IP Library › Granted Patent US 9,249,093

Granted Patent B2

US 9,249,093 · App. 14/395,795 · Granted Feb 2, 2016

Deuterated rigosertib

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Quick Facts

Patent No.: US 9,249,093
App. No.: 14/395,795
Granted: Feb 2, 2016
Kind: B2

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Abstract

This invention relates to novel substituted styryl benzylsulfones that are multikinase inhibitors and pharmaceutically acceptable acid addition salts thereof. The invention also provides compositions comprising a compound of this invention and the use of such compositions in methods of treating diseases and conditions beneficially treated by an agent that inhibits kinases, such as phosphatidylinositol 3-kinase (PI3-K) and polo-like kinase (PLK-1).

Claims (219)

1. A compound of Formula II:

or a pharmaceutically acceptable salt thereof wherein

R 1 is CD 3 or CH 3 ;

R 2 is CD 3 or CH 3 ;

R 3 is CD 3 , CH 3 or R 2 ;

R 4 is CD 3 or CH 3 ;

each Y 1 is independently hydrogen or deuterium;

each Y 2 is independently hydrogen or deuterium;

X is hydrogen, C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2 -C 7 alkadienyl, C 6 -C 10 aryl or 5- to 10-membered heteroaryl, wherein X is optionally substituted with one or more substituents independently selected from halogen, a —OC 1 -C 6 alkyl group, a 5- to 10- membered heteroaryl group and a 3- to 10-membered heterocycloalkyl wherein the heterocycloalkyl group is optionally substituted with one or more C 1 -C 2 alkyl groups, and wherein if X is C 1 -C 7 alkyl, one or two carbons of the C 1 -C 7 alkyl are optionally replaced with —NR 5 , and one carbon of the C 1 -C 7 alkyl other than the carbon bonded to the —C(O)O— group of formula II is optionally replaced with oxygen;

each R 5 is hydrogen or C 1 -C 4 alkyl optionally substituted with R 6 ; and

each R 6 is (C 1 -C 4 alkyl)NH; (C 1 -C 4 alkyl) 2 N, wherein the (C 1 -C 4 ) alkyl groups in the (C 1 -C 4 alkyl) 2 N are the same or different; 3- to 10-membered heterocycloalkyl optionally substituted with C 1 -C 2 alkyl; or OC 1 -C 4 alkyl;

provided that if each R 1 , R 2 , R 3 , and R 4 are each CH 3 and each Y 1 is hydrogen, then at least one Y 2 is deuterium.

2. The compound of claim 1 , represented by structural Formula IIa:

or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 , wherein R 2 is CD 3 .

4. The compound of claim 1 , wherein R 2 is CH 3 .

5. The compound of claim 1 , wherein R 1 is CD 3 .

6. The compound of claim 1 , wherein R 1 is CH 3 .

7. The compound of claim 1 , wherein R 4 is CD 3 .

8. The compound of claim 1 , wherein R 4 is CH 3 .

9. The compound of claim 1 , wherein each Y 1 is deuterium.

10. The compound of claim 1 , wherein each Y 1 is hydrogen.

11. The compound of claim 1 , wherein each Y 2 is deuterium.

12. The compound of claim 1 , wherein each Y 2 is hydrogen.

13. The compound of claim 1 , wherein X is hydrogen and the compound is a carboxylic acid, or a pharmaceutically acceptable salt thereof.

14. The compound of claim 1 , wherein any atom not designated as deuterium is present at its natural isotopic abundance.

15. The compound of claim 2 , wherein X is hydrogen, wherein the compound is selected from any one of the compounds set forth in Table 1 below:

R 1

R 2

R 4

Each Y 1

Each Y 2

CH 3

CD 3

CH 3

CD 3

CH 3

CD 3

CH 3

CD 3

CH 3

CD 3

CH 3

CD 3

CH 3

CD 3

CH 3

CD 3

CH 3

CD 3

CH 3

CD 3

CH 3

CD 3

CH 3

CD 3

CH 3

CD 3

CH 3

CD 3

CH 3

CD 3

CH 3

CD 3

CH 3

CD 3

CH 3

CD 3

CH 3

CD 3

CH 3

CD 3

CH 3

CD 3

CH 3

CD 3

CH 3

CD 3

CH 3

CD 3

or a pharmaceutically acceptable salt thereof, wherein any atom not designated as deuterium is present at its natural isotopic abundance.

16. The compound of claim 15 wherein R 1 is CD 3 and the isotopic enrichment factor for the deuterium atoms of the R 1 CD 3 group is at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), or at least 6333.3 (95% deuterium incorporation); wherein any atom not designated as deuterium is present at its natural isotopic abundance.

17. A pharmaceutical composition comprising a compound of claim 1 , and a pharmaceutically acceptable carrier.

18. The composition of claim 17 , additionally comprising a second therapeutic agent selected from gemcitabine, oxaliplatin, and irinotecan, or combinations thereof.

19. A method of treating a disease or condition selected from myelodysplastic syndrome (MDS), solid tumors, ovarian cancer, pancreatic cancer, hepatoma, ovarian cancer, breast cancer, colon cancer, renal cancer, AML, or lymphocytic leukemia, in a subject, the method comprising the step of administering to the subject the compound of claim 1 .

20. The method of claim 19 , wherein the disease is myelodysplastic syndrome.

21. A compound of Formula I:

or a pharmaceutically acceptable salt thereof wherein

R 1 is CD 3 or CD 3 ;

R 2 is CD 3 or CH 3 ;

R 3 is CD 3 , CH 3 or R 2 ;

R 4 is CD 3 or CH 3 ;

each Y 1 is independently hydrogen or deuterium;

each Y 2 is independently hydrogen or deuterium;

W is O or NH;

X is hydrogen, C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2 -C 7 alkadienyl, C 6 -C 10 aryl, 5- to 10-membered heteroaryl,

—CH 2 —C(O)OR 12 or —CH(R 11 )—C(O)OR 12 ;

wherein if X is other than —CH 2 —C(O)OR 12 or —CH(R 11 )—C(O)OR 12 , X is optionally substituted with one or more substituents independently selected from halogen, a —OC 1 -C 6 alkyl group, a 5- to 10-membered heteroaryl group and a 3- to 10-membered heterocycloalkyl wherein the heterocycloalkyl group is optionally substituted with one or more C 1 -C 2 alkyl groups, and wherein if X is C 1 -C 7 alkyl, one or two carbons of the C 1 -C 7 alkyl are optionally replaced with —NR 5 , and one carbon of the C 1 -C 7 alkyl other than the carbon bonded to the —C(O)O— group of formula I is optionally replaced with oxygen;

each R 5 is hydrogen or C 1 -C 4 alkyl optionally substituted with R 6 ; and

R 8 is C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2 -C 7 alkadienyl, C 6 -C 10 aryl, or 5- to 10-membered heteroaryl; R 11 is C 1-6 alkyl, C 2-10 alkoxyalkyl, phenyl, —(C 1-3 alkyl)-(C 3-6 cycloalkyl),

or C 3-6 cycloalkyl, wherein R 11 is optionally substituted with C 1-3 alkyl, C 1-3 alkoxy, phenyl, or —O—(CH 2 CH 2 O) n —CH 3 , wherein n is 1, 2, or 3;

R 12 is hydrogen; —C 1-4 alkyl optionally substituted with phenyl; —(C 3-6 cycloalkyl) optionally substituted with phenyl or methyl; —CH 2 —(C 3-6 cycloalkyl) wherein the C 3-6 cycloalkyl is optionally substituted with phenyl; phenyl; or biphenyl;

provided that if X is not

and if each R 1 , R 2 , R 3 , and R 4 are each CH 3 and each Y 1 is hydrogen, then at least one Y 2 is deuterium.

22. A compound of claim 21 , wherein R 2 and R 3 are the same and the compound of Formula I is a compound of Formula Ia:

or a pharmaceutically acceptable salt thereof,

wherein

X is hydrogen, C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2 -C 7 alkadienyl, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, —CH 2 —C(O)OR 12 or —CH(R 11 )—C(O)OR 12 ; and

each of R 1 , R 2 , R 4 , Y 1 , Y 2 , R 11 and R 12 is as defined above for a compound of Formula I in claim 21 .

23. A compound of claim 21 , wherein R 2 and R 3 are the same and the compound of Formula I is a compound of Formula Ib:

or a pharmaceutically acceptable salt thereof.

Assignments (2)

MERGER Recorded Aug 8, 2023

From: CONCERT PHARMACEUTICALS, INC.

To: SUN PHARMACEUTICAL INDUSTRIES, INC.

Reel/Frame 064523/0014 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Sep 29, 2015

From: TUNG, ROGER D.

To: CONCERT PHARMACEUTICALS, INC.

Reel/Frame 036677/0680 →