Modulators of DUX4 for Regulation of Muscle Function

A kit comprising:

• a) a pharmaceutical composition comprising a compound of Formula (I)
• or a pharmaceutically acceptable salt thereof, wherein:
• A is selected from C5-12 carbocycle and 5- to 12-membered heterocycle;
• B is selected from C5-12 carbocycle and 5- to 12-membered heterocycle;
• C is selected from bond, C5-12 carbocycle, and 5- to 12-membered heterocycle;
• D is selected from bond, C5-12 carbocycle, and 5- to 12-membered heterocycle;
• each of L1 and L2 is independently selected from bond,
• —O—, —S—, —N(R51)—, N(R51)CH2—,
• —C(O)—, —C(O)O—, —OC(O)—, —OC(O)02-,
• —C(O)N(R51)—, —C(O)N(R51)C(O)—, —C(O)N(R51)C(O)N(R51)—, —N(R51)C(O)—, —N(R51)C(O)N(R51)—, —N(R51)C(O)O—, —OC(O)N(R51)—,
• —C(NR51)—, —N(R51)C(NR51)—, —C(NR51)N(R51)—, —N(R51)C(NR51) N(R51)—, —S(O)2,
• —OS(O)—, —S(O)O—, —S(O)—, —OS(O)2—,
• —OS(O)2O—, —N(R51)S(O)2—, —S(O)2N(R51)—,
• —N(R51)S(O)—, —S(O)N(R51)—, —N(R51)S(O)2N(R51)—, and —N(R51)S(O)N(R51)— or from alkylene, alkenylene, alkynylene, heteroalkylene, heteroalk-enylene, and heteroalkynylene, each of which is optionally substituted with one or more R50,
• R50 is, at each occurrence, independently selected from:
• halogen, —NO2, —CN, —OR52, —SR52, —N(R52),
• —NR53R54, —S(═O)R52, —S(═O)2R52,
• —S(═O)2R522, —S(═O)2NR53R54, —NR52S(═O)2R52, —NR52S(═O)2N(R52)2, —NR52S(═O)2NR53R54, —C(O)R52, —C(O)OR52, —OC(O)R52,
• —OC(O)OR52, —OC(O)N(R52)2, —OC(O)NR53R54, —NR52C(O)R52, —NR52C(O)OR52,
• —NR52C(O)N(R52)2, —NR52C(O)NR53R54,
• —C(O)N(R52)2, —C(O)NR53R54, —P(O)(OR52)2,
• —P(O)(R52)2, —P(O)(OR52)(R52), —P(O)(NR52)(R52), —NR52P(O)(R52), —P(O)(NR52)(OR52), —P(O)(NR52)2, ═O, ═S, ═N(R52);
• C1-10 alkyl, C1-10 alkenyl, and C2-10 alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, —NO2, —CN, —OR52, —SR52, —N(R52)2, —NR53R54, —S(═O)R52, —S(═O)2R52, —S(═O)N(R52)2, —S(═O)2NR53R54,
• —NR52S(═O)2R52, —NR52S(═O)2N(R52)2,
• —NR52S(═O)2NR53R54, —C(O)R52, —C(O)OR52,
• —OC(O)R52, —OC(O)OR52, —OC(O)N(R52)2,
• —OC(O)N53R54, —NR52C(O)R52, —NR52C(O)OR52, —NR52C(O)N(R52)2, —NR52C(O)NR53R54,
• —C(O)N(R52)2, —C(O)NR53R54, —P(O)(OR52)2,
• —P(O)(R52)2, —P(O)(OR52)(R52), —P(O)(NR52)(R52), —NR52P(O)(R52), —P(O)(NR52)(OR52),
• —P(O)(NR52)2, ═O, ═S, ═N(R52) C3-12 carbocycle, and 3- to 12-membered heterocycle;
• and
• C3-12 carbocycle and 3- to 12-membered heterocycle, wherein each C3-12 carbocycle and 3- to 12-membered heterocycle in R50 is independently optionally substituted with one or more substituents selected from halogen, —NO2, —CN, —OR52, —SR52, —N(R52)2, —NR53R54, —S(═O)R52, —S(═O)2R52, —S(═O)2N(R52)2, —S(═O)2NR53R54, —NR52S(═O)2R52, —NR52S(═O)2N(R52)2, —NR52S(═O)2NR53R54, —C(O)R52, —C(O)OR52, —OC(O)R52, —OC(O)OR52, —OC(O)N(R52)2, —OC(O)N53R54, —NR52C(O)R52, —NR52C(O)OR52, —NR52C(O)N(R52)2, —NR52C(O)NR53R54, —C(O)N(R52)2, —C(O)NR53R54, —P(O)(OR52)2, —P(O)(R52)2, —P(O)(OR52)(R52), —P(O)(NR52)(R52), —NR52P(O)(R52), —P(O)(NR52)(OR52), —P(O)(NR52)2, ═O, ═S, ═N(R52), C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl;
• R51 is independently selected at each occurrence from:
• hydrogen, —C(O) R52, —C(O)OR52, —C(O)N(R52)2, —C(O)NR53R54;
• C1-6 alkyl, C2-6 alkenyl, and C2-6 alkenyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, —NO2, —CN, —OR52, —SR52, —N(R52)2, —NR53R54, —S(═O)R52, —S(═O)2R52, —S(═O)2N(R52)2, —S(═O)2NR53R54, —NR52S(═O)2R52, —NR52S(═O)2N(R52)2, —NR52S(═O)2NR53R54, —C(O)R52, —C(O)OR52, —OC(O)R52, —OC(O)OR52, —OC(O)N(R52)2, —OC(O)N53R54, —NR52C(O)R52, —NR52C(O)OR52, —NR52C(O)N(R52)2, —NR52C(O)NR53R54, —C(O)N(R52)2, —C(O)NR53R54, —P(O)(OR52)2, —P(O)(R52)2, —P(O)(OR52)(R52), —P(O)(NR52)(R52), —NR52P(O)(R52), —P(O)(NR52)(OR52), —P(O)(NR52)2, ═O, ═S, ═N(R52), C3-12 carbocycle and 3- to 12-membered heterocycle;
• and
• C3-12 carbocycle and 3- to 12-membered heterocycle, wherein each C3-12 carbocycle and 3- to 12-membered heterocycle in R51 is independently optionally substituted with one or more substituents selected from halogen, —NO2, —CN, —OR52, —SR52, —N(R52)2, —NR53R54, —S(═O)R52, —S(═O)2R52, —S(═O)2N(R52)2, —S(═O)2NR53R54, —NR52S(═O)2R52, —NR52S(═O)2N(R52)2, —NR52S(═O)2NR53R54, —C(O)R52, —C(O)OR52, —OC(O)R52, —OC(O)OR52, —OC(O)N(R52)2, —OC(O)N53R54, —NR52C(O)R52, —NR52C(O)OR52, —NR52C(O)N(R52)2, —NR52C(O)NR53R54, —C(O)N(R52)2, —C(O)NR53R54, —P(O)(OR52)2, —P(O)(R52)2, —P(O)(OR52)(R52), —P(O)(NR52)(R52), —NR52P(O)(R52), —P(O)(NR52)(OR52), —P(O)(NR52)2, ═O, ═S, ═N(R52), C1-6 alkyl, C1-6 haloalkyl, C1-6 alkenyl, and C2-6 alkynyl;
• R52 is independently selected at each occurrence from hydrogen;
• and C1-20 alkyl, C2-20 alkenyl, C2-20 alkynyl, 1- to 6-membered heteroalkyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted by halogen, —CN, —NO2, —NH2, —NHCH3, —NHCH2CH3, ═O, —OH, —OCH3, —OCH2CH3, C3-12 carbocycle, or 3- to 6-membered heterocycle;
• R53 and R54 are taken together with the nitrogen atom to which they are attached to form a heterocycle, optionally substituted with one or more R50;
• each of RA, RB and RC is independently selected from R50;
• RD is, at each occurrence, independently selected from hydrogen or R50;
• and
• each of m, n, p, and q is independently an integer from 0-12;
• and
• b) packaging materials.

A method of determining D4Z4 de-repression activity of a compound in a cell, comprising:

• administering a DNA methyltransferase inhibitor to the cell, thereby inducing DUX4 expression in the cell;
• administering a compound to the cell, wherein the compound is of Formula (I):
• or a pharmaceutically acceptable salt thereof, wherein:
• A is selected from C5-12 carbocycle and 5- to 12-membered heterocycle;
• B is selected from C5-12 carbocycle and 5- to 12-membered heterocycle;
• C is selected from bond, C5-12 carbocycle, and 5- to 12-membered heterocycle;
• D is selected from bond, C5-12 carbocycle, and 5- to 12-membered heterocycle;
• each of L1 and L2 is independently selected from bond,
• —O—, —S—, —N(R51)—, N(R51)CH2—,
• —C(O)—, —C(O)O—, —OC(O)—, —OC(O)02-,
• —C(O)N(R51)—, —C(O)N(R51)C(O)—, —C(O)N(R51)C(O)N(R51)—, —N(R51)C(O)—, —N(R51)C(O)N(R51)—, —N(R51)C(O)O—, —OC(O)N(R51)—,
• —C(NR51)—, —N(R51)C(NR51)—, —C(NR51)N(R51)—, —N(R51)C(NR51) N(R51)—, —S(O)2,
• —OS(O)—, —SO(O)O—, —S(O)—, —OS(O)02-,
• —OS(O)2O—, —N(R51)S(O)2—, —S(O)2N(R51)—,
• —N(R51)S(O)—, —S(O)N(R51)—, —N(R51)S(O)2N(R51)—, and —N(R51)S(O)N(R51)— or from alkylene, alkenylene, alkynylene, heteroalkylene, heteroalk-enylene, and heteroalkynylene, each of which is optionally substituted with one or more R50;
• R50 is, at each occurrence, independently selected from:
• halogen, —NO2, —CN, —OR52, —SR52, —N(R52)2,
• —NR53R54, —S(═O)R52, —S(═O)2R52,
• —S(═O)2R522, —S(═O)2NR53R54, —NR52S(═O)2R52, —NR52S(═O)2N(R52)2, —NR52S(═O)2NR53R54, —C(O)R52, —C(O)OR52, —OC(O)R52,
• —OC(O)OR52, —OC(O)N(R52)2, —OC(O)NR53R54, —NR52C(O)R52, —NR52C(O)OR52,
• —NR52C(O)N(R52)2, —NR52C(O)NR53R54,
• —C(O)N(R52)2, —C(O)NR53R54, —P(O)(OR52)2,
• —P(O)(R52)2, —P(O)(OR52)(R52), —P(O)(NR52)(R52), —NR52P(O)(R52), —P(O)(NR52)(OR52), —P(O)(NR52)2, ═O, ═S, ═N(R52);
• C1-10 alkyl, C1-10 alkenyl, and C2-10 alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, —NO2, —CN, —OR52, —SR52, —N(R52), —NR53R54, —S(═O)R52, —S(═O)2R52, —S(═O)2N(R52)2, —S(═O)2NR53R54,
• —NR52S(═O)2R52, —NR52S(═O)2N(R52)2,
• —NR52S(═O)2NR53R54, —C(O)R52, —C(O)OR52,
• —OC(O)R52, —OC(O)OR52, —OC(O)N(R52)2,
• —OC(O)N53R54, —NR52C(O)R52, —NR52C(O)OR52, —NR52C(O)N(R52)2, —NR52C(O)NR53R54,
• —C(O)N(R52)2, —C(O)NR53R54, —P(O)(OR52)2,
• —P(O)(R52)2, —P(O)(OR52)(R52), —P(O)(NR52)(R52), —NR52P(O)(R52), —P(O)(NR52)(OR52),
• —P(O)(NR52)2, ═O, ═S, ═N(R52), C3-12 carbocycle, and 3- to 12-membered heterocycle;
• and
• C3-12 carbocycle and 3- to 12-membered heterocycle, wherein each C3-12 carbocycle and 3- to 12-membered heterocycle in R50 is independently optionally substituted with one or more substituents selected from halogen —NO2, —CN, —OR52, —SR52, —N(R52), —NR53R54, —S(═O)R52, —S(═O)2R52, —S(═O)2N(R52)2, —S(═O)2NR53R54, —NR52S(═O)2R52, —NR52S(═O)2N(R52)2, —NR52S(═O)2NR53R54, —C(O)R52, —C(O)OR52, —OC(O)R52, —OC(O)OR52, —OC(O)N(R52)2, —OC(O)N53R54, —NR52C(O)R52, —NR52C(O)OR52, —NR52C(O)N(R52)2, —NR52C(O)NR53R54, —C(O)N(R52)2, —C(O)NR53R54, —P(O)(OR52)2, —P(O)(R52)2, —P(O)(OR52)(R52), —P(O)(NR52)(R52), —NR52P(O)(R52), —P(O)(NR52)(OR52), —P(O)(NR52)2, ═O, ═S, ═N(R52), C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl;
• R51 is independently selected at each occurrence from:
• hydrogen, —C(O) R52, —C(O)OR52, —C(O)N(R52)2, —C(O)NR53R54;
• C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, —NO2, —CN, —OR52, —SR52, —N(R52)2, —NR53R54, —S(═O)R52, —S(═O)2R52, —S(═O)2N(R52)2, —S(═O)2NR53R54, —NR52S(═O)2R52, —NR52S(═O)2N(R52)2, —NR52S(═O)2NR53R54, —C(O)R52, —C(O)OR52, —OC(O)R52, —OC(O)OR52, —OC(O)N(R52)2, —OC(O)N53R54, —NR52C(O)R52, —NR52C(O)OR52, —NR52C(O)N(R52)2, —NR52C(O)NR53R54, —C(O)N(R52)2, —C(O)NR53R54, —P(O)(OR52)2, —P(O)(R52)2, —P(O)(OR52)(R52), —P(O)(NR52)(R52), —NR5—P(O)(R52), —P(O)(NR52)(OR52), —P(O)(NR52)2, ═O, ═S, ═N(R52), C3-12 carbocycle and 3- to 12-membered heterocycle;
• and
• C3-12 carbocycle and 3- to 12-membered heterocycle, wherein each C3-12 carbocycle and 3- to 12-membered heterocycle in R51 is independently optionally substituted with one or more substituents selected from halogen, —NO2, —CN, —OR52, —SR52, —N(R52), —NR53R54, —S(═O)R52, —S(═O)2R52, —S(═O)2N(R52)2, —S(═O)2NR53R54, —NR52S(═O)2R52, —NR52S(═O)2N(R52)2, —NR52S(═O)2NR53R54, —C(O)R52, —C(O)OR52, —OC(O)R52, —OC(O)OR52, —OC(O)N(R52)2, —OC(O)N53R54, —NR52C(O)R52, —NR52C(O)OR52, —NR52C(O)N(R52)2, —NR52C(O)NR53R54, —C(O)N(R52)2, —C(O)NR53R54, —P(O)(OR52)2, —P(O)(R52)2, —P(O)(OR52)(R52), —P(O)(NR52)(R52), —NR52P(O)(R52), —P(O)(NR52)(OR52), —P(O)(NR52)2, ═O, ═S, ═N(R52), C1-6 alkyl, C1-6 haloalkyl, C1-6 alkenyl, and C2-6 alkynyl;
• R52 is independently selected at each occurrence from hydrogen;
• and C1-20 alkyl, C2-20 alkenyl, C2-20 alkynyl, 1- to 6-membered heteroalkyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted by halogen, —CN, —NO2, —NH2, —NHCH3, —NHCH2CH3, ═O, —OH, —OCH3, —OCH2CH3, C3-12 carbocycle, or 3- to 6-membered heterocycle;
• R53 and R54 are taken together with the nitrogen atom to which they are attached to form a heterocycle, optionally substituted with one or more R50;
• each of RA, RB and RC is independently selected from R50;
• RD is, at each occurrence, independently selected from hydrogen or R50;
• and
• each of m, n, p, and q is independently an integer from 0-12;
• and
• measuring DUX4 expression, thereby determining D4Z4 de-repression activity of the compound in the cell.