USP30 INHIBITORS

• US 20200131121A1
• Filed: 05/14/2018
• Published: 04/30/2020
• Est. Priority Date: 05/15/2017
• Status: Active Grant

• Current Assignee: Mitobridge, Inc. (Astellas Pharma Incorporated)
• Original Assignee: Mitobridge, Inc. (Astellas Pharma Incorporated)
• Inventors: Kluge, Arthur, Lagu, Bharat, Maiti, Pranab, Panigrahi, Sunil Kumar
• Granted Patent: US 10,968,172 B2
• Time in Patent Office: Days
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: C07C 2601/02 with a three-membered ring
• CPC Class Codes: C07C 2601/06 with a five-membered ring
• CPC Class Codes: C07C 2601/14 The ring being saturated
• CPC Class Codes: C07C 2601/18 with a ring being at least seven-membered
• CPC Class Codes: C07C 2603/74 Adamantanes
• CPC Class Codes: C07C 311/16 having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
• CPC Class Codes: C07C 311/46 Y being a hydrogen or a carbon atom
• CPC Class Codes: C07D 207/16 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 207/34 with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 213/56 Amides
• CPC Class Codes: C07D 213/81 Amides; Imides
• CPC Class Codes: C07D 233/64 with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
• CPC Class Codes: C07D 233/96 having three double bonds between ring members or between ring members and non-ring members
• CPC Class Codes: C07D 237/24 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
• CPC Class Codes: C07D 239/28 with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
• CPC Class Codes: C07D 263/34 : with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 277/56 : Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
• CPC Class Codes: C07D 307/24 : Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
• CPC Class Codes: C07D 307/68 : Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
• CPC Class Codes: C07D 309/04 : with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 309/06 : Radicals substituted by oxygen atoms
• CPC Class Codes: C07D 309/08 : with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 333/24 : Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 333/38 : Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 409/12 : linked by a chain containing hetero atoms as chain links

Abstract

The application relates to phenyl- or naphthylsulfonamide derivatives of the structural formula (I). The compounds are described as inhibitors of USP30 (ubiquitin specific peptidase 30) useful for the treatment of conditions involving mitochondrial defects including neurodegenerative diseases such as Alzheimer'"'"'s and Parkinson'"'"'s or a neoplastic disease such as leukemia.

Claims

1. A compound represented by structural formula (I):

2. The compound of claim 1, wherein the compound is represented by structural formula (Ia):

3. The compound of claim 2, wherein the compound is represented by structural formula (Ib):

4. The compound of claim 2, wherein the compound is represented by structural formula (Ic):

5. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein R₂ is 3-7 membered cycloalkyl optionally substituted with one or more substituents selected from the group consisting of (C₁-C₄)alkyl, (C₁-C₄)alkoxy, (C₁-C₄)alkylthio, hydroxyl, halogen, and halo(C₁-C₄)alkyl;

phenyl optionally substituted with one or more substituents selected from the group consisting of halogen, CN, —

CO₂H, —

CO₂Me, (C₁-C₄)alkyl, halo(C₁-C₄)alkyl, (C₁-C₄)alkoxy, and hydroxyl;

5-6 membered heterocyclyl optionally substituted with one or more substituents selected from the group consisting of (C₁-C₄)alkyl, halo(C₁-C₄)alkyl, and (C₁-C₄)alkoxy;

5-6 membered heteroaryl optionally substituted with one or more substituents selected from the group consisting of halogen, (C₁-C₄)alkyl, halo(C₁-C₄)alkyl, and (C₁-C₄)alkoxy;

or adamantyl.

6. The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein R₁ is (C₁-C₄)alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, —

CN, hydroxyl, (C₁-C₄)alkyl, halo(C₁-C₄)alkyl, (C₁-C₄)alkoxy, halo(C₁-C₄)alkoxy, and (C₁-C₄)alkylthio;

3-7 membered cycloalkyl optionally substituted with one or more substituents selected from the group consisting of halogen, CN, hydroxyl, (C₁-C₄)alkyl, halo(C₁-C₄)alkyl, (C₁-C₄)alkoxy, halo(C₁-C₄)alkoxy, and (C₁-C₄)alkylthio;

5-6 membered heterocyclyl optionally substituted with one or more substituents selected from the group consisting of halogen, —

CN, hydroxyl, (C₁-C₄)alkyl, halo(C₁-C₄)alkyl, (C₁-C₄)alkoxy, halo(C₁-C₄)alkoxy, and (C₁-C₄)alkylthio;

phenyl optionally substituted with one or more substituents selected from the group consisting of halogen, CN, hydroxyl, (C₁-C₄)alkyl, halo(C₁-C₄)alkyl, (C₁-C₄)alkoxy, halo(C₁-C₄)alkoxy, methylenedioxy, and phenyl;

or 5-6 membered heteroaryl optionally substituted with one or more substituents selected from the group consisting of halogen, —

CN, hydroxyl, (C₁-C₄)alkyl, halo(C₁-C₄)alkyl, (C-C₄)alkoxy, halo(C₁-C₄)alkoxy, and (C₁-C₄)alkylthio.

7. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein R₂ is 3-7 membered cycloalkyl optionally substituted with one or more substituents selected from the group consisting of halogen and (C₁-C₄)alkyl;

phenyl optionally substituted with one or more substituents selected from the group consisting of halogen, CN, —

CO₂H, —

CO₂Me, (C₁-C₄)alkyl, halo(C₁-C₄)alkyl, (C₁-C₄)alkoxy, and hydroxyl;

5-6 membered heterocyclyl selected from tetrahydrofuranyl or tetrahydro-2H-pyranyl;

5-6 membered heteroaryl optionally substituted with one or more substituents selected from the group consisting of halogen, (C₁-C₄)alkyl, halo(C₁-C₄)alkyl, and (C₁-C₄)alkoxy, wherein the heteroaryl is pyridyl, pyridazinyl, pyrimidinyl, thiazolyl, oxazolyl, furanyl, pyrrolyl, or thiophenyl.

8. The compound of claim 7, or a pharmaceutically acceptable salt thereof, wherein R₁ is (C₁-C₄)alkyl;

3-7 membered cycloalkyl;

tetrahydro-2H-pyranyl;

phenyl optionally substituted with one or more substituents selected from the group consisting of halogen, CN, hydroxyl, (C₁-C₄)alkyl, halo(C₁-C₄)alkyl, (C₁-C₄)alkoxy, halo(C₁-C₄)alkoxy, and phenyl;

5-6 membered heteroaryl selected from pyridyl, imidazolyl, and thiophenyl.

9. The compound of claim 8, or a pharmaceutically acceptable salt thereof, wherein R₃ is t-butyl.

10. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein R₁ is (C₁-C₄)alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, —

CN, hydroxyl, (C₁-C₄)alkyl, halo(C₁-C₄)alkyl, (C₁-C₄)alkoxy, halo(C₁-C₄)alkoxy, and (C₁-C₄)alkylthio;

a 3-7 membered cycloalkyl optionally substituted with one or more substituents selected from the group consisting of halogen, CN, hydroxyl, (C₁-C₄)alkyl, halo(C₁-C₄)alkyl, (C₁-C₄)alkoxy, halo(C₁-C₄)alkoxy, and (C₁-C₄)alkylthio;

5-6 membered heterocyclyl optionally substituted with one or more substituents selected from the group consisting of halogen, —

CN, hydroxyl, (C₁-C₄)alkyl, halo(C₁-C₄)alkyl, (C₁-C₄)alkoxy, halo(C₁-C₄)alkoxy, and (C₁-C₄)alkylthio;

6-10 membered aryl optionally substituted with one or more substituents selected from the group consisting of halogen, CN, hydroxyl, (C₁-C₄)alkyl, halo(C₁-C₄)alkyl, (C₁-C₄)alkoxy, halo(C₁-C₄)alkoxy, methylenedioxy, and phenyl;

5-6 membered heteroaryl optionally substituted with one or more substituents selected from the group consisting of halogen, —

CN, hydroxyl, (C₁-C₄)alkyl, halo(C₁-C₄)alkyl, (C₁-C₄)alkoxy, halo(C₁-C₄)alkoxy, and (C₁-C₄)alkylthio;

or a 5-10 membered bicycloalkyl selected from the group consisting of bicyclo[2.2.2]oct-1-yl, bicyclo[2.2.2]oct-2-yl, bicyclo[2.2.1]hept-1-yl, bicyclo[2.2.1]hept-2-yl;

bicyclo[1.1.1]pentan- 1yl;

R₂ is a 3-7 membered cycloalkyl optionally substituted with one or more substituents selected from the group consisting of (C₁-C₄)alkyl, (C₁-C₄)alkoxy, (C₁-C₄)alkylthio, hydroxyl, halogen, and halo(C₁-C₄)alkyl;

a 6-10 membered aryl optionally substituted with one or more substituents selected from the group consisting of halogen, CN, —

CO₂H, —

CO₂Me, (C₁-C₄)alkyl, halo(C₁-C₄)alkyl, (C₁-C₄)alkoxy, and hydroxyl;

a 5-6 membered heterocyclyl optionally substituted with one or more substituents selected from the group consisting of (C₁-C₄)alkyl, halo(C₁-C₄)alkyl, (C₁-C₄)alkoxy;

or a 5-6 membered heteroaryl optionally substituted with one or more substituents selected from the group consisting of halogen, (C₁-C₄)alkyl, halo(C₁-C₄)alkyl, and (C₁-C₄)alkoxy.

11. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and the compound of claim 1.

12. A method of treating a ubiquitin specific peptidase 30 (USP30) mediated disorder in a subject comprising administering to the subject an effective amount of the compound of claim 1.

13. The method of claim 12, wherein the USP30 mediated disorder involves a mitochondrial defect is selected from the group consisting of a condition involving a mitophagy defect, a condition involving a mutation in mitochondrial DNA, a condition involving mitochondrial oxidative stress, a condition involving a defect in mitochondrial shape or morphology, a condition involving a defect in mitochondrial membrane potential, and a condition involving a lysosomal storage defect.

14. The method of claim 12, wherein the mitochondrial defect is selected from the group consisting of a neurodegenerative disease;

mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome;

Leber'"'"'s hereditary optic neuropathy (LHON);

neuropathy, ataxia, retinitis pigmentosa-maternally inherited Leigh syndrome (NARP-MILS);

Danon disease;

ischemic heart disease leading to myocardial infarction;

multiple sulfatase deficiency (MSD);

mucolipidosis II (ML II);

mucolipidosis III (ML III);

mucolipidosis IV (ML IV);

GM1-gangliosidosis (GM1);

neuronal ceroid-lipofuscinoses (NCL1);

Alpers disease;

Barth syndrome;

Beta-oxidation defects;

carnitine-acyl-carnitine deficiency;

carnitine deficiency;

creatine deficiency syndromes;

coenzyme Q10 deficiency;

complex I deficiency;

complex II deficiency;

complex III deficiency;

complex IV deficiency;

complex V deficiency;

COX deficiency;

chronic progressive external ophthalmoplegia syndrome (CPEO);

CPT I deficiency;

CPT II deficiency;

glutaric aciduria type II;

Kearns-Sayre syndrome;

lactic acidosis;

long-chain acyl-CoA dehydrongenase deficiency (LCHAD);

Leigh disease or syndrome;

lethal infantile cardiomyopathy (LIC);

Luft disease;

glutaric aciduria type II;

medium-chain acyl-CoA dehydrongenase deficiency (MCAD);

myoclonic epilepsy and ragged-red fiber (MERRF) syndrome;

mitochondrial recessive ataxia syndrome;

mitochondrial cytopathy;

mitochondrial DNA depletion syndrome;

myoneurogastointestinal disorder and encephalopathy;

Pearson syndrome;

pyruvate carboxylase deficiency;

pyruvate dehydrogenase deficiency;

POLG mutations;

medium/short-chain 3-hydroxyacyl-CoA dehydrogenase (M/SCHAD) deficiency;

and very long-chain acyl-CoA dehydrongenase (VLCAD) deficiency.

15. The method of claim 14, wherein the neurodegenerative disease is selected from Alzheimer'"'"'s disease, Parkinson'"'"'s disease, amyotrophic lateral sclerosis (ALS), Huntington'"'"'s disease, ischemia, stroke, dementia with Lewy bodies, and frontotemporal dementia.

16. The method of claim 15, wherein the neurodegenerative disease is Parkinson'"'"'s disease, or amyotrophic lateral sclerosis (ALS).

17. The method of claim 12, wherein the USP30 mediated disorder is a neoplastic disease selected from metastatic carcinoma, multiple myeloma, osteosarcoma, chondosarcoma, Ewing'"'"'s sarcoma, nasopharyngeal carcinoma, and leukemia.

18. A method of administering to the subject an effective amount of the compound of claim 1 to promote apoptosis in cells.

19. The method of claim 18, wherein the cells are cancer cells.

20. The method of claim 19, wherein the cancer cells are melanoma.

21-24. -24. (canceled)