Protease inhibitors, preparation, and uses thereof

A compound of the following structural formula IIIb-1:

• a tautomer thereof, a deuterated derivative of the compound or the tautomer, or a pharmaceutically acceptable salt of the foregoing;
• wherein:
• Y is C3-C10 cycloalkyl;
• Ra and Rd, for each occurrence, are each independently hydrogen or C1-C4 alkyl;
• R1, R2, and R3, for each occurrence, are each independently selected from halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, —C(═O)(C1-C6 alkyl), —C(═O)NRpRq, —NRpRq, —NRpC(═O)Rs, —NRpC(═O)ORs, —NRpC(═O)NRqRr, —NRpS(═O)wRs, —NO2, —ORs, —OC(═O)Rs, —OC(═O)ORs, —OC(═O)NRpRq, —S(═O)wRs, —S(═O)wNRpRq, —SO3−, C3-C12 carbocyclyl, 3 to 12-membered heterocyclyl, phenyl, and 5 to 10-membered heteroaryl;
• wherein:
• the C1-C6 alkyl, the C2-C6 alkenyl, and the C1-C6 alkoxy of any one of R1, R2, and R3 and the C1-C6 alkyl of —C(═O)(C1-C6 alkyl) are each optionally substituted with 1 to 3 groups selected from halogen, cyano, —C(═O)Rs,
• —C(═O)ORs, —C(═O)NRpRq, —NRpRq, —NRpC(═O)Rs, —NRpC(═O)ORs, —NRpC(═O)NRqRr, —NRpS(═O)wRs, —ORs, —OC(═O)Rs, —OC(═O)ORs, —OC(═O)NRpRq, —S(═O)wRs, —S(═O)wNRpRq, C3-C6 cycloalkyl, and phenyl that is optionally substituted with 1 to 3 halogen atoms;
• the C3-C12 carbocyclyl, the 3 to 12-membered heterocyclyl, the phenyl, and the 5 to 10-membered heteroaryl of any one of R1, R2, and R3 are each optionally substituted with 1 to 3 groups selected from halogen, cyano, C1-C4 alkyl, —NRpRq, and —ORs;
• Rp, Rq, and Rr, for each occurrence, are each independently selected from hydrogen, C1-C4 alkyl, and C3-C6 cycloalkyl;
• wherein:
• the C1-C4 alkyl of any one of Rp, Rq, and Rr is optionally substituted with 1 to 3 groups selected from halogen, cyano, and —OH;
• Rs, for each occurrence, is each independently selected from hydrogen, C1-C4 alkyl, and C3-C6 cycloalkyl;
• w is an integer selected from 1 and 2;
• and
• R1, for each occurrence, may be attached to any of the ring atoms of the isoquinoline in formula IIIb-1, as long as valency permits;
• m is an integer selected from 0, 1, 2, 3, 4, 5, and 6;
• n is an integer selected from 1, 2, 3, 4, and 5;
• and
• is an integer selected from 0 and 1.

A compound of the following structural formula IIIb-2:

• a tautomer thereof, a deuterated derivative of the compound or the tautomer, or a pharmaceutically acceptable salt of the foregoing;
• wherein:
• X is absent, and Z is —NH—, —[CH(CH(CH3)2)]NH—, —C(═O)NHCH[(CONHCH3)]CH2—, or —CH(C2H5)CH2NH—;
• or
• X is —NH—, or —NHCH2—, and Z is absent, —NH—, —[CH(CH(CH3)2)]NH—, —C(═O)NHCH[(CONHCH3)]CH2—, or —CH(C2H5)CH2NH—;
• Y is 3- to 10-membered heterocyclyl containing at least one N atom and optionally at least one other heteroatom selected from O and S;
• at least one of T and U is N;
• and
• R1 and R2, for each occurrence, are each independently selected from halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, —C(═O)(C1-C6 alkyl), —C(═O)NRpRq, —NRpRq, —NRpC(═O)Rs, —NRpC(═O)Rs, —NRpC(═O)NRqRr, —NRpS(═O)wRs, —NO2, —ORs, —OC(═O)Rs, —OC(═O)ORs, —OC(═O)NRpRq, —S(═O)wRs, —S(═O)wNRpRq, and —SO3−;
• R3, for each occurrence, is each independently selected from halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, —C(═O)(C1-C6 alkyl), —C(═O)NRpRq, —NRpRq, —NRpC(═O)Rs, —NRpC(═O)ORs, —NRpC(═O)NRqRr, —NRpS(═O)wRs, —NO2, —ORs, —OC(═O)Rs, —OC(═O)ORs, —OC(═O)NRpRq, —S(═O)wRs, —S(═O)wNRpRq, —SO3 and phenyl;
• wherein:
• the C1-C6 alkyl, the C2-C6 alkenyl, and the C1-C6 alkoxy of any one of R1, R2, and R3, and the C1-C6 alkyl of —C(═O)(C1-C6 alkyl) are each optionally substituted with 1 to 3 groups selected from halogen, cyano, —C(═O)Rs, —C(═O)ORs, —C(═O)NRpRq, —NRpRq, —NRpC(═O)Rs, —NRpC(═O)ORs, —NRpC(═O)NRqRr, —NRpS(═O)wRs, —ORs, —OC(═O)Rs, —OC(═O)ORs, —OC(═O)NRpRq, —S(═O)wRs, —S(═O)wNRpRq, C3-C6cycloalkyl, and phenyl that is optionally substituted with 1 to 3 halogen atoms;
• the phenyl of R3 is each optionally substituted with 1 to 3 groups selected from halogen, cyano, and —OH;
• Rp, Rq, and Rr, for each occurrence, are each independently selected from hydrogen, C1-C4 alkyl, and C3-C6 cycloalkyl;
• wherein:
• the C1-C4 alkyl of any one of Rp, Rq, and Rrr is optionally substituted with 1 to 3 groups selected from halogen, cyano, and —OH;
• Rs, for each occurrence, is each independently selected from hydrogen, C1-C4 alkyl, and C3-C6 cycloalkyl;
• w is an integer selected from 1 and 2;
• and
• R1, for each occurrence, may be attached to any of the ring atoms of the isoquinoline in formula IIIb-2, as long as valency permits;
• m is an integer selected from 0, 1, 2, 3, 4, 5, and 6;
• n is an integer selected from 1, 2, 3, and 4;
• and
• is an integer selected from 0, 1, and 2.

A compound of the following structural formula IIIc:

• a tautomer thereof, a deuterated derivative of the compound or the tautomer, or a pharmaceutically acceptable salt of the foregoing;
• wherein:
• X is absent, —NH—, or —NHCH2—;
• Y is C3-C12 carbocyclyl, azetidinyl, piperidinyl, piperazinyl, 2,7-diazaspiro[4.4]nonanyl, octahydrocyclopenta[c]pyrrolyl, 2-oxa-6-azaspiro[3.4]octanyl, or octahydro-1H-isoindolyl;
• wherein the C3-C12 carbocyclyl of Y, the azetidinyl, piperidinyl, piperazinyl, 2,7-diazaspiro[4.4]nonanyl, octahydrocyclopenta[c]pyrrolyl, 2-oxa-6-azaspiro[3.4]octanyl, or octahydro-1H-isoindolyl of Y are each substituted with o groups of R3;
• Z is absent, —NH—, —[CH(CH(CH3)2)]NH—, C(═O)NHCH[(CONHCH3)]CH2— or —CH(C2H5)CH2NH—;
• R2′ is cyano, —NO2, or —SO3−;
• wherein:
• R1 and R2, for each occurrence, are each independently selected from halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, —C(═O)(C1-C6 alkyl), —C(═O)NRpRq, —NRpRq, —NRpC(═O)Rs, —NRpC(═O)ORs, —NRpC(═O)NRqRr, —NRpS(═O)wRs, —NO2, —ORs, —OC(═O)Rs, —OC(═O)ORs, —OC(═O)NRpRq, —S(═O)wRs, —S(═O)wNRpRq, and —SO3−;
• R3, for each occurrence, is each independently selected from halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, —C(═O)(C1-C6 alkyl), —C(═O)NRpRq, —NRpRq, —NRpC(═O)Rs, —NRpC(═O)ORs, —NRpC(═O)NRqRr, —NRpS(═O)wRs, —NO2, —ORs, —OC(═O)Rs, —OC(═O)ORs, —OC(═O)NRpRq, —S(═O)wRs, —S(═O)wNRpRq, —SO3 and phenyl;
• wherein:
• the C1-C6 alkyl, the C2-C6 alkenyl, and the C1-C6 alkoxy of any one of R1, R2, and R3 and the C1-C6 alkyl of —C(═O)(C1-C6 alkyl) are each optionally substituted with 1 to 3 groups selected from halogen, cyano, —C(═O)RS, —C(═O)ORs, —C(═O)NRpRq, —NRpRq, —NRpC(═O)Rs, —NRpC(═O)ORs, —NRpC(═O)NRpRr, —NRpS(═O)wRs, —ORs, —OC(═O)Rs, —OC(═O)ORs, —OC(═O)NRpRq, —S(═O)wRs, —S(═O)wNRpRq, C3-C6 cycloalkyl, and phenyl that is optionally substituted with 1 to 3 halogen atoms;
• the phenyl of R3 is each optionally substituted with 1 to 3 groups selected from halogen, cyano, and —OH;
• Rp, Rq, and Rr, for each occurrence, are each independently selected from hydrogen, C1-C4 alkyl, and C3-C6 cycloalkyl;
• wherein:
• the C1-C4 alkyl ofany one of Rp, Rq, and Rr is optionally substituted with 1 to 3 groups selected from halogen, cyano, and —OH;
• Rs, for each occurrence, is each independently selected from hydrogen, C1-C4 alkyl, and C3-C6 cycloalkyl;
• w is an integer selected from 1 and 2;
• and
• R1, for each occurrence, may be attached to any of the ring atoms of the isoquinoline in formula IIIc, as long as valency permits;
• m is an integer selected from 0, 1, 2, 3, 4, 5, and 6;
• is an integer selected from 0, 1, 2, and 3;
• and
• n is an integer selected from 1, 2, 3, and 4.