Patent EA-001739-B1 (EA)
Title: Substituted sulfonic acid n-[(aminoiminomethyl)phenylalkyl]-azaheterocyclamide compounds
Inventor: EWING WILLIAM R
IPC: C07D223/10
Filed: 1997-12-01
Abstract: 1. A compound of formula I   wherein    is phenyl or monocyclic heteroaryl; R is hydrogen, optionally substituted alkyl, optionally substituted aralkyl, optionally substituted heteroaralkyl, R6O(CH2)x-, R6O2C(CH2)x-, Y<1>Y<2>NC(O)(CH2)x-, or Y<1>Y<2>N(CH2)x-; R1 is hydrogen, alkyl, hydroxy, alkoxy, Y<1>Y<2>N-, halogen, -CO2R6, -C(O)NY<1>Y<2>, -(CH2)xOR6, -(CH2)xNY<1>Y<2>, or -CN; R2 and R3 are independently selected from hydrogen, hydroxy, alkoxy, Y<1>Y<2>N-, halogen, -CO2R6, -C(O)NY<1>Y<2>, -(CH2)xOR6, -(CH2)xNY<1>Y<2>, -CN, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted aralkenyl or optionally substituted heteroaralkenyl, or R2 and R3 taken together with the carbon atoms through which they are linked form an optionally substituted 5 to 7 membered fused cycloalkyl, optionally substituted 5 to 7 membered fused heterocyclyl ring or an optionally substituted 6 membered fused aryl, or an optionally substituted 5 to 7 membered fused heteroaryl ring; R4 is hydrogen or optionally substituted lower alkyl, optionally substituted aralkyl or optionally substituted heteroaralkyl; X1 and X1a are independently selected from hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl or optionally substituted heteroaralkyl, or X1 and X1a taken together form oxo; X2 and X2a are hydrogen, or taken together form oxo; X3 is hydrogen, hydroxy, optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl or optionally substituted heteroaralkyl, or X3 and one of X1 and X1a taken together with the carbon atoms through which X3 and one of X1 and X1a are linked form a 4 to 7 membered cycloalkyl or heterocyclyl ring; X4 is hydrogen, optionally substituted alkyl or an optionally substituted aralkyl; X5 and X5a are hydrogen or taken together are =NR5; R5 is hydrogen, R6O2C-, R6O-, cyano, R6CO-, optionally substituted lower alkyl, nitro or Y<1>Y<2>N-; Y<1> and Y<2> are independently hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl or optionally substituted heteroaralkyl, or Y<1> and Y<2> taken together with the N through which Y<1> and Y<2> are linked form a 4 to 7 membered heterocyclyl; X6 and X6a are independently hydrogen, R7R8N-, R9O-, R7R8NCO-, R7R8NSO2-, R7R8NSO2N-, R7R8SO2O-, R9CO-, -CO2R6, -C(O)NY<1>Y<2>, -(CH2)xCO2R6, -(CH2)xC(O)NY<1>Y<2>, -(CH2)xOR6, -(CH2)xNY<1>Y<2>, halo, cyano or nitro; R6 is hydrogen, optionally substituted alkyl, optionally substituted aralkyl or optionally substituted heteroaralkyl; R7 and R8 are independently hydrogen or optionally substituted lower alkyl, or one of R7 and R8 is hydrogen and the other of R7 and R8 is R10(O)CCH2- or lower acyl; R9 is hydrogen, optionally substituted lower alkyl, optionally substituted lower acyl or R10(O)CCH2-; R10 is hydrogen, optionally substituted lower alkyl, optionally substituted alkoxy or hydroxy; A is S or -CH=CH-; m is 0, 1, 2 or 3; n is 0, 1, 2 or 3; and x is 1, 2, 3, 4, or 5, or wherein if it is not defined separately, alkyl can be straight or branched and contains 1 to 20 carbon atoms and lower alkyl contains from 1 to 4 carbon atoms, cycloalkyl is saturated or partly unsaturated mono- or polycyclic system, which comprises 3 to 10 carbon atoms, heterocyclyl is non-aromatic, saturated or partly unsaturated mono- or polycyclic system, which comprises 3 to 10 ring atoms, at least one of which is oxygen atom, sulfur or nitrogen atom, alkoxy is an alkoxyl group, wherein alkyl is such as determined above, and lower alkoxy comprises 1 to 4 carbon atoms, acyl is an acyl group, wherein alkyl is such as determined above, and lower acyl comprises 1 to 4 carbon atoms, aryl is an aromatic mono- or polycyclic system, which comprises 6 to 10 carbon atoms, aralkyl is an aralkyl group, wherein aryl and alkyl are such as determined above, heteroaryl is a heteroaromatic mono- or polycyclic system, which comprises 5 to 10 ring atoms, at least one of which is oxygen atom, sulfur or nitrogen atom, heteroaralkyl is a heteroaralkyl group, wherein heteroaryl and alkyl are such as determined above, aralkenyl is an aralkenyl group, wherein aryl is such as determined above, and alkenyl is alkyl, determined above, which comprises at least one double bond in aliphatic chain, heteroaralkyl is a heteroaralkyl group, wherein heteroaryl and alkyl are such as determined above, heteroalkenyl is a heteroalkenyl group, wherein heteroaryl and alkenyl are such as determined above, a pharmaceutically acceptable salt thereof, an N-oxide thereof, a hydrate thereof or a solvate thereof. 2. The compound of Claim 1 wherein n=1 and m=1. 3. The compound of Claim 1 wherein X2 and X2a taken together are oxo. 4. The compound of Claim 1 wherein X1 X1a, X4 are hydrogen, and X3 is hydrogen or alkyl. 5. The compound of Claim 1 wherein X5 and X5a taken together are =NR5 wherein R5 is R6O2C-. 6. The compound of Claim 1 wherein X5 and X5a taken together are =NR5 wherein R5 is -OH. 7. The compound of Claim 1 wherein X5 and X5a taken together are =NR5 wherein R5 is H. 8. The compound of Claim 1 wherein   is phenyl and the carbon substituted with X5, X5a and R4HN- is attached in meta-position relative to the attachment of the -(CH)nN- moiety to the phenyl. 9. The compound of Claim 1 wherein   is thienyl and the carbon substituted with X5, X5a and R4HN- is attached in the 2 position relative to the sulfur of the thienyl and the attachment of the -(CH)nN- moiety is to the 4 position of the thienyl. 10. The compound of Claim 1 wherein R is hydrogen, methyl, aralkyl, heteroaralkyl, HO2CCH2-, H2NCO(O)CH2-, or R6HNC(O)CH2-. 11. The compound of Claim 1 wherein R1 is hydrogen, alkyl, or halogen. 12. The compound of Claim 1 wherein R2 and R3 are independently hydrogen, halogen, alkoxy, amino, aryl, or heteroaryl. 13. The compound of Claim 1 wherein R2 and R3 form an optionally substituted fused aryl or an optionally substituted fused heteroaryl wherein the substituent is halogen, alkyl, amino, hydroxy, or alkoxy. 14. The compound of Claim 1 wherein R2 and R3 form an optionally substituted fused cycloalkyl or an optionally substituted fused heterocyclyl in which the heteroatom is nitrogen wherein the substituent is hydrogen, Y<1>Y<2>N, or alkyl. 15. The compound of Claim 1 wherein   is phenyl and one of X6 and X6a is amino or hydroxy in a para position relative to the moiety   16. The compound of Claim 1 wherein X6 and X6a are hydrogen. 17. The compound of Claim 1 wherein A is -CH=CH-; and R2 and R3 taken together with the carbon atoms through which R2 and R3 are linked form an optionally substituted 5 or 6 membered heteroaryl ring or an optionally substituted 6 membered aryl ring. 18. The compound of Claim 1 wherein A is -CH=CH-; R2 is hydrogen; and R3 is an optionally substituted heteroaryl ring or an optionally substituted 6 membered aryl ring. 19. The compound of Claim 1 wherein A is S. 20. The compound of Claim 1 wherein A is S; and R2 and R3 taken together with the carbon atoms through which R2 and R3 are linked form an optionally substituted 5 or 6 membered heteroaryl ring or an optionally substituted 6 membered aryl ring. 21. The compound of Claim 1 wherein A is S; R2 is hydrogen; and R3 is an optionally substituted heteroaryl ring or an optionally substituted 6 membered aryl ring. 22. A compound according to Claim 1 which is 3-[3-(S)-(benzo[b]thiophene-2-sulfonylamino)-2-oxopyrrolidin-1-ylmethyl]benzamidine trifluoroacetate; 3-[3-(S)-[(benzo[b]thiophene-2-sulfonyl)methylamino]-2-oxopyrrolidin-1-ylmethyl]benzamidine trifluoroacetate; 4-[3-(S)-(benzo[b]thiophene-2-sulfonylamino)-2-oxopyrrolidin-1-ylmethyl]thiophene-2-carboxamidine trifluoroacetate; 4-[3-(S)-[(benzo[b]thiophene-2-sulfonyl]methylamino]-2-oxopyrrolidin-1-ylmethyl]thiophene-2-carboxamidine trifluoroacetate; 3-[3-(S)-(4-chlorobenzo[b]thiophene-2-sulfonylamino)-2-oxopyrrolidin-1-ylmethyl]benzamidine trifluoroacetate; 3-[3-(S)-(6-chlorobenzo[b]thiophene-2-sulfonylamino)-2-oxopyrrolidin-1-ylmethyl]benzamidine trifluoroacetate; 3-[3-(S)-[(4-chlorobenzo[b]thiophene-2-sulfonyl)methylamino]-2-oxopyrrolidin-1-ylmethyl]benzamidine trifluoroacetate; 3-[3-(S)-[(6-chlorobenzo[b]thiophene-2-sulfonyl)methylamino]-2-oxopyrrolidin-1-ylmethyl]benzamidine trifluoroacetate; 3-[3-(S)-(5-chlorobenzo[b]thiophene-2-sulfonylamino)-2-oxopyrrolidin-1-ylmethyl]benzamidine trifluoroacetate; 3-[3-(S)-[(5-chlorobenzo[b]thiophene-2-sulfonyl)methylamino]-2-oxopyrrolidin-1-ylmethyl]benzamidine trifluoroacetate; 3-[3-(S)-(4-methylbenzo[b]thiophene-2-sulfonylamino)-2-oxopyrrolidin-1-ylmethyl]benzamidine trifluoroacetate; 3-[3-(S)-(6-methylbenzo[b]thiophene-2-sulfonylamino)-2-oxopyrrolidin-1-ylmethyl]benzamidine trifluoroacetate; 3-[3-(S)-(5-methylbenzo[b]thiophene-2-sulfonylamino)-2-oxopyrrolidin-1-ylmethyl]benzamidine trifluoroacetate; 3-[3-(S)-(4,6-dichlorobenzo[b]thiophene-2-sulfonylamino)-2-oxopyrrolidin-1-ylmethyl]benzamidine trifluoroacetate; ([3-[3-(S)-(4,6-dichlorobenzo[b]thiophene-2-sulfonylamino)-2-oxopyrrolidin-1-ylmethyl]phenyl)iminomethyl]carbamic acid 2,2,2-trichloroethyl ester; 4-amino-3-[3-(S)-(4,6-dichlorobenzo[b]thiophene-2-sulfonylamino)-2-oxopyrrolidin-1-ylmethyl]benzamidine trifluoroacetate; 4-hydroxy-3-[3-(S)-(4,6-dichlorobenzo[b]thiophene-2-sulfonylamino)-2-oxopyrrolidin-1-ylmethyl]benzamidine trifluoroacetate; 3-[3-(S)-(6-fluorobenzo[b]thiophene-2-sulfonylamino)-2-oxopyrrolidin-1-ylmethyl]benzamidine trifluoroacetate; 4-amino-3-[3-(S)-(6-fluorobenzo[b]thiophene-2-sulfonylamino)-2-oxopyrrolidin-1-ylmethyl]benzamidine trifluoroacetate; 4-hydroxy-3-[3-(S)-(6-fluorobenzo[b]thiophene-2-sulfonylamino)-2-oxopyrrolidin-1-ylmethyl]benzamidine trifluoroacetate; 4-amino-3-[3-(S)-(4-chlor