SUBSTITUTED 4-AMINOISOINDOLINE-1,3-DIONE COMPOUNDS, COMPOSITIONS THEREOF, AND METHODS OF TREATMENT THEREWITH

• US 20190322647A1
• Filed: 04/22/2019
• Published: 10/24/2019
• Est. Priority Date: 04/23/2018
• Status: Active Grant

• Current Assignee: Celgene Corporation (Bristol-Myers Squibb Company)
• Original Assignee: Celgene Corporation (Bristol-Myers Squibb Company)
• Inventors: Alexander, Matthew D., Carrancio, Soraya, Correa, Matthew D., Grant, Virginia Heather Sharron, Hansen, Joshua, Harris, Roy L., Huang, Dehua, Kercher, Timothy S., Lopez-Girona, Antonia, Nagy, Mark A., Plantevin-Krenitsky, Veronique
• Granted Patent: US 11,358,952 B2
• Time in Patent Office: Days
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07D 401/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 403/14 containing three or more hetero rings
• CPC Class Codes: C07D 407/14 containing three or more hetero rings
• CPC Class Codes: C07D 417/14 containing three or more hetero rings
• CPC Class Codes: C07D 491/08 Bridged systems
• CPC Class Codes: C07D 491/10 Spiro-condensed systems

Abstract

Provided herein are 4-aminoisoindoline-1,3-dione compounds having the following structure:

• • wherein R, Ring A, and n are as defined herein, compositions comprising an effective amount of a 4-aminoisoindoline-1,3-dione compound, and methods for treating or preventing disorders.

Claims

1. A compound of formula (I):

2. The compound of claim 1, wherein the compound is a compound of formula (II):

3. The compound of claim 1, wherein the compound is a compound of formula (III):

4. The compound of claim 1, wherein the compound is a compound of formula (IV):

5. The compound of claim 4, wherein the compound is a compound of formula (V):

6. The compound of claim 4, wherein the compound is a compound of formula (VI):

7. The compound of claim 1, wherein the compound is a compound of formula (VII):

8. The compound of claim 7, wherein the compound is a compound of formula (VIII):

9. The compound of claim 7, wherein the compound is a compound of formula (IX):

10. The compound of claim 1, wherein Ring A is

11. The compound of claim 1, wherein Ring A is

12. The compound of claim 1, wherein Ring A is

13. The compound of claim 1, wherein Ring A is an optionally substituted non-aromatic heterocyclyl selected from azetidyl;

piperidyl;

piperazinyl;

morpholinyl;

5-azaspiro[2,3]hexyl;

2-azaspiro[3.3]heptyl;

2-oxa-6-azaspiro[3.3]heptyl;

2-azaspiro[3.4]octyl;

5-oxa-2-azaspiro[3.4]octyl;

6-oxa-2-azaspiro[3.4]octyl;

2-azaspiro[3.5]nonyl;

7-oxa-2-azaspiro[3.5]nonyl;

octahydrocyclopenta[c]pyrrolyl;

1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrolyl;

6-azaspiro[3.4]octyl;

2-oxa-6-azaspiro[3.4]octyl;

6-azaspiro[2.5]octyl;

7-azaspiro[3.5]nonyl;

1-oxa-8-azaspiro[4.5]decanyl;

2-oxa-8-azaspiro[4.5]decanyl;

2,8-diazaspiro[4.5]decan-1-onyl;

3-oxa-9-azaspiro[5.5]undecanyl;

1,4-oxazepanyl;

8-azabicyclo[3.2.1]octyl; and

isoindolinyl.

14. The compound of claim 13, wherein Ring A is substituted with one or more substituents independently selected from halogen, C_1-6 alkyl, OR¹, CON(R²)₂, SO₂(C_1-4 alkyl), N(R²)SO₂(C_1-4 alkyl), —

(C_0-3 alkyl)-(C_3-7 cycloalkyl), (non-aromatic heterocyclyl), aryl, heteroaryl, O-aryl, O-heteroaryl, and C(O)aryl;

wherein the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl are optionally substituted;

wherein R¹ is H, optionally substituted C_1-6 alkyl, or optionally substituted —

(C_0-3 alkyl)-(C_3-7 cycloalkyl); and

each R² is independently H, or C_1-6 alkyl.

15. The compound of claim 13, wherein Ring A is substituted with one or more substituents independently selected from F, Cl, Br, CH₃, CH₂CH₃, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, CH₂F, CHF₂, CF₃, CH₂CH₂F, CH₂CHF₂, CH₂CF₃, CH(CH₃)CF₃, CH₂CH₂CF₃, OH, OCH₃, OCH₂CH₃, O-isopropyl, O-n-propyl, O-n-butyl, O-isobutyl, O-t-butyl, OCF₃, O-cyclopropyl, O-cyclobutyl, OCH₂-cyclopropyl, OCH₂-cyclobutyl, CONH₂, CONH(CH₃), CON(CH₃)₂, SO₂CH₃, SO₂CH₂CH₃, SO₂-isopropyl, cyclopropyl, cyclobutyl, CH₂-cyclopropyl, CH₂-cyclobutyl;

(non-aromatic heterocyclyl) selected from azetidyl, pyrrolidyl, pyrrolidonyl, isothiazolidyl, isothiazolidine 1,1-dioxidyl, piperidyl, piperazinyl, morpholinyl, 3-oxa-8-azabicyclo[3.2.1]octyl, or 8-oxa-3-azabicyclo[3.2.1]octyl, wherein the heterocyclyl is optionally substituted with one or more substituents independently selected from CH₃, CH₂CH₃, or CF₃, phenyl, O-phenyl or C(O)-phenyl, wherein the phenyl is optionally substituted with one or more substituents independently selected from F, Cl, CH₃, CN, or CONH₂;

heteroaryl selected from pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidyl, or benzoisoxazolyl, wherein the heteroaryl is optionally substituted with one or more substituents independently selected from F, Cl, CF₃, CN, CONH₂, CONH(CH₃)₂ or CON(CH₃)₂;

O-pyridyl, and O-pyrimidyl.

16. The compound of claim 13, wherein Ring A is substituted with one or more substituents independently selected from F, CH₃, CH₂CH₃, isopropyl, t-butyl, CH₂F, CF₃, CH(CH₃)CF₃, OH, OCH₃, OCH₂CH₃, O-isopropyl, O-n-propyl, O-isobutyl, O-t-butyl, OCF₃, O-cyclobutyl, OCH₂-cyclopropyl, CON(CH₃)₂, SO₂CH₂CH₃, SO₂-isopropyl, cyclopropyl, cyclobutyl, CH₂-cyclopropyl;

(non-aromatic heterocyclyl) selected from pyrrolidyl, pyrrolidonyl, isothiazolidine 1,1-dioxidyl, morpholinyl, 3-oxa-8-azabicyclo[3.2.1]octyl, or 8-oxa-3-azabicyclo[3.2.1]octyl, wherein the heterocyclyl is optionally substituted with one or more substituents independently selected from CH₃, phenyl, O-phenyl or C(O)-phenyl, wherein the phenyl is optionally substituted with one or more substituents independently selected from F, Cl, CH₃, CN, or CONH₂;

heteroaryl selected from pyrazolyl, oxazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrazinyl, pyrimidyl or benzoisoxazolyl, wherein the heteroaryl is optionally substituted with one or more substituents independently selected from F, Cl, CF₃, CN, CONH₂, CON(CH₃)₂;

O-pyridyl, and O-pyrimidyl.

17. The compound of claim 13, wherein Ring A is azetidyl, substituted with one or more substituents independently selected from C_1-6 alkyl, (non-aromatic heterocyclyl), aryl, heteroaryl, O-aryl, and O-heteroaryl;

wherein the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl are optionally substituted.

18. The compound of claim 13, wherein Ring A is azetidyl, substituted with one or more substituents independently selected from CH₂CH₃, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, t-butyl;

CF₃;

pyrrolidyl;

pyrolidonyl;

piperidyl;

piperazinyl;

morpholinyl, optionally substituted with one or more CH₃;

3-oxa-8-azabicyclo[3.2.1]octyl;

8-oxa-3-azabicyclo[3.2.1]octyl;

pyrazolyl;

2-pyridyl;

3-pyridyl;

4-pyridyl, phenyl; and

0-phenyl;

wherein the phenyl optionally is substituted with one or more substituents selected from F or CN.

19. The compound of claim 13, wherein Ring A is piperidyl, substituted with one or more substituents independently selected from halogen, C_1-6 alkyl, OR¹, CON(R²)₂, SO₂(C_1-4 alkyl), C_3-7 cycloalkyl, non-aromatic heterocyclyl, aryl, heteroaryl and O-heteroaryl;

wherein the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl are optionally substituted;

wherein R¹ is H, optionally substituted C_1-6 alkyl, or optionally substituted —

(C_0-3 alkyl)-(C_3-7 cycloalkyl); and

each R² is independently H, or C_1-6 alkyl.

20. The compound of claim 13, wherein Ring A is piperidyl, substituted with one or more substituents independently selected from F, Cl, CH₃, CH₂CH₃, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, t-butyl, CH₂F, CHF₂, CF₃, OH, OCH₃, OCH₂CH₃, O-n-propyl, O-isopropyl, O-n-butyl, O-isobutyl, O-t-butyl, OCF₃, O-cyclopropyl, O-cyclobutyl, OCH₂-cyclopropyl, OCH₂-cyclobutyl, CONH₂, CONH(CH₃), CON(CH₃)₂, SO₂CH₃, SO₂CH₂CH₃, SO₂-isopropyl, cyclopropyl, cyclobutyl, pyrrolidonyl, isothiazolidine 1,1-dioxidyl, morpholinyl;

tetrahydrofuranyl, tetrahydropyranyl, pyrazolyl;

oxadiazolyl, optionally substituted with CH₃;

phenyl, optionally substituted with one or more F;

2-pyridyl, 3-pyridyl, 4-pyridyl, O-2-pyridyl, O-3-pyridyl, and O-4-pyridyl.

21. The compound of claim 13, wherein Ring A is piperidyl, substituted with one or more substituents independently selected from F, CH₃, CH₂CH₃, isopropyl, t-butyl, CHF₂, CF₃, OH, OCH₃, OCH₂CH₃, O-isopropyl, O-isobutyl, O-t-butyl, OCF₃, O-cyclobutyl, OCH₂-cyclopropyl, CON(CH₃)₂, SO₂CH₂CH₃, SO₂-isopropyl, cyclopropyl, pyrrolidonyl, isothiazolidine 1,1-dioxidyl, morpholinyl;

tetrahydropyranyl, pyrazolyl, oxadiazolyl, substituted with CH₃;

phenyl, substituted with one or more F;

2-pyridyl, and O-2-pyridyl.

22. The compound of claim 13, wherein Ring A is piperazinyl, substituted with one or more substituents independently selected from C_1-6 alkyl, SO₂(C_1-4 alkyl), —

(C_0-3 alkyl)-(C_3-7 cycloalkyl), aryl, heteroaryl and CO-aryl;

wherein the alkyl, cycloalkyl, aryl, or heteroaryl are optionally substituted.

23. The compound of claim 13, wherein Ring A is piperazinyl, substituted with one or more substituents independently selected from CH₃, CH₂CH₃, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, t-butyl, CF₃, CH₂CF₃, CH(CH₃)CF₃, SO₂CH₃, SO₂CH₂CH₃, SO₂-isopropyl, cyclopropyl, cyclobutyl, (CH₂)cyclopropyl, (CH₂)cyclobutyl, phenyl, optionally substituted with one or more Cl, F, CN, CH₃, CONH₂;

pyrazolyl, optionally substituted with CH₃ or CH₂CH₃;

oxazolyl, optionally substituted with CH₃ or CH₂CH₃;

oxadiazolyl, optionally substituted with CH₃ or CH₂CH₃;

thiadiazolyl, optionally substituted with CH₃, CH₂CH₃, or CF₃;

2-pyridyl, 3-pyridyl, or 4-pyridyl, each optionally substituted with Cl, F, CF₃, CN, CONH₂, CONH(CH₃) or CON(CH₃)₂;

pyrazinyl, optionally substituted with CH₃ or CH₂CH₃;

pyrimidyl, optionally substituted with OCH₃;

benzoisoxazolyl; and

CO(phenyl), wherein the phenyl is optionally fluorinated.

24. The compound of claim 13, wherein Ring A is piperazinyl, substituted with one or more substituents independently selected from CH₃, isopropyl, t-butyl, CH(CH₃)CF₃, SO₂CH₂CH₃, SO₂-isopropyl, cyclopropyl, cyclobutyl, (CH₂)cyclopropyl, phenyl, optionally substituted with one or more Cl, F, CN, CH₃, CONH₂;

pyrazolyl, optionally substituted with CH₃;

oxazolyl, optionally substituted with CH₃;

oxadiazolyl, optionally substituted with CH₂CH₃;

thiadiazolyl, optionally substituted with CH₃, or CH₂CH₃;

2-pyridyl, optionally substituted with Cl, F, CF₃, CN, or CONH₂;

3-pyridyl, optionally substituted with CF₃, CN, CONH₂, or CON(CH₃)₂;

4-pyridyl, optionally substituted with CONH₂;

pyrazinyl, optionally substituted with CH₃;

pyrimidyl, optionally substituted with OCH₃;

benzoisoxazolyl; and

CO(phenyl), wherein the phenyl is optionally fluorinated.

25. The compound of claim 13, wherein Ring A is morpholinyl, and R is F or CH₃, and n is 1.

26. The compound of claim 13, wherein Ring A is selected from 5-azaspiro[2,3]hexyl;

2-azaspiro[3.3]heptyl;

2-oxa-6-azaspiro[3.3]heptyl;

2-azaspiro[3.4]octyl;

5-oxa-2-azaspiro[3.4]octyl;

6-oxa-2-azaspiro[3.4]octyl;

2-azaspiro[3.5]nonyl;

7-oxa-2-azaspiro[3.5]nonyl;

octahydrocyclopenta[c]pyrrolyl;

1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrolyl;

6-azaspiro[3.4]octyl;

2-oxa-6-azaspiro[3.4]octyl;

6-azaspiro[2.5]octyl;

7-azaspiro[3.5]nonyl;

1-oxa-8-azaspiro[4.5]decanyl;

2-oxa-8-azaspiro[4.5]decanyl;

2,8-diazaspiro[4.5]decan-1-onyl;

3-oxa-9-azaspiro[5.5]undecanyl;

1,4-oxazepanyl;

8-azabicyclo[3.2.1]octyl; and

isoindolinyl;

each optionally substituted with one or more CH₃ or F.

27. The compound of claim 1, wherein R is F.

28. The compound of claim 1, wherein R is CH₃.

29. The compound of claim 1, wherein n is 1.

30. The compound of claim 1, wherein the compound is selected from Table 1.

31. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt, tautomer, isotopologue, or stereoisomer thereof, and a pharmaceutically acceptable carrier, excipient or vehicle.

32. A method for the treatment of diffuse large B-cell lymphoma (DLBCL), comprising administering to a subject in need thereof an effective amount of a compound of claim 1.

33-41. -41. (canceled)

42. A method for preparing a compound of formula (I):