Title of Invention

FUSED CYCLIC SYSTEMS USEFUL AS INHIBITORS OF TEC FAMILY PROTEIN KINASES

Abstract The present invention relates to compounds useful as inhibitors of protein kinases. The invention also provides pharmaceutically acceptable compositions comprising said compounds and methods of using the compositions in the treatment of various disease, conditions, or disorders.
Full Text COMPOSITIONS USEFUL AS INHIBITORS OF PROTEIN KINASES
*■* fa
TECHNICAL FIELD OF THE INVENTION
[0001] The present invention relates to compounds useful as inhibitors of protein kinases.
The invention also provides pharmaceutically acceptable compositions comprising the
compounds of the invention and methods of using the compositions in the treatment of
various disorders.
BACKGROUND OF THE INVENTION
[0002] The search for new therapeutic agents has been greatly aided in recent years by a
better understanding of the structure of enzymes and other biomolecules associated with
diseases. One important class of enzymes that has been the subject of extensive study is
protein kinases.
[0003] Protein kinases constitute a large family of structurally related enzymes that are
responsible for the control of a variety of signal transduction processes within the cell. (See,
Hardie, G. and Hanks, S. The Protein Kinase Facts Book, I and II, Academic Press, San
Diego, CA: 1995). Protein kinases are thought to have evolved from a common ancestral
gene due to the conservation of their structure and catalytic function. Almost all kinases
contain a similar 250-300 amino add catalytic domain. The kinases may be categorized into
families by the substrates they pbosphorylate (e.g., protein-tyrosine, protein-serine/threonine,
lipids, etc.). Sequence motifs have been identified that generally correspond to each of these
kinase families (See, for example, Hanks, S.K., Hunter, T, FASEB J. 1995, 9, 576-596;
Knighton et ai, Science 1991, 253, 407-414; Hiles et al, Cell 1992, 70, 419-429; Kunz et al,
Cell 1993, 73, 585-596; Garcia-Bustos et ai, EMBOJ. 1994,13, 2352-2361).
[0004] In general, protein kinases mediate intracellular signaling by effecting a
phosphoryi transfer from a nucleoside triphosphate to a protein acceptor that is involved in a
signaling pathway. These phosphorylation events act as molecular on/off switches that can
modulate or regulate the target protein biological function. These phosphorylation events are

ultimately triggered in response to a variety of extracellular and other stimuli. Examples of
such stimuli include environmental and chemical stress signals (e.g., osmotic shock, heat
shock, ultraviolet radiation, bacterial endotoxin, and H2O2), cytokines (e.g., .interleukin-1
(H-l) and tumor necrosis factor a (TNF-a)), and growth factors (e.g., granulocyte
macrophage-colony-stimulating factor (GM-CSF), and fibroblast growth factor (FGF)). An
extracellular stimulus may affect one or more cellular responses related to cell growth,
migration, differentiation, secretion of hormones, activation of transcription factors, muscle
contraction, glucose metabolism, control of protein synthesis, and regulation of the cell cycle.
[0005] Many diseases are associated with abnormal cellular responses triggered by
protein kinase-mediated events as described above. These diseases include, but are not
limited to, autoimmune diseases, inflammatory diseases, bone diseases, metabolic diseases,
neurological and neurodegenerative diseases, cancer, cardiovascular diseases, allergies and
asthma, Alzheimer's disease, and hormone-related diseases. Accordingly, -there has been a
substantial effort in medicinal chemistry to find protein kinase inhibitors that are effective as
therapeutic agents.
[0006] The Tec family of non-receptor tyrosine kinases plays a central role in signalling
through antigen-receptors such as the TCR, BCR and Fee receptors (reviewed in Miller A, et
al. Current Opinion in Immunology 14;331-340 (2002). Tec family kinases are essential for
T cell activation. Three members of the Tec family, Itk, Rlk and Tec, are activated
downstream of antigen receptor engagement in T cells and transmit signals to downstream
effectors, including PLC-y. Deletion of Itk in mice results in reduced T cell receptor (TCR)-
induced proliferation and secretion of the cytokines EL-2, IL-4, IL-5, IL-10 and IFN-y
(Schaeffer et al, Science 284; 638-641 (1999)), Fowell et al, Immunity ll;399-409 (1999),
Schaeffer et al Nature Immunology 2,12; 1183-1188 (2001))). The immunological
symptoms of allergic asthma are attenuated in Itk-/- mice. Lung inflammation, eosinophil
infiltration and mucous production are drastically reduced in Itk-/- mice in response to
challenge with the allergen OVA (Mueller et al, Journal of Immunology 170: 5056-5063
(2003)). Itk has also been implicated in atopic dermatitis. This gene has been reported to be
more highly expressed in peripheral blood T cells from patients with moderate and/or severe
atopic dermatitis than in controls or patients with mild atopic dermatitis (Matsumoto et al,
International archives of Allergy and Immunology 129; 327-340 (2002)).
[0007] • Splenocytes from Rlk-/- mice secrete half the IL-2 produced by wild type animals
in response to TCR engagement (Schaeffer et al, Science 284; 638-641 (1999)), while

combined deletion of Itk and Rlk in mice leads to a profound inhibition of TCR-induced
responses including proliferation and production of the cytokines IL-2, IL-4, IL-5 and IFN-y
(Schaeffer et al Nature Immunology 2,12; 1183-1188 (2001)), Schaeffer et al, Science 284;
638-641 (1999)). Intracellular signalling following TCR engagement is effected in Itk/Rlk
deficient T cells; inositol triphosphate production, calcium mobilization, MAP kinase
activation, and activation of the transcription factors NFAT and AP-1 are all reduced
(Schaeffer et al, Science 284; 638-641 (1999), Schaeffer et al Nature Immunology 2,12;
1183-1188(2001)).
[0008] Tec family kinases are also essential for B cell development and activation.
Patients with mutations in Btk have a profound block in B cell development, resulting in the
almost complete absence of B lymphocytes and plasma cells, severely reduced Ig levels and a
profound inhibition of humoral response to recall antigens (reviewed in Vihinen et al
Frontiers in Bioscience 5:d917-928). Mice deficient in Btk also have a reduced number of
peripheral B cells and greatly decreased levels of IgM and IgG3. Btk deletion in mice has a
profound effect on B cell proliferation induced by anti-IgM, and inhibits immune responses
to thymus-independent type II antigens (Ellmeier et al, J Exp Med 192:1611-1623 (2000)).
[0009] Tec kinases also play a role in mast cell activation through the high-affinity IgE
receptor (FceRJ). Itk and Btk are expressed in mast cells and are activated by FceRI cross-
linking (Kawakami et al, Journal of Immunology; 3556-3562 (1995)). Btk deficient murine
mast cells have reduced degranulation and decreased production of proinfllammatory
cytokines following FceRI cross-linking (Kawakami et al. Journal of leukocyte biology
65:286-290). Btk deficiency also results in a decrease of macrophage effector functions
(Mukhopadhyay et al, Journal of Immunology; 168,2914-2921 (2002)).
[0010] Accordingly, there is a great need to develop compounds useful as inhibitors of
protein kinases. In particular, it would be desirable to develop compounds that are useful as
inhibitors of Tec family (e.g.,Tec, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk) protein kinases,
particularly given the inadequate treatments currently available for the majority of the
disorders implicated in their activation.
SUMMARY OF THE INVENTION
[0011] It has now been found that compounds of this invention, and pharmaceutically
acceptable compositions thereof, are effective as inhibitors of protein kinases. In certain

embodiments, these compounds are effective as inhibitors Tec family (e.g.,Tec, Btk,
Itk/Emt/Tsk, Bmx, Txk/Rlk) protein kinases. These compounds have the general formula I:

or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, R5, G, Cy1, and X
are as defined below.
[0012] These compounds and pharmaceutically acceptable compositions thereof are
useful for treating or preventing a variety of diseases, disorders or conditions, including, but
not limited to, an autoimmune, inflammatory, proliferative, or hyperproliferative disease or
an immunologically-mediated disease. The compositions are also useful in methods for
preventing thrombin-induced platelet aggregation.
[0013] The compounds provided by this invention are also useful for the study of kinases
in biological and pathological phenomena; the study of intracellular signal transduction
pathways mediated by such kinases; and the comparative evaluation of new kinase inhibitors.
DETAILED DESCRIPTION OF THE INVENTION
[0014] I. General Description of Compounds of the Invention:
[0015] The present invention relates to a compound of formula I:

or a pharmaceutically acceptable salt thereof,
wherein R1 is -QRX; wherein Q is a bond or is a Ci-Cg alkylidene chain wherein up to
two methylene units of Q are optionally and independently replaced by -CO-, -CS-, -COCO-,
-CONR-, -CONRNR-, -C02-, -OCO-, -NRCO2-, -0-, -NRCONR-, -OCONR-, -NRNR,
-NRNRCO-, -NRCO-, -S-, -SO, -S02-, -NR-, -S02NR-, -NRS02-, -NRS02NR-, and each

occurrence of Rx is independently R\ halogen, NO2, or CN, provided R1 is hydrogen or is
bonded to the nitrogen atom through a carbon atom;
each occurrence of R is independently selected from hydrogen or an optionally
substituted Ci-s aliphatic group; and each occurrence of R' is independently selected from
hydrogen or an optionally substituted group selected from Ci-g aliphatic, Q-Cio aryl, a
heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 3-10 ring atoms, or
wherein R and R' taken together with the atom(s) to which they are bound, two occurrences
of R taken together with the atom(s) to which they are bound, or two occurrences of R' taken
together with the atom(s) to which they are bound, from an optionally substituted group
selected from a 3-10 membered cycloalkyl ring, a C6-Cioaryl ring, a heteroaryl ring having 5-
10 ring atoms, or a heterocyclyl ring having 3-10 ring atoms;
Cy1 is a 5-7-membered mono'cyclic aryl ring or an 8-10-membered bicyclic aryl ring
having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or is a 3-8-
membered saturated or partially unsaturated monocyclic ring having 0-3 heteroatoms
independently selected from nitrogen, oxygen, or sulfur, wherein Cy1 is optionally substituted
with y occurrences of -YRY, wherein y is 0-5, Y is a bond or is a Ci-Ce alkylidene chain
wherein up to two methylene units of Y are optionally and independently replaced by -CO-,
-CS-, -COCO-, -CONR-, -CONRNR-, -C02-, -OCO-, -NRCO2-, -0-, -NRCONR-,
-OCONR-, -NRNR, -NRNRCO-, -NRCO-, -S-, -SO, -S02-, -NR-, -S02NR-, -NRSO2-,
-NRSO2NR-, and each occurrence of RY is independently R', halogen, NO2, or CN;
R2, R3, R4, and R5 are each independently halogen, -CN, -NO2, or -VRV, or R2 and
R3, or R4 and Rs, taken together, form an optionally substituted 5-, 6-, or 7-membered
monocyclic aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen,
or sulfur or a 5-, 6-, or 7-membered saturated or partially unsaturated monocyclic ring having
0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein any ring
formed by R2 and R3 taken together is optionally substituted at one or more carbon or
nitrogen atoms with m independent occurrences of-WRw, or any ring formed by R4 and R5,
taken together is optionally substituted at one or more carbon or nitrogen atoms with n
independent occurrences of Z-Rz, wherein m and n are each independently 0-5;
V, W, and Z are each independently a bond or is an optionally substituted C1-C6
alkylidene chain wherein up to two methylene units of V, W, or Z are optionally replaced by
-CO-, -CS-, -COCO-, -CONR-, -CONRNR-, -C02-, -OCO-, -NRCO^, -0-, -NRCONR-,
-OCONR-, -NRNR, -NRNRCO-, -NRCO-, -S-, -SO, -S02~, -NR-, -S02NR-, -NRSO2-,

-NRSO2NR-, and each occurrence of Rv, Rw, and Rz is independently R', halogen, N02, or
CN;
X is 0, S, or [C(R1)2]q, where q is 1 or 2; and
G is N or CR6, wherein R6 is halogen, CN, NO2, or QRX,
provided that:
when X is O; R1 is hydrogen; R2 is hydrogen, methyl, or bromine; R3 is hydrogen; G
is N; and R4 and R5, taken together, are unsubstituted phenyl; then Cy1 is not unsubstituted
phenyl, or phenyl substituted in the ortho position with CO2R' or CONRR'; and
when X is O; R1 is hydrogen; R2 and R3, taken together are unsubstituted phenyl; R4
and R5, taken together are unsubstituted phenyl; and G is N; then Cy1 is not unsubstituted
phenyl.
[0016] 2. Compounds and Definitions:
[00171 Compounds of this invention include those described generally above, and are
further illustrated by the classes, subclasses, and species disclosed herein. As used herein, the
following definitions shall apply unless otherwise indicated. For purposes of this invention,
the chemical elements are identified in accordance with the Periodic Table of the Elements,
CAS version, Handbook of Chemistry and Physics, 75th Ed. Additionally, general principles
of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University
Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry", 5th Ed., Ed.:
Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of
which are hereby incorporated by reference.
[0018] As described herein, compounds of the invention may optionally be substituted
with one or more substituents, such as are illustrated generally above, or as exemplified by
particular classes, subclasses, and species of the invention. It will be appreciated that the
phrase "optionally substituted" is used interchangeably with the phrase "substituted or
unsubstituted." In general, the term "substituted", whether preceded by the term "optionally"
or not, refers to the replacement of hydrogen radicals in a given structure with the radical of a
specified substituent. Unless otherwise indicated, an optionally substituted group may have a
substituent at each substitutable position of the group, and when more than one position in
any given structure may be substituted with more than one substituent selected from a
specified group, the substituent may be either the same or different at every position.
Combinations of substituents envisioned by this invention are preferably those that result in

the formation of stable or chemically feasible compounds. The term "stable", as used herein,
refers to compounds that are not substantially altered when subjected to conditions to allow
for their production, detection, and preferably their recovery, purification, and use for one or
more of the purposes disclosed herein. In some embodiments, a stable compound or
chemically feasible compound is one that is not substantially altered when kept at a
temperature of 40°C or less, in the absence of moisture or other chemically reactive
conditions, for at least a week.
[00191 The term "aliphatic" or "aliphatic group", as used herein, means a straight-chain
(i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is
completely saturated or that contains one or more units of unsaturation, or a monocyclic
hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more
units of unsaturation, but which is not aromatic (also referred to herein as "carbocycle"
"cycloaliphatic" or "cycloalkyl"), that has a single point of attachment to the rest of the
molecule. Unless otherwise specified, aliphatic groups contain 1-20 aliphatic carbon atoms.
In some embodiments, aliphatic groups contain 1-10 aliphatic carbon atoms. In other
embodiments, aliphatic groups contain 1-8 aliphatic carbon atoms. In still other
embodiments, aliphatic groups contain 1-6 aliphatic carbon atoms, and in yet other
embodiments aliphatic groups contain 1-4 aliphatic carbon atoms. In some embodiments,
"cycloaliphatic" (or "carbocycle" or "cycloalkyl") refers to a monocyclic C3-C8 hydrocarbon
or bicyclic Cg-Ci2 hydrocarbon that is completely saturated or that contains one or more units
of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of
the molecule wherein any individual ring in said bicyclic ring system has 3-7 members.
Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or
unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl,
(cycloalkenyl)alkyl or (cycloalkyl)alkenyl.
[0020] The term "heteroaliphatic", as used herein, means aliphatic groups wherein one or
two carbon atoms are independently replaced by one or more of oxygen, sulfur, nitrogen,
phosphorus, or silicon. Heteroaliphatic groups may be substituted or unsubstituted, branched
or unbranched, cyclic or acyclic, and include "heterocycle", "heterocyclyl",
"heterocycloaliphatic", or "heterocyclic" groups.
[0021] The term "heterocycle", "heterocyclyl", "heterocycloaliphatic", or "heterocyclic"
as used herein means non-aromatic, monocyclic, bicyclic, or tricyclic ring systems in which
one or more ring members are an independently selected heteroatom. In some embodiments,

the "heterocycle", "heterocyclyl", "heteocycloaliphatic", or "heterocyclic" group has three to
fourteen ring members in which one or more ring members is a heteroatom independently
selected from oxygen, sulfur, nitrogen, or phosphorus, and each ring in the system contains 3
to 7 ring members.
[0022] The term "heteroatom" means one or more of oxygen, sulfur, nitrogen,
phosphorus, or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or
silicon; the quaternized form of any basic nitrogen or; a substitutable nitrogen of a
heterocyclic ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or
NR+ (as in N-substituted pyrrolidinyl)).
[0023] The term "unsaturated", as used herein, means that a moiety has one or more units
ofunsaturation.
[0024] The term "alkoxy", or "thioalkyl", as used herein, refers to an alkyl group, as
previously defined, attached to the principal carbon chain through an oxygen ("alkoxy") or
sulfur ("thioalkyl") atom.
[0025] The terms "haloalkyl", "haloalkenyl" and "haloalkoxy" means alkyl, alkenyl or
alkoxy, as the case may be, substituted with one or more halogen atoms. The term "halogen"
means F, CI, Br, or I.
[0026] The term "aryl" used alone or as part of a larger moiety as in "aralkyl",
"aralkoxy", or "aryloxyalkyl", refers to monocyclic, bicyclic, and tricyclic ring systems
having a total of five to fourteen ring members, wherein at least one ring in the system is
aromatic and wherein each ring in the system contains 3 to 7 ring members. The term "aryl"
may be used interchangeably with the term "aryl ring".
[0027] The term "heteroaryl", used alone or as part of a larger moiety as in
"heteroaralkyl" or "heteroarylalkoxy", refers to monocyclic, bicyclic, and tricyclic ring
systems having a total of five to fourteen ring members, wherein at least one ring in the
system is aromatic, at least one ring in the system contains one or more heteroatoms, and
wherein each ring in the system contains 3 to 7 ring members. The term "heteroaryl" may be
used interchangeably with the term "heteroaryl ring" or the term "heteroaromatic".
[0028] An aryl (including aralkyl, aralkoxy, aryloxyalkyl and the like) or heteroaryl
(including heteroaralkyl and heteroarylalkoxy and the like) group may contain one or more
substituents. Suitable substituents on the unsaturated carbon atom of an aryi or heteroaryl
group are selected from halogen; -R°; -OR0; -SR°; 1,2-methylenedioxy; 1,2-ethylenedioxy,
phenyl (Ph.) optionally substituted with R°; -0(Ph) optionally substituted with R°;

-(CH2)i.2(Ph), optionally substituted with R°; -CH=CH(Ph), optionally substituted with R°;
-N02; -CN; -N(R°)2; -NR°C(0)R°; -NR°C(S)R°; -NR°C(0)N(R°)2; -NR°C(S)N(R°)2;
-NR°C02R°; -NR°NR°C(0)R°; -NR°NR°C(0)N(Ro)2; -NR°NR0C02R0; -C(0)C(0)R°;
-C(0)CH2C(0)R°; -CO2R0; -C(0)R°; -C(S)R°; -C(0)N(R°)2; -C(S)N(R°)2; -0C(0)N(R°)2;
-0C(O)R0; -C(0)N(OR°)R°; -C(NOR0)R0; -S^R0; -S(0)3R°; -S02N(R°)2; -S(0)R°;
-NR°S02N(R°)2; -NR°SOaR°; -N(OR°)R°; -C(=NH)-N(R°)2; or -(CH2)o.2NHC(0)R° wherein
each independent occurrence of R° is selected from hydrogen, optionally substituted Ci-6
aliphatic, an unsubstituted 5-6 membered heteroaryl or heterocyclic ring, phenyl, -0(Ph), or
-CH2(Ph), or, notwithstanding the definition above, two independent occurrences of R°, on
the same substituent or different substituents, taken together with the atom(s) to which each
R° group is bound, form a 5-8-membered heterocyclyl, aryl, or heteroaryl ring or a 3-8-
membered cycloalkyl ring having 0-3 heteroatoms independently selected from nitrogen,
oxygen, or sulfur. Optional substituents on the aliphatic group of R° are selected from NH2,
NII(Ci-4aliphatic), N(CMaliphatic)2, halogen, CMaliphatic, OH, 0(Ci-4aliphatic), N02, CN,
C02H, C02(Ci4aliphatic), 0(haloCi-4 aliphatic), or haloCi4aliphatic, wherein each of the
foregoing Ci^aliphatic groups of R° is unsubstituted.
[0029] An aliphatic or heteroaliphatic group, or a non-aromatic heterocyclic ring may
contain one or more substituents. Suitable substituents on the saturated carbon of an aliphatic
or heteroaliphatic group, or of a non-aromatic heterocyclic ring are selected from those listed
above for the unsaturated carbon of an aryl or heteroaryl group and additionally include the
following: =0, =S, =NNHR*, =NN(R*)2, =NNHC(0)R*, =NNHC02(alkyl),
=NNHS02(alkyl), or =NR*, where each R* is independently selected from hydrogen or an
optionally substituted C1-6 aliphatic. Optional substituents on the aliphatic group of R* are
selected from NH2, NH(CM aliphatic), N(Ci-4 aliphatic^, halogen, CM aliphatic, OH, 0(CM
aliphatic), N02, CN, C02H, C02(CM aliphatic), 0(halo C14 aliphatic), or halo(Ci-4 aliphatic),
wherein each of the foregoing Ci^aliphatic groups of R* is unsubstituted.
[0030] Optional substituents on the nitrogen of a non-aromatic heterocyclic ring are
selected from -R+, -N(R\ -C(0)R+, -C02R+, -C(0)C(0)R+, -C(0)CH2C(0)R+, -S02R+,
-SOaNtR^, -C(=S)N(R+)2, -C(=NH)-N(R4)2, or -NR+S02R+; wherein R+ is hydrogen, an
optionally substituted Ci^ aliphatic, optionally substituted phenyl, optionally substituted
-0(Ph), optionally substituted -CH2(Ph), optionally substituted -(CH2)i.2(Ph); optionally
substituted -CH=CH(Ph); or an unsubstituted 5-6 membered heteroaryl or heterocyclic ring
having one to four heteroatoms independently selected from oxygen, nitrogen, or sulfur, or,

notwithstanding the definition above, two independent occurrences of R , on the same
substituent or different substituents, taken together with the atom(s) to which each R+ group
is bound, form a 5-8-membered heterocyclyl, aryl, or heteroaryl ring or a 3-8-membered
cycloalkyl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or
sulfur. Optional substituents on the aliphatic group or the phenyl ring of R+ are selected from
NH2, NH(Ci-4 aliphatic), N(CM aliphatic^, halogen, CM aliphatic, OH, 0(CM aliphatic),
NO2, CN, CO2H, C02(Ci4 aliphatic), 0(halo CM aliphatic), or halo(Ci-4 aliphatic), wherein
each of the foregoing C1.4alipb.atic groups of R+ is unsubstituted.
[0031] The term "alkylidene chain" refers to a straight or branched carbon chain that may
be fully saturated or have one or more units of unsaruration and has two points of attachment
to the rest of the molecule, wherein one or more methylene units may optionally and
independently be replaced with a group including, but not limited to, CO, CO2, COCO,
CONR, OCONR, NRNR, NRNRCO, NRCO, NRC02, NRCONR, SO, SO2, NRSO2, SO2NR,
NRS02NR,0, S.orNR.
[0032] As detailed above, in some embodiments, two independent occurrences of R° (or
R+, or any other variable similarly defined herein), are taken together together with the
atom(s) to which each variable is bound to form a 5-8-membered heterocyclyl, aryl, or
heteroaryl ring or a 3-8-membered cycloalkyl ring having 0-3 heteroatoms independently
selected from nitrogen, oxygen, or sulfur. Exemplary rings that are formed when two
independent occurrences of R° (or R+, or any other variable similarly defined herein) are
taken together with the atom(s) to which each variable is bound include, but are not limited to
the following: a) two independent occurrences of R° (or R+, or any other variable similarly
defined herein) that are bound to the same atom and are taken together with that atom to form
a ring, for example, N(R°)2, where both occurrences of R° are taken together with the
nitrogen atom to form a piperidin-1-yl, piperazin-1-yl, or morpholin-4-yl group; and b) two
independent occurrences of R° (or R+, or any other variable similarly defined herein) that are
bound to different atoms and are taken together with both of those atoms to form a ring, for
example where a phenyl group is substituted with two occurrences of OR0
these two occurrences of R° are taken together with the oxygen atoms to which they are
bound to form a fused 6-membered oxygen containing ring: It will be

appreciated that a variety of other rings can be formed when two independent occurrences of
R° (or R+, or any other variable similarly defined herein) are taken together with the atorn(s)
to which each variable is bound and that the examples detailed above are not intended to be
limiting.
[0033] Unless otherwise stated, structures depicted herein are also meant to include all
isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the
structure; for example, the R and S configurations for each asymmetric center, (Z) and (E)
double bond isomers, and (Z) and (E) conformational isomers. Therefore, single
stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or
conformational) mixtures of the present compounds are within the scope of the invention.
Unless otherwise stated, all tautomeric forms of the compounds of the invention are within
the scope of the invention. Additionally, unless otherwise stated, structures depicted herein
are also meant to include compounds that differ only in the presence of one or more
isotopically enriched atoms. For example, compounds having the present structures except
for the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a
13C- or 14C-enriched carbon are within the scope of this invention. Such compounds are
useful, for example, as analytical tools or probes in biological assays.
[0034] 3. Description ofExemplary Compounds:
[0035] As described generally above, R1 is -QRX; wherein Q is a bond or is a Q-C6
alkylidene chain wherein up to two methylene units of Q are optionally and independently
replaced by -CO-, -CS-, -COCO-, -CONR-, -CONRNR-, -CO2-, -OCO-, -NRCO2-, -0-,
-NRCONR-, -OCONR-, -NRNR, -NRNRCO-, -NRCO-, -S-, -SO, -S02-, -NR-, -SOzNR-,
-NRSO2-, -NRSO2NR-, and each occurrence of Rx is independently R', halogen, NO2, or CN,
provided R1 is hydrogen or is bonded to the nitrogen atom through a carbon atom. In certain
embodiments, R1 is hydrogen, -COR', CONRR', or is an optionally substituted Ci-Cg alkyl
group. In still other embodiments, for compounds of general formula I and classes and
subclasses described herein, R1 is hydrogen.
[0036] As described generally above, Cy1 is a 5-7-membered monocyclic aryl ring or an
8-10-membered bicyclic aryl ring having 0-3 heteroatoms independently selected from
nitrogen, oxygen, or sulfur, or is a 3-8-membered saturated or partially unsaturated
monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or



[0037] In other embodiments, Cy1 is phenyl (i), pyridyl (iii), pyrimidinyl (iv), imidazolyl
(vi), pyrazolyl (vii), triazolyl (x), thiazolyl (xiv), or indazole (six) or (xxi). In still other
embodiments, Cy1 is phenyl (i) or pyrazolyl (vii).
[0038] It will be appreciated that, as described generally above, Cy1 is optionally
substituted at any substitutable carbon or nitrogen atom with y occurrences of-YRY, wherein
y is 0-5, Y is a bond or is a C4-C6 alkylidene chain wherein up to two methylene units of Y
are optionally and independently replaced by -CO-, -CS-, -COCO-, -CONR-, -CONRNR-,
-CO2-, -OCO-, -NRCO2-, -0-, -NRCONR-, -OCONR-, -NRNR, -NRNRCO-, -NRCO-, -S-,
-SO, -SO2-, -NR-, -SO2NR-, -NRSO2-, -NRSO2NR-, and each occurrence of RY is
independently R', halogen, NO2, or CN. In some embodiments, each occurrence of -YRY,
when present, is independently halogen, R', CN, N02, -N(R')2, -CH2N(R')2, -(CH2)2N(R')2,
-(CH2)3N(R')2, -OR', -CH2OR\ -iCH&pQL'h -(CH2)30(R')2, -SR', -CH2SR-(CHj^SCR'^, -(CH2)3S(R')2, -COOR', -NRCOR', NRCOOR', -CON(R')2, or -S(0)2N(R')2.
In other embodiments, -YRY groups are each independently F, CI, Br, I, -CN, -COOMe,
-COOH, -OH, NH2, SH, -S02NH2, -CON(CH3)2, -0(Ci-C6alkyl), -CH^Q-Cealkyl),
-(CHz^OCCi-Cealkyl), -(CH2)30(Ci-C6alkyl), -S(Ci-C6alkyl), -CH2S(Ci-C6alkyl),
-(CHz^SCC-Cfialkyl), -(CH2)3S(Ci-C6alkyl), -N(Ci-C6alkyl)2, -CH2N(C,-C6alkyl)2,
-(CH2)2N(Ci-C6alkyl)2, -(CH2)3N(Ci-C6alkyl)2j wherein each CrC6alkyl group is optionally
substituted with R\ -OR', -N(R')2, -SR', -S02N(R')2, -NRSO2R', -CON(R')2, or -NRCOR',
or -YRY groups are each independently an optionally substituted group selected from linear or
branched Ci.Cealkyl, C3-C8cycloalkyl, phenyl, phenyloxy, benzyl, benzyloxy, pyridyl,
pyrimidinyl, thiophene, N-morpholinyl, N-piperidinyl, N-piperazinyl, or furanyl. In still
other embodiments, y is 1 and YRY is cyclopropyl, cyclobutyl, cyclopenyl, cyclohexyl,
methyl, ethyl, n-propyl, isopropyl, n-butyl, phenyl, NH2, (CH2)3OR', or (CH2)2N(R')2.
[0039] As described generally above for compounds of formula I, R2 and R3 are each
independently halogen, -CN, -NO2, or -VRV, or R2 and R3, taken together with the atoms to
which they are bound, form an optionally substituted 5-, 6-, or 7-membered monocyclic aryl
ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur or a 5-,
6-, or 7-membered saturated or partially unsaturated monocyclic ring having 0-3 heteroatoms
independently selected from nitrogen, oxygen, or sulfur.
[0040] In certain embodiments, R2 and R3 are each independently halogen, -CN, -N02, or
-VRV. In other embodiments, R2 and R are each independently hydrogen, OR', SR', N(R')2,

-COR', NRCOR', NRS02R', -S02N(R')2, or an optionally substituted group selected from
Ci-C6alkyl, or a 5- or 6-membered saturated, partially unsaturated, or fully unsaturated ring.
[0041] In certain embodiments, R2 and R3, taken together with the atoms to which they
are bound, form an optionally substituted 5-, 6-, or 7-membered monocyclic aryl ring having
0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur or a 5-, 6-, or 7-
membered saturated or partially unsaturated monocyclic ring having 0-3 heteroatoms
independently selected from nitrogen, oxygen, or sulfur. In certain other embodiments, R2
and R3, taken together with the carbon atoms to which they are bound form an optionally
substituted ring selected from one of the following groups:



[0042] In still other embodiments, R2 and R3, taken together with the carbon atoms to
which they are bound form an optionally substituted 5- or 6-membered ring selected from
phenyl (a), pyridyl (b, c, d, or e), cyclohexyl (nn), or cyclopentyl (oo).
[0081] It will be appreciated that any ring formed by R2 and R3 taken together is
optionally optionally substituted at any substitutable carbon or nitrogen atom with m
occurrences of -WRW, wherein m is 0-5, W is a bond or is a C1-C6 alkylidene chain wherein
up to two methylene units of W are optionally and independently replaced by -CO-, -CS-,
-COCO-, -CONR-, -CONRNR-, -C02-, -OCO-, -NRCQj-, -0-, -NRCONR-, -OCONR-,
-NRNR, -NKNRCO-, -NRCO-, -S-, -SO, -SO2-, -NR-, -SO2NR-, -NRS02-, -NRS02NR-, and
each occurrence of Rw is independently R', halogen, NO2, or CN. In some embodiments,

each occurrence of-WRw, when present, is independently halogen, R', CN, NC% -N(R')2,
-CH2N(R')2, -(CH2)2NCR,)2, -CCH&N(R% -OR', -CH2OR', -(CH^OCR'h, -(CH2)30(R')2,
-SR', -CH2SR', -(CH2)2S(R')2, -(CH2)3S(R')2, -COOR', -NRCOR', NRCOOR', -CON(R'>2,
or -S(0)2N(R')2. In other embodiments, -WRW groups are each independently F, CI, Br, I,
-CN, -COOMe, -COOH, -OH, NH2) SH, -S02NH2, -CON(CH3)2, -0(Ci-C6alkyl),
-CH20(Ci-C6alkyl), -(CH2)20(Ci-C6alkyl), -(CH2)30(C,-C6alkyl), -S(C,-C6alkyl),
-CH2S(C,-C6alkyl), -(CH^SCCi-Cgalkyl), -(CH2)3S(Ci-C6alkyl), -N(Ci-C6alkyl)2,
-CH^CCi-Cfialkyl^, -(CH^NCCi-Qalkyl^, -(CH2)3N(Ci-C6alkyl)2, wherein each
Ci-C6alkyl group is optionally substituted with R', -OR', -NtR'fe, -SR', -SC^NfR'^,
-NRSC^R', -CON(R')2, or -NRCOR', or -WRW groups are each independently an optionally
substituted group selected from Ci-Cgalkyl, C3-Cgcycloalkyl, phenyl, phenyloxy, benzyl,
benzyloxy, pyridyl, pyrirnidinyl, thiophene, N-morpholinyl, N-piperidinyl, N-piperazinyl, or
furanyl.
[0043] As described generally above, G is N or CR6 wherein R6 is halogen, CN, N02 or
-QRX. In some embodiments, G is CH or C(Ci-C6alkyl). In other embodiments G is N and
compounds have the general formula II:

[0044] In other embodiments X is O and compounds have the general formula III:


[0045] In still other embodiments X is O and G is N and compounds have the general
formula IV:
[0046] As described generally above for compounds of formula I, R4 and R5 are each
independently halogen, -CN, -NO2, or -VRV, or R4 and R5, taken together with the atoms to
which they are bound, form an optionally substituted 5-, 6-, or 7-membered monocyclic aryl
ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur or a 5-,
6-, or 7-membered saturated or partially unsaturated monocyclic ring having 0-3 heteroatoms
independently selected from nitrogen, oxygen, or sulfur.
[0047] In certain embodiments, R4 and R5 are each independently halogen, -CN, -NO2, or
-VRV. In other embodiments, R4 and R5 are each independently hydrogen, OR', SR', N(R')2,
-COR', NRCOR', NRSO2R', -S02N(R')2, or an optionally substituted group selected from
Ct-C6alkyl, or a 5- or 6-membered saturated, partially unsaturated, or fully unsaturated ring.
[0048] In certain embodiments, R4 and Rs, taken together with the atoms to which they
are bound, form an optionally substituted 5-, 6-, or 7-membered monocyclic aryl ring having
0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur or a 5-, 6-, or 7-
membered saturated or partially unsaturated monocyclic ring having 0-3 heteroatoms
independently selected from nitrogen, oxygen, or sulfur. In certain other embodiments, R4
and R5, taken together with the carbon atoms to which they are bound form an optionally
substituted ring selected from one of the following groups:





[00491 In still other embodiments, R4 and R5, taken together with the carbon atoms to
which they are bound form an optionally substituted 5- or 6-membered ring selected from
phenyl (a-i), pyridyl (b-i, c-i, d-i, or e-i), cyclohexyl (nn-i), or cyclopentyl (oo-i).
[0082] It will be appreciated that any ring formed by R4 and Rs taken together is
optionally optionally substituted at any substitutable carbon or nitrogen atom with n
occurrences of-ZRZ, wherein n is 0-5, Z is a bond or is a Q-C6 alkylidene chain wherein up
to two methylene units of Z are optionally and independently replaced by -CO-, -CS-,
-COCO-, -CONR-, -CONRNR-, -C02-, -OCO-, -NRC02-, -0-, -NRCONR-, -OCONR-,
-NRNR, -NRNRCO-, -NRCO-, -S-, -SO, -SO2-, -NR-, -S02NR-, -NRSO2-, -NRS02NR-, and
each occurrence of Rz is independently R', halogen, NO2, or CN. In some embodiments,
each occurrence of -ZRZ, when present, is independently halogen, R', CN, N02, -N(R')2,
-CH2N(R')2, -(CH2)2N(R')2, -(CH2)3N(R')2, -OR', -CH2OR', -(CH2)20(R')2, -(CH2)30(R')2,
-SR', -CH2SR', -(CH2)2S(R')2, -(CH2)3S(R')2, -COOR', -NRCOR', NRCOOR', -CON(R')2,
or -S(0)2N(R')2. In other embodiments, -ZRz groups are each independently F, Cl, Br, I,
-CN, -COOMe, -COOH, -OH, NH2, SH, -S02NH2, -C0N(CH3)2, -OCQ-Cealkyl),
-CH20(Ci-C6alkyl), -(CH2)20(Ci-C6alkyl), -(CH2)30(C,-C6alkyl), -S(Ci-C6alkyl),
-CH^C^alkyl), -(CH2)2S(C1-C6alkyl), -(CH^SCQ-Csalkyl), -N(CrC6alkyl)2,
-CH2N(Ci-C6alkyl)2, -(CH2)2N(Ci-C6alkyl)2, -(CH2)3N(Ci-C6alkyl)2, wherein each
Ci-C6alkyl group is optionally substituted with R', -OR', -NOR.% -SR', -S02N(R')2,
-NRS02R', -CON(R')2, or -NRCOR', or -ZRz groups are each independently an optionally

substituted group selected from Ci.Cealkyl, C3-Cscycloalkyl, phenyl, phenyloxy, benzyl,
benzyloxy, pyridyl, pyrimidinyl, thiophene, N-morpholinyl, N-piperidinyl, N-piperazdnyl, or
furanyl.
[0083] In other embodiments, for compounds of formula I, G is N, X is O and R4 and R5,
taken together form an optionally substituted phenyl group and compounds have formula V:

[0050] In some embodiments, R2 and R3 are each independently halogen, -CN, -N02, or
-VRV. In other embodiments, R2 and R3 are each independently hydrogen, OR', SR\ N(R%
-COR', NRCOR', NRS02R', -S02N(R')2, or an optionally substituted group selected from
Ci-C6alkyl, or a 5- or 6-membered saturated, partially unsaturated, or fully unsaturated ring.
[0051] In still other embodiments, R2 and R3, taken together with the atoms to which they
are bound, form an optionally substituted 5-, 6-, or 7-membered monocyclic aryl ring having
0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur or a 5-, 6-, or 7-
membered saturated or partially unsaturated monocyclic ring having 0-3 heteroatoms
independently selected from nitrogen, oxygen, or sulfur. In certain other embodiments, R2
and R3, taken together with the carbon atoms to which they are bound form an optionally
substituted ring selected from one of the following groups:






[0054] It will be appreciated that for compounds of formulae V-A, V-B, V-C, V-D, V-E,
or V-F, Cy1, R1, WRW, m, ZRZ, and n are defined generally above and in subsets above and
herein. In certain other embodiments, R1 is hydrogen, -COR', CONRR', or is an optionally
substituted Q-C6 alkyl group. In still other embodiments, R1 is hydrogen and compounds of
general formulae V-A-i, V-B-i, V-C-i, V-D-i, V-E-i, and V-F-i are provided.

[0055] In certain other embodiments, Cy1 phenyl (i), pyridyl (iii), pyrirnidinyl (iv),
imidazolyl (vi), pyrazolyl (vii), triazolyl (x), thiazolyl (xiv), or indazole (xix) or (xxi). In still
other embodiments, Cy1 is phenyl (i) or pyrazolyl (vii). In yet other embodiments, Cy1 is
pyrazolyl (vii).

[0056] As described generally above, Cy1 is optionally substituted at any substitutable
carbon or nitrogen atom with y occurrences of -YRY, wherein y is 0-5. In certain
embodiments, y is 0,1, or 2. In some embodiments, each occurrence of-YRY, when present,
is independently halogen, R\ CN, NO* -N(R')2, -CH2N(R')2, -(CH^NGl')* -(CH2)3N(R')2,
-OR', -CH2OR', -(CH2)20(R')2, -(CH2)30(R')2, -SR', -CH2SR', -(CH2)2S(R')2,
-(CH^SCR'^, -COOR', -NRCOR', NRCOOR', -CON(R')2, or -^OfcWfc- In other
embodiments, -YRY groups are each independently F, CI, Br, I, -CN, -COOMe, -COOH,
-OH, NH2, SH, -S02NH2, -CONCCHs^ -0(Ci-C6alkyl), -CH20(Ci-C6alkyl),
-(CH2)20(C!-C6alkyl), -(CH2)30(Ci-C6alkyl), -S(Ci-C6alkyl), -CH2S(d-C6alkyl),
-(CH^SCCi-Cgalkyl), -(CH2)3S(d-C6alkyl), -Nfd-Cealkyl^, -CH2N(d-C6alkyl)2,
-(CH^^Ci-Cealkyl^, -(CH2)3N(Ci-C6alkyl)2, wherein each Ci-C6alkyl group is optionally
substituted with R', -OR', -N(R')2, -SR', -SOaNCt'k, -NRSC^R', -C0N(R')2, or -NRCOR',
or -YRY groups are each independently an optionally substituted group selected from
Ci-C6alkyl, phenyl, phenyloxy, benzyl, benzyloxy, pyridyl, pyrimidinyl, thiophene,
N-morpholinyl, N-piperidinyl, N-piperazinyl, or furanyl. In other embodiments, y is 0 or 1
and-YRY groups, when present, are each independently F, CI, Br, I, -CN, -COOMe, -COOH,
-OH, NH2, SH, -S02NH2, -CONCCHsfc, -0(Ci-C6alkyl), -CH20(Ci-C6alkyl),
-(CH2)20(Ci-C6alkyl), -(CH2)30(Ci-C6alkyl), -S(Ci-C6alkyl), -CHzSCd-Qalkyl),
-(CH^SCC-Cealkyl), -(CH2)3S(d-C6alkyl), -N(d-C6alkyl)2, -CHzNCd-Qsalkylk,
-(CH^N^i-Cealkyl^, -(CH^NCd-Cealkyl^, wherein each Ci-C6alkyl group is optionally
substituted with R', -OR', -N(R')2, -SR', -S02N(R')2, -NRS02R', -CON(R')2, or -NRCOR',
or YRY groups are each independently an optionally substituted group selected from linear or
branched Ci.Cgalkyl, d-Cscycloalkyl, phenyl, phenyloxy, benzyl, benzyloxy, pyridyl,
pyrimidinyl, thiophene, N-morpholinyl, N-piperidinyl, N-piperazinyl, or furanyl. In still
other embodiments, y is 1 and YRY is cyclopropyl, cyclobutyl, cyclopenyl, cyclohexyl,
methyl, ethyl, n-propyl, isopropyl, n-butyl, phenyl, NH2, (CH2)30R', or (CH^NCR'^.
[0084] In still other embodiments, m and n are each independently 0, 1, or 2. In some
embodiments, each occurrence of -WRW and -ZRZ, when present, are each independently
halogen, R', CN, N02, -NCR')* -CH2N(R')2, -(CH2)2N(R')2, -(CH2)3N(R')2, -OR', -CH2OR',
-(CH2)20(R')2, -(CH2)30(R')2, -SR', -CH2SR', -(CH2)2S(R')2, -(CH2)3S(R')2, -COOR',
-NRCOR', NRCOOR', -CON(R')2, or -S(0)2N(R')2. In other embodiments, -WRw and
-ZRZ groups are each independently F, CI, Br, I, -CN, -COOMe, -COOH, -OH, NH2, SH,
-S02NH2, -CONCCHj^, -0(d-Cfialkyl), -CH20(Ci-C6alkyl), -(CH2)20(d-C6alkyl),

-(CH^OCQ-Qalkyl), -SCd-Qalkyl), -CH^CrCgalkyl), -(CH2)2S(Ci-C6alkyl),
-(CH2)3S(Ci-C6aIkyl), -N(Ci-C6alkyl)2, -CH2N(CL-C6alkyl)2, -(CHz^NCC-Cfialkyi^,
-(CH2)3N(Ci-C6alkyl)2s wherein each Chalky! group is optionally substituted with R',
-OR', -N(R')2, -SEC, -S02N(R')2, -NRSOaR', -CON(R')2, or -NRCOR', or -WRW and -ZRZ
groups are each independently an optionally substituted group selected from Ci-Cgalkyl,
phenyl, phenyloxy, benzyl, benzyloxy, pyridyl, pyrimidinyl, thiophene, N-morpholinyl,
N-piperidinyl, N-piperazinyl, or furanyl. In other embodiments, m and n are each
independently 0 or 1 and -WRW and -ZRZ groups, when present, are each independently F,
CI, Br, I, -CN, -COOMe, -COOH, -OH, NH2, SH, -S02NH2, -CON(CH3)2, -0(Ci-C6alkyl),
-CH20(Ci-C6alkyl), -(CH2)20(Ci-C6alkyl), -(CH2)30(Ci-C6alkyl), -S(Ci-C6alkyl),
-CH2S(CrC6alkyl), -(CH^Q-Cealkyl), -(CH2)3S(Ci-C6alkyl), -N(Ci-C6alkyl)2,
-CH^Ci-Qalkyl)* -(CK^NCCi-Qalkylk -(CH2)3N(Ci-C6alkyl)2, wherein each
Ci-C6alkyl group is optionally substituted with R', -OR', -NCR'K -SR', -S02N(R')2,
-NRS02R', -CON(R'>2, or -NRCOR', or-WRw and -ZRz groups are each independently an
optionally substituted group selected from Ci-Cgalkyl, C3-Cgcycloalkyl, phenyl, phenyloxy,
benzyl, benzyloxy, pyridyl, pyrimidinyl, thiophene, N-morpholinyl, N-piperidinyl,
N-piperazinyl, or furanyl.
[0057] Representative examples of compounds of formula I are depicted in Table 1.








[0105] Scheme II above shows an alternative synthetic route which has been used for
preparing compounds of formula 5 of this invention when Cy1, R4 and Rs is as described
above. The 2-chloro-4-ethoxyquinazoline 6 may be prepared by methods described by Lange
et al, J. Am. Chetn. Soc, 1930,52, 3696. Intermediate 8 is prepared by methods substantially
similar to those described by Butler et al, J. Chem. Soc; 1959,1512 according to scheme II
steps (a) and (b). Intermediate 8 is treated with amines of formula 2 according to step (c) in
some cases by methods substantially similar to those described by Jingjun Y, et al., Organic
Letters, 2002, 4, 3481. This reaction is amenable to a variety of Cy1-NH2 to form compounds
of formula 5.

Reagents and conditions: (a) Et3N, EtOH, 120°C, 24 hours; (b) 135°C, 4 hours.
[0107] Scheme III above shows another general synthetic route which has been used for
preparing the compounds 11 of this invention when Cy1, R2, R3, R4 and R5 is as described
above. The formation of the dichloropyrimidine derivatives 9 is achieved by using methods
well known for those skilled in the art. Intermediate 10 is prepared according the scheme III
step (a). Compound 10 is treated with aminoesters 4 according to step (b). This reaction is
amenable to a variety of aminoesters 4 to form compounds of formula 11.


[0109] Scheme IV above shows an alternative synthetic route which has been used for
preparing compounds of formula 5 of this invention when Cy1, R4 and R5 is as described
above. Intermediate 7 is alternatively prepared by methods substantially similar to those
described by Deady et al, J. Heterocyclic. Chem.; 1989, 26, 161 according to scheme IV step
(a). Intermediate 8 is treated with amines of formula 2 according to step (c). This reaction is
amenable to a variety of Cy!-NH2 to form compounds of formula 5.
[0110] Atthough certain exemplary embodiments are depicted and described above and
herein, it will be appreciated that a compounds of the invention can be prepared according to
the methods described generally above using appropriate starting materials by methods
generally available to one of ordinary skill in the art.
[0111] 5. Uses, Formulation and Administration
[0112] Pharmaceutically acceptable compositions
[0113] As discussed above, the present invention provides compounds that are inhibitors
of protein kinases, and thus the present compounds are useful for the treatment of diseases,
disorders, and conditions including, but not limited to an autoimmune, inflammatory,
proliferative, or hyperproliferative disease or an immunologically-mediated disease.
Accordingly, in another aspect of the present invention, pharmaceutically acceptable

compositions are provided, wherein these compositions comprise any of the compounds as
described herein, and optionally comprise a pharmaceutically acceptable carrier, adjuvant or
vehicle. In certain embodiments, these compositions optionally further comprise one or more
additional therapeutic agents.
[0114] It will also be appreciated that certain of the compounds of present invention can
exist in free form for treatment, or where appropriate, as a pharmaceutically acceptable
derivative thereof. According to the present invention, a pharmaceutically acceptable
derivative includes, but is not limited to, pharmaceutically acceptable salts, esters, salts of
such esters, or any other adduct or derivative which upon administration to a patient in need
is capable of providing, directly or indirectly, a compound as otherwise described herein, or a
metabolite or residue thereof.
As used herein, the term "pharmaceutically acceptable salt" refers to those salts which are,
within the scope of sound medical judgement, suitable for use in contact with the tissues of
humans and lower animals without undue toxicity, irritation, allergic response and the like,
and are commensurate with a reasonable benefit/risk ratio. A "pharmaceutically acceptable
salt" means any non-toxic salt or salt of an ester of a compound of this invention that, upon
administration to a recipient, is capable of providing, either directly or indirectly, a compound
of this invention or an inhibitorily active metabolite or residue thereof. As used herein, the
term "inhibitorily active metabolite or residue thereof means that a metabolite or residue
thereof is also an inhibitor of a Tec family (e.g.,Tec, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk)
protein kinases kinase.
[0115] Pharmaceutically acceptable salts are well known in the art. For example, S. M.
Berge et at, describe pharmaceutically acceptable salts in detail in J. Pharmaceutical
Sciences, 1977, 66,1-19, incorporated herein by reference. Pharmaceutically acceptable salts
of the compounds of this invention include those derived from suitable inorganic and organic
acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are
salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic
acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic
acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by
using other methods used in the art such as ion exchange. Other pharmaceutically acceptable
salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate,
borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate,
dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate,

gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate,
lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-
naphmalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate,
persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate,
sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like.
Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium
and N*(Ci.talkyl)4 salts. This invention also envisions the quaternization of any basic
nitrogen-containing groups of the compounds disclosed herein. Water or oil-soluble or
dispensable products may be obtained by such quaternization. Representative alkali or
alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the
like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic
ammonium, quaternary ammonium, and amine cations formed using counterfoils such as
halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl
sulfonate.
[0116] As described above, the pharmaceutically acceptable compositions of the present
invention additionally comprise a pharmaceutically acceptable carrier, adjuvant, or vehicle,
which, as used herein, includes any and all solvents, diluents, or other liquid vehicle,
dispersion or suspension aids, surface active agents, isotonic agents, thickening or
emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the
particular dosage form desired. Remington's Pharmaceutical Sciences, Sixteenth Edition, E.
W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers used in
formulating pharmaceutically acceptable compositions and known techniques for the
preparation thereof. Except insofar as any conventional carrier medium is incompatible with
the compounds of the invention, such as by producing any undesirable biological effect or
otherwise interacting in a deleterious manner with any other components) of the
pharmaceutically acceptable composition, its use is contemplated to be within the scope of
this invention. Some examples of materials which can serve as pharmaceutically acceptable
carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin,
serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine,
sorbic acid, or potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids,
water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate,
potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium
trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-

block polymers, wool fat, sugars such as lactose, glucose and sucrose; starches such as corn
starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl
cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc;
excipicnts such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil;
safflower oil; sesame oil; olive oil; corn oil and soybean oil; glycols; such a propylene glycol
or polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents
such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water;
isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as
other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate,
as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and
perfuming agents, preservatives and antioxidants can also be present in the composition,
according to the judgment of the formulator.
[0117] Uses of Compounds and Pharmaceutically acceptable compositions
[0118] In yet another aspect, a method for the treatment or lessening the severity of a
Tec family (e.g.,Tec, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk)-mediated diseases is provided
comprising administering an effective amount of a compound, or a pharmaceutically
acceptable composition comprising a compound to a subject in need thereof. In certain
embodiments of the present invention an "effective amount" of the compound or
pharmaceutically acceptable composition is that amount effective for a Tec family (e.g.,Tec,
Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk)-mediated disease. The compounds and compositions,
according to the method of the present invention, may be administered using any amount and
any route of administration effective for treating or lessening the severity of a Tec family
(e.g.,Tec, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk)-mediated disease. The exact amount required
will vary from subject to subject, depending on the species, age, and general condition of the
subject, the severity of the infection, the particular agent, its mode of administration, and the
like. The compounds of the invention are preferably formulated in dosage unit form for ease
of administration and uniformity of dosage. The expression "dosage unit form" as used herein
refers to a physically discrete unit of agent appropriate for the patient to be treated. It will be
understood, however, that the total daily usage of the compounds and compositions of the
present invention will be decided by the attending physician within the scope of sound
medical judgment. The specific effective dose level for any particular patient or organism
will depend upon a variety of factors including the disorder being treated and the severity of

the disorder, the activity of the specific compound employed; the specific composition
employed; the age, body weight, general health, sex and diet of the patient; the time of
administration, route of administration, and rate of excretion of the specific compound
employed; the duration of the treatment; drags used in combination or coincidental with the
specific compound employed, and like factors well known in the medical arts. The term
"patient", as used herein, means an animal, preferably a mammal, and most preferably a
human.
[0119] The pharmaceutically acceptable compositions of this invention can be
administered to humans and other animals orally, rectally, parenterally, intracisternally,
intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, as an
oral or nasal spray, or the like, depending on the severity of the infection being treated. In
certain embodiments, the compounds of the invention may be administered orally or
parenterally at dosage levels of about 0.01 mg/kg to about 50 mg/kg and preferably from
about 1 mg/kg to about 25 mg/kg, of subject body weight per day, one or more times a day, to
obtain the desired therapeutic effect.
[0120] Liquid dosage forms for oral administration include, but are not limited to,
pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and
elixirs. In addition to the active compounds, the liquid dosage forms may contain inert
diluents commonly used in the art such as, for example, water or other solvents, solubilizing
agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate,
benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide,
oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils),
glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan,
and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants
such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and
perfuming agents.
[0121] Injectable preparations, for example, sterile injectable aqueous or oleaginous
suspensions may be formulated according to the known art using suitable dispersing or
wetting agents and suspending agents. The sterile injectable preparation may also be a sterile
injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or
solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and
solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium
chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or

suspending medium. For this purpose any bland fixed oil can be employed including ^
synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the
preparation of injectables.
[0122] The injectable formulations can be sterilized, for example, by filtration through a
bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid
compositions which can be dissolved or dispersed in sterile water or other sterile injectable
medium prior to use.
[0123] In order to prolong the effect of a compound of the present invention, it is often
desirable to slow the absorption of the compound from subcutaneous or intramuscular
injection. This may be accomplished by the use of a liquid suspension of crystalline or
amorphous material with poor water solubility. The rate of absorption of the compound then
depends upon its rate of dissolution that, in turn, may depend upon crystal size and crystalline
form. Alternatively, delayed absorption of a parenterally administered compound form is
accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot
forms are made by forming microencapsule matrices of the compound in biodegradable
polymers such as polylactide-polyglycolide. Depending upon me ratio of compound to
polymer and the nature of the particular polymer employed, the rate of compound release can
be controlled. Examples of other biodegradable polymers include poly(orthoesters) and
poly(anhydrides). Depot injectable formulations are also prepared by entrapping the
compound in liposomes or microemulsions that are compatible with body tissues.
[0124] Compositions for rectal or vaginal administration are preferably suppositories
which can be prepared by mixing the compounds of this invention with suitable non-irritating
excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which
are solid at ambient temperature but liquid at body temperature and therefore melt in the
rectum or vaginal cavity and release the active compound.
[0125] Solid dosage forms for oral administration include capsules, tablets, pills,
powders, and granules. In such solid dosage forms, the active compound is mixed with at
least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or
dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose,
mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates,
gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d)
disintegrating agents such as agar—agar, calcium carbonate, potato or tapioca starch, alginic
acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f)

absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as,
for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and
bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid
polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules,
tablets and pills, the dosage form may also comprise buffering agents.
[0126] Solid compositions of a similar type may also be employed as fillers in soft and
hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high
molecular weight polyethylene glycols and the like. The solid dosage forms of tablets,
dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric
coatings and other coatings well known in the pharmaceutical formulating art. They may
optionally contain opacifying agents and can also be of a composition that they release the
active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally,
in a delayed manner. Examples of embedding compositions that can be used include
polymeric substances and waxes. Solid compositions of a similar type may also be employed
as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar
as well as high molecular weight polethylene glycols and the like.
[0127] The active compounds can also be in micro-encapsulated form with one or more
excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and
granules can be prepared with coatings and shells such as enteric coatings, release controlling
coatings and other coatings well known in the pharmaceutical formulating art. In such solid
dosage forms the active compound may be admixed with at least one inert diluent such as
sucrose, lactose or starch. Such dosage forms may also comprise, as is normal practice,
additional substances other than inert diluents, e.g., tableting lubricants and other tableting
aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets
and pills, the dosage forms may also comprise buffering agents. They may optionally contain
opacifying agents and can also be of a composition that they release the active ingredient(s)
only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
Examples of embedding compositions that can be used include polymeric substances and
waxes.
[0128] Dosage forms for topical or transdermal administration of a compound of this
invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays,
inhalants or patches. The active component is admixed under sterile conditions with a
pharmaceutically acceptable carrier and any needed preservatives or buffers as may be

required. Ophthalmic formulation, ear drops, and eye drops are also contemplated as being
within the scope of this invention. Additionally, the present invention contemplates the use of
transdermal patches, which have the added advantage of providing controlled delivery of a
compound to the body. Such dosage forms can be made by dissolving or dispensing the
compound in the proper medium. Absorption enhancers can also be used to increase the flux
of the compound across the skin. The rate can be controlled by either providing a rate
controlling membrane or by dispersing the compound in a polymer matrix or gel.
[0129] As described generally above, the compounds of the invention are useful as
inhibitors of protein kinases. In one embodiment, the compounds and compositions of the
invention are inhibitors of one or more of Tec family (e.g.,Tec, Btk, Itk/Emt/Tsk, Bmx,
Txk/Rlk) kinase, and thus, without wishing to be bound by any particular theory, the
compounds and compositions are particularly useful for treating or lessening the severity of a
disease, condition, or disorder where activation of one or more of a Tec family (e.g.,Tec, Btk,
Itk/Emt/Tsk, Bmx, Txk/Rlk) kinase is implicated in the disease, condition, or disorder.
When activation of Tec family (e.g.,Tec, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk) is implicated in a
particular disease, condition, or disorder, the disease, condition, or disorder may also be
referred to as a "Tec family (e.g.,Tec, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk)-mediated disease" or
disease symptom. Accordingly, in another aspect, the present invention provides a method
for treating or lessening the severity of a disease, condition, or disorder where activation or
one or more of Tec family (e.g.,Tec, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk) is implicated in the
disease state.
[0130] The activity of a compound utilized in this invention as an inhibitor of a Tec
family (e.g.,Tec, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk) kinase may be assayed in vitro, in vivo or
in a cell line. In vitro assays include assays that determine inhibition of either the
phosphorylation activity or ATPase activity of activated Tec family (e.g.,Tec, Btk,
Itk/Emt/Tsk, Bmx, Txk/Rlk) kinase. Alternate in vitro assays quantitate the ability of the
inhibitor to bind to a Tec family (e.g.,Tec, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk) kinase.
Inhibitor binding may be measured by radiolabelling the inhibitor prior to binding, isolating
the inhibitor/Tec family (e.g.,Tec, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk), complex and
determining the amount of radiolabel bound. Alternatively, inhibitor binding may be
determined by running a competition experiment where new inhibitors are incubated with a
Tec family (e.g.,Tec, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk) kinase bound to known radioligands.

[0131] The term "measurably inhibit", as used herein means a measurable change in a
Tec family (e.g.,Tec, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk) kinase activity between a sample
comprising said composition and a Tec family (e.g.,Tec, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk)
kinase and an equivalent sample comprising a Tec family (e.g.,Tec, Btk, Itk/Emt/Tsk, Bmx,
Txk/Rlk) kinase in the absence of said composition.
[0132] The term "Tec family tyrosine kinases-mediated condition", as used herein means
any disease or other deleterious condition in which Tec family kinases are known to play a
role. Such conditions include, without limitation, autoimmune, inflammatory, proliferative,
and hyperproliferative diseases and immunologically-mediated diseases including rejection of
transplanted organs or tissues and Acquired Immunodeficiency Syndrome (AIDS).
[0133] For example, Tec family tyrosine kinases -mediated conditions include diseases of
the respiratory tract including, without limitation, reversible obstructive airways diseases
including asthma, such as bronchial, allergic, intrinsic, extrinsic and dust asthma, particularly
chronic or inveterate asthma (e.g. late asthma airways hyper-responsiveness) and bronchitis.
Additionally, Tec family tyrosine kinases diseases include, without limitation, those
conditions characterised by inflammation of the nasal mucus membrane, including acute
rhinitis, allergic, atrophic thinitis and chronic rhinitis including rhinitis caseosa, hypertrophic
rhinitis, rhinitis purulenta, rhinitis sicca and rhinitis medicamentosa; membranous rhinitis
including croupous, fibrinous and pseudomembranous rhinitis and scrofoulous rhinitis,
seasonal rhinitis including rhinitis nervosa (hay fever) and vasomotor rhinitis, sarcoidosis,
farmer's lung and related diseases, fibroid lung and idiopathic interstitial pneumonia.
[0134] Tec family tyrosine kinases -mediated conditions also include diseases of the bone
and joints including, without limitation, (pannus formation in) rheumatoid arthritis,
seronegative spondyloarthropathis (including ankylosing spondylitis, psoriatic arthritis and
Reiter's disease), Behcet's disease, Sjogren's syndrome, and systemic sclerosis.
[0135] Tec family kinases-mediated conditions also include diseases and disorders of
the skin, including, without limitation, psoriasis, systemic sclerosis, atopical dermatitis,
contact dermatitis and other eczematous dermatitis, seborrhoetic dermatitis, Lichen planus,
Pemphigus, bullous Pemphigus, epidermolysis bullosa, urticaria, angiodermas, vasculitides,
erythemas, cutaneous eosinophilias, uveitis, Alopecia, areata and vernal conjunctivitis.
[0136] Tec family tyrosine kinases-mediated conditions also include diseases and
disorders of the gastrointestinal tract, including, without limitation, Coeliac disease, proctitis,
eosinophilic gastro-enteritis, mastocytosis, pancreatitis, Crohn's disease, ulcerative colitis,

food-related allergies which have effects remote from the gut, e.g. migraine, rhinitis and
eczema.
[0137] Tec family tyrosine kinases-mediated conditions also include those diseases and
disorders of other tissues and systemic disease, including, without limiation, multiple
sclerosis, artherosclerosis, acquired immunodeficiency syndrome (AIDS), lupus
erythematosus, systemic lupus, erythematosus, Hashimoto's thyroiditis, myasthenia gravis,
type I diabetes, nephrotic syndrome, eosinophilia fascitis, hyper IgE syndrome, lepromatous
leprosy, sezary syndrome and idiopathic thrombocytopenia purpura, restenosis following
angioplasty, tumours (for example leukemia, lymphomas), artherosclerosis, and systemic
lupus erythematosus.
[0138] Tec family tyrosine kinases-mediated conditions also include allograft rejection
including, without limitation, acute and chronic allograft rejection following for example
transplantation of kidney, heart, liver, lung, bone marrow, skin and cornea; and chronic graft
versus host disease.
[0139] It will also be appreciated that the compounds and pharmaceutically acceptable
compositions of the present invention can be employed in combination therapies, that is, the
compounds and pharmaceutically acceptable compositions can be administered concurrently
with, prior to, or subsequent to, one or more other desired therapeutics or medical procedures.
The particular combination of therapies (therapeutics or procedures) to employ in a
combination regimen will take into account compatibility of the desired therapeutics and/or
procedures and the desired therapeutic effect to be achieved. It will also be appreciated that
the therapies employed may achieve a desired effect for the same disorder (for example, an
inventive compound may be administered concurrently with another agent used to treat the
same disorder), or they may achieve different effects (e.g., control of any adverse effects). As
used herein, additional therapeutic agents that are normally administered to treat or prevent a
particular disease, or condition, are known as "appropriate for the disease, or condition, being
treated".
[0140] For example, chemotherapeutic agents or other anti-proliferative agents may be
combined with the compounds of this invention to treat proliferative diseases and cancer.
Examples of known chemotherapeutic agents include, but are not limited to, For example,
other therapies or anticancer agents that may be used in combination with the inventive
anticancer agents of the present invention include surgery, radiotherapy (in but a few
examples, gamma.-radiation, neutron beam radiotherapy, electron beam radiotherapy, proton

therapy, brachytherapy, and systemic radioactive isotopes, to name a few), endocrine therapy,
biologic response modifiers (interferons, interleukins, and tumor necrosis factor (TNF) to
name a few), hyperthermia and cryotherapy, agents to attenuate any adverse effects (e.g.,
antiemetics), and other approved chemotherapeutic drugs, including, but not limited to,
alkylating drugs (mechlorethamine, chlorambucil, Cyclophosphamide, Melphalan,
Ifosfamide), antimetabolites (Methotrexate), purine antagonists and pyrimidine antagonists
(6-Mercaptopurine, 5-Fluorouracil, Cytarabile, Gemcitabine), spindle poisons (Vinblastine,
Vincristine, Vinorelbine, Paclitaxel), podophyllotoxins (Etoposide, Mnotecan, Topotecan),
antibiotics (Doxorubicin, Bleomycin, Mitomycin), nitrosoureas (Carmustine, Lomustine),
inorganic ions (Cisplatin, Carboplatin), enzymes (Asparaginase), and hormones (Tamoxifen,
Leuprolide, Flutamide, and Megestrol), Gleevec™, adriamycin, dexamethasone, and
cyclophosphamide. For a more comprehensive discussion of updated cancer therapies see,
http://www.nci.nih.gov/, a list of the FDA approved oncology drugs at
http://www.fda.gov/cder/cancer/druglistframe.htm, and The Merck Manual, Seventeenth Ed.
1999, the entire contents of which are hereby incorporated by reference.
[0141] Other examples of agents the inhibitors of this invention may also be combined
with include, without limitation: treatments for Alzheimer's Disease such as Aricept® and
Excelon®; treatments for Parkinson's Disease such as L-DOPA/carbidopa, entacapone,
ropinrole, pramipexole, bromocriptine, pergolide, trihexephendyl, and amantadine; agents for
treating Multiple Sclerosis (MS) such as beta interferon (e.g., Avonex® and Rebif8),
Copaxone®, and mitoxantrone; treatments for asthma such as albuterol and Singulair®; agents
for treating schizophrenia such as zyprexa, risperdal, seroquel, and haloperidol; anti-
inflammatory agents such as corticosteroids, TNF blockers, IL-1 RA, azathioprine,
cyclophosphamide, and sulfasalazine; immunomodulatory and immunosuppressive agents
such as cyclosporin, tacrolimus, rapamycin, mycophenolate mofetil, interferons,
corticosteroids, cyclophosphamide, azathioprine, and sulfasalazine; neurotrophic factors such
as acetylcholinesterase inhibitors, MAO inhibitors, interferons, anti-convulsants, ion channel
blockers, riluzole, and anti-Parkinsonian agents; agents for treating cardiovascular disease
such as beta-blockers, ACE inhibitors, diuretics, nitrates, calcium channel blockers, and
statins; agents for treating liver disease such as corticosteroids, cholestyramine, interferons,
and anti-viral agents; agents for treating blood disorders such as corticosteroids, anti-
leukemic agents, and growth factors; and agents for treating immunodeficiency disorders
such as gamma globulin.

[0142] The amount of additional therapeutic agent present in the compositions of this
invention will be no more than the amount that would normally be administered in a
composition comprising that therapeutic agent as the only active agent. Preferably the
amount of additional therapeutic agent in the presently disclosed compositions will range
from about 50% to 100% of the amount normally present in a composition comprising that
agent as the only therapeutically active agent.
[0143] The compounds of this invention or pharmaceutically acceptable compositions
thereof may also be incorporated into compositions for coating implantable medical devices,
such as prostheses, artificial valves, vascular grafts, stents and catheters. Accordingly, the
present invention, in another aspect, includes a composition for coating an implantable device
comprising a compound of the present invention as described generally above, and in classes
and subclasses herein, and a carrier suitable for coating said implantable device. In still
another aspect, the present invention includes an implantable device coated with a
composition comprising a compound of the present invention as described generally above,
and in classes and subclasses herein, and a carrier suitable for coating said implantable
device.
[0144] Vascular stents, for example, have been used to overcome restenosis (re-
narrowing of the vessel wall after injury). However, patients using stents or other
implantable devices risk clot formation or platelet activation. These unwanted effects may be
prevented or mitigated by pre-coating the device with a pharmaceutically acceptable
composition comprising a kinase inhibitor. Suitable coatings and the general preparation of
coated implantable devices are described in US Patents 6,099,562; 5,886,026; and 5,304,121.
The coatings are typically biocompatible polymeric materials such as a hydrogel polymer,
polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl
acetate, and mixtures thereof. The coatings may optionally be further covered by a suitable
topcoat of fluorosilicone, polysaccarides, polyethylene glycol, phospholipids or combinations
thereof to impart controlled release characteristics in the composition.
[0145] Another aspect of the invention relates to inhibiting Tec family (e.g.,Tec, Btk,
Itk/Emt/Tsk, Bmx, Txk/Rlk) activity in a biological sample or a patient, which method
comprises administering to the patient, or contacting said biological sample with a compound
of formula I or a composition comprising said compound. The term "biological sample", as
used herein, includes, without limitation, cell cultures or extracts thereof; biopsied material

obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears, or
other body fluids or extracts thereof.
[0146] Inhibition of Tec family (e.g.,Tec, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk) kinase
activity in a biological sample is useful for a variety of purposes that are known to one of
skill in the art. Examples of such purposes include, but are not limited to, blood transfusion,
organ-transplantation, biological specimen storage, and biological assays.
SYNTHETIC EXAMPLES
[0147] As used herein, The term "Rt(min)" refers to the HPLC retention time, in minutes,
associated with the compound. Unless otherwise indicated, the HPLC method utilized to
obtain the reported retention time is as follows:
Column: Ace 5 C8,15cm x 4.6mm id
Gradient: 0-100% acetonitrile+methanol (50:50) (20mM Tris phosphate at pH 7.0)
Flow rate: 1.5 ml/min
Detection: 225 nm
[0148] Example 1
[0149] (2-ChIoro-quinazolin-4-yI)-(5-cyclopentyl-2i/-pyrazol-3-yl)-amine
[0150] 2,4-Dichloroquinazoline (0.657g, 3.3mmol) in ethanol (9 ml) was treated with 3-
amino-5-cyclopentyl pyrazole (0.5g, 3.3 mmol) and triethylamine (0.46ml, 3.3 mmol) and
stirred overnight at room temperature. The mixture was filtered and the solid washed with
ethanol to give (2-chloro-quinazolm-4-yl)-(5-cyclopentyl-2i7-pyrazol-3-yl)-amine as
colourless crystals (684mg, 66%).
[0151] MS (ES*) 313
[0152] 8H (d6 DMSO) 1.55-1.80 (6H, m), 2.03-2.13 (2H, m), 3.06-3.13 (1H, m), 6.60
(1H, s), 7,60 (1H, t), 7.70 (1H. d), 7.87 (1H, t), 8.64 (1H, d), 10.77 (1H, s), 12.37 (1H, s).

[0153] Example 2
[0154] 5-(5-Cyclopentyl-2^-pyrazol-3-yIamino)-quinazollno[3,2-a]quinazolin-12-one
[0155] (2-CUoro-quinazolin-4-yl)-(5-cyclopentyl-2/T-pyrazol-3-yl)-amine (O.lg, 0.319
mmol) and methyl anthranilate (0.124 ml, 0.957 mmol) was stirred at 130° C for 3 hours.
The reaction mixture was suspended in methanol and added to a mixture of ethyl acetate and
dilute aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate and the
extracts dried over magnesium sulphate and concentrated. The residue was purified by flash
chromatography on silica gel eluting with 50% ethyl acetate/petrol to give a yellow glass
(95mg). This was dissolved in methanol and treated with 4M HCl/dioxane to give 5-(5-
Cyclopentyl-2/T-pyrazol-3-ylammo)-qumazolmo[3,2-a]quinazolin-12-one hydrochloride as
very pale yellow crystals (85 mg, 62%).
[0156] MS (ES+) 396
[0157] 5H (d6 DMSO) 1.62-1.83 (6H, m), 2.03-2.15 (2H, m), 3.10-3.20 (1H, m), 7.06
(lH,s), 7.59 (lH,t), 7.77-7.85 (2H, m), 7.93-8.05 (2H, m), 8.30 (1H, d), 8.86 (1H, d), 12.23
(lH,brs), 14.15 (lH,brs).
[0158] A variety of other compounds of Formula I have been prepared by methods
substantially similar to those described in Example 2. The characterization data for these
compounds is summarized in Table 2 below and includes HPLC, LC/MS (observed) and ]H
NMR data.
[0159] 'H NMR data is summarized in Table 2 below wherein !H NMR data was
obtained at 400 MHz in deuterated DMSO, unless otherwise indicated, and was found to be
consistent with structure.



[0161] Example 3
[0162] 5-Hydroxy-quinazolino[3,2-a]quinazoIiii-12-one
[0163] To the 2-chloro-4-ethoxy-quinazoline (500mg, 2.40mmol) in a boiling tube was
added methyl anthranilate (372pL, 2.88mmol). The mixture was heated with a hot air gun
(approx. 400 deg C) for 15 minutes before cooling to room temperature. The resulting crude
product was suspended in ethyl acetate (lOmL) and heated to boiling. The mixture was then
cooled and the pure off-white product isolated by filtration (257mg).
[0164] MS (ES*) 263
[0165] 6H (d6 DMSO) 7.39(1H, t), 7.47(1H, d), 7.59(1H, t), 7.78(1H, m), 7.81(1H, m),
8.18(2H, d), 9.17(1H, d) and 12.33(1H, br s).
[0166] Example 4
[0167] S-(5-Propyl-LEr-pyrazol-3-ylammo)-quinazolino[3,2-a]quinazolin-12-one
[0168] The 5-hydroxy-quinazolino[3,2-a]quinazolin-12-one (72mg, 0.27mmol) was
suspended in thionyl chloride (3mL) and the mixture refluxed for 2 hours. The desired
chloride intermediate was isolated by evaporation in vacuo.
[0169] The above was suspended in 1:1 THF/ !PrOH (3mL) and treated with 5-propyl-
l/f-pyrazol-3-ylamine (68mg, 0.54mmol) and triethylamine (113uL, 0.81mmol). The mixture
was stirred under a nitrogen atmosphere at 50 deg C for 4 hours before concentrating in
vacuo.
[0170] The above crude product was dissolved in DMSO/methanol and purified by
preparative chromatography to yield the product as a TFA salt (46mg).
[0171] MS (ES+) 371

[0172] 8H (d6 DMSO) 0.95(3H, t), 1.72(2H, q), 2.69(2H, m), 6.93(1H, s), 7.58(1H, m),
7.66(1H, d), 7.80(1H, m), 7.97(1H, m), 8.05(1H, m), 8.29(1H, d), 8.80(1H, d), 9.21(1H, d),
12.12(1H, br s), 12.75(1H, br m) and 13.60(1H, br m).
[0173] A variety of other compounds of Formula I have been prepared by methods
substantially similar to those described in Example 4. The characterization data for these
compounds is summarized in Table 3 below and includes HPLC, LC/MS (observed) and 'H
NMRdata.
[0174] !H NMR data is summarized in Table 3 below wherein !H NMR data was
obtained at 400 MHz in deuterated DMSO, unless otherwise indicated, and was found to be
consistent with structure.


[0176] Example 5
[0177] 5-(Thiazol-2-ylaniino)-quinazolmo[3^-a]qumazolin-12-one
[0178] A pressure tube was charged with 5-cMoro-qumazolmo[3,2-a]qumazolin-12-one
(200mg, O.71mmol), Pd2(dba)3 (25mg, 0.028mmol), Xantphos (25mg, 0.043mmol), 2-
aminothiazole (71mg, 0.85mmol), Na2C03 (fine powder, 71mg, 0.85mmol) and anhydrous
dioxane/toluene (1:1, 5mL). The mixture was stirred with heating at 100 deg C for 17 hours.
After this period the mixture was cooled, concentrated in vacuo and purified by preparative
chromatography, to yield the desired product (TFA salt) as a yellow powder (130mg).
[0179] MS (ES*) 346, (ES-) 344
[0180] 8H (d6 DMSO) 7.51(1H, t), 7.68(1H, m), 7.71(2H, m), 7.85(1H, m), 7.95(2H, m),
8.24(1H, d), 8.58(1H, d), 9.28(1H, d) and 13.40-14.00 (1H, br s)
[0181] A variety of other compounds of Formula I have been prepared by methods
substantially similar to those described in Example 5. The characterization data for these
compounds is summarized in Table 4 below and includes HPLC, LC/MS (observed) and 'H
NMRdata.
[0182] !H NMR data is summarized in Table 4 below wherein !H NMR. data was
obtained at 400 MHz in deuterated DMSO, unless otherwise indicated, and was found to be
consistent with structure.


[0184] Example 6
[0185] (2-Chloro-l^^,6,7,8-hexahydro-quinazolin-4-yl>-(5-cyclopropyl-2fl^pyrazol-
3-yl>amine
[0186] 2,4-I^cMoro-l,2,5,6>7,8-hexahydro-qrinazoline (lg, 4.93 mmol) and 3-amino-5-
cyclopropylpyrazole (0.606g, 4.93 mmol) in ethanol (8 ml) was treated with triethylamine
(1.24 ml, 8.87 mmol) and the mixture heated at 120°C for 3 days, cooled and filtered to give
(2^Uoro-l^,5,6,7,8-hexahydro-qumazolm^yl)-(5K;yclopropyl-2if-pyrazol-3-yl)-amme
(0.72 g, 51%) as a colourless solid.
[0187] MS (ES4) 286
[0188] 5H (d6 DMSO) 0.60-0.65 (2H, m), 0.80-0.90 (2H, m), 1.62-1.70 (4H, m), 1.80-
1.87 (1H, m), 2.30-2.32 (2H, m), 2.52-2.56 (2H, m), 6.15 (1H, s), 8.99 (1H, s).
[0189] Example 7

[0190] 5-(5-Cyclopropyl-2ir-pyrazol-3-ylanTmo)-l,2,3,4-tetrahydro-qiiinazoliiio[3,2-
a] quinazolin-12-one
[0191] (2-Chloro-1,2,5,6,7,8-hexahydro-quinazolin-4-yl)-(5-cyclopropyl-2iy-pyrazol-3-
yl)-amine (150 mg, 0.518mmol), in methyl anthranilate (0.1ml, 0.777mmol) was heated to
135°C for 4 hours to give a brown gum. This was dissolved in methanol/dichloromethane
and added to a mixture of ethyl acetate and aqueous sodium bicarbonate. The mixture was •
extracted with ethyl acetate and the extracts dried over magnesium sulphate and concentrated.
Purification by flash chromatography on silica gel eluting with 4%

methanol/dichloromethane gave a pale yellow gum. This was dissolved in 0.5M HC1 in
methanol and crystallised by the dropwise addition of diethyl ether to give cream coloured
crystals of 5-(5-cycloi>ropyl-2fl'-pyrazoW-ylammo)-l,23,4-tetrahydro^uma2olino[3,2-
a]quinazolin-12-one hydrochloride (15 mg, 7%).
[0192] MS (ES4) 372
[0193] 8li (d6 DMSO) 0.78-0.89 (2H, m), 0.96-1.03 (2H, m), 1.64-1.74 (2H, m), 1.78-
1.85 (2H, m), 1.94-2.02 (1H, m), 2.65-2.74 (2H, m), 3.19-3.28 (2H, m), 6.71 (1H, s), 7.51
(1H, t), 7.72 (1H, d), 7.94 (1H, t), 8.14 (1H, d), 10.73 (1H, s), 11.58 (1H, br s).
[0194] A variety of other compounds of Formula I have been prepared by methods
substantially similar to those described in Example 7. The characterization data for these
compounds is summarized in Table 5 below and includes HPLC, LC/MS (observed) and 'H
NMRdata.
[0195] !H NMR data is summarized in Table 5 below wherein JH NMR data was
obtained at 400 MHz in deuterated DMSO, unless otherwise indicated, and was found to be
consistent with structure.

[0197] Example 8: UK Inhibition Assay (radioactive):
[0059] Compounds were screened for their ability to inhibit Itk using a radioactive-
phosphate incorporation assay. Assays were carried out in a mixture of 100 mM HEPES (pH
7.5), lOmM MgCl2,25mM NaCl, 0.01% BSA and ImM DTT. Final substrate concentrations
were 15 uM [y-33P]ATP (400mCi 33P ATP/ mmol ATP, Amersham Pharmacia Biotech /
Sigma Chemicals) and 2uM peptide (SAM68 protein D332-443). Assays were carried out at

25 °C. in the presence of 30 nM Itk. An assay stock buffer solution was prepared containing
all of the reagents listed above, with the exception of ATP and the test compound of interest.
50 uL of the stock solution was placed in a 96 well plate followed by addition of 1.5uL of
DMSO stock containing serial dilutions of the test compound (typically starting from a final
concentration of 15uM with 2-fold serial dilutions) in duplicate (final DMSO concentration
1.5%). The plate was pre-incubated for 10 minutes at 25°C and the reaction initiated by
addition of 50uL [y-33P]ATP (final concentration 15uM).
[0060] The reaction was stopped after 10 minutes by the addition of 50uL of a TCA /
ATP mixture (20% TCA, 0.4mM ATP). A Unifilter GF/C 96 well plate (Perkin Elmer Life
Sciences, Cat no. 6005174) was pretreated with 50uL Milli Q water prior to the addition of
the entire reaction mixture (150 uL). The plate was washed with 200uL Milli Q water
followed by 200mL of a TCA / ATP mixture (5% TCA, ImM ATP). This wash cycle was
repeated a further 2 times. After drying, 30uL Optiphase 'SuperMix' liquid scintillation
cocktail (Perkin Elmer) was added to the well prior to scintillation counting (1450 Microbeta
Liquid Scintillation Counter, Wallac).
[0061J IC50 data were calculated from non-linear regression analysis of the initial rate
data using the Prism software package (GraphPad Prism version 3.0cx for Macintosh,
GraphPad Software, San Diego California, USA).
[0062] Assays were carried out in a mixture of 20 mM MOPS (pH 7.0), lOmM MgCl2,
0.1% BSA and ImM DTT. Final substrate concentrations in the assay were 7.5 uM [y-
33PJATP (400mCi 33P ATP/ mmol ATP, Amersham Pharmacia Biotech/ Sigma Chemicals)
and 3uM peptide (SAM68 protein D332-443). Assays were carried out at 25 oC. in the
presence of 50 nM Itk. An assay stock buffer solution was prepared containing all of the
reagents listed above, with the exception of ATP and the test compound of interest. 50 uL of
the stock solution was placed in a 96 well plate followed by addition of 2uL of DMSO stock
containing serial dilutions of the test compound (typically starting from a final concentration
of 50uM with 2-fold serial dilutions) in duplicate (final DMSO concentration 2%). The plate
was pre-incubated for 10 minutes at 25°C and the reaction initiated by addition of 50uL [y-
33P]ATP (final concentration 7.5uM).
[0063] The reaction was stopped after 10 minutes by the addition of lOOmL 0.2M
phosphoric acid + 0.01% TWEEN 20. A multiscreen phosphocellulose filter 96-well plate
(Millipore, Cat no. MAPHN0B50) was pretreated with lOOuL 0.2M phosphoric acid +
0.01% TWEEN 20 prior to the addition of 170mL of the stopped assay mixture. The plate

was washed with 4 x 200jiL 0.2M phosphoric acid + 0.01% TWEEN 20. After drying, 30uL
Optiphase 'SuperMix' liquid scintillation cocktail (Perkin Elmer) was added to the well prior
to scintillation counting (1450 Microbeta Liquid Scintillation Counter, Wallac).
[0064] Ki(app) data were calculated from non-linear regression analysis of the initial rate
data using the Prism software package (GraphPad Prism version 3.0cx for Macintosh,
GraphPad Software, San Diego California, USA).
[0198] Example 9: ITK Inhibition Assay (AlphaScreen.™):
[0199] Compounds were screened for their ability to inhibit Itk using an AlphaScreen™
phosphotyrosine assay at Vertex Pharmaceuticals. Assays were carried out in a mixture of 20
mM MOPS (pH 7.0), lOmM MgCl2, 0.1% BSA and ImM DTT. Final substrate
concentrations in the assay were lOOuM ATP (Sigma Chemicals) and 2\iM peptide
(Biotinylated SAM68 A332-443). Assays were carried out at 25°C and in the presence of Itk
(30nM). An assay stock buffer solution was prepared containing all of the reagents listed
above, with the exception of ATP and the test compound of interest. 25 u-L of the stock
solution was placed in each well of a 96 well plate followed by luL of DMSO containing
serial dilutions of the test compound (typically starting from a final concentration of 15|*M)
in duplicate (final DMSO concentration 2%). The plate was preincubated for 10 minutes at
25°C and the reaction initiated by addition of 25uL ATP (final concentration lOOuM).
Background counts were determined by the addition of 5uL 500mM EDTA to control wells
containing assay stock buffer and DMSO prior to initiation with ATP.
[0200] The reaction was stopped after 30 minutes by diluting the reaction 225-fold into
MOPS buffer (20mM MOPS (pH 7.0), ImM DTT, lOmM MgCl2, 0.1% BSA) containing
50mM EDTA to bring the final concentration of Biotin-SAM68 to 9nM.
[0201] AlphaScreen™ reagents were prepared according to the manufacturers
instructions (AlphaScreen™ phosphotyrosine (P-Tyr-100) assay kit, PerkinElmer catalogue
number 6760620C). Under subdued lighting, 20uL of AlphaScreen™ reagents were placed
in each well of a white half area 96 well plate (Corning Inc. - COSTAR 3693) with 30\iL of
the stopped, diluted kinase reactions. Plates were incubated in the dark for 60 minutes prior
to reading on a Fusion Alpha plate reader (PerkinElmer).
[0202] After removing mean background values for all of the data points, Ki(app) data
were calculated from non-linear regression analysis using the Prism software package

(GraphPad Prism version 3.0cx for Macintosh, GraphPad Software, San Diego California,
USA).
[0203] In general, compounds of the invention, including compounds in Table 1, are
effective for the inhibition of Itk. Preferred compounds show Ki below 1 uM in the
AlphaScreen™ assay (1-1, 1-2,1-3, 1-7, 1-9, 1-10, 1-11, M3, 1-14, 1-15, 1-16, 1-17, 1-20,
1-21).
[0204] Example 10: BTK Inhibition Assay (radioactive'):
[0205] Compounds were screened for their ability to inhibit Btk using a radioactive-
phosphate incorporation assay at Vertex Pharmaceuticals. Assays were carried out in a
mixture of 20 mM MOPS (pH 7.0), lOmM MgCl2, 0.1% BSA and ImM DTT. Final
substrate concentrations in the assay were 50^M [y-33P]ATP (200mCi 33P ATP/ mmol
ATP, Amersham Pharmacia Biotech, Amersham, UK / Sigma Chemicals) and 2uM peptide
(SAM68 D332-443). Assays were carried out at 25°C and in the presence of 25 nM Btk. An
assay stock buffer solution was prepared containing all of the reagents listed above, with the
exception of the peptide and the test compound of interest. 75 JJ.L of the stock solution was
placed in a 96 well plate followed by addition of 2uL of DMSO stock containing serial
dilutions of the test compound (typically starting from a final concentration of 15uM) in
duplicate (final DMSO concentration 2%). The plate was preincubated for 15 minutes at
25°C and the reaction initiated by addition of 25uL peptide (final concentration 2uM).
Background counts were determined by the addition of lOOmL 0.2M phosphoric acid +
0.01% TWEEN to control wells containing assay stock buffer and DMSO prior to initiation
with peptide.
[0206] The reaction was stopped after 10 minutes by the addition of lOOmL 0.2M
phosphoric acid + 0.01% TWEEN. A multiscreen phosphocellulose filter 96-well plate
(Millipore, Cat no. MAPHN0B50) was preheated with lOOuL 0.2M phosphoric acid +
0.01% TWEEN 20 prior to the addition of 170mL of the stopped assay mixture. The plate
was washed with 4 x 200uL 0.2M phosphoric acid + 0.01% TWEEN 20. After drying, 30JJ.L
Optiphase 'SuperMix' liquid scintillation cocktail (Perkin Elmer) was added to the well prior
to scintillation counting (1450 Microbeta Liquid Scintillation Counter, Wallac).
[0207] After removing mean background values for all of the data points, Ki(app) data
were calculated from non-linear regression analysis using the Prism software package
(GraphPad Prism version 3.0cx for Macintosh, GraphPad Software, San Diego California,
USA).

[0208] Example 11: BTK Inhibition Assay (AlphaScreen™):
[0209J Compounds were screened for (heir ability to inhibit Btk using an AlphaScreen™
phosphotyrosine assay at Vertex Pharmaceuticals. Assays were carried out in a mixture of 20
mM MOPS (pH 7.0), lOmM MgCl2, 0.1% BSA and ImM DTT. Final substrate
concentrations in the assay were 50uM ATP (Sigma Chemicals) and 2uM peptide
(Biotinylated SAM68 D332-443). Assays were carried out at 25 °C and in the presence of 25
nM Btk. An assay stock buffer solution was prepared containing all of the reagents listed
above, with the exception of peptide and the test compound of interest. 37.5uL of the stock
solution was placed in each well of a 96 well plate followed by luL of DMSO containing
serial dilutions of the test compound (typically starting from a final concentration of 15uM)
in duplicate (final DMSO concentration 2%). The plate was preincubated for 15 minutes at
25°C and the reaction initiated by addition of 12.5uL peptide (final concentration 2uM).
Background counts were determined by the addition of 5uL 500mM EDTA to control wells
containing assay stock buffer and DMSO prior to initiation with Biotin-SAM68.
[0210] The reaction was stopped after 30 minutes by diluting the reaction 225-fold into
MOPS buffer (20mM MOPS (pH 7.0), ImM DTT, lOmM MgCl2, 0.1% BSA) containing
50mM EDTA to bring the final concentration of peptide to 9nM.
[0211] AlphaScreen™ reagents were prepared according to the manufacturers
instructions (AlphaScreen™ phosphotyrosine (P-Tyr-100) assay kit, PerkinElmer catalogue
number 6760620C). Under subdued lighting, 20uL of AlphaScreen™ reagents were placed
in each well of a white half area 96 well plate (Corning Inc. - COSTAR 3693) with 30uL of
the stopped, diluted kinase reactions. Plates were incubated in the dark for 60 minutes prior
to reading on a Fusion Alpha plate reader (PerkinElmer).
[0212] After removing mean background values for all of the data points, Ki(app) data
were calculated from non-linear regression analysis using the Prism software package
(GraphPad Prism version 3.0cx for Macintosh, GraphPad Software, San Diego CaUfornia,
USA).
[0213] In general, compounds of me invention, including compounds in Table 1, are
effective for the inhibition of Btk.
[0214] Example 12: RT/K Inhibition Assay (TJV>:
[0215] Compounds were screened for their ability to inhibit Rlk using a standard coupled
enzyme assay (Fox et al, Protein Sci., (1998) 7,2249). Assays were carried out in a mixture

of 20 mM MOPS (pH 7.0), lOmM MgCl2, 0.1% BSA and ImM DTT. Final substrate
concentrations in the assay were lOOuM ATP (Sigma Chemicals) and lOuM peptide (Poly
Glu:Tyr 4:1). Assays were carried out at 30 °C and in the presence of 40nM Rlk. Final
concentrations of the components of the coupled enzyme system were 2.5 mM
phosphoenolpyruvate, 300 uM NADH, 30 ug/ml pyruvate kinase and 10 ug/ml lactate
dehydrogenase.
[0216] An assay stock buffer solution was prepared containing all of the reagents listed
above, with the exception of ATP and the test compound of interest. 60 fj.1 of the stock
solution was placed in a 96 well plate followed by addition of 2 ul of DMSO stock
containing serial dilutions of the test compound (typically starting from a final concentration
of 7.5uM). The plate was preincubated for 10 minutes at 30°C and the reaction initiated by
addition of 5 \il of ATP. Initial reaction rates were determined with a Molecular Devices
SpectraMax Plus plate reader over a 10 minute time course. IC50 and Ki data were
calculated from non-linear regression analysis using the Prism software package (GraphPad
Prism version 3.0cx for Macintosh, GraphPad Software, San Diego California, USA).
[0217] In general, compounds of the invention, including compounds in Table 1, are
effective for the inhibition of RLK.

WE CLAIM :
1. A compound of formula (I):
or a pharmaceutically acceptable salt thereof,
wherein R1 is -QRX; wherein Q is a bond or is a CrC6 alkylidene chain wherein up to two
methylene units of Q are optionally and independently replaced by -CO-, -CS-, -COCO-,
-CONR-, -CONRNR-, -C02-, -OCO-, -NRC02-, -0-, -NRCONR-, -OCONR-, -NRNR,
-NRNRCO-, -NRCO-, -S-, -SO, -S02-, -NR-, -S02NR-, -NRS02-, -NRS02NR-, and RX is R',
halogen, N02, or CN; R1 is bonded to the nitrogen atom through a carbon atom of R'except
when R1 is hydrogen;
each occurrence of R is independently selected from hydrogen or an optionally
substituted G-8 aliphatic group wherein if said aliphatic group contains one or more units of
unsaturation, said aliphatic group is a C2.C8 aliphatic chain, and wherein if said aliphatic
group is a cycloaliphatic group, said cycloaliphatic group is a C3-C8 cycloaliphatic group; and
R' is selected from hydrogen or an optionally substituted group selected from G-g
aliphatic, C6-C10 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having
3-10 ring atoms, or wherein R and R' taken together with the atom(s) to which they are
bound, or two occurrences of R taken together with the atom(s) to which they are bound, form
an optionally substituted group selected from a 3-10 membered cycloalkyl ring, a C6-Cioaryl
ring, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 3-10 ring atoms;
Cy1 is a 5-7-membered monocyclic aryl ring or an 8-10-membered bicyclic aryl ring
having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or is a 3-8-
membered saturated or partially unsaturated monocyclic ring having 0-3 heteroatoms
independently selected from nitrogen, oxygen, or sulfur, wherein Cy1 is optionally substituted
with y occurrences of-YRY, wherein y is 0-5, Y is a bond or is a CrC6 alkylidene chain

wherein up to two methylene units of Y are optionally and independently replaced by -CO-,
-CS-, -COCO-, -CONR-, -CONRNR-, -C02-, -OCO-, -NRC02-, -0-, -NRCONR-, -OCONR-,
-NRNR, -NRNRCO-, -NRCO-, -S-, -SO, -S02-, -NR-, -SO2NR-, -NRS02-, -NRS02NR-, and
each occurrence of RY is independently R', halogen, N02, or CN;
R2 and R3, taken together, form an optionally substituted 5-, 6-, or 7-membered
monocyclic aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen,
or sulfur or a 5-, 6-, or 7-membered saturated or partially unsaturated monocyclic ring having
0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein the ring
formed by R2 and R3 taken together is optionally substituted at one or more carbon or nitrogen
atoms with m independent occurrences of -WRW,
R4 and R5, taken together, form an optionally substituted 5-, 6-, or 7-membered
monocyclic aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen,
or sulfur or a 5-, 6-, or 7-membered saturated or partially unsaturated monocyclic ring having
0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein the ring
formed by R4 and R5, taken together is optionally substituted at one or more carbon or
nitrogen atoms with n independent occurrences of Z-Rz; m and n are each independently 0-5;
W and Z are each independently a bond or is an optionally substituted C1-C6
alkylidene chain wherein up to two methylene units of W or Z are optionally replaced by
-CO-, -CS-, -COCO-, -CONR-, -CONRNR-, -C02-, -OCO-, -NRC02-, -0-, -NRCONR-,
-OCONR-, -NRNR, -NRNRCO-, -NRCO-, -S-, -SO, -S02-, -NR-, -S02NR-, -NRS02-,
-NRSO2NR-, and each occurrence of Rw and Rz is independently R', halogen, N02, or CN;
X is O, S, or [C(R')2]q, where q is 1 or 2; and
G is N or CR6, wherein R6 is halogen, CN, N02, or QRX,
wherein the heteroatoms of a heterocyclyl or heteroaryl ring are selected from oxygen,
sulfur, or nitrogen;
optional substituents on the unsaturated carbon atom of an aryl or heteroaryl group are
selected from halogen; -R°; -OR0; -SR°; 1,2-methylenedioxy; 1,2-ethylenedioxy; phenyl (Ph)
optionally substituted with R°; -O(Ph) optionally substituted with R°; -(CH2)i.2(Ph), optionally
substituted with R°; -CH=CH(Ph), optionally substituted with R°; -N02; -CN; -N(R°)2;
-NR°C(0)R°; -NR°C(S)R°; -NR°C(0)N(R°)2; -NR°C(S)N(R°)2; -NR°C02R°;
-NR°NR°C(0)R°; -NR°NR°C(0)N(R°)2; -NR°NR°CO2R0; -C(0)C(0)R°; -C(0)CH2C(0)R°;

-C02R°; -C(0)R°; -C(S)R°; -C(0)N(R°)2; -C(S)N(R°)2; -0C(0)N(R°)2; -OC(0)R°;
-C(0)N(OR°)R°; -C(NOR°)R°; -S(0)2R°; -S(0)3R°; -S02N(R°)2; -S(0)R°; -NR°S02N(R°)2;
-NR°S02R°; -N(OR°)R°; -C(=NH)-N(R°)2; or -(CH2)0-2NHC(O)R° wherein each independent
occurrence of R° is selected from hydrogen, optionally substituted C|.6 aliphatic, an
unsubstituted 5-6 membered heteroaryl or heterocyclic ring, phenyl, -O(Ph), or -CH2(Ph), or,
notwithstanding the definition above, two independent occurrences of R°, on the same
substituent or different substituents, taken together with the atom(s) to which each R° group is
bound, form a 5-8-membered heterocyclyl, aryl, or heteroaryl ring or a 3-8-membered
cycloalkyl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or
sulfur; Optional substituents on the aliphatic group of R° are selected from NH2, NH(Ci.
4aliphatic), N(Ci.4aliphatic)2, halogen, CMaliphatic, OH, 0(Ci-4aliphatic), N02, CN, C02H,
C02(Ci.4aliphatic), 0(haloC,.4 aliphatic), or haloCi.4aliphatic, wherein each of the foregoing
Ci.4aliphatic groups of R° is unsubstituted;
optional substituents on the saturated carbon of an aliphatic or heteroaliphatic group,
or of a non-aromatic heterocyclic ring are selected from those listed above for the unsaturated
carbon of an aryl or heteroaryl group and additionally include the following: =0, =S,
=NNHR\ =NN(R*)2, =NNHC(0)R\ =NNHC02(alkyl), =NNHS02(alkyI), or =NR\ where
each R* is independently selected from hydrogen or an optionally substituted C|.6 aliphatic;
optional substituents on the aliphatic group of R* are selected from NH2, NH(Ci_4
aliphatic), N(CM aliphatic)2, halogen, CM aliphatic, OH, 0(C,.4 aliphatic), N02, CN, C02H,
C02(Ci-4 aliphatic), 0(halo C,_4 aliphatic), orhalo(Ci_4 aliphatic), wherein each of the
foregoing Ci_4aliphatic groups of R* is unsubstituted; and
optional substituents on the nitrogen of a non-aromatic heterocyclic ring are selected
from -R', -N(R12, -C(0)R\ -C02R+, -C(0)C(0)R\ -C(0)CH2C(0)R+, -S02R+, -S02N(R+)2,
-C(=S)N(R+)2, -C(=NH)-N(R% or -NR+S02R+; wherein R^ is hydrogen, an optionally
substituted Ci_6 aliphatic, optionally substituted phenyl, optionally substituted -O(Ph),
optionally substituted -CH2(Ph), optionally substituted -(CH2)i.2(Ph); optionally substituted
-CH=CH(Ph); or an unsubstituted 5-6 membered heteroaryl or heterocyclic ring having one to
four heteroatoms independently selected from oxygen, nitrogen, or sulfur, or, notwithstanding
the definition above, two independent occurrences of R , on the same substituent or different
substituents, taken together with the atom(s) to which each R+ group is bound, form a 5-8-

membered heterocyclyl, aryl, or heteroaryl ring or a 3-8-membered cycloalkyl ring having 0-3
heteroatoms independently selected from nitrogen, oxygen, or sulfur;
optional substituents on the aliphatic group or the phenyl ring of R+ are selected from
NH2, NH(C|_4 aliphatic), N(CM aliphatic)2, halogen, CM aliphatic, OH, 0(CM aliphatic), N02,
CN, C02H, C02(Ci-4 aliphatic), 0(halo CM aliphatic), or halo(Ci_4 aliphatic), wherein each of
the foregoing CMaliphatic groups of R+ is unsubstituted;
provided that:
when X is O; R1 is hydrogen; R2 and R3, taken together are unsubstituted phenyl; R4
and R5, taken together are unsubstituted phenyl; and G is N; then Cy1 is not unsubstituted
phenyl.
2. The compound as claimed in claim 1, wherein R1 is hydrogen, -COR', CONRR', or is
an optionally substituted G-Cs alkyl group.
3. The compound as claimed in claim 1, wherein R1 is hydrogen.
4. The compound as claimed in any one of claims 1-3, wherein Cy1 is a group selected
from:


5. The compound as claimed in claim 3, wherein Cy1 is phenyl (i), pyridyl (iii),
pyrimidinyl (iv), imidazolyl (vi), pyrazolyl (vii), triazolyl (x), thiazolyl (xiv), or indazolyl
(xix) or (xxi).
6. The compound as claimed in claim 5, wherein Cy1 is pyrazolyl (vii).
7. The compound as claimed in claim 6, wherein each occurrence of -YRY, when present,
is independently halogen, R\ CN, N02, -N(R')2, -CH2N(R')2) -(CH2)2N(R')2, -(CH2)3N(R')2,
-OR', -CH2OR', -(CH2)2OR\ -(CH2)3OR'; -SR', -CH2SR', -(CH2)2SR', -(CH2)3SR\ -COOR',
-NRCOR', NRCOOR', -CON(R')2, or -S(0)2N(R')2.
8. The compound as claimed in claim 6, wherein -YRY groups are each independently F,
CI, Br, I, -CN, -COOMe, -COOH, -OH, NH2, SH, -S02NH2, -CON(CH3)2, -0(CrC6alkyl),
-CH20(Ci-C6alkyl), -(CH2)20(Ci-C6alkyl), (CH2)30(CrC6alkyl), -S(CrC6alkyl), -CH2S(C,-
C6alkyl), -(CH^SCC-Csalkyl), -(CH2)3S(C,-C6alkyl), -N(C,-C6alkyl)2, -CH2N(C,-C6alkyl)2,

C6alkyl), -(CH2)2S(Ci-C6alkyl), -(CH2)3S(Ci-C6alkyl), -NCQ-Cgalkyl^, -CH^d-Cealkyl)^
-(CH2)2N(Ci-C6alkyl)2, -(CH2)3N(Ci-C6alkyl)2, wherein each Ci-C6alkyl group is optionally
substituted with R', -OR', -N(R')2, -SR\ -S02N(R')2, -NRS02R\ -CON(R')2, or -NRCOR',
or -YRY groups are each independently an optionally substituted group selected from
Ci.Cealkyl, C3-C8cycloalkyl, phenyl, phenyloxy, benzyl, benzyloxy, pyridyl, pyrimidinyl,
thienyl, N-morpholinyl, N-piperidinyl, N-piperazinyl, or furanyl.
9. The compound as claimed in claim 4, wherein R2 and R3, taken together with the atoms
to which they are bound, form an unsubstituted 5-, 6-, or 7-membered monocyclic aryl ring
having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur or a 5-, 6-, or
7-membered saturated or partially unsaturated monocyclic ring having 0-3 heteroatoms
independently selected from nitrogen, oxygen, or sulfur.
10. The compound as claimed in claim 4, wherein R2 and R3, taken together with the carbon
atoms to which they are bound form an optionally substituted ring selected from one of the
following groups:




The compound as claimed in claim 4, wherein R2 and R\ taken together with the carbon
atoms to which they are bound form an optionally substituted 5- or 6-membered ring selected
from phenyl (a), pyridyl (b, c, d, or e), cyclohexyl (nn), or cyclopentyl (oo).
12. The compound as claimed in claim 11, wherein -WRW, when present, is independently
halogen, R', CN, N02) -N(R')2> -CH2N(R')2, -(CH2)2N(R')2, -(CH2)3N(R')2, -OR', -CH2OR',
-(CH2)20R\ -(CH2)3OR\ -SR', -CH2SR', -(CH2)2SR', -(CH2)3SR\ -COOR', -NRCOR',
NRCOOR', -CON(R')2, or -S(0)2N(R')2.
13. The compound as claimed in claim 11, wherein -WRW groups are each independently F,
CI, Br, I, -CN, -COOMe, -COOH, -OH, NH2> SH, -S02NH2, -CON(CH3)2, -0(CrC6alkyl),
-CHiOCd-C^alkyl), -(CH2)20(C,-C6alkyl), -(CH2)30(C1-C6alkyl), -S(C1-C6alkyl),
-CH2S(C,-C6alkyl), -(CH2)2S(C,-C6alkyl), -(CH2)3S(CrC6alkyl), -N(Ci-C«alkyl)2,
-CH2N(C,-C6alkyl)2, -(CH2)2N(C,-C6alkyl)2, -(CH2)3N(C,-C6alkyl)2, wherein each C,-C6alkyl
group is optionally substituted with R\ -OR', -N(R')2, -SR', -S02N(R')2, -NRS02R',
-CON(R')2, or -NRCOR', or-WRWgroups are each independently an optionally substituted
group selected from Ci-Cealkyl, C3-Cgcycloalkyl, phenyl, phenyloxy, benzyl, benzyloxy,
pyridyl, pyrimidinyl, thienyl, N-morpholinyl, N-piperidinyl, N-piperazinyl, or furanyl.
14. The compound as claimed in claim 4, wherein G is CH or C(Ci-C6alkyl).
15. The compound as claimed in claim 4, wherein G is N and compounds have the general
formula II:
or a pharmaceutical^ acceptable salt thereof.
16. The compound as claimed in claim 4, wherein X is O and compounds have the general
formula III:


or a pharmaceutically acceptable salt thereof.
17. The compound as claimed in claim 4, wherein X is O and G is N and compounds have
the general formula IV:
or a pharmaceutically acceptable salt thereof.
18. The compound as claimed in claim 4, wherein R4 and R5, taken together with the atoms
to which they are bound, form an unsubstituted 5-, 6-, or 7-membered monocyclic aryl ring
having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur or a 5-, 6-, or
7-membered saturated or partially unsaturated monocyclic ring having 0-3 heteroatoms
independently selected from nitrogen, oxygen, or sulfur.
19. The compound as claimed in claim 4, wherein R4 and R5, taken together with the carbon
atoms to which they are bound form an optionally substituted ring selected from one of the
following groups:





20. The compound as claimed in claim 19, wherein R4 and R5, taken together with the
carbon atoms to which they are bound form an optionally substituted 5- or 6-membered ring
selected from phenyl (a-i), pyridyl (b-i, c-i, d-i, or e-i), cyclohexyl (nn-i), or cyclopentyl
(oo-i).
21. The compound as claimed in claim 20, wherein each occurrence of-ZRz, when present,
is independently halogen, R', CN, N02, -N(R')2, -CH2N(R')2, -(CH2)2N(R')2, -(CH2)3N(R')2,
-OR', -CH2OR', -(CH2)2OR\ -(CH2)3OR\ -SR', -CH2SR', -(CH2)2SR', -(CH2)3SR\ -COOR',
-NRCOR', NRCOOR', -CON(R')2, or -S(0)2N(R')2.
22. The compound as claimed in claim 22, wherein -ZRZ groups are each independently F,
CI, Br, I, -CN, -COOMe, -COOH, -OH, NH2, SH, -S02NH2, -C0N(CH3)2, -0(Ci-C6alkyl),
-CHaOCd-Csalkyl), -(CH2)20(C,-C6alkyl), -(O^OCC-Csalkyl), -S(CrC6alkyl),
-CH2S(Ci-C6alkyl), -(CH2)2S(Cl-C6alkyl), -(CH^SCd-Csalkyl), -N(C,-C«alkyl)2,
-CH2N(C,-Csalkyl)2) -(CH2)2N(CrC6alkyl)2, -(CH2)3N(C,-Csalkyl)2, wherein each G-C6alkyl

group is optionally substituted with R\ -OR', -N(R')2, -SR\ -S02N(R')2, -NRS02R-CON(R')2, or -NRCOR', or -ZRZgroups are each independently an optionally substituted
group selected from Ci-Csalkyl, C3-Cscycloalkyl, phenyl, phenyloxy, benzyl, benzyloxy,
pyridyl, pyrimidinyl, thienyl, N-morpholinyl, N-piperidinyl, N-piperazinyl, or furanyl.
23. The compound as claimed in any one of claims 5-8, 9-13, or 21-22, wherein G is N, X is
O and R4 and R5, taken together form an optionally substituted phenyl group and compounds
have formula V:
or a pharmaceutical^ acceptable salt thereof.
24. The compound as claimed in claim 1, wherein G is N, X is O, and R4 and R5, taken
together form an optionally substituted phenyl group and compounds have formula V:

or a pharmaceutical^ acceptable salt thereof.
25. The compound as claimed in claim 24, wherein R2 and R\ taken together with the
carbon atoms to which they are bound form an optionally substituted phenyl, cyclopentyl,
cyclohexyl, piperidinyl, pyrazolyl, or pyridyl group and compounds have formula V-A, V-B,
V-C,V-D,V-E,orV-F:


26. The compound as claimed in claim 24 or claim 25, wherein
a) R1 is hydrogen, -COR', CONRR', or is an optionally substituted Ci-C6 alkyl
group;
b) Cy1 phenyl (i), pyridyl (iii), pyrimidinyl (iv), imidazolyl (vi), pyrazolyl (vii),
triazolyl (x), thiazolyl (xiv), or indazolyl (xix) or (xxi);
c) each occurrence of-YRY, when present, is independently halogen, R', CN,
N02, -N(R')2, -CH2N(R')2, -(CH2)2N(R')2, -(CH2)3N(R')2, -OR', -CH2OR',
-(CH2)2OR', -(CH2)3OR\ -SR', -CH2SR', -(CH2)2SR', -(CH2)3SR\ -COOR',
-NRCOR', NRCOOR', -CON(R')2, or -S(0)2N(R')2; and/or
d) m and n are each independently 0 or 1 and -WRW and -ZRZ groups, when
present, are each independently F, CI, Br, I, -CN, -COOMe, -COOH, -OH, NH2, SH,
-S02NH2, -C0N(CH3)2, -0(C,-C6alkyl), -CH20(d-Csalkyl), -(CH2)20(C,-C«alkyl),

-(CH2)30(Ci-C6alkyl), -S(C,-C6alkyl), -CH2S(C,-C6alkyl), -(CH2)2S(C,-C6alkyl)J
-(CH2)3S(Ci-C6alkyl), -N(C,-C6alkyl)2, -CH2N(C,-C6alkyl)2, -(CH2)2N(C.-C6alkyl)2,
-(CH2)3N(Ci-C6alkyl)2, wherein each Ci-Cealkyl group is optionally substituted with
R\ -OR', -N(R')2, -SR\ -S02N(R')2) -NRS02R', -CON(R')2, or -NRCOR', or -WRw
and -ZR2 groups are each independently an optionally substituted group selected from
Ci.C6alkyl, C3-Cscycloalkyl, phenyl, phenyloxy, benzyl, benzyloxy, pyridyl,
pyrimidinyl, thienyl, N-morpholinyl, N-piperidinyl, N-piperazinyl, or furanyl.
27. The compound as claimed in claim 26, wherein R1 is hydrogen.
28. The compound as claimed in claim 26, wherein Cy1 is phenyl (i) or pyrazolyl (vii).
29. The compound as claimed in claim 28, wherein Cy1 is pyrazolyl (vii).
30. The compound as claimed in claim 29, wherein -YRY groups are each independently F,
CI, Br, I, -CN, -COOMe, -COOH, -OH, NH2, SH, -S02NH2, -CON(CH3)2, -OCC-Csalkyl),
-CH20(Ci-C6alkyl), -(CH2)20(C,-C6alkyl), -(CH2)30(Ci-C6alkyl), -S(C-Csalkyl),
-CH2S(CrC6alkyl), -(CH2)2S(CrC«alkyl), -(CH2)3S(CrC6alkyl), -N(Ci-C6alkyl)2,
-CH.NCd-CealkyOz, -(CH2)2N(C,-C6alkyl)2, -(CH^NCd-Qalkyl),, wherein each Ci-C6alkyl
group is optionally substituted with R', -OR', -N(R')2, -SR', -S02N(R')2, -NRS02R',
-CON(R')2, or -NRCOR', or-YRYgroups are each independently an optionally substituted
group selected from Ci_C6alkyl, C3-C8cycloalkyl, phenyl, phenyloxy, benzyl, benzyloxy,
pyridyl, pyrimidinyl, thienyl, N-morpholinyl, N-piperidinyl, N-piperazinyl, or furanyl.
31. The compound as claimed in claim 30, wherein y is 0 or 1.
32. The compound as claimed in claim 1, selected from:





A composition comprising a compound as claimed in claim 1, or a pharmaceutically
acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.
34. The composition as claimed in claim 33, comprising an additional therapeutic agent
selected from an agent for the treatment of an autoimmune, inflammatory, proliferative,
hyperproliferative disease, or an immunologically-mediated disease including rejection of
transplanted organs or tissues and Acquired Immunodeficiency Syndrome (AIDS).


The present invention relates to compounds useful as inhibitors of protein kinases. The
invention also provides pharmaceutically acceptable compositions comprising said
compounds and methods of using the compositions in the treatment of various disease,
conditions, or disorders.

Documents:

02112-kolnp-2006-abstract.pdf

02112-kolnp-2006-claims.pdf

02112-kolnp-2006-correspondence others-1.1.pdf

02112-kolnp-2006-correspondence others.pdf

02112-kolnp-2006-description(complete).pdf

02112-kolnp-2006-form-1.pdf

02112-kolnp-2006-form-3.pdf

02112-kolnp-2006-form-5.pdf

02112-kolnp-2006-international publication.pdf

02112-kolnp-2006-international search authority report.pdf

02112-kolnp-2006-priority document-1.1.pdf

02112-kolnp-2006-priority document.pdf

2112-KOLNP-2006-(01-11-2011)-CORRESPONDENCE.pdf

2112-KOLNP-2006-(01-11-2011)-PA.pdf

2112-KOLNP-2006-ABSTRACT 1.1.pdf

2112-KOLNP-2006-AMANDED CLAIMS.pdf

2112-KOLNP-2006-ASSIGNMENT.1.2.pdf

2112-KOLNP-2006-ASSIGNMENT.pdf

2112-KOLNP-2006-CORRESPONDENCE.1.2.pdf

2112-KOLNP-2006-CORRESPONDENCE.pdf

2112-KOLNP-2006-CORRESPONDENCE1.1.pdf

2112-KOLNP-2006-DESCRIPTION (COMPLETE) 1.1.pdf

2112-KOLNP-2006-EXAMINATION REPORT REPLY RECIEVED.pdf

2112-KOLNP-2006-EXAMINATION REPORT.1.2.pdf

2112-KOLNP-2006-FORM 1 1.1.pdf

2112-KOLNP-2006-FORM 13.1.2.pdf

2112-KOLNP-2006-FORM 13.pdf

2112-KOLNP-2006-FORM 18.1.2.pdf

2112-KOLNP-2006-FORM 3-1.1.pdf

2112-KOLNP-2006-FORM 3.1.2.pdf

2112-KOLNP-2006-FORM 5.1.2.pdf

2112-KOLNP-2006-GPA.1.2.pdf

2112-KOLNP-2006-GRANTED-ABSTRACT.pdf

2112-KOLNP-2006-GRANTED-CLAIMS.pdf

2112-KOLNP-2006-GRANTED-DESCRIPTION (COMPLETE).pdf

2112-KOLNP-2006-GRANTED-FORM 1.pdf

2112-KOLNP-2006-GRANTED-FORM 2.pdf

2112-KOLNP-2006-GRANTED-SPECIFICATION.pdf

2112-KOLNP-2006-OTHERS.1.2.pdf

2112-KOLNP-2006-OTHERS.pdf

2112-KOLNP-2006-PA.pdf

2112-KOLNP-2006-PETITON UNDER RULE 137.pdf

2112-KOLNP-2006-REPLY TO EXAMINATION REPORT.1.2.pdf


Patent Number 250432
Indian Patent Application Number 2112/KOLNP/2006
PG Journal Number 01/2012
Publication Date 06-Jan-2012
Grant Date 03-Jan-2012
Date of Filing 26-Jul-2006
Name of Patentee VERTEX PHARMACEUTICALS INCORPORATED
Applicant Address 130 WAVERLY STREET, CAMBRIDGE, MA 02139
Inventors:
# Inventor's Name Inventor's Address
1 JIMENEZ JUAN-MIGUEL 39 ALEXANDER CLOSE, ABINGDON, OXFORDSHIRE OX14 1XA
2 KAY DAVID 4 CHURCH PATH, PURTON, WILTSHIRE SN5 9DR
3 KNEGTEL RONALD 92 ANDERSEY WAY, ABINGDON, OXFORDSHIRE OX14 5NW
4 PHILPS OLIVER 23 READE AVENUE, ABINGDON, OXFORDSHIRE OX14 3YE
5 PATEL SANJAY 10 KNOLLYS CLOSE, ABINGDON, OXFORDSHIRE OX14 1XN
PCT International Classification Number C07D 487/04
PCT International Application Number PCT/US2005/002725
PCT International Filing date 2005-01-26
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 60/539,176 2004-01-26 U.S.A.