US2012225846A1PendingUtilityA1
Heterocyclic compounds for the inhibition of pask
Est. expiryMar 2, 2031(~4.6 yrs left)· nominal 20-yr term from priority
A61P 5/48A61P 35/00A61P 3/10A61P 3/06A61P 3/04A61P 3/00C07D 405/14C07D 487/04A61K 31/404C07D 241/12C07F 9/5728C07D 413/04C07F 5/025A61P 1/16C12N 9/1205C07D 209/10C07D 209/18C07F 9/65068C07D 471/04C07F 9/650952C07D 213/74
54
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Claims
Abstract
Disclosed herein are new heterocyclic compounds and compositions and their application as pharmaceuticals for the treatment of disease. Methods of inhibiting PAS Kinase (PASK) activity in a human or animal subject are also provided for the treatment of diseases such as diabetes mellitus.
Claims
exact text as granted — not AI-modified1 . A compound of structural Formula I:
or a pharmaceutically acceptable salt, ester, or prodrug thereof, wherein:
X 1 and X 2 are each independently chosen from CH, N, and a bond;
X 3 is chosen from C and N;
X 4 is chosen from CR 3 , a bond and null;
X 5 is chosen from CH, N, O, S, and null;
X 6 is chosen from CH, N, NH, O, and S;
X 7 is chosen from C and N;
R 1 and R 2 are each independently chosen from alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, OR 5 , SR 5 , and NR 5 R 6 , any of which may be optionally substituted, with the proviso that at least one of R 1 or R 2 is NR 5 R 6 , OR 5 , or SR 5 ;
R 3 is chosen from hydrogen, halogen, trifluoromethyl, hydroxyl, C 1 -C 5 alkyl, and C 1 -C 5 alkoxy, any of which may be optionally substituted;
R 4 is chosen from COOR 7 , NO 2 , CONR 8 R 9 , CONR 10 OR 11 , PO 3 H, SO 2 NHR 5 , CONHSO 2 R 5 , SO 2 NH 2 , CF3, SO 3 H, SO 2 NHCOR 5 , B(OH) 2 and tetrazolyl;
R 5 and R 6 are each independently chosen from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkenyl, C 1 -C 6 alkynyl, C 1 -C 7 cycloalkyl, C 1 -C 7 heterocycloalkyl, aryl, heteroaryl, aralkyl, and heteroaralkyl, any of which may be optionally substituted; or taken together, R 5 and R 6 may form a heterocycloalkyl or heteroaryl, either of which may be optionally substituted; and
R 7 , R 8 , R 9 , R 10 , and R 11 are each independently chosen from hydrogen, C 1 -C 6 alkyl, aryl, heteroaryl, aralkyl and heteroaralkyl, any of which may be optionally substituted.
2 . The compound as recited in claim 1 wherein
X 1 is a bond;
X 2 is CH;
X 3 is C; and
X 7 is N.
3 . The compound as recited in claim 2 wherein
X 5 and X 6 are both CH; and
X 4 is CR 3 .
4 . The compound as recited in claim 3 wherein said compound has structural formula II:
or a salt, ester or prodrug thereof, wherein:
R 1 and R 2 are each independently chosen from alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, OR 5 , SR 5 , and NR 5 R 6 , any of which may be optionally substituted;
R 3 is chosen from hydrogen, halogen, trifluoromethyl, hydroxyl, C 1 -C 5 alkyl, and C 1 -C 5 alkoxy, any of which may be optionally substituted;
R 4 is chosen from COOR 7 , NO 2 , CONR 8 R 9 , CONR 10 OR 11 , PO 3 H, SO 2 NHR 5 , CONHSO 2 R 5 , SO 2 NH 2 , CF3, SO 3 H, SO 2 NHCOR 5 , B(OH) 2 and tetrazolyl;
R 5 and R 6 are each independently chosen from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkenyl, C 1 -C 6 alkynyl, C 1 -C 7 cycloalkyl, C 1 -C 7 heterocycloalkyl, aryl, heteroaryl, aralkyl, and heteroaralkyl, any of which may be optionally substituted; or taken together, R 5 and R 6 may form a heterocycloalkyl or heteroaryl, either of which may be optionally substituted; and
R 7 , R 8 , R 9 , R 10 , and R 11 are each independently chosen from hydrogen, C 1 -C 6 alkyl, aryl, heteroaryl, aralkyl and heteroaralkyl, any of which may be optionally substituted.
5 . The compound as recited in claim 1 wherein
X 1 is a bond;
X 2 is N;
X 3 is C; and
X 7 is N.
6 . The compound as recited in claim 5 wherein
X 5 and X 6 are both CH; and
X 4 is CR 3 .
7 . The compound as recited in claim 6 wherein said compound has structural formula III:
or a salt, ester or prodrug thereof, wherein:
R 1 and R 2 are each independently chosen from alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, OR 5 , SR 5 , and NR 5 R 6 , any of which may be optionally substituted, with the proviso that at least one of R 1 or R 2 is NR 5 R 6 ;
R 3 is chosen from hydrogen, halogen, trifluoromethyl, hydroxyl, C 1 -C 5 alkyl, and C 1 -C 5 alkoxy, any of which may be optionally substituted;
R 4 is chosen from COOR 7 , NO 2 , CONR 8 R 9 , CONR 10 OR 11 , PO 3 H, SO 2 NHR 5 , CONHSO 2 R 5 , SO 2 NH 2 , CF3, SO 3 H, SO 2 NHCOR 5 , B(OH) 2 and tetrazolyl;
R 5 and R 6 are each independently chosen from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkenyl, C 1 -C 6 alkynyl, C 1 -C 7 cycloalkyl, C 1 -C 7 heterocycloalkyl, aryl, heteroaryl, aralkyl, and heteroaralkyl, any of which may be optionally substituted; or taken together, R 5 and R 6 may form a heterocycloalkyl or heteroaryl, either of which may be optionally substituted; and
R 7 , R 8 , R 9 , R 10 , and R 11 are each independently chosen from hydrogen, C 1 -C 6 alkyl, aryl, heteroaryl, aralkyl and heteroaralkyl, any of which may be optionally substituted.
8 . The compound as recited in claim 1 wherein
X 3 is C;
X 4 and X 5 are null; and
X 6 is CH.
9 . The compound as recited in claim 8 wherein said compound has structural formula IV:
or a salt, ester or prodrug thereof, wherein:
X 1 is chosen from CH and N;
X 2 is chosen from CH and N;
R 1 and R 2 are each independently chosen from alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, OR 5 , SR 5 , and NR 5 R 6 , any of which may be optionally substituted;
R 4 is chosen from COOR 7 , NO 2 , CONR 8 R 9 , CONR 10 OR 11 , PO 3 H, SO 2 NHR 5 , CONHSO 2 R 5 , SO 2 NH 2 , CF3, SO 3 H, SO 2 NHCOR 5 , B(OH) 2 and tetrazolyl;
R 5 and R 6 are each independently chosen from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkenyl, C 1 -C 6 alkynyl, C 1 -C 7 cycloalkyl, C 1 -C 7 heterocycloalkyl, aryl, heteroaryl, aralkyl, and heteroaralkyl, any of which may be optionally substituted; or taken together, R 5 and R 6 may form a heterocycloalkyl or heteroaryl, either of which may be optionally substituted; and
R 7 , R 8 , R 9 , R 10 , and R 11 are each independently chosen from hydrogen, C 1 -C 6 alkyl, aryl, heteroaryl, aralkyl and heteroaralkyl, any of which may be optionally substituted.
10 . The compound as recited in claim 9 wherein X 1 and X 2 are N.
11 . The compound as recited in claim 9 wherein
X 1 is CH; and
X 2 is N.
12 . The compound as recited in claim 9 wherein
X 1 is N; and
X 2 is CH.
13 . The compound as recited in claim 1 wherein
X 1 and X 2 are N;
X 3 is C;
X 4 is CR 3 ; and
X 5 and X 6 are independently chosen from CH and N.
14 . The compound as recited in claim 13 wherein said compound has structural formula V:
R 1 and R 2 are each independently chosen from alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, OR 5 , SR 5 , and NR 5 R 6 , any of which may be optionally substituted, with the proviso that at least one of R 1 or R 2 is NR 5 R 6 ;
R 3 is chosen from hydrogen, halogen, trifluoromethyl, hydroxyl, C 1 -C 5 alkyl, and C 1 -C 5 alkoxy, any of which may be optionally substituted;
R 4 is chosen from COOR 7 , NO 2 , CONR 8 R 9 , CONR 10 OR 11 , PO 3 H, SO 2 NHR 5 , CONHSO 2 R 5 , SO 2 NH 2 , CF3, SO 3 H, SO 2 NHCOR 5 , B(OH) 2 and tetrazolyl;
R 5 and R 6 are each independently chosen from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkenyl, C 1 -C 6 alkynyl, C 1 -C 7 cycloalkyl, C 1 -C 7 heterocycloalkyl, aryl, heteroaryl, aralkyl, and heteroaralkyl, any of which may be optionally substituted; or taken together, R 5 and R 6 may form a heterocycloalkyl or heteroaryl, either of which may be optionally substituted; and
R 7 , R 8 , R 9 , R 10 , and R 11 are each independently chosen from hydrogen, C 1 -C 6 alkyl, aryl, heteroaryl, aralkyl and heteroaralkyl, any of which may be optionally substituted.
15 . The compound as recited in claim 13 wherein said compound has structural formula VI:
R 1 and R 2 are each independently chosen from alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, OR 5 , SR 5 , and NR 5 R 6 , any of which may be optionally substituted, with the proviso that at least one of R 1 or R 2 is NR 5 R 6 ;
R 3 is chosen from hydrogen, halogen, trifluoromethyl, hydroxyl, C 1 -C 5 alkyl, and C 1 -C 5 alkoxy, any of which may be optionally substituted;
R 4 is chosen from COOR 7 , NO 2 , CONR 8 R 9 , CONR 10 OR 11 , PO 3 H, SO 2 NHR 5 , CONHSO 2 R 5 , SO 2 NH 2 , CF3, SO 3 H, SO 2 NHCOR 5 , B(OH) 2 and tetrazolyl;
R 5 and R 6 are each independently chosen from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkenyl, C 1 -C 6 alkynyl, C 1 -C 7 cycloalkyl, C 1 -C 7 heterocycloalkyl, aryl, heteroaryl, aralkyl, and heteroaralkyl, any of which may be optionally substituted; or taken together, R 5 and R 6 may form a heterocycloalkyl or heteroaryl, either of which may be optionally substituted; and
R 7 , R 8 , R 9 , R 10 , and R 11 are each independently chosen from hydrogen, C 1 -C 6 alkyl, aryl, heteroaryl, aralkyl and heteroaralkyl, any of which may be optionally substituted.
16 . The compound as recited in claim 1 wherein
X 1 and X 2 are N;
X 3 is C;
X 4 is a bond;
X 5 is chosen from CH and N; and
X 6 is chosen from NH, O, and S.
17 . The compound as recited in claim 16 wherein said compound has structural formula VII:
or a salt, ester or prodrug thereof, wherein:
X 5 is chosen from CH and N;
X 6 is chosen from NH, O, and S;
R 1 and R 2 are each independently chosen from alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, OR 5 , SR 5 , and NR 5 R 6 , any of which may be optionally substituted, with the proviso that at least one of R 1 or R 2 is NR 5 R 6 ;
R 4 is chosen from COOR 7 , NO 2 , CONR 8 R 9 , CONR 10 OR 11 , PO 3 H, SO 2 NHR 5 , CONHSO 2 R 5 , SO 2 NH 2 , CF3, SO 3 H, SO 2 NHCOR 5 , B(OH) 2 and tetrazolyl;
R 5 and R 6 are each independently chosen from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkenyl, C 1 -C 6 alkynyl, C 1 -C 7 cycloalkyl, C 1 -C 7 heterocycloalkyl, aryl, heteroaryl, aralkyl, and heteroaralkyl, any of which may be optionally substituted; or taken together, R 5 and R 6 may form a heterocycloalkyl or heteroaryl, either of which may be optionally substituted; and
R 7 , R 8 , R 9 , R 10 , and R 11 are each independently chosen from hydrogen, C 1 -C 6 alkyl, aryl, heteroaryl, aralkyl and heteroaralkyl, any of which may be optionally substituted.
18 . The compound as recited in claim 17 wherein said compound has structural formula VIII
or a salt, ester or prodrug thereof, wherein:
R 1 and R 2 are each independently chosen from alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, OR 5 , SR 5 , and NR 5 R 6 , any of which may be optionally substituted, with the proviso that at least one of R 1 or R 2 is NR 5 R 6 ;
R 4 is chosen from COOR 7 , NO 2 , CONR 8 R 9 , CONR 10 OR 11 , PO 3 H, SO 2 NHR 5 , CONHSO 2 R 5 , SO 2 NH 2 , CF3, SO 3 H, SO 2 NHCOR 5 , B(OH) 2 and tetrazolyl;
R 5 and R 6 are each independently chosen from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkenyl, C 1 -C 6 alkynyl, C 1 -C 7 cycloalkyl, C 1 -C 7 heterocycloalkyl, aryl, heteroaryl, aralkyl, and heteroaralkyl, any of which may be optionally substituted; or taken together, R 5 and R 6 may form a heterocycloalkyl or heteroaryl, either of which may be optionally substituted; and
R 7 , R 8 , R 9 , R 10 , and R 11 are each independently chosen from hydrogen, C 1 -C 6 alkyl, aryl, heteroaryl, aralkyl and heteroaralkyl, any of which may be optionally substituted.
19 . The compound as recited in claim 17 wherein said compound has structural formula IX
or a salt, ester or prodrug thereof, wherein:
R 1 and R 2 are each independently chosen from alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, OR 5 , SR 5 , and NR 5 R 6 , any of which may be optionally substituted, with the proviso that at least one of R 1 or R 2 is NR 5 R 6 ;
R 4 is chosen from COOR 7 , NO 2 , CONR 8 R 9 , CONR 10 OR 11 , PO 3 H, SO 2 NHR 5 , CONHSO 2 R 5 , SO 2 NH 2 , CF3, SO 3 H, SO 2 NHCOR 5 , B(OH) 2 and tetrazolyl;
R 5 and R 6 are each independently chosen from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkenyl, C 1 -C 6 alkynyl, C 1 -C 7 cycloalkyl, C 1 -C 7 heterocycloalkyl, aryl, heteroaryl, aralkyl, and heteroaralkyl, any of which may be optionally substituted; or taken together, R 5 and R 6 may form a heterocycloalkyl or heteroaryl, either of which may be optionally substituted; and
R 7 , R 8 , R 9 , R 10 , and R 11 are each independently chosen from hydrogen, C 1 -C 6 alkyl, aryl, heteroaryl, aralkyl and heteroaralkyl, any of which may be optionally substituted.
20 . The compound as recited in claim 17 wherein said compound has structural formula X
or a salt, ester or prodrug thereof, wherein:
R 1 and R 2 are each independently chosen from alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, OR 5 , SR 5 , and NR 5 R 6 , any of which may be optionally substituted, with the proviso that at least one of R 1 or R 2 is NR 5 R 6 ;
R 4 is chosen from COOR 7 , NO 2 , CONR 8 R 9 , CONR 10 OR 11 , PO 3 H, SO 2 NHR 5 , CONHSO 2 R 5 , SO 2 NH 2 , CF3, SO 3 H, SO 2 NHCOR 5 , B(OH) 2 and tetrazolyl;
R 5 and R 6 are each independently chosen from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkenyl, C 1 -C 6 alkynyl, C 1 -C 7 cycloalkyl, C 1 -C 7 heterocycloalkyl, aryl, heteroaryl, aralkyl, and heteroaralkyl, any of which may be optionally substituted; or taken together, R 5 and R 6 may form a heterocycloalkyl or heteroaryl, either of which may be optionally substituted; and
R 7 , R 8 , R 9 , R 10 , and R 11 are each independently chosen from hydrogen, C 1 -C 6 alkyl, aryl, heteroaryl, aralkyl and heteroaralkyl, any of which may be optionally substituted.
21 . The compound as recited in claim 17 wherein said compound has structural formula XI
or a salt, ester or prodrug thereof, wherein:
R 1 and R 2 are each independently chosen from alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, OR 5 , SR 5 , and NR 5 R 6 , any of which may be optionally substituted, with the proviso that at least one of R 1 or R 2 is NR 5 R 6 ;
R 4 is chosen from COOR 7 , NO 2 , CONR 8 R 9 , CONR 10 OR 11 , PO 3 H, SO 2 NHR 5 , CONHSO 2 R 5 , SO 2 NH 2 , CF3, SO 3 H, SO 2 NHCOR 5 , B(OH) 2 and tetrazolyl;
R 5 and R 6 are each independently chosen from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkenyl, C 1 -C 6 alkynyl, C 1 -C 7 cycloalkyl, C 1 -C 7 heterocycloalkyl, aryl, heteroaryl, aralkyl, and heteroaralkyl, any of which may be optionally substituted; or taken together, R 5 and R 6 may form a heterocycloalkyl or heteroaryl, either of which may be optionally substituted; and
R 7 , R 8 , R 9 , R 10 , and R 11 are each independently chosen from hydrogen, C 1 -C 6 alkyl, aryl, heteroaryl, aralkyl and heteroaralkyl, any of which may be optionally substituted.
22 . The compound as recited in claim 17 wherein said compound has structural formula XII
or a salt, ester or prodrug thereof, wherein:
R 1 and R 2 are each independently chosen from alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, OR 5 , SR 5 , and NR 5 R 6 , any of which may be optionally substituted, with the proviso that at least one of R 1 or R 2 is NR 5 R 6 ;
R 4 is chosen from COOR 7 , NO 2 , CONR 8 R 9 , CONR 10 OR 11 , PO 3 H, SO 2 NHR 5 , CONHSO 2 R 5 , SO 2 NH 2 , CF3, SO 3 H, SO 2 NHCOR 5 , B(OH) 2 and tetrazolyl;
R 5 and R 6 are each independently chosen from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkenyl, C 1 -C 6 alkynyl, C 1 -C 7 cycloalkyl, C 1 -C 7 heterocycloalkyl, aryl, heteroaryl, aralkyl, and heteroaralkyl, any of which may be optionally substituted; or taken together, R 5 and R 6 may form a heterocycloalkyl or heteroaryl, either of which may be optionally substituted; and
R 7 , R 8 , R 9 , R 10 , and R 11 are each independently chosen from hydrogen, C 1 -C 6 alkyl, aryl, heteroaryl, aralkyl and heteroaralkyl, any of which may be optionally substituted.
23 . The compound as recited in claim 17 wherein said compound has structural formula XII
or a salt, ester or prodrug thereof, wherein:
R 1 and R 2 are each independently chosen from alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, OR 5 , SR 5 , and NR 5 R 6 , any of which may be optionally substituted, with the proviso that at least one of R 1 or R 2 is NR 5 R 6 ;
R 4 is chosen from COOR 7 , NO 2 , CONR 8 R 9 , CONR 10 OR 11 , PO 3 H, SO 2 NHR 5 , CONHSO 2 R 5 , SO 2 NH 2 , CF3, SO 3 H, SO 2 NHCOR 5 , B(OH) 2 and tetrazolyl;
R 5 and R 6 are each independently chosen from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkenyl, C 1 -C 6 alkynyl, C 1 -C 7 cycloalkyl, C 1 -C 7 heterocycloalkyl, aryl, heteroaryl, aralkyl, and heteroaralkyl, any of which may be optionally substituted; or taken together, R 5 and R 6 may form a heterocycloalkyl or heteroaryl, either of which may be optionally substituted; and
R 7 , R 8 , R 9 , R 10 , and R 11 are each independently chosen from hydrogen, C 1 -C 6 alkyl, aryl, heteroaryl, aralkyl and heteroaralkyl, any of which may be optionally substituted.
24 . A compound as recited in claim 1 for use as a medicament.
25 . A compound as recited in claim 1 for use in the manufacture of a medicament for the prevention or treatment of a disease or condition ameliorated by the inhibition of PASK.
26 . A compound as recited in claim 1 for use in the manufacture of a medicament for the prevention or treatment of a disease or condition ameliorated by the inhibition of PASK.
27 . A pharmaceutical composition comprising a compound as recited in claim 1 - 23 together with a pharmaceutically acceptable carrier.
28 . A method of inhibiting PASK comprising contacting PASK with a compound as recited in claims 1 - 23 .
29 . A method of treatment of a disease comprising the administration of a therapeutically effective amount of a compound as recited in claims 1 - 23 to a patient in need thereof.
30 . The method as recited in claim 29 wherein said disease is chosen from cancer and a metabolic disease.
31 . The method as recited in claim 29 wherein said disease is a metabolic disease.
32 . The method as recited in claim 31 wherein said metabolic disease is chosen from metabolic syndrome, diabetes, dyslipidemia, fatty liver disease, non-alcoholic steatohepatitis, obesity, and insulin resistance.
33 . The method of claim 32 wherein said diabetes is Type II diabetes.
34 . The method of claim 32 wherein said dyslipidemia is hyperlipidemia.
35 . A method for achieving an effect in a patient comprising the administration of a therapeutically effective amount of a compound as recited in any of claims 1 - 23 to a patient, wherein the effect is selected from the group consisting of reduction of triglycerides, reduction of cholesterol, and reduction of hemoglobin A1c.
36 . The method of claim 35 wherein said cholesterol is chosen from LDL and VLDL cholesterol.
37 . The method of claim 35 wherein said triglycerides are chosen from plasma triglycerides and liver triglycerides.
38 . A method of treatment of a PASK-mediated disease comprising the administration of:
a. a therapeutically effective amount of a compound as recited in claim 1 ; and b. another therapeutic agent.Cited by (0)
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