US 2022/0177451 A1 · 1-CYANO-PYRROLIDINE DERIVATIVES AS DUB INHIBITORS

Abstract

The present invention relates to novel compounds 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 novel compounds have formula (I): (Formula (I)) or are pharmaceutically acceptable salts thereof, wherein: R1a, R1b, R1c, R1d, R1e and R1f each independently represent hydrogen, optionally substituted C1-C6 alkyl or optionally substituted C3-C4 cycloalkyl, or R1b and R1c together form an optionally substituted C3-C6 cycloalkyl ring, or R1d and R1e together form an optionally substituted C3-C6 cycloalkyl ring; R2 represents hydrogen or optionally substituted C1-C6 alkyl; A represents an optionally further substituted 5 to 10 membered monocyclic or bicyclic heteroaryl, heterocyclyl or aryl ring; L represents a covalent bond or linker; B represents an optionally substituted 3 to 10 membered monocyclic or bicyclic heterocyclyl, heteroaryl, cycloalkyl or aryl ring; and when -A-L-B is at position x attachment to A is via a carbon ring atom of A, and either: A cannot be triazolopyridazinyl, triazolopyridinyl, imidazotriazinyl, imidazopyrazinyl or pyrrolopyrimidinyl; or B cannot be substituted with phenoxyl; or B cannot be cyclopentyl when L is an oxygen atom.

Claims21

Dependent claims

1-21. (canceled)

A compound having formula (I):

a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer, wherein:
R1a, R1b, R1c, R1d, R1e and R1f each independently represent hydrogen, optionally substituted C1-C6 alkyl or optionally substituted C3-C4 cycloalkyl, or R1b and R1c together form an optionally substituted C3-C6 cycloalkyl ring, or R1d and R1e together form an optionally substituted C3-C6 cycloalkyl ring;
R2 represents hydrogen or optionally substituted C1-C6 alkyl;
A represents an optionally further substituted 9 to 10-membered bicyclic heteroaryl, heterocyclyl or aryl ring;
L represents a covalent bond, an oxygen atom, a sulphur atom, —OR8—, —SO—, —SO2—, —CO—, —C(O)O—, C0-C3 alkylene-CONR6—C0-C3 alkylene-, —C0-C3 alkylene-NR6—C0-C3 alkylene, —C0-C3 alkylene-NR6CO—C0-C3 alkylene, —C0-C3 alkylene-NR6CONR7—C0-C3 alkylene, —C0-C3 alkylene-SO2NR6—C0-C3 alkylene, —C0-C3 alkylene-NR6SO2—C0-C3 alkylene, —C0-C3 alkylene-NR6SO2NR7—C0-C3 alkylene, —C0-C3 alkylene-NR6C(O)O—C0-C3 alkylene, —C0-C3 alkylene-NR6C(O)OR7—C0-C3 alkylene, optionally substituted —C1-C6 alkylene or optionally substituted —C2-C6 alkenylene;
B represents an optionally substituted 3 to 10-membered monocyclic or bicyclic heterocyclyl, heteroaryl, cycloalkyl or aryl ring;
when -A-L-B is at position x, then (i) attachment to A is via a carbon ring atom of A, (ii) A cannot be triazolopyridazinyl, triazolopyridinyl, imidazotriazinyl, imidazopyrazinyl, pyrrolopyrimidinyl or [1,2,4]triazolo[1,5-a]pyrazinyl, (iii) B cannot be substituted with phenoxyl, and (iv) B cannot be cyclopentyl when L is an oxygen atom;
wherein A is optionally substituted with one to four substituents, each independently selected from halogen, cyano, oxo, nitro, hydroxyl, —SR3, —NR3R4, —CONR3R4, —NR3COR4, —NR3CONR4R5, —COR3, —C(O)OR3, —SO2R3, —SO2NR3R4, —NR3SO2R4, NR3SO2NR4R5, —NR3C(O)OR4, optionally substituted —C1-C6 alkyl, optionally substituted —C1-C6 alkoxy, optionally substituted —C2-C6 alkenyl, optionally substituted —C2-C6 alkynyl and C3-C4 cycloalkyl;
wherein B is optionally substituted with one to four substituents independently, each selected from halogen, cyano, oxo, nitro, hydroxyl, —SR9, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, -Q1a-R12, -Q1a-O-Q1b-R12, Q1a-S-Q1b-R12, Q1a-SO-Q1b-R12, -Q1a-NR9CONR10R11, -Q1a-NR9CONR10-Q1b-R12, -Q1a-NR9R10, -Q1a-NR9-Q1b-R12—, -Q1a-COR9, -Q1a-CO-Q1b-R12—, -Q1a-NR9COR10, -Q1a-NR9CO-Q1b-R12, -Q1a-NR9C(O)OR10, -Q1a-NR9C(O)O-Q1b-R12, -Q1a-SO2R9, -Q1a-SO2-Q1c-R12, -Q1a-CONR9R10, -Q1a-CONR9-Q1b-R12, -Q1a-CO2R9, -Q1a-CO2-Q1b-R12, -Q1a-SO2NR9R10, -Q1a-SO2NR9-Q1b-R12, -Q1a-NR9SO2R10, -Q1a-NR9SO2-Q1b-R12, -Q1a-NR9SO2NR10R11 and -Q1a-NR9SO2NR10-Q1b-R12;
Q1a and Q1b each independently represent a covalent bond, optionally substituted C1-C6 alkylene or optionally substituted C2-C6 alkenylene;
R3, R4 and R5 each independently represent hydrogen or optionally substituted C1-C6 alkyl;
R6 and R7 each independently represent hydrogen or optionally substituted C1-C6 alkyl;
R8 represents optionally substituted C1-C6 alkylene or optionally substituted C2-C6 alkenylene;
R9, R10 and R11 each independently represent hydrogen or optionally substituted C1-C6 alkyl;
R12 represents an optionally substituted, 3 to 10-membered, heterocyclyl, heteroaryl, aryl or cycloalkyl;
wherein R12 is optionally substituted with one to three substituents each independently selected from halogen, cyano, oxo, nitro, hydroxyl, —SR3, —CONR3R4, —NR3COR4, —NR3CONR4R5, —COR3, —C(O)OR3, —SO2R3, —SO2NR3R4, —NR3SO2R4, NR3SO2NR4R5, —NR3C(O)OR4, optionally substituted —C1-C3 alkyl and optionally substituted —C1-C3 alkoxy;
wherein the alkyl or alkoxy is optionally substituted with one to four halogen;
and
wherein C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkylene and C2-C6 alkenylene of R1a, R1b, R1c, R1d, R1e, R1f, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, A, B, L, Q1a and Q1b and C3-C4 cycloalkyl of R1a, R1b, R1c, R1d, R1e and R1f are each optionally substituted with one to four substituents independently selected from halogen, hydroxyl, thiol, cyano, amino, amido, nitro and SF5.

16 more elements

A compound, selected from the group consisting of:

3-(6-(3-cyanophenyl)-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carbonitrile;
3-(6-(2-(benzyloxy)phenyl)-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carbonitrile;
4-(2-(1-cyanopyrrolidin-3-yl)-1H-benzo[d]imidazol-6-yl)benzamide;
4-(2-(1-cyanopyrrolidin-3-yl)-1H-benzo[d]imidazol-6-yl)-N-methylbenzamide;
3-(6-(2-fluoro-5-methylphenyl)-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carbonitrile;
3-(6-(6-isopropoxypyridin-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carbonitrile;
3-(6-(1-isobutyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carbonitrile;
N-benzyl-4-(2-(1-cyanopyrrolidin-3-yl)-1H-benzo[d]imidazol-6-yl)benzamide;
3-(6-(pyridin-4-yl)-3H-imidazo[4,5-b]pyridin-2-yl)pyrrolidine-1-carbonitrile;
(S)-3-(6-(pyridin-4-yl)-3H-imidazo[4,5-b]pyridin-2-yl)pyrrolidine-1-carbonitrile;
(R)-3-(6-(pyridin-4-yl)-3H-imidazo[4,5-b]pyridin-2-yl)pyrrolidine-1-carbonitrile;
3-(6-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)pyrrolidine-1-carbonitrile;
3-(6-(4-cyanophenyl)-3H-imidazo[4,5-b]pyridin-2-yl)pyrrolidine-l-carbonitrile;
3-(6-(3-cyanophenyl)-3H-imidazo[4,5-b]pyridin-2-yl)pyrrolidine-l-carbonitrile;
3-(6-(6-methoxypyridin-3-yl)-3H-imidazo[4,5-b]pyridin-2-yl)pyrrolidine-1-carbonitrile;
3-(6-(1H-indazol-5-yl)-3H-imidazo[4,5-b]pyridin-2-yl)pyrrolidine-1-carbonitrile;
3-(6-(1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-yl)pyrrolidine-1-carbonitrile;
3-(2-(1-cyanopyrrolidin-3-yl)-3H-imidazo[4,5-b]pyridin-6-yl)-N-methylbenzamide;
3-(6-(4-cyanophenyl)-3H-imidazo[4,5-b]pyridin-2-yl)pyrrolidine-1-carbonitrile:
Enantiomer 1;
3-(6-(4-cyanophenyl)-3H-imidazo[4,5-b]pyridin-2-yl)pyrrolidine-1-carbonitrile:
Enantiomer 2;
3-(2-(1-cyanopyrrolidin-3-yl)-3H-imidazo[4,5-b]pyridin-6-yl)-N-methylbenzamide:
Enantiomer 1;
3-(2-(1-cyanopyrrolidin-3-yl)-3H-imidazo[4,5-b]pyridin-6-yl)-N-methylbenzamide:
Enantiomer 2;
(S)-2-(6-phenyl-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carbonitrile;
3-(5-phenyl-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carbonitrile;
(S)-2-(1-methyl-5-phenyl-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carbonitrile;
3-(5-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)pyrrolidine-1-carbonitrile;
3-(7-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)pyrrolidine-1-carbonitrile;
3-(5-methyl-6-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)pyrrolidine-1-carbonitrile;
3-(7-methyl-6-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)pyrrolidine-1-carbonitrile;
3-(3-methyl-6-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)pyrrolidine-1-carbonitrile;
trans-3-methyl-4-(6-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)pyrrolidine-1-carbonitrile:
Enantiomer 1;
trans-3-methyl-4-(6-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)pyrrolidine-1-carbonitrile:
Enantiomer 2;
trans-3-methyl-4-(5-phenyl-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carbonitrile:
Enantiomer 1;
(R)-3-(7-(4-methyl-1H-imidazol-1-yl)-1,6-dioxo-1,3,4,6-tetrahydro-2H-pyrido[1,2-a]pyrazin-2-yl)pyrrolidine-1-carbonitrile;
(S)-2-(1-cyanopyrrolidin-2-yl)-N-methyl-6-phenylbenzo[d]oxazole-4-carboxamide;
3-(7-phenylimidazo[1,2-a]pyridin-3-yl)pyrrolidine-1-carbonitrile;
3-(7-(3,5-dimethylisoxazol-4-yl)imidazo[1,2-a]pyridin-3-yl)pyrrolidine-1-carbonitrile;
(S)-2-(5-(3-cyanophenyl)benzo[d]oxazol-2-yl)pyrrolidine-1-carbonitrile;
(S)-6-(2-(1-cyanopyrrolidin-2-yl)benzo[d]oxazol-5-yl)picolinonitrile;
(S)-2-(6-(3-cyanophenyl)benzo[d]oxazol-2-yl)pyrrolidine-1-carbonitrile;
(S)-2-(5-(3-ethylphenyl)benzo[d]oxazol-2-yl)pyrrolidine-1-carbonitrile;
(S)-2-(6-(3-ethylphenyl)benzo[d]oxazol-2-yl)pyrrolidine-1-carbonitrile;
(S)-2-(1-cyanopyrrolidin-2-yl)-6-(3-ethylphenyl)-N-methylbenzo[d]oxazole-4-carboxamide;
(S)-6-(2-(1-cyanopyrrolidin-2-yl)benzo[d]oxazol-6-yl)picolinonitrile;
(S)-2-(5-(3-(trifluoromethoxy)phenyl)benzo[d]oxazol-2-yl)pyrrolidine-1-carbonitrile;
(S)-2-(5-(3-methyl-1H-indazol-6-yl)benzo[d]oxazol-2-yl)pyrrolidine-1-carbonitrile;
(S)-2-(5-(1-methyl-1H-indazol-5-yl)benzo[d]oxazol-2-yl)pyrrolidine-1-carbonitrile;
(S)-2-(5-(3-nitrophenyl)benzo[d]oxazol-2-yl)pyrrolidine-1-carbonitrile;
(S)-2-(5-(3-cyano-2-fluorophenyl)benzo[d]oxazol-2-yl)pyrrolidine-1-carbonitrile;
(S)-2-(5-(3-cyano-5-fluorophenyl)benzo[d]oxazol-2-yl)pyrrolidine-1-carbonitrile;
and
(S)—N-benzyl-3-(2-(1-cyanopyrrolidin-2-yl)benzo[d]oxazol-5-yl)-4-methylbenzenesulfonamide;
or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer.

57 more elements

Dependencies are inferred from the claim text.

Facts

Application

17/674,943Filed 18 Feb 2022

Priority

GB 1605059.324 Mar 2016

Published

9 Jun 2022

Term ends

Not estimatedThe source records don’t support an estimate.

Classification16 codes

C07D 401/14
Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a…:…
A61P 3/00
Drugs for disorders of the metabolism
A61P 9/00
Drugs for disorders of the cardiovascular system
A61P 25/00
Drugs for disorders of the nervous system

1-cyano-pyrrolidine derivatives as dub inhibitors

Life of this patent

1-cyano-pyrrolidine derivatives as dub inhibitors

Life of this patent

Abstract

Claims21