Benzopiperazine 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), (IV), (V), or (VI):

• wherein:
• X is selected from N or CR3;
• Y is selected from N or CR5;
• Z is selected from N or CR6;
• R1 is hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl;
• R2 is —C(O)(CRkRl)nO(CRkRl)mRd, —C(O)(CRkRl)nRe, —S(O)2(CRkRl)nRf, —(CRkRl)nRg, —C(O)(CRkRl)nNRaRg or —C(O)(CRkRl)nS(CRkRl)mRf;
• R3 and R6 are each independently selected from hydrogen or halogen;
• R4 is hydrogen, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, C6-C10 aryl, heterocycloalkyl, heteroaryl, —NRaRb, —C(O)Rh, —ORh, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, —C1-C4 alkyl(aryl), —C1-C4 alkyl(heteroaryl), or —C1-C4 alkyl(heterocycloalkyl), wherein the cycloalkyl, aryl, heterocycloalkyl, heteroaryl, and alkyl are optionally substituted with one or more R10;
• R5 is hydrogen, halogen, C1-C6 alkyl, nitro, —NH2, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 aminoalkyl, C1-C6 aminoalkoxy, CN, C1-C6 alkoxy, —C(O)NRaRb, —NRaS(O)2Rb, —NRaC(O)Rb, —NRaC(O)ORb, —NRaC(O)NRbRc, C1-C6 haloalkyl, C1-C6 haloalkoxy, —S(O)2NRaRb, or —S(O)2Ra;
• R7 is —C(O)R8, —C(O)OR8, —C(O)NR8R9, or —S(O)2R8;
• R8 and R9 are each independently hydrogen, —(CRkRl)mORa, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
• each R10 is independently at each occurrence selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, —ORi, —NRaRi, CN, oxo, —(CRkRl)nS(O)2Ri, —(CRkRl)nNRaS(O)2Ri, —(CRkRl)nS(O)2NRaRi, —(CRkRl)nNRaRiS(O)2NRaRi, —(CRkRl)nC(O)ORa, —(CRkRl)nC(O)Ri, —(CRkRl)nC(O)NRaRi, —(CRkRl)nRi, —(CRkRl)nNRaC(O)NRb, —(CRkRl)nNRaC(O)ORb, and oxo, wherein each alkyl is substituted with one or more R11;
• or
• two R10 together when on adjacent carbons form an aryl ring optionally substituted with one or more R11;
• or two R10 together when on adjacent carbons form a heteroaryl ring optionally substituted with one or more R11;
• or two R10 together when on adjacent carbons form a heterocycloalkyl ring optionally substituted with one or more R11;
• each R11 is independently at each occurrence selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxy, CN, C1-C6 hydroxyalkyl, —(CRkRl)mNH2, C1-C6 alkylamino, C1-C6 dialkylamino, —C(O)NRaRb, —C(O)ORa, —C(O)Ra, —S(O)2Ra, —C(O)H, —NRaC(O)ORa, —NRaC(O)C1-C6 alkyl, or oxo;
• or two R11 together can form a heterocycloalkyl ring;
• Ra, Rb, and Rc are each independently at each occurrence hydrogen, C1-C6 alkyl, —C1-C4 alkyl(aryl), or aryl, wherein the alkyl and aryl are optionally substituted with one or more R10;
• Rd is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, CN, —C(O)C1-C6 alkyl, C3-C7 cycloalkyl, aryl, heteroaryl, or heterocycloalkyl, wherein cycloalkyl, aryl, heteroaryl, and heterocycloalkyl are optionally substituted with one or more R12;
• Re is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkoxy, CN, C3-C7 cycloalkyl, aryl, heteroaryl, or heterocycloalkyl, wherein cycloalkyl, aryl, heteroaryl, and heterocycloalkyl are optionally substituted with one or more R12;
• Rf is C3-C7 cycloalkyl, aryl, heteroaryl, or heterocycloalkyl, wherein cycloalkyl, aryl, heteroaryl and heterocycloalkyl are optionally substituted with one or more R12;
• Rg is C1-C6 alkyl, C3-C7 cycloalkyl, —C1-C4 alkyl(C3-C7 cycloalkyl), aryl, —C1-C4 alkyl(aryl), heteroaryl, —C1-C4 alkyl(heteroaryl), heterocycloalkyl, or —C1-C4 alkyl(heterocycloalkyl), wherein cycloalkyl, aryl, heteroaryl, and heterocycloalkyl are optionally substituted with one or more R12;
• Rh is C3-C7 cycloalkyl, aryl, heteroaryl, or heterocycloalkyl, wherein cycloalkyl, aryl, heteroaryl, and heterocycloalkyl are optionally substituted with one or more R10;
• Ri is hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, —(CH2)qN(H)C1-C6 alkyl, —(CH2)qN(C1-C6 alkyl)2, —(CRkRl)mC3-C7 cycloalkyl, —(CRkRl)maryl, —(CRkRl)mheteroaryl, or —(CRkRl)mheterocycloalkyl, wherein alkyl, cycloalkyl, aryl, heteroaryl, and heterocycloalkyl are optionally substituted with one or more R11;
• each R12 is independently at each occurrence selected from C1-C6 alkyl, halogen, CN, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxy, NO2, —NH2, CH2NH2, —(CH2)qN(C1-C6 alkyl)2, C1-C6 alkylamino, C1-C6 dialkylamino, —O(CH2)qN(H)C1-C6 alkyl, —O(CH2)qN(C1-C6 alkyl)2, aryl, heteroaryl, —NH-heteroaryl, —O-aryl, —S(O)p—C1-C6 alkyl, —S(O)p—N(H)C1-C6 alkyl, —S(O)p—N(C1-C6 alkyl)2, —C(O)C1-C6 alkyl, —C(O)OC1-C6 alkyl, —NHC(O)(C1-C6 alkyl), or oxo, wherein aryl and heteroaryl are optionally substituted with one or more substituents selected from C1-C6 alkyl, halogen, CN, C1-C6 alkoxy, hydroxy, NO2, —NH2, C1-C6 alkylamino, or C1-C6 dialkylamino;
• or
• two R12 together with the carbon to which they are attached can form a 4- to 6 membered heterospirocycle;
• or two R12 together when on adjacent carbons form a C4-C6 cycloalkyl optionally substituted with one or more R13;
• or two R12 together when on adjacent carbons form an aryl optionally substituted with one or more R13;
• or two R12 together when on adjacent carbons form a heteroaryl optionally substituted with one or more R13;
• or two R12 together when on adjacent carbons form a heterocycloalkyl optionally substituted with one or more R13;
• or R12 with the carbon to which it is attached and the adjacent carbon form a C3 cycloalkyl optionally substituted with one or more R13;
• each R13 is independently at each occurrence selected from C1-C6 alkyl, halogen, CN, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxy, NO2, —NH2, CH2NH2, —(CH2)qN(C1-C6 alkyl)2, C1-C6 alkylamino, C1-C6 dialkylamino, —O(CH2)qN(H)C1-C6 alkyl, —O(CH2)qN(C1-C6 alkyl)2, aryl, heteroaryl, —NH-heteroaryl, —O-aryl, —S(O)p—C1-C6 alkyl, —S(O)p—N(H)C1-C6 alkyl, —S(O)p—N(C1-C6 alkyl)2, —C(O)C1-C6 alkyl, —NHC(O)(C1-C6 alkyl), or oxo, wherein aryl and heteroaryl are optionally substituted with one or more substituents selected from the group consisting of C1-C6 alkyl, halogen, CN, C1-C6 alkoxy, hydroxy, NO2, —NH2, C1-C6 alkylamino, and C1-C6 dialkylamino;
• Rk and Rl are each independently at each occurrence selected from H, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, or halogen;
• each m, n, and p is independently at each occurrence 0, 1, or 2;
• and
• each q is independently at each occurrence 1, 2, 3 or 4;
• provided that when m is 0, Rd is not C1-C6 alkoxy, C1-C6 haloalkoxy, or CN;
• wherein:
• Ar is C6-C10 aryl or heteroaryl;
• R2 is —C(O)(CRkRl)nO(CRkRl)mRd, —C(O)(CRkRl)nRe, —S(O)2(CRkRl)nRf, —(CRkRl)nRg, —C(O)(CRkRl)nNRaRg or —C(O)(CRkRl)nS(CRkRl)mRf;
• R8 is —(CRkRl)mORa, C1-C6 alkyl, or C3-C6 cycloalkyl;
• each R10 is independently at each occurrence selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, —ORi, —NRaRi, CN, oxo, —(CRkRl)nS(O)2Ri, —(CRkRl)nNRaS(O)2Ri, —(CRkRl)nS(O)2NRaRi, —(CRkRl)nNRaRiS(O)2NRaRi, —(CRkRl)nC(O)ORa, —(CRkRl)nC(O)Ri, —(CRkRl)nC(O)NRaRi, —(CRkRl)nRi, —(CRkRl)nNRaC(O)NRb, and —(CRkRl)nNRaC(O)ORb, wherein each alkyl is substituted with one or more R11;
• or
• two R10 together when on adjacent carbons form an aryl ring optionally substituted with one or more R11;
• or two R10 together when on adjacent carbons form a heteroaryl ring optionally substituted with one or more R11;
• or two R10 together when on adjacent carbons form a heterocycloalkyl ring optionally substituted with one or more R11;
• each R11 is independently at each occurrence selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, CN, C1-C6 hydroxyalkyl, —(CRkRl)mNH2, C1-C6 alkylamino, C1-C6 dialkylamino, —C(O)NRaRb, —C(O)ORa, —C(O)Ra, —S(O)2Ra, —C(O)H, —NRaC(O)ORa, —NRaC(O)C1-C6 alkyl, or oxo;
• or two R11 together can form a heterocycloalkyl ring;
• Ra and Rb are each independently at each occurrence hydrogen, C1-C6 alkyl, —C1-C6 alkyl(aryl), or aryl, wherein the alkyl and aryl are optionally substituted with one or more R10;
• Rd is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, CN, —C(O)C1-C6 alkyl, C3-C7 cycloalkyl, aryl, heteroaryl, or heterocycloalkyl, wherein cycloalkyl, aryl, heteroaryl, and heterocycloalkyl are optionally substituted with one or more R12;
• Re is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkoxy, CN, C3-C7 cycloalkyl, aryl, heteroaryl, or heterocycloalkyl, wherein cycloalkyl, aryl, heteroaryl, and heterocycloalkyl are optionally substituted with one or more R12;
• Rf is C3-C7 cycloalkyl, aryl, heteroaryl, or heterocycloalkyl, wherein cycloalkyl, aryl, heteroaryl, and heterocycloalkyl are optionally substituted with one or more R12;
• Rg is C1-C6 alkyl, C3-C7 cycloalkyl, C3-C7 cycloalkyl, —C1-C4 alkyl(cycloalkyl), aryl, —C1-C4 alkyl(aryl), heteroaryl, —C1-C4 alkyl(heteroaryl), heterocycloalkyl, or —C1-C4 alkyl(heterocycloalkyl), wherein cycloalkyl, aryl, heteroaryl, and heterocycloalkyl are optionally substituted with one or more R12;
• Ri is hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, —(CH2)qN(H)C1-C6 alkyl, —(CH2)qN(C1-C6 alkyl)2, —(CRkRl)mC3-C7 cycloalkyl, —(CRkRl)maryl, —(CRkRl)mheteroaryl, or —(CRkRl)mheterocycloalkyl, wherein alkyl, cycloalkyl, aryl, heteroaryl, and heterocycloalkyl are optionally substituted with one or more R11;
• each R12 is independently at each occurrence selected from C1-C6 alkyl, halogen, CN, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxy, NO2, —NH2, CH2NH2, —(CH2)qN(C1-C6 alkyl)2, C1-C6 alkylamino, C1-C6 dialkylamino, —O(CH2)qN(H)C1-C6 alkyl, —O(CH2)qN(C1-C6 alkyl)2, aryl, heteroaryl, —NH-heteroaryl, —O-aryl, —S(O)p—C1-C6 alkyl, —S(O)p—N(H)C1-C6 alkyl, —S(O)p—N(C1-C6alkyl)2, —C(O)C1-C6 alkyl, —C(O)OC1-C6 alkyl, —NHC(O)(C1-C6 alkyl), or oxo, wherein aryl and heteroaryl are optionally substituted with one or more substituents selected from C1-C6 alkyl, halogen, CN, C1-C6 alkoxy, hydroxy, NO2, —NH2, C1-C6 alkylamino, or
• C1-C6 dialkylamino;
• or
• two R12 together with the carbon to which they are attached can form a 4- to 6 membered heterospirocycle;
• or two R12 together when on adjacent carbons form a C4-C6 cycloalkyl optionally substituted with one or more R13;
• or two R12 together when on adjacent carbons form an aryl optionally substituted with one or more R13;
• or two R12 together when on adjacent carbons form a heteroaryl optionally substituted with one or more R13;
• or two R12 together when on adjacent carbons form a heterocycloalkyl optionally substituted with one or more R13;
• or R12 with the carbon to which it is attached and the adjacent carbon form a C3 cycloalkyl optionally substituted with one or more R13;
• each R13 is independently at each occurrence selected from C1-C6 alkyl, halogen, CN, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxy, NO2, —NH2, CH2NH2, —(CH2)qN(C1-C6 alkyl)2, C1-C6 alkylamino, C1-C6 dialkylamino, —O(CH2)qN(H)C1-C6 alkyl, —O(CH2)qN(C1-C6 alkyl)2, aryl, heteroaryl, —NH-heteroaryl, —O-aryl, —S(O)p—C1-C6 alkyl, —S(O)p—N(H)C1-C6 alkyl, —S(O)p—N(C1-C6 alkyl)2, —C(O)C1-C6 alkyl, —NHC(O)(C1-C6 alkyl), or oxo, wherein aryl and heteroaryl are optionally substituted with one or more substituents selected from the group consisting of C1-C6 alkyl, halogen, CN, C1-C6 alkoxy, hydroxy, NO2, —NH2, C1-C6 alkylamino, and C1-C6 dialkylamino;
• Rk and Rl are each independently at each occurrence selected from H, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, or halogen;
• each m, n, and p is independently at each occurrence 0, 1, or 2;
• each q is independently at each occurrence 1, 2, 3 or 4;
• and
• s is 1, 2, 3, 4, or 5;
• provided that when m is 0, Rd is not C1-C6 alkoxy, C1-C6 haloalkoxy, or CN;
• wherein:
• Ar is C6-C10 aryl or heteroaryl;
• each R10 is independently at each occurrence selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, —ORi, —NRaRi, CN, oxo, —(CRkRl)nS(O)2Ri, —(CRkRl)nNRaS(O)2Ri, —(CRkRl)nS(O)2NRaRi, —(CRkRl)nNRaRiS(O)2NRaRi, —(CRkRl)nC(O)ORa, —(CRkRl)nC(O)Ri, —(CRkRl)nC(O)NRaRi, —(CRkRl)nRi, —(CRkRl)nNRaC(O)NRb, and —(CRkRl)nNRaC(O)ORb, wherein each alkyl is substituted with one or more R11;
• or
• two R10 together when on adjacent carbons form an aryl ring optionally substituted with one or more R11;
• or two R10 together when on adjacent carbons form a heteroaryl ring optionally substituted with one or more R11;
• or two R10 together when on adjacent carbons form a heterocycloalkyl ring optionally substituted with one or more R11;
• each R11 is independently at each occurrence selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, CN, C1-C6 hydroxyalkyl, —(CRkRl)mNH2, C1-C6 alkylamino, C1-C6 dialkylamino, —C(O)NRaRb, —C(O)ORa, —C(O)Ra, —S(O)2Ra, —C(O)H, —NRaC(O)ORa, —NRaC(O)C1-C6 alkyl, or oxo;
• or two R11 together can form a heterocycloalkyl ring;
• Ra and Rb are each independently at each occurrence hydrogen, C1-C6 alkyl, —C1-C4 alkyl(aryl), or aryl, wherein the alkyl and aryl are optionally substituted with one or more R10;
• Ri is hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, —(CH2)qN(H)C1-C6 alkyl, —(CH2)qN(C1-C6alkyl)2, —(CRkRl)mC3-C7 cycloalkyl, —(CRkRl)maryl, —(CRkRl)mheteroaryl, or —(CRkRl)mheterocycloalkyl, wherein alkyl, cycloalkyl, aryl, heteroaryl, and heterocycloalkyl are optionally substituted with one or more R11;
• Rk and Rl are each independently at each occurrence selected from H, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, or halogen;
• each m and n is independently at each occurrence 0, 1, or 2;
• each q is independently at each occurrence 1, 2, 3 or 4;
• and
• s is 1, 2, 3, 4, or 5;
• wherein:
• Ar is C6-C10 aryl or heteroaryl;
• each R10 is independently at each occurrence selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, —ORi, —NRaRi, CN, oxo, —(CRkRl)nS(O)2Ri, —(CRkRl)nNRaS(O)2Ri, —(CRkRl)nS(O)2NRaRi, —(CRkRl)nNRaRiS(O)2NRaRi, —(CRkRl)nC(O)ORa, —(CRkRl)nC(O)Ri, —(CRkRl)nC(O)NRaRi, —(CRkRl)nRi, —(CRkRl)nNRaC(O)NRb, and —(CRkRl)nNRaC(O)ORb, wherein each alkyl is substituted with one or more R11;
• or
• two R10 together when on adjacent carbons form an aryl ring optionally substituted with one or more R11;
• or two R10 together when on adjacent carbons form a heteroaryl ring optionally substituted with one or more R11;
• or two R10 together when on adjacent carbons form a heterocycloalkyl ring optionally substituted with one or more R11;
• each R11 is independently at each occurrence selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, CN, C1-C6 hydroxyalkyl, —(CRkRl)mNH2, C1-C6 alkylamino, C1-C6 dialkylamino, —C(O)NRaRb, —C(O)ORa, —C(O)Ra, —S(O)2Ra, —C(O)H, —NRaC(O)ORa, —NRaC(O)C1-C6 alkyl, or oxo;
• or two R11 together can form a heterocycloalkyl ring;
• Ra and Rb are each independently at each occurrence hydrogen, C1-C6 alkyl, —C1-C4 alkyl(aryl), or aryl, wherein the alkyl and aryl are optionally substituted with one to three R10;
• Ri is hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, —(CH2)qN(H)C1-C6 alkyl, —(CH2)qN(C1-C6 alkyl)2, —(CRkRl)mC3-C7 cycloalkyl, —(CRkRl)maryl, —(CRkRl)mheteroaryl, or —(CRkRl)mheterocycloalkyl, wherein alkyl, cycloalkyl, aryl, heteroaryl, and heterocycloalkyl are optionally substituted with one or more R11;
• Rk and Rl are each independently at each occurrence selected from H, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, or halogen;
• each m and n is independently at each occurrence 0, 1, or 2;
• each q is independently at each occurrence 1, 2, 3 or 4;
• and
• s is 1, 2, 3, 4, or 5;
• wherein:
• Ar is C6-C10 aryl or heteroaryl;
• each R10 is independently at each occurrence selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, —ORi, —NRaRi, CN, oxo, —(CRkRl)nS(O)2Ri, —(CRkRl)nNRaS(O)2Ri, —(CRkRl)nS(O)2NRaRi, —(CRkRl)nNRaRiS(O)2NRaRi, —(CRkRl)nC(O)ORa, —(CRkRl)nC(O)Ri, —(CRkRl)nC(O)NRaRi, —(CRkRl)nRi, —(CRkRl)nNRaC(O)NRb, and —(CRkRl)nNRaC(O)ORb, wherein each alkyl is substituted with one or more R11;
• or
• two R10 together when on adjacent carbons form an aryl ring optionally substituted with one or more R11;
• or two R10 together when on adjacent carbons form a heteroaryl ring optionally substituted with one or more R11;
• or two R10 together when on adjacent carbons form a heterocycloalkyl ring optionally substituted with one or more R11;
• each R11 is independently at each occurrence selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, CN, C1-C6 hydroxyalkyl, —(CRkRl)mNH2, C1-C6 alkylamino, C1-C6 dialkylamino, —C(O)NRaRb, —C(O)ORa, —C(O)Ra, —S(O)2Ra, —C(O)H, —NRaC(O)ORa, —NRaC(O)C1-C6 alkyl, or oxo;
• or two R11 together can form a heterocycloalkyl ring;
• Ra and Rb are each independently at each occurrence hydrogen, C1-C6 alkyl, —C1-C4 alkyl(aryl), or aryl, wherein the alkyl and aryl are optionally substituted with one or more R10;
• Rd is C1-C6 alkyl, C1-C6 haloalkyl, C3-C7 cycloalkyl, aryl, heteroaryl, or heterocycloalkyl, wherein cycloalkyl, aryl, heteroaryl, and heterocycloalkyl are optionally substituted with one or more R12;
• Ri is hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, —(CH2)qN(H)C1-C6 alkyl, —(CH2)qN(C1-C6 alkyl)2, —(CRkRl)mC3-C7 cycloalkyl, —(CRkRl)maryl, —(CRkRl)mheteroaryl, or —(CRkRl)mheterocycloalkyl, wherein alkyl, cycloalkyl, aryl, heteroaryl, and heterocycloalkyl are optionally substituted with one or more R11;
• each R12 is independently at each occurrence selected from C1-C6 alkyl, halogen, CN, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxy, NO2, —NH2, CH2NH2, —(CH2)qN(C1-C6 alkyl)2, C1-C6 alkylamino, C1-C6 dialkylamino, —O(CH2)qN(H)C1-C6 alkyl, —O(CH2)qN(C1-C6 alkyl)2, aryl, heteroaryl, —NH-heteroaryl, —O-aryl, —S(O)p—C1-C6 alkyl, —S(O)p—N(H)C1-C6 alkyl, —S(O)p—N(C1-C6 alkyl)2, —C(O)C1-C6 alkyl, —C(O)OC1-C6 alkyl, —NHC(O)(C1-C6 alkyl), or oxo, wherein aryl and heteroaryl are optionally substituted with one or more substituents selected from C1-C6 alkyl, halogen, CN, C1-C6 alkoxy, hydroxy, NO2, —NH2, C1-C6 alkylamino, or C1-C6 dialkylamino;
• or
• two R12 together with the carbon to which they are attached can form a 4- to 6 membered heterospirocycle;
• or two R12 together when on adjacent carbons form a C4-C6 cycloalkyl optionally substituted with one or more R13;
• or two R12 together when on adjacent carbons form an aryl optionally substituted with one or more R13;
• or two R12 together when on adjacent carbons form a heteroaryl optionally substituted with one or more R13;
• or two R12 together when on adjacent carbons form a heterocycloalkyl optionally substituted with one or more R13;
• or R12 with the carbon to which it is attached and the adjacent carbon form a C3 cycloalkyl optionally substituted with one or more R13;
• each R13 is independently at each occurrence selected from C1-C6 alkyl, halogen, CN, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxy, NO2, —NH2, CH2NH2, —(CH2)qN(C1-C6 alkyl)2, C1-C6 alkylamino, C1-C6 dialkylamino, —O(CH2)qN(H)C1-C6 alkyl, —O(CH2)qN(C1-C6 alkyl)2, aryl, heteroaryl, —NH-heteroaryl, —O-aryl, —S(O)p—C1-C6 alkyl, —S(O)p—N(H)C1-C6 alkyl, —S(O)p—N(C1-C6 alkyl)2, —C(O)C1-C6 alkyl, —NHC(O)(C1-C6 alkyl), or oxo, wherein aryl and heteroaryl are optionally substituted with one or more substituents selected from the group consisting of C1-C6 alkyl, halogen, CN, C1-C6 alkoxy, hydroxy, NO2, —NH2, C1-C6 alkylamino, and C1-C6 dialkylamino;
• Rk and Rl are each independently at each occurrence selected from H, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, or halogen;
• each m, n, and p is independently at each occurrence 0, 1, or 2;
• each q is independently at each occurrence 1, 2, 3 or 4;
• and
• s is 1, 2, 3, 4, or 5;
• or
• wherein:
• R10 is independently selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, —ORi, —NRaRi, CN, oxo, —(CRkRl)nS(O)2Ri, —(CRkRl)nNRaS(O)2Ri, —(CRkRl)nS(O)2NRaRi, —(CRkRl)nNRaRiS(O)2NRaRi, —(CRkRl)nC(O)ORa, —(CRkRl)nC(O)Ri, —(CRkRl)nC(O)NRaRi, —(CRkRl)nRi, —(CRkRl)nNRaC(O)NRb, and —(CRkRl)nNRaC(O)ORb, wherein each alkyl is substituted with one or more R11;
• or
• two R10 together when on adjacent carbons form an aryl ring optionally substituted with one or more R11;
• or two R10 together when on adjacent carbons form a heteroaryl ring optionally substituted with one or more R11;
• or two R10 together when on adjacent carbons form a heterocycloalkyl ring optionally substituted with one or more R11;
• each R11 is independently at each occurrence selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, CN, C1-C6 hydroxyalkyl, —(CRkRl)mNH2, C1-C6 alkylamino, C1-C6 dialkylamino, —C(O)NRaRb, —C(O)ORa, —C(O)Ra, —S(O)2Ra, —C(O)H, —NRaC(O)ORa, —NRaC(O)C1-C6 alkyl, or oxo;
• or two R11 together can form a heterocycloalkyl ring;
• Ra and Rb are each independently hydrogen, C1-C6 alkyl, —C1-C4alkyl(aryl), or aryl, wherein the alkyl and aryl are optionally substituted with one or more R10;
• Rd is C1-C6 alkyl, C1-C6 haloalkyl, C3-C7 cycloalkyl, aryl, heteroaryl, or heterocycloalkyl, wherein cycloalkyl, aryl, heteroaryl, and heterocycloalkyl are optionally substituted with one or more R12;
• Ri is hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, —(CH2)qN(H)C1-C6 alkyl, —(CH2)qN(C1-C6 alkyl)2, —(CRkRl)mC3-C7 cycloalkyl, —(CRkRl)maryl, —(CRkRl)mheteroaryl, or —(CRkRl)mheterocycloalkyl, wherein alkyl, cycloalkyl, aryl, heteroaryl, and heterocycloalkyl are optionally substituted with one or more R11;
• each R12 is independently at each occurrence selected from C1-C6 alkyl, halogen, CN, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxy, NO2, —NH2, CH2NH2, —(CH2)qN(C1-C6 alkyl)2, C1-C6 alkylamino, C1-C6 dialkylamino, —O(CH2)qN(H)C1-C6 alkyl, —O(CH2)qN(C1-C6alkyl)2, aryl, heteroaryl, —NH-heteroaryl, —O-aryl, —S(O)p—C1-C6 alkyl, —S(O)p—N(H)C1-C6 alkyl, —S(O)p—N(C1-C6 alkyl)2, —C(O)C1-C6 alkyl, —C(O)OC1-C6 alkyl, —NHC(O)(C1-C6 alkyl), or oxo, wherein aryl and heteroaryl are optionally substituted with one or more substituents selected from C1-C6 alkyl, halogen, CN, C1-C6 alkoxy, hydroxy, NO2, —NH2, C1-C6 alkylamino, or C1-C6 dialkylamino;
• or
• two R12 together with the carbon to which they are attached can form a 4- to 6 membered heterospirocycle;
• or two R12 together when on adjacent carbons form a C4-C6 cycloalkyl optionally substituted with one or more R13;
• or two R12 together when on adjacent carbons form an aryl optionally substituted with one or more R13;
• or two R12 together when on adjacent carbons form a heteroaryl optionally substituted with one or more R13;
• or two R12 together when on adjacent carbons form a heterocycloalkyl optionally substituted with one or more R13;
• or R12 with the carbon to which it is attached and the adjacent carbon form a C3 cycloalkyl optionally substituted with one or more R13;
• each R13 is independently at each occurrence selected from C1-C6 alkyl, halogen, CN, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxy, NO2, —NH2, CH2NH2, —(CH2)qN(C1-C6 alkyl)2, C1-C6 alkylamino, C1-C6 dialkylamino, —O(CH2)qN(H) C1-C6 alkyl, —O(CH2)qN(C1-C6 alkyl)2, aryl, heteroaryl, —NH-heteroaryl, —O-aryl, —S(O)p—C1-C6 alkyl, —S(O)p—N(H)C1-C6 alkyl, —S(O)p—N(C1-C6 alkyl)2, —C(O)C1-C6 alkyl, —NHC(O)(C1-C6 alkyl), or oxo, wherein aryl and heteroaryl are optionally substituted with one or more substituents selected from consisting of C1-C6 alkyl, halogen, CN, C1-C6 alkoxy, hydroxy, NO2, —NH2, C1-C6 alkylamino, and C1-C6 dialkylamino;
• Rk and Rl are each independently at each occurrence selected from H, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, or halogen;
• each m, n, and p is independently at each occurrence 0, 1, or 2;
• and
• each q is independently at each occurrence 1, 2, 3 or 4;
• provided that when m is 0, Rd is not C1-C6 alkoxy, C1-C6 haloalkoxy, or CN;
• or a pharmaceutically acceptable salt, enantiomer, hydrate, solvate, isomer, or tautomer of the compound of Fomulae (I), (II), (III) or (IV);
• wherein the cancer is selected from the group consisting of prostate, ovary, pancreas, esophagus, thyroid, bladder, bone, bile duct, testicle, uterus, head, neck, salivary gland, small cell ling cancer, non-small cell lung cancer, castration-resistant prostate cancer, glioblastoma, astrocytoma, mebulloblastoma, neuroblastoma, neurofibromatosis, merkel cell carcinoma, soft tissue sarcoma, osteosarcoma, Ewing's sarcoma, cholangiocarcinoma, PD-L1 positive tumors, and DNA mismatch repair deficient tumors.
• or a pharmaceutically acceptable salt, enantiomer, hydrate, solvate, isomer, or tautomer of the compound of Formulae (I), (II), (III), (IV), (V), or (VI);
• 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), (IV), (V), or (VI):

• wherein:
• X is selected from N or CR3;
• Y is selected from N or CR5;
• Z is selected from N or CR6;
• R1 is hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl;
• R2 is —C(O)(CRkRl)nO(CRkRl)mRd, —C(O)(CRkRl)nRe, —S(O)2(CRkRl)nRf, —(CRkRl)nRg, —C(O)(CRkRl)nNRaRg or —C(O)(CRkRl)nS(CRkRl)mRf;
• R3 and R6 are each independently selected from hydrogen or halogen;
• R4 is hydrogen, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, C6-C10 aryl, heterocycloalkyl, heteroaryl, —NRaRb, —C(O)Rh, —ORh, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, —C1-C4 alkyl(aryl), —C1-C4 alkyl(heteroaryl), or —C1-C4 alkyl(heterocycloalkyl), wherein the cycloalkyl, aryl, heterocycloalkyl, heteroaryl, and alkyl are optionally substituted with one or more R10;
• R5 is hydrogen, halogen, C1-C6 alkyl, nitro, —NH2, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 aminoalkyl, C1-C6 aminoalkoxy, CN, C1-C6 alkoxy, —C(O)NRaRb, —NRaS(O)2Rb, —NRaC(O)Rb, —NRaC(O)ORb, —NRaC(O)NRbRc, C1-C6 haloalkyl, C1-C6haloalkoxy, —S(O)2NRaRb, or —S(O)2Ra;
• R7 is —C(O)R8, —C(O)OR8, —C(O)NR8R9, or —S(O)2R8;
• R8 and R9 are each independently hydrogen, —(CRkRl)mORa, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
• each R10 is independently at each occurrence selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, —ORi, —NRaRi, CN, oxo, —(CRkRl)nS(O)2Ri, —(CRkRl)nNRaS(O)2Ri, —(CRkRl)nS(O)2NRaRi, —(CRkRl)nNRaRiS(O)2NRaRi, —(CRkRl)nC(O)ORa, —(CRkRl)nC(O)Ri, —(CRkRl)nC(O)NRaRi, —(CRkRl)nRi, —(CRkRl)nNRaC(O)NRb, —(CRkRl)nNRaC(O)ORb, and oxo, wherein each alkyl is substituted with one or more R11;
• or
• two R10 together when on adjacent carbons form an aryl ring optionally substituted with one or more R11;
• or two R10 together when on adjacent carbons form a heteroaryl ring optionally substituted with one or more R11;
• or two R10 together when on adjacent carbons form a heterocycloalkyl ring optionally substituted with one or more R11;
• each R11 is independently at each occurrence selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxy, CN, C1-C6 hydroxyalkyl, —(CRkRl)mNH2, C1-C6 alkylamino, C1-C6 dialkylamino, —C(O)NRaRb, —C(O)ORa, —C(O)Ra, —S(O)2Ra, —C(O)H, —NRaC(O)ORa, —NRaC(O)C1-C6 alkyl, or oxo;
• or two R11 together can form a heterocycloalkyl ring;
• Ra, Rb, and Rc are each independently at each occurrence hydrogen, C1-C6 alkyl, —C1-C4 alkyl(aryl), or aryl, wherein the alkyl and aryl are optionally substituted with one or more R10;
• Rd is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, CN, —C(O)C1-C6 alkyl, C3-C7 cycloalkyl, aryl, heteroaryl, or heterocycloalkyl, wherein cycloalkyl, aryl, heteroaryl, and heterocycloalkyl are optionally substituted with one or more R12;
• Re is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkoxy, CN, C3-C7 cycloalkyl, aryl, heteroaryl, or heterocycloalkyl, wherein cycloalkyl, aryl, heteroaryl, and heterocycloalkyl are optionally substituted with one or more R12;
• Rf is C3-C7 cycloalkyl, aryl, heteroaryl, or heterocycloalkyl, wherein cycloalkyl, aryl, heteroaryl and heterocycloalkyl are optionally substituted with one or more R12;
• Rg is C1-C6 alkyl, C3-C7 cycloalkyl, —C1-C4 alkyl(C3-C7 cycloalkyl), aryl, —C1-C4 alkyl(aryl), heteroaryl, —C1-C4 alkyl(heteroaryl), heterocycloalkyl, or —C1-C4 alkyl(heterocycloalkyl), wherein cycloalkyl, aryl, heteroaryl, and heterocycloalkyl are optionally substituted with one or more R12;
• Rh is C3-C7 cycloalkyl, aryl, heteroaryl, or heterocycloalkyl, wherein cycloalkyl, aryl, heteroaryl, and heterocycloalkyl are optionally substituted with one or more R10;
• Ri is hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, —(CH2)qN(H)C1-C6 alkyl, —(CH2)qN(C1-C6 alkyl)2, —(CRkRl)mC3-C7 cycloalkyl, —(CRkRl)maryl, —(CRkRl)mheteroaryl, or —(CRkRl)mheterocycloalkyl, wherein alkyl, cycloalkyl, aryl, heteroaryl, and heterocycloalkyl are optionally substituted with one or more R11;
• each R12 is independently at each occurrence selected from C1-C6 alkyl, halogen, CN, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxy, NO2, —NH2, CH2NH2, —(CH2)qN(C1-C6 alkyl)2, C1-C6 alkylamino, C1-C6 dialkylamino, —O(CH2)qN(H)C1-C6 alkyl, —O(CH2)qN(C1-C6 alkyl)2, aryl, heteroaryl, —NH-heteroaryl, —O-aryl, —S(O)p—C1-C6 alkyl, —S(O)p—N(H)C1-C6 alkyl, —S(O)p—N(C1-C6 alkyl)2, —C(O)C1-C6 alkyl, —C(O)OC1-C6 alkyl, —NHC(O)(C1-C6 alkyl), or oxo, wherein aryl and heteroaryl are optionally substituted with one or more substituents selected from C1-C6 alkyl, halogen, CN, C1-C6 alkoxy, hydroxy, NO2, —NH2, C1-C6 alkylamino, or C1-C6 dialkylamino;
• or
• two R12 together with the carbon to which they are attached can form a 4- to 6 membered heterospirocycle;
• or two R12 together when on adjacent carbons form a C4-C6 cycloalkyl optionally substituted with one or more R13;
• or two R12 together when on adjacent carbons form an aryl optionally substituted with one or more R13;
• or two R12 together when on adjacent carbons form a heteroaryl optionally substituted with one or more R13;
• or two R12 together when on adjacent carbons form a heterocycloalkyl optionally substituted with one or more R13;
• or R12 with the carbon to which it is attached and the adjacent carbon form a C3 cycloalkyl optionally substituted with one or more R13;
• each R13 is independently at each occurrence selected from C1-C6 alkyl, halogen, CN, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxy, NO2, —NH2, CH2NH2, —(CH2)qN(C1-C6 alkyl)2, C1-C6 alkylamino, C1-C6 dialkylamino, —O(CH2)nN(H)C1-C6 alkyl, —O(CH2)qN(C1-C6 alkyl)2, aryl, heteroaryl, —NH-heteroaryl, —O-aryl, —S(O)p—C1-C6 alkyl, —S(O)p—N(H)C1-C6 alkyl, —S(O)p—N(C1-C6 alkyl)2, —C(O)C1-C6 alkyl, —NHC(O)(C1-C6 alkyl), or oxo, wherein aryl and heteroaryl are optionally substituted with one or more substituents selected from the group consisting of C1-C6 alkyl, halogen, CN, C1-C6 alkoxy, hydroxy, NO2, —NH2, C1-C6 alkylamino, and C1-C6 dialkylamino;
• Rk and Rl are each independently at each occurrence selected from H, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, or halogen;
• each m, n, and p is independently at each occurrence 0, 1, or 2;
• and
• each q is independently at each occurrence 1, 2, 3 or 4;
• provided that when m is 0, Rd is not C1-C6 alkoxy, C1-C6 haloalkoxy, or CN;
• wherein:
• Ar is C6-C10 aryl or heteroaryl;
• R2 is —C(O)(CRkRl)nO(CRkRl)mRd, —C(O)(CRkRl)nRe, —S(O)2(CRkRl)nRf, —(CRkRl)nRg, —C(O)(CRkRl)nNRaRg or —C(O)(CRkRl)nS(CRkRl)mRf;
• R8 is —(CRkRl)mORa, C1-C6 alkyl, or C3-C6 cycloalkyl;
• each R10 is independently at each occurrence selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, —ORi, —NRaRi, CN, oxo, —(CRkRl)nS(O)2Ri, —(CRkRl)nNRaS(O)2Ri, —(CRkRl)nS(O)2NRaRi, —(CRkRl)nNRaRiS(O)2NRaRi, —(CRkRl)nC(O)ORa, —(CRkRl)nC(O)Ri, —(CRkRl)nC(O)NRaRi, —(CRkRl)nRi, —(CRkRl)nNRaC(O)NRb, and —(CRkRl)nNRaC(O)ORb, wherein each alkyl is substituted with one or more R11;
• or
• two R10 together when on adjacent carbons form an aryl ring optionally substituted with one or more R11;
• or two R10 together when on adjacent carbons form a heteroaryl ring optionally substituted with one or more R11;
• or two R10 together when on adjacent carbons form a heterocycloalkyl ring optionally substituted with one or more R11;
• each R11 is independently at each occurrence selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, CN, C1-C6 hydroxyalkyl, —(CRkRl)mNH2, C1-C6 alkylamino, C1-C6 dialkylamino, —C(O)NRaRb, —C(O)ORa, —C(O)Ra, —S(O)2Ra, —C(O)H, —NRaC(O)ORa, —NRaC(O)C1-C6 alkyl, or oxo;
• or two R11 together can form a heterocycloalkyl ring;
• Ra and Rb are each independently at each occurrence hydrogen, C1-C6 alkyl, —C1-C4 alkyl(aryl), or aryl, wherein the alkyl and aryl are optionally substituted with one or more R10;
• Rd is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, CN, —C(O)C1-C6 alkyl, C3-C7 cycloalkyl, aryl, heteroaryl, or heterocycloalkyl, wherein cycloalkyl, aryl, heteroaryl, and heterocycloalkyl are optionally substituted with one or more R12;
• Re is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkoxy, CN, C3-C7 cycloalkyl, aryl, heteroaryl, or heterocycloalkyl, wherein cycloalkyl, aryl, heteroaryl, and heterocycloalkyl are optionally substituted with one or more R12;
• Rf is C3-C7 cycloalkyl, aryl, heteroaryl, or heterocycloalkyl, wherein cycloalkyl, aryl, heteroaryl, and heterocycloalkyl are optionally substituted with one or more R12;
• Rg is C1-C6 alkyl, C3-C7 cycloalkyl, C3-C7 cycloalkyl, —C1-C4 alkyl(cycloalkyl), aryl, —C1-C4 alkyl(aryl), heteroaryl, —C1-C4 alkyl(heteroaryl), heterocycloalkyl, or —C1-C4 alkyl(heterocycloalkyl), wherein cycloalkyl, aryl, heteroaryl, and heterocycloalkyl are optionally substituted with one or more R12;
• Ri is hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, —(CH2)qN(H)C1-C6 alkyl, —(CH2)qN(C1-C6 alkyl)2, —(CRkRl)mC3-C7 cycloalkyl, —(CRkRl)maryl, —(CRkRl)mheteroaryl, or —(CRkRl)mheterocycloalkyl, wherein alkyl, cycloalkyl, aryl, heteroaryl, and heterocycloalkyl are optionally substituted with one or more R11;
• each R12 is independently at each occurrence selected from C1-C6 alkyl, halogen, CN, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxy, NO2, —NH2, CH2NH2, —(CH2)qN(C1-C6 alkyl)2, C1-C6 alkylamino, C1-C6 dialkylamino, —O(CH2)qN(H)C1-C6 alkyl, —O(CH2)qN(C1-C6alkyl)2, aryl, heteroaryl, —NH-heteroaryl, —O-aryl, —S(O)p—C1-C6 alkyl, —S(O)p—N(H)C1-C6 alkyl, —S(O)p—N(C1-C6alkyl)2, —C(O)C1-C6 alkyl, —C(O)OC1-C6 alkyl, —NHC(O)(C1-C6 alkyl), or oxo, wherein aryl and heteroaryl are optionally substituted with one or more substituents selected from C1-C6 alkyl, halogen, CN, C1-C6 alkoxy, hydroxy, NO2, —NH2, C1-C6 alkylamino, or
• C1-C6 dialkylamino;
• or
• two R12 together with the carbon to which they are attached can form a 4- to 6 membered heterospirocycle;
• or two R12 together when on adjacent carbons form a C4-C6 cycloalkyl optionally substituted with one or more R13;
• or two R12 together when on adjacent carbons form an aryl optionally substituted with one or more R13;
• or two R12 together when on adjacent carbons form a heteroaryl optionally substituted with one or more R13;
• or two R12 together when on adjacent carbons form a heterocycloalkyl optionally substituted with one or more R13;
• or R12 with the carbon to which it is attached and the adjacent carbon form a C3 cycloalkyl optionally substituted with one or more R13;
• each R13 is independently at each occurrence selected from C1-C6 alkyl, halogen, CN, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxy, NO2, —NH2, CH2NH2, —(CH2)qN(C1-C6 alkyl)2, C1-C6 alkylamino, C1-C6 dialkylamino, —O(CH2)qN(H)C1-C6 alkyl, —O(CH2)qN(C1-C6 alkyl)2, aryl, heteroaryl, —NH-heteroaryl, —O-aryl, —S(O)p—C1-C6 alkyl, —S(O)p—N(H)C1-C6 alkyl, —S(O)p—N(C1-C6 alkyl)2, —C(O)C1-C6 alkyl, —NHC(O)(C1-C6 alkyl), or oxo, wherein aryl and heteroaryl are optionally substituted with one or more substituents selected from the group consisting of C1-C6 alkyl, halogen, CN, C1-C6 alkoxy, hydroxy, NO2, —NH2, C1-C6 alkylamino, and C1-C6 dialkylamino;
• Rk and Rl are each independently at each occurrence selected from H, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, or halogen;
• each m, n, and p is independently at each occurrence 0, 1, or 2;
• each q is independently at each occurrence 1, 2, 3 or 4;
• and
• s is 1, 2, 3, 4, or 5;
• provided that when m is 0, Rd is not C1-C6 alkoxy, C1-C6 haloalkoxy, or CN;
• wherein:
• Ar is C6-C10 aryl or heteroaryl;
• each R10 is independently at each occurrence selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, —ORi, —NRaRi, CN, oxo, —(CRkRl)nS(O)2Ri, —(CRkRl)nNRaS(O)2Ri, —(CRkRl)nS(O)2NRaRi, —(CRkRl)nNRaRiS(O)2NRaRi, —(CRkRl)nC(O)ORa, —(CRkRl)nC(O)Ri, —(CRkRl)nC(O)NRaRi, —(CRkRl)nRi, —(CRkRl)nNRaC(O)NRb, and —(CRkRl)nNRaC(O)ORb, wherein each alkyl is substituted with one or more R11;
• or
• two R10 together when on adjacent carbons form an aryl ring optionally substituted with one or more R11;
• or two R10 together when on adjacent carbons form a heteroaryl ring optionally substituted with one or more R11;
• or two R10 together when on adjacent carbons form a heterocycloalkyl ring optionally substituted with one or more R11;
• each R11 is independently at each occurrence selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, CN, C1-C6 hydroxyalkyl, —(CRkRl)mNH2, C1-C6 alkylamino, C1-C6 dialkylamino, —C(O)NRaRb, —C(O)ORa, —C(O)Ra, —S(O)2Ra, —C(O)H, —NRaC(O)ORa, —NRaC(O)C1-C6 alkyl, or oxo;
• or two R11 together can form a heterocycloalkyl ring;
• Ra and Rb are each independently at each occurrence hydrogen, C1-C6 alkyl, —C1-C4 alkyl(aryl), or aryl, wherein the alkyl and aryl are optionally substituted with one or more R10;
• Ri is hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, —(CH2)qN(H)C1-C6 alkyl, —(CH2)qN(C1-C6alkyl)2, —(CRkRl)mC3-C7 cycloalkyl, —(CRkRl)maryl, —(CRkRl)mheteroaryl, or —(CRkRl)mheterocycloalkyl, wherein alkyl, cycloalkyl, aryl, heteroaryl, and heterocycloalkyl are optionally substituted with one or more R11;
• Rk and Rl are each independently at each occurrence selected from H, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, or halogen;
• each m and n is independently at each occurrence 0, 1, or 2;
• each q is independently at each occurrence 1, 2, 3 or 4;
• and
• s is 1, 2, 3, 4, or 5;
• wherein:
• Ar is C6-C10 aryl or heteroaryl;
• each R10 is independently at each occurrence selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, —ORi, —NRaRi, CN, oxo, —(CRkRl)nS(O)2Ri, —(CRkRl)nNRaS(O)2Ri, —(CRkRl)nS(O)2NRaRi, —(CRkRl)nNRaRiS(O)2NRaRi, —(CRkRl)nC(O)ORa, —(CRkRl)nC(O)Ri, —(CRkRl)nC(O)NRaRi, —(CRkRl)nRi, —(CRkRl)nNRaC(O)NRb, and —(CRkRl)nNRaC(O)ORb, wherein each alkyl is substituted with one or more R11;
• or
• two R10 together when on adjacent carbons form an aryl ring optionally substituted with one or more R11;
• or two R10 together when on adjacent carbons form a heteroaryl ring optionally substituted with one or more R11;
• or two R10 together when on adjacent carbons form a heterocycloalkyl ring optionally substituted with one or more R11;
• each R11 is independently at each occurrence selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, CN, C1-C6 hydroxyalkyl, —(CRkRl)mNH2, C1-C6 alkylamino, C1-C6 dialkylamino, —C(O)NRaRb, —C(O)ORa, —C(O)Ra, —S(O)2Ra, —C(O)H, —NRaC(O)ORa, —NRaC(O)C1-C6 alkyl, or oxo;
• or two R11 together can form a heterocycloalkyl ring;
• Ra and Rb are each independently at each occurrence hydrogen, C1-C6 alkyl, —C1-C4 alkyl(aryl), or aryl, wherein the alkyl and aryl are optionally substituted with one to three R10;
• Ri is hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, —(CH2)qN(H)C1-C6 alkyl, —(CH2)qN(C1-C6 alkyl)2, —(CRkRl)mC3-C7 cycloalkyl, —(CRkRl)maryl, —(CRkRl)mheteroaryl, or —(CRkRl)mheterocycloalkyl, wherein alkyl, cycloalkyl, aryl, heteroaryl, and heterocycloalkyl are optionally substituted with one or more R11;
• Rk and Rl are each independently at each occurrence selected from H, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, or halogen;
• each m and n is independently at each occurrence 0, 1, or 2;
• each q is independently at each occurrence 1, 2, 3 or 4;
• and
• s is 1, 2, 3, 4, or 5;
• wherein:
• Ar is C6-C10 aryl or heteroaryl;
• each R10 is independently at each occurrence selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, —ORi, —NRaRi, CN, oxo, —(CRkRl)nS(O)2Ri, —(CRkRl)nNRaS(O)2Ri, —(CRkRl)nS(O)2NRaRi, —(CRkRl)nNRaRiS(O)2NRaRi, —(CRkRl)nC(O)ORa, —(CRkRl)nC(O)Ri, —(CRkRl)nC(O)NRaRi, —(CRkRl)nRi, —(CRkRl)nNRaC(O)NRb, and —(CRkRl)nNRaC(O)ORb, wherein each alkyl is substituted with one or more R11;
• or
• two R10 together when on adjacent carbons form an aryl ring optionally substituted with one or more R11;
• or two R10 together when on adjacent carbons form a heteroaryl ring optionally substituted with one or more R11;
• or two R10 together when on adjacent carbons form a heterocycloalkyl ring optionally substituted with one or more R11;
• each R11 is independently at each occurrence selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, CN, C1-C6 hydroxyalkyl, —(CRkRl)mNH2, C1-C6 alkylamino, C1-C6 dialkylamino, —C(O)NRaRb, —C(O)ORa, —C(O)Ra, —S(O)2Ra, —C(O)H, —NRaC(O)ORa, —NRaC(O)C1-C6 alkyl, or oxo;
• or two R11 together can form a heterocycloalkyl ring;
• Ra and Rb are each independently at each occurrence hydrogen, C1-C6 alkyl, —C1-C4 alkyl(aryl), or aryl, wherein the alkyl and aryl are optionally substituted with one or more R10;
• Rd is C1-C6 alkyl, C1-C6 haloalkyl, C3-C7 cycloalkyl, aryl, heteroaryl, or heterocycloalkyl, wherein cycloalkyl, aryl, heteroaryl, and heterocycloalkyl are optionally substituted with one or more R12;
• Ri is hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, —(CH2)qN(H)C1-C6 alkyl, —(CH2)qN(C1-C6 alkyl)2, —(CRkRl)mC3-C7 cycloalkyl, —(CRkRl)maryl, —(CRkRl)mheteroaryl, or —(CRkRl)mheterocycloalkyl, wherein alkyl, cycloalkyl, aryl, heteroaryl, and heterocycloalkyl are optionally substituted with one or more R11;
• each R12 is independently at each occurrence selected from C1-C6 alkyl, halogen, CN, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxy, NO2, —NH2, CH2NH2, —(CH2)qN(C1-C6 alkyl)2, C1-C6 alkylamino, C1-C6 dialkylamino, —O(CH2)qN(H)C1-C6 alkyl, —O(CH2)qN(C1-C6 alkyl)2, aryl, heteroaryl, —NH-heteroaryl, —O-aryl, —S(O)p—C1-C6 alkyl, —S(O)p—N(H)C1-C6 alkyl, —S(O)p—N(C1-C6 alkyl)2, —C(O)C1-C6 alkyl, —C(O)OC1-C6 alkyl, —NHC(O)(C1-C6 alkyl), or oxo, wherein aryl and heteroaryl are optionally substituted with one or more substituents selected from C1-C6 alkyl, halogen, CN, C1-C6 alkoxy, hydroxy, NO2, —NH2, C1-C6 alkylamino, or C1-C6 dialkylamino;
• or
• two R12 together with the carbon to which they are attached can form a 4- to 6 membered heterospirocycle;
• or two R12 together when on adjacent carbons form a C4-C6 cycloalkyl optionally substituted with one or more R13;
• or two R12 together when on adjacent carbons form an aryl optionally substituted with one or more R13;
• or two R12 together when on adjacent carbons form a heteroaryl optionally substituted with one or more R13;
• or two R12 together when on adjacent carbons form a heterocycloalkyl optionally substituted with one or more R13;
• or R12 with the carbon to which it is attached and the adjacent carbon form a C3 cycloalkyl optionally substituted with one or more R13;
• each R13 is independently at each occurrence selected from C1-C6 alkyl, halogen, CN, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxy, NO2, —NH2, CH2NH2, —(CH2)qN(C1-C6 alkyl)2, C1-C6 alkylamino, C1-C6 dialkylamino, —O(CH2)qN(H)C1-C6 alkyl, —O(CH2)qN(C1-C6 alkyl)2, aryl, heteroaryl, —NH-heteroaryl, —O-aryl, —S(O)p—C1-C6 alkyl, —S(O)p—N(H)C1-C6 alkyl, —S(O)p—N(C1-C6 alkyl)2, —C(O)C1-C6 alkyl, —NHC(O)(C1-C6 alkyl), or oxo, wherein aryl and heteroaryl are optionally substituted with one or more substituents selected from the group consisting of C1-C6 alkyl, halogen, CN, C1-C6 alkoxy, hydroxy, NO2, —NH2, C1-C6 alkylamino, and C1-C6 dialkylamino;
• Rk and Rl are each independently at each occurrence selected from H, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, or halogen;
• each m, n, and p is independently at each occurrence 0, 1, or 2;
• each q is independently at each occurrence 1, 2, 3 or 4;
• and
• s is 1, 2, 3, 4, or 5;
• or
• wherein:
• R10 is independently selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, —ORi, —NRaRi, CN, oxo, —(CRkRl)nS(O)2Ri, —(CRkRl)nNRaS(O)2Ri, —(CRkRl)nS(O)2NRaRi, —(CRkRl)nNRaRiS(O)2NRaRi, —(CRkRl)nC(O)ORa, —(CRkRl)nC(O)Ri, —(CRkRl)nC(O)NRaRi, —(CRkRl)nRi, —(CRkRl)nNRaC(O)NRb, and —(CRkRl)nNRaC(O)ORb, wherein each alkyl is substituted with one or more R11;
• or
• two R10 together when on adjacent carbons form an aryl ring optionally substituted with one or more R11;
• or two R10 together when on adjacent carbons form a heteroaryl ring optionally substituted with one or more R11;
• or two R10 together when on adjacent carbons form a heterocycloalkyl ring optionally substituted with one or more R11;
• each R11 is independently at each occurrence selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, CN, C1-C6 hydroxyalkyl, —(CRkRl)mNH2, C1-C6 alkylamino, C1-C6 dialkylamino, —C(O)NRaRb, —C(O)ORa, —C(O)Ra, —S(O)2Ra, —C(O)H, —NRaC(O)ORa, —NRaC(O)C1-C6 alkyl, or oxo;
• or two R11 together can form a heterocycloalkyl ring;
• Ra and Rb are each independently hydrogen, C1-C6 alkyl, —C1-C4alkyl(aryl), or aryl, wherein the alkyl and aryl are optionally substituted with one or more R10;
• Rd is C1-C6 alkyl, C1-C6 haloalkyl, C3-C7 cycloalkyl, aryl, heteroaryl, or heterocycloalkyl, wherein cycloalkyl, aryl, heteroaryl, and heterocycloalkyl are optionally substituted with one or more R12;
• Ri is hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, —(CH2)qN(H)C1-C6 alkyl, —(CH2)qN(C1-C6 alkyl)2, —(CRkRl)mC3-C7 cycloalkyl, —(CRkRl)maryl, —(CRkRl)mheteroaryl, or —(CRkRl)mheterocycloalkyl, wherein alkyl, cycloalkyl, aryl, heteroaryl, and heterocycloalkyl are optionally substituted with one or more R11;
• each R12 is independently at each occurrence selected from C1-C6 alkyl, halogen, CN, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxy, NO2, —NH2, CH2NH2, —(CH2)qN(C1-C6 alkyl)2, C1-C6 alkylamino, C1-C6 dialkylamino, —O(CH2)qN(H)C1-C6 alkyl, —O(CH2)qN(C1-C6alkyl)2, aryl, heteroaryl, —NH-heteroaryl, —O-aryl, —S(O)p—C1-C6 alkyl, —S(O)p—N(H)C1-C6 alkyl, —S(O)p—N(C1-C6 alkyl)2, —C(O)C1-C6 alkyl, —C(O)OC1-C6 alkyl, —NHC(O)(C1-C6 alkyl), or oxo, wherein aryl and heteroaryl are optionally substituted with one or more substituents selected from C1-C6 alkyl, halogen, CN, C1-C6 alkoxy, hydroxy, NO2, —NH2, C1-C6 alkylamino, or C1-C6 dialkylamino;
• or
• two R12 together with the carbon to which they are attached can form a 4- to 6 membered heterospirocycle;
• or two R12 together when on adjacent carbons form a C4-C6 cycloalkyl optionally substituted with one or more R13;
• or two R12 together when on adjacent carbons form an aryl optionally substituted with one or more R13;
• or two R12 together when on adjacent carbons form a heteroaryl optionally substituted with one or more R13;
• or two R12 together when on adjacent carbons form a heterocycloalkyl optionally substituted with one or more R13;
• or R12 with the carbon to which it is attached and the adjacent carbon form a C3 cycloalkyl optionally substituted with one or more R13;
• each R13 is independently at each occurrence selected from C1-C6 alkyl, halogen, CN, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxy, NO2, —NH2, CH2NH2, —(CH2)qN(C1-C6 alkyl)2, C1-C6 alkylamino, C1-C6 dialkylamino, —O(CH2)qN(H) C1-C6 alkyl, —O(CH2)qN(C1-C6 alkyl)2, aryl, heteroaryl, —NH-heteroaryl, —O-aryl, —S(O)p—C1-C6 alkyl, —S(O)p—N(H)C1-C6 alkyl, —S(O)p—N(C1-C6 alkyl)2, —C(O)C1-C6 alkyl, —NHC(O)(C1-C6 alkyl), or oxo, wherein aryl and heteroaryl are optionally substituted with one or more substituents selected from consisting of C1-C6 alkyl, halogen, CN, C1-C6 alkoxy, hydroxy, NO2, —NH2, C1-C6 alkylamino, and C1-C6 dialkylamino;
• Rk and Rl are each independently at each occurrence selected from H, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, or halogen;
• each m, n, and p is independently at each occurrence 0, 1, or 2;
• and
• each q is independently at each occurrence 1, 2, 3 or 4;
• provided that when m is 0, Rd is not C1-C6 alkoxy, C1-C6 haloalkoxy, or CN;
• or a pharmaceutically acceptable salt, enantiomer, hydrate, solvate, isomer, or tautomer of the compound of Fomulae (I), (II), (III) or (IV);
• wherein the cancer is selected from the group consisting of prostate, ovary, pancreas, esophagus, thyroid, bladder, bone, bile duct, testicle, uterus, head, neck, salivary gland, small cell ling cancer, non-small cell lung cancer, castration-resistant prostate cancer, glioblastoma, astrocytoma, mebulloblastoma, neuroblastoma, neurofibromatosis, merkel cell carcinoma, soft tissue sarcoma, osteosarcoma, Ewing's sarcoma, cholangiocarcinoma, PD-L1 positive tumors, and DNA mismatch repair deficient tumors.
• or a pharmaceutically acceptable salt, enantiomer, hydrate, solvate, isomer, or tautomer of the compound of Formulae (I), (II), (III), (IV), (V), or (VI);
• a pharmaceutically acceptable carrier;
• and
• one or more immune check point inhibitors.