Sommaire du brevet 3180977 - Base de données sur les brevets canadiens (2024)

=
INHERITORS OF BR(JTON'S TYROSINE IONASE
10001]
FIELD OF THE INVENTION
10802) Described herein are compounds, methods of making such compounds,
pharmaceutical compositions
and medicaments containing such compounds, and methods of using such compounds
and compositions to inhibit
the activity of tyrosine kin' ases.
BACKGROUND OF THE INVENTION
10003] Burton's tyrosine bane (Btk), a member of the Tec family of nun-
receptor tyrosine Idnases, is a key
signaling enzyme expressed in all hematc=poietic culls types except T
lymphocytes and natural killer cells. Btk plays
an essential role in the B-cell signaling pathway linking cell surface B-cell
receptor (BCR) stimulation to
downstream intracellular responses.
100041 -13dr is a key regulator of B-cell development, activation, signaling,
and survival (Kurosalti, Our Op bun,
2000, 276-281; Schaeffer and Schwartzberg, Curr Op Brun 2000,282-288). In
addition, Btk plays a role in a number
of other hematopoetic cell signaling pathways, e.g., Toll like receptor (TLR)
and crokine receptor¨mediated TNF-ct
production in macrophages. IgB receptor (FeepeilonR1) signaling in Mast cells,
inhibition of Fas/AP0-1 apoptotie
signaling in B-lineage lymphoid cells, and collagen-stiinulated platelet
aggregation. See, e.g., C. A. Jeffties, et al.,
(2003), Journal of Biological Chentitny 278:26258-26264; N. J. Horwood, at al,
(2003), The Journal of
Experimental Medicine 197:1603-1611; Ivraki at al. (2005),Jountal of
Biological Chemistry 280(48):40261-40270;
Vassilev at al. (1999), Journal of Biological Chemistry 274(3):1646-1656, and
Qua. et al. (1998), Current Biology
8(20):1137-1140.
SUMMARY OF THE INVENTION
100051 Described herein are inhibitors of Bruton's tyrosine lcinase
(Btk). Also described herein are irreversible
inhibitors of Stk. Further described are irreversible inhibitors of Bdr that
forms covalent bond with a cysteine
residue on Btlt. Further described herein are hroversible inhibitors of other
tyrosine kinasesõ wherein the other
tyrosine kinases share hom*ology with ark by having a eysteroe residue
(including a Cys 481 residue) that can form a
covalent bond with the irreversible inhibitor (such tyrosine kinetics, are
referred herein as "Btk tyrosine lcinase
eysteine hom*ologs"). Also described herein are methods for synthesizing such
irreversible ininlitors, methods for
using such irreversible inhibitors in the treatment of diseases (including
diseases wherein irreversible inhibition of
131k provides therapeutic benefit to a patient baying the disease). Further
described are pharmaceutical formulations
that include an irreversible inhibitor of Mk_
100061 Compounds described herein include those that have a structure of
any of Formula (A), Formula (3),
Formula (C), or Formula PI and pharmaceutically acceptable salts, solvates,
esters, acids and prodrugs thereof In
certain embodiments, isomers and chemically Protected forms of compounds
having a structure represented by any
of Formula (A), Formula (13), Formula (C), or Formula (D), are also provided.
100071 In one aspect, provided herein is a compound of Formula (D).
Formula (D) is as follows:
1
Date Recue/Date Received 2022-11-04

NHa
= N =
N N
Re
R8 R7 Formula (D)
wherein:
La is CH2, 0, NH or S;
Ax is a substituted or =substituted aryl, or a substituted or =substituted
heteroaryl;
Y is an optionally substituted group selected from among alkyl, beteroalkyl,
cycloancyl, heterocycloalkyl,
aryl, and heteroaryl;
Z is C(-O), OC(=0), NHC(=0), C(=S), S(=0)s, 0S(=0)õ, NHS(=0)õ where x is 1 or
2;
R7 and Rs are independently selected from among H, unsubstituted CI-Csalkyl,
substituted C1-Csalkyl,
unsubstituted Ci-Cshetemallcyl, substituted CI-C4heteroalkyl, =substituted Cs-
Cscycloalkyl,
substituted C3-C6cycloalkyl, =substituted Cs-Csheterocycloalkyl, and
substituted Cr
Csheterocycloalkyl; or
R7 and Rs taken together form a bond;
R8 is H, substituted or unsubstituted C1-Csalkyl, substituted or unsubstituted
C1-Csheteroalkyl, C1-
Csallcoxyallcyl, C1-05allcylaminoalky1, substituted or =substituted Cs-
Cscycloalkyl, substituted or
unsubstituted aryl, substituted or unsubstituted C2-Csbeterocycloalkyl,
substituted or unsubstituted
heteroaryl, C1-asalky1(ary1), CI-C.sa1kyl(heteroary1), C1-C4alky1(C3-
C.scycloalkyl), or CI-C4alkyl(C2-
05heterocycloalkyl); and
pharmaceutically active metabolites, or pharmaceutically acceptable solvates,
pharmaceutically acceptable salts, or
= pharmaceutically acceptable prodrugs thereof.
100081 For any and all of the embodiments, substituents can be selected
float among from a subset of the
listed alternatives. For example, in some embodiments, L is C112, 0, or NH. In
other embodiments, Ls is 0 or NH.
In yet other embodiments, 1, is O.
100091 In some embodiments, Ar is a substituted or unsubstituted aryl. In
yet other embodiments, Ar is a 6-
membered aryl. In some other embodiments, Ar is phenyl.
100101 In some embodiments, xis 2. In yet other embodiments, Z is C(-0),
OC(=0), NHC(-0), S(-0)õ,
or NHS(=0)õ. In some other embodiments, Z is C(=0). NHC(20), or S(-0)2.
100111 In some embodiments, R7 and Re are independently selected from
among H, unsubstituted CI-C4 alkyl,
substituted C1 unsubstituted C1-C4heteroalkyl, and substituted CI-
C4heteroalkyl; or R7 and R8 taken
together form a bond. In yet other embodiments, each of R7 and R8 is H; or R7
and R8 taken together fonn a bond.
100121 In some embodiments, R6 is H, substituted or =substituted Ci-
C4allcyl, substituted or =substituted C1-
C1heteroalkyl, C1-C6alkoxyallcyl, C1-C3alkylaminoalkyl, substituted or
=substituted aryl, substituted or
=substituted heteroaryl, CI-Csa1lrygary1), C1-e4elkyl(heteroary1), C1-
C4alkYkC5-05cYoloolicY1), or CI-C4allcy1(C2-
C8heterocYcloallcyl). In some other embodiments, R6 is H, substituted or
=substituted C1-C4alkyl, substituted or
2
Date Recue/Date Received 2022-11-04

unsubstituted C1-C4heteroallcyl, C1-C6alkoxyalkyl, C1-C2allcyl-N(CI-C3alky1)2,
C1-C4allcyl(ary1),
C4a1kyl(heteroary1), CI-C4ancyl(C3-C2cycloalkyl), or CI-C4alkyl(C2-
Clbeterocycloalkyl). In yet other embodiments,
R6 is H, substituted or unsubstituted C1-C4alkyl, -CH2-
N(C1-C3alicyl)2, CI-Collcyl(phenyl), or
C1-C4allcyl(5- or 6-membered heteroaryl). In yet other embodiments, 114 is H,
substituted or unsubstituted C1-
Colkyl, -CH2-0-(CrC3alicyl), -CH2-(C1-C6alkylamino), CI-Colkyl(phenyl), or CI-
C4alky1(5- or 6-membered
beteroary1). In some embodiments, Rs is H, substituted or unsubstituted C1-
C4alkyl, -CH2-0-(C1-C3alky1), -CH2-
N(C2-C3allcy1)2, CI-C4alkyl(phenyl), or C1-C4alkyl(5- or 6-membered heteroaryl
containing 1 or 2 N atoms), or C1-
C4allcy1(5- or 6-membered heterocycloalkyl containing 1 or 2 N atoms).
100131 In some embodiments, Y is an optionally substituted group selected
from among alkyl, heteroalkyl,
cycloalkyl, and heterocycloalkyl. In other embodiments, Y is an optionally
substituted group selected from among
C1-C6alkyl, CI-C6heteroalky), 4-, 5-, 6-, or 7-membered cycloalkyl, and 4-, 5-
, 6-, or 7-membered heterocycloalkyl.
In yet other embodiments, Y is an optionally substituted group selected from
among Ci-C6alkyl, C,-C6heteroalkyl,
5-or 6-membered cycloalkyl, and 5- or 6-membered heterocycloalkyl containing 1
or 2 N atoms. In some other
embodiments, Y is a 5-or 6-membered cycloalkyl, or a 5-or 6-membered
heterocycloalkyl containing 1 or 2 N
atoms. In some embodiments, Y is a 4-, 5-, 6-, or 7-memebered cycloalkyl ring;
or Y is a 4-, 5-, 6-, or 7-membered
heterocycloalkyl ring.
100141 Any combination of the groups described above for the various
variables is contemplated herein. It is
understood that substituents and substitution patterns on the compounds
provided herein can be selected by one of
ordinary skill in the art to provide compounds that are chemically stable and
that can be synthesized by techniques
known in the art, as well as those set forth herein.
100151 In one aspect, provided herein is a compound selected from among:
1-(3-(4-amino-3-(4-phenoxypheny1)-1H-pyrazolo[3,4-cl]pyrimidin- 1 -
yl)piperidin-l-yl)prop-2-en-l-one (Compound
4); (E)- -(3-(4-amino-3-(4-phenoxypheny1)-1H-pyrazolo[3,4-cl]pyrimidin-l-
y1)piperidin- 1-yl)but-2-en-l-one
(Compound 5); 1-(3-(4-amino-3-(4-phenoxypheny1)-1H-pyrazolo [3,4-d]pyrimidin-1-
yl)piperidin-1-
yl)sulfonylethene (Compound 6); 1-(3-(4-amino-3-(4-phenoxypheny1)-1H-
pyrazolo[3,4-d)pyrirnidin-1-yppiperidin-
1-y1)prop-2-yn-l-one (Compound 8); 1-(4-(4-amino-3-(4-phenoxypheny1)-1H-
pyrazolo[3,4-d]pyrintidin-l-
y1)piperidin-l-y1)prop-2-en-l-one (Compound 9); N-((l6,4s)-4-(4-amino-3-(4-
phenoxypheny1)-1H-pyrazolo[3,4-
d]pyrirnidin-l-yl)cyclohexyl)acrylamide (Compound 10); 14(R)-3-(4-amino-3-(4-
phenoxypheny1)-1H-
pyrazolo[3,4-dlpyrimidin-1-y1)pyrrolidin-1-y1)prop-2-en-1-one (Compound 11);
14(S)-3-(4-amino-3-(4-
phenoxypheny1)-1H-pyrazolo[3,4-djpyrimidin-1-y1)pyrrolidin-l-ypprop-2-en-1-one
(Compound 12); 14(R)-3-(4-
amino-3-(4-phenoxypheny1)-1H-pyrazolo[3,4-d]pyrimidin-l-y1)piperidin-l-y1)prop-
2-en-1-one (Compound 13); 1-
((S)-3-(4-amino-3-(4-phenoxypheny1)-1H-pyrazolo[3,4-d]pyrimidin-l-y1)piperidin-
1-y1)prop-2-en-1-one
(Compound 14); and (E)-1-(3-(4-amino-3-(4-phenoxypheny1)-1H-pyrazolo[3,4-
d]pyrimidin-1-y1)piperidin- 1-y1)-4-
(dimethylamino)but-2-en-l-one (Compound 15).
100161 In a thither aspect are provided pharmaceutical compositions, which
include a therapeutically effective
amount of at least one of any of the compounds herein, or a pharmaceutically
acceptable salt, pharmaceutically
active metabolite, pharmaceutically acceptable prodrug, or pharmaceutically
acceptable solvate. In certain
embodiments, compositions provided herein further include a pharmaceutically
acceptable diluent, excipient and/or
binder.
100171 Pharmaceutical compositions formulated for administration by an
appropriate route and means
containing effective concentrations of one or more of the compounds provided
herein, or pharmaceutically effective
derivatives thereof; that deliver amounts effective for the treatment,
prevention, or amelioration of one or more
3
Date Recue/Date Received 2022-11-04

symptoms of dieases, disorders or conditions that are modulated or otherwise
affected by tyrosine kinase activity, or
in which tyrosine kinase activity is implicated, are provided. The effective
amounts and concentrations are effective
for ameliorating any of the symptoms of any of the diseases, disorders or
conditions disclosed herein.
100181 In certain embodiments, provided herein is a pharmaceutical
composition containing: i) a
physiologically acceptable carrier, diluent, and/or excipien and is) one or
more compounds provided herein.
100191 In one aspect, provided herein are methods for treating a patient
by administering a compound
provided herein. In some embodiments, provided herein is a method of
inhibiting the activity of tyreoine kinase(s),
such as Btk, or of treating a disease, disorder, or condition, which would
benefit from inhibition of tyrosine
kiliase(s), such as Mk, in a patient, which includes administering to the
patient a therapeutically effective amount of
at least one of any of the compounds herein, or pharmaceutically acceptable
salt, pharmaceutically active metabolite,
pharmaceutically acceptable prodrug, or pharnuiceutically acceptable solvate.
100201 In another aspect, provided herein is the use of a compound
disclosed herein for inhibiting Bruton's
tyrosine kinase (Mk) activity or for the treatment of a disease, disorder, or
condition, which would benefit from
inhibition of Bruton's tyrosine kinase (Bdc) activity.
100211 In some embodiments, compounds provided herein are administered to a
human.
100221 In sonic embodiments, compounds provided herein are orally
administered.
100231 In other embodiments, compounds provided herein are used for the
formulation of a medicament for
the inhibition of tyrosine kinase activity. In some other embodilueub,
compounds provided herein are used for the
formulation of a medicament for the inhibition of Bruton's tyrosine kinase
(Btk) activity.
100241 Articles of manufacture including packaging material, a compound or
composition or pharmaceutically
acceptable derivative thereof provided herein, which is effective for
inhibiting the activity of tyrosine kinase(s), such
as Btic, within the packaging material, and a label that indicates that the
compound or composition, or
pharmaceutically acceptable salt, pharmaceutically active metabolite,
pharmaceutically acceptable prodrug, or
pharmaceutically acceptable solvate thereof, is used for inhibiting the
activity of tyrosine Icinase(s), such as Btk, are
provided.
100251 In another aspect are inhibited tyrosine ldnases comprising a
Bruton's tyrosine Irinacp, a Bruton's
tyrosine kinase hom*olog, or a Btk tyrosine kinase cysteine hom*olog thereof
covalently bound to an inhibitor
having the structure:
ts¨Ar
NH2
=
R,
R8 sid4sr , wherein aVVIP indicates the point of attachment
between the inhibitor and the
tyrosine kinase. In a further embodiment, the inibitor is covalently bound to
a cysteine residue on the tyrosine
kin' ase.
. [00261 In a fitrther aspect, provided herein is a method for inhibiting
Bruton's tyrosine kinase in a subject in need
thereof by administering to the subject thereof a composition containing a
therapeutically effective amount of at
least one compound having the structure of any of Formula (A), Formula (13),
Formula (C), or Formula (D). In some
4
Date Recue/Date Received 2022-11-04

embodiments, the subject in need is suffering from an autoimmune disease,
e.g., inflammatory bowel disease,
arthritis, lupus, rheumatoid arthritis, psoriatic arthritis, osteoarthritis,
Still's disease, juvenile arthritis, diabetes,
znyasthenia gravis, Hashimoto's thyroiditis, Ord's thyroiditis, Graves'
disease Sjogren's syndrome, multiple sclerosis,
Gin-Baird syndrome, acute disseminated encephalomyelitis, Addison's disease,
opsoclonns-myoclomis
syndrome, ankylosing spondylitisis, antiphospholipid antibody syndrome,
aplastic anemia, autoimname hepatitis,
coeliac disease, Goodpashire's syndrome, idiopathic linombocytopenic punzura,
optic neuritis, sclerodeama, primary
biliary cirrhosis, Reiter's syndrome, Takayasu's arteritis, temporal
arteritis, warm autoinmaine hemolytic anemia,
Wegener's granulOrnatosis, psoriasis, alopecia universalis, Beheefs disease,
chronic fatigue, dysautonomia,
endornetriosis, interstitial cystitis, neuromyotonia, scleroderme, or
viilvodynia.
(0027] In other embodiments, the subject in need is suffering from a
heteroimmune condition or disease, e.g., graft
versus host disease, transplantation, transfusion, anaphylaxis, allergy, type
I hypersensitivity, allergic conjunctivitis,
allergic zhinitis, or atopic dermatitis.
[0028] In certain embodiments, the subject in need is suffering from an
inflammatory disease, e.g., asthma,
appendicitis, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis,
cholangitis, cholecystitis, colitis, conjunctivitis,
cystitis, dacryoadenitis, dermatitis, dermatornyositis, encephalitis,
endocarditis, endomeftitis, enteritis, enterocolitie,
epicOndylitis, epididymitis, fasciitis, fibrositis, gastritis,
gastroenteritis, hepatitis, hidradenitis suppurative, laryngitis,
mastitis, meningitis, myelitis myocarditis, myositis, neplwitis, oophoritis,
orchitis, osteitis, otitis, pancreatitis,
Parotids, Pericarditis, Peritonitis, pharyngitis, pleuritis, phlebitis,
pneumonitis, pneumonia, proctitis, prostatitisõ
pyelonephritis, rhinitis, salphigitis, sinusitis, stomatitis, synovitis,
tendonitis, tonsillitis, uveitis, vaginitis, vasculitis,
or vulvitis.
[0029] In Rusher embodiments, the subject in need is suffering from a cancer.
In one embodiment, the cancer is a
B-cell proliferative disorder, e.g., diffuse large B cell lymphoma, follicular
lymphoma, chronic lymphocytic
/ymphoma, chronic lymphocytic leukemia, B-cell prolymphocytic leukemia,
lymphoplasmacytic
lymphoma/Waldenstrem macroglobulinemia, splenic marginal zone lymphoma, plasma
cell myelotna,
plasmacytoma, extranodal marginal zone B cell lymphoma, nodal marginal zone B
cell lymphoma, mantle cell
lymphoma, mediastinal (thymic) large B cell lymphoma, inftevascular large B
cell lymphoma, primary effusion
lymphoma, burkitt lymphoma/leukemia, or lymphomatoid grannlomatosis. In some
embodiments, where the subject
is suffering from a cancer, an anti-cancer agent is administered to the
subject in addition to one of the above-
mentioned compounds. In one embodiment, the anti-cancer agent is an inhibitor
of mitogen-activated protein kinase
signaling, e.g., U0126, PD98059, PD184352, PD0325901, ARRY-142886, SB239063,
SP600125, BAY 43-9006,
wortmannin, or LY294002.
100301 In further embodiments, the subject in need is suffering from a
thrcnnboembolic disorder, e.g., myocardial
infarct, angina pectoris, reocclusion after angioplasty, restenosis after
angioplasty, reoectusion after aortosoronary
bypass, restenosis after aortocoronary bypass, stroke, transitory ischernia, a
peripheral arterial occlusive disorder,
= 35 puhnonary embolism, or deep venous thrombosis.
[0031] In a further aspect, provided herein is a method for treating an
autoimmune disease by administering to a
subject in need thereof a composition containing a therapeutically effective
amount of at least one compound having
the structure of any of Formula (A), Pomade (B), Formula (C), or Formula (D).
In one embodiment, the
autoimmune disease is arthritis. In another embodiment, the autoinunune
disease is lupus. In some embodiments, the
autoimmtuae disease is inflammatory bowel disease (including Crohn's disease
and ulcerative colitis), rheumatoid
arthritis, moths& arthritis, osteoarthritis, Still's disease, juvenile
arthritis, lupus, diabetes, myasthenia gravis,
Hashimoto's thyroiditis, Ord's thyroiditis, Graves' disease Sjagren's
syndrome, multiple sclerosis, Guillain-Barre
5
Date Recue/Date Received 2022-11-04

syndrome, acute disseminated encephalomyelitis, Addison's disease, opsoclonus-
myoclonus syndrome, ankylosing
spondylitisis, andphospholipid antibody syndrome, aplastic anemia, autoimmune
hepatitis, coeliac disease,
Goodpasture's syndrome, idiopathic thrombocytopenic purpura, optic neuritis,
sclerodemia, primary biliary
cirrhosis, Reiter's syndrome, Talcayasu's arteritis, temporal arteritis, warm
autoixnmune hemolytic anemia,
Wegener's granulomatosis, psoriasis, alopecia universalis, Behcees disease,
chronic fatigue, dysautonomia,
endomttriosis, interstitial cystitis, neuromyotonia, sclerodenna, or
vulvodynia.
[0032] In a further aspect, provided herein is a method for treating a
heteroinunune condition or disease by
administering to a subject in need thereof a composition containing a
therapeutically effective amount of at least one
compound having the structure of any of Formula (A), Formula (B), Formula (C),
or Formula (D). In some
embodiments, the heteroimmune conelitioin or disease is graft versus host
disease, transplantation, transfusion,
anaphylaxis, allergy, type I hypersensitivity, allergic conjunctivitis,
allergic rhinitis, or atopic dermatitis.
[0033] In a further aspect, provided herein is a method for treating an
inflammatory disease by administering to a
subject in need thereof a composition containing a therapeutically effective
amount of at least one compound having
the structure of any of Formula (A). Formula (B), Formula (C), or Formula (D).
In some embodiments, the
inflammatory disease is asthma, inflammatory bowel disease (including Crohn's
disease and ulcerative colitis),
appendicitis, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis,
cholangitis, cholecystitis, colitis, conjunctivitis,
cystitis, dacryoadenitis, dermatitis, dennatomyositis, encephalitis,
endocarditis, endometritis, enteritis, enterocolids,
epicondylitis, epididymitis, fasciitis, fibrositis, gastritis,
gastroenteritis, hepatitis, hidradenitis suppurative, laryngitis,
mastitis, meningitis, myelitis myocarditis, myositis, nephritis, oophoritis,
orchids, osteitis, otitis, pancreatitis,
parotitis, pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis,
pneunionitis, pneumonia, proctitis, prostatitis,
pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis,
tendonitis, tonsillitis, uveitis, vaginitis, vasculitis,
or vulvitis.
[0034] In yet another aspect, provided herein is a method for treating a
cancer by administering to a subject in
need thereof a composition containing a therapeutically effective amount of at
least one compound having the
structure of any of Formula (A), Formula (B), Formula (C), or Formula (D). In
one embodiment, the cancer is a B-
cell proliferative disorder, e.g., diffuse large B cell lymphoma, follicular
lymphoma, chronic lymphocytic
lymphoma, chronic lymphocytic leukemia, B-cell prolyinphocytic leukemia,
lymphoplasmacytic
lymphoms/Viraldenstrom rnacroglobulinenda, splenic marginal zone lymphoma,
plasma cell myeloma,
plasmacytoma, extranodal marginal zone B cell lymphoma, nodal marginal zone B
cell lymphoma, mantle cell
lymphoma, mediastinal (thymic) large B cell lymphoma, intravascular large B
cell lymphoma, primary effusion
lymphoma, burkitt lymphoma/leukemia, or lymphomatoid granulomatosis. In some
embodiments, where the subject
is suffering from a cancer, an anti-cancer agent is administered to the
subject in addition to one of the above-
mentioned compounds. In one embodiment, the anti-cancer agent is an inhibitor
of mitogen-activated protein ldnase
signaling, e.g., U0126, PD98059, PD184352, PD0325901, ARRY-142886, SB239063,
SP600125, BAY 43-9006,
wortrnannin, or LY294002.
100351 In another aspect, provided herein is a method for treating a
thromboembolic disorder by administering to a
subject in need thereof a composition containing a therapeutically effective
amount of at least one compound having
the structure of any of Formula (A), Formula (B), Formula (C), or Formula (D).
In some embodiments, the
thromboembolic disorder is myocardial infarct, angina pectoris, reocclusion
after angioplasty, restenosis after
angioplasty, reocclusion after aortocoronary bypass, restenosis after
aortocoronary bypass, stroke, transitory
ischernia, a peripheral arterial occlusive disorder, pulmonary embolism, or
deep venous thrombosis.
6
Date Recue/Date Received 2022-11-04

100361 In a further aspect, provided herein is a method for treating an
autoinunune disease by administering to a
subject in need thereof a composition containing a therapeutically effective
amount of a compound that forms a
covalent bond with Bruton's tyrosine kinase. In one embodiment, the compound
forms a covalent bound with the
activated form of Bruton's tyrosine kinase. In further or alternative
embodiments, the compound irreversibly inhibits
the Bruton's tyrosine kinase to which it is covalently bound. In a further or
alternative embodiment, the compound
forms a covalent bond with a cysteine residue on Bmton's tyrosine kinase.
100371 hi a further aspect, provided herein is a method for treating a
heteroimmune condition or disease by
administering to a subject in need thereof a composition containing a
therapeutically effective amount of a
compound that forms a covalent bond with Bruton's tyrosine kinase. In one
embodiment, the compound forms a
covalent bound with the activated form of Bruton's tyrosine kinase. In further
or alternative embodiments, the
compound irreversibly inhibits the Bruton's tyrosine kinase to which it is
covalently bound. In a further or
alternative embodiment, the compound forms a covalent bond with a cysteine
residue on Bruton's tyrosine kinase.
100381 In a further aspect, provided herein is a method for treating an
inflammatory disease by administering to a
subject in need thereof a composition containing a therapeutically effective
amount of a compound that forms a
covalent bond with Bruton's tyrosine kinase. In one embodiment, the compound
forms a covalent bound with the
activated form of Bruton's tyrosine kinase. In further or alternative
embodiments, the compound irreversibly inhibits
the Bruton's tyrosine kinase to which it is covalently bound. In a further or
alternative embodiment, the compound
forms a covalent bond with a cysteine residue on Bruton's tyrosine kinase. In
yet another aspect, provided herein is
a method for treating a cancer by administering to a subject in need thereof a
composition containing a
therapeutically effective amount of a compound that forms a covalent bond with
Bruton's tyrosine kinase. In one
embodiment, the compound forms a covalent bound with the activated form of
Bruton's tyrosine kinase. In further
or alternative embodiments, the compound irreversibly inhibits the Bruton's
tyrosine kinase to which it is covalently
bound. In a further or alternative embodiment, the compound forms a covalent
bond with a cysteine residue on.
Bruton's tyrosine kinase. In another aspect, provided herein is a method for
treating a thromboembolic disorder by
administering to a subject in need thereof a composition containing a
therapeutically effective amount of a
compound that forms a covalent bond with Bruton's tyrosine kinase. In one
embodiment, the compound forms a
covalent bound with the activated form of Bmton's tyrosine kinase. In further
or alternative embodiments, the
compound irreversibly inhibits the Bruton's tyrosine kinase to which it is
covalently bound. In a further or
alternative embodiment, the compound forms a covalent bond with a cysteine
re,sidue on Bruton's tyrosine kinase.
[00391 In another aspect are methods for modulating, including irreversibly
inhibiting the activity of Btk or
other tyrosine lcinases, wherein the other tyrosine Icinases share hom*ology
with Btk by having a cysteine residue
(including a Cys 481 residue) that can form a covalent bond with at least one
irreversible inhibitor described herein,
in a mammal comprising administering to the mammal at least once an effective
amount of at least one compound
having the structure of any of Formula (A), Formula (B), Formula (C), or
Formula (D). In another aspect are
methods for modulating, including including irreversibly inhibiting, the
activity of Btk in a mammal comprising
administering to the mammal at least once an effective amount of at least one
compound having the structure of any
of Formula (A), Formula (B), Formula (C), or Formula (D). In another aspect
are methods for treating Btk-
dependent or Mk mediated conditions or diseases, comprising administering to
the mammal at least once an
effective amount of at least one compound having the structure of any of
Formula (A), Formula (B), Formula (C), or
Formula (D).
[00401 In another aspect are methods for (leafing inflammation comprising
administering to the mammal at
least once an effective amount of at least one compound having the structure
of Formula (A), (B), (C), or (I)).
7
Date Recue/Date Received 2022-11-04

100411 A further aspect are methods for the treatment of cancer
comprising administering to the mammal at
least once an effective amount of at least one compound having the structure
of Formula (A), (B), (C), or (D). The
type of cancer may include, but is not limited to, pancreatic cancer and other
solid or hematological tumors.
100421 In another aspect are methods for treating respiratory diseases
comprising administering to the
mammal at least once an effective amount of at least one compound having the
structure of Formula (A), (B), (C), or
(D). In a further embodiment of this aspect, the respiratory disease is
asthma. In a further embodiment of this aspect,
the respiratory disease includes, but is not limited to, adult respiratory
distress syndrome and allergic (extrinsic)
asthma, non-allergic (intrinsic) asthma, acute severe asthma, chronic asthma,
clinical asthma, nocturnal asthma,
allergen-induced asthma, aspirin-sensitive asthma, exercise-induced asthma,
isocapnic hyperventilation, child-onset
asthma, adult-onset asthma, cough-variant asthma, occupational asthma, steroid-
resistant asthma, seasonal asthma,
[0043] In another aspect are methods for preventing rheumatoid arthritis
and osteoartluitis comprising
administering to the mammal at least once an effective amount of at least one
compound having the structure of
Formula (A), (B), (C), or (D).
[0044] In another aspect are methods for treating inflammatory responses
of the slcin comprising
administering to the mammal at least once an effective amount of at least one
compound having the structure of
Formula (A), (B), (C), or (D). Such inflammatory responses of the skin
include, by way of example, dermatitis,
contact dermatitis, eczema, urticaria, rosacea, and scarring. In another
aspect are methods for reducing psoriatic
lesions in the skin, joints, or other tissues or organs, comprising
administering to the mammal an effective amount of
a first compound having the structure of FommLa (A), (B), (C), or (D).
[0045] In another aspect is the use of a compound of Fonnula (A), (B), (C),
or (D) in the manufacture of a
medicament for treating an inflammatory disease or condition in an animal in
which the activity of Stir or other
tyrosine kinases, wherein the other tyrosine Icinases share hom*ology with Btk
by having a cysteine residue
(including a Cys 481 residue) that can form a covalent bond with at least one
irreversible inhibitor described herein,
contributes to the pathology and/or symptoms of the disease or condition. In
one embodiment of this aspect, the
tyrosine kinase protein is Btk. In another or further embodiment of this
aspect, the inflammatory disease or
conditions are respiratory, cardiovascular, or proliferative diseases.
[0046] In any of the aforementioned aspects are further embodiments in
which administration is enteral,
parenteral, or both, and wherein (a) the effective amount of the compound is
systemically administered to the
mammal; (b) the effective amount of the compound is administered orally to the
mammal; (c) the effective amount
of the compound is intravenously administered to the mammal; (d) the effective
amount of the compound
administered by inhalation; (e) the effective amount of the compound is
administered by nasal administration; or (f)
the effective amount of the compound is administered by injection to the
mammal; (g) the effective amount of the
compound is administered topically (dermal) to the mammal; (h) the effective
amount of the compound is
administered by ophthalmic administration; or (i) the effective amount of the
compound is administered rectally to
the mammal.
(0047] In any of the aforementioned aspects are further embodiments
comprising single administrations
of the effective amount of the compound, including further embodiments in
which (i) the compound is administered
once; (ii) the compound is administered to the mammal multiple times over the
span of one day; (iii) continually; or
(iv) continuously.
100481 In any of the aforementioned aspects are further embodiments
comprising multiple administrations
of the effective amount of the compound, including further embodiments in
which (i) the compound is administered
in a single dose; (ii) the time between multiple administrations is every 6
hours; (iii) the compound is administered
8
Date Recue/Date Received 2022-11-04

=
to the mammal every 8 hours. In tbrther or alternative embodiments, the method
comprises a drug holiday, wherein
the administration of the compound is temporarily suspended or the dose of the
compound being administered is
temporarily reduced; at the end of the drug holiday, dosing of the compoundis
resumed. 'The length of the drug
= holiday C.an vary from 2 days to I year.
100491 In any of the aforementioned aspects involving the treatment of
proliferative disorders, including
cancer, are further embodiments comprising administering at least one
additional agent selected from the group
consisting of alemtummab, arsenic trioxide, asparaginaso (pegylated or non-),
bevecizumab, cetiorimab, platinum-
based compounds such as cisplatin, dadribine,
daunombicin/doxorubicinfularubieln, irinotecan, fludarabine, 5-
fluorouracal,.gerntuzimiab, methotrexate, ParlitaxeP2t, tajol, temozolomide,
thioguanine, or classes of drugs
including hormones (an antiestrogen, an antiandrogen, or gonadotropin
releasing hormone analogues, interferons
such as alpha interfenin, nitrogen innate:de Such as busulfan or melphalan or
mechloretbamine, retinoids such as
tretinoin; topoisomerase inhibitors such as irinotecan or topotecan, tyrosine
kinase inhibitors such as germitink or .
imatimb; or agents to treat signs or symptoms induced by such therapy
including allopurinol. filgrastink
. granisetrodondansetronfpalonosetron, dronaldnol.
100501 In any of the aforementioned aspects involving the prevention or
treatment of Btk-dependent or
tyrosine kin= mediated diseases or conditions are further embodiments
comprising identifying patients by
screening for a tyrosine kinase gene haplotype. In farther or alternative
embodiments the tyrosine kinase gene
haplotype is a tyrosine kinase pathway gene, while in still further or
alternative embodiments, the tyrosine kinase
gene haplotype is a Btk baplotype. '
(00511 . Ins further or alternative embodiment, the compound of formula
(A). (B), (C) or (B) are
irreversible inhibitors of Briton's tyrosine 'chine (Btk), while in still
further or alternative embodiments, such
irreversible inhibitors are selective for Btk. In even further or alternative
embodiments, such inhibitors have an IC50
below 10 mkroM in enzyme assay. In one embodiment, a Bdc irreversible
inhibitor has an IC.30 of less than 1
micsoM, and in another embodiment, less than 0.25 microM.
100521 = In further or alternative embodiment, the compound of formula
((A), (B), (C) or (B) are selcaive
irreversible inhibitors for Mk over 10c. In Bird= or alternative embodiment,
the compound of formula (A). (B), (C)
or (13) are selective irreversible inhibitors for Btk over Lck In Butler or
alternative embodiment, the compound of
formula (A), (B), (C) or (D) are selective irreversible inhibitors for Btk
over AIM- In further or alternative
embodirneo. t, the compound of formula (A), (B), (C) or 0;9 are selective
irreversible inhibitors for Btk over MET.
In further or alternative embodiment, the compound of foam's (A), (B), (C) or
(D) are selective irreversible
inhibitors for Btk over EMIR. In further or alternative embodimeru, the
compound of formula (A), (B), (C) or (D)
are selective irreversible inhibitors for Bfic over Lyn.
100531 In further or alternative embodiments, the irreversible Mk
inluliitors are also inhibitors of EGER.
9
Date Recue/Date Received 2022-11-04

=
Certain Terminology
[00551 'Unless defined otherwise, all teelmical and ..-6-.Afir terms used
herein have the same meaning as is
commonly understood by one of skill in the art to which the claimed eubject
matter belongs. In the event that there
are a plurality of definitions for terms herein, those in this section
prevail. Where reference is made to a UFtL or
other such identifier or address, it is understood that such identifiers can
change and particular information on the
Internet can come and go, but equivalent information can be found by searching
the interact. Reference thereto
evidences the availability and public dissemination of such information.
100561 It is to be understood that the foregoing general description and
the following detailed description are
exemplary and explanatory only and are not restrictive of any subject matter
claimed. In this application, the use of
the singular includes the plural unless specifically stated otherwise. It must
be noted that, as used in the specification
and the appended claims, the singular forms *a," "an" and "the" include plural
referents unless the context clearly
dictates otherwise. In this application, the use of "or" means "and/or plea
stated otherwise. Furthermore, use of
the term Including' as well as other forms, such as "include", Includes," and
"included," is not limiting.
100571 The section headings used herein are for organizational purposes
only and are not to be construed as
limiting the subject matter described.
[00581 Definition of standard chemistry terms may be found in reference
works, including Carey and
Sundbmg "ADVANCED ORGANIC Clismitivitir 4'13D." Vols. A (2000) and B (2001),
Plenum Press, New York.
Lintels otherwise indicated, conventional methods of mass spectroscopy, NMR,
IIPLC, protein chemistry.
biochemistry, recombinant DNA techniques and phatmacology, within the skill of
the art are employed. Unless
specific definitions are provided, the nomenclature employed in connection
with, and the laboratory procedures and
techniques of; analytical chemistry, synthetic organic chemistry, and
medicinal and pharmaceutical chemistry
described herein are those known in the art. Standard techniques can be used
for chemical syntheses. chemical
analyses, pharmaceutical preparation, formulation, and delivery, and treatment
of patients. Standard techniques can
be used for recombinant DNA, oligonuclemide synthesis, and tissue culture and
transformation (e_g,
electroporation. lipofection). Reactions and purification techniques can be
performed e.g., using kits of
memufacturees specifications or as conenonly accomplished in the art or as
described herein. The foregoing
techniques and procedures can be generallyperfonned of conventional methods
well known in the art and as
described in various general and mom specific ref n. that am cited and
dismissed throughout the present
specification.
10059) It is to be understood that the methods and compositions described
herein are not limited to the
particular methodology, protocols, cell lines, constructs, and reagents
described herein and as such may vary. It is
also to be understood that the terminology used herein is for the purpose of
describing particular embodiments only,
and is not intended to limit the scope of the methods and compositions
described herein, which will be limited only
by the appended claims.
100601 All publications and patents discussed herein are provided solely
for their disclosure prior to the filing
date of the present application. Nothing herein is to be construed as an
admission that the inventors described herein are
not entitled to antedate such disclosure by virtue of prior invention or for
any other reason.
Date Recue/Date Received 2022-11-04

100611 An "alkyl" group refers to an aliphatic hydrocarbon group. The
alkyl moiety may be a "saturated
alkyl" group, which means that it does not contain any alkene or allcyne
moieties. The alkyl moiety may also be an
"unsaturated alkyl" moiety, which means that it contains at least one alkene
or allcyne moiety. An "alkene" moiety
refers to a group that has at least one carbon-carbon double bond, and an
"alkyne" moiety refers to a group that has
at least one carbon-carbon triple bond. The allcyl moiety, whether saturated
or unsaturated, may be branched,
straight chain, or cyclic. Depending on the structure, an alkyl group can be a
monoradical or a diradical (i.e., an
allcylene group). The alkyl group could also be a "lower alkyl" having Ito 6
carbon atoms.
[0062) As used herein, C1-C.õ includes C1-C2, CI-C3 . . . CI-Cõ.
100631 The "allcyr' moiety may have Ito 10 carbon atoms (whenever it
appears herein, a numerical range
such as "1 to 10" refers to each integer in the given range; e.g.,"1. to 10
carbon atoms" means that the alkyl group
may have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and
including 10 carbon atoms, although the
present definition also covers the occurrence of the term "alkyl" where no
numerical range is designated). The alkyl
group of the compounds described herein may be designated as "Ci-C4 alkyl" or
similar designations. By way of
example only, "CI-C, alkyl" indicates that there are one to four carbon atoms
in the alkyl chain, Le., the alkyl chain
is selected from among methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl,
sec-butyl, and t-butyl. Thus C1-C4 alkyl
includes C1-C2 alkyl and C1-C3 alkyl. Alkyl groups can be substituted or
tuisubstituted. Typical alkyl groups include,
but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl,
isobutyl, tertiary butyl, pentyl, hexyl, ethenyl,
propenyl, butenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the
like.
100641 As used herein, the term "non-cyclic alkyl" refers to an alkyl
that is not cyclic (i.e., a straight or
branched chain containing at least one carbon atom). Non-cyclic alkyls can be
fully saturated or can contain non-
cyclic alkenes and/or alkynes. Non-cyclic alkyls can be optionally
substituted.
' 100651 The term "alkenyl" refers to a type of alkyl group in which the
first two atoms of the alkyl group form
a double bond that is not part of an aromatic group. That is, an alkenyl group
begins with the atoms -C(R)(R)-R,
wherein R refers to the remaining portions of the alkenyl group, which may be
the same or different. The alkenyl
moiety may be branched, straight chain, or cyclic (in which case, it would
also be known as a "cycloalkenyl"
group). Depending on the structure, an alkenyl group can be a monoradical or a
diradical (i.e., an alkenylene group).
Alkenyl groups can be optionally substituted. Non-limiting examples of an
alkenyl group include -CH:1-12, -
C(CH3)=CH2, -CH=CHCH3, -C(CH3)=CHCH3. Alkenylene groups include, but are not
bruited to, -CH=CH-, -
C(CH3)-CH-, -CH=CHCH2-, -CH.-CHCH2CH2- and -C(CH3)-CHC/12-. Alkenyl groups
could have 2 to 10
carbons. The alkenyl group could also be a "lower alkenyl" having 2 to 6
carbon atoms.
(0066) The term "alkynyl" refers to a type of alkyl group in which the
rust two atoms of the alkyl group form
a triple bond. That is, an alkynyl group begins with the atoms -C aC-R,
wherein R refers to the remaining portions
of the alkynyl group, which may be the same or different. The "R" portion of
the alkynyl moiety may be branched,
straight chain, or cyclic. Depending on the structure, an alkynyl group can be
a monoradical or a diradical (i.e., an
alkynylene group). Alkynyl groups can be optionally substituted. Non-limiting
examples of an alkynyl group
include, but are not limited to, -C aCH, -6 cr-13, -c CH2CH3, -c and -C
Alkynyl groups can
have 2 to 10 carbons. The alkynyl group could also be a "lower alkynyl" having
2 to 6 carbon atoms.
100671 An "allcoxy" group refers to a (alkyl)0- group, where alkyl is as
defined herein.
[00681 "Hydroxyalkyl" refers to an alkyl radical, as defined herein,
substituted with at least one hydroxy
group. Non-limiting examples of a hydroxyallcyl include, but are not limited
to, hydroxymethyl, 2-hydroxyethyl, 2-
hydroxypropyl, 3-hydroxypropyl, 1-(hydroxymethyl)-2-methylpropyl, 2-
hydroxybutyl, 3-hydroxybutyl, 4-
11
Date Recue/Date Received 2022-11-04

= hydroxybutyl, 2,3-dihydroxypropyl, 1-(hydroxymethyl)-2-hydroxyethyl, 2,3-
dihydroxybutyl, 3,4-dthydroxybutyl
and 2-(hydroxymethyl)-3-hydroxypropyl.
100691 "Allwxyalkyl" refers to an alkyl radical, as defined herein,
substituted with an alkoxy group, as defined
herein.
loom An "alkenyloxy" group refers to a (alkeny1)0- group, where alkenyl is
as defined herein.
100711 The term "alkylamine" refers to the ¨14(alkyl),111 group, where x
and y are selected from among x=l,
mid x-2, y=0. When the alkyl groups, taken together with the N atom to
which they are attached, can
optionally form a cyclic ring system.
100721 "Alkylaminoalkyl" refers to an alkyl radical, as defined herein,
substituted with an alkylamine, as
defined herein.
100731 An "amide" is a chemical moietY with the formula -C(0)NIIR or -
MIC(0)1t, where R is selected from
among alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and
heteroalicyclic (bonded through a ring
= carbon). An amide moiety may form a linkage between an amino acid or a
peptide molecule and a compound
= described herein, thereby forming a prodrug. Any amine, or carboxyl side
chain on the compounds described herein
can be amidified. The procedures and specific groups to make such amities are
known to those of skill in the art and
can readily be found in reference sources such as Greene and Wuts, Protective
Groups in Organic Synthesis, 3'd Ed.,
John Wiley & Sons, New York, NY, 1999.
100741 = The term "ester" refers to a chemical moiety with formula -COOR,
where R is selected from among
alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and
hetemalicyclic (bonded through a ring
carbon). Any hydroxy. or carboxyl side 'chain on the compounds described
herein can be esteriA ed. The procedures:
and specific groups to make such esters are known to those of skill in the art
and can readily be found in reference
sources such as Greene and Wuts, Protective Groups in Organic Synthesis, 3'
Ed., John Wiley dr Sons, New York.
NY, 1999.
100751 As used herein, the term "ring" refers to any covalently closed
structure. Rings include, for example,
carbocycics (e.g., aryls and cycloalkyls), heterocycles (e.g., hetemaryls and
non-aromatic heterocycles), aromatics
(e.g. aryls and lietcroaryls), and non-aromatics (e.g., cycloalkyls and non-
aromatic heterocycles). Rings can be
optionally substituted. Rings can be monocyclic or polycyclic.
100761 As used herein, the term "ring system" refers to one, or more than
one ring.
100771 The term "membered ring" can embrace any cyclic structure. The
term "membered" is meant to denote
the number of skeletal atoms that constitute the ring. Thus, for example,
cyclohexyl, pyridine, jiyran and thiopyran
are frinembered rings and cyclopentyl, pyrrole, furan, and thiophene are 5-
membered rings:
100781 The term "fused" refers to structures in which two or more rings
share one or more bonds.
10079] The term "carbocyclic" or "carbocycle" refers to a ring wherein
each of the atoms forming the ring is a
carbon atom. Carbocycle includes aryl and cycloalkyL The term thus
distinguishes carbocycle from heterocycle
(1eterocyclic") in which the ring backbone contains at least one atom which is
different from carbon (i.e a
heteroatom). Heterocycle includes heteroaryl and heterocycloalkyl. Carbocycles
and heterocycles can be optionally
substituted.
100801 The term "aromatic" refers to a planar ring having a delocalized
it-electron system containing 4n+2 it
electrons, where n is an integer. Aromatic rings can he formed from five, six,
seven, eight, nine, or more than nine
atoms. Aromatics can be optionally substituted. The term "aromatic" includes
both carbecyclic aryl (e.g.. phenyl)
and betcrocYclic aryl (or "heteroaryl" or "heteroaromatic") groups (e.g.,
pyridine). The term includes monocyclic or
fused-ring polycyclic (i.e., rings which share adjacent pairs oicarbon atoms)
groups.
12
=
Date Recue/Date Received 2022-11-04

100811 As used herein, the term "aryr' refers to an aromatic ring wherein
each of the atoms forming the ring is
a carbon atom. Aryl rings can be formed by five, six, seven, eight, nine, or
more than nine carbon atoms. Aryl
groups can be optionally substituted. Examples of aryl groups include, but are
not limited to phenyl, naphthalenyl,
phenanthrenyl, anthracenyl, fluorenyl, and indenyl. Depending on the
structure, an aryl group can be a monoradical
or a diradical (i.e., an arylene group).
100821 An "aryloxy" group refers to an (aryl)O- group, where aryl is as
defined herein.
100831 "Arallcyr' means an alkyl radical, as defined herein, substituted
with an aryl group. Non-limiting
aralkyl groups include, benzyl, phenethyl, and the like.
100841 "Arallcenyl" means an alkenyl radical, as defined herein,
substituted with an aryl group, as defined
herein.
100851 The term "cycloalkyl" refers to a monocyclic or polycyclic radical
that contains only carbon and
hydrogen, and may be saturated, partially unsaturated, or fully unsaturated.
Cycloalkyl groups include groups having
from 3 to 10 ring atoms. Illustrative examples of cycloalkyl groups include
the following moieties:
. .01> , Lb, a). o3
>JD, C), C),(""),a)
C:C> , . . OC.hCi
,and the like. Depending on the structure, a cycloalkyl group can
be a monoradical or a diradical (e.g., an cycloallcylene group). The
cycloalkyl group could also be a "lower
cycloalkyl" having 3 to 8 carbon atoms.
1110861 "Cycloalkylalkyl" means an alkyl radical, as defined herein,
substituted with a cycloalkyl group. Non-
limiting groups include cyclopropylmethyl, cyclobutylmethyl,
cyclopentylmethyl,
cyclohexylmethyl, and the like.
10087] The term "heterocycle" refers to heteroaromatic and
beteroalicyclic groups containing one to four
heteroatoms each selected from 0, S and N, wherein each heterocyclic group has
from 4 to 10 atoms in its ring
.. system, and with the proviso that the ring of said group does not contain
two adjacent 0 or S atoms. Herein,
whenever the number of carbon atoms in a heterocycle is indicated (e.g., C1-C6
heterocycle), at least one other atom
(the heteroatom) must be present in the ring. Designations such as "C1-C6
heterocycle" refer only to the number of
carbon atoms in the ring and do not refer to the total number of atoms in the
ring. It is understood that the
heterocylic ring can have additional heteroatoms in the ring. Designations
such as "4-6 membered heterocycle" refer
to the total number of atoms that are contained in the ring (i.e., a four,
five, or six membered ring, in which at least
one atom is a carbon atom, at least one atom is a heteroatom and the remaining
two to four atoms are either carbon
atoms or heteroatoms). In heterocycles that have two or more heteroatoms,
those two or more heteroatoms can be
the same or different from one another. Heterocycles can be optionally
substituted. Binding to a heterocycle can be
at a heteroatom or via a carbon atom. Non-aromatic heterocyclic groups include
groups having only 4 atoms in their
ring system, but aromatic heterocyclic groups must have at least 5 atoms in
their ring system. The heterocyclic
13
Date Recue/Date Received 2022-11-04

groups include benzo-fused ring systems. An example of a 4-membered
heterocyclic group is azetidinyl (derived
from azetidine). An example of a 5-membered heterocyclic group is thiazolyl.
An example of a 6-membered
heterocyclic group is pyridyl, and an example of a 10-membered heterocyclic
group is quinolinyl. Examples of non-
aromatic heterocyclic groups are pyrrolidinyl, tetinhydrofuranyl,
dihydrofuranyl, tetrahydrothienyl,
tetrahydropyranyl, dthydropyranyl, tetrahydrothiopyranyl, piperidino,
morpholino, thiornorpholino, thioxanyl,
piperazinyl, azetidinyl, oxetanyl, thietanyl, hornopiperidinyl, oxepanyl,
thiepanyl, oxazepinyl, diazepinyl,
thiazepinyl, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl,
indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl,
1,3-dioxolanyl, pyrazolinyl, didrianyl, dithiolanyl, dihydropyranyl,
clihydrothienyl, dihydrofuranyl, pyrazolidinyi,
imidazolinyl, imidazOlidinyl, 3-azabicyclo(3.1.0]hexanyt 3-
azabicyclo[4.1.0]heptanyl, 3H-indoly1 and quinolizinyl.
Examples of aromatic heterocyclic groups are pyridinyl, imidazolyi,
pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl,
teirazolyl, Buy!, fidenyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl,
pyrrolyl, quinolinyl, isoquinolinyl, indolyl,
benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthilainyl,
pyridazinyi, triazinyl, isoindobt
pteridinyl, purinyl, oicadiazrdyl, thiadiazolyl, furazanyl, benzofurazanyl,
benzothiophenyl, benzothiazolyl,
benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyi
The foregoing groups, as derived from
the groups listed above, may be C-attached or N-attached where such is
possible. For instance, a group derived from
pyrrole may be pyrrol-1-y1 (N-attached) or pyrrol-3-y1 (C-attached). Further,
a group derived from imidazole may be
imidazol-1-y1 or imidazol-3-y1 (both N-attached) or imidazol-2-yl, inddazol-4-
y1 or imidazol-5-y1 (all C-attached).
The heterocyclic groups include benzo-fused ring'systems and ring systems
substituted with one or two oxo (=0)
moieties such as pyrrolidin-2-one. Depending on the structure, a heterocycle
group can be a monoradical or a
diradical (i.e., a heterocyclene group).
100881 The terms "heteroaryl" or, alternatively, "heteroaromatic" refers
to an aryl group that includes one or
more ring hetematoms selected from nitrogen, oxygen and sulfur. An N-
containing "heteroarcenatic" or "heteroaryl"
moiety refers to an aromatic group in which at least one of the skeletal atoms
of the ring is a nitrogen atom.
Illustrative examples of heteroaryl groups include the following moieties:
cc> Ites:XN
. N
çN 1 (-- ) r* , NC)
_________________ , N Nk.¨ .
¨AS Nõ..1
and the like. Depending on the structure, a heteroaryl group can be a
monoradical or a diradical (i.e., a
heteroarylene group).
[00891 As used herein, the term "non-aromatic heterocycle",
"heterocycloalkyl" or "heteroalicyclic" refers to
a non-aromatic ring wherein one or more atoms forming the ring is a
heteroatom. A "non-aromatic heterocycle" or
"hetcrocycloalicyl" group refers to a cycloalkyl group that includes at least
one heteroatom selected from nitrogen,
oxygen and sulfur. The radicals may be fused with an aryl or heterornyl.
Heterocycloalicyl rings can be formed by
three, four, five, six, seven, eight, nine, or more than nine atoms.
Heterocycloalkyl rings can be optionally
substituted. In certain embodiments, non-aromatic heterocycles contain one or
more carbonyl or thiocarbonyl groups
such as, for example, oxo- and thin-containing groups. Examples of
heterocycloalkyls include, but are not limited to,
lactams, lactones, cyclic imides, cyclic thioimides, cyclic carbamates,
tetrahydrothiopyran, 4H-pyran,
14
Date Recue/Date Received 2022-11-04

=
tetrahydropyran, piperidine, 1,3-dioxin, 1,3-dioxane, 1,4-dioxane,
piperazine, 1,3-oxathiane, 1,4-
oxathiin, 1,4-oxathiane, tetrahydro-1,4-thiazine, 214-1,2-oxazine, rnaleimide,
succinimide, barbituric acid,
. thiobarbittuic acid, dioxopiperazine, hydantoin, dihydrouracil;
morpholine, trioxane, hexahydro-1,3,5-hiazine,
tetrahydiothiophene, tetrahydrofuran, pyrroline, pyrrolidine, pyrrolidone,
pyrrolidione, pyrazoline, pyrazolidine,
imidazoline, imidazolidine, 1,3-dioxole, 1,3-dioxolane, 1,3-dithiole, 1,3-
dithiolane, isoxazoline, isoxazolidine,
oxazoline, oxazolidine, oxazolidinone, thiazoline, thiazolidine, and 1,3-
oxathiolane. Illustrative examples of
heterocycloalkyl groups, also referred to as non-aromatic heterocycles,
include:
0 0 0 0
(kIS %op :jts.
(ILIN60 _10 0 0
s . ________________________________________________
= 0
cN) (o) c0) N 0 0 c
N ' _______________ N ,N--N pm,
0 0
Li cN N)L)) L.13 00 oNo .)
and
the like. The term heteroalicyclic also includes all ring forms of the
carbohydrates, including but not limited to the
monosaccharides, the disaccharides and the oligosaccharides. Depending on the
structure, a heterocycloallcyl group
can be a monoradical or a diradical (i.e., a heterocycloallcylerte group).
100901 The term "halo" or, alternatively, "halogen" or "halide" means
fluoro, chloro, bromo and iodo.
(0091] The terms "haloalkyl," "haloalkenyl," "haloalkynyl" and "haloalkoxy"
include alkyl, alkenyl, allcynyl
and alkoxy structures in which at least one hydrogen is replaced with a
halogen atom. In certain embodiments in
which two or more hydrogen atoms are replaced with halogen atoms, the halogen
atoms are all the same as one
another. In other embodiments in which two or more hydrogen atoms are replaced
with halogen atoms, the halogen
atoms are not all the same as one another.
100921 The term "iluoroallcyl," as used herein, refers to alkyl group in
which at least one hydrogen is replaced
with a fluorine atom. Examples of fluoroallcyl groups include, but are not
limited to, -CF3, ¨CH2CF37¨CF5CF3, ¨
CH2CH2CF3and the like.
1009311 As used herein, the terms "heteroalkyl" "heteroalkenyl" and
"heteroalkynyl" include optionally
substituted alkyl, alicenyl and alkynyl radicals in which one or more skeletal
chain atoms is a heteroatom, e.g.,
oxygen, nitrogen, sulfur, silicon, phosphorus or combinations thereof. The
heteroatom(s) may be placed at any
interior position of the heteroalkyl group or at the position at which the
heteroalkyl group is attached to the
remainder of the molecule. Examples include, but are not limited to, -CHrO-
CH3, -CH2-CH2-0-CH3, -CH2-NH-
CF13, -C1-12-CH2-NH-CH3, -C112-N(CH3)-CH3, -C112-CH2-NH-CI-13, -0-12-OH2-
N(CH3)-013, -CH2-S-al2-CF13, -
CH2-CH2,-S(0)-CH3, -CH2-CH2-S(0)2-CH3, -CH=CH-O-CH3, -Si(CH3)3, -CH2-CH=N-
OCH3, and ¨CHH-
N(CH3)-CH3. In addition, up to two heteroatoms may be consecutive, such as, by
way of example, -CHrNH-OCH3
and ¨CH2-0-Si(CH3)3.
(0094) The term "heteroatom" refers to an atom other than carbon or
hydrogen. Heteroatoms are typically
independently selected from among oxygen, sulfur, nitrogen, silicon and
phosphorus, but are not limited to these
atoms. In embodiments in which two or more heteroatoms are present, the two or
more heteroatoms can all be the
same as one another, or some or all of the two or more heteroatoms can each be
different from the others.
Date Recue/Date Received 2022-11-04

[00951 The term "bond" or "single bond" refers to a chemical bond between
two atoms, or two moieties when
the atoms joined by the bond are considered to be part of larger substructure.
[0096] An "isocyanato" group refers to a -NCO group.
[0097) An "isotbiocyanato" group refers to a -NCS group.
[0098] The term "moiety" refers to a specific segment or functional group
of a molecule. Chemical moieties
are often recognized chemical entities embedded in or appended to a molecule.
[0099] A "sulftnyl" group refers to a
[00100] A "sulfonyl" group refers to a -S(=D)2-R.
[00101] A "thioalkoxy" or "alkylthio" group refers to a ¨S-alkyl group.
[00102] A "alkylthioalkyl" group refers to an alkyl group substituted with
a ¨S-alkyl group.
100103] As used herein, the term "0-carboxy" or "acyloxy" refers to a
group of formula RC(=0)0-.
[00104] "Carboxy" means a -C(0)0H radical.
[00105] As used herein, the term "acetyl" refers to a group of formula -
C.(0)CH3.
[00106] "Acyl" refers to the group -C(0)R.
[00107] As used herein, the tenn atribaloniethanesulfonyl" refers to a
group of formula X3CS(-0)2- where Xis
a halogen.
1001081 As used herein, the term "cyano" refers to a group of formula -CN.
[00109] "Cyanoalkyl" means an alkyl radical, as defined herein,
substituted with at least one cyano group.
[00110] As used herein, the term "N-sulfonamido" or "sulfonylamino" refers
to a group of formula
RS(=O)2NH-.
[00111] As used herein, the term "0-carbamyl" refers to a group of formula
-0C(=0)NR2.
[00112] As used herein, the term "N-carbamyl" refers to a group of formula
ROC(=0)NH-.
(00113] As used herein, the term "0-thiocarbarnyl" refers to a group of
formula -0C(=S)NR2.
[00114] As used herein, the term "N-thiocarbamyl" refers to a group of
formula ROC(=S)NH-.
[00115] As used herein, the term "C-amido" refers to a group of formula -
C(=0)NR2.
[00116] "Aminocarbonyl" refers to a -CONH2 radical.
[00117] As used herein, the term "N-amido" refers to a group of formula
RC(=0)NH-.
[00118] As used herein, the substituent "R" appearing by itself and
without a number designation refers to a
substituent selected from among from alkyl, cycloalkyl, aryl, heteroaryl
(bonded through a ring carbon) and non-
__ aromatic heterocycle (bonded through a ring carbon).
[00119] The term "optionally substituted" or "substituted" means that the
referenced group may be substituted
with one or More additional group(s) individually and independently selected
from alkyl, cycloallcyl, aryl,
heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, alkylthio, arylthio,
allcylsulfoxide, arylsulfoxide, allcylsulfone,
arylsulfone, cyano, halo, acyl, nitro, haloalkyl, fluoroallcyl, amino,
including mono- and di-substituted amino
__ groups, and the protected derivatives thereof. By way of example an
optional substituents may be L,R.õ wherein
each L, is independently selected from a bond, -0-, -C(=0)-, -S-, -S(=0)-, -S(-
0)2-, -NH-, -NHC(0)-, -C(0)NW,
S(=0)2NH-, -NHS(=0)2, -0C(0)NH-, -NHC(0)0-, -(substituted or unsubstituted CI-
C6 alkyl), or -(substituted or
unsubstituted C2-C6 alkenyl); and each R, is independently selected from H,
(substituted or unsubstituted C1-
C4alkyl), (substituted or unsubstituted C3-C6cycloalkyl), heteroaryl, or
heteroallcyl. The protecting groups that may
form the protective derivatives of the above substituents are known to those
of skill in the art and may be found in
references such as Greene and Wuts, above.
16
Date Recue/Date Received 2022-11-04

1001201 The term "Michael acceptor moiety" refers to a functional group
that can participate in a Michael
reaction, wherein a new covalent bond is formed between a portion of the
Michael acceptor moiety and the donor
moiety. The Michael acceptor moiety is an electrophile and the "donor moiety"
is a nucleophile. The "G" groups
presented in any of Formula (A), Formula (B), or Formula (C) are non-limiting
examples of Michael acceptor
moieties.
1001211 The term "nucleophile" or "nucleophilic" refers to an electron
rich compound, or moiety thereof. An
example of a nucleophile includes, but in no way is Hinted to, a cysteine
residue of a molecule, such as, for example
Cys 481 of Mk.
1001221 The term "electrophile", or "electrophilic" refers to an electron
poor or electron deficient molecule, or
moiety thereof. Examples of electrophiles include, but in no way are limited
to, Micheal acceptor moieties.
[001231 The term "acceptable" or "pharmaceutically acceptable", with
respect to a formulation, composition or
ingredient, as used herein, means having no persistent detrimental effect on
the general health of the subject being
treated or does not abrogate the biological activity or properties of the
compound, and is relatively nontoxic.
[001241 As used herein, the term "agonist" refers to a compound, the
presence of which results in a biological
activity of a protein that is the same as the biological activity resulting
from the presence of a naturally occurring
ligand for the protein, such as, for example, Btk.
100125] As used herein, the term "partial agoniSt" refers to a compound
the presence of which results in a
biological activity of a protein that is of the same type as that resulting
from the presence of a naturally occurring
ligand for the protein, but of a lower magnitude.
[001261 As used herein, the term "antagonist" refers to a compound, the
presence of which results in a decrease
in the magnitude of a biological activity of a protein. In certain
embodiments, the presence of an antagonist results
in complete inhibition of a biological activity of a protein, such as, for
example, Btk. In certain embodiments, an
antagonist is an inhibitor.
1001271 As used herein, "amelioration" of the symptoms of a particular
disease, disorder or condition by
administration of a particular compound or pharmaceutical composition refers
to any lessening of severity, delay in
onset, slowing of progression, or shortening of duration, whether permanent or
temporary, lasting or transient that
can be attributed to or associated with administration of the compound or
composition.
1001281 "Bioavailability" refers to the percentage of the weight of
compounds disclosed herein, such as,
compounds of any of Formula (A), Formula (B), Formula (C), or Formula (D),
dosed that is delivered into the
general circulation of the animal or human being studied. The total exposure
(AI.JC.0_õ0) of a drug when administered
intravenously is tumidly defined as 100% bioavailable (F%). "Oral
bioavailability" refers to the extent to which
compounds disclosed herein, such as, compounds of any of Formula (A), Formula
(B), Formula (C), or Formula
(D), are absorbed into the general circulation when the pharmaceutical
composition is taken orally as compared to
intravenous injection.
[00129] "Blood plasma concentration" refers to the concentration of
compounds disclosed herein, such as,
compounds of any of Formula (A), Formula (B), Formula (C), or Formula (D), in
the plasma component of blood of
a subject. It is understood that the plasma concentration of compounds of any
of Formula (A), Formula (B), Formula
(C), or Formula (D), may vary significantly between subjects, due to
variability with respect to metabolism and/or
possible interactions with other therapeutic agents. In accordance with one
embodiment disclosed herein, the blood
plasma concentration of the compounds of any of Formula (A), Formula (B),
Formula (C), or Formula (D), may
vary from subject to subject. Likewise, values such as maximum plasma
concentration (Cõ,õ,,) or time to reach
maximum plasma concentration (T.), or total area under the plasma
concentration time curve (AUC(0.4) may vary
17
Date Recue/Date Received 2022-11-04

from subject to subject Due to this variability, the amount necessary to
constitute "a therapeutically effective
= amount" of a compound of any of Fonnula (A), Formula (B), Formula (C), or
Formula (D), may vary from subject
to subject.
1001301 The term "Bruton's tyrosine Iciness," as used herein, refers to
Bruton's tyrosine kinase from hom*o
sapiens, as disclosed in, e.g., U.S. Patent No. 6,326,469 (GenBank Accession
No. NP 000052). .
1001311 The term "Bruton's tyrosine kinase hom*olog," as used herein,
refers to orthologs of Bruton's tyrosine
kinase, e.g., the ordiologs from mouse (GenBank Acession No. AAI347246), dog
(GenBank Acession No.
XP_549139.), rat (GenBank Acession No. NP_001007799), chicken (GenBank
Acession No. NP_989564), or zebra
fish (GenBank Acession No. XP_698117), and fusion proteins of any of the
foregoing that exhibit kinase activity
towards one or more substrates of Bruton's tyrosine kinase (e.g. a peptide
substrate having the amino acid sequence
"AVLESEEELYSSARQ").
1001321 The terms "co-administration" or the lice, as used herein, are
meant to encompass administration of the
selected therapeutic agents to a single patient, and are intended to include
treatment regimens in which the agents
are administered by the same or different route of administration or at the
same or different time.
100133) The terms "effective amount" or "therapeutically effective amount,"
as used herein, refer to a
sufficient amount of an agent or a compound beingAdrninigtered which will
relieve to some extent one or more of
the symptoms of the disease or condition being treated. The result can be
reduction and/or alleviation of the signs,
symptoms, or causes Of a disease, or any other dashed alteration of a
biological system. For example, an "effective
amount" for therapeutic uses is the amount of the composition including a
compound as disclosed herein required to
provide a clinically significant decrease in disease symptoms without undue
adverse side effects. An appropriate
"effective amount" in any individual case may be determined using techniques,
such as a dose escalation study. The
term "therapeutically effective amount" includes, for example, a
prophylactically effective amount .An "effective
amount" of a compound disclosed herein is an amount effective to achieve a
desired pharrnacologic effect or
therapeutic improvement without undue adverse side effects. It is understood
that "an effect amount" or "a
therapeutically effective amount" can vary from subject to subject, due to
variation in metabolism of the compound
of any of Formula (A), Formula (B), Formula (C), or Formula (1)), age, weight,
general condition of the subject, the
condition being treated, the severity of the condition being treated, and the
judgment of the prescribing physician.
By way of example only, therapeutically effective amounts may be determined by
routine experimentation,
including but not limited to a dose escalation clinical trial.
100134] The terms "enhance" or "enhancing" means to increase or prolong
either in potency or duration a
desired effect. By way of example, "enhancing" the effect of therapeutic
agents refers to the ability to increase or
prolong, either in potency or duration, the effect of therapeutic agents on
during treatment of a disease, disorder or
condition. An "enhancing-effective amount," as used herein, refers to an
amount adequate to enhance the effect of a
therapeutic agent in the treatment of a disease, disorder or condition. When
used ins patient, amounts effective for
this use will depend on the severity and course of the disease, disorder or
condition, previous therapy, the patient's
health status and response to the drugs, and the judgment of the treating
physician.
100135) The term "hom*ologous cysteine," as used herein refers to a
cysteine residue found with in a sequence
position that is hom*ologous to that of cysteine 481 of Bruton's tyrosine
kinase, as defined herein. For example.
cysteine 482 is the hom*ologous cysteine of the rat ortholog of Bruton's
tyrosine lcinase; cysteine 479 is the
hom*ologous cysteine of the chicken ortholog; and cysteine 481 is the
hom*ologous cysteine in the zebra fish
ortholog. In another example, the hom*ologous cysteine of TIM, a Tec kinase
family meinber related to Bruton's
tyrosine, is Cys 350. Other examples of kinases having hom*ologous cysteines
are shown in FIG. 1. See also the
18
Date Recue/Date Received 2022-11-04

sequence alignments of tyrosine Icinases (TK) published on the world wide web
at
kinase.comihuman(kinome/phylogeny.html.
[00136) The term "identical," as used herein, refers to two or more
sequences or subsequences which are the
same In addition, the term "substantially identical," as used herein, refers
to two or more sequences which have a
percentage of sequential units which are the same when compared and aligned
for maximum correspondence over a
comparison window, or designated region as measured using comparison
algoritiuns or by manual alignment and
visual inspection. By way of example only, two or more sequences may be
"substantially identical" if the sequential
units are about 60% identical, about 65% identical, about 70% identical, about
75% identical, about 80% identical,
about 85% identical, about 90% identical, or about 95% identical over a
specified region. Such percentages to
describe the "percent identity" of two or more sequences. The identity of a
sequence can exist over a region that is at
least about 75-100 sequential units in length, over a region that is about 50
sequential units in length, or, where not
specified, across the entire sequence. This definition also refers to the
complement of a test sequence. By way of
example only, two or more polypeptide sequences are identical when the amino
acid residues are the same, while
two or more polypeptide sequences are "substantially identical" if the amino
acid residues are about 60% identical,
about 65% identical, about 70% identical, about 75% identical, about 80%
identical, about 85% identical, about
90% ideritirni, or about 95% identical over a specified region. The identity
can exist over a region that is at least
about 75-100 amino acids in length, over a region that is about 50 amino acids
in length, or, where not specified,
across the entire sequence of a polypeptide sequence. In addition, by way of
example only, two or more
polynucleotide sequences are identical when the nucleic acid residues are the
same, while two or more
polynucleotide sequences are "substantially identical" if the nucleic acid
residues are about 60% identical, about
65% identical, about 70% identical, about 75% identical, about 80% identical,
about 85% identical, about 90%
identical, or about 95% identical over a specified region. The identity can
exist over a region that is at least about
75-100 nucleic acids in length, over a region that is about 50 nucleic acids
in length, or, where not specified, across
the entire sequence of a polynucleotide sequence.
[001371 The terms "inhibits", "inhibiting", or "inhibitor" of a ldnase, as
used herein, refer to inhibition of
enzymatic phosphotransferase activity.
1001381 The term "irreversible inhibitor," as used herein, refers to a
compound that, upon contact with a target
protein (e.g., a Ichiase) causes the formation of a new covalent bond with or
within the protein, whereby one or more
of the target protein's biological activities (e.g., phosphotransferase
activity) is diminished or abolished
notwithstanding the subsequent presence or absence of the irreversible
inhibitor.
[00139) The term "irreversible Mr inhibitor," as used herein, refers to an
inhibitor of Stir that can form a
covalent bond with an amino acid residue of Btic. In one embodiment the
irreversible inhibitor of Btic can form a
covalent bond with a Cys residue of Bac; in particular embodiments, the
irreversible inhibitor can form a covalent
bond with a Cys 481 residue (or a hom*olog thereof) of Btk or a cysteine
residue in the hom*ologous corresponding
position of another tyrosine kinase, as shown in Fig. 1.
[001401 The term "isolated," as used herein, refers to separating and
removing a component of interest from
components not of interest. Isolated substances can be in either a dry or semi-
dry state, or in solution, including but
not limited to an aqueous solution. The isolated component can be in a
hom*ogeneous state or the isolated component
can be a part of a pharmaceutical composition that comprises additional
pharmaceutically acceptable carriers and/or
excipients. By way of example only, nucleic acids or proteins are "isolated"
when such nucleic acids or proteins are
free of at least some of the cellular components with which it is associated
in the natural state, or that the nucleic
acid or protein has been concentrated to a level greater than the
concentration of its in vivo or in vitro production.
19
Date Recue/Date Received 2022-11-04

Also, by way of example, a gene is isolated when separated from open reading
frames which flank the gene and
= encode a protein other than the gene of interest.
1001411 A "metabolite" of a compound disclosed herein is a derivative of
that compound that is formed when
the compound is metabolized. The term "active metabolite" refers to a
biologically active derivative of a compound
that is formed when the compound is metabolized. The term "metabolized," as
used herein, refers to the sum of the
processes (including, but not limited to, hydrolysis reactions and reactions
catalyzed by enzymes, such as, oxidation
reactions) by which a particular substance is changed by an organism. Thus,
enzymes may produce specific
structural alterations to a compound. For example, cytochrome P450 catalyzes a
variety of oxidative and reductive
reactions while uridine diphosphate glucuronyl transferases catalyze the
transfer of an activated glucuronic-acid
molecule to aromatic alcohols, aliphatic alcohols, carboxylic acids, amines
and free sulfhydryl groups. Further
information on metabolism may be obtained from The Pharmacological Basis of
Therapeutics, 9th Edition,
McGraw-Hill (1996). Metabolites of the compounds disclosed herein can be
identified either by administration of
compounds to a host and analysis of tissue samples from the host, or by
incubation of compounds with hepatic cells
in vitro and analysis of the resulting compounds. Both methods are well known
in the art. In some embodiments,
metabolites of a compound are formed by oxidative processes and correspond to
the corresponding hydroxy-
containing compound. In some embodimets, a compound is metaboli7Pd to
pharmacologically active metabolites.
1001421 The term "modulate," as used herein, means to interact with a
target either directly or indirectly so as
to alter the activity of the target, including, by way of example only, to
eehance the activity of the target, to inhibit
the activity of the target, to limit the activity of the target, or to extend
the activity of the target
10014311 .. As used herein, the term "modulator" refers to a compound that
alters an activity of a molecule. For
example, a modulator can cause an increase or decrease in the magnitude of a
certain activity of a molecule
compared to the magnitude of the activity in the absence of the modulator. In
certain embodiments, a modulator is.
an inhibitor, which decreases the magnitude of one or more activities of a
molecule. In certain embodiments, an
inhibitor completely prevents one or more activities of a molecule. In certain
embodiments, a modulator is an
activator, which increases the magnitude of at least one activity of a
molecule. In certain embodiments the presence
of a modulator results in an activity that does not occur in the absence of
the modulator.
1001441 The Willi "prophylactically effective amount," as used herein,
refers that amount of a composition
applied to a patient which will relieve to some extent one or more of the
symptoms of a disease, condition or
disorder being treated. In such prophylactic applications, such amounts may
depend on the patient's state of health,
weight, and the like. It is considered well within the skill of the art for
one to determine such prophylactically
effective amounts by routine experimentation, including, but not limited to, a
dose escalation clinical trial.
1001451 As used herein, the term "selective binding compound" refers to a
compound that selectively binds to
any portion of one or more target proteins.
1001461 As used herein, the term "selectively binds" refers to the ability
of a selective binding compound to
bind to a target protein, such as, for example, Btic, with greater affinity
than it binds to a non-target protein. In
certain embodiments, specific binding refers to binding to a target with an
affinity that is at least 10,50, 100, 250,
500, 1000 or more times greater than the affinity for a non-target.
1001471 As used herein, the term "selective modulator" refers to a
compound that selectively modulates a target
activity relative to a non-target activity. In certain embodiments, specific
modulater refers to modulating a target
activity at least 10, 50, 100, 250, 500, 1000 times more than a non-target
activity.
1001481 The term "substantially purified," as used herein, refers to a
component of interest that may be
substantially or essentially free of other components which normally accompany
or interact with the component of'
Date Recue/Date Received 2022-11-04

interest prior to purification. By way of example only, a component of
interest may be "substantially purified" when
the preparation of the component of interest contains less than about 30%,
less than about 25%, less than about 20%,
less than about 15%, less than about 10%, less than about 5%, less than about
4%, less than about 3%, less than
about 2%, or less than about 1% (by dry weight) of contaminating components.
Thus, a "substantially purified"
component of interest may have a purity level of about 70%, about 75%, about
80%, about 85%, about 90%, about
95%, about 96%, about 97%, about 98%, about 99% or greater.
[001491 The term "subject" as used herein, refers to an annual which is
the object of treatment, observation or
experiment. By way of example only, a subject may be, but is not limited to, a
mammal including, but not limited to,
a human.
(00150) As used herein, the term "target activity" refers to a biological
activity capable of being modulated by
a selective modulator. Certain exemplary target activities include, but are
not limited to, binding affinity, signal
transduction, enzymatic activity, Minor growth, inflammation or inflammation-
related processes, and amelioration
of one or more symptoms associated with a disease or condition.
1001511 As used herein, the term "target protein" refers to a molecule or
a portion of a protein capable of being
bound by a selective binding compound. In certain embodiments, a target
protein is Btk.
[001521 The terms "treat," "treating" or "treatment", as used herein,
include alleviating, abating or ameliorating
a disease or condition symptoms, preventing additional symptoms, ameliorating
or preventing the underlying
metabolic causes of symptoms, inhibiting the disease or condition, e.g.,
arresting the development of the disease or
condition, relieving the disease or condition, causing regression of the
disease or condition, relieving a condition
caused by the disease or condition, or stopping the symptoms of the disease or
condition. The terms "treat,"
"treating" or "treatna.nr, include, but are not limited to, prophylactic
and/or therapeutic treatments.
[001531 As used herein, the ICso refers to an amount, concentration or
dosage of a particular test compound that
achieves a 50% inhibition of a maximal response, such as inhibition of Btk, in
an assay that measures such response.
1001541 As used herein, EC50 refers to a dosage, concentration or amount
of a particular test compound that
elicits a dose-dependent response at 50% of maximal expression of a particular
response that is induced, provoked
or potentiated by the particular test compound.
BRIEF DESCRIPTION OF THE FIGURES
1001551 Fig. 1 presents a sequence comparison of Btk with other tyrosine
kinases.
1001561 Fig. 2 presents illustrative cell data regarding inhibition ofB
cell receptor induced Fhospholipase-ey
phosphorylation by compound 4. In this example, there were 2E6 Ramos
cells/well in serum free media; the cells
were pretreated with compound for 1.5 hr. The B cell receptor was stimulated
with anti-IgM for 3 min; the 10X lysis
buffer containing DNAse was added directly to cells. The sample buffer was
suirle.d and loaded directly on geL The
samples were analyzed with western blot - phosphorylated Btk and PLOyl and
total Btk and PLOyl. The blot was
imaged with ChemiDoo CCD and quantitated with ImageQuant. The phosphorylated
band was normalized to total
band and the IC50 was calculated.
(00157) Fig. 3 presents illustrative cell data showing that compound 4 and
compound 15 inhibit growth of
DHL-6 cells. In this example, there were 3E4 DHL-6 cells/well in complete
media. The cells were treated for the
indicated time with compound (4) 0.1% DMSO final concentration. The cell
number was measuured using Alarnar
Blue assay according to standard protocol.
1001581 Fig. 4 presents illustrative mass spectra showing that compound 4
covalently modifies Btk. In this
example, Incubate 30uM compound 4 with 6-7uM recombinant BTIC ( Y->D mutant,
kinase domain only) overnight
=
21
Date Recue/Date Received 2022-11-04

at E.T. Desalt protein-inhibitor complex by reversed-phase IIPLC and analyze
directly in masa spec to determine
molecular weight. >99% of recombinant Blic protein is covalently modifiedby
compound 4. I
100159) Fig. 5 presents illustrative inhibition of arthritis development
in a mouse model by compound 4.
100160) Fig. 6 memento illustrative data demonstrating that the efficacy
of compound 41* associated with
reduction of Rheumatoid Factor and Anti-citnillinated cyclic peptide
antibodies in the CATA model. In these
exansples. *p<0.01; **p<0.001 vs vehicle or saline treatment
100161] Fig. 7 presents illustrative data regarding the inhibition of
arthritis development in smearee model bY
compound 13. 'This enandosner of compound 4 completed inhibited the
development of arthritis in the CA.1A model
at dose levels of 10 and 30 mg/kg. For comparison, data reminding inhibition
of arthritis development in the =MC
mouse model is presented for dexamethasove.
100162] ,
DETAILED DESCRIPTION OF THE INVENTION
100163] The methods described herein include administering to a subject in
need a composition containing a
therapeutically effective amount of one or more irreversible Btk inhibitor
compounds described herein. Without
being bound by theory, the diverse roles played by Mk signaling in various
hemstopoietic cell functions, e.g., B-cell
receptor activation, suggests that small molecule Btk inhibitors are useful
for reducing the risk of or treating a
variety of diseases affected by or affecting many cell types of the
hematoprietic lineage including e.g., autoimmune
diseases, leteroimmuile conditinns or diseases, inflammatrsy ____ cancer
(e.g., B-cell proliferative disorders),
and thromboembolic disorders. Further, the irreversible Btk inhibitor
compounds described herein can be Used to
inhibit a small subset of other tyrosine biasses that share hom*ology with Btk
by having a cysteine residue (including
a Cys 481 residue) that can form a covalent bond with the irreversible
inhibitor. See, e.g., protein kinlicr3 in 1:10.1.
Thius, a subset of tyrosine kinetics other than 336r are also expected to be
useful as therapeutic targets in a number of
health conditions.
100164l In some embodiments, the methods described herein can.be used to
treat an autoimmune disease,
which includes, but is not limited to, rhairoatold arthritis, pietistic
arthritis, osasoardnitis, Still's dite.te, juvenile
arthritis, lupus, diabetes, myasthenia gravis, Hashimoto's thyroiditis. Ord' s
thyroiditis, Graves' disease Sjogren's
syndrome, multiple sclerosis, Gnillain-Bane syndrome, acute disseminated
encephikmyelitis, Additon's disease,
opsoclonus-myoclorms syndrome, antylosing spondylitisis, endphospholipid
antibody syndrome, aplastic anemia,
autoimniune lepatitiµcoeliac disease, Goodpasture's syndrome, Idiopathic
thrornbocytopenic purpura, optic
neuritis, sclerodenna, primary biliary cinimsis, Reliefs syndrome, Takayasu's
arteritis, temporal arteritis, warm
airtoimraune hemolytic anemia, Wegener's grarationiatosis, psoriasis, alopecia
univinsalis..Belmers dic=-agar, chronic
fatigue, dysautonomia, endonietriosis, interstitial cystitis, neunuoyotonia,
sclerodemia, and velvodynia.
100165] In some embodiments, the methods described herein can be used to
treat heteroimmtme conditions or
di.ipaare, which include, but are not limited to graft versus host disease,
transplantation, transfusion, anaphylaxis,
allergies (e.g., allergies to plant poll.us, latex, drugs, foods, insect
poisons, animal hair, animal dander, dust mites,
or co*ckroach calyx). type 1.hypersensitivity, allergic oinjunctivitis' ,
allergic rhinitis, and atopic dermatitis
100166] In further
embodiments, the methods described herein can be used to treat an inflammatory
disease,
which includes, bat is not limited to asthma, inflammatory bowel disease,
appendioitie. bielshatida.
22
Date Recue/Date Received 2022-11-04

bronchitis, bursitis, oervicitis, cholangitis, cholecystitis, colitis,
conjunctivitis, cystitis, damyoadenitis, dermatitis,
derin. atomyositis, encephalitis, endocarditie, endometritis, enteritis,
enterocolitis, epicondylitis, epididymitia,
fascl*tis, fibrositis, gastritis, gastroenteritis, hepatitis, hidradenitis
suppurative, laryngitis, mastitis, meningitis,
myelitis myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis,
otitis, pancreatitis, parotitis, pericarditis,
peritonitis, pharyngitis, pleuritis, phlebitis, pneumonitis, pneumonia,
proctitis, prostatitis, pyelonephritis, rhinitis,
salpingitis, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis,
uveitis, vaginitis, vasculitis, and vulvitis.
1001671 In yet other embodiments, the methods described herein can be used
to treat a cancer, e.g., B-cell
proliferative disorders, which include, but are not limited to diffuse large B
cell lymphoma, follicular lymphoma,
chronic lynaphocytic lymphoma, chronic lymphocric leukemia, B-cell
prolymphocytic leukemia,
lymphoplasmacric lymphomatWaldenstrom macroglobulinemia, splenic marginal zone
lymphoma, plasma cell
myeloma, plasmacytoma, extranodal marginal zone B cell lymphoma, nodal
marginal zone B cell lymphoma,
mantle cell lymphoma, mediastinal (thymic' ) large B cell lymphoma,
ireravascular large B cell lymphoma, primary
effusion lymphoma, burkitt lymphounitleukemia, and lymphomatoid
granulomatosis.
(00168] In further embodiments, the methods described herein can be used
to treat thromboembolic disorders,
which include, but are not limited to myocardial infarct, angina pectoris
(including unstable angina), reocclusions or
restemoses after angioplasty or aortocoronary bypass, stroke, transitory
ischemia, peripheral arterial occlusive
disorders, pulmonary embolisms, and deep venous thromboses.
1001691 Symptoms, diagnostic tests, and prognostic tests for each of the
above-mentioned conditions are
known in the art. See, e.g., Harrison's Principles of Internal hfedidne ,"
16th ed., 2004, The McGraw-Hill
Companies, Inc. Dey eta]. (2006), Cytojournal 3(24), and the "Revised European
American Lymphoma" (REAL)
classification system (see, e.g., the website maintained by the National
Cancer Institute).
1001701 A number of animal models of are useful for establishing a range
of therapeutically effective doses of
irreversible Mk inhibitor compounds for treating any of the foregoing
diseases.
10017111 For example, dosing of irreversible Btk inhibitor compounds for
treating an autoimmune disease can
be assessed in a mouse model of rheumatoid arthitis. In this model, arthritis
is induced in Balbk mice by
administering anti-collegen antibodies and lipopolysaccharide. See Nandakumar
et al. (2003), Am. J Patkol
163:1827-1837.
1001721 In another example, dosing of irreversible Btk inhibitors for the
treatment of B-cell proliferative
disorders can be examined in, e.g., a human-to-mouse xenograft model in which
human B-cell lymphoma cells (e.g.
RIIM03 cells) are implanted into hnrawiodefficient mice (e.g., "nude" mice) as
described in, e.g., Pagel et al. (2005),
Clin Cancer Res 11(13):4857-4866.
[001731 Animal models for treatment of thromboembolic disorders are also
known.
(001741 The therapeutic efficacy of the compound for one of the foregoing
diseases can be optimized during a
course of treatment. For example, a subject being treated can undergo a
diagnostic evaluation to correlate the relief
of disease symptoms or pathologies to inhibition of in vivo Btk activity
achieved by administering a given dose of an .
irreversible Mk inhibitor. Cellular assays known in the art can be used to
determine in vivo activity of Btk in the
presence or absence of an irreversible Btk inhibitor. For example, since
activated Btk is phosphorylated at tyrosine
223 (Y223) and tyrosine 551 (Y551), phospho-specific immunocytochetnical
staining of P-Y223 or P-Y551-positive
cells can be used to detect or quantify activation of Bid in a population of
cells (e.g., by FACS analysis of stained vs
unstained cells). See, e.g., Nisitani et a/. (1999), Proc. Natl. Acad. Sc; USA
96:2221-2226. Thus, the amount of the
Btk inhibitor inhibitor compound that is administered to a subject can be
increased or decreased as needed so as to
maintain a level of Btk inhibition optimal for treating the subject's disease
state.
23
Date Recue/Date Received 2022-11-04

Compounds
1001751 In the following description of irreversible Mk compounds suitable
for use in the methods described
herein, definitions of referred-to standard chemistry terms may be found in
reference works (if not otherwise defined
herein), including Carey and Sundberg "Advanced Organic Chemistry 4th Ed."
Vols. A (2000) and B (2001),
Plenum Press, New York. Unless otherwise indicated, conventional methods of
mass spectroscopy, NMR, HPLC,
protein chemistry, biochemistry, recombinant DNA techniques and pharmacology,
within the ordinary skill of the
art are employed. In addition, nucleic acid and amino acid sequences for Btk
(e.g., human Btk) are known in the art
as disclosed in, e.g., U.S. Patent No. 6,326,469. Unless specific definitions
are provided, the nomenclature employed
in connection with, and the laboratory procedures and techniques of,
analytical chemistry, synthetic organic
chemistry, and medicinal and pharmaceutical chemistry described herein are
those known in the art. Standard
techniques can be used for chemical syntheses, chemical analyses,
pharmaceutical preparation, formulation, and
delivery, and treatment of patients
1001761 The Btk inhibitor compounds described herein are selective for Mk
and lcinases having a cysteine
residue in an amino acid sequence position of the tyrosine kinase that is
hom*ologous to the amino acid sequence
position of cysteine 481 in Btk. See, e.g., kinases in FIG. 1. Inhibitor
compounds described herein include a Michael
acceptor moiety.
[001771 Generally, an irreversible inhibitor compound of Btk used in the
methods described herein is identified
or characterized in an in vitro assay, e.g., an acellular biochemical assay or
a cellular functional assay. Such assays
are useful to determine an in vim? ICse for an irreversible Mk inhibitor
compound.
[001781 For example, an acellular kinase assay can be used to determine Btk
activity after incubation of the
kinase in the absence or presence of a range of concentrations of a candidate
irreversible Btk inhibitor compound. If
the candidate compound is in fact an irreversible Btk inhibitor, Btk kinase
activity will not be recovered by repeat
washing with inhibitor-free medium. See, e.g., J. B. Small], etal. (1999), J.
Med. Chem,. 42(10):1803-1815. Further,
covalent complex formation between Btk and a candidate irreversible Btk
inhibitor is a useful indicator of
irreversible inhibition of Btk that can be readily determined by a number of
methods known in the art (e.g., mass
spectrometry). For example, some irreversible Btk-inhibitor compounds can form
a covalent bond with Cys 481 of
Mc (e.g., via a Michael reaction).
[001791 Cellular functional assays for Btk inhibition include measuring
one or more cellular endpoints in
response to stimulating a Btk-mediated pathway in a cell line (e.g., BCR
activation in Ramos cells) in the absence or
presence of a range of concentrations of a candidate irreversible Btk
inhibitor compound. Useful endpoints for
determining a response to BCR activation include, e.g., autophosphorylation of
Btk, phosphorylation of a Btk target
protein (e.g., PLC-y), and cytoplasmic calcium flux.
[001801 High throughput assays for many acellular biochemical assays
(e.g., kinase assays) and cellular
functional assays (e.g., calcium flux) are well known to those of ordinary
skill in the art. In addition, high
throughput screening systems are commercially available (see, e.g., Zymark
Corp., Hopkinton, MA; Air Technical
Industries, Mentor, OH; Beckman Instruments, Inc. Fullerton, CA; Precision
Systems, Inc., Natick, MA, etc.). These
systems typically automate entire procedures including all sample and reagent
pipetting, liquid dispensing, timed
incubations, and final readings of the microplate in detector(s) appropriate
for the assay. Automated systems thereby
allow the identification and characterization of a large number of
irreversible Btk compounds without undue effort. .
[00181] Irreversible Btk inhibitor compounds can used for the manufacture
of a medicament for treating any of
the foregoing conditions (e.g., autoimmune diseases, inflammatory diseases,
allergy disorders, B-cell proliferative
disorders, or thromboembolic disorders).
24
=
Date Recue/Date Received 2022-11-04

(001821 In some embodiments, the irreversible Btk inhibitor compound used
for the methods described herein
inhibits Btk or a Btk hom*olog kinase activity with an in vitro IC50 of less
than 10 AM. (e.g., less than 1 M, less than
0.5 ILM, less than 0.4 AM, less than 0.3 aM, less than 0.1, less than 0.08 AM,
less than 0.06 p.M, less than 0.05 AM,
less than 0.04 AM, less than 0.03 a.M, less than less than 0.02 AM, less than
0.01, less than 0.008 aM, less than 0.006
AM, less than 0.005 p.M, less than 0.004 tiM, less than 0.003 aM, less than
less than 0.002 M, less than 0.001, less
than 0.00099 /AM, less than 0.00098 AM, less than 0.00097 aM, less than
0.00096 /AM, less than 0.00095 AM, less
than 0.00094 pivI, less than 0.00093 p.M, less than 0.00092, or less than
0.00090 ah4).
[001831 In one embodiment, the irreversible Btk inhibitor compound
selectively and irreversibly inhibits an
activated form of its target tyrosine kinase (e.g., a phosphorylated form of
the tyrosine kinase). For example,
activated Btk is transphosphorylated at tyrosine 551. Thus, in these
embodiments the irreversible Bdc inhibitor
inhibits the target kinase in cells only once the target kinase is activated
by the signaling events.
1001841 Described herein are compounds of any of Formula (A), Formula (B),
Formula (C), or Formula (D).
Also described herein are pharmaceutically acceptable salts, pharmaceutically
acceptable solvates, pharmaceutically
active metabolites, and pharmaceutically acceptable prodrugs of such
compounds. Pharmaceutical compositions that
include at least one such compound or a pharmaceutically acceptable salt,
pharmaceutically acceptable solvate,
pharmaceutically active metabolite or pharmaceutically acceptable prodrug of
such compound, are provided. In
some embodiments, when compounds disclosed herein contain an oxidizable
nitrogen atom, the nitrogen atom can
be converted to an N-oxide by methods well known in the art. In certain
embodiments, isomers and chemically
protected farms of compounds having a structure represented by any of Formula
(A), Formula (B), Formula (C), or
Formula (D), are also provided.
1001851 In one aspect arc compounds of Formula (A), pharmaceutically
acceptable salts, pharmaceutically
active metabolites, pharmaceutically acceptable prodrugs, and pharmaceutically
acceptable solvates thereof.
Formula (A) is as follows:
R3- N..R2
N
A
N
"4 Formula (A)
.. wherein
A is independently selected from N or CR5;
R1 is H, L2-(substituted or =substituted alkyl), L2-(substituted or
unsubstituted cycloalkyl), Lr(substituted or
=substituted alkenyl), Lr(substituted or =substituted cycloalkenyl), L2-
(substituted or unsubstituted
heterocycle), L2-(substituted or unsubstituted heteroaryl), or L2-(substituted
or =substituted aryl), where L2
. 30 = is a bond, 0, S, -S(=0), -S(=D)2, C(=0), -(substituted or
=substituted C1-C6 alkyl), or -(substituted or
unsubstituted C2-C6 alkenyl);
R2 and R3 are independently selected from H, lower alkyl and substituted lower
alkyl;
R4 is L3-X-L4-G, wherein,
L3 is optional, and when present is a bond, optionally substituted or
unsubstituted alkyl, optionally
substituted or unsubstituted cycloalkyl, optionally substituted or
=substituted alkenyl, optionally
substituted or unsubstituted alkynyl;
X is optional, and when present is a bond, 0, S, -S(:))2, -NH, -NR9,
-NHC(0), -C(0)NH,
-NR9C(0), -C(0)NR9, -5(=0)2NH, -NHS(=0)2, -5(0)2NR9-, -NR9S(=0)2, -0C(0)NH-, -
NHC(0)0-,
Date Recue/Date Received 2022-11-04

=
-O(0)NR-, -NR9C(0)0-, -CH=NO-, -ON=CH-, -NRI0C(0)NR10-, heteroaryl, aryl, =
N11.10C(=NR,I)NR10-, -N12.10C(=NR11)-= -C&NRI1)NR10-, -0C(=NR11)-, or
Loa is optional, and when present is a bond, substituted or unsubstituted
alkyl, substituted or unsubstituted
cycloallcyl, substituted or unsubstituted alkenyl, substituted Or
unsubstituted allcynyl, substituted or
=substituted aryl, substituted or unsubstituted heteroaryl, substituted or
unsubstituted heterocycle;
or Le, X and 1.4 taken together form a nitrogen containing heterocyclic ring;
0 Re R6 9 Ra 9 Re
0
\ R7 \ R7 r, rµ.7
G. is 7
R8 R8 ,or
, wherein,
R6o R7 and Re are independently selected from among H, lower alkyl or
substituted lower alkyl, lower
heteroalkyl or substituted lower heteroalkyl, substituted or =substituted
lower cycloalkyl, and
substituted or unsubstituted lower heterocycloallcyl;
Re is H, halogen, -L6-(substituted or =substituted C1-C3 alkyl); -L6-
(substituted or unsubstituted C2-C4 alkenyl),
-L6-(substituted or unsubstituted heteroaryl), or -L6-(substituted or
unsubstituted aryl), wherein Le is a
bond, 0, S, S(=0)2, NH, C(0), -NHC(0)0, -0C(0)NH, -NHC(0), or -
C(0)NH;
each Re is independently selected from among H, substituted or =substituted
lower alkyl, and substituted or
unsubstituted lower cycloallcyl;
each R10 is independently H, substituted or unsubstituted lower alkyl, or
substituted or unsubstituted lower
cycloalkyl; or
two Rio groups can together form a 5-, 6-, 7-, or 8-membered heterocyclic
ring; or
Re and R10 can together form a 5-, 6-, 7-, or 8-membered heterocyclic ring; or
each R11 is independently selected from H, -S(=0)2R5, -S(-0)2NH2, -C(0)Rs, -
CN, -NO2, heteroaryl, or
heteroalkyl; and
pharmaceutically active metabolites, pharmaceutically acceptable solvates,
pharmaceutically acceptable salts, or
pharmaceutically acceptable prodrugs thereof.
[001861 In a further or alternative embodiment, the compound of Formula
(A) has the following structure of
.. Formula (B):
Ra
Ra
R
Ra a
NH2
Ra
N
ii N
R12-N'
Formula (B)
wherein:
Y is alkyl or substituted alkyl, or a 4-, 5-, or 6-membered cycloalkyl ring;
each Rõ is independently H, halogen, -CF3, -CN, -NO2, OH, NH2, -L,-
(substituted or unsubstituted alkyl), -La-
(substituted or unsubstituted alkenyl), -1,-(substituted or unsubstituted
heteroaryl), or -L,-(substituted or
unsubstituted aryl), wherein La is a bond, 0, S, -3(=0), -S(-0)2, NH, C(0),
CH2, -NHC(0)0, -NHC(0), or
-C(0)NH;
26
Date Reeue/Date Received 2022-11-04

0 Rs 0 R6 9 RB
0R7
\ R7 \ yk R7
R20
Re \ ==''' R6 R8 R8 R8
G is , or , wherein,
R6, R7 and Rs are independently selected from among H, lower alkyl or
substituted lower alkyl, lower
heteroalkyl or substituted lower heteroalkyl, substituted or unsubstituted
lower cycloalkyl, and substituted '
or unsubstituted lower heterocycloalkyl;
R12 is H or lower alkyl; or
Y and R12 taken together form a 4-, 5-, or 6-membered heterocyclic ring; and
pharmaceutically acceptable active metabolites, pharmaceutically acceptable
solvates, pharmaceutically
acceptable salts, or pharmaceutically acceptable prodrugs thereof.
=
1001871 In further or alternative
embodiments, G is selected from among 0 , 0
0 0 , 0
, and C)/
Y.N= R12
1001881 In further or alternative embodiments, =========
is selected from among
I:11)
/
N>, HN , and
, . ,
100189] In further or alternative embodiment, the compound of Formula (B)
has the following structure of
Formula (C):
*
NH2
N
=N
N
R12-N"
S Formula (C)
Y is alkyl or substituted alkyl, or a 4-, 5-, or 6-membered cycloalkyl ring;
R12 is H or lower alkyl; or
Y and R12 taken together form a 4-, 5-, or 6-membered heterocyclic ring;
0 Rs 00R6 9 R6
0
Re
\All,R7 R7 \ R7 Ft-2011R
G is Rs Re wherein,
R6, R7 and Rs are independently selected from among H, lower alkyl or
substituted lower alkyl, lower
heteroalkyl or substituted lower heteroalkyl, substituted or unsubstituted
lower cycloalkyl, and substituted
or =substituted lower heberrocycloalkyl; and
27
Date Recue/Date Received 2022-11-04

pharmaceutically acceptable active metabolites, pharmaceutically acceptable
solvates, pharmaceutically
acceptable salts, or pharmaceutically acceptable prodmgs thereof.
1001901 In a further or alternative embodiment, the "G" group of any of
Formula (A), Formula (B), or Formula
(C) is any group that is used to tailor the physical and biological properties
of the molecule. Such
tailoring/modifications are achieved using groups which modulate Michael
acceptor chemical reactivity, acidity,
basicity, lipophilicity, solubility and other physical properties of the
molecule. The physical and biological
properties modulated by such modifications to G include, by way of example
only, enhancing chemical reactivity of
Michael acceptor group, solubility, in vivo absorption, and in vivo
metabolism. In addition, in vivo metabolism may
include, by way of example only, controlling in vivo PK properties, off-target
activities, potential toxicities
associated with cypP450 interactions, drug-drug interactions, and the like.
Further, modifications to (3 allow for the
tailoring of the in vivo. efficacy of the compound through the modulation of,
by way of example, specific and non-
specific protein binding to plasma proteins and lipids and tissue distribution
in vivo.
100191) In a further embodiment are compounds having the structure of
Formula (D):
Ar
Ni12
kNI 7
Re
Formula (D)
wherein
La is CH, 0, NH or S;
Ar is an optionally substituted aromatic carbocycle or an aromatic
heterocycle;
Y is an optionally substituted alkyl, heteroalkyl, carbocycle, heterocycle, or
combination thereof,
Z is C(0), OC(0), NHC(0), C(S), S(0)õ, OS(0),õ NI1S(0)õ, where x is 1 or 2;
and
Rd, R7, and Rs are independently selected from H, alkyl, heteroalkyl,
carbocycle, heterocycle, or combinations
thereof.
100192] Ian further or alternative embodiment, La is 0.
100193] In a further or alternative embodiment, Ar is phenyl.
1001941 In a further or alternative embodiment, Z is C(0).
100195] In a further or alternative embodiment, each of RI, R2, and R3 is
H.
1001961 In another embodiment, provided herein is a compound of Formula
(1)). Formula (D) is as follows:
28
Date Recue/Date Received 2022-11-04

a
L'r Ar .
=
NFI2
it hf
N ...
I
lk,
i--118 - R7 Formula (D)
wheriehe
L. is CH2, 0, NH or S;
Ar is a substituted or unsubstituted aryl, or a substituted or =substituted
heteroaryl;
Y is an optionally substituted group selected from among alkyl, heteroalkyl,
cycloalkyl, heterocycloalkyl,
aryl, and heteroaryl;
Z is C(=0), 0C(=0), NHC(=0), C(=S), S(0), OS(=0)., NHS(=0),õ where xis 1 or 2;
R7 and Re are independently selected from among H, unsubstituted CI-Cealicyl,
substituted CI-Colkyl,
=substituted C1-C4heteroalkyl, substituted CrCeheteroallcyl, unsubstituted C3-
Cecycloa1kyl,
substituted C3-Cecycloalky1, unsubstituted C-rC.heterocycloalkyl, and
substituted C2-
Coheterocycloalkyl; or
R.7 and Re taken together form a bond;
Re is H, substituted or =substituted Ci-Cealkyl, substituted or =substituted
CI-Cebetemalkyl, Ct-
reellroxyalltyl, C1-Cealkylaminoalkyl, substituted or unsubstituted C3-
C6cycloalkyl, substituted or
unsubstituted aryl, substituted or unsubstituted C2-C1heterocycloalkyl,
substituted or unsubstituted
heteroaryl, C1-CealkYkarYI), C1-Cealkyl(heteroary1), C1-Cealkyl(C3-
Cecycloalkyl), or CresalkykCe-
Csbeterocycloalkyl); and
pharmaceutically active metabolites, or pharmaceutically acceptable solvates,
pharmaceutically acceptable salts, or
pharmaceutically acceptable prodrugs thereof. =
1001971 For any and all of the embodiments, substituents can be selected
from among from a subset of the
listed alternatives. For example, in some embodiments, L. is CH2, 0, or NH. In
other embodiments, L. is 0 or NH.
In yet other embodiments, L. is O.
1001981 In some embodiments. Ar is a substituted or =substituted aryl. In
yet other embodiments, Ar is a 6-
membered aryl. In some other embodiments, Ar is phenyL
100199] In some embodiments, x is 2. In yet other embodiments, Z is C(=0),
0C(=0), NHC(=0), S(=0).,
OS(=0)., or NHS(-0).. In some other embodiments, Z is C(D), NHC(=0), or S(-
0)2. .
[002001 In some embodiments, 12.7 and Re are independently selected from
among H, =substituted C1-C4 alkyl,
Substituted CI-Cialkyl, unsubstituted C1-C4heteroallcyl, and substituted C1-
C4heteroalltyl; or R7 and Re taken
together form a bond. In yet other embodiments, each of RI and R. is H; or R7
and Re taken together form a bond.
(002011 In some embodiments, R6 is H, substituted or unsubstituted CI-
C.alkyl, substituted or unsubstituted C1-
C.heteroalkyl, CrCealkoxyalkyl, C1-C2alkyl-N(C1-C3allcyl)2, substituted or
unsubstituted aryl, substituted or
unsubstituted heteroaryl, CI-C4alkykary1), CI-C4ilkyl(heteroary1), C1-
Cealkyl(C3-C1cycloallcyl), or CI-C4a1icyl(C.2-
Ceheterocycloalkyl). In some other embodiments, R6 is H, substituted or
unsubstituted CI-C4alkyl, substituted or
29
Date Recue/Date Received 2022-11-04

=
. unsubstituted CrC4heteroa1kyl, CrC6a1koxyalkyl, CrC2alkyl-
N(CrC3allcyl)2, CrC4allcyl(ary1), C1-
C4alkyl(heteroary1), CrC4a1kyl(C3-C3cycloalkyll, or CrC4alkyl(C2-
C3heterocycloalkyl). In yet other embodiments,
Itµ is H, substituted or unsubstituted C1-C4allcyl, -CH2-0-(C1-C3alkyll, -CH2-
N(C1-C3alky1)2, CrCoallcyl(phenyl), or
C1-C4alicy1(5- or 6-membered heteroaryl). In some embodiments, R6 is H,
substituted or unsubstituted C1-C4alkyl, -
C112-0-(C1-C3alky1), -C112-N(C1-C3alky1)2, CI-C4allcyl(phenyl), or C1-
e4alky1(5- or 6-membered heteroaryl
containing 1 or 2 N atoms), or CI-C4allcy1(5- or 6-membered heterocycloalkyl
containing 1 or 2 N atoms).
100202) In some embodiments, Y is an optionally substituted group
selected from among alkyl, heteroalkyl,
cycloallcyl, and heterocycloalkyl. In other embodiments, Y is an optionally
substituted group selected from among
01-C.6allcyl, CrC6lieteroalkyl, 4-, 5-, 6-or 7-membered cycloalkyl, and 4-, 5-
,6- or 7-membered heterocycloalkyl. In
yet other embodiments, Y is an optionally substituted group selected from
among CrColkyl, C1-C6heteroallcyl, 5-,
or 6-membered cycloalkyl, and 5-, or 6-membered heterocycloalkyl containing 1
or 2 N atoms. In some other
embodiments, Y is a 5-, or 6-membered cycloallcyl, or a 5-, or 6-membered
heterocycloalkyl containing 1 or 2 N
atoms.
100203] Any combination of the groups described above for the various
variables is contemplated herein. It is
understood that substituents and substitution patterns on the compounds
provided herein can be selected by one of
ordinary skill in the art to provide compounds that are chemically stable and
that can be synthesized by techniques
known in the art, as well as those set forth herein.
100204) Further embodiments of compounds of Formula (A), Formula (B),
Formula (C), Formula (D), include,
but are not limited to, compounds selected from the group consisting of .
=-0 o it
_0 ..õ,
NH2 NH2 * 1r12 NH2 0 NH2 *
N N
* .-0
0 0-0
o 40 ¨ .
NH2 NH216 NH2 * NH2
NH2 N -", N --=== , N *".= . N
N -`=== kN N (1.N " It.N 1' k "
N
vs. N
-- /
N N." 0 4?FiN-C.-
/-
= d b , o o . -
o V o * .. o *
NH2
e
isH, . N NH2 * NH2 NH2
-",
N t'. N It.N --'' N
N N== N# N N '
i, õ. p ... ti. -, "4 p ..... #
N
N -shr ..__ ..._ -'14 ''', N......
Date Recue/Date Received 2022-11-04

a
o * = 0* 0* * . *
NH2 * NH2 * NH2 * NH2 Q NH2 *
r IC
N -N N
it tr ,N I
N 14;.... 1\4
N ..... H
-.. N N." IL. ,
N N
1 )...._%
N
btl)r......%0".. c....kr,õ.õ. c....h.s....N,
0 o cr 1) t3=t
I .
. . 5
. 0*
*
0* 0*. 0 .
NH2 *
NH2
*
N -`-= NI-12 NH2 *
I, ,N NH2 .
N )N IL S N = N N -`= pl
\ ---N) a u_
-14 N N -N.
.....A N
IL N e
N
b
0 , =
, 0¨,
*it . *
it 0-0
NH, 4* NH2 NH2 NI-12 *
NH2
N
LW-- 7:14 P1, ,N
- N l'IL N NL N Ni
N
õ ..tf-- HNI-44,. , N.y. -%=...,
HN..õ(%,õ,.....w., ,,Ny'"kk.ey
0 0 0 0 I 0
$ . $ . '
0* * 0-0
.1
NH 'WV NH2 NH2 NH2
NH2 * N "-- N
rt.
Lr
N ,N II, N ,N
L.1
ILN t N NL
-.) N isi t N-- Nt
1)
HN.õA,_/-
0 0 0 0 (1-'70
. , $ .
0*
NH2 *
N "... \
,N
li-N Nt
--*)
N,
." A.:::k...õ
and do .
1002051 In still another embodiment, compounds provided herein are selected
from among:
31
Date Recue/Date Received 2022-11-04

2
= *
= 0 * 0* = * = *
NH2
NH2 * NH2 * NH2 * NI-I2 * N **-- \
N --.. \ IC \,N IC \14
ii ..., ,N LL .., fi
...'N N, N Nµ___ NI' N N
C--,14--(- CN-e/ oN-dr"---
Cr % 0_,(7 N
0 0 , = = 9
= *
= * 0* = * = = *
NH2 .1
*
NH2 * NI12
L\ N NH2 * NH2 .
N''. .,.....\Nt U t'l --. \
' '1', ',4 N .."=== \
N...,
N Is! =
ON
HN--C---- ur -, oN-e--- Cs N'-e-----
0* '
NH2 SP
'''',
N \
v .., ,N
-"N
/
r) .
1002061 In one aspect, provided herein is a compound selected from among:
1-(3-(4-amino-3-(4-phenoxypheny1)-)H-pyrazolo[3,4-clipyrimidin-1-y1)piperidin-
1-y1)prop-2-en-1-one (Compound
4); (E)-1-(3-(4-amin' o-3-(4-phenoxypheny1)-1H-pyrazolo[3,4-d]pyrimidin-l-
y1)piperidin-1-y1)but-2-en-1-one
(Compound 5); 1-(3-(4-amino-3-(4-phenoxypheny1)-1H-pyrazolo[3,4-d]pyrimidin-l-
y1)piperidin-1-
y1)sulfonylethene (Compound 6); 1-(3-(4-amino-3-(4-phenoxypheny1)-1H-
pyrazolo[3,4-d]pyrimidin-l-yOpiperidin,
1-yl)prop-2-yn-l-one (Compound 8); 1-(4-(4-amino-3-(4-phenoxypheny1)-1H-
pyrazolo[3,4-d]pyrimidin-1-
yl)piperidin-1-yl)prop-2-en-1-one (Compound 9); N-((1s,4s)-4-(4-amino-3-(4-
phenoxypheny1)-111-pyrazolo[3,4-
d]pyrimidin-1-y1)cyclohexyl)acrylamide (Compound 10); 14(R)-3-(4-amino-3-(4-
phenoxypheny1)-1H-
pyrazolo[3,4-d]pyrimidin-1 -yl)pyrrolidin-1-yl)prop-2-en-1 -one (Compound 11);
14(S)-3-(4-amino-3-(4-
phenoxypheny1)-1H-pyrazolo[3,4-d]pyrimidin-l-y1)pyrrolidin-1 -yl)prop-2-en-l-
one (Compound 12); 14(R)-3-(4-
mino-3-(4-phenoxypheny1)-1H-pyrazolo[3,4-cl]pyrimidin-1-y1)piperidin-1-y1)proP-
2-en-1-one (Compound 13); 1-
((S)-3-(4- amino-3-(4-phenoxypheny1)-1H-pyrazolo p ,4-cfjpyrimidin-l-
yl)piperidin-l-yl)prop-2-en-l-one
(Compound 14); and (E)-1-(3-(4-amino-3-(4-phenoxypheny1)-1H-pyrazolo[3,4-
d]pyrimidin-l-yl)piperidin-l-y1)-4-
(dimethylarnino)but-2-en-1 -one (Compound 15).
1002071 Throughout the specification, groups and subsfituents thereof can
be chosen by one skilled in the field
. to provide stable moieties and compounds. .
1002081 The compounds of any of Formula (A), or Formula (B), or Formula
(C), or Formula (D) can
irreversibly inhibit 8th and may be used to treat patients suffering from
Bruton's tyrosine kinase-dependent or
32
,
Date Recue/Date Received 2022-11-04

Rruton's tyrosine Idnase mediated conditions or diseases, including, but not
limited to, cancer, autoimmune and
other inflammatory diseases.
Preparation of Compounds
(002091 Compounds of any of Formula (A), (B), (C) or (D) may be synthesized
using standard synthetic
techniques known to those of skill in the art or using methods known in the
art in combination with methods
described herein. In additions, solvents, temperatures and other reaction
conditions presented herein may vary
according to those of skill in the art. As a further guide the following
synthetic methods may also be utilized.
1002101 The reactions can be employed in a linear sequence to provide the
compounds described herein or they
may be used to synthesize fragments which are subsequently joined by the
methods described herein and/or known
in the art.
Formation of Covalent Linkages by Reaction of an Electrophile with a
Nucleophile
1002111 The compounds described herein can be modified using various
electrophiles or nucleophiles to form
new functional groups or substituents. Table 1 entitled "Examples of Covalent
Linkages and Precursors Thereof'
lists selected examples of covalent linkages and precursor functional groups
which yield and can be used as
guidance toward the variety of electrophiles and nucleophiles combinations
available. Precursor functional groups
are shown as electrophilic groups and nucleophilic groups.
Table 1: Examples of Covalent Linkages and Precursors Thereof
Covalent-LinkapPrOdneV,=,;;/=,:l'..,:40.Eteilttoplilleiii:.,, = = .*:j.
Nucleophile
Carboxamides Activated esters amines/anilines
Carboxamides acyl azides amines/anilines
Carboxamides acyl halides amines/anilines
Esters acyl halides alcohols/phenols
Esters acyl nitriles alcohols/phenols
Carboxamides acyl niniles amines/anilines
manes Aldehydes amines/anilines
Hydrazones aldehydes or ketones Hydrazines
Oximes aldehydes or ketones Hydroxylamines
Alkyl amines alkyl halides amines/anilines
Esters alkyl halides carboxylic acids
Thioethers alkyl halides Thiols
Ethers alkyl halides alcohols/phenols
Thioethers alkyl sulfonates Thiols
Esters alkyl sulfonates carboxylic acids
Ethers alkyl sulfonates alcohols/phenols
Esters Anhydrides alcohols/phenols
Carboxamides Anhydrides amines/anilines
'Thiophenols aryl halides Thiols
Aryl amines aryl halides Amines
Thioethers Azindines Thiols
Boronate esters Boronates Glycols
Carboxamides carboxylic acids amines/anilines
Esters carboxylic acids Alcohols
hydrazines Hydrazides carboxylic acids
N4cylureas or Anhydrides carbodiimides carboxylic acids
Esters diazoallcanes carboxylic acids
Thioethers Epoxides Thiols
Thioethers baloacetamides Thiols
Ammotriazines halotriazin.es amines/anilines
Triazinyl ethers haloniazines alcohols/phenols
Amidines imido esters amines/anilines
=
Ureas Isocyanates amines/anilines
Urethanes Isocyanates alcohols/phenols
Thioureas isothiocyanates amines/anilines
33
Date Recue/Date Received 2022-11-04

Thioethers Maleimides Thiols
Phosphite esters phosphorarnidites Alcohols
Silly1 ethers sily1 halides Alcohols
Alkyl amines sulfonate esters amines/anilines
Thioethers sulfonate esters Thiols
Esters , sulfonate esters carboxylic acids
Ethers sulfonate esters Alcohols
Sulfonamides sulfonyl halides amines/anilines
Su'foliate esters sulfonyl halides phenols/alcohols
.Alkyl thiol c1-unsaturated ester thiols
Allcyl ethers 0-unsaturated ester alcohols
Alkyl amines 0-unsaturated ester amines
Alkyl thiol Vinyl sulfone thiols
Alkyl ethers Vinyl sulfone alcohols
Alkyl amines Vinyl sulfone amines
Vinyl sulfide Propargyl amide thiol
Use of Protecting Groups
1002121 In the reactions described, it may be necessary to protect
reactive functional groups, for example
hydroxy, amino, imino, thio or carboxy groups, where these are desired in the
final product, to avoid their unwanted
participation in the reactions. Protecting groups are used to block some or
all reactive moieties and prevent such
groups from participating in chemical reactions until the protective group is
removed. In one embodiment, each
protective group be removable by a different means. Protective groups that are
cleaved under totally disparate
reaction conditions fulfill the requirement of differential removal.
Protective groups can be removed by acid, base,
and hydrogenolysis. Groups such as hityl, dimethoxytrityl, acetal and t-
butyldimethylsily1 are acid labile and may be
used to protect carboxy and hydroxy reactive moieties in the presence of amino
groups protected with Cbz groups,
which are removable by hydrogenolysis, and Fume groups, which are base labile.
Carboxylic acid and hydroxy
reactive moieties may be blocked with base labile groups such as, but not
limited to, methyl, ethyl, and acetyl in the
presence of amines blocked with acid labile groups such as t-butyl carbamate
or with carbamates that are both acid
and base stable but hydrolytically removable.
(00213I Carboxylic acid and hydroxy reactive moieties may also be blocked
with hydrolytically removable
protective groups such as the benzyl group, while amine groups capable of
hydrogen bonding with acids may be
blocked with base labile groups such as Fmoc. Carboxylic acid reactive
moieties may be protected by conversion to
simple ester compounds as exemplified herein, or they may be blocked with
oxidatively-removable protective
groups such as 2,4-dimethoxybenzyl, while co-existing amino groups may be
blocked with fluoride labile silyl
carbarnatcs.
1002141 Allyl blocking groups are useful in then presence of acid- and
base- protecting groups since the former
are stable and can be subsequently removed by metal or pi-acid catalysts. For
example, an allyl-blocked carboxylic
acid can be deprotected with a Pd -catalyzed reaction in the presence of acid
labile t-butyl carbamate or base-labile
acetate amine protecting groups. Yet another form of protecting group is a
resin to which a compound or
intermediate may be attached. As long as the residue is attached to the resin,
that functional group is blocked and
cannot react. Once released from the resin, the ftmctional group is available
to react.
1002151 Typically blocking/protecting groups may be selected from:
34
Date Recue/Date Received 2022-11-04

=
Hz
H2 3LN
H OrC H20 Cy NO
HICIL 143C".
.Ha 0
altyl = Bn Cbs alloc Me
=
HsC\ ,CHz
HaC (1=11C13C.....- 0=11G/JC.".81s's (CHs)*C-
Et t-butyl TIMMS Teoc
0
H
(C1-1s)se()T-- of3re--- Haci, Ole
0
HsC
Roc }'MB = trityl acetyl
FITIOC
1002161 Other protecting groups, plus a detailed description of
techniques applicable to the creation of
protecting groups and their removal are described in Greene and Wuts,
Protective Groups in Organic Synthesis, 3rd
= Ed., John Wiley & Spin, New York, NY, 1999, and Kocienski, Protective
Groups, 'Thie' me Verlag, New York, NY,
1994..
Synthesis of Compounds
1002171 In certain embodiments, provided herein are methods of making and
methods of using tyrosine kinase
inhiliitrar.compomds described herein. In certain embodiment; compounds
described herein can be synthesized
using the following synthetic schemes. Compounds may be synthesized using
methodologies analogous to those
described below by the use of appropriate altemativeltarting materials.
(002181 Described herein are compounds that inhabit the activity of
tyrosine lrinue(s), such as Btk, and
processes for their preparation. Also described herein are pharmaceutically
acceptable salts, pharmaceutically
acceptable solvates, pharmaceutically active metabolites and pharmaceutically
acceptable prodrugs of such
compounds. Pharmaceutical co:Repositions that include at least one such
compound or a pharmaceutically acceptable
salt, pharmaceutically acceptable solvate, pharmaceutically active metabolite
or pharmaceutically acceptable
prodrug pf such compound, are provided_
1002191 The starting material used for the synthesis of the compounds
descrilied herein may be synthesized or
can be obtained from cotranercial sources, such as, but not limited to,
Aldrich Chemical Co. (Milwaukee,
Wisconsin), Sachem (Torrance, California), or Sigma Chemical Co. (St Louis,
Mo.). The compounds described
herein, and other related compounds having different substituents can be
synthesized using techniques and materials
Imam to those of skill in the art, such as described, for example, in March,
ADVANCED ORGANIC CHEMISTRY 4*
Ed., (Wiley 1992); Carey and Sundberg. ADVANCED ORGANIC CHEMISTRY 4* Ed.,
Vols. A and B (Plenum 2000,
2001); Green and Wuts, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS 35 lid, (Wiley
1999); Fiescr and Fieser's
Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991);
Redd's Chemistry of Carbon
Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989);
Organic Reactions, Volumes 1-
40 (John Wiley and Sons, 1991); and Larocles Comprehensive Organic
Transformations (VCH Publishers Inc.,
1989), Other methods for the synthesis of compounds
described herein may be found in International Patent Publication No. WO
01/01982901, Amold et aL Bioarganic
&Medicinal Chemistry Leiters 10(2000)2167-2170; Burchat etal. Bioorganic &
Medicinal Chemisay l-etters 12.
(2002) 1687-1690. General methods for the preparation of compound as disclosed
Wein 'nay be derived from
known reactions in the field, and the reactions may be modified by the use of
appropriate reagents and conditions, as
= =
Date Recue/Date Received 2022-11-04

would be recognized by the skilled person, for the introduction of the various
moieties found in the formulae as
provided herein. As a guide the following synthetic methods may be utilized.
1002201 The products of the reactions may be isolated and purified, if
desired, using conventional techniques,
including, but not limited to, filtration, distillation, crystallization,
chromatography and the like. Such materials may
be characterized using conventional Means, including physical constants and
spectral data.
1002211 Compounds described herein may be prepared using the synthetic
methods described herein as a single
isomer or a mixture of isomers.
1002221 A non-limiting example of a synthetic approach towards the
preparation of compounds of any of
Formula (A), (B), (C) or (D) is shown in Scheme I. =
Scheme I.
NH2 NH2 1100 ,iiõ.õ7
(140)zE3 NH2
N-iodeauceinamIde
,N __________________________________________
- DMF, heat
cat Pd(dppf)C12-CH2C12 +
aq. IC.S.01/dloxene v'shl 0
mirgewave,150 C, 10 min 2
.
11
NH 2 / 1.) 4.0M HCIldlonne, 2 hr NHe
011eopropyl aaadlearboxylate
N
resin bound PPN, 24 hr t't 2.)Acryloyl chtedde. N
N CI12012. TEA
R.T.. 21w
4 3 0 0
1002231 Halogenation of commercially avalaible 1H-pyrazolo[3,4-d]pyrimidin-
4-arnine provides an entry into
the synthesis of compounds of Formula (A), (B), (C) and/or (D). In one
embodiment, 1H-pyrazolo[3,4-clipyrimidin-
4-amine is treated with N-iodosuccinamide to give 3-iodo-IH-pyrazolo[3,4-
d]pyriroidin4-amine. Metal catalyzed
cross coupling reactions are then carried out on 3-iodo-- 1H-pyrazolo[3,4-
d]pyrimidin-4-amine. In one embodiment,
palladium mediated cross-coupling of a suitably substituted phenyl boronic
acid under basic conditions constructs
intermediate 2. Intermediate 2,is coupled with N-Boc-3-hydroxypiperidine (as
non-limiting example) via Mitsunobu
reaction to give the Boc (tert-butyloxycarbonyl) protected intermediate 3.
After deprotection with acid, coupling
with, but not limited to, an acid chloride, such as, but not limited to,
acryloyl chloride, completes the synthesis to
give compound 4.
(002241 Using the synthetic methods described herein, as well as those
known in the art, tyrosine kirtase
inhibitors as disclosed herein are obtained in good yields and purity. The
compounds prepared by the methods
disclosed herein are purified by conventional means known in the art, such as,
for example, filtration,
recrystAni7ation, chromatography, distillation, and combinations thereof.
1002251 Any combination of the groups described above for the various
variables is contemplated herein. It is
understood that substituents and substitution patterns on the compounds
provided herein can be selected by one of
ordinary skill in the art to provide compounds that are chemically stable and
that can be synthesized by techniques
known in the art, as well as those set forth herein.
Further Forms of Compounds
1002261 Compounds disclosed herein have a structure of any of Formula (A),
Formula (B), Formula (C), or
Formula 0D). It is understood that when reference is made to compounds
described herein, it is meant to include
36
Date Recue/Date Received 2022-11-04

compounds of any of Formula (A), Formula (B), Formula (C), or Formula (D), as
well as to all of the specific
compounds that fall within the scope of these generic formulae, unless
otherwise indicated.
1002271 The compounds described herein may possess one or more
stereocenters and each center may exist in .
the R or S configuration. The compounds presented herein include all
diastereomeric, enantiomeric, and epimeric
forms as well as the appropriate mixtures thereof. Stereoisomers may be
obtained, if desired, by methods known in
the art as, for example, the separation of stereoisonters by chiral
chromatographic columns.
[002281 Diasteanmeric mixtures can be separated into their individual
diastereomers on the basis of their
physical chemical differences by methods known, for example, by chromatography
and/or fractional crystallization.
In one embodiment, enantiomers can be separated by chiral chromatographic
columns. In other embodiments,
enantiomers can be separated by converting the enanfiomeric mixture into a
diastereomeric 'mixture by reaction with
an appropriate optically active compound (e.g., alcohol), separating the
diastereomers and convecting (e.g.,
hydrolyzing) the individual diasterecaners to the corresponding pure
enantiomers. All such isomers, including
diastereomers, enantiomers, and mixtures thereof are considered as part of the
compositions described herein.
1002291 The methods and formulations described herein include the use of N-
oxides, crystalline forms (also
known as polynimphs), or pharmaceutically acceptable salts of compounds
described herein, as well as active
metabolites of these compounds having the same type of activity. In some
situations, compounds may exist as
tautomers. All tautomers are included within the scope of the compounds
presented herein. In addition, the
compounds described herein can exist in =solvated as well as solvated forms
with pharmaceutically acceptable
solvents such as water, ethanol, and the like. The solvated forms of the
compounds presented herein are also
considered to be disclosed herein.
1002301 Compounds of any of Formula (A), Formula (B), Formula (C), or
Formula (D) in unoxidized form can
be prepared from N-oxides of compounds of any of Formula (A), Formula (13),
Formula (C), or Formula (D) by
treating with a reducing agent, such as, but not limited to, sulfur, sulfur
dioxide, triphenyl phospbine, lithium
borohydride, sodium borohydride, phosphorus trichloride, tribromide, or the
like in a suitable inert organic solvent,
such as, but not limited to, acetonitrile, ethanol, aqueous dioxane, or the
like at 0 to 80 C.
1002311 In some embodiments, compounds described hecein are prepared as
prodrugs. A "prodrug" refers to an
agent that is converted into the parent drug in vivo. Prodrugs are often
useful because, in some situations, they may
be easier to administer than the parent drug. They may, for instance, be
bioavailable by oral administration whereas
the parent is not. The prodrug may also have improved solubility in
pharmaceutical compositions over the parent
drug. An example, without limitation, of a prodrug would be a compound
described herein, which is administered as
an ester (the "prodrug") to facilitate transmittal across a cell membrane
where water solubility is detrimental to
mobility but which then is metabolically hydrolyzed to the carboxylic acid,
the active entity, once inside the cell
where water-solubility is beneficial. A further example of a prodrug might be
a short peptide (polyaminoacid)
bonded to an acid group where the peptide is metabolized to reveal the active
moiety. In certain embodiments, upon
in vivo administration, a prodrug is chemically converted to the biologically,
pharmaceutically or therapeutically
active form of the compound. In certain embodiments, a prodrug is
enzymatically metabolized by one or more steps
or processes to the biologically, pharmaceutically or therapeutically active
form of the compmmd. To produce a
prodrug, a pharmaceutically active compound is modified such that the active
compound will be regenerated upon in
vivo administration. The prodrug can be designed to alter the metabolic
stability or the transport characteristics of a
drug, to mask side effects or toxicity, to improve the flavor of a chug or to
alter other characteristics or properties of
a drug. By virtue of knowledge of pharmacodynamic processes and drug
metabolism in vivo, those of skill in this
art, once a pharmaceutically active compound is known, can design prodrUgs of
the compound. (see, for example, =
37
Date Recue/Date Received 2022-11-04

. Nogrady (1985)M:did:sal atemistry A Biocheniical Approach, Oxford
University Press, New York, pages 388-
392; Silverman 09921 The Organic Chemistry ofDrog Design and Drag Action,
Academic Pies; Inc., San Diego,
pages 352-401, Sauhder at of., (1994), Bioorganic and Medicinal C.Itemirtr;
Letters, Vol. 4, p. 1985).
1002321 Prodriig forms of the herein described compounds, wherein the
prodrug is metabolized is vivo to
produce a derivative as set forth herein are included within the scope of the
claims. In some cases, some of the
herein-described compounds may be a prodrug for another derivative or active
compound.
1002331 Predmgs are often useful because, in some situations, they may be
easier to administer than the parent
drug. They may, for instance, be bioaviulable by cad administration whereas
the parent is not. The prodrug nay also
have improved solubility in pharmaceutical compositions over the parent drug.
Prodruga may be designed as
reversible drug derivatives, for use as modifiers to enhance drug transport to
site-specific tissues. In some
embodiments, the design of a prodrug increases the effective water solubility-
See. eg., Fedorak et aL, Am. J.
PhysioL, 269G210-218 (1995); MeLoed at al., Gastroenterol, 106:405-413 (1994);
Elodthaus at al.. Siomed.
aiterie,4283-286 (1992); J. Larsen and B. Bundgaard, Int. J. Pharmaceutics,
37, 87 (1987); J. Larsen at al, Int..4
Pharmaceutics, 47, 103 (1988); Sinkula at .1,J. Pharm. Sd, 64:181-210(1975);
T. Higuchl and V. Stella, Pro-
drugs r s Novel Delivery Systems, VoL 14 of the A.C.S. Symposium Series; and
Edward B. Reche, itioreversible
Carriers in Drug Design, American Pharmaceutical Association and Pergamon
Press, 1987.
100234] Sites on the aromatic ring portion of coropormds of any of
Formula (A), Foam& (B), Formula (C), or
= Formula (D) can be susceptible to various metabolic reactions, thensfore
incorporation of appropriate substituents on
the aromatic ring structures, such as, by way of example Only, halogens can
reduce, minimize or eliminate this
metabolic pathway.
1002351 Compounds described herein include isotopically-labeled
compounds, which are identical to those
recited in the various formulas and structures presented herein, but for the
act that one or more atoms are replaced
by an atom having an atomic mass or mass number different from the atomic mass
or mass manlier usually found In
nature. Examples of isotopes that can be incorporated into the present
compounds include isotopes of hydrogen,
carbon, nitrogen, oxygen, fluorine and chlorine, such as 211,3p, "C, "C, "N,
l'13, lb, US, 111F. "Cl, respectively.
Certain isotopieslly-labeled compounds described herein, for maniple those
into which radioactive isotopes such as
311 and "C am incorporated, are useful hi, drug and/or substrate tissue
distribution assays. Further, substitution with
isotopes such as deuterium, i.e., zit can afford certain therapeutic
advantages resulting from greater metabolic
stability, for example increased in vivo half-life or reduced dosage
requirements.
1002361 In additional or further embodiments, the compounds described
herein are metabolized upon
administration to an organism in need to produce a metabolite that is then
used to produce a desired effect, including
a desired therapeutic effect
1002371 Compounds described herein may be formed as, andfor used as,
pharmaceutically sea:03We salts. The
type ofpharmaceutical acceptable salts, include, but are not limited to: (1)
acid addition salts, formed) by reacting
the free base foam of the compound with a pharmaceutically aeceptable:
inorganic acid such as hydrochloric nit),
hydrobrcanic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric
acid, and the hie; or with an organic
acid such as acetic acid, propiordc acid, hexanoic acid, cyclopentanepropionic
acid, glycolic acid, pyruvic acid,
-lactic acid. =ionic acid, succinic acid, milk acid, =oleic acid, finnaric
acid, triflueroacetie acid, ratio acid. citric
acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid.einnamie acid, rnanitelic
acid, metlumesulfdnie acid,
ethanesulfbnic acid, 1,2-ethenedisulfonic acid, 2-hydroxydlianesulfonic add,
benzenesulfonic acid, Iola. enesolfonie
add, 2-raphthaleoesalftinic acid, 4-methylbicyclo-[2.2.2]oct-2-ene-1-
carboxylic acid, glucoheptonic acid, 4,4-
38
=
=
=
Date Recue/Date Received 2022-11-04

methylenebis-(3-hydroxy-2-ene-1 -carboxylic acid), 3-phenylpropionic acid,
trimethylac,etic acid, tertiary
butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid,
hydroxynaphthoic acid, salicylic acid, stearic
acid, muconic acid, and the like; (2) salts formed when an acidic proton
present in the parent compound either is
replaced by a metal ion, e.g., an alkali metal ion (e.g. lithium, sodium,
potassium), an alkaline earth ion (e.g.
magnesium, or calcium), or an aluminum ion; or coordinates with an organic
base. Acceptable organic bases include
ethanolamine, diethanolamine, Iriethanolarnine, tromethamine, N-
methylglucamine, and the like. Acceptable
inorganic bases include aluminum hydroxide, calcium hydroxide, potassium
hydroxide, sodium carbonate, sodium
hydroxide, and the like.
(002381 The corresponding counterions of the pharmaceutically acceptable
salts may be analyzed and identified
using various methods including, but not limited to, ion exchange
chromatography, ion chromatography, capillary
electrophoresis, inductively coupled plasma, atomic absorption spectroscopy,
mass spectrometry, or any
combination thereof.
[00239] The salts are recovered by using at least one of the following
techniques: filtration, precipitation with a
non-solvent followed by filtration, evaporation of the solvent, or, in the
case of aqueous solutions, lyophilization.
[002401 It should be understood that a reference to a pharmaceutically
acceptable salt includes the solvent
addition forms or crystal forms thereof, particularly solvates or polymorphs.
Solvates contain either stoichiometric
or non-stoichiomehic amounts of a solvent, and may be formed during the
process of crystallization with
pharmaceutically acceptable solvents such as water, ethanol, and the like.
Hydrates are formed when the solvent is
water, or alcoholates are formed when the solvent is alcohol. Solvates of
compounds described herein can be
conveniently prepared or formed during the processes described herein. In
addition, the compounds provided herein
can exist in unsolvated as well as solvated forms. In general, the solvated
forms are considered equivalent to the
unsolvated forms for the purposes of the compounds and methods provided
herein.
1[002411 It should be understood that a reference to a salt includes the
solvent addition forms or crystal forms
= thereof, particularly solvates or polymorphs. Solvates contain either
stoichiometric or non-stoichiometric amounts of
a solvent, and are often formed during the process of crystallization with
pharmaceutically acceptable solvents such
as water, ethanol, and the like. Hydrates are formed when the solvent is
water, or alcoholates are formed when the
solvent is alcohol. Polymorphs include the different crystal packing
arrangements of the same elemental
composition of a compound. Polymorphs usually have different X-ray diffraction
patterns, infrared spectra, melting
points, density, hardness, crystal shape, optical and electrical properties,
stability, and solubility. Various factors
such as the recrystallization solvent, rate of crystallization, and storage
temperature may cause a single crystal form
to dominate.
1002421 Compounds described herein may be in various forms, including but
not limited to, amorphous forms,
milled forms and nano-particulate forms. In addition, compounds described
herein include crystalline forms, also
known as polymorphs. Polymorphs include the different crystal packing
arrangements of the same elemental
composition of a compound. Polymorphs usually have different X-ray diffraction
patterns, infrared spectra, melting
points, density, hardness, crystal shape, optical and electrical properties,
stability, and solubility. Various factors
such as the recrystallization solvent, rate of crystallization, and storage
temperature may cause a single crystal form
to dominate.
1002431 The screening and characterization of the pharmaceutically
acceptable salts, polymorphs and/or
solvates may be accomplished using a variety of techniques including, but not
limited to, thermal analysis, x-ray
diffraction, spectroscopy, vapor sorption, and microscopy. Thermal analysis
methods address themio chemical
degradation or thermo physical processes including, but not limited to,
polymorphic transitions, and such methods
39
Date Recue/Date Received 2022-11-04

are used to analyze the relationships between polymorphic forms, determine
weight kiss, to find the glees transition
tennerature, or for micipient comma/silky studies. Such methods include, but
are not limited to. Differential
scanning calorimetry (DSC), Modulated Differential Scanning Odcaimetry (MDCS),
Tbermogcavimetric analysis
=
(TGA), and Thermogravianetric and Infrared analysis (Tt3/IR). X-ray
diffraction methods include, but are not
limited to, single crystal and powder diffractometas and synchrotron sources.
The various spectroscopic techniques
used include, but are not limited to, Raman, FTIR, UVIS, and NMR (liquid and
solid sate). The various microscopy
techniques include, but are not limited to, polarized light microscopy,
Scanning Electron Microscopy (SEM) with
Energy Dispersive X-Ray Analysis (BOX), Environmental Scanning Electron
Microscopy with BOX (in gas or
water vapor atmosphere), IR microscopy, and Raman microscopy.
1002441 Throughout the specification, groups and substituents thereof can
be chosen by one skilled in the field
to provide stable moieties and compounds.
Pharmaceutical CompositiondlForninlation
100245) Pharmaceutical compositions may be &mulcted in a
conventional manner using one or more
physiologically acceptable carriers including excipients and auxiliaries which
facilitate processing of the active
compounds into preparation' which can be used plaurnaceirtically. Proper
formulation is dependent upon the mute ,
of administration chosen. Any of the well-known teelmirines, carriers, and
excipients nay be used as suitable and as
'understood in the an. A summary of pharmaceutical compositions described
herein maybe found, for example, in
=
Remington: The SCitiliCe and Practice of Pharmacy. Nineteenth Ed (Easton. Pa.:
Mack Publishing Company, 199$);
Hoover, John E., Remington's Pharmaceutical Sciences. Mack Publishing Co-,
Easton, Pennsylvania 1975;
Liberman, HA. and 7 wthrriall, L, Eds., Pharmacetaical Dosage Forms. Marcel
booker, New York, N.Y, 1980; and
Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott
Williams 8c Wi1kins1999).
[00246] A pharmaceutical composition, as used herein, refers to a
mixture of a compound described herein,
such as, for example, compounds of any of Formula (A), Font-ma (13), Formula
(C), or Familia (0), with other
chemical components, such as carriers, stabilizers, diluents, dispersing
agents, suspending agents, thickening agents,
and/or excipients. The pharmaceutical composition facilitates administration
of the compound to an organism_ In
practicing the methods of treatment or use provided herein, therapeutically
effective amounts of compounds
described herein are achninistered in a pharmaceutical composition to a mammal
having a disease, disorder, or
condition to be treated. Preferably, the mammal is a human. A therapeutically
effective amount can vary widely
depending on the severity of the disease, the age and relative health of the
subject, the potency of the compound
used and other factors. The compounds can be used singly or in combination
with one or more therapeutic agents as
components of mixtures.
1002471 In certain embodiments, compositions may also include one or
more pH adjusting agents or buffering ,
agents, inchading acids such as acetic, boric, citric, lactic, phosphoric and
hydrochloric acids; bases such as sodium
hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate,
sodium lactate and tris-
hydrraymethylaminomethane; and buffers such as citrate/dextrose, sodium
bicarbonate and ammonium chloride.
Such acids, bases and buffers ere included in an amount required to maintain
pH of the composition in an acceptable
range.
1002481 In other embodiments, compositions may also include one or
more salts in an amount required to bring
eanolality of the composition into an acceptable range. Such salts include
those having sodium, potassium or
ammoninm cations and chloride, citrate, manilas borate, phosphate,
bicarbonate, sulfate, thiosulfate or bisulfue
Date Recue/Date Received 2022-11-04

=
anions; suitable salts include sodium chloride, potassium chloride, sodium
thiosulfate, sodium bisulfite and
ammonium sulfate.
[00249] The term "pharmaceutical combination" as used herein, means a
product that results from the mixing
or combining of more than one active ingredient and includes both fixed and
non-fixed combinations of the active
ingredients. The term "fixed combination" means that the active ingredients,
e.g. a compound described herein and a
co-agent, are both administered to a patient simultaneously in the form of a
single entity or dosage. The term "non-
fixed combination" means that the active ingredients, e.g. a compound
described herein and a co-agent, are
administered to a patient as separate entities either simultaneously,
concurrently or sequentially with no specific
Intervening time limits, wherein such administration provides effective levels
of the two compounds in the body of
the patient. The latter also applies to co*cktail therapy, e.g. the
administration of three or more active ingredients.
. [00250] The pharmaceutical formulations described herein can be
administered to a subject by multiple
administration routes, including but not limited to, oral, parenteral (e.g.,
intravenous, subcutaneous, intramuscular),
intranasal, buccal, topical, rectal, or transdermal administration routes. The
pharmaceutical formulations described
herein include, but are not limited to, aqueous liquid dispersions, self-
emulsifying dispersions, solid solutions,
liposomal dispersions, aerosols, solid dosage forms, powders, immediate
release formulations, controlled release
formulations, fast melt formulations, tablets, capsules, pills, delayed
release formulations, extended release
formulations, pulsatile release formulations, multiparticulate formulations,
and mixed immediate and controlled
release formulations.
[00251] Pharmaceutical compositions including a compound described herein
may be manufactured in a
conventional manner, such as, by way of example only, by means of conventional
mixing, dissolving, granulating,
dragee-making, levigating, emulsifying, encapsulating, entrapping or
compression processes.
[00252] The pharmaceutical compositions will include at least one compound
described herein, such as, for
example, a compound of any of Formula (A), Formula (B), Formula (C), or
Formula (D), as an active ingredient in
free-acid or free-base form, or in a pharmaceutically acceptable salt form. In
addition, the methods and
pharmaceutical compositions described herein include the use of N-oxides,
crystalline forms (also known as
polymorphs), as well as active metabolites of these compounds having the same
type of activity. In some situations,
compounds may exist as tautomers. All tautomers are included within the scope
of the compounds presented herein.
Additionally, the compounds described herein can exist in =solvated as well as
solvated forms with
pharmaceutically acceptable solvents such as water, ethanol, and the like. The
solvated forms of the compounds
3() presented herein are also considered to be disclosed herein.
1002531 "Antifoaming agents" reduce foaming during processing which can
result in coagulation of aqueous
dispersions, bubbles in the finished film, or generally impair processing.
Exemplary anti-foaming agents include
silicon emulsions or sorbitan sesquoleate.
[00254] "Antioxidants" include, for example, butylated hydroxytoluene
(Bin), sodium ascorbate, ascorbic
acid, sodium metabisulfite and tocopherol. In certain embodiments,
antioxidants enhance chemical stability where
required.
[00255] In certain embodiments, compositions provided herein may also
include one or more preservatives to
inhibit microbial activity. Suitable preservatives include mercury-containing
substances such as merfen and
thiomersal; stabilized chlorine dioxide; and quatemary ammonium compounds such
as benzalkonium chloride,
cetyltrimethylammonitun bromide and cetylpyridinium chloride.
[00256] Formulations described herein may benefit from antioxidants, metal
chelating agents, thiol containing
compounds and other general stabilizing agents. Examples of such stabilizing
agents, include, but are not limited to:
41
Date Recue/Date Received 2022-11-04

(a) about 0.5% to about 2% w/v glycerol, (b) about 0.1% to about 1% w/v
mettionine, (a) about 0.1% to about 2%
w/v monothioglycerol, (d) about 1 nIM to about 10 inM EDTA, (e) about 0.01% to
about 2% w/v ascorbic acid, (f)
0.003% to about 0.02% w/v polysorbate 80, (g) 0.001% to about 0.05% w/v.
polysorbate 20, (h) arginine, (i)
heparin, (j dextran sulfate, (k) cyclodedains, (I) pentostm polysulfate and
other heparinoids, (m) divalent cations
such as magnesium and zinc; or (n) combinations thereof.
[00257] "Binders" impart cohesive qualities and include, e.g., alginic
acid and salts thereof; cellulose
derivatives such as carboxymethylcelhalose, methylcellnlose (e.g., Methocels),
hydroxypropylmethylcellulose,
hydroxyethylcellulose, hydroxypropylcellulose (e.g., Kluce15), ethylcellulose
(e.g., Ethoce15), and microcrystalline
cellulose (e.g., Avicee); rnicrocrystalline dextrose; amylose; magnesium
aluminum silicate; polysaccharide acids;
bentonites; gelatin; polyvinylpyrrolidone/vinyl acetate copolymer;
crosspovidone; povidone; starch; pregelatinized
starch; tragacanth, dextrin, a sugar, such as sucrose (e.g., Dipae), glucose,
dextrose, molasses, marmite', sorbitol,
xylitol Xylitabt), and lactose; a natural or synthetic gum such as acacia,
tragacandr, ghatti gum, mucilage of
isapol husks, polyvinylpyrrolidone (e.g., Polyvidone CL, Kollidon CL,
Polyplasdone XL-10), larch
arabogalactan, Veegure, polyethylene glycol, waxes, sodium alginate, and the
like.
[00258] A "carrier" or "carrier materials" include any commonly used
excipients in pharmaceutics and should
be selected on the basis of compatibility with compounds disclosed herein,
such as, compounds of any of Formula
(A), Formula (B), Formula (C), or Formula (D), and the release profile
properties of the desired dosage form.
Exemplary carrier materials include, e.g., binders, suspending agents,
disintegration agents, filling agents,
surfactants, solubilizers, stabilizers, ubricants, wetting agents, diluents,
and the like. "Pharmaceutically compatible
carrier materials" may include, but are not limited to, acacia, gelatin,
colloidal silicon dioxide, calcium
glycerophosphate, calcium lactate, maltodextrin, glycerine, magnesium
silicate, polyvinylpyrrollidone (PVP),
cholesterol, cholesterol esters, sodium caseinate, soy lecithin, taurocholic
acid, phosphotidylcholhae, sodium
chloride, tricalcium phosphate, dipotassium phosphate, cellulose and cellulose
conjugates, sugars sodium stearoyl
lactylate, carrageemm, monoglyceride, diglyceride, pregelatinized starch, and
the like. See, e.g., Remington: The
.. Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack
Publishing Company, 1995); Hoover, John E.,
Remington 's Pharmaceutical Sciences, Mack Publishing Co., Easton,
Pennsylvania 1975; Liberman. H.A. and
Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y,
1980; and Pharmaceutical
Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams &
Wilkins1999).
1007491 "Dispersing agents," and/or "viscosity modulating agents" include
materials that control the diffusion
.. and hom*ogeneity of a chug through liquid media or a granulation method or
blend method. In some embodiments,
these agents also facilitate the effectiveness of a coating or eroding matrix.
Exemplary diffusion
facilitators/dispersing agents include, e.gõ hydrophilic polymers,
electrolytes, Tween '60 or 80, PEG,
polyvinylpyrrolicione (PVP; commercially known as Plasdone5), and the
carbohydrate-based dispersing agents such
as, for example, hydroxypropyl celluloses (e.g., HPC, HPC-SL, and HPC-1.),
hydroxypropyl methylcelluloses (e.g.,
HPMC K100, IIPMC K4M, HPMC Kl5M, and HPMC KlOOM), carboxymethylr-ellulose
co4i,im, methyiceilujose,
hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose
phthalate,
hydroxypropylmethylcelltdose acetate stearate (HPMCAS), noncrystalline
cellulose, magnesium aluminum silicate,
trietbanolamine, polyvinyl alcohol (PVA), vinyl pyrrolidone/vinyl acetate
copolymer (S630), 441,1,3,3-
tetramethylbuty1)-phenol polymer with ethylene oxide and formaldehyde (also
known as tyloxapol), poloxamers
(e.g., Pluronics F685,F8815, and F1085, which are block copolymers of ethylene
oxide and propylene oxide); and
poloxamines (e.g.. Tetronic 9086, also known as Poloxamine 9085, which is a
tetrafunctional block copolymer
derived from sequential addition of propylene oxide and ethylene oxide to
ethylenediamine (BASF Corporation,
42
Date Recue/Date Received 2022-11-04

Parsippany, NJ.)), polyvinylpyrrolidone K12, polyvinylpyrrolidone K17,
polyvinylpyrrolidone K25, or
polyvinylpyrrolidone K30, polyvinylpyrrolidone/vinyl acetate copolymer (S-
630), polyethylene glycol, e.g., the
polyethylene glycol can have a molecular weight of about 300 to about 6000, or
about 3350 to about 4000, or about
7000 to about 5400, sodium carboxymethylcellulose, methylcellulose,
polysorbate-80, sodium alginate, gums, such
as, e.g., gum tragammth and gum acacia, guar gum, xanthans, including xanthan
guru, sugars, cellulosics, such as,
e.g., sodium carboxymethylcellulose, methylcellulose, sodium
carboxymethylcellulose, polysorbate-80, sodium
alginate, polyethoxylated sorbitan monolaurate, polyethoxylated ambit=
monolaurate, povidone, carbomers,
polyvinyl alcohol (PVA), alginates, chitosans and combinations thereof.
Plasticizcers such as cellulose or triethyl
cellulose can also be used as dispersing agents. Dispersing agents
particularly useful in liposomal dispersions and
self-emulsifying dispersions are diznyristoyl phosphatidyl choline, natural
phosphatidyl choline from eggs, natural
phosphatidyl glycerol from eggs, cholesterol and isopropyl myristate.
(00260l Combinations of one or more erosion facilitator with one or more
diffusion facilitator can also be used
in the present compositions.
1002611 The term "diluent" refers to chemical compounds that are used to
dilute the compound of interest prior
.. to delivery. Diluents can also be used to stabilize compounds because they
can provide a more stable environment.
Salts dissolved in buffered solutions (which also can provide pH control or
maintenance) are utilized as diluents in
the art, including, but not limited to a phosphate buffered saline solution.
In certain embodiments, diluents increase
bulk of the composition to facilitate compression or create sufficient bulk
for hom*ogenous blend for capsule filling.
Such compounds include e.g., lactose, starch, marmitol, sorbitol, dextrose,
microcrystalline cellulose such as
Avicer; dibasic calcium phosphate, dicalcium phosphate diliydrate; tricalcium
phosphate, calcium phosphate;
anhydrous lactose, spray-dried lactose; pregelatinized starch, compressible
sugar, such as Di-Pacm (Amstar);
mannitol, hydroxypropylmethykellulme, hydroxypropyhnethylcellulose acetate
stearate, sucrose-based diluents,
confectioner's sugar; monobasic calcium sulfate monohydrate, calcium sulfate
dihydrate; calcium lactate trihydrate,
dextrates; hydrolyzed cereal solids, amylose; powdered cellulose, calcium
carbonate; glycine, kaolin; mannitol,
sodium chloride; inositol, bentonite, and the like.
1002621 The term "disintegrate" includes both the dissolution and
dispersion of the dosage form when
contacted with gastrointestinal fluid. "Disintegration agents or
disintegrants" facilitate the breakup or disintegration
of a substance. Examples ofd lain Pgiration agents include a starch, e.g., a
natural starch such as corn starch or potato
starch, a pregelatinixed starch such as National 1551 or Andjer, or sodium
starch glycolate such as Promoger or
Explotab6, a cellulose such as a wood product, methylcrystalline cellulose,
e.g., Avicer, Avicer PHI 01, Avicer
PH102, Avicel PHI 05, Elcema. P100, Emceed., Vivacer, Ming Tie, and Solka-
Flocib, znethylcellulose,
croscarmellose, or a cross-linked cellulose, such as cross-linked sodium
carboxymethylcellulose
cross-linked carboxymethyleellulose., or cross-linked croscarmellose, a cross-
linked starch such as sodium starch
glycolate, a cross-linked polymer such as crosspovidone, a cross-linked
polyvinylpyrrolidone, alginate such as
alginic acid or a salt of alginic acid such as sodium alginate, a clay such as
Veegum. HV (magnesium aluminum
silicate), a gum such as agar, guar, locust bean, Karaya, pectin, or
tragacanth, sodium starch glycolate, bentonite, a
natural sponge, a surfactant, a resin such as a cation-exchange resin, citrus
pulp, sodium lauryl sulfate, sodium lauryl
sulfate in combination starch, and the like.
1002631 'Drug absorption" or "absorption" typically refers to the process
of movement of drug from site of
administration of a drug across a barrier into a blood vessel or the site of
action, e.g., a drug moving from the
gastrointestinal tract into the portal vein or lymphatic system.
43
Date Recue/Date Received 2022-11-04

1002641 An "enteric coating" is a substance that remains substantially
intact in the stomach but dissolves and
releases the chug in the small intestine or colon. Generally, the enteric
coating comprises a polymeric material that
prevents release in the low pH environment of the stomach but that ionizes at
it higher pH, typically a pH of 6 to 7,
and thus dissolves sufficiently in the small intestine or colon to release the
active agent therein.
5' 1002651 "Erosion facilitators" include materials that control the
erosion of a particular material in
gastrointestinal fluid. Erosion facilitators are generally known to those of
ordinary skill in the art. Exemplary erosion
facilitators include, e.g., hydrophilic polymers, electrolytes,
proteins,.peptides, and amino acids.
1002661 "Filling agents" include compounds such as lactose, calcium
carbonate, calcium phosphate, dibasic
calcium phosphate, calcium sulfate, microczystalline cellulose, cellulose
powder, dextrose, dextrates, dextran,
starches, pregelatinized starch, sucrose, xylitol, lactitol, mannitol,
sorbitol, sodium chloride, polyethylene glycol,
and the like.
[002671 "Flavoring agents" and/or "sweeteners" useful in the formulations
described herein, include, e.g.,
acacia syrup, acesnlfame K, alitame, anise, apple, aspartame, banana, Bavarian
cream, berry, black currant,
butterscotch, calcium citrate, camphor, caramel, cherry, cherry cream,
chocolate, cinnamon, bubble gum, citrus,
citrus punch, citrus cream, cotton candy, cocoa, cola, cool cherry, cool
citrus, cyclamate, cylamate, dextrose,
eucalyptus, eugenol, fructose, fruit punch, ginger, g,lycyrrhetinate,
glycyrrhiza (licorice) syrup, grape, grapefruit,
honey, isomalt, lemon, lime, lemon cream, monoammonium glyrrhizinate
(MagnaSweet.), maltol, mannitol, maple,
marshmallow, menthol, mint cream, mixed berry, neohesperidine DC, neotame,
orange, pear, peach, peppermint,
peppermint cream, Prosweet. Powder, raspberry, root beer, rum, saccharin,
safiuk, sorbitol, spearmint, spearmint
cream, strawberry, strawberry cream, stevia, sucralose, sucrose, sodium
saccharin, saccharin, aspartame, acesulfame
potassium, mamtitol, talin, sylitol, sucralose, sorbitol, Swiss cream,
tagatose, tangerine, thamatin, tutti fruitti,
vanilla, walnut, watermelon, wild cherry, wintergreen, xylitol, or any
combination of these flavoring ingredients,
e.g., anise-menthol, cherry-anise, cinnamon-orange, cherry-cinnamon, chocolate-
mint, honey-lemon, lemon-lime,
lemon-mint, menthol-eucalyptus, orange-cream, vanilla-mint, and mixtures
thereof.
1002681 "Lubricants" and "glidants" are compounds that prevent, reduce or
inhibit adhesion or friction of
materials. Exemplary lubricants include, e.g., stearin acid, calcium
hydroxide, talc, sodium sbatuyl fimserate, a
hydrocarbon such as mineral oil, or hydrogenated vegetable oil such as
hydrogenated soybean oil (Sterotee), higher
fatty acids and their alkali-metal and alkaline earth metal salts, such as
aluminum, calcium, magnesium, zinc, steak
acid, sodium stearates, glycerol, talc, waxes, Stearowei", boric acid, sodium
benzoate, sodium acetate, sodium
chloride, leucine, a polyethylene glycol (e.g., PEG-4000) or a
methoxypolyethylene glycol such as Carbowarirm,
sodium oleate, sodium benzoate, glyceryl behenate, polyethylene glycol,
magnesium or sodium lauryl sulfate,
colloidal silica such as SyloidTm, Cab-O-Se, a starch such as corn starch,
silicone oil, a surfactant, and the
1002691 A "measurable serum concentration" or "measurable plasma
concentration" describes the blood serum
or blood plasma concentration, typically measured in mg, pg, or ng of
therapeutic agent per ml, dl, or 1 of blood
serum, absorbed into the bloodstream after administration. As used herein,
measurable plasma concentrations arc
typically measured in ng,/m1 or geml.
1002701 "Phannacodynamics" refers to the factors which determine the
biologic response observed relative to
the concentration of drug at a site of action.
1002711 "Pharroaco*kinetics" refers to the factors which determine the
attainment and maintenance of the
appropriate concentration of drug at a site of action.
1002721 "Plasticizers" are compounds used to soften the microencapsulation
material or film coatings to make
them less brittle. Suitable plasticizers include, e.g., polyethylene glycols
such as PEG 300, PEG 400, PEG 600, PEG
44
Date Recue/Date Received 2022-11-04

1450, PEG 3350, and PEG 800, stearic acid, propylene glycol, oleic acid,
Methyl cellulose and triacetin. In some
embodiments, plasticizers can also function as dispersing agents or wetting
agents.
1002731 "Solubilizers" include compounds such as triacetin,
triethylcitrate, ethyl oleate, ethyl caprylate, sodium
lauryl sulfides, sodium doccusate, vitamin E TPGS, dimethylacetamide, N-
methylpyrrolidone, N-
hyciroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropylmethyl cellulose,
hydroxypropyl cyclodextrins,
ethanol, n-butanol, isopropyl alcohol, cholesterol, bile salts, polyethylene
glycol 200-600, glycofinol, transcutol,
propylene glycol, and diniethyl isosorbide and the like.
1002741 "Stabilizers" include compounds such as any antioxidation agents,
buffers, acids, preservatives and the
laze.
1002751 "Steady state," as used herein, is when the amount of drug
administered is equal to the amount of drug
eliminated within one dosing interval resulting in a plateau or constant
plasma drug exposure.
002761 "Suspending agents" include compounds such as
polyvinylpyrrolidone, e.g., polyvinylpyrrolidone
K12, polyvinylpyrrolidone K17, polyvinylpyrrolidone K25, or
polyvinylpyrrolidone K30, vinyl pyrrolidone/vinyl
acetate copolymer (S630), polyethylene glycol, e.g., the polyethylene glycol
can have a molecular weight of about
300 to about 6000, or about 3350 to about 4000, or about 7000 to about 5400,
sodium carboxymethylcellulose,
rnethylcellulose, hydroxypropylmethylcelhdose, hydroxymethylcellulose acetate
stearate, polysorbate-80,
hydroxyethylcellulose, sodium alginate, gums, such as, e.g., gum tragacanth
and gum acacia, guar gum, seemshang,
including xanthan gum, sugars, cellulosics, such as, e.g., sodium
carboxymethylcellulose, methylcellulose, sodium
carboxymethylcelhslose, hydroxypropyhnethylcellulose, hydroxyethylcellulose,
polysorbate-80, sodium alginate,
polyethoxylated sorbitan monolaurate, polyethoxylated sorbitan monolaurate,
povidone and the isle.
1002771 "Suriitctants" include compounds such as sodium lauryl sulfate,
sodium docusate, Tween 60 or 80,
triacetin, vitamin 13 TPGS, sorbitan monooleate, polyoxyethylene sorbitan
monooleate, polysorbates, polaxomers,
bile salts, glyceryl monostearate, copolymers of ethylene oxide and propylene
oxide, e.g., Pluronic (BASF), and
the lac. Some other surfactants include polyckyethylene fatty acid glycerides
and vegetable oils, eg.,
polyoxyethylene (60) hydrogenated castor oil; and polyoxyethylene allrylethers
and alkylphenyl ethers, e.g.,
octoxynol 10, octoxynol 40. In some embodiments, surfactants may be included
to enhance physical stability or for
other purposes.
[00278] "Viscosity enhancing agents" include, e.g., methyl cellulose,
xanthan gum, carboxyrnethyl cellulose,
hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxypropylmethyl
cellulose acetate stearate,
hydroxypropyhnethyl cellulose phthalate, carbomer, polyvinyl alcohol,
alginates, acacia, chitoesans and
combinations thereof.
1002791 "Wetting agents" include compounds such as oleic acid, glyceryl
monostearate, sorbitan monooleate,
sorbitan monolaurate, triethanolamine oleate, polyoxyethylene sorbitan
monooleate, polyoxyethylene sorbitan
monolaurate, sodium docusate, sodium oleate, sodium lauryl sulfate, sodium
doccusate, triacetin, Tween 80, vitamin
E TPGS, ammonium salts and the like.
Dosage Forms
1002801 The compositions described herein can be formulated for
administration to a subject via any
conventional means including, but not limited to, oral, parenteral (e.g.,
intravenous, subcutaneous, or intramuscular),
buccal, intranasal, rectal or transdennal administration routes. As used
herein, the term "subject" is used to mean an
animal, preferably a mammal, including a human or non-human. The terms patient
and subject may be used
interchangeably.
Date Recue/Date Received 2022-11-04

(002811 Moreover, the pharmaceutical compositions described herein, which
include a compound of any of
Formula (A), Formula (B), Formula (C), or Formula (D) can be formulated into
any suitable dosage form, including
but not limited to, aqueous oral dispersions, liquids, gels, syrups, elixirs,
slurries, suspensions and the like, for oral
ingestion by a patient to be. treated, solid oral dosage forms, aerosols,
controlled release formulations, fast melt
formulations, effervescent formulations, lyophilized formulations, tablets,
powders, pills, dragees, capsules, delayed
release formulations, extended release formulations, pulsatile release
formulations, multiparticulate formulations,
and mixed immediate release and controlled release formulations.
1002821 Pharmaceutical preparations for oral use can be obtained by mixing
one or more solid excipient with
one or more of the compounds described herein, optionally grinding the
resulting mixture, and processing the
mixture of granules, after adding suitable auxiliaries, if desired, to obtain
tablets or dragee cores. Suitable excipients
include, for example, fillers such as sugars, including lactose, sucrose,
mannitol, or sorbitol; cellulose preparations
such as, for example, maize starch, wheat starch, rice starch, potato starch,
gelatin, gum tragacanth, methylcellulose,
microcrystalline cellulose, hydroxypropylmethylcellulose, sodium
carboxymethylcellulose; or others such as:
polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. If desired,
disintegrating agents may be added, such
as the cross-linked croscamiello.se sodium, polyvinylpyrrolidone, agar, or
alginic acid or a salt thereof such as
sodium alginate.
1002831 Dragee cores are provided with suitable coatings. For this
purpose, concentrated sugar solutions may
be used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone,
carbopol gel, polyethylene glycol,
and/or titanium dioxide, lacquer solutions, and suitable organic solvents or
solvent mixtures. Dyestuffs or pigments
may be added to the tablets or dragee coatings for identification or to
characterize different combination; of active
compound doses.
1002841 Pharmaceutical preparations which can be used orally include push-
fit capsules made of gelatin, as
well as soft, scaled capsules made of gelatin and a plasticizer, such as
glycerol or sorbitol. The push-fit capsules can
contain the active ingredients in admixture with filler such as lactose,
binders such as starches, and/or lubricants
such as talc or magnesium stearate and, optionally, stabilizers. In soft
capsules, the active compounds may be
dissolved or suspended in suitable liquids, such as fatty oils, liquid
paraffin, or liquid polyethylene glycols. In
addition, stabilizers may be added. All formulations for oral administration
should be in dosages suitable for such
administration.
1002851 In some embodiments, the solid dosage forms disclosed herein may
be in the form of a tablet,
(including a suspension tablet, a fast-melt tablet, a bite-disintegration
tablet, a rapid-disintegration tablet, an
effervescent tablet, or a caplet), a pill, a powder (including a sterile
packaged powder, a dispensable powder, or an
effervescent powder) a capsule (including both soft or hard capsules, e.g.,
capsules made from animal-derived
gelatin or plant-derived HPMC, or "sprinkle capsules"), solid dispersion,
solid solution, bioerodible dosage form,
controlled release formulations, pulsatile release dosage forms,
multiparticulate dosage forms, pellets, granules, or
an aerosol. In other embodiments, the pharmaceutical formulation is in the
form of a powder. In still other
embodiments, the pharmaceutical formulation is in the form of a tablet,
including but not limited to, a fast-melt
tablet. Additionally, pharmaceutical formulations described herein may be
administered as a single capsule or in
multiple capsule dosage form. In some embodiments, the pharmaceutical
formulation is administered in two, or
three, or four, capsules or tablets.
1002861 In some embodiments, solid dosage forms, e.g., tablets,
effervescent tablets, and capsules, are prepared
by mixing particles of a compound of any of Formula (A), Formula (B), Formula
(C), or Formula (D), with one or
more pharmaceutical excipients to form a bulk blend composition. When
referring to these bulk blend compositions
46
Date Reeue/Date Received 2022-11-04

as hom*ogeneous, it is meant that the particles of the compound of any of
Formula (A), Formula (B), Formula (C), or
Formula (D), are dispersed evenly throughout the composition so that the
composition may be readily subdivided
into equally effective unit dosage forms, such as tablets, pills, and
capsules. The individual unit dosages may also
include film coatings, which disintegrate upon oral ingestion or upon contact
with diluent. These formulations can
be manufactured by conventional pharmacological techniques.
100287) Conventional pharmacological techniques include, e.g., one or a
combination of methods: (1) dry
mixing, (2) direct compression. (3) milling. (4) dry or non-aqueous
granulation, (5) wet granulation, or (6) fusion.
See, e.g., Lachman et al., The Theory and Practice ofindustrial Pharmacy
(1986). Other methods include, e.g.,
spray drying, pan coating, melt granulation, granulation, fluidized bed spray
drying or coating wurster
coating), tangential coating, top spraying, tableting, extruding and the lice.
10028131 The pharmaceutical solid dosage forms described herein can include
a compound described herein and
one or more pharmaceutically acceptable additives such as a compatible
carrier, binder, filling agent, suspending
agent, flavoring agent, sweetening agent, disintegrating agent, dispersing
agent, surfactant, lubricant, colorant,
diluent, sohibllizer, moistening agent, plasticizer, stabilizer, penetration
enhancer, wetting agent, anti-foaming agent,
antioxidant, preservative, or one or more combination thereof. In still other
aspects, using standard coating
procedures, such as those described in Remington's Pharmaceutical Sciences,
20th Edition (2000), a film coating is
provided around the formulation of the compound of any of Formula (A), Formula
(B), Formula (C), or Formula
(I)). In one embodiment, some or all of the particles of the compound of any
of Formula (A), Formula (13), Formula
(C), or Formula (D), are coated. In another embodiment, some or all of the
particles of the compound of any of
Formula (A), Formula (B), Formula (C), or Formula (D), are microencapsulated.
In still another embodiment, the
particles of the compound of any of Formula (A), Formula (B), Formula (C), or
Formula (D), are not
microencapsulated and are uncoated.
1002891 Suitable carriers for use in the solid dosage forms described
herein include, but are not limited to,
acacia, gelatin, colloidal silicon dioxide, calcium glycerophosphate, calcium
lactate, maltodeadrin, glycerine,
magnesium silicate, sodium caseinate, soy lecithin, sodium chloride,
tricalcium phosphate, dipotassium phosphate,
sodium stearoyl lactylate, carrageenan, monoglyceride, diglyceride,
pregelatinized starch,
hydroxypropylmethyicellulose, hydroxypropylmethylcellulose acetate stearate
sucrose, microcrystalline cellulose,
lactose, mannitol and the like.
1002901 Suitable filling agents for use in the solid dosage forms
described herein include, but are not limited to,
lactose, calcium carbonate, calcium phosphate, dibasic calcium phosphate,
calcium sulfate, tnicrocrystalline
cellulose, cellulose powder, dextrose, dextrates, dextran, starches,
pregelatinized starch,
hydroxypropylmethycellulose (HPMC), hydroxyprapylmethycellulose phthalate,
hydroxypropylmethylcellulose
acetate stearate (HPMCAS), sucrose, xylitol, lactitol, mannitol, scabitol,
sodium chloride, polyethylene glycol, and
the like.
1002911 In order to release the compound of any of Formula (A), Fornaila
(B), Formula (C), or Formula (D),
from a solid dosage form matrix as efficiently as possible, disiategrants are
often used in the formulation, especially
when the dosage forms are compressed with binder. Disintegrants help rupturing
the dosage form matrix by swelling
or capillary action when moisture is absorbed into the dosage form. Suitable
disintegrants for use in the solid dosage
forms described herein include, but are not limited to, natural starch such as
corn starch or potato starch, a
pregelatinized starch such as National 1551 or Amijelt or sodium starch
glycolate such as Promogel. or Explotabt
a cellulose such as a wood product, methylcrystalline cellulose, e.g.,
Avicel*, Avicel. PHI 01, Avicel PHIO2,
Avicel PH105, Elcema. P100, Emcocele. Vivacele, Ming Tie , and Soars-Floc.,
methylcellulose, croscannellose,
47
Date Recue/Date Received 2022-11-04

or a cross-linked cellulose, such as cross-linked sodium
carboxymethylcellulose (Ac-Di-Sor), cross-linked
carboxymethylcellulose, or cross-linked croscannellose, a cross-linked starch
such as sodium starch glycolate, a
cross-linked polymer such as crospovidone, a cross-linked
polyvinylpyrrolidone, alginate such as alginic acid or a
salt of alginic acid such as sodium alginate, a clay such as Veegum HV
(magnesium aluminum silicate), a gum
such as agar, guar, locust bean, Karaya, pectin, or Migacanth, sodium starch
glycolate, bentonite, a natural sponge, a
surfactant, a resin such as a cation-exchange resin, citrus pulp, sodium
lauryl sulfate, sodium lauryl sulfide in
combination starch, and the like.
[00292] Binders impart cohesiveness to solid oral dosage form
formulations: for powder filled capsule
formulation, they aid in plug formation that can be filled into soft or hard
shell capsules and for tablet formulation,
. 10 they ensure the tablet remaining intact after compression and help
assure blend uniformity prior to a compression or
fill step. Materials suitable for use as binders in the solid dosage forms
described herein include, but are not limited
to, carboxymethylcellulose, rnethylcellulose (e.g., Methocel ),
hydroxypropylmethylcellulose (e.g. Hypromellose
TJSP Phannacoat-603, hydroxypropylmethylcelkdose acetate stearate (Aqoate 11S-
LF and HS),
hydroxyethylcellulose, hydroxypropylcellulose (e.g., Klucel ), ethylcellulose
(e.g., Ethocell), and microcrystalline
cellulose (e.g., Avicee), microcrystalline dextrose, amylose, magnesium
aluminum silicate, polysaccharide acids,
bentonites, gelatin, polyvinylpyrrolidone/vinyl acetate copolymer,
crospovidone, povidone, starch, pregelatinized
. starch, tragacanth, dextrin, a sugar, such as sucrose (e.g., Dipae),
glucose, dextrose, molasses, mannitol, sorbitol,
xylitol (e.g., Xylitabt), lactose, a natural or synthetic gum such as acacia,
tragacanthõ ghat-6 gum, mucilage of isapol
husks, starch, polyvinylpyrrolidone (e.g., Povidone CL, Kollidon CL,
Polyplasdone XL-10, and Povidone K-
12), larch arabogalactan, Veegum , polyethylene glycol, waxes, sodium
alginate, and the like.
[00293] In general, binder levels of 20-70% are used in powder-filled
gelatin capsule formulations. Binder
usage level in tablet formulations varies whether direct compression, wet
granulation, roller compaction, or usage of
other excipients such as fillers which itself can act as moderate binder.
Formulators skilled in art can determine the
binder level for the formulations, but binder usage level of up to 70% in
tablet formulations is common.
[00294] Suitable lubricants or glidants for use in the solid dosage forms
described herein include, but are not
limited to, stearic acid, calcium hydroxide, talc, corn starch, sodium stearyl
furnerate, alkali-metal and alkaline earth
metal salts, such as aluminum, calcium, magnesium, zinc, stearic acid, sodium
stearates, magnesium stearate, zinc
stearate, waxes, Stearowet , boric acid, sodium benzoate, sodium acetate,
sodium chloride, leucine, a polyethylene
glycol or a methoxypolyethylene glycol such as CarbowaxTm, PEG 4000, PEG 5000,
PEG 6000, propylene glycol,
sodium oleate, glyceryl behenate, glyceryl palmitostearate, glyceryl benzoate,
magnesium or sodium lauryl sulfate,
and the like.
[00295] Suitable diluents for use in the solid dosage forms described
herein include, but are not limited to,
sugars (including lactose, sucrose, and dextrose), polysaccharides (including
dextrates and maltodextrin), polyols
(including mannitol, xylitol, and sorbitol), cyclodextrins and the him.
[00296] The term "non water-soluble diluent" represents compounds typically
used in the formulation of
pharmaceuticals, such as calcium phosphate, calcium sulfate, starches,
modified starches and microcrystalline
cellulose, and microcellulose (e.g., having a density of about 0.45 g/cm3,
e.g. Avicel, powdered cellulose), and talc.
[00297] Suitable wetting agents for use in the solid dosage forms
described herein include, for example, oleic
acid, glyceryl monostearate, sorbitan Inonooleate, sorbitan monolaurate,
triethanolarnine oleate, polyoxyethylene
sorbitan monooleate, polyoxyethylene sorbitan monolaurate, quaternary ammonium
compounds (e.g., Polyquat
101), sodium oleate, sodium lauryl sulfate, magnesium stearate, sodium
docusate, triacetin, vitamin E TPGS and the
like.
48
Date Recue/Date Received 2022-11-04

[002981 Suitable surfactants for use in the solid dosage forma described
herein include, for example, sodium
hairy! sulfate, scubitan monooleate, polyoxyethylene sorbitan monooleate,
polysorbates, polaxomers, bile salts,
glyceryl monostearate, copolymers of ethylene oxide and propylene oxide, e.g.,
Pluronic (BASF), and the like.
[002991 Suitable suspending agents for use in the solid dosage forms
described here include, but are not limited
to, polyvinylpyrrolidone, e.g., polyvinylpyrrolidone K12, polyvinylpyrrolidone
KI7, polyvinylpyrrolidone /125, or
polyvinylpyrrolidone K.30, polyethylene glycol, e.g., the polyethylene glycol
can have a molecular weight of about
300 to about 6000, or about 3350 to about 4000, or about 7000 to about 5400,
vinyl pyrrolidone/vinyl acetate
copolymer (S630), sodium carboxymethylcellulose, methylcelhdose, hydroxy-
propylmethylcellulose, polysorbate-
80, hydroxyethylcellulose, sodium alginate, gums, such as, e.g,., gum
tragacanth and gum acacia, guar gum,
xanthans, including xanthan gum, sugars, cellulosics, such as, e.g., sodium
carboxymethylcellulose, methylcellulose,
sodium carboxymethylcellulose, hydroxypropylmethylcellulose,
hydroxyethylcellulose, polysorbate-80, sodium
alginate, polyethoxylated sorbitan monolaurate, polyethoxylated sorbitan
monolaurate, povidone and the like.
[003001 Suitable antioxidants forum in the solid dosage forms described
herein include, for example, e.g.,
butylated hydroxytoluene (BHT), sodium ascorbate, and tocopherol.
[003011 It should be appreciated that there is considerable overlap between
additives used in the solid dosage
forms described herein. Thus, the above-listed additives should be taken as
merely exemplary, and not limiting, of
the types of additives that can be included in solid dosage forms described
herein. The amounts of such additives
can be readily determined by one skilled in the art, according to the
particular properties desired.
[003021 In other embodiments, one or more layers of the pharmaceutical
formulation are plasticized.
Illustratively, a plasticizer is generally a high boiling point solid or
liquid. Suitable plasticizers can be added from
about 0.01% to about 50% by weight (w/w) of the coating composition.
Plasticizers include, but are not limited to,
diethyl phthalate, citrate esters, polyethylene glycol, glycerol, acetylated
glycerides, triacetin, polypropylene glycol,
polyethylene glycol, triediy1 citrate, dibutyl sebacate, stearic acid,
stearol, stearate, and castor oiL
1003031 Compressed tablets are solid dosage forms prepared by compacting
the bulk blend of the formulations
described above. In various embodiments, compressed tablets which are designed
to dissolve in the mouth will
include one or more flavoring agents. In other embodiments, the compressed
tablets will include a film surrounding
the final compressed tablet. In some embodiments, the film coating can provide
a delayed release of the compound
of of any of Formula (A), Formula (B), Formula (C), or Formula (D), from the
formulation. In other embodiments,
the ftlin coating aids in patient compliance (e.g., Opade coatings or sugar
coating). Film coatings including
Opadry. typically range from about 1% to about 3% of the tablet weight. In
other embodiments, the compressed
tablets include one or more excipients.
[00304) A capsule may be prepared, for example, by placing the bulk blend
of the formulation of the
compound of any of Formula (A), Formula (B), Formula (C), or Formula (D),
described above, inside of a capsule.
In some embodiments, the formulations (non-aqueous suspensions and solutions)
are placed in a soft gelatin
capsule. In other embodiments, the formulations are placed in standard gelatin
capsules or non-gelatin capsules such
as capsules comprising HPMC. In other embodiments, the formulation is placed
in a sprinkle capsule, wherein the
capsule may be swallowed whole or the capsule may be opened and the contents
sprinkled on food prior to eating.
In some embodiments, the therapeutic dose is split into multiple (e.g., two,
three, or four) capsules. In some
embodiments, the entire dose of the formulation is delivered in a capsule
form.
1003051 In various embodiments, the particles of the compound of any of
Formula (A), Formula (B), Formula
(C), or Formula (D), and one or more excipients are dry blended and compressed
into a mass, such as a tablet,
having a hardness sufficient to provide a pharmaceutical composition that
substantially disintegrates within less than
49
Date Recue/Date Received 2022-11-04

about 30 minutes, less than about 35 minutes, less than about 40 minutes, less
than about 45 minutes, less than about
50 minutes, less than about 55 minutes, or less than about 60 minutes, after
oral administration, thereby releasing the
formulation into the gastrointestinal fluid.
[003061 In another aspect, dosage forms may include microencapsulated
formulations. In some embodiments,
one or more other compatible materials are present in the microencapsulation
material. Exemplary materials include,
but are not limited to, pH modifiers, erosion facilitators, anti-foaming
agents, antioxidants, flavoring agents, and
carrier materials such as binders, suspending agents, disintegration agents,
filling agents, surfactants, solubilizers,
stabilizers, lubricant;, wetting agents, and diluents.
[003071 Materials useful for the microencapsulation described herein
include materials compatible with
compounds of any of Formula (A), Fominla (B), Formula (C), or Formula (D),
which sufficiently isolate the
compound of any of Formula (A), Formula (B), Formula (C), or Formula (D), from
other non-compatible excipients.
Materials compatible with compounds of any of Formula (A), Formula (B),
Formula (C), or Formula (D), are those
that delay the release of the compounds of of any of Formula (A), Formula (B),
Formula (C), or Formula (D), in
vivo.
[003081 Exemplary microencapsulation materials useful for delaying the
release of the formulations including
compounds described herein, include, but are not limited to, hydroxypropyl
cellulose ethers (HPC) such as Klucele
or Nisso HPC, low-substituted hydroxypropyl cellulose ethers (L-HPC),
hydroxypropyl methyl cellulose ethers
(FIPMC) such as Seppifilm-LC, Pharmacoate, Metolose SR, Methocel -E, Opadry
YS, PrimaFlo, Benecel MP824,
and Benecel MP843, methylcellulose polymers such as Methocele-A,
hydroxypropylmethylcellulose acetate stearate
Aqoat (HF-LS, HF-LG,HF-MS) and Metolosee, Ethylcelluloses (EC) and mixtures
thereof such as E461, Ethocel ,
Aqualorte-EC, Sureleasee, Polyvinyl alcohol (PVA) such as Opadry AMB,
hydroxyethylcelluloses such as
Natrosole, carboxymethylcelluloses and salts of carboxymethylcelluloses (CMC)
such as Aqualcme-CMC, polyvinyl
alcohol and polyethylene glycol co-polymers such as Kollicoat IR ,
monoglycerides (Myverol), triglycerides
(ICLX), polyethylene glycols, modified food starch, acrylic polymers and
mixtures of acrylic polymers with
cellulose ethers such as Eudragit EPO, Eudragit L30D-55, Eudragite FS 30D
Eudragit L100-55, Eudragit L100,
Eudragite S100, Eudragite RD100, Eudragite E100, Eudragite L12.5, Eudragite
S12.5, Eudragit NE30D, and
Eudragit NE 40D, cellulose acetate phthalate, sepifilms such as mixtures of
HPMC and stearic acid, cyclodextrin' s,
and mixtures of these materials.
[003091 In still other embodiments, plasticizers such as polyethylene
glycols, e.g., PEG 300, PEG 400, PEG
600, PEG 1450, PEG 3350, and PEG 800, stearic acid, propylene glycol, oleic
acid, and triacetin are incorporated
into the microencapsulation material. In other embodiments, the
microencapsulating material useful for delaying the
release of the pharmaceutical compositions is from the USP or the National
Formulary (NF). In yet other
embodiments, the microencapsulation material is Mucci. In still other
embodiments, the microencapsulation
material is methocel.
1003101 Microencapsulated compounds of any of Formula (A), Formula (B),
Formula (C), or Formula (D), may
be formulated by methods known by one of ordinary skill in the an. Such known
methods include, e.g., spray drying
processes, spinning disk-solvent processes, hot melt processes, spray chilling
methods, fluidized bed, electrostatic
deposition, centrifugal extrusion, rotational suspension separation,
polymerization at liquid-gas or solid-gas
interface, pressure extrusion, or spraying solvent extraction bath. In
addition to these, several chemical techniques,
e.g., complex coacervation, solvent evaporation, polymer-polymer
incompatibility, interfacial polymerization in
liquid media, in situ polymerization, in-liquid drying, and desolvation in
liquid media could also be used.
Date Recue/Date Received 2022-11-04

Furthermore, other methods such as roller conipaction.
extrusion/splanortization, coacervation. Or nanopatide
coating may also be used.
003111 In one embodiment, the particles of compounds of any of Formula
(A), POMO!' (B), Formula (C), or
Formula (D), are microencapsulated prior to being formulated into one of the
above foram. In still another
embodiment, some or most of the particles are coated prior to being further
formulated by using standard coating
procedures, such as those described in Remington'b -Pharmaceutical Sciences,
20th Edition (2000).
1003121 In other embodiments, the solid dosage formulations of the
compounds of any of Formula (A),
Formula (B), Formula (C), or Formula (D), am plasticized (coated) with one or
more layers. Illustratively, a
plasticizer is generally a high boiling point solid or liquid. Suitable
plasticizers can be added from about 0.01% to
about 50% by weight (wive) of the coating composition. Plasticizers include,
but are not limited to, diethyl phthalate,
citrate esters, polyethylene glycol, glycerol; acetylated glycerides,
triacetin, polypropylene glycol, polyethylene
glycol, triethyl citrate, dibutyl sebacate, deaths acid, shiainl, acerate, and
castor oil.
1003131 In other embodiments, a powder including the formulations with a
compound of any of Formula (A),
Farm& (B), Formula (C), or Formula (B), described herein, may be formulated to
include one or more
=
pharmaceutical excipients and flavors. Such a powder may be prepared, for
example, by mixing the formulation and ,
optional pharmaceutical excipients to form a bulk blend composition.
Additional embodiments also include a
suspending agent and/or a wetting agent This bulk blend is uniformly
subdivided into unit dosage packaging or
multi-dosage packaging units.
1003141 In still other embodiments, effervescent powders are also
prepared in accordance with the present
disclosure. Effervescent salts have bemused to disperse medicines in water for
oral administration. Effervescent
salts are granules or coarse powders containing a medicinal agent in a dry
mixture, usually composed of sodium
bicarbonate, citric acid said/or tartaric acid. When salts of the compositions
described herein are added to water, the
acids and the base react to liberate carbon dioxide gas, thereby causing
"effervescence." Examples of effervescent
salts include, e.g., the following ingredients: sodium bicarbonate or a
mixture of sodium bicarbonate and sodium
carbonate, citric acid and/or tartaric acid. Any acid-base combination that
results in the liberation of carbon dioxide
can be used in place of the combination of sodium bicarbonate and citric and
tartaric acids, as long as the ingredients
were suitable for pharmaceutical use and result in a pH of about 6.0 or
higher.
1003151 In other embodiments, the formulations descnlied herein, which
include a compound of Formula (A),
are :gelid dispersions. Methods of producing such solid dispersions are known
in the art and include, but are not
limited to, for example, U.S. Pat. Nos. 4,343,789. 5,340,591, 5,456,923,
5,700,485, 5,723,269, and U.S. Pub. Appl
2004/0013734. In mill other embodiments, the formulations
described herein are solid solutions. Solid solutions incorporate i substance
together with the active agent and other
excipients such that heating the mixture results in dissolution of the drug
and the resulting composition is then
cooled to provide a solid blend which can be further formulated or directly
added to a capsule or compressed into a
tablet Methods of producing such solid solutions are known in the art and
include, but are not limited to, for
example, U.S. Pat Nos. 4,131,273,5,281,420, and 6,083.518.
(00316) The pharmaceutical solid oral dosage forms including formulations
described herein, which include a
compound of any of Formula (A), Formula (B), Formula (C), or Formula (D), can
be further formulated to provide a
controlled release of the compound of Formula (A). Controlled release refers
to the release of the compound of any
of Formula (A), Formula (B), Formula (C), or FOTM11117 (D), from a dosage form
in which it is incorporated
according to a desired profile over an extended period of time..Controlled
release profiles include, for example,
51
Date Recue/Date Received 2022-11-04

=
sustained release, prolonged release, pulsatile release, and delayed release
profiles. In contrast to immediate release
compositions, controlled release compositions allow delivery of an agent to a
subject over an extended period of
time according to a predetermined profile. Such release rates can provide
therapeutically effective levels of agent for
an extended period of time and thereby provide a longer period of
phamiacologic response while minimizing side
effects as compared to conventional rapid release dosage forms. Such longer
periods of response provide for many
inherent benefits that are not achieved with the corresponding short acting,
immediate release preparations.
1003171 In some embodiments, the solid dosage forms described herein can
be formulated as enteric coated
delayed release oral dosage forms, i.e., as an oral dosage form of a
pharmaceutical composition as described herein
which utilizes an enteric coating to affect release in the small intestine of
the gastrointestinal tract The enteric
coated dosage form may be a compressed or molded or extruded tablet/mold
(coated or uncoated) containing
granules, powder, pellets, beads or particles of the active ingredient and/or
other composition components, which
are themselves coated or uncoated. The enteric coated oral dosage form may
also be a capsule (coated or uncoated)
containing pellets, beads or granules of the solid carrier or the composition,
which are themselves coated or
uncoated.
1003181 The term "delayed release" as used herein refers to the delivery so
that the release can be accomplished
at some generally predictable location in the intestinal tract more distal to
that which would have been accomplished
if there had been no delayed release alterations. In some embodiments the
method for delay of release is coating.
Any coatings should be applied to a sufficient thickness such that the entire
coating does not dissolve in the
gastrointestinal fluids at pH below about 5, but does dissolve at pH about 5
and above. It is expected that any
anionic polymer exhibiting a pH-dependent solubility profile can be used as an
enteric coating in the methods and
compositions described herein to achieve delivery to the lower
gastrointestinal tract In some embodiments the
polymers described herein are anionic carboxylic polymers. In other
embodiments, the polymers and compatible
mixtures thereof, and some of their properties, include, but are not limited
to:
1003191 Shellac, also called purified lac, a refined product obtained from
the resinous secretion of an insect.
This coating dissolves in media of pH >7;
1003201 Acrylic polymers. The performance of acrylic polymers (primarily
their solubility in biological fluids)
can vary based on the degree and type of substitution. Examples of suitable
acrylic polymers include methacrylic
acid copolymers and ammonium methacrylate copolyrners.-The Eudragit series E,
L, S, RL, RS and NE (Rohm
Pharma) are available as solubilized in organic solvent, aqueous dispersion,
or dry powders. The Eudragit series ltL,
NE, and RS are insoluble in the gastrointestinal tract but are permeable and
are used primarily for colonic targeting.
The Eudragit series E dissolve in the stomach. The Eudragit series L, L-30D
and S are insoluble in stomach and
dissolve in the intestine;
1003211 Cellulose Derivatives. Examples of suitable cellulose derivatives
are: ethyl cellulose; reaction mixtures
of partial acetate esters of cellulose with phthalic anhydride. The
performance can vary based on the degree and type
of substitution. Cellulose acetate phthalate (CAP) dissolves in pH >6.
Aquateric (FMC) is an aqueous based system
and is a spray dried CAP psuedolatex with particles <1 rim. Other components
in Aquateric can include pluronics,
Tweens, and acetylated monoglycerides. Other suitable cellulose derivatives
include: cellulose acetate trimellitate
(Eastman); methylcellulose (Pharmacoat, Methocel); hydroxypropylmethyl
cellulose phthalate (HPMCP);
hydroxypropyhnethyl cellulose succinate (HPMCS); and
hydroxypropyhnethylcellulose acetate succinate (e.g.,
AQOAT (Shin Etsu)). The performance can vary based on the degree and type of
substitution. For example,
HPMCP such as, HP-50, HP-55, HP-55S, HP-55F grades are suitable. The
performance can vary based on the
degree and type of substitution. For example, suitable grades of
hydroxypropylmethylcellulose acetate succinate
52
Date Recue/Date Received 2022-11-04

inthula, but are not limited to. AS-LO (LP), which dissolves at pH 5, AS-MG
(MP), which dissolves at pH 5.5, and
AS-HO (HF), which dissohes at higher pH. These polymers are offered as
granules, or as fine powders for aqueous
dispersions;
(003121 Poly Vinyl Acetate Phthalate (PVAP). PVAP dissolves in pH >5, and
it is much Jess permeable to
. water vapor and gastric fluids.
10o3231 In some embodiments, the coating can, and usually does, contain a
*Wei= and possibly Other
coaling exciplento such as colorants, talc, and/or magnesium stellate, which
are well known in the art Suitable
plasticizers include triethyl citrate (Moil= 2), trim& (glyceryl triacetate),
acetyl tidily' citrate (abaft A2),
Carbovaix.400 (polyethylene glycol 400), diethyl phthalate, tributyi chute,
acetylated monoglyeeridea glycerol,
fatly acid esters, propylene glycol, and dibutyl phthalate. In pardeular,
anionic carboxylic acrylic polymers usually
will contain 10-25% by weight of a plasticiier, especially dibutyl phthalate,
polyethylene glycol, biethyl citrate and
thiamin. Conventional coating techniques such as spray or pan coating are
employed to apply coatings. The coating
Thicirnerii must be sufficient to ensure that the oral dosage form remains
intact until the dashed site of topical
= delivay in the intestinal tact is reached.
1003241 co*krants, dctacicillers, surfactmts, 'seaming agents, lubricants
(e.g., cared& wax or PEG) may be
added to the coatings besides plasticizers to solubilize or disperse the
coating material, and to improve coating
perfbrreance and the coated product =
1003251. In other embodiniento, the formulations described herein, which
includes compound of Formula (A),
are delivered using a pulsatile dosage form. A pulse& dosage form is capable
of providing one or more immediate
release pulses at predetermined time points after a controlled lag time or at
specific sites. Puluble dosage foznii
inrtiuting the formulations demand bezeiu, which include a compound of any of
Formula (A), Formula (B),,
Formula (C), or Formula (D), may be administered using a variety ofpulsable
formulations known in the art For
example, such formulations include, but are not limited to, those described in
U.S. Pat. Nos_ 5,011,692,5,017,381,
5,229,135, and 5,840,329 . Other pulsatile release dosage
fomis suitable for use with the present formulations include, but are not
limited to, for example, 'U.S. Pat Nos.
4,871,549, 5,260,068, 5,260,069, 5,508,040, 5,567,441 and 5,837,284 ,
none erobodimmit, the conlzolled release dosage foam is pulsatile zeleasi
solid oral dosage form
including at least two groups ofparticles, (La multiparticulate) each
containing the Ibmulation described herein.
The fiat group of particles provides a substantially immediate dose of the
compound of any of Formula (A),
Formula (B), Formula (C), or Formula (D), upon ingestion by a mammal. The
first group of policies can be either
uncoated or include a coating smdfor sealant. The second group ofputicles
inel.(1.4 coated particles, which includes
from about 2% to about 75%, from about 2.5% to about 70%, or from about 40% to
about 70%, by weight of the
total dose of the compound of any of Fcarauki (A), Formula (13), Formula (C),
or Formula (D), in said formulation;
in admixture with one or MOTO binders. The coating includes a pharmaceutically
acceptable ingredient titan amount
sufficient to provide a delay of from about 2 hours to about 7 hours following
ingestion before release of the second
= dose. Suitable coatings include one or mom differentially degradable
coatings such as, byway of example only, pH
sensitive coatings (enteric coatings) stick as acrylic resins (e.g.., Suffrage
MFG, 'incluse L30D-55, Budragie FS
30D Endue. Li00-55, Eudrage LIOO, Eudrage 3100, Endragit. RD100, Budrage B100,
Maine L12.5,
Endrage S12-5, and &duet NE30D, Budragit. NB 401).) either alone or blended
with cellulose derivatives,
e.g., ethyleellulose, or non-enteric coatings having variable thickness to
provide differential release of the
formulation that includes a compound of any of Formula (A), Formula (B),
Formula (C), or Forinula (1)).
53
Date Recue/Date Received 2022-11-04

1003261 Many other types of controlled release systems known to those of
ordinary skill in the art and are
suitable for use with the formulations deacnbed herein. Examples of such
delivery systems include, e.g., polymer-
based systems, such as polylactic and polyglycolic acid, plyanhydrides and
polyeaprolactnne; porous matrices,
nonpolytner-baseti systems that are lipids, including sterols, such as
cholesterol, cholesterol esters and fifty acids, or
neutral fats, such as mono-, di- and niglycerides; hydrogel release systems;
silastic systems; peptide-based systems;
wax coatings, bioerodibie dosage forms, compressed tablets using conventional
binders and the lilts. See, e.g.,
Liberman et al-, Pharmaceutical Dosage Forms, 2 Ed., VoL 1,pp. 209-214(1990);
Singh at al., Encyclopedia of
Pharmaceutical Technology, 2" Ed., pp. 751-753 (2002); U.S. Pat. Nos.
4,327,725, 4,624,848, 4,968,509,
5,461,140, 5,456,923, 5,516,527, 5,622,721, 5,686,105, 5,700,410, 5,977.175,
4465,014 and 6,932,983
1003271 ba some embodiments, pharmaceutical formulations arc provided
that include pinkies of the
compounds of any of Formula (A.), Formula (B), Formula (C), or Formula (0),
described benzin and at least one
dispersing swat or suspending agent for oral administration to a subject. The
formulations may be a powder andfor
granules for suspension, and upon admixture with water, a substantially
uniform suspension is obtained.
1003281 Liquid formulation dosage forms for oral administration can be
aqueous suspensions selected flora the
group including, but not limited to, pharmaceutically acceptable aqueous oral
dispersions, emulsions, solutions,
elixirs, eels, and syrups. See, e.g., Singh at al., Encyclopedia
ofPharmaceutical Technology, 214 Ed., pp. 754-757
= (2002). In addition to the particles of compound of Fantails (A), the
liquid dosage forms may include additives,
such as (a) disintegrating agents; (b) dispersing agents; (c) wetting agents;
(d) at least one preservative, (e) viscosity
, 20 enhancing agents, (1) at least one sweetening agent, and (g) at
least one flavoring agent. In some embodiments, the
aqueous dispersions can thither includes crystalline inhibitor.
100329) The aqueous suspensions and dispersions described herein can
remain in a hom*ogenous state, as
defined in The USP Phannaciste Pharmacopeia (2005 edition, chapter 905), for
at least 4 hours. The hom*ogeneity
should be determined by a sampling method consistent with regard to
determining hom*ogeneity of the entire
composition. In one embodiment, an aqueous suspension can be re-suspended into
a hom*ogenous suspension by
physical agitation lasting less thsn 1 7minnir. In another embodiment, an
aqueous suspension can be re-suspended
into a hom*ogenous suspension by physical agitation lasting less than 45
seconds. In yet another embodiment, an
aqueous suspension can be re-suspended into a hom*ogenous suspension by
physical agitation lasting less than 30
seconds. In still another embodimmt, no agitation is necessary to maintain a
hom*ogeneous aqueous div...ision.
1003301 Examples of disintegrating agents for in the
aqueous suspensions and dispersions include, but aro
not limited to, a starch, e.g., a natural starch such as corn starch or potato
starch, a pregelaiinized starch such as
National 1551 or Amijer, or sodium starch glycohtte such as Promogel or
Explotabs; a cellulose such as a wood
product, methylcrystalline cellulose, Avicel ,
Avicet P11101. Avicel 211102, Avicel PHI05, Oceans P100,
Emcocer, Vivacel , Ming rue, and SoBra-Floc , methyleAlrilose, croscannellose,
or a cross-linked cellulose, such
as cross-linked sodium carboxymethylcellulose (Ac-Di-Sol'), cross-linked
carboxymethylcellulose, or cross-linked
croscarmellose; a cross-linked starch such as sodium starch gbjcolate; a cross-
linked polymer such as crospavidone;
a cross-linked polyvinylpyrrolidone; alginate such as alginic acid or a salt
of alginic acid such as sodium alginate; a
clay such as Veegurn FIV (magnesium aluminwn silicate); a gum such as agar,
guar, locust bean, ICaraya, pectin, or
tragacandi; sodium starch glycolate; bcntearite; a natural sponge.; a
surfactant; a resin such ass cation-exchange ,
resin; citrus Pulps sodium lauryl sulfate; sodium butyl sulfate in combination
starch; and the like.
100331) In some embodiments, the dispersing agents suitable for the
aqueous suspensions and dispersions
described herein are known in the art and include, for example, hydrophilic
polymers, electrolytes. Tween 60 or
54
Date Recue/Date Received 2022-11-04

= 80, PEG, polyviuylpyrrolidone (PVP; commercially known as Plasdonee), and
the carbohydrate-based dispersing
agents such as, for example, hydroxypropykellulose and hydroxypropyl cellulose
ethers (e.g., HPC, HPC-SL, and
HPC-L), hydroxypropyl methylcellulose and hydroxypropyl methylcellulose ethers
(e.g. HPMC 1(100, HPMC
X4M, HPMC K15M, and RPMC KlOOM), cuboxymethylcelklose sodium, methylcellulose,
hydroxyethylcellulose,
hydroxypropylmethyl-cellulose phthalate, hydroxypropylmethyl-cellulose acetate
steamte, noncrystalline cellulose,
magnesium aluminum silicate, triethanolamine, polyvinyl alcohol (PVA);
polyvinylpyrrolidone/vinyl acetate
copolymer (Plasdonet e.g., 5-630), 4-(1,1,3,3-tetmmethylbuty1)-phenol polymer
with ethylene oxide and
formaldehyde (also known as tyloxapol), poloitarners (e.g., Pluronics F68e,
F88e, and F108e, which are block
copolymers of ethylene oxide and propylene oxide); and poloxamines (e.g.,
Tetronic 908", also known as
Pokciamine 908*, which is a teuafunciional block copolymer derived from
sequential addition of propylene oxide
and ethylene oxide to ethylenediamine (BASF Corporation, Parsippany, N.J.)).
In other embodiments, the dispersing
agent is selected from a group not comprising one of the following agents:
hydrophilic polymers; electrolytes;
Tamen = 60 or 80; PEG; polyvinylpprolidone (PVP); hydroxypropylcellulose and
hydroxypropyl cellulose ethers
(e.g., WC. HPC-SL, and HPC-L); hydroxypropyl methylcelhdose and hydroxypropyl
methylcellulose ethers (e.g.
HPMC 1(100, HPMC 1(414, HPMC K15M. HPMC K1OOM, and Pharmacoate USP 2910 (Shin-
Etsu));
carboxymethylcellulose sodium methylcellulose; hydroxyethylcelhilose;
hydroxypropyhnethyl-cellulose phthalate;
hydroxypropylmethyl-cellulose acetate stearate; non-crystalline cellulose;
magnesium alinnimun silicate;
triethanolamine; polyvinyl alcohol (PVA); 4-(1,1,3,3-tetramedrylbuty1)-phenol
polymer with ethylene oxide and
formaldehyde; polexamers (e.g., Pluronks F68e, F88., and F108e, which are
block copolymers of ethylene oxide
and propylene oxide); or poloxamines (e.g., Tetronic 908., also known as
Poloxamine 908.).
. 1003321 Wetting agents suitable for the aqueous suspensions and
dispersions described herein are known in the
art and include, but are not limited to, cetyl alcohol, glycerol monostearate,
polyoxyethylene sorbitan fatty acid
esters (e.g., the commercially available Tweens* such as e.g., Tween 20' and
Tween 80* (ICI Specialty
Chemicals)), and polyethylene glycols (e.g., Carbowaxs 3350* and 1450e, and
Carbopol 934e (Union Carbide)),
oleic acid, glyceryl monostearate, sorbitan monooleate, sorbitan monolaurate,
niethanolamine oleate,
polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaucate,
sodium oleate, sodium lauryl sulfate,
sodium docusate, triacetin, vitamin E TPGS, sodium taurocholate, simethicone,
phosphotidykholine and the like
j003331 Suitable preservatives for the aqueous suspensions or dispersions
described herein include, for
example, potassium sorbate, parabens (e.g., methylparaben and propy)paraben),
benzoic acid and its salts, other
esters of painhydroxybenzoic acid such as butylparaben, alcohols such as ethyl
alcohol or benzyl alcohol, phenolic
compounds such as phenol, or quaternary compounds such as benzalkonium
chloride. Preservatives, as used herein,
are incorporated into the dosage form at a concentration sufficient to inhibit
microbial growth.
1003341 Suitable viscosity enhancing agents for the aqueous suspensions or
dispersions described herein
include, but are not limited to, methyl cellulose, xanthan gum, carboxymethyl
cellulose, hydroxypropyl cellulose,
hydroxypropylmethyl cellulose, Plasdone S-630, carbomex, polyvinyl alcohol,
alginates, acacia, chitosans and
combinations thereof. The concentration of the viscosity enhancing agent will
depend upon the agent selected and
the viscosity desired.
1003351 Examples of sweetening agents suitable for the aqueous suspensions
or dispersions described herein
include, for example, acacia syrup, acesulfame K, alitame, anise, apple,
aspartame, banana, Bavarian cream, berry,
black currant, butterscotch, calcium citrate, camphor, caramel, cherry, cherry
cream, chocolate, cinnamon, bubble
gum, citrus, citrus punch, citrus comm, cotton candy, cocoa, cola, cool
cherry, cool citrus, cyclamate, cylamate,
dextrose, eucalyptus, eugenol, fructose, fruit punch, ginger,
g,lycyrrhetinate, glycyrrhiza (licorice) syrup, grape,
Date Recue/Date Received 2022-11-04

=
grapefruit. honey, 'same% lemon. Bine lemon cream, toonoarranontum
glrzhistinsto (MagoaSweet.),
mannItell, ample, neushmallow, nd5v1,nthil crean. mixed berry, neoheepecidine
DC, mann" orange, pear,
peach, peppermint, peppermint cream, Plowed Powder, napbeay, root beer, rum,
saccharin. imitate. 'orbital,
spearmint, spearmint cream, strawberry, strawberry cream, stevia, sucralose,
sucrose, sodium sacchsrin, saccharin,
aspartame, acesulme potassium, marmite% tali; sueralose, sorbitol, swiss
cream, tagatose, tangerine, ibiumatin,
tuni fiuitti, vanilla, walnut, watermelon, wild cherry, wintergreen, rrylitol,
or any combhatian of these flavoring
ingredients, e.g., anise-nrenthol, cherry-anise, cinnamon-orange, ebony-
cinnamon, chocolate-whit, honey-lemon,
lemon-lime, lemon-mint, mendiol-mamdyptm, oninge-creato, vanilla-mint, and
mixture' thereat In one
embodiment, the,squeous liquid dispersion can comprise a sweetening agent or
flavoring agent in a concentration
11) ranging from about 0.001% to about 1.0% the volume of the aqueous
dispersion. In another embodiment, the
aqueous liquid dispersion can comprim a sweetening agent or flavoring agent in
a concentration ranging from about
0.005% to about 0.5% the volume of the aqueous dispersion. In yet another
embodiment, the aqueous liquid
dispersian can ocmq:aletra sweetening agent or flavoring agent in a
concentration ranging from about 0.01% to about
. 1.0% the volume of the aqueous dispersion.
15 1003361 In addition to the additives lined above, the liquid
forundadons can also include inert diluents
commonly used in the art, such as water or other solvents, solubilixing
agents, and emulsifiers. Exemplary
enmbifiers are ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl
acetate, bensyl alcohol, beautyl benzoate,
propylemeglycol, 1,3-betylemeglycol. dintedryfformamide, wenn beryl sulfate,
sodhun &mensal; cholesterol,
cholesterol asters, taurocholic acid, phosphotidylcholine, oils, such as
cottonseed oil, grotmdaut oil, corn germ oil,
20 olive oil, castor oil, and sesame oil, glycerol, tetrohydrofurfistyl
alcohol, polyethylene glycols, fatty acid esters of
sorbitan, or mixtures of these substimr,.., and the like.
= 1003371 In some embodiments, the pharmaceutical fbonulalions
described herein can be self-emulsifying drug
delivery systems (SEDDS). Emulsions are dispersions of one heroin:Me phase in
mother, usually in the form of
droplets. Generally, emulsions are crated by vigorous mechanical dispersion.
SEDDS, as opposed to emulsions or
25 microemulsions, spontaneously form emulsions when added to an excess of
water without any external mechanical
dispersion or agitation. An advantage of SEDDS is that only gentle mixing is
required to distribute the droplets
throughout the solution. Additionally, water or the aqueous phase can be added
just prior to administration, which
ensures stability of an unstable or hydrophobic naive ingredient, This, the
SEDDS provides an effective delivery
system for oral and perenteral delivery of hydrophobic active ingredients.
SEDDS may provide Improvements in the
30 bioavailability of hydrophobic active ingredients. Methods of producing
self-emulsifying dosage forms are known in
the art and include, but are not limited to, fbr example, US. Pat. Nos.
5,858,401,6,667,048, and 6,960,563
M03381 It is to be appreciated that them is overlap between the above-
listed additives used in the aqueous
dispersions or suspensions described herein, since a given additive is often
classified differently by different
35 practitioners in the field, or i; commonly used for any of several
different functions. This, the above-listed additives
should be taken as merely exemplary, and not limiting, of the types of
additives that can be included in fornsdations
described herein. The amounts of such additives can be readily determined by
one skilled in the art, according to the
particular properties desired.
II:Manual Formulations
40 1003391 Intranasal formulations are known in the an and are described
in, for example, U.S. Pat. Nos.
4,476,116,5,116,817 end d,391,452 Formulations that
= include a compound of any of Folimula (A), Formula (13), Formula (C), or
Formula (D), which are prepared .
56
Date Recue/Date Received 2022-11-04

according to these and other techniques well-known intim art are prepared as
solutions in saline, employing benz)4
alcohol or other suitable preservatives, fluorocarbons, ancVor other
solubilizing or dispersing agents blown in the
art. See, for example, Ansel, H. C. et at, Pharmaceutical Dosage Forms and
Drug Delivery Systems, Sixth Ed.
(1995). Preferably these compositions and formulations are prepared with
suitable nontoxic pharmaceutically
acceptable ingredients. These ingredients are known to those skilled in the
preparation of nasal dosage forms mid
some of these can be found in REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY,
21st edition,
2005,a standard refinance in the field. The choice of suitable minim is highly
dependent upon the exact nature of
the nasal dosage form desired, e.g., solutions, suspensions, ointments, or
gels. Nasal dosage forms generally contain
large amounts of water in addition to the active ingredient ivfmor amounts of
other ingredients such as pH adjusters,
emulsifiers or dispersing agents, preservatives, surfactants, gelling agents,
or buffering and other stabilizing and
solubilizing agents may also be present The nasal dosage form should be
isotonic with nasal secretions.
1003401 For administration by inhalation, the compounds of any of
Formula (A), Formula (B), Formula (C), or
Formula (I)), described herein may be in a form as an aerosol, s mist or a
powder. Pharmaceutical compositions
described herein are conveniently delivered in the fonn of an aerosol spray
presentation from pressurized packs or a
=
nebnliser, with the use of a suitable propellant e,g., dichlerodifinommethane,
hichlorofluorcanethane,
dichlorobstmituoroediane, carbon dioxide or other suitable gas. In the case of
a pressurized aerosol, the dosage unit
may be determined by providing a valve to deliver a metered amount Capsules
and cartridges such as, by way of
example. only, gelatin for use in an inhaler or insufflator may be formulated
containing a powder mix of the
compound described herein and a suitable powder base such as lactose or
starch.
Blirrial Formulations
1003411 Buccal formuletions that include compounds of any of Forrmila
(A), Formula (B), Formula (C), or
Female (I)), may be administered using a variety of formulations known in the
art. For example, such formulations
include, but am not limited to, U.S. Pat Nos. 4,229,447,4,596,795, 4,755,386,
and 5,739,136.
In addition, the buccal dosage forms described herein can further include a
bioerodible (bydrolysable) polymeric carrier that also serves to adhere the
dosage form to the buccal mucous. The
buccal dosage form is fabricated so as bo erode gradually over a predetermined
time period, wherein the delivery of
the compound of any of Formula (A), Formula (B), Formula (C), or Formula (D),
is provided essentially throughout
Buccal drug delivery, as will be appreciated by those stalled hi the art,
avoids the disadvantages encountered with
oral drug administration, e.g., slow absorption, degradation oldie active
agent by fluids present in the
gastrointestinal tract andtor first-pass inactivation in the liver. With
regard to the bioerodible (hydrolysable)
polymeric carrier, it will be appreciated that virtually any such carrier can
be used, so long as the desired drug
release profile is not compromised, and the carrier is compatible with the
compound of any of Formula (A), Formula
(B), Formula (C), or Formula (D), and any other components that may be present
in the buccal dosage unit.
Generally, the polymeric carrier comprises hydrophilic (water-soluble and
water-swellahle) polymers that adhere to
the wet surface of the buccal =3COM Examples of polymeric carriers useful
herein include acrylic acid polymers
and co, e.g., those known as "clubmen- (Csrbopor, which may be obtained from
B.F. Goodrich, is one such
polymer). Other components may also be incorporated into the buccal dosage
forms described herein include, but
are not limited to, disintegrants, diluents, binders, lubricants, flavoring,
colorants, preservatives, and the like. For
buccal or sublingual administration, the compositions may take the form of
tablets, lozenges, or gels formulated in a
conventional manner.
57
Date Recue/Date Received 2022-11-04

Thoodermal Formulations
10034211 Tnmsdemid fonnulations described herein maybe administered
using a variety of devices which have
been described in the art. For example, such devices include, but are not
limited to, U.S. Pat. Nos. 3,598,122,
3,598,123, 3,710,795, 3.731,683, 3,742,951, 3,814,097, 3,921,636, 3,972,995,
3,993,072, 3,993,073, 3,994934,
4,031,894,4,060,084, 4,069.307, 4,077,407, 4,201,211, 4,230.105, 4,292,299,
4,292,303, 5,336,168, 5,665.378,
5,837,280, 5.869,090, 6,923,983, 6,929,801 and 6,946,144.
=
100343] The transdermal dosage forms described herein may incorporate
certain pharmaceutically acceptable =
=alphas whithere conventional in the art. lactic enbodiments, the ftandennal
formulations described herein
include at least three components: (1) a formulation of a compound of any of
Formula (A), Formula (B), Formula
(C), or Formula (D); (2) a penetration canner; and (3) Nu aqueous adjuvant- In
addition, handermal foundations
can include additional components such as, but not limited to, gelling agents,
creams and ointment bases, and the
like. In some embodiments, the transdermal formulation can further include a
woven or non-woven tacking material
= to enhance absorption arid prevent the removal of the tranedennal
&emulation from the skin. In other' embodiments.
the transdennal formulations described herein can maintain a saturated or
supersaturated state to promote diffusion
into the skin.
100344) Fomadations suitable for bandanna], administration of
compormda described herein may employ
transdarmal delivery devices and tranedermel delivery patches and can be
lipophilic anultiOnli or buffered, aqueous
solutions, dissolved and/or dispersed in a polymer or an adhesive. Such
patches may be constructed for continuous,
= 20 pulsatile, or on demand delivery of pharmaceutical agents.
Still further, transdermal delivery of the compounds
described herein can be accomplithed by means of iontophozetic patches and the
like. Additionally, transdermal
patches can provide controlled delivery of the compounds of any of Fomasla
(A), Formula (B), Formula (C), or
Pomade (D). The rate of absorption can be slowed by using rite-controlling
membranes or by trapping the
compound within a polymer matrix or geL Conversely, absorption enhancers can
be used to increase absorption. An
absorption enhancer or carrier can include absorbable pharmaceutically
acceptable solvents to assist passage through
the skin. For exempla, transdermal devices are in the form of a bandage
comprising a backing member, a reservoir
containing the compound optionally with carriers, optionally a rate
controlling barrier to deliver the compound to
the skin of the host at a controlled and predetermined mate over a prolonged
period of time, and means to secure the
device to the skin.
Injectable Fornulaiions
1003451 Formulations that include a compound of any of Familia (A),
Formula (B), Formula (C), or Rank
(D), suitable for inixanma cuter, subcutaneous, or intravenous injection may
include physiologically acceptable
sterile aqueous or non-aqueous solutions, dispersions, suspensions or
emulsions, and sterile powders for
reconstitution into sterile injectable solutions or dispersions. Examples of
suitable aqueous and non-aqueous
carriers, Moen% solvents, or vehicles including water, ethanol, polyols
(propyleneglycol, polyethylene-glycol,
glycerol, creanophor and the Re), suitable mixtures thereof, vegetable oils
(such as olive oil) and injectable organic
=
esters such as ethyl oleate. Proper fluidity can be maintained, for example,
by the use of a coating such as lecithin,
by the maintenance of the required particle size in the case of dispersions,
and by the use of surfactants.
Forneihtiens suitable fix subcutaneous injection may also contain additives
such as preserving. wetting,
emulsifying, and dispensing agents. Prevention of the growth of microorganisms
can be ensured by various
antibacterial and antillmgal agents, such.. peahens, clikaobotanol, phenol,
torbic acid, and the Me. It may also be
desirable to include isotonic agents, such as sugars, sodiumchloride, and the
lac. Prolonged absorption of the
58
=
Date Recue/Date Received 2022-11-04

injectable pharmaceutical form can be brought about by the use of agents
delaying absorption, such as aluminum
monostearate and gelatin.
1003461 For intravenous injections, compounds described herein may be
formulated hi aqueous solutions,
preferably in physiologically compatible buffers such as Hank's solution,
Ringer's solution, or physiological saline
buffer. For triuismucosal administration, penetrants appropriate to the
barrier to be permeated are used in the
formulation. Such penetrants are generally known in the art. For other
parenteral injections, appropriate
fonmilations may include aqueous or nonaqueous solutions, preferably with
physiologically compatible buffers or
excipients. Such excipients are generally known in the art.
1003471 Parenteral injections may involve bolus injection or continuous
infusion. Formulations for injection
may be presented in unit dosage form, e.g., in ampoules or in multi-dose
containers, with an added preservative. The
pharmaceutical composition described herein may be in a form suitable for
parenteral injection as a sterile
suspensions, solutions or emulsions in oily or aqueous vehicles, and may
contain formulatory agents such as
suspending. stabilizing and/or dispersing agents. Pharmaceutical fonnulations
for parenteral administration include
aqueous solutions of the active compounds in water-soluble form. Additionally,
suspensions of the active
.15 compounds may be prepared as appropriate oily injection suspensions.
Suitable lipophilic solvents or vehicles
Include fatty oils such as sesame oil, or synthetic fatty acid esters, such as
ethyl oleate or triglycerides, or liposomes.
Aqueous injection suspensions may contain substances which increase the
viscosity of the suspension, such as
sodium cathoxymethyl cellulose, sothitol, or dextran. Optionally, the
suspension may also contain suitable
stabilizers or agents which increase the solubility of the compounds to allow
for the preparation of highly
concentrated solutions. Alternatively, the active ingredient may be in powder
form for constitution with a suitable
vehicle, e.g., sterile pyrogen-free water, before use.
Other Formulations =
1003481 In certain embodiments, delivery systems for pharmaceutical
compounds may be employed, such as,
for example, liposomes and emulsions. In certain embodiments, compositions
provided herein can also include an
mucoadhesive polymer, selected from among, for example,
carboxymethylcellulose, carbomer (acrylic acid
polymer), poly(methylmethacrylate), polyacrylamide, polycarbophil, acrylic
acid/butyl acrylate copolymer, sodium
alginate and dextran.
[00349] In some embodiments, the compounds described herein may be
administered topically and can be
formulated into a variety of topically administrable compositions, such as
solutions, suspensions, lotions, gels,
pastes, medicated sticks, balms, creams or ointments. Such pharmaceutical
compounds can contain solubilizers,
stabilizers, tonicity enhancing agents, buffers and preservatives.
[00350] The compounds described herein may also be formulated in rectal
Compositions such as enemas, rectal
gels, rectal foams, rectal aerosols, suppositories, jelly suppositories, or
retention enemas, containing conventional
suppository bases such as cocoa butter or other glycerides, as well as
synthetic polymers such as
polyvinylpyrrolidone, PEG, and the like. In suppository forms of the
compositions, a low-melting wax such as, but
not limited to, a mixture of fatty acid glycerides, optionally in combination
with cocoa butter is first melted.
Examples of Methods of Dosing and Treatment Regimens
1003511 The compounds described herein can be used in the ;separation of
medicaments for the inhibition of
/Mk or a hornolog thereog or for the treatment of diseases or conditions that
would benefit, at least in part, from
inhibition of Mk or a hom*olog thereof. hi addition, a method for treating any
of the diseases or conditions described
herein in a subject in need of such treatment, involves administration of
pharmaceutical compositions containing at
least one compound of any of Formula (A), Formula (B), Formula (C), or Formula
(D), described herein, or a
59
Date Recue/Date Received 2022-11-04

pharmaceutically acceptable salt, pharmaceutically acceptable N-oxide,
pharmaceutically active metabolite,
pharmaceutically exceptable prodrug, or pharmaceutically acceptable solvate
thereof, in therapeutically effective
amounts to said subject.
1003521 The compositions containing the compound(s) described herein can be
administered for prophylactic
and/or therapeutic treatments. In therapeutic applications, the compositions
are administered to a patient already
suffering from a disease or condition, in an amount sufficient to cure or at
least partially arrest the symptoms of the
disease or condition. Amounts effective for this use will depend on the
severity and course of the disease or
condition, previous therapy, the patient's health status, weight, and response
to the drugs, and the judgment of the
treating physician. It is considered well within the skill of the art for one
to determine such therapeutically effective
amounts by routine experimentation (including, but not limited to, a dose
escalation clinical trial).
1003531 In prophylactic applications, compositions containing the compounds
described herein are
'administered to a patient susceptible to or otherwise at risk of a particular
disease, disorder or condition. Such an
amount is defined to be a "prophylactically effective amount or dose." In this
use, the precise amounts also depend
on the patient's state of health, weight, and the like. It is considered well
within the skill of the art for one to
determine such prophylactically effective amounts by routine experimentation
(e.g., a dose escalation clinical trial).
When used in a patient, effective amounts for this use will depend on the
severity and course of the disease, disorder
or condition, previous therapy, the patient's health status and response to
the drugs, and the judgment of the treating
physician.
1003541 In the case wherein the patient's condition does not improve, upon
the doctor's discretion the
administration of the compounds may be administered chronically, that is, for
an extended period of time, including
throughout the duration of the patient's life in order to ameliorate or
otherwise control or limit the symptoms of the
patient's disease or condition.
1003551 In the case wherein the patient's status does improve, upon the
doctor's discretion the administration of
the compounds may be given continuously; alternatively, the dose of drug being
administered may be temporarily
reduced or temporarily suspended for a certain length of time (i.e., a "drug
holiday"). The length of the drug holiday
can vary between 2 days and 1 year, including by way of example only, 2 days,
3 days, 4 days, 5 days, 6 days, 7
days, 10 days, 12 days, 15 days, 20 days, 28 days, 35 days, 50 days, 70 days,
100 days, 120 days, 150 days, 180
days, 200 days, 250 days. 280 days, 300 days, 320 days, 350 days, or 365 days.
The dose reduction during a drug
holiday may be from 10%400%, including, by way of example only, 10%, 15%, 20%,
25%, 30%, 35%, 40%, 45%,
50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%.
1003561 Once improvement of the patient's conditions has occurred, a
maintenance dose is administered if
necessary. Subsequently, the dosage or the frequency of administration, or
both, can be reduced, as a function of the
symptoms, to a level at which the improved disease, disorder or condition is
retained. Patients can, however, require
intermittent treatment on a long-term basis upon any recurrence of symptoms.
1003571 The amount of a given agent that will correspond to such an amount
will vary depending upon factors
such as the particular compound, disease or condition and its severity, the
identity (e.g., weight) of the subject or
host in need of treatment, but can nevertheless be routinely determined in a
manner known in the art according to
the particular circ*mstances surrounding the case, including, e.g., the
specific agent being administered, the route of
administration, the condition being treated, and the subject or host being
treated. In general, however, doses
employed for adult human treatment will typically be in the range of 0.02-5000
mg per day, or from about 1-1500
mg per day. The desired dose may conveniently be presented in a single dose or
as divided doses administered
Date Recue/Date Received 2022-11-04

simultaneously (or over a short period of tune) or at appropriate intervals,
for example as two, three, four or more
sub-doses per day.
1003581 The pharmaceutical composition described herein may be in unit
dosage forms suitable for single
administration of precise dosages. In unit dosage form, the formulation is
divided into unit doses containing
appropriate quantities of one or more compound. The unit dosage may be in the
form of a package containing
discrete quantities of the formulation. Non-limiting examples are packaged
tablets or capsules, and powders in vials
or ampoules. Aqueous suspension compositions can be packaged in single-dose
non-reclosable containers.
Alternatively, multiple-dose reclosable containers can be used, in which case
it is typical to include a preservative in
the composition. By way of example only, formulations for parenteral injection
may be presented in unit dosage
form, which include, but are not limited to ampoules, or in multi-dose
containers, with an added preservative.
1003591 The foregoing ranges are merely suggestive, as the number of
variables in regard to an individual
treatment regime is large, and considerable excursions from these recommended
values are not uncommon. Such
dosages may be altered depending on a number of variables, not limited to the
activity of the compound used, the
disease or condition to be treated, the mode of administration, the
requirements of the individual subject, the severity
of the disease or condition being treated, and the judgment of the
practitioner.
1003601 Toxicity and therapeutic efficacy of such therapeutic regimens can
be detemrined by standard
pharmaceutical procedures in cell cultures or experimental animals, including,
but not limited to, the determination
of the LD50 (the dose lethal to 50% of the population) and the ED5D (the dose
therapeutically effective in 50% of the
population). The dose ratio between the toxic and therapeutic effects is the
therapeutic index and it can be expressed
as the ratio between i.D50 and ED50. Compounds exhibiting high therapeutic
indices are preferred. The data obtained
from cell culture assays and animal studies can be used in formulating a range
of dosage for use in human. The
dosage of such compounds lies preferably within a range of circulating
concentrations that include the ED50 with
minimal toxicity. The dosage may vary within this range depending upon the
dosage form employed and the route
of administration utilized.
Combination Treatments
1003611 The irreversible Et* inhibitor compositions described herein can
also be used in combination with
other well known therapeutic reagents that are selected for their therapeutic
value for the condition to be treated. In
general, the compositions described herein and, in embodiments where
combinational therapy is employed, other
agents do not have to be administered in the same pharmaceutical composition,
and may, because of different
physical and chemical characteristics, have to be administered by different
routes. The determination of the mode of
administration and the advisability of administration, where possible, in the
same pharmaceutical composition, is
well within the knowledge of the skilled clinician. The initial administration
can be made according to established
protocols known in the art, and then, based upon the observed effects, the
dosage, modes of administration and times
of administration can be modified by the skilled clinician.
100362] In certain instances, it may be appropriate to administer at least
one irreversible Bdc inhibitor
compound described herein in combination with another therapeutic agent. By
way of example only, if one of the
side effects experienced by a patient upon receiving one of the irreversible
Btk inhibitor compounds described
herein is nausea, then it may be appropriate to administer an anti-nausea
agent in combination with the initial
therapeutic agent. Or, by way of example only, the therapeutic effectiveness
of one of the compounds described
herein may be enhanced by administration of an adjuvant (i.e., by itself the
adjuvant may have minimal therapeutic
benefit, but in combination with another therapeutic agent, the overall
therapeutic benefit to the patient is enhanced).
Or, by way of example only, the benefit experienced by a patient may be
increased by administering one of the
61
Date Recue/Date Received 2022-11-04

a
compounds described herein with another therapeutic agent (which also includes
a therapeutic regimen) that also has
therapeutic benefit. In any case, regardless of the disease, disorder or
condition being treated, the overall benefit
experienced by the patient may simply be additive of the two therapeutic
agents or the patient may experience a
synergistic benefit.
1003631 The particular choice of compounds used will depend upon the
diagnosis of the attending physicians
and their judgment of the condition of the patient and the appropriate
treatment protocol. The compounds may be
administered concurrently (e.g., simultaneously, essentially simultaneously or
within the same treatment protocol) or
sequentially, depending upon the nature of the disease, disorder, or
condition, the condition of the patient, and the
actual choice of compounds used. The determination of the order of
administration, and the number of repetitions of
administration of each therapeutic agent during a treatment protocol, is well
within the knowledge of the skilled
physician after evaluation of the disease being treated and the condition of
the patient.
1003641 It is known to those of skill in the art that therapeutically-
effective dosages can vary when the drugs
are used in treatment combinations. Methods for experimentally determining
therapeutically-effective dosages of
drugs and other agents for use in combination treatment regimens aresiescribed
in the literature. For example, the
use of metronomic dosing, i.e., providing more frequent, lower doses in order
to minimize toxic side effects, has
been described extensively in the literature Combination treatment further
includes periodic treatments that start and
stop at various times to assist with the clinical managementof the patient.
=
1003651 For combination therapies described herein, dosages of the co-
administered compounds will of course
vary depending on the type of co-drug employed, on the specific drug employed,
on the disease or condition being
treated and so forth. In addition, when co-administered with one or more
biologically active agents, the compound
provided herein may be administered either simultaneously with the
biologically active agent(s), or sequentially. If
administered sequentially, the attending physician will decide on the
appropriate sequence of administering protein
in combination with the biologically active agent(s).
1003661 In any case, the multiple therapeutic agents (one of which is a
compound of Formula (A), (B), (C), or
(D) described herein) may be administered in any order or even simultaneously.
If simultaneously, the multiple
therapeutic agents may be provided in a single, unified form, or in multiple
forms (by way of example only, either as
a single pill or as two separate pills). One of the therapeutic agents may be
given in multiple doses, or both may be
given as multiple doses. If not simultaneous, the timing between the multiple
doses may vary from more than zero
weeks to less than four weeks. In addition, the combination methods,
compositions and formulations are not to be
limited to the use of only two agents; the use of multiple therapeutic
combinations are also envisioned.
1003671 It is understood that the dosage regimen to treat, prevent, or
ameliorate the condition(s) for which relief
is sought, can be modified in accordance with a variety of factors. These
factors include the disorder from which the
subject suffers, as well as the age, weight, sex, diet, and medical condition
of the subject. Thus, the dosage regimen
actually employed can vary widely and therefore can deviate from the dosage
regimens set forth herein.
1003681 The pharmaceutical agents which make up the combination therapy
disclosed herein may be a
combined dosage form or in separate dosage forms intended for substantially
simultaneous administration. The
pharmaceutical agents that make up the combination therapy may also be
administered sequentially, with either
therapeutic compound being administered by a regimen calling for two-step
administration. The two-step
administration regimen may call for sequential administration of the active
agents or spaced-apart administration of
the separate active agents. The time period between the multiple
administration steps may range from, a few minutes
to several hours, depending upon the properties of each pharmaceutical agent,
such as potency, solubility,
62
Date Recue/Date Received 2022-11-04

=
bioavailability, plasma half-life and kinetic profile of the pharmaceutical
agent. Circadian variation of the target
molecule concentration may also determine the optimal dose interval.
1003691 In addition, the compounds described herein also may be used in
combination with procedures that
may provide additional or synergistic benefit to the patient. By way of
example only, patients are expected to find
therapeutic and/or prophylactic benefit in the methods described herein,
wherein pharmaceutical composition of a
compound diskosed herein and /or combinations with other therapeutics are
combined with genetic testing to
determine whether that individual is.a carrier of a mutant gene that is known
to be correlated with certain diseases or
conditions.
1003701 The compounds described herein and combination therapies can be
administered before, during or after
the occurrence of a disease or condition, and the timing of administering the
composition containing a compound
can vary. Thus, for example, the compounds can be used as a prophylactic and
can be administered continuously to
subjects with a propensity to develop conditions or diseases in order to
prevent the occurrence of the disease or
condition. The compounds and compositions can be administered to a subject
during or as soon as possible after the
onset of the symptoms. The administration of the compounds can be initiated
within the first 48 hours of the onset of
the symptoms, within the first 6 hours of the onset of the symptoms, or within
3 hours of the onset of the symptoms.
The initial administration can be via any route practical, such as, for
example, an intravenous injection, a bolus
injection, infusion over 5 minutes to about 5 hours, a pill, a capsule,
transdenual patch, buccal delivery, and the like,
or combination thereof. A compound should be administered as soon as is
practicable after the onset of a disease or
condition is detected or suspected, and for a length of time necessary for the
treatment of the disease, such as, for
example, from about 1 month to about 3 months. The length of treatment can
vary for each subject, and the length
can be determined using the known criteria. For example, the compound or a
formulation containing the compound
can be administered for at least 2 weeks, between about 1 month to about 5
years, or from about 1 month to about 3
years.
Exemplary Therapeutic Agents for Use in Combination with an Irreversible Mk
Inhibitor Compound
1003711 Where the subject is suffering from or at risk of suffering from an
autoinumme disease, an
inflammatory disease, or an allergy disease, an irreversible Btk inhibitor
compound can be used in with one or more
of the following therapeutic agents in any combination: immunosuppressants
(e.g., tacrolimus, cyclosporin,
rapamicin, metlaotrexate, cyclophosphamide, azathioprine, rnercaptopurine,
znycophenolate, or FTY720),
glucocorticoids (e.g., prednisone, cortisone acetate, prednisolone,
methylprednisolone, dexamethasone,
betamethasone, triamcinolone, beclometasone, fludrocortisone acetate,
deoxycorticosterone acetate, aldosterone),
non-steroidal anti-inflammatory drugs (e.g., salicylates, arylalkanoic acids,
2-arylpropionic acids, N-arylanthranilic
acids, oxicams, coxibs, or sulphonanilides), Cox-2-specific inhibitors (e.g.,
valdecoxib, celecoxib, or rofecoxib),
leflunornide, gold thioglucose, gold thiomalate, aurofin, sulfasalazine,
hydroxychloroquinine, minocycline, TNF-a
binding proteins (e.g., infliximab, etanercept, or adalimumab), abatacept,
anakinra, 1nter1eron4, interferon-y,
interleutsin-2, allergy vaccines, antihistamines, antileukotrienes, beta-
agonists, theophylline, or anticholinergics.
1003721 Where the subject is suffering from or at risk of suffering from a
B-cell proliferative disorder (e.g.,
plasma cell myeloma), the subjected can be treated with an irreversible Btic
inhibitor compound in any combination
with one or snore other anti-cancer agents. IN some embodiments, one or more
of the anti-cancer agents are
proapoptotic agents. Examples of anti-cancer agents include, but are not
limited to, any of the following: gossyphol,
genasense, polyphenn1E, Chlorofusin, all trans-reiinoic acid (ATRA),
bryostatin, tumor necrosis factor-related
apoptosis-inducing ligand (TRAIL), 5-aza-2'-deoxycytidine, all trans retinoic
acid, doxorubicin, vincristine,
etoposide, gemcitabine, imatinib (Gleevoce)), geldanamycin, 17-N-Allylamino-17-
Demethoxygeldanamycin
63
Date Recue/Date Received 2022-11-04

(17-AAO), flavopiridol, LY294002, bortezomib, trastuzumab, BAY 11-7082,
P1CC412, or P1)184352, Taxolzw, also
. reihrred to as "pacl*taxer', which is a well-known anti-cancer drug which
acts by enhancing and stabilizing
microtubule formation, and analogs of Taxorm, such as TaxotereThi. Compounds
that have the basic taxane skeleton
as a common structure feature, have also been shown to have the ability to
arrest cells in the 02-M phases due to
stabilized microtubules and may be useful for treating cancer in combination
with the compounds described herein.
1003731 Further examples of anti-cancer agents for use in combination with
an irreversible Btk inhibitor
compound include inhibitors of mitogeo-activated protein kinase signaling,
e.g., U0126, P1)98059, PDI84352,
PD0325901, ARRY-142886, SB239063, 5P600125, BAY 43-9006, wortmannin, or
LY294002; Syk inhibitors;
mTOR inhibitors; and antibodies (e.g., rituxan).
1003741 Other anti-cancer agents that can be employed in combination with
an irreversible Btk inhibitor
compound include Adriarnycin, Dactinomycin, Bleomycin, Vinblastine, Cisplatin,
acivicin; aclarubicin; acodazole
hydrochloride; acronine; adcrzelesin; aldesleukin; altretamine; ambomycin;
ametantrone acetate; aminoglutethimide;
annacrine; anastrozole; anthramycin; asparaginase; asperlin; azacitidine;
azetepa; azototnycin; batimastat;
benzodepa; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate;
bizelesin; bleomycin sulfide; brequinar
sodium; bropiriznine; busulfan; cactinomycin; calusterone; carecemide;
carbetimea; carboplatin; carmustine;
carubicin hydrochloride; carzelesin; cedefingol; chloratnbucil; ciroletnycin;
cladribine; crisnatol mesylate;
cyclophosphamide; cytarabine; .dacarbazine; daunorubicin hydrochloride;
decitabine; dercormaplatire dezaguanine;
dezaguanine mesylate; diaziquone; doxombicin; doxorubicin hydrochloride;
droloxifene; droloxifene citrate;
dromostanolone propionate; duazomycin; edatrexate; eflomithine hydrochloride;
elsamitrucin; enloplatin;
enpromate; epipropidine; epirubicin hydrochloride; erbulozole; esorubicin
hydrochloride; estratnustine; estrarnustine
phosphate sodium; etanidazole; etoposide; etoposide phosphate; etoprine;
fadrozole hydrochloride; fazarabine;
fematinide; floxuridine; fludarabine phosphate; fluorouracil; flurocitabine;
fosquidone; fostriecin sodium;
gemcitabine; gemcitabine hydrochloride; hydroxyurea; idarubicin hydrochloride;
ifosfitinide; iimotit*ine; interleulcin
11 (including recombinant interleulcin II, or r1L2), interferon alfs-2a;
interferon alfa-2b; interferon alfa-nl; interferon
alfa-n3; interferon beta-1 a; interferon gamma-I b; iproplatin; irinotecan
hydrochloride; lanrcotide acetate; letrozole;
leuprolide acetate; liarozole hydrochloride; lometexol sodium; lomustine;
losortantrone hydrochloride; masoprocol;
maytansine; mechlorethamine hydrochloride; megestrol acetate; melengestrol
acetate; melphalan; xnenogaril;
mercaptopurine; methotrexate; methotrexate sodium; metoprine; meturedepa;
mitindomide; mitocarcin; mitocromin;
mitomalcin; mitomycin; mitosper; mitotane; raitoxantrone hydrochloride;
mycophenolic acid;
nocodazoie; nogalaznycin; ormaplatin; oxisuran; pegaspargase; peliomycin;
pentamustine; peplomycin sulfate;
perfosfiunide; pipobroman; piposullan; piroxantrone hydrochloride; plicamycin;
plomestane; porftmer sodium;
porfiromycin; prednimustine; procarbRzirP hydrochloride; puromycin; puromycin
hydrochloride; pyrazofurin;
riboprine; rogletimide; safingol; safingol hydrochloride; semustin' c;
simtrazene; sparfosate sodium; sparsomycin;
spirogermanium hydrochloride; spiromustine; spiroplatin; streptonigrin;
streptozocin; sulofenur; talisomycin;
tecogalan sodium; tegathr; teloxantrone hydrochloride; temoporfm; teniposide;
teroxirone; testolactone; thiamiprine;
thioguanine; thiotepa; tiazofurin; tirapazamine; toremifene citrate;
trestolone acetate; triciribine phosphate;
trimetrexate; trimerxexate glucuronate; triptorelin; tubulozole hydrochloride;
uracil mustard; uredepa; vapreotide;
verteportIn; vinblastine sulfate; vinctistine sulfate; vindesine; vindesine
sulfide; vinepidine sulfite; vinglycinate
sulfate; vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate;
vinzolidizie sulfate; vorozole; zeniplatin;
zinostatin; zorubicin hydrochloride.
1003751 Other anti-cancer agent; that can be employed in combination with
an irreversible Btk inhibitor
. compound include: 20-epi4, 25 dihydroxyvinunin D3; 5-ethynyluracil;
abiraterone; aclarubiche acylfulvene;
64
Date Recue/Date Received 2022-11-04

adecypenol; adozelesin; aldesleukin; ALL-TX antagonists; altretamine;
ambamustine; amidox; arnifostine;
arainolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozok;
andrographolide; angiogenesis inhibitors;
antagonist D; antagonist 0; antarelix; anti-dorsalizing morphogenetic protein-
1; antiandrogen, prostatic carcinoma;
antiestrogen; antineoplaston; antisense oligcmucleotides; aphidicolin
glycinate; apoptosis gene modulators; apoptosis
regulators; apurinic acid; ara-CDP-DL-PTBA; arginine deaminase; asulacrine;
attmestane; surinsistine; axinastatin
1; axinastatin 2; axinastatin 3; azasetron; azatoxin; azatyrosine; baccatin
III derivatives; balanol; batimastat;
BCR/ABL antagonists; benzochlorins; benzoylstaurosporine; beta lactam
derivatives; beta-alethine; betaclamycin B;
botanic acid; bFGF inhibitor; bicandamide; bisantrene; bisaziridinylspennine;
bisnafide; bistratene A; bizelesin;
breflate; bropiri' mine; budotitane; buthionine sulfoximine; calcipotriol;
calphostin C; camptothecin derivatives;
canaxypox IL-2; capocitabine; carboxamide-anino-triazok; carboxyamidotriazole;
CaRest M3; CARN 700;
cartilage derived inhibitor; carzelesin; casein kinase inhibitors (1COS);
castanosperrnine; cecropin B; cetrorelix;
chlorins; chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin; cladribine;
clomiferne analogues; clotrimazole;
collismycin A; collismycin B; combretastatin A4; combretastatin analogue;
oonagenin; cramtescidin 816; crisnatol;
criptophycin 8; cryptophycin A derivatives; curacin A;
cyclopentanthraquinones; cycloplatam; cypemycin;
cytarabine ocfosfate; cytolytic factor; cytostatin; dacliximab; decitabine;
dehydrodidemnin B; deslorelin;
dexamethasone; dexifosSurdde; deicrazoatane; dexverapamil; diaziquone;
didemnin B; didox; diethylnorspermine;
dilydro-5-azacyticiine; 9- dioxamycin; diphenyl spiromustine; docosanol;
dolasetron; doxifluridine; droloxifene;
dronabinol; duocarmycin SA; ebselen; ecomustine; edelfosine; edreoolonxtb;
eflornithine; elemene; emitefur;
epir' ubicin; epristeride; estramus-tine analogue; estrogen agonists; estrogen
antagonists; etanidazole; etoposide
phosphate; exemestane; fadrozole; fazarabine; fenretinide; filgrastirn;
finasteride; flavopiridol; fiezelastine;
fluasterone; fludarabihe; fluorodsumorunicin hydrochloride; forfenimex;
formestane; fostriecire foteinustine;
gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelbs; gelatinase
inhibitors; gemcitabine; giutathione
inhibitors; hepsulfam; heregulin; hexamethylene bisacetamide; hypericin;
ibandronic acid; idarubicin; idoxifene;
idramantone; Rmofosine; ilomastat; imidazoacridones; imiquimod;
inmumostimulant peptides; insulin-like growth
factor-1 receptor inhibitor; interferon agonists; interferons; interleukins;
iobenguane; iododoxorubicin; ipomeanol,
4-; iroplac4 irsogIsuline; isobengazole; isohom*ohalicondrin B; itasetron;
jasplalrinolide; kahaklide F; lamellarin-N
triacetate; lanreotide; leinamycin; lenograstint; lentinan sulfate;
leptolstatin; letrozole; leukemia inhibiting Actor;
leukocyte alpha interferon; leuprolide+estrogen+progesterone; leuprorelin;
kvamisole; liarozole; linear polyamine
analogue; lipophilic disaccharide peptide; lipophilic platinum compounds;
lissoclinamide 7; lobaplatin; lombricine;
Icenetrexol; lonidamine; losoxantrone; lovastatin; loxonbine; lurtotecan;
lutetium texaphyrin; lysofylline; lytic
peptides; maitansine; mannostatin A; marimastat; masoprocol; maspin;
matrilysin inhibitors; matrix
roetalloproteinase inhibitors; menogaril; merbarone; raeterelin;
rnethioninase; metoclopraniide; MIF inhibitor;
mifepristone; miltefosine; mirimostim; mismatched double stranded RNA;
mitoguazone; mitolactol; mitomycin
analogues; mitonafide; mitotoxin fibroblast growth factor-saporin;
mitoicantrone; mofarotene; molgramostiag
monoclonal antibody, human choricrnic gonadotrophin; monophosphoryl lipid
A+myobacterium cell wall sit;
mopidamol; multiple drug resistance gene inhibitor; multiple tumor suppressor
1 -based therapy; mustard anticancer
agent; mycapercedde B; mycobacterkd Cell wall extract; myriaporone; N-
acetyldinaline; N-substituted benzarnides;
nafarelin; nagrestip; naloxone+pentazocine; napavin; naphterpin; nartograstim;
nedaplatin; nemorubicin; neridronic
acid; neutral endopeptidase; niluramide; nissunycin; nitric oxide modulators;
nitroxide antioxidant; nitrullyn; 06-
benzylguanine; octreotide; okicenone; oligonuckotides; onapristone;
ondansetron; ondansetrort; oracin; oral
cytokine inducer; ormaplatin; osaterone; oxaliplatin; oxaunomycin; palauamine;
palmitoylrhizredn; pamidronic
acid; panaxytriol; panomifene; parabactin; pazeliipfine; pegaspargase;
peldesine; pentosan polysulfate sodium;
Date Recue/Date Received 2022-11-04

pentostatin ; pentrozole; perflubron; perfosfamide; perillyl alcohol;
phenazinownycin; phenylacetate; phosphatase
inhibitors; pit:Ilan* pilocarpine hydrochloride; pirarubicin; piritrestine
placetin A; placetin B; plasminogen
activator inhibitor; platinum complex; platinum compounds; platinum-triamine
complex; port-Direr sodium;
porfiromycin; prednisone; propyl bis-acridone; prostaglandin J2; proteasome
inhibitors; protein A-based immune
modulator; protein kinase C inhibitor protein kinase C inhibitors, microalgal;
protein tyrosine phosphatase
inhibitors; purine nucleoside phosphorylase inhibitors; purpurins;
pyrazoloacridine; pyridoxylated hemoglobin
polyoxyethylerie conjugate; ref antagonists; raltitrexed; ramosehon; ins
farnesyl protein trimsferase inhibitors; ins
Inhibitors; ras-GAP inhibitor; retelliptine demethylated; rhenium Re 186
etidronate; rhizoxin; ribozymes; RII
retinamide; rogledmide; robitukine; romurtide; roquinimex; rubiginone B1;
ruboxyl; safuigol; saintopin; SarCNU;
sarcophytol A; sargramostim; Sdi 1 rnimetics; semustine; senescence derived
inhibitor 1; sense oligonueleotides;
signal transduction inhibitors; signal transduction modulators; single chain
antigen-binding protein; sizofiran;
sobuzostane; sodium borocaptate; sodium phenylacetate; solverol; somatomedin
binding protein; sonermin; sparfosic
acid; spicamycin D; spiromustine; splenopentin; spongistatin 1; squalamine;
stem cell inhibitor; stern-cell division
inhibitors; stipiamide; stromelysin inhibitors; sulfutosine; superactive
vasoactive intestinal peptide antagonist;
suradista; suramin; swainsonine; synthetic glycosaminoglycans; tallimustine;
tamoxifen methiodide; tauromustine;
tazarotene; tecogalan sodium; tegafur; tellurapyrylium; telomerase inhibitors;
temoporfin; temozolomide;
toniposide; tetracblorodecaoxide; tetrazornine; thallblastine; thiocoraline;
thrombopoietin; thrombopoietin minietic;.
thymalfasin; thymopoietin receptor agonist; thymotrbliin; thyroid stimulating
hormone; tin ethyl etiopurpurin;
tirapazamine; titanocene bichloride; topsentin; tonsmifene; totipotent stem
cell factor; translation inhibitors;
tretinoin; triacetyluridine; triciribine; trimetreirate; triptorelin;
tropisetron; turostende; tyrosine kinase inhibitors;
tyrphostins; UBC inhibitors; ubenimex; urogenital sinus-derived growth
inhibitory factor; urokinase receptor
antagonists; vapreotide; variolin B; vector system, erythrocyte gene therapy;
velaresol; veramine; verdins;
verteporfin; vinorelbine; vinxaltine; vitaxin; vorozole; zanoterone;
zeniplatin; zilascorb; and zinostatin stimalamer.
1003761 Yet other anticancer agents that can be employed in combination
with an irreversible Btk inhibitor
compound include allcylating agents, antimetaboliters, natural products, or
hormones, e.g., nitrogen mustards (e.g.,
mechloroetharnine, cyclophosphamide, chlorambucil, etc.), alkyl sulfonates
(e.g., busulfan), nitrosoureas (e.g.,
carmnstine, lomusitne, ete.), or triazenes (decarbazine, etc.). Examples of
antimetabolites include but are not limited
to folic acid analog (e.g., methotrexate), or pyrimidine analogs (e.g.,
Cytarabine), purine analogs (e.g.,
mercaptopurine, thioguanine, pentostatin).
1003771 Examples of natural products useful in combination with an
irreversible Ink inhibitor compound
include but are not limited to vines alkaloids (e.g., vinblastin,
vincristine), epipodophyllotoxins (e.g., etoposide),
antibiotics (e.g., dannorubicin, doxorubicin, bleomycin), enzymes (e.g., L-
asparaginase), or biological response
modifiers (e.g., interferon alpha).
1003781 Examples of allcylating agents that can be employed in combination
an irreversible Btk inhibitor
compound include, but are not limited to, nitrogen mustards (e.g.,
mechloroethamine, cyclophosphainide,
chlorambucil, meiphalan, etc.), ethylenimine and methylmelamines (e.g.,
hexamethlymelamine, thiotepa), alkyl
sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine, lomusime,
semustine, streptozocin, etc), or triazenes
(decarbazine, etc.). Examples of antimetabolites include, but are not limited
to folic acid analog (e.gõ methotrexate),
or pyrimidine analogs (e.g., fluorouracil, floxouridine, Cytarabine), purine
analogs (e.g., mercaptopurine,
thioguanine, pentostatin.
[003791 Examples of hormones and antagonists useful in combination with an
irreversible Btk inhibitor
compound include, but are not limited to, adrenocceti'costeroids (e.g.,
prednisone), progestins (e.g..
66
Date Recue/Date Received 2022-11-04

hydroxyprogesterone caproate, megestrol acetate, medroxyprogesterone acetate),
estrogens (e.g., diethlystilbestrol,
ethinyl estradiol), antiestrogen (e.g., tammtifen), androgens (e.g.,
testosterone propionate, fluoxymesterone),
antiandrogen (e.g., flutamide), gonadotropin releasing honnonc analog (e.g.,
leuprolide). Other agents that can be
used in the methods and compositions described herein for the treatment or
prevention of cancer include platinum
coordination complexes (e.g., cisplatin, carboblatin), anthracenedione (e.g.,
mitoxantoone), substituted urea (e.g.,
hydroxyurea), methyl hydrazine derivative (e.g., procarbazine), adrenocortical
suppressant (e.g., mitotane,
aminoglutethimide).
100380] Examples of anti-cancer agents which act by arresting cells in the
G2-M phases due to stabilized
microtubules and which can be used in combination with an irreversible Btic
inhibitor compound include without
limitation the following marketed drugs and drugs in development: Erbulozole
(also known as R-55104), Dolastalin
10 (also known as DLS-10 and NSC-376128), Mivobulin bethionate (also known as
CI-980), Vincristine, NSC-
639829, Discodermolide (also known as NVP-XX-A-296), ABT-751 (Abbott, also
known as E-7010), Altorhyrtins
(such as Altorhyrtin A and Altorhyrtin C), Spongistatins (such as Spongistatin
1, Spongistatin 2, Spongistatin 3,
Spongistatin 4, Spongistatin 5, Spongistatin 6, Spongistatin 7, Sisongistatin
8, and Spongistatin 9), C.emadotin
hydrochloride (also known as LU-103793 and NSC-D-669356), Epothilones (such as
Epothilone A, Epothilone B,
Epothilone C (also known as desoxyepothilone A OT dEpoA), Epothilone D (also
referred to as KOS-862, cHipoB,
and desoxyepothilone B), Epothilone E, Epothilone F, Epothilone B N-oxide,
Epothilone A N-oxide, 16-aza-
epothilone B, 21-aminoepodrilone B (also known as BMS-310705), 21-
hydroxyepothilone D (also known as
Desoxyepothilone F and dEpoF), 26-fluoroepothilone), Auristatin PE (also known
as NSC-654663), Soblidotin (also
known as TZT-1027), LS-4559-P (Pharmacia, also known as LS-4577), LS-4578
(Pharmacia, also blown as LS-
477-P), LS-4477 (Pharmacia), LS-4559 (Pharmacia), RPR-112378 (Aventis),
Vincristine sulfate, DZ-3358
(Daiichi), FR-182877 (Fujisavia, also known as WS-9885B), 65-164 (Takeda), 68-
198 (Takeda), KAR-2
(Hungarian Academy of Sciences), BSF-223651 (BASF, also known as ILX-651 and
LU-223651 ), SAH-49960
(Lilly/blovartis), SDZ-268970 (Lilly/Novartis), AM-97 (Arraad/Kyowa Hakko), AM-
132 (Armad), AM-138
(Armad/Kyowa Hakko), 1DN-5005 (Indena), Cryptophycin 52 (also known as LY-
355703), AC-7739 (Ajinomoto,
also known as AVE-8063A and CS-39.HO), AC-7700 (Ajinomoto, also known as AVE-
8062. AVE-8062A, CS-39-
L-Ser.HC1, and RPR-258062A), Vitilevuamide, Tubulysin A, Canadensol,
Centaureidin (also known as NSC-
106969), T-138067 (Tularilc, also known as T-67, TL-138067 and TI-138067),
COBRA-1 (Parker Hughes Institute,
also known as DDE-261 and WHI-261), 1110 (Kansas State University), H16
(Kansas State University), Oncocidin
Al (abo known as ET0-956 and DIME), DDE-313 (Parker Hughes Institute),
Fijianolide B, Laulimalide, SPA-2
(Parker Hughes Institute), SPA-1 (Parker Hughes Institute, also known as
SPIKET-P), 3-IAA13U (Cytoskeleton/Mt.
Sinai School of Medicine, also known as MF-569), Narcosine (also known as NSC-
5366), Nascapints, D-24851
(Asta Medica), A-105972 (Abbott), Hemiasterlin, 3-BAABU (Cytoskeleton/Mt.
Sinai School of Medicine, also
known as MF-191), TMPN (Arizona State University), Vanadocene acetylacetonate,
T-138026 (Tularik),
Monsatrol, lnanocine (also known as NSC-698666), 3-1AABE (Cytco*keleton/Mt.
Sinai School of Medicine), A-
204197 (Abbott), T-607 (Tuba, also known as T-900607), RPR- 115781 (Aventis),
Elentherobins (such as
Desmethyleleutherobin, Desaetyleleutherobin, boeleutherobin A, and Z-
Eleutherobin), Caribaeoside, Caribaeolin,
Halichondrin B, D-64131 (Asta Medical 0-68144 (Asta Medic:a), Diazonamide A, A-
293620 (Abbott), NPI-2350
(Nereus), Taccalonolide A, TUB-245 (Aventis), A-259754 (Abbott), Diozostatin,
(-)-Phenylahistin (also known as
NSCL-96F037), D-68838 (Asia Medina), D-68836 (Asta Medic,a), Myoseverin B, D-
43411 (Zentaris, also known as
0-81862), A-289099 (Abbott), A-318315 (Abbott), HTI-286 (also known as SPA-
110, trifluoroacetate salt)
67
Date Recue/Date Received 2022-11-04

(Wyeth), D-82317 (Zentaris), D-82318 (Zentaris), SC-12983 (NCI), Resverastatin
phosphate sodium, BPR-0Y-007
(National Health Research Institutes), and SSR-250411 (Sanofi).
1003811 Where the subject is suffering from or at risk of suffering from a
thromboembolic disorder (e.g.,
stroke), the subject can be treated with an irreversible Etic inhibitor
compound in any combination with one or snore
other anti-duronthoembolic agents. Examples of anti-thromboembolic agents
include, but are not limited any of the
following thrornbolytic agents (e.g., alteplase anistreplase, streptokinase,
uroldnase, or tissue plasminogen
activator), heparin, tinzaparin, warfarin,' dabigalran (e.g., dabigatran
etwdlate), factor Xa inhibitors (e.g.,
fondaparinwc, draparinux, rivaroxaban, DX-9065a, otamixaban, LY517717, or
YM150), ticlopidine, clopidogrel,
CS-747 (prasugrel, LY640315), xhnelagatran, or BIER 1048.
Kits/Articles of Manufacture
1003821 For use in the therapeutic applications described herein, kits and
articles of manufacture are also
described herein. Such kits can include a carrier, package, or container that
is compartmentalized to receive one or
more containers such as vials, tubes, and the like, each of the container(s)
including one of the separate elements to
be used in a method described herein. Suitable containers include, for
example, bottles, vials, syringes, and test
tubes. The containers can be formed from a variety of materials such as glass
or plastic.
1003831 The articles of manufacture provided herein contain packaging
materials. Packaging materials for use
in packaging pharmaceutical products are well known to those of skill in the
art. See, e.g., U.S. Patent Nos.
5,323,907, 5,052,558 and 5,033,252. Examples of pharmaceutical packaging
materials include, but are not limited
to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers,
syringes, bottles, and any packaging material
suitable for a selected formulation and intended mode of administration and
treatment. A wide array of formulations
of the compounds and compositions provided herein are contemplated as are a
variety of treatments for any disease,
disorder; or condition that avoid benefit by inhibition of Btic, or in which
Mk is a mediator or contributor to the
symptoms or cause.
1003841 For example, the container(s) can include one or more compounds
described herein, optionally in a
composition or in combination with another agent as disclosed herein. The
container(s) optionally have a sterile
access port (for example the container can be an intravenous solution bag or a
vial having a stopper pierceable by a
hypodermic injection needle). Such kits optionally comprising a compound with
an identifying description or label
or instructions relating to its use in the methods described herein.
(00385] A kit will typically may include one or more additional
containers, each with one or more of various
materials (such as reagents, optionally in concentrated form, and/or devices)
desirable from a commercial and user
standpoint for use of a compound described herein. Non-limiting examples of
such materials include, but not limited
to, buffers, diluent% filters, needles, syringes; carrier, package, container,
vial and/or tub- labels listing contents
and/or instructions for use, and package inserts with instructions for use. A
set of instructions will also typically be ,
included.
1003861 A label can be on or associated with the container. A label can be
on a container when letters, numbers
or other characters forming the label are attached, molded or etched into the
container itself; a label can be
associated with a container when it is present within a receptacle or carrier
that also holds the container, e.g., as a
package insert. A label can be used to indicate that the contents are to be
used for a specific therapeutic application.
The label can also indicate directions for use of the contents, such as in the
methods described herein.
1003071 In certain embodiments, the pharmaceutical compositions can be
presented ins pack or dispenser
device which can contain one or more unit dosage forms cone+ icing a compound
provided herein. The pack can for
. example contain metal or plastic foil, such as a blister pack. The pack or
dispenser device can be accompanied by
68
Date Recue/Date Received 2022-11-04

=
=
instructions for administration. The pack or dispenser can also be accompanied
with a notice associated with the
container in farmpteseribed by a govermnental agency regulating the
nenuthetuns, use, or sale ofphannacentieala.
' which notioe is reflective of approval by the agency of the fonnof the
ding for human or veterinary adinhilstration.
Such notice, for example, can he the labeling approved by the U.S. Food and
Drug Administration for prescription
3 drugs, or the approved product insert. Compositions containing a compound
provided herein formulated in a
compatible phenticeutical carrier can aim be prepared, placed Man appropriate
container, and labeled for treatment
of an indicated condition.
Examples
100388) The following specific and non-limiting examples are to be
construed els merely illustrative, and do
not limit the present disclosure in any way whatsoever. Without Anther
elaboratinn, it is believed that one dolled in
the art can, based on tho.descriptionlmein, utilize the present disclosure to
its folly* extent.
Where reference is made to a URL or other such
Identifier or address, it is understood that such identifiers can change and
particular information on the interact can
= come end go, but equivalent information can be found by searching
thelotemet Reference thereto evidences the
availability and public dissemination of such information.
Example 1: Synthesis of Compounds =
Preparation of 4-Amlno-344-phenompheilyi)-1B-pyranolo13,4-Apyrhnldlne
(Intermediate 2)
100389) = 4-Amino-3-(4-phenoxypheny1)-1B-pyrazolo[3,4-d]pyrinxkline
(Intermediate 2) is prepared as
disclosed in International Patent Publication/fa-WO 01/019829. Briefly, 4-
phenoxybenzoic acid (48g) is added to
thinnyi chloride (100 ml) and heated under gentle influx for 1 hour. Thicnyl
chloride is removed by &Malian, the
residual oil dissolved in toluene and volatile material removed at
80bC/20rnbar. The resulting acid chloride is
dissolved in toluene (200 ml) and tetrahydrofInan (35 mL). Malononitrile
(14.88) is added and the solution and
stirred at -10 "C while adding dilsoptopylethylethylarnine (5798) hi toluene
(150mL), what maintaining the
temperatuns below 0 C. Ater 1 hour at 0 C, the mixture is stirred at 20 C
overnight. Amine hydzochloride is
25. V removed by filtration and the filtrate evaporated in vacua. The residue
is taken. up in ethyl acetate and washed with
1.25 M sulphuric acid, then with brine and dried over sodium sulfate.
Evaporation of the solvents gives a semisolid
residue which is treated with a little ethyl acetate to give 4.1 g of 1,1-
dieyano-2-hydmity-2-(4-
phenoxyphenyl)athene as a white solid (nip. 160- 162 C). The filtrate on
evaporation gives 56.58 (96%) of 1,1-
dicyano-2-hydroxy-2-(4-phenoxyphenyl)ethene as a grey-brown solid, which is
sufficiently pure for further use.
1003901 1,1-Dicyano-2-hydroxy-2-(4-phenoxyphenyl)erthene (5658) in
acetonitrile (780 m1.) and methanol
(85 roL) is Mined under nitrogen at 0 C while adding Ms' opropylethylamine
(52.5 in1.) followed by 2M
trimethylsilytdiazomethane (150 mL) in 713F. The reaction is stirred for 2
days at 20 C, and then 2 g of silica Is
added (for chronntography). The brown-red solutions evaporated in vi7C110, the
residue dissolved in ethyl acetate
and washed well with water then brine, dried and evaporated. The residue is
extracted with died* ether (3x250
mL), decanting from insoluble oil. Evaporation of the ether extracts gives
22.5 got 1,1-dicyano-2-methoxy-2-(4-
phenorryplxmyl)ethene as a pale orange solid. The insoluble oil is purified by
flash chromatography to give 15.0 got
a red-orange oiL
100391j 1,1-Dicyano-2-methoxy-2-(4-phenoxyphenyl)ethene (22.58) and 1,1-
dicyano-2-methoxy-2-(4-
phenoxyphenypethene oil (15 g) are treated with a solution of hydrazine
hydrate (18 mL) in ethanol (25 roL) and
heated on tbe nemnbath fbr 1 hour. Ethanol (15 ml.) is added Mowed by water
(10 mL). The precipitated solid is
collected and washed with ethanol:water (4:1) and then dried in air to give 3-
arohni-4-cyano-5-(4-
phenoxyphenyl)pyrazole as a pale orange solid.
69
=
=
=
= =
Date Recue/Date Received 2022-11-04

1003921 3-Amino-4-cyano-5-(4-phenoxyphenyl)pyrazole (29.5 g) is suspended
in forrnamide (300 mL) and
heated under nitrogen at 180 C for 4 hours. The reaction mixture is cooled to
30 C and water (300 mL) is added.
The solid is collected, washed well with water, then with methanol and dried
in air to give of 4-amino-3-(4-
phenoxypheny1)-1H-pyrazolo[3,4-dipyrimidine.
Example is: Synthesis of 1-(3-(4-amino-3-(4-phenoxypheny1)-111-pyrazoloP,4-
d)pyrimidin-l-y1)piperldin-1-
y1)prop-2-en-1-one (Compound 4)
Scheme 1.
0*
0 *
a NH2 NH2 *
NH2 * ____________________ )r,
OH N,N µ,N
NI N N N N
,N
N
0 . 0
2 3 4
Synthesis of compound 4; a) polymer-bound triphenylphosphine (TPP),
diisopropyl diazodicarboxylate (D1AD), tetrahydrofuran (THE); b) HCVdioxane;
then acryloyl chloride, triethylamine (TEA).
1003931 Compounds described herein were synthesized by following the steps
oultined in Scheme 1. A detailed
illustrative example of the reaction conditions shown in Scheme 1 is described
for the synthesis of 1-(3-(4-amino-3-
(4-phenoxypheny1)-1H-pyrazolo[3,4-13]pyrimidin-l-y1)piperidin-l-y1)prop-2-en-1
-one (Compound 4).
[00394j 101 mg of 4-amino-3-(4-phenoxypheny1)-1H-pyrazolo[3,4-cl]pyrimidine
and 330 mg of polymer-
bound triphenylphosphine(TPP) (polymerlab) were mixed together with 5 mL of
tetrahydrofuran (THF). tert-Butyl
3-hydroxypiperidine-l-carboxylate (200 mg; 2.0 equivalents) was added to the
mixture followed by the addition of
diisopropyl diazodicarboxylate (0.099 mL). The reaction mixture was stirred at
room temperature overnight. The
reaction mixture was filtered to remove the resins and the reaction mixture
was concentrated and purified by flash
chromatography (pentane/ethyl acetate = 1/1) to give intermediate 3(55 mg).
1003951 Intermediate 3(48.3 mg) was treated with 1 mt. of 4N HC1 in
dioxane for 1 hour and then concentrated
to dryness. The residue was dissolved in dichloromethane and triethylamine
(0.042 mL) was added followed by
acryl chloride (0.010 mL). The reaction was stopped after 2 hours. The
reaction mixture was washed with 5% by
weight aqueous citric acid and then with brine. The organic layer was dried
with MgE04, and concentrated. Flash
chromatography (with CH2C12/Me0H = 25/1) gave 22 mg of compound 4 as a white
solid. MS (M+1): 441.2; 1H-
NMR. (400MHz): 8.26, s, 1H; 7.65, in, 2H; 7.42, in, 2H; 7.1-7.2, in, 5H; 6.7-
6.9, in, 1H; 6.1, in, 1H; 5.5-5.7, in, 1H;
4.7, in, 1H; 4.54, in, 0.5H; 4.2, in, 1H; 4.1, m, 0.5H; 3.7, in, 0.5H; 3.2, m,
1H; 3.0, ni, 0.5H; 2.3, in, 1H; 2.1, in, 1H;
1.9, in, 1H; 1.6, in, 1H.
=
Date Recue/Date Received 2022-11-04

Example lb: Synthesis of 14(R)-3-(4-amino-3-(4-pheuoxypheny1)-1H-pyraxolo(3,4-
d]pyrimidin-1-
yl)piperidin-1.-y1)prop-2-en-1-one (Compound 13).
41,
= NH2 * = =
N \
L ,N
N
of
1003961 The synthesis of compound 13 was accomplished using a procedure
analogous to that described in
Example la. EM (calc.): 440.2; MS (ES1) in& (M+1H) : 441.1, (M-1H)': 439.2.
Example le: Synthesis of 1-0)-3-(4-amino-3-(4-phenoxypheny1)-1H-pyrazoloP,4-
d]pyrimidin-l-y1)piperidin-
1-y1)prop-2-en-1-one (Compound 14).
= *
NH2 *
= N '
,N
N
0
10039'71 The synthesis of compound 14 was accomplished using a procedure
analogous to that described for
Example in. EM (Gale.): 440.2; MS (ES1) nile (M+111)-1-: 441.5, (M-1H)-:
439.2.
Example Id: Synthesis of 1-0)-3-(4-amino-3-(4-phenoxyphenyl)-1H-.pyrazolor3,4-
d)pyrimidin-1-
y1)pyrrolidin-1-y1)prop-2-en-1-one (Compound 12).
NH2
N \
L ,N
01
1003981 The synthesis of this compound was accomplished using a procedure
analogous to that described for
Example la. EM (calc.): 426.18; MS (ESI) wile (M+1H)+: 427.2, (M-111)-: 425.2.
71
Date Recue/Date Received 2022-11-04

Example le: Synthesis of 14(R)-3-(4-amino-3-(4-phenoxypheny1)-1H-pyrazolop,4-
dlpyrimidin-l-
yl)pyrrolldin-l-yl)prop-2-en-l-one (Compound 11).
= *
NH2 *
N
lAt. ,N
N =
= 0
1003991 The synthesis of this compound was accomplished using a procedure
analogous to that described for
Example la. EM (vale.): 426.18; MS (ES!) xi* (M+1/1)+: 427.2.
Example 11: Synthesis of N-K1s,4s)-4-(4-amino-3-(4-phenoxypheny1)-111-
pyrazolop,4-d)pyrimidin-l-
y1)cydohexyl)acrylamide (Compound 10).
I,
=
NH2IN
*
N
N
=
H
0
1004001 The synthesis of this compound was accomplished using a procedure
analogous to that described for
Example la. EM (vale.): 454.21; MS (ES!) ink (M+1H)+: 455.1, (M-IH)-: 453.1.
Example lg: Synthesis of 1-(3-(4-amino-3-(4-phenoxypheny1)-1H-pyraxolop,4-
d)pyrimidits-1-y1)piperidin-1-
yosulfonylethene (Compound 6).
0-0
NH2
(N ,N
1004011 The synthesis of compound 6 was accomplished using a procedure
analogous to that described for
Example la. EM (vale.): 476.16; MS (ES1) !rile (M+1H) : 478.0, (M-111)':
475.3.
72
Date Recue/Date Received 2022-11-04

Example lh: Synthesii of 1-(3-(4-amino-3-(4-phenoxypheny1)-1H-pyrazolo(3,4-
dlpyrimidin-1-y1)piperldin-1-
y1)prop-2-yn-1-one (Compound 8).
*
NH2
N
,N
N
0
[004021 The synthesis of compound 8 was accomplished using a procedure
analogous to that described for
Example la. EM (cab.): 438.18; MS (EST) mie (M+1H): 439.2, (M-1H)-: 437.2.
Example li: Synthesis of (E)-1-(344-amino-3-(4-phenoxyphenyi)-11I-pyrazolo(3,4-
d1pyrimidin-1-y1)piperidin-
1-y1)-4-(dimethylamino)but-2-en-1-one (Compound 15).
0 *
NH2
N
N =
N
0
[00403] The synthesis of compound 15 was accomplished using a procedure
analogous to that described for
Example la. EM (calc.): 497.25; MS (EST) m/e (M+1H): 498.4, M-1H)-: 496.
Example 2: Btk in vitro Inhibitory Activity
[004041 The Btic IC20s of compounds disclosed herein was determined in
both an acellular kinase assay and in a
cellular functional assay of BCR-induced calcium flux as described below.
[00405] Btic Jeinase activity was determined using a time-resolved
fluorescence resonance energy transfer (TR.-
FRET) methodology. Measurements were performed in a reaction volume of 50 eLL
using 96-well assay plates.
Kinase enzyme, inhibitor, ATP (at the K. for the kinase), and 1 AM peptide
substrate (Biotin-
AVLESEEELYSSARQ-NH2) were incubated in a reaction buffer composed of 20 mM
Tris, 50 mM NaC1, MgCl2
(5-25 mM depending on the kinase), MnC12(0-10 mM), 1 iriM DTT, 0.1 mM EDTA,
0.01% bovine serum albumin,
0.005% Tween-20, and 10% DMSO at pH 7.4 for one hour. The reaction was
quenched by the addition of 1.2
equivalents of EDTA (relative to divalent cation) in 25 AL of lx Lance buffer
(Perkin-Elmer). Streptavidin-APC
(Perkin-Elmer) and Eu-labeled p-Tyr100 antibody (Perkin-Elmer) in lx Lance
buffer were added in a 25 [iL volume
to give final concentrations of 100 nM and 2.5 nM, respectively, and the
mixture was allowed to incubate for one
hour. The TR-FRET signal was measured on a multimode plate reader with an
excitation wavelength (X.E.) of 330
nm and detection wavelengths (X2,,õ) of 615 and 665 urn. Activity was
determined by the ratio of the fluorescence at
665 nm to that at 615 MTh For each compound, enzyme activity was measured at
various concentrations of
compound. Negative control reactions were performed in the absence of
inhibitor in replicates of six, and two no-
enzyme controls were used to determine baseline fluorescence levels.
Inhibition constants, lqapp), were obtained
73
Date Recue/Date Received 2022-11-04

using the program BatcbKi (Kuzmic et al. (2000), Anal. Mechem. 286:45-50).
IC50 were obtained according to the
equation:
1004061 ICso = {Ki(app)/(1+[A1P]/1C.õTh) +
1004071 For all kinases,. [ATP] = KmATP, [Mimi = 0.5 nM and (Ultima = 6
nM. e
100408) Calcium flux ftuoresence-based assays were performed in a
Flex.Station 11384 fluorornetric imaging
plate reader (Molecular Devices) according to manufactuier instructions. In
brief actively growing Ramos cells
(ATCC) in RPMI medium supplemented with 10% PBS (Invitrogen) were washed and
re-plated in low serum
medium at approximately 5 X i0 cells per 100 pl per well in a 96-well plate.
Compounds to be assayed were
dissolved in DMSO and then diluted in low serum medium to final concentrations
ranging from 0 to 10 pM (at a
dilution factor of 0.3). The diluted compounds were then added to each well
(final DMSO concentration was 0.01%)
and incubated at 37 degree in 5% CO2 incubator for one hour. Afterwards, 100
pl of a calcium-sensitive dye (from
the Calcium 3 assay kit, Molecular Devices) was added to each well and
incubated for an additional hour. The
compound-treated cells were stimulated with a goat anti-human IgM antibody
(80ug/m1; Jackson brimunoReseiurh)
and read in the FlexStation11384 using a 7.,22, 485nm and A.B. = 538nm for 200
seconds. The relative fluorescence
unit (RFU) and the 1C.20 were recorded and analyzed using a built-in SoftMax
program (Molecular devices).
Table 2: Assay data for representative compounds
0
NH2
ii N \ N
0- =
N N,
Compound No. R Btk IC22 (nM) Ramos
Cell Ca Flux
IC20 (nM)
4 0.72 10
oNy
0
5
¨20 89
0
6 0.52 92
0 0 =
7 0.58 9
CNrc
74
Date Recue/Date Received 2022-11-04

Compound No. R Btk IC50(141) Ramos
Cell Ca Flux
ICso (n111)
8 ofr 0.72 9
at
9 3.6 48
A(:5 0.58 3
HNy
11 1.6 24
12
1.9 90
CN1
13 T
<0.5 10
0
14 1.4 7
0
2.5 36
(00409) Two lines of evidence demonstrated irreversible inhibition of Btk
by these compounds. First, after
recombinant Btk was pretreated with compounds, its activity was not recovered
by repeat washing with inhibitor.
free medium (see, e.g., J. B. Smaill, et cd, J. Med. Chem. 1999, 42, 1803).
Second, a major mass peak was observed
5 by MEWS spectrometry corresponding to the molecular weight of a 1:1
covalent complex between compound 4 and
Btk (Compound 4: 440 Da, recombinant Btk kinase domain: 33,487 Da; Complex:
expected 33,927 Da, observed
33,927 Da).
Date Recue/Date Received 2022-11-04

1004101 These compounds are highly potent inhibitors of Btk kinase activity
with ICsos in the sub-nanomolar to
single digit nanomolar range for in vitro kinase activity. Their ICsos in the
(Ramos cell) Ca 2+ flux assay ranged from
3 to 92 nM.
1004111 Of note, we found that three types of Michael acceptors,
acrylamide, vinyl sulfonamide and
propargylamide, exhibited strong interactions with Btk. Adding a trans-
oriented methyl group to the vinyl group
decreased potency as shown by compounds, which was 28-fold less potent than 4.
This presumably relates to the
reduced electrophilicity of the more substituted olefin. Compound 15 with a
tertiary amine group gained back some
potency compared to 5, even though it still suffered a potency drop relative
to compound 13. Compound 10 was
about 6-fold more potent than 9, presumably due to the difference in the
electrophile orientation. Finally, R
configuration was determined as the slightly preferred absolute
stereochemistry configuration by two sets of
enarttiomers (11 vs. 12 and 13 vs. 14).
Example 3: Inhibition of Btk
10041211 We Rutter characterized the properties of these compounds by
assaying a number of cellular
biochemical and functional endpoints. In particular, we sought to assess the
selectivity of these compounds for
inhibition of Btk versus the closely related protein lcinases Lck, Lyn, and
Syk. In anti-IgM-stimulated Ramos cells (a
human B cell line), we assayed Btk-dependent phosphorylation of PLC-yl ; Lyn
and Syk-dependent phosphorylation
of tyrosine 551 on Btk-, and BCR-activated calcium flux. We also measured the
effect of compound 4 on Iurkat
cells, a human T cell line in which Lck and Itic, but not Btk are required for
T cell receptor mediated Ca2+ flux. As
shown in Table 3, compound 4 exhibited significant selectivity for Eric in
cellular assays. In anti-IgM stimulated
Ramos cells; compound 4 inhibited the phosphorylation of PLC-yl with an ICso =
0.014 M, while the Lyn and
Syk-dependent phosphorylation of tyrosine 551 on Btk was inhibited more weakly
(ICso > 7.5 M). Thus,
compound 4 exhibits a >500-fold selectivity between Btk and Lyn or Syk in
cells. Further, compound 4 was 11-fold
less active in inhibiting Ca 24 flux than in Ramos cells, supporting the
expected selectivity for B versus T cells.
Table 3. Cellular assay data for compound 4
Cinpd Lek' Lyn' Btk 051 ppLC-yl Ramos
Ca Flux" Jurkat Ca flux"
(nM) (nM) (11M) (PM) (PM) (PM) (PM)
4 0.72 97 14 >7.5 0.014 0.0405 0.466
[a] ti (app) Lb] IC50
Example 4: Use of Compound 4 to treat rheumatoid arthritis
1004131 Them vivo efficacy of compound 4 was evaluated in a mouse model of
rheumatoid arthitis. Arthritis
was induced in Balb/c mice by administration of anti-collagen antibodies and
lipopolysaccharide (LPS). See
Nandakurom etal. (2003), Am. ./. Pathol. 163:1827-1837.
1004141 Female Balb/c mice were treated with 100 mg/kg of Chemicon mAb
co*cktail to Type II collagen
Intravenously on Day 0 and 1.25 mg/kg of LPS intraperitoneally on Day 1.
Compound 4 was administered orally in
a methylcellulose-based aqueous suspension formulation at 1.3, 10 and 30 mg/kg
once daily starting on Day 2
through Day 12. Blood samples were collected at 0.5 and 2 hours post dose of
compound 4 administration on Day
12 (see Table 4). The serum concentrations of compound 4 were quantified by
LC/MS/MS. Twenty four hours post
dose, levels of compound 4 were below the level of quantitation.
76
Date Recue/Date Received 2022-11-04

=
Table 4. Dose and Time Dgiendence of Compound 4 Concentration in Plasma
Cone (pM)
Dose (mg/kg/day) Collection Time (h)
Mean SD
0.5 0.0657 0.0153
1
2 0.0485 0.0200
0.5 0.250 0.019
3
2 0.135 0.059 =
0.5 0.635 0.053
2 0.670 0.190
0.5 1.72 0.15
2 1.10 0.19
[00415] Inhibition of arthritis by compound 4 was dose-dependent, with a
maximum effect (>95% inhibition)
at dose levels of 10 and 30 mg/kg. The plasma concentrations of compound 4
that induced this maximum effect .
were in the 0.6-1.7 nM range at (2 hr) and did not need to be sustained at
high levels for 24 hours to achieve
5 efficacy, which is not surprising for an irreversible inhibitor. Based on
sequence analysis and molecular modeling,
the irreversible inhibitors described herein are proposed to form a covalent
bond with Cys 481 of Btk (e.g., the
Michael reaction acceptor portion of the compounds described herein react with
the Cys 481 residue of Btk). Based
on sequence hom*ology analysis (Figure 1), the compounds presented herein are
also expected to act as irreversible
inhibitors of kinases having a Cys 481 or a hom*ologous cysteine residue, but
to bind reversibly with kinases having
10 a different amino acid at the 481 position within a catalytic domain
sequence that is otherwise hom*ologous to that of
Btk. See, e.g., the sequences listed in Figure 1. See also the sequence
alignments of tyrosine kinases (TIC) published
on the world wide web at kinase.com/human/lcinome/phylogeny.html.
Example 5: Inhibition of Mast Cell Dearanulation
[00416] Human CD34+ cells differentiated to mast cells by 9 weeks in
culture in the presence of Inginil IL-3,
15 50 ng/ml IL-6, 100 ng/inl SCF. Cells were incubated with IgE + IL-4 for
4 days and then degranulation was induced
by cross-linking with anti-IgE. Degramilation quantitated using hexosaminidase
assay. Compound did not inhibit
degranulation induced by the
ionophore ionomycin and did not affect cell viability as determined by Alamar
Blue assay. Compound 4 has an IC50 in MC degranulation less than 100
nanomolar. As such, compounds described
herein can be used for the treatment of inflammatory diseases, such as asthma.
20 jExamPle 6: Pharmaceutical Compositions;
1004171 The compositions described below are presented with a compound of
Formula (A) for illustrative
purposes; any of the compounds of any of Formulas (A), (B), (C), or (D) can be
used in such pharmaceutical
compositions.
Example 6a: Parenteral Composition
25 1004181 .. To prepare a parenteral pharmaceutical composition suitable
for administration by injection, 100 mg of
a water-soluble salt of a compound of Formula (A) is dissolved in DMSO and
then mixed with 10 Ira. of 0.9%
sterile saline. The mixture is incorporated into a dosage unit form suitable
for administration by injection.
Example 66: Oral Composition
[004191 To prepare a pharmaceutical composition for oral delivery, 100 mg
of a compound of Formula (A) is
30 mixed with 750 mg of starch. The mixture is incorporated into an oral
dosage unit for, such as a hard gelatin
capsule, which is suitable for oral administration.
77
Date Recue/Date Received 2022-11-04

=
Ji&ample 6c: Sublingual (Irani Lozongo) Composition =
1004201 To prepare a phannneeutiml composition for buccal delivery, such
as a hard lozenge, mix 100 mg of a
compound of Form& (A), with 420 mg of powdered sugar mixed, with 1.6 ml. of
lied corn prop, 2.4 mL distilled
water, and 0.42 mL mint extract The nib:tore is gently blended and poured into
a mold to form a forrange suitable
for buccal administration.
Example ifot Inindalion Companion
100421] To prepare aphanunceutleal composition for inhalation delivery,
20 rug of a compound of FormUla
(A) Is mixed with 50 mg of anhydroua citric acid and 100 mL of 0.954 sodium
chloride solution. The mixture is
Incorporated into in inhalation delivery unit, such as a nebulirer, which is
suitable for Inhalation administration.
Example 6er Sider Od Cestpeckhur
100422) To prepare a pharmaceutical composition for rectal delivery, 100
mg of a compound of Formula (A) is
mixed with 2.5 g of methyloalluose (1500 taa), 100 mg of methylparapen, 5 g
ofglycarin and 100 mL of purified
water. Tire revoking gel mixture is then incorporated into rectal delivery
units, such as syringes, which are suitable
= for rectal administration:
Example 4fi Topical Gel Composition
(00423) To prepare a phmatecentical topical gel composition, 100 mg of a
compound ofFornork (A) is mixed
with 1.75 g of hydroxypropyl creme, 10 mL ofpropylene glycol, 10 mL of
isopropyl myristate and 100 ml. of
purified alcohol USP. The resulting gel mixture is then incorporated into
container; such as tube; which are
suitable for topic! administration.
itramplar 6g: Ophthalmic Madam Composition
1004241 To prepare a phannaceutical opthehnic solution composition, 100
mg of a compound of Pomade (A) is
mixed with 0.9 g of NaCI in 100 inL of purified water and filterd using a 0.2
micron filter. The resulting isotonic
solution is limn incarcerated into ophthalmic delivery units, such as eye drop
containers, which are suitable for
ophthalmic administration-
'.(00425) It is understood that the examples and embodiments described
heroin ere for illustrative purposes only
and that various modifications or changes in light thereof will be suggested
to persons skilled in the art and are lobe
included within the spirit and purview of this application and scope of the
appended claims.
=
78
=
Date Recue/Date Received 2022-11-04