Substituted pyrazolylamides useful as glucokinase activators
Compounds are provided which are phosphonate and phosphinate activators and thus are useful in treating diabetes and related diseases and have the structure is a heteroaryl ring; R 4 is —(CH 2 ) n —Z—(CH 2 ) m —PO(OR 7 )(OR 8 ), —(CH 2 ) n Z—(CH 2 ) m —PO(OR 7 )R 9 , —(CH 2 ) n —Z—(CH 2 ) m —OPO(OR 7 )R 9 , —(CH 2 ) n Z—(CH 2 ) m —OPO(R 9 )(R 10 ), or —(CH 2 ) n Z—(CH 2 ) m —PO(R 9 )(R 10 ); R 5 and R 6 are independently selected from H, alkyl and halogen; Y is R 7 (CH 2 ) s or is absent; and X, n, Z, m, R 4 , R 5 , R 6 , R 7 , and s are as defined herein; or a pharmaceutically acceptable salt thereof. A method for treating diabetes and related diseases employing the above compounds is also provided.
1. A method for modulating glucokinase activity, which comprises administering to a mammalian patient in need thereof a therapeutically effective amount of a compound having the structure:
or a pharmaceutically acceptable salt thereof, wherein:
R 4 is selected from the group consisting of:
—(CH 2 ) n —Z—(CH 2 ) m —PO(OR 7 )(OR 8 ),
—(CH 2 ) n Z—(CH 2 ) m —PO(OR 7 )R 9 , and
—(CH 2 ) n Z—(CH 2 ) m —PO—(R 9 )R 10 ;
R 7 and R 8 are independently alkyl, or
R 7 and R 8 can be cyclized into a ring
where q=1, 2, or 3;
R 9 and R 10 are independently selected from the group consisting of alkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl;
or R 9 and R 10 can be cyclized into a ring
where q=1, 2, or 3, or
where q=1, 2, or 3;
or R 7 and R 9 can be cyclized into a ring
where q=1, 2, or 3 or
where q=1, 2, or 3;
Z is a single bond, alkylene, or alkenylene wherein said alkylene or alkenylene may be optionally substituted with hydroxy, alkoxy, aminoalkyl, aminoaralkyl, aminoheteroaralkyl, aminoaryl, aminoheteroaryl, or carboxy;
m is zero, 1, or 2;
n is 1 or 2;
R 5 and R 6 are independently selected from the group consisting of hydrogen, alkyl, halogen and carboxy;
X is a single bond;
Y is R 3 —(CH 2 ) s —;
s is zero; and
R 3 is phenyl substituted with zero, 1, or 2 substituent groups independently selected:
(a) —OR a wherein R a is:
(i) alkyl, wherein said alkyl may be further substituted with at least one of halo, alkoxy or phenyl;
(ii) phenyl, optionally substituted with —SO 2 R c wherein R c is alkyl;
(iii) a 4- to 7-membered heterocyclo optionally substituted with —SO 2 R c wherein R c is alkyl;
(iv) pyridinyl or pyrazinyl, optionally substituted with —C(═O)NR d R b or —SO 2 R c wherein R d and R b may join together with the N to which they are attached to form a 4- to 7-membered heterocyclo and R c is alkyl; and/or
(b) —C(═O)R a wherein R a is a 4- to 7-membered heterocyclo.
2. The method according to claim 1 where, in said compound or a pharmaceutically acceptable salt, thereof:
R 3 is phenyl substituted with zero, 1, or 2 substituent groups selected from —OR a wherein each R a is independently selected from:
(i) alkyl, wherein said alkyl may be further substituted with at least one of halo, alkoxy or phenyl;
(ii) phenyl, optionally substituted with —SO 2 R c wherein R c is alkyl; or
(iii) pyridinyl or pyrazinyl, optionally substituted with —C(═O)NR d R b or —SO 2 R c wherein R d and R b may join together with the N to which they are attached to form a 4- to 7-membered heterocyclo and R c is alkyl.
3. The method according to claim 2 where, in said compound or a pharmaceutically acceptable salt thereof, R 4 is —(CH 2 ) n Z—(CH 2 ) m —PO(OR 7 )R 9 .
4. The method according to claim 2 where, in said compound or a pharmaceutically acceptable salt thereof, R 4 is —(CH 2 ) n Z—(CH 2 ) m —PO—(R 9 )R 10 .
5. The method according to claim 2 where, in said compound or a pharmaceutically acceptable salt thereof, R 4 is —(CH 2 ) n —Z—(CH 2 ) m —PO(OR 7 )(OR 8 ).
6. The method according to claim 5 where, in said compound or a pharmaceutically acceptable salt thereof,
Z is a single bond;
m is zero;
n is 1 or 2;
R 7 is alkyl; and
R 8 is alkyl.
7. The method according to claim 5 wherein said compound has the structure:
or a pharmaceutically acceptable salt thereof.
8. The method according to claim 7 where, in said compound or a pharmaceutically acceptable salt thereof, R 4 is —(CH 2 ) n Z—(CH 2 ) m —PO(OR 7 )R 9 .
9. The method according to claim 7 where, in said compound or a pharmaceutically acceptable salt thereof, R 4 is —(CH 2 ) n Z—(CH 2 ) m —PO—(R 9 )R 10 .
10. The method according to claim 7 where, in said compound or a pharmaceutically acceptable salt thereof, R 4 is —(CH 2 ) n —Z—(CH 2 ) m —PO(OR 7 )(OR 8 ).
11. The method according to claim 10 where, in said compound or a pharmaceutically acceptable salt thereof,
Z is a single bond;
m is zero;
n is 1 or 2;
R 7 is alkyl; and
R 8 is alkyl.
12. The method according to claim 1 wherein said disease is Type II diabetes.
13. The method according to claim 1 where, in said compound or a pharmaceutically acceptable salt thereof, Y—X—CO— is:
14. The method according to claim 1 wherein said compound has the structure:
or a pharmaceutically acceptable salt thereof, wherein:
wherein R 4 is:
and R a is C 1-4 -alkyl.
15. The method according to claim 1 , wherein said compound is:
or a pharmaceutically acceptable salt thereof, wherein R 4 is:
16. The method according to claim 1 wherein said compound is:
or a pharmaceutically acceptable salt thereof.
17. A method for modulating glucokinase activity, which comprises administering to a human in need thereof a compound having the structure:
or a pharmaceutically acceptable salt thereof.
18. The method of claim 1 wherein a therapeutically effective amount of said compound is administered.