U.S. patent application number 16/547675 was filed with the patent office on 2019-12-19 for substituted tetrahydrocarbazole and carbazole carboxamide compounds.
The applicant listed for this patent is BRISTOL-MYERS SQUIBB COMPANY. Invention is credited to Douglas G. BATT, Myra Beaudoin Bertrand, George V. De Lucca, Michael A. Galella, Soo Sung Ko, Charles M. Langevine, Qingjie Liu, Qing Shi, Anurag S. Srivastava, Joseph A. Tino, Scott Hunter Watterson.
Application Number | 20190382416 16/547675 |
Document ID | / |
Family ID | 51210830 |
Filed Date | 2019-12-19 |
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United States Patent
Application |
20190382416 |
Kind Code |
A1 |
BATT; Douglas G. ; et
al. |
December 19, 2019 |
SUBSTITUTED TETRAHYDROCARBAZOLE AND CARBAZOLE CARBOXAMIDE
COMPOUNDS
Abstract
Disclosed are compounds of Formula (I) ##STR00001## wherein: the
two dotted lines represent either two single or two double bonds; Q
is: ##STR00002## R.sub.1 is F, Cl, --CN, or --CH.sub.3; R.sub.2 is
Cl or --CH.sub.3; R.sub.3 is --C(CH.sub.3).sub.2OH or
--CH.sub.2CH.sub.2OH; R.sub.a is H or --CH.sub.3; each R.sub.b is
independently F, Cl, --CH.sub.3, and/or --OCH.sub.3; and n is zero,
1, or 2. Also disclosed are methods of using such compounds as
inhibitors of Bruton's tyrosine kinase (Btk), and pharmaceutical
compositions comprising such compounds. These compounds are useful
in treating, preventing, or slowing the progression of diseases or
disorders in a variety of therapeutic areas, such as autoimmune
diseases and vascular disease.
Inventors: |
BATT; Douglas G.;
(Wilmington, DE) ; Beaudoin Bertrand; Myra;
(Lambertville, NJ) ; De Lucca; George V.; (Tampa,
FL) ; Galella; Michael A.; (Kendall Park, NJ)
; Ko; Soo Sung; (Hockessin, DE) ; Langevine;
Charles M.; (Brooklyn, NY) ; Liu; Qingjie;
(Newtown, PA) ; Shi; Qing; (Princeton, NJ)
; Srivastava; Anurag S.; (Belle Mead, NJ) ; Tino;
Joseph A.; (Lawrenceville, NJ) ; Watterson; Scott
Hunter; (Pennington, NJ) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
BRISTOL-MYERS SQUIBB COMPANY |
Princeton |
NJ |
US |
|
|
Family ID: |
51210830 |
Appl. No.: |
16/547675 |
Filed: |
August 22, 2019 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16140750 |
Sep 25, 2018 |
10435415 |
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16547675 |
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15809437 |
Nov 10, 2017 |
10106559 |
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16140750 |
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15625417 |
Jun 16, 2017 |
9850258 |
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15809437 |
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15067915 |
Mar 11, 2016 |
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15625417 |
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14314602 |
Jun 25, 2014 |
9334290 |
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15067915 |
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61839141 |
Jun 25, 2013 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/517 20130101;
A61P 37/02 20180101; A61P 25/28 20180101; C07D 471/04 20130101;
C07D 513/04 20130101; C07B 2200/13 20130101; C07D 239/70 20130101;
C07D 403/10 20130101; C07D 209/88 20130101; A61P 37/06 20180101;
C07D 209/88 20130101; A61P 19/02 20180101; C07D 239/70 20130101;
A61P 35/00 20180101; C07D 239/70 20130101; A61P 37/00 20180101;
A61P 43/00 20180101; C07B 2200/07 20130101; A61P 29/00 20180101;
C07B 2200/13 20130101; C07D 209/88 20130101; C07B 2200/07 20130101;
C07B 2200/07 20130101; C07B 2200/13 20130101 |
International
Class: |
C07D 513/04 20060101
C07D513/04; C07D 239/70 20060101 C07D239/70; C07D 209/88 20060101
C07D209/88; C07D 471/04 20060101 C07D471/04; C07D 403/10 20060101
C07D403/10 |
Claims
1. (canceled)
2. (canceled)
3. (canceled)
4. (canceled)
5. (canceled)
6. (canceled)
7. (canceled)
8. (canceled)
9. (canceled)
10. (canceled)
11. (canceled)
12. (canceled)
13. (canceled)
14. A compound of Formula (IA): ##STR00252## wherein: Q is:
##STR00253## R.sub.1 is F, Cl, --CN, or --CH.sub.3; R.sub.2 is Cl
or --CH.sub.3; R.sub.3 is --C(CH.sub.3).sub.2OH or
--CH.sub.2CH.sub.2OH; each R.sub.b is independently F, Cl,
--CH.sub.3, and/or --OCH.sub.3; and n is zero, 1, or 2.
15. The compound according to claim 14 having the structure of
Formula (IIIA-1): ##STR00254##
16. The compound according to claim 14 having the structure of
Formula (IIIA-2): ##STR00255##
17. The compound according to claim 14 wherein R.sub.1 is F or
Cl.
18. The compound according to claim 14 wherein R.sub.2 is
--CH.sub.3.
19. The compound according to claim 14 wherein R.sub.3 is
--C(CH.sub.3).sub.2OH.
20. The compound according to claim 14 wherein: R.sub.b is F or Cl;
and n is 1.
21. The compound according to claim 14 wherein: R.sub.1 is F or Cl;
R.sub.2 is --CH.sub.3; R.sub.3 is --C(CH.sub.3).sub.2OH; R.sub.b is
F or Cl; and n is 1.
22. The compound according to claim 14 wherein said compound is:
##STR00256##
23. A pharmaceutical composition comprising a compound according to
claim 14 and a pharmaceutically acceptable carrier.
24. A method for treating a disease comprising the administration
to a subject in need thereof a therapeutically-effective amount of
at least one compound according to claim 14, wherein said disease
is selected from systemic lupus erythematosus (SLE), rheumatoid
arthritis, multiple sclerosis (MS), or transplant rejection,
wherein treatment is inhibiting, arresting the development,
relieving and/or causing regression of the disease.
25. The method according to claim 24 wherein said disease is
rheumatoid arthritis.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation application of U.S.
patent application Ser. No. 16/140,750, filed Sep. 25, 2018, which
is a continuation application of U.S. patent application Ser. No.
15/809,437, filed Nov. 10, 2017, which is a continuation
application of U.S. patent application Ser. No. 15/625,417, filed
Jun. 16, 2017, which is a continuation application of U.S. patent
application Ser. No. 15/067,915, filed Mar. 11, 2016, which is a
continuation application of U.S. patent application Ser. No.
14/314,602 filed Jun. 25, 2014, which claims priority to U.S.
Provisional Application 61/839,141, filed Jun. 25, 2013, the
contents of which are herein incorporated by reference in their
entirety.
DESCRIPTION
[0002] The present invention generally relates to substituted
tetrahydrocarbazole and carbazole carboxamide compounds useful as
kinase inhibitors, including the modulation of Bruton's tyrosine
kinase (Btk) and other Tec family kinases such as Itk. Provided
herein are substituted tetrahydrocarbazole and carbazole
carboxamide compounds, compositions comprising such compounds, and
methods of their use. The invention further pertains to
pharmaceutical compositions containing at least one compound
according to the invention that are useful for the treatment of
conditions related to kinase modulation and methods of inhibiting
the activity of kinases, including Btk and other Tec family kinases
such as Itk, in a mammal.
[0003] Protein kinases, the largest family of human enzymes,
encompass well over 500 proteins. Btk is a member of the Tec family
of tyrosine kinases, and is a regulator of early B-cell
development, as well as mature B-cell activation, signaling, and
survival.
[0004] B-cell signaling through the B-cell receptor (BCR) leads to
a wide range of biological outputs, which in turn depend on the
developmental stage of the B-cell. The magnitude and duration of
BCR signals must be precisely regulated. Aberrant BCR-mediated
signaling can cause disregulated B-cell activation and/or the
formation of pathogenic auto-antibodies leading to multiple
autoimmune and/or inflammatory diseases. Mutation of Btk in humans
results in X-linked agammaglobulinaemia (XLA). This disease is
associated with the impaired maturation of B-cells, diminished
immunoglobulin production, compromised T-cell-independent immune
responses and marked attenuation of the sustained calcium signal
upon BCR stimulation.
[0005] Evidence for the role of Btk in allergic disorders and/or
autoimmune disease and/or inflammatory disease has been established
in Btk-deficient mouse models. For example, in standard murine
preclinical models of systemic lupus erythematosus (SLE), Btk
deficiency has been shown to result in a marked amelioration of
disease progression. Moreover, Btk deficient mice are also
resistant to developing collagen-induced arthritis and are less
susceptible to Staphylococcus-induced arthritis.
[0006] A large body of evidence supports the role of B-cells and
the humoral immune system in the pathogenesis of autoimmune and/or
inflammatory diseases. Protein-based therapeutics (such as
RITUXAN.RTM.) developed to deplete B-cells, represent an important
approach to the treatment of a number of autoimmune and/or
inflammatory diseases. Because of Btk's role in B-cell activation,
inhibitors of Btk can be useful as inhibitors of B-cell mediated
pathogenic activity (such as autoantibody production).
[0007] Btk is also expressed in mast cells and monocytes and has
been shown to be important for the function of these cells. For
example, Btk deficiency in mice is associated with impaired
IgE-mediated mast cell activation (marked diminution of TNF-alpha
and other inflammatory cytokine release), and Btk deficiency in
humans is associated with greatly reduced TNF-alpha production by
activated monocytes.
[0008] Thus, inhibition of Btk activity can be useful for the
treatment of allergic disorders and/or autoimmune and/or
inflammatory diseases including, but not limited to: SLE,
rheumatoid arthritis, multiple vasculitides, idiopathic
thrombocytopenic purpura (ITP), myasthenia gravis, allergic
rhinitis, multiple sclerosis (MS), transplant rejection, type I
diabetes, membranous nephritis, inflammatory bowel disease,
autoimmune hemolytic anemia, autoimmune thyroiditis, cold and warm
agglutinin diseases, Evans syndrome, hemolytic uremic
syndrome/thrombotic thrombocytopenic purpura (HUS/TTP),
sarcoidosis, Sjogren's syndrome, peripheral neuropathies (e.g.,
Guillain-Barre syndrome), pemphigus vulgaris, and asthma.
[0009] In addition, Btk has been reported to play a role in
controlling B-cell survival in certain B-cell cancers. For example,
Btk has been shown to be important for the survival of
BCR-Abl-positive B-cell acute lymphoblastic leukemia cells. Thus
inhibition of Btk activity can be useful for the treatment of
B-cell lymphoma and leukemia.
[0010] In view of the numerous conditions that are contemplated to
benefit by treatment involving modulation of protein kinases, it is
immediately apparent that new compounds capable of modulating
protein kinases such as Btk and methods of using these compounds
should provide substantial therapeutic benefits to a wide variety
of patients.
[0011] U.S. Pat. No. 8,084,620 and WO 2011/159857 disclose
tricyclic carboxamide compounds useful as kinase inhibitors,
including the modulation of Btk and other Tec family kinases.
[0012] There still remains a need for compounds useful as Btk
inhibitors and yet having selectivity over Jak2 tyrosine kinase.
Further, there still remains a need for compounds useful as Btk
inhibitors that have selectivity over Jak2 tyrosine kinase and also
have improved potency in the whole blood BCR-stimulated CD69
expression assay.
[0013] Applicants have found potent compounds that have activity as
Btk inhibitors. Further, applicants have found compounds that have
activity as Btk inhibitors and are selective over Jak2 tyrosine
kinase. Further still, applicants have found compounds that have
activity as Btk inhibitors, are selective over Jak2 tyrosine
kinase, and have improved potency in the whole blood BCR-stimulated
CD69 expression assay. These compounds are provided to be useful as
pharmaceuticals with desirable stability, bioavailability,
therapeutic index, and toxicity values that are important to their
drugability.
SUMMARY OF THE INVENTION
[0014] The present invention provides substituted
tetrahydrocarbazole and carbazole compounds, which are useful as
inhibitors of Btk, and are useful for the treatment of
proliferative diseases, allergic diseases, autoimmune diseases and
inflammatory diseases, including prodrugs thereof.
[0015] The present invention also provides pharmaceutical
compositions comprising at least one compound of Formula (I) and a
pharmaceutically acceptable carrier.
[0016] The present invention also provides a method of inhibiting
Btk activity comprising administering to a mammal in need thereof
at least one compound of Formula (I).
[0017] The present invention also provides a method for treating
allergic disorders and/or autoimmune and/or inflammatory diseases,
comprising administering to a mammal in need thereof at least one
compound of Formula (I).
[0018] The present invention also provides a method for treating
proliferative diseases, such as cancer, comprising administering to
a mammal in need thereof at least one compound of Formula (I).
[0019] The present invention also provides a method of treating a
disease or disorder associated with Btk activity, the method
comprising administering to a mammal in need thereof, at least one
compound of Formula (I).
[0020] The present invention also provides processes and
intermediates for making the compounds of Formula (I).
[0021] The present invention also provides a compound of Formula
(I) for use in therapy.
[0022] The present invention also provides the use of the compounds
of Formula (I) for the manufacture of a medicament for the
treatment or prophylaxis of Btk related conditions, such as
proliferative diseases, allergic diseases, autoimmune diseases and
inflammatory diseases.
[0023] The present invention also provides the use of the compounds
of Formula (I) for the manufacture of a medicament for treatment of
cancer.
[0024] The compounds of Formula (I) and compositions comprising the
compounds of Formula (I) may be used in treating, preventing, or
curing various Btk related conditions.
[0025] Pharmaceutical compositions comprising these compounds are
useful in treating, preventing, or slowing the progression of
diseases or disorders in a variety of therapeutic areas, such as
proliferative diseases, allergic diseases, autoimmune diseases and
inflammatory diseases.
[0026] These and other features of the invention will be set forth
in expanded form as the disclosure continues.
BRIEF DESCRIPTION OF THE DRAWINGS
[0027] The invention is illustrated by reference to the
accompanying drawings described below.
[0028] FIG. 1 shows the absolute stereochemistry of Intermediate 30
diacetic acid solvate.
[0029] FIG. 2 shows the absolute stereochemistry of Intermediate
35.
[0030] FIG. 3 shows the absolute stereochemistry of Example 2
methanolate, crystal Form M-1.
[0031] FIG. 4 shows the absolute stereochemistry of Example 11
methanolate, crystal Form M-1.
[0032] FIG. 5 shows the absolute stereochemistry of Example 28
dimethanolate, crystal Form M2-1.
[0033] FIG. 6 shows the absolute stereochemistry of Example 33
dimethanolate, crystal Form M2-1.
[0034] FIG. 7 shows the experimental and the simulated PXRD
patterns at room temperature (Cu K.alpha. radiation .lamda.=1.5418
.ANG.) of Example 11 monohydrate, crystal Form H-1.
[0035] FIG. 8 shows the simulated PXRD pattern at room temperature
(Cu K.alpha. radiation .lamda.=1.5418 .ANG.) of the crystal Form
N-2 of Example 11.
[0036] FIG. 9 shows the experimental and the simulated PXRD
patterns at room temperature (Cu K.alpha. radiation .lamda.=1.5418
.ANG.) of Example 11 methanolate, crystal Form M-1.
[0037] FIG. 10 shows the simulated PXRD pattern at 173 K (Cu
K.alpha. radiation .lamda.=1.5418 .ANG.) of Example 28
dimethanolate, crystal Form M2-1.
[0038] FIG. 11 shows the experimental PXRD pattern at room
temperature and the simulated PXRD pattern at 173 K (Cu K.alpha.
radiation .lamda.=1.5418 .ANG.) of Example 33 dimethanolate,
crystal Form M2-1.
DETAILED DESCRIPTION
[0039] The first aspect of the present invention provides at least
one compound of Formula (I):
##STR00003##
wherein: the two dotted lines represent either two single or two
double bonds;
Q is:
##STR00004##
[0040] R.sub.1 is F, Cl, --CN, or --CH.sub.3; R.sub.2 is Cl or
--CH.sub.3; R.sub.3 is --C(CH.sub.3).sub.2OH or
--CH.sub.2CH.sub.2OH; R.sub.a is H or --CH.sub.3; each R.sub.b is
independently F, Cl, --CH.sub.3, and/or --OCH.sub.3; and n is zero,
1, or 2.
[0041] Atropisomers are stereoisomers resulting from hindered
rotation about a single bond axis where the rotational barrier is
high enough to allow for the isolation of the individual rotational
isomers. (LaPlante et al., J. Med. Chem., 54:7005-7022 (2011).)
[0042] The compounds of Formula (A):
##STR00005##
have two stereogenic axes: bond (a) between the tricyclic
tetrahydrocarbazole/carbazole group and the phenyl group; and bond
(b) between the asymmetric heterocyclic dione group Q and the
phenyl group. Due to the non-symmetric nature of the substitutions
on the rings connected by the single bonds labeled a and b, and due
to limited rotation about these bonds caused by steric hindrance,
the compounds of Formula (A) can form rotational isomers. If the
rotational energy barriers are sufficiently high, hindered
rotations about bond (a) and/or bond (b) occur at rates that are
slow enough to allow isolation of the separated atropisomers as
different compounds. Thus, the compounds of Formula (A) can form
four rotational isomers, which under certain conditions, such as
chromatography on a chiral stationary phase, can be separated into
individual atropisomers. In solution, the compounds of Formula (A)
can be provided as a mixture of four diastereomers, or mixtures of
two pairs of diastereomers, or single atropisomers.
[0043] For the compounds of Formula (A), the pair of rotational
isomers formed by hindered rotation about stereogenic axis (a) can
be represented by the compounds of Formula (I) and Formula (B)
having the structures:
##STR00006##
The compounds of Formula (I) and the compounds of Formula (B) were
found to be separable and stable in solution at ambient and
physiological temperatures. Additionally, rotational isomers are
formed by hindered rotation about stereogenic axis (b). These two
atropisomers of the compounds of Formula (I) were also found to be
separable and stable in solution at ambient and physiological
temperatures.
[0044] Chiral compounds, such as the compounds of Formula (A), can
be separated by various techniques including Supercritical Fluid
Chromatography (SFC). SFC, which is a form of normal phase HPLC, is
a separation technique that uses super/subcritical fluid CO.sub.2
and polar organic modifiers such as alcohols as mobile phases.
(White et al., J. Chromatography A, 1074:175-185 (2005).)
[0045] The compounds of Formula (I) wherein Q is
##STR00007##
can be represented by the structure of Formula (II):
##STR00008##
[0046] The four rotational isomers of the compound of Formula (A)
wherein Q is
##STR00009##
can be represented by compounds of Formula (II) having the
structures of Formula (II-1) and (II-2):
##STR00010##
and the compounds of Formula (B) having the structures of Formula
(B-1) and (B-2):
##STR00011##
[0047] The compounds of Formula (I) wherein Q is
##STR00012##
can be represented by the structure of Formula (III):
##STR00013##
[0048] The four rotational isomers of the compound of Formula (A)
wherein Q is
##STR00014##
can be represented by the compounds of Formula (III) having the
structures of Formula (III-1) and (III-2):
##STR00015##
and the compounds of Formula (B) having the structures of Formula
(B-3) and (B-4):
##STR00016##
[0049] The compounds of Formula (I) wherein Q is
##STR00017##
can be represented by the structure of Formula (IV):
##STR00018##
[0050] The four rotational isomers of the compound of Formula (A)
wherein Q is
##STR00019##
can be represented by the compounds of Formula (IV) having the
structures of Formula (IV-1) and (IV-2):
##STR00020##
and the compounds of Formula (B) having the structures of Formula
(B-5) and (B-6):
##STR00021##
[0051] The compounds of Formula (I) wherein Q is
##STR00022##
can be represented by the structure of Formula (V):
##STR00023##
[0052] The four rotational isomers of the compound of Formula (A)
wherein Q is
##STR00024##
can be represented by the compounds of Formula (V), having the
structures of Formula (V-1) and (V-2):
##STR00025##
and the compounds of Formula (B) having the structures of Formula
(B-7) and (B-8):
##STR00026##
[0053] The absolute spacial configurations of the atropisomers can
be determined by single crystal x-ray crystallography.
[0054] The compounds of Formula (I) can be provided as individual
atropisomers or as mixtures comprising the two atropisomers of
Formula (I) in any proportions. The mixture of the two atropisomers
of Formula (I) may optionally contain one or both atropisomers of
Formula (B) in any proportions.
[0055] The compounds of Formula (I) in which R.sub.1 is F, Cl, or
--CH.sub.3 correspond to the (R)-atropisomer with respect to the
stereogenic axis formed by bond (a). The compounds of Formula (B)
in which R.sub.1 is F, Cl, or --CH.sub.3 correspond to the
(S)-atropisomer with respect to the stereogenic axis formed by bond
(a).
[0056] The compounds of Formula (I) in which R.sub.1 is --CN
correspond to the (S)-atropisomer with respect to the stereogenic
axis formed by bond (a). The compounds of Formula (B) in which
R.sub.1 is --CN correspond to the (R)-atropisomer with respect to
the stereogenic axis formed by bond (a).
[0057] As used herein, the phase "the two dotted lines represent
either two single or two double bonds" refers to compounds of
Formula (A), (B), (I), (II), (III), (IV), and (V) in which the two
dotted lines are simultaneously single bonds or the two dotted
lines are simultaneously double bonds. For example, the compounds
of Formula (I) in which the two dotted lines are simultaneously
single bonds are tetrahydrocarbazole compounds having the structure
of Formula (IA) and the compounds of Formula (I) in which the two
dotted lines are simultaneously double bonds are carbazole
compounds having the structure of Formula (IB):
##STR00027##
[0058] The tetrahydrocarbazole compounds represented by Formula
(IA) also have a chiral center at the carbon atom to which the
substituent R.sup.3 is attached, and thus can exist as S- and
R-isomers at this chiral center.
##STR00028##
[0059] These isomers are separable and are stable. One embodiment
provides compounds of Formula (IA) with the carbon chiral center to
which the R.sup.3 substituent is attached, as the S-isomer. One
embodiment provides the compounds of Formula (IA) with the carbon
chiral center to which the R.sup.3 substituent is attached, as the
R-isomer.
[0060] One embodiment provides compounds of Formula (I) wherein
R.sub.3 is --C(CH.sub.3).sub.2OH; and R.sub.1, R.sub.2, and Q are
defined in the first aspect. Included in this embodiment are
compounds in which Q is:
##STR00029##
and R.sub.a, R.sub.b, and n are defined in the first aspect. Also
included in this embodiment are compounds of Formula (IA). Other
compounds included in this embodiment are the compounds of Formula
(IB).
[0061] One embodiment provides compounds of Formula (II) wherein
R.sub.3 is --C(CH.sub.3).sub.2OH; and R.sub.1, R.sub.2, R.sub.a,
R.sub.b, and n are defined in the first aspect. Included in this
embodiment are compounds in which in which R.sub.a is --CH.sub.3
including --CD.sub.3.
[0062] One embodiment provides compounds of Formula (III) wherein
R.sub.3 is --C(CH.sub.3).sub.2OH; and R.sub.1, R.sub.2, R.sub.b,
and n are defined in the first aspect. Included in this embodiment
are compounds in which in which each R.sub.b is independently F or
Cl.
[0063] One embodiment provides compounds of Formula (IV) wherein
R.sub.3 is --C(CH.sub.3).sub.2OH; and R.sub.1 and R.sub.2 are
defined in the first aspect. Included in this embodiment are
compounds in which R.sub.1 is F, Cl, or --CH.sub.3.
[0064] One embodiment provides compounds of Formula (V) wherein
R.sub.3 is --C(CH.sub.3).sub.2OH; and R.sub.1 and R.sub.2 are
defined in the first aspect. Included in this embodiment are
compounds in which R.sub.1 is F, Cl, or --CH.sub.3.
[0065] One embodiment provides compounds of Formula (I) wherein
R.sub.1 is F. Included in this embodiment are compounds of Formula
(IA). Other compounds included in this embodiment are the compounds
of Formula (IB).
[0066] One embodiment provides compounds of Formula (I) wherein
R.sub.1 is Cl. Included in this embodiment are compounds of Formula
(IA). Other compounds included in this embodiment are the compounds
of Formula (IB).
[0067] One embodiment provides compounds of Formula (I) wherein
R.sub.1 is F or Cl.
[0068] Included in this embodiment are compounds of Formula (IA).
Other compounds included in this embodiment are the compounds of
Formula (IB).
[0069] One embodiment provides compounds of Formula (I) wherein
R.sub.1 is --CH.sub.3.
[0070] Included in this embodiment are compounds of Formula (IA).
Other compounds included in this embodiment are the compounds of
Formula (IB).
[0071] One embodiment provides compounds of Formula (I) wherein
R.sub.1 is --CN.
[0072] Included in this embodiment are compounds of Formula (IA).
Other compounds included in this embodiment are the compounds of
Formula (IB).
[0073] One embodiment provides compounds of Formula (I) wherein
R.sub.1 is F, Cl, or --CN.
[0074] Included in this embodiment are compounds of Formula (IA).
Other compounds included in this embodiment are the compounds of
Formula (IB).
[0075] One embodiment provides compounds of Formula (I) wherein
R.sub.1 is --CH.sub.3 or --CN.
[0076] Included in this embodiment are compounds of Formula (IA).
Other compounds included in this embodiment are the compounds of
Formula (IB).
[0077] One embodiment provides compounds of Formula (I) wherein
R.sub.1 is F, Cl, or --CH.sub.3. Included in this embodiment are
compounds of Formula (IA). Other compounds included in this
embodiment are the compounds of Formula (IB).
[0078] One embodiment provides compounds of Formula (I) wherein
R.sub.2 is Cl. Included in this embodiment are compounds of Formula
(IA). Other compounds included in this embodiment are the compounds
of Formula (IB). Also, included in this embodiment are compounds in
which R.sub.3 is --C(CH.sub.3).sub.2OH.
[0079] One embodiment provides compounds of Formula (I) wherein
R.sub.2 is --CH.sub.3. Included in this embodiment are compounds of
Formula (IA). Other compounds included in this embodiment are the
compounds of Formula (IB). Also, included in this embodiment are
compounds in which R.sub.3 is --C(CH.sub.3).sub.2OH.
[0080] One embodiment provides compounds of Formula (I) wherein
R.sub.3 is --C(CH.sub.3).sub.2OH. Included in this embodiment are
compounds of Formula (IA). Other compounds included in this
embodiment are the compounds of Formula (IB).
[0081] One embodiment provides compounds of Formula (I) wherein
each R.sub.b is independently F and/or Cl. Included in this
embodiment are compounds in which n is 1 or 2. Also included in
this embodiment are compounds in which n is 2 and each R.sub.b is
F.
[0082] One embodiment provides compounds of Formula (I) wherein n
is 1 and R.sub.b is --CH.sub.3 or --OCH.sub.3.
[0083] One embodiment provides compounds of Formula (I) wherein n
is zero. Included in this embodiment are compounds of Formula (IA).
Other compounds included in this embodiment are the compounds of
Formula (IB).
[0084] One embodiment provides compounds of Formula (II) in which
the two dotted lines are simultaneously single bonds and R.sub.1,
R.sub.2, R.sub.3, R.sub.a, R.sub.b, and n are defined in the first
aspect. Compounds of this embodiment have the structure of Formula
(IIA):
##STR00030##
[0085] The two rotational isomers of the compound of Formula (IIA)
are represented by the structures of Formula (IIA-1) and
(IIA-2):
##STR00031##
[0086] Included in this embodiment are compounds of Formula (IIA),
(IIA-1), and (IIA-2) in which R.sub.3 is --C(CH.sub.3).sub.2OH.
[0087] One embodiment provides compounds of Formula (II) in which
the two dotted lines are simultaneously double bonds and R.sub.1,
R.sub.2, R.sub.3, R.sub.a, R.sub.b, and n are defined in the first
aspect. Compounds of this embodiment have the structure of Formula
(IIB):
##STR00032##
[0088] The two rotational isomers of the compound of Formula (IIB)
are represented by the structures of Formula (IIB-1) and
(IIB-2):
##STR00033##
[0089] Included in this embodiment are compounds of Formula (IIB),
(IIB-1), and (IIB-2) in which R.sub.3 is --C(CH.sub.3).sub.2OH.
[0090] One embodiment provides compounds of Formula (II) wherein
R.sub.a is H. Included in this embodiment are compounds of Formula
(IIA). Other compounds included in this embodiment are the
compounds of Formula (IIB).
[0091] One embodiment provides compounds of Formula (II) wherein
R.sub.a is --CH.sub.3.
[0092] Included in this embodiment are compounds in which R.sub.a
is --CD.sub.3. Also, included in this embodiment are compounds of
Formula (IIA). Other compounds included in this embodiment are the
compounds of Formula (IIB).
[0093] One embodiment provides compounds of Formula (III) in which
the two dotted lines are simultaneously single bonds and R.sub.1,
R.sub.2, R.sub.3, R.sub.b, and n are defined in the first aspect.
Compounds of this embodiment have the structure of Formula
(IIIA):
##STR00034##
[0094] The two rotational isomers of the compound of Formula (IIIA)
are represented by the structures of Formula (IIIA-1) and
(IIIA-2):
##STR00035##
[0095] Included in this embodiment are compounds of Formula (IIIA),
(IIIA-1), and (IIIA-2) in which R.sub.3 is
--C(CH.sub.3).sub.2OH.
[0096] One embodiment provides compounds of Formula (III) in which
the two dotted lines are simultaneously double bonds and R.sub.1,
R.sub.2, R.sub.3, R.sub.b, and n are defined in the first aspect.
Compounds of this embodiment have the structure of Formula
(IIIB):
##STR00036##
[0097] The two rotational isomers of the compound of Formula (IIIB)
are represented by the structures of Formula (IIIB-1) and
(IIIB-2):
##STR00037##
[0098] Included in this embodiment are compounds of Formula (IIIB),
(IIIB-1), and (IIIB-2) in which R.sub.3 is
--C(CH.sub.3).sub.2OH.
[0099] One embodiment provides compounds of Formula (IV) in which
the two dotted lines are simultaneously single bonds and R.sub.1,
R.sub.2, and R.sub.3 are defined in the first aspect.
[0100] Compounds of this embodiment have the structure of Formula
(IVA):
##STR00038##
The two rotational isomers of the compound of Formula (IVA) are
represented by the structures of Formula (IVA-1) and (IVA-2):
##STR00039##
Included in this embodiment are compounds of Formula (IVA),
(IVA-1), and (IVA-2) in which R.sub.3 is --C(CH.sub.3).sub.2OH.
[0101] One embodiment provides compounds of Formula (IV) in which
the two dotted lines are simultaneously double bonds and R.sub.1,
R.sub.2, and R.sub.3 are defined in the first aspect.
[0102] Compounds of this embodiment have the structure of Formula
(IVB):
##STR00040##
[0103] The two rotational isomers of the compound of Formula (IVB)
are represented by the structures of Formula (IVB-1) and
(IVB-2):
##STR00041##
[0104] Included in this embodiment are compounds of Formula (IVB),
(IVB-1), and (IVB-2) in which R.sub.3 is --C(CH.sub.3).sub.2OH.
[0105] One embodiment provides compounds of Formula (V) in which
the two dotted lines are simultaneously single bonds and R.sub.1,
R.sub.2, and R.sub.3 are defined in the first aspect.
[0106] Compounds of this embodiment have the structure of Formula
(VA):
##STR00042##
[0107] The two rotational isomers of the compound of Formula (VA)
are represented by the structures of Formula (VA-1) and (VA-2):
##STR00043##
[0108] Included in this embodiment are compounds of Formula (VA),
(VA-1), and (VA-2) in which R.sub.3 is --C(CH.sub.3).sub.2OH.
[0109] One embodiment provides compounds of Formula (V) in which
the two dotted lines are simultaneously double bonds and R.sub.1,
R.sub.2, and R.sub.3 are defined in the first aspect.
[0110] Compounds of this embodiment have the structure of Formula
(VB):
##STR00044##
[0111] The two rotational isomers of the compound of Formula (VB)
are represented by the structures of Formula (VB-1) and (VB-2):
##STR00045##
[0112] Included in this embodiment are compounds of Formula (VB),
(VB-1), and (VB-2) in which R.sub.3 is --C(CH.sub.3).sub.2OH.
[0113] One embodiment provides a compound of Formula (I) having the
structure:
##STR00046##
wherein R.sub.1 is Cl or F; and R.sub.a is --CH.sub.3 including
--CD.sub.3.
[0114] One embodiment provides a compound of Formula (I) having the
structure:
##STR00047##
wherein R.sub.1 is Cl or F; and R.sub.a is --CH.sub.3 including
--CD.sub.3.
[0115] One embodiment provides a compound of Formula (I) having the
structure:
##STR00048##
wherein R.sub.1 is Cl or F; and R.sub.a is --CH.sub.3 including
--CD.sub.3.
[0116] One embodiment provides a compound of Formula (I) having the
structure:
##STR00049##
[0117] One embodiment provides a compound of Formula (I) or having
the structure:
##STR00050##
[0118] One embodiment provides a compound of Formula (I) having the
structure:
##STR00051##
[0119] One embodiment provides a compound selected from the
exemplified examples within the scope of the first aspect.
[0120] One embodiment provides a compound selected from any subset
list of compounds within the scope of the first aspect or of any of
the above embodiments.
[0121] One embodiment provides a compound of Formula (II) wherein
the compound is:
3-chloro-4-(R)-(3-(R)-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin--
3
(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxa-
mide (1);
3-chloro-4-(R)-(3-(S)-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroqu-
inazolin-3(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-
-carboxamide (2);
3-chloro-7-(2-hydroxypropan-2-yl)-4-(R)-(2-methyl-3-(1-methyl-2,4-dioxo-1-
,2-dihydroquinazolin-3 (4H)-yl)phenyl)-9H-carbazole-1-carboxamide
(3);
3-chloro-4-(R)-(3-(1,8-dimethyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-
-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
(4);
3-chloro-7-(2-hydroxypropan-2-yl)-4-(R)-(3-(R)-(7-methoxy-1-methyl-2,4-di-
oxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-9H-carbazole-1-carboxa-
mide (5);
3-chloro-7-(2-hydroxypropan-2-yl)-4-(R)-(3-(S)-(7-methoxy-1-meth-
yl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-9H-carbazole--
1-carboxamide (6);
3-chloro-7-(2-hydroxypropan-2-yl)-4-(R)-(3-(8-methoxy-1-methyl-2,4-dioxo--
1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-9H-carbazole-1-carboxamide
(7);
3-chloro-4-(R)-(3-(6-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-
-3
(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carbox-
amide (8);
3-chloro-4-(R)-(3-(7-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquina-
zolin-3(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-ca-
rboxamide (9);
3-chloro-4-(R)-(3-(6,8-difluoro-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-
-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
(10);
3-chloro-4-(R)-(3-(S)-(8-fluoro-1-methyl(d.sub.3)-2,4-dioxo-1,2-dihydroqu-
inazolin-3
(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole--
1-carboxamide (11);
3-chloro-4-(R)-(3-(R)-(8-fluoro-1-methyl(d.sub.3)-2,4-dioxo-1,2-dihydroqu-
inazolin-3
(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole--
1-carboxamide (12);
3-chloro-4-(R)-(3-(8-fluoro-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-m-
ethylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
(13);
3-chloro-4-(R)-(3-(R)-(8-fluoro-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-
-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
(14);
3-cyano-4-(S)-(3-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-
-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
(15 and 16);
3-fluoro-4-(R)-(3-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H-
)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
(17);
3-fluoro-4-(R)-(3-(S)-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquina-
zolin-3(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-ca-
rboxamide (18);
3-fluoro-4-(R)-(3-(S)-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin--
3(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxam-
ide (19);
3-fluoro-4-(R)-(3-(8-fluoro-2,4-dioxo-1,2-dihydroquinazolin-3
(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxam-
ide (20);
3-fluoro-4-(R)-(3-(R)-(8-fluoro-2,4-dioxo-1,2-dihydroquinazolin--
3(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxam-
ide (21);
3-fluoro-4-(R)-(3-(S)-(8-fluoro-2,4-dioxo-1,2-dihydroquinazolin--
3(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxam-
ide (22);
6-chloro-5-(R)-(3-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinaz-
olin-3(4H)-yl)-2-methylphenyl)-2-(S)-(2-hydroxypropan-2-yl)-2,3,4,9-tetrah-
ydro-1H-carbazole-8-carboxamide (25);
6-chloro-5-(R)-(3-(S)-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin--
3(4H)-yl)-2-methylphenyl)-2-(S)-(2-hydroxypropan-2-yl)-2,3,4,9-tetrahydro--
1H-carbazole-8-carboxamide (26);
6-fluoro-5-(R)-(3-(S)-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin--
3(4H)-yl)-2-methylphenyl)-2-(R)-(2-hydroxypropan-2-yl)-2,3,4,9-tetrahydro--
1H-carbazole-8-carboxamide (27);
6-fluoro-5-(R)-(3-(S)-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin--
3(4H)-yl)-2-methylphenyl)-2-(S)-(2-hydroxypropan-2-yl)-2,3,4,9-tetrahydro--
1H-carbazole-8-carboxamide (28);
4-(R)-(3-(S)-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-
-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-3-methyl-9H-carbazole-1-carboxam-
ide (29);
3-chloro-4-(2-chloro-3-(1-methyl-2,4-dioxo-1,2-dihydroquinazolin-
-3
(4H)-yl)phenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
(42);
3-chloro-4-(R)-(2-chloro-3-(R)-(1-methyl-2,4-dioxo-1,2-dihydroquina-
zolin-3(4H)-yl)phenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
(43);
3-chloro-4-(2-chloro-3-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquin-
azolin-3(4H)-yl)phenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamid-
e (44);
3-chloro-4-(R)-(2-chloro-3-(R)-(8-fluoro-1-methyl-2,4-dioxo-1,2-di-
hydroquinazolin-3(4H)-yl)phenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-c-
arboxamide (45);
4-(2-chloro-3-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3
(4H)-yl)phenyl)-3-fluoro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxam-
ide (46);
3-chloro-4-(R)-(2-chloro-3-(8-fluoro-2,4-dioxo-1,2-dihydroquinaz-
olin-3(4H)-yl)phenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
(47);
##STR00052## ##STR00053## ##STR00054## ##STR00055##
##STR00056##
[0122] One embodiment provides a compound of Formula (III) wherein
the compound is:
3-chloro-4-(R)-(3-(3-(4-fluorophenyl)-2,6-dioxo-2,3-dihydropyrimidin-1(6H-
)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
(23);
4-(R)-(3-(5-chloro-1,3-dioxo-1H-pyrido[1,2-c]pyrimidin-2(3H)-yl)-2--
methylphenyl)-3-fluoro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
(30 and 31);
3-chloro-4-(R)-(3-(R)-(5-chloro-1,3-dioxo-1H-pyrido[1,2-c]pyrimidin-2(3H)-
-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
(32);
3-chloro-4-(R)-(3-(S)-(5-chloro-1,3-dioxo-1H-pyrido[1,2-c]pyrimidin-
-2(3H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxa-
mide (33);
3-chloro-4-(R)-(3-(5-fluoro-1,3-dioxo-1H-pyrido[1,2-c]pyrimidin-
-2(3H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxa-
mide (34);
3-chloro-4-(R)-(3-(5-fluoro-1,3-dioxo-1H-pyrido[1,2-c]pyrimidin-
-2(3H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxa-
mide (35 and 36);
3-chloro-7-(2-hydroxypropan-2-yl)-4-(R)-(3-(5-methoxy-1,3-dioxo-1H-pyrido-
[1,2-c]pyrimidin-2(3H)-yl)-2-methylphenyl)-9H-carbazole-1-carboxamide
(37);
3-fluoro-4-(R)-(3-(5-fluoro-1,3-dioxo-1H-pyrido[1,2-c]pyrimidin-2(3-
H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
(40 and 41);
##STR00057## ##STR00058##
[0123] One embodiment provides a compound of Formula (IV) wherein
the compound is:
3-chloro-4-(R)-(3-(5,7-dioxo-5H-thiazolo[3,2-c]pyrimidin-6(7H)-yl)-2-meth-
ylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide (38
and 39).
[0124] One embodiment provides a compound of Formula (V) wherein
the compound is:
3-chloro-4-(R)-(3-(3-(4-fluorophenyl)-2,6-dioxo-2,3-dihydropyrimidin-1(6H-
)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
(24).
[0125] In one embodiment, a composition is provided comprising a
compound of Formula (I). Included in this embodiment is a
composition comprising a mixture in any proportion of (i) a
compound of Formula (I) and (ii) a compound of Formula (B).
[0126] In one embodiment, a composition is provided comprising at
least 98 equivalent weight % of a compound of Formula (I), based on
the total equivalent weight of the compound of Formula (I) and its
atropisomer compound of Formula (B). Included in this embodiment,
are compositions comprising at 99 equivalent weight %, 99.5
equivalent weight %, 99.8 equivalent weight %, and 99.9 equivalent
weight % of a compound of Formula (I) based on the total equivalent
weight of the compound of Formula (I) and its atropisomer compound
of Formula (B). Compositions of this embodiment include
pharmaceutical compositions.
[0127] In one embodiment, a composition is provided comprising a
compound of Formula (II). Included in this embodiment is a
composition comprising a mixture in any proportion of (i) a
compound of Formula (II) and (ii) one or both of its atropisomer
compounds of Formula (B-1) and (B-2).
[0128] In one embodiment, a composition is provided comprising at
least 98 equivalent weight % of a compound of Formula (II), based
on the total equivalent weight of the compound of Formula (II) and
its atropisomer compounds of Formula (B-1) and (B-2).
[0129] Included in this embodiment, are compositions comprising at
99 equivalent weight %, 99.5 equivalent weight %, 99.8 equivalent
weight %, and 99.9 equivalent weight % of a compound of Formula
(II) based on the total equivalent weight of the compound of
Formula (II) and its atropisomer compounds of Formula (B-1) and
(B-2). Compositions of this embodiment include pharmaceutical
compositions.
[0130] In one embodiment, a composition is provided comprising a
compound of Formula (III). Included in this embodiment is a
composition comprising a mixture in any proportion of (i) a
compound of Formula (III) and (ii) one or both of its atropisomer
compounds of Formula (B-3) and (B-4).
[0131] In one embodiment, a composition is provided comprising at
least 98 equivalent weight % of a compound of Formula (III), based
on the total equivalent weight of the compound of Formula (III) and
its atropisomer compounds of Formula (B-3) and (B-4). Included in
this embodiment, are compositions comprising at 99 equivalent
weight %, 99.5 equivalent weight %, 99.8 equivalent weight %, and
99.9 equivalent weight % of a compound of Formula (III) based on
the total equivalent weight of the compound of Formula (III) and
its atropisomer compounds of Formula (B-3) and (B-4). Compositions
of this embodiment include pharmaceutical compositions.
[0132] In one embodiment, a composition is provided comprising a
compound of Formula (IV). Included in this embodiment is a
composition comprising a mixture in any proportion of (i) a
compound of Formula (IV) and (ii) one or both of its atropisomer
compounds of Formula (B-5) and (B-6).
[0133] In one embodiment, a composition is provided comprising at
least 98 equivalent weight % of a compound of Formula (IV), based
on the total equivalent weight of the compound of Formula (IV) and
its atropisomer compounds of Formula (B-5) and (B-6).
[0134] Included in this embodiment, are compositions comprising at
99 equivalent weight %, 99.5 equivalent weight %, 99.8 equivalent
weight %, and 99.9 equivalent weight % of a compound of Formula
(IV) based on the total equivalent weight of the compound of
Formula (IV) and its atropisomer compounds of Formula (B-5) and
(B-6). Compositions of this embodiment include pharmaceutical
compositions.
[0135] In one embodiment, a composition is provided comprising a
compound of Formula (V). Included in this embodiment is a
composition comprising a mixture in any proportion of (i) a
compound of Formula (V) and (ii) one or both of its atropisomer
compounds of Formula (B-7) and (B-8).
[0136] In one embodiment, a composition is provided comprising at
least 98 equivalent weight % of a compound of Formula (V), based on
the total equivalent weight of the compound of Formula (V) and its
atropisomer compounds of Formula (B-7) and (B-8).
[0137] Included in this embodiment, are compositions comprising at
99 equivalent weight %, 99.5 equivalent weight %, 99.8 equivalent
weight %, and 99.9 equivalent weight % of a compound of Formula (V)
based on the total equivalent weight of the compound of Formula (V)
and its atropisomer compounds of Formula (B-7) and (B-8).
Compositions of this embodiment include pharmaceutical
compositions.
[0138] In one embodiment, a composition is provided comprising a
compound of Formula (II-1). Included in this embodiment is a
composition comprising a mixture in any proportion of (i) a
compound of Formula (II-1) and (ii) one or more of its atropisomer
compounds of Formula (II-2), Formula (B-1) and (B-2).
[0139] In one embodiment, a composition is provided comprising at
least 98 equivalent weight % of a compound of Formula (II-1), based
on the total equivalent weight of the compounds of Formula (II-1),
(II-2), (B-1), and (B-2). Included in this embodiment, are
compositions comprising at 99 equivalent weight %, 99.5 equivalent
weight %, 99.8 equivalent weight %, and 99.9 equivalent weight % of
a compound of Formula (II-1) based on the total equivalent weight
of the compounds of Formula (II-1), (II-2), (B-1), and (B-2).
Compositions of this embodiment include pharmaceutical
compositions.
[0140] In one embodiment, a composition is provided comprising a
compound of Formula (II-2). Included in this embodiment is a
composition comprising a mixture in any proportion of (i) a
compound of Formula (II-2) and (ii) one or more of its atropisomer
compounds of Formula (II-1), Formula (B-1) and (B-2).
[0141] In one embodiment, a composition is provided comprising at
least 98 equivalent weight % of a compound of Formula (II-2), based
on the total equivalent weight of the compounds of Formula (II-1),
(II-2), (B-1), and (B-2). Included in this embodiment, are
compositions comprising at 99 equivalent weight %, 99.5 equivalent
weight %, 99.8 equivalent weight %, and 99.9 equivalent weight % of
a compound of Formula (II-2) based on the total equivalent weight
of the compounds of Formula (II-1), (II-2), (B-1), and (B-2).
Compositions of this embodiment include pharmaceutical
compositions.
[0142] In one embodiment, a composition is provided comprising a
compound of Formula (III-1). Included in this embodiment is a
composition comprising a mixture in any proportion of (i) a
compound of Formula (III-1) and (ii) one or more of its atropisomer
compounds of Formula (III-2), Formula (B-3) and (B-4).
[0143] In one embodiment, a composition is provided comprising at
least 98 equivalent weight % of a compound of Formula (III-1),
based on the total equivalent weight of the compounds of Formula
(III-1), (III-2), (B-3), and (B-4). Included in this embodiment,
are compositions comprising at 99 equivalent weight %, 99.5
equivalent weight %, 99.8 equivalent weight %, and 99.9 equivalent
weight % of a compound of Formula (III-1) based on the total
equivalent weight of the compounds of Formula (III-1), (III-2),
(B-3), and (B-4). Compositions of this embodiment include
pharmaceutical compositions.
[0144] In one embodiment, a composition is provided comprising a
compound of Formula (III-2). Included in this embodiment is a
composition comprising a mixture in any proportion of (i) a
compound of Formula (III-2) and (ii) one or more of its atropisomer
compounds of Formula (III-1), Formula (B-3) and (B-4).
[0145] In one embodiment, a composition is provided comprising at
least 98 equivalent weight % of a compound of Formula (III-2),
based on the total equivalent weight of the compounds of Formula
(III-1), (III-2), (B-3), and (B-4). Included in this embodiment,
are compositions comprising at 99 equivalent weight %, 99.5
equivalent weight %, 99.8 equivalent weight %, and 99.9 equivalent
weight % of a compound of Formula (III-2) based on the total
equivalent weight of the compounds of Formula (III-1), (III-2),
(B-3), and (B-4). Compositions of this embodiment include
pharmaceutical compositions.
[0146] In one embodiment, a composition is provided comprising a
compound of Formula (IV-1). Included in this embodiment is a
composition comprising a mixture in any proportion of (i) a
compound of Formula (IV-1) and (ii) one or more of its atropisomer
compounds of Formula (IV-2), Formula (B-5) and (B-6).
[0147] In one embodiment, a composition is provided comprising at
least 98 equivalent weight % of a compound of Formula (IV-1), based
on the total equivalent weight of the compounds of Formula (IV-1),
(IV-2), (B-5), and (B-6). Included in this embodiment, are
compositions comprising at 99 equivalent weight %, 99.5 equivalent
weight %, 99.8 equivalent weight %, and 99.9 equivalent weight % of
a compound of Formula (IV-1) based on the total equivalent weight
of the compounds of Formula (IV-1), (IV-2), (B-5), and (B-6).
Compositions of this embodiment include pharmaceutical
compositions.
[0148] In one embodiment, a composition is provided comprising a
compound of Formula (IV-2). Included in this embodiment is a
composition comprising a mixture in any proportion of (i) a
compound of Formula (IV-2) and (ii) one or more of its atropisomer
compounds of Formula (IV-1), Formula (B-5) and (B-6).
[0149] In one embodiment, a composition is provided comprising at
least 98 equivalent weight % of a compound of Formula (IV-2), based
on the total equivalent weight of the compounds of Formula (IV-1),
(IV-2), (B-5), and (B-6). Included in this embodiment, are
compositions comprising at 99 equivalent weight %, 99.5 equivalent
weight %, 99.8 equivalent weight %, and 99.9 equivalent weight % of
a compound of Formula (IV-2) based on the total equivalent weight
of the compounds of Formula (IV-1), (IV-2), (B-5), and (B-6).
Compositions of this embodiment include pharmaceutical
compositions.
[0150] In one embodiment, a composition is provided comprising a
compound of Formula (V-1). Included in this embodiment is a
composition comprising a mixture in any proportion of (i) a
compound of Formula (V-1) and (ii) one or more of its atropisomer
compounds of Formula (V-2), Formula (B-7) and (B-8).
[0151] In one embodiment, a composition is provided comprising at
least 98 equivalent weight % of a compound of Formula (V-1), based
on the total equivalent weight of the compounds of Formula (V-1),
(V-2), (B-7), and (B-8). Included in this embodiment, are
compositions comprising at 99 equivalent weight %, 99.5 equivalent
weight %, 99.8 equivalent weight %, and 99.9 equivalent weight % of
a compound of Formula (V-1) based on the total equivalent weight of
the compounds of Formula (V-1), (V-2), (B-7), and (B-8).
Compositions of this embodiment include pharmaceutical
compositions.
[0152] In one embodiment, a composition is provided comprising a
compound of Formula (V-2). Included in this embodiment is a
composition comprising a mixture in any proportion of (i) a
compound of Formula (V-2) and (ii) one or more of its atropisomer
compounds of Formula (V-1), Formula (B-7) and (B-8).
[0153] In one embodiment, a composition is provided comprising at
least 98 equivalent weight % of a compound of Formula (V-2), based
on the total equivalent weight of the compounds of Formula (V-1),
(V-2), (B-7), and (B-8). Included in this embodiment, are
compositions comprising at 99 equivalent weight %, 99.5 equivalent
weight %, 99.8 equivalent weight %, and 99.9 equivalent weight % of
a compound of Formula (V-2) based on the total equivalent weight of
the compounds of Formula (V-1), (V-2), (B-7), and (B-8).
Compositions of this embodiment include pharmaceutical
compositions.
Crystal Forms
TABLE-US-00001 [0154] TABLE 1 Example Form 2 M-1 11 H-1 11 N-2 11
M-1 28 M2-1 33 M2-1
[0155] In one embodiment, the compound of Example 2 is provided as
a crystalline material comprising Form M-1. This crystalline form
of the compound of Example 2 comprises a methanol solvate
crystalline form referred to herein as "Form M-1" or "M-1 Form" of
Example 2. The M-1 Form of Example 2 comprises one molecule of
methanol for each molecule of Example 2.
[0156] In one embodiment, the M-1 Form of the compound of Example 2
is characterized by unit cell parameters approximately equal to the
following:
[0157] Cell Dimensions: [0158] a=9.75 .ANG. [0159] b=14.21 .ANG.
[0160] c=21.26 .ANG. [0161] .alpha.=90.0.degree. [0162]
.beta.=90.0.degree. [0163] .gamma.=90.0.degree.
[0164] Space group: P2.sub.12.sub.12.sub.1
[0165] Molecules of Example 2/asymmetric unit: 1
[0166] Volume/Number of molecules in the unit cell=736
.ANG..sup.3
[0167] Density (calculated)=1.391 g/cm.sup.3,
wherein the unit cell parameters of Form M-1 are measured at a
temperature of about 203 K.
[0168] In yet an even further embodiment, the M-1 Form of Example 2
is characterized by fractional atomic coordinates substantially as
listed in Table 2.
TABLE-US-00002 TABLE 2 Fractional Atomic Coordinates of Example 2,
Form M-1 Calculated at a Temperature of about 203K; Atomic
Coordinates (.times. 104) Atom X Y Z Cl1 0.5111 0.2098 0.2452 N1
0.4284 -0.0941 0.0651 C1 0.4089 0.0402 0.2141 C2 0.4430 -0.0331
0.1143 C3 0.5134 -0.0987 -0.0462 C4 0.5311 0.0412 0.0962 C5 0.5042
-0.0618 0.0142 C6 0.3830 -0.0362 0.1748 C7 0.6528 0.0676 -0.0127 C8
0.4911 0.1146 0.1945 C9 0.5570 0.1167 0.1365 C10 0.5928 -0.0859
-0.1587 C11 0.5718 0.0218 0.0316 C12 0.5929 -0.0521 -0.0902 C13
0.6628 0.0308 -0.0728 O1 0.5612 -0.1842 -0.1607 C14 0.4745 -0.0373
-0.1922 C15 0.2943 -0.1171 0.1922 C16 0.7270 -0.0662 -0.1926 O2
0.2647 -0.1777 0.1522 N2 0.2483 -0.1213 0.2514 C17 0.6935 0.3440
0.0689 C18 0.8335 0.3314 0.0747 C19 0.6506 0.1944 0.1165 C20 0.5982
0.2769 0.0896 C21 0.8827 0.2492 0.1010 C22 0.7908 0.1819 0.1221 C23
0.4470 0.2921 0.0824 N3 0.6425 0.4284 0.0392 C24 0.6079 0.5032
0.0785 N4 0.5449 0.5793 0.0505 C25 0.5043 0.5772 -0.0128 C26 0.6347
0.4289 -0.0265 C27 0.3810 0.6409 -0.1018 C28 0.5564 0.5079 -0.0530
C29 0.5260 0.5081 -0.1169 C30 0.4122 0.6409 -0.0392 C31 0.4401
0.5750 -0.1415 O3 0.6826 0.3654 -0.0574 O4 0.6337 0.5004 0.1344 C32
0.5414 0.6667 0.0876 F1 0.3478 0.7048 -0.0014 O5 0.4744 -0.2738
-0.2654 C33 0.3392 -0.2608 -0.2825 H1 0.3792 -0.1452 0.0656 H2
0.3702 0.0415 0.2546 H3 0.4665 -0.1543 -0.0570 H4 0.7002 0.1230
-0.0020 H5 0.7175 0.0617 -0.1027 H6 0.6298 -0.2150 -0.1502 H7
0.4710 -0.0582 -0.2356 H8 0.4881 0.0302 -0.1910 H9 0.3890 -0.0531
-0.1713 H10 0.8030 -0.0882 -0.1671 H11 0.7361 0.0009 -0.1996 H12
0.7275 -0.0988 -0.2327 H13 0.1959 -0.1676 0.2631 H14 0.2709 -0.0777
0.2782 H15 0.8945 0.3782 0.0608 H16 0.9776 0.2391 0.1046 H17 0.8245
0.1265 0.1406 H18 0.3989 0.2335 0.0902 H19 0.4275 0.3135 0.0399 H20
0.4165 0.3393 0.1122 H21 0.3195 0.6857 -0.1180 H22 0.5646 0.4622
-0.1434 H23 0.4213 0.5761 -0.1848 H24 0.4485 0.6782 0.1021 H25
0.5711 0.7190 0.0615 H26 0.6021 0.6608 0.1234 H27 0.4880 -0.2496
-0.2304 H28 0.2809 -0.3001 -0.2565 H29 0.3273 -0.2780 -0.3263 H30
0.3142 -0.1953 -0.2767
[0169] In one embodiment, the compound of Example 11 is provided as
a crystalline material comprising Form H-1. This crystalline form
of the compound of Example 11 comprises a monohydrate crystalline
form referred to herein as "Form H-1" or "H-1 Form" of Example 11.
The H-1 Form of Example 11 comprises one molecule of water for each
molecule of Example 11.
[0170] In one embodiment, the H-1 Form of the compound of Example
11 is characterized by unit cell parameters approximately equal to
the following:
[0171] Cell Dimensions: [0172] a=9.41 .ANG. [0173] b=14.51 .ANG.
[0174] c=21.12 .ANG. [0175] .alpha.=90.0.degree. [0176]
.beta.=90.0.degree. [0177] .gamma.=90.0.degree.
[0178] Space group: P2.sub.12.sub.12.sub.1
[0179] Molecules of Example 11/asymmetric unit: 1
[0180] Volume/Number of molecules in the unit cell=721
.ANG..sup.3
[0181] Density (calculated)=1.396 g/cm.sup.3,
wherein the unit cell parameters of Form H-1 are measured at a
temperature of about room temperature.
[0182] In another embodiment, H-1 form of Example 11 is
characterized by a simulated powder x-ray diffraction (PXRD)
pattern substantially in accordance with the pattern shown in FIG.
7 and/or by an experimental PXRD pattern substantially in
accordance with the pattern shown in FIG. 7.
[0183] In yet an even further embodiment, the H-1 Form of Example
11 is characterized by fractional atomic coordinates substantially
as listed in Table 3.
TABLE-US-00003 TABLE 3 Fractional Atomic Coordinates of Example 11,
Form H-1 Calculated at Room Temperature; Atomic Coordinates
(.times. 10.sup.4) Atom X Y Z Cl1 0.4783 0.2052 0.2387 N1 0.4348
-0.0990 0.0600 C1 0.4427 -0.0381 0.1093 C2 0.3961 0.0338 0.2082 C3
0.5280 0.0384 0.0908 C4 0.5215 -0.0998 -0.0525 C5 0.3806 -0.0431
0.1694 C6 0.6503 0.0680 -0.0190 C7 0.5093 -0.0648 0.0087 C8 0.5466
0.1131 0.1314 C9 0.4735 0.1097 0.1887 C10 0.5719 0.0201 0.0261 C11
0.6615 0.0322 -0.0793 C12 0.5970 -0.0514 -0.0970 C13 0.5968 -0.0824
-0.1662 O1 0.5643 -0.1789 -0.1705 C14 0.7370 -0.0628 -0.1994 C15
0.4767 -0.0343 -0.1997 C16 0.3010 -0.1271 0.1879 O2 0.2749 -0.1874
0.1484 N2 0.2591 -0.1344 0.2483 C17 0.6425 0.1917 0.1143 C18 0.6863
0.3413 0.0723 C19 0.7866 0.1827 0.1254 C20 0.8297 0.3327 0.0837 C21
0.8807 0.2530 0.1104 C22 0.5887 0.2724 0.0870 C23 0.4341 0.2839
0.0745 N3 0.6351 0.4252 0.0428 C24 0.6028 0.4987 0.0826 N4 0.5451
0.5756 0.0548 C25 0.5048 0.5763 -0.0091 C26 0.5515 0.5068 -0.0496
C27 0.6265 0.4268 -0.0234 C28 0.5218 0.5088 -0.1139 C29 0.4158
0.6426 -0.0357 C30 0.3848 0.6446 -0.0985 C31 0.4396 0.5789 -0.1388
O3 0.6707 0.3631 -0.0545 O4 0.6282 0.4945 0.1389 C32 0.5492 0.6607
0.0922 D1 0.4548 0.6763 0.1057 D2 0.5866 0.7098 0.0666 D3 0.6089
0.6519 0.1285 F1 0.3543 0.7073 0.0021 O5 0.3852 -0.2732 -0.2607 H1
0.3903 -0.1507 0.0608 H2 0.3536 0.0342 0.2480 H3 0.4788 -0.1556
-0.0631 H4 0.6945 0.1233 -0.0086 H5 0.7136 0.0645 -0.1094 H6 0.6241
-0.2085 -0.1509 H7 0.8132 -0.0904 -0.1760 H8 0.7514 0.0026 -0.2019
H9 0.7344 -0.0882 -0.2414 H10 0.4742 -0.0535 -0.2431 H11 0.4909
0.0312 -0.1976 H12 0.3885 -0.0499 -0.1795 H13 0.2127 -0.1822 0.2605
H14 0.2789 -0.0913 0.2748 H15 0.8211 0.1285 0.1433 H16 0.8915
0.3806 0.0735 H17 0.9774 0.2462 0.1183 H18 0.3940 0.3251 0.1052 H19
0.3878 0.2250 0.0774 H20 0.4206 0.3088 0.0328 H21 0.5571 0.4629
-0.1402 H22 0.3260 0.6907 -0.1143 H23 0.4216 0.5818 -0.1821 H24
0.4426 -0.2428 -0.2322 H25 0.2940 -0.2508 -0.2576
[0184] In one embodiment, the compound of Example 11 is provided as
a crystalline material comprising Form N-2. This crystalline form
of the compound of Example 11 comprises a neat crystalline form
referred to herein as "Form N-2" or "N-2 Form" of Example 11.
[0185] In one embodiment, the N-2 Form of the compound of Example
11 is characterized by unit cell parameters approximately equal to
the following:
[0186] Cell Dimensions: [0187] a=10.89 .ANG. [0188] b=9.47 .ANG.
[0189] c=14.28 .ANG. [0190] .alpha.=90.0.degree. [0191]
.beta.=105.5.degree. [0192] .gamma.=90.0.degree.
[0193] Space group: P2.sub.1
[0194] Molecules of Example 11/asymmetric unit: 1
[0195] Volume/Number of molecules in the unit cell=710
.ANG..sup.3
[0196] Density (calculated)=1.369 g/cm.sup.3,
wherein the unit cell parameters of Form N-2 are measured at a
temperature of about room temperature.
[0197] In another embodiment, N-2 form of Example 11 is
characterized by a simulated powder x-ray diffraction (PXRD)
pattern substantially in accordance with the pattern shown in FIG.
8.
[0198] In yet an even further embodiment, the N-2 Form of Example
11 is characterized by fractional atomic coordinates substantially
as listed in Table 4.
TABLE-US-00004 TABLE 4 Fractional Atomic Coordinates of Example 11,
Form N-2 Calculated at Room Temperature; Atomic Coordinates
(.times. 10.sup.4) Atom X Y Z Cl1 0.0126 0.5814 -0.0398 N28 0.4096
0.6892 -0.1985 N1 0.3977 0.4748 0.3228 C6 0.2421 0.6140 0.0877 C3
0.1740 0.4291 0.2250 C4 0.0901 0.4607 0.1367 C7 0.3291 0.5833
0.1771 C10 0.6696 0.7241 0.2527 C8 0.4600 0.6251 0.2204 C2 0.2949
0.4910 0.2436 C5 0.1241 0.5497 0.0709 C11 0.7085 0.6521 0.3424 C12
0.6222 0.5671 0.3708 C13 0.4986 0.5553 0.3100 C9 0.5476 0.7104
0.1920 C14 0.8476 0.6567 0.4037 O15 0.8564 0.6165 0.5020 C18 0.1439
0.3323 0.2987 C17 0.9207 0.5431 0.3663 C16 0.9095 0.7999 0.4029 O19
0.2223 0.3164 0.3783 N20 0.0317 0.2672 0.2766 C21 0.2745 0.7085
0.0137 C22 0.3280 0.6518 -0.0566 C23 0.3515 0.7447 -0.1255 C26
0.2482 0.8516 0.0138 C24 0.3252 0.8854 -0.1258 C25 0.2734 0.9408
-0.0553 C27 0.3567 0.4978 -0.0589 C29 0.3283 0.6529 -0.2889 N30
0.3839 0.5912 -0.3541 C36 0.5943 0.5995 -0.2422 C31 0.5122 0.5507
-0.3280 C32 0.5654 0.4577 -0.3830 C35 0.7220 0.5668 -0.2168 C37
0.5426 0.6797 -0.1732 C34 0.7717 0.4812 -0.2747 C33 0.6929 0.4253
-0.3569 O38 0.6061 0.7269 -0.0972 O39 0.2156 0.6776 -0.3073 C40
0.3090 0.5904 -0.4562 F41 0.4905 0.3950 -0.4631 H1 0.3995 0.4230
0.3726 H4 0.0089 0.4214 0.1210 H10 0.7276 0.7822 0.2338 H12 0.6458
0.5184 0.4295 H9 0.5245 0.7578 0.1329 H15 0.8171 0.6734 0.5263 H17A
1.0065 0.5391 0.4070 H17B 0.9217 0.5650 0.3009 H17C 0.8800 0.4535
0.3675 H16A 0.8623 0.8699 0.4274 H16B 0.9097 0.8236 0.3375 H16C
0.9956 0.7969 0.4432 H20A 0.0121 0.2121 0.3182 H20B -0.0212 0.2801
0.2206 H26 0.2130 0.8882 0.0612 H24 0.3419 0.9439 -0.1733 H25
0.2557 1.0368 -0.0544 H27A 0.2879 0.4513 -0.1048 H27B 0.3664 0.4581
0.0045 H27C 0.4341 0.4851 -0.0779 H35 0.7752 0.6032 -0.1598 H34
0.8585 0.4614 -0.2581 H33 0.7257 0.3648 -0.3955 D40A 0.2768 0.4970
-0.4739 D40B 0.3622 0.6185 -0.4968 D40C 0.2390 0.6551 -0.4647
[0199] In one embodiment, the compound of Example 11 is provided as
a crystalline material comprising Form M-1. This crystalline form
of the compound of Example 11 comprises a methanol solvate
crystalline form referred to herein as "Form M-1" or "M-1 Form" of
Example 11. The M-1 Form of Example 11 comprises one molecule of
methanol for each molecule of Example 11.
[0200] In one embodiment, the M-1 Form of the compound of Example
11 is characterized by unit cell parameters approximately equal to
the following:
[0201] Cell Dimensions: [0202] a=9.78 .ANG. [0203] b=14.26 .ANG.
[0204] c=21.38 .ANG. [0205] .alpha.=90.0.degree. [0206]
.beta.=90.0.degree. [0207] .gamma.=90.0.degree.
[0208] Space group: P2.sub.12.sub.12.sub.1
[0209] Molecules of Example 11/asymmetric unit: 1
[0210] Volume/Number of molecules in the unit cell=746
.ANG..sup.3
[0211] Density (calculated)=1.381 g/cm.sup.3,
wherein the unit cell parameters of Form M-1 are measured at a
temperature of about room temperature.
[0212] In another embodiment, M-1 form of Example 11 is
characterized by a simulated powder x-ray diffraction (PXRD)
pattern substantially in accordance with the pattern shown in FIG.
9 and/or by an experimental PXRD pattern substantially in
accordance with the pattern shown in FIG. 9.
[0213] In yet an even further embodiment, the M-1 Form of Example
11 is characterized by fractional atomic coordinates substantially
as listed in Table 5.
TABLE-US-00005 TABLE 5 Fractional Atomic Coordinates of Example 11,
Form M-1 Calculated at Room Temperature; Atomic Coordinates
(.times. 10.sup.4) Atom X Y Z Cl1 0.5122 0.2066 0.2450 N1 0.4273
-0.0936 0.0641 C1 0.5289 0.0415 0.0955 C2 0.5116 -0.0974 -0.0464 C3
0.5023 -0.0607 0.0136 C4 0.4097 0.0384 0.2129 C5 0.3831 -0.0373
0.1735 C6 0.4422 -0.0331 0.1135 C7 0.5686 0.0224 0.0311 C8 0.5550
0.1158 0.1358 C9 0.6496 0.0688 -0.0131 C10 0.4913 0.1125 0.1938 C11
0.5915 -0.0838 -0.1580 C12 0.5911 -0.0506 -0.0901 C13 0.6594 0.0319
-0.0724 O1 0.5610 -0.1824 -0.1606 C14 0.2956 -0.1183 0.1908 C15
0.4743 -0.0364 -0.1918 C16 0.7257 -0.0643 -0.1914 O2 0.2663 -0.1785
0.1512 N2 0.2503 -0.1229 0.2496 C17 0.6898 0.3431 0.0697 C18 0.8290
0.3311 0.0758 C19 0.5954 0.2757 0.0893 C20 0.6478 0.1941 0.1162 C21
0.7878 0.1825 0.1226 C22 0.8782 0.2501 0.1022 C23 0.4452 0.2902
0.0817 N3 0.6391 0.4273 0.0400 C24 0.6052 0.5019 0.0789 N4 0.5432
0.5777 0.0514 C25 0.5035 0.5761 -0.0117 C26 0.6313 0.4281 -0.0253
C27 0.5542 0.5067 -0.0516 C28 0.5238 0.5074 -0.1149 C29 0.3824
0.6403 -0.1003 C30 0.4126 0.6400 -0.0381 C31 0.4398 0.5745 -0.1396
O3 0.6783 0.3646 -0.0559 O4 0.6315 0.4993 0.1345 C32 0.5414 0.6652
0.0884 D1 0.4501 0.6772 0.1028 D2 0.5715 0.7164 0.0628 D3 0.6014
0.6588 0.1237 F1 0.3490 0.7042 -0.0007 O5 0.4716 -0.2733 -0.2643
C33 0.3374 -0.2588 -0.2808 H1 0.3791 -0.1440 0.0644 H2 0.4656
-0.1521 -0.0572 H3 0.3719 0.0392 0.2528 H4 0.6960 0.1235 -0.0027 H5
0.7131 0.0626 -0.1019 H6 0.6289 -0.2124 -0.1504 H7 0.4747 -0.0549
-0.2350 H8 0.4845 0.0304 -0.1890 H9 0.3894 -0.0547 -0.1729 H10
0.8000 -0.0891 -0.1672 H11 0.7373 0.0021 -0.1964 H12 0.7247 -0.0938
-0.2318 H13 0.1990 -0.1687 0.2610 H14 0.2724 -0.0800 0.2760 H15
0.8889 0.3773 0.0621 H16 0.8214 0.1281 0.1410 H17 0.9719 0.2410
0.1065 H18 0.4004 0.2305 0.0788 H19 0.4283 0.3257 0.0444 H20 0.4104
0.3238 0.1173 H21 0.5610 0.4617 -0.1409 H22 0.3229 0.6851 -0.1163
H23 0.4215 0.5757 -0.1823 H24 0.4869 -0.2481 -0.2306 H25 0.3304
-0.2025 -0.3052 H26 0.2828 -0.2527 -0.2437 H27 0.3053 -0.3110
-0.3050
[0214] In one embodiment, the compound of Example 28 is provided as
a crystalline material comprising Form M2-1. This crystalline form
of the compound of Example 28 comprises a methanol solvate
crystalline form referred to herein as "Form M2-1" or "M2-1 Form"
of Example 28. The M2-1 Form of Example 28 comprises two molecules
of methanol for each molecule of Example 28.
[0215] In one embodiment, the M2-1 Form of the compound of Example
28 is characterized by unit cell parameters approximately equal to
the following:
[0216] Cell Dimensions: [0217] a=9.24 .ANG. [0218] b=7.97 .ANG.
[0219] c=22.12 .ANG. [0220] .alpha.=90.0.degree. [0221]
.beta.=94.10 [0222] .gamma.=90.0.degree.
[0223] Space group: P2.sub.1
[0224] Molecules of Example 28/asymmetric unit: 1
[0225] Volume/Number of molecules in the unit cell=813
.ANG..sup.3
[0226] Density (calculated)=1.301 g/cm.sup.3,
wherein the unit cell parameters of Form M2-1 are measured at a
temperature of about 173 K.
[0227] In another embodiment, M2-1 form of Example 28 is
characterized by a simulated powder x-ray diffraction (PXRD)
pattern substantially in accordance with the pattern shown in FIG.
10.
[0228] In yet an even further embodiment, the M2-1 Form of Example
28 is characterized by fractional atomic coordinates substantially
as listed in Table 6.
TABLE-US-00006 TABLE 6 Fractional Atomic Coordinates of Example 28,
Form M2-1 Calculated at a Temperature of about 173K; Atomic
Coordinates (.times. 10.sup.4) Atom X Y Z N1 0.1027 0.4043 0.3748
C1 -0.2232 0.3960 0.2673 C2 0.0404 0.5638 0.2929 C3 -0.0029 0.4268
0.3288 C4 -0.0521 0.6188 0.2437 C5 -0.1336 0.3399 0.3162 C6 -0.1814
0.5329 0.2339 C7 0.5794 0.6873 0.4355 C8 0.1792 0.6199 0.3196 C9
0.3425 0.5311 0.4117 C10 0.4312 0.7276 0.3333 C11 0.4282 0.6926
0.4013 C12 0.2800 0.7581 0.3027 C13 0.2107 0.5221 0.3691 O1 0.6379
0.8543 0.4304 C14 -0.1722 0.2005 0.3567 C15 0.5688 0.6482 0.5022
C16 0.6824 0.5649 0.4077 O2 -0.0922 0.1697 0.4030 N2 -0.2929 0.1124
0.3427 C17 0.0680 1.0435 0.1406 C18 -0.0136 0.7640 0.2053 C19
-0.0685 0.9224 0.2173 C20 0.0824 0.7434 0.1594 C21 -0.0291 1.0613
0.1851 C22 0.1220 0.8874 0.1288 C23 0.1432 0.5751 0.1445 N3 0.2335
0.8729 0.0858 C24 0.3767 0.8784 0.1096 C25 0.4864 0.8571 0.0663 N4
0.2979 0.8380 -0.0149 C26 0.4453 0.8370 0.0049 C27 0.6314 0.8568
0.0885 C28 0.5591 0.8157 -0.0330 C29 0.7023 0.8160 -0.0107 C30
0.1898 0.8520 0.0243 C31 0.7397 0.8355 0.0497 O3 0.4038 0.8977
0.1639 O4 0.0618 0.8482 0.0081 C32 0.2483 0.8261 -0.0793 F1 -0.2771
0.5872 0.1879 F2 0.5324 0.7902 -0.0930 O5 -0.0788 -0.0991 0.4776
C33 0.0326 -0.1899 0.4513 O6 0.4799 1.1498 0.2473 C34 0.3561 1.2372
0.2578 H1 0.1019 0.3275 0.4033 H2 -0.3127 0.3410 0.2567 H3 0.4049
0.4324 0.4058 H4 0.3136 0.5287 0.4540 H5 0.4925 0.8272 0.3274 H6
0.4759 0.6309 0.3137 H7 0.3737 0.7870 0.4190 H8 0.2426 0.8676
0.3159 H9 0.2850 0.7612 0.2582 H10 0.7202 0.8591 0.4490 H11 0.6640
0.6644 0.5240 H12 0.5377 0.5317 0.5067 H13 0.4979 0.7236 0.5189 H14
0.7009 0.6021 0.3668 H15 0.6384 0.4529 0.4058 H16 0.7742 0.5607
0.4329 H17 -0.3176 0.0302 0.3664 H18 -0.3477 0.1365 0.3097 H19
0.0970 1.1384 0.1185 H20 -0.1342 0.9351 0.2480 H21 -0.0683 1.1683
0.1933 H22 0.1200 0.5506 0.1014 H23 0.1005 0.4889 0.1693 H24 0.2488
0.5761 0.1530 H25 0.6555 0.8714 0.1307 H26 0.7765 0.8024 -0.0380
H27 0.8387 0.8345 0.0646 H28 0.2762 0.7168 -0.0952 H29 0.2933
0.9156 -0.1019 H30 0.1425 0.8377 -0.0839 H31 -0.0943 -0.0091 0.4585
H32 0.1274 -0.1480 0.4674 H33 0.0232 -0.1756 0.4072 H34 0.0242
-0.3092 0.4612 H35 0.4597 1.0733 0.2219 H36 0.3799 1.3281 0.2866
H37 0.2857 1.1614 0.2746 H38 0.3141 1.2845 0.2195
[0229] In one embodiment, the compound of Example 33 is provided as
a crystalline material comprising Form M2-1. This crystalline form
of the compound of Example 33 comprises a methanol solvate
crystalline form referred to herein as "Form M2-1" or "M2-1 Form"
of Example 33. The M2-1 Form of Example 33 comprises two molecules
of methanol for each molecule of Example 33.
[0230] In one embodiment, the M2-1 Form of the compound of Example
33 is characterized by unit cell parameters approximately equal to
the following:
[0231] Cell Dimensions: [0232] a=7.41 .ANG. [0233] b=9.74 .ANG.
[0234] c=44.55 .ANG. [0235] .alpha.=90.0.degree. [0236]
.beta.=90.0.degree. [0237] .gamma.=90.0.degree.
[0238] Space group: P2.sub.12.sub.12.sub.1
[0239] Molecules of Example 33/asymmetric unit: 1
[0240] Volume/Number of molecules in the unit cell=3214
.ANG..sup.3
[0241] Density (calculated)=1.346 g/cm.sup.3,
wherein the unit cell parameters of Form M2-1 are measured at a
temperature of about 173 K.
[0242] In another embodiment, M2-1 form of Example 33 is
characterized by a simulated powder x-ray diffraction (PXRD)
pattern substantially in accordance with the pattern shown in FIG.
11 and/or by an experimental PXRD pattern substantially in
accordance with the pattern shown in FIG. 11.
[0243] In yet an even further embodiment, the M2-1 Form of Example
33 is characterized by fractional atomic coordinates substantially
as listed in Table 7.
TABLE-US-00007 TABLE 7 Fractional Atomic Coordinates of Example 33,
Form M2-1 Calculated at a Temperature of about 173K; Atomic
Coordinates (.times. 10.sup.4) Atom X Y Z Cl1 0.4450 -0.0974 0.0917
Cl2 0.2679 0.9390 -0.0104 N1 0.7146 0.2778 0.1831 C1 0.6840 -0.0285
0.1346 C2 0.4628 0.1463 0.1208 C3 0.7574 0.0528 0.1572 C4 0.5932
0.3851 0.1807 C5 0.4797 0.3617 0.1559 C6 0.4364 0.5908 0.1933 C7
0.5330 0.2289 0.1438 C8 0.3277 0.5712 0.1678 C9 0.5744 0.4989
0.1993 C10 0.3475 0.4586 0.1493 C11 0.6778 0.1810 0.1617 C12 0.5397
0.0174 0.1173 C13 0.4025 0.7166 0.2133 O1 0.2131 0.7465 0.2141 C14
0.9038 0.0063 0.1779 C15 0.4684 0.6951 0.2453 C16 0.4889 0.8419
0.1994 O2 0.9372 0.0751 0.2007 N2 0.9916 -0.1089 0.1715 C17 0.3100
0.1985 0.1022 C18 0.1348 0.1615 0.1093 C19 0.1945 0.3479 0.0644 C20
0.0197 0.3118 0.0715 C21 -0.0095 0.2166 0.0941 C22 0.3427 0.2931
0.0791 C23 0.5305 0.3367 0.0708 N3 0.2226 0.4569 0.0426 C24 0.2578
0.4191 0.0134 N4 0.2870 0.5312 -0.0066 C25 0.2192 0.5925 0.0539 C26
0.2741 0.6673 0.0027 C27 0.2455 0.6972 0.0321 C28 0.2898 0.7686
-0.0207 C29 0.3530 0.5950 -0.0567 C30 0.3340 0.4967 -0.0359 C31
0.3249 0.7337 -0.0493 O3 0.1923 0.6096 0.0807 O4 0.2649 0.3023
0.0050 O5 -0.0568 0.6980 0.1220 C32 -0.1535 0.5826 0.1313 O6 0.9895
0.0341 0.2613 C33 0.9227 -0.0982 0.2682 H1 0.8003 0.2727 0.1961 H2
0.7322 -0.1151 0.1310 H3 0.2399 0.6362 0.1632 H4 0.6524 0.5129
0.2154 H5 0.2733 0.4474 0.1327 H6 0.1580 0.6793 0.2204 H7 0.4410
0.7750 0.2571 H8 0.5965 0.6803 0.2452 H9 0.4092 0.6166 0.2538 H10
0.4409 0.8558 0.1796 H11 0.6171 0.8286 0.1982 H12 0.4636 0.9209
0.2116 H13 1.0747 -0.1382 0.1834 H14 0.9653 -0.1543 0.1555 H15
0.1144 0.0986 0.1246 H16 -0.0771 0.3508 0.0613 H17 -0.1264 0.1899
0.0990 H18 0.5554 0.3096 0.0504 H19 0.6156 0.2937 0.0840 H20 0.5405
0.4346 0.0725 H21 0.2431 0.7886 0.0381 H22 0.3851 0.5712 -0.0762
H23 0.3524 0.4052 -0.0410 H24 0.3306 0.8009 -0.0641 H25 0.0254
0.6742 0.1108 H26 -0.0765 0.5242 0.1430 H27 -0.1958 0.5332 0.1140
H28 -0.2548 0.6110 0.1432 H29 0.9836 0.0467 0.2431 H30 0.8087
-0.1118 0.2584 H31 0.9071 -0.1064 0.2896 H32 1.0070 -0.1664
0.2614
[0244] The present invention may be embodied in other specific
forms without departing from the spirit or essential attributes
thereof. This invention encompasses all combinations of the aspects
and/or embodiments of the invention noted herein. It is understood
that any and all embodiments of the present invention may be taken
in conjunction with any other embodiment or embodiments to describe
additional embodiments. It is also to be understood that each
individual element of the embodiments is meant to be combined with
any and all other elements from any embodiment to describe an
additional embodiment.
Definitions
[0245] The features and advantages of the invention may be more
readily understood by those of ordinary skill in the art upon
reading the following detailed description. It is to be appreciated
that certain features of the invention that are, for clarity
reasons, described above and below in the context of separate
embodiments, may also be combined to form a single embodiment.
Conversely, various features of the invention that are, for brevity
reasons, described in the context of a single embodiment, may also
be combined so as to form sub-combinations thereof. Embodiments
identified herein as exemplary or preferred are intended to be
illustrative and not limiting.
[0246] Unless specifically stated otherwise herein, references made
in the singular may also include the plural. For example, "a" and
"an" may refer to either one, or one or more.
[0247] As used herein, the phase "compounds" refers to at least one
compound. For example, a compound of Formula (I) includes a
compound of Formula (I) and two or more compounds of Formula
(I).
[0248] Unless otherwise indicated, any heteroatom with unsatisfied
valences is assumed to have hydrogen atoms sufficient to satisfy
the valences.
[0249] The definitions set forth herein take precedence over
definitions set forth in any patent, patent application, and/or
patent application publication incorporated herein by
reference.
[0250] Listed below are definitions of various terms used to
describe the present invention. These definitions apply to the
terms as they are used throughout the specification (unless they
are otherwise limited in specific instances) either individually or
as part of a larger group.
[0251] Throughout the specification, groups and substituents
thereof may be chosen by one skilled in the field to provide stable
moieties and compounds.
[0252] In accordance with a convention used in the art,
##STR00059##
is used in structural formulas herein to depict the bond that is
the point of attachment of the moiety or substituent to the core or
backbone structure.
[0253] The phrase "pharmaceutically acceptable" is employed herein
to refer to those compounds, materials, compositions, and/or dosage
forms which are, within the scope of sound medical judgment,
suitable for use in contact with the tissues of human beings and
animals without excessive toxicity, irritation, allergic response,
or other problem or complication, commensurate with a reasonable
benefit/risk ratio.
[0254] The compounds of Formula (I) can be provided as amorphous
solids or crystalline solids. Lyophilization can be employed to
provide the compounds of Formula (I) as amorphous solids.
[0255] It should further be understood that solvates (e.g.,
hydrates) of the Compounds of Formula (I) are also within the scope
of the present invention. The term "solvate" means a physical
association of a compound of Formula (I) with one or more solvent
molecules, whether organic or inorganic. This physical association
includes hydrogen bonding. In certain instances the solvate will be
capable of isolation, for example when one or more solvent
molecules are incorporated in the crystal lattice of the
crystalline solid. "Solvate" encompasses both solution-phase and
isolable solvates. Exemplary solvates include hydrates,
ethanolates, methanolates, isopropanolates, acetonitrile solvates,
and ethyl acetate solvates. Methods of solvation are known in the
art.
[0256] Various forms of prodrugs are well known in the art and are
described in: [0257] a) Wermuth, C. G. et al., The Practice of
Medicinal Chemistry, Chapter 31, Academic Press (1996); [0258] b)
Bundgaard, H. ed., Design of Prodrugs, Elsevier (1985); [0259] c)
Bundgaard, H., Chapter 5, "Design and Application of Prodrugs", A
Textbook of Drug Design and Development, pp. 113-191,
Krogsgaard-Larsen, P. et al., eds., Harwood Academic Publishers
(1991); and [0260] d) Testa, B. et al., Hydrolysis in Drug and
Prodrug Metabolism, Wiley-VCH (2003).
[0261] In addition, compounds of Formula (I), subsequent to their
preparation, can be isolated and purified to obtain a composition
containing an amount by weight equal to or greater than 99% of a
compound of Formula (I) ("substantially pure"), which is then used
or formulated as described herein. Such "substantially pure"
compounds of Formula (I) are also contemplated herein as part of
the present invention.
[0262] "Stable compound" and "stable structure" are meant to
indicate a compound that is sufficiently robust to survive
isolation to a useful degree of purity from a reaction mixture, and
formulation into an efficacious therapeutic agent. The present
invention is intended to embody stable compounds.
[0263] "Therapeutically effective amount" is intended to include an
amount of a compound of the present invention alone or an amount of
the combination of compounds claimed or an amount of a compound of
the present invention in combination with other active ingredients
effective to act as an inhibitor to Btk, or effective to treat or
prevent autoimmune and/or inflammatory disease states, such as
multiple sclerosis and rheumatoid arthritis.
[0264] As used herein, "treating" or "treatment" cover the
treatment of a disease-state in a mammal, particularly in a human,
and include: (a) preventing the disease-state from occurring in a
mammal, in particular, when such mammal is predisposed to the
disease-state but has not yet been diagnosed as having it; (b)
inhibiting the disease-state, i.e., arresting its development;
and/or (c) relieving the disease-state, i.e., causing regression of
the disease state.
[0265] The compounds of the present invention are intended to
include all isotopes of atoms occurring in the present compounds.
Isotopes include those atoms having the same atomic number but
different mass numbers. By way of general example and without
limitation, isotopes of hydrogen include deuterium (D) and tritium
(T). Isotopes of carbon include .sup.13C and .sup.14C.
Isotopically-labeled compounds of the invention can generally be
prepared by conventional techniques known to those skilled in the
art or by processes analogous to those described herein, using an
appropriate isotopically-labeled reagent in place of the
non-labeled reagent otherwise employed. For example, methyl
(--CH.sub.3) also includes deuterated methyl groups such as
--CD.sub.3.
[0266] Compounds in accordance with Formula (I) can be administered
by any means suitable for the condition to be treated, which can
depend on the need for site-specific treatment or quantity of
Formula (I) compound to be delivered.
[0267] Also embraced within this invention is a class of
pharmaceutical compositions comprising a compound of Formula (I)
and one or more non-toxic, pharmaceutically-acceptable carriers
and/or diluents and/or adjuvants (collectively referred to herein
as "carrier" materials) and, if desired, other active ingredients.
The compounds of Formula (I) may be administered by any suitable
route, preferably in the form of a pharmaceutical composition
adapted to such a route, and in a dose effective for the treatment
intended. The compounds and compositions of the present invention
may, for example, be administered orally, mucosally, or parentally
including intravascularly, intravenously, intraperitoneally,
subcutaneously, intramuscularly, and intrasternally in dosage unit
formulations containing conventional pharmaceutically acceptable
carriers, adjuvants, and vehicles. For example, the pharmaceutical
carrier may contain a mixture of mannitol or lactose and
microcrystalline cellulose. The mixture may contain additional
components such as a lubricating agent, e.g., magnesium stearate
and a disintegrating agent such as crospovidone. The carrier
mixture may be filled into a gelatin capsule or compressed as a
tablet. The pharmaceutical composition may be administered as an
oral dosage form or an infusion, for example.
[0268] For oral administration, the pharmaceutical composition may
be in the form of, for example, a tablet, capsule, liquid capsule,
suspension, or liquid. The pharmaceutical composition is preferably
made in the form of a dosage unit containing a particular amount of
the active ingredient. For example, the pharmaceutical composition
may be provided as a tablet or capsule comprising an amount of
active ingredient in the range of from about 0.1 to 1000 mg,
preferably from about 0.25 to 250 mg, and more preferably from
about 0.5 to 100 mg. A suitable daily dose for a human or other
mammal may vary widely depending on the condition of the patient
and other factors, but, can be determined using routine
methods.
[0269] Any pharmaceutical composition contemplated herein can, for
example, be delivered orally via any acceptable and suitable oral
preparations. Exemplary oral preparations, include, but are not
limited to, for example, tablets, troches, lozenges, aqueous and
oily suspensions, dispersible powders or granules, emulsions, hard
and soft capsules, liquid capsules, syrups, and elixirs.
Pharmaceutical compositions intended for oral administration can be
prepared according to any methods known in the art for
manufacturing pharmaceutical compositions intended for oral
administration. In order to provide pharmaceutically palatable
preparations, a pharmaceutical composition in accordance with the
invention can contain at least one agent selected from sweetening
agents, flavoring agents, coloring agents, demulcents,
antioxidants, and preserving agents.
[0270] A tablet can, for example, be prepared by admixing at least
one compound of Formula (I) with at least one non-toxic
pharmaceutically acceptable excipient suitable for the manufacture
of tablets. Exemplary excipients include, but are not limited to,
for example, inert diluents, such as, for example, calcium
carbonate, sodium carbonate, lactose, calcium phosphate, and sodium
phosphate; granulating and disintegrating agents, such as, for
example, microcrystalline cellulose, sodium croscarmellose, corn
starch, and alginic acid; binding agents, such as, for example,
starch, gelatin, polyvinyl-pyrrolidone, and acacia; and lubricating
agents, such as, for example, magnesium stearate, stearic acid, and
talc. Additionally, a tablet can either be uncoated, or coated by
known techniques to either mask the bad taste of an unpleasant
tasting drug, or delay disintegration and absorption of the active
ingredient in the gastrointestinal tract thereby sustaining the
effects of the active ingredient for a longer period. Exemplary
water soluble taste masking materials, include, but are not limited
to, hydroxypropyl-methylcellulose and hydroxypropyl-cellulose.
Exemplary time delay materials, include, but are not limited to,
ethyl cellulose and cellulose acetate butyrate.
[0271] Hard gelatin capsules can, for example, be prepared by
mixing at least one compound of Formula (I) with at least one inert
solid diluent, such as, for example, calcium carbonate; calcium
phosphate; and kaolin.
[0272] Soft gelatin capsules can, for example, be prepared by
mixing at least one compound of Formula (I) with at least one water
soluble carrier, such as, for example, polyethylene glycol; and at
least one oil medium, such as, for example, peanut oil, liquid
paraffin, and olive oil.
[0273] An aqueous suspension can be prepared, for example, by
admixing at least one compound of Formula (I) with at least one
excipient suitable for the manufacture of an aqueous suspension.
Exemplary excipients suitable for the manufacture of an aqueous
suspension, include, but are not limited to, for example,
suspending agents, such as, for example, sodium
carboxymethylcellulose, methylcellulose,
hydroxypropylmethyl-cellulose, sodium alginate, alginic acid,
polyvinyl-pyrrolidone, gum tragacanth, and gum acacia; dispersing
or wetting agents, such as, for example, a naturally-occurring
phosphatide, e.g., lecithin; condensation products of alkylene
oxide with fatty acids, such as, for example, polyoxyethylene
stearate; condensation products of ethylene oxide with long chain
aliphatic alcohols, such as, for example
heptadecaethylene-oxycetanol; condensation products of ethylene
oxide with partial esters derived from fatty acids and hexitol,
such as, for example, polyoxyethylene sorbitol monooleate; and
condensation products of ethylene oxide with partial esters derived
from fatty acids and hexitol anhydrides, such as, for example,
polyethylene sorbitan monooleate. An aqueous suspension can also
contain at least one preservative, such as, for example, ethyl and
n-propyl p-hydroxybenzoate; at least one coloring agent; at least
one flavoring agent; and/or at least one sweetening agent,
including but not limited to, for example, sucrose, saccharin, and
aspartame.
[0274] Oily suspensions can, for example, be prepared by suspending
at least one compound of Formula (I) in either a vegetable oil,
such as, for example, arachis oil; olive oil; sesame oil; and
coconut oil; or in mineral oil, such as, for example, liquid
paraffin. An oily suspension can also contain at least one
thickening agent, such as, for example, beeswax; hard paraffin; and
cetyl alcohol. In order to provide a palatable oily suspension, at
least one of the sweetening agents already described hereinabove,
and/or at least one flavoring agent can be added to the oily
suspension. An oily suspension can further contain at least one
preservative, including, but not limited to, for example, an
anti-oxidant, such as, for example, butylated hydroxyanisol, and
alpha-tocopherol.
[0275] Dispersible powders and granules can, for example, be
prepared by admixing at least one compound of Formula (I) with at
least one dispersing and/or wetting agent; at least one suspending
agent; and/or at least one preservative. Suitable dispersing
agents, wetting agents, and suspending agents are as already
described above. Exemplary preservatives include, but are not
limited to, for example, anti-oxidants, e.g., ascorbic acid. In
addition, dispersible powders and granules can also contain at
least one excipient, including, but not limited to, for example,
sweetening agents; flavoring agents; and coloring agents.
[0276] An emulsion of at least one compound of Formula (I) thereof
can, for example, be prepared as an oil-in-water emulsion. The oily
phase of the emulsions comprising compounds of Formula (I) may be
constituted from known ingredients in a known manner. The oil phase
can be provided by, but is not limited to, for example, a vegetable
oil, such as, for example, olive oil and arachis oil; a mineral
oil, such as, for example, liquid paraffin; and mixtures thereof.
While the phase may comprise merely an emulsifier, it may comprise
a mixture of at least one emulsifier with a fat or an oil or with
both a fat and an oil. Suitable emulsifying agents include, but are
not limited to, for example, naturally-occurring phosphatides,
e.g., soy bean lecithin; esters or partial esters derived from
fatty acids and hexitol anhydrides, such as, for example, sorbitan
monooleate; and condensation products of partial esters with
ethylene oxide, such as, for example, polyoxyethylene sorbitan
monooleate. Preferably, a hydrophilic emulsifier is included
together with a lipophilic emulsifier which acts as a stabilizer.
It is also preferred to include both an oil and a fat. Together,
the emulsifier(s) with or without stabilizer(s) make-up the
so-called emulsifying wax, and the wax together with the oil and
fat make up the so-called emulsifying ointment base which forms the
oily dispersed phase of the cream formulations. An emulsion can
also contain a sweetening agent, a flavoring agent, a preservative,
and/or an antioxidant. Emulsifiers and emulsion stabilizers
suitable for use in the formulation of the present invention
include Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol,
glyceryl monostearate, sodium lauryl sulfate, glyceryl distearate
alone or with a wax, or other materials well known in the art.
[0277] The compounds of Formula (I) can, for example, also be
delivered intravenously, subcutaneously, and/or intramuscularly via
any pharmaceutically acceptable and suitable injectable form.
Exemplary injectable forms include, but are not limited to, for
example, sterile aqueous solutions comprising acceptable vehicles
and solvents, such as, for example, water, Ringer's solution, and
isotonic sodium chloride solution; sterile oil-in-water
microemulsions; and aqueous or oleaginous suspensions.
[0278] Formulations for parenteral administration may be in the
form of aqueous or non-aqueous isotonic sterile injection solutions
or suspensions. These solutions and suspensions may be prepared
from sterile powders or granules using one or more of the carriers
or diluents mentioned for use in the formulations for oral
administration or by using other suitable dispersing or wetting
agents and suspending agents. The compounds may be dissolved in
water, polyethylene glycol, propylene glycol, ethanol, corn oil,
cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium
chloride, tragacanth gum, and/or various buffers. Other adjuvants
and modes of administration are well and widely known in the
pharmaceutical art. The active ingredient may also be administered
by injection as a composition with suitable carriers including
saline, dextrose, or water, or with cyclodextrin (i.e.,
CAPTISOL.RTM.), cosolvent solubilization (i.e., propylene glycol)
or micellar solubilization (i.e., Tween 80).
[0279] The sterile injectable preparation may also be a sterile
injectable solution or suspension in a non-toxic parenterally
acceptable diluent or solvent, for example as a solution in
1,3-butanediol. Among the acceptable vehicles and solvents that may
be employed are water, Ringer's solution, and isotonic sodium
chloride solution. In addition, sterile, fixed oils are
conventionally employed as a solvent or suspending medium. For this
purpose any bland fixed oil may be employed, including synthetic
mono- or diglycerides. In addition, fatty acids such as oleic acid
find use in the preparation of injectables.
[0280] A sterile injectable oil-in-water microemulsion can, for
example, be prepared by 1) dissolving at least one compound of
Formula (I) in an oily phase, such as, for example, a mixture of
soybean oil and lecithin; 2) combining the Formula (I) containing
oil phase with a water and glycerol mixture; and 3) processing the
combination to form a microemulsion.
[0281] A sterile aqueous or oleaginous suspension can be prepared
in accordance with methods already known in the art. For example, a
sterile aqueous solution or suspension can be prepared with a
non-toxic parenterally-acceptable diluent or solvent, such as, for
example, 1,3-butane diol; and a sterile oleaginous suspension can
be prepared with a sterile non-toxic acceptable solvent or
suspending medium, such as, for example, sterile fixed oils, e.g.,
synthetic mono- or diglycerides; and fatty acids, such as, for
example, oleic acid.
[0282] Pharmaceutically acceptable carriers, adjuvants, and
vehicles that may be used in the pharmaceutical compositions of
this invention include, but are not limited to, ion exchangers,
alumina, aluminum stearate, lecithin, self-emulsifying drug
delivery systems (SEDDS) such as d-alpha-tocopherol
polyethyleneglycol 1000 succinate, surfactants used in
pharmaceutical dosage forms such as Tweens, polyethoxylated castor
oil such as CREMOPHOR.RTM. surfactant (BASF), or other similar
polymeric delivery matrices, serum proteins, such as human serum
albumin, buffer substances such as phosphates, glycine, sorbic
acid, potassium sorbate, partial glyceride mixtures of saturated
vegetable fatty acids, water, salts or electrolytes, such as
protamine sulfate, disodium hydrogen phosphate, potassium hydrogen
phosphate, sodium chloride, zinc salts, colloidal silica, magnesium
trisilicate, polyvinyl pyrrolidone, cellulose-based substances,
polyethylene glycol, sodium carboxymethylcellulose, polyacrylates,
waxes, polyethylene-polyoxypropylene-block polymers, polyethylene
glycol and wool fat. Cyclodextrins such as alpha-, beta-, and
gamma-cyclodextrin, or chemically modified derivatives such as
hydroxyalkylcyclodextrins, including 2- and
3-hydroxypropyl-cyclodextrins, or other solubilized derivatives may
also be advantageously used to enhance delivery of compounds of the
formulae described herein.
[0283] The pharmaceutically active compounds of this invention can
be processed in accordance with conventional methods of pharmacy to
produce medicinal agents for administration to patients, including
humans and other mammals. The pharmaceutical compositions may be
subjected to conventional pharmaceutical operations such as
sterilization and/or may contain conventional adjuvants, such as
preservatives, stabilizers, wetting agents, emulsifiers, buffers
etc. Tablets and pills can additionally be prepared with enteric
coatings. Such compositions may also comprise adjuvants, such as
wetting, sweetening, flavoring, and perfuming agents.
[0284] The amounts of compounds that are administered and the
dosage regimen for treating a disease condition with the compounds
and/or compositions of this invention depends on a variety of
factors, including the age, weight, sex, the medical condition of
the subject, the type of disease, the severity of the disease, the
route and frequency of administration, and the particular compound
employed. Thus, the dosage regimen may vary widely, but can be
determined routinely using standard methods. A daily dose of about
0.001 to 100 mg/kg body weight, preferably between about 0.0025 and
about 50 mg/kg body weight and most preferably between about 0.005
to 10 mg/kg body weight, may be appropriate. The daily dose can be
administered in one to four doses per day. Other dosing schedules
include one dose per week and one dose per two day cycle.
[0285] For therapeutic purposes, the active compounds of this
invention are ordinarily combined with one or more adjuvants
appropriate to the indicated route of administration. If
administered orally, the compounds may be admixed with lactose,
sucrose, starch powder, cellulose esters of alkanoic acids,
cellulose alkyl esters, talc, stearic acid, magnesium stearate,
magnesium oxide, sodium and calcium salts of phosphoric and
sulfuric acids, gelatin, acacia gum, sodium alginate,
polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted
or encapsulated for convenient administration. Such capsules or
tablets may contain a controlled-release formulation as may be
provided in a dispersion of active compound in hydroxypropylmethyl
cellulose.
[0286] Pharmaceutical compositions of this invention comprise at
least one compound of Formula (I) and optionally an additional
agent selected from any pharmaceutically acceptable carrier,
adjuvant, and vehicle. Alternate compositions of this invention
comprise a compound of the Formula (I) described herein, or a
prodrug thereof, and a pharmaceutically acceptable carrier,
adjuvant, or vehicle.
Utility
[0287] The compounds of the invention modulate kinase activity,
including the modulation of Btk. Other types of kinase activity
that may be modulated by the compounds of the instant invention
include, but are not limited to, the Tec family of compounds, such
as BMX, Btk, ITK, TXK and Tec, and mutants thereof.
[0288] Accordingly, compounds of Formula (I) have utility in
treating conditions associated with the modulation of kinase
activity, and particularly the selective inhibition of Btk
activity. Such conditions include B-cell mediated diseases in which
cytokine levels are modulated as a consequence of intracellular
signaling.
[0289] As used herein, the terms "treating" or "treatment"
encompass either or both responsive and prophylaxis measures, e.g.,
measures designed to inhibit or delay the onset of the disease or
disorder, achieve a full or partial reduction of the symptoms or
disease state, and/or to alleviate, ameliorate, lessen, or cure the
disease or disorder and/or its symptoms.
[0290] In view of their activity as selective inhibitors of Btk,
compounds of Formula (I) are useful in treating cytokine-associated
conditions including, but not limited to, inflammatory diseases
such as Crohn's and ulcerative colitis, asthma, graft versus host
disease, chronic obstructive pulmonary disease; autoimmune diseases
such as Graves' disease, rheumatoid arthritis, systemic lupus
erythematosis, psoriasis; destructive bone disorders such as bone
resorption disease, osteoarthritis, osteoporosis, multiple
myeloma-related bone disorder; proliferative disorders such as
acute myelogenous leukemia, chronic myelogenous leukemia;
angiogenic disorders such as angiogenic disorders including solid
tumors, ocular neovasculization, and infantile haemangiomas;
infectious diseases such as sepsis, septic shock, and Shigellosis;
neurodegenerative diseases such as Alzheimer's disease, Parkinson's
disease, cerebral ischemias or neurodegenerative disease caused by
traumatic injury, oncologic and viral diseases such as metastatic
melanoma, Kaposi's sarcoma, multiple myeloma, and HIV infection and
CMV retinitis, AIDS, respectively.
[0291] More particularly, the specific conditions or diseases that
may be treated with the inventive compounds include, without
limitation, pancreatitis (acute or chronic), asthma, allergies,
adult respiratory distress syndrome, chronic obstructive pulmonary
disease, glomerulonephritis, rheumatoid arthritis, systemic lupus
erythematosis, scleroderma, chronic thyroiditis, Graves' disease,
autoimmune gastritis, diabetes, autoimmune hemolytic anemia,
autoimmune neutropenia, thrombocytopenia, atopic dermatitis,
chronic active hepatitis, myasthenia gravis, multiple sclerosis,
inflammatory bowel disease, ulcerative colitis, Crohn's disease,
psoriasis, graft vs. host disease, inflammatory reaction induced by
endotoxin, tuberculosis, atherosclerosis, muscle degeneration,
cachexia, psoriatic arthritis, Reiter's syndrome, gout, traumatic
arthritis, rubella arthritis, acute synovitis, pancreatic
.beta.-cell disease; diseases characterized by massive neutrophil
infiltration; rheumatoid spondylitis, gouty arthritis and other
arthritic conditions, Kawasaki disease, chronic inflammatory
demyelinating polyneuropathy (CIDP), dermatomyositis, uveitis,
anti-factor-VIII disease, ankylosing spondylitis, myasthenia
gravis, Goodpasture's disease, antiphospholipid syndrome,
ANCA-associated vasculitis, dermatomyositis/polymyositis, cerebral
malaria, chronic pulmonary inflammatory disease, silicosis,
pulmonary sarcoidosis, bone resorption disease, allograft
rejections, fever and myalgias due to infection, cachexia secondary
to infection, myeloid formation, scar tissue formation, ulcerative
colitis, pyresis, influenza, osteoporosis, osteoarthritis, acute
myelogenous leukemia, chronic myelogenous leukemia, metastatic
melanoma, Kaposi's sarcoma, multiple myeloma, sepsis, septic shock,
and Shigellosis; Alzheimer's disease, Parkinson's disease, cerebral
ischemias or neurodegenerative disease caused by traumatic injury;
angiogenic disorders including solid tumors, ocular
neovasculization, and infantile haemangiomas; viral diseases
including acute hepatitis infection (including hepatitis A,
hepatitis B and hepatitis C), HIV infection and CMV retinitis,
AIDS, ARC or malignancy, and herpes; stroke, myocardial ischemia,
ischemia in stroke heart attacks, organ hypoxia, vascular
hyperplasia, cardiac and renal reperfusion injury, thrombosis,
cardiac hypertrophy, thrombin-induced platelet aggregation,
endotoxemia and/or toxic shock syndrome, conditions associated with
prostaglandin endoperoxidase syndase-2, and pemphigus vulgaris.
Preferred methods of treatment are those wherein the condition is
selected from Crohn's and ulcerative colitis, allograft rejection,
rheumatoid arthritis, psoriasis, ankylosing spondylitis, psoriatic
arthritis, and pemphigus vulgaris. Alternatively preferred methods
of treatment are those wherein the condition is selected from
ischemia reperfusion injury, including cerebral ischemia
reperfusions injury arising from stroke and cardiac ischemia
reperfusion injury arising from myocardial infarction. Another
preferred method of treatment is one in which the condition is
multiple myeloma.
[0292] In addition, the Btk inhibitors of the present invention
inhibit the expression of inducible pro-inflammatory proteins such
as prostaglandin endoperoxide synthase-2 (PGHS-2), also referred to
as cyclooxygenase-2 (COX-2). Accordingly, additional Btk-associated
conditions include edema, analgesia, fever and pain, such as
neuromuscular pain, headache, pain caused by cancer, dental pain
and arthritis pain. The inventive compounds also may be used to
treat veterinary viral infections, such as lentivirus infections,
including, but not limited to equine infectious anemia virus; or
retro virus infections, including feline immunodeficiency virus,
bovine immunodeficiency virus, and canine immunodeficiency
virus.
[0293] When the terms "Btk-associated condition" or "Btk-associated
disease or disorder" are used herein, each is intended to encompass
all of the conditions identified above as if repeated at length, as
well as any other condition that is affected by Btk kinase
activity.
[0294] "Therapeutically effective amount" is intended to include an
amount of a compound of the present invention that is effective
when administered alone or in combination to inhibit Btk.
[0295] One embodiment provides methods for treating such Btk
kinase-associated conditions, comprising administering to a subject
in need thereof at least one compound of Formula (I). A
therapeutically-effective amount for treating such conditions may
be administered. The methods of the present embodiment may be
employed to treat Btk kinase-associated conditions such as
treatment of allergic disorders and/or autoimmune and/or
inflammatory diseases including, but not limited to, SLE,
rheumatoid arthritis, multiple vasculitides, idiopathic
thrombocytopenic purpura (ITP), myasthenia gravis, allergic
rhinitis, multiple sclerosis (MS), transplant rejection, Type I
diabetes, membranous nephritis, inflammatory bowel disease,
autoimmune hemolytic anemia, autoimmune thyroiditis, cold and warm
agglutinin diseases, Evans syndrome, hemolytic uremic
syndrome/thrombotic thrombocytopenic purpura (HUS/TTP),
sarcoidosis, Sjogren's syndrome, peripheral neuropathies (e.g.,
Guillain-Barre syndrome), pemphigus vulgaris, and asthma.
[0296] The methods of treating Btk kinase-associated conditions may
comprise administering at least one compound of Formula (I) alone
or in combination with each other and/or other suitable therapeutic
agents useful in treating such conditions.
Therapeutically-effective amounts of at least one compound of
Formula (I) and other suitable therapeutic agents for treating such
conditions may be administered. Accordingly, "therapeutically
effective amount" is also intended to include an amount of the
combination of compounds claimed that is effective to treat Btk
kinase-associated conditions. The combination of compounds is
preferably a synergistic combination. Synergy, as described, for
example, by Chou et al., Adv. Enzyme Regul., 22:27-55 (1984),
occurs when the effect (in this case, inhibition of Btk) of the
compounds when administered in combination is greater than the
additive effect of the compounds when administered alone as a
single agent. In general, a synergistic effect is most clearly
demonstrated at sub-optimal concentrations of the compounds.
Synergy can be in terms of lower cytotoxicity, increased anti-Btk
effect, or some other beneficial effect of the combination compared
with the individual components.
[0297] Exemplary of such other therapeutic agents include
corticosteroids, rolipram, calphostin, cytokine-suppressive
anti-inflammatory drugs (CSAIDs), 4-substituted
imidazo[1,2-A]quinoxalines as disclosed in U.S. Pat. No. 4,200,750;
Interleukin-10, glucocorticoids, salicylates, nitric oxide, and
other immunosuppressants; nuclear translocation inhibitors, such as
deoxyspergualin (DSG); non-steroidal antiinflammatory drugs
(NSAIDs) such as ibuprofen, celecoxib and rofecoxib; steroids such
as prednisone or dexamethasone; antiviral agents such as abacavir;
antiproliferative agents such as methotrexate, leflunomide, FK506
(tacrolimus, PROGRAF.RTM.); cytotoxic drugs such as azathiprine and
cyclophosphamide; TNF-.alpha. inhibitors such as tenidap, anti-TNF
antibodies or soluble TNF receptor, and rapamycin (sirolimus or
RAPAMUNE.RTM.) or derivatives thereof.
[0298] The above other therapeutic agents, when employed in
combination with the compounds of the present invention, may be
used, for example, in those amounts indicated in the Physicians'
Desk Reference (PDR) or as otherwise determined by one of ordinary
skill in the art. In the methods of the present invention, such
other therapeutic agent(s) may be administered prior to,
simultaneously with, or following the administration of the
inventive compounds. The present invention also provides
pharmaceutical compositions capable of treating Btk
kinase-associated conditions, including IL-1, IL-6, IL-8,
IFN.gamma. and TNF-.alpha.-mediated conditions, as described
above.
[0299] The inventive compositions may contain other therapeutic
agents as described above and may be formulated, for example, by
employing conventional solid or liquid vehicles or diluents, as
well as pharmaceutical additives of a type appropriate to the mode
of desired administration (e.g., excipients, binders,
preservatives, stabilizers, flavors, etc.) according to techniques
such as those well known in the art of pharmaceutical
formulation.
[0300] Another embodiment provides the compounds of Formula (I) for
use in therapy. In the present embodiment, the use in therapy may
include the administration of a therapeutically-effective amount of
a compound of Formula (I).
[0301] The present invention also provides the use of the compounds
of Formula (I) for the manufacture of a medicament for the
treatment or prophylaxis of an allergic disorder and/or autoimmune
and/or inflammatory disease. In the present embodiment, the use for
the manufacture of a medicament may include the administration of a
therapeutically-effective amount of a compound of Formula (I) for
the treatment of prophylaxis of an allergic disorder and/or
autoimmune and/or inflammatory disease.
[0302] The present invention also provides the use of the compounds
of Formula (I) for the manufacture of a medicament for treatment of
cancer. The present embodiment may include the use for the
manufacture of a medicament includes the administration of a
therapeutically-effective amount of a compound of Formula (I) for
the treatment of prophylaxis of an allergic disorder and/or
autoimmune and/or inflammatory disease.
[0303] Accordingly, the present invention further includes
compositions comprising one or more compounds of Formula (I) and a
pharmaceutically acceptable carrier.
[0304] A "pharmaceutically acceptable carrier" refers to media
generally accepted in the art for the delivery of biologically
active agents to animals, in particular, mammals. Pharmaceutically
acceptable carriers are formulated according to a number of factors
well within the purview of those of ordinary skill in the art.
These include without limitation the type and nature of the active
agent being formulated; the subject to which the agent-containing
composition is to be administered; the intended route of
administration of the composition; and, the therapeutic indication
being targeted. Pharmaceutically acceptable carriers include both
aqueous and non-aqueous liquid media, as well as a variety of solid
and semi-solid dosage forms. Such carriers can include a number of
different ingredients and additives in addition to the active
agent, such additional ingredients being included in the
formulation for a variety of reasons, e.g., stabilization of the
active agent, binders, etc., well known to those of ordinary skill
in the art. Descriptions of suitable pharmaceutically acceptable
carriers, and factors involved in their selection, are found in a
variety of readily available sources such as, for example,
Remington's Pharmaceutical Sciences, 17th Edition (1985), which is
incorporated herein by reference in its entirety.
[0305] The compounds of Formula (I) may be administered by any
means suitable for the condition to be treated, which may depend on
the need for site-specific treatment or quantity of drug to be
delivered. Topical administration is generally preferred for
skin-related diseases, and systematic treatment preferred for
cancerous or pre-cancerous conditions, although other modes of
delivery are contemplated. For example, the compounds may be
delivered orally, such as in the form of tablets, capsules,
granules, powders, or liquid formulations including syrups;
topically, such as in the form of solutions, suspensions, gels or
ointments; sublingually; bucally; parenterally, such as by
subcutaneous, intravenous, intramuscular or intrasternal injection
or infusion techniques (e.g., as sterile injectable aqueous or
non-aqueous solutions or suspensions); nasally such as by
inhalation spray; topically, such as in the form of a cream or
ointment; rectally such as in the form of suppositories; or
liposomally. Dosage unit formulations containing non-toxic,
pharmaceutically acceptable vehicles or diluents may be
administered. The compounds may be administered in a form suitable
for immediate release or extended release. Immediate release or
extended release may be achieved with suitable pharmaceutical
compositions or, particularly in the case of extended release, with
devices such as subcutaneous implants or osmotic pumps.
[0306] Exemplary compositions for topical administration include a
topical carrier such as Plastibase (mineral oil gelled with
polyethylene).
[0307] Exemplary compositions for oral administration include
suspensions which may contain, for example, microcrystalline
cellulose for imparting bulk, alginic acid or sodium alginate as a
suspending agent, methylcellulose as a viscosity enhancer, and
sweeteners or flavoring agents such as those known in the art; and
immediate release tablets which may contain, for example,
microcrystalline cellulose, dicalcium phosphate, starch, magnesium
stearate and/or lactose and/or other excipients, binders,
extenders, disintegrants, diluents and lubricants such as those
known in the art. The inventive compounds may also be orally
delivered by sublingual and/or buccal administration, e.g., with
molded, compressed, or freeze-dried tablets. Exemplary compositions
may include fast-dissolving diluents such as mannitol, lactose,
sucrose, and/or cyclodextrins. Also included in such formulations
may be high molecular weight excipients such as celluloses
(AVICEL.RTM.) or polyethylene glycols (PEG); an excipient to aid
mucosal adhesion such as hydroxypropyl cellulose (HPC),
hydroxypropyl methyl cellulose (HPMC), sodium carboxymethyl
cellulose (SCMC), and/or maleic anhydride copolymer (e.g.,
Gantrez); and agents to control release such as polyacrylic
copolymer (e.g., Carbopol 934). Lubricants, glidants, flavors,
coloring agents and stabilizers may also be added for ease of
fabrication and use.
[0308] Exemplary compositions for nasal aerosol or inhalation
administration include solutions which may contain, for example,
benzyl alcohol or other suitable preservatives, absorption
promoters to enhance absorption and/or bioavailability, and/or
other solubilizing or dispersing agents such as those known in the
art.
[0309] Exemplary compositions for parenteral administration include
injectable solutions or suspensions which may contain, for example,
suitable non-toxic, parenterally acceptable diluents or solvents,
such as mannitol, 1,3-butanediol, water, Ringer's solution, an
isotonic sodium chloride solution, or other suitable dispersing or
wetting and suspending agents, including synthetic mono- or
diglycerides, and fatty acids, including oleic acid.
[0310] Exemplary compositions for rectal administration include
suppositories which may contain, for example, suitable
non-irritating excipients, such as cocoa butter, synthetic
glyceride esters or polyethylene glycols, which are solid at
ordinary temperatures but liquefy and/or dissolve in the rectal
cavity to release the drug.
[0311] The therapeutically-effective amount of a compound of the
present invention may be determined by one of ordinary skill in the
art, and includes exemplary dosage amounts for a mammal of from
about 0.05 to 1000 mg/kg; 1-1000 mg/kg; 1-50 mg/kg; 5-250 mg/kg;
250-1000 mg/kg of body weight of active compound per day, which may
be administered in a single dose or in the form of individual
divided doses, such as from 1 to 4 times per day. It will be
understood that the specific dose level and frequency of dosage for
any particular subject may be varied and will depend upon a variety
of factors, including the activity of the specific compound
employed, the metabolic stability and length of action of that
compound, the species, age, body weight, general health, sex and
diet of the subject, the mode and time of administration, rate of
excretion, drug combination, and severity of the particular
condition. Preferred subjects for treatment include animals, most
preferably mammalian species such as humans, and domestic animals
such as dogs, cats, horses, and the like. Thus, when the term
"patient" is used herein, this term is intended to include all
subjects, most preferably mammalian species, that are affected by
mediation of Btk enzyme levels.
[0312] Examples of compounds of Formula (I) as specified in the
"Examples" section below, have been tested in one or more of the
assays described below.
[0313] In one embodiment, the compounds of Formula (I) inhibit Btk
enzymes with IC.sub.50 values of 6 nM or less, for example, from
0.001 to 6 nM, as measured by the Human Recombinant Btk enzyme
assay. Preferably, the compounds of Formula (I) inhibit Btk enzymes
with IC.sub.50 values of 2 nM and less, for example, from 0.001 to
2 nM. Other preferred compounds inhibit Btk enzymes with IC.sub.50
values of 1.0 nM and less, for example, from 0.001 to 1.0 nM.
[0314] In one embodiment, the compounds of Formula (I) have reduced
inhibition of the Jak2 kinase characterized by IC.sub.50 values
above 50 nM, for example, greater than 250 nM, as measured by the
Jak2 tyrosine kinase assay. Preferably, the compounds of Formula
(I) inhibit Jak2 enzymes with IC.sub.50 values of greater than 400
nM, for example, with IC.sub.50 values of greater than 700 nM.
[0315] In one embodiment, the compounds of Formula (I) have kinase
selectivity ratios of Btk inhibition activity over Jak2 inhibition
activity characterized by ratios of Jak2 IC.sub.50 inhibition
values, as measured by the Jak2 tyrosine kinase assay, to Btk
IC.sub.50 inhibition values, as measured by the Human Recombinant
Btk enzyme assay, of 150 and greater, for example, ratios of 300
and greater. Preferably, the compounds of Formula (I) have ratios
of Jak2 IC.sub.50 inhibition values to Btk IC.sub.50 inhibition
values of 400 and greater, for example, ratios of 500 and
greater.
[0316] In one embodiment, the compounds of Formula (I) have
improved potency in the whole blood BCR-stimulated CD.sub.69
expression assay with IC.sub.50 values of 250 nM or less, for
example, from 0.1 to 250 nM. More preferably, the compounds of
Formula (I) have potency in the whole blood BCR-stimulated
CD.sub.69 expression assay with IC.sub.50 values of 160 nM or less,
for example, from 0.1 to 160 nM; and with IC.sub.50 values of 100
nM or less, for example, from 0.1 to 100 nM.
Methods of Preparation
[0317] Compounds of Formula (I) can be prepared using methods shown
in Scheme 1.
##STR00060##
[0318] Substituted boronic esters 1, wherein Z represents a
substituted monocyclic or fused bicyclic heterocyclic ring
(substituent Q in compounds of Formula (I)), can be reacted with
substituted carbazolecarboxamides or
tetrahydrocarbazolecarboxamides 2 (wherein Y is an appropriate
group such as Br, Cl or trifluoromethanesulfonyloxy) to provide
compounds 3. This reaction may be performed by using a suitable
base such as potassium carbonate, cesium carbonate or tripotassium
phosphate, and a suitable catalyst such as
tetrakis(triphenylphosphine)palladium,
1,1'-bis(diphenylphosphino)ferrocene palladium(II) chloride, or
1,1'-bis(di-tert-butylphosphino)ferrocene palladium(II) chloride,
in a suitable solvent such as dioxane or tetrahydrofuran,
optionally with a suitable cosolvent such as water. Such coupling
reactions are commonly known as Suzuki-Miyaura coupling reactions,
and are well known in the chemical literature (see, for example,
Heravi, M. M. et al., Tetrahedron, 68:9145 (2012), and references
cited therein).
[0319] Due to the non-symmetric nature of the rings connected by
the single bonds labeled a and b in Scheme 1, and due to limited
rotation about these bonds caused by steric hindrance, compounds of
the current invention display chirality, known as atropisomerism.
Thus, under certain conditions, such as chromatography on a chiral
stationary phase, the four diastereomeric atropisomers (arising
from limited rotation about the two stereogenic axes) can be
observed as four separate peaks in the chromatogram. Compounds of
Formula (I) can be isolated either as stable mixtures of from two
to four diastereomeric atropisomers, or as single stable
atropisomers.
[0320] Since 1 is racemic, compounds 3 will normally be isolated as
mixtures of four diastereomeric atropisomers. Alternatively,
racemic compounds 1 can be converted into single atropisomers 1a
and 1b, with the absolute configurations shown, using methods known
in the art, such as preparative chromatography on a chiral
stationary phase. Suzuki-Miyaura coupling reactions as described
above can then convert 1a into compounds 3a, or 1b into 3b, having
the absolute configurations shown about bond b but a mixture of two
configurations about bond a, as long as the conditions of the
Suzuki-Miyaura coupling reaction are such that isomerization about
bond b does not occur. Compounds 3a and 3b will thus exist as a
mixture of two diastereomeric atropisomers.
[0321] As shown in Scheme 2, compounds 3, which are mixtures of
four diastereomeric atropisomers, can be separated into four single
stable diastereomeric atropisomers 3c, 3d, 3e and 3f, using methods
known in the art, such as chromatography on a chiral stationary
phase. Alternatively, compounds 3a (mixtures of two diastereomeric
atropisomers) can be separated into single stable atropisomers 3c
and 3d, and compounds 3b (mixtures of two diastereomeric
atropisomers) can likewise be separated into single stable
atropisomers 3e and 3f.
##STR00061##
[0322] In the case where 2 is a substituted tetrahydrocarbazole
carboxamide (where the dashed lines represent single bonds), 2 also
contains a chiral center, and thus can exist as a racemate. In this
case, compounds 3 prepared from these compounds 2 will exist as a
mixture of eight diastereomers, each of 3a and 3b will exist as a
mixture of four diastereomers, and each of 3c, 3d, 3e and 3f will
exist as a mixture of two diastereomers. Any of these mixtures can
also be separated into single stable diastereomers using methods
known in the art, such as chromatography on a chiral stationary
phase. Alternatively, compounds 2 can be converted into two
separated enantiomers using methods known in the art, such as
chromatography on a chiral stationary phase.
[0323] In some cases where one of the coupling intermediates 1 or 2
in Scheme 1 is non-racemic, chiral induction can occur during the
Suzuki-Miyaura coupling reactions shown in Scheme 1. In these
cases, mixtures of diastereomers can be obtained which are not
equimolar mixtures; that is, the product 3 can be a mixture of
diastereomers in which one or more of the diastereomers, having
bond a with one absolute configuration, is present to a greater
extent than one or more diastereomers having bond a with the
opposite absolute configuration.
[0324] An alternative method for the synthesis of certain compounds
of Formula (I) is shown in Scheme 3. A suitably substituted
4-arylimino-1H-benzo[d][1,3]oxazin-2(4H)-one 4 can react with 2
under conditions of the Suzuki-Miyaura coupling reaction as
described above, to provide compounds of Formula (I) having
structure 5. During the course of the reaction, the
4-arylimino-1H-benzo[d][1,3]oxazin-2(4H)-one moiety present in 4
rearranges to the 3-arylquinazoline-2,4(1H,3H)-dione moiety present
in the reaction product 5.
##STR00062##
[0325] Compounds 1 of Scheme 1, used in the preparation of
compounds of Formula (I), can be prepared by a variety of methods.
Some of these methods are shown in Scheme 4.
[0326] An isatoic anhydride 6 can react with a substituted aniline
7 (wherein Y' is an appropriate group such as Br, Cl or
trifluoromethanesulfonyloxy) to produce an amide 8. Such reactions
can be carried out under a variety of conditions, for example by
heating in a suitable solvent, or by heating in the presence of an
auxiliary reagent such as trimethylaluminum. A compound 8 can be
converted into a substituted quinazolinedione 9, for example by
treatment in a suitable solvent with phosgene or triphosgene.
Optionally, 9 can be converted to the corresponding boronate ester
10 (which is an example of a compound 1 of Scheme 1) using methods
well known in the chemical literature (see, for example, Ishiyama,
T. et al., Tetrahedron, 57:9813 (2001), and references cited
therein). Examples of such methods are the reaction of 9 with a
borylating reagent such as
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) or
5,5,5',5'-tetramethyl-2,2'-bi(1,3,2-dioxaborinane) in the presence
of a base such as potassium acetate and a suitable catalyst such as
1,1'-bis(diphenylphosphino)ferrocene palladium(II) chloride in a
suitable solvent.
[0327] Alternatively, a compound 9 can optionally be converted into
a compound 11 where R.sub.a is an alkyl group, using methods known
well known in the chemical literature, for example by treatment
with an alkylating agent such as iodomethane or
trideuteroiodomethane in the presence of a suitable base such as
cesium carbonate. A compound 11 can then be converted into the
corresponding boronate ester 12 (which is an example of compound 1
of Scheme 1) using the same methods described above. A compound 10
can also be optionally converted into the corresponding compound 12
by methods similar to those described for the conversion of 9 into
11.
[0328] Compounds 10 and 12 display chirality due to hindered
rotation about the single bond connecting the substituted phenyl
ring to the quinazolinedione moiety. If desired, these compounds
can be resolved into separate enantiomeric atropisomers, for
example by chromatography on a chiral stationary phase. The
separated enantiomeric atropisomers of 10 can then optionally be
converted into stable enantiomeric atropisomers of 12 as described
above to provide certain examples of the compounds 1a or 1b of
Scheme 1. Likewise, racemic quinazolinediones 12 can also be
resolved into separate enantiomeric atropisomers.
##STR00063##
[0329] An alternative synthesis of intermediate compounds 8 of
Scheme 4 is shown in Scheme 5. A substituted 2-nitrobenzoic acid 13
can be converted to a compound 14 using well-known amide bond
forming reactions, for example by conversion of 8 to the
corresponding carboxylic acid chloride and reaction with a
substituted aniline 7, or by direct reaction of 13 and 7 in the
presence of a suitable coupling reagent such
O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium
hexafluorophosphate (HATU), or a mixture of
1-[3-(dimethylamino)propyl]-3-ethyl-carbodiimide hydrochloride
(EDC) and 1-hydroxybenzotriazole hydrate (HOBT), using methods well
known in the literature. The nitro group of 14 can then be reduced,
using one of a wide variety of methods known in the literature, to
give a compound 8 of Scheme 4.
##STR00064##
[0330] Compounds 4 of Scheme 3 can be prepared using the method
shown in Scheme 6. An N-substituted isatoic anhydride 15, wherein
R.sub.a is an alkyl group, can react with a substituted aniline 7
to produce an amide 16. Such reactions can be carried out under a
variety of conditions as described above, for example by heating in
a suitable solvent, or by heating in the presence of an auxiliary
reagent such as trimethylaluminum. A compound 16 can be converted
into a substituted aryliminobenzoxazinone 17, for example by
treatment in a suitable solvent with phosgene or triphosgene. A
compound 17 can then be converted into the corresponding boronate
ester 4 using methods similar to those described above for the
conversion of a compound 10 or a compound 11 into a compound 12
(see Scheme 4).
##STR00065##
[0331] Some additional methods which can be used to prepare certain
compounds 1, used in the preparation of compounds of Formula (I),
are shown in Scheme 7. A substituted pyridyl-2-acetic acid 18, or a
salt of a substituted pyridyl-2-acetic acid such as a sodium salt
(which are either commercially available or can be prepared by
methods well known in the chemical literature), can be reacted with
an aniline 7 under a variety of methods well known in the chemical
literature to provide an amide 19. For example, the reaction can be
performed in the presence of a coupling reagent such as
O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium
hexafluorophosphate (HATU), or a mixture of
1-[3-(dimethylamino)propyl]-3-ethyl-carbodiimide hydrochloride
(EDC) and 1-hydroxybenzotriazole hydrate (HOBT). An amide 19 can be
converted into the corresponding substituted
1H-pyrido[1,2-c]pyrimidine-1,3(2H)-dione 20 by heating with a
reagent such as carbonyldiimidazole in an appropriate solvent such
as toluene. A compound 20 can be converted into the corresponding
boronate ester 21 (which is an example of an intermediate 1 of
Scheme 1) using methods previously described (see Scheme 4).
Alternatively, a compound 19 can be converted into the
corresponding boronate ester 22 using methods previously described
(see Scheme 4), followed by conversion of 22 to 2.sub.1 by heating
with a reagent such as carbonyldiimidazole.
##STR00066##
[0332] In Scheme 7, the pyridyl ring in the structures shown can
also be replaced with another nitrogen heterocycle, such as a
thiazole. In this case, the corresponding compounds 20 and 21 will
contain a 5H-thiazolo[3,2-c]pyrimidine-5,7(6H)-dione moiety in
place of the 1H-pyrido[1,2-c]pyrimidine-1,3(2H)-dione moiety
shown.
[0333] Compounds 21 display chirality due to hindered rotation
about the single bond joining the substituted phenyl ring with the
substituted 1H-pyrido[1,2-c]pyrimidine-1,3(2H)-dione moiety. If
desired, these racemic compounds can be resolved into separate
enantiomeric atropisomers, for example by chromatography on a
chiral stationary phase, to provide certain examples of the
intermediates 1a and 1b of Scheme 1.
##STR00067##
[0334] Preparation of a compound 1 of Scheme 1, wherein Z
represents a substituted pyrimidine-1,3-dione moiety, can be
achieved using the method shown in Scheme 8, following a general
procedure reported by Cao, J. et al. (Synthetic Commun., 39:205
(2009)). Compound 23 can be prepared by reacting
p-methoxybenzylamine, methyl acrylate and phenyl
hypobromoselenoite. This material can be reacted with an
appropriate aryl isocyanate 24 (which can be prepared from the
aniline 7 shown in Scheme 4, using methods well known in the
chemical literature) to provide the substituted
dihydropyrimidine-1,3-dione 25. Treatment of this compound with an
oxidizing agent such as hydrogen peroxide can provide the
substituted pyrimidine-1,3-dione 26. Removal of the p-methoxybenzyl
group of 26 can be achieved using a number of methods reported in
the chemical literature, for example by treatment with a mixture of
trifluoromethanesulfonic acid and trifluoroacetic acid (as reported
by Wu, F. et al., J. Org. Chem., 69:9307 (2004)). The resulting
pyrimidine-1,3-dione 27 can be reacted with an aryl boronic acid
such as 4-fluorobenzeneboronic acid, for example using conditions
described by Jacobsen, M. F. et al. (J. Org. Chem., 71:9183 (2006))
to provide 28 (wherein Ar represents 4-fluorophenyl). This can then
be converted to the boronate ester 29, which is an example of a
compound 1 of Scheme 1, using methods similar to those described
above.
[0335] Compounds 2 shown in Scheme 1, used in the preparation of
compounds of Formula (I), can be prepared using procedures shown in
Scheme 9. A substituted 2-aminobenzoic acid 30 (known in the
literature, or prepared using procedures known in the literature)
can be converted to the corresponding 2-hydrazinylbenzoic acid 31
as the hydrochloric acid salt using methods well known in the
literature, for example by conversion to the corresponding
diazonium salt by treatment with sodium nitrite in aqueous
hydrochloric acid, followed by reduction with tin(II) chloride.
Reaction of 31 with ethyl 3-oxocyclohexanecarboxylate 32 (which can
be prepared from ethyl 3-hydroxybenzoate; see for example Hirsch,
J. et al., J. Org. Chem., 51:2218 (1986)) in a suitable solvent
with an appropriate catalyst, for example ethanol with hydrochloric
acid, toluene with p-toluenesulfonic acid or trifluoroacetic acid,
or acetic acid (in which case the solvent also can serve as the
catalyst), can provide the corresponding tetrahydrocarbazole
derivative 33. This reaction is commonly known as the Fischer
indole synthesis, and is well known in the chemical literature (for
example, see Kamata, J. et al., Chem. Pharm. Bull., 52:1071
(2004)). Alternatively, the Fischer indole synthesis can be carried
out in two consecutive steps: 31 can react with 32 under suitable
conditions (such as in an appropriate solvent such as ethanol or
toluene, optionally with a suitable catalyst such as
p-toluenesulfonic acid) to form an intermediate hydrazone, which
can be isolated and then reacted further under suitable conditions
(for example, ethanol with hydrochloric acid, acetic acid with zinc
chloride, or toluene with trifluoroacetic acid) to provide 33.
##STR00068##
[0336] A carboxylic acid 33 can be converted to the corresponding
carboxamide 34 using methods well known in the chemical literature,
for example by conversion of 33 to the acid chloride by treatment
with oxalyl chloride or thionyl chloride, followed by treatment
with ammonia; or by treatment of 33 with ammonia in the presence of
a coupling reagent such as carbodiimide, or a mixture of
N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride and
1-hydroxybenzotriazole or 1-hydroxy-7-azabenzotriazole. Conversion
of a tetrahydrocarbazole 34 to the corresponding carbazole 35 can
be performed using methods well known in the chemical literature,
for example by treatment of 34 with an oxidizing agent such as
2,3-dichloro-5,6-dicyanobenzoquinone in a suitable solvent.
[0337] Alternatively, the order of the amide formation and
oxidation steps can be reversed to convert 33 to 35. Thus, a
compound 33 can be oxidized using the procedure described above, or
a similar procedure, to give the corresponding compound 36. The
carboxylic acid of this compound can then be converted into the
corresponding primary amide, again using a procedure described
above or a similar procedure, to give the corresponding compound
35.
[0338] Conversion of 35 to the corresponding tertiary carbinol
substituted carbazolecarboxamide 37 (which is an example of
compound 2 in Scheme 1) can be performed using methods well known
in the chemical literature, for example by treatment of 35 with a
reagent such as methyllithium, methylmagnesium bromide or
methylmagnesium chloride. Alternatively, conversion of 34 to the
corresponding tertiary carbinol substituted tetrahydrocarbazole
carboxamide 38 (which is another example of compound 2 in Scheme 1)
can be performed using a similar procedure.
[0339] Compounds 33, 34 and 38 contain a chiral center, and thus
exist as two enantiomers. Preparation of 33, 34 and 38 as shown in
Scheme 9 provides racemic products, which may be used to prepare
compounds of Formula (I) as shown in Scheme 1. Alternatively, 33,
34 and 38 may be resolved into separated enantiomers, using
well-known methods such as chromatography on a chiral stationary
phase.
[0340] Certain compounds 2 of Scheme 1, used to prepare compounds
of Formula (I), may also be prepared using procedures shown in
Scheme 10. Compound 39, prepared from the appropriate
2-hydrazinylbenzoic acid as shown in Scheme 9 (see U.S. Pat. No.
8,084,620, Intermediate 48-1) can be treated with an appropriate
halogenating reagent to give 40, where R.sub.1 is a halogen atom.
For example, treatment of 39 with a chlorinating reagent such as
N-chlorosuccinimide can give 40 where R.sub.1 is Cl, and treatment
of 39 with a fluorinating reagent such as
1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane-bis(tetrafluor-
oborate) [SELECTFLUOR.RTM.] can give 40 where R.sub.1 is F.
Treatment of 40 with methyllithium or a methylmagnesium halide as
described for Scheme 9 can then provide compounds 37 where R.sub.1
is F or Cl (which are examples of compounds 2 in Scheme 1).
##STR00069##
[0341] Compound 37 where R.sub.1 is CN can be prepared by an
alternative procedure, also shown in Scheme 10. Compound 41, which
can be prepared from compound 39 (see U.S. Pat. No. 8,084,620,
Example 73-2) can be treated with an iodinating reagent such as
N-iodosuccinimide to provide 37 where R.sub.1 is I. This compound
can be converted to 37 where R.sub.1 is CN (an example of compound
2 in Scheme 1), for example by treatment with zinc cyanide in the
presence of a catalyst such as
tetrakis(triphenylphosphine)palladium.
[0342] Another example of the preparation of a compound 2 of Scheme
1 is shown in Scheme 11. Using procedures described in Scheme 9 and
similar procedures, the ketone 42 (which can be prepared by
reaction of diethyl malonate with cyclohex-2-enone, using a number
of methods reported in the literature) can be reacted with a
hydrazinylbenzoic acid 31 to give a compound 43, which can then be
converted to a compound 44 and subsequently to a compound 45 using
methods described above for Scheme 9. Using methods known in the
literature, for example heating with sodium chloride and water in a
suitable solvent such as dimethyl sulfoxide, a compound 45 can be
converted to a compound 46. The ester moiety of a compound 46 can
then be reduced to the carbinol using procedures known in the
literature, for example by treatment with lithium borohydride, to
give a compound 47, which is an example of compound 2 of Scheme
1.
##STR00070##
EXAMPLES
[0343] Compounds of the current invention, and intermediates used
in the preparation of compounds of the current invention, can be
prepared using procedures shown in the following examples and
related procedures. The methods and conditions used in these
examples, and the actual compounds prepared in these examples, are
not meant to be limiting, but are meant to demonstrate how the
compounds of the current invention can be prepared. Starting
materials and reagents used in these examples, when not prepared by
a procedure described herein, are generally either commercially
available, or are reported in the chemical literature, or may be
prepared by using procedures described in the chemical literature.
The invention is further defined in the following Examples. It
should be understood that the Examples are given by way of
illustration only. From the above discussion and the Examples, one
skilled in the art can ascertain the essential characteristics of
the invention, and without departing from the spirit and scope
thereof, can make various changes and modifications to adapt the
invention to various uses and conditions. As a result, the
invention is not limited by the illustrative examples set forth
herein below, but rather defined by the claims appended hereto.
[0344] In the examples given, the phrase "dried and concentrated"
generally refers to drying of a solution in an organic solvent over
either sodium sulfate or magnesium sulfate, followed by filtration
and removal of the solvent from the filtrate (generally under
reduced pressure and at a temperature suitable to the stability of
the material being prepared).
[0345] Column chromatography was generally performed using the
flash chromatography technique (Still, W. C. et al., J. Org. Chem.,
43:2923 (1978)), or with pre-packed silica gel cartridges using an
Isco medium pressure chromatography apparatus (Teledyne
Corporation), eluting with the solvent or solvent mixture
indicated.
[0346] Preparative high performance liquid chromatography (HPLC)
was performed using a reverse phase column (Waters SunFire
C.sub.18, Waters XBridge C.sub.18, PHENOMENEX.RTM. Axia C.sub.18,
YMC S5 ODS or the like) of a size appropriate to the quantity of
material being separated, generally eluting with a gradient of
increasing concentration of methanol or acetonitrile in water, also
containing 0.05% or 0.1% trifluoroacetic acid or 10 mM ammonium
acetate, at a rate of elution suitable to the column size and
separation to be achieved. Chiral super-critical fluid
chromatographic separation of enantiomers or atropisomers was
performed using conditions described for the individual cases. Mass
spectral data were obtained by liquid chromatography-mass
spectrometry using electrospray ionization.
[0347] Single crystal x-ray diffraction data were collected on a
Bruker-AXS APEX2 CCD system using Cu K.alpha. radiation (X=1.5418
.ANG.). Indexing and processing of the measured intensity data were
carried out with the APEX2 software package/program suite (see the
APEX2 User Manual, v1.27; Bruker AXS, Inc., WI 53711 USA). When
indicated, crystals were cooled in the cold stream of an Oxford
Cryosystems cryostream cooler (Cosier, J. et al., J. Appl. Cryst.,
19:105 (1986)) during data collection. The structures were solved
by direct methods and refined on the basis of observed reflections
using the crystallographic package SHELXTL (see the APEX2 User
Manual, v1.27; Bruker AXS, Inc., WI 53711 USA). The derived atomic
parameters (coordinates and temperature factors) were refined
through full matrix least-squares. The function minimized in the
refinements was .SIGMA..sub.w(|F.sub.o|-|F.sub.c|).sup.2. R is
defined as
.SIGMA..parallel.F.sub.o|-|F.sub.c.parallel./.SIGMA.|F.sub.o| while
R.sub.w=[.SIGMA..sub.w(|F.sub.o|-|F.sub.c|).sup.2/.SIGMA..sub.w|F.s-
ub.o|.sup.2].sup.1/2 where w is an appropriate weighting function
based on errors in the observed intensities. Difference maps were
examined at all stages of refinement. Hydrogens were introduced in
idealized positions with isotropic temperature factors, but no
hydrogen parameters were varied. Unit cell parameters were obtained
according to the procedure described in Stout et al., X-Ray
Structure Determination: A Practical Guide, MacMillan (1968).
[0348] Chemical names were determined using CHEMDRAW.RTM. Ultra,
version 9.0.5 (CambridgeSoft). The following abbreviations are
used:
ABBREVIATIONS
[0349] CDI carbonyldiimidazole [0350] DCM dichloromethane [0351]
DIEA diisopropylethylamine [0352] DMF N,N-dimethylformamide [0353]
DMSO dimethyl sulfoxide [0354] dppf
1,1'-bis(diphenylphosphino)ferrocene [0355] DSC differential
scanning calorimetry [0356] DTT dithiothreitol [0357] EDC
1-[3-(dimethylamino)propyl]-3-ethyl-carbodiimide hydrochloride
[0358] EDTA ethylenediamine tetraacetate [0359] EtOAc ethyl acetate
[0360] EtOH ethanol [0361] g gram(s) [0362] h hour(s) [0363] HATU
O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium
hexafluorophosphate [0364] HOBT 1-hydroxybenzotriazole hydrate
[0365] HPLC High Pressure Liquid Chromatography [0366] IPA
isopropanol [0367] MeCN acetonitrile [0368] MeOH methanol [0369]
min minute(s) [0370] mmol millimole(s) [0371] NBS
N-bromosuccinimide [0372] NCS N-chlorosuccinimide [0373] NMP
N-methylpyrrolidinone [0374] t-butyl tertiary butyl [0375] TEA
triethylamine [0376] TFA trifluoroacetic acid [0377] THF
tetrahydrofuran
Intermediate 1
3-(3-Bromo-2-methylphenyl)-8-fluoroquinazoline-2,4(1H,3H)-dione
##STR00071##
[0378] Intermediate 1A:
2-Amino-N-(3-bromo-2-methylphenyl)-3-fluorobenzamide
##STR00072##
[0380] Method 1: A solution of
8-fluoro-1H-benzo[d][1,3]oxazine-2,4-dione (2.00 g, 11.04 mmol) and
3-bromo-2-methylaniline (4.11 g, 22.08 mmol) in dioxane (20 mL) in
sealed reaction vessels was heated at 110.degree. C. for 4 days.
The cooled mixture was treated with 10% aqueous K.sub.2CO.sub.3 and
stirred at room temperature for 30 min. The mixture was extracted
with DCM 3 times, and the combined organic phases were washed with
water, dried and concentrated. The residue was triturated with
ether to give a gray solid (2.50 g). The mother liquor was
concentrated and the residue was again triturated with ether to
give a gray solid (230 mg). The two solids were combined to provide
2-amino-N-(3-bromo-2-methylphenyl)-3-fluorobenzamide as a gray
solid (2.73 g, 78% yield). Mass spectrum m/z 323, 325
(M+H).sup.+.
[0381] Method 2. A suspension of
8-fluoro-1H-benzo[d][1,3]oxazine-2,4-dione (3.00 g, 16.6 mmol) in
xylenes (50 mL) was treated with 3-bromo-2-methylaniline (3.08 g,
16.6 mmol) and heated to reflux. After 6 h the mixture was allowed
to cool to room temperature overnight. The resulting suspension was
diluted with hexanes and the precipitate was collected by
filtration, rinsed with hexanes and air-dried to provide
2-amino-N-(3-bromo-2-methylphenyl)-3-fluorobenzamide as a white
solid (4.50 g, 84% yield). .sup.1H NMR (400 MHz, chloroform-d)
.delta. 7.69 (d, J=7.9 Hz, 1H), 7.65 (br. s., 1H), 7.50-7.46 (m,
1H), 7.32 (d, J=8.1 Hz, 1H), 7.19-7.11 (m, 2H), 6.73-6.64 (m, 1H),
5.69 (br. s., 2H), 2.44 (s, 3H).
Intermediate 1
[0382] A solution of
2-amino-N-(3-bromo-2-methylphenyl)-3-fluorobenzamide (5.70 g, 17.6
mmol) in THF (100 mL) was treated with bis(trichloromethyl)
carbonate (triphosgene) (6.28 g, 21.2 mmol) at room temperature and
stirred for 15 min. The mixture was diluted with EtOAc, carefully
treated with saturated aqueous NaHCO.sub.3 and stirred at room
temperature until gas evolution stopped. The separated organic
phase was washed sequentially with saturated aqueous NaHCO.sub.3,
water and brine, and was dried and concentrated. The residue was
triturated with ether to provide
3-(3-bromo-2-methylphenyl)-8-fluoroquinazoline-2,4(1H,3H)-dione as
an off-white solid (6.00 g, 97% yield). Mass spectrum m/z 349, 351
(M+H).sup.+. .sup.1H NMR (400 MHz, chloroform-d) .delta. 8.59 (d,
J=17.6 Hz, 1H), 7.99 (d, J=8.1 Hz, 1H), 7.70 (dd, J=7.8, 1.2 Hz,
1H), 7.54-7.43 (m, 1H), 7.28-7.21 (m, 2H), 7.21-7.17 (m, 1H), 2.28
(s, 3H).
Intermediate 2
8-Fluoro-1-methyl-3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2--
yl)phenyl)quinazoline-2,4(1H,3H)-dione
##STR00073##
[0383] Intermediate 2A:
3-(3-Bromo-2-methylphenyl)-8-fluoro-1-methylquinazoline-2,4(1H,3H)-dione
##STR00074##
[0385] A solution of
3-(3-bromo-2-methylphenyl)-8-fluoroquinazoline-2,4(1H,3H)-dione[Intermedi-
ate 1] (4.80 g, 13.8 mmol) in DMF (25 mL) was treated with
Cs.sub.2CO.sub.3 (13.4 g, 41.2 mmol). The suspension was stirred at
room temperature and treated dropwise (but quickly) with
iodomethane (4.30 mL, 68.7 mmol) and stirred rapidly at room
temperature for 1 h. The mixture was diluted with EtOAc and water
(200 mL). The organic phase was separated and washed sequentially
with water and brine, then was dried and concentrated to provide
3-(3-bromo-2-methylphenyl)-8-fluoro-1-methylquinazoline-2,4(1H,3H)-dione
as a tan glassy foam (4.80 g, 96% yield). Mass spectrum m/z 363,
365 (M+H).sup.+.
Intermediate 2
[0386] A mixture of
3-(3-bromo-2-methylphenyl)-8-fluoro-1-methylquinazoline-2,4(1H,3H)-dione
(4.80 g, 13.2 mmol),
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (4.36
g, 17.2 mmol), potassium acetate (3.89 g, 39.6 mmol) and
PdCl.sub.2(dppf) DCM adduct (0.540 g, 0.661 mmol) in dioxane (65
mL) was heated to reflux for 2 h. After cooling to room
temperature, the mixture was filtered through CELITE.RTM. and the
solids were rinsed with EtOAc. The filtrate was diluted with EtOAc,
washed with water, and dried and concentrated. The residue was
subjected to column chromatography on silica gel (80 g), eluting
with EtOAc-hexanes (gradient from 20-50%), to provide
8-fluoro-1-methyl-3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
-yl)phenyl) quinazoline-2,4(1H,3H)-dione as a white solid (4.61 g,
85% yield). Mass spectrum m/z 411 (M+H).sup.+. .sup.1H NMR (400
MHz, chloroform-d) .delta. 8.14-8.08 (m, 1H), 7.93 (dd, J=7.5, 1.3
Hz, 1H), 7.48 (ddd, J=14.0, 8.0, 1.5 Hz, 1H), 7.34 (t, J=7.6 Hz,
1H), 7.27-7.20 (m, 2H), 3.88 (d, J=7.9 Hz, 3H), 2.36 (s, 3H), 1.36
(s, 12H).
Intermediate 3
4-Bromo-3-chloro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
##STR00075##
[0388] Intermediate 3A: Ethyl
5-bromo-8-carbamoyl-6-chloro-9H-carbazole-2-carboxylate
##STR00076##
[0389] A mixture of ethyl
5-bromo-8-carbamoyl-9H-carbazole-2-carboxylate [synthesized
according to the procedure described in U.S. Pat. No. 8,084,620,
Intermediate 48-1] (0.100 g, 0.277 mmol) and NCS (recrystallized
from toluene; 0.037 g, 0.277 mmol) in CCl.sub.4 (10 mL) and DMF (2
mL) was stirred at room temperature for 112 h. The mixture was
filtered, and the collected precipitate was washed with CCl.sub.4
and dried overnight under vacuum. The residue was purified by
column chromatography on silica gel (40 g), eluting with hexanes,
then with EtOAc-hexanes (30%, then 50%), to give ethyl
5-bromo-8-carbamoyl-6-chloro-9H-carbazole-2-carboxylate as a fluffy
white solid (0.071 g, 65% yield). Mass spectrum m/z 395, 397,
(M+H).sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 12.13 (s,
1H), 8.77 (d, J=8.6 Hz, 1H), 8.53 (d, J=1.1 Hz, 1H), 8.36 (br. s.,
1H), 8.29 (s, 1H), 7.89 (dd, J=8.4, 1.5 Hz, 1H), 7.74 (br. s., 1H),
4.38 (q, J=7.0 Hz, 2H), 1.38 (t, J=7.0 Hz, 3H).
Alternative Preparation of Intermediate 3A
[0390] To a mixture of ethyl
5-bromo-8-carbamoyl-9H-carbazole-2-carboxylate (90 g, 249 mmol),
CCl.sub.4 (2900 mL), and NMP (600 mL) was added NCS (36.1 g, 271
mmol). The reaction mixture was stirred at 45.degree. C. for 2 h.
After cooling to room temperature, the solid was collected by
vacuum filtration. The solid was stirred in methanol (1 L) at
60.degree. C. for 2 h and then cooled to room temperature. The
solid was collected and dried to give ethyl
5-bromo-8-carbamoyl-6-choro-9H-carbazole-2-carboxylate (69.5 g, 167
mmol, 67% yield) (95% purity).
[0391] The filtrate was concentrated under reduced pressure to
remove CCl.sub.4. To the NMP residue was then added water (2 L).
The resulting precipitate was collected and dried to give an
additional 13.7 g of product (25% yield, 75% purity).
Intermediate 3
[0392] A solution of ethyl
5-bromo-8-carbamoyl-6-chloro-9H-carbazole-2-carboxylate (4.14 g,
10.5 mmol) in THF (200 mL) cooled in a dry ice-acetone bath was
treated portionwise over 30 min with 1.6 M methyllithium in hexanes
(45.8 mL, 73.2 mmol). The mixture was stirred at -78.degree. C. for
60 min, then was treated portionwise with saturated aqueous
NH.sub.4Cl. Water was added and the mixture was extracted twice
with EtOAc. The combined organic phases were washed twice with
water. All aqueous phases were combined and extracted with DCM, and
this organic phase was washed with water. All organic phases were
combined, dried and concentrated. The residue was crystallized from
EtOAc to give a solid. The residue from concentration of the mother
liquor was purified by chromatography on silica gel (330 g),
eluting with EtOAc-hexanes (gradient from 0-100%), to give
additional solid. The two solids were combined to give
4-bromo-3-chloro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
as a light yellow solid (3.13 g, 78% yield). Mass spectrum m/z 363,
365, (M+H--H.sub.2O).sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 11.71 (s, 1H), 8.56 (d, J=8.6 Hz, 1H), 8.29 (br. s., 1H),
8.17 (s, 1H), 7.97 (d, J=1.3 Hz, 1H), 7.66 (br. s., 1H), 7.42 (dd,
J=8.6, 1.8 Hz, 1H), 1.52 (s, 6H).
Alternative Preparation of Intermediate 3
[0393] A suspension of ethyl
5-bromo-8-carbamoyl-6-chloro-9H-carbazole-2-carboxylate (58.56 g,
148 mmol) in THF (700 mL) under nitrogen was cooled to -15.degree.
C. in an acetone-dry ice bath. The mixture was treated dropwise
with 3 M methylmagnesium chloride in THF (395 mL, 1.19 mol) at a
rate that the internal temperature remained between -15.degree. C.
and -10.degree. C. After 5 h the mixture was poured into 3 vessels,
each containing ca. 1.5 L of crushed ice and 500 mL of saturated
aqueous NH.sub.4Cl. The resulting mixtures were extracted with
EtOAc, and the combined organic phases were dried and
concentrated.
[0394] The residue was combined with material from two additional
batches, one starting from 146 mmol of ethyl
5-bromo-8-carbamoyl-6-chloro-9H-carbazole-2-carboxylate and the
other starting from 142 mmol of ethyl
5-bromo-8-carbamoyl-6-chloro-9H-carbazole-2-carboxylate, and
stirred for 1 h in acetone (250 mL). The precipitate was collected
by filtration, washed with hexane and dried to provide
4-bromo-3-chloro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
as a solid (134.56 g). The filtrate was concentrated and the
residue was again stirred for 1 h in acetone, forming a precipitate
which was collected by filtration, washed with hexane and dried to
give additional
4-bromo-3-chloro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
as a solid (7.36 g) for a total of 141.92 g (88% yield). The
filtrate from the second filtration was combined with impure
material from other batches and subjected to column chromatography
on silica gel (2.times.1.5 kg), eluting with EtOAc-hexanes
(gradient from 40-100%), providing additional product.
Intermediate 4
1-Methyl-3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl-
)quinazoline-2,4(1H,3H)-dione
##STR00077##
[0395] Intermediate 4A:
2-Amino-N-(3-bromo-2-methylphenyl)benzamide
##STR00078##
[0397] Method 1. A solution of 2-aminobenzoic acid (5.00 g, 36.5
mmol) and thionyl chloride (8.68 g, 72.9 mmol) in toluene (50 mL)
was heated at reflux for 60 min. The mixture was concentrated in
vacuo, and the residue was suspended in THF (50 mL), cooled in an
ice-water bath and treated with 3-bromo-2-methylaniline (20.35 g,
109 mmol). The resulting suspension was heated at reflux for 2 h.
The cooled mixture was treated with 10% aqueous K.sub.2CO.sub.3 (50
mL), stirred vigorously for 15 min, and extracted with EtOAc. The
organic phase was dried and concentrated. The residue was purified
by column chromatography on silica gel to give
2-amino-N-(3-bromo-2-methylphenyl) benzamide as a light yellow
solid (4.70 g, 42% yield). Mass spectrum m/z 305, 307 (M+H).sup.+.
.sup.1H NMR (400 MHz, chloroform-d) .delta. 7.72 (d, J=7.9 Hz, 1H),
7.67 (br. s., 1H), 7.54 (dd, J=8.3, 1.2 Hz, 1H), 7.48 (dd, J=7.9,
0.9 Hz, 1H), 7.36-7.31 (m, 1H), 7.15 (t, J=8.0 Hz, 1H), 6.81-6.73
(m, 2H), 5.59 (br. s., 2H), 2.45 (s, 3H).
[0398] Method 2. A suspension of 1H-benzo[d][1,3]oxazine-2,4-dione
(5.00 g, 30.7 mmol) and 3-bromo-2-methylaniline (5.70 g, 30.7 mmol)
in xylenes (50 mL) was heated at reflux for 8 h. The solvent was
removed by distillation and the residue was purified by column
chromatography on silica gel (120 g), eluting with EtOAc-hexanes
(gradient from 0-50%), to give
2-amino-N-(3-bromo-2-methylphenyl)benzamide as an off-white solid
(2.30 g, 24% yield).
[0399] Method 3. A suspension of 1H-benzo[d][1,3]oxazine-2,4-dione
(10.00 g, 61.3 mmol) in DMF (150 mL) was treated with
3-bromo-2-methylaniline (13.69 g, 73.6 mmol) and heated to reflux
overnight. The cooled mixture was diluted with water and extracted
with EtOAc. The whole mixture was filtered to remove grey solids
and the layers of the filtrate were separated. The organic phase
was washed with water, dried and concentrated. The residue was
purified by column chromatography on silica gel (330 g), eluting
with EtOAc-hexanes (gradient from 0-50%), to give
2-amino-N-(3-bromo-2-methylphenyl)benzamide as tan solid (1.1 g, 6%
yield). A second eluent from the column gave
3-(3-bromo-2-methylphenyl)quinazoline-2,4(1H,3H)-dione
[Intermediate 4B] as a tan solid (3.4 g, 17% yield).
Intermediate 4B:
3-(3-Bromo-2-methylphenyl)quinazoline-2,4(1H,3H)-dione
##STR00079##
[0401] A solution of 2-amino-N-(3-bromo-2-methylphenyl)benzamide
(2.00 g, 6.55 mmol) in THF (50 mL) was treated with
bis(trichloromethyl)carbonate[triphosgene] (2.92 g, 9.83 mmol) and
heated at reflux for 60 min. The cooled mixture was treated with
saturated aqueous NaHCO.sub.3, extracted with EtOAc, and the
combined organic phases were washed twice with saturated
NaHCO.sub.3, then with water, dried and concentrated. The residue
was triturated with DCM to give a white solid which was collected
by filtration. The residue from concentration of the filtrate was
triturated with DCM to give additional white solid which was
collected by filtration. The two solids were combined to give
3-(3-bromo-2-methylphenyl)quinazoline-2,4(1H,3H)-dione as a white
solid (2.10 g, 97% yield). Mass spectrum m/z 331, 333 (M+H).sup.+.
.sup.1H NMR (400 MHz, MeOH-d.sub.4) .delta. 8.07 (dd, J=7.92, 1.32
Hz, 1H), 7.65-7.75 (m, 2H), 7.21-7.32 (m, 4H), 2.20 (s, 3H).
.sup.1H NMR (400 MHz, chloroform-d) .delta. 9.38 (br. s., 1H), 8.19
(dd, J=7.9, 1.1 Hz, 1H), 7.76-7.69 (m, 1H), 7.69-7.60 (m, 1H),
7.35-7.17 (m, 3H), 7.04-6.97 (m, 1H), 2.28 (s, 3H).
Intermediate 4C:
3-(3-Bromo-2-methylphenyl)-1-methylquinazoline-2,4(1H,3H)-dione
##STR00080##
[0403] A suspension of
3-(3-bromo-2-methylphenyl)quinazoline-2,4(1H,3H)-dione (23.02 g,
69.5 mmol) and Cs.sub.2CO.sub.3 (34.0 g, 104 mmol) in DMF (70 mL)
cooled in an ice-water bath was treated portionwise with
iodomethane (5.22 mL, 83 mmol). The mixture was warmed to room
temperature and stirred for 30 min. The mixture was filtered and
the filtrate was concentrated. The residue was partitioned between
EtOAc and water. A precipitate which formed was collected by
filtration. The collected solid was washed with water and dried
overnight under vacuum to give a white solid. The organic phase of
the filtrate was separated, washed 3 times with 10% aqueous LiCl,
then was washed twice with water, dried and concentrated to give
additional solid. The two solids were combined to give
3-(3-bromo-2-methylphenyl)-1-methylquinazoline-2,4(1H,3H)-dione as
a white solid (15.56 g, 92% yield). Mass spectrum m/z 345, 347
(M+H).sup.+.
Intermediate 4
[0404] A mixture of
3-(3-bromo-2-methylphenyl)-1-methylquinazoline-2,4(1H,3H)-dione
(36.39 g, 105 mmol),
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (40.2
g, 158 mmol), PdCl.sub.2(dppf) DCM adduct (4.30 g, 5.27 mmol) and
potassium acetate (31.0 g, 316 mmol) in dioxane (500 mL) and DMSO
(50 mL) was heated at reflux for 24 h. Additional PdCl.sub.2(dppf)
DCM adduct (1.47 g) was added and the mixture was heated at reflux
for 6 h more. The cooled mixture was filtered through CELITE.RTM.
and the filtrate was concentrated. The residue was diluted with
EtOAc, shaken with water, and both phases were filtered through
CELITE.RTM. to remove a black precipitate. The organic phase of the
filtrate was separated, washed sequentially with water and brine,
dried and concentrated. The residue was purified by column
chromatography on silica gel (two 330 g columns), eluting with
EtOAc-hexanes (gradient from 20-100%). The resulting solid was
triturated with EtOAc to give a solid which was collected by
filtration. The filtrate was concentrated and crystallized from
EtOAc to give additional solid. The mother liquor from this
crystallization was concentrated and the residue was purified by
column chromatography on silica gel (330 g), eluting with
EtOAc-hexanes (gradient from 20-50%), to give additional solid. The
three solids were combined to give
1-methyl-3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pheny-
l) quinazoline-2,4(1H,3H)-dione as a white solid (21.2 g, 51%
yield). Mass spectrum m/z 393 (M+H).sup.+. .sup.1H NMR (400 MHz)
.delta. 8.35 (d, J=7.9 Hz, 1H), 7.64 (ddd, J=8.5, 7.3, 1.5 Hz, 1H),
7.59 (dd, J=7.4, 1.4 Hz, 1H), 7.33-7.27 (m, 1H), 7.24-7.17 (m, 1H),
7.12 (d, J=8.1 Hz, 2H), 3.55 (s, 3H), 1.59 (s, 3H), 1.39 (s,
12H).
Intermediate 5
8-Chloro-1-methyl-3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2--
yl)phenyl)quinazoline-2,4(1H,3H)-dione
##STR00081##
[0405] Intermediate 5A:
2-Amino-N-(3-bromo-2-methylphenyl)-3-chlorobenzamide
##STR00082##
[0407] A suspension of 8-chloro-1H-benzo[d][1,3]oxazine-2,4-dione
(4.00 g, 20.3 mmol) and 3-bromo-2-methylaniline (5.65 g, 30.4 mmol)
in xylene (20 mL) was heated at reflux for 2.5 h. The cooled
mixture formed a yellow precipitate. The mixture was diluted with
hexanes, and the precipitate was collected by filtration, washed
with hexanes and dried to give
2-amino-N-(3-bromo-2-methylphenyl)-3-chlorobenzamide as a yellow
solid (6.28 g, 91% yield). Mass spectrum m/z 339, 341 (M+H).sup.+.
.sup.1H NMR (400 MHz, chloroform-d) .delta. 7.68 (d, J=8.1 Hz, 1H),
7.61 (br. s., 1H), 7.52-7.43 (m, 3H), 7.15 (t, J=8.0 Hz, 1H), 6.70
(t, J=7.8 Hz, 1H), 6.12 (br. s., 2H), 2.44 (s, 3H).
Intermediate 5B:
3-(3-Bromo-2-methylphenyl)-8-chloroquinazoline-2,4(1H,3H)-dione
##STR00083##
[0409] A solution of
2-amino-N-(3-bromo-2-methylphenyl)-3-chlorobenzamide (780 mg, 2.30
mmol) in THF (20 mL) was treated with bis(trichloromethyl)
carbonate (1.02 g, 3.45 mmol) and the solution stirred at room
temperature for 21 h. The mixture was diluted with DCM and washed
sequentially with saturated aqueous NaHCO.sub.3, water and
brine.
[0410] The organic phase was dried and concentrated. The residue
was purified by column chromatography on silica gel (80 g), eluting
with EtOAc-hexanes (gradient from 25-50%), to give
3-(3-bromo-2-methylphenyl)-8-chloroquinazoline-2,4(1H,3H)-dione as
a white solid (800 mg, 95% yield). Mass spectrum m/z 365, 367
(M+H)+.
Intermediate 5C:
3-(3-Bromo-2-methylphenyl)-8-chloro-1-methylquinazoline-2,4(1H,3H)-dione
##STR00084##
[0412] A solution of
3-(3-bromo-2-methylphenyl)-8-chloroquinazoline-2,4(1H,3H)-dione
(1.45 g, 3.97 mmol) in DMF (15 mL) was treated with
Cs.sub.2CO.sub.3 (3.88 g, 11.9 mmol) and iodomethane (2.48 mL, 39.7
mmol) and stirred at room temperature for 1.5 h. The mixture was
diluted with water and a mixture of EtOAc and hexanes. The organic
phase was washed with water, dried and concentrated. The residue
was purified by column chromatography on silica gel (80 g), eluting
with EtOAc-hexanes (gradient from 5-40%), to give
3-(3-bromo-2-methylphenyl)-8-chloro-1-methylquinazoline-2,4(1H,3H)-dione
as a white solid (1.3 g, 81% yield). Mass spectrum m/z 379, 391
(M+H).sup.+.
Intermediate 5
[0413] A solution of
3-(3-bromo-2-methylphenyl)-8-chloro-1-methylquinazoline-2,4(1H,3H)-dione
(1.14 g, 3.00 mmol) in dioxane (20 mL) was treated with
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (0.915
g, 3.60 mmol), potassium acetate (0.884 g, 9.01 mmol), and
PdCl.sub.2(dppf) DCM adduct (0.123 g, 0.150 mmol). The mixture was
sealed in a pressure reaction vial and heated at 110.degree. C. for
4 h. The cooled mixture was diluted with EtOAc, filtered through
CELITE.RTM., and the filtrate was washed with water, dried and
concentrated. The residue was purified by column chromatography on
silica gel (80 g), eluting with EtOAc-hexanes (gradient from
20-50%), to give
8-chloro-1-methyl-3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
-yl)phenyl)quinazoline-2,4(1H,3H)-dione as a white solid (1.00 g,
78% yield). Mass spectrum m/z 427 (M+H).sup.+. .sup.1H NMR (400
MHz, chloroform-d) .delta. 8.23 (dd, J=7.8, 1.7 Hz, 1H), 7.93 (dd,
J=7.5, 1.3 Hz, 1H), 7.76 (dd, J=7.9, 1.5 Hz, 1H), 7.37-7.31 (m,
1H), 7.27-7.20 (m, 2H), 3.94 (s, 3H), 2.36 (s, 3H), 1.36 (s,
15H).
Intermediates 6 and 7
8-Chloro-1-methyl-3-(S)-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborola-
n-2-yl)phenyl)quinazoline-2,4(1H,3H)-dione (I-6), and
8-Chloro-1-methyl-3-(R)-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborola-
n-2-yl)phenyl)quinazoline-2,4(1H,3H)-dione (I-7
##STR00085##
[0415] A sample of racemic
8-chloro-1-methyl-3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
-yl)phenyl)quinazoline-2,4(1H,3H)-dione [Intermediate 5] was
separated by chiral super-critical fluid chromatography as follows:
column: Regis WHELK-O.RTM. R,R (3.times.25 cm, 5 .mu.m); Mobile
Phase: CO.sub.2-MeOH (60:40) at 85 mL/min; sample preparation: 17
mg/mL in MeOH-MeCN (1:1). The first peak eluting from the column
provided the S enantiomer,
8-chloro-1-methyl-3-(S)-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-
an-2-yl)phenyl)quinazoline-2,4(1H,3H)-dione [Intermediate 6]. The
second peak eluting from the column gave the R enantiomer,
8-chloro-1-methyl-3-(R)-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-
an-2-yl)phenyl)quinazoline-2,4(1H,3H)-dione [Intermediate 7]. The
mass spectrum and .sup.1H NMR for each enantiomeric atropisomer
were the same as those for Intermediate 5.
Intermediate 8
8-Chloro-3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl-
)quinazoline-2,4(1H,3H)-dione
##STR00086##
[0417] A mixture of
3-(3-bromo-2-methylphenyl)-8-chloroquinazoline-2,4(1H,3H)-dione
[Intermediate 5B] (1.00 g, 2.74 mmol),
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (0.833
g, 3.28 mmol), potassium acetate (0.805 g, 8.21 mmol) and
PdCl.sub.2(dppf) DCM adduct (0.112 g, 0.137 mmol) in dioxane (20
mL) was heated at 90.degree. C. for 8 h. The cooled mixture was
filtered, concentrated, and the residue was partitioned between DCM
and water. The organic phase was dried and concentrated, and the
residue was purified by column chromatography on silica gel (120
g), eluting with EtOAc-DCM (gradient from 0-10%), to give
8-chloro-3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pheny-
l)quinazoline-2,4(1H,3H)-dione (782 mg, 58% yield). Mass spectrum
m/z 413 (M+H).sup.+.
Intermediate 9
1,8-Dimethyl-3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ph-
enyl)quinazoline-2,4(1H,3H)-dione
##STR00087##
[0418] Intermediate 9A:
2-Amino-N-(3-bromo-2-methylphenyl)-3-methylbenzamide
##STR00088##
[0420] A mixture of thionyl chloride (3.15 g, 26.5 mmol) and
2-amino-3-methylbenzoic acid (2.00 g, 13.23 mmol) in THF (50 mL)
was heated at reflux for 2 h. The cooled mixture was concentrated
and the residue was combined with 3-bromo-2-methylaniline (4.92 g,
26.5 mmol) in THF (50 mL) and heated at reflux for 5 h. The mixture
was cooled to room temperature, treated with 10% aqueous
K.sub.2CO.sub.3 and stirred at room temperature for 30 min. The
resulting mixture was extracted 3 times with DCM, and the combined
organic phases were washed with water, dried and concentrated. The
residue was purified by column chromatography on silica gel (330
g), eluting with EtOAc-hexanes (gradient from 0-20%), to give
2-amino-N-(3-bromo-2-methylphenyl)-3-methylbenzamide as a yellow
solid (1.71 g, 40% yield). Mass spectrum m/z 319, 321 (M+H).sup.+.
.sup.1H NMR (400 MHz, chloroform-d) .delta. 7.70 (d, J=7.9 Hz, 1H),
7.64 (br. s., 1H), 7.50-7.40 (m, 2H), 7.24 (d, J=7.3 Hz, 1H), 7.14
(t, J=8.0 Hz, 1H), 6.70 (t, J=7.6 Hz, 1H), 5.67 (br. s., 2H), 2.44
(s, 3H), 2.23 (s, 3H).
Intermediate 9B:
3-(3-Bromo-2-methylphenyl)-8-methylquinazoline-2,4(1H,3H)-dione
##STR00089##
[0422] A solution of
2-amino-N-(3-bromo-2-methylphenyl)-3-methylbenzamide (1.71 g, 5.36
mmol) and triphosgene (2.07 g, 6.96 mmol) in THF (20 mL) was heated
at reflux for 1 h. The mixture was cooled on an ice-water bath and
treated with saturated aqueous NaHCO.sub.3. Stirring was continued
until gas evolution ceased. The resulting mixture was extracted 3
times with DCM. The combined organic phases were washed with water,
dried and concentrated. The residue was triturated with ether to
give a white solid, collected by filtration. A second trituration
of the concentrated filtrate gave additional solid, collected by
filtration. The filtrate from this was concentrated and purified by
column chromatography on silica gel (40 g), eluting with
EtOAc-hexanes (gradient from 0-100%), to provide additional solid.
The three solids were combined to provide
3-(3-bromo-2-methylphenyl)-8-methylquinazoline-2,4(1H,3H)-dione as
a white solid (1.69 g, 91% yield). Mass spectrum m/z 345, 347
(M+H).sup.+. .sup.1H NMR (400 MHz, chloroform-d): .delta. 8.07 (d,
J=7.9 Hz, 1H), 7.70 (dd, J=7.9, 1.3 Hz, 1H), 7.54 (d, J=7.3 Hz,
1H), 7.27-7.17 (m, 3H), 2.41 (s, 3H), 2.28 (s, 3H).
Intermediate 9C:
3-(3-Bromo-2-methylphenyl)-1,8-dimethylquinazoline-2,4(1H,3H)-dione
##STR00090##
[0424] A mixture of
3-(3-bromo-2-methylphenyl)-8-methylquinazoline-2,4(1H,3H)-dione
(470 mg, 1.36 mmol) and Cs.sub.2CO.sub.3 (1.33 g, 4.08 mmol) in DMF
(8 mL) was treated with iodomethane (0.85 mL, 13.6 mmol) and
stirred at room temperature for 1.5 h. The mixture was diluted with
EtOAc, washed sequentially with water and two portions of 10%
aqueous LiCl. The combined aqueous phases were extracted with
EtOAc. The combined organic phases were washed sequentially with
10% aqueous LiCl and water, dried and concentrated to give impure
3-(3-bromo-2-methylphenyl)-1,8-dimethylquinazoline-2,4(1H,3H)-dione
as a white solid (510 mg), used without further purification. Mass
spectrum m/z 359, 361 (M+H).sup.+.
Intermediate 9
[0425] Using the same procedure described for the preparation of
Intermediate 2,
3-(3-bromo-2-methylphenyl)-1,8-dimethylquinazoline-2,4(1H,3H)-dione
(489 mg, 1.36 mmol) was converted to
1,8-dimethyl-3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)p-
henyl)quinazoline-2,4(1H,3H)-dione as a white solid (410 mg, 74%
yield). Mass spectrum m/z 407 (M+H).sup.+.
Intermediates 10 and 11
8-Fluoro-1-methyl-3-(S)-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborola-
n-2-yl) phenyl)quinazoline-2,4(1H,3H)-dione (I-10), and
8-Fluoro-1-methyl-3-(R)-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborola-
n-2-yl)phenyl)quinazoline-2,4(1H,3H)-dione (I-11
##STR00091##
[0427] A sample of racemic
8-fluoro-1-methyl-3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
-yl)phenyl)quinazoline-2,4(1H,3H)-dione [Intermediate 2] was
separated by chiral super-critical fluid chromatography as follows:
column: (R,R)-WHELK-O.RTM. 1 (3.times.25 cm, 5 .mu.m); Mobile
Phase: CO.sub.2-MeOH (70:30) at 200 mL/min, 100 bar, 30.degree. C.;
sample preparation: 97.3 mg/mL in MeOH:DCM (1:1); injection; 4 mL.
The first peak eluting from the column provided the (S) isomer,
8-fluoro-1-methyl-3-(S)-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-
an-2-yl)phenyl)quinazoline-2,4(1H,3H)-dione [Intermediate 10] as a
white solid. Mass spectrum m/z 411 (M+H).sup.+. .sup.1H NMR (400
MHz, chloroform-d) .delta. 8.14-8.08 (m, 1H), 7.93 (dd, J=7.5, 1.3
Hz, 1H), 7.48 (ddd, J=14.0, 8.0, 1.5 Hz, 1H), 7.34 (t, J=7.6 Hz,
1H), 7.27-7.20 (m, 2H), 3.88 (d, J=7.9 Hz, 3H), 2.36 (s, 3H), 1.36
(s, 12H).
[0428] The second peak eluting from the column provided the (R)
isomer,
8-fluoro-1-methyl-3-(R)-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-
an-2-yl)phenyl) quinazoline-2,4(1H,3H)-dione [Intermediate 11] as a
white solid. Mass spectrum m/z 411 (M+H).sup.+. .sup.1H NMR (400
MHz, chloroform-d) .delta. 8.13-8.08 (m, 1H), 7.93 (dd, J=7.5, 1.3
Hz, 1H), 7.48 (ddd, J=13.9, 8.1, 1.5 Hz, 1H), 7.37-7.31 (m, 1H),
7.27-7.20 (m, 2H), 3.88 (d, J=7.9 Hz, 3H), 2.36 (s, 3H), 1.36 (s,
12H).
Alternative Preparation of Intermediate 10
[0429] A solution of
8-fluoro-3-(2-methyl-3-(S)-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)p-
henyl)quinazoline-2,4(1H,3H)-dione [Intermediate 19] (40 g, 101
mmol) in tetrahydrofuran (400 mL) was treated with cesium carbonate
(99 g, 303 mmol) and iodomethane (12.6 mL, 202 mmol). The resulting
cloudy solution was stirred at room temperature overnight. Water
(300 mL) was added and the reaction mixture was extracted with
EtOAc (3.times.150 mL). The combined organic phases were washed
sequentially with brine and water, and dried and concentrated. The
residue was purified by recrystallization from EtOAc to provide
8-fluoro-1-methyl-3-(S)-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-
an-2-yl)phenyl)quinazoline-2,4(1H,3H)-dione as a white solid (38 g,
92% yield).
Intermediate 12
3-(3-Bromo-2-methylphenyl)-8-methoxy-1-methylquinazoline-2,4(1H,3H)-dione
##STR00092##
[0430] Intermediate 12A:
2-Amino-N-(3-bromo-2-methylphenyl)-3-methoxybenzamide
##STR00093##
[0432] A mixture of 3-bromo-2-methylaniline (482 mg, 2.59 mmol) and
8-methoxy-1H-benzo[d][1,3]oxazine-2,4-dione (500 mg, 2.59 mmol) in
toluene (20 mL) was treated with 2 M trimethylaluminum in toluene
(3.24 mL, 6.47 mmol) at 0.degree. C. The mixture was stirred at
room temperature for 10 minutes, then was heated at 70.degree. C.
overnight. The mixture was cooled to room temperature, treated with
1 N aqueous HCl and extracted 3 times with EtOAc. The combined
organic phases were washed sequentially with saturated aqueous
NaHCO.sub.3 and water, dried and concentrated. The residue was
subjected to column chromatography on silica gel (40 g), eluting
with EtOAc-hexanes (gradient from 0-100%), to provide
2-amino-N-(3-bromo-2-methylphenyl)-3-methoxybenzamide as a white
solid (302 mg, 35% yield). Mass spectrum m/z 335, 337 (M+H).sup.+.
.sup.1H NMR (400 MHz, chloroform-d) .delta. 7.72 (d, J=7.3 Hz, 2H),
7.46 (dd, J=8.0, 0.8 Hz, 1H), 7.17-7.10 (m, 2H), 6.90 (dd, J=7.9,
0.9 Hz, 1H), 6.72-6.66 (m, 1H), 5.88 (br. s., 2H), 3.92 (s, 3H),
2.43 (s, 3H).
Intermediate 12B:
3-(3-Bromo-2-methylphenyl)-8-methoxyquinazoline-2,4(1H,3H)-dione
##STR00094##
[0434] A solution of
2-amino-N-(3-bromo-2-methylphenyl)-3-methoxybenzamide (302 mg,
0.901 mmol) and triphosgene (321 mg, 1.081 mmol) in THF (20 mL) was
stirred at room temperature for 2 h. The mixture was treated
carefully with saturated aqueous NaHCO.sub.3 and stirred until gas
evolution ceased. The mixture was extracted twice with DCM, and the
combined organic phases were washed with water, dried and
concentrated to provide
3-(3-bromo-2-methylphenyl)-8-methoxyquinazoline-2,4(1H,3H)-dione
(339 mg) which was used without further purification. Mass spectrum
m/z 361, 363 (M+H).sup.+.
Intermediate 12C:
3-(3-Bromo-2-methylphenyl)-8-methoxy-1-methylquinazoline-2,4(1H,3H)-dione
##STR00095##
[0436] A mixture of
3-(3-bromo-2-methylphenyl)-8-methoxyquinazoline-2,4(1H,3H)-dione
(535 mg, 1.48 mmol), iodomethane (0.185 mL, 2.96 mmol) and
Cs.sub.2CO.sub.3 (965 mg, 2.96 mmol) in THF (20 mL) was stirred at
room temperature overnight. The mixture was filtered and
concentrated. The residue was dissolved in DCM, washed sequentially
with saturated aqueous NaHCO.sub.3 and water, dried and
concentrated. The residue was purified by column chromatography on
silica gel (40 g silica), eluting with EtOAc-hexanes (gradient from
0-100%), to give
3-(3-bromo-2-methylphenyl)-8-methoxy-1-methylquinazoline-2,4(1H,3H)-dione
(442 mg). Mass spectrum m/z 375, 377 (M+H).sup.+. .sup.1H NMR (400
MHz, chloroform-d) .delta. 7.90 (dd, J=7.2, 2.3 Hz, 1H), 7.66 (dd,
J=8.0, 1.2 Hz, 1H), 7.31-7.22 (m, 2H), 7.22-7.19 (m, 1H), 7.17-7.13
(m, 1H), 3.97 (s, 3H), 3.89 (s, 3H), 2.23 (s, 3H).
Intermediate 12
[0437] A mixture of
3-(3-bromo-2-methylphenyl)-8-methoxy-1-methylquinazoline-2,4(1H,3H)-dione
(380 mg, 1.01 mmol),
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (309
mg, 1.22 mmol), potassium acetate (298 mg, 3.04 mmol) and
PdCl.sub.2(dppf) DCM adduct (41.4 mg, 0.051 mmol) in dioxane (20
mL) was heated at 90.degree. C. overnight. The cooled mixture was
filtered and the filtrate was concentrated. The residue was
purified by column chromatography on silica gel (24 g), eluting
with EtOAc-hexanes (gradient from 20-55%), to give
8-methoxy-1-methyl-3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan--
2-yl)phenyl)quinazoline-2,4(1H,3H)-dione in 75% purity, used
without further purification (486 mg, 85% yield). Mass spectrum m/z
423 (M+H).sup.+.
Intermediate 13
3-(3-Bromo-2-methylphenyl)-6-fluoro-1-methylquinazoline-2,4(1H,3H)-dione
##STR00096##
[0438] Intermediate 13A:
2-Amino-N-(3-bromo-2-methylphenyl)-5-fluorobenzamide
##STR00097##
[0440] A mixture of 3-bromo-2-methylaniline (1.50 g, 8.06 mmol) and
6-fluoro-1H-benzo[d][1,3]oxazine-2,4-dione (1.46 g, 8.06 mmol) in
toluene (40 mL) was cooled on an ice-water bath and treated
portionwise with 2 M trimethylaluminum in toluene (10.1 mL, 20.2
mmol). The mixture was stirred at room temperature for 30 min, then
was heated at 70.degree. C. overnight. The mixture was cooled to
0.degree. C., carefully treated with 1 M aqueous HCl, and extracted
3 times with EtOAc. The combined organic phases were washed
sequentially with saturated aqueous NaHCO.sub.3 and water, dried
and concentrated. The residue was subjected to column
chromatography on silica gel (120 g), eluting with EtOAc-hexanes
(gradient from 5-40%), to provide
2-amino-N-(3-bromo-2-methylphenyl)-5-fluorobenzamide (0.893 g, 87%
purity, 30% yield). Mass spectrum m/z 323, 325 (M+H).sup.+. .sup.1H
NMR (400 MHz, MeOH-d.sub.4) .delta. 7.54 (1H, dd, J=8.03, 0.99 Hz),
7.48 (1H, dd, J=9.68, 3.08 Hz), 7.33 (1H, d, J=7.26 Hz), 7.16 (1H,
t, J=7.92 Hz), 7.04-7.12 (1H, m), 6.83 (1H, dd, J=9.02, 4.62 Hz),
2.39 (3H, s).
Intermediate 13B:
3-(3-Bromo-2-methylphenyl)-6-fluoroquinazoline-2,4(1H,3H)-dione
##STR00098##
[0442] A solution of
2-amino-N-(3-bromo-2-methylphenyl)-5-fluorobenzamide (0.893 g, 2.76
mmol) and triphosgene (0.984 g, 3.32 mmol) in THF (30 mL) was
stirred at room temperature for 2 h. The mixture was carefully
treated with saturated aqueous NaHCO.sub.3 and stirred until gas
evolution ceased. The mixture was extracted twice with DCM. The
combined organic phases were washed with water, dried and
concentrated. The residue was triturated with DCM to give a white
solid, isolated by filtration. The filtrate was concentrated and
subjected to column chromatography on silica gel (40 g), eluting
with EtOAc-hexanes (gradient from 0-80%), to provide additional
solid. The two solids were combined to provide
3-(3-bromo-2-methylphenyl)-6-fluoroquinazoline-2,4(1H,3H)-dione as
a white solid (845 mg, 87% yield). Mass spectrum m/z 349, 351
(M+H).sup.+.
Intermediate 13C:
3-(3-Bromo-2-methylphenyl)-6-fluoro-1-methylquinazoline-2,4(1H,3H)-dione
##STR00099##
[0444] A mixture of
3-(3-bromo-2-methylphenyl)-6-fluoroquinazoline-2,4(1H,3H)-dione
(742 mg, 2.13 mmol), iodomethane (0.159 mL, 2.55 mmol) and
Cs.sub.2CO.sub.3 (1.039 g, 3.19 mmol) in THF (20 mL) was stirred at
room temperature overnight. The mixture was filtered and
concentrated. The residue was dissolved in DCM and washed
sequentially with saturated aqueous NaHCO.sub.3 and water, dried
and concentrated to provide
3-(3-bromo-2-methylphenyl)-6-fluoro-1-methylquinazoline-2,4(1H,3H)-dione
(742 mg, 96% yield). Mass spectrum m/z 363, 365 (M+H).sup.+.
Intermediate 13
[0445] A mixture of
3-(3-bromo-2-methylphenyl)-6-fluoro-1-methylquinazoline-2,4(1H,3H)-dione
(742 mg, 2.04 mmol),
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (623
mg, 2.45 mmol), potassium acetate (602 mg, 6.13 mmol) and
PdCl.sub.2(dppf) DCM adduct (83 mg, 0.102 mmol) in dioxane (20 mL)
was heated at 90.degree. C. overnight. The cooled mixture was
filtered and the filtrate was concentrated. The residue was
purified by column chromatography on silica gel (120 g), eluting
with EtOAc-hexanes (gradient from 0-40%), to give
6-fluoro-1-methyl-3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
-yl)phenyl)quinazoline-2,4(1H,3H)-dione (866 mg), used without
further purification. Mass spectrum m/z 411 (M+H).sup.+.
Intermediate 14
7-Methoxy-1-methyl-3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
-yl) phenyl)quinazoline-2,4(1H,3H)-dione
##STR00100##
[0446] Intermediate 14A:
2-Amino-N-(3-bromo-2-methylphenyl)-4-methoxybenzamide
##STR00101##
[0448] A mixture of 3-bromo-2-methylaniline (482 mg, 2.59 mmol)
7-methoxy-1H-benzo[d][1,3]oxazine-2,4-dione (500 mg, 2.59 mmol) in
toluene (20 mL) was treated with 2 M trimethylaluminum in toluene
(3.24 mL, 6.48 mmol) at 0.degree. C. The mixture was stirred at
room temperature for 10 min, then heated at 70.degree. C.
overnight. The cooled mixture was treated with 1 M aqueous HCl,
extracted 3 times with EtOAc, and the combined organic phases were
washed sequentially with saturated aqueous NaHCO.sub.3 and water,
dried and concentrated. The residue was purified by column
chromatography on silica gel (40 g), eluting with EtOAc-hexanes
(gradient from 0-100%), to give a 4:1 mixture of
2-amino-N-(3-bromo-2-methylphenyl)-4-methoxybenzamide and
3-(3-bromo-2-methylphenyl)-7-methoxyquinazoline-2,4(1H,3H)-dione
(592 mg). Mass spectrum m/z 335, 337 (M+H).sup.+.
Intermediate 14B:
3-(3-Bromo-2-methylphenyl)-7-methoxyquinazoline-2,4(1H,3H)-dione
##STR00102##
[0450] A solution of
2-amino-N-(3-bromo-2-methylphenyl)-4-methoxybenzamide (596 mg, 1.78
mmol) and triphosgene (633 mg, 2.13 mmol) in THF (30 mL) was
stirred at room temperature for 2 h. The mixture was treated with
saturated aqueous NaHCO.sub.3 and stirred until gas evolution
ceased. The resulting mixture was extracted twice with DCM, and the
combined organic phases were washed with water, dried and
concentrated. The residue was purified by column chromatography on
silica gel (40 g), eluting with EtOAc-hexanes (gradient from
0-100%), to give
3-(3-bromo-2-methylphenyl)-7-methoxyquinazoline-2,4(1H,3H)-dione as
a white solid (440 mg, 68% yield). Mass spectrum m/z 361, 363
(M+H).sup.+.
Intermediate 14C:
3-(3-Bromo-2-methylphenyl)-7-methoxy-1-methylquinazoline-2,4(1H,3H)-dione
##STR00103##
[0452] A solution of
3-(3-bromo-2-methylphenyl)-7-methoxyquinazoline-2,4(1H,3H)-dione
(440 mg, 1.22 mmol) in THF (30 mL) was treated with iodomethane
(303 mg, 2.13 mmol) and Cs.sub.2CO.sub.3 (869 mg, 2.67 mmol) at
room temperature. The mixture was stirred at room temperature
overnight, then was filtered and concentrated. The residue was
dissolved in DCM and washed sequentially with saturated aqueous
NaHCO.sub.3 and water, dried and concentrated to give
3-(3-bromo-2-methylphenyl)-7-methoxy-1-methylquinazoline-2,4(1H,3H)--
dione (502 mg), used without further purification. Mass spectrum
m/z 375, 377 (M+H).sup.+. .sup.1H NMR (400 MHz, chloroform-d)
.delta. 8.21 (d, J=8.8 Hz, 1H), 7.67 (dd, J=7.9, 1.3 Hz, 1H),
7.24-7.18 (m, 1H), 7.17-7.13 (m, 1H), 6.88 (dd, J=8.8, 2.2 Hz, 1H),
6.72 (d, J=2.2 Hz, 1H), 3.99 (s, 3H), 3.64 (s, 3H), 2.24 (s,
3H).
Intermediate 14
[0453] A mixture of
3-(3-bromo-2-methylphenyl)-7-methoxy-1-methylquinazoline-2,4(1H,3H)-dione
(390 mg, 1.04 mmol),
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (317
mg, 1.25 mmol), potassium acetate (306 mg, 3.12 mmol) and
PdCl.sub.2(dppf) DCM adduct (42.4 mg, 0.052 mmol) in dioxane (20
mL) was heated at 90.degree. C. overnight. The cooled mixture was
filtered and concentrated. The residue was purified by column
chromatography on silica gel (40 g), eluting with EtOAc-hexanes
(gradient from 10-55%), to give
7-methoxy-1-methyl-3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan--
2-yl)phenyl)quinazoline-2,4(1H,3H)-dione (504 mg, 76% purity, 87%
yield), used without further purification. Mass spectrum m/z 423
(M+H).sup.+.
Intermediate 15
7-Fluoro-1-methyl-3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2--
yl) phenyl)quinazoline-2,4(1H,3H)-dione
##STR00104##
[0454] Intermediate 15A:
2-Amino-N-(3-bromo-2-methylphenyl)-4-fluorobenzamide
##STR00105##
[0456] A mixture of 7-fluoro-1H-benzo[d][1,3]oxazine-2,4-dione
(5.00 g, 27.6 mmol) and 3-bromo-2-methylaniline (5.14 g, 27.6 mmol)
in xylene (50 mL) was heated at reflux for 8 h. The cooled mixture
was filtered. The collected solid was washed with 3 times with DCM
and the combined filtrates were concentrated. The residue was
purified by column chromatography on silica gel (330 g), eluting
with EtOAc-hexanes (gradient from 0-45%), to give
2-amino-N-(3-bromo-2-methylphenyl)-4-fluorobenzamide (3.65 g, 41%
yield). Mass spectrum m/z 323, 325 (M+H).sup.+. .sup.1H NMR (400
MHz, chloroform-d) .delta. 7.65 (1H, d, J=8.14 Hz), 7.45-7.57 (3H,
m), 7.14 (1H, t, J=8.03 Hz), 6.39-6.50 (2H, m), 5.80 (2H, br. s.),
2.43 (3H, s).
Intermediate 15B:
3-(3-Bromo-2-methylphenyl)-7-fluoroquinazoline-2,4(1H,3H)-dione
##STR00106##
[0458] A solution of
2-amino-N-(3-bromo-2-methylphenyl)-4-fluorobenzamide (3.65 g, 11.3
mmol) in THF (50 mL) was treated with triphosgene (3.69 g, 12.4
mmol) at room temperature. The solution was stirred at room
temperature for 2 h, then was treated slowly with saturated aqueous
NaHCO.sub.3 and stirred until no more gas evolution was observed.
The resulting mixture was extracted twice with EtOAc. The combined
organic phases were washed twice with water, then with brine, dried
and concentrated to give
3-(3-bromo-2-methylphenyl)-7-fluoroquinazoline-2,4(1H,3H)-dione
(4.20 g), used without further purification. Mass spectrum m/z 349,
351 (M+H).sup.+.
Intermediate 15C:
3-(3-Bromo-2-methylphenyl)-7-fluoro-1-methylquinazoline-2,4(1H,3H)-dione
##STR00107##
[0460] A mixture of
3-(3-bromo-2-methylphenyl)-7-fluoroquinazoline-2,4(1H,3H)-dione
(2.70 g, 7.73 mmol), iodomethane (0.580 mL, 9.28 mmol) and
Cs.sub.2CO.sub.3 (3.78 g, 11.6 mmol) in THF (20 mL) was stirred at
room temperature for 3 h. The mixture was filtered and the filtrate
was diluted with DCM and washed with water. The aqueous phase was
extracted with DCM, and the combined organic phases were dried and
concentrated to give
3-(3-bromo-2-methylphenyl)-7-fluoro-1-methylquinazoline-2,4(1H,3H)-dione
(2.85 g), used without further purification. Mass spectrum m/z 363,
365 (M+H).sup.+, 385, 387 (M+Na).sup.+.
Intermediate 15
[0461] A mixture of
3-(3-bromo-2-methylphenyl)-7-fluoro-1-methylquinazoline-2,4(1H,3H)-dione
(2.81 g, 7.74 mmol),
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (2.36
g, 9.28 mmol), potassium acetate (1.52 g, 15.5 mmol) and
PdCl.sub.2(dppf) DCM adduct (0.190 g, 0.232 mmol) in dioxane (20
mL) was heated at 90.degree. C. for 8 h. Additional
PdCl.sub.2(dppf) DCM adduct (0.190 g, 0.232 mmol) and potassium
acetate (0.80 g) were added and the mixture was heated at
90.degree. C. for another 7 h. The cooled mixture was diluted with
EtOAc and washed sequentially with saturated aqueous NaHCO.sub.3
and water. The combined aqueous phases were extracted with EtOAc.
The combined organic phases were filtered through CELITE.RTM. and
concentrated. The residue was purified by column chromatography on
silica gel (220 g), eluting with EtOAc-hexanes (gradient from
0-40%), to give
7-fluoro-1-methyl-3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
-yl)phenyl)quinazoline-2,4(1H,3H)-dione (1.76 g, 56% yield). Mass
spectrum m/z 411 (M+H).sup.+.
Intermediate 16
6,8-Difluoro-3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)
phenyl)quinazoline-2,4(1H,3H)-dione
##STR00108##
[0462] Intermediate 16A:
N-(3-Bromo-2-methylphenyl)-3,5-difluoro-2-nitrobenzamide
##STR00109##
[0464] A solution of 3,5-difluoro-2-nitrobenzoic acid (522 mg, 2.57
mmol) in DCM (10 mL) was treated with oxalyl chloride (0.337 mL,
3.86 mmol), then with DMF (3 drops). The resulting solution was
stirred at room temperature for 60 min. The mixture was
concentrated and the residue was re-concentrated twice from dry
DCM. The residue was dissolved in DCM (10 mL) and treated dropwise
with 3-bromo-2-methylaniline (478 mg, 2.57 mmol), followed by
dropwise addition of TEA (0.537 mL, 3.86 mmol). The resulting
mixture was stirred at room temperature overnight. The mixture was
treated with saturated aqueous NaHCO.sub.3, forming a white
precipitate. The organic phase was separated, and the aqueous phase
and the white solid were extracted twice with DCM, then filtered.
The collected solid was washed with water and dried. The combined
organic phases were dried and concentrated, and the residue was
triturated with DCM to give additional solid. Both solids were
combined with DCM and MeOH and concentrated to give
N-(3-bromo-2-methylphenyl)-3,5-difluoro-2-nitrobenzamide (821 mg,
86% yield). Mass spectrum m/z 371, 373 (M+H).sup.+393, 395
(M+Na).sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 10.65 (s,
1H), 7.98-7.90 (m, 1H), 7.81 (d, J=8.1 Hz, 1H), 7.55 (d, J=7.9 Hz,
1H), 7.40 (d, J=7.7 Hz, 1H), 7.21 (t, J=7.9 Hz, 1H), 2.32 (s,
3H).
Intermediate 16B:
2-Amino-N-(3-bromo-2-methylphenyl)-3,5-difluorobenzamide
##STR00110##
[0466] A mixture of
N-(3-bromo-2-methylphenyl)-3,5-difluoro-2-nitrobenzamide (821 mg,
2.21 mmol), NH.sub.4Cl (1.18 g, 22.1 mmol) and zinc (1.45 g, 22.1
mmol) in MeOH (10 mL) was stirred at room temperature for 60 min.
The mixture was filtered and the filtrate was concentrated. The
residue was suspended in DCM and washed with saturated aqueous
NaHCO.sub.3. The organic phase, with an insoluble precipitate, was
separated from the aqueous phase and concentrated to give
2-amino-N-(3-bromo-2-methylphenyl)-3,5-difluorobenzamide (760 mg),
used without further purification. Mass spectrum m/z 341, 343
(M+H).sup.+, 363, 365 (M+Na).sup.+.
Intermediate 16C:
3-(3-Bromo-2-methylphenyl)-6,8-difluoroquinazoline-2,4(1H,3H)-dione
##STR00111##
[0468] A solution of
2-amino-N-(3-bromo-2-methylphenyl)-3,5-difluorobenzamide (760 mg,
2.23 mmol) in THF (10 mL) was treated portionwise with triphosgene
(722 mg, 2.43 mmol). The solution was stirred at room temperature
for 60 min, then was treated dropwise with saturated aqueous
NaHCO.sub.3 and stirred until no more gas evolution was observed.
The organic phase was separated, washed with water, dried and
concentrated. The residue was purified by column chromatography on
silica gel (40 g), eluting with EtOAc-hexanes (gradient from
0-100%), to give
3-(3-bromo-2-methylphenyl)-6,8-difluoroquinazoline-2,4(1H,3H)-dione
(820 mg), used without further purification. Mass spectrum m/z 367,
369 (M+H).sup.+, 389, 391 (M+Na).sup.+.
Intermediate 16
[0469] A mixture of
3-(3-bromo-2-methylphenyl)-6,8-difluoroquinazoline-2,4(1H,3H)-dione
(1.43 g, 3.89 mmol),
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (1.29
g, 5.06 mmol), potassium acetate (0.956 g, 9.74 mmol) and
PdCl.sub.2(dppf) DCM adduct (0.159 g, 0.195 mmol) in dioxane (20
mL) was heated at 100.degree. C. for 5 h. The cooled mixture was
filtered and the filtrate was concentrated. The residue was
purified by column chromatography on silica gel (40 g+12 g stacked
columns), eluting with EtOAc-hexanes (gradient from 0-100%), to
give
6,8-difluoro-3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)p-
henyl)quinazoline-2,4(1H,3H)-dione (1.20 g, 74% yield). Mass
spectrum m/z 415 (M+H).sup.+.
Intermediate 17
8-Fluoro-3-(RS)-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)
phenyl)quinazoline-2,4(1H,3H)-dione
##STR00112##
[0471] A stirred mixture of
3-(3-bromo-2-methylphenyl)-8-fluoroquinazoline-2,4(1H,3H)-dione
[Intermediate 1] (0.349 g, 1.00 mmol),
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (0.305
g, 1.20 mmol), PdCl.sub.2(dppf) DCM adduct (0.041 g, 0.050 mmol)
and potassium acetate (0.245 g, 2.50 mmol) in dioxane (20 mL) and
DMSO (4 mL) was bubbled with nitrogen for 5 min, then heated at
90.degree. C. overnight. The cooled mixture was partitioned between
EtOAc and water. The organic phase was washed sequentially with
saturated aqueous NaHCO.sub.3, water and brine, and dried and
concentrated. The residue was purified by column chromatography on
silica gel, eluting with EtOAc-hexanes (20:80) to give
8-fluoro-3-(RS)-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-
phenyl)quinazoline-2,4(1H,3H)-dione as a white solid (0.326 g, 82%
yield). Mass spectrum m/z 397 (M+H).sup.+. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 11.78 (s, 1H), 7.80 (d, J=7.2 Hz, 1H), 7.72
(dd, J=7.4, 1.5 Hz, 1H), 7.71-7.56 (m, 1H), 7.45-7.35 (m, 1H),
7.35-7.29 (m, 1H), 7.29-7.16 (m, 1H), 2.22 (s, 3H), 1.33 (s,
12H).
Intermediates 18 and 19
8-Fluoro-3-(R)-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)
phenyl)quinazoline-2,4(1H,3H)-dione (18), and
8-Fluoro-3-(S)-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ph-
enyl)quinazoline-2,4(1H,3H)-dione (19)
##STR00113##
[0473] A sample of
8-fluoro-3-(RS)-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-
phenyl)quinazoline-2,4(1H,3H)-dione [Intermediate 17] was separated
by super-critical fluid chromatography as follows: column:
CHIRALCEL.RTM. OD-H (5.times.25 cm, 5 .mu.m); Mobile Phase:
CO.sub.2-MeOH (70:30) at 300 mL/min, 100 bar, 40.degree. C.; sample
preparation: 103 mg/mL in DCM-MeOH (44:56); injection: 5.0 mL. The
first peak eluting from the column provided the R enantiomer,
8-fluoro-3-(R)-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)p-
henyl)quinazoline-2,4(1H,3H)-dione [Intermediate 18] as a white
solid. The second peak eluting from the column provided the S
enantiomer,
8-fluoro-3-(S)-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)p-
henyl)quinazoline-2,4(1H,3H)-dione [Intermediate 19] as a white
solid. The mass spectrum and .sup.1H NMR for each enantiomeric
atropisomer were the same as those for Intermediate 17.
Intermediate 20
8-Fluoro-1-methyl(d.sub.3)-3-(RS)-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-d-
ioxaborolan-2-yl) phenyl)quinazoline-2,4(1H,3H)-dione
##STR00114##
[0474] Intermediate 20A:
3-(3-Bromo-2-methylphenyl)-8-fluoro-1-methyl(d.sub.3)quinazoline-2,4(1H,3-
H)-dione
##STR00115##
[0476] A mixture of
3-(3-bromo-2-methylphenyl)-8-fluoroquinazoline-2,4(1H,3H)-dione
[Intermediate 1] (3.00 g, 8.59 mmol) and Cs.sub.2CO.sub.3 (5.60 g,
17.2 mmol) in DMF (45 mL) was treated with iodomethane-d.sub.3
(0.80 mL, 12.9 mmol) and the mixture was stirred at room
temperature for 1.75 h. The mixture was poured into rapidly-stirred
water (400 mL) and stirred at room temperature, forming a suspended
solid. The precipitate was collected by filtration, washed with
water and dried under vacuum to provide
3-(3-bromo-2-methylphenyl)-8-fluoro-1-methyl(d.sub.3)
quinazoline-2,4(1H,3H)-dione as an off-white solid (3.05 g, 97%
yield). Mass spectrum m/z 366, 368 (M+H).sup.+. .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 7.93 (dt, J=7.9, 0.7 Hz, 1H), 7.82-7.63
(m, 2H), 7.45-7.18 (m, 3H), 2.12 (s, 3H).
Intermediate 20
[0477] A mixture of
3-(3-bromo-2-methylphenyl)-8-fluoro-1-methyl(d.sub.3)quinazoline-2,4(1H,3-
H)-dione (3.00 g, 8.19 mmol),
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (2.70
g, 10.7 mmol) and potassium acetate (2.41 g, 24.6 mmol) in dioxane
(40 mL) was bubbled with argon with sonication for ca. 2 min, then
was treated with PdCl.sub.2(dppf) DCM adduct (0.335 g, 0.410 mmol).
The mixture was heated at 90.degree. C. for 15.75 h. The cooled
mixture was diluted with EtOAc, filtered through CELITE.RTM., and
the solids were rinsed with EtOAc. The combined filtrates were
concentrated, and the residue was purified by column chromatography
on silica gel (330 g), eluting with EtOAc-hexanes (gradient from
0-40%), to give
8-fluoro-1-methyl(d.sub.3)-3-(RS)-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2--
dioxaborolan-2-yl)phenyl)quinazoline-2,4(1H,3H)-dione as an
off-white solid (3.23 g, 95% yield). Mass spectrum m/z 414
(M+H).sup.+. .sup.1H NMR (400 MHz, chloroform-d) .delta. 8.14-8.07
(m, 1H), 7.93 (dd, J=7.4, 1.4 Hz, 1H), 7.48 (ddd, J=13.9, 8.1, 1.5
Hz, 1H), 7.37-7.31 (m, 1H), 7.27-7.19 (m, 2H), 2.36 (s, 3H), 1.36
(s, 12H).
Intermediates 21 and 22
8-Fluoro-1-methyl(d.sub.3)-3-(S)-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-di-
oxaborolan-2-yl) phenyl)quinazoline-2,4(1H,3H)-dione (21), and
8-Fluoro-1-methyl(d.sub.3)-3-(R)-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-di-
oxaborolan-2-yl)phenyl)quinazoline-2,4(1H,3H)-dione (22)
##STR00116##
[0479] A sample of
8-fluoro-1-methyl(d.sub.3)-3-(RS)-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2--
dioxaborolan-2-yl)phenyl)quinazoline-2,4(1H,3H)-dione [Intermediate
20] was separated by super-critical fluid chromatography as
follows: column: WHELK-O.RTM. R,R (3.times.25 cm, 5 .mu.m); Mobile
Phase: CO.sub.2-MeOH (70:30) at 200 mL/min, 100 bar, 30.degree. C.;
sample preparation: 97.3 mg/mL in MeOH:DCM (1:1); injection: 4 mL.
The first peak eluting from the column provided the S enantiomer,
8-fluoro-1-methyl(d.sub.3)-3-(S)-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-d-
ioxaborolan-2-yl)phenyl)quinazoline-2,4(1H,3H)-dione [Intermediate
21] as a white solid. The second peak eluting from the column
provided the R enantiomer,
8-fluoro-1-methyl(d.sub.3)-3-(R)-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-d-
ioxaborolan-2-yl)phenyl)quinazoline-2,4(1H,3H)-dione [Intermediate
22] as a white solid. The mass spectrum and .sup.1H NMR for each
enantiomeric atropisomer were the same as those for Intermediate
20.
Alternative Synthesis of
8-Fluoro-1-methyl(d.sub.3)-3-(S)-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-d-
ioxaborolan-2-yl)phenyl)quinazoline-2,4(1H,3H)-dione [Intermediate
21]
[0480] A solution of
8-fluoro-3-(S)-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)p-
henyl)quinazoline-2,4(1H,3H)-dione [Intermediate 19] (5.42 g, 13.7
mmol) in THF (100 mL) was stirred on an ice-water bath and treated
with Cs.sub.2CO.sub.3 (6.24 g, 19.2 mmol), then with
iodomethane-d.sub.3 (1.02 mL, 16.4 mmol) and the mixture was
stirred at room temperature for 16.25 h. The mixture was filtered,
the solid was rinsed with EtOAc, and the combined filtrates were
concentrated. The residue was dissolved in EtOAc and washed
sequentially with water and brine, dried and concentrated to
provide
8-fluoro-1-methyl(d.sub.3)-3-(S)-(2-methyl-3-(4,4,5,5-tetramethyl-
-1,3,2-dioxaborolan-2-yl)phenyl) quinazoline-2,4(1H,3H)-dione as a
white solid (5.538 g, 98% yield). Mass spectrum m/z 414
(M+H).sup.+. .sup.1H NMR (400 MHz, chloroform-d) .delta. 8.11 (dq,
J=7.8, 0.8 Hz, 1H), 7.93 (dd, J=7.5, 1.3 Hz, 1H), 7.48 (ddd,
J=13.9, 8.1, 1.5 Hz, 1H), 7.38-7.30 (m, 1H), 7.27-7.20 (m, 2H),
2.36 (s, 3H), 1.36 (s, 12H).
Intermediate 23
3-4-Bromo-3-cyano-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
##STR00117##
[0481] Intermediate 23A:
4-Bromo-7-(2-hydroxypropan-2-yl)-3-iodo-9H-carbazole-1-carboxamide
##STR00118##
[0483] A mixture of
4-bromo-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
[synthesized according to the procedure described in U.S. Pat. No.
8,084,620, Example 73-2] (2.00 g, 5.76 mmol), N-iodosuccinimide
(1.69 g, 7.49 mmol), and pyridine (1.9 mL, 23.0 mmol) in DMF (20
mL) was heated at 65.degree. C. for 2 days. The cooled mixture was
diluted with EtOAc, washed twice with 10% aqueous LiCl and then
with brine. The aqueous layers were extracted with EtOAc. The
combined organic layers were dried and concentrated, and the
residue was purified by column chromatography on silica gel,
eluting with EtOAc-hexanes (gradient from 50%-65%), to provide
4-bromo-7-(2-hydroxypropan-2-yl)-3-iodo-9H-carbazole-1-carboxamide
as a yellow solid (0.609 g, 23% yield). Mass spectrum m/z 473, 475
(M+H--H.sub.2O).sup.+. .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta.
11.66 (s, 1H), 8.49 (d, J=8.6 Hz, 1H), 8.38 (s, 1H), 8.26 (br. s.,
1H), 7.94 (d, J=1.1 Hz, 1H), 7.58 (br. s., 1H), 7.40 (dd, J=8.6,
1.4 Hz, 1H), 5.09 (s, 1H), and 1.51 (s, 6H).
Intermediate 23
[0484] A mixture of
4-bromo-7-(2-hydroxypropan-2-yl)-3-iodo-9H-carbazole-1-carboxamide
(0.609 g, 1.29 mmol) and zinc cyanide (0.076 g, 0.644 mmol) in DMF
(7 mL) was subjected to three evacuate-fill cycles with nitrogen.
The mixture was treated with tetrakis(triphenylphosphine)palladium
(0.074 g, 0.064 mmol) and heated overnight at 95.degree. C. The
cooled mixture was diluted with EtOAc, washed twice with 10%
aqueous LiCl, then with brine. The aqueous layers were extracted
with EtOAc. The combined organic layers were dried and
concentrated. The residue was triturated and sonicated with DCM and
the precipitate was collected by filtration to give
4-bromo-3-cyano-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
as a pale yellow solid (0.400 g, 83% yield). Mass spectrum m/z 372,
374 (M+H--H.sub.2O).sup.+. .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 12.12 (s, 1H), 8.55 (d, J=8.6 Hz, 1H), 8.38 (s, 1H), 8.31
(br. s., 1H), 8.03 (s, 1H), 7.74 (br. s., 1H), 7.49 (dd, J=8.6, 1.1
Hz, 1H), and 1.52 (s, 6H).
Intermediate 24
5-Bromo-6-fluoro-2-(2-hydroxypropan-2-yl)-2,3,4,9-tetrahydro-1H-carbazole--
8-carboxamide (racemic)
##STR00119##
[0485] Intermediate 24A: 4-Bromo-2,5-difluorobenzoic acid
##STR00120##
[0487] A solution of 1,4-dibromo-2,5-difluorobenzene (640 mg, 2.35
mmol) in dry diethyl ether (10 mL) cooled in a dry ice-acetone bath
was treated dropwise with 2.5 M n-butyllithium in hexanes (1.04 mL,
2.59 mmol). The solution was stirred at -78.degree. C. for 30 min,
then was treated with a piece of dry ice. The cooling bath was
removed after 5 min and the mixture was stirred for another 30 min
while warming to room temperature. The mixture was diluted with
EtOAc and water. The organic phase was separated and washed twice
with saturated aqueous NaHCO.sub.3. The combined aqueous phases
were acidified with 1 M aqueous HCl, extracted twice with DCM, and
the combined organic phases were dried and concentrated to give
4-bromo-2,5-difluorobenzoic acid as a white solid (297 mg, 53%
yield).
Intermediate 24B: 4-Bromo-5-fluoro-2-hydrazinylbenzoic acid
hydrochloride
##STR00121##
[0489] A mixture of 4-bromo-2,5-difluorobenzoic acid (2.50 g, 10.6
mmol) and hydrazine (3.81 mL, 121 mmol) in N-methyl-2-pyrrolidinone
(2 mL) was heated at 95.degree. C. for 4 h. The cooled mixture was
poured into vigorously stirred 6 M aqueous HCl (400 mL) which was
cooled in an NaCl-ice bath. The resulting precipitate was collected
by filtration, washed with 6 M aqueous HCl (200 mL) and dried under
vacuum to give 4-bromo-5-fluoro-2-hydrazinylbenzoic acid
hydrochloride as a yellow solid (1.88 g, 71% purity, 44% yield),
used without further purification.
Alternative Synthesis of 4-Bromo-5-fluoro-2-hydrazinylbenzoic acid
hydrochloride
[0490] A suspension of 2-amino-4-bromo-5-fluorobenzoic acid (10.0
g, 42.7 mmol) in a mixture of 37% aqueous HCl (42.7 mL) and water
(14.3 mL), cooled with a NaCl-ice bath, was treated dropwise with a
solution of sodium nitrite (3.24 g, 47.0 mmol) in water (15.7 mL).
When addition was complete, the mixture was stirred for 30 min
more. A solution of tin(II) chloride dihydrate (28.9 g, 128 mmol)
in 37% aqueous HCl (27.5 mL) was added dropwise. The cooling bath
was removed and the mixture was stirred at room temperature for 45
min. The thick suspension was filtered and the collected
precipitate was washed thoroughly with water and dried overnight
under reduced pressure. The solid was triturated with MeOH with
sonication, and the precipitate was collected by filtration, washed
with MeOH and dried. The filtrate was concentrated, and the residue
was triturated with DCM. The resulting solid was collected by
filtration, dried and combined with the other solid to give
4-bromo-5-fluoro-2-hydrazinylbenzoic acid hydrochloride (5.37 g,
44% yield) as a white solid. Mass spectrum m/z 249, 251
(M+H).sup.+.
Intermediate 24C:
5-Bromo-2-(ethoxycarbonyl)-6-fluoro-2,3,4,9-tetrahydro-1H-carbazole-8-car-
boxylic acid
##STR00122##
[0492] A mixture of 4-bromo-5-fluoro-2-hydrazinylbenzoic acid
hydrochloride (5.37 g, 18.8 mmol), ethyl
3-oxocyclohexanecarboxylate (3.52 g, 20.7 mmol) and acetic acid
(3.23 mL, 56.4 mmol) in toluene (90 mL) was heated at 110.degree.
C. for 20 h. The solvent was removed under reduced pressure, and
the residue was diluted with toluene (43 mL) and trifluoroacetic
acid (11 mL). The mixture was stirred at 90-94.degree. C.
overnight. The cooled mixture was diluted with EtOAc, sonicated,
and the precipitate was collected by filtration. The filtrate was
concentrated and resuspended in EtOAc with sonication, resulting in
another precipitate which was also collected by filtration and
washed with EtOAc. The combined solids were triturated twice with
MeOH to give a solid. The combined filtrates were concentrated and
the residue was triturated with MeOH to give additional solid. The
solids were combined to give
5-bromo-2-ethoxycarbonyl-6-fluoro-2,3,4,9-tetrahydro-1H-carbazole-8-carbo-
xylic acid as a pale yellow solid (3.38 g). Mass spectrum m/z 384,
386 (M+H).sup.+.
Intermediate 24D: Ethyl
5-bromo-8-carbamoyl-6-fluoro-2,3,4,9-tetrahydro-1H-carbazole-2-carboxylat-
e
##STR00123##
[0494] A mixture of
5-bromo-2-(ethoxycarbonyl)-6-fluoro-2,3,4,9-tetrahydro-1H-carbazole-8-car-
boxylic acid (0.513 g, 1.34 mmol), EDC (0.384 g, 2.00 mmol), and
HOBT (0.307 g, 2.00 mmol) in THF (10 mL) and DCM (1.65 mL) was
stirred at room temperature for 20 min. Ammonium hydroxide (0.078
mL, 2.00 mmol) was added, and the mixture was stirred at room
temperature for 60 min. The mixture was diluted with EtOAc and
washed twice with saturated aqueous of NaHCO.sub.3, then with
brine. The aqueous layers were extracted with EtOAc, and the
combined organic layers were dried and concentrated. The residue
was triturated in MeOH with sonication to provide ethyl
5-bromo-8-carbamoyl-6-fluoro-2,3,4,9-tetrahydro-1H-carbazole-2-carboxylat-
e as a yellow solid (0.432 g, 84% yield). Mass spectrum m/z 383,
385 (M+H).sup.+.
Intermediate 24
[0495] A solution of ethyl
5-bromo-8-carbamoyl-6-fluoro-2,3,4,9-tetrahydro-1H-carbazole-2-carboxylat-
e (10.0 g, 26.1 mmol) in THF (200 mL) at -78.degree. C. was treated
dropwise over 30 min with 1.6 M methyllithium in ether (49 mL, 78
mmol). The mixture was stirred at -78.degree. C. for 45 min, then
was treated with additional methyllithium solution (33 mL) over 25
min. The mixture was stirred at -78.degree. C. for an additional 90
min, then was treated with saturated aqueous NH.sub.4Cl and warmed
to room temperature. The mixture was diluted with EtOAc and washed
sequentially with water and brine. The aqueous layers were
extracted with EtOAc. The combined organic layers were dried and
concentrated. The residue was dissolved in EtOAc (about 100 mL) and
filtered through a pad of CELITE.RTM. topped with a pad of silica
gel, washing further with EtOAc (about 1000 mL). Concentration of
the filtrate gave racemic
5-bromo-6-fluoro-2-(2-hydroxypropan-2-yl)-2,3,4,9-tetrahydro-1H-carbazole-
-8-carboxamide as a pale yellow solid (9.24 g, 96% yield). Mass
spectrum m/z 369, 371 (M+H).sup.+.
Alternative Synthesis of Intermediate 24
[0496] To a solution of ethyl
5-bromo-8-carbamoyl-6-fluoro-2,3,4,9-tetrahydro-1H-carbazole-2-carboxylat-
e (10.0 g, 26.1 mmol) in tetrahydrofuran (200 mL) at -78.degree. C.
was added methyllithium (1.6 M in ether) (3 equiv.; 49 mL, 78 mmol)
dropwise over 30 min. The reaction mixture was stirred at
-78.degree. C. for 45 minutes. An additional 2 equivalents of
methyllithium (33 mL) was added over 25 min., and the reaction
mixture was stirred at -78.degree. C. for an additional 1.5 h. The
reaction was quenched at -78.degree. C. with a saturated aqueous
solution of ammonium chloride and warmed to room temperature. The
mixture was diluted with ethyl acetate, washed with water, and
washed with brine. The organic layer was collected, and the aqueous
layers were sequentially extracted with ethyl acetate. The combined
organic layers were dried over anhydrous sodium sulfate and
concentrated under reduced pressure. The residue was dissolved in
-100 mL of ethyl acetate and filtered through a pad of CELITE.RTM.
topped with a pad of silica gel in a 600 mL fritted funnel using
ethyl acetate (.about.1 L). Concentration under reduced pressure
afforded
5-bromo-6-fluoro-2-(2-hydroxypropan-2-yl)-2,3,4,9-tetrahydro-1H-carbazole-
-3-carboximide (9.24 g, 25.03 mmol, 96% yield) as a pale yellow
solid.
Intermediates 25 and 26
(R)-5-Bromo-6-fluoro-2-(2-hydroxypropan-2-yl)-2,3,4,9-tetrahydro-1H-carbaz-
ole-8-carboxamide (I-25), and
(S)-5-Bromo-6-fluoro-2-(2-hydroxypropan-2-yl)-2,3,4,9-tetrahydro-1H-carbaz-
ole-8-carboxamide (I-26)
##STR00124##
[0498] A sample of racemic
5-bromo-6-fluoro-2-(2-hydroxypropan-2-yl)-2,3,4,9-tetrahydro-1H-carbazole-
-8-carboxamide [Intermediate 24] was separated by chiral
super-critical fluid chromatography as follows: column:
CHIRALPAK.RTM. OD-H (3.times.25 cm, 5 .mu.m); Mobile Phase:
CO.sub.2-MeOH (70:30) at 150 mL/min, 40.degree. C. The first peak
eluting from the column provided
(R)-5-bromo-6-fluoro-2-(2-hydroxypropan-2-yl)-2,3,4,9-tetrahydro-1H-carba-
zole-8-carboxamide [Intermediate 25]. The second peak eluting from
the column provided
(S)-5-bromo-6-fluoro-2-(2-hydroxypropan-2-yl)-2,3,4,9-tetrahydro-1H-carba-
zole-8-carboxamide [Intermediate 26]. The mass spectra and .sup.1H
NMR spectra of the two enantiomers were the same. Mass spectrum m/z
369, 371 (M+H).sup.+. .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta.
10.96 (s, 1H), 8.07 (br. s., 1H), 7.55 (d, J=10.3 Hz, 1H), 7.50
(br. s., 1H), 4.24 (s, 1H), 3.26 (dd, J=15.8, 4.4 Hz, 1H), 2.93
(dd, J=17.1, 4.6 Hz, 1H), 2.72 (t, J=11.7 Hz, 1H), 2.48-2.40 (m,
1H), 2.12 (d, J=9.2 Hz, 1H), 1.70-1.62 (m, 1H), and 1.32 (qd,
J=12.4, 5.3 Hz, 1H).
Alternative SFC Separation to Give Intermediate 26
[0499] CHIRALPAK.RTM. AD-H (3.times.25 cm, 5 .mu.m); Mobile Phase:
CO.sub.2-MeOH (55:45) at 150 mL/min, 40.degree. C. The first peak
eluting from the column provided
(S)-5-bromo-6-fluoro-2-(2-hydroxypropan-2-yl)-2,3,4,9-tetrahydro-1H-carba-
zole-8-carboxamide [Intermediate 26]. The second peak eluting from
the column provided
(R)-5-bromo-6-fluoro-2-(2-hydroxypropan-2-yl)-2,3,4,9-tetrahydro-1H-carba-
zole-8-carboxamide [Intermediate 25].
Intermediate 27
4-Bromo-3-fluoro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
##STR00125##
[0500] Intermediate 27A:
4-Bromo-7-ethoxycarbonyl-3-fluoro-9H-carbazole-1-carboxylic
acid
##STR00126##
[0502] A solution of
5-bromo-2-(ethoxycarbonyl)-6-fluoro-2,3,4,9-tetrahydro-1H-carbazole-8-car-
boxylic acid (2.87 g, 7.47 mmol) and
2,3-dichloro-5,6-dicyanobenzoquinone (3.73 g, 16.4 mmol) in THF (45
mL) was heated at 60.degree. C. for 90 min. The cooled mixture was
diluted with EtOAc (about 50 mL) and stirred for 60 min. The
resulting precipitate was collected by filtration, washed with
EtOAc and dried. The filtrate was concentrated, and the residue was
triturated with MeOH with sonication, filtered, and the precipitate
was washed with MeOH and dried. The two precipitates were combined
to give 4-bromo-7-ethoxycarbonyl-3-fluoro-9H-carbazole-1-carboxylic
acid as a pale yellow solid (2.39 g, 84% yield). Mass spectrum m/z
380, 382 (M+H).sup.+.
Intermediate 26B: Ethyl
5-bromo-8-carbamoyl-6-fluoro-9H-carbazole-2-carboxylate
##STR00127##
[0504] A mixture of
4-bromo-7-(ethoxycarbonyl)-3-fluoro-9H-carbazole-1-carboxylic acid
(2.39 g, 6.29 mmol), EDC (1.81 g, 9.43 mmol) and HOBT (1.44 g, 9.43
mmol) in THF (30 mL) and DCM (5 mL) was stirred at room temperature
for 20 min. Ammonium hydroxide (0.367 mL, 9.43 mmol) was added, and
the mixture was stirred at room temperature for 4 h. The mixture
was diluted with EtOAc, washed twice with saturated aqueous
NaHCO.sub.3, then with brine. The aqueous layers were extracted
with EtOAc, and the combined organic layers were dried and
concentrated. The residue was triturated with MeOH with sonication
to provide ethyl
5-bromo-8-carbamoyl-6-fluoro-9H-carbazole-2-carboxylate as a pale
yellow solid (2.26 g, 95% yield). Mass spectrum m/z 379, 381
(M+H).sup.+. .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 12.02 (s,
1H), 8.70 (d, J=8.3 Hz, 1H), 8.51 (d, J=1.1 Hz, 1H), 8.29 (br. s.,
1H), 8.10 (d, J=10.3 Hz, 1H), 7.87 (dd, J=8.5, 1.5 Hz, 1H), 7.74
(br. s., 1H), 4.37 (q, J=6.9 Hz, 2H), and 1.37 (t, J=7.1 Hz, 3H).
.sup.1H NMR (500 MHz, MeOH-d.sub.4) .delta. 8.77 (d, J=8.2 Hz, 1H),
8.36 (d, J=0.9 Hz, 1H), 7.83 (d, J=8.2 Hz, 1H), 7.46 (d, J=8.2 Hz,
1H), 4.12 (q, J=7.0 Hz, 2H), 1.58-1.36 (m, 4H), and 1.26 (t, J=7.2
Hz, 3H).
Alternative Synthesis of Ethyl
5-bromo-8-carbamoyl-6-fluoro-9H-carbazole-2-carboxylate
[0505] A mixture of ethyl
5-bromo-8-carbamoyl-9H-carbazole-2-carboxylate [synthesized
according to the procedure described in U.S. Pat. No. 8,084,620,
Intermediate 48-1] (0.100 g, 0.277 mmol) and
1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane
bis(tetrafluoroborate) [SELECTFLUOR.RTM.] (0.100 g, 0.554 mmol) in
THF (2 mL) and MeCN (2 mL) was heated at 60.degree. C. overnight.
The cooled mixture was filtered and the filtrate was concentrated.
The residue was purified using reverse-phase preparative HPLC to
give ethyl 5-bromo-8-carbamoyl-3-fluoro-9H-carbazole-2-carboxylate
as a tan solid (0.035 g).
Intermediate 27
[0506] A solution of ethyl
5-bromo-8-carbamoyl-6-fluoro-9H-carbazole-2-carboxylate (0.500 g,
1.32 mmol) in THF (9.0 mL) at -78.degree. C. was treated dropwise
over 10 min with 1.6 M methyllithium in ether (2.47 mL, 3.96 mmol).
The mixture was stirred at -78.degree. C. for 30 min, then was
treated with additional methyllithium solution (1.65 mL, 2.64 mmol)
and the mixture was stirred at -78.degree. C. for 45 min more. The
mixture was treated with saturated aqueous NH.sub.4Cl and allowed
to warm to room temperature. The mixture was diluted with EtOAc and
washed sequentially with water and brine. The aqueous layers were
extracted with EtOAc and the combined organic layers were dried and
concentrated to provide a pale yellow solid which was purified by
reverse phase preparative HPLC. The appropriate fractions were
neutralized with saturated aqueous NaHCO.sub.3 and concentrated.
The residue was partitioned between EtOAc and water, and the
organic layer was washed with brine. The aqueous layers were
extracted with EtOAc, and the combined organic layers were dried
and concentrated to provide
4-bromo-3-fluoro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
as a pale yellow solid (0.240 g, 50% yield). Mass spectrum m/z 347,
349 (M+H--H.sub.2O).sup.+. .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 11.58 (s, 1H), 8.50 (d, J=8.6 Hz, 1H), 8.22 (br. s., 1H),
7.96 (d, J=10.3 Hz, 1H), 7.94 (d, J=1.1 Hz, 1H), 7.65 (br. s., 1H),
7.39 (dd, J=8.5, 1.5 Hz, 1H), 5.09 (s, 1H), and 1.51 (s, 6H).
Alternative Synthesis of
4-Bromo-3-fluoro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
[0507] A solution of ethyl
5-bromo-8-carbamoyl-6-fluoro-9H-carbazole-2-carboxylate (10 g, 26.4
mmol) in THF (300 mL) was cooled in an ice-water bath and treated
dropwise with 3.0 M methylmagnesium chloride in THF (70.3 mL, 211
mmol). The solution was stirred at 0.degree. C. for 18 h. The
mixture was poured into 1000 mL of well-stirred saturated aqueous
NH.sub.4Cl cooled in an ice-water bath. The resulting mixture was
diluted with water and extracted twice with EtOAc. The combined
organic phases were washed twice with water, then with brine, and
dried and concentrated. The residue was purified by column
chromatography on silica gel (330 g), eluting with EtOAc-DCM
(gradient from 20-100%), to give
4-bromo-3-fluoro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
(6.36 g, 65% yield).
Intermediate 28
4-Bromo-7-(2-hydroxypropan-2-yl)-3-methyl-9H-carbazole-1-carboxamide
##STR00128##
[0508] Intermediate 28A: 5-Bromo-2-iodo-4-methylaniline
##STR00129##
[0510] A solution of 3-bromo-4-methylaniline (5.00 g, 26.9 mmol),
N-iodosuccinimide (4.53 g, 20.2 mmol) and bis(pyridine)iodonium
tetrafluoroborate (2.70 g, 7.26 mmol) in DCM (100 mL) was stirred
at room temperature overnight. The mixture was diluted with DCM,
washed sequentially with saturated aqueous NaHSO.sub.3 and water,
and dried and concentrated. The residue was purified by column
chromatography on silica gel, eluting with EtOAc-hexanes
(sequentially 1%, 2% and 3%), to provide
5-bromo-2-iodo-4-methylaniline as a yellow solid (5.27 g, 63%
yield). Mass spectrum m/z 312, 314 (M+H).sup.+. .sup.1H NMR (500
MHz, CDCl.sub.3) .delta. 7.49 (d, J=0.6 Hz, 1H), 6.94 (s, 1H),
4.17-3.91 (br.s, 2H), and 2.25 (s, 3H).
Intermediate 28B: 2-Amino-4-bromo-5-methylbenzonitrile
##STR00130##
[0512] A mixture of 5-bromo-2-iodo-4-methylaniline (5.25 g, 16.8
mmol) and zinc cyanide (0.988 g, 8.41 mmol) in DMF (80 mL) was
subjected to three evacuate-fill cycles with nitrogen. The mixture
was treated with tetrakis(triphenylphosphine)palladium (0.972 g,
0.841 mmol) and heated at 90.degree. C. overnight. The cooled
mixture was diluted with EtOAc and washed sequentially with 10%
aqueous LiCl (twice) and brine. The aqueous layers were extracted
with EtOAc, and the combined organic layers were dried and
concentrated. The residue was purified by column chromatography on
silica gel, eluting with EtOAc-hexanes (sequentially 1%, 2.5%, 5%
and 50%), to give a brown solid. The residue was further purified
by trituration with MeOH to give three crops of solid. The filtrate
was again purified by column chromatography on silica gel, eluting
with EtOAc-hexanes (5%, then 10%). The resulting solid was combined
with the other crops to provide
2-amino-4-bromo-5-methylbenzonitrile as a tan solid (2.95 g, 83%
yield). Mass spectrum m/z 211, 213 (M+H).sup.+.
Intermediate 28C: 2-Amino-4-bromo-5-methylbenzoic acid
##STR00131##
[0514] A mixture of 2-amino-4-bromo-5-methylbenzonitrile (2.95 g,
14.0 mmol) in a mixture of EtOH (21 mL) and 2 M aqueous NaOH (34.9
mL, 69.9 mmol) was heated at reflux overnight. After cooling to
room temperature, the ethanol was removed under reduced pressure,
and the aqueous residue was diluted with water. After adjustment of
the pH to about 5 with concentrated aqueous HCl, the mixture was
stirred for 30 min and the precipitate was collected by filtration
and washed with water. The resulting wet solid was dissolved in
EtOAc, washed with brine, dried and concentrated to provide
2-amino-4-bromo-5-methylbenzoic acid as a pale yellow solid (2.92
g, 91% yield). Mass spectrum m/z 212, 214 (M+H).sup.+.
Intermediate 28D: 4-Bromo-2-hydrazinyl-5-methylbenzoic acid
hydrochloride
##STR00132##
[0516] A suspension of 2-amino-4-bromo-5-methylbenzoic acid (2.92
g, 12.7 mmol) in a mixture of 37% aqueous HCl (12.7 mL) and water
(4.3 mL), cooled in a NaCl-ice bath, was treated slowly dropwise
with a solution of sodium nitrite (0.963 g, 14.0 mmol) in water
(4.5 mL). The resulting mixture was stirred for 45 min, then was
treated slowly dropwise with a solution of tin(II) chloride
dihydrate (8.59 g, 38.1 mmol) in 37% aqueous HCl (8.2 mL). The
cooling bath was removed, and the mixture was stirred at room
temperature for 60 min. The mixture was filtered, and the collected
precipitate was washed with water and dried. The solid was
triturated and sonicated in MeOH, and the mixture was concentrated.
The residue was triturated and sonicated with DCM, and the
precipitate was collected by filtration and washed with DCM to give
4-bromo-2-hydrazinyl-5-methylbenzoic acid hydrochloride as a white
solid (2.17 g, 61% yield). Mass spectrum m/z 245, 247
(M+H).sup.+.
Intermediate 28E:
5-Bromo-2-(ethoxycarbonyl)-6-methyl-2,3,4,9-tetrahydro-1H-carbazole-8-car-
boxylic acid
##STR00133##
[0518] A mixture of 4-bromo-2-hydrazinyl-5-methylbenzoic acid
hydrochloride (2.17 g, 7.71 mmol), ethyl
3-oxocyclohexanecarboxylate (1.44 g, 8.48 mmol) and acetic acid
(1.32 mL, 23.1 mmol) in toluene (40 mL) was heated in an oil bath
at 117.degree. C. for 5 h. The mixture was concentrated and dried
under vacuum, and the residue was diluted with toluene (18 mL) and
TFA (4.5 mL). The mixture was heated at 90.degree. C. overnight.
The cooled mixture was diluted with EtOAc, sonicated, and the
precipitate was collected by filtration and washed with EtOAc to
give a yellow solid. The filtrate was concentrated and the residue
was suspended in EtOAc with sonication. The precipitate was
collected by filtration and combined with the first precipitate.
The solid was triturated with MeOH to give
5-bromo-2-(ethoxycarbonyl)-6-methyl-2,3,4,9-tetrahydro-1H-carbazo-
le-8-carboxylic acid as a pale yellow solid (1.60 g, 55% yield).
Mass spectrum m/z 380, 382 (M+H).sup.+.
Intermediate 28F:
4-Bromo-7-(ethoxycarbonyl)-3-methyl-9H-carbazole-1-carboxylic
acid
##STR00134##
[0520] A solution of
5-bromo-2-(ethoxycarbonyl)-6-methyl-2,3,4,9-tetrahydro-1H-carbazole-8-car-
boxylic acid (1.60 g, 4.21 mmol) and
2,3-dichloro-5,6-dicyanobenzoquinone (2.10 g, 9.26 mmol) in THF (45
mL) was heated at 60.degree. C. for 60 min. The cooled mixture was
diluted with EtOAc (about 70 mL), stirred for 15 min, and the
precipitate was collected by filtration, washed with EtOAc and
dried. The filtrate was concentrated, and the residue was
triturated with MeOH, filtered, and the collected precipitate was
washed with MeOH. The two solids were combined to give
4-bromo-7-(ethoxycarbonyl)-3-methyl-9H-carbazole-1-carboxylic acid
as a pale yellow solid (1.40 g, 88% yield). Mass spectrum m/z 376,
378 (M+H).sup.+.
Intermediate 28G: Ethyl
5-bromo-8-carbamoyl-6-methyl-9H-carbazole-2-carboxylate
##STR00135##
[0522] A mixture of
4-bromo-7-(ethoxycarbonyl)-3-methyl-9H-carbazole-1-carboxylic acid
(1.40 g, 3.72 mmol), EDC (1.070 g, 5.58 mmol), and HOBT (0.855 g,
5.58 mmol) in a mixture of THF (30 mL) and DCM (5 mL) was stirred
at room temperature for 60 min. Ammonium hydroxide (0.217 mL, 5.58
mmol) was added, and the mixture was stirred at room temperature
overnight. The mixture was diluted with EtOAc and washed with
saturated aqueous NaHCO.sub.3. Phase separation could not be
achieved, so the mixture was filtered, and the collected solid was
washed sequentially with water and EtOAc, triturated with MeOH and
dried. The EtOAc-water filtrate was separated and the organic phase
was washed with brine, dried and concentrated. The residue was
triturated with MeOH, and the resulting solid was combined with the
first solid to give ethyl
5-bromo-8-carbamoyl-6-methyl-9H-carbazole-2-carboxylate as an
off-white solid (1.27 g, 91% yield). Mass spectrum m/z 375, 377
(M+H).sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 11.88 (s,
1H), 8.77 (d, J=8.6 Hz, 1H), 8.48 (d, J=0.9 Hz, 1H), 8.20 (br. s.,
1H), 7.84 (dd, J=8.5, 1.4 Hz, 1H), 7.59 (br. s., 1H), 4.37 (q,
J=7.0 Hz, 2H), 2.55 (s, 3H), and 1.37 (t, J=7.0 Hz, 3H).
Intermediate 28
[0523] A solution of ethyl
5-bromo-8-carbamoyl-6-methyl-9H-carbazole-2-carboxylate (0.500 g,
1.33 mmol) in THF (12 mL) at -78.degree. C. was treated dropwise
over 10 min with 1.6 M methyllithium in ether (2.50 mL, 4.00 mmol).
The mixture was stirred at -78.degree. C. for 30 min, then was
treated with additional methyllithium solution (1.67 mL, 2.67
mmol). After 30 min more, additional methyllithium solution (1.67
mL, 2.67 mmol) was added and stirring was continued for 45 min. The
mixture was then treated with saturated aqueous NH.sub.4Cl and
allowed to warm to room temperature. The mixture was diluted with
EtOAc and washed sequentially with water and brine. The aqueous
layers were extracted with EtOAc, and the combined organic layers
were dried and concentrated to provide an off-white solid. The
solid was triturated and sonicated with MeOH and collected by
filtration. The filtrate was purified by reverse-phase preparative
HPLC. The appropriate fractions were treated with saturated aqueous
NaHCO.sub.3 and concentrated. The residue was partitioned between
EtOAc and water. The organic phase was washed with brine, and the
aqueous layers were extracted with EtOAc. The combined organic
layers were dried and concentrated, and the residue was combined
with the first solid to give
4-bromo-7-(2-hydroxypropan-2-yl)-3-methyl-9H-carbazole-1-carboxamide
as a tan solid (0.409 g, 85% yield). Mass spectrum m/z 343, 345
(M+H--H.sub.2O)+. .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 11.42
(s, 1H), 8.56 (d, J=8.6 Hz, 1H), 8.12 (br. s., 1H), 7.91-7.89 (m,
2H), 7.48 (br. s., 1H), 7.36 (dd, J=8.3, 1.7 Hz, 1H), 5.06 (s, 1H),
2.53 (s, 3H), and 1.51 (s, 6H).
Intermediate 29
5-Bromo-6-chloro-2-(RS)-(2-hydroxypropan-2-yl)-2,3,4,9-tetrahydro-1H-carba-
zole-8-carboxamide (racemic mixture)
##STR00136##
[0524] Intermediate 29A: 4-Bromo-5-chloro-2-hydrazinylbenzoic acid
hydrochloride
##STR00137##
[0526] A solution of sodium nitrite (3.03 g, 43.9 mmol) in water
(14.8 mL) was added dropwise to a cooled (-10.degree. C., NaCl-ice
bath) suspension of 2-amino-4-bromo-5-chlorobenzoic acid (10.0 g,
39.9 mmol) in 37% aqueous HCl (39.9 mL) and water (13.3 mL), at
such rate that the temperature did not exceed 0.degree. C. The
resulting suspension was stirred at 0.degree. C. for 15 min, then
was treated with a solution of tin(II) chloride hydrate (22.7 g,
120 mmol) in 37% aqueous HCl (17 mL). The resulting mixture was
warmed to room temperature and stirred for 60 min. The precipitate
was collected by filtration, washed with water and air-dried
overnight to give 4-bromo-5-chloro-2-hydrazinylbenzoic acid
hydrochloride as an off-white solid (12.86 g, 96% yield). Mass
spectrum m/z 365, 267 (M+H).sup.+. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 9.05 (br. s., 1H), 7.95 (s, 1H), 7.55 (s,
1H).
Intermediate 29B:
5-Bromo-6-chloro-2-(ethoxycarbonyl)-2,3,4,9-tetrahydro-1H-carbazole-8-car-
boxylic acid
##STR00138##
[0528] A suspension of 4-bromo-5-chloro-2-hydrazinylbenzoic acid
hydrochloride (12.89 g, 37.6 mmol), ethyl
3-oxocyclohexanecarboxylate (7.03 g, 41.3 mmol), and acetic acid
(6.45 mL, 113 mmol) in toluene (188 mL) was heated at 105.degree.
C. overnight. After 16 h, more acetic acid (6 mL) and ethyl
3-oxocyclohexanecarboxylate (2.00 g) were added and the mixture was
heated at 110.degree. C. for 4.5 h. The mixture was concentrated,
and the residue was combined with toluene (100 mL) and TFA (20 mL).
The suspension was heated at 90.degree. C. overnight. The cooled
mixture was concentrated and the residue was suspended in EtOAc.
The resulting solid was collected by filtration, washed with EtOAc
and air-dried to give
5-bromo-6-chloro-2-(ethoxycarbonyl)-2,3,4,9-tetrahydro-1H-carbazole-8-car-
boxylic acid as a yellow solid (11.0 g, 73% yield). Mass spectrum
m/z 400, 402 (M+H).sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 13.44 (br. s., 1H), 11.24 (s, 1H), 7.69 (s, 1H), 4.12 (qd,
J=7.1, 2.3 Hz, 2H), 3.23-2.81 (m, 5H), 2.23-2.09 (m, 1H), 1.91-1.75
(m, 1H), 1.22 (t, J=7.0 Hz, 3H).
Intermediate 29C: Ethyl
5-bromo-8-carbamoyl-6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-carboxylat-
e
##STR00139##
[0530] Following the procedure used to prepare Intermediate 24D,
5-bromo-6-chloro-2-(ethoxycarbonyl)-2,3,4,9-tetrahydro-1H-carbazole-8-car-
boxylic acid was converted into ethyl
5-bromo-8-carbamoyl-6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-carboxylat-
e as a light brown solid (8.54 g, 78% yield). Mass spectrum m/z
399, 401 (M+H).sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
13.44 (br. s., 1H), 11.24 (s, 1H), 7.69 (s, 1H), 4.12 (qd, J=7.1,
2.3 Hz, 2H), 3.23-2.81 (m, 5H), 2.23-2.09 (m, 1H), 1.91-1.75 (m,
1H), 1.22 (t, J=7.0 Hz, 3H).
Intermediate 29
[0531] A solution of ethyl
5-bromo-8-carbamoyl-6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-carboxylat-
e (7.03 g, 17.6 mmol) in THF (200 mL) was cooled in a dry
ice-acetone bath and treated portionwise over 40 min with 1.6 M
methyllithium in THF (66.0 mL, 106 mmol). After 60 min, the mixture
was treated slowly at -78.degree. C. with saturated aqueous
NH.sub.4Cl and stirred for 10 min while warming to room
temperature. The mixture was extracted 3 times with DCM, and the
combined organic phases were washed sequentially with water and
brine, and dried and concentrated. The residue was purified by
column chromatography on silica gel (120 g), eluting with
EtOAc-hexanes (gradient from 0-100%), to give
5-bromo-6-chloro-2-(2-hydroxypropan-2-yl)-2,3,4,9-tetrahydro-1H-carbazole-
-8-carboxamide as a yellow solid (4.66 g). Mass spectrum m/z 385,
387 (M+H).sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 11.08
(s, 1H), 8.13 (br. s., 1H), 7.76 (s, 1H), 7.50 (br. s., 1H), 3.28
(d, J=5.5 Hz, 1H), 2.94 (dd, J=17.1, 4.7 Hz, 1H), 2.79-2.66 (m,
1H), 2.49-2.39 (m, 1H), 2.14 (d, J=9.5 Hz, 1H), 1.66 (td, J=11.4,
4.1 Hz, 1H), 1.33 (qd, J=12.4, 5.2 Hz, 1H), 1.15 (s, 6H).
Intermediates 30 and 31
(R)-5-Bromo-6-chloro-2-(2-hydroxypropan-2-yl)-2,3,4,9-tetrahydro-1H-carbaz-
ole-8-carboxamide (I-30), and
(S)-5-Bromo-6-chloro-2-(2-hydroxypropan-2-yl)-2,3,4,9-tetrahydro-1H-carbaz-
ole-8-carboxamide (I-31)
##STR00140##
[0533] A sample of racemic
5-bromo-6-chloro-2-(2-hydroxypropan-2-yl)-2,3,4,9-tetrahydro-1H-carbazole-
-8-carboxamide [Intermediate 29] (2.35 g) was separated by chiral
super-critical fluid chromatography as follows: column:
CHIRALPAK.RTM. IA (3.times.25 cm, 5 .mu.m); Mobile Phase:
CO.sub.2-MeOH (50:50) at 124 mL/min, 100 bar, 45.degree. C.; sample
preparation: 39 mg/mL in MeOH-DMSO (4:1); injection: 2.33 mL. The
first peak eluting from the column provided the (R) isomer,
(R)-5-bromo-6-chloro-2-(2-hydroxypropan-2-yl)-2,3,4,9-tetrahydro-1H-carba-
zole-8-carboxamide [Intermediate 30] as a yellow solid (1.15 g).
Mass spectrum m/z 385, 387 (M+H).sup.+. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 11.07 (s, 1H), 8.12 (br. s., 1H), 7.75 (s,
1H), 7.57-7.45 (m, 1H), 4.23 (s, 1H), 3.27 (d, J=4.7 Hz, 1H), 2.93
(dd, J=17.2, 4.7 Hz, 1H), 2.78-2.67 (m, 1H), 2.48-2.39 (m, 1H),
2.16-2.08 (m, 1H), 1.69-1.59 (m, 1H), 1.37-1.26 (m, 1H), 1.14 (s,
6H).
[0534] The second peak eluting from the column provided the (S)
isomer,
(S)-5-bromo-6-chloro-2-(2-hydroxypropan-2-yl)-2,3,4,9-tetrahydro-1H-carba-
zole-8-carboxamide [Intermediate 31] as an off-white solid (0.92
g). Mass spectrum m/z 385, 387 (M+H).sup.+. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 11.06 (s, 1H), 8.12 (br. s., 1H), 7.74 (s,
1H), 7.49 (br. s., 1H), 4.23 (s, 1H), 3.27 (d, J=5.0 Hz, 1H), 2.93
(dd, J=17.1, 4.6 Hz, 1H), 2.72 (t, J=11.8 Hz, 1H), 2.48-2.37 (m,
1H), 2.12 (d, J=9.2 Hz, 1H), 1.69-1.59 (m, 1H), 1.38-1.24 (m, 1H),
1.14 (s, 6H).
[0535] The absolute configuration of Intermediate 30 was confirmed
by single crystal x-ray analysis of crystals prepared by dissolving
the compound in excess 1,2-dichloroethane/EtOAc/acetic acid and
slowly evaporating the solvent at room temperature to provide a
di-acetic acid solvate. Unit cell dimensions: a=11.690(2) .ANG.,
b=7.0901(9) .ANG., c=14.427(3) .ANG., .alpha.=90.degree.,
.beta.=110.607(5).degree., .gamma.=90.degree.; Volume=1119.2(3)
.ANG..sup.3; Volume/Number of molecules in the unit cell=560
.ANG..sup.3; Space group: P2.sub.1; Molecules of Intermediate
30/asymmetric unit (Z'): 1; Density, calc g-cm.sup.-3: 1.501.
Fractional atomic coordinates at room temperature are given in
Table 8, and a depiction of the structure is given in FIG. 1.
TABLE-US-00008 TABLE 8 Fractional Atomic Coordinates for the
Di-acetic Acid Solvate of Intermediate 30 at Room Temperature Atom
X Y Z Br1 0.7129 0.3740 0.6642 Cl1 0.7740 0.3738 0.4607 N1 0.2665
0.3652 0.4430 O1 0.2004 0.3636 0.2416 C1 0.1772 0.3609 0.5790 C2
0.5901 0.3791 0.5379 C3 0.2812 0.3738 0.5418 C4 0.3773 0.3661
0.4329 C5 0.4669 0.3740 0.5291 C6 0.3082 0.3690 0.2482 C7 0.5312
0.3740 0.3598 C8 0.4074 0.3753 0.3462 C9 0.4036 0.3762 0.5976 C10
0.4463 0.3870 0.7085 C11 0.6203 0.3747 0.4534 C12 0.2289 0.3165
0.6913 N2 0.3387 0.3721 0.1672 O2 0.1932 0.2852 0.8423 C13 0.1290
0.3293 0.7384 C14 0.0723 0.5210 0.7302 C15 0.0325 0.1757 0.6967 C16
0.3389 0.4360 0.7413 O3 0.0996 0.3570 -0.0085 C17 0.0053 0.3621
0.0046 O4 -0.0020 0.3642 0.0929 C18 -0.1174 0.3580 -0.0772 C19
0.6259 0.3810 0.0872 O5 0.5910 0.4309 0.1503 O6 0.7118 0.4731
0.0663 C20 0.5791 0.2200 0.0206 H1 0.1973 0.3602 0.3950 H2 0.1212
0.2621 0.5441 H3 0.1327 0.4793 0.5676 H4 0.5548 0.3721 0.3046 H5
0.5091 0.4833 0.7321 H6 0.4813 0.2674 0.7370 H7 0.2569 0.1852
0.6979 H8 0.2826 0.3705 0.1095 H9 0.4142 0.3755 0.1729 H10 0.1460
0.2951 0.8728 H11 0.0219 0.5258 0.7703 H12 0.0232 0.5455 0.6624 H13
0.1355 0.6145 0.7528 H14 0.0720 0.0559 0.7005 H15 -0.0148 0.2037
0.6289 H16 -0.0205 0.1714 0.7347 H17 0.3637 0.4190 0.8124 H18
0.3175 0.5675 0.7267 H19 0.0671 0.3654 0.1347 H20 -0.1430 0.4843
-0.0980 H21 -0.1761 0.2992 -0.0536 H22 -0.1116 0.2873 -0.1321 H23
0.7379 0.5591 0.1062 H24 0.6424 0.1271 0.0321 H25 0.5538 0.2622
-0.0469 H26 0.5107 0.1656 0.0330
Intermediate 32
5-Methoxy-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pheny-
l)-1H-pyrido[1,2-c]pyrimidine-1,3(2H)-dione
##STR00141##
[0536] Intermediate 32A: Ethyl 2-(3-methoxypyridin-2-yl)acetate
##STR00142##
[0538] A stirred solution of diisopropylamine (0.385 mL, 2.70 mmol)
in THF (2 mL) at 0.degree. C. was treated slowly with 1.6 M
n-butyllithium in hexanes (1.69 mL, 2.70 mmol). The mixture was
stirred for 15 min, then was added over 5 min to a stirred solution
of 3-methoxy-2-picoline (0.133 g, 1.08 mmol) and diethyl carbonate
(0.262 mL, 2.16 mmol) in THF (5 mL) at -78.degree. C. After
stirring for 45 min more, the cooling bath was removed and stirring
was continued overnight at room temperature. The mixture was
treated with saturated aqueous NH.sub.4Cl and diluted with EtOAc.
The organic phase was separated, washed sequentially with saturated
aqueous NaHCO.sub.3 and brine, and dried and concentrated. The
residue was purified by column chromatography on silica gel (12 g),
eluting with 50% EtOAc-hexanes, to provide ethyl
2-(3-methoxypyridin-2-yl)acetate as an oil (0.17 g, 81% yield).
Mass spectrum m/z 196 (M+H).sup.+.
Intermediate 32B: Sodium 2-(3-methoxypyridin-2-yl)acetate
##STR00143##
[0540] A stirred solution of ethyl 2-(3-methoxypyridin-2-yl)acetate
(0.17 g, 0.871 mmol) in THF (2.5 mL) at room temperature was
treated with 3 M aqueous NaOH (0.581 mL, 1.74 mmol). After 7 h, the
mixture was concentrated to remove the THF and the aqueous residue
was frozen on dry ice and lyophilized to provide sodium
2-(3-methoxypyridin-2-yl)acetate as a white solid. A quantitative
yield was assumed and the material used without further
purification. Mass spectrum m/z 168 (M+H).sup.+.
Intermediate 32C:
N-(3-Bromo-2-methylphenyl)-2-(3-methoxypyridin-2-yl) acetamide
##STR00144##
[0542] A mixture of sodium 2-(3-methoxypyridin-2-yl)acetate (0.166
g, 0.871 mmol), 3-bromo-2-methylaniline (0.118 mL, 0.958 mmol),
DIEA (0.608 mL, 3.48 mmol) and HATU (0.397 g, 1.05 mmol) in DMF
(4.0 mL) was stirred at room temperature. After 1 h, the mixture
was diluted with EtOAc and washed twice with 10% aqueous LiCl, then
with brine, dried and concentrated. The residue was purified by
column chromatography on silica gel to provide
N-(3-bromo-2-methylphenyl)-2-(3-methoxypyridin-2-yl)acetamide as a
pale yellow solid (0.213 g, 73% yield). Mass spectrum m/z 335, 337
(M+H).sup.+.
Intermediate 32D:
2-(3-Methoxypyridin-2-yl)-N-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxab-
orolan-2-yl)phenyl)acetamide
##STR00145##
[0544] A mixture of
N-(3-bromo-2-methylphenyl)-2-(3-methoxypyridin-2-yl)acetamide (4.00
g, 11.9 mmol) and
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (3.48
g, 13.7 mmol) in DMSO (7 mL) and dioxane (35 mL) was bubbled with
argon for 5 min, then was treated with potassium acetate (2.93 g,
29.8 mmol). Bubbling was continued for 2 min, then the mixture was
treated with PdCl.sub.2(dppf) DCM adduct (0.487 g, 0.597 mmol). The
reaction vessel was sealed and heated at 90.degree. C. overnight.
The cooled mixture was diluted with EtOAc and washed sequentially
with water and brine. The combined aqueous layers were extracted
with EtOAc, and the combined organic layers were dried and
concentrated. The residue was filtered through a plug of silica gel
with 60% EtOAc-hexanes, and the filtrate was concentrated. The
residue was purified by column chromatography on silica gel,
eluting with EtOAc-hexanes, to give
2-(3-methoxypyridin-2-yl)-N-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxab-
orolan-2-yl)phenyl)acetamide as a tan solid (5.1 g, 82% yield).
.sup.1H NMR (400 MHz, chloroform-d) .delta. 9.65 (br. s., 1H), 8.20
(dd, J=4.3, 1.7 Hz, 1H), 8.14 (d, J=8.1 Hz, 1H), 7.54 (d, J=7.3 Hz,
1H), 7.24-7.17 (m, 3H), 4.01 (s, 2H), 3.88 (s, 3H), 2.45 (s, 3H),
1.35 (s, 12H).
Intermediate 32
[0545] A mixture of
2-(3-methoxypyridin-2-yl)-N-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxab-
orolan-2-yl)phenyl)acetamide (1.45 g, 3.78 mmol) and CDI (2.45 g,
15.1 mmol) in toluene (19 mL) was heated at 110.degree. C. for 3 h.
The cooled mixture was partitioned between EtOAc and water. The
organic layer was washed sequentially with water and brine, dried
and concentrated. The residue was purified by column chromatography
on silica gel, eluting with EtOAc-hexanes, to give
5-methoxy-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phen-
yl)-1H-pyrido[1,2-c]pyrimidine-1,3(2H)-dione as a yellow solid
(0.571 g, 37% yield). Mass spectrum m/z 409 (M+H).sup.+. .sup.1H
NMR (400 MHz, chloroform-d) .delta. 7.96 (d, J=7.0 Hz, 1H), 7.91
(dd, J=7.4, 1.2 Hz, 1H), 7.33 (t, J=7.6 Hz, 1H), 7.22 (dd, J=7.8,
1.2 Hz, 1H), 6.39-6.30 (m, 2H), 6.24 (s, 1H), 3.93 (s, 3H), 2.34
(s, 3H), 1.34 (s, 12H).
Intermediate 33
5-Chloro-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl-
)-1H-pyrido[1,2-c]pyrimidine-1,3(2H)-dione (racemic mixture)
##STR00146##
[0546] Intermediate 33A: Diethyl
2-(3-chloropyridin-2-yl)malonate
##STR00147##
[0548] A mixture of 3-chloro-2-fluoropyridine (5.00 g, 38.0 mmol),
diethyl malonate (14.6 g, 91 mmol) and Cs.sub.2CO.sub.3 (29.7 g, 91
mmol) in DMSO (42 mL) was heated at 100.degree. C. for 7 h. After
stirring overnight at room temperature, the mixture was diluted
with EtOAc, washed twice with water, then with brine. The combined
aqueous layers were extracted with EtOAc, and the combined organic
phases were dried and concentrated to give crude diethyl
2-(3-chloropyridin-2-yl) malonate as a colorless oil, used without
further purification. Mass spectrum m/z 272 (M+H).sup.+.
Intermediate 33B: Ethyl 2-(3-chloropyridin-2-yl)acetate
##STR00148##
[0550] A mixture of diethyl 2-(3-chloropyridin-2-yl) malonate
(10.32 g, 38 mmol), sodium chloride (5.55 g, 95 mmol) and water
(3.42 mL, 190 mmol) in DMSO (40 mL) was heated at 145.degree. C.
for 8 h. The mixture was cooled to room temperature, diluted with
EtOAc and washed twice with water, then with brine. The organic
phase was dried and concentrated to provide crude ethyl
2-(3-chloropyridin-2-yl)acetate, used without further purification.
Mass spectrum m/z 200 (M+H)+.
Intermediate 33C: Sodium 2-(3-chloropyridin-2-yl)acetate
##STR00149##
[0552] A solution of ethyl 2-(3-chloropyridin-2-yl)acetate (7.59 g,
38 mmol) in THF (76 mL) was treated at room temperature with 3 M
aqueous NaOH (25.3 mL, 76 mmol). The mixture was stirred at room
temperature overnight and concentrated to remove the THF. The
aqueous residue was frozen on dry ice and lyophilized to give
sodium 2-(3-chloropyridin-2-yl)acetate as an off-white solid, used
without further purification. Mass spectrum m/z 172
(M+H).sup.+.
Intermediate 33D:
N-(3-Bromo-2-methylphenyl)-2-(3-chloropyridin-2-yl)acetamide
##STR00150##
[0554] A mixture of sodium 2-(3-chloropyridin-2-yl)acetate (7.39 g,
38 mmol), 3-bromo-2-methylaniline (4.7 mL, 38.4 mmol), DIEA (13.3
mL, 76 mmol) and HATU (14.6 g, 38.4 mmol) in DMF (127 mL) was
stirred at room temperature. After 90 min the mixture was diluted
with EtOAc and washed twice with 10% LiCl, then with brine. The
combined aqueous layers were extracted with EtOAc, and the combined
organic phases were dried and concentrated to a small volume. The
solution was seeded with a crystal from an earlier batch and
allowed to stand overnight to provide a precipitate which was
collected by filtration and washed with 50% EtOAc-hexanes to
provide a white solid. The filtrate was concentrated and
recrystallized similarly three times to provide additional solid.
The solids were combined to give
N-(3-bromo-2-methylphenyl)-2-(3-chloropyridin-2-yl)acetamide as a
white solid (11.43 g, 89% yield). Mass spectrum m/z 339, 341
(M+H).sup.+. .sup.1H NMR (400 MHz, chloroform-d) .delta. 9.76 (br.
s., 1H), 8.52 (d, J=3.5 Hz, 1H), 7.92 (d, J=7.9 Hz, 1H), 7.80 (dd,
J=8.1, 1.1 Hz, 1H), 7.36 (d, J=7.9 Hz, 1H), 7.32-7.23 (m, 1H), 7.06
(t, J=8.0 Hz, 1H), 4.16 (s, 2H), 2.39 (s, 3H).
Intermediate 33E:
2-(3-Chloropyridin-2-yl)-N-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxabo-
rolan-2-yl)phenyl)acetamide
##STR00151##
[0556] A mixture of
N-(3-bromo-2-methylphenyl)-2-(3-chloropyridin-2-yl)acetamide (4.0
g, 11.78 mmol) and
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (3.29
g, 12.96 mmol) in DMSO (5 mL) and dioxane (25 mL) was bubbled with
argon for 7 min, followed by addition of potassium acetate (2.89 g,
29.4 mmol). Argon bubbling was continued for 7 min after which
PdCl.sub.2(dppf) DCM adduct (0.481 g, 0.589 mmol) was added. The
mixture was heated at 90.degree. C. for 7 h. The cooled mixture was
diluted with EtOAc and filtered through CELITE.RTM.. The filtrate
was washed sequentially with water and brine. The combined aqueous
layers were extracted with EtOAc, and the combined organic phases
were dried and concentrated. The residue was recrystallized from
EtOAc to provide a white solid. The mother liquor was concentrated
and the residue was recrystallized from EtOAc. The two solids were
combined to provide
2-(3-chloropyridin-2-yl)-N-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxabo-
rolan-2-yl)phenyl)acetamide as a white solid (3.88 g, 85% yield).
Mass spectrum m/z 387 (M+H).sup.+.
Intermediate 33
[0557] A mixture of
2-(3-chloropyridin-2-yl)-N-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxabo-
rolan-2-yl)phenyl)acetamide (0.192 g, 0.497 mmol) and CDI (0.322 g,
1.986 mmol) in toluene (2 mL) was heated at 110.degree. C. After 5
h, the cooled mixture was diluted with EtOAc and washed
sequentially with water and brine. The combined aqueous layers were
extracted with EtOAc, and the combined organic phases were dried
and concentrated. The residue was purified by column chromatography
on silica gel, eluting with EtOAc-hexanes, to provide racemic
5-chloro-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pheny-
l)-1H-pyrido[1,2-c]pyrimidine-1,3(2H)-dione as a bright yellow
solid (0.133 g, 65% yield). Mass spectrum m/z 413 (M+H).sup.+.
.sup.1H NMR (400 MHz, chloroform-d) .delta. 8.26 (dt, J=7.6, 0.9
Hz, 1H), 7.94 (dd, J=7.5, 1.3 Hz, 1H), 7.36 (t, J=7.6 Hz, 1H),
7.27-7.18 (m, 2H), 6.36 (t, J=7.3 Hz, 1H), 6.31 (s, 1H), 1.57 (s,
3H), 1.36 (s, 12H).
Intermediates 34 and 35
5-Chloro-2-(R)-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ph-
enyl)-1H-pyrido[1,2-c]pyrimidine-1,3(2H)-dione (I-34), and
5-Chloro-2-(S)-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ph-
enyl)-1H-pyrido[1,2-c]pyrimidine-1,3(2H)-dione (I-35)
##STR00152##
[0559] A sample of racemic
5-chloro-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pheny-
l)-1H-pyrido[1,2-c]pyrimidine-1,3(2H)-dione [Intermediate 33] was
separated by chiral super-critical fluid chromatography as follows:
column: WHELK-O.RTM. R,R (3.times.25 cm, 5 .mu.m); Mobile Phase:
CO.sub.2-MeOH (55:45) at 200 mL/min, 100 bar, 35.degree. C.; sample
preparation: 96 mg/mL in MeCN-DCM (1:4); injection: 5 mL. The first
peak eluting from the column provided
5-chloro-2-(R)-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)p-
henyl)-1H-pyrido[1,2-c]pyrimidine-1,3(2H)-dione [Intermediate 34].
The second peak eluting from the column provided
5-chloro-2-(S)-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)p-
henyl)-1H-pyrido[1,2-c]pyrimidine-1,3(2H)-dione [Intermediate 35].
The mass spectrum and .sup.1H NMR for each enantiomeric atropisomer
were the same as those for Intermediate 33.
[0560] Alternatively, a sample of racemic
5-chloro-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pheny-
l)-1H-pyrido[1,2-c]pyrimidine-1,3(2H)-dione [Intermediate 33] was
separated by chiral super-critical fluid chromatography as follows:
column: WHELK-O.RTM. R,R (3.times.25 cm, 5 .mu.m); Mobile Phase:
CO.sub.2--CH.sub.3CN (55:45) at 200 mL/min, 100 bar, 35.degree. C.;
sample preparation: 96 mg/mL in MeCN-DCM (1:4); injection: 5 mL.
The first peak eluting from the column provided
5-chloro-2-(S)-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)p-
henyl)-1H-pyrido[1,2-c]pyrimidine-1,3(2H)-dione [Intermediate 35].
The material could be further purified by dissolving in THF,
diluting with hexanes and collecting the precipitate by
filtration.
[0561] The absolute configuration of Intermediate 35 was confirmed
by single crystal x-ray analysis of crystals prepared by dissolving
the compound in excess acetone and slowly evaporating the solvent
at room temperature. Unit cell dimensions: a=19.6161(8) .ANG.,
b=9.1411(4) .ANG., c=12.7541(6) .ANG., .alpha.=90.degree.,
.beta.=113.165(2).degree., .gamma.=90.degree.; Space group: C2;
Molecules of Intermediate 35/asymmetric unit (Z'): 1; Density, calc
g-cm.sup.-3: 1.304. Fractional atomic coordinates at room
temperature are given in Table 9, and a depiction of the structure
is given in FIG. 2.
TABLE-US-00009 TABLE 9 Fractional Atomic Coordinates for
Intermediate 35 at Room Temperature Atom X Y Z Cl1 -0.1755 -0.1003
0.3365 O1 0.2261 0.6937 0.2037 C1 0.2132 0.8050 0.1156 C2 0.1347
0.7655 0.0313 O2 0.1028 0.6968 0.1045 B1 0.1597 0.6467 0.1980 C3
0.1403 0.4028 0.4772 C4 0.1906 0.5142 0.4966 C5 0.1012 0.4308
0.2727 C6 0.1966 0.5843 0.4048 C7 0.0966 0.3615 0.3668 C8 0.1517
0.5466 0.2926 C9 0.0863 0.8966 -0.0281 C10 0.0532 0.3809 0.1539 C11
0.1298 0.6565 -0.0585 C12 0.2226 0.9474 0.1724 C13 0.2710 0.7829
0.0643 N1 0.0457 0.2404 0.3528 C14 0.0746 0.1035 0.3564 N2 0.0270
-0.0148 0.3551 C15 -0.0287 0.2712 0.3397 C16 -0.0453 0.0086 0.3467
C17 -0.0720 0.1477 0.3375 C18 0.0561 -0.1540 0.3608 C19 -0.0563
-0.2557 0.3562 C20 -0.0863 -0.1218 0.3472 C21 0.0166 -0.2724 0.3622
O3 -0.0487 0.3988 0.3318 O4 0.1356 0.0809 0.3596 H1 0.1356 0.3551
0.5384 H2 0.2203 0.5422 0.5706 H3 0.2313 0.6587 0.4179 H4 0.0388
0.8624 -0.0807 H5 0.1101 0.9509 -0.0687 H6 0.0796 0.9586 0.0279 H7
0.0613 0.2788 0.1461 H8 0.0655 0.4356 0.0994 H9 0.0019 0.3967
0.1400 H10 0.1556 0.5689 -0.0231 H11 0.1519 0.6967 -0.1073 H12
0.0787 0.6339 -0.1029 H13 0.1871 0.9571 0.2066 H14 0.2151 1.0241
0.1175 H15 0.2718 0.9545 0.2304 H16 0.3176 0.8231 0.1147 H17 0.2550
0.8312 -0.0083 H18 0.2769 0.6801 0.0543 H19 -0.1208 0.1615 0.3296
H20 0.1039 -0.1652 0.3637 H21 -0.0838 -0.3378 0.3584 H22 0.0370
-0.3652 0.3671
Intermediate 36
6-(2-Methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-5H-thia-
zolo[3,2-c]pyrimidine-5,7(6H)-dione
##STR00153##
[0562] Intermediate 36A:
N-(3-Bromo-2-methylphenyl)-2-(thiazol-2-yl)acetamide
##STR00154##
[0564] A mixture of 3-bromo-2-methylaniline (0.764 mL, 6.20 mmol),
1,3-thiazol-2-ylacetic acid (0.74 g, 5.17 mmol) and DIEA (1.63 mL,
9.30 mmol) in DMF (15 mL) was treated with HATU (2.36 g, 6.20
mmol). After stirring overnight, the mixture was diluted with
EtOAc, washed twice with 10% aqueous LiCl followed by brine, and
the combined aqueous layers were extracted with EtOAc. The combined
organic layers were dried and concentrated, and the residue was
purified by column chromatography on silica gel, eluting with
EtOAc-hexanes, to give
N-(3-bromo-2-methylphenyl)-2-(thiazol-2-yl)acetamide as a white
solid (0.681 g, 42% yield). .sup.1H NMR (400 MHz, chloroform-d)
.delta. 9.84-9.65 (m, 1H), 7.91 (d, J=7.9 Hz, 1H), 7.84 (d, J=3.3
Hz, 1H), 7.42-7.35 (m, 2H), 7.07 (t, J=8.0 Hz, 1H), 4.18 (s, 2H),
2.38 (s, 3H).
Intermediate 36B:
N-(2-Methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-(thi-
azol-2-yl)acetamide
##STR00155##
[0566] A mixture of
N-(3-bromo-2-methylphenyl)-2-(thiazol-2-yl)acetamide (0.53 g, 1.70
mmol) 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane)
(0.476 g, 1.87 mmol) and potassium acetate (0.418 g, 4.26 mmol) in
DMSO (1.6 mL) and dioxane (8 mL) was bubbled with nitrogen for 5
min, followed by the addition of PdCl.sub.2(dppf) DCM adduct (0.070
g, 0.085 mmol). After bubbling with nitrogen for another 5 min, the
mixture was heated at 90.degree. C. for 7 h. The cooled mixture was
diluted with EtOAc and filtered through CELITE.RTM.. The filtrate
was washed sequentially with water and brine, and dried and
concentrated. The residue was purified by column chromatography on
silica gel (40 g), eluting with 50% EtOAc-hexanes, to give
N-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-(thi-
azol-2-yl)acetamide as an off-white solid (0.45 g, 74% yield). Mass
spectrum m/z 359 (M+H).sup.+.
Intermediate 36
[0567] A mixture of
N-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)
phenyl)-2-(thiazol-2-yl)acetamide (0.45 g, 1.26 mmol) and CDI
(0.815 g, 5.02 mmol) in toluene (6.5 mL) was heated at 110.degree.
C. for 2 h. The cooled mixture was partitioned between EtOAc and
water. The organic layer was washed with brine, and the combined
aqueous layers were extracted with EtOAc. The combined organic
layers were dried and concentrated. The residue was purified by
column chromatography on silica gel (40 g), eluting with 70%
EtOAc-hexanes, to give slightly impure
6-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-5H-thi-
azolo[3,2-c]pyrimidine-5,7(6H)-dione as a tan solid (34% yield).
The material was used without further purification. Mass spectrum
m/z 385 (M+H).sup.+.
Intermediate 37
Racemic
5-fluoro-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-y-
l)phenyl)-1H-pyrido[1,2-c]pyrimidine-1,3(2H)-dione
##STR00156##
[0568] Intermediate 37A: Diethyl
2-(3-fluoropyridin-2-yl)malonate
##STR00157##
[0570] A mixture of 2,3-difluoropyridine (2.00 g, 17.4 mmol),
Cs.sub.2CO.sub.3 (13.59 g, 41.7 mmol) and diethyl malonate (6.68 g,
41.7 mmol) in DMSO (19 mL) was heated at 100.degree. C. for 4.5 h.
The mixture was poured onto ice, diluted with EtOAc, and the
organic phase was separated, washed sequentially with water and
brine, and dried and concentrated. The residue was purified by
column chromatography on silica gel (80 g), eluting with
EtOAc-hexanes (sequentially 10%, 20% and 30%), to provide diethyl
2-(3-fluoropyridin-2-yl)malonate as a pale colored oil (2.68 g, 60%
yield). .sup.1H NMR (400 MHz, chloroform-d) .delta. 8.42 (dt,
J=4.6, 1.3 Hz, 1H), 7.43 (ddd, J=9.4, 8.3, 1.4 Hz, 1H), 7.30 (dt,
J=8.5, 4.3 Hz, 1H), 5.09 (d, J=1.1 Hz, 1H), 4.30 (q, J=7.0 Hz, 4H),
1.33-1.26 (m, 6H).
Intermediate 37B: Ethyl 2-(3-fluoropyridin-2-yl)acetate
##STR00158##
[0572] A mixture of diethyl 2-(3-fluoropyridin-2-yl)malonate (2.68
g, 10.5 mmol), sodium chloride (0.675 g, 11.6 mmol) and water
(0.378 mL, 21.0 mmol) in DMSO (15 mL) was heated at 145.degree. C.
for 4.5 h. The mixture was cooled, diluted with EtOAc and washed
sequentially with water and brine. The organic phase was dried and
concentrated to provide ethyl 2-(3-fluoropyridin-2-yl)acetate as a
pale colored oil (1.90 g, 99% yield) which was used without further
purification. Mass spectrum m/z 184 (M+H).sup.+.
Intermediate 37C: Sodium 2-(3-fluoropyridin-2-yl)acetate
##STR00159##
[0574] A stirred solution of ethyl 2-(3-fluoropyridin-2-yl)acetate
(1.90 g, 10.4 mmol) in THF (26 mL) was treated with 3 M aqueous
NaOH (6.9 mL, 20.7 mmol) and stirred at room temperature overnight.
The mixture was concentrated to remove the THF, and the residual
aqueous solution was frozen and lyophilized to provide sodium
2-(3-fluoropyridin-2-yl)acetate as a white solid (assumed 100%
yield), which was used without further purification. Mass spectrum
m/z 156 (M+H).sup.+.
Intermediate 37D:
N-(3-Bromo-2-methylphenyl)-2-(3-fluoropyridin-2-yl)acetamide
##STR00160##
[0576] A mixture of sodium 2-(3-fluoropyridin-2-yl)acetate (1.847
g, 10.37 mmol), 3-bromo-2-methylaniline (1.41 mL, 11.4 mmol), DIEA
(5.4 mL, 31.1 mmol) and HATU (4.73 g, 12.4 mmol) in DMF (30 mL) was
stirred at room temperature for 1.25 h. The mixture was diluted
with EtOAc and washed twice with 10% aqueous LiCl, then with brine.
The combined aqueous layers were extracted with EtOAc, and the
combined organic phases were dried and concentrated. The residue
was dissolved in hot EtOAc, allowed to cool, and the resulting
white solid collected by filtration and washed with 60%
EtOAc-hexanes. The combined filtrates were concentrated and the
residue was recrystallized twice using the same procedure. The
residue from concentration of the final filtrate was purified by
column chromatography on silica gel, eluting with EtOAc-hexanes, to
provide a solid which was combined with the recrystallized batches
to provide
N-(3-bromo-2-methylphenyl)-2-(3-fluoropyridin-2-yl)acetamide as a
white solid (2.03 g, 61% yield). Mass spectrum m/z 323, 325
(M+H).sup.+.
Intermediate 37E:
2-(3-Fluoropyridin-2-yl)-N-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxabo-
rolan-2-yl)phenyl)acetamide
##STR00161##
[0578] A mixture of
N-(3-bromo-2-methylphenyl)-2-(3-fluoropyridin-2-yl)acetamide (4.20
g, 13.6 mmol) and
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (3.80
g, 14.9 mmol) in dioxane (40 mL) was bubbled with nitrogen for 10
min. Potassium acetate (3.33 g, 34.0 mmol) was added to the
mixture, bubbling was continued for another 5 min, and
PdCl.sub.2(dppf) DCM adduct (0.555 g, 0.679 mmol) was added. The
mixture was heated at 100.degree. C. overnight. The cooled mixture
was diluted with EtOAc, washed sequentially with water and brine,
dried and concentrated. The residue was purified by column
chromatography on silica gel, eluting with DCM-methyl t-butyl
ether, to provide
2-(3-fluoropyridin-2-yl)-N-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxabo-
rolan-2-yl)phenyl)acetamide as a white solid (3.80 g, 76% yield).
Mass spectrum m/z 371 (M+H).sup.+.
Intermediate 37
[0579] A mixture of
2-(3-fluoropyridin-2-yl)-N-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxabo-
rolan-2-yl)phenyl)acetamide (9.01 g, 24.3 mmol) and CDI (15.78 g,
97 mmol) in toluene (97 mL) was heated at 120.degree. C. for 7 h.
The cooled mixture was diluted with EtOAc and washed sequentially
with water and brine. The combined aqueous layers were extracted
with EtOAc, and the combined organic phases were dried and
concentrated. The residue was purified by column chromatography on
silica gel (220 g), eluting with EtOAc-hexanes (gradient from
20-100%), to provide
5-fluoro-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pheny-
l)-1H-pyrido[1,2-c]pyrimidine-1,3(2H)-dione as a yellow solid (6.26
g, 65% yield). Mass spectrum m/z 397 (M+H).sup.+. .sup.1H NMR (400
MHz, chloroform-d) .delta. 8.11 (dd, J=7.6, 0.8 Hz, 1H), 7.94 (dd,
J=7.5, 1.3 Hz, 1H), 7.35 (t, J=7.5 Hz, 1H), 7.23 (dd, J=7.8, 1.4
Hz, 1H), 6.85-6.76 (m, 1H), 6.35 (td, J=7.4, 5.0 Hz, 1H), 6.09 (s,
1H), 2.36 (s, 3H), 1.36 (s, 12H).
Intermediates 38 and 39
5-Fluoro-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl-
)-1H-pyrido[1,2-c]pyrimidine-1,3(2H)-dione (single
atropisomers)
##STR00162##
[0581] A sample of racemic
5-fluoro-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pheny-
l)-1H-pyrido[1,2-c]pyrimidine-1,3(2H)-dione [Intermediate 37] (7.5
g) was separated by chiral super-critical fluid chromatography as
follows: column: CHIRALCEL.RTM. OD-H (5.times.25 cm, 5 .mu.m);
Mobile Phase: CO.sub.2-MeOH (76:24) at 280 mL/min, 100 bar,
40.degree. C.; sample preparation: 62.5 mg/mL in DCM-MeOH (1:1);
injection: 0.83 mL. The first peak eluting from the column provided
one atropisomer of
5-fluoro-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pheny-
l)-1H-pyrido[1,2-c]pyrimidine-1,3(2H)-dione [Intermediate 38] as a
yellow solid (3.2 g, chiral purity 99.3%). The second peak eluting
from the column provided the other atropisomer of
5-fluoro-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pheny-
l)-1H-pyrido[1,2-c]pyrimidine-1,3(2H)-dione [Intermediate 39] as a
yellow solid (2.98 g, chiral purity 98.6%). The mass spectrum and
.sup.1H NMR for both enantiomers were the same as those for
Intermediate 37.
Intermediate 40
(Z)-4-((2-Chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)imi-
no)-1-methyl-1H-benzo[d][1,3]oxazin-2(4H)-one
##STR00163##
[0582] Intermediate 40A:
N-(3-Bromo-2-chlorophenyl)-2-(methylamino)benzamide
##STR00164##
[0584] A mixture of 3-bromo-2-chloroaniline [prepared according to
the procedure described in U.S. Pat. No. 8,242,260] (240 mg, 1.162
mmol) and toluene (10 mL) at 0.degree. C. was slowly treated with 2
M trimethylaluminum in toluene (0.99 mL, 1.98 mmol). The mixture
was allowed to warm to room temperature and stirred for 15 min. A
partial suspension of 1-methyl-1H-benzo[d][1,3]oxazine-2,4-dione
(300 mg, 1.52 mmol) in toluene (4 mL) was added slowly. The
resulting mixture was heated at 50.degree. C. for 4 h, cooled to
0.degree. C., and treated dropwise with 1 M aqueous HCl until no
more gas evolution was observed. The mixture was stirred for 2 h
while warming to room temperature, then was extracted with EtOAc.
The organic phase was washed sequentially with NaHCO.sub.3 and
brine, dried and concentrated. The residue was purified by column
chromatography on silica gel (80 g), eluting with EtOAc-hexanes
(gradient from 0-30%), to provide
N-(3-bromo-2-chlorophenyl)-2-(methylamino)benzamide as a yellow
solid (110 mg, 28% yield). Mass spectrum m/z 339, 341 (M+H).sup.+.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 10.00 (s, 1H), 7.78
(dd, J=7.9, 1.5 Hz, 1H), 7.67 (dd, J=8.1, 1.5 Hz, 1H), 7.57 (dd,
J=8.0, 1.4 Hz, 1H), 7.53 (d, J=1.3 Hz, 1H), 7.38 (ddd, J=8.4, 7.1,
1.4 Hz, 1H), 7.32 (t, J=8.0 Hz, 1H), 6.70 (d, J=8.4 Hz, 1H),
6.68-6.61 (m, 1H), 2.79 (d, J=5.1 Hz, 3H).
Intermediate 40B:
(Z)-4-((3-Bromo-2-chlorophenyl)imino)-1-methyl-1H-benzo[d][1,3]oxazin-2(4-
H)-one
##STR00165##
[0586] A solution of
N-(3-bromo-2-chlorophenyl)-2-(methylamino)benzamide (150 mg, 0.442
mmol) in THF (15 mL) cooled to 0.degree. C. and treated with
triphosgene (197 mg, 0.663 mmol). The mixture was stirred at room
temperature for 1 h, then was cooled to 0.degree. C. and treated
with water until gas evolution ceased. The mixture was
concentrated, and the residue was dissolved in EtOAc and washed
sequentially with saturated aqueous NaHCO.sub.3, water and brine,
dried and concentrated. The residue was purified by column
chromatography on silica gel, eluting with EtOAc-hexanes (gradient
from 0-50%), to provide
(Z)-4-((3-bromo-2-chlorophenyl)imino)-1-methyl-1H-benzo[d][1,3]oxazin-2(4-
H)-one as a beige solid (130 mg, 81% yield). .sup.1H NMR (400 MHz,
chloroform-d) .delta. 8.33 (dd, J=7.8, 1.4 Hz, 1H), 7.72-7.61 (m,
1H), 7.41 (dd, J=7.9, 1.5 Hz, 1H), 7.36-7.28 (m, 1H), 7.16-7.08 (m,
2H), 7.07-7.01 (m, 1H), 3.55 (s, 3H).
Intermediate 40
[0587] A mixture of
(Z)-4-((3-bromo-2-chlorophenyl)imino)-1-methyl-1H-benzo[d][1,3]oxazin-2(4-
H)-one (130 mg, 0.356 mmol),
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (117
mg, 0.462 mmol) and potassium acetate (87 mg, 0.889 mmol) in
dioxane (4 mL) was bubbled with nitrogen for 10 min. The mixture
was treated with PdCl.sub.2(dppf) DCM adduct (14.5 mg, 0.018 mmol),
and heated at 90.degree. C. overnight. The cooled mixture was
partitioned between EtOAc and water. The organic phase was dried
and concentrated and the residue was purified by column
chromatography on silica gel, eluting with EtOAc-hexanes (gradient
from 0-50%), to provide
(Z)-4-((2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)im-
ino)-1-methyl-1H-benzo[d][1,3]oxazin-2(4H)-one as a yellow solid
(120 mg, 82% yield). Mass spectrum m/z 413 (M+H).sup.+. .sup.1H NMR
(400 MHz, chloroform-d) .delta. 8.40-8.30 (m, 1H), 7.67-7.58 (m,
1H), 7.48-7.44 (m, 1H), 7.27 (s, 4H), 7.16-7.07 (m, 2H), 3.55-3.47
(m, 3H), 1.40-1.37 (m, 12H).
Intermediate 41
3-(2-Chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-8-fluor-
o-1-methylquinazoline-2,4(1H,3H)-dione
##STR00166##
[0588] Intermediate 41A:
2-Amino-N-(3-bromo-2-chlorophenyl)-3-fluorobenzamide
##STR00167##
[0590] A mixture of 3-bromo-2-chloroaniline [prepared according to
the procedure described in U.S. Pat. No. 8,242,260] (600 mg, 2.91
mmol) and toluene (10 mL) was cooled to 0.degree. C. and slowly
treated with 2 M trimethylaluminum in toluene (2.47 mL, 4.94 mmol).
The mixture was allowed to warm to room temperature and stirred for
15 min. The mixture was treated with
8-fluoro-1H-benzo[d][1,3]oxazine-2,4-dione (684 mg, 3.78 mmol) and
heated at 50.degree. C. for 16 h. The mixture was cooled to
0.degree. C. and treated dropwise with 1 M aqueous HCl until gas
evolution stopped, and stirred for 2 h while allowing to warm to
room temperature. The mixture was extracted three times with EtOAc.
The combined organic phases were washed sequentially with saturated
aqueous NaHCO.sub.3 and brine, dried and concentrated. The residue
was purified by column chromatography on silica gel (24 g), eluting
with EtOAc-hexanes (gradient from 0-30%), to provide
2-amino-N-(3-bromo-2-chlorophenyl)-3-fluorobenzamide as a pale
yellow solid (350 mg, 35% yield). Mass spectrum m/z 343, 345
(M+H)+. .sup.1H NMR (400 MHz, chloroform-d) .delta. 8.46 (dd,
J=8.4, 1.3 Hz, 1H), 8.42 (br. s., 1H), 7.43 (dd, J=8.0, 1.4 Hz,
1H), 7.34 (d, J=8.1 Hz, 1H), 7.22 (t, J=8.3 Hz, 1H), 7.15 (ddd,
J=11.0, 8.0, 1.2 Hz, 1H), 6.69 (td, J=8.0, 5.1 Hz, 1H), 5.72 (br.
s., 2H).
Intermediate 41B:
3-(3-Bromo-2-chlorophenyl)-8-fluoroquinazoline-2,4(1H,3H)-dione
##STR00168##
[0592] Triphosgene (453 mg, 1.53 mmol) was added in one portion to
a solution of amino-N-(3-bromo-2-chlorophenyl)-3-fluorobenzamide
(350 mg, 1.019 mmol) in THF (10 mL) at 0.degree. C. The mixture was
stirred at room temperature for 1 h, then was cooled to 0.degree.
C. and treated with water until no more gas evolution was observed.
The mixture was concentrated and the residue was dissolved in
EtOAc, washed sequentially with saturated aqueous NaHCO.sub.3,
water and brine, and dried and concentrated. The residue was
purified by column chromatography on silica gel (24 g), eluting
with EtOAc-hexanes (gradient from 0-50%), to provide
3-(3-bromo-2-chlorophenyl)-8-fluoroquinazoline-2,4(1H,3H)-dione as
a yellow solid (320 mg, 85% yield). Mass spectrum m/z 369, 371
(M+H).sup.+. .sup.1H NMR (400 MHz, chloroform-d) .delta. 8.54 (br.
s., 1H), 7.97 (d, J=8.1 Hz, 1H), 7.77 (dd, J=6.8, 2.6 Hz, 1H), 7.46
(ddd, J=9.8, 8.3, 1.2 Hz, 1H), 7.36-7.29 (m, 2H), 7.24 (td, J=8.0,
4.8 Hz, 1H).
Intermediate 41C:
3-(3-Bromo-2-chlorophenyl)-8-fluoro-1-methylquinazoline-2,4(1H,3H)-dione
##STR00169##
[0594] Iodomethane (0.102 mL, 1.62 mmol) was added slowly to a
mixture of
3-(3-bromo-2-chlorophenyl)-8-fluoroquinazoline-2,4(1H,3H)-dione
(300 mg, 0.812 mmol), DMF (5 mL) and Cs.sub.2CO.sub.3 (529 mg, 1.62
mmol). The mixture was stirred at room temperature for 2 h, then
was diluted with EtOAc, washed sequentially with water and brine,
and dried and concentrated. The residue was purified by column
chromatography on silica gel (24 g), eluting with EtOAc-hexanes
(gradient from 0-30%), to provide
3-(3-bromo-2-chlorophenyl)-8-fluoro-1-methylquinazoline-2,4(1H,3H)-dione
as a yellow solid (280 mg, 90% yield). Mass spectrum m/z 383, 385
(M+H).sup.+. .sup.1H NMR (400 MHz, chloroform-d) .delta. 8.09 (dq,
J=7.8, 0.8 Hz, 1H), 7.79-7.71 (m, 1H), 7.49 (ddd, J=13.9, 8.1, 1.5
Hz, 1H), 7.32-7.29 (m, 2H), 7.29-7.22 (m, 2H), 3.88 (s, 1.5H), 3.86
(s, 1.5H).
Intermediate 41
[0595] A mixture of
3-(3-bromo-2-chlorophenyl)-8-fluoro-1-methylquinazoline-2,4(1H,3H)-dione
(150 mg, 0.391 mmol),
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (129
mg, 0.508 mmol), potassium acetate (96 mg, 0.978 mmol) and dioxane
(8 mL) was bubbled with nitrogen for 10 min and treated with
PdCl.sub.2(dppf) DCM adduct (16 mg, 0.020 mmol). The mixture was
heated at 90.degree. C. for 16 h, then was cooled and partitioned
between EtOAc and water. The organic phase was dried and
concentrated, and the residue was purified by column chromatography
on silica gel (12 g), eluting with EtOAc-hexanes (gradient from
0-50%), to give
3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-8-fluo-
ro-1-methylquinazoline-2,4(1H,3H)-dione as a white glassy solid (52
mg, 31% yield). Mass spectrum m/z 431 (M+H).sup.+. .sup.1H NMR (400
MHz, chloroform-d) .delta. 8.14-8.05 (m, 1H), 7.90-7.82 (m, 1H),
7.51-7.35 (m, 3H), 7.26-7.19 (m, 1H), 3.86 (d, J=8.1 Hz, 3H), 1.36
(s, 12H).
Intermediate 42
3-(2-Chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-8-fluor-
oquinazoline-2,4(1H,3H)-dione
##STR00170##
[0597] A mixture of
3-(3-bromo-2-chlorophenyl)-8-fluoroquinazoline-2,4(1H,3H)-dione
[Intermediate 41B] (990 mg, 2.68 mmol),
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (884
mg, 3.48 mmol) and potassium acetate (657 mg, 6.70 mmol) in dioxane
(8 mL) was bubbled with nitrogen for 10 min. PdCl.sub.2(dppf) DCM
adduct (109 mg, 0.134 mmol) was added and the mixture was heated at
90.degree. C. overnight. The cooled mixture was diluted with EtOAc,
filtered, and the filtrate was concentrated. The residue was
purified by column chromatography on silica gel, eluting with
MeOH-DCM (gradient from 0-5%), to give
3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl-
)-8-fluoroquinazoline-2,4(1H,3H)-dione as a brown solid (710 mg,
64% yield). Mass spectrum m/z 416 (M+H).sup.+. .sup.1H NMR (400
MHz, chloroform-d) .delta. 8.55-8.38 (m, 1H), 8.06-7.93 (m, 1H),
7.90-7.75 (m, 1H), 7.51-7.38 (m, 3H), 7.26-7.13 (m, 1H), 1.26 (br.
s., 12H)
Intermediate 43
7-Fluoro-3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl-
)quinazoline-2,4(1H,3H)-dione
##STR00171##
[0599] Using the procedure used to prepare Intermediate 8,
3-(3-bromo-2-methylphenyl)-7-fluoroquinazoline-2,4(1H,3H)-dione
[Intermediate 15B] was converted into
7-fluoro-3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pheny-
l)quinazoline-2,4(1H,3H)-dione. Mass spectrum m/z 397
(M+H).sup.+.
Intermediate 44
1-(4-Fluorophenyl)-3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
-yl) phenyl)pyrimidine-2,4(1H,3H)-dione
##STR00172##
[0600] Intermediate 44A: Methyl
3-(4-methoxybenzylamino)-2-(phenylselanyl)propanoate
##STR00173##
[0602] A suspension of phenyl hypobromoselenoite (5.54 g, 23.5
mmol) and zinc(II) chloride (1.27 g, 9.29 mmol) in DCM (116 mL) was
treated with methyl acrylate (2.09 mL, 23.2 mmol). The mixture was
stirred at room temperature for 30 min, then was treated with
(4-methoxyphenyl)methanamine (6.4 mL, 48.8 mmol), forming a thick
suspension. After stirring for 16 h, the mixture was filtered, the
collected precipitate was washed with EtOAc, and the combined
filtrates were concentrated. The residue was purified by column
chromatography on silica gel (120 g), eluting with EtOAc-hexanes
(gradient from 0-50%), to provide methyl
3-(4-methoxybenzylamino)-2-(phenylselanyl) propanoate as a light
brown oil (3.68 g, 42% yield). Mass spectrum m/z 380 (M+H).sup.+.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.53-7.49 (m, 2H),
7.39-7.28 (m, 3H), 7.18 (d, J=8.6 Hz, 2H), 6.88-6.82 (m, 2H), 3.89
(dd, J=8.8, 5.9 Hz, 1H), 3.73 (s, 3H), 3.61 (s, 2H), 3.55 (s, 3H),
2.93-2.78 (m, 2H).
Intermediate 44B: 1-Bromo-3-isocyanato-2-methylbenzene
##STR00174##
[0604] A solution of triphosgene (2.25 g, 7.58 mmol) in toluene (27
mL), cooled in an ice-water bath, was treated slowly with a
solution of 3-bromo-2-methylaniline (3.00 g, 16.1 mmol) and DIEA
(5.6 mL, 32.2 mmol) in toluene (5.4 mL). The resulting suspension
was stirred at room temperature for 2 h. The precipitate was
removed by filtration and washed with EtOAc. The combined filtrates
were diluted with EtOAc, washed with brine, dried and concentrated
to provide 1-bromo-3-isocyanato-2-methylbenzene as a brown oil
(3.68 g, 98% yield), used without purification. .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 7.49 (dd, J=8.1, 0.9 Hz, 1H), 7.31 (dd,
J=7.9, 0.7 Hz, 1H), 7.15 (td, J=8.0, 0.7 Hz, 1H), 2.38 (s, 3H).
Intermediate 44C:
3-(3-Bromo-2-methylphenyl)-1-(4-methoxybenzyl)-5-(phenylselanyl)
dihydropyrimidine-2,4(1H,3H)-dione
##STR00175##
[0606] A mixture of methyl
3-((4-methoxybenzyl)amino)-2-(phenylselanyl)propanoate (3.68 g,
9.73 mmol), 1-bromo-3-isocyanato-2-methylbenzene (2.27 g, 10.7
mmol), and K.sub.2CO.sub.3 (0.672 g, 4.86 mmol) in DMF (49 mL) was
heated at 65.degree. C. for 5 h. The cooled mixture was partitioned
between water and EtOAc. And the organic phase was washed with
brine, dried and concentrated to provide
3-(3-bromo-2-methylphenyl)-1-(4-methoxybenzyl)-5-(phenylselanyl)dihydropy-
rimidine-2,4(1H,3H)-dione as a light brown solid (5.43 g), used
without further purification. Mass spectrum m/z 557, 559, 561
(M+H).sup.+.
Intermediate 44D:
3-(3-Bromo-2-methylphenyl)-1-(4-methoxybenzyl)pyrimidine-2,4(1H,3H)-dione
##STR00176##
[0608] A solution of
3-(3-bromo-2-methylphenyl)-1-(4-methoxybenzyl)-5-(phenylselanyl)dihydropy-
rimidine-2,4(1H,3H)-dione (5.43 g, 9.73 mmol) in THF (97 mL) was
treated with 30% aqueous hydrogen peroxide (5.0 mL, 48.6 mmol) and
the mixture was stirred at room temperature for 30 min. Water was
added and the mixture was extracted with EtOAc. The organic phase
was washed with brine, dried and concentrated. The residue was
purified by column chromatography on silica gel (220 g), eluting
with EtOAc-hexanes (gradient from 25-70%), to provide
3-(3-bromo-2-methylphenyl)-1-(4-methoxybenzyl)pyrimidine-2,4(1H,3H)-dione
as a white solid (2.10 g, 54% yield). Mass spectrum m/z 401, 403
(M+H).sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.95 (d,
J=7.9 Hz, 1H), 7.70-7.65 (m, 1H), 7.32-7.28 (m, 2H), 7.25-7.22 (m,
2H), 6.96-6.91 (m, 2H), 5.86 (d, J=7.9 Hz, 1H), 4.89 (d, J=2.4 Hz,
2H), 3.74 (s, 3H), 2.02 (s, 3H).
Intermediate 44E:
3-(3-Bromo-2-methylphenyl)pyrimidine-2,4(1H,3H)-dione
##STR00177##
[0610] A solution of
3-(3-bromo-2-methylphenyl)-1-(4-methoxybenzyl)pyrimidine-2,4(1H,3H)-dione
(0.87 g, 2.17 mmol) in TFA (5.5 mL) was treated with
trifluoromethanesulfonic acid (0.55 mL) and the mixture was stirred
at room temperature overnight. The mixture was slowly poured onto
ice and stirred while warming to room temperature. The precipitate
was collected by filtration, washed with water and dried to provide
3-(3-bromo-2-methylphenyl)pyrimidine-2,4(1H,3H)-dione as a purple
solid (0.62 g, 96% yield). Mass spectrum m/z 281, 283 (M+H).sup.+.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 11.36 (d, J=4.4 Hz,
1H), 7.67 (dd, J=6.5, 2.8 Hz, 1H), 7.60 (dd, J=7.7, 5.9 Hz, 1H),
7.27-7.21 (m, 2H), 5.72 (dd, J=7.7, 1.3 Hz, 1H), 2.07 (s, 3H).
Intermediate 44F:
3-(3-Bromo-2-methylphenyl)-1-(4-fluorophenyl)pyrimidine-2,4(1H,3H)-dione
##STR00178##
[0612] A stirred suspension of copper(II) acetate (0.543 g, 2.99
mmol), 3-(3-bromo-2-methylphenyl)pyrimidine-2,4(1H,3H)-dione (0.42
g, 1.49 mmol), (4-fluorophenyl) boronic acid (0.418 g, 2.99 mmol),
and activated molecular sieves (750 mg) in dry DCM (25 mL) was
treated with pyridine (0.363 mL, 4.48 mmol) and stirred at room
temperature overnight. The mixture was diluted with DCM, filtered
through CELITE.RTM., and the solids were washed with DCM and THF.
The combined filtrates were washed with water, dried and
concentrated. The residue was purified by column chromatography on
silica gel (40 g), eluting with EtOAc-hexanes (gradient from
20-40%), to give
3-(3-bromo-2-methylphenyl)-1-(4-fluorophenyl)pyrimidine-2,4(1H,3H)-dione
as a yellow glassy solid (0.36 g, 43% yield). Mass spectrum m/z
375, 377 (M+H).sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
7.91 (d, J=7.9 Hz, 1H), 7.68 (dd, J=7.9, 1.3 Hz, 1H), 7.60-7.51 (m,
2H), 7.40-7.22 (m, 4H), 5.95 (d, J=7.9 Hz, 1H), 2.21-2.12 (m,
3H).
Intermediate 44
[0613] A mixture of
3-(3-bromo-2-methylphenyl)-1-(4-fluorophenyl)pyrimidine-2,4(1H,3H)-dione
(250 mg, 0.666 mmol),
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (186
mg, 0.733 mmol), potassium acetate (131 mg, 1.33 mmol), and
PdCl.sub.2(dppf) DCM adduct (16 mg, 0.020 mmol) in dioxane (4.4 mL)
was heated at 110.degree. C. After 3 h, additional PdCl.sub.2(dppf)
DCM adduct was added and the mixture was heated at 110.degree. C.
for 6 h more. The cooled mixture was diluted with EtOAc, filtered
through CELITE.RTM. and the solids were washed with EtOAc. The
combined filtrates were washed sequentially with saturated aqueous
NaHCO.sub.3 and brine, and dried and concentrated. The residue was
purified by column chromatography on silica gel (24 g), eluting
with EtOAc-hexanes (gradient from 25-100%), to give impure
1-(4-fluorophenyl)-3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxab-
orolan-2-yl)phenyl) pyrimidine-2,4(1H,3H)-dione as a yellow glassy
solid (217 mg), used without further purification. Mass spectrum
m/z 423 (M+H).sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
7.90 (d, J=7.9 Hz, 1H), 7.69 (dd, J=7.0, 1.8 Hz, 1H), 7.61-7.52 (m,
2H), 7.40-7.26 (m, 4H), 5.94 (d, J=7.9 Hz, 1H), 2.24 (s, 3H), 1.32
(s, 12H).
Intermediate 45
4-Bromo-3-fluoro-7-(2-hydroxyethyl)-9H-carbazole-1-carboxamide
##STR00179##
[0614] Intermediate 45A: Diethyl 2-(3-oxocyclohexyl)malonate
##STR00180##
[0616] A solution of cyclohex-2-enone (3.05 mL, 30 mmol) and
diethyl malonate (4.58 mL, 30.0 mmol) in THF (30 mL) was treated
with 1,8-diazabicyclo[5.4.0]undec-7-ene (4.52 mL, 30.0 mmol) and
heated at 50.degree. C. for 16 h. The cooled mixture was poured
into EtOAc and washed sequentially with 1 M aqueous HCl and brine.
The combined aqueous layers were extracted with EtOAc, and the
combined organic phases were dried and concentrated to give diethyl
2-(3-oxocyclohexyl)malonate as an oil (8.0 g), used without further
purification. Mass spectrum m/z 257 (M+H).sup.+.
Intermediate 45B:
5-Bromo-2-(1,3-diethoxy-1,3-dioxopropan-2-yl)-6-fluoro-2,3,4,9-tetrahydro-
-1H-carbazole-8-carboxylic acid
##STR00181##
[0618] A solution of diethyl 2-(3-oxocyclohexyl)malonate (15.26 g,
59.5 mmol) and 4-bromo-5-fluoro-2-hydrazinylbenzoic acid
hydrochloride [Intermediate 24B] (17.0 g, 59.5 mmol) in acetic acid
(120 mL) was heated at reflux for 2 h, then was stirred overnight
at room temperature. The precipitate which formed was collected by
filtration to provide a white solid. The filtrate was concentrated
and purified by column chromatography on silica gel (80 g), eluting
with EtOAc-hexanes (gradient from 0-100%). The resulting oily
product was crystallized from a mixture of EtOAc, ether and hexanes
to provide additional solid, which was combined with the first
solid to provide
5-bromo-2-(1,3-diethoxy-1,3-dioxopropan-2-yl)-6-fluoro-2,3,4,9-tetrahydro-
-1H-carbazole-8-carboxylic acid as a white solid (10.5 g, 49%
yield). Mass spectrum m/z 470, 472 (M+H).sup.+.
Intermediate 45C: Diethyl
2-(5-bromo-8-carbamoyl-6-fluoro-2,3,4,9-tetrahydro-1H-carbazol-2-yl)malon-
ate
##STR00182##
[0620] A mixture of
5-bromo-2-(1,3-diethoxy-1,3-dioxopropan-2-yl)-6-fluoro-2,3,4,9-tetrahydro-
-1H-carbazole-8-carboxylic acid (0.981 g, 2.09 mmol), EDC (0.600 g,
3.13 mmol) and HOBT (0.383 g, 2.50 mmol) in THF (5 mL) was stirred
at room temperature for 60 min. The mixture was treated with
NH.sub.4OH (1.74 mL, 12.5 mmol) and stirred at room temperature
overnight. The mixture was diluted with EtOAc, washed sequentially
with saturated aqueous Na.sub.2CO.sub.3 and brine. The combined
aqueous layers were extracted with EtOAc, and the combined organic
phases were dried and concentrated. The residue was purified by
column chromatography on silica gel (40 g), eluting with
EtOAc-hexanes (gradient from 0-100%), to provide diethyl
2-(5-bromo-8-carbamoyl-6-fluoro-2,3,4,9-tetrahydro-1H-carbazol-2-yl)malon-
ate as a slightly yellow solid (440 mg, 45% yield). Mass spectrum
m/z 469, 471 (M+H).sup.+.
Intermediate 45D: Diethyl
2-(5-bromo-8-carbamoyl-6-fluoro-9H-carbazol-2-yl)malonate
##STR00183##
[0622] A solution of diethyl
2-(5-bromo-8-carbamoyl-6-fluoro-2,3,4,9-tetrahydro-1H-carbazol-2-yl)malon-
ate (2.26 g, 4.82 mmol) and 2,3-dichloro-5,6-dicyanobenzoquinone
(2.30 g, 10.1 mmol) in THF (30 mL) was heated at reflux for 3 h.
The cooled mixture was diluted with EtOAc and washed sequentially
with saturated aqueous Na.sub.2CO.sub.3 and brine. The combined
aqueous layers were extracted with EtOAc, and the combined organic
phases were dried and partially concentrated. A white solid which
formed was collected by filtration. The filtrate was passed through
a pad of silica gel, eluting with EtOAc, and the effluent was
concentrated to provide additional solid. The two solids were
combined to provide diethyl
2-(5-bromo-8-carbamoyl-6-fluoro-9H-carbazol-2-yl) malonate as a
white solid (1.86 g, 83% yield). Mass spectrum m/z 465, 467
(M+H).sup.+.
Intermediate 45E: Ethyl
2-(5-bromo-8-carbamoyl-6-fluoro-9H-carbazol-2-yl)acetate
##STR00184##
[0624] A mixture of diethyl
2-(5-bromo-8-carbamoyl-6-fluoro-9H-carbazol-2-yl) malonate (1.30 g,
2.80 mmol), sodium chloride (0.28 g, 7.01 mmol) and water (0.25 mL,
14.01 mmol) in DMSO (6 mL) was heated at 150.degree. C. for 20 h.
The cooled mixture was poured into water, forming a precipitate.
The precipitate was collected by filtration and dried, then was
triturated with DCM. The solid was collected by filtration and
dried to provide ethyl
2-(5-bromo-8-carbamoyl-6-fluoro-9H-carbazol-2-yl)acetate as a gray
solid (930 mg, 84% yield). Mass spectrum m/z 393, 395 (M+H).sup.+.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 11.70 (s, 1H), 8.54 (d,
J=8.4 Hz, 1H), 8.25 (br. s., 1H), 8.00 (d, J=10.1 Hz, 1H), 7.72 (s,
1H), 7.69 (br. s., 1H), 7.19 (dd, J=8.4, 1.5 Hz, 1H), 4.11 (q,
J=7.0 Hz, 2H), 3.82 (s, 2H), 1.21 (t, J=7.2 Hz, 3H).
Intermediate 45
[0625] A solution of ethyl
2-(5-bromo-8-carbamoyl-6-fluoro-9H-carbazol-2-yl)acetate (500 mg,
1.27 mmol) in THF (10 mL) was treated with lithium borohydride (139
mg, 6.36 mmol) and stirred at room temperature overnight. The
mixture was treated with saturated aqueous NH.sub.4Cl and stirred
for 15 min. The mixture was diluted with water and extracted twice
with EtOAc. The combined organic phases were dried and
concentrated, and the residue was purified by column chromatography
on silica gel (40 g), eluting with EtOAc-hexanes (gradient from
30-100%), to provide
4-bromo-3-fluoro-7-(2-hydroxyethyl)-9H-carbazole-1-carboxamide as a
white solid (310 mg, 69% yield). Mass spectrum m/z 351, 353
(M+H).sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 11.58 (s,
1H), 8.50 (d, J=8.4 Hz, 1H), 8.24 (br. s., 1H), 7.98 (d, J=10.3 Hz,
1H), 7.72-7.63 (m, 2H), 7.15 (dd, J=8.4, 1.3 Hz, 1H), 4.68 (t,
J=5.3 Hz, 1H), 3.73-3.64 (m, 2H), 2.90 (t, J=7.0 Hz, 2H).
Examples 1 and 2
3-Chloro-4-(R)-(3-(R)-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3
(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxam-
ide (1), and
3-Chloro-4-(R)-(3-(S)-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3-
(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxami-
de (2)
##STR00185##
[0626] Preparation 1A:
3-Chloro-4-(3-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl-
)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
(mixture of four atropisomers)
[0627] A mixture of
4-bromo-3-chloro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
[Intermediate 3] (100 mg, 0.262 mmol),
8-fluoro-1-methyl-3-(RS)-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboro-
lan-2-yl)phenyl)quinazoline-2,4(1H,3H)-dione [Intermediate 2] (161
mg, 0.393 mmol), tetrakis(triphenylphosphine)palladium (15 mg,
0.013 mmol) and 2 M aqueous K.sub.3PO.sub.4 (0.26 mL, 0.524 mmol)
in THF (2 mL) in a pressure reaction vial was heated at 90.degree.
C. for 2.5 h. The cooled mixture was concentrated, and the residue
was purified by column chromatography on silica gel (40 g), eluting
with DCM-MeOH--NH.sub.4OH (gradient from 90:9:1-97:2.7:0.3). The
resulting impure product was again purified by column
chromatography on silica gel (40 g), eluting with EtOAc-hexanes
(gradient from 50-100%), to give
3-chloro-4-(3-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl-
)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
(mixture of four atropisomers) as a white solid (110 mg, 68%
yield). Mass spectrum m/z 567 (M+H--H.sub.2O).sup.+. .sup.1H NMR
(400 MHz, chloroform-d) .delta. 10.46 (s, 1H), 8.17-8.10 (m, 1H),
7.76 (s, 1H), 7.69 (d, J=1.1 Hz, 1H), 7.59-7.53 (m, 1H), 7.48 (ddt,
J=13.9, 8.1, 1.8 Hz, 1H), 7.39 (dd, J=12.4, 7.8 Hz, 2H), 7.28-7.19
(m, 2H), 6.97 (t, J=8.5 Hz, 1H), 3.87-3.93 (m, 3H), 1.87 (d, J=1.8
Hz, 3H), 1.65 (s, 3H), 1.65 (s, 3H).
Examples 1 and 2
[0628] A sample of the mixture of four atropisomers of
3-chloro-4-(3-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl-
)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
(90 mg) was separated by chiral super-critical fluid chromatography
as follows: column: CHIRALPAK.RTM. AD-H (3.times.25 cm, 5 .mu.m);
Mobile Phase: CO.sub.2-IPA (55:45) at 120 mL/min; sample
preparation: 10 mg/mL; injection: 1 mL. The second peak eluting
from the column provided
3-chloro-4-(R)-(3-(R)-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin--
3(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxam-
ide [Example 1] as a white solid. The isomeric purity was
determined to be 97.7%. Mass spectrum m/z 567
(M+H--H.sub.2O).sup.+. .sup.1H NMR (400 MHz, chloroform-d) .delta.
10.46 (s, 1H), 8.15 (d, J=7.3 Hz, 1H), 7.75 (s, 1H), 7.69 (d, J=1.1
Hz, 1H), 7.59-7.54 (m, 1H), 7.49 (ddd, J=13.9, 8.0, 1.7 Hz, 1H),
7.43-7.36 (m, 2H), 7.28-7.19 (m, 2H), 6.97 (d, J=8.4 Hz, 1H), 3.89
(d, J=7.9 Hz, 3H), 1.88 (s, 3H), 1.65 (s, 6H).
[0629] The fourth peak eluting from the column provided
3-chloro-4-(R)-(3-(S)-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin--
3(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxam-
ide [Example 2] as a white solid. The isomeric purity was
determined to be 99.5%. Mass spectrum m/z 567
(M+H--H.sub.2O).sup.+. .sup.1H NMR (400 MHz, chloroform-d) .delta.
10.46 (s, 1H), 8.13 (d, J=7.3 Hz, 1H), 7.75 (s, 1H), 7.69 (d, J=1.3
Hz, 1H), 7.59-7.53 (m, 1H), 7.48 (ddd, J=13.9, 8.0, 1.7 Hz, 1H),
7.39 (dd, J=11.1, 7.8 Hz, 2H), 7.27-7.21 (m, 2H), 6.99 (d, J=8.4
Hz, 1H), 3.91 (d, J=7.9 Hz, 3H), 1.88 (s, 3H), 1.66 (s, 6H).
[0630] The absolute configuration of Example 2 was confirmed by
single crystal x-ray analysis of crystals prepared by dissolving
the compound in excess methanol and slowly evaporating the solvent
at room temperature to provide a methanol solvate (crystalline form
M-1). Unit cell dimensions: a=9.75 .ANG., b=14.21 .ANG., c=21.26
.ANG., .alpha.=90.0.degree., .beta.=90.0.degree.,
.gamma.=90.0.degree.; Space group: P2.sub.12.sub.12.sub.1;
Molecules of Example 2/asymmetric unit: 1; Volume/Number of
molecules in the unit cell=736 .ANG..sup.3; Density
(calculated)=1.391 g/cm.sup.3. Fractional atomic coordinates at 203
K are given in Table 2, and a depiction of the structure is given
in FIG. 3.
Example 3
3-Chloro-7-(2-hydroxypropan-2-yl)-4-(R)-(2-methyl-3-(1-methyl-2,4-dioxo-1,-
2-dihydroquinazolin-3(4H)-yl)phenyl)-9H-carbazole-1-carboxamide
(single atropisomer)
##STR00186##
[0631] Preparation 3A:
3-Chloro-7-(2-hydroxypropan-2-yl)-4-(2-methyl-3-(1-methyl-2,4-dioxo-1,2-d-
ihydroquinazolin-3(4H)-yl)phenyl)-9H-carbazole-1-carboxamide
(mixture of four atropisomers)
[0632] A mixture of
4-bromo-3-chloro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
[Intermediate 3] (100 mg, 0.262 mmol),
1-methyl-3-(RS)-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-
phenyl)quinazoline-2,4(1H,3H)-dione [Intermediate 4] (154 mg, 0.393
mmol), 2 M aqueous K.sub.3PO.sub.4 (0.26 mL, 0.524 mmol) and
tetrakis(triphenylphosphine)palladium (15 mg, 0.013 mmol) in THF (2
mL) in a pressure reaction vial was heated at 90.degree. C. for 4
h. The cooled mixture was concentrated and the residue was purified
by column chromatography on silica gel (40 g), eluting with
DCM:MeOH:NH.sub.4OH (gradient from 90:9:1-97:2.7:0.3). The
resulting impure product was again purified by column
chromatography on silica gel (40 g), eluting with EtOAc-hexanes
(gradient from 50-100%), to give
3-chloro-7-(2-hydroxypropan-2-yl)-4-(2-methyl-3-(1-methyl-2,4-dioxo-1,2-d-
ihydroquinazolin-3(4H)-yl)phenyl)-9H-carbazole-1-carboxamide
(mixture of four atropisomers) as a white solid (105 mg, 68%
yield). Mass spectrum m/z 549 (M+H--H.sub.2O).sup.+. .sup.1H NMR
(400 MHz, chloroform-d) .delta. 10.46 (s, 1H), 8.33 (ddd, J=11.8,
7.9, 1.4 Hz, 1H), 7.80-7.74 (m, 2H), 7.69 (t, J=1.7 Hz, 1H),
7.58-7.52 (m, 1H), 7.41 (d, J=7.5 Hz, 1H), 7.38-7.30 (m, 3H), 7.24
(ddd, J=13.9, 8.4, 1.7 Hz, 1H), 6.98 (dd, J=12.8, 8.4 Hz, 1H),
3.67-3.76 (m, 3H), 1.88 (d, J=1.8 Hz, 3H), 1.65 (s, 3H), 1.65 (s,
3H).
Example 3
[0633] A sample of the mixture of four atropisomers of
3-chloro-7-(2-hydroxypropan-2-yl)-4-(2-methyl-3-(1-methyl-2,4-dioxo-1,2-d-
ihydroquinazolin-3(4H)-yl)phenyl)-9H-carbazole-1-carboxamide was
separated by chiral super-critical fluid chromatography as follows:
column: CHIRALPAK.RTM. IB (2.times.25 cm, 5 .mu.m); Mobile Phase:
CO.sub.2-MeOH (65:35) at 55 mL/min. The third peak eluting from the
column provided a single atropisomer of
3-chloro-7-(2-hydroxypropan-2-yl)-4-(R)-(2-methyl-3-(1-methyl-2,4-dioxo-1-
,2-dihydroquinazolin-3(4H)-yl)phenyl)-9H-carbazole-1-carboxamide as
a white solid. The chiral purity was determined to be 97.7%. Mass
spectrum m/z 549 (M+H--H.sub.2O).sup.+. .sup.1H NMR (400 MHz,
chloroform-d) .delta. 10.45 (s, 1H), 8.32 (dd, J=8.0, 1.7 Hz, 1H),
7.80-7.73 (m, 2H), 7.69 (d, J=1.1 Hz, 1H), 7.59-7.53 (m, 1H),
7.44-7.31 (m, 4H), 7.26 (dd, J=8.4, 1.5 Hz, 1H), 7.01 (d, J=8.4 Hz,
1H), 3.72 (s, 3H), 1.89 (s, 3H), 1.66 (s, 6H).
Example 4
3-Chloro-4-(R)-(3-(1,8-dimethyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)--
2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
(single atropisomer)
##STR00187##
[0634] Preparation 4A:
3-Chloro-4-(3-(1,8-dimethyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-m-
ethylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
(mixture of four atropisomers)
[0635] A mixture of
4-bromo-3-chloro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
[Intermediate 3] (100 mg, 0.262 mmol),
1,8-dimethyl-3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)p-
henyl)quinazoline-2,4(1H,3H)-dione [Intermediate 9] (138 mg, 0.341
mmol), Cs.sub.2CO.sub.3 (171 mg, 0.524 mmol) and PdCl.sub.2(dppf)
DCM adduct (10.7 mg, 0.013 mmol) in THF (2 mL) and water (500
.mu.l) was heated at 60.degree. C. for 18 h. The cooled mixture was
concentrated, and the residue was purified by column chromatography
on silica gel (40 g), eluting with EtOAc-hexanes (gradient from
30-100%), to give
3-chloro-4-(RS)-(3-(RS)-(1,8-dimethyl-2,4-dioxo-1,2-dihydroquinazolin-3(4-
H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
(mixture of four atropisomers) as a light yellow solid (97 mg, 57%
yield).
[0636] Mass spectrum m/z 563 (M+H--H.sub.2O).sup.+. .sup.1H NMR
(400 MHz, chloroform-d) .delta. 10.45 (s, 1H), 8.21-8.15 (m, 1H),
7.75 (d, J=0.9 Hz, 1H), 7.69 (d, J=1.5 Hz, 1H), 7.59-7.51 (m, 2H),
7.44-7.40 (m, 1H), 7.36 (dd, J=7.7, 1.1 Hz, 1H), 7.26-7.19 (m, 2H),
6.98 (t, J=7.9 Hz, 1H), 3.80 (d, J=9.9 Hz, 3H), 2.70 (d, J=5.7 Hz,
3H), 1.88 (s, 3H), 1.64-1.66 (m, 6H).
Example 4
[0637] A sample of the mixture of four atropisomers of
3-chloro-4-(3-(1,8-dimethyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-m-
ethylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
(90 mg) was separated by chiral super-critical fluid chromatography
as follows: column: CHIRALPAK.RTM. AD-H (3.times.25 cm, 5 .mu.m);
Mobile Phase: CO.sub.2-IPA (55:45) at 85 mL/min; sample
preparation: 18 mg/mL in MeOH; injection: 2.5 mL. The fourth peak
eluting from the column provided a single atropisomer of
3-chloro-4-(R)-(3-(1,8-dimethyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-
-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
as a white solid (17 mg). The chiral purity was determined to be
greater than 99%. Mass spectrum m/z 563 (M+H--H.sub.2O).sup.+.
.sup.1H NMR (400 MHz, chloroform-d) .delta. 10.45 (s, 1H), 8.17
(dd, J=7.8, 1.2 Hz, 1H), 7.75 (s, 1H), 7.69 (d, J=1.1 Hz, 1H),
7.58-7.51 (m, 2H), 7.42 (dd, J=7.9, 1.1 Hz, 1H), 7.36 (dd, J=7.7,
1.1 Hz, 1H), 7.27-7.19 (m, 2H), 6.99 (d, J=8.4 Hz, 1H), 3.81 (s,
3H), 2.71 (s, 3H), 1.87 (s, 3H), 1.65 (s, 6H).
Examples 5 and 6
3-Chloro-7-(2-hydroxypropan-2-yl)-4-(R)-(3-(R)-(7-methoxy-1-methyl-2,4-dio-
xo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-9H-carbazole-1-carboxam-
ide, and
3-Chloro-7-(2-hydroxypropan-2-yl)-4-(R)-(3-(S)-(7-methoxy-1-methyl-2,4-dio-
xo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-9H-carbazole-1-carboxam-
ide (single atropisomers)
##STR00188##
[0639] A mixture of
4-bromo-3-chloro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
[Intermediate 3] (200 mg, 0.524 mmol),
7-methoxy-1-methyl-3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan--
2-yl)phenyl)quinazoline-2,4(1H,3H)-dione [Intermediate 14] (221 mg,
0.524 mmol), Cs.sub.2CO.sub.3 (512 mg, 1.57 mmol) and
PdCl.sub.2(dppf) DCM adduct (21.4 mg, 0.026 mmol) in THF (3 mL) and
water (0.50 mL) was heated at 60.degree. C. overnight, then at
90.degree. C. for 4 h. The cooled mixture was concentrated, and the
residue was purified by column chromatography on silica gel (40 g),
eluting with EtOAc-hexanes (gradient from 50-100%), to give
3-chloro-7-(2-hydroxypropan-2-yl)-4-(3-(7-methoxy-1-methyl-2,4-dioxo-1,2--
dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-9H-carbazole-1-carboxamide
(mixture of four atropisomers) (164 mg, 92% yield). This material
was separated by chiral super-critical fluid chromatography as
follows: column: CHIRALPAK.RTM. AD-H (3.times.25 cm, 5 .mu.m);
Mobile Phase: CO.sub.2-IPA (60:40) at 85 mL/min; sample
preparation: 20.3 mg/mL in MeOH; injection: 0.75 mL.
[0640] The third peak eluting from the column provided a single
atropisomer of
3-chloro-7-(2-hydroxypropan-2-yl)-4-(R)-(3-(7-methoxy-1-methyl-2,4-dioxo--
1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-9H-carbazole-1-carboxamide
[Example 5] (14 mg). The chiral purity was determined to be greater
than 99%. Mass spectrum m/z 579 (M+H--H.sub.2O).sup.+. .sup.1H NMR
(400 MHz, chloroform-d) .delta. 10.43 (s, 1H), 8.24 (d, J=8.8 Hz,
1H), 7.73 (s, 1H), 7.65 (d, J=1.1 Hz, 1H), 7.55-7.49 (m, 1H),
7.44-7.34 (m, 1H), 7.35-7.31 (m, 1H), 7.19 (dd, J=8.5, 1.7 Hz, 1H),
6.94 (d, J=8.4 Hz, 1H), 6.85 (dd, J=8.8, 2.2 Hz, 1H), 6.69 (d,
J=2.2 Hz, 1H), 3.95 (s, 3H), 3.63 (s, 3H), 1.85 (s, 3H), 1.62 (s,
6H).
[0641] The fourth peak eluting from the column provided the other
single atropisomer
3-chloro-7-(2-hydroxypropan-2-yl)-4-(R)-(3-(7-methoxy-1-methyl-2,4-dioxo--
1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-9H-carbazole-1-carboxamide
[Example 6] (28 mg). The chiral purity was determined to be greater
than 99%. Mass spectrum m/z 579 (M+H--H.sub.2O).sup.+. .sup.1H NMR
(400 MHz, chloroform-d) .delta. 10.41 (s, 1H), 8.21 (d, J=8.8 Hz,
1H), 7.71 (s, 1H), 7.66 (d, J=1.1 Hz, 1H), 7.55-7.49 (m, 1H),
7.41-7.36 (m, 1H), 7.35-7.31 (m, 1H), 7.22 (dd, J=8.4, 1.5 Hz, 1H),
6.97 (d, J=8.4 Hz, 1H), 6.84 (dd, J=9.0, 2.2 Hz, 1H), 6.70 (d,
J=2.2 Hz, 1H), 3.95 (s, 3H), 3.65 (s, 3H), 1.85 (s, 3H), 1.63 (s,
6H).
Example 7
3-Chloro-7-(2-hydroxypropan-2-yl)-4-(R)-(3-(8-methoxy-1-methyl-2,4-dioxo-1-
,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-9H-carbazole-1-carboxamide
(single atropisomer)
##STR00189##
[0643] A mixture of
4-bromo-3-chloro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
[Intermediate 3](200 mg, 0.524 mmol),
8-methoxy-1-methyl-3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan--
2-yl)phenyl)quinazoline-2,4(1H,3H)-dione [Intermediate 12] (221 mg,
0.524 mmol), Cs.sub.2CO.sub.3 (512 mg, 1.57 mmol) PdCl.sub.2(dppf)
DCM adduct (21.4 mg, 0.026 mmol) in THF (3 mL) and water (0.50 mL)
in a pressure reaction vial was heated at 60.degree. C. overnight,
then at 90.degree. C. for 4 hours. The cooled mixture was diluted
with DCM and MeOH, and concentrated. The residue was purified by
column chromatography on silica gel (24 g), eluting with
EtOAc-hexanes (gradient from 20-55%), to give a mixture of four
atropisomers of
3-chloro-7-(2-hydroxypropan-2-yl)-4-(3-(8-methoxy-1-methyl-2,4-dioxo-1,2--
dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-9H-carbazole-1-carboxamide
(136 mg, 41% yield). This material was separated by chiral
super-critical fluid chromatography as follows: column:
CHIRALPAK.RTM. AD-H (3.times.25 cm, 5 .mu.m); Mobile Phase:
CO.sub.2-IPA (55:45) at 85 mL/min; sample preparation: 17 mg/mL in
MeOH; injection: 1.0 mL. The fourth peak eluting from the column
provided a single atropisomer of
3-chloro-7-(2-hydroxypropan-2-yl)-4-(R)-(3-(8-methoxy-1-methyl-2,4-dioxo--
1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-9H-carbazole-1-carboxamide
(26 mg, 20% yield). The chiral purity was determined to be greater
than 99%. Mass spectrum m/z 579 (M+H--H.sub.2O).sup.+. .sup.1H NMR
(400 MHz, chloroform-d) .delta. 10.42 (s, 1H), 7.90 (dd, J=7.2, 2.3
Hz, 1H), 7.71 (s, 1H), 7.66 (d, J=1.1 Hz, 1H), 7.55-7.49 (m, 1H),
7.40-7.36 (m, 1H), 7.35-7.31 (m, 1H), 7.25-7.19 (m, 3H), 6.97 (d,
J=8.4 Hz, 1H), 3.94 (s, 3H), 3.91 (s, 3H), 1.85 (s, 3H), 1.63 (s,
6H).
Example 8
3-Chloro-4-(R)-(3-(6-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-
-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
(single atropisomer)
##STR00190##
[0645] A mixture of
4-bromo-3-chloro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
[Intermediate 3] (200 mg, 0.524 mmol),
6-fluoro-1-methyl-3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
-yl)phenyl)quinazoline-2,4(1H,3H)-dione [Intermediate 13] (215 mg,
0.524 mmol), Cs.sub.2CO.sub.3 (512 mg, 1.57 mmol) and
PdCl.sub.2(dppf) DCM adduct (21.4 mg, 0.026 mmol) in THF (3 mL) and
water (1 mL) was heated at 60.degree. C. overnight, then at
90.degree. C. for 4 h. The cooled mixture was concentrated and the
residue was purified twice by column chromatography on silica gel
(40 g), eluting with EtOAc-hexanes (gradient from 50-100%), to give
a mixture of four atropisomers of
3-chloro-4-(3-(6-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl-
)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
(129 mg, 39% yield). This material was separated by chiral
super-critical fluid chromatography as follows: column:
CHIRALPAK.RTM. AD-H (3.times.25 cm, 5 atm); Mobile Phase:
CO.sub.2-MeOH-MeCN (65:17.5:17.5) at 85 mL/min; sample preparation:
15.4 mg/mL in MeOH; injection: 0.5 mL. The third peak eluting from
the column provided a single atropisomer of
3-chloro-4-(R)-(3-(6-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H-
)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
(33 mg). The isomeric purity was determined to be greater than 98%.
Mass spectrum m/z 567 (M+H--H.sub.2O).sup.+. .sup.1H NMR (400 MHz,
chloroform-d) .delta. 10.44 (br. s., 1H), 8.29 (dd, J=8.1, 6.4 Hz,
1H), 7.73 (s, 1H), 7.66 (s, 1H), 7.56-7.49 (m, 1H), 7.36 (dd,
J=15.2, 7.3 Hz, 2H), 7.22 (d, J=6.8 Hz, 1H), 7.04-6.92 (m, 3H),
3.65 (s, 3H), 1.84 (s, 3H), 1.63 (s, 6H).
Example 9
3-Chloro-4-(R)-(3-(7-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-
-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
(single atropisomer)
##STR00191##
[0647] A mixture of
4-bromo-3-chloro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
[Intermediate 3] (200 mg, 0.524 mmol),
7-fluoro-1-methyl-3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
-yl)phenyl)quinazoline-2,4(1H,3H)-dione [Intermediate 15] (215 mg,
0.524 mmol), Cs.sub.2CO.sub.3 (512 mg, 1.57 mmol) and
PdCl.sub.2(dppf) DCM adduct (21.4 mg, 0.026 mmol) in THF (3 mL) and
water (0.50 mL) was heated at 90.degree. C. for 4 h. The cooled
mixture was concentrated, and the residue was purified by column
chromatography on silica gel (220 g), eluting with EtOAc-hexanes
(gradient from 0-40%), to provide a mixture of four atropisomers of
3-chloro-4-(3-(7-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl-
)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
(164 mg, 53% yield). The material was separated by chiral
super-critical fluid chromatography as follows: column: Lux Cel2
(3.times.25 cm, 5 .mu.m); Mobile Phase: CO.sub.2-MeOH-MeCN
(62:19:19) at 85 mL/min; sample preparation: 30 mg/mL in MeOH;
injection: 0.5 mL. The material isolated from the third peak
eluting from the column was again separated by chiral
super-critical fluid chromatography as follows: column:
CHIRALPAK.RTM. AS (3.times.25 cm, 5 .mu.m); Mobile Phase:
CO.sub.2-MeOH-MeCN (68:16:16) at 85 mL/min; sample preparation:
11.4 mg/mL in MeOH; injection: 3.5 mL. The first peak eluting from
the column provided a single atropisomer of
3-chloro-4-(R)-(3-(7-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H-
)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
as a white solid (25 mg, 15% yield). The isomeric purity was
determined to be greater than 98%. Mass spectrum m/z 567
(M+H--H.sub.2O).sup.+. .sup.1H NMR (400 MHz, chloroform-d) .delta.
10.46 (s, 1H), 8.31 (dd, J=8.6, 6.2 Hz, 1H), 7.76 (s, 1H), 7.68 (d,
J=1.1 Hz, 1H), 7.58-7.52 (m, 1H), 7.38 (ddd, J=14.1, 7.8, 1.0 Hz,
2H), 7.24 (dd, J=8.4, 1.5 Hz, 1H), 7.06-6.95 (m, 3H), 3.67 (s, 4H),
1.86 (s, 3H), 1.65 (s, 6H).
Example 10
3-Chloro-4-(RS)-(3-(RS)-(6,8-difluoro-2,4-dioxo-1,2-dihydroquinazolin-3(4H-
)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
(Mixture of Four Atropisomers)
##STR00192##
[0649] A mixture of
4-bromo-3-chloro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
[Intermediate 3] (10 mg, 0.026 mmol),
6,8-difluoro-3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)p-
henyl)quinazoline-2,4(1H,3H)-dione [Intermediate 16] (14.1 mg,
0.034 mmol), 1,1'-bis(di-tert-butylphosphino)ferrocene
palladium(II) chloride (12.8 mg, 0.020 mmol) and THF (2 mL) in a
reaction vial was treated with 2 M aqueous K.sub.3PO.sub.4 (0.039
mL, 0.079 mmol). The vial was sealed and subjected to three
evacuate-fill cycles with nitrogen. The mixture was stirred at room
temperature overnight. The phases of the mixture were separated,
the aqueous phase was extracted twice with EtOAc, and the combined
organic phases were dried and concentrated. The residue was
purified by column chromatography on silica gel (40 g), eluting
with EtOAc-hexanes (gradient from 80-100%). The isolated material
was triturated with MeOH to give a solid after filtration. The
filtrate was concentrated and subjected to column chromatography on
silica (40 g), eluting with DCM-MeOH--NH.sub.4OH (gradient from
90:9:1-97:2.7:0.3) to give additional solid. The two solids were
combined to provide
3-chloro-4-(3-(6,8-difluoro-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-m-
ethylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
(mixture of four atropisomers) as a pale yellow solid (164 mg, 71%
yield). Mass spectrum m/z 571 (M+H--H.sub.2O).sup.+. .sup.1H NMR
(500 MHz, MeOH-d.sub.4) .delta. 8.04 (d, J=2.0 Hz, 1H), 7.70-7.68
(m, 1H), 7.65 (dd, J=7.2, 3.2 Hz, 1H), 7.57-7.52 (m, 1H), 7.43-7.34
(m, 3H), 7.18-7.07 (m, 1H), 6.90 (dd, J=8.4, 3.0 Hz, 1H), 1.84 (s,
3H), 1.62-1.56 (m, 6H).
Example 11
3-Chloro-4-(R)-(3-(S)-(8-fluoro-1-methyl(d.sub.3)-2,4-dioxo-1,2-dihydroqui-
nazolin-3(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1--
carboxamide (single atropisomer)
##STR00193##
[0651] A solution of
4-bromo-3-chloro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
[Intermediate 3] (3.08 g, 8.07 mmol) and
8-fluoro-1-methyl(d.sub.3)-3-(S)-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-d-
ioxaborolan-2-yl)phenyl)quinazoline-2,4(1H,3H)-dione [Intermediate
21] (4.00 g, 9.68 mmol) in THF (33 mL) was treated with 2 M aqueous
K.sub.3PO.sub.4 (8.25 mL, 16.5 mmol). The mixture was bubbled with
argon for ca. 4 min while agitating on an ultrasonic bath, then was
treated with 1,1'-bis(di-tert-butylphosphino)ferrocene
palladium(II) chloride (447 mg, 0.686 mmol). The reaction vessel
was sealed and subjected to six evacuate-fill cycles with argon.
The mixture was stirred at 50.degree. C. for 16.5 h, then was
cooled to room temperature. The mixture was diluted with EtOAc and
washed with water. The aqueous phase was extracted twice with EtOAc
and the combined organic phases were washed with brine, dried and
concentrated. The residue was purified by column chromatography on
silica gel (330 g), eluting with EtOAc-hexanes (gradient from
40-100%), to provide
3-chloro-4-(3-(S)-(8-fluoro-1-methyl(d.sub.3)-2,4-dioxo-1,2-dihydroquinaz-
olin-3
(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-ca-
rboxamide (mixture of two diastereomers) as a light yellow-tan
solid (3.877 g, 78% yield).
[0652] Material prepared by this method (5.01 g) was separated by
chiral super-critical fluid chromatography as follows: column:
CHIRALPAK.RTM. AS-H (3.times.25 cm, 5 .mu.m); Mobile Phase:
CO.sub.2-MeOH (70:30) at 160 mL/min, 40.degree. C.; sample
preparation: 22.75 mg/mL in 2:1 MeOH-dichloromethane; injection:
1.4 mL. Pooled fractions containing the first peak eluting from the
column were concentrated, and the residue was sonicated in a small
amount of methanol. The precipitate was collected by filtration,
rinsed with methanol and dried to provide
3-chloro-4-(R)-(3-(S)-(8-fluoro-1-methyl(d.sub.3)-2,4-dioxo-1,2-dihydroqu-
inazolin-3
(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole--
1-carboxamide as a white solid (2.029 g). Mass spectrum m/z 570
(M+H--H.sub.2O).sup.+, 610 (M+Na).sup.+. .sup.1H NMR (400 MHz,
MeOH-d.sub.4) .delta. 8.12-8.03 (m, 2H), 7.74 (d, J=1.1 Hz, 1H),
7.67-7.53 (m, 2H), 7.46 (dd, J=7.9, 1.1 Hz, 1H), 7.39-7.29 (m, 2H),
7.17 (dd, J=8.5, 1.7 Hz, 1H), 6.96-6.87 (m, 1H), 1.81 (s, 3H), 1.61
(d, J=1.3 Hz, 6H). [.alpha.].sub.D: +85.10 (c 2.38, CHCl.sub.3).
DSC melting point onset temperature=255.6.degree. C. (heating
rate=10.degree. C./min.).
[0653] The absolute configuration of Example 11 was confirmed by
single crystal x-ray analysis of crystals prepared by dissolving
the compound in 1:1:1 methanol/acetonitrile/acetone and slowly
evaporating the solvent at room temperature to provide a methanol
solvate (crystalline form M-1). Unit cell dimensions: a=9.78 .ANG.,
b=14.26 .ANG., c=21.38 .ANG., .alpha.=90.0.degree.,
.beta.=90.0.degree., .gamma.=90.0.degree.; Space group:
P2.sub.12.sub.12.sub.1; Molecules of Example 11/asymmetric unit: 1;
Volume/Number of molecules in the unit cell=746 .ANG..sup.3;
Density (calculated)=1.381 g/cm.sup.3. Fractional atomic
coordinates at room temperature are given in Table 5, and a
depiction of the structure is given in FIG. 4. The absolute
configuration was further confirmed by single crystal x-ray
analysis of crystals prepared by dissolving Example 11 in excess
aqueous acetone and slowly evaporating the solvent at room
temperature to provide a monohydrate (crystalline form H-1). Unit
cell dimensions: a=9.41 .ANG., b=14.51 .ANG., c=21.12 .ANG.,
a=90.0.degree., 3=90.0.degree., .gamma.=90.0.degree.; Space group:
P2.sub.12.sub.12.sub.1; Molecules of Example 11/asymmetric unit: 1;
Volume/Number of molecules in the unit cell=721 .ANG..sup.3;
Density (calculated)=1.396 g/cm.sup.3. Fractional atomic
coordinates at room temperature are given in Table 3.
Example 12
3-Chloro-4-(R)-(3-(R)-(8-fluoro-1-methyl(d.sub.3)-2,4-dioxo-1,2-dihydroqui-
nazolin-3
(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-
-carboxamide (single atropisomer)
##STR00194##
[0655] A mixture of
4-bromo-3-chloro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
[Intermediate 3] (76 mg, 0.20 mmol),
8-fluoro-1-methyl(d.sub.3)-3-(R)-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-d-
ioxaborolan-2-yl)phenyl) quinazoline-2,4(1H,3H)-dione [Intermediate
22] (75 mg, 0.18 mmol), and Cs.sub.2CO.sub.3 (118 mg, 0.363 mmol)
in THF (1.6 mL) and water (0.40 mL) in a vial was bubbled with
argon for 1 min with sonication. The mixture was treated with
PdCl.sub.2(dppf) DCM adduct (7.4 mg, 0.009 mmol) and the vial was
sealed and heated at 45.degree. C. for 19 h. The cooled mixture was
diluted with EtOAc and water. The layers were separated and the
aqueous layer was extracted again with EtOAc. The combined organic
layers were washed with brine, dried and concentrated. The residue
was subjected to column chromatography on silica gel (12 g),
eluting with EtOAc-hexanes (gradient from 60%-100%). The resulting
impure product was purified by reverse phase HPLC (Luna Axia 5 Cis
30.times.100 mm), eluting with MeCN-water containing 0.1% TFA
(gradient from 10-100%, 30 mL/min). The appropriate fractions were
treated with saturated aqueous NaHCO.sub.3 and concentrated to an
aqueous suspension. The precipitate was collected by filtration,
washed with water and dried under vacuum to provide a mixture of
two atropisomers of
3-chloro-4-(3-(R)-(8-fluoro-1-methyl(d.sub.3)-2,4-dioxo-1,2-dihydroquinaz-
olin-3(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-car-
boxamide as a white solid (60.9 mg, 57% yield). This material was
separated by chiral super-critical fluid chromatography as follows:
column: CHIRALPAK.RTM. AD-H (5.times.25 cm, 5 .mu.m); Mobile Phase:
CO.sub.2-IPA (60:40) at 250 mL/min, 35.degree. C.; sample
preparation: 7.5 mg/mL in MeOH; injection: 2.5 mL. The residue
obtained from concentration of the second peak eluting from the
column was further purified by column chromatography on silica gel
(4 g), eluting with EtOAc-hexanes (gradient from 40%-100%), to
provide
3-chloro-4-(R)-(3-(R)-(8-fluoro-1-methyl(d.sub.3)-2,4-dioxo-1,2-dihydroqu-
inazolin-3(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-
-carboxamide as a white solid (19.7 mg, 68% yield). Mass spectrum
m/z 570 (M+H--H.sub.2O).sup.+, 610 (M+Na).sup.+. .sup.1H NMR (400
MHz, MeOH-d.sub.4) .delta. 8.11-8.04 (m, 2H), 7.74 (d, J=1.1 Hz,
1H), 7.66-7.53 (m, 2H), 7.46 (dd, J=7.9, 1.1 Hz, 1H), 7.38-7.28 (m,
2H), 7.14 (dd, J=8.5, 1.7 Hz, 1H), 6.90 (d, J=8.6 Hz, 1H), 1.80 (s,
3H), 1.60 (d, J=0.9 Hz, 6H).
Example 13
3-Chloro-4-(3-(8-fluoro-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methyl-
phenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
(mixture of four atropisomers)
##STR00195##
[0657] A mixture of
4-bromo-3-chloro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
[Intermediate 3] (0.360 g, 0.943 mmol),
8-fluoro-3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pheny-
l)quinazoline-2,4(1H,3H)-dione [Intermediate 17] (0.392 g, 0.990
mmol), PdCl.sub.2(dppf) DCM adduct (0.039 g, 0.047 mmol) and
Cs.sub.2CO.sub.3 (0.615 g, 1.89 mmol) in dioxane (10 mL) and water
(2.5 mL) was heated at 100.degree. C. overnight. The cooled mixture
was diluted with EtOAc and washed with water, dried and
concentrated. The residue was purified by column chromatography on
silica gel, eluting with EtOAc-hexanes (gradient from 0-50%, then
to 70% containing 1% MeOH), to provide
3-chloro-4-(3-(8-fluoro-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methy-
lphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
(mixture of four atropisomers) as a white solid (0.361 g, 67%
yield). Mass spectrum m/z 354 (M+H--H.sub.2O).sup.+, 394
(M+Na).sup.+. .sup.1H NMR (500 MHz, MeOH-d.sub.4) .delta. 8.09 (d,
J=1.1 Hz, 1H), 7.95 (d, J=8.0 Hz, 1H), 7.81-7.69 (m, 1H), 7.64-7.54
(m, 2H), 7.48 (dd, J=7.8, 1.1 Hz, 1H), 7.43-7.29 (m, 1H), 7.31-7.24
(m, 1H), 7.18 (dd, J=8.3, 1.7 Hz, 1H), 7.16-7.07 (m, 1H), 6.92 (dd,
J=8.6, 5.3 Hz, 1H), 1.94-1.71 (m, 3H), 1.65-1.50 (m, 6H).
Example 14
3-Chloro-4-(R)-(3-(R)-(8-fluoro-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)--
2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
(Single Atropisomer)
##STR00196##
[0659] A sample of the mixture of four atropisomers of
3-chloro-4-(3-(8-fluoro-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methy-
lphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
[Example 13] (250 mg) was separated by chiral super-critical fluid
chromatography as follows: column: CHIRALPAK.RTM. AD-H (5.times.25
cm, 5 .mu.m); Mobile Phase: CO.sub.2-IPA (60:40) at 220 mL/min,
35.degree. C., 100 bar; sample preparation: 2.sub.1 mg/mL in MeOH;
injection: 3.0 mL. The third peak eluting from the column provided
3-chloro-4-(R)-(3-(R)-(8-fluoro-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-
-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
(single atropisomer) as a white solid (24 mg). The chiral purity
was determined to be greater than 95%. Mass spectrum m/z 553
(M+H--H.sub.2O).sup.+, 593(M+Na).sup.+. .sup.1H NMR (400 MHz,
MeOH-d.sub.4) .delta. 8.09 (s, 1H), 7.95 (d, J=7.9 Hz, 1H), 7.74
(d, J=1.1 Hz, 1H), 7.60-7.54 (m, 2H), 7.54-7.43 (m, 1H), 7.37 (d,
J=7.5 Hz, 1H), 7.28 (d, J=4.6 Hz, 1H), 7.11 (dd, J=8.6, 1.5 Hz,
1H), 6.91 (d, J=8.6 Hz, 1H), 2.00-1.76 (m, 3H), 1.69-1.52 (m,
6H).
Examples 15 and 16
3-Cyano-4-(S)-(3-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)--
yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
(single atropisomers)
##STR00197##
[0660] Preparation 15A:
3-Cyano-4-(3-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-
-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
(mixture of 4 atropisomers)
[0661] A mixture of
4-bromo-3-cyano-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
[Intermediate 23] (0.400 g, 1.08 mmol),
8-fluoro-1-methyl-3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
-yl)phenyl)quinazoline-2,4(1H,3H)-dione [Intermediate 2] (0.573 g,
1.40 mmol), Cs.sub.2CO.sub.3 (0.700 g, 2.15 mmol), and dioxane (5
mL) was subjected to 3 evacuate-fill cycles with nitrogen. The
mixture was treated with PdCl.sub.2(dppf) DCM adduct (0.053 g,
0.064 mmol) and subjected to 2 more evacuate-fill cycles with
nitrogen. The mixture was heated at 88.degree. C. for 2 days. The
cooled mixture was diluted with EtOAc, washed sequentially with
water and brine, and dried and concentrated. The residue was
purified by column chromatography on silica gel, eluting with
EtOAc-hexanes (sequentially 50%, 75%, 85% and 100%). The resulting
impure product was purified by reverse-phase preparative HPLC to
give
3-cyano-4-(3-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-
-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
(mixture of four atropisomers) as a white solid (0.200 g, 32%
yield). Mass spectrum m/z 576 (M+H)+. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 11.96 (s, 1H), 8.45 (s, 1H), 8.35 (br. s.,
1H), 8.00-7.94 (m, 1H), 7.92 (s, 1H), 7.77-7.68 (m, 2H), 7.60-7.52
(m, 2H), 7.41 (dd, J=6.6, 2.2 Hz, 1H), 7.38-7.29 (m, 1H), 7.13 (t,
J=10.1 Hz, 1H), 6.85 (t, J=8.1 Hz, 1H), 5.05 (d, J=2.0 Hz, 1H),
3.74 (dd, J=8.1, 2.6 Hz, 3H), 1.73 (s, 3H), and 1.48-1.43 (m,
6H).
Examples 15 and 16
[0662] A sample of
3-cyano-4-(3-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-
-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
(mixture of 4 atropisomers) was separated by chiral super-critical
fluid chromatography as follows: column: CHIRALPAK.RTM. AD-H
(3.times.25 cm, 5 .mu.m); Mobile Phase: CO.sub.2-IPA (65:35) at 150
mL/min, 45.degree. C. The second peak eluting from the column
provided one single atropisomer of
3-cyano-4-(S)-(3-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(-
4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamid-
e [Example 15]. The chiral purity was determined to be greater than
94%. The fourth peak eluting from the column provided the other
single atropisomer of
3-cyano-4-(S)-(3-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-
-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
[Example 16]. The chiral purity was determined to be 99%. The mass
spectrum of each single atropisomer was the same as that of the
mixture of four atropisomers.
Example 17
3-Fluoro-4-(3-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-
-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
(mixture of four atropisomers)
##STR00198##
[0664] A mixture of
4-bromo-3-fluoro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
[Intermediate 27] (0.080 g, 0.219 mmol),
8-fluoro-1-methyl-3-(S)-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-
an-2-yl)phenyl)quinazoline-2,4(1H,3H)-dione [Intermediate 2] (0.094
g, 0.230 mmol), PdCl.sub.2(dppf) DCM adduct (9.0 mg, 11.0 mol) and
Cs.sub.2CO.sub.3 (0.143 g, 0.438 mmol) in dioxane (8.0 mL) and
water (2.0 mL) was heated at 100.degree. C. overnight. The cooled
mixture was diluted with EtOAc and filtered. The filtrate was
washed with water, dried and concentrated. The residue was purified
by reverse-phase preparative HPLC, followed by purification by
column chromatography on silica gel, eluting with EtOAc-hexanes
(gradient from 50%-100%), to give
3-fluoro-4-(3-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl-
)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
(mixture of four atropisomers) as an off-white solid (0.018 g, 15%
yield). Mass spectrum m/z 551 (M+H--H.sub.2O).sup.+. .sup.1H NMR
(500 MHz, MeOH-d.sub.4) .delta. 7.66 (d, J=10.4 Hz, 1H), 7.51 (s,
1H), 7.47-7.34 (m, 3H), 7.29 (t, J=7.2 Hz, 2H), 7.22-7.11 (m, 1H),
7.09-6.97 (m, 1H), 6.90 (t, J=8.1 Hz, 1H), 3.81-3.63 (m, 3H), 2.06
(br. s., 3H), and 1.77-1.58 (m, 6H).
Example 18
3-Fluoro-4-(3-(S)-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3
(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxam-
ide (mixture of two atropisomers)
##STR00199##
[0666] A mixture of
4-bromo-3-fluoro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
[Intermediate 27] (0.100 g, 0.274 mmol),
8-fluoro-1-methyl-3-(S)-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-
an-2-yl)phenyl)quinazoline-2,4(1H,3H)-dione [Intermediate 10]
(0.146 g, 0.356 mmol), 2 M aqueous K.sub.3PO.sub.4 (0.41 mL, 0.821
mmol), and THF (2.0 mL) was subjected to 3 evacuate-fill cycles
with nitrogen. The mixture was treated with
1,1'-bis(di-tert-butylphosphino)ferrocene palladium(II) chloride
(8.9 mg, 0.014 mmol), and subjected to 2 more evacuate-fill cycles
with nitrogen. The mixture was stirred at room temperature
overnight. The mixture was diluted with EtOAc, washed sequentially
with water and brine, and dried and concentrated. The residue was
purified by column chromatography on silica gel, eluting with
EtOAc-hexanes (sequentially 50%, 62%, 75% and 85%), to provide
3-fluoro-4-(3-(S)-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H-
)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
(mixture of two atropisomers) as an off-white solid (0.084 g, 53%
yield). Mass spectrum m/z 551 (M+H--H.sub.2O).sup.+. .sup.1H NMR
(500 MHz, DMSO-d.sub.6) .delta. 11.39 (s, 1H), 8.21 (br. s., 1H),
7.99-7.92 (m, 3H), 7.84 (s, 1H), 7.73 (ddt, J=14.4, 8.0, 1.4 Hz,
1H), 7.59 (br. s., 1H), 7.54-7.47 (m, 3H), 7.40 (dd, J=7.2, 1.7 Hz,
1H), 7.34 (tt, J=7.9, 4.0 Hz, 1H), 7.04 (ddd, J=11.5, 8.6, 1.5 Hz,
1H), 6.88 (t, J=8.0 Hz, 1H), 4.99 (d, J=2.2 Hz, 1H), 3.74 (dd,
J=8.2, 1.0 Hz, 3H), 1.77 (s, 3H), and 1.49-1.42 (m, 6H).
Alternative Synthesis of
3-Fluoro-4-(3-(S)-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H-
)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
(mixture of two atropisomers)
[0667] A mixture of
4-bromo-3-fluoro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
[Intermediate 27] (0.050 g, 0.137 mmol),
8-fluoro-1-methyl-3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
-yl)phenyl)quinazoline-2,4(1H,3H)-dione [Intermediate 10] (0.073 g,
0.178 mmol), Cs.sub.2CO.sub.3 (0.089 g, 0.274 mmol), and dioxane
(0.8 mL) was subjected to 3 evacuate-fill cycles with nitrogen. The
mixture was treated with PdCl.sub.2(dppf) DCM adduct (6.7 mg, 8.21
.mu.mol), subjected to 2 more evacuate-fill cycles with nitrogen,
and heated at 52.degree. C. overnight. The cooled mixture was
diluted with EtOAc, washed sequentially with water and brine, and
dried and concentrated. The residue was purified by column
chromatography on silica gel, eluting with EtOAc-hexanes
(sequentially 50%, 62% and 75%), to give
3-fluoro-4-(3-(S)-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H-
)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
(mixture of two atropisomers) as a white solid (0.034 g, 42%
yield).
Example 19
3-Fluoro-4-(R)-(3-(S)-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3
(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxam-
ide (single atropisomer)
##STR00200##
[0669] A sample of
3-fluoro-4-(3-(S)-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H-
)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
(mixture of two atropisomers) [Example 18] was separated by chiral
super-critical fluid chromatography as follows: column:
CHIRALPAK.RTM. AS-H (3.times.25 cm, 5 .mu.m); Mobile Phase:
CO.sub.2-MeOH (70:30) at 120 mL/min, 40.degree. C., 100 bar; sample
preparation: 3.6 mg/mL in MeOH; injection: 2.0 mL. The first peak
eluting from the column provided
3-fluoro-4-(R)-(3-(S)-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin--
3(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxam-
ide. The chiral purity was determined to be greater than 99.4%.
Mass spectrum m/z 551 (M+H--H.sub.2O).sup.+. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 11.39 (s, 1H), 8.21 (br. s., 1H), 8.00-7.92
(m, 2H), 7.84 (s, 1H), 7.73 (ddd, J=14.4, 8.0, 1.4 Hz, 1H), 7.59
(br. s., 1H), 7.55-7.47 (m, 2H), 7.40 (dd, J=7.2, 1.4 Hz, 1H), 7.33
(td, J=8.0, 4.0 Hz, 1H), 7.05 (dd, J=8.3, 1.4 Hz, 1H), 6.89 (d,
J=8.3 Hz, 1H), 4.99 (s, 1H), 3.74 (d, J=8.0 Hz, 3H), 3.17 (d, J=5.3
Hz, 3H), 1.77 (s, 3H), and 1.46 (d, J=4.2 Hz, 6H).
Example 20
3-Fluoro-4-(3-(8-fluoro-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methyl-
phenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
(mixture of 4 atropisomers)
##STR00201##
[0671] A mixture of
4-bromo-3-fluoro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
[Intermediate 27] (0.104 g, 0.285 mmol),
8-fluoro-3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pheny-
l)quinazoline-2,4(1H,3H)-dione [Intermediate 17] (0.147 g, 0.370
mmol), Cs.sub.2CO.sub.3 (0.186 g, 0.570 mmol), and dioxane (1.6 mL)
was subjected to 3 evacuate-fill cycles with nitrogen. The mixture
was treated with PdCl.sub.2(dppf) DCM adduct (14 mg, 0.017 mmol),
and subjected to two more evacuate-fill cycles with nitrogen. The
mixture was heated at 88.degree. C. overnight. The cooled mixture
was diluted with EtOAc, washed sequentially with water and brine,
and dried and concentrated. The residue was purified by reverse
phase preparative HPLC. The appropriate fractions were treated with
saturated aqueous NaHCO.sub.3 and concentrated to an aqueous
residue which was extracted with EtOAc. The organic layer was
washed with brine. The combined aqueous layers were extracted with
EtOAc, and the combined organic layers were dried and concentrated.
The residue was purified by column chromatography on silica gel,
eluting with EtOAc-hexanes (sequentially 50%, 65% and 75%), to
provide
3-fluoro-4-(3-(8-fluoro-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-
-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
(mixture of four atropisomers) as a white solid (0.029 g, 18%
yield). Mass spectrum m/z 537 (M+H--H.sub.2O).sup.+. .sup.1H NMR
(500 MHz, DMSO-d.sub.6) .delta. 11.81 (br. s., 1H), 11.39 (d, J=1.4
Hz, 1H), 8.21 (br. s., 1H), 7.95 (dd, J=10.7, 2.1 Hz, 1H),
7.86-7.80 (m, 2H), 7.64 (t, J=9.2 Hz, 1H), 7.59 (br. s., 1H),
7.53-7.50 (m, 2H), 7.42-7.38 (m, 1H), 7.26-7.20 (m, 1H), 7.07-6.99
(m, 1H), 6.97-6.88 (m, 1H), 4.98 (d, J=9.7 Hz, 1H), 1.81-1.75 (m,
3H), and 1.48-1.41 (m, 6H).
Examples 21 and 22
3-Fluoro-4-(R)-(3-(R)-(8-fluoro-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)--
2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide,
and
3-Fluoro-4-(R)-(3-(S)-(8-fluoro-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)--
2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
(Single Atropisomers)
##STR00202##
[0673] A sample of
3-fluoro-4-(3-(8-fluoro-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methy-
lphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
(mixture of 4 atropisomers) [Example 20] was separated by chiral
super-critical fluid chromatography as follows: column:
CHIRALPAK.RTM. AD-H (3.times.25 cm, 5 .mu.m); Mobile Phase:
CO.sub.2-IPA (75:25) at 180 mL/min, 40.degree. C., 100 bar. The
third peak eluting from the column provided
3-fluoro-4-(R)-(3-(R)-(8-fluoro-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-
-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
[Example 2.sub.1]. The chiral purity was determined to be 98%. Mass
spectrum m/z 537 (M+H--H.sub.2O).sup.+. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 11.83 (br. s., 1H), 11.38 (s, 1H), 8.21 (br.
s., 1H), 7.95 (d, J=10.8 Hz, 1H), 7.83 (d, J=1.1 Hz, 1H), 7.81 (d,
J=8.0 Hz, 1H), 7.65-7.57 (m, 2H), 7.54-7.47 (m, 2H), 7.39 (dd,
J=6.7, 1.9 Hz, 1H), 7.20 (br. s., 1H), 7.03-6.99 (m, 1H), 6.99-6.94
(m, 1H), 4.97 (s, 1H), 1.77 (s, 3H), and 1.44 (d, J=5.3 Hz,
6H).
[0674] The fourth peak eluting from the column provided
3-fluoro-4-(R)-(3-(S)-(8-fluoro-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-
-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
[Example 22]. The chiral purity was determined to be 95%. Mass
spectrum m/z 537 (M+H--H.sub.2O).sup.+. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 11.80 (br. s., 1H), 11.39 (s, 1H), 8.21 (br.
s., 1H), 7.95 (d, J=10.8 Hz, 1H), 7.85-7.78 (m, 2H), 7.59 (br. s.,
2H), 7.54-7.46 (m, 2H), 7.38 (d, J=6.1 Hz, 1H), 7.19 (br. s., 1H),
7.05 (dd, J=8.5, 1.5 Hz, 1H), 6.90 (d, J=8.3 Hz, 1H), 4.99 (s, 1H),
1.77 (s, 3H), and 1.46 (d, J=4.7 Hz, 6H).
Alternative Procedure for the Preparation of
3-Fluoro-4-(R)-(3-(R)-(8-fluoro-2,4-dioxo-1,2-dihydroquinazolin-3
(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxam-
ide [Example 21]
[0675] A mixture of
4-bromo-3-fluoro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
[Intermediate 27] (0.118 g, 0.323 mmol),
8-fluoro-3-(R)-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)p-
henyl)quinazoline-2,4(1H,3H)-dione [Intermediate 18] (0.166 g,
0.420 mmol), 2 M aqueous K.sub.3PO.sub.4 (0.485 mL, 0.969 mmol) and
THF (2.0 mL) was subjected to 3 evacuate-fill cycles with nitrogen.
The mixture was treated with
1,1'-bis(di-tert-butylphosphino)ferrocene palladium(II) chloride
(11 mg, 0.016 mmol) and subjected to 2 more evacuate-fill cycles
with nitrogen. The mixture was stirred at room temperature
overnight, diluted with EtOAc, washed sequentially with water and
brine, and dried and concentrated. The residue was purified by
column chromatography on silica gel, eluting with EtOAc-hexanes
(sequentially 50%, 62%, 75% and 85%), to provide
3-fluoro-4-(3-(R)-(8-fluoro-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-m-
ethylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
(mixture of two atropisomers) as an off-white solid (0.117 g, 65%
yield). A sample of this material was separated by chiral
super-critical fluid chromatography as follows: column:
CHIRALPAK.RTM. AD-H (3.times.25 cm, 5 .mu.m); Mobile Phase:
CO.sub.2-MeOH (70:30) at 180 mL/min, 45.degree. C.; sample
preparation: 30 mg/mL; injection: 1.0 mL. The second peak eluting
from the column provided
3-fluoro-4-(R)-(3-(R)-(8-fluoro-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-
-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide.
The chiral purity was determined to be greater than 99.9%. Mass
spectrum m/z 537 (M+H--H.sub.2O).sup.+. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 11.83 (br. s., 1H), 11.38 (s, 1H), 8.21 (br.
s., 1H), 7.95 (d, J=10.8 Hz, 1H), 7.83 (d, J=1.1 Hz, 1H), 7.81 (d,
J=8.0 Hz, 1H), 7.65-7.57 (m, 2H), 7.54-7.47 (m, 2H), 7.39 (dd,
J=6.7, 1.9 Hz, 1H), 7.20 (br. s., 1H), 7.03-6.99 (m, 1H), 6.99-6.94
(m, 1H), 4.97 (s, 1H), 1.77 (s, 3H), and 1.44 (d, J=5.3 Hz,
6H).
Alternative Procedure for the Preparation of
3-Fluoro-4-(R)-(3-(S)-(8-fluoro-2,4-dioxo-1,2-dihydroquinazolin-3
(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxam-
ide [Example 22]
[0676] Following the same procedure as that used for the
alternative preparation of Example 21,
4-bromo-3-fluoro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
[Intermediate 27] (0.118 g, 0.323 mmol) and
8-fluoro-3-(S)-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)p-
henyl)quinazoline-2,4(1H,3H)-dione [Intermediate 19] (0.166 g,
0.420 mmol) were converted to
3-fluoro-4-(3-(S)-(8-fluoro-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-m-
ethylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
(mixture of two atropisomers) as an off-white solid (0.119 g, 66%
yield). A sample of this material was separated by chiral
super-critical fluid chromatography as follows: column:
CHIRALPAK.RTM. AS-H (3.times.25 cm, 5 .mu.m); Mobile Phase:
CO.sub.2-MeOH (75:25) at 180 mL/min, 45.degree. C.; sample
preparation: 10 mg/mL; injection: 1.0 mL. The second peak eluting
from the column provided
3-fluoro-4-(R)-(3-(S)-(8-fluoro-2,4-dioxo-1,2-dihydroquinazolin-3
(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxam-
ide. The chiral purity was determined to be greater than 99.9%.
Example 23
3-Chloro-4-(3-(3-(4-fluorophenyl)-2,6-dioxo-2,3-dihydropyrimidin-1(6H)-yl)-
-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
(mixture of four atropisomers)
##STR00203##
[0678] A mixture of
4-bromo-3-chloro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
[Intermediate 3] (135 mg, 0.354 mmol),
1-(4-fluorophenyl)-3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan--
2-yl)phenyl)pyrimidine-2,4(1H,3H)-dione [Intermediate 44] (164 mg,
0.389 mmol), and tetrakis(triphenylphosphine)palladium (20 mg,
0.018 mmol) in toluene (5.3 mL) and ethanol (1.8 mL) was bubbled
with argon for several min. The mixture was treated with 2 M
aqueous Na.sub.2CO.sub.3 (354 .mu.l, 0.707 mmol), bubbled again
with argon, and heated at 90.degree. C. for 16 h. The cooled
mixture was partitioned between EtOAc and water. The organic phase
was dried and concentrated. The residue was purified by column
chromatography on silica gel (24 g), eluting with EtOAc-hexanes
(gradient from 25-100%), to give
3-chloro-4-(3-(3-(4-fluorophenyl)-2,6-dioxo-2,3-dihydropyrimidin-1(6H)-yl-
)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
(mixture of four atropisomers) as a white solid (103 mg, 49%
yield). Mass spectrum m/z 579 (M+H--H.sub.2O).sup.+. .sup.1H NMR
(500 MHz, DMSO-d.sub.6) .delta. 11.52 (d, J=4.5 Hz, 1H), 8.29 (br.
s., 1H), 8.13 (d, J=2.5 Hz, 1H), 7.91 (dd, J=7.9, 6.4 Hz, 1H),
7.85-7.80 (m, 1H), 7.64-7.54 (m, 3H), 7.53-7.45 (m, 2H), 7.36 (dt,
J=11.9, 8.7 Hz, 2H), 7.25 (ddd, J=7.3, 4.3, 1.2 Hz, 1H), 7.03-6.83
(m, 1H), 6.73-6.47 (m, 1H), 5.97 (dd, J=7.9, 3.5 Hz, 1H), 5.04-4.92
(m, 1H), 1.75 (d, J=1.5 Hz, 3H), 1.47-1.33 (m, 6H).
Example 24
3-Chloro-4-(R)-(3-(3-(4-fluorophenyl)-2,6-dioxo-2,3-dihydropyrimidin-1(6H)-
-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
(single atropisomer)
##STR00204##
[0680] A sample of
3-chloro-4-(3-(3-(4-fluorophenyl)-2,6-dioxo-2,3-dihydropyrimidin-1
(6H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxam-
ide (mixture of four atropisomers) [Example 23] (103 mg) was
separated by chiral super-critical fluid chromatography as follows:
column: CHIRALPAK.RTM. AD-H (3.times.25 cm, 5 m); Mobile Phase:
CO.sub.2-IPA (60:40) at 85 mL/min; sample preparation: 6.1 mg/mL in
1:1 MeCN-MeOH; injection: 1.0 mL. The fourth peak eluting from the
column was further purified by column chromatography on silica gel
(4 g), eluting with EtOAc-hexanes (gradient from 60-80%), to give a
single atropisomer of
3-chloro-4-(R)-(3-(3-(4-fluorophenyl)-2,6-dioxo-2,3-dihydropyrimidin-1(6H-
)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
as an off-white solid (16 mg, 13% yield). Mass spectrum m/z 579
(M+H--H.sub.2O).sup.+. .sup.1H NMR (400 MHz, MeOH-d.sub.4) .delta.
8.06 (s, 1H), 7.78 (d, J=7.9 Hz, 1H), 7.73 (d, J=1.1 Hz, 1H),
7.57-7.50 (m, 3H), 7.47-7.43 (m, 1H), 7.32 (dd, J=7.5, 1.1 Hz, 1H),
7.27 (t, J=8.7 Hz, 2H), 7.11 (dd, J=8.5, 1.7 Hz, 1H), 6.88 (d,
J=8.4 Hz, 1H), 6.01 (d, J=7.9 Hz, 1H), 1.84 (s, 3H), 1.58 (d, J=3.1
Hz, 6H).
Example 25
6-Chloro-5-(3-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-
-2-methylphenyl)-2-(S)-(2-hydroxypropan-2-yl)-2,3,4,9-tetrahydro-1H-carbaz-
ole-8-carboxamide (mixture of four atropisomers)
##STR00205##
[0682] A mixture of
(S)-5-bromo-6-chloro-2-(2-hydroxypropan-2-yl)-2,3,4,9-tetrahydro-1H-carba-
zole-8-carboxamide [Intermediate 31] (100 mg, 0.259 mmol),
8-fluoro-1-methyl-3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
-yl)phenyl)quinazoline-2,4(1H,3H)-dione [Intermediate 2] (112 mg,
0.272 mmol), Cs.sub.2CO.sub.3 (169 mg, 0.519 mmol) and
PdCl.sub.2(dppf) DCM adduct (16.9 mg, 0.021 mmol) in THF (4.3 mL)
and water (1.1 mL) was heated at 50.degree. C. for 17.5 h. The
cooled mixture was diluted with EtOAc, washed sequentially with
water and brine, dried and concentrated. The residue was purified
by column chromatography on silica gel (24 g), eluting with
EtOAc-hexanes (gradient from 50-80%). The impure product was
further purified by preparative HPLC to give
6-chloro-5-(3-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3
(4H)-yl)-2-methylphenyl)-2-(S)-(2-hydroxypropan-2-yl)-2,3,4,9-tetrahydro--
1H-carbazole-8-carboxamide (mixture of four atropisomers) (76 mg,
50% yield). Mass spectrum m/z 589 (M+H).sup.+. .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. 10.89 (s, 1H), 8.13 (br. s., 1H), 7.94
(d, J=7.9 Hz, 1H), 7.76-7.68 (m, 2H), 7.46 (br. s., 1H), 7.40-7.28
(m, 3H), 7.22-7.16 (m, 1H), 4.21-4.13 (m, 1H), 3.77-3.64 (m, 3H),
2.95-2.82 (m, 1H), 2.40 (d, J=16.3 Hz, 1H), 1.94-1.70 (m, 3H),
1.70-1.61 (m, 3H), 1.58-1.48 (m, 1H), 1.16-1.02 (m, 7H).
Example 26
6-Chloro-5-(R)-(3-(S)-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3-
(4H)-yl)-2-methylphenyl)-2-(S)-(2-hydroxypropan-2-yl)-2,3,4,9-tetrahydro-1-
H-carbazole-8-carboxamide (single atropisomer)
##STR00206##
[0684] A sample of
6-chloro-5-(3-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl-
)-2-methylphenyl)-2-(S)-(2-hydroxypropan-2-yl)-2,3,4,9-tetrahydro-1H-carba-
zole-8-carboxamide (mixture of four atropisomers) [Example 25] (76
mg) was separated by chiral super-critical fluid chromatography as
follows: column: CHIRALPAK.RTM. OD-H (3.times.25 cm, 5 .mu.m);
Mobile Phase: CO.sub.2-MeOH (70:30) at 180 mL/min, 35.degree. C.,
100 bar; sample preparation: 8.35 mg/mL in MeOH-DCM (4:1);
injection: 3.0 mL. The first peak eluting from the column was
further purified by column chromatography on silica gel (4 g),
eluting with EtOAc-hexanes (gradient from 50-80%), to give
6-chloro-5-(R)-(3-(S)-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin--
3(4H)-yl)-2-methylphenyl)-2-(S)-(2-hydroxypropan-2-yl)-2,3,4,9-tetrahydro--
1H-carbazole-8-carboxamide as a white solid (33.6 mg, 47% yield).
Mass spectrum m/z 589 (M+H).sup.+. .sup.1H NMR (400 MHz,
MeOH-d.sub.4) .delta. 8.06-7.99 (m, 1H), 7.69 (s, 1H), 7.60 (ddd,
J=14.3, 8.1, 1.4 Hz, 1H), 7.40 (d, J=7.5 Hz, 1H), 7.34-7.27 (m,
2H), 7.24 (dd, J=7.5, 1.1 Hz, 1H), 3.85 (d, J=7.9 Hz, 3H), 2.90
(dd, J=16.5, 5.1 Hz, 1H), 2.56 (dd, J=16.4, 12.0 Hz, 1H), 2.10-2.02
(m, 1H), 2.00-1.84 (m, 2H), 1.77 (s, 3H), 1.75-1.68 (m, 1H), 1.28
(d, J=3.1 Hz, 1H), 1.22 (d, J=2.2 Hz, 6H).
Example 27
6-Fluoro-5-(R)-(3-(S)-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3
(4H)-yl)-2-methylphenyl)-2-(R)-(2-hydroxypropan-2-yl)-2,3,4,9-tetrahydro--
1H-carbazole-8-carboxamide (single atropisomer)
##STR00207##
[0685] Preparation 27A:
6-Fluoro-5-(3-(S)-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H-
)-yl)-2-methylphenyl)-2-(R)-(2-hydroxypropan-2-yl)-2,3,4,9-tetrahydro-1H-c-
arbazole-8-carboxamide (mixture of 2 atropisomers)
[0686] A mixture of
(R)-5-bromo-6-fluoro-2-(2-hydroxypropan-2-yl)-2,3,4,9-tetrahydro-1H-carba-
zole-8-carboxamide (single enantiomer) [Intermediate 25] (5.00 g,
13.5 mmol),
8-fluoro-1-methyl-3-(S)-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dio-
xaborolan-2-yl)phenyl) quinazoline-2,4(1H,3H)-dione [Intermediate
10] (6.94 g, 16.9 mmol), 2 M aqueous K.sub.3PO.sub.4 (20.3 mL, 40.6
mmol) and THF (60 mL) was subjected to three evacuate-fill cycles
with nitrogen. The mixture was treated with
1,1'-bis(di-tert-butylphosphino) ferrocene palladium(II) chloride
(441 mg, 677 .mu.mol) and subjected to two more evacuate-fill
cycles with nitrogen. The mixture was stirred at room temperature
overnight. The mixture was diluted with EtOAc, washed sequentially
with water and brine, and dried and concentrated. The residue was
purified by column chromatography on silica gel, eluting with
EtOAc-hexanes (sequentially 50%, 62%, 75% and 85%), to give
6-fluoro-5-(3-(S)-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3
(4H)-yl)-2-methylphenyl)-2-(R)-(2-hydroxypropan-2-yl)-2,3,4,9-tetrahydro--
1H-carbazole-8-carboxamide (mixture of two atropisomers) as an
off-white solid (6.77 g, 87% yield). Mass spectrum m/z 573
(M+H).sup.+. .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta.
10.79-10.74 (m, 1H), 8.05 (br. s., 1H), 7.98-7.93 (m, 1H),
7.76-7.69 (m, 1H), 7.57-7.51 (m, 1H), 7.43 (br. s., 1H), 7.40-7.26
(m, 4H), 4.19-4.13 (m, 1H), 3.74-3.68 (m, 3H), 2.94-2.84 (m, 1H),
2.49-2.35 (m, 2H), 1.92-1.80 (m, 3H), 1.76-1.68 (m, 3H), 1.62-1.52
(m, 1H), and 1.12-1.06 (m, 6H).
Example 27
[0687] A sample of
6-fluoro-5-(3-(S)-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H-
)-yl)-2-methylphenyl)-2-(R)-(2-hydroxypropan-2-yl)-2,3,4,9-tetrahydro-1H-c-
arbazole-8-carboxamide (mixture of two atropisomers) was separated
by chiral super-critical fluid chromatography as follows: column:
CHIRALPAK.RTM. AS-H (3.times.25 cm, 5 .mu.m); Mobile Phase:
CO.sub.2-MeOH (70:30) at 120 mL/min, 35.degree. C., 100 bar; sample
preparation: 9 mg/mL in MeOH; injection: 1.7 mL. The first peak
eluting from the column provided
6-fluoro-5-(R)-(3-(S)-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroqu-
inazolin-3(4H)-yl)-2-methylphenyl)-2-(R)-(2-hydroxypropan-2-yl)-2,3,4,9-te-
trahydro-1H-carbazole-8-carboxamide. The chiral purity was
determined to be greater than 99.5%. Mass spectrum m/z 573
(M+H).sup.+. .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 10.76 (s,
1H), 8.05 (br. s., 1H), 7.96 (d, J=7.8 Hz, 1H), 7.72 (ddd, J=14.3,
8.0, 1.2 Hz, 1H), 7.55 (d, J=10.8 Hz, 1H), 7.44 (br. s., 1H),
7.40-7.36 (m, 1H), 7.35-7.28 (m, 3H), 4.18 (s, 1H), 3.72 (d, J=8.0
Hz, 3H), 2.89 (dd, J=16.9, 4.4 Hz, 1H), 2.45-2.37 (m, 1H),
2.02-1.93 (m, 1H), 1.91-1.82 (m, 2H), 1.57 (td, J=11.7, 3.6 Hz,
1H), and 1.15-1.11 (m, 1H).
Example 28
6-Fluoro-5-(R)-(3-(S)-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3
(4H)-yl)-2-methylphenyl)-2-(S)-(2-hydroxypropan-2-yl)-2,3,4,9-tetrahydro--
1H-carbazole-8-carboxamide (single atropisomer)
##STR00208##
[0689] Following the procedure used to prepare Example 27,
(S)-5-bromo-6-fluoro-2-(2-hydroxypropan-2-yl)-2,3,4,9-tetrahydro-1H-carba-
zole-8-carboxamide (single enantiomer) [Intermediate 26] (0.045 g,
0.122 mmol) and
8-fluoro-1-methyl-3-(S)-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2--
dioxaborolan-2-yl)phenyl)quinazoline-2,4(1H,3H)-dione [Intermediate
10] (0.065 g, 0.158 mmol) were converted into
6-fluoro-5-(3-(S)-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H-
)-yl)-2-methylphenyl)-2-(S)-(2-hydroxypropan-2-yl)-2,3,4,9-tetrahydro-1H-c-
arbazole-8-carboxamide (mixture of two atropisomers) as a yellow
solid (0.035 g, 49% yield). Separation of a sample of this material
by chiral super-critical fluid chromatography, using the conditions
used to separate Example 27, provided (as the first peak to elute
from the column)
6-fluoro-5-(R)-(3-(S)-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroqui-
nazolin-3(4H)-yl)-2-methylphenyl)-2-(S)-(2-hydroxypropan-2-yl)-2,3,4,9-tet-
rahydro-1H-carbazole-8-carboxamide. The chiral purity was
determined to be greater than 99.5%. The relative and absolute
configurations were determined by x-ray crystallography. Mass
spectrum m/z 573 (M+H).sup.+. .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 10.77 (s, 1H), 8.05 (br. s., 1H), 7.94 (dd, J=7.9, 1.2 Hz,
1H), 7.56-7.52 (m, 1H), 7.43 (br. s., 1H), 7.40-7.36 (m, 1H),
7.35-7.30 (m, 2H), 7.28 (dd, J=7.5, 1.4 Hz, 1H), 4.15 (s, 1H),
3.75-3.70 (m, 3H), 2.90 (dd, J=16.8, 4.6 Hz, 1H), 2.47-2.39 (m,
1H), 1.93-1.82 (m, 3H), 1.74 (s, 3H), 1.57 (td, J=11.7, 4.2 Hz,
1H), 1.16-1.11 (m, 1H), and 1.10 (d, J=1.9 Hz, 6H).
[.alpha.].sub.D: +63.80 (c 2.1, CHCl.sub.3). DSC melting point
onset temperature=202.9.degree. C. (heating rate=10.degree.
C./min.).
[0690] The absolute configuration of Example 28 was confirmed by
single crystal x-ray analysis of crystals prepared by dissolving
the compound in excess methanol and slowly evaporating the solvent
at room temperature to provide a di-methanol solvate (crystalline
form M2-1). Unit cell dimensions: a=9.24 .ANG., b=7.97 .ANG.,
c=22.12 .ANG., .alpha.=90.0.degree., .beta.=94.10,
.gamma.=90.0.degree.; Space group: P2.sub.1; Molecules of Example
28/asymmetric unit: 1; Volume/Number of molecules in the unit
cell=813 .ANG..sup.3; Density (calculated)=1.301 g/cm.sup.3.
Fractional atomic coordinates at 173 K are given in Table 6, and a
depiction of the structure is given in FIG. 5.
Alternative Synthesis of Example 28
[0691] A mixture of
(S)-5-bromo-6-fluoro-2-(2-hydroxypropan-2-yl)-2,3,4,9-tetrahydro-1H-carba-
zole-8-carboxamide [Intermediate 11] (5.00 g, 13.54 mmol),
8-fluoro-1-methyl-3-(S)-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-
an-2-yl)phenyl)quinazoline-2,4(1H,3H)-dione [Intermediate 10] (6.67
g, 16.25 mmol), tripotassium phosphate (2 M in water) (20.31 mL,
40.6 mmol), and tetrahydrofuran (25 mL) was subjected to 3
evacuate-fill cycles with nitrogen. The mixture was treated with
1,1'-bis(di-tert-butylphosphino)ferrocene palladium dichloride
(0.441 g, 0.677 mmol) and the mixture was subjected to 2 more
evacuate-fill cycles with nitrogen. The mixture was stirred at room
temperature overnight, then was diluted with EtOAc, washed
sequentially with water and brine, and dried and concentrated. The
residue was purified by column chromatography on silica gel,
eluting with EtOAc-hexanes (sequentially 50%, 62%, 75% and 85%), to
provide
6-fluoro-5-(3-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3-(S)-3(-
4H)-yl)-2-methylphenyl)-2-(S)-(2-hydroxypropan-2-yl)-2,3,4,9-tetrahydro-1H-
-carbazole-8-carboxamide as a white solid (6.58 g, 85% yield).
[0692] Material prepared by this method (40.03 g, 69.9 mmol) was
separated by chiral super-critical fluid chromatography to give
(2S,
5R)-6-fluoro-5-(3-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H-
)-yl)-2-methylphenyl)-2-(S)-(2-hydroxypropan-2-yl)-2,3,4,9-tetrahydro-1H-c-
arbazole-8-carboxamide. Further purification was achieved by
suspending this material in methanol, sonicating for 5 min,
collection of the solid by filtration, rinsing the collected solid
with methanol and drying at room temperature under reduced pressure
to give a white solid (22.0 g, 90% yield).
Example 29
4-(R)-(3-(S)-(8-Fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3
(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-3-methyl-9H-carbazole-1-
-carboxamide (single atropisomer)
##STR00209##
[0694] A mixture of
4-bromo-7-(2-hydroxypropan-2-yl)-3-methyl-9H-carbazole-1-carboxamide
[Intermediate 28] (0.091 g, 0.252 mmol),
8-fluoro-1-methyl-3-(S)-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-
an-2-yl)phenyl)quinazoline-2,4(1H,3H)-dione [Intermediate 10]
(0.134 g, 0.327 mmol), 2 M aqueous K.sub.3PO.sub.4 (0.378 mL, 0.756
mmol), and THF (2.0 mL) was subjected to three evacuate-fill cycles
with nitrogen. The mixture was treated with
1,1'-bis(di-tert-butylphosphino)ferrocene palladium(II) chloride
(8.2 mg, 0.013 mmol) and subjected to two additional evacuate-fill
cycles with nitrogen. The mixture was stirred at room temperature
overnight, then was diluted with EtOAc, washed sequentially with
water and brine, and dried and concentrated. The residue was
purified by column chromatography on silica gel, eluting with
EtOAc-hexanes (sequentially 50%, 62%, 75% and 85%) to give
4-(3-(S)-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3
(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-3-methyl-9H-carbazole-1-
-carboxamide (mixture of two atropisomers) as pale yellow solid
(0.087 g, 59% yield). Mass spectrum m/z 547 (M+H--H.sub.2O).sup.+.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 11.20 (s, 1H), 8.10
(br. s., 1H), 7.97 (ddd, J=7.9, 7.2, 1.0 Hz, 1H), 7.90 (s, 1H),
7.78 (s, 1H), 7.76-7.68 (m, 1H), 7.53-7.48 (m, 1H), 7.44 (dd,
J=7.9, 1.2 Hz, 1H), 7.40 (br. s., 1H), 7.36-7.30 (m, 1H), 7.23 (dd,
J=7.4, 1.2 Hz, 1H), 6.98 (ddd, J=12.0, 8.4, 1.5 Hz, 1H), 6.68 (t,
J=7.9 Hz, 1H), 4.94 (d, J=3.1 Hz, 1H), 3.73 (dd, J=8.2, 3.5 Hz,
3H), 2.17 (s, 3H), 1.66 (s, 3H), and 1.48-1.41 (m, 6H).
[0695] A sample of this material was separated by chiral
super-critical fluid chromatography as follows: column:
CHIRALPAK.RTM. AD-H (3.times.25 cm, 5 .mu.m); Mobile Phase:
CO.sub.2-MeOH (65:35) at 150 mL/min, 40.degree. C.; sample
preparation: 15 mg/mL in MeOH; injection: 1.5 mL. The second peak
eluting from the column provided
4-(R)-(3-(S)-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-
-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-3-methyl-9H-carbazole-1-carboxam-
ide. The chiral purity was determined to be greater than 99%. Mass
spectrum m/z 547 (M+H--H.sub.2O).sup.+. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 11.19 (s, 1H), 8.10 (br. s., 1H), 7.97 (dd,
J=7.9, 1.0 Hz, 1H), 7.90 (s, 1H), 7.78 (d, J=1.1 Hz, 1H), 7.72
(ddd, J=14.3, 8.0, 1.5 Hz, 1H), 7.53-7.48 (m, 1H), 7.44 (dd, J=7.8,
1.1 Hz, 1H), 7.40 (br. s., 1H), 7.33 (td, J=8.0, 4.2 Hz, 1H), 7.23
(dd, J=7.5, 1.1 Hz, 1H), 6.99 (dd, J=8.5, 1.5 Hz, 1H), 6.69 (d,
J=8.6 Hz, 1H), 4.94 (s, 1H), 2.20-2.14 (m, 3H), 1.66 (s, 3H), and
1.45 (d, J=3.6 Hz, 6H).
Examples 30 and 31
4-(R)-(3-(5-Chloro-1,3-dioxo-1H-pyrido[1,2-c]pyrimidin-2(3H)-yl)-2-methylp-
henyl)-3-fluoro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
(single atropisomers)
##STR00210##
[0696] Preparation 30A:
4-(3-(5-Chloro-1,3-dioxo-1H-pyrido[1,2-c]pyrimidin-2(3H)-yl)-2-methylphen-
yl)-3-fluoro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
(mixture of four atropisomers)
[0697] A mixture of
4-bromo-3-fluoro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
[Intermediate 27] (0.098 g, 0.268 mmol),
5-chloro-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pheny-
l)-1H-pyrido[1,2-c]pyrimidine-1,3(2H)-dione [Intermediate 33]
(0.144 g, 0.349 mmol), Cs.sub.2CO.sub.3 (0.175 g, 0.537 mmol), and
dioxane (1.6 mL) was subjected to three evacuate-fill cycles with
nitrogen. The mixture was treated with PdCl.sub.2(dppf) DCM adduct
(0.013 g, 0.016 mmol) and subjected to two more evacuate-fill
cycles with nitrogen. The mixture was heated at 52.degree. C.
overnight. The cooled mixture was diluted with EtOAc, washed
sequentially with water and brine, and dried and concentrated. The
residue was purified by reverse-phase preparative HPLC. The
appropriate fractions were treated with saturated aqueous
NaHCO.sub.3 and concentrated. The residue was partitioned between
EtOAc and water, and the organic layer was washed with brine. The
aqueous layers were extracted with EtOAc, and the combined organic
layers were dried and concentrated. The residue was purified twice
by column chromatography on silica gel, eluting with EtOAc-hexanes
(sequentially 50%, 65% and 75%) to give
4-(3-(5-chloro-1,3-dioxo-1H-pyrido[1,2-c]pyrimidin-2(3H)-yl)-2-methy-
lphenyl)-3-fluoro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
(mixture of four atropisomers) as a yellow solid (0.013 g, 8%
yield). Mass spectrum m/z 571, 573 (M+H).sup.+. .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. 11.39 (d, J=5.3 Hz, 1H), 8.30-8.24 (m,
1H), 8.21 (br. s., 1H), 7.95 (dd, J=10.5, 1.7 Hz, 1H), 7.84 (s,
1H), 7.60 (d, J=7.2 Hz, 2H), 7.55-7.47 (m, 2H), 7.42-7.39 (m, 1H),
7.04-6.99 (m, 1H), 6.93 (d, J=8.6 Hz, 0.6H), 6.84 (d, J=8.6 Hz,
0.4H), 6.57 (td, J=7.3, 3.5 Hz, 1H), 6.00 (d, J=8.6 Hz, 1H), 4.98
(s, 1H), 1.78 (d, J=1.9 Hz, 3H), and 1.45 (d, J=3.9 Hz, 6H).
Examples 30 and 31
[0698] A sample of
4-(3-(5-chloro-1,3-dioxo-1H-pyrido[1,2-c]pyrimidin-2(3H)-yl)-2-methylphen-
yl)-3-fluoro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
(mixture of 4 atropisomers) was separated by chiral super-critical
fluid chromatography as follows: column: CHIRALPAK.RTM. AD-H
(3.times.25 cm, 5 .mu.m); Mobile Phase: CO.sub.2-IPA (55:45) at 120
mL/min, 45.degree. C., 100 bar; sample preparation: 5.6 mg/mL in
MeOH; injection: 1.7 mL. The second peak eluting from the column
provided one single atropisomer of
4-(R)-(3-(5-chloro-1,3-dioxo-1H-pyrido[1,2-c]pyrimidin-2(3H)-yl)-2-methyl-
phenyl)-3-fluoro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
[Example 30]. The chiral purity was determined to be greater than
97.5%. Mass spectrum m/z 571 (M+H).sup.+. The fourth peak eluting
from the column provided the other single atropisomer of
4-(R)-(3-(5-chloro-1,3-dioxo-1H-pyrido[1,2-c]pyrimidin-2(3H)-yl)-2-methyl-
phenyl)-3-fluoro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
[Example 31]. The chiral purity was determined to be greater than
99.5%. Mass spectrum m/z 553 (M+H--H.sub.2O).sup.+.
Examples 32 and 33
3-Chloro-4-(R)-(3-(R)-(5-chloro-1,3-dioxo-1H-pyrido[1,2-c]pyrimidin-2(3H)--
yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
(32), and
3-Chloro-4-(R)-(3-(S)-(5-chloro-1,3-dioxo-1H-pyrido[1,2-c]pyrimidin-2(3H)--
yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
(33) (Single Atropisomers)
##STR00211##
[0700] A mixture of
4-bromo-3-chloro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
[Intermediate 3] (1.11 g, 2.91 mmol),
5-chloro-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pheny-
l)-1H-pyrido[1,2-c]pyrimidine-1,3(2H)-dione [Intermediate 33] (1.00
g, 2.42 mmol) and Cs.sub.2CO.sub.3 (1.58 g, 4.85 mmol) in THF (8
mL) and water (2 mL) was bubbled with argon for three min. The
mixture was treated with PdCl.sub.2(dppf) DCM adduct (0.099 g,
0.121 mmol) and heated at 60.degree. C. overnight. The cooled
mixture was diluted with EtOAc and washed sequentially with water
and brine. The combined aqueous layers were extracted with DCM
containing a small amount of MeOH. The combined organic layers were
dried and concentrated until a tan precipitate formed, which was
removed by filtration. The filtrate was concentrated and purified
by column chromatography on silica gel (120 g), eluting with
EtOAc-DCM (sequentially 70%, 80%, and 100%), to give
3-chloro-4-(3-(5-chloro-1,3-dioxo-1H-pyrido[1,2-c]pyrimidin-2(3H)-yl)-2-m-
ethylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
(mixture of four atropisomers) as a yellow solid (993 mg, 69%
yield). The material was separated by chiral super-critical fluid
chromatography as follows: column: CHIRALPAK.RTM. AD-H (3.times.25
cm, 5 .mu.m); Mobile Phase: CO.sub.2-IPA (50:50) at 150 mL/min,
45.degree. C., 100 bar; sample preparation: 5.6 mg/mL in MeOH-DCM
(1:1); injection: 3 mL. The second peak eluting from the column
provided
3-chloro-4-(R)-(3-(R)-(5-chloro-1,3-dioxo-1H-pyrido[1,2-c]pyrimidin-2(3H)-
-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
[Example 32]. Mass spectrum m/z 587 (M+H).sup.+. .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 11.50 (s, 1H), 8.27 (s, 2H), 8.14 (s,
1H), 7.84 (d, J=1.1 Hz, 1H), 7.59 (d, J=6.8 Hz, 1H), 7.56-7.46 (m,
2H), 7.29 (dd, J=7.4, 1.2 Hz, 1H), 7.01 (dd, J=8.4, 1.5 Hz, 1H),
6.64 (d, J=8.6 Hz, 1H), 6.55 (t, J=7.3 Hz, 1H), 5.98 (s, 1H), 5.75
(s, 1H), 4.98 (s, 1H), 1.71 (s, 3H), 1.46-1.42 (m, 6H).
[0701] The fourth peak eluting from the column provided
3-chloro-4-(R)-(3-(S)-(5-chloro-1,3-dioxo-1H-pyrido[1,2-c]pyrimidin-2(3H)-
-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
[Example 33]. Mass spectrum m/z 569 (M+H--H.sub.2O).sup.+. .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. 11.49 (s, 1H), 8.34-8.24 (m,
2H), 8.14 (s, 1H), 7.84 (d, J=1.1 Hz, 1H), 7.60 (d, J=6.6 Hz, 1H),
7.56-7.46 (m, 2H), 7.28 (dd, J=7.4, 1.4 Hz, 1H), 6.99 (dd, J=8.5,
1.7 Hz, 1H), 6.72 (d, J=8.4 Hz, 1H), 6.57 (t, J=7.3 Hz, 1H), 5.99
(s, 1H), 5.75 (s, 1H), 4.98 (s, 1H), 1.71 (s, 3H), 1.45-1.42 (m,
6H). [.alpha.].sub.D: +332.34.degree. (c 2.0, CHCl.sub.3).
Alternative Preparation of Example 33
[0702] A mixture of
4-bromo-3-chloro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
[Intermediate 3] (50.5 g, 132 mmol),
5-chloro-2-(S)-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)p-
henyl)-1H-pyrido[1,2-c]pyrimidine-1,3(2H)-dione [Intermediate 35]
(60.1 g, 146 mmol) and Cs.sub.2CO.sub.3 (86 g, 265 mmol) in THF
(342 mL) and water (85 mL) was bubbled with nitrogen for 5 min,
then was treated with PdCl.sub.2(dppf) DCM adduct (11.9 g, 14.57
mmol). Bubbling with nitrogen was continued for 5 min more, then
the mixture was heated at 62.degree. C. under nitrogen for 20 h.
The mixture was cooled to room temperature, MeOH (300 mL) was added
with stirring followed 15 min later by the addition of water (2 L)
to give a rusty brown colored gum. The supernatant was removed, the
gummy residue was washed twice with water and then suspended in
EtOAc (2 L) with stirring for one h. The mixture was filtered, the
filtrate was concentrated to about 1-1.5 L and treated with heptane
(3 L). The mixture was stirred for two days, the precipitate was
collected by filtration, washed with heptane and dried under vacuum
to give a yellow solid (104 g). The solid was dissolved in THF,
absorbed on CELITE.RTM., dried under vacuum, placed on a silica gel
plug and eluted with heptane/EtOAc (10:90) to give an orange-yellow
oil (74.87 g). The material was subjected to column chromatography
on silica gel (3 kg), eluting with EtOAc-hexanes (gradient from
40-90%), to give
3-chloro-4-(3-(S)-(5-chloro-1,3-dioxo-1H-pyrido[1,2-c]pyrimidin-2(3H)-yl)-
-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
(mixture of two atropisomers) as a yellow foam (44 g, 51% yield).
To remove residual palladium, the residue was dissolved in EtOAc
(about 300 mL) and stirred with a 10% aqueous solution of
N-acetyl-L-cysteine (500 mL) overnight. The organic layer was
treated again with a 10% solution of N-acetyl-L-cysteine (500 mL)
for six h, then was washed sequentially with 5% NH.sub.4OH (twice)
and brine, dried and concentrated to a yellow foam (43 g). The
material was separated by chiral super-critical fluid
chromatography as follows: column: CHIRALPAK.RTM. AS-H (2.times.50
cm, 10 .mu.m); Mobile Phase: CO.sub.2-MeOH (55:45) at 140 mL/min,
40.degree. C., 100 bar; sample preparation: 56 mg/mL in MeOH-DCM
(1:1); injection: 3.33 mL. The first peak eluting from the column
provided
3-chloro-4-(R)-(3-(S)-(5-chloro-1,3-dioxo-1H-pyrido[1,2-c]pyrimidin-2(3H)-
-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
[Example 33] as a yellow solid (18.3 g, 24% yield).
[0703] The absolute configuration of Example 33 was confirmed by
single crystal x-ray analysis of crystals prepared by dissolving
the compound in excess methanol and slowly evaporating the solvent
at room temperature to provide a di-methanol solvate (crystalline
form M2-1). Unit cell dimensions: a=7.41 .ANG., b=9.74 .ANG.,
c=44.55 .ANG., .alpha.=90.0.degree., .beta.=90.0.degree.,
.gamma.=90.0.degree.; Space group: P2.sub.12.sub.12.sub.1;
Molecules of Example 33/asymmetric unit: 1; Volume/Number of
molecules in the unit cell=3214 .ANG..sup.3; Density
(calculated)=1.346 g/cm.sup.3. Fractional atomic coordinates at 173
K are given in Table 7, and a depiction of the structure is given
in FIG. 6.
Example 34
3-Chloro-4-(3-(5-fluoro-1,3-dioxo-1H-pyrido[1,2-c]pyrimidin-2(3H)-yl)-2-me-
thylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
(Mixture of Four Atropisomers)
##STR00212##
[0705] A mixture of
4-bromo-3-chloro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
[Intermediate 3] (0.076 g, 0.200 mmol),
5-fluoro-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pheny-
l)-1H-pyrido[1,2-c]pyrimidine-1,3(2H)-dione [Intermediate 37]
(0.072 g, 0.182 mmol) and Cs.sub.2CO.sub.3 (0.118 g, 0.363 mmol) in
THF (3 mL) and water (0.75 mL) was bubbled with nitrogen for 2 min,
then was treated with PdCl.sub.2(dppf) DCM adduct (7.4 mg, 9.09
.mu.mol). Bubbling with nitrogen was continued for 30 sec and the
reaction vessel was sealed. The mixture was stirred at room
temperature overnight, then was diluted with EtOAc and washed
sequentially with water and brine. The combined aqueous layers were
extracted with DCM. The combined organic layers were dried and
concentrated. The residue was purified by column chromatography on
silica gel, eluting with EtOAc-hexanes, to give
3-chloro-4-(3-(5-fluoro-1,3-dioxo-1H-pyrido[1,2-c]pyrimidin-2(3H)-yl)-2-m-
ethylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
(mixture of four atropisomers) as a yellow solid (0.049 g, 43%
yield). Mass spectrum m/z 571 (M+H).sup.+. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 11.52-11.48 (m, 1H), 8.27 (br. s., 1H),
8.15-8.09 (m, 2H), 7.84 (s, 1H), 7.59 (br. s., 1H), 7.56-7.46 (m,
2H), 7.30-7.26 (m, 1H), 7.03-6.97 (m, 1H), 6.72 (d, J=8.4 Hz, 1H),
6.60-6.51 (m, 2H), 5.85 (s, 1H), 4.98 (s, 1H), 1.71 (s, 3H),
1.46-1.42 (m, 6H).
Examples 35 and 36
3-Chloro-4-(R)-(3-(5-fluoro-1,3-dioxo-1H-pyrido[1,2-c]pyrimidin-2(3H)-yl)--
2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
(Single Atropisomers)
##STR00213##
[0707] A sample of
3-chloro-4-(3-(5-fluoro-1,3-dioxo-1H-pyrido[1,2-c]pyrimidin-2(3H)-yl)-2-m-
ethylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
(mixture of four atropisomers) [Example 34] (690 mg) was separated
by chiral super-critical fluid chromatography as follows: column:
CHIRALPAK.RTM. IB (2.times.25 cm, 5 .mu.m); Mobile Phase:
CO.sub.2-MeOH (63:37) at 50 mL/min, 45.degree. C., 100 bar. The
first peak eluting from the column provided one single atropisomer
of
3-chloro-4-(R)-(3-(5-fluoro-1,3-dioxo-1H-pyrido[1,2-c]pyrimidin-2(3H)-yl)-
-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
[Example 35]. Mass spectrum m/z 571 (M+H).sup.+. .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 11.50 (s, 1H), 8.27 (br. s., 1H), 8.14
(s, 1H), 8.11 (d, J=7.5 Hz, 1H), 7.84 (d, J=1.1 Hz, 1H), 7.59 (br.
s., 1H), 7.56-7.51 (m, 1H), 7.49-7.46 (m, 1H), 7.29 (dd, J=7.5, 1.3
Hz, 1H), 7.23 (dd, J=10.3, 7.5 Hz, 1H), 7.01 (dd, J=8.4, 1.5 Hz,
1H), 6.65 (d, J=8.6 Hz, 1H), 6.54 (td, J=7.4, 5.2 Hz, 1H), 5.85 (s,
1H), 4.98 (s, 1H), 1.71 (s, 3H), 1.48-1.41 (m, 6H).
[0708] The third peak eluting from the column provided the other
single atropisomer of
3-chloro-4-(R)-(3-(5-fluoro-1,3-dioxo-1H-pyrido[1,2-c]pyrimidin-2(3H)-yl)-
-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
[Example 36]. Mass spectrum m/z 553 (M+H--H.sub.2O).sup.+. .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. 11.49 (s, 1H), 8.27 (br. s.,
1H), 8.14 (s, 1H), 8.10 (d, J=7.7 Hz, 1H), 7.83 (s, 1H), 7.59 (br.
s., 1H), 7.56-7.45 (m, 2H), 7.30-7.20 (m, 2H), 6.99 (d, J=8.6 Hz,
1H), 6.72 (d, J=8.6 Hz, 1H), 6.56 (td, J=7.5, 5.3 Hz, 1H), 5.85 (s,
1H), 4.98 (s, 1H), 1.71 (s, 3H), 1.45-1.42 (m, 6H).
Example 37
3-Chloro-7-(2-hydroxypropan-2-yl)-4-(3-(5-methoxy-1,3-dioxo-1H-pyrido[1,2--
c]pyrimidin-2(3H)-yl)-2-methylphenyl)-9H-carbazole-1-carboxamide
(mixture of four atropisomers)
##STR00214##
[0710] A mixture of
4-bromo-3-chloro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
[Intermediate 3] (0.051 g, 0.135 mmol),
5-methoxy-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phen-
yl)-1H-pyrido[1,2-c]pyrimidine-1,3(2H)-dione [Intermediate 32]
(0.050 g, 0.122 mmol) and Cs.sub.2CO.sub.3 (0.080 g, 0.245 mmol) in
THF (2 mL) and water (0.5 mL) was bubbled with nitrogen for 2 min,
then was treated with PdCl.sub.2(dppf) DCM adduct (5.0 mg, 6.12
.mu.mol). Bubbling with nitrogen was continued for 30 sec and the
reaction vessel was sealed. The mixture was heated at 60.degree. C.
overnight.
[0711] The cooled mixture was diluted with DCM and MeOH, dried and
concentrated. The residue was purified by column chromatography on
silica gel, eluting with EtOAc-hexanes, to give
3-chloro-7-(2-hydroxypropan-2-yl)-4-(3-(5-methoxy-1,3-dioxo-1H-pyrido[1,2-
-c]pyrimidin-2(3H)-yl)-2-methylphenyl)-9H-carbazole-1-carboxamide
(mixture of four atropisomers) as a yellow solid (32.8 mg, 44%
yield). Mass spectrum m/z 583 (M+H).sup.+. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 11.51-11.47 (m, 1H), 8.27 (br. s., 1H), 8.14
(d, J=1.5 Hz, 1H), 7.93 (d, J=7.5 Hz, 1H), 7.83 (s, 1H), 7.59 (br.
s., 1H), 7.55-7.45 (m, 3H), 7.30-7.25 (m, 1H), 7.03-6.97 (m, 1H),
6.71 (d, J=8.1 Hz, 1H), 6.56 (q, J=7.6 Hz, 1H), 5.90 (s, 1H), 4.98
(s, 1H), 3.91 (s, 3H), 1.69 (s, 3H), 1.45-1.42 (m, 6H).
Examples 38 and 39
3-Chloro-4-(R)-(3-(5,7-dioxo-5H-thiazolo[3,2-c]pyrimidin-6(7H)-yl)-2-methy-
lphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
(single atropisomers)
##STR00215##
[0713] A mixture of
4-bromo-3-chloro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
[Intermediate 3] (0.139 g, 0.364 mmol),
6-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-5H-thi-
azolo[3,2-c]pyrimidine-5,7(6H)-dione [Intermediate 36] (0.127 g,
0.331 mmol) and Cs.sub.2CO.sub.3 (0.215 g, 0.661 mmol) in THF (3.0
mL) and water (0.75 mL) was bubbled with argon for 3 min, then was
treated with PdCl.sub.2(dppf) DCM adduct (0.013 g, 0.017 mmol). The
mixture was bubbled with argon for 30 sec more and the reaction
vessel was sealed. The mixture was stirred at 50.degree. C. for 5
h. The cooled mixture was diluted with EtOAc and washed
sequentially with water and brine. The combined aqueous layers was
extracted with EtOAc, and the combined organic layers were dried
and concentrated. The residue was purified by column chromatography
on silica gel (80 g), eluting with EtOAc-hexanes (90%, then 100%),
to give
3-chloro-4-(3-(5,7-dioxo-5H-thiazolo[3,2-c]pyrimidin-6(7H)-yl)-2-methylph-
enyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide (mixture
of four atropisomers) as a tan solid (62.7 mg, 32% yield). This
material was separated by chiral super-critical fluid
chromatography as follows: column: CHIRALPAK.RTM. AD-H (3.times.25
cm, 5 .mu.m); Mobile Phase: CO.sub.2-MeOH (60:40) at 85 mL/min;
sample preparation: 9 mg/mL in MeOH-DMSO; injection: 2 mL. The
third peak eluted from the column provided one single atropisomer
of
3-chloro-4-(R)-(3-(5,7-dioxo-5H-thiazolo[3,2-c]pyrimidin-6(7H)-yl)-2-meth-
ylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
[Example 38]. Mass spectrum m/z 559 (M+H).sup.+. .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 11.50 (s, 1H), 8.27 (br. s., 1H), 8.14
(s, 1H), 7.83 (d, J=0.9 Hz, 1H), 7.69 (dd, J=4.6, 0.7 Hz, 1H), 7.59
(br. s., 1H), 7.54-7.49 (m, 1H), 7.47-7.43 (m, 1H), 7.26 (dd,
J=7.4, 1.2 Hz, 1H), 7.03 (d, J=4.6 Hz, 1H), 6.99 (dd, J=8.6, 1.5
Hz, 1H), 6.62 (d, J=8.4 Hz, 1H), 6.28 (s, 1H), 4.98 (s, 1H), 1.70
(s, 3H), 1.45-1.42 (m, 6H).
[0714] The fourth peak eluted from the column provided the other
single atropisomer of
3-chloro-4-(R)-(3-(5,7-dioxo-5H-thiazolo[3,2-c]pyrimidin-6(7H)-yl)-2-meth-
ylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
[Example 39]. Mass spectrum m/z 541 (M+H--H.sub.2O).sup.+. .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. 11.49 (s, 1H), 8.27 (br. s.,
1H), 8.13 (s, 1H), 7.83 (d, J=0.9 Hz, 1H), 7.73-7.65 (m, 2H), 7.59
(br. s., 1H), 7.54-7.43 (m, 2H), 7.26 (dd, J=7.5, 1.3 Hz, 1H), 7.05
(d, J=4.6 Hz, 1H), 6.98 (dd, J=8.5, 1.7 Hz, 1H), 6.71 (d, J=8.6 Hz,
1H), 6.28 (s, 1H), 1.70 (s, 3H), 1.43 (d, J=2.9 Hz, 6H).
Examples 40 and 41
3-Fluoro-4-(R)-(3-(5-fluoro-1,3-dioxo-1H-pyrido[1,2-c]pyrimidin-2(3H)-yl)--
2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
(Single Atropisomers)
##STR00216##
[0715] Preparation 40A:
3-Fluoro-4-(R)-(3-(5-fluoro-1,3-dioxo-1H-pyrido[1,2-c]pyrimidin-2(3H)-yl)-
-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
(Mixture of Two Atropisomers)
[0716] A mixture of
4-bromo-3-fluoro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
[Intermediate 27] (0.200 g, 0.548 mmol),
5-fluoro-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pheny-
l)-1H-pyrido[1,2-c]pyrimidine-1,3(2H)-dione [Intermediate 37]
(0.260 g, 0.657 mmol) and Cs.sub.2CO.sub.3 (0.357 g, 1.10 mmol) in
dioxane (4 mL) and water (1 mL) was bubbled with nitrogen for 2
min, then was treated with PdCl.sub.2(dppf) DCM adduct (0.022 g,
0.027 mmol). Bubbling with nitrogen was continued for 30 sec and
the reaction vessel was sealed. The mixture was heated at
60.degree. C. overnight. The cooled mixture was diluted with EtOAc
and washed sequentially with water and brine. The combined aqueous
layers were extracted with DCM, and combined organic layers were
dried and concentrated. The residue was purified by column
chromatography on silica gel, eluting with EtOAc-hexanes, to give
3-fluoro-4-(3-(5-fluoro-1,3-dioxo-1H-pyrido[1,2-c]pyrimidin-2(3H)-yl)-2-m-
ethylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
(mixture of four atropisomers) as a yellow solid (0.194 g, 63%
yield).
Examples 40 and 41
[0717] A sample of
3-fluoro-4-(3-(5-fluoro-1,3-dioxo-1H-pyrido[1,2-c]pyrimidin-2(3H)-yl)-2-m-
ethylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
(mixture of four atropisomers) was separated by chiral
super-critical fluid chromatography as follows: column:
CHIRALPAK.RTM. OD-H (5.times.25 cm, 5 .mu.m); Mobile Phase:
CO.sub.2-IPA (55:45) at 120 mL/min, 50.degree. C., 100 bar; sample
preparation: 6.8 mg/mL in MeOH--CHCl.sub.3 (1:1); injection: 1 mL.
The first peak eluting from the column provided one single
atropisomer of
3-fluoro-4-(R)-(3-(5-fluoro-1,3-dioxo-1H-pyrido[1,2-c]pyrimidin-2(3H)-yl)-
-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
[Example 40]. Mass spectrum m/z 555 (M+H).sup.+. .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 11.40 (s, 1H), 8.21 (br. s., 1H), 8.12
(d, J=7.5 Hz, 1H), 7.95 (d, J=10.8 Hz, 1H), 7.84 (d, J=1.1 Hz, 1H),
7.60 (br. s., 1H), 7.56-7.46 (m, 2H), 7.41 (dd, J=7.4, 1.4 Hz, 1H),
7.23 (dd, J=10.2, 7.4 Hz, 1H), 7.02 (dd, J=8.6, 1.5 Hz, 1H),
6.88-6.82 (m, 1H), 6.56 (td, J=7.4, 5.2 Hz, 1H), 5.86 (s, 1H), 4.98
(s, 1H), 1.77 (s, 3H), 1.47-1.42 (m, 6H).
[0718] The third peak eluting from the column provided the other
single atropisomer of
3-fluoro-4-(R)-(3-(5-fluoro-1,3-dioxo-1H-pyrido[1,2-c]pyrimidin-2(3H)-yl)-
-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
[Example 41]. Mass spectrum m/z 537 (M+H--H.sub.2O).sup.+. .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. 11.41 (s, 1H), 8.29-8.17 (m,
1H), 8.13 (d, J=7.3 Hz, 1H), 7.96 (d, J=10.8 Hz, 1H), 7.85 (d,
J=1.1 Hz, 1H), 7.65-7.57 (m, 1H), 7.57-7.47 (m, 2H), 7.43 (d, J=1.5
Hz, 1H), 7.28-7.21 (m, 1H), 7.02 (d, J=1.5 Hz, 1H), 6.90-6.83 (m,
1H), 6.64-6.53 (m, 1H), 5.87 (s, 1H), 4.99 (s, 1H), 1.78 (s, 3H),
1.48-1.44 (m, 6H).
Alternative Preparation of
3-Fluoro-4-(R)-(3-(5-fluoro-1,3-dioxo-1H-pyrido[1,2-c]pyrimidin-2(3H)-yl)-
-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
(Single Atropisomer) [Example 41]
[0719] A mixture of
4-bromo-3-fluoro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
[Intermediate 27] (6.00 g, 16.4 mmol),
5-fluoro-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pheny-
l)-1H-pyrido[1,2-c]pyrimidine-1,3(2H)-dione (single enantiomer)
[Intermediate 38] (7.81 g, 19.7 mmol), 2 M aqueous K.sub.3PO.sub.4
(24.6 mL, 49.3 mmol), and THF (70 mL) was subjected to three
evacuate-fill cycles with nitrogen. The mixture was treated with
1,1'-bis(di-tert-butylphosphino)ferrocene palladium(II) chloride
(0.535 g, 0.821 mmol), and subjected to two more evacuate-fill
cycles with nitrogen. The mixture was stirred at room temperature
overnight. The mixture was diluted with EtOAc, washed sequentially
with water and brine, and dried. The aqueous layer was filtered and
the collected solid was added to the organic layer. The organic
layer was concentrated, and the residue was purified by column
chromatography on silica gel, eluting with EtOAc-hexanes
(sequentially 50%, 62%, 75%, 85% and 100%), to provide
3-fluoro-4-(3-(5-fluoro-1,3-dioxo-1H-pyrido[1,2-c]pyrimidin-2(3H)-yl)-2-m-
ethylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
(mixture of two atropisomers) as a yellow solid (8.55 g, 94%
yield). A sample of this material (combined with other batches of
the same material) was separated by chiral super-critical fluid
chromatography as follows: column: CHIRALPAK.RTM. IC (3.times.25
cm, 5 .mu.m); Mobile Phase: CO.sub.2-MeOH (50:50) at 165 mL/min,
45.degree. C., 100 bar; sample preparation: 55 mg/mL in
MeOH-THF-DMSO (2:1:1); injection: 3 mL. The first peak eluting from
the column provided a single atropisomer of
3-fluoro-4-(R)-(3-(5-fluoro-1,3-dioxo-1H-pyrido[1,2-c]pyrimidin-2(3H)-yl)-
-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
[Example 41].
Example 42
3-Chloro-4-(2-chloro-3-(1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-
phenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
(mixture of four atropisomers)
##STR00217##
[0721] A mixture of
4-bromo-3-chloro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
[Intermediate 3] (36 mg, 0.094 mmol),
(Z)-4-((2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)im-
ino)-1-methyl-1H-benzo[d][1,3]oxazin-2(4H)-one [Intermediate 40]
(42.8 mg, 0.104 mmol), EtOH (1 mL), toluene (1 mL) and 2 M aqueous
Na.sub.2CO.sub.3 (0.16 mL, 0.311 mmol) was bubbled with nitrogen
for 5 min. The mixture was treated with
tetrakis(triphenylphosphine)palladium (8.7 mg, 7.55 .mu.mol), and
the reaction vessel was sealed and heated at 90.degree. C. for 16
h. The cooled mixture was partitioned between EtOAc and water, and
the organic phase was dried and concentrated. The residue was
purified by column chromatography on silica gel (4 g), eluting with
MeOH-DCM containing 1% TEA (gradient from 0-5%). The resulting
material was further purified using preparative HPLC
(PHENOMENEX.RTM. Axia Cis 30.times.100 mm), eluting with MeCN-water
containing 0.1% TFA (gradient from 20-100%, 30 mL/min). The
appropriate fractions were treated with saturated aqueous
NaHCO.sub.3 and concentrated. The residue was partitioned between
EtOAc and water, and the organic phase was washed with brine, dried
and concentrated to give
3-chloro-4-(2-chloro-3-(1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl-
)phenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
(mixture of four atropisomers) as a white solid (2.5 mg, 4% yield).
Mass spectrum m/z 569 (M+H--H.sub.2O).sup.+. .sup.1H NMR (400 MHz,
chloroform-d) .delta. 8.38-8.23 (m, 1H), 7.73 (d, J=1.5 Hz, 2H),
7.70-7.66 (m, 1H), 7.64 (s, 1H), 7.60-7.55 (m, 1H), 7.51-7.45 (m,
1H), 7.37-7.28 (m, 2H), 7.26-7.20 (m, 1H), 7.10-6.78 (m, 1H), 3.70
(s, 2H), 3.67 (s, 1H), 1.65 (s, 4H), 1.64 (s, 2H).
Example 43
3-Chloro-4-(R)-(2-chloro-3-(1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3
(4H)-yl)
phenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide (single
atropisomer)
##STR00218##
[0723] A sample of
3-chloro-4-(2-chloro-3-(1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl-
)phenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
(mixture of four atropisomers) [Example 42] (110 mg) was separated
by chiral super-critical fluid chromatography as follows: column:
Lux Cel-4 (3.times.25 cm, 5 .mu.m); Mobile Phase: CO.sub.2-MeOH
(60:40) at 85 mL/min; sample preparation: 6.7 mg/mL in MeOH-acetone
(9:1); injection: 3.0 mL. The fourth peak eluting from the column
provided a single atropisomer of
3-chloro-4-(R)-(2-chloro-3-(1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H-
)-yl)phenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide as
a yellow solid (20 mg, 18% yield). Mass spectrum m/z 569
(M+H--H.sub.2O).sup.+. .sup.1H NMR (400 MHz, chloroform-d) .delta.
10.44 (s, 1H), 8.41-8.17 (m, 1H), 7.78-7.72 (m, 2H), 7.68 (s, 1H),
7.65-7.60 (m, 1H), 7.59-7.54 (m, 1H), 7.46 (d, J=7.5 Hz, 1H),
7.34-7.28 (m, 2H), 7.25 (s, 1H), 7.01 (d, J=8.6 Hz, 1H), 3.70 (s,
3H), 1.64 (s, 6H).
Example 44
3-Chloro-4-(2-chloro-3-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin--
3(4H)-yl)
phenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
(mixture of four atropisomers)
##STR00219##
[0725] A mixture of
4-bromo-3-chloro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
[Intermediate 3] (30 mg, 0.079 mmol),
3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-8-fluo-
ro-1-methylquinazoline-2,4(1H,3H)-dione [Intermediate 41] (40.6 mg,
0.094 mmol), EtOH (1 mL), toluene (1 mL) and 2 M aqueous
Na.sub.2CO.sub.3 (0.13 mL, 0.26 mmol) was bubbled with nitrogen for
5 min. The mixture was treated with
tetrakis(triphenylphosphine)palladium (7.3 mg, 6.29 .mu.mol), and
the reaction vessel was sealed and heated at 90.degree. C. for 16
h. The cooled mixture was partitioned between EtOAc and water, and
the organic phase was dried and concentrated. The residue was
purified by column chromatography on silica gel (12 g), eluting
with MeOH-DCM containing 1% TEA (gradient from 0-5%). The resulting
material was further purified using preparative HPLC
(PHENOMENEX.RTM. Axia Cis 30.times.100 mm), eluting with MeCN-water
containing 0.1% TFA (gradient from 20-100%, 10 min, 30 mL/min). The
appropriate fractions were treated with saturated aqueous
NaHCO.sub.3 and concentrated. The residue was partitioned between
EtOAc and water, and the organic phase was washed with brine, dried
and concentrated to provide
3-chloro-4-(2-chloro-3-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-
-3(4H)-yl)phenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
(mixture of four atropisomers) as a white solid (6 mg, 11% yield).
Mass spectrum m/z 587 (M+H--H.sub.2O).sup.+. .sup.1H NMR (400 MHz,
chloroform-d) .quadrature..delta. 10.46 (s, 1H), 7.74 (s, 1H), 7.68
(s, 1H), 7.66-7.61 (m, 1H), 7.59-7.54 (m, 1H), 7.51-7.46 (m, 2H),
7.27-7.17 (m, 2H), 7.06-6.88 (m, 1H), 3.88 (dd, J=11.6, 8.0 Hz,
3H), 1.64 (s, 6H). .sup.19F NMR (400 MHz, chloroform-d) .delta.
-121.34.
Example 45
3-Chloro-4-(R)-(2-chloro-3-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazo-
lin-3(4H)-yl)phenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
(single atropisomer)
##STR00220##
[0727] A sample of
3-chloro-4-(2-chloro-3-(1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl-
)phenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
(mixture of four atropisomers) [Example 44] (100 mg) was separated
by chiral super-critical fluid chromatography as follows: column:
Lux Cel-4 (3.times.25 cm, 5 .mu.m); Mobile Phase: CO.sub.2-MeOH
(60:40) at 85 mL/min, 50.degree. C., 100 bar; sample preparation:
6.7 mg/mL in MeOH-acetone (1:1); injection: 3.0 mL. The fourth peak
eluting from the column provided a single atropisomer of
3-chloro-4-(R)-(2-chloro-3-(1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H-
)-yl)phenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide as
a yellow solid (9.3 mg). Mass spectrum m/z 569
(M+H--H.sub.2O).sup.+. .sup.1H NMR (400 MHz, chloroform-d) .delta.
10.45 (s, 1H), 8.11 (d, J=7.3 Hz, 1H), 7.73 (s, 1H), 7.72 (d, J=9.0
Hz, 1H), 7.68 (d, J=1.1 Hz, 1H), 7.67-7.61 (m, 1H), 7.56 (dd,
J=7.9, 1.8 Hz, 1H), 7.54-7.52 (m, 1H), 7.51-7.42 (m, 2H), 7.26-7.19
(m, 2H), 7.00 (d, J=8.6 Hz, 1H), 3.90 (d, J=8.1 Hz, 3H), 1.64 (s,
6H). .sup.19F NMR (376 MHz, chloroform-d) .delta. -121.33.
Example 46
4-(2-Chloro-3-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-
phenyl)-3-fluoro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
(mixture of four atropisomers)
##STR00221##
[0729] A mixture of
4-bromo-3-fluoro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
[Intermediate 27] (40 mg, 0.110 mmol),
3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-8-fluo-
ro-1-methylquinazoline-2,4(1H,3H)-dione [Intermediate 41] (47 mg,
0.110 mmol), Cs.sub.2CO.sub.3 (107 mg, 0.329 mmol), dioxane (8 mL)
and water (2 mL) was bubbled with nitrogen for 10 min. The mixture
was treated with PdCl.sub.2(dppf) DCM adduct (7.2 mg, 8.76
.mu.mol), and heated at 60.degree. C. overnight. The cooled mixture
was partitioned between EtOAc and water. The organic phase was
dried and concentrated. The residue was purified by column
chromatography on silica gel, eluting with MeOH-DCM (gradient from
0-5%), to give
4-(2-chloro-3-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl-
)phenyl)-3-fluoro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
(mixture of four atropisomers) as a white solid (20 mg, 31% yield).
Mass spectrum m/z 569 (M+H--H.sub.2O).sup.+. .sup.1H NMR (400 MHz,
chloroform-d) .delta. 10.46 (s, 1H), 7.74 (s, 1H), 7.68 (s, 1H),
7.66-7.61 (m, 1H), 7.59-7.54 (m, 1H), 7.51-7.46 (m, 2H), 7.27-7.17
(m, 2H), 7.06-6.88 (m, 1H), 3.88 (dd, J=11.6, 8.0 Hz, 3H), 1.64 (s,
6H). .sup.19F NMR (400 MHz, chloroform-d) .delta. -121.34,
-127.34.
Example 47
3-Chloro-4-(R)-(2-chloro-3-(8-fluoro-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-
-yl)phenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
(single atropisomer)
##STR00222##
[0731] A mixture of
4-bromo-3-chloro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
[Intermediate 3] (103 mg, 0.269 mmol),
3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-8-fluo-
roquinazoline-2,4(1H,3H)-dione [Intermediate 42](140 mg, 0.336
mmol), THF (5 mL), 2 M aqueous K.sub.3PO.sub.4 (0.504 mL, 1.01
mmol) was bubbled with nitrogen for 15 min. The mixture was treated
with 1,1'-bis(di-tert-butylphosphino)ferrocene palladium(II)
chloride (17.5 mg, 0.027 mmol) and was stirred at room temperature
overnight. The mixture was concentrated, and the residue was
partitioned between EtOAc and water. The organic phase was dried
and concentrated. The residue was purified by preparative HPLC. The
appropriate fractions were treated with saturated aqueous
NaHCO.sub.3 and concentrated. The aqueous residue was extracted
with EtOAc. The organic phase was washed sequentially with water
and brine, and dried and concentrated to give
3-chloro-4-(2-chloro-3-(8-fluoro-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl-
)phenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
(mixture of four atropisomers) (30 mg, 15% yield). This material
was separated by chiral super-critical fluid chromatography as
follows: column: CHIRALCEL.RTM. OJ-H (3.times.25 cm, 5 .mu.m);
Mobile Phase: CO.sub.2-MeOH-MeCN (65:17.5:17.5) at 85 mL/min;
sample preparation: 6.8 mg/mL in MeOH--CHCl.sub.3 (1:1); injection:
3.0 mL. The first peak eluting from the column provided a single
atropisomer of
3-chloro-4-(R)-(2-chloro-3-(8-fluoro-2,4-dioxo-1,2-dihydroquinazolin-3(4H-
)-yl)phenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide.
Mass spectrum m/z 573 (M+H--H.sub.2O).sup.+. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 11.63-11.48 (m, 1H), 8.39-8.25 (m, 1H),
8.17-8.12 (m, 1H), 7.99-7.92 (m, 1H), 7.88-7.85 (m, 1H), 7.85-7.81
(m, 1H), 7.81-7.76 (m, 1H), 7.76-7.70 (m, 1H), 7.70-7.62 (m, 2H),
7.57-7.46 (m, 1H), 7.32-7.20 (m, 1H), 7.13-6.99 (m, 1H), 6.77-6.63
(m, 1H), 5.10-4.98 (m, 1H), 1.47-1.45 (m, 6H). .sup.19F NMR (400
MHz, chloroform-d) 8-129.63.
[0732] The compounds in Table 10 were prepared by procedures
analogous to those described above, using Intermediates described
or prepared by methods similar to those described.
TABLE-US-00010 TABLE 10 Formula Mass Ex. Structure Description
weight spectrum 48 ##STR00223## Single atropisomer Peak 4 589.00
571 (M + H - H.sub.2O).sup.+ 49 ##STR00224## Mixture of four
atropisomers 572.54 555 (M + H - H.sub.2O).sup.+ 50 ##STR00225##
Single atropisomer Peak 2 572.54 555 (M + H - H.sub.2O).sup.+ 51
##STR00226## Single atropisomer Peak 3 554.55 537 (M + H -
H.sub.2O).sup.+ 52 ##STR00227## Single atropisomer Peak 2 571.60
554 (M + H - H.sub.2O).sup.+ 53 ##STR00228## Single atropisomer
Peak 3 571.01 553 (M + H - H.sub.2O).sup.+ 54 ##STR00229## Single
atropisomer Peak 4 571.01 553 (M + H - H.sub.2O).sup.+ 55
##STR00230## Single atropisomer Peak 2 575.04 575 (M + H) 56
##STR00231## Single atropisomer Peak 4 575.04 575 (M + H).sup.+ 57
##STR00232## Single atropisomer Peak 1 593.03 593 (M + H).sup.+ 58
##STR00233## Single atropisomer Peak 2 592.08 592 (M + H).sup.+ 59
##STR00234## Single atropisomer Peak 2 558.58 559 (M + H).sup.+ 60
##STR00235## Single atropisomer Peak 4 589.00 569 (M + H -
H.sub.2O).sup.+ 61 ##STR00236## Single atropisomer Peak 2 589.00
569 (M + H - H.sub.2O).sup.+ 62 ##STR00237## Single atropisomer
Peak 2 575.63 576 (M + H).sup.+ 63 ##STR00238## Single atropisomer
Peak 3 575.04 575 (M + H).sup.+ 64 ##STR00239## Single atropisomer
Peak 2 575.04 575 (M + H).sup.+ 65 ##STR00240## Single atropisomer
Peak 4 575.04 575 (M + H).sup.+ 66 ##STR00241## Single atropisomer
Peak 1 550.59 533 (M + H - H.sub.2O).sup.+ 67 ##STR00242## Single
atropisomer Peak 1 558.58 559 (M + H).sup.+ 68 ##STR00243## Single
atropisomer Peak 2 558.58 559 (M + H).sup.+ 69 ##STR00244## Single
atropisomer Peak 1 558.58 559 (M + H).sup.+ 70 ##STR00245## Mixture
of four atropisomers 540.52 541 (M + H).sup.+ 71 ##STR00246##
Single atropisomer Peak 2 567.04 549 (M + H - H.sub.2O).sup.+ 72
##STR00247## Single atropisomer Peak 2 578.03 560 (M + H -
H.sub.2O).sup.+ 73 ##STR00248## Single atropisomer Peak 1 572.54
555 (M + H - H.sub.2O).sup.+ 74 ##STR00249## Single atropisomer
Peak 2 568.58 551 (M + H - H.sub.2O).sup.+
Comparative Example 75
7-(2-Hydroxypropan-2-yl)-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-9-
H-carbazole-1-carboxamide
##STR00250##
[0734] Comparative Example 75 was disclosed in U.S. Pat. No.
8,084,620 as Example 76-15 and was prepared according to the
procedure described therein.
Comparative Example 76
7-(2-Hydroxypropan-2-yl)-3-methyl-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)-
phenyl)-9H-pyrido[3,4-b]indole-1-carboxamide
##STR00251##
[0736] Comparative Example 76 was disclosed in WO 2011/159857 as
Example 38 and was prepared according to the procedure described
therein.
Biological Assays
[0737] The pharmacological properties of the compounds of this
invention may be confirmed by a number of biological assays. The
exemplified biological assays, which follow, have been carried out
with compounds of the invention.
Human Recombinant Btk Enzyme Assay
[0738] To V-bottom 384-well plates were added test compounds, human
recombinant Btk (1 nM, Invitrogen Corporation), fluoresceinated
peptide (1.5 .mu.M), ATP (20 .mu.M), and assay buffer (20 mM HEPES
pH 7.4, 10 mM MgCl.sub.2, 0.015% Brij 35 surfactant and 4 mM DTT in
1.6% DMSO), with a final volume of 30 .mu.L. After incubating at
room temperature for 60 min, the reaction was terminated by adding
45 .mu.L of 35 mM EDTA to each sample. The reaction mixture was
analyzed on the Caliper LABCHIP 3000 (Caliper, Hopkinton, Mass.) by
electrophoretic separation of the fluorescent substrate and
phosphorylated product. Inhibition data were calculated by
comparison to no enzyme control reactions for 100% inhibition and
no inhibitor controls for 0% inhibition. Dose response curves were
generated to determine the concentration required for inhibiting
50% of kinase activity (IC.sub.50). Compounds were dissolved at 10
mM in DMSO and evaluated at eleven concentrations.
Ramos FLIPR Assay
[0739] Ramos RA1 B cells (ATCC CRL-1596) at a density of
2.times.10.sup.6 cells/mL in RPMI minus phenol red (Invitrogen
11835-030) and 50 mM HEPES (Invitrogen 15630-130) containing 0.1%
BSA (Sigma A8577) were added to one half volume of calcium loading
buffer (BD bulk kit for probenecid sensitive assays, #640177) and
incubated at room temperature in the dark for 1 hour. Dye-loaded
cells were pelleted (Beckmann GS-CKR, 1200 rpm, room temperature, 5
min) and resuspended at room temperature in RPMI minus phenol red
with 50 mM HEPES and 10% FBS to a density of 1.times.10.sup.6
cells/mL. 150 L aliquots (150,000 cells/well) were plated into 96
well poly-D-lysine coated assay plates (BD 35 4640) and briefly
centrifuged (Beckmann GS-CKR 800 rpm, 5 min, without brake). Next,
50 .mu.L compound dilutions in 0.4% DMSO/RPMI minus phenol red+50
mM HEPES+10% FBS were added to the wells and the plate was
incubated at room temperature in the dark for 1 hour. The assay
plate was briefly centrifuged as above prior to measuring calcium
levels.
[0740] Using the FLIPR1 (Molecular Devices), cells were stimulated
by adding goat anti-human IgM (Invitrogen AHI0601) to 2.5 .mu.g/mL.
Changes in intracellular calcium concentrations were measured for
180 seconds and percent inhibition was determined relative to peak
calcium levels seen in the presence of stimulation only.
Jak2 Tyrosine Kinase Assay
[0741] Compounds with activity against Jak2 tyrosine kinase have
been observed to cause thrombocytopenia, anemia and neutropenia in
human patients in clinical trials (see, for example, Pardanani, A.,
Leukemia, 26:1449-1451 (2012)). Jak2 signaling occurs thru EPO and
TPO, which control erythrocyte and platelet proliferation,
respectively. Thus, inhibition of Jak2 tyrosine kinase can
potentially lead to side-effects in the clinic. Btk inhibitors with
improved selectivity over Jak2 tyrosine kinase are desired in order
to minimize off target side-effects related to the inhibition of
Jak2 tyrosine kinase.
[0742] The assays were performed in V-bottom 384-well plates. The
final assay volume was 30 .mu.l prepared from 15 .mu.l additions of
enzyme and substrates (fluoresceinated peptide and ATP) and test
compounds in assay buffer (100 mM HEPES pH 7.4, 10 mM MgCl.sub.2,
25 mM beta-glycerolphosphate, 0.015% Brij 35 surfactant and 4 mM
DTT). The reaction was initiated by the combination of Jak2
tyrosine kinase with substrates and test compounds. The reaction
mixture was incubated at room temperature for 60 minutes and
terminated by adding 45 .mu.L of 35 mM EDTA to each sample. The
reaction mixture was analyzed on the Caliper LABCHIP.RTM. 3000 by
electrophoretic separation of the fluorescent substrate and
phosphorylated product. Inhibition data were calculated by
comparison to no enzyme control reactions for 100% inhibition and
vehicle-only reactions for 0% inhibition. The final concentration
of reagents in the assays is ATP, 30 .mu.M; Jak2 fluorescent
peptide, 1.5 .mu.M; Jak2, 1 nM; and DMSO, 1.6%. Dose response
curves were generated to determine the concentration required
inhibiting 50% of kinase activity (IC.sub.50). Compounds were
dissolved at 10 mM in DMSO and evaluated at eleven concentrations,
each in duplicate. IC.sub.50 values were derived by non-linear
regression analysis.
Whole Blood Assay of BCR-Stimulated CD69 Expression on B Cells
[0743] The efficacy of Btk inhibitor compounds in suppressing CD69
expression on B cells human in whole blood assays is useful for
predicting efficacious doses in the clinic and minimizing potential
side-effects. Btk inhibitor compounds having higher activity in the
whole blood CD.sub.69 expression assay are expected to require
lower doses than compounds having lower activity, and are expected
to cause fewer unwanted side-effects. (Uetrecht, Chem. Res.
Toxicol., 12:387-395 (1999); Nakayama, Drug Metabolism and
Disposition, 37(9):1970-1977 (2009); Sakatis, Chem. Res. Toxicol.
(2012)).
[0744] To measure BCR-stimulated B cells, ACD-A human whole blood
was treated with various concentrations of test compound and
stimulated with 30 .mu.g/mL AffiniPure F(ab')2 fragment goat anti
human IgM (Jackson 109-006-1299--endotoxin cleared) and 10 ng/mL
human IL-4 (PeproTech 200-04) for 18 h at 37.degree. C. with
agitation. The cells were blocked with human gamma globulin
(Jackson 009-000-002) and stained with FITC-conjugated mouse
anti-human CD20 (BD Pharmingen 555622) and PE-conjugated mouse
anti-human CD69 monoclonal antibody (BD Pharmingen 555531), lysed
and fixed, then washed. The amount of CD69 expression was
quantitated by the median fluorescence intensity (MFI) after gating
on the CD20-positive B cell population as measured by FACS
analysis.
[0745] In the whole blood assay of BCR-Stimulated CD69 expressio