# Patent

## Title
Pyridazinone derivatives useful as glucan synthase inhibitors

## Abstract

Disclosed is a set of compounds useful as glucan synthase inhibitors having the generic structure of Formula I:




wherein the various moieties A, D, R6, etc., are as defined in the specification. These compounds are useful in treating or preventing fungal infections in a patient.

## Background
The present application claims the benefit of U.S. provisional patent application No. 60/918,171; filed Mar. 15, 2007; which is herein incorporated by reference in its entirety.


FIELD OF THE INVENTION
This invention relates to novel compounds, which are useful as glucan synthase inhibitors, pharmaceutical compositions containing the compounds, and methods of treating or preventing fungal infections. In one embodiment, the compounds are piperazine-substituted pyridazinone compounds.
BACKGROUND OF THE INVENTION
The enzymes involved in fungal cell wall biogenesis are attractive targets for antifungal intervention. These enzymes are unique to fungi and therefore provide highly selective antifungal targets. Furthermore, disruption of cell wall synthesis generally leads to a fungicidal response due to cell lysis induced by the osmotic instability of cells lacking an intact wall. Major structural components of fungal cell walls are β(1,3)-linked D-glucan polymers. These polymers are generated by β(1,3)-D-glucan synthase, an integral membrane protein complex that is required for fungal cell viability. Compounds described as inhibitors of glucan synthase have been described previously. Reference is made to Károlyházy, László et al. Arzneim.-Forsch./Drug Res. 2003, Vol. 53, No. 10, 738-743, which discloses 3-(2H)-pyridazinones of the formula:




where the various elements are defined therein. An illustrative compound of that series is:





Reference is made to Kondoh, Osamu et al., Biol. Pharm. Bull. 2005, 28, 2138-2141, which discloses piperazine propanol derivatives. An illustrative compound of that series is:





Reference is made to Brayman, Timothy et al., Antimicrobial Agents and Chemotherapy 2003 Vol. 47, No. 10, 3305-3310, which discloses the use of several compounds identified as glucan synthase inhibitors to test an assay for antifungal activity of glucan synthase inhibitors that uses germ tube formation in Candida albicans as an end point. An illustrative compound used to test the assay is:





Reference is made to Gomez, Gil et al., ES 540813 1985, which discloses 1,2-diazin-3(2H)-ones as compounds of pharmaceutical interest useful as antihypertensives, β-adrenergic blockers, antiulcer agents or as intermediates thereof. An illustrative compound of that series is:





Reference is made to Pauline C. Ting and Scott S. Walker, “New Agents to Treat Life-Threatening Fungal Infections” in Current Topics in Medicinal Chemistry, 2008, which discloses Antifungals that are inhibitors of glucan synthase. These antifungals include cyclic hexapeptides that are either approved for antifungal chemotherapy (caspofungin, micafungin anidulafungin) or under clinical development (aminocandin).
SUMMARY OF THE INVENTION
In its many embodiments, the present invention provides a novel class of compounds, methods of preparing such compounds, pharmaceutical compositions comprising one or more of such compounds, pharmaceutical compositions comprising a combination of one or more of such compounds and other antifungal agents, bacterial agents, and steroids, methods of preparing pharmaceutical formulations comprising one or more of such compounds, and methods of treatment, prevention, inhibition or amelioration of one or more diseases associated with glucan synthase using such compounds or pharmaceutical compositions.
A compound of Formula I:




or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, wherein:

     represents a double bond or a single bond, as permitted by the valency requirement, with the proviso that when E is N, the double bond is present and R6 is absent;
    A is O or S;
    D and E are independently C or N,
    
        provided that when D is carbon, D is substituted with hydrogen, alkyl, —Oalkyl, —Nalkyl or —Salkyl;
    
    
    R3 is a moiety selected from the group consisting of alkyl, alkenyl, aryl, arylalkyl, arylalkenyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cyclenyl, cyclenylalkyl, cyclenylalkenyl, heterocyclyl, heterocyclyalkyl, heterocyclylalkenyl, heterocyclenyl, heterocyclenylalkyl, heterocyclenylalkenyl, arylalkoxylalkyl, arylalkoxylalkenyl, cycloalkoxylalkyl, cycloalkoxylalkenyl, cycloalkenoxylalkyl, and cycloalkenyoxylalkenyl,
    wherein each of said alkyl, alkenyl, aryl, arylalkyl, arylalkenyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cyclenyl, cyclenylalkyl, cyclenylalkenyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclenyl, heterocyclenylalkyl, heterocyclenylalkenyl, arylalkoxylalkyl, arylalkoxylalkenyl, cycloalkoxylalkyl, cycloalkoxylalkenyl, cycloalkenoxylalkyl, cycloalkenyoxylalkenyl can be unsubstituted or substituted with one or more moieties, which can be the same or different, each moiety being independently selected from the group consisting of alkyl, alkenyl, alkynyl cycloalkyl, halogen, trihaloalkyl, dihaloalkyl, monohaloalkyl, —NR92, —OR9, —SR9, —NO2, —CN, —NR16COR9, —R16SO2R9, —COR9, —CO2R9, —SO2R9, —CONR9R16, and —N═C═O;
    Y can be present or absent; or






    
    
        provided that when Y is O, Y—R4 taken together is not alkoxyl of the formula
    
    






    
    
         wherein CH2R11 and —OR10 together with the CH to which they are attached, form a heterocyclyl that is substituted with one or more moieties, which can be the same or different, selected from the group consisting of alkyl and aryl, or
        wherein R10 is H and R11 is hydroxyl or butylamine;
    
    
    R4 is alkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxyalkoxyalkyl, alkenyl-O-alkyl, alkoxyalkenyl, alkenyl-O-alkenyl, alkynyl-O-alkyl, hydroxyalkyl, hydroxyalkenyl, alkyl-S-alkyl, alkenyl-S-alkyl, alkyl-S-alkenyl, alkenyl-S-alkenyl, alkyl-SO-alkyl, alkenyl-SO-alkyl, alkyl-SO-alkenyl, alkenyl-SO-alkenyl, alkyl-SO2-alkyl, alkenyl-SO2-alkyl, alkyl-SO2-alkenyl, alkenyl-SO2-alkenyl, alkyl-NR9-alkyl, alkenyl-NR9-alkyl, alkyl-NR9-alkenyl, alkenyl-NR9-alkenyl, alkyl-CO2-alkyl, alkenyl-CO2-alkyl, alkyl-CO2-alkenyl, alkenyl-CO2-alkenyl, alkyl-O2C-alkyl, alkenyl-O2C-alkyl, alkyl-O2-alkenyl, alkenyl-O2C-alkenyl, alkyl-NCO-alkyl, alkenyl-NCO-alkyl, alkyl-NCO-alkenyl, alkenyl-NCO-alkenyl, alkyl-CON-alkyl, alkenyl-CON-alkyl, alkyl-CON-alkenyl, alkenyl-CON-alkenyl, alkyl-NCON-alkyl, alkenyl-NCON-alkyl, alkyl-NCON-alkenyl, alkenyl-NCON-alkenyl, alkyl-CO-alkyl, alkenyl-CO-alkyl, alkyl-CO-alkenyl, alkenyl-CO-alkenyl, cycloalkyl, cycloalkylalkyl, spiroheteroaryl, spiroheterocyclenyl, spiroheterocyclyl, spiroheteroarylalkyl, spiroheteroarylalkenyl, spiroheterocyclenylalkyl, spiroheterocyclenylalkenyl, spiroheterocyclylalkyl, spiroheterocyclylalkenyl, spirocycloalkyl, spirocycloalkylalkyl, spirocycloalkylalkenyl, spirocyclenyl, spirocyclenylalkyl, spirocyclenylalkenyl, spiroaryl, spiroarylalkyl, spiroarylalkenyl, alkylcycloalkyl, alkylcycloalkylalkyl, alkylcycloalkylalkenyl, cyclenyl, cyclenylalkyl, cyclenylalkenyl, aryl, arylalkyl, arylalkenyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heterocyclyl, heterocyclenyl, heterocyclenylalkyl heterocyclenylalkenyl, heterocyclylalkyl, heterocyclylalkenyl, benzofused-cycloalkyl, benzofused-heterocycloalkyl, benzofused-cycloalkylalkyl or benzofused-heterocycloalkylalkyl;
    wherein said alkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxyalkoxyalkyl, alkenyl-O-alkyl, alkoxyalkenyl, alkenyl-O-alkenyl, alkyl-O-alkyl, hydroxyalkyl, hydroxyalkenyl, alkyl-S-alkyl, alkenyl-S-alkyl, alkyl-S-alkenyl, alkenyl-S-alkenyl, alkyl-SO-alkyl, alkenyl-SO-alkyl, alkyl-SO-alkenyl, alkenyl-SO-alkenyl, alkyl-SO2-alkyl, alkenyl-SO2-alkyl, alkyl-SO2-alkenyl, alkenyl-SO2-alkenyl, alkyl-NR9-alkyl, alkenyl-NR9-alkyl, alkyl-NR9-alkenyl, alkenyl-NR9-alkenyl, alkyl-CO2-alkyl, alkenyl-CO2-alkyl, alkyl-CO2-alkenyl, alkenyl-CO2-alkenyl, alkyl-O2C-alkyl, alkenyl-O2C-alkyl, alkyl-O2C-alkenyl, alkenyl-O2C-alkenyl, alkyl-NCO-alkyl, alkenyl-NCO-alkyl, alkyl-NCO-alkenyl, alkenyl-NCO-alkenyl, alkyl-CON-alkyl, alkenyl-CON-alkyl, alkyl-CON-alkenyl, alkenyl-CON-alkenyl, alkyl-NCON-alkyl, alkenyl-NCON-alkyl, alkyl-NCON-alkenyl, alkenyl-NCON-alkenyl, alkyl-CO-alkyl, alkenyl-CO-alkyl, alkyl-CO-alkenyl, alkenyl-CO-alkenyl, cycloalkyl, cycloalkylalkyl, spiroheteroaryl, spiroheterocyclenyl, spiroheterocyclyl, spiroheteroarylalkyl, spiroheteroarylalkenyl, spiroheterocyclenylalkyl, spiroheterocyclenylalkenyl, spiroheterocyclylalkyl, spiroheterocyclylalkenyl, spirocycloalkyl, spirocycloalkylalkyl, spirocycloalkylalkenyl, spirocyclenyl, spirocyclenylalkyl, spirocyclenylalkenyl, spiroaryl, spiroarylalkyl, spiroarylalkenyl, alkylcycloalkyl, alkylcycloalkylalkyl, cyclenyl, cyclenylalkyl, cyclenylalkenyl, aryl, arylalkyl, arylalkenyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heterocyclyl, heterocyclenyl, heterocyclenylalkyl, heterocyclenylalkenyl, heterocyclylalkyl, heterocyclylalkenyl, benzofused-cycloalkyl, benzofused-heterocycloalkyl, benzofused-cycloalkylalkyl or benzofused-heterocycloalkylalkyl can be unsubstituted or substituted with at least one moiety independently selected from the group consisting of alkyl, alkenyl, aryl, OR9, arylalkyl, arylalkenyl, cyclenylalkyl, cyclenylalkenyl, cycloalkylalkyl, cycloalkylalkenyl, alkylCO2alkyl-, halogen, trihaloalkyl, dihaloalkyl, monohaloalkyl, cycloalkyl, cyclenyl, hydroxyalkyl, hydroxyalkenyl, thiohydroxyalkyl, thiohydroxyalkenyl, hydroxyalkenyl, heteroaryl, heteroarylalkyl, heterocyclenyl, heterocyclenylalkyl, heterocyclyl, heterocyclylalkyl, alkoxyalkyl, —CN, —NO2, —OSiR93, —NR16COR9, —OCONR92, —NR16CONR92, —NR16SO2R9, —NR92, —N═C═O,






     —NR16CO2R9, —COR9, —CO2R9, —OCOR9, —SO2R9, —SOR9, —SR9, —SO2N(R9)2 or CONR9R16, wherein each of said alkyl, alkenyl, aryl, arylalkyl, arylalkenyl, cyclenylalkyl, cyclenylalkenyl, cycloalkylalkyl, cycloalkylalkenyl, halogen, trihaloalkyl, dihaloalkyl, monohaloalkyl, cycloalkyl, cyclenyl, hydroxyalkyl, hydroxyalkenyl, thiohydroxyalkyl, thiohydroxyalkenyl, hydroxyalkenyl, heteroaryl, heteroarylalkyl, heterocyclenyl, heterocyclenylalkyl, heterocyclyl, heterocyclylalkyl, alkoxyalkyl, can be unsubstituted or substituted with one or more moieties which can be the same or different, each moiety being independently selected from R9;
    Z is a linker attached at either end of said linker to the parent ring of Formula I, wherein said linker is selected from the group consisting of:






    
    
        wherein
        n is 1 to 4,
        p is 0 to 2,
        q is 1 to 3;
    
    
    R5 is






     —CR92, —SO2NR13-alkyl-C(O)-aryl, or heteroaryl, wherein each of said






     is attached at one end to Z and at the second end substituted with one or more moieties, which can be the same or different, each moiety being independently selected from the group consisting of H, alkyl, alkenyl, cycloalkyl, cyclenyl, aryl, heterocyclyl, heterocyclenyl, heteroaryl, cycloalkylalkyl, cyclenylalkyl, arylalkyl, heterocyclylalkyl, heterocyclenylalkyl, heteroarylalkyl, cycloalkylalkenyl, cyclenylalkenyl, arylalkenyl, heterocyclylalkenyl, heterocyclenylalkenyl, heteroarylalkenyl, —OR9 and —NR92,
    further, wherein each of said alkyl, alkenyl, cycloalkyl, cyclenyl, aryl, heterocyclyl, heterocyclenyl, heteroaryl, cycloalkylalkyl, cyclenylalkyl, arylalkyl, heterocyclylalkyl, heterocyclenylalkyl, heteroarylalkyl, cycloalkylalkenyl, cyclenylalkenyl, arylalkenyl, heterocyclylalkenyl, heterocyclenylalkenyl, or heteroarylalkenyl can be unsubstituted or substituted with one or more moieties, which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, alkenyl, cycloalkyl, —OR9, alkylOR9, alkylCO2R9, alkylNR16COR9, alkylNR16CONR9, alkylSO2R9, alkylCOR9, alkylSO2NR92, alkylNR92, alkylaryl, alkylheteroaryl, alkylSR9, alkylSOR9, —CN, —CO2R9, trihaloalkyl, dihaloalkyl, monohaloalkyl, —NR16COR9, —NR16CONR92, —NR16SO2—R13, —SO2R9, —COR9, —NO2, —SO2NR92, aryl, heteroaryl, —NR92, —SR9, —SOR9, —C(═NOH)—NR13,






    or Y—R4 taken together are H, provided that R6 is not H; or Y—R4 taken together are H and R6 is H, provided that when Z is






     R8 is not H;
    or when Y is —O— and R5 is —SO2—, R4 and the second end substituent on R5 together are -alkyl-, -alkenyl-, -alkyl-NH—, or -alkenyl-NH— forming a ring with the —O— and —SO2— groups to which they are attached;
    or when R3 is a group having an —OR9 substituent and Y is —O—, R4 and the R9 portion of the R3 group together are a divalent alkyl group, forming a ring with the —O— atoms to which they are attached;
    or when Y is —O— and R5 is —SO2—, R4 and the second end substituent of R5 together are an -alkyl-phenylene-alkyl-NR13— group or an -alkyl-phenylene-alkyl- group, forming a ring with the —O— and —SO2— groups to which they are attached;
    or when Y is —O— and R5 is —SO2—, R4 and the second end substituent of R5 together are an -alkyl-heteroarylene-alkyl- group or an -alkyl-heteroarylene-alkyl-NR13— group, forming a ring with the —O— and —SO2— groups to which they are attached;
    or Z and R5 taken together is






    
    
        wherein
        r is 1 or 2;
        s is 0 or 1;
    
    
    or —Y—R4, —ZR5 and the carbons to which they are attached form the group






     wherein J is —O—, —S— or —NR13;
    R6 is H, alkyl, aryl, arylalkyl, arylalkenyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, arylalkoxylalkyl, arylalkoxylalkenyl, arylalkoxyl, cycloalkoxyl, cycloalkoxylalkyl, cycloalkoxylalkenyl, cycloalkylalkoxyl, cycloalkenoxyl, cycloalkenoxylalkyl, cycloalkenyoxylalkenyl, —NR92, —OR9, —NO2, —NR16COR9, —NR16CON(R17)2, —NR16SO2R9, —COR9, —CO2R9 or —CONR9R16;
    wherein each of said alkyl, aryl, arylalkyl, arylalkenyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, arylalkoxylalkyl, arylalkoxylalkenyl, arylalkoxyl, cycloalkoxyl, cycloalkoxylalkyl, cycloalkoxylalkenyl, cycloalkylalkoxy, cycloalkenoxyl, cycloalkenoxylalkyl, cycloalkenyoxylalkenyl can be unsubstituted or substituted with one or more moieties, which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, trihaloalkyl, dihaloalkyl, monohaloalkyl, —NR92, —OR9, —SR9, —NO2, —CN, —NR16COR9, —NR16SO2R9, —COR9, —CO2R9, —SO2R9, —CONR9R16 and —NR16CON(R17)2;
    each R7 is independently selected from the group consisting of H and alkyl;
    R8 is one or more moieties, which can be the same or different, each being independently selected from the group consisting of H, aryl, arylalkyl, alkyl,






     arylalkenyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cyclenyl, cyclenylalkyl, cyclenylalkenyl, alkenyl, alkynyl, trihaloalkyl, dihaloalkyl, monohaloalkyl, NR92, —OR9, —SR9, —NR16COR9, —NR16CON(R17)2, —NR16SO2R9, —COR9, —CO2R9, —SO2R9, and —CONR9R16,
    wherein each of said aryl, arylalkyl, alkyl, arylalkenyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cyclenyl, cyclenylalkyl, cyclenylalkenyl, alkenyl and alkynyl can be unsubstituted or substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, trihaloalkyl, dihaloalkyl, monohaloalkyl, —NR92, —OR9, —SR9, —NO2, —CN, —NR16COR9, —NR16SO2R9, —COR9, —CO2R9, —SO2R9, —CONR9R16 and —NR16CON(R17)2;
    R9 is one or more moieties, which can be the same or different, each moiety being independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, cyclenyl, aryl, heteroalkyl, heterocycloalkyl, heterocyclenyl, heteroaryl, hydroxyalkyl, hydroxyalkenyl, alkylthioalkyl, alkylthioalkenyl, alkenylthioalkyl, alkenylthioalkenyl, alkoxylalkyl, arylalkyl, cycloalkylalkyl, cyclenylalkyl, heterocyclylalkyl, heterocyclenylalkyl, heteroarylalkyl, arylalkenyl, cycloalkyalkenyl, cyclenylalkenyl, heterocyclylalkenyl, heterocyclenylalkenyl, heteroarylalkenyl, alkoxyaryl, trihaloalkyl, trihaloalkenyl, dihaloalkyl, dihaloalkenyl, monohaloalkyl, and monohaloalkenyl,
    wherein each of said alkyl, alkenyl, alkynyl, cycloalkyl, cyclenyl, aryl, heterocycloalkyl, heterocyclenyl, heteroaryl, hydroxyalkyl, hydroxyalkenyl, alkoxylalkyl, arylalkyl, cycloalkylalkyl, cyclenylalkyl, heterocyclylalkyl, heterocyclenylalkyl, heteroarylalkyl, arylalkenyl, cycloalkyalkenyl, cyclenylalkenyl, heterocyclylalkenyl, heterocyclenylalkenyl, heteroarylalkenyl, and alkoxyaryl can be unsubstituted or substituted with one or more moieties, which can be the same or different, each moiety being independently selected from the group consisting of halogen, trihaloalkyl, dihaloalkyl, monohaloalkyl, trihaloalkenyl, dihaloalkenyl, monohaloalkenyl, hydroxyl, alkoxy, hydroxyalkyl, —N(R12)2, alkyl, alkynyl, cycloalkyl, alkenyl, cyclenyl, aryl, heteroaryl, heterocycloalkyl, heterocyclenyl, cycloalkylalkyl, cyclenylalkyl, arylalkyl, heteroarylalkyl, heterocycloalkylalkyl, heterocyclenylalkyl, cycloalkylalkenyl, cyclenylalkenyl, arylalkenyl, heteroarylalkenyl, heterocycloalkylalkenyl, heterocyclenylalkenyl, —CN, —NO2, —SO2R17, —C(O)N(R20)2, —CO2R19,






     —NR16—C(O)R19, —NR16CON(R17)2, —NR16SO2R17, trihaloalkoxy, dihaloalkoxy, monohaloalkoxy,






     further wherein when two R9 moieties are attached to a N, the two R9 moieties, together with the N to which they are attached, can form a heterocyclyl or heterocyclenyl ring of 4 to 7 members, wherein 1 or 2 of said ring members can be —O—, —S— or —NR18—, provided that there are no heteroatoms adjacent to each other; and wherein the heterocyclyl or heterocyclenyl ring is optionally substituted on 1 or 2 ring carbon atoms by a substituent independently selected from the group consisting of alkyl, alkoxy, —OH and —NR16, or two hydrogen atoms on the same carbon are replaced by ═O;
    each R12 is independently selected from the group consisting of H, alkyl, aryl and arylalkyl;
    each R13 is independently selected from the group consisting of H, alkyl, aryl, arylalkyl, cycloalkyl and cycloalkylalkyl;
    R14 is alkyl or alkoxy;
    R15 is aryl, arylalkyl, —N(R13)aryl —N(R13)-alkylaryl, —O-aryl or O-alkylaryl;
    R16 is independently selected from the group consisting of H and alkyl;
    R17 is alkyl, aryl or arylalkyl;
    R18 is H, alkyl, —COOR19, —COR17 or —CON(R17)2;
    each R19 is independently selected from the group consisting of H, alkyl and arylalkyl;
    each R20 is independently selected from the group consisting of H, alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, and alkoxyalkyl;
    provided that Formula I does not include the compounds of Table A:









TABLE A













 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 








 















The invention also relates to a pharmaceutical composition for human or veterinary use comprising one or more compounds of Formula I and a pharmaceutically acceptable carrier.
The invention also relates to a pharmaceutical composition for human or veterinary use comprising combination of one or more compounds of Formula I and one or more other antifungal agents with or without a pharmaceutically acceptable carrier.
The invention also relates to a method of treating or preventing growth of fungal pathogens in plants, and to a method of reducing or eliminating fungal growth on inanimate surfaces, comprising applying a compound of Formula I to said plant or surface.
The invention also relates to a method of treating or preventing growth of fungal pathogens on inanimate surface by applying one or more compounds of Formula I to said surface.
Further, the invention relates to a method of treating or preventing growth of fungal pathogens on inanimate surface by applying other antifungal agents along with the compounds of Formula I.
The invention also relates to a method of treating fungal pathogens by administering pharmaceutical compositions for human or veterinary use comprising one or more compounds of Formula I and a pharmaceutically acceptable carrier.
The invention also relates to the use of a glucan synthase inhibitor of Formula I for the preparation of a medicament for treating or preventing fungal infections.
The invention also relates to a method of treating or preventing fungal infections by administering a combination of one or more compounds of Formula I and one or more other antifungal agents.
Further, the invention relates to a method of treating or preventing fungal infections by administering a human or veterinary pharmaceutical composition comprising one or more compounds of Formula I and one or more other antifungal agents in a pharmaceutically acceptable carrier. Also contemplated the method of preparing a kit comprising in a single package, one container comprising one or more compounds of Formula I in a pharmaceutically acceptable carrier, and a separate container comprising one or more other antifungal agents in a pharmaceutically acceptable carrier, with the compounds of Formula I and the other antifungal agents being present in amounts such that the combination is therapeutically effective.
Also, the invention relates to a method of inhibiting one or more glucan synthase comprising administering at least one compound of claim 1 or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof to a patient in need of such inhibition.


DETAILED DESCRIPTION OF THE INVENTION
In an embodiment, the present invention provides novel compounds represented by structural Formula I, or pharmaceutically acceptable salts, solvates, esters or prodrugs thereof, wherein the various moieties are as described above, provided that the compounds of Formula I do not include the compounds of Table A listed above.
In another embodiment, in Formula I, A is O.
In another embodiment, in Formula I, D is N or C.
In another embodiment, in Formula I, D is N.
In another embodiment, in Formula I, D is C.
In another embodiment, in Formula I, E is C.
In another embodiment, in Formula I,




absent.

In another embodiment, in Formula I, Y is S.
In another embodiment, in Formula I, Y is O.
In another embodiment, in Formula I, Y is




In another embodiment, in Formula I, Y is




In another embodiment, in Formula I, Y is




In another embodiment, in Formula I, Y is absent.
In another embodiment, in Formula I, Z is




In another embodiment, in Formula I, Z is




In another embodiment, in Formula I, Z is




In another embodiment, in Formula I, Z is




In another embodiment, in Formula I, R5 is




In another embodiment, in Formula I, R5 is




In another embodiment, in Formula I, R5 is




In another embodiment, in Formula I, R5 is —CR92—.
In another embodiment, in Formula I, R5 is heteroaryl.
In another embodiment, in Formula I, E is C and R6 is H.
In another embodiment, in Formula I, D is N, E is C, a double bond is present between D and E, and R6 is H.
In another embodiment, this invention discloses a compound of Formula A:




or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, wherein

Y is —O—,
provided that Y—R4 taken together is not alkoxyl of the formula




wherein —CH2R11 and OR10 together with the CH to which they are attached, form a heterocyclyl that is substituted with one or more moieties, which can be the same or different, selected from the group consisting of alkyl and aryl, or

wherein R10 is H and R11 is hydroxyl or butylamine;

Z is a linker attached at either end of said linker to the parent ring of Formula A, wherein said linker is selected from the group consisting of:




wherein

n is 1 to 4,

p is 0 to 2,

q is 1 to 3:

R3, R4, R5, R7, R8, R9 and R12 are as described in Formula I above;
provided that Formula A does not include the compounds of Table A as defined above.
In another embodiment, this invention discloses a compound of Formula B:




or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, wherein

Y is absent;
R3, R4, R5, R7, R8, R9 and R12 are as described in Formula I above;
Z is a linker attached at either end of said linker to the parent ring of Formula B, wherein said linker is selected from the group consisting of:




wherein

n is 1 to 4,

p is 0 to 2,

q is 1 to 3;

provided that Formula B does not include the compounds of Table A as defined above.

In another embodiment, this invention discloses a compound of Formula C:




or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof wherein

Y is S—,




R3, R4, R5, R7, R8R9 and R12 as described in Formula I above;
Z is a linker attached at either end of said tinker to the parent ring of Formula C, wherein said linker is selected from the group consisting of:




wherein

n is 1 to 4,

p is 0 to 2,

q is 1 to 3;

provided that Formula C does not include the compounds of Table A as defined above.

In another embodiment, this invention discloses compounds of the Formula D:




or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, wherein

Y is NR92;
R3, R4, R7, R8R9 and R12 as described in Formula I above;
Z is a linker attached at either end of said linker to the parent ring of Formula D, wherein said linker is selected from the group consisting of:




wherein

n is 1 to 4,

p is 0 to 2,

q is 1 to 3;

provided that Formula D does not include the compounds of Table A as defined above.

In another embodiment, this invention discloses compounds of Formula E:




or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, wherein

Y, R3, R4, R7, R8, R9 and R12 as described in Formula I above;
Z is a linker attached at either end of said linker to the parent ring of Formula F,
wherein said linker is selected from the group consisting of:




wherein

n is 1 to 4,

p is 0 to 2,

q is 1 to 3;

R5 is




wherein each of said





is attached at one end to Z and at the second end substituted with one or more moieties, which can be the same or different, each moiety being independently selected from the group consisting of H, alkyl, alkenyl, cycloalkyl, cyclenyl, aryl, heterocyclyl, heterocyclenyl, heteroaryl, cycloalkylalkyl, cyclenylalkyl, arylalkyl, heterocyclylalkyl, heterocyclenylalkyl, heteroarylalkyl, cycloalkylalkenyl, cyclenylalkenyl, arylalkenyl, heterocyclylalkenyl, heterocyclenylalkenyl, heteroarylalkenyl, —OR9 and —NR92,

further, wherein each of said alkyl, alkenyl, cycloalkyl, cyclenyl, aryl, heterocyclyl, heterocyclenyl, heteroaryl, cycloalkylalkyl, cyclenylalkyl, arylalkyl, heterocyclylalkyl, heterocyclenylalkyl, heteroarylalkyl, cycloalkylalkenyl, cyclenylalkenyl, arylalkenyl, heterocyclylalkenyl, heterocyclenylalkenyl, or heteroarylalkenyl can be unsubstituted or substituted with one or more moieties, which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, alkenyl, cycloalkyl, —OR9, alkylOR9, alkylCO2R9, alkylNR16COR9, alkylNR16CONR9, alkylSO2R9, alkylCOR9, alkylSO2NR92, alkylNR92, alkylaryl, alkylheteroaryl, alkylSR9, alkylSOR9, —CN, —CO2R9, trihaloalkyl, dihaloalkyl, monohaloalkyl, —NR16COR9, —NR16CONR92, —NR16SO2—R13, —SO2R9, —COR9, —NO2, —SO2NR92, aryl, heteroaryl, —NR92, —SR9, —SOR9,





provided that Formula E does not include the compounds of Table A as defined above.

In another embodiment, this invention discloses compounds of Formula F:




or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, wherein

Y, R3, R4, R7, R8, R9 and R12 are as described in Formula I above;
Z is a linker attached at either end of said linker to the parent ring of Formula F, wherein said linker is selected from the group consisting of:




wherein

n is 1 to 4,

p is 0 to 2,

q is 1 to 3;

R5 is heteroaryl, optionally substituted by 1 to 3 ring system substituents, provided that Formula F does not include the compounds of Table A as defined above.
In another embodiment, this invention discloses a compound of Formula G:




or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, wherein:

Y, R3, R4, R7, R8, R9 and R12 are as described in Formula I above;
Z is a link attached at either end of said linker to the parent ring of Formula G, wherein said linker is selected from the group consisting of:




wherein

n is 1 to 4,

p is 0 to 2,

q is 1 to 3;

R5 is




wherein said





is attached at one end to Z and at the second end substituted with one or more moieties, which can be the same or different, each moiety being independently selected from the group consisting of H, alkyl, alkenyl, cycloalkyl, cyclenyl, aryl, heterocyclyl, heterocyclenyl, heteroaryl, cycloalkylalkyl, cyclenylalkyl, arylalkyl, heterocyclylalkyl, heterocyclenylalkyl, heteroarylalkyl, cycloalkylalkenyl, cyclenylalkenyl, arylalkenyl, heterocyclylalkenyl, heterocyclenylalkenyl, heteroarylalkenyl, —OR9 and —NR92,

further, wherein each of said alkyl, alkenyl, cycloalkyl, cyclenyl, aryl, heterocyclyl, heterocyclenyl, heteroaryl, cycloalkylalkyl, cyclenylalkyl, arylalkyl, heterocyclylalkyl, heterocyclenylalkyl, heteroarylalkyl, cycloalkylalkenyl cyclenylalkenyl, arylalkenyl, heterocyclylalkenyl, heterocyclenylalkenyl, or heteroarylalkenyl can be unsubstituted or substituted with one or more moieties, which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, alkenyl, cycloalkyl, —OR9, alkylOR9, alkylCO2R9, alkylNR16COR9, alkylNR16CONR9, alkylSO2R9, alkylCOR9, alkylSO2NR92, alkylNR92, alkylaryl, alkylheteroaryl, alkylSR9, alkylSO2R9, —CN, —CO2R9, trihaloalkyl, dihaloalkyl, monohaloalkyl, —NR16COR9, —NR16CONR92, —NR16SO2—R13, —SO2R9, —COR9, —NO2, —SO—NR92, aryl, heteroaryl, —NR92, —SR9, —SOR9,





provided that said Formula G does not include the compounds of Table A as defined above.

In another embodiment, this invention discloses a compound of Formula H:




or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, wherein:

Y, R3, R4, R7, R8, R9 and R12 are as described in Formula I above;
Z is a linker attached at either end of said liner to the parent ring of Formula H, wherein said linker is selected from the group consisting of;




wherein

n is 1 to 4,

p is 0 to 2,

q is 1 to 3;

R5 is —CR92— wherein said —CR92— is attached at one end to Z and at the second end substituted with one or more moieties, which can be the same or different, each moiety being independently selected from the group consisting of H, alkyl, alkenyl, cycloalkyl, cyclenyl, aryl, heterocyclyl, heterocyclenyl, heteroaryl, cycloalkylalkyl, cyclenylalkyl, arylalkyl, heterocyclylalkyl, heterocyclenylalkyl, heteroarylalkyl, cycloalkylalkenyl, cyclenylalkenyl, arylalkenyl, heterocyclylalkenyl, heterocyclenylalkenyl, heteroarylalkenyl, —OR9 and —NR92, further, wherein each of said alkyl, alkenyl, cycloalkyl, cyclenyl, aryl, heterocyclyl, heterocyclenyl, heteroaryl, cycloalkylalkyl, cyclenylalkyl, arylalkyl, heterocyclylalkyl, heterocyclenylalkyl, heteroarylalkyl, cycloalkylalkenyl, cyclenylalkenyl, arylalkenyl, heterocyclylalkenyl, heterocyclenylalkenyl, or heteroarylalkenyl can be unsubstituted or substituted with one or more moieties, which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, alkenyl, cycloalkyl, —OR9, alkylOR9, alkylCO2R9, alkylNR16COR9, alkylNR16CONR9, alkylSO2R9, alkylCOR9, alkylSO2NR92, alkylNR92, alkylaryl, alkylheteroaryl, alkylSR9, alkylSOR9, —CN, —CO2R9, trihaloalkyl, dihaloalkyl, monohaloalkyl, —NR16COR9, —NR16CONR92, —NR16SO2—R13, —SO2R9, —COR9, —NO2, —SO2NR92, aryl, heteroaryl, —NR92, —SR9, —SOR9,




provided that Formula H does not include the compounds of Table A as defined above.

In another embodiment, this invention discloses a compound of Formula J




or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, wherein:

Y, R3, R4, R5, R8, R9 and R12 are as described in Formula I above,
wherein
q is 1,
p is 0-1,
provided that Formula J does not include the compounds of Table A as defined above.
In another embodiment, this invention discloses a compound of Formula K




or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, wherein:

    Y is —O— and R5 is —SO2—, and R4 and the second end substituent on R5 together are -alkyl-, -alkenyl-, -alkyl-NH—, or -alkenyl-NH—, forming a ring with the —O— and —SO2— groups to which they are attached;
    or Y is —O— and R5 is —SO2—, and R4 and the second end substituent of R5 together are an -alkyl-phenylene-alkyl-NR13— group or a -alkyl-phenylene-alkyl- group, forming a ring with the —O— and —SO2— groups to which they are attached;
    or Y is —O— and R5 is —SO2—, and R4 and the second end substituent of R5 together are an -alkyl-heteroarylene-alkyl- group or an -alkyl-heteroarylene-alkyl-NR13— group, forming a ring with the —O— and —SO2— groups to which they are attached; and
    R3, R7, R8 and R13 are as described in Formula I above;
    provided that Formula K does not include the compounds of Table A as defined above.


In another embodiment, this invention discloses a compound of Formula L




wherein R13 is mono- or dihalo-phenyl;

R4 is alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted benzyl, or optionally substituted benzofused cycloalkyl;

R5 is —SO2— wherein the second end substituent is alkyl, haloalkyl, optionally substituted arylalkyl, or optionally substituted heteroarylalkyl; or —N(R9)2, wherein one R9 is H and the other is optionally substituted arylalkyl or optionally substituted heteroarylalkyl; or R4 and the second end substituent on R5 together are -alkenyl-;

provided that Formula L does not include the compounds of Table A as defined above.

In each of Formulas I, A, B, C, D, B, F, G, H, J, K and L, R3 is preferably optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl or optionally substituted heteroaryl alkyl. R3 is more preferably optionally substituted phenyl, with the preferred optional substituents being 1 or 2 halogens.
In each of Formulas I, A, B, C, D, E, F, G, H, J, K and L, when the R4 group has a substituent that includes an R9 group, R9 is preferably H, alkyl, aryl or arylalkyl, more preferably H, alkyl, phenyl or benzyl.
In each of Formulas I, A, B, C, D, E, F, G, H, J, K and L, R6 is preferably H, alkyl or optionally substituted alkyl (e.g., -alkyl-OR9). When the R6 group has a substituent that includes an R9 group, R9 is preferably H, alkyl, aryl or arylalkyl, more preferably H, alkyl, phenyl or benzyl.
In each of Formulas I, A, B, C, D, E, F, G, H and J, R8 is preferably H or alkyl. When the R8 group has a substituent that includes an R9 group, R9 is preferably H, alkyl, aryl or arylalkyl, more preferably H, alkyl, phenyl or benzyl.
Preferred compounds of Formula I include:





































More preferred compounds of Formula I include:




















Further, the compounds of the present invention, represented by structural Formulas I, A, B, C, D, E, F, G, H, J, K and L are inhibitors of glucan synthase and therefore are useful in the treatment or prevention of fungal infections caused by pathogens such as Candida, Cryptococcus, Pichia, Rhodotorula, Saccharomyces, Trichosporon, Absidia, Apophysomyces, Aspergillus, Bjerkandera, Blastomyces, Coccidioides, Cunninghamella, Exophiala, Fusarium, Histoplasma, Microsporum, Mucor, Paecilomyces, Penicillium, Pseudallescheria, Ramichloridium, Rhizomucor, Rhizopus, Saksenaea, Scedosporium, Sporothrix, Trichophyton, Wangiella, Alternaria, Aphanomyces, Ascophyta, Biploaris, Botrytis, Cercospora, Claviceps, Cochlhioobolus, Colletotrichum, Erysiphe, Gibberella, Glomerella, Gomyces, Guignardia, Helminthosporium, Leptosphaeria, Magnaporthe, Microdochium, Monolinia, Mycosphaerella, Nectria, Penicillium, Plasmopara, Podosphaera, Puccinia, Pyrenophora, Pyricularia, Pythium, Phytophthora, Rhizoctonia, Sclerotina, Sclerotium, Septoria, Sphaerotheca, Thielaviopsis, Tilletia, Uncinula, Urocystis, Ustilago, Venturia, Verticillium, Microsporum, Malassezia, Paracoccidioides, Trichosporon, Aureobasidium, Etserophilum, and Geotrichum. 
As used above, and throughout this disclosure, the following terms, unless otherwise indicated, shall be understood to have the following meanings:
“Patient” includes both human and animals.
“Mammal” means humans and other mammalian animals.
“Alkyl” means an aliphatic hydrocarbon group which may be straight or branched and comprising about 1 to about 20 carbon atoms in the chain. Preferred alkyl groups contain about 1 to about 12 carbon atoms in the chain. More preferred alkyl groups contain about 1 to about 6 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkyl chain. “Lower alkyl” means a group having about 1 to about 6 carbon atoms in the chain which may be straight or branched. “Alkyl” may be unsubstituted or optionally substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of halo, alkyl, aryl, cycloalkyl, cyano, hydroxy, alkoxy, alkoxyalkoxy alkylthio, amine, —NH(alkyl), —NH(cycloalkyl), —N(alkyl)2, carboxy and —C(O)O-alkyl. Non-limiting examples of suitable alkyl groups include methyl, ethyl, n-propyl, isopropyl and t-butyl.
“Alkenyl” means an aliphatic hydrocarbon group containing at least one carbon-carbon double bond and which may be straight or branched and comprising about 2 to about 15 carbon atoms in the chain. Preferred alkenyl groups have about 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 6 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkenyl chain. “Lower alkenyl” means about 2 to about 6 carbon atoms in the chain which may be straight or branched. “Alkenyl” may be unsubstituted or optionally substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of halo, alkyl, aryl, cycloalkyl, cyano, alkoxy and —S(alkyl). Non-limiting examples of suitable alkenyl groups include ethenyl, propenyl, n-butenyl, 3-methylbut-2-enyl, n-pentenyl, octenyl and decenyl.
“Alkylene” means a difunctional group obtained by removal of a hydrogen atom from an alkyl group that is defined above. Non-limiting examples of alkylene include methylene, ethylene and propylene.
“Alkynyl” means an aliphatic hydrocarbon group containing at least one carbon-carbon triple bond and which may be straight or branched and comprising about 2 to about 15 carbon atoms in the chain. Preferred alkynyl groups have about 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 4 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkynyl chain. “Lower alkynyl” means about 2 to about 6 carbon atoms in the chain which may be straight or branched. Non-limiting examples of suitable alkynyl groups include ethynyl, propynyl, 2-butynyl and 3-methylbutynyl. “Alkynyl” may be unsubstituted or optionally substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of alkyl, aryl and cycloalkyl.
“Amine” is a type of functional group that contains a nitrogen as the key atom. Structurally it resembles ammonia, wherein one or more hydrogen atoms are replaced by organic substituents such as alkyl, cycloalkyl, aryl or any of the other organic substituents defined herein. “Amino” is the amine, as defined above, as a functional group or substituent.
“Aryl” means an aromatic monocyclic or multicyclic ring system comprising about 6 to about 14 carbon atoms, preferably about 6 to about 10 carbon atoms. The aryl group can be optionally substituted with one or more “ring system substituents” which may be the same or different, and are as defined herein. Non-limiting examples of suitable aryl groups include phenyl and naphthyl.
“Heteroaryl” means an aromatic monocyclic or multicyclic ring system comprising about 5 to about 14 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the ring atoms is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination. Preferred heteroaryls contain about 5 to about 6 ring atoms. The “heteroaryl” can be optionally substituted by one or more “ring system substituents” which may be the same or different, and are as defined herein. The prefix aza, oxa or thia before the heteroaryl root name means that at least a nitrogen, oxygen or sulfur atom respectively, is present as a ring atom. A nitrogen atom of a heteroaryl can be optionally oxidized to the corresponding N-oxide. “Heteroaryl” may also include a heteroaryl as defined above fused to an aryl as defined above. Non-limiting examples of suitable heteroaryls include pyridyl, pyrazinyl, furanyl, thienyl, primidinyl, pyridone (including N-substituted pyridones), isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl, 1,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl, oxindolyl, imidazo[1,2-a]pyridinyl, imidazo[2,1-b]thiazolyl, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl, imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl, pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl, 1,2,4-triazinyl, benzothiazolyl, carbazolyl and the like. The term “heteroaryl” also refers to partially saturated heteroaryl moieties such as, for example, tetrahydroisoquinolyl, tetrahydroquinolyl and the like.
“Aralkyl” or “arylalkyl” an aryl-alkyl- group in which the aryl and alkyl are as previously described. Preferred aralkyls comprise a lower alkyl group. Non-limiting examples of suitable aralkyl groups include benzyl, 2-phenethyl and naphthalenylmethyl. Arylalkenyl an aryl-alkenyl group in which the aryl and alkenyl are as previously described. The bond to the parent moiety is through the alkyl or alkenyl respectively.
“Alkylaryl” means an alkyl-aryl- group in which the alkyl and aryl are as previously described. Preferred alkylaryls comprise a lower alkyl group. Non-limiting example of a suitable alkylaryl group is tolyl. The bond to the parent moiety is through the aryl.
“Cycloalkyl” means a non-aromatic mono- or multicyclic ring system comprising about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoms. Preferred cycloalkyl rings contain about 5 to about 7 ring atoms. The cycloalkyl can be optionally substituted with one or more “ring system substituents” which may be the same or different, and are as defined above. Non-limiting examples of suitable monocyclic cycloalkyls include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. Non-limiting examples of suitable multicyclic cycloalkyls include 1-decalinyl, norbornyl, adamantyl and the like.
“Cycloalkylalkyl” means a cycloalkyl moiety as defined above linked via an alkyl moiety (defined above) to a parent core. Non-limiting examples of suitable cycloalkylalkyls include cyclohexylmethyl, adamantylmethyl and the like,
“Cycloalkylalkenyl” means a cycloalkyl moiety as defined above linked via an alkenyl moiety (defined above) to a parent core.
“Cycloalkenyl” or “cyclenyl” means a non-aromatic mono or multicyclic ring system comprising about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoms which contains at least one carbon-carbon double bond. Preferred cycloalkenyl rings contain about 5 to about 7 ring atoms. The cycloalkenyl can be optionally substituted with one or more “ring system substituents” which may be the same or different, and are as defined above. Non-limiting examples of suitable monocyclic cycloalkenyls include cyclopentenyl, cyclohexenyl, cyclohepta-1,3-dienyl, and the like. Non-limiting example of a suitable multicyclic cycloalkenyl is norbornylenyl.
“Cycloalkenylalkyl” or “cyclenylalkyl” means a cycloalkenyl or cyclenyl moiety as defined above linked via an alkyl moiety (defined above) to a parent core. Non-limiting examples of suitable cycloalkenylalkyls include cyclopentenylmethyl, cyclohexenylmethyl and the like.
“Cycloalkenylalkenyl” or “cyclenylalkenyl” means a cycloalkenyl or cyclenyl moiety as defined above linked via an alkenyl moiety (defined above) to a parent core.
“Halogen” means fluorine, chlorine, bromine, or iodine. Preferred are fluorine, chlorine and bromine.
“Ring system substituent” means a substituent attached to an aromatic or non-aromatic ring system which, for example, replaces an available hydrogen on the ring system. Ring system substituents may be the same or different, each being independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, alkylaryl, heteroaralkyl, heteroarylalkenyl, heterorylalkynyl, alkylheteroaryl, hydroxy, hydroxyalkyl, alkoxy, trihaloalkoxy, aryloxy, aralkoxy, alkoxyalkoxy, acyl, aroyl, halo, monohaloalkyl, dihaloalkyl, trihaloalkyl, nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylthio, arylthio, heteroarylthio, aralkylthio, heteroaralkylthio, cycloalkyl, heterocyclyl, —C(═N—CN)—NH2, —C(═NH)—NH2, —C(═NH)—NH(alkyl), —NY1Y2, -alkyl-NY1Y2, —C(O)NY1Y2 and —SO2NY1Y2, wherein Y1 and Y2 can be the same or different and are independently selected from the group consisting of hydrogen, alkyl aryl, cycloalkyl, and aralkyl. “Ring system substituent” may also mean a single moiety which simultaneously replaces two available hydrogens on two adjacent carbon atoms (one H on each carbon) on a ring system. Examples of such moiety are methylene dioxy, ethylenedioxy, —C(CH3)2— and the like which form moieties such as, for example:




“Heteroarylalkyl” means a heteroaryl moiety as defined above linked via an alkyl moiety (defined above) to a parent core. Non-limiting examples of suitable heteroaryls include 2-pyridinylmethyl, quinolinylmethyl and the like.
“Heteroalkyl” is a saturated or unsaturated chain containing carbon and at least one heteroatom, wherein one or more of the chain atoms is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination, wherein no two heteroatoms are adjacent. Heteroalkyl chains contain from 2 to 15 member atoms (carbon and heteroatoms) in the chain, preferably 2 to 10, more preferably 2 to 5. For example, alkoxy (i.e., —O-alkyl or —O-heteroalkyl) radicals are included in heteroalkyl. Heteroalkyl chains may be straight or branched. Preferred branched heteroalkyl have one or two branches, preferably one branch. Preferred heteroalkyl are saturated. Unsaturated heteroalkyl have one or more carbon-carbon double bonds and/or one or more carbon-carbon triple bonds. Preferred unsaturated heteroalkyls have one or two double bonds or one triple bond, more preferably one double bond. Heteroalkyl chains may be unsubstituted or substituted with from 1 to 4 substituents. Preferred substituted heteroalkyl are mono-, di-, or tri-substituted. Heteroalkyl may be substituted with lower alkyl, haloalkyl, halo, hydroxy, aryloxy, heteroaryloxy, acyloxy, carboxy, monocyclic aryl, heteroaryl, cycloalkyl, heterocyclyl, spirocycle, amine, acylamino, amido, keto, thioketo, cyano, or any combination thereof.
“Heterocyclyl” or “Heterocycloalkyl” means a non-aromatic saturated monocyclic or multicyclic ring system comprising about 3 to about 10 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the atoms in the ring system is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination. There are no adjacent oxygen and/or sulfur atoms present in the ring system. Preferred heterocyclyls contain about 5 to about 6 ring atoms. The prefix aza, oxa or thia before the heterocyclyl root name means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom. Any —NH in a heterocyclyl ring may exist protected such as, for example, as —N(Boc), —N(CBz), —N(Tos) group and the like; such protections are also considered part of this invention. The heterocyclyl can be optionally substituted by one or more “ring system substituents” which may be the same or different, and are as defined herein. The nitrogen or sulfur atom of the heterocyclyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Non-limiting examples of suitable monocyclic heterocyclyl rings include piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, lactam, lactone, and the like. “Heterocyclyl” may also mean heterocyclyl ring wherein a single moiety (e.g., carbonyl) simultaneously replaces two available hydrogens on the same carbon atom on a ring system. Example of such moiety is pyrrolidone:




“Heterocyclylalkyl” or “Heterocycloalkylalkyl” means a heterocyclyl moiety as defined above linked via an alkyl moiety (defined above) to a parent core. Non-limiting examples of suitable heterocyclylalkyls include piperidinylmethyl, piperazinylmethyl and the like.
“Heterocyclylalkenyl” or “Heterocycloalkylalkenyl” means a heterocyclyl moiety as defined above linked via an alkenyl moiety (defined above) to a parent core.
“Heterocyclenyl” or “Heterocycloalkenyl” means a non-aromatic monocyclic or multicyclic ring system comprising about 3 to about 15 ring atoms, preferably about 5 to about 14 ring atoms, in which one or more of the atoms in the ring system is an element other than carbon, for example nitrogen, oxygen or sulfur atom, alone or in combination, and which contains at least one carbon-carbon double bond or carbon-nitrogen double bond. There are no adjacent oxygen and/or sulfur atoms present in the ring system. Preferred heterocyclenyl rings contain about 5 to about 13 ring atoms. The prefix aza, oxa or thia before the heterocyclenyl root name means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom. The heterocyclenyl can be optionally substituted by one or more ring system substituents, wherein “ring system substituent” is a defined above. The nitrogen or sulfur atom of the heterocyclenyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Non-limiting examples of suitable heterocyclenyl groups include 1,2,3,4-tetrahydropyridinyl, 1,2-dihydropyridinyl, 1,4-dihydropyridinyl, 1,2,3,6-tetrahydropyridinyl, 1,4,5,6-tetrahydropyrimidinyl, 2-pyrrolinyl, 3-pyrrolinyl, 2-imidazolinyl, 2-pyrazolinyl, dihydroimidazolyl, dihydrooxazolyl, dihydrooxadiazolyl dihydrothiazolyl, 3,4-dihydro-2H-pyranyl, dihydrofuranyl, fluorodihydrofuranyl, 7-oxabicyclo[2.2.1]heptenyl, dihydrothiophenyl, dihydrothiopyranyl, and the like. “Heterocyclenyl” may also mean a heterocyclenyl ring wherein a single moiety (e.g., carbonyl) simultaneously replaces two available hydrogens on the same carbon atom on a ring system. Example of such moiety is pyrrolidinone:




“Heterocyclenylalkyl” means a heterocyclenyl moiety as defined above linked via an alkyl moiety (defined above) to a parent core.
“Heterocyclenylalkenyl” means a heterocyclenyl moiety as defined above linked via an alkenyl moiety (defined above) to a parent core.
It should be noted that in hetero-atom containing ring systems of this invention, there are no hydroxyl groups on carbon atoms adjacent to a N, O or S, as well as there are no N or S groups on carbon adjacent to another heteroatom. Thus, for example, in the ring:




there is no —OH attached directly to carbons marked 2 and 5.

It should also be noted that tautomeric forms such as, for example, the moieties:




are considered equivalent in certain embodiments of this invention.

“Heterocyclenylalkenyl” means a heterocyclenyl moiety as defined above linked via an alkenyl moiety (defined above) to a parent core.
“Heteroalkyl” is a saturated or unsaturated chain containing carbon and at least one heteroatom, wherein no two heteroatoms are adjacent. Heteroalkyl chains contain from 2 to 15 member atoms (carbon and heteroatoms) in the chain, preferably 2 to 10, more preferably 2 to 5. For example, alkoxy (i.e., —O-alkyl or —O-heteroalkyl) radicals are included in heteroalkyl. Heteroalkyl chains may be straight or branched. Preferred branched heteroalkyl have one or two branches, preferably one branch. Preferred heteroalkyl are saturated. Unsaturated heteroalkyl have one or more carbon-carbon double bonds and/or one or more carbon-carbon triple bonds. Preferred unsaturated heteroalkyls have one or two double bonds or one triple bond, more preferably one double bond. Heteroalkyl chains may be unsubstituted or substituted with from 1 to 4 substituents. Preferred substituted heteroalkyl are mono-, di-, or tri-substituted. Heteroalkyl may be substituted with lower alkyl, haloalkyl, halo, hydroxy, aryloxy, heteroaryloxy, acyloxy, carboxy, monocyclic aryl, heteroaryl, cycloalkyl, heterocycloalkyl, spirocycle, amine, acylamine, amido, keto, thioketo, cyano, or any combination thereof.
“Alkynylalkyl” means an alkynyl-alkyl- group in which the alkynyl and alkyl are as previously described. Preferred alkynylalkyls contain a lower alkynyl and a lower alkyl group. The bond to the parent moiety is through the alkyl. Non-limiting examples of suitable alkynylalkyl groups include propargylmethyl.
“Heteroaralkyl” means a heteroaryl-alkyl- group in which the heteroaryl and alkyl are as previously described. Preferred heteroaralkyls contain a lower alkyl group. Non-limiting examples of suitable aralkyl groups include pyridylmethyl, and quinolin-3-ylmethyl. The bond to the parent moiety is through the alkyl.
“Hydroxyalkyl” means a HO-alkyl- group in which alkyl is as previously defined. Preferred hydroxyalkyls contain lower alkyl. Non-limiting examples of suitable hydroxyalkyl groups include hydroxymethyl and 2-hydroxyethyl.
“Spiro ring systems” have two or more rings linked by one common atom. Preferred spiro ring systems include spiroheteroaryl, spiroheterocyclenyl, spiroheterocyclyl, spirocycloalkyl, spirocyclenyl, and spiroaryl. Non-limiting examples of suitable spiro ring systems include




spiro[4.5]decane,





8-azaspiro[4.5]dec-2-ene, and





spiro[4.4]nona-2,7-diene.

“Acyl” means an H—C(O)—, alkyl-C(O)— or cycloalkyl-C(O)—, group in which the various groups are as previously described. The bond to the parent moiety is through the carbonyl. Preferred acyls contain a lower alkyl. Non-limiting examples of suitable acyl groups include formyl, acetyl and propanoyl.
“Aroyl” means an aryl-C(O)— group in which the aryl group is as previously described. The bond to the parent moiety is through the carbonyl. Non-limiting examples of suitable groups include benzoyl and 1-naphthoyl.
“Alkoxy” means an alkyl-O— group in which the alkyl group is as previously described. Non-limiting examples of suitable alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. The bond to the parent moiety is through the ether oxygen. An alkoxy linked directly to another alkoxy is an “alkoxyalkoxy”.
“Aryloxy” means an aryl-O— group in which the aryl group is as previously described. Non-limiting examples of suitable aryloxy groups include phenoxy and naphthoxy. The bond to the parent moiety is through the ether oxygen.
“Aralkyloxy” means an aralkyl-O— group in which the aralkyl group is as previously described. Non-limiting examples of suitable aralkyloxy groups include benzyloxy and 1- or 2-naphthalenemethoxy. The bond to the parent moiety is through the ether oxygen.
“Alkylthio” or “thioalkoxy” means an alkyl-S— group in which the alkyl group is as previously described. Non-limiting examples of suitable alkylthio groups include methylthio and ethylthio. The bond to the parent moiety is through the sulfur.
“Arylthio” means an aryl-S— group in which the aryl group is as previously described. Non-limiting examples of suitable arylthio groups include phenylthio and naphthylthio. The bond to the parent moiety is through the sulfur.
“Aralkylthio” means an aralkyl-S— group in which the aralkyl group is as previously described. Non-limiting example of a suitable aralkylthio group is benzylthio. The bond to the parent moiety is through the sulfur.
“Alkoxycarbonyl” means an alkyl-O—CO— group. Non-limiting examples of suitable alkoxycarbonyl groups include methoxycarbonyl and ethoxycarbonyl. The bond to the parent moiety is through the carbonyl.
“Aryloxycarbonyl” means an aralkyl-O—C(O)— group. Non-limiting examples of suitable aryloxycarbonyl groups include phenoxycarbonyl and naphthoxycarbonyl. The bond to the parent moiety is through the carbonyl.
“Aralkoxycarbonyl” means an aralkyl-O—C(O)— group. Non-limiting example of a suitable aralkoxycarbonyl group is benzyloxycarbonyl. The bond to the parent moiety is through the carbonyl.
“Alkylsulfonyl” means an alkyl-S(O2)— group. Preferred groups are those in which the alkyl group is lower alkyl. The bond to the parent moiety is through the sulfonyl.
“Arylsulfonyl” means an aryl-S(O2)— group. The bond to the parent moiety is through the sulfonyl.
The terms “arylene” and heteroarylene” mean divalent aryl and heteroaryl groups, e.g.,




“Benzofused-cycloalkyl” and benzofused-heterocycloalkyl” mean that a benzene ring is fused to two adjacent carbon atoms of a cycloalkyl or heterocycloalkyl ring. The group is joined to the rest of the molecule through a carbon atom in the cycloalkyl or heterocycloalkyl ring. Both the aromatic and saturated ring moieties are optionally substituted by suitable ring system substituents as defined above. Examples of benzofused-cycloalkyl and benzofused-heterocycloalkyl groups are




In the terms above “oxyl” means the same as “oxy”, i.e., alkoxyl and alkoxy both refer to an alkyl-O— group.
In the terms above, where a nitrogen atom appears in a chain of atoms and a substituent on the third bond to the nitrogen is not identified, the third bond is understood to be hydrogen, e.g., -alkyl-N-alkyl- is -alkyl-NH-alkyl.
In the terms above, when two R9 groups on a N form a ring, non-limiting examples of such rings are




In the terms above, when an nitrogen-containing radical is written as, for example, —CONR9R16, the two “R” groups are each attached to the nitrogen, i.e.,




In the definitions above, notably in the “R” groups, where no hyphen is present to indicate the point of attachment and the term is not otherwise defined, the radical is attached to the rest of the molecule through the group on the right side of the term, e.g., “alkylalkenyl” is “alkylalkenyl-”.
The term “substituted” means that one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency under the existing circumstances is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds. By “stable compound’ or “stable structure” is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
The term “optionally substituted” means optional substitution with the specified groups radicals or moieties.
The terms “one or more” and “at least one”, when referring to the number of substituents on a group (e.g., alkyl, aryl or heteroaryl) means 1 to 6 substituents, preferably 1 to 3 substituents, unless otherwise specified.
The term “purified”, “in purified form” or “in isolated and purified form” for a compound refers to the physical state of said compound after being isolated from a synthetic process (e.g. from a reaction mixture), or natural source or combination thereof. Thus, the term “purified”, “in purified form” or “in isolated and purified form” for a compound refers to the physical state of said compound after being obtained from a purification process or processes described herein or well known to the skilled artisan (e.g., chromatography, recrystallization and the like), in sufficient purity to be characterizable by standard analytical techniques described herein or well known to the skilled artisan.
It should also be noted that any carbon as well as heteroatom with unsatisfied valences in the text, schemes, examples and Tables herein is assumed to have the sufficient number of hydrogen atom(s) to satisfy the valences.
When a functional group in a compound is termed “protected”, this means that the group is in modified form to preclude undesired side reactions at the protected site when the compound is subjected to a reaction. Suitable protecting groups will be recognized by those with ordinary skill in the art as well as by reference to standard textbooks such as, for example, T. W. Greene et al, Protective Groups in organic Synthesis (1991), Wiley, New York.
When any variable (e.g., aryl, heterocycle, R2, etc.) occurs more than one time in any constituent or in Formulas I, A, B, C, D, E, F, G, H, J, K and L, its definition on each occurrence is independent of its definition at every other occurrence.
As used herein, the term “composition” is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
Prodrugs and solvates of the compounds of the invention are also contemplated herein. A discussion of prodrugs is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems (1987) 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, (1987) Edward B. Roche, ed., American Pharmaceutical Association and Pergamon Press. The term “prodrug” means a compound (e.g, a drug precursor) that is transformed in vivo to yield a compound of Formulas I, A, B, C, D, E, F, G, H, J, K and L or a pharmaceutically acceptable salt, hydrate or solvate of the compound. The transformation may occur by various mechanisms (e.g., by metabolic or chemical processes), such as, for example, through hydrolysis in blood. A discussion of the use of prodrugs is provided by T. Higuchi and W. Stella, “Pro-drugs as Novel Delivery Systems,” Vol. 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.
For example, if a compound of Formula I, Formula A, Formula B, Formula C, Formula D, Formula E, Formula F, Formula G, Formula H, Formula J, Formula K or Formula L or a pharmaceutically acceptable salt, hydrate or solvate of the compound contains a carboxylic acid functional group, a prodrug can comprise an ester formed by the replacement of the hydrogen atom of the acid group with a group such as, for example, (C1-C8)alkyl, (C2-C12)alkanoyloxymethyl, 1-(alkanoyloxy)ethyl having from 4 to 9 carbon atoms, 1-methyl-1-(alkanoyloxy)-ethyl having from 5 to 11 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms, 1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, N-(alkoxycarbonyl)aminemethyl having from 3 to 9 carbon atoms, 1-(N-(alkoxycarbonyl)amine)ethyl having from 4 to 10 carbon atoms, 3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl, di-N,N—(C1-C2)alkylamine(C2-C3)alkyl (such as β-dimethylamineethyl), carbamoyl-(C1-C2)alkyl, N,N-di(C1-C2)alkylcarbamoyl-(C1-C2)alkyl and piperidino-, pyrrolidino- or morpholino(C2-C3)alkyl, and the like.
Similarly, if a compound of Formula I, Formula A, Formula B, Formula C, Formula D, Formula E, Formula F, Formula G, Formula H, Formula J, Formula K or Formula L contains an alcohol functional group, a prodrug can be formed by the replacement of the hydrogen atom of the alcohol group with a group such as, for example, (C1-C6)alkanoyloxymethyl, 1-((C1-C6)alkanoyloxy)ethyl, 1-methyl-1-((C1-C6)alkanoyloxy)ethyl, (C1-C6)alkoxycarbonyloxymethyl, N—(C1-C6)alkoxycarbonylaminomethyl, succinoyl, (C1-C6)alkanoyl, α-amino(C1-C4)alkanyl, arylacyl and α-aminoacyl, or α-aminoacyl-α-aminoacyl, where each α-aminoacyl group is independently selected from the naturally occurring, L-amino acids, P(O)(OH)2, —P(O)(O(C1-C6)alkyl) or glycosyl (the radical resulting from the removal of a hydroxyl group of the hemiacetal form of a carbohydrate) and the like.
If a compound of Formula I, Formula A, Formula B, Formula C, Formula D, Formula E, Formula F, Formula G, Formula U, Formula J, Formula K or Formula L incorporates an amine functional group, a prodrug can be formed by the replacement of a hydrogen atom in the amine group with a group such as, for example, R-carbonyl, RO-carbonyl, NRR′-carbonyl where R and R′ are each independently (C1-C10)alkyl, (C3-C7)cycloalkyl, benzyl, or R-carbonyl is a natural α-aminoacyl or natural α-aminoacyl, —C(OH)C(O)OY1 wherein Y1 is H, (C1-C6)alkyl or benzyl, —C(OY2)Y3 wherein Y2 is (C1-C4)alkyl and Y3 is (C1-C6)alkyl, carboxy (C1-C6)alkyl, amino(C1-C4)alkyl or mono-N— or di-N,N—(C1-C6)alkylaminoalkyl, —C(Y4)Y5 wherein Y4 is H or methyl and Y5 is mono-N— or di-N,N—(C1-C6)alkylamino morpholino, piperidin-1-yl or pyrrolidin-1-yl, and the like.
One or more compounds of the invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the invention embrace both solvated and unsolvated forms. “Solvate” means a physical association of a compound of this invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. “Solvate” encompasses both solution-phase and isolatable solvates. Non-limiting examples of suitable solvates include ethanolates, methanolates, and the like. “Hydrate” is a solvate wherein the solvent molecule is H2O.
One or more compounds of the invention may optionally be converted to a solvate. Preparation of solvates is generally known. Thus, for Example, M. Caira et al, J. Pharmaceutical Sci. 93(3), 601-611 (2004) describe the preparation of the solvates of the antifungal fluconazole in ethyl acetate as well as from water. Similar preparations of solvates, hemisolvate, hydrates and the like are described by E. C. van Tonder et al, AAPS Pharm SciTech., 5(1), article 12 (2004); and A. L. Bingham et al, Chem. Commun., 603-604 (2001). A typical, non-limiting, process involves dissolving the inventive compound in desired amounts of the desired solvent (organic or water or mixtures thereof) at a higher than ambient temperature, and cooling the solution at a rate sufficient to form crystals which are then isolated by standard methods. Analytical techniques such as, for example I. R. spectroscopy, show the presence of the solvent (or water) in the crystals as a solvate (or hydrate).
“Effective amount” or “therapeutically effective amount” is meant to describe an amount of compound or a composition of the present invention effective in inhibiting the above-noted diseases and thus producing the desired therapeutic, ameliorative, inhibitory or preventative effect.
The compounds of Formulas I, A, B, C, D, E, F, G, H, J, K and L can form salts which are also within the scope of this invention. Reference to a compound of Formulas I, A, B, C, D, E, F, G, H, J, K and L herein is understood to include reference to salts thereof, unless otherwise indicated. The term “salt(s)”, as employed herein, denotes acidic salts formed with inorganic and/or organic acids, as well as basic salts formed with inorganic and/or organic bases. In addition, when a compound of Formulas I, A, B, C, D, E, F, G, H, J, K and L contains both a basic moiety, such as, but not limited to a pyridine or imidazole, and an acidic moiety, such as, but not limited to a carboxylic acid, zwitterions (“inner salts”) may be formed and are included within the term “salt(s)” as used herein. Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful. Salts of the compounds of the Formulas I, A, B, C, D, F, F, G, H, J, K and L may be formed, for example, by reacting a compound of Formulas I, A, B, C, D, E, F, G, H, J, K and L with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.
Exemplary acid addition salts include acetates, ascorbates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, fumarates, hydrochlorides, hydrobromides, hydroiodides, lactates, maleates, methanesulfonates, naphthalenesulfonates, nitrates, oxalates, phosphates, propionates, salicylates, succinates, sulfates, tartarates, thiocyanates, toluenesulfonates (also known as tosylates,) and the like. Additionally, acids which are generally considered suitable for the formation of pharmaceutically useful salts from basic pharmaceutical compounds are discussed, for example, by P. Stahl et al, Camille G. (eds.) Handbook of Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiley-VCH; S. Berge et al, Journal of Pharmaceutical Sciences (1977) 1-19; P. Gould, International of Pharmaceutics (1986) 33 201-217; Anderson et al, The Practice of Medicinal Chemistry (1996), Academic Press, New York; and in The Orange Book (Food & Drug Administration, Washington, D.C. on their website). These disclosures are incorporated herein by reference thereto.
Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as dicyclohexylamines, t-butyl amines, and salts with amino acids such as arginine, lysine and the like. Basic nitrogen-containing groups may be quarternized with agents such as lower alkyl halides (e.g. methyl, ethyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g. dimethyl, diethyl, and dibutyl sulfates), long chain halides (e.g. decyl, lauryl, and stearyl chlorides, bromides and iodides), aralkyl halides (e.g. benzyl and phenethyl bromides), and others.
All such acid salts and base salts are intended to be pharmaceutically acceptable salts within the scope of the invention and all acid and base salts are considered equivalent to the free forms of the corresponding compounds for purposes of the invention.
Pharmaceutically acceptable esters of the present compounds include the following groups: (1) carboxylic acid esters obtained by esterification of the hydroxy groups, in which the non-carbonyl moiety of the carboxylic acid portion of the ester grouping is selected from straight or branched chain alkyl (for example, acetyl, n-propyl, t-butyl, or n-butyl), alkoxyalkyl (for example, methoxymethyl), aralkyl (for example, benzyl), aryloxyalkyl (for example, phenoxymethyl), aryl (for example, phenyl optionally substituted with, for example, halogen, C1-4alkyl, or C1-4alkoxy or amino); (2) sulfonate esters, such as alkyl- or aralkylsulfonyl (for example, methanesulfonyl); (3) amino acid esters (for example, L-valyl or L-isoleucyl); (4) phosphonate esters and (5) mono-, di- or triphosphate esters. The phosphate esters may be further esterified by, for example, a C1-20 alcohol or reactive derivative thereof, or by a 2,3-di(C6-24)acyl glycerol.
Compounds of Formulas I, A, B, C, D, E, F, G, H, J, K and L, and salts, solvates, esters and prodrugs thereof, may exist in their tautomeric form (for example, as an amide or imino ether). All such tautomeric forms are contemplated herein as part of the present invention.
The compounds of Formulas I, A, B, C, D, E, F, G, H, J, K and L may contain asymmetric or chiral centers, and, therefore, exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of Formulas I, A, B, C, D, F, F, G, H, X, K and L as well as mixtures thereof including racemic mixtures, form part of the present invention. In addition, the present invention embraces all geometric and positional isomers. For example, if a compound of Formulas I, A, B, C, D, F, F, G, H, J, K and L incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are embraced within the scope of the invention.
Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as, for example, by chromatography and/or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g. chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. Also, some of the compounds of Formulas I, A, B, C, D, E, F, G, H, J, K and L may be atropisomers (e.g., substituted biaryls) and are considered as part of this invention. Enantiomers can also be separated by use of chiral HPLC column.
It is also possible that the compounds of Formulas I, A, B, C, D, E, F, G, H, J, K and L may exist in different tautomeric forms, and all such forms are embraced within the scope of the invention. Also, for example, all keto-enol and imine-enamine forms of the compounds are included in the invention.
All stereoisomers (for example, geometric isomers, optical isomers and the like) of the present compounds (including those of the salts, solvates, esters and prodrugs of the compounds as well as the salts, solvates and esters of the prodrugs), such as those which may exist due to asymmetric carbons on various substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomeric forms, are contemplated within the scope of this invention, as are positional isomers (such as, for example, 4-pyridyl and 3-pyridyl). (For example, if a compound of Formulas I, A, B, C, D, F, F, G, H, J, K and L incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are embraced within the scope of the invention. Also, for example all keto-enol and imine-enamine form-s of the compounds are included in the invention.) Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers. The chiral centers of the present invention can have the S or R configuration as defined by the IUPAC 1974 Recommendations. The use of the terms “salt”, “solvate”, “ester”, “prodrug” and the like, is intended to equally apply to the salt, solvate, ester and prodrug of enantiomers, stereoisomers, rotamers, tautomers, positional isomers, racemates or prodrugs of the inventive compounds.
The present invention also embraces isotopically-labelled compounds of the present invention which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as 2H, 3H, 13C, 14C, 15N, 18O, 17O, 31P, 32P, 35S, 18F, and 36Cl, respectively.
Certain isotopically-labelled compounds of Formulas I, A, B, C, D, F, F, G, H, J, K and L (e.g., those labeled with 3H and 14C) are useful in compound and/or substrate tissue distribution assays. Tritiated (i.e., 3H) and carbon-14 (i.e., 14C) isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., 2H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances. Isotopically labelled compounds of Formulas I, A, B, C, D, E, F, G, H, J, K and L can generally be prepared by following procedures Analogous to those disclosed in the Schemes and/or in the Examples hereinbelow, by substituting an appropriate isotopically labelled reagent for a non-isotopically labelled reagent.
Polymorphic forms of the compounds of Formulas I, A, B, C, D, E, F, G, H, J, K and L and of the salts, solvates, esters and prodrugs of the compounds of Formulas I, A, B, C, D, F, F, G, H, J, K and L are intended to be included in the present invention.
Capsule—refers to a special container or enclosure made of methyl cellulose, polyvinyl alcohols, or denatured gelatins or starch for holding or containing compositions comprising the active ingredients. Hard shell capsules are typically made of blends of relatively high gel strength bone and pork skin gelatins. The capsule itself may contain small amounts of dyes, opaquing agents, plasticizers and preservatives.
Tablet—refers to a compressed or molded solid dosage form containing the active ingredients with suitable diluents. The tablet can be prepared by compression of mixtures or granulations obtained by wet granulation, dry granulation or by compaction.
Oral gels—refer to the active ingredients dispersed or solubilized in a hydrophillic semi-solid matrix.
Powders for constitution refer to powder blends containing the active ingredients and suitable diluents which can be suspended in water or juices.
Diluent—refers to substances that usually make up the major portion of the composition or dosage form. Suitable diluents include sugars such as lactose, sucrose, mannitol and sorbitol; starches derived from wheat, corn rice and potato; and celluloses such as microcrystalline cellulose. The amount of diluent in the composition can range from about 10 to about 90% by weight of the total composition, preferably from about 25 to about 75%, more preferably from about 30 to about 60% by weight, even more preferably from about 12 to about 60%.
Disintegrants—refers to materials added to the composition to help it break apart (disintegrate) and release the medicaments. Suitable disintegrants include starches; “cold water soluble” modified starches such as sodium carboxymethyl starch; natural and synthetic gums such as locust bean, karaya, guar, tragacanth and agar; cellulose derivatives such as methylcellulose and sodium carboxymethylcellulose; microcrystalline celluloses and cross-linked microcrystalline celluloses such as sodium croscarmellose; alginates such as alginic acid and sodium alginate; clays such as bentonites; and effervescent mixtures. The amount of disintegrant in the composition can range from about 2 to about 15% by weight of the composition, more preferably from about 4 to about 10% by weight.
Binders—refers to substances that bind or “glue” powders together and make them cohesive by forming granules, thus serving as the “adhesive” in the formulation. Binders add cohesive strength already available in the diluent or bulking agent. Suitable binders include sugars such as sucrose; starches derived from wheat, corn rice and potato; natural gums such as acacia, gelatin and tragacanth; derivatives of seaweed such as alginic acid, sodium alginate and ammonium calcium alginate; cellulosic materials such as methylcellulose and sodium carboxymethylcellulose and hydroxypropylmethylcellulose; polyvinylpyrrolidone; and inorganics such as magnesium aluminum silicate. The amount of binder in the composition can range from about 2 to about 20% by weight of the composition, more preferably from about 3 to about 10% by weight, even more preferably from about 3 to about 6% by weight.
Lubricant—refers to a substance added to the dosage form to enable the tablet, granules, etc. after it has been compressed, to release from the mold or die by reducing friction or wear. Suitable lubricants include metallic stearates such as magnesium stearate, calcium stearate or potassium stearate; stearic acid; high melting point waxes; and water soluble lubricants such as sodium chloride, sodium benzoate, sodium acetate, sodium oleate, polyethylene glycols and d,l-leucine. Lubricants are usually added at the very last step before compression, since they must be present on the surfaces of the granules and in between them and the parts of the tablet press. The amount of lubricant in the composition can range from about 0.2 to about 5% by weight of the composition, preferably from about 0.5 to about 2%, more preferably from about 0.3 to about 1.5% by weight.
Glidents—materials that prevent caking and improve the flow characteristics of granulations, so that flow is smooth and uniform. Suitable glidents include silicon dioxide and talc. The amount of glident in the composition can range from about 0.1% to about 5% by weight of the total composition, preferably from about 0.5 to about 2% by weight.
Coloring agents—excipients that provide coloration to the composition or the dosage form. Such excipients can include food grade dyes and food grade dyes adsorbed onto a suitable adsorbent such as clay or aluminum oxide. The amount of the coloring agent can vary from about 0.1 to about 5% by weight of the composition, preferably from about 0.1 to about 1%.
Bioavailability—refers to the rate and extent to which the active drug ingredient or therapeutic moiety is absorbed into the systemic circulation from an administered dosage form as compared to a standard or control.
Conventional methods for preparing tablets are known. Such methods include dry methods such as direct compression and compression of granulation produced by compaction, or wet methods or other special procedures. Conventional methods for making other forms for administration such as, for example, capsules, suppositories and the like are also well known.
The compounds listed above are inhibitors of glucan synthase and therefore are useful in the treatment or prevention of fungal infections caused by pathogens such as Absidia corymbifera; Absidia spp; Acrenionium spp; Ajellomyces capsulatus; Ajellomyces dermatitidis; Alternaria spp; Aphanoascus fulvescens; Apophysomyces spp; Arthroderma benhamiae; Arthroderma fulvum; Arthroderma gypseum; Arthroderma incurvatum; Arthroderma otae; Arthroderma vanbreuseghemii; Aspergillus flavus; Aspergillus fumigatus; Aspergillus glaucus; Aspergillus nidulans; Aspergillus niger; Aspergillus oryzae; Aspergillus spp; Aspergillus sydowi; Aspergillus terreus; Aspergillus ustus; Aspergillus versicolor; Aureobasidium pullulans; Basidiomycetes; Beauveria spp; Bipolaris hawaiiensis; Bipolaris spicifera; Bipolaris spp; Bjerkandera adusta; Blastomyces dermatitidis; Blastoschizomyces capitals; Candida albicans; Candida beigelii, Candida colluculosa; Candida dubliniensis; Candida dubliniensis; Candida famata; Candida glabrata; Candida guilliermondii; Candida haemulonii; Candida holmii; Candida inconspicua; Candida intermedia; Candida keyfyr; Candida krusei; Candida lambica; Candida lipolytica; Candida lusitaniae; Candida maris; Candida melibiosica; Candida norvegensis; Candida parapsilosis; Candida pelliculosa; Candida pseudotropicalis; Candida pulcherrima; Candida rugosa; Candida sake; Candida sphaerica; Candida spp; Candida stellatoidea; Candida tropicalis; Candida viswanathii; Candida zeylanoides; Chrysosporium spp; Cladophialophora bantiana; Cladophialophora carrionii; Cladosporium spp; Coccidioides immitis; Cokeromyces recurvatus; Coprinus spp; Cryptococcus albidus; Cryptococcus gattii; Cryptococcus laurentii; Cryptococcus neoformans; Cunninghamella bertholletiae; Cunninghamella spp; Curvularia lunata; Curvularia spp; Dekkera bruxellensis; Epidermopkyton floccosum; Exophiala dermatitidis; Exophiala jeanselmei; Exophiala moniliae; Exserohilum rostratum; Filobasidiella neoformans; Fonsecaea pedrosoi; Fusarium dimerum; Fusarium moniliforme; Fusarium oxysporum; Fusarium proliferatum; Fusarium solani; Fusarium spp; Geotrichum canedidum; Geotrichum spp; Histoplasma capsulatum; Hortaea werneckii; Issatschenkia orientalis; Kluveromyces lactis; Kluyveromyces marxianus; Madurella grisae; Malassezia furfur; Malassezia globosa; Malassezia obtusa; Malassezia pachydermatis; Malassezia restricta; Malassezia slooffiae; Malassezia sympodialis; Metarrhizium anisopliae; Microsporum audouinii; Microsporum canis; Microsporum fulvum; Microsporum gypseum; Microsporum persicolor; Mucor circinelloides; Mucor hiemalis; Mucor racemosus; Mucor rouxii; Mucor spp; Nattrassia mangiferae; Nectria haematococca; Onychocola canadensis; Paecilomyces lilacinus; Paecilomyces spp; Paecilomyces variotii; Paracoccidioides brasiliensis; Penicillium marneffei; Penicillium spp; Phialophora spp; Phialophora verrucosa; Phoma spp; Pichia anomala; Pichia etchellsii; Pichia guilliermondii; Pichia ohmeri; Pithomyces spp; Pneumocystis carinii; Pseudallescheria boydii; Ramichloridium obovoideum; Rhizomucor miehei; Rhizomucor pusillus; Rhizomucor spp; Rhizopus arrhizus; Rhizopus microsporus; Rhizopus oryzae, Rhizopus schipperae; Rhizopus spp; Rhodotorula mucilaginosa; Rhodotorula rubra; Rhodotorula spp; Saccharomyces cerevisiae; Saccharomyces spp; Sagrahamala spp; Saksenaea vasiformis; Scedosporium apiospermum; Scedosporim prolificans; Schizophyllum commune; Schizosaccharomyces pombe; Scopulariopsis brevicaulis; Scytalidium dimidiatum Ulocladium spp; Sporobolomyces spp; Sporothrix schenckii; Trichoderma spp; Trichophyton krajdenii; Trichophyton mentagrophytes; Trichophyton raubitschekii; Trichophyton rubrum; Trichophyton soudanense; Trichophyton spp; Trichophyton terrestre; Trichophyton tonsurans; Trichophyton verrucosum; Trichophyton violaceum; Trichosporon asahii; Trichosporon beigelii; Trichosporon capitatum; Trichosporon cutaneum; Trichosporon inkin; Trichosporon mucoides; Trichosporon spp; Tritirachium spp; Wangiella dermatitidis and Yarrowia lipolytica 
For pharmaceutical use, treatment of yeasts (e.g., Candida, Cryprococcus, Pichia, Rhodotorula, Saccharomyces, and Trichosporon) or moulds (e.g., Absidia, Alternaria, Apophysomyces, Aspergillus, Bjerkandera, Blastomyces, Coccidioides, Cunninghamella, Exophiala, Fusarium, Histoplasma, Microsporum, Mucor, Paecilomyces, Penicillium, Pseudallescheria, Ramichloridium, Rhizomucor, Rhizopus, Saksenaea, Scedosporium, Sporothrix, Trichophyton and Wangiella) are preferred.
As used herein, the terms “treat” or “treating” mean eliminating the fungal infection, reducing the fungal burden, or stopping the progression of fungal growth.
The terms “prevent” or “preventing”, as used herein, mean administering at least one compound listed above before exposure to a potential fungal pathogen. For example at least one compound listed above can be administered to an animal before organ transplant surgery, a procedure known to frequently result in fungal infections, or an animal known to be susceptible to fungal infections can be treated in advance of likely exposure. In the case of fungal plant pathogens, at least one compound listed above can be applied to a plant regularly throughout the growing season, before a potential pathogen can cause any harm to the plant.
When used to treat plant pathogens, at least one compound listed above can be applied to the leaves and stems of the plant using a method well known in the art, for example as a topical spray (e.g., an aqueous solution) or powder, or as a solution or powder added to the soil to allow systemic absorption. Topical application to plants is preferred. Similarly, when applied to the surfaces of inanimate objects to reduce or eliminate fungal growth, at least one compound listed above can be applied as a solution, a spray or a powder.
As indicated above, it is contemplated that more than one compound as listed above can be administered to treat fungal infections. When used herein, the terms “at least one” or “one or more” preferably mean one to three compounds, but more preferably one compound listed above is administered. When administered in combination with another antifungal agent, preferably one compound listed above and one other antifungal agent are administered.
Other antifungal agents for use in combination are: for example azoles (e.g. fluconazole, miconazole, itraconazole, voriconazole, posaconazole), echinocandins (e.g. caspofungin, micafungin, anidulafungin), polyenes (e.g. amphotericin B, including liposomal formulations of amphotericin B, and nystatin), allylamines (e.g. terbinafine), thiocarbamates (e.g. tolnaftate), nikkomycins, pradimicins, 5-fluorocytosines, oxaboroles, ciclopiroxolamine, griseofulvin and morpholines (e.g., fenpropimorph).
As used herein, “animal” means a mammalian or non-mammalian (e.g., birds, fish, crustaceans, reptiles) species, preferably a mammal and more preferably a human. As used herein, “patient” refers to an animal, more preferably a human.
As well known in the art, a bond drawn from a particular atom wherein no moiety is depicted at the terminal end of the bond indicates a methyl group bound through that bond to the atom, unless stated otherwise. For example:




It should also be noted that any carbon or heteroatom with unsatisfied valences in the text, schemes, examples, structural formulae, and any Tables herein is assumed to have the hydrogen atom or atoms to satisfy the valences.
As used herein, the term “composition” is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
The term “pharmaceutical composition” is also intended to encompass both the bulk composition and individual dosage units comprised of more than one (e.g., two) pharmaceutically active agents such as, for example, a compound of the present invention and an additional agent selected from the lists of the additional agents described herein, along with any pharmaceutically inactive excipients. The bulk composition and each individual dosage unit can contain fixed amounts of the afore-said “more than one pharmaceutically active agents”. The bulk composition is material that has not yet been formed into individual dosage units. An illustrative dosage unit is an oral dosage unit such as tablets, pills and the like. Similarly, the herein-described method of treating a patient by administering a pharmaceutical composition of the present invention is also intended to encompass the administration of the afore-said bulk composition and individual dosage units.
Experimental Procedures
Compounds useful in the method of the invention will show utility as antifungal agents in the following assays.
β(1,3) Glucan Synthase Assay:
1. Preparation of Permeabilized Saccharomyces cerevisiae Cells.
Permeabilization of yeast cells was performed according to Crotti et al. (Analytical Biochemistry, 292, 8-16, 2001) with some modifications. A 10 ml-starter culture of the S. cerevisiae strain in YPD medium (1% yeast extract, 2% bacto-peptone, 2% dextrose) with OD600=3-4 was used to inoculate 1 liter of YPD. The culture was grown at 30° C. until OD600=0-0.8. Cells were collected by centrifugation (5,300 g for 15 min at 4° C.) and resuspended in buffer (40 mM EDTA, 100 mM β-mercaptoethanol) at 1 g of cell pellet/3.5 ml buffer. The cell suspension was shaken for 30 min at 30° C., followed by centrifugation at 12,000 g for 10 min at 4° C. The cell pellet was washed with 5 ml 0.8 M sorbitol and resuspended in 6.8 ml of 2.9 mM citric acid, 11.3 mM dibasic sodium phosphate, 1 mM EDTA, 0.8 M sorbitol, with constant shaking at 30)C for 30 min. After centrifugation at 12,000 g for 10 ml at 4° C., the pellet was resuspended in 31.3 ml 50 mM Tris-HCl, pH 7.0, and incubated on ice for 5 min. The mixture was then centrifuged at 12,000 g for 10 min at 4 AC, and the pellet was resuspended in 1 ml of 50 mM Tris-HCl and 33% glycerol, pH 7.5. The permeabilized cell preparation was stored at 80° C. in aliquots.
2. Preparation of Membrane Fraction of Yeast Cells
The protocol was modified from Douglas et al. (Journal of Bacteriology, 176, 5686-5696, 1994). For the preparation of S. cerevisiae and C. albicans membrane fractions, 1 liter of YPD supplemented with 0.02 mg/mL adenine and 0.08 mg/mL uracil was inoculated with 10 mL starter culture of PM503 (OD600=4) or the C. albicans strain BWP17 (OD600=12) in the same medium and grown at 30° C. until OD600 reached about 1. A. fumigatus (stain ND158) membranes were prepared by first preparing a spore suspension from agar slants by adding 6 mL of sterile saline, 0.1% Tween-20 solution to each slant, and resuspending by pipetting and scraping. The spore suspensions were used to inoculate two 200 mL flasks containing Sabouraud dextrose broth media. Cultures were incubated at 37° C., 250 rpm for  ̃8 hrs. All cells, S. cerevisiae, C. albicans or A. fumigatus were harvested by centrifugation at 5,300 g at 4° C. for 40 minutes. After washing with 100 mL of breakage buffer (0.1 M KPi, pH 7.0, 1 mM EDTA, 1 mM DTT), the cell pellet was resuspended in 50 ml ice-cold breakage buffer. The mixture was transferred to a bead-beater chamber packed in ice (BioSpec Products, Bartlesville, Okla.). To each 50 mL sample was added 50 g of acid-washed glass beads (0.45 μM, Sigma). Cells were disrupted using 12×20 second pulses with 2 min-cooling intervals. Cell debris was removed by centrifugation at 3,000 g for 20 minutes at 4° C., and the supernatant was collected and centrifuged at 100,000 g for 1 hour at 4° C. to pellet the membrane fraction. The pellet was resuspended in 5 mL of ice-cold breakage buffer containing 25% glycerol, homogenized with a Dounce tissue homogenizer and stored at −80° C. in small aliquots.
3. Glucan Synthase Assay and Compound Screening
The assay was performed according to Mo et at (Journal of Biological Chemistry, 269, 31267-31274, 1994) and Taft et al. (The Journal of Antibiotics, 47, 1001-1009, 1994), in a 96-well Optiplate (PerkinElmer). To each well was added 3 μL 10× compound stock (in 100% DMSO), or 3 μL of 30 μg/mL caspofungin in 100% DMSO (as positive control), or 3 μL 100% DMSO (as negative control), followed by the addition of appropriate amount of glucan synthase sources (2 μL permeabilized PM503 cells, or 3 μL membrane preparations from either PM503, BWP17, or ND158). The reaction was initiated by adding 25 μL reaction buffer (0.6 mM UDP-Glucose 0.6 nCi [U-14C]DUP-Glucose (327 mCi/mmol, Amersham Bioscience), 20 μM GTP-γ-S, 25 mM NaF, 7.5 mg/mL BSA, 8% glycerol in 75 mM Tris-HCl, pH 7.5). The plate was incubated on a shaker for 1.5 hour at room temperature before being quenched with 250 μL 1% TCA (Trichloroacetic Acid). The quenched reaction was mixed by pipetting, and immediately transferred to a 96-well filter plate (Glass fiber B on 0.65 μm hydrophilic durapore membrane, Millipore) pre-wetted with wash buffer (5% TCA, 60 mM NaPPi). The glucan product was retained on the filter membrane by applying vacuum to the plate using a MultiScreen Resist Vacuum Manifold (Millipore). The filter plate was further washed 4 times with 200 μL wash buffer. The plate was dried at 50° C. for 30 minutes. 100 μL of Microscint-0 (PerkinElmer) was added to each well, and plate was counted in a TopCount NXT plate reader (PerkinElmer).
IC50 Determinations:
Dose-response curves were plotted from inhibition data generated. IC50 was determined by fitting the CPM versus the Concentration of the test compound plot with the following equation (4-parameter logistic model, ID Business Solutions XLfit 4.2).
Microbroth Susceptibility Testing Methods
Yeast susceptibility testing procedure followed the NCCLS document M27-A2 (Reference Method for Broth Dilution Antifungal Susceptibility Testing of Yeasts; Approved Standard-Second Edition (ISBN 1-56238-469-4). NCCLS, 940 West Valley Road, Suite 1400 Wayne, Pa. 19087-1898 USA, 2002) with the following modifications:
1. The final test volume was 100 μl and not 200 μl as stipulated,
2. For testing Saccharomyces cerevisiae strain PM503 YPD was used in place of RPMI 1640 broth.
Filamentous fungi susceptibility testing procedure follows the NCCLS document M38-A (Reference Method for Broth Dilution Antifungal Susceptibility Testing of Filamentous Fungi; Approved Standard (ISBN 1-56238-470-8). NCCLS, 940 West Valley Road, Suite 1400 Wayne, Pa. 19087-1898 USA, 2002) with the following modifications:
1. The final test volume was 100 μl and not 200 μl as stipulated.
2. The end point used to assess the in vitro activity of glucan synthase inhibitors may require microscopic evaluation of cell morphology in the test wells (Kurtz et al., Antimicrobial Agents and Chemotherapy, 38, 1480-1489, 1994; Arikan et al., Antimicrobial Agents and Chemotherapy, 45, 327-330, 2001). This endpoint, termed the minimum effective concentration (MEC), is characterized by changes in the fungal growth that resulted in truncated and highly branched hyphae.
The invention disclosed herein is exemplified by the following preparations of the inventive compounds and examples which should not be construed to limit the scope of the disclosure. Alternative mechanistic pathways and Analogous structures will be apparent to those skilled in the art.




Step 1:





To a solution of sodium hydroxide (22.3 g, 0559 mol) dissolved in water (50 mL) was added ethanol (300 mL) and 3-chlorophenylhydrazine hydrochloride (100 g, 0.559 mol). The reaction mixture was stirred at room temperature for 15 mins, and then mucochloric acid 1 (94.4, 0.559 mol) was added. The resulting slurry was heated at 100° C. for 24 h then cooled to room temperature. Water (1500 mL) was added. The slurry was stirred and then filtered. The yellow solid was air-dried overnight to give 149.4 g (97%) of the product 2 as a yellow solid. MS (M+1): m/e 277.
Step 2:




To a solution of compound 2 (50.2 g, 0.182 mol) dissolved in ethanol (300 mL) was added N—BOC-piperazine (36.3 g, 0.195 mol) and triethylamine (22.1 g, 30.5 mL, 0.218 mol). The reaction mixture was heated at reflux for 19 h and then cooled to room temperature. The solvent was evaporated, and the solid was triturated with 5% EtOH-Et2O (800 mL). The product was filtered and air-dried to give 79.7 g (99%) of the product 3 as a beige solid. MS (M+1): m/e 425.
Step 3 (Method 1):




A solution of compound 3A (484 mg, 1.18 mmol) and morpholine (1.04 mL, 11.9 mmol) in 5 mL toluene was heated in a sealed tube in a 138° C. oil bath for 28 h. The mixture was cooled to room temperature and filtered. The solvent was evaporated. Purification by silica gel chromatography (eluant: EtOAc-hexanes gradient) provided 60.7 mg (11% yield) of the product 4A as a solid. MS (M+1): m/e 460.
Step 3 (Method 2):




To a solution of compound 3B (1.5 g, 3.70 mmol) dissolved in toluene (35 mL) was added 3-ethoxypropylamine (0.46 g, 4.45 mmol), potassium carbonate (2.6 g, 18.5 mmol), palladium acetate (33 mg, 0.15 mmol), and racemic BINAP (93 mg 0.15 mmol) under a nitrogen atmosphere. The reaction mixture was heated at 120° C. for 40 h then cooled to room temperature. EtOAc was added, and the organic solution was washed with saturated aqueous NaCl, dried (MgSO4), filtered, and concentrated. Purification by silica gel chromatography (eluant: 1-4% MeOH—CH2Cl2) gave 0.92 g (53%) of the product 4B as a yellow foam. MS (M+1): m/e 472.
Step 4:




To a solution of 2-ethoxyethanol (0.24 g, 2.69 mmol) dissolved in dry THF (10 mL) under a nitrogen atmosphere was added sodium bis(trimethylsilyl)amide (1 M in THF, 2.3 mL, 2.30 mmol) via syringe. The reaction mixture was stirred at room temperature for 15 mins then compound 3C (0.75 g, 1.92 mmol) was added in dry THF (5 mL). The resulting solution was stirred at room temperature for 16 h. The solvent was evaporated, water (30 mL) was added, and the aqueous solution was extracted with EtOAc. The combined organic extract was dried (MgSO4), filtered, and concentrated. Purification by silica gel chromatography (eluant: 15-40% EtOAc—CH2Cl2) gave 0.66 g (78%) of the product 5A as a light yellow solid. MS (M+1): m/e 445.
Step 5:




To a solution of compound 3D (242 mg, 0.59 mmol) in methanol (3 mL) was added sodium thiomethoxide (124 mg, 1.77 mmol). The reaction mixture was stirred at reflux for 1 h. The solvent was evaporated. The residue was partitioned between water and ethyl acetate. The organic phase was washed with brine, dried (Na2SO4), filtered, and concentrated to give 248 mg (100%) of the product 6A as an off-white solid. MS (M+1): m/e 421.
Step 6:




To a solution of compound 5A (0.65 g, 1.46 mmol) dissolved in CH2Cl2 (10 mL) was added HCl-dioxane (4 N, 3.7 mL, 14.6 mmol). The reaction mixture was stirred at room temperate for 3 h. The solvent was evaporated, and the product was dried under high vacuum to give 0.56 g (100%) of the HCl salt of the product 7A as a white solid. MS (M+1): m/e 345.
Step 7:




To a solution of compound 7B (107 mg, 0.30 mmol) dissolved in 1:1 DMF:CH2Cl2 (10 mL) was added Hunig's base (116 mg, 0.16 mL, 0.90 mmol), HATU (171 mg, 0.45 mmol), and BOC-glycine (58 mg, 0.33 mmol). The reaction mixture was stirred at room temperature for 1 h. The solvent was evaporated. Water was added, and the aqueous solution was extracted with CH2Cl2. The combined organic extract was dried (MgSO4), filtered, and concentrated. Purification by silica gel chromatography (eluant: 10-25% EtOAc—CH2Cl2 gradient) gave 125 mg (83%) of the product 8A. MS (M+1): m/e 515.
Step 8:




To a solution of compound 7C (65 mg, 0.147 mmol) in dichloromethane (2.5 mL) was added diisopropylethylamine (100 uL) and cyclohexylisocyanate (28 uL, 0.22 mmol). The reaction mixture was stirred at room temperature for 1.5 h. The solvent was evaporated. The residue was dissolved in DMF (2 mL) and purified by chromatography on a C-18 reverse phase column (eluant: acetonitrile/water gradient with 0.1% formic acid). The appropriate fractions were combined and concentrated to give 61.7 mg (79%) of the product 9A as a pale-yellow solid. MS (M+1): m/e 532.
Step 9:




To a solution of the HCl salt of compound 7A (75 mg, 0.197 mmol) dissolved in DMF (1.5 mL) was added Hunigs base (127 mg, 0.16 mL, 0.985 mmol) and α-toluenesulfonyl chloride (56 mg, 0.295 mmol). The reaction mixture was stirred at room temperature for 3 h. The product was purified by chromatography on a C-18 reverse phase column (eluant: acetonitrile/water gradient with 0.1% formic acid) to give 55 mg (56%) of the product 10A as a cream solid. MS (M+1): m/e 499.
Step 10:




To a solution of compound 7D TFA salt (130 mg, 0.26 mmol) dissolved in toluene (4 mL) was added 2,6-dichlorobenzylchloride (65 mg, 0.33 mmol) and Hunigs base (104 uL, 0.63 mmol). The reaction mixture was heated at reflux for 18 h. The solvent was evaporated. Purification by silica gel chromatography (eluant: 10% MeOH/NH3-CH2Cl2) gave 50 mg (36%) of the product 1A. MS (M+1): m/e 539.




Compound 12 can be synthesized using steps 1 and 2 from Scheme 1.
Step 11:




Suspended compound 12A (4.00 g, 9.41 mmol) in CH2Cl2 (100 mL). Added HCl in dioxane (4 N, 23.5 mL, 94.1 mmol). The reaction mixture was stirred at room temperature for 5 h and precipitate formed. The solvent was evaporated, and the solid was dried under high vacuum to give 3.40 g (100%) of the product 13A as a yellow solid, MS (M+1): m/e 327.
Step 12:




Suspended compound 13A (3.40 g, 9.41 mmol) in CH2Cl2 (100 mL) and added triethylamine (2.86 g, 3.9 mL, 28.2 mmol). Cooled reaction mixture to 0° C. and added isopropylsulfonyl chloride (1.74 g, 1.4 mL, 12.2 mmol). The reaction mixture was stirred at 0° C. for 30 mins then at room temperature for 24 h. Water (100 mL) was added, and the aqueous solution was extracted with CH2Cl2. The combined organic extract was dried (MgSO4), filtered, and concentrated. Purification by silica gel chromatography (eluant: 10-20% EtOAc—Cl2Cl2) gave 2.47 g (61% yield) of the product 14A as a yellow solid. MS (M+1): m/e 431.
Step 13:




A solution of compound 14B (207 mg, 0.50 mmol) and piperidine (170 mg, 2.0 mmol) dissolved in dichlorobenzene (5 mL) was heated at 250° C. for 60 mins. The reaction mixture was cooled to room temperature. Purification by silica gel chromatography (eluant: EtOAc hexanes gradient) gave 112 mg (48%) of the product 15A. MS (M+1): m/e 464.
Step 14 (Method 1):




To a solution of 2-(2-methoxyethoxy)ethanol (244 mg, 0.24 mL, 2.03 mmol) dissolved in dry THF (5 mL) was added NaNTMS2 (1 M in THF, 1.74 mL, 1.74 mmol). The reaction mixture was stirred at room temperature for 15 mins then compound 14A (250 mg, 0.580 mmol) was added. The reaction mixture was heated at reflux for 5 h. The solvent was evaporated. Water (25 mL) was added, and the aqueous solution was extracted with EtOAc. The combined organic extract was dried (MgSO4), filtered, and concentrated. Purification by silica gel chromatography (eluant: 20-30% EtOAc-hexanes) gave 233 mg (78%) of the product 16A as an orange solid. MS (M+1): m/e 515.
Step 14 (Method 2):




A mixture of anhydrous cesium carbonate (0.114 g, 3.5 mmol) and phenol (0.066 g, 7.0 mmol) in anhydrous methanol (5 mL) was stirred at room temperature for 30 mins. The solvent was evaporated. To the residue at room temperature was added dropwise a solution of compound 14A (0.086 g, 2.0 mmol) in anhydrous DMF (5 mL). The resulting solution was stirred for at 110° C. for 8 h, and then the solvent was evaporated. The residue was quenched with aqueous NH4Cl solution (10 mL) and extracted with CH2Cl2 (3×50 mL). The combined organic extract was washed with H2O (2×10 mL), brine (10 mL), dried over MgSO4, filtered, and concentrated. Purification by silica gel chromatography (1:20 EtOAc-hexanes) gave 42 mg (41%) of the product 16B as a colorless oil. MS (M+1): m/e 489.
Step 15:




To a solution of compound 14C (240 mg, 0.50 mmol) and potassium carbonate (70 mg, 0.5 mmol) in acetonitrile (2 mL) was added 4-methoxybenzenethiol (100 uL, 0.81 mmol). The reaction mixture was stirred at reflux for 6 h. The solvent was evaporated. The residue was partitioned between water and EtOAc. The organic phase was washed consecutively with water, 1 N sodium hydroxide, and brine, dried (Na2SO4), filtered, and concentrated. Purification by silica gel chromatography (eluant: EtOAc hexanes gradient) gave 272 mg (93% yield) of the product 17A as a yellow solid. MS (M+1): m/e 583.
Step 16:




Compound 14D (34 mg 0.070 mmol), 4-methylphenylboronic acid (14 mg, 0.11 mmol), Na2CO3 (11 mg, 0.11 mmol), and PdCl2(PPh3)2 catalyst (2.5 mg, 0.004 mmol) were combined in 5:1 acetonitrile:water (2 mL). The reaction mixture was heated in a microwave at 140° C. for 20 mins then filtered through a Si-carbonate column with CH2Cl2. Purification by chromatography on a C-18 reverse phase column (eluant: acetonitrile/water gradient with 0.1 formic acid) gave 22 mg (59%) of the product 18A. MS (M+1): m/e 537.







TABLE 1







Sulfur Linked Analogs with Amide


The following compounds can be synthesized


using steps 1, 2, 5, 6, and 7 of Scheme 1.









Compound No.
Structure
MS M + 1





1Z




564


 


2Z




517
















TABLE 2







Sulfur Linked Analogs with Sulfonamide


The following compounds can be synthesized using steps 1, 2,


5, 6, and 9 of Scheme 1 or steps 11, 12, and 15 of Scheme 2.









Comp. No.
Structure
MS M + 1





3Z




537


 


4Z




571


 


5Z




533


 


6Z




487


 


7Z




541


 


8Z




451


 


9Z




537


 


10Z




515


 


11Z




487


 


12Z




500


 


13Z




529


 


14Z




583


 


15Z




479


 


16Z




473


 


17Z




437


 


18Z




465


 


19Z




507


 


20Z




541


 


21Z




521
















TABLE 3







Nitrogen Linked Analogs with Amide


The following compounds can be synthesized using


steps 1, 2, 3, 6, and 7 of Scheme 1.









Comp. No.
Structure
MS M + 1





22Z




403


 


23Z




415


 


24Z




429


 


25Z




529


 


26Z




444


 


27Z




472


 


28Z




429


 


29Z




429
















TABLE 4







Nitrogen Linked Analogs with Sulfonamide


The following compounds can be synthesized using steps 1, 2,


3, 6, and 9 of Scheme 1 or steps 11, 12, and 13 of Scheme 2.









Comp. No.
Structure
MS M + 1





30Z




562


 


31Z




604


 


32Z




554


 


33Z




479


 


34Z




514


 


35Z




526


 


36Z




518


 


37Z




524


 


38Z




516


 


39Z




516


 


40Z




580


 


41Z




584


 


42Z




632


 


43Z




530


 


44Z




482


 


45Z




464


 


46Z




530


 


47Z




554 556


 


48Z




584


 


49Z




548


 


50Z




465


 


51Z




538 540


 


52Z




514


 


53Z




512


 


54Z




479


 


55Z




510


 


56Z




448


 


57Z




630


 


58Z




528


 


59Z




632


 


60Z




502


 


61Z




512


 


62Z




498


 


63Z




447


 


64Z




466


 


65Z




544
















TABLE 5







Carbon Analogs with Sulfonamide


The following compounds can be synthesized


by using steps 11, 12, and 16 in Scheme 2.









Comp. No.
Structure
MS M + 1





66Z




505


 


67Z




503


 


68Z




457


 


69Z




593


 


70Z




525


 


71Z




476


 


72Z




493


 


73Z




510


 


74Z




505


 


75Z




476


 


76Z
no compound


 


77Z




547


 


78Z




477


 


79Z




523


 


80Z




524


 


81Z




553


 


82Z




548


 


83Z




581


 


84Z




554


 


85Z




574


 


86Z




594


 


87Z




565


 


88Z




568


 


89Z




616


 


90Z




551


 


91Z




591


 


92Z




635


 


93Z




582


 


94Z




551


 


95Z




565


 


96Z




605


 


97Z




591


 


98Z




548


 


99Z




551


 


100Z




595


 


101Z




557


 


102Z




567


 


103Z




601


 


104Z




537


 


105Z




581


 


106Z




524


 


107Z




513


 


108Z




549


 


109Z




485


 


110Z




491


 


111Z




559


 


112Z




501


 


113Z




491


 


114Z




489


 


115Z




497


 


116Z




495


 


117Z




541


 


118Z




473


 


119Z




503


 


120Z




493


 


121Z




626


 


122Z




483


 


123Z




515


 


124Z




469


 


125Z




465


 


126Z




493


 


127Z




545


 


128Z




470


 


129Z




519


 


130Z




503


 


131Z




503


 


132Z




525


 


133Z




457


 


134Z




545


 


135Z




603


 


136Z




511


 


137Z




559


 


138Z




510


 


139Z




542


 


140Z




481


 


141Z




519


 


142Z
no compound


 


143Z




506


 


144Z




519


 


145Z




557


 


146Z




537


 


147Z




599


 


148Z




591


 


149Z




595


 


150Z




574


 


151Z




581


 


152Z




539


 


153Z




580


 


154Z




566


 


155Z




601


 


156Z




551


 


157Z




558


 


158Z




579


 


159Z




567


 


160Z




502


 


161Z




565


 


162Z




471


 


163Z




552


 


164Z




553


 


165Z




565


 


166Z




541


 


167Z




607


 


168Z




566


 


169Z




615


 


170Z




565


 


171Z




541


 


172Z




565


 


173Z




512


 


174Z




538


 


175Z




525


 


176Z




447


 


177Z




487


 


178Z




541


 


179Z




462


 


180Z




517


 


181Z




505


 


182Z




528


 


183Z




541


 


184Z




499


 


185Z




519


 


186Z




502


 


187Z




527


 


188Z




467


 


189Z




468


 


190Z




439


 


191Z




494


 


192Z




592


 


193Z




507


 


194Z




504


 


195Z




503


 


196Z




519


 


196ZA




580


 


196ZB




580


 


196ZC




610


 


196ZD




610


 


196ZE




572


 


196ZF




568


 


196ZG




538


 


196ZH




594


 


196ZI




594


 


196ZJ




564


 


196ZK




564


 


196ZL




552


 


196ZM




556
















TABLE 6







Oxygen Linked Analogs with Urea


The following compounds can be synthesized by


using steps 1, 2, 4, 6, and 8 in Scheme 1.









Comp. No.
Structure
MS M + 1





197Z




492


 


198Z




474


 


199Z




518


 


200Z




494


 


201Z




448


 


202Z




488


 


203Z




532


 


204Z




508


 


204Za




512


 


204Zb




511


 


204Zc




531


 


204Zd




456


 


204Ze




481


 


204Zf




551


 


204Zg




484


 


204Zh




559


 


204Zi




455


 


204Zj




503


 


204Zk




529
















TABLE 7







Oxygen Analogs with Amine


The following compounds can be synthesized


by using steps 1, 2, 4, 6, and 10 in Scheme 1.









Comp. No.
Structure
MS M + 1





205Z




571


 


206Z




517


 


207Z




469


 


208Z




533


 


209Z




481


 


210Z




481


 


211Z




467


 


212Z




503


 


213Z




539


 


214Z




573


 


215Z




465


 


216Z




570


 


217Z




455


 


217ZA




539
















TABLE 8







Oxygen Linked Analogs with Amide


The following compounds can be synthesized by using steps 1, 2, 4, 6, and 7 in Scheme 1.









Comp.

MS


No.
Structure
M + 1





218Z




552


 


219Z




557


 


220Z




481


 


221Z




629


 


222Z




445


 


223Z




469


 


224Z




485


 


225Z




531


 


226Z




479


 


227Z




415


 


228Z




479


 


229Z




499


 


230Z




505


 


231Z




500


 


232Z




525


 


233Z




413


 


234Z




517


 


235Z




513


 


236Z




463


 


237Z




524


 


238Z




493


 


238A




471


 


238B




523


 


238C




511


 


238D




509


 


238E




525


 


238F




477


 


238G




475
















TABLE 9







Oxygen Linked Analogs with Heterocycle


The following compounds can be synthesized by using steps 1, 2, and 4 in Scheme I.









Compound

MS


No.
Structure
M + 1





239Z




449


 


240Z




487


 


241Z




488
















TABLE 10







Oxygen Linked Analogs with Sulfonamide


The following compounds can be synthesized using steps 1, 2, 4, 6, and


9 of Scheme 1 or steps 11, 12, and 14 of Scheme 2.









Comp.

MS


No.
Structure
M + 1





242Z




517


 


243Z




525


 


244Z




463


 


245Z




491


 


246Z




475


 


247Z




512


 


248Z




517


 


249Z




489


 


250Z




531


 


251Z




603


 


252Z




587


 


253Z




529


 


254Z




483


 


255Z




547


 


256Z




503


 


257Z




450


 


258Z




481


 


259Z




593


 


260Z




512


 


261Z




593


 


262Z




517


 


263Z




433


 


264Z




447


 


265Z




475


 


266Z




557


 


267Z




499


 


268Z




423


 


269Z




515


 


270Z




648


 


271Z




463


 


272Z




473


 


273Z




529


 


274Z




517


 


275Z




501


 


276Z




528


 


277Z




668


 


278Z




475


 


279Z




516


 


280Z




467


 


281Z




495


 


282Z




509


 


283Z




422


 


284Z




498


 


285Z




584


 


286Z




481


 


287Z




483


 


288Z




499


 


289Z




536


 


290Z




489


 


291Z




484


 


292Z




577


 


293Z




517


 


294Z




704


 


295Z




545


 


296Z




708


 


297Z




547


 


298Z




509


 


299Z




571


 


300Z




569


 


301Z




567


 


302Z




529


 


303Z




518


 


304Z




431


 


305Z




561


 


306Z




478


 


307Z




512


 


308Z




521


 


309Z




519


 


310Z




535


 


311Z




547


 


312Z




599 601


 


313Z




553


 


314Z




583


 


315Z




535


 


316Z




562


 


317Z




451


 


318Z




509


 


319Z




496


 


320Z




547


 


321Z




501


 


322Z




485


 


323Z




491


 


324Z




517


 


325Z




567


 


326Z




544


 


327Z




567


 


328Z




485


 


329Z




533


 


330Z




519


 


331Z




462


 


332Z




452


 


333Z




469


 


334Z




517


 


335Z




469


 


336Z




517


 


337Z




481


 


338Z




529


 


339Z




497


 


340Z




545


 


341Z




491


 


342Z




498


 


343Z




517


 


344Z




545


 


345Z




501


 


346Z




577


 


347Z




504


 


348Z




527


 


349Z




464


 


350Z




473


 


351Z




523


 


352Z




555


 


353Z




489


 


354Z




526


 


355Z




483


 


356Z




499


 


357Z




465


 


358Z




491


 


359Z




484


 


360Z




523


 


361Z




539


 


362Z




526


 


363Z




513


 


364Z




541


 


365Z




541


 


366Z




559


 


367Z




561


 


368Z




567


 


369Z




568


 


370Z




519


 


371Z




478


 


372Z




578


 


373Z




381


 


374Z




465


 


375Z




535


 


376Z




491


 


377Z




573


 


378Z




505


 


379Z




442 for M + 1- methyl


 


380Z




547


 


381Z




497


 


382Z




547


 


383Z




527


 


384Z




499


 


385Z




569


 


386Z




535


 


387Z




629


 


388Z




549


 


389Z




615


 


390Z




495


 


391Z




543 545


 


392Z




539


 


393Z




466


 


394Z




571


 


395Z




617


 


396Z




645


 


397Z




469


 


398Z




467


 


399Z




527


 


400Z




543


 


401Z




531


 


402Z




479


 


403Z




471


 


404Z




606


 


405Z




503


 


406Z




520


 


407Z




529


 


408Z




577


 


409Z




591


 


410Z




544


 


411Z




686


 


412Z




495


 


413Z




531


 


414Z




455


 


415Z




592


 


416Z




573


 


417Z




565


 


418Z




532


 


419Z




518


 


420Z




581


 


421Z




553


 


422Z




566


 


423Z




471


 


424Z




560


 


425Z




658


 


426Z




566


 


427Z




592


 


428Z




513


 


429Z




517


 


430Z




541


 


431Z




493


 


432Z




507


 


433Z




588


 


434Z




470


 


435Z




581


 


436Z




574


 


437Z




616


 


438Z




573


 


439Z




578


 


440Z




469


 


441Z




497


 


442Z




543


 


443Z




553


 


444Z




569


 


445Z




615


 


446Z




516


 


447Z




663


 


448Z




483


 


449Z




520


 


450Z




561


 


451Z




489


 


452Z




562


 


453Z




603


 


454Z




568


 


455Z




636


 


456Z




593


 


457Z




570


 


458Z




549


 


459Z




541


 


460Z




579


 


461Z




579


 


462Z




479


 


463Z




495


 


464Z




495


 


465Z




598


 


466Z




610


 


467Z




448


 


468Z




465


 


469Z




545


 


470Z




537


 


471Z




574


 


472Z




558


 


473Z




544


 


474Z




525


 


475Z




466 (M − H)


 


476Z




561


 


477Z




507


 


478Z




482


 


479Z




526


 


480Z




447


 


481Z




547


 


482Z




471


 


483Z




544


 


484Z




577


 


485Z




591


 


486Z




571


 


487Z




575


 


488Z




497


 


489Z




529


 


490Z
no compound


 


491Z




482 (M − BOC)


 


492Z




661


 


493Z




530


 


494Z




583


 


495Z




521


 


496Z




660


 


497Z




499


 


498Z




547


 


499Z




543


 


500Z




513


 


501Z




437


 


502Z




524


 


503Z




608


 


504Z




608


 


505Z




568 (M + 2)


 


506Z




552


 


507Z




546


 


508Z




510


 


509Z




577


 


510Z




516


 


511Z




553


 


512Z




501


 


513Z




487


 


514Z




515


 


515Z




539


 


516Z




527


 


517Z




557


 


518Z




561


 


519Z




650


 


520Z




481


 


521Z




499


 


522Z




559


 


523Z




463


 


524Z




664


 


525Z




557


 


526Z




559


 


527Z




573


 


528Z




551


 


529Z




574


 


530Z




543


 


531Z




539


 


532Z




603


 


533Z




544


 


534Z




493


 


535Z




425 (M + 1- ethylene)


 


536Z




525


 


537Z




570


 


538Z




513


 


539Z




554


 


540Z




602


 


541Z




607


 


542Z




467


 


543Z




515


 


544Z




664


 


545Z




563


 


546Z




521


 


547Z




571


 


548Z




479


 


549Z




527


 


550Z




545


 


551Z




513


 


552Z




607


 


553Z




597


 


554Z




509 (M − 1)


 


555Z




547


 


556Z




596


 


557Z




570


 


558Z




489


 


559Z




475


 


560Z




540


 


561Z




496


 


562Z




665


 


563Z




566


 


564Z




589


 


565Z




509


 


566Z




533


 


567Z




495


 


568Z




567


 


569Z




584


 


570Z




548


 


571Z




434


 


572Z




597


 


573Z




565


 


574Z




711


 


575Z




557


 


576Z




517


 


577Z




411


 


578Z




439


 


579Z




510


 


580Z




538


 


581Z




568


 


582Z




574


 


583Z




541























584Z




545


 


585Z




499


 


586Z




485


 


587Z




565


 


588Z




543


 


589Z




544


 


590Z




411


 


591Z




455


 


592Z




487


 


593Z




624


 


594Z




568


 


595Z




511


 


596Z




599


 


597Z




571


 


598Z




591


 


599Z




503


 


600Z




425


 


601Z




453


 


602Z




617


 


603Z




527


 


604Z




596


 


605Z




473


 


606Z




501


 


607Z




597


 


608Z




505


 


609Z




481


 


610Z




527


 


611Z




451


 


612Z




635


 


613Z




523


 


614Z




628


 


615Z




614


 


616Z




546


 


617Z




510


 


618Z




557


 


619Z




455


 


620Z




501


 


621Z




466


 


622Z




515


 


623Z




563


 


624Z




562


 


625Z




516


 


626Z




577


 


627Z




561


 


628Z




481


 


629Z




512 (M + 2)


 


630Z




580


 


631Z




543


 


632Z




553


 


633Z




648


 


634Z




607


 


635Z




521


 


636Z




586


 


637Z




519


 


638Z




574


 


639Z




593


 


640Z




509


 


641Z




588


 


642Z




501


 


643Z




467 (M + Na)


 


644Z




453


 


645Z




547


 


646Z




549


 


647Z




600


 


648Z




582


 


649Z




614


 


650Z




439


 


651Z




467


 


652Z




563


 


653Z




582


 


654Z




543


 


655Z




619


 


656Z




451


 


657Z




479


 


658




513


 


659Z




493


 


660Z




622


 


661Z




597


 


662Z




554


 


663Z




565


 


664Z




497 (M + 1- BOC)


 


665Z




560


 


666Z




510


 


667Z




462


 


668Z




462


 


669Z




496


 


670Z




497


 


671Z




531


 


672Z




606


 


673Z




496


 


674Z




556


 


675Z




557


 


676Z




550


 


677Z




550


 


678Z




548


 


679Z




552


 


680Z




597


 


681Z




531


 


682Z




572


 


683Z




583


 


684Z




544


 


685Z




551


 


686Z




439


 


687Z




487


 


688Z




538


 


689Z




568


 


690Z




574


 


691Z




525


 


692Z




523


 


693Z




526


 


694Z




471


 


695Z




591


 


696Z




572


 


697Z




543


 


698Z




578


 


699Z




439


 


700Z




439


 


701Z




481


 


702Z




568


 


703Z




499


 


704Z




688 (M − 1)


 


705Z




599


 


706Z




607


 


707Z




539


 


708Z




483


 


709Z




453


 


710Z




501


 


711Z




529


 


712Z




456 (M + 1- BOC)


 


713Z




596


 


714Z




487


 


715Z




605


 


716Z




585


 


717Z




513


 


718Z




519


 


719Z




479


 


720Z




485


 


721Z




493


 


723Z




559


 


724Z




547


 


725Z




502


 


726Z




637


 


727Z




581


 


728Z




563


 


729Z




568


 


730Z




567


 


731Z




517


 


732Z




559


 


733Z




499


 


734Z




612


 


735Z




546


 


738Z




546


 


739Z




503


 


740Z




533


 


741Z




562


 


742Z




549


 


743Z




567


 


744Z




559


 


745Z




545


 


746Z




574


 


747Z




549


 


748Z
no compound


 


749Z




553


 


750Z




579


 


751Z




469


 


752Z




553


 


753Z




574


 


754Z




481


 


755Z




545


 


756Z




512


 


757Z




541


 


758Z




525


 


759Z




538


 


760Z




549


 


761Z




496


 


762Z




462


 


763Z




475


 


764Z




551


 


765Z




507


 


766Z




595


 


767Z




546


 


768Z




559


 


769Z




529


 


770Z




583


 


771Z




533


 


772Z




528


 


773Z




572


 


774Z




601


 


775Z




497


 


776Z




496


 


777Z




493


 


778Z




517


 


779Z




595


 


780Z
no compound


 


781Z




529


 


782Z




533


 


783Z




545


 


784Z




561


 


785Z




548


 


786Z




510


 


787Z




663


 


788Z




470


 


789Z




504


 


790Z




605


 


791Z




547


 


792Z




419


 


793Z




565


 


794Z




529


 


795Z




487


 


796Z




531


 


797Z




493


 


798Z




529


 


799Z




563


 


800Z




575


 


801Z




541


 


802Z




521


 


803Z




583


 


804Z




565


 


805Z




568


 


806Z




551


 


807Z




523


 


808Z




544


 


809Z




562


 


810Z
no compound


 


811Z




499


 


812Z




480


 


813Z




462


 


814Z
no compound


 


815Z




529


 


816Z
no compound


 


817Z




472


 


818Z
no compound


 


819Z




547


 


820Z




498


 


821Z




579


 


822Z




462


 


823Z
no compound


 


824Z




558


 


825Z




510


 


826Z




662


 


827Z




491


 


828Z




490


 


829Z




476


 


830Z




477


 


831Z




541


 


832Z




582


 


833Z




580


 


834Z




610


 


835Z




669


 


836Z




544


 


837Z




541


 


838Z




589


 


839Z




561


 


840Z




619


 


841Z




542


 


842Z




542


 


843Z




547


 


844Z
no compound


 


845Z




519


 


846Z




491


 


847Z




594


 


848Z




491


 


849Z




576


 


850Z




499


 


851Z




515


 


852Z




555


 


853Z




487


 


854Z




515


 


855Z




547


 


856Z




567


 


857Z




546


 


858Z




502


 


859Z




501


 


860Z




537


 


861Z




546


 


862Z




581


 


863Z




515


 


864Z




561


 


865Z




569


 


866Z




532


 


867Z




454


 


868Z




572


 


869Z




514


 


870Z




529


 



no compound


 


871Z




540


 


872Z




582


 


873Z




497


 


874Z




545


 


875Z




550


 


876Z




555


 


877Z




497


 


878Z




483


 


879Z




538


 


880Z




588


 


881Z




542


 


882Z




531


 


883Z




532


 


884Z




538


 


885Z




504


 


886Z




600


 


887Z




503


 


888Z




595


 


889Z




608


 


890Z




559


 


891Z




529


 


892Z




549


 


893Z




549


 


894Z




498


 


895Z




574


 


896Z




598


 


897Z




462


 


898Z




501


 


899Z




530


 


900Z




441


 


901Z




595


 


902Z




565


 


903Z
no compound


 


904Z




528


 


905Z




513


 


906Z




509


 


907Z




530


 


908Z




508


 


909Z




501


 


910Z




(M − 98) = 489


 


911Z




469


 


912Z




467


 


913Z




561


 


914Z
no compound


 


915Z




445


 


916Z




495


 


917Z




448


 


918Z




519


 


919Z




565


 


920Z




516


 


921Z




610


 


922Z




563


 


923Z




529


 


924Z




539


 


925Z




565


 


926Z
no compound


927Z
no compound


 


928Z




513


 


929Z




583


 


930Z




606


 


931Z




517


 


932Z




564


 


933Z
no compound


 


934Z




480


 


935Z
no compound


 


936Z




480


 


937Z




510


 


938Z




522


 


939Z
no compound


 


940Z




673


 


941Z




546


 


942Z
no compound


 


943Z




481


 


944Z




462


 


945Z




493


 


946Z




533


 


947Z




617


 


948Z




569


 


949Z




476


 


950Z




477


 


951Z




490


 


952Z




476


 


953Z




564


 


954Z




580


 


955Z




632


 


956Z




500


 


957Z




530


 


958Z




530


 


959Z




530


 


960Z




510


 


961Z




632


 


962Z




513


 


963Z




594


 


964Z




546


 


965Z




609


 


966Z




540


 


967Z




584


 


968Z




476


 


969Z




553


 


970Z




476


 


971Z




677


 


971Za




545


 


971Zb




573


 


971Zc




546


 


971Zd




573


 


971Ze




588


 


971Zf




562


 


971Zg




561


 


971Zh




576


 


971Zi




561


 


971Zj




467


 


971Zk




465


 


971Zl




559


 


971Zm




551


 


971Zn




558


 


971Zo




563


 


971Zp




574


 


971Zq




517


 


971Zr




579


 


971Zs




590


 


971Zt




545


 


971Zu




590


 


971Zv




563


 


971Zw




609


 


971Zx




577


 


971Zy




513


 


971Zz




592


 


971Zaa




606


 


971Zbb




562


 


971Zcc




620


 


971Zdd




578


 


971Zee




620


 


971Zff




578


 


971Zgg




543


 


971Zhh




555


 


971Zii




560


 


971Zjj




576


 


971Zkk




606


 


971Zll




561


 


971Zmm




590


 


971Znn




608


 


971Zoo




576


 


971Zpp




608


 


971Zqq




559


 


971Zrr




608


 


971Zss




572


 


971Ztt




578


 


971Zuu




517


 


971Zvv




560


 


971Zww




517


 


971Zxx




561


 


971Zyy




588


 


971Zzz




559


 


971ZA




578


 


971ZB




547


 


971ZC




578


 


971ZD




608


 


971ZE




527


 


971ZF




608


 


971ZG




541


 


971ZH




475


 


971ZI




575


 


971ZJ




581


 


971ZK




581


 


971ZL




581


 


971ZM




757


 


971ZN




595


 


971ZO




519


 


971ZP




547


 


971ZQ




611


 


971ZR




548


 


971ZS




548


 


971ZT




548


 


971ZU




559


 


971ZV




560


 


971ZW




577


 


971ZX




586


 


971ZY




628


 


971ZZ




612


 


971Za1




557


 


971Zb1




543


 


971Zc1




509


 


971Zd1




561


 


971Ze1




557


 


971Zf1




529


 


971Zg1




529


 


971Zh1




561


 


971Zi1




557


 


971Zj1




509


 


971Zk1




557


 


971Zl1




559
















TABLE 11







Oxygen Linked Analogs with Sulfonamide


The following compounds can be synthesized using steps 1, 2,


4, 6, and 9 of Scheme 1 or steps 11, 12, and 14 of Scheme 2.









Comp.

MS


No.
Structure
M + 1





 972Z




521


 


 973Z




592


 


 974Z




515


 


 975Z




483


 


 976Z




483


 


 977Z




555


 


 978Z




529


 


 979Z




541


 


 980Z




469


 


 981Z




589


 


 982Z




545


 


 983Z




499


 


 984Z




587


 


 985Z




481


 


 986Z




540


 


 987Z




629


 


 988Z




509


 


 989Z




557


 


 990Z




535


 


 991Z




537


 


 992Z




515


 


 993Z




543


 


 994Z




535


 


 995Z




571


 


 996Z




499


 


 997Z




465


 


 998Z




517


 


 999Z




547


 


1000Z




580


 


1001Z




453


 


1002Z




525


 


1003Z




533


 


1004Z




501


 


1005Z




495


 


1006Z




537


 


1007Z




601


 


1008Z




583


 


1009Z




586


 


1010Z




503


 


1011Z




571


 


1012Z




583


 


1013Z




601


 


1014Z




537


 


1015Z




532


 


1016Z




518


 


1017Z




439


 


1018Z




570


 


1019Z




547


 


1020Z




467


 


1021Z




  469.5


 


1022Z




549


 


1023Z




606


 


1024Z




519


 


1025Z




497


 


1026Z




495


 


1027Z




475


 


1028Z




517


 


1029Z




613


 


1030Z
no compound


 


1031Z




557


 


1032Z




509


 


1033Z




551


 


1034Z




545


 


1035Z




529


 


1036Z




540


 


1037Z




515


 


1038Z




529


 


1039Z




573


 


1040Z




582


 


1041Z




541


 


1042Z




533


 


1043Z




581


 


1044Z




481 (M − OH)


 


1045Z




541


 


1046Z




572


 


1047Z




533


 


1048Z




532


 


1049Z




577


 


1050Z




543


 


1051Z




533


 


1052Z




529


 


1053Z




467


 


1054Z




495


 


1055Z




497


 


1056Z




537


 


1057Z




494


 


1058Z




507


 


1059Z




517


 


1060Z




539


 


1061Z




574


 


1062Z




558


 


1063Z




501


 


1064Z




569


 


1065Z




571


 


1066Z




549


 


1067Z




567


 


1068Z




589


 


1069Z




512


 


1070Z




561


 


1071Z




461


 


1072Z




511


 


1073Z




529


 


1074Z




509


 


1075Z




560


 


1076Z




496


 


1077Z




572


 


1078Z




509


 


1079Z




503


 


1080Z




575


 


1081Z




576


 


1082Z




598


 


1083Z




549


 


1084Z




606


 


1085Z




549


 


1086Z




513


 


1087Z




586


 


1088Z




570


 


1089Z




567


 


1090Z




499


 


1091Z




555


 


1092Z




527


 


1093Z




533


 


1094Z




612


 


1095Z




612


 


1096Z




555


 


1097Z




573


 


1098Z




505


 


1099Z




598


 


1100Z




583


 


1101Z




587


 


1102Z




563


 


1103Z




549


 


1104Z




584


 


1105Z




621


 


1106Z




535


 


1107Z




564


 


1108Z




577


 


1109Z




485


 


1110Z




449


 


1111Z




477


 


1112Z




523


 


1113Z




561


 


1114Z




477


 


1115Z




525


 


1116Z




524


 


1117Z




498


 


1118Z




471


 


1119Z




525


 


1120Z




523


 


1121Z




501


 


1122Z




547


 


1123Z




500


 


1124Z




523


 


1125Z




608


 


1126Z




507


 


1127Z




522


 


1128Z




623


 


1129Z




601


 


1130Z




471


 


1131Z




547


 


1132Z




607


 


1133Z




501


 


1134Z




501


 


1135Z




549


 


1136Z




475


 


1137Z




523


 


1138Z




555


 


1139Z




593


 


1140Z




447


 


1141Z




475


 


1142Z




469


 


1143Z




531


 


1144Z




517


 


1145Z




511


 


1146Z




547


 


1147Z




545


 


1148Z




549


 


1149Z




546


 


1150Z




515


 


1151Z




574


 


1152Z




626


 


1153Z




461


 


1154Z




509


 


1155Z




545


 


1156Z




513


 


1157Z




489


 


1158Z




433


 


1159Z




461


 


1160Z




527


 


1161Z




561


 


1162Z




529


 


1163Z




527


 


1164Z




532


 


1165Z




543


 


1166Z




497


 


1167Z




541


 


1168Z




569


 


1169Z




516


 


1170Z




582


 


1171Z




529 (M − H)


 


1172Z




591


 


1173Z




541


 


1174Z




555


 


1175Z




677


 


1176Z




510


 


1177Z




545


 


1178Z




576


 


1179Z




535


 


1180Z




537


 


1181Z




527


 


1182Z




530


 


1183Z




565


 


1184Z




461


 


1185Z




532


 


1186Z




567


 


1187Z




521


 


1188Z




489


 


1189Z




489


 


1190Z




677 (M + OH)


 


1191Z




616


 


1192Z




541


 


1193Z




537


 


1194Z




507


 


1195Z




592


 


1196Z




495


 


1197Z




495


 


1198Z




575


 


1199Z




580


 


1200Z




563


 


1201Z




544


 


1202Z




525


 


1203Z




535


 


1204Z




564


 


1205Z




598


 


1206Z




509


 


1207Z




593


 


1208Z




579


 


1209Z




546


 


1210Z




549


 


1211Z




579


 


1212Z




642


 


1213Z




642


 


1214Z




575


 


1215Z




610


 


1216Z




547


 


1217Z




576


 


1218Z




567


 


1219Z




565


 


1220Z




451


 


1221Z




547


 


1222Z




576


 


1223Z




543


 


1224Z




516


 


1225Z




550


 


1226Z




479


 


1227Z




575


 


1228Z




610


 


1229Z




515


 


1230Z




571


 


1231Z




577


 


1232Z




605


 


1233Z




653


 


1234Z




606


 


1235Z




605


 


1236Z




581


 


1237Z




536


 


1238Z




580


 


1239Z




547


 


1240Z




575


 


1241Z




623


 


1242Z




571


 


1243Z




549


 


1244Z




567


 


1245Z




565


 


1246Z




475


 


1247Z




567


 


1248Z




563


 


1249Z




523


 


1250Z




539


 


1251Z




549


 


1252Z




549


 


1253Z




566


 


1254Z




559


 


1255Z




557


 


1256Z




568


 


1257Z




633


 


1258Z




561


 


1259Z




621


 


1260Z




584


 


1261Z




536


 


1262Z




576


 


1263Z




510


 


1264Z




576


 


1265Z




576


 


1266Z




497


 


1267Z




553


 


1268Z




479


 


1269Z




478


 


1270Z




449


 


1271Z




477


 


1272Z




547


 


1273Z




551


 


1274Z




559


 


1275Z




543


 


1276Z




503


 


1277Z




559


 


1278Z




611


 


1279Z




671


 


1280Z




559


 


1281Z




511


 


1282Z




477


 


1283Z




537


 


1284Z




573


 


1285Z




432


 


1286Z




527


 


1287Z




593


 


1288Z




570


 


1289Z




531


 


1290Z




461


 


1291Z




585


 


1292Z




461


 


1293Z




551


 


1294Z




517


 


1295Z




561


 


1296Z




634


 


1297Z




435


 


1298Z




529


 


1299Z




487


 


1300Z




509


 


1301Z




527


 


1302Z




499


 


1303Z




598


 


1304Z




427


 


1305Z




399


 


1306Z




481


 


1307Z




495


 


1308Z




509


 


1309Z




553


 


1310Z




484


 


1311Z




555


 


1312Z




504


 


1313Z




495


 


1314Z




499


 


1315Z




529


 


1316Z




511


 


1317Z




471


 


1318Z




553


 


1319Z




545


 


1320Z




556


 


1321Z




682


 


1322Z




618


 


1323Z




498


 


1324Z




523


 


1325Z




511


 


1326Z




577 579


 


1327Z




563


 


1328Z




545


 


1329Z




525


 


1330Z




470


 


1331Z




529


 


1332Z




506


 


1333Z




532


 


1334Z




579


 


1335Z




477


 


1336Z




441


 


1337Z




553


 


1338Z




513


 


1339Z




561


 


1340Z




513


 


1341Z




563


 


1342Z




393


 


1343Z




451


 


1344Z




515


 


1345Z




461


 


1346Z




555


 


1347Z




507


 


1348Z




485


 


1349Z




479


 


1350Z




519


 


1351Z




519


 


1352Z




547


 


1353Z




496


 


1354Z




457


 


1355Z




485


 


1356Z




491


 


1357Z




510


 


1358Z




500


 


1359Z




441


 


1360Z




469


 


1361Z




441


 


1362Z




469


 


1363Z




453


 


1364Z




481


 


1365Z




469


 


1366Z




497


 


1367Z




491


 


1368Z




511


 


1369Z




512


 


1370Z




516


 


1371Z




481


 


1372Z




529


 


1373Z




449


 


1374Z




511


 


1375Z




527


 


1376Z




521


 


1377Z




556


 


1378Z




539


 


1379Z




539


 


1380Z




517


 


1381Z




486


 


1382Z




511


 


1383Z




555


 


1384Z




491


 


1385Z




532


 


1386Z




519


 


1387Z




517


 


1388Z




489


 


1389Z




513


 


1390Z




533


 


1391Z




493


 


1392Z




493


 


1393Z




559


 


1394Z




531


 


1395Z




581


 


1396Z




561


 


1397Z




535


 


1398Z




541


 


1399Z




544


 


1400Z




437


 


1401Z




465


 


1402Z




513


 


1403Z




525


 


1404Z




547


 


1405Z




451


 


1406Z




513


 


1407Z




545


 


1408Z
no compound


 


1409Z




557


 


1410Z




471


 


1411Z




499


 


1412Z




499


 


1413Z
no compound


 


1414Z




563


 


1415Z




535


 


1416Z




467


 


1417Z




535


 


1418Z




481


 


1419Z




521


 


1420Z




577


 


1421Z




619


 


1422Z




605


 


1423Z




546


 


1424Z




475


 


1425Z




531


 


1426Z




561


 


1427Z




601


 


1428Z




451


 


1429Z




543


 


1430Z




579


 


1431Z




563


 


1432Z




518


 


1433Z




517


 


1434Z




515


 


1435Z




631


 


1436Z




605


 


1437Z




610


 


1438Z




496


 


1439Z




459


 


1440Z




483


 


1441Z




516


 


1442Z




544


 


1443Z




560


 


1444Z




484


 


1445Z




603


 


1446Z




595


 


1447Z




527


 


1448Z




563


 


1449Z




530


 


1450Z




499


 


1451Z




588


 


1452Z




532


 


1453Z




516


 


1454Z




585


 


1455Z




527


 


1456Z




527


 


1457Z




531


 


1458Z




512


 


1459Z




497


 


1460Z




684


 


1461Z




511


 


1462Z




515


 


1463Z




544


 


1464Z




668


 


1465Z




502


 


1466Z




469


 


1467Z




497


 


1468Z




516


 


1469Z




555


 


1470Z




608


 


1471Z




587


 


1472Z




555


 


1473Z




560


 


1474Z




560


 


1475Z




515


 


1476Z




526


 


1477Z




499


 


1478Z




413


 


1479Z




485


 


1480Z




586


 


1481Z




551


 


1482Z




513


 


1483Z




530


 


1484Z




479


 


1485Z




507


 


1486Z




543


 


1487Z




579


 


1488Z




576


 


1489Z




467


 


1490Z




535


 


1491Z




515


 


1492Z




523


 


1493Z




624


 


1494Z




479


 


1495Z




479


 


1496Z




591


 


1497Z




574


 


1498Z




503


 


1499Z




598


 


1500Z




524


 


1501Z




537


 


1502Z




557


 


1503Z




487


 


1504Z




495


 


1505Z




521


 


1506Z




495


 


1507Z




482


 


1508Z




499


 


1509Z




603


 


1510Z




530


 


1511Z




509


 


1512Z




545


 


1513Z




557


 


1514Z




463


 


1515Z




553


 


1516Z




481


 


1517Z




527


 


1518Z




534


 


1519Z




577


 


1520Z




530


 


1521Z




525


 


1522Z




521


 


1523Z




471


 


1524Z




499


 


1525Z




583


 


1526Z




531


 


1527Z




465


 


1528Z




482


 


1529Z




509


 


1529Z-1




603


 


1529Z-2




589


 


1529Z-3




541


 


1529Z-4




519


 


1529Z-5




647


 


1529Z-6




564


 


1529Z-7




634


 


1529Z-8




586


 


1529Z-9




651


 


1529Z-10




628


 


1529Z-11




604


 


1529Z-12




454 (M − 1)


 


1529Z-13




606


 


1529Z-14




527


 


1529Z-15




576


 


1529Z-16




550


 


1529Z-17




596


 


1529Z-18




530


 


1529Z-19




566


 


1529Z-20




701


 


1529Z-21




587


 


1529Z-22




671


 


1529Z-23




632


 


1529Z-24




677


 


1529Z-25




602


 


1529Z-26




647


 


1529Z-27




568


 


1529Z-28




572


 


1529Z-29




609


 


1529Z-30




578


 


1529Z-31




558


 


1529Z-32




548


 


1529Z-33




611


 


1529Z-34




548


 


1529Z-35




487


 


1529Z-36




596


 


1529Z-37




630


 


1529Z-38




566


 


1529Z-39




543


 


1529Z-40




546


 


1529Z-41




605 (M − 1)


 


1529Z-42




609


 


1529Z-43




586


 


1529Z-44




588


 


1529Z-45




701


 


1529Z-46




603


 


1529Z-47




671


 


1529Z-48




648


 


1529Z-49




677


 


1529Z-50




618


 


1529Z-51




647


 


1529Z-52




648


 


1529Z-53




647


 


1529Z-54




618


 


1529Z-55




617


 


1529Z-56




554


 


1529Z-57




546


 


1529Z-58




547


 


1529Z-59




544


 


1529Z-60




654


 


1529Z-61




496


 


1529Z-62




592


 


1529Z-63




496


 


1529Z-64




521


 


1529Z-65




524


 


1529Z-66




589


 


1529Z-67




646


 


1529Z-68




554


 


1529Z-69




646


 


1529Z-70




524


 


1529Z-71




574


 


1529Z-72




510


 


1529Z-73




544


 


1529Z-74




574


 


1529Z-75




574


 


1529Z-76




544


 


1529Z-77




544


 


1529Z-78




574


 


1529Z-79




598


 


1529Z-80




544


 


1529Z-81




546


 


1529Z-82




557


 


1529Z-83




547


 


1529Z-84




618 (M − 1)


 


1529Z-85




669


 


1529Z-86




529


 


1529Z-87




588


 


1529Z-88




562


 


1529Z-89




669


 


1529Z-90




532


 


1529Z-91




517


 


1529Z-92




518


 


1529Z-93




562


 


1529Z-94




532


 


1529Z-95




532


 


1529Z-96




570


 


1529Z-97




532


 


1529Z-98




547


 


1529Z-99




543


 


1529Z-100




532


 


1529Z-101




543


 


1529Z-102




532


 


1529Z-103




594


 


1529Z-104




518


 


1529Z-105




543


 


1529Z-106




569


 


1529Z-107




605


 


1529Z-108




616


 


1529Z-109




714


 


1529Z-110




586


 


1529Z-111




560


 


1529Z-112




582


 


1529Z-113




530


 


1529Z-114




616


 


1529Z-115




516


 


1529Z-116




586


 


1529Z-117




530


 


1529Z-118




616


 


1529Z-119




571 (M − 1)


 


1529Z-120




586


 


1529Z-121




562


 


1529Z-122




456


 


1529Z-123




562


 


1529Z-124




574


 


1529Z-125




563


 


1529Z-126




628


 


1529Z-127




565


 


1529Z-128




598


 


1529Z-129




602


 


1529Z-130




547


 


1529Z-131




535


 


1529Z-132




507


 


1529Z-133




530


 


1529Z-134




505


 


1529Z-135




568


 


1529Z-136




607


 


1529Z-137




636


 


1529Z-138




628


 


1529Z-139




606


 


1529Z-140




598


 


1529Z-141




717


 


1529Z-142




523


 


1529Z-143




558


 


1529Z-144




571


 


1529Z-145




653 (M − 1)


 


1529Z-146




523


 


1529Z-147




645


 


1529Z-148




523


 


1529Z-149




599


 


1529Z-150




571


 


1529Z-151




546


 


1529Z-152




571


 


1529Z-153




709


 


1529Z-154




587


 


1529Z-155




546


 


1529Z-156




504


 


1529Z-157




572


 


1529Z-158




539


 


1529Z-159




657


 


1529Z-160




567


 


1529Z-161




659


 


1529Z-162




585


 


1529Z-163




567


 


1529Z-164




600


 


1529Z-165




589


 


1529Z-166




541


 


1529Z-167




676


 


1529Z-1689




489


 


1529Z-169




646


 


1529Z-170




454


 


1529Z-171




631


 


1529Z-172




554


 


1529Z-173




455


 


1529Z-174




548


 


1529Z-175




511


 


1529Z-176




587


 


1529Z-177




580


 


1529Z-178




572


 


1529Z-179




569


 


1529Z-180




553


 


1529Z-181




569


 


1529Z-182




531


 


1529Z-183




558


 


1529Z-184




556


 


1529Z-185




515


 


1529Z-186




533


 


1529Z-187




614


 


1529Z-188




580


 


1529Z-189




599


 


1529Z-190




548


 


1529Z-191




531


 


1529Z-192




533


 


1529Z-193




556


 


1529Z-194




533


 


1529Z-195




568


 


1529Z-196




555


 


1529Z-197




530


 


1529Z-198




507


 


1529Z-199




601


 


1529Z-200




521


 


1529Z-201




600


 


1529Z-202




521


 


1529Z-203




588


 


1529Z-104




521


 


1529Z-105




588


 


1529Z-106




517


 


1529Z-107




511


 


1529Z-108




571


 


1529Z-109




555


 


1529Z-110




571


 


1529Z-111




530


 


1529Z-112




571


 


1529Z-113




530


 


1529Z-114




504


 


1529Z-115




621


 


1529Z-116




546


 


1529Z-117




585


 


1529Z-118




563


 


1529Z-119




589


 


1529Z-120




547


 


1529Z-121




558


 


1529Z-122




504


 


1529Z-123




561


 


1529Z-124




563


 


1529Z-125




585 (M − 1)


 


1529Z-126




595


 


1529Z-127




562


 


1529Z-128




563


 


1529Z-129




571


 


1529Z-130




547


 


1529Z-131




578


 


1529Z-132




551


 


1529Z-133




578


 


1529Z-134




569













Step 17:





To a stirred solution of dimethyl malonate 19 (13.20 g, 0.10 mol) in MeOH (100 mL) was added dropwise sodium methoxide (220 mL, 0.5 M in MeOH, 0.11 mol) and then heptylbromide (16.90 g, 0.09 mol) in MeOH (30 mL). The reaction mixture was heated evaporated and CHCl3 (50 mL) was added to the mixture, the resulting precipitate was removed by filtration. The concentrated filtrate was distilled under vacuum (140° C./14 mmHg) to give the product 20 as a colorless oil (21.0 g, 90.9%). MS (M+1): m/e 231.
Step 18:




To a mixture of chloroaniline 21 (25.0 g, 0.20 mol) and KSCN (30.0 g, 0.30 mol) in anhydrous THF (50 mL) cooled to 0° C. was added dropwise 4N HCl in dioxane (50 mL, 0.20 mol). After the reaction mixture was heated at 80° C. for 20 h. the solvent was evaporated, and water (20 mL) was added to the residue. After filtration, the precipitate was washed with water (20 mL) and dried to gave a yellow solid. This solid was further washed with hot ethyl acetate and dried to give the product 22 (20.5 g, 55%) as a white solid.
Step 19:




To a solution of thiourea 22 (1.86 g, 0.010 mol) dissolved in anhydrous MeOH (20 mL), was added sodium methoxide (1.08 g, 0.020 mol) and compound 20 (2.30 g, 0.010 mol) at once. After the reaction mixture was heated at 65° C. for 3 h, methyl iodide (1.42 g, 0.010 mol) was added to the reaction mixture slowly over 10 min at 50° C. The reaction mixture was further stirred at 50° C. for 30 min. The solvent was evaporated, and water (20 mL) was added. After neutralization with cold acetic acid, the white precipitate was filtered and dried under vacuum to give the desired compound 23 (3.12 g, 85%) as a white solid. MS (M+1): m/e 367.
Step 20:




To a solution of compound 23 (1.46 g, 4.0 mmol) in anhydrous CH2Cl2 (15 mL) was added dropwise triflic acid (0.7 mL, 4.2 mmol) and 2,6-lutidine (0.93 mL, 8.0 mmol) at −78° C. The resulting solution was stirred for 2 h at 78° C., and then allowed to warm to room temperature for 12 h. The reaction was quenched with aqueous NH4Cl solution (10 mL) and extracted with CH2Cl2 (3×50 mL). The combined organic extract was washed with 1 N HCl (10 mL), H2O (10 mL), brine (10 mL), dried (MgSO4), filtered, and concentrated. Purification by silica gel chromatography (eluant: 1:10 EtOAc:hexanes) gave the desired product 24 as a white solid (1.5 g, 75%). MS (M+1): m/e 499.
Step 21:




To a solution of compound 24 (0.498 g, 0.001 mol) in anhydrous chlorobenzene (10 mL) in a microwave tube was added diisopropylethyl amine (1.29 g, 0.010 mol) and benzenesulfonylpiperizine (2.26 g, 0.010 mol). After the reaction mixture was stirred at 160° C. for 2 h under microwave irradiation, the chlorobenzene was removed under vacuum. Purification by silica gel chromatography (1:5 EtOAc:hexanes) gave the desired compound 25 (0.345 g, 60%) as a light yellow oil. MS (M+1): m/e 575.
Step 22:




To a solution of compound 25 (0.058 g, 0.1 mmol) in anhydrous 3:1 MeOH:THF (10 mL) was added slowly NiCl2.6H2O (0.237 g, 1.0 mmol) and NaBH4 (0.038 g, 1.0 mmol). After the reaction mixture was stirred at 0° C. for 1 h, the reaction mixture was filtered through celite and washed with 1:1 MeOH:THF (100 mL). The solvent was evaporated, and the resulting residue was purified by silica gel chromatography (1:5 EtOAc:hexanes) to give the desired compound 26 (0.030 g, 52%) as a light yellow oil. MS (M+1): m/e 529.







TABLE 12







Carbon Linked Analogs with Sulfonamide


The following compounds can be synthesized using the steps of Scheme 3.









Comp. No.
Structure
MS M + 1





1530Z




543


 


1531Z




461


 


1532Z




495


 


1533Z




495













Compound 27 can be synthesized using steps 1 and 2 from Scheme 1 and steps 11 and 12 from Scheme 2.
Step 23:




To a solution of compound 27 (0.290 g, 0.60 mmol), diisopropylethyl amine (0.154 g, 1.2 mmol) in 4:1 α,α,αtrifluorotoluene:toluene (10 mL) in a microwave tube, allyl tributyltin (0.397 g, 1.2 mmol) and Pd(PPh3)4 (0.080 g, 0.07 mmol) was added successively under an argon atmosphere. After the reaction mixture was stirred at 165° C. for 40 min under microwave irradiation, the reaction mixture was filtered through short path of silica gel, and the solvent was evaporated. Purification by silica gel chromatography (1:5 EtOAc:hexanes) gave the desired compound 28 (0.220 g, 87%) as a yellow oil. MS (M+1): m/e 421.
Step 24:




To a solution of the pyridazinone 28 (0.210 g, 0.50 mmol) in 10:1 acetone:H2O (5 mL) was added NMO (0.073 g, 1.5 mmol) and OsO4 (0.025 g, 0.1 mmol) at 20° C. under a nitrogen atmosphere. The reaction mixture was stirred for 2 h at −20° C. to 0° C. then treated with saturated aqueous Na2SO3 solution (10 mL) and extracted with EtOAc (6×50 mL). The combined organic extract was dried (MgSO4), filtered, and concentrated. Purification by silica gel chromatography (eluant: EtOAc) gave the product 29 (0.182 g, mg, 80%) as a white solid. (M+1): m/e 456.
Step 25:




To a solution of compound 29 (0.090 g, 0.20 mmol), diisopropylethyl amine (0.077 g, 0.60 mmol) in CH2Cl2 (10 mL), triethyloxonium tetrafluoroborate (0.114 g, 0.60 mmol) was added at 0° C. The reaction mixture was stirred at 0° C. to room temperature for 24 h then treated with saturated aqueous NaHCO3 solution (10 mL), and the aqueous phase was extracted with CH2Cl2 (50 mL). The combined organic extract was washed with H2O (2×10 mL), brine (10 mL), dried (MgSO4), filtered, and concentrated. Purification by silica get chromatography (1:10 EtOAc:hexanes) gave the desired compound 30 (0.220 g, 87%) as a colorless oil. MS (M+1): m/e 511.







TABLE 13







Carbon Linked Analogs with Sulfonamide


The following compounds can be synthesized using the steps of Scheme 4.









Com-




pound

MS


No.
Structure
M + 1





1534Z




429


 


1535Z




531


 


1536Z




503


 


1537Z




483













Steps 26 and 27:





To a solution of 2,4-dihydroxypyridine 31 (10 g, 0.090 mol) and DMF (120 mL) was added in 4 portions NaH (60%, 4.32 g, 0.108 mol) at room temperature. The reaction mixture was cooled to 0° C. N-Phenyltrifluoromethanesulfonimide (35.4 g, 0.099 mol) was then added in four separate portions. The reaction was warmed to room temperature and stirred for 5 h then quenched with saturated NH4Cl (50 mL). EtOAc (200 mL) was added, and the organic layer was washed with brine (3×100 mL), dried (MgSO4), filtered, and concentrated. To the crude was added DMF (120 mL) and BOC piperazine (21.1 g, 0.113 mol). The reaction mixture was heated to 80° C. for 6 h then cooled to room temperature. EtOAc (200 mL) was added, and the organic layer was washed with brine (3×100 mL), dried (MgSO4), filtered, and concentrated. Purification by silica gel chromatography (eluant: 10-30%% MeOH-EtOAc) to gave compound 32 (21.3 g) as a orange-white solid. MS (M+1): m/e 280.
Step 28:




To a solution of compound 33 (2.74 g, 9.81 mmol) in CH2Cl2 (120 mL) was added phenyl boronic acid (2.40 g, 19.68 mmol), Cu(OAC)2 (3.56 g, 19.560 mmol), 4 Å MS (11 g), pyridine (1.6 mL, 19.78 mmol), and triethylamine (2.7 mL, 19.37 mmol). The reaction mixture was stirred at room temperature for 72 h then filtered through celite, concentrated, and purified by silica gel chromatography (1:1 hexanes:EtOAc to 5% MeOH in EtOAc) to give compound 34 (1.65 g) as a brown oil. MS (M+1): m/e 356.
Step 29:




To a solution of compound 34 (186.5 mg, 0.525 mmol) in AcOH (8 mL) was added NBS (121.4 mg, 0.682 mmol) and stirred at room temperature for 3 h. The reaction mixture was evaporated and purified by silica gel chromatography (3:1 to 1:1 hexanes:EtOAc) to give compound 35 (149.9 mg) as a light yellow solid. MS (M+1): m/e 434.
Step 30:




To a solution of compound 35 (144.6 mg) in degassed THF (10 mL) was added LiCl (28 mg, 0.661 mmol), tributyl(4-fluorophenyl)stannane (640 mg, 1.66 mmol), and tetrakis(triphenylphosphine)palladium(0) (42 mg, 0.036 mmol). The reaction mixture was heated at reflux for 42 h. The reaction was then cooled to room temperature, quenched with 1 N HCl (3 mL), and extracted with EtOAc (3×20 mL). The combined organic extract was washed with brine (20 mL), dried (MgSO4), filtered, and concentrated. Purification by preparative TLC (eluted twice with 5% acetone in CH2Cl2) gave compound 36 (24.3 mg) as a white solid. MS (M+1): m/e 450.
Steps 6 and 9 of Scheme 1:




Using the procedures described above, compound 37 was synthesized. MS (M+1): m/e 504.




Step 31:





A solution of compound 39 (5.0 g, 0.030 mol) in AcOH (20 mL) was heated at 60° C. for 30 min then cooled to room temperature. Compound 38 (4.33 g, 0.030 mol) was then added, and the reaction mixture was heated at 120° C. for 1 h. The reaction mixture was cooled to room temperature, and the resulting solid was filtered and washed with AcOH to give compound 40 (6.47 g) as a white solid. MS (M+1): m/e 257.
Step 32:




To a solution of compound 40 (1.0 g, 3.89 mmol) in DMF (30 mL) was added NaH (60%, 2-33 mg, 5.83 mmol) and stirred at room temperature for 15 h. The reaction was then quenched with saturated NH4Cl (10 mL). EtOAc (250 mL) was added, and the organic layer was washed with brine (3×50 mL), dried (MgSO4), filtered, and concentrated. Purification by silica gel chromatography (8:1 hexanes:EtOAc) gave compound 41 (177.4 mg) as a light yellow solid. MS (M+1): m/e 533.
Step 2 of Scheme 1:




Using the procedure described above, compound 42 was synthesized. MS (M+1): m/e 480.
Step 33:




To a solution of compound 42 (94.3 mg, 0.197 mmol) in EtOH (10 mL) was added Pd(OH)2/C (20%, 70 mg) and stirred under H2 (50 psi) at room temperature for 6 h, then filtered through celite. The solvent was evaporated, and purification by silica gel chromatography (2:1 to 1:1 hexanes:EtOAc) gave compound 43 (65.5 mg) as a colorless oil. MS (M+1): m/e 445.
Step 34:




To a solution of compound 42 (102.3 mg, 0.214 mmol) and 2-ethoxyethanol (111.5 uL, 0.779 mmol) in THF (20 mL) was added NaH (60%, 37 mg, 0.925 mmol) and stirred at room temperature for 17 h. The reaction was then quenched with saturated NH4Cl (10 mL) and extracted with EtOAc (3×20 mL). The combined organic extract was washed with brine (20 mL), dried (MgSO4), filtered, and concentrated. Purification by silica gel chromatography (3:1 to 2:1 hexanes:EtOAc) gave compound 44 (98.2 mg) as a colorless oil. MS (M+1): m/e 533.
Steps 6 and 9 of Scheme 1:







TABLE 13A







Sulfonamide analogs


The following compounds can be synthesized using the steps of Scheme 6.









Com-




pound

MS


No.
Structure
M + 1





1537Za




499


 


1537Zb




511


 


1537Zc




587













Step 35:





A solution of compound 47 (3.46 g, 0.013 mol) in POCl3 (25 mL) was heated at 100° C. for 2 h. The reaction mixture was cooled to room temperate then concentrated. Saturated NaHCO3 (50 mL) was added, and the aqueous solution was extracted with CH2Cl2 (3×100 mL). The combined organic extract was washed with brine (100 mL), dried (MgSO4), filtered, and concentrated. Purification by silica gel chromatography (8:1 to 1:1 gradient of hexanes:EtOAc) gave compound 48 (2.82 g) as an orange solid. MS (M+1): m/e 283.
Step 2 of Scheme 1;




Using the procedure described above, compound 49 was synthesized. MS (M+1): m/e 433.
Step 36:




To a solution of compound 49 (100 mg, 0.231 mmol) in EtOH (10 mL) at 0° C. was added NaBH4 (88 mg, 2.33 mmol). The reaction mixture was slowly warmed to room temperature and then stirred for 17 h. The reaction was quenched with saturated Rochelle's salt at 0° C. and extracted with EtOAc (3×20 mL). The combined organic extract was washed with brine (20 mL), dried (MgSO4), filtered, and concentrated. Purification by silica gel chromatography (2:1 to 1:2 hexanes:EtOAc) gave compound 50 as a white foam. MS (M+1): m/e 405.
Step 37:




To a solution of compound 50 (80.3 mg, 0.199 mmol) in DMF (7 mL) at 0° C. was added NaH (60%, 24 mg, 0.600 mmol). Bromoethylether (134 uL, 1.19 mmol) was then added and the reaction mixture stirred at room temperature for 17 h. The reaction was quenched with saturated NH4Cl (5 mL) and extracted with EtOAc (3×15 mL). The combined organic extract was washed with brine (20 mL), dried (MgSO4), filtered, and concentrated. Purification by silica gel chromatography (3:1 to 1:1 hexanes:EtOAc) gave compound 51 (93.9 mg) as a light yellow oil. MS (M+1): m/e 477.
Steps 6 and 9 of Scheme 1:







TABLE 14







Sulfonamide Analogs


The following compouns can be synthesized using the steps of Scheme 7.









Compound No.
Structure
MS M + 1





1538Z




487


 


1539Z




531


 


1540Z




483













Compound 53 can be synthesized using steps 1, 2, 4, 6, and 9 of Scheme 1.
Step 38:
To a solution of compound 53 (31.5 mg, 0.063 mmol) in toluene (5 mL) was added Lawesson's reagent (26.0 mg, 0.064 mmol). The reaction mixture was heated to reflux (120° C.) for 48 h then cooled to room temperature and concentrated. Purification by Gilson reverse phase HPLC gave compound 54 (10.0 mg) as a light yellow oil. MS (M+1): m/e 515.




Step 39:

To a solution of compound 53 (100 mg, 0.201 mmol) in THF (20 mL) was added N-fluorobenzenesulfonimide (189.7 mg, 0.602 mmol), and the reaction mixture was cooled to −78° C. NaHMDS (1 M, 421.2 uL, 0.421 mmol) was added slowly over 30 min to the reaction mixture then gradually warmed to room temperature and stirred overnight for 15 h. The reaction was quenched with saturated NH4Cl (10 mL) and extracted with ethyl acetate (3×25 mL). The combined organic extract was washed with brine (25 mL), (MgSO4), filtered, and concentrated. Purification by prep TLC (112 hexanes:ethyl acetate) gave compound 54 (20.2 mg) as a yellow solid and compound 55 (8.2 mg) as yellow oils. MS (M+1): m/e 535, m/e 517.







TABLE 15







Oxygen Linked Analogs with Sulfonamide


Using similar procedures described above, the following compounds were


synthesized.









Com-




pound

MS


No.
Structure
M + 1





1541Z




547


 


1542Z




525


 


1543Z




549













Step 40:

To a solution of compound 56 (150 mg, 0.290 mmol) dissolved in dry DMF (4 mL) was added methyl iodide (124 mg, 0.054 mL, 0.871 mmol) and potassium t-butoxide (1 M in THF, 0.87 mL, 0.87 mmol) under a nitrogen atmosphere. The reaction was stirred at room temperature for 24 h. The solvent was evaporated, water (25 mL) was added, and the aqueous solution was extracted with CH2Cl2. The combined organic extract was dried (MgSO4), filtered, and concentrated. Purification by reverse phase chromatography (eluant: acetonitrile:water gradient with 0.1% formic acid) gave 90 mg (57%) of compound 57 and 37 mg (24%) of compound 58 as colorless oils. MS (M+1): m/e 545 for compound 57 and 531 for compound 58.
Using similar procedures described above, the following compounds were synthesized.












Cmpd. No.
Structure
MS M + 1







1543Za




579


 


1543Zb




565













Compound 59 can be synthesized using steps 1, 2, 4, 6, and 9 of Scheme 1.
Step 41:




To a solution of compound 59 (150 mg, 0.289 mmol) dissolved in dry THF (4 mL) was added pyrrolidine (103 mg, 0.12 mL, 1.44 mmol). The reaction mixture was heated at reflux for 18 h. The solvent was evaporated, and purification by silica gel chromatography (eluant: 5-10% MeOH/NH3—CH2Cl2) gave 133 mg (83%) of the product 60 as a colorless oil. MS (M+1): m/e 554.
Step 42:




To a solution of compound 59 (250 mg, 0.481 mmol) dissolved in dry DMF (5 mL) was added potassium carbonate (200 mg, 1.44 mmol), potassium iodide (20 mg, 0.120 mmol), and phenol (136 mg, 1.44 mmol). The reaction mixture was heated at 100° C. for 16 h. The solvent was evaporated, water (25 mL) was added, and the aqueous solution was extracted with CH2Cl2. The combined organic extract was dried (MgSO4), filtered, and concentrated. Purification by silica gel chromatography (eluant: 20-30% EtOAc-hexanes) gave 212 mg (76%) of the product 61 as a yellow solid. MS (M+1): m/e 599.







TABLE 16







Oxygen Linked Analogs with Sulfonamide


Using similar procedures described above, the following compound was synthesized.









Compound No.
Structure
MS M + 1





1544Z




578













Compound 62 can be synthesized using steps 1, 2, 4, and 6 of Scheme 1.
Step 43:




Diisopropylethylamine (0.17 mL, 1.0 mmol) was added to a suspension of tert-butylsulfinyl chloride (0.04 mL, 0.30 mmol) and compound 62 (150 mg, 0.36 mmol) in anhydrous CH2Cl2 (5 mL) at room temperature under nitrogen. The mixture was stirred for 22 h after which it was directly purified by CombiFlash Companion (40-g silica gel cartridge, eluant: 2:8 to 7:3 gradient ethyl acetate/hexanes), to provide sulfinamide 63 (120 mg, 82%) as a white solid: APCI MS m/z 479 [M+H]+.
Step 44:




meta-Chloroperoxylbenzoic acid (190 mg, 0.78 mmol) was added to a solution of compound 63 (310 mg, 0.65 mmol) in anhydrous CH2Cl2 (10 mL) at room temperature under nitrogen. The mixture was stirred for 2.5 h after which it was diluted with CH2Cl2 (50 mL), washed with saturated aqueous sodium bisulfite solution (50 mL) and the solvents were evaporated. The residue was purified by CombiFlash Companion (80-g silica gel cartridge, eluant 1:9 to 7:3 gradient ethyl acetate/hexanes) to provide product 64 (290 mg, 91%) as a white solid: APCI MS m/z 495 [M+H]+.




Step 45:

To a solution of 2-bromo-4-methylpyridine 65 (1.0 g, 5.81 mmol) in THF (20 mL) was added at room temperature isopropyl magnesium chloride (2 M, 3.2 mL, 6.40 mmol). The reaction mixture was heated to reflux for 3 h then cooled to −40° C. SO2(g) was bubbled through the reaction mixture for 5 min then stirred at −40° C. for 1 h. SO2Cl2 (607 uL, 7.49 mmol) was added, and the reaction mixture was stirred for 30 min. BOC piperazine (3.2 g, 17.2 mmol) was then added, and the reaction mixture was slowly warmed to room temperature and stirred for 17 h. Water was added, and the aqueous solution was extracted with EtOAc (3×30 mL). The combined organic extract was washed with brine (30 mL), dried (MgSO4), filtered, and concentrated. Purification by silica gel chromatography (3:1 to 1:1 hexanes:EtOAc) gave compound 67 (1.41 g) as a colorless oil. MS (M+1): m/e 342.
Steps 6, 2, and 4 of Scheme 1;











TABLE 17







Oxygen Linked Analogs with Sulfonamide


Using the procedures described above, the following compounds were


synthesized.









Com-




pound

MS


No.
Structure
M + 1





1545Z




530


 


1546Z




530


 


1547Z




558


 


1548Z




496


 


1549Z




496













Step 46:





To a solution of N,N′-sulfuryldiimidazole 68 (2.00 g, 10.1 mmol) in anhydrous methylene chloride (40 mL) at 0° C. under nitrogen was added dropwise methyl triflate (1.4 mL, 12.4 mmol). The mixture was stirred at 0° C. for 3 h after which the solid was collected by vacuum filtration to provide product 69 (3.33 g, 91%) as a white solid.
Step 47:




To a solution of compound 69 (2.09 g, 5.77 mmol) in anhydrous acetonitrile (15 mL) at room temperature under nitrogen was added N-methylaniline (414 mg, 3.86 mmol). The mixture was stirred for 2.5 h after which the solvent was evaporated. The residue was purified by CombiFlash Companion (40-g silica gel cartridge, eluant 9:1 to 1:1 gradient hexanes/ethyl acetate) to provide product 70 (372 mg, 47%) as a viscous orange oil.
Step 48:




To a solution of compound 70 (372 mg, 1.57 mmol) in anhydrous methylene chloride (7 mL) at 0° C. under nitrogen was added methyl triflate (0.25 mL, 2.21 mmol). The mixture was stirred at 0° C. for 2 h after which the solvent was removed under reduced pressure to provide product 71 (373 mg, 59%) as a light-brown solid.
Step 49:




To a solution of compound 71 (373 mg, 0.93 mmol) in anhydrous methylene chloride (3 mL) at room temperature under nitrogen was added a solution of compound 73 (255 mg, 0.62 mmol) and N,N-diisopropylethylamine (0.11 mL, 0.631 mmol) in CH2Cl2 (3 mL). The mixture was stirred for 6 h after which the solvent was removed under reduced pressure. The residue was purified by CombiFlash Companion (40-g silica gel cartridge, eluant 9:1 to 3:1 gradient hexanes/ethyl acetate) to provide product 72 (249 mg, 74%) as a white solid: APCI MS m/z 544 [M+H]+.







TABLE 18







Oxygen Linked Analogs with Sulfonamide


Using the procedures described above, the following compounds were


synthesized.









Comp.

MS


No.
Structure
M + 1





1550Z




526


 


1551Z




514













Step 50:





Dry t-butanol (0.96 mL, 10 mmol) in 20 mL of dry methylene chloride was cooled to 0° C. Chlorosulfonyl isocyanate 74 (0.9 mL, 10 mmol) was then added dropwise. The resulting solution was stirred at 0° C. for 30 min, then at room temperature for 1 h. This 0.5 M solution of compound 75 was used directly in the next step.




Step 51:

Compound 76 (0.43 g, 1.0 mmol) in 10 mL of dry methylene chloride was mixed with diisopropylethylamine (0.52 mL, 3.0 mmol). A 0.5 M solution of compound 75 in methylene chloride (2.4 mL, 1.2 mmol) was added dropwise. The resulting mixture was then stirred at room temperature for 16 h. EtOAc was added, and the organic solution was washed with 1 N HCl, then dried (Na2SO4), filtered, and concentrated to give quantitative yield of product 77 as a white solid.
Step 52:




To compound 77 (1.0 mmol) dissolved in methylene chloride was added 4 N HCl in dioxane at room temperature and stirred overnight. The solvent was evaporated, and purification by silica gel chromatography gave 0.45 g (96% from 76) of product 78 as a white solid. MS (M+1): m/e 470.
Step 53:




To compound 78 (52 mg, 0.11 mmol) dissolved in DMF (1 mL) was added 1,4-diiodobutane (0.015 mL, 0.11 mmol) and NaH (60%, 10 mg, 0.22 mmol). The resulting mixture was stirred at room temperature for 16 h, EtOA was added, and the organic solution was washed with brine, dried (Na2SO4), filtered, and concentrated. Purification by silica gel chromatography gave 48 mg (83%) of product 79 as a white solid. MS (M+1): m/e 524.







TABLE 19







Oxygen Linked Analog with Sulfonamide


Using the procedures described above, the following compound was


synthesized.









Com-




pound

MS


No.
Structure
M + 1





1552Z




508









Step 54:





Compound 78 (50 mg, 0.1 mmol) was mixed with 4,6-dichloropyrimidine (20 mg, 0.13 mmol) in 1 mL of dry DMF. Phosphazene base P1-t-Bu (0.038 mL, 0.15 mmol) was added. The mixture was stirred at room temperature for 16 h. The crude mixture was purified by prep HPLC to give 0.033 g of product 80 as a white solid. MS (M+1): m/e 582.
Step 55:




To compound 80 in dry DMF was added methyl iodide (0.1 mL), and the resulting mixture was stirred at room temperature for 3 days. The crude mixture was purified by prep HPLC to give 0.035 g of product 81 as a white solid. MS (M+1): m/e 596.




Step 56:





1-Boc-piperazine 82 (25.0 g, 0.13 mol) was mixed with diisopropylethylamine (28 mL, 0.16 mol) in dry methylene chloride (40 mL), and the mixture was cooled to −25° C. 2-Isopropanesulfonyl chloride (16.5 mL, 0.15 mol) was added dropwise. The resulting mixture was slowly warmed up to room temperature, and stirred for 16 h. The solvent was evaporated, and EtOAc was added. The organic solution was washed with 1 N HCl, brine, dried (Na2SO4), filtered, and concentrated to give 39 g of product 83 as white solid. MS (M+1): m/e 293.
Step 57:




To compound 83 dissolved in methylene chloride (30 mL) was added of 4 N HCl in dioxane (100 mL). The resulting mixture was stirred at room temperature for 16 h. The solvent was evaporated, and diethyl ether was added. The precipitate was collected by filtration and dried in a vacuum oven at 50° C. for two days to give 28.6 g of product 84 as the HCl salt. MS (M+1): m/e 193.
Step 58:




Compound 84 (9.6 g, 42 mmol) was mixed with 4,5-dichloro-3-hydroxy pyridazine (6.6 g, 40 mmol) and TEA (11.4 mL, 82 mmol) in ethanol (80 mL). The resulting mixture was stirred at 70° C. for 2 days then cooled to room temperature and diluted with water (160 mL). The precipitate was collected by filtration, washed with water/ethanol (1:1), and dried in a vacuum oven at 50° C. for 2 days to give 7.8 g of product 85 as a white solid. MS (M+1): m/e 321.
Step 59:




A 20-mL microwave reaction vial was charged with compound 85 (1.92 g, 6.0 mmol), 3,5-difluorophenyl boronic acid (1.04 g, 6.6 mmol), sodium carbonate (1.33 g, 12.6 mmol), and Pd(PPh3)2Cl2 (0.21 g, 0.3 mmol) in 1:1 CH1CN:H2O (16 mL). The reaction mixture was heated in the microwave with stirring at 150° C. for 12 mins. After cooling to room temperature, EtOAc was added. The organic solution was washed with 1 N HCl then brine, dried (Na2SO4), filtered, and concentrated. Purification by silica get chromatography gave 1.35 g of the product 86 as a white solid. MS (M+1): m/e 399.
Step 60:




A 5-mL microwave reaction vial was charged with compound 86 (50 mg, 0.125 mmol), 3-methoxybromobenzene (0.12 mL), Cu powder (10 mg), anhydrous potassium carbonate (40 mg), and dry pyridine (3 mL). The reaction mixture was heated in the microwave with stirring at 190° C. for 15 min. After cooling to room temperature, the mixture was filtered, and the solution was concentrated. The residue was dissolved in DMF and purification by reverse phase chromatography on a Gilson prep HPLC gave 50.5 mg of product 87 as light-yellow solid. MS (M+1): m/e 505.
Step 61:




A 5-mL microwave reaction vial was charged with compound 85 (100 mg, 0.3 mmol), 3-bromopyridine (0.3 mL), Cu powder (20 mg), anhydrous potassium carbonate (100 mg), and dry pyridine (4 mL). The reaction mixture was heated in a microwave with stirring at 200° C. for 30 min. After cooling to room temperature, the mixture was filtered, and the solution was concentrated. Purification by silica gel chromatography gave 103 ma of product 88 as light-yellow solid. MS (M+1): m/e 398.
Step 62:




Compound 88 (85 mg, 0.21 mmol) and was mixed with cyclopentanol (55 mg, 0.63 mmol) in dry THF (2 mL). Sodium hydride (60 wt % in oil, 20 mg) was added. The reaction mixture was stirred at room temperature for 16 h. EtOAc was added, and the organic solution was washed with water and brine, dried (Na2SO4), filtered, and concentrated. Purification by silica gel chromatography gave 83 mg of product 89 as a light-yellow solid. MS (M+1): m/e 448.







TABLE 20







Oxygen Linked Analog with Sulfonamide


Using the procedures described above, the follow compound was


synthesized.









Com-




pound

MS


No.
Structure
M + 1





1553Z




478













Compound 90 can be synthesized using steps 1 and 2 of Scheme 1.
Step 63:
A mixture of anhydrous KCN (0.065 g, 1.0 mmol) and compound 90 (0.451 g, 1.0 mmol) in DMSO (5 mL) was stirred at room temperature for 24 h. The resulting solution was poured into ice H2O (10 mL), and a white precipitate formed. The solid was filtered and dried under vacuum. Purification by silica eel chromatography (1:10 EtOAc:hexanes) gave the product 91 as a white solid (0.320 g, 80%). MS (M+1): m/e 400.
Steps 6 and 9 of Scheme 1:




Using the procedure described above, compound 92 was synthesized. MS (M+1): m/e 440.




Step 64:





A mixture of 2-chloroethyl methyl ether 93 (25 g) and Na2SO3 (33 g) dissolved in H2O (100 mL) was heated at reflux for 24 h. After cooling to room temperature, the solid was filtered, washed with ether/toluene (5:1), and dried under vacuum to give product 94.
Step 65:




Compound 94 was added in small portions to POCl3 (60 mL). The resulting heterogeneous mixture was stirred at room temperature for 16 h and then heated at reflux for 12 h. CH2Cl2 (100 mL) was added to the reaction mixture. After filtration, ethyl acetate was added to the residue and then poured into crushed ice. The organic phase was separated and washed with brine (2×50 mL), dried (MgSO4), filtered, and concentrated to give product 95.







TABLE 21







Oxygen Linked Analogs with Sulfonamide


The following compounds can be synthesized by using compound 95 in step 9 of Scheme 1.









Compound

MS


No.
Structure
M + 1





1554Z




467


 


1555Z




541


 


1556Z




501


 


1557Z




497













Step 66:





Compound 3 (0.43 g, 1 mmol) was mixed with Pd(OAc)2 (4.5 mg), (±) BINAP (12.5 mg), Ph2C═NH (0.2 mL, 1.2 mmol), and potassium carbonate (0.7 g, 5 mmol) in dry toluene (9 mL). The reaction mixture was heated at 110° C. under nitrogen for 2 days. After cooling to room temperature, the mixture was filtered, and the solid was washed with methylene chloride. The combined filtrate was concentrated, and purification by silica gel chromatography gave 0.21 g of product 97 and 0.15 g of product 98. For compound 97: MS (M+1): m/e 570 and for compound 98; MS (M+1): m/e 406.
Step 67:




Compound 97 (0.15 mg) dissolved in methanol (2 mL) was treated with 2 N HCl (4 mL), and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was extracted with ethyl acetate and washed with brine. The organic extract was evaporated, and purification by silica gel chromatography gave the product 3 (100%).
Step 68:




To a solution of compound 98 (0.13 g, 0.3 mmol) in dry DMF (2 mL) was added diisopropylethylamine (0.2 mL) and isobutyryl chloride (0.035 mL, 0.33 mmol). The reaction mixture was stirred at room temperature for 3 days. The mixture was diluted with ethyl acetate, and washed with saturated sodium bicarbonate solution, water, 1 N HCl, and brine. The organic solution was evaporated to give the product 99 which was used in the next step without further purification.
Steps 6 and 9 of Scheme 1:




Using the procedures described above, compound 100 was synthesized. MS (M+1): m/e 530.




Step 69:





Chlorosulfonylacetyl chloride (0.16 mL, 1.5 mmol) in dry diethyl ether (2 mL) was cooled to −78° C., and methanol (1.5 mmol) in dry ether (1 mL) was added. After warming to room temperature, the mixture was stirred at room temperature for 1 h, then added to a solution of compound 76 and diisopropylethylamine (0.88 mL, 5 mmol) in DMF (3 mL). The resulting mixture was stirred at room temperature for 16 h. EtOAc was added, and the organic solution was washed with 1 N HCl and brine, dried (Na2SO4), filtered and concentrated. Purification by silica gel chromatography gave 0.2 g of product 101 as a white solid. MS (M+1): m/e 527.
Step 70:




To compound 101 (0.17 g) dissolved in THF (3.8 mL) and water (1.5 mL) was added lithium hydroxide (0.019 g). The resulting mixture was stirred at room temperature for 3 h. 1 N HCl (5 mL) was added, and the aqueous solution was extracted with EtOAc. The combined organic extract was dried (Na2SO4), filtered, and concentrated to give the product 102. MS M+1): m/e 513.
Step 71:




Compound 102 (40 mg) was mixed with ethyl amine (0.5 mmol), diisopropylethylamine (0.1 mL), and HATU (0.3 g) in DMF (1 mL). The mixture was stirred at room temperature for 16 h, then purified directly with the Gilson reverse phase prep HPLC (acetonitrile-water gradient with 0.1% formic acid) to give 21 mg of the product 103 as light-yellow solid. MS (M+1): m/e 640.







TABLE 22







Oxygen Linked Analog with Sulfonamide


Using the procedures described above, the follow compound was synthesized.









Compound

MS


No.
Structure
M + 1





1558Z




600
















Step 72:





Compound 76 (2.1 g, 5.1 mmol) was mixed with diisopropylethylamine (2.1 mL, 12.7 mmol) in 1:1 DMF:CH2Cl2 (20 mL) and cooled to −30° C. Chloromethanesulfonyl chloride (0.91 g, 6.11 mmol) was added, and the resulting mixture was slowly warmed up to room temperature and stirred for 16 h. EtOAc was added, and the organic solution was washed with 1 N HCl, water, and brine, dried (Na2SO4), and concentrated. Purification by silica gel chromatography gave 2.3 g of the product 104 as a white solid MS (M+1): m/e 489.
Step 73:




Potassium tertbutoxide (0.22 g, 2 mmol) was dissolved in dry THF (4 mL) and cooled to −78° C. A solution of compound 104 (0.24 g, 0.5 mmol) and 3,6-dichloropyridazine (0.10 g, 0.65 mmol) dissolved in dry THF (2 mL) was added. The reaction mixture was stirred at −78° C. for 1 h, and then 1 N aqueous HCl (4 mL) was added. EtOAc was added, and the organic solution was washed with water and brine, dried (Na2SO4), filtered, and concentrated. Purification by silica gel chromatography gave 0.25 g of the product 105 as white solid. MS (M+1): m/e 601.
Step 74:




To compound 104 (0.24 g, 0.5 mmol) and 2-nitropyridine (0.12 g, 1.0 mmol) dissolved in DMSO (3 mL) was added potassium tert-butoxide (0.22 g, 2 mmol) was added portionwise at room temperature. After stirring for 5 mins, 1 N aqueous HCl (5 mL) was added. EtOAc was added, and the organic solution was washed with water and brine, dried (Na2SO4), filtered, and concentrated. Purification by silica gel chromatography (10% hexane/CH2CH2 to 10% EtOAc/CH2CH2) gave 0.12 g of the product 106 as a white solid and 0.065 g of the product 107 as a white solid.
The structure of each isomer was assigned by its 1H NMR spectrum.
MS (M+1): m/e 577 (compound 106) and 577 (compound 107).
Step 75:




To compound 106 (100 mg) dissolved in THF (10 mL) was added 10% Pd/C (200 mg). The reaction mixture was stirred under a balloon of hydrogen gas at room temperature for 2 h. The catalyst was removed by filtration and washed with EtOAc. The filtrate was concentrated, and purification by silica gel chromatography gave 0.085 g of the product 108 as white solid. MS (MM+1): m/e 547.







TABLE 23







Oxygen Linked Analogs with Sulfonamide


Using the procedures described above, the following compounds were synthesized.









Comp.

MS


No.
Structure
M + 1





1559Z




547


 


1560Z




655


 


1561Z




612


 


1562Z




580


 


1563Z




597


 


1564Z




591


 


1565Z




564


 


1566Z




547


 


1567Z




577


 


1568Z




625


 


1569Z




582


 


1570Z




594


 


1571Z




577


 


1572Z




591


 


1573Z




547


 


1574Z




563


 


1574Za




608


 


1574Zb




580


 


1574Zc




618 (M − 1)


 


1574Zd




596


 


1574Ze




564


 


1574Zf




589


 


1574Zg




564


 


1574Zh




604


 


1574Zi




625


 


1574Zj




589


 


1574Zk




610


 


1574Zl




575


 


1574Zm




610


 


1574Zn




575


 


1574Zo




580


 


1574Zp




545


 


1574Zq




580


 


1574Zr




545


 


1574Zs




599


 


1574Zt




561


 


1574Zu




599


 


1574Zv




625


 


1574Zw




569


 


1574Zx




595


 


1574Zy




587


 


1574Zz




614


 


1574ZA




587


 


1574ZB




584


 


1574ZC




569


 


1574ZD




584


 


1574ZE




604


 


1574ZF




616


 


1574ZG




574


 


1574ZH




586


 


1574ZI




574


 


1574ZJ




586


 


1574ZK




642


 


1574ZL




562


 


1574ZM




586


 


1574ZN




574


 


1574ZO




628


 


1574ZP




576


 


1574ZQ




586


 


1574ZR




604


 


1574ZS




629


 


1574ZT




574


 


1574ZU




597


 


1574ZV




574


 


1574ZW




567


 


1574ZX




650


 


1574ZY




714


 


1574ZZ




620


 


1574Z-1




714


 


1574Z-2




620


 


1574Z-3




684


 


1574Z-4




616


 


1574Z-5




684


 


1574Z-6




568


 


1574Z-7




672


 


1574Z-8




604


 


1574Z-9




534


 


1574Z-10 1401482




574


 


1574Z-11




604


 


1574Z-12




576


 


1574Z-13




574


 


1574Z-14




576


 


1574Z-15




596


 


1574Z-16




590


 


1575Z-17




596


 


1574Z-18




545


 


1574Z-19




594


 


1574Z-20




618


 


1574Z-21




592


 


1574Z-22




588


 


1574Z-23




607


 


1574Z-24




574


 


1574Z-25




590


 


1574Z-26




574


 


1574Z-27




618


 


1574Z-28




580


 


1574Z-29




601


 


1574Z-30




602


 


1574Z-31




640


 


1574Z-32




602


 


1574Z-33




610


 


1574Z-34




588


 


1574Z-35




640


 


1574Z-36




604


 


1574Z-37




610


 


1574Z-38




601


 


15742-39




658


 


1574Z-40




603


 


15742Z-41




628


 


1574Z-42




573


 


1574Z-43




658


 


1574Z-44




573


 


1574Z-45




628


 


1574Z-46




571


 


1574Z-47




640


 


1574Z-48




562


 


1574Z-49




610


 


1574Z-50




629


 


1574Z-51




640


 


1574Z-52




601


 


1574Z-53




610


 


1574Z-54




629


 


1574Z-55




610


 


1574Z-56




601


 


1574Z-57




598


 


1574Z-58




628


 


1574Z-59




625


 


1574Z-60




628


 


1574Z-61




599


 


1574Z-62




655


 


1574Z-63




569


 


1574Z-64




655


 


1574Z-65




535


 


1574Z-66




625


 


1574Z-67




599


 


1574Z-68




722


 


1574Z-69




569


 


1574Z-70




722


 


1574Z-71




569


 


1574Z-72




576


 


1574Z-73




626


 


1574Z-74




576


 


1574Z-75




600


 


1574Z-76




602


 


1574Z-77




598


 


1574Z-78




614


 


1574Z-79




598


 


1574Z-80




584


 


1574Z-81




632


 


1574Z-82




615


 


1574Z-83




602


 


1574Z-84




606


 


1574Z-85




643


 


1574Z-86




641


 


1574Z-87




634


 


1574Z-88




615


 


1574Z-89




604


 


1574Z-90




611


 


1574Z-91




595


 


1574Z-92




577


 


1574Z-93




599


 


1574Z-94




639


 


1574-95




672


 


1574Z-96




609


 


1574Z-97




658


 


1574Z-98




613


 


1574Z-99




628


 


1574Z-100




617


 


1574Z-101




610













Step 76:





In a three necked flask containing a reflux condenser, dropping funnel, inner thermometer, a mixture of ketone 110 (2.64 g, 0.020 mol) and MeI (10 mL, 0.160 mol) was added to a suspension of KOH (22.40 g, 0.400 mol) in DMSO (30 mL) at 50-60° C. The reaction mixture was stirred at this temperature for 1.5 h and then the slurry was poured into ice water. The mixture was extracted with pentane (3×50 mL). The combined organic extract was washed with 120 (2×10 mL), brine (10 mL), dried (MgSO4) filtered, and concentrated. Purification by silica get chromatography (50:1 hexanes:EtOAc) gave the product 111 as a colorless oil (2.10 g, 56%). MS (M+1): m/e 187
Step 77:




A solution of lithium aluminum hydride (5.0 mL, 1.0 M in TH, 5.0 mmol) was added to compound 111 (1.88 g, 10 mmol) dissolved in anhydrous ether (20 mL) and cooled to 0° C. The reaction mixture was stirred for 4 h and then water (0.2 mL), 1 N NaOH (0.2 ml), and water (0.6 mL) were added sequentially. The mixture was filtered through celite and washed with ether. The filtrate was concentrated and purification by silica gel chromatography (20:1 hexanes:EtOAc) gave 1.0 g (53%) of the product 112 as a colorless oil.
Step 78:




A mixture of anhydrous NaH (0.011 g, 0.30 mmol, 60%) and methoxylindanol 112 (0.062 g, 0.33 mmol) in anhydrous THF (5 mL) was stirred at room temperature for 10 mins. To this mixture, a solution of compound 14A (0.070 g, 0.16 mmol) in anhydrous THF (5 mL) was added dropwise at room temperature. The resulting solution was refluxed for 8 h, and then the solvent was evaporated. Aqueous NH4Cl (10 mL) was added and the aqueous solution was extracted with CH2Cl2 (3×50 mL). The combined organic extract was washed with H2O (2×10 mL) and brine (10 mL), dried (MgSO4), filtered, and concentrated. Purification by silica gel chromatography (10:1 hexanes:EtOAc) gave the product 113 as a colorless oil (0.042 g, 46%). MS (M+1): m/e 569.




Step 79. Organic Syntheses, Vol. 80, p. 111 (2003).





To compound 114 (2.0 g, 15.6 mmol) and chlorotitanium triisopropoxide (11.2 mL, 11.2 mmol of 1 M in hexane) dissolved in anhydrous ether (54 mL) under a nitrogen atmosphere was added n-butylmagnesium chloride in ether (1 M, 52 mL, 52 mmol) over 6.5 h via a syringe pump at room temperature. After the addition is complete, the resulting black reaction mixture is stirred for an additional 20 mins and then cooled to 0° C. Ether (50 mL) was added followed by the slow addition of water (14 mL). The resulting mixture was stirred for 3 h at room temperature. The organic phase was separated, and the aqueous phase was extracted with ether (3×100 mL). The combined organic extract was washed with brine (2×50 mL), dried (MgSO4), filtered, and concentrated. Purification by silica gel chromatography (eluant: 5-10% ether/pentane) gave 1.09 g (71%) of the product 115 as a colorless oil.
Step 14 of Scheme 2:




Using the procedure described above, compound 116 was synthesized. MS (M+1): m/e 477.




Step 80:





Ethyl vinyl ether (43 mL, 0.45 mol) was added to a suspension of cyclohexane-1,4-diol (117, 52 g, 0.45 mol, mixture of cis and trans isomers) in anhydrous tetrahydrofuran (300 mL) at 0° C. under nitrogen, after which 4-toluenesulfonic acid (15 mg, catalytic amount) was added. The mixture was warmed to room temperature and stirred for 1 h, after which sodium carbonate (30 g) was added to the clear solution. The solids were removed by filtration and the solvent was evaporated. Purification by flash column chromatography on silica gel (eluant: 1:1 ethyl acetate:hexanes) gave acetal 118 (19 g, 22%, mixture of cis and trans isomers) as a colorless oil.
Step 81:




Methylmagnesium bromide (55 mL, 165 mmol, 3.0 M in tetrahydrofuran) was added to a solution of acetal 118 (7.8 g, 41.3 mmol, mixture of cis and trans isomers) in anhydrous toluene (500 mL) at room temperature under nitrogen, and the mixture was heated at 105° C. for 36 h. The mixture was cooled to 0° C., diluted with water (100 mL) and the pH was adjusted to 4-5 with 2 N HCl. The mixture was extracted with diethyl ether (100 mL) and the organic extract was washed with brine (3×200) dried (Na2SO4), filtered, and concentrated. Purification by flash column chromatography on silica gel (eluant: 1:1 ethyl acetate:hexanes) to first produce cis compound 119a (1.8 g, 28%) as a colorless oil. Additional elution produced the trans compound 119b (0.9 g, 14%) as a colorless oil







TABLE 24







Oxygen Linked Analogs with Sulfonamide


Step 14 of Scheme 2:


Using the procedure described above, the following compounds were


synthesized.









Comp.

MS


No.
Structure
M + 1





1575Z




588


 


1576Z




554


 


1577Z




541


 


1578Z




539


 


1579Z




588


 


1580Z




554


 


1581Z




587













Compound 117 can be synthesized using steps 1 and 2 of Scheme 1 and steps 11 and 12 of Scheme 2.
Step 82:
A mixture of 117 (238 mg, 0.500 mmol), p-fluorophenylacetylene (0.10 mL, 0.10 g, 0.87 mmol), triethylamine (0.70 mL, 0.51 g, 5.0 mmol), bis(triphenylphosphine)palladium(II) dichloride (20 mg, 0.028 mmol) and copper(I) iodide (50 mg, 0.26 mmol) in anhydrous acetonitrile (3 mL) was sealed under nitro-en in a microwave tube. The mixture was heated to 130° C. over 5 mins and irradiated at 150° C. for 30 mins. The cooled mixture was poured into water (100 mL) and extracted with ethyl acetate (2×100 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated. Purification by flash column chromatography on silica gel (eluant: 1:1 ethyl acetate:hexanes) gave the product 118 (50 mg, 19%) as a yellow solid: MS (M+1): m/e 515.




Compound 119 can be synthesized using steps 1 and 2 of Scheme 1.
Compound 121 can be synthesized using steps 1, 2, and 4 of Scheme 1.
Step 83:




Argon was bubbled through a mixture of compound 119 (1.00 g, 2.13 mmol) and trans-benzyl(chloro)bis(triphenylphosphine)palladium(II) (81 mg, 0.11 mmol) in anhydrous tetrahydrofuran (25 mL) at room temperature under nitrogen. The yellow solution was heated to reflux and p-chlorobenzylzinc chloride (5.0 mL, 2.5 mmol, 0.5 M in tetrahydrofuran) was added dropwise, after which the mixture was heated at reflux for 12 h. The cooled mixture was treated with saturated aqueous NH4Cl solution (10 mL) followed by water (200 mL), and the mixture was extracted with ethyl acetate (3×100 mL). The combined organic extract was dried (Na2SO4), filtered, and concentrated. Purification by flash column chromatography on silica gel (eluant: 0:100 to 3:7 gradient of ethyl acetate:hexanes) gave the product 120 (807 mg, 74%) as a white solid: MS (M+1): m/e 515.
Step 84:




To a solution of 121 (350 mg, 0.832 mmol) in anhydrous tetrahydrofuran (20 mL) at −78° C. under nitrogen was added cyclopentylmagnesium chloride (0.85 mL, 1.7 mmol, 2.0 M in diethyl ether) at a rate which kept the internal reaction temperature below −70° C. The mixture was slowly warmed to room temperature, stirring for a total of 18 h. The mixture was diluted with saturated aqueous NH4Cl solution (10 mL) and water (100 mL) and extracted with ethyl acetate (2×100 mL). The combined organic extract was dried (Na2SO4), filtered, and concentrated. Purification by flash column chromatography on silica gel (eluant: 3:7 ethyl acetate:hexanes) gave the product 122 (351 mg, 92%) as a white solid: MS (M+1): m/e 45%.







TABLE 25







Carbon Linked Analogs with Sulfonamide


Steps 6 and 9 of Scheme 1:


Using the procedures described above, the following compounds were synthesized.









Comp. No.
Structure
MS M + 1





1582Z




417


 


1583Z




493


 


1584Z




437


 


1585Z




521


 


1586Z




487


 


1587Z




513


 


1588Z




517


 


1589Z




501


 


1590Z




555


 


1591Z




505


 


1592Z




509


 


1593Z




527


 


1594Z




479


 


1595Z




569


 


1596Z




537


 


1597Z




465


 


1598Z




565


 


1599Z




549


 


1600Z




527


 


1601Z




512













Step 85:





To a solution of SO2Cl2 (0.08 mL, 1.0 mmol) in CH2Cl2 (5 mL) at −78° C. was added a solution of the compound 124 (0.36 g, 1.0 mmol) and Et3N (0.16 mL, 1.1 mmol) in CH2Cl2 (5 mL). The reaction was slowly warmed up from −78 to −20° C. over a period of 1 h. The solvent was evaporated and purification by silica gel chromatography (eluant 20:1 CH2Cl2:EtOAc) gave 82 mg (18%) of the product 125 as a white solid. MS (M+1): m/e 457.
Step 86:




To a solution of phenol (47 mg, 0.50 mmol) in dry THF (3 mL), was added NaH (20 mg 60% by weight in oil, 0.50 mmol). The reaction mixture was stirred for 15 min at room temperature. A solution of the compound 125 (0.11 g 0.25 mmol) in THF (2 mL) was added, and the reaction mixture was stirred for 1 h. The mixture was diluted with EtOAc (20 mL) and washed with 1 N HCl and brine, dried (MgSO4), filtered, and concentrated. Purification by silica gel chromatography (eluant: 0-25%. EtOAc in hexanes) gave 40 mg (31%) of the product 126 as a pale yellow solid. MS (M+1): m/e 515.




Step 87:





Sodium hydride (60%, 2.40 g, 60 mmol) was added to a solution of 1,3-cyclopentadiol 127 (8.16 g, 80 mmol) in THF (200 mL) and the mixture was stirred for 15 mins at room temperature. Benzyl bromide (6.80 g, 40 mmol) was then added, and the resulting mixture was stirred at room temperature for 20 h. Solid sodium bicarbonate 10 g) was added, and stirring was continued for 30 mins. The reaction mixture was filtered, and the filtrate was concentrated. Purification by silica gel chromatography (eluant: 0-30% EtOAc in hexanes) gave 3.5 g (46%) of the product 128 as colorless oil.
Step 88:




To a solution of the compound 128 (2.77 g, 14.4 mmol) in CH2Cl2 (50 mL) was added Dess-Martin periodinane (12.22 g, 28.8 mmol) followed by stirring for 2 h at room temperature. The reaction mixture was treated with 2.0 M NaOH (50 mL). The organic phase was separated, and the aqueous solution was extracted with 110 mL of EtOAc. The combined organic extract was washed with brine, dried (MgSO4), filtered, and concentrated to give 2.5 g (93%) of the product 129 as a colorless oil.
Step 89:




DAST (3.18 g, 19.7 mmol) was added dropwise to a solution of compound 129 (1.50 g, 7.9 mmol) in 1,2-dichloroethane at room temperature. The reaction was heated at 90° C. for 24 h. After cooling to room temperature, the reaction mixture was filtered through a short silica gel plug and washed with CH2Cl2. The filtrate was concentrated and purification by silica gel chromatography (eluant: hexane) gave 0.99 g (59%) of the product 130 as colorless oil.
Step 90:




A flask was charged with Pd/C (10% wt, 1.00 g). Compound 130 (0.90 g, 4.3 mmol) dissolved in 5:1 MeOH:AcOH (30 mL) was added under nitrogen. The reaction mixture was shaken under hydrogen (50 psi) at room temperature for 48 h. The Pd/C catalyst was filtered and washed with CH2Cl2. The solvent was removed from the filtrate by distillation at 90° C. The residue was diluted with Et2O and treated with Na2CO3 (4.5 g) over 30 mins at room temperature. The solid was filtered off, and the filtrate was concentrated to give 0.37 g (71%) of the product 131 as a colorless oil.
Step 91:




A solution of compound 129 (0.49 g, 2.6 mmol) in THF (10 mL) was cooled to −78° C., and MeMgBr (1.4 M, 2.8 ml, 3.9 mmol) was added dropwise. The reaction mixture was warmed slowly from −78 to −10° C. over 1 h. Saturated NH4Cl solution (5 mL) and then EtOAc were added. The organic solution was washed with brine, dried (MgSO4), filtered, and concentrated. Purification by silica gel chromatography (eluant: 0-10% EtOAc in CH2Cl2) to give 0.20 g (37%) of the product 133 as a colorless oil.







TABLE 26







Oxygen Linked Analogs with Sulfonamide


Step 14 of Scheme 2:


Using the procedures described above, the following compounds were


synthesized.









Comp.

MS


No.
Structure
M + 1





1601Z




519


 


1602Z




567


 


1603Z




515


 


1604Z




501


 


1605Z




517


 


1606Z




495









Step 92:





A solution of DAST (52 mg, 0.325 mmol) dissolved in CH2Cl2 (5 mL) and cooled to −78° C. was added dropwise a solution of the alcohol 132 (80 mg, 0.16 mmol) in CH2Cl2 (5 mL). The reaction mixture was slowly warmed up to room temperature and stirred for 3 h. Saturated NaHCO3 solution (0.1 mL) was added. Purification of the mixture by silica gel chromatography (eluant: 0-359%. EtOAc in hexanes) gave 68 mg (86%) of the product 133 as a pale yellow solid (86%). MS (M+1): m/e 497.




Step 93: Tetrahedron v. 53, p. 1983 (1997) and Org. Process Res. Dev. v 2, p. 357 (1998)





Sodium hydride (11.6 g, 289 mmol, 60% dispersion in mineral oil) was added to a solution of 1,3-cyclopentanediol 127 (28.1 g, 275 mmol, mixture of cis and trans isomers) in anhydrous tetrahydrofuran (500 mL) at 0° C. under nitrogen. The mixture was stirred for 1 h after which a solution of tert-butyldimethylchlorosilane (49.8 g, 330 mmol) in anhydrous tetrahydrofuran (200 mL) was added. The mixture was slowly warmed to room temperature and stirred for a total of 18 h after which the mixture was diluted with brine (500 mL) and extracted with ethyl acetate (2×200 mL). The combined organic extract was dried (MgSO4), filtered, and concentrated. The residue was purified in two batches by CombiFlash Companion (330-g silica gel cartridge), eluting with ethyl acetate/hexanes (1:9 to 3:7), to provide the cis isomer 134A (2.45 g, 4%) as a colorless oil. The later eluting trans isomer 134B (15.18 g, 25%) was also isolated as a colorless oil.
Step 94:




To a solution of compound 134A (2.4 g, 11.1 mmol) in anhydrous THF (100 mL) at room temperature under nitrogen was added sodium bis(trimethylsilyl)amide (12 mL, 12.1 mmol, 1.0 M in THF). The mixture was stirred for 10 mins, after which chloropyridazinone (4.3 g, 10.1 mmol) was added portion wise. The mixture was stirred for 28 h after which the mixture was diluted with brine (100 mL) and extracted with ethyl acetate (300 mL). The organic extract was dried (MgSO4), filtered and concentrated. The residue was purified by CombiFlash Companion (120-g silica gel cartridge), eluting with ethyl acetate/hexanes (9:1 to 8:2), to give the product 135 (4.3 g, 71%) as an off-white solid. MS (M−H—SiMe2tBu): m/e 491.
Step 95:




To a solution of compound 135 (4.3 g, 7.1 mmol) in anhydrous THF (50 mL) at 0° C. under nitrogen was added tetra-n-butylammonium fluoride (8.5 mL, 8.5 mmol, 1 M in THF), and the mixture was slowly warmed to room temperature and stirred for a total of 18 h. The mixture was diluted with ethyl acetate (200 mL), washed with brine (100 mL), dried (MgSO4), filtered, and concentrated. Purification by CombiFlash Companion (80-g silica gel cartridge), eluting with ethyl acetate/hexanes (2:8 to 8:2) gave the product 136 (2.88 g 82% c) as an off-white solid. MS (M−H): m/e 491.
Step 96:




Diethylaminosulfur trifluoride (DAST, 1.2 mL, 8.8 mmol) was added dropwise to a solution of compound 136 (2.88 g, 5.8 mmol) in anhydrous methylene chloride (100 mL) at −20° C. under nitrogen. The mixture was stirred for 3.5 h after which it was warmed to 0° C. and diluted with saturated aqueous sodium bicarbonate solution (50 mL) and extracted with methylene chloride (2×100 mL). The combined organic extract was washed with brine (100 mL) and then concentrated. Purification by CombiFlash Companion (80-g silica gel cartridge), eluting with ethyl acetate/hexanes (1:9 to 4:6) gave the product 137 (2.16 g, 75%) as a white solid. MS (M+1): m/e 495.
Steps 6 and 9 of Scheme 1:











TABLE 27







Oxygen Linked Analogs with Sulfonamide


Using the procedures described above, the following compounds were synthesized.









Comp.

MS


No.
Structure
M + 1





1607Z




547


 


1608Z




500


 


1609Z




497


 


1610Z




602


 


1611Z




483


 


1612Z




473


 


1613Z




473


 


1614Z




527


 


1615Z




549


 


1616Z




499


 


1617Z




534


 


1618Z




533


 


1619Z




501


 


1620Z




501


 


1621Z




501


 


1622Z




527









Using the procedure of Scheme 29, the following, compounds listed above in Tables 10 and 11 are prepared: 448Z, 569Z, 570Z, 678Z, 733Z, 765Z, 766Z, 779Z, 793Z, 803Z, 804Z, 821Z, 847Z, 850Z, 851Z, 859Z, 875Z, 888Z, 902Z, 919Z, 925Z, 928Z, 1055Z, 1085Z, 1089Z, 1128Z, 1132Z, 1152Z, 1173Z, 1224Z and 1477Z.




Step 97:





Diisopropylethylamine (0.50 mL, 3.0 mmol) was added to a suspension of phenylacetyl chloride (0.16 mL, 1.2 mmol) and amine hydrochloride salt 62 (500 mg, 1.2 mmol) in anhydrous methylene chloride (10 mL) at room temperature under nitrogen. The mixture was stirred for 4 h after which it was directly purified by CombiFlash Companion (80-g silica gel cartridge), eluting with ethyl acetate/hexanes (2:8 to 100% ethyl acetate), to provide the product 139 (460 mg, 77%) as an off-white solid: MS (M+1): m/e 493.
Step 98:




A mixture of benzamide 139 (400 mg, 0.81 mmol) and p-methoxyphenyl-thionophosphine sulfide dimer (Lawesson's reagent, 164 mg, 0.41 mmol) in anhydrous toluene (10 mL) was heated at reflux under nitrogen for 3 h. The solvent was removed from the cooled mixture under reduced pressure, and the residue was purified by CombiFlash Companion (80-g silica gel cartridge), eluting with ethyl acetate/hexanes (2:8 to 4:6), to provide the product 140 (420 mg, 99%) as a light yellow solid: MS (M+1): m/e 509.







TABLE 28







Oxygen Linked Analogs with Sulfamide


Using the procedures described above, the following compounds were synthesized.









Comp.

MS


No.
Structure
M + 1





1623Z




476


 


1624Z




524


 


1625Z




462


 


1626Z




510


 


1627Z




495


 


1628Z




524













Step 99:





Compound 141 (20 g) in 50 mL of CH2Cl2 was treated with 150 mL of 4N HCl/dioxane solution at room temperature for 2 days. Ether (300 mL) was added, and the precipitate was collected by filtration and further washed with ether. The white solid was dried in a vacuum oven at 50° C. overnight to give 16.2 g of the product 142 as the HCl salt. MS (M+1): m/e 325.
Step 100:




Compound 142 (7.2 g, 20 mmol) was mixed with methylcyclopropanemethanol (2.6 g, 30 mmol) in 100 mL of dry THF. NaH (60%, 2.0 g, 50 mmol) was added. The resulting mixture was stirred at room temperature for one hour, then heated to 70° C. for 30 mins. The reaction mixture was cooled to room temperature, and water (100 mL) was added. The aqueous solution was extracted with ethyl ether (3×100 mL). The combined organic solutions were washed with brine, concentrated, and further dried by co-evaporation with toluene to give the product 143 as the free amine, which is used in the next step without further purification.
Step 101:




Dry t-butanol (4.0 mL, 42 mmol) in 80 mL of dry CH2Cl2 was cooled to 0° C. Chlorosulfonyl isocyanate (3.5 mL, 40 mmol) was then added dropwise. The resulting solution was stirred at 0° C. for 3 h. This 0.5 M solution of BocNHSO2Cl was used directly in the next step. Compound 143 (20 mmol) in 100 mL of dry CH2Cl2 was mixed with isopropyldiethylamine (7 mL, 40 mmol), and cooled to 0° C. in an ice-water bath. A 0.5 M solution of BocNHSO2Cl (50 mL, 25 mmol) was added dropwise. The resulting mixture was then stirred at room temperature overnight. The mixture was diluted with 500 mL of CH2Cl2, and washed with 0.5 N HCl solution and water. The organic layer was separated and dried over anhydrous Na2SO4. The solution was concentrated to about 70 mL, and the precipitate was collected by filtration to give the first batch of product 144 (9.1 g after drying). Further concentration of the solution affords another 1.5 g of the product 144. The product was dried in vacuum over at 50° C. for 2 days before use in the next step.
Step 102:




Compound 144 (0.11 g, 0.2 mmol) was mixed with (4-bromomethyl)-2-methoxy-1-nitrobenzene (0.054 g, 0.22 mmol) and phosphazene base P1-t-Bu (60L, 0.24 mmol) in 2 mL of dry THF. The resulting mixture was stirred at room temperature overnight, and the whole mixture was used directly in the next step.
Step 103:




Water (0.5 mL) was added to the reaction mixture from step 104. The resulting mixture was heated to 155° C. for 5 mins in the microwave reactor. After cooling to room temperature, the mixture was concentrated and purified by flash chromatography (eluant: 0%-10% EtOAc—CH2Cl2 gradient) to give 98 mg of compound 146 as a yellow solid. MS (M+1): m/e 619.
Step 104:




Compound 146 (93 mg) was dissolved in 8 mL of EtOAc/MeOH (3:1) mixed solvent system, PtO2 (20 mg) was added. The mixture was stirred under atmospheric H2 for one h. The reaction mixture was concentrated, and the crude product was purified by flash chromatography (eluant: 0%-20% EtOAc—CH2Cl2 gradient) to give 75 mg of compound 147 as a yellow solid. MS (M+1): m/e 589.
Step 105:




Compound 144 (0.11 g, 0.2 mmol) was mixed with (4-hydroxymethyl)-2-amino-pyridine (37 mg, 0.3 mmol), triphenylphosphine (0.12 g, 0.44 mmol), and DEAD (88 mg, 0.48 mmol) in 2 mL of dry THF. The mixture was stirred at room temperature for 3 days.
Water (0.5 mL) was added, and the mixture was heated to 155° C. for 5 mins in the microwave reactor. After cooling to room temperature, the mixture was concentrated and purified by Gilson prep HPLC to give 65 mg (56%) of compound 148 as a white solid. MS (M+1): m/e 560.
Using the procedures described above, the following compounds were synthesized.







TABLE 29







Oxygen Analogues with Sulfamide Tails


Using the procedures described above, the following compounds were synthesized.









Comp.

MS


No.
Structure
M + 1





1629Z




544 (M − 1)


 


1630Z




582


 


1631Z




571


 


1632Z




591


 


1633Z




576


 


1634Z




561


 


1635Z




632


 


1636Z




613


 


1637Z




591


 


1638Z




621


 


1639Z




612


 


1640Z




561


 


1641Z




547


 


1642Z




582


 


1643Z




547


 


1644Z




547


 


1645Z




591


 


1646Z




561


 


1647Z




588


 


1648Z




560


 


1649Z




619


 


1650Z




619


 


1651Z




555


 


1652Z




589


 


1653Z




555


 


1654Z




589


 


1655Z




561


 


1656Z




563


 


1657Z




595


 


1658Z




561


 


1659Z




563


 


1660Z




595


 


1661Z




602


 


1662Z




597


 


1663Z




569


 


1664Z




569


 


1665Z




575


 


1666Z




602


 


1667Z




563


 


1668Z




661


 


1669Z




604


 


1670Z




562


 


1671Z




558


 


1672Z




587


 


1673Z




615


 


1674Z




616


 


1675Z




579


 


1676Z




720


 


1677Z




560


 


1678Z




602


 


1679Z




603


 


1680Z




603


 


1681Z




647


 


1682Z




573


 


1683Z




573


 


1684Z




588


 


1685Z




647


 


1686Z




671


 


1687Z




630


 


1688Z




601


 


1689Z




687


 


1690Z




630


 


1691Z




617


 


1692Z




641


 


1693Z




671


 


1694Z




627


 


1695Z




643


 


1696Z




603


 


1697Z




623


 


1698Z




617


 


1699Z




631


 


1700Z




603


 


1701Z




693


 


1702Z




601


 


1703Z




607


 


1704Z




584


 


1705Z




577


 


1706Z




573


 


1707Z




605


 


1708Z




605


 


1709Z




621


 


1710Z




575


 


1711Z




575


 


1712Z




577


 


1713Z




623


 


1714Z




603


 


1715Z




593


 


1716Z




573


 


1717Z




577


 


1718Z




603


 


1719Z




607


 


1720Z




565


 


1721Z




593


 


1722Z




643


 


1723Z




619


 


1724Z




621


 


1725Z




591


 


1726Z




619


 


1727Z




589


 


1728Z




589


 


1729Z




621


 


1730Z




591


 


1731Z




591


 


1732Z




522


 


1733Z




522


 


1734Z




564


 


1735Z




599


 


1736Z




618


 


1737Z




601


 


1738Z




603


 


1739Z




621


 


1740Z




604


 


1741Z




654


 


1742Z




668


 


1743Z




603


 


1744Z




657


 


1745Z




675


 


1745Za




615


 


1745Zb




633


 


1745c




637


 


1745d




668













Step 106:





To a solution of fluoropropyl methylsulfonate 149 (4.7 g, 30 mmol) in DMF (40 mL) was added potassium thioacetate (7 g, 60 mmol) at room temperature. The reaction mixture was warmed to 70° C. for 12 h. After cooling to room temperature, saturated aqueous NH4Cl solution was added, and the aqueous solution was extracted with EtOAc. The combined organic extract was washed with brine, dried (Na2SO4), filtered, and concentrated. Purification by silica gel chromatography (eluant: 257 EtOAc-hexane) gave 5.2 g (100% yield) of the product 150 as a colorless liquid.
Step 107:




Chlorine gas was bubbled through a stirred solution of fluoropropyl thioacetate 150 (2 g, 14.7 mmol) in CH2Cl2 (30 mL) and H2O (6 mL) at 6° C. to 9° C. After compound 150 was completely consumed, water and CH2Cl2 were added, and the CH2Cl2 layer was separated, washed with brine, dried (Na2SO4), filtered, and concentrated to give 2.3 g (100% yield) of the product 151 as a colorless liquid.
Step 108:




To a suspension of chloropyridazinone 142 (468 mg, 1.29 mmol, HCl salt) in CH2Cl2 (5 mL) at 0° C. was added iPr2NEt (673 uL, 3.87 mmol) followed by the addition of fluoropropylsulfonyl chloride 151 (250 mg, 1.55 mol) in CH2Cl2 (2.5 mL) over 2 mins. After 2 h at 0° C. and 1.5 h at room temperature, water was added to the reaction mixture, and the aqueous solution was extracted with CH2Cl2. The combined organic extract was washed with brine, dried (Na2SO4), filtered, and concentrated to provide 560 mg (96% yield) of the product 152 as a white solid. MS (M+1): 449.
Step 109:




To a solution of 3-methylcyclopentanol (95 mg, 0.21 mmol) in THF (3 mL) at room temperature was added NaN(TMS)2 (0.63 mL, 0.63 mmol) over 2 mins. After 15 mins, dichloropyridazinone 152 was added as a solid in one portion. The reaction mixture was stirred for 1 h and quenched with saturated aqueous NH4Cl solution, and the aqueous solution was extracted with EtOAc. The combined organic extract was washed with brine, dried (Na2SO4), filtered, and concentrated. Purification by Gilson reverse phase chromatography (eluant: CH3CN—H2O) gave 82 mg (80% yield) of the product 153 as a white solid. MS (M+1): 513.
Using the procedures described above, the following compounds were synthesized.







TABLE 30







Oxygen Analogues with Fluoropropyl Sulfonamide









Cmpd. No.
Structure
MS M + 1





1746Z




533


 


1747Z




555


 


1748Z




533


 


1749Z




519


 


1750Z




531


 


1751Z




497


 


1752Z




499


 


1753Z




487


 


1754Z




515


 


1755Z




549


 


1756Z




527


 


1757Z




485


 


1758Z




483


 


1759Z




483


 


1760Z




499


 


1761Z




513


 


1762Z




547


 


1763Z




521


 


1764Z




513


 


1765Z




501


 


1766Z




501


 


1767Z




487


 


1768Z




523


 


1769Z




583


 


1770Z




614













Step 110:





To a suspension of chloropyridazinone 154 (1.95 g, 4.74 mmol, HCl salt) in C2Cl2 (30 mL) at −35° C. was added iPr2NEt (2.06 mL, 11.85 mmol) followed by the addition of chloromethylsulfonyl chloride (918 mg, 6.16 mmol) in CH2Cl2 (20 mL) over 20 mins. After 2 h at −35° C. to 10° C., water was added to the reaction mixture and the aqueous solution was extracted with CH2Cl2. The combined organic extract was washed with 1 N HCl, brine, dried (Na2SO4), filtered, and concentrated. Purification by ISCO silica gel chromatography (eluant: EtOAc-hexane) gave 1.5 g (65% yield) of the product 155 as a white foam. MS (M+1): 487.
Step 111:




A reaction mixture of chloropyridazinone 155 (292 mg, 0.6 mmol), thiophenol (79 mg, 0.72 mmol) and K2CO3 (124 mg, 0.9 mmol) in DMF (3 mL) was heated to 80° C. for 30 mins via microwave irradiation. The reaction mixture was quenched with saturated aqueous NH4Cl solution, and the aqueous solution was extracted with EtOAc. The combined organic extract was washed with brine, dried (Na2SO4), filtered, and concentrated. Purification by Gilson reverse phase chromatography (eluant: CH3CN—H2O) gave 242 mg (72% yield) of the product 156 as a white solid. MS (M+1): 561.
Using the procedures described above, the following compounds were synthesized.







TABLE 31







Oxygen Analogues with Thioether/Ether Sulfonamide









Cmpd.

MS


No.
Structure
M + 1





1771Z




563


 


1772Z




671


 


1773Z




595


 


1774Z




579


 


1775Z




561


 


1776Z




591


 


1777Z




577


 


1778Z




563


 


1779Z




611


 


1780Z




591


 


1781Z




545


 


1782Z




611


 


1783Z




576


 


1784Z




589


 


1785Z




633


 


1786Z




597


 


1787Z




577


 


1788Z




591


 


1789Z




605


 


1790Z




645


 


1791Z




579


 


1792Z




579


 


1793Z




619


 


1794Z




645


 


1795Z




577


 


1796Z




563


 


1797Z




563


 


1798Z




599


 


1799Z




621


 


1800Z




547


 


1801Z




605


 


1802Z




619


 


1803Z




563


 


1804Z




618


 


1805Z




591


 


1806Z




617


 


1807Z




591


 


1808Z




578


 


1809Z




620
















Step 112:





To a solution of aniline (2.3 g, 25.12 mmol) and iPr2NEt (3.3 mL, 18.84 mmol) in CH2Cl2 (50 mL) at 0° C. was added a solution of Cbz-piperidinylsulfonyl chloride 157 (4.0 g, 12.56 mmol) in CH2Cl2 (20 mL) over 10 mins. After 1 h at 0° C. and 2.5 h at room temperature, water was added to the reaction mixture, and the aqueous solution was extracted with Cl2Cl2. The combined organic extract was washed with 1 N HCl, brine, dried (Na2SO4), filtered and concentrated. Purification by ISCO silica gel chromatography (eluant: EtOAc hexane) gave 3.7 g (79% yield) of the product 158 as a white solid. MS (M+1): 375.
Step 113:




To a solution of sulfonamide 158 (810 mg, 2.16 mmol) in MeOH (50 mL) and EtOAc (15 mL) was added Pd/C (500 mg) and the reaction mixture was treated with H2 (44 psi) for 18 h. The reaction mixture was filtered, and the filtrate was concentrated to give 440 mg (85% yield) of the product 159 as a white solid. MS (M+1): 241.
Step 114:




The reaction mixture of sulfonamide 159 (400 mg, 1.67 mmol), dichloropyridazinone (460 mg, 1.67 mmol) and iPr2NEt (580 uL, 3.34 mmol) in EtOH (8 mL) was heated to 92° C. for 15 h, and then concentrated to provide a solid residue. To the above residue was added saturated aqueous NH2Cl solution and the aqueous solution was extracted with C2Cl2. The combined organic extract was washed with brine, dried (Na2SO4), filtered, and concentrated. ISCO silica gel chromatography (eluant: CH2Cl2-MeOH) gave 551 mg (69% yield) of the product 160 as a white solid. MS (M+1): 480.
Step 115:




To a solution of methylcyclopropylmethanol (158 mg, 1.84 mmol) in THF (3 mL) and DMF (1 mL) at room temperature was added NaN(TMS)2 (1.84 mL, 1.84 mmol) over 2 mins. After 20 mins, dichloropyridazinone 160 was added as a solid in one portion. The reaction mixture was stirred for 1 h and quenched with saturated aqueous NH4Cl solution, and the aqueous solution was extracted with EtOAc. The combined organic extract was washed with brine, dried (Na2SO4), filtered, and concentrated. Purification by Gilson reverse phase chromatography (eluant: CH3CN—H2O) gave 148 mg (61% yield) of the product 161 as a white solid. MS (M+1): 529.
Step 116:




To a solution of sulfonamide 161 (110 mg, 0.21 mmol) in DMF (2 mL) at room temperature was added NaH (17 mg, 0.42 mmol, 60% in oil) in one portion. After 25 mins, methyl iodide (60 mg, 0.42 mmol) was added in one portion. After 1 h, the reaction mixture was added slowly to a saturated aqueous NH4Cl solution, and the aqueous solution was extracted with EtOAc. The combined organic extract was washed with brine, dried (Na2SO4), filtered, and concentrated. Purification by Gilson reverse phase chromatography (eluant: CH3CN—H2O) gave 85 mg (79% yield) of the product 162 as a white solid. MS (M+1): 543.
Step 117:




The reaction mixture of sulfonamide 163 (1.1 g, 2.83 mmol) in 33% HBr/HOAc (26 mL) was stirred at room temperature for 2 h, and then poured into ice water. To the aqueous reaction mixture was added NaOH solution until the pH 12-13, then the aqueous solution was extracted with EtOAc. The combined organic extract was washed with brine, dried (Na2SO4), filtered, and concentrated to give a solid. The solid was washed with a mixture of Et2O and hexane to remove the benzyl bromide impurity and dried to give 530 mg (68% yield) of the product 164 as a white solid. MS (M+1): 276.
Using the procedures described above, the following compounds were synthesized.







TABLE 32







Oxygen Analogues with Reverse Sulfonamide









Cmpd.

MS


No.
Structure
M + 1





1810Z




529


 


1811Z




529


 


1812Z




529


 


1813Z




577


 


1814Z




543


 


1815Z




543


 


1816Z




543


 


1817Z




565


 


1818Z




557


 


1819Z




591


 


1820Z




513


 


1821Z




603


 


1822Z




507


 


1823Z




507













Step 118:





4,5-Dichloropyridazinone (25 g, 150 mmol) was mixed with dihydropyrane (41 mL, 450 mmol), and p-toluenesulfonic acid monohydrate (1.0 g) in a mixed solvent of toluene (120 mL) and THF (20 mL). The mixture was heated at reflux for 4 h. After cooling, the mixture was then diluted with 300 mL of EtOAc and 150 mL of water. The solid was removed by filtration. The organic layer was washed with diluted NaHCO3 then brine, dried over anhydrous sodium sulfate, and concentrated. Purification by flash chromatography gave 24.4 g of the product 166 as an oil.
Step 119:




Compound 166 (12.5 g, 50 mmol) was mixed with 1-(isopropylsulfonyl)-piperazine HCl salt (16.8 g, 52.5 mmol) and triethylamine (14.6 mL, 105 mmol) in 180 mL of ethanol. The mixture was heated to 70° C. overnight. After cooling, the solvent was evaporated. The crude product was stirred in 200 mL of MeOH/water (1:1). The product was collected by filtration, washed with water and MeOH/water (1:1), and dried in a vacuum oven at 70° C. for 3 days to give 13.6 g of the product 167. MS (M+1): m/e 405.
Step 120:




Compound 167 (6.1 g, 15 mmol) was mixed with cyclopentanol (2.1 mL, 23 mmol) in 80 mL of dry THF. NaH (60%, 0.72 g, 18 mmol) was added. The resulting mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to give the product 168 as an oil, which was dried under high vacuum overnight before use in the next step.
Step 121:




Compound 168 ( ̃15 mmol) in 150 mL of dry methylene chloride was cooled to 0° C. BF3.Et2O (5.6 mL, 45 mmol) was added slowly. The mixture was then stirred at 0° C. for 1 h. Ice-water was added to quench the reaction. The mixture was diluted with methylene chloride then washed with water, diluted sodium bicarbonate, and brine. The organic solution was dried over anhydrous sodium sulfate, filtered, and concentrated. The product was further dried in a vacuum oven to give 5.2 g of the product 169 as a pale yellow solid. MS (M+1): m/e 371.
Step 122 (Method A):




Compound 169 (100 mg) was mixed with 2-iodo-4-fluoroaniline (100 mg), CuI (10 mg), 8-hydroxylquinoline (10 mmol), and potassium carbonate (100 mg) in 3.5 mL of dry pyridine. The mixture was heated to 175° C. for 30 mins in a microwave reactor. After cooling, the mixture was filtered through celite which was washed with EtOAc. The filtrate was concentrated, and the crude product was purified by Gilson prep HPLC (eluant: CH3CN-water gradient with 0.1% HCOOH) to give 60 mg of pure product 170A as pale solid. MS (M+1): m/e 480.
Step 122 (Method B):




Compound 169 (100 mg, 0.27 mmol) was mixed with 2,4,6-trifluoropyridine (53 mg, 0.4 mmol), and phosphazene base P1-t-Bu (0.13 mL, 0.5 mmol) in 0.7 mL of dry DMF. The mixture was stirred at room temperature overnight then diluted to 4 mL with DMF, and purified by Gilson prep HPLC (eluant: CH3CN-water gradient with 0.1% HCOOH) to give 51 mg of compound 170B as light-yellow solid. MS (M+1): m/e 484.
Using the procedures described above, the following compounds were synthesized.







TABLE 33







R3 Substituent Analogs









Cmpd. No.
Structure
MS M + 1





1824Z




489


 


1825Z




449


 


1826Z




505


 


1827Z




463


 


1828Z




506


 


1829Z




454


 


1830Z




515


 


1831Z




504


 


1832Z




437


 


1833Z




497


 


1834Z




453













Step 123:

Compound 173 was prepared via the method of William W. Paudler and The-Kuei Chen, J. Hetero. Chem. Vol. 7 (1970) 767-771.
A solution of sodium bicarbonate (3.7 g, 44 mmol) and 40% glyoxal 172 (7 g, 48 mmol) in ice water (100 mL) was added to a solution of S-methylthiosemicarbazide hydroiodide 171 (9.32 g, 40 mmol) dissolved in ice water (60 mL) set in an ice bath. The resulting mixture was placed in the refrigerator (about −10° C.) for 5 h. The reaction mixture was extracted several times with CH2Cl2. The combined organic extract was dried (Na2SO4), filtered, and concentrated to give an oil (4.37 g, 86% yield). 1H-NMR 9.0 ppm s (1H), 8.4 ppm s (1H), 2.7 ppm s (3H).
Step 124:
A solution of compound 174 (430 mg, 0.88 mmol) and compound 173 (102 mg, 0.8 mmol) in DMSO (1 mL) was added dropwise to a mixture of potassium hydroxide powder (320 mg, 5.7 mmol) in DMSO (1.5 mL) at room temperature. The darkened mixture was stirred for 1 h, then poured into a saturated ammonium chloride solution. The precipitate was collected by filtration. Purification by silica gel chromatography (eluant: 0%-40% EtOAc-hexanes gradient) gave 300 mg (65% yield) of the product 175 as a pale-yellow foam. MS (M+1): m/e 580.
Using the procedures described above, the following compounds were synthesized.












Cmpd.

MS


No
Structure
M + 1







1835Z




578


 


1836Z




580


 


1837Z




578













Step 125:

m-Chloroperbenzoic acid (77%, 23 mg, 0.1 mmol) was added to compound 175 (58 mg, 0.1 mmol) in CH2Cl2 (1.5 mL) at 0° C. The mixture was allowed to warm to 25° C. and stir for 15 h. A second dose of m-chloroperbenzoic acid (77%, 23 mg, 0.1 mmol) was added. After 5 h, additional CH2Cl2 was added, and the solution was washed with 10% sodium thiosulfate, saturated sodium bicarbonate, then brine. The dried (Na2SO4) organic layer was concentrated to a residue. Purification by silica gel chromatography (eluant: 0%-100% EtOAc hexanes gradient) gave 44 mg (74% yield) of the product 176 as a beige solid. MS (M+1): m/e 596.




Step 126:





Compound 177 was prepared via the method of William W. Paudler and The-Kuei Chen, J. Hetero. Chem. Vol. 7 (1970) 767-771
Sodium methoxide (1.18 g, 21.8 mmol) was added to compound 173 (2.54 g, 20 mmol) in absolute methanol (35 mL). The mixture was stirred for 15 h. Ground dry ice was added slowly, and the mixture was filtered with a methanol rinse. The filtrate was concentrated to a residue. Purification by silica gel chromatography (eluant: 0%-40% EtOAc-hexanes gradient) gave 804 mg (36% yield) of the product 177 as a solid. MS (M+1): m/e 112.
Step 127:




Using the procedure described in step 124, with compounds 174 and 177, compound 178 was prepared (53% yield) as a yellow solid. MS (M+1): m/e 564.




m-Chloroperbenzoic acid (77%, 48.6 mg, 0.22 mmol) was added to compound 175 (53 mg, 0.09 mmol) in CH2Cl2 (2 mL) at 25° C. The mixture was allowed to stir for 12 days. The solution was diluted with CH2Cl2 washed with 10% sodium thiosulfate, saturated sodium bicarbonate and brine. The dried (Na2SO4) organic layer was concentrated to a residue. Exposure to silica gel thin layer chromatography (60% EtOAc hexanes) for 15 h gave 32 mg (65% yield) of the product 179 as a solid. MS (M+1): m/e 550.




Step 128:





To cyclopropanedimethanol (11.2 g, 98.7 mmol) dissolved in dry THF (200 mL) under a nitrogen atmosphere was added sodium hexamethyldisilazane (1.0 M in THF, 49 mL, 49 mmol). The cloudy reaction mixture was stirred at room temperature for 20 mins then chloropyridazinone 180 (10.4 g, 24.4 mmol) was added. The reaction mixture was stirred at room temperature for 20 mins then heated at 80° C. for 10 h. The solvent was evaporated from the cooled mixture. Water (300 mL) was added, and the aqueous solution was extracted with CH2Cl2. The combined organic extract was dried (MgSO4), filtered, and concentrated. Purification by silica gel chromatography (eluant: 20% EtOAc—CH2Cl2) gave 8.8 g (73% yield) of the product 181 as a yellow solid. MS (M+1): m/e 493.
Step 129:




To compound 181 (2.00 g, 4.06 mmol) dissolved in CH2Cl2 (40 mL) was added dimethylaminopyridine (0.25 g, 2.03 mmol), triethylamine (1.23 g, 1.7 mL, 12.2 mmol), and then p-toluenesulfonyl chloride (1.93 g, 10.2 mmol). The reaction mixture was stirred at room temperature for 24 h. Water (50 mL) was added, and the aqueous solution was extracted with CH2Cl2. The combined organic extract was dried (MgSO4), filtered, and concentrated. Purification by silica gel chromatography (eluant: 5% 10% EtOAc—CH2Cl2 gradient) gave 1.69 g (64% yield) of the product 182 as a yellow foam. MS (M+1): m/e 647.
Step 130:




To copper iodide (1.48 g, 7.79 mmol) suspended in dry diethyl ether (20 mL) and cooled in −10° C. isopropanol bath (Neslab ethylene glycol circulator) under a nitrogen atmosphere was added methyl lithium (1.6 M in diethyl ether, 9.7 mL, 15.6 mmol) via syringe. The reaction mixture became cloudy yellow then colorless and was stirred for 30 mins in the −10° C. bath. The tosylate compound 182 (1.68 g, 2.60 mmol) was dissolved in diethyl ether (50 mL) and added via addition funnel. The reaction mixture was stirred in the −10° C. bath for 45 mins, then warmed slowly to room temperature, and stirred at room temperature for 16 h. Saturated NH4Cl (50 mL) was added, and the aqueous solution was extracted with EtOAc. The combined organic extract was dried (MgSO4), filtered, and concentrated. Purification by silica gel chromatography (eluant: 5% EtOAc—CH2Cl2) gave 0.51 g (40% yield) of the product 183 as a yellow oil. MS (M+1): m/e 491.
Step 131:




To compound 183 (0.50 g, 1.02 mmol) dissolved in CH2Cl2 (10 mL) and cooled to 0° C. was added trifluoroacetic acid (2 mL). The reaction mixture was stirred at 0° C. for 2 h then the solvent was evaporated. Aqueous 0.5 N NaOH (15 mL) was added, and the aqueous solution was extracted with CH2Cl2. The combined organic extract was dried (MgSO4), filtered, and concentrated to give 0.25 g (63% yield) of the product 184 as a yellow oil. MS (M+1): m/e 391.
Step 132:




To compound 184 (185 mg, 0.474 mmol) dissolved in CH2Cl2 (8 mL) was added pyridine (0.11 mL, 1.4 mmol) then (4-nitrophenyl)methanesulfonyl chloride (160 mg, 0.62 mmol). The reaction mixture was stirred at room temperature for 4 h. Water was added, and the aqueous solution was extracted with CH2C2. The combined organic extract was dried (MgSO4), filtered, and concentrated. Purification by silica gel chromatography (eluant: 10% EtOAc—CH2Cl2) gave 110 mg (39% yield) of the product 185 as a yellow oil. MS (M+1): m/e 590.
Step 133:




To compound 185 (116 mg, 0197 mmol) suspended in EtOAc (20 mL) and iPrOH (10 mL) was added platinum oxide (26.7 mg, 0.098 mmol). The reaction mixture was stirred under a hydrogen balloon for 4 h. The platinum oxide catalyst was removed by filtration, washed with iPrOH, and the filtrate was evaporated. Purification by silica gel chromatography (eluant: 40% EtOAc-hexane) gave 65 mg (56% yield) of the product 186 as a yellow foam. MS (M+1): m/e 560.
Using the procedures described above, the following compounds were synthesized.












Cmpd.

MS


No.
Structure
M + 1







1838Z




545


 


1839Z




560
















Step 134:





To ethyl 2-formyl-1-cyclopropane carboxylate 187 (10.00 g, 0.0703 mol) dissolved in ethanol (250 mL) was added sodium borohydride (3.99 g, 0.106 mol). The reaction mixture was stirred at room temperature for 5 h. The solvent was evaporated, and water (200 mL) was added. The aqueous solution was extracted with CH2Cl2. The combined organic extract was dried (MgSO4), filtered, and concentrated. Purification by silica gel chromatography (eluant: 5-8% MeOH—CH2Cl2) gave 9.19 g (91% yield) of the product 188 as a colorless oil. MS (M−17): m/e 127.
Step 135:




To compound 188 (2.00 g, 13.9 mmol) dissolved in CH2Cl2 (50 mL) was added dimethylaminopyridine (0.42 g, 3.47 mmol), triethylamine (2.11 g, 2.9 mL, 20.8 mmol), and t-butyldimethylsilyl chloride (2.72 g, 18.0 mmol). The reaction mixture was stirred at room temperature for 18 h. Water (50 mL) was added, and the aqueous solution was extracted with CH2Cl2. The combined organic extract was dried (MgSO4), filtered, and concentrated. Purification by silica gel chromatography (eluant: 3% EtOAc—CH2Cl2) gave 3.59 g (100% yield) of the product 189 as a colorless oil. MS (M+1): m/e 259.
Step 136:




To compound 189 (3.59 g, 13.9 mmol) dissolved in dry THF (50 mL) was added solid lithium aluminum hydride (0.53 g, 13.9 mmol) portionwise. The reaction mixture was stirred at room temperature for 16 h under nitrogen. Carefully added water (0.5 mL), 1 N NaOH (0.5 mL) then water (1.5 mL) to precipitate the aluminum salts. Additional CH2Cl2 (50 mL) and MgSO4 was added and stirred. The mixture was filtered, and the aluminum salts washed with CH2Cl2. The filtrate was evaporated. Purification by silica gel chromatography (eluant: 20% EtOAc—CH2Cl2) gave 2.15 g (71% yield) of the product 190 as a colorless oil. MS (M+1): m/e 217.
Step 137:




To compound 190 (2.14 g, 9.89 mmol) dissolved in dry THF (50 mL) was added sodium bis(trimethylsilyl)amide (1.0 M in THF, 9.5 mL, 9.50 mmol) via syringe. The reaction mixture was stirred at room temperature for 15 mins under nitrogen. Chloropyridazinone 180 (3.52 g, 8.24 mmol) was added, and the reaction mixture was heated at 80° C. for 1 h then stirred at room temperature for 16 h. The solvent was evaporated. Water (75 mL) was added, and the aqueous solution was extracted with CH2Cl2. The combined organic extract was dried (MgSO4), filtered, and concentrated. Purification by silica gel chromatography (eluant: 5-10% EtOAc—CH2Cl2) gave 4.94 g (99% yield) of the product 191 as a yellow oil. MS (M+1): m/e 607.8.
Step 138:




To compound 191 (4.93 g, 8.12 mmol) dissolved in dry THF (60 mL) was added tetrabutylammonium fluoride (1.0 M in THF, 12.2 mL, 12.2 mmol). The reaction mixture was stirred at room temperature for 16 h. The solvent was evaporated. Water (75 mL) was added, and the aqueous solution was extracted with CH2Cl2. The combined organic extract was dried (MgSO4), filtered, and concentrated. Purification by silica gel chromatography (eluant: 5% MeOH(CH2Cl2) gave 4.00 g (100% yield) of the product 192 as a yellow oil. MS (M+1): m/e 493.
Step 139:




To compound 192 (1.07 g, 2.17 mmol) dissolved in CH2Cl2 (25 mL) was added dimethylaminopyridine (0.053 g, 0.434 mmol), triethylamine (0.33 g, 0.45 mL, 3.26 mmol), and methanesulfonic anhydride (0.45 g, 2.61 mmol). The reaction mixture was stirred at room temperature for 5 h. Saturated NaHCO3 (30 mL) was added, and the aqueous solution was extracted with CH2Cl2. The combined organic extract was dried (MgSO4), filtered, and concentrated to give 1.24 g (100% yield) of the product 193 as a yellow oil. MS (M+1): m/e 571.
Step 140:




To compound 193 (1.24 g, 2.17 mmol) dissolved in dry THF (25 mL) was added tetrabutylammonium fluoride (1.0 M in THF, 3.3 mL, 3.3 mmol). The reaction mixture was heated at 45° C. for 4.5 h. The solvent was evaporated. Water (30 mL) was added, and the aqueous solution was extracted with CH2Cl2. The combined organic extract was dried (MgSO4), filtered, and concentrated. Purification by silica gel chromatography (eluant: 5-10% EtOAc—CH2Cl2) gave 0.67 g (63% yield) of the product 194 as a yellow oil. MS (M+1): m/e 495.
Step 141:




To compound 194 (0.66 g, 1.33 mmol) dissolved in CH2Cl2 (15 mL) was added trifluoroacetic acid (2 mL). The reaction mixture was stirred at room temperature for 3.5 h then the solvent was evaporated. Aqueous 0.5 N NaOH (20 mL) was added, and the aqueous solution was extracted with CH2Cl2. The combined organic extract was dried (MgSO4), filtered, and concentrated to give 0.52 g (100% yield) of the product 195 as a yellow oil. MS (M+1): m/e 395.7.
Step 142:




To compound 195 (100 mg, 0.254 mmol) dissolved in CH2Cl2 (5 mL) was added pyridine (0.062 mL, 0.762 mmol) then □-toluenesulfonyl chloride (63 mg, 0.33 mmol). The reaction mixture was stirred at room temperature for 7 h. Water was added, and the aqueous solution was extracted with CH2Cl2. The combined organic extract was dried (MgSO4), filtered, and concentrated. Purification by silica gel chromatography (eluant: 5% EtOAc—CH2Cl2) gave 74 mg (53% yield) of the product 196 as a yellow oil. MS (M+1): m/e 549.
Using the procedures described above, the following compounds were synthesized.












Cmpd. No.
Structure
MS M + 1







1840Z




564


 


1841Z




501


 


1842Z




564













Step 143:





To compound 197 (5.00 g, 45.0 mmol) dissolved in CH2Cl2 (200 mL) was added dimethylaminopyridine (1.37 g, 11.2 mmol), triethylamine (6.83 g, 9.4 mL, 67.5 mmol), and t-butyldimethylsilyl chloride (8.82 g, 58.5 mmol). The reaction mixture was stirred at room temperature for 5 h. Water (150 mL) was added, and the aqueous solution was extracted with CH2Cl2. The combined organic extract was dried (MgSO4), filtered, and concentrated. Purification by silica gel chromatography (eluant: 3% EtOAc—CH2Cl2) gave 9.57 g (94% yield) of the product 198 as a colorless oil. MS (M+1): m/e 226.
Step 144:




To compound 198 (9.56 g, 49.4 mmol) dissolved in CH2Cl2 (150 mL) and cooled to −78° C. under nitrogen was added diisobutylaluminum hydride (1 M in hexane, 46.7 mL, 46.7 mmol) via addition funnel over 10 mins. The reaction mixture was warmed slowly to 0° C. over 45 mins and stirred at 0° C. for 30 mins. Carefully added 1 N HCl (200 mL) and then extracted with CH2Cl2. The combined organic extract was dried (MgSO4), filtered, and concentrated to give 9.69 g (100% yield) of the product 199 as a yellow oil. MS (M+1): m/e 228.
Step 145:




To compound 199 (9.69 g, 42.4 mmol) dissolved in ethanol (200 mL) was added sodium borohydride (2.41 g, 63.6 mmol). The reaction mixture was stirred at room temperature for 3 h. The solvent was evaporated. Water (200 mL) was added, and the aqueous solution was extracted with CH2Cl2. The combined organic extract was dried (MgSO4), filtered, and concentrated. Purification by silica gel chromatography (eluant: 10% EtOAc—CH2Cl2) gave 6.86 g (70% yield) of the product 200 as a yellow oil. MS (M+1): m/e 231.
Steps 137-142 from Scheme 41:




Using the procedures from steps 137-142 from Scheme 41, the following compounds were synthesized.












Cmpd. No.
Structure
MS M + 1







1843Z




563


 


1844Z




578


 


1845Z




578









Step 146:





To compound 200 (5.45 g, 23.7 mmol) dissolved in dry THF (100 mL) under nitrogen was added sodium bis(trimethylsilyl)amide via syringe. The reaction mixture was stirred at room temperature for 15 mins then p-methoxybenzylbromide (6.18 g, 30.8 mmol) was added. The resulting mixture was stirred at room temperature for 18 h. The solvent was evaporated. Water (100 mL) was added, and the aqueous solution was extracted with CH2Cl2. The combined organic extract was dried (MgSO4), filtered, and concentrated. Purification by silica gel chromatography (eluant: 2% EtOAc—CH2Cl2) gave 7.59 g (92% yield) of the product 202 as a colorless oil. MS (M+1): m/e 351.
Step 147:




To compound 202 (7.58 g, 21.6 mmol) dissolved in dry THF (100 mL) was added tetrabutylammonium fluoride (1.0 M in THF, 27.0 mL 27.0 mmol). The reaction mixture was stirred at room temperature for 16 h. The solvent was evaporated. Water (100 mL) was added, and the aqueous solution was extracted with CH2Cl2. The combined organic extract was dried (MgSO4), filtered, and concentrated. Purification by silica gel chromatography (eluant: 15% EtOAc—CH2Cl2) gave 5.03 g (98% yield) of the product 203 as a colorless oil. MS (M+1): m/e 237.
Step 148:




To compound 203 (2.16 g, 9.14 mmol) dissolved in dry THF (40 mL) was added sodium bis(trimethylsilyl)amide (1.0 M in THF, 8.4 mL, 8.40 mmol) via syringe. The reaction mixture was stirred at room temperature for 15 mins under nitrogen. Chloropyridazinone 180 (3.00 g, 7.03 mmol) was added, and the reaction mixture was heated at 80° C. for 1 h then stirred at room temperature for 16 h. The solvent was evaporated. Water (50 mL) was added, and the aqueous solution was extracted with EtOAc. The combined organic extract was dried (MgSO4), filtered, and concentrated. Purification by silica gel chromatography (eluant: 5-15% EtOAc—CH2Cl2) gave 4.40 g (100% yield) of the product 204 as a yellow oil. MS (M+1): m/e 628.
Step 149:




To compound 204 (4.40 g, 7.03 mmol) dissolved in CH2Cl2 (50 mL) and water (3 mL) was added 2,3-dichloro-5,6-dicyano-benzoquinone (1.92 g, 8.44 mmol). The reaction mixture was stirred at room temperature for 60 mins. Saturated NaHCO3 (100 mL) was added and the aqueous solution was extracted with EtOAc. The combined organic extract was dried (MgSO4), filtered, and concentrated. Purification by silica gel chromatography (eluant: 15% EtOAc—CH2Cl2 then 5% MeOH—CH2Cl2) gave 2.90 g (81% yield) of the product 205 as a white foam. MS (M+1): m/e 508.
Step 139-142 from Scheme 41:




Using the procedures from steps 139-142 from Scheme 41, the following compounds were synthesized.












Cmpd. No.
Structure
MS M + 1







1846Z




578


 


1847Z




578
















Step 150:





Compound 207 (1.0 g, 2.8 mmol) and 5-hexenol-1 (0.83 g, 8.3 mmol) were mixed in 15 mL of dry THF. NaH (60%, 0.28 g, 7 mmol) was added. The resulting mixture was stirred at room temperature overnight. The reaction was quenched with 10 mL of water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by flash chromatography (eluant: 0-0.5% 7 M NH3/MeOH in CH2Cl2 gradient) to give 1.1 g (100%) of compound 208 as a colorless oil. MS (M+1): m/e 389.
Step 151:




Compound 208 (2.7 mmol) dissolved in 10 mL of dry CH2Cl2 was mixed with isopropyldiethylamine (1.5 ml, 8.8 mmol), and cooled to 0° C. with an ice-water bath. A freshly prepared 0.5 M solution of BocNHSO2Cl in CH2Cl2 (8 mL, 4 mmol) was added dropwise. The resulting mixture was then stirred at room temperature overnight. The mixture was diluted with 500 mL of CH2Cl2, and washed with 1 N HCl solution then water. The organic layer was separated, dried over anhydrous Na2SO4, and concentrated. Purification by flash chromatography gave 1.4 g of compound 209 as a white solid. MS (M+1): m/e 568.
Step 152:




Compound 209 (0.38 g, 0.7 mmol) was mixed with allyl bromide (0.3 mL), and phosphazene base P1-t-Bu (0.25 mL, 1 mmol) in 5 mL of dry THF. The resulting mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc, and washed with water then brine. The organic layer was dried over anhydrous Na2SO4, and then concentrated. Purification by flash chromatography gave 0.35 g of compound 210 as a white solid. MS (M+1): m/e 608.
Step 153:




Compound 210 (92 mg, 0.15 mmol) in 60 mL of CH2Cl2 was mixed with 25 mg of 2nd generation Grubbs' catalyst under nitrogen. The mixture was then heated to 50° C. under nitrogen overnight. After cooling, the mixture was concentrated. Purification by flash chromatography (eluant: 10% 30% EtOAc-hexane gradient) gave 81 mg of compound 211 as a white solid. MS (M+1): m/e 580.
Step 154:




Compound 211 (70 mg) was treated with 10 mL of 4 N HCl in dioxane at room temperature overnight. The mixture was concentrated, and the crude product was purified by flash chromatography (eluant: 10%-40% EtOAc-hexane gradient) to give 51 mg of compound 212 as a white solid. MS (M+1): m/e 480.
Scheme 44




Step 155:





Compound 209 (0.20 g, 0.35 mmol) was mixed with 3-buten-1-ol (0.06 mL, 0.7 mmol), triphenylphosphine (0.18 g, 0.7 mmol), and DIAD (0.14 mL, 0.7 mmol) in 3 mL of dry THF. The mixture was stirred at room temperature overnight then concentrated. Purification by flash chromatography (eluant: 10%-30% EtOAc-hexane gradient) gave 0.21 g of compound 213 as a white solid. MS (M+1): m/e 622.
Steps 153-154:




Using the procedures from step 153-154 from Scheme 43, the following compounds were synthesized.












Cmpd.

MS


No
Structure
M + 1







1848Z




493


 


1849Z




479


 


1850Z




521


 


1851Z




507













Step 156:





Compound 210 (220 mg) was treated with 10 mL of 4 N HCl in dioxane at room temperature overnight. Mixture was concentrated, and the crude was purified by flash chromatography (eluant: 10%-40% EtOAc-hexane gradient) to give 180 mg of compound 215 as a white solid. MS (M+1): m/e 508.
Step 157:




Compound 215 (0.11 g, 0.22 mmol) was mixed with benzyl bromide (40 mg, 0.23 mmol), and 60% NaH (10 mg, 0.24 mmol) in 2 mL of dry DMF at 0° C. The resulting mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc, and washed with water then brine. The organic layer was dried over anhydrous Na2SO4, and concentrated. Purification by flash chromatography gave 0.10 g of compound 216 as a white solid. MS (M+1): m/e 598.
Step 158:




Compound 216 (90 mg, 0.15 mmol) in 50 mL of CH2Cl2 was mixed with 25 mg of 2nd generation Grubbs' catalyst under nitrogen. The mixture was then heated to 50° C. under nitrogen overnight. After cooling, the mixture was concentrated, and the crude product was purified by Gilson Prep HPLC (eluant: CH3CN-water gradient) to give 69 mg of compound 217 as a white solid. MS (M+1): m/e 570.




Step 159:





A round bottom flask was charged with [1,1′-Bis(diphenylphosphino)ferrocene]-dichloropalladium(II), complex with dichloromethane (1:1) (6.70 mg, 0.00820 mmol); compound 218 (100 mg, 0.164 mmol); bis(pinacolato)diboron (50.0 mg, 0.197 mmol); and potassium acetate (80.5 mg, 0.820 mmol) in 14-dioxane (20 mL). The reaction mixture was placed under a nitrogen atmosphere and was degassed under vacuum three times. The reaction was stirred at 100° C. overnight. After cooling, the mixture was filtered through a short path silica column (eluant: ethyl acetate). The solvent was concentrated then purification by flash chromatography (eluant: 1:1 hexane:EtOAc) gave 75 mg (70% yield) of the product 219. MS (M+1): m/e 657.
Step 160:




Compound 219 (80 mg, 0.1 mmol) was dissolved in ethanol, and 1 M of sodium bicarbonate (200 uL) and hydrogen peroxide (50 uL, 0.5 mmol) were added at 0° C. The reaction was stirred at 0° C. overnight then concentrated. 1 M Hydrogen chloride in water (5 mL) was added, the mixture was extracted with ethyl acetate (150 mL), dried over sodium sulfate, and concentrated. Purification by silica gel chromatography (eluant: 1:1 hexane:EtOAc) gave 42 mg (63% yield) of the product 220. MS (M+1): m/e 547.
Using the procedures described above, the following compounds were synthesized.












Cmpd. No
Structure
MS M + 1







1852Z




547


 


1853Z




562









Step 161:





A round bottom flask was charged with compound 218 (70.0 mg, 0.115 mmol), tetrakis(triphenylphosphine)palladium(0) (5.69 mg, 0.00492 mmol), 4-pyridylboronic acid (20.0 mg, 0.163 mmol), and cesium carbonate (38.5 mg, 0.118 mmol) in 1,4-dioxane (20 mL) and water (2 mL). The reaction was placed under an atmosphere of nitrogen and degassed under vacuum three times. The reaction mixture was stirred at 100° C. overnight. After cooling, the mixture was filtered through a short path silica column (eluant: ethyl acetate). The solvent was concentrated, and purification by silica gel chromatography (eluant: 1:2 hexane:EtOAc) gave 70 mg (100% yield) of the product 221. MS (M+1): m/e 608.
Using the procedures described above, the following compounds were synthesized.












Cmpd. No.
Structure
MS M + 1







1854Z




624


 


1855Z




598


 


1856Z




651


 


1857Z




614


 


1858Z




610













Step 162:

A round bottom flask was charged with compound 222 (50 mg, 0.102 mmol), 3 thienylboronic acid (26.2 mg, 0.204 mmol), L-proline (2.82 mg, 0.0245 mmol), potassium bis(trimethylsilyl)amide (40.8 mg, 0.204 mmol), isopropyl alcohol (0.5 mL, 6 mmol), and nickel chloride dimethoxyethane (2.70 mg, 0.0123 mmol). The reaction was placed under an atmosphere of nitrogen and degassed under vacuum three times. The reaction was filtered through a short path silica get column (eluant: ethyl acetate), and the solvent was concentrated. Purification by silica gel chromatography (eluant: 1:2 hexane:EtOAc) gave the product which was further purified on the Gilson reverse phase HPLC (eluant: water:CH3CN gradient) to give 5 mg (9% yield) of the product 223. MS (M+1): m/e 537.




Step 163:





Compound 224 (100 mg, 0.216 mmol), potassium carbonate (60 mg, 0.432 mmol), and N-hydroxyacetimidamide (18 mg, 0.24 mmol) in toluene (10 mL) was heated at reflux for 48 h. After cooling, the reaction mixture was filtered through a short path silica gel column (eluant: ethyl acetate). The solvent was concentrated, and purification by silica gel chromatography (eluant: 1:2 hexane:ethyl acetate) gave 81 mg (77% yield) of the product 225. MS (M+1): m/e 487.
Step 164:




To methylcyclopropanemethanol (168 mg, 1.94 mmol) in dry THF (6 mL) was added sodium hydride (60.2 mg of 60 wt % in oil, 1.50 mmol). The reaction mixture was stirred at room temperature for 10 mins, and then compound 225 (50 mg, 0.103 mmol) was added. The reaction mixture was stirred at room temperature overnight and then the solvent was concentrated. Water was added, and the aqueous solution was extracted with ethyl acetate. The organic phase was dried over magnesium sulfate, filtered, and concentrated. Purification by silica gel chromatography (eluant: 1:1 hexane:EtOAc) gave 30 mg (54% yield) of the product 226. MS (M+1): m/e 537.




Step 165:





To 5-hexen-1-ol (48 mg, 0.483 mmol) dissolved in dry THF (5 mL) was added 1 M sodium hexamethyldisilazane in THF (0.323 mL, 0.323 mmol). The reaction was stirred at room temperature for 10 mins then compound 227 (80.0 mg, 0.161 mmol) was added. The reaction was stirred at room temperature overnight, and the solvent was evaporated. Water was added, and the mixture was extracted with ethyl acetate. The organic phase was dried over magnesium sulfate, filtered, and concentrated. Purification by silica gel chromatography (eluant: 1:1 hexane:EtOAc) gave 80 mg (89% yield) of the product 228. MS (M+1): m/e 560.
Step 166:




To a Schlenk flask charged with diiodomethane (0.034 mL, 0.43 mmol) in methylene chloride (10 mL) was slowly added trifluoroacetic acid (49 mg, 0.032 mL, 0.43 mmol) then 1.0 M of diethyl zinc in pentane (0.43 mL, 0.43 mmol). The reaction mixture was stirred for 30 mins at 0° C. Compound 228 (80 mg, 0.143 mmol) in methylene chloride was added. The reaction mixture was warmed slowly to room temperature and stirred overnight. Saturated ammonium chloride was added, and the aqueous solution was extracted with methylene chloride, dried over MgSO4, filtered, and concentrated. Purification by silica gel chromatography (eluant: 1:1 hexane:EtOAc) gave 10 mg (12% yield) of the product 229 MS (M+1): m/e 574 and 30 mg (36% yield) of the product 230 MS (M+1): m/e 588.
Using the procedures described above, the following compounds were synthesized.












Cmpd.

MS


No.
Structure
M + 1







1859Z




546


 


1860Z




546


 


1861Z




560


 


1862Z




560













Step 167:





To a solution of 2-iodophenol 231 (2.0 g, 9.09 mmol) in dry DMF (40 mL) was added K2CO3 (4.93 g, 35.7 mmol) and 5-bromopentyl acetate (4.16 mL, 25.0 mmol) under a nitrogen atmosphere. The reaction mixture was heated to 50° C. and stirred for 17 h. The reaction mixture was diluted with ethyl acetate then washed with brine. The organic extract was dried with MgSO4, filtered, and concentrated. Purification by silica gel chromatography (eluant: 5% ethyl acetate in hexanes) yielded 1.81 g (57% yield) of the product 233 as a yellow liquid.
Step 168:




    Reference: Pu, Y. M. et. al. Tet. Lett. 2006, 47, 149-153.


To a solution of iodide 233 (829.6 mg, 2.38 mmol) and pyridazinone 234 (500 mg, 1.59 mmol) in dry DMF (10 mL) in a sealed flask was added K2CO3 (329.3 mg, 2.38 mmol) and Cu catalyst (69.2 mg, 0.159 mmol) and flushed with nitrogen. The reaction mixture was heated to 120° C. for 17 h. The reaction mixture was diluted with ethyl acetate and washed with 1 N HCl then brine. The organic extract was dried with MgSO4, filtered, and concentrated. Purification by silica gel chromatography (eluant: 50% ethyl acetate in hexanes) yielded 81 mg (10%) of the product 235 as a yellow oil. MS (M+1): m/e 535.
Step 169:




To a solution of acetate 235 (81 mg, 0.151 mmol) in MeOH (5 mL) was added water (3 drops) and K2CO3 (105 mg, 0.760 mmol) under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was quenched with saturated NH2Cl, then extracted with ethyl acetate. The organic extract was washed with brine, dried with MgSO4, filtered, and concentrated. Purification by silica gel chromatography (eluant: 65% ethyl acetate in hexanes) yielded 52.6 mg (71%) of the product 236 as a white foam. MS (M+1): m/e 493.
Step 170:




To a solution alcohol 236 (42.3 mg, 0.086 mmol) in THF (15 mL) was added NaH (60%, 6.9 mg, 0.479 mmol) under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was quenched with saturated NH4Cl then extracted with ethyl acetate. The organic extract was washed with brine, dried with MgSO4, filtered, and concentrated. Purification by silica gel chromatography (eluant: 35% ethyl acetate in hexanes) yielded 12 mg (31%) of the product 237 as a white solid. MS (M+1): m/e 457.
Step 171:




4 N HCl in dioxane (5 mL) was added to macrocycle 237 (52 mg, 0.114 mmol) under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 1.5 h. The reaction was then concentrated and dried under high vacuum. To a solution of this crude product in CH2Cl2 (10 mL) was added isopropyl sulfonyl chloride (51.2 uL, 0.456 mol) and Hunig's base (119 uL, 0.683 mmol). The reaction was stirred at room temperature for 17 h then concentrated. Purification by silica gel chromatography yielded 16.3 mg (31%) of the product 238 as a brown solid. MS (M+1): m/e 463.




Step 172:





To a solution of 2-iodophenol 231 (2.0 g, 9.09 mmol) in dry DMF (40 mL) was added K2CO3 (3.77 g, 27.3 mmol) and 1-iodooctane (1.98 mL, 10.9 mmol) under a nitrogen atmosphere. The reaction mixture was heated to 40° C. and stirred for 17 h. The reaction mixture was diluted with ethyl acetate then washed with brine. The organic extract was dried with MgSO4, filtered, and concentrated. Purification by silica gel chromatography (eluant: 3% ethyl acetate in hexanes) yielded 3.02 g (99% yield) of the product 239 as a yellow liquid.
Step 173:




To a solution of iodide 239 (1.27 g, 3.82 mmol) and pyridazinone 234 (1 g, 3.18 mmol) in dry DMF (14 mL) in a sealed flask was added K2CO3 (483 mg, 3.50 mmol) and Cu catalyst (139 mg, 0.319 mmol) and flushed with nitrogen. The reaction mixture was heated to 120° C. for 17 h. The reaction mixture was diluted with ethyl acetate and washed with 1 N HCl then brine. The organic extract was dried with MgSO4, filtered, and concentrated. Purification by silica gel chromatography (eluant: 50% ethyl acetate in hexanes) yielded 300 mg (15%) of the product 240 as a yellow oil. MS (M+1): m/e 519.
Step 174:




4 N HCl in dioxane (5 mL) was added to compound 240 (50 mg, 0.096 mmol) under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 1.5 h. The reaction was then concentrated and dried under high vacuum. To a solution of this crude product in CH2Cl2 (5 mL) was added □-toluenesulfonyl chloride (55.1 mg, 0.289 mmol) and Hunig's base (100 uL, 0.574 mmol). The reaction was stirred at room temperature for 17 h then concentrated. Purification by silica gel chromatography yielded 44.9 mg (81%) of the product 241 as a colorless oil. MS (M+1): m/e 573.
Step 175:




To a solution of benzyl alcohol (39.1 mg, 0.362 mmol) in THF (10 mL) was added NaH (60% in oil, 11.6 mg, 0.290 mmol) under a nitrogen atmosphere. To the reaction solution was added chloride 241 (41.4 mg, 0.072 mmol), and the reaction mixture was stirred at room temperature for 17 h. The reaction was quenched with saturated NH4Cl and extracted with ethyl acetate. The organic extract was then washed with brine, dried with MgSO4, filtered, and concentrated. Purification by silica gel chromatography (eluant: 65% ethyl acetate in hexanes) yielded 34.6 mg (74%) of the product 242 as a brown oil. MS (M+1): m/e 645.




Steps 176 and 177:

A mixture of 2-(pyridin-2-yl)ethanesulfonic acid (243) (60 mg, 0.32 mmol) and thionyl chloride (2.3 mL, 31.6 mmol) under nitrogen was stirred at 55° C. for 5 h. The mixture was cooled to room temperature and concentrated to dryness under reduced pressure. The resulting residue was further diluted with toluene (5 mL), which was removed under reduced pressure to give crude 2-(pyridin-2-yl)ethanesulfonyl chloride (244) as a fine powder. Compound 244 was diluted with methylene chloride (2 mL) and the solution was cooled to 0° C. and a cold solution of 2-(3-chlorophenyl)-4-((1-methyl cyclopropyl)methoxy)-5-(piperazin-1-yl)pyridazin-3(2H)-one (120 mg, 0.32 mmol) and triethylamine (0.54 mL, 3.87 mmol) in methylene chloride (3 mL) was added dropwise. The reaction mixture was slowly warmed to room temperature, stirring for a total of 18 h after which the solvents were removed under reduced pressure. The residue was purified by CombiFlash Companion (80-g silica gel cartridge), eluting with ethyl acetate/hexanes (1:9 to 7:3), to provide the product 245 (66 mg, 38%) as a white solid. MS (M+1): m/e 544.




Step 178:





A mixture of 1-bromo-4-methyl-2-nitrobenzene 246 (10.0 g, 46.29 mmol), N-bromosuccinimide (9.06 g, 50.92 mmol) and AIBN (0.76 g, 4.63 mmol) in carbon tetrachloride (50 mL) at room temperature was purged with nitrogen (subsurface bubbling) for 10 mins after which the mixture was heated to reflux and stirred for 17 h. The cooled mixture was vacuum filtered, and the filtrate was concentrated. The resulting residue was purified by CombiFlash Companion (330-g silica gel cartridge), eluting with ethyl acetate/hexanes (3:97 to 1:9), to provide 6.88 g (50% yield) of the product 247 as a yellow solid.
Step 179:




A solution of 1-bromo-4-(bromomethyl)-2-nitrobenzene 247 (6.88 g, 23.33 mmol) and potassium thioacetate (3.46 g, 30.33 mmol) in anhydrous DMF (100 mL) was heated at 55° C. under nitrogen for 17 h. The cooled mixture was diluted with water (300 mL) and extracted with ethyl acetate (3×200 mL). The combined organic extracts were washed with water (3×50 mL), brine (100 mL) and then concentrated to afford the product 248 (6.73 g, 99% yield) as a dark-red oil that was used in the next step without further purification.
Step 180:




Chlorine gas was slowly bubbled through a biphasic mixture of S-4-bromo-3-nitrobenzyl ethanethioate 8 (6.73 g, 23.2 mmol) in methylene chloride (100 mL) and water (20 mL) at 0° C. for 45 mins, during which time the solution became a persistent yellow color. Nitrogen gas was slowly bubbled through the solution to displace the chlorine gas, and the reaction mixture was extracted with methylene chloride (100 mL). The aqueous layer was further extracted with methylene chloride (2×30 mL), and the combined organic extracts were washed with brine (100 mL), dried (Na2SO4), filtered, and concentrated to afford (4-bromo-3-nitrophenyl)methanesulfonyl chloride 9 (7.00 g, 96% yield) as a yellow solid which was used in the next step without further purification.
Step 181:




Triethylamine (1.64 mL, 11.8 mmol) was added to a mixture of 2-(3-chlorophenyl)-4-((1-methylcyclopropyl)methoxy)-5-(piperazin-1-yl)pyridazin-3(2H)-one 250 (2.21 g, 5.89 mmol) and (4-bromo-3-nitrophenyl)methanesulfonyl chloride 249 (1.86 g, 5.91 mmol) in anhydrous methylene chloride (25 mL) at 0° C. under nitrogen. The mixture was stirred at 0° C. for 1 h after which it was slowly warmed to room temperature, stirring for a total of 16 h. The mixture was diluted with methylene chloride (150 mL), washed with water (50 mL) then brine (50 mL), and the solvents were removed under reduced pressure. The residue was purified by CombiFlash Companion (120-g SiO2 cartridge), eluting with ethyl acetate/hexanes (1:9 to 4:6), to provide 980 mg (25% yield) of the product 251 as a yellow solid. MS (M+1): m/e 652.
Step 182:




Cesium carbonate (46 mg, 0.14 mmol) and potassium carbonate (39 mg, 0.28 mmol) were added to a degassed solution of 5-(4-(4-bromo-3-nitrobenzylsulfonyl)piperazin-1-yl)-2-(3-chlorophenyl)-4-((1-methylcyclopropyl)methoxy)pyridazin-3(2H)-one 10 (93 mg, 0.142 mmol) in 1,4-dioxane (5 mL) at room temperature under nitrogen after which Pd(PPh3)4 (16 mg, 0.014 mmol) and trimethylboroxine (44 uL, 0.315 mmol) were added. The reaction mixture was stirred at reflux for 16 h after which the cooled mixture was concentrated. The resulting residue was diluted with water (30 mL) and extracted with methylene chloride (2×30 mL). The combined organic extracts were washed with brine (50 mL) then concentrated. The residue was purified by CombiFlash Companion (40-g SiO2 cartridge), eluting with ethyl acetate/hexanes (1:9 to 4:6), to provide 75 mg (90% yield) of the product 252 as a yellow solid. MS (M+1): m/e 588.
Step 183:




A mixture of 2-(3-chlorophenyl)-5-(4-(4-methyl-3-nitrobenzylsulfonyl)piperazin-1-yl)-4-((1-methylcyclopropyl)methoxy)pyridazin-3(2H)-one 252 (75 mg, 0.13 mmol) and platinum(II) oxide (11 mg, 0.048 mmol) in ethanol (5 mL) and THF (5 mL) at room temperature was stirred under an atmosphere of hydrogen (balloon) for 18 h. The mixture was filtered through a plug of celite under reduced pressure, and the filtrate was concentrated. The residue was purified by CombiFlash Companion (40-g SiO2 cartridge), eluting with ethyl acetate/hexanes (15:85 to 8:2), to provide 36 mg (51% yield) of the product 253 as a white solid. MS (M+1): m/e 558.
Using the procedures described above, the following compounds were synthesized.







TABLE 34







Oxygen Analogs with Methyl-or Methoxy-Substituted Sulfonamide









Cmpd. No.
Structure
MS M + 1





1863Z




574


 


1864Z




576


 


1865Z




604


 


1866Z




634


 


1867Z




592


 


1868Z




622


 


1869Z




558


 


1870Z




560


 


1871Z




576


 


1872Z




576


 


1873Z




560


 


1874Z




562


 


1875Z




583


 


1876Z




594


 


1877Z




612


 


1878Z




558













Step 184:





A mixture of 5-(4-(4-bromo-3-nitrobenzylsulfonyl)piperazin-1-yl)-2-(3-chlorophenyl)-4-((1-methylcyclopropyl)methoxy)pyridazin-3(2H)-one 251 (49 mg, 0.075 mmol) and platinum(II) oxide (10 mg 0.044 mmol) in ethanol (5 mL) and THF (2 mL) at room temperature was stirred under an atmosphere of hydrogen (balloon) for 16 h. The mixture was filtered through a plug of celite under reduced pressure, and the filtrate was concentrated. The residue was purified by CombiFlash Companion (40-g, SiO2 cartridge), eluting with ethyl acetate/hexanes (1:9 to 8:2) to provide 11 mg (45% yield) of the product 254 as a white solid. MS (M+1): m/e 622.
Step 185:




A solution of potassium phosphate (66 mg, 0.31 mmol) in water (2 mL) was added to a degassed solution of 5-(4-(4-bromo-3-nitrobenzylsulfonyl)piperazin-1-yl)-2-(3-chlorophenyl)-4-((1-methylcyclopropyl)methoxy)pyridazin-3(2H)-one 251 (92 mg, 0.141 mmol) in THF (5 mL) after which PdCl2(dppf) (8 mg, 0.01 mmol) and triethyl borane (1.0 M in THF 0.17 mL, 0.17 mmol) were added, and the mixture was heated to reflux, stirring for a total of 18 h. The cooled mixture was diluted with water (30 mL) and extracted with methylene chloride (3×30 mL). The combined organic extracts were washed with brine (50 mL) then concentrated. The residue was purified by CombiFlash Companion (40-g SiO2 cartridge), eluting with ethyl acetate/hexanes (1:9 to 4:6), to provide 34 mg (40% yield) of the product 255 as a yellow solid. MS (M+1): m/e 602.
Step 184:




Hydrogenation of 2-(3-chlorophenyl)-5-(4-(4-ethyl-3-nitrobenzylsulfonyl)piperazin-1-yl)-4-((1-methylcyclopropyl)methoxy)pyridazin-3(2H)-one 255 (34 mg, 0.057 mmol) was performed as described above to provide 26 mg (80% yield) of the product 256 as a white solid. MS (M+1): m/e 572.
Using the procedures described above, the following compounds were synthesized.












Cmpd.

MS


No.
Structure
M + 1







1879Z




572


 


1880Z




574









Step 186:





Tributylethoxyvinyltin (126 uL, 0.373 mmol) and PdCl2(PPh3)2 (20 mg, 0.028 mmol) were added to a degassed solution of 5-(4-(4-bromo-3-nitrobenzylsulfonyl)piperazin-1-yl)-2-(3-chlorophenyl)-4-((1-methylcyclopropyl)methoxy)pyridazin-3(2H)-one 251 (187 mg, 0.286 mmol) in 1,4-dioxane (6 mL) at room temperature under nitro-en after which the mixture was heated to reflux, stirring for a total of 18 h. The cooled mixture was diluted with 1 M HCl (4 mL) and stirred at room temperature for an additional 90 mins. Aqueous sodium hydroxice (1 M, 4.5 mL) was added, and the mixture was extracted with methylene chloride (60 mL×2). The solvent was concentrated, and the residue was purified by CombiFlash Companion (40-g SiO2 cartridge), eluting with ethyl acetate/hexanes (1:9 to 6:4), to provide 139 mg (79% yield) of the product 257 as a white solid. MS (M+1): m/e 616.
Step 184:




Hydrogenation of 5-(4-(4-acetyl-3-nitrobenzylsulfonyl)piperazin-1-yl)-2-(3-chloro phenyl)-4-((1-methylcyclopropyl)methoxy)pyridazin-3(2H)-one 257 (139 mg, 0.226 mmol) was performed as described above to provide 99 mg (74% yield) of the product 258 as a yellow solid. MS (M+1): m/e 586.
Step 187:




A solution of sodium carbonate (2 M, 0.4 mL, 0.8 mmol) and 4-fluorophenylboronic acid (34 mg, 0.24 mmol) was added to a degassed solution of 5-(4-(3-amino-4-bromobenzylsulfonyl)piperazin-1-yl)-2-(3-chloro phenyl)-4-((1-methylcyclopropyl)methoxy)pyridazin-3(2H)-one 254 (60 mg, 0.096 mmol) in 1,4-dioxane (4 mL) at room temperature under nitrogen, after which Pd(PPh3)4 (20 mg, 0.017 mmol) was added, and the mixture was stirred at 95° C. 16 h. The cooled mixture was diluted with methylene chloride (150 mL), washed with brine (40 mL) and then concentrated. The residue was purified by CombiFlash Companion (40-g SiO2 cartridge), eluting with ethyl acetate/hexanes (1:9 to 4:6), to provide 14 mg (23% yield) of the product 259 as a white solid. MS (M+1): m/e 638.




Step 188:





Iron powder (448 mg, 8.02 mmol) was added portionwise to a solution of 5-(4-(4-bromo-3-nitrobenzylsulfonyl)piperazin-1-yl)-2-(3,5-difluoro phenyl)-4-((1-methylcyclopropyl)methoxy)pyridazin-3(2H)-one 260 (105 mg, 0.160 mmol) in THF (3 mL) at room temperature under nitrogen, after which acetic acid (3.7 mL, 64 mmol) was added slowly. The reaction mixture was stirred at room temperature for 4 h then the solids were removed by vacuum filtration. The filtrate was concentrated, and the residue was purified by CombiFlash Companion (40-g SiO2 cartridge), eluting with ethyl acetate/hexanes (1:9 to 1:1), to provide 82 mg (82% yield) of the product 261 as a white solid. MS (M+1): m/e 624.
Step 189:




Acetyl chloride (28 uL, 0.394 mmol) was added to a solution of 5-(4-(3-amino-4-bromobenzyl sulfonyl)piperazin-1-yl)-2-(3,5-difluorophenyl)-4-((1-methylcyclopropyl)methoxy)pyridazin-3(2H)-one 261 (82 mg, 0.131 mmol) and triethylamine (110 uL, 0.79 mmol) in THF (3 mL) at room temperature under nitrogen, and the mixture was stirred for 18 h then concentrated. The crude product was purified by CombiFlash Companion (40-g SiO2 cartridge), eluting with ethyl acetate/hexanes (1:9 to 6:4), to provide 57 mg (65% yield) of the product 262 as a yellow solid. MS (M+1): m/e 666.




Step 190:





A mixture of 4-(hydroxymethyl)-2-nitrophenol 263 (3.27 g, 19.33 mmol), potassium carbonate (5.34 g, 38.64 mmol) and benzyl bromide (2.53 mL, 21.30 mmol) in acetone (200 mL) was stirred at reflux for 18 h. After cooling, the solvent was concentrated, and the residue was triturated with methylene chloride (300 mL) and vacuum filtered. The filtrate was concentrated, and the residue was purified by CombiFlash Companion (80-g silica gel cartridge), eluting with ethyl acetate/hexanes (1:1), to provide 5.49 g (95% yield) of the product 264 as a yellow solid.
Step 191:




Triphenylphosphine (1112 g, 42.39 mmol) was added to a solution of N-bromosaccharin (11.11 g, 42.39 mmol) in methylene chloride (180 mL) at 0° C. under nitrogen, and the mixture was stirred for 5 mins. The mixture was warmed to room temperature, and a solution of (4-(benzyloxy)-3-nitrophenyl)methanol 264 (5.49 g, 21.17 mmol) in methylene chloride (60 mL) was added dropwise. The mixture was stirred at room temperature for 1 h after which the white precipitate was removed by filtration under reduced pressure. The filtrate was concentrated, and the residue was purified by CombiFlash Companion (80-g silica gel cartridge), eluting with methylene chloride/hexanes (1:1), to provide 5.57 g (82% yield) of the product 265 as a yellow solid.
Steps 179-181 in Scheme 53:




Using the described procedures for step 179-181 in Scheme 53, compound 266 was synthesized. MS (M+1): m/e 682.
Step 192:




A mixture of 5-(4-(4-(benzyloxy)-nitrobenzylsulfonyl)piperazin-1-yl-(3,5-difluorophenyl)-4-((1-methylcyclopropyl)methoxy)pyridazin-3(2H)-one 266 (166 mg, 0.244 mmol) and platinum(II) oxide (24 mg, 0.098 mmol) in ethyl acetate (6 mL) and ethanol (6 mL) was stirred at room temperature under an atmosphere of hydrogen (balloon) for 18 h. The mixture, was filtered through a plug of celite, and the filtrate was concentrated. The resulting residue was purified by CombiFlash Companion (40-g SiO2 cartridge), eluting with ethyl acetate/hexanes (1:9 to 8:2), to provide 85 mg (54% yield) of the product 267 as a white solid: MS (M+1): m/e 652 and 10 mg (7% yield) of the product 268; MS (M+1): m/e 562.
Step 193:




A mixture of 5-(4-(3-amino-4-hydroxybenzylsulfonyl)piperazin-1-yl)-2-(3,5-difluorophenyl)-4-((1-methylcyclopropyl)methoxy)pyridazin-3(2H)-one 268 (66 mg, 0.12 mmol) and 1,1′-thiocarbonyldiimidazole (42 mg, 0.24 mmol) in DMF (3 mL) at room temperature under nitrogen was stirred for 24 h, after which the mixture was diluted with water (30 mL) and extracted with ethyl acetate (50 mL×3). The combined organic extracts were washed with water (30 mL×3) then brine (70 mL), and the solvent was concentrated. The resulting residue was purified by CombiFlash Companion (40-g silica gel cartridge), eluting with ethyl acetate/hexanes (1:9 to 6:4), to provide 56 mg (79% yield) of the product 269 as a white solid. MS (M+1): m/e 604.
Using the procedures described above, the following compounds were synthesized.







TABLE 35







Oxygen Analogs with Cyclized Sulfonamide









Cmpd.

MS


No.
Structure
M + 1





1881Z




588


 


1882Z




587


 


1883Z




602


 


1884Z




588


 


1885Z




646


 


1886Z




610


 


1887Z




613









Step 194:





A mixture of 5-(4-(3-amino-4-hydroxybenzylsulfonyl)piperazin-1-yl)-2-(3,5-difluorophenyl)-4-((1 methylcyclopropyl)methoxy)pyridazin-3(2H)-one 268 (110 mg, 0.196 mmol) and trimethyl orthoformate (4 mL, 36.6 mmol) was heated at 100° C. under nitrogen for 24 h. The cooled mixture was concentrated, and the resulting residue was purified by CombiFlash Companion (40-g silica gel cartridge), eluting with ethyl acetate/methylene chloride (3:7), to provide 91 mg (81% yield) of the product 270 as a white solid, MS (M+1): m/e 572.
Using the procedures described above, the following compound was synthesized.







TABLE 36







Oxygen Analogs with Cyclized Sulfonamide









Cmpd.

MS


No.
Structure
M + 1





1888Z




586


 


1889Z




600


 


1890Z




536


 


1891Z




572


 


1892Z




664


 


1893Z




644


 


1894Z




658


 


1895Z




614


 


1896Z




666


 


1897Z




616


 


1898Z




586


 


1899Z




630


 


1900Z




616


 


1901Z




569


 


1902Z




602


 


1902ZA




590


 


1902ZB




590













Step 195:





Solid Zn(CN)2 (48 mg, 0.41 mmol) was added to a degassed solution of 2-(3-chlorophenyl)-5-(4-(4-iodo-3-nitrobenzylsulfonyl)piperazin-1-yl)-4-((1-methylcyclopropyl)methoxy)pyridazin-3(2H)-one 271 (260 mg, 0.371 mmol) in DMF (5 mL) at room temperature under nitrogen, after which Pd(PPh3)4 (64 mg, 0.056 mmol) was added and the mixture was stirred at 85° C. under nitrogen for 18 h. The cooled mixture was diluted with ethyl acetate (150 mL), washed with water (15 mL×3) and brine (75 mL), and the solvent was concentrated. The resulting residue was purified by CombiFlash Companion (40-g SiO2 cartridge), eluting, with ethyl acetate/hexanes (1:9 to 1:1), to provide 196 mg (88% yield) of the product 272 as a yellow solid. MS (M+1): m/e 599.
Step 196:




A mixture of 4-((4-(1-(3-chlorophenyl)-5-((1-methylcyclopropyl)methoxy)-6-oxo-1,6-dihydropyridazin-4-yl)piperazin-1-ylsulfonyl)methyl)-2-nitrobenzonitrile 272 (172 mg, 0.287 mmol) and palladium on carbon (100 mg) in methylene chloride (6 mL) and methanol (12 mL) at room temperature was stirred under an atmosphere of hydrogen (45 psi) for 3 h. The mixture was filtered through a plug of celite under reduced pressure, after which the filtrate was concentrated. The resulting residue was purified by CombiFlash Companion (40-g SiO2 cartridge), eluting with ethyl acetate/hexanes (1:9 to 1:1), to provide first 95 mg (58% yield) of the product 274 as an off-white solid. MS (M+1): m/e 569 and second 27 mg (18% yield) of the product 273 as a white solid: MS (M+1): m/e 535.
Step 197:




Sodium bicarbonate (89 mg, 1.06 mmol), Bu4NBr (151 mg, 0.468 mmol), allyl alcohol (102 uL, 1.50 mmol) and Pd(OAc)2 (8 mg, 0.03 mmol) were sequentially added to a degassed solution of 2-(3-chlorophenyl)-5-(4-(4-iodo-3-nitrobenzylsulfonyl)piperazin-1)-4-((1 methylcyclopropyl)methoxy pyridazin-3(2H)-one 271 (298 mg, 0.426 mmol) in DMF (8 mL) at room temperature under nitrogen, after which the mixture was stirred at 50° C. for 24 h. The cooled mixture was diluted with water (80 mL) and extracted with ethyl acetate (80 mL×3). The combined organic extracts were washed with water (30 mL×3) and brine (80 mL), and the solvents was concentrated. The resulting residue was purified by CombiFlash Companion (40-g SiO2 cartridge), eluting with ethyl acetate/methylene chloride (5:95 to 3:7), to provide 177 mg (66% yield) of the product 275 as a yellow solid. MS (M+1): m/e 630.
Step 198:




A mixture of 3-(4-((4-(1-(3-chlorophenyl)-5-((1-methylcyclopropyl)methoxy)-6-oxo-1,6-dihydropyridazin-4-yl)piperazin-1-ylsulfonyl)methyl)-2-nitrophenyl)propanal 275 (100 mg, 0.159 mmol) and platinum(IV) oxide (14 mg, 0.062 mmol) in ethyl acetate (8 mL) and methanol (8 mL) at room temperature was stirred under an atmosphere of hydrogen (balloon) for 18 h. The mixture was filtered through a plug of celite under reduced pressure and the filtrate was concentrated. The resulting residue was purified by CombiFlash Companion (40-g SiO2 cartridge), eluting with ethyl acetate/methylene chloride (1:99 to 15:85) to provide 47 mg (51% yield) of the product 276. MS (M+1): m/e 584.
Step 199:




Sodium borohydride (14 mg, 0.37 mmol) was added to a solution of 3-(4-((4-(1-(3-chlorophenyl)-5-((1-methylcyclopropyl)methoxy)-6-oxo-1,6-dihydropyridazin-4-yl)piperazin-1-ylsulfonyl)methyl)-2-nitrophenyl)propanal 275 (77 mg, 0.122 mmol) in methanol (8 mL) at 0° C. under nitrogen and the mixture was stirred for 90 mins. Water (0.5 mL) was added, and the mixture was concentrated. The residue was diluted with water (15 mL) and adjusted to pH  ̃7 with 1 M HCl and then extracted with ethyl acetate (30 mL×2). The combined organic extracts were washed with brine (30 mL) and the solvent was concentrated. The resulting residue was purified by CombiFlash Companion (40 g silica gel cartridge), eluting with ethyl acetate/methylene chloride (5:95 to 3:7), to provide 56 mg (72% yield) of the product 277 as a white solid. MS (M+1): m/e 632.
Step 200:




A mixture of 2-(3-chlorophenyl)-5-(4-(4-(3-hydroxypropyl)-3-nitrobenzylsulfonyl)piperazin-1-yl)-4-((1-methylcyclopropyl)methoxy)pyridazin-3(2H)-one 277 (42 mg, 0.066 mmol) and platinum(IV) oxide (8 mg, 0.033 mmol) in ethyl acetate (6 mL) and methanol (6 mL) at room temperature was stirred under an atmosphere of hydrogen (balloon) for 18 h. The mixture was filtered through a plug of celite under reduced pressure and the filtrate was concentrated. The resulting residue was purified by CombiFlash Companion (40-g silica gel cartridge), eluting with ethyl acetate/methylene chloride (5:95 to 8:2), to provide 31 mg (77% yield) of the product 278 as a white solid. MS (M+1): m/e 602.




Step 201:





Methylene chloride (30 mL) was added to a solution of cyanuric chloride (1.84 g, 10.0 mmol) in dimethylformamide (1.90 g, 25.8 mmol) at room temperature under nitrogen, after which (4-fluoro-3-nitrophenyl)methanol 279 (2.22 g, 9.5 mmol) was added. The mixture was stirred for 3 h, diluted with methylene chloride, and washed sequentially with water (125 mL), saturated sodium carbonate solution (125 mL), 1 N hydrochloric acid (125 mL) and brine (150 mL). The organic solution was dried over sodium sulfate, filtered, and concentrated. The residue was purified by CombiFlash Companion (40-g silica cartridge), eluting with methylene chloride, to provide 1.62 g (90% yield) of the product 280 as a clear oil which solidified upon refrigeration, and was used without purification.
Step 202:




A mixture of 4-(chloromethyl)-1-fluoro-2-nitrobenzene 280 (1.62 g, 8.54 mmol) and thiourea (0.65 g, 8.54 mmol) in ethanol (10 mL) was heated at reflux under nitrogen for 15 h. The solvent was removed from the cooled mixture under reduced pressure, and the residue triturated with ethyl acetate (75 mL) for 30 mins at room temperature. The solids were collected by filtration, washed with ethyl acetate, and dried under reduced pressure to provide 1.32 g (58% yield) of the product 281 as a white solid that was used without purification.
Step 203:




A stream of chlorine gas was introduced subsurface for 30 mins to a rapidly-stirred suspension of 4-fluoro-3-nitrobenzylcarbamimidothioate hydrochloride 281 (1.30 g, 4.96 mmol) in 1 N hydrochloric acid (40 mL) at 0° C., after which the ice-bath was removed, and chlorine addition was continued for an additional 30 mins. The solids were collected by filtration under reduced pressured washed with watery and dried under reduced pressure to provide 1.02 g (81% yield) of the product 282 as a white solid that was used without purification.
Steps 181 and 183 in Scheme 53:




Using the described procedures for steps 181 and 183 in Scheme 53, compound 283 was synthesized. MS (M+1): m/e 562.
Using the procedures described above, the following compounds were synthesized.












Cmpd.

MS


No.
Structure
M + 1







1903Z




592


 


1904Z




562


 


1905Z




604


 


1906Z




574


 


1907Z




648


 


1908Z




618


 


1909Z




640


 


1910Z




610


 


1910ZA




604













Step 204:





To a solution of 1-Bloc-4-piperidone 284 (1 g, 5.01 mmol) in chloroform (20 mL) was slowly added bromine (0.26 mL, 5.02 mmol) over 30 mins under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 2 h. The resulting solid was filtered and dried to give 684 mg (53% yield) of the product 285 as brown solid. MS (M+1): m/e 179.
Step 205:




To a solution of bromine 285 (494 mg, 1.91 mmol) in DMF (10 mL) was added thiobenzamide (314 mg, 2.29 mmol) under a nitrogen atmosphere. The reaction mixture was heated to 100° C. for 7 h then cooled to room temperature and stirred for 11 h. The reaction mixture was diluted with ethyl acetate and washed with water. The aqueous extract was concentrated to give 312 mg (59% yield) of thiazole 286 as brown oil. MS (M+1): m/e 217.
Step 206:




To a solution of thiazole 286 (1.12 g, 5.18 mmol) in EtOH (20 mL) was added pyradizinone 287 (1.26 g, 4.57 mmol) and triethylamine (960 ul, 6.89 mmol) under a nitrogen atmosphere. The reaction mixture was heated to 80° C. for 17 h. The reaction was concentrated and purification with silica gel chromatography (eluant: 25% ethyl acetate in hexanes) gave 816 mg (39% yield) of the product 288 as a brown oil. MS (M+1): m/e 455.
Step 207:




To a solution of cyclopentanol (47.3 mg, 0.549 mmol) in THF (10 mL) was added NaH (60%, 17.6 mg, 0.440 mmol) under a nitrogen atmosphere. To the solution was added compound 288 (50 mg, 0.110 mmol), and the reaction mixture was stirred at room temperature for 17 h. The reaction was quenched with saturated NH4Cl and extracted with ethyl acetate. The organic extract was then washed with brine, dried with MgSO4, filtered, and concentrated. Purification with silica gel chromatography (eluant: 25% ethyl acetate in hexanes) gave 23.5 mg (42% yield) of the product 289 as brown oil. MS (M+1): m/e 505.




Step 208:





To a solution of sulfuryl chloride (4.57 mL, 56.38 mmol) in acetonitrile (9 mL) was added very slowly isopropylamine (1.44 mL, 16.91 mmol) under a nitrogen atmosphere. The reaction was then heated to 55° C. for 17 h. The reaction mixture was concentrated then diluted with water and extracted with ether. The organic extract was washed with brine, dried with MgSO4, filtered, and concentrated to give 683 mg (26% yield) of the product 291 as a white solid.
Step 209:




4N HCl in dioxane (5 mL) was added to ether 292 (50 mg, 0.145 mmol) under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 1.5 h. The reaction was then concentrated and dried under high vacuum. To a solution of the crude product in CH2Cl2 (5 mL) was added sulfamoyl chloride 291 (51.3 mg, 0.325 mmol) and Hunig's base (113.3 uL, 0.650 mmol). The reaction was stirred at room temperature for 17 h then concentrated. Purification with silica gel chromatography (eluant: 20% ethyl acetate in hexanes) gave 19.6 mg (38% yield) of the product 293 as a yellow oil. MS (M+1): m/e 482.
Using the procedures described above, the following compounds were synthesized.












Cmpd.

MS


No.
Structure
M + 1







1911Z




496


 


1912Z




490


 


1913Z




454













Step 210:





A mixture of 4,5-dichloro-2-(3-chlorophenyl)pyridazin-3(2H)-one 294 (1.0 g, 3.6 mmol), diisopropylethylamine (1.0 mL, 5.43 mmol) and 1-phenyl-1,3,8-triazaspiro[45]decan-4-one 295 (1.0 g, 4.4 mmol) in absolute ethanol (15 mL) was heated at reflux under nitrogen for 16 h. The mixture was cooled to room temperature and purified by CombiFlash Companion (80-g silica gel cartridge), eluting with ethyl acetate, to provide 1.1 (64% yield) of the product 296 as an off-white solid. MS (M+1): m/e 470.
Step 211:




Sodium hydride (45 mg, 1.1 mmol, 60%; suspension in mineral oil) was added to a solution of 1-methylcyclopropylmethanol (55 mg, 0.64 mmol) and 8-(5-chloro-1-(3-chlorophenyl)-6-oxo-1,6-dihydropyridazin-4-yl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one 296 (200 mg, 0.43 mmol) in anhydrous tetrahydrofuran (5 mL) at room temperature tinder nitrogen and the mixture was heated at reflux for 4 h. The cooled mixture was diluted with ethyl acetate (200 mL), washed with water (100 mL) and brine (100 mL), dried (MgSO4) and filtered. The solvent was concentrated, and the residue was purified by CombiFlash Companion (40-g silica gel cartridge), eluting with ethyl acetate/hexanes (1:1 to 100% ethyl acetate), to provide 60 mg (27% yield) of the product 297 as a yellow solid. MS (M+1): m/e 520.
Using the procedures described above, the following compounds were synthesized.












Cmpd.

MS


No.
Structure
M + 1







1914Z




533


 


1915Z




519













Step 212:





Oxalyl chloride (4.8 mL, 9.6 mmol, 2 M solution in methylene chloride) was added to a solution of diethyl 4-nitrobenzylphosphonate 298 (546 mg, 2.0 mmol) in methylene chloride (10 mL) at room temperature under nitrogen, and the mixture was stirred for 48 h. The mixture was diluted with chloroform (10 mL), and the solvent was concentrated to provide 520 mg (99% yield) of ethyl 4-nitrobenzylphosphonochloridate 299 as a thick yellow oil that was used in the next step without purification.
Step 213:




A solution of ethyl 4-nitrobenzylphosphonochloridate 299 (197 mg, 0.75 mmol) in methylene chloride (1 mL) was added dropwise to a mixture of 4,5-dichloro-2-(3-chlorophenyl)-pyridazin-3(2H)-one hydrochloride 300 (205 mg, 0.50 mmol) and diisopropylethylamine (0.22 mL, 1.25 mmol) in methylene chloride (5 mL) at 0° C. under nitrogen, and the mixture was slowly warmed to room temperature, stirring for a total of 16 h. The solvent was concentrated, and the residue was purified by CombiFlash Companion (12-g silica gel cartridge), eluting with ethyl acetate/hexanes (1:9 to 100% ethyl acetate), to provide 96 mg (32% yield) of the product 301 as a light yellow solid. MS (M+1): m/e 600.
Using the procedures described above, the following compounds were synthesized.












Cmpd.

MS


No.
Structure
M + 1







1916Z




513









Step 214:





A mixture of ethyl 4-(1-(3-chlorophenyl)-5-((1-methylcyclopropyl)methoxy)-6-oxo-1,6 dihydropyridazin-4-yl)piperazin-1-yl(4-nitrobenzyl)phosphinate 301 (130 mg, 0.22 mmol) and platinum(II) oxide (24 mg, 0.11 mmol) in ethanol (4 mL) and ethyl acetate (4 mL) at room temperature was stirred under an atmosphere of hydrogen (balloon) for 90 mins. The mixture was filtered through a plug of celite under reduced pressure and the filtrate was concentrated. The residue was purified by CombiFlash Companion (40-g SiO2 cartridge), eluting with methanol/methylene chloride (1:99 to 1:9), to provide 88 mg (71% yield) of the product 302 as an off-white solid. MS (M+1): m/e 572.




Step 215:





A solution of ethyl phosphorodichloridate (90 mg, 0.55 mmol) in methylene chloride (1 mL) was added dropwise to a solution of 4,5-dichloro-2-(3-chlorophenyl)pyridazin-3(2H)-one hydrochloride 300 (205 mg, 0.50 mmol) and diisopropylethylamine (0.26 mL, 1.50 mmol) in methylene chloride (5 mL) at room temperature under nitrogen, after which the mixture was slowly warmed to room temperature, stirring for a total of 16 h. The solvent was concentrated, and the residue was purified by CombiFlash Companion (12-g SiO2 cartridge), eluting with ethyl acetate/hexanes (1:9 to 2:3), to provide 121 mg (48% yield) of the product 303 as a viscous yellow oil that was used without purification.
Step 216:




Diisopropylethylamine (84 uL, 0.48 mmol) was added over a period of 10 mins to a solution of ethyl 4-(1-(3-chlorophenyl)-5-((1-methylcyclopropyl)methoxy)-6-oxo-1,6-dihydropyridazin-4-yl)piperazin-1-ylphosphonochloridate 303 (110 mg, 0.22 mmol) and (4-nitrophenyl)methylamine hydrochloride (38 mg, 0.20 mmol) in methylene chloride (1 mL) at 0° C. under nitrogen, and the mixture was slowly warmed to room temperature, stirring for a total of 16 h. The solvent was concentrated, and the residue purified by CombiFlash Companion (12-g SiO2 cartridge), eluting with ethyl acetate/hexanes (2:3 to 100% ethyl acetate), to provide 96 mg (78% yield) of the product 304 as a light yellow foam. MS (M−1): m/e 615.
Using the procedures described above, the following compounds were synthesized.












Cmpd.

MS


No.
Structure
M + 1







1917Z




618























1918Z




559


 


1918ZA




558









Step 214:





Using the procedure described above in step 214 in Scheme 62, compound 305 was synthesized. MS (M+1): m/e 587.




Step 217:





Methylene chloride (30 mL) was added to a mixture of cyanuric chloride (1.83 g, 100 mmol) in dimethylformamide (1.89 g, 25.8 mmol) at room temperature under nitrogen, after which (3-iodophenyl)methanol 306 (2.22 g, 9.5 mmol) was added, and the mixture was stirred for 1 h. The mixture was washed sequentially with water (25 mL), saturated sodium carbonate solution (125 mL), 1 N hydrochloric acid (125 mL) and brine (150 mL), dried over sodium sulfate, filtered, and concentrated. The residue was purified by CombiFlash Companion (40-g SiO2 cartridge), eluting with hexanes, to provide 1.64 g (68% yield) of the product 307 as a clear, colorless oil.
Step 218:




A mixture of 1-(chloromethyl)-3-iodobenzene 307 (1.64 g, 6.50 mmol) and thiourea (0.49 g, 6.50 mmol) in ethanol (10 mL) was heated at reflux under nitrogen for 20 h, after which the solvent was removed from the cooled mixture under reduced pressure. The residue was triturated with ethyl acetate (75 mL) for 30 mins, after which the solids were collected by filtration, washed with ethyl acetate (75 mL) and dried under reduced pressure to provide 2.02 g (94% yield) of the product 308 as a white solid that was used in the next step without purification.
Step 219:




A stream of chlorine gas was introduced subsurface for 30 mins to a rapidly-stirred suspension of 3-iodobenzyl carbamimidothioate hydrochloride 308 (2.00 g, 6.09 mmol) in 1 N hydrochloric acid (100 mL) at 0° C., after which the ice-bath was removed, and chlorine addition was continued for an additional 30 mins. The solids were collected by filtration under reduced pressure, washed with water, and dried under reduced pressure. The dried solid was then suspended in hot toluene (45 mL), and the solids were removed by decantation. The filtrate was diluted with hexanes (15 mL), and the mixture was allowed to stand for 3 h at room temperature, and then placed into a freezer for 12 h. The resulting crystals were collected by filtration, washed with hexanes (75 mL), and dried under reduced pressure to give 1.02 g (53% yield) of the product chloride 309 as opaque crystals.
Step 220:




Diisopropylamine (2.80 mL, 16.60 mmol) was added dropwise to a mixture of 2-(3-chlorophenyl)-4-((1-methylcyclopropyl)methoxy)-5-(piperazin-1-yl)pyridazin-3(2H)-one hydrochloride (3.00 g, 7.30 mmol) and (3-iodophenyl)methanesulfonyl chloride 309 (2.55 g, 8.03 mmol) in anhydrous dimethylformamide (5 mL) at 0° C. under nitrogen. The mixture was slowly warmed to room temperature and stirred for a total of 17 h. The mixture was poured into rapidly-stirred cold water (200 mL) and stirred for 30 mins. The precipitated solid was collected by filtration under reduced pressure, washed with water, and dried under reduced pressure at 45° C. The crude product was purified by CombiFlash Companion (40-g SiO2 cartridge), eluting with ethyl acetate/methylene chloride (100% methylene chloride to 1:9), to provide 2.48 g (52% yield) of the product 310 as a light-yellow foam: MS (M+1): m/e 655.
Step 221:




A degassed mixture of 2-(3-chlorophenyl)-5-(4-(3-iodobenzylsulfonyl)piperazin-1-yl)-4-((1-methylcyclopropyl)methoxy)pyridazin-3(2H)-one 310 (150 mg, 0.23 mmol), (+/−)-1-aminopropan-2-ol (35 mg, 0.46 mmol), copper(I) iodide (11 mg, 0.06 mmol), L-proline (13 mg, 0.11 mmol), and potassium carbonate (63 mg, 0.46 mmol) in anhydrous dimethyl sulfoxide (1.0 mL) was heated at 95° C. under nitrogen for 16 h. The cooled mixture was diluted with dimethyl sulfoxide (3 mL), filtered through a pad of celite under reduced pressure, and washed with ethyl acetate (35 mL). The filtrate was washed with brine (3×15 mL), dried over sodium sulfate, filtered, and concentrated. The residue was purified by CombiFlash Companion (12-g SiO2 cartridge), eluting with hexanes/ethyl acetate (1:4 to 1:1), to provide 88 mg (64% yield) of the product 311 as a white solid: MS (M+1): m/e 602.
Step 222:




A degassed mixture of 2-(3-chlorophenyl)-5-(4-(4-iodobenzylsulfonyl)piperazin-1-yl)-4-((1-methylcyclopropyl)methoxy)pyridazin-3(2H)-one 312 (328 mg, 0.50 mmol), acetamide (36 mg, 0.61 mmol), copper(I) iodide (18 mg, 0.09 mmol), N,N′-dimethylethylene-diamine (12 mg, 0.14 mmol), and potassium carbonate (212 mg, 2.0 mmol) in dimethylformamide (3 mL) was heated in a resealable reaction vessel at 85° C. for 18 h. The cooled mixture was diluted with ethyl acetate (35 mL), washed with brine (35 mL), dried over sodium sulfate, filtered, and concentrated. The residue was purified by CombiFlash Companion (40-g SiO2 cartridge), eluting with ethyl acetate/hexanes (1:1 to 100% ethyl acetate), to provide 165 mg (57% yield) of the product 313 as a white solid: MS (M+1): m/e 586.
Step 223:




A degassed mixture of 5-(4-(4-bromobenzylsulfonyl)piperazin-1-yl)-2-(3-chlorophenyl)-4-((1-methylcyclopropyl)methoxy)pyridazin-3(2H)-one 314 (152 mg, 0.25 mmol), 4-aminopyridine (26 mg, 0.28 mmol), tris(dibenzylideneacetone)dipalladium (4 mg, 0.008 mmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (XPhos, 12 mg, 0.012 mmol), and potassium phosphate (74 mg, 0.35 mmol) in anhydrous 1,4-dioxane (1.0 mL) was heated in a resealable reaction vessel at 105° C. for 18 h. The cooled mixture was diluted with ethyl acetate (2 mL), methylene chloride (2 mL) and methanol (2 mL), filtered through a plug of celite under reduced pressure, and the filtrate was concentrated. The residue was purified by CombiFlash Companion (12-g SiO2 cartridge) eluting with methanol/methylene chloride (1:99 to 1:9), to provide 35 mg (23% yield) of the product 315 as a light brown solid: MS (M+1): m/e 621.
Using the procedures described above, the following compounds were synthesized.







TABLE 37







Oxygen Analogs with Substituted Sulfonamide









Cmpd.

MS


No.
Structure
M + 1





1919Z




595


 


1920Z




593 (M − 1)


 


1921Z




592 (M − 1)


 


1922Z




620 (M − 1)


 


1923Z




594 (M − 1)


 


1924Z




594 (M − 1)


 


1925Z




646 (M − 1)


 


1926Z




613 (M − 1)


 


1927Z




614


 


1928Z




598


 


1929Z




621


 


1930Z




620


 


1931Z




642 (M − 1)


 


1932Z




645


 


1933Z




609


 


1934Z




609


 


1935Z




600


 


1936Z




558


 


1937Z




627


 


1938Z




595


 


1939Z




713


 


1940Z




630


 


1941Z




641


 


1942Z




646


 


1943Z




595


 


1944Z




597


 


1945Z




646


 


1946Z




645


 


1947Z




623


 


1948Z




614 (M − 1)


 


1949Z




616


 


1950Z




747


 


1951Z




602


 


1952Z




602


 


1953Z




645


 


1954Z




614


 


1955Z




657


 


1956Z




599


 


1957Z




649


 


1958Z




597


 


1959Z




621


 


1960Z




613


 


1961Z




622


 


1962Z




621


 


1963Z




621


 


1964Z




588


 


1965Z




615


 


1966Z




602


 


1967Z




616


 


1968Z




616


 


1969Z




558


 


1970Z




630


 


1971Z




600


 


1972Z




600


 


1973Z




644


 


1974Z




628


 


1975Z




632


 


1976Z




616


 


1977Z




616


 


1978Z




587


 


1979Z




618


 


1980Z




601


 


1981Z




615


 


1982Z




603


 


1983Z




651


 


1984Z




617













Step 224:

A mixture of (+/−)-2-(3-chlorophenyl)-5-(4-(3-(2-hydroxypropylamino)-benzylsulfonyl)piperazin-1-yl)-4-((1-methylcyclopropyl)methoxy)pyridazin-3 (2H)-one 316 (43 mg, 0.071 mmol), carbonyl diimidazole (46 mg, 0.29 mmol), and 4-dimethylaminopyridine (2 mg, 0.016 mmol) in tetrahydrofuran (5 mL) was heated at 80° C. under nitrogen for 6 h. The solvent was removed from the cooled mixture under reduced pressure, and the residue was purified by CombiFlash Companion (4-g SiO2 cartridge), eluting with hexanes/ethyl acetate (1:19 to 1:1), to provide 28 mg (62% yield) of the product 317 as a light yellow solid: MS (M+1): m/e 628.




Step 225:

Acetyl chloride (22 mg, 0.28 mmol) was added dropwise to a mixture of 5-(4-(3-aminobenzylsulfonyl)piperazin-1-yl)-2-(3-chlorophenyl)-4-((1-methylcyclopropyl)-methoxy)pyridazin-3(2H)-one 318 (125 mg, 0.23 mmol) in pyridine (0.5 mL) at 0° C. under nitrogen. The mixture was slowly warmed to room temperature, stirring for a total of 22 h. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (25 mL). The combined organic extracts were washed with 0.2 N HCl (4×50 mL), water (50 mL) and brine (50 mL), dried over sodium sulfate, filtered, and concentrated to provide 112 mg (83% yield) of the product 319 as an off-white foam: MS (M+1): m/e 586.
Using the procedure described above, the following compounds were synthesized,












Cmpd.

MS


No.
Structure
M + 1







1985Z




630


 


1986Z




673


 


1987Z




631













Step 226:

Dimethyl sulfate (26 mg, 0.22 mmol) was added to a mixture of N-(4-((4-(1-(3-chlorophenyl)-5-((1-methylcyclopropyl)methoxy)-6-oxo-1,6-dihydropyridazin-4-yl)piperazin-1-ylsulfonyl)methylphenyl)acetamide 320 (100 mg, 0.17 mmol) and potassium hydroxide (14 mg, 0.26 mmol) in dimethylformamide (0.5 mL) at room temperature under nitrogen, and the mixture was stirred for 15 h. The mixture was poured into cold water (30 mL), and the solids were removed by filtration under reduced pressure. The filtrate was concentrated, and the residue was purified by preparative TLC on silica gel, eluting with ethyl acetate, to provide 10 mg (10% yield) of the product 321 as an off-white solid: MS (M+1): m/e 600.




Step 227:

A mixture of 2-(3-chlorophenyl)-5-(4-(4-iodobenzylsulfonyl)piperazin-1-yl)-4-((1-methylcyclopropyl)methoxy)pyridazin-3(2H)-one 322 (66 mg, 0.10 mmol), n-butanol (15 mg, 0.20 mmol), copper(I) iodide (2 mg, 0.01 mmol), cesium carbonate (65 mg, 0.20 mmol) and 1,10-phenanthroline (4 mg, 0.02 mmol) in toluene (0.5 mL) was heated at 105° C. under nitrogen for 16 h. Then additional 1,10-phenanthroline (8 mg, 0.04 mmol), cesium carbonate (130 mg, 0.40 mmol), n-butanol (30 mg, 0.40 mmol) and copper(I) iodide (4 mg, 0.02 mmol) were added, and the reaction was heated for an additional 16 h. The cooled mixture was triturated with methylene chloride (5 mL) and methanol (5 mL), and the solids were removed by filtration. The filtrate was concentrated, and the residue was purified by CombiFlash Companion (12-g SiO2 cartridge), eluting with ethyl acetate/hexanes (1:19 to 2:3), to provide 10 mg, (17% yield) of the product 323 as an off-white solid: MS (M+1): m/e 601. The byproduct 324 was also isolated as a white solid: MS (M+1): m/e 589.
Using the procedure described above, the following compounds were synthesized.












Cmpd.

MS


No.
Structure
M + 1







1988Z




603


 


1989Z




594


 


1990Z




637


 


1991Z




590













Step 228:

To a solution of 5-(4-(3-bromobenzylsulfonyl)piperazin-1-yl)-2-(3-chlorophenyl)-4-((1-methylcyclopropyl)methoxy)pyridazin-3(2H)-one 325 (200 mg, 0.329 mmol) in anhydrous DMF (6.0 mL) was added Pd(dppf)Cl2 (24.1 mg, 0.0329 mmol), bis(pinacolato)diboron (94.4 mg, 0.372 mmole), and potassium acetate (96.7 mg, 0.987 mmole), the reaction mixture was heated to 95° C. for a total of 18 h. LCMS confirmed the boron ester intermediate. Into the reaction mixture was added Pd(dppf)Cl2 (24.1 mg, 0.0329 mmol), 2-chloropyridine (56.0 mg, 0.494 mmole), and sodium carbonate (0.5 mL, 2 N). The reaction mixture was heated to 95° C. for a total of 18 h. The mixture was diluted with ethyl acetate (100 mL), washed with water/brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by preparatory TLC (Analtech silica gel GF, 200 microns) eluting with hexanes/ethyl acetate (3:2), to provide 14 mg (7% yield) of the product 326 as a white solid: MS (M+1): m/e 606.
Using the procedure described above, the following compounds were synthesized.







TABLE 38







Oxygen Analogs with C-Linked Substituted Sulfonamide









Cmpd.

MS


No.
Structure
M + 1





1992Z




606


 


1993Z




606


 


1994Z




608


 


1995Z




611


 


1996Z




609


 


1997Z




624


 


1998Z




607


 


1999Z




620


 


2000Z




622


 


2001Z




608


 


2002Z




597


 


2003Z




609


 


2004Z




611


 


2005Z




611


 


2006Z




611


 


2007Z




595













Step 229:

A mixture of 2-(3-chlorophenyl)-5-(4-(3-iodobenzylsulfonyl piperazin-1-yl)-4-((1 methylcyclopropyl)methoxy)pyridazin-3(2H)-one 310 (200 mg, 0.305 mmol), morpholine (39.9 mg, 0.458 mmol), and Pd(dppf)Cl2 (22.3 mg, 0.03 mmole) in anhydrous DMSO (12 mL) at room temperature was charged with an atmosphere of carbon monoxide, after which the mixture was heated at 80° C. for 16 h. The cooled mixture was diluted with ethyl acetate (200 mL), washed with brine (300 mL), died over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by preparative TLC on silica gel, eluting with ethyl acetate, to provide 79 mg (41% yield) of the product 327 as a light brown solid: MS (M+1): m/e 642.
Using the procedure described above, the following compounds were synthesized.







TABLE 39







Oxygen Analogs with Carbonyl Substituted Sulfonamide









Cmpd.

MS


No.
Structure
M + 1





2008Z




586


 


2009Z




629


 


2010Z




643


 


2011Z




629


 


2012Z




602


 


2013Z




665


 


2014Z




665


 


2015Z




658


 


2016Z




651
















Step 230:





KNO3 (20.0 g, mmol) was added portionwise to a mixture of fuming H2SO4 (30.0 mL) and 98%. H2SO4 (16.0 mL) at 0° C. followed by stirring for 5 mins. Then 4,5-dichloropyridazinone 328 (1.0 g, 6.1 mmol) was added, and the reaction mixture was heated at 100° C. for 6 h. The reaction mixture was cooled to room temperature, poured into ice-water, and stirred for 5 mins to obtain a precipitate. The precipitate was collected by filtration, washed with H2O (3×50 mL), and dried in a vacuum oven at 50° C. to afford 5.2 g (32% yield) of the crude product 329 as a white solid.
Step 231:




Compound 329 (6.16 g, 29.3 mmol) was added to a solution of 3,4-dihydropyran (24.7 g 293 mmol) and p-toluene sulfuric acid monohydrate (0.56 g, 2.93 mmol) in THF (200 mL) The solution was refluxed for 29 h at 80° C. then cooled to room temperature, and the solvent was concentrated. The residue was purified by chromatography on a silica-gel column (eluant: 0-8% EtOAc/hexane gradient) to afford 6.5 g (75% yield) of the product 330 as pale yellow solid.
Step 232:




A solution of compound 330 (6.5 g, 22.1 mmol) and piperazine (3.8 g, 44.2 mmol) in EtOH (100 mL) was refluxed for 4 h at 80° C. then cooled to room temperature. The solvent was concentrated, and the residue was purified by chromatography on a silica-gel column (eluant: 4:1 to 1:2 EtOAc/MeOH gradient) to afford 5.1 g (67% yield) of a 1:1 mixture of products 331 and 332 as a yellow solid. MS (M+1): m/e 344.
Step 233:
α-Toluenesulfonyl chloride (0.81 g, 6.3 mmol) was added to a solution of the compounds 4 and 5 (1.8 g, 5.2 mmol) and i-Pr2NEt (0.81 g, 6.3 mmol) in CH2Cl2 (50 mL) at 0° C. followed by slowly warming to room temperature over 2 h. The solvent was concentrated. The residue was purified by chromatography on a silica-gel column (eluant: 0-40% EtOAc/hexane gradient) to afford 0.65 g (25% yield) of the first isomer 332 as pale yellow solid, MS (M+1): m/e 498; and 0.68 g (26% yield) of the second isomer 331 as pale yellow solid, MS (M+1): m/e 498.
Step 234:




Compound 333 (0.68 g, 1.4 mmol) and PtO2 (68 mg) dissolved in EtOAc/MeOH (15/30 mL) was stirred under a hydrogen atmosphere. The reaction was stirred overnight at room temperature under a hydrogen balloon. The solution was filtered through celite to remove the PtO2. The filtrate was concentrated, and the product was purified by Prep Gilson HPLC to afford 0.48 g (75% yield) of the product 335 as a pale yellow solid. MS (M+1): m/e 468.
Step 235:




To compound 335 (0.24 g, 0.5 mmol) in MeOH (5 mL) was added a solution of 6 M aqueous HCl (2.5 mL) followed by stirring for 1 h at 75° C. The reaction mixture was cooled to room temperature, and the solvent was concentrated. The residue was dissolved in EtOAc (25 mL) and washed with saturated NaHCO3 (20 mL). The organic phase was separated, dried over MgSO4, filtered, and concentrated to afford 75 mg (39% yield) of the product 336 as a pale yellow solid. MS (M+1): m/e 384.
Step 236:




A suspension of compound 336 (75 mg, 0.20 mmol), 3,5-difluoroiodobenzene (72 mg, 0.30 mmol), 8-hydroxyquinoline (11 mg, 0.08 mmol), CuI (10 mg, 0.05 mmol), and K2CO3 (55 mg, 0.40 mmol) in pyridine (5 mL) was heated for 1.5 h at 170° C. in a microwave reactor. The reaction mixture was cooled to room temperature, and the solution was filtered to remove the solid. The filtrate was concentrated and purified by prep Gilson HPLC to afford 51 mg (52% yield) of the product 337 as a pale yellow solid. MS (M+1): m/e 496.
Step 237:




NaH (11 mg, 0.27 mmol) was added to a solution of 1-methylcyclopropanemethanol (26 μL, 0.27 mmol) in THF (3.0 mL) followed by stirring for 5 mins at room temperature. Compound 337 (45 mg, 0.09 mmol) was then added, and the reaction was heated for 2 h at 75° C. The reaction mixture was cooled to room temperature, concentrated, and purified by chromatography on a silica-gel column (eluant: 0-35% EtOAc/hexane gradient) to afford 24 mg (49% yield) of the product 338 as a pale yellow solid. MS (M+1): m/e 546.
Using the procedures described above, the following compounds were synthesized.












Cmpd.

MS


No.
Structure
M + 1







2017Z




546


 


2018Z




544


 


2019Z




546













Step 238:

To compound 339 (45.4 mg, 0.0999 mmol) and 4-bromo-2-methylanisole (42.5 mg, 0.211 mmol) dissolved in anhydrous toluene (2 mL) at room temperature was added lithium hexamethyldisilazide in THF (0.200 mL, 1.0 M), palladium acetate (1.79 mg, 0.00799 mmol) and triphenylphosphine (6.55 mg, 0.0250 mmol). The reaction was degassed, placed under an atmosphere of nitrogen, and stirred at 100° C. overnight. The reaction mixture was filtered through a short path silica column and washed with ethyl acetate (150 mL). The solvent was concentrated, and the product was chromatographed on silica gel (eluant: 1:2 hexanes:EtOAc) to give 36 mg (63% yield) of the product 340. MS (M+1): m/e 575.
Using the procedure described above, the following compound was synthesized.












Cmpd.

MS


No.
Structure
M + 1







2020Z




521













Step 239:





Compound 341 can be prepared according to Scheme 34.
To a solution of sulfonamide 341 (200 mg, 0.39 mmol) in DMF (4 mL) at room temperature was added NaH (39 mg, 0.98 mmol, 60% in oil) in one portion. After stirring for 20 mins, 1,2-dibromoethane (840 mg, 4.2 mmol) was added in one portion followed by the addition of K2CO3 (540 mg, 3.9 mmol). The reaction mixture was heated at 120° C. for 8 h then cooled and slowly added to a saturated aqueous NH4Cl solution. The aqueous solution was extracted with EtOAc. The combined organic extract was washed with brine, dried (Na2SO4), filtered, and concentrated. Purification by Gilson reverse phase chromatography (eluant: CH3CN—H2O) gave 180 mg (74% yield) of the product 342 as a white solid. MS (M+1): 621.
Step 240:




To a solution of bromosulfonamide 342 (160 mg, 0.26 mmol) in THF/HMPA (2 mL/0.4 mL) at −78° C. was added KN(TMS)2 (1.55 mL, 0.77 mmol) over 2 mins. After stirring for 30 mins, the reaction mixture was raised to room temperature and stirred over night. Saturated aqueous NH4Cl solution was then added, and the aqueous solution was extracted with EtOAc. The combined organic extract was washed with brine, dried (Na2SO4), filtered, and concentrated. Purification by Gilson reverse phase chromatography (eluant: CH3CN—H2O) gave 10 mg (7.4% yield) of the product 343 as a solid. MS (M+1): 539.
Scheme 74




Step 241:

A mixture of 2-(3-chlorophenyl)-5-(4-(3-iodobenzylsulfonyl)piperazin-1-yl)-4-((1-methylcyclopropyl)methoxy)pyridazin-3(2H)-one 344 (100 mg, 0.153 mmol), methylsulfonyl sodium (19 mg, 0.18 mmol), copper iodide (6 mg, 0.03 mmole), L-proline (7.0 mg, 0.06 mmole) and sodium hydroxide (3 mg, 0.06 mmole) in anhydrous DMSO (0.5 mL) was heated at 90° C. under nitrogen for 17 h. The cooled mixture was diluted with ethyl acetate (200 mL), washed with brine (300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by preparatory TLC (Analtech silica gel GF, 200 microns) eluting with methylene chloride/methanol (19:1), to provide 21.8 mg (24% yield) of the product 345 as a white solid: MS (M+1): m/e 607.




Step 242:





Compound 346 can be synthesized according to Scheme 64.
A mixture of 3-[(4-(1-(3-chlorophenyl]-5-[(1-methylcyclopropyl)methoxy-6-oxo-1,6-dihydropyridazin-4-yl)piperazin-1-ylsulfonyl)methyl]benzonitrile 346 (100 mg, 0.180 mmol), sodium azide (36.6 mg, 0.564 mmol) and triethylamine hydrochloride (74.5 mg, 0.541 mmol) in anhydrous toluene (1 mL) was heated at 90° C. under nitrogen for 16 h. The cooled mixture was diluted with brine (100 mL), extracted with ethyl acetate (150 mL) dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by CombiFlash Companion (40-g silica gel cartridge), eluting with methylene chloride/methanol (19:1 to 3:1), to provide 44 mg (41% yield) of the product 347 as a yellow solid: MS (M+1): m/e 597.
Step 243:




A mixture of 3-[(4-(1-(3-chlorophenyl]-5-[(1-methylcyclopropyl)methoxy-6-oxo-1,6-dihydropyridazin-4-yl)piperazin-1-ylsulfonyl)methyl]benzonitrile 346 (100 mg, 0.180 mmol), hydroxylamine hydrochloride (56.0 mg, 0.80 mmol), and sodium carbonate (84.0 mg, 1.01 mmol) in a biphasic mixture of water, (3 mL), methylene chloride (1 mL), and ethanol (9 mL) was heated at reflux under nitrogen for 19 h. The cooled suspension was diluted with water (100 mL), extracted with methylene chloride (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to provide a clear oil, which was triturated with diethyl ether (20 mL). The resulting solids were collected under reduced pressure to provide 130 mg (64% yield) of the product 348 as a yellow solid: MS (M+1): m/e 587.
Using the procedures described above, the following compound was synthesized.












Cmpd.

MS


No
Structure
M + 1







2021Z




587













Step 244:





A solution of benzylsulfonyl chloride (210 mg, 1.1 mmol) in methylene chloride (0.5 mL) was added dropwise to a mixture of (+/−)-tert-butyl 3-(hydroxymethyl)piperazine-1-carboxylate 349 (216 mg, 1.0 mmol) and diisopropylethylamine (0.35 mL, 2.0 mmol) in methylene chloride (1.0 mL) at 0° C. under nitrogen, after which the mixture was slowly warmed to room temperature, stirring for a total of 2 h. The solvent was concentrated, and the residue was purified by CombiFlash Companion (12-g silica gel cartridge), eluting with ethyl acetate/hexanes (1:19 to 1:1), to provide 102 mg (28% yield) of the product 350 as a white solid.
Step 245:




A solution of (+/−)-tert-butyl 4-(benzylsulfonyl)-3-(hydroxymethyl)piperazine-1-carboxylate 350 (222 mg, 0.60 mmol) and (cyanomethylene)tributylphosphorane (0.30 g, 1.24 mmol) in toluene (5 mL) was heated at 105° C. under nitrogen for 16 h. The solvents were removed from the cooled mixture under reduced pressure, and the residue was purified by CombiFlash Companion (12-g silica gel cartridge), eluting with ethyl acetate/hexanes (100% hexanes to 1:1), to provide 162 mg (77% yield) of the product 351 as a light brown oil.
Step 246:




Solid (+/−)-bicyclic sulfonamide 351 (75 mg, 0.21 mmol) was treated with hydrochloric acid (2 mL, 8 mmol, 4 N in dioxane), and the mixture was stirred at room temperature for 2 h. The thick suspension was dissolved in methanol (25 mL), and the solvents were removed under reduced pressure to provide 63 mg (100% yield) of the product 352 as an off-white solid.
Step 247:




Diisopropylethylamine (0.11 mL, 0.63 mmol) was added to a mixture of 4,5-dichloro-2-(3-chlorophenyl)pyridazin-3(2H)-one (57 mg, 0.21 mmol) and (+/−)-bicyclic sulfonamide hydrochloride 352 (60 mg, 0.21 mmol) in DMF (0.5 mL) at room temperature under nitrogen, and the mixture was heated at 95° C. for 17 h. The cooled mixture was diluted with ethyl acetate (15 mL), washed with brine (3×15 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by CombiFlash Companion (4-g silica gel cartridge), eluting with ethyl acetate/hexanes (1:19 to 1:1), to provide 61 mg (59% yield) of the product 353 as a tan solid: MS (M+1): m/e 491.
Step 248:




A solution of (1-methylcyclopropyl)methanol (20 mg, 0.23 mmol) and sodium hexamethyldisilazide (0.17 mL, 0.17 mmol, 1 N in THF) combined in THF (1 mL) was added dropwise to a solution of (+/−)-bicyclic sulfonamide pyridazinone 353 (55 mg, 0.11 mmol) dissolved in THF (1 mL) at room temperature under nitrogen. The mixture was heated at reflux for 6 h then cooled to room temperature and concentrated. The residue was purified by CombiFlash Companion (12-g silica gel cartridge), elating with ethyl acetate/hexanes (1:19 to 1:1), to provide 17 mg (28% yield) of the product 354 as an off-white solid: MS (M+1) m/e 541.




Step 249:





A solution of benzylsulfonyl chloride (458 mg, 2.4 mmol) in methylene chloride (5 mL) was added dropwise to a mixture of (+/−)-tert-butyl 3-(2-methoxy-2-oxoethyl)piperazine-1-carboxylate 355 (517 mg, 2.0 mmol) and diisopropylethylamine (0.52 mL, 3.0 mmol) in methylene chloride (10.0 mL) at 0° C. under nitrogen after which the mixture was slowly warmed to room temperature, stirring for a total of 5 days. The solvents were removed under reduced pressure, and the residue was purified by CombiFlash Companion (40-g silica gel cartridge), eluting with ethyl acetate/hexanes (100% hexanes to 2:3), to provide 450 mg (55% yield) of the product 356 as a white foam.
Step 250:




A mixture of (+/−)-tert-butyl 4-(benzylsulfonyl)-3-(2-methoxy-2-oxoethyl)piperazine-1-carboxylate 356 (1.29 g, 3.12 mmol) and sodium borohydride in THF (25 mL) was heated at reflux under nitrogen, after which methanol (0.75 mL) was added in small portions over 1 h. The resulting mixture was heated at reflux for an additional 4 h, after which the cooled mixture was diluted with brine (15 mL) and aqueous HCl (40 mL, 0.1 N). The mixture was extracted with ethyl acetate (10 mL), washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by CombiFlash Companion (80-g silica gel cartridge), eluting with ethyl acetate/hexanes (1:9 hexanes to 1:1), to provide 0.95 g (79% yield) of the product 357 as a colorless viscous oil.
Steps 245-248 from Scheme 76:




Using the procedures described above, compound 358 was synthesized. MS (M+1): m/e 555.







Step 251:





BH3.SMe2 (1.65 ml, 16.5 mmol) was added dropwise to a solution of 1,3-phenylenediacetic acid 359 (0.80 g, 4.12 mmol) in THF (20 mL) at room temperature followed by heating at 75° C. for 3. After cooling, the reaction mixture was diluted with EtOAc (20 mL) and treated with saturated aq. NH4Cl. The organic phase was separated, and the aqueous solution was extracted with EtOAc (20 mL). The combined organic phase was washed with sat. NaHCO3, dried (MgSO4), filtered, and concentrated. The crude product was purified on a silica-gel column (eluant: 5:1 to 1:1 CH2Cl2/EtOAc gradient) to afford 0.53 g (78% yield) of the product 360 as a white solid.
Step 252:




Sodium hydride (0.13 mg, 3.2 mmol) was added to a solution of 1,3-diphenylenediethanol 360 (0.53 g, 3.2 mmol) in THF at 0° C. followed by stirring for 15 mins. To the above mixture was added compound 361 (0.54 g, 1.5 mmol), and the reaction was heated for 1 h at 60° C. The reaction mixture was cooled, concentrated, and purified by chromatography on a silica-gel column (eluant: 2:1 CH2Cl2/EtOAc mixed with 2 M ammonia in 5-20% CH3OH gradient) to afford 0.41 g (60% yield) of the product 362 as a pale yellow solid. MS (M+1): m/e 455.
Step 253:




tBuOH (61 mg, 0.9 mmol) was added dropwise to a solution of ClSO2NCO (127 mg, 0.9 mmol) in CH2Cl2 (10 mL) at 0° C. followed by stirring for 30 mins. The resulting solution was then added to a solution of compound 362 (410 mg, 0.9 mmol) and i-Pr2NEt (174 mg, 1.35 mmol) in CH2Cl2 (10 mL) at 0° C. followed by stirring for 2 h, while temperature was slowly allowed to rise to room temperature. The mixture was concentrated, and the residue was purified by chromatography on a silica-gel column (eluant: 0-60% EtOAc/hexane gradient) to afford 0.30 g (53% yield) of the product 363 as a pale yellow solid. MS (M+1): m/e 634.
Step 254:




Methanesulfonic anhydride (42 mg, 0.24 mmol) was added to a solution of compound 363 (140 mg, 0.22 mmol), DMAP (54 mg, 0.44 mmol) and Et3N in CH2Cl2 (5 mL) at 0° C. After the reaction mixture was warmed to room temperature, the reaction was stirred for 2 h. The solvent was concentrated, and the crude product was purified by Prep Gilson HPLC to afford 0.12 g (92% yield) of the product 364 as a pale yellow solid. MS (M+1): m/e 612.
Step 255:




Compound 364 (52 mg, 0.07 mmol), K2CO3 (39 mg, 0.28 mmol) and DMF (5 mL) were mixed in a microwave reaction vial, which was then capped and heated to 90° C. for 1 ̃2 h in a microwave reactor. The progress of the reaction was monitored by mass spectral data. After the reaction was complete, the mixture was diluted with EtOAc (25 mL) and washed with H2O (20 mL). The organic phase was separated, and the aqueous solution was extracted with EtOAc (20 mL). The organic phase was combined, dried (MgSO4), filtered, and concentrated. The residue was purified by Prep Gilson HPLC to afford 18 mg (42% yield) of the product 365 as a pale yellow solid. MS (M+1): m/e 616.
Step 256:




Compound 365 (18 mg, 0.03 mmol) and THF/H2O (4 mL, 3:1) was mixed in a microwave reaction vial, which was then capped and heated at 145° C. for 20 mins in a microwave reactor. After cooling, the reaction mixture was concentrated and purified on a silica-gel column (eluant: 0-35% EtOAc/hexane gradient) to afford 12 mg (80% yield) of the product 366 as a pale yellow solid. MS (M+1): m/e 516.







Step 257:





Compound 361 (1.06 g, 2.9 mmol) dissolved in CH2Cl2 (20 mL) was mixed with diisopropylethylamine (0.6 mL) at 0° C. 4-Pyridylmethanesulfonyl chloride TfOH (1.0 g 2.9 mmol) was added. The mixture was stirred at room temperature overnight then diluted with ethyl acetate (100 mL). The organic solution was washed with water then brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by flash chromatography gave 0.81 g (59% yield) of the product 367 as a solid. MS (M+1): m/e 480.
Step 258:




Compound 367 (0.1 g, 0.21 mmol) and 4-pentyn-1-ol (0.06 mL, 0.63 mmol) in dry THF (3 mL) were mixed with 60% NaH (12 mg, 0.3 mmol). The mixture was stirred at room temperature for 2 h then diluted with ethyl acetate. The organic solution washed with water then brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by flash chromatography gave 0.081 g (73% yield) of the product 368 as a solid. MS (M+1): m/e 528.
Step 259:




Compound 368 (90 mg, 0.17 mmol) in dry THF (5 mL) was mixed with TCNEO (tetracyanoethylene oxide, 0.1 g). The resulting mixture was then stirred at room temperature overnight then concentrated. Purification by prep Gilson HPLC gave 62 mg (62% yield) of the product 369 as a bright yellow solid. MS (M+1): m/e 592.
Step 260:




Compound 369 (20 mg, 0.034 mmol) in 3 mL of toluene and 0.5 mL of acetonitrile was heated to 180° C. for 15 mins in a microwave reactor. The mixture was concentrated and then purified by prep Gilson HPLC to give 9.5 mg (50% yield) of the product 370. MS (M+1): m/e 565.
Using the procedure above, the following compound was synthesized.














MS


Cmpd.
Structure
M + 1







2022Z




509













Step 261:





Compound 371 (2.15 g, 15 mmol) was mixed with triphenylphosphine (5.24 g, 20 mmol) and thioacetic acid (1.2 mL, 16 mmol) in dry THF (20 mL). DIAD (diisopropyl azodicarboxylate, 3.9 mL, 20 mmol) was added at 0° C. The mixture was stirred at room temperature for 6 h and then concentrated. Purification by flash chromatography gave 1.9 g (63% yield) of the product 372 as a solid. MS (M+1): m/e 202.
Step 262:




Compound 372 (0.35 g, 1.7 mmol) was mixed with water (0.09 mL, 5 mmol) and trifluoromethanesulfonic acid (0.3 mL, 3.4 mmol) in CH2Cl2 (15 mL) and cooled to 0° C. Chlorine gas was bubbled into the solution for 5 mins. The yellow solution was stirred at 0° C. for 1 h. Dry diethyl ether and hexane were added to the mixture, which was immediately cooled to −78° C. A solid formed at the bottom of the solution, and the solvent was decanted. The solid was washed again with cold hexane, cooled to −78° C., and the solvent was decanted to give the sulfonyl chloride product 373 as the triflate salt which was used in the next step immediately.
Step 263:




Compound 373 ( ̃1.7 mmol) at −78° C. was mixed with compound 374 (750 mg, 2 mmol) and diisopropylethylamine (5 mmol) in CH2Cl2 (10 mL). The mixture was stirred at room temperature overnight then diluted with ethyl acetate (100 mL). The organic solution was washed with water then brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by flash chromatography gave 0.26 g (27% yield) of the product 375 as a solid. MS (M+1): m/e 564.
Step 264:




Compound 375 (35 mg) was mixed with palladium acetate (0.5 mg), BINAP (1.5 mg), benzophenone imine (20 mg), and cesium carbonate (100 mg). The mixture was heated to at 90° C. under nitrogen overnight then diluted with EtOAc (50 mL). The organic solution was washed with water then brine, dried, filtered, and concentrated. The crude product 376 was used in the next step without further purification.
Step 265:




Compound 376 was treated with sodium acetate (0.1 g) and hydroxylamine hydrochloride (0.1 g) in methanol (3 mL) at room temperature for 1 h. The mixture was concentrated and then purified by prep Gilson HPLC to give 12 mg of the product 377 as the formate salt. MS (M+1): m/e 545.




Step 266:





N-benzylhydroxymethylpiperazine was prepared according to the reported literature procedure: A. Naylor et al, J. Med. Chem. 1993, 36, 2075-2083. To compound 379 (2.48 g, 12.00 mmol), which was dried just before use by azeotropic distillation with toluene under reduced pressure, dissolved in anhydrous DMF (24 mL) under an argon atmosphere was successively added N,N-diisopropylethylamine (3.15 mL, 17.95 mmol), 4 Å molecular sieves and dichloropyridazinone 378 (1.68 g, 5.98 mmol). The reaction mixture was heated at 100° C. for 23 h. Upon cooling to room temperature, the mixture was poured into an aqueous pH 7 phosphate buffer solution (400 mL) and diluted with ethyl acetate (300 mL). After decantation, the aqueous solution was extracted with ethyl acetate (3×350 mL). The combined organic extract was successively washed with water (400 mL) then brine (400 mL), dried (MgSO4), filtered, and concentrated. The crude oil was recrystallized from boiling ethyl acetate (250 mL), filtered and rinsed with cold methylene chloride (70 mL) to give 1.08 g of the product 380 (41% yield) as an off-white solid. MS (M+1): m/e 447.
Step 267:




To chloropyridazinone 380 (100.0 mg, 0.224 mmol) dissolved in ethyl acetate (0.84 mL) and methanol (0.28 mL) at room temperature was added platinum oxide (20.4 mg, 0.090 mmol). A hydrogen atmosphere was introduced using a rubber balloon as the gas source, and the reaction mixture was stirred at room temperature for 6 h. The crude suspension was filtered over a 1⁄4 inch celite pad under a positive pressure of nitrogen, thoroughly rinsed with methanol (50 mL) and concentrated. Purification by silica gel chromatography (eluant: 100% CH2Cl2 to 100% EtOAc gradient) gave 19.6 mg (20% yield) of the product 381 as a pale yellow oil. MS (M+1): m/e 413.
Step 268:




To compound 381 (19.0 mg, 0.045 mmol), dissolved in anhydrous THF (0.45 mL) under an argon atmosphere at 0° C. was added tetrabutylammonium iodide (16.6 mg, 0.045 mmol), followed by 6-bromo-1-hexene (30.1 μL, 0.225 mmol). Sodium hydride was then added (60% dispersion in oil, 3 mg, ca. 0.068 mmol). The milky reaction mixture was then vigorously stirred at room temperature. Additional portions of 6-bromo-1-hexene (30.1 μL, 0.225 mmol) and NaH (60% dispersion in oil, 3 mg, ca. 0.068 mmol) were added until complete consumption of starting material was indicated by TLC and MS. The reaction mixture was diluted with Et2O (30 mL) and carefully quenched with an aqueous pH 7 phosphate buffer solution (20 mL). The aqueous solution was extracted with Et2O (3×30 mL). The combined organic extract was washed successively with an aqueous pH 7 phosphate buffer solution (30 mL) then brine (30 mL), dried (MgSO4), filtered, and concentrated to give 23.7 mg (98% yield) of the product 382 as a light yellow oil which was used for the next step without purification. MS (M+1): m/e 495.
Step 269:




To compound 382 (23.7 mg, 0.045 mmol) dissolved in a methanolic solution of formic acid (v/v 5%, 0.45 mL) at room temperature was added 5% palladium over carbon (37.0 mg). The reaction mixture was vigorously stirred for 4 h, after which an additional portion of 5% Pd—C (20 mg) and methanolic solution of formic acid (v/v 5%, 0.1 mL) were added. After 3 h of additional stirring, the crude suspension was filtered over a celite pad under a positive pressure of nitrogen, thoroughly rinsed with methanol (50 mL) and concentrated to give 10.8 mg of crude oil containing the product 383. MS (M+1): m/e 407. This material was used for the next step without purification.
Step 270:




To compound 383 (10.8 mg of crude material from step 269, ca. 0.045 mmol) dissolved in CH2Cl2 (0.25 mL) was successively added triethylamine (10 μL, 0.062 mmol) and α-toluenesulfonyl chloride (7.1 mg, 0.037 mmol) at 0° C. The reaction mixture was stirred at room temperature for 18 h and then concentrated to dryness. Purification by silica gel chromatography (eluant: 100% hexanes to 100% EtOAc gradient) gave 2.8 mg (21% yield over steps 267 and 270 combined) of the product 384 as a white solid. MS (M+1): m/e 561.
Using procedures similar to the ones described above, the following compounds were synthesized.












Cmpd.

MS


No
Structure
M + 1







2023Z




519


 


2024Z




545


 


2025Z




567


 


2026Z




531













Step 266 from Scheme 81:





Using the procedure of step 266 from Scheme 81, compound 386 was synthesized. MS (M+1): m/e 457.
Step 271:




To chloropyridazinone 386 (176 mg, 0.385 mmol) dissolved in dry THF (10 mL) was added sodium hexamethyldisilazide (1.0 M in THF, 2.0 mL, 2.0 mmol). The reaction mixture was stirred at room temperature for 16 h. Saturated NH4Cl (5 mL) and water were added, and the aqueous solution was extracted with CH2Cl2. The organic solution was dried (MgSO4), filtered, and concentrated. Purification by silica gel chromatography (eluant: EtOAc-hexanes gradient) gave 58 mg (36% yield) of the product 387 as a yellow solid. MS (M+1): m/e 421.
Steps 131-132 from Scheme 40:




Using the procedures of steps 131-132 from Scheme 40, compound 389 was synthesized. MS (M+1): m/e 427.
Step 272:




To compound 386 (250 mg, 0.547 mmol) dissolved in CH2Cl2 (20 mL) was added 4 N HCl in dioxane (2 mL, 8 mmol). The reaction mixture was stirred at room temperature for 4 h then concentrated. Additional MeOH and CH2Cl2 were added, and the solution was concentrated again to give 215 mg (100% yield) of the product 390 as the hydrochloride salt as a white solid. MS (M+1): m/e 357.
Step 273:




To compound 390 (108 mg, 0.275 mmol) dissolved in CH2Cl2 (10 mL) was added Hunig's base (0.20 mL, 0.15 g, 1.1 mmol) and isopropylsulfonyl chloride (0.10 mL, 0.13 g, 0.89 mmol). The reaction mixture was stirred at room temperature for 4 h and then water was added. The aqueous solution was extracted with CH2Cl2. The organic solution was dried (MgSO4), filtered, and concentrated to give 156 mg (100% yield) of the product 391 as an orange solid. MS (M+1): m/e 569.
Step 274:




To compound 391 (156 mg, 0.275 mmol) dissolved in dry DMSO (3 mL) was added disodiumsulfide (108 mg, 0.450 mmol). The reaction mixture was stirred at room temperature for 16 h and then water was added. The aqueous solution was extracted with EtOAc. The organic solution was dried (MgSO4), filtered, and concentrated. Purification by silica gel chromatography (eluant: 50% EtOAc in hexanes) gave 30 mg (25% yield) of the product 392 as an oil. MS (M+1): m/e 443.







Step 266 from Scheme 81:





Using the procedure of step 266 from Scheme 81, compound 386 was synthesized. MS (M+1): m/e 457.
Step 275:




To oxalyl chloride (33.0 μL, 0.394 mmol) in anhydrous methylene chloride (0.20 mL) at −78° C. was added dropwise a solution of anhydrous DMSO (58.0 μL, 0.788 mmol) in anhydrous methylene chloride (0.20 mL). After stirring for 10 mins, chloropyridazinone 386 (100.0 mg, 0.197 mmol) suspended in anhydrous methylene chloride (1.00 mL) was added using a canula. After 40 mins additional stirring at −78° C., anhydrous triethylamine (220.0 μL, 1.576 mmol) was added, and the reaction mixture was allowed to warm up to −10° C. over 1 h. The reaction mixture was then quenched with an aqueous pH 7 phosphate buffer solution (20 mL) and diluted with ethyl acetate (30 mL). After decantation, the aqueous solution was extracted with diethyl ether (2×30 mL) and finally once with ethyl acetate (30 mL). The combined organic extract was successively washed with an aqueous pH 7 phosphate buffer solution (40 mL), water (40 mL) and then brine (40 mL), dried (MgSO4), filtered, and concentrated. Purification by silica gel chromatography (eluant: EtOAc-methylene chloride gradient) gave 34.9 mg (39% yield) of the product 393 as a yellow solid. MS (M+1): m/e 455.
Step 276:




To chloropyridazinone 393 (63.5 mg, 0.138 mmol), which was dried just before use by azeotropic distillation with toluene under reduced pressure, dissolved in anhydrous THF (1.20 mL) at −40° C. was added dropwise a solution of methylmagnesium bromide (116.0 μL, 3.0 M in diethyl ether). After 40 mins, the reaction mixture was quenched at −40° C. with an aqueous pH 7 phosphate buffer solution (20 mL) and diluted with ethyl acetate (20 mL). After decantation, the aqueous solution was extracted with ethyl acetate (2×40 mL). The combined organic extract was successively washed with an aqueous pH 7 phosphate buffer solution (40 mL), and then brine (40 mL), dried (MgSO4), filtered, and concentrated. The crude material (82.1 mg, obtained with trace-amount of residual solvents) showed exclusively the product 394 by MS and NMR and was used for the next step without additional purification. MS (M+1): m/e 471
Step 277:




To compound 394 (80.0 mg, ca 0.112 mmol crude), which was dried just before use by azeotropic distillation with toluene under reduced pressure, dissolved in anhydrous THF (111.20 mL) at room temperature was added sodium hydride (4.5 mg, 60% dispersion in oil, 0.112 mmol), followed by palladium acetate (1.3 mg, 0.0056 mmol) and rac-BINAP (3.5 mg, 0.0056 mmol). After stirring for 3 h at room temperature, sodium hydride (2.0 mg, 60% dispersion in oil, 0.050 mmol) was then added, and the mixture was heated to 35° C. for an additional 3 h period. The reaction mixture was quenched with an aqueous pH 7 phosphate buffer solution (20 mL) and diluted with diethyl ether (30 mL). After decantation, the aqueous solution was extracted with diethyl ether (2×30 mL) and finally once with ethyl acetate (40 mL). The combined organic extract was successively washed with an aqueous pH 7 phosphate buffer solution (20 mL), and then brine (20 mL), dried (MgSO4), filtered, and concentrated. Purification by silica gel chromatography (eluant: EtOAc-methylene chloride gradient) gave 49.2 mg of a mixture of alcohol 394 (31% yield based on 393) and the product 395 (40% yield over two steps) as a yellow oil. MS for 395 (M+1): m/e 435. Further purification is possible but the mixture was used as such for the next step.
Step 278:




To compound 395 (48.0 mg of a mixture with 394, 0.098 mmol total), dissolved in dry methylene chloride (0.80 mL) was added TFA (0.14 mL, 1.88 mmol). The reaction mixture was stirred at room temperature for 70 mins and then quenched with a saturated aqueous solution of Na2CO3 (30 mL) and diluted with ethyl acetate (30 mL). The aqueous solution was extracted with ethyl acetate (3×30 mL). The combined organic extract was successively washed with a saturated aqueous solution of Na2CO3 (30 mL) and brine (20 mL), dried (MgSO4), filtered, and concentrated to give 37.7 mg of yellow foam which was used for the next step without purification. MS analysis showed exclusively 396 and the amine corresponding to residual 394. MS for 396 (M+1): m/e 335.
Step 279:




To compound 396 (37.7 mg of mixture, ca 0.090 mmol total), which was dried just before use by azeotropic distillation with toluene under reduced pressure, dissolved in anhydrous CH2Cl2 (0.30 mL) was added dry diisopropylethylamine (0.235 ml, 1.35 mmol), followed by α-tosyl chloride (120.0 mg, 0.63 mmol). The reaction mixture was stirred at room temperature for 48 h, then quenched with an aqueous pH 7 phosphate buffer solution (25 mL) and diluted with diethyl ether (30 mL). After decantation, the aqueous solution was extracted with ethyl acetate (2×35 mL). The combined organic extract was successively washed with an aqueous pH 7 phosphate buffer solution (30 mL), and then brine (30 mL), dried (MgSO4), filtered, and concentrated. Purification by silica gel chromatography (eluant: EtOAc-methylene chloride gradient) gave 7.8 mg (26% yield) of the product 397 as a yellow glass. MS (M+1): m/e 489.







Step 280:





To chloropyridazinone 2 (955.4 mg, 3.47 mmol) and N—BOC hydroxypiperazine 385 (1.50 g, 6.936 mmol) dissolved in anhydrous DMF (13.90 mL) was added 4 Å molecular sieves and dry diisopropylethylamine (1.81 mL, 10.40 mmol). The reaction mixture was heated at 100° C. for 12 h, then cooled down to room temperature, poured onto water (60 mL) and diluted with ethyl acetate (100 mL). After decantation, the aqueous solution was extracted with ethyl acetate (3×120 mL). The combined organic extract was successively washed with water (100 mL), and then brine (100 mL), dried (MgSO4), filtered, and concentrated. Purification by silica gel chromatography (eluant: EtOAc-methylene chloride gradient) gave 1.10 g (70% yield) of the product 398 as a light yellow solid. MS (M+1): m/e 455.
Step 281:




To chloropyridazinone 398 (100.0 mg, 0.210 mmol) dissolved in anhydrous methylene chloride (1.05 mL) at 0° C. was added dry triethylamine (117.0 μL, 0.840 mmol) and methanesulfonyl anhydride (54.9 mg, 0.315 mmol). The reaction mixture was stirred at 0° C. for 30 mins, then quenched with an aqueous pH 7 phosphate buffer solution (20 mL) and diluted with ethyl acetate (20 mL). After decantation, the aqueous solution was extracted with ethyl acetate (2×30 mL). The combined organic extract was successively washed with an aqueous pH 7 phosphate buffer solution (30 mL), and then brine (30 mL), dried (MgSO4), filtered, and concentrated. The crude light tan solid obtained (123.0 mg, ca. 99% yield) showed exclusively the mesylate 399 by MS and NMR. MS (M+1): m/e 533.
Step 282:




To chloropyridazinone 399 (115.0 mg, 0.210 mmol) dissolved in anhydrous toluene (1.50 mL) was added palladium acetate (2.4 mg, 0.011 mmol) and rac-BINAP (6.6 mg, 0.011 mmol), followed by K2CO3 (72.6 mg, 0.525 mmol) and phenethylamine (132 μL, 1.05 mmol). The reaction mixture was stirred at 110° C. for 16 h, then cooled to room temperature, quenched with an aqueous pH 7 phosphate buffer solution (20 mL) and diluted with ethyl acetate (20 mL). After decantation, the aqueous solution was extracted with ethyl acetate (3×20 mL). The combined organic extract was successively washed with an aqueous pH 7 phosphate buffer solution (30 mL), and then brine (30 mL), dried (MgSO4), filtered, and concentrated. Purification by silica gel chromatography (eluant: hexanes-ethyl acetate gradient) gave 30.0 mg of the product 400 (25% yield) as a light tan solid. MS (M+1): m/e 522.
Step 283:




To compound 400 (28.0 mg, 0.051 mmol), dissolved in dry methylene chloride (0.80 mL) was added TFA (0.135 mL, 1.79 mmol). The reaction mixture was stirred at room temperature for 3.5 h, then quenched with a saturated aqueous solution of Na2CO3 (20 mL) and diluted with ethyl acetate (30 mL). The aqueous solution was extracted with ethyl acetate (2×30 mL). The combined organic extract was successively washed with water (20 mL) and brine (20 mL), dried (MgSO4), filtered, and concentrated to give 23.6 mg of yellow foam which was used for the next step without purification. MS and NMR analysis showed exclusively the product 401 (ca. 91% yield from crude). MS (M+1): m/e 422.
Step 284:




To compound 401 (23.5 mg, 0.045 mmol), which was dried just before use by azeotropic distillation with toluene under reduced pressure, dissolved in anhydrous methylene chloride (0.75 mL) was added dry diisopropylethylamine (0.118 mL, 0.675 mmol), followed by isopropylsulfonyl chloride (36.0 μL, 0.315 mmol). The reaction mixture was stirred at room temperature for 48 h, then quenched with an aqueous pH 7 phosphate buffer solution (40 mL) and diluted with diethyl ether (25 mL). After decantation, the aqueous solution was extracted with diethyl ether (3×30 mL) and finally with ethyl acetate (2×50 mL). The combined organic extract was successively washed with an aqueous pH 7 phosphate buffer solution (30 mL), and then brine (40 mL), dried (MgSO4), filtered, and concentrated. Purification by reverse phase HPLC (eluant: H2O-acetonitrile gradient) gave 7.0 mg (28% yield) of the product 402 as a light yellow glass. MS (M+1): m/e 528.
Results of the in vitro fungal enzyme activity assay for representative compounds of Formula I are listed in Table 40:







TABLE 40







Biological Data












IC50 (μg/mL)
IC50 (μg/mL)



Compound
Saccharomyces
Candida



No.
cerevisiae
albicans















1Z
NT
10



7Z
0.34
1.1



11Z
1.2
6.2



19Z
0.081
1.7



25Z
NT
48



30Z
0.4
9



47Z
0.025
0.23



61Z
0.32
1.3



82Z
0.048
0.45



96Z
0.22
0.94



119Z
0.063
0.81



197Z
0.078
1.9



204Z
103
35



208Z
0.11
1.4



214Z
0.75
0.28



227Z
152
152



232Z
2
8.2



240Z
98
98



244Z
0.093
0.41



402Z
0.073
0.38



553Z
0.11
0.21



1402Z
0.02
0.06



974Z
0.13
0.33



1035Z
0.04
0.03



1122Z
0.03
0.03



1267Z
0.11
0.35



738Z
0.04
0.07



801Z
0.01
0.03



808Z
0.03
0.05



1629Z
0.02
0.05



1734Z
0.06
0.13



1574Zq
0.04
0.08



312*
0.06
0.07



1529Z-33
0.01
0.02



1633Z
0.08
0.05



1634Z
0.17
0.11



1529Z-56
0.17
0.06



1574ZI
0.05
0.05



1529Z-150
0.04
0.10



1574Z-82
0.16
0.29



1529Z-180
0.001
0.003



1529Z-182
0.001
0.01



1529Z-185
0.006
0.02



1675Z
0.08
0.20



1529Z-191
0.11
0.02



1712Z
0.08
0.06



1761Z
0.07
0.16



270*
0.03
0.02



1891Z
0.05
0.07



1898Z
0.05
0.06



1743Z
0.07
0.06



2022Z
0.04
0.08



745Z
0.04
0.06



755Z
0.05
0.04



767Z
0.05
0.13



809Z
0.04
0.11



932Z
0.04
0.13



1529Z-6
0.02
0.06



1574Zo
0.03
0.04



1529Z-19
0.04
0.13



1529Z-40
0.03
0.03



1574Zr
0.06
0.13



1529Z-70
0.07
0.08



1529Z-73
0.09
0.19



1951Z
0.06
0.05



1869Z
0.03
0.08



1864Z
0.06
0.05



1529Z-151
0.07
0.09



1529Z-174
0.07
0.10



186*
0.05
0.12



1529Z-190
0.05
0.12



1683Z
0.08
0.07



1870Z
0.03
0.07



1969Z
0.12
0.12



1715Z
0.10
0.31



1529Z-131
0.03
0.06



1904Z
0.06
0.08



971Zbb
0.33
1.6







NT = not tested;



*numbers refer to structures in the reaction Schemes






The compounds listed above can be administered to an animal orally, intravenously, subcutaneously, intrathecally, by inhalation (e.g., to treat fungal infections in the lungs) or topically (e.g. to treat fungal infections of the skin or mucous membranes). Preferably the compound(s) of the invention listed above is administered orally or intravenously, more preferably orally.
For preparing pharmaceutical compositions from the compounds useful in the method of this invention, inert, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories. The powders and tablets may be comprised of from about 0.1 to about 99 percent active ingredient. Suitable solid carriers are known in the art, e.g. magnesium carbonate, magnesium stearate, talc, sugar, lactose. Tablets, powders, cachets and capsules can be used as solid dosage forms suitable for oral administration.
For preparing suppositories, a low melting wax such as a mixture of fatty acid glycerides or cocoa butter is first melted, and the active ingredient is dispersed homogeneously therein as by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool and thereby solidify.
Liquid form preparations include solutions, suspensions and emulsions. As an example may be mentioned water or water-propylene glycol solutions for parenteral injection.
Liquid form preparations may also include solutions for intranasal administration.
Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable carrier, such as an inert compressed gas.
Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration. Such liquid forms include solutions, suspensions and emulsions.
The compounds useful in the method of the invention may also be deliverable transdermally. The transdermal compositions can take the form of creams, lotions, aerosols and/or emulsions and can be included in a transdermal patch of the matrix or reservoir type as are conventional in the art for this purpose.
Preferably, the pharmaceutical preparation is in unit dosage form. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component, e.g., an effective amount to achieve the desired purpose.
The quantity of compound listed above in a unit dose of preparation may be varied or adjusted from about 0.1 mg to 1000 mg, more preferably from about 1 mg to 300 mg, according to the particular application.
The actual dosage employed may be varied depending upon the requirements of the patient and the severity of the condition being treated. Determination of the proper dosage for a particular situation is within the skill of the art. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached. For convenience, the total daily dosage may be divided and administered in portions during the day if desired.
The amount and frequency of administration of the compound listed above useful in the method of the invention will be regulated according to the judgment of the attending clinician considering such factors as age, condition and size of the patient as well as severity of the symptoms being treated. A typical recommended dosage regimen for a compound listed above is oral administration of about 10 mg to 2000 mg/day preferably 10 to 1000 mg/day, in two to four divided doses to provide relief from the fungal infection.
When the invention comprises a combination of one or more compounds listed above and one or more other antifungal agents, the active components may be co-administered simultaneously or sequentially, or a single pharmaceutical composition comprising one or more compounds listed above and one or more other antifungal agents in a pharmaceutically acceptable carrier can be administered. The components of the combination can be administered individually or together in any conventional dosage form such as capsule, tablet, powder, cachet, suspension, solution, suppository, nasal spray, etc. The dosages of the other antifungal agents can be determined from published material, and may range from 1 to 1000 mg per dose. When used in combination, the dosage levels of the individual components are preferably lower than the recommended individual dosages because of the advantageous effect of the combination.
When separate pharmaceutical compositions of compounds listed above and other antifungal agents are to be administered, they can be provided in a kit comprising in a single package, one container comprising one or more compounds of the present invention listed above in a pharmaceutically acceptable carrier, and a separate container comprising one or more other antifungal agents in a pharmaceutically acceptable carrier, with the compounds listed above and the other antifungal agents being present in amounts such that the combination is therapeutically effective. A kit is advantageous for administering a combination when, for example, the components must be administered at different time intervals or when they are in different dosage forms.
While the present invention has been described in conjunction with the specific embodiments set forth above, many alternatives, modifications and variations thereof will be apparent to those of ordinary skill in the art. All such alternatives, modifications and variations are intended to fall within the spirit and scope of the present invention.

## Claims

1. A compound of Formula I:



or a pharmaceutically acceptable salt, or ester thereof, wherein:
 represents a double bond or a single bond, as permitted by the valency requirement, with the proviso that when E is N, the double bond is present and R6 is absent;
A is O or S;
D and E are independently C or N,
provided that when D is carbon, D is substituted with hydrogen, alkyl, —Oalkyl, —Nalkyl or —Salkyl;

R3 is a moiety selected from the group consisting of aryl, arylalkyl, arylalkenyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cyclenyl, cyclenylalkyl, cyclenylalkenyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclenyl, heterocyclenylalkyl, heterocyclenylalkenyl, cycloalkoxylalkyl, cycloalkoxylalkenyl, cycloalkenoxylalkyl, and cycloalkenyoxylalkenyl,
wherein each of said alkyl, alkenyl, aryl, arylalkyl, arylalkenyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cyclenyl, cyclenylalkyl, cyclenylalkenyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclenyl, heterocyclenylalkyl, heterocyclenylalkenyl, arylalkoxylalkyl, arylalkoxylalkenyl, cycloalkoxylalkyl, cycloalkoxylalkenyl, cycloalkenoxylalkyl, cycloalkenyoxylalkenyl can be unsubstituted or substituted with one or more moieties, which can be the same or different, each moiety being independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, halogen, trihaloalkyl, dihaloalkyl, monohaloalkyl, —NR92, —OR9, —SR9, —NO2, —CN, —NR16COR9, —NR16SO2R9, —COR9, —CO2R9, —SO2R9, —CONR9, R16, and —N═C═O;




 or a single bond,
provided that when Y is O, Y—R4 taken together is not alkoxyl of the formula






 wherein —CH2R11 and —OR10 together with the CH to which they are attached, form a heterocyclyl that is substituted with one or more moieties, which can be the same or different , selected from the group consisting of alkyl and aryl, or
wherein R10 is H and R11 is hydroxyl or butylamine;

R4 is alkyl, alkenyl, alkynyl, alkoxyalkyl, alkenyl-O-alkyl, alkoxyalkenyl, alkenyl-O-alkenyl, alkynyl-O-alkyl, hydroxyalkyl, hydroxyalkenyl, alkyl-S-alkyl, alkenyl-S-alkyl, alkyl-S-alkenyl, alkenyl-S-alkenyl, alkyl-SO-alkyl, alkenyl-SO-alkyl, alkyl-SO-alkenyl, alkenyl-SO-alkenyl, alkyl-SO2-alkyl, alkenyl-SO2-alkyl, alkyl-SO2-alkenyl, alkenyl-SO2-alkenyl, alkyl-NR9-alkyl, alkenyl-NR9-alkyl, alkyl-NR9-alkenyl, alkenyl-NR9-alkenyl, alkyl-CO2-alkyl, alkenyl-CO2-alkyl, alkyl-CO2-alkenyl, alkenyl-CO2-alkenyl, alkyl-O2C-alkyl, alkenyl-O2C-alkyl, alkyl-O2C-alkenyl, alkenyl-O2C-alkenyl, alkyl-CO-alkyl, alkenyl-CO-alkyl, alkyl-CO-alkenyl, alkenyl-CO-alkenyl, cycloalkyl, cycloalkylalkyl, spiroheteroaryl, spiroheterocyclenyl, spiroheterocyclyl, spiroheteroarylalkyl, spiroheteroarylalkenyl, spiroheterocyclenylalkyl, spiroheterocyclenylalkenyl, spiroheterocyclylalkyl, spiroheterocyclylalkenyl, spirocycloalkyl, spirocycloalkylalkyl, spirocycloalkylalkenyl, spirocyclenyl, spirocyclenylalkyl, spirocyclenylalkenyl, spiroaryl, spiroarylalkyl, spiroarylalkenyl, alkylcycloalkyl, cyclenyl, cyclenylalkyl, cyclenylalkenyl, aryl, arylalkyl, arylalkenyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heterocyclyl, heterocyclenyl, heterocyclenylalkyl heterocyclenylalkenyl, heterocyclylalkyl, heterocyclylalkenyl, benzofused-cycloalkyl, benzofused-heterocycloalkyl, benzofused-cycloalkylalkyl or benzofused-heterocycloalkylalkyl;
wherein said alkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxyalkoxyalkyl, alkenyl-O-alkyl, alkoxyalkenyl, alkenyl-O-alkenyl, alkynyl-O-alkyl, hydroxyalkyl, hydroxyalkenyl, alkyl-S-alkyl, alkenyl-S-alkyl, alkyl-S-alkenyl, alkenyl-S-alkenyl, alkyl-SO-alkyl, alkenyl-SO-alkyl, alkyl-SO-alkenyl, alkenyl-SO-alkenyl, alkyl-SO2-alkyl, alkenyl-SO2-alkyl, alkyl-SO2-alkenyl, alkenyl-SO2-alkenyl, alkyl-NR9-alkyl, alkenyl-NR9-alkyl, alkyl-NR9-alkenyl, alkenyl-NR9-alkenyl, alkyl-CO2-alkyl, alkenyl-CO2-alkyl, alkyl-CO2-alkenyl, alkenyl-CO2-alkenyl, alkyl-O2C-alkyl, alkenyl-O2C-alkyl, alkyl-O2C-alkenyl, alkenyl-O2C-alkenyl, alkyl-CO-alkyl, alkenyl-CO-alkyl, alkyl-CO-alkenyl, alkenyl-CO-alkenyl, cycloalkyl, cycloalkylalkyl, spiroheteroaryl, spiroheterocyclenyl, spiroheterocyclyl, spiroheteroarylalkyl, spiroheteroarylalkenyl, spiroheterocyclenylalkyl, spiroheterocyclenylalkenyl, spiroheterocyclylalkyl, spiroheterocyclylalkenyl, spirocycloalkyl, spirocycloalkylalkyl, spirocycloalkylalkenyl, spirocyclenyl, spirocyclenylalkyl, spirocyclenylalkenyl, spiroaryl, spiroarylalkyl, spiroarylalkenyl, alkylcycloalkyl, alkylcycloalkylalkyl, cyclenyl, cyclenylalkyl, cyclenylalkenyl, aryl, arylalkyl, arylalkenyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heterocyclyl, heterocyclenyl, heterocyclenylalkyl heterocyclenylalkenyl, heterocyclylalkyl, heterocyclylalkenyl, benzofused-cycloalkyl, benzofused-heterocycloalkyl, benzofused-cycloalkylalkyl or benzofused-heterocycloalkylalkyl can be unsubstituted or substituted with at least one moiety independently selected from the group consisting of alkyl, alkenyl, aryl, OR9, arylalkyl, arylalkenyl, cyclenylalkyl, cyclenylalkenyl, cycloalkylalkyl, cycloalkylalkenyl, alkylCO2alkyl-, halogen, trihaloalkyl, dihaloalkyl, monohaloalkyl, cycloalkyl, cyclenyl, hydroxyalkyl, hydroxyalkenyl, thiohydroxyalkyl, thiohydroxyalkenyl, hydroxyalkenyl, heteroaryl, heteroarylalkyl, heterocyclenyl, heterocyclenylalkyl, heterocyclyl, heterocyclylalkyl, alkoxyalkyl, —CN, —NO2, —OSiR93, —NR16COR9, —OCONR92, —NR16CONR92, —NR16SO2R9, —NR92, —N═C═O,




 —NR16CO2R9, —COR9, —CO2R9, —OCOR9, —SO2R9, —SOR9, —SR9, —SO2N(R9)2 or —CONR9R16, wherein each of said alkyl, alkenyl, aryl, arylalkyl, arylalkenyl, cyclenylalkyl, cyclenylalkenyl, cycloalkylalkyl, cycloalkylalkenyl, halogen, trihaloalkyl, dihaloalkyl, monohaloalkyl, cycloalkyl, cyclenyl, hydroxyalkyl, hydroxyalkenyl, thiohydroxyalkyl, thiohydroxyalkenyl, hydroxyalkenyl, heteroaryl, heteroarylalkyl, heterocyclenyl, heterocyclenylalkyl, heterocyclyl, heterocyclylalkyl, alkoxyalkyl, can be unsubstituted or substituted with one or more moieties which can be the same or different, each moiety being independently selected from R9;
Z is a linker attached at either end of said linker to the parent ring of Formula I,
wherein said linker is selected from the group consisting of:






wherein
n is 1 to 4,
p is 0 to 2,
q is 1 to 3;

R5 is




 wherein each of said




 is attached at one end to Z and at the second end substituted with a moiety, selected from the group consisting of alkyl, alkenyl, cycloalkyl, cyclenyl, aryl, heterocyclyl, heterocyclenyl, cycloalkylalkyl, cyclenylalkyl, arylalkyl, heterocyclylalkyl, heterocyclenylalkyl, heteroarylalkyl, cycloalkylalkenyl, cyclenylalkenyl, arylalkenyl, heterocyclylalkenyl, heterocyclenylalkenyl, heteroarylalkenyl, —OR9 and —NR92, further, wherein each of said alkyl, alkenyl, cycloalkyl, cyclenyl, aryl, heterocyclyl, heterocyclenyl, heteroaryl, cycloalkylalkyl, cyclenylalkyl, arylalkyl, heterocyclylalkyl, heterocyclenylalkyl, heteroarylalkyl, cycloalkylalkenyl, cyclenylalkenyl, arylalkenyl, heterocyclylalkenyl, heterocyclenylalkenyl, or heteroarylalkenyl can be unsubstituted or substituted with one or more moieties, which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, alkenyl, cycloalkyl, —OR9, alkylOR9, alkylCO2R9, alkylNR16COR9, alkylNR16CONR9, alkylSO2R9, alkylCOR9, alkylSO2NR92, alkylNR92, alkylaryl, alkylheteroaryl, alkylSR9, alkylSOR9, —CN, —CO2R9, trihaloalkyl, dihaloalkyl, monohaloalkyl, —NR16COR9, —NR16CONR92, —NR16SO2—R13, —SO2R9, —COR9, —NO2, —SO2NR92, aryl, heteroaryl, —NR92, —SR9, —SOR9, —C(═NOH)—NR13,




or Y—R4 taken together are H, provided that R6 is not H; or Y—R4 taken together are H and R6 is H, provided that when Z is




 R8 is not H;
or Z and R5 taken together is





wherein
r is 1 or 2;
s is 0 or 1;

or —Y—R4, —ZR5 and the carbons to which they are attached form the group




 wherein J is —O—, —S—, or —NR13—;
R6 is H, alkyl, aryl, arylalkyl, arylalkenyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, arylalkoxylalkyl, arylalkoxylalkenyl, arylalkoxyl, cycloalkoxyl, cycloalkoxylalkyl, cycloalkoxylalkenyl, cycloalkylalkoxyl, cycloalkenoxyl, cycloalkenoxylalkyl, cycloalkenyoxylalkenyl, —NR92, —OR9, —NO2, —NR16COR9, —NR16CON(R17)2, —NR16SO2R9, —COR9, —CO2R9, or —CONR9R16;
wherein each of said alkyl, aryl, arylalkyl, arylalkenyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, arylalkoxylalkyl, arylalkoxylalkenyl, arylalkoxyl, cycloalkoxyl, cycloalkoxylalkyl, cycloalkoxylalkenyl, cycloalkylalkoxyl, cycloalkenoxyl, cycloalkenoxylalkyl, cycloalkenyoxylalkenyl can be unsubstituted or substituted with one or more moieties, which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, trihaloalkyl, dihaloalkyl, monohaloalkyl, —NR92, —OR9, —SR9, —NO2, —CN, —NR16COR9, —NR16SO2R9, —COR9, —CO2R9, —SO2R9, —CONR9R16 and —NR16CON(R17)2;
each R7 is independently selected from the group consisting of H and alkyl;
R8 is one or more moieties, which can be the same or different, each being independently selected from the group consisting of H, aryl, arylalkyl, alkyl,




 arylalkenyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cyclenyl, cyclenylalkyl, cyclenylalkenyl, alkenyl, alkynyl, trihaloalkyl, dihaloalkyl, monohaloalkyl, —NR92, —OR9, —SR9, —NR16COR9, —NR16CON(R17)2, —NR16SO2R9, —COR9, —CO2R9, —SO2R9, and —CONR9R16,
wherein each of said aryl, arylalkyl, alkyl, arylalkenyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cyclenyl, cyclenylalkyl, cyclenylalkenyl, alkenyl and alkynyl can be unsubstituted or substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, trihaloalkyl, dihaloalkyl, monohaloalkyl, —NR92, —OR9, —SR9, —NO2, —CN, —NR16COR9, —NR16SO2R9, —COR9, —CO2R9, —SO2R9, —CONR9R16 and —NR16CON(R17)2;
R9 is one or more moieties, which can be the same or different, each moiety being independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, cyclenyl, aryl, heteroalkyl, heterocycloalkyl, heterocyclenyl, heteroaryl, hydroxyalkyl, hydroxyalkenyl, alkylthioalkyl, alkylthioalkenyl, alkenylthioalkyl, alkenylthioalkenyl, alkoxylalkyl, arylalkyl, cycloalkylalkyl, cyclenylalkyl, heterocyclylalkyl, heterocyclenylalkyl, heteroarylalkyl, arylalkenyl, cycloalkyalkenyl, cyclenylalkenyl, heterocyclylalkenyl, heterocyclenylalkenyl, heteroarylalkenyl, alkoxyaryl, trihaloalkyl, trihaloalkenyl, dihaloalkyl, dihaloalkenyl, monohaloalkyl, and monohaloalkenyl,
wherein each of said alkyl, alkenyl, alkynyl, cycloalkyl, cyclenyl, aryl, heterocycloalkyl, heterocyclenyl, heteroaryl, hydroxyalkyl, hydroxyalkenyl, alkoxylalkyl, arylalkyl, cycloalkylalkyl, cyclenylalkyl, heterocyclylalkyl, heterocyclenylalkyl, heteroarylalkyl, arylalkenyl, cycloalkyalkenyl, cyclenylalkenyl, heterocyclylalkenyl, heterocyclenylalkenyl, heteroarylalkenyl, and alkoxyaryl can be unsubstituted or substituted with one or more moieties, which can be the same or different, each moiety being independently selected from the group consisting of halogen, trihaloalkyl, dihaloalkyl, monohaloalkyl, trihaloalkenyl, dihaloalkenyl, monohaloalkenyl, hydroxyl, alkoxy, hydroxyalkyl, —N(R12)2, alkyl, alkynyl , cycloalkyl, alkenyl, cyclenyl, aryl, heteroaryl, heterocycloalkyl, heterocyclenyl, cycloalkylalkyl, cyclenylalkyl, arylalkyl, heteroarylalkyl, heterocycloalkylalkyl, heterocyclenylalkyl, cycloalkylalkenyl, cyclenylalkenyl, arylalkenyl, heteroarylalkenyl, heterocycloalkylalkenyl, heterocyclenylalkenyl, —CN, —NO2, —SO2R17, —C(O)N(R20)2, —CO2R19,




 —NR16—C(O)R19, —NR16CON(R17)2, —NR16SO2R17, trihaloalkoxy, dihaloalkoxy, monohaloalkoxy,





further wherein when two R9 moieties are attached to a N, the two R9 moieties, together with the N to which they are attached, can form a heterocyclyl or heterocyclenyl ring of 4 to 7 members, wherein 1 or 2 of said ring members can be —O—, —S— or —NR18—, provided that there are no heteroatoms adjacent to each other; and wherein the heterocyclyl or heterocyclenyl ring is optionally substituted on 1 or 2 ring carbon atoms by a substituent independently selected from the group consisting of alkyl, alkoxy, —OH and —NR16, or two hydrogen atoms on the same carbon are replaced by ═O;

each R12 is independently selected from the group consisting of H, alkyl, aryl and arylalkyl;
each R13 is independently selected from the group consisting of H, alkyl, aryl, arylalkyl, cycloalkyl and cycloalkylalkyl;
R14 is alkyl or alkoxy;
R15 is aryl, arylalkyl, —N(R13)-aryl, —N(R13)-alkylaryl, —O-aryl or —O-alkylaryl;
R16 is independently selected from the group consisting of H and alkyl;
R17 is alkyl, aryl or arylalkyl;
R18 is H, alkyl, —COOR19, —COR17 or —CON(R17)2;
each R19 is independently selected from the group consisting of H, alkyl and benzyl;
each R20 is independently selected from the group consisting of H, alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, and alkoxyalkyl;
provided that Formula I does not include the compounds of Table A:








TABLE A

2. The compound of claim 1, wherein A is O.

3. The compound of claim 1, wherein D is N.

4. The compound of claim 1, wherein E is C.

5. The compound of claim 1, wherein Y is O.

6. The compound of claim 1, wherein Y is

7. The compound of claim 1, wherein Y is —S—,

8. The compound of claim 1, wherein Y a single bond.

9. The compound of claim 1, wherein Z is

10. The compound of claim 1, wherein R5 is

11. The compound of claim 1, wherein R5 is

12. The compound of claim 1, wherein R5 is

13. The compound of claim 1, wherein E is C and R6 is H.

14. A compound of claim 1 having the structure



wherein R3 is mono- or dihalo-phenyl;
R4 is alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted benzyl, or optionally substituted benzofused cycloalkyl;
R5 is —SO2—, wherein the second end substituent is alkyl, haloalkyl, optionally substituted arylalkyl, or optionally substituted heteroarylalkyl; or —N(R9)2, wherein one R9 is H and the other is optionally substituted arylalkyl or optionally substituted heteroarylalkyl.

15. A compound selected from the group consisting of:




































or a pharmaceutically acceptable salt thereof.

16. A compound selected from the group consisting of


















or a pharmaceutically acceptable salt thereof.

17. A pharmaceutical composition comprising a therapeutically effective amount of at least one compound of claim 1 or a pharmaceutically acceptable salt, or ester thereof, in combination with at least one pharmaceutically acceptable carrier.

18. The pharmaceutical composition according to claim 17, further comprising one or more anti-fungal agents different from the compound of claim 1.

19. The pharmaceutical composition according to claim 18, wherein the one or more anti-fungal agents are selected from the group consisting of azoles, echinocandins, polyenes, allylamines, thiocarbamates, nikkomycins, pradimicins, 5-fluorocytosines, oxaboroles, ciclopiroxolamine, griseofulvin and morpholines.

20. The pharmaceutical composition according to claim 18, wherein the one or more anti-fungal agents are selected from the group consisting of fluconazole, miconazole, itraconazole, voriconazole, posaconazole, caspofungin, micafungin, anidulafungin, amphotericin B, liposomal formulations of amphotericin B, nystatin, terbinafine, tolnaftate, ciclopiroxolamine, griseofulvin and fenpropimorph.