Building IP: CELG Patent Grant re "SUBSTITUTED 1-OXO-ISOINDOLINE-5-CARBOXAMIDE COMPOUNDS, COMPOSITIO | BMY Message Board Posts


Bristol-Myers Squibb Co.

  BMY website

BMY   /  Message Board  /  Read Message

 

 






Keyword
Subject
Between
and
Rec'd By
Authored By
Minimum Recs
  
Previous Message  Next Message    Post Message    Post a Reply return to message boardtop of board
Msg  5216 of 10557  at  12/3/2020 12:54:10 AM  by

JBWIN


Building IP: CELG Patent Grant re "SUBSTITUTED 1-OXO-ISOINDOLINE-5-CARBOXAMIDE COMPOUNDS, COMPOSITIONS THEREOF, AND METHODS OF TREATMENT THEREWITH"

 
United States Patent Application20200377512
Kind CodeA1
Baculi; Frans ; et al.December 3, 2020

SUBSTITUTED 1-OXO-ISOINDOLINE-5-CARBOXAMIDE COMPOUNDS, COMPOSITIONS THEREOF, AND METHODS OF TREATMENT THEREWITH

Abstract

Provided herein are 1-oxo-isoindoline-5-carboxamide compounds having the following structure: ##STR00001## wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4 and n are as defined herein, compositions comprising an effective amount of a 1-oxo-isoindoline-5-carboxamide compound, and methods for treating or preventing disorders.


Inventors:Baculi; Frans; (San Diego, CA) ; Northcote; Katherine; (San Diego, CA) ; Correa; Matthew D.; (San Diego, CA) ; Hansen; Joshua; (La Jolla, CA) ; Lebrun; Laurie A.; (San Diego, CA) ; Lu; Chin-Chun; (San Diego, CA) ; Lu; Gang; (San Diego, CA) ; Nagy; Mark A.; (San Diego, CA) ; Peng; Sophie; (San Diego, CA) ; Perrin-Ninkovic; Sophie; (La Jolla, CA)
Applicant:
NameCityStateCountryType

Celgene Corporation

Summit

NJ

US
Family ID:1000004900227
Appl. No.:16/887766
Filed:May 29, 2020

Related U.S. Patent Documents

Application NumberFiling DatePatent Number
62855619May 31, 2019

Current U.S. Class:1/1
Current CPC Class:C07D 405/14 20130101; C07D 491/107 20130101; C07D 401/04 20130101; C07D 413/14 20130101; A61P 35/02 20180101; C07D 401/14 20130101
International Class:C07D 491/107 20060101 C07D491/107; C07D 401/04 20060101 C07D401/04; C07D 401/14 20060101 C07D401/14; C07D 405/14 20060101 C07D405/14; C07D 413/14 20060101 C07D413/14; A61P 35/02 20060101 A61P035/02

Claims



1. A compound of Formula (I) ##STR00274## or a pharmaceutically acceptable salt, tautomer, isotopolog, or stereoisomer thereof, wherein: R.sup.1 is C.sub.1-3 alkyl, or C.sub.1-3 fluoroalkyl; R.sup.2 is substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.3-10 cycloalkyl, substituted or unsubstituted 3-6-membered heterocyclyl, substituted or unsubstituted C.sub.6-10 aryl, or substituted or unsubstituted 5-10-membered heteroaryl; R.sup.3 is H; R.sup.4 is halogen; and n is 0-3.

2. The compound of claim 1, wherein the compound is a compound of Formula (II) ##STR00275## or a pharmaceutically acceptable salt, tautomer, isotopolog, or stereoisomer thereof.

3. The compound of claim 1, wherein the compound is a compound of Formula (III) ##STR00276## or a pharmaceutically acceptable salt, tautomer, isotopolog, or stereoisomer thereof.

4. The compound of claim 1, wherein the compound is a compound of Formula (IV) ##STR00277## or a pharmaceutically acceptable salt, tautomer, isotopolog, or stereoisomer thereof.

5. The compound of claim 1, wherein the compound is a compound of Formula (V) ##STR00278## or a pharmaceutically acceptable salt, tautomer, isotopolog, or stereoisomer thereof.

6. The compound of claim 1, wherein the compound is a compound of Formula (VI) ##STR00279## or a pharmaceutically acceptable salt, tautomer, isotopolog, or stereoisomer thereof.

7. The compound of claim 1, wherein the compound is a compound of Formula (VII) ##STR00280## or a pharmaceutically acceptable salt, tautomer, isotopolog, or stereoisomer thereof.

8. The compound of claim 1, wherein the compound is a compound of Formula (VIII) ##STR00281## or a pharmaceutically acceptable salt, tautomer, isotopolog, or stereoisomer thereof.

9. The compound of claim 1, wherein the compound is a compound of Formula (IX) ##STR00282## or a pharmaceutically acceptable salt, tautomer, isotopolog, or stereoisomer thereof.

10. The compound of claim 1, wherein the compound is a compound of Formula (X) ##STR00283## or a pharmaceutically acceptable salt, tautomer, isotopolog, or stereoisomer thereof.

11. The compound of claim 1, wherein the compound is a compound of Formula (XI) ##STR00284## or a pharmaceutically acceptable salt, tautomer, isotopolog, or stereoisomer thereof.

12. The compound of claim 1, wherein R is methyl, ethyl, n-propyl, isopropyl, CH.sub.2F, CHF.sub.2, CF.sub.3, CH.sub.2CH.sub.2F, CH.sub.2CHF.sub.2, CH.sub.2CF.sub.3, CHFCH.sub.3, CF.sub.2CH.sub.3, or CF.sub.2CF.sub.3.

13. The compound of claim 1, wherein R.sup.1 is methyl, ethyl, isopropyl, CHF.sub.2, CF.sub.3, CH.sub.2CF.sub.3, or CF.sub.2CH.sub.3.

14. The compound of claim 1, wherein R.sup.2 is substituted with one or more substituents selected from halogen, CN, OR', substituted or unsubstituted C.sub.1-3 alkyl, and substituted or unsubstituted --(C.sub.0-3 alkyl)(3-6 membered heterocyclyl); wherein each R' is independently selected from H, substituted or unsubstituted C.sub.1-3 alkyl, substituted or unsubstituted C.sub.3-6 cycloalkyl, and phenyl.

15. The compound of claim 1, wherein R.sup.2 is substituted with one or more substituents selected from F, Cl, Br, CN, OH, OCH.sub.3, OCF.sub.3, OCH.sub.2CH.sub.3, O-n-propyl, O-isopropyl, O-n-butyl, O-sec-butyl, O-tert-butyl, O-cyclopropyl, O-cyclobutyl, O-phenyl, CH.sub.3, CH.sub.2CH.sub.3, CF.sub.3, CH.sub.2CF.sub.3, CH.sub.2NHCH.sub.3, CH.sub.2N(CH.sub.3).sub.2, and a --(C.sub.0-3 alkyl)(3-6 membered heterocyclyl) selected from piperidyl, piperazinyl, morpholino, CH.sub.2-aziridyl, CH.sub.2-pyrrolidyl, CH.sub.2-piperazinyl, CH.sub.2-piperidyl, CH.sub.2-morpholinyl, and CH.sub.2(2-oxa-6-azaspiro[3.3]heptyl), wherein the --(C.sub.0-3 alkyl)(3-6 membered heterocyclyl) is optionally substituted with one or more F, Cl or CH.sub.3.

16. The compound of claim 1, wherein R.sup.2 is substituted with one or more substituents selected from F, Cl, CN, OH, OCH.sub.3, OCF.sub.3, O-isopropyl, O-cyclopropyl, O-phenyl, CH.sub.3, CF.sub.3, CH.sub.2CF.sub.3, CH.sub.2N(CH.sub.3).sub.2, and a --(C.sub.0-3 alkyl)(3-6 membered heterocyclyl) selected from morpholino, piperazinyl, CH.sub.2-aziridyl, CH.sub.2-pyrrolidyl, CH.sub.2-piperazinyl, CH.sub.2-morpholinyl, and CH.sub.2(2-oxa-6-azaspiro[3.3]heptyl), wherein the --(C.sub.0-3 alkyl)(3-6 membered heterocyclyl) is optionally substituted with one or more F or CH.sub.3.

17. The compound of claim 1, wherein R.sup.2 is C.sub.1-6 alkyl, unsubstituted or substituted with one or more substituents independently selected from halogen, CN, and OR'; C.sub.3-10 cycloalkyl, unsubstituted, or substituted with one or more substitutents independently selected from halogen, OR', and substituted or unsubstituted C.sub.1-3 alkyl; 3-6-membered heterocyclyl, unsubstituted, or substituted with one or more substituted or unsubstituted C.sub.1-3 alkyl; C.sub.6-10 aryl, unsubstituted or substituted with one or more substituents independently selected from halogen, CN, OR', substituted or unsubstituted C.sub.1-3 alkyl, and substituted or unsubstituted --(C.sub.0-3 alkyl)(3-6 membered heterocyclyl); or 5-10-membered heteroaryl unsubstituted or substituted with one or more substituents independently selected from halogen, OR', and substituted or unsubstituted C.sub.1-3 alkyl; wherein each R' is independently selected from H, substituted or unsubstituted C.sub.1-3 alkyl, substituted or unsubstituted C.sub.3-6 cycloalkyl, and phenyl.

18. The compound of claim 1, wherein R.sup.2 is C.sub.1-6 alkyl, unsubstituted or substituted with one or more substituents independently selected from F, CN, and OH.

19. The compound of claim 18, wherein R.sup.2 is CH.sub.3, isopropyl, ter-butyl, C(CH.sub.3).sub.2CH.sub.2OH, C(CH.sub.3).sub.2CN, or C(CH.sub.3).sub.2CF.sub.3.

20. The compound of claim 1, wherein R.sup.2 is C.sub.3-10 cycloalkyl, unsubstituted, or substituted with one or more substitutents independently selected from F, OH, CH.sub.3, C(CH.sub.3).sub.2OH, and CF.sub.3.

21. The compound of claim 20 wherein R.sup.2 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, spiro[3.5]nonyl, bicyclo[1.1.1]pentyl, or spiro[2.5]octyl.

22. The compound of claim 1, wherein R.sup.2 is 3-6-membered heterocyclyl, unsubstituted, or substituted with one or more CH.sub.3, and CH.sub.2CF.sub.3.

23. The compound of claim 22, wherein R.sup.2 is oxetanyl, tetrahydropyranyl or piperidyl.

24. The compound of claim 1, wherein R.sup.2 is C.sub.6-10 aryl, unsubstituted or substituted with one or more substituents independently selected from F, Cl, CN, OH, OCH.sub.3, OCF.sub.3, O-isopropyl, O-cyclopropyl, O-phenyl, CH.sub.3, CF.sub.3, and CH.sub.2N(CH.sub.3).sub.2; and --(C.sub.0-3 alkyl)(3-6 membered heterocyclyl) selected from piperazinyl, morpholino, CH.sub.2-aziridyl, CH.sub.2-pyrrolidyl, CH.sub.2-piperazinyl, CH.sub.2-morpholinyl, and CH.sub.2(2-oxa-6-azaspiro[3.3]heptyl), wherein the --(C.sub.0-3 alkyl)(3-6 membered heterocyclyl) is optionally substituted with one or more F, or CH.sub.3.

25. The compound of claim 24, wherein R.sup.2 is phenyl.

26. The compound of claim 1, wherein R.sup.2 is 5-10-membered heteroaryl, unsubstituted or substituted with one or more substituents independently selected from F, Cl, OCH.sub.3, CH.sub.3, CF.sub.3, and CH.sub.2N(CH.sub.3).sub.2.

27. The compound of claim 1, wherein R.sup.2 is pyrazolyl, pyridyl, pyrazinyl, or pyrimidyl.

28. The compound of claim 1, wherein R.sup.4 is F or Cl.

29. The compound of claim 1, wherein n is 0, 1 or 2.

30. A compound from Table 1 or a pharmaceutically acceptable salt, tautomer, isotopolog, or stereoisomer thereof.

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

32. A method for treating or preventing acute myeloid leukemia, the method comprising administering to a subject in need thereof an effective amount of a compound of claim 1.

33. A method for treating or preventing acute myeloid leukemia, the method comprising administering to a subject in need thereof an effective amount of the pharmaceutical composition of claim 31.

34. The method of claim 32, wherein the acute myeloid leukemia is newly diagnosed acute myeloid leukemia.

35. The method of claim 34, wherein the acute myeloid leukemia is relapsed, refractory or resistant to conventional therapy.

36. A method for reducing CK1.alpha. protein levels, the method comprising contacting a cell with an effective amount of a compound of claim 1.

37. The method of claim 36, wherein the cell is in a subject.

38. A method for reducing CK1.alpha. protein levels in a cell ex vivo or in vitro, the method comprising contacting a cell with an effective amount of a compound of claim 1.
Description



RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application No. 62/855,619, filed May 31, 2019, the disclosure of which is incorporated herein by reference in its entirety.

FIELD

[0002] Provided herein are certain 1-oxo-isoindoline-5-carboxamide compounds, compositions comprising an effective amount of such compounds, and methods for treating or preventing acute myeloid leukemia (AML), comprising administering an effective amount of such 1-oxo-isoindoline-5-carboxamide compounds to a subject in need thereof. Further provided herein are such 1-oxo-isoindoline-5-carboxamide compounds and compositions comprising an effective amount of such compounds for use in said methods.

BACKGROUND

[0003] Acute myeloid leukemia is the most commonly reported type of acute leukemia in adults in the United States (US). Based on the American Cancer Society's estimates, approximately 20,830 people will be diagnosed with AML in 2015 in the US and 10,460 patients will die from the disease (American Cancer Society. Cancer Facts & Figures 2015. Atlanta, Ga.: American Cancer Society; 2015). The median age at diagnosis is approximately 67 years.

[0004] Acute myeloid leukemia can arise de novo, be secondary to previous cytotoxic chemotherapy, or arise through transformation of existing myelodysplasia. Therapy-related AML arising from exposure to environmental toxins, cytotoxic drugs, or radiation currently accounts for about 5% to 10% of all cases of AML (Leone et al, Haematologica 1999; 84(10):937-945). It is estimated that 35% to 40% of patients with myelodysplastic syndromes will go on to develop AML, with the disease often refractory to current therapy (Silverman et al, Cancer Medicine. 5th ed. Hamilton, Canada: BC Decker; 2000. p. 1931-1946). Preexisting myelodysplastic or myeloproliferative disorders are common in older patients with AML, occurring in 24% to 40% of cases (Gajewski et al, J Clin Oncol 1989; 7:1637-1645). Patients with secondary AML due to prior hematologic disease have a lesser response to therapy than those with de novo disease.

[0005] The usual treatment of AML is divided into two phases: induction of remission and consolidation therapy. For more than 30 years, the combination of cytarabine and an anthracycline has been the mainstay of treatments to induce remission (Lowenberg et al, N Engl J Med 1999; 341:1051-1062; Tallman, Hematology Am Soc Hematol Educ Program 2005:143-150). The remission induction therapy in leukemia is designed to produce the rapid restoration of normal bone marrow function. A common induction regimen consists of cytarabine, 7 days combined with daunorubicin for 3 days, often referred to as the "7+3 protocol." With the combination of cytarabine and daunorubicin or their analogues, a CR, conventionally defined morphologically by the presence of <5% blasts in the bone marrow together with the recovery of peripheral-blood absolute neutrophil and platelet counts, can be achieved in up to 70% to 80% of adults with de novo AML who are <60 years of age (Lowenberg et al, N Engl J Med 1999; 341:1051-1062; Tallman, Hematology Am Soc Hematol Educ Program 2005:143-150). If CR is achieved, there are 3 basic treatment choices for post-remission therapy: additional chemotherapy, stem cell transplantation from a donor (allogeneic stem cell transplantation), or stem cell transplantation using the patient's own stem cells (autologous stem cell transplantation). For post-remission chemotherapy, the same chemotherapy regimen used for remission induction or a higher dose regimen of cytarabine is often repeated for one or more cycles, referred to as consolidation chemotherapy. When several courses of consolidation are given, survival rates at 2-3 years are 35% to 50% for young to middle-age adults who have achieved CR (Milligan et al, B J Hem 2006; 135:450-474). However, consolidation or post-remission chemotherapy for elderly patients with AML has not been proven beneficial.

[0006] Given the poor overall outcome and high treatment-related mortality in older AML patients, some physicians do not pursue aggressive induction therapy, opting for less aggressive therapies. Treatment options are few for patients who choose not to receive intensive chemotherapy or are considered ineligible (unfit) to receive intensive chemotherapy by their physician. Treatment options for these patients include low-intensity therapies such as low-dose cytarabine or supportive care only.

[0007] Due to the extensive work involving the sequencing of AML patient samples, mutational profiles associated with AML have been uncovered, which has led to routine comprehensive sequencing in clinical care and the development of targeted therapies (Pollyea, Hematology 2018; 45-50, 2018; Michaelis, Hematology 2018; 51-62). Recently, several new treatments for AML have received FDA approval. In 2017, the FDA approved enasidenib (Idhifa.RTM.) for the treatment of relapsed/refractory AML with an IDH2 mutation. In 2018, the FDA approved ivosidenib (Tibsovo.RTM.), for the treatment of relapsed/refractory AML with an IDH1 mutation. In 2018, the FDA approved gilteritinib (Xospata.RTM.) for treating patients whose AML tests positive for a FLT3 gene mutation, as well as glasdegib (Daurismo.TM.) and venetoclax (Venclexta.RTM.) for treating patients with newly diagnosed AML who are age 75 or older, or who have chronic health conditions or diseases that prevent them being treated with the standard intensive chemotherapy. All are targeted therapies and, except for gilteritinib, are indicated to be used in combination treatments (glasdegib with low dose cytarabine, and venetoclax with azacitidine or decitabine or low-dose cytarabine). Despite these recent advances, the majority of patients treated with these agents will relapse or be refractory.

[0008] Casein kinase-1.alpha. (CK1.alpha.), also named Csnk1a1, is a serine-threonine kinase, and is a central regulator of multiple pathways that are critical for normal and malignant stem cell biology, including the .beta. catenin and p53 pathways (Liu et al., Cell 2002; 108:837-847; Wang et al., Science 2010; 327:1650-1653; Zhao et al., Genes Dev. 2010; 24:1389-1402; Elyada et al., Nature 2011; 470:409-413; Luis et al., Cell Stem Cell 2011; 9:345-356). Additionally, CK1.alpha. has been shown to play a critical role in the biology of AML (Jaras M et al, J Exp Med. 2014; 211(4):605-612). CK1.alpha. inhibitors have been reported, however, none have been approved for the treatment of AML.

[0009] There remains a significant need for safe and effective methods of treating, preventing and managing AML, particularly for AML that is refractory to standard treatments, such as surgery, radiation therapy, chemotherapy and biological therapy, while reducing or avoiding the toxicities and/or side effects associated with conventional therapies.

[0010] Citation or identification of any reference in this section of this application is not to be construed as an admission that the reference is prior art to the present application.

SUMMARY

[0011] Provided herein are compounds having the following formula (I):

##STR00002##

[0012] or a pharmaceutically acceptable salt, tautomer, isotopolog, or stereoisomer thereof, wherein R.sup.1, R.sup.2, R.sup.3 R.sup.4, and n are as defined herein.

[0013] A compound of formula (I) or a pharmaceutically acceptable salt, tautomer, isotopolog, or stereoisomer thereof (each being referred to herein as an "Isoindolinone Carboxamide Compound") is useful for reducing CK1.alpha. protein levels and for treating or preventing AML.

[0014] In one aspect, provided herein are Isoindolinone Carboxamide Compounds as described in the instant disclosure, such as, for example, in Table 1 or a pharmaceutically acceptable salt, tautomer, isotopolog, and stereoisomer thereof. In one aspect, provided herein are Isoindolinone Carboxamide Compounds as described in Table 1 or a pharmaceutically acceptable salt thereof. In one aspect, provided herein are Isoindolinone Carboxamide Compounds as described in Table 1.

[0015] In one aspect, provided herein are pharmaceutical compositions comprising an effective amount of an Isoindolinone Carboxamide Compound as described herein, and a pharmaceutically acceptable carrier, excipient or vehicle. In some embodiments the pharmaceutical composition is suitable for oral, parenteral, mucosal, transdermal or topical administration.

[0016] In one aspect, provided herein are methods for treating or preventing AML, comprising administering to a subject in need thereof an effective amount of an Isoindolinone Carboxamide Compound as described herein; and a pharmaceutically acceptable carrier, excipient or vehicle. In one aspect, provided herein are methods for reducing CK1.alpha. protein levels, comprising administering to a subject in need thereof an effective amount of an Isoindolinone Carboxamide Compound as described herein; and a pharmaceutically acceptable carrier, excipient or vehicle. In another aspect, provided herein are Isoindolinone Carboxamide Compounds for use in the treatment of AML. In another aspect, provided herein are Isoindolinone Carboxamide Compounds for use in reducing CK1.alpha. protein levels.

[0017] In another aspect provided herein are methods for preparing Isoindolinone Carboxamide Compounds as described herein.

[0018] The present embodiments can be understood more fully by reference to the detailed description and examples, which are intended to exemplify non-limiting embodiments.


     e-mail to a friend      printer-friendly     add to library      
|  
Recs: 1  
   Views: 0 []
Previous Message  Next Message    Post Message    Post a Reply return to message boardtop of board




Financial Market Data provided by
.
Loading...