Compounds and formulations useful as vaccine adjuvants

Abstract

The invention relates to novel compounds having a structure as set forth in any one of Formulas I, Ia, II, IIa, III, IIIa, IV or IVa, as described herein, and formulations comprising such novel compounds. The novel compounds and formulations of the invention may be useful in vaccine compositions. In some embodiments, the invention relates to compositions comprising at least one antigen and compounds having a structure as set forth in any one of Formulas I, Ia, II, IIa, III, IIIa, IV or IVa, as described herein, or pharmaceutically acceptable salt(s) thereof, wherein the compositions are prepared as stable nanoemulsions (herein referred to as "SNE adjuvant compositions" or "SNEs").

Description

Abstract This invention relates to novel compounds having any of the structures described herein, namely, Formula I, Ia, II, IIa, III, IIIa, IV, or IVa, and formulations comprising such novel compounds. The novel compounds and formulations described herein can be used in vaccine compositions. In some embodiments, this invention relates to compositions comprising at least one antigen and a compound having any of the structures described herein, namely, Formula I, Ia, II, IIa, III, IIIa, IV, or IVa, or a pharmaceutically acceptable salt thereof; said compositions are prepared as stable nanoemulsions (hereinafter referred to as “SNE adjuvant compositions” or “SNE”).

Claims

25693WHAT IS CLAIMED IS:

1. A compound having the structure set forth in Formula I:wherein: Rais selected from H, -OH, (C1-C6)alkyl, (C1-C6)alkenyl, (C1-C6)alkynyl, -O(C1- C6)alkyl, -O(C1-C6)alkenyl, -O(C1-C6)alkynyl, chlorine, fluorine, and NR’R’’, wherein said (C1- C6)alkyl, (C1-C6)alkenyl, (C1-C6)alkynyl, -O(C1-C6)alkyl, -O(C1-C6)alkenyl, and -O(C1- C6)alkynyl are optionally substituted with one to four substituents, independently selected from the group consisting of -OH, -O(C1-C4)alkyl, -O(C1-C4)alkenyl, -O(C1-C4)alkynyl, chlorine and fluorine; Ra’is selected from H, -OH, (C1-C6)alkyl, (C1-C6)alkenyl, (C1-C6)alkynyl, -O(C1- C6)alkyl, -O(C1-C6)alkenyl, -O(C1-C6)alkynyl, chlorine, fluorine, and -NR’R’’, wherein said (C1- C6)alkyl, (C1-C6)alkenyl, (C1-C6)alkynyl, -O(C1-C6)alkyl, -O(C1-C6)alkenyl, and -O(C1- C6)alkynyl are optionally substituted with one to four substituents, independently selected from the group consisting of -OH, -O(C1-C4)alkyl, -O(C1-C4)alkenyl, -O(C1-C4)alkynyl, chlorine and fluorine; Ra’’is selected from H, -OH, (C1-C6)alkyl, (C1-C6)alkenyl, (C1-C6)alkynyl, -O(C1- C6)alkyl, -O(C1-C6)alkenyl, -O(C1-C6)alkynyl, chlorine, fluorine, and -NR’R’’, wherein said (C1- C6)alkyl, (C1-C6)alkenyl, (C1-C6)alkynyl, -O(C1-C6)alkyl, -O(C1-C6)alkenyl, and -O(C1- C6)alkynyl are optionally substituted with one to four substituents, independently selected from the group consisting of -OH, -O(C1-C4)alkyl, -O(C1-C4)alkenyl, -O(C1-C4)alkynyl, chlorine and fluorine; R’ and R’’ are independently selected from H, (C1-C6)alkyl, (C1-C6)alkenyl, and (C1-C6)alkynyl, wherein said (C1-C6)alkyl, (C1-C6)alkenyl and (C1-C6)alkynyl are optionally substituted with one to four substituents, independently selected from the group consisting of - OH, -O(C1-C4)alkyl, -O(C1-C4)alkenyl, -O(C1-C4)alkynyl, chlorine and fluorine, or R’ and R’’, together with the nitrogen to which they are attached, join together to form a (C3-25693 C6)heterocycloalkyl, wherein said (C3-C6)heterocycloalkyl is optionally substituted with one to four substituents, independently selected from the group consisting of -OH, -O(C1-C4)alkyl, - O(C1-C4)alkenyl, -O(C1-C4)alkynyl, chlorine and fluorine; each occurrence of Rbis independently selected from H, -OH, (C1-C6)alkyl, (C1- C6)alkenyl, (C1-C6)alkynyl, -O(C1-C6)alkyl, -O(C1-C6)alkenyl, -O(C1-C6)alkynyl, chlorine, fluorine, or NR’R’’, wherein said (C1-C6)alkyl, (C1-C6)alkenyl, (C1-C6)alkynyl, -O(C1-C6)alkyl, - O(C1-C6)alkenyl, and -O(C1-C6)alkynyl are optionally substituted with one to four substituents, independently selected from the group consisting of -OH, -O(C1-C4)alkyl, -O(C1-C4)alkenyl, - O(C1-C4)alkynyl, chlorine and fluorine; A is a carbon- or nitrogen-linked spacer selected from (C1-C6)alkyl, heterocycloalkyl, heterocycloalkyl-C(O)-Rz-, (C1-C4)alkyl-N(Rz)-Rz-, aryl, and heteroaryl, wherein said (C1-C6)alkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one to six substituents, independently selected from the group consisting of -OH, (C1-C6)alkyl, (C1-C6)alkenyl, (C1-C6)alkynyl, -O(C1-C6)alkyl, -O(C1-C6)alkenyl, -O(C1-C6)alkynyl, chlorine, fluorine, and NR’R’’, wherein said (C1-C6)alkyl, (C1-C6)alkenyl, (C1-C6)alkynyl, -O(C1-C6)alkyl, -O(C1-C6)alkenyl, and -O(C1-C6)alkynyl are optionally substituted with one to six substituents, independently selected from the group consisting of -OH, -O(C1-C4)alkyl, -O(C1-C4)alkenyl, - O(C1-C4)alkynyl, chlorine and fluorine; each occurrence of Rzis independently H or (C1-C6)alkyl; B is a functional group selected from ;wherein said (C6-C20)alkyl, (C6-C20)alkenyl, and (C6-C20)alkynyl are optionally substituted with one to six substituents, independently selected from the group consisting of -OH, -O(C1-C4)alkyl, -O(C1-C4)alkenyl, -O(C1-C4)alkynyl, chlorine and fluorine; or ;each occurrence of Z is independently selected C20)alkyl, (C6- C20)alkenyl, and (C6-C20)alkynyl, wherein said (C6-C20)alkyl, (C6-C20)alkenyl, and (C6- C20)alkynyl are optionally substituted with one to six substituents, independently selected from the group consisting of -OH, -O(C1-C4)alkyl, -O(C1-C4)alkenyl, -O(C1-C4)alkynyl, chlorine and fluorine; m is 0, 1, 2, 3, 4 or 5; and25693 n is 0, 1, 2, 3, 4 or 5; or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 having the structure set forth in Formula Ia:wherein: R’ and R’’ are independently selected from H, (C1-C6)alkyl, (C1-C6)alkenyl, and (C1-C6)alkynyl, wherein said (C1-C6)alkyl, (C1-C6)alkenyl and (C1-C6)alkynyl are optionally substituted with one to four substituents, independently selected from the group consisting of - OH, -O(C1-C4)alkyl, -O(C1-C4)alkenyl, -O(C1-C4)alkynyl, chlorine and fluorine, or R’ and R’’, together with the nitrogen to which they are attached, join together to form a (C3- C6)heterocycloalkyl, wherein said (C3-C6)heterocycloalkyl is optionally substituted with one to four substituents, independently selected from the group consisting of -OH, -O(C1-C4)alkyl, - O(C1-C4)alkenyl, -O(C1-C4)alkynyl, chlorine and fluorine; each occurrence of Rbis -O(C1-C4)alkyl, wherein said -O(C1-C4)alkyl is optionally substituted with one or two substituents, independently selected from the group consisting of -OH, -O(C1-C4)alkyl, -O(C1-C4)alkenyl, -O(C1-C4)alkynyl, chlorine and fluorine; A is selected from ;each occurrence of Rdis independently selected from -OH, (C1-C4)alkyl, -O(C1- C4)alkyl, chlorine and fluorine; ;25693 D is a lipid chain selected from: ,-O(C1-C4)alkyl, -O(C1- C4)alkenyl, -O(C1-C4)alkynyl, chlorine and fluorine, wherein is cis or trans stereochemistry, X1is -O-, -C(R)2-, or -NR-, and each occurrence of R is independently selected from H, (C1-C4)alkyl, (C1- C4)alkenyl, (C1-C4)alkynyl, -OH, -O(C1-C4)alkyl, -O(C1-C4)alkenyl, -O(C1-C4)alkynyl, chlorine and fluorine; m is 0, 1 or 2; n is 0, 1, 2 or 3; p is 0, 1 or 2; q is 0, 1, 2, 3, 4, 5, 6, 7, 8 or 9; s is, 1, 2, 3, 4, 5, 6, 7 or 8; and t is 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or 18; or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 having the structure set forth in Formula II: wherein:25693 R1is (C1-C6)alkyl, wherein said (C1-C6)alkyl is optionally substituted with one to four substituents independently selected from -OH and -O(CH3); R2is H, methyl or -O(CH3); each occurrence of R3is independently H, (C1-C4)alkyl, (C1-C4)alkenyl, (C1- C4)alkynyl or -O(C1-C4)alkyl wherein said (C1-C4)alkyl, (C1-C4)alkenyl, (C1-C4)alkynyl or - O(C1-C4)alkyl are optionally substituted with one or two substituents independently selected from -OH and -O(CH3); each occurrence of R4is independently H, (C1-C4)alkyl, (C1-C4)alkenyl, (C1- C4)alkynyl or -O(C1-C4)alkyl wherein said (C1-C4)alkyl, (C1-C4)alkenyl, (C1-C4)alkynyl or - O(C1-C4)alkyl are optionally substituted with one or two substituents independently selected from -OH and -O(CH3); ; alkyl, (C6-C20)alkenyl and (C6-C20)alkynyl, whereinsaid (C6-C20)alkyl, (C6-C20)alkenyl, and (C6-C20)alkynyl are optionally substituted with one to six substituents independently selected from -OH, -O(C1-C4)alkyl, -O(C1-C4)alkenyl, -O(C1- C4)alkynyl, chlorine and fluorine; and each occurrence of n is 4; or a pharmaceutically acceptable salt thereof.

4. The compound of claim 3 having the structure set forth in Formula IIa: wherein:R1is butyl, wherein said butyl is optionally substituted with one or two -OH; each occurrence of R3is independently H or -O(CH3); and25693 R6is selected from (C10-C20)alkyl, (C10-C20)alkenyl and (C10-C20)alkynyl; or a pharmaceutically acceptable salt thereof.

5. The compound of claim 1 having the structure set forth in Formula III: wherein:R1is (C1-C6)alkyl, wherein said (C1-C6)alkyl is optionally substituted with one to four substituents independently selected from -OH and -O(CH3); R2is H, methyl or -O(CH3); each occurrence of R3is independently H, (C1-C4)alkyl, (C1-C4)alkenyl, (C1- C4)alkynyl or -O(C1-C4)alkyl wherein said (C1-C4)alkyl, (C1-C4)alkenyl, (C1-C4)alkynyl or - O(C1-C4)alkyl are optionally substituted with one or two substituents independently selected from -OH and -O(CH3); R4is selected from (C6-C20)alkyl, (C6-C20)alkenyl and (C6-C20)alkynyl, wherein said (C6-C20)alkyl, (C6-C20)alkenyl and (C6-C20)alkynyl are optionally substituted with one to six substituents selected from -OH, -O(C1-C4)alkyl, -O(C1-C4)alkenyl, -O(C1-C4)alkynyl, chlorine and fluorine; and n is 4; or a pharmaceutically acceptable salt thereof.

6. The compound of claim 5 having the structure set forth in Formula IIIa:25693 wherein: 1R is with one or two -OH; each occurrence of R3is independently H or -O(CH3); and R4is selected from (C10-C20)alkyl, (C10-C20)alkenyl and (C10-C20)alkynyl; or a pharmaceutically acceptable salt thereof.

7. The compound of claim 1 having the structure set forth in Formula IV: wherein:R1is (C1-C6)alkyl, wherein said (C1-C6)alkyl is optionally substituted with one to four substituents selected from -OH and -O(CH3); R2is H, methyl or -O(CH3); each occurrence of R3is independently H, (C1-C4)alkyl, (C1-C4)alkenyl, (C1- C4)alkynyl, or -O(C1-C4)alkyl wherein said (C1-C4)alkyl, (C1-C4)alkenyl, (C1-C4)alkynyl, and - O(C1-C4)alkyl are optionally substituted with one or two substituents independently selected from -OH and -O(CH3); each occurrence of R4is independently selected from (C6-C20)alkyl, (C6- C20)alkenyl and (C6-C20)alkynyl, wherein said (C6-C20)alkyl, (C6-C20)alkenyl and (C6-C20)alkynyl25693 are optionally substituted with one to six substituents independently selected from -OH, -O(C1- C4)alkyl, -O(C1-C4)alkenyl, -O(C1-C4)alkynyl, chlorine or fluorine; and n is 4; or a pharmaceutically acceptable salt thereof.

8. The compound of claim 7 having the structure set forth in Formula IVa: wherein:R1is butyl, wherein said butyl is optionally substituted with one or two -OH; each occurrence of R3is independently H or -O(CH3); and each occurrence of R4is independently selected from (C10-C20)alkyl, (C10- C20)alkenyl and (C10-C20)alkynyl; or a pharmaceutically acceptable salt thereof.

9. The compound of claim 1 selected from: (N-(5-(4-(4-((5-amino-7-(butylamino)-2H-pyrazolo[4,3-d]pyrimidin-2-yl)methyl)-3,5- dimethoxyphenyl)piperazin-1-yl)-5-oxopentyl)stearamide; (S)-N-(5-(4-(4-((5-amino-7-((1-hydroxypentan-2-yl)amino)-2H-pyrazolo[4,3-d]pyrimidin-2- yl)methyl)-3,5-dimethoxyphenyl)piperazin-1-yl)-5-oxopentyl)stearamide; N-(5-(4-(4-((5-amino-7-(butylamino)-2H-pyrazolo[4,3-d]pyrimidin-2-yl)methyl)-3- methoxyphenyl)piperazin-1-yl)-5-oxopentyl)stearamide; N-(5-(4-(4-((5-amino-7-(butylamino)-2H-pyrazolo[4,3-d]pyrimidin-2-yl)methyl)-3- methoxyphenyl)piperazin-1-yl)-5-oxopentyl)tetradecanamide; N-(5-(4-(4-((5-amino-7-(butylamino)-2H-pyrazolo[4,3-d]pyrimidin-2-yl)methyl)-3- methoxyphenyl)piperazin-1-yl)-5-oxopentyl)oleamide; (9Z,12Z)-N-(5-(4-(4-((5-amino-7-(butylamino)-2H-pyrazolo[4,3-d]pyrimidin-2-yl)methyl)-3- methoxyphenyl)piperazin-1-yl)-5-oxopentyl)octadeca-9,12-dienamide;25693 N-(5-(4-(4-((5-amino-7-(butylamino)-2H-pyrazolo[4,3-d]pyrimidin-2-yl)methyl)-3- methoxyphenyl)-1,4-diazepan-1-yl)-5-oxopentyl)stearamide; N-(5-(4-(4-((5-amino-7-(butylamino)-2H-pyrazolo[4,3-d]pyrimidin-2-yl)methyl)-3- methoxyphenyl)piperidin-1-yl)-5-oxopentyl)stearamide; N-(5-(3-(4-((5-amino-7-(butylamino)-2H-pyrazolo[4,3-d]pyrimidin-2-yl)methyl)-3- methoxyphenyl)azetidin-1-yl)-5-oxopentyl)stearamide; 1-(4-((5-amino-7-(butylamino)-2H-pyrazolo[4,3-d]pyrimidin-2-yl)methyl)-3-methoxyphenyl)-N- (3-stearamidopropyl)piperidine-4-carboxamide; (1s,3s)-3-(2-(4-(4-((5-amino-7-(butylamino)-2H-pyrazolo[4,3-d]pyrimidin-2-yl)methyl)-3- methoxyphenyl)piperazin-1-yl)-2-oxoethyl)-N-hexadecylcyclobutane-1-carboxamide; N-(3-(4-(4-((5-amino-7-(butylamino)-2H-pyrazolo[4,3-d]pyrimidin-2-yl)methyl)-3- methoxyphenyl)piperazin-1-yl)-3-oxopropyl)stearamide; N-(7-(4-(4-((5-amino-7-(butylamino)-2H-pyrazolo[4,3-d]pyrimidin-2-yl)methyl)-3- methoxyphenyl)piperazin-1-yl)-7-oxoheptyl)stearamide; N-(3-(2-(4-(4-((5-amino-7-(butylamino)-2H-pyrazolo[4,3-d]pyrimidin-2-yl)methyl)-3- methoxyphenyl)piperazin-1-yl)-2-oxoethyl)cyclobutyl)stearamide; N-(5-(4-(4-((5-amino-7-(butylamino)-2H-pyrazolo[4,3-d]pyrimidin-2-yl)methyl)-3- methoxyphenyl)piperazin-1-yl)-4,4-dimethyl-5-oxopentyl)stearamide; N-(5-(4-(4-((5-amino-7-(butylamino)-3-methyl-2H-pyrazolo[4,3-d]pyrimidin-2-yl)methyl)-3- methoxyphenyl)piperazin-1-yl)-5-oxopentyl)stearamide; (9Z,12Z)-N-(4-((4-((5-amino-7-(butylamino)-2H-pyrazolo[4,3-d]pyrimidin-2-yl)methyl)-3,5- dimethoxybenzyl)(methyl)amino)butyl)octadeca-9,12-dienamide; N-(4-((4-((5-amino-7-(butylamino)-2H-pyrazolo[4,3-d]pyrimidin-2-yl)methyl)-3,5- dimethoxybenzyl)(methyl)amino)butyl)tetradecanamide; N-(4-((4-((5-amino-7-(butylamino)-2H-pyrazolo[4,3-d]pyrimidin-2-yl)methyl)-3,5- dimethoxybenzyl)(methyl)amino)butyl)oleamide; N-(4-((4-((5-amino-7-(butylamino)-2H-pyrazolo[4,3-d]pyrimidin-2-yl)methyl)-3,5- dimethoxybenzyl)(methyl)amino)butyl)stearamide; N-(4-((4-((5-amino-7-(butylamino)-2H-pyrazolo[4,3-d]pyrimidin-2-yl)methyl)-3,5- dimethoxybenzyl)(methyl)amino)-4-oxobutyl)stearamide; (6Z,9Z,28Z,31Z)-heptatriaconta-6,9,28,31-tetraen-19-yl (4-((4-((5-amino-7-(butylamino)-2H- pyrazolo[4,3-d]pyrimidin-2-yl)methyl)-3,5-dimethoxybenzyl)(methyl)amino)butyl)carbamate; 4-(4-((5-amino-7-(butylamino)-2H-pyrazolo[4,3-d]pyrimidin-2-yl)methyl)-3-methoxyphenyl)-N- (3-stearamidopropyl)piperazine-1-carboxamide; and25693 3-stearamidopropyl 4-(4-((5-amino-7-(butylamino)-2H-pyrazolo[4,3-d]pyrimidin-2-yl)methyl)-3- methoxyphenyl)piperazine-1-carboxylate; or a pharmaceutically acceptable salt thereof.

10. A compound which is: N-(5-(4-(4-((5-amino-7-(butylamino)-2H-pyrazolo[4,3-d]pyrimidin-2-yl)methyl)-3- methoxyphenyl)piperazin-1-yl)-5-oxopentyl)stearamide; or a pharmaceutically acceptable salt thereof.

11. A formulation comprising: (i) a compound of any one of claims 1-10 or a pharmaceutically acceptable salt thereof; (ii) one or more emulsifiers; and (iii) a terpene.

12. A formulation comprising: (i) a compound of any one of claims 1-10 or a pharmaceutically acceptable salt thereof; (ii) sorbitan trioleate (SPAN-85); (iii) polysorbate-20 (PS-20) or polysorbate-80 (PS-80); and (iv) squalene.

13. The formulation of claim 12 wherein the compound is N-(5-(4-(4-((5- amino-7-(butylamino)-2H-pyrazolo[4,3-d]pyrimidin-2-yl)methyl)-3-methoxyphenyl)piperazin-1- yl)-5-oxopentyl)stearamide, or a pharmaceutically acceptable salt thereof.

14. A pharmaceutical composition comprising: (i) at least one antigen; (ii) a compound of any one of claims 1-10 or a pharmaceutically acceptable salt thereof; (iii) one or more emulsifiers; (iv) a terpene; and (v) a pharmaceutically acceptable carrier.

15. A pharmaceutical composition comprising: (i) at least one antigen; (ii) a compound of any one of claims 1-10 or a pharmaceutically acceptable salt thereof; (iii) sorbitan trioleate (SPAN-85); (iv) polysorbate-20 (PS-20) or polysorbate-80 (PS-80); (v) squalene; and (vi) a pharmaceutically acceptable carrier.

16. The pharmaceutical composition of claim 15, wherein the compound is N- (5-(4-(4-((5-amino-7-(butylamino)-2H-pyrazolo[4,3-d]pyrimidin-2-yl)methyl)-3- methoxyphenyl)piperazin-1-yl)-5-oxopentyl)stearamide, or a pharmaceutically acceptable salt thereof.25693 17. An immunogenic composition comprising: (i) at least one antigen; (ii) a compound of any one of claims 1-10 or a pharmaceutically acceptable salt thereof; (iii) one or more emulsifiers; (iv) a terpene; and (v) a pharmaceutically acceptable carrier.

18. An immunogenic composition comprising: (i) at least one antigen; (ii) a compound of any one of claims 1-10 or a pharmaceutically acceptable salt thereof; (iii) sorbitan trioleate (SPAN-85); (iv) polysorbate-20 (PS-20) or polysorbate-80 (PS-80); (v) squalene; and (vi) a pharmaceutically acceptable carrier.

19. The immunogenic composition of claim 18, wherein the compound is N- (5-(4-(4-((5-amino-7-(butylamino)-2H-pyrazolo[4,3-d]pyrimidin-2-yl)methyl)-3- methoxyphenyl)piperazin-1-yl)-5-oxopentyl)stearamide, or a pharmaceutically acceptable salt thereof.

20. A single-dose vaccine composition comprising: (i) at least one antigen; (ii) a compound of any one of claims 1-10 or a pharmaceutically acceptable salt thereof; (iii) one or more emulsifiers; (iv) a terpene; and (v) a pharmaceutically acceptable carrier, wherein a single dose of the vaccine composition is sufficient to elicit a desired immune response against the at least one antigen.

21. A single-dose vaccine composition comprising: (i) at least one antigen; (ii) a compound of any one of claims 1-10 or a pharmaceutically acceptable salt thereof; (iii) sorbitan trioleate (SPAN-85); (iv) polysorbate-20 (PS-20) or polysorbate-80 (PS-80); (v) squalene; and (vi) a pharmaceutically acceptable carrier, wherein a single dose of the vaccine composition is sufficient to elicit a desired immune response against the at least one antigen.

22. The single-dose vaccine composition of claim 21, wherein the compound is N-(5-(4-(4-((5-amino-7-(butylamino)-2H-pyrazolo[4,3-d]pyrimidin-2-yl)methyl)-3- methoxyphenyl)piperazin-1-yl)-5-oxopentyl)stearamide, or a pharmaceutically acceptable salt thereof.

23. A method of treating or preventing a disease in a patient in need thereof comprising administrating to the patient a pharmaceutical composition comprising: (i) at least one antigen; (ii) a compound of any one of claims 1-10, or a pharmaceutically acceptable salt25693 thereof; (iii) one or more emulsifiers; (iv) a terpene; and (v) a pharmaceutically acceptable carrier.

24. A method of treating or preventing a disease in a patient in need thereof comprising administrating to the patient a pharmaceutical composition comprising: (i) at least one antigen; (ii) a compound of any one of claims 1-10, or a pharmaceutically acceptable salt thereof; (iii) sorbitan trioleate (SPAN-85); (iv) polysorbate-20 (PS-20) or polysorbate-80 (PS- 80); (v) squalene; and (vi) a pharmaceutically acceptable carrier.

25. The method of claim 24, wherein the compound is N-(5-(4-(4-((5-amino-7- (butylamino)-2H-pyrazolo[4,3-d]pyrimidin-2-yl)methyl)-3-methoxyphenyl)piperazin-1-yl)-5- oxopentyl)stearamide, or a pharmaceutically acceptable salt thereof.

26. The method of any one of claims 23-25, wherein the patient is a human.

27. The method of any one of claims 23-25, wherein the patient is a non- human animal.

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