Nitrile-Containing Antiviral Compounds

Abstract

The invention relates to compounds of Formula I″wherein R, R1, R2, R3, p, q and q′ are as defined herein, pharmaceutical compositions comprising the compounds, methods of treating coronavirus infection such as COVID-19 in a patient by administering therapeutically effective amounts of the compounds, and methods of inhibiting or preventing replication of coronaviruses such as SARS-CoV-2 with the compounds.

1 . A compound of Formula I″ 
       
         
           
           
               
               
           
         
         or a solvate or hydrate thereof, or a pharmaceutically acceptable salt of said compound, solvate or hydrate thereof; 
         wherein 
         R at each occurrence is independently hydroxy or oxo; 
         q and q′ are each independently selected from 0, 1 and 2; 
         p is 0, 1 or 2; 
         R 1  is selected from the group consisting of C 1 -C 6  alkyl which is optionally substituted with a cyano or with one to five fluoro; C 2 -C 6  alkynyl; and (C 3 -C 6  cycloalkyl)-C 1 -C 3  alkyl which is optionally substituted with one to two substituents selected from trifluoromethyl and C 1 -C 3  alkyl, or optionally substituted with one to five fluoro; 
         R 2  is hydrogen or R 2  and R 1  taken together with the nitrogen and carbon atoms to which they are attached are a pyrrolidine or piperidine ring which is optionally substituted with one to four R 2a ; 
         R 2a  at each occurrence is independently selected from the group consisting of fluoro, hydroxy, C 1 -C 6  alkyl optionally substituted with one to three fluoro, and C 1 -C 6  alkoxy optionally substituted with one to three fluoro; or two R 2a  groups when attached to adjacent carbons and taken together with the carbons to which they are attached are a fused C 3 -C 6  cycloalkyl which is optionally substituted with one to four R 2b ; or two R 2a  groups when attached to the same carbon and taken together with the carbon to which they are attached are a spiro C 3 -C 6  cycloalkyl which is optionally substituted with one to four R 2b ; 
         R 2b  at each occurrence is independently selected from fluoro, hydroxy, C 1 -C 3  alkyl optionally independently substituted with one to three fluoro or hydroxy, and C 1 -C 3  alkoxy optionally independently substituted with one to three fluoro or hydroxy; 
         R 3  is selected from the group consisting of C 1 -C 8  alkyl, C 1 -C 8  alkoxy, (C 1 -C 6  alkoxy)-C 1 -C 6  alkyl, C 2 -C 6  alkynyl, C 2 -C 6  alkynyloxy, C 3 -C 12  cycloalkyl optionally fused with a 5- to 6-membered heteroaryl or phenyl, (C 3 -C 12  cycloalkyl)-C 1 -C 6  alkyl, C 3 -C 12  cycloalkoxy, (C 3 -C 12  cycloalkoxy)-C 1 -C 6  alkyl, 4- to 12-membered heterocycloalkyl which is optionally fused with a 5- to 6-membered heteroaryl or phenyl and wherein said heterocycloalkyl comprises one to four heteroatoms independently selected from N, O and S(O) n , and (4- to 12-membered heterocycloalkyl)-C 1 -C 6  alkyl wherein said heterocycloalkyl moiety comprises one to four heteroatoms independently selected from N, O and S(O) n ; wherein 
         each R 3  group is optionally substituted with one to five R 4 ; 
         R 4  at each occurrence is independently selected from the group consisting of oxo, halo, hydroxy, cyano, phenyl, benzyl, amino, (C 1 -C 6  alkyl)amino optionally substituted with one to five fluoro, di(C 1 -C 6  alkyl)amino optionally substituted with one to ten fluoro, C 1 -C 6  alkyl optionally substituted with one to five fluoro, (5- to 6-membered heteroaryl)amino- wherein the heteroaryl moiety comprises one to four heteroatoms independently selected from N, O and S; (4- to 7-membered heterocycloalkyl)amino- wherein the heterocycloalkyl moiety comprises one to three heteroatoms independently selected from N, O and S(O) n , C 1 -C 6  alkoxy optionally substituted with one to five fluoro, C 1 -C 3  alkoxy-C 1 -C 3  alkyl optionally substituted with one to five fluoro, C 3 -C 6  cycloalkyl optionally substituted with one to three fluoro or C 1 -C 3  alkyl, C 1 -C 6  alkyl-C(O)NH— optionally substituted with one to five fluoro, C 1 -C 6  alkyl-OC(O)NH— optionally substituted with one to five fluoro or with one R 5 , C 1 -C 6  alkyl-NHC(O)NH— optionally substituted with one to five fluoro or with one R 5 , C 1 -C 6  alkyl-S(O) 2 NH— optionally substituted with one to five fluoro or with one R 5 , C 1 -C 6  alkyl-C(O)— optionally substituted with one to five fluoro or with one R 5 , C 1 -C 6  alkyl-S(O) n — optionally substituted with one to five fluoro or with one R 5 ; 
         R 5  is selected from phenyl, phenoxy, C 3 -C 6  cycloalkyl, C 3 -C 6  cycloalkoxy, 4- to 7-membered heterocycloalkyl- wherein the heterocycloalkyl moiety comprises one to three heteroatoms independently selected from N, O and S(O) n  and 5- to 6-membered heteroaryl- wherein the heteroaryl moiety comprises one to four heteroatoms independently selected from N, O and S; wherein each R 5  is optionally independently substituted with one to three halo, C 1 -C 3  alkyl and C 1 -C 3  alkoxy; and 
         n at each occurrence is independently selected from 0, 1 and 2. 
       
     
     
         2 . A compound selected from the group consisting of 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein R 4  is selected from the group consisting of (C 1 -C 6  alkyl)amino optionally substituted with one to five fluoro, C 1 -C 6  alkyl-C(O)NH— optionally substituted with one to five fluoro, and C 1 -C 6  alkyl-S(O) 2 NH— optionally substituted with one to five fluoro; 
         or a solvate or hydrate thereof, or a pharmaceutically acceptable salt of said compound, solvate or hydrate. 
       
     
     
         3 . The compound of  claim 2  wherein R 4  is selected from the group consisting of CF 3 C(O)NH—, CF 3 S(O) 2 NH—, CH 3 C(O)NH—, CH 3 CH 2 C(O)NH— and CF 3 CH 2 NH—; or a solvate or hydrate thereof, or a pharmaceutically acceptable salt of said compound, solvate or hydrate. 
     
     
         4 . The compound of  claim 3  wherein R 4  is CF 3 C(O)NH— or CF 3 S(O) 2 NH—; or
 a solvate or hydrate thereof. 
 
     
     
         5 .- 30 . (canceled) 
     
     
         31 . A pharmaceutical composition comprising the compound (1R,2S,5S)—N-{(1S)-1-Cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-6,6-dimethyl-3-[3-methyl-N-(trifluoroacetyl)-L-valyl]-3-azabicyclo[3.1.0]hexane-2-carboxamide having the structure 
       
         
           
           
               
               
           
         
         or a solvate or hydrate thereof and a pharmaceutically acceptable carrier; wherein the pharmaceutical composition is an oral dosage form. 
       
     
     
         32 . The pharmaceutical composition of  claim 31 , wherein the oral dosage form is a tablet, capsule, lozenge, emulsion, suspension, syrup or solution. 
     
     
         33 . The pharmaceutical composition of  claim 32 , which comprises 10 mg to 1500 mg of (1R,2S,5S)—N-{(1S)-1-Cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-6,6-dimethyl-3-[3-methyl-N-(trifluoroacetyl)-L-valyl]-3-azabicyclo[3.1.0]hexane-2-carboxamide. 
     
     
         34 . The pharmaceutical composition of  claim 33 , which comprises 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg or 750 mg of (1R,2S,5S)—N-{(1S)-1-Cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-6,6-dimethyl-3-[3-methyl-N-(trifluoroacetyl)-L-valyl]-3-azabicyclo[3.1.0]hexane-2-carboxamide. 
     
     
         35 . The pharmaceutical composition of  claim 34 , wherein the pharmaceutical composition is a tablet. 
     
     
         36 . The pharmaceutical composition of  claim 35 , which comprises one or more components selected from the group consisting of a diluent, disintegrant, glidant and a lubricant. 
     
     
         37 . The pharmaceutical composition of  claim 36 , which comprises one or more components selected from the group consisting of micro crystalline cellulose, lactose monohydrate, crospovidone, colloidal silicon dioxide, intra-granular sodium stearyl fumarate and extra-granular sodium stearyl fumarate. 
     
     
         38 . The pharmaceutical composition of  claim 37 , which comprises 100 mg, 150 mg or 250 mg of (1R,2S,5S)—N-{(1S)-1-Cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-6,6-dimethyl-3-[3-methyl-N-(trifluoroacetyl)-L-valyl]-3-azabicyclo[3.1.0]hexane-2-carboxamide. 
     
     
         39 . The pharmaceutical composition of  claim 38 , which comprises 100 mg of (1R,2S,5S)—N-{(1S)-1-Cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-6,6-dimethyl-3-[3-methyl-N-(trifluoroacetyl)-L-valyl]-3-azabicyclo[3.1.0]hexane-2-carboxamide, 246.67 mg microcrystalline cellulose, 123.33 mg lactose monohydrate, 15.00 mg crospovidone, 5.00 mg colloidal silicon dioxide, 5.00 mg intra-granular sodium stearyl fumarate and 5.00 mg extra-granular sodium stearyl fumarate. 
     
     
         40 . The pharmaceutical composition of  claim 39 , which is coated. 
     
     
         41 . The pharmaceutical composition of  claim 38 , which comprises 150 mg of (1R,2S,5S)—N-{(1S)-1-Cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-6,6-dimethyl-3-[3-methyl-N-(trifluoroacetyl)-L-valyl]-3-azabicyclo[3.1.0]hexane-2-carboxamide, 370.00 mg microcrystalline cellulose, 185.00 mg lactose monohydrate, 22.50 mg crospovidone, 7.50 mg colloidal silicon dioxide, 7.50 mg intra-granular sodium stearyl fumarate and 7.50 mg extra-granular sodium stearyl fumarate. 
     
     
         42 . The pharmaceutical composition of  claim 41 , which is coated. 
     
     
         43 . The pharmaceutical composition of  claim 38 , which comprises 250 mg of (1R,2S,5S)—N-{(1S)-1-Cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-6,6-dimethyl-3-[3-methyl-N-(trifluoroacetyl)-L-valyl]-3-azabicyclo[3.1.0]hexane-2-carboxamide, 460.00 mg microcrystalline cellulose, 230.00 mg lactose monohydrate, 30.00 mg crospovidone, 10.00 mg colloidal silicon dioxide, 10.00 mg intra-granular sodium stearyl fumarate and 10.00 mg extra-granular sodium stearyl fumarate. 
     
     
         44 . The pharmaceutical composition of  claim 43 , which is coated. 
     
     
         45 . The pharmaceutical composition of  claim 31  which further comprises ritonavir. 
     
     
         46 . The pharmaceutical composition of  claim 32  which further comprises ritonavir. 
     
     
         47 . The pharmaceutical composition of  claim 33  which further comprises ritonavir. 
     
     
         48 . The pharmaceutical composition of  claim 34  which further comprises ritonavir. 
     
     
         49 . A compound selected from the group consisting of
 (1R,2S,5S)—N-{(1S)-1-Cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-6,6-dimethyl-3-[N-(trifluoroacetyl)-L-valyl]-3-azabicyclo[3.1.0]hexane-2-carboxamide;   (2S,4R)-4-tert-Butyl-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-1-{N-[(trifluoromethyl)sulfonyl]-L-valyl}piperidine-2-carboxamide;   (2R,4S)-4-tert-Butyl-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-1-{N-[(trifluoromethyl)sulfonyl]-L-valyl}piperidine-2-carboxamide;   3-Methyl-N-(trifluoroacetyl)-L-valyl-(4R)—N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide;   (1R,2S,5S)—N-{(1S)-1-Cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-6,6-dimethyl-3-[3-methyl-N-(methylcarbamoyl)-L-valyl]-3-azabicyclo[3.1.0]hexane-2-carboxamide;   Methyl {(2S)-1-[(1R,2S,5S)-2-({(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}carbamoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl]-3,3-dimethyl-1-oxobutan-2-yl}carbamate;   N-(Trifluoroacetyl)-L-valyl-(4R)—N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide;   (1R,2S,5S)—N-{(1S)-1-Cyano-2-[(3R)-5-hydroxy-2-oxopyrrolidin-3-yl]ethyl}-6,6-dimethyl-3-[3-methyl-N-(trifluoroacetyl)-L-valyl]-3-azabicyclo[3.1.0]hexane-2-carboxamide;   (1R,2S,5S,6R)—N-{(1S)-1-Cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-6-(hydroxymethyl)-6-methyl-3-[3-methyl-N-(trifluoroacetyl)-L-valyl]-3-azabicyclo[3.1.0]hexane-2-carboxamide;   (1R,2S,5S,6S)—N-{(1S)-1-Cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-6-(hydroxymethyl)-6-methyl-3-[3-methyl-N-(trifluoroacetyl)-L-valyl]-3-azabicyclo[3.1.0]hexane-2-carboxamide;   (1R,2S,5S)—N-{(1S)-1-Cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-3-[3-(hydroxymethyl)-N-(trifluoroacetyl)-L-valyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide;   (1R,2S,5S)—N-{(1S)-1-Cyano-2-[(3R)-2,5-dioxopyrrolidin-3-yl]ethyl}-6,6-dimethyl-3-[3-methyl-N-(trifluoroacetyl)-L-valyl]-3-azabicyclo[3.1.0]hexane-2-carboxamide;   (1R,2S,5S)—N-{(1S)-1-Cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-6,6-dimethyl-3-[5,5,5-trifluoro-2-(2,2,2-trifluoroacetamido)pentanoyl]-3-azabicyclo[3.1.0]hexane-2-carboxamide;   (1R,2S,5S)—N-{(1S)-1-Cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-3-[(2S)-2-cyclohexyl-2-{[(trifluoromethyl)sulfonyl]amino}acetyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide;   (1R,2S,5S)—N-{(1S)-1-Cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-3-[3-cyclobutyl-N-(trifluoroacetyl)-L-alanyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide;   (1R,2S,5S)—N-{(1S)-1-Cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-3-[3-cyclobutyl-N-(trifluoroacetyl)-D-alanyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide;   (1R,2S,5S)—N-{(1S)-1-Cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-6,6-dimethyl-3-[3-(pyridin-2-yl)-N-(trifluoroacetyl)-L-alanyl]-3-azabicyclo[3.1.0]hexane-2-carboxamide;   (1R,2S,5S)—N-{(1S)-1-Cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-3-{N-[(4-fluorophenoxy)acetyl]-3-methyl-L-valyl}-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide;   3-Methyl-N-[(4-methylphenyl)acetyl]-L-valyl-(4R)—N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide;   (1R,2S,5S)—N-{(1S)-1-Cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-6,6-dimethyl-3-[3-(1H-pyrazol-1-yl)-N-(trifluoroacetyl)-L-alanyl]-3-azabicyclo[3.1.0]hexane-2-carboxamide;   (1R,2S,5S)—N-{(1S)-1-Cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-3-[(2S)-4,4-difluoro-2-(2,2,2-trifluoroacetamido)butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; and   (1R,2S,5S)—N-{(1S)-1-Cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-6,6-dimethyl-3-[2-(2,2,2-trifluoroacetamido)-3-(trifluoromethyl)pentanoyl]-3-azabicyclo[3.1.0]hexane-2-carboxamide;   or a solvate or hydrate thereof.   
     
     
         50 . A pharmaceutical composition comprising a compound of  claim 49  or a solvate or hydrate thereof and a pharmaceutically acceptable carrier. 
     
     
         51 . A combination comprising:
 (1R,2S,5S)—N-{(1S)-1-Cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-6,6-dimethyl-3-[3-methyl-N-(trifluoroacetyl)-L-valyl]-3-azabicyclo[3.1.0]hexane-2-carboxamide having the structure   
       
         
           
           
               
               
           
         
       
       and
 ritonavir. 
 
     
     
         52 . The combination according to claim  55 , wherein the (1R,2S,5S)—N-{(1S)-1-Cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-6,6-dimethyl-3-[3-methyl-N-(trifluoroacetyl)-L-valyl]-3-azabicyclo[3.1.0]hexane-2-carboxamide and the ritonavir are in separate dosage forms.