Methods of using ehmt2 inhibitors in treating or preventing blood disorders

The method of any one of the preceding claims, wherein

• (1) the EHMT2-inhibitor is not a compound selected from the group consisting of:
• 4-(((2-((1-acetylindolin-6-yl)amino)-6-(trifluoromethyl)pyrimidin-4-yl)amino)methyl)benzenesulfonamide;
• 5-bromo-N4-(4-fluorophenyl)-N2-(4-methoxy-3-(2-(pyrrolidin-1-yl)ethoxy)phenyl)pyrimidine-2,4-diamine;
• N2-(4-methoxy-3-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-N4-(5-(tert-pentyl)-1H-pyrazol-3-yl)pyrimidine-2,4-diamine;
• 4-((2,4-dichloro-5-methoxyphenyl)amino)-2-((3-(2-(pyrrolidin-1-yl)ethoxy)phenyl)amino)pyrimidine-5-carbonitrile;
• N-(naphthalen-2-yl)-2-(piperidin-1-ylmethoxy)pyrimidin-4-amine;
• N-(3,5-difluorobenzyl)-2-(3-(pyrrolidin-1-yl)propyl)pyrimidin-4-amine;
• N-(((4-(3-(piperidin-1-yl)propyl)pyrimidin-2-yl)amino)methyl)benzamide;
• N-(2-((2-(3-(dimethylamino)propyl)pyrimidin-4-yl)amino)ethyl)benzamide;
• and
• 2-(hexahydro-4-methyl-1H-1,4-diazepin-1-yl)-6,7-dimethoxy-N-[1-(phenylmethyl)-4-piperidinyl]-4-quinazolinamine;
• (2) when T is a bond, B is substituted phenyl, and R6 is NR8R9, in which R9 is -Q3-RS2, and RS2 is optionally substituted 4- to 7-membered heterocycloalkyl or a 5- to 6-membered heteroaryl, then B is substituted with at least one substituent selected from (i) -Q2-OR11 in which R11 is -Q6-RS3 and Q6 is optionally substituted C2-C6 alkylene, C2-C6 alkenylene, or C2-C6 alkynylene linker and (ii) -Q2-NR10R11 in which R11 is -Q6-RS3;
• (3) when T is a bond and B is optionally substituted phenyl, then R6 is not OR9 or NR8R9 in which R9 is optionally substituted naphthyl;
• (4) when T is a bond and B is optionally substituted phenyl, naphthyl, indanyl or 1,2,3,4-tetrahydronaphthyl, then R6 is not NR8R9 in which R9 is optionally substituted phenyl, naphthyl, indanyl or 1,2,3,4-tetrahydronaphthyl;
• (5) when T is a bond and B is optionally substituted phenyl or thiazolyl, then R6 is not optionally substituted imidazolyl, pyrazolyl, pyridyl, pyrimidyl, or NR8R9 in which Ry is optionally substituted imidazolyl or 6- to 10-membered heteroaryl;
• or
• (6) when T is a C1-C6 alkylene linker and B is absent or optionally substituted C6-C10 aryl or 4- to 12-membered heterocycloalkyl;
• or when T is a bond and B is optionally substituted C3-C10 cycloalkyl or 4- to 12-membered heterocycloalkyl, then R6 is not NR8C(O)R13;
• (7) when X1 and X3 are N, X2 is CR3, X4 is CR5, X5 is C, R5 is 4- to 12-membered heterocycloalkyl substituted with one or more C1-C6 alkyl, and R6 and R3 together with the atoms to which they are attached form phenyl which is substituted with one or more of optionally substituted C1-C3 alkoxyl, then B is absent, C6-C10 aryl, C3-C10 cycloalkyl, or 5- to 10-membered heteroaryl, or
• (8) when X2 and X3 are N, X1 is CR2, X4 is CR5, X5 is C, R5 is C3-C8 cycloalkyl or 4- to 12-membered heterocycloalkyl, each optionally substituted with one or more C1-C6 alkyl, and R6 and R2 together with the atoms to which they are attached form phenyl which is substituted with one or more of optionally substituted C1-C3 alkoxyl, then B is absent, C6-C10 aryl, C3-C10 cycloalkyl, or 5- to 10-membered heteroaryl.

The method of any one of the preceding claims, wherein the EHMT2 inhibitor is a compound of Formula (II):

• wherein
• ring B is phenyl or pyridyl,
• one or both of X1 and X2 are N while X3 is CR4 and X4 is CR5 or one or both of X1 and X3 are N while X2 is CR3 and X4 is CR5, and
• n is 1, 2, or 3.

The method of any one of the preceding claims, wherein the EHMT2 inhibitor is a compound of Formula (ID):

• wherein
• ring B is phenyl or pyridyl,
• at least one of X2 and X3 is N;
• and
• n is 1 or 2.

The method of any one of the preceding claims, wherein the EHMT2 inhibitor is a compound of Formula (IV):

• wherein
• ring B is C3-C6 cycloalkyl;
• each of R20, R21, R22 and R23 independently is H, halo, C1-C3 alkyl, hydroxyl, or C1-C3 alkoxyl;
• and
• n is 1 or 2.

The method of any one of the preceding claims, wherein the EHMT2 inhibitor is a compound of Formula (V):

• wherein
• ring B is absent or C3-C6 cycloalkyl;
• X3 is N or CR4 in which R4 is H or C1-C4 alkyl;
• R1 is H or C1-C4 alkyl;
• or when B is absent, T and R1 together with the atoms to which they are attached optionally form a 4-7 membered heterocycloalkyl or 5-6 membered heteroaryl, each of which is optionally substituted with (R7)n;
• or when B is absent, T is H and n is 0;
• each R7 is independently oxo (═O) or -Q2-T2, in which each Q2 independently is a bond or C1-C6 alkylene, C2-C6 alkenylene, or C2-C6 alkynylene linker optionally substituted with one or more of halo, cyano, hydroxyl, amino, mono- or di-alkylamino, or C1-C6 alkoxyl, and each T2 independently is H, halo, OR10, OR11, C(O)R11, NR10R11, C(O)NR10R11, NR10C(O)R11, C3-C8 cycloalkyl, or 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, and wherein the C3-C8 cycloalkyl or 4- to 12-membered heterocycloalkyl is optionally substituted with one or more of halo, C1-C6 alkyl optionally substituted with NRxRy, hydroxyl, oxo, N(R8)2, cyano, C1-C6 haloalkyl, —SO2R8, or C1-C6 alkoxyl, each of Rx and Ry independently being H or C1-C6 alkyl, and R7 is not H or C(O)OR8;
• R5 is selected from the group consisting of C1-C6 alkyl, C3-C8 cycloalkyl and 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O and S, wherein the C3-C8 cycloalkyl and 4- to 12-membered heterocycloalkyl is optionally substituted with one or more of 4- to 7-membered heterocycloalkyl, —C1-C6 alkylene-4- to 7-membered heterocycloalkyl, —C(O)C1-C6 alkyl or C1-C6 alkyl optionally substituted with one or more of halo or ORa;
• R9 is -Q3-T3, in which Q3 is a bond or C1-C6 alkylene, C2-C6 alkenylene, or C2-C6 alkynylene linker optionally substituted with one or more of halo, cyano, hydroxyl, or C1-C6 alkoxyl, and T3 is 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, optionally substituted with one or more -Q4-T4, wherein each Q4 independently is a bond or C1-C3 alkylene, C2-C3 alkenylene, or C2-C3 alkynylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or C1-C6 alkoxy, and each T4 independently is selected from the group consisting of H, halo, cyano, C1-C6 alkyl, C3-C8 cycloalkyl, C6-C10 aryl, 4- to 7-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, 5- to 6-membered heteroaryl, ORc, C(O)Rc, S(O)2Rc, NRcRd, C(O)NRcRd, and NRcC(O)Rd, each of Rc and Rd independently being H or C1-C6 alkyl;
• or -Q4-T4 is oxo;
• and
• n is 0, 1 or 2.

The method of any one of the preceding claims, wherein the EHMT2 inhibitor is a compound of Formula (VIIIa):

• wherein
• X1 is N or CR2;
• X2 is N or CR3;
• X3 is N or CR4;
• X4 is N or CR5;
• R2 is selected from the group consisting of H, C3-C8 cycloalkyl, and C1-C6 alkyl optionally substituted with one or more of halo, ORa, or NRaRb;
• each of R3 and R4 is H;
• and
• R5 are independently selected from the group consisting of H, C3-C8 cycloalkyl, and C1-C6 alkyl optionally substituted with one or more of halo or ORa;
• or
• R5 and one of R3 or R4 together with the atoms to which they are attached form phenyl or a 5- or 6-membered heteroaryl;
• or R5 and one of R3′ or R4′ together with the atoms to which they are attached form a 5- or 6-membered heteroaryl, in which the phenyl or 5- or 6-membered heteroaryl as formed is optionally substituted with one or more of halo, C1-C3 alkyl, hydroxyl or C1-C3 alkoxyl;
• and
• wherein at least one of R2 or R5 are not H.

The method of any one of the preceding claims, wherein the EHMT2 inhibitor is a compound of Formula (VIIIb):

• wherein
• X1 is N or CR2;
• X2 is N or CR3;
• X3 is N or CR4;
• X4 is N or CR5;
• R2 is selected from the group consisting of H, C3-C8 cycloalkyl, and C1-C6 alkyl each of R3 and R4 is H;
• and
• R5 is selected from the group consisting of H, C3-C8 cycloalkyl, and C1-C6 alkyl;
• or
• R5 and one of R3 or R4 together with the atoms to which they are attached form phenyl or a 5- or 6-membered heteroaryl;
• or R5 and one of R3′ or R4′ together with the atoms to which they are attached form a 5- or 6-membered heteroaryl, in which the phenyl or 5- or 6-membered heteroaryl as formed is optionally substituted with one or more of halo, C1-C3 alkyl, hydroxyl or C1-C3 alkoxyl;
• and
• wherein at least one of R2 or R5 are not H.

The method of any one of the preceding claims, wherein the EHMT2 inhibitor is a compound of Formula (VIIIc):

• wherein
• X1 is N or CR2;
• X2 is N or CR3;
• X3 is N or CR4;
• X4 is N or CR5;
• R2 is selected from the group consisting of H, C3-C8 cycloalkyl, and C1-C6 alkyl each of R3 and R4 is H, and
• R5 is selected from the group consisting of H, C3-C8 cycloalkyl, and C1-C6 alkyl;
• or
• R5 and one of R3 or R4 together with the atoms to which they are attached form phenyl or a 5- or 6-membered heteroaryl;
• or R5 and one of R3′ or R4′ together with the atoms to which they are attached form a 5- or 6-membered heteroaryl, in which the phenyl or 5- or 6-membered heteroaryl as formed is optionally substituted with one or more of halo, C1-C3 alkyl, hydroxyl or C1-C3 alkoxyl;
• and
• wherein at least one of R2 or R5 are not H.

The method of any one of the preceding claims, wherein the EHMT2 inhibitor is a compound of (IX):

• or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or the tautomer, wherein
• X6 is N or CH;
• X7 is N or CH;
• X3 is N or CR4;
• R4, independently is selected from the group consisting of H, halo, cyano, C1-C6 alkoxyl, C6-C10 aryl, NRaRb, C(O)NRaRb, NRaC(O)Rb, C3-C8 cycloalkyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, and C1-C6 alkyl, wherein C1-C6 alkoxyl and C1-C6 alkyl are optionally substituted with one or more of halo, ORa, or NRaRb, in which each of Ra and Rb independently is H or C1-C6 alkyl;
• each R9 is independently -Q3-T3, in which Q3 is a bond or C1-C6 alkylene, C2-C6 alkenylene, or C2-C6 alkynylene linker optionally substituted with one or more of halo, cyano, hydroxyl, or C1-C6 alkoxyl, and T3 is H, halo, OR12, OR13, NR12R13, NR12C(O)R13, C(O)NR12R13, C(O)R13, S(O)2R13, S(O)2NR12R13, or RS2, in which RS2 is C3-C8 cycloalkyl, C6-C10 aryl, 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, or a 5- to 10-membered heteroaryl, and RS2 is optionally substituted with one or more -Q4-T4, wherein each Q4 independently is a bond or C1-C3 alkylene, C2-C3 alkenylene, or C2-C3 alkynylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or C1-C6 alkoxy, and each T4 independently is selected from the group consisting of H, halo, cyano, C1-C6 alkyl, C3-C8 cycloalkyl, C6-C10 aryl, 4- to 7-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, 5- to 6-membered heteroaryl, ORc, C(O)Rc, S(O)2Rc, NRcRd, C(O)NRcRd, and NRcC(O)Rd, each of Rc and Rd independently being H or C1-C6 alkyl;
• or -Q4-T4 is oxo;
• or
• R12 is H or C1-C6 alkyl;
• R13 is C1-C6 alkyl, C3-C8 cycloalkyl, C6-C10 aryl, 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, or a 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more -Q8-T8, wherein each Q8 independently is a bond or C1-C3 alkylene, C2-C3 alkenylene, or C2-C3 alkynylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or C1-C6 alkoxy, and each T8 independently is selected from the group consisting of H, halo, cyano, C1-C6 alkyl, C3-C8 cycloalkyl, C6-C10 aryl, 4- to 7-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, and 5- to 6-membered heteroaryl;
• or -Q8-T8 is oxo;
• R15 is C1-C6 alkyl, NHR17, C3-C8 cycloalkyl, C6-C10 aryl, 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, or 5- to 10-membered heteroaryl, wherein each of said C1-C6 alkyl, C3-C8 cycloalkyl, C6-C10 aryl, 4- to 12-membered heterocycloalkyl, and 5- to 10-membered heteroaryl is optionally substituted with one or more -Q9-T9, wherein each Q9 independently is a bond or C1-C3 alkylene, C2-C3 alkenylene, or C2-C3 alkynylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or C1-C6 alkoxy, and each T9 independently is selected from the group consisting of H, halo, cyano, C1-C6 alkyl, C3-C8 cycloalkyl, C6-C10 aryl, 4- to 7-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, and 5- to 6-membered heteroaryl;
• or -Q9-T9 is oxo;
• R16 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C6-C10 aryl, 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, or a 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more -Q10-T10, wherein each Q10 independently is a bond or C1-C3 alkylene, C2-C3 alkenylene, or C2-C3 alkynylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or C1-C6 alkoxy, and each T10 independently is selected from the group consisting of H, halo, cyano, C1-C6 alkyl, C3-C8 cycloalkyl, C6-C10 aryl, 4- to 7-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, and 5- to 6-membered heteroaryl;
• or -Q10-T10 is oxo;
• R17 is H or C1-C6 alkyl;
• and
• v is 0, 1, or 2.

The method of any one of the preceding claims, wherein:

• X1c is N or CR2c;
• X2c is N or CRk;
• X3c is N or CR4c;
• X4c is N or CR5c;
• each of X5c, X6c and X7c is independently N or CH;
• X8c is NR13c or CR11cR12c;
• R1c is H or C1-C4 alkyl;
• each of R2c, R3c, R4c, and R5c, independently is selected from the group consisting of H, halo, cyano, C1-C6 alkoxyl, C6-C10 aryl, OH, NRacRbc, C(O)NRacRbc, NRacC(O)Rbc, C(O)ORac, OC(O)Rac, OC(O)NRacRbc, NRacC(O)ORbc, C3-C8 cycloalkyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C1-C6 alkyl, C2-C6 alkenyl, and C1-C6 alkynyl, wherein the C6-C10 aryl, C3-C8 cycloalkyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C1-C6 alkoxyl, C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl, are each optionally substituted with one or more of halo, ORac, or NRacRbc, in which each of Rac and Rbc independently is H or C1-C6 alkyl;
• R6c is -Q1c-T1c, in which Q1c is a bond, or C1-C6 alkylene, C2-C6 alkenylene, or C2-C6 alkynylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, oxo, or C1-C6 alkoxyl, and T1c is H, halo, cyano, or RS1c, in which RS1c is C3-C8 cycloalkyl, phenyl, 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, or a 5- or 6-membered heteroaryl and RS1c is optionally substituted with one or more of halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, hydroxyl, oxo, —C(O)Rcc, —C(O)ORcc, —SO2Rcc, —SO2N(Rcc)2, —NRccC(O)Rdc, —C(O)NRccRdc, —NRccC(O)ORdc, —OC(O)NRccRdc, NRccRdc, or C1-C6 alkoxyl, in which each of Rcc and Rdc independently is H or C1-C6 alkyl;
• R7c is -Q2c-T2c, in which Q2c is a bond, C1-C6 alkylene, C2-C6 alkenylene, or C2-C6 alkynylene linker optionally substituted with one or more of halo, cyano, hydroxyl, amino, mono- or di-alkylamino, and T2c is H, halo, cyano, ORec, ORfc, C(O)Rfc, NRecRfc, C(O)NRecRfc, NRecC(O)Rfc, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C12 cycloalkyl, or 4- to 12-membered heterocycloalkyl, and wherein the C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C12 cycloalkyl, or 4- to 12-membered heterocycloalkyl is optionally substituted with one or more -Q3c-T3c, wherein each Q3c independently is a bond or C1-C3 alkylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or C1-C6 alkoxy, and each T3c independently is selected from the group consisting of H, halo, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C6-C10 aryl, 4- to 7-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, 5- to 6-membered heteroaryl, ORec, ORfc, C(O)Rfc, C(O)ORfc, OC(O)Rfc, S(O)2Rfc, NRfcRgc, OC(O)NRfcRgc, NRfcC(O)ORgc, C(O)NRfcRgc, and NRfcC(O)Rgc;
• or -Q3c-T3c is oxo;
• each Rec independently is H or C1-C6 alkyl optionally substituted with one or more of halo, cyano, hydroxyl, amino, mono- or di-alkylamino, or C1-C6 alkoxyl;
• each of Rfc and Rgc, independently, is -Q6c-T6c, in which Q6c is a bond or C1-C6 alkylene, C2-C6 alkenylene, or C2-C6 alkynylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or C1-C6 alkoxyl, and T6c is H, halo, ORm1c, NRm1cRm2c, NRm1cC(O)Rm2c, C(O)NRm1cRm2c, C(O)Rm1c, C(O)ORm1c, NRm1cC(O)ORm2c, OC(O)NRm1cRm2c, S(O)2Rm1c, S(O)2NRm1cRm2c, or RS3c, in which each of Rm1c and Rm2c independently is H or C1-C6 alkyl, and RS3c is C3-C8 cycloalkyl, C6-C10 aryl, 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, or a 5- to 10-membered heteroaryl, and RS3c is optionally substituted with one or more -Q7c-T7c, wherein each Q7c independently is a bond or C1-C3 alkylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or C1-C6 alkoxy, and each T7c independently is selected from the group consisting of H, halo, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C6-C10 aryl, 4- to 7-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, 5- to 6-membered heteroaryl, ORn1c, C(O)Rn1c, C(O)ORn1c, OC(O)Rn1c, S(O)2Rn1c, NRn1cRn2c, OC(O)NRn1cRn2c, NRn1cC(O)ORn2c, C(O)NRn1cRn2c, and NRn1cC(O)Rn2c, each of Rn1c and Rn2c independently being H or C1-C6 alkyl;
• or -Q7c-T7c is oxo;
• R8c is H or C1-C6 alkyl;
• R9c is -Q4c-T4c, in which Q4c is a bond or C1-C6 alkylene, C2-C6 alkenylene, or C2-C6 alkynylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or C1-C6 alkoxyl, and T4c is H, halo, ORhc, NRhcRic, NRhcC(O)Ric, C(O)NRhcRic, C(O)Rhc, C(O)ORhc, NRhcC(O)ORic, OC(O)NRhcRic, S(O)2Rhc, S(O)2NRhcRic, or RS2c, in which each of Rhc and Ric independently is H or C1-C6 alkyl, and RS2c is C3-C8 cycloalkyl, C6-C10 aryl, 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, or a 5- to 10-membered heteroaryl, and RS2c is optionally substituted with one or more -Q5c-T5c, wherein each Q5c independently is a bond or C1-C3 alkylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or C1-C6 alkoxy, and each T5 independently is selected from the group consisting of H, halo, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C6-C10 aryl, 4- to 7-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, 5- to 6-membered heteroaryl, ORjc, C(O)Rjc, C(O)ORjc, OC(O)Rjc, S(O)2Rjc, NRjcRkc, OC(O)NRjcRkc, NRjcC(O)ORkc, C(O)NRjcRkc, and NRjcC(O)Rkc, each of Rjc and Rkc independently being H or C1-C6 alkyl;
• or -Q5c-T5c is oxo;
• R10c is halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, or 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, wherein each of the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, and 4- to 12-membered heterocycloalkyl is optionally substituted with one or more halo, cyano, hydroxyl, oxo, amino, mono- or di-alkylamino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C(O)NRjcRkc, or NRjcC(O)Rkc;
• R11c and R12c together with the carbon atom to which they are attached form a C3-C12 cycloalkyl or 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, wherein the C3-C12 cycloalkyl or 4- to 12-membered heterocycloalkyl is optionally substituted with one or more of halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, hydroxyl, oxo, amino, mono- or di-alkylamino, or C1-C6 alkoxyl;
• R13c is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, or 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S;
• and
• each of R14c and R15c, independently, is H, halo, cyano, C1-C6 alkyl optionally substituted with one or more of halo or cyano, C2-C6 alkenyl optionally substituted with one or more of halo or cyano, C2-C6 alkynyl optionally substituted with one or more of halo or cyano, C3-C8 cycloalkyl optionally substituted with one or more of halo or cyano, or —OR6c.

The method of any one of the preceding claims, being of Formula (IA′″) or (IIA′″):

• a tautomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of the tautomer, wherein:
• R8c is C1-C6 alkyl;
• Rjc, is C1-C6 alkyl;
• R11c and R12c each independently is C1-C6 alkyl, or R11c and R12c together with the carbon atom to which they are attached form C3-C12 cycloalkyl;
• R14c and R15c each independently is H, halogen, or C1-C6 alkoxyl;
• and
• R7c is 5- to 10-membered heteroaryl or 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, wherein the 5- to 10-membered heteroaryl or 4- to 12-membered heterocycloalkyl is optionally substituted with one or more of R7cS;
• each R7cS independently is oxo, C1-C6 alkyl, or 4- to 12-membered heterocycloalkyl, wherein the C1-C6 alkyl or 4- to 12-membered heterocycloalkyl is optionally substituted with one or more of oxo, C1-C6 alkyl, or NR7cSaR7cSb, R7cSa and R7cSb each independently is H or C1-C6 alkyl, or R7cSa and R7cSb together with the nitrogen atom to which they are attached form C3-C6 heterocycloalkyl.

The method of any one of the preceding claims, wherein:

• R8c is C1-C6 alkyl;
• R5c is C1-C6 alkyl;
• R11c and R12c each independently is C1-C6 alkyl, or R11c and R12c together with the carbon atom to which they are attached form C3-C12 cycloalkyl;
• R14c and R15c each independently is H, halogen, or C1-C6 alkoxyl;
• and
• R7c is 5- to 10-membered heteroaryl or 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, wherein the 5- to 10-membered heteroaryl or 4- to 12-membered heterocycloalkyl is optionally substituted with one or more of R7cS;
• each R7cS independently is C1-C6 alkyl or 4- to 12-membered heterocycloalkyl, wherein the C1-C6 alkyl or 4- to 12-membered heterocycloalkyl is optionally substituted with one or more of NR7cSaR7cSb;
• R7cSa and R7cSb each independently is H or C1-C6 alkyl, or R7cSa and R7cSb together with the nitrogen atom to which they are attached form C3-C6 heterocycloalkyl.

The method of any one of the preceding claims, wherein the one or more additional therapeutic agent comprises 6R-BH4 (sapropterin dihydrochloride), A-001 (Varespladib sodium), Abatacept, Abrisentan, Acetaminophen, Acetylcholine, Aes-103 (BAX-555, 5-hydroxymethyl-2-furfural (5-HMF)), Albuterol, Alemtuzumab, alpha-lipoic acid, acetyl-L-camitine, ambrisentan, anti-thymocyte globulin (ATG), Apixaban, Arginine (e.g., arginine butyrate, arginine hydrochloride;

• continuous or loading,), aspirin, atorvastatin, azacitadine, azithromycin, benzerazide, BG-45, BMD, BPX-501 (rivogenlecleucel), API903 (rimiducid), budesonide, busulfan, busulfex, butyrate, canakinumab, clotrimazole, codeine, cogmed, crizanlizumab, cyclophosphamide (CTX), cyclosporine, dalteparin, decitabine, tetrahydrouridine, deferasirox (ICL670), deferiprone, deferoxamine (DFO), defibrotide, desloratidine, desmopressin, dihydroartemisinin-piperaquine (DP), diphenhydramine, a DNMT inhibitor, docosahexaenoic acid, erythropoietin, hydroxyurea, etinostat, FBS0701, fentanyl citrate, ferriprox, fludarabine, gabapentin, GBT440, GCSF, gene therapy, GMI-1070, granulocyte colony-stimulating factor, GSK1024850A (Synflorix), graft-versus-host-disease (GVHD) prophylaxis, a HD AC inhibitor, a HDAC1/2 inhibitor, HIDA, high dose ICA-17043, HQK-1001, hydromorphone, hydroxyurea, a hypomethylating agent, ICL670, ilaris, intravenous immune globulin, IMR-687, a vaccine (e.g., inactivated influenza A (H1N1) virus vaccine), INCB059872, citrulline, magnesium sulfate, isobutyramide, ketamine, LDV/SOF, LentiGlobin BB305, levetiracetam, L-Glutamine, lidocaine, L-NMMA, losartan, low dose ICA-17043, low dose ketamine, an LSD1 inhibitor, macitentan, magnesium pidolate, a TR2/TR4 agonist, a DRED (direct repeat eryhtroid definitive) agonist, a BCL11 inhibitor, a c-MYB inhibitor, a GATA1 inhibitor, a KLF inhibitor, mefloquine, artesunate, melphalan, memantine hydrochloride, meperidine, mesna (e.g., mesnex), metformin, methadone, methotrexate, methylphenidate, methylprednisolone, prednisone, mometasone furoate, montelukast (e.g., in combination with hydroxyurea), morphine, MP4CO, MST-188 (vepoloxamer), mycophenolate mofetil (MMF), N-acetylcysteine (NAC), niacin-ER, NiCord (ex vivo expanded cell graft derived from umbilical cord stem cells), nitric oxide (e.g., by inhalation), nitroglycerin, NKTT120 (NKT Therapeutics), NO-CO (e.g., by inhalation and expiration), nubain (nalbuphine hydrochloride), NVX-508, omega-3 fatty acids, tetrahydrouridine, L-citrulline, oxypurinol, paludrine, folic acid, panobinostat, PDE9i, penicillin, pentostatin, plerixafor, poloxamer 188, pomalidomide, prasugrel, a PRMT1 inhibitor, a PRMT5 inhibitor, proguanil, propranolol, PSI697, a RAS Inhibitors, r-ATG, recombinant-methionyl human stem cell factor, riociguat, rivaroxaban, rivipansel, sangstat, sanguinate, SC411, SCD-101, SCD-Omegatex, SelG1 (crizanlizumab), sevuparin, siklos (hydroxycarbamide), sildenafil, simvastatin, sirolimus, sodium bicarbonate, sodium nitrite, SPD602 (FBS0701, SSP-004184), sulfadoxine pyrimethamine, synthetic zinc finger transcriptional activators, tacrolimus, t-butylhydroquinone, tDCS plus PES, thiotepa, thymoglobulin, ticagrelor, TLI, treosulfan, tritanrix-HepB/Hib, unfractionated heparin, Vaccination (e.g., Polio Sabin, Prevenar, Pneumo 23), vepoloxamer, vitamin D3, vorinostat, or zileuton, or any combination thereof.

An EHMT2 inhibitor of any one of the preceding claims for preventing or treating a blood disorder, wherein the blood disorder is Acute lymphoblastic leukemia (ALL), Acute myeloid leukemia (AML) (e.g., acute promyelocytic leukemia, APL), Amyloidosis, Anemia, Aplastic anemia, Bone marrow failure syndromes, Chronic lymphocytic leukemia (CLL), Chronic myeloid leukemia (CML), Deep vein thrombosis (DVT), Diamond-Blackfan anemia, Dyskeratosis congenita (DKC), Eosinophilic disorder, Essential thrombocythemia, Fanconi anemia, Gaucher disease, Hemochromatosis, Hemolytic anemia, Hemophilia, Hereditary spherocytosis, Hodgkin's lymphoma, Idiopathic thrombocytopenic purpura (ITP), Inherited bone marrow failure syndromes, Iron-deficiency anemia, Langerhans cell histiocytosis, Large granular lymphocytic (LGL) leukemia, Leukemia, Leukopenia, Mastocytosis, Monoclonal gammopathy, Multiple myeloma, Myelodysplastic syndromes (MDS), Myelofibrosis, Myeloproliferative neoplasms (MPN), Non-Hodgkin's lymphoma, Paroxysmal nocturnal hemoglobinuria (PNH), Pernicious anemia (B12 deficiency), Polycythemia vera, Porphyria, Post-transplant lymphoproliferative disorder (PTLD), Pulmonary embolism (PE), Shwachman-Diamond syndrome (SDS), Sickle-cell disease (SCD), Thalassemia, Thrombocytopenia, Thrombotic thrombocytopenic purpura (TTP), Venous thromboembolism, Von Willebrand disease, or Waldenstrom's macroglobulinemia (lymphoplasmacytic lymphoma).

An EHMT2 inhibitor of any one of the preceding claims for use in combination with one or more additional therapeutic agent for preventing or treating a blood disorder, wherein the blood disorder is Acute lymphoblastic leukemia (ALL), Acute myeloid leukemia (AML) (e.g., acute promyelocytic leukemia, APL), Amyloidosis, Anemia, Aplastic anemia, Bone marrow failure syndromes, Chronic lymphocytic leukemia (CLL), Chronic myeloid leukemia (CML), Deep vein thrombosis (DVT), Diamond-Blackfan anemia, Dyskeratosis congenita (DKC), Eosinophilic disorder, Essential thrombocythemia, Fanconi anemia, Gaucher disease, Hemochromatosis, Hemolytic anemia, Hemophilia, Hereditary spherocytosis, Hodgkin's lymphoma, Idiopathic thrombocytopenic purpura (ITP), Inherited bone marrow failure syndromes, Iron-deficiency anemia, Langerhans cell histiocytosis, Large granular lymphocytic (LGL) leukemia, Leukemia, Leukopenia, Mastocytosis, Monoclonal gammopathy, Multiple myeloma, Myelodysplastic syndromes (MDS), Myelofibrosis, Myeloproliferative neoplasms (MPN), Non-Hodgkin's lymphoma, Paroxysmal nocturnal hemoglobinuria (PNH), Pernicious anemia (B12 deficiency), Polycythemia vera, Porphyria, Post-transplant lymphoproliferative disorder (PTLD), Pulmonary embolism (PE), Shwachman-Diamond syndrome (SDS), Sickle-cell disease (SCD), Thalassemia, Thrombocytopenia, Thrombotic thrombocytopenic purpura (ITP), Venous thromboembolism, Von Willebrand disease, or Waldenstrom's macroglobulinemia (lymphoplasmacytic lymphoma).

Use of an EHMT2 inhibitor of any one of the preceding claims in the manufacture of a medicament for preventing or treating a blood disorder, wherein the blood disorder is Acute lymphoblastic leukemia (ALL), Acute myeloid leukemia (AML) (e.g., acute promyelocytic leukemia, APL), Amyloidosis, Anemia, Aplastic anemia, Bone marrow failure syndromes, Chronic lymphocytic leukemia (CLL), Chronic myeloid leukemia (CML), Deep vein thrombosis (DVT), Diamond-Blackfan anemia, Dyskeratosis congenita (DKC), Eosinophilic disorder, Essential thrombocythemia, Fanconi anemia, Gaucher disease, Hemochromatosis, Hemolytic anemia, Hemophilia, Hereditary spherocytosis, Hodgkin's lymphoma, Idiopathic thrombocytopenic purpura (ITP), Inherited bone marrow failure syndromes, Iron-deficiency anemia, Langerhans cell histiocytosis, Large granular lymphocytic (LGL) leukemia, Leukemia, Leukopenia, Mastocytosis, Monoclonal gammopathy, Multiple myeloma, Myelodysplastic syndromes (MDS), Myelofibrosis, Myeloproliferative neoplasms (MPN), Non-Hodgkin's lymphoma, Paroxysmal nocturnal hemoglobinuria (PNH), Pernicious anemia (B12 deficiency), Polycythemia vera, Porphyria, Post-transplant lymphoproliferative disorder (PTLD), Pulmonary embolism (PE), Shwachman-Diamond syndrome (SDS), Sickle-cell disease (SCD), Thalassemia, Thrombocytopenia, Thrombotic thrombocytopenic purpura (TTP), Venous thromboembolism, Von Willebrand disease, or Waldenstrom's macroglobulinemia (lymphoplasmacytic lymphoma).

Use of an EHMT2 inhibitor of any one of the preceding claims in the manufacture of a medicament for use in combination with one or more additional therapeutic agent for preventing or treating a blood disorder, wherein the blood disorder is Acute lymphoblastic leukemia (ALL), Acute myeloid leukemia (AML) (e.g., acute promyelocytic leukemia, APL), Amyloidosis, Anemia, Aplastic anemia, Bone marrow failure syndromes, Chronic lymphocytic leukemia (CLL), Chronic myeloid leukemia (CML), Deep vein thrombosis (DVT), Diamond-Blackfan anemia, Dyskeratosis congenita (DKC), Eosinophilic disorder, Essential thrombocythemia, Fanconi anemia, Gaucher disease, Hemochromatosis, Hemolytic anemia, Hemophilia, Hereditary spherocytosis, Hodgkin's lymphoma, Idiopathic thrombocytopenic purpura (ITP), Inherited bone marrow failure syndromes, Iron-deficiency anemia, Langerhans cell histiocytosis, Large granular lymphocytic (LGL) leukemia, Leukemia, Leukopenia, Mastocytosis, Monoclonal gammopathy, Multiple myeloma, Myelodysplastic syndromes (MDS), Myelofibrosis, Myeloproliferative neoplasms (MPN), Non-Hodgkin's lymphoma, Paroxysmal nocturnal hemoglobinuria (PNH), Pernicious anemia (B12 deficiency), Polycythemia vera, Porphyria, Post-transplant lymphoproliferative disorder (PTLD), Pulmonary embolism (PE), Shwachman-Diamond syndrome (SDS), Sickle-cell disease (SCD), Thalassemia, Thrombocytopenia, Thrombotic thrombocytopenic purpura (TTP), Venous thromboembolism, Von Willebrand disease, or Waldenstrom's macroglobulinemia (lymphoplasmacytic lymphoma).