Immunomodulator compounds

A compound of Formula (II)

• or a pharmaceutically acceptable salt thereof, wherein:
• R1 is selected from the group consisting of halogen, C5-8 cycloalkyl, C6-10 aryl and thienyl, wherein the C6-10 aryl and thienyl are optionally substituted with 1 to 5 Rx substituents;
• each Rx is independently selected from the group consisting of halogen, —CN, —Rc, —CO2Ra, —CONRaRb, —C(O)Ra, —OC(O)NRaRb, —NRbC(O)Ra, —NRbC(O)2Rc, —NRa—C(O)NRaRb, —NRaRb, —ORa, —O—X1—ORa, —O—X1—CO2Ra, —O—X1—CONRaRb,
• —X1—ORa, —X1—NRaRb, —X1—CO2Ra, —X1—CONRaRb, —SF5, and —S(O)2NRaRb, wherein each X1 is a C1-4 alkylene;
• each Ra and Rb is independently selected from hydrogen, C1-8 alkyl, and C1-8 haloalkyl, or when attached to the same nitrogen atom can be combined with the nitrogen atom to form a five or six-membered ring having from 0 to 2 additional heteroatoms as ring members selected from N, O, and S, wherein the five or six-membered ring is optionally substituted with oxo;
• each RC is independently selected from the group consisting of C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl and C1-8 haloalkyl;
• and optionally when two Rx substituents are on adjacent atoms, they are combined to form a fused five, six or seven-membered carbocyclic or heterocyclic ring optionally substituted with from 1 to 3 substituents independently selected from halo, oxo, C1-8 haloalkyl and C1-8 alkyl;
• each R2a, R2b and R2c is independently selected from the group consisting of H, halogen, —CN, —Rd, —CO2Re, —CONReRf, —C(O)Re, —OC(O)NReRf, —NRfC(O)Re, —NRfC(O)2Rd, —NRe—C(O)NReRf, —NReRf, —ORe, —O—X2—ORe, —O—X2—NReRf, —O—X2—CO2Re, —O—X2—CONReRf, —X2—ORe, —X2—NReRf, —X2—CO2Re, —X2—CONReRf, —SF5, —S(O)2NReRf, C6-10 aryl and C5-10 heteroaryl, wherein each X2 is a C1-4 alkylene;
• each Re and Rf is independently selected from hydrogen, C1-8 alkyl, and C1-8 haloalkyl, or when attached to the same nitrogen atom can be combined with the nitrogen atom to form a five or six-membered ring having from 0 to 2 additional heteroatoms as ring members selected from N, O and S, and optionally substituted with oxo;
• each Rd is independently selected from the group consisting of C1-8 alkyl, C2-8 alkenyl, and C1-8 haloalkyl;
• R3 is selected from the group consisting of —NRgRh and C4-12 heterocyclyl, wherein the C4-12 heterocyclyl is optionally substituted with 1 to 6 Ry;
• each Ry is independently selected from the group consisting of halogen, —CN, —Ri, —CO2Rj, —CONRjRk, —CONHC1-6 alkyl-OH, —C(O)Rj, —OC(O)NRjRk, —NRjC(O)Rk, —NRjC(O)2Rk, CONOH, PO3H2, —NRj—C1-6 alkyl-C(O)2Rk, —NR2C(O)NRjRk, —NRjRk, —ORj, —S(O)2NRjRk, —O—C1-6alkyl-ORj, —O—C1-6 alkyl-NRjRk, —O—C1-6 alkyl-CO2R, —O—C1-6 alkyl-CONRjRk, —C1-6 alkyl-ORj, C1-6 alkyl-NRjRk, —C1-6 alkyl-CO2R, —C1-6 alkyl-CONRjRk, and SF5,
• wherein the C1-6 alkyl portion of R is optionally further substituted with OH, SO2NH2, CONH2, CONOH, PO3H2, COO—C1-8alkyl or CO2H, wherein each Rj and Rk is independently selected from hydrogen, C1-8 alkyl optionally substituted with 1 to 2 substituents selected from OH, SO2NH2, CONH2, CONOH, PO3H2, COO—C1-8alkyl and CO2H, and C1-8 haloalkyl optionally substituted with 1 to 2 substituents selected from OH, SO2NH2, CONH2, CONOH, PO3H2, COO—C1-8alkyl and CO2H, or when attached to the same nitrogen atom Rj and Rk can be combined with the nitrogen atom to form a five or six-membered ring having from 0 to 2 additional heteroatoms as ring members selected from N, O and S, and optionally substituted with oxo;
• each Ri is independently selected from the group consisting of —OH, C1-8 alkyl, C2-8 alkenyl, and C1-8 haloalkyl, each of which may be optionally substituted with OH, SO2NH2, CONH2, CONOH, PO3H2, COO—C1-8alkyl or CO2H;
• Rg is selected from the group consisting of H, C1-8 haloalkyl and C1-8 alkyl;
• Rh is selected from —C1-8 alkyl, C1-8 haloalkyl, C1-8 alkyl-COOH, C1-8 alkyl-OH,
• C1-8 alkyl-CONH2, C1-8 alkyl-SO2NH2, C1-8 alkyl-PO3H2, C1-8 alkyl-CONOH,
• C1-8 alkyl-NRh1Rh2, —C(O)—C1-8alkyl, —C(O)—C1-8alkyl-OH, —C(O)—C1-8alkyl-COOH, C3-10 cycloalkyl, —C3-10 cycloalkyl-COOH, —C3-10 cycloalkyl-OH, C4-8 heterocyclyl, —C4-8 heterocyclyl-COOH, —C4-8 heterocyclyl-OH, —C1-8 alkyl-C4-8 heterocyclyl, —C1-8 alkyl-C3-10 cycloalkyl, C5-10 heteroaryl, —C1-8alkyl-C5-10 heteroaryl, C10 carbocyclyl, —C1-8 alkyl-C6-10 aryl, —C1-8 alkyl-(C═O)—C6-10 aryl, —C1-8 alkyl-NH(C═O)—C1-8 alkenyl, —C1-8 alkyl-NH(C═O)—C1-8 alkyl, —C1-8 alkyl-NH(C═O)—C1-8 alkynyl, —C1-8 alkyl-(C═O)—NH—C1-8 alkyl-COOH, and —C1-8 alkyl-(C═O)—NH—C1-8 alkyl-OH optionally substituted with CO2H;
• or
• Rh combined with the N to which it is attached is a mono-, di- or tri-peptide comprising 1-3 natural amino acids and 0-2 non-natural amino acids, wherein:
• the non-natural amino acids have an alpha carbon substituent selected from the group consisting of C2-4 hydroxyalkyl, C1-3 alkyl-guanidinyl, and C1-4 alkyl-heteroaryl,
• the alpha carbon of each natural or non-natural amino acid is optionally further substituted with a methyl group, and
• the terminal moiety of the mono-, di-, or tri-peptide is selected from the group consisting of C(O)OH, C(O)O—C1-6 alkyl, and PO3H2, wherein
• Rh1 and Rh2 are each independently selected from the group consisting of H, C1-6 alkyl, and C1-4 hydroxyalkyl;
• the C1-8 alkyl portions of Rh are optionally further substituted with from 1 to 3 substituents independently selected from OH, COOH, SO2NH2, CONH2, CONOH, COO—C1-8 alkyl, PO3H2 and C5-6 heteroaryl optionally substituted with 1 to 2 C1-3 alkyl substituents,
• the C10 carbocyclyl, C5-10 heteroaryl and the C6-10 aryl portions of Rh are optionally substituted with 1 to 3 substituents independently selected from OH, B(OH)2, COOH, SO2NH2, CONH2, CONOH, PO3H2, COO—C1-8alkyl, C1-4alkyl, C1-4alkyl-OH, C1-4alkyl-SO2NH2, C1-4alkyl CONH2, C1-4alkyl-CONOH, C1-4alkyl-PO3H2, C1-4alkyl-COOH, and phenyl and
• the C4-8 heterocyclyl and C3-10 cycloalkyl portions of Rh are optionally substituted with 1 to 4 Rw substituents;
• each Rw substituent is independently selected from C1-4 alkyl, C1-4 alkyl-OH, C1-4 alkyl-COOH, C1-4 alkyl-SO2NH2, C1-4 alkyl CONH2, C1-4 alkyl-CONOH, C1-4 alkyl-PO3H, OH, COO—C1-8 alkyl, COOH, SO2NH2, CONH2, CONOH, PO3H2 and oxo;
• R4 is selected from the group consisting of O—C1-8 alkyl, O—C1-8 haloalkyl, O—C1-8 alkyl-Rz, C6-10 aryl, C5-10 heteroaryl, —O—C1-4 alkyl-C6-10aryl and —O—C1-4 alkyl-C5-10 heteroaryl, wherein the C6-10 aryl and the C5-10 heteroaryl are optionally substituted with 1 to 5 Rz;
• each Rz is independently selected from the group consisting of halogen, —CN, —Rm, —CO2Rn, —CONRnRp, —C(O)Rn, —OC(O)NRnRp, —NRnC(O)Rp, —NRnC(O)2Rm, —NRn—C(O)NRnRp, —NRnRp, —ORn, —O—X3—ORn, —O—X3—NRnRp, —O—X3—CO2Rn, —O—X3—CONRnRp, —X3—ORn, —X3—NRnRp, —X3—CO2Rn, —X3—CONRnRp, —SF5, —S(O)2RnRp, —S(O)2NRnRp, and three to seven-membered carbocyclic or four to seven-membered heterocyclic ring, wherein the three to seven-membered carbocyclic or four to seven-membered heterocyclic ring is optionally substituted with 1 to 5 Rt, wherein each Rt is independently selected from the group consisting of C1-8 alkyl, C1-8haloalkyl, —CO2Rn, —CONRnRp, —C(O)Rn, —OC(O)NRnRp, —NRnC(O)Rp, —NRnC(O)2Rm, —NRn—C(O)NRnRp, —NRnRp, —ORn, —O—X3—ORn, —O—X3—NRnRp, —O—X3—CO2Rn, —O—X3—CONRnRp, —X3—ORn, —X3—NRnRp, X3—CO2Rn, —X3—CONRnRp, —SF5, and —S(O)2NRnRp;
• wherein each X3 is a C1-4 alkylene;
• each Rn and Rp is independently selected from hydrogen, C1-8 alkyl, and C1-8 haloalkyl, or when attached to the same nitrogen atom can be combined with the nitrogen atom to form a five or six-membered ring having from 0 to 2 additional heteroatoms as ring members selected from N, O, and S, and optionally substituted with oxo;
• each Rm is independently selected from the group consisting of C1-8 alkyl, C2-8 alkenyl, and C1-8 haloalkyl;
• and optionally when two Rz substituents are on adjacent atoms, they are combined to form a fused five or six-membered carbocyclic or heterocyclic ring optionally substituted with oxo;
• n is 0, 1, 2 or 3;
• each R5 is independently selected from the group consisting of halogen, —CN, —Rq, —CO2Rr, —CONRrRs, —C(O)Rr, —OC(O)NRrRs, —NRrC(O)Rs, —NRrC(O)2Rq, —NRr—C(O)NRrRs, —NRrRs, —OR r, —O—X4—ORr, —O—X4—NRrRs, —O—X4—CO2Rr, —O—X4—CONRrRs, —X4—OR, —X4—NRrRs, —X4—CO2Rr, —X4—CONRrRs, —SF5, and —S(O)2NRrRs, wherein each X4 is a C1-4 alkylene;
• each Rr and Rs is independently selected from hydrogen, C1-8 alkyl, and C1-8 haloalkyl, or when attached to the same nitrogen atom can be combined with the nitrogen atom to form a five or six-membered ring having from 0 to 2 additional heteroatoms as ring members selected from N, O and S, and optionally substituted with oxo;
• each Rq is independently selected from the group consisting of C1-8 alkyl and C1-8 haloalkyl;
• R6a is selected from the group consisting of H, C1-4 alkyl and C1-4 haloalkyl;
• each Rb is independently selected from the group consisting of F, C1-4 alkyl, O—Ru, C1-4 haloalkyl, and NRuRv, wherein each Ru and R is independently selected from hydrogen, C1-8 alkyl, and C1-8 haloalkyl, or when attached to the same nitrogen atom can be combined with the nitrogen atom to form a five or six-membered ring having from 0 to 2 additional heteroatoms as ring members selected from N, O, and S, and optionally substituted with oxo;
• and
• m is 0, 1, 2, 3 or 4.