Tetrahydroquinoline compositions as bet bromodomain inhibitors

A method of treating or inhibiting an inflammatory condition associated with the activity of one or more BET-family bromodomains in a patient comprising administering to said patient in need thereof a therapeutically effective amount of a compound of Formulae (I), (II), (III) or (IV):

• wherein:
• W is O, S, C(O), or CHR3;
• X is N or CR4;
• Y is N or CR6;
• Z is N or CR7;
• R1 is C1-C6 alkyl, or C1-C6 haloalkyl;
• R2 is hydrogen or NRaRb;
• R3 is hydrogen, halogen, hydroxyl, C1-C6 alkyl, or C1-C6 haloalkyl;
• R4 is hydrogen, —(CH2)nRd, —O(CH2)nRd, —N(CH2)nRd, —O(CH2)nC(O)Rd, or —O(CH2)nS(O)2Rd;
• R5 is halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, heteroaryl, —(C1-C6)-alkylene-aryl, —(C1-C6)-alkylene-heteroaryl, —(C1-C6)-alkylene-heterocycloalkyl, —(CRaRb)nORc, —(CRaRb)nRc, —O(CRaRb)nNRaRb, —NRaRb, —NRaC(O)Rb, —NRaS(O)2Rb, or Rc, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl are optionally substituted with one or more substituents independently selected from Ra, Rb, and RC;
• R6 is hydrogen, halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, heteroaryl, —(C1-C6)-alkylene-aryl, —(C1-C6)-alkylene-heteroaryl, —(C1-C6)-alkylene-heterocycloalkyl, —(CRaRb)nOR, —(CRaRb)nRc, —O(CRaRb)nNRaRb, —NRaRb, —NRaC(O)Rb, —NRaS(O)2Rb, or Rc, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl are optionally substituted with one or more substituents independently selected from Ra, Rb, and Rc;
• R7 is hydrogen or halogen;
• R8 is Ra, —ORa, —NRa, or heterocycloalkyl;
• Ra and Rb are each independently hydrogen, halogen, C1-C6 alkyl, cycloalkyl, or heterocycloalkyl, wherein C1-C6 alkyl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more Re;
• Rc is —NH2, OH, —NH(C1-C6 alkyl), —O(CH2)nNRaRb, —NH(C1-C6 alkoxy), —(CH2)nRa, —(CH2)nORa, —C(O)Ra, —C(O)ORa, —C(O)NRaRb, —(CH2)nS(O)2CH3, —S(O)2Ra, —S(O)2NRaRb, —NRa—S(O)2Rb, —NHC(O)Ra, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, halo, cyano, or oxo, wherein C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally susbtitued with one or more Re;
• or two adjacent Rc can combine with the carbons to which they are attached to form a carbocycle or heterocycle;
• Rd is hydrogen, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein said alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one or more substituents independently selected from Ra, Rb, and Rc;
• Re is hydrogen, halogen, OH, C1-C6 alkyl, cycloalkyl, heterocycloalkyl, oxo, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkoxy, or S(O)2(C1-C6 alkyl);
• and
• n is 0, 1, or 2;
• wherein:
• W is O, C(O), or CHR3;
• Ar is aryl or heteroaryl;
• R2 is hydrogen or NRaRb;
• R3 is hydrogen, hydroxy, or halo;
• R4 hydrogen, —O(CH2)nRd, —O(CH2)nC(O)Rd, or —O(CH2)nS(O)2Rd;
• R7 is hydrogen or halo;
• R8 is Ra, —ORa, or heterocycloalkyl;
• Ra and Rb are independently hydrogen, C1-C6 alkyl, heterocycloalkyl, or cycloalkyl;
• Rc is Ra, —(CH2)nORa, —C(O)Ra, —C(O)ORa, —C(O)NRaRb—S(O)2Ra, halo, or oxo;
• and
• n is 0, 1, or 2;
• wherein:
• Ar is pyrazolyl or phenyl;
• R4 is hydrogen, —O(CH2)nRd, —O(CH2)nC(O)Rd, or —O(CH2)nS(O)2Rd;
• R8 is methyl, methoxy, or cyclopropyl;
• Ra and Rb are independently hydrogen or C1-C6 alkyl;
• Rc is —(CH2)nRa, —(CH2)nORa, —C(O)Ra, —C(O)ORa, —C(O)NRaRb, —(CH2)nS(O)2CH3, —S(O)2Ra, —S(O)2NRaRb, C1-C6 haloalkyl, C1-C6 haloalkoxy, cycloalkyl, heterocycloalkyl, halo, cyano, or oxo;
• Rd is hydrogen, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, C1-C6 alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein said alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one or more substituents independently selected from Ra, Rb, and Rc;
• and
• n is 0, 1, or 2;
• wherein:
• R4 is —O(CH2)nRd, —O(CH2)nC(O)Rd, or —O(CH2)nS(O)2Rd;
• R8 is alkyl, cycloalkyl, O-alkyl, or O-cycloalkyl
• Ra and Rb are independently hydrogen or C1-C6 alkyl;
• Rc is —(CH2)nRa, —(CH2)nORa, —C(O)Ra, —C(O)ORa, —C(O)NRaRb—S(O)2Ra, —S(O)2NRaRb, C1-C6 haloalkyl, C1-C6 haloalkoxy, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, halo, cyano, or oxo;
• Rd is hydrogen, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, C1-C6 alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein said alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one or more substituents independently selected from Ra, Rb, and Rc;
• and
• n is 0, 1, or 2;
• or a pharmaceutically acceptable salt, enantiomer, hydrate, solvate, isomer, or tautomer of the compound of Formulae (I), (II), (III) or (IV);
• wherein the inflammatory disorder is periodontitis, psoriatic arthritis, ankylosing spondylitis, HIV-associated nephropathy, amyotrophic lateral sclerosis, systemic sclerosis, pulmonary arterial hypertension, acute allograft rejection, chronic organ transplant rejection, lupus nephritis, and severe celiac/coeliac disease.

A pharmaceutical composition comprising a compound of Formulae (I), (II), (III) or (IV):

• wherein:
• W is O, S, C(O), or CHR3;
• X is N or CR4;
• Y is N or CR6;
• Z is N or CR7;
• R1 is C1-C6 alkyl, or C1-C6 haloalkyl;
• R2 is hydrogen or NRaRb;
• R3 is hydrogen, halogen, hydroxyl, C1-C6 alkyl, or C1-C6 haloalkyl;
• R4 is hydrogen, —(CH2)nRd, —O(CH2)nRd, —N(CH2)nRd, —O(CH2)nC(O)Rd, or —O(CH2)nS(O)2Rd;
• R5 is halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, heteroaryl, —(C1-C6)-alkylene-aryl, —(C1-C6)-alkylene-heteroaryl, —(C1-C6)-alkylene-heterocycloalkyl, —(CRaRb)nOR, —(CRaRb)nRc, —O(CRaRb)nNRaRb, —NRaRb, —NRaC(O)Rb, —NRaS(O)2Rb, or Rc, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl are optionally substituted with one or more substituents independently selected from Ra, Rb, and RC;
• R6 is hydrogen, halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, heteroaryl, —(C1-C6)-alkylene-aryl, —(C1-C6)-alkylene-heteroaryl, —(C1-C6)-alkylene-heterocycloalkyl, —(CRaRb)nOR, —(CRaRb)nRc, —O(CRaRb)nNRaRb, —NRaRb, —NRaC(O)Rb, —NRaS(O)2Rb, or Rc, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl are optionally substituted with one or more substituents independently selected from Ra, Rb, and RC;
• R7 is hydrogen or halogen;
• R8 is Ra, —ORa, —NRa, or heterocycloalkyl;
• Ra and Rb are each independently hydrogen, halogen, C1-C6 alkyl, cycloalkyl, or heterocycloalkyl, wherein C1-C6 alkyl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more Re;
• Rc is —NH2, OH, —NH(C1-C6 alkyl), —O(CH2)nNRaRb, —NH(C1-C6 alkoxy), —(CH2)nRa, —(CH2)nORa, —C(O)Ra, —C(O)ORa, —C(O)NRaRb, —(CH2)nS(O)2CH3, —S(O)2Ra, —S(O)2NRaRb, —NRa—S(O)2Rb, —NHC(O)Ra, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, halo, cyano, or oxo, wherein C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally susbtitued with one or more Re;
• or two adjacent Rc can combine with the carbons to which they are attached to form a carbocycle or heterocycle;
• Rd is hydrogen, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein said alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one or more substituents independently selected from Ra, Rb, and Re;
• Re is hydrogen, halogen, OH, C1-C6 alkyl, cycloalkyl, heterocycloalkyl, oxo, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkoxy, or S(O)2(C1-C6 alkyl);
• and
• n is 0, 1, or 2;
• wherein:
• W is O, C(O), or CHR3;
• Ar is aryl or heteroaryl;
• R2 is hydrogen or NRaRb;
• R3 is hydrogen, hydroxy, or halo;
• R4 hydrogen, —O(CH2)nRd, —O(CH2)nC(O)Rd, or —O(CH2)nS(O)2Rd;
• R7 is hydrogen or halo;
• R8 is Ra, —ORa, or heterocycloalkyl;
• Ra and Rb are independently hydrogen, C1-C6 alkyl, heterocycloalkyl, or cycloalkyl;
• Rc is Ra, —(CH2)nORa, —C(O)Ra, —C(O)ORa, —C(O)NRaRb—S(O)2Ra, halo, or oxo;
• and
• n is 0, 1, or 2;
• wherein:
• Ar is pyrazolyl or phenyl;
• R4 is hydrogen, —O(CH2)nR, —O(CH2)nC(O)Rd, or —O(CH2)nS(O)2Rd;
• R8 is methyl, methoxy, or cyclopropyl;
• Ra and Rb are independently hydrogen or C1-C6 alkyl;
• Rc is —(CH2)nRa, —(CH2)nORa, —C(O)Ra, —C(O)ORa, —C(O)NRaRb, —(CH2)nS(O)2CH3, —S(O)2Ra, —S(O)2NRaRb, C1-C6 haloalkyl, C1-C6 haloalkoxy, cycloalkyl, heterocycloalkyl, halo, cyano, or oxo;
• Rd is hydrogen, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, C1-C6 alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein said alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one or more substituents independently selected from Ra, Rb, and Rc;
• and
• n is 0, 1, or 2;
• wherein:
• R4 is —O(CH2)nRd, —O(CH2)nC(O)Rd, or —O(CH2)nS(O)2Rd;
• R8 is alkyl, cycloalkyl, O-alkyl, or O-cycloalkyl
• Ra and Rb are independently hydrogen or C1-C6 alkyl;
• Rc is —(CH2)nRa, —(CH2)nORa, —C(O)Ra, —C(O)ORa, —C(O)NRaRb—S(O)2Ra, —S(O)2NRaRb, C1-C6 haloalkyl, C1-C6 haloalkoxy, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, halo, cyano, or oxo;
• Rd is hydrogen, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, C1-C6 alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein said alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one or more substituents independently selected from Ra, Rb, and Rc;
• and
• n is 0, 1, or 2;
• or a pharmaceutically acceptable salt, enantiomer, hydrate, solvate, isomer, or tautomer of the compound of Fomulae (I), (II), (III) or (IV);
• a pharmaceutically acceptable carrier;
• and
• one or more additional therapeutic agents selected from the group consisting of an AKT inhibitor, alcohol dehydrogenase inhibitor, alkylating agent, all-trans retinoic acid, antiandrogen, Anti-human immunodeficiency virus monoclonal antibody, azacitidine, BCL2 inhibitor, BCL-XL inhibitor, BCR-ABL inhibitor, BTK inhibitor, BTK/LCK/LYN inhibitor, CDK1/2/4/6/7/9 inhibitor, CDK4/6 inhibitor, CDK9 inhibitor, CBP/p300 inhibitor, EGFR inhibitor, endothelin receptor antagonist, ERK inhibitor, farnesyltransferase inhibitor, FLT3 inhibitor, glucocorticoid receptor agonist, HDM2 inhibitor, histone deacetylase inhibitor, IKKb inhibitor, immunomodulatory drug (IMiD), ingenol, ionizing radiation, ITK inhibitor, JAK1/JAK2/JAK3/TYK2 inhibitor, MEK inhibitor, midostaurin, MTOR inhibitor, PI3 kinase inhibitor, dual PI3 kinase/MTOR inhibitor, proteasome inhibitor, protein kinase C agonist, SUV39H1 inhibitor, TRAIL, VEGFR2 inhibitor, Wnt/β-catenin signalling inhibitor, decitabine, and anti-CD20 monoclonal antibody.

A pharmaceutical composition comprising a compound of Formulae (I), (II), (III) or (IV):

• wherein:
• W is O, S, C(O), or CHR3;
• X is N or CR4;
• Y is N or CR6;
• Z is N or CR7;
• R1 is C1-C6 alkyl, or C1-C6 haloalkyl;
• R2 is hydrogen or NRaRb;
• R3 is hydrogen, halogen, hydroxyl, C1-C6 alkyl, or C1-C6 haloalkyl;
• R4 is hydrogen, —(CH2)nRd, —O(CH2)nRd, —N(CH2)nRd, —O(CH2)nC(O)Rd, or —O(CH2)nS(O)2Rd;
• R5 is halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, heteroaryl-, —(C1-C6)-alkylene-aryl, —(C1-C6)-alkylene-heteroaryl, —(C1-C6)-alkylene-heterocycloalkyl, —(CRaRb)nOR, —(CRaRb)nR, —O(CRaRb)nNRaRb, —NRaRb, —NRaC(O)Rb, —NRaS(O)2Rb, or Rc, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl are optionally substituted with one or more substituents independently selected from Ra, Rb, and Rc;
• R6 is hydrogen, halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, heteroaryl, —(C1-C6)-alkylene-aryl, —(C1-C6)-alkylene-heteroaryl, —(C1-C6)-alkylene-heterocycloalkyl, —(CRaRb)nOR, —(CRaRb)nR, —O(CRaRb)nNRaRb, —NRaRb, —NRaC(O)Rb, —NRaS(O)2Rb, or Rc, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl are optionally substituted with one or more substituents independently selected from Ra, Rb, and Rc;
• R7 is hydrogen or halogen;
• R8 is Ra, —ORa, —NRa, or heterocycloalkyl;
• Ra and Rb are each independently hydrogen, halogen, C1-C6 alkyl, cycloalkyl, or heterocycloalkyl, wherein C1-C6 alkyl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more Re;
• Rc is —NH2, OH, —NH(C1-C6 alkyl), —O(CH2)nNRaRb, —NH(C1-C6 alkoxy), —(CH2)nRa, —(CH2)nORa, —C(O)Ra, —C(O)ORa, —C(O)NRaRb, —(CH2)nS(O)2CH3, —S(O)2Ra, —S(O)2NRaRb, —NRa—S(O)2Rb, —NHC(O)Ra, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, halo, cyano, or oxo, wherein C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more Re;
• or two adjacent Rc can combine with the carbons to which they are attached to form a carbocycle or heterocycle;
• Rd is hydrogen, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein said alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one or more substituents independently selected from Ra, Rb, and Rc;
• Re is hydrogen, halogen, OH, C1-C6 alkyl, cycloalkyl, heterocycloalkyl, oxo, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkoxy, or S(O)2(C1-C6 alkyl);
• and
• n is 0, 1, or 2;
• wherein:
• W is O, C(O), or CHR3;
• Ar is aryl or heteroaryl;
• R2 is hydrogen or NRaRb;
• R3 is hydrogen, hydroxy, or halo;
• R4 hydrogen, —O(CH2)nRd, —O(CH2)nC(O)Rd, or —O(CH2)nS(O)2Rd;
• R7 is hydrogen or halo;
• R8 is Ra, —ORa, or heterocycloalkyl;
• Ra and Rb are independently hydrogen, C1-C6 alkyl, heterocycloalkyl, or cycloalkyl;
• Rc is Ra, —(CH2)nORa, —C(O)Ra, —C(O)ORa, —C(O)NRaRb—S(O)2Ra, halo, or oxo;
• and
• n is 0, 1, or 2;
• wherein:
• Ar is pyrazolyl or phenyl;
• R4 is hydrogen, —O(CH2)nRd, —O(CH2)nC(O)Rd, or —O(CH2)nS(O)2Rd;
• R8 is methyl, methoxy, or cyclopropyl;
• Ra and Rb are independently hydrogen or C1-C6 alkyl;
• Rc is —(CH2)nRa, —(CH2)nORa, —C(O)Ra, —C(O)ORa, —C(O)NRaRb, —(CH2)nS(O)2CH3, —S(O)2Ra, —S(O)2NRaRb, C1-C6 haloalkyl, C1-C6 haloalkoxy, cycloalkyl, heterocycloalkyl, halo, cyano, or oxo;
• Rd is hydrogen, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, C1-C6 alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein said alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one or more substituents independently selected from Ra, Rb, and Rc;
• and
• n is 0, 1, or 2;
• wherein:
• R4 is —O(CH2)nRd, —O(CH2)nC(O)Rd, or —O(CH2)nS(O)2Rd;
• R8 is alkyl, cycloalkyl, O-alkyl, or O-cycloalkyl
• Ra and Rb are independently hydrogen or C1-C6 alkyl;
• Rc is —(CH2)nRa, —(CH2)nORa, —C(O)Ra, —C(O)ORa, —C(O)NRaRb—S(O)2Ra, —S(O)2NRaRb, C1-C6 haloalkyl, C1-C6 haloalkoxy, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, halo, cyano, or oxo;
• Rd is hydrogen, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, C1-C6 alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein said alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one or more substituents independently selected from Ra, Rb, and Rc;
• and
• n is 0, 1, or 2;
• or a pharmaceutically acceptable salt, enantiomer, hydrate, solvate, isomer, or tautomer of the compound of Formulae (I), (II), (III) or (IV);
• a pharmaceutically acceptable carrier;
• and
• one or more immune check point inhibitors.