PHD inhibitor compounds, compositions, and uses

Abstract

The present invention provides, in part, novel small molecule inhibitors of PHD having a structure according to Formula (A), and subformulas thereof: or pharmaceutically acceptable salts thereof. The compounds provided herein may be useful in the treatment of diseases, including diseases of the heart (e.g., ischemic heart disease, congestive heart failure, and valvular heart disease), lung (e.g., acute lung injury, pulmonary hypertension, pulmonary fibrosis, and chronic obstructive pulmonary disease), liver (e.g., acute liver failure, liver fibrosis, and cirrhosis), and kidney (e.g., acute kidney injury and chronic kidney disease). [Formula 1] TIFF2023518262000403.tif31170

Claims

1. Compounds of formula III: 【Chemistry 1】 or a pharmaceutically acceptable salt thereof, in the formula, A is C １－３ Alkyl or C ３－６ It is a cycloalkyl, R １ Each time, independently, hydrogen, halogen, CN, OH, and C optionally substituted with one or more halogens are used. １－３ Alkyl and C １－３ Selected from the group consisting of alkoxys, R １ａ CN, halogen, C １－３ C optionally substituted with alkoxy, OH, or CN １－３ It is alkyl, R ２ is independently selected each time from the group consisting of hydrogen, NR ４ R ５ , OH, C １－３ alkyl, and C ３－６ cycloalkyl, R ３ SO ２ R ６ , SOR ７ R ８ , SOR ９ COR １０ , (CH ２ ) ｐ COOH, NHR １１ POR １２ R １３ SO ２ R １４ Alternatively, a heterocycloalkyl group substituted with =O, or C １－３ A heteroaryl compound optionally substituted with alkyl or phenyl, R ４ and R ５ Each is independently H or C １－３ It is alkyl, R ６ C １－３ Alkyl, NHCOR １５ , NR １６ R １７ , or phenyl, R ７ C １－３ Alkyl, C ３－５ Cycloalkyl, phenyl, or NR １８ R １９ And, R ８ NH, NCN, or NCH ３ And, R ９ C １－３ It is alkyl, R １０ C １－３ It is alkyl, R １１ SO ２ R ２２ And, R １２ and R １３ Each is independent of C １－３ It is alkyl, R １４ C １－３ It is alkyl, R １５ C １－３ It is alkyl, R １６ and R １７ H and C are independent of each other. １－３ Alkyl, aryl, cycloalkyl, or R １６ and R １７ They form heterocycloalkyl groups with the nitrogen to which they bind, R １８ and R １９ H or C １－３ It is alkyl, R ２２ NR ２３ R ２４ , or C optionally substituted with carboxyl １－３ It is alkyl, R ２３ and R ２４ H or C １－３ It is alkyl, m is 1, 2, 3, or 4. n is 0, 1, 2, or 3. p is a compound or a pharmaceutically acceptable salt thereof, where p is 1, 2, or 3.

2. R ３ teeth, 【Chemistry 2】 The compound according to claim 1, which is a heteroaryl selected from the above.

3. R ３ SO ２ R １４ or a heterocycloalkyl substituted with =O; and R １４ is C １－３ It is alkyl, R ３ teeth, 【Transformation 3】 A compound according to claim 1, selected from the following.

4. Formula IV: 【Chemistry 4】 It has a structure that follows the formula, A is C １ - ３ Alkyl or C ３－６ It is a cycloalkyl, R １ Each time, independently, hydrogen, halogen, CN, OH, and C optionally substituted with one or more halogens are used. １－３ Alkyl and C １－３ Selected from the group consisting of alkoxys, R １ａ CN, halogen, C １－３ C optionally substituted with alkoxy, OH, or CN １－３ It is alkyl, R ２ is independently selected each time from the group consisting of hydrogen, NR ４ R ５ , OH, C １－３ alkyl, and C ３－６ cycloalkyl R ４ and R ５ Each is independently H or C １－３ It is alkyl, R ７ is C １－３ alkyl, C ３－５ cycloalkyl, phenyl, or NR １８ R １９ and is R ８ NH, NCN, or NCH ３ And, R １８ and R １９ Each is independently H or C １－３ It is alkyl, m is 1, 2, 3, or 4. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, 2, or 3.

5. Formula IVa: 【Transformation 5】 It has the structure, and in the formula, (a) A is C １ - ３ It is alkyl, or (b) R １ａ is either CN or halogen, or (c) R ２ is hydrogen or C １－３ It is alkyl, or (d) R ７ C １－３ Alkyl, C3-5 cycloalkyl, phenyl, or NR18 R19, where R18 and R19 are each independently H or C1-3 alkyl, or (h)R ８ NH, NCN, or NCH ３ That is, The compound according to claim 4, or a pharmaceutically acceptable salt thereof.

6. (a) A, C １－３ It is alkyl or cycloalkyl, (b) R １ａ However, it is a C1-3 alkyl group optionally substituted with CN, halogen, C1-3 alkoxy, OH, or CN. (c) R １ However, H, CN, C １－３ Alkyl or C1-3 alkoxy, (d) R ２ However, H or C １－３ It is alkyl, (e) R ６ However, C １－３ The elements are alkyl, NHCOR 15, NH2, or NR 16 R 17, where R 15 is C1-3 alkyl, and R 16 and R 17 are each independently H, C1-3 alkyl, aryl, or cycloalkyl, or R 16 and R 17, together with the nitrogen to which they are bound, form a heterocycloalkyl. The compound according to claim 1.

7. Formula VI: 【Transformation 6】 It has a structure that follows the formula, A is C １ - ３ Alkyl or C ３－６ It is a cycloalkyl, R １ Each time, independently, hydrogen, halogen, CN, OH, and C optionally substituted with one or more halogens are used. １－３ Alkyl and C １－３ Selected from the group consisting of alkoxys, R １ａ CN, halogen, C １－３ C optionally substituted with alkoxy, OH, or CN １－３ It is alkyl, R ２ Each time, independently, hydrogen, NR ４ R ５ OH, C １－３ Alkyl and C ３－６ Selected from the group consisting of cycloalkyl groups, R ３ SO ２ R １４ Alternatively, it is a heterocycloalkyl substituted with =O, R ４ and R ５ Each is independently H or C １－３ It is alkyl, R １４ C １－３ It is alkyl, m is 1, 2, 3, or 4. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, 2, or 3.

8. Formula VIa: 【Transformation 7】 It has the structure, and in the formula, A is C １ - ３ Is it alkyl? R ２ is hydrogen or C １－３ Is it alkyl? R ３ SO ２ R １４ Alternatively, it is a heterocycloalkyl group substituted with =O, where R14 is a C1-3 alkyl group, and R3 is 【Transformation 8】 A compound according to claim 7, or a pharmaceutically acceptable salt thereof, selected from the above.

9. Formula VII: 【Chemistry 9】 It has a structure that follows the formula, A is C １ - ３ Alkyl or C ３－６ It is a cycloalkyl, R １ Each time, independently, hydrogen, halogen, CN, OH, and C optionally substituted with one or more halogens are used. １－３ Alkyl and C １－３ Selected from the group consisting of alkoxys, R １ａ CN, halogen, C １－３ C optionally substituted with alkoxy, OH, or CN １－３ It is alkyl, R ２ Each time, independently, hydrogen, NR ４ R ５ OH, C １－３ Alkyl and C ３－６ Selected from the group consisting of cycloalkyl groups, R ４ and R ５ Each is independently H or C １－３ It is alkyl, R １１ SO ２ R ２２ And, R ２２ NR ２３ R ２４ , or C optionally substituted with carboxyl １－３ It is alkyl, R ２３ and R ２４ H or C １－３ It is alkyl, m is 1, 2, 3, or 4. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, 2, or 3.

10. Formula VIIa: 【Chemistry 10】 It has the structure, and in the formula, A is C ３－６ Cycloalkyl or C １ - ３ It is alkyl, R ２ is hydrogen, C ３－６ Cycloalkyl, or C １－３ It is alkyl, R １１ SO ２ R ２２ And in the formula, R ２２ NR ２３ R ２４ , or C optionally substituted with carboxyl １－３ It is an alkyl group, and in the formula, R ２３ and R ２４ H or C １－３ It is alkyl, R ２２ is a C which is optionally substituted with a carboxyl. １－３ It is alkyl, or R ２２ NR ２３ R ２４ And in the formula, R ２３ and R ２４ H or C １－３ It is alkyl, and R ２３ and R ２４ H or C １－３ It is alkyl. The compound according to claim 9, or a pharmaceutically acceptable salt thereof.

11. Formula VIII: 【Chemistry 11】 It has a structure that follows the formula, A is C １ - ３ Alkyl or C ３－６ It is a cycloalkyl, R １ Each time, independently, hydrogen, halogen, CN, OH, and C optionally substituted with one or more halogens are used. １－３ Alkyl and C １－３ Selected from the group consisting of alkoxys, R １ａ CN, halogen, C １－３ C optionally substituted with alkoxy, OH, or CN １－３ It is alkyl, R ２ Each time, independently, hydrogen, NR ４ R ５ OH, C １－３ Alkyl and C ３－６ Selected from the group consisting of cycloalkyl groups, R ３ C １－３ A heteroaryl compound optionally substituted with alkyl or phenyl, R ４ and R ５ Each is independently H or C １－３ It is alkyl, m is 1, 2, 3, or 4. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, 2, or 3.

12. Formula VIIIa: 【Chemistry 12】 It has the structure, and in the formula, A is C １ - ３ Alkyl or C ３－６ It is a cycloalkyl, R ３ C １－３ The compound according to claim 11, or a pharmaceutically acceptable salt thereof, which is a heteroaryl optionally substituted with alkyl or phenyl.

13. Formula IX: 【Chemistry 13】 It has a structure that follows the formula, A is C １ - ３ Alkyl or C ３－６ It is a cycloalkyl, R １ Each time, independently, hydrogen, halogen, CN, OH, and C optionally substituted with one or more halogens are used. １－３ Alkyl and C １－３ Selected from the group consisting of alkoxys, R １ａ CN, halogen, C １－３ C optionally substituted with alkoxy, OH, or CN １－３ It is alkyl, R ２ Each time, independently, hydrogen, NR ４ R ５ OH, C １－３ Alkyl and C ３－６ Selected from the group consisting of cycloalkyl groups, R ４ and R ５ Each is independently H or C １－３ It is alkyl, R １０ C １－３ It is alkyl, m is 1, 2, 3, or 4. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, 2, or 3.

14. Formula IXa: 【Chemistry 14】 It has the structure, and in the formula, A is C １ - ３ It is alkyl, R １ａ It is CN or halogen, R １０ C １－３ The compound according to claim 13, which is alkyl, or a pharmaceutically acceptable salt thereof.

15. Formula X: 【Chemistry 15】 It has a structure that follows the formula, A is C ３－６ Cycloalkyl or C １ - ３ It is alkyl, R １ Each time, independently, hydrogen, halogen, CN, OH, and C optionally substituted with one or more halogens are used. １－３ Alkyl and C １－３ Selected from the group consisting of alkoxys, R １ａ CN, halogen, C １－３ C optionally substituted with alkoxy, OH, or CN １－３ It is alkyl, R ２ Each time, independently, hydrogen, NR ４ R ５ OH, C １－３ Alkyl and C ３－６ Selected from the group consisting of cycloalkyl groups, R ４ and R ５ Each is independently H or C １－３ It is alkyl, R ９ C １－３ It is alkyl, m is 1, 2, 3, or 4. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, 2, or 3.

16. Formula XI: 【Chemistry 16】 It has a structure that follows the formula, A is C ３－６ Cycloalkyl or C １ - ３ It is alkyl, R １ Each time, independently, hydrogen, halogen, CN, OH, and C optionally substituted with one or more halogens are used. １－３ Alkyl and C １－３ Selected from the group consisting of alkoxys, R １ａ CN, halogen, C １－３ C optionally substituted with alkoxy, OH, or CN １－３ It is alkyl, R ２ Each time, independently, hydrogen, NR ４ R ５ OH, C １－３ Alkyl and C ３－６ Selected from the group consisting of cycloalkyl groups, R ４ and R ５ Each is independently H or C １－３ It is alkyl, m is 1, 2, 3, or 4. n is 0, 1, 2, or 3. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein p is 1, 2, or 3.

17. Equation XII: 【Chemistry 17】 It has a structure that follows the formula, A is C １ - ３ Alkyl or C ３－６ It is a cycloalkyl, R １ Each time, independently, hydrogen, halogen, CN, OH, and C optionally substituted with one or more halogens are used. １－３ Alkyl and C １－３ Selected from the group consisting of alkoxys, R １ａ CN, halogen, C １－３ C optionally substituted with alkoxy, OH, or CN １－３ It is alkyl, R ２ Each time, independently, hydrogen, NR ４ R ５ OH, C １－３ Alkyl and C ３－６ Selected from the group consisting of cycloalkyl groups, R ４ and R ５ Each is independently H or C １－３ It is alkyl, m is 1, 2, 3, or 4. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, 2, or 3.

18. Equation XIII: [Chemistry 18] It has a structure that follows the formula, A is C ３－６ Cycloalkyl or C １ - ３ It is alkyl, R １ Each time, independently, hydrogen, halogen, CN, OH, and C optionally substituted with one or more halogens are used. １－３ Alkyl and C １－３ Selected from the group consisting of alkoxys, R １ａ CN, halogen, C １－３ C optionally substituted with alkoxy, OH, or CN １－３ It is alkyl, R ２ Each time, independently, hydrogen, NR ４ R ５ , OH, and C ３－６ Cycloalkyl and C １－３ Selected from the group consisting of alkyl groups, R ４ and R ５ Each is independently H or C １－３ It is alkyl, R １２ C １－３ It is alkyl, R １３ C １－３ It is alkyl, The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein m is 1, 2, 3, or 4.

19. The aforementioned compound, Table 1 The compound according to claim 1, selected from the group consisting of or pharmaceutically acceptable salts thereof.

20. The aforementioned compound, Table 2 The compound according to claim 19, selected from the group consisting of or pharmaceutically acceptable salts thereof.

21. The aforementioned compound, 【Chemistry 19】 The compound according to claim 20, or a pharmaceutically acceptable salt thereof.

22. The aforementioned compound, 【Chemistry 20】 The compound according to claim 20, or a pharmaceutically acceptable salt thereof.

23. The aforementioned compound, 【Chemistry 21】 The compound according to claim 20, or a pharmaceutically acceptable salt thereof.

24. The aforementioned compound, 【Chemistry 22】 The compound according to claim 20, or a pharmaceutically acceptable salt thereof.

25. The aforementioned compound, 【Chemistry 23】 The compound according to claim 20, or a pharmaceutically acceptable salt thereof.

26. The aforementioned compound, 【Chemistry 24】 The compound according to claim 20, or a pharmaceutically acceptable salt thereof.

27. The aforementioned compound, 【Chemistry 25】 The compound according to claim 20, or a pharmaceutically acceptable salt thereof.

28. The aforementioned compound, 【Chemistry 26】 The compound according to claim 20, or a pharmaceutically acceptable salt thereof.

29. The aforementioned compound, 【Chemistry 27】 The compound according to claim 20, or a pharmaceutically acceptable salt thereof.

30. The aforementioned compound, 【Chemistry 28】 The compound according to claim 20, or a pharmaceutically acceptable salt thereof.

31. The aforementioned compound, Table 3 The compound according to claim 19, selected from the group consisting of or pharmaceutically acceptable salts thereof.

32. The compound is Table 4 The compound according to claim 19, selected from the group consisting of or pharmaceutically acceptable salts thereof.

33. The compound is Table 5 The compound according to claim 17, selected from the group consisting of or pharmaceutically acceptable salts thereof.

34. The compound is Table 6 The compound according to claim 4, selected from the group consisting of or pharmaceutically acceptable salts thereof.

35. A compound according to any one of claims 1 to 34, or a pharmaceutically acceptable salt thereof, wherein at least one hydrogen atom is replaced by a deuterium atom.

36. A pharmaceutical composition comprising a compound according to any one of claims 1 to 34, or a pharmaceutically acceptable salt thereof.

37. A pharmaceutical composition for treating a disease mediated by PHD activity, comprising a compound according to any one of claims 1 to 34, or a pharmaceutically acceptable salt thereof, wherein the disease mediated by PHD activity is selected from the group consisting of ischemia-reperfusion injury, inflammatory bowel disease, cancer, liver disease, atherosclerosis, cardiovascular disease, eye disease or condition, anemia, chronic kidney disease, and hyperoxia-related diseases.

38. The ischemia-reperfusion injury is selected from stroke, myocardial infarction, and acute kidney injury. The aforementioned inflammatory bowel disease is ulcerative colitis or Crohn's disease. The aforementioned cancer is colorectal cancer. The aforementioned disease or condition of the eye is selected from radiation retinopathy, retinopathy of prematurity, diabetic retinopathy, age-related macular degeneration, and ocular ischemia. The aforementioned anemia is anemia associated with chronic kidney disease, The disease associated with the aforementioned hyperoxia is retinopathy of prematurity or bronchopulmonary dysplasia (BPD). The pharmaceutical composition according to claim 37.

39. A pharmaceutical composition for treating a disease mediated by PHD activity, comprising a compound according to any one of claims 1 to 34 or a pharmaceutically acceptable salt thereof, wherein the disease mediated by PHD activity is selected from the group consisting of ischemic heart disease, valvular heart disease, congestive heart failure, acute lung injury, pulmonary fibrosis, pulmonary hypertension, chronic obstructive pulmonary disease (COPD), acute liver failure, hepatic fibrosis, and cirrhosis.

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