Compounds

• US 10,640,498 B2
• Filed: 02/16/2017
• Issued: 05/05/2020
• Est. Priority Date: 02/18/2016
• Status: Active Grant

• Current Assignee: MISSION Therapeutics Ltd.
• Original Assignee: MISSION Therapeutics Ltd.
• Inventors: Gibson, Karl Richard, Jones, Alison, Kemp, Mark Ian, Madin, Andrew, Stockley, Martin Lee, Whitlock, Gavin Alistair, Woodrow, Michael D.
• Primary Examiner(s): Otton, Alicia L
• Application Number:
  US16/070,936
• Publication Number:
  US 20190055232A1
• Time in Patent Office: 1,174 Days
• Field of Search: None
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/08 Antiepileptics; Anticonvulsants
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07D 401/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 403/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 403/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 403/14 containing three or more hetero rings
• CPC Class Codes: C07D 413/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 413/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 413/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 417/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 417/14 : containing three or more hetero rings
• CPC Class Codes: C07D 471/04 : Ortho-condensed systems
• CPC Class Codes: C07D 487/04 : Ortho-condensed systems
• CPC Class Codes: C07D 487/10 : Spiro-condensed systems

Abstract

The present invention relates to novel compounds of formula (I) and methods for the manufacture of inhibitors of deubiquitylating enzymes (DUBs). In particular, the invention relates to the inhibition of ubiquitin C-terminal hydrolase 30 or ubiquitin specific peptidase 30 (USP30). The invention further relates to the use of DUB inhibitors in the treatment of conditions involving mitochondrial dysfunction and in the treatment of cancer.

Claims

1. A compound of formula I:

2. The compound according to claim 1, wherein R^1a is hydrogen or fluorine.

3. The compound according to claim 1, wherein R^1a, R^1b, R^1c, R^1d, R^1e, R^1f and R^1g each represent hydrogen.

4. The compound according to claim 1, wherein R² is C₁-C₃ alkyl, which is optionally substituted with one or more fluorine.

5. The compound according to claim 1, wherein R² together with R^1a or R^1g forms an optionally further substituted 5 or ti-membered heterocyclyl ring.

6. The compound according to claim 1, wherein R³ or the ring formed by R² and R³ is substituted or substituted with one or two -Q¹-(R⁴)_n moieties, which are the same or different, and wherein n is 1 for at least one of the moieties.

7. The compound according to claim 1, wherein R³ is an optionally substituted, 5 to 10-membered, nitrogen-containing, monocyclic or bicyclic, heteroaryl ring, or optionally substituted phenyl.

8. The compound according to claim 7, wherein R³ is selected from optionally substituted, thiazolyl, pyridinyl, pyridazinyl, benzothiazolyl, isoxazolyl, and phenyl.

9. The compound according to claim 1, wherein R² and R³ together form an optionally substituted, 9 or 10-membered bicyclic, heterocyclyl or heteroaryl, ring.

10. The compound according to claim 9, wherein R² together with R³ form a ring selected from optionally substituted, indolinyl, dihydropyrrolopyridinyl, tetrahydroquinolinyl and dihydrobenzoxazinyl.

11. The compound according to claim 1, wherein when n is 0, Q¹ is selected from halogen, cyano, C₁-C₆ alkyl, and C₁-C₃ alkyl optionally substituted with one or more fluorine;

and when n is 1, Q¹ is a covalent bond.

12. The compound according to claim 1, wherein R⁴ is selected from optionally substituted, phenyl, pyridinyl, pyrazolyl and indazolyl.

13. The compound according to claim 12, wherein R⁴ is optionally substituted with one to three substituents selected from halogen, cyano, C₁-C₆ alkyl, C₁-C₆ alkoxy, and NR⁸SO₂R⁹, wherein R⁸ and R⁹ are each independently selected from hydrogen, C₁-C₃ alkyl, and C₃-C₆ cycloalkyl;

wherein the alkyl or alkoxy may be optionally substituted with one or more fluorine.

14. The compound according to claim 1, of formula (II):

15. A compound of formula I according to claim 1 selected from the group consisting of:

1-cyano-N-ethyl-N-(4-phenylthiazol-2-yl)pyrrolidine-3-carboxamide;

1-cyano-N-ethyl-N-(5-phenylthiazol-2-yl)pyrrolidine-3-carboxamide;

(S)-1-cyano-N-methyl-N-(5-phenylthiazol-2-yl)pyrrolidine-3-carboxamide;

(S)-1-cyano-N-methyl-N-(4-phenylpyridin-2-yl)pyrrolidine-3-carboxamide;

(S)-1-cyano-N-methyl-N-(6-phenylpyridin-2-yl)pyrrolidine-3-carboxamide;

1-cyano-N-isopropyl-N-(5-(pyridin-4-yl)thiazol-2-yl)pyrrolidine-3-carboxamide;

1-cyano-N-isopropyl-N-(4-phenylthiazol-2-yl)pyrrolidine-3-carboxamide;

1-cyano-3-fluoro-N-methyl-N-(5-phenylthiazol-2-yl)pyrrolidine-3-carboxamide;

N-(benzo[d]thiazol-2-yl)-1-cyano-3-fluoro-N-methylpyrrolidine-3-carboxamide;

(S)-3-(4-phenylindoline-1-carbonyl)pyrrolidine-1-carbonitrile;

(R)-3-(6-phenylindoline-1-carbonyl)pyrrolidine-1-carbonitrile;

(S)-3-(5-(3-chlorophenyl)indoline-1-carbonyl)pyrrolidine-1-carbonitrile;

(3S,4S)-3-(5-(2-chlorophenyl)indoline-1-carbonyl)-4-methylpyrrolidine-1-carbonitrile;

3-fluoro-3-(5-phenylindoline-1-carbonyl)pyrrolidine-1-carbonitrile;

3-fluoro-3-(6-phenylindoline-1-carbonyl)pyrrolidine-1-carbonitrile;

3-fluoro-3-(6-phenyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carbonyl)pyrrolidine-1-carbonitrile;

(R)-3-(5-phenylindoline-1-carbonyl)pyrrolidine-1-carbonitrile;

(S)-3-(5-phenylindoline-1-carbonyl)pyrrolidine-1-carbonitrile;

(3 S,4S)-3-methyl-4-(5-phenylindoline-1-carbonyl)pyrrolidine-1-carbonitrile;

(3R,4R)-3-methyl-4-(5-phenylindoline-1-carbonyl)pyrrolidine-1-carbonitrile;

(S)-3-(5-phenyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carbonyl)pyrrolidine-1-carbonitrile;

3-fluoro-3-(5-phenyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carbonyl)pyrrolidine-1-carbonitrile;

(S)-3-(6-phenyl-1,2,3,4-tetrahydroquinoline-1-carbonyl)pyrrolidine-1-carbonitrile;

(R)-3-(7-phenyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-4-carbonyl)pyrrolidine-1-carbonitrile;

(R)-3-(6-phenyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-4-carbonyl)pyrrolidine-1-carbonitrile;

(R)-3-(8-phenyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-4-carbonyl)pyrrolidine-1-carbonitrile;

(S)-3-(4-phenyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carbonyl)pyrrolidine-1-carbonitrile;

(S)-3-(4-(3-chlorophenyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carbonyl)pyrrolidine-1-carbonitrile;

(S)-1-(1-cyanopyrrolidine-3-carbonyl)-5-(1-methyl-1H-pyrazol-4-yl)indoline-6-carbonitrile;

(R)-3-(7-(1H-pyrazol-1-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-4-carbonyl)pyrrolidine-1-carbonitrile;

(S)-1-cyano-N-methyl-N-(5-phenylpyridin-2-yl)pyrrolidine-3-carboxamide;

(R)-1-cyano-N-methyl-N-(5-phenylpyridazin-3-yl)pyrrolidine-3-carboxamide;

1-cyano-3-fluoro-N-methyl-N-(5-phenylisoxazol-3-yl)pyrrolidine-3-carboxamide;

(3 S,4S)-1-cyano-4-(hydroxymethyl)-N-methyl-N-(5-phenylthiazol-2-yl)pyrrolidine-3-carboxamide;

3-(5-(1-benzyl-1H-pyrazol-5-yl)indoline-1-carbonyl)-3-fluoropyrrolidine-1-carbonitrile;

3-fluoro-3-(5-(1-methyl-1H-pyrazol-5-yl)indoline-1-carbonyl)pyrrolidine-1-carbonitrile;

3-fluoro-3-(5-(4-(4-methylpiperazin-1-yl)phenyl)indoline-1-carbonyl)pyrrolidine-1-carbonitrile;

3-fluoro-3-(5-(4-(4-methylpiperazine-1-carbonyl)phenyl)indoline-1-carbonyl)pyrrolidine-1-carbonitrile;

3-fluoro-3-(5-(1-methyl-1H-indazol-5-yl)indoline-1-carbonyl)pyrrolidine-1-carbonitrile;

3-fluoro-3-(5-(2-fluoro-5-methylphenyl)indoline-1-carbonyl)pyrrolidine-1-carbonitrile;

3-fluoro-3-(5-(5-methyl-1H-indazol-4-yl)indoline-1-carbonyl)pyrrolidine-1-carbonitrile;

N-(3-(1-(1-cyano-3-fluoropyrrolidine-3-carbonyl)indolin-5-yl)phenyl)cyclopropanesulfonamide;

3-fluoro-3-(5-(6-methoxypyridin-3-yl)indoline-1-carbonyl)pyrrolidine-1-carbonitrile;

(R)-1-cyano-N-(5-(4-cyanophenyl)pyridin-2-yl)-N-ethylpyrrolidine-3-carboxamide;

N-(benzo[d]thiazol-2-ylmethyl)-1-cyano-N-methylpyrrolidine-3-carboxamide;

1-cyano-N-methyl-N-((3-phenylisoxazol-5-yl)methyl)pyrrolidine-3-carboxamide;

1-cyano-N-methyl-N-((2-phenylthiazol-4-y)methyl)pyrrolidine-3-carboxamide;

(3aR,6aS)-4-oxo-5-(5-phenylthiazol-2-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carbonitrile; and

7-([1,1′

-biphenyl]-3-yl)-6-oxo-2,7-diazaspiro[4.4]nonane-2-carbonitrile;

a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer.

16. A compound of formula I according to claim 1, selected from the group consisting of:

(R)-3-(4-(3-ethylphenyl)indoline-1-carbonyl)pyrrolidine-1-carbonitrile;

(R)-1-(1-cyanopyrrolidine-3-carbonyl)-N-methyl-4-phenylindoline-6-carboxamide;

(R)-1-(1-cyanopyrrolidine-3-carbonyl)-4-(3-ethylphenyl)-N-methylindoline-6-carboxamide;

(R)-3-(5-(1H-indazol-4-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carbonyl)pyrrolidine-1-carbonitrile;

(S)-3-(5-(1H-indazol-4-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carbonyl)pyrrolidine-1-carbonitrile;

3-(5-phenyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-1-carbonyl)pyrrolidine-1-carbonitrile;

(trans)-3-methyl-4-(5-phenyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carbonyl)pyrrolidine-1-carbonitrile;

3-fluoro-3-(5-(1-isobutyl-1H-pyrazol-5-yl)indoline-1-carbonyl)pyrrolidine-1-carbonitrile;

3-(5-(1-benzyl-1H-pyrazol-4-yl)indoline-1-carbonyl)-3-fluoropyrrolidine-1-carbonitrile;

3-fluoro-3-(5-(1-(pyridin-2-ylmethyl)-1H-pyrazol-5-yl)indoline-1-carbonyl)pyrrolidine-1-carbonitrile;

N-benzyl-1-(1-cyano-3-fluoropyrrolidine-3-carbonyl)indoline-5-carboxamide;

3-(5-(1-(2-chlorobenzyl)-1H-pyrazol-5-yl)indoline-1-carbonyl)-3-fluoropyrrolidine-1-carbonitrile;

3-(5-(1-(3-chlorobenzyl)-1H-pyrazol-5-yl)indoline-1-carbonyl)-3-fluoropyrrolidine-1-carbonitrile;

3-(5-(1-(4-chlorobenzyl)-1H-pyrazol-5-yl)indoline-1-carbonyl)-3-fluoropyrrolidine-1-carbonitrile;

3-fluoro-3-(5-(1-(pyridin-3-ylmethyl)-1H-pyrazol-5-yl)indoline-1-carbonyl)pyrrolidine-1-carbonitrile;

3-fluoro-3-(5-(pyridin-3-yl)indoline-1H-carbonyl)pyrrolidine-1-carbonitrile;

(R)-3-fluoro-3-(5-phenylindoline-1-carbonyl)pyrrolidine-1-carbonitrile;

(S)-3-fluoro-3-(5-phenylindoline-1-carbonyl)pyrrolidine-1-carbonitrile;

(S)-3-(5-(3-chlorophenyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carbonyl)-3-fluoropyrrolidine-1-carbonitrile; and

(R)-3-(5-(3-chlorophenyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carbonyl)-3-fluoropyrrolidine-1-carbonitrile;

a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer.

17. A pharmaceutical composition comprising a compound of formula I as defined in claim 1, a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer, together with one or more pharmaceutically acceptable excipients.