Pyrazolo[3,4-d]pyrimidin-6-yl-sulfonamide derivatives for inhibiting SGK-1

Abstract

Formula I: [Formula 1] JPEG2024502178000410.jpg32170 and pharmaceutically acceptable salts thereof are provided as inhibitors of SGK-1 for the treatment of conditions such as long QT syndrome, heart failure, arrhythmias, ischemic injury, ischemic infarction, cardiac fibrosis, vascular proliferation, restenosis, dilated cardiomyopathy, stent failure, prostate cancer, epilepsy, colorectal cancer, breast cancer, Parkinson's disease, and Lafora's disease.

Claims

1. Formula Vb: 【Chemistry 1】 or a pharma- ceutically acceptable salt thereof, During the ceremony, R ２ teeth, 【Chemistry 2】 and Z １ and Z ２ are each independently selected from halogen; W １ is selected from halogen, or a pharma- ceutically acceptable salt thereof.

2. W １ The compound of claim 1 , wherein is F or Cl.

3. R ２ but, 【Chemistry 3】 3. The compound according to claim 1 or 2,

4. The compound is 【Chemistry 4】 or a pharma- ceutically acceptable salt thereof.

5. Formula V: 【Chemistry 5】 or a pharma- ceutically acceptable salt thereof, During the ceremony, R ２ but, 【Chemistry 6】 and Z １ and Z ２ are each independently a halogen, (C １ ~C ４ ) alkyl, —OH, —O—(C １ ~C ４ ) alkyl, -CF ３ and -CN; Z ３ H, halogen, (C １ ~C ４ ) alkyl, —OH, —O—(C １ ~C ４ ) alkyl, -CF ３ and -CN; W １ is selected from the group consisting of H and halogen; R ３３ But -CH ３ or -(CH ２ )-(CH ２ ) -OR ２７ and R ２７ is H, -C(=O)-(C １ ~C ４ ) alkyl, natural amino acids linked by an α-carboxyl group, and -P(=O)(OH) ２ 1. A compound selected from the group consisting of:

6. W １ The compound of claim 5 , wherein is F or Cl.

7. R ２ but, 【Chemistry 7】 7. The compound according to claim 5 or 6,

8. R ３３ - (CH ２ )-(CH ２ ) -OR ２７ The compound according to any one of claims 5 to 7,

9. R ２７ is H and -C(=O)-(C １ ~C ４ 9. The compound of claim 8, wherein said alkyl is selected from the group consisting of:

10. The compound is 【Chemistry 8】 or a pharma- ceutically acceptable salt thereof, During the ceremony, R ２ but, 【Chemistry 9】 selected from the group consisting of: W １ is selected from the group consisting of H, Cl and F; R ２７ But, H, 【Chemistry 10】 6. The compound of claim 5, selected from the group consisting of:

11. The compound is 【Chemistry 11】 or a pharma- ceutically acceptable salt thereof, During the ceremony, R ２ but, 【Chemistry 12】 selected from the group consisting of: W １ 6. The compound of claim 5, wherein is selected from the group consisting of H, Cl and F, or a pharma- ceutically acceptable salt thereof.

12. The compound is 【Chemistry 13】 【Chemistry 14】 【Chemistry 15】 【Chemistry 16】 【Chemistry 17】 The compound according to claim 5, or a pharma- ceutically acceptable salt thereof.

13. Formula IV; 【Chemistry 18】 or a pharma- ceutically acceptable salt thereof, During the ceremony, Z is selected from the group consisting of O and NH; R ３ is -(CH ２ ) ｐ -N(R ３３ ) R ３４ , 【Chemistry 19】 is selected from the group consisting of p is 2, 3 or 4; R ３３ and R ３４ are, independently of one another, unsubstituted or one or more identical or different substituents R ５０ (C １ ~C ４ )-alkyl; R ３５ is H or is unsubstituted or has one or more identical or different substituents R ５０ (C １ ~C ４ )-alkyl; R ５０ is halogen, -OR ２７ , -O-(C １ ~C ４ )-alkyl, -CF ３ -CN; R ２７ is H, -C(=O)-(C １ ~C ４ ) alkyl, natural amino acids linked by an α-carboxyl group, and -P(=O)(OH) ２ selected from the group consisting of: R ２ teeth, 【Chemistry 20】 and Z １ and Z ２ are each independently a halogen, (C １ ~C ４ ) alkyl, —OH, —O—(C １ ~C ４ ) alkyl, -CF ３ -CN; Z ３ is H, halogen, (C １ ~C ４ ) alkyl, —OH, —0—(C １ ~C ４ ) alkyl, -CF ３ and -CN; W １ is a halogen, or a pharma- ceutically acceptable salt thereof.

14. The compound is 【Chemistry 21】 or a pharma- ceutically acceptable salt thereof, During the ceremony, R ２ but, 【Chemical 22】 selected from the group consisting of: W １ is selected from the group consisting of Cl and F; R ３５ 14. The compound of claim 13, or a pharma- ceutically acceptable salt thereof, wherein is selected from the group consisting of methyl and isopropyl.

15. The compound is 【Chemistry 23】 【Chemistry 24】 【Chemistry 25】 【Chemistry 26】 or a pharma- ceutically acceptable salt thereof.

16. Formula Vb: 【Chemical 27】 or a pharma- ceutically acceptable salt thereof, During the ceremony, R 2 is 【Chemistry 28】 and Z 1 and Z 2 are Cl; A compound, or a pharma- ceutically acceptable salt thereof, wherein W 1 is F.

17. A pharmaceutical composition comprising a compound according to any one of claims 1 to 16, or a pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically acceptable carrier or excipient.

18. 20. Use of a compound according to any one of claims 1 to 16, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for inhibiting SGK-1 in a subject.

19. 17. Use of a compound according to any one of claims 1 to 16, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of prostate cancer, colorectal cancer, breast cancer, Parkinson's disease, Lafora's disease or epilepsy.

20. 17. Use of a compound according to any one of claims 1 to 16, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a cardiovascular disease selected from the group consisting of long QT syndrome, heart failure, arrhythmia, ischemic injury, ischemic infarction, cardiac fibrosis, vascular proliferation, restenosis, dilated cardiomyopathy, and stent failure.

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