Granted Patent B2

US 8,916,585 · App. 13/599,161 · Granted Dec 23, 2014

Inventors: Michael P. Arend (San Mateo, CA); Lee A. Flippin (Woodside, CA); Volkmar Guenzler-Pukall (San Leandro, CA); Wen-Bin Ho (Los Altos, CA); Eric D. Turtle (Belmont, CA); Xiaohui Du (Foster City, CA)

Assignee: Fibrogen, Inc.

A61K38/1816C07D217/26A61K31/472C07D401/04C07D401/06C07D221/08C07D217/24C07D401/12C07D403/12

Abstract

Claims (209)

1. A compound represented by formula

wherein:

q is zero or one;

W is selected from the group consisting of oxygen, —S(O) n — and —NR 9 — where n is zero, one or two, R 9 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic and R 8 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, or when W is —NR 9 — then R 8 and R 9 , together with the nitrogen atom to which they are bound, can be joined to form a heterocyclic or a substituted heterocyclic group, provided that when W is —S(O) n — and n is one or two, then R 8 is not hydrogen;

R 1 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, aminoacyl, aryl, substituted aryl, halo, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, and —XR 6 where X is oxygen, —S(O) n — or —NR 7 — where n is zero, one or two, R 6 is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and R 7 is hydrogen, alkyl or aryl or, when X is —NR 7 —, then R 7 and R 6 , together with the nitrogen atom to which they are bound, can be joined to form a heterocyclic or substituted heterocyclic group;

R 2 and R 3 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, halo, hydroxy, cyano, —S(O) n —N(R 6 )—R 6 where n is 0, 1, or 2, —NR 6 C(O)NR 6 R 6 , —XR 6 where X is oxygen, —S(O) n — or —NR 7 — where n is zero, one or two, each R 6 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic provided that when X is —SO— or —SO 2 —, then R 6 is not hydrogen, and R 7 is selected from the group consisting of hydrogen, alkyl, aryl, or R 2 , R 3 together with the carbon atoms pendent thereto, form an aryl substituted aryl, heteroaryl, or substituted heteroaryl;

R 4 and R 5 are independently selected from the group consisting of hydrogen, halo, alkyl, substituted alkyl, alkoxy, substituted alkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl and —XR 6 where X is oxygen, —S(O) n — or —NR 7 — where n is zero, one or two. R 6 is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and R 7 is hydrogen, alkyl or aryl or, when X is —NR 7 —, then R 7 and R 6 , together with the nitrogen atom to which they are bound, can be joined to form a heterocyclic or substituted heterocyclic group;

R″ is selected from the group consisting of hydrogen and alkyl or R″ together with R′ and the nitrogen pendent thereto can be joined to form a heterocyclic or substituted heterocyclic group;

R′″ is selected from the group consisting of hydroxy, alkoxy, substituted alkoxy, acyloxy, cycloalkoxy, substituted cycloalkoxy, aryloxy, substituted aryloxy, heteroaryloxy, substituted heteroaryloxy, aryl, —S(O) n —R 10 wherein R 10 is selected from the group consisting or alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl and n is zero, one or two;

or a pharmaceutically acceptable salt thereof;

with the proviso that when R″ is hydrogen, q is zero, W is oxygen, and R 8 is hydrogen, then at least one of the following occurs:

1) R 1 is fluoro, bromo, iodo, alkyl, substituted alkyl, alkoxy, aminoacyl, substituted alkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, or —XR 6 where X is oxygen, —S(O) n — or —NR 7 — where n is zero, one or two, R 6 is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and R 7 is hydrogen, alkyl or aryl;

2) R 2 is substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, fluoro, bromo, iodo, cyano, or —XR 6 where X is oxygen, —S(O) n — or —NR 7 — where n is zero, one or two, R 6 is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and R 7 is hydrogen, alkyl or aryl, provided that:

a) when R 2 is substituted alkyl such a substituent does not include trifluoromethyl;

b) —XR 6 is not alkoxy; and

c) when —XR 6 is substituted alkoxy such a substituent does not include benzyl or benzyl substituted by a substituent selected from the group consisting of (C 1 -C 5 ) alkyl and (C 1 -C 5 ) alkoxy or does not include a fluoroalkoxy substituent of the formula:

—O—[CH 2 ] x —C f H (2f+1−g) F g

where x is zero or one; f is an integer of from 1 to 5; and g is an integer of from 1 to (2f+1);

3) R 3 is substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, bromo, iodo, or —XR 6 where X is oxygen, —S(O) n — or —NR 7 — where n is zero, one or two, R 6 is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and R 7 is hydrogen, alkyl or aryl, provided that:

a) when R 3 is substituted alkyl such a substituent does not include trifluoromethyl;

b) —XR 6 is not alkoxy; and

c) when —XR 6 is substituted alkoxy such a substituent does not include benzyl or benzyl substituted by a substituent selected from the group consisting of (C 1 -C 5 ) alkyl and (C 1 -C 5 ) alkoxy or does not include a fluoroalkoxy substituent of the formula:

—O—[CH ] x —C f H (2f+1−g) F g

where x is zero or one; f is an integer of from 1 to 5, and g is an integer of from 1 to (2f+1);

4) R 4 is iodo, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, or —XR 6 where X is oxygen, —S(O) n — or —NR 7 — where n is zero, one or two, R 6 is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and R 7 is hydrogen, alkyl or aryl provided that:

a) when R 4 is substituted alkyl such a substituent does not include trifluoromethyl;

b) —XR 6 is not alkoxy; and

c) when —XR 6 is substituted alkoxy such a substituent does not include a fluoroalkoxy substituent of the formula:

—O—[CH 2 ] x —C f H (2f+1−g) F g

where x is zero or one; f is an integer of from 1 to 5; and g is an integer of from 1 to (2f+1); or

5) R 5 is iodo, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, or —XR 6 where X is oxygen, —S(O) n — or —NR 7 — where n is zero, one or two, R 6 is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and R 7 is hydrogen, alkyl or aryl, provided that:

a) when R 5 is substituted alkyl such a substituent does not include trifluoromethyl;

b) —XR 6 is not alkoxy; and

c) when —XR 6 is substituted alkoxy such a substituent does not include a fluoroalkoxy substituent of the formula:

—O—[CH 2 ] x —C f H (2f+1−g) F g

where x is zero or one; f is an integer of from 1 to 5; and g is an integer of from 1 to (2f+1).

2. A compound as in claim 1 , wherein R 1 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, halo, alkoxy, aryloxy, substituted aryloxy, substituted aryl, alkylthio, aminoacyl, aryl, substituted amino, heteroaryl, heteroaryloxy, —S(O) n -aryl, —S(O) n -substituted aryl, —S(O) n -heteroaryl, and —S(O) n -substituted heteroaryl, where n is zero, one or two.

3. A compound as in claim 1 , wherein R 1 is selected from the group consisting of:

(4-methoxy)phenylsulfonylamino;

2,6-dimethylphenoxy;

3,4-difluorophenoxy;

3,5-difluorophenoxy;

3-chloro-4-fluorophenoxy;

3-methoxy-4-fluorophenoxy;

3-methoxy-5-fluorophenoxy;

4-(methylsulfonamido)phenoxy;

4-(phenylsulfonamido)phenoxy;

4-CF 3 —O-phenoxy;

4-CF 3 -phenoxy;

4-chlorophenoxy;

4-fluorophenoxy;

4-(4-fluorophenoxy)phenoxy;

4-methoxyphenoxy;

4-nitrophenoxy;

benzyloxy;

bromo;

butoxy,

CF 3 ;

chloro;

fluoro;

hydrogen;

iodo;

isopropoxy;

methyl;

phenoxy;

phenyl;

phenylsulfanyl;

phenylsulfinyl;

phenylsulfonyl;

phenylurea;

pyridin-1-ylsulfanyl;

pyridin-3-yloxy; and

pyridin-4-ylsulfanyl.

4. A compound as in claim 1 , wherein R 2 is selected from the group consisting of substituted amino, aryloxy, substituted aryloxy, alkoxy, substituted alkoxy, halo, hydrogen, alkyl, substituted alkyl, aryl, —S(O) n -aryl, —S(O) n -substituted aryl, —S(O) n -cycloalkyl, where n is zero, one or two, aminocarbonylamino, heteroaryloxy, and cycloalkyloxy.

5. A compound as in claim 4 , wherein R 2 is selected from the group consisting of:

(4-methoxy)phenylsulfonylamino;

2,6-dimethylphenoxy;

3,4-difluorophenoxy;

3,5-difluorophenoxy;

3-chloro-4-fluorophenoxy;

3-methoxy-4-fluorophenoxy;

3-methoxy-5-fluorophenoxy;

4-(methylsulfonamido)phenoxy;

4-(phenylsulfonamido)phenoxy;

4-CF 3 —O-phenoxy;

4-CF 3 -phenoxy;

4-chlorophenoxy;

4-fluorophenoxy;

4-(4-fluorophenoxy)phenoxy;

4-methoxyphenoxy;

4-nitrophenoxy;

benzyloxy;

bromo;

butoxy;

CF 3 ;

chloro;

cyclohexyloxy;

cyclohexylsulfanyl;

cyclohexylsulfonyl;

fluoro;

hydrogen;

iodo;

isopropoxy;

methyl;

phenoxy;

phenyl;

phenylsulfanyl;

phenylsulfinyl;

phenylsulfonyl;

phenylurea;

pyridin-1-ylsulfanyl;

pyridin-3-yloxy, and

pyridin-4-ylsulfanyl.

6. A compound as in claim 1 , wherein R 3 is selected from the group consisting of: substituted aryloxy, substituted alkoxy, alkoxy, substituted alkyl, alkyl, amino, cycloalkyloxy, hydrogen, halo, aryl, —S(O) n -aryl, —S(O) n ,-substituted aryl, —S(O) n -heteroaryl, —S(O) n -substituted heteroaryl, where n is zero, one or two, aminocarbonylamino, and heteroaryloxy.

7. A compound as in claim 6 , wherein R 3 is selected from the group consisting of:

amino;

(4-methyl)phenylsulfonylaminophenoxy;

3,4-difluorophenoxy;

3,5-difluorophenoxy;

3-fluoro-5-methoxy-phenoxy;

3-chloro-4-fluorophenoxy;

4-CF 3 —O-phenoxy;

4-CF 3 -phenoxy;

4-chlorophenoxy;

4-fluorophenoxy;

4-(4-fluorophenoxy)phenoxy;

4-methoxyphenoxy;

benzyloxy;

bromo;

butoxy;

CF 3 ;

chloro;

cyclohexyloxy,

hydrogen;

iodo;

isopropoxy;

phenoxy;

phenyl;

phenylsulfanyl;

phenyl sulfonyl;

phenylsulfinyl;

phenylurea;

pyridin-1-ylsulfanyl;

pyridin-3-yloxy; and

pyridin-4-ylsulfanyl.

8. A compound as in claim 1 , wherein R 2 and R 3 , combined with the carbon atoms pendent thereto, join to form an aryl group.

9. A compound as in claim 8 , wherein said aryl group is phenyl.

10. A compound as in claim 1 , wherein R 4 is selected from the group consisting of substituted arylthio, halo, hydrogen, substituted alkyl and aryl.

11. A compound as in claim 10 , wherein R 4 is selected from the group consisting of:

4-chlorophenyl sulfanyl;

chloro;

hydrogen;

methoxymethyl; and

phenyl.

12. A compound as in claim 1 , wherein R 5 is hydrogen or aryl.

13. A compound as in claim 12 , wherein R 5 phenyl.

14. A compound as in claim 1 , wherein R″ is hydrogen.

15. A compound as in claim 1 , wherein R′″ is selected from

the group consisting of hydrogen, hydroxy, alkoxy, substituted alkoxy, thiol, and acyloxy.

16. A compound as in claim 15 , wherein R′″ is selected from the group consisting of:

hydroxy;

benzyloxy;

ethoxy;

hydrogen;

thiol;

methoxy; and

methylcarbonyloxy.

17. A compound as in claim 1 , wherein WR 8 is selected from the group consisting of amino, substituted amino, hydroxy, and alkoxy.

18. A compound as in claim 17 , wherein WR 8 is selected from the group consisting of:

amino;

dimethylamino;

hydroxy;

methoxy; and

methylcarbonylamino.

19. A compound as in claim 1 , wherein said compound is represented by formula IIB:

wherein:

q is zero or one;

W is selected from the group consisting of oxygen, —S(O) n — and —NR 9 — where n is zero, one or two, R 9 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and R 8 is selected from the group consisting or hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic;

R″ is selected from hydrogen and alkyl;

R 1 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, aryl, substituted aryl, halo, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, and —XR 6 where X is oxygen, —S(O) n — or —NR 7 — where n is zero, one or two, R 6 is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and R 7 is hydrogen, alkyl or aryl;

R 2 and R 3 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, halo, hydroxy, cyano, and —XR 6 where X is oxygen, —S(O) n — or —NR 7 — where n is zero, one or two, R 6 is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and R 7 is hydrogen, alkyl or aryl;

R 4 and R 5 are independently selected from the group consisting of hydrogen, halo, alkyl, substituted alkyl, alkoxy, substituted alkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl and —XR 6 where X is oxygen, —S(O) n — or —NR 7 — where n is zero, one or two, R 6 is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and R 7 is hydrogen, alkyl or aryl; or

a pharmaceutically acceptable salt thereof.

20. A compound selected from the group consisting of:

1-Chloro-4-hydroxy-isoquinoline-3-carboxylic acid (2-amino-ethyl)-amide (trifluoro-acetic acid salt);

1-Chloro-4-hydroxy-isoquinoline-3-carboxylic acid (2-methoxy-ethyl)-amide;

1-Chloro-4-hydroxy-isoquinoline-3-carboxylic acid (2-hydroxy-ethyl)-amide;

1-Chloro-4-hydroxy-isoquinoline-3-carboxylic acid (2-dimethylamino-ethyl)-amide;

1-Chloro-4-hydroxy-isoquinoline-3-carboxylic acid (2-acetylamino-ethyl)-amide;

1-Chloro-4-hydroxy-6-isopropoxy-isoquinoline-3-carboxylic acid (2-methoxy-ethyl)-amide;

1-Chloro-4-hydroxy-6-isopropoxy-isoquinoline-3-carboxylic acid (2-amino-ethyl)-amide (trifluoro-acetic acid salt);

1-Chloro-4-hydroxy-6-isopropoxy-isoquinoline-3-carboxylic acid (2-dimethylamino-ethyl)-amide;

1-Chloro-4-hydroxy-7-isopropoxy-isoquinoline-3-carboxylic acid (2-amino-ethyl)-amide (trifluoro-acetic acid salt);

1-Chloro-4-hydroxy-7-isopropoxy-isoquinoline-3-carboxylic acid (2-methoxy-ethyl)-amide; and

1-Chloro-4-hydroxy-7-isopropoxy-isoquinoline-3-carboxylic acid (2-dimethylamino-ethyl)-amide;

or a pharmaceutically acceptable salt thereof.

21. A compound represented by the formula:

wherein:

R 2 and R 3 are independently selected from hydrogen or alkoxy;

W is selected from the group consisting of oxygen, and —NR 9 — where R 9 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, and acyl;

R 8 is selected from the group consisting of hydrogen, and alkyl;

or a pharmaceutically acceptable salt thereof;

with the proviso that when W is oxygen, then R 8 is not hydrogen.

22. A compound as in claim 21 , wherein R 2 is hydrogen or isopropoxy.

23. A compound as in claim 21 , wherein R 3 is hydrogen or isopropoxy.

24. A compound as in claim 21 , wherein WR 8 is selected from the group consisting of methoxy, amino, dimethylamino, and methylcarbonylamino.

25. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier or excipient.

26. A composition comprising the compound of claim 1 or a mixture of compounds of claim 1 in combination with at least one additional therapeutic agent.

27. The composition of claim 26 wherein the additional therapeutic agent is erythropoietin.

Assignments (3)

Continuity (8)