IP Library › Granted Patent US 11,548,893

Granted Patent B2

US 11,548,893 · App. 16/629,882 · Granted Jan 10, 2023

Enantiomerically pure adamantane carboxamides for the treatment of filovirus infection

Inventors: Michael Bruno Plewe (San Diego, CA); Kenneth McCormack (Oceanside, CA); Gregory Henkel (Carlsbad, CA); Nadezda V. Sokolova (San Diego, CA); Eric Brown (Santee, CA); Vidyasagar Reddy Gantla (San Diego, CA)

Assignee: Arisan Therapeutics Inc.

C07D471/10 A61K45/06 C07C235/40 C07D205/12 C07D209/54 C07D211/58 C07D295/192 C07D471/08 C07D487/04

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Quick Facts

Patent No.: US 11,548,893
App. No.: 16/629,882
Granted: Jan 10, 2023
Kind: B2

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Abstract

The compounds of the invention as shown by general structure I, as shown below, are effective in treating filovirus infections. X is selected from the group consisting of O and H; R 1 is selected from (C 6 to C 10 ) aryl and (C 2 to C 9 ) heteroaryl, and R 2 is selected from (C 1 to C 10 ) alkyl, (C 1 to C 10 ) alkenyl, (C 1 to C 10 ) alkynyl, (C 3 to C 10 ) cycloalkyl, and (C 5 to C 10 ) cycloalkenyl, and NR 3a R 3b is defined in the specification. These compounds are effective in treating filovirii infections including Ebolavirus and Marburg virus.

Claims (381)

1. A method of treating infections associated with viruses of the Filoviridae enveloped virus, or any virus expressing filovirus glycoproteins to mediate cell entry comprising administration of a therapeutically effective amount of a compound of Structural Formula I

or a pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier, diluent, or vehicle thereof, wherein:

R 1 is phenyl;

R 2 is selected from the group consisting of (C 1 to C 10 ) alkyl, (C 2 to C 10 ) alkenyl, (C 2 to C 10 ) alkynyl, (C 3 to C 10 ) cycloalkyl, and (C 5 to C 10 ) cycloalkenyl, wherein

each of the said (C 1 to C 10 ) alkyl, (C 2 to C 10 ) alkenyl, (C 2 to C 10 ) alkynyl, (C 3 to C 10 ) cycloalkyl, and (C 5 to C 10 ) cycloalkenyl is optionally substituted with at least one R 8 group;

NR 3a R 3b b is selected from the group consisting of

each R 8 is independently selected from hydrogen, halogen, OH, nitro, CF 3 , —NR 9a R 9b , oxo, (C 1 to C 10 ) alkyl, (C 1 to C 10 ) alkenyl, (C 1 to C 10 ) alkynyl, (C 1 to C 10 ) alkoxy, aryloxy, cyano, (C 3 to C 10 ) cycloalkyl, (C 5 to C 10 ) cycloalkenyl, (C 2 to C 9 ) cycloheteroalkyl, (C 6 to C 10 ) aryl, (C 2 to C 9 ) heteroaryl, (C 6 to C 10 ) arylene, (C 2 to C 9 ) heteroarylene, (C 3 to C 10 ) cycloalkylene, (C 2 to C 10 ) cycloheteroalkylene, —C(O)R 10 , —C(O)NR 9a R 9b , —S(O) m R 10 , —S(O) m NR 9a R 9b , —NR 9a S(O) m R 10 , —(CH 2 ) n C(O)OR 10 , —(CH 2 ) n C(O)N(R 9a R 9b ), —(CH 2 ) n N(R 9a R 9b ), —OC(O)R 15 , —O(CH 2 ) n O—, —NR 9a C(O)R 10 , and —NR 9a C(O)N(R 9a R 9b ), wherein

each of the said (C 1 to C 10 ) alkyl, (C 2 to C 10 ) alkenyl, (C 2 to C 10 ) alkynyl, (C 1 to C 10 ) alkoxy, aryloxy, (C 3 to C 10 ) cycloalkyl, (C 5 to C 10 ) cycloalkenyl, (C 2 to C 10 ) cycloheteroalkyl, (C 6 to C 10 ) aryl, (C 2 to C 9 ) heteroaryl, (C 6 to C 10 ) arylene, (C 2 to C 9 ) heteroarylene, (C 3 to C 10 ) cycloalkylene, and (C 2 to C 10 ) cycloheteroalkylene is optionally substituted with at least one R 11 group;

each of the R 9a and R 9b is independently selected from hydrogen, (C 1 to C 10 ) alkyl, (C 2 to C 10 ) alkenyl, (C 2 to C 10 ) alkynyl, (C 1 to C 10 ) alkoxy, aryloxy, (C 3 to C 10 ) cycloalkyl, (C 5 to C 10 ) cycloalkenyl, (C 2 to C 5 ) cycloheteroalkyl, (C 6 to C 10 ) aryl, (C 2 to C 9 ) heteroaryl, (C 6 to C 10 ) arylene, and (C 2 to C 9 ) heteroarylene, wherein

each of the said (C 1 to C 10 ) alkyl, (C 2 to C 10 ) alkenyl, (C 2 to C 10 ) alkynyl, (C 1 to C 10 ) alkoxy, aryloxy, (C 3 to C 10 ) cycloalkyl, (C 5 to C 10 ) cycloalkenyl, (C 2 to C 10 ) cycloheteroalkyl, (C 6 to C 10 ) aryl, (C 2 to C 9 ) heteroaryl, (C 6 to C 10 ) arylene, and (C 2 to C 9 ) heteroarylene is optionally substituted with at least one R 11 group,

or R 9a and R 9b may be taken together with the nitrogen atom to which they are attached to form a (C 2 to C 10 ) cycloheteroalkyl ring, wherein

said (C 2 to C 10 ) cycloheteroalkyl ring has 1 to 3 ring heteroatoms selected from the group consisting of N, O, and S, and wherein the said (C 2 to C 10 ) cycloheteroalkyl ring is optionally substituted with at least one R 11 group;

each R 10 is independently selected from hydrogen, (C 1 to C 10 ) alkyl, (C 2 to C 10 ) alkenyl, (C 2 to C 10 ) alkynyl, (C 3 to C 10 ) cycloalkyl, (C 5 to C 10 ) cycloalkenyl, (C 2 to C 10 ) cycloheteroalkyl, (C 6 to C 10 ) aryl, and (C 2 to C 9 ) heteroaryl, wherein

each of the said (C 1 to C 10 ) alkyl, (C 2 to C 10 ) alkenyl, (C 2 to C 10 ) alkynyl, (C 3 to C 10 ) cycloalkyl, (C 5 to C 10 ) cycloalkenyl, (C 2 to C 10 ) cycloheteroalkyl, (C 6 to C 10 ) aryl, and (C 2 to C 9 ) heteroaryl is optionally substituted with at least one R 11 group;

each R 4 is independently selected from hydrogen, (C 1 to C 10 ) alkyl, (C 1 to C 10 ) alkenyl, (C 1 to C 10 ) alkynyl, (C 1 to C 10 ) alkoxy, aryloxy, (C 3 to C 10 ) cycloalkyl, (C 5 to C 10 ) cycloalkenyl, (C 2 to C 9 ) cycloheteroalkyl, (C 6 to C 10 ) aryl, (C 2 to C 9 ) heteroaryl, (C 6 to C 10 ) arylene, and (C 2 to C 9 ) heteroarylene, wherein

each of the said (C 1 to C 10 ) alkyl, (C 2 to C 10 ) alkenyl, (C 2 to C 10 ) alkynyl, (C 1 to C 10 ) alkoxy, aryloxy, (C 3 to C 10 ) cycloalkyl, (C 5 to C 10 ) cycloalkenyl, (C 2 to C 10 ) cycloheteroalkyl, (C 2 to C 9 ) heteroaryl, (C 6 to C 10 ) aryl, (C 6 to C 10 ) arylene, (C 2 to C 9 ) heteroarylene, (C 3 to C 10 ) cycloalkylene, and (C 2 to C 10 ) cycloheteroalkylene is optionally substituted with at least one R 14 group;

each of the R 12a and R 12b is independently selected from hydrogen, (C 1 to C 10 ) alkyl, (C 2 to C 10 ) alkenyl, (C 2 to C 10 ) alkynyl, (C 1 to C 10 ) alkoxy, aryloxy, (C 3 to C 10 ) cycloalkyl, (C 5 to C 10 ) cycloalkenyl, (C 2 to C 10 ) cycloheteroalkyl, (C 6 to C 10 ) aryl, (C 2 to C 9 ) heteroaryl, (C 6 to C 10 ) arylene, and (C 2 to C 9 ) heteroarylene, wherein

each of the said (C 1 to C 10 ) alkyl, (C 2 to C 10 ) alkenyl, (C 2 to C 10 ) alkynyl, (C 1 to C 10 ) alkoxy, aryloxy, (C 3 to C 10 ) cycloalkyl, (C 5 to C 10 ) cycloalkenyl, (C 2 to C 10 ) cycloheteroalkyl, (C 6 to C 10 ) aryl, (C 2 to C 9 ) heteroaryl, (C 6 to C 10 ) arylene, and (C 2 to C 9 ) heteroarylene is optionally substituted with at least one R 14 group,

or R 12a and R 12b may be taken together with the nitrogen atom to which they are attached to form a (C 2 to C 10 ) cycloheteroalkyl ring, wherein

said (C 2 to C 10 ) cycloheteroalkyl ring has 1 to 3 ring heteroatoms selected from the group consisting of N, O, and S, and wherein

the said (C 2 to C 10 ) cycloheteroalkyl ring is optionally substituted with at least one R 14 group;

each R 13 is independently selected from hydrogen, halogen, OH, nitro, CF 3 , (C 1 to C 10 ) alkyl, (C 2 to C 10 ) alkenyl, (C 2 to C 10 ) alkynyl, (C 1 to C 10 ) alkoxy, aryloxy, cyano, (C 3 to C 10 ) cycloalkyl, (C 5 to C 10 ) cycloalkenyl, (C 2 to C 10 ) cycloheteroalkyl, (C 6 to C 10 ) aryl, and (C 2 to C 9 ) heteroaryl, wherein

each of the said (C 1 to C 10 ) alkyl, (C 2 to C 10 ) alkenyl, (C 2 to C 10 ) alkynyl, (C 3 to C 10 ) cycloalkyl, (C 5 to C 10 ) cycloalkenyl, (C 2 to C 10 ) cycloheteroalkyl, (C 2 to C 9 ) heteroaryl, and (C 5 to C 10 ) aryl is optionally substituted with at least one R 14 group; each R 4 is independently selected from hydrogen, (C 1 to C 10 ) alkyl, (C 1 to C 10 ) alkenyl, (C 1 to C 10 ) alkynyl, (C 1 to C 10 ) alkoxy, aryloxy, (C 3 to C 10 ) cycloalkyl, (C 5 to C 10 ) cycloalkenyl, (C 2 to C 9 ) cycloheteroalkyl, (C 6 to C 10 ) aryl, (C 2 to C 9 ) heteroaryl, (C 6 to C 10 ) arylene, and (C 2 to C 9 ) heteroarylene, wherein

each of the R 16a and R 16b is independently selected from hydrogen, (C 1 to C 10 ) alkyl, (C 2 to C 10 ) alkenyl, (C 2 to C 10 ) alkynyl, (C 1 to C 10 ) alkoxy, aryloxy, (C 3 to C 10 ) cycloalkyl, (C 5 to C 10 ) cycloalkenyl, (C 2 to C 10 ) cycloheteroalkyl, (C 6 to C 10 ) aryl, and (C 2 to C 9 ) heteroaryl, wherein

or R 16a and R 16b may be taken together with the nitrogen atom to which they are attached to form a (C 2 to C 10 ) cycloheteroalkyl ring, wherein

each R 16 is independently selected from hydrogen, halogen, OH, nitro, CF 3 , (C 1 to C 10 ) alkyl, (C 2 to C 10 ) alkenyl, (C 2 to C 10 ) alkynyl, (C 1 to C 10 ) alkoxy, aryloxy, cyano, (C 3 to C 10 ) cycloalkyl, (C 5 to C 10 ) cycloalkenyl, (C 2 to C 10 ) cycloheteroalkyl, (C 6 to C 10 ) aryl, and (C 2 to C 9 ) heteroaryl; each R 4 is independently selected from hydrogen, (C 1 to C 10 ) alkyl, (C 1 to C 10 ) alkenyl, (C 1 to C 10 ) alkynyl, (C 1 to C 10 ) alkoxy, aryloxy, (C 3 to C 10 ) cycloalkyl, (C 5 to C 10 ) cycloalkenyl, (C 2 to C 9 ) cycloheteroalkyl, (C 6 to C 10 ) aryl, (C 2 to C 9 ) heteroaryl, (C 6 to C 10 ) arylene, and (C 2 to C 9 ) heteroarylene, wherein

each of the R 18a and R 18b is independently selected from hydrogen, (C 1 to C 10 ) alkyl, (C 2 to C 10 ) alkenyl, (C 2 to C 10 ) alkynyl, (C 3 to C 10 ) cycloalkyl, (C 5 to C 10 ) cycloalkenyl, (C 2 to C 10 ) cycloheteroalkyl, (C 2 to C 9 ) heteroaryl, and (C 5 to C 10 ) aryl;

each R 19 is independently selected from hydrogen, halogen, OH, nitro, CF 3 , (C 1 to C 10 ) alkyl, (C 2 to C 10 ) alkenyl, (C 2 to C 10 ) alkynyl, (C 1 to C 10 ) alkoxy, aryloxy, cyano, (C 3 to C 10 ) cycloalkyl, (C 5 to C 10 ) cycloalkenyl, (C 2 to C 10 ) cycloheteroalkyl, (C 6 to C 10 ) aryl, (C 2 to C 9 ) heteroaryl;

each R 20 is independently selected from hydrogen, halogen, OH, nitro, CF 3 , —NR 21a R 21b , oxo, (C 1 to C 10 ) alkyl, (C 1 to C 10 ) alkenyl, (C 1 to C 10 ) alkynyl, (C 1 to C 10 ) alkoxy, aryloxy, cyano, (C 3 to C 10 ) cycloalkyl, (C 5 to C 10 ) cycloalkenyl, (C 2 to C 10 ) cycloheteroalkyl, (C 6 to C 10 ) aryl, (C 2 to C 9 ) heteroaryl, (C 6 to C 10 ) arylene, (C 2 to C 9 ) heteroarylene, (C 3 to C 10 ) cycloalkylene, (C 2 to C 10 ) cycloheteroalkylene, —C(O)R 22 , —C(O)NR 21a R 21b , —S(O) m R 22 , —S(O) m NR 21a R 21b , —NR 21a S(O) m R 22 , —(CH 2 ) n C(O)OR 22 , —(CH 2 ) n C(O)N(R 21a R 21b ), —(CH 2 ) n N(R 21a R 21b ), —OC(O)R 22 , —NR 21a C(O)R 22 , and —NR 21a C(O)N(R 21a R 21b ), wherein

each of the R 21a and R 21b is independently selected from hydrogen, (C 1 to C 10 ) alkyl, (C 2 to C 10 ) alkenyl, (C 2 to C 10 ) alkynyl, (C 1 to C 10 ) alkoxy, aryloxy, (C 3 to C 10 ) cycloalkyl, (C 5 to C 10 ) cycloalkenyl, (C 2 to C 10 ) cycloheteroalkyl, (C 6 to C 10 ) aryl, and (C 2 to C 9 ) heteroaryl,

or R 21a and R 21b may be taken together with the nitrogen atom to which they are attached to form a (C 2 to C 10 ) cycloheteroalkyl ring, wherein

said (C 2 to C 10 ) cycloheteroalkyl ring has 1 to 3 ring heteroatoms selected from the group consisting of N, O, and S;

each R 22 is independently selected from hydrogen, halogen, OH, nitro, CF 3 , (C 1 to C 10 ) alkyl, (C 2 to C 10 ) alkenyl, (C 2 to C 10 ) alkynyl, (C 1 to C 10 ) alkoxy, aryloxy, cyano, (C 3 to C 10 ) cycloalkyl, (C 5 to C 10 ) cycloalkenyl, (C 2 to C 10 ) cycloheteroalkyl, (C 6 to C 10 ) aryl, and (C 2 to C 9 ) heteroaryl;

i is 2, 3, 4, 5, or 6;

j is 0, 1, 2, 3, 4, or 5;

k is 1, 2, 3, 4, or 5;

m is 0, 1 or 2;

n is 0, 1, 2, 3, or 4.

2. The method of claim 1 , wherein

R 2 is selected from the group consisting of methyl, ethyl, propyl, fluoromethyl, ethoxymethyl, chloroethyl, and fluoroethyl.

3. The method of claim 1 , wherein the infection is associated with filovirus selected from the group consisting of Ebolavirus and Marburgvirus.

4. The method of claim 3 , wherein the filovirus is Ebolavirus.

5. The method of claim 3 , wherein the filovirus is Marburgvirus.

6. The method of claim 3 , including administering a therapeutic amount of a therapeutic agent selected from the group consisting of Ribavirin, viral RNA-dependent-RNA polymerase inhibitors including favipiravir, Triazavirin, and Remdesivir (GS-5734), monoclonal antibody therapies including ZMapp, REGN3470-3471-3479, and mAb 114, vaccines including cAd3-EBOZ, and rVSV-ZEBOV, small interfering RNAs and microRNAs and immunomodulators.

7. The method of claim 4 , including the inhibition of Ebolavirus glycoprotein.

8. The method of claim 5 , including the inhibition of Marburgvirus glycoprotein.

9. A method of treating infections associated with viruses of the Filoviridae enveloped virus, or any virus expressing filovirus glycoproteins to mediate cell entry comprising administration of a therapeutically effective amount of an enantiomerically pure compound of Structural Formula Ia

or a pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier, diluent, or vehicle thereof, wherein:

R 1 is selected from (C 6 to C 10 ) aryl and (C 2 to C 9 ) heteroaryl, wherein

each of the said (C 6 to C 10 ) aryl and (C 2 to C 9 ) heteroaryl is optionally substituted with at least one R 4 group;

R 2 is selected from (C 1 to C 10 ) alkyl, (C 2 to C 10 ) alkenyl, (C 2 to C 10 ) alkynyl, (C 3 to C 10 ) cycloalkyl, and (C 5 to C 10 ) cycloalkenyl, wherein

NR 3a R 3b is selected from the group consisting of

Z is selected from the group consisting of —O—, —S—, —S(O)—, and —S(O) 2 —;

each R 4 is independently selected from hydrogen, (C 1 to C 10 ) alkyl, (C 2 to C 10 ) alkenyl, (C 2 to C 10 ) alkynyl, (C 1 to C 10 ) alkoxy, aryloxy, (C 3 to C 10 ) cycloalkyl, (C 5 to C 10 ) cycloalkenyl, (C 2 to C 9 ) cycloheteroalkyl, (C 6 to C 10 ) aryl, (C 2 to C 9 ) heteroaryl, (C 6 to C 10 ) arylene, and (C 2 to C 9 ) heteroarylene, wherein

each of the said (C 1 to C 10 ) alkyl, (C 2 to C 10 ) alkenyl, (C 2 to C 10 ) alkynyl, (C 1 to C 10 ) alkoxy, aryloxy, (C 3 to C 10 ) cycloalkyl, (C 5 to C 10 ) cycloalkenyl, (C 2 to C 9 ) cycloheteroalkyl, (C 6 to C 10 ) aryl, (C 2 to C 9 ) heteoaryl, (C 6 to C 10 ) arylene, and (C 2 to C 9 ) heteroarylene is optionally substituted with at least one R 8 group;

each of the R 5a , R 5b , and R 5c is independently selected from hydrogen, halogen, OH, nitro, CF 3 , —NR 6a R 6b , (C 1 to C 10 ) alkyl, (C 2 to C 10 ) alkenyl, (C 2 to C 10 ) alkynyl, (C 1 to C 10 ) alkoxy, aryloxy, cyano, (C 3 to C 10 ) cycloalkyl, (C 5 to C 10 ) cycloalkenyl, (C 2 to C 9 ) cycloheteroalkyl, (C 6 to C 10 ) aryl, (C 2 to C 9 ) heteroaryl, —C(O)R 7 , —C(O)NR 6a R 6b , —S(O) m R 7 , —S(O) m NR 6a R 6b , —NR 6a S(O) m R 7 , —(CH 2 ) n C(O)OR 7 , —(CH 2 ) n C(O)N(R 6a R 6b ), —(CH 2 ) n N(R 6a R 6b ), —OC(O)R 7 , —NR 6a C(O)R 7 , and —NR 6a C(O)N(R 6a R 6b ), wherein

each of the said (C 1 to C 10 ) alkyl, (C 2 to C 10 ) alkenyl, (C 2 to C 10 ) alkynyl, (C 1 to C 10 ) alkoxy, aryloxy, (C 3 to C 10 ) cycloalkyl, (C 5 to C 10 ) cycloalkenyl, (C 2 to C 9 ) cycloheteroalkyl, (C 6 to C 10 ) aryl, and (C 2 to C 9 ) heteroaryl is optionally substituted with at least one R 8 group;

each of the R 6a and R 6b is independently selected from hydrogen, (C 1 to C 10 ) alkyl, (C 2 to C 10 ) alkenyl, (C 2 to C 10 ) alkynyl, (C 1 to C 10 ) alkoxy, aryloxy, (C 3 to C 10 ) cycloalkyl, (C 5 to C 10 ) cycloalkenyl, (C 2 to C 9 ) cycloheteroalkyl, (C 6 to C 10 ) aryl, (C 2 to C 9 ) heteroaryl, (C 6 to C 10 ) arylene, and (C 2 to C 9 ) heteroarylene, wherein

each of the said (C 1 to C 10 ) alkyl, (C 2 to C 10 ) alkenyl, (C 2 to C 10 ) alkynyl, (C 1 to C 10 ) alkoxy, aryloxy, (C 3 to C 10 ) cycloalkyl, (C 5 to C 10 ) cycloalkenyl, (C 2 to C 9 ) cycloheteroalkyl, (C 6 to C 10 ) aryl, (C 2 to C 9 ) heteroaryl, (C 6 to C 10 ) arylene, and (C 2 to C 9 ) heteroarylene is optionally substituted with at least one R 8 group,

or R 6a and R 6b may be taken together with the nitrogen atom to which they are attached to form a (C 2 to C 10 ) cycloheteroalkyl ring, wherein

said (C 2 to C 10 ) cycloheteroalkyl ring has 1 to 3 ring heteroatoms selected from the group consisting of N, O, and S, and wherein

the said (C 2 to C 10 ) cycloheteroalkyl ring is optionally substituted with at least one R 8 group;

each of the R 7 is independently selected from hydrogen, (C 1 to C 10 ) alkyl, (C 2 to C 10 ) alkenyl, (C 2 to C 10 ) alkynyl, (C 3 to C 10 ) cycloalkyl, (C 5 to C 10 ) cycloalkenyl, (C 2 to C 9 ) cycloheteroalkyl, (C 6 to C 10 ) aryl, and (C 2 to C 9 ) heteroaryl, wherein

each of the said (C 1 to C 10 ) alkyl, (C 2 to C 10 ) alkenyl, (C 2 to C 10 ) alkynyl, (C 3 to C 10 ) cycloalkyl, (C 5 to C 10 ) cycloalkenyl, (C 2 to C 9 ) cycloheteroalkyl, (C 6 to C 10 ) aryl, and (C 2 to C 9 ) heteroaryl is optionally substituted with at least one R 8 group;

each R 8 is independently selected from hydrogen, halogen, OH, nitro, CF 3 , —NR 9a R 9b , oxo, (C 1 to C 10 ) alkyl, (C 2 to C 10 ) alkenyl, (C 2 to C 10 ) alkynyl, (C 1 to C 10 ) alkoxy, aryloxy, cyano, (C 3 to C 10 ) cycloalkyl, (C 5 to C 10 ) cycloalkenyl, (C 2 to C 9 ) cycloheteroalkyl, (C 6 to C 10 ) aryl, (C 2 to C 9 ) heteroaryl, (C 6 to C 10 ) arylene, (C 2 to C 9 ) heteroarylene, (C 3 to C 10 ) cycloalkylene, (C 2 to C 10 ) cycloheteroalkylene, —C(O)R 10 , —C(O)NR 9a R 9b , —S(O) m R 10 , —S(O) m NR 9a R 9b , —NR 9a S(O) m R 10 , —(CH 2 ) n C(O)OR 10 , —(CH 2 ) n C(O)N(R 9a R 9b ), —(CH 2 ) n N(R 9a R 9b ), —OC(O)R 15 , —O(CH 2 ) n O—, —NR 9a C(O)R 10 , and —NR 9a C(O)N(R 9a R 9b ), wherein

each of the R 9a and R 9b is independently selected from hydrogen, (C 1 to C 10 ) alkyl, (C 2 to C 10 ) alkenyl, (C 2 to C 10 ) alkynyl, (C 1 to C 10 ) alkoxy, aryloxy, (C 3 to C 10 ) cycloalkyl, (C 5 to C 10 ) cycloalkenyl, (C 2 to C 9 ) cycloheteroalkyl, (C 6 to C 10 ) aryl, (C 2 to C 9 ) heteroaryl, (C 6 to C 10 ) arylene, and (C 2 to C 9 ) heteroarylene, wherein

each of the said (C 1 to C 10 ) alkyl, (C 2 to C 10 ) alkenyl, (C 2 to C 10 ) alkynyl, (C 1 to C 10 ) alkoxy, aryloxy, (C 3 to C 10 ) cycloalkyl, (C 5 to C 10 ) cycloalkenyl, (C 2 to C 10 ) cycloheteroalkyl, (C 6 to C 10 ) aryl, (C 2 to C 9 ) heteroaryl, (C 6 to C 10 ) arylene, and (C 2 to C 9 ) heteroarylene is optionally substituted with at least one R 11 group,

or R 9a and R 9b may be taken together with the nitrogen atom to which they are attached to form a (C 2 to C 10 ) cycloheteroalkyl ring, wherein

said (C 2 to C 10 ) cycloheteroalkyl ring has 1 to 3 ring heteroatoms selected from the group consisting of N, O, and S, and wherein

the said (C 2 to C 10 ) cycloheteroalkyl ring is optionally substituted with at least one R 11 group;

each R 11 is independently selected from hydrogen, halogen, OH, nitro, CF 3 , —NR 12a R 12b , oxo, (C 1 to C 10 ) alkyl, (C 2 to C 10 ) alkenyl, (C 2 to C 10 ) alkynyl, (C 1 to C 10 ) alkoxy, aryloxy, cyano, (C 3 to C 10 ) cycloalkyl, (C 5 to C 10 ) cycloalkenyl, (C 2 to C 10 ) cycloheteroalkyl, (C 6 to C 10 ) aryl, (C 2 to C 9 ) heteroaryl, (C 6 to C 10 ) arylene, (C 2 to C 9 ) heteroarylene, (C 3 to C 10 ) cycloalkylene, (C 2 to C 10 ) cycloheteroalkylene, —C(O)R 10 , —C(O)NR 9a R 9b , —S(O) m R 10 , —S(O) m NR 9a R 9b , —NR 9a S(O) m R 10 , —(CH 2 ) n C(O)OR 10 , —(CH 2 ) n C(O)N(R 9a R 9b ), —(CH 2 ) n N(R 9a R 9b ), —OC(O)R 15 , —O(CH 2 ) n O—, —NR 9a C(O)R 10 , and —NR 9a C(O)N(R 9a R 9b ), wherein

each of the said (C 1 to C 10 ) alkyl, (C 2 to C 10 ) alkenyl, (C 2 to C 10 ) alkynyl, (C 1 to C 10 ) alkoxy, aryloxy, (C 3 to C 10 ) cycloalkyl, (C 5 to C 10 ) cycloalkenyl, (C 2 to C 10 ) cycloheteroalkyl, (C 2 to C 9 ) heteroaryl, (C 6 to C 10 ) aryl, (C 6 to C 10 ) arylene, (C 2 to C 9 ) heteroarylene, (C 3 to C 10 ) cycloalkylene, and (C 2 to C 10 ) cycloheteroalkylene is optionally substituted with at least one R 14 group;

each of the said (C 1 to C 10 ) alkyl, (C 2 to C 10 ) alkenyl, (C 2 to C 10 ) alkynyl, (C 1 to C 10 ) alkoxy, aryloxy, (C 3 to C 10 ) cycloalkyl, (C 5 to C 10 ) cycloalkenyl, (C 2 to C 10 ) cycloheteroalkyl, (C 6 to C 10 ) aryl, (C 2 to C 9 ) heteroaryl, (C 6 to C 10 ) arylene, and (C 2 to C 9 ) heteroarylene is optionally substituted with at least one R 14 group,

or R 12a and R 12b may be taken together with the nitrogen atom to which they are attached to form a (C 2 to C 10 ) cycloheteroalkyl ring, wherein

said (C 2 to C 10 ) cycloheteroalkyl ring has 1 to 3 ring heteroatoms selected from the group consisting of N, O, and S, and wherein

the said (C 2 to C 10 ) cycloheteroalkyl ring is optionally substituted with at least one R 14 group;

each R 14 is independently selected from hydrogen, halogen, OH, nitro, CF 3 , —NR 15a R 15b , oxo, (C 1 to C 10 ) alkyl, (C 1 to C 10 ) alkenyl, (C 1 to C 10 ) alkynyl, (C 1 to C 10 ) alkoxy, aryloxy, cyano, (C 3 to C 10 ) cycloalkyl, (C 5 to C 10 ) cycloalkenyl, (C 2 to C 10 ) cycloheteroalkyl, (C 6 to C 10 ) aryl, (C 2 to C 9 ) heteroaryl, (C 6 to C 10 ) arylene, (C 2 to C 9 ) heteroarylene, (C 3 to C 10 ) cycloalkylene, (C 2 to C 10 ) cycloheteroalkylene, —C(O)R 16 , —C(O)NR 15a R 15b , —S(O) m R 16 , —S(O) m NR 15a R 15b , —NR 15a S(O) m R 16 , —(CH 2 ) n C(O)OR 16 , —(CH 2 ) n C(O)N(R 15a R 15b ), —(CH 2 ) n N(R 15a R 15b ), —OC(O)R 16 , —NR 15a C(O)R 16 , and —NR 15a C(O)N(R 15a R 15b ), wherein

each of the R 15a and R 15b is independently selected from hydrogen, (C 1 to C 10 ) alkyl, (C 2 to C 10 ) alkenyl, (C 2 to C 10 ) alkynyl, (C 1 to C 10 ) alkoxy, aryloxy, (C 3 to C 10 ) cycloalkyl, (C 5 to C 10 ) cycloalkenyl, (C 2 to C 10 ) cycloheteroalkyl, (C 6 to C 10 ) aryl, and (C 2 to C 9 ) heteroaryl, wherein

or R 15a and R 15b may be taken together with the nitrogen atom to which they are attached to form a (C 2 to C 10 ) cycloheteroalkyl ring, wherein

said (C 2 to C 10 ) cycloheteroalkyl ring has 1 to 3 ring heteroatoms selected from the group consisting of N, O, and S, and wherein

the said (C 2 to C 10 ) cycloheteroalkyl ring is optionally substituted with at least one R 17 group;

each R 17 is independently selected from hydrogen, halogen, OH, nitro, CF 3 , —NR 18a R 18b , oxo, (C 1 to C 10 ) alkyl, (C 2 to C 10 ) alkenyl, (C 2 to C 10 ) alkynyl, (C 1 to C 10 ) alkoxy, aryloxy, cyano, (C 3 to C 10 ) cycloalkyl, (C 5 to C 10 ) cycloalkenyl, (C 2 to C 10 ) cycloheteroalkyl, (C 6 to C 10 ) aryl, (C 2 to C 9 ) heteroaryl, (C 6 to C 10 ) arylene, (C 2 to C 9 ) heteroarylene, (C 3 to C 10 ) cycloalkylene, (C 2 to C 10 ) cycloheteroalkylene, —C(O)R 19 , —C(O)NR 18a R 18b , —S(O) m R 19 , —S(O) m NR 18a R 18b , —NR 18a S(O) m R 19 , (CH 2 ) n C(O)OR 19 , —(CH 2 ) n C(O)N(R 18a R 18b ), —(CH 2 ) n N(R 18a R 18b ), —OC(O)R 19 , —NR 18a C(O)R 19 , and —NR 18a C(O)N(R 18a R 18b ), wherein

or R 21a and R 21b may be taken together with the nitrogen atom to which they are attached to form a (C 2 to C 10 ) cycloheteroalkyl ring, wherein

said (C 2 to C 10 ) cycloheteroalkyl ring has 1 to 3 ring heteroatoms selected from the group consisting of N, O, and S;

i is 2, 3, 4, 5, or 6;

j is 0, 1, 2, 3, 4, or 5;

k is 1, 2, 3, 4, or 5;

m is 0, 1 or 2;

n is 0, 1, 2, 3, or 4.

10. The method of claim 9 , wherein R 1 is phenyl.

11. The method of claim 10 , wherein

R 2 is selected from the group consisting of methyl, ethyl, propyl, fluoromethyl, ethoxymethyl, chloroethyl, and fluoroethyl.

12. The method of claim 10 , wherein NR 3a R 3b is selected from the group consisting of

13. The method of claim 9 , wherein the infection is associated with filovirus selected from the group consisting of Ebolavirus and Marburgvirus.

14. The method of claim 13 , wherein the filovirus is Ebolavirus.

15. The method of claim 13 , wherein the filovirus is Marburgvirus.

16. The method of claim 13 , including administering a therapeutic amount of a therapeutic agent selected from the group consisting of Ribavirin, viral RNA-dependent-RNA polymerase inhibitors including favipiravir, Triazavirin, and Remdesivir (GS-5734), monoclonal antibody therapies including ZMapp, REGN3470-3471-3479, and mAb 114, vaccines including cAd3-EBOZ, and rVSV-ZEBOV, small interfering RNAs and microRNAs and immunomodulators.

17. The method of claim 14 , including the inhibition of Ebolavirus glycoprotein.

18. The method of claim 15 , including the inhibition of Marburgvirus glycoprotein.

19. A method of treating infections associated with viruses of the Filoviridae enveloped virus, or any virus expressing filovirus glycoproteins to mediate cell entry comprising administration of a therapeutically effective amount of a compound of Structural Formula Ib

or a pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier, diluent, or vehicle thereof, wherein:

R 1 is selected from (C 6 to C 10 ) aryl and (C 2 to C 9 ) heteroaryl, wherein

each of the said (C 6 to C 10 ) aryl and (C 2 to C 9 ) heteroaryl is optionally substituted with at least one R 4 group;

R 2 is selected from (C 1 to C 10 ) alkyl, (C 2 to C 10 ) alkenyl, (C 2 to C 10 ) alkynyl, (C 3 to C 10 ) cycloalkyl, and (C 5 to C 10 ) cycloalkenyl, wherein

NR 3a R 3b is selected from the group consisting of

Z is selected from the group consisting of —O—, —S—, —S(O)—, and —S(O) 2 —;

each of the R 5a , R 5b , and R 5c is independently selected from hydrogen, halogen, OH, nitro, CF 3 , —NR 6a R 6b , (C 1 to C 10 ) alkyl, (C 1 to C 10 ) alkenyl, (C 1 to C 10 ) alkynyl, (C 1 to C 10 ) alkoxy, aryloxy, cyano, (C 3 to C 10 ) cycloalkyl, (C 5 to C 10 ) cycloalkenyl, (C 2 to C 9 ) cycloheteroalkyl, (C 6 to C 10 ) aryl, (C 2 to C 9 ) heteroaryl, —C(O)R 7 , —C(O)NR 6a R 6b , —S(O) m R 7 , —S(O) m NR 6a R 6b , —NR 6a S(O) m R 7 , —(CH 2 ) n C(O)OR 7 , —(CH 2 ) n C(O)N(R 6a R 6b ), —(CH 2 ) n N(R 6a R 6b ), —OC(O)R 7 , —NR 6a C(O)R 7 , and —NR 6a C(O)N(R 6a R 6b ), wherein

each of the said (C 1 to C 10 ) alkyl, (C 2 to C 10 ) alkenyl, (C 2 to C 10 ) alkynyl, (C 1 to C 10 ) alkoxy, aryloxy, (C 3 to C 10 ) cycloalkyl, (C 5 to C 10 ) cycloalkenyl, (C 2 to C 9 ) cycloheteroalkyl, (C 6 to C 10 ) aryl, and (C 2 to C 9 ) heteroaryl is optionally substituted with at least one R 8 group;

each of the said (C 1 to C 10 ) alkyl, (C 2 to C 10 ) alkenyl, (C 2 to C 10 ) alkynyl, (C 1 to C 10 ) alkoxy, aryloxy, (C 3 to C 10 ) cycloalkyl, (C 5 to C 10 ) cycloalkenyl, (C 2 to C 9 ) cycloheteroalkyl, (C 6 to C 10 ) aryl, (C 2 to C 9 ) heteroaryl, (C 6 to C 10 ) arylene, and (C 2 to C 9 ) heteroarylene is optionally substituted with at least one R 8 group,

or R 6a and R 6b may be taken together with the nitrogen atom to which they are attached to form a (C 2 to C 10 ) cycloheteroalkyl ring, wherein

said (C 2 to C 10 ) cycloheteroalkyl ring has 1 to 3 ring heteroatoms selected from the group consisting of N, O, and S, and wherein

the said (C 2 to C 10 ) cycloheteroalkyl ring is optionally substituted with at least one R 8 group;

each R 8 is independently selected from hydrogen, halogen, OH, nitro, CF 3 , —NR 9a R 9b , oxo, (C 1 to C 10 ) alkyl, (C 2 to C 10 ) alkenyl, (C 2 to C 10 ) alkynyl, (C 1 to C 10 ) alkoxy, aryloxy, cyano, (C 3 to C 10 ) cycloalkyl, (C 5 to C 10 ) cycloalkenyl, (C 2 to C 9 ) cycloheteroalkyl, (C 6 to C 10 ) aryl, (C 2 to C 9 ) heteroaryl, (C 6 to C 10 ) arylene, (C 2 to C 9 ) heteroarylene, (C 3 to C 10 ) cycloalkylene, (C 2 to C 10 ) cycloheteroalkylene, cycloheteroalkylene, —C(O)R 10 , —C(O)NR 9a R 9b , —S(O) m R 10 , —S(O) m NR 9a R 9b , —NR 9a S(O) m R 10 , —(CH 2 ) n C(O)OR 10 , —(CH 2 ) n C(O)N(R 9a R 9b ), —(CH 2 ) n N(R 9a R 9b ), —OC(O)R 15 , —O(CH 2 ) n O—, —NR 9a C(O)R 10 , and —NR 9a C(O)N(R 9a R 9b ), wherein

each of the R 9a and R 9b is independently selected from hydrogen, (C 1 to C 10 ) alkyl, (C 2 to C 10 ) alkenyl, (C 2 to C 10 ) alkynyl, (C 1 to C 10 ) alkoxy, aryloxy, (C 3 to C 10 ) cycloalkyl, (C 5 to C 10 ) cycloalkenyl, (C 2 to C 9 ) cycloheteroalkyl, (C 6 to C 10 ) aryl, (C 2 to C 9 ) heteroaryl, (C 6 to C 10 ) arylene, and (C 2 to C 9 ) heteroarylene, wherein

each of the said (C 1 to C 10 ) alkyl, (C 2 to C 10 ) alkenyl, (C 2 to C 10 ) alkynyl, (C 1 to C 10 ) alkoxy, aryloxy, (C 3 to C 10 ) cycloalkyl, (C 5 to C 10 ) cycloalkenyl, (C 2 to C 10 ) cycloheteroalkyl, (C 6 to C 10 ) aryl, (C 2 to C 9 ) heteroaryl, (C 6 to C 10 ) arylene, and (C 2 to C 9 ) heteroarylene is optionally substituted with at least one R 11 group,

or R 9a and R 9b may be taken together with the nitrogen atom to which they are attached to form a (C 2 to C 10 ) cycloheteroalkyl ring, wherein

said (C 2 to C 10 ) cycloheteroalkyl ring has 1 to 3 ring heteroatoms selected from the group consisting of N, O, and S, and wherein

the said (C 2 to C 10 ) cycloheteroalkyl ring is optionally substituted with at least one R 11 group;

each R 11 is independently selected from hydrogen, halogen, OH, nitro, CF 3 , —NR 12a R 12b , oxo, (C 1 to C 10 ) alkyl, (C 1 to C 10 ) alkenyl, (C 1 to C 10 ) alkynyl, (C 1 to C 10 ) alkoxy, aryloxy, cyano, (C 3 to C 10 ) cycloalkyl, (C 5 to C 10 ) cycloalkenyl, (C 2 to C 10 ) cycloheteroalkyl, (C 6 to C 10 ) aryl, (C 2 to C 9 ) heteroaryl, (C 6 to C 10 ) arylene, (C 2 to C 9 ) heteroarylene, (C 3 to C 10 ) cycloalkylene, (C 2 to C 10 ) cycloheteroalkylene, —C(O)R 18 , —C(O)NR 12a R 12b , —S(O) m R 13 , —S(O) m NR 12a R 12b , —NR 12a S(O) m R 13 , —(CH 2 ) n C(O)OR 13 , —(CH 2 ) n C(O)N(R 12a R 12b ), —(CH 2 ) n N(R 12a R 12b ), —OC(O)R 13 , —NR 12a C(O)R 13 , and —NR 12a C(O)N(R 12a R 12b ), wherein