U.S. patent application number 17/368582 was filed with the patent office on 2022-03-17 for solid forms of a compound for modulating kinases.
The applicant listed for this patent is Plexxikon Inc.. Invention is credited to Prabha N. Ibrahim, Marika Nespi, Rashmin Patel, Ben Powell, Hamid Rezaei.
Application Number | 20220081436 17/368582 |
Document ID | / |
Family ID | |
Filed Date | 2022-03-17 |
United States Patent
Application |
20220081436 |
Kind Code |
A1 |
Ibrahim; Prabha N. ; et
al. |
March 17, 2022 |
SOLID FORMS OF A COMPOUND FOR MODULATING KINASES
Abstract
Forms of
4-(6-(3,5-dimethylisoxazol-4-yl)-1-[(1S)-1-(2-pyridyl)ethyl]pyrr-
olo[3,2-b]pyridin-3-yl)benzoic acid (Compound I) were prepared and
characterized in the solid state: ##STR00001## Also provided are
processes of manufacture and methods of using the forms of Compound
I.
Inventors: |
Ibrahim; Prabha N.;
(Mountain View, CA) ; Rezaei; Hamid; (Berkeley,
CA) ; Nespi; Marika; (Berkeley, CA) ; Powell;
Ben; (Pleasant Hill, CA) ; Patel; Rashmin;
(Fremont, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Plexxikon Inc. |
South San Francisco |
CA |
US |
|
|
Appl. No.: |
17/368582 |
Filed: |
July 6, 2021 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16894683 |
Jun 5, 2020 |
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17368582 |
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16158107 |
Oct 11, 2018 |
10717735 |
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16894683 |
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62572099 |
Oct 13, 2017 |
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International
Class: |
C07D 471/04 20060101
C07D471/04; A61P 35/00 20060101 A61P035/00; A61K 31/437 20060101
A61K031/437; A61K 31/496 20060101 A61K031/496; A61K 31/519 20060101
A61K031/519; A61K 31/5377 20060101 A61K031/5377; A61K 45/06
20060101 A61K045/06 |
Claims
1. A crystalline form of Compound I: ##STR00005## characterized by
an X-ray powder diffractogram comprising peaks (.+-.0.2.degree.) at
17.1, 19.4, and 23.5 .degree.2.theta. as determined on a
diffractometer using Cu-K.alpha. radiation.
2. The crystalline form of Compound I according to claim 1, wherein
the diffractogram further comprises one or more peaks
(.+-.0.2.degree.) at 6.7, 9.7, 10.3, 12.1, 12.5, 15.8, 19.0, and
21.4 .degree.2.theta. as determined on a diffractometer using Cu-Ka
radiation.
3. The crystalline form of Compound I according to claim 1, further
characterized by a differential scanning calorimetry (DSC)
thermogram comprising an endotherm with a peak maximum at about
238.0.degree. C.
4. The crystalline form of Compound I according to claim 1,
comprising an X-ray powder diffractogram substantially as shown in
FIG. 1.
5. The crystalline form of Compound I according to claim 1,
comprising a thermogram substantially as shown in FIG. 2.
6. A pharmaceutical composition comprising one or more
pharmaceutically acceptable carriers, and the crystalline form of
Compound I according to claim 1.
7. A method for treating a subject suffering from, or at risk of, a
disease or condition mediated by a bromodomain, the method
comprising administering to the subject in need thereof an
effective amount of the crystalline form of Compound I according to
claim 1, wherein the disease or condition is myelodysplastic
syndromes (MDS), rheumatoid arthritis, uveal melanoma, chronic
lymphocytic leukemia, acute myeloid leukemia, synovial sarcoma,
osteoarthritis, acute gout, psoriasis, systemic lupus
erythematosus, multiple sclerosis, inflammatory bowel disease
(Crohn's disease and Ulcerative colitis), asthma, chronic
obstructive airways disease, pneumonitis, myocarditis,
pericarditis, myositis, eczema, dermatitis, alopecia, vitiligo,
bullous skin diseases, nephritis, vasculitis, atherosclerosis,
Alzheimer's disease, depression, retinitis, uveitis, scleritis,
hepatitis, pancreatitis, primary biliary cirrhosis, sclerosing
cholangitis, Addison's disease, hypophysitis, thyroiditis, type I
diabetes, or acute rejection of transplanted organs.
8. A method of treating chronic lymphocytic leukemia (CLL) or
Richter's Syndrome in a subject in need thereof by administering to
the subject an effective amount of the crystalline form of Compound
I according to claim 1, in combination with an effective amount of
a Bruton's Tyrosine Kinase (BTK) inhibitor.
9. The method of claim 8, wherein the BTK inhibitor is
ibrutinib.
10. A method of treating chronic lymphocytic leukemia (CLL) in a
subject in need thereof by administering to the subject an
effective amount of the crystalline form of Compound I according to
claim 1, in combination with an effective amount of a B-cell
lymphoma 2 (BCL-2) inhibitor.
11. The method of claim 10, wherein the BCL-2 inhibitor is
venetoclax.
12. A method of treating uveal melanoma in a subject in need
thereof by administering to the subject an effective amount of the
crystalline form of Compound I according to claim 1, in combination
with an effective amount of a CTLA-4 inhibitor or a checkpoint
inhibitor.
13. A method of treating acute myeloid leukemia in a subject in
need thereof by administering to the subject an effective amount of
the crystalline form of Compound I according to claim 1, in
combination with an effective amount of quizartinib.
14. A method of treating acute myeloid leukemia in a subject in
need thereof by administering to the subject an effective amount of
the crystalline form of Compound I according to claim 1, in
combination with an effective amount of azacitidine.
15. A method of treating myelodysplastic syndromes (MDS) in a
subject in need thereof by administering to the subject an
effective amount of the crystalline form of Compound I according to
claim 1, in combination with an effective amount of azacitidine.
Description
CROSS-REFERENCE TO RELATED PATENT APPLICATIONS
[0001] This application is a continuation of U.S. application Ser.
No. 16/894,683, filed Jun. 5, 2020, which is a divisional of U.S.
application Ser. No. 16/158,107, filed Oct. 11, 2018, which claims
the benefit under 35 U.S.C. .sctn. 119(e) of U.S. Provisional
Application 62/572,099, filed Oct. 13, 2017, each which is hereby
incorporated by reference in its entirety.
FIELD
[0002] The present disclosure relates generally to solid forms of
compounds that modulate or inhibit the activity of bromodomain
proteins, pharmaceutical compositions thereof, therapeutic uses
thereof, and processes for making the solid forms. The present
disclosure also provides embodiments directed to methods of
treating myelodysplastic syndromes (MDS) or acute myeloid leukemia
(AML) in a subject in need thereof by administering to the subject
an effective amount of any one of the solid forms of Compound I in
combination with an effective amount of a hypomethylating agent
(HMA).
BACKGROUND
[0003] There remains a need to develop effective treatments for
subjects suffering from or at risk of protein kinase mediated
disease or condition. Suitable compounds, including Compound I, for
the treatment of such diseases and conditions are disclosed in U.S.
Patent Publication No. 2015/0133400, the disclosure of which is
hereby incorporated by reference in its entirety.
[0004] There also remains a need for high purity solid forms of
Compound I that are efficacious for the treatment of diseases
modulated by bromodomain proteins.
SUMMARY
[0005] The present disclosure provides solid forms of Compound I of
the formula:
##STR00002##
and salts, co-crystals, solvates, and hydrates thereof. Also
described herein are processes for making the forms of Compound I,
pharmaceutical compositions comprising solid forms of Compound I,
and methods for using such forms and pharmaceutical compositions in
the treatment of diseases mediated by bromodomain proteins.
[0006] Accordingly, the present disclosure provides, in one
embodiment, a free acid amorphous form of Compound I.
[0007] In some embodiments, the free acid amorphous form of
Compound I is characterized by an X-ray powder diffractogram as
substantially shown in FIG. 18.
[0008] In some embodiments, the free acid amorphous form of
Compound I is characterized by a thermogravimetric analysis (TGA)
thermogram showing a weight loss of about 17% up to about
250.degree. C. In some embodiments, the free acid amorphous form of
Compound I is characterized by the TGA thermogram as substantially
shown in FIG. 19.
[0009] In some embodiments, the free acid amorphous form of
Compound I is characterized by a differential scanning calorimetry
(DSC) curve that comprises an exotherm with a peak maximum at about
237.degree. C. In some embodiments, the free acid amorphous form of
Compound I according to claim 5 characterized by the DSC curve as
substantially shown in FIG. 20.
[0010] In some embodiments, the free acid amorphous form of
Compound I is a free acid amorphous salt form of Compound I
molecularly dispersed in polymer matrix. In some embodiments, the
polymer matrix comprises hypromellose acetate succinate,
hydroxypropyl methylcellulose phthalate, Eudragit.RTM., or
combinations thereof.
[0011] The present disclosure provides, in one embodiment, a
crystalline form of Compound I.
[0012] In some embodiments, the crystalline form of Compound I is
Compound I Form A characterized by an X-ray powder diffractogram
comprising peaks (.+-.0.2.degree.) at 17.1, 19.4, and 23.5
.degree.2.theta. as determined on a diffractometer using
Cu-K.alpha. radiation. In some embodiments, Compound I Form A is
further characterized by one or more of the following:
[0013] i) one or more peaks at 6.7, 9.7, 10.3, 12.1, 12.5, 15.8,
19.0, and 21.4 .degree.2.theta..+-.0.2.degree.; and
[0014] ii) a differential scanning calorimetry (DSC) thermogram
comprising an endotherm with a peak maximum at about 238.0.degree.
C.
[0015] In some embodiments, the crystalline form of Compound I is
Compound I Form B characterized by an X-ray powder diffractogram
comprising peaks (.+-.0.2.degree.) at 16.8, 17.4, and 21.1
.degree.2.theta..+-.0.2 .degree.2.theta. as determined on a
diffractometer using Cu-K.alpha. radiation. In some embodiments,
Compound I Form B is further characterized by one or more of the
following:
[0016] i) one or more peaks at 13.7, 14.0, 14.2, 15.7, 19.7, 22.4,
23.2, and 24.6 .degree.2.theta..+-.0.2.degree.; and
[0017] ii) a differential scanning calorimetry (DSC) thermogram
comprising an endotherm with a peak maximum at about 277.degree.
C.
[0018] In some embodiments, the crystalline form of Compound I is
Compound I Form C characterized by an X-ray powder diffractogram
comprising peaks (.+-.0.2.degree.) at 13.7, 14.6, and 22.6
.degree.2.theta. as determined on a diffractometer using
Cu-K.alpha. radiation. In some embodiments, Compound I Form C is
further characterized by one or more of the following:
[0019] i) one or more peaks at 10.0, 11.2, 12.4, 13.7, 14.6, 15.6,
18.6, 20.2, 21.3, 21.9, 22.6, and 23.8
.degree.2.theta..+-.0.2.degree.; and
[0020] ii) a differential scanning calorimetry (DSC) thermogram
comprising an endotherm with a peak maximum at about 235.degree.
C.
[0021] In some embodiments, the crystalline form of Compound I is
Compound I Form D characterized by an X-ray powder diffractogram
comprising peaks (.+-.0.2.degree.) at 3.5, 18.0, and 19.1
.degree.2.theta. as determined on a diffractometer using
Cu-K.alpha. radiation. In some embodiments, Compound I Form D is
further characterized by one or more of the following:
[0022] i) peaks at 7.0, 10.8, 11.4, 13.1, 15.5, 17.4, 17.5, 18.5,
19.7, and 21.2 .degree.2.theta..+-.0.2.degree.; and
[0023] ii) a differential scanning calorimetry (DSC) thermogram
comprising an endotherm with a peak maximum at about 235.0.degree.
C.
[0024] The present disclosure provides, in one embodiment, a
pharmaceutical composition comprising one or more pharmaceutically
acceptable carriers, and a free acid amorphous form of Compound I
as described herein.
[0025] The present disclosure provides, in one embodiment, a
pharmaceutical composition comprising one or more pharmaceutically
acceptable carriers, and one or more compounds selected from
Compound I Form A, Compound I Form B, Compound I Form C, and
Compound I Form D as described herein.
[0026] The present disclosure provides, in one embodiment, a method
for modulating bromodomain in a subject in need thereof, the method
comprising administering to the subject an effective amount of a
free acid amorphous form of Compound I as described herein.
[0027] The present disclosure provides, in one embodiment, a method
for treating a subject suffering from, or at risk of, a disease or
condition mediated by a bromodomain, the method comprising
administering to the subject in need thereof an effective amount
of: a free acid amorphous form of Compound I as described
herein.
[0028] In some embodiments, the disease or condition treated by the
methods described herein is a cancer, a neurological condition, an
autoimmune condition, an inflammatory condition, a metabolic
disease, or combinations thereof. In some embodiment, the disease
or condition is rheumatoid arthritis, uveal melanoma, chronic
lymphocytic leukemia, acute myeloid leukemia, synovial sarcoma,
osteoarthritis, acute gout, psoriasis, systemic lupus
erythematosus, multiple sclerosis, inflammatory bowel disease
(Crohn's disease and Ulcerative colitis), asthma, chronic
obstructive airways disease, pneumonitis, myocarditis,
pericarditis, myositis, eczema, dermatitis, alopecia, vitiligo,
bullous skin diseases, nephritis, vasculitis, atherosclerosis,
Alzheimer's disease, depression, retinitis, uveitis, scleritis,
hepatitis, pancreatitis, primary biliary cirrhosis, sclerosing
cholangitis, Addison's disease, hypophysitis, thyroiditis, type I
diabetes, or acute rejection of transplanted organs.
[0029] The present disclosure provides, in one embodiment, a method
for treating a subject suffering from, or at risk of, a disease or
condition mediated by a bromodomain, the method comprising
administering to the subject in need thereof an effective amount of
a free acid amorphous form of Compound I as described herein,
wherein the disease or condition is rheumatoid arthritis, uveal
melanoma, chronic lymphocytic leukemia, acute myeloid leukemia,
synovial sarcoma, osteoarthritis, acute gout, psoriasis, systemic
lupus erythematosus, multiple sclerosis, inflammatory bowel disease
(Crohn's disease and Ulcerative colitis), asthma, chronic
obstructive airways disease, pneumonitis, myocarditis,
pericarditis, myositis, eczema, dermatitis, alopecia, vitiligo,
bullous skin diseases, nephritis, vasculitis, atherosclerosis,
Alzheimer's disease, depression, retinitis, uveitis, scleritis,
hepatitis, pancreatitis, primary biliary cirrhosis, sclerosing
cholangitis, Addison's disease, hypophysitis, thyroiditis, type I
diabetes, or acute rejection of transplanted organs.
[0030] The present disclosure provides, in one embodiment, a method
of treating chronic lymphocytic leukemia (CLL) or Richter's
Syndrome in a subject in need thereof by administering to the
subject an effective amount of a free acid amorphous form of
Compound I as described herein. In one embodiment, the subject is
also optionally administered a Bruton's Tyrosine Kinase (BTK)
inhibitor. In one embodiment, the BTK inhibitor is ibrutinib.
[0031] The present disclosure provides, in one embodiment, a method
of treating myelodysplastic syndromes (MDS) or acute myeloid
leukemia (AML) in a subject in need thereof by administering to the
subject an effective amount of a free acid amorphous form of
Compound I as described herein, in combination with an effective
amount of a hypomethylating agent (HMA).
[0032] The present disclosure provides, in one embodiment, a method
of treating chronic lymphocytic leukemia (CLL) or Richter's
Syndrome in a subject in need thereof by administering to the
subject an effective amount of a free acid amorphous form of
Compound I as described herein, in combination with an effective
amount of a Bruton's Tyrosine Kinase (BTK) inhibitor. In one
embodiment, the BTK inhibitor is ibrutinib.
[0033] The present disclosure provides, in one embodiment, a method
of treating chronic lymphocytic leukemia (CLL) in a subject in need
thereof by administering to the subject an effective amount of a
free acid amorphous form of Compound I as described herein, in
combination with an effective amount of a B-cell lymphoma 2 (BCL-2)
inhibitor.
[0034] The present disclosure provides, in one embodiment, a method
of treating chronic lymphocytic leukemia (CLL) in a subject in need
thereof by administering to the subject an effective amount of a
free acid amorphous form of Compound I as described herein, in
combination with an effective amount of a
phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)
inhibitor.
[0035] The present disclosure provides, in one embodiment, a method
of treating uveal melanoma in a subject in need thereof by
administering to the subject an effective amount of a free acid
amorphous form of Compound I as described herein, in combination
with an effective amount of a CTLA-4 inhibitor or a checkpoint
inhibitor.
[0036] The present disclosure provides, in one embodiment, a method
of treating acute myeloid leukemia in a subject in need thereof by
administering to the subject an effective amount of a free acid
amorphous form of Compound I as described herein, in combination
with an effective amount of quizartinib.
BRIEF DESCRIPTION OF THE DRAWINGS
[0037] FIG. 1 is an X-ray powder diffractogram of Compound I Form
A.
[0038] FIG. 2 is a thermogravimetric analysis (TGA) of Compound I
Form A.
[0039] FIG. 3 is a differential scanning calorimeter (DSC) curve of
Compound I Form A.
[0040] FIG. 4 is a dynamic vapor sorption (DVS) curve of Compound I
Form A.
[0041] FIG. 5 is an X-ray powder diffractogram of Compound I Form
B.
[0042] FIG. 6 is a thermogravimetric analysis (TGA) of Compound I
Form B.
[0043] FIG. 7 is a differential scanning calorimeter (DSC) curve of
Compound I Form B.
[0044] FIG. 8 is an X-ray powder diffractogram of Compound I Form
C.
[0045] FIG. 9 is a thermogravimetric analysis (TGA) of Compound I
Form C.
[0046] FIG. 10 is a differential scanning calorimeter (DSC) curve
of Compound I Form C.
[0047] FIG. 11 is an X-ray powder diffractogram of Compound I Form
D.
[0048] FIG. 12 is a thermogravimetric analysis (TGA) of Compound I
Form D.
[0049] FIG. 13 is a differential scanning calorimeter (DSC) curve
of Compound I Form D.
[0050] FIG. 14 are X-ray powder diffractograms of Compound I Form
A, Compound I Form B, Compound I Form C, Compound I Form D,
Compound I Material E, Compound I Material F and Compound I
Material G.
[0051] FIG. 15 are X-ray powder diffractograms of Compound I
Material G and Compound I Form B.
[0052] FIG. 16 is a thermogravimetric analysis (TGA) of Compound I
Material G.
[0053] FIG. 17 is a differential scanning calorimeter (DSC) curve
of Compound I Material G.
[0054] FIG. 18 is a X-ray powder diffractogram of Compound I Free
Acid Amorphous.
[0055] FIG. 19 is a thermogravimetric analysis (TGA) of Compound I
Free Acid Amorphous.
[0056] FIG. 20 is a differential scanning calorimeter (DSC) curve
of Compound I Free Acid Amorphous.
[0057] FIG. 21 are X-ray powder diffractogram of Compound I sodium
Material A and Compound I Free Acid Amorphous.
[0058] FIG. 22 is a thermogravimetric analysis (TGA) of Compound I
sodium Material A.
[0059] FIG. 23 is a differential scanning calorimeter (DSC) curve
of Compound I sodium Material A.
[0060] FIG. 24 panels A-H provide graphical representations
demonstrating the potent anti-leukemic effects of targeting BRD4
with the free acid amorphous form of Compound I (Compound I Free
Acid Amorphous, "Cmpd. I FAA") in disease models of aggressive
chronic lymphocytic leukemia (CLL) and Richter's Transformation.
[0061] FIG. 24 panels A-C illustrate data related to the
pharmacodynamic evaluation of antitumor effects of Compound I Free
Acid Amorphous in E.mu.-TCL1 with advanced leukemia. Mice were
stratified according to leukemic peripheral blood lymphocytes
(PBLs) and spleen palpation score to receive either vehicle or
Compound I Free Acid Amorphous (20 mg/kg, qd, oral gavage) for 8
days. Compound I Free Acid Amorphous reduced leukemic cells in
systemic circulation (FIG. 24A) and locally in spleen (FIG. 24B),
where the red line in FIGS. 24A-24B represents average values. FIG.
24C is a representative immunoblot analysis of relative protein
levels of cMYC, P21, BTK, IKZF1, IKZF3 and TCL1A protein at the end
of the 8 day study. [0062] FIG. 24 panels D-G: using an adaptive
transfer model of E.mu.-TCL1, recipient wild type mice were
randomized to receive vehicle (n=12) or Compound I Free Acid
Amorphous (20 mg/kg, qd, oral gavage, n=10) at leukemia onset and
disease progression was measured by flow cytometry as %
CD19/CD5/CD45 positive PBL. Treatment was ended at 150 days. FIG.
24D is a Kaplan-Meier curve showing overall survival (OS)
(p<0.0001), with the median OS for Compound I Free Acid
Amorphous and the vehicle being 93 days and 34 days, respectively.
Survival comparisons for FIG. 24D were made with the log-rank test,
and p-values were adjusted for multiple comparisons. Compound I
Free Acid Amorphous decreased the percentage of circulating
leukemic PBL (FIG. 24E), and reduced spleen mass (FIG. 24F). FIG.
24G shows the HE and Ki67 staining of spleen, lung and blood from
Compound I Free Acid Amorphous treated mice, where said mice are
depleted of lymphocytes, and Ki67 staining is mostly absent. [0063]
FIG. 24H is a Kaplan-Meier curve showing overall survival for
C57BL/6 mice engrafted with E.mu.-TCL1 leukemic splenocytes treated
with Ibrutinib or Compound I Free Acid Amorphous (20 mg/kg, qd,
oral gavage) at leukemia onset, where the median OS is: 41 days
(Compound I Free Acid Amorphous, n=7), 32 days (Ibrutinib, n=8) and
21 days (vehicle, n=7). Compound I Free Acid Amorphous
significantly increased survival compared with vehicle (p=0.024)
and Ibrutinib (p=0.049). Survival comparisons for FIG. 24H were
made with the log-rank test, and p-values were adjusted for
multiple comparisons.
DETAILED DESCRIPTION
[0064] The compound
4-(6-(3,5-dimethylisoxazol-4-yl)-1-[(15)-1-(2-pyridyl)ethyl]pyrrolo[3,2-b-
]pyridin-3-yl)benzoic acid, designated herein as Compound I or
Compound I (free acid), has the following formula:
##STR00003##
Compound I is an inhibitor or modulator of bromodomain proteins.
The synthesis and method of use thereof is described in U.S. Patent
Publication No. 2015/0133400, which is herein incorporated by
reference in its entirety.
[0065] The present disclosure relates to various solid forms of
Compound I and processes for making such solid forms.
[0066] Additional solid forms of Compound I are also described
herein, as well as the processes of making such forms. For
instance, in some embodiments, solid forms of Compound I may
include salts or co-crystals of Compound I. In some embodiments,
solid forms of Compound I may include an amorphous form of Compound
I.
1. DEFINITIONS
[0067] As used in the present specification, the following words
and phrases are generally intended to have the meanings as set
forth below, except to the extent that the context in which they
are used indicates otherwise.
[0068] The term "comprise" and variations thereof, such as,
"comprises" and "comprising" are to be construed in an open,
inclusive sense, that is, as "including, but not limited to."
Further, the singular forms "a," "an," and "the" include plural
references unless the context clearly dictates otherwise. Thus,
reference to "the compound" includes a plurality of such compounds,
and reference to "the assay" includes reference to one or more
assays and equivalents thereof known to those skilled in the
art.
[0069] Reference to "about" a value or parameter herein includes
(and describes) embodiments that are directed to that value or
parameter per se. In some embodiments, the term "about" includes
the indicated amount.+-.10%. In some embodiments, the term "about"
includes the indicated amount.+-.5%. In some other embodiments, the
term "about" includes the indicated amount.+-.1%. Also, the term
"about X" includes description of "X".
[0070] In some embodiments, the term "about," when applied to a
thermogravimetric analysis (TGA) thermogram, includes a variation
of .+-.2% in weight loss. In some embodiments, the term "about,"
when applied to a differential scanning calorimetry (DSC) curve,
includes a variation of .+-.3.degree. C.
[0071] In some embodiments, the phrase "substantially as shown in
Figure" as applied to DSC curves is meant to include a variation of
.+-.3.degree. C.elsius, and as applied to TGA thermograms is meant
to include a variation of .+-.2% in weight loss.
[0072] Recitation of numeric ranges of values throughout the
disclosure is intended to serve as a shorthand notation of
referring individually to each separate value falling within the
range inclusive of the values defining the range, and each separate
value is incorporated in the specification as it were individually
recited herein.
[0073] Forms of Compound I or salts, co-crystals, solvates, or
hydrates thereof are provided herein. In one embodiment, reference
to a form of Compound I or a salt, co-crystal, solvate, or hydrate
thereof means that at least 50% to 99% (e.g., at least 50%, at
least 55%, at least 60%, at least 65%, at least 70%, at least 75%,
at least 80%, at least 85%, at least 90%, at least 95%, or at least
99%) of Compound I or a salt, co-crystal, solvate, or hydrate
thereof present in a composition is in the designated form. For
instance, in one embodiment, reference to Compound I Form A means
that at least 50%, at least 55%, at least 60%, at least 65%, at
least 70%, at least 75%, at least 80%, at least 85%, at least 90%,
at least 95%, or at least 99% of Compound I present in a
composition is in Form A. Reference to Compound I Free Acid
Amorphous means that at least 50%, at least 55%, at least 60%, at
least 65%, at least 70%, at least 75%, at least 80%, at least 85%,
at least 90%, at least 95%, or at least 99% of Compound I present
in a composition is in the free acid amorphous form as described
herein.
[0074] The term "solid form" refers to a type of solid-state
material that includes amorphous as well as crystalline forms. The
term "crystalline form" refers to polymorphs as well as solvates,
hydrates, etc. The term "polymorph" refers to a particular crystal
structure having particular physical properties such as X-ray
diffraction, melting point, and the like.
[0075] The term "co-crystal" refers to a molecular complex of a
compound disclosed herein and one or more non-ionized co-crystal
formers connected via non-covalent interactions. In some
embodiments, the co-crystals disclosed herein may include a
non-ionized form of Compound I (e.g., Compound I free acid) and one
or more non-ionized co-crystal formers, where non-ionized Compound
I and the co-crystal former(s) are connected through non-covalent
interactions. In some embodiments, co-crystals disclosed herein may
include an ionized form of Compound I (e.g., a salt of Compound I)
and one or more non-ionized co-crystals formers, where ionized
Compound I and the co-crystal former(s) are connected through
non-covalent interactions. Co-crystals may additionally be present
in anhydrous, solvated or hydrated forms. In some embodiments,
co-crystals may have improved properties as compared to the parent
form (i.e., the free molecule, zwitterion, etc.) or a salt of the
parent compound. Improved properties can be increased solubility,
increased dissolution, increased bioavailability, increased dose
response, decreased hygroscopicity, a crystalline form of a
normally amorphous compound, a crystalline form of a difficult to
salt or unsaltable compound, decreased form diversity, more desired
morphology, and the like. Methods for making and characterizing
co-crystals are known to those of skill in the art.
[0076] The term "co-crystal former" or "co-former" refers to one or
more pharmaceutically acceptable bases or pharmaceutically
acceptable acids disclosed herein in association with Compound I,
or any other compound disclosed herein.
[0077] The term "solvate" refers to a complex formed by combination
of solvent molecules with molecules or ions of the solute. The
solvent can be an organic compound, an inorganic compound, or a
mixture of both. As used herein, the term "solvate" includes a
hydrate (i.e., a complex formed by combination of water molecules
with molecules or ions of the solute), hemi-hydrate, channel
hydrate, etc. Some examples of solvents include, but are not
limited to, methanol, N,N-dimethylformamide, tetrahydrofuran,
dimethylsulfoxide, and water. In general, the solvated forms are
equivalent to unsolvated forms and are encompassed within the scope
of the present disclosure.
[0078] The term "desolvated" refers to a Compound I form that is a
solvate as described herein, and from which solvent molecules have
been partially or completely removed. Desolvation techniques to
produce desolvated forms include, without limitation, exposure of a
Compound I form (solvate) to a vacuum, subjecting the solvate to
elevated temperature, exposing the solvate to a stream of gas, such
as air or nitrogen, or any combination thereof. Thus, a desolvated
Compound I form can be anhydrous, i.e., completely without solvent
molecules, or partially solvated wherein solvent molecules are
present in stoichiometric or non-stoichiometric amounts.
[0079] The term "amorphous" refers to a state in which the material
lacks long range order at the molecular level and, depending upon
temperature, may exhibit the physical properties of a solid or a
liquid. Typically such materials do not give distinctive X-ray
diffraction patterns and, while exhibiting the properties of a
solid, are more formally described as a liquid. Upon heating, a
change from solid to liquid properties occurs which is
characterized by a change of state, typically second order (glass
transition).
[0080] The term "solid dispersion" refers to any solid composition
having at least two components. In certain embodiments, a solid
dispersion as disclosed herein includes an active ingredient (for
example Compound I, or a solid or amorphous form of Compound I);
preferably dispersed among at least one other component, for
example a polymer. In certain embodiments, a solid dispersion as
disclosed herein is a pharmaceutical dispersion that includes at
least one pharmaceutically or biologically active ingredient (for
example Compound I, or a solid or amorphous form of Compound I). In
some embodiments, a solid dispersion includes Compound I
molecularly dispersed with a polymer. In some embodiments, a solid
dispersion includes a free acid amorphous form of Compound I, as
disclosed herein, molecularly dispersed with a polymer. In some
embodiments, a solid dispersion includes a free acid amorphous salt
form of Compound I, as described herein, molecularly dispersed with
a polymer. In some embodiments, the solid dispersion exists as a
one phase system.
[0081] The term "molecularly dispersed", as used herein, refers to
the random distribution of a compound (e.g., Compound I, a solid or
amorphous form of Compound I) with a polymer. In certain
embodiments the compound is present in the polymer in a final state
of subdivision. See, e.g., M.G. Vachon et al., J.
Microencapsulation, 14:281-301 (1997) and Vandelli et al., J.
Microencapsulation, 10: 55-65 (1993). In some embodiments, a
compound (for example, Compound I) may be dispersed within a matrix
formed by the polymer in its solid state such that the compound is
immobilized in its amorphous form. Whether a compound is
molecularly dispersed in a polymer may be evidenced in a variety of
ways, e.g., by the resulting solid molecular complex having a
single glass transition temperature.
[0082] The term "immobilize", as used herein with reference to the
immobilization of the active compound in the polymer matrix, means
that molecules of the compound interact with molecules of the
polymer in such a way that the molecules of the compound are held
in the aforementioned matrix and prevented from crystal nucleation
due to lack of mobility. In some embodiments the polymer may
prevent intermolecular hydrogen bonding or weak dispersion forces
between two or more drug molecules of Compound I. See, for example,
Matsumoro and Zografi, Pharmaceutical Research, Vo. 16, No. 11, p
1722-1728, 1999.
[0083] Any formula or structure given herein, including Compound I,
is also intended to represent unlabeled forms as well as
isotopically labeled forms of the compounds. It is understood that
for any given atom, the isotopes may be present essentially in
ratios according to their natural occurrence, or one or more
particular atoms may be enhanced with respect to one or more
isotopes using synthetic methods known to one skilled in the art.
Thus, hydrogen includes for example .sup.1H, .sup.2H, .sup.3H;
carbon includes for example .sup.11C, .sup.12C, .sup.13C, .sup.14C;
oxygen includes for example .sup.16O, .sup.17O, .sup.18O; nitrogen
includes for example .sup.13N, .sup.14N, .sup.15N; sulfur includes
for example .sup.32S, .sup.33S, .sup.34S, .sup.35S, .sup.36S,
.sup.37S, .sup.38S; fluoro includes for example .sup.17F, .sup.18F,
.sup.19F; chloro includes for example .sup.35Cl, .sup.36Cl,
.sup.37Cl, .sup.38Cl, .sup.39Cl; and the like.
[0084] As used herein, the terms "treat," "treating," "therapy,"
"therapies," and like terms refer to the administration of
material, e.g., any one or more solid or amorphous forms of
Compound I as described herein in an amount effective to prevent,
alleviate, or ameliorate one or more symptoms of a disease or
condition, e.g., indication, and/or to prolong the survival of the
subject being treated.
[0085] The term "administering" refers to oral administration,
administration as a suppository, topical contact, intravenous,
intraperitoneal, intramuscular, intralesional, intranasal or
subcutaneous administration, or the implantation of a slow-release
device e.g., a mini-osmotic pump, to a subject. Administration is
by any route, including parenteral and transmucosal (e.g., buccal,
sublingual, palatal, gingival, nasal, vaginal, rectal, or
transdermal). Parenteral administration includes, e.g.,
intravenous, intramuscular, intra-arteriole, intradermal,
subcutaneous, intraperitoneal, intraventricular, and intracranial.
Other modes of delivery include, but are not limited to, the use of
liposomal formulations, intravenous infusion, transdermal patches,
etc.
[0086] As used herein, the term "modulating" or "modulate" refers
to an effect of altering a biological activity, especially a
biological activity associated with a particular biomolecule such
as a protein kinase. For example, an agonist or antagonist of a
particular biomolecule modulates the activity of that biomolecule,
e.g., an enzyme, by either increasing (e.g. agonist, activator), or
decreasing (e.g. antagonist, inhibitor) the activity of the
biomolecule, such as an enzyme. Such activity is typically
indicated in terms of an inhibitory concentration (ICso) or
excitation concentration (EC.sub.50) of the compound for an
inhibitor or activator, respectively, with respect to, for example,
an enzyme.
[0087] As used herein, the term "protein kinase mediated disease or
condition," refers to a disease or condition in which the
biological function of a protein kinase, including any mutations
thereof, affects the development, course, and/or symptoms of the
disease or condition, and/or in which modulation of the protein
kinase alters the development, course, and/or symptoms of the
disease or condition. The protein kinase mediated disease or
condition includes a disease or condition for which inhibition
provides a therapeutic benefit, e.g. wherein treatment with protein
kinase inhibitor(s), including one or more solid or amorphous forms
of Compound I as described herein, provides a therapeutic benefit
to the subject suffering from or at risk of the disease or
condition.
[0088] As used herein, the term "composition" refers to a
pharmaceutical preparation suitable for administration to an
intended subject for therapeutic purposes that contains at least
one pharmaceutically active compound, including any solid or
amorphous form thereof. The composition may include at least one
pharmaceutically acceptable component to provide an improved
formulation of the compound, such as a suitable carrier or
excipient.
[0089] Other embodiments of this disclosure include compositions of
any of the crystalline or amorphous forms of Compound I in
combination with nanoparticles (such as naturally-equipped
nanocarriers, for example, exosomes) and the like. It is known that
exosomes can be highly effective drug carriers, and there are
various ways in which drugs can be loaded into exosomes, including
those techniques described in J Control Release, 2015 Dec. 10; 219:
396-405, the contents of which are incorporated by reference in its
entirety.
[0090] As used herein, the term "subject" or "patient" refers to a
living organism that is treated with compounds as described herein,
including, but not limited to, any mammal, such as a human, other
primates, sports animals, animals of commercial interest such as
cattle, farm animals such as horses, or pets such as dogs and
cats.
[0091] The term "pharmaceutically acceptable" indicates that the
indicated material does not have properties that would cause a
reasonably prudent medical practitioner to avoid administration of
the material to a subject, taking into consideration the disease or
conditions to be treated and the respective route of
administration. For example, it is commonly required that such a
material be essentially sterile, e.g., for injectables.
[0092] The term "pharmaceutically acceptable salt" refers to a salt
which is acceptable for administration to a subject, such as a
mammal (e.g., salts having acceptable mammalian safety for a given
dosage regime). Such salts can be derived from pharmaceutically
acceptable inorganic or organic bases and from
pharmaceutically-acceptable inorganic or organic acids, depending
on the particular substituents found on the compounds described
herein. When compounds of the present disclosure contain relatively
acidic functionalities, base addition salts can be obtained by
contacting the neutral form of such compounds with a sufficient
amount of the desired base, either neat or in a suitable inert
solvent. Salts derived from pharmaceutically acceptable inorganic
bases include aluminum, ammonium, calcium, copper, ferric, ferrous,
lithium, magnesium, manganic, manganous, potassium, sodium, zinc
and the like. Salts derived from pharmaceutically acceptable
organic bases include salts of primary, secondary, tertiary and
quaternary amines, including substituted amines, cyclic amines,
naturally-occurring amines and the like, such as arginine, betaine,
caffeine, choline, N, N'-dibenzylethylenediamine, diethylamine,
2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,
ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine,
glucosamine, histidine, hydrabamine, isopropylamine, lysine,
methylglucamine, morpholine, piperazine, piperidine, polyamine
resins, procaine, purines, theobromine, triethylamine,
trimethylamine, tripropylamine, tromethamine,
N,N'-dibenzylethylenediamine, chloroprocaine, choline,
diethanolamine, meglumine (N-methyl-glucamine) and the like. When
compounds of the present disclosure contain relatively basic
functionalities, acid addition salts can be obtained by contacting
the neutral form of such compounds with a sufficient amount of the
desired acid, either neat or in a suitable inert solvent. Salts
derived from pharmaceutically acceptable acids include acetic,
trifluoroacetic, propionic, ascorbic, benzenesulfonic, benzoic,
camphosulfonic, citric, ethanesulfonic, fumaric, glycolic,
gluconic, glucoronic, glutamic, hippuric, hydrobromic,
hydrochloric, isethionic, lactic, lactobionic, maleic, malic,
mandelic, methanesulfonic, mucic, naphthalenesulfonic, nicotinic,
nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric,
hydroiodic, carbonic, tartaric, p-toluenesulfonic, pyruvic,
aspartic, benzoic, anthranilic, mesylic, salicylic,
p-hydroxybenzoic, phenylacetic, embonic (pamoic), ethanesulfonic,
benzenesulfonic, 2-hydroxyethanesulfonic, sulfanilic, stearic,
cyclohexylaminosulfonic, algenic, hydroxybutyric, galactaric and
galacturonic acid and the like.
[0093] Also included are salts of amino acids such as arginate and
the like, and salts of organic acids like glucuronic or
galactunoric acids and the like (see, for example, Berge, S. M. et
al., "Pharmaceutical Salts", J. Pharmaceutical Science, 1977,
66:1-19). Certain specific compounds of the present disclosure
contain both basic and acidic functionalities that allow the
compounds to be converted into either base or acid addition
salts.
[0094] The neutral forms of the compounds may be regenerated by
contacting the salt with a base or acid and isolating the parent
compound in the conventional manner. The parent form of the
compound differs from the various salt forms in certain physical
properties, such as solubility in polar solvents, but otherwise the
salts are equivalent to the parent form of the compound for the
purposes of the present disclosure.
[0095] In the present context, the term "therapeutically effective"
or "effective amount" indicates that the materials or amount of
material is effective to prevent, alleviate, or ameliorate one or
more symptoms of a disease or medical condition, and/or to prolong
the survival of the subject being treated. The therapeutically
effective amount will vary depending on the compound, the disorder
or condition and its severity and the age, weight, etc., of the
mammal to be treated. For example, an effective amount is an amount
sufficient to effectuate a beneficial or desired clinical result.
The effective amounts can be provided all at once in a single
administration or in fractional amounts that provide the effective
amount in several administrations. The precise determination of
what would be considered an effective amount may be based on
factors individual to each subject, including their size, age,
injury, and/or disease or injury being treated, and amount of time
since the injury occurred or the disease began. One skilled in the
art will be able to determine the effective amount for a given
subject based on these considerations which are routine in the
art.
[0096] In the context of the use, testing, or screening of
compounds that are or may be modulators, the term "contacting"
means that the compound(s) are caused to be in sufficient proximity
to a particular molecule, complex, cell, tissue, organism, or other
specified material that potential binding interactions and/or
chemical reaction between the compound and other specified material
can occur.
[0097] In addition, abbreviations as used herein have respective
meanings as follows:
TABLE-US-00001 ACN acetonitrile DCM dichloromethane DMF
dimethylformamide DMSO dimethylsulfoxide DSC differential scanning
calorimetry EtOAc ethyl acetate EtOH ethanol IPA isopropanol MeOH
methanol RH relative humidity RT room temperature TGA
thermogravimetric analysis THF tetrahydrofuran v/v volume to volume
Wt weight w/w weight to weight XRPD X-ray powder diffraction
2. FORMS OF COMPOUND I
[0098] As described generally above, the present disclosure
provides crystalline forms of Compound I and salts, co-crystals,
solvates, or hydrates thereof. Additional forms (including
amorphous forms) are also discussed further herein. It is of note
that the crystalline forms of Compound I and salts, co-crystals,
solvates, or hydrates thereof, and other forms (e.g., amorphous
forms) of Compound I and salts, co-crystals, solvates, or hydrates
thereof are collectively referred to herein as "forms of Compound
I" or "solid forms of Compound I."
[0099] It has been found that the crystalline forms of Compound I
have surprisingly poor solubility as shown in Table A below, which
provides solubility data of the active pharmaceutical ingredient of
Compound I.
TABLE-US-00002 TABLE A Solubility of Active Pharmaceutical
Ingredient of Compound I Acetone 3 mg/mL Acetonitrile <1 mg/mL
Dichloromethane <1 mg/mL Dimethyl sulfoxide >93 mg/mL Ethyl
acetate <1 mg/mL Ethanol <1 mg/mL Isopropanol <1 mg/mL
Methanol 1 mg/mL Tetrahydrofuran 19 mg/mL Water <1 mg/mL
Thus, in some embodiments disclosed herein, techniques, methods and
compositions for improving the solubility and/or bioavailability of
Compound I are provided. In some embodiments, provided are
compositions and methods involving Compound I in a composition,
form, or formulation having improved solubility and/or
bioavailability as compared to Compound I in a crystalline form.
Accordingly, in some embodiments, provided are compositions and
methods involving a free acid amorphous form of Compound I or a
free acid amorphous salt form of Compound I, as disclosed herein.
In some embodiments, provided are compositions and methods
involving a free acid amorphous form of Compound I or a free acid
amorphous salt form of Compound I molecularly dispersed within a
polymer matrix.
[0100] a. Compound I Form A
[0101] The present disclosure provides, in one embodiment, a
crystalline form of
4-(6-(3,5-dimethylisoxazol-4-yl)-1-[(1S)-1-(2-pyridyl)ethyl]pyrro-
lo[3,2-b]pyridin-3-yl)benzoic acid (Compound I Form A)
characterized by an X-ray powder diffractogram comprising the
following peaks: 17.1, 19.4, and 23.5 .degree.2.theta..+-.0.2
.degree.2.theta., as determined on a diffractometer using
Cu-K.alpha. radiation. In one embodiment, the diffractogram of
Compound I Form A further comprises one or more peaks at: 6.7, 9.7,
10.3, 12.1, 12.5, 15.8, 19.0, and 21.4, 20.+-.0.2 .degree.2.theta..
In one embodiment, the diffractogram of Compound I Form A comprises
at least two of the following peaks: 6.7, 9.7, 10.3, 12.1, 12.5,
15.8, 17.1, 19.0, 19.4, 21.4, and 23.5 .degree.2.theta..+-.0.2
.degree.2.theta.. In one embodiment, the diffractogram of Compound
I Form A comprises at least four of the following peaks: 6.7, 9.7,
10.3, 12.1, 12.5, 15.8, 17.1, 19.0, 19.4, 21.4, and 23.5
.degree.2.theta..+-.0.2 .degree.2.theta.. In one embodiment, the
diffractogram of Compound I Form A comprises at least six of the
following peaks: 6.7, 9.7, 10.3, 12.1, 12.5, 15.8, 17.1, 19.0,
19.4, 21.4, and 23.5 .degree.2.theta..+-.0.2 .degree.2.theta.. In
one embodiment, the diffractogram of Compound I Form A comprises at
least eight of the following peaks: 6.7, 9.7, 10.3, 12.1, 12.5,
15.8, 17.1, 19.0, 19.4, 21.4, and 23.5 .degree.2.theta..+-.0.2
.degree.2.theta.. In one embodiment, the diffractogram of Compound
I Form A comprises each of the following peaks: 6.7, 9.7, 10.3,
12.1, 12.5, 15.8, 17.1, 19.0, 19.4, 21.4, and 23.5
.degree.2.theta..+-.0.2 .degree.2.theta.. In one embodiment,
Compound I Form A is characterized by the full X-ray powder
diffractogram as substantially shown in FIG. 1.
[0102] In one embodiment, Compound I Form A is characterized by a
thermogravimetric analysis (TGA) thermogram showing a weight loss
of about 3.0% up to about 250.degree. C. In one embodiment,
Compound I Form A is characterized by the thermogram as
substantially shown in FIG. 2.
[0103] In one embodiment, Compound I Form A is characterized by a
differential scanning calorimetry (DSC) curve that comprises an
endotherm with a peak maximum at about 238.degree. C. In one
embodiment, the DSC curve of Compound I Form A comprises an
additional endotherm with a peak maximum at about 124.degree. C. In
one embodiment, Compound I Form A is characterized by the full DSC
curve as substantially shown in FIG. 3.
[0104] In one embodiment, Compound I Form A is characterized by a
dynamic vapor sorption (DVS) analysis showing minimal weight loss
upon equilibrium at about 5% RH, and a weight gain of about 0.8%
from about 5% to about 95% RH corresponding to about 0.2 moles of
water. In one embodiment, Compound I Form A is characterized by the
full DVS sorption curve as substantially shown in FIG. 4.
[0105] In one embodiment, Compound I Form A is characterized as a
hydrate.
[0106] b. Compound I Form B
[0107] The present disclosure provides, in one embodiment, a
crystalline form of
4-(6-(3,5-dimethylisoxazol-4-yl)-1-[(1S)-1-(2-pyridyl)ethyl]pyrro-
lo[3,2-b]pyridin-3-yl)benzoic acid (Compound I Form B)
characterized by an X-ray powder diffractogram comprising the
following peaks: 16.8, 17.4, and 21.1 .degree.2.theta..+-.0.2
.degree.2.theta., as determined on a diffractometer using
Cu-K.alpha. radiation. In one embodiment, the diffractogram of
Compound I Form B further comprises one or more peaks at: 13.7,
14.0, 14.2, 15.7, 19.7, 22.4, 23.2, and 24.6
.degree.2.theta..+-.0.2 .degree.2.theta.. In one embodiment, the
diffractogram of Compound I Form B comprises at least two of the
following peaks: 13.7, 14.0, 14.2, 15.7, 19.7, 22.4, 23.2, and 24.6
.degree.2.theta..+-.0.2 .degree.2.theta.. 13.7, 14.0, 14.2, 15.7,
16.8, 17.4, 19.7, 21.1, 22.4, 23.2, and 24.6
.degree.2.theta..+-.0.2 .degree.2.theta.. In one embodiment, the
diffractogram of Compound I Form B comprises at least four of the
following peaks: 13.7, 14.0, 14.2, 15.7, 19.7, 22.4, 23.2, and 24.6
.degree.2.theta..+-.0.2 .degree.2.theta.. 13.7, 14.0, 14.2, 15.7,
16.8, 17.4, 19.7, 21.1, 22.4, 23.2, and 24.6
.degree.2.theta..+-.0.2 .degree.2.theta.. In one embodiment, the
diffractogram of Compound I Form B comprises at least six of the
following peaks: 13.7, 14.0, 14.2, 15.7, 19.7, 22.4, 23.2, and 24.6
.degree.2.theta..+-.0.2 .degree.2.theta.. 13.7, 14.0, 14.2, 15.7,
16.8, 17.4, 19.7, 21.1, 22.4, 23.2, and 24.6
.degree.2.theta..+-.0.2 .degree.2.theta.. In one embodiment, the
diffractogram of Compound I Form B comprises at least eight of the
following peaks: 13.7, 14.0, 14.2, 15.7, 19.7, 22.4, 23.2, and 24.6
.degree.2.theta..+-.0.2 .degree.2.theta.. 13.7, 14.0, 14.2, 15.7,
16.8, 17.4, 19.7, 21.1, 22.4, 23.2, and 24.6
.degree.2.theta..+-.0.2 .degree.2.theta.. In one embodiment, the
diffractogram of Compound I Form B comprises each of the following
peaks: 13.7, 14.0, 14.2, 15.7, 19.7, 22.4, 23.2, and 24.6
.degree.2.theta..+-.0.2 .degree.2.theta.. 13.7, 14.0, 14.2, 15.7,
16.8, 17.4, 19.7, 21.1, 22.4, 23.2, and 24.6
.degree.2.theta..+-.0.2 .degree.2.theta.. In one embodiment,
Compound I Form B is characterized by the full X-ray powder
diffractogram as substantially shown in FIG. 5.
[0108] In one embodiment, Compound I Form B is characterized by a
thermogravimetric analysis (TGA) thermogram showing a weight loss
of about 2.9% up to about 275.degree. C. In one embodiment,
Compound I Form B is characterized by the thermogram as
substantially shown in FIG. 6.
[0109] In one embodiment, Compound I Form B is characterized by a
differential scanning calorimetry (DSC) curve that comprises an
endotherm with a peak maximum at about 277.degree. C. In one
embodiment, the DSC curve of Compound I Form B additionally
comprises an exotherm with a peak maximum at about 247.degree. C.
In one embodiment, Compound I Form B is characterized by the full
DSC curve as substantially shown in FIG. 7.
[0110] In one embodiment, Compound I Form B is characterized as a
racemic mixture comprising about an equal amount (50:50) of the R
and S enantiomers of
4-(6-(3,5-dimethylisoxazol-4-yl)-1-[1-(2-pyridyl)ethyl]pyrrolo[3,2-b]pyri-
din-3-yl)benzoic acid. As indicated above, Compound I is the S
enantiomer of
4-(6-(3,5-dimethylisoxazol-4-yl)-1-[1-(2-pyridyl)ethyl]pyrrolo[3,2-b]p-
yridin-3-yl)benzoic acid.
[0111] In one embodiment, Compound I Form B may exist as a solid
solution comprising about an equal amount (50:50) of the R and S
enantiomers of Compound I.
[0112] c. Compound I Form C
[0113] The present disclosure provides, in one embodiment, a
crystalline form of
4-(6-(3,5-dimethylisoxazol-4-yl)-1-[(1S)-1-(2-pyridyl)ethyl]pyrro-
lo[3,2-b]pyridin-3-yl)benzoic acid (Compound I Form C)
characterized by an X-ray powder diffractogram comprising the
following peaks: 13.7, 14.6, and 22.6 .degree.2.theta..+-.0.2
.degree.2.theta., as determined on a diffractometer using
Cu-K.alpha. radiation. In one embodiment, the diffractogram of
Compound I Form C further comprises one or more peaks at: 10.0,
11.2, 12.4, 13.7, 14.6, 15.6, 18.6, 20.2, 21.3, 21.9, 22.6, and
23.8 .degree.2.theta..+-.0.2 .degree.2.theta.. In one embodiment,
the diffractogram of Compound I Form C comprises at least two of
the following peaks: 10.0, 11.2, 12.4, 13.7, 14.6, 15.6, 18.6,
20.2, 21.3, 21.9, 22.6, and 23.8 .degree.2.theta..+-.0.2
.degree.2.theta.. In one embodiment, the diffractogram of Compound
I Form C comprises at least four of the following peaks: 10.0,
11.2, 12.4, 13.7, 14.6, 15.6, 18.6, 20.2, 21.3, 21.9, 22.6, and
23.8 .degree.2.theta..+-.0.2 .degree.2.theta.. In one embodiment,
the diffractogram of Compound I Form C comprises at least six of
the following peaks: 10.0, 11.2, 12.4, 13.7, 14.6, 15.6, 18.6,
20.2, 21.3, 21.9, 22.6, and 23.8 .degree.2.theta..+-.0.2
.degree.2.theta.. In one embodiment, the diffractogram of Compound
I Form C comprises at least eight of the following peaks: 10.0,
11.2, 12.4, 13.7, 14.6, 15.6, 18.6, 20.2, 21.3, 21.9, 22.6, and
23.8 .degree.2.theta..+-.0.2 .degree.2.theta.. In one embodiment,
the diffractogram of Compound I Form C comprises each of the
following peaks: 10.0, 11.2, 12.4, 13.7, 14.6, 15.6, 18.6, 20.2,
21.3, 21.9, 22.6, and 23.8 .degree.2.theta..+-.0.2
.degree.2.theta.. In one embodiment, Compound I Form C is
characterized by the full X-ray powder diffractogram as
substantially shown in FIG. 8.
[0114] In one embodiment, Compound I Form C is characterized by a
thermogravimetric analysis (TGA) thermogram showing a weight loss
of about 7.4% up to about 240.degree. C. In one embodiment,
Compound I Form C is characterized by the thermogram as
substantially shown in FIG. 9.
[0115] In one embodiment, Compound I Form C is characterized by a
differential scanning calorimetry (DSC) curve that comprises an
endotherm with a peak maximum at about 234.5.degree. C. In one
embodiment, the DSC curve of Compound I Form C additionally
comprises an exotherm with a peak maximum at about 148.degree. C.
In one embodiment, Compound I Form C is characterized by the full
DSC curve as substantially shown in FIG. 10.
[0116] In one embodiment, Compound I Form C is characterized as
anhydrous.
[0117] d. Compound I Form D
[0118] The present disclosure provides, in one embodiment, a
crystalline form of
4-(6-(3,5-dimethylisoxazol-4-yl)-1-[(1S)-1-(2-pyridyl)ethyl]pyrro-
lo[3,2-b]pyridin-3-yl)benzoic acid (Compound I Form D)
characterized by an X-ray powder diffractogram comprising the
following peaks: 3.5, 18.0, and 19.1 .degree.2.theta..+-.0.2
.degree.2.theta., as determined on a diffractometer using
Cu-K.alpha. radiation. In one embodiment, the diffractogram of
Compound I Form D further comprises one or more peaks at: 7.0,
10.8, 11.4, 13.1, 15.5, 17.4, 17.5, 18.5, 19.7, and 21.2
.degree.2.theta..+-.0.2 .degree.2.theta.. In one embodiment, the
diffractogram of Compound I Form D comprises at least two of the
following peaks: 3.5, 7.0, 10.8, 11.4, 13.1, 15.5, 17.4, 17.5,
18.0, 18.5, 19.1, 19.7, and 21.2 .degree.2.theta..+-.0.2
.degree.2.theta.. In one embodiment, the diffractogram of Compound
I Form D comprises at least four of the following peaks: 3.5, 7.0,
10.8, 11.4, 13.1, 15.5, 17.4, 17.5, 18.0, 18.5, 19.1, 19.7, and
21.2 .degree.2.theta..+-.0.2 .degree.2.theta.. In one embodiment,
the diffractogram of Compound I Form D comprises at least six of
the following peaks: 3.5, 7.0, 10.8, 11.4, 13.1, 15.5, 17.4, 17.5,
18.0, 18.5, 19.1, 19.7, and 21.2 .degree.2.theta..+-.0.2
.degree.2.theta.. In one embodiment, the diffractogram of Compound
I Form D comprises at least eight of the following peaks: 3.5, 7.0,
10.8, 11.4, 13.1, 15.5, 17.4, 17.5, 18.0, 18.5, 19.1, 19.7, and
21.2 .degree.2.theta..+-.0.2 .degree.2.theta.. In one embodiment,
the diffractogram of Compound I Form D comprises each of the
following peaks: 3.5, 7.0, 10.8, 11.4, 13.1, 15.5, 17.4, 17.5,
18.0, 18.5, 19.1, 19.7, and 21.2 .degree.2.theta..+-.0.2
.degree.2.theta.. In one embodiment, Compound I Form D is
characterized by the full X-ray powder diffractogram as
substantially shown in FIG. 11.
[0119] In one embodiment, Compound I Form D is characterized by a
thermogravimetric analysis (TGA) thermogram showing a weight loss
of about 0.5% up to about 125.degree. C. In one embodiment, the TGA
thermogram of Compound I Form D may additionally show a weight loss
of about 11.1% from about 125.degree. C. to about 195.degree. C. In
one embodiment, the TGA thermogram of Compound I Form D may further
show a weight loss of about 1.5% from about 195.degree. C. to about
225.degree. C. In one embodiment, Compound I Form D is
characterized by the thermogram as substantially shown in FIG.
12.
[0120] In one embodiment, Compound I Form D is characterized by a
differential scanning calorimetry (DSC) curve that comprises an
endotherm with a peak maximum at about 235.degree. C. In one
embodiment, the DSC curve of Compound I Form C additionally
comprises exotherms with peak maxima at about 107.degree. C. and
237.degree. C. In one embodiment, Compound I Form C is
characterized by the full DSC curve as substantially shown in FIG.
13.
[0121] In one embodiment, Compound I Form D is characterized as a
solvate. In one embodiment, Compound I Form D is characterized as
an isopropanol solvate.
[0122] e. Compound I Material E
[0123] The present disclosure provides, in one embodiment, a
crystalline form of
4-(6-(3,5-dimethylisoxazol-4-yl)-1-[(1S)-1-(2-pyridyl)ethyl]pyrro-
lo[3,2-b]pyridin-3-yl)benzoic acid (Compound I Material E)
characterized by an X-ray powder diffractogram comprising the
following peaks: 6.4, 22.4, and 25.1 .degree.2.theta..+-.0.2
.degree.2.theta., as determined on a diffractometer using
Cu-K.alpha. radiation. In one embodiment, the diffractogram of
Compound I Material E further comprises one or more peaks at: 9.2,
10.6, 13.1, 19.0, 22.9, and 23.4 .degree.2.theta..+-.0.2
.degree.2.theta.. In one embodiment, the diffractogram of Compound
I Material E comprises at least two of the following peaks: 6.4,
9.2, 10.6, 13.1, 19.0, 22.4, 22.9, 23.4, and 25.1
.degree.2.theta..+-.0.2 .degree.2.theta.. In one embodiment, the
diffractogram of Compound I Material E comprises at least four of
the following peaks: 6.4, 9.2, 10.6, 13.1, 19.0, 22.4, 22.9, 23.4,
and 25.1 .degree.2.theta..+-.0.2 .degree.2.theta.. In one
embodiment, the diffractogram of Compound I Material E comprises at
least six of the following peaks: 6.4, 9.2, 10.6, 13.1, 19.0, 22.4,
22.9, 23.4, and 25.1 .degree.2.theta..+-.0.2 .degree.2.theta.. In
one embodiment, the diffractogram of Compound I Material E
comprises at least eight of the following peaks: 6.4, 9.2, 10.6,
13.1, 19.0, 22.4, 22.9, 23.4, and 25.1 .degree.2.theta..+-.0.2
.degree.2.theta.. In one embodiment, the diffractogram of Compound
I Material E comprises each of the following peaks: 6.4, 9.2, 10.6,
13.1, 19.0, 22.4, 22.9, 23.4, and 25.1 .degree.2.theta..+-.0.2
.degree.2.theta..
[0124] In one embodiment, Compound I Material E is present as a
mixture with Form C. In one embodiment, Compound I Material E is
characterized by the full X-ray powder diffractogram as
substantially shown in FIG. 14. FIG. 14 also includes the X-ray
powder diffractograms of Compound I Form A, Compound I Form B,
Compound I Form C, Compound I Form D, Compound I Material F
(discussed in detail below) and Compound I Material G (discussed in
detail below) for reference.
[0125] f. Compound I Material F
[0126] The present disclosure provides, in one embodiment, a
crystalline form of
4-(6-(3,5-dimethylisoxazol-4-yl)-1-[(1S)-1-(2-pyridyl)ethyl]pyrro-
lo[3,2-b]pyridin-3-yl)benzoic acid (Compound I Material F)
characterized by an X-ray powder diffractogram comprising the
following peaks: 12.8, 18.6, and 21.1 .degree.2.theta..+-.0.2
.degree.2.theta., as determined on a diffractometer using
Cu-K.alpha. radiation. In one embodiment, the diffractogram of
Compound I Material F further comprises one or more peaks at: 5.5,
7.7, 11.6, 16.1, 16.9, 19.0, 20.4, 21.9, and 23.3
.degree.2.theta..+-.0.2 .degree.2.theta.. In one embodiment, the
diffractogram of Compound I Material F comprises at least two of
the following peaks: 5.5, 7.7, 11.6, 12.8, 16.1, 16.9, 18.6, 19.0,
20.4, 21.1, 21.9, and 23.3 .degree.2.theta..+-.0.2
.degree.2.theta.. In one embodiment, the diffractogram of Compound
I Material F comprises at least four of the following peaks: 5.5,
7.7, 11.6, 12.8, 16.1, 16.9, 18.6, 19.0, 20.4, 21.1, 21.9, and 23.3
.degree.2.theta..+-.0.2 .degree.2.theta.. In one embodiment, the
diffractogram of Compound I Material F comprises at least six of
the following peaks: 5.5, 7.7, 11.6, 12.8, 16.1, 16.9, 18.6, 19.0,
20.4, 21.1, 21.9, and 23.3 .degree.2.theta..+-.0.2
.degree.2.theta.. In one embodiment, the diffractogram of Compound
I Material F comprises at least eight of the following peaks: 5.5,
7.7, 11.6, 12.8, 16.1, 16.9, 18.6, 19.0, 20.4, 21.1, 21.9, and 23.3
.degree.2.theta..+-.0.2 .degree.2.theta.. In one embodiment, the
diffractogram of Compound I Material F comprises each of the
following peaks: 5.5, 7.7, 11.6, 12.8, 16.1, 16.9, 18.6, 19.0,
20.4, 21.1, 21.9, and 23.3 .degree.2.theta..+-.0.2
.degree.2.theta..
[0127] In one embodiment, Compound I Material F is present as a
mixture with Form C. In one embodiment, Compound I Material F is
characterized by the full X-ray powder diffractogram as
substantially shown in FIG. 14.
[0128] g. Compound I Material G
[0129] The present disclosure provides, in one embodiment, a
crystalline form of
4-(6-(3,5-dimethylisoxazol-4-yl)-1-[(1S)-1-(2-pyridyl)ethyl]pyrro-
lo[3,2-b]pyridin-3-yl)benzoic acid (Compound I Material G)
characterized by an X-ray powder diffractogram comprising the
following peaks: 15.3, 17.0, and 23.0 .degree.2.theta..+-.0.2
.degree.2.theta., as determined on a diffractometer using
Cu-K.alpha. radiation. In one embodiment, the diffractogram of
Compound I Material G further comprises one or more peaks at: 15.7,
18.7, 20.2, 21.9, 22.1, and 25.7, .degree.2.theta..+-.0.2
.degree.2.theta.. In one embodiment, the diffractogram of Compound
I Material G comprises at least two of the following peaks: 15.3,
15.7, 17.0, 18.7, 20.2, 21.9, 22.1, 23.0, and 25.7,
.degree.2.theta..+-.0.2 .degree.2.theta.. In one embodiment, the
diffractogram of Compound I Material G comprises at least four of
the following peaks: 15.3, 15.7, 17.0, 18.7, 20.2, 21.9, 22.1,
23.0, and 25.7, .degree.2.theta..+-.0.2 .degree.2.theta.. In one
embodiment, the diffractogram of Compound I Material G comprises at
least six of the following peaks: 15.3, 15.7, 17.0, 18.7, 20.2,
21.9, 22.1, 23.0, and 25.7, .degree.2.theta..+-.0.2
.degree.2.theta.. In one embodiment, the diffractogram of Compound
I Material G comprises at least eight of the following peaks: 15.3,
15.7, 17.0, 18.7, 20.2, 21.9, 22.1, 23.0, and 25.7,
.degree.2.theta..+-.0.2 .degree.2.theta.. In one embodiment, the
diffractogram of Compound I Material G comprises each of the
following peaks: 15.3, 15.7, 17.0, 18.7, 20.2, 21.9, 22.1, 23.0,
and 25.7, .degree.2.theta..+-.0.2 .degree.2.theta..
[0130] In one embodiment, Compound I Material G is present as a
mixture with Form B. In one embodiment, Compound I Material G is
characterized by the full X-ray powder diffractogram as
substantially shown in FIG. 15. FIG. 15 also includes the X-ray
powder diffractogram of Compound I Form B for reference.
[0131] In one embodiment, Compound I Material G is characterized by
a thermogravimetric analysis (TGA) thermogram showing a weight loss
of about 5.2% up to about 250.degree. C. In one embodiment,
Compound I Material G is characterized by the thermogram as
substantially shown in FIG. 16. In one embodiment, heating Compound
I Material G up to about 235.degree. C. results in a weight loss of
about 4.2% and the formation of Compound I Form B. The X-ray powder
diffractogram of Compound I Form B formed via heating Material G to
about 235.degree. C. is also shown in FIG. 15.
[0132] In one embodiment, Compound I Material G is characterized by
a differential scanning calorimetry (DSC) curve that comprises an
endotherm with a peak maximum at about 278.degree. C. In one
embodiment, the DSC curve of Compound I Material G comprises an
additional endotherm with a peak maximum at about 217.degree. C. In
one embodiment, the DSC curve of Compound I Material G further
comprises an exotherm with a peak maximum at about 219.degree. C.
In one embodiment, Compound I Material G is characterized by the
full DSC curve as substantially shown in FIG. 17.
[0133] h. Compound I Free Acid Amorphous
[0134] The present disclosure provides, in one embodiment, a free
acid amorphous form of
4-(6-(3,5-dimethylisoxazol-4-yl)-1-[(1S)-1-(2-pyridyl)ethyl]pyrrolo[3,2-b-
]pyridin-3-yl)benzoic acid (Compound I Free Acid Amorphous, also
referred to herein as the free acid amorphous form of Compound I)
characterized by an X-ray powder diffractogram as substantially
shown in FIG. 18.
[0135] In one embodiment, Compound I Free Acid Amorphous is
characterized by a thermogravimetric analysis (TGA) thermogram
showing a weight loss of about 17% up to about 250.degree. C. In
one embodiment, Compound I Free Acid Amorphous is characterized by
the thermogram as substantially shown in FIG. 19.
[0136] In one embodiment, Compound I Free Acid Amorphous is
characterized by a differential scanning calorimetry (DSC) curve
that comprises an exotherm with a peak maximum at about 237.degree.
C. In one embodiment, the DSC curve of Compound I Free Acid
Amorphous indicates a potential glass transition at about
57.degree. C. In one embodiment, Compound I Free Acid Amorphous is
characterized by the full DSC curve as substantially shown in FIG.
20.
[0137] i. Sodium Salt of Compound I
[0138] The present disclosure provides, in one embodiment, a
crystalline form of a sodium salt of
4-(6-(3,5-dimethylisoxazol-4-yl)-1-[(1S)-1-(2-pyridyl)ethyl]pyrrolo[3,2-b-
]pyridin-3-yl)benzoic acid (Compound I sodium Material A)
characterized by an X-ray powder diffractogram as substantially
shown in FIG. 21.
[0139] In one embodiment, Compound I sodium Material A is
characterized by a thermogravimetric analysis (TGA) thermogram
showing a weight loss of about 6.4% up to about 175.degree. C. In
one embodiment, Compound I sodium Material A is characterized by
the thermogram as substantially shown in FIG. 22.
[0140] In one embodiment, Compound I sodium Material A is
characterized by a differential scanning calorimetry (DSC) curve
that comprises an endotherm with a peak maximum at about 85.degree.
C. In one embodiment, the DSC curve of Compound I sodium Material A
additionally comprises an endotherm with a peak maximum at about
294.degree. C. In one embodiment, Compound I sodium Material A is
characterized by the full DSC curve as substantially shown in FIG.
23.
3. PHARMACEUTICAL COMPOSITIONS AND MODES OF ADMINISTRATION
[0141] Compound I, and the forms thereof as described herein may be
administered in a pharmaceutical composition. Thus, provided herein
are pharmaceutical compositions comprising Compound I or a salt
thereof, or one or more of the forms of Compound I described
herein, and one or more pharmaceutically acceptable vehicles such
as carriers, adjuvants and excipients. Suitable pharmaceutically
acceptable vehicles may include, for example, inert solid diluents
and fillers, diluents, including sterile aqueous solution and
various organic solvents, permeation enhancers, solubilizers and
adjuvants. Such compositions are prepared in a manner well known in
the pharmaceutical art. See, e.g., Remington's Pharmaceutical
Sciences, Mace Publishing Co., Philadelphia, Pa. 17th Ed. (1985);
and Modern Pharmaceutics, Marcel Dekker, Inc. 3rd Ed. (G. S. Banker
& C. T. Rhodes, Eds.). The pharmaceutical compositions may be
administered alone or in combination with other therapeutic
agents.
[0142] Some embodiments are directed to pharmaceutical compositions
comprising Compound I. Some embodiments are directed to
pharmaceutical compositions comprising a salt of Compound I.
[0143] Some embodiments are directed to pharmaceutical compositions
comprising a crystalline form of Compound I as described herein. In
one embodiment, a pharmaceutical composition comprises Compound I,
wherein at least 95% of Compound I is in a crystalline form as
described herein. In one embodiment, a pharmaceutical composition
comprises Compound I, wherein at least 95% of Compound I is in Form
A. In one embodiment, a pharmaceutical composition comprises
Compound I, wherein at least 95% of Compound I is in Form B. In one
embodiment, a pharmaceutical composition comprises Compound I,
wherein at least 95% of Compound I is in Form C. In one embodiment,
a pharmaceutical composition comprises Compound I, wherein at least
95% of Compound I is in Form D. In one embodiment, a pharmaceutical
composition comprises Compound I, wherein at least 95% of Compound
I is Compound I Material E. In one embodiment, a pharmaceutical
composition comprises Compound I, wherein at least 95% of Compound
I is Compound I Material F. In one embodiment, a pharmaceutical
composition comprises Compound I, wherein at least 95% of Compound
I is Compound I Material G.
[0144] In one embodiment, a pharmaceutical composition comprises
Compound I, wherein at least 97% of Compound I is in a crystalline
form as described herein. In one embodiment, a pharmaceutical
composition comprises Compound I, wherein at least 97% of Compound
I is in Form A. In one embodiment, a pharmaceutical composition
comprises Compound I, wherein at least 97% of Compound I is in Form
B. In one embodiment, a pharmaceutical composition comprises
Compound I, wherein at least 97% of Compound I is in Form C. In one
embodiment, a pharmaceutical composition comprises Compound I,
wherein at least 97% of Compound I is in Form D. In one embodiment,
a pharmaceutical composition comprises Compound I, wherein at least
97% of Compound I is Compound I Material E. In one embodiment, a
pharmaceutical composition comprises Compound I, wherein at least
97% of Compound I is Compound I Material F. In one embodiment, a
pharmaceutical composition comprises Compound I, wherein at least
97% of Compound I is Compound I Material G.
[0145] In one embodiment, a pharmaceutical composition comprises
Compound I, wherein at least 99% of Compound I is in a crystalline
form as described herein. In one embodiment, a pharmaceutical
composition comprises Compound I, wherein at least 99% of Compound
I is in Form A. In one embodiment, a pharmaceutical composition
comprises Compound I, wherein at least 99% of Compound I is in Form
B. In one embodiment, a pharmaceutical composition comprises
Compound I, wherein at least 99% of Compound I is in Form C. In one
embodiment, a pharmaceutical composition comprises Compound I,
wherein at least 99% of Compound I is in Form D. In one embodiment,
a pharmaceutical composition comprises Compound I, wherein at least
99% of Compound I is Compound I Material E. In one embodiment, a
pharmaceutical composition comprises Compound I, wherein at least
99% of Compound I is Compound I Material F. In one embodiment, a
pharmaceutical composition comprises Compound I, wherein at least
99% of Compound I is Compound I Material G.
[0146] In one embodiment, a pharmaceutical composition comprises an
amorphous form of Compound I as described herein. In one
embodiment, a pharmaceutical composition comprises a free acid
amorphous form of Compound I as described herein. In one
embodiment, a pharmaceutical composition comprises Compound I,
where at least 95% of Compound I is Compound I Free Acid Amorphous.
In one embodiment, a pharmaceutical composition comprises Compound
I, where at least 97% of Compound I is Compound I Free Acid
Amorphous. In one embodiment, a pharmaceutical composition
comprises Compound I, wherein at least 99% of Compound I is
Compound I Free Acid Amorphous.
[0147] In one embodiment, a pharmaceutical composition comprises a
free acid amorphous salt form of Compound I (an amorphous form of a
salt of Compound I) as described herein. In one embodiment, a
pharmaceutical composition comprises Compound I, where at least 95%
of Compound I is a free acid amorphous salt form of Compound I, as
described herein. In one embodiment, a pharmaceutical composition
comprises Compound I, where at least 97% of Compound I is a free
acid amorphous salt form of Compound I, as described herein. In one
embodiment, a pharmaceutical composition comprises Compound I,
wherein at least 99% of Compound I is a free acid amorphous salt
form of Compound I, as described herein.
[0148] In some embodiments, a pharmaceutical composition comprises
Compound I Free Acid Amorphous molecularly dispersed in a polymer
matrix. In some embodiments, a pharmaceutical composition comprises
a free acid amorphous salt form of Compound I molecularly dispersed
in a polymer matrix. Non-limiting examples of a polymer matrix that
can be used include, but are not limited to, hypromellose Acetate
Succinate (HPMCAS), hydroxypropyl methylcellulose phthalate
(HPMCP), and Eudragit.RTM..
[0149] Some embodiments are directed to pharmaceutical compositions
comprising a salt of Compound I in a crystalline form as described
herein. In one embodiment, a pharmaceutical composition comprises a
sodium salt of Compound I, wherein at least 95% of Compound I is
Compound I sodium Material A. In one embodiment, a pharmaceutical
composition comprises a sodium salt of Compound I, wherein at least
97% of Compound I is Compound I sodium Material A. In one
embodiment, a pharmaceutical composition comprises a sodium salt of
Compound I, wherein at least 99% of Compound I is Compound I sodium
Material A.
[0150] Some embodiments are directed to pharmaceutical compositions
comprising a therapeutically effective amount of a compound
selected from: Compound I or a salt thereof, Compound I Form A,
Compound I Form B, Compound I Form C, Compound I Form D, Compound I
Material E, Compound I Material F, Compound I Material G, Compound
I Free Acid Amorphous, a free acid amorphous salt form of Compound
I, and Compound I sodium Material A as described herein; and one or
more pharmaceutically acceptable carriers.
[0151] In some embodiments, compositions will comprise
pharmaceutically acceptable carriers or excipients, such as
fillers, binders, disintegrants, glidants, lubricants, complexing
agents, solubilizers, and surfactants, which may be chosen to
facilitate administration of the compound by a particular route.
Examples of carriers include calcium carbonate, calcium phosphate,
various sugars such as lactose, glucose, or sucrose, types of
starch, cellulose derivatives, gelatin, lipids, liposomes,
nanoparticles, and the like. Carriers also include physiologically
compatible liquids as solvents or for suspensions, including, for
example, sterile solutions of water for injection (WFI), saline
solution, dextrose solution, Hank's solution, Ringer's solution,
vegetable oils, mineral oils, animal oils, polyethylene glycols,
liquid paraffin, and the like. Excipients may also include, for
example, colloidal silicon dioxide, silica gel, talc, magnesium
silicate, calcium silicate, sodium aluminosilicate, magnesium
trisilicate, powdered cellulose, macrocrystalline cellulose,
carboxymethyl cellulose, cross-linked sodium
carboxymethylcellulose, sodium benzoate, calcium carbonate,
magnesium carbonate, stearic acid, aluminum stearate, calcium
stearate, magnesium stearate, zinc stearate, sodium stearyl
fumarate, syloid, stearowet C, magnesium oxide, starch, sodium
starch glycolate, glyceryl monostearate, glyceryl dibehenate,
glyceryl palmitostearate, hydrogenated vegetable oil, hydrogenated
cotton seed oil, castor seed oil mineral oil, polyethylene glycol
(e.g. PEG 4000-8000), polyoxyethylene glycol, poloxamers, povidone,
crospovidone, croscarmellose sodium, alginic acid, casein,
methacrylic acid divinylbenzene copolymer, sodium docusate,
cyclodextrins (e.g. 2-hydroxypropyl-.beta.-cyclodextrin),
polysorbates (e.g. polysorbate 80), cetrimide, TPGS
(d-alpha-tocopheryl polyethylene glycol 1000 succinate), magnesium
lauryl sulfate, sodium lauryl sulfate, polyethylene glycol ethers,
di-fatty acid ester of polyethylene glycols, or a polyoxyalkylene
sorbitan fatty acid ester (e.g., polyoxyethylene sorbitan ester
Tween.RTM.), polyoxyethylene sorbitan fatty acid esters, sorbitan
fatty acid ester, e.g. a sorbitan fatty acid ester from a fatty
acid such as oleic, stearic or palmitic acid, mannitol, xylitol,
sorbitol, maltose, lactose, lactose monohydrate or lactose spray
dried, sucrose, fructose, calcium phosphate, dibasic calcium
phosphate, tribasic calcium phosphate, calcium sulfate, dextrates,
dextran, dextrin, dextrose, cellulose acetate, maltodextrin,
simethicone, polydextrosem, chitosan, gelatin, HPMC (hydroxypropyl
methyl celluloses), HPC (hydroxypropyl cellulose), hydroxyethyl
cellulose, and the like.
[0152] Pharmaceutical formulations may be presented in unit dose
forms containing a predetermined amount of active ingredient per
unit dose. Such a unit may contain, for example, 0.5 mg to 1 g,
preferably 1 mg to 700 mg, more preferably 5 mg to 100 mg of a
compound of the present disclosure (as a free-acid, solvate
(including hydrate) or salt, in any form), depending on the
condition being treated, the route of administration, and the age,
weight and condition of the subject. Preferred unit dosage
formulations are those containing a daily dose, weekly dose,
monthly dose, a sub-dose or an appropriate fraction thereof, of an
active ingredient. Furthermore, such pharmaceutical formulations
may be prepared by any of the methods well known in the pharmacy
art.
[0153] Pharmaceutical formulations may be adapted for
administration by any appropriate route, for example by the oral
(including capsules, tablets, liquid-filled capsules,
disintegrating tablets, immediate, delayed and controlled release
tablets, oral strips, solutions, syrups, buccal and sublingual),
rectal, nasal, inhalation, topical (including transdermal), vaginal
or parenteral (including subcutaneous, intramuscular, intravenous
or intradermal) route. Such formulations may be prepared by any
method known in the art of pharmacy, for example by bringing into
association the active ingredient with the carrier(s), excipient(s)
or diluent. Generally, the carrier, excipient or diluent employed
in the pharmaceutical formulation is "non-toxic," meaning that
it/they is/are deemed safe for consumption in the amount delivered
in the pharmaceutical composition, and "inert" meaning that it/they
does/do not appreciably react with or result in an undesired effect
on the therapeutic activity of the active ingredient.
[0154] In some embodiments, oral administration may be used.
Pharmaceutical preparations for oral use can be formulated into
conventional oral dosage forms such as discreet units capsules,
tablets, and liquid preparations such as syrups, elixirs, and
concentrated drops. Compounds described herein may be combined with
solid excipients, optionally grinding a resulting mixture, and
processing the mixture of granules, after adding suitable
auxiliaries, if desired, to obtain, for example, tablets, coated
tablets, hard capsules, soft capsules, solutions (e.g. aqueous,
alcoholic, or oily solutions) and the like. Suitable excipients
are, in particular, fillers such as sugars, including lactose,
glucose, sucrose, mannitol, or sorbitol; cellulose preparations,
for example, corn starch, wheat starch, rice starch, potato starch,
gelatin, gum tragacanth, methyl cellulose,
hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose (CMC),
and/or polyvinylpyrrolidone (PVP: povidone); oily excipients,
including vegetable and animal oils, such as sunflower oil, olive
oil, or cod-liver oil. The oral dosage formulations may also
contain disintegrating agents, such as the cross-linked
polyvinylpyrrolidone, agar, or alginic acid, or a salt thereof such
as sodium alginate; a lubricant, such as talc or magnesium
stearate; a plasticizer, such as glycerol or sorbitol; a sweetening
such as sucrose, fructose, lactose, or aspartame; a natural or
artificial flavoring agent, such as peppermint, oil of wintergreen,
or cherry flavoring; or dye-stuffs or pigments, which may be used
for identification or characterization of different doses or
combinations, such as unit dosages. Also provided are dragee cores
with suitable coatings. For this purpose, concentrated sugar
solutions may be used, which may optionally contain, for example,
gum arabic, talc, poly-vinylpyrrolidone, carbopol gel, polyethylene
glycol, and/or titanium dioxide, lacquer solutions, and suitable
organic solvents or solvent mixtures. Oral fluids such as
solutions, syrups and elixirs can be prepared in dosage unit form
so that a given quantity contains a predetermined amount of the
compound.
[0155] Pharmaceutical preparations that can be used orally include
push-fit capsules made of gelatin ("gelcaps"), as well as soft,
sealed capsules made of gelatin, and a plasticizer, such as
glycerol or sorbitol. The push-fit capsules can contain the active
ingredients in admixture with filler such as lactose, binders such
as starches, and/or lubricants such as talc or magnesium stearate
and, optionally, stabilizers. In soft capsules, the active
compounds may be dissolved or suspended in suitable liquids, such
as fatty oils, liquid paraffin, or liquid polyethylene glycols.
[0156] In some embodiments, injection (parenteral administration)
may be used, e.g., intramuscular, intravenous, intraperitoneal,
and/or subcutaneous. Compounds described herein for injection may
be formulated in sterile liquid solutions, preferably in
physiologically compatible buffers or solutions, such as saline
solution, Hank's solution, or Ringer's solution. Dispersions may
also be prepared in non-aqueous solutions, such as glycerol,
propylene glycol, ethanol, liquid polyethylene glycols, triacetin,
and vegetable oils. Solutions may also contain a preservative, such
as methylparaben, propylparaben, chlorobutanol, phenol, sorbic
acid, thimerosal, and the like. In addition, the compounds may be
formulated in solid form, including, for example, lyophilized
forms, and redissolved or suspended prior to use. The formulations
may be presented in unit-dose or multi-dose containers, for example
sealed ampoules and vials, and may be stored in a freeze-dried
(lyophilized) condition requiring only the addition of the sterile
liquid carrier, for example water for injection, immediately prior
to use.
[0157] In some embodiments, transmucosal, topical or transdermal
administration may be used. In such formulations of compounds
described herein, penetrants appropriate to the barrier to be
permeated are used. Such penetrants are generally known in the art,
and include, for example, for transmucosal administration, bile
salts and fusidic acid derivatives. In addition, detergents may be
used to facilitate permeation. Transmucosal administration, for
example, may be through nasal sprays or suppositories (rectal or
vaginal). Compositions of compounds described herein for topical
administration may be formulated as oils, creams, lotions,
ointments, and the like by choice of appropriate carriers known in
the art. Suitable carriers include vegetable or mineral oils, white
petrolatum (white soft paraffin), branched chain fats or oils,
animal fats and high molecular weight alcohol (greater than
C.sub.12). In some embodiments, carriers are selected such that the
active ingredient is soluble. Emulsifiers, stabilizers, humectants
and antioxidants may also be included as well as agents imparting
color or fragrance, if desired. Creams for topical application are
preferably formulated from a mixture of mineral oil,
self-emulsifying beeswax and water in which mixture the active
ingredient, dissolved in a small amount of solvent (e.g., an oil),
is admixed. Additionally, administration by transdermal means may
comprise a transdermal patch or dressing such as a bandage
impregnated with an active ingredient and optionally one or more
carriers or diluents known in the art. To be administered in the
form of a transdermal delivery system, the dosage administration
will be continuous rather than intermittent throughout the dosage
regimen.
[0158] In some embodiments, the compounds as disclosed herein
(e.g., Compound I or a salt thereof, or one or more solid or
amorphous forms of Compound I) are administered as inhalants.
Compounds described herein may be formulated as dry powder or a
suitable solution, suspension, or aerosol. Powders and solutions
may be formulated with suitable additives known in the art. For
example, powders may include a suitable powder base such as lactose
or starch, and solutions may comprise propylene glycol, sterile
water, ethanol, sodium chloride and other additives, such as acid,
alkali and buffer salts. Such solutions or suspensions may be
administered by inhaling via spray, pump, atomizer, or nebulizer,
and the like. The compounds described herein may also be used in
combination with other inhaled therapies, for example
corticosteroids such as fluticasone proprionate, beclomethasone
dipropionate, triamcinolone acetonide, budesonide, and mometasone
furoate; beta agonists such as albuterol, salmeterol, and
formoterol; anticholinergic agents such as ipratroprium bromide or
tiotropium; vasodilators such as treprostinal and iloprost; enzymes
such as DNAase; therapeutic proteins; immunoglobulin antibodies; an
oligonucleotide, such as single or double stranded DNA or RNA,
siRNA; antibiotics such as tobramycin; muscarinic receptor
antagonists; leukotriene antagonists; cytokine antagonists;
protease inhibitors; cromolyn sodium; nedocril sodium; and sodium
cromoglycate.
[0159] The amounts of various compounds to be administered can be
determined by standard procedures taking into account factors such
as the compound activity (in vitro, e.g. the compound IC.sub.50 vs.
target, or in vivo activity in animal efficacy models),
pharmacokinetic results in animal models (e.g. biological half-life
or bioavailability), the age, size, and weight of the subject, and
the disorder associated with the subject. The importance of these
and other factors are well known to those of ordinary skill in the
art. Generally, a dose will be in the range of about 0.01 to 50
mg/kg, also about 0.1 to 20 mg/kg of the subject being treated.
Multiple doses may be used.
[0160] The compounds described herein (e.g., Compound I or a salt
thereof, or one or more solid or amorphous forms of Compound I) may
also be used in combination with other therapies, drugs, medical
procedures, etc. for treating the same disease. In some
embodiments, such combination use includes administration of one or
more other therapies, drugs, or medical procedures at different
times (e.g. within a short time, such as within hours (e.g. 1, 2,
3, 4-24 hours), or within a longer time (e.g. 1-2 days, 2-4 days,
4-7 days, 1-4 weeks)) than a compound described herein, or at the
same time as a compound described herein. In some embodiments, use
in combination includes use with at least one other therapy, drug
or medical procedure that is administered once or infrequently,
such as surgery, along with a compound described herein
administered within a short time or longer time before or after the
other therapy, drug or procedure. In some embodiments, use in
combination includes delivery of a compound described herein and
one or more other drug therapeutics by the same route or different
routes of administration. In some embodiments, a compound described
herein and one or more other drug therapeutics may be delivered
together in any formulation by the same route of administration,
including formulations where the compounds and other drug
therapeutic(s) are chemically linked in such a way that they
maintain their therapeutic activity when administered. In some
embodiments, the other drug therapeutic(s) may be co-administered
with a compound described herein. In some embodiments,
co-administration includes administration of co-formulations or
formulations of chemically joined compounds, or administration of
two or more compounds in separate formulations within a short time
of each other (e.g. within an hour, 2 hours, 3 hours, up to 24
hours), administered by the same or different routes.
Co-administration of separate formulations includes
co-administration by delivery via one device, for example the same
inhalant device, the same syringe, etc., or administration from
separate devices within a short time of each other. Co-formulations
of a compound described herein and one or more additional drug
therapeutics delivered by the same route includes preparation of
the materials together such that they can be administered by one
device, including the separate compounds combined in one
formulation, or compounds that are modified such that they are
chemically joined, yet still maintain their biological activity.
Such chemically joined compounds may have a linkage that is
substantially maintained in vivo, or the linkage may break down in
vivo, separating the two active components. In some embodiments,
the compounds as disclosed herein may be used in adjuvant or
neoadjuvant therapy in combination with other therapies or
therapeutic agents as described herein. In some embodiments
involving combination use, dosage may be modified for one or more
of the compounds of the present disclosure or other therapeutics
used in combination, e.g., reduction in the amount dosed relative
to a compound or therapy used alone, by methods well known to those
of ordinary skill in the art. Exemplary combination therapies are
discussed below.
4. DISEASE INDICATIONS AND MODULATIONS OF BROMODOMAIN
[0161] Members of the BET (Bromodomain and Extra Terminal) family
of bromodomain proteins (BRD2, BRD3, BRD4 and BRDT) have been
associated with a variety of disorders including neurological
diseases, autoimmune and inflammatory diseases, metabolic diseases
(Muller et al. Expert Rev. Mol. Med. 2011, Sep. 13; 13:e29; Prinjha
et al. Trends Pharmacol. Sci. 2012, 33, 146-153; Belkina et al. J.
Immunol. 2013, 190, 3670-3678; and Belkina et al. Nature Rev.
Cancer 2012, 12, 465-477) and cancers (Alsarraj et al.
International Journal of Breast Cancer 2012, 1-7; Barbieri et al.
Briefings in Functional Genomics 2013, 1-12; Blobel et al. Cancer
Cell 2011, 20, 287-288; Dang Cell 2012, 149, 22-35). In addition,
some viruses make use of these proteins to tether their genomes to
the host cells chromatin, as part of the process of viral
replication (You et al. Cell, 2004 117, 349-60).
[0162] The compounds as described herein (e.g., Compound I or a
salt thereof, or one or more solid or amorphous forms of Compound
I) are useful for treating disorders related to one or more
proteins involved in epigenetic regulation, such as proteins
containing acetyl-lysine recognition motifs, i.e., bromodomains
(e.g., BET proteins, such as BRD2, BRD3, BRD4, and/or BRDT), and
e.g., diseases related to abnormal expression of bromodomains,
including cell proliferative disorders, cancers, chronic
autoimmune, inflammatory conditions, among others.
[0163] The presence of bromodomains has been associated with a
number of different types of cancers, and other diseases and
conditions, as described below. Bromodomain inhibitors are useful
in the treatment of systemic or tissue inflammation, inflammatory
responses to infection or hypoxia, cellular activation and
proliferation, lipid metabolism, fibrosis and in the prevention and
treatment of viral infections.
[0164] Bromodomain inhibitors such as the compounds described
herein (e.g., Compound I or a salt thereof, or one or more solid or
amorphous forms of Compound I) are useful in the prevention and
treatment of chronic autoimmune and inflammatory conditions such as
rheumatoid arthritis, uveal melanoma, chronic lymphocytic leukemia,
acute myeloid leukemia, synovial sarcoma, osteoarthritis, acute
gout, psoriasis, systemic lupus erythematosus, multiple sclerosis,
inflammatory bowel disease (Crohn's disease and Ulcerative
colitis), asthma, chronic obstructive airways disease, pneumonitis,
myocarditis, pericarditis, myositis, eczema, dermatitis, alopecia,
vitiligo, bullous skin diseases, nephritis, vasculitis,
atherosclerosis, Alzheimer's disease, depression, retinitis,
uveitis, scleritis, hepatitis, pancreatitis, primary biliary
cirrhosis, sclerosing cholangitis, Addison's disease, hypophysitis,
thyroiditis, type I diabetes, and acute rejection of transplanted
organs.
[0165] Bromodomain inhibitors such as the compounds described
herein (e.g., Compound I or a salt thereof, or one or more solid or
amorphous forms of Compound I) are useful in the prevention and
treatment of acute inflammatory conditions, including, but not
limiting to, acute gout, giant cell arteritis, nephritis including
lupus nephritis, vasculitis with organ involvement such as
glomerulonephritis, vasculitis including giant cell arteritis,
Wegener's granulomatosis, Polyarteritis nodosa, Behcet's disease,
Kawasaki disease, Takayasu's Arteritis, vasculitis with organ
involvement and acute rejection of transplanted organs.
[0166] Bromodomain inhibitors such as the compounds described
herein (e.g., Compound I or a salt thereof, or one or more solid or
amorphous forms of Compound I) are useful in the prevention and
treatment of autoimmune and inflammatory diseases or conditions
which involve inflammatory responses to infections with bacteria,
viruses, such as herpes virus, human papilloma virus, adenovirus
and poxvirus and other DNA viruses; fungi, parasites or their
toxins, such as sepsis, sepsis syndrome, septic shock,
endotoxaemia, systemic inflammatory response syndrome (SIRS),
multi-organ dysfunction syndrome, toxic shock syndrome, acute lung
injury, ARDS (adult respiratory distress syndrome), acute renal
failure, fulminant hepatitis, burns, acute pancreatitis,
post-surgical syndromes, sarcoidosis, Herxheimer reactions,
encephalitis, myelitis, meningitis, malaria and SIRS associated
with viral infections such as influenza, herpes zoster, herpes
simplex and coronavirus.
[0167] Bromodomain inhibitors such as the compounds described
herein (e.g., Compound I or a salt thereof, or one or more solid or
amorphous forms of Compound I) are useful in the prevention and
treatment of diseases or conditions associated with
ischemia-reperfusion injury, including, but not limiting to,
myocardial infarction, cerebro-vascular ischemia (stroke), acute
coronary syndromes, renal reperfusion injury, organ
transplantation, coronary artery bypass grafting, cardio-pulmonary
bypass procedures, pulmonary, renal, hepatic, gastro-intestinal or
peripheral limb embolism.
[0168] Bromodomain inhibitors such as the compounds described
herein (e.g., Compound I or a salt thereof, or one or more solid or
amorphous forms of Compound I) are useful in the prevention and
treatment of hypercholesterolemia, atherosclerosis and Alzheimer's
disease.
[0169] Bromodomain inhibitors such as the compounds described
herein (e.g., Compound I or a salt thereof, or one or more solid or
amorphous forms of Compound I) are useful in the prevention and
treatment of cancers including, but not limiting to, hematological,
epithelial including lung, breast and colon carcinomas, midline
carcinomas, mesenchymal, hepatic, renal, neurological tumors,
adrenal cancer, acinic cell carcinoma, acoustic neuroma, acral
lentiginous melanoma, acrospiroma, acute eosinophilic leukemia,
acute erythroid leukemia, acute lymphoblastic leukemia, acute
megakaryoblastic leukemia, acute monocytic leukemia, acute
promyelocytic leukemia, adenocarcinoma, adenoid cystic carcinoma,
adenoma, adenomatoid odontogenic tumor, adenosquamous carcinoma,
adipose tissue neoplasm, adrenocortical carcinoma, adult T-cell
leukemia/lymphoma, aggressive NK-cell leukemia, AIDS-related
lymphoma, alveolar rhabdomyosarcoma, alveolar soft part sarcoma,
ameloblastic fibroma, anaplastic large cell lymphoma, anaplastic
thyroid cancer, angioimmunoblastic T-cell lymphoma, angiomyolipoma,
angiosarcoma, astrocytoma, atypical teratoid rhabdoid tumor, B-cell
chronic lymphocytic leukemia, B-cell prolymphocytic leukemia,
B-cell lymphoma, basal cell carcinoma, biliary tract cancer,
bladder cancer, blastoma, bone cancer, Brenner tumor, Brown tumor,
Burkitt's lymphoma, breast cancer, brain cancer, carcinoma,
carcinoma in situ, carcinosarcoma, cartilage tumor, cementoma,
myeloid sarcoma, chondroma, chordoma, choriocarcinoma, choroid
plexus papilloma, clear-cell sarcoma of the kidney,
craniopharyngioma, cutaneous T-cell lymphoma, cervical cancer,
colorectal cancer, Degos disease, desmoplastic small round cell
tumor, diffuse large B-cell lymphoma, dysembryoplastic
neuroepithelial tumor, dysgerminoma, embryonal carcinoma, endocrine
gland neoplasm, endodermal sinus tumor, enteropathy-associated
T-cell lymphoma, esophageal cancer, fetus in fetu, fibroma,
fibrosarcoma, follicular lymphoma, follicular thyroid cancer,
ganglioneuroma, gastrointestinal cancer, germ cell tumor,
gestational choriocarcinoma, giant cell fibroblastoma, giant cell
tumor of the bone, glial tumor, glioblastoma multiforme, glioma,
gliomatosis cerebri, glucagonoma, gonadoblastoma, granulosa cell
tumor, gynandroblastoma, gallbladder cancer, gastric cancer, hairy
cell leukemia, hemangioblastoma, head and neck cancer,
hemangiopericytoma, hematological malignancy, hepatoblastoma,
hepatosplenic T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's
lymphoma, invasive lobular carcinoma, intestinal cancer, kidney
cancer, laryngeal cancer, lentigo maligna, lethal midline
carcinoma, leukemia, leydig cell tumor, liposarcoma, lung cancer,
lymphangioma, lymphangiosarcoma, lymphoepithelioma, lymphoma, acute
lymphocytic leukemia, acute myelogenous leukemia, chronic
lymphocytic leukemia, liver cancer, small cell lung cancer,
non-small cell lung cancer, MALT lymphoma, malignant fibrous
histiocytoma, malignant peripheral nerve sheath tumor, malignant
triton tumor, mantle cell lymphoma, marginal zone B-cell lymphoma,
mast cell leukemia, mediastinal germ cell tumor, medullary
carcinoma of the breast, medullary thyroid cancer, medulloblastoma,
melanoma, meningioma, merkel cell cancer, mesothelioma, metastatic
urothelial carcinoma, mixed Mullerian tumor, mucinous tumor,
multiple myeloma, muscle tissue neoplasm, mycosis fungoides, myxoid
liposarcoma, myxoma, myxosarcoma, nasopharyngeal carcinoma,
neurinoma, neuroblastoma, neurofibroma, neuroma, nodular melanoma,
ocular cancer, oligoastrocytoma, oligodendroglioma, oncocytoma,
optic nerve sheath meningioma, optic nerve tumor, oral cancer,
osteosarcoma, ovarian cancer, Pancoast tumor, papillary thyroid
cancer, paraganglioma, pinealoblastoma, pineocytoma, pituicytoma,
pituitary adenoma, pituitary tumor, plasmacytoma, polyembryoma,
precursor T-lymphoblastic lymphoma, primary central nervous system
lymphoma, primary effusion lymphoma, primary peritoneal cancer,
prostate cancer, pancreatic cancer, pharyngeal cancer, pseudomyxoma
peritonei, renal cell carcinoma, renal medullary carcinoma,
retinoblastoma, rhabdomyoma, rhabdomyosarcoma, Richter's
transformation (also known as Richter's Syndrome), rectal cancer,
sarcoma, Schwannomatosis, seminoma, Sertoli cell tumor, sex
cord-gonadal stromal tumor, signet ring cell carcinoma, skin
cancer, small blue round cell tumors, small cell carcinoma, soft
tissue sarcoma, somatostatinoma, soot wart, spinal tumor, splenic
marginal zone lymphoma, squamous cell carcinoma, synovial sarcoma,
Sezary's disease, small intestine cancer, squamous carcinoma,
stomach cancer, T-cell lymphoma, testicular cancer, thecoma,
thyroid cancer, transitional cell carcinoma, throat cancer, urachal
cancer, urogenital cancer, urothelial carcinoma, uveal melanoma,
uterine cancer, verrucous carcinoma, visual pathway glioma, vulvar
cancer, vaginal cancer, Waldenstrom's macroglobulinemia, Warthin's
tumor, and Wilms' tumor.
5. METHODS FOR TREATING CONDITIONS MEDIATED BY BROMODOMAIN
[0170] The present disclosure provides, in some embodiments, a
method for modulating or inhibiting a bromodomain (e.g., a BET
protein or BRD4 protein) or mutant thereof, wherein modulation or
inhibition of bromodomain plays a role or provides some benefits.
For instance, in some embodiments, the present disclosure provides
a method for modulating or inhibiting a bromodomain or mutant
thereof by contacting any one or more solid or amorphous forms of
Compound I as described herein (e.g., Compound I Form A, Compound I
Form B, Compound I Form C, Compound I Form D, Compound I Material
E, Compound I Material F, Compound I Material G, Compound I Free
Acid Amorphous, a free acid amorphous salt form of Compound I, or
Compound I sodium Material A), or a composition comprising any one
or more solid or amorphous forms of Compound I as described herein,
with a cell or a bromodomain protein in vitro or in vivo. In some
embodiments, the present disclosure provides a method for
modulating or inhibiting a bromodomain or mutant thereof by
contacting Compound I or a salt thereof, or a composition
comprising Compound I or a salt thereof, with a cell or a
bromodomain protein in vitro or in vivo.
[0171] In some embodiments, the present disclosure provides a
method for treating a subject suffering from or at risk of a
bromodomain mediated disease or condition by administering to the
subject an effective amount of any one or more solid or amorphous
forms of Compound I as described herein (e.g., Compound I Form A,
Compound I Form B, Compound I Form C, Compound I Form D, Compound I
Material E, Compound I Material F, Compound I Material G, Compound
I Free Acid Amorphous, a free acid amorphous salt form of Compound
I, or Compound I sodium Material A), or a composition comprising a
compound as described herein. In some embodiments, the present
disclosure provides a method for treating a subject suffering from
or at risk of a bromodomain mediated disease or condition by
administering to the subject an effective amount of Compound I or a
salt thereof, or a composition comprising Compound I or a salt
thereof. In some embodiments, the subject is a human. In some
embodiments, the subject is a non-human animal.
[0172] In some embodiments, the present disclosure provides a
method of suppressing undesired proliferation of tumor cells
mediated by bromodomain. The method includes contacting tumor cells
with an effective amount of a compound as described herein (e.g.,
Compound I or a salt thereof, Compound I Form A, Compound I Form B,
Compound I Form C, Compound I Form D, Compound I Material E,
Compound I Material F, Compound I Material G, Compound I Free Acid
Amorphous, a free acid amorphous salt form of Compound I, or
Compound I sodium Material A), or a composition comprising a
compound as described herein. In some instances, the tumor cells
are mediated by BET protein, BRD4 protein or a mutant thereof.
[0173] In some embodiments, the diseases or conditions treatable
with one or more compounds as described herein (e.g., Compound I or
a salt thereof, Compound I Form A, Compound I Form B, Compound I
Form C, Compound I Form D, Compound I Material E, Compound I
Material F, Compound I Material G, Compound I Free Acid Amorphous,
a free acid amorphous salt form of Compound I, or Compound I sodium
Material A) include a cancer, a neurological condition, an
autoimmune condition, an inflammatory condition, a metabolic
disease, or combinations thereof.
[0174] In some embodiments, the diseases or conditions treatable
with one or more compounds as described herein (e.g., Compound I or
a salt thereof, Compound I Form A, Compound I Form B, Compound I
Form C, Compound I Form D, Compound I Material E, Compound I
Material F, Compound I Material G, Compound I Free Acid Amorphous,
a free acid amorphous salt form of Compound I, or Compound I sodium
Material A) include, but are not limited to, a cancer, e.g.,
hematological, epithelial including lung, breast and colon
carcinomas, midline carcinomas, mesenchymal, hepatic, renal,
neurological tumors, adrenal cancer, acinic cell carcinoma,
acoustic neuroma, acral lentiginous melanoma, acrospiroma, acute
eosinophilic leukemia, acute erythroid leukemia, acute
lymphoblastic leukemia, acute megakaryoblastic leukemia, acute
monocytic leukemia, acute promyelocytic leukemia, adenocarcinoma,
adenoid cystic carcinoma, adenoma, adenomatoid odontogenic tumor,
adenosquamous carcinoma, adipose tissue neoplasm, adrenocortical
carcinoma, adult T-cell leukemia/lymphoma, aggressive NK-cell
leukemia, AIDS-related lymphoma, alveolar rhabdomyosarcoma,
alveolar soft part sarcoma, ameloblastic fibroma, anaplastic large
cell lymphoma, anaplastic thyroid cancer, angioimmunoblastic T-cell
lymphoma, angiomyolipoma, angiosarcoma, astrocytoma, atypical
teratoid rhabdoid tumor, B-cell chronic lymphocytic leukemia,
B-cell prolymphocytic leukemia, B-cell lymphoma, basal cell
carcinoma, biliary tract cancer, bladder cancer, blastoma, bone
cancer, Brenner tumor, Brown tumor, Burkitt's lymphoma, breast
cancer, brain cancer, carcinoma, carcinoma in situ, carcinosarcoma,
cartilage tumor, cementoma, myeloid sarcoma, chondroma, chordoma,
choriocarcinoma, choroid plexus papilloma, clear-cell sarcoma of
the kidney, craniopharyngioma, cutaneous T-cell lymphoma, cervical
cancer, colorectal cancer, Degos disease, desmoplastic small round
cell tumor, diffuse large B-cell lymphoma, dysembryoplastic
neuroepithelial tumor, dysgerminoma, embryonal carcinoma, endocrine
gland neoplasm, endodermal sinus tumor, enteropathy-associated
T-cell lymphoma, esophageal cancer, fetus in fetu, fibroma,
fibrosarcoma, follicular lymphoma, follicular thyroid cancer,
ganglioneuroma, gastrointestinal cancer, germ cell tumor,
gestational choriocarcinoma, giant cell fibroblastoma, giant cell
tumor of the bone, glial tumor, glioblastoma multiforme, glioma,
gliomatosis cerebri, glucagonoma, gonadoblastoma, granulosa cell
tumor, gynandroblastoma, gallbladder cancer, gastric cancer, hairy
cell leukemia, hemangioblastoma, head and neck cancer,
hemangiopericytoma, hematological malignancy, hepatoblastoma,
hepatosplenic T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's
lymphoma, invasive lobular carcinoma, intestinal cancer, kidney
cancer, laryngeal cancer, lentigo maligna, lethal midline
carcinoma, leukemia, leydig cell tumor, liposarcoma, lung cancer,
lymphangioma, lymphangiosarcoma, lymphoepithelioma, lymphoma, acute
lymphocytic leukemia, acute myelogenous leukemia, chronic
lymphocytic leukemia, liver cancer, small cell lung cancer,
non-small cell lung cancer, MALT lymphoma, malignant fibrous
histiocytoma, malignant peripheral nerve sheath tumor, malignant
triton tumor, mantle cell lymphoma, marginal zone B-cell lymphoma,
mast cell leukemia, mediastinal germ cell tumor, medullary
carcinoma of the breast, medullary thyroid cancer, medulloblastoma,
melanoma, meningioma, merkel cell cancer, mesothelioma, metastatic
urothelial carcinoma, mixed Mullerian tumor, mucinous tumor,
multiple myeloma, muscle tissue neoplasm, mycosis fungoides, myxoid
liposarcoma, myxoma, myxosarcoma, nasopharyngeal carcinoma,
neurinoma, neuroblastoma, neurofibroma, neuroma, nodular melanoma,
ocular cancer, oligoastrocytoma, oligodendroglioma, oncocytoma,
optic nerve sheath meningioma, optic nerve tumor, oral cancer,
osteosarcoma, ovarian cancer, Pancoast tumor, papillary thyroid
cancer, paraganglioma, pinealoblastoma, pineocytoma, pituicytoma,
pituitary adenoma, pituitary tumor, plasmacytoma, polyembryoma,
precursor T-lymphoblastic lymphoma, primary central nervous system
lymphoma, primary effusion lymphoma, primary peritoneal cancer,
prostate cancer, pancreatic cancer, pharyngeal cancer, pseudomyxoma
peritonei, renal cell carcinoma, renal medullary carcinoma,
retinoblastoma, rhabdomyoma, rhabdomyosarcoma, Richter's
transformation (also known as Richter's Syndrome), rectal cancer,
sarcoma, Schwannomatosis, seminoma, Sertoli cell tumor, sex
cord-gonadal stromal tumor, signet ring cell carcinoma, skin
cancer, small blue round cell tumors, small cell carcinoma, soft
tissue sarcoma, somatostatinoma, soot wart, spinal tumor, splenic
marginal zone lymphoma, squamous cell carcinoma, synovial sarcoma,
Sezary's disease, small intestine cancer, squamous carcinoma,
stomach cancer, T-cell lymphoma, testicular cancer, thecoma,
thyroid cancer, transitional cell carcinoma, throat cancer, urachal
cancer, urogenital cancer, urothelial carcinoma, uveal melanoma,
chronic lymphocytic leukemia, uterine cancer, verrucous carcinoma,
visual pathway glioma, vulvar cancer, vaginal cancer, Waldenstrom's
macroglobulinemia, Warthin's tumor, and Wilms' tumor.
[0175] In some embodiments, the cancer treatable with the compounds
of the present disclosure (e.g., Compound I or a salt thereof,
Compound I Form A, Compound I Form B, Compound I Form C, Compound I
Form D, Compound I Material E, Compound I Material F, Compound I
Material G, Compound I Free Acid Amorphous, a free acid amorphous
salt form of Compound I, or Compound I sodium Material A) is
selected from adenocarcinoma, adult T-cell leukemia/lymphoma,
bladder cancer, blastoma, bone cancer, breast cancer, brain cancer,
carcinoma, myeloid sarcoma, cervical cancer, colorectal cancer,
esophageal cancer, gastrointestinal cancer, glioblastoma
multiforme, glioma, gallbladder cancer, gastric cancer, head and
neck cancer, Hodgkin's lymphoma, non-Hodgkin's lymphoma, intestinal
cancer, kidney cancer, laryngeal cancer, leukemia, lung cancer,
lymphoma, liver cancer, small cell lung cancer, non-small cell lung
cancer, mesothelioma, multiple myeloma, ocular cancer, optic nerve
tumor, oral cancer, ovarian cancer, pituitary tumor, primary
central nervous system lymphoma, prostate cancer, pancreatic
cancer, pharyngeal cancer, renal cell carcinoma, rectal cancer,
sarcoma, skin cancer, spinal tumor, small intestine cancer, stomach
cancer, T-cell lymphoma, testicular cancer, thyroid cancer, throat
cancer, urogenital cancer, urothelial carcinoma, uterine cancer,
vaginal cancer, or Wilms' tumor.
[0176] In some embodiments, the cancers or tumors treatable with
the compounds of the present disclosure (e.g., Compound I or a salt
thereof, Compound I Form A, Compound I Form B, Compound I Form C,
Compound I Form D, Compound I Material E, Compound I Material F,
Compound I Material G, Compound I Free Acid Amorphous, a free acid
amorphous salt form of Compound I, or Compound I sodium Material A)
include benign soft tissue tumors, bone tumors, brain and spinal
tumors, eyelid and orbital tumors, granuloma, lipoma, meningioma,
multiple endocrine neoplasia, nasal polyps, pituitary tumors,
prolactinoma, pseudotumor cerebri, seborrheic keratosis, stomach
polyps, thyroid nodules, cystic neoplasms of the pancreas,
hemangiomas, vocal cord nodules, polyps, and cysts, Castleman
disease, chronic pilonidal disease, dermatofibroma, pilar cyst,
pyogenic granuloma, and juvenile polyposis syndrome.
[0177] In some embodiments, the diseases or conditions treatable
with the compounds of the present disclosure (e.g., Compound I or a
salt thereof, Compound I Form A, Compound I Form B, Compound I Form
C, Compound I Form D, Compound I Material E, Compound I Material F,
Compound I Material G, Compound I Free Acid Amorphous, a free acid
amorphous salt form of Compound I, or Compound I sodium Material A)
include non-small cell lung cancer, small cell lung cancer, ovarian
cancer, melanoma, midline carcinomas, breast cancer, lymphomas,
neuroblastoma, or castration resistant prostate cancer,
myelofibrosis, myelodysplastic syndromes, or acute myeloid
leukemia.
[0178] In some embodiments, the diseases or conditions treatable
with the compounds of the present disclosure (e.g., Compound I or a
salt thereof, Compound I Form A, Compound I Form B, Compound I Form
C, Compound I Form D, Compound I Material E, Compound I Material F,
Compound I Material G, Compound I Free Acid Amorphous, a free acid
amorphous salt form of Compound I, or Compound I sodium Material A)
include non-small cell lung cancer, small cell lung cancer, ovarian
cancer, melanoma, neuroblastoma, and castration resistant prostate
cancer.
[0179] In some embodiments, the present disclosure provides a
method for treating a subject suffering or at risk of a disease or
condition mediated by a bromodomain, or mutant thereof, by
administering to the subject in need thereof an effective amount of
any one or more solid or amorphous forms of Compound I as described
herein (e.g., Compound I Form A, Compound I Form B, Compound I Form
C, Compound I Form D, Compound I Material E, Compound I Material F,
Compound I Material G, Compound I Free Acid Amorphous, a free acid
amorphous salt form of Compound I, or Compound I sodium Material
A), or a composition comprising any one or more solid or amorphous
forms of Compound I as described herein, where the disease or
condition is chronic lymphocytic leukemia (CLL), Ricther's
Syndrome, uveal melanoma, acute myeloid leukemia (AML), or
myelodysplastic syndromes (MDS). In some embodiments, the present
disclosure provides a method for treating a subject suffering or at
risk of a disease or condition mediated by a bromodomain, or mutant
thereof, by administering to the subject in need thereof an
effective amount of Compound I or a salt thereof, or a composition
comprising Compound I or a salt thereof, where the disease or
condition is chronic lymphocytic leukemia (CLL), Ricther's
Syndrome, uveal melanoma, acute myeloid leukemia (AML), or
myelodysplastic syndromes (MDS). In one embodiment, the disease is
chronic lymphocytic leukemia (CLL). In one embodiment, the disease
or condition is Ricther's Syndrome. In one embodiment, the disease
or condition is uveal cancer. In one embodiment, the disease or
condition is myeloid leukemia. In one embodiment, the disease or
condition is myelodysplastic syndromes (MDS).
[0180] In some embodiments, the present disclosure provides a
method for treating a subject suffering or at risk of a disease or
condition mediated by a bromodomain, or mutant thereof, by
administering to the subject in need thereof an effective amount of
any one or more solid or amorphous forms of Compound I as described
herein (e.g., Compound I Form A, Compound I Form B, Compound I Form
C, Compound I Form D, Compound I Material E, Compound I Material F,
Compound I Material G, Compound I Free Acid Amorphous, a free acid
amorphous salt form of Compound I, or Compound I sodium Material
A), or a composition comprising any one or more solid or amorphous
forms of Compound I as described herein, where the disease or
condition is chronic lymphocytic leukemia (CLL) or Ricther's
Syndrome. In some embodiments, the present disclosure provides a
method for treating a subject suffering or at risk of a disease or
condition mediated by a bromodomain, or mutant thereof, by
administering to the subject in need thereof an effective amount of
Compound I or a salt thereof, or a composition comprising Compound
I or a salt thereof, where the disease or condition is chronic
lymphocytic leukemia (CLL) or Ricther's Syndrome. In one
embodiment, the disease is chronic lymphocytic leukemia (CLL). In
one embodiment, the disease or condition is Ricther's Syndrome.
[0181] In some embodiments, the present disclosure provides a
method for treating a subject suffering or at risk of a disease or
condition mediated by a bromodomain, or mutant thereof, by
administering to the subject in need thereof an effective amount of
any one or more solid or amorphous forms of Compound I as described
herein (e.g., Compound I Form A, Compound I Form B, Compound I Form
C, Compound I Form D, Compound I Material E, Compound I Material F,
Compound I Material G, Compound I Free Acid Amorphous, a free acid
amorphous salt form of Compound I, or Compound I sodium Material
A), or a composition comprising any one or more solid or amorphous
forms of Compound I as described herein, where the disease or
condition is acute myeloid leukemia (AML) or myelodysplastic
syndromes (MDS). In some embodiments, the present disclosure
provides a method for treating a subject suffering or at risk of a
disease or condition mediated by a bromodomain, or mutant thereof,
by administering to the subject in need thereof an effective amount
of Compound I or a salt thereof, or a composition comprising
Compound I or a salt thereof, where the disease or condition is
acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS). In
one embodiment, the disease or condition is acute myeloid leukemia
(AML). In one embodiment, the disease or condition is
myelodysplastic syndromes (MDS).
[0182] In some embodiments, the diseases or conditions treatable
with one or more compounds disclosed herein (e.g., Compound I or a
salt thereof, Compound I Form A, Compound I Form B, Compound I Form
C, Compound I Form D, Compound I Material E, Compound I Material F,
Compound I Material G, Compound I Free Acid Amorphous, a free acid
amorphous salt form of Compound I, or Compound I sodium Material A)
include autoimmune or inflammatory diseases or conditions. These
autoimmune or inflammatory diseases or conditions may be chronic or
acute and include, but are not limited to, inflammatory pelvic
disease, urethritis, skin sunburn, sinusitis, pneumonitis,
encephalitis, meningitis, myocarditis, pericarditis, nephritis
including lupus nephritis, osteomyelitis, myositis, eczema,
hepatitis, gastritis, enteritis, dermatitis, gingivitis,
appendicitis, pancreatitis, primary biliary cirrhosis,
cholecystitis, sclerosing cholangitis, agammaglobulinemia,
psoriasis, allergy, Crohn's disease, irritable bowel syndrome,
ulcerative colitis, Sjogren's disease, tissue graft rejection such
as acute graft-versus-host disease, hyperacute rejection of
transplanted organs, asthma, chronic obstructive airways disease,
allergic rhinitis, chronic obstructive pulmonary disease (COPD),
autoimmune polyglandular disease (also known as autoimmune
polyglandular syndrome), autoimmune alopecia, pernicious anemia,
vasculitis, glomerulonephritis, giant cell arteritis, Wegener's
granulomatosis, Polyarteritis nodosa, dermatomyositis, multiple
sclerosis, scleroderma, autoimmune hemolytic and thrombocytopenic
states, Goodpasture's syndrome, atherosclerosis, Addison's disease,
hypophysitis, Parkinson's disease, Alzheimer's disease, Kawasaki
disease, Takayasu's Arteritis, depression, retinitis, uveitis,
scleritis, Type I diabetes, septic shock, systemic lupus
erythematosus (SLE), rheumatoid arthritis, psoriatic arthritis,
juvenile arthritis, osteoarthritis, gout, chronic idiopathic
thrombocytopenic purpura, Waldenstrom macroglobulinemia, myasthenia
gravis, Hashimoto's thyroiditis, atopic dermatitis, degenerative
joint disease, vitiligo, bullous skin diseases, autoimmune
hypopituitarism, Guillain-Barre syndrome, Behcet's disease,
scleracierma, mycosis fungoides, acute inflammatory responses (such
as acute respiratory distress syndrome and ischemia/reperfusion
injury), and Graves' disease. In some embodiments, the autoimmune
and inflammatory diseases and conditions may also include systemic
or tissue inflammation, inflammatory responses to hypoxia, cellular
activation and proliferation, lipid metabolism, fibrosis,
infections with bacteria, infections with viruses (e.g., herpes
virus, human papilloma virus, adenovirus, poxvirus and other DNA
viruses), fungi, parasites or their toxins, such as sepsis, sepsis
syndrome, septic shock, endotoxaemia, systemic inflammatory
response syndrome (SIRS), multi-organ dysfunction syndrome, toxic
shock syndrome, acute lung injury, ARDS (adult respiratory distress
syndrome), acute renal failure, fulminant hepatitis, burns, acute
pancreatitis, post-surgical syndromes, sarcoidosis, Herxheimer
reactions, encephalitis, myelitis, meningitis, malaria and SIRS
associated with viral infections such as influenza, herpes zoster,
herpes simplex and coronavirus.
[0183] In some embodiments, the present disclosure provides methods
for treating a subject suffering or at risk of ischemia-reperfusion
injury by administering to the subject in need thereof an effective
amount of a compound as described herein (e.g., Compound I or a
salt thereof, Compound I Form A, Compound I Form B, Compound I Form
C, Compound I Form D, Compound I Material E, Compound I Material F,
Compound I Material G, Compound I Free Acid Amorphous, a free acid
amorphous salt form of Compound I, or Compound I sodium Material
A), or a composition comprising a compound as described herein. The
ischemia-reperfusion injury, includes, but is not limited to,
myocardial infarction, cerebro-vascular ischemia (stroke), acute
coronary syndromes, renal reperfusion injury, organ
transplantation, coronary artery bypass grafting, cardio-pulmonary
bypass procedures, pulmonary, renal, hepatic, gastro-intestinal and
peripheral limb embolism.
[0184] In some embodiments, the present disclosure provides a
method for treating a subject suffering or at risk of a disease or
condition mediated by a bromodomain, or mutant thereof, by
administering to the subject in need thereof an effective amount of
any one or more solid or amorphous forms of Compound I as described
herein (e.g., Compound I Form A, Compound I Form B, Compound I Form
C, Compound I Form D, Compound I Material E, Compound I Material F,
Compound I Material G, Compound I Free Acid Amorphous, a free acid
amorphous salt form of Compound I, or Compound I sodium Material
A), or a composition comprising any one or more solid or amorphous
forms of Compound I as described herein, where the disease or
condition is rheumatoid arthritis, uveal melanoma, chronic
lymphocytic leukemia, acute myeloid leukemia, synovial sarcoma,
osteoarthritis, acute gout, psoriasis, systemic lupus
erythematosus, multiple sclerosis, inflammatory bowel disease
(Crohn's disease and Ulcerative colitis), asthma, chronic
obstructive airways disease, pneumonitis, myocarditis,
pericarditis, myositis, eczema, dermatitis, alopecia, vitiligo,
bullous skin diseases, nephritis, vasculitis, atherosclerosis,
Alzheimer's disease, depression, retinitis, uveitis, scleritis,
hepatitis, pancreatitis, primary biliary cirrhosis, sclerosing
cholangitis, Addison's disease, hypophysitis, thyroiditis, type I
diabetes, or acute rejection of transplanted organs. In some
embodiments, the present disclosure provides a method for treating
a subject suffering or at risk of a disease or condition mediated
by a bromodomain, or mutant thereof, by administering to the
subject in need thereof an effective amount of Compound I or a salt
thereof, or a composition comprising Compound I or a salt thereof,
where the disease or condition is rheumatoid arthritis, uveal
melanoma, chronic lymphocytic leukemia, osteoarthritis, acute
myeloid leukemia, synovial sarcoma, acute gout, psoriasis, systemic
lupus erythematosus, multiple sclerosis, inflammatory bowel disease
(Crohn's disease and Ulcerative colitis), asthma, chronic
obstructive airways disease, pneumonitis, myocarditis,
pericarditis, myositis, eczema, dermatitis, alopecia, vitiligo,
bullous skin diseases, nephritis, vasculitis, atherosclerosis,
Alzheimer's disease, depression, retinitis, uveitis, scleritis,
hepatitis, pancreatitis, primary biliary cirrhosis, sclerosing
cholangitis, Addison's disease, hypophysitis, thyroiditis, type I
diabetes, or acute rejection of transplanted organs. In one
embodiment, the disease or condition is rheumatoid arthritis. In
one embodiment, the disease or condition is osteoarthritis. In one
embodiment, the disease or condition is acute gout. In one
embodiment, the disease or condition is psoriasis. In one
embodiment, the disease or condition is systemic lupus. In one
embodiment, the disease or condition is systemic lupus. In one
embodiment, the disease or condition iserythematosus. In one
embodiment, the disease or condition is multiple sclerosis. In one
embodiment, the disease or condition is inflammatory bowel disease.
In one embodiment, the disease or condition is Crohn's disease. In
one embodiment, the disease or condition is ulcerative colitis. In
one embodiment, the disease or condition is asthma. In one
embodiment, the disease or condition is chronic obstructive airways
disease. In one embodiment, the disease or condition is
pneumonitis. In one embodiment, the disease or condition is
myocarditis. In one embodiment, the disease or condition is
pericarditis. In one embodiment, the disease or condition is
myositis. In one embodiment, the disease or condition is eczema. In
one embodiment, the disease or condition is dermatitis. In one
embodiment, the disease or condition is alopecia. In one
embodiment, the disease or condition is vitiligo. In one
embodiment, the disease or condition is bullous skin diseases. In
one embodiment, the disease or condition is nephritis. In one
embodiment, the disease or condition is vasculitis. In one
embodiment, the disease or condition is atherosclerosis. In one
embodiment, the disease or condition is Alzheimer's disease. In one
embodiment, the disease or condition is depression. In one
embodiment, the disease or condition is retinitis. In one
embodiment, the disease or condition is uveitis. In one embodiment,
the disease or condition is scleritis. In one embodiment, the
disease or condition is hepatitis. In one embodiment, the disease
or condition is pancreatitis. In one embodiment, the disease or
condition is primary biliary cirrhosis. In one embodiment, the
disease or condition is sclerosing cholangitis. In one embodiment,
the disease or condition is Addinson's disease. In one embodiment,
the disease of condition is hypophysitis. In one embodiment, the
disease or condition is thyroiditis. In one embodiment, the disease
or condition is Type I diabetes. In one embodiment, the disease or
condition is acute rejection of transplanted organs.
[0185] In some embodiments, the present disclosure provides methods
for treating a subject suffering or at risk of hypercholesterolemia
by administering to the subject in need thereof an effective amount
of any one or more solid or amorphous forms of Compound I as
described herein (e.g., Compound I Form A, Compound I Form B,
Compound I Form C, Compound I Form D, Compound I Material E,
Compound I Material F, Compound I Material G, Compound I Free Acid
Amorphous, a free acid amorphous salt form of Compound I, or
Compound I sodium Material A), or a composition comprising any one
or more solid or amorphous forms of Compound I as described herein.
In some embodiments, the present disclosure provides methods for
treating a subject suffering or at risk of hypercholesterolemia by
administering to the subject in need thereof an effective amount of
Compound I or a salt thereof, or a composition comprising Compound
I or a salt thereof.
[0186] In some embodiments, the present disclosure provides use of
a compound as described herein (e.g., Compound I or a salt thereof,
Compound I Form A, Compound I Form B, Compound I Form C, Compound I
Form D, Compound I Material E, Compound I Material F, Compound I
Material G, Compound I Free Acid Amorphous, a free acid amorphous
salt form of Compound I, or Compound I sodium Material A), or a
composition comprising a compound as described herein, in the
manufacture of a medicament for the treatment of a disease or
condition as described herein. In some embodiments, the present
disclosure provides a compound as described herein, or a
composition comprising a compound as described herein, for use in
treating a disease or condition as described herein.
[0187] As discussed in detail below, the present disclosure
provides combination therapies for treating a subject suffering
from or at risk of the diseases or conditions described herein,
where such combination therapies comprise administering to the
subject in need thereof any one or more of the compounds disclosed
herein (e.g., Compound I or a salt thereof, Compound I Form A,
Compound I Form B, Compound I Form C, Compound I Form D, Compound I
Material E, Compound I Material F, Compound I Material G, Compound
I Free Acid Amorphous, a free acid amorphous salt form of Compound
I, or Compound I sodium Material A), or a composition comprising
any one or more of the compounds as described herein, in
combination with one or more other therapeutic agents including,
but not limited to, a BCL-2 inhibitor, a PI3K inhibitor, BTK
inhibitor, a CTLA-4 inhibitor, a checkpoint inhibitor, or
quizartinib.
[0188] The following literature publications describe just some
examples of these uses for bromodomain inhibitors.
[0189] Since compounds described herein have been shown to be
bromodomain inhibitors, then the following publications confirm
utilities of the claimed compounds.
Cancer
[0190] Bromodomain inhibitors have been administered to humans in
clinical trials for breast cancer, non-small cell lung cancer,
small cell lung cancer, acute myeloid leukemia, myelodysplastic
neoplasm, myelodysplastic syndrome, midline carcinoma, castration
resistant prostate cancer, pancreatic cancer, multiple myeloma,
colorectal cancer, and neuroblastoma (C.A. French, Small-Molecule
Targeting of BET Proteins in Cancer, Advances in Cancer Research,
(2016), 131, 21-58).
[0191] Bromodomain 4 (BRD4) inhibitor inhibits colorectal cancer
growth and metastasis colorectal cancer (Y. Hu, et al., BRD4
Inhibitor Inhibits Colorectal Cancer Growth and Metastasis, Int. J.
Mol. Sci. (2015), 16, 1928-1948).
[0192] Bromodomain inhibitors inhibits castration-resistant
prostate cancer (L.A. Asangani, et al., Therapeutic targeting of
BET bromodomain proteins in castration-resistant prostate cancer,
Nature (2014), 510, 278-282).
[0193] A panel of neuroblastoma cell lines were administered
bromodomain inhibitors which resulted in potent growth inhibition
and cytotoxicity in most cell lines (A. Wyce, et al., BET
Inhibition Silences Expression of MYCN and BCL2 and Induces
Cytotoxicity in Neuroblastoma Tumor Models, PLOS ONE (2013), 8, 8,
1-16).
[0194] Bromodomain inhibitors potently reduces the viability in
acute lymphoblastic leukemia (C. J. Ott, et al., BET bromodomain
inhibition targets both c-MYC and IL7R in high-risk acute
lymphyoblastic leukemia, Blood Journal (2012), 1-23).
[0195] Bromodomain inhibitors selectively suppress proliferation of
mouse and human AML cell lines. (A. F. Hohmann et al., Sensitivity
and engineered resistance of myeloid leukemia cells to BRD9
inhibition, Nature Chemical Biology (2016), 12, 672-679).
[0196] Compound I of this disclosure was found to be a structurally
distinct BET inhibitor with novel in vitro and in vivo
pharmacologic properties that emulatesor exceeds the efficacy of
B-cell receptor (BCR) signaling agents in pre-clinical models of
CLL. (H. G. Ozer et al., BRD4 profiling identifies critical Chronic
Lymphocytic Leukemia oncogenic circuits and reveals sensitivity to
PLX51107, a novel structurally distinct BET inhibitor, Cancer
Discovery, Published Online Mar. 14, 2018 doi:
10.1158/2159-8290.CD-17-0902).
[0197] In mouse xenograft models of uveal melanoma (UM) Compound I
of this disclosure significantly inhibited tumor growth. (G.
Ambrosini et al., Cytotoxic Effects of a Novel BRD4 Inhibitor in
Uveal Melanoma Cells with Gnaq/11 Mutations, Molecular and Cellular
Biology, Genetics, DOI: 10.1158/1538-7445.AM2016-4462 Published
July 2016).
[0198] Several bromodomain inhibitor drug candidates have
progressed into clinical trials for myelodysplastic syndrome, AML,
multiple myeloma, and Glioblastoma Multiform (G.W. Rhyasen, et al.,
AZD5153: A Novel Bivalent BET Bromodomain Inhibitor Highly Active
against Hematologic Malignancies, Mol. Cancer Ther. (2016), 15, 11,
2563-2574).
[0199] Bromodomain 4 (BRD4) inhibitors have been found to lead to
selective inhibition of MYC oncogene in multiple myeloma (J. Loven,
et al., Selective Inhibition of Tumor Oncogenes by Disruption of
Super-Enhancers, Cell (2013), 153, 320-334).
[0200] Potent antimyeloma activity was observed with bromodomain
inhibitors (A. Chaidos, et al., Potent antimyeloma activity of the
novel bromodomain inhibitors I-BET151 and I-BET762, Blood (2014),
123, 5, 697-705).
[0201] Bromodomain inhibitors were found induce cell cycle arrest
in Glioblastoma Multiforme cells (C. Pastori, et al., The
Bromodomain protein BRD4 controls HOTAIR, a long noncoding RNA
essential for glioblastoma proliferation, PNAS (2015), 1-6).
[0202] It has been demonstrated that suppression of BRD4 correlates
with suppression of Merkel Cell Carcinoma xenograft tumor growth
(D. Sengupta, et al., Disruption of BRD4 at H3K27Ac-enriched
enhancer region correlates with decreased c-Myc expression in
Merkel cell carcinoma, Epigenetics (2015), 10, 6, 460-466).
[0203] BRD4 inhibitors have suppressed breast cancer cell growth
(J. Shi, et al., Disrupting the Interaction of BRD4 with
Diacetylated Twist Suppresses Tumorigenesis in Basal-like Breast
Cancer, Cancer Cell (2014), 25, 210-225).
[0204] It has been demonstrated that bromodomain inhibition primes
NSCLC cells for induction of apoptosis, and BRD inhibitors show
differential anti-proliferative activity in a panel of NSCLC cell
lines (O. Klingbeil, et al., Inhibition of BET
bromodomain-dependent XIAP and FLIP expression sensitizes
KRAS-mutated NSCLC to pro-apoptic agents, Cell Death and Disease
(2016), 7, e2365, doi:10.1038/cddis.2016.271, 1-13).
[0205] BRD4 inhibitors significantly inhibit the proliferation and
survival of osteosarcoma cells (D.H. Lee et al., Synergistic Effect
of JQ1 2014 and Rapamycin for Treatment of Human Osteosarcoma, Int.
J. Cancer (2015), 135, 2055-2064).
[0206] Bromodomain inhibitors demonstrated inhibitory effects on
ovarian cancer cell lines (A.M Kurimchak, et al., Resistance to BET
Bromodomain Inhibitors is Mediated by Kinome Reprogramming in
Ovarian Cancer, Cell Reports (2016), 16, 1273-1286).
[0207] Bromodomain inhibitors potently inhibit gastric cancer cell
growth (R. C. Montenegro, et al., BET inhibition as a new strategy
for the treatment of gastric cancer, Oncotarget (2016), 7, 28,
43997-44012).
[0208] Certain LAC cell lines are acutely susceptible to
bromodomain inhibition (W.W. Lockwood, et al., Sensitivity of human
lung adenocarcinoma cell lines to targeted inhibition of BET
epigenetic signaling proteins, PNAS (2012), 109, 47,
19408-19413)
[0209] BRD4 is a promising target for midline carcinoma (J. Lu et
al., Hijacking the E3 Ubiquitin Ligase Cereblon to Efficiently
Target BRD4, Chemistry & Biology (2015), 22, 755-763).
[0210] It has been found that BRD4 inhibitors suppress both growth
and tumorigenesis of malignant peripheral nerve sheath tumors
(MPNST) (A.J. Patel et al., BET Bromodomain Inhibition Triggers
Apoptosis of NF1-Associated Malignant Peripheral Nerve Sheath
Tumors through Bim Induction, Cell Reports (2014), 6, 1-12).
[0211] Bromodomain inhibitors have been found to cause apoptosis
and reduce growth of melanoma cells (A. Heinemann et al., Combining
BET and HDAC inhibitors synergistically induces apoptosis of
melanoma and suppresses AKT and YAP signaling, Oncotarget (2015) 6,
25, 21507-21521).
[0212] BRD4 inhibition has been characterized as a novel
therapeutic intervention against uveal melanoma (G. Ambrosini et
al., BRD4-targeted therapy induces Myc-independent cytotoxicity in
Gnaq/11-mutatant uveal melanoma cells, Oncotarget (2015), 6, 32,
33397-33409).
[0213] Mice harboring medulloblastoma xenografts exhibited
prolonged survival when treated with bromodomain inhibitors (A.
Hennsen et al., BET bromodomain protein inhibition is a therapeutic
option for medulloblastoma, Oncotarget (2013), 4, 11,
2080-2095).
Lymphoma
[0214] Bromodomain inhibitors inhibit the proliferation of lymphoma
cell lines of different origins (M. Jung, et al., Targeting BET
bromodomains for cancer treatment, Epigenomics (2015), 7(3),
487-501).
[0215] Bromodomain inhibitors have been shown to be affective
against Burkitt's Lymphoma (S. Wu, et al., Phospho Switch Triggers
Brd4 Chromotin Binding and Activator Recruitment for Gene-Specific
Targeting, Molecular Cell (2013), 49, 1-15; J. Lu et al., Hijacking
the E3 Ubiquitin Ligase Cereblon to Efficiently Target BRD4,
Chemistry & Biology (2015), 22, 755-763).
[0216] Bromodomain inhibition induces apoptosis in B-cell lymphoma
(S.J. Hogg et al., BET inhibition Induces Apoptosis in Aggressive
B-Cell Lymphoma via Epigenetic Regulation of BCL-2 Family Members,
Mol Cancer Ther (2016), 15, 9, 2030-2041).
[0217] Inflammation and Autoimmune Disorders
[0218] Bromodomain inhibitors have been shown to be effective for
the treatment of disease indications such as autoimmune diseases
and inflammation (O.A. Kharenko, et al., RVX-297--a novel BD2
selective inhibitor of BET bromodomains, Biochemical and
Biophysical Research Communication (2016), 477, 62-67).
[0219] It has been found that bromodomain inhibition provides
beneficial activity for the disease area of autoimmunity (D.U. Lee
et al., Nonselective inhibition of the epigenetic transcriptional
regulator BET induces marked lymphoid and hematopoietic toxicity in
mice, Toxicology and Applied Pharmacology (2016), 300, 47-54).
[0220] It has been found that bromodomain inhibition ameliorates
colitis in mice (K. Cheung et al., BET N-terminal bromodomain
inhibition selectively blocks Thl7 cell differentiation and
ameliorates colitis in mice, PNAS (2017), 114, 11, 2952-2957).
[0221] BRD4 inhibitors reduces IL-1-induced inflammation in human
airway epithelial cells and may be effective for treating chronic
obstructive pulmonary disease (Y.M. Khan, et al., Brd4 is Essential
for IL-10-Induced Inflammation in Human Airway Epithelial Cells,
PLOS ONE (2014), 9, 4, 1-17).
[0222] Bromodomain inhibition provides beneficial activity for
atherosclerosis (D.U. Lee et al., Nonselective inhibition of the
epigenetic transcriptional regulator BET induces marked lymphoid
and hematopoietic toxicity in mice, Toxicology and Applied
Pharmacology (2016), 300, 47-54).
Arthritic/Joint Related Diseases
[0223] Bromodomain inhibitors decreases joint swelling and
inflammation and helps to prevent bone loss, which can be useful
for treating rheumatoid arthritis and osteoarthritis (K. Park-Min,
et al., Inhibition of osteoclastogenesis and inflammatory bone
resorption by targeting BET proteins and epigenetic regulation,
Nature Communications (2014), 5:5418, 1-9).
[0224] Bromodomains mediate inflammatory-related pathologies such
as rheumatoid arthritis (K.A. Papavassiliou, et al., Bromodomains:
pockets with therapeutic potential, Trends in Molecular Medicine
(2014), 20, 9, 477-478).
6. COMBINATION THERAPY
[0225] Bromodomain modulators may be usefully combined with another
pharmacologically active compound, or with two or more other
pharmacologically active compounds, particularly in the treatment
of cancer and other diseases and indications described herein. In
one embodiment, the composition includes any one or more
compound(s) as described (e.g., Compound I or a salt thereof, or
any one or more solid or amorphous forms of Compound I) along with
one or more compounds that are therapeutically effective for the
same disease indication, wherein the compounds have a synergistic
effect on the disease indication. In one embodiment, the
composition includes any one or more compound(s) as described
herein effective in treating a cancer and one or more other
compounds that are effective in treating the same cancer, further
wherein the compounds are synergistically effective in treating the
cancer.
[0226] In some embodiments, the present disclosure provides a
composition, e.g., a pharmaceutical composition comprising any one
or more solid or amorphous forms of Compound I as described herein
(e.g., Compound I or a salt thereof, Compound I Form A, Compound I
Form B, Compound I Form C, Compound I Form D, Compound I Material
E, Compound I Material F, Compound I Material G, Compound I Free
Acid Amorphous, a free acid amorphous salt form of Compound I, or
Compound I sodium Material A) and one or more other therapeutic
agents. In some embodiments, the present disclosure provides a
composition, e.g., a pharmaceutical composition comprising Compound
I or a salt thereof and one or more other therapeutic agents. In
some embodiments, the one or more other therapeutic agents are
selected from an alkylating agent, including, but not limiting to,
adozelesin, altretamine, bendamustine, bizelesin, busulfan,
carboplatin, carboquone, carmofur, carmustine, chlorambucil,
cisplatin, cyclophosphamide, dacarbazine, estramustine, etoglucid,
fotemustine, hepsulfam, ifosfamide, improsulfan, irofulven,
lomustine, mannosulfan, mechlorethamine, melphalan, mitobronitol,
nedaplatin, nimustine, oxaliplatin, piposulfan, prednimustine,
procarbazine, ranimustine, satraplatin, semustine, streptozocin,
temozolomide, thiotepa, treosulfan, triaziquone,
triethylenemelamine, triplatin tetranitrate, trofosphamide, and
uramustine; an antibiotic, including, but not limiting to,
aclarubicin, amrubicin, bleomycin, dactinomycin, daunorubicin,
doxorubicin, elsamitrucin, epirubicin, idarubicin, menogaril,
mitomycin, neocarzinostatin, pentostatin, pirarubicin, plicamycin,
valrubicin, and zorubicin; an antimetabolite, including, but not
limiting to, aminopterin, azacitidine, azathioprine, capecitabine,
cladribine, clofarabine, cytarabine, decitabine, floxuridine,
fludarabine, 5-fluorouracil, gemcitabine, hydroxyurea,
mercaptopurine, methotrexate, nelarabine, pemetrexed, raltitrexed,
tegafur-uracil, thioguanine, trimethoprim, trimetrexate, and
vidarabine; an immunotherapy, an antibody therapy, including, but
not limiting to, alemtuzumab, bevacizumab, cetuximab, galiximab,
gemtuzumab, panitumumab, pertuzumab, rituximab, brentuximab,
tositumomab, trastuzumab, 90 Y ibritumomab tiuxetan, ipilimumab,
tremelimumab and anti-CTLA-4 antibodies; a hormone or hormone
antagonist, including, but not limiting to, anastrozole, androgens,
buserelin, diethylstilbestrol, exemestane, flutamide, fulvestrant,
goserelin, idoxifene, letrozole, leuprolide, magestrol, raloxifene,
tamoxifen, and toremifene; a taxane, including, but not limiting
to, DJ-927, docetaxel, TPI 287, larotaxel, ortataxel, paclitaxel,
DHA-paclitaxel, and tesetaxel; a retinoid, including, but not
limiting to, alitretinoin, bexarotene, fenretinide, isotretinoin,
and tretinoin; an alkaloid, including, but not limiting to,
demecolcine, homoharringtonine, vinblastine, vincristine,
vindesine, vinflunine, and vinorelbine; an antiangiogenic agent,
including, but not limiting to, AE-941 (GW786034, Neovastat),
ABT-510, 2-methoxyestradiol, lenalidomide, and thalidomide; a
topoisomerase inhibitor, including, but not limiting to, amsacrine,
belotecan, edotecarin, etoposide, etoposide phosphate, exatecan,
irinotecan (also active metabolite SN-38
(7-ethyl-10-hydroxy-camptothecin)), lucanthone, mitoxantrone,
pixantrone, rubitecan, teniposide, topotecan, and
9-aminocamptothecin; a kinase inhibitor, including, but not liming
to, axitinib (AG 013736), dasatinib (BMS 354825), erlotinib,
gefitinib, flavopiridol, imatinib mesylate, lapatinib, motesanib
diphosphate (AMG 706), nilotinib (AMN107), seliciclib, sorafenib,
sunitinib malate, AEE-788, BMS-599626, UCN-01
(7-hydroxystaurosporine), vemurafenib, dabrafenib, selumetinib,
LGX818, BGB-283, PLX3397 and vatalanib; a targeted signal
transduction inhibitor including, but not limiting to bortezomib,
geldanamycin, and rapamycin; a biological response modifier,
including, but not limiting to, imiquimod, interferon-.alpha., and
interleukin-2; and other chemotherapeutics, including, but not
limiting to 3-AP (3-amino-2-carboxyaldehyde thiosemicarbazone),
altrasentan, aminoglutethimide, anagrelide, asparaginase,
bryostatin-1, cilengitide, elesclomol, eribulin mesylate (E7389),
ixabepilone, lonidamine, masoprocol, mitoguanazone, oblimersen,
sulindac, testolactone, tiazofurin, mTOR inhibitors (e.g.
sirolimus, temsirolimus, everolimus, deforolimus), BCL-2 inhibitors
(e.g., venetocalx), PI3K inhibitors (e.g. BEZ235, venetocalx,
idelalisib, IDH1, IDH2, EZH2, GDC-0941, XL147, XL765), BTK
inhibitor s (e.g., ibrutinib, alacabrutinib), Cdk4 inhibitors (e.g.
PD-332991), Akt inhibitors, CTLA-4 inhibitors (ipilimumab), Hsp90
inhibitors (e.g. geldanamycin, radicicol, tanespimycin), checkpoint
inhibitors (PD-1 inhibitors such as nivolumab, or PDL-1 inhibitors
such as pembrolizumab), farnesyltransferase inhibitors (e.g.
tipifarnib), and Aromatase inhibitors (anastrozole letrozole
exemestane).
[0227] In some embodiments, the present disclosure provides a
composition, e.g., a pharmaceutical composition comprising any one
or more solid or amorphous forms of Compound I as described herein
(e.g., Compound I or a salt thereof, Compound I Form A, Compound I
Form B, Compound I Form C, Compound I Form D, Compound I Material
E, Compound I Material F, Compound I Material G, Compound I Free
Acid Amorphous, a free acid amorphous salt form of Compound I, or
Compound I sodium Material A) and one or more other therapeutic
agents selected from an alkylating agent, including, but not
limiting to, adozelesin, altretamine, bendamustine, bizelesin,
busulfan, carboplatin, carboquone, carmofur, carmustine,
chlorambucil, cisplatin, cyclophosphamide, dacarbazine,
estramustine, etoglucid, fotemustine, hepsulfam, ifosfamide,
improsulfan, irofulven, lomustine, mannosulfan, mechlorethamine,
melphalan, mitobronitol, nedaplatin, nimustine, oxaliplatin,
piposulfan, prednimustine, procarbazine, ranimustine, satraplatin,
semustine, streptozocin, temozolomide, thiotepa, treosulfan,
triaziquone, triethylenemelamine, triplatin tetranitrate,
trofosphamide, and uramustine; an antibiotic, including, but not
limiting to, aclarubicin, amrubicin, bleomycin, dactinomycin,
daunorubicin, doxorubicin, elsamitrucin, epirubicin, idarubicin,
menogaril, mitomycin, neocarzinostatin, pentostatin, pirarubicin,
plicamycin, valrubicin, and zorubicin; an antimetabolite,
including, but not limiting to, aminopterin, azacitidine,
azathioprine, capecitabine, cladribine, clofarabine, cytarabine,
decitabine, floxuridine, fludarabine, 5-fluorouracil, gemcitabine,
hydroxyurea, mercaptopurine, methotrexate, nelarabine, pemetrexed,
raltitrexed, tegafur-uracil, thioguanine, trimethoprim,
trimetrexate, and vidarabine; an immunotherapy, an antibody
therapy, including, but not limiting to, alemtuzumab, bevacizumab,
cetuximab, galiximab, gemtuzumab, panitumumab, pertuzumab,
rituximab, brentuximab, tositumomab, trastuzumab, 90 Y ibritumomab
tiuxetan, ipilimumab, tremelimumab and anti-CTLA-4 antibodies; a
hormone or hormone antagonist, including, but not limiting to,
anastrozole, androgens, buserelin, diethylstilbestrol, exemestane,
flutamide, fulvestrant, goserelin, idoxifene, letrozole,
leuprolide, magestrol, raloxifene, tamoxifen, and toremifene; a
taxane, including, but not limiting to, DJ-927, docetaxel, TPI 287,
larotaxel, ortataxel, paclitaxel, DHA-paclitaxel, and tesetaxel; a
retinoid, including, but not limiting to, alitretinoin, bexarotene,
fenretinide, isotretinoin, and tretinoin; an alkaloid, including,
but not limiting to, demecolcine, homoharringtonine, vinblastine,
vincristine, vindesine, vinflunine, and vinorelbine; an
antiangiogenic agent, including, but not limiting to, AE-941
(GW786034, Neovastat), ABT-510, 2-methoxyestradiol, lenalidomide,
and thalidomide; a topoisomerase inhibitor, including, but not
limiting to, amsacrine, belotecan, edotecarin, etoposide, etoposide
phosphate, exatecan, irinotecan (also active metabolite SN-38
(7-ethyl-10-hydroxy-camptothecin)), lucanthone, mitoxantrone,
pixantrone, rubitecan, teniposide, topotecan, and
9-aminocamptothecin; a kinase inhibitor, including, but not liming
to, axitinib (AG 013736), dasatinib (BMS 354825), erlotinib,
gefitinib, flavopiridol, imatinib mesylate, lapatinib, motesanib
diphosphate (AMG 706), nilotinib (AMN107), seliciclib, sorafenib,
sunitinib malate, AEE-788, BMS-599626, UCN-01
(7-hydroxystaurosporine), vemurafenib, dabrafenib, selumetinib,
paradox breakers (such as PLX8394 or PLX7904), LGX818, BGB-283,
pexidartinib (PLX3397) and vatalanib; a targeted signal
transduction inhibitor including, but not limiting to bortezomib,
geldanamycin, and rapamycin; a biological response modifier,
including, but not limiting to, imiquimod, interferon-.alpha., and
interleukin-2; and other chemotherapeutics, including, but not
limiting to 3-AP (3-amino-2-carboxyaldehyde thiosemicarbazone),
altrasentan, aminoglutethimide, anagrelide, asparaginase,
bryostatin-1, cilengitide, elesclomol, eribulin mesylate (E7389),
ixabepilone, lonidamine, masoprocol, mitoguanazone, oblimersen,
sulindac, testolactone, tiazofurin, mTOR inhibitors (e.g.
sirolimus, temsirolimus, everolimus, deforolimus, INK28, AZD8055,
PI3K inhibitors (e.g. BEZ235, GDC-0941, XL147, XL765, BMK120), Cdk4
inhibitors (e.g. PD-332991), Akt inhibitors, Hsp90 inhibitors (e.g.
geldanamycin, radicicol, tanespimycin), farnesyltransferase
inhibitors (e.g. tipifarnib), and Aromatase inhibitors (anastrozole
letrozole exemestane).
[0228] In some embodiments, the present disclosure provides a
composition, e.g., a pharmaceutical composition comprising Compound
I or a salt thereof, and one or more other therapeutic agents
selected from an alkylating agent, including, but not limiting to,
adozelesin, altretamine, bendamustine, bizelesin, busulfan,
carboplatin, carboquone, carmofur, carmustine, chlorambucil,
cisplatin, cyclophosphamide, dacarbazine, estramustine, etoglucid,
fotemustine, hepsulfam, ifosfamide, improsulfan, irofulven,
lomustine, mannosulfan, mechlorethamine, melphalan, mitobronitol,
nedaplatin, nimustine, oxaliplatin, piposulfan, prednimustine,
procarbazine, ranimustine, satraplatin, semustine, streptozocin,
temozolomide, thiotepa, treosulfan, triaziquone,
triethylenemelamine, triplatin tetranitrate, trofosphamide, and
uramustine; an antibiotic, including, but not limiting to,
aclarubicin, amrubicin, bleomycin, dactinomycin, daunorubicin,
doxorubicin, elsamitrucin, epirubicin, idarubicin, menogaril,
mitomycin, neocarzinostatin, pentostatin, pirarubicin, plicamycin,
valrubicin, and zorubicin; an antimetabolite, including, but not
limiting to, aminopterin, azacitidine, azathioprine, capecitabine,
cladribine, clofarabine, cytarabine, decitabine, floxuridine,
fludarabine, 5-fluorouracil, gemcitabine, hydroxyurea,
mercaptopurine, methotrexate, nelarabine, pemetrexed, raltitrexed,
tegafur-uracil, thioguanine, trimethoprim, trimetrexate, and
vidarabine; an immunotherapy, an antibody therapy, including, but
not limiting to, alemtuzumab, bevacizumab, cetuximab, galiximab,
gemtuzumab, panitumumab, pertuzumab, rituximab, brentuximab,
tositumomab, trastuzumab, 90 Y ibritumomab tiuxetan, ipilimumab,
tremelimumab and anti-CTLA-4 antibodies; a hormone or hormone
antagonist, including, but not limiting to, anastrozole, androgens,
buserelin, diethylstilbestrol, exemestane, flutamide, fulvestrant,
goserelin, idoxifene, letrozole, leuprolide, magestrol, raloxifene,
tamoxifen, and toremifene; a taxane, including, but not limiting
to, DJ-927, docetaxel, TPI 287, larotaxel, ortataxel, paclitaxel,
DHA-paclitaxel, and tesetaxel; a retinoid, including, but not
limiting to, alitretinoin, bexarotene, fenretinide, isotretinoin,
and tretinoin; an alkaloid, including, but not limiting to,
demecolcine, homoharringtonine, vinblastine, vincristine,
vindesine, vinflunine, and vinorelbine; an antiangiogenic agent,
including, but not limiting to, AE-941 (GW786034, Neovastat),
ABT-510, 2-methoxyestradiol, lenalidomide, and thalidomide; a
topoisomerase inhibitor, including, but not limiting to, amsacrine,
belotecan, edotecarin, etoposide, etoposide phosphate, exatecan,
irinotecan (also active metabolite SN-38
(7-ethyl-10-hydroxy-camptothecin)), lucanthone, mitoxantrone,
pixantrone, rubitecan, teniposide, topotecan, and
9-aminocamptothecin; a kinase inhibitor, including, but not liming
to, axitinib (AG 013736), dasatinib (BMS 354825), erlotinib,
gefitinib, flavopiridol, imatinib mesylate, lapatinib, motesanib
diphosphate (AMG 706), nilotinib (AMN107), seliciclib, sorafenib,
sunitinib malate, AEE-788, BMS-599626, UCN-01
(7-hydroxystaurosporine), vemurafenib, dabrafenib, selumetinib,
paradox breakers (such as PLX8394 or PLX7904), LGX818, BGB-283,
pexidartinib (PLX3397) and vatalanib; a targeted signal
transduction inhibitor including, but not limiting to bortezomib,
geldanamycin, and rapamycin; a biological response modifier,
including, but not limiting to, imiquimod, interferon-.alpha., and
interleukin-2; and other chemotherapeutics, including, but not
limiting to 3-AP (3-amino-2-carboxyaldehyde thiosemicarbazone),
altrasentan, aminoglutethimide, anagrelide, asparaginase,
bryostatin-1, cilengitide, elesclomol, eribulin mesylate (E7389),
ixabepilone, lonidamine, masoprocol, mitoguanazone, oblimersen,
sulindac, testolactone, tiazofurin, mTOR inhibitors (e.g.
sirolimus, temsirolimus, everolimus, deforolimus, INK28, AZD8055,
PI3K inhibitors (e.g. BEZ235, GDC-0941, XL147, XL765, BMK120), Cdk4
inhibitors (e.g. PD-332991), Akt inhibitors, Hsp90 inhibitors (e.g.
geldanamycin, radicicol, tanespimycin), farnesyltransferase
inhibitors (e.g. tipifarnib), and Aromatase inhibitors (anastrozole
letrozole exemestane).
[0229] In some embodiments, the present disclosure provides a
composition, e.g., a pharmaceutical composition comprising any one
or more solid or amorphous forms of Compound I as described herein
(e.g., Compound I or a salt thereof, Compound I Form A, Compound I
Form B, Compound I Form C, Compound I Form D, Compound I Material
E, Compound I Material F, Compound I Material G, Compound I Free
Acid Amorphous, a free acid amorphous salt form of Compound I, or
Compound I sodium Material A) and one or more other therapeutic
agents selected from i) an alkylating agent selected from
adozelesin, altretamine, bizelesin, busulfan, carboplatin,
carboquone, carmustine, chlorambucil, cisplatin, cyclophosphamide,
dacarbazine, estramustine, fotemustine, hepsulfam, ifosfamide,
improsulfan, irofulven, lomustine, mechlorethamine, melphalan,
oxaliplatin, piposulfan, semustine, streptozocin, temozolomide,
thiotepa, and treosulfan; ii) an antibiotic selected from
bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin,
idarubicin, menogaril, mitomycin, mitoxantrone, neocarzinostatin,
pentostatin, and plicamycin; iii) an antimetabolite selected from
azacitidine, capecitabine, cladribine, clofarabine, cytarabine,
decitabine, floxuridine, fludarabine, 5-fluorouracil, ftorafur,
gemcitabine, hydroxyurea, mercaptopurine, methotrexate, nelarabine,
pemetrexed, raltitrexed, thioguanine, and trimetrexate; iv) an
antibody therapy agent selected from alemtuzumab, bevacizumab,
cetuximab, galiximab, gemtuzumab, nivolumab, panitumumab,
pembrolizumab, pertuzumab, rituximab, tositumomab, trastuzumab, and
90 Y ibritumomab tiuxetan; v) a hormone or hormone antagonist
selected from anastrozole, androgens, buserelin,
diethylstilbestrol, exemestane, flutamide, fulvestrant, goserelin,
idoxifene, letrozole, leuprolide, magestrol, raloxifene, tamoxifen,
and toremifene; vi) a taxane selected from DJ-927, docetaxel, TPI
287, paclitaxel and DHA-paclitaxel; vii) a retinoid selected from
alitretinoin, bexarotene, fenretinide, isotretinoin, and tretinoin;
viii) an alkaloid selected from etoposide, homoharringtonine,
teniposide, vinblastine, vincristine, vindesine, and vinorelbine;
ix) an antiangiogenic agent selected from AE-941 (GW786034,
Neovastat), ABT-510, 2-methoxyestradiol, lenalidomide, and
thalidomide; x) a topoisomerase inhibitor selected from amsacrine,
edotecarin, exatecan, irinotecan, SN-38
(7-ethyl-10-hydroxy-camptothecin), rubitecan, topotecan, and
9-aminocamptothecin; xi) a kinase inhibitor selected from
erlotinib, gefitinib, flavopiridol, imatinib mesylate, lapatinib,
sorafenib, sunitinib malate, AEE-788, AG-013736, AMG 706, AMN107,
BMS-354825, BMS-599626, UCN-01 (7-hydroxystaurosporine),
vemurafenib, dabrafenib, trametinib, cobimetinib selumetinib and
vatalanib; xii) a targeted signal transduction inhibitor selected
from bortezomib, geldanamycin, and rapamycin; xiii) a biological
response modifier selected from imiquimod, interferon-.alpha. and
interleukin-2; xiv) an IDO inhibitor; and xv) a chemotherapeutic
agent selected from 3-AP (3-amino-2-carboxyaldehyde
thiosemicarbazone), altrasentan, aminoglutethimide, anagrelide,
asparaginase, bryostatin-1, cilengitide, elesclomol, eribulin
mesylate (E7389), ixabepilone, lonidamine, masoprocol,
mitoguanazone, oblimersen, sulindac, testolactone, tiazofurin, a
mTOR inhibitor, a PI3K inhibitor, a Cdk4 inhibitor, an Akt
inhibitor, a Hsp90 inhibitor, a farnesyltransferase inhibitor or an
aromatase inhibitor (anastrozole letrozole exemestane); xvi) a Mek
inhibitor; xvii) a tyrosine kinase inhibitor; xviii) a c-Kit mutant
inhibitor, xix) an EGFR inhibitor, or xx) an epigenetic modulator.
In further embodiments, a bromodomain modulator, particularly a
solid or amorphous form of Compound I as described herein (e.g.,
Compound I Form A, Compound I Form B, Compound I Form C, Compound I
Form D, Compound I Material E, Compound I Material F, Compound I
Free Acid Amorphous, a free acid amorphous salt form of Compound I,
or the sodium salt of Compound I), may be administered
simultaneously, sequentially or separately in combination with one
or more agents as described above.
[0230] In some embodiments, the present disclosure provides a
composition, e.g., a pharmaceutical composition comprising Compound
I or a salt thereof, and one or more other therapeutic agents
selected from i) an alkylating agent selected from adozelesin,
altretamine, bizelesin, busulfan, carboplatin, carboquone,
carmustine, chlorambucil, cisplatin, cyclophosphamide, dacarbazine,
estramustine, fotemustine, hepsulfam, ifosfamide, improsulfan,
irofulven, lomustine, mechlorethamine, melphalan, oxaliplatin,
piposulfan, semustine, streptozocin, temozolomide, thiotepa, and
treosulfan; ii) an antibiotic selected from bleomycin,
dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin,
menogaril, mitomycin, mitoxantrone, neocarzinostatin, pentostatin,
and plicamycin; iii) an antimetabolite selected from azacitidine,
capecitabine, cladribine, clofarabine, cytarabine, decitabine,
floxuridine, fludarabine, 5-fluorouracil, ftorafur, gemcitabine,
hydroxyurea, mercaptopurine, methotrexate, nelarabine, pemetrexed,
raltitrexed, thioguanine, and trimetrexate; iv) an antibody therapy
agent selected from alemtuzumab, bevacizumab, cetuximab, galiximab,
gemtuzumab, nivolumab, panitumumab, pembrolizumab, pertuzumab,
rituximab, tositumomab, trastuzumab, and 90 Y ibritumomab tiuxetan;
v) a hormone or hormone antagonist selected from anastrozole,
androgens, buserelin, diethylstilbestrol, exemestane, flutamide,
fulvestrant, goserelin, idoxifene, letrozole, leuprolide,
magestrol, raloxifene, tamoxifen, and toremifene; vi) a taxane
selected from DJ-927, docetaxel, TPI 287, paclitaxel and
DHA-paclitaxel; vii) a retinoid selected from alitretinoin,
bexarotene, fenretinide, isotretinoin, and tretinoin; viii) an
alkaloid selected from etoposide, homoharringtonine, teniposide,
vinblastine, vincristine, vindesine, and vinorelbine; ix) an
antiangiogenic agent selected from AE-941 (GW786034, Neovastat),
ABT-510, 2-methoxyestradiol, lenalidomide, and thalidomide; x) a
topoisomerase inhibitor selected from amsacrine, edotecarin,
exatecan, irinotecan, SN-38 (7-ethyl-10-hydroxy-camptothecin),
rubitecan, topotecan, and 9-aminocamptothecin; xi) a kinase
inhibitor selected from erlotinib, gefitinib, flavopiridol,
imatinib mesylate, lapatinib, sorafenib, sunitinib malate, AEE-788,
AG-013736, AMG 706, AMN107, BMS-354825, BMS-599626, UCN-01
(7-hydroxystaurosporine), vemurafenib, dabrafenib, trametinib,
cobimetinib selumetinib and vatalanib; xii) a targeted signal
transduction inhibitor selected from bortezomib, geldanamycin, and
rapamycin; xiii) a biological response modifier selected from
imiquimod, interferon-.alpha. and interleukin-2; xiv) an IDO
inhibitor; and xv) a chemotherapeutic agent selected from 3-AP
(3-amino-2-carboxyaldehyde thiosemicarbazone), altrasentan,
aminoglutethimide, anagrelide, asparaginase, bryostatin-1,
cilengitide, elesclomol, eribulin mesylate (E7389), ixabepilone,
lonidamine, masoprocol, mitoguanazone, oblimersen, sulindac,
testolactone, tiazofurin, a mTOR inhibitor, a PI3K inhibitor, a
Cdk4 inhibitor, an Akt inhibitor, a Hsp90 inhibitor, a
farnesyltransferase inhibitor or an aromatase inhibitor
(anastrozole letrozole exemestane); xvi) a Mek inhibitor; xvii) a
tyrosine kinase inhibitor; xviii) a c-Kit mutant inhibitor, xix) an
EGFR inhibitor, or xx) an epigenetic modulator. In further
embodiments, a bromodomain modulator, particularly Compound I or a
salt thereof, may be administered simultaneously, sequentially or
separately in combination with one or more agents as described
above.
[0231] Epigenetic modulators include DNA methylating agents and
agents that modulate posttranslational modification of histones
and/or proteins by the activity of chromatin modifiers.
Non-limiting examples of Epigenetic modulators include:
[0232] (a) DNA methyltransferases (for example, azacytidine,
decitabine or zebularine);
[0233] (b) histone and protein methyltransferases, including, but
not limited to, DOT1L inhibitors such as EPZ004777
(7-[5-Deoxy-5-[[3-[[[[4-(1,1-dimethylethyl)phenyl]amino]carbonyl]amino]pr-
opyl](1-methylethyl)amino]-3-D-ribofuranosyl]-7H-pyrrolo[2,3-d]pyrimidin-4-
-amine), EZH1 inhibitors, EZH2 inhibitors or EPX5687;
[0234] (c) histone demethylases;
[0235] (d) histone deacetylase inhibitors (HDAC inhibitors)
including, but not limited to, vorinostat, romidepsin, chidamide,
panobinostat, belinostat, valproic acid, mocetinostat, abexinostat,
entinostat, resminostat, givinostat, or quisinostat;
[0236] (e) histone acetyltransferase inhibitors (also referred to
as HAT inhibitors) including, but not limited to, C-646,
(4-[4-[[5-(4,5-Dimethyl-2-nitrophenyl)-2-furanyl]methylene]-4,5-dihydro-3-
-methyl-5-oxo-1H-pyrazol-1-yl]benzoic acida), CPTH2
(cyclopentylidene-[4-(4'-chlorophenyl)thiazol-2-yl]hydrazine), CTPB
(N-(4-chloro-3-trifluoromethyl-phenyl)-2-ethoxy-6-pentadecyl-benzamide),
garcinol
((1R,5R,7R)-3-(3,4-Dihydroxybenzyol)-4-hydroxy-8,8-dimethyl-1,7--
bis(3-methyl-2-buten-1-yl)-5-[(2S)-5-methyl-2-(1-methylethenyl)-4-hexen-1--
yl]bicyclo[3.3.1]non-3-ene-2,9-dione), anacardic acid, EML 425
(5-[(4-hydroxy-2,6-dimethylphenyl)methylene]-1,3-bis(phenylmethyl)-2,4,6(-
1H,3H,5H)-pyrimidinetrione), ISOX DUAL
([3-[4-[2-[5-(Dimethyl-1,2-oxazol-4-yl)-1-[2-(morpholin-4-yl)ethyl]-1H-1,-
3-benzodiazol-2-yl]ethyl]phenoxy]propyl]dimethylamine), L002
(4-[0-[(4-methoxyphenyl)sulfonyl]oxime]-2,6-dimethyl-2,5-cyclohexadiene-1-
,4-dione), NU 9056 (5-(1,2-thiazol-5-yldisulfanyl)-1,2-thiazole),
SI-2 hydrochloride (1-(2-pyridinyl)ethanone
2-(1-methyl-1H-benzimidazol-2-yl)hydrazone hydrochloride); or
[0237] (f) other chromatin remodelers.
[0238] In some embodiments, the epigenetic modulator is vorinostat,
romidepsin, belinostat, or panobinostat.
[0239] In some embodiments, compositions are provided that include
a therapeutically effective amount of any one or more compound(s)
as described herein (e.g., Compound I or a salt thereof, or any a
solid or amorphous form of Compound I) and at least one
pharmaceutically acceptable carrier, excipient, and/or diluent. In
some embodiments, compositions are provided that include a
therapeutically effective amount of any two or more compound(s) as
described herein (e.g., Compound I or a salt thereof, or a solid or
amorphous form of Compound I) and at least one pharmaceutically
acceptable carrier, excipient, and/or diluent. In some embodiments,
the compositions can further include a plurality of different
pharmacologically active compounds, which can include a plurality
of compounds as described herein. In some embodiments, the
composition can include any one or more compound(s) as described
herein along with one or more compounds that are therapeutically
effective for the same disease indication. In some embodiments, the
composition includes any one or more compound(s) as described
herein along with one or more compounds that are therapeutically
effective for the same disease indication, wherein the compounds
have a synergistic effect on the disease indication. In one
embodiment, the composition includes any one or more compound(s) as
described herein effective in treating a cancer and one or more
other compounds that are effective in treating the same cancer,
further wherein the compounds are synergistically effective in
treating the cancer. The compounds can be administered
simultaneously or sequentially.
[0240] In some embodiments, the present disclosure provides a
composition, e.g., a pharmaceutical composition comprising any one
or more solid or amorphous forms of Compound I as described herein
(e.g., Compound I or a salt thereof, Compound I Form A, Compound I
Form B, Compound I Form C, Compound I Form D, Compound I Material
E, Compound I Material F, Compound I Material G, Compound I Free
Acid Amorphous, a free acid amorphous salt form of Compound I, or
Compound I sodium Material A), in combination with a FMS inhibitor,
such as quizartinib or pexidartinib. In some embodiments, the
present disclosure provides a pharmaceutical composition
comprising: any one or more solid or amorphous forms of Compound I
as described herein; a pharmaceutically acceptable carrier; and
quizartinib or pexidartinib.
[0241] In some embodiments, the present disclosure provides a
composition, e.g., a pharmaceutical composition comprising a free
acid amorphous form of Compound I as described herein, or a
pharmaceutically acceptable salt thereof, in combination with a FMS
inhibitor, such as quizartinib or pexidartinib. In some
embodiments, the present disclosure provides a pharmaceutical
composition comprising: a free acid amorphous form of Compound I as
described herein, or a pharmaceutically acceptable salt thereof; a
pharmaceutically acceptable carrier; and quizartinib or
pexidartinib.
[0242] In some embodiments, the present disclosure provides a
composition, e.g., a pharmaceutical composition comprising Compound
I or a salt thereof, in combination with a FMS inhibitor, such as
quizartinib or pexidartinib. In some embodiments, the present
disclosure provides a pharmaceutical composition comprising:
Compound I or a salt thereof; a pharmaceutically acceptable
carrier; and quizartinib or pexidartinib.
[0243] In some embodiments, the present disclosure provides a
composition, e.g., a pharmaceutical composition comprising any one
or more of the solid or amorphous forms of Compound I as described
herein (e.g., Compound I or a salt thereof, Compound I Form A,
Compound I Form B, Compound I Form C, Compound I Form D, Compound I
Material E, Compound I Material F, Compound I Material G, Compound
I Free Acid Amorphous, a free acid amorphous salt form of Compound
I, or Compound I sodium Material A), in combination with
quizartinib. In some embodiments, the present disclosure provides a
pharmaceutical composition comprising: any one or more of the solid
or amorphous forms of Compound I as described herein; a
pharmaceutically acceptable carrier; and quizartinib.
[0244] In some embodiments, the present disclosure provides a
composition, e.g., a pharmaceutical composition comprising a free
acid amorphous form of Compound I as described herein, or a
pharmaceutically acceptable salt thereof, in combination with
quizartinib. In some embodiments, the present disclosure provides a
pharmaceutical composition comprising: a free acid amorphous form
of Compound I as described herein, or a pharmaceutically acceptable
salt thereof; a pharmaceutically acceptable carrier; and
quizartinib.
[0245] In some embodiments, the present disclosure provides a
composition, e.g., a pharmaceutical composition comprising Compound
I or a salt thereof in combination with quizartinib. In some
embodiments, the present disclosure provides a pharmaceutical
composition comprising: Compound I or a salt thereof; a
pharmaceutically acceptable carrier; and quizartinib.
[0246] In some embodiments, the present disclosure provides a
composition, e.g., a pharmaceutical composition comprising any one
or more solid or amorphous forms of Compound I as described herein
(e.g., Compound I or a salt thereof, Compound I Form A, Compound I
Form B, Compound I Form C, Compound I Form D, Compound I Material
E, Compound I Material F, Compound I Material G, Compound I Free
Acid Amorphous, a free acid amorphous salt form of Compound I, or
Compound I sodium Material A), in combination with pexidartinib. In
some embodiments, the present disclosure provides a pharmaceutical
composition comprising: any one or more of the solid or amorphous
forms of Compound I as described herein; a pharmaceutically
acceptable carrier; and pexidartinib.
[0247] In some embodiments, the present disclosure provides a
composition, e.g., a pharmaceutical composition comprising a free
acid amorphous form of Compound I as described herein, or a
pharmaceutically acceptable salt thereof, in combination with
pexidartinib. In some embodiments, the present disclosure provides
a pharmaceutical composition comprising: a free acid amorphous form
of Compound I as described herein, or a pharmaceutically acceptable
salt thereof; a pharmaceutically acceptable carrier; and
pexidartinib.
[0248] In some embodiments, the present disclosure provides a
composition, e.g., a pharmaceutical composition comprising Compound
I or a salt thereof, in combination with pexidartinib. In some
embodiments, the present disclosure provides a pharmaceutical
composition comprising: Compound I or a salt thereof; a
pharmaceutically acceptable carrier; and pexidartinib.
[0249] In some embodiments, the present disclosure provides a
composition, e.g., a pharmaceutical composition comprising any one
or more of the solid or amorphous forms of Compound I as described
herein (e.g., Compound I or a salt thereof, Compound I Form A,
Compound I Form B, Compound I Form C, Compound I Form D, Compound I
Material E, Compound I Material F, Compound I Material G, Compound
I Free Acid Amorphous, a free acid amorphous salt form of Compound
I, or Compound I sodium Material A), in combination with a
hypomethylating agent (HMA). In some embodiments, the present
disclosure provides a pharmaceutical composition comprising: any
one or more of the solid or amorphous forms of Compound I as
described herein; a pharmaceutically acceptable carrier; and a
hypomethylating agent (HMA).
[0250] In some embodiments, the present disclosure provides a
composition, e.g., a pharmaceutical composition comprising a free
acid amorphous form of Compound I as described herein, or a
pharmaceutically acceptable salt thereof, in combination with a
hypomethylating agent (HMA). In some embodiments, the present
disclosure provides a pharmaceutical composition comprising: a free
acid amorphous form of Compound I as described herein, or a
pharmaceutically acceptable salt thereof; a pharmaceutically
acceptable carrier; and a hypomethylating agent (HMA).
[0251] In some embodiments, the present disclosure provides a
composition, e.g., a pharmaceutical composition comprising Compound
I or a salt thereof, in combination with a hypomethylating agent
(HMA). In some embodiments, the present disclosure provides a
pharmaceutical composition comprising: Compound I or a salt
thereof; a pharmaceutically acceptable carrier; and a
hypomethylating agent (HMA).
[0252] In some embodiments, the present disclosure provides a
composition, e.g., a pharmaceutical composition comprising any one
or more solid or amorphous forms of Compound I as described herein
(e.g., Compound I or a salt thereof, Compound I Form A, Compound I
Form B, Compound I Form C, Compound I Form D, Compound I Material
E, Compound I Material F, Compound I Material G, Compound I Free
Acid Amorphous, a free acid amorphous salt form of Compound I, or
Compound I sodium Material A), in combination with a Bruton's
Tyrosine Kinase (BTK) inhibitor. In some embodiments, the present
disclosure provides a pharmaceutical composition comprising: any
one or more of the solid or amorphous forms of Compound I as
described herein; a pharmaceutically acceptable carrier; and a
Bruton's Tyrosine Kinase (BTK) inhibitor. In some embodiments, the
BTK inhibitor is ibrutinib or alacabrutinib. In some embodiments,
the BTK inhibitor is ibrutinib. In some embodiments, the BTK
inhibitor is alacabrutinib.
[0253] In some embodiments, the present disclosure provides a
composition, e.g., a pharmaceutical composition comprising a free
acid amorphous form of Compound I as described herein, or a
pharmaceutically acceptable salt thereof, in combination with a
Bruton's Tyrosine Kinase (BTK) inhibitor. In some embodiments, the
present disclosure provides a pharmaceutical composition
comprising: a free acid amorphous form of Compound I as described
herein, or a pharmaceutically acceptable salt thereof; a
pharmaceutically acceptable carrier; and a Bruton's Tyrosine Kinase
(BTK) inhibitor. In some embodiments, the BTK inhibitor is
ibrutinib or alacabrutinib. In some embodiments, the BTK inhibitor
is ibrutinib. In some embodiments, the BTK inhibitor is
alacabrutinib.
[0254] In some embodiments, the present disclosure provides a
composition, e.g., a pharmaceutical composition comprising Compound
I or a salt thereof, in combination with a Bruton's Tyrosine Kinase
(BTK) inhibitor. In some embodiments, the present disclosure
provides a pharmaceutical composition comprising: Compound I or a
salt thereof; a pharmaceutically acceptable carrier; and a Bruton's
Tyrosine Kinase (BTK) inhibitor. In some embodiments, the BTK
inhibitor is ibrutinib or alacabrutinib. In some embodiments, the
BTK inhibitor is ibrutinib. In some embodiments, the BTK inhibitor
is alacabrutinib.
[0255] In some embodiments, the present disclosure provides a
composition, e.g., a pharmaceutical composition comprising any one
or more solid or amorphous forms of Compound I as described herein
(e.g., Compound I or a salt thereof, Compound I Form A, Compound I
Form B, Compound I Form C, Compound I Form D, Compound I Material
E, Compound I Material F, Compound I Material G, Compound I Free
Acid Amorphous, a free acid amorphous salt form of Compound I, or
Compound I sodium Material A), in combination with a B-cell
lymphoma 2 (BCL-2) inhibitor. In some embodiments, the present
disclosure provides a pharmaceutical composition comprising: any
one or more of the solid or amorphous forms of Compound I as
described herein; a pharmaceutically acceptable carrier; and a
B-cell lymphoma 2 (BCL-2) inhibitor. In some embodiments, the BCL-2
inhibitor is venetoclax.
[0256] In some embodiments, the present disclosure provides a
composition, e.g., a pharmaceutical composition comprising a free
acid amorphous form of Compound I as described herein, or a
pharmaceutically acceptable salt thereof in combination with a
B-cell lymphoma 2 (BCL-2) inhibitor. In some embodiments, the
present disclosure provides a pharmaceutical composition
comprising: a free acid amorphous form of Compound I as described
herein, or a pharmaceutically acceptable salt thereof; a
pharmaceutically acceptable carrier; and a B-cell lymphoma 2
(BCL-2) inhibitor. In some embodiments, the BCL-2 inhibitor is
venetocalx.
[0257] In some embodiments, the present disclosure provides a
composition, e.g., a pharmaceutical composition comprising Compound
I or a salt thereof, in combination with a B-cell lymphoma 2
(BCL-2) inhibitor. In some embodiments, the present disclosure
provides a pharmaceutical composition comprising: a free acid
amorphous form of Compound I as described herein, or
pharmaceutically acceptable salt thereof; a pharmaceutically
acceptable carrier; and a B-cell lymphoma 2 (BCL-2) inhibitor. In
some embodiments, the BCL-2 inhibitor is venetocalx.
[0258] In some embodiments, the present disclosure provides a
composition, e.g., a pharmaceutical composition comprising any one
or more solid or amorphous forms of Compound I as described herein
(e.g., Compound I or a salt thereof, Compound I Form A, Compound I
Form B, Compound I Form C, Compound I Form D, Compound I Material
E, Compound I Material F, Compound I Material G, Compound I Free
Acid Amorphous, a free acid amorphous salt form of Compound I, or
Compound I sodium Material A), in combination with a
phosphatidylinositol-4,5-bisphosphate 3-kinase(PI3K) inhibitor. In
some embodiments, the present disclosure provides a pharmaceutical
composition comprising: any one or more of the solid or amorphous
forms of Compound I as described herein; and a
phosphatidylinositol-4,5-bisphosphate 3-kinase(PI3K) inhibitor. In
some embodiments, the PI3K inhibitor is venetocalx, idelalisib,
IDH1, IDH2 or EZH2.
[0259] In some embodiments, the present disclosure provides a
composition, e.g., a pharmaceutical composition comprising a free
acid amorphous form of Compound I as described herein, or a
pharmaceutically acceptable salt thereof, in combination with a
phosphatidylinositol-4,5-bisphosphate 3-kinase(PI3K) inhibitor. In
some embodiments, the present disclosure provides a pharmaceutical
composition comprising: a free acid amorphous form of Compound I as
described herein, or a pharmaceutically acceptable salt thereof; a
pharmaceutically acceptable carrier; and a
phosphatidylinositol-4,5-bisphosphate 3-kinase(PI3K) inhibitor. In
some embodiments, the PI3K inhibitor is venetocalx, idelalisib,
IDH1, IDH2 or EZH2.
[0260] In some embodiments, the present disclosure provides a
composition, e.g., a pharmaceutical composition comprising Compound
I or a salt thereof, in combination with a
phosphatidylinositol-4,5-bisphosphate 3-kinase(PI3K) inhibitor. In
some embodiments, the present disclosure provides a pharmaceutical
composition comprising: Compound I or a salt thereof; a
pharmaceutically acceptable carrier; and a
phosphatidylinositol-4,5-bisphosphate 3-kinase(PI3K) inhibitor. In
some embodiments, the PI3K inhibitor is venetocalx, idelalisib,
IDH1, IDH2 or EZH2.
[0261] In some embodiments, the present disclosure provides a
composition, e.g., a pharmaceutical composition comprising any one
or more solid or amorphous forms of Compound I as described herein
(e.g., Compound I or a salt thereof, Compound I Form A, Compound I
Form B, Compound I Form C, Compound I Form D, Compound I Material
E, Compound I Material F, Compound I Material G, Compound I Free
Acid Amorphous, a free acid amorphous salt form of Compound I, or
Compound I sodium Material A), in combination with a CTLA-4
inhibitor or a checkpoint inhibitor. In some embodiments, the
present disclosure provides a pharmaceutical composition
comprising: any one or more of the solid or amorphous forms of
Compound I as described herein; and a CTLA-4 inhibitor or a
checkpoint inhibitor. In some embodiments, the CTLA-4 inhibitor is
ipilimumab. In some embodiments, the checkpoint inhibitor is a PD-1
or PDL-1 inhibitor. In some embodiments, the PD-1 inhibitor is
nivolumab. In some embodiments, the PDL-1 inhibitor is
pembrolizumab.
[0262] In some embodiments, the present disclosure provides a
composition, e.g., a pharmaceutical composition comprising a free
acid amorphous form of Compound I as described herein, or a
pharmaceutically acceptable salt thereof, in combination with a
CTLA-4 inhibitor or a checkpoint inhibitor. In some embodiments,
the present disclosure provides a pharmaceutical composition
comprising: a free acid amorphous form of Compound I as described
herein, or a pharmaceutically acceptable salt thereof; a
pharmaceutically acceptable carrier; and a CTLA-4 inhibitor or a
checkpoint inhibitor. In some embodiments, the CTLA-4 inhibitor is
ipilimumab. In some embodiments, the checkpoint inhibitor is a PD-1
or PDL-1 inhibitor. In some embodiments, the PD-1 inhibitor is
nivolumab. In some embodiments, the PDL-1 inhibitor is
pembrolizumab.
[0263] In some embodiments, the present disclosure provides a
composition, e.g., a pharmaceutical composition comprising Compound
I or a salt thereof, in combination with a CTLA-4 inhibitor or a
checkpoint inhibitor. In some embodiments, the present disclosure
provides a pharmaceutical composition comprising: Compound I or a
salt thereof; a pharmaceutically acceptable carrier; and a CTLA-4
inhibitor or a checkpoint inhibitor. In some embodiments, the
CTLA-4 inhibitor is ipilimumab. In some embodiments, the PD-1
inhibitor is nivolumab. In some embodiments, the PDL-1 inhibitor is
pembrolizumab.
[0264] In some embodiments, the present disclosure provides methods
for treating a bromodomain mediated or mutant bromodomain mediated
disease or condition in a subject in need thereof, the method
comprising administering to the subject an effective amount of any
one or more compounds as described herein (e.g., Compound I or a
salt thereof, or any one or more solid or amorphous forms of
Compound I), or a composition comprising any one or more compounds
as described herein, in combination with one or more other
therapeutic agents as described herein. In some embodiments, the
bromodomain modulator, particularly a compound as described herein
(e.g., Compound I or a salt thereof, or any one or more solid or
amorphous forms of Compound I), may be administered simultaneously,
sequentially or separately in combination with the one or more
other therapeutic agents as described above.
[0265] In some embodiments, the present disclosure provides methods
for treating a bromodomain mediated or mutant bromodomain mediated
disease or condition in a subject in need thereof, the method
comprising administering to the subject an effective amount of any
one or more solid or amorphous forms of Compound I as described
herein (e.g., Compound I or a salt thereof, Compound I Form A,
Compound I Form B, Compound I Form C, Compound I Form D, Compound I
Material E, Compound I Material F, Compound I Material G, Compound
I Free Acid Amorphous, a free acid amorphous salt form of Compound
I, or Compound I sodium Material A), or a composition comprising
any one or more solid or amorphous forms of Compound I as described
herein, in combination with one or more other therapeutic agents as
described herein, wherein the disease or condition is a cancer, a
neurological condition, an autoimmune condition, an inflammatory
condition, a metabolic disease, or combinations thereof. In some
embodiments, the bromodomain modulator, particularly a solid or
amorphous form of Compound I as described herein, may be
administered simultaneously, sequentially or separately in
combination with the one or more other therapeutic agents as
described above.
[0266] In some embodiments, the present disclosure provides methods
for treating a bromodomain mediated or mutant bromodomain mediated
disease or condition in a subject in need thereof, the method
comprising administering to the subject an effective amount of
Compound I or a salt thereof, or a composition comprising Compound
I or a salt thereof, in combination with one or more other
therapeutic agents as described herein, wherein the disease or
condition is a cancer, a neurological condition, an autoimmune
condition, an inflammatory condition, a metabolic disease, or
combinations thereof. In some embodiments, the bromodomain
modulator, particularly Compound I or a salt thereof, may be
administered simultaneously, sequentially or separately in
combination with the one or more other therapeutic agents as
described above.
[0267] In some embodiments, the present disclosure provides methods
for treating a bromodomain mediated or mutant bromodomain mediated
disease or condition in a subject in need thereof, the method
comprising administering to the subject an effective amount of any
one or more solid or amorphous forms of Compound I as described
herein (e.g., Compound I or a salt thereof, Compound I Form A,
Compound I Form B, Compound I Form C, Compound I Form D, Compound I
Material E, Compound I Material F, Compound I Material G, Compound
I Free Acid Amorphous, a free acid amorphous salt form of Compound
I, or Compound I sodium Material A), or a composition comprising
any one or more solid or amorphous forms of Compound I as described
herein, in combination with one or more other therapeutic agents as
described herein, wherein the disease or condition is rheumatoid
arthritis, uveal melanoma, chronic lymphocytic leukemia, acute
myeloid leukemia, synovial sarcoma, osteoarthritis, acute gout,
psoriasis, systemic lupus erythematosus, multiple sclerosis,
inflammatory bowel disease (Crohn's disease and Ulcerative
colitis), asthma, chronic obstructive airways disease, pneumonitis,
myocarditis, pericarditis, myositis, eczema, dermatitis, alopecia,
vitiligo, bullous skin diseases, nephritis, vasculitis,
atherosclerosis, Alzheimer's disease, depression, retinitis,
uveitis, scleritis, hepatitis, pancreatitis, primary biliary
cirrhosis, sclerosing cholangitis, Addison's disease, hypophysitis,
thyroiditis, type I diabetes, or acute rejection of transplanted
organs. In some embodiments, the bromodomain modulator,
particularly a compound as described herein (e.g., any one or more
solid or amorphous forms of Compound I), may be administered
simultaneously, sequentially or separately in combination with the
one or more other therapeutic agents as described above.
[0268] In some embodiments, the present disclosure provides methods
for treating a bromodomain mediated or mutant bromodomain mediated
disease or condition in a subject in need thereof, the method
comprising administering to the subject an effective amount of
Compound I or a salt thereof, or a composition comprising Compound
I or a salt thereof, in combination with one or more other
therapeutic agents as described herein, wherein the disease or
condition is rheumatoid arthritis, uveal melanoma, chronic
lymphocytic leukemia, acute myeloid leukemia, synovial sarcoma,
osteoarthritis, acute gout, psoriasis, systemic lupus
erythematosus, multiple sclerosis, inflammatory bowel disease
(Crohn's disease and Ulcerative colitis), asthma, chronic
obstructive airways disease, pneumonitis, myocarditis,
pericarditis, myositis, eczema, dermatitis, alopecia, vitiligo,
bullous skin diseases, nephritis, vasculitis, atherosclerosis,
Alzheimer's disease, depression, retinitis, uveitis, scleritis,
hepatitis, pancreatitis, primary biliary cirrhosis, sclerosing
cholangitis, Addison's disease, hypophysitis, thyroiditis, type I
diabetes, or acute rejection of transplanted organs. In some
embodiments, the bromodomain modulator, particularly a compound as
described herein (e.g., any one or more solid or amorphous forms of
Compound I), may be administered simultaneously, sequentially or
separately in combination with the one or more other therapeutic
agents as described above.
[0269] In one embodiment, the present disclosure provides methods
for treating a cancer mediated by bromodomain or mutant bromodomain
in a subject in need thereof by administering to the subject an
effective amount of any one or more compounds as described herein
(e.g., Compound I or a salt thereof, or any one or more solid or
amorphous forms of Compound I), or a composition including any one
or more compound(s) as described herein. In some embodiments, the
bromodomain modulator, particularly a compound as described herein
(e.g., Compound I or a salt thereof, or any one or more solid or
amorphous forms of Compound I), may be administered simultaneously,
sequentially or separately in combination with one or more agents
as described above.
[0270] In one embodiment, the present disclosure provides methods
for treating a cancer mediated by bromodomain in a subject in need
thereof by administering to the subject an effective amount of any
one or more compounds as described herein (e.g., Compound I or a
salt thereof, or any one or more solid or amorphous forms of
Compound I), or a composition comprising any one or more
compound(s) as described herein, in combination with one or more
suitable anticancer therapies, such as one or more chemotherapeutic
drugs or agents as described herein.
[0271] In one embodiment, the present disclosure provides a method
of treating a cancer in a subject in need thereof, comprising
administering to the subject an effective amount of any one or more
solid or amorphous forms of Compound I as described herein (e.g.,
Compound I Form A, Compound I Form B, Compound I Form C, Compound I
Form D, Compound I Material E, Compound I Material F, Compound I
Free Acid Amorphous, a free acid amorphous salt form of Compound I,
or the sodium salt of Compound I), or a composition comprising any
one or more solid or amorphous forms of Compound I as described
herein, in combination with a chemotherapeutic agent selected from
capecitabine, 5-fluorouracil, carboplatin, dacarbazine, gefitinib,
oxaliplatin, paclitaxel, SN-38, temozolomide, vinblastine,
bevacizumab, cetuximab, interferon-.alpha., interleukin-2, or
erlotinib. In one embodiment, the present disclosure provides a
method of treating a cancer in a subject in need thereof,
comprising administering to the subject an effective amount of
Compound I or a salt thereof, or a composition comprising Compound
I or a salt thereof, in combination with a chemotherapeutic agent
selected from capecitabine, 5-fluorouracil, carboplatin,
dacarbazine, gefitinib, oxaliplatin, paclitaxel, SN-38,
temozolomide, vinblastine, bevacizumab, cetuximab,
interferon-.alpha., interleukin-2, or erlotinib. In some
embodiments, the bromodomain modulator, particularly a compound as
described herein (e.g., Compound I or a salt thereof, or any one or
more solid or amorphous forms of Compound I), may be administered
simultaneously, sequentially or separately in combination with one
or more agents as described above.
[0272] In one embodiment, the chemotherapeutic agent is a Mek
inhibitor. Exemplary Mek inhibitors include, but are not limited
to, AS703026, AZD6244 (Selumetinib), AZD8330, BIX 02188, CI-1040
(PD184352), GSK1120212 (also known as trametinib or JTP-74057),
cobimetinib, PD0325901, PD318088, PD98059, RDEA119(BAY 869766),
TAK-733 and U0126-EtOH.
[0273] In one embodiment, the chemotherapeutic agent is a tyrosine
kinase inhibitor. Exemplary tyrosine kinase inhibitors include, but
are not limited to, AEE788, AG-1478 (Tyrphostin AG-1478), AG-490,
Apatinib (YN968D1), AV-412, AV-951(Tivozanib), Axitinib, AZD8931,
BIBF1120 (Vargatef), BIBW2992 (Afatinib), BMS794833, BMS-599626,
Brivanib (BMS-540215), Brivanib alaninate(BMS-582664), Cediranib
(AZD2171), Chrysophanic acid (Chrysophanol), Crenolanib
(CP-868569), CUDC-101, CYC116, Dovitinib Dilactic acid (TKI258
Dilactic acid), E7080, Erlotinib Hydrochloride (Tarceva, CP-358774,
OSI-774, NSC-718781), Foretinib (GSK1363089, XL880), Gefitinib
(ZD-1839 or Iressa), Imatinib (Gleevec), Imatinib Mesylate, Ki8751,
KRN 633, Lapatinib (Tykerb), Linifanib (ABT-869), Masitinib
(Masivet, AB1010), MGCD-265, Motesanib (AMG-706), MP-470,
Mubritinib(TAK 165), Neratinib (HKI-272), NVP-BHG712, OSI-420
(Desmethyl Erlotinib,CP-473420), OSI-930, Pazopanib HCl, PD-153035
HCl, PD173074, Pelitinib (EKB-569), PF299804, Ponatinib (AP24534),
PP121, RAF265 (CHIR-265), Raf265 derivative, Regorafenib (BAY
73-4506), Sorafenib Tosylate (Nexavar), Sunitinib Malate (Sutent),
Telatinib (BAY 57-9352), TSU-68 (SU6668), Vandetanib (Zactima),
Vatalanib dihydrochloride (PTK787), WZ3146, WZ4002, WZ8040,
quizartinib, Cabozantinib, XL647, EGFR siRNA, FLT4 siRNA, KDR
siRNA, Antidiabetic agents such as metformin, PPAR agonists
(rosiglitazone, pioglitazone, bezafibrate, ciprofibrate,
clofibrate, gemfibrozil, fenofibrate, indeglitazar), and DPP4
inhibitors (sitagliptin, vildagliptin, saxagliptin, dutogliptin,
gemigliptin, alogliptin).
[0274] In one embodiment, the agent is an EGFR inhibitor. Exemplary
EGFR inhibitors include, but are not limited to, AEE-788, AP-26113,
BIBW-2992 (Tovok), CI-1033, GW-572016, Iressa, LY2874455,
RO-5323441, Tarceva (Erlotinib, OSI-774), CUDC-101 and WZ4002.
[0275] In one embodiment, the therapeutic agent for combination is
a c-Fms and/or c-Kit inhibitor as described in US Patent
Application Publication Nos. 2009/0076046 and 2011/0112127, which
are incorporated herein by reference in their entirety and for all
purposes.
[0276] In one embodiment, the present disclosure provides methods
for treating a disease or condition mediated by a bromodomain or
mutant bromodomain protein in a subject in need thereof, by
administering to the subject an effective amount of any one or more
solid or amorphous forms of Compound I as described herein (e.g.,
Compound I Form A, Compound I Form B, Compound I Form C, Compound I
Form D, Compound I Material E, Compound I Material F, Compound I
Free Acid Amorphous, a free acid amorphous salt form of Compound I,
or the sodium salt of Compound I), in combination with quizartinib
for treating the disease or condition.
[0277] In one embodiment, the present disclosure provides methods
for treating a disease or condition mediated by a bromodomain or
mutant bromodomain protein in a subject in need thereof, by
administering to the subject an effective amount of Compound I or a
salt thereof, in combination with quizartinib for treating the
disease or condition.
[0278] In some embodiments, the disclosure provides a method of
treating a subject suffering from a disease or condition described
in this disclosure, said method comprising administering to the
subject an effective amount of any one or more solid or amorphous
forms of Compound I as described herein (e.g., Compound I Form A,
Compound I Form B, Compound I Form C, Compound I Form D, Compound I
Material E, Compound I Material F, Compound I Free Acid Amorphous,
a free acid amorphous salt form of Compound I, or the sodium salt
of Compound I), in combination with a mutant c-Kit protein kinase
inhibitor. In some embodiments, the disclosure provides a method of
treating a subject suffering from a disease or condition described
in this disclosure, said method comprising administering to the
subject an effective amount of Compound I or a salat thereof, in
combination with a mutant c-Kit protein kinase inhibitor. In some
embodiments, the mutant c-Kit protein kinase inhibitor is selected
from (2-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-(3-pyridyl)methanol,
(2-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-(3-pyridyl)methanone,
N-(3-carbamoylphenyl)-2-phenyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide,
2-phenyl-N-(1H-pyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide,
4-bromo-N-(2-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazole-5-carboxam-
ide, ethyl
3-[(2-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)carbamoylamino]propa-
noate,
3,4-dimethyl-N-(2-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazole-
-5-carboxamide,
4-methyl-3-phenyl-N-(2-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazole--
5-carboxamide,
3-cyclopropyl-N-(2-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazole-5-ca-
rboxamide,
5-fluoro-N-(2-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-indazole-
-3-carboxamide,
N-(2-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidine-4-carboxamide,
3-fluoro-N-(2-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridine-2-carboxamide-
,
3,5-dimethyl-N-(2-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)isoxazole-4-carbo-
xamide,
N-(2-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridazine-3-carboxamide-
,
N-(2-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2H-triazole-4-carboxamide,
3-methyl-N-(2-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridine-2-carboxamide-
,
4,5-dimethyl-N-(2-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)isoxazole-3-carbo-
xamide or
N-(2-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazole-4-sulfona-
mide. In some embodiments, a compound as described herein is
combined with any of the mutant c-Kit mutant inhibitors described
in this specification for treating GIST--which includes, without
limitation, 1.sup.st line, 2.sup.nd line and neoadjuvant GIST.
[0279] In some embodiments, the present disclosure provides methods
for treating a subject suffering or at risk of a disease or
condition mediated by a bromodomain, said method comprising
administering to the subject in need thereof an effective amount of
any one or more solid or amorphous forms of Compound I as described
herein (e.g., Compound I Form A, Compound I Form B, Compound I Form
C, Compound I Form D, Compound I Material E, Compound I Material F,
Compound I Free Acid Amorphous, a free acid amorphous salt form of
Compound I, or the sodium salt of Compound I), and a pharmaceutical
acceptable excipient or carrier, in combination with
quizartinib.
[0280] In some embodiments, the present disclosure provides methods
for treating a subject suffering or at risk of a disease or
condition mediated by a bromodomain, said method comprising
administering to the subject in need thereof an effective amount of
a free acid amorphous form of Compound I as described herein, or a
pharmaceutically acceptable salt thereof, and a pharmaceutical
acceptable excipient or carrier, in combination with
quizartinib.
[0281] In some embodiments, the present disclosure provides methods
for treating a subject suffering or at risk of a disease or
condition mediated by a bromodomain, said method comprising
administering to the subject in need thereof an effective amount of
Compound I or a salt thereof, and a pharmaceutical acceptable
excipient or carrier, in combination with quizartinib.
[0282] In some embodiments, the present disclosure provides methods
for treating a subject suffering or at risk of a disease or
condition mediated by a bromodomain, said method comprising
administering to the subject in need thereof an effective amount of
a pharmaceutical composition comprising: any of one or more solid
or amorphous forms of Compound I as described herein (e.g.,
Compound I Form A, Compound I Form B, Compound I Form C, Compound I
Form D, Compound I Material E, Compound I Material F, Compound I
Free Acid Amorphous, a free acid amorphous salt form of Compound I,
or the sodium salt of Compound I); at least one pharmaceutically
acceptable excipient or carrier; and quizartinib.
[0283] In some embodiments, the present disclosure provides methods
for treating a subject suffering or at risk of a disease or
condition mediated by a bromodomain, said method comprising
administering to the subject in need thereof a composition
comprising: an effective amount of a free acid amorphous form of
Compound I as described herein, or a pharmaceutically acceptable
salt thereof; at least one pharmaceutically acceptable excipient or
carrier; and quizartinib.
[0284] In some embodiments, the present disclosure provides methods
for treating a subject suffering or at risk of a disease or
condition mediated by a bromodomain, said method comprising
administering to the subject in need thereof a composition
comprising: an effective amount of Compound I or a salt thereof; at
least one pharmaceutically acceptable excipient or carrier; and
quizartinib
[0285] In some embodiments, the present disclosure provides a
method of treating myelodysplastic syndromes (MDS) or acute myeloid
leukemia (AML) in a subject in need thereof by administering to the
subject an effective amount of a free acid amorphous form of
Compound I as described herein, or a pharmaceutically acceptable
salt thereof, in combination with an effective amount of a
hypomethylating agent (HMA).
[0286] In some embodiments, the present disclosure provides a
method of treating myelodysplastic syndromes (MDS) or acute myeloid
leukemia (AML) in a subject in need thereof by administering to the
subject an effective amount of any one or more solid or amorphous
forms of Compound I as described herein (e.g., Compound I Form A,
Compound I Form B, Compound I Form C, Compound I Form D, Compound I
Material E, Compound I Material F, Compound I Free Acid Amorphous,
a free acid amorphous salt form of Compound I, or the sodium salt
of Compound I), in combination with an effective amount of a
hypomethylating agent (HMA).
[0287] In some embodiments, the present disclosure provides a
method of treating myelodysplastic syndromes (MDS) or acute myeloid
leukemia (AML) in a subject in need thereof by administering to the
subject an effective amount of Compound I or a salt thereof, in
combination with an effective amount of a hypomethylating agent
(HMA).
[0288] In some embodiments, the present disclosure provides a
method of treating chronic lymphocytic leukemia (CLL) or Richter's
Syndrome in a subject in need thereof by administering to the
subject an effective amount of a free acid amorphous form of
Compound I as described herein, or a pharmaceutically acceptable
salt thereof, optionally in combination with an effective amount of
a Bruton's Tyrosine Kinase (BTK) inhibitor. In some embodiments,
the BTK inhibitor is ibrutinib or alacabrutinib. In some
embodiments, the BTK inhibitor is ibrutinib. In some embodiments,
the BTK inhibitor is alacabrutinib.
[0289] In some embodiments, the present disclosure provides a
method of treating chronic lymphocytic leukemia (CLL) or Richter's
Syndrome in a subject in need thereof by administering to the
subject an effective amount of any one or more solid or amorphous
forms of Compound I as described herein (Compound I Form A,
Compound I, Form B, Compound I Form C, Compound I Form D, Compound
I Material E, Compound I Material F, Compound I Free Acid
Amorphous, or the sodium salt of Compound I), optionally in
combination with an effective amount of a Bruton's Tyrosine Kinase
(BTK) inhibitor. In some embodiments, the BTK inhibitor is
ibrutinib or alacabrutinib. In some embodiments, the BTK inhibitor
is ibrutinib. In some embodiments, the BTK inhibitor is
alacabrutinib.
[0290] In some embodiments, the present disclosure provides a
method of treating chronic lymphocytic leukemia (CLL) or Richter's
Syndrome in a subject in need thereof by administering to the
subject an effective amount of Compound I or a salt thereof, in
combination with an effective amount of a Bruton's Tyrosine Kinase
(BTK) inhibitor. In some embodiments, the BTK inhibitor is
ibrutinib or alacabrutinib. In some embodiments, the BTK inhibitor
is ibrutinib. In some embodiments, the BTK inhibitor is
alacabrutinib.
[0291] In some embodiments, the present disclosure provides a
method of treating chronic lymphocytic leukemia (CLL) in a subject
in need thereof by administering to the subject an effective amount
of a free acid amorphous form of Compound I as described herein, or
a pharmaceutically acceptable salt thereof, in combination with an
effective amount of a B-cell lymphoma 2 (BCL-2) inhibitor. In some
embodiments, the BCL-2 inhibitor is venetocalx.
[0292] In some embodiments, the present disclosure provides a
method of treating chronic lymphocytic leukemia (CLL) in a subject
in need thereof by administering to the subject an effective amount
of any one or more solid or amorphous forms of Compound I as
described herein (Compound I Form A, Compound I, Form B, Compound I
Form C, Compound I Form D, Compound I Material E, Compound I
Material F, Compound I Free Acid Amorphous, or the sodium salt of
Compound I), in combination with an effective amount of a (BCL-2)
inhibitor. In some embodiments, the BCL-2 inhibitor is
venetocalx.
[0293] In some embodiments, the present disclosure provides a
method of treating chronic lymphocytic leukemia (CLL) in a subject
in need thereof by administering to the subject an effective amount
of Compound I or a salt thereof, in combination with an effective
amount of a B-cell lymphoma 2 (BCL-2) inhibitor. In some
embodiments, the BCL-2 inhibitor is venetocalx.
[0294] In some embodiments, the present disclosure provides a
method of treating chronic lymphocytic leukemia (CLL) in a subject
in need thereof by administering to the subject an effective amount
of a free acid amorphous form of Compound I as described herein, or
a pharmaceutically acceptable salt thereof, in combination with an
effective amount of a phosphatidylinositol-4,5-bisphosphate
3-kinase(PI3K) inhibitor. In some embodiments, the PI3K inhibitor
is venetocalx, idelalisib, IDH1, IDH2 or EZH2.
[0295] In some embodiments, the present disclosure provides a
method of treating chronic lymphocytic leukemia (CLL) in a subject
in need thereof by administering to the subject an effective amount
of any one or more solid or amorphous forms of Compound I as
described herein (Compound I Form A, Compound I, Form B, Compound I
Form C, Compound I Form D, Compound I Material E, Compound I
Material F, Compound I Free Acid Amorphous, or the sodium salt of
Compound I), in combination with an effective amount of a (PI3K)
inhibitor. In some embodiments, the PI3K inhibitor is venetocalx,
idelalisib, IDH1, IDH2 or EZH2.
[0296] In some embodiments, the present disclosure provides a
method of treating chronic lymphocytic leukemia (CLL) in a subject
in need thereof by administering to the subject an effective amount
of Compound I or a salt thereof, in combination with an effective
amount of a phosphatidylinositol-4,5-bisphosphate 3-kinase(PI3K)
inhibitor. In some embodiments, the PI3K inhibitor is venetocalx,
idelalisib, IDH1, IDH2 or EZH2.
[0297] In some embodiments, the present disclosure provides a
method of treating uveal melanoma in a subject in need thereof by
administering to the subject an effective amount of a free acid
amorphous form of Compound I as described herein, or a
pharmaceutically acceptable salt thereof, in combination with an
effective amount of a CTLA-4 inhibitor or a checkpoint inhibitor.
In some embodiments, the CTLA-4 inhibitor is ipilimumab. In some
embodiments, the checkpoint inhibitor is a PD-1 or PDL-1 inhibitor.
In some embodiments, the PD-1 inhibitor is nivolumab. In some
embodiments, the PDL-1 inhibitor is pembrolizumab.
[0298] In some embodiments, the present disclosure provides a
method of treating uveal melanoma in a subject in need thereof by
administering to the subject an effective amount of any one or more
solid or amorphous forms of Compound I as described herein (e.g.,
Compound I Form A, Compound I Form B, Compound I Form C, Compound I
Form D, Compound I Material E, Compound I Material F, Compound I
Free Acid Amorphous, a free acid amorphous salt form of Compound I,
or the sodium salt of Compound I), in combination with an effective
amount of a CTLA-4 inhibitor or a checkpoint inhibitor. In some
embodiments, the CTLA-4 inhibitor is ipilimumab. In some
embodiments, the checkpoint inhibitor is a PD-1 or PDL-1 inhibitor.
In some embodiments, the PD-1 inhibitor is nivolumab. In some
embodiments, the PDL-1 inhibitor is pembrolizumab.
[0299] In some embodiments, the present disclosure provides a
method of treating uveal melanoma in a subject in need thereof by
administering to the subject an effective amount of a Compound I or
a salt thereof, in combination with an effective amount of a CTLA-4
inhibitor or a checkpoint inhibitor. In some embodiments, the
CTLA-4 inhibitor is ipilimumab. In some embodiments, the checkpoint
inhibitor is a PD-1 or PDL-1 inhibitor. In some embodiments, the
PD-1 inhibitor is nivolumab. In some embodiments, the PDL-1
inhibitor is pembrolizumab.
[0300] In some embodiments, the present disclosure provides a
method of treating acute myeloid leukemia (AML) in a subject in
need thereof by administering to the subject an effective amount of
a free acid amorphous form of Compound I as described herein, or a
pharmaceutically acceptable salt thereof, in combination with an
effective amount of a flt3 inhibitor, such as quizartinib.
[0301] In some embodiments, the present disclosure provides a
method of treating AML in a subject in need thereof by
administering to the subject an effective amount of any one or more
solid or amorphous forms of Compound I as described herein (e.g.,
Compound I Form A, Compound I Form B, Compound I Form C, Compound I
Form D, Compound I Material E, Compound I Material F, Compound I
Free Acid Amorphous, a free acid amorphous salt form of Compound I,
or the sodium salt of Compound I), in combination with an effective
amount of a flt3 inhibitor, such as quizartinib.
[0302] In some embodiments, the present disclosure provides a
method of treating acute myeloid leukemia (AML) in a subject in
need thereof by administering to the subject an effective amount of
Compound I or a salt thereof, in combination with an effective
amount of a flt3 inhibitor, such as quizartinib.
[0303] In some embodiments, the present disclosure provides methods
for treating a bromodomain or mutant bromodomain mediated disease
or condition in a subject in need thereof, the method comprising
administering to the subject any one or more compounds as described
herein (e.g., Compound I or a salt thereof, or any one or more
solid or amorphous forms of Compound I), or a composition
comprising any one or more compounds as described herein, in
combination with one or more other suitable therapies for treating
the disease or condition. In some embodiments, the bromodomain
modulator, particularly a compound as described herein (e.g.,
Compound I or a salt thereof, or any one or more solid or amorphous
forms of Compound I), may be administered simultaneously,
sequentially or separately in combination with one or more the one
or more other suitable therapies.
[0304] In one embodiment, the present disclosure provides methods
for treating a cancer mediated by bromodomain or mutant bromodomain
by administering to the subject an effective amount of a
composition including any one or more compound(s) as described
herein. In one embodiment, the present disclosure provides methods
for treating a cancer mediated by bromodomain by administering to
the subject an effective amount of a composition including any one
or more compound(s) as described herein in combination with one or
more suitable anticancer therapies, such as one or more
chemotherapeutic drugs or agents as described herein.
[0305] In some embodiments, the present disclosure provides a
method of treating a cancer as described herein in a subject in
need thereof by administering to the subject an effective amount of
any one or more solid or amorphous forms of Compound I as described
herein (Compound I Form A, Compound I Form B, Compound I Form C,
Compound I Form D, Compound I Material E, Compound I Material F,
Compound I Free Acid Amorphous, a free acid amorphous salt form of
Compound I, or the sodium salt of Compound I), or a composition
including any one or more solid or amorphous forms of Compound I as
described herein, in combination with one or more other therapies
or medical procedures effective in treating the cancer. In some
embodiments, the present disclosure provides a method of treating a
cancer as described herein in a subject in need thereof by
administering to the subject an effective amount of Compound I or a
salt thereof, in combination with one or more other therapies or
medical procedures effective in treating the cancer. Other
therapies or medical procedures include suitable anticancer therapy
(e.g. drug therapy, vaccine therapy, gene therapy, photodynamic
therapy) or medical procedure (e.g. surgery, radiation treatment,
hyperthermia heating, bone marrow or stem cell transplant). In one
embodiment, the one or more suitable anticancer therapies or
medical procedures is selected from treatment with a
chemotherapeutic agent (e.g. chemotherapeutic drug), radiation
treatment (e.g. x-ray, 7-ray, or electron, proton, neutron, or a
particle beam), hyperthermia heating (e.g. microwave, ultrasound,
radiofrequency ablation), Vaccine therapy (e.g. AFP gene
hepatocellular carcinoma vaccine, AFP adenoviral vector vaccine,
AG-858, allogeneic GM-CSF-secretion breast cancer vaccine,
dendritic cell peptide vaccines), gene therapy (e.g. Ad5CMV-p53
vector, adenovector encoding MDA7, adenovirus 5-tumor necrosis
factor alpha), photodynamic therapy (e.g. aminolevulinic acid,
motexafin lutetium), oncolytic viral or bacterial therapy, surgery,
or bone marrow and stem cell transplantation. In some embodiments,
the present disclosure provides a method of treating a cancer in a
subject in need thereof by administering to the subject an
effective amount of a compound as described herein and applying a
radiation treatment as described herein either separately or
simultaneously.
[0306] In one embodiment, the present disclosure provides a method
for treating a cancer in a subject in need thereof by administering
an effective amount of any one or more solid or amorphous forms of
Compound I as described herein (e.g., Compound I Form A, Compound I
Form B, Compound I Form C, Compound I Form D, Compound I Material
E, Compound I Material F, Compound I Free Acid Amorphous, a free
acid amorphous salt form of Compound I, or the sodium salt of
Compound I) to the subject followed by a radiation treatment (e.g.
x-ray, 7-ray, or electron, proton, neutron, or a particle beam). In
one embodiment, the present disclosure provides a method for
treating a cancer in a subject in need thereof by administering an
effective amount of Compound I or a salt thereof to the subject
followed by a radiation treatment (e.g. x-ray, 7-ray, or electron,
proton, neutron, or a particle beam).
[0307] In some embodiments, the present disclosure provides a
method for treating a cancer in a subject in need thereof by
applying a radiation treatment (e.g. x-ray, 7-ray, or electron,
proton, neutron, or a particle beam) to the subject followed by
administering an effective amount of a compound as described herein
to the subject. In yet another embodiment, the present disclosure
provides a method for treating a cancer in a subject in need
thereof by administering a compound as described herein and a
radiation therapy (e.g. x-ray, 7-ray, or electron, proton, neutron,
or a particle beam) to the subject simultaneously.
[0308] In some embodiments, the present disclosure provides kits or
containers that include a compound as described herein (e.g.,
Compound I or a salt thereof, or any one or more solid or amorphous
forms of Compound I), or a composition thereof as described herein.
In some embodiments, the compound or composition is packaged, e.g.,
in a vial, bottle, flask, which may be further packaged, e.g.,
within a box, envelope, or bag; the compound or composition is
approved by the U.S. Food and Drug Administration or similar
regulatory agency for administration to a mammal, e.g., a human;
the compound or composition is approved for administration to a
mammal, e.g., a human, for a bromodomain protein mediated disease
or condition; the kit or container disclosed herein may include
written instructions for use and/or other indication that the
compound or composition is suitable or approved for administration
to a mammal, e.g., a human, for a bromodomain-mediated disease or
condition; and the compound or composition may be packaged in unit
dose or single dose form, e.g., single dose pills, capsules, or the
like.
EXAMPLES
A. Experimental Methods
[0309] Solubility Estimates
[0310] Aliquots of various solvents were added to measured amounts
of Compound I or forms of Compound I as described herein with
agitation (typically sonication) at ambient temperature until
complete dissolution was achieved, as judged by visual observation.
Solubilities were calculated based on the total solvent used to
give a solution; actual solubilities may be greater because of the
volume of solvent portions utilized or a slow rate of dissolution.
If dissolution did not occur as determined by visual assessment,
the value was reported as "<". If dissolution occurred at the
first aliquot the value was reported as ">".
[0311] Anti-Solvent Additions
[0312] Solutions comprising Compound I or forms of Compound I as
described herein were contacted with anti-solvents of Compound I to
induce crystallization.
[0313] Cooling
[0314] Solutions comprising Compound I or forms of Compound I as
described herein were chilled below room temperature for varying
lengths of time to induce nucleation, after which the presence of
absence of solids was noted. Solids were isolated for analysis wet
or as dry powders.
[0315] Crystallization From Solution
[0316] Saturated solutions comprising Compound I or forms of
Compound I as described herein were generated at room temperature
and capped. Nucleation was observed to occur in such systems.
[0317] Fast Evaporation
[0318] Solutions comprising Compound I or forms of Compound I as
described herein were prepared in selected solvents and agitated
between aliquot additions to assist in dissolution. Once a mixture
reached complete dissolution, as judged by visual observation, the
solution was allowed to evaporate at ambient temperature in an
uncapped vial or under nitrogen. The solids that formed were
isolated for evaluation.
[0319] Slurry
[0320] Solutions of Compound I or forms of Compound I as described
herein were prepared by adding sufficient solids to a given solvent
or solvent system at ambient conditions such that undissolved
solids were present. The mixture was then agitated in a closed vial
at ambient or elevated temperature for an extended period of time.
Solids were collected by vacuum filtration and analyzed.
[0321] Temperature and Relative Humidity (RH) Stress
[0322] Solids of Compound I or forms of Compound I as described
herein were placed in an RH chamber of approximately 75% RH
containing a saturated aqueous solution of a NaCl with excess salt
present. The chamber was sealed and left at ambient temperature or
placed in an oven at elevated temperature.
[0323] Vacuum
[0324] Selected materials were dried under reduced pressure for a
set time period. Drying was conducted with absolute pressure
readings<500 mTorr, typically 30 to 50 mTorr (0.030 to 0.05 mm
Hg).
B. Instrumental Techniques
[0325] Differential Scanning Calorimetry (DSC)
[0326] DSC was performed using a TA Instruments Q2000 differential
scanning calorimeter. Temperature calibration was performed using
NIST-traceable indium metal. The sample was placed into an aluminum
DSC pan, covered with a lid, and the weight was accurately
recorded. A weighed aluminum pan configured as the sample pan was
placed on the reference side of the cell. The data acquisition
parameters and pan configuration for each thermogram are displayed
in the image in the Data section of this report. The method code on
the thermogram is an abbreviation for the start and end temperature
as well as the heating rate; e.g., -30-250-10 means "from
-30.degree. C. to 250.degree. C., at 10.degree. C./min." The
abbreviation used in each image for pan configurations, TOC means
"Tzero crimped pan."
[0327] Dynamic Vapor Solution
[0328] DVS data were collected on a VTI SGA-100 Vapor Sorption
Analyzer. NaCl and PVP were used as calibration standards. Samples
were not dried prior to analysis. Adsorption and desorption data
were collected over a range from 5 to 95% RH at 10% RH increments
under a nitrogen purge. The equilibrium criterion used for analysis
was less than 0.0100% weight change in 5 minutes with a maximum
equilibration time of 3 hours. Data were not corrected for the
initial moisture content of the samples.
[0329] Proton Solution Nuclear Magnetic Resonance Spectroscopy
(.sup.1H NMR)
[0330] Samples were prepared for NMR spectroscopy as .about.5-50 mg
solutions in deuterated DMSO. The specific acquisition parameters
are listed on the plot of the first full spectrum of each sample in
the data section for samples run at SSCI. The chemical shift
observed at approximately 2.5 ppm is assigned to residual protons
in the NMR solvent (DMSO-d6) and the chemical shift observed at
approximately 3.3 ppm is due to water.
[0331] Thermogravimetric Analysis (TGA)
[0332] TG analyses were performed using a TA Instruments 2050
thermogravimetric analyzer. Temperature calibration was performed
using nickel and Alumel.TM.. Each sample was placed in an aluminum
pan and inserted into the TG furnace. The furnace was heated under
a nitrogen purge. The data acquisition parameters are displayed
above each thermogram in the Data section of this report. The
method code on the thermogram is an abbreviation for the start and
end temperature as well as the heating rate; e.g., 25-350-10 means
"from 25.degree. C. to 350.degree. C., at 10.degree. C./min." The
use of 00 as the initial temperature indicates sample run initiated
from ambient.
[0333] X-Ray Powder Diffraction (XRPD)
[0334] (i) Inel: XRPD patterns were collected with an Inel XRG-3000
diffractometer. An incident beam of Cu K.alpha. radiation was
produced using a fine-focus tube and a parabolically graded
multilayer mirror. Prior to the analysis, a silicon standard (NIST
SRM 640d) was analyzed to verify the Si 111 peak position. A
specimen of the sample was packed into a thin-walled glass
capillary, and a beam-stop was used to minimize the background from
air. Diffraction patterns were collected in transmission geometry
using Windif v. 6.6 software and a curved position-sensitive
Equinox detector with a 20 range of 120.sup.0. The data-acquisition
parameters for each pattern are displayed above the image in the
Data section of this report.
[0335] (ii) PANalytical: XRPD patterns were collected with a
PANalytical X'Pert PRO MPD diffractometer using an incident beam of
Cu radiation produced using an Optix long, fine-focus source. An
elliptically graded multilayer mirror was used to focus Cu K.alpha.
X-rays through the specimen and onto the detector. Prior to the
analysis, a silicon specimen (NIST SRM 640d) was analyzed to verify
the Si 111 peak position. A specimen of the sample was sandwiched
between 3 m thick films and analyzed in transmission geometry. A
beam-stop, short antiscatter extension, and an antiscatter knife
edge were used to minimize the background generated by air. Soller
slits for the incident and diffracted beams were used to minimize
broadening from axial divergence. Diffraction patterns were
collected using a scanning position-sensitive detector
(X'Celerator) located 240 mm from the specimen and Data Collector
software v. 2.2b. The data-acquisition parameters for each pattern
are displayed above the image in the Data section of this report
including the divergence slit (DS) before the mirror and the
incident-beam antiscatter slit (SS).
[0336] Supercritical Fluid Chromatography
[0337] Supercritical fluid chromatography (SFC) was used to purify
certain compounds disclosed herein. Purification via SFC employed
the following materials and conditions:
TABLE-US-00003 Analytical SFC Method Column 4.6 .times. 100 mm
(S,S) Whelk0-1 from Regis Technologies (Morton Grove, IL) CO.sub.2
co-solvent Methanol w/0.1% isopropylamine Isocratic method 45%
co-solvent at 4 mL/min System pressure 100 bar Column temperature
25.degree. C. Sample diluent Ethanol Preparative SFC method Column
2.1 .times. 25 cm (S,S) Whelk0-1 from Regis Technologies (Morton
Grove, IL) CO.sub.2 co-solvent Methanol w/0.5% isopropylamine
Isocratic method 45% co-solvent at 80 g/min System pressure 100 bar
Column temperature 40.degree. C. Sample diluent Methanol/methylene
chloride (1:1) with 1% isopropylamine
C. Preparation and Characterization of Solid Forms of Compound
I
[0338] Several solid form screening experiments were conducted
using Compound I Form A or Compound I Form D as the starting
material. Compound I Form A and Form D were prepared according to
the following scheme.
##STR00004##
[0339]
4-(3-iodo-1H-pyrrolo[3,2-b]pyridin-6-yl)-3,5-dimethylisoxazole (1)
was synthesized as described in WO 2017/053243. To (1) was added
triphenylphosphate (TPP) and diisopropyl azodicarboxylate (DIAD)
under Mitsunobu reaction conditions to form
(S)-4-(3-iodo-1-(1-(pyridin-2-yl)ethyl)-1H-pyrrolo[3,2-b]pyridin-6-yl)-3,-
5-dimethylisoxazole (2). To (2) was added 2,6-difluorophenylboronic
acid, (Pd(dppf)Cl.sub.2, and HCl under Suzuki coupling reaction
conditions to obtain Compound I Form A. Compound I Form A was
purified via supercritical fluid chromatography (SFC) to obtain
Compound I Form D.
[0340] All forms discussed below in Table 1 were obtained starting
from Compound I Form A using a wide range of solvents and solvent
mixtures under kinetic and thermodynamic conditions.
TABLE-US-00004 TABLE 1 Solid Form Screening Experiments Using
Compound I Form A Solvent Method Observation XRPD Results Acetone
Precipitated from solution Irregular blades, and Form B fine
particles, birefringent Precipitated from Fine blades, Not analyzed
solution, and birefringent, and based on above refrigerated sheets
Dissolved; treated with Fine particles Form B + Form C ether; fast
evaporation seeded with a sample of a form B + C; rinsed solids
into vial and sonicated; resulting solids filtered and dried in
vacuum oven ACN Precipitated from solution Solids Form B + Form C
Sonicated for about 5 Fine particles, very Form B + Form C minutes;
left at ambient small rectangular conditions overnight; blades,
birefringent solids harvested and dried in vacuum oven ACN/acetone
Treated with activated Fine particles and Form C + Form B
(filtrates from charcoal; N.sub.2 evaporated; rosettes of Fine
(minor) a sample of a scratched particles, birefringent, form B and
oil present and a sample of a nucleated form B + C) ACN/acetone
Filtrates added together, Fine particles, Form C (filtrates from
left overnight and filtered birefringent samples of a form B + C)
DCM Contacted with solvent then Solids, glassy film, Form B
sonicated; filtered; and small tablets, evaporated birefringent
Added solvent (59 mg/mL); Fine particles, Form B treated with water
and DCM; birefringent organic layer isolated and dried, MgSO.sub.4;
treated with activated carbon.sup.; evaporated, N.sub.2; small
amount DCM/sonicated and evaporated DCM/ether 7 mg/ml suspension in
1:1 Aciculars and blades, Form B 1:1 v/v ether/DCM; treated with
birefringent MgSO.sub.4 and filtered; stored at ambient conditions
MeOH Dissolved; treated with Dendritic and plates, Form B + Form C
activated charcoal; singles evaporation (partial); evaporation to
dryness Isolated single crystals In solution and dry Form B
(racemate) Rapid addition of solvent, Fine particles, Form B + Form
C sonicated; filtered and birefringent rinsed in MeOH; vacuum dried
Sonicated in filtrate from Solids Form B + Form C a sample of a
form B + C; filtered, wet cake isolated; wet cake treated with
MeOH, filtered, rinsed with MeOH and vacuum dried Toluene Slurry,
ambient Solids with some Form A aggregated portions being less
soluble
[0341] All forms discussed below in Table 2 were obtained starting
from Compound I Form D using a wide range of solvents and solvent
mixtures under kinetic and thermodynamic conditions.
TABLE-US-00005 TABLE 2 Solid Form Screening Experiments Using
Compound I Form D Solvent Method Observation XRPD Results Acetone
Fast evaporation Fine aciculars, Form D birefringent ACN Slurry,
ambient Capillary preparation Form D (shifted) Chloroform
Evaporation heated, 2x; oil Solids, glassy, NB Amorphous contacted
with heptane Solution, seeded with sample Seeds remained -- of a
form C overnight; drop of water added; left overnight Sample with
above seeds added; Fine particles, no Form D (shifted) heated,
50.degree. C.; filtered, birefringent cooled; seeded with sample of
a form C; treated with heptane and sonicated; ambient, 3 days
filtered, dried under N.sub.2 DCM Fast evaporation Fine particles,
Form D (shifted birefringent peaks) Diethyl ether Slurry, ambient
Capillary preparation Form D (shifted) Dioxane Fast evaporation
Film no birefringence, Form C areas with nucleated fines EtOH Fast
evaporation (partial) Single crystals, off Form C + Form D white
film tablets, chunks birefringent EtOAc Slurry, ambient Capillary
preparation Form D (shifted) Slurry, ambient using sample Fine
particles, Form D of amorphous form birefringent (shifted) IPA Fast
evaporation Fine particles and Form D (shifted) + tablets,
birefringent Form C MEOH Fast evaporation Cracked glass and film,
Form D (shifted few plates, birefringent peaks) THF Fast
evaporation Sheets of fine aciculars Amorphous in upper vial, lower
brittle glassy material Toluene Slurry, ambient Capillary
preparation Form D (shifted) Water Fast evaporation Aciculars and
dendritic, Form C + Material E birefringent Saturated solution;
seeded with Blades, birefringent, Material F + Form C sample of a
form C and some singles present (minor) sonicated; seeded with
Sample of Material E + Form C and sonicated; ambient storage
overnight and filtered; dried briefly, N.sub.2 -- No results
observed/obtained
D. Solubility Estimates
[0342] Compound I Form A
[0343] Solubility estimates of Compound I Form A in various
solvents are provided in Table 3 below. It is of note that an
impurity observed in some of the samples of Compound I Form A, as
well as the presence of precipitation of Compound I Form B may have
affected the solubility estimates.
TABLE-US-00006 TABLE 3 Solubility Estimates of Compound I Form A
Solvent Solubility (mg/ml) Acetone 36 Acetonitrile (ACN) 6
Dichloromethane (DCM) 12 Methanol (MeOH) 6 Toluene <4
[0344] Compound I Form D
[0345] Solubility estimates of Compound I Form D in various
solvents are provided in Table 4 below. It is of note that such
solubility estimates may have been influenced due to the solvated
nature of Compound I Form D.
TABLE-US-00007 TABLE 4 Solubility Estimates of Compound I Form D
Solvent Solubility (mg/ml) acetone 4 acetonitrile (ACN) <3
chloroform >59 dichloromethane (DCM) 24 diethyl ether <2
dioxane <2 ethanol (EtOH) 9 ethyl acetate (EtOAc) <2
isopropyl alcohol (IPA) 4 methanol (MeOH) >72 tetrahydrofuran
(THF) 4 toluene <2 water 23
E. Preparation and Characterization of Compound I Sodium Material
A
[0346] The formation of sodium salts of Compound I discussed below
in Table 5 below were obtained starting from Compound I Form A
using various solvents and solvent mixtures under kinetic and
thermodynamic conditions.
TABLE-US-00008 TABLE 5 Sodium Salt Screening From Compound I Form A
Source Method Observation Results Compound I 53 mg/mL suspension in
DCM, Solids, NB Diffuse scattering Form A filtered; treated with
charcoal; with some molar eq. of NaOH in MeOH Sodium Material A
added; DCM added; sub sample peaks indicated material exhibiting B
after evaporation seeded bulk solution; placed in freezer
overnight; N.sub.2 evaporated; ether added, formed slurry and left
overnight Compound I 121 mg/ml suspension in Powder, free Compound
I Form A MeOH, sonicated about 5 flowing Sodium Material A minutes;
filtered, dried under N.sub.2 with heat; molar eq. of NaOH in MeOH
added to solids; treated with EtOAc; sub sample evaporated; seeded
bulk with sub sample, partial evaporation; freezer overnight,
filtered Filtrate from Reduced volume using water Fine aciculars,
Diffuse scattering Sample of aspirator by about 1/4 capillary
birefringent with limited Compound I sub sample reflections Form A
bulk collected and dried under White solids Compound I N.sub.2
Sodium Material A Filtrate from Reduced volume using water Wet
paste Compound I Sample of aspirator by about 1/4 and stored Sodium
diffuse Compound I in freezer; reduced volume scattering + peaks,
sodium Material under N.sub.2 to increase yield; wet A sonicated,
left for about 1 hr at ambient, isolated sub sample on slide, bulk
stored in freeze; sub sample isolated and evaporated; decanted
Compound I Filtered and N.sub.2 dried White opaque Compound I
sodium Material solids, Sodium Material A A birefringent in areas
Sample of a 8 mg/ml suspension in acetone, Solids Compound I form B
+ Form C slurry; molar eq. of NaOH in collapsed, Sodium similar
water added, slurry and oil/gel present to Material A, sonication;
reduced volume disordered under N.sub.2 to about 1/4 of initial;
left at ambient, capped; filtered Solution of sample of Solids,
not, Generation of Compound I sodium similar to powder like seed
material Material A (disordered) added to ether; evaporated under
N.sub.2 Solution of sample of -- Diffuse scattering + peaks
Compound I sodium similar to Material A (disordered) wet 18 mg/ml
suspension in MeOH, Glassy, not Compound I slurry; molar eq. of
NaOH in birefringent Sodium Amorphous MeOH added; reduced volume
under N.sub.2 to about 1/2 of initial; treated with ether; stored
in freezer; and evaporated Sub sample of Compound I Flocculent and
generation of sodium amorphous added to fines, birefringent seed
material ether -- No results observed/obtained
F. Compound I Free Acid Amorphous
[0347] Targeting BRD4 with Compound I Free Acid Amorphous ("Cmpd. I
FAA") shows potent anti-leukemic effects in disease models of
aggressive CLL and Richter's Transformation. FIGS. 24-24C show the
results of a pharmacodynamic evaluation of antitumor effects of
Compound I Free Acid Amorphous in E.mu.-TCL1 with advanced
leukemia. Mice were stratified according to leukemic peripheral
blood lymphocytes (PBLs) and spleen palpation score to receive
either vehicle or Compound I Free Acid Amorphous (20 mg/kg, qd,
oral gavage) for 8 days. Compound I Free Acid Amorphous reduced
leukemic cells in systemic circulation (FIG. 24A) and locally in
spleen (FIG. 24B), where the red line in FIGS. 24A-24B represents
average values. FIG. 24C is a representative immunoblot analysis of
relative protein levels of cMYC, P21, BTK, IKZF1, IKZF3 and TCL1A
protein at the end of the 8 day study.
[0348] Using an adaptive transfer model of E.mu.-TCL1, recipient
wild type mice were randomized to receive vehicle (n=12) or
Compound I Free Acid Amorphous (20 mg/kg, qd, oral gavage, n=10) at
leukemia onset and disease progression was measured by flow
cytometry as % CD19/CD5/CD45 positive PBL. Treatment was ended at
150 days. FIG. 24D is a Kaplan-Meier curve showing overall survival
(OS) (p<0.0001), with the median OS for Compound I Free Acid
Amorphous and the vehicle being 93 days and 34 days, respectively.
Survival comparisons for FIG. 24D were made with the log-rank test,
and p-values were adjusted for multiple comparisons. Compound I
Free Acid Amorphous decreased the percentage of circulating
leukemic PBL (FIG. 24E), and reduced spleen mass (FIG. 24F). FIG.
24G shows the HE and Ki67 staining of spleen, lung and blood from
Compound I Free Acid Amorphous treated mice, where said mice are
depleted of lymphocytes, and Ki67 staining is mostly absent.
G. Comparative Data
[0349] Compound I Free Acid vs. Ibrutinib
[0350] FIG. 24H is a Kaplan-Meier curve showing overall survival
(OS) for C57BL/6 mice engrafted with E.mu.-TCL1 leukemic
splenocytes treated with Ibrutinib or Compound I Free Acid
Amorphous (Cmpd. I FAA) (20 mg/kg, qd, oral gavage) at leukemia
onset. Survival comparisons for FIG. 24H were made with the
log-rank test, and p-values were adjusted for multiple
comparisons.
[0351] Ibrutinib is currently the standard of care (first-in-line)
treatment. Surprisingly, the median OS was 41 days for Compound I
Free Acid Amorphous compared to 32 days for ibrutinib and 21 days
for the vehicle. Compound I Free Acid Amorphous significantly
increased survival compared with vehicle (p=0.024) and Ibrutinib
(p=0.049).
[0352] All patents and other references cited in the specification
are indicative of the level of skill of those skilled in the art to
which the disclosure pertains, and are incorporated by reference in
their entireties, including any tables and figures, to the same
extent as if each reference had been incorporated by reference in
its entirety individually.
[0353] One skilled in the art would readily appreciate that the
present disclosure is well adapted to obtain the ends and
advantages mentioned, as well as those inherent therein. The
methods, variances, and compositions described herein as presently
representative of preferred embodiments are exemplary and are not
intended as limitations on the scope of the disclosure. Changes
therein and other uses will occur to those skilled in the art,
which are encompassed within the spirit of the disclosure, are
defined by the scope of the claims.
* * * * *