Substituted piperidines as inhibitors of ubiquitin specific protease 7

1. A compound of formula (I):

or a pharmaceutically acceptable salt or stereoisomer thereof,

wherein:

W represents:

wherein:

ring A represents heteroaryl, wherein the heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of halogen, cyano, nitro, N-oxide, oxo, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, C(O)R′, C(O)NR′R″, C(O)OR′, OC(O)R′, Y 1 —NR′R″, Y 1 —NR′—C(O)—R″, Y 1 —NR′—C(O)—OR″, Y 1 —OR′, Y 1 —S(O) m —R′, cyclopropyl, and pyridinyl, and further wherein the pyridinyl substituent is optionally substituted with a (C 1 -C 6 ) alkyl substituent;

R 4 represents hydrogen, halogen, oxo, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, Y 1 —NR 6 R 7 , Y 1 —NR 6 —C(O)—R 7 , Y 1 —OR 6 , Y 1 -Cy 1 , Cy 1 —R 7 , or Cy 1 —ORS;

R 5 represents hydrogen, halogen, cyano, (C 1 -C 6 ) alkyl, or (C 1 -C 6 ) hydroxyalkyl;

R 6 represents hydrogen or (C 1 -C 6 ) alkyl;

R 7 represents hydrogen, (C 1 -C 6 ) alkyl, Y 2 —SR 8 , or Y 2 -Cy 2 ;

R 8 represents hydrogen or (C 1 -C 6 ) alkyl;

X represents C, CH, or N;

Y 1 represents a bond or (C 1 -C 4 ) alkylene;

Y 2 represents a bond or (C 1 -C 4 ) alkylene;

Cy 1 represents cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of halogen, cyano, nitro, N-oxide, oxo, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, C(O)R′, C(O)NR′R″, C(O)OR', OC(O)R′, Y 1 —NR′R″, Y 1 —NR′—C(O)—R″, Y 1 —NR′—C(O)—OR″, Y 1 —OR′, Y 1 —S(O) m —R′, cyclopropyl, and pyridinyl, and further wherein the pyridinyl substituent is optionally substituted with a (C 1 -C 6 ) alkyl substituent; and

Cy 2 represents cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of halogen, cyano, nitro, N-oxide, oxo, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, C(O)R′, C(O)NR′R″, C(O)OR′, OC(O)R′, Y 1 —NR′R″, Y 1 —NR′—C(O)—R″, Y 1 —NR′—C(O)—OR″, Y 1 —OR′, Y 1 —S(O) m —R′, cyclopropyl, and pyridinyl, and further wherein the pyridinyl substituent is optionally substituted with a (C 1 -C 6 ) alkyl substituent;

represents:

wherein:

R 1 represents cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of halogen, cyano, nitro, N-oxide, oxo, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, C(O)R′, C(O)NR′R″, C(O)OR′, OC(O)R′, Y 1 —NR′R″, Y 1 —NR′—C(O)—R″, Y 1 —NR′—C(O)—OR″, Y 1 —OR', Y 1 —S(O) m —R′, cyclopropyl, and pyridinyl, and further wherein the pyridinyl substituent is optionally substituted with a (C 1 -C 6 ) alkyl substituent;

each R 3 independently represents hydrogen, halogen, oxo, (C 1 -C 6 ) alkyl, or OH; and

m represents 0, 1, or 2;

each R 2 independently represents hydrogen or halogen;

each R′ independently represents hydrogen, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) hydroxyalkyl, (C 1 -C 6 ) alkyl—O(C 1 -C 6 ) alkyl, CH 2 -cyclopropyl, (C 2 -C 6 ) alkenyl, O(Ci-C 6 ) alkyl, tetrahydropyranyl, or phenyl;

each R″ independently represents hydrogen, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) hydroxyalkyl, (C 1 -C 6 ) alkyl—O(C 1 -C 6 ) alkyl, CH 2 -cyclopropyl, (C 2 -C 6 ) alkenyl, O(C 1 -C 6 ) alkyl, tetrahydropyranyl, or phenyl; or

each R′ and R″, together with the nitrogen atom to which they are attached, independently forms a non-aromatic ring having 5, 6, or 7 ring members, wherein each non-aromatic ring optionally and independently contains one additional heteroatom or heteroatomic group selected from the group consisting of N, NH, N(C 1 -C 6 ) alkyl, N + [(C 1 -C 6 ) alkyl] 2 , and O; and

n represents 0, 1, or 2;

wherein cycloalkyl represents a non-aromatic, monocyclic, or fused bicyclic carbocyclic ring having 3, 4, 5, 6, or 7 ring members;

wherein heterocycloalkyl represents a non-aromatic, monocyclic, or fused bicyclic ring having 3, 4, 5, 6, 7, 8, 9, or 10 ring members, and further having 1, 2, or 3 heteroatoms or heteroatomic groups independently selected from the group consisting of N, NH, O, and S;

wherein aryl represents phenyl, naphthyl, or indanyl; and

wherein heteroaryl represents a monocyclic or fused bicyclic ring having at least one aromatic moiety and further having 5, 6, 7, 8, 9, or 10 ring members and 1, 2, or 3 heteroatoms independently selected from the group consisting of N, O, and S.

2. The compound according to claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein W represents:

3. The compound according to claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 1 represents pyrrolidinyl, phenyl, pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, or pyridinyl.

4. The compound according to claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein each R 2 independently represents hydrogen or fluoro.

5. The compound according to claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein each R 3 independently represents hydrogen, fluoro, oxo, CH 3 , or OH.

6. The compound according to claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 4 represents hydrogen, halogen, (C 1 -C 6 ) alkyl, Y 1 —NR 6 R 7 , Y 1 —NR 6 —C(O)—R 7 , or Y 1 -Cy 1 .

7. The compound according to claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

R 5 represents hydrogen; and

R 6 represents hydrogen.

8. The compound according to claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 7 represents hydrogen, Y 2 —SR 8 , or Y 2 -Cy 2 .

9. The compound according to claim 1 , wherein the compound, or stereoisomer thereof, is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

10. A pharmaceutical composition comprising one or more pharmaceutically acceptable excipients together with the compound according to claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof.

11. A combination comprising the compound according to claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, and an anticancer agent;

wherein the anticancer agent is selected from the group consisting of an antibody, an anti-metabolite, a chimeric antigen receptor T-cell therapy, an E3 ligase inhibitor, a genotoxic agent, an immunomodulator, a kinase inhibitor, a mitotic poison, a proteasome inhibitor, and a protein-protein interaction inhibitor.

12. A pharmaceutical composition comprising one or more pharmaceutically acceptable excipients together with the combination according to claim 11 .