Substituted pyrazolylamide compounds 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 wherein 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 —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 hydrogen, 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 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 the same or different and are independently selected from alkyl, or
R 7 and R 8 can be cyclized into a ring
R 9 and R 10 are the same or different and 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
or R 7 and R 9 can be cyclized into a ring
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 the same or different and are selected from the group consisting of hydrogen, alkyl, halogen and carboxy;
X is a single bond;
Y is R 3 —(CH 2 ) s —;
s=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 compound according to claim 1 having the structure:
or a pharmaceutically acceptable salt thereof; wherein:
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; 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 compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein R 4 is —(CH 2 ) n Z—(CH 2 ) m —PO(OR 7 )R 9 .
4. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein R 4 is —(CH 2 ) n Z—(CH 2 ) m —PO—(R 9 )R 10 .
5. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein R 4 is:
6. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein R 4 is —(CH 2 ) n Z—(CH 2 ) m —PO(OR 7 )(OR 8 ).
7. The compound according to claim 6 or a pharmaceutically acceptable salt thereof, wherein:
Z is a single bond;
m is zero;
n is 1 or 2;
R 7 is alkyl; and
R 8 is alkyl.
8. The compound according to claim 1 having the structure:
or a pharmaceutically acceptable salt thereof.
9. The compound according to claim 8 or a pharmaceutically acceptable salt thereof, wherein R 4 is —(CH 2 ) n Z—(CH 2 ) m —PO(OR 7 )R 9 .
10. The compound according to claim 8 or a pharmaceutically acceptable salt thereof, wherein R 4 is —(CH 2 ) n Z—(CH 2 ) m —PO—(R 9 )R 10 .
11. The compound according to claim 8 or a pharmaceutically acceptable salt thereof, wherein R 4 is:
12. The compound according to claim 8 or a pharmaceutically acceptable salt thereof, wherein R 4 is —(CH 2 ) n —Z—(CH 2 ) m —PO(OR 7 )(OR 8 ).
13. The compound according to claim 12 or a pharmaceutically acceptable salt thereof, wherein:
R 7 is alkyl; and
R 8 is alkyl.
14. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Y—X—CO— is:
15. The compound according to claim 1 having the structure:
or a pharmaceutically acceptable salt thereof, wherein:
wherein R 4 is:
R a is C 1-4 alkyl.
16. A pharmaceutical composition comprising a compound as according to claim 1 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.
17. The pharmaceutical composition according to claim 16 , wherein said compound according to claim 1 is:
or a pharmaceutically acceptable salt thereof, wherein R 4 is: