Claims for Patent: 8,110,682

Summary for Patent: 8,110,682

Title:	Preparation and use of compounds as aspartyl protease inhibitors
Abstract:	Disclosed are compounds of the formula I ##STR00001## or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof, wherein A is a bond, --C(O)--, or --C(R.sup.3\')(R.sup.4\')--; X is --N(R.sup.1)-- or --C(R.sup.6)(R.sup.7)--; Y is --S(O).sub.2--, --C(.dbd.O)--, --PO(OR.sup.9) or --C(R.sup.6\'R.sup.7\')--; is a single or double bond and R, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.3\', R.sup.4\', R.sup.5, R.sup.6, R.sup.6\', R.sup.7 and R.sup.7\' are as defined in the specification; and pharmaceutical compositions comprising the compounds of formula I. Also disclosed is the method of inhibiting aspartyl protease, and in particular, the methods of treating cardiovascular diseases, cognitive and neurodegenerative diseases, and the methods of inhibiting of Human Immunodeficiency Virus, plasmepins, cathepsin D and protozoal enzymes. Also disclosed are methods of treating cognitive or neurodegenerative diseases using the compounds of formula I in combination with a cholinesterase inhibitor or a muscarinic antagonist.
Inventor(s):	McKittrick; Brian (New Vernon, NJ), Zhu; Zhaoning (Plainsboro, NJ), Stamford; Andrew (Chatham Township, NJ), Smith; Elizabeth M. (Verona, NJ)
Assignee:	Schering Corporation (Kenilworth, NJ)
Application Number:	11/451,262
Patent Claims:	1. A compound having the structural Formula IA: ##STR00052## or a stereoisomer, tautomer, or pharmaceutically acceptable salt of said compound, said stereoisomer, or said tautomer, wherein Y is --C(.dbd.O)-- or --C(R.sup.6'R.sup.7')--; R.sup.1 is selected from the group consisting of alkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, arylcycloalkylalkyl, heteroarylcycloalkylalkyl, arylheterocycloalkylalkyl, heteroarylheterocycloalkylalkyl, cycloalkyl, arylcycloalkyl, heteroarylcycloalkyl, heterocycloalkyl, arylheterocycloalkyl, heteroarylheterocycloalkyl, alkenyl, arylalkenyl, cycloalkenyl, arylcycloalkenyl, heteroarylcycloalkenyl, heterocycloalkenyl, arylheterocycloalkenyl, heteroarylheterocycloalkenyl, alkynyl, arylalkynyl, aryl, cycloalkylaryl, heterocycloalkylaryl, heterocycloalkenylaryl, heteroaryl, cycloalkylheteroaryl, heterocycloalkylheteroaryl, cycloalkenylaryl, heterocycloalkenylaryl, --OR.sup.15, --C(O)R.sup.8, --C(O)OR.sup.9, --S(O)R.sup.10, --S(O).sub.2R.sup.10, --C(O)N(R.sup.11)(R.sup.12), --S(O)N(R.sup.11)(R.sup.12), --S(O).sub.2N(R.sup.11)(R.sup.12), --NO.sub.2, --N.dbd.C(R.sup.8).sub.2 and --N(R.sup.8).sub.2; R.sup.2 is H; R.sup.5 is selected from the group consisting of H, alkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, arylcycloalkylalkyl, heteroarylcycloalkylalkyl, arylheterocycloalkylalkyl, heteroarylheterocycloalkylalkyl, cycloalkyl, arylcycloalkyl, heteroarylcycloalkyl, heterocycloalkyl, arylheterocycloalkyl, heteroarylheterocycloalkyl, alkenyl, arylalkenyl, cycloalkenyl, arylcycloalkenyl, heteroarylcycloalkenyl, heterocycloalkenyl, arylheterocycloalkenyl, heteroaryiheterocycloalkenyl, alkynyl, arylalkynyl, aryl, cycloalkylaryl, heterocycloalkylaryl, heterocycloalkenylaryl, heteroaryl, cycloalkylheteroaryl, heterocycloalkylheteroaryl, cycloalkenylaryl, heterocycloalkenylaryl, --OR.sup.15, --CN, --C(O)R.sup.8, --C(O)OR.sup.9, --S(O)R.sup.10, --S(O).sub.2R.sup.10, --C(O)N(R.sup.11)(R.sup.12), --S(O)N(R.sup.11)(R.sup.12), --S(O).sub.2N(R.sup.11)(R.sup.12), --NO.sub.2, --N.dbd.C(R.sup.8).sub.2 and --N(R.sup.8).sub.2; R.sup.3 and R.sup.4 are each independently selected from the group consisting of alkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, arylcycloalkylalkyl, heteroarylcycloalkylalkyl, arylheterocycloalkylalkyl, heteroarylheterocycloalkylalkyl, cycloalkyl, arylcycloalkyl, heteroarylcycloalkyl, arylheterocycloalkyl, heteroarylheterocycloalkyl, alkenyl, arylalkenyl, cycloalkenyl, arylcycloalkenyl, heteroarylcycloalkenyl, heterocycloalkenyl, arylheterocycloalkenyl, heteroarylheterocycloalkenyl, alkynyl, arylalkynyl, aryl, cycloalkylaryl, heterocycloalkylaryl, heterocycloalkenylaryl, heteroaryl, cycloalkylheteroaryl,heterocycloalkylheteroaryl, cycloalkenylaryl, heterocycloalkenylaryl, cycloalkenylheteroaryl, --CH.sub.2--O--Si(R.sup.9)(R.sup.10)(R.sup.19), --CN, --C(O)R.sup.8, --C(O)OR.sup.9, --C(O)N(R.sup.11)(R.sup.12), --SR.sup.19, --S(O)N(R.sup.11)(R.sup.12), --S(O).sub.2N(R.sup.11)(R.sup.12), --N(R.sup.11)(R.sup.12), --N(R.sup.11)C(O)R.sup.8, --N(R.sup.11)S(O)R.sup.10, --N(R.sup.11)S(O).sub.2R.sup.10--, --N(R.sup.11)C(O)N(R.sup.12)(R.sup.13), --N(R.sup.11)C(O)OR.sup.9 and --C(.dbd.NOH)R.sup.8; R.sup.6' and R.sup.7' , together with the carbon atom to which they are attached, form a 3- to 7-membered cycloalkyl ring optionally substituted by 1 to 5 R.sup.14 moieties or oxo; or, optionally, R.sup.6' and R.sup.7, together with the carbon atom to which they are attached, form a 3- to 7-membered cycloalkylether group having one oxygen atom optionally substituted by 1 to 5 R.sup.14 moieties or oxo; or optionally, R.sup.3 and R.sup.4, together with the carbon atom to which they are attached, form a 3--to 7--membered cycloalkyl ring optionally substituted by 1 to 5 R.sup.14 moieties and/or oxo; or, optionally, R.sup.3 and R.sup.4, together with the carbon atom to which they are attached, form a 3- to 7-membered cycloalkylether group having one oxygen atom optionally substituted by 1 to 5 R.sup.14 moieties and/or oxo; or, optionally, R.sup.4 and R.sup.5, together with the atoms to which they are shown attached, form a 4- to 7-membered heterocyclyl, heterocyclenyl or heteroaryl ring having, in addition to the N atom, 1 or 2 additional hetero atoms selected from the group consisting of O, N, --N(R)--and S, wherein said rings are optionally substituted by 1 to 5 independently selected R.sup.14 moieties and/or by oxo when said rings are heterocyclyl or heterocyclenyl; or, optionally, when R.sup.4 and R.sup.5 together form a 4- to 7-membered heterocyclyl, heterocyclenyl or heteroaryl ring and X is N(R.sup.1) and Y is --C(R.sup.6')(R.sup.7)--, then R.sup.1 and R.sup.6' together form a 3- to 7-membered cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, aryl or heteroaryl ring having 0 to 3 heteroatoms selected from the group consisting of O, N, --N(R)--and S, wherein said rings are optionally substituted by 1 to 5 independently selected R.sup.14 moieties and/or by oxo when said rings are cycloalkyl, cycloalkenyl, heterocyclyl or heterocyclenyl, provided that i) R.sup.4 and R.sup.5 and ii) R.sup.5 and R.sup.6' do not simultaneously cyclize to form a ring; or, optionally, R.sup.3 and R.sup.4, together, with the carbon atom to which they are shown attached, or, optionally, R.sup.6' and R.sup.7', together with the carbon atom to which they are attached, from one of the following multicyclic groups: ##STR00053## wherein: M is independently --(CH.sub.2)--, --S--, --N(R.sup.19)--, --O--, --S(O)--, --S(O).sub.2--, or --C(O)--; q is 0, 1, or 2; A and B are independently aryl, heteroaryl, cycloalkyl, cycloalkenyl or heterocyclyl; E is aryl or heteroaryl; and F is cycloalkyl, cycloalkenyl, heterocyclyl or heterocyclenyl provided that R.sup.3 and R.sup.4 and R.sup.6' and R.sup.7' are not simultaneously combined to form said multicyclic croups: ##STR00054## each R is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, arylcycloalkyl, --OR.sup.15, --C(O)R.sup.8, --C(O)OR.sup.9, --S(O)R.sup.10, --S(O).sub.2R.sup.10, --C(O)N(R.sup.11)(R.sup.12), --S(O)N(R.sup.11)(R.sup.12), or --S(O).sub.2N(R.sup.11)(R.sup.12); R.sup.8 is independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, --OR.sup.15, --N(R.sup.15)(R.sup.16), --N(R.sup.15)C(O)R.sup.16, --N(R.sup.15)S(O)R.sup.16, --N(R.sup.15)S(O).sub.2R.sup.16, --N(R.sup.15)S(O).sub.2N(R.sup.16)(R.sup.17), --N(R.sup.15)S(O)N(R.sup.16)(R.sup.17), --N(R.sup.15)C(O)N(R.sup.16)(R.sup.17) and --N(R.sup.15)C(O)OR.sup.16; R.sup.9 is independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl; R.sup.10 is independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl and --N(R.sup.15)(R.sup.16); R.sup.11, R.sup.12 and R.sup.13 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, --C(O)R.sup.8, --C(O)OR.sup.9, --S(O)R.sup.10, --S(O).sub.2R.sup.10, --C(O)N(R.sup.15)(R.sup.16), --S(O)N(R.sup.15)(R.sup.16), and --S(O).sub.2N(R.sup.15)(R.sup.16); R.sup.14 is 1-5 substituents independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, halo, --CN, --OR.sup.15, --C(O)R.sup.15, --C(O)OR.sup.15, --C(O)N(R.sup.15)(R.sup.16), --SR.sup.15, --S(O)N(R.sup.15)(R.sup.16), --S(O).sub.2N(R.sup.15)(R.sup.16), --C(.dbd.NOR.sup.15)R.sup.16, --P(O)(OR.sup.15)(OR.sup.16), --N(R.sup.15)(R.sup.16), --N(R.sup.15)C(O)R.sup.16, --N(R.sup.15)S(O)R.sup.16, --N(R.sup.15)S(O).sub.2R.sup.16, --N(R.sup.15)S(O).sub.2N(R.sup.16)(R.sup.17), --N(R.sup.15)S(O)N(R.sup.16)(R.sup.17), --N(R.sup.15)C(O)N(R.sup.16)(R.sup.17) and --N(R.sup.15)C(O)OR.sup.16; R.sup.15, R.sup.16 and R.sup.17 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, arylcycloalkyl, arylheterocycloalkyl, R.sup.18-alkyl, R.sup.18-cycloalkyl, R.sup.18-cycloalkylalkyl, R.sup.18-heterocycloalkyl, R.sup.18-heterocycloalkylalkyl, R.sup.18-aryl, R.sup.18-arylalkyl, R.sup.18-heteroaryl and R.sup.18-heteroarylalkyl; or R.sup.15, R.sup.16 and R.sup.17 are ##STR00055## wherein R.sup.23 numbers 0 to 5 substituents, m is 0 to 6 and n is 1 to 5; R.sup.18 is 1-5 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, --NO.sub.2, halo, heteroaryl, HO-alkyoxyalkyl, --CF.sub.3, --CN, alkyl-CN, --C(O)R.sup.19, --C(O)OH, --C(O)OR.sup.19, --C(O)NHR.sup.20, --C(O)NH.sub.2, --C(O)NH.sub.2--C(O)N(alkyl).sub.2, --C(O)N(alkyl)(aryl), --C(O)N(alkyl)(heteroaryl), --SR.sup.19, --S(O).sub.2R.sup.20, --S(O)NH.sub.2, --S(O)NH(alkyl), --S(O)N(alkyl)(alkyl), --S(O)NH(aryl), --S(O).sub.2NH.sub.2, --S(O).sub.2NHR.sup.19, --S(O).sub.2NH(heterocycloalkyl), --S(O).sub.2N(alkyl).sub.2, --S(O).sub.2N(alkyl)(aryl), --OCF.sub.3, --OH, --OR.sup.20, --O--heterocycloalkyl, --O--cycloalkylalkyl, --O--heterocycloalkylalkyl, --NH.sub.2, --NHR.sup.20, --N(alkyl).sub.2, --N(arylalkyl).sub.2, --N(arylalkyl)-(heteroarylalkyl), --NHC(O)R.sup.20, --NHC(O)NH.sub.2, --NHC(O)NH(alkyl), --NHC(O)N(alkyl)(alkyl), --N(alkyl)C(O)NH(alkyl), --N(alkyl)C(O)N(alkyl)(alkyl), --NHS(O).sub.2R.sup.20, --NHS(O).sub.2NH(alkyl), --NHS(O).sub.2N(alkyl)(alkyl), --N(alkyl)S(O).sub.2NH(alkyl) and --N(alkyl)S(O).sub.2N(alkyl)(alkyl); or two R.sup.18 moieties on adjacent carbons can be linked together to form ##STR00056## R.sup.19 is alkyl, cycloalkyl, aryl, arylalkyl or heteroarylalkyl; R.sup.20 is alkyl, cycloalkyl, aryl, halo substituted aryl, arylalkyl, heteroaryl or heteroarylalkyl; and wherein: i) each of the alkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, arylcycloalkylalkyl, heteroarylcycloalkylalkyl, arylheterocycloalkylalkyl, heteroarylheterocycloalkylalkyl, cycloalkyl, arylcycloalkyl, heteroarylcycloalkyl, heterocycloalkyl, arylheterocycloalkyl, heteroarylheterocycloalkyl, alkenyl, arylalkenyl, cycloalkenyl, arylcycloalkenyl, heteroarylcycloalkenyl, heterocycloalkenyl, arylheterocycloalkenyl, heteroarylheterocycloalkenyl, alkynyl, Arylalkynyl, Aryl, cycloalkylaryl, heterocycloalkylaryl, cycloalkenylaryl, heterocycloalkenylaryl, heteroaryl, cycloalkylheteroaryl, heterocycloalkylheteroaryl, heterocycloalkenylaryl, in R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, and R.sup.6, and ii) each of the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, arylcycloalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkenyl and alkynyl groups in R, R.sup.8, R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13 and R.sup.14, are independently unsubstituted or substituted by 1 to 5 R.sup.21 groups independently selected from the group consisting of alkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, arylcycloalkylalkyl, heteroarylcycloalkylalkyl, arylheterocycloalkylalkyl, heteroarylheterocycloalkylalkyl, cycloalkyl, arylcycloalkyl, heteroarylcycloalkyl, heterocycloalkyl, arylheterocycloalkyl, heteroarylheterocycloalkyl, alkenyl, arylalkenyl, cycloalkenyl, arylcycloalkenyl, heteroarylcycloalkenyl, heterocycloalkenyl, arylheterocycloalkenyl, heteroarylheterocycloalkenyl, alkynyl, arylalkynyl, aryl, cycloalkylaryl, heterocycloalkylaryl, cycloalkenylaryl, heterocycloalkenylaryl, heteroaryl, cycloalkylheteroaryl, heterocycloalkylheteroaryl, cycloalkenylaryl, heterocycloalkenylaryl, halo, --CN, --OR.sup.15, --C(O)R.sup.15, --C(O)OR.sup.15, --C(O)N(R.sup.15)(R.sup.16), --SR.sup.15, --S(O)N(R.sup.15)(R.sup.16), --CH(R.sup.15)(R.sup.16), --S(O).sub.2N(R.sup.15)(R.sup.16), --C(.dbd.NOR.sup.15)R.sup.16, --P(O)(OR.sup.15)(OR.sup.16), --N(R.sup.15)(R.sup.16), -alkyl-N(R.sup.15)(R.sup.16), --N(R.sup.15)C(O)R.sup.16, --CH.sub.2--N(R.sup.15)C(O)R.sup.16, --CH.sub.2--N(R.sup.15)C(O)N(R.sup.16)(R.sup.17), --CH.sub.2--R.sup.15; --CH.sub.2N(R.sup.15)(R.sup.16), --N(R.sup.15)S(O)R.sup.16, --N(R.sup.15)S(O).sub.2R.sup.16, --CH.sub.2--N(R.sup.15)S(O).sub.2R.sup.16, --N(R.sup.15)S(O).sub.2N(R.sup.16)(R.sup.17), --N(R.sup.15)S(O)N(R.sup.16)(R.sup.17), --N(R.sup.15)C(O)N(R.sup.16)(R.sup.17), --CH.sub.2--N(R.sup.15)C(O)N(R.sup.16)(R.sup.17), --N(R.sup.15)C(O)OR.sup.16, --CH.sub.2--N(R.sup.15)C(O)OR.sup.16, --S(O)R.sup.15, --N.sub.3, --NO.sub.2 and --S(O).sub.2R.sup.15; and wherein each of the alkyl, cycloalkenyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkenyl and alkynyl groups in R.sup.21 are independently unsubstituted or substituted by 1 to 5 R.sup.22 groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, heteroaryl, halo, --CF.sub.3, --CN, --OR.sup.15, --C(O)R.sup.15, --C(O)OR.sup.15, -alkyl-C(O)OR.sup.15, C(O)N(R.sup.15)(R.sup.16), --SR.sup.15, --S(O)N(R.sup.15)(R.sup.16), --S(O).sub.2N(R.sup.15)(R.sup.16), --C(.dbd.NOR.sup.15)R.sup.16, --P(O)(OR.sup.15)(OR.sup.16), --N(R.sup.15)(R.sup.16), -alkyl-N(R.sup.15)(R.sup.16), --N(R.sup.15)C(O)R.sup.16, --CH.sub.2--N(R.sup.15)C(O)R.sup.16, --N(R.sup.15)S(O)R.sup.16, --N(R.sup.15)S(O).sub.2R.sup.16, --CH.sub.2--N(R.sup.15)S(O).sub.2R.sup.16, --N(R.sup.15)S(O).sub.2N(R.sup.16)(R.sup.17), --N(R.sup.15)S(O)N(R.sup.16)(R.sup.17), --N(R.sup.15)C(O)N(R.sup.16)(R.sup.17), --CH.sub.2--N(R.sup.15)C(O)N(R.sup.16)(R.sup.17), --N(R.sup.15)C(O)OR.sup.16, --CH.sub.2--N(R.sup.15)C(O)OR.sup.16, --N.sub.3, --NO.sub.2, --S(O)R.sup.15 and --S(O).sub.2R.sup.15; or two R.sup.21 or two R.sup.22 moieties on adjacent carbons can be linked together to form ##STR00057## and when R.sup.21 or R.sup.22 are selected from the group consisting of --C(.dbd.NOR.sup.15)R.sup.16, --N(R.sup.15)C(O)R.sup.16, --CH.sub.2--N(R.sup.15)C(O)R.sup.16, --N(R.sup.15)S(O)R.sup.16, --N(R.sup.15)S(O).sub.2R.sup.16, --CH.sub.2--N(R.sup.15)S(O).sub.2R.sup.16, --N(R.sup.15)S(O).sub.2N(R.sup.16)(R.sup.17), --N(R.sup.15)S(O)N(R.sup.16)(R.sup.17), --N(R.sup.15)C(O)N(R.sup.16)(R.sup.17), --CH.sub.2--N(R.sup.15)C(O)N(R.sup.16)(R.sup.17), --N(R.sup.15)C(O)OR.sup.16 and --CH.sub.2--N(R.sup.15)C(O)OR.sup.16, R.sup.15 and R.sup.16 together can be a C.sub.2 to C.sub.4 chain wherein, optionally, one, two or three ring carbons can be replaced by --C(O)-- or --N(H)-- and R.sup.15 and R.sup.16, together with the atoms to which they are attached, form a 5 to 7 membered ring, optionally substituted by R.sup.23; R.sup.23 is 1 to 5 groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, halo, --CN, --OR.sup.24, --C(O)R.sup.24, --C(O)OR.sup.24, --C(O)N(R.sup.24)(R.sup.25), --SR.sup.24, --S(O)N(R.sup.24)(R.sup.25), --S(O).sub.2N(R.sup.24)(R.sup.25), --C(.dbd.NOR.sup.24)R.sup.25, --P(O)(OR.sup.24)(OR.sup.25), --N(R.sup.24)(R.sup.25), -alkyl-N(R.sup.24)(R.sup.25), --N(R.sup.24)C(O)R.sup.25, --CH.sub.2--N(R.sup.24)C(O)R.sup.25, --N(R.sup.24)S(O)R.sup.25, --N(R.sup.24)S(O).sub.2R.sup.25, --CH.sub.2--N(R.sup.24)S(O).sub.2R.sup.25, --N(R.sup.24)S(O).sub.2N(R.sup.25)(R.sup.26), --N(R.sup.24)S(O)N(R.sup.25)(R.sup.26), --N(R.sup.24)C(O)N(R.sup.25)(R.sup.26), --CH.sub.2--N(R.sup.24)C(O)N(R.sup.25)(R.sup.26), --N(R.sup.24)C(O)OR.sup.25, --CH.sub.2--N(R.sup.24)C(O)OR.sup.25, --S(O)R.sup.24 and --S(O).sub.2R.sup.24; and wherein each of the alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkenyl and alkynyl groups in R.sup.23 are independently unsubstituted or substituted by 1 to 5 R.sup.27 groups independently selected from the group consisting of alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, halo, --CF.sub.3, --CN, --OR.sup.24, --C(O)R.sup.24, --C(O)OR.sup.24, alkyl-C(O)OR.sup.24, C(O)N(R.sup.24)(R.sup.25), --SR.sup.24, --S(O)N(R.sup.24)(R.sup.25), --S(O).sub.2N(R.sup.24)(R.sup.25), --C(.dbd.NOR.sup.24)R.sup.25, --P(O)(OR.sup.24)(OR.sup.25), --N(R.sup.24)(R.sup.25), -alkyl-N(R.sup.24)(R.sup.25), --N(R.sup.24)C(O)R.sup.25, --CH.sub.2--N(R.sup.24)C(O)R.sup.25, --N(R.sup.24)S(O)R.sup.25, --N(R.sup.24)S(O).sub.2R.sup.25, --CH.sub.2--N(R.sup.24)S(O).sub.2R.sup.25, --N(R.sup.24)S(O).sub.2N(R.sup.25)(R.sup.26), --N(R.sup.24)S(O)N(R.sup.25)(R.sup.26), --N(R.sup.24)C(O)N(R.sup.25)(R.sup.26), --CH.sub.2--N(R.sup.24)C(O)N(R.sup.25)( R.sup.26), --N(R.sup.24)C(O)OR.sup.25, --CH.sub.2--N(R.sup.24)C(O)OR.sup.25, --S(O)R.sup.24 and --S(O).sub.2R.sup.24; R.sup.24, R.sup.25 and R.sup.26 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, arylcycloalkyl, R.sup.27-alkyl, R.sup.27-cycloalkyl, R.sup.27-cycloalkylalkyl, R.sup.27-heterocycloalkyl, R.sup.27-heterocycloalkylalkyl, R.sup.27-aryl, R.sup.27-arylalkyl, R.sup.27-heteroaryl and R.sup.27-heteroarylalkyl; R.sup.27 is 1-5 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, arylalkyl, --NO.sub.2, halo, --CF.sub.3, --CN, alkyl-CN, --C(O)R.sup.28, --C(O)OH, --C(O)OR.sup.28, --C(O)NHR.sup.29, --C(O)N(alkyl).sub.2, --C(O)N(alkyl)(aryl), --C(O)N(alkyl)(heteroaryl), --SR.sup.28, --S(O).sub.2R.sup.29, --S(O)NH.sub.2, --S(O)NH(alkyl), --S(O)N(alkyl)(alkyl), --S(O)NH(aryl), --S(O).sub.2NH.sub.2, --S(O).sub.2NHR.sup.28, --S(O).sub.2NH(aryl), --S(O).sub.2NH(heterocycloalkyl), --S(O).sub.2N(alkyl).sub.2, --S(O).sub.2N(alkyl)(aryl), --OH, --OR.sup.29, --O -heterocycloalkyl, --O-cycloalkylalkyl, --O-heterocycloalkylalkyl, --NH.sub.2, --NHR.sup.29, --N(alkyl).sub.2, --N(arylalkyl).sub.2, --N(arylalkyl)(heteroarylalkyl), --NHC(O)R.sup.29, --NHC(O)NH.sub.2, --NHC(O)NH(alkyl), --NHC(O)N(alkyl)(alkyl), --N(alkyl)C(O)NH(alkyl), --N(alkyl)C(O)N(alkyl)(alkyl), --NHS(O).sub.2R.sup.29, --NHS(O).sub.2NH(alkyl), --NHS(O).sub.2N(alkyl)(alkyl), --N(alkyl)S(O).sub.2NH(alkyl) and --N(alkyl)S(O).sub.2N(alkyl)(alkyl); R.sup.28 is alkyl, alkenyl, alkynyl, cycloalkyl, arylalkyl or heteroarylalkyl; and R.sup.29 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl. 2. A compound of claim 1, or a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt of said compound, said tautomer, or said stereoisomer, said compound having the structure: ##STR00058## 3. A compound of claim 2, or a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt of said compound, said tautomer, or said stereoisomer, wherein: R.sup.1 is alkyl, R.sup.21-alkyl or cycloalkyl; R.sup.2 is H; R.sup.3 is R.sup.21-aryl or R.sup.21-heteroaryl R.sup.4 is alkyl and R.sup.5 is hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, or heteroarylalkyl. 4. A compound according to claim 1, or a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt of said compound, said tautomer, or said stereoisomer, said compound having the structure IE: ##STR00059## where n' is an integer from 0 to 3. 5. A compound of claim 1, or a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt of said compound, said tautomer, or said stereoisomer, wherein said compound is selected from the group consisting of: ##STR00060## 6. A pharmaceutical composition comprising an effective amount of a compound of claim 1, or a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt of said compound, said tautomer, or said stereoisomer, and a pharmaceutically effective carrier. 7. A pharmaceutical composition comprising an effective amount of a compound of claim 1, or a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt of said compound, said tautomer, or said stereoisomer, and an effective amount of a cholinesterase inhibitor, a muscarinic m.sub.2 antagonist or a muscarinic m.sub.1 agonist in a pharmaceutically effective carrier. 8. A pharmaceutical composition comprising an effective amount of a compound of claim 1, or a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt of said compound, said tautomer, or said stereoisomer, and at least one second pharmaceutical agent selected from the group consisting of beta secretase inhibitors; gamma secretase inhibitors; HMG-CoA reductase inhibitors; non-steroidal anti-inflammatory agents; N-methyl-D-aspartate receptor antagonists; anti-amyloid antibodies; vitamin E; nicotinic acetylcholine receptor agonists; CB1 receptor inverse agonists or CB1 receptor antagonists; an antibiotic; growth hormone secretagogues; histamine H3 antagonists; AMPA agonists; PDE4 inhibitors; GABA.sub.A inverse agonists; inhibitors of amyloid aggregartion; glycogen synthase kinase beta inhibitors; promoters of alpha secretase activity or a cholesterol absorption inhibitor. 9. A compound of claim 1, or a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt of said compound, said tautomer, or said stereoisomer, wherein: R.sup.3 and R.sup.4 are each independently selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, --CH.sub.2--O--Si(R.sup.9)(R.sup.10)(R.sup.19), --CN, --C(O)R.sup.8, --C(O)OR.sup.9, --C(O)N(R.sup.11)(R.sup.12), --SR.sup.19, --S(O)N(R.sup.11)(R.sup.12), --S(O).sub.2N(R.sup.11)(R.sup.12), --N(R.sup.11)(R.sup.12), --N(R.sup.11)C(O)R.sup.8, --N(R.sup.11)S(O)R.sup.10, --N(R.sup.11)C(O)N(R.sup.12)(R.sup.13), --N(R.sup.11)C(O)OR.sup.9 and --C(.dbd.NOH)R.sup.8. 10. A compound of claim 2, or a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt of said compound, said tautomer, or said stereoisomer, wherein: R.sup.3 and R.sup.4 are each independently selected from the group consisting of aryl, heteroaryl, heteroarylalkyl, arylalkyl, cycloalkyl, heterocycloalkylalkyl, alkyl and cycloalkylalkyl; ##STR00061## where T is R''C(O)--, R''S(O).sub.2, R''NCO-- and n'' is 1 to 4, ##STR00062## where T is R''C(O)--, R''S(O).sub.2, R''NCO-- and n'' is 1 to 4, where R'' is H, alkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, arylcycloalkylalkyl, heteroarylcycloalkylalkyl, arylheterocycloalkylalkyl, heteroarylheterocycloalkylalkyl, cycloalkyl, arylcycloalkyl, heteroarylcycloalkyl, heterocycloalkyl, arylheterocycloalkyl, heteroarylheterocycloalkyl, alkenyl, arylalkenyl, cycloalkenyl, arylcycloalkenyl, heteroarylcycloalkenyl, heterocycloalkenyl, arylheterocycloalkenyl, heteroarylheterocycloalkenyl, alkynyl, arylalkynyl, aryl, cycloalkylaryl, heterocycloalkylaryl, heterocycloalkenylaryl, heteroaryl, cycloalkylheteroaryl, heterocycloalkylheteroaryl, cycloalkenylaryl, heterocycloalkenylaryl; ##STR00063## and R.sup.3 and R.sup.4 are each independently methyl, ethyl, cyclopropyl, ##STR00064## 11. A compound of claim 2, or a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt of said compound, said tautomer, or said stereoisomer, wherein: R.sup.1 is H, alkyl, R.sup.21-alkyl, cycloalkyl, arylalkyl, R.sup.21-arylalkyl, cycloalkylalkyl, R.sup.21-cycloalkylalkyl, heterocycloalkyalkyl or R.sup.21-heterocycloalkylalkyl, R.sup.2 is H; R.sup.3 is alkyl, cycloalkylalkyl, cycloalkyl, aryl, arylalkyl, R.sup.21-alkyl, R.sup.21-cycloalkylalkyl, R.sup.21-cycloalkyl, R.sup.21-aryl, R.sup.21-arylalkyl, or R.sup.21-heteroaryl; R.sup.4 is alkyl, cycloalkylalkyl, cycloalkyl, aryl, arylalkyl, R.sup.21-alkyl, R.sup.21-cycloalkylalkyl, R.sup.21-cycloalkyl, R.sup.21-aryl, R.sup.21-arylalkyl, or R.sup.21-heteroaryl; R.sup.5 is H, alkyl, R.sup.21-alkyl, cycloalkyl, aryl, arylalkyl, R.sup.21-arylalkyl, cycloalkylalkyl, R.sup.21-cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyalkyl or R.sup.21-heterocycloalkylalkyl; R.sup.15, R.sup.16 and R.sup.17 is H, R.sup.18-alkyl, alkyl or ##STR00065## R.sup.21 is alkyl, aryl, halo, --OR.sup.15, --NO.sub.2, --C(O)R.sup.15, --CH.sub.2--N(R.sup.15)C(O)N(R.sup.16)(R.sup.17) or --CH(R.sup.15)(R.sup.16); n is 1; m is 1; R.sup.18 is --OR.sup.20 R.sup.20 is aryl; and R.sup.23 is alkyl. 12. A compound of claim 1, or a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt of said compound, said tautomer, or said stereoisomer, wherein: R.sup.1 is H, CH.sub.3, --CH.sub.2CF.sub.3, cyclopropyl, ##STR00066## wherein each R.sup.21 is independently alkyl, halo, phenyl, R.sup.22-phenyl, wherein each R.sup.22 is indendently alkyl, halo or --OR.sup.15. 13. A compound of claim 2, or a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt of said compound, said tautomer, or said stereoisomer, wherein: R.sup.1 is --CH.sub.3; R.sup.5 is H, CH.sub.3, or cyclopropyl; R.sup.2 is H; R.sup.3 is alkyl, cycloalkylalkyl, cycloalkyl, aryl, arylalkyl, R.sup.21-alkyl, R.sup.21-cycloalkylalkyl, R.sup.21-cycloalkyl, R.sup.2-aryl, R.sup.21-arylalkyl, heteroarylalkyl, heteroaryl, heterocycloalkylalkyl, R.sup.21-heteroarylalkyl, R.sup.21-heteroaryl, R.sup.21-heterocycloalkyl or R.sup.21-heterocycloalkylalkyl; R.sup.4 is alkyl, cycloalkylalkyl, cycloalkyl, aryl, arylalkyl, R.sup.21-alkyl, R.sup.21-cycloalkylalkyl, R.sup.21-cycloalkyl, R.sup.21-aryl, R.sup.21-arylalkyl, heteroarylalkyl, heteroaryl, heterocycloalkylalkyl, R.sup.21-heteroarylalkyl, R.sup.21-heteroaryl, R.sup.21-heterocycloalkyl or R.sup.21-heterocycloalkylalkyl; R.sup.5 is H, alkyl, R.sup.21-alkyl, arylalkyl, R.sup.21-arylalkyl, cycloalkylalkyl, R.sup.21-cycloalkylalkyl, heterocycloalkyalkyl or R.sup.21-heterocycloalkylalkyl; R.sup.15, R.sup.16 and R.sup.17 is H, cycloalkyl, cycloalkylalkyl, R.sup.18-alkyl, alkyl, aryl, R.sup.18-aryl, R.sup.18-arylalkyl, arylalkyl, ##STR00067## n is 1 or 2; m is 0 or 1; R.sup.18 is --OR.sup.20 or halo; R.sup.20 is aryl or halo substituted aryl; R.sup.21 is alkyl, aryl, heteroaryl, R.sup.22-alkyl, R.sup.22-aryl, R.sup.22-heteroaryl, halo, heterocycloalkyl, --N(R.sup.15)(R.sup.16), --OR.sup.15, --NO.sub.2, --C(O)R.sup.15, --N(R.sup.15)C(O)R.sup.16, --N(R.sup.15)S(O).sub.2R.sup.16, --CH.sup.2--N(R.sup.15)C(O)N(R.sup.16)(R.sup.17), --N(R.sup.15)C(O)N(R.sup.16)(R.sup.17) or --CH(R.sup.15)(R.sup.16); R.sup.22 is --OR.sup.15, halo, alkenyl, --C.ident.C(CH.sub.3), or --CN and R.sup.23 is H or alkyl. 14. A compound of claim 2, or a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt of said compound, said tautomer, or said stereoisomer, wherein: R.sup.1 is hydrogen, alkyl, R.sup.21-alkyl, cycloalkyl, R.sup.21-cycloalkyl, arylalkyl, R.sup.21-arylalkyl, heterocyclalkylalkyl, R.sup.21-heterocyclalkyl, or R.sup.21-arylalkyl; R.sup.2 is H; R.sup.3 is R.sup.21-aryl; R.sup.4 is alkyl, R.sup.21-alkyl, cycloalkyl, R.sup.21-cycloalkyl, aryl or R.sup.21-aryl; and R.sup.5 is H, alkyl, cycloalkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl. 15. A compound having the structural formula IA: ##STR00068## wherein: R.sup.1 is C.sub.1-C.sub.6 alkyl; R.sup.2 is H; R.sup.3 is phenyl optionally substituted with R.sup.21; R.sup.21 is halogen or phenyl optionally substituted with R.sup.22; R.sup.22 is methyl, cyano, or halo; R.sup.4 is C.sub.1-C.sub.6 alkyl; and R.sup.5 is hydrogen, C.sub.1-C.sub.6 alkyl.

Details for Patent 8,110,682

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Jubilant Hollisterstier Llc	N/A	positive skin test control-histamine	Injection	103891	03/13/1924		2025-06-14