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1. WO2020163689 - INHIBITEURS DE FORMATION DE 20-HETE

Note: Texte fondé sur des processus automatiques de reconnaissance optique de caractères. Seule la version PDF a une valeur juridique

[ EN ]

WHAT IS CLAIMED IS:

1. A compound of formula I:

or a pharmaceutically acceptable salt or solvate thereof, wherein:

X is optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted hetercycle;

Y is a bond, O, S, S=O, SO2, or an optionally substituted methylene;

Z is N or CH; and

R1 is an optionally substituted pyrazolyl.

2. The compound of claim 1 or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is optionally substituted pyrazol-5-yl, optionally substituted pyrazol-4-yl, or optionally substituted pyrazol-3-yl.

3. The compound of claim 1 or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is optionally methyl substituted pyrazol-5-yl, optionally methyl substituted pyrazol-4-yl, or optionally methyl substituted pyrazol-3-yl.

4. The compound of claim 1 or a pharmaceutically acceptable salt or solvate thereof, wherein Y is a bond.

5. The compound of claim 1 or a pharmaceutically acceptable salt or solvate thereof, wherein X is optionally substituted phenyl, optionally substituted pyridinyl, or optionally substituted pyrimidinyl.

6. The compound of claim 1 or a pharmaceutically acceptable salt or solvate thereof, wherein X is:


, wherein:

each R2 is independently selected from a group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted heterocyclyl, C1-C6 alkoxy, halo, -SR3, -S(O)R3, -CH2OR3, -(CH2)nS(O)R3, -(CH2)nS(O)2R3, -SO2R3, -CO2R3, -SO2NHR4, -(CH2)n-OR4, -OR4, -CO2R4, -NR5R6, -NR5C(O)R6, -(CH2)n-NR5C(O)R6, -CH(CH3)-NR5C(O)R6 -CONR5R6, -N(R5)S(O)2R6,-N(R5)(CH2)nS(O)R6, -N(R5)(CH2)nS(O)2R6, -SO2NR5R6, and -NR4C(O)R3;

R3 is an optionally substituted C1-C6 alkyl or an optionally substituted C3-C6 cycloalkyl or an optionaly substituted alkylene forming a 4, 5 or 6-member ring with the aromatic carbon atom adjacent to the location of the R2 substituent;

R4 is H, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted tertahydrofuranyl, optionally substituted piperidinyl, optionally substituted pyrrolidinyl, optionally substituted azetidinyl, or optionally substituted oxetanyl;

R5 and R6 are each independently H, optionally substituted C1-C6 alkyl, or optionally substituted C3-C6 cycloalkyl; or R5 and R6 and the atoms to which they are attached, together form an optionally substituted 4 to 6 membered ring;

A, B and C are–(C(R2’)2)1-2– where in R2’ is H or F and one of A, B and C is O or SO2;

Y is a bond;

Z is CH; and

n and p are each independently 1, 2, or 3.

7. The compound of claim 6 or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is


, wherein

Q is N or CH;

L is N, CH or CCH3, provided that L is not N when Q is N, and L is not CH or CCH3 when Q is CH; and

M is H or CH3.

8. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein


, and wherein:

each R2 is independently selected from a group consisting of H, F, Cl, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted heterocyclyl, -SR3, -S(O)R3, -SO2R3, -SO2NHR4, -OR4, -(CH2)n-OR4, -CO2R4, -NR5R6, -NR5C(O)R6 , -CONR5R6, -N(R5)SO2R6, and -SO2NR5R6;

R3 is optionally substituted C1-C6 alkyl or optionally substituted C3-C6 cycloalkyl; R4 is H, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted tertahydrofuranyl, optionally substituted piperidinyl, optionally substituted pyrrolidinyl, optionally substituted azetidinyl, or optionally substituted oxetanyl;

R5 and R6 are each independently H, optionally substituted C1-C6 alkyl, or optionally substituted C3-C6 cycloalkyl; or R5 and R6 and the atoms to which they are attached, together form an optionally substituted 4 to 6 membered ring;

Y is O;

Z is CH;

Q is N or CH;

L is N, CH or CCH3, provided that L is not N when Q is N, and L is not CH or CCH3 when Q is CH;

M is H or CH3; and

n and p are each independently 1, 2, or 3.

9. The compound of claim 1 or a pharmaceutically acceptable salt or solvate thereof, wherein:

each R2 is independently selected from a group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted heterocyclyl, C1- C6 alkoxy, halo, -SR3, -S(O)R3, -CH2OR3, -(CH2)nS(O)R3, -(CH2)nS(O)2R3, -SO2R3, -CO2R3, -SO2NHR4, -(CH2)n-OR4, -OR4, -CO2R4, -NR5R6, -NR5C(O)R6, -(CH2)n-NR5C(O)R6, -CH(CH3)-NR5C(O)R6 -CONR5R6, -N(R5)S(O)2R6,-N(R5)(CH2)nS(O)R6, -N(R5)(CH2)nS(O)2R6, -SO2NR5R6, and -NR4C(O)R3;

R3 is an optionally substituted C1-C6 alkyl or an optionally substituted C3-C6 cycloalkyl or an optionaly substituted alkylene forming a 4, 5 or 6-member ring with the aromatic carbon atom adjacent to the location of the R2 substituent;

R4 is H, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted tertahydrofuranyl, optionally substituted piperidinyl, optionally substituted pyrrolidinyl, optionally substituted azetidinyl, or optionally substituted oxetanyl;

R5 and R6 are each independently H, optionally substituted C1-C6 alkyl, or optionally substituted C3-C6 cycloalkyl; or R5 and R6 and the atoms to which they are attached, together form an optionally substituted 4 to 6 membered ring;

Y is S, S=O, or SO2;

Z is CH;

Q is N or CH;

L is N, CH or CCH3, provided that L is not N when Q is N, and L is not CH or CCH3 when Q is CH;

M is H or CH3; and

n and p are each independently 1, 2, or 3.

10. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein:


, and wherein:

each R2 is independently selected from a group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted heterocyclyl, C1-C6 alkoxy, halo, -SR3, -S(O)R3, -CH2OR3, -(CH2)nS(O)R3, -(CH2)nS(O)2R3, -SO2R3, -CO2R3, -SO2NHR4, -(CH2)n-OR4, -OR4, -CO2R4, -NR5R6, -NR5C(O)R6, -(CH2)n-NR5C(O)R6, -CH(CH3)-NR5C(O)R6 -CONR5R6, -N(R5)S(O)2R6,-N(R5)(CH2)nS(O)R6, -N(R5)(CH2)nS(O)2R6, -SO2NR5R6, and -NR4C(O)R3;

R3 is an optionally substituted C1-C6 alkyl or an optionally substituted C3-C6 cycloalkyl or an optionaly substituted alkylene forming a 4, 5 or 6-member ring with the aromatic carbon atom adjacent to the location of the R2 substituent;

R4 is H, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted tertahydrofuranyl, optionally substituted piperidinyl, optionally substituted pyrrolidinyl, optionally substituted azetidinyl, or optionally substituted oxetanyl;

R5 and R6 are each independently H, optionally substituted C1-C6 alkyl, or optionally substituted C3-C6 cycloalkyl; or R5 and R6 and the atoms to which they are attached, together form an optionally substituted 4 to 6 membered ring;

Y is CH2;

Z is CH;

Q is N or CH;

L is N, CH or CCH3, provided that L is not N when Q is N, and L is not CH or CCH3 when Q is CH;

M is H or CH3; and

n and p are each independently 1, 2, or 3.

11. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein:


, and wherein:

R2 is selected from a group consisting of H, F, Cl, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted heterocyclyl, -OR4, -(CH2)n-OR4, -CO2R4, -NR5R6, -NR5C(O)R6 , -CONR5R6, and -N(R5)SO2R6;

R4 is H, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted tertahydrofuranyl, optionally substituted piperidinyl, optionally substituted pyrrolidinyl, optionally substituted azetidinyl, or optionally substituted oxetanyl;

R5 and R6 are each independently H, optionally substituted C1-C6 alkyl, or optionally substituted C3-C6 cycloalkyl; or R5 and R6 and the atoms to which they are attached, together form an optionally substituted 4 to 6 membered ring;

Y is a bond or CH2;

Z is CH;

Q is N or CH;

L is N, CH or CCH3, provided that L is not N when Q is N, and L is not CH or CCH3 when Q is CH;

M is H or CH3; and

n and p are each independently 1, 2, or 3.

12. The compound of claim 1 or a pharmaceutically acceptable salt or solvate thereof, wherein:

each R2 is independently selected from a group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted heterocyclyl, C1-C6 alkoxy, halo, -SR3, -S(O)R3, -CH2OR3, -(CH2)nS(O)R3, -(CH2)nS(O)2R3, -SO2R3, -CO2R3, -SO2NHR4, -(CH2)n-OR4, -OR4, -CO2R4, -NR5R6, -NR5C(O)R6, -(CH2)n-NR5C(O)R6, -CH(CH3)-NR5C(O)R6 -CONR5R6, -N(R5)S(O)2R6,-N(R5)(CH2)nS(O)R6, -N(R5)(CH2)nS(O)2R6, -SO2NR5R6, and -NR4C(O)R3;

R3 is an optionally substituted C1-C6 alkyl or an optionally substituted C3-C6 cycloalkyl or an optionaly substituted alkylene forming a 4, 5 or 6-member ring with the aromatic carbon atom adjacent to the location of the R2 substituent;

R4 is H, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted tertahydrofuranyl, optionally substituted piperidinyl, optionally substituted pyrrolidinyl, optionally substituted azetidinyl, or optionally substituted oxetanyl;

R5 and R6 are each independently H, optionally substituted C1-C6 alkyl, or optionally substituted C3-C6 cycloalkyl; or R5 and R6 and the atoms to which they are attached, together form an optionally substituted 4 to 6 membered ring;

Y is a bond or CH2;

Z is N;

Q is N or CH;

L is N, CH or CCH3, provided that L is not N when Q is N, and L is not CH or CCH3 when Q is CH;

M is H or CH3; and

n and p are each independently 1, 2, or 3.

13. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein:


, and wherein:

R2 is selected from a group consisting of H, F, Cl, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted heterocyclyl, -OR4, -(CH2)n-OR4, -CO2R4, -NR5R6, -NR5C(O)R6 , and -CONR5R6;

R4 is H, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted tertahydrofuranyl, optionally substituted piperidinyl, optionally substituted pyrrolidinyl, optionally substituted azetidinyl, or optionally substituted oxetanyl;

R5 and R6 are each independently H, optionally substituted C1-C6 alkyl, or optionally substituted C3-C6 cycloalkyl; or R5 and R6 and the atoms to which they are attached, together form an optionally substituted 4 to 6 membered ring;

Y is a bond or CH2;

Z is CH or N;

Q is N or CH;

L is N, CH or CCH3, provided that L is not N when Q is N, and L is not CH or CCH3 when Q is CH;

M is H or CH3; and

n and p are each independently is 1, 2, or 3.

14. The compound of claim 1 or a pharmaceutically acceptable salt or solvate thereof, wherein:

each R2 is independently selected from a group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted

heterocyclyl, C1-C6 alkoxy, halo, -SR3, -S(O)R3, -CH2OR3, -(CH2)nS(O)R3, -(CH2)nS(O)2R3, -SO2R3, -CO2R3, -SO2NHR4, -(CH2)n-OR4, -OR4, -CO2R4, -NR5R6, -NR5C(O)R6, -(CH2)n-NR5C(O)R6, -CH(CH3)-NR5C(O)R6 -CONR5R6, -N(R5)S(O)2R6,-N(R5)(CH2)nS(O)R6, -N(R5)(CH2)nS(O)2R6, -SO2NR5R6, and -NR4C(O)R3;

R3 is an optionally substituted C1-C6 alkyl or an optionally substituted C3-C6 cycloalkyl or an optionaly substituted alkylene forming a 4, 5 or 6-member ring with the aromatic carbon atom adjacent to the location of the R2 substituent;

R4 is H, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted tertahydrofuranyl, optionally substituted piperidinyl, optionally substituted pyrrolidinyl, optionally substituted azetidinyl, or optionally substituted oxetanyl;

R5 and R6 are each independently H, optionally substituted C1-C6 alkyl, or optionally substituted C3-C6 cycloalkyl; or R5 and R6 and the atoms to which they are attached, together form an optionally substituted 4 to 6 membered ring;

Y is S;

Z is CH;

Q is N or CH;

L is N, CH or CCH3, provided that L is not N when Q is N, and L is not CH or CCH3 when Q is CH;

M is H or CH3; and

n and p are each independently 1, 2, or 3.

15. The compound of claim 1, wherein Z is CH.

16. A compound selected from a group consisting of:

and a pharmaceutically acceptable salt or solvate thereof.

17. A method of inhibiting the biosynthesis of 20-hydroxyeicosatetraenoic acid (20-HETE) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound of any one of claims 1-16, or a pharmaceutically acceptable salt or solvate thereof.

18. A method of inhibiting CYP4, comprising contacting CYP4 with a compound of any one of claims 1-16, or a pharmaceutically acceptable salt or solvate thereof.

19. The method of claim 18, wherein the contacting is in vitro.

20. The method of claim 18, wherein the contacting is in vivo in a subject in need.

21. A method of producing neuroprotection and decreased brain damage by preventing cerebral microvascular blood flow impairment and anti-oxidant mechanisms in a subject experiencing or having experienced an ischemic event, comprising administering to the subject a therapeutically effective amount of the compound of any one of claims 1-16, or a pharmaceutically acceptable salt or solvate thereof.

22. The method of claim 21, wherein the ischemic event comprises trauma, focal ischemia (TFI), subarachnoid hemorrhage (SAH), vasoconstriction, thrombosis, embolism, cardiac arrest, stroke, aneurysm, hypertension, sickle cell disease, application of g-forces, arteriovenous malformation, peripheral artery occlusive disease, central nervous system (CNS) depressant overdose, or a combination thereof.

23. A method of reducing the size or slowing the growth of kindey cysts by preventing 20-HETE formation and/or 20-HETE driven renal epithelial cell proliferation in a subject suffering from polycystic kidney disease, comprising administering a pharmacologically

effective amount of a compound of any of the claims 1-16 or pharmaceutically acceptable salt thereof.

24. The method of claim 23, wherein PKD is of the autosomal dominant or recessive type.

25. The method of any one of claims 17 and 20-24, wherein the subject is a human.