Compositions and methods for activating pyruvate kinase

JP2026097841APending Publication Date: 2026-06-16THE RGT UNIV OF MICHIGAN
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Authority / Receiving Office
JP · JP
Patent Type
Applications
Current Assignee / Owner
THE RGT UNIV OF MICHIGAN
Filing Date
2026-02-10
Publication Date
2026-06-16

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Abstract

This invention provides a composition for activating pyruvate kinase. [Solution] A composition comprising the pyruvate kinase activator shown below is provided. JPEG2026097841000362.jpg41150
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Claims

1. A composition containing the following compounds. 【Chemistry 1】 [In the formula, X is non-existent, -H, -CH ２ -, -CHR ３ -, -CR ３ R ４ -, -(CH ２ ) ｎ -, -(CHR ３ ) ｎ -, -(CR ３ R ４ ) ｎ is selected from, and n is from 1 to 6; R １ -H, -CN, -NO ２ , -NH ２ , - NHR ３ , NR ３ R ４ -OH, OR ３ , -SOR ３ , -SO ２ R ３ C may be substituted. １ -C ６ Selected from the group consisting of alkyl, optionally substituted monocyclic cycloalkyl, optionally substituted bicyclic cycloalkyl, optionally substituted tricyclic cycloalkyl, optionally substituted monocyclic heterocycle, optionally substituted bicyclic heterocycle, and optionally substituted tricyclic heterocycle; R ２ -H, -CN, -NO ２ , -NH ２ , - NHR ３ , NR ３ R ４ -OH, OR ３ , -SOR ３ , -SO ２ R ３ C may be substituted. １ -C ６ Selected from the group consisting of alkyl, optionally substituted monocyclic cycloalkyl, optionally substituted bicyclic cycloalkyl, optionally substituted monocyclic heterocycle, optionally substituted bicyclic heterocycle, and optionally substituted tricyclic heterocycle; R ３ and R ４ Each of these can be substituted independently. １ -C ６ Selected from the group consisting of alkyl, optionally substituted monocyclic cycloalkyl, optionally substituted bicyclic cycloalkyl, optionally substituted tricyclic cycloalkyl, optionally substituted monocyclic heterocycle, optionally substituted bicyclic heterocycle, and optionally substituted tricyclic heterocycle.

2. R １ but, 【Chemistry 2】 【change】 Selected from the group consisting of, R ２ but, 【Transformation 3】 A composition according to claim 1, selected from the group consisting of the following.

3. The composition according to claim 1 or 2, wherein the compound is selected from the group consisting of the following: 【Chemistry 4】 【change】 【change】 【change】

4. A composition containing the following: 【Transformation 5】 [In the formula, R １ -H, -F, -Cl, -Br, -CN, -NO ２ , -NH ２ , - NHR ３ , -NR ３ R ４ -OH, -OR ３ C may be substituted. １ -C ６ Selected from the group consisting of alkyl, optionally substituted monocyclic cycloalkyl, optionally substituted bicyclic cycloalkyl, optionally substituted tricyclic cycloalkyl, optionally substituted monocyclic heterocycle, optionally substituted bicyclic heterocycle, and optionally substituted tricyclic heterocycle; R ２ is -H, -CH ３ ,-(CH ２ ) ｎ -R ５、 - (CHR ３ ) ｎ -R ５ ,-(CR ３ R ４ ) ｎ -R ５ C may be substituted. １ -C ６ Selected from the group consisting of alkyl, optionally substituted monocyclic cycloalkyl, optionally substituted bicyclic cycloalkyl, optionally substituted monocyclic heterocycle, optionally substituted bicyclic heterocycle, and optionally substituted tricyclic heterocycle; R ３ and R ４ Each of these can be substituted independently. １ -C ６ Selected from the group consisting of alkyl, optionally substituted monocyclic cycloalkyl, optionally substituted bicyclic cycloalkyl, optionally substituted tricyclic cycloalkyl, optionally substituted monocyclic heterocycle, optionally substituted bicyclic heterocycle, and optionally substituted tricyclic heterocycle; R ５ -H, -F, -Cl, -Br, -NO ２ -CN, -NO ２ , -NH ２ , - NHR ３ , -NR ３ R ４ -OH, -OR ３ C may be substituted. １ -C ６ Selected from the group consisting of alkyl, optionally substituted monocyclic cycloalkyl, optionally substituted bicyclic cycloalkyl, optionally substituted tricyclic cycloalkyl, optionally substituted monocyclic heterocycle, optionally substituted bicyclic heterocycle, and optionally substituted tricyclic heterocycle.

5. R １ But, OCH ３ 、OH、NH ２ 、NCH ３ 、N(CH ３ ) ２ 、 【Transformation 6】 Selected from the group consisting of, R ２ but, 【Transformation 7】 A composition according to claim 4, selected from the group consisting of the following.

6. The aforementioned compound, 【Transformation 8】 【change】 A composition according to any one of claims 4 or 5, selected from the group consisting of the following.

7. The composition according to any one of claims 1 to 6, wherein at least one hydrogen atom of the compound is replaced by deuterium.

8. The composition according to any one of claims 1 to 7, wherein the composition is a pharmaceutical composition.

9. The composition according to any one of claims 1 to 8, wherein the composition is formulated for injection, oral delivery, or as eye drops.

10. The composition according to any one of claims 1 to 9, wherein the composition comprises a pharmaceutically acceptable carrier.

11. The composition according to any one of claims 1 to 10, wherein the composition is a pyruvate kinase activator.

12. The composition according to claim 16, wherein the pyruvate kinase is selected from the group consisting of PKM1 and PKM2.

13. A method for activating pyruvate kinase in subjects, 【Chemistry 9】 Formula I or 【Chemistry 10】 Formula II: compounds selected from [In the formula, X １ , X ２ , X ３ , and X ４ These are independently selected from the group consisting of CH, CO, N, NH, S, and O; Z is non-existent, a bond, or an optionally substituted C １－６ alkyl, -O-, -S-, -CH ２ -, -CHR ５ -, -CR ５ R ６ -, -S(=O)CH ２ -, -S(=O) ２ CH ２ , -NR ５ , -NR ５ C(=O)-, -C(O)NR ５ , -C(=O)-, -OC(=O)-, -C(=O)O-, -NR ５ C(=O)O-, -OC(=O)NR ５ , -NR ５ C(=O)NR ５ , -OC(R ５ ) ２ , -C(R ５ ) ２ O-, -NR ４ C(R ５ ) ２ , C(R ６ ) ２ NR ５ , -S(=O)-, S(=O) ２ , -S(=O) ２ O-, -OS(=O) ２ , -S(=O) ２ NR ５ , -NR ５ S(=O) ２ , -S(=O)NR ５ , -NR ５ S(=O)-, -OS(=O)NR ５ , -NR ５ S(=O)O-, and -S(=O)(=NR ５ )-, and is selected from the group consisting of; the bonding position to R １ or R ２ is on the left side; R ５ and R ６ These are independently hydrogen, halogen, -CN, OR ７ , NR ７ R ８ , -N(R ７ )C(=O)R ８ , -C(=O)N(R ７ ), -C(=O)R ７ , -C (=O) OR ７ , -SR ７ , -S(=O)R ７ , -S (=O) ２ R ７ -C which is optimally substituted in either case. １ -C ６ Selected from the group consisting of alkyl groups; R ７ and R ８ Each of these is independently substituted with hydrogen, or -C whichever is optimally substituted. １ -C ６ Selected from the group consisting of alkyl groups; R ７ and R ８ C can be substituted together with these two. １ -C ６ A monocyclic cycloalkyl ring or a monocyclic heterocycle which may be substituted; Y is non-existent, -CH ２ -----CHR ９ -, -CR ９ R １０ -, - (CH ２ ) ｎ -, - (CHR ９ ) ｎ -, - (CR ９ R １０ ) ｎ - (n is 1 to 6), -C(=O)-, -S(=O)-, - and S(=O) ２ Selected from the group consisting of: R ９ and R １０ Each of these is independently substituted with hydrogen, halogen, or -CN, or -C as optimally substituted. １ -C ６ Selected from the group consisting of alkyl groups, R ９ and R １０ C can be substituted together with these two. １ -C ６ A monocyclic cycloalkyl ring or a monocyclic heterocycle which may be substituted; R １ -H, -F, -Cl, -Br, -NO ２ -CN, -NO ２ , -NH ２ , - NHR １１ , -NR １１ R １２ -OH, -OR １１ ,CH ２ -----CHR ９ -, -CR ９ R １０、 - (CH ２ ) ｎ -, - (CHR ９ ) ｎ -, - (CR ９ R １０ ) ｎ - C may be substituted. １ -C ６ Selected from the group consisting of alkyl, optionally substituted monocyclic cycloalkyl, optionally substituted bicyclic cycloalkyl, optionally substituted tricyclic cycloalkyl, optionally substituted monocyclic heterocycle, optionally substituted bicyclic heterocycle, and optionally substituted tricyclic heterocycle; R ２ -H, -F, -Cl, -Br, -NO ２ -CN, -NO ２ , -NH ２ , - NHR １１ , -NR １１ R １２ -OH, -OR １１ C may be substituted. １ -C ６ Selected from the group consisting of alkyl, optionally substituted monocyclic cycloalkyl, optionally substituted bicyclic cycloalkyl, optionally substituted tricyclic cycloalkyl, optionally substituted monocyclic heterocycle, optionally substituted bicyclic heterocycle, and optionally substituted tricyclic heterocycle; R ３ -H, -F, -Cl, -Br, -NO ２ -CN, -NO ２ , -NH ２ , - NHR １１ , -NR １１ R １２ -OH, -OR １１ C may be substituted. １ -C ６ Selected from the group consisting of alkyl, optionally substituted monocyclic cycloalkyl, optionally substituted bicyclic cycloalkyl, optionally substituted tricyclic cycloalkyl, optionally substituted monocyclic heterocycle, optionally substituted bicyclic heterocycle, and optionally substituted tricyclic heterocycle; R １１ and R １２ Each of these can be substituted independently. １ -C ６ Selected from the group consisting of alkyl, optionally substituted monocyclic cycloalkyl, optionally substituted bicyclic cycloalkyl, optionally substituted tricyclic cycloalkyl, optionally substituted monocyclic heterocycle, optionally substituted bicyclic heterocycle, and optionally substituted tricyclic heterocycle; R ４ is hydrogen, -CH ３ ----CHR １３ , -CR １３ R １４ , -S(=O)R １３ , -S (=O) ２ R １３ , optionally substituted alkyl, optimally substituted haloalkyl, optimally substituted alkenyl, optimally substituted alkynyl, optimally substituted cycloalkyl, optimally substituted heterocycle, optimally substituted aryl, -C(=O)R １５ Selected from the group consisting of , and nitrogen protecting groups; R １３ and R １４ Each of these can be substituted independently. １ -C ６ Selected from the group consisting of alkyl, optionally substituted monocyclic cycloalkyl, optionally substituted bicyclic cycloalkyl, optionally substituted tricyclic cycloalkyl, optionally substituted monocyclic heterocycle, optionally substituted bicyclic heterocycle, and optionally substituted tricyclic heterocycle; R １５ is hydrogen, -CH ３ Selected from the group consisting of alkyl groups that may be substituted, optimally substituted haloalkyl groups, optimally substituted alkenyl groups, optimally substituted alkynyl groups, optimally substituted cycloalkyl groups, optimally substituted heterocyclic groups, and optimally substituted aryl groups. The process includes administering a composition containing the above-mentioned subject to the subject, An activation method wherein the administration activates the pyruvate kinase in the subject.

14. The method according to claim 13, wherein the pyruvate kinase is selected from the group consisting of PKM1 and PKM2.

15. The method according to claim 13 or 14, wherein the activation treats or alleviates the disease or condition in the subject.

16. The method according to claim 15, wherein the disease or condition is selected from the group consisting of eye disorders, cancer, and blood disorders.

17. The method according to claim 16, wherein the eye disorder is selected from the group consisting of decreased visual acuity, retinal dystrophy, macular degeneration, retinal degeneration, diabetic retinopathy, proliferative vitreoretinopathy, and retinal detachment.

18. The method according to claim 16, wherein the blood disorder is selected from the group consisting of anemia, hemolytic anemia, sickle cell disease, thalassemia, hereditary spherocytosis, hereditary ellipsoidosis, abetalipoproteinemia, and Bassen-Konzweig syndrome.

19. A method for activating PKM2 in the eyes of a subject, 【Chemistry 11】 Formula I or 【Chemistry 12】 Formula II: compounds selected from [In the formula, X １ , X ２ , X ３ , and X ４ The elements are independently selected from CH, CO, N, NH, S, or O; Z may be nonexistent, bound, or substituted by C. １－６ Alkyl, -O-, -S-, -CH ２ -----CHR ５ -, -CR ５ R ６ -, - (CH ２ ) ｎ -, - (CHR ５ ) ｎ -, - (CR ５ R ６ ) ｎ -, -S(=O)CH ２ , -S (=O) ２ CH ２ -, -NR ５ -, -NR ５ C(=O)-, -C(O)NR ５ -, -C(=O)-, -OC(=O)-, -C(=O)O-, -NR ５ C(=O)O-, -OC(=O)NR ５ -, -NR ５ C(=O)NR ５ -, -OC(R ５ ) ２ -, -C(R ５ ) ２ O-, -NR ４ C(R ５ ) ２ -, C(R ６ ) ２ NR ５ -, -S(=O)-,S(=O) ２ -, -S (=O) ２ O-, -OS (=O) ２ -, -S (=O) ２ NR ５ -, -NR ５ S (=O) ２ -, -S(=O)NR ５ -, -NR ５ S(=O)-, -OS(=O)NR ５ -, -NR ５ S(=O)O-, or -S(=O)(=NR ５ ) - and R １ or R ２ The connection point is on the left side, and n = 1 to 6; R ５ and R ６ These are independently hydrogen, halogen, -CN, OR ７ , NR ７ R ８ , -N(R ７ )C(=O)R ８ , -C(=O)N(R ７ ), -C(=O)R ７ , -C (=O) OR ７ , -SR ７ , -S(=O)R ７ , -S (=O) ２ R ７ , or either of the most optimally substituted -C １ -C ６ It is alkyl; R ７ and R ８ Each of these is independently substituted with hydrogen, or -C whichever is optimally substituted. １ -C ６ alkyl; or R ７ and R ８ C may be substituted as a whole. １ -C ６ A monocyclic cycloalkyl ring or a monocyclic heterocycle which may be substituted; Y is non-existent, -CH ２ -----CHR ９ -, -CR ９ R １０ -, - (CH ２ ) ｎ -, - (CHR ９ ) ｎ -, - (CR ９ R １０ ) ｎ -, -C(=O)-, -S(=O)-, -S(=O) ２ - and n = 1 to 6; R ９ and R １０ Each is independently substituted with hydrogen, halogen, -CN, or any of the most optimally substituted -C １ -C ６ Alkyl; or R ９ and R １０ C may be substituted as a whole. １ -C ６ It can be a monocyclic cycloalkyl ring or a monocyclic heterocycle which may be substituted; R １ -H, -F, -Cl, -Br, -NO ２ -CN, -NH ２ , - NHR １１ , -NR １１ R １２ -OH, -OR １１ C may be substituted. １ -C ６ Alkyl, optionally substituted monocyclic cycloalkyl, optionally substituted bicyclic cycloalkyl, optionally substituted tricyclic cycloalkyl, optionally substituted monocyclic heterocycle, optionally substituted bicyclic heterocycle, or optionally substituted tricyclic heterocycle; R ２ -H, -F, -Cl, -Br, -NO ２ -CN, -NO ２ , -NH ２ , - NHR １１ , -NR １１ R １２ -OH, -OR １１ C may be substituted. １ -C ６ Alkyl, optionally substituted monocyclic cycloalkyl, optionally substituted bicyclic cycloalkyl, optionally substituted tricyclic cycloalkyl, optionally substituted monocyclic heterocycle, optionally substituted bicyclic heterocycle, optionally substituted tricyclic heterocycle; R ３ -H, -F, -Cl, -Br, -NO ２ -CN, -NO ２ , -NH ２ , - NHR １１ , -NR １１ R １２ -OH, -OR １１ C may be substituted. １ -C ６ Alkyl, optionally substituted monocyclic cycloalkyl, optionally substituted bicyclic cycloalkyl, optionally substituted tricyclic cycloalkyl, optionally substituted monocyclic heterocycle, optionally substituted bicyclic heterocycle, optionally substituted tricyclic heterocycle; R １１ and R １２ Each of these can be substituted independently. １ -C ６ Alkyl, optionally substituted monocyclic cycloalkyl, optionally substituted bicyclic cycloalkyl, optionally substituted tricyclic cycloalkyl, optionally substituted monocyclic heterocycle, optionally substituted bicyclic heterocycle, or optionally substituted tricyclic heterocycle; R ４ is hydrogen, -CH ３ ----CHR １３ , -CR １３ R １４ , -S(=O)R １３ , -S (=O) ２ R １３ , optionally substituted alkyl, optimally substituted haloalkyl, optimally substituted alkenyl, optimally substituted alkynyl, optimally substituted cycloalkyl, optimally substituted heterocycle, optimally substituted aryl, -C(=O)R １５ , or a nitrogen protecting group; R １３ and R １４ Each of these can be substituted independently. １ -C ６ Alkyl, optionally substituted monocyclic cycloalkyl, optionally substituted bicyclic cycloalkyl, optionally substituted tricyclic cycloalkyl, optionally substituted monocyclic heterocycle, optionally substituted bicyclic heterocycle, optionally substituted tricyclic heterocycle; R １５ is hydrogen, -CH ３ These are alkyl groups that may be substituted, optimally substituted haloalkyl groups, optimally substituted alkenyl groups, optimally substituted alkynyl groups, optimally substituted cycloalkyl groups, optimally substituted heterocyclic groups, and optimally substituted aryl groups. or a pharmaceutically acceptable salt thereof An activation method comprising administering a composition containing to the eye of a subject, wherein the administration activates PKM2 in the eye of the subject.

20. A method of treating a disease or condition, 【Chemistry 13】 Formula I or 【Chemistry 14】 Formula II: compounds selected from [In the formula, X １ , X ２ , X ３ , and X ４ The elements are independently selected from CH, CO, N, NH, S, or O; Z may be nonexistent, bound, or substituted by C. １－６ Alkyl, -O-, -S-, -CH ２ -----CHR ５ -, -CR ５ R ６ -, - (CH ２ ) ｎ -, - (CHR ５ ) ｎ -, - (CR ５ R ６ ) ｎ -, -S(=O)CH ２ , -S (=O) ２ CH ２ -, -NR ５ -, -NR ５ C(=O)-, -C(O)NR ５ -, -C(=O)-, -OC(=O)-, -C(=O)O-, -NR ５ C(=O)O-, -OC(=O)NR ５ -, -NR ５ C(=O)NR ５ -, -OC(R ５ ) ２ -, -C(R ５ ) ２ O-, -NR ４ C(R ５ ) ２ -, C(R ６ ) ２ NR ５ -, -S(=O)-,S(=O) ２ -, -S (=O) ２ O-, -OS (=O) ２ -, -S (=O) ２ NR ５ -, -NR ５ S (=O) ２ -, -S(=O)NR ５ -, -NR ５ S(=O)-, -OS(=O)NR ５ -, -NR ５ S(=O)O-, or -S(=O)(=NR ５ ) - and R １ or R ２ The connection point is on the left side, and n = 1 to 6; R ５ and R ６ These are independently hydrogen, halogen, -CN, OR ７ , NR ７ R ８ , -N(R ７ )C(=O)R ８ , -C(=O)N(R ７ ), -C(=O)R ７ , -C (=O) OR ７ , -SR ７ , -S(=O)R ７ , -S (=O) ２ R ７ , or either of the most optimally substituted -C １ -C ６ It is alkyl; R ７ and R ８ Each of these is independently substituted with hydrogen, or -C whichever is optimally substituted. １ -C ６ alkyl; or R ７ and R ８ C may be substituted as a whole. １ -C ６ A monocyclic cycloalkyl ring or a monocyclic heterocycle which may be substituted; Y is non-existent, -CH ２ -----CHR ９ -, -CR ９ R １０ -, - (CH ２ ) ｎ -, - (CHR ９ ) ｎ -, - (CR ９ R １０ ) ｎ -, -C(=O)-, -S(=O)-, -S(=O) ２ - and n = 1 to 6; R ９ and R １０ Each is independently substituted with hydrogen, halogen, -CN, or any of the most optimally substituted -C １ -C ６ Alkyl; or R ９ and R １０ C may be substituted as a whole. １ -C ６ It can be a monocyclic cycloalkyl ring or a monocyclic heterocycle which may be substituted; R １ -H, -F, -Cl, -Br, -NO ２ -CN, -NH ２ , - NHR １１ , -NR １１ R １２ -OH, -OR １１ C may be substituted. １ -C ６ Alkyl, optionally substituted monocyclic cycloalkyl, optionally substituted bicyclic cycloalkyl, optionally substituted tricyclic cycloalkyl, optionally substituted monocyclic heterocycle, optionally substituted bicyclic heterocycle, or optionally substituted tricyclic heterocycle; R ２ -H, -F, -Cl, -Br, -NO ２ -CN, -NO ２ , -NH ２ , - NHR １１ , -NR １１ R １２ -OH, -OR １１ C may be substituted. １ -C ６ Alkyl, optionally substituted monocyclic cycloalkyl, optionally substituted bicyclic cycloalkyl, optionally substituted tricyclic cycloalkyl, optionally substituted monocyclic heterocycle, optionally substituted bicyclic heterocycle, optionally substituted tricyclic heterocycle; R ３ -H, -F, -Cl, -Br, -NO ２ -CN, -NO ２ , -NH ２ , - NHR １１ , -NR １１ R １２ -OH, -OR １１ C may be substituted. １ -C ６ Alkyl, optionally substituted monocyclic cycloalkyl, optionally substituted bicyclic cycloalkyl, optionally substituted tricyclic cycloalkyl, optionally substituted monocyclic heterocycle, optionally substituted bicyclic heterocycle, optionally substituted tricyclic heterocycle; R １１ and R １２ Each of these can be substituted independently. １ -C ６ Alkyl, optionally substituted monocyclic cycloalkyl, optionally substituted bicyclic cycloalkyl, optionally substituted tricyclic cycloalkyl, optionally substituted monocyclic heterocycle, optionally substituted bicyclic heterocycle, or optionally substituted tricyclic heterocycle; R ４ is hydrogen, -CH ３ ----CHR １３ , -CR １３ R １４ , -S(=O)R １３ , -S (=O) ２ R １３ , optionally substituted alkyl, optimally substituted haloalkyl, optimally substituted alkenyl, optimally substituted alkynyl, optimally substituted cycloalkyl, optimally substituted heterocycle, optimally substituted aryl, -C(=O)R １５ , or a nitrogen protecting group; R １３ and R １４ Each of these can be substituted independently. １ -C ６ Alkyl, optionally substituted monocyclic cycloalkyl, optionally substituted bicyclic cycloalkyl, optionally substituted tricyclic cycloalkyl, optionally substituted monocyclic heterocycle, optionally substituted bicyclic heterocycle, optionally substituted tricyclic heterocycle; R １５ is hydrogen, -CH ３ These are alkyl groups that may be substituted, optimally substituted haloalkyl groups, optimally substituted alkenyl groups, optimally substituted alkynyl groups, optimally substituted cycloalkyl groups, optimally substituted heterocyclic groups, and optimally substituted aryl groups. or a pharmaceutically acceptable salt thereof A treatment method comprising administering a pyruvate kinase activator containing the above to a person requiring treatment, wherein the administration treats or alleviates the symptoms of the disease or condition in the person.

21. The method according to claim 20, wherein the disease or condition is selected from the group consisting of eye disorders, cancer, and blood disorders.

22. The method according to claim 21, wherein the eye disorder is selected from the group consisting of decreased visual acuity, retinal dystrophy, macular degeneration, retinal degeneration, diabetic retinopathy, proliferative vitreoretinopathy, and retinal detachment.

23. The method according to claim 22, wherein the blood disorder is selected from the group consisting of anemia, hemolytic anemia, sickle cell disease, thalassemia, hereditary spherocytosis, hereditary ellipsoidosis, abetalipoproteinemia, and Bassen-Konzweig syndrome.

24. The aforementioned administration prevents photoreceptor death in the eyes of the base subject and R １ The method according to any one of claims 13 to 23, wherein -Z-s or reduced.

25. The method according to any one of claims 13 to 24, wherein the activator is formulated for injection, oral delivery, or as eye drops.

26. The method according to claim 25, wherein the injection is an intravitreous injection.

27. R ２ -Z- is H; R １ -Z may be nonexistent, combined, or substituted for C. １－６ Alkyl, -O-, -S-, -CH ２ -----CHR ５ -, -CR ５ R ６ -, - (CH ２ ) ｎ -, - (CHR ５ ) ｎ -, - (CR ５ R ６ ) ｎ -, -S(=O)CH ２ , -NR ５ -, -NR ５ C(=O)-, -C(O)NR ５ Selected from the group consisting of -, -C(=O)-, and -S(=O), R １ The connection point is on the left side, and n = 1 to 6; R ５ and R ６ Each independently produces hydrogen, -CN, and OR ７ , NR ７ R ８ -C which is optimally substituted in either case. １ -C ６ Selected from the group consisting of alkyl, and R ７ and R ８ C may be substituted as a whole. １ -C ６ A monocyclic cycloalkyl ring or a monocyclic heterocycle which may be substituted; R ７ and R ８ Each of these is independently substituted with hydrogen, or -C which is optimally substituted. １ -C ６ Selected from the group consisting of alkyl groups; and R ７ and R ８ C may be substituted as a whole. １ -C ６ A monocyclic cycloalkyl ring or a monocyclic heterocycle which may be substituted; Y is non-existent, -CH ２ -----CHR ９ -, -CR ９ R １０ -, - (CH ２ ) ｎ -, - (CHR ９ ) ｎ -, - (CR ９ R １０ ) ｎ A group consisting of the following is selected, where n = 1 to 3; R ９ and R １０ Each of these is independently substituted with hydrogen, or -C which is optimally substituted. １ -C ６ Selected from the group consisting of alkyl, and R ９ and R １０ C may be substituted as a whole. １ -C ６ A monocyclic cycloalkyl ring or a monocyclic heterocycle which may be substituted; R １ However, -H, -F, -Cl, -Br, -NO ２ -CN, -NO ２ , -NH ２ , - NHR １１ , -NR １１ R １２ -OH, -OR １１ C may be substituted. １ -C ６ Alkyl, optionally substituted monocyclic cycloalkyl, optionally substituted bicyclic cycloalkyl, optionally substituted tricyclic cycloalkyl, optionally substituted monocyclic heterocycle, optionally substituted bicyclic heterocycle, or optionally substituted tricyclic heterocycle; R ２ However, -H, -F, -Cl, -Br, -NO ２ -CN, -NO ２ , -NH ２ , - NHR １１ , -NR １１ R １２ -OH, -OR １１ C may be substituted. １ -C ６ Alkyl, optionally substituted monocyclic cycloalkyl, optionally substituted bicyclic cycloalkyl, optionally substituted tricyclic cycloalkyl, optionally substituted monocyclic heterocycle, optionally substituted bicyclic heterocycle, or optionally substituted tricyclic heterocycle; R ３ However, -H, -F, -Cl, -Br, -NO ２ -CN, -NO ２ , -NH ２ , - NHR １１ , -NR １１ R １２ -OH, -OR １１ C may be substituted. １ -C ６ Alkyl, optionally substituted monocyclic cycloalkyl, optionally substituted bicyclic cycloalkyl, optionally substituted tricyclic cycloalkyl, optionally substituted monocyclic heterocycle, optionally substituted bicyclic heterocycle, optionally substituted tricyclic heterocycle; R １１ and R １２ Each of these can be substituted independently. １ -C ６ Selected from the group consisting of alkyl, optionally substituted monocyclic cycloalkyl, optionally substituted bicyclic cycloalkyl, optionally substituted tricyclic cycloalkyl, optionally substituted monocyclic heterocycle, optionally substituted bicyclic heterocycle, and optionally substituted tricyclic heterocycle; R ４ ga-CH ３ The method according to any one of claims 13 to 26.

28. Z-R １ Z-R ２、 Z-R ３ , and Y-R ３ However, individually or in combination, 【Chemistry 15】 [In the formula, R １６ and R １７ These are located at the ortho, meta, or para position on the aryl ring, and are H, -OCH ３ , C １ -C ４ Alkyl, -NH ２ -Halogen, -CN, -OH, -S(=O)Me, -S(=O) ２ Me, -CH ２ OMe, and -CH ２ NR １８ R １９ Selected from the group consisting of; R １８ and R １９ is -H, C １ -C ４ Selected from alkyl, optimally substituted aryl, or heterocycles, or collectively forming a carbocyclic or heterocycle. 【Chemistry 16】 A method according to any one of claims 13 to 28, selected from the group consisting of the following.

29. The aforementioned compound is the compound of formula I, and Z-R ２ H is Z-R １ ga 8-OCH ３ No, RI ４ but 【Chemistry 17】 Instead, Y-R ３ but [Chemistry 18] The method according to any one of claims 13 to 28.

30. The aforementioned compound is the compound of formula I, and Z-R ２ H is Z-R １ It is not 8-Cl, but R ４ ga CH ３ but 【Chemistry 19】 Not Y-R ３ ga CH ３ but 【Chemistry 20】 However, the method according to any one of claims 13 to 28.

31. The aforementioned compound is the compound of formula I, R ２ but 【Chemistry 21】 But CH ３ Not Y-R ３ but 【Chemistry 22】 The method according to any one of claims 13 to 28.

32. The aforementioned compound is the compound of formula I, and Z-R １ but 【Chemistry 23】 X １ It is R, not CO. ２ ga CH ３ Instead, Y-R ３ but 【Chemistry 24】 The method according to any one of claims 13 to 28.

33. The aforementioned compound, 【Chemistry 25】 [In the formula, R １ and R ２ CH is independently ３ or 【Chemistry 26】 That is. 【Chemistry 27】 The method according to any one of claims 13 to 32.

34. The method according to any one of claims 13 to 33, wherein the compound is selected from the compounds listed in Table 2.

35. The aforementioned compound 【Chemistry 28】 And R １ A monocyclic or bicyclic carbon ring or heterocyclic portion to which R is substituted, ２ The method according to any one of claims 13 to 34, wherein the substituted part is a monocyclic or bicyclic heterocyclic part.

36. The aforementioned compound 【Chemistry 29】 【change】 【change】 【change】 【change】 【change】 The method according to any one of claims 13 to 35.

37. The method according to any one of claims 13 to 26, wherein the base compound is one of the following compounds. 【Transformation 30】 [In the formula, X is either nonexistent, -H, or -CH. ２ -----CHR ３ -, -CR ３ R ４ -, - (CH ２ ) ｎ -, - (CHR ３ ) ｎ -, - (CR ３ R ４ ) ｎ - is selected from, where n is 1 to 6; R １ -H, -CN, -NO ２ , -NH ２ , - NHR ３ , NR ３ R ４ -OH, OR ３ , -SOR ３ , -SO ２ R ３ C may be substituted. １ -C ６ Selected from the group consisting of alkyl, optionally substituted monocyclic cycloalkyl, optionally substituted bicyclic cycloalkyl, optionally substituted tricyclic cycloalkyl, optionally substituted monocyclic heterocycle, optionally substituted bicyclic heterocycle, and optionally substituted tricyclic heterocycle; R ２ -H, -CN, -NO ２ , -NH ２ , - NHR ３ , NR ３ R ４ -OH, OR ３ , -SOR ３ , -SO ２ R ３ C may be substituted. １ -C ６ Selected from the group consisting of alkyl, optionally substituted monocyclic cycloalkyl, optionally substituted bicyclic cycloalkyl, optionally substituted monocyclic heterocycle, optionally substituted bicyclic heterocycle, and optionally substituted tricyclic heterocycle; R ３ and R ４ Each of these can be substituted independently. １ -C ６ Selected from the group consisting of alkyl, optionally substituted monocyclic cycloalkyl, optionally substituted bicyclic cycloalkyl, optionally substituted tricyclic cycloalkyl, optionally substituted monocyclic heterocycle, optionally substituted bicyclic heterocycle, and optionally substituted tricyclic heterocycle.

38. R １ but, 【Chemistry 31】 Selected from the group consisting of, R ２ but, 【Chemistry 32】 【change】 The method according to claim 37, selected from the group consisting of the following.

39. The method according to any one of claims 13 to 26, wherein the compound is one of the following compounds. 【Transformation 33】 [In the formula, R １ -H, -F, -Cl, -Br, -CN, -NO ２ , -NH ２ , - NHR ３ , -NR ３ R ４ -OH, -OR ３ C may be substituted. １ -C ６ Selected from the group consisting of alkyl, optionally substituted monocyclic cycloalkyl, optionally substituted bicyclic cycloalkyl, optionally substituted tricyclic cycloalkyl, optionally substituted monocyclic heterocycle, optionally substituted bicyclic heterocycle, and optionally substituted tricyclic heterocycle; R ２ is -H, -CH ３ ,-(CH ２ ) ｎ -R ５、 - (CHR ３ ) ｎ -R ５ ,-(CR ３ R ４ ) ｎ -R ５ C may be substituted. １ -C ６ Selected from the group consisting of alkyl, optionally substituted monocyclic cycloalkyl, optionally substituted bicyclic cycloalkyl, optionally substituted monocyclic heterocycle, optionally substituted bicyclic heterocycle, and optionally substituted tricyclic heterocycle; R ３ and R ４ Each of these can be substituted independently. １ -C ６ Selected from the group consisting of alkyl, optionally substituted monocyclic cycloalkyl, optionally substituted bicyclic cycloalkyl, optionally substituted tricyclic cycloalkyl, optionally substituted monocyclic heterocycle, optionally substituted bicyclic heterocycle, and optionally substituted tricyclic heterocycle; R ５ -H, -F, -Cl, -Br, -NO ２ -CN, -NO ２ , -NH ２ , - NHR ３ , -NR ３ R ４ -OH, -OR ３ C may be substituted. １ -C ６ Selected from the group consisting of alkyl, optionally substituted monocyclic cycloalkyl, optionally substituted bicyclic cycloalkyl, optionally substituted tricyclic cycloalkyl, optionally substituted monocyclic heterocycle, optionally substituted bicyclic heterocycle, and optionally substituted tricyclic heterocycle.

40. R １ But, OCH ３ 、OH、NH ２ 、NCH ３ 、N(CH ３ ) ２ 、 【Transformation 34】 The method according to claim 39, selected from the group consisting of the following.

41. R ２ but, 【Chemistry 35】 The method according to claim 39, selected from the group consisting of the following.

42. For the treatment or alleviation of symptoms of a disease or condition in the subject, 【Transformation 36】 Formula I or 【Chemistry 37】 Formula II [In the formula, X １ , X ２ , X ３ , and X ４ The elements are independently selected from CH, CO, N, NH, S, or O; Z may be nonexistent, bound, or substituted by C. １－６ Alkyl, -O-, -S-, -CH ２ -----CHR ５ -, -CR ５ R ６ -, - (CH ２ ) ｎ -, - (CHR ５ ) ｎ -, - (CR ５ R ６ ) ｎ -, -S(=O)CH ２ , -S (=O) ２ CH ２ -, -NR ５ -, -NR ５ C(=O)-, -C(O)NR ５ -, -C(=O)-, -OC(=O)-, -C(=O)O-, -NR ５ C(=O)O-, -OC(=O)NR ５ -, -NR ５ C(=O)NR ５ -, -OC(R ５ ) ２ -, -C(R ５ ) ２ O-, -NR ４ C(R ５ ) ２ -, C(R ６ ) ２ NR ５ -, -S(=O)-,S(=O) ２ -, -S (=O) ２ O-, -OS (=O) ２ -, -S (=O) ２ NR ５ -, -NR ５ S (=O) ２ -, -S(=O)NR ５ -, -NR ５ S(=O)-, -OS(=O)NR ５ -, -NR ５ S(=O)O-, or -S(=O)(=NR ５ ) - and R １ or R ２ The connection point is on the left side, and n = 1 to 6; R ５ and R ６ These are independently hydrogen, halogen, -CN, OR ７ , NR ７ R ８ , -N(R ７ )C(=O)R ８ , -C(=O)N(R ７ ), -C(=O)R ７ , -C (=O) OR ７ , -SR ７ , -S(=O)R ７ , -S (=O) ２ R ７ , or either of the most optimally substituted -C １ -C ６ It is alkyl; R ７ and R ８ Each of these is independently substituted with hydrogen, or -C whichever is optimally substituted. １ -C ６ Alkyl; or R ７ and R ８ C may be substituted as a whole. １ -C ６ A monocyclic cycloalkyl ring or a monocyclic heterocycle which may be substituted; Y is non-existent, -CH ２ -----CHR ９ -, -CR ９ R １０ -, - (CH ２ ) ｎ -, - (CHR ９ ) ｎ -, - (CR ９ R １０ ) ｎ -, -C(=O)-, -S(=O)-, -S(=O) ２ - and n = 1 to 6; R ９ and R １０ Each is independently substituted with hydrogen, halogen, -CN, or any of the most optimally substituted -C １ -C ６ Alkyl; or R ９ and R １０ C may be substituted as a whole. １ -C ６ It can be a monocyclic cycloalkyl ring or a monocyclic heterocycle which may be substituted; R １ -H, -F, -Cl, -Br, -NO ２ -CN, -NH ２ , - NHR １１ , -NR １１ R １２ -OH, -OR １１ C may be substituted. １ -C ６ Alkyl, optionally substituted monocyclic cycloalkyl, optionally substituted bicyclic cycloalkyl, optionally substituted tricyclic cycloalkyl, optionally substituted monocyclic heterocycle, optionally substituted bicyclic heterocycle, or optionally substituted tricyclic heterocycle; R ２ -H, -F, -Cl, -Br, -NO ２ -CN, -NO ２ , -NH ２ , - NHR １１ , -NR １１ R １２ -OH, -OR １１ C may be substituted. １ -C ６ Alkyl, optionally substituted monocyclic cycloalkyl, optionally substituted bicyclic cycloalkyl, optionally substituted tricyclic cycloalkyl, optionally substituted monocyclic heterocycle, optionally substituted bicyclic heterocycle, optionally substituted tricyclic heterocycle; R ３ -H, -F, -Cl, -Br, -NO ２ -CN, -NO ２ , -NH ２ , - NHR １１ , -NR １１ R １２ -OH, -OR １１ C may be substituted. １ -C ６ Alkyl, optionally substituted monocyclic cycloalkyl, optionally substituted bicyclic cycloalkyl, optionally substituted tricyclic cycloalkyl, optionally substituted monocyclic heterocycle, optionally substituted bicyclic heterocycle, optionally substituted tricyclic heterocycle; R １１ and R １２ Each of these can be substituted independently. １ -C ６ Alkyl, optionally substituted monocyclic cycloalkyl, optionally substituted bicyclic cycloalkyl, optionally substituted tricyclic cycloalkyl, optionally substituted monocyclic heterocycle, optionally substituted bicyclic heterocycle, or optionally substituted tricyclic heterocycle; R ４ is hydrogen, -CH ３ ----CHR １３ , -CR １３ R １４ , -S(=O)R １３ , -S (=O) ２ R １３ , optionally substituted alkyl, optimally substituted haloalkyl, optimally substituted alkenyl, optimally substituted alkynyl, optimally substituted cycloalkyl, optimally substituted heterocycle, optimally substituted aryl, -C(=O)R １５ , or a nitrogen protecting group; R １３ and R １４ Each of these can be substituted independently. １ -C ６ Alkyl, optionally substituted monocyclic cycloalkyl, optionally substituted bicyclic cycloalkyl, optionally substituted tricyclic cycloalkyl, optionally substituted monocyclic heterocycle, optionally substituted bicyclic heterocycle, optionally substituted tricyclic heterocycle; R １５ is hydrogen, -CH ３ Use of a composition comprising a compound selected from [an alkyl group which may be substituted, optimally substituted haloalkyl, optimally substituted alkenyl, optimally substituted alkynyl, optimally substituted cycloalkyl, optimally substituted heterocyclic, or optimally substituted aryl] or a pharmaceutically acceptable salt of said compound.

43. In the manufacture of pharmaceuticals for the treatment of a disease or condition, 【Transformation 38】 Formula I or 【Chemistry 39】 Formula II [In the formula, X １ , X ２ , X ３ , and X ４ The elements are independently selected from CH, CO, N, NH, S, or O; Z is non-existent, a bond, or optionally substituted C １－６ alkyl, -O-, -S-, -CH ２ -, -CHR ５ -, -CR ５ R ６ -, -(CH ２ ) ｎ -, -(CHR ５ ) ｎ -, -(CR ５ R ６ ) ｎ -, -S(=O)CH ２ , -S(=O) ２ CH ２ -, -NR ５ -, -NR ５ C(=O)-, -C(O)NR ５ -, -C(=O)-, -OC(=O)-, -C(=O)O-, -NR ５ C(=O)O-, -OC(=O)NR ５ -, -NR ５ C(=O)NR ５ -, -OC(R ５ ) ２ -, -C(R ５ ) ２ O-, -NR ４ C(R ５ ) ２ , C(R ６ ) ２ NR ５ -, -S(=O)-, S(=O) ２ -, -S(=O) ２ O-, -OS(=O) ２ -, -S(=O) ２ NR ５ -, -NR ５ S(=O) ２ -, -S(=O)NR ５ -, -NR ５ S(=O)-, -OS(=O)NR ５ -, -NR ５ S(=O)O-, or -S(=O)(=NR ５ )-, and the bonding position to R １ or R ２ is on the left side, and n = 1 to 6; R ５ and R ６ These are independently hydrogen, halogen, -CN, OR ７ , NR ７ R ８ , -N(R ７ )C(=O)R ８ , -C(=O)N(R ７ ), -C(=O)R ７ , -C (=O) OR ７ , -SR ７ , -S(=O)R ７ , -S (=O) ２ R ７ , or either of the most optimally substituted -C １ -C ６ It is alkyl; R ７ and R ８ Each of these is independently substituted with hydrogen, or -C whichever is optimally substituted. １ -C ６ Alkyl; or R ７ and R ８ C may be substituted as a whole. １ -C ６ A monocyclic cycloalkyl ring or a monocyclic heterocycle which may be substituted; Y is non-existent, -CH ２ -----CHR ９ -, -CR ９ R １０ -, - (CH ２ ) ｎ -, - (CHR ９ ) ｎ -, - (CR ９ R １０ ) ｎ -, -C(=O)-, -S(=O)-, -S(=O) ２ - and n = 1 to 6; R ９ and R １０ are each independently hydrogen, halogen, -CN, or optionally substituted -C １ -C ６ alkyl; or R ９ and R １０ together form an optionally substituted C １ -C ６ monocyclic cycloalkyl ring or an optionally substituted monocyclic heterocyclic ring; R １ -H, -F, -Cl, -Br, -NO ２ -CN, -NH ２ , - NHR １１ , -NR １１ R １２ -OH, -OR １１ C may be substituted. １ -C ６ Alkyl, optionally substituted monocyclic cycloalkyl, optionally substituted bicyclic cycloalkyl, optionally substituted tricyclic cycloalkyl, optionally substituted monocyclic heterocycle, optionally substituted bicyclic heterocycle, or optionally substituted tricyclic heterocycle; R ２ -H, -F, -Cl, -Br, -NO ２ -CN, -NO ２ , -NH ２ , - NHR １１ , -NR １１ R １２ -OH, -OR １１ C may be substituted. １ -C ６ Alkyl, optionally substituted monocyclic cycloalkyl, optionally substituted bicyclic cycloalkyl, optionally substituted tricyclic cycloalkyl, optionally substituted monocyclic heterocycle, optionally substituted bicyclic heterocycle, optionally substituted tricyclic heterocycle; R ３ -H, -F, -Cl, -Br, -NO ２ -CN, -NO ２ , -NH ２ , - NHR １１ , -NR １１ R １２ -OH, -OR １１ C may be substituted. １ -C ６ Alkyl, optionally substituted monocyclic cycloalkyl, optionally substituted bicyclic cycloalkyl, optionally substituted tricyclic cycloalkyl, optionally substituted monocyclic heterocycle, optionally substituted bicyclic heterocycle, optionally substituted tricyclic heterocycle; R １１ and R １２ Each of these can be substituted independently. １ -C ６ Alkyl, optionally substituted monocyclic cycloalkyl, optionally substituted bicyclic cycloalkyl, optionally substituted tricyclic cycloalkyl, optionally substituted monocyclic heterocycle, optionally substituted bicyclic heterocycle, or optionally substituted tricyclic heterocycle; R ４ is hydrogen, -CH ３ ----CHR １３ , -CR １３ R １４ , -S(=O)R １３ , -S (=O) ２ R １３ , optionally substituted alkyl, optimally substituted haloalkyl, optimally substituted alkenyl, optimally substituted alkynyl, optimally substituted cycloalkyl, optimally substituted heterocycle, optimally substituted aryl, -C(=O)R １５ , or a nitrogen protecting group; R １３ and R １４ Each of these can be substituted independently. １ -C ６ Alkyl, optionally substituted monocyclic cycloalkyl, optionally substituted bicyclic cycloalkyl, optionally substituted tricyclic cycloalkyl, optionally substituted monocyclic heterocycle, optionally substituted bicyclic heterocycle, optionally substituted tricyclic heterocycle; R １５ is hydrogen, -CH ３ Use of a composition comprising a compound selected from [an alkyl group which may be substituted, optimally substituted haloalkyl, optimally substituted alkenyl, optimally substituted alkynyl, optimally substituted cycloalkyl, optimally substituted heterocyclic, or optimally substituted aryl] or a pharmaceutically acceptable salt of said compound.