Compounds for Improving mRNA Splicing

1 - 70 . (canceled)

71 . A compound of Formula (Ir):

or a pharmaceutically acceptable salt thereof, wherein:

L is absent or selected from the group consisting of C 1-6 alkylene, C 2-6 alkenylene, and C 2-6 alkynylene, wherein the C 1-6 alkylene, C 2-6 alkenylene, and C 2-6 alkynylene are each optionally substituted by 1, 2, 3, or 4 independently selected R 20 groups;

R 1 is selected from the group consisting of a C 6-10 aryl, 2-benzofuranyl, 4-quinolinyl, a 5-6 member heteroaryl, and a 5-6 member heterocycloalkyl, each optionally substituted by 1, 2, 3, or 4 independently selected R 1A groups;

each R 1A is independently selected from halo, CN, NO 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, —C(═O)OH, —C(═O)C 1-6 alkyl, —C(═O)C 1-6 haloalkyl, and —C(═O)C 1-6 alkoxy;

R 2 is selected from the group consisting of H, oxo, azido, halo, CN, NO 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, OR a2 , C(═O)R b2 , C(═O)OR b2 , NR c2 R d2 , C(═O)NR c2 R d2 , —OC(═O)NR c2 R d2 , NR c2 C(═O)R b2 , NR c2 C(═O)OR b2 , N c2 C(═O)NR c2 R d2 , NR c2 S(═O) 2 R b2 , NR c2 S(═O) 2 NR c2 R d2 , S(O)NR c2 R d2 , and S(O) 2 NR c2 R d2 , wherein the C 1-6 alkyl, C 3-10 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted by 1, 2, 3, or 4 independently selected R 20 groups;

R 3 is selected from the group consisting of H, oxo, azido, halo, CN, NO 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, OR a3 , SR a3 , C(═O)R b3 , C(═O)OR b3 , NR c3 R d3 , C(═O)NR c3 R d3 , —OC(═O)NR c3 R d3 , NR c3 C(═O)R b3 , NR c3 C(═O)OR b3 , NR c3 C(═O)NR c3 R d3 , NR c3 S(═O) 2 R b3 , NR c3 S(═O) 2 NR c3 R d3 , S(O)NR c3 R d3 , and S(O) 2 NR c3 R d3 , wherein the C 1-6 alkyl, C 3-10 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted by 1, 2, 3, or 4 independently selected R 20 groups;

R 5 is selected from the group consisting of H, oxo, azido, halo, CN, NO 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, OR a5 , SR a5 , C(═O)R b5 , C(═O)OR b5 , NR c5 R d5 , C(═O)NR c5 R d5 , —OC(═O)NR c5 R d5 , NR c5 C(═O)R b5 , NR c5 C(═O)OR b5 , NR c5 C(═O)NR c5 R d5 NR c5 S(═O) 2 R b5 , NR c5 S(═O) 2 NR c5 R d5 , S(O)NR c5 R d5 , and S(O) 2 NR c5 R d5 , wherein the C 1-6 alkyl, C 3-10 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted by 1, 2, 3, or 4 independently selected R 20 groups;

R 6 is selected from the group consisting of H, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, and C 1-6 alkoxy;

each R a2 , R b2 , R c2 , R d2 , R a3 , R b3 , R c3 , R d3 , R a5 , R b5 , R c5 , and R d5 is independently selected from the group consisting of H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, —(C 1-6 alkylene)-C 1-6 alkoxy, C 3-10 cycloalkyl, —(C 1-6 alkylene)-C 3-10 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, —(C 1-6 alkylene)-C 3-10 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted by 1, 2, 3, or 4 independently selected R 20 groups;

or R c2 and R d2 together with the N atom to which they are connected, come together to form a 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl ring, each optionally substituted by 1, 2, 3, or 4 independently selected R 20 groups;

or R c3 and R d3 together with the N atom to which they are connected, come together to form a 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl ring, each optionally substituted by 1, 2, 3, or 4 independently selected R 20 groups; and

each R 20 is independently selected from the group consisting of OH, SH, CN, NO 2 , halo, oxo, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, C 1-4 cyanoalkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy, —(C 1-4 alkyl)-(C 1-4 alkoxy), —(C 1-4 alkoxy)-(C 1-4 alkoxy), C 1-4 haloalkoxy, C 3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl, 5-6 membered heterocycloalkyl, amino, C 1-4 alkylamino, di(C 1-4 alkyl)amino, carbamyl, C 1-4 alkylcarbamyl, di(C 1-4 alkyl)carbamyl, carbamoyl, C 1-4 alkylcarbamoyl, di(C 1-4 alkyl)carbamoyl, C 1-4 alkylcarbonyl, C 1-4 alkoxycarbonyl, C 1-4 alkylcarbonylamino, C 1-4 alkylsulfonylamino, aminosulfonyl, C 1-4 alkylaminosulfonyl, di(C 1-4 alkyl)aminosulfonyl, aminosulfonylamino, C 1-4 alkylaminosulfonylamino, di(C 1-4 alkyl)aminosulfonylamino, aminocarbonylamino, C 1-4 alkylaminocarbonylamino, and di(C 1-4 alkyl)aminocarbonylamino.

72 . The compound of claim 71 , wherein L is C 1-6 alkylene optionally substituted by 1, 2, 3, or 4 independently selected R 20 groups.

73 . The compound of claim 71 , wherein L is unsubstituted methylene or unsubstituted ethylene.

74 . The compound of claim 71 , wherein R 1 is selected from the group consisting of 2-benzofuranyl, 4-quinolinyl, phenyl, 5-6 membered heteroaryl, and 5-6 membered heterocycloalkyl, each optionally substituted by 1 or 2 independently selected R 1A groups.

75 . The compound of claim 71 , wherein R 1 is selected from the group consisting of:

76 . The compound of claim 71 , wherein each R 1A is independently selected from the group consisting of halo, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, and —C(═O)OH.

77 . The compound of claim 71 , wherein each R 1A is independently selected from the group consisting of CN, fluoro, chloro, methyl, trifluoromethyl, methoxy, and —C(═O)OH.

78 . The compound of claim 71 , wherein R 2 is selected from the group consisting of H, oxo, halo, CN, C 1-6 alkyl, OR a2 , NR c2 R d2 , 5-6 membered heteroaryl, 5-6 membered heterocycloalkyl, C(═O)OR a2 , and C(═O)NR c2 R d2 , wherein the C 1-6 alkyl and 4-10 membered heterocycloalkyl are each optionally substituted by 1, 2, 3, or 4 independently selected R 20 groups.

79 . The compound of claim 71 , wherein R 3 is selected from the group consisting of H, oxo, azido, CN, C 1-6 alkyl, C 3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl, 5-6 membered heterocycloalkyl, OR a3 , SR a3 , NR c3 R d3 , C(═O)OR a3 , —C(═O)NR c3 R d3 , —OC(═O)R b3 , wherein the C 1-6 alkyl, C 3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl, and 5-6 membered heterocycloalkyl, are each optionally substituted by 1, 2, 3, or 4 independently selected R 20 groups.

80 . The compound of claim 71 , wherein R 3 is selected from the group consisting of H, azido, CN, methyl, cyclopropyl, cyclobutyl, phenyl, 3-pyridinyl, N-morpholino, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, —OCH 2 CH 2 OH, —OCH 2 CH 2 CH 2 OH, —OCH 2 CH 2 OCH 3 , —OCH 2 CH 2 CH 2 OCH 3 , —ONHCH 3 , —OCH 2 CHF 2 , —OCH 2 CF 3 , —OCH 2 CH 2 CF 3 , —OCH 2 CHF 2 CH 3 , —OCH 2 CH 2 NHC(═O)CH 3 , cyclobutoxy, —OCH 2 CH 2 —O-phenyl, —SCH 3 , —NH 2 , —NHCH 3 , —NHCH 2 CH 3 , —N(CH 3 ) 2 , —NHCH 2 CH 2 CH 2 OH, —CH 2 OCH 3 , —CH 2 OH, —CH 2 NHCH 3 , —CH 2 N(CH 3 ) 2 , —C(═O)OCH 3 , —C(═O)NH 2 , —C(═O)NHCH 3 , —C(═O)N(CH 3 ) 2 , —NHCH 2 CH 2 OH, —C(═O)NHCH 2 CH 2 OH, —OC(═O)CH 3 , —OCH 2 -azetidinyl, —OCH 2 -oxetanyl,

81 . The compound of claim 71 , wherein R 5 is selected from the group consisting of H, halo, CN, C 1-6 alkyl, C 1-6 haloalkyl, OR a5 , SR a5 , NR c5 R d5 , C 3-6 cycloalkyl, C 6-10 aryl, and 5-6 membered heteroaryl.

82 . The compound of claim 71 , wherein R 5 is selected from the group consisting of H, fluoro, chloro, bromo, iodo, CN, methyl, isopropyl, OH, OCH 3 , NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —SCH 3 , phenyl, cyclopropyl, and

83 . The compound of claim 71 , wherein R 5 is chloro or fluoro.

84 . The compound of claim 71 , wherein R 6 is H or C 1-6 alkyl.

85 . The compound of claim 71 , wherein:

L is unsubstituted C 1-6 alkylene;

R 1 is selected from the group consisting of 2-benzofuranyl, 4-quinolinyl, C 6-10 aryl, 5-6 membered heteroaryl, 5-6 membered heterocycloalkyl, optionally substituted by 1, 2, 3, or 4 independently selected R 1A groups;

each R 1A is independently selected from the group consisting of halo, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, and —C(═O)OH;

R 2 is selected from the group consisting of H, oxo, halo, CN, C 1-6 alkyl, OR a2 , NR c2 R d2 , 5-6 membered heteroaryl, 5-6 membered heterocycloalkyl, C(═O)OR a2 , and C(═O)NR c2 R d2 , wherein the C 1-6 alkyl and 4-10 membered heterocycloalkyl are each optionally substituted by 1, 2, 3, or 4 independently selected R 20 groups;

R 3 is selected from the group consisting of H, oxo, azido, CN, C 1-6 alkyl, C 3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl, 5-6 membered heterocycloalkyl, OR a3 , SR a3 , NR c3 R d3 , C(═O)OR a3 , —C(═O)NR c3 R d3 , —OC(═O)R b3 , wherein the C 1-6 alkyl, C 3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl, 5-6 membered heterocycloalkyl, are each optionally substituted by 1, 2, 3, or 4 independently selected R 20 groups;

R 4 is selected from the group consisting of H, oxo, azido, halo, CN, C 1-6 alkyl, OR a4 , NR c4 R d4 , and 4-10 membered heterocycloalkyl, wherein the C 1-6 alkyl and 4-10 membered heterocycloalkyl are each optionally substituted by 1, 2, 3, or 4 independently selected R 20 groups; and

R 5 is selected from the group consisting of H, halo, CN, C 1-6 alkyl, C 1-6 haloalkyl, OR a5 , SR a5 , NR c5 R d5 , C 3-6 cycloalkyl, C 6-10 aryl, and 5-6 membered heteroaryl.

86 . The compound of claim 71 , wherein:

L is unsubstituted methylene or unsubstituted ethylene;

R 1 is selected from the group consisting of unsubstituted 2-furanyl, unsubstituted 4-quinolinyl, and unsubstituted phenyl;

R 5 is halo; and

R 6 is H.

87 . The compound of claim 86 , wherein:

L is unsubstituted methylene; and

R 1 is unsubstituted 2-furanyl.

88 . The compound of claim 71 , wherein the compound of Formula (Ir) has formula:

or a pharmaceutically acceptable salt thereof.

89 . A pharmaceutical composition comprising a compound of claim 71 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

90 . A method of reducing or alleviating one or more symptoms of familial dysautonomia, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 71 , or a pharmaceutically acceptable salt thereof.