3, -OCF3, or -OMe; R8 is, -NH2, -N(H)Alk, -N(Alk)2, [ka] is selected from the group consisting of R7 is H or alkyl; m is 3 to 6; p is 1 to 4; q is 1 to 4; p+q is 3 to 6; each Alk is independently an aliphatic carbon group of 1 to 6 carbon atoms; and EDG provides one or more amino, aryl, acylamide, acyloxy, alkoxy or alkyl electron donating groups.

[0009] In other embodiments, the present disclosure provides a compound of formula (V): [ka] (In the formula, R1 is H, Cl, F, -CF3, -OCF3, or -OMe; R8 is, -NH2, -N(H)Alk, -N(Alk)2, [ka] is selected from the group consisting of R7 is H or alkyl; m is 3 to 6; p is 1 to 4; q is 1 to 4; p+q is 3 to 6, and Each Alk is independently an aliphatic carbon group of 1 to 6 carbon atoms.

[0010] In other embodiments, the present disclosure provides a compound of formula (VI): [ka] (In the formula, R1 is H, Cl, F, -CF3, -OCF3, -OMe or methyl; R8 is, -NH2, -N(H)Alk, -N(Alk)2, [ka] is selected from the group consisting of R7 is H or alkyl; m is 3 to 6; p is 1 to 4; q is 1 to 4; p+q is 3 to 6, and Each Alk is independently an aliphatic carbon group of 1 to 6 carbon atoms.

[0011] In other embodiments, the present disclosure provides a compound of formula (VII): [ka] (In the formula, R 1a is H, Cl, F, -CF3, -OMe or methyl, R 1b is H, Cl, F, -CF3 or -OCF3, R 1c is H, Cl, F or -OMe, R 1d is H, Cl, F, -CF3 or -OCF3, R 1e is H, Cl, F, -CF3, -OMe or methyl, R2 and R3 are each independently H or alkyl, or taken together with the adjacent nitrogen atom form a 4- to 8-membered heterocycle; R4 is H or alkyl, and R5 is H or one or more electron donating groups.

[0012] In other embodiments, the present disclosure provides a compound of formula (VIIIa): [ka] (In the formula, R2=H or Me; R3=H or Me; R4=alkyl, R5=O-alkyl, and alkyl = aliphatic C1-C4 alkyl).

[0013] In other embodiments, the present disclosure provides a compound of formula (VIIIb): [ka] (In the formula, R2=H or Me; R3=H or Me; R4=alkyl, R5=O-alkyl, and alkyl = aliphatic C1-C4 alkyl).

[0014] In other embodiments, the present disclosure provides a compound of formula (VIIIc): [ka] (In the formula, R2=H or Me; R3=H or Me; R4=alkyl, R5=O-alkyl, and alkyl = aliphatic C1-C4 alkyl).

[0015] In other embodiments, the present disclosure provides a compound of formula (VIIId): [ka] (In the formula, R2=H or Me; R3=H or Me; R4=alkyl, R5=O-alkyl, and alkyl = aliphatic C1-C4 alkyl).

[0016] In other embodiments, the present disclosure provides a compound of formula (VIIIe): [ka] (In the formula, R2=H or Me; R3=H or Me; R4=alkyl, R5=O-alkyl, and alkyl = aliphatic C1-C4 alkyl).

[0017] In other embodiments, the present disclosure provides a compound of formula (VIIIf): [ka] (In the formula, R2=H or Me; R3=H or Me; R4=alkyl, R5=O-alkyl, and alkyl = aliphatic C1-C4 alkyl).

[0018] In other embodiments, the present disclosure provides a compound of formula (VIIIg): [ka] (In the formula, R2=H or Me; R3=H or Me; R4=alkyl, R5=O-alkyl, and alkyl = aliphatic C1-C4 alkyl).

[0019] In other embodiments, the present disclosure provides a compound of formula (VIIIh): [ka] (In the formula, R2=H or Me; R3=H or Me; R4=alkyl, R5=O-alkyl, and alkyl = aliphatic C1-C4 alkyl).

[0020] In other embodiments, the present disclosure provides a compound of formula (VIIIi): [ka] (In the formula, R2=H or Me; R3=H or Me; R4=alkyl, R5=O-alkyl, and alkyl = aliphatic C1-C4 alkyl).

[0021] In other embodiments, the present disclosure provides a compound of formula (VIIIj): [ka] (In the formula, R2=H or Me; R3=H or Me; R4=alkyl, R5=O-alkyl, and alkyl = aliphatic C1-C4 alkyl).

[0022] In other embodiments, the present disclosure provides a compound of formula (VIIIk): [ka] (In the formula, R2=H or Me; R3=H or Me; R4=alkyl, R5=O-alkyl, and alkyl = aliphatic C1-C4 alkyl).

[0023] In other embodiments, the present disclosure provides a compound of formula (VIIIm): [ka] (In the formula, R2=H or Me; R3=H or Me; R4=alkyl, R5=O-alkyl, and alkyl = aliphatic C1-C4 alkyl).

[0024] In other embodiments, the present disclosure provides a compound of formula (VIIIn): [ka] (In the formula, A=C or N, R4=alkyl, R5=O-alkyl; If A=C, then R 10 =R 11 If A=H, or A=N, then R 10 = alkyl and R 11 = null, and alkyl = aliphatic C1-C4 alkyl).

[0025] In other embodiments, the present disclosure provides a compound of formula (IX): [ka] (In the formula, R1 = H, m-chloro, 3,4-dichloro, o-methoxy, p-methoxy, o-methyl, m-trifluoromethoxy, m-trifluoromethyl, p-chloro, 2,5-dichloro, 3-chloro-4-fluoro, 2-fluoro-3-chloro, or o-trifluoromethyl).

[0026] In other embodiments, the present disclosure provides a compound of formula (X): [ka] (In the formula, R1 = H, m-chloro, 3,4-dichloro, o-methoxy, p-methoxy, o-methyl, m-trifluoromethoxy, m-trifluoromethyl, p-chloro, 2,5-dichloro, 3-chloro-4-fluoro, 2-fluoro-3-chloro, or o-trifluoromethyl).

[0027] In other embodiments, the present disclosure provides a compound of formula (XI): [ka] (In the formula, R1 = H, m-chloro, 3,4-dichloro, o-methoxy, p-methoxy, o-methyl, m-trifluoromethoxy, m-trifluoromethyl, p-chloro, 2,5-dichloro, 3-chloro-4-fluoro, 2-fluoro-3-chloro, or o-trifluoromethyl).

[0028] In other embodiments, the present disclosure provides a compound of formula (XII): [ka] (In the formula, R1 = H, m-chloro, 3,4-dichloro, o-methoxy, p-methoxy, o-methyl, m-trifluoromethoxy, m-trifluoromethyl, p-chloro, 2,5-dichloro, 3-chloro-4-fluoro, 2-fluoro-3-chloro, or o-trifluoromethyl).

[0029] In other embodiments, the present disclosure provides a compound of formula (XIII): (XIII) (In the formula, R8 = NH2, NH(Me), N(Me)2, [ka] ) is provided.

[0030] In other embodiments, the present disclosure provides a compound of formula (XIII): (XIII) (In the formula, R8 = NH2, NH(Me), N(Me)2, [ka] ) is provided.

[0031] In other embodiments, the present disclosure provides a compound of formula (XIII): [ka] (In the formula, R8 = NH2, NH(Me), N(Me)2, [ka] ) is provided.

[0032] In other embodiments, the present disclosure provides a compound of formula (XIV): [ka] (In the formula, R8 = NH2, NH(Me), N(Me)2, [ka] ) is provided.

[0033] In other embodiments, the present disclosure provides a compound of formula (XV): [ka] (In the formula, R8 = NH2, NH(Me), N(Me)2, [ka] ) is provided.

[0034] In other embodiments, the present disclosure provides a compound of formula (XVI): [ka] (In the formula, R8 = NH2, NH(Me), N(Me)2, [ka] ) is provided.

[0035] In other embodiments, the present disclosure provides a compound of formula (XVII): [ka] (In the formula, R8 = NH2, NH(Me), N(Me)2, [ka] ) is provided.

[0036] In other embodiments, the present disclosure provides a compound of formula (XVIII): [ka] (In the formula, R8 = NH2, NH(Me), N(Me)2, [ka] ) is provided.

[0037] In other embodiments, the present disclosure provides a compound of formula (XIX): [ka] (In the formula, R8 = NH2, NH(Me), N(Me)2, [ka] ) is provided.

[0038] In other embodiments, the present disclosure provides a compound of formula (XX): [ka] (In the formula, R8 = NH2, NH(Me), N(Me)2, [ka] ) is provided.

[0039] In other embodiments, the present disclosure provides a compound of formula (XXI): [ka] (In the formula, R8 = NH2, NH(Me), N(Me)2, [ka] ) is provided.

[0040] In other embodiments, the present disclosure provides a compound of formula (XXII): [ka] (In the formula, R8 = NH2, NH(Me), N(Me)2, [ka] ) is provided.

[0041] In other embodiments, the present disclosure provides a compound of formula (XXIII): [ka] (In the formula, R8 = NH2, NH(Me), N(Me)2, [ka] ) is provided.

[0042] In other embodiments, the present disclosure provides a compound of formula (XXIV): [ka] (In the formula, R8 = NH2, NH(Me), N(Me)2, [ka] ) is provided.

[0043] In other embodiments, the disclosure provides a composition comprising a compound of any one of formulas (I)-(XXIV).

[0044] In other embodiments, the disclosure provides a method of treating or preventing pain in a subject, comprising topically applying a composition comprising a compound of any one of Formulas (I)-(XXIV) to the subject's skin proximal to the perceived or anticipated pain. [Brief description of the drawings]

[0045] [Figure 1] FIG. 1 shows a representative synthetic route for preparing compounds of formula (I).

[0046] [Diagram 2] FIG. 2 shows a representative synthetic route for preparing compounds of formula (II).

[0047] [Diagram 3] FIG. 3 shows a representative synthetic route for preparing compounds of formula (III).

[0048] [Figure 4] FIG. 4 shows a representative synthetic route for preparing compounds of formula (IV).

[0049] [Diagram 5] FIG. 5 shows a representative synthetic route for preparing compounds of formula (V).

[0050] [Figure 6] FIG. 6 shows a representative synthetic route for preparing compounds of formula (VI).

[0051] [Figure 7] FIG. 7 shows a representative synthetic route for preparing compounds of formula (VII).

[0052] [Figure 8] FIG. 8 shows a representative synthetic route for preparing compounds of formula (VIIIa).

[0053] [Figure 9] FIG. 9 shows a representative synthetic route for preparing compounds of formula (VIIIb).

[0054] [Figure 10] FIG. 10 shows a representative synthetic route for preparing compounds of formula (VIIIc).

[0055] [Figure 11] FIG. 11 shows a representative synthetic route for preparing compounds of formula (VIIId).

[0056] [Figure 12] FIG. 12 shows a representative synthetic route for preparing compounds of formula (VIIIe).

[0057] [Figure 13] FIG. 13 shows a representative synthetic route for preparing compounds of formula (VIIIf).

[0058] [Figure 14] FIG. 14 shows a representative synthetic route for preparing compounds of formula (VIIIg).

[0059] [Figure 15] FIG. 15 shows a representative synthetic route for preparing compounds of formula (VIIIh).

[0060] [Figure 16] FIG. 16 shows a representative synthetic route for preparing compounds of formula (VIIIi).

[0061] [Figure 17] FIG. 17 shows a representative synthetic route for preparing compounds of formula (VIIIj).

[0062] [Figure 18] FIG. 18 shows a representative synthetic route for preparing compounds of formula (VIIIk).

[0063] [Figure 19] FIG. 19 shows a representative synthetic route for preparing compounds of formula (VIIIm).

[0064] [Figure 20] FIG. 20 shows a representative synthetic route for preparing compounds of formula (VIIIn).

[0065] [Figure 21] FIG. 21 shows a representative synthetic route for preparing compounds of formula (IX).

[0066] [Figure 22] FIG. 22 shows a representative synthetic route for preparing compounds of formula (X).

[0067] [Figure 23] FIG. 23 shows a representative synthetic route for preparing compounds of formula (XI).

[0068] [Figure 24] FIG. 24 shows a representative synthetic route for preparing compounds of formula (XII).

[0069] [Diagram 25] FIG. 25 shows a representative synthetic route for preparing compounds of formula (XIII).

[0070] [Figure 26] FIG. 26 shows a representative synthetic route for preparing compounds of formula (XIV).

[0071] [Figure 27] FIG. 27 shows a representative synthetic route for preparing compounds of formula (XV).

[0072] [Figure 28] FIG. 28 shows a representative synthetic route for preparing compounds of formula (XVI).

[0073] [Figure 29] FIG. 29 shows a representative synthetic route for preparing compounds of formula (XVII).

[0074] [Diagram 30] FIG. 30 shows a representative synthetic route for preparing compounds of formula (XVIII).

[0075] [Diagram 31] FIG. 31 shows a representative synthetic route for preparing compounds of formula (XIX).

[0076] [Diagram 32] FIG. 32 shows a representative synthetic route for preparing compounds of formula (XX).

[0077] [Diagram 33] FIG. 33 shows a representative synthetic route for preparing compounds of formula (XXI).

[0078] [Diagram 34] FIG. 34 shows a representative synthetic route for preparing compounds of formula (XXII).

[0079] [Diagram 35] FIG. 35 shows a representative synthetic route for preparing compounds of formula (XXIII).

[0080] [Diagram 36] FIG. 36 shows a representative synthetic route for preparing compounds of formula (XXIV). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0081] Detailed Description The present disclosure provides compounds useful as anesthetics, e.g., for treating or preventing pain when applied topically to the skin of a subject, and methods of making such compounds and using such compounds to treat or prevent pain.

[0082] 1. Anesthetic Compounds The present disclosure relates to a compound of formula (I): [ka] (In the formula, R1 is H, alkyl, alkoxy, or one or more electron withdrawing groups; R2 and R3 are each independently H or alkyl, or taken together with the adjacent nitrogen atom form a 4- to 8-membered heterocycle; R4 is H or alkyl; R5 is H or one or more electron donating groups; and and n is 1 to 4.

[0083] The present disclosure also provides salts of compounds of formula (I), which may be prepared, for example, by contacting a neutral compound of formula (I) with an acid (e.g., hydrochloric acid) to form a salt (e.g., hydrochloride) of the compound of formula (I). Suitable salts of compounds of formula (I) are salts of mineral or organic acids. Suitable mineral acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid or sulfuric acid. Suitable organic acids are, for example, organic achiral acids such as acetic acid, trifluoroacetic acid, oxalic acid or p-toluenesulfonic acid, or organic chiral acids such as L-tartaric acid, dibenzoyl-L-tartaric acid or di-p-toluoyl-L-tartaric acid.

[0084] The present disclosure also provides hydrates of compounds of formula (I).

[0085] In some embodiments, R1 is selected from the group consisting of H, alkyl, alkoxy, and electron withdrawing groups. In some embodiments, only one R1 group is present and may be at the ortho, meta, or para position of the aryl ring. In other embodiments, there are 2-5 R1 groups, each R1 group is independently selected from the group consisting of H, alkyl, alkoxy, and electron withdrawing groups, and each R1 group is located at any combination of the ortho, meta, and para positions of the aryl ring. For example, without limitation, there may be two R1 groups in a compound of formula (I) consistent with the present disclosure, each R1 group is independently selected from the group consisting of H, alkyl, alkoxy, and electron withdrawing groups. In other embodiments, there are three R1 groups, each R1 group is independently selected from the group consisting of H, alkyl, alkoxy, and electron withdrawing groups. In yet other embodiments, there are four R1 groups. In other embodiments, there are five R1 groups, each R1 group is independently selected from the group consisting of H, alkyl, alkoxy, and electron withdrawing groups.

[0086] When R1 is alkyl, the alkyl group may be linear or branched and may consist of 1 to 6 carbon atoms (i.e., C 1-6 The alkyl group may be cyclic, in which case the alkyl group may consist of 3 to 6 carbon atoms (i.e., C 3-6 Cycloalkyl). Alkyl groups can be saturated or unsaturated with one or more carbon-carbon double bonds and / or carbon-carbon triple bonds.

[0087] When R1 is alkoxy, the alkoxy group may be linear or branched and may consist of 1 to 6 carbon atoms (i.e., C 1-6 The alkoxy group may be cyclic, in which case the alkoxy group may consist of 3 to 6 carbon atoms (i.e., C 3-6 Alkoxy groups may be saturated or unsaturated with one or more carbon-carbon double bonds and / or carbon-carbon triple bonds.

[0088] When R1 is an electron-withdrawing group, the electron-withdrawing group may be a halogen, a halogenated alkyl group, or a halogenated alkoxy group. For example, but not limited to, the electron-withdrawing group may be a halogen, a halogen-substituted alkyl, a halogen-substituted alkoxyl, a perhaloalkyl, or a perhaloalkoxyl. In some embodiments, each electron-withdrawing group may be fluoro, and is independently selected from chloro, bromide, iodide, halomethyl, dihalomethyl, trihalomethyl, halomethoxyl, dihalomethoxyl, and trihalomethoxyl. In some embodiments, each electron-withdrawing group is independently selected from the group consisting of fluoro, chloro, trifluoromethyl, and trifluoromethoxyl.

[0089] Each R2 and R3 is independently H or alkyl, or taken together with the adjacent nitrogen atom, forms a 4-8 membered heterocyclic ring. In some embodiments, R2 is H and R3 is alkyl. In some embodiments, both R2 and R3 are alkyl. When R2 and / or R3 are alkyl, the alkyl group may be linear or branched and may consist of 1 to 6 carbon atoms (i.e., C 1-6 The alkyl group may be cyclic, in which case the alkyl group may consist of 3 to 6 carbon atoms (i.e., C 3-6 Cycloalkyl). Alkyl groups can be saturated or unsaturated with one or more carbon-carbon double bonds and / or carbon-carbon triple bonds.

[0090] In some embodiments, R2 and R3 are covalently linked to adjacent nitrogen atoms to form a heterocyclic ring. The heterocyclic ring may contain 1-3 nitrogen atoms and a total of 4-8 atoms in the ring. The heterocyclic ring may be unsubstituted or substituted, for example, with alkyl or alkoxyl groups. For example, but not limited to, R2 and R3 may be covalently linked to form a piperidinyl ring containing a total of 5 carbon atoms and including the nitrogen atom adjacent to R2 and R3. In other embodiments, R2 and R3 together are represented by the general formula: -(CH2) pN(R7)(CH2) q - (wherein p is 1 to 4, q is 1 to 4, the sum of p and q together is 3 to 8, and R7 is H or alkyl). When R7 is alkyl, the alkyl group may be linear or branched and may consist of 1 to 6 carbon atoms (i.e., C 1-6 The alkyl group may be cyclic, in which case the alkyl group may consist of 3 to 6 carbon atoms (i.e., C 3-6 Cycloalkyl). Alkyl groups can be saturated or unsaturated with one or more carbon-carbon double bonds and / or carbon-carbon triple bonds.

[0091] R4 is H or alkyl. When R4 is alkyl, the alkyl group may be linear or branched and may consist of 1 to 6 carbon atoms (i.e., C 1-6 The alkyl group may be cyclic, in which case the alkyl group may consist of 3 to 6 carbon atoms (i.e., C 3-6 Cycloalkyl). Alkyl groups can be saturated or unsaturated with one or more carbon-carbon double bonds and / or carbon-carbon triple bonds.

[0092] R5 is H or one or more electron donating groups. When R5 is one or more electron donating groups, R5 can be a single electron donating group at the ortho, meta or para positions of the aryl ring. In other embodiments, R5 can be 2 to 5 electron donating groups at any combination of the ortho, meta and para positions of the aryl ring. Each electron donating group can be independently selected from alkyl and alkoxyl. When R5 is alkyl, the alkyl group can be linear or branched and can consist of 1 to 6 carbon atoms (i.e., C 1-6 The alkyl group may be cyclic, in which case the alkyl group may consist of 3 to 6 carbon atoms (i.e., C 3-6Cycloalkyl). The alkyl group may be saturated or unsaturated with one or more carbon-carbon double bonds and / or carbon-carbon triple bonds. When R5 is alkoxyl, the alkoxy group may be linear or branched and may consist of 1 to 6 carbon atoms (i.e., C 1-6 The alkoxy group may be cyclic, in which case the alkoxy group may consist of 3 to 6 carbon atoms (i.e., C 3-6 Alkoxy groups may be saturated or unsaturated with one or more carbon-carbon double bonds and / or carbon-carbon triple bonds.

[0093] The number of methylene groups (n) in the compound of Formula (I) can be 1 to 4. In some embodiments, n is 1. In other embodiments, n is 2. In other embodiments, n is 3. In other embodiments, n is 4.

[0094] Some exemplary compounds of formula (I) are provided in Table 1 below. [Table 1]

[0095] Referring now to FIG. 1, compounds consistent with formula (I) include, for example, aniline 8. I with bromoacetyl bromide to give the α-bromoamide intermediate 9 I Intermediate 11 can be synthesized by forming I In the presence of base, aniline 10 I β-haloamine 12 I In the presence of a base, intermediate 11 can be formed by alkylation with I to the α-bromoamide intermediate 9 I to give a compound of formula (I).

[0096] The present disclosure also relates to a compound of formula (II): [ka] (In the formula, EWG is one or more electron withdrawing groups selected from the group consisting of Cl, F, alkyl halides and alkoxy halides; R2 and R3 are each independently H or alkyl; Alk is an aliphatic carbon group of 1 to 6 carbon atoms, and EDG is one or more alkoxy or alkyl electron donating groups).

[0097] In the compound of formula (II), EWG is one or more electron withdrawing groups each independently selected from the group consisting of Cl, F, alkyl halide, and alkoxy halide. For example, but not limited to, EWG can be a single electron withdrawing group located at the ortho, meta, or para position of the aryl ring in some embodiments. In other embodiments, EWG is two or more electron withdrawing groups located at any combination of the ortho, meta, and para positions of the aryl ring.

[0098] Each EWG may be independently selected from the group consisting of chloro, fluoro, halogenated alkyl, and halogenated alkoxyl. The halogenated alkyl may be monohaloalkyl, dihaloalkyl, trihaloalkyl, or perhaloalkyl and may have 1 to 6 carbon atoms (i.e., C 1-6 haloalkyl). The haloalkyl electron withdrawing group may be saturated or unsaturated. The alkyl halide may be branched, linear or cyclic. In some embodiments, the electron withdrawing group is trifluoromethyl. The alkoxy halide may be monohaloalkoxyl, dihaloalkoxyl, trihaloalkoxyl or perhaloalkoxyl and may have 1 to 6 carbon atoms (i.e., C 1-6 haloalkoxyl). The haloalkoxyl electron-withdrawing group may be saturated or unsaturated. The halogenated alkoxyl may be branched, linear or cyclic. In some embodiments, the electron-withdrawing group is trifluoromethoxyl.

[0099] Each R2 and R3 is independently H or alkyl. When R2 and / or R3 is alkyl, the alkyl group may be linear or branched and may consist of 1 to 6 carbon atoms (i.e., C 1-6 The alkyl group may be cyclic, in which case the alkyl group may consist of 3 to 6 carbon atoms (i.e., C 3-6 Cycloalkyl). Alkyl groups can be saturated or unsaturated with one or more carbon-carbon double bonds and / or carbon-carbon triple bonds.

[0100] Alk is an aliphatic carbon group consisting of 1 to 6 carbon atoms (i.e., C 1-6 Alk may be linear, branched, or cyclic. When Alk is cyclic, the alkyl group may consist of 3 to 6 carbon atoms (i.e., C 3-6 Cycloalkyl). Alkyl groups can be saturated or unsaturated with one or more carbon-carbon double bonds and / or carbon-carbon triple bonds.

[0101] EDG is one or more alkoxy or alkyl electron donating groups. EDG can be a single electron donating group in the ortho, meta or para positions of the aryl ring. In other embodiments, EDG can be 2 to 5 electron donating groups in any combination of the ortho, meta and para positions of the aryl ring. Each EDG can be independently selected from alkyl and alkoxyl. When EDG is alkyl, the alkyl group can be linear or branched and can consist of 1 to 6 carbon atoms (i.e., C 1-6 The alkyl group may be cyclic, in which case the alkyl group may consist of 3 to 6 carbon atoms (i.e., C 3-6Cycloalkyl). The alkyl group may be saturated or unsaturated with one or more carbon-carbon double bonds and / or carbon-carbon triple bonds. When EDG is an alkoxyl, the alkoxy group may be linear or branched and may consist of 1 to 6 carbon atoms (i.e., C 1-6 The alkoxy group may be cyclic, in which case the alkoxy group may consist of 3 to 6 carbon atoms (i.e., C 3-6 Alkoxy). The alkoxy group may be saturated or unsaturated with one or more carbon-carbon double bonds and / or carbon-carbon triple bonds. In some embodiments, EDG is para-alkoxy, such as para-methoxy, para-ethoxy, or para-propoxy.

[0102] Some exemplary compounds of formula (II) are provided in Table 2 below. [Table 2-1] [Table 2-2]

[0103] Referring now to FIG. 2, compounds consistent with formula (II) include, for example, alkylanilines 8 II with bromoacetyl bromide to give the α-bromoamide intermediate 9 II Intermediate 11 can be synthesized by forming II In the presence of base, aniline 10 II β-haloamine 12 II In the presence of a base, intermediate 11 can be formed by alkylation with II to the α-bromoamide intermediate 9 II to give a compound of formula (II).

[0104] The present disclosure also relates to a compound of formula (III): [ka] (In the formula, EWG is one or more electron withdrawing groups selected from the group consisting of Cl, F, CF3, and OCF3; R8 is -NH2, -N(H)Alk, -N(Alk)2, [ka] is selected from the group consisting of R7 is H or alkyl; m is 3 to 6; p is 1 to 4; q is 1 to 4; p+q is 3 to 6; each Alk is independently an aliphatic carbon group of 1 to 6 carbon atoms; and EDG is one or more alkoxy or alkyl electron donating groups).

[0105] In the compound of formula (III), EWG is one or more electron-withdrawing groups each independently selected from the group consisting of chloro, fluoro, trifluoromethyl, and trifluoromethoxy. For example, without limitation, EWG can be a single electron-withdrawing group that is chloro, fluoro, trifluoromethyl, or trifluoromethoxy located in the ortho, meta, or para positions of an aryl ring in some embodiments. In other embodiments, EWG is two or more electron-withdrawing groups independently selected from chloro, fluoro, trifluoromethyl, and trifluoromethoxy located in any combination of the ortho, meta, and para positions of an aryl ring.

[0106] R8 is -NH2, -N(H)Alk, -N(Alk)2, [ka] is an n-amino substituent selected from:

[0107] When R8 is -N(H)Alk or -N(Alk)2, Alk is an aliphatic carbon group of 1 to 6 carbon atoms (i.e., C 1-6 Alk may be linear, branched, or cyclic. When Alk is cyclic, the alkyl group may consist of 3 to 6 carbon atoms (i.e., C 3-6 Cycloalkyl). Alkyl groups can be saturated or unsaturated with one or more carbon-carbon double bonds and / or carbon-carbon triple bonds.

[0108] R8 [ka] When R7 is alkyl, the alkyl group is an aliphatic carbon group of 1 to 6 carbon atoms (i.e., C 1-6 The alkyl group can be linear, branched, or cyclic. When the alkyl group is cyclic, it can consist of 3 to 6 carbon atoms (i.e., C 3-6cycloalkyl). The alkyl group may be saturated or unsaturated with one or more carbon-carbon double bonds and / or carbon-carbon triple bonds. In some embodiments, R7 is H. In other embodiments, R7 is methyl. In other embodiments, R7 is ethyl. In other embodiments, R7 is propyl (e.g., n-propyl or isopropyl). In other embodiments, R7 is butyl (e.g., 1-butyl, 2-butyl, or t-butyl). In other embodiments, R7 is pentyl (e.g., 1-n-pentyl, 2-n-pentyl, 3-n-pentyl, 2-methylbut-4-yl, 2-methylbut-3-yl, or 1-dimethylprop-1-yl). In other embodiments, R7 is hexyl (e.g., 1-n-hexyl, 2-n-hexyl, 3-n-hexyl, 2-methylpent-5-yl, 2-methylpent-4-yl, 2-methylpent-3-yl, 3-methylpent-5-yl, 2-methylpent-1-yl, 2,3-dimethylbut-4-yl, 2,2-dimethylbut-4-yl, 3,3-dimethylbut-4-yl, 2,3,3-trimethylprop-3-yl, 1,1-dimethylbut-1-yl, or 1,2,2-trimethylbut-1-yl).

[0109] R8 [ka] where m is 3-6. In some embodiments, m is 3, resulting in a 4-membered N-azetidinyl group. In other embodiments, m is 4, resulting in a 5-membered N-pyrrolidinyl group. In other embodiments, m is 5, resulting in a 6-membered N-piperidinyl group. In other embodiments, m is 6, resulting in a 7-membered N-azepanyl group.

[0110] R8 [ka] where p is 1 to 4, q is 1 to 4, and p and q together are 3 to 6. For example, and without limitation, p may be 1 and q is 2, 3, 4, or 5. Alternatively, p may be 2 and q is 1, 2, 3, or 4. In other embodiments, p is 3 and q is 1, 2, or 3.

[0111] EDG is one or more alkoxy or alkyl electron donating groups. EDG can be a single electron donating group in the ortho, meta or para positions of the aryl ring. In other embodiments, EDG can be 2 to 5 electron donating groups in any combination of the ortho, meta and para positions of the aryl ring. Each EDG can be independently selected from alkyl and alkoxyl. When EDG is alkyl, the alkyl group can be linear or branched and can consist of 1 to 6 carbon atoms (i.e., C 1-6 The alkyl group may be cyclic, in which case the alkyl group may consist of 3 to 6 carbon atoms (i.e., C 3-6 Cycloalkyl). The alkyl group may be saturated or unsaturated with one or more carbon-carbon double bonds and / or carbon-carbon triple bonds. When EDG is an alkoxyl, the alkoxy group may be linear or branched and may consist of 1 to 6 carbon atoms (i.e., C 1-6 The alkoxy group may be cyclic, in which case the alkoxy group may consist of 3 to 6 carbon atoms (i.e., C 3-6 Alkoxy). The alkoxy group may be saturated or unsaturated with one or more carbon-carbon double bonds and / or carbon-carbon triple bonds. In some embodiments, EDG is para-alkoxy, such as para-methoxy, para-ethoxy, or para-propoxy.

[0112] Some exemplary compounds of formula (III) are provided in Table 3 below. [Table 3]

[0113] Referring now to FIG. 3, compounds consistent with formula (III) include, for example, alkylanilines 8 III with bromoacetyl bromide to give the α-bromoamide intermediate 9 III Intermediate 11 can be synthesized by forming III In the presence of base, aniline 10 III β-haloamine 12 III In the presence of a base, intermediate 11 can be formed by alkylation with III to the α-bromoamide intermediate 9 III to give a compound of formula (III).

[0114] The present disclosure further relates to a compound of formula (IV): [ka] (In the formula, R1 is H, Cl, F, -CF3, -OCF3, or -OMe; R8 is, -NH2, -N(H)Alk, -N(Alk)2, [ka] is selected from the group consisting of R7 is H or alkyl; m is 3 to 6; p is 1 to 4; q is 1 to 4; p+q is 3 to 6; each Alk is independently an aliphatic carbon group of 1 to 6 carbon atoms; and EDG provides one or more amino, aryl, acylamide, acyloxy, alkoxy or alkyl electron donating groups.

[0115] In the compound of formula (IV), R1 is H or one or more substituents each independently selected from the group consisting of chloro, fluoro, trifluoromethyl, trifluoromethoxy and methoxy. For example, without limitation, R1 can be a single substituent that is chloro, fluoro, trifluoromethyl, trifluoromethoxy or methoxy located in the ortho, meta or para position of the aryl ring in some embodiments. In other embodiments, R1 is two or more substituents each independently selected from chloro, fluoro, trifluoromethyl, trifluoromethoxy and methoxy located in any combination of the ortho, meta and para positions of the aryl ring.

[0116] R8 is -NH2, -N(H)Alk, -N(Alk)2, [ka] is an n-amino substituent selected from:

[0117] When R8 is -N(H)Alk or -N(Alk)2, Alk is an aliphatic carbon group of 1 to 6 carbon atoms (i.e., C 1-6 Alk may be linear, branched, or cyclic. When Alk is cyclic, the alkyl group may consist of 3 to 6 carbon atoms (i.e., C 3-6 Cycloalkyl). Alkyl groups can be saturated or unsaturated with one or more carbon-carbon double bonds and / or carbon-carbon triple bonds.

[0118] R8 [ka] When R7 is alkyl, the alkyl group is an aliphatic carbon group of 1 to 6 carbon atoms (i.e., C 1-6The alkyl group can be linear, branched, or cyclic. When the alkyl group is cyclic, it can consist of 3 to 6 carbon atoms (i.e., C 3-6 cycloalkyl). The alkyl group may be saturated or unsaturated with one or more carbon-carbon double bonds and / or carbon-carbon triple bonds. In some embodiments, R7 is H. In other embodiments, R7 is methyl. In other embodiments, R7 is ethyl. In other embodiments, R7 is propyl (e.g., n-propyl or isopropyl). In other embodiments, R7 is butyl (e.g., 1-butyl, 2-butyl, or t-butyl). In other embodiments, R7 is pentyl (e.g., 1-n-pentyl, 2-n-pentyl, 3-n-pentyl, 2-methylbut-4-yl, 2-methylbut-3-yl, or 1-dimethylprop-1-yl). In other embodiments, R7 is hexyl (e.g., 1-n-hexyl, 2-n-hexyl, 3-n-hexyl, 2-methylpent-5-yl, 2-methylpent-4-yl, 2-methylpent-3-yl, 3-methylpent-5-yl, 2-methylpent-1-yl, 2,3-dimethylbut-4-yl, 2,2-dimethylbut-4-yl, 3,3-dimethylbut-4-yl, 2,3,3-trimethylprop-3-yl, 1,1-dimethylbut-1-yl, or 1,2,2-trimethylbut-1-yl).

[0119] R8 [ka] where m is 3-6. In some embodiments, m is 3, resulting in a 4-membered N-azetidinyl group. In other embodiments, m is 4, resulting in a 5-membered N-pyrrolidinyl group. In other embodiments, m is 5, resulting in a 6-membered N-piperidinyl group. In other embodiments, m is 6, resulting in a 7-membered N-azepanyl group.

[0120] R8 [ka] where p is 1 to 4, q is 1 to 4, and p and q together are 3 to 6. For example, and without limitation, p may be 1 and q is 2, 3, 4, or 5. Alternatively, p may be 2 and q is 1, 2, 3, or 4. In other embodiments, p is 3 and q is 1, 2, or 3.

[0121] EDG is one or more amino, aryl, acylamide, acyloxy, alkoxy, or alkyl electron donating groups. EDG can be a single electron donating substituent at the ortho, meta, or para position of an aryl ring. In some embodiments, a single EDG substituent is at the ortho position of an aryl ring. In other embodiments, a single EDG substituent is at the para position of an aryl ring. In other embodiments, EDG can be 2-5 electron donating groups at any combination of ortho, meta, and para positions of an aryl ring. In some embodiments, two EDG substituents are at two ortho positions of an aryl ring. In other embodiments, one EDG substituent is at an ortho position and a second same or different EDG substituent is at the para position of an aryl ring. In other embodiments, one EDG substituent is at one ortho position of an aryl ring and a second same or different EDG substituent is at the other ortho position of an aryl ring. In some embodiments, one EDG substituent is at the ortho position on one of the aryl rings, a second, same or different, EDG substituent is at the ortho position on the other of the aryl rings, and a third, same or different, EDG substituent is at the para position on the aryl ring.

[0122] Each EDG may be independently selected from amino, aryl, acylamido, acyloxy, alkoxy, or alkyl. When EDG is amino, the amino group may be -NH2, -N(H)Alk, or -N(Alk)2, where each Alk is an aliphatic carbon group of 1 to 6 carbon atoms (i.e., C 1-6 Alk may be linear, branched, or cyclic. When Alk is cyclic, the alkyl group may consist of 3 to 6 carbon atoms (i.e., C 3-6cycloalkyl). The alkyl group may be saturated or unsaturated with one or more carbon-carbon double bonds and / or carbon-carbon triple bonds. When EDG is aryl, the aryl substituent may be substituted or unsubstituted. The aryl substituent may be a heteroatom, such as a substituted or unsubstituted pyridine ring, pyrazine ring, or triazine ring. When EDG is acylamido, the acylamido group has the general formula -N(H)COR9, where R9 is a substituted or unsubstituted alkyl. When EDG is acyloxy, the acyloxy group has the general formula -OC(O)R9, where R9 is a substituted or unsubstituted alkyl. When EDG is alkyl, the alkyl group may be linear or branched and may consist of 1 to 6 carbon atoms (i.e., C 1-6 The alkyl group may be cyclic, in which case the alkyl group may consist of 3 to 6 carbon atoms (i.e., C 3-6 Cycloalkyl). The alkyl group may be saturated or unsaturated with one or more carbon-carbon double bonds and / or carbon-carbon triple bonds. When EDG is an alkoxyl, the alkoxy group may be linear or branched and may consist of 1 to 6 carbon atoms (i.e., C 1-6 The alkoxy group may be cyclic, in which case the alkoxy group may consist of 3 to 6 carbon atoms (i.e., C 3-6 Alkoxy). The alkoxy group may be saturated or unsaturated with one or more carbon-carbon double bonds and / or carbon-carbon triple bonds. In some embodiments, EDG is para-alkoxy, such as para-methoxy, para-ethoxy, or para-propoxy.

[0123] Some exemplary compounds of formula (IV) are provided in Table 4 below. [Table 4]

[0124] Referring now to FIG. 4, compounds consistent with formula (IV) include, for example, alkylanilines 8 IV with bromoacetyl bromide to give the α-bromoamide intermediate 9 IV Intermediate 11 can be synthesized by forming IV In the presence of base, aniline 10 IV β-haloamine 12 IV In the presence of a base, intermediate 11 can be formed by alkylation with IV to the α-bromoamide intermediate 9 IV to give a compound of formula (IV).

[0125] The present disclosure relates to a compound of formula (V): [ka] (In the formula, R1 is H, Cl, F, -CF3, -OCF3, or -OMe; R8 is, -NH2, -N(H)Alk, -N(Alk)2, [ka] is selected from the group consisting of R7 is H or alkyl; m is 3 to 6; p is 1 to 4; q is 1 to 4; p+q is 3 to 6, and Each Alk is independently an aliphatic carbon group of 1 to 6 carbon atoms.

[0126] In the compound of formula (V), R1 is H or one or more substituents each independently selected from the group consisting of chloro, fluoro, trifluoromethyl, trifluoromethoxy and methoxy. For example, without limitation, R1 can be a single substituent that is chloro, fluoro, trifluoromethyl, trifluoromethoxy or methoxy located in the ortho, meta or para position of the aryl ring in some embodiments. In other embodiments, R1 is two or more substituents each independently selected from chloro, fluoro, trifluoromethyl, trifluoromethoxy and methoxy located in any combination of the ortho, meta and para positions of the aryl ring.

[0127] R8 is -NH2, -N(H)Alk, -N(Alk)2, [ka] is an n-amino substituent selected from:

[0128] When R8 is -N(H)Alk or -N(Alk)2, Alk is an aliphatic carbon group of 1 to 6 carbon atoms (i.e., C 1-6 Alk may be linear, branched, or cyclic. When Alk is cyclic, the alkyl group may consist of 3 to 6 carbon atoms (i.e., C 3-6 Cycloalkyl). Alkyl groups can be saturated or unsaturated with one or more carbon-carbon double bonds and / or carbon-carbon triple bonds.

[0129] R8 [ka] When R7 is alkyl, the alkyl group is an aliphatic carbon group of 1 to 6 carbon atoms (i.e., C 1-6The alkyl group can be linear, branched, or cyclic. When the alkyl group is cyclic, it can consist of 3 to 6 carbon atoms (i.e., C 3-6 cycloalkyl). The alkyl group may be saturated or unsaturated with one or more carbon-carbon double bonds and / or carbon-carbon triple bonds. In some embodiments, R7 is H. In other embodiments, R7 is methyl. In other embodiments, R7 is ethyl. In other embodiments, R7 is propyl (e.g., n-propyl or isopropyl). In other embodiments, R7 is butyl (e.g., 1-butyl, 2-butyl, or t-butyl). In other embodiments, R7 is pentyl (e.g., 1-n-pentyl, 2-n-pentyl, 3-n-pentyl, 2-methylbut-4-yl, 2-methylbut-3-yl, or 1-dimethylprop-1-yl). In other embodiments, R7 is hexyl (e.g., 1-n-hexyl, 2-n-hexyl, 3-n-hexyl, 2-methylpent-5-yl, 2-methylpent-4-yl, 2-methylpent-3-yl, 3-methylpent-5-yl, 2-methylpent-1-yl, 2,3-dimethylbut-4-yl, 2,2-dimethylbut-4-yl, 3,3-dimethylbut-4-yl, 2,3,3-trimethylprop-3-yl, 1,1-dimethylbut-1-yl, or 1,2,2-trimethylbut-1-yl).

[0130] R8 [ka] where m is 3-6. In some embodiments, m is 3, resulting in a 4-membered N-azetidinyl group. In other embodiments, m is 4, resulting in a 5-membered N-pyrrolidinyl group. In other embodiments, m is 5, resulting in a 6-membered N-piperidinyl group. In other embodiments, m is 6, resulting in a 7-membered N-azepanyl group.

[0131] R8 [ka] where p is 1 to 4, q is 1 to 4, and p and q together are 3 to 6. For example, and without limitation, p may be 1 and q is 2, 3, 4, or 5. Alternatively, p may be 2 and q is 1, 2, 3, or 4. In other embodiments, p is 3 and q is 1, 2, or 3.

[0132] Alk is an aliphatic carbon group consisting of 1 to 6 carbon atoms (i.e., C 1-6 Alk may be linear, branched, or cyclic. When Alk is cyclic, the alkyl group may consist of 3 to 6 carbon atoms (i.e., C 3-6 Cycloalkyl). Alkyl groups can be saturated or unsaturated with one or more carbon-carbon double bonds and / or carbon-carbon triple bonds.

[0133] Some exemplary compounds of formula (V) are provided in Table 5 below. [Table 5]

[0134] Referring now to FIG. 5, compounds consistent with formula (V) include, for example, alkylaminoalkylphenols 8. V with bromoacetyl bromide to give the α-bromoamide intermediate 9 V Intermediate 11 can be synthesized by forming V In the presence of base, aniline 10 V β-haloamine 12 V In the presence of a base, intermediate 11 can be formed by alkylation with V to the α-bromoamide intermediate 9 V to give a compound of formula (V).

[0135] The present disclosure relates to a compound of formula (VI): [ka] (In the formula, R1 is H, Cl, F, -CF3, -OCF3, -OMe or methyl; R8 is, -NH2, -N(H)Alk, -N(Alk)2, [ka] is selected from the group consisting of R7 is H or alkyl; m is 3 to 6; p is 1 to 4; q is 1 to 4; p+q is 3 to 6, and Each Alk is independently an aliphatic carbon group of 1 to 6 carbon atoms.

[0136] In the compound of formula (VI), R1 is H or one or more substituents each independently selected from the group consisting of chloro, fluoro, trifluoromethyl, trifluoromethoxy, methoxy and methyl. For example, without limitation, R1 can be a single substituent that is chloro, fluoro, trifluoromethyl, trifluoromethoxy or methoxy located in the ortho, meta or para position of the aryl ring in some embodiments. In other embodiments, R1 is two or more substituents each independently selected from chloro, fluoro, trifluoromethyl, trifluoromethoxy and methoxy located in any combination of the ortho, meta and para positions of the aryl ring.

[0137] R8 is -NH2, -N(H)Alk, -N(Alk)2, [ka] is an n-amino substituent selected from:

[0138] When R8 is -N(H)Alk or -N(Alk)2, Alk is an aliphatic carbon group of 1 to 6 carbon atoms (i.e., C 1-6Alk may be linear, branched, or cyclic. When Alk is cyclic, the alkyl group may consist of 3 to 6 carbon atoms (i.e., C 3-6 Cycloalkyl). Alkyl groups can be saturated or unsaturated with one or more carbon-carbon double bonds and / or carbon-carbon triple bonds.

[0139] R8 [ka] When R7 is alkyl, the alkyl group is an aliphatic carbon group of 1 to 6 carbon atoms (i.e., C 1-6 The alkyl group can be linear, branched, or cyclic. When the alkyl group is cyclic, it can consist of 3 to 6 carbon atoms (i.e., C 3-6cycloalkyl). The alkyl group may be saturated or unsaturated with one or more carbon-carbon double bonds and / or carbon-carbon triple bonds. In some embodiments, R7 is H. In other embodiments, R7 is methyl. In other embodiments, R7 is ethyl. In other embodiments, R7 is propyl (e.g., n-propyl or isopropyl). In other embodiments, R7 is butyl (e.g., 1-butyl, 2-butyl, or t-butyl). In other embodiments, R7 is pentyl (e.g., 1-n-pentyl, 2-n-pentyl, 3-n-pentyl, 2-methylbut-4-yl, 2-methylbut-3-yl, or 1-dimethylprop-1-yl). In other embodiments, R7 is hexyl (e.g., 1-n-hexyl, 2-n-hexyl, 3-n-hexyl, 2-methylpent-5-yl, 2-methylpent-4-yl, 2-methylpent-3-yl, 3-methylpent-5-yl, 2-methylpent-1-yl, 2,3-dimethylbut-4-yl, 2,2-dimethylbut-4-yl, 3,3-dimethylbut-4-yl, 2,3,3-trimethylprop-3-yl, 1,1-dimethylbut-1-yl, or 1,2,2-trimethylbut-1-yl).

[0140] R8 [ka] where m is 3-6. In some embodiments, m is 3, resulting in a 4-membered N-azetidinyl group. In other embodiments, m is 4, resulting in a 5-membered N-pyrrolidinyl group. In other embodiments, m is 5, resulting in a 6-membered N-piperidinyl group. In other embodiments, m is 6, resulting in a 7-membered N-azepanyl group.

[0141] R8 [ka] where p is 1 to 4, q is 1 to 4, and p and q together are 3 to 6. For example, and without limitation, p may be 1 and q is 2, 3, 4, or 5. Alternatively, p may be 2 and q is 1, 2, 3, or 4. In other embodiments, p is 3 and q is 1, 2, or 3.

[0142] Some exemplary compounds of formula (VI) are provided in Table 6 below. [Table 6]

[0143] Referring now to FIG. 6, a compound consistent with formula (VI) is, for example, methylaniline 8. VI with bromoacetyl bromide to give intermediate 9 VI Intermediate 11 can be synthesized by forming VI In the presence of base, aniline 10 VI β-haloamine 12 VI In the presence of a base, intermediate 11 can be formed by alkylation with VI to intermediate 9 VI to give a compound of formula (VI).

[0144] The present disclosure relates to a compound of formula (VII): [ka] (In the formula, R 1a is H, Cl, F, -CF3, -OMe or methyl, R 1b is H, Cl, F, -CF3 or -OCF3, R 1c is H, Cl, F or -OMe, R 1d is H, Cl, F, -CF3 or -OCF3, R 1e is H, Cl, F, -CF3, -OMe or methyl, R2 and R3 are each independently H or alkyl, or taken together with the adjacent nitrogen atom form a 4- to 8-membered heterocycle; R4 is H or alkyl, and R5 is H or one or more electron donating groups.

[0145] In the compound of formula (VII), R 1a R is H or an ortho-substituent selected from the group consisting of chloro, fluoro, trifluoromethyl, methoxy, or methyl. 1b is H or a meta substituent selected from the group consisting of chloro, fluoro, trifluoromethyl, or trifluoromethoxy. 1c is a para substituent selected from the group consisting of H, chloro, fluoro, or methoxy. 1d is H, or (e.g., R 1b If R is not H, it is a meta substituent selected from the group consisting of chloro, fluoro, trifluoromethyl, or trifluoromethoxy. 1e is H, or (e.g., R 1a is not H) is an ortho substituent selected from the group consisting of chloro, fluoro, trifluoromethyl, methoxy, or methyl. In some embodiments, R 1a is chloro and R 1d is chloro and R 1b , R 1c and R 1e Each is H. In another embodiment, R 1a is fluoro and R 1b is chloro and R 1c , R 1d and R 1e Each is H. In another embodiment, R 1a is trifluoromethyl, R 1b , R 1c , R 1d and R 1e Each is H. In another embodiment, R 1a is methoxy and R 1b , R 1c , R 1dand R 1e Each is H. In another embodiment, R 1a is methyl, R 1b , R 1c , R 1d and R 1e Each is H. In another embodiment, R 1b is chloro and R 1c is fluoro and R 1a , R 1d and R 1e Each is H. In another embodiment, R 1b is trifluoromethyl, R 1c is chloro and R 1a , R 1d and R 1e Each is H. In another embodiment, R 1b is trifluoromethoxyl, and R 1a , R 1c , R 1d and R 1e Each is H. In another embodiment, R 1b is chloro and R 1c is chloro and R 1a , R 1d and R 1e Each is H. In another embodiment, R 1b is chloro and R 1a , R 1c , R 1d and R 1e Each is H. In another embodiment, R 1c is methoxyl, and R 1a , R 1b , R 1d and R 1e are H, respectively.

[0146] Each R2 and R3 is independently H or alkyl. When R2 and / or R3 is alkyl, the alkyl group may be linear or branched and may consist of 1 to 6 carbon atoms (i.e., C 1-6 The alkyl group may be cyclic, in which case the alkyl group may consist of 3 to 6 carbon atoms (i.e., C 3-6Cycloalkyl). Alkyl groups can be saturated or unsaturated with one or more carbon-carbon double bonds and / or carbon-carbon triple bonds.

[0147] In some embodiments, R2 and R3 are covalently linked to adjacent nitrogen atoms to form a heterocyclic ring. The heterocyclic ring may contain 1-3 nitrogen atoms and a total of 4-8 atoms in the ring. The heterocyclic ring may be unsubstituted or substituted, for example, with alkyl or alkoxyl groups. For example, but not limited to, R2 and R3 may be covalently linked to form a piperidinyl ring containing a total of 5 carbon atoms and including the nitrogen atom adjacent to R2 and R3. In other embodiments, R2 and R3 together are represented by the general formula: -(CH2) p N(R7)(CH2) q - (wherein p is 1 to 4, q is 1 to 4, the sum of p and q together is 3 to 8, and R7 is H or alkyl). When R7 is alkyl, the alkyl group may be linear or branched and may consist of 1 to 6 carbon atoms (i.e., C 1-6 The alkyl group may be cyclic, in which case the alkyl group may consist of 3 to 6 carbon atoms (i.e., C 3-6 cycloalkyl). The alkyl group may be saturated or unsaturated with one or more carbon-carbon double bonds and / or carbon-carbon triple bonds. In some embodiments, R2 and R3 are both H. In other embodiments, R2 and R3 are both methyl. In yet other embodiments, R2 is H and R3 is methyl.

[0148] R4 is H or alkyl. When R4 is alkyl, the alkyl group may be linear or branched and may consist of 1 to 6 carbon atoms (i.e., C 1-6 The alkyl group may be cyclic, in which case the alkyl group may consist of 3 to 6 carbon atoms (i.e., C 3-6Cycloalkyl). Alkyl groups can be saturated or unsaturated with one or more carbon-carbon double bonds and / or carbon-carbon triple bonds.

[0149] R5 is H or one or more electron donating groups. When R5 is one or more electron donating groups, R5 can be a single electron donating group at the ortho, meta or para positions of the aryl ring. In other embodiments, R5 can be 2 to 5 electron donating groups at any combination of the ortho, meta and para positions of the aryl ring. Each electron donating group can be independently selected from alkyl and alkoxyl. When R5 is alkyl, the alkyl group can be linear or branched and can consist of 1 to 6 carbon atoms (i.e., C 1-6 The alkyl group may be cyclic, in which case the alkyl group may consist of 3 to 6 carbon atoms (i.e., C 3-6 Cycloalkyl). The alkyl group may be saturated or unsaturated with one or more carbon-carbon double bonds and / or carbon-carbon triple bonds. When R5 is alkoxyl, the alkoxy group may be linear or branched and may consist of 1 to 6 carbon atoms (i.e., C 1-6 The alkoxy group may be cyclic, in which case the alkoxy group may consist of 3 to 6 carbon atoms (i.e., C 3-6 Alkoxy groups may be saturated or unsaturated with one or more carbon-carbon double bonds and / or carbon-carbon triple bonds.

[0150] Some exemplary compounds of formula (VII) are provided in Table 7 below. [Table 7-1] [Table 7-2]

[0151] Referring now to FIG. 7, compounds consistent with formula (VII) include, for example, aniline 8. VII with bromoacetyl bromide to give intermediate 9 VII Intermediate 11 can be synthesized by forming VII In the presence of base, aniline 10 VII β-haloamine 12 VII In the presence of a base, intermediate 11 can be formed by alkylation with VII to intermediate 9 VII to give a compound of formula (VII).

[0152] In other embodiments, the present disclosure provides a compound of formula (VIIIa): [ka] (In the formula, R2=H or Me; R3=H or Me; R4=alkyl, R5=O-alkyl, and alkyl = aliphatic C1-C4 alkyl).

[0153] In the compound of formula (VIIIa), each R2 and R3 is independently H or methyl. In some embodiments, both R2 and R3 are H. In other embodiments, both R2 and R3 are methyl. In some embodiments, one of R2 and R3 is H and the other is methyl.

[0154] R4 is alkyl, which may be linear or branched, and may consist of 1 to 4 carbon atoms (i.e., C 1-4 The alkyl group may be cyclic, in which case the alkyl group may consist of 3 or 4 carbon atoms (i.e., C 3-4 Cycloalkyl). Alkyl groups can be saturated or unsaturated with one or more carbon-carbon double bonds and / or carbon-carbon triple bonds.

[0155] R5 is an O-alkyl (i.e., alkoxy) in the para position. The alkyl group may be linear or branched and may consist of 1 to 4 carbon atoms (i.e., C 1-4 The alkyl group may be cyclic, in which case the alkyl group may consist of 3 or 4 carbon atoms (i.e., C 3-4 Cycloalkyl). Alkyl groups can be saturated or unsaturated with one or more carbon-carbon double bonds and / or carbon-carbon triple bonds.

[0156] Some exemplary compounds of formula (VIIIa) are provided in Table 8a below. [Table 8-1] [Table 8-2]

[0157] 8, compounds consistent with formula (VIIIa) can be synthesized, for example, by acylation of para-substituted aniline 8a with bromoacetyl bromide to form intermediate 9a. Intermediate 11a can be formed by alkylation of aniline 10a with β-haloamine 12a in the presence of base. Combination of intermediate 11a with intermediate 9a in the presence of base provides compounds of formula (VIIIa).

[0158] In other embodiments, the present disclosure provides a compound of formula (VIIIb): [ka] (In the formula, R2=H or Me; R3=H or Me; R4=alkyl, R5=O-alkyl, and alkyl = aliphatic C1-C4 alkyl).

[0159] In the compound of formula (VIIIb), each R2 and R3 is independently H or methyl. In some embodiments, both R2 and R3 are H. In other embodiments, both R2 and R3 are methyl. In some embodiments, one of R2 and R3 is H and the other is methyl.

[0160] R4 is alkyl, which may be linear or branched, and may consist of 1 to 4 carbon atoms (i.e., C 1-4 The alkyl group may be cyclic, in which case the alkyl group may consist of 3 or 4 carbon atoms (i.e., C 3-4 Cycloalkyl). Alkyl groups can be saturated or unsaturated with one or more carbon-carbon double bonds and / or carbon-carbon triple bonds.

[0161] R5 is an O-alkyl (i.e., alkoxy) in the para position. The alkyl group may be linear or branched and may consist of 1 to 4 carbon atoms (i.e., C 1-4 The alkyl group may be cyclic, in which case the alkyl group may consist of 3 or 4 carbon atoms (i.e., C 3-4 Cycloalkyl). Alkyl groups can be saturated or unsaturated with one or more carbon-carbon double bonds and / or carbon-carbon triple bonds.

[0162] Some exemplary compounds of formula (VIIIb) are provided in Table 8b below. [Table 8-3] [Table 8-4]

[0163] 9, compounds consistent with formula (VIIIb) can be synthesized, for example, by acylation of para-substituted aniline 8b with bromoacetyl bromide to form intermediate 9b. Intermediate 11b can be formed by alkylation of m-chloroaniline 10b with β-haloamine 12b in the presence of base. Combination of intermediate 11b with intermediate 9b in the presence of base provides compounds of formula (VIIIb).

[0164] In other embodiments, the present disclosure provides a compound of formula (VIIIc): [ka] (In the formula, R2=H or Me; R3=H or Me; R4=alkyl, R5=O-alkyl, and alkyl = aliphatic C1-C4 alkyl).

[0165] In the compound of formula (VIIIc), each R2 and R3 is independently H or methyl. In some embodiments, both R2 and R3 are H. In other embodiments, both R2 and R3 are methyl. In some embodiments, one of R2 and R3 is H and the other is methyl.

[0166] R4 is alkyl, which may be linear or branched, and may consist of 1 to 4 carbon atoms (i.e., C 1-4 The alkyl group may be cyclic, in which case the alkyl group may consist of 3 or 4 carbon atoms (i.e., C 3-4 Cycloalkyl). Alkyl groups can be saturated or unsaturated with one or more carbon-carbon double bonds and / or carbon-carbon triple bonds.

[0167] R5 is an O-alkyl (i.e., alkoxy) in the para position. The alkyl group may be linear or branched and may consist of 1 to 4 carbon atoms (i.e., C 1-4 The alkyl group may be cyclic, in which case the alkyl group may consist of 3 or 4 carbon atoms (i.e., C 3-4 Cycloalkyl). Alkyl groups can be saturated or unsaturated with one or more carbon-carbon double bonds and / or carbon-carbon triple bonds.

[0168] Some exemplary compounds of formula (VIIIc) are provided in Table 8c below. [Table 8-5] [Table 8-6]

[0169] 10, compounds consistent with formula (VIIIc) can be synthesized, for example, by acylation of para-substituted aniline 8c with bromoacetyl bromide to form intermediate 9c. Intermediate 11c can be formed by alkylation of m-chloroaniline 10c with β-haloamine 12c in the presence of base. Combination of intermediate 11c with intermediate 9c in the presence of base provides compounds of formula (VIIIc).

[0170] In other embodiments, the present disclosure provides a compound of formula (VIIId): [ka] (In the formula, R2=H or Me; R3=H or Me; R4=alkyl, R5=O-alkyl, and alkyl = aliphatic C1-C4 alkyl).

[0171] In the compound of formula (VIIId), each R2 and R3 is independently H or methyl. In some embodiments, both R2 and R3 are H. In other embodiments, both R2 and R3 are methyl. In some embodiments, one of R2 and R3 is H and the other is methyl.

[0172] R4 is alkyl, which may be linear or branched, and may consist of 1 to 4 carbon atoms (i.e., C 1-4 The alkyl group may be cyclic, in which case the alkyl group may consist of 3 or 4 carbon atoms (i.e., C 3-4 Cycloalkyl). Alkyl groups can be saturated or unsaturated with one or more carbon-carbon double bonds and / or carbon-carbon triple bonds.

[0173] R5 is an O-alkyl (i.e., alkoxy) in the para position. The alkyl group may be linear or branched and may consist of 1 to 4 carbon atoms (i.e., C 1-4 The alkyl group may be cyclic, in which case the alkyl group may consist of 3 or 4 carbon atoms (i.e., C 3-4 Cycloalkyl). Alkyl groups can be saturated or unsaturated with one or more carbon-carbon double bonds and / or carbon-carbon triple bonds.

[0174] Some exemplary compounds of formula (VIIId) are provided in Table 8d below. [Table 8-7] [Table 8-8]

[0175] 11, compounds consistent with formula (VIIId) can be synthesized, for example, by acylation of para-substituted aniline 8d with bromoacetyl bromide to form intermediate 9d. Intermediate 11d can be formed by alkylation of o-methoxyaniline 10d with β-haloamine 12d in the presence of base. Combination of intermediate 11d with intermediate 9d in the presence of base provides compounds of formula (VIIId).

[0176] In other embodiments, the present disclosure provides a compound of formula (VIIIe): [ka] (In the formula, R2=H or Me; R3=H or Me; R4=alkyl, R5=O-alkyl, and alkyl = aliphatic C1-C4 alkyl).

[0177] In the compound of formula (VIIIe), each R2 and R3 is independently H or methyl. In some embodiments, both R2 and R3 are H. In other embodiments, both R2 and R3 are methyl. In some embodiments, one of R2 and R3 is H and the other is methyl.

[0178] R4 is alkyl, which may be linear or branched, and may consist of 1 to 4 carbon atoms (i.e., C 1-4 The alkyl group may be cyclic, in which case the alkyl group may consist of 3 or 4 carbon atoms (i.e., C 3-4 Cycloalkyl). Alkyl groups can be saturated or unsaturated with one or more carbon-carbon double bonds and / or carbon-carbon triple bonds.

[0179] R5 is an O-alkyl (i.e., alkoxy) in the para position. The alkyl group may be linear or branched and may consist of 1 to 4 carbon atoms (i.e., C 1-4 The alkyl group may be cyclic, in which case the alkyl group may consist of 3 or 4 carbon atoms (i.e., C 3-4 Cycloalkyl). Alkyl groups can be saturated or unsaturated with one or more carbon-carbon double bonds and / or carbon-carbon triple bonds.

[0180] Some exemplary compounds of formula (VIIIe) are provided in Table 8e below. [Table 8-9] [Table 8-10]

[0181] 12, compounds consistent with formula (VIIIe) can be synthesized, for example, by acylation of para-substituted aniline 8e with bromoacetyl bromide to form intermediate 9e. Intermediate 11e can be formed by alkylation of p-methoxyaniline 10e with β-haloamine 12e in the presence of base. Combination of intermediate 11e with intermediate 9e in the presence of base provides compounds of formula (VIIIe).

[0182] In other embodiments, the present disclosure provides a compound of formula (VIIIf): [ka] (In the formula, R2=H or Me; R3=H or Me; R4=alkyl, R5=O-alkyl, and alkyl = aliphatic C1-C4 alkyl).

[0183] In the compound of formula (VIIIf), each R2 and R3 is independently H or methyl. In some embodiments, both R2 and R3 are H. In other embodiments, both R2 and R3 are methyl. In some embodiments, one of R2 and R3 is H and the other is methyl.

[0184] R4 is alkyl, which may be linear or branched, and may consist of 1 to 4 carbon atoms (i.e., C 1-4 The alkyl group may be cyclic, in which case the alkyl group may consist of 3 or 4 carbon atoms (i.e., C 3-4 Cycloalkyl). Alkyl groups can be saturated or unsaturated with one or more carbon-carbon double bonds and / or carbon-carbon triple bonds.

[0185] R5 is an O-alkyl (i.e., alkoxy) in the para position. The alkyl group may be linear or branched and may consist of 1 to 4 carbon atoms (i.e., C 1-4 The alkyl group may be cyclic, in which case the alkyl group may consist of 3 or 4 carbon atoms (i.e., C 3-4 Cycloalkyl). Alkyl groups can be saturated or unsaturated with one or more carbon-carbon double bonds and / or carbon-carbon triple bonds.

[0186] Some exemplary compounds of formula (VIIIf) are provided in Table 8f below. [Table 8-11] [Table 8-12]

[0187] 13, compounds consistent with formula (VIIIf) can be synthesized, for example, by acylation of para-substituted aniline 8f with bromoacetyl bromide to form intermediate 9f. Intermediate 11f can be formed by alkylation of p-methoxyaniline 10f with β-haloamine 12f in the presence of base. Combination of intermediate 11f with intermediate 9f in the presence of base provides compounds of formula (VIIIf).

[0188] In other embodiments, the present disclosure provides a compound of formula (VIIIg): [ka] (In the formula, R2=H or Me; R3=H or Me; R4=alkyl, R5=O-alkyl, and alkyl = aliphatic C1-C4 alkyl).

[0189] In the compound of formula (VIIIg), each R2 and R3 is independently H or methyl. In some embodiments, both R2 and R3 are H. In other embodiments, both R2 and R3 are methyl. In some embodiments, one of R2 and R3 is H and the other is methyl.

[0190] R4 is alkyl, which may be linear or branched, and may consist of 1 to 4 carbon atoms (i.e., C 1-4 The alkyl group may be cyclic, in which case the alkyl group may consist of 3 or 4 carbon atoms (i.e., C 3-4 Cycloalkyl). Alkyl groups can be saturated or unsaturated with one or more carbon-carbon double bonds and / or carbon-carbon triple bonds.

[0191] R5 is an O-alkyl (i.e., alkoxy) in the para position. The alkyl group may be linear or branched and may consist of 1 to 4 carbon atoms (i.e., C 1-4 The alkyl group may be cyclic, in which case the alkyl group may consist of 3 or 4 carbon atoms (i.e., C 3-4 Cycloalkyl). Alkyl groups can be saturated or unsaturated with one or more carbon-carbon double bonds and / or carbon-carbon triple bonds.

[0192] Some exemplary compounds of formula (VIIIg) are provided in Table 8g below. [Table 8-13] [Table 8-14]

[0193] 14, a compound consistent with formula (VIIIg) can be synthesized, for example, by acylation of para-substituted aniline 8g with bromoacetyl bromide to form intermediate 9g. Intermediate 11g can be formed by alkylation of m-trifluoromethoxyaniline 10g with β-haloamine 12g in the presence of base. Combining intermediate 11g with intermediate 9g in the presence of base provides a compound of formula (VIIIg).

[0194] In other embodiments, the present disclosure provides a compound of formula (VIIIh): [ka] (In the formula, R2=H or Me; R3=H or Me; R4=alkyl, R5=O-alkyl, and alkyl = aliphatic C1-C4 alkyl).

[0195] In the compound of formula (VIIIh), each R2 and R3 is independently H or methyl. In some embodiments, both R2 and R3 are H. In other embodiments, both R2 and R3 are methyl. In some embodiments, one of R2 and R3 is H and the other is methyl.

[0196] R4 is alkyl, which may be linear or branched, and may consist of 1 to 4 carbon atoms (i.e., C 1-4 The alkyl group may be cyclic, in which case the alkyl group may consist of 3 or 4 carbon atoms (i.e., C 3-4 Cycloalkyl). Alkyl groups can be saturated or unsaturated with one or more carbon-carbon double bonds and / or carbon-carbon triple bonds.

[0197] R5 is an O-alkyl (i.e., alkoxy) in the para position. The alkyl group may be linear or branched and may consist of 1 to 4 carbon atoms (i.e., C 1-4 The alkyl group may be cyclic, in which case the alkyl group may consist of 3 or 4 carbon atoms (i.e., C 3-4 Cycloalkyl). Alkyl groups can be saturated or unsaturated with one or more carbon-carbon double bonds and / or carbon-carbon triple bonds.

[0198] Some exemplary compounds of formula (VIIIh) are provided in Table 8h below. [Table 8-15] [Table 8-16]

[0199] 15, compounds consistent with formula (VIIIh) can be synthesized, for example, by acylation of para-substituted aniline 8h with bromoacetyl bromide to form intermediate 9h. Intermediate 11h can be formed by alkylation of p-chloro-m-trifluoromethylaniline 10h with β-haloamine 12h in the presence of base. Combination of intermediate 11h with intermediate 9h in the presence of base provides compounds of formula (VIIIh).

[0200] In other embodiments, the present disclosure provides a compound of formula (VIIIi): [ka] (In the formula, R2=H or Me; R3=H or Me; R4=alkyl, R5=O-alkyl, and alkyl = aliphatic C1-C4 alkyl).

[0201] In the compound of formula (VIIIi), each R2 and R3 is independently H or methyl. In some embodiments, both R2 and R3 are H. In other embodiments, both R2 and R3 are methyl. In some embodiments, one of R2 and R3 is H and the other is methyl.

[0202] R4 is alkyl, which may be linear or branched, and may consist of 1 to 4 carbon atoms (i.e., C 1-4 The alkyl group may be cyclic, in which case the alkyl group may consist of 3 or 4 carbon atoms (i.e., C 3-4 Cycloalkyl). Alkyl groups can be saturated or unsaturated with one or more carbon-carbon double bonds and / or carbon-carbon triple bonds.

[0203] R5 is an O-alkyl (i.e., alkoxy) in the para position. The alkyl group may be linear or branched and may consist of 1 to 4 carbon atoms (i.e., C 1-4 The alkyl group may be cyclic, in which case the alkyl group may consist of 3 or 4 carbon atoms (i.e., C 3-4 Cycloalkyl). Alkyl groups can be saturated or unsaturated with one or more carbon-carbon double bonds and / or carbon-carbon triple bonds.

[0204] Some exemplary compounds of formula (VIIIi) are provided in Table 8i below. [Table 8-17] [Table 8-18]

[0205] 16, compounds consistent with formula (VIIIi) can be synthesized, for example, by acylation of para-substituted aniline 8i with bromoacetyl bromide to form intermediate 9i. Intermediate 11i can be formed by alkylation of 2,5-dichloroaniline 10i with β-haloamine 12i in the presence of base. Combination of intermediate 11i with intermediate 9i in the presence of base provides compounds of formula (VIIIi).

[0206] In other embodiments, the present disclosure provides a compound of formula (VIIIj): [ka] (In the formula, R2=H or Me; R3=H or Me; R4=alkyl, R5=O-alkyl, and alkyl = aliphatic C1-C4 alkyl).

[0207] In the compound of formula (VIIIj), each R2 and R3 is independently H or methyl. In some embodiments, both R2 and R3 are H. In other embodiments, both R2 and R3 are methyl. In some embodiments, one of R2 and R3 is H and the other is methyl.

[0208] R4 is alkyl, which may be linear or branched, and may consist of 1 to 4 carbon atoms (i.e., C 1-4 The alkyl group may be cyclic, in which case the alkyl group may consist of 3 or 4 carbon atoms (i.e., C 3-4 Cycloalkyl). Alkyl groups can be saturated or unsaturated with one or more carbon-carbon double bonds and / or carbon-carbon triple bonds.

[0209] R5 is an O-alkyl (i.e., alkoxy) in the para position. The alkyl group may be linear or branched and may consist of 1 to 4 carbon atoms (i.e., C 1-4 The alkyl group may be cyclic, in which case the alkyl group may consist of 3 or 4 carbon atoms (i.e., C 3-4 Cycloalkyl). Alkyl groups can be saturated or unsaturated with one or more carbon-carbon double bonds and / or carbon-carbon triple bonds.

[0210] Some exemplary compounds of formula (VIIIj) are provided in Table 8j below. [Table 8-19] [Table 8-20]

[0211] 17, compounds consistent with formula (VIIIj) can be synthesized, for example, by acylation of para-substituted aniline 8j with bromoacetyl bromide to form intermediate 9j. Intermediate 11j can be formed by alkylation of 3-chloro-4-fluoroaniline 10j with β-haloamine 12j in the presence of base. Combination of intermediate 11j with intermediate 9j in the presence of base provides compounds of formula (VIIIj).

[0212] In other embodiments, the present disclosure provides a compound of formula (VIIIk): [ka] (In the formula, R2=H or Me; R3=H or Me; R4=alkyl, R5=O-alkyl, and alkyl = aliphatic C1-C4 alkyl).

[0213] In the compound of formula (VIIIk), each R2 and R3 is independently H or methyl. In some embodiments, both R2 and R3 are H. In other embodiments, both R2 and R3 are methyl. In some embodiments, one of R2 and R3 is H and the other is methyl.

[0214] R4 is alkyl, which may be linear or branched, and may consist of 1 to 4 carbon atoms (i.e., C 1-4 The alkyl group may be cyclic, in which case the alkyl group may consist of 3 or 4 carbon atoms (i.e., C 3-4 Cycloalkyl). Alkyl groups can be saturated or unsaturated with one or more carbon-carbon double bonds and / or carbon-carbon triple bonds.

[0215] R5 is an O-alkyl (i.e., alkoxy) in the para position. The alkyl group may be linear or branched and may consist of 1 to 4 carbon atoms (i.e., C 1-4 The alkyl group may be cyclic, in which case the alkyl group may consist of 3 or 4 carbon atoms (i.e., C 3-4 Cycloalkyl). Alkyl groups can be saturated or unsaturated with one or more carbon-carbon double bonds and / or carbon-carbon triple bonds.

[0216] Some exemplary compounds of formula (VIIIk) are provided in Table 8k below. [Table 8-21] [Table 8-22]

[0217] 18, compounds consistent with formula (VIIIk) can be synthesized, for example, by acylation of para-substituted aniline 8k with bromoacetyl bromide to form intermediate 9k. Intermediate 11k can be formed by alkylation of 2-fluoro-3-chloroaniline 10k with β-haloamine 12k in the presence of base. Combination of intermediate 11k with intermediate 9k in the presence of base provides compounds of formula (VIIIk).

[0218] In other embodiments, the present disclosure provides a compound of formula (VIIIm): [ka] (In the formula, R2=H or Me; R3=H or Me; R4=alkyl, R5=O-alkyl, and alkyl = aliphatic C1-C4 alkyl).

[0219] In the compound of formula (VIIIm), each R2 and R3 is independently H or methyl. In some embodiments, both R2 and R3 are H. In other embodiments, both R2 and R3 are methyl. In some embodiments, one of R2 and R3 is H and the other is methyl.

[0220] R4 is alkyl, which may be linear or branched, and may consist of 1 to 4 carbon atoms (i.e., C 1-4 The alkyl group may be cyclic, in which case the alkyl group may consist of 3 or 4 carbon atoms (i.e., C 3-4 Cycloalkyl). Alkyl groups can be saturated or unsaturated with one or more carbon-carbon double bonds and / or carbon-carbon triple bonds.

[0221] R5 is an O-alkyl (i.e., alkoxy) in the para position. The alkyl group may be linear or branched and may consist of 1 to 4 carbon atoms (i.e., C 1-4 The alkyl group may be cyclic, in which case the alkyl group may consist of 3 or 4 carbon atoms (i.e., C 3-4 Cycloalkyl). Alkyl groups can be saturated or unsaturated with one or more carbon-carbon double bonds and / or carbon-carbon triple bonds.

[0222] Some exemplary compounds of formula (VIIIm) are provided in Table 8m below. [Table 8-23] [Table 8-24]

[0223] 19, compounds consistent with formula (VIIIm) can be synthesized, for example, by acylation of para-substituted aniline 8m with bromoacetyl bromide to form intermediate 9m. Intermediate 11m can be formed by alkylation of o-trifluoromethylaniline 10m with β-haloamine 12m in the presence of base. Combination of intermediate 11m with intermediate 9m in the presence of base provides compounds of formula (VIIIm).

[0224] In other embodiments, the present disclosure provides a compound of formula (VIIIn): [ka] (In the formula, A=C or N, R2=H or Me; R3=H or Me; R4=alkyl, R5=O-alkyl; If A=C, then R 10 =R 11 If A=H, or A=N, then R 10 = alkyl and R 11 = null, and alkyl = aliphatic C1-C4 alkyl).

[0225] In the compounds of formula (VIIIn), A is selected from the group consisting of carbon and nitrogen.

[0226] Each R2 and R3 is independently H or methyl, and in some embodiments, both R2 and R3 are H. In other embodiments, both R2 and R3 are methyl. In some embodiments, one of R2 and R3 is H and the other is methyl.

[0227] R4 is alkyl, which may be linear or branched, and may consist of 1 to 4 carbon atoms (i.e., C 1-4 The alkyl group may be cyclic, in which case the alkyl group may consist of 3 or 4 carbon atoms (i.e., C3-4 Cycloalkyl). Alkyl groups can be saturated or unsaturated with one or more carbon-carbon double bonds and / or carbon-carbon triple bonds.

[0228] R5 is an O-alkyl (i.e., alkoxy) in the para position. The alkyl group may be linear or branched and may consist of 1 to 4 carbon atoms (i.e., C 1-4 The alkyl group may be cyclic, in which case the alkyl group may consist of 3 or 4 carbon atoms (i.e., C 3-4 Cycloalkyl). Alkyl groups can be saturated or unsaturated with one or more carbon-carbon double bonds and / or carbon-carbon triple bonds.

[0229] If A is carbon, then R 10 and R 11 are both hydrogen. If A is nitrogen, then R 10 is alkyl, R 11 is null.

[0230] Some exemplary compounds of formula (VIIIn) are provided in Table 8n below. [Table 8-25] [Table 8-26] [Table 8-27] [Table 8-28] [Table 8-29] [Table 8-30] [Table 8-31] [Table 8-32]

[0231] 20, compounds consistent with formula (VIIIn) can be synthesized, for example, by acylation of para-substituted aniline 8n with bromoacetyl bromide to form intermediate 9n. Intermediate 11n can be formed by alkylation of aniline 10n with β-halogenated cycloamine 12n in the presence of base. Combination of intermediate 11n with intermediate 9n in the presence of base provides compounds of formula (VIIIn).

[0232] In other embodiments, the present disclosure provides a compound of formula (IX): [ka] wherein R1 is selected from the group consisting of H, m-chloro, 3,4-dichloro, o-methoxy, p-methoxy, o-methyl, m-trifluoromethoxy, m-trifluoromethyl-p-chloro, 2,5-dichloro, 3-chloro-4-fluoro, 2-fluoro-3-chloro, and o-trifluoromethyl.

[0233] Some exemplary compounds of formula (IX) are provided in Table 9 below. [Table 9]

[0234] Referring now to FIG. 21, a compound consistent with formula (IX) is, for example, para-methoxy-N-methylaniline 8. IX with bromoacetyl bromide to give the intermediate N-bromoacetyl-N-methyl-p-methoxyaniline 9. IX Intermediate 11 can be synthesized by forming IX In the presence of base, R1-substituted aniline 10 IX β-Halo-N,N-dimethylamine 12 IXIn the presence of a base, intermediate 11 can be formed by alkylation with IX to intermediate 9 IX to give a compound of formula (IX).

[0235] In other embodiments, the present disclosure provides a compound of formula (X): [ka] wherein R1 is selected from the group consisting of H, m-chloro, 3,4-dichloro, o-methoxy, p-methoxy, o-methyl, m-trifluoromethoxy, m-trifluoromethyl-p-chloro, 2,5-dichloro, 3-chloro-4-fluoro, 2-fluoro-3-chloro, and o-trifluoromethyl.

[0236] Some exemplary compounds of formula (X) are provided in Table 10 below. [Table 10]

[0237] Referring now to FIG. 22, a compound consistent with formula (X) is, for example, para-methoxy-N-methylaniline 8. X with bromoacetyl bromide to give the intermediate N-bromoacetyl-N-methyl-p-methoxyaniline 9. X Intermediate 11 can be synthesized by forming X In the presence of base, R1-substituted aniline 10 X β-haloamine 12 X In the presence of a base, intermediate 11 can be formed by alkylation with X to intermediate 9 X to give a compound of formula (X).

[0238] In other embodiments, the present disclosure provides a compound of formula (XI): [ka] wherein R1 is selected from the group consisting of H, m-chloro, 3,4-dichloro, o-methoxy, p-methoxy, o-methyl, m-trifluoromethoxy, m-trifluoromethyl-p-chloro, 2,5-dichloro, 3-chloro-4-fluoro, 2-fluoro-3-chloro, and o-trifluoromethyl.

[0239] Some exemplary compounds of formula (XI) are provided in Table 11 below. [Table 11]

[0240] Referring now to FIG. 23, a compound consistent with formula (XI) is, for example, para-methoxy-N-methylaniline 8. XI with bromoacetyl bromide to give the intermediate N-bromoacetyl-N-methyl-p-methoxyaniline 9. XI Intermediate 11 can be synthesized by forming XI In the presence of base, R1-substituted aniline 10 XI N-(β-haloethyl)piperidine 12 XI In the presence of a base, intermediate 11 can be formed by alkylation with XI to intermediate 9 XI to give a compound of formula (XI).

[0241] In other embodiments, the present disclosure provides a compound of formula (XII): [ka] wherein R1 is selected from the group consisting of H, m-chloro, 3,4-dichloro, o-methoxy, p-methoxy, o-methyl, m-trifluoromethoxy, m-trifluoromethyl-p-chloro, 2,5-dichloro, 3-chloro-4-fluoro, 2-fluoro-3-chloro, or o-trifluoromethyl.

[0242] Some exemplary compounds of formula (XII) are provided in Table 12 below. [Table 12]

[0243] Referring now to FIG. 24, a compound consistent with formula (XII) is, for example, para-methoxy-N-methylaniline 8. XII with bromoacetyl bromide to give the intermediate N-bromoacetyl-N-methyl-p-methoxyaniline 9. XII Intermediate 11 can be synthesized by forming XII In the presence of base, R1-substituted aniline 10 XII N-(β-haloethyl)-N'-methylpiperazine 12 XII In the presence of a base, intermediate 11 can be formed by alkylation with XII to intermediate 9 XII to give a compound of formula (XII).

[0244] In other embodiments, the present disclosure provides a compound of formula (XIII): [ka] (Wherein, R8 is NH2, NH(Me), N(Me)2, [ka] (selected from the group consisting of:

[0245] Some exemplary compounds of formula (XIII) are provided in Table 13 below. [Table 13]

[0246] Referring now to FIG. 25, a compound consistent with formula (XIII) is, for example, para-methoxy-N-methylaniline 8. XIII with bromoacetyl bromide to give the intermediate N-bromoacetyl-N-methyl-p-methoxyaniline 9. XIIIIntermediate 11 can be synthesized by forming XIII In the presence of base, aniline 10 XIII β-R8-substituted α-haloethane 12 XIII In the presence of a base, intermediate 11 can be formed by alkylation with XIII to intermediate 9 XIII to give a compound of formula (XIII).

[0247] In other embodiments, the present disclosure provides a compound of formula (XIV): [ka] (Wherein, R8 is NH2, NH(Me), N(Me)2, [ka] (selected from the group consisting of:

[0248] Some exemplary compounds of formula (XIV) are provided in Table 14 below. [Table 14]

[0249] Referring now to FIG. 26, a compound consistent with formula (XIV) is, for example, para-methoxy-N-methylaniline 8. XIV with bromoacetyl bromide to give the intermediate N-bromoacetyl-N-methyl-p-methoxyaniline 9. XIV Intermediate 11 can be synthesized by forming XIV m-Chloroaniline 10 in the presence of base XIV β-R8-substituted α-haloethane 12 XIV In the presence of a base, intermediate 11 can be formed by alkylation with XIV to intermediate 9 XIV to give a compound of formula (XIV).

[0250] In other embodiments, the present disclosure provides a compound of formula (XV): [ka] (Wherein, R8 is NH2, NH(Me), N(Me)2, [ka] (selected from the group consisting of:

[0251] Some exemplary compounds of formula (XV) are provided in Table 15 below. [Table 15]

[0252] Referring now to FIG. 27, a compound consistent with formula (XV) is, for example, para-methoxy-N-methylaniline 8. XV with bromoacetyl bromide to give the intermediate N-bromoacetyl-N-methyl-p-methoxyaniline 9. XV Intermediate 11 can be synthesized by forming XV In the presence of base, 3,4-dichloroaniline 10 XV β-R8-substituted α-haloethane 12 XV In the presence of a base, intermediate 11 can be formed by alkylation with XV to intermediate 9 XV to give a compound of formula (XV).

[0253] In other embodiments, the present disclosure provides a compound of formula (XVI): [ka] (Wherein, R8 is NH2, NH(Me), N(Me)2, [ka] (selected from the group consisting of:

[0254] Some exemplary compounds of formula (XVI) are provided in Table 16 below. [Table 16]

[0255] Referring now to FIG. 28, a compound consistent with formula (XVI) is, for example, para-methoxy-N-methylaniline 8. XVI with bromoacetyl bromide to give the intermediate N-bromoacetyl-N-methyl-p-methoxyaniline 9. XVI Intermediate 11 can be synthesized by forming XVI In the presence of base, o-methoxyaniline 10 XVI β-R8-substituted α-haloethane 12 XVI In the presence of a base, intermediate 11 can be formed by alkylation with XVI to intermediate 9 XVI to give a compound of formula (XVI).

[0256] In other embodiments, the present disclosure provides a compound of formula (XVII): [ka] (Wherein, R8 is NH2, NH(Me), N(Me)2, [ka] (selected from the group consisting of:

[0257] Some exemplary compounds of formula (XVII) are provided in Table 17 below. [Table 17]

[0258] Referring now to FIG. 29, a compound consistent with formula (XVII) is, for example, para-methoxy-N-methylaniline 8. XVIIwith bromoacetyl bromide to give the intermediate N-bromoacetyl-N-methyl-p-methoxyaniline 9. XVII Intermediate 11 can be synthesized by forming XVII p-Methoxyaniline 10 in the presence of base XVII β-R8-substituted α-haloethane 12 XVII In the presence of a base, intermediate 11 can be formed by alkylation with XVII to intermediate 9 XVII to give a compound of formula (XVII).

[0259] In other embodiments, the present disclosure provides a compound of formula (XVIII): [ka] (Wherein, R8 is NH2, NH(Me), N(Me)2, [ka] (selected from the group consisting of:

[0260] Some exemplary compounds of formula (XVIII) are provided in Table 18 below. [Table 18]

[0261] Referring now to FIG. 30, a compound consistent with formula (XVIII) is, for example, para-methoxy-N-methylaniline 8. XVIII with bromoacetyl bromide to give the intermediate N-bromoacetyl-N-methyl-p-methoxyaniline 9. XVIII Intermediate 11 can be synthesized by forming XVIII In the presence of base, o-methylaniline 10 XVIII (also called o-toluidine or 2-aminotoluene) is converted to β-R8-substituted α-haloethane 12 XVIII In the presence of a base, intermediate 11 can be formed by alkylation with XVIIIto intermediate 9 XVIII to give a compound of formula (XVIII).

[0262] In other embodiments, the present disclosure provides a compound of formula (XIX): [ka] (Wherein, R8 is NH2, NH(Me), N(Me)2, [ka] (selected from the group consisting of:

[0263] Some exemplary compounds of formula (XIX) are provided in Table 19 below. [Table 19]

[0264] Referring now to FIG. 31, a compound consistent with formula (XIX) is, for example, para-methoxy-N-methylaniline 8. XIX with bromoacetyl bromide to give the intermediate N-bromoacetyl-N-methyl-p-methoxyaniline 9. XIX Intermediate 11 can be synthesized by forming XIX In the presence of base, 3-trifluoromethoxyaniline 10 XIX β-R8-substituted α-haloethane 12 XIX In the presence of a base, intermediate 11 can be formed by alkylation with XIX to intermediate 9 XIX to give a compound of formula (XIX).

[0265] In other embodiments, the present disclosure provides a compound of formula (XX): [ka] (Wherein, R8 is NH2, NH(Me), N(Me)2, [ka] (selected from the group consisting of:

[0266] Some exemplary compounds of formula (XX) are provided in Table 20 below. [Table 20]

[0267] Referring now to FIG. 32, a compound consistent with formula (XX) is, for example, para-methoxy-N-methylaniline 8. XX with bromoacetyl bromide to give the intermediate N-bromoacetyl-N-methyl-p-methoxyaniline 9. XX Intermediate 11 can be synthesized by forming XX In the presence of base, 4-chloro-3-trifluoromethylaniline 10 XX β-R8-substituted α-haloethane 12 XX In the presence of a base, intermediate 11 can be formed by alkylation with XX to intermediate 9 XX When combined with the above, a compound of formula (XX) is obtained.

[0268] In other embodiments, the present disclosure provides a compound of formula (XXI): [ka] (Wherein, R8 is NH2, NH(Me), N(Me)2, [ka] (selected from the group consisting of:

[0269] Some exemplary compounds of formula (XXI) are provided in Table 21 below. [Table 21]

[0270] Referring now to FIG. 33, a compound consistent with formula (XXI) is, for example, para-methoxy-N-methylaniline 8. XXI with bromoacetyl bromide to give the intermediate N-bromoacetyl-N-methyl-p-methoxyaniline 9. XXI Intermediate 11 can be synthesized by forming XXI In the presence of base, 2,5-dichloroaniline 10 XXI β-R8-substituted α-haloethane 12 XXI In the presence of a base, intermediate 11 can be formed by alkylation with XXI to intermediate 9 XXI to give a compound of formula (XXI).

[0271] In other embodiments, the present disclosure provides a compound of formula (XXII): [ka] (Wherein, R8 is NH2, NH(Me), N(Me)2, [ka] (selected from the group consisting of:

[0272] Some exemplary compounds of formula (XXII) are provided in Table 22 below. [Table 22]

[0273] Referring now to FIG. 34, a compound consistent with formula (XXII) is, for example, para-methoxy-N-methylaniline 8. XXII with bromoacetyl bromide to give the intermediate N-bromoacetyl-N-methyl-p-methoxyaniline 9. XXII Intermediate 11 can be synthesized by forming XXII In the presence of base, 3-chloro-4-fluoroaniline 10 XXII β-R8-substituted α-haloethane 12 XXIIIn the presence of a base, intermediate 11 can be formed by alkylation with XXII to intermediate 9 XXII to give a compound of formula (XXII).

[0274] In other embodiments, the present disclosure provides a compound of formula (XXIII): [ka] (Wherein, R8 is NH2, NH(Me), N(Me)2, [ka] (selected from the group consisting of:

[0275] Some exemplary compounds of formula (XXIII) are provided in Table 23 below. [Table 23]

[0276] Referring now to FIG. 35, a compound consistent with formula (XXIII) is, for example, para-methoxy-N-methylaniline 8. XXIII with bromoacetyl bromide to give the intermediate N-bromoacetyl-N-methyl-p-methoxyaniline 9. XXIII Intermediate 11 can be synthesized by forming XXIII In the presence of base, 3-chloro-2-fluoroaniline 10 XXIII β-R8-substituted α-haloethane 12 XXIII In the presence of a base, intermediate 11 can be formed by alkylation with XXIII to intermediate 9 XXIII to give a compound of formula (XXIII).

[0277] In other embodiments, the present disclosure provides a compound of formula (XXIV): [ka] (Wherein, R8 is NH2, NH(Me), N(Me)2, [ka] (selected from the group consisting of:

[0278] Some exemplary compounds of formula (XXIV) are provided in Table 24 below. [Table 24]

[0279] Referring now to FIG. 36, a compound consistent with formula (XXIV) can be found, for example, para-methoxy-N-methylaniline 8. XXIV with bromoacetyl bromide to give the intermediate N-bromoacetyl-N-methyl-p-methoxyaniline 9. XXIV Intermediate 11 can be synthesized by forming XXIV In the presence of base, 3-chloro-2-fluoroaniline 10 XXIV β-R8-substituted α-haloethane 12 XXIV In the presence of a base, intermediate 11 can be formed by alkylation with XXIV to intermediate 9 XXIV to give a compound of formula (XXIV).

[0280] 2. Anesthetic Composition The present disclosure provides a composition comprising any one of the compounds of formula (I)-(XXIV). The compositions of the present disclosure may be in any form suitable for delivery to a subject in need thereof, including, but not limited to, topical (dermal and transdermal), injectable (IV, IM, SQ), intrathecal, oral, sublingual, buccal, otic, ophthalmic, intravesical, rectal, vaginal, inhaled, or nasal formulations.

[0281] A) Topical Compositions The composition of the present disclosure can be a topical formulation in the form of lotion, cream, gel, stick, spray, ointment or paste.In some embodiments, the composition can be applied to the skin of a subject using a dispenser.In other embodiments, the composition can be applied to the skin of a subject using a dressing, patch or pad.

[0282] In some embodiments, a compound of any one of Formulae (I)-(XXIV) is present in the topical composition in an amount effective to treat perceived pain or prevent anticipated pain in a subject after the composition is applied to the subject's skin proximal to the perceived or anticipated pain. In some embodiments, the compound is present in an amount of about 0.01% w / w to about 5% w / w, about 0.05% w / w to about 2% w / w, or about 0.1% w / w to about 1% w / w. In some embodiments, the compound is present at about 0.01% w / w, about 0.02% w / w, about 0.03% w / w, about 0.04% w / w, about 0.05% w / w, about 0.06% w / w, about 0.07% w / w, about 0.08% w / w, about 0.09% w / w, about 0.1% w / w, about 0.15% w / w, about 0.2% w / w, about 0.25% w / w, about 0.3% w / w, about 0.35% w / w. / w, about 0.4% w / w, about 0.45% w / w, about 0.5% w / w, about 0.55% w / w, about 0.6% w / w, about 0.65% w / w, about 0.7% w / w, about 0.75% w / w, about 0.8% w / w, about 0.85% w / w, about 0.9% w / w, about 0.95% w / w, about 1% w / w, about 1.1% w / w, about 1.2% w / w, about 1.3% w / w, about 1.4% w / w, about 1 0.5% w / w, about 1.6% w / w, about 1.7% w / w, about 1.8% w / w, about 1.9% w / w, about 2% w / w, about 2.1% w / w, about 2.2% w / w, about 2.3% w / w, about 2.4% w / w, about 2.5% w / w, about 2.6% w / w, about 2.7% w / w, about 2.8% w / w, about 2.9% w / w, about 3% w / w, about 3.1% w / w, about 3.2% w / w, about 3.3% w / w / w, about 3.4% w / w, about 3.5% w / w, about 3.6% w / w, about 3.7% w / w, about 3.8% w / w, about 3.9% w / w, about 4% w / w, about 4.1% w / w, about 4.2% w / w, about 4.3% w / w, about 4.4% w / w, about 4.5% w / w, about 4.6% w / w, about 4.7% w / w, about 4.8% w / w, about 4.9% w / w, or about 5% w / w.

[0283] In some embodiments, the topical composition further comprises a carrier. In some embodiments, the carrier comprises water, consists essentially of water, or consists of water. In some embodiments, the carrier comprises one or more solubilizers, such as hydrophobic solvents, amphiphilic solvents, cosolvents, emulsifiers, surfactants, etc.

[0284] In some embodiments, the topical composition further comprises a penetration enhancer, for example, to facilitate passage of the compound through the skin of the subject. For example, but not limited to, the compositions of the present disclosure can include a vasodilator.

[0285] B) Injectable preparations The compositions of the present disclosure may be injectable formulations in the form of intravenous, intramuscular, or subcutaneous formulations.

[0286] In some embodiments, a compound of any one of Formulae (I)-(XXIV) is present in the injectable composition in an amount effective to treat perceived pain or prevent anticipated pain in a subject after the composition is injected intravenously, intramuscularly, or subcutaneously into the subject. In some embodiments, the compound is present in an amount of about 0.01% w / w to about 10% w / w, about 0.1% w / w to about 8% w / w, about 1% w / w to about 6% w / w, or about 2% w / w to about 5% w / w. In some embodiments, the compound is at about 0.01% w / w, about 0.02% w / w, about 0.03% w / w, about 0.04% w / w, about 0.05% w / w, about 0.06% w / w, about 0.07% w / w, about 0.08% w / w, about 0.09% w / w, about 0.1% w / w, about 0.15% w / w, about 0.2% w / w, about 0.25% w / w, about 0.3% w / w, about 0.35% w / w, about 0.4% w / w, about 0.45% w / w, about 0.5% w / w, about 0. 55% w / w, about 0.6% w / w, about 0.65% w / w, about 0.7% w / w, about 0.75% w / w, about 0.8% w / w, about 0.85% w / w, about 0.9% w / w, about 0.95% w / w, about 1% w / w, about 1.1% w / w, about 1.2% w / w, about 1.3% w / w, about 1.4% w / w, about 1.5% w / w, about 1.6% w / w, about 1.7% w / w, about 1.8% w / w, about 1.9% w / w, about 2% w / w, about 2.1% w / w, about 2.2% w / w, about 2.3% w / w, about 2.4% w / w, about 2.5% w / w, about 2.6% w / w, about 2.7% w / w, about 2.8% w / w, about 2.9% w / w, about 3% w / w, about 3.1% w / w, about 3.2% w / w, about 3.3% w / w, about 3.4% w / w, about 3.5% w / w, about 3.6% w / w, about 3.7% w / w, about 3.8% w / w, about 3.9% w / w, about 4% w / w, about 4.1% w / w, about 4.2% w / w, about 4.3% w / w, about 4.4% w / w, about 4.5% w / w, about 4.6% w / w, about 4.7% w / w, about 4.8% w / w, about 4.9% w / w, about 5% w / w, about 5.1% w / w, about 5.2% w / w, about 5.3% w / w, about 5.4% w / w, about 5.5% w / w, about 5.6% w / w, about 5.7% w / w, about 5.8% w / w, about 5.9% w / w, about 6% w / w, about 6.1% w / w, about 6.2% w / w, about 6.3% w / w, about 6.4% w / w, about 6.5% w / w, about 6.6% w / w, about 6.7% w / w, about 6.8% w / w, about 6.9% w / w, about 7% w / w, about 7.1% w / w, about 7.2% w / w, about 7.3% w / w, about 7.4% w / w, about 7.5% w / w, about 7.6% w / w, about 7.7% w / w, about 7.8% w / w, about 7.9% w / w, about 8% w / w, about 8.1% w / w, about 8.2% w / w, about 8.3% w / w, about 8.4% w / The glycerol is present in an amount of about 8.5% w / w, about 8.6% w / w, about 8.7% w / w, about 8.8% w / w, about 8.9% w / w, about 9% w / w, about 9.1% w / w, about 9.2% w / w, about 9.3% w / w, about 9.4% w / w, about 9.5% w / w, about 9.6% w / w, about 9.7% w / w, about 9.8% w / w, about 9.9% w / w, or about 10 w / w%.

[0287] In some embodiments, the injectable composition further comprises a solvent system. The solvent system may comprise one or more solvents. In some embodiments, the solvent system comprises water (e.g., water for injection). In some embodiments, the solvent system comprises, consists essentially of, or consists of water (e.g., water for injection). In other embodiments, the solvent system comprises water (e.g., water for injection) and a co-solvent, such as polyethylene glycol 300, polyethylene glycol 400, ethanol, propylene glycol, glycerin, N-methyl-2-pyrrolidone, dimethylacetamide, and / or dimethylsulfoxide.

[0288] In some embodiments, the injectable composition further comprises an isotonicity agent, such as sodium chloride or sodium sulfite.

[0289] In some embodiments, the injectable composition includes a pH adjusting agent, such as an acid or a base.

[0290] In some embodiments, the injectable composition comprises a buffer system to maintain the pH level of the injectable composition within a desired pH range.

[0291] In some embodiments, the injectable composition comprises a non-ionic surfactant, such as Cremophor EL, Cremophor RH 40, Cremophor RH 60, d-alpha-tocopherol polyethylene glycol 1000 succinate, polysorbate 20, polysorbate 80, Solutol HS 15, sorbitan monooleate, poloxamer 407, Labrafil M-1944CS, Labrafil M-2125CS, Labrasol, Gellucire 44 / 14, Softigen 767, mono fatty acid esters of PEG 300, mono fatty acid esters of PEG 400, mono fatty acid esters of PEG 1750, di fatty acid esters of PEG 300, di fatty acid esters of PEG 400, and / or di fatty acid esters of PEG 1750.

[0292] In some embodiments, the injectable composition comprises a water-insoluble lipid such as castor oil, corn oil, cottonseed oil, olive oil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil, hydrogenated vegetable oil, hydrogenated soybean oil, medium chain triglycerides of coconut oil, and / or medium chain triglycerides of palm seed oil.

[0293] In some embodiments, the injectable composition comprises organic liquids / semi-solids such as beeswax, d-α-tocopherol, oleic acid, medium chain monoglycerides, and / or medium chain diglycerides.

[0294] In some embodiments, the injectable composition comprises a cyclodextrin, such as alpha-cyclodextrin, beta-cyclodextrin, hydroxypropyl-beta-cyclodextrin, and / or sulfobutylether-beta-cyclodextrin.

[0295] In some embodiments, the injectable composition comprises a phospholipid, such as hydrogenated soy phosphatidylcholine, distearoylphosphatidylglycerol, L-alpha-dimyristoylphosphatidylcholine and / or L-alpha-dimyristoylphosphatidylglycerol.

[0296] C) Intrathecal preparation The compositions of the present disclosure may be an intrathecal formulation in the form of a solution suitable for injection into the spinal cord or intrathecal space.

[0297] In some embodiments, a compound of any one of Formulae (I)-(XXIV) is present in the intrathecal composition in an amount effective to treat perceived pain or prevent anticipated pain in a subject after the composition is provided to the cerebrospinal fluid of the subject. In some embodiments, the compound is present in an amount of about 0.01% w / w to about 10% w / w, about 0.1% w / w to about 8% w / w, about 1% w / w to about 6% w / w, or about 2% w / w to about 5% w / w. In some embodiments, the compound is at about 0.01% w / w, about 0.02% w / w, about 0.03% w / w, about 0.04% w / w, about 0.05% w / w, about 0.06% w / w, about 0.07% w / w, about 0.08% w / w, about 0.09% w / w, about 0.1% w / w, about 0.15% w / w, about 0.2% w / w, about 0.25% w / w, about 0.3% w / w, about 0.35% w / w, about 0.4% w / w, about 0.45% w / w, about 0.5% w / w, about 0.55% w / w, about 0.60% w / w, about 0.65% w / w, about 0.70% w / w, about 0.75% w / w, about 0.80% w / w, about 0.85% w / w, about 0.90% w / w, about 0.10% w / w, about 0.15% w / w, about 0.20% w / w, about 0.25% w / w, about 0.30% w / w, about 0.35% w / w, about 0.40% w / w, about 0.45% w / w, about 0.55% w / w, about 0.55% w / w, about 0.60% w / w, about 0.70% w / w, about 0.80% w / w, about 0.90% w / w, about 0.10% w / w, about 0.15% w / w, about 0.20% w / w, about 0.25% w / w, about 0.30% w / w, about 0.35% w / w, about %w / w, about 0.6%w / w, about 0.65%w / w, about 0.7%w / w, about 0.75%w / w, about 0.8%w / w, about 0.85%w / w, about 0.9%w / w, about 0.95%w / w, about 1%w / w, about 1.1%w / w, about 1.2%w / w, about 1.3%w / w, about 1.4%w / w, about 1.5%w / w, about 1.6%w / w, about 1.7%w / w, about 1.8%w / w, about 1.9%w / w, about 2%w / w, about 2.1%w / w, about 2.2%w / w, about 2.3 %w / w, about 2.4%w / w, about 2.5%w / w, about 2.6%w / w, about 2.7%w / w, about 2.8%w / w, about 2.9%w / w, about 3%w / w, about 3.1%w / w, about 3.2%w / w, about 3.3%w / w, about 3.4%w / w, about 3.5%w / w, about 3.6%w / w, about 3.7%w / w, about 3.8%w / w, about 3.9%w / w, about 4%w / w, about 4.1%w / w, about 4.2%w / w, about 4.3%w / w, about 4.4%w / w, about 4.5%w / w , about 4.6% w / w, about 4.7% w / w, about 4.8% w / w, about 4.9% w / w, about 5% w / w, about 5.1% w / w, about 5.2% w / w, about 5.3% w / w, about 5.4% w / w, about 5.5% w / w, about 5.6% w / w, about 5.7% w / w, about 5.8% w / w, about 5.9% w / w, about 6% w / w, about 6.1% w / w, about 6.2% w / w, about 6.3% w / w, about 6.4% w / w, about 6.5% w / w, about 6.6% w / w, about 6.7% w / w, about 6.8% w / w, about 6.9% w / w, about 7% w / w, about 7.1% w / w, about 7.2% w / w, about 7.3% w / w, about 7.4% w / w, about 7.5% w / w, about 7.6% w / w, about 7.7% w / w, about 7.8% w / w, about 7.9% w / w, about 8% w / w, about 8.1% w / w, about 8.2% w / w, about 8.3% w / w, about 8.4% w / w, about 8 The composition is present in an amount of about 0.5% w / w, about 8.6% w / w, about 8.7% w / w, about 8.8% w / w, about 8.9% w / w, about 9% w / w, about 9.1% w / w, about 9.2% w / w, about 9.3% w / w, about 9.4% w / w, about 9.5% w / w, about 9.6% w / w, about 9.7% w / w, about 9.8% w / w, about 9.9% w / w, or about 10 w / w%.

[0298] In some embodiments, the intrathecal composition further comprises a solvent system. The solvent system may comprise one or more solvents. In some embodiments, the solvent system comprises water (e.g., water for injection). In some embodiments, the solvent system comprises, consists essentially of, or consists of water (e.g., water for injection). In other embodiments, the solvent system comprises water (e.g., water for injection) and a co-solvent, such as polyethylene glycol 300, polyethylene glycol 400, ethanol, propylene glycol, glycerin, N-methyl-2-pyrrolidone, dimethylacetamide, and / or dimethylsulfoxide.

[0299] In some embodiments, the osmolality of the intrathecal composition is from about 260 mOsm / kg to about 320 mOsm / kg.

[0300] In some embodiments, the intrathecal composition further comprises an isotonicity agent, such as sodium chloride or sodium sulfite.

[0301] In some embodiments, the intrathecal composition includes a pH adjusting agent, such as an acid or a base.

[0302] In some embodiments, the intrathecal composition comprises a buffer system to maintain the pH level of the intrathecal composition within a desired pH range.

[0303] In some embodiments, the intrathecal composition comprises a non-ionic surfactant, such as Cremophor EL, Cremophor RH 40, Cremophor RH 60, d-alpha-tocopherol polyethylene glycol 1000 succinate, polysorbate 20, polysorbate 80, Solutol HS 15, sorbitan monooleate, poloxamer 407, Labrafil M-1944CS, Labrafil M-2125CS, Labrasol, Gellucire 44 / 14, Softigen 767, mono fatty acid esters of PEG 300, mono fatty acid esters of PEG 400, mono fatty acid esters of PEG 1750, di fatty acid esters of PEG 300, di fatty acid esters of PEG 400, and / or di fatty acid esters of PEG 1750.

[0304] In some embodiments, the intrathecal composition comprises a water-insoluble lipid such as castor oil, corn oil, cottonseed oil, olive oil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil, hydrogenated vegetable oil, hydrogenated soybean oil, medium chain triglycerides of coconut oil, and / or medium chain triglycerides of palm seed oil.

[0305] In some embodiments, the intrathecal composition comprises an organic liquid / semi-solid such as beeswax, d-α-tocopherol, oleic acid, medium chain monoglycerides, and / or medium chain diglycerides.

[0306] In some embodiments, the intrathecal composition comprises a cyclodextrin, such as alpha-cyclodextrin, beta-cyclodextrin, hydroxypropyl-beta-cyclodextrin, and / or sulfobutylether-beta-cyclodextrin.

[0307] In some embodiments, the intrathecal composition comprises a phospholipid, such as hydrogenated soy phosphatidylcholine, distearoylphosphatidylglycerol, L-alpha-dimyristoylphosphatidylcholine and / or L-alpha-dimyristoylphosphatidylglycerol.

[0308] D) Oral Formulations The compositions of the present disclosure may be in oral dosage formulations in the form of capsules, lozenges, syrups, solutions, elixirs, emulsions, tinctures, decoctions, tablets, films, or powders.

[0309] In some embodiments, a compound of any one of Formulae (I)-(XXIV) is present in the oral composition in an amount effective to treat perceived pain or prevent anticipated pain in a subject after the composition is ingested by the subject. In some embodiments, the compound is present in an amount of about 0.01% w / w to about 10% w / w, about 0.1% w / w to about 8% w / w, about 1% w / w to about 6% w / w, or about 2% w / w to about 5% w / w. In some embodiments, the compound is present at about 0.01% w / w, about 0.02% w / w, about 0.03% w / w, about 0.04% w / w, about 0.05% w / w, about 0.06% w / w, about 0.07% w / w, about 0.08% w / w, about 0.09% w / w, about 0.1% w / w, about 0.15% w / w, about 0.2% w / w, about 0.25% w / w, about 0.3% w / w, about 0.35% w / w, about 0.4% w / w, about 0.45% w / w, about 0.5% w / w, about 0.55% w / w, w, about 0.6% w / w, about 0.65% w / w, about 0.7% w / w, about 0.75% w / w, about 0.8% w / w, about 0.85% w / w, about 0.9% w / w, about 0.95% w / w, about 1% w / w, about 1.1% w / w, about 1.2% w / w, about 1.3% w / w, about 1.4% w / w, about 1.5% w / w, about 1.6% w / w, about 1.7% w / w, about 1.8% w / w, about 1.9% w / w, about 2% w / w, about 2.1% w / w, about 2.2% w / w, about 2.3% w / w, About 2.4% w / w, about 2.5% w / w, about 2.6% w / w, about 2.7% w / w, about 2.8% w / w, about 2.9% w / w, about 3% w / w, about 3.1% w / w, about 3.2% w / w, about 3.3% w / w, about 3.4% w / w, about 3.5% w / w, about 3.6% w / w, about 3.7% w / w, about 3.8% w / w, about 3.9% w / w, about 4% w / w, about 4.1% w / w, about 4.2% w / w, about 4.3% w / w, about 4.4% w / w, about 4.5% w / w, about 4.6% w / w, about 4.7%w / w, about 4.8%w / w, about 4.9%w / w, about 5%w / w, about 5.1%w / w, about 5.2%w / w, about 5.3%w / w, about 5.4%w / w, about 5.5%w / w, about 5.6%w / w, about 5.7%w / w, about 5.8%w / w, about 5.9%w / w, about 6%w / w, about 6.1%w / w, about 6.2%w / w, about 6.3%w / w, about 6.4%w / w, about 6.5%w / w, about 6.6%w / w, about 6.7%w / w, about 6.8%w / w, about 6.9% w / w, about 7% w / w, about 7.1% w / w, about 7.2% w / w, about 7.3% w / w, about 7.4% w / w, about 7.5% w / w, about 7.6% w / w, about 7.7% w / w, about 7.8% w / w, about 7.9% w / w, about 8% w / w, about 8.1% w / w, about 8.2% w / w, about 8.3% w / w, about 8.4% w / w, about 8.5% w / The glycerol is present in an amount of about 8.6% w / w, about 8.7% w / w, about 8.8% w / w, about 8.9% w / w, about 9% w / w, about 9.1% w / w, about 9.2% w / w, about 9.3% w / w, about 9.4% w / w, about 9.5% w / w, about 9.6% w / w, about 9.7% w / w, about 9.8% w / w, about 9.9% w / w, or about 10 w / w%.

[0310] In some embodiments, the oral composition includes an outer coating material, such as a polyvinyl alcohol-based film coating system (e.g., Opadry Clear Coating system 85F190000, further including talc and PEG). When present, the outer coating material may comprise about 4% w / w to about 14% w / w (e.g., about 4% w / w, about 6% w / w, about 8% w / w, about 10% w / w, about 12% w / w, or about 14% w / w) relative to the weight of the other components of the oral composition.

[0311] In some embodiments, the oral compositions may further comprise a disintegrant, such as alginic acid (Kelacid™, Protacid™, Satialgine H8™), calcium phosphate tribasic (Tri-Cafos™, TRI-CAL WG™, TRI-TAB™), calcium carboxymethylcellulose (ECG 505™, Nymcel ZSC™), sodium carboxymethylcellulose (Akucell™, Aquasorb™, Blanose™, Finnfix™, Nymcel Tylose CB™), colloidal silicon dioxide (Aerosil™, Cab-O-Sil™, Cab-O-Si™-5P™, Wacker HDK™), croscarmellose sodium (Ac-Di-SoI™, Explocel™, Nymcel ZSX™, Pharmacel XL™, Primellose™, Solutab™, Vivasol™), Crospovidone (Kollidon CL™, Kollidon CL-M™, Polyplasdone XL™, Polyplasdone XL-IO™), Docusate Sodium, Guar Gum (Galactosol™, Meprogat™, Meyprodor™, Meyprofin™, Meyproguar™), Low-substituted Hydroxypropylcellulose, Magnesite Aluminum Silicate (Carrisorb™, Gelsorb™, Magnabite™, Neusilin™, Pharmsorb™, Veegum™), Methylcellulose (Benecel™, Culminal MC™, Methocel™, Metolose™), Microcrystalline Cellulose (Avicel™, PH(TM), Celex(TM), Celphere(TM), CeolusKG™, Emcoel™, Ethispheres™, Fibrocel™, Pharmacel™, Tabulose™, Vivapur™), Povidone (Kollidon™, Plasdone™), Sodium Alginate (Kelcosol™, Keltone™, Protanal™), Sodium Starch Glycolate (Explotab™, Primojel™, Vivastar P™), Polacrilin Potassium (Amberlite IRP88™), Silica-Silic Microcrystalline Cellulose (ProSolv™), Starch (Aytex P™, Fluftex W™, Instant Pure-Cote™, Melojel™, Meritena™, Paygel 55™, Perfectamyl D6PH™, Pure-Bind™, Pure-Cote™, Pure-Dent™, Pure-Gel™, Pure-Set™, Purity 21™, Purity 826™, Tablet White™) or pregelatinized starch (Instanstarch™, Lycatab C™, Lycatab PGS™, Merigel™, National 78-1551™, Pharma-Gel™, Prejel™, Sepistab ST 200™, Spress B820™, Starch 1500 G™, Tablitz™, Unipure LD™ and Unipure WG220™), or mixtures thereof. If present, the disintegrant may constitute about 2% w / w to about 16% w / w (e.g., about 2% w / w, about 4% w / w, about 6% w / w, about 8% w / w, about 10% w / w, about 12% w / w, about 14% w / w or about 16% w / w) of the total weight of the oral composition.

[0312] In some embodiments, the oral compositions may contain binders such as acacia, alginic acid (Kelacid™, Protacid™, Satialgine H8™), carbomer (Acritamer™, Carbopol™, Pemulen™, Ultrez™), sodium carboxymethylcellulose (Akucell™, Aquasorb™, Blanose™, Finnfix™, Nymcel™, Tylose™), ceratonia (Meyprofleur™), cottonseed oil, dextrin (Avedex™, Caloreen™, Crystal Gum™, Primogran W™), dextrose (Caridex™, Dextrofm™, Lycedex PF™, Roferose™, Tabfme™), glycerol (Glycerol™, G ... D-IOO™), Gelatin (Cryogel™, Instagel™, Solugel™), Guar Gum (Galactosol™, Meprogat™, Meyprodor™, Meyprofm™, Meyproguar™), Hydrogenated Vegetable Oil Type I (Akofine™, Lubritab™, Sterotex™, Dynasan P[omicron]O™, Softisan 154™, Hydrocote™, Lipovol™, HS-K™, Sterotex HM™), Hydroxyethylcellulose (Alcoramnosan™, Cellosize™, Idroramnosan™, Liporamnosan™, Natrosol™, Tylose PHA™), Hydroxyethylmethylcellulose (Culminal™, Tylopur™, MH™, Tylopur MHB™, Tylose MB™, Tylose MH™, Tylose MHB™), Hydroxypropylcellulose (Klucel™, Methocel™ Nisso HPC™), Low-substituted Hydroxypropylcellulose, Hypromellose (BenecelMHPC (trademark), Methocel (trademark), Metolose (trademark), Pharmacoat (trademark), Spectracel 6 (trademark), Spectracel 15 (trademark), Tylopur (trademark), acetylamino amide Magnesium (Carrisorb (trademark), Gelsorb (trademark), Magnabite (trademark), Neusilin (trademark), Pharmsorb (trademark), Veegum (trademark)), Maltodextrin (C*Dry MD (trademark), Glucidex (trademark), Glucodry (trademark), Lycatab DSH (trademark), Maldex (trademark), Maltagran (trademark), Maltrin (trademark), Maltrin QD (trademark), Paselli MD 10 PH (trademark), Star-Dri (trademark)), Maltos (Advantose 100(trademark)), Methicelloses (Benecel(trademark), Culminal MC(trademark), Methocel(trademark), Metolose(trademark)), Microcrystalline celloyses (Avicel PH(trademark), CelexV(trademark), Celphere(trademark), Ceolus KG(trademark), Emcocel(trademark), Ethispheres(trademark), Fibrocel(trademark), Pharmacel(trademark), Tabulose(trademark), Vivapur(trademark)), Polydectes (Litesse(trademark)), Polyethylene Glycol (Polyox(trademark)), Polymedacryl (Eastacryl 30D(trademark), Eudragit(trademark), Kollicoat MAE 30D(trademark), Kollicoat MAE 30DP (trademark)), Popiton (Kollidon (trademark), Plasdone (trademark)), Natrium Alginate (Kelcosol (trademark), Keltone (trademark), Protanal (trademark)), Denpon (Aytex P (trademark), Fluftex W (trademark), Instant Pure-Cote (trademark), Melojel (trademark), Meritena Paygel 55 (trademark), Perfectamyl D6PH (trademark), Pure-Bind (trademark), Pure-Cote (trademark), Pure-Dent (trademark), Pure-Gel (trademark), Pure-Set (trademark), Purity 21 (trademark), Purity826™, Tablet White™), pregelatinized starch (Instastarch™, Lycatab C™, Lycatab PGS™, Merigel™, National 78-1551™, Pharma-Gel™, Prejel™, Sepistab ST 200™, Spress B820™, Starch 1500 G™, Tablitz™, Unipure LD™, Unipure WG 220™), stearic acid (Crodacid™, Emersol Hystrene™, Industrene™, Kortacid 1895™, Pristerene™), sucrose and zein, or mixtures thereof. If present, the binder may constitute from about 0.5% w / w to about 20% w / w (e.g., about 0.5% w / w, about 1% w / w, about 2% w / w, about 3% w / w, about 4% w / w, about 5% w / w, about 6% w / w, about 7% w / w, about 8% w / w, about 9% w / w, about 10% w / w, about 11% w / w, about 12% w / w, about 13% w / w, about 14% w / w, about 15% w / w, about 16% w / w, about 17% w / w, about 18% w / w, about 19% w / w or about 20% w / w) of the total weight of the oral composition.

[0313] In some embodiments, the oral compositions may further comprise a diluent (also called a bulking agent), such as calcium carbonate (Barcroft™, Cal-Carb™, CalciPure™, Destab™, MagGran™, Millicarb™, Pharma-Carb™, Precarb™, Sturcal™, Vivapres Ca™), calcium phosphate dibasic anhydrous (A-TAB™, Di-Cafos AN™, Emcompress Anhydrous™, Fujicalin™), calcium phosphate dibasic dihydrate (Cafos™, Calipharm™, Calstar™, Di-Cafos™, Emcompress™), calcium phosphate tribasic (Tri-Cafos™, TRI-CAL WG™, TRI-TAB™), calcium sulfate (Destab™, Drierite™, Snow White™, Cal-Tab™, Compactrol™, USG Terra Alba™), Cellulose Powder (Arbocel™, Elcema™, Sanacel™, Solka-Floc™), Silicified Microcrystalline Cellulose (ProSolv™), Cellulose Acetate, Compressible Sugar (Di-Pac™), Refined Sugar, Dextran (Candex™, Emdex™), Dextrin (Avedex™, Caloreen™, Crystal Gum™, Primogran W™), Dextrose (Caridex™, Dextrofin™, Lycadex PF™, Roferose™, Tab fine DT-IOO™), Fructose (Advantose™, Fructamyl™, Fructofin™, Krystar™), Kaolin (Lion™, Sim 90™), Lactitol (Finlac ACX™, Finlac DC™, Finlac MCX™), Lactose (Aero Flo 20™, Aero Flo65(trademark), Anhydrox(trademark), CapsuLac(trademark), Fast-Flo(trademark), FlowLac(trademark), GranuLac(trademark), InhaLac(trademark), Lactochem(trademark), Lactohale(trademark), Lactopressr(trademark), Microfine(trademark), Microtose(trademark), Pharmatose(trademark), Prisma Lac(trademark), Respitose(trademark), SacheLac(trademark), SorboLac(trademark), Super-Tab(trademark), Tablettose(trademark), Wyndale(trademark), Zeparox(trademark), Carbonic acid Magnesium, Acidified Magnesium (MagGran MO(trademark)), Marudecistrin (C*Dry MD(trademark), Glucidex(trademark), Glucodry(trademark), Lycatab DSH (trademark), Maldex (trademark), Maltagran (trademark), Maltrin (trademark), Maltrin QD (trademark), Paselli MD 10 PH (trademark), Star-Dri (trademark), Marutol (Advantose 100 (trademark)), Mannitol (Mannogem (trademark), Pearlitol (trademark)), Microcrystalline Celulose (Avicel PH (trademark), Celex (trademark), Celphere (trademark), Ceolus KG (trademark), Emcocel (trademark), Ethispheres (trademark), Fibrocel (trademark), Pharmacel (trademark), Tabulose (trademark), Vivapur (trademark)), Polydecesto (Litesse (trademark)), Cimetcon (Dow Corning Q7-2243 LVA (trademark), Cow Corning Q7-2587 (trademark), Sentry Simethicone (trademark)), alginic acid natrium (Kelcosol (trademark), Keltone (trademark), Protanal (trademark)), salinated natrium (Alberger (trademark)), solvate (Liponec 70-NC (trademark), Liponic 76-NCv, Meritol (trademark), Neosorb (trademark), Sorbifin (trademark), Sorbitol Instant (trademark), Sorbogem (trademark)), denpon (Aytex P (trademark), Fluftex W (trademark), InstantPure-Cote(TM), Melojel(TM), Meritena Paygel 55(TM), Perfectamyl D6PH(TM), Pure-Bind(TM), Pure-Cote(TM), Pure-Dent(TM), Pure-Gel(TM), Pure-Set(TM), Purity 21(TM), Purity 826(TM), Tablet White(TM)), pregelatinized starch (Instastarch(TM), Lycatab C(TM), Lycatab PGS(TM), Merigel(TM), National 78-1551(TM), Pharma-Gel(TM), Prejel(TM), Sepistab ST 200(TM), Spress B820(TM), Starch 1500 G(trademark), Tablitz(trademark), Unipure LD(trademark), Unipure WG220™), sucrose, trehalose and xylitol (Klinit™, Xylifm™, Xylitab™, Xylisorb™, Xylitolo™), or mixtures thereof. When present, the diluent may constitute up to about 20% w / w (e.g., about 1% w / w, about 2% w / w, about 3% w / w, about 4% w / w, about 5% w / w, about 6% w / w, about 7% w / w, about 8% w / w, about 9% w / w, about 10% w / w, about 11% w / w, about 12% w / w, about 13% w / w, about 14% w / w, about 15% w / w, about 16% w / w, about 17% w / w, about 18% w / w, about 19% w / w, or about 20% w / w) of the total weight of the oral composition.

[0314] In some embodiments, the oral composition may contain lubricants such as calcium stearate (HyQual™), glyceryl monostearate (Capmul GMS-50™, Cutina GMS™, Imwitor™ 191 and 900, Kessco GMS5™, Lipo GMS™ 410, 450 and 600, Myvaplex 600P™, Myvatex™, Protachem GMS-450™, Rita GMS™, Stepan GMS™, Tegin™, Tegin™ 503 and 515, Tegin 4100™, Tegin M™, Unimate GMS™), glyceryl behenate (Compritol 888 ATO™), glyceryl palmitostearate (Precirol ATO™), glyceryl stearate (Glyceryl Palmitostearate ... 5™), Hydrogenated Castor Oil (Castorwax™, Castorwax MP 70™, Castorwax MP 80™, Crodure™, Cutina HR™, Fancol™, Simulsol 1293™), Hydrogenated Vegetable Oil Type I (Akofine™, Lubritab™, Sterotex™, Dynasan P60™, Softisan 154™, Hydrocote™, Lipovol HS-K™, Sterotex HM™), Magnesium Lauryl Sulfate, Magnesium Stearate, Medium Chain Triglycerides (Captex 300™, Captex 355™, Crodamol GTC / C™, Labrafac CC™, Miglyol 810™, Miglyol 812(TM), Myritol(TM), Neobee M5(TM), Nesatol(TM), Waglinol 3 / 9280(TM)), Poloxamers (Lutrol(TM), Monolan(TM), Pluronic(TM), Synperonic(TM)), Polyethylene Glycol(Carbowax(TM)), Carbowax Sentry(TM), Lipo(TM), Lipoxol(TM), Lutrol E(TM), PluriolE™), sodium benzoate (Antimol™), sodium chloride (Alberger™), sodium lauryl sulfate (Elfan 240™, Texapon K1 2P™), sodium stearyl fumarate (Pruvr™), stearic acid (Crodacid E570™, Emersol™, Hystrene™, Industrene™, Kortacid 1895™, Pristerene™), talc (Altaic™, Luzenac™, Luzenac Pharma™, Magsil Osmanthus™, Magsil Star™, Superiore™), sucrose stearate (Surfhope SE Pharma D-1803 F™) and zinc stearate (HyQual™), or mixtures thereof. If present, the lubricant may constitute from about 0.1% w / w to about 6% w / w (e.g., about 0.1% w / w, about 0.25% w / w, about 0.5% w / w, about 0.75% w / w, about 1% w / w, about 2% w / w, about 3% w / w, about 4% w / w, about 5% w / w or about 6% w / w) of the total weight of the oral composition.

[0315] In some embodiments, the oral composition may contain glidants such as tribasic calcium phosphate (Tri-Cafos™, TRI-CAL™, TRI-TAB™), calcium silicate, cellulose, powders (Arbocel™, Elcema™, Sanacel™, Solka-Floc™), colloidal silicon dioxide (Aerosil™, Cab-O-Sil™, Cab-O-Sil M-5P™, Wacker HDK™), magnesium silicate, magnesium trisilicate, starch (Aytex P™, Fluftex W™, Instant Pure-Cote™, Melojel™, Meritena™, Paygel 55™, Perfectamyl D6PH™, Pure-Bind™, Pure-Cote™, Pure-Dent™, Pure-Gel™, Pure-Set™, Purity21™, Purity826™, Tablet White™) and talc (Altaic™, Luzenac™, Luzenac Pharma™, Magsil Osmanthus™, Magsil Star™, Superiore™), or mixtures thereof. When present, the glidant may comprise from about 0.1% w / w to about 4% w / w (e.g., about 0.1% w / w, about 0.25% w / w, about 0.5% w / w, about 0.75% w / w, about 1% w / w, about 2% w / w, about 3% w / w, or about 4% w / w) of the total weight of the oral composition.

[0316] In some embodiments, the oral composition further comprises an inner protective barrier coating material, such as a methacrylic acid and ethyl acrylate copolymer system (e.g., Acrylic-EZE II), a methacrylic acid, methyl methacrylate (1:1) polymer system (e.g., Eudragit L100), a methacrylic acid, methyl methacrylate (1:2) polymer system (e.g., Eudragit S100), or a hydroxypropyl methylcellulose-based film coating system (e.g., Opadry Complete film coating system 03B28796 further comprising titanium dioxide and PEG). The protective barrier coating material may be present in an amount of about 1% w / w to about 10% w / w (e.g., about 2% w / w or about 4% w / w) of the oral composition weight.

[0317] E) Sublingual Formulations The compositions of the present disclosure may be in a sublingual formulation in the form of a sublingual tablet, a sublingual strip, a dissolvable sublingual tablet, a sublingual drop, a sublingual spray, a lozenge, or an effervescent sublingual tablet.

[0318] In some embodiments, a compound of any one of Formulae (I)-(XXIV) is present in the sublingual composition in an amount effective to treat perceived pain or prevent anticipated pain in a subject after the composition is absorbed by the mucosa of the subject. In some embodiments, the compound is present in an amount of about 0.01% w / w to about 10% w / w, about 0.1% w / w to about 8% w / w, about 1% w / w to about 6% w / w, or about 2% w / w to about 5% w / w. In some embodiments, the compound is at about 0.01% w / w, about 0.02% w / w, about 0.03% w / w, about 0.04% w / w, about 0.05% w / w, about 0.06% w / w, about 0.07% w / w, about 0.08% w / w, about 0.09% w / w, about 0.1% w / w, about 0.15% w / w, about 0.2% w / w, about 0.25% w / w, about 0.3% w / w, about 0.35% w / w, about 0.4% w / w, about 0.45% w / w, about 0.5% w / w, about 0.55% w / w, about 0.60% w / w, about 0.65% w / w, about 0.70% w / w, about 0.75% w / w, about 0.80% w / w, about 0.85% w / w, about 0.90% w / w, about 0.10% w / w, about 0.15% w / w, about 0.20% w / w, about 0.25% w / w, about 0.30% w / w, about 0.35% w / w, about 0.40% w / w, about 0.45% w / w, about 0.55% w / w, about 0.55% w / w, about 0.60% w / w, about 0.70% w / w, about 0.80% w / w, about 0.90% w / w, about 0.10% w / w, about 0.15% w / w, about 0.20% w / w, about 0.25% w / w, about 0.30% w / w, about 0.35% w / w, about %w / w, about 0.6%w / w, about 0.65%w / w, about 0.7%w / w, about 0.75%w / w, about 0.8%w / w, about 0.85%w / w, about 0.9%w / w, about 0.95%w / w, about 1%w / w, about 1.1%w / w, about 1.2%w / w, about 1.3%w / w, about 1.4%w / w, about 1.5%w / w, about 1.6%w / w, about 1.7%w / w, about 1.8%w / w, about 1.9%w / w, about 2%w / w, about 2.1%w / w, about 2.2%w / w, about 2.3 %w / w, about 2.4%w / w, about 2.5%w / w, about 2.6%w / w, about 2.7%w / w, about 2.8%w / w, about 2.9%w / w, about 3%w / w, about 3.1%w / w, about 3.2%w / w, about 3.3%w / w, about 3.4%w / w, about 3.5%w / w, about 3.6%w / w, about 3.7%w / w, about 3.8%w / w, about 3.9%w / w, about 4%w / w, about 4.1%w / w, about 4.2%w / w, about 4.3%w / w, about 4.4%w / w, about 4.5%w / w , about 4.6% w / w, about 4.7% w / w, about 4.8% w / w, about 4.9% w / w, about 5% w / w, about 5.1% w / w, about 5.2% w / w, about 5.3% w / w, about 5.4% w / w, about 5.5% w / w, about 5.6% w / w, about 5.7% w / w, about 5.8% w / w, about 5.9% w / w, about 6% w / w, about 6.1% w / w, about 6.2% w / w, about 6.3% w / w, about 6.4% w / w, about 6.5% w / w, about 6.6% w / w, about 6.7% w / w, about 6.8% w / w, about 6.9% w / w, about 7% w / w, about 7.1% w / w, about 7.2% w / w, about 7.3% w / w, about 7.4% w / w, about 7.5% w / w, about 7.6% w / w, about 7.7% w / w, about 7.8% w / w, about 7.9% w / w, about 8% w / w, about 8.1% w / w, about 8.2% w / w, about 8.3% w / w, about 8.4% w / w, about 8 The composition is present in an amount of about 0.5% w / w, about 8.6% w / w, about 8.7% w / w, about 8.8% w / w, about 8.9% w / w, about 9% w / w, about 9.1% w / w, about 9.2% w / w, about 9.3% w / w, about 9.4% w / w, about 9.5% w / w, about 9.6% w / w, about 9.7% w / w, about 9.8% w / w, about 9.9% w / w, or about 10 w / w%.

[0319] In some embodiments, the sublingual composition is a molded sublingual tablet comprising an effective amount of a compound of any one of Formulae (I)-(XXIV) in addition to excipients such as lactose, dextrose, sucrose, mannitol, finely divided kaolin, calcium carbonate, calcium phosphate, antioxidants (e.g., sodium bisulfate), buffers, glucose, sucrose, acacia, povidone, or a mixture of any two or more of the foregoing.

[0320] In some embodiments, the sublingual composition is a compressed sublingual tablet comprising an effective amount of a compound of any one of Formulae (I)-(XXIV) in addition to a disintegrant (e.g., a superdisintegrant), a lubricant, microcrystalline cellulose, a dry binder, a buffer system, a surfactant, a sweetener, a flavoring, a filler (e.g., a sugar-based filler), a sugar-based material, an effervescent agent, or a mixture of any two or more of the foregoing.

[0321] F) Buccal preparation The compositions of the present disclosure may be in a buccal formulation in the form of a buccal tablet, such as an effervescent buccal tablet.

[0322] In some embodiments, a compound of any one of Formulae (I)-(XXIV) is present in the buccal composition in an amount effective to treat perceived pain or prevent anticipated pain in a subject after the composition is absorbed by the mucous membrane of the subject. In some embodiments, the compound is present in an amount of about 0.01% w / w to about 10% w / w, about 0.1% w / w to about 8% w / w, about 1% w / w to about 6% w / w, or about 2% w / w to about 5% w / w. In some embodiments, the compound is at about 0.01% w / w, about 0.02% w / w, about 0.03% w / w, about 0.04% w / w, about 0.05% w / w, about 0.06% w / w, about 0.07% w / w, about 0.08% w / w, about 0.09% w / w, about 0.1% w / w, about 0.15% w / w, about 0.2% w / w, about 0.25% w / w, about 0.3% w / w, about 0.35% w / w, about 0.4% w / w, about 0.45% w / w, about 0.5% w / w, about 0.55% w / w, about 0.60% w / w, about 0.65% w / w, about 0.70% w / w, about 0.75% w / w, about 0.80% w / w, about 0.85% w / w, about 0.90% w / w, about 0.10% w / w, about 0.15% w / w, about 0.20% w / w, about 0.25% w / w, about 0.30% w / w, about 0.35% w / w, about 0.40% w / w, about 0.45% w / w, about 0.55% w / w, about 0.55% w / w, about 0.60% w / w, about 0.70% w / w, about 0.80% w / w, about 0.90% w / w, about 0.10% w / w, about 0.15% w / w, about 0.20% w / w, about 0.25% w / w, about 0.30% w / w, about 0.35% w / w, about %w / w, about 0.6%w / w, about 0.65%w / w, about 0.7%w / w, about 0.75%w / w, about 0.8%w / w, about 0.85%w / w, about 0.9%w / w, about 0.95%w / w, about 1%w / w, about 1.1%w / w, about 1.2%w / w, about 1.3%w / w, about 1.4%w / w, about 1.5%w / w, about 1.6%w / w, about 1.7%w / w, about 1.8%w / w, about 1.9%w / w, about 2%w / w, about 2.1%w / w, about 2.2%w / w, about 2.3 %w / w, about 2.4%w / w, about 2.5%w / w, about 2.6%w / w, about 2.7%w / w, about 2.8%w / w, about 2.9%w / w, about 3%w / w, about 3.1%w / w, about 3.2%w / w, about 3.3%w / w, about 3.4%w / w, about 3.5%w / w, about 3.6%w / w, about 3.7%w / w, about 3.8%w / w, about 3.9%w / w, about 4%w / w, about 4.1%w / w, about 4.2%w / w, about 4.3%w / w, about 4.4%w / w, about 4.5%w / w , about 4.6% w / w, about 4.7% w / w, about 4.8% w / w, about 4.9% w / w, about 5% w / w, about 5.1% w / w, about 5.2% w / w, about 5.3% w / w, about 5.4% w / w, about 5.5% w / w, about 5.6% w / w, about 5.7% w / w, about 5.8% w / w, about 5.9% w / w, about 6% w / w, about 6.1% w / w, about 6.2% w / w, about 6.3% w / w, about 6.4% w / w, about 6.5% w / w, about 6.6% w / w, about 6.7% w / w, about 6.8% w / w, about 6.9% w / w, about 7% w / w, about 7.1% w / w, about 7.2% w / w, about 7.3% w / w, about 7.4% w / w, about 7.5% w / w, about 7.6% w / w, about 7.7% w / w, about 7.8% w / w, about 7.9% w / w, about 8% w / w, about 8.1% w / w, about 8.2% w / w, about 8.3% w / w, about 8.4% w / w, about 8 The composition is present in an amount of about 0.5% w / w, about 8.6% w / w, about 8.7% w / w, about 8.8% w / w, about 8.9% w / w, about 9% w / w, about 9.1% w / w, about 9.2% w / w, about 9.3% w / w, about 9.4% w / w, about 9.5% w / w, about 9.6% w / w, about 9.7% w / w, about 9.8% w / w, about 9.9% w / w, or about 10 w / w%.

[0323] In some embodiments, the buccal composition further comprises a penetration enhancer, such as a surfactant (e.g., sodium lauryl sulfate, cetylpyridinium chloride, poloxamer, Brij®, Span®, Myrj, or Tween®), a bile salt (e.g., sodium glycocholate, sodium taurodeoxycholate, or sodium taurocholate), a fatty acid (e.g., oleic acid, caprylic acid, lauric acid, lysophosphatidylcholine or phosphatidylcholine), a cyclodextrin (e.g., α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, or methylated β-cyclodextrin), a chelating agent (e.g., EDTA, citric acid, sodium salicylate or methoxy salicylate), a positively charged polymer (e.g., chitosan or trimethylchitosan), or a cationic compound (e.g., poly-L-arginine or L-lysine).

[0324] In some embodiments, the buccal composition further comprises an enzyme inhibitor, such as aprotinin, bestatin, puromycin, any bile salt, polyacrylic acid (e.g., carbomer), chitosan derivatives (e.g., chitosan-EDTA), thiol derivatives of polyacrylate, or thiol derivatives of chitosan.

[0325] In some embodiments, the buccal composition further comprises a solubility modifier, such as a cyclodextrin (eg, hydroxypropyl-β-cyclodextrin) or hydroxypropylmethylcellulose.

[0326] In some embodiments, the buccal composition further comprises an acid to promote paracellular transport of the compounds of Formulae (I)-(XXIV) across the buccal mucosa.

[0327] In some embodiments, the buccal composition further comprises a mucoadhesive polymer, such as agarose, chitosan, gelatin, hyaluronic acid, guar gum, hakea gum, xanthan gum, gellan, carrageenan, pectin, sodium alginate, cellulose derivatives (e.g., CMC, thiolated CMC, sodium CMC, HEC, HPC, HPMC, or MC), poly(acrylic acid) based polymers (e.g., CP, PC, PAA, or copolymers of acrylic acid and PEG), PVA, PVP, thiolated polymers (e.g., thiolated polyacrylate, thiolated chitosan, or deacetylated gellan gum), aminodextran, dimethylaminoethyl (DEAE)-dextran, trimethylated chitosan, chitosan-EDTA, hydroxyethyl starch, poly(ethylene oxide), scleroglucan, cyanoacrylate, lectin, or bacterial adhesive.

[0328] G) Ear preparations The compositions of the present disclosure may be an otic formulation in the form of a solution, suspension, emulsion, drops, or spray.

[0329] In some embodiments, a compound of any one of Formulae (I)-(XXIV) is present in the otic composition in an amount effective to treat perceived pain or prevent anticipated pain in a subject after the composition is administered to the ear canal of the subject. In some embodiments, the compound is present in an amount of about 0.01% w / w to about 10% w / w, about 0.1% w / w to about 8% w / w, about 1% w / w to about 6% w / w, or about 2% w / w to about 5% w / w. In some embodiments, the compound is at about 0.01% w / w, about 0.02% w / w, about 0.03% w / w, about 0.04% w / w, about 0.05% w / w, about 0.06% w / w, about 0.07% w / w, about 0.08% w / w, about 0.09% w / w, about 0.1% w / w, about 0.15% w / w, about 0.2% w / w, about 0.25% w / w, about 0.3% w / w, about 0.35% w / w, about 0.4% w / w, about 0.45% w / w, about 0.5% w / w, about 0.55% w / w, about 0.60% w / w, about 0.65% w / w, about 0.70% w / w, about 0.75% w / w, about 0.80% w / w, about 0.85% w / w, about 0.90% w / w, about 0.10% w / w, about 0.15% w / w, about 0.20% w / w, about 0.25% w / w, about 0.30% w / w, about 0.35% w / w, about 0.40% w / w, about 0.45% w / w, about 0.55% w / w, about 0.55% w / w, about 0.60% w / w, about 0.70% w / w, about 0.80% w / w, about 0.90% w / w, about 0.10% w / w, about 0.15% w / w, about 0.20% w / w, about 0.25% w / w, about 0.30% w / w, about 0.35% w / w, about %w / w, about 0.6%w / w, about 0.65%w / w, about 0.7%w / w, about 0.75%w / w, about 0.8%w / w, about 0.85%w / w, about 0.9%w / w, about 0.95%w / w, about 1%w / w, about 1.1%w / w, about 1.2%w / w, about 1.3%w / w, about 1.4%w / w, about 1.5%w / w, about 1.6%w / w, about 1.7%w / w, about 1.8%w / w, about 1.9%w / w, about 2%w / w, about 2.1%w / w, about 2.2%w / w, about 2.3 %w / w, about 2.4%w / w, about 2.5%w / w, about 2.6%w / w, about 2.7%w / w, about 2.8%w / w, about 2.9%w / w, about 3%w / w, about 3.1%w / w, about 3.2%w / w, about 3.3%w / w, about 3.4%w / w, about 3.5%w / w, about 3.6%w / w, about 3.7%w / w, about 3.8%w / w, about 3.9%w / w, about 4%w / w, about 4.1%w / w, about 4.2%w / w, about 4.3%w / w, about 4.4%w / w, about 4.5%w / w , about 4.6% w / w, about 4.7% w / w, about 4.8% w / w, about 4.9% w / w, about 5% w / w, about 5.1% w / w, about 5.2% w / w, about 5.3% w / w, about 5.4% w / w, about 5.5% w / w, about 5.6% w / w, about 5.7% w / w, about 5.8% w / w, about 5.9% w / w, about 6% w / w, about 6.1% w / w, about 6.2% w / w, about 6.3% w / w, about 6.4% w / w, about 6.5% w / w, about 6.6% w / w, about 6.7% w / w, about 6.8% w / w, about 6.9% w / w, about 7% w / w, about 7.1% w / w, about 7.2% w / w, about 7.3% w / w, about 7.4% w / w, about 7.5% w / w, about 7.6% w / w, about 7.7% w / w, about 7.8% w / w, about 7.9% w / w, about 8% w / w, about 8.1% w / w, about 8.2% w / w, about 8.3% w / w, about 8.4% w / w, about 8 The composition is present in an amount of about 0.5% w / w, about 8.6% w / w, about 8.7% w / w, about 8.8% w / w, about 8.9% w / w, about 9% w / w, about 9.1% w / w, about 9.2% w / w, about 9.3% w / w, about 9.4% w / w, about 9.5% w / w, about 9.6% w / w, about 9.7% w / w, about 9.8% w / w, about 9.9% w / w, or about 10 w / w%.

[0330] In some embodiments, the otic composition further comprises a pH adjuster, such as acetic acid, calcium carbonate, citric acid, hydrochloric acid, benzethonium chloride, benzyl alcohol, hydrochloric acid, lactic acid, monopotassium phosphate, sodium acetate, sodium borate, sodium citrate, dibasic sodium phosphate, monobasic sodium diphosphate, sodium hydroxide, sulfuric acid, or tromethamine.

[0331] In some embodiments, the otic composition further comprises an antimicrobial preservative, such as aluminum acetate, benzalkonium chloride, benzethonium chloride, benzyl alcohol, boric acid, chlorobutanol, isopropyl alcohol, phenethyl alcohol, methylparaben, potassium metabisulfate, propylparaben, or thiomersal.

[0332] In some embodiments, the otic composition further comprises a suspending agent, such as aluminum sulfate, cetyl alcohol, hydroxyethyl cellulose, methylparaben, or polyvinyl alcohol.

[0333] In some embodiments, the otic composition further comprises a stabilizer, such as creatinine, hydrogenated soy lecithin, povidone K30, povidone K90, or poloxamer 407.

[0334] In some embodiments, the otic composition further comprises an emollient, such as cupric sulfate, glycerol, or polyoxyl 40 stearate.

[0335] In some embodiments, the otic composition further comprises a solubilizing agent, such as polysorbate 20, polysorbate 80, or tyloxapol.

[0336] In some embodiments, the otic composition further comprises an isotonicity agent, such as sodium chloride or sodium sulfite.

[0337] In some embodiments, the otic composition further comprises an ointment base, such as mineral oil, peanut oil, or petrolatum.

[0338] H) Ophthalmic preparations The compositions of the present disclosure may be ophthalmic formulations in the form of eye drops, ointments, in situ gels, inserts, multi-compartment drug delivery systems, or bioadhesive formulations.

[0339] In some embodiments, the compound of any one of Formulae (I)-(XXIV) is present in the ophthalmic composition in an amount effective to treat perceived pain or prevent anticipated pain in a subject after the composition is administered to the ear canal of the subject. In some embodiments, the compound is present in an amount of about 0.01% w / w to about 10% w / w, about 0.1% w / w to about 8% w / w, about 1% w / w to about 6% w / w, or about 2% w / w to about 5% w / w. In some embodiments, the compound is at about 0.01% w / w, about 0.02% w / w, about 0.03% w / w, about 0.04% w / w, about 0.05% w / w, about 0.06% w / w, about 0.07% w / w, about 0.08% w / w, about 0.09% w / w, about 0.1% w / w, about 0.15% w / w, about 0.2% w / w, about 0.25% w / w, about 0.3% w / w, about 0.35% w / w, about 0.4% w / w, about 0.45% w / w, about 0.5% w / w, about 0.55% w / w, about 0.60% w / w, about 0.65% w / w, about 0.70% w / w, about 0.75% w / w, about 0.80% w / w, about 0.85% w / w, about 0.90% w / w, about 0.10% w / w, about 0.15% w / w, about 0.20% w / w, about 0.25% w / w, about 0.30% w / w, about 0.35% w / w, about 0.40% w / w, about 0.45% w / w, about 0.55% w / w, about 0.55% w / w, about 0.60% w / w, about 0.70% w / w, about 0.80% w / w, about 0.90% w / w, about 0.10% w / w, about 0.15% w / w, about 0.20% w / w, about 0.25% w / w, about 0.30% w / w, about 0.35% w / w, about %w / w, about 0.6%w / w, about 0.65%w / w, about 0.7%w / w, about 0.75%w / w, about 0.8%w / w, about 0.85%w / w, about 0.9%w / w, about 0.95%w / w, about 1%w / w, about 1.1%w / w, about 1.2%w / w, about 1.3%w / w, about 1.4%w / w, about 1.5%w / w, about 1.6%w / w, about 1.7%w / w, about 1.8%w / w, about 1.9%w / w, about 2%w / w, about 2.1%w / w, about 2.2%w / w, about 2.3 %w / w, about 2.4%w / w, about 2.5%w / w, about 2.6%w / w, about 2.7%w / w, about 2.8%w / w, about 2.9%w / w, about 3%w / w, about 3.1%w / w, about 3.2%w / w, about 3.3%w / w, about 3.4%w / w, about 3.5%w / w, about 3.6%w / w, about 3.7%w / w, about 3.8%w / w, about 3.9%w / w, about 4%w / w, about 4.1%w / w, about 4.2%w / w, about 4.3%w / w, about 4.4%w / w, about 4.5%w / w , about 4.6% w / w, about 4.7% w / w, about 4.8% w / w, about 4.9% w / w, about 5% w / w, about 5.1% w / w, about 5.2% w / w, about 5.3% w / w, about 5.4% w / w, about 5.5% w / w, about 5.6% w / w, about 5.7% w / w, about 5.8% w / w, about 5.9% w / w, about 6% w / w, about 6.1% w / w, about 6.2% w / w, about 6.3% w / w, about 6.4% w / w, about 6.5% w / w, about 6.6% w / w, about 6.7% w / w, about 6.8% w / w, about 6.9% w / w, about 7% w / w, about 7.1% w / w, about 7.2% w / w, about 7.3% w / w, about 7.4% w / w, about 7.5% w / w, about 7.6% w / w, about 7.7% w / w, about 7.8% w / w, about 7.9% w / w, about 8% w / w, about 8.1% w / w, about 8.2% w / w, about 8.3% w / w, about 8.4% w / w, about 8 The composition is present in an amount of about 0.5% w / w, about 8.6% w / w, about 8.7% w / w, about 8.8% w / w, about 8.9% w / w, about 9% w / w, about 9.1% w / w, about 9.2% w / w, about 9.3% w / w, about 9.4% w / w, about 9.5% w / w, about 9.6% w / w, about 9.7% w / w, about 9.8% w / w, about 9.9% w / w, or about 10 w / w%.

[0340] In some embodiments, the ophthalmic composition further comprises a solvent system. The solvent system may comprise one or more solvents. In some embodiments, the solvent system comprises water (e.g., water for injection). In some embodiments, the solvent system comprises, consists essentially of, or consists of water (e.g., water for injection). In other embodiments, the solvent system comprises water (e.g., water for injection) and a co-solvent, such as polyethylene glycol 300, polyethylene glycol 400, ethanol, propylene glycol, glycerin, N-methyl-2-pyrrolidone, dimethylacetamide, and / or dimethylsulfoxide.

[0341] In some embodiments, the ophthalmic composition further comprises a preservative, such as benzyl alcohol.

[0342] In some embodiments, the ophthalmic composition further comprises a buffer system configured to maintain a pH level of the composition within the range of about 4 to about 8 (eg, about 7.4).

[0343] In some embodiments, the ophthalmic composition further comprises a viscosity agent to maintain the viscosity of the composition within the range of about 15 mPas to about 150 mPas. If present, the viscosity agent may optionally be polyvinyl alcohol, a poloxamer (e.g., poloxamer 407), hyaluronic acid, a carbomer, a polysaccharide (e.g., a cellulose derivative, gellan gum, or xanthan gum).

[0344] In some embodiments, the ophthalmic composition further comprises a penetration enhancer, such as a chelating agent, a preservative (e.g., benzalkonium chloride), a surfactant, or a bile salt. If present, the penetration enhancer should be included in an amount sufficient to improve the bioavailability (e.g., in the aqueous humor) of any one of the compounds of Formulae (I)-(XXIV) without inducing irritation or local tissue toxicity.

[0345] In some embodiments, the ophthalmic composition further comprises a solubilizing agent, such as a cyclodextrin (e.g., 2-hydroxypropyl-β-cyclodextrin). When present, the solubilizing agent may comprise from about 1% w / w to about 15% w / w (e.g., about 1% w / w, about 2% w / w, about 3% w / w, about 4% w / w, about 5% w / w, about 6% w / w, about 7% w / w, about 8% w / w, about 9% w / w, about 10% w / w, about 11% w / w, about 12% w / w, about 13% w / w, about 14% w / w, about 15% w / w) of the total weight of the composition.

[0346] I) Intravesical preparations The compositions of the present disclosure may be in an intravesical formulation in the form of nanoparticles, hydrogels, dendrimers, or liposomes.

[0347] In some embodiments, a compound of any one of Formulae (I)-(XXIV) is present in the intravesical composition in an amount effective to treat perceived pain or prevent anticipated pain in a subject after the composition is administered to the ear canal of the subject. In some embodiments, the compound is present in an amount of about 0.01% w / w to about 10% w / w, about 0.1% w / w to about 8% w / w, about 1% w / w to about 6% w / w, or about 2% w / w to about 5% w / w. In some embodiments, the compound is at about 0.01% w / w, about 0.02% w / w, about 0.03% w / w, about 0.04% w / w, about 0.05% w / w, about 0.06% w / w, about 0.07% w / w, about 0.08% w / w, about 0.09% w / w, about 0.1% w / w, about 0.15% w / w, about 0.2% w / w, about 0.25% w / w, about 0.3% w / w, about 0.35% w / w, about 0.4% w / w, about 0.45% w / w, about 0.5% w / w, about 0.55% w / w, about 0.60% w / w, about 0.65% w / w, about 0.70% w / w, about 0.75% w / w, about 0.80% w / w, about 0.85% w / w, about 0.90% w / w, about 0.10% w / w, about 0.15% w / w, about 0.20% w / w, about 0.25% w / w, about 0.30% w / w, about 0.35% w / w, about 0.40% w / w, about 0.45% w / w, about 0.55% w / w, about 0.55% w / w, about 0.60% w / w, about 0.70% w / w, about 0.80% w / w, about 0.90% w / w, about 0.10% w / w, about 0.15% w / w, about 0.20% w / w, about 0.25% w / w, about 0.30% w / w, about 0.35% w / w, about %w / w, about 0.6%w / w, about 0.65%w / w, about 0.7%w / w, about 0.75%w / w, about 0.8%w / w, about 0.85%w / w, about 0.9%w / w, about 0.95%w / w, about 1%w / w, about 1.1%w / w, about 1.2%w / w, about 1.3%w / w, about 1.4%w / w, about 1.5%w / w, about 1.6%w / w, about 1.7%w / w, about 1.8%w / w, about 1.9%w / w, about 2%w / w, about 2.1%w / w, about 2.2%w / w, about 2.3 %w / w, about 2.4%w / w, about 2.5%w / w, about 2.6%w / w, about 2.7%w / w, about 2.8%w / w, about 2.9%w / w, about 3%w / w, about 3.1%w / w, about 3.2%w / w, about 3.3%w / w, about 3.4%w / w, about 3.5%w / w, about 3.6%w / w, about 3.7%w / w, about 3.8%w / w, about 3.9%w / w, about 4%w / w, about 4.1%w / w, about 4.2%w / w, about 4.3%w / w, about 4.4%w / w, about 4.5%w / w , about 4.6% w / w, about 4.7% w / w, about 4.8% w / w, about 4.9% w / w, about 5% w / w, about 5.1% w / w, about 5.2% w / w, about 5.3% w / w, about 5.4% w / w, about 5.5% w / w, about 5.6% w / w, about 5.7% w / w, about 5.8% w / w, about 5.9% w / w, about 6% w / w, about 6.1% w / w, about 6.2% w / w, about 6.3% w / w, about 6.4% w / w, about 6.5% w / w, about 6.6% w / w, about 6.7% w / w, about 6.8% w / w, about 6.9% w / w, about 7% w / w, about 7.1% w / w, about 7.2% w / w, about 7.3% w / w, about 7.4% w / w, about 7.5% w / w, about 7.6% w / w, about 7.7% w / w, about 7.8% w / w, about 7.9% w / w, about 8% w / w, about 8.1% w / w, about 8.2% w / w, about 8.3% w / w, about 8.4% w / w, about 8 The composition is present in an amount of about 0.5% w / w, about 8.6% w / w, about 8.7% w / w, about 8.8% w / w, about 8.9% w / w, about 9% w / w, about 9.1% w / w, about 9.2% w / w, about 9.3% w / w, about 9.4% w / w, about 9.5% w / w, about 9.6% w / w, about 9.7% w / w, about 9.8% w / w, about 9.9% w / w, or about 10 w / w%.

[0348] In some embodiments, the intravesical composition further comprises a mucoadhesive system, such as a polymer capable of interacting with urothelial glycosaminoglycans.

[0349] In some embodiments, the intravesical composition further comprises a viscosity increasing agent, such as a thermosensitive polymer (eg, TCGel®) that has a relatively low viscosity at low temperatures and a gel-like consistency at relatively high temperatures.

[0350] In some embodiments, the intravesical composition further comprises an effervescent (eg, CO2- or gas-generating) agent, such as sodium bicarbonate, ammonium bicarbonate, or perfluoropentane.

[0351] In some embodiments, the intravesical composition is contained within an intravesical drug reservoir having a pressure responsive valve (eg, UROS injector, Situs Corp.).

[0352] In some embodiments, the intravesical composition is contained within an intravesical balloon that is delivered to the bladder via a magnetic or other controlled device.

[0353] In some embodiments, the intravesical composition is contained within a microsphere matrix (e.g., polydimethylsiloxane microspheres) optionally bound together by resorbable sutures. In such embodiments, the microspheres can be provided to the bladder where the compounds of Formulae (I)-(XXIV) elute from the microsphere matrix.

[0354] In some embodiments, the intravesical composition is provided to the bladder (e.g., by a catheter) and then contained within a silicone tube, such as a retaining silicone tube-nitinol wire device, where the compound of Formulae (I)-(XXIV) is eluted from the silicone tube.

[0355] In some embodiments, the intravesical composition is contained within a biodegradable elastomer-based device that includes an osmotic release mechanism. Upon delivery of the device to the bladder, the compound of Formulae (I)-(XXIV) elutes by osmosis and diffusion.

[0356] In some embodiments, the intravesical composition is contained within a U-shaped or spiral shaped PVA matrix. Upon delivery of the PVA matrix to the bladder, a compound of any one of Formulae (I)-(XXIV) is eluted.

[0357] J) Rectal preparations The compositions of the present disclosure may be in rectal formulation in the form of a suppository or enema.

[0358] In some embodiments, a compound of any one of Formulae (I)-(XXIV) is present in the rectal composition in an amount effective to treat perceived pain or prevent anticipated pain in a subject after the composition is administered to the subject's ear canal. In some embodiments, the compound is present in an amount of about 0.01% w / w to about 10% w / w, about 0.1% w / w to about 8% w / w, about 1% w / w to about 6% w / w, or about 2% w / w to about 5% w / w. In some embodiments, the compound is at about 0.01% w / w, about 0.02% w / w, about 0.03% w / w, about 0.04% w / w, about 0.05% w / w, about 0.06% w / w, about 0.07% w / w, about 0.08% w / w, about 0.09% w / w, about 0.1% w / w, about 0.15% w / w, about 0.2% w / w, about 0.25% w / w, about 0.3% w / w, about 0.35% w / w, about 0.4% w / w, about 0.45% w / w, about 0.5% w / w, about 0.55% w / w, about 0.60% w / w, about 0.65% w / w, about 0.70% w / w, about 0.75% w / w, about 0.80% w / w, about 0.85% w / w, about 0.90% w / w, about 0.10% w / w, about 0.15% w / w, about 0.20% w / w, about 0.25% w / w, about 0.30% w / w, about 0.35% w / w, about 0.40% w / w, about 0.45% w / w, about 0.55% w / w, about 0.55% w / w, about 0.60% w / w, about 0.70% w / w, about 0.80% w / w, about 0.90% w / w, about 0.10% w / w, about 0.15% w / w, about 0.20% w / w, about 0.25% w / w, about 0.30% w / w, about 0.35% w / w, about %w / w, about 0.6%w / w, about 0.65%w / w, about 0.7%w / w, about 0.75%w / w, about 0.8%w / w, about 0.85%w / w, about 0.9%w / w, about 0.95%w / w, about 1%w / w, about 1.1%w / w, about 1.2%w / w, about 1.3%w / w, about 1.4%w / w, about 1.5%w / w, about 1.6%w / w, about 1.7%w / w, about 1.8%w / w, about 1.9%w / w, about 2%w / w, about 2.1%w / w, about 2.2%w / w, about 2.3 %w / w, about 2.4%w / w, about 2.5%w / w, about 2.6%w / w, about 2.7%w / w, about 2.8%w / w, about 2.9%w / w, about 3%w / w, about 3.1%w / w, about 3.2%w / w, about 3.3%w / w, about 3.4%w / w, about 3.5%w / w, about 3.6%w / w, about 3.7%w / w, about 3.8%w / w, about 3.9%w / w, about 4%w / w, about 4.1%w / w, about 4.2%w / w, about 4.3%w / w, about 4.4%w / w, about 4.5%w / w , about 4.6% w / w, about 4.7% w / w, about 4.8% w / w, about 4.9% w / w, about 5% w / w, about 5.1% w / w, about 5.2% w / w, about 5.3% w / w, about 5.4% w / w, about 5.5% w / w, about 5.6% w / w, about 5.7% w / w, about 5.8% w / w, about 5.9% w / w, about 6% w / w, about 6.1% w / w, about 6.2% w / w, about 6.3% w / w, about 6.4% w / w, about 6.5% w / w, about 6.6% w / w, about 6.7% w / w, about 6.8% w / w, about 6.9% w / w, about 7% w / w, about 7.1% w / w, about 7.2% w / w, about 7.3% w / w, about 7.4% w / w, about 7.5% w / w, about 7.6% w / w, about 7.7% w / w, about 7.8% w / w, about 7.9% w / w, about 8% w / w, about 8.1% w / w, about 8.2% w / w, about 8.3% w / w, about 8.4% w / w, about 8 The composition is present in an amount of about 0.5% w / w, about 8.6% w / w, about 8.7% w / w, about 8.8% w / w, about 8.9% w / w, about 9% w / w, about 9.1% w / w, about 9.2% w / w, about 9.3% w / w, about 9.4% w / w, about 9.5% w / w, about 9.6% w / w, about 9.7% w / w, about 9.8% w / w, about 9.9% w / w, or about 10 w / w%.

[0359] In some embodiments, the rectal composition is a suppository and further comprises an excipient system configured to melt at body temperature. In some embodiments, the excipient system comprises an oleaginous base (e.g., cocoa butter, emulsified cocoa butter, hardened oil), a hydrophilic base (e.g., glycerol-gelatin base, soap-glycerin base, or PEG), an emulsifying base (e.g., witepsol, massa estarinum, or massuppol).

[0360] In some embodiments, the rectal composition is an enema and further comprises a solvent system. The solvent system may comprise one or more solvents. In some embodiments, the solvent system comprises water (e.g., water for injection). In some embodiments, the solvent system comprises, consists essentially of, or consists of water (e.g., water for injection). In other embodiments, the solvent system comprises water (e.g., water for injection) and a co-solvent, such as polyethylene glycol 300, polyethylene glycol 400, ethanol, propylene glycol, glycerin, N-methyl-2-pyrrolidone, dimethylacetamide, and / or dimethylsulfoxide. In some embodiments, the enema composition further comprises an isotonicity agent, such as sodium chloride or sodium sulfite.

[0361] K) Vaginal preparations The compositions of the present disclosure may be in a vaginal formulation in the form of a hydrogel, vaginal tablet, pessary, suppository, microparticle system, or intravaginal ring.

[0362] In some embodiments, the compound of any one of Formulae (I)-(XXIV) is present in the vaginal composition in an amount effective to treat perceived pain or prevent anticipated pain in a subject after the composition is administered to the ear canal of the subject. In some embodiments, the compound is present in an amount of about 0.01% w / w to about 10% w / w, about 0.1% w / w to about 8% w / w, about 1% w / w to about 6% w / w, or about 2% w / w to about 5% w / w. In some embodiments, the compound is at about 0.01% w / w, about 0.02% w / w, about 0.03% w / w, about 0.04% w / w, about 0.05% w / w, about 0.06% w / w, about 0.07% w / w, about 0.08% w / w, about 0.09% w / w, about 0.1% w / w, about 0.15% w / w, about 0.2% w / w, about 0.25% w / w, about 0.3% w / w, about 0.35% w / w, about 0.4% w / w, about 0.45% w / w, about 0.5% w / w, about 0.55% w / w, about 0.60% w / w, about 0.65% w / w, about 0.70% w / w, about 0.75% w / w, about 0.80% w / w, about 0.85% w / w, about 0.90% w / w, about 0.10% w / w, about 0.15% w / w, about 0.20% w / w, about 0.25% w / w, about 0.30% w / w, about 0.35% w / w, about 0.40% w / w, about 0.45% w / w, about 0.55% w / w, about 0.55% w / w, about 0.60% w / w, about 0.70% w / w, about 0.80% w / w, about 0.90% w / w, about 0.10% w / w, about 0.15% w / w, about 0.20% w / w, about 0.25% w / w, about 0.30% w / w, about 0.35% w / w, about %w / w, about 0.6%w / w, about 0.65%w / w, about 0.7%w / w, about 0.75%w / w, about 0.8%w / w, about 0.85%w / w, about 0.9%w / w, about 0.95%w / w, about 1%w / w, about 1.1%w / w, about 1.2%w / w, about 1.3%w / w, about 1.4%w / w, about 1.5%w / w, about 1.6%w / w, about 1.7%w / w, about 1.8%w / w, about 1.9%w / w, about 2%w / w, about 2.1%w / w, about 2.2%w / w, about 2.3 %w / w, about 2.4%w / w, about 2.5%w / w, about 2.6%w / w, about 2.7%w / w, about 2.8%w / w, about 2.9%w / w, about 3%w / w, about 3.1%w / w, about 3.2%w / w, about 3.3%w / w, about 3.4%w / w, about 3.5%w / w, about 3.6%w / w, about 3.7%w / w, about 3.8%w / w, about 3.9%w / w, about 4%w / w, about 4.1%w / w, about 4.2%w / w, about 4.3%w / w, about 4.4%w / w, about 4.5%w / w , about 4.6% w / w, about 4.7% w / w, about 4.8% w / w, about 4.9% w / w, about 5% w / w, about 5.1% w / w, about 5.2% w / w, about 5.3% w / w, about 5.4% w / w, about 5.5% w / w, about 5.6% w / w, about 5.7% w / w, about 5.8% w / w, about 5.9% w / w, about 6% w / w, about 6.1% w / w, about 6.2% w / w, about 6.3% w / w, about 6.4% w / w, about 6.5% w / w, about 6.6% w / w, about 6.7% w / w, about 6.8% w / w, about 6.9% w / w, about 7% w / w, about 7.1% w / w, about 7.2% w / w, about 7.3% w / w, about 7.4% w / w, about 7.5% w / w, about 7.6% w / w, about 7.7% w / w, about 7.8% w / w, about 7.9% w / w, about 8% w / w, about 8.1% w / w, about 8.2% w / w, about 8.3% w / w, about 8.4% w / w, about 8 The composition is present in an amount of about 0.5% w / w, about 8.6% w / w, about 8.7% w / w, about 8.8% w / w, about 8.9% w / w, about 9% w / w, about 9.1% w / w, about 9.2% w / w, about 9.3% w / w, about 9.4% w / w, about 9.5% w / w, about 9.6% w / w, about 9.7% w / w, about 9.8% w / w, about 9.9% w / w, or about 10 w / w%.

[0363] In some embodiments, the vaginal composition is a hydrogel and further comprises a vehicle, a gelling agent, a humectant, a preservative, and / or a mucoadhesive agent (eg, hydroxypropyl methylcellulose).

[0364] In some embodiments, the vaginal composition is a pessary and further comprises one or more of lactose monohydrate, microcrystalline cellulose, lactic acid, corn starch, crospovidone, calcium lactate pentahydrate, magnesium stearate, colloidal anhydrous silica, and / or hypromellose.

[0365] In some embodiments, the vaginal composition is a vaginal tablet and further comprises one or more of a diluent, a binder, a disintegrant, a glidant, a lubricant, and / or an anti-adhesive agent.

[0366] In some embodiments, the vaginal composition is a particulate system further comprising a polymer matrix in which a compound of any one of formulae (I)-(XXIV) is included. In some embodiments, the matrix comprises a natural polymer, such as polysaccharides, zein, gluten, collagen, gelatin, albumin, or elastin. In some embodiments, the matrix comprises a synthetic biodegradable polymer, such as poly(DL-lactic acid), poly(lactic acid-co-glycolic acid), polycaprolactone, polyacrylate, polymethacrylate, cellulose derivatives, poly(ethylene oxide) / poly(propylene oxide) or poloxamer triblock copolymers, poly(vinyl alcohol), poly(ethylene glycol), or alginate. In some embodiments, the matrix comprises a synthetic non-biodegradable polymer, such as poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammonioethyl methacrylate chloride) (Eudragit® RS 100).

[0367] In some embodiments, the vaginal composition is contained in an intravaginal ring matrix comprising polyurethane, ethylene vinyl acetate, silicone, gum acacia, or a copolymer of 2-hydroxyethyl methacrylate and sodium methacrylate.

[0368] L) Inhalation formulations Compositions of the present disclosure may be inhalation formulations in the form of dry powder, aerosol, or atomizable solution.

[0369] In some embodiments, a compound of any one of Formulae (I)-(XXIV) is present in the inhalable composition in an amount effective to treat perceived pain or prevent anticipated pain in a subject after the composition is administered to the ear canal of the subject. In some embodiments, the compound is present in an amount of about 0.01% w / w to about 10% w / w, about 0.1% w / w to about 8% w / w, about 1% w / w to about 6% w / w, or about 2% w / w to about 5% w / w. In some embodiments, the compound is at about 0.01% w / w, about 0.02% w / w, about 0.03% w / w, about 0.04% w / w, about 0.05% w / w, about 0.06% w / w, about 0.07% w / w, about 0.08% w / w, about 0.09% w / w, about 0.1% w / w, about 0.15% w / w, about 0.2% w / w, about 0.25% w / w, about 0.3% w / w, about 0.35% w / w, about 0.4% w / w, about 0.45% w / w, about 0.5% w / w, about 0.55% w / w, about 0.60% w / w, about 0.65% w / w, about 0.70% w / w, about 0.75% w / w, about 0.80% w / w, about 0.85% w / w, about 0.90% w / w, about 0.10% w / w, about 0.15% w / w, about 0.20% w / w, about 0.25% w / w, about 0.30% w / w, about 0.35% w / w, about 0.40% w / w, about 0.45% w / w, about 0.55% w / w, about 0.55% w / w, about 0.60% w / w, about 0.70% w / w, about 0.80% w / w, about 0.90% w / w, about 0.10% w / w, about 0.15% w / w, about 0.20% w / w, about 0.25% w / w, about 0.30% w / w, about 0.35% w / w, about %w / w, about 0.6%w / w, about 0.65%w / w, about 0.7%w / w, about 0.75%w / w, about 0.8%w / w, about 0.85%w / w, about 0.9%w / w, about 0.95%w / w, about 1%w / w, about 1.1%w / w, about 1.2%w / w, about 1.3%w / w, about 1.4%w / w, about 1.5%w / w, about 1.6%w / w, about 1.7%w / w, about 1.8%w / w, about 1.9%w / w, about 2%w / w, about 2.1%w / w, about 2.2%w / w, about 2.3 %w / w, about 2.4%w / w, about 2.5%w / w, about 2.6%w / w, about 2.7%w / w, about 2.8%w / w, about 2.9%w / w, about 3%w / w, about 3.1%w / w, about 3.2%w / w, about 3.3%w / w, about 3.4%w / w, about 3.5%w / w, about 3.6%w / w, about 3.7%w / w, about 3.8%w / w, about 3.9%w / w, about 4%w / w, about 4.1%w / w, about 4.2%w / w, about 4.3%w / w, about 4.4%w / w, about 4.5%w / w , about 4.6% w / w, about 4.7% w / w, about 4.8% w / w, about 4.9% w / w, about 5% w / w, about 5.1% w / w, about 5.2% w / w, about 5.3% w / w, about 5.4% w / w, about 5.5% w / w, about 5.6% w / w, about 5.7% w / w, about 5.8% w / w, about 5.9% w / w, about 6% w / w, about 6.1% w / w, about 6.2% w / w, about 6.3% w / w, about 6.4% w / w, about 6.5% w / w, about 6.6% w / w, about 6.7% w / w, about 6.8% w / w, about 6.9% w / w, about 7% w / w, about 7.1% w / w, about 7.2% w / w, about 7.3% w / w, about 7.4% w / w, about 7.5% w / w, about 7.6% w / w, about 7.7% w / w, about 7.8% w / w, about 7.9% w / w, about 8% w / w, about 8.1% w / w, about 8.2% w / w, about 8.3% w / w, about 8.4% w / w, about 8 The composition is present in an amount of about 0.5% w / w, about 8.6% w / w, about 8.7% w / w, about 8.8% w / w, about 8.9% w / w, about 9% w / w, about 9.1% w / w, about 9.2% w / w, about 9.3% w / w, about 9.4% w / w, about 9.5% w / w, about 9.6% w / w, about 9.7% w / w, about 9.8% w / w, about 9.9% w / w, or about 10 w / w%.

[0370] In some embodiments, the inhalable composition is a dry powder and further comprises an amino acid, a sugar, a stabilizer, a surfactant and / or a lipid.

[0371] In some embodiments, the inhalable composition is an aerosol and further comprises a propellant, a sugar (eg, lactose), and / or a co-solvent.

[0372] In some embodiments, the inhalable composition is a nebulizable solution that further comprises a solvent (e.g., water), a pH adjuster, a buffer system, a starch, a chelating agent, an emulsifier, a viscosity agent, a tonicity agent, and / or a surfactant.

[0373] M) Nasal preparation The compositions of the present disclosure may be in nasal formulations in the form of aqueous solutions, oils, suspensions, emulsions, or dry powders.

[0374] In some embodiments, a compound of any one of Formulae (I)-(XXIV) is present in the nasal composition in an amount effective to treat perceived pain or prevent anticipated pain in a subject after the composition is administered to the ear canal of the subject. In some embodiments, the compound is present in an amount of about 0.01% w / w to about 10% w / w, about 0.1% w / w to about 8% w / w, about 1% w / w to about 6% w / w, or about 2% w / w to about 5% w / w. In some embodiments, the compound is at about 0.01% w / w, about 0.02% w / w, about 0.03% w / w, about 0.04% w / w, about 0.05% w / w, about 0.06% w / w, about 0.07% w / w, about 0.08% w / w, about 0.09% w / w, about 0.1% w / w, about 0.15% w / w, about 0.2% w / w, about 0.25% w / w, about 0.3% w / w, about 0.35% w / w, about 0.4% w / w, about 0.45% w / w, about 0.5% w / w, about 0.55% w / w, about 0.60% w / w, about 0.65% w / w, about 0.70% w / w, about 0.75% w / w, about 0.80% w / w, about 0.85% w / w, about 0.90% w / w, about 0.10% w / w, about 0.15% w / w, about 0.20% w / w, about 0.25% w / w, about 0.30% w / w, about 0.35% w / w, about 0.40% w / w, about 0.45% w / w, about 0.55% w / w, about 0.55% w / w, about 0.60% w / w, about 0.70% w / w, about 0.80% w / w, about 0.90% w / w, about 0.10% w / w, about 0.15% w / w, about 0.20% w / w, about 0.25% w / w, about 0.30% w / w, about 0.35% w / w, about %w / w, about 0.6%w / w, about 0.65%w / w, about 0.7%w / w, about 0.75%w / w, about 0.8%w / w, about 0.85%w / w, about 0.9%w / w, about 0.95%w / w, about 1%w / w, about 1.1%w / w, about 1.2%w / w, about 1.3%w / w, about 1.4%w / w, about 1.5%w / w, about 1.6%w / w, about 1.7%w / w, about 1.8%w / w, about 1.9%w / w, about 2%w / w, about 2.1%w / w, about 2.2%w / w, about 2.3 %w / w, about 2.4%w / w, about 2.5%w / w, about 2.6%w / w, about 2.7%w / w, about 2.8%w / w, about 2.9%w / w, about 3%w / w, about 3.1%w / w, about 3.2%w / w, about 3.3%w / w, about 3.4%w / w, about 3.5%w / w, about 3.6%w / w, about 3.7%w / w, about 3.8%w / w, about 3.9%w / w, about 4%w / w, about 4.1%w / w, about 4.2%w / w, about 4.3%w / w, about 4.4%w / w, about 4.5%w / w , about 4.6% w / w, about 4.7% w / w, about 4.8% w / w, about 4.9% w / w, about 5% w / w, about 5.1% w / w, about 5.2% w / w, about 5.3% w / w, about 5.4% w / w, about 5.5% w / w, about 5.6% w / w, about 5.7% w / w, about 5.8% w / w, about 5.9% w / w, about 6% w / w, about 6.1% w / w, about 6.2% w / w, about 6.3% w / w, about 6.4% w / w, about 6.5% w / w, about 6.6% w / w, about 6.7% w / w, about 6.8% w / w, about 6.9% w / w, about 7% w / w, about 7.1% w / w, about 7.2% w / w, about 7.3% w / w, about 7.4% w / w, about 7.5% w / w, about 7.6% w / w, about 7.7% w / w, about 7.8% w / w, about 7.9% w / w, about 8% w / w, about 8.1% w / w, about 8.2% w / w, about 8.3% w / w, about 8.4% w / w, about 8 The composition is present in an amount of about 0.5% w / w, about 8.6% w / w, about 8.7% w / w, about 8.8% w / w, about 8.9% w / w, about 9% w / w, about 9.1% w / w, about 9.2% w / w, about 9.3% w / w, about 9.4% w / w, about 9.5% w / w, about 9.6% w / w, about 9.7% w / w, about 9.8% w / w, about 9.9% w / w, or about 10 w / w%.

[0375] In some embodiments, the nasal composition is an aqueous solution and further comprises a solvent (eg, water), a pH adjusting agent, a buffer system, a starch, a chelating agent, an emulsifier, a viscosity agent, a tonicity agent, and / or a surfactant.

[0376] In some embodiments, the nasal composition is an oil and further comprises a solvent (e.g., a hydrophobic liquid), a pH adjusting agent, a buffer system, a starch, a chelating agent, an emulsifier, a viscosity agent, a tonicity agent, and / or a surfactant.

[0377] In some embodiments, the nasal composition is a suspension and further comprises a solvent (eg, water), a pH adjusting agent, a buffer system, a starch, a chelating agent, an emulsifier, a viscosity agent, a tonicity agent, and / or a surfactant.

[0378] In some embodiments, the nasal composition is an emulsion and further comprises a solvent (eg, water), a pH adjusting agent, a buffer system, a starch, a chelating agent, an emulsifier, a viscosity agent, a tonicity agent, and / or a surfactant.

[0379] In some embodiments, the nasal composition is a dry powder and further comprises an amino acid, a sugar, a stabilizer, a surfactant, and / or a lipid.

[0380] 3. Methods for Treating or Preventing Pain The present disclosure provides a method for treating or preventing pain in a subject. In general, a method consistent with the present disclosure includes administering to a subject experiencing or expected to experience a pain condition a composition comprising an effective amount of a compound of any one of formulas (I)-(XXIV).

[0381] In some embodiments, the method includes topically applying to a tissue (e.g., skin) of a subject a composition of the present disclosure comprising a compound of any one of formulas (I)-(XXIV). In some embodiments, the step of topically applying the composition occurs after the subject observes a pain sensation, and the composition is applied to a tissue proximal to the observed pain sensation. In other embodiments, the step of topically applying the composition occurs before the subject observes a pain sensation, and the composition is applied to a tissue proximal to a location where the pain sensation is expected to be observed by the subject.

[0382] In some embodiments, the method includes administering a composition of the present disclosure comprising a compound of any one of formulas (I)-(XXIV) to a subject by injecting the composition intravenously, intramuscularly, or subcutaneously. In some embodiments, the step of administering the composition occurs after the subject observes a pain sensation, and the composition is injected proximal to the observed pain sensation. In other embodiments, the step of administering the composition occurs before the subject observes a pain sensation, and the composition is injected proximal to a location where the pain sensation is expected to be observed by the subject.

[0383] In some embodiments, the method includes administering a composition of the present disclosure comprising a compound of any one of Formulae (I)-(XXIV) to a subject by injecting the composition intrathecally, such as intraspinal or intrathecally, into the subject. In some embodiments, the step of administering the composition occurs after the subject observes a pain sensation, and the composition is injected intrathecally proximal to the observed pain sensation. In other embodiments, the step of administering the composition occurs before the subject observes a pain sensation, and the composition is injected intrathecally proximal to where the pain sensation is expected to be observed by the subject.

[0384] In some embodiments, the method includes orally administering to a subject a composition of the present disclosure comprising a compound of any one of formulas (I)-(XXIV). In some embodiments, the step of administering the composition occurs after the subject observes a sensation of pain, and the composition is orally administered to the subject to reduce or eliminate the observed pain. In other embodiments, the step of administering the composition occurs before the subject observes a sensation of pain, and the composition is orally administered to the subject to completely avoid or reduce the severity of the pain that the subject would otherwise experience.

[0385] In some embodiments, the method includes administering a composition of the present disclosure comprising any one of the compounds of formula (I)-(XXIV) sublingually to a subject. In some embodiments, the step of administering the composition occurs after the subject observes a sensation of pain, and the composition is administered sublingually to the subject to reduce or eliminate the observed pain. In other embodiments, the step of administering the composition occurs before the subject observes a sensation of pain, and the composition is administered sublingually to the subject to completely avoid or reduce the severity of the pain that the subject would otherwise experience.

[0386] In some embodiments, the method includes administering a composition of the present disclosure comprising a compound of any one of formulas (I)-(XXIV) to a subject buccally. In some embodiments, the step of administering the composition occurs after the subject observes a sensation of pain, and the composition is administered to the subject's cheek to reduce or eliminate the observed pain. In other embodiments, the step of administering the composition occurs before the subject observes a sensation of pain, and the composition is administered to the subject's cheek to completely avoid or reduce the severity of the pain that the subject would otherwise experience.

[0387] In some embodiments, the method includes administering to a subject a composition of the present disclosure comprising a compound of any one of formulas (I)-(XXIV). In some embodiments, the step of administering the composition occurs after the subject observes a sensation of pain, and the composition is administered to the subject's ear canal to reduce or eliminate the observed pain. In other embodiments, the step of administering the composition occurs before the subject observes a sensation of pain, and the composition is administered to the subject's ear canal to completely avoid or reduce the severity of the pain that the subject would experience.

[0388] In some embodiments, the method includes administering a composition of the present disclosure comprising any one of the compounds of formula (I)-(XXIV) to one or both eyes of a subject. In some embodiments, the step of administering the composition occurs after the subject observes a sensation of pain, and the composition is administered to one or both eyes of the subject to reduce or eliminate the observed pain. In other embodiments, the step of administering the composition occurs before the subject observes a sensation of pain, and the composition is administered to one or both eyes of the subject to completely avoid or reduce the severity of the pain that the subject would otherwise experience.

[0389] In some embodiments, the method includes administering a composition of the present disclosure comprising any one of the compounds of formula (I)-(XXIV) to a subject intravesically. In some embodiments, the step of administering the composition occurs after the subject observes a sensation of pain, and the composition is administered intravesically to the subject to reduce or eliminate the observed pain. In other embodiments, the step of administering the composition occurs before the subject observes a sensation of pain, and the composition is administered intravesically to the subject to completely avoid or reduce the severity of the pain that the subject would otherwise experience.

[0390] In some embodiments, the method includes rectally administering to a subject a composition of the present disclosure comprising a compound of any one of formulas (I)-(XXIV). In some embodiments, the step of administering the composition occurs after the subject observes a sensation of pain, and the composition is administered rectally to the subject to reduce or eliminate the observed pain. In other embodiments, the step of administering the composition occurs before the subject observes a sensation of pain, and the composition is administered rectally to the subject to completely avoid or reduce the severity of the pain that the subject would otherwise experience.

[0391] In some embodiments, the method includes vaginally administering to a subject a composition of the present disclosure comprising a compound of any one of formulas (I)-(XXIV). In some embodiments, the step of administering the composition occurs after the subject observes a sensation of pain, and the composition is administered vaginally to the subject to reduce or eliminate the observed pain. In other embodiments, the step of administering the composition occurs before the subject observes a sensation of pain, and the composition is administered vaginally to the subject to completely avoid or reduce the severity of the pain that the subject would otherwise experience.

[0392] In some embodiments, the method includes administering a composition of the present disclosure comprising any one of the compounds of formula (I)-(XXIV) to a subject via an inhalation route. In some embodiments, the step of administering the composition occurs after the subject observes a sensation of pain, and the composition is administered to the subject via an inhalation route to reduce or eliminate the observed pain. In other embodiments, the step of administering the composition occurs before the subject observes a sensation of pain, and the composition is administered to the subject via an inhalation route to completely avoid or reduce the severity of the pain that the subject would experience.

[0393] In some embodiments, the method includes intranasally administering to a subject a composition of the present disclosure comprising a compound of any one of formulas (I)-(XXIV). In some embodiments, the step of administering the composition occurs after the subject observes a sensation of pain, and the composition is administered intranasally to the subject to reduce or eliminate the observed pain. In other embodiments, the step of administering the composition occurs before the subject observes a sensation of pain, and the composition is administered intranasally to the subject to completely avoid or reduce the severity of the pain that the subject would otherwise experience. EXAMPLES

[0394] Example 1. Patch clamp test Adult epithelial (ovarian) tissue from Chinese hamsters (C. griseus) transformed with adenovirus 5 DNA and transfected with human ion channel cDNA, CHO cells (ATCC, Manassas, VA; ChanTest Corp., Cleveland, OH), were used to measure the expression of the ion channel Na V 1.5 (sodium voltage-dependent channel alpha subunit found primarily in cardiac myocytes) and Na V Testing of the in vitro effects of compounds consistent with the present disclosure on 1.7, a sodium voltage-gated channel alpha subunit normally expressed at high levels in nociceptive pain neurons of the dorsal root ganglion (DRG) and trigeminal ganglion as well as sympathetic ganglion neurons, was performed. Cells were cultured in Ham's F-12 medium supplemented with 10% fetal bovine serum, 100 U / mL penicillin G sodium, 100 μg / mL streptomycin sulfate, and 500 μg / mL G418 aminoglycoside antibiotic.

[0395] Each compound was analyzed at concentrations of 1000 μM, 300 μM, 100 μM, 30 μM, 10 μM, 3 μM, 1 μM, and 0.3 μM. Lidocaine was included as a positive control at concentrations of 3000 μM, 1000 μM, 300 μM, 100 μM, 30 μM, 10 μM, 3 μM, and 1 μM. All test compound formulations contained 0.3% DMSO. Each compound at each concentration was loaded into the wells of a 384-well polypropylene compound plate using an automated liquid handling system (Integra Assist Plus, Integra) and then placed into the plate wells of a SyncroPatch 384PE (SP384PE; Nanion Technologies, Livingston, NJ) immediately prior to application of the cells.

[0396] The observed IC of channel current inhibition for each test article 50 The values ​​in Table 25 (Na V 1.5 Ion Channel Inhibition) and Table 26 (Na V 1.7 Ion channel inhibition). [Table 25-1] [Table 25-2] [Table 26]

Claims

1. Compound of formula (I): 【Chemical 123】 [In the formula, R １ is H, -OMe, Me, or one or more electron-withdrawing groups, R ２ and R ３ Each of them is either independently H or alkyl, or together forms a 4- to 8-membered heterocycle with the adjacent nitrogen atom. R ４ is H or alkyl, R ５ is an electron-donating group of H or 1 or more, and n is between 1 and 4. 【Request Item 2】 【Chemistry 182】 A compound selected from the group consisting of the following.

3. A composition comprising the compound described in Claim 1.

4. The composition according to claim 3, wherein the composition is for topical administration and further comprises a carrier.

5. The composition according to claim 3 or 4, wherein, after the composition is applied to the skin of a subject proximal to perceived pain or expected pain, the compound is present in an amount sufficient to treat the perceived pain or prevent the expected pain in the subject.

6. The composition according to claim 3 for treating or preventing pain in a subject.

7. The composition according to claim 6, characterized in that the composition is administered to the subject proximal to perceived or expected pain.

8. The composition according to claim 3, wherein the composition is a topical composition further comprising at least one of a carrier and a penetration enhancer.

9. The composition according to claim 3, wherein the composition is an injectable composition further comprising at least one of a solvent system, an isotonic agent, a pH adjuster, a buffer system, a nonionic surfactant, a water-insoluble lipid, an organic liquid / semi-solid, a cyclodextrin, and a phospholipid.

10. The composition according to claim 3, wherein the composition is an intrathecal composition further comprising at least one of a solvent system, an isotonic agent, a pH adjuster, a buffer system, a nonionic surfactant, a water-insoluble lipid, an organic liquid / semi-solid, a cyclodextrin, or a phospholipid.

11. The composition according to claim 10, wherein the intrathecal composition has a weight osmolality of about 260 mOsm / kg to about 320 mOsm / kg.

12. The composition according to claim 3, wherein the composition is an oral composition further comprising at least one of an outer coating material, a disintegrant, a binder, a diluent, a lubricant, a flow promoter, and an inner protective barrier coating material.

13. The composition according to claim 3, wherein the composition is a molded sublingual tablet further comprising lactose, dextrose, sucrose, mannitol, fine kaolin powder, calcium carbonate, calcium phosphate, an antioxidant (e.g., sodium bisulfate), a buffer, glucose, sucrose, acacia, and povidone.

14. The composition according to claim 3, wherein the composition is a compressed sublingual tablet further comprising at least one excipient selected from the group consisting of a lubricant, microcrystalline cellulose, a drying binder, a buffer system, a surfactant, a sweetener, a flavoring agent, a bulking agent (e.g., a sugar-based bulking agent), a sugar-based material, and a foaming agent.

15. The composition according to claim 3, wherein the composition is a buccal composition further comprising at least one of a penetration enhancer, an enzyme inhibitor, a solubility modifier, an acid, and a mucosal adhesive polymer.

16. The composition according to claim 3, wherein the composition further comprises at least one of an antimicrobial preservative, a suspension agent, a stabilizer, a skin emollient, a solubilizer, an isotonic agent, and an ointment base.

17. The composition according to claim 3, wherein the composition further comprises at least one of a solvent system, a preservative, a buffer system, a viscosity agent, a penetration enhancer, and a solubilizer.

18. The composition according to claim 3, wherein the composition is an intrabladder composition further comprising a mucosal adhesion agent, a thickener, and a foaming agent.

19. The composition according to claim 18, wherein the composition is contained within an intravesical balloon, within a microsphere matrix, within a silicone tube, within a biodegradable elastomer-based device, within a U-shaped PVA matrix, or within a helical PVA matrix.

20. The composition according to claim 3, wherein the composition further comprises an excipient system configured to melt at body temperature.

21. The composition according to claim 3, wherein the composition further comprises a vehicle, a gelling agent, a wetting agent, a preservative and / or a mucosal adhesive.

22. The composition according to claim 3, wherein the composition is an inhalable composition further comprising at least one of amino acids, sugars, stabilizers, surfactants, lipids, propellants, sugars, solvents, cosolvents, pH adjusters, buffer systems, starches, chelating agents, emulsifiers, viscous agents, and isotonic agents.

23. The composition according to claim 3, wherein the composition is a nasal composition further comprising at least one of a solvent, a pH adjuster, a buffer system, starch, a chelating agent, an emulsifier, a viscosity agent, an isotonic agent, a surfactant, an amino acid, a sugar, a stabilizer, and a lipid.

24. The composition according to claim 3, wherein the composition comprises the compound in an amount of about 0.01% w / w to about 10% w / w.

25. R1 is one or more electron-withdrawing groups, R2 and R3 are either independently H or alkyl, or together form a 4- to 8-membered heterocycle with the adjacent nitrogen atom. R4 is a C1-C4 alkyl group, R5 is O-alkyl, and n is 2, The composition according to claim 3, wherein the alkyl is a C1-C4 saturated alkyl.

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