Quinazolinones and azaquinazolinones as ubiquitin-specific protease 7 inhibitors

1. A method of inhibiting USP7 in a patient suffering from a disease or disorder associated with modulation of USP7, comprising administering to the patient an effective amount of a compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

X 1 is C, S, or S(O);

Y 1 is N or CH;

Y 2 is N or CR 5 ;

Y 3 is N or CR 6 ;

Y 4 is N or CR 7 ;

R 1 is OH;

R 2 is (C 1 -C 6 ) alkyl or (C 6 -C 14 ) aryl, wherein the alkyl or aryl are optionally substituted with one to three R 8 ;

R 4 and R 4′ are independently H;

R 5 is H;

R 6 is H, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, halogen, —NH 2 , —NHC(O)(C 1 -C 6 ) alkyl, or (C 6 -C 14 ) aryl, wherein the alkyl or aryl are optionally substituted with one to three R 13 ;

R 7 is H, (C 1 -C 6 ) alkyl, (C 6 -C 14 ) aryl, or —O—(C 6 -C 14 ) aryl, wherein the alkyl or aryl are optionally substituted with one to three R 14 ;

each R 8 is independently (C 1 -C 6 ) alkyl, halogen, or —(C 0 -C 4 )-alkylene-(C 6 -C 14 ) aryl, wherein the alkyl or aryl are optionally substituted with one to three R 9 ;

or two R 8 together when on adjacent atoms form a (C 3 -C 8 ) cycloalkyl optionally substituted with one to three R 9 ;

each R 9 is independently (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, or —(C 0 -C 3 )-alkylene-(C 6 -C 14 ) aryl, wherein alkyl or aryl are optionally substituted with one to three R 19 ;

each R 13 is independently (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, CN, —OH, —NH 2 , (C 1 -C 6 ) alkylamino, di(C 1 -C 6 ) alkylamino, or heterocycloalkyl independently selected from the group consisting of oxetanyl, azetadinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, thiazolinyl, thiazolidinyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxalinyl, piperidinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S-dioxide, piperazinyl, azepinyl, oxepinyl, diazepinyl, tropanyl, oxazolidinonyl, and homotropanyl;

wherein the alkyl and heterocycloalkyl are optionally substituted with one to three R 15 ;

each R 14 is independently (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, CN, —OH, —NH 2 , —C(O)(C 1 -C 6 ) alkyl, —S(O) q (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkylamino, or di(C 1 -C 6 ) alkylamino;

each R 15 is independently (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, —C(O)(C 1 -C 6 ) alkyl, —S(O) q (C 1 -C 6 ) alkyl, —NH 2 , (C 1 -C 6 ) alkylamino, di(C 1 -C 6 ) alkylamino, —OH, or CN;

each R 19 is independently at each occurrence (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, —OH, or CN;

m is 0;

n is 1;

q is independently at each occurrence 0, 1, or 2; and

provided that

(a) when R 2 is optionally substituted (C 1 -C 6 ) alkyl, R 5 is H; and R 7 is H; then R 6 is not chloro;

(b) R 5 , R 6 , and R 7 are not all simultaneously H; and

(c) the compound is further characterized by any one or more of the following:

i. at least one of Y 1 , Y 2 , Y 3 , or Y 4 is N;

ii. at least one of R 6 or R 7 is an optionally substituted (C 6 -C 14 ) aryl;

iii. R 6 is (C 1 -C 6 ) alkyl, —NHC(O)(C 1 -C 6 ) alkyl, or (C 6 -C 14 ) aryl, wherein the alkyl or aryl of R 6 is substituted with a R 13 that is (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, CN, —OH, —NH 2 , (C 1 -C 6 ) alkylamino, or di(C 1 -C 6 ) alkylamino;

iv. R 6 is (C 1 -C 6 ) alkyl, —NHC(O)(C 1 -C 6 ) alkyl, or (C 6 -C 14 ) aryl, wherein the alkyl or aryl of R 6 is substituted with a R 13 that is (C 1 -C 6 ) alkyl or a heterocycloalkyl, independently selected from the group consisting of oxetanyl, azetadinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, thiazolinyl, thiazolidinyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxalinyl, piperidinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S-dioxide, piperazinyl, azepinyl, oxepinyl, diazepinyl, tropanyl, oxazolidinonyl, and homotropanyl; wherein the heterocycloalkyl is substituted with one to three R 15 ; or

V. R 7 is H, (C 1 -C 6 ) alkyl, (C 6 -C 14 ) aryl, or —O—(C 6 -C 14 ) aryl, wherein the alkyl or aryl of R 7 is substituted with a R 14 that is (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, CN, —OH, —NH 2 , —C(O)(C 1 -C 6 ) alkyl, S(O) q (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkylamino, or di(C 1 -C 6 ) alkylamino.

2. The method of claim 1 , wherein:

R 2 is (C 1 -C 6 ) alkyl or (C 6 -C 14 ) aryl, wherein the alkyl or aryl are optionally substituted with one to two R 8 ;

each R 8 is independently halogen or —(C 0 -C 4 )-alkylene-(C 6 -C 14 ) aryl, wherein the aryl is optionally substituted with one to three R 9 ; or two R 8 together when on adjacent atoms form a (C 3 -C 8 ) cycloalkyl optionally substituted with one to three R 9 ; and

each R 9 is —(C 0 -C 3 )-alkylene-(C 6 -C 14 ) aryl.

3. The method of claim 2 , wherein R 2 is (C 1 -C 6 ) alkyl substituted with one R 8 ; and R 8 is —(C 0 -C 4 )-alkylene-(C 6 -C 14 ) aryl.

4. The method of claim 2 , wherein R 2 is (C 6 -C 14 ) aryl.

5. The method of claim 4 , wherein two R 8 together when on adjacent atoms form a (C 3 -C 8 ) cycloalkyl optionally substituted with one to three R 9 .

6. The method of claim 5 , wherein the (C 3 -C 8 )cycloalkyl formed by two R 8 together on adjacent atoms is substituted with one R 9 and R 9 is —(C 0 -C 3 )-alkylene-(C 6 -C 14 ) aryl.

7. The method of claim 2 , wherein

R 6 is H;

R 7 is (C 1 -C 6 ) alkyl, C 6 -aryl, or —O—C 6 -aryl, wherein the alkyl or aryl are optionally substituted with one to three R 14 ; and

each R 14 is independently (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, CN, —OH, —NH 2 , (C 1 -C 6 ) alkylamino, or di(C 1 -C 6 ) alkylamino.

8. The method of claim 7 , wherein R 14 is halogen.

9. The method of claim 8 , wherein R 7 is C 6 -aryl.

10. The method of claim 8 , wherein R 7 is —O—C 6 -aryl.

11. The method of claim 2 , wherein

R 6 is (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, halogen, —NH 2 , —NHC(O)(C 1 -C 6 ) alkyl, or (C 6 -C 14 ) aryl, wherein the alkyl or aryl are optionally substituted with one to three R 13 ;

R 13 is independently (C 1 -C 6 ) alkyl or heterocycloalkyl selected from the group consisting of oxetanyl, azetadinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, thiazolinyl, thiazolidinyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxalinyl, piperidinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S-dioxide, piperazinyl, azepinyl, oxepinyl, diazepinyl, tropanyl, oxazolidinonyl, and homotropanyl;

wherein the alkyl and heterocycloalkyl are optionally substituted with one to three R 15 ;

each R 15 is independently (C 1 -C 6 ) alkyl; and

R 7 is H.

12. The method of claim 11 , wherein R 6 is NHC(O)(C 1 -C 6 ) alkyl.

13. The method of claim 1 , wherein the compound is of formula (Ic):

or a pharmaceutically acceptable salt thereof; wherein:

R 2 is (C 1 -C 6 ) alkyl or (C 6 -C 14 ) aryl, wherein the alkyl or aryl are optionally substituted with one to three R 8 ;

R 6 is H, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, halogen, —NH 2 , —NHC(O)(C 1 -C 6 ) alkyl, or (C 6 -C 14 ) aryl, wherein the alkyl or aryl are optionally substituted with one to three R 13 ;

R 7 is H, (C 1 -C 6 ) alkyl, (C 6 -C 14 ) aryl, or —O—(C 6 -C 14 ) aryl, wherein the alkyl or aryl are optionally substituted with one to three R 14 ;

each R 8 is independently (C 1 -C 6 ) alkyl, halogen, or —(C 0 -C 4 )-alkylene-(C 6 -C 14 ) aryl, wherein the alkyl or aryl are optionally substituted with one to three R 9 ;

or two R 8 together when on adjacent atoms form a (C 3 -C 8 ) cycloalkyl optionally substituted with one to three R 9 ;

each R 9 is independently (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, or —(C 0 -C 3 )-alkylene-(C 6 -C 14 ) aryl, wherein alkyl and aryl are optionally substituted with one to three R 19 ;

each R 13 is independently (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, CN, —OH, —NH 2 , (C 1 -C 6 ) alkylamino, di(C 1 -C 6 ) alkylamino, or heterocycloalkyl independently selected from the group consisting of oxetanyl, azetadinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, thiazolinyl, thiazolidinyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxalinyl, piperidinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S-dioxide, piperazinyl, azepinyl, oxepinyl, diazepinyl, tropanyl, oxazolidinonyl, and homotropanyl;

wherein the alkyl and heterocycloalkyl are optionally substituted with one to three R 15 ;

each R 14 is independently (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, CN, —OH, —NH 2 , —C(O)(C 1 -C 6 ) alkyl, —S(O) q (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkylamino, or di(C 1 -C 6 ) alkylamino;

each R 15 is independently (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, —C(O)(C 1 -C 6 ) alkyl, —S(O) q (C 1 -C 6 ) alkyl, —NH 2 , (C 1 -C 6 ) alkylamino, di(C 1 -C 6 ) alkylamino, —OH, or CN; and

each R 19 is independently at each occurrence (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, —OH, or CN.

14. The method of claim 13 , wherein

R 2 is (C 1 -C 6 ) alkyl, optionally substituted with one R 8 ; and

R 8 is independently —(C 0 -C 4 )-alkylene-(C 6 ) aryl, wherein the aryl are optionally substituted with one to three R 9 .

15. The method of claim 14 , wherein R 8 is not substituted with R 9 .

16. The method of claim 15 , wherein

R 6 is (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, halogen, —NH 2 , —NHC(O)(C 1 -C 6 ) alkyl, or (C 6 -C 14 ) aryl, wherein the alkyl or aryl are optionally substituted with one to three R 13 ; and

R 7 is H.

17. The method of claim 16 , wherein R 6 is (C 1 -C 6 ) alkyl NH 2 , or NHC(O)(C 1 -C 6 ) alkyl wherein the alkyl is optionally substituted with one to three R 13 .

18. The method of claim 17 , wherein R 13 is a heterocycloalkyl independently selected from the group consisting of oxetanyl, azetadinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, thiazolinyl, thiazolidinyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxalinyl, piperidinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S-dioxide, piperazinyl, azepinyl, oxepinyl, diazepinyl, tropanyl, oxazolidinonyl, and homotropanyl; optionally substituted with one to three R 15 .

19. The method of claim 18 , wherein R 15 is (C 1 -C 6 ) alkyl.

20. The method of claim 15 , wherein

R 6 is H; and

R 7 is (C 1 -C 6 ) alkyl, (C 6 -C 14 ) aryl, or —O—(C 6 -C 14 ) aryl, wherein the alkyl or aryl are optionally substituted with one to three R 14 .

21. The method of claim 20 , wherein R 7 is (C 6 -C 14 ) aryl or —O—(C 6 -C 14 ) aryl, wherein the aryl is optionally substituted with one R 14 , wherein R 14 is halogen.

22. The method of claim 1 , selected from formula (Id) or formula (Ie):

or a pharmaceutically acceptable salt thereof; wherein:

R 2 is (C 1 -C 6 ) alkyl, optionally substituted with R 8 ;

R 6 is (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, halogen, —NH 2 , —NHC(O)(C 1 -C 6 ) alkyl, (C 6 -C 14 ) aryl, wherein the alkyl or aryl are optionally substituted with one to three R 13 ;

R 7 is (C 1 -C 6 ) alkyl, (C 6 -C 14 ) aryl, or —O—(C 6 -C 14 ) aryl, wherein the alkyl or aryl are optionally substituted with one to three R 14 ;

R 8 is independently (C 1 -C 6 ) alkyl, halogen, or —(C 0 -C 4 )-alkylene-(C 6 -C 14 ) aryl, wherein the alkyl or aryl are optionally substituted with one to three R 9 ;

each R 13 is independently (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, CN, —OH, —NH 2 , (C 1 -C 6 ) alkylamino, di(C 1 -C 6 ) alkylamino, or heterocycloalkyl independently selected from the group consisting of oxetanyl, azetadinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, thiazolinyl, thiazolidinyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxalinyl, piperidinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S-dioxide, piperazinyl, azepinyl, oxepinyl, diazepinyl, tropanyl, oxazolidinonyl, and homotropanyl;

wherein the alkyl and heterocycloalkyl are optionally substituted with one to three R 15 ;

each R 14 is independently (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, CN, —OH, —NH 2 , —C(O)(C 1 -C 6 ) alkyl, —S(O) q (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkylamino, or di(C 1 -C 6 ) alkylamino;

each R 15 is independently (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, —C(O)(C 1 -C 6 ) alkyl, —S(O) q (C 1 -C 6 ) alkyl, —NH 2 , (C 1 -C 6 ) alkylamino, di(C 1 -C 6 ) alkylamino, —OH, or CN; and

each R 19 is independently at each occurrence (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, —OH, or CN.

23. The method of claim 22 , wherein R 2 is (C 1 -C 6 ) alkyl substituted with R 8 ; and R 8 is —(C 0 -C 4 )-alkylene-(C 6 -C 14 ) aryl.

24. The method of claim 23 , wherein:

R 6 is (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, —NH 2 , —NHC(O)(C 1 -C 6 ) alkyl, wherein the alkyl is optionally substituted with one to three R 13 ; and

R 7 is (C 1 -C 6 ) alkyl, (C 6 -C 14 ) aryl, or —O—(C 6 -C 14 ) aryl, wherein the alkyl or aryl are optionally substituted with one to three R 14 .

25. The method of claim 24 , wherein the compound is of formula (Ie) wherein R 7 is (C 6 -C 14 ) aryl or —O—(C 6 -C 14 ) aryl, wherein the aryl is optionally substituted with one to three R 14 ; and each R 14 is independently (C 1 -C 6 ) alkyl or halogen.

26. The method of claim 24 , wherein the compound is of formula (Ie) wherein R 7 is (C 1 -C 6 ) alkyl.

27. The method of claim 1 , wherein the patient is suffering from cancer, a neurodegenerative disease, an immunological disorder, diabetes, a bone and joint disease, osteoporosis, an arthritis, an inflammatory disorder, a cardiovascular disease, an ischemic disease, a viral infection or disease, a viral infectivity and/or latency, or a bacterial infection or disease.

28. The method of claim 27 , wherein the patient is suffering from

liposarcoma, neuroblastoma, glioblastoma, bladder cancer, adrenocortical cancer, multiple myeloma, colorectal cancer, non-small cell lung cancer, Human Papilloma Virus-associated cervical, oropharyngeal, penis, anal, thyroid or vaginal cancer or Epstein-Barr Virus-associated nasopharyngeal carcinoma, gastric cancer, rectal cancer, thyroid cancer, Hodgkin lymphoma, or diffuse large B-cell lymphoma; or

Alzheimer's disease, multiple sclerosis, Huntington's disease, infectious meningitis, encephalomyelitis, Parkinson's disease, amyotrophic lateral sclerosis, or encephalitis; or herpes simplex-1 or -2 viral infections, hepatitis A, hepatitis C, SARS coronavirus infection and disease, Epstein-Barr virus, rhinoviral infections and diseases, adenoviral infections and diseases, or poliomyelitis; or

Type II diabetes, insulin resistance cardiovascular disease, arrhythmia, atherosclerosis, coronary artery disease, hypertriglyceridemia, dyslipidemia, retinopathy, nephropathy, neuropathy, or macular edema; or

ileitis, ulcerative colitis, Barrett's syndrome, or Crohn's disease.