US 11,306,096 B2 · 4,6 dihydropyrrolo [3,4-C] pyrazole-5 (1H)-carbonitrile derivates for treating cancer

Abstract

The present invention relates to novel compounds and methods for the manufacture of inhibitors of deubiquitylating enzymes (DUBs) and/or desumoylating enzymes. In particular, the invention relates to the inhibition of ubiquitin C-terminal hydrolase 7 or ubiquitin specific peptidase 7 (USP7). The invention further relates to the use of DUB or desumoylating inhibitors in the treatment of cancer. Described herein are compounds of formula (I) or a pharmaceutically acceptable salt thereof, wherein R1a, R1b, R1c and R1d each independently represent hydrogen, optionally substituted C1-C6 alkyl or R1a and R1b together form an optionally substituted C3-C6 cycloalkyl ring, or R1c and R1d together form an optionally substituted C3-C6 cycloalkyl ring; A is a 5 membered nitrogen-containing aromatic ring and is substituted with at least one optionally substituted 5 to 10 membered monocyclic or bicyclic heteroaryl or aryl ring attached through an optional linker.

A compound of formula II:

or a pharmaceutically acceptable salt thereof, wherein
represents an aromatic bond;
p is 0 or 1;
q is 0 or 1;
wherein p and q are not both 0 and one of p and q is 1;
R8 is hydrogen, -Q1-B or -Q2-(D)m;
R9 is hydrogen or C1-C6 alkyl, which is optionally substituted by halogen, hydroxyl or cyano;
R10 is hydrogen, -Q1-B or -Q2-(D)m;
wherein one of R8 or R10 is -Q1-B;
R1a, R1b, R1c, R1d are each independently hydrogen or C1-C6 alkyl, or R1a and R1b together form a C3-C6, cycloalkyl ring, or R1c and R1d together form a C3-C6 cycloalkyl ring;
m is 0 or 1,
Q1 is a covalent bond, an oxygen atom, a sulphur atom, —OR4—, —SO—, —SO2—, —C(O)—, —C(O)O—, —C0-C3-alkylene-C(O)NR2—C0-C3 alkylene, —C0-C3-alkylene-NR2—C0-C3-alkylene-, —C0-C3-alkylene-NR2C(O)—C0-C3-alkylene, —NR2C(O)NR3—, —SO2NR2—, NR2SO2—, —NR2SO2—, —NR2SO2NR3—, —NR2C(O)—, —NR2C(O)OR4—, —C1-C6 alkylene, or —C2-C6 alkenylene;
R2 and R3 are each independently hydrogen or C1-C6 alkyl;
R4 is C1-C6 alkylene;
B is a 5 to 10-membered, monocyclic or bicyclic, aryl or heteroaryl ring, wherein said heteroaryl ring comprises 1 to 5 heteroatoms, each independently selected from N, O and S;
wherein B is unsubstituted or substituted with one to four substituents, each independently selected from halogen, cyano, oxo, hydroxyl, —SR11, —C1-C6 alkyl, —C1-C6 alkoxy, —C2-C6 alkenyl, —C2-C6 alkynyl, -Q3a-R13, -Q3a-O-Q3b-R13, -Q3a-S-Q3b-R13, -Q3a-SO-Q3b-R13, -Q3a-NR11CONR12R12a, -Q3a-NR11CONR12-Q3a-R13, -Q3a-NR11R12, -Q3a-NR11-Q3b-R13, -Q3a-COR11, -Q3a-CO-Q3b-R13, -Q3a-NR11COR12, -Q3a-NR11CO-Q3b-R13, -Q3a-NR11C(O)OR12, -Q3a-SO2R11, -Q3a-SO2-Q3b-R13, Q3a-CONR11R12, -Q3a-CONR11-Q3b-R13, -Q3a-CO2R11, -Q3a-CO2-Q3b-R13, -Q3a-SO2NR11R12, -Q3a-SO2NR11-Q3b-R13, -Q3a-NR11SO2R12, -Q3a-NR11SO2-Q3b-R13 and -Q3a-NR11SO2NR12R12a, -Q3a-NR11SO2NR12-Q3b-R13;
Q3a and Q3b are each independently a covalent bond, C1-C6 alkylene, or C2-C6 alkenylene;
R11, R12 and R12a are each independently hydrogen or C1-C6 alkyl;
R13 is a 3 to 10-membered, monocyclic or bicyclic, heterocyclyl, heteroaryl, aryl, or cycloalkyl ring;
wherein said heterocyclyl and heteroaryl rings comprise 1 to 5 heteroatoms, each independently selected from N, O and S;
wherein R13 is unsubstituted or substituted with one to four substituents, each independently selected from halogen, hydroxyl, thiol, cyano, amino, amido, nitro, SF5, C1-C3 alkyl, and C1-C3 alkoxy;
each Q2 is independently halogen, cyano, nitro, OR5, —SR5, —NR5R6, —CONR5R6, —C0-C3-alkylene-NR5COR6—, —NR5CONR6R6a, —COR5, —C(O)OR5, —SO2R5, —SO2NR5R6, —NR5SO2R6, —NR5SO2NR6R6a, —NR5C(O)OR6, —C1-C6 alkyl, —C2-C6 alkenyl, a covalent bond, an oxygen atom, a sulphur atom, —OR7—, —SO—, —SO2—, —CO—, —C(O)O—, —C0-C3-alkylene-C(O)NR5—C0-C3 alkylene, —C0-C3-alkylene-NR5—C0-C3 alkylene, —C0-C3 alkylene-NR5C(O)—C0-C3 alkylene, —NR5CONR6—, —SO2NR5—, NR5SO2—, —NR5SO2NR6—, —NR5C(O)O—, —NR5C(O)OR7—, C1-C6 alkylene, or —C2-C6 alkenylene,
R5, R6, R6a are each independently hydrogen or C1-C6 alkyl,
R7 is C1-C6 alkylene;
each D is independently a 3 to 10-membered, monocyclic or bicyclic, heterocyclyl, heteroaryl, cycloalkyl or aryl ring;
wherein said heterocyclyl and heteroaryl rings comprise 1 to 5 heteroatoms, each independently selected from N, O and S;
wherein D is unsubstituted or substituted with one to four substituents, each independently selected from C1-C6 alkyl, C1-C6 alkoxy, and —CONR14R15;
R14 and R15 are each independently hydrogen or C1-C6 alkyl, and
wherein the alkyl, alkoxy, alkenyl, alkynyl, alkylene and alkenylene groups of R1a, R1b, R1c, R1d, R2, R3, R4, R5, R6, R6a, R7, R11, R12, R12a, R14, R15, Q1, Q2, Q3a, Q3b, ring B substituents and ring D substituents, are optionally substituted with halogen, hydroxyl or cyano.

26 more elements

4,6 dihydropyrrolo [3,4-C] pyrazole-5 (1H)-carbonitrile derivates for treating cancer

Life of this patent

4,6 dihydropyrrolo [3,4-C] pyrazole-5 (1H)-carbonitrile derivates for treating cancer

Life of this patent

Abstract

Claims11