Inhibitors of cysteine proteases and methods of use thereof

An engineered SARS-COV2-3CL viral protease represented by SEQ ID NO:

• 1, wherein the cysteine at position 145 of SEQ ID NO:
• 1 has a non-naturally occurring covalent modification resulting from a reaction between an exogenous nitrile modifier, and the cysteine at position 145 of SEQ ID NO:
• 1, wherein the exogenous nitrile modifier is represented by:
• wherein the sulfur atom at the cysteine residue and the —C≡N of the exogenous nitrile modifier undergoes a reaction to form a thioimidate adduct, and wherein
• R1 is C1-C6alkyl or —CH2-C3-10cycloalkyl;
• RG is —C(O)RB;
• RB is C1-C6alkyl (optionally substituted by one, two or three substituents each independently selected from the group consisting of halo, —NRmRm, and —NRm(C═O)Rm, wherein Rm is selected for each occurrence from H or C1-3 alkyl (optionally substituted by one, two or three halo));
• or a 8-10 membered bicyclic heteroaryl (optionally substituted by one, two, or three substituents each independently selected from halo or methoxy);
• Rt is independently, for each occurrence, H or methyl;
• or each Rt may be taken, together with the carbon to which they are attached, to form a cyclopropyl;
• R1a is H;
• or
• R1 and R1a, taken together with the nitrogen and the carbon to which they are attached, form a 4-10 membered monocyclic, bicyclic or spirocyclic heterocycle optionally substituted by one or two substituents on a free carbon each selected from methyl, halo or CF3.

A compound represented by:

• or a pharmaceutically acceptable salt or stereoisomer thereof, wherein
• R1 is C1-C6alkyl or —CH2-C3-10cycloalkyl;
• RG is —C(O)RB;
• RB is C1-C6alkyl (optionally substituted by one, two or three substituents each independently selected from the group consisting of halo, —NRmRm, and —NRm(C═O)Rm, wherein Rm is selected for each occurrence from H or C1-3 alkyl (optionally substituted by one, two or three halo));
• or a 8-10 membered bicyclic heteroaryl (optionally substituted by one, two, or three substituents each independently selected from halo or methoxy);
• Rt is independently, for each occurrence, H or methyl;
• or each Rt may be taken, together with the carbon to which they are attached, to form a cyclopropyl;
• R1a is H;
• or
• R1 and R1a, taken together with the nitrogen and the carbon to which they are attached, form a 4-10 membered monocyclic, bicyclic or spirocyclic heterocycle optionally substituted by one or two substituents on a free carbon each selected from methyl, halo or CF3.

A compound represented by Formula IV-A or Formula IV-B:

• or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
• R1a is selected from the group consisting of hydrogen, C1-C8alkyl, C1-C8heteroalkyl, —(C1-C8alkyl)-R1, —(C1-C8alkyl)-CN, C3-C10cycloalkyl, C6-C14aryl, 4-10 membered heterocycle and 5-10 membered heteroaryl;
• R1b is selected from hydrogen and C1-C8alkyl;
• or R1a and R1b may be joined together to form, together with the carbon to which they are attached, a 4-10 membered heterocycle having a ring nitrogen NRG, or a C3-C10cycloalkyl;
• R1 is selected from the group consisting of C1-C8alkyl, C2-C10alkenyl, C2-C10alkynyl, C3-C10cycloalkyl, C6-C14aryl, 5-10 membered heteroaryl and 4-10 membered heterocycle, wherein R1 may optionally be substituted by one, two, or three substituents each selected from RA;
• RA is independently selected for each occurrence from the group consisting of halogen, cyano, hydroxyl, oxo, SF5, —CH2CF3, —CF3, —O—CF3, —O—CHF2, —S—CH3, —S(O)2—CH3, —NH2, —O-phenyl, —O—(C1-C8alkyl)-phenyl, —NHC(O)RB, —NHC(O)ORB, —NHC(O)O—(C1-C8alkyl)-RB, —N(Ry)2, —N(Ry)(C1-C8alkyl)C(O)O-phenyl, —N(Ry)(C1-C8alkyl)C(O)N(Ry)2, —C(O)—OC(CH3)3, C1-C8alkyl, C2-C10alkenyl, C2-C10alkynyl, C1-C8heteroalkyl, C1-C8alkoxy, C3-C10cycloalkyl, —(C1-C8alkyl)-(C3-C10cycloalkyl), —(C1-C8alkyl)-(C6-C14aryl), —(C1-C8alkyl)-(5-10 membered heteroaryl), C6-C14aryl, 5-10 membered heteroaryl and 4-10 membered heterocyclyl, wherein the RB, alkyl, heterocyclyl, heteroaryl, or aryl may optionally be substituted by one, two or three substituents each independently selected from the group consisting of halogen, C1-C8alkyl, C1-C8alkoxy, SF5, —NH2, hydroxyl and oxo;
• R2 is selected from the group consisting of —NHC(O)RB, —NHC(O)ORB, —NHC(O)N(RB)2, —NHC(O)C(RC)2RB, —NHS(O)2RB, —O—(C1-C8alkyl)-(C3-C10cycloalkyl), 4-10 membered heterocycle, C6-C14aryl and 5-10 membered heteroaryl bound through the carbon or nitrogen atom, wherein RB or R2 may optionally be substituted by one, two, or three substituents each selected from Rx;
• or R1a and R2 may be joined together to form, together with the carbon to which they are attached, a 4-10 membered mono or bicyclic heterocycle having a ring nitrogen NRG, or a C3-C10cycloalkyl, wherein the cycloalkyl or heterocycle may optionally be substituted by one, two or three substituents on a free carbon each selected from RA;
• R3b is selected from hydrogen and C1-C8alkyl;
• RB is independently selected, for each occurrence, from the group consisting of C1-C8alkyl, C2-C10alkenyl, C2-C10alkynyl, C3-C6cycloalkyl, fluorenylmethyloxy, C6-C14aryl, 5-10 membered heteroaryl and 4-10 membered heterocycle;
• RC is independently selected, for each occurrence, from hydrogen, halogen and C1-C8alkyl;
• Rx is independently selected, for each occurrence, from the group consisting of halogen, hydroxyl, oxo, CF3, SF5, cyano, —O—(Rxx)—OCH3, —OCHF2, —OCF3, —O—(C1-C8alkyl), —C(O)O(CH3), —N(Ry)2, —N(Ry)C(O)Ry, —N(Ry)(C1-C8alkyl)C(O)N(Ry)2, —N(Ry)(C1-C8alkyl)C(O)OH, —(C1-C8alkyl)-(C3-C10cycloalkyl), C1-C8alkyl, C1-C8alkoxy, C3-C10cycloalkyl, C6-C14aryl, —O—C6-C14aryl, 5-10 membered heteroaryl and 4-10 membered heterocycle;
• wherein two geminal C1-C8alkyl groups, together with the carbon to which they are attached, may be joined together to form a C3-C6cycloalkyl optionally substituted by one, two or three substituents each independently selected from halogen, hydroxyl and oxo;
• and
• wherein the alkyl, aryl, heterocycle or heteroaryl may optionally be substituted by one or more substituents each independently selected from oxo, halogen and C1-C8alkyl;
• RG is selected from the group consisting of hydrogen, C1-6 alkyl optionally substituted by one, two or three Rgg, —C(═O)—C1-6 alkyl optionally substituted by one, two or three Rhh, —C(═O)—C3-6 cycloalkyl, —C(O)—(C2-C10alkenyl)-(C6-C14aryl), —C(O)-(5-10 membered heteroaryl), —C(O)—(C1-C6alkyl)-O—(C6-C14aryl), —C(O)-(4-10 membered heterocyclyl), and —C(O)-(4-10 membered heterocyclyloxy);
• wherein the aryl, heterocyclyl, or heteroaryl may optionally be substituted by one, two or three Rjj;
• Rgg is independently selected for each occurrence from the group consisting of —C(═O), halo, cyano, —NRmRm, and —NH(C═O)Rm;
• Rhh is independently selected for each occurrence from the group consisting of halo, cyano, —NRmRm, —NRm(C═O)Rm, phenyl, cycloalkyl, heterocyclyl and C1-C6alkoxy;
• Rjj is independently selected for each occurrence from the group consisting of halo, oxo, hydroxyl, cyano, C1-C6alkyl, C1-6 haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, C3-6 cycloalkyl, SF5, and NH2;
• Rm is independently selected for each occurrence from the group consisting of hydrogen, C1-3alkyl, phenyl, —S(O)2—CH3, C3-6cycloalkyl, and 5-6 membered heteroaryl;
• wherein C1-3alkyl, phenyl, and C3-6cycloalkyl may optionally be substituted by one, two or three halo;
• Rxx is —(OCH2CH2)nn—, wherein nn is selected from 1, 2, 3, 4, 5 and 6;
• and
• Ry is independently selected, for each occurrence, from the group consisting of hydrogen, C1-C8alkyl, C1-C8heteroalkyl, —CF3, —CH2CF3, C1-C8alkoxy, —(C1-C8alkoxy)-(5-10 membered aryl), C3-C6cycloalkyl and —(C1-C8alkyl)COOH.