Prmt5 inhibitors and uses thereof

A compound of Formula (I)

• or a pharmaceutically acceptable salt thereof, wherein
• is a single or double bond;
• ring A is C5-7 cycloalkyl, phenyl, 5 to 7 membered heterocyclyl, or 5 or 6 membered heteroaryl;
• the cycloalkyl, phenyl, heterocyclyl, or heteroaryl of ring A is optionally substituted with one to four R6, which may be the same or different;
• X is N or CR7;
• R1 is H, C1-6 alkyl, C1-6 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, 3 to 10 membered heterocyclyl, or 5 to 10 membered heteroaryl;
• wherein the alkyl, haloalkyl, aryl, cycloalkyl, heterocyclyl, or heteroaryl of R1 is each optionally substituted with one to four Z1, which may be the same or different;
• R2 is H, —CN, C1-5 alkyl, C1-5 haloalkyl, C2-6 alkynyl, cyclopropyl, cyclobutyl, or oxetanyl;
• wherein the alkyl, haloalkyl, alkoxyalkyl, alkynyl, cyclopropyl, or cyclobutyl of R2 is each optionally substituted with one to four Z2, which may be the same or different;
• each Z2 is independently C2-6 alkynyl, halo, —CN, —OR2a, cyclopropyl, cyclobutyl, or oxetanyl;
• R2a is H, C1-3 haloalkyl, C3-6 cycloalkyl, or C1-3 alkyl;
• R5 is H, C1-3 alkyl, or C1-3 haloalkyl;
• or R1 and R2 together with the carbon to which they are attached form C3-10 cycloalkyl, 3 to 10 membered heterocyclyl;
• the cycloalkyl or heterocyclyl formed from R1 and R2 is optionally substituted with one to four Z5, which may be the same or different;
• or R2 and R5 together with the carbon to which they are attached form cyclopropyl, cyclobutyl, or oxetanyl;
• the cyclopropyl, or cyclobutyl formed from R2 and R5 is optionally substituted with one to four halo;
• R3 is H, C1-6 alkyl, C1-6 haloalkyl, —COR3a, —COOR3a, —CONR3aR3b, —SO2R3a, —SO2NR3aR3b, C6-10 aryl, C3-10 cycloalkyl, 3 to 10 membered heterocyclyl, or 5 to 10 membered heteroaryl;
• wherein the alkyl, aryl, cycloalkyl, heterocyclyl, or heteroaryl of R3 is each optionally substituted with one to four Z3, which may be the same or different,
• R4 is H, C1-6 alkyl, C1-6 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, 3 to 10 membered heterocyclyl, or 5 to 10 membered heteroaryl;
• wherein the alkyl, aryl, cycloalkyl, heterocyclyl, or heteroaryl of R4 is each optionally substituted with one to four Z4, which may be the same or different,
• or R3 and R4 together with the nitrogen to which they are attached form a 3 to 10 membered heterocyclyl, or 5 to 10 membered heteroaryl;
• wherein the heterocyclyl or heteroaryl formed from R3 and R4 is optionally substituted with one to four Z9, which may be the same or different, wherein the heterocyclyl formed from R3 and R4 is a heterocyclyl having 0 to 2 additional heteroatoms each independently N, O, or S, wherein the heteroaryl formed from R3 and R4 is a heteroaryl having 0 to 2 additional heteroatoms each independently N, O, or S,
• or R2 and R4 together with the atoms to which they are attached form a 5 to 10 membered heterocyclyl;
• wherein the heterocyclyl formed from R2 and R4 is optionally substituted with one to four Z8, which may be the same or different;
• each R6 is independently halo, —OH, —OCH3, oxo, —CN, C1-3 alkyl, C1-3 haloalkyl, or cyclopropyl;
• R7 is H, halo, CN, halomethyl, —CH3, or —OCH3;
• each Z1, Z3, Z4, Z5, Z8, or Z9 is independently C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C2-6 alkoxyalkyl, C2-6 alkenyl, C2-6 alkynyl, halogen, C3-10 cycloalkyl, 3 to 10 membered heterocyclyl, C6-10 aryl, 5 to 10 membered heteroaryl, oxo, —NO2, —CN, —O—R12a, —C(O)—R12a, —C(O)O—R12a, —C(O)—N(R12a)(R12b), —N(R12a)(R12b), —N(R12a)2(R12b)+, —N(R12a)C(O)—R12b, —N(R12a)C(O)O—R12b, —N(R12a)C(O)N(R12b)(R12c), —N(R12a)S(O)2(R12b), —NR12aS(O)2N(R12b)(R12c), —NR12aS(O)2O(R12b), —OC(O)R12a, —OC(O)OR12a, —OC(O)—N(R12a)(R12b), —S—R12a, —S(O)R12a, —S(O)(NH)R12a, —S(O)2R12a, —S(O)2N(R12a)(R12b), —S(O)(NR12a)R12b, or —Si(R12a)3;
• wherein the alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl of each Z1, Z3, Z4, Z3, Z8, or Z9 is each optionally substituted with one to four Z1a, which may be the same or different;
• each Z1a is independently C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C2-6 alkoxyalkyl, C2-6 alkenyl, C2-6 alkynyl, halogen, C3-10 cycloalkyl, 3 to 10 membered heterocyclyl, C6-10 aryl, 5 to 10 membered heteroaryl, oxo, —NO2, —CN, —O—R12a, —C(O)R12a, —C(O)O—R12a, —C(O)N(R12a)(R12b), —N(R12a)(R12b), —N(R12a)2(R12b)+, —N(R12a)—C(O)R12b, —N(R12a)C(O)O(R12b), —N(R12a)C(O)N(R12b)(R12c), —N(R12a)S(O)2(R12b), —N(R12a)S(O)2—N(R12b)(R12c), —N(R12a)S(O)2O(R12b), —OC(O)R12a, —OC(O)OR12a, —OC(O)—N(R12a)(R12b), —S—R12a, —S(O)R12a, —S(O)(NH)R12a, —S(O)2R12a, —S(O)2N(R12a)(R12b), —S(O)(NR12a)R12b, or —Si(R12a)3;
• wherein the alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl of Z1a is each optionally substituted with one to four Z1b, which may be the same or different;
• each Z1b is independently C1-9 alkyl, C1-8 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, halogen, C3-15 cycloalkyl, heterocyclyl, C6-10 aryl, heteroaryl, oxo, —OH, —CN, —NO2, —NH2, —N3, —SH, —O(C1-9 alkyl), —O(C1-8 haloalkyl), —O(C2-6 alkenyl), —O(C2-6 alkynyl), —O(C3-15 cycloalkyl), —O(heterocyclyl), —O(C6-10 aryl), —O(heteroaryl), —NH(C1-9 alkyl), —NH(C1-8 haloalkyl), —NH(C2-6 alkenyl), —NH(C2-6 alkynyl), —NH(C3-15 cycloalkyl), —NH(heterocyclyl), —NH(C6-10 aryl), —NH(heteroaryl), —N(C1-9 alkyl)2, —N(C1-8 haloalkyl)2, —N(C2-6 alkenyl)2, —N(C2-6 alkynyl)2, —N(C3-15 cycloalkyl)2, —N(heterocyclyl)2, —N(C6-10 aryl)2, —N(heteroaryl)2, —N(C1-9 alkyl)(C1-8 haloalkyl), —N(C1-9 alkyl)(C2-6 alkenyl), —N(C1-9 alkyl)(C2-6 alkynyl), —N(C1-9 alkyl)(C3-15 cycloalkyl), —N(C1-9 alkyl)(heterocyclyl), —N(C1-9 alkyl)(C6-10 aryl), —N(C1-9 alkyl)(heteroaryl), —C(O)(C1-9 alkyl), —C(O)(C1-8 haloalkyl), —C(O)(C2-6 alkenyl), —C(O)(C2-6 alkynyl), —C(O)(C3-15 cycloalkyl), —C(O)(heterocyclyl), —C(O)(C6-10 aryl), —C(O)(heteroaryl), —C(O)O(C1-9 alkyl), —C(O)O(C1-8 haloalkyl), —C(O)O(C2-6 alkenyl), —C(O)O(C2-6 alkynyl), —C(O)O(C3-15 cycloalkyl), —C(O)O(heterocyclyl), —C(O)O(C6-10 aryl), —C(O)O(heteroaryl), —C(O)NH2, —C(O)NH(C1-9 alkyl), —C(O)NH(C1-8 haloalkyl), —C(O)NH(C2-6 alkenyl), —C(O)NH(C2-6 alkynyl), —C(O)NH(C3-15 cycloalkyl), —C(O)NH(heterocyclyl), —C(O)NH(C6-10 aryl), —C(O)NH(heteroaryl), —C(O)N(C1-9 alkyl)2, —C(O)N(C1-8 haloalkyl)2, —C(O)N(C2-6 alkenyl)2, —C(O)N(C2-6 alkynyl)2, —C(O)N(C3-15 cycloalkyl)2, —C(O)N(heterocyclyl)2, —C(O)N(C6-10 aryl)2, —C(O)N(heteroaryl)2, —NHC(O)(C1-9 alkyl), —NHC(O)(C1-8 haloalkyl), —NHC(O)(C2-6 alkenyl), —NHC(O)(C2-6 alkynyl), —NHC(O)(C3-15 cycloalkyl), —NHC(O)(heterocyclyl), —NHC(O)(C6-10 aryl), —NHC(O)(heteroaryl), —NHC(O)O(C1-9 alkyl), —NHC(O)O(C1-8 haloalkyl), —NHC(O)O(C2-6 alkenyl), —NHC(O)O(C2-6 alkynyl), —NHC(O)O(C3-15 cycloalkyl), —NHC(O)O(heterocyclyl), —NHC(O)O(C6-10 aryl), —NHC(O)O(heteroaryl), —NHC(O)NH(C1-9 alkyl), —NHC(O)NH(C1-8 haloalkyl), —NHC(O)NH(C2-6 alkenyl), —NHC(O)NH(C2-6 alkynyl), —NHC(O)NH(C3-15 cycloalkyl), —NHC(O)NH(heterocyclyl), —NHC(O)NH(C6-10 aryl), —NHC(O)NH(heteroaryl), —NHS(O)(C1-9 alkyl), —N(C1-9 alkyl)(S(O)(C1-9 alkyl), —S(C1-9 alkyl), —S(C1-8 haloalkyl), —S(C2-6 alkenyl), —S(C2-6 alkynyl), —S(C3-15 cycloalkyl), —S(heterocyclyl), —S(C6-10 aryl), —S(heteroaryl), —S(O)N(C1-9 alkyl)2, —S(O)(C1-9 alkyl), —S(O)(C1-8 haloalkyl), —S(O)(C2-6 alkenyl), —S(O)(C2-6 alkynyl), —S(O)(C3-15 cycloalkyl), —S(O)(heterocyclyl), —S(O)(C6-10 aryl), —S(O)(heteroaryl), —S(O)2(C1-9 alkyl), —S(O)2(C1-8 haloalkyl), —S(O)2(C2-6 alkenyl), —S(O)2(C2-6 alkynyl), —S(O)2(C3-15 cycloalkyl), —S(O)2(heterocyclyl), —S(O)2(C6-10 aryl), —S(O)2(heteroaryl), —S(O)(NH)(C1-9 alkyl), —S(O)2NH(C1-9 alkyl), or —S(O)2N(C1-9 alkyl)2;
• wherein the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl of Z1b is optionally substituted with one to three C1-9 alkyl, C1-8 haloalkyl, halogen, —OH, —NH2, —O(C1-9 alkyl), —O(C1-8 haloalkyl), —O(C3-15 cycloalkyl), —O(heterocyclyl), —O(aryl), —O(heteroaryl), —NH(C1-9 alkyl), —NH(C1-8 haloalkyl), —NH(C3-15 cycloalkyl), —NH(heterocyclyl), —NH(aryl), —NH(heteroaryl), —N(C1-9 alkyl)2, —N(C3-15 cycloalkyl)2, —NHC(O)(C1-8 haloalkyl), —NHC(O)(C3-15 cycloalkyl), —NHC(O)(heterocyclyl), —NHC(O)(aryl), —NHC(O)(heteroaryl), —NHC(O)O(C1-9 alkyl), —NHC(O)O(C1-8 haloalkyl), —NHC(O)O(C2-6 alkynyl), —NHC(O)O(C3-15 cycloalkyl), —NHC(O)O(heterocyclyl), —NHC(O)O(aryl), —NHC(O)O(heteroaryl), —NHC(O)NH(C1-9 alkyl), S(O)2(C1-9 alkyl), —S(O)2(C1-8 haloalkyl), —S(O)2(C3-15 cycloalkyl), —S(O)2(heterocyclyl), —S(O)2(aryl), —S(O)2(heteroaryl), —S(O)(NH)(C1-9 alkyl), —S(O)2NH(C1-9 alkyl), or —S(O)2N(C1-9 alkyl)2, wherein the heteroaryl of Z1b is 5 to 10 membered heteroaryl, the heterocyclyl of Z1b is 3 to 10 membered heterocyclyl;
• and
• each R3a, R3b, R12a, R12b, or R12c is independently H, C1-6 alkyl, C3-10 cycloalkyl, 3 to 10 membered heterocyclyl, C6-10 aryl, or 5 to 10 heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl of each R3a, R3b, R12a, R12b, or R12c is each optionally substituted with one to four Z1b, which may be the same or different;
• wherein each heteroaryl or heterocyclyl of the compound of Formula (I) unless otherwise specified has one to three heteroatoms each independently N, O, or S.