PD-L1/STING conjugates and methods of use

A compound of Formula (I):

• P-L-S (I)
• or a pharmaceutically acceptable salt thereof, wherein P is a ligand that binds to cell surface PD-L1 protein and induces PD-L1 internalization, L is a linking group, and S is a moiety that agonizes STING,
• wherein P has Formula (P-1b):
• wherein:
• L is attached to ring A or ring B by a direct bond or to an RA or RB substituent;
• L1 and L2 are each independently selected from a bond, —C(O)NR13—, —NR13C(O)—, —0—, —(CR14R15)t2—, —(CR14R15)t2—O—, —O(CR14R15)t2—, —(CR14R15)t2—NR13—, —NR13—(CR14R15)t2—, S(O)2NR13—, —NR13S(O)2—, —NR13S(O)2NR13—, —NR13C(O)O—, —OC(O)NR13— and —NR13C(O)NR13—;
• ring A and ring B are each independently selected from 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl, and C3-10 cycloalkyl;
• R1 is C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, CN, halo, OH, —C(O)OH, NH2—, -C1-4 alkylamino, or di-(C1-4 alkyl)amino;
• R2 is C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, CN, halo, OH, —C(O)OH, NH2, -C1-4 alkylamino, or di-(C1-4 alkyl)amino;
• R3 is methyl, Cl, F, CN, or C1-2 haloalkyl;
• each subscript t2 is independently an integer of 1, 2, 3 or 4;
• the subscript m is an integer of 0, 1, 2, or 3;
• the subscript n is an integer of 0, 1, 2, or 3;
• the subscript u is an integer of 0, 1, 2, 3, 4, or 5;
• the subscript v is an integer of 0, 1, 2, 3, 4, or 5;
• RA and RB are each independently selected from H, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 haloalkoxy, C6-14 aryl, C3-14 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C6-14 aryl-C1-4 alkyl-, C3-14 cycloalkyl-C1-4 alkyl-, (5-14 membered heteroaryl)-C1-4 alkyl-, (4-14 membered heterocycloalkyl)-C1-4 alkyl-, CN, NO2, ORa, SRa, NHORa, C(O)Ra, C(O)NRaRa, C(O)ORa, C(O)NRaS(O)2Ra, OC(O)Ra, OC(O)NRaRa, NHRa, NRaRa, NRaC(O)Ra, NRaC(═NRa)Ra, NRaC(O)ORa, NRaC(O)NRaRa, C(═NRa)Ra, C(═NOH)Ra, C(═NOH)NRa, C(═NCN)NRaRa, NRaC(═NCN)NRaRa, C(═NRa)NRaRa, NRaC(═NRa)NRaRa, NRaS(O)Ra, NRaS(O)2Ra, NRaS(O)2NRaRa, S(O)Ra, S(O)NRaRa, S(O)2Ra, S(O)2NRaC(O)Ra, —P(O)RaRa, —P(O)(ORa)(ORa), —B(OH)2, —B(ORa)2 and S(O)2NRaRa, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-14 aryl, C3-14 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C6-14 aryl-C1-4 alkyl-, C3-14 cycloalkyl-C1-4 alkyl-, (5-14 membered heteroaryl)-C1-4 alkyl- and (4-14 membered heterocycloalkyl)-C1-4 alkyl- are each optionally substituted with 1, 2, 3, 4 or 5 independently selected Rb substituents;
• or two RA substituents attached to the same ring carbon atom taken together with the ring carbon atom to which they are attached form spiro C3-6 cycloalkyl or spiro 4- to 7-membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 independently selected Rf substituents;
• or two RB substituents attached to the same ring carbon atom taken together with the ring carbon atom to which they are attached form spiro C3-6 cycloalkyl or spiro 4- to 7-membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 independently selected Rf substituents;
• each Ra is independently selected from H, CN, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-14 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-14 cycloalkyl-C1-4 alkyl-, (5-14 membered heteroaryl)-C1-4 alkyl-, and (4-14 membered heterocycloalkyl)-C1-4 alkyl-, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-14 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-14 cycloalkyl-C1-4 alkyl-, (5-14 membered heteroaryl)-C1-4 alkyl- and (4-14 membered heterocycloalkyl)-C1-4 alkyl- are each optionally substituted with 1, 2, 3, 4, or 5 independently selected Rd substituents;
• each Rb substituent is independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 haloalkoxy, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, (4-10 membered heterocycloalkyl)-C1-4 alkyl-, CN, OH, NH2, NO2, NHORc, ORc, SRc, C(O)Rc, C(O)NRcRc, C(O)ORc, C(O)NRcS(O)2Rc, OC(O)Rc, OC(O)NRcRc, C(═NOH)Rc, C(═NOH)NRc, C(═NCN)NRcRc, NRcC(═NCN)NRcRc, C(═NRc)NRcRc, NRcC(═NRc)NRcRc, NHRc, NRcRc, NRcC(O)Rc, NRcC(═NRc)Rc, NRcC(O)ORc, NRcC(O)NRcRc, NRcS(O)Rc, NRcS(O)2Rc, NRcS(O)2NRcRc, S(O)Rc, S(O)NRcRc, S(O)2Rc, S(O)2NRcC(O)Rc, —P(O)RcRc, —P(O)(ORc)(ORc), —B(OH)2, —B(ORc)2 and S(O)2NRcRc;
• wherein the C1-6 alkyl, C1-6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl- and (4-10 membered heterocycloalkyl)-C1-4 alkyl- are each further optionally substituted with 1, 2 or 3 independently selected Rd substituents;
• each Rc is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl-, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl- and (4-10 membered heterocycloalkyl)-C1-4 alkyl- are each optionally substituted with 1, 2, 3, 4, or 5 independently selected Rf substituents;
• or two Rc attached to the same nitrogen atom are taken together to form a 4-14 membered heterocycloalkyl ring which is optionally substituted with 1, 2, or 3 independently selected Rf substituents;
• each Rd is independently selected from C1-6 alkyl, C1-6 haloalkyl, halo, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5-10 membered heteroaryl, C3-14 cycloalkyl, 4-14 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-14 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, (4-14 membered heterocycloalkyl)-C1-4 alkyl-, CN, NH2, NHORe, ORe, SRe, C(O)Re, C(O)NReRe, C(O)ORe, C(O)NReS(O)2Re, OC(O)Re, OC(O)NReRe, NHRe, NReRe, NReC(O)Re, NReC(═NRe)Re, NReC(O)NReRe, NReC(O)ORe, C(═NRe)NReRe, NReC(═NRe)NReRe, NReC(═NOH)NReRe, NReC(═NCN)NReRe, S(O)Re, S(O)NReRe, S(O)2Re, S(O)2NReC(O)Re, NReS(O)2Re, NReS(O)2NReRe, —P(O)ReRe, —P(O)(ORe)(ORe), —B(OH)2, —B(ORe)2 and S(O)2NReRe, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5-10 membered heteroaryl, C3-14 cycloalkyl, 4-14 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-14 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, and (4-14 membered heterocycloalkyl)-C1-4 alkyl- are each optionally substituted with 1, 2, or 3 independently selected Rf substituents;
• each Re is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl-, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl- and (4-10 membered heterocycloalkyl)-C1-4 alkyl- are each optionally substituted with 1, 2 or 3 independently selected Rf substituents;
• each Rf is independently selected from C1-4 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, (4-10 membered heterocycloalkyl)-C1-4 alkyl-, halo, CN, NHORg, ORg, SRg, C(O)Rg, C(O)NRgRg, C(O)ORg, C(O)NRgS(O)2Rg, OC(O)Rg, OC(O)NRgRg, NHRg, NRgRg, NRgC(O)Rg, NRgC(═NRg)Rg, NRgC(O)NRgRg, NRgC(O)ORg, C(═NRg)NRgRg, NRgC(═NRg)NRgRg, S(O)Rg, S(O)NRgRg, S(O)2Rg, S(O)2NRgC(O)Rg, NRgS(O)2Rg, NRgS(O)2NRgRg, —P(O)RgRg, —P(O)(ORg)(ORg), —B(OH)2, —B(ORg)2 and S(O)2NRgRg;
• wherein the C1-4 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl- are each optionally substituted with 1, 2, 3, 4, or 5 independently selected Rn substituents;
• each Rgis independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl-, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl- and (4-10 membered heterocycloalkyl)-C1-4 alkyl- are each optionally substituted with 1, 2, or 3 independently selected Rp substituents;
• each Rn is substituents independently selected from C1-4 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, (4-10 membered heterocycloalkyl)-C1-4 alkyl-, halo, CN, NHORo, ORo, SRo, C(O)Ro, C(O)NRoRo, C(O)ORo, C(O)NRoS(O)2Ro, OC(O)Ro, OC(O)NRoRo, NHRo, NRoRo, NRoC(O)Ro, NRoC(═NRoRo, NRoC(O)NRoRo, NRoC(O)ORo, C(═NRoNRoRo, NRoC(═NRoNRoRo, S(O)Ro, S(O)NRoRo, S(O)2Ro, S(O)2NRoC(O)Ro, NRoS(O)2Ro, NRoS(O)2NRoRo, —P(O)RoRo, —P(O)(ORo(ORo), —B(OH)2, —B(ORo)2 and S(O)2NRoRo, wherein the C1-4 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl- are each optionally substituted with 1, 2 or 3 independently selected Rq substituents;
• each Rp is independently selected from C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, (4-10 membered heterocycloalkyl)-C1-4 alkyl-, halo, CN, NHORr, ORr, SRr, C(O)Rr, C(O)NRrRr, C(O)ORr, C(O)NRrS(O)2Rr, OC(O)Rr, OC(O)NRrRr, NHRr, NRrRr, NRrC(O)Rr, NRrC(═NRr)Rr, NRrC(O)NRrRr, NRrC(O)ORr, C(═NRr)NRrRr, NRrC(═NRr)NRrRr, NRrC(═NOH)NRrRr, NRrC(═NCN)NRrRr, S(O)Rr, S(O)NRrRr, S(O)2Rr, S(O)2NRrC(O)Rr, NRrS(O)2Rr, NRrS(O)2NRrRr, —P(O)RrRr, —P(O)(ORr)(0Rr), —B(OH)2, —B(ORr)2 and S(O)2NRrRr, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl- and (4-10 membered heterocycloalkyl)-C1-4 alkyl- is optionally substituted with 1, 2 or 3 independently selected Rq substituents;
• each Ro or Rr is independently selected from H, C1-4 alkyl, C3-6 cycloalkyl, C6-10 aryl, 5 or 6-membered heteroaryl, 4-7 membered heterocycloalkyl, C1-6 haloalkyl, C1-6 haloalkoxy, C2-4 alkenyl, and C2-4 alkynyl, wherein the C1-4 alkyl, C3-6 cycloalkyl, C6-10 aryl, 5 or 6-membered heteroaryl, 4-7 membered heterocycloalkyl, C2-4 alkenyl, and C2-4 alkynyl are each optionally substituted with 1, 2 or 3 independently selected Rq substituents;
• and
• each Rq is independently selected from OH, NO2, CN, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, phenyl, C3-7 cycloalkyl, 4-6 membered heterocycloalkyl, and 5-6 membered heteroaryl, C1-6 alkoxy, C1-6 haloalkoxy, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, thio, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, carbamyl, C1-6 alkylcarbamyl, di(C1-6 alkyl)carbamyl, carboxy, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, C1-6 alkylcarbonyloxy, C1-6 alkylcarbonylamino, C1-6 alkoxycarbonylamino, C1-6 alkylaminocarbonyloxy, C1-6 alkylsulfonylamino, aminosulfonyl, C1-6 alkylaminosulfonyl, di(C1-6 alkyl)aminosulfonyl, aminosulfonylamino, C1-6 alkylaminosulfonylamino, di(C1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C1-6 alkylaminocarbonylamino, and di(C1-6 alkyl)aminocarbonylamino, wherein the C1-6 alkyl, phenyl, C3-7 cycloalkyl, 4-6 membered heterocycloalkyl, and 5-6 membered heteroaryl are each optionally substituted with 1, 2 or 3 substituents independently selected from halo, OH, CN, —COOH, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, amino, C1-3 alkylamino, and di(C1-3 alkyl)amino;
• and
• wherein S has Formula (S-1c):
• wherein:
• L is attached to Ra1;
• each Ra1 is independently selected from H, Rc1, C(O)Rc1, C(O)OH, C(O)ORc1, S(O)Rc1, S(O)2Rc1, C(O)NH2, C(O)NRc1Rd1, S(O)2NH2, and S(O)2NRc1Rd1;
• each Rc1 is independently selected from C1-4 alkyl, C1-4 haloalkyl, -(C1-4 alkyl)-OH, -(C1-4 alkyl)-O—P(O)(OH)2, -(C1-4 alkyl)-O—P(O)(RIRII)2, -(C1-4 alkyl)-O-(C1-4 alkyl), -(C1-4 alkyl)-N(Re1)(Rf1), -(C1-4 alkyl)-O—C(O)(C1-4 alkyl), -(C1-4 alkyl)-C(O)—O-(C1-4 alkyl), optionally substituted C3-6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-6 membered heterocycloalkyl, optionally substituted 5-6 membered heteroaryl, optionally substituted 9-10 membered heteroaryl, optionally substituted -C1-4 alkyl-C3-6 cycloalkyl, optionally substituted -C1-4 alkyl-phenyl, optionally substituted -C1-4 alkyl-4-6 membered heterocycloalkyl, optionally substituted -C1-4 alkyl-5-6 membered heteroaryl, and optionally substituted -C1-4 alkyl-9-10 membered heteroaryl;
• wherein the C3-6 cycloalkyl, phenyl, 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl and 9-10 membered heteroaryl moieties of said optionally substituted C3-6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-6 membered heterocycloalkyl, optionally substituted 5-6 membered heteroaryl, optionally substituted 9-10 membered heteroaryl, optionally substituted -C1-4 alkyl-C3-6 cycloalkyl, optionally substituted -C1-4 alkyl-phenyl, optionally substituted -C1-4 alkyl-4-6 membered heterocycloalkyl, optionally substituted -C1-4 alkyl-5-6 membered heteroaryl, and optionally substituted -C1-4 alkyl-9-10 membered heteroaryl are each optionally substituted by 1, 2, 3, or 4 substituents independently selected from halo, OH, OP(O)(OH)2, OP(O)(RIRII)2, amino, (C1-4 alkyl)NH2, (C1-4 alkyl)amino, di-(C1-4 alkyl)amino, C1-4 alkyl, C1-4 haloalkyl, C1-4 haloalkoxy, C1-6 alkoxy-, OH-(C2-4 alkoxy)-, -(C1-4 alkyl)-O—P(O)(OH)2, -(C1-4 alkyl)-O—P(O)(RIRII)2, C1-4 alkoxy-(C1-4 alkoxy)-, C(O)Rd1, C(O)NRd1Rf1, and C(O)ORd1;
• each Rd1 is independently selected from H and C1-4 alkyl;
• each Re1 is independently selected from H, C1-4 alkyl, —C(O)(C1-4 alkyl), —OC(O)(C1-4 alkyl), —C(O)O(C1-4 alkyl), -(C1-4 alkyl)NH2, -(C1-4 alkyl)-C1-4 alkoxy, —C(O)-(optionally substituted 5-6 membered heterocycloalkyl), —C(O)(C1-4 alkyl)-(optionally substituted 5-6 membered heterocycloalkyl), —C(O) (optionally substituted 5-6 membered heteroaryl), and —C(O)(C1-4 alkyl)-(optionally substituted 5-6 membered heteroaryl), wherein the optionally substituted 5-6 membered heterocycloalkyl and optionally substituted 5-6 membered heteroaryl are each optionally substituted 1, 2, 3, or 4 substituents independently selected from halo, OH, —OP(O)(OH)2, OP(O)(RIRII)2, amino, (C1-4 alkyl)NH2, (C1-4 alkyl)amino-, di-(C1-4 alkyl)amino-, C1-4 alkyl, C1-4 haloalkyl, C1-4 haloalkoxy, C1-4 alkoxy-, OH-(C2-4 alkoxy)-, -(C1-4 alkyl)-O—P(O)(OH)2, -(C1-4 alkyl)-O—P(O)(RIRII)2, C1-4 alkoxy-(C1-4 alkoxy)-, C1-4 alkoxy-(C1-4 alkoxy)-, C(O)Rd1, C(O)NRd1Rf1, and C(O)ORd1;
• each Rf1 is independently selected from H and C1-4 alkyl;
• and
• each occurrence of RI and RII are independently C1-6 alkoxy;
• or
• wherein S has Formula (S-2b):
• wherein:
• L is attached to Ra4;
• Ra4 is selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-C1-4 alkyl, C6-10 aryl-C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl, and 5-10 membered heteroaryl-C1-4 alkyl, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-C1-4 alkyl, C6-10 aryl-C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl, and 5-10 membered heteroaryl-C1-4 alkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R4A groups;
• each R4A is independently selected from H, halo, CN, NO2C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-C1-4 alkyl, phenyl-C1-4 alkyl, 4-7 membered heterocycloalkyl-C1-4 alkyl, 5-6 membered heteroaryl-C1-4 alkyl, ORa41, SRa41, C(═O)Rb41, C(═O)NRc41Rd41, C(═O)ORa41, OC(═O)Rb41, OC(═O)NRc41Rd41, NRc41Rd41, NRc41C(═O)Rb41, NRc1C(═O)ORb41, NRc1C(═O)NRc41Rd41, C(═NRe41)Rb41, C(═NRe41)NRc41Rd41, NRc41C(═NRe41)NRc41Rd41, NRc41S(═O)2Rb41, NRc41S(═O)2NRc41Rd41, S(═O)2Rb41, S(═O)2NRc41Rd41, and OP(O)(ORf41), wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-C1-4 alkyl, phenyl-C1-4 alkyl, 4-7 membered heterocycloalkyl-C1-4 alkyl, and 5-6 membered heteroaryl-C1-4 alkyl are each optionally substituted by 1, 2, 3, or 4 independently selected R4B groups;
• each Ra41, Rc41, and Rd41 is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-C1-4 alkyl, phenyl-C1-4 alkyl, 4-7 membered heterocycloalkyl-C1-4 alkyl, and 5-6 membered heteroaryl-C1-4 alkyl, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-C1-4 alkyl, phenyl-C1-4 alkyl, 4-7 membered heterocycloalkyl-C1-4 alkyl, and 5-6 membered heteroaryl-C1-4 alkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R4B groups;
• each Rb41 is independently selected from C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-C1-4 alkyl, phenyl-C1-4 alkyl, 4-7 membered heterocycloalkyl-C1-4 alkyl, and 5-6 membered heteroaryl-C1-4 alkyl, which are each optionally substituted with 1, 2, 3, or 4 independently selected R4B groups;
• each Re41 is independently selected from H, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, and C1-4 haloalkoxy;
• each Rf41 is independently OH or C1-6 alkoxy;
• each R4B is independently selected from H, halo, CN, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-C1-4 alkyl, phenyl-C1-4 alkyl, 4-7 membered heterocycloalkyl-C1-4 alkyl, 5-6 membered heteroaryl-C1-4 alkyl, ORa42, SRa42, C(═O)Rb42, C(═O)NRc42dd42, C(═O)ORa42, OC(═O)Rb42, OC(═O)NRc42Rd42, NRc42Rd42, NRc42C(═O)Rb42, NRc42C(═O)ORb42, NRc42C(═O)NRc42Rd42, C(═NRe42)Rb42, C(═NRe42)NRc42Rd42, NRc42C(═NRe42)NRc42Rd42, NRc42S(═O)2l Rb42, NRc42S(═O)2NRc42Rd42, S(═O)2Rb42, S(═O)2NRc42Rd42, and OP(O)(ORf42), wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-C1-4 alkyl, phenyl-C1-4 alkyl, 4-7 membered heterocycloalkyl-C1-4 alkyl, and 5-6 membered heteroaryl-C1-4 alkyl are each optionally substituted by 1, 2, 3, or 4 independently selected RG groups;
• each Ra42, Rc42, and Rd42 is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-C1-4 alkyl, phenyl-C1-4 alkyl, 4-7 membered heterocycloalkyl-C1-4 alkyl, and 5-6 membered heteroaryl-C1-4 alkyl, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-C1-4 alkyl, phenyl-C1-4 alkyl, 4-7 membered heterocycloalkyl-C1-4 alkyl, and 5-6 membered heteroaryl-C1-4 alkyl are each optionally substituted with 1, 2, 3, or 4 independently selected RG groups;
• each Rb42 is independently selected from C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-C1-4 alkyl, phenyl-C1-4 alkyl, 4-7 membered heterocycloalkyl-C1-4 alkyl, and 5-6 membered heteroaryl-C1-4 alkyl, which are each optionally substituted with 1, 2, 3, or 4 independently selected RG groups;
• each Re42 is independently selected from H, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, and C1-4 haloalkoxy;
• each Rf42 is independently OH or C1-6 alkoxy;
• and
• each RG is independently selected from OH, NO2, CN, halo, C1-3 alkyl, C2-3 alkenyl, C2-3 alkynyl, C1-3 haloalkyl, cyano-C1-3 alkyl, HO-C1-3 alkyl, C1-3 alkoxy-C1-3 alkyl, C3-7 cycloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, amino, C1-3 alkylamino, di(C1-3 alkyl)amino, thio, C1-3 alkylthio, C1-3 alkylsulfinyl, C1-3 alkylsulfonyl, carbamyl, C1-3 alkylcarbamyl, di(C1-3 alkyl)carbamyl, carboxy, C1-3 alkylcarbonyl, C1-3 alkoxycarbonyl, C1-3 alkylcarbonyloxy, C1-3 alkylcarbonylamino, C1-3 alkoxycarbonylamino, C1-3 alkylaminocarbonyloxy, C1-3 alkylsulfonylamino, aminosulfonyl, C1-3 alkylaminosulfonyl, di(C1-3 alkyl)aminosulfonyl, aminosulfonylamino, C1-3 alkylaminosulfonylamino, di(C1-3 alkyl)aminosulfonylamino, aminocarbonylamino, C1-3 alkylaminocarbonylamino, and di(C1-3 alkyl)aminocarbonylamino.