Granted Patent B2

US 9,249,089 · App. 13/741,072 · Granted Feb 2, 2016

Inventors: Xin Jiang (Dallas, TX); Xiaofeng Liu (Dallas, TX); Jack Greiner (Milltown, NJ); Stephen S. Szucs (Lawrenceville, NJ); Melean Visnick (Irving, TX)

Assignee: REATA PHARMACEUTICALS, INC.

C07C255/47C07C53/18C07D209/48C07D257/04C07D261/08C07D303/36C07D317/28C07D493/08C07F9/09C07J63/008

Abstract

Claims (124)

1. A compound of the formula:

wherein:

Y is alkanediyl (C≦8) , alkenediyl (C≦8) , alkynediyl (C≦8) , or a substituted version of any of these groups;

R a is:

hydrogen, hydroxy, halo, amino, nitro, cyano, azido, phosphate, 1,3-dioxoisoindolin-2-yl, mercapto or silyl; or

alkyl (C≦12) , alkenyl (C≦12) , alkynyl (C≦12) , aryl (C≦12) , aralkyl (C≦12) , heteroaryl (C≦12) , heteroaralkyl (C≦12) , acyl (C≦12) , alkoxy (C≦12) , alkenyloxy (C≦12) , alkynyloxy (C≦12) , aryloxy (C≦12) , aralkoxy (C≦12) , heteroaryloxy (C≦12) , heteroaralkoxy (C≦12) , acyloxy (C≦12) , alkylamino (C≦12) , dialkylamino (C≦12) , alkenylamino (C≦12) , alkynylamino (C≦12) , arylamino (C≦12) , aralkylamino (C≦12) , heteroarylamino (C≦12) , heteroaralkylamino (C≦12) , alkylsulfonylamino (C≦12) , amido (C≦12) , alkylthio (C≦12) , alkenylthio (C≦12) , alkynylthio (C≦12) , arylthio (C≦12) , aralkylthio (C≦12) , heteroarylthio (C≦12) , heteroaralkylthio (C≦12) , acylthio (C≦12) , thioacyl (C≦12) , alkylsulfonyl (C≦12) , alkenylsulfonyl (C≦12) , alkynylsulfonyl (C≦12) , arylsulfonyl (C≦12) , aralkylsulfonyl (C≦12) , heteroarylsulfonyl (C≦12) , heteroaralkylsulfonyl (C≦12) , alkylsulfinyl (C≦12) , alkenylsulfinyl (C≦12) , alkynylsulfinyl (C≦12) , arylsulfinyl (C≦12) , aralkylsulfinyl (C≦12) , heteroarylsulfinyl (C≦12) , heteroaralkylsulfinyl (C≦12) , alkylphosphonyl (C≦12) , alkylphosphate (C≦12) , dialkylphosphate (C≦12) , alkylammonium (C≦12) , alkylsulfonium (C≦12) , alkylsilyl (C≦12) , or a substituted version of any of these groups; or

Y and R a form a three to seven-membered ring, such that Y and R a are further connected to one another through one or more of —O— and alkanediyl (C1-5) , further wherein Y is —CH— and R a is —CH 2 —; or

Y, R a , and carbon numbers 13, 17 and 18 form a ring such that R a is bound to carbon 13, wherein Y is alkanediyl (C=1) or substituted alkanediyl (C=1) and R a is —O—;

X 1 and X 2 are independently:

hydrogen, OR b , NR b R c , or SR b , wherein R b and R c are each independently:

hydrogen or hydroxy;

alkyl (C≦8) , aryl (C≦8) , aralkyl (C≦8) , acyl (C≦8) , alkoxy (C≦8) , aryloxy (C≦8) , acyloxy (C≦8) , alkylamino (C≦8) , arylamino (C≦8) , amido (C≦8) , or a substituted version of any of these groups; or

a substituent convertible in vivo to hydrogen;

provided that R b is absent when the atom to which it is bound is part of a double bond, further provided that when R b is absent the atom to which it is bound is part of a double bond;

R 1 is:

hydrogen, cyano, hydroxy, halo or amino; or

alkyl (C≦8) , alkenyl (C≦8) , alkynyl (C≦8) , aryl (C≦8) , aralkyl (C≦8) , heteroaryl (C≦8) , heteroaralkyl (C≦8) , acyl (C≦8) , alkoxy (C≦8) , aryloxy (C≦8) , acyloxy (C≦8) , alkylamino (C≦8) , arylamino (C≦8) , amido (C≦8) , or a substituted version of any of these groups;

R 2 is:

cyano;

R 3 is:

absent or hydrogen;

alkyl (C≦8) , aryl (C≦8) , aralkyl (C≦8) , acyl (C≦8) , or a substituted version of any of these groups; or

a substituent convertible in vivo to hydrogen;

provided that R 3 is absent when the oxygen atom to which it is bound is part of a double bond, further provided that when R 3 is absent the oxygen atom to which it is bound is part of a double bond;

R 4 and R 5 are each independently alkyl (C≦8) or substituted alkyl (C≦8) ;

R 6 is hydrogen, hydroxy or oxo; and

R 7 is hydrogen or hydroxy;

R 8 , R 9 , R 10 and R 11 are each independently hydrogen, hydroxy, alkyl (C≦8) , substituted alkyl (C≦8) , alkoxy (C≦8) or substituted alkoxy (C≦8) ;

or a pharmaceutically acceptable salt or tautomer thereof.

2. The compound of claim 1 , further defined as:

wherein:

Y is alkanediyl (C≦8) , alkenediyl (C≦8) , alkynediyl (C≦8) , or a substituted version of any of these groups;

R a is:

hydrogen, hydroxy, halo, amino, nitro, cyano, azido, phosphate, 1,3-dioxoisoindolin-2-yl, mercapto or silyl; or

alkyl (C≦12) , alkenyl (C≦12) , alkynyl (C≦12) , aryl (C≦12) , aralkyl (C≦12) , heteroaryl (C≦12) , heteroaralkyl (C≦12) , acyl (C≦12) , alkoxy (C≦12) , alkenyloxy (C≦12) , alkynyloxy (C≦12) , aryloxy (C≦12) , aralkoxy (C≦12) , heteroaryloxy (C≦12) , heteroaralkoxy (C≦12) , acyloxy (C≦12) , alkylamino (C≦12) , dialkylamino (C≦12) , alkenylamino (C≦12) , alkynylamino (C≦12) , arylamino (C≦12) , aralkylamino (C≦12) , heteroarylamino (C≦12) , heteroaralkylamino (C≦12) , alkylsulfonylamino (C≦12) , amido (C≦12) , alkylthio (C≦12) , alkenylthio (C≦12) , alkynylthio (C≦12) , arylthio (C≦12) , aralkylthio (C≦12) , heteroarylthio (C≦12) , heteroaralkylthio (C≦12) , acylthio (C≦12) , thioacyl (C≦12) , alkylsulfonyl (C≦12) , alkenylsulfonyl (C≦12) , alkynylsulfonyl (C≦12) , arylsulfonyl (C≦12) , aralkylsulfonyl (C≦12) , heteroarylsulfonyl (C≦12) , heteroaralkylsulfonyl (C≦12) , alkylsulfinyl (C≦12) , alkenylsulfinyl (C≦12) , alkynylsulfinyl (C≦12) , arylsulfinyl (C≦12) , aralkylsulfinyl (C≦12) , heteroarylsulfinyl (C≦12) , heteroaralkylsulfinyl (C≦12) , alkylphosphonyl (C≦12) , alkylphosphonyl (C≦12) , alkylphosphate (C≦12) , dialkylphosphate (C≦12) , alkylammonium (C≦12) , alkylsulfonium (C≦12) , alkylsilyl (C≦12) , or a substituted version of any of these groups; or

Y and R a form a three to six-membered ring, such that Y and R a are further connected to one another through one or more of —O— and alkanediyl (C1-4) , further wherein Y is —CH— and R a is —CH 2 —;

X 1 and X 2 are independently:

hydrogen, OR b , NR b R c , or SR b , wherein R b and R c are each independently:

hydrogen;

alkyl (C≦8) , aryl (C≦8) , aralkyl (C≦8) , acyl (C≦8) , or a substituted version of any of these groups; or

a substituent convertible in vivo to hydrogen;

provided that R b is absent when the atom to which it is bound is part of a double bond, further provided that when R b is absent the atom to which it is bound is part of a double bond;

R 1 is:

hydrogen, cyano, hydroxy, halo or amino; or

alkyl (C≦8) , alkenyl (C≦8) , alkynyl (C≦8) , aryl (C≦8) , aralkyl (C≦8) , heteroaryl (C≦8) , heteroaralkyl (C≦8) , acyl (C≦8) , alkoxy (C≦8) , aryloxy (C≦8) , acyloxy (C≦8) , alkylamino (C≦8) , arylamino (C≦8) , amido (C≦8) , or a substituted version of any of these groups;

R 2 is:

cyano;

R 3 is:

absent or hydrogen;

alkyl (C≦8) , aryl (C≦8) , aralkyl (C≦8) , acyl (C≦8) , or a substituted version of any of these groups; or

a substituent convertible in vivo to hydrogen;

provided that R 3 is absent when the oxygen atom to which it is bound is part of a double bond, further provided that when R 3 is absent the oxygen atom to which it is bound is part of a double bond;

R 4 and R 5 are each independently alkyl (C≦8) or substituted alkyl (C≦8) ; and

R 6 and R 7 are each independently hydrogen or hydroxy;

or a pharmaceutically acceptable salt or tautomer thereof.

3. The compound of claim 2 , further defined as:

wherein:

Y is alkanediyl (C≦5) or substituted alkanediyl (C≦5) ;

R a is:

hydrogen, hydroxy, halo, amino, phosphate, 1,3-dioxoisoindolin-2-yl, or cyano; or

alkyl (C≦12) , alkenyl (C≦12) , alkynyl (C≦12) , aryl (C≦12) , aralkyl (C≦12) , heteroaryl (C≦12) , heteroaralkyl (C≦12) , acyl (C≦12) , alkoxy (C≦12) , alkenyloxy (C≦12) , alkynyloxy (C≦12) , aryloxy (C≦12) , aralkoxy (C≦12) , heteroaryloxy (C≦12) , heteroaralkoxy (C≦12) , acyloxy (C≦12) , alkylamino (C≦12) , dialkylamino (C≦12) , alkenylamino (C≦12) , alkynylamino (C≦12) , arylamino (C≦12) , aralkylamino (C≦12) , heteroarylamino (C≦12) , heteroaralkylamino (C≦12) , alkylsulfonylamino (C≦12) , amido (C≦12) , arylsulfonyl (C≦12) , arylsulfinyl (C≦12) , alkylphosphate (C≦12) , dialkylphosphate (C≦12) , or a substituted version of any of these groups; or

Y and R a form a three to five-membered ring, such that Y and R a are further connected to one another through one or more of —O— and alkanediyl (C1-3) , further wherein Y is —CH— and R a is —CH 2 —;

R 2 is:

cyano; and

R 3 is:

absent or hydrogen;

alkyl (C≦8) , aryl (C≦8) , aralkyl (C≦8) , acyl (C≦8) , or a substituted version of any of these groups; or

a substituent convertible in vivo to hydrogen;

provided that R 3 is absent when the oxygen atom to which it is bound is part of a double bond, further provided that when R 3 is absent the oxygen atom to which it is bound is part of a double bond;

or a pharmaceutically acceptable salt or tautomer thereof.

4. The compound of claim 2 , further defined as:

wherein:

Y is alkanediyl (C≦8) , alkenediyl (C≦8) , alkynediyl (C≦8) , or a substituted version of any of these groups;

R a is:

hydrogen, hydroxy, halo, amino, nitro, cyano, azido, phosphate, 1,3-dioxoisoindolin-2-yl, mercapto or silyl; or

alkyl (C≦12) , alkenyl (C≦12) , alkynyl (C≦12) , aryl (C≦12) , aralkyl (C≦12) , heteroaryl (C≦12) , heteroaralkyl (C≦12) , acyl (C≦12) , alkoxy (C≦12) , alkenyloxy (C≦12) , alkynyloxy (C≦12) , aryloxy (C≦12) , aralkoxy (C≦12) , heteroaryloxy (C≦12) , heteroaralkoxy (C≦12) , acyloxy (C≦12) , alkylamino (C≦12) , dialkylamino (C≦12) , alkenylamino (C≦12) , alkynylamino (C≦12) , arylamino (C≦12) , aralkylamino (C≦12) , heteroarylamino (C≦12) , heteroaralkylamino (C≦12) , alkylsulfonylamino (C≦12) , amido (C≦12) , alkylammonium (C≦12) , alkylsulfonium (C≦12) , alkylsilyl (C≦12) , arylsulfonyl (C≦12) , arylsulfinyl (C≦12) , alkylphosphate (C≦12) , dialkylphosphate (C≦12) , or a substituted version of any of these groups; or

Y and R a form a three to five-membered ring, such that Y and R a are further connected to one another through one or more of —O— and alkanediyl (C1-3) , further wherein Y is —CH— and R a is —CH 2 —;

X 1 and X 2 are independently:

OR b , NR b R c , or SR b , wherein R b and R c are each independently:

hydrogen;

alkyl (C≦8) , aryl (C≦8) , aralkyl (C≦8) , acyl (C≦8) , or a substituted version of any of these groups; or

a substituent convertible in vivo to hydrogen;

provided that R b is absent when the atom to which it is bound is part of a double bond, further provided that when R b is absent the atom to which it is bound is part of a double bond;

R 1 is:

hydrogen, cyano, hydroxy, halo or amino; or

alkyl (C≦8) , alkenyl (C≦8) , alkynyl (C≦8) , aryl (C≦8) , aralkyl (C≦8) , heteroaryl (C≦8) , heteroaralkyl (C≦8) , acyl (C≦8) , alkoxy (C≦8) , aryloxy (C≦8) , acyloxy (C≦8) , alkylamino (C≦8) , arylamino (C≦8) , amido (C≦8) , or a substituted version of any of these groups;

R 2 is:

cyano; and

R 4 is alkyl (C≦8) or substituted alkyl (C≦8) ;

or a pharmaceutically acceptable salt or tautomer thereof.

5. The compound of claim 2 , further defined as:

wherein:

Y is alkanediyl (C≦8) , alkenediyl (C≦8) , alkynediyl (C≦8) , or a substituted version of any of these groups;

R a is:

hydrogen, hydroxy, halo, amino, nitro, cyano, azido, phosphate, 1,3-dioxoisoindolin-2-yl, mercapto or silyl; or

alkyl (C≦12) , alkenyl (C≦12) , alkynyl (C≦12) , aryl (C≦12) , aralkyl (C≦12) , heteroaryl (C≦12) , heteroaralkyl (C≦12) , acyl (C≦12) , alkoxy (C≦12) , alkenyloxy (C≦12) , alkynyloxy (C≦12) , aryloxy (C≦12) , aralkoxy (C≦12) , heteroaryloxy (C≦12) , heteroaralkoxy (C≦12) , acyloxy (C≦12) , alkylamino (C≦12) , dialkylamino (C≦12) , alkenylamino (C≦12) , alkynylamino (C≦12) , arylamino (C≦12) , aralkylamino (C≦12) , heteroarylamino (C≦12) , heteroaralkylamino (C≦12) , amido (C≦12) , arylsulfonyl (C≦12) , arylsulfinyl (C≦12) , alkylphosphate (C≦12) , dialkylphosphate (C≦12) , alkylphosphate (C≦12) , dialkylphosphate (C≦12) , or a substituted version of any of these groups; or

Y and R a form a three to five-membered ring, such that Y and R a are further connected to one another through one or more of —O— and alkanediyl (C1-3) , further wherein Y is —CH— and R a is —CH 2 —;

X 1 is:

OR b , NR b R c , or SR b , wherein R b and R c are each independently:

hydrogen;

alkyl (C≦8) , aryl (C≦8) , aralkyl (C≦8) , acyl (C≦8) , or a substituted version of any of these groups; or

a substituent convertible in vivo to hydrogen;

provided that R b is absent when the atom to which it is bound is part of a double bond, further provided that when R b is absent the atom to which it is bound is part of a double bond;

R 1 is:

hydrogen, cyano, hydroxy, halo or amino; or

alkyl (C≦8) , alkenyl (C≦8) , alkynyl (C≦8) , aryl (C≦8) , aralkyl (C≦8) , heteroaryl (C≦8) , heteroaralkyl (C≦8) , acyl (C≦8) , alkoxy (C≦8) , aryloxy (C≦8) , acyloxy (C≦8) , alkylamino (C≦8) , arylamino (C≦8) , amido (C≦8) , or a substituted version of any of these groups; and

R 2 is:

cyano;

or a pharmaceutically acceptable salt or tautomer thereof.

6. The compound of claim 5 , wherein Y is alkanediyl (C1-4) or substituted alkanediyl (C1-4) .

7. The compound of claim 5 , wherein X 1 is OR b and R b is absent.

8. The compound of claim 4 , wherein X 2 is hydrogen.

9. The compound of claim 5 , wherein R a is —OH.

10. The compound of claim 5 , wherein R a is acyl (C1-3) or substituted acyl (C1-3) .

11. The compound of claim 10 , wherein R a is selected from the group consisting of —C(═O)OH, —C(═O)OCH 3 , —C(═O)NHCH 3 , —C(═O)NHCH 2 CH 3 , and —C(═O)NHCH 2 CF 3 .

12. The compound of claim 5 , wherein R a is acyloxy (C1-8) or substituted acyloxy (C1-3) .

13. The compound of claim 3 , wherein R 3 is absent.

14. The compound of claim 2 , wherein R 4 and R 5 are each methyl.

15. The compound of claim 2 , wherein R 6 and R 7 are each hydrogen.

16. The compound of claim 1 , wherein R 8 and R 9 are each hydrogen.

17. The compound of claim 1 , wherein R 10 and R 11 are each methyl.

18. The compound of claim 5 , wherein the bond between carbons 9 and 11 is a single bond.

19. The compound of claim 5 , wherein the bond between carbons 9 and 11 is a double bond.

20. A pharmaceutical composition comprising as an active ingredient a compound of claim 5 and a pharmaceutically acceptable carrier.

Assignments (9)

Continuity (5)