US 2022/0033397 A1 · PHARMACEUTICAL COMPOUNDS AND THEIR USE AS INHIBITORS OF UBIQUITIN SPECIFIC PROTEASE 19 (USP19)

Abstract

Provided are USP19 inhibitors, methods of treating obesity, metabolic syndrome and/or diabetes using the USP19 inhibitor compounds, as well as those compounds for use in methods of treating obesity, metabolic syndrome and/or diabetes. Also provided are methods of treating muscular atrophy, for example cachexia or sarcopenia with USP19 inhibitor compounds, plus those a compounds for use in methods of treating muscular atrophy.

A compound of formula (I):

wherein
R1 is optionally substituted C1-C6 alkyl, optionally substituted C4-C10 alkylcycloalkyl, optionally substituted C6-C10 alkylaryl, optionally substituted C5-C8 aryl, optionally substituted C3-C8 heteroaryl, optionally substituted C3-C8 heterocycloalkyl, NRaRb, NRaCH2Rb, ORa, or OCH2Ra
wherein Ra and Rb are independently selected from H, C1-C6 alkyl, CF3, optionally substituted C3-C6 cycloalkyl, optionally substituted C5-C8 aryl, optionally substituted C6-C9 arylalkyl, and optionally substituted C2-C8 heteroaryl, and
wherein when R1 is NRaCH2Rb, the methylene group may be optionally substituted with CF3,
or R1 is NRaRb and Ra and Rb together form an optionally substituted C2-C9 heterocycle together with the N to which they are attached;
R2 and R3 are independently selected from H, and C1-C6 alkyl, or together form a C3-C6 cycloalkyl or C3-C6 heterocycloalkyl with the carbon to which they attached;
X is absent, C, CR4a, CR4aR4b, N, NR4a, or C═O,
wherein R4a and R4b are independently selected from H, optionally substituted C1-C6 alkyl and halo;
or wherein R4a and R4b together form a C3-C6 cycloalkyl or C3-C6 heterocycloalkyl including the carbon to which they are attached;
Y is C, CR5, CR5R6, N, NR5, or O,
wherein R5 and R6 are independently selected from H, halo, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 heterocycloalkyl, optionally substituted C5-C8 aryl, optionally substituted C6-C9 arylalkyl, optionally substituted C3-C8 heteroaryl, CH2OH, NR′R″, NS(O)R′R″, SO2R′, C(O)R′, COR′, C(O)OR′, C(O)NR′R″, OR′, wherein R′ and R″ are independently selected from H, C1-C6 alkyl, C5-C8 aryl, C6-C9 arylalkyl, and C3-C8 heteroaryl, or wherein R5 is NR′R″ and R′ and R″ together form an optionally substituted C3-6 heterocycloalkyl including the nitrogen to which they are attached,
or wherein R5 and R8 together form a C3-6 cycloalkyl or C3-C6 heterocycloalkyl including the carbon to which they are attached;
Z is N, NR7, C, CR7, CR7R8, or C═O,
wherein R7 and R8 are independently selected from H, halo, C1-C6 alkyl, C2-C6 alkene, C2-C6 alkyne, C3-C6 cycloalkyl, optionally substituted C3-C6 heterocycloalkyl, C5-C8 aryl, C6-C9 arylalkyl, C3-C8 heteroaryl, CN, C(O)ORc, CONRcRd, NRcRd, NS(O)RcRd, S(O)(Rc)NRd, SORc, SO2Rc, and SRc, wherein Rc and Rd are independently H, C1-C6 alkyl, C3-C6 cycloalkyl, C5-C6 aryl, C6-C9 arylalkyl, C3-C6 heteroaryl, CN, COOH, or COCH3 or Rc and Rd together form an optionally substituted C3-C7 heterocycle together with the heteroatom to which they are attached;
or wherein R7 and R8 together form a C3-6 cycloalkyl or C3-C6 heterocycloalkyl including the carbon to which they are attached;
M is absent, C, CR13 or CR13R14, wherein R13 and R14 are independently selected from H, and C1-C6 alkyl, or wherein R13 and R14 together form a C3-C6 cycloalkyl or C3-C6 heterocycloalkyl together with the carbon to which they are attached;
and
A is CR9, CHR9, N, NR9, S, or O;
D is CR9, CHR9, N or NR9,
G is absent, CR9, CHR9, or N,
wherein R9 is independently selected from H, halo, C1-C6 alkyl, CF3, and OR*, wherein R* is selected from optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, and optionally substituted C3-C6 heterocycloalkyl,
E is CR10, CHR10, N, NR10, S, or O,
wherein R10 is selected from H, halo, C1-C6 alkyl, C3-C6 cycloalkyl, C5-C8 aryl, C6-C9 arylalkyl, C4-C8 heteroaryl, SRx, ORx, NRxRy, and NS(O)RxRy, S(O)(Rx)NRy
wherein Rx and Ry are independently selected from H, C1-C6 alkyl, CF3, C3-C6 cycloalkyl, C5-C8 aryl, C6-C9 arylalkyl, C4-C8 heteroaryl, COOH, amido, cyano, C2-C6 alkene, C2-C6 alkyne, or wherein Rx and Ry together form an optionally substituted C4-C6 heterocycloalkyl together with the nitrogen to which they are attached;
or A, D, E and G are all absent, optionally wherein X and M are absent, or optionally wherein Y and Z together form an optionally substituted C5-C6 aryl or C5-C6 heteroaryl fused ring or Z and M together form an optionally substituted C5-C6 aryl or C5-C6 heteroaryl fused ring;
or a stereoisomer, tautomer, hydrate, N-oxide derivative or pharmaceutically acceptable salt thereof.

23 more elements

Pharmaceutical compounds and their use as inhibitors of ubiquitin specific protease 19 (usp19)

Life of this patent

Pharmaceutical compounds and their use as inhibitors of ubiquitin specific protease 19 (usp19)

Life of this patent

Abstract

Claims63