Deuterated rigosertib

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

1. A compound of Formula II: ##STR00028## or a pharmaceutically acceptable salt thereof wherein R.sup.1 is CD.sub.3 or CH.sub.3; R.sup.2 is CD.sub.3 or CH.sub.3; R.sup.3 is CD.sub.3, CH.sub.3 or R.sup.2; R.sup.4 is CD.sub.3 or CH.sub.3; each Y.sup.1 is independently hydrogen or deuterium; each Y.sup.2 is independently hydrogen or deuterium; X is hydrogen, C.sub.1-C.sub.7 alkyl, C.sub.2-C.sub.7 alkenyl, C.sub.2-C.sub.7 alkadienyl, C.sub.6-C.sub.10 aryl or 5- to 10-membered heteroaryl, wherein X is optionally substituted with one or more substituents independently selected from halogen, a —OC.sub.1-C.sub.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.sub.1-C.sub.2 alkyl groups, and wherein if X is C.sub.1-C.sub.7 alkyl, one or two carbons of the C.sub.1-C.sub.7 alkyl are optionally replaced with —NR.sup.5, and one carbon of the C.sub.1-C.sub.7 alkyl other than the carbon bonded to the —C(O)O— group of formula II is optionally replaced with oxygen; each R.sup.5 is hydrogen or C.sub.1-C.sub.4 alkyl optionally substituted with R.sup.6; and each R.sup.6 is (C.sub.1-C.sub.4 alkyl)NH; (C.sub.1-C.sub.4 alkyl).sub.2N, wherein the (C.sub.1-C.sub.4) alkyl groups in the (C.sub.1-C.sub.4 alkyl).sub.2N are the same or different; 3- to 10-membered heterocycloalkyl optionally substituted with C.sub.1-C.sub.2 alkyl; or OC.sub.1-C.sub.4 alkyl; provided that if each R′, R.sup.2, R.sup.3, and R.sup.4 are each CH.sub.3 and each Y.sup.1 is hydrogen, then at least one Y.sup.2 is deuterium; wherein any atom not designated as deuterium is present at its natural isotopic abundance, and wherein the deuterium incorporation at each atom designated as deuterium is at least 90%.

2. The compound of claim 1, represented by structural Formula Ha: ##STR00029## or a pharmaceutically acceptable salt thereof.

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

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

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

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

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

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

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

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

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

12. The compound of claim 1, wherein each Y.sup.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 2 wherein X is hydrogen, wherein the compound is selected from any one of the compounds set forth in Table 1 below: TABLE-US-00003 R.sup.1 R.sup.2 R.sup.4 Each Y.sup.1 Each Y.sup.2 CH.sub.3 CH.sub.3 CH.sub.3 H D CH.sub.3 CH.sub.3 CH.sub.3 D H CH.sub.3 CH.sub.3 CH.sub.3 D D CH.sub.3 CH.sub.3 CD.sub.3 H H CH.sub.3 CH.sub.3 CD.sub.3 H D CH.sub.3 CH.sub.3 CD.sub.3 D H CH.sub.3 CH.sub.3 CD.sub.3 D D CH.sub.3 CD.sub.3 CH.sub.3 H H CH.sub.3 CD.sub.3 CH.sub.3 H D CH.sub.3 CD.sub.3 CH.sub.3 D H CH.sub.3 CD.sub.3 CH.sub.3 D D CH.sub.3 CD.sub.3 CD.sub.3 H H CH.sub.3 CD.sub.3 CD.sub.3 H D CH.sub.3 CD.sub.3 CD.sub.3 D H CH.sub.3 CD.sub.3 CD.sub.3 D D CD.sub.3 CH.sub.3 CH.sub.3 H D CD.sub.3 CH.sub.3 CH.sub.3 D H CD.sub.3 CH.sub.3 CH.sub.3 D D CD.sub.3 CH.sub.3 CD.sub.3 H H CD.sub.3 CH.sub.3 CD.sub.3 H D CD.sub.3 CH.sub.3 CD.sub.3 D H CD.sub.3 CH.sub.3 CD.sub.3 D D CD.sub.3 CD.sub.3 CH.sub.3 H H CD.sub.3 CD.sub.3 CH.sub.3 H D CD.sub.3 CD.sub.3 CH.sub.3 D H CD.sub.3 CD.sub.3 CH.sub.3 D D CD.sub.3 CD.sub.3 CD.sub.3 H H CD.sub.3 CD.sub.3 CD.sub.3 H D CD.sub.3 CD.sub.3 CD.sub.3 D H CD.sub.3 CD.sub.3 CD.sub.3 D D or a pharmaceutically acceptable salt thereof.

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

16. The composition of claim 15, additionally comprising a second therapeutic agent selected from gemcitabine, oxaliplatin, and irinotecan, or combinations thereof.

17. A method of treating a disease or condition selected from myelodysplastic syndrome (MDS), solid tumors, ovarian cancer, pancreatic cancer, hepatoma, 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.

18. The method of claim 17, wherein the disease is myelodysplastic syndrome.

19. A compound of Formula I: ##STR00030## or a pharmaceutically acceptable salt thereof wherein R.sup.1 is CD.sub.3 or CH.sub.3; R.sup.2 is CD.sub.3 or CH.sub.3; R.sup.3 is CD.sub.3, CH.sub.3 or R.sup.2; R.sup.4 is CD.sub.3 or CH.sub.3; each Y.sup.1 is independently hydrogen or deuterium; each Y.sup.2 is independently hydrogen or deuterium; W is O or NH; X is hydrogen, C.sub.1-C.sub.7 alkyl, C.sub.2-C.sub.7 alkenyl, C.sub.2-C.sub.7 alkadienyl, C.sub.6-C.sub.10 aryl, 5- to 10-membered heteroaryl, ##STR00031## —CH.sub.2—C(O)OR.sup.12 or —CH(R.sup.11)—C(O)OR.sup.12; wherein if X is other than —CH.sub.2—C(O)OR.sup.12 or —CH(R.sup.11)—C(O)OR.sup.12, X is optionally substituted with one or more substituents independently selected from halogen, a —OC.sub.1-C.sub.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.sub.1-C.sub.2 alkyl groups, and wherein if X is C.sub.1-C.sub.7 alkyl, one or two carbons of the C.sub.1-C.sub.7 alkyl are optionally replaced with —NR.sup.5, and one carbon of the C.sub.1-C.sub.7 alkyl other than the carbon bonded to the —C(O)O— group of formula I is optionally replaced with oxygen; each R.sup.5 is hydrogen or C.sub.1-C.sub.4 alkyl optionally substituted with R.sup.6; and each R.sup.6 is (C.sub.1-C.sub.4 alkyl)NH; (C.sub.1-C.sub.4 alkyl).sub.2N, wherein the (C.sub.1-C.sub.4) alkyl groups in the (C.sub.1-C.sub.4 alkyl).sub.2N are the same or different; 3- to 10-membered heterocycloalkyl optionally substituted with C.sub.1-C.sub.2 alkyl; or OC.sub.1-C.sub.4 alkyl; R.sup.8 is C.sub.1-C.sub.7 alkyl, C.sub.2-C.sub.7 alkenyl, C.sub.2-C.sub.7 alkadienyl, C.sub.6-C.sub.10 aryl, or 5- to 10-membered heteroaryl; R.sup.11 is C.sub.1-6 alkyl, C.sub.2-10 alkoxyalkyl, phenyl, —(C.sub.1-3 alkyl)-(C.sub.3-6 cycloalkyl), or C.sub.3-6 cycloalkyl, wherein R.sup.11 is optionally substituted with C.sub.1-3 alkyl, C.sub.1-3 alkoxy, phenyl, or —O—(CH.sub.2CH.sub.2O).sub.n—CH.sub.3, wherein n is 1, 2, or 3; R.sup.1-2 is hydrogen; —C.sub.1-4 alkyl optionally substituted with phenyl; —(C.sub.3-6 cycloalkyl) optionally substituted with phenyl or methyl; —CH.sub.2—(C.sub.3-6 cycloalkyl) wherein the C.sub.3-6 cycloalkyl is optionally substituted with phenyl; phenyl; or biphenyl; provided that if X is not ##STR00032## and if each R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are each CH.sub.3 and each Y.sup.1 is hydrogen, then at least one Y.sup.2 is deuterium; wherein any atom not designated as deuterium is present at its natural isotopic abundance, and wherein the deuterium incorporation at each atom designated as deuterium is at least 90%.

20. A compound of claim 19, wherein R.sup.2 and R.sup.3 are the same and the compound of Formula I is a compound of Formula Ia: ##STR00033## or a pharmaceutically acceptable salt thereof, wherein X is hydrogen, C.sub.1-C.sub.7 alkyl, C.sub.2-C.sub.7 alkenyl, C.sub.2-C.sub.7 alkadienyl, C.sub.6-C.sub.10 aryl, 5- to 10-membered heteroaryl, —CH.sub.2—C(O)OR.sup.12 or —CH(R.sup.11)—C(O)OR.sup.12; and each of R.sup.1, R.sup.2, R.sup.4, Y.sup.1, Y.sup.2, R.sup.11 and R.sup.12 is as defined above for a compound of Formula I in claim 19.

21. A compound of claim 19, wherein R.sup.2 and R.sup.3 are the same and the compound of Formula I is a compound of Formula Ib: ##STR00034## or a pharmaceutically acceptable salt thereof.

22. A compound of claim 1, wherein the deuterium incorporation at each atom designated as deuterium is at least 95%.

23. A compound of claim 19, wherein the deuterium incorporation at each atom designated as deuterium is at least 95%.

Description

EXAMPLE 1. EVALUATION OF METABOLIC STABILITY

(1) Microsomal Assay:

(2) Human liver microsomes (20 mg/mL) are obtained from Xenotech, LLC (Lenexa, Kans.). β-nicotinamide adenine dinucleotide phosphate, reduced form (NADPH), magnesium chloride (MgCl.sub.2), and dimethyl sulfoxide (DMSO) are purchased from Sigma-Aldrich.

(3) Determination of Metabolic Stability:

(4) 7.5 mM stock solutions of test compounds are prepared in DMSO. The 7.5 mM stock solutions are diluted to 12.5-50 μM in acetonitrile (ACN). The 20 mg/mL human liver microsomes are diluted to 0.625 mg/mL in 0.1 M potassium phosphate buffer, pH 7.4, containing 3 mM MgCl.sub.2. The diluted microsomes are added to wells of a 96-well deep-well polypropylene plate in triplicate. A 10 μL aliquot of the 12.5-50 μM test compound is added to the microsomes and the mixture is pre-warmed for 10 minutes. Reactions are initiated by addition of pre-warmed NADPH solution. The final reaction volume is 0.5 mL and contains 0.5 mg/mL human liver microsomes, 0.25-1.0 μM test compound, and 2 mM NADPH in 0.1 M potassium phosphate buffer, pH 7.4, and 3 mM MgCl.sub.2. The reaction mixtures are incubated at 37° C., and 50 μL aliquots are removed at 0, 5, 10, 20, and 30 minutes and added to shallow-well 96-well plates which contain 50 μL of ice-cold ACN with internal standard to stop the reactions. The plates are stored at 4° C. for 20 minutes after which 100 μL of water is added to the wells of the plate before centrifugation to pellet precipitated proteins. Supernatants are transferred to another 96-well plate and analyzed for amounts of parent remaining by LC-MS/MS using an Applied Bio-systems API 4000 mass spectrometer. The same procedure is followed for the non-deuterated counterpart of the compound of Formula I and the positive control, 7-ethoxycoumarin (1 μM). Testing is done in triplicate.

(5) Data Analysis:

(6) The in vitro t.sub.1/2s for test compounds are calculated from the slopes of the linear regression of % parent remaining (ln) vs incubation time relationship.
in vitro t.sub.1/2=0.693/k
k=−[slope of linear regression of % parent remaining(ln) vs incubation time]

(7) Data analysis is performed using Microsoft Excel Software.

(8) Without further description, it is believed that one of ordinary skill in the art can, using the preceding description and the illustrative examples, make and utilize the compounds of the present invention and practice the claimed methods. It should be understood that the foregoing discussion and examples merely present a detailed description of certain preferred embodiments. It will be apparent to those of ordinary skill in the art that various modifications and equivalents can be made without departing from the spirit and scope of the invention.